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Home > 2 SYSTEM-BASED DISEASES > 22 Neurological disease
22 Neurological disease
C.M.C. ALLEN
C.J. LUECK
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The brain, spinal cord and peripheral nerves constitute an organ responsible for perception of the environment, a person's behaviour within it, and the maintenance of the body's internal milieu in readiness for this behaviour. Some 10% of the population consult their general practitioner each year with a neurological symptom in the United Kingdom, where neurological disorders account for about one-fifth of acute medical admissions and a large proportion of chronic physical disability. However, neurological symptoms are often not associated with disease and considerable clinical skill is needed to distinguish those with significant disease from those who need sympathetic reassurance.
ISSUES IN OLDER PEOPLE
NEUROLOGICAL EXAMINATION
The assessment of limb tone is often difficult in older people because of:
increased difficulty in relaxing the limbs
concomitant joint disease.
Ankle reflexes may be bilaterally absent without diagnostic significance.
Gait assessment may be more difficult because of:
concurrent musculoskeletal disease
pre-existing neurological deficits (N.B. cerebrovascular disease).
Sensory testing may be especially difficult when there is cognitive impairment.
Vibration sense in the lower extremities may be reduced in old age without diagnostic significance.
A carefully taken history of the pattern of presenting neurological symptoms should suggest a short list of diagnoses that can then be tested on examination. During the neurological examination knowledge of the relevant anatomy and physiology of the nervous system helps to determine the site of the lesion. The underlying pathology is often suggested by the time course of the symptoms and the epidemiological context. Increasingly sophisticated investigations, particularly imaging, are available to refine this clinical diagnosis.
Once the patient's neurological lesion (the deficit) is identified, the clinician needs to assess what impact this has had on the patient's functioning (the disability) and, in turn, how this is affecting his or her life (the handicap). Even when a complete cure cannot be effected, much can be done to improve the disability by pharmacological correction of the pathophysiology and through rehabilitation (see p. 243).
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Home > 2 SYSTEM-BASED DISEASES > 22 Neurological disease >FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
ANATOMY AND PHYSIOLOGY
CELLS OF THE NERVOUS SYSTEM
Figure 22.1 Cells of the nervous system.
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In addition to a variety of neurons, the nervous system includes specialised blood vessels, ependymal cells lining the cerebral ventricles and glial cells, of which there are three types. Astrocytes form the structural framework for the neurons and control their biochemical environment. Astrocyte foot processes are closely associated with the blood vessels to form the blood-brain barrier (see Fig. 22.1). Oligodendrocytes are responsible for the formation and maintenance of the myelin sheath, which surrounds axons and is essential for the rapid transmission of action potentials by saltatory conduction. Microglia are blood-derived mononuclear macrophages.
THE GENERATION AND TRANSMISSION OF THE NERVOUS IMPULSE
The functioning of the nervous system rests upon two physiological processes: the generation of an action potential with its conduction down axons, and the synaptic transmission of these impulses between neurons and/or muscle cells. These processes depend upon the energy-demanding maintenance of an electrochemical gradient across neuron cell membranes, and alterations in this are effected by specialised ion channels in the membrane. Synaptic transmission involves the release from a neuron of neurotransmitter molecules that bind to specific receptors on the membrane of the receptor cell. These molecules alter either that cell's membrane potential, via effects upon ion channel permeability, or its metabolic function (see Fig. 22.2). There are over 20 different neurotransmitters known to act at different sites in the nervous system, all potentially amenable to pharmacological manipulation (see Box 22.1).
22.1 NEUROTRANSMITTERS
Neurotransmitter Effect Clinical relevance Pharmacology
Acetylcholine Excitatory Alzheimer's disease
Myasthenia gravis
Parkinson's disease
Huntington's chorea
Motion sickness
Bladder control
Vomiting Donepezil, rivastigmine
Acetylcholinesterase inhibitors
Anticholinergics
Noradrenaline/adrenaline Excitatory Migraine
Mood disorders
Cardiovascular control
Bladder control
Appetite
Sleep disorders a-adrenoceptor antagonists (a-blockers)
Clonidine
Antidepressants
Dexamfetamine
ß-adrenoceptor antagonists (ß-blockers)
Glutamate Aspartate Excitatory Cerebral ischaemia
Epilepsy
Memory
Degenerative diseases (motor neuron disease) Lamotrigine
Riluzole
Topiramate
Dopamine Excitatory Parkinson's disease
Schizophrenia
Vomiting Levodopa
Dopamine agonists
Major tranquillisers
Metoclopramide
5-hydroxytryptamine (5-HT, serotonin) Excitatory Migraine
Depression
Pain
Sleep Pizotifen, sumatriptan
Antidepressants
Gamma-aminobutyric acid (GABA) Glycine Inhibitory Epilepsy
Spasticity Phenobarbital
Anticonvulsants
Benzodiazepines
Baclofen
Histamine Inhibitory Uncertain
Neuropeptides Excitatory and inhibitory Morphine
Vasopressin Memory
Adrenocorticotrophic hormone (ACTH) Uncertain
Melanocyte-stimulating hormone (MSH)
Substance P Pain
Opioid peptides (> 20)
Endorphins
Enkephalins
Dynorphins
Purines Excitatory and Uncertain
Adenosine triphosphate/ modulation of
diphosphate (ATP/ADP) neurotransmission
Adenosine monophosphate (AMP)
Adenosine
Nitric oxide Modulation of neurotransmission Memory Cerebral ischaemia
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The neuronal cell bodies are acted upon by synapses with large numbers of other neurons. Each neuron therefore acts as a microprocessor, reacting to the influences upon it by changes to its cell membrane potential, causing it to be more or less ready to discharge an impulse down its axon(s). The synapsing neuron terminals are also subject to regulation by receptor sites on their pre-synaptic membrane, which modify the release of transmitter across the synaptic cleft. The effect of some neurotransmitters is to produce long-term modulation of metabolic function or gene expression rather than simply to change the membrane potential. This effect probably underlies more complex processes in cognition, such as long-term memory.
Figure 22.2 Neurotransmission and neurotransmitters. (1) An action potential arriving at the nerve terminal depolarises the membrane and this opens voltage-gated calcium channels. (2) Entry of calcium causes the fusion of synaptic vesicles containing neurotransmitters with the pre-synaptic membrane and release of the neurotransmitter across the synaptic cleft. (3) The neurotransmitter binds to receptors on the post-synaptic membrane to either (A) open ligand-gated ion channels which, by allowing ion entry, depolarise the membrane and initiate an action potential (4), or (B) bind to metabotrophic receptors, which activate an effector enzyme (e.g. adenylyl cyclase) and thus via the intracellular second messenger system modulate gene transcription, leading to changes in synthesis of ion channels or modulating enzymes. (5) Neurotransmitters are taken up at the pre-synaptic membrane and/or metabolised.
MAJOR ANATOMICAL DIVISIONS OF THE NERVOUS SYSTEM (see Fig. 22.3)
Cerebral hemispheres
The cerebral cortex constitutes the highest level of nervous function, the anterior half dealing with executive ('doing') functions and the posterior half constructing a perception of the environment ('receiving and perceiving'). Collections of cells in the depths of the hemispheres deal with motor control (the basal ganglia), the appropriate attention to sensory perception (the thalamus), emotion and memory (the limbic system), and control over internal bodily functions (the hypothalamus). The cerebral ventricles contain the choroid plexus; this produces the cerebrospinal fluid (CSF), which cushions the brain within the cranium. From the fourth ventricle the CSF leaves through foramina in the brain stem to circulate down around the spinal cord and over the surface of brain, where it is reabsorbed into the cerebral venous system (see Fig. 22.56, p. 1208).
The brain stem
In addition to containing all the sensory and motor pathways entering and leaving the hemispheres, the brain stem houses the nuclei of the cranial nerves and the other important collections of neurons. These are involved in the control of conjugate eye movements, the maintenance of balance, cardiorespiratory control and the maintenance of arousal.
Figure 22.3 The major anatomical components of the nervous system.
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The spinal cord
The spinal cord contains not only the afferent and efferent fibres arranged in functionally discrete bundles but also, in the grey matter, collections of cells which are responsible for lower-order motor reflexes and the primary processing of sensory information, including pain.
The peripheral nervous system
The sensory cell bodies of peripheral nerves are situated in the dorsal root ganglia in the spinal exit foramina, whilst the distal ends of their neurons are invested with various specialised endings for the transduction of external stimuli into nervous impulses. The motor cell bodies are in the anterior horns of the spinal cord. Motor neurons initiate muscle contraction by the release of acetylcholine across the neuromuscular junction, with the resultant change in potential in the muscle end plate. To increase the speed of impulse conduction peripheral nerve axons are variably invested in myelin sheaths consisting of the wrapped membranes of Schwann cells.
The autonomic system
The unconscious neural control of the body's physiology is effected through the autonomic system. This innervates the cardiovascular and respiratory systems, smooth muscle of the gastrointestinal tract, and glands throughout the body. The autonomic system is controlled centrally by diffuse modulatory systems in the brain stem, limbic system and frontal lobes, which are concerned with arousal and background behavioural responses to threat. The output of the autonomic system is divided functionally and pharmacologically into two divisions: the parasympathetic and sympathetic systems.
INVESTIGATION OF NEUROLOGICAL DISEASE
TESTS OF FUNCTION (CLINICAL NEUROPHYSIOLOGY)
In the investigation of neurological disease, tests of function have a somewhat more restricted application than tests of structure (i.e. imaging). Nevertheless, recording of electrical activity over the brain and assessment of nerve and muscle function are essential in certain conditions. The major tests are electroencephalography (EEG), evoked potentials (EPs) and nerve conduction studies/electromyography (NCS/EMG).
Electroencephalography
Electrical activity arising in the cerebral cortex can be detected using electrodes placed on the scalp, although this is estimated to detect only 0.1-1% of the brain's electrical activity at any one time. An array of electrodes provides spatial information. Rhythmical waveforms can be detected and are distinguished by their frequency. When the eyes are shut, the most obvious frequency over the occipital cortex is 7-13/s; this is known as alpha rhythm, and disappears when the eyes are opened. Other frequency bands seen over different parts of the brain in different circumstances are beta (faster than 13/s), theta (4-6/s) and delta (slower than 4/s). Lower frequencies predominate in the very young and during sleep.
Figure 22.4 EEGs in epilepsy. A Primary generalised epileptic discharge. B Focal sharp waves over the right parietal region (between electrodes 7 and 8-shown in purple) with secondary generalised discharge.
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Various diseases result in abnormalities of the EEG.These may be continuous or episodic, focal or diffuse. Examples of continuous abnormalities include a global increase in fast frequencies (beta) seen with sedating drugs (e.g. benzodiazepines), or marked slowing seen over a structural lesion such as a tumour or an infarct. With the advent of modern neuro-imaging, EEG has lost its use in localising lesions, except in the management of epilepsy (see below and Fig. 22.4). However, it is still useful in the management of patients who have disturbance of consciousness or disorders of sleep, in the diagnosis of cerebral diseases such as encephalitis, and in certain dementias (e.g. Creutzfeldt-Jakob disease).
The most important use of EEG is in the management of epilepsy. It must be stressed, however, that only in rare circumstances will an EEG provide unequivocal evidence of epilepsy, and it is therefore not useful as a diagnostic test for the presence of epilepsy. Its use is predominantly to distinguish the type of epilepsy present, and whether there is an epileptic focus, particularly if surgery for epilepsy is contemplated.
During an epileptic seizure, high-voltage disturbances of the background activity ('transients') can be recorded. These may be generalised, as in the 3 cycle/s 'spike and wave' of childhood absence epilepsy (petit mal), or more focal, as in partial epilepsies (see Fig. 22.4). However, it is unusual to record a seizure itself, except in the case of childhood absence epilepsy. Nevertheless, it is often possible to detect 'epileptiform' abnormalities in between seizures in the form of 'spikes' and 'sharp waves' that lend support to a clinical diagnosis. The likelihood of detecting these abnormalities is enhanced by hyperventilation, photic flicker, sleep and some drugs. Note that, even so, some 50% of patients with proven epilepsy will have a normal 'routine' EEG, and conversely, the presence of features often seen in association with epilepsy does not, of itself, make a diagnosis (although the false positive rate for clear-cut epileptiform features is < 1/1000).
It is possible to enhance the information provided by a variety of means. For example, the usual 30-minute recording session can be lengthened to 24 hours by the use of a lightweight tape recorder. The addition of video information to the EEG allows comparison of behaviour with cerebral activity. In special circumstances, electrodes can be surgically positioned, e.g. through the foramen ovale, to record from the inferior temporal surface.
Evoked potentials
If a stimulus is provided-for example, to the eye-it would normally be impossible to detect the small EEG response evoked over the occipital cortex as the signal would be lost in background noise. However, if the EEG data from 100-1000 repeated stimuli are averaged electronically, this noise is removed and an evoked potential recorded whose latency (the time interval between stimulus onset and the maximum positive value of the evoked potential, P100) and amplitude can be measured.
Figure 22.5 Visual evoked responses (VER) recording showing abnormal delay on right. The latency of the P100 (the point of maximum positivity) on the left is 90 ms, that on the right 115 ms.
Evoked potentials can be measured following visual, auditory or somatosensory stimuli if electrodes are appropriately positioned, though visual evoked potentials are by far the most commonly used (see Fig. 22.5). Abnormalities of the evoked potential indicate damage to the relevant pathway, either in the form of a conduction delay (increased latency), or reduced amplitude, or both.
With the advent of magnetic resonance imaging (MRI), the use of evoked potentials is becoming restricted to specialised indications, such as providing a semi-objective measure of visual function.
Nerve conduction studies and electromyography
Using surface or needle electrodes, it is possible to record action potentials from nerves which lie close to the skin surface as well as from muscles. If a nerve trunk is stimulated with a small electric potential, it is possible to record the resulting compound action potential (the sum of all the individual nerves' action potentials) as it travels down the nerve. A normal compound action potential would have an amplitude of 5-30 microvolts, depending upon the nerve. If the recorded potential is smaller than expected, this provides evidence of a reduction in the overall number of functioning axons. Central conduction times can be measured using electromagnetic induction of action potential in the cortex or spinal cord by the local application of specialised coils.
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Compound motor action potentials (CMAPs) can also be recorded over muscles in response to motor nerve stimulation (see Fig. 22.6). These are easier to record because the muscle amplifies the response, typical amplitudes being 1-20 millivolts. By measuring the response latency to stimulation of a nerve at two different points along its length, it is possible to calculate nerve conduction velocities (NCVs). This can be done for both sensory and motor nerves; typical values are 50-60 m/s. Slowing of conduction velocity is suggestive of peripheral nerve demyelination which may be either diffuse (as in a demyelinating peripheral neuropathy) or focal (as in pressure palsies or conduction block).
The principal use of nerve conduction studies is to identify damage to peripheral nerves, and to determine whether the pathological process is focal or diffuse and whether the damage is principally axonal or demyelinating. It is also possible to obtain some information about nerve roots by more sophisticated analysis of responses to impulses initially conducted antidromically (i.e. the 'wrong' way) back up to the spinal cord, and then returning orthodromically (the 'right' way) down to the stimulation point ('F waves').
Fine concentric needle electrodes can be inserted into muscle bellies themselves and the potentials from individual motor units recorded. It is possible to record abnormal spontaneous activity arising from muscles at rest, such as fibrillations (a sign of denervation) or myotonic discharges. Abnormalities in the shape and size of muscle potentials can help in the differential diagnosis of denervation and structural muscle diseases. Myopathies caused by metabolic abnormalities (causing electromechanical dissociation rather than loss of fibre structure) show no changes on needle EMG.
Figure 22.6 Motor nerve conduction tests. Bipolar electrodes (R) on the muscle (abductor pollicis brevis here) record the compound motor action potential (CMAP) from stimulation at the median nerve at the elbow (S1) and from the wrist (S2). The CMAP amplitude is related to the number of axons, and the velocity can be determined if the distance between the two stimulating electrodes (d) is known. The latency (L) of the F wave is a measure of the conduction time in the nerve proximal to the elbow (see text). (NCV = nerve conduction velocity)
Electromyography can also be used to investigate the neuromuscular junction. Repetitive stimulation of a nerve with trains of electrical impulses at 3-15/s does not normally result in a significant fall-off in the amplitude of the resulting muscle action potential. However, such a decrement is seen in myasthenia gravis (see p. 1183) and provides one of the key diagnostic features. Augmentation of the response to repetitive stimulation is seen in the Lambert-Eaton myasthenic syndrome, though usually at higher stimulation frequencies.
IMAGING
Imaging is crucial to the identification of lesions of the nervous system in disease. There are various techniques, based on the use of X-rays (plain radiographs, computed tomography (CT), myelography and angiography), magnetic resonance (MR imaging-MRI, or MR angiography-MRA), ultrasound (Doppler imaging of blood vessels), and radioisotopes (single photon emission computerised tomography-SPECT, and positron emission tomography-PET). The indications, usefulness and limits of each technique are listed in Box 22.2. The choice of technique depends upon the area of the neuraxis that is being investigated.
Head and orbit
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22.2 TECHNIQUES AVAILABLE FOR IMAGING THE NERVOUS SYSTEM
Technique Principle Applications Advantages Disadvantages Comments
X-ray Attenuation of X-ray beam by radio-opaque substances (calcium, metal, contrast etc.) Plain radiographs
CT
Radiculography
Myelography
Contrast angiography Widely available
Relatively cheap
Relatively quick Ionising radiation
Reactions to contrast
Myelography and angiography are invasive and therefore carry risks In neurology, plain radiographs only demonstrate fracture or foreign bodies
CT is investigation of choice for trauma and stroke Intra-arterial X-ray contrast angiography still 'gold standard'
Magnetic resonance imaging (MRI) Magnetic resonance of different tissues depends on free hydrogen/water content; signals changed by movement (e.g. flowing blood) Structural imaging
MR angiography
(MRA)
Functional MR
MR spectroscopy High-quality soft tissue delineation
Better views of posterior fossa and temporal lobes
No ionising radiation
Non-invasive Expensive
Not yet widely available
Angiography looks at blood flow not anatomy
Scans uncomfortable/claustrophobic Increasing application
Functional MR and MR
spectroscopy still research tools
Ultrasound Echoes from high-frequency sound source localise structure;
Doppler phenomenon used to measure rate of flow Doppler
Duplex scans Cheap
Quick
Non-invasive Operator-dependent
Poor anatomical definition Useful as screening tool
Radio-isotope imaging Radio-labelled isotopes bind to structure(s) of interest, or used to assess relative blood flow Isotope brain scan
SPECT
PET In vivo demonstration of functional anatomy (e.g. ligand binding, blood flow) Poor spatial resolution Ionising radiation
Expensive, especially
PET Not widely available Isotope scans now obsolete
SPECT and PET largely research tools
(CT = computerised tomography; MR = magnetic resonance; PET = positron emission tomography; SPECT = single photon emission computerised tomography)
The use of plain skull radiographs is largely restricted to the diagnosis of fractures and sinus disease. CT or MRI is needed to image pathology inside the skull. Which is used depends on what information is being sought and, to some extent, how urgently it is required, as CT is often more easily available than MRI. CT will show bone and calcium well, and will easily image collections of blood. It will also detect abnormalities of the brain and ventricles, such as atrophy, tumours, cysts, abscesses, vascular lesions and hydrocephalus. Diagnostic yield is often improved by the use of intravenous contrast and spiral CT methods. It is, however, limited in its ability to image the posterior fossa (because of the surrounding bone density), and it is poor at detecting abnormalities of white matter and at allowing detailed analysis of grey matter.
MRI is much more useful in the investigation of posterior fossa disease as it is not affected by the surrounding bone. It is much more sensitive than CT to abnormalities of white and grey matter, and is therefore useful in the investigation of inflammatory conditions such as multiple sclerosis, and in investigating epilepsy. MRI can also provide additional information about structural brain lesions which may complement that available from CT. It is also useful in imaging the orbits, where special imaging sequences can be used to compensate for orbital fat, and thereby allow clear views of extraocular muscles, optic nerve and other orbital structures.
Standard isotope brain scans are of little value in assessing structure if other imaging facilities are available. However, the blood flow and function of the cerebral hemispheres can be assessed by using either SPECT or PET. Examples of brain imaged by the various techniques are shown in Figure 22.7.
Neck
Plain radiographs of the neck are useful in the investigation of structural damage to vertebrae, such as that resulting from trauma or inflammatory damage (e.g. rheumatoid arthritis). They can also provide implicit information about intervertebral disc disease, but not detailed information about the cervical cord or nerve roots, for which myelography or MRI is needed.
Myelography is invasive. Potential complications include headache, seizures and meningitis. With the advent of MRI its use is declining. Nevertheless, it is still of value if MRI is not available, or the patient cannot tolerate lying within an MRI scanner. Radio-opaque contrast is injected into the lumbar theca and then moved up to the cervical region by tilting the patient. The contrast outlines the nerve roots and spinal cord, thereby providing information about abnormal structure. Examples of the neck imaged by plain radiographs, myelography and MRI are shown in Figure 22.8.
Lumbo-sacral region
Imaging of this region is similar to imaging the neck, and plain radiographs are of limited use. Contrast can be injected into the lumbar thecal space and used to outline the lower nerve roots only (radiculography), or it can be run up to outline the conus and spinal cord (myelography). The information obtained may be enhanced by the additional use of CT following myelography (contrast CT). Non-contrast CT of the lumbar spine can only be used to image the vertebrae and discs. As with the cervical spine, MRI provides a non-invasive way of obtaining high-resolution images of both the vertebral column and the relevant neural structures.
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Figure 22.7 Different techniques of imaging the head and brain. A Skull radiograph showing lytic vault lesion (eosinophilic granuloma-arrow). B CT showing complete middle cerebral artery infarct (arrows). C MRI showing widespread areas of high signal in multiple sclerosis (arrows). D SPECT after caudate infarct shows relative hypoperfusion of overlying right cerebral cortex (arrows).
Blood vessels
Various techniques are available to investigate extracranial and intracranial blood vessels. The least invasive is ultrasound (Doppler or duplex scanning), which is used to investigate the carotid and the vertebral arteries in the neck, usually as part of the investigation of stroke. In skilled hands, reliable information can be provided about the degree of arterial stenosis, and the technique often gives useful anatomical information, e.g. whether there is an ulcerated plaque. Information concerning the blood flow in the intracerebral vessels is also becoming increasingly possible to obtain using transcranial Doppler. The anatomical resolution of Doppler imaging is limited, and formal angiography may still be required. The latter is, however, invasive, and therefore carries a small but significant risk of stroke or even death. Thus, the major role of Doppler imaging is as a screening test to determine whether invasive angiography is indicated.
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Figure 22.8 Different techniques of imaging the cervical spine. A Lateral radiograph showing bilateral C6/7 facet dislocation. B Myelogram showing widening of cervical cord due to astrocytoma (arrows). C MRI showing posterior epidural compression from adenocarcinomatous metastasis to the posterior arch of T1 (arrows).
Blood vessels can be outlined by the injection of radio-opaque contrast. The X-ray images obtained can be enhanced by the use of computer-assisted digital subtraction, or by the use of spiral CT. Contrast may be injected intravenously or intra-arterially. The former requires a much higher total dose of contrast, and the images obtained are not as good, but the latter involves feeding catheters up through the arterial tree and is thus associated with a higher complication rate. Formal intra-arterial angiography is usually required to delineate lesions of the extracranial carotid artery prior to endarterectomy, and is also used to investigate abnormalities of intracerebral vessels such as arterial (berry) aneurysms or arteriovenous malformations, or to delineate the blood supply of tumours prior to surgery.
Flowing blood can be detected by specialised MR sequences in MR angiography. The anatomical resolution is still not comparable to that of intra-arterial angiography, but the investigation is non-invasive. Examples of these different techniques are given in Figure 22.9.
SPECIAL TESTS
Blood tests
Many systemic conditions affect the nervous system and these can often be diagnosed with the help of blood tests: for example, confusion due to hypothyroidism, a stroke due to systemic lupus erythematosus, ataxia due to vitamin B12 deficiency, or myelopathy due to syphilis. The blood tests relating to general medical conditions which affect the nervous system are dealt with in the sections dealing with the conditions themselves.
There are, however, a number of blood tests which are used in investigating specific neurological diseases. These include haematological tests (e.g. looking for acanthocytes to diagnose neuroacanthocytosis), biochemical tests (e.g. creatine kinase in muscle diseases, copper studies to diagnose Wilson's disease) or tests to help diagnose innumerable infections of the nervous system. In addition, there are a number of specific antibodies that are useful diagnostically. These include antibodies to acetylcholine receptors and skeletal muscle, seen in myasthenia gravis, and to voltage-gated calcium channels in Lambert-Eaton myasthenic syndrome. Antibodies to different types of ganglioside (glycoproteins expressed on nerve membranes) can be seen in various types of neuropathy including multifocal motor neuronopathy, and the Guillain-Barré syndrome (particularly the Miller Fisher variant). Also, antineuronal antibodies provide markers of paraneoplastic cerebellar or neuropathic syndromes.
An increasing number of inherited neurological conditions can now be diagnosed by DNA analysis (see p. 349). These include diseases caused by increased numbers of trinucleotide repeats, such as Huntington's disease, myotonic dystrophy and some types of spinocerebellar ataxia. Also, defects of mitochondrial DNA can be detected in many conditions including Leber's hereditary optic neuropathy, and some syndromes causing epilepsy or stroke-like syndromes.
Lumbar puncture
This involves the insertion of a needle between lumbar spinous processes, through the dura and into the CSF under local anaesthetic. Intracranial pressure can be measured and CSF removed for analysis. CSF is normally clear and colourless. Tests usually performed on CSF include centrifuging to determine the colour of the supernatant (yellow, or xanthochromic, some hours after subarachnoid haemorrhage), biochemistry (glucose, total protein, and protein electrophoresis to detect oligoclonal bands), microbiology, immunology (e.g. Venereal Diseases Research Laboratory (VDRL) test-see p. 98, paraneoplastic antibodies) and cytology (to detect malignant cells). Normal values and various abnormalities found in diseases are shown in Box 22.3.
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Figure 22.9 Different techniques of imaging blood vessels. A Doppler scan showing 80% stenosis of internal carotid artery (arrow). B 3-D reconstruction of CT angiogram showing stenosis at the carotid bifurcation (arrow). C MR angiogram showing giant aneurysm at the middle cerebral artery bifurcation (arrow). D Intra-arterial angiography showing arteriovenous malformation (arrow).
22.3 CSF PARAMETERS IN HEALTH AND SOME COMMON DISORDERS*
Normal Subarachnoid haemorrhage Acute bacterial meningitis Viral meningitis Tuberculous meningitis Multiple sclerosis
Pressure 50-180 mm of water Increased Normal/increased Normal Normal/increased Normal
Colour Clear Blood-stained Xanthochromic Cloudy Clear Clear/cloudy Clear
Red cell count 0-4/mm3 Raised Normal Normal Normal Normal
White cell count 0-4/mm3 Normal/slightly raised 1000-5000 polymorphs 10-2000 lymphocytes 50-5000 lymphocytes 0-50 lymphocytes
Glucose > 60% of blood level Normal Decreased Normal Decreased Normal
Protein < 0.45 g/l Increased Increased Normal/increased Increased Normal/increased
Microbiology Sterile Sterile Organisms on Gram stain and/or culture Sterile/virus detected Ziehl-Neelsen/auramine stain or tuberculosis culture positive Sterile
Oligoclonal bands Negative Negative Can be positive Can be positive Can be positive Often positive
* See also Box 22.85, page 1193.
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Lumbar puncture is indicated in the investigation of infections (e.g. meningitis or encephalitis), subarachnoid haemorrhage, inflammatory conditions (e.g. multiple sclerosis, sarcoidosis and cerebral lupus) and some neurological malignancies (e.g. carcinomatous meningitis, lymphoma and leukaemia), and to measure CSF pressure (e.g. in idiopathic intracranial hypertension). It is, of course, part of the procedure of myelography, and can be part of the therapeutic procedures, either to lower CSF pressure or to administer drugs.
If there is a space-occupying lesion in the head, lumbar puncture can result in a shift of intracerebral contents downwards, towards and into the spinal canal. This process is known as coning, and is potentially fatal (see p. 1203). Consequently, lumbar puncture is contraindicated if there is any suggestion of raised intracranial pressure (e.g. papilloedema), depressed level of consciousness, or focal neurological signs suggesting a cerebral lesion, until imaging of the head (by CT or MRI) has excluded a space-occupying lesion or hydrocephalus. It is also contraindicated if the patient is likely to bleed, as in thrombocytopenia, disseminated intravascular coagulation or warfarin therapy, unless specific measures are taken to compensate for the clotting deficit on a temporary basis. Lumbar puncture is not contraindicated in those on aspirin.
About 30% of lumbar punctures are followed by low-pressure headache, which can be severe. Other minor complications involve transient radicular pain during the procedure, and pain over the lumbar region. Provided the test is performed under sterile conditions, infections such as meningitis are extremely rare.
Biopsies
Nerve and muscle are occasionally biopsied to assist in the diagnosis and management of a number of neurological conditions. Likewise, it is occasionally necessary to biopsy brain or meninges.
Nerve is sometimes biopsied as part of the investigation of peripheral neuropathies. Usually, the sural nerve is sampled at the ankle or the radial nerve at the wrist. Histology is often able to help identify underlying causes in demyelinating neuropathies (e.g. vasculitic) or, occasionally, infiltration with abnormal substances such as amyloid. However, nerve biopsy is not performed unless it is reasonably likely to diagnose a potentially treatable condition such as an inflammatory neuropathy, since there is an appreciable morbidity.
Skeletal muscle biopsy is performed more frequently. The quadriceps muscle is often sampled, though this depends somewhat on which muscles are affected. Indications include the investigation of primary muscle disease, as muscle histology can be used to distinguish neurogenic wasting, myositis and myopathy, which may be difficult to distinguish clinically. Histology and enzyme histochemistry can also be helpful in the diagnosis of more widespread metabolic disorders, such as mitochondrial and some storage diseases. Though pain and infection can follow the procedure, these are much less of a problem than after nerve biopsy.
The nature of lesions demonstrated by brain imaging can often be inferred from the appearances as well as the history, examination and other, less invasive, investigations. However, there are situations in which the nature of lesions is not clear, and it is important to obtain tissue for histological examination. Likewise, it is sometimes necessary to biopsy the brain parenchyma itself in unexplained degenerative diseases (e.g. unusual dementias) so as not to miss potentially treatable disease.
Brain biopsy used to require full craniotomy. However, owing to the increased availability and sophistication of cerebral imaging, it is now possible to biopsy most lesions stereotactically through a burrhole in the skull. The complication rate of such stereotactic biopsies is much lower than that of open craniotomy, but haemorrhage, infection and death still occur. Hence, brain biopsy is only considered if diagnosis cannot be reached in any other way.
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Home > 2 SYSTEM-BASED DISEASES > 22 Neurological disease > MAJOR MANIFESTATIONS OF NERVOUS SYSTEM DISEASE
MAJOR MANIFESTATIONS OF NERVOUS SYSTEM DISEASE
HEADACHE AND FACIAL PAIN
Headache is one of the most frequent neurological symptoms but it is seldom associated with significant neurological disease unless accompanied by other symptoms or neurological signs. Nevertheless, patients suffering from headaches usually fear serious brain disease. In order to manage them effectively, it is important to be aware of this mismatch between fear of disease and its actual likelihood. Careful clinical assessment usually identifies one of a limited number of headache or facial pain syndromes (see Box 22.4). After taking a careful history and performing the appropriate neurological examination, it is often not necessary to perform further investigations. The patient can be reassured and provided with symptomatic treatment.
22.4 COMMON HEADACHE AND FACIAL PAIN SYNDROMES
· Tension headache
· Migraine
· Cluster headache
· Raised intracranial pressure
· Benign paroxysmal headaches (see Box 22.7, p. 1120)
· Trigeminal neuralgia
· Atypical facial pain
· Post-herpetic neuralgia
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Pathophysiology
It is often difficult to explain the pain of headaches, especially in those not caused by serious disease, by reference to current neurobiological understanding of the mechanisms of pain. Within the skull the dura (including the dural sinuses and falx cerebri) and the proximal parts of the large pial blood vessels are the main structures sensitive to pain. The brain parenchyma, pial arteries over the convexities, and the cerebral ventricles and choroid plexus are known to be insensitive to pain. The pain-sensitive intracranial structures are mostly innervated by branches of the trigeminal nerve and some by branches of the upper cervical nerves. This probably accounts for the patterns of pain referral seen in intracranial disease when these pain-sensitive parts of the intracranial contents are stretched, distended or otherwise irritated.
A DIAGNOSTIC APPROACH TO THE PATIENT WITH HEADACHE
Unless the history is suggestive of structural disease, patients with headache who are normal on neurological examination are unlikely to have a serious disorder, however distressing their symptoms. The features of a patient's history that are helpful in making a clear diagnosis of the cause of a headache are shown in Box 22.5.
Patients can be divided into those with chronic headache (a duration of several weeks or more) and those with more acute headache. Serious acute neurological disease should always be considered in patients with headaches of very sudden onset. Subarachnoid haemorrhage (see p. 1162) causes a very sudden headache which may or may not be localised, although only one person in eight who has such a 'thunderclap' headache will have had a subarachnoid haemorrhage. A patient with subarachnoid haemorrhage almost invariably develops other symptoms including vomiting and neck stiffness, though the latter may take some hours to develop. The main differential diagnosis in a patient with a sudden severe headache is between subarachnoid haemorrhage and a migraine variant (see Fig. 22.32, p. 1163). Meningitis occasionally presents apoplectically, but the headache is usually less dramatic in onset.
22.5 IMPORTANT POINTS IN THE HEADACHE HISTORY
· The tempo of onset
· The time of day of onset of maximal pain
· The effect of posture, coughing and straining
· The location of the pain
· Any associated symptoms
Headache coming on over a matter of hours is less likely to be associated with structural disease and more likely to be due to migraine, unless accompanied by other significant symptoms or signs. Patients with bacterial meningitis are usually generally ill and pyrexial, and exhibit meningism. Patients with viral meningitis may present with a pyrexia and quite sudden and severe headache coming on over an hour or so, but are less likely to have neck stiffness or other signs of meningism. Migraine headaches (see below) may be accompanied or preceded by vomiting and focal neurological symptoms (usually in the form of zigzag 'fortification spectra' or tingling moving slowly over part of the body).
When headaches are intermittent rather than continuous over a period of days or weeks they are most likely to be migrainous but it is worth while paying attention to the time of day they occur and the presence or absence of precipitating factors. The headache of raised intracranial pressure is present on waking and often resolves or improves as the patient becomes upright (reducing the intracranial pressure) or takes simple analgesia (see Box 22.6). It is unusual for a patient to present with such a headache alone since it is usually not sufficiently severe to cause alarm, the presentation of the causative mass lesion more often being provoked by a seizure or by focal neurological dysfunction (aphasia, hemiplegia etc.). The exceptions to this are patients with acute hydrocephalus who present with a more severe headache. As with other causes of raised intracranial pressure, this is worse when lying, bending forward or coughing, and frequently causes vomiting in the morning (especially in children). Hydrocephalus may cause no other symptoms except gait ataxia, though examination may reveal papilloedema.
22.6 HEADACHE OF RAISED INTRACRANIAL PRESSURE
· Worse in morning, improves through the day
· Associated with morning vomiting
· Worse bending forward
· Worse with cough and straining
· Relieved by analgesia
· Dull ache, often mild
Headaches that persist for weeks, are present all day and are poorly responsive to simple analgesia are very likely to be tension-type headaches, whatever their other characteristics. Headaches so well localised by the patient that a finger is used to locate the exact spot on the skull are never associated with significant disease.
In a patient over 60 years with head pain localised to one or both temples, giant cell arteritis (see p. 1041) should be considered, especially if the temporal pulses are not palpable and/or the arteries are enlarged and tender.
TENSION-TYPE HEADACHE
Clinical features
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This is the most common type of headache and is experienced at some time by the majority of the population in some form. The pain is usually constant and generalised but often radiates forward from the occipital region. It is described as 'dull', 'tight' or like a 'pressure', and there may be a sensation of a band round the head or pressure at the vertex. In contrast to migraine, the pain may continue for weeks or months without interruption, although the severity may vary, and there is no associated vomiting or photophobia. The patient can usually continue normal activities and the pain may be less noticeable when the patient is occupied. The pain is characteristically less severe in the early part of the day and becomes more troublesome as the day goes on. Local tenderness may be present over the skull vault or in the occiput but this should be distinguished from the acute pain precipitated by skin contact in trigeminal neuralgia and the exquisite tenderness of temporal arteritis. Typically, the headache is reported to be poorly responsive to ordinary analgesia.
Pathogenesis
The cause of tension-type headaches is obscure. There is little evidence for the hypothesis that it is caused by excessive contraction of the muscles of the head and neck. Emotional strain or anxiety is a common precipitant to tension-type headache and there is sometimes an underlying depressive illness. Anxiety about the headache itself may lead to continuation of symptoms, and patients often become convinced of a serious underlying condition.
Management
Careful assessment followed by discussion of likely precipitants and explanation of the fact that the symptoms are not due to any sinister underlying pathology is more likely to be beneficial than analgesics. Excessive use of analgesics, particularly of codeine, may actually worsen the headache (analgesic headache). Physiotherapy (with courses of muscle relaxation and stress management) is usually beneficial, but low-dose amitriptyline (10 mg nocte increased gradually to 30-50 mg) may be necessary. There is evidence that patients with this syndrome benefit from a perception that their problem has been taken seriously and rigorously assessed, but over-extensive investigations can worsen a patient's anxiety.
MIGRAINE
Clinical features
Patients may refer to any episodic paroxysmal headache as migraine. However, it is best to look upon migraine as a triad of paroxysmal headache, nausea and/or vomiting, and an 'aura' of focal neurological events (usually visual). Patients with all three of these features are said to have migraine with aura ('classical' migraine). Those with paroxysmal headache (with or without vomiting) but no 'aura' are said to have migraine without aura ('common' migraine). It has been estimated that the lifetime prevalence of migraine is about 20% in females and 6% in males. Over 90% of migraine sufferers will have their first attack by the time they are 40 years old. Typically, a classical migraine attack starts with a non-specific prodrome of malaise and irritability followed by the 'aura' of a focal neurological event, and then a severe throbbing hemicranial headache with photophobia and vomiting. During the headache phase patients prefer to be in a quiet, darkened room and to sleep. The headache may persist for several days.
The 'aura' most often takes the form of 'fortification spectra': shimmering, silvery zigzag lines which march across the visual fields over 20 minutes, sometimes leaving a trail of temporary visual field loss. In some patients there is a sensory aura: a spreading front of tingling followed by numbness which moves, over 20-30 minutes, from one part of the body to another. If the dominant hemisphere is involved, the patient may also experience transient aphasia. True weakness is distinctly unusual in migraine, so 'hemiplegic migraine' should be diagnosed with extreme caution. In a small number of patients the focal events may occur by themselves ('migraine equivalent') but in this case other structural disorders of the brain, or even focal epilepsy, need to be considered in the differential diagnosis. In an even smaller number of patients, the symptoms of the aura do not resolve, leaving more permanent neurological disturbance ('complicated migraine').
Aetiology and pathogenesis
The aetiology of migraine is largely unknown. There is often a family history of migraine, suggesting a genetic predisposition. The great female preponderance and the tendency for some women to have migraine attacks at certain points in their menstrual cycle hint at hormonal influences. The relevance of the contraceptive pill in this context is difficult to establish, but it does appear to exacerbate migraine in many patients, and to increase the risk of stroke in patients who suffer from migraine with aura (see EBM panel). In some patients there are identifiable dietary precipitants such as cheese, chocolate or red wine. When psychological stress is involved, the migraine attack often occurs after the period of strain so that some patients tend to have attacks at weekends or at the beginning of a holiday.
EBM
MIGRAINE-risk of thromboembolic stroke
'RCTs and case-control studies suggest that there is a slight increase in the risk of thromboembolic stroke in patients who suffer from migraine, particularly migraine with aura, and that this risk is considerably elevated by concomitant use of hormonal contraception.'
Buring JE, Hebert P, Romero J, et al. Migraine and subsequent risk of stroke in the Physicians' Health Study. Arch Neurol 1995; 52:129-134.
Chang CL, Donaghy M, Poulter N. Migraine and stroke in young women: case-control study. World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. BMJ 1999; 318:13-18.
Further information: www.cochrane.co.uk
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The 'aura' of classical migraine probably represents a spreading front of electrical excitation followed by depression of activity of cortical cells. The cause of this is not understood but it probably represents a paroxysmal alteration in cortical modulation pathways from the brain stem (especially serotoninergic projections). The observation that migraine-like phenomena occur in rare genetic disorders associated with mutations in calcium channel genes suggests the possibility that the aura may be due to paroxysmal changes in the function of neuronal ion channels. The headache is thought to be caused by vasodilatation of extracranial vessels and may, like the headache following an epileptic seizure, be a non-specific effect of the disturbance of neuronal function.
Management
Identification and avoidance of precipitants or exacerbating factors (such as the contraceptive pill) may prevent attacks. Treatment of an acute attack consists of simple analgesia with aspirin or paracetamol, often combined with an antiemetic such as metoclopramide or domperidone. Long-term use of codeine-containing analgesic preparations should be avoided. Severe attacks can be treated with one of the 'triptans', 5-HT agonists that are potent vasoconstrictors of the extracranial arteries. These can be administered orally, sublingually, by subcutaneous injection or by nasal spray. Ergotamine preparations should be avoided since they easily lead to dependence. This is less likely to occur with the triptans, but it can occur. If attacks are frequent, they can often be prevented with propranolol (80-160 mg daily, in a sustained-release preparation), pizotifen (a 5-HT antagonist, 1.5-3.0 mg daily), a tricyclic such as amitriptyline (10-50 mg at night) or sodium valproate (300-600 mg/day). As above, the small risk of ischaemic stroke in women attributable to taking oral contraception is increased if they have migraine, especially if they also smoke.
MIGRAINOUS NEURALGIA (CLUSTER HEADACHE)
Clinical features
This is some 10-50 times less common than migraine. There is a 5:1 predominance of males and onset is usually in the third decade. The characteristic syndrome comprises periodic, severe, unilateral periorbital pain, accompanied by conjunctival injection, unilateral lacrimation, nasal congestion and often a Horner's syndrome. The pain, whilst being very severe, is characteristically brief (30-90 minutes). Typically, the patient develops these symptoms at a particular time of day (often in the early hours of the morning). The syndrome may occur repeatedly for a number of weeks, followed by a respite for a number of months before another cluster occurs.
Pathogenesis
There is little genetic predisposition, no provoking dietary factors and a male predominance, which suggest a different aetiology from that of migraine, but this remains unknown. Patients are usually heavy smokers with a higher than average alcohol consumption.
Management
Acute attacks are usually halted by subcutaneous injections of sumatriptan or by inhalation of 100% oxygen; other migraine therapies are ineffective, probably because of the brevity of the individual attacks. Preventative therapy with the agents used for migraine is often ineffective but attacks can be prevented in some patients by verapamil (80-120 mg 8-hourly), methysergide (4-10 mg daily, for a maximum of 3 months only) or short courses of corticosteroids. Patients with severe and debilitating clusters can be helped with lithium therapy although the usual precautions concerning the use of this drug should be observed (see p. 258).
COITAL AND EXERCISE-INDUCED CEPHALGIA
Clinical features
Patients are almost exclusively middle-aged men who develop a sudden, often very severe, headache at the climax of sexual intercourse. There is usually no vomiting and no neck stiffness, and the severe headache does not persist for more than 10-15 minutes, though a less severe dull headache may persist for some hours. This type of paroxysmal headache often needs to be distinguished, by CT and/or CSF examination, from the thunderclap headache of a subarachnoid haemorrhage (see Fig. 22.32, p. 1163). A very similar headache may occur during physical exertion, especially if this is attempted with unaccustomed vigour in an unfit person. The pathogenesis is unknown.
Management
Coital or exertional cephalgia is usually brief though frightening and may not need more than ordinary analgesia for the residual headache. The syndrome may not recur but prevention with propranolol (as for migraine) or indometacin (75 mg daily) may be necessary.
Other paroxysmal headaches are described in Box 22.7.
ISSUES IN OLDER PEOPLE
HEADACHES
Headaches are less common in those aged over 60 years than in younger people.
Common causes of headache which occur in old age, and either rarely or not at all in younger patients, include trigeminal neuralgia, temporal arteritis and post-herpetic neuralgia.
Migraine and tension headache are much less common than in younger people.
Raised intracranial pressure is not always associated with headache, vomiting or papilloedema.
Intracranial mass lesions can often reach larger sizes before presentation as the involutional process that occurs in most ageing brains allows the accommodation of an expanding lesion more easily than in younger patients.
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22.7 BENIGN PAROXYSMAL HEADACHES
Character of pain Duration Location Comment
Ice pick Stabbing Very brief (split-second) Variable, usually temporal or parietal Benign, more common in migraine
Ice cream Sharp, severe 30-120 seconds Bitemporal/occipital Obvious trigger by cold stimuli
Exertional Bursting Minutes to hours Generalised Intracranial pathology needs exclusion
Cough Bursting Seconds to minutes Occipital or generalised Intracranial pathology needs exclusion (especially cranio-cervical junction)
A DIAGNOSTIC APPROACH TO THE PATIENT WITH FACIAL PAIN
Pain in and around the eye, when not caused by ocular disease, should be considered as a headache (above). This includes the dramatic pain of migrainous neuralgia or cluster headache. Rarely, inflammatory or infiltrative lesions at the apex of the orbit or the cavernous sinus may cause pain in or around the eye but tell-tale signs from involvement of the ocular motor nerves usually accompany this. Pain in the eye may accompany disorders of the carotid artery, particularly dissections, and may then be accompanied by a Horner's syndrome.
Pain in the other parts of the face can be due to problems with the teeth or the temporo-mandibular joint. Inflamed nasal sinuses are seldom the cause of lasting facial pain in the absence of obvious nasal congestion. The very rare but serious condition of subdural empyema (see p. 1200) needs to be considered if 'sinusitis' is followed by very severe unilateral facial pain and signs of cerebral irritation (seizures and/or obtundation). Destructive lesions of the trigeminal nerve causing pain are extremely rare since such lesions usually cause loss of sensation in the nerve's territory rather than pain.
Most patients with persisting pain in the face have trigeminal neuralgia, atypical facial pain or post-herpetic neuralgia. The main distinction between these is in the nature of the pain. Trigeminal neuralgia typically occurs in patients older than 55 years. The pain is very brief, though severe and recurrent, described as 'like lightning', and is most frequently felt in the second and third divisions of the nerve. Atypical facial pain, on the other hand, is continuous and unremitting, centred over the maxilla, usually on the left side. It occurs most frequently in middle-aged women. Post-herpetic neuralgia is continuous and is felt as a burning pain throughout the affected territory, which is often very sensitive to light touch. The cause is usually obvious from a history of 'shingles' in the ophthalmic division of the trigeminal nerve.
TRIGEMINAL NEURALGIA
Clinical features
This condition causes very sharp lancinating pains in the second and third divisions of the trigeminal nerve territory, usually in middle-aged or elderly patients. The pain is severe and very brief, but repetitive, causing the patient to flinch as if with a motor tic; hence the French term for the condition, 'tic douloureux'. The pain may be precipitated by touching trigger zones within the trigeminal territory or by eating and so on. Usually there are no other signs, although similar symptoms may occur in advanced multiple sclerosis or, rarely, with other lesions, in which case there may be sensory changes in the trigeminal nerve territory or other brain-stem symptoms and signs. There is a tendency for the condition to remit and relapse over many years.
Pathogenesis
The current hypothesis as to aetiology suggests that the neuralgia is most commonly caused by compression of the trigeminal nerve rootlets at their entry to the brain stem by aberrant loops of the cerebellar arteries. Other compressive lesions, usually benign, are occasionally found in the site. When trigeminal neuralgia occurs in multiple sclerosis there is a plaque of demyelination in the trigeminal root entry zone.
Management
The pain usually responds to carbamazepine, in doses of up to 1200 mg daily. It is wise to start with much lower doses and escalate the dose according to effect, as one might when using this drug for epilepsy. In patients who cannot tolerate carbamazepine, phenytoin or gabapentin may be effective, but other anticonvulsants are not. If drug treatment fails and/or when the condition does not remit, various surgical treatments are available. The simplest is the injection of alcohol or phenol into a peripheral branch of the nerve. Probably more effective is the percutaneous placing of a radiofrequency lesion in the nerve near the Gasserian ganglion. Care has to be taken not to cause excessive damage to sensation in the face to prevent the complication of neurogenic pain ('anaesthesia dolorosa') which is worse than the neuralgia. Alternatively, the vascular compression of the trigeminal nerve can be relieved through a small posterior craniotomy, often with substantial success. This latter approach is usually favoured in younger patients in whom the other injection treatments may have to be repeated and become less effective.
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DIZZINESS, BLACKOUTS AND 'FUNNY TURNS'
Episodes of lost or altered consciousness are a frequent symptom in primary care and in hospital practice, especially in the elderly (see below). A patient may complain of 'blacking out', 'going dizzy', 'coming over queer', 'having a funny turn' or other local variants. The first task is to discover exactly what the patient means by the terms used. Some patients, for example, mean by 'blackout' that their vision darkens without alteration in consciousness (defined here as an awareness of the environment and ability to respond to it). More often 'blackout' is used to describe an episode of lost consciousness with or without falling down. The terms 'blackout' and 'funny turn' can also be used to refer to transient periods of amnesia, when the patient loses memory for a period of time. 'Dizziness' is used frequently to describe an abnormal perception of movement of the environment (vertigo), but may be used to mean a feeling of faintness, some other alteration of consciousness, or unsteadiness.
After a careful history from the patient, supplemented by a witness account, it should be clear whether the patient is describing an episode of loss of consciousness, altered consciousness, vertigo, transient amnesia or something else. The former two symptoms suggest a problem in mechanisms maintaining normal awareness. Vertigo is caused by an alteration in function of the peripheral vestibular organs or the central control mechanisms of balance and posture.
ISSUES IN OLDER PEOPLE
DIZZINESS
Recurrent dizzy spells affect at least 30% of people aged over 65 years.
These are most frequently described as a combination of unsteadiness and lightheadedness.
Most have more than one contributing factor.
Postural hypotension, cerebrovascular disease and cervical spondylosis are common underlying diagnoses.
Arrhythmia must be excluded in those with predominant lightheadedness which occurs at rest as well as on activity.
Anxiety and poor vision are frequent concomitants but are rarely the only cause at this age.
If the patient is falling as a result, a multidisciplinary workup is required (see p. 241).
A DIAGNOSTIC APPROACH TO THE PATIENT WITH VERTIGO (see Fig. 22.10)
Figure 22.10 A diagnostic approach to the patient with dizziness, funny turns or blackouts.
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Abnormal perception of movement of the environment occurs as a result of a mismatch between the information about a person's position in the environment reaching the brain from the eyes, the limb proprioceptive apparatus and the vestibular system. Vertigo arising from inappropriate input from the labyrinthine apparatus is within the experience of most people, since this is the 'dizziness' which occurs after someone has spun round vigorously and then stops. Vertigo caused by labyrinthine disorders is usually short-lived, though it may recur, whilst vertigo arising from central disorders (of the brain stem) is often persistent and accompanied by other signs of brain-stem dysfunction. A careful analysis of the history will reveal the likely cause in most patients.
VERTIGO CAUSED BY LABYRINTHINE DISTURBANCES
Labyrinthitis ('vestibular neuronitis')
This is the most common cause of severe vertigo, but the cause of the labyrinthitis is unknown; it usually presents in the third or fourth decade as severe vertigo, with vomiting and ataxia but no tinnitus or deafness, often coming on when waking. The vertigo is most severe at onset and settles down over the next few days, though afterwards head movement may provoke vertigo (positional vertigo) for some time. During the attack nystagmus will be present but does not persist for long.
Integration link: Semi-circular canal function
Taken from Medical Neuroscience
Benign paroxysmal positional vertigo
In older patients paroxysms of vertigo occurring with certain head movements may be due to the presence of degenerative material affecting the free flow of endolymph in the labyrinth (cupulolithiasis). Each attack of vertigo lasts seconds but patients often become very distressed and reluctant to move their head, which can in turn produce a muscle tension type of headache. Secondary hyperventilation attacks and associated depressive features are also common. Positional vertigo may also occur after concussive head injuries.
Ménière's disease
This is a cause of labyrinthine vertigo that is probably diagnosed too readily. Patients usually present first with tinnitus and distorted hearing, and then develop paroxysmal attacks of vertigo preceded by a sense of fullness in the ear. Examination in this circumstance shows sensorineural hearing loss on the affected side.
Symptomatic relief of labyrinthine causes of vertigo can be achieved with 'vestibular sedatives' (e.g. cinnarizine, prochlorperazine, betahistine). Positional vertigo can be improved with exercises that are designed to habituate the central mechanisms to the inappropriate signals from the labyrinth. Patients with intractable symptoms should be referred to an ENT specialist for assessment.
CENTRAL CAUSES OF VERTIGO
Any disease that affects the vestibular nucleus in the brain stem or its connections can cause vertigo. This can be distinguished from peripheral causes of vertigo by its persistence and the usual association of other signs. Positionally induced central vertigo persists for as long as the position is maintained, unlike the common peripheral positional vertigo that fatigues quite quickly if the inducing position is maintained. The same is true of any accompanying nystagmus. Transient causes such as brain-stem ischaemia can be recognised by the association with other symptoms of brain-stem dysfunction such as dysarthria or diplopia. If deafness is present and the history is not suggestive of Ménière's disease, extra-axial compression of the 8th cranial nerve by a lesion such as an acoustic neuroma (see p. 1206) should be suspected. Rarely, vertigo originating from the cerebral cortex may be a manifestation of a partial seizure in the temporal lobe.
A DIAGNOSTIC APPROACH TO THE PATIENT WITH EPISODIC LOSS OF CONSCIOUSNESS
Loss of consciousness, other than in sleep, suggests a global dysfunction of the brain. As a transient phenomenon, this most commonly comes about because of a recoverable loss of adequate blood supply to the brain, i.e. syncope (see below). Alternatively, loss of consciousness occurs from sudden dysfunction of the electrical mechanisms of the brain during a seizure (epileptic fit). Episodes of loss of consciousness are therefore either fits or faints, though some patients who have various types of psychogenic blackout or non-epileptic seizure confuse this clear distinction.
The distinction of a seizure from a faint can only be made from the patient's history, with help from the account of someone who witnessed the attack. No amount of investigation can replace a clear history in these circumstances. Features in the history useful in distinguishing a seizure from a faint are shown in Box 22.8.
22.8 FEATURES HELPFUL IN DISTINGUISHING SEIZURES FROM FAINTS
Seizure Faint
Aura (e.g. olfactory) + -
Cyanosis + -
Tongue-biting + -
Post-ictal confusion + -
Post-ictal amnesia + -
Post-ictal headache + -
SYNCOPE
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A brief feeling of 'lightheadedness' often precedes a faint; vision then darkens and there may be a ringing in the ears. Vasovagal syncope (see p. 397) may be provoked by some emotionally charged event (e.g. venepuncture) and usually occurs from the standing position. Cardiac syncope (see p. 397), caused by a sudden decline in cardiac output and hence cerebral perfusion, may be provoked by exertion (e.g. with severe aortic stenosis), or occur completely 'out of the blue' (as in heart block).
In vasovagal syncope, the loss of consciousness is gradual and brief, and the patient recovers quickly without confusion as long as he or she has assumed the horizontal position. It is rare for the syncope to cause injury and there is no amnesia for events that occur after regaining awareness. During a syncopal attack, incontinence of urine can occur and there may be some stiffening and even some brief twitching of the limbs, but tongue-biting never occurs.
SEIZURES
A seizure is any abnormal clinical event caused by an electrical discharge in the brain, whilst epilepsy is the tendency to have recurrent seizures (see p. 1125). Major seizures cause loss of consciousness, with the patient falling to the ground and presenting with a history of 'blackouts'. Minor seizures causing alteration of consciousness, without the patient falling to the ground, may also be described as 'blackouts'.
Pathophysiology
In the normally functioning cortex, recurrent and collateral inhibitory circuits limit synchronous discharge amongst neighbouring groups of neurons. The inhibitory transmitter gamma-aminobutyric acid (GABA) is particularly important in this role, and drugs that block GABA receptors provoke seizures. There are also a large number of excitatory neurotransmitters, of which acetylcholine and the amino acids glutamate and aspartate are examples (see Box 22.1, p. 1107). 'Epileptic' cerebral cortex exhibits hypersynchronous repetitive discharges involving large groups of neurons. Intracellular recordings show bursts of rapid action potential firing, with reduction of the transmembrane potential (paroxysmal depolarisation shift). It is likely that both reduction in inhibitory systems and excessive excitation play a part in the genesis of seizure activity. Cells undergoing repetitive 'epileptic' discharges undergo morphological and physiological changes which make them more likely to produce subsequent abnormal discharges ('kindling').
The chief division of seizure types on physiological grounds is between partial (focal) seizures in which paroxysmal neuronal activity is limited to one part of the cerebrum, and generalised seizures where the electrophysiological abnormality involves both hemispheres simultaneously and synchronously (see Fig. 22.11). If partial seizures remain localised, the symptomatology depends on the cortical area affected. If consciousness (the awareness of and ability to respond to the environment) is preserved, the attack is termed a 'simple partial seizure'. If, however, the activity involves some parts of the brain dealing with awareness (such as the temporal or frontal lobes), then consciousness is affected and a 'complex partial seizure' results. Further spread into the diencephalon and thence throughout the remainder of the cortex leads to a secondarily generalised seizure.
In primary generalised seizures, the abnormal activity is seen to begin synchronously throughout the cortex without an initial partial onset. It probably originates in the central diencephalic mechanisms controlling cortical activation (see Fig. 22.11). This is recognisable on an EEG which shows spikes and waves of abnormal activity (see Fig. 22.4, p. 1109) and quite often provocation of abnormalities with hyperventilation and/or photic stimulation. This may cause a major seizure identical to a secondarily generalised seizure, or a more restricted clinical manifestation if the abnormal electrical activity fails to affect muscle tone. In this case there is an 'absence', in which consciousness is lost but the patient remains standing or sitting. Such attacks may be difficult to distinguish clinically from a complex partial seizure in the temporal lobe.
Figure 22.11 The pathophysiological classification of seizures. A A partial seizure originates from a paroxysmal discharge in a focal area of the cerebral cortex (often the temporal lobe); the seizure may subsequently spread to the rest of the brain (secondary generalisation) via diencephalic activating pathways. B In primary generalised seizures the abnormal electrical discharges originate from the diencephalic activating system and spread simultaneously to all areas of the cortex.
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Clinical features
Tonic clonic seizures
A tonic clonic seizure may be preceded by a partial seizure (the 'aura') which can take various forms, described below. However, a history of such an 'aura' is commonly not obtained, probably because the subsequent generalised seizure causes some retrograde amnesia for immediately preceding events. The patient then goes rigid and becomes unconscious, falling down heavily if standing, often sustaining injury. During this phase, respiration is arrested and central cyanosis may be witnessed. After a few moments, the rigidity is periodically relaxed, producing clonic jerks. Some patients do not have a clonic phase and the rigidity is replaced by a flaccid state of deep coma which can persist for some minutes. The patient then gradually regains consciousness, but is in a confused and disorientated state for half an hour or more after regaining consciousness. Full memory function may not be recovered for some hours. During the attack urinary incontinence may occur, as may tongue-biting. (A severely bitten, bleeding tongue after an attack of loss of consciousness is pathognomonic of a generalised seizure.) After a generalised seizure the patient usually feels terrible, may have a headache and will want to sleep. Witnesses of a seizure are usually frightened by the events, often believing the person to be dying, and may not give a clear account; this is in itself a helpful diagnostic pointer since syncope seldom produces such fear in onlookers. Patients may have no tonic or clonic phase, and may not become cyanosed or bite their tongue. However, post-ictal confusion or headache and a period of subsequent malaise and/or confusion are usually seen, and this is useful in differentiating seizures from faints. Psychogenic non-epileptic attacks ('pseudo-seizures') may be accompanied by dramatic flailing of the limbs and arching of the back; however, these are not usually followed by the same degree of post-ictal confusion and do not cause cyanosis.
Complex partial seizures
Partial seizures may cause episodes of altered consciousness without the patient collapsing to the ground, especially if arising from the temporal or, less frequently, the frontal lobe. These may be referred to as 'blackouts'. The patient stops what he or she is doing and stares blankly, often making rhythmic smacking movements of the lips or displaying other automatisms, such as picking at their clothes. After a few minutes the patient returns to consciousness but may be initially muddled and feel drowsy. Immediately before such an attack the patient may report alterations of mood, memory and perception such as undue familiarity (déjà vu) or unreality (jamais vu), complex hallucinations of sound, smell, taste, vision, emotional changes (fear, sexual arousal) or visceral sensations (nausea, epigastric discomfort). If these changes of memory or perception occur without subsequent alteration in awareness, the seizure is said to be a simple partial seizure.
Absence seizures
A type of minor seizure that resembles a complex partial seizure occurs in the generalised absence epilepsy of childhood known as 'petit mal'. In petit mal epilepsy, the attacks are usually briefer and very much more frequent (up to 20 or 30 a day) than complex partial seizures and are not associated with post-ictal confusion. Absence attacks are caused by a generalised discharge that does not spread out of the hemispheres and so does not cause loss of posture.
Partial motor seizures
Epileptic activity arising in the pre-central gyrus causes partial motor seizures affecting the contralateral face, arm, trunk or leg. Seizures are characterised by rhythmical jerking or sustained spasm of the affected parts. They may remain localised to one part, or may spread to involve the whole side. Some attacks begin in one part (e.g. mouth, thumb, great toe etc.) and spread gradually; this is Jacksonian epilepsy. Attacks vary in duration from a few seconds to several hours. More prolonged episodes may leave paresis of the involved limb lasting for several hours after the seizure ceases (Todd's palsy).
Partial sensory seizures
Seizures arising in the sensory cortex cause unpleasant tingling or 'electric' sensations in the contralateral face and limbs. A spreading pattern like a Jacksonian seizure may occur, the abnormal sensation spreading much faster over the body (in seconds) than the 'march' of a migrainous focal sensory attack, which spreads over 10-15 minutes.
Versive seizures
A frontal epileptic focus may involve the frontal eye field, causing forced deviation of the eyes to the opposite side. This type of attack often becomes generalised to a tonic clonic seizure.
Partial visual seizures
Occipital epileptic foci cause simple visual hallucinations such as balls of light or patterns of colour. Formed visual hallucinations of faces or scenes arise more anteriorly in the temporal lobes.
Factors precipitating seizures
Sometimes specific trigger factors can be identified. Some are listed in Box 22.9.
22.9 TRIGGER FACTORS FOR SEIZURES
Sleep deprivation
Alcohol (particularly withdrawal)
Recreational drug misuse
Physical and mental exhaustion
Flickering lights, including TV and computer screens (primary generalised epilepsies only)
Intercurrent infections and metabolic disturbances
Uncommonly: loud noises, music, reading, hot baths
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EPILEPSY
Epilepsy means a tendency to have seizures and is a symptom of brain disease rather than a disease itself. A single seizure is not epilepsy but an indication for investigation. Medication should await evidence of a tendency to recurrent seizures. However, the recurrence rate after a first seizure approaches 70% during the first year, most recurrent attacks occurring within a month or two of the first. Further seizures are less likely if a trigger factor is definable and avoidable (e.g. sleep deprivation, alcohol withdrawal etc.). There is a group of disorders whose only or main symptom is epilepsy, whilst in other disorders epilepsy is just one of the manifestations. The annual incidence of new cases of epilepsy after infancy is 20-70/100 000. The lifetime risk of having a single seizure is about 5%, whilst the prevalence of epilepsy in European countries is about 0.5%. Prevalence in developing countries is up to five times higher than in developed countries; incidence is double.
Types of epilepsy
The classification of epilepsy is best achieved by considering the clinical events (the seizures), the abnormal electrophysiology, the anatomical site of seizure genesis and the pathological cause of the problem (see Box 22.10).
Primary generalised epilepsies
The primary or idiopathic epilepsies make up some 10% of all epilepsies, including some 40% of those with tonic clonic seizures. Onset is almost always in childhood or adolescence. No structural abnormality is present and there is often a substantial genetic predisposition. Some, like childhood absence epilepsy, are relatively uncommon, whilst others, like juvenile myoclonic epilepsy, are common (5-10% of all patients with epilepsy). The more common varieties of primary generalised epilepsy are listed in Box 22.11, along with their clinical features and management.
Secondary generalised epilepsy
22.10 CLASSIFICATION OF EPILEPSY
Seizure type
Simple partial
Complex partial
Absence
Tonic clonic
Tonic
Atonic
Myoclonic
Physiology (EEG)
Focal spikes/sharp waves
Generalised spike and wave
Anatomical site
Cortex
Temporal
Frontal
Parietal
Occipital
Generalised (diencephalon)
Multifocal
Pathological cause
Genetic
Developmental
Tumours
Trauma
Vascular
Infections
Inflammation
Metabolic
Drugs and alcohol
Degenerative
22.11 PRIMARY GENERALISED EPILEPSIES
Incidence Age of onset Type of seizure EEG features Provoking factors Treatment Prognosis
Childhood absence epilepsy 6-8/100 000 4-8 yrs Frequent brief absences 3/s spike and wave Hyperventilation, fatigue Ethosuximide Sodium valproate 40% develop tonic clonic seizures, 80% remit in adulthood
Juvenile absence epilepsy 1-2/100 000 10-15 yrs Less frequent absences than childhood absence Poly-spike and wave Hyperventilation, sleep deprivation Sodium valproate 80% develop tonic clonic seizures, 80% seizure-free in adulthood
Juvenile myoclonic epilepsy 25-50/100 000 15-20 yrs GTCS, absences, morning myoclonus Poly-spike and wave, photosensitivity Sleep deprivation, alcohol withdrawal Sodium valproate 90% remit with sodium valproate but relapse on AED withdrawal
GTCS on awakening Common 10-25 yrs GTCS, sometimes myoclonus Spike and wave on waking and sleep onset Sleep deprivation Sodium valproate 65% controlled with AEDs but relapse off treatment
(GTCS = generalised tonic clonic seizure; AED = anti-epilepsy drug)
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22.12 CAUSES OF SECONDARY GENERALISED EPILEPSY
Cerebral birth injury
Hydrocephalus
Cerebral anoxia
Drugs
Antibiotics: penicillin, isoniazid, metronidazole
Antimalarials: chloroquine, mefloquine
Ciclosporin
Cardiac anti-arrhythmics: lidocaine (lignocaine), disopyramide
Psychotropic agents: phenothiazines, tricyclics, lithium
Amphetamines (withdrawal)
Alcohol (especially withdrawal)
Metabolic disease
Hypocalcaemia
Hyponatraemia
Hypomagnesaemia
Hypoglycaemia
Renal failure
Liver failure
Infective
Meningitis
Post-infectious encephalopathy
Inflammatory
Multiple sclerosis (uncommon)
SLE
Diffuse degenerative diseases
Alzheimer's disease
Creutzfeldt-Jakob disease
Secondary generalisation from partial seizures
See Box 22.13 for causes of partial seizures
Genetic
Inborn errors of metabolism
Storage diseases
Generalised epilepsy may arise from spread of partial seizures due to structural disease or may be secondary to drugs or metabolic disorders (see Box 22.12). Epilepsy presenting in adult life is almost always secondary generalised, even if there is no clear history of a partial seizure before the onset of a major attack (an 'aura').
Partial epilepsy
Partial seizures may arise from any disease of the cerebral cortex, congenital or acquired, and frequently generalise. With the exception of a few idiopathic partial epilepsies of benign outcome in childhood, the presence of partial seizures signifies the presence of focal cerebral pathology. Common causes are listed in Box 22.13.
Investigations
22.13 CAUSES OF PARTIAL SEIZURES
Focal structural lesions
Infantile hemiplegia
Mesial temporal sclerosis (associated with febrile convulsions)
Tumours
Trauma (including neurosurgery)
Idiopathic
Benign rolandic epilepsy of childhood
Benign occipital epilepsy of childhood
Genetic
Tuberous sclerosis
Neurofibromatosis
von Hippel-Lindau disease
Dysembryonic
Cortical dysgenesis
Sturge-Weber syndrome
Cerebrovascular disease
Intracerebral haemorrhage
Cerebral embolus
Arteriovenous malformation
Infective
Cerebral abscess (pyogenic)
Toxoplasmosis
Cysticercosis
Tuberculoma
Subdural empyema
Encephalitis
Human immunodeficiency virus (HIV)
Inflammatory
Sarcoidosis
Vasculitis
After a single seizure cerebral imaging with CT or MRI is advisable, although the yield of structural lesions is low unless there are focal features to the seizure or there are focal signs. Similarly, toxic and metabolic causes (see Box 22.13) should be considered. EEG is only necessary when more than one seizure has occurred and the type of epilepsy needs to be established to guide therapy. The increasing sophistication of imaging techniques now allows the identification of the cause of epilepsy in an increasing number of patients, especially those with partial seizures. These patients warrant intensive investigation, especially if seizures arise for the first time in adult life. Investigations should be pursued more vigorously if the epilepsy is intractable to treatment. The investigations that may be undertaken in a patient with suspected epilepsy are shown in Box 22.14.
Electroencephalography (EEG)
The EEG (see p. 1109) may help to establish a diagnosis and characterise the type of epilepsy (i.e. primary generalised or partial with or without secondary generalisation). Inter-ictal records are abnormal in only about 50% of patients so the EEG is not a sensitive test for the presence of epilepsy. However, epileptiform changes (sharp waves or spikes) are fairly specific (falsely positive in only 1/1000). The sensitivity can be increased to about 85% by prolonging recording time and including a period of natural or drug-induced sleep. Ambulatory EEG recording or video/EEG monitoring may provide helpful information when attacks are frequent.
Brain imaging
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22.14 INVESTIGATION OF SUSPECTED EPILEPSY
Epileptic nature of attacks?
Ambulatory EEG
Videotelemetry
Type of epilepsy?
Standard EEG
Sleep EEG
EEG with special electrodes (foramen ovale, subdural)
Structural lesion?
CT
MRI
Metabolic disorder?
Blood urea and electrolytes
Liver function tests
Blood glucose
Serum calcium, magnesium
Inflammatory or infective disorder?
Blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)
Chest radiograph
Serology for syphilis, HIV, collagen disease
CSF
22.15 INDICATIONS FOR BRAIN IMAGING IN EPILEPSY
Epilepsy starts after the age of 20 years
Seizures have focal features clinically
EEG shows a focal seizure source
Control of seizures is difficult or deteriorates
Imaging does not help establish a diagnosis of epilepsy but is useful in defining or excluding a structural cause; indications are summarised in Box 22.15. Imaging is not required if a confident diagnosis of primary generalised epilepsy can be made with an EEG. CT is often sufficient to exclude a major structural cause of epilepsy. MRI of the brain may be indicated if CT shows no abnormality but a subtle structural change is still suspected, as in the case of patients with partial seizures (with or without secondary generalisation) which are resistant to therapy.
Management
It is important to explain the nature and cause of seizures to patients and their relatives, and to instruct relatives in the first aid management of major seizures. Many people with epilepsy feel stigmatised by society and may become unnecessarily isolated from work and social life. It should be emphasised that any brain can develop a seizure, that epilepsy is a common disorder which affects just under 1% of the population, and that good or complete control of seizures can be expected in more than 80% of patients.
Immediate care of seizures
Little can or need be done for a person whilst a major seizure is occurring except first aid and common-sense manoeuvres to limit damage or secondary complications (see Box 22.16).
Restrictions
22.16 IMMEDIATE CARE OF SEIZURES
First aid (by relatives and witnesses)
Move person away from danger (fire, water, machinery, furniture)
After convulsions cease, turn into 'recovery' position (semi-prone)
Ensure airway is clear
Do NOT insert anything in mouth (tongue-biting occurs at seizure onset and cannot be prevented by observers)
If convulsions continue for more than 5 minutes or recur without person regaining consciousness, summon urgent medical attention
Person may be drowsy and confused for some 30-60 minutes and should not be left alone until fully recovered
Immediate medical attention
Ensure airway is patent
Give oxygen to offset cerebral hypoxia
Give intravenous anticonvulsant (e.g. diazepam 10 mg) ONLY IF convulsions are continuous or repeated (if so, manage as for status epilepticus)
Consider taking blood for anticonvulsant levels (if known epileptic)
Investigate cause
22.17 UK DRIVING REGULATIONS
Single seizure
Cease driving for 1 year free of recurrence, then Driver and Vehicle Licensing Authority (DVLA) will restore a full licence (i.e. until age of 70 years)
Epilepsy
Licence restored when patient is free from all types of seizure for 1 year or seizures exclusively during sleep for a period of 3 years (licence will require renewal every 3 years thereafter until 10 seizure-free years)
Withdrawal of anticonvulsants
Cease driving during withdrawal and for 6 months thereafter
Vocational drivers (heavy goods and public service vehicles)
No licence permitted if any seizure occurs after the age of 5 years until off medication and seizure-free for more than 10 years, and no potentially epileptogenic brain lesion
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22.18 ANTICONVULSANT DRUGS
Seizure types Dose range (mg/day) Doses per day Therapeutic range (lmol/l) Dose-related side-effects Idiosyncratic side-effects Long-term side-effects Interactions
Acetazolamide Primary and secondary GTCS, absences, partial 250-1000 2-3 Not applicable Paraesthesia, anorexia, headache, nausea, diarrhoea, visual changes Rashes, agranulocytosis, thrombocytopenia, photosensitivity, liver damage Renal calculi Aspirin, quinidine, phenytoin, carbamazepine, digoxin, ulcer-healing drugs
Carbamazepine Partial, secondary GTCS 200-2000 2-3 30-50 Drowsiness, ataxia, nystagmus, diplopia, hyponatraemia Rashes, thrombocytopenia, other blood dyscrasias None Other AEDs, warfarin, OCP, steroids, antimalarials, cimetidine
Clobazam Partial (adjunctive) 20-30 1 Not applicable Sedation, irritability Anticonvulsant effect wears off after a few weeks Other AEDs
Clonazepam Partial (adjunctive), myoclonus 1-8 2-4 Not applicable Sedation, irritability Blood dyscrasias Anticonvulsant effect wears off after a few weeks Other AEDs
Ethosuximide Childhood absence 500-1500 2 200-700 Dizziness, insomnia, ataxia Rashes, blood dyscrasias Other AEDs, antidepressants
Gabapentin Partial 300-2400 3 Not applicable Drowsiness, ataxia Not yet known Antacids
Lamotrigine Partial, secondary GTCS 25-500 1-2 Not applicable Drowsiness, ataxia, diplopia, confusion Rashes, blood dyscrasias Not yet known Carbamazepine
Levetiracetam Partial, secondary GTCS 1000-3000 2 Not applicable Somnolence, tiredness, dizziness, headache None recorded Not yet known Phenytoin
Oxcarbazepine Partial, secondary GTCS 600-2400 2 50-125 Drowsiness, ataxia, nystagmus, diplopia, hyponatraemia Rash None known Fewer than carbamazepine, but equally problematic for OCP
Phenobarbital Partial, secondary GTCS 60-180 1 50-150 Drowsiness, ataxia, nystagmus, diplopia Rashes, depression (adults), excitement (children), megaloblastic anaemia, SLE Folate deficiency, osteomalacia, neuropathy Other AEDs, anticoagulants, calcium channel blockers, digoxin, steroids, OCP, theophylline, levothyroxine sodium (thyroxine sodium), antidepressants, antimalarials
Phenytoin Partial, secondary GTCS 150-350 1 40-80 Drowsiness, ataxia, nystagmus, diplopia, tremor, dystonia, asterixis Rashes, blood dyscrasias, liver damage, SLE Gum hypertrophy, facial dysmorphism, hirsutism, folate deficiency, osteomalacia, neuropathy Other AEDs, warfarin, amiodarone and other anti-arrhythmics, antimalarials, steroids, OCP, cimetidine, oral hypoglycaemics, theophylline, thyroxine
Piracetam Myoclonus 7200-20 000 2-3 Not applicable Dizziness, insomnia, nausea, weight gain, drowsiness, tremor, agitation Rash None known None known
Primidone Partial, secondary GTCS 250-1000 1-2 50-150 Drowsiness, ataxia, nystagmus, diplopia Rashes, depression (adults), excitement (children), megaloblastic anaemia, SLE As for phenobarbital* As for phenobarbital*
Sodium valproate Primary and secondary GTCS, absences, myoclonus 400-2500 1-2 Not applicable Drowsiness, nausea, ataxia, nystagmus, diplopia, tremor Alopecia, rashes, blood dyscrasias, liver damage, pancreatitis Weight gain Other AEDs, anticoagulants, antimalarials, cimetidine
Tiagabine Partial, secondary GTCS 15-30 2-3 Not applicable Drowsiness, nausea, ataxia, tremor Headache, psychosis, depression Reduced peripheral vision Other AEDs
Topiramate Partial, secondary GTCS 200-600 1-2 Not applicable Drowsiness, nausea, ataxia, confusion Nephrolithiasis, depression, taste alteration, diarrhoea, weight loss Not yet known Other AEDs, OCP
Vigabatrin Partial, secondary GTCS, infantile spasms 2000-6000 1-2 Not applicable Drowsiness, nausea, ataxia, confusion Aggression, alopecia, skin rash, increase in seizures, retinal atrophy Reduced peripheral vision
* Primidone is converted in the liver to phenobarbital.
(GTCS = generalised tonic clonic seizures; AEDs = anti-epileptic drugs; OCP = oral contraceptive pill; SLE = systemic lupus erythematosus)
N.B. Doses of all drugs should be adjusted for patient age and body mass.
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Until good control of seizures has been established, work or recreation above ground level, with dangerous machinery or near open fires or water should be avoided. Patients should take only a shallow bath, and then when a relative is in the house, and should not lock the bathroom door. Cycling should be discouraged until at least 6 months' freedom from seizures has been achieved. Recreations requiring prolonged proximity to water (e.g. swimming, fishing or boating) should always be in the company of someone who is aware of the chance of a seizure occurring and could rescue the patient if necessary. Any activity where loss of awareness might be very dangerous (e.g. mountaineering) should be discouraged. In the UK and many other countries, legal restrictions regarding vehicle driving apply to patients with epilepsy, defined as more than one seizure over the age of 5 years (see Box 22.17). The patient should inform the licensing authorities about the onset of seizures. It is also wise for patients to notify their motor insurance company. Certain occupations, such as airline pilot, are not open to anyone who has ever had an epileptic seizure; further information is often available from epilepsy support organisations.
Anticonvulsant drug therapy
EBM
EPILEPSY-use of anti-epileptic drugs (AEDs) after a single seizure
'After a single seizure there is a 40% risk of subsequent seizures. The use of AEDs after a single seizure reduces the frequency of second seizures by half over 2 years but does not alter the long-term prognosis.'
Berg AT, Shinnar S. The risk of seizure recurrence following a first unprovoked seizure: a quantitative review. Neurology 1991; 41:965-972.
Musicco M, Beghi E, Solari A, Viani F, for the FIRST group. Treatment of first tonic clonic seizure does not improve the prognosis of epilepsy. Neurology 1997; 49:991-998.
Further information: www.clinicalevidence.org
22.19 GUIDELINES FOR ANTICONVULSANT THERAPY
Start with one first-line drug (see Box 22.20)
Start with low dose, gradually increase to effective control of seizures or until side-effects (drug levels occasionally helpful)
Check compliance (use minimum division of doses)
If first drug fails (seizures continue or side-effects), start second-line drug whilst gradually withdrawing first
Try three agents singly before using combinations (beware interactions)
Do not use more than two drugs in combination at any one time
If above fails, consider whether occult structural or metabolic lesion is present and whether seizures are truly epileptic
Drug treatment should be considered after more than one seizure has occurred and the patient agrees that seizure control is worth while (see EBM panel). Quite a range of anti-epilepsy drugs (AEDs) are available (see Box 22.18). The mode of action is either to increase inhibitory neurotransmission in the brain or to alter neuronal sodium channels in such a way as to prevent abnormally rapid transmission of impulses. Of patients whose epilepsy is controllable, only a single drug is necessary in 80%, providing the choice of agent is appropriate and the dosage correct. The combination of more than two drugs is seldom necessary. Dose regimens should be kept as simple as possible to promote compliance. Some useful guidelines are listed in Box 22.19.
EBM
EPILEPSY-relative efficacy of the main
AEDs in generalised tonic clonic seizures
'RCTs comparing the main AEDs as monotherapy for generalised tonic clonic seizures failed to demonstrate any difference in efficacy between different AEDs. There were differences in side-effects observed with different drugs.'
Heller AJ, Chesterman P, Crawford P, et al. Phenobarbitone, phenytoin, or sodium valproate for newly diagnosed epilepsy: a randomized comparative monotherapy trial. J Neurol Neurosurg Psychiatry 1995; 8:44-50.
Richens A, Davidson DL, Cartlidge NE, Easter DJ. A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy: adult EPITEG collaborative group. J Neurol Neurosurg Psychiatry 1994; 57:682-687.
Further information: www.clinicalevidence.org
22.20 GUIDELINES FOR CHOICE OF AED
Epilepsy type First-line Second-line Third-line
Partial and/or secondary GTCS Carbamazepine Lamotrigine
Sodium
valproate
Topiramate
Tiagabine
Gabapentin Clobazam
Phenytoin
Primidone
Phenobarbital
Oxcarbazepine
Levetiracetam
Vigabatrin
Acetazolamide
Primary GTCS Sodium valproate Lamotrigine
Topiramate
Carbamazepine Phenytoin
Gabapentin
Primidone
Phenobarbital
Tiagabine
Acetazolamide
Absence Ethosuximide Sodium
valproate Lamotrigine
Clonazepam
Acetazolamide
Myoclonic Sodium valproate Clonazepam Piracetam
Lamotrigine
Phenobarbital
N.B. Preferably one and no more than two drugs should be used at one time.
Choice of drug. With the exception of absence attacks and juvenile myoclonic epilepsy, there is no hard evidence indicating that one drug is superior to another in the treatment of epilepsy (see EBM panel). In general, the first line of treatment should be one of the established first-line drugs (see Box 22.20), with the more recently introduced drugs as second choice. Phenytoin and carbamazepine are not ideal agents for a young woman wishing to use oral contraception, because the drugs induce liver enzymes. Carbamazepine, lamotrigine and sodium valproate are preferable to phenytoin as first-line drugs because of the side-effect profile of the latter and its complicated pharmacokinetics.
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Anticonvulsant drug blood levels. With some AEDs, such as phenytoin and carbamazepine, occasional measurement of the blood level can be a guide to whether the patient is on a useful dose and is complying with the medication, but blood levels need to be interpreted intelligently. With other AEDs, such as sodium valproate, there is no relationship between drug levels and anticonvulsant efficacy. Repeated measurement of plasma levels of AEDs is not generally useful since the dose used in any individual patient will be determined by the efficacy of seizure control and the development of side-effects, whatever the plasma level happens to be. Plasma level monitoring is especially useful in dealing with suspected toxicity (particularly if more than one drug is being taken), dealing with the effects of pregnancy, or in suspected non-compliance.
Prognosis
Overall, generalised seizures are more readily controlled than partial seizures. The presence of a structural lesion makes complete control of the epilepsy less likely. The overall prognosis for epilepsy is shown in Box 22.21.
22.21 EPILEPSY: OUTCOME AFTER 20 YEARS
50% seizure-free, without drugs, for last 5 years
20% seizure-free for last 5 years but continue to take medication
30% seizures continue in spite of anti-epileptic therapy
Withdrawal of anticonvulsant therapy
EBM
EPILEPSY-withdrawal of AEDs
'A large RCT showed that withdrawal of AEDs from those in remission from epilepsy was associated with twice the likelihood of a relapse after 2 years compared with continuation of treatment. The likelihood of relapse was greater in those under 16 years, those with tonic clonic seizures, those with myoclonus, those treated with more than one AED, those who had had seizures after starting AEDs and those with any EEG abnormality.'
Medical Research Council Antiepileptic Drug Withdrawal Study Group. Prognostic index for recurrence of seizures after remission of epilepsy. BMJ 1993; 306:1374-1378.
Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomised study of antiepileptic drug withdrawal in patients in remission. Lancet 1991; 337:1175-1180.
Further information: www.clinicalevidence.org
After complete control of seizures for 2-4 years, withdrawal of medication may be considered. Childhood-onset epilepsy, particularly classical absence seizures, carries the best prognosis for successful drug withdrawal. Other primary generalised epilepsies, such as juvenile myoclonic epilepsy, have a marked liability to recur after AED withdrawal. Seizures that begin in adult life, particularly those with partial features, are also likely to recur, especially if there is an identified structural lesion. Overall, the recurrence rate of seizures after drug withdrawal is about 40% (see EBM panel). Some adult patients tend to opt for continuation of therapy because they feel that the threat of further attacks (especially regarding driving) outweighs the complications of continuing with medication. The EEG is a poor predictor of seizure recurrence but if the record is still very abnormal, drug withdrawal is unwise. Withdrawal should be undertaken slowly, reducing the drug dose gradually over 6-12 months. In the UK patients must desist from driving whilst withdrawing from their anti-epileptic medication and not drive for 6 months after full withdrawal of the drugs.
Status epilepticus
Status epilepticus exists when a series of seizures occurs without the patient regaining awareness between attacks. Most commonly, this refers to recurrent tonic clonic seizures (major status) and is a life-threatening medical emergency. Partial motor status is obvious clinically, but complex partial status and absence status may be difficult to diagnose, because the patient may merely present in a dazed, confused state. Status is never the presenting feature of idiopathic epilepsy but may be precipitated by abrupt withdrawal of anticonvulsant drugs, the presence of a major structural lesion or acute metabolic disturbance, and tends to be more common with frontal epileptic foci. Management is summarised in Box 22.22. It should be remembered that psychogenic or non-epileptic attacks commonly masquerade as 'status epilepticus', so electrophysiological confirmation of the seizures should be obtained as early as possible.
22.22 MANAGEMENT OF STATUS EPILEPTICUS
General
Immediate care (see Box 22.16, p. 1127)
Secure intravenous access
Draw blood for glucose and electrolytes etc. and save some for future analysis (drugs etc.)
Give diazepam 10 mg intravenously (or rectally)-repeat once only after 15 mins; or lorazepam 4 mg intravenously
Transfer to intensive care area, monitoring neurological condition, blood pressure, respiration and blood gases
Pharmacological
If seizures continue after 30 mins
Intravenous infusion (with cardiac monitoring) with one of:
Phenytoin: i.v. infusion of 15 mg/kg at 50 mg/min
Fosphenytoin: i.v. infusion of 15 mg/kg at 100 mg/min
Phenobarbital: i.v. infusion of 10 mg/kg at 100 mg/min
If seizures still continue after 30-60 mins
Start treatment for refractory status with intubation and ventilation, and general anaesthesia using propofol or thiopental
Once status controlled
Commence longer-term anticonvulsant medication with one of:
Sodium valproate 10 mg/kg i.v. over 3-5 mins, then 800-2000 mg/day
Phenytoin: give loading dose (if not already used as above) of 15 mg/kg, infuse at < 50 mg/min, then 300 mg/day Carbamazepine 400 mg by nasogastric tube, then 400-1200 mg/day
Other
Investigate cause
Integration link: Hippocampal damage and anterograde amnesia - case study
Taken from Medical Neuroscience
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Epilepsy, pregnancy and oral contraception
Hepatic enzyme induction caused by carbamazepine, phenytoin, topiramate and barbiturates accelerates metabolism of oestrogen, causing breakthrough bleeding and contraceptive failure. The safest policy is to use an alternative contraceptive method, but it is sometimes possible to overcome the problem by giving a higher oestrogen dose preparation. Sodium valproate has little interaction with oral contraception.
Epilepsy may worsen during pregnancy, particularly during the third trimester when plasma anticonvulsant levels tend to fall. Monitoring of blood levels during pregnancy may therefore be advisable. Almost all the major anticonvulsant drugs have been associated with an increased incidence of fetal congenital abnormalities (e.g. cleft lip, spina bifida and cardiac defects), but this has not yet been demonstrated for lamotrigine or gabapentin. The risk of fetal abnormality, which is greatest if the exposure is in the first trimester, rises from the background risk of 1-3% to about 7% with one anti-epileptic drug and to about 15% if there are two or more drugs. Folic acid (5 mg daily) taken 2 months before conception may reduce the risk of some fetal abnormalities. Occasionally, in a well-controlled patient, anticonvulsants can be withdrawn before conception, but if major seizures have occurred in the preceding year this is unwise as the risk to the fetus from uncontrolled maternal major seizures is probably greater than the teratogenic effects. Partial seizures probably carry little risk to the fetus.
Integration link: Drug use in pregnancy
Taken from Pharmacology 5e
The incidence of haemorrhagic disease of the newborn due to vitamin K deficiency may be increased by maternal use of hepatic enzyme-inducing anticonvulsants. Therefore maternal vitamin K supplements (20 mg orally per day) in the last month of pregnancy and intramuscular vitamin K (1 mg) at birth for the infant are widely advised.
Non-epileptic attack disorder ('psychogenic attacks', 'pseudo-seizures')
Patients may present with attacks that superficially resemble epileptic seizures but which are caused by psychological phenomena and not associated with abnormal epileptic discharge in the brain. Such patients may even present in apparent status epilepticus. People with epilepsy may have non-epileptic attacks as well, and this diagnosis should be considered if a patient fails to respond to anti-epileptic therapy. Non-epileptic attacks may be quite difficult to distinguish from truly epileptic attacks. In the history, some clues pointing towards non-epileptic attacks include elaborate arching of the back in an attack, pelvic thrusting and/or wild flailing of limbs. Cyanosis and severe biting of the tongue are rare in non-epileptic attacks, but urinary incontinence can occur. The distinction between epileptic attacks originating in the frontal lobes and non-epileptic attacks may be especially difficult, and may require videotelemetry with prolonged EEG recordings. Non-epileptic attacks are three times more common in women than in men and have been associated with a history of sexual abuse in childhood. They are not necessarily associated with formal psychiatric illness. Treatment is often difficult and usually requires psychotherapy and/or counselling rather than drug therapy (see p. 256).
ISSUES IN OLDER PEOPLE
EPILEPSY
Late-onset epilepsy is very common and the annual incidence in those over 60 years is rising.
The features that usually differentiate fits from faints may be less definitive in older than in younger patients.
Complex partial status epilepticus should be considered as a cause of confusion in the frail older patient.
Cerebrovascular disease is the most commonly identified cause of epilepsy in people over the age of 50 years and accounts for 30-50% of cases. A seizure may occur with an overt stroke or with otherwise occult vascular disease (e.g. identified on CT). Such patients should receive aspirin and appropriate cardiovascular risk factor reduction.
Anti-epileptic drug regimens should be as simple as possible and care should be taken to avoid potential interactions with other drugs being prescribed.
Carbamazepine-induced hyponatraemia increases significantly with age and this is particularly important in patients on diuretics or who have heart failure.
Late-onset epilepsy is associated with an increased relapse rate so the withdrawal of anticonvulsant therapy should not be attempted in older patients in whom it was commenced appropriately.
A DIAGNOSTIC APPROACH TO THE PATIENT WITH TRANSIENT AMNESIA
Loss of memory for a period of time may be due to a transient toxic confusional state, a psychological fugue state, the post-ictal period after seizure or the syndrome known as transient global amnesia. These are usually distinguished on the basis of the history. A period of amnesia often follows either a complex partial or generalised seizure, and this may cause diagnostic confusion if the seizure was not witnessed-for example, if it occurred in sleep.
TRANSIENT GLOBAL AMNESIA
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This is a syndrome affecting predominantly middle-aged patients in which there is an abrupt, discrete and reversible loss of short-term memory function for a period of some hours. During this time patients know who they are and can perform motor acts normally, but act in a bemused way, repeatedly asking the same questions. During the attack there is retrograde amnesia for the events of the past few weeks. After 4-6 hours memory functions and behaviour return to normal but the patient is left with a period of time for which he or she has complete amnesia. There are none of the phenomena associated with seizures and, unlike epileptic amnesia, transient global amnesia tends not to recur. There are no associated cerebrovascular risk factors, making a vascular aetiology unlikely. Transient global amnesia is thought to be due to a benign process similar to that causing a migraine aura, occurring in the hippocampus. The patient has no physical signs and further investigation may not be needed if epilepsy can be excluded.
SLEEP DISORDERS
Disturbances of sleep are common. Apart from insomnia (see p. 267), patients may complain of excessive day-time sleepiness, disturbed behaviour during night-time sleep, the parasomnias (sleep walking and talking, or night terrors) or disturbing subjective experiences during sleep and/or its onset (nightmares, hypnagogic hallucinations, sleep paralysis). A careful history will allow certain patterns of sleep disturbance to be identified.
Normal sleep is controlled by the reticular activating system in the upper brain stem and diencephalon. During overnight sleep, a series of repeated cycles of EEG patterns can be recorded. As drowsiness occurs, alpha rhythm disappears and the EEG gradually becomes dominated by deepening slow-wave activity. After 60-80 minutes this slow-wave pattern is replaced by a short spell of low-amplitude EEG background on which are superimposed rapid eye movements (REM). After a few minutes of REM sleep, another slow-wave spell starts and the cycle repeats several times throughout the night. The REM periods tend to become longer as the sleep period progresses. Dreaming takes place during REM sleep, which is accompanied by muscle relaxation, penile erection and loss of tendon reflexes. REM sleep seems to be the most important part of the sleep cycle for refreshing cognitive processes. Deprivation of REM sleep causes tiredness, irritability and impaired judgement.
PARASOMNIAS
Automatic behaviour that is not recalled may take place during light sleep. Sleep talking and sleep walking are innocuous and common in normal children. Sleep walking is uncommon in adults and has no pathological significance. Nightmares are frightening dreams from which the sufferer wakes in a state of fear or agitation. Most normal people have experienced such phenomena and they are not of any significance in terms of organic disease.
Night terrors occur as sudden arousals from deep slow-wave sleep. They are more common in children but may affect adults. The sufferer wakes in a state of agitation, screaming and fearful. Occasionally, violent behaviour occurs. The agitation may last many minutes. Such events may be confused with nocturnal seizures, particularly those arising from the frontal lobe, or their post-ictal effects.
DAY-TIME SOMNOLENCE
Excessive sleepiness in the day is most commonly due to inadequate night-time sleep related to fatigue and poor sleep hygiene, including the excessive use of caffeine and/or alcohol in the evening. Night-time sleep may also be disturbed by sleep apnoea (see p. 504), periodic limb movements and the restless leg syndrome. Somnolence due to disturbed night-time sleep particularly occurs after meals and during dull monotonous activities, such as long car journeys. Such causes of day-time sleepiness need to be distinguished from narcolepsy.
NARCOLEPSY
This disorder has a prevalence of about 1 in 4000 and is associated with HLA (human leucocyte antigen) DR-1501 and DQB1-0602 in 85% of cases. There is a familial tendency suggesting an autosomal dominant inheritance with low penetrance. Recurrent bouts of irresistible sleep are experienced, during which the EEG often shows direct entry into REM sleep. Sufferers tend to fall asleep when eating or talking, not just when under-stimulated. The periods of sleep are usually short and the person can be woken relatively easily. He or she usually feels refreshed after waking. In addition, patients with narcolepsy will report at least one other of the 'narcolepsy tetrad' (see Box 22.23). These four symptoms may occur together or in combinations in the same patient; most often, sleep attacks and cataplexy occur together.
22.23 THE NARCOLEPSY TETRAD
Sleep attacks
Brief, frequent and unlike normal somnolence
Cataplexy
Sudden loss of muscle tone set off by surprise, laughter, strong emotion etc.
Hypnagogic hallucinations
Frightening hallucinations experienced during sleep onset or waking (can occur in normal people)
Sleep paralysis
Brief paralysis on waking (can occur in normal people)
Narcoleptic attacks can be treated with CNS stimulants such as dexamfetamine (5-10 mg 8-hourly) or methylphenidate (10-60 mg per day) but fewer side-effects occur with modafinil (200-400 mg per day). Cataplexy responds to clomipramine (25-50 mg 8-hourly) or fluoxetine (20 mg per day).
OTHER DISORDERS OF SLEEP
Restless leg syndrome
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This is a common syndrome, also known as Ekbom's syndrome, affecting up to 2% of the population. Unpleasant sensations in the legs that are ameliorated by moving the legs occur when the patient is tired in the evenings and at the onset of sleep. This condition has a strong familial tendency and can present with day-time somnolence due to disturbed night-time sleep. It needs to be distinguished from the day-time sense of restlessness of the limbs known as akathisia that is a side-effect of major tranquillisers, and the related condition of periodic limb movements during sleep. Restless legs can be symptomatic of an underlying peripheral neuropathy or general medical condition (for example, uraemia).
Treatment is with clonazepam (0.5-2.0 mg) or with small doses of levodopa (100-200 mg) at night.
Periodic limb movements
In this syndrome sleep is disturbed by repetitive jerky flexion movements of the limbs which occur in the early stages of sleep. The history of abnormal limb movements during sleep may need to be obtained from the patient's bed partner, since the patient may not be aware of the arousals that are occurring as a result of the movements, even though they may be sufficient to cause day-time somnolence. Treatment may be effected with small doses of levodopa (100-200 mg at night) or a dopaminergic agent (see p. 1176).
DISORDERS OF MOVEMENT
Lesions in various parts of the motor system produce distinctive patterns of motor deficit. These can be in the form of the negative symptoms of weakness, lack of coordination, lack of stability and stiffness, or positive symptoms such as tremor, dystonia, chorea, athetosis, hemiballismus, tics and myoclonus. When the lower limbs are affected, characteristic patterns of gait disorder may result.
THE MOTOR SYSTEM
A programme of movement formulated by the pre-motor cortex is converted into a series of muscle movements in the motor cortex and then transmitted to the spinal cord in the pyramidal tract (see Fig. 22.12). This passes through the internal capsule and the ventral brain stem before decussating in the medulla to enter the lateral columns of the spinal cord. The pyramidal tract 'upper motor neurons' end by synapsing with the anterior horn cells of the spinal cord grey matter, which form the 'lower motor neurons'.
Movement of a body part necessitates changes in posture and alteration in the tone of many muscles, some quite distant from the part being moved. The motor system consists of a hierarchy of control mechanisms that maintain body posture and baseline muscle tone upon which a specific movement is superimposed. The lowest order of this hierarchy comprises the mechanisms housed in the grey matter of the spinal cord which control the muscle tone response to stretch and the reflex withdrawal response to noxious stimuli. The afferent side of the stretch reflex consists of the muscle spindles that detect lengthening of the muscle and initiate a monosynaptic reflex leading to muscle contraction. The predominantly inhibitory descending input from the brain stem and cerebral hemispheres modulates the sensitivity of the stretch reflex.
Polysynaptic connections in the spinal cord grey matter control more complex reflex actions of flexion and extension of the limbs which form the basic building blocks of coordinated actions, but which require control from above to function usefully. Above the spinal cord, circuits between the basal ganglia and the motor cortex constitute the extrapyramidal system which controls background muscle tone and body posture, and gates the initiation of movement (see Figs 22.12 and 22.13).
Figure 22.12 The motor system. Neurons from the motor cortex descend as the pyramidal tract in the internal capsule and cerebral peduncle to the ventral brain stem, where most cross low in the medulla (A). In the spinal cord the upper motor neurons form the cortico-spinal tract in the lateral column before synapsing with the lower motor neurons in the anterior horns. The activity in the motor cortex is modulated by influences from the basal ganglia and cerebellum (B). Pathways descending from these structures control posture and balance (see also Fig. 22.13).
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Figure 22.13 Hierarchies of motor control. In addition to direct descending pathways from the cerebral motor cortex, motor neurons in the anterior horn are influenced by descending pathways controlling balance and posture as well as monosynaptic and polysynaptic spinal reflex pathways.
Accurately targeted and coordinated movements require the functioning of the cerebellum, which acts as an on-line guidance computer to fine-tune goal-directed movements initiated by the motor cortex. In addition, the cerebellum, through its reciprocal connections with the thalamus and cortex, participates in the planning and learning of skilled movements.
Pathophysiology
Lower motor neuron lesions
Groups of muscle fibres innervated by a single anterior horn cell (lower motor neuron) form a 'motor unit'. Loss of function of lower motor neurons will cause the loss of contraction in their units' muscle fibres and the muscle will be weak and flaccid. Denervated muscle fibres atrophy in time, causing wasting of the muscle, and depolarise spontaneously, causing fibrillations which, except in the tongue, are only perceptible on an EMG. Re-innervation from neighbouring intact motor neurons may occur but the neuromuscular junctions of the enlarged motor units are unstable and depolarise spontaneously, causing fasciculations (twitches which are visible to the naked eye). Fasciculations therefore imply chronic partial denervation.
Upper motor neuron (pyramidal) lesions
When the spinal cord is disconnected from the modulating influence of the higher motor hierarchies, the anterior horn motor neurons are under the uninhibited influence of the spinal reflex mechanisms. Their innervated muscles will have an exaggerated response to stretch. The limbs show reflex patterns of movement, like flexion withdrawal to noxious stimuli and spasms of extension. An upper motor neuron lesion therefore manifests clinically with brisk tendon stretch reflexes, 'spastic' increase in tone greater in the extensors of the lower limbs and the flexors of the upper limbs, and extensor plantar responses. Spastic increase in tone can be seen on clinical examination to vary with both the degree and speed of stretch; this is the 'clasp-knife' phenomenon. Spasticity takes some time to develop and may not be present for weeks after the onset of an upper motor neuron lesion. Spasticity will be exacerbated by increased sensory input into the reflex arc, as may be caused by a bed sore or urinary tract infection in a patient with a spinal cord lesion. The weakness found in upper motor neuron lesions is more pronounced in the extensors of the upper limbs and the flexors of the lower limbs.
Extrapyramidal lesions
Lesions of the extrapyramidal system produce an increase in tone, which is not an exaggerated response to stretch but is continuous throughout the range of movement (rigidity). Involuntary movements are also a feature of extrapyramidal lesions (see below), and a tremor combined with rigidity produces typical 'cogwheel' rigidity. Rapid movements are slowed and clumsy (bradykinesia). Extrapyramidal lesions also cause postural instability, precipitating falls.
Cerebellar lesions
A lesion in a cerebellar hemisphere causes lack of coordination on the same side of the body. The initial part of movement is normal but as the target is approached the accuracy of the movement deteriorates, producing an 'intention tremor'. The distances of targets are misjudged (dysmetria), resulting in 'past-pointing'. The ability to produce rapid, accurate, regularly alternating movements is impaired, which is known as 'dysdiadochokinesis'.
The central vermis of the cerebellum is concerned with the coordination of gait and posture. Disorders of this part therefore produce a characteristic ataxic gait (see below).
'MEDICALLY UNEXPLAINED' ('PSYCHOGENIC'/'NON-ORGANIC') WEAKNESS
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Patients may present with limb weakness which is not due to organic (structural, physiological or biochemical) disease but which is caused by psychological phenomena: for example, a 'conversion' disorder (see p. 265). In this case the weakness does not conform to known pathophysiological patterns (e.g. reflexes are usually normal) and the deficit cannot be attributed to a lesion in a specific anatomical site in the nervous system. During formal testing of power, a patient's strength may appear to 'give way', yet demonstrate bursts of full power at other times. Alternatively, if a 'weak' limb is held up and then suddenly allowed to drop, the limb may be momentarily held up, something which would not happen in organic weakness. Note that apparent 'non-organic' weakness may occur as elaboration upon a 'genuine' organic weakness, and physical signs such as 'give-way weakness' therefore do not necessarily imply absence of pathology. Great care should be exercised in making the diagnosis of a functional disorder and all unusual manifestations of nervous system disease should be considered before such a diagnosis is made.
A DIAGNOSTIC APPROACH TO THE PATIENT WITH LIMB WEAKNESS
Establishing the diagnosis in a patient with weakness requires the application of basic anatomy, physiology and some pathology to the interpretation of the history and clinical findings (see Box 22.24 and Fig. 22.14). Points to consider are shown in Box 22.25.
22.24 PHYSICAL SIGNS IN DIFFERENT TYPES OF MOTOR DEFICIT
Clinical sign Upper motor (pyramidal) lesion Lower motor lesion Extrapyramidal lesion Cerebellar lesion
Power Weak
Upper limbs: extensors weaker
Lower limbs: flexors weaker Weak No weakness No weakness
Wasting None Yes, after interval None None
Fasciculation None Yes, after interval None None
Tone Spastic increase (after interval) Flaccid from onset Rigidity (cogwheel) Normal/reduced
Reflexes Increased Reduced/absent Normal Normal
Plantar response Extensor Flexor Flexor Flexor
Coordination Reduced by weakness Reduced by weakness Normal (but slowed) Impaired
Figure 22.14 Patterns of motor loss according to the anatomical site of the lesion.
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22.25 ASSESSMENT OF WEAKNESS
Distribution
A few muscles
A limb
Both lower limbs (paraparesis)
Both limbs on one side (hemiparesis)
Type of weakness
Upper motor neuron lesion
Lower motor neuron lesion
Evolution of the weakness
Sudden and improving
Gradually worsening over days or weeks
Evolving over months or years
Weakness in only some muscles in a limb suggests a problem in the peripheral nerve(s) or motor root(s). Weakness of the whole of one limb may be due to problems in the brachial or lumbosacral plexuses, or to a central lesion. Weakness in both lower limbs (paraparesis) or all four limbs (tetraparesis) suggests either a spinal cord lesion or a diffuse peripheral nerve problem such as Guillain-Barré syndrome. In such cases the condition of the reflexes is the most discriminating sign. The reflexes are absent in the Guillain-Barré syndrome (or other lower motor nerve lesions) and brisk in spinal cord (upper motor neuron) lesions. The paraparesis or tetraparesis of spinal cord lesions may be associated with a specific pattern of sensory loss (see p. 1140) which gives a clue to the site of the lesion in the spinal cord.
Patients with a bradykinetic limb often complain of weakness. Therefore, if there are no reflex, wasting or sensory changes when a patient is complaining of weakness in a limb, extrapyramidal signs of rigidity (cogwheel or leadpipe) and bradykinesia should be sought. Patients with Parkinson's disease usually present with symptoms in one limb that may be described as weak and clumsy, especially for fine manipulations. Often the typical rest tremor is a clue to the diagnosis.
Weakness down one side of the body (hemiparesis) is almost always due to a cerebral hemisphere lesion, although it can be caused by spinal cord or brain-stem lesions. The lesion is of upper motor neuron type, and the site and often the size of the lesion can be deduced by the concurrence of other signs and symptoms, such as higher cerebral function abnormalities or sensory change.
The evolution of a motor deficit over time suggests the likely underlying pathology (see Box 22.26).
GAIT DISORDERS
22.26 LIMB WEAKNESS-ASSESSING THE CAUSE
Vascular lesions
Sudden onset (over minutes) followed by a stable period and gradual recovery
Neoplastic lesions
Deficit is gradual in onset and progressive over weeks or months
There may be signs caused by the mass effect of the lesion
Inflammatory lesions
May be fairly acute in onset (over a few days), persist for a time and then improve (e.g. in multiple sclerosis)
Degenerative disorders
May evolve over months or years (e.g. motor neuron disease or cervical spondylotic myelopathy)
As well as being an important element of assessing a patient's disability, seeing a patient walk can be very revealing for neurological diagnosis. Patterns of weakness, loss of coordination and proprioceptive sensory loss produce a range of abnormal neurological gaits. Neurogenic gait disorders need to be distinguished from those due to skeletal abnormalities, usually characterised by pain producing an antalgic gait, or limp. Gaits that do not fit either pattern may be due to 'functional' or non-organic disorders and are usually incompatible with any anatomical or physiological deficit.
Pyramidal gait
Upper motor neuron (pyramidal) lesions cause a gait in which the upper limb is held in flexion and the lower limb kept relatively extended. The pyramidal tract lesion slows the normally rapid ankle dorsiflexion needed to keep the toes from striking the ground as the leg swings through. In an attempt to overcome this, the leg is swung out at the hip (circumduction), but the affected foot still scuffs along the ground at the toes. The shoe on the affected side may be worn at the toes as evidence of this type of gait. In a hemiplegia the asymmetry between the affected and normal sides is obvious in walking. In a paraparesis both lower limbs move slowly, swung from the hips and dragged stiffly on the ground in extension, an effect that can often be heard as well as seen.
Foot drop
In normal walking, toe strike follows heel strike during the gait cycle. Weakness of ankle dorsiflexion disrupts this pattern. The result is a less controlled descent of the foot making a slapping noise. If the distal weakness is more severe, the foot will have to be lifted higher at the knee to allow room for the inadequately dorsiflexed foot to swing through, producing a high stepping gait.
Waddling gait of proximal muscle weakness
During walking, alternate placement of the body's weight through each leg requires careful control of the hips by the gluteal muscles. In proximal muscle weakness, usually caused by muscle disease, the hips are not properly fixed by these muscles and trunk movements are exaggerated, producing a rolling or waddling gait.
Cerebellar ataxia
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Patients with lesions of the central parts of the cerebellum (the vermis) walk with a characteristic broad-based gait, 'like a drunken sailor' (cerebellar function is particularly sensitive to alcohol). Patients with acute vestibular disturbances walk in a similar broad-based fashion, though the accompanying vertigo distinguishes them from those with cerebellar lesions. Less severe degrees of cerebellar ataxia can be detected by asking the patient to walk heel to toe; patients with vermis lesions are unable to do this.
Gait apraxia
In an apraxic gait there is normal power in the legs and no abnormal cerebellar signs or proprioception loss, yet the patient cannot formulate the motor act of walking. This is a higher cerebral dysfunction in which the feet appear stuck to the floor and the patient cannot walk, even though movement is normal on the examination couch. Gait apraxia occurs in bilateral hemisphere disease such as normal pressure hydrocephalus and diffuse frontal lobe disease.
Marche à petits pas
Patients with multiple small-vessel cerebrovascular disease walk with small slow steps with instability. This looks different from the festinant gait of Parkinson's disease (see below) in that it does not have the variable pace and freezing. There are usually signs of bilateral upper motor neuron disease (bilateral extensor plantar responses and brisk jaw jerk).
Sensory ataxia
Loss of joint position sense makes walking unreliable, especially in poor light. The feet tend to be placed on the ground with greater emphasis, presumably in an attempt to increase what proprioceptive input is available. This results in a 'stamping' gait which is often combined with foot drop when caused by a peripheral neuropathy, but can occur in disorders of the dorsal columns in the spinal cord.
Extrapyramidal gait
Patients with Parkinson's disease and other extrapyramidal diseases have difficulty initiating walking and difficulty controlling the pace of their gait. The patient may get stuck whilst trying to start walking or when walking through doorways ('freezing'), but once started may then have problems controlling the speed of walking and have trouble stopping. This produces the festinant gait: initial stuttering steps that quickly increase in frequency while decreasing in length.
INVOLUNTARY MOVEMENTS
Abnormal movements usually imply a disorder in the basal ganglia, in which there is disinhibition of the activity of intrinsic rhythm generators or a disorder of postural control. Some, like tremor, are commonplace. Others, like chorea, athetosis and dystonia, have become more common as a result of adverse effects from pharmacological treatment of Parkinson's disease and psychiatric disease.
Tremor
A tremor is a rhythmic oscillating movement of a limb or part of a limb, or of the head. Tremors are usefully divided into those occurring at rest and those seen only when a limb is in action. The other characteristic by which tremors can be classified is their frequency.
Rest tremor
This is pathognomonic of Parkinson's disease (see p. 1174). The tremor is characteristically 'pill-rolling' and usually presents asymmetrically. However, patients with Parkinson's disease may have an abnormal action tremor as well. Tremor of the head in the upright position ('titubation') is not a rest tremor since this is a postural tremor, disappearing when the head is supported.
Action tremor
This is more frequently seen than rest tremor and potential causes are more numerous (see Box 22.27). A physiological tremor (frequency between 8 and 12 Hz) can be identified in the limbs of normal subjects; exaggeration of this physiological tremor occurs in anxiety and other situations, listed in Box 22.28.
22.27 CAUSES OF TREMOR ON ACTION
Exaggerated physiological tremor (see Box 22.28)
Essential tremor (may be familial)
Parkinson's disease (rest tremor more usual)
Wilson's disease
Postural tremor
Multiple sclerosis
Other lesions in cerebellar outflow/red nucleus
Intention tremor
Cerebellar hemisphere disease
22.28 CAUSES OF EXAGGERATED PHYSIOLOGICAL TREMOR
Anxiety
Fatigue
Alcohol withdrawal
Endocrine
Thyrotoxicosis
Cushing's disease
Phaeochromocytoma
Hypoglycaemia
Drugs
ß-agonists (e.g. salbutamol)
Theophylline
Caffeine
Lithium
Dopamine agonists
Sodium valproate
Tricyclics
Phenothiazines
Amphetamines
Toxins
Mercury
Lead
Arsenic
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Essential tremor is distinct from a physiological tremor, although resembling it superficially. It is slower than a physiological action tremor and may become quite disabling. The condition is often familial and in some families the tremor is most obvious during certain specific actions such as writing; here there is an overlap with focal dystonias (see below). Characteristic of essential tremor is that alcohol suppresses it, sometimes to the extent that the patient becomes addicted. Centrally acting ß-adrenoceptor antagonists (ß-blockers) such as propranolol are often effective in treatment.
An 'intention tremor' is the characteristic oscillation at the end of a movement which occurs in cerebellar disease, due to the breakdown of feedback control of targeted movements. Asterixis, the 'flapping' tremor seen in metabolic disturbances (see Box 22.29), is the result of intermittent failure of the parietal mechanisms required to maintain a posture. Thus, when a patient is asked to hold out the arms with the hands extended at the wrists, this posture is periodically dropped, allowing the hands to drop transiently before the posture is taken up again. Occasionally, unilateral asterixis can be seen in an acute parietal vascular lesion.
22.29 CAUSES OF ASTERIXIS
Renal failure
Liver failure
Hypercapnia
Drug toxicity (e.g. phenytoin)
Acute focal parietal or thalamic lesions
A more dramatic action tremor occurs with lesions in the superior cerebellar peduncle (the site of the cerebellar outflow towards the red nucleus). This 'peduncular' or 'rubral' tremor is a violent, large-amplitude postural tremor that worsens as a target is approached. This is common in advanced multiple sclerosis and may be a source of considerable disability. Stereotactic thalamotomy can reduce the tremor, although the overall functional result is often disappointing.
Chorea, athetosis, ballism and dystonia
Non-rhythmic involuntary movements may be combinations of fragments of purposeful movements and abnormal postures. All of these abnormal movements represent disorders of the balance of activity in the complex basal ganglia circuitry. Jerky, small-amplitude, purposeless involuntary movements are termed 'chorea' (the Greek for 'dance'). In the limbs they resemble fidgety movements, and in the face, grimaces; they suggest disease in the caudate nucleus (as in Huntington's disease, see p. 1177) or excessive activity in the striatum due to dopaminergic drugs used to treat Parkinson's disease. There are a range of other causes (see Box 22.30). More dramatic ballistic movements of the limbs usually occur unilaterally (hemiballismus) in vascular lesions of the subthalamic structures. Slower writhing movements of the limbs are called athetosis. These are often combined with chorea (and have a similar list of causes) and are then termed 'choreo-athetoid' movements.
22.30 CAUSES OF CHOREA
Hereditary
Huntington's disease
Wilson's disease
Neuroacanthocytosis
Porphyria
Paroxysmal choreoathetosis
Cerebral birth injury (including kernicterus)
Cerebral trauma
Drugs
Levodopa
Dopamine agonists
Phenothiazines
Tricyclics
Oral contraceptive
Endocrine
Pregnancy
Oral contraceptive
Thyrotoxicosis
Hypoparathyroidism
Hypoglycaemia
Infective/inflammatory
Rheumatic fever (Sydenham's chorea)
Systemic lupus erythematosus
Henoch-Schönlein purpura
Creutzfeldt-Jakob disease
Vascular
Lacunar infarction
Arteriovenous malformation
The term 'dystonia' is used to describe the movement disorder in which a limb (or the head) involuntarily takes up an abnormal posture. This may be generalised in various diseases of the basal ganglia or may be focal or segmental, as in spasmodic torticollis when the head involuntarily turns to one side. Other segmental dystonias may cause abnormal disabling postures of a limb to be taken up during certain specific actions, such as in writer's cramp or numerous other occupational 'cramps'. These segmental dystonias can be treated by the administration of botulinum toxin to a few of the responsible muscles, which seems to overcome the abnormal distribution of muscle activity for a period of time.
Myoclonus
Myoclonus refers to brief, isolated, random, non-purposeful jerks of muscle groups in the limbs. Myoclonic jerks occur normally at the onset of sleep (hypnic jerks). Similarly, a myoclonic jerk is a component of the normal startle response which may be exaggerated in some rare (mostly genetic) disorders. Unlike the movement disorders discussed so far, myoclonus may occur in disorders of the cerebral cortex, when groups of pyramidal cells fire spontaneously. Such myoclonus occurs in some forms of epilepsy in which the jerks are fragments of seizure activity. Alternatively, myoclonus can arise from subcortical structures or, more rarely, from diseased segments of the spinal cord. Myoclonus, especially of cortical origin, often responds to clonazepam, sodium valproate or piracetam.
Tics
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Tics are repetitive semi-purposeful movements such as blinking, winking, grinning or screwing up of the eyes. They are distinguished from other involuntary movements by the ability of the patient to suppress their occurrence, at least for a short time. An isolated tic may be no more than a mild embarrassment, but may become frequent at certain times in childhood and then disappear. The uncommon syndrome of Gilles de la Tourette consists of a tendency to multiple tics and odd vocalisations, with obsessive behavioural abnormalities. The pathogenic basis is not understood, but there may be some response to major tranquillisers.
SENSORY DISTURBANCE
Sensory symptoms are very common but do not always denote nervous system disorder. For example, tingling in the fingers of both hands and around the mouth commonly suggests hyperventilation (see pp. 496-497) or, very rarely, hypocalcaemia (see p. 716). The accuracy of patients in describing sensory disturbances is very variable and skill is needed in sifting through the history to make anatomical and pathophysiological sense of the complaints. Damage to the afferent nervous pathways conveying sensations of touch and pain produces either the negative sensation of numbness or positive symptoms, such as paraesthesia and pain. When there is dysfunction of the cerebral mechanisms of somatic sensation there may be distortion of the patient's perception of the wholeness or actual presence of the relevant part of the body.
A DIAGNOSTIC APPROACH TO THE PATIENT WITH SENSORY SYMPTOMS
In the history, the most useful features are the anatomical distribution and mode of onset of numbness, paraesthesia or pain. Certain patterns of onset of sensory symptoms can be recognised. For example, in a migraine attack the aura may consist of a front of tingling paraesthesia followed by numbness which takes 20-30 minutes to spread over one half of the body, splitting the tongue. Sensory loss due to a vascular lesion, on the other hand, will occur over the whole territory of the lesion more or less instantaneously. The rare, unpleasant paraesthesia of sensory epilepsy 'shoots' down one side of the body in seconds. The numbness and paraesthesia of spinal cord lesions often ascend one or both lower limbs to a level on the trunk over hours or days. Sensory symptoms of tingling and numbness can be of 'functional' or non-organic origin as a manifestation of anxiety or as part of a conversion disorder (see p. 265). In these circumstances the pattern of sensory symptoms does not conform to known anatomical distribution or fit with any known pattern of sensory involvement in organic disease. As with weakness (see above), care should be taken to avoid misdiagnosing an unusual organic sensory impairment as a functional disorder.
Examination of the sensory system needs to be approached with care since it is easy to produce confusing false positive results because of the inescapably subjective nature of sensory testing. However, the distribution of sensory loss and associated deficits in motor and/or cranial nerve function may enable a diagnostically helpful pattern of sensory loss to be identified.
Patterns of sensory disturbance (see Fig. 22.15)
Peripheral nerve lesions
In peripheral nerve lesions the symptoms are usually of sensory loss and simple paraesthesia (pins and needles). Single peripheral nerve lesions will, as expected, cause disturbance in the sensory distribution of that nerve. In diffuse neuropathies the longest neurons are first affected, giving the characteristic 'glove and stocking' distribution. If the smaller nerve fibres are preferentially affected (e.g. in alcoholic neuropathy), temperature and pin-prick (pain) are lost, whilst modalities served by the larger sensory nerves (vibration and joint position) may be spared. On the other hand, the latter are particularly affected if the neuropathy is demyelinating in character (e.g. Guillain-Barré syndrome, see p. 1180).
Nerve root lesions
Pain is more often a feature of lesions of nerve roots, within the spine or of the limb plexuses. Pain is often felt in the muscles innervated by a root, i.e. the myotome rather than the dermatome. The site of nerve root lesions may be deduced from the dermatomal pattern of sensory loss, although this is often smaller than would be expected because of the overlap of sensory 'territories'.
Spinal cord lesions
Somatic sensory information from the limbs ascends the nervous system in two anatomically discrete systems, differential involvement of which is often of diagnostic assistance (see Fig. 22.16). Fibres from proprioceptive organs and those mediating well-localised touch (including vibration) enter the spinal cord at the posterior horn and pass without synapsing into the ipsilateral posterior columns. Fibres conveying pain and temperature sensory information synapse with second-order neurons which cross the midline in the spinal cord before ascending in the contralateral anterolateral spinothalamic tract to the brain stem.
Transverse lesions of the spinal cord produce loss of all modalities below that segmental level, although the level obtained clinically may vary by two or three segments. Very often at the top of the area of sensory loss there is a band of paraesthesia or hyperaesthesia. If the transverse lesion is vascular in origin (e.g. due to anterior spinal artery thrombosis), the posterior one-third of the spinal cord (and therefore the dorsal column modalities) may be spared.
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Figure 22.15 Patterns of sensory loss. A Generalised peripheral neuropathy. B Sensory roots. C Single dorsal column lesion (proprioception and some touch loss). D Transverse thoracic spinal cord lesion. E Unilateral cord lesion (Brown-Séquard): ipsilateral dorsal column (and motor) deficit and contralateral spinothalamic deficit. F Central cord lesion: 'cape' distribution of spinothalamic loss. G Mid-brain-stem lesion: ipsilateral facial sensory loss and contralateral loss on body below the vertex. H Hemisphere (thalamic) lesion: contralateral loss on one side of face and body.
Figure 22.16 The main somatic sensory pathways.
Lesions damaging one side of the spinal cord will produce sensory loss for spinothalamic modalities (pain and temperature) on the opposite side and for dorsal column modalities (joint position and vibration) on the same side as the lesion. This is the pattern seen in the Brown-Séquard syndrome (see p. 1188).
Lesions in the centre of the spinal cord (e.g. syringomyelia, see p. 1191) spare the dorsal columns but affect the spinothalamic fibres crossing the cord from both sides over the length of the lesion. The sensory loss is therefore dissociated (in terms of the modalities affected) and suspended (in the sense that segments above and below the lesion are spared), often with reflex loss if afferent fibres of the reflex arc within the cord are affected.
There may be a lesion in the dorsal column alone, particularly in multiple sclerosis. This produces a characteristic unpleasant tight feeling over the limb involved and loss of proprioception that may severely affect the function of the limb without any loss of pin-prick or temperature sensation.
Brain-stem lesions
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The second-order neurons of the dorsal column sensory system cross the midline in the upper medulla to ascend through the brain stem. Here they lie just medial to the (already crossed) spinothalamic pathway. Brain-stem lesions can therefore cause sensory loss affecting all modalities of the contralateral side of the body. Sensory loss on the face due to brain-stem lesions is dependent upon the anatomy of the trigeminal fibres within the brain stem. Fibres from the back of the face (near the ears) descend within the brain stem to the upper part of the spinal cord before synapsing, the second-order neurons crossing the midline and then ascending with the spinothalamic fibres. Fibres conveying sensation from progressively more forward areas of the face descend a shorter distance in the brain stem. Thus sensory loss in the face from low brain-stem lesions is in a 'balaclava helmet' distribution as the longer descending trigeminal fibres are affected.
Hemisphere lesions
Both the dorsal column and spinothalamic tracts end in the thalamus, relaying from there to the parietal cortex through the internal capsule. Lesions in the hemispheres can therefore affect all modalities of sensation. In the thalamus discrete lesions (as may occur in small lacunar strokes) can cause loss of sensation over the whole contralateral half of the body. Lesions in the sensory cortex have to be very small (and therefore affect only a restricted area of the body) to avoid affecting the motor tracts deeper in the hemispheres. With substantial lesions of the parietal cortex (as with large strokes) there is severe loss of proprioception and even conscious awareness of the existence of the affected limb(s). The resulting loss of function in the limb may be impossible to distinguish from paralysis.
Pain
Figure 22.17 The pain perception system.
Pain is a complex percept that is only partly related to activity in nociceptor neurons (see Fig. 22.17). In the posterior horn of the spinal cord the second-order neuron of the spinothalamic tract is subject to modulation by a number of influences in addition to its synapse with the fibres from nociceptors. Branches from the larger mechanoceptor fibres destined for the posterior column also synapse with the second-order spinothalamic neurons and with interneurons of the grey matter of the posterior horn. The nociceptor neurons release, in addition to excitatory transmitters, other neurotransmitters (such as substance P) which influence the excitability of the spinothalamic neurons. Neurons in the posterior horn are also subject to modulation by fibres descending from the peri-aqueductal grey matter of the mid-brain and raphe nuclei of the medulla. Neurons of this 'descending analgesia system' are activated by endogenous opiate (endorphin) peptides. The spinal cord's posterior horn is therefore much more than a way-station in the transmission of nociceptive sensory information; it is a complex organ for gating and modulating information of painful stimuli before this ascends in the spinothalamic tract. In the diencephalon the perception of pain is further influenced by the rich interconnections of the thalamus with the limbic system.
Neuropathic pain
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Pain is of two main types: nociceptive pain, arising from a pathological process in a body part, and neuropathic pain, caused by dysfunction of the pain perception apparatus itself. Neuropathic pain has distinctive features and is described as a very unpleasant persistent burning paraesthetic sensation. There is often increased sensitivity to touch, so that light brushing touches cause exquisite pain (hyperpathia). Painful stimuli appear to come from a larger area than that touched and spontaneous bursts of pain may occur. The perception of pain may be elicited by stimuli from other modalities such as loud sounds (allodynia) and is considerably affected by emotional influences. The most common syndromes of neuropathic pain are seen where there is partial damage to peripheral nerves ('causalgia'), to the trigeminal nerve (post-herpetic neuralgia) or to the thalamus. Treatment of these syndromes is very difficult. Drugs which modulate various parts of the nociceptive system, such as carbamazepine, tricyclics or phenothiazines, may help but usually only do so partially. Neurosurgical attempts to interrupt various pain pathways sometimes succeed but often increase the sensory deficit and may worsen the situation. Implantation of electrical stimulators has occasionally proved successful. For further information, see Chapter 6.
COMA AND BRAIN DEATH
COMA
22.31 CAUSES OF COMA
Metabolic disturbance
Drug overdose
Diabetes mellitus
Hypoglycaemia
Ketoacidosis
Hyperosmolar coma
Hyponatraemia
Uraemia
Hepatic failure
Respiratory failure
Hypothermia
Hypothyroidism
Trauma
Cerebral contusion
Extradural haematoma
Subdural haematoma
Cerebrovascular disease
Subarachnoid haemorrhage
Intracerebral haemorrhage
Brain-stem infarction/haemorrhage
Cerebral venous sinus thrombosis
Infections
Meningitis
Encephalitis
Cerebral abscess
General sepsis
Others
Epilepsy
Brain tumour
Thiamin deficiency
Persistent loss of consciousness or coma indicates disorder of the arousal mechanisms in the brain stem and diencephalon and indicates bilateral hemisphere or brain-stem disease. There are many causes of coma (see Box 22.31). The history of the mode of onset of coma and of any precipitating event is crucial to establishing the cause and this should be obtained from family or other witnesses. As with any medical emergency, the top priority is assessment and stabilisation of the vital functions. Neurological examination may reveal important findings, e.g. evidence of head injury, papilloedema, meningism or eye movement disorder. In the majority of cases, however, there are no focal neurological signs since drug overdose and metabolic disturbance are the most common causes of unexplained coma requiring hospital admission. Some patients will require intensive care unit (ICU) support.
Assessment of conscious level
This is an essential component of the neurological examination. Terms such as 'stuporose', 'semiconscious' and 'obtunded' are ill defined, and a clear description of the patient's level of arousal and response to stimuli is more helpful. Systematic assessment of the unconscious patient by the application of the Glasgow Coma Scale provides a grading of coma by using a numerical scale which allows serial comparison and may provide prognostic information, particularly in traumatic coma (see Box 22.32).
22.32 GLASGOW COMA SCALE
Eye-opening (E)
Spontaneous 4
To speech 3
To pain 2
Nil 1
Best motor response (M)
Obeys 6
Localises 5
Withdraws 4
Abnormal flexion 3
Extensor response 2
Nil 1
Verbal response (V)
Orientated 5
Confused conversation 4
Inappropriate words 3
Incomprehensible sounds 2
Nil 1
Coma score = E + M + V
Minimum 3
Maximum 15
BRAIN DEATH
The widespread availability of mechanical ventilators has resulted in the survival of patients with severe and irreversible brain damage but functioning cardiovascular systems. Diagnostic criteria for brain death have been established in order that those patients without functioning brains who have no chance of recovery may be identified and ventilation discontinued.
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22.33 DIAGNOSIS OF BRAIN DEATH
Preconditions for considering a diagnosis of brain death
The patient is deeply comatose
There must be no suspicion that coma is due to depressant drugs, e.g. narcotics, hypnotics, tranquillisers
Hypothermia has been excluded-rectal temperature must exceed 35°C
There is no profound abnormality of serum electrolytes, acid-base balance or blood glucose concentrations, and any metabolic or endocrine cause of coma has been excluded
The patient is maintained on a ventilator because spontaneous respiration had been inadequate or had ceased. Drugs, including neuromuscular blocking agents, must have been excluded as a cause of the respiratory failure
The diagnosis of the disorder leading to brain death has been firmly established. There must be no doubt that the patient is suffering from irremediable structural brain damage
Tests for confirming brain death
All brain-stem reflexes are absent
The pupils are fixed and unreactive to light
The corneal reflexes are absent
The vestibulo-ocular reflexes are absent-there is no eye movement following the injection of 20 ml of ice-cold water into each external auditory meatus in turn
There are no motor responses to adequate stimulation within the cranial nerve distribution
There is no gag reflex and no reflex response to a suction catheter in the trachea
No respiratory movement occurs when the patient is disconnected from the ventilator long enough to allow the carbon dioxide tension to rise above the threshold for stimulating respiration (PaCO2 must reach 6.7 kPa)
The diagnosis of brain death should be made by two experienced doctors, one of whom should be a consultant and the other a consultant or specialist registrar. The tests are usually repeated after an interval of 6-24 hours, depending on the clinical circumstances, before brain death is finally confirmed
The diagnosis of brain death depends on meeting a set of preconditions, all of which must coexist, and then applying a series of clinical tests (see Box 22.33), all of which must be fulfilled.
ISSUES IN OLDER PEOPLE
COMA AND BRAIN DEATH
Hypothermia is an easily missed cause of coma in the elderly.
An unconscious patient's temperature should always be taken with a low-reading thermometer. For more information, see page 331.
DISTURBANCE OF CORTICAL FUNCTION
Many areas of cerebral cortex have a specialised function (e.g. the primary motor areas, language areas etc.). Focal lesions of the cerebral hemispheres can therefore cause disturbance of these individual functions, e.g. aphasia. These are dealt with below. Alternatively, diffuse or multifocal damage affects many areas, causing more global disturbance of higher cerebral function. Depending on speed of onset, and whether consciousness is impaired, global disturbances are broadly divided into acute confusional states and dementias.
ACUTE CONFUSIONAL STATE
This is also known as delirium, and is seen much more commonly than dementia. Unlike dementia, there is a disturbance of arousal that accompanies the global impairment of mental function. This usually takes the form of drowsiness with disorientation, perceptual disturbances and muddled thinking. Patients typically fluctuate, confusion being worse at night, and there may be associated emotional disturbance (e.g. anxiety, irritability or depression) or psychomotor changes (e.g. agitation, restlessness or retardation).
There are many possible causes of acute confusion (see Box 22.34), including acute decompensation of a more chronic dementia.
Diagnosis
The diagnosis of an acute confusional state involves careful history-taking. Patients are usually disorientated, often in both time and place, and therefore their account may not be helpful. As with dementia, it is vital to take a history from a witness (either a relative or a nurse). Examination may yield other clues to the cause (e.g. pyrexia, or focal chest or neurological signs). It is important to distinguish confusion from a fluent aphasia, since patients with this speech disorder often appear confused. Often, however, the cause is not immediately obvious, and a wide screen of tests must be performed (see Box 22.35).
Management
The management of acute confusional states involves identifying the cause and correcting it if possible. Confused patients should be nursed in a well-lit room. During the period of confusion drugs are best avoided, as they may exacerbate the confusion, though occasionally sedative drugs such as chlorpromazine (25-100 mg 8-hourly) or haloperidol (2.5-10 mg 8-hourly) may be required. In delirium tremens (alcohol withdrawal), the treatment is a tapered course of clomethiazole or chlordiazepoxide to accompany high-dose intravenous thiamin (see p. 260).
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22.34 CAUSES OF ACUTE CONFUSIONAL STATE
Type Common Unusual
Infective Chest infection
Urinary infection
Septicaemia
Viral illness
Meningitis
Encephalitis Cerebral abscess
Subdural empyema
AIDS
Metabolic/endocrine Hypoxia (respiratory failure)
Cardiac failure
Acute (internal) haemorrhage
Hyper-/hypoglycaemia
Hyper-/hypocalcaemia
Hyponatraemia
Liver failure, renal failure Hypo-/hyperthyroidism
Adrenal disease
Porphyria
Vascular Acute cerebral haemorrhage/infarction
Subarachnoid haemorrhage Vasculitis (e.g. systemic lupus erythematosus)
Cortical venous thrombosis
Toxic Alcohol intoxication/withdrawal
Drugs (therapeutic/illicit) Carbon monoxide poisoning
Neoplastic Secondary deposits Primary cerebral tumour
Paraneoplastic syndrome
Trauma Head injury (cerebral contusions)
Subdural haematoma
Other Post-ictal state
Acute decompensation of dementia (see Box 22.36) Acute hydrocephalus
Complex partial status epilepticus
22.35 INVESTIGATION OF ACUTE CONFUSIONAL STATE
First-line Other useful tests
Blood tests Full blood count, Cardiac enzymes
ESR Protein electrophoresis
Urea and electrolytes, glucose
Vitamin B12,
Calcium, magnesium copper studies
Liver function tests Syphilis serology
Thyroid function tests Antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA)
Tumour markers, prostate-specific antigen
CNS investigations Head imaging (CT and/or MRI) Lumbar puncture EEG
Other Arterial blood gases ECG
Infection screen (blood cultures, chest radiograph, urine culture) Viral screen, as appropriate (e.g. consider HIV)
Urinary porphyrins
ISSUES IN OLDER PEOPLE
ACUTE CONFUSIONAL STATE
Neuronal loss occurs with age, so older people are at increased risk of acute confusion in the context of relatively minor systemic disturbances.
Dementia is a risk factor for delirium, and delirium may herald the onset of dementia.
Other predisposing factors include:
malnutrition
visual and/or auditory impairments
infections: chest or urinary tract infections are the most common causes of acute confusion in old age, and a low threshold of suspicion is essential. Typical symptoms including pyrexia may not be present, so if there is no other obvious cause for confusion, it may be appropriate to treat the elderly patient with antibiotics 'blind' once cultures have been taken
surgery: acute confusion is very common after emergency surgery in old age, and only slightly less so after elective surgery
drugs: confusional states are common because of polypharmacy and changes in the response to and elimination of drugs in old age.
GENERAL COGNITIVE DECLINE (DEMENTIA)
Dementia is a clinical syndrome characterised by a loss of previously acquired intellectual function in the absence of impairment of arousal. There are many different potential causes of dementia (see Box 22.36) but Alzheimer's disease and diffuse vascular disease are the most common. The distinction of senile from pre-senile dementia is unhelpful. However, rarer causes of dementia should be more actively sought in younger patients and those with short histories.
When a patient presents with disturbance of personality or memory dysfunction, the first step is to exclude a focal lesion by determining that there is cognitive disturbance in more than one area. A careful history is, of course, essential and it is important to interview not just the patient but a close family member too. Simple bedside tests such as the Mini-Mental State Examination (MMSE; see p. 248) are useful in assessing the cognitive deficit, but more formal help from clinical psychology may be required. General history and examination may give further clues to aetiology.
Dementias are broadly divided into 'cortical' and 'sub-cortical' types, depending upon their clinical features (see Box 22.37). Many of the primary degenerative diseases that cause dementia have characteristic features that may allow a specific diagnosis during life. Creutzfeldt-Jakob disease is usually relatively rapidly progressive (over months), is associated with myoclonus, and there may be characteristic abnormalities on EEG. Of the more slowly progressive dementias, Pick's disease presents with rather focal (temporal or frontal lobe) dysfunction often affecting language function early, and Lewy body dementia may present with visual disturbance. However, it is often difficult to distinguish these dementias from each other or from Alzheimer's disease during life.
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22.36 CAUSES OF DEMENTIA
Type Common Unusual Rare
Vascular Diffuse small-vessel disease Amyloid angiopathy
Multiple emboli Cerebral vasculitis
Degenerative/inherited Alzheimer's disease Huntington's disease
Wilson's disease
Pick's disease
Cortical Lewy body disease
Others (e.g. cortico-basal degeneration)
Neoplastic Secondary deposits Primary cerebral tumour Paraneoplastic syndrome (limbic encephalitis)
Traumatic Chronic subdural haematoma Post-head injury Punch-drunk syndrome
Hydrocephalus Communicating/non-communicating 'Normal pressure' hydrocephalus
Toxic/nutritional Alcohol Thiamin deficiency B12 deficiency Anoxia/carbon monoxide poisoning Heavy metal poisoning
Infective Syphilis HIV Post-encephalitic
Prion diseases Creutzfeldt-Jakob disease Kuru Gerstmann-Strãussler-Scheinker disease
22.37 CORTICAL VS SUBCORTICAL DEMENTIA
'Cortical' dementia 'Subcortical' dementia
Severity Severe Mild to moderate
Speed of cognition Normal Slow
Cognitive deficits Dysphasia, dyspraxia, agnosia 'Frontal' memory disturbance
Psychiatric disturbance Occasionally depression Depression, apathy
Motor abnormalities Uncommon Extrapyramidal
Examples Alzheimer's disease
Lewy body dementia Progressive supranuclear palsy
Investigations
The aim is to discover a treatable cause, if present, and to try to give an idea of prognosis if not, using a fairly standard set of investigations (see Box 22.38). Imaging of the brain is important to exclude potentially treatable structural lesions such as hydrocephalus, cerebral tumour or chronic subdural haematoma, though often the only abnormality seen is generalised atrophy. If the initial tests fail to yield an answer, more invasive tests such as lumbar puncture or, rarely, brain biopsy may be indicated. It is always worth remembering that the memory disturbance may be a manifestation of depressive illness (pseudo-dementia) and here formal neuropsychological evaluation is helpful.
22.38 INVESTIGATION OF DEMENTIA
In most patients
Imaging of head (CT and/or MRI)
Blood tests
Full blood count, ESR
Urea and electrolytes, glucose
Calcium, liver function tests
Thyroid function tests
Vitamin B12
Venereal Diseases Reference Laboratory (VDRL) test
ANA, anti-dsDNA
Chest radiograph
EEG
In selected patients
Lumbar puncture
HIV serology
Brain biopsy
Management
This is directed at removing correctable causes, and at providing support for patient and carers if no specific treatment exists. Anticholinesterases, such as donepezil and rivastigmine, appear to improve cognitive function to some extent in Alzheimer's disease (see p. 1173).
FOCAL DEFICITS
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Figure 22.18 The anatomy of the cerebral cortex.
It is easiest to consider the individual cortical functions lobe by lobe, and the areas discussed are shown in Figure 22.18. Many of the functions are lateralised; to which side depends on which of the two hemispheres is dominant, this being the one in which language function is represented. In right-handed individuals this is almost always the left hemisphere, while in left-handers either hemisphere may be dominant with about equal frequency.
Frontal lobes
These are concerned with executive function, movement and behaviour. Well-defined functional areas in the frontal lobe include the primary motor cortex in the pre-rolandic gyrus, and Broca's speech area just anterior to the inferior end of this gyrus. The frontal eye fields lie higher up, anterior to the primary motor cortex. There is also a supplementary motor area on the medial surface which is involved in higher-order motor control, and a micturition centre in the mesial frontal lobe (the medial aspect adjacent to the falx cerebri) involved in the maintenance of urinary continence. The positive and negative features of damage to these areas are listed in Box 22.39.
More diffuse damage to the frontal lobe results in behavioural disturbance. Personality can be affected in three broad directions. Patients with mesial frontal lesions become increasingly withdrawn, unresponsive and mute (abulic), and this is often associated with urinary incontinence, gait apraxia, and the type of increase in tone known as gegenhalten, in which the patient varies the resistance to movement in proportion to the force exerted by the examiner. Patients with lesions of the dorsolateral pre-frontal cortex develop difficulties with speech and motor planning and organisation (dysexecutive syndrome). Those with orbitofrontal lesions of the frontal lobes become disinhibited, sometimes to the point of grandiosity, or exhibit irresponsible behaviour (e.g. with financial affairs). Memory is substantially intact, and there may be focal physical signs such as a grasp reflex, palmo-mental response or pout. As the frontal lobe overlies the olfactory bulb and tracts, structural lesions such as tumours in the inferior frontal lobes may be associated with anosmia.
Parietal lobe
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22.39 CORTICAL LOBAR FUNCTIONS
Effects of damage
Lobe Function Cognitive/behavioural Associated physical signs Positive phenomena
Frontal Personality
Emotional control
Social behaviour
Contralateral motor control
Language
Micturition Disinhibition
Lack of initiation
Antisocial behaviour
Impaired memory
Expressive dysphasia
Incontinence Impaired smell
Contralateral hemiparesis
Frontal release signs Versive seizures
Focal motor seizures (Jacksonian march)
Continuous partial seizures (epilepsia partialis continua)
Parietal: dominant Language Calculation Dysphasia
Dyscalculia
Dyslexia
Apraxia
Agnosia Contralateral hemisensory loss
Astereognosis
Agraphaesthesia
Contralateral homonymous lower quadrantanopia
Asymmetry of optokinetic nystagmus (OKN) Focal sensory seizures
Parietal: non-dominant Spatial orientation
Constructional skills
Spatial disorientation Neglect of non-dominant side
Astereognosis
Constructional apraxia
Dressing apraxia Contralateral hemisensory loss
Agraphaesthesia
Contralateral homonymous lower quadrantanopia
Asymmetry of OKN Focal sensory seizures
Temporal: dominant Auditory perception
Language Verbal memory
Smell
Balance Receptive aphasia
Dyslexia
Impaired verbal memory Contralateral homonymous upper quadrantanopia Complex hallucinations (smell, sound, vision, memory)
Temporal: non-dominant Auditory perception
Melody/pitch perception
Non-verbal memory
Smell
Balance Impaired non-verbal memory Impaired musical skills (tonal perception) Contralateral homonymous upper quadrantanopia Complex hallucinations (smell, sound, vision, memory)
Occipital Visual processing Visual inattention
Visual loss
Visual agnosia Homonymous hemianopia (± macular sparing) Simple visual hallucinations (e.g. phosphenes, zigzag lines)
The parietal lobes are concerned with the integration of sensory perception. The dominant parietal lobe contains part of the area which is involved in language (discussed below). Closely allied to the speech area are regions dealing with numerical function. The primary sensory cortex lies in the post-rolandic gyrus. Much of the remainder is devoted to 'association' cortex, damage to which gives rise to sensory (including visual) inattention and disorders of spatial perception and hence the disruption of spatially orientated behaviour leading to apraxia. Apraxia is the inability to perform complex, organised activity in the presence of a normal basic motor, sensory and cerebellar system (i.e. after weakness, numbness and ataxia have been excluded as causes). Such complex activities include dressing, the use of tools and finding one's way around geographically. As discussed below in the section on vision, parietal lobe lesions may also involve the optic radiations deep to the cortex, giving rise to homonymous inferior quadrantanopias of the contralateral visual space.
Temporal lobe
Well-defined functional areas in the temporal lobes include the primary auditory cortex and primary vestibular cortex. On the medial side lies the olfactory cortex, and the parahippocampal cortex which is involved in memory function. The temporal lobe contains many structures associated with the limbic system, including the hippocampus and the amygdala. Damage to these areas causes memory disturbance, and may also cause personality change.
The dominant temporal lobe shares the specialised language areas with the parietal lobe, and is particularly involved in verbal comprehension. Music processing occurs in both temporal lobes, rhythm being processed on the dominant side, and melody/pitch more on the non-dominant side. Temporal lobe lesions may be associated with contralateral homonymous superior quadrantanopias.
Occipital lobe
The occipital lobe is principally concerned with visual processing. The contralateral visual hemifield is represented in the primary visual (striate) cortex, and areas immediately surrounding this are involved in the processing of specific visual submodalities such as colour, movement or depth, and the analysis of more complex visual patterns such as faces.
SPEECH, SWALLOWING AND BRAIN-STEM DISTURBANCE
SPEECH
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Speech is the process whereby vocal sounds are used to convey meaning between individuals. A large volume of the cerebral cortex is involved in this complex cognitive process, mostly in the dominant hemisphere. The decoding of speech sounds (phonemes) is a function of the upper part of the posterior temporal lobe. The perception of these sounds as meaningful language, as well as the formulation of the language required for the expression of ideas and concepts, occurs predominantly in the lower parts of the anterior parietal lobe (the angular and supramarginal gyri). The temporal speech comprehension region is referred to as Wernicke's area. Other parts of the temporal lobe contribute to language processing in areas specialising in verbal memory, where lexicons of meaningful words are 'stored'. The language information so generated then passes anteriorly via the arcuate fasciculus to Broca's area in the posterior end of the inferior frontal gyrus on the dominant side. The motor commands generated in Broca's area pass to the cranial nerve nuclei in the pons and medulla, as well as to the anterior horn cells in the spinal cord. The cerebellum has an important coordinating function. Nerve impulses then travel to the lips, tongue, palate, pharynx, larynx and respiratory muscles via the facial nerve and cranial nerves 9, 10 and 12, and result in the series of ordered sounds known as speech (see Fig. 22.19).
These ordered sounds are detected by a listener in whom nerve impulses are passed from the ears to the auditory cortex in the temporal lobe and hence to the speech comprehension areas. Parts of the non-dominant parietal lobe appear to contribute to non-verbal aspects of language in the recognition of meaningful intonation patterns of spoken words.
Aphasia
Figure 22.19 Areas of the cerebral cortex involved in the generation of spoken language.
Aphasia is a disorder of the language content of speech. It can occur with lesions over a wide area of the dominant hemisphere. The term aphasia, rather than dysphasia, is now used to designate any degree of spoken language deficit. Aphasia is detected by the patient's inability to produce the correct word (anomia). When patients are asked to name objects or parts of objects, if anomia is present either no word will be produced or the wrong word or a nonsense word produced (paraphasia). Aphasia can be classified according to whether the speech output is 'fluent', in which a normal or increased number of (the wrong) words is produced, or 'non-fluent' if the verbal output is reduced. Patients with lesions anterior to the central fissure have non-fluent aphasia whilst those with lesions posterior to the central fissure in the speech areas have a fluent aphasia (and are often mistakenly thought to be 'confused'). If patients are tested for the comprehension of words and their ability to repeat, their aphasia can be further classified into distinct syndromes of aphasia which have localising and prognostic implications (see Fig. 22.20).
Figure 22.20 Classification of aphasia, according to the site of the lesion and type of language deficit. All have naming difficulty (anomia). Fluent aphasias arise from lesions posterior to the central fissure; repetition is affected by lesions around the sylvian fissure. (1) Wernicke aphasia: fluent aphasia with poor comprehension and poor repetition. (2) Conduction aphasia: fluent aphasia with good comprehension and poor repetition. (3) Broca aphasia: non-fluent aphasia with good comprehension and poor repetition. (4) Transcortical sensory aphasia: fluent aphasia with poor comprehension and good repetition. (5) Transcortical motor aphasia: non-fluent aphasia with good comprehension and good repetition. N.B. Large lesions affecting all regions 1-5 cause global aphasia.
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22.40 CAUSES OF DYSARTHRIA
Type Site Characteristics Associated features
Myopathic Muscles of speech Indistinct, poor articulation Weakness of face, tongue and neck
Myasthenic Motor end plate Indistinct with fatigue and dysphonia Fluctuating severity Ptosis, diplopia, facial and neck weakness
Bulbar Brain stem Indistinct, slurred, often nasal Dysphagia, diplopia, ataxia
'Scanning' Cerebellum Slurring, impaired timing and cadence, 'sing-song' quality Ataxia of limbs and gait, tremor of head/limbs
Spastic Pyramidal tracts Indistinct, breathy, mumbling Poor rapid tongue movements, increased reflexes and jaw jerk
Parkinsonian Basal ganglia Indistinct, rapid, stammering, quiet Tremor, rigidity, slow shuffling gait
Dystonic Basal ganglia Strained, slow Dystonia, athetosis
If a patient is found to have difficulty with speech comprehension there is likely to be a lesion in the superior part of the posterior temporal lobe and/or the adjoining part of the parietal lobe. Patients with lesions around the sylvian (lateral) fissure will have difficulty with repetition, whilst those with lesions away from the sylvian fissure can repeat and may do so compulsively. Patients with large lesions over much of the speech area are not testable in such a refined manner, having no language production, and are said to have 'global aphasia'. Some patients with patchy lesions in the speech areas may not be easily classified according to the above scheme and are said to have anomic aphasia. Patients with fluent aphasia tend not to have an associated hemiparesis since the pyramidal tract is not involved, whilst those with the more anteriorly placed lesions causing non-fluent aphasia often do have a hemiparesis.
Dysphonia and dysarthria
Speech can be disturbed in a number of ways. At a simple level, the vocal cords may fail to generate sound properly, and this results in hoarse or whispered speech (dysphonia). If the muscles or nerves controlling the mouth, tongue, pharynx and lips are not functioning correctly, poorly articulated speech will result (dysarthria). There is no problem with choice of words, but the speech may or may not be intelligible, depending on severity. Cerebellar or brain-stem disease, lower cranial nerve lesions, myasthenia or muscle disease may all result in dysarthria. The quality of the speech tends to differ somewhat depending on the cause (see Box 22.40).
SWALLOWING
Swallowing is a complex activity involving the coordinated action of lips, tongue, soft palate, pharynx and larynx, which are innervated by the facial nerve and cranial nerves 9, 10, 11 and 12. This mechanism is potentially vulnerable to damage to many different areas of the nervous system, resulting in dysphagia which is usually accompanied by dysarthria. Structural causes of dysphagia are considered on page 761. Acute onset of dysphagia may occur as a result of brain-stem stroke, a rapidly developing neuropathy such as the Guillain-Barré syndrome or diphtheria. The upper motor neuron innervation of the cranial nerves responsible for swallowing is bilateral, so persistent dysphagia is unusual with a unilateral upper motor lesion. However, dysphagia may occur in the early stages of such a lesion if it is very acute, such as a hemisphere stroke. Dysphagia developing subacutely may be seen in myasthenia gravis, motor neuron disease, polymyositis, basal meningitis and inflammatory brain-stem disease. More slowly developing dysphagia suggests a myopathy or possibly a brain-stem or skull-base tumour.
BULBAR AND PSEUDOBULBAR PALSY
The lower cranial nerves, 9, 10, 11 and 12, are frequently affected bilaterally, producing dysphagia and dysarthria. The term 'bulbar palsy' is used if this results from lower motor neuron lesions, either at nuclear or fascicular level within the medulla, or from bilateral lesions of the lower cranial nerves outside the brain stem. The tongue is wasted and fasciculating and the palate moves very little. A 'pseudobulbar palsy' arises from an upper motor neuron lesion of the bulbar muscles from lesions of the corticobulbar pathways in the pyramidal tracts. Here the tongue is small and contracted, and moves slowly; the jaw jerk is brisk. Causes of bulbar and pseudobulbar palsies are shown in Box 22.41.
22.41 CAUSES OF BULBAR AND PSEUDOBULBAR PALSY
Pseudobulbar Bulbar
Genetic Kennedy's disease (X-linked bulbospinal neuronopathy)
Vascular Bilateral hemisphere (lacunar) infarction Medullary infarction
Degenerative Motor neuron disease Motor neuron disease
Syringobulbia
Inflammatory/infective Multiple sclerosis
Cerebral vasculitis Myasthenia
Guillain-Barré
Poliomyelitis
Lyme disease
Vasculitis
Neoplastic High brain-stem tumours Brain-stem glioma
Malignant meningitis
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BRAIN-STEM FUNCTION
Many different functional areas are tightly packed into the brain stem (see Fig. 22.21). Long motor and sensory tracts course through its length, and are punctuated by individual brain-stem nuclei and cranial nerves, along with their respective interconnections and connections to the cerebrum and cerebellum. Thus, damage to even a small area of the brain stem potentially causes major disturbance of several systems. As the anatomy of the brain stem is very precisely organised, it is usually possible to localise the site of a lesion on the basis of careful history and examination to determine exactly which tracts/nuclei are affected. Lesions can occur singly, multiply or diffusely, but the standard neurological approach is to try to explain all of a patient's problems in the minimum number of lesions (ideally just one).
An example would be a patient presenting with sudden onset of upper motor neuron features affecting the right face, arm and leg in association with a left 3rd nerve palsy. The lesion would have to be in the left cerebral peduncle in the brain stem where the pathology is likely to have been a small stroke, as the onset was sudden. This combination of signs is known as Weber's syndrome, and this is one of several well-described brain-stem stroke syndromes which are listed in Box 22.42.
Figure 22.21 Anatomy of the brain stem.
22.42 MAJOR BRAIN-STEM STROKE SYNDROMES
Name of syndrome Site of lesions Clinical features
Weber Anterior cerebral peduncle (mid-brain) Ipsilateral 3rd palsy
Contralateral upper motor neuron 7th palsy
Contralateral hemiplegia
Claude Cerebral peduncle involving red nucleus Ipsilateral 3rd palsy
Contralateral cerebellar signs
Parinaud Dorsal mid-brain (tectum) Vertical gaze palsy
Convergence disorders
Convergence retraction nystagmus
Pupillary and lid disorders
Millard-Gubler Ponto-medullary junction Ipsilateral 6th palsy
Ipsilateral lower motor neuron
7th palsy
Contralateral hemiplegia
Wallenberg Lateral medulla Ipsilateral 5th, 9th, 10th, 11th palsy Ipsilateral Horner's syndrome Ipsilateral cerebellar signs
Contralateral spinothalamic sensory loss Vestibular disturbance
LOWER CRANIAL NERVE LESIONS
Bilateral lesions of cranial nerves 9, 10, 11 and 12 present as bulbar and pseudobulbar palsies and are discussed above (see Box 22.41). Cranial nerves 9, 10 and 11 may be affected together on one side as they pass through the jugular foramen at the skull base. The hypoglossal (12th) nerve exits the skull in its own foramen and lies close to the 9th, 10th and 11th nerves just outside the skull. All four lower cranial nerves are here anatomically related to the carotid artery and the ascending sympathetic innervation to the eye. Lesions affecting the lower cranial nerves at the skull base include tumours and dissection of the carotid artery (see Box 22.43).
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22.43 SYNDROMES OF THE LOWER CRANIAL NERVE LESIONS OUTSIDE THE BRAIN STEM
Syndrome Cranial nerves involved Site of lesion Cause
Vernet 9, 10 and 11 Jugular foramen (inside skull) Metastases, neurinoma, meningioma, epidermoid, carotid body tumour
Collet-Sicard 9, 10, 11 and 12 Jugular foramen just outside skull, near foramen lacerum Metastases, neurinoma, meningioma, epidermoid, carotid body tumour
Villaret 9, 10, 11, 12 and Horner's Posterior retropharyngeal space, near carotid artery Carotid dissection, metastases, neurinoma, meningioma, epidermoid, carotid body tumour
Isolated 12th 12 Skull base (hypoglossal canal) Metastases, neurinoma, meningioma, epidermoid
VISUAL DISTURBANCE
Disturbances of vision are common and often related to problems with the eye rather than disorder of the nervous system. A common reason for presentation is loss of vision, but patients may also present with positive visual symptoms (e.g. hallucinations). The movements of the two eyes may be disturbed and give rise to double vision (diplopia) or blurred vision. Alternatively, patients may present with disordered appearance of their visual apparatus, and this can include the eyelids, the globe, the eye movements, the pupils or the appearance of the optic disc on fundoscopy (e.g. papilloedema).
Integration link: Structure of the retina
Taken from Medical Neuroscience
Integration link: Vertebrate visual transduction (retinal rods)
Taken from Cell Biology
VISUAL LOSS
The visual pathway from the retina to the occipital cortex is topographically organised, so the pattern of visual field loss allows precise localisation of the site of the lesion. Fibres from ganglion cells in the retina pass to the optic disc and then backwards through the lamina cribrosa to the optic nerve. Nasal optic nerve fibres (subserving the temporal visual field because the image on the retina is inverted) cross at the chiasm, but temporal fibres do not. Hence all fibres in the optic tract and further posteriorly subserve both eyes' representation of contralateral visual space. From the lateral geniculate nucleus, lower fibres pass through the temporal lobes on their way to the primary visual area in the occipital cortex, while the upper fibres pass through the parietal lobe. Patterns of visual field loss are explained by this anatomy, as seen in Figure 22.22, and associated clinical manifestations are described in Box 22.44.
Figure 22.22 Visual pathways and visual field defects. Schematic representation of eyes and brain in transverse section.
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22.44 CLINICAL MANIFESTATIONS OF VISUAL FIELD LOSS
Site Common causes Complaint Visual field loss Associated physical signs
Retina/optic disc Vascular disease (including vasculitis)
Glaucoma
Inflammation Partial/complete visual loss depending on site Altitudinal field defect
Arcuate scotoma Reduced acuity
Visual distortion (macula)
Abnormal retinal appearance
Optic nerve Optic neuritis
Sarcoidosis
Tumour
Leber's hereditary optic neuropathy Partial/complete loss of vision in one eye
Often painful
Central vision particularly affected Central scotoma
Paracentral scotoma
Uniocular blindness Reduced acuity
Reduced colour vision
Relative afferent pupillary defect
Optic atrophy (late)
Optic chiasm Pituitary tumours
Craniopharyngioma
Sarcoidosis May be none
Rarely diplopia ('hemifield slide') Bitemporal hemianopia Pituitary function abnormalities
Optic tract Tumour
Inflammatory disease Disturbed vision to one side of midline Incongruous contralateral homonymous hemianopia
Temporal lobe Stroke
Tumour
Inflammatory disease Disturbed vision to one side of midline Contralateral homonymous upper quadrantanopia Memory/language disorders
Parietal lobe Stroke
Tumour
Inflammatory disease Disturbed vision to one side of midline
Bumping into things Contralateral homonymous lower quadrantanopia Contralateral sensory disturbance
Asymmetry of optokinetic nystagmus
Occipital lobe Stroke
Tumour
Inflammatory disease Disturbed vision to one side of midline
Difficulty reading
Bumping into things Homonymous hemianopia (may be macula-sparing) Damage to other structures supplied by posterior cerebral circulation
It is uncommon for patients to present with transient visual loss. Visual loss lasting from 1-20 minutes is likely to have a vascular cause. This can affect one eye (amaurosis fugax) or one visual field. Whether the field loss was uniocular (carotid circulation) or a homonymous hemianopia (vertebro-basilar circulation) is crucial to further management, and this must be distinguished by careful history (e.g. did the patient try shutting each eye in turn?). Transient visual loss lasting 20-30 minutes suggests migraine, especially if accompanied by headache and/or positive visual phenomena.
ISSUES IN OLDER PEOPLE
VISUAL LOSS
Presbyopia is the progressive inability to focus on near objects due to the stiffening of the lens which occurs with ageing.
The retina and optic pathways lose cells with ageing, making it harder to see detail and contrast.
Older people are particularly prone to certain causes of visual loss: cataract, age-related macular degeneration, glaucoma, anterior ischaemic optic neuropathy (N.B. vasculitic due to temporal arteritis) and occipital lobe stroke.
They are much less likely to suffer from certain other causes, such as optic neuritis and Leber's hereditary optic neuropathy.
POSITIVE VISUAL SYMPTOMS
The most common cause of a positive visual disturbance is migraine, in which patients may see silvery zigzag lines (fortification spectra) or flashing coloured lights (teichopsia) which precede the headache. Simple flashes of light (phosphenes) can also be seen as a result of damage to the retina (e.g. detachment) or damage to the primary visual cortex. More complex visual percepts (hallucinations) may be caused by drugs, or may be due to structural damage resulting in epilepsy or 'release phenomena' (hallucinations which occur in a blind visual field).
EYE MOVEMENT DISORDERS
Under normal circumstances, the eyes move conjugately, though horizontal vergence allows visual fusion of objects at different distances. The control of eye movements begins in the cerebral hemispheres, particularly within the frontal eye fields, and the pathway then descends to the brain stem with input from the visual cortex, superior colliculus and cerebellum. Horizontal and vertical gaze centres in the pons and mid-brain, respectively, coordinate output to the ocular motor nerve nuclei (3, 4 and 6), which are connected to each other by the medial longitudinal fasciculus (MLF) (see Fig. 22.23). The MLF is particularly important in yoking the horizontal movements of the two eyes. The extraocular muscles are then supplied by the oculomotor (3rd), trochlear (4th) and abducens (6th) nerves.
Diplopia
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Figure 22.23 Control of conjugate eye movements. Downward projections from the cortex to pontine lateral gaze centre (A). Pontine gaze centre projects to the 6th cranial nerve nucleus, which innervates the ipsilateral lateral rectus and projects to the contralateral 3rd nerve nucleus (and hence medial rectus) via the medial longitudinal fasciculus (MLF) (B). Tonic inputs from the vestibular apparatus via the vestibular nuclei project to the contralateral 6th nerve nucleus (C).
This arises when eye movement is impaired so that the image of an object is not projected to homologous points on the two retinae. Impairment may result from central disorders, or from disturbance of the ocular motor nerves, muscles or the neuromuscular junction. The pattern of double vision, along with any associated features, usually allows localisation of the lesion whilst the mode of onset and subsequent behaviour (e.g. fatigability) suggest the aetiology.
The trochlear (4th) nerve innervates the superior oblique muscle, and the abducens (6th) nerve innervates the lateral rectus. The oculomotor (3rd) nerve innervates the remainder of the extraocular muscles along with the levator palpebrae superioris and the ciliary body (pupil constriction and accommodation). Causes of oculomotor nerve palsies are given in Box 22.45.
Complete oculomotor nerve lesions cause ptosis and a dilated pupil, and the eye tends to rest in a 'down and out' position due to unopposed tonic activity of the unaffected lateral rectus and superior oblique muscles. The pupil is often spared in ischaemic lesions (e.g. in diabetes), and its involvement requires that compressive lesions such as aneurysm be excluded. Trochlear nerve palsy presents with vertical diplopia (especially noticeable going downstairs), and the patient may have a head tilt and double vision when looking down to the side opposite the lesion. Abducens nerve palsy causes horizontal double vision when trying to look towards the side of the lesion. In diplopia of any cause, the image projected furthest away from primary position arises from the paretic eye, and covering each eye in turn can often determine this. Note that this image is not necessarily any less clear than the image from the non-paretic eye-it is the relative position, not the clarity, of the images which is important in determining which muscle is weak.
22.45 COMMON CAUSES OF DAMAGE TO CRANIAL NERVES 3, 4 AND 6
Site Common pathology Nerve(s) involved Associated features
Brain stem Infarction
Haemorrhage
Demyelination
Intrinsic tumour 3 (mid-brain)
6 (ponto-medullary junction) Contralateral pyramidal signs
Ipsilateral lower motor neuron 7 palsy (ponto-medullary junction)
Other brain-stem/cerebellar signs
Intrameningeal course Meningitis (infective/malignant)
Raised intracranial pressure
Aneurysms
Cerebello-pontine angle tumour
Trauma 3, 4 and/or 6
6
3 (uncal herniation)
3 (posterior communicating artery)
6 (basilar artery)
6
3, 4 and/or 6 Meningism, features of primary disease
Papilloedema
Features of space-occupying lesion
Pain
Features of subarachnoid haemorrhage
8, 7, 5 lesions
Ipsilateral cerebellar signs
Other features of trauma
Cavernous sinus Infection/thrombosis
Carotid artery aneurysm
Caroticocavernous fistula 3, 4 and/or 6 May be 5 involvement also
Pupil may be fixed, mid-position (sympathetic plexus on carotid may also be affected)
Superior orbital fissure Tumour (e.g. sphenoid wing meningioma)
Granuloma 3, 4 and/or 6 May be proptosis, chemosis
Orbit Vascular (e.g. diabetes, vasculitis)
Infections
Tumour
Granuloma
Trauma 3, 4 and/or 6 Pain
Pupil often spared in vascular 3 palsy
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Myasthenia gravis can cause diplopia by affecting any or all of the extraocular muscles. It is often associated with ptosis, and the hallmark is fatigability. Similarly, diseases of the extraocular muscles themselves can cause diplopia. Such diseases include thyroid eye disease, myopathies and orbital myositis.
Central lesions can also give rise to diplopia. Brain-stem lesions affecting the 3rd, 4th or 6th nerves or nuclei will cause diplopia, as will lesions of the MLF. The hallmark of an MLF lesion is an internuclear ophthalmoplegia (INO). The lateral gaze centre in the pons sends fibres to the ipsilateral 6th nerve nucleus. The nucleus contains two populations of neurons. Half the cells send their axons directly into the 6th nerve to supply the lateral rectus, while the remaining half send their fibres into the contralateral MLF and up to the contralateral 3rd nerve nucleus, where they synapse with neurons destined for the medial rectus (see Fig. 22.23). Hence, damage to the 6th nerve nucleus itself will prevent both eyes from moving ipsilaterally (gaze palsy), and a lesion of the MLF will interfere with adduction of the ipsilateral eye (INO). An INO may be partial or complete, and may be associated with nystagmus of the contralateral, abducting eye.
Nystagmus
If the eye movement control systems are defective, the eyes may drift off target and it becomes necessary to perform recurrent corrections to return fixation to the object of interest. This results in a repetitive to-and-fro movement (drift-correction-drift etc.) which is known as nystagmus. Usually the drifts are slower than the corrections (slow and quick phases, respectively). The direction of the fast phase is usually designated as the direction of the nystagmus because it is easier to see, although the abnormality is the slower drift of the eyes off target. Nystagmus may be horizontal, vertical or torsional, and is usually conjugate, i.e. the two eyes usually move together. Nystagmus is seen as a physiological phenomenon in response to sustained vestibular stimulation or movement of the visual world (optokinetic nystagmus). There are, however, many different causes of pathological nystagmus, the most common being disorders of the vestibular system (peripheral and central components) and brain-stem/cerebellar lesions.
In lesions of the vestibular system (most commonly peripheral labyrinthine lesions), damage to one side will allow the tonic output from the healthy, contralateral side to cause the eyes to drift towards the side of the lesion. This causes recurrent compensatory fast movements away from the side of the lesion; hence unidirectional nystagmus to the opposite side is seen, often with a torsional element. The nystagmus of peripheral labyrinthine lesions disappears (fatigues) quite quickly and is always accompanied by vertigo and quite often nausea and vomiting. Central vestibular nystagmus is more persistent.
The brain stem and the cerebellum are involved in maintaining eccentric positions of gaze. Lesions will therefore allow the eyes to drift back in towards primary position (gaze-evoked nystagmus). This produces nystagmus whose fast component beats in the direction of gaze. This is the most common type of 'central' nystagmus and is most commonly bi-directional and not usually accompanied by vertigo, but there may be other signs of brain-stem dysfunction. Brain-stem disease may also cause vertical nystagmus.
Unilateral cerebellar lesions may result in gaze-evoked nystagmus when looking in the direction of the lesion, where the fast phases are directed towards the side of the lesion. Cerebellar hemisphere lesions also cause 'ocular dysmetria', an overshoot of target-directed, fast eye movements (saccades) resembling 'past-pointing' in limbs.
Nystagmus also occurs as a result of toxicity (especially drugs) and nutritional deficiency (thiamin deficiency). The severity is variable, and it may or may not result in visual degradation, though it may be associated with a sensation of movement of the visual world (oscillopsia). Nystagmus may occur as a congenital phenomenon, in which case the nystagmus is often quasi-sinusoidal ('pendular') rather than having alternating fast and slow phases ('jerk').
EYELID, GLOBE AND PUPIL DISORDERS
Various disorders may cause drooping or ptosis of the eyelid, and these are listed in Box 22.46.
In some circumstances the globe is pushed forward in the orbit, either unilaterally (proptosis) or bilaterally (exophthalmos). By far the most common cause of both is thyroid eye disease, but other causes include orbital tumours or granulomas, cavernous sinus disease and inflammatory orbital disease ('pseudotumour').
Disorders of the pupil
Figure 22.24 Right-sided Horner's syndrome due to paravertebral metastasis at T1.
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Pupillary response to light is achieved by a combination of parasympathetic and sympathetic activity. Parasympathetic fibres originate in the Edinger-Westphal subnucleus of the 3rd nerve, and pass with the 3rd nerve to synapse in the ciliary ganglion before supplying the constrictor pupillae of the iris. Sympathetic fibres originate in the hypothalamus, pass down the brain stem and cervical spinal cord to emerge at T1, return back up to the eye in association with the internal carotid artery and supply the dilator pupillae. Lesions in the sympathetic pathway cause Horner's syndrome (see Fig. 22.24). The pupils also constrict as part of the near reflex (in association with accommodation and convergence).
22.46 CAUSES OF PTOSIS
Mechanism Causes Associated clinical features
3rd nerve palsy Isolated palsy (see Box 22.45)
Central/supranuclear lesion Ptosis is usually complete
Extraocular muscle palsy (eye 'down and out')
Depending on site of lesion, other cranial nerve palsies (e.g. 4, 5 and 6) or contralateral upper motor neuron signs
Sympathetic lesion (Horner's syndrome) (see Fig. 22.24) Central (hypothalamus/brain stem)
Peripheral (lung apex, carotid artery pathology)
Idiopathic Ptosis is partial
Lack of sweating on affected side
Depending on site of lesion, brain-stem signs, signs of apical lung/brachial plexus disease, or ipsilateral carotid artery stroke
Myopathic Myasthenia gravis
Dystrophia myotonica
Progressive external ophthalmoplegia Extraocular muscle palsies
More widespread muscle weakness, with fatigability in myasthenia
Other characteristic features of individual causes
Other Pseudo-ptosis (e.g. blepharospasm)
Local orbital/lid disease
Age-related levator dehiscence Eyebrows depressed rather than raised
May be local orbital abnormality
22.47 PUPILLARY DISORDERS
Disorder Cause Ophthalmological features Associated features
3rd nerve palsy See Box 22.45 Dilated pupil
Extraocular muscle palsy (eye is typically 'down and out')
Complete ptosis Other features of 3rd nerve palsy (see Box 22.46)
Horner's syndrome (see Fig. 22.24) Lesion to sympathetic supply Small pupil
Partial ptosis
Iris heterochromia (if congenital) Ipsilateral failure of sweating (anhidrosis)
Holmes-Adie syndrome (Adie pupil) Lesion of ciliary ganglion (usually idiopathic) Dilated pupil
Light-near dissociation (accommodate but do not react to light)
Vermiform movement of iris during contraction
Disturbance of accommodation Generalised areflexia
Argyll Robertson pupil Dorsal mid-brain lesion (usually syphilis) Small, irregular pupils
Light-near dissociation Other features of tabes dorsalis (see p. 1202)
Local pupillary damage Trauma/inflammatory disease Irregular pupils, often with adhesions to lens (synechiae)
Variable degree of reactivity Other features of trauma/underlying inflammatory disease (e.g. cataract, blindness etc.)
Relative afferent pupillary defect (Marcus Gunn pupil) Damage to optic nerve (see Box 22.44, p. 1153) Pupils symmetrical, but degree of dilatation depends on which eye stimulated Decreased visual acuity/colour vision
Central scotoma
Papilloedema/optic disc pallor
ISSUES IN OLDER PEOPLE
DISORDERS OF THE PUPIL
The average pupil size decreases progressively with age, which makes it more difficult for older people to see in poor lighting.
It also becomes more difficult to view the optic disc at ophthalmoscopy, as the pupil size drops below 1-2 mm; dilatation of the pupil with eye drops may be necessary. This should not be attempted if assessment of pupil size is likely to be necessary, as in the management of an unconscious or confused patient.
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Lesions of the oculomotor nerve, ciliary ganglion and sympathetic supply produce characteristic 'efferent' disorders of pupillary function. 'Afferent' defects occur as a result of damage to an optic nerve, impairing the direct response of a pupil to light, although leaving the consensual response from stimulation of the normal eye intact. Structural damage to the iris itself can also result in pupillary abnormalities. A summary is given in Box 22.47.
Optic disc disorders
Optic disc swelling
Figure 22.25 Mechanism of optic disc oedema (papilloedema). A Normal. B Disc oedema (e.g. due to cerebral tumour). C Fundus photograph of the left eye showing optic disc oedema with a small haemorrhage on the nasal side of the disc.
There are several causes of swelling of the optic disc, but the term 'papilloedema' is reserved for swelling in association with raised intracranial pressure. In raised intracranial pressure from any cause, axoplasmic flow from retinal ganglion cells is held up at the cribriform plate. This results in swollen nerve fibres, which in turn cause capillary and venous congestion, producing papilloedema. The first sign is the cessation of normal venous pulsation seen at the disc, and the disc margins then become red (hyperaemic). The margins become indistinct and the whole disc is raised up, often with haemorrhages in the retina (see Fig. 22.25).
Other causes of optic disc swelling are listed in Box 22.48. Some normal variations of disc appearance can look like pathological disc swelling (pseudo-papilloedema).
Optic atrophy
22.48 COMMON CAUSES OF OPTIC DISC SWELLING
Raised intracranial pressure
Cerebral mass lesion (tumour, abscess)
Hydrocephalus, haemorrhage, haematoma
Idiopathic intracranial hypertension
Obstruction of ocular venous drainage
Central retinal vein occlusion
Cavernous sinus thrombosis
Systemic disorders affecting retinal vessels
Hypertension
Vasculitis
Hypercapnia
Optic nerve damage
Demyelination (optic neuritis/papillitis)
Leber's hereditary optic neuropathy
Ischaemia
Toxins (e.g. methanol)
Infiltration of optic disc
Sarcoidosis
Glioma
Lymphoma
Figure 22.26 Fundus photograph of the left eye of a patient with familial optic atrophy. Note marked pallor of optic disc.
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Loss of nerve fibres causes the optic disc to appear pale, as the choroid becomes visible (see Fig. 22.26). A pale disc (optic atrophy) follows optic nerve damage, and causes include previous optic neuritis, or ischaemic damage, long-standing papilloedema, optic nerve compression, trauma and degenerative conditions (e.g. Friedreich's ataxia, see p. 1178).
SPHINCTER DISTURBANCE
Incontinence and its management are discussed on pages 592-593. However, many different symptoms of bladder and bowel disturbance can arise as a result of nervous system dysfunction.
BLADDER
The bladder is analogous to skeletal muscle in that neural control can be divided into upper and lower 'motor neuron' components. Conscious control of micturition resides within the right pre-frontal cortex. Connections pass from here to the main controlling and coordinating centre in the pons, the pontine micturition centre, and from here down into the spinal cord, where they are found in the lateral columns bilaterally. The sympathetic supply to the bladder leaves from T10-L2 to synapse in the inferior hypogastric plexus, while the parasympathetic supply leaves from S2-4. In addition, a further somatic supply to the distal (voluntary) sphincter arises from S2-4, travelling via the pudendal nerves. Stimulation of sympathetic fibres causes relaxation of the detrusor muscle and contraction of the bladder neck, while stimulation of the parasympathetic fibres causes the reverse effects.
Afferent fibres from the bladder wall pass via the pelvic and hypogastric nerves. In the absence of conscious control (stroke, dementia) distension of the bladder to near-capacity evokes reflex detrusor contraction (analogous to the muscle stretch reflex). Reciprocal changes in sympathetic activation and relaxation of the distal sphincter result in coordinated bladder emptying. Normally, however, conscious control from the medial pre-frontal cortex inhibits bladder emptying until it is socially acceptable.
Damage to the 'lower motor neuron' component, i.e. the pelvic and pudendal nerves, gives rise to a flaccid bladder and sphincter with overflow incontinence, often accompanied by loss of pudendal sensation. Such damage may be due to disease of the conus medullaris or sacral nerve roots, either within the dura (as in inflammatory or carcinomatous meningitis), or as they pass through the sacrum (trauma or malignancy), or due to damage to the nerves themselves in the pelvis (infection, haematoma, trauma or malignancy).
Damage to the pons or spinal cord results in an 'upper motor neuron' pattern of bladder dysfunction due to uncontrolled overactivity of the parasympathetic supply. The bladder is small and highly sensitive to being stretched (analogous to spasticity). This results in frequency, urgency and urge incontinence. The loss of the coordinating control of the pontine micturition centre will also result in the phenomenon of detrusor-sphincter dyssynergia, where detrusor contraction and sphincter relaxation are not coordinated; hence the spastic bladder will often try to empty against a closed sphincter. This manifests as both urgency and an inability to pass urine, which is distressing and painful, and may last some minutes before partial emptying of the bladder is achieved. There is often a post-micturition residuum of urine which is prone to infection and the prolonged high bladder pressure may result in renal failure. More severe lesions of the spinal cord, as in spinal cord compression or trauma, can result in urinary retention; this will be painless, as bladder sensation, normally carried in the lateral spinothalamic tracts, will be cut off.
Damage to the mesial frontal lobes gives rise to loss of awareness of bladder fullness and consequent incontinence. Coexisting cognitive impairment may result in inappropriate micturition. These features are seen typically in hydrocephalus, frontal tumours, dementia and bifrontal subdural haematomas.
22.49 NEUROGENIC BLADDER: CLINICAL FEATURES AND TREATMENT
Site of lesion Result Treatment
Atonic
('lower motor neuron') Lesions of sacral segments of cord (conus medullaris)
Lesions of sacral roots and nerves Loss of detrusor contraction
Difficulty initiating micturition
Bladder distension with overflow Intermittent self-catheterisation
Catheterisation
Hypertonic
('upper motor neuron') Pyramidal tract lesion in spinal cord or brain stem Urgency with urge incontinence
Bladder sphincter incoordination (dyssynergia)
Incomplete bladder emptying Anticholinergics
Oxybutynin (5 mg 8-12-hourly)
Imipramine (25 mg 12-hourly)
Tolterodine (2 mg 12-hourly)
Intermittent self-catheterisation
Cortical Post-central
Pre-central
Frontal Loss of awareness of bladder fullness
Difficulty initiating micturition
Inappropriate micturition
Loss of social control Intermittent catheterisation
Intermittent catheterisation
Catheterisation
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When faced with a patient who has bladder symptoms, it is important to try to localise the lesion on the basis of history and examination remembering, however, that most bladder problems are not neurological unless there are overt neurological signs. Clinical features are summarised in Box 22.49.
Management of bladder disturbance involves identifying the cause and correcting it if possible. Overactive (spastic) bladders are common in neurological disease and the unwanted detrusor activity (and hence urgency) can be lessened by anticholinergic drugs such as oxybutynin, tolterodine or imipramine. This will not solve the problem of detrusor-sphincter dyssynergia, however, and it may be necessary to teach the patient how to perform intermittent clean self-catheterisation (ISC); by emptying the bladder regularly, urinary frequency is reduced, as is the likelihood of infection. Bladder ultrasound is often helpful in this regard; a large (> 100 ml) post-micturition residual volume suggests that ISC will be necessary. Flaccid bladders are less common and unfortunately there is no effective drug treatment. These patients therefore need to perform ISC. Long-term catheterisation (urethral or suprapubic) may be necessary in either spastic or flaccid bladders, but this is avoided if at all possible as it is associated with increased infection as well as with technical problems such as blockage.
RECTUM
The rectum has an excitatory cholinergic input from the parasympathetic sacral outflow, and inhibitory sympathetic supply similar to the bladder. Continence depends largely on skeletal muscle contraction in the puborectalis and pelvic floor muscles supplied by the pudendal nerves, as well as the internal and external anal sphincters. Damage to the autonomic components causes constipation. Lesions affecting the conus medullaris, the somatic S2-4 roots and the pudendal nerves cause faecal incontinence.
PENILE ERECTION AND EJACULATION
These related functions are under autonomic control via the pelvic nerves (parasympathetic, S2-4) and hypogastric nerves (sympathetic, L1-2). Descending influences from the cerebrum are important for psychogenic erection, but erection can occur as a purely reflex phenomenon in response to genital stimulation. Erection is largely parasympathetic, and is impaired by drugs which have anticholinergic effects and also by some antihypertensive and antidepressant agents. Sympathetic activity is important for ejaculation, and may be inhibited by a-adrenoceptor antagonists (a-blockers). For further information on erectile impotence, see page 707.
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Home > 2 SYSTEM-BASED DISEASES > 22 Neurological disease > CEREBROVASCULAR DISEASES
CEREBROVASCULAR DISEASES
Integration link: Circle of Willis
Taken from Medical Neuroscience
Integration link: Systemic blood supply to brain
Taken from Medical Neuroscience
Diseases of the cerebral blood vessels are the third most common cause of death in the developed world after cancer and ischaemic heart disease, and are responsible for a large proportion of physical disability, becoming more frequent with increasing age. The annual incidence of acute cerebrovascular disease in the over-45 age group in the UK is about 350 per 100 000.
Cerebrovascular disease can cause death and disability by ischaemia from occlusion of blood vessels (producing cerebral ischaemia and infarction) or haemorrhage through their rupture.
Clinical features of cerebrovascular disease
Cerebral arterial disease most commonly presents as an acute focal stroke, but ischaemic cerebral arterial disease may present, particularly in the elderly, with a gradual decline in intellectual function (dementia), with or without sensorimotor limb deficits or gait disorder. Haemorrhage from the major cerebral arteries of the circle of Willis into the subarachnoid space usually presents with a sudden, severe headache, vomiting and neck stiffness, with or without signs of focal brain damage (see p. 1162). Disease of the cerebral venous circulation is rare and presents with characteristic clinical features which are usually distinct from those caused by cerebral arterial disease.
ACUTE FOCAL STROKE
Acute focal stroke is characterised by the sudden appearance of a focal deficit of brain function, most commonly a hemiplegia with or without signs of focal higher cerebral dysfunction (such as aphasia), hemisensory loss, visual field defect or brain-stem deficit. Provided that a clear history of such a sudden focal deficit is available, the chance of the brain lesions being anything other than vascular is 1% or less. However, care needs to be taken to exclude other differential diagnoses, especially if the history is not clearly one of a sudden deficit (see Box 22.50).
Clinical classification of focal stroke
A stroke is defined as:
transient if the deficit recovers within 24 hours
completed if the focal deficit is persistent and not worsening
evolving if the focal deficit continues to worsen after about 6 hours from onset.
22.50 DIFFERENTIAL DIAGNOSIS OF ACUTE STROKE
Primary cerebral tumours
Metastatic cerebral tumours
Subdural haematoma
Cerebral abscess
Todd's paresis (after epileptic seizure)
Demyelination
Hypoglycaemia
Encephalitis
Hysterical conversion
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Transient stroke
Since transient strokes are almost always ischaemic, the term 'transient ischaemic attack' (TIA) is often used, although occasionally small intracerebral haemorrhages present with a transient stroke deficit. Transient strokes are a major risk factor for disabling stroke, implying a 13-fold increased risk of stroke in the next year. The management of a patient with a transient stroke is therefore directed at secondary prevention of future disabling stroke. Many transient strokes last only for a few minutes, whilst some stroke deficits persist for some days before recovery. These minor completed strokes are managed in the same way as shorter-duration deficits.
Completed stroke
Of patients presenting with a persistent acute focal stroke, 85% have sustained a cerebral infarction and the remainder an intracerebral haemorrhage. It is not possible to distinguish between these reliably at the bedside. Headache may accompany the onset of both haemorrhagic and ischaemic strokes, although the combination of headache with vomiting at the onset strongly suggests that the stroke is primarily haemorrhagic. A history of hypertension and/or raised blood pressure is common in both types of stroke lesion, although other risk factors for atherosclerosis are more likely to be found with ischaemic strokes.
Evolving stroke
The majority of persistent stroke deficits have completed within 6 hours, many within minutes, but some evolve in a stuttering fashion over days. It is this small group of patients with evolving deficits who should be viewed with diagnostic suspicion in case a mass lesion has been misdiagnosed. However, the lesion is often due to progressive occlusion of a cerebral artery (either a major extracranial vessel or a small perforating artery).
Figure 22.27 Syndromes of acute stroke. Total anterior circulation syndrome-TACS (A). Partial anterior circulation syndromes-PACS (B, C, D and E). Pure motor stroke-lacunar syndrome (F). Posterior circulation syndromes-POCS (G, H, I, J and K).
22.51 GENERAL EXAMINATION OF STROKE PATIENTS
Eyes
Diabetic changes
Hypertensive changes
Retinal emboli
Arcus senilis
Cardiovascular system
Blood pressure (hypertension, hypotension)
Heart rhythm (atrial fibrillation)
Murmurs (sources of embolism)
Jugular venous pressure (heart failure, hypovolaemia)
Peripheral pulses and bruits (generalised arteriopathy)
Respiratory system
Pulmonary oedema
Respiratory infection
Abdomen
Urinary retention
The size of the deficit
The site of the lesion (in terms of which arterial territory is involved) and its size, which will have a bearing on management, can be determined by assessing the patient's neurological deficit in a fairly simple way. This involves assessing the patient for the presence of a motor deficit (hemiplegia), higher cerebral function deficit (e.g. aphasia or parietal deficit) or a hemianopia. In addition, the presence of simple sensory loss or a brain-stem deficit (e.g. an eye movement abnormality or vertigo) should be noted. Permutations of these deficits can define several syndromes of stroke, as shown in Figure 22.27.
Clinical assessment of the patient with a stroke should also include attention to the general examination, particularly the heart and peripheral arterial system (see Box 22.51).
CEREBRAL INFARCTION
Cerebral infarction is mostly due to thromboembolic disease secondary to atherosclerosis in the major extracranial arteries (carotid artery and aortic arch). About 20% of infarctions are consequent upon embolism from the heart, and a further 20% are due to occlusion of the small lenticulostriate perforating vessels by intrinsic disease (lipohyalinosis), producing so-called 'lacunar' infarctions. The risk factors for ischaemic stroke reflect the risk factors for these underlying vascular diseases (see Box 22.52).
Pathophysiology
Cerebral infarction is a process which takes some hours to complete, even though the patient's deficit may be maximal close to the onset of the causative vascular occlusion. After the occlusion of a cerebral artery, the opening of anastomotic channels from other arterial territories may restore perfusion of its territory. Furthermore, a reduction in perfusion pressure leads to other homeostatic changes to maintain oxygenation to the brain (see Fig. 22.28). These compensatory changes can prevent even occlusion of a carotid artery from having any clinically apparent effect.
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22.52 STROKE RISK FACTORS
¨ Irreversible
Age
Gender (male > female, except in the very young and very old)
Race (Afro-Caribbean > Asian > European)
Heredity
Previous vascular event, e.g. myocardial infarction, stroke or peripheral embolism
¨ Modifiable
Hypertension
Heart disease (heart failure, atrial fibrillation, endocarditis)
Diabetes
Hyperlipidaemia
Smoking
Excess alcohol consumption
Polycythaemia
Oral contraceptives
Figure 22.28 Homeostatic responses to falling perfusion pressure in the brain following arterial occlusion. Vasodilatation initially maintains cerebral blood flow (A), but after maximal vasodilatation further falls in perfusion pressure lead to a decline in blood flow. An increase in tissue oxygen extraction, however, maintains the cerebral metabolic rate for oxygen (B). Still further falls in perfusion, and therefore blood flow, cannot be compensated; cerebral oxygen availability falls and symptoms appear, then infarction (C).
Figure 22.29 Thresholds of cerebral ischaemia. Symptoms of cerebral ischaemia appear when the blood flow has fallen to less than half of normal and energy supply is insufficient to sustain neuronal electrical function. Full recovery can occur unless this level of flow is sustained for long periods. Further blood flow reduction below the next threshold causes failure of cell ionic pumps and starts the ischaemic cascade, leading to cell death. Brain tissue can sustain such depths of blood flow reduction only for brief periods without infarction.
When these homeostatic mechanisms fail, the process of ischaemia starts; this ultimately leads to infarction. As the cerebral blood flow declines, various neuronal functions fail at various thresholds (see Fig. 22.29). Once flow falls below the threshold for the maintenance of electrical activity, neurological deficit appears. At this level of blood flow the neurons are still viable; if the flow increases again, function returns and the patient will have had a transient ischaemic attack. However, if the flow falls further, a level is reached at which the process of cell death starts. Hypoxia leads to an inadequate supply of adenosine triphosphate (ATP), which in turn leads to loss of function of membrane pumps, thereby allowing influx of sodium and water into the cell (cytotoxic oedema) and the release of the excitatory neurotransmitter glutamate into the extracellular fluid. Glutamate opens membrane channels, allowing the influx of calcium and more sodium into the neurons. Calcium entering the neurons activates intracellular enzymes that complete the destructive process. The infarction process is worsened by the anaerobic production of lactic acid (see Fig. 22.30) and consequent fall in tissue pH.
The final result of the occlusion of a cerebral blood vessel therefore depends upon the competence of the circulatory homeostatic mechanisms, and the severity and duration of the reduction in blood flow. If ischaemic damage has occurred to the vascular endothelium, restoration of blood flow may cause haemorrhage into the infarcted area. This is particularly likely to occur following embolic occlusion when the embolus is lysed by the blood's thrombolytic mechanisms.
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Figure 22.30 The process of neuronal ischaemia and infarction. (1) Reduction of blood flow reduces supply of oxygen and hence ATP. H+ is produced by anaerobic metabolism of available glucose. (2) Energy-dependent membrane ionic pumps fail, leading to cytotoxic oedema and membrane depolarisation, allowing calcium entry and releasing glutamate. (3) Calcium enters cells via glutamate-gated channels and (4) activates destructive intracellular enzymes, (5) destroying intracellular organelles and cell membrane, with release of free radicals. Free fatty acid release activates pro-coagulant pathways which exacerbate local ischaemia. (6) Glial cells take up H+, can no longer take up extracellular glutamate and also suffer cell death, leading to liquefactive necrosis of whole arterial territory.
Radiologically, a cerebral infarct can be seen as a lesion which comprises brain tissue that is ischaemic and swollen but recoverable (the ischaemic penumbra), and dead brain tissue that is already undergoing autolysis. The infarct swells with time and is at its maximal size a couple of days after the stroke onset. At this stage it may be big enough to exert some mass effect both clinically and radiologically. As the weeks go by the oedema subsides and the infarcted area is replaced by a sharply defined fluid-filled cavity.
INTRACEREBRAL HAEMORRHAGE
Of the 15% of acute cerebrovascular disease that is caused by haemorrhage, about half occurs through the rupture of a blood vessel within the brain parenchyma (primary intracerebral haemorrhage), resulting in an acute focal stroke. In addition, a patient with a subarachnoid haemorrhage may present with an acute focal stroke if the artery ruptures into the brain substance as well as into the subarachnoid space. Haemorrhage frequently occurs into an area of brain infarction (see above) and such haemorrhagic infarctions may be difficult to distinguish from primary intracerebral haemorrhage. The causes and risk factors of primary intracerebral haemorrhage are listed in Box 22.53.
Pathophysiology
The explosive entry of blood into the brain parenchyma during a primary intracerebral haemorrhage causes immediate cessation of function in that area as neurons are structurally disrupted and white matter fibre tracts are split apart. A rim of cerebral oedema forms around the resulting blood clot, which, with the haematoma, acts like a mass lesion. If big enough, this can cause shift of the intracranial contents, producing transtentorial coning and sometimes rapid death. If the patient survives, the haematoma is gradually absorbed, leaving a haemosiderin-lined slit in the brain parenchyma (see Fig. 22.31).
22.53 CAUSES OF INTRACEREBRAL HAEMORRHAGE AND ASSOCIATED RISK FACTORS
Disease Risk factors
Charcot-Bouchard microaneurysms Age
Hypertension
Amyloid angiopathy Familial (rare)
Age
Impaired blood clotting Anticoagulant therapy
Blood dyscrasia
Thrombolytic therapy
Vascular anomaly Arteriovenous malformation
Cavernous haemangioma
Substance misuse
Alcohol
Amphetamines
Cocaine
SUBARACHNOID HAEMORRHAGE
Clinical features
About three-quarters of those presenting with a subarachnoid haemorrhage are under 65 years and many are in their fourth decade. Women are more frequently affected than men and this difference increases with advancing age.
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Figure 22.31 CTs of intracerebral haemorrhage. A Acute intracerebral haematoma (arrows). B Resolved lesion leaving a slit-shaped defect (arrows).
Subarachnoid haemorrhage typically presents with a sudden severe 'thunderclap' headache (usually occipital) which lasts for hours (or even days), often accompanied by vomiting. Physical exertion, straining and sexual excitement are common antecedents. There may be loss of consciousness at the onset, so subarachnoid haemorrhage should be considered if a patient is found comatose at home. Since subarachnoid haemorrhage is rare (incidence 6/100 000) and only 1 patient in 8 with a sudden severe headache has had a subarachnoid haemorrhage, clinical vigilance is necessary to avoid a missed diagnosis. All patients with a sudden severe headache require investigation to exclude a subarachnoid haemorrhage (see Fig. 22.32).
Figure 22.32 The investigation of sudden severe headache.
On examination the patient is usually distressed and irritable, with photophobia. There may be neck stiffness due to subarachnoid blood but this takes some 6 hours to develop. Focal hemisphere signs (hemiparesis, aphasia etc.) may be present at onset if there is an associated intracerebral haematoma. Alternatively, these signs may develop after some days due to arterial vasospasm induced by the presence of blood in the subarachnoid space. A 3rd nerve palsy may be present due to local pressure from an aneurysm of the posterior communicating artery, though this is rare. Fundoscopy may reveal a subhyaloid haemorrhage, which represents blood tracking along the subarachnoid space.
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Pathology
Of all subarachnoid haemorrhages, 85% are caused by 'berry' aneurysms bulging out from the bifurcations of the cerebral arteries, particularly in the region of the circle of Willis. These develop during life from defects in the media of the arterial wall and rarely present before the age of 20. There is an increased risk in association with polycystic kidney disease and congenital collagen defects (e.g. Ehlers-Danlos syndrome). Of the remainder, 5% are due to rarities including arteriovenous malformations, and 10% are non-aneurysmal haemorrhages. The cause of these is not known, but they give rise to a very characteristic pattern on CT of peri-mesencephalic blood. Such haemorrhages are known to have a benign outcome in terms of mortality and recurrence.
INVESTIGATION OF ACUTE STROKE
Investigation of a patient presenting with an acute stroke should be planned with a view to confirming the vascular nature of the lesion, the pathological type of vascular lesion, the underlying vascular disease, and the risk factors present (see Box 22.54). Whether the answer to these questions is important depends upon the type of stroke.
Transient stroke
Most transient strokes are due to transient cerebral ischaemia but CT occasionally reveals a small intracerebral haemorrhage. Which arterial territory was involved can be determined from the history of the attack. Approximately 80% occur in the carotid territory. Vertebro-basilar attacks are recognisable from a history of transient hemianopia or brain-stem features such as diplopia or vertigo. If these are not present, a transient hemiplegia, hemisensory loss and, if the dominant hemisphere is affected, dysphasia can be assumed to arise from carotid territory ischaemia.
22.54 INVESTIGATION OF A PATIENT WITH AN ACUTE STROKE
Diagnostic question Investigation
Is it a vascular lesion? CT/MRI
Is it ischaemic or haemorrhagic? CT
Is it a subarachnoid haemorrhage? CT
Lumbar puncture
What is the underlying vascular disease? ECG
Cardiac ultrasound
MRA
Doppler ultrasound
Contrast angiography
What are the risk factors? Blood count
Cholesterol
Clotting/thrombophilia screen
Blood glucose
Most transient strokes are caused by atherosclerotic thromboembolic disease of the major extracranial vessels. The risk of a disabling stroke or death after a transient ischaemic stroke can be reduced by 20-30% with aspirin (75-150 mg daily; see first EBM panel). If patients have a major stenosis (more than 70%) of their carotid artery, carotid endarterectomy is of proven benefit (see second EBM panel). However, only 20% of patients presenting with a carotid territory transient ischaemic attack will have a major carotid stenosis. These patients need to be identified with a non-invasive method of vascular imaging (MRA or ultrasound) before using the more invasive (and therefore risky) contrast angiography that is necessary to delineate the lesion for the surgeon. A suggested scheme for the management of transient stroke is shown in Figure 22.33. A carotid bruit in isolation bears no relationship to the severity of the underlying stenosis or risk of stroke. Only those presenting with a confirmed ischaemic-centred event should undergo further investigation.
EBM
ACUTE ISCHAEMIC STROKE-role of aspirin
'After transient stroke, aspirin is effective in reducing the risk of subsequent vascular events. After an acute persistent stroke RCTs have shown that aspirin started within 48 hours of onset improves long-term outcome.'
Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308:81-106.
International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349:1569-1581.
Further information: www.cochrane.co.uk
EBM
ACUTE ISCHAEMIC STROKE-role of carotid endarterectomy
'After a transient stroke in the carotid territory and in the presence of a significant stenosis (70%) carotid endarterectomy is effective in reducing the risk of subsequent stroke. In asymptomatic carotid stenosis RCTs have shown that endarterectomy has only a small benefit.'
European Carotid Surgery Trialists' Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998; 351:1379-1387.
Barnett HJM, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1999; 339:1415-1425.
Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273:1421-1428.
Further information: www.cochrane.co.uk
Rarely, a cardiac source of embolism is thought to be the cause of a transient stroke. In this case anticoagulation with warfarin is necessary. In most transient strokes, however, anticoagulation has no net benefit since as many haemorrhagic strokes are caused as ischaemic ones prevented.
Evolving stroke
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Figure 22.33 The management of transient stroke.
Worsening of the focal deficit for more than 6 hours occurs in about 10% of patients with acute stroke. This should not be confused with a global deterioration of a patient's general condition-in particular, level of arousal, which can occur some time after a large stroke due to the mass effect of a large swollen infarct. If the focal deficit worsens, the likely cause is progression of the vascular lesion causing the stroke, but the possibility of a non-vascular lesion, such as a tumour, must be considered. Carotid or basilar stenosis can present with a progressive deficit, but this is unusual. About 30% of lacunar strokes evolve over a matter of days. These are recognisable by the presenting syndromes (see Fig. 22.27, p. 1160) which suggest the small size of the brain lesion.
If haemorrhagic stroke has been excluded by imaging, attempts are sometimes made to halt progression of a stroke caused by carotid or basilar stenosis by anticoagulation with heparin. This is, however, of unproved value, as is the use of thrombolytic agents.
Completed stroke
A CT scan is necessary if a subarachnoid haemorrhage is suspected or there is doubt about the vascular nature of the lesion underlying the patient's presentation. In addition, if anticoagulant or thrombolytic drugs are to be given, a haemorrhagic lesion must be excluded. The scan will often reveal clues as to the nature of the arterial lesion. For example, the scan may show a small, deep lacunar infarct following occlusion of a perforating artery, or a more peripheral infarct if a leptomeningeal artery is involved (see Fig. 22.34). In a haemorrhagic lesion, the presence of a haematoma in the sylvian fissure with subarachnoid blood suggests a ruptured middle cerebral artery aneurysm.
After a completed ischaemic stroke it may be 12 hours or more before an area of low density appears on CT, and very small (lacunar) infarcts may not appear at all. By the second week after an infarct the unenhanced CT may appear normal, even with substantial infarction. This is because invasion of the infarcted area by macrophages and new blood vessels renders it isodense. However, contrast enhancement usually shows at least the rim of the lesion (see Fig. 22.35).
Other investigations
Figure 22.34 CTs of lacunar and peripheral infarction. A Lacunar infarction caused by occlusion of a deep perforating artery (arrow). B Peripheral infarction from occlusion of a middle cerebral artery branch (arrows).
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Figure 22.35 CTs showing progressive changes of cerebral infarction due to middle cerebral artery branch occlusion. A Within 6 hours of the stroke little change is seen on the scan except some effacement of sylvian fissure (arrow). B At 3 weeks an enhanced scan shows a low-density lesion with enhancement at the periphery (arrow). C After 2 months there is resolution of the swelling in the lesion and a more clearly defined low density denoting the established infarct (arrow).
Lumbar puncture to examine the CSF is only indicated if a subarachnoid haemorrhage is suspected but has not been seen on a CT scan; in this case it is mandatory. It is best to wait 12 hours since it takes this long for xanthochromia to appear (see Fig. 22.32, p. 1163). After an acute focal stroke other investigations necessary to exclude disorders which may be important in immediate management and in secondary prevention are listed in Box 22.54 (see p. 1164). In younger patients without risk factors for stroke, investigations for the rarer causes are indicated (see Box 22.55).
MANAGEMENT OF COMPLETED STROKE
After a completed stroke, management is aimed at minimising the volume of brain that is irreversibly infarcted, preventing complications (see Box 22.56), reducing the patient's disability and handicap through rehabilitation, and preventing recurrent episodes. Patients with subarachnoid haemorrhage should be referred urgently to a neurosurgical centre, since these patients require investigation for and surgical treatment of the berry aneurysm which may be the cause.
Thrombolysis and other revascularisation treatments
Intravenously delivered thrombolysis with urokinase, streptokinase or recombinant tissue plasminogen activator (rt-PA) increases the risk of haemorrhagic conversion of the cerebral infarct with potentially fatal results. However, this risk may be offset by an improvement in overall outcome if thrombolysis is given within 6 hours of onset of an ischaemic stroke, in the absence of hypertension, when the CT does not show extensive low density. Rt-PA seems to be preferable to other thrombolytic agents (see EBM panel). In the acute phase surgical revascularisation of a cerebral infarct seems to have no practical value since more deficit is often caused by consequent haemorrhage into the ischaemic brain. Vasodilator drugs have no value in the acute management of stroke.
22.55 CAUSES AND INVESTIGATION OF ACUTE STROKE IN YOUNG PATIENTS
Cause Investigation
Cardiac embolism Cardiac ultrasound (including transoesophageal)
Premature atherosclerosis Serum lipids
Arterial dissection MRI
Angiography
Thrombophilia Protein C
Protein S
Antithrombin
Homocystinuria Urinary amino acids
Methionine loading test
Anticardiolipin syndrome Anticardiolipin antibodies
Systemic lupus erythematosus Lupus serology
Vasculitis ESR
CRP
Antineutrophil cytoplasmic antibody (ANCA)
Mitochondrial cytopathy Serum lactate
Muscle biopsy
Primary intracerebral haemorrhage
Arteriovenous malformation (AVM)
Drug misuse cocaine)
Coagulopathy Angiography
Drug screen (amphetamine, Prothrombin time (PT) and activated partial thromboplastin time (APTT)
Platelet count
Subarachnoid haemorrhage
Berry aneurysm
AVM
Carotid dissection Angiography
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22.56 COMPLICATIONS OF ACUTE STROKE
Complication Prevention Treatment
Chest infection Nurse semi-erect
Physiotherapy Antibiotics
Physiotherapy
Dehydration Check swallowing
Nasogastric tube Careful rehydration
Hyponatraemia Check causes (e.g. diuretics)
Avoid excess water replacement Water deprivation
Hypoxaemia Avoid and treat chest complications
Treat heart failure As for cause
Seizures Maintain cerebral oxygenation
Avoid metabolic disturbance Anticonvulsants
Hyperglycaemia Treat diabetes Insulin if necessary
Deep venous thrombosis/pulmonary embolism Anti-embolism stockings
Subcutaneous heparin Anticoagulation (check if haemorrhagic stroke)
Frozen shoulder Physiotherapy Physiotherapy
Local steroid injections
Pressure sores Frequent turning
Monitor pressure areas
Avoid urinary contamination Nursing care
Special mattress
Urinary infection Use penile sheath
Avoid catheterisation if possible Antibiotics
Constipation Appropriate aperients and diet Appropriate aperients
EBM
ACUTE ISCHAEMIC STROKE-role of thrombolytic therapy
'Thrombolysis after ischaemic stroke increases the risk of fatal intracranial haemorrhage, but these risks may be offset by an improvement in long-term outcome amongst survivors. The maximum benefit appears to be when thrombolysis is given within 6 hours of onset.'
Hacke W, Kaste M, Fieschi C, et al., for the Second European-Australasian Acute Stroke Study Investigators. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998; 352:1245-1251.
Wardlaw JM, Warlow CP, Counsell C. Systematic review of evidence on thrombolytic therapy for acute ischaemic stroke. Lancet 1997; 350:607-614.
Further information: www.cochrane.co.uk
Anticoagulation and aspirin
Anticoagulation after an acute stroke is only indicated if the cause is embolism from the heart, such as with atrial fibrillation (see EBM panel). In this case, provided imaging has demonstrated the absence of haemorrhage, oral anticoagulation with warfarin should be started (aiming for an international normalised ratio of 2-3). It is not necessary to start anticoagulation with heparin first since in the acute phase any benefit from this in preventing further embolism is offset by the increased risk of haemorrhagic conversion of the infarct. Aspirin (300 mg daily) should be started immediately after an ischaemic stroke, and carries a far lower risk of haemorrhagic complications.
Blood pressure
EBM
ACUTE ISCHAEMIC STROKE-role of anticoagulants
'There is no benefit to be gained in the routine use of anticoagulants after acute stroke except in the presence of non-rheumatic atrial fibrillation, where anticoagulation halves the odds of serious vascular events. Patients with rheumatic atrial fibrillation have a high risk of recurrent stroke and probably also benefit from anticoagulation.'
International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349:1569-1581.
Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Arch Intern Med 1994; 154:1449-1457.
Further information: www.cochrane.co.uk
The blood pressure is usually acutely raised after a stroke and, unless acute end-organ damage is present, should not be lowered in the acute stage since it will always return towards the patient's normal level within 24-48 hours. Survival of the ischaemic penumbra may depend upon the raised perfusion pressure. The blood pressure tends to stay higher for longer with cerebral haematomas than with cerebral infarcts but, in terms of preventing further haemorrhage, there is no value in reducing this pressure until at least some days after the stroke. After 10 days gentle reduction of blood pressure may be contemplated as part of a secondary preventative strategy for ischaemic stroke.
Hydration and oxygenation
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Adequate hydration and arterial oxygenation are important to preserve as much as possible of ischaemic but recoverable brain. After a stroke a patient may have difficulty in protecting the airway and therefore difficulty in safely maintaining adequate nutrition and hydration orally. In this case, intravenous hydration may be necessary in the first few hours and thereafter; if a patient's swallowing fails to recover, hydration should be maintained by nasogastric tube or gastrostomy.
Blood glucose
A raised blood sugar after a stroke increases infarct size and adversely affects functional outcome. This is probably because hyperglycaemia exacerbates the anaerobic production of lactic acid in the ischaemic penumbra. Hence, a blood sugar above 7 mmol/l should be normalised with insulin.
Nursing care and rehabilitation
Many patients after a stroke are, at least initially, physically dependent, and require expert nursing care to avoid complications. Bladder and bowel care need special consideration. Care may be better provided in specialised stroke units, which have been shown to reduce patient mortality and accelerate functional recovery (see p. 243). Depression is common after a stroke and will often respond to antidepressant medication. Consideration of a patient's rehabilitation needs should commence at the same time as the acute medical management (see above).
Prognosis and secondary prevention
About 75% of patients survive the acute stage of focal stroke due to cerebral infarction or primary intracerebral haemorrhage. The immediate mortality of aneurysmal subarachnoid haemorrhage is 30%, with a recurrence rate of 50% in the first 6 months and 3% annually thereafter. Secondary prevention requires appropriate neurosurgical management. Half to three-quarters of those surviving an acute stroke achieve functional independence, mostly within the first 3 months. After a completed focal stroke there is an annual recurrence rate of 8-11%. Secondary prevention of stroke involves attention to those risk factors that are reversible and, in the case of ischaemic stroke, the use of aspirin. Patients with a cardiac cause for their ischaemic stroke, such as atrial fibrillation, should be anticoagulated in the absence of any contraindication. If the residual deficit after an ischaemic stroke is minimal, that patient should be managed in the same way as for a transient stroke.
CEREBRAL VENOUS DISEASE
Thrombosis of cerebral veins and venous sinuses is uncommon. The causes are listed in Box 22.57.
Cerebral venous occlusion causes an increase in intracranial pressure and patchy ischaemia, which is often haemorrhagic. The clinical features vary according to the part of the cerebral venous system involved (see below).
Cortical vein thrombosis
This may present with focal cortical deficits (aphasia, hemiparesis etc.) and epilepsy (focal or generalised), according to the area involved. The deficit may enlarge if spreading thrombophlebitis occurs.
Cerebral venous sinus thrombosis
The clinical features of cerebral venous sinus thrombosis depend on the sinus involved (see Box 22.58).
22.57 CAUSES OF CEREBRAL VENOUS THROMBOSIS
Predisposing causes
Dehydration
Pregnancy
Behçet's disease
Thrombophilia
Hypotension
Oral contraceptives
Local causes
Paranasal sinusitis
Meningitis, subdural empyema
Penetrating head and eye wounds
Facial skin infection
Otitis media, mastoiditis
Skull fracture
22.58 CLINICAL FEATURES OF CEREBRAL VENOUS THROMBOSIS
Cavernous sinus
Proptosis, ptosis, headache, external and internal ophthalmoplegia, papilloedema, reduced sensation in trigeminal first division
Often bilateral, patient ill and febrile
Superior sagittal sinus
Headache, papilloedema, seizures
May involve veins of both hemispheres, causing advancing motor and sensory focal deficits
Transverse sinus
Hemiparesis, seizures, papilloedema
May spread to jugular foramen to involve cranial nerves 9, 10, 11
ISSUES IN OLDER PEOPLE
STROKE
Two-thirds of stroke patients are aged over 60 years.
A clear history in establishing a diagnosis of stroke is as important in older people as in younger patients, but will be more difficult to obtain if there is pre-existing cognitive impairment or if there are communication difficulties.
The benefits of carotid endarterectomy accrue quickly after transient stroke; therefore when it is indicated, advanced age alone is not a contraindication for surgery.
Older patients with stroke are more likely to have other pathology such as ischaemic heart disease, cardiac failure, chronic obstructive pulmonary disease (COPD), osteoarthritis and visual impairments. All such comorbidities will have to be addressed as part of overall stroke management.
The older the patient, the more he or she will need an active programme of rehabilitation to regain maximum function. Cognitive impairment will adversely affect outcome, as much of rehabilitation involves the learning and retention of new skills (see p. 243).
The reappearance of neurological signs from a previous stroke in a patient who is ill or hypotensive is a common cause of over-diagnosis of recurrent stroke.
Diffuse small-vessel cerebrovascular disease is very common in older people and may present insidiously with gait abnormalities and/or significant memory impairment. It also predisposes to confusional states when intercurrent infection or metabolic disturbance intervenes.
Whilst anticoagulation for secondary prevention after stroke may be indicated in certain circumstances, it must be used with caution. The associated risks in frail older patients are higher because of increased comorbidity, particularly falls and cognitive impairment, and the potential for interaction with other medication.
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Home > 2 SYSTEM-BASED DISEASES > 22 Neurological disease > INFLAMMATORY DISEASES
INFLAMMATORY DISEASES
MULTIPLE SCLEROSIS
In multiple sclerosis, one of the most common neurological causes of long-term disability, the myelin-producing oligodendrocytes of the central nervous system are the target of recurrent cell-mediated autoimmune attack. In the UK the prevalence is 80 per 100 000 of the population, with an annual incidence of around 5 per 100 000. The lifetime risk of developing multiple sclerosis is about 1 in 800. The incidence is higher in temperate climates and in people of European extraction, and the disease is more common in women (male:female ratio of 1:1.5).
Aetiology
Epidemiological evidence suggests an environmental influence on causation. The incidence varies with latitude, being low in equatorial areas and higher in the temperate zones of both hemispheres. A genetic influence is suggested by a 10-fold increase in risk in first-degree relatives and from twin studies in which there is higher concordance for multiple sclerosis in monozygotic twins compared to dizygotic twins. HLA tissue-typing has demonstrated an increased prevalence of haplotypes A3, B7, Dw2 and DR2 in affected patients in the UK, but different haplotypes are associated in other countries. An immune mechanism is suggested by increased levels of activated T lymphocytes in the CSF, and increased immunoglobulin synthesis within the central nervous system. There are increased levels of antibody to some viruses, including measles virus, in the CSF, but this may be a result of the disease process rather than directly related to the cause. The relative importance of environmental, genetic and immunological factors is unresolved. Multiple sclerosis is likely to be multifactorial in origin.
Pathology
An attack of central nervous system inflammation in multiple sclerosis starts with the entry through the blood-brain barrier of activated T lymphocytes. These recognise myelin-derived antigens on the surface of the nervous system's antigen-presenting cells, the microglia, and undergo clonal proliferation. The resulting inflammatory cascade releases cytokines and initiates destruction of the oligodendrocytemyelin unit by macrophages. Histologically, the characteristic lesion is a plaque of inflammatory demyelination occurring most commonly in the periventricular regions of the brain, the optic nerves and the subpial regions of the spinal cord (see Fig. 22.36). Initially, this is a circumscribed area of disintegration of the myelin sheath, accompanied by infiltration by activated lymphocytes and macrophages, often with conspicuous perivascular inflammation. After an acute attack gliosis follows, leaving a shrunken grey scar.
Much of the initial acute clinical deficit is caused by the effect of inflammatory cytokines upon transmission of the nervous impulse rather than structural disruption of the myelin, which explains the rapid recovery of some deficits and probably the efficacy of steroids in ameliorating the acute deficit. However, the myelin loss that results from an attack reduces the safety factor for impulse propagation or causes complete conduction block, which lowers the efficiency of central nervous system functions. In established multiple sclerosis there is progressive axonal loss, probably due to direct damage to axonal integrity by the inflammatory mediators released in acute attacks (including nitrous oxide), and this is the cause of the phase of the disease where there is progressive and persistent disability (see Fig. 22.37).
Integration link: Myelin destruction - MS and Guillain-Barre
Taken from Medical Neuroscience
Clinical features
A diagnosis of multiple sclerosis requires the demonstration of lesions in more than one anatomical site at more than one time for which there is no other explanation. Around 80% of patients have a relapsing and remitting clinical course of episodic dysfunction of the central nervous system with variable recovery. Of the remaining 20%, most follow a slowly progressive clinical course, with a tiny minority who have a fulminant variety leading to early death (see Fig. 22.37). The peak age of onset is in the fourth decade, onset before puberty or after the age of 60 years being rare. There are a number of clinical symptoms and syndromes characteristic of multiple sclerosis, some of which may occur at presentation while others may develop in the course of the illness (see Boxes 22.59 and 22.60).
Figure 22.36 Multiple sclerosis. A Photomicrograph from demyelinating plaque showing perivascular cuffing of blood vessel by lymphocytes. B Section through pons showing demyelinating plaques in white matter (arrows) (Weigert-Pal).
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Demyelinating lesions cause symptoms and signs that usually come on subacutely over days or weeks, and resolve over weeks or months. After a variable interval there may be a recurrence, often within 2 years. Frequent relapses with incomplete recovery indicate a poor prognosis, and in many patients a phase of secondary progression supersedes the phase of relapse and remission. In a minority of patients there may be an interval of years or even decades between attacks, and in some, particularly if optic neuritis is the initial manifestation, there is no recurrence. Some presentations, such as optic neuritis with purely sensory relapses, have a good prognosis.
Figure 22.37 The progression of disability in fulminant, relapsing-remitting and progressive multiple sclerosis.
22.59 COMMON PRESENTATIONS OF MULTIPLE SCLEROSIS
Optic neuritis
Relapsing and remitting sensory symptoms
Subacute painless spinal cord lesion
Acute brain-stem syndrome
Subacute loss of function of upper limb
6th cranial nerve palsy
22.60 SYMPTOMS AND SYNDROMES SUGGESTIVE OF CNS DEMYELINATION
Optic neuritis (afferent pupillary defect)
Tingling in spine or limbs on neck flexion (Lhermitte's phenomenon)
Dorsal column loss in one limb
Progressive non-compressive paraparesis
Partial Brown-Séquard syndrome
Internuclear ophthalmoplegia with ataxia
Focal brain-stem lesions
Postural ('rubral') tremor
Trigeminal neuralgia under the age of 50
Recurrent facial palsy
The physical signs observed in multiple sclerosis depend on the anatomical site of demyelination. Combinations of spinal cord and brain-stem signs are common, maybe with evidence of previous optic neuritis in the form of an afferent pupillary deficit. Significant intellectual impairment is unusual until late in the disease, when loss of frontal functions and impairment of memory are common.
Investigations
There is no specific test for multiple sclerosis and the results of investigation are taken in conjunction with the clinical picture in making a diagnosis of varying probability (see Box 22.61). The clinical diagnosis of multiple sclerosis can be supported by investigations which aim to exclude other conditions, provide evidence for an inflammatory disorder and identify multiple sites of neurological involvement (see Box 22.62).
22.61 CLINICAL DIAGNOSTIC CRITERIA FOR MULTIPLE SCLEROSIS
Clinically definite
Requires all of:
Age < 60 years
History or signs of deficits in two or more anatomical sites in CNS
Abnormal signs are present on CNS examination which indicate white matter involvement
CNS involvement in one of two patterns
Relapsing and remitting: two or more episodes lasting at least 24 hours and > 1 month apart
Progressive: slow and/or stepwise progression over at least 6 months
No other explanation of symptoms
Clinically probable
Relapsing and remitting symptoms with one neurological sign commonly associated with MS
or
Documented single episode with partial or complete recovery, with signs on examination of multifocal white matter disease and
No other explanation
Clinically possible
Relapsing and remitting symptoms without documented or objective signs to establish more than one anatomical site of CNS involvement
No other explanation
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22.62 INVESTIGATIONS IN A PATIENT SUSPECTED OF HAVING MULTIPLE SCLEROSIS
Exclude other structural disease and identify plaques of demyelination
Imaging (MRI, myelography)
Demonstrate other sites of involvement
Visual evoked potentials
Other evoked potentials
Demonstrate inflammatory nature of lesion(s)
CSF examination:
Cell count
Protein electrophoresis (oligoclonal bands)
Exclude other conditions
Chest radiograph
Serum angiotensin-converting enzyme (ACE)
Serum B12
Antinuclear antibodies
Following the first clinical event, investigations may help in confirming the disseminated nature of the disease. Visual evoked potentials (see p. 1110) can detect clinically silent lesions in up to 70% of patients, but auditory and somatosensory evoked potentials are seldom of diagnostic value. The CSF may show a lymphocytic pleocytosis in the acute phase and oligoclonal bands of IgG in 70-90% of patients between attacks. Oligoclonal bands are not specific to multiple sclerosis but denote intrathecal inflammation and occur in a range of other disorders. MRI is the most sensitive technique for imaging lesions in both brain and spinal cord (see Fig. 22.7C, p. 1113) and in excluding other causes of the neurological deficit. However, the MRI appearances in multiple sclerosis may be difficult to distinguish from those of cerebrovascular disease or cerebral vasculitis. Diagnosis depends on the clinical history and examination, taken in combination with the investigative findings. It is important to exclude other potentially treatable alternative conditions such as infections, vitamin B12 deficiency and spinal cord compression.
Management
The management of multiple sclerosis involves treatment of the acute relapse, prevention of future relapse, treatment of complications, and management of the patient's disability.
Acute relapse
In a function-threatening relapse, high-dose intravenous steroids (methylprednisolone 1 g daily for 3 days) are indicated to shorten the duration of the relapse but do not affect long-term outcome (see EBM panel). Pulsed intravenous steroids also have some effect in reducing spasticity. Prolonged administration of steroids does not alter the long-term outcome and is therefore avoided. Pulses of intravenous steroids can be given up to 3-4 times in a year but their administration should be restricted to those with significant function-threatening deficits.
EBM
MULTIPLE SCLEROSIS-role of pulsed steroid therapy to shorten relapse
'In patients with optic neuritis and acute MS relapse, short courses of steroids improve recovery at 4 weeks but have no effect on long-term disability. Two RCTs have shown little difference between oral and intravenous high-dose steroids in the treatment of MS relapse.'
Sellebjerg F, Frederiksen JL, Nielsen PM, Olesen J. Double-blind, randomised, placebo-controlled study of oral, high-dose methylprednisolone in attacks of MS. Neurology 1998; 51:529-534.
Barnes D, Hughes RAC, Morris RW, et al. Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet 1997; 349:902-906.
Further information: www.clinicalevidence.org
Preventing relapses
Immunosuppressive agents including azathioprine have a marginal effect in reducing relapses and improving long-term outcome. In relapsing and remitting multiple sclerosis subcutaneous or intramuscular interferon beta-1a/b reduces the number of relapses by some 30%, with a small effect on long-term disability (see EBM panel). The immune modulator glatiramer acetate has similar effects. The effects of other immune modulation therapies are currently being evaluated and may have some use in the future. Special diets including a gluten-free diet, linoleic acid supplements or hyperbaric oxygen therapy are of no proven benefit.
EBM
MULTIPLE SCLEROSIS-role of interferon beta-1a/b in reducing relapse rate
'In patients with active relapsing and remitting MS, interferon beta-1a/b reduces relapse rate by one-third and may have some effect on the progression of disability. One trial has shown that, in patients with secondary progressive disease, the development of disability may be delayed by 9-12 months.'
PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352:1498-1504.
IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. Clinical results of a multicenter, randomised, double-blind, placebo-controlled trial. Neurology 1993; 43:655-661.
European Study Group on Interferon Beta-1b in Secondary Progressive MS. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998; 352:1491-1497.
Further information: www.clinicalevidence.org
Complications
The treatment of the complications of multiple sclerosis is summarised in Box 22.63. Of prime importance are a careful explanation of the nature of the disease and its outcome and the support of patients and their relatives when disability occurs. A frank discussion of the diagnosis and prognosis is necessary and may dispel fears, which are often ill founded. Periods of physiotherapy may improve functional capacity in those patients who become disabled, and assessment by the occupational therapist will provide guidance in the provision of aids within the home and in reducing handicap.
22.63 TREATMENT OF COMPLICATIONS OF MULTIPLE SCLEROSIS
Complication Treatment
Spasticity Physiotherapy
Baclofen 15-100 mg*
Diazepam 2-15 mg*
Dantrolene 25-400 mg*
Tizanidine 18-32 mg
Local injection of botulinum toxin
Chemical neuronectomy
Ataxia Isoniazid 600-1200 mg*
Clonazepam 2-8 mg*
Dysaesthesia Carbamazepine 200-1800 mg*
Phenytoin 200-400 mg
Gabapentin 900-2400 mg
Amitriptyline 10-100 mg
Bladder symptoms See Box 22.49, page 1158
* In divided doses.
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Care of the bladder is particularly important. Infections should be treated with an appropriate antibiotic. Incontinence, urgency and frequency may be treated pharmacologically, by external drainage or by urinary catheter, which may be passed intermittently by the patient rather than left permanently in-dwelling. The choice of treatment is difficult and urodynamic assessment may be necessary in patients with troublesome symptoms. Sexual dysfunction is a source of anxiety in many patients and may be relieved by skilled counselling and, if necessary, prosthetic aids. Sildenafil may help impotence.
Prognosis
The outlook is difficult to predict with confidence in any individual patient, especially early in the disease. Furthermore, the ability to diagnose disease at an earlier stage means that older studies may not reliably reflect the outcome of those diagnosed with modern techniques. About 15% of those having one attack of demyelination do not suffer any more events, whilst those with relapsing and remitting multiple sclerosis have, on average, 1-2 relapses every 2 years. Approximately 5% of patients die within 5 years of onset, whilst others have a very benign outcome. Overall, after 10 years about one-third of patients are disabled to the point of needing help with walking, whilst after 15 years about 50% have this degree of disability.
ACUTE DISSEMINATED ENCEPHALOMYELITIS
This is an acute monophasic demyelinating condition in which there are areas of perivenous demyelination widely disseminated throughout the brain and spinal cord. The illness may apparently occur spontaneously but often occurs a week or so after a viral infection, especially measles and chickenpox, or following vaccination, suggesting that it is immunologically mediated.
Clinical features
Headache, vomiting, pyrexia, confusion and meningism may be presenting features, often with focal or multifocal brain and spinal cord signs. Seizures or coma may occur. Flaccid paralysis with extensor plantar responses is common and cerebellar signs may be present, particularly when the disorder follows chickenpox.
Investigations
MRI shows multiple high-signal areas in a pattern similar to that of multiple sclerosis, although often with larger areas of abnormality. The CSF may be normal or show a small increase in mononuclear cells and protein. The differential diagnosis from a first severe attack of what turns out to be multiple sclerosis may be difficult.
Management
The disease may be fatal in the acute stages but is otherwise self-limiting. Treatment with high-dose intravenous methylprednisolone, using the same regimen as for a relapse of multiple sclerosis, is recommended.
ACUTE TRANSVERSE MYELITIS
Transverse myelitis is an acute monophasic inflammatory demyelinating disorder affecting the spinal cord over a variable number of segments. Patients may be of any age and present with a subacute paraparesis with a sensory level, often with severe pain in the neck or back at the onset. MRI is needed to distinguish this from a compressive lesion of the spinal cord. CSF examination shows cellular pleocytosis, often with polymorphs at the onset. Treatment is with high-dose intravenous methylprednisolone. The outcome is variable; in some cases, near-complete recovery occurs despite a severe initial deficit. A small proportion of patients who present with acute transverse myelitis go on to develop multiple sclerosis in later years.
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Home > 2 SYSTEM-BASED DISEASES > 22 Neurological disease > DEGENERATIVE DISEASES
DEGENERATIVE DISEASES
Many diseases cause degeneration in different parts of the nervous system without an identifiable external cause. Genetic factors are known to be involved in several, but the cause is still unknown for the majority. Clinical features depend on which structures are affected. Degeneration of the cerebral cortex causes dementia, the most common type being Alzheimer's disease. Degeneration of the basal ganglia results in movement disorder, which may manifest as either too little or too much movement, depending on the structures involved. Examples of these conditions are Parkinson's disease and Huntington's disease. Cerebellar degeneration usually causes ataxia. Degeneration can also occur in the spinal cord or peripheral nerves, giving rise to motor, sensory or autonomic disturbance.
DEGENERATIVE CAUSES OF DEMENTIA
As many as 5% of the population over 65 years of age suffer from a dementing illness. Over the age of 80, this rises to over 20%. Dementia therefore has major implications for health resources.
ALZHEIMER'S DISEASE
This is the most common cause of dementia, occurring mostly in patients over 45 years. Genetic factors are important, particularly if the age of onset is under 65 years; the familial disease may account for some 15% of cases, though genetic abnormalities on several different chromosomes have been described, particularly chromosomes 1, 14 and 21. The inheritance of one of the alleles of apolipoprotein e (apo e), e4, is associated with a fourfold increase in the risk of developing the disease.
Pathology
Macroscopically, the brain is atrophic, particularly the cerebral cortex and hippocampus. Histology reveals the presence of senile plaques and neurofibrillary tangles in the cerebral cortex. Histochemical staining demonstrates significant quantities of amyloid in plaques (see Fig. 22.38). Many different neurotransmitter abnormalities have been described, in particular impairment of cholinergic transmission, though noradrenaline, 5-HT, glutamate and substance P are also involved (see Box 22.1, p. 1107).
Integration link: Alzheimer's disease - description and morphology
Taken from Robbins & Cotran's Pathologic Basis of Disease 7e
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Figure 22.38 Alzheimer's disease. Section of neocortex stained with polyclonal antibody against ßA4 peptide showing amyloid deposits in plaques in brain substance (arrow A) and in blood vessel walls (arrow B).
Clinical features
The key clinical feature is impairment of delayed recall, i.e. the inability to retrieve (remember) information acquired in the past. Hence, patients present with gradual impairment of memory, usually in association with disorders of other cortical function. Both short-term and long-term memory are affected, but defects in the former are usually more obvious. Later in the course of the disease, typical features are apraxia, visuo-spatial impairment and aphasia. In the early stages, patients themselves may complain of difficulties but, as the disease progresses, it is common for patients to deny that there is anything wrong (anosognosia). In this situation, patients are often brought to medical attention by their carers. Depression is common. Occasionally, patients become aggressive, and the clinical features are made acutely worse by coexistent intercurrent illness.
Investigations and management
EBM
ALZHEIMER'S DISEASE-role of donepezil and rivastigmine
'In selected patients with mild or moderate Alzheimer's disease treated for periods of up to a year, donepezil and rivastigmine produce modest improvements in cognitive function. However, the effects on quality of life of both patient and carer are still not clear, and hence the practical importance of these drugs has not been established.'
Birks JS, Melzer D, Beppu H. Donepezil for mild and moderate Alzheimer's disease (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Birks J, Grimley Evans J, Iakovidou V, Tsolaki M. Rivastigmine for Alzheimer's disease (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.cochrane.co.uk
Investigation is aimed at excluding other treatable causes of dementia (see Box 22.38, p. 1146), as histological confirmation of the diagnosis usually occurs only after death. There is no known treatment, though recently donepezil and rivastigmine, inhibitors of cerebral acetylcholinesterase, have been shown to be of some benefit (see EBM panel). Management consists largely of providing a familiar environment for the patient, and providing support for the carers.
OTHER CAUSES OF DEMENTIA
Wernicke-Korsakoff disease
Deficiency of thiamin (vitamin B1) usually presents with an acute confusional state (Wernicke's encephalopathy) and brain-stem abnormalities such as ataxia, nystagmus and extraocular muscle weakness (particularly lateral rectus weakness). If inadequately treated, this results in a dementia characterised by a profound disturbance of short-term memory associated with a tendency to confabulate, called Korsakoff's syndrome. The deficiency can arise as a result of malnutrition (including that occasioned by chronic alcohol misuse), malabsorption or even protracted vomiting (as in hyperemesis gravidarum). The diagnosis can be made biochemically by the finding of a reduced red cell transketolase, but this test is often difficult to obtain and so the diagnosis is usually made clinically. Because it is potentially treatable, the condition must be considered in any confused or demented patient; if there is any doubt, it is usually better to treat anyway. Treatment consists of administering high-dose vitamins, often intravenously in the initial stages, followed by oral thiamin (initially 100 mg 8-hourly), in addition to treating the underlying cause.
Pick's disease
In this condition, which is much rarer than Alzheimer's, degeneration predominantly affects frontal and temporal lobes. The histology is characterised by the presence of argyrophilic cytoplasmic inclusion bodies (Pick bodies) and chromatolytic ballooned neurons (Pick cells) (see Fig. 22.39). Patients may present with personality change due to frontal lobe involvement or with progressive aphasia. Memory is relatively preserved in the early stages. There is no specific treatment for Pick's disease.
Lewy body dementia
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Figure 22.39 Pick's disease. A Lateral view of formalin-fixed brain from a patient who died of Pick's disease showing gyral atrophy of frontal and parietal lobes and a more severe degree of atrophy affecting the anterior half of the temporal lobe. B High power (x 200) of hippocampal pyramidal layer, prepared with monoclonal anti-tau antibody. Many neuronal cell bodies contain sharply circumscribed, spherical cytoplasmic inclusion bodies (Pick bodies).
In diffuse Lewy body disease, pathology similar to that found in the substantia nigra in Parkinson's disease is found in the cerebral cortex. This condition usually presents as cognitive impairment in the context of an extrapyramidal syndrome, and the cognitive features may be indistinguishable from those of Alzheimer's disease. Patients' cognitive state often fluctuates; they have a high incidence of visual hallucinations, and are particularly sensitive to this side-effect of anti-parkinsonian medication. They are also particularly sensitive to neuroleptic medication. There is no specific treatment for this condition.
PARKINSON'S DISEASE AND AKINETIC-RIGID SYNDROMES
There are a number of degenerative diseases affecting the basal ganglia, which present with differing combinations of slowness of movement (bradykinesia), increased tone (rigidity), tremor and loss of postural reflexes. The most common cause of these parkinsonian or akinetic-rigid syndromes is idiopathic Parkinson's disease.
IDIOPATHIC PARKINSON'S DISEASE
This condition has an annual incidence of about 0.2/1000 and a prevalence of 1.5/1000 in the UK. Prevalence rates are similar throughout the world, though lower rates have been reported for China and West Africa. Whilst 10% of the patients are under 45 years at presentation, the incidence and prevalence both increase with age, the latter rising to over 1% in those over 60. Sex incidence is about equal. It is less common in cigarette smokers.
Aetiology
The cause is unknown, and no strong genetic factors have been identified, though recent work on twins has suggested that the genetic influence may be greater than previously thought. The discovery that methyl-phenyl-tetrahydropyridine (MPTP) caused severe parkinsonism in young drug users suggests that the idiopathic disease might be due to an environmental toxin; many candidate toxins have been studied, but there is no strong evidence in favour of any of them.
Pathology
Figure 22.40 Parkinson's disease. High power (x 400) of substantia nigra of a patient with Parkinson's disease to show classical Lewy body (haematoxylin and eosin).
There is depletion of the pigmented dopaminergic neurons in the substantia nigra, hyaline inclusions in nigral cells (Lewy bodies-see Fig. 22.40), atrophic changes in the substantia nigra and depletion of neurons in the locus coeruleus. Reduced dopaminergic output from the substantia nigra to the globus pallidus leads to reduced inhibitory effects on the subthalamic nucleus, neurons which become more active than usual in inhibiting activation of the cortex. This in turn results in bradykinesia.
Clinical features
The classical syndrome of tremor, rigidity and bradykinesia may be absent initially, when non-specific symptoms of tiredness, aching limbs, mental slowness, depression (see p. 251) and small handwriting (micrographia) may be noticed.
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22.64 PHYSICAL ABNORMALITIES IN PARKINSONISM
General
Expressionless face
Greasy skin
Soft, rapid, indistinct speech
Flexed posture
Impaired postural reflexes
Gait
Slow to start walking
Shortened stride
Rapid, small steps, tendency to run (festination)
Reduced arm swing
Impaired balance on turning
Tremor
Resting 4-6 Hz
Usually first in fingers/thumb
Coarse, complex movements, flexion/extension of fingers
Abduction/adduction of thumb
Supination/pronation of forearm
May affect arms, legs, feet, jaw, tongue
Intermittent, present at rest and when distracted
Diminished on action
Postural 8-10 Hz
Less obvious, faster, finer amplitude
Present on action or posture, persists with movement
Rigidity
Cogwheel type, mostly upper limbs
Plastic (leadpipe) type, mostly legs
Bradykinesia
Slowness in initiating or repeating movements
Impaired fine movements, especially of fingers
The presentation is almost always unilateral, a rest tremor in an upper limb being a common presenting feature. The tremor may also affect the legs, mouth and tongue. It may remain the predominant symptom for some years. Bradykinesia may develop gradually. Most patients have difficulty with rapid fine movements, and this manifests itself as slowness of gait and difficulty with tasks such as fastening buttons, shaving or writing. Rigidity, or increased muscular tone, causes stiffness and a flexed posture. Postural righting reflexes are impaired early on in the disease, but falls tend not to occur until later on. As the disease advances, speech becomes softer and indistinct. There are a number of abnormalities on neurological examination, and these are listed in Box 22.64.
Although parkinsonian features are initially unilateral, gradual bilateral involvement is the rule. Muscle strength and reflexes remain normal, and plantar responses are flexor. There is a paucity of facial expression (hypomimia) and the blink reflex may be exaggerated and fail to habituate (glabellar tap sign). Eye movements are normal to standard clinical testing, provided one allows for the normal limitation of upward gaze with age. Sensation is normal and intellectual faculties are not affected initially. As the disease progresses, about one-third of patients develop cognitive impairment.
Investigations
The diagnosis is made clinically, as there is no diagnostic test for Parkinson's disease. Sometimes it is necessary to investigate patients to exclude other causes of parkinsonism if there are any unusual features. Patients presenting before the age of 50 are usually tested for Wilson's disease, and imaging (CT or MRI) of the head may be needed if there are any features suggestive of pyramidal, cerebellar or autonomic involvement, or the diagnosis is otherwise in doubt.
Management
Drug therapy
Levodopa combined with a peripheral-acting dopa-decarboxylase inhibitor provides the mainstay of treatment in Parkinson's disease but should only be started to help overcome significant disability. Other agents include anticholinergic drugs, dopamine receptor agonists, selegiline and amantadine (see Fig. 22.41).
Levodopa. Although the number of dopamine-releasing terminals in the striatum is diminished in Parkinson's disease, remaining neurons can be driven to produce more dopamine by administering its precursor, levodopa. If levodopa is administered orally, however, more than 90% is decarboxylated to dopamine peripherally in the gastrointestinal tract and blood vessels, and only a small proportion reaches the brain. This peripheral conversion of levodopa is responsible for the high incidence of side-effects if used alone. The problem is largely overcome by giving a decarboxylase inhibitor that does not cross the blood-brain barrier along with the levodopa. Two peripheral decarboxylase inhibitors, carbidopa and benserazide, are available as combination preparations with levodopa.
The initiation of levodopa therapy should be delayed until there is significant disability, since there is concern regarding long-term side-effects (see EBM panel). Levodopa is particularly effective at improving bradykinesia and rigidity. Tremor is also helped but rather unpredictably. The initial dose is 50 mg 8- or 12-hourly, increased if necessary. The total levodopa dose may be increased to over 1000 mg/day, but should be kept as low as possible. Side-effects include postural hypotension and nausea and vomiting, which may be offset by the use of a peripheral dopamine antagonist such as domperidone. Other dose-related side-effects are involuntary movements, particularly orofacial dyskinesias, limb and axial dystonias, and occasionally depression, hallucinations and delusions.
EBM
PARKINSON'S DISEASE-delaying treatment with levodopa by the use of bromocriptine
'The early use of bromocriptine instead of levodopa may be beneficial in delaying motor complications and dyskinesias but methodological differences between trials mean that it is not possible to reach a clear conclusion at this point.'
Ramaker C, Hilten JJ van. Bromocriptine versus levodopa in early Parkinson's disease (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Hilten JJ van, Ramaker C, Beek WJT van de, Finken MJJ. Bromocriptine for levodopa-induced motor complications in Parkinson's disease (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.cochrane.co.uk
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Figure 22.41 Mechanisms of drug action in Parkinson's disease. (1) Decarboxylase inhibitors (carbidopa and benserazide) reduce side-effects by reducing peripheral conversion of levodopa to dopamine by aromatic amino acid decarboxylase (AAAD). (2) Active transport of levodopa into the brain may be inhibited by competition from dietary amino acids after a high-protein meal. (3) In the nigrostriatal neurons levodopa is converted into dopamine. (4) Amantadine enhances the release of dopamine at the nerve terminal. (5) Dopamine agonists act directly on striatal receptors. (6) The monoamine oxidase type B (MAO-B) inhibitor selegiline increases the availability of neuronal dopamine by reducing its metabolism outside the neuron. (7) The catechol-O-methyl-transferase (COMT) inhibitor entacapone prolongs the availability of dopamine by inhibiting the metabolism of dopamine and levodopa outside the neuron.
Late deterioration despite levodopa therapy occurs after 3-5 years in one-third to one-half of patients. Usually this manifests as fluctuation in response. The simplest form of this is end-of-dose deterioration due to progression of the disease and loss of capacity to store dopamine. More complex fluctuations present as sudden, unpredictable changes in response, in which periods of severe parkinsonism alternate with dyskinesia and agitation (the 'on-off' phenomenon). End-of-dose deterioration can often be improved by dividing the levodopa into smaller but more frequent doses, or by converting to a slow-release preparation. The 'on-off' phenomenon is difficult to treat, but sometimes subcutaneous injections of apomorphine (a dopamine agonist) are helpful to 'rescue' the patient rapidly from an 'off' period.
Involuntary movements (dyskinesia) may occur as a peak-dose phenomenon, or as a biphasic phenomenon (occurring during both the build-up and wearing-off phases). Management is difficult, but again involves modifying the way levodopa is administered to obtain constant levels in the brain, and the use of alternative drugs, particularly dopamine agonists.
Anticholinergic agents. These have a useful effect on tremor and rigidity, but do not help bradykinesia. They can be prescribed early in the disease before bradykinesia is a problem, but should be avoided in elderly patients in whom they cause confusion and hallucinations. Other side-effects include dry mouth, blurred vision, difficulty with micturition and constipation. Many anticholinergics are available-for example, trihexyphenidyl (benzhexol; 1-4 mg 8-hourly) and orphenadrine (50-100 mg 8-hourly).
Amantadine. This has a mild, usually short-lived effect on bradykinesia, but may be used early in the disease before more potent treatment is needed. Amantadine is also useful in controlling the dyskinesias produced by dopaminergic treatment later in the disease. The dose is 100 mg 8- or 12-hourly. Side-effects include livedo reticularis, peripheral oedema, confusion and seizures.
Selegiline. Selegiline has a mild therapeutic effect in its own right. Evidence that it slows the progression of the disease is highly controversial. There has been some doubt as to its safety, but this is also controversial and the subject of ongoing research. The usual dose is 5-10 mg in the morning.
COMT (catechol-O-methyl-transferase) inhibitors. Entacapone (200 mg with each dose of levodopa) reduces motor fluctuations when used with levodopa. This allows the levodopa dose to be reduced and given less frequently.
Dopamine receptor agonists. An increasing number of these drugs is becoming available. They all have slightly different activity at the various dopamine receptors in the brain. Apomorphine given alone causes marked vomiting and has to be administered parenterally. The vomiting can be overcome by the concomitant use of domperidone, and parenteral administration achieved through continuous subcutaneous infusion from a portable pump, or direct injection as needed. Dealing with the drug thus requires considerable nursing support but, used correctly, it can be very useful.
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EBM
PARKINSON'S DISEASE-comparison of different dopamine agonists
'Methodological differences between trials comparing the use of dopamine agonists such as bromocriptine, lisuride, pergolide and pramipexole currently do not allow a clear statement as to which, if any, is superior to the others in the management of levodopa-induced complications.'
Clarke CE, Speller JM. Lisuride versus bromocriptine for levodopa-induced complications in Parkinson's disease (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Clarke CE, Speller JM. Pergolide versus bromocriptine for levodopa-induced motor complications in Parkinson's disease (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Clarke CE, Speller JM, Clarke JA. Pramipexole versus bromocriptine for levodopa-induced complications in Parkinson's disease (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.cochrane.co.uk
More easily administered drugs include bromocriptine, lisuride, pergolide, cabergoline, ropinirole and pramipexole, which can all be taken orally (see EBM panel). These drugs are less powerful than levodopa in controlling features of parkinsonism, but they are much less likely to cause dose fluctuations or dyskinesia, though they will certainly exacerbate the latter once these have developed. Side-effects include nausea, vomiting, confusion and hallucinations. The dose of bromocriptine is 1 mg initially, increased to 2.5 mg 8-hourly, and thereafter up to 30 mg/day. Pergolide dose starts at 50 µg, increased to 250 µg 8-hourly, and possibly to 3000 µg/day.
Surgery
Stereotactic thalamotomy can be used to treat tremor, though this is relatively infrequently needed because of the medical treatments available. Other stereotactic lesions are currently undergoing evaluation, in particular pallidotomy to help in the management of drug-induced dyskinesia. The implantation of fetal mid-brain cells into the basal ganglia to enhance dopaminergic activity remains experimental.
Physiotherapy and speech therapy
Patients at all stages of Parkinson's disease benefit from physiotherapy, which helps reduce rigidity and corrects abnormal posture. Speech therapy may help in cases where dysarthria and dysphonia interfere with communication.
Prognosis
The outlook for patients with Parkinson's disease is variable, and depends partly on the age of onset. If symptoms start in middle life, the disease is usually slowly progressive and likely to shorten lifespan because of the complications of immobility and tendency to fall. Onset after 70 is unlikely to shorten life or become severe.
ISSUES IN OLDER PEOPLE
PARKINSON'S DISEASE
Parkinson's disease is increasingly common in the elderly.
The long-term side-effects of levodopa, such as dyskinesia, are less of a problem in patients whose disease starts after age 70. It is therefore reasonable to prescribe levodopa as the first-line agent in this situation as opposed to a dopamine agonist in a younger patient.
The side-effects of medications are much more common, particularly confusion and hallucinations. Anticholinergic medication is especially bad in this respect.
Older people are more likely to develop autonomic disturbances, especially medication-induced postural hypotension and bladder instability.
Cognitive changes and dementia are more common in older than in younger people with Parkinson's disease.
Prognosis is somewhat better in those developing the disease above age 70.
OTHER AKINETIC-RIGID SYNDROMES
There are several degenerative conditions that can mimic idiopathic Parkinson's disease, particularly in the early stages. These conditions are relatively uncommon, but about 10% of those thought to have idiopathic Parkinson's disease have one of these variants. The variants are notable in causing a more rapid clinical deterioration than idiopathic Parkinson's disease and in being more resistant to treatment with dopaminergic medication.
Multiple systems atrophy (MSA)
This is a sporadic condition seen in middle-aged and elderly patients. Features of parkinsonism, often without tremor, are combined with varying degrees of autonomic failure, cerebellar involvement and pyramidal tract dysfunction. The combination of parkinsonism with autonomic failure was called the Shy-Drager syndrome, but this term is declining in use. Degeneration is more widespread than in idiopathic Parkinson's disease, and the disappointing response to levodopa and other anti-parkinsonian drugs is probably because of degeneration of post-synaptic neurons in the basal ganglia. Autonomic features include postural hypotension, sphincter disturbance and sometimes respiratory stridor; diagnosis is often assisted by performing tests of autonomic function. Management of postural hypotension includes physical measures such as head-up sleeping position and compressive stockings, and drugs such as fludrocortisone and adrenergic stimulants. Falls are much more common than in idiopathic Parkinson's disease, and life expectancy is considerably reduced.
Progressive supranuclear palsy
Like MSA, this sporadic condition presents in middle-aged patients, and is due to more widespread degeneration in the brain than is seen in idiopathic Parkinson's disease. The clinical features include parkinsonism, though with rigidity in extension rather than flexion, and tremor is usually minimal. In addition, there must be a supranuclear paralysis of eye movements, usually downgaze, for the diagnosis to be made. Other features include pyramidal signs and cognitive impairment (see Box 22.37, p. 1146).
WILSON'S DISEASE
This is an inherited disorder transmitted in an autosomal recessive manner, involving a defect of copper metabolism. It is discussed on page 871. It is a treatable cause of various movement disorders, including ataxia and akinetic rigid syndromes, and so must always be considered in the differential diagnosis of these disorders.
HUNTINGTON'S DISEASE
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This is an inherited disorder with autosomal dominant transmission, affecting both males and females, and usually starting in adult life. It is due to expansion of a trinucleotide repeat on chromosome 4 (see p. 346) and frequently demonstrates anticipation, i.e. a younger age of onset in subsequent generations. Slightly different features of the disease occur, depending on whether the abnormal gene is inherited from father or mother.
Clinical features
Symptoms usually begin in middle adult life with the development of chorea, which gradually worsens. This is accompanied by cognitive impairment which often manifests initially as psychiatric symptoms, but later becomes frank dementia. In juvenile-onset disease, there may be parkinsonian features with rigidity. Seizures may occur late in the disease.
Investigations
The diagnosis is made clinically but is supported by the finding of atrophy of the caudate nucleus on CT or MRI. DNA analysis can be used to confirm the diagnosis and provide pre-symptomatic testing after appropriate counselling.
Management
At present this is symptomatic only. The chorea may respond to tetrabenazine or dopamine antagonists such as sulpiride. Long-term psychological support and eventually institutional care are often needed as dementia progresses. Depressive symptoms are common, and may be helped by antidepressant medication. Genetic counselling of relatives is important.
HEREDITARY ATAXIAS
This is a group of inherited disorders in which degenerative changes occur to varying extents in the cerebellum, brain stem, pyramidal tracts, spinocerebellar tracts, optic and peripheral nerves. Onset may be in childhood or early adult life, and different disorders demonstrate recessive or dominant inheritance. Recently, the genetic abnormalities responsible for a few types of spinocerebellar ataxia (types 1-8) have been shown to be due to abnormal numbers of trinucleotide repeats in various genes, and these can now be detected by DNA analysis, allowing diagnostic confirmation, pre-diagnostic testing and genetic counselling. Clinically, various combinations of cerebellar, pyramidal, sensory, extrapyramidal and cognitive features may occur. Patterns of involvement of several conditions are given in Box 22.65.
MOTOR NEURON DISEASE
This is a progressive disorder of unknown cause, in which there is degeneration of motor neurons in the spinal cord and cranial nerve nuclei, and of pyramidal neurons in the motor cortex. About 5% of cases are familial, showing autosomal dominant inheritance. In many such families, the genetic defect lies on chromosome 21, the enzyme involved being a superoxide dismutase (SOD1). For the remaining 95%, possible causes include viral infection, trauma, exposure to toxins and electric shock, but no sound evidence exists to support any of these. The prevalence of the disease is about 5/100 000.
Clinical features
Patients present with a combination of lower and upper motor neuron signs without sensory involvement. The presence of brisk reflexes in wasted fasciculating limb muscles is typical. Common presenting features are listed in Boxes 22.66 and 22.67.
Investigations
In many patients the clinical features are highly suggestive but alternative diagnoses need to be carefully excluded. In particular, potentially treatable disorders such as diabetic amyotrophy, spinal disorders and multifocal motor neuronopathy should be excluded. Electromyography helps to confirm the presence of fasciculation and denervation, and is particularly helpful when pyramidal features predominate. Sensory nerve conduction and motor conduction studies are normal but there may be some reduction in amplitude of action potentials due to loss of axons. Spinal imaging and brain scanning may be necessary to exclude focal spinal or cerebral disease. CSF examination is usually normal, though a slight elevation in protein concentration may be found.
Management
22.65 TYPES OF HEREDITARY ATAXIA
Type Inheritance Onset Clinical features
Friedreich's ataxia Autosomal recessive 8-16 years Ataxia, nystagmus, dysarthria, spasticity, areflexia, proprioceptive impairment, diabetes mellitus, optic atrophy, cardiac abnormalities. Usually chairbound by age 20
Ataxia telangiectasia Autosomal recessive Childhood Progressive ataxia, athetosis, telangiectasia on conjunctivae, impaired DNA repair, immunodeficiency, tendency to malignancies
Olivopontocerebellar atrophy Autosomal dominant Adult life Slowly progressive ataxia, spasticity, dysarthria, extrapyramidal features, optic atrophy, deafness, pyramidal signs
Hereditary spastic paraplegia Autosomal dominant Adult life Slowly progressive spasticity affecting legs > arms, extensor plantar responses, sensory signs minimal or absent
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22.66 CLINICAL FEATURES OF MOTOR NEURON DISEASE
Onset
Usually after the age of 50 years
Very uncommon before the age of 30 years
Affects males more commonly than females
Symptoms
Limb muscle weakness, cramps, occasionally fasciculation
Disturbance of speech/swallowing (dysarthria/dysphagia)
Signs
Wasting and fasciculation of muscles
Weakness of muscles of limbs, tongue, face and palate
Pyramidal tract involvement causes spasticity, exaggerated tendon reflexes, extensor plantar responses
External ocular muscles and sphincters usually remain intact
No objective sensory deficit
No intellectual impairment in most cases
Course
Symptoms often begin focally in one part and spread gradually but relentlessly to become widespread
22.67 PATTERNS OF INVOLVEMENT OF MOTOR NEURON DISEASE
Progressive muscular atrophy
Predominantly spinal motor neurons affected
Weakness and wasting of distal limb muscles at first
Fasciculation in muscles
Tendon reflexes may be absent
Progressive bulbar palsy
Early involvement of tongue, palate and pharyngeal muscles
Dysarthria/dysphagia
Wasting and fasciculation of tongue
May be pyramidal signs as well
Amyotrophic lateral sclerosis
Combination of distal and proximal muscle-wasting and weakness, fasciculation
Spasticity, exaggerated reflexes, extensor plantars
Bulbar and pseudobulbar palsy follow eventually
Pyramidal tract features may predominate
The glutamate antagonist, riluzole, has recently been shown to have a small effect in prolonging life expectancy by a mean of 3 months (see EBM panel). It is not clear at which stage of the illness this prolongation occurs, and therefore it may not be particularly helpful. Other agents such as nerve growth factor show promise. Psychological and physical support, with help from occupational and speech therapists and physiotherapists, is essential to keep the patient's quality of life as good as possible. Mechanical aids such as splints, walking aids, wheelchairs and communication devices all help to reduce handicap. Feeding by percutaneous gastrostomy may be necessary if bulbar palsy is marked. Sometimes non-invasive ventilatory support may help distress from weak respiratory muscles although maintenance ventilation is usually not requested. Relief of distress in the terminal stages usually requires the use of opiates and sedative drugs.
EBM
MOTOR NEURON DISEASE-role of riluzole
'Riluzole 100 mg per day appears to be modestly effective in prolonging survival for patients with motor neuron disease. However, the economics of its use have yet to be fully assessed.'
Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND) (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.cochrane.co.uk
Prognosis
Motor neuron disease is progressive; the mean time from diagnosis to death is 1 year, with most patients dying within 3-5 years of the onset of symptoms. Younger patients and those with early bulbar symptoms tend to show a more rapid course. Death is usually from respiratory infection and failure, and the complications of immobility.
SPINAL MUSCULAR ATROPHIES
This is a group of genetically determined disorders affecting spinal motor and cranial motor neurons, characterised by proximal and distal wasting, fasciculation and weakness of muscles. Involvement is usually symmetrical but occasional localised forms occur. With the exception of the infantile form, progression is slow and the prognosis better than for motor neuron disease (see Box 22.68).
22.68 TYPES OF SPINAL MUSCULAR ATROPHY
Type Onset Inheritance Features Prognosis
Werdnig-Hoffmann Infancy Autosomal recessive Severe muscle-wasting/weakness Poor
Kugelberg-Welander Childhood, adolescence Autosomal recessive Proximal weakness and wasting, EMG shows denervation Slowly progressive disability
Distal forms Early adult life Autosomal dominant Distal weakness and wasting of hands and feet Good, seldom disabling
Bulbospinal Adult life, males only X-linked Facial and bulbar weakness, proximal limb weakness, gynaecomastia Good
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Home > 2 SYSTEM-BASED DISEASES > 22 Neurological disease > DISEASES OF NERVE AND MUSCLE
DISEASES OF NERVE AND MUSCLE
DISEASES OF PERIPHERAL NERVES
Peripheral nerves may be damaged by diffuse processes affecting all nerves to a greater or lesser extent, or individual nerves may be affected by local pathology including trauma, compression and entrapment. Alternatively, several individual nerves may be affected by multifocal pathology (mononeuritis multiplex), or there may be focal pathology in nerve plexuses.
ACQUIRED PERIPHERAL NEUROPATHIES
There are numerous causes of peripheral neuropathy (see Box 22.69). The diagnostic possibilities are limited in an individual patient by the clinical features (motor, sensory, autonomic or mixed) and by whether axons or myelin are predominantly affected (determined electrophysiologically).
Clinical features
The first manifestations are usually at the distal ends of the longest nerves. Distal paraesthesia is a frequent symptom, usually first affecting the feet and then the hands, and subsequently progressing proximally up the limbs. This is often associated with diminution of superficial sensation in a 'glove and stocking' distribution (see Fig. 22.15A, p. 1141). There may be distal weakness, usually with diminished or absent tendon reflexes, and possibly autonomic disturbance. In hereditary neuropathies there may be a positive family history.
Investigations
22.69 CAUSES OF PERIPHERAL NEUROPATHY
Type Common Unusual Rare
Metabolic/endocrine Diabetes mellitus
Chronic renal failure Paraproteinaemia
Cryoglobulinaemia
Amyloidosis
Hypothyroidism
Liver failure Porphyria
Toxic Alcohol Drugs (e.g. isoniazid, phenytoin, vincristine) Heavy metals
Organic solvents
Inflammatory Acute (Guillain-Barré syndrome) Chronic inflammatory demyelinating polyneuropathy
Connective tissue disease (e.g. SLE, polyarteritis nodosa, Sj[scaron]gren's syndrome)
Infective (leprosy) Multifocal motor neuropathy with conduction block
Genetic Hereditary motor and sensory neuropathies (Charcot-Marie-Tooth)
Friedreich's ataxia Other hereditary neuropathies
Deficiency states Vitamin B12 deficiency
Thiamin deficiency Vitamin A, E deficiency
Pyridoxine deficiency
Others Malignant disease
Critical illness neuropathy
A careful clinical history is essential, including details of family history, drug intake and potential exposure to toxins. Screening tests are listed in Box 22.70. Nerve conduction studies confirm the presence of a neuropathy and indicate whether axons or myelin are primarily affected. In some cases, nerve biopsy may be indicated, particularly if an inflammatory aetiology is suspected.
Management
In about one-third of patients, a treatable cause is identified. Toxins and offending drugs should be removed and metabolic abnormalities or deficiency states corrected. Inflammatory neuropathies can often be treated with immunosuppressive agents or intravenous immunoglobulin. However, in many patients (about another third) a cause is identified for which there is no specific treatment and in the remainder no specific cause is found. Particularly if there is no specific therapy available (e.g. hereditary neuropathies), advice from physiotherapists and occupational therapists is important in helping patients to maintain their functional capacity. Carbamazepine and gabapentin can be helpful in relieving pain, particularly in neuropathy due to diabetes mellitus.
GUILLAIN-BARRÉ SYNDROME
Also known as acute inflammatory or post-infective demyelinating polyneuropathy, this develops 1-4 weeks after respiratory infection or diarrhoea in 70% of patients, but can follow surgery or immunisation. Pathologically, there is demyelination of spinal roots or peripheral nerves, which is immunologically mediated.
Clinical features
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22.70 INVESTIGATION OF PERIPHERAL NEUROPATHY
First-line tests Second-line tests Occasionally useful tests
Haematology Full blood count
ESR
B12
Folate
Biochemistry Urea, electrolytes, calcium Serum lipids, lipoproteins Vitamin assays (e.g. vitamin E)
Creatinine Cryoglobulins Phytanic acid (Refsum's disease)
Liver function tests Toxic metal and drug screen
Blood glucose ± tolerance test/HbAlc Prostate-specific antigen
Thyroxine and thyroid-stimulating hormone (TSH) Urinary porphyrins
Plasma protein electrophoresis Urinary Bence Jones protein
Faecal occult blood
Immunology VDRL Antiganglioside antibodies
Serum autoantibodies (antinuclear factor, dsDNA, rheumatoid factor, extractable nuclear antigens) Antineuronal antibodies
Other Nerve conduction/EMG Genetic screening tests (e.g. hereditary neuropathies, Friedreich's ataxia) In divided doses. Abdominal imaging Nerve biopsy
The characteristic clinical feature is rapidly progressive muscle weakness, often ascending from lower to upper limbs and more marked proximally than distally. Distal paraesthesia and limb pains often precede the weakness. Facial or bulbar weakness commonly develops, and respiratory weakness requiring ventilatory support occurs in 20% of cases. In most patients muscle weakness progresses for 1-3 weeks, but rapid deterioration with respiratory failure can develop within hours. The most striking findings on examination are diffuse weakness with widespread loss of reflexes. An unusual variant described by Miller Fisher comprises the triad of ophthalmoplegia, ataxia and areflexia.
Investigations
The protein content of the CSF is raised at some stage of the illness, but may be normal in the first 10 days. There is usually no rise in CSF cell number and a lymphocytosis > 50/mm3 suggests an alternative diagnosis. Electrophysiological studies are often normal in the early stages, but show typical changes after a week or so, with multifocal motor slowing and proximal slowing. Investigation to identify an underlying cause, such as cytomegalovirus, mycoplasma or campylobacter, requires a chest radiograph, stool culture and appropriate immunological blood tests. Antibodies to the ganglioside GQ1b are found in the Miller Fisher variant described above. Acute porphyria (see p. 325) can be excluded by urinary porphyrin estimation, and serum lead should be measured if there are only motor signs.
Management
During the phase of deterioration, regular monitoring of respiratory function (vital capacity and blood gases) is required, as respiratory failure may develop with little warning and require ventilatory support. If the vital capacity falls below 1 litre, help from anaesthetists should be sought as ventilation may be required. Intubation and ventilation are often required because of bulbar incompetence leading to aspiration. General management to protect the airway and prevent pressure sores and venous thrombosis is essential. Steroid therapy is ineffective, but plasma exchange and intravenous immunoglobulin therapy shorten the duration of ventilation and improve prognosis, provided treatment is started within 14 days of the onset of symptoms (see EBM panels).
EBM
GUILLAIN-BARRÉ SYNDROME-role of corticosteroids
'Corticosteroids are ineffective and should not be used in the treatment of Guillain-Barré syndrome itself, though if a patient with Guillain-Barré syndrome needs corticosteroid treatment for some other reason its use will probably not do harm.'
Hughes RAC, van der Meché FGA. Corticosteroids for treating Guillain-Barré syndrome (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Guillain-Barré Syndrome Steroid Trial Group. Double-blind trial of intravenous methylprednisolone in Guillain-Barré syndrome. Lancet 1993; 3341:586-590.
Further information: www.cochrane.co.uk
EBM
GUILLAIN-BARRÉ SYNDROME-role of intravenous immunoglobulin (IVIg) and plasma exchange (PE)
'If used within the first 2 weeks of developing the illness, IVIg and PE are equally efficient in reducing the severity and duration of Guillain-Barré syndrome, but there is no advantage in combining the two treatments.'
Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet 1997; 349:225-230.
Bril V, Ilse WK, Pearce R, et al. Pilot trial of immunoglobulin versus plasma exchange in patients with Guillain-Barré syndrome. Neurology 1996; 46:100-103.
Further information: www.cochrane.co.uk
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Prognosis
Overall, 80% of patients recover completely within 3-6 months, 4% die, and the remainder suffer residual neurological disability which can be severe.
ENTRAPMENT NEUROPATHIES
These conditions often have a characteristic clinical history and physical signs (see Box 22.71).
Management
Lateral popliteal nerve palsies and radial nerve palsies are commonly due to local compression, and complete recovery over 6-8 weeks can be expected without intervention. Meralgia paraesthetica often develops in relation to weight loss or gain, and may respond to dietary advice and reassurance. Carpal tunnel syndrome and ulnar nerve palsy may remit if patients avoid activities involving repetitive wrist movement or pressure on the elbows, and may respond to nocturnal splinting of joints. Precipitating causes including diabetes mellitus and hypothyroidism should be excluded. In some patients surgical decompression of the carpal tunnel or transposition of the ulnar nerve may be necessary. Electrophysiological investigation is advisable pre-operatively to confirm both diagnosis and site of compression.
22.71 SYMPTOMS AND SIGNS IN COMMON ENTRAPMENT NEUROPATHIES
Nerve Symptoms Muscle weakness/muscle-wasting Area of sensory loss
Median (at wrist) (carpal tunnel syndrome) Pain and paraesthesia on palmar aspect of hands and fingers, waking the patient from sleep. Pain may extend to arm and shoulder Abductor pollicis brevis Lateral palm and thumb, index, middle and half ring finger
Ulnar (at elbow) Paraesthesia on medial border of hand, wasting and weakness of hand muscles All small hand muscles, excluding abductor pollicis brevis Medial palm and little finger, and half ring finger
Radial Weakness of extension of wrist and fingers, often precipitated by sleeping in abnormal posture, e.g. arm over back of chair Wrist and finger extensors, supinator Dorsum of thumb
Peroneal Foot drop, trauma to head of fibula Dorsiflexion and eversion of foot Nil or dorsum of foot
Lateral cutaneous nerve of the thigh (meralgia paraesthetica) Tingling and dysaesthesia on lateral border of the thigh Nil Lateral border of thigh
22.72 PHYSICAL SIGNS IN BRACHIAL PLEXUS LESIONS
Site Root Affected muscles Sensory loss
Upper plexus (Erb-Duchenne) C5/6 Biceps, deltoid, spinati, rhomboids, brachioradialis (triceps, serratus anterior) Patch over deltoid
Lower plexus (Dejerine-Klumpke) C8/T1 All small hand muscles, claw hand (ulnar wrist flexors) Ulnar border hand/forearm
Thoracic outlet syndrome C8/T1 Small hand muscles, ulnar forearm Ulnar border hand/forearm/upper arm
MONONEURITIS MULTIPLEX
In this condition, multifocal peripheral or spinal nerve lesions occur serially or concurrently. Pathologically, the nerves are rendered susceptible to mechanical compression by ischaemia of the peripheral nerves due to vasculopathy of the vasa nervorum or infiltration of the nerves. Common causes are diabetes mellitus, leprosy, polyarteritis nodosa and rheumatoid arthritis.
BRACHIAL PLEXUS LESIONS
Trauma is the most common cause of damage to the brachial plexus, and frequently involves traction between the head and shoulder, or excessive abduction of the arm. Other causes include neoplasia in the cervical lymph nodes or pulmonary apex, compression at the thoracic outlet, radiotherapy and inflammatory/vascular disease (e.g. neuralgic amyotrophy-see below).
Clinical features
The clinical signs depend on the anatomical site of damage (see Box 22.72). There may be associated vascular symptoms and signs in the thoracic outlet syndrome.
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Neuralgic amyotrophy presents with severe pain over one shoulder and sometimes follows infection, inoculation or operation. Within days, paralysis develops in the painful muscles (most commonly deltoid, spinati and serratus anterior), and is rapidly followed by muscle-wasting. Occasionally, there is more extensive involvement of the muscles of the upper arm and there may be sensory loss over the deltoid. Pain usually subsides within 1-2 weeks and complete recovery of paralysis and wasting can be expected in 3-6 months without treatment.
Management
Surgical treatment may be indicated for congenital anomalies such as cervical rib or for traumatic lesions where grafts of nerve or muscle may aid regeneration. In this situation, regular passive movements of the affected limb prevent contractures while nerve fibres are regenerating. The prognosis for recovery in traumatic lesions is dependent on the site and severity of neuronal damage, which may be assessed electrophysiologically.
DISEASES AFFECTING THE CRANIAL NERVES
Cranial nerves may be affected as part of a generalised peripheral neuropathy, but are often involved singly or in groups by intracranial disease. Intracranial disease such as cerebral tumour may involve a cranial nerve directly (e.g. acoustic neuroma, see p. 1206), or may cause secondary dysfunction by stretching or compressing it against other structures (e.g. 3rd nerve palsy due to tentorial herniation of the medial temporal lobe). Diseases of most of the individual cranial nerves have already been discussed elsewhere (see pp. 1150-1157).
IDIOPATHIC FACIAL NERVE PALSY (BELL'S PALSY)
This is a common condition affecting all ages and both sexes. The cause is unknown, but the site of damage is probably the portion of the facial nerve lying within the facial canal. Recent evidence suggests that Bell's palsy may be due to reactivation of latent herpes simplex virus-1 infection since HSV-1 virus genome has been identified in facial nerve endoneural fluid and in saliva of patients with Bell's palsy. The onset is subacute, with symptoms usually developing over a few hours. Pain around the ear may precede loss of movement on one side of the face, initially noticed either by the patient or by family. Patients may describe the face as being numb, but there is no objective loss of sensation (except possibly taste, due to involvement of the chorda tympani). Hyperacusis occurs if the nerve to stapedius is involved, and there may also be loss of salivation and tear secretion.
Examination reveals only a lower motor neuron facial nerve palsy on one side. Vesicles in the ear or on the palate indicate that the facial palsy is due to herpes zoster infection rather than Bell's palsy (see p. 1199). A reduction in the amplitude of the facial muscle action potential on EMG after the first week predicts a slow/poor recovery.
There is no proven medical treatment, though a course of steroids such as prednisolone 40-60 mg daily for a week may speed recovery, and the use of aciclovir has been suggested (see EBM panel). To prevent exposure of the cornea, artificial teardrops and ointment are applied to the eye, and the eye is taped shut overnight. About 70-80% of patients recover spontaneously within 2-12 weeks, but elderly patients with complete facial palsy have a poorer prognosis. Aberrant re-innervation may occur during the course of recovery, giving rise to unwanted facial movements (e.g. eye closure when the mouth is moved) or 'crocodile tears' (tearing during salivation).
EBM
BELL'S PALSY-role of aciclovir
'RCTs have shown that aciclovir alone is not as effective as corticosteroids in the treatment of Bell's palsy, but the combination of aciclovir and prednisolone appears to be more effective than steroids alone.'
De Diego JI, Prim MP, De Sarria MJ, et al. Idiopathic facial paralysis: a randomized, prospective, and controlled study using single-dose prednisone versus acyclovir three times daily. Laryngoscope 1998; 108:573-575.
Adour KK, Ruboyianes JM, Von Doersten PG, et al. Bell's palsy treatment with acyclovir and prednisone compared with prednisone alone: a double-blind, randomized, controlled trial. Ann Otol Rhinol Laryngol 1996; 105:371-378.
Further information: www.cochrane.co.uk
CLONIC FACIAL (HEMIFACIAL) SPASM
This disorder usually presents after middle age. Symptoms start with intermittent twitching around one eye, which spreads ipsilaterally over months to years to affect other parts of the face. The spasms of twitching are intermittent, often exacerbated by talking or eating, or when the patient is under stress. The cause is thought to be an aberrant loop of artery irritating the facial nerve as it emerges from the pons. It is important to image the facial nerve to exclude a structural lesion, especially in a young patient. Drug treatment is not effective, but injections of botulinum toxin into affected muscles can help, although these usually have to be repeated every 3 months or so. Occasionally, microvascular decompression is necessary, but this involves a posterior craniotomy.
DISORDERS OF THE NEUROMUSCULAR JUNCTION
MYASTHENIA GRAVIS
This condition is characterised by progressive inability to sustain a maintained or repeated contraction of striated muscle (fatigability).
Aetiology and pathology
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Figure 22.42 Myasthenia gravis and Lambert-Eaton myasthenic syndrome (LEMS). In myasthenia there are antibodies to the acetylcholine receptors on the post-synaptic membrane which block conduction across the neuromuscular junction (NMJ). Myasthenic symptoms can be transiently improved by inhibition of acetylcholinesterase (e.g. with Tensilon-edrophonium bromide) which normally removes the acetylcholine. A cell-mediated immune response produces simplification of the post-synaptic membrane, further impairing the 'safety factor' of neuromuscular conduction. In LEMS, antibodies to the pre-synaptic voltage calcium channels impair release of acetylcholine from the motor nerve ending; calcium is required for the acetylcholine-containing vesicle to fuse with the pre-synaptic membrane for release into the NMJ.
Acetylcholine receptors in the post-junctional membrane of neuromuscular junctions are blocked or lysed by a complement-mediated autoimmune reaction between receptor protein and anti-acetylcholine receptor antibody (see Fig. 22.42). About 15% of patients (mainly those with late onset) have a thymoma, and the majority of the remainder have one of a number of thymic abnormalities, the most characteristic of which is thymic hyperplasia. There is an increased incidence of other autoimmune diseases, and the disease is linked with certain HLA haplotypes, the strongest associations in a north European population being with B8 and DRw3. Nothing is known about factors which trigger the disease itself, but penicillamine can cause an antibody-mediated myasthenic syndrome which may persist even after drug withdrawal. Some drugs, especially aminoglycosides and ciprofloxacin, may exacerbate the neuromuscular blockade and should be avoided in patients with myasthenia.
Clinical features
The disease usually presents between the ages of 15 and 50 years, with women affected more often than men. It tends to run a relapsing and remitting course, especially during the early years.
The cardinal symptom is abnormal fatigable weakness of the muscles (which is different from a sensation of muscle fatigue). Although movement is initially strong, it rapidly weakens. Worsening of symptoms towards the end of the day or following exercise is characteristic. There are no sensory signs or signs of involvement of the central nervous system although weakness of the oculomotor muscles may mimic a central eye movement disorder.
The first symptoms are usually intermittent ptosis or diplopia, but weakness of chewing, swallowing, speaking or limb movement also occurs. Any limb muscle may be affected, most commonly those of the shoulder girdle; the patient is unable to undertake work above shoulder level, such as combing hair, without frequent rests. Respiratory muscles may be involved, and respiratory failure is a not uncommon cause of death. Aspiration may occur if the cough is ineffectual. Sudden weakness from a cholinergic or myasthenic crisis (see below) may require ventilatory support.
Investigations
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The intravenous injection of the short-acting anticholinesterase, edrophonium bromide, is a valuable diagnostic aid (the Tensilon test); 2 mg is injected initially, with a further 8 mg given half a minute later if there are no undesirable side-effects. Improvement in muscle power occurs within 30 seconds and usually persists for 2-3 minutes. EMG with repetitive stimulation may show the characteristic decremental response. Anti-acetylcholine receptor antibody is found in over 80% of cases, though less frequently in purely ocular myasthenia. Positive antiskeletal muscle antibodies suggest the presence of thymoma but all patients should have a thoracic CT to exclude this condition, which may not be visible on plain radiographic examination. Screening for other autoimmune disorders, particularly thyroid disease, is important.
Management
The principles of treatment are:
to maximise the activity of acetylcholine at remaining receptors in the neuromuscular junctions
to limit or abolish the immunological attack on motor end plates.
The duration of action of acetylcholine is greatly prolonged by inhibiting its hydrolysing enzyme, acetylcholinesterase. The most commonly used anticholinesterase drug is pyridostigmine, which is given orally in a dosage of 30-120 mg, usually 6-hourly. Muscarinic side-effects, including diarrhoea and colic, may be controlled by propantheline (15 mg as required). Over-dosage of anticholinesterase drugs may cause a cholinergic crisis due to depolarisation block of motor end plates, with muscle fasciculation, paralysis, pallor, sweating, excessive salivation and small pupils. This may be distinguished from severe weakness due to exacerbation of myasthenia (myasthenic crisis) by the clinical features and, if necessary, by the injection of a small dose of edrophonium.
The immunological treatment of myasthenia is outlined in Box 22.73. Thymectomy in the early stages of the disease leads to a much better overall prognosis, whether a thymoma is present or not.
22.73 IMMUNOLOGICAL TREATMENT OF MYASTHENIA
Thymectomy
Should be performed as soon as feasible in any antibody-positive patient with symptoms not confined to extraocular muscles, unless the disease has been established for more than 7 years
Plasma exchange
Removing antibody from the blood may produce marked improvement but, as this is usually brief, such therapy is normally reserved for myasthenic crisis or for pre-operative preparation
Intravenous immunoglobulin
An alternative to plasma exchange in the treatment of severe myasthenia
Corticosteroid treatment
Improvement is commonly preceded by marked exacerbation of myasthenic symptoms and treatment should be initiated in hospital
It is usually necessary to continue treatment for months or years, often resulting in adverse effects
Other immunosuppressant treatment
Treatment with azathioprine 2.5 mg/kg daily is of value in reducing the dosage of steroids necessary and may allow steroids to be withdrawn
The effect of treatment on clinical disease is often delayed for several months
EBM
MYASTHENIA GRAVIS-role of azathioprine
'Azathioprine as an adjunct to alternate-day prednisolone in the treatment of antibody-positive generalised myasthenia reduces the maintenance dose of prednisolone and is associated with fewer treatment failures, longer remissions and fewer side-effects. However, a small trial suggested that it is probably not useful as an initial immunosuppressive treatment on its own.'
Palace J, Newsom-Davis J, Lecky B. A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Neurology 1998; 50:1778-1783.
Bromberg MB, Wald JJ, Forshew DA, et al. Randomized trial of azathioprine or prednisone for initial immunosuppressive treatment of myasthenia gravis. J Neurol Sci 1997; 150:59-62.
Further information: www.cochrane.co.uk
Prognosis
Prognosis is variable. Remissions sometimes occur spontaneously. When myasthenia is confined to the eye muscles, the prognosis is excellent and disability slight. Young female patients with generalised disease have high remission rates after thymectomy, whilst older patients are less likely to have a remission despite treatment. Rapid progression of the disease more than 5 years after its onset is uncommon.
OTHER MYASTHENIC SYNDROMES
There are other conditions which present with muscle weakness due to impaired transmission across the neuromuscular junction. The most common of these is the Lambert-Eaton myasthenic syndrome (LEMS), in which transmitter release is impaired, often in association with antibodies to pre-junctional voltage-gated calcium channels (see Fig. 22.42). Patients may have autonomic dysfunction (and a dry mouth) in addition to muscle weakness, but the cardinal clinical sign is absence of tendon reflexes, which can return immediately after sustained contraction of the relevant muscle. The condition is associated with underlying malignancy in a high percentage of cases, and investigation must be directed towards detecting such a cause. The condition is diagnosed electrophysiologically by the presence of post-tetanic potentiation of motor response to nerve stimulation at a frequency of 20-50/s. Treatment is with 3,4-diaminopyridine (see EBM panel).
EBM
LAMBERT-EATON MYASTHENIC SYNDROME-role of 3,4-diaminopyridine (DAP)
'DAP is a safe and effective treatment for Lambert-Eaton myasthenic syndrome.'
Sanders DB, Massey JM, Sanders LL, Edwards LJ. A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome. Neurology 2000; 54:603-607.
Further information: www.cochrane.co.uk
DISEASES OF MUSCLE
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22.74 INVESTIGATION OF MUSCLE DISEASE
First-line tests Second-line tests Occasionally useful tests
Haematology Full blood count
ESR
Biochemistry Urea, electrolytes
Calcium, phosphate
Creatine kinase
Lactate dehydrogenase
Liver function tests
Thyroxine and TSH
Plasma and urinary corticosteroids
Urinary calcium Faecal occult blood Ischaemic lactate test
Immunology Antinuclear factor
Anti-dsDNA
Anti-acetylcholine receptor antibodies Anti-voltage-gated calcium channel antibodies
Other Nerve conduction/EMG Genetic screening tests (e.g. some muscular dystrophies, mitochondrial DNA)
Muscle biopsy*
Chest radiograph/CT
Mammogram
Abdominal imaging
* Histology (light and electron microscopy), histochemistry and/or tissue enzyme assay (e.g. myophosphorylase, phosphofructokinase, acid maltase, carnitine-palmityl transferase) may be necessary.
Voluntary muscle is subject to a range of disorders that result in a limited spectrum of symptoms and physical signs. Diagnosis depends upon consideration of the clinical picture along with the results of EMG studies and muscle biopsy. In some muscular dystrophies, e.g. Duchenne dystrophy and dystrophia myotonica, a specific genetic abnormality has been identified. Screening tests are given in Box 22.74.
MUSCULAR DYSTROPHY
Integration link: Principles of inheritance
Taken from Davidson's Principles & Practice of Medicine 19e
Several inherited disorders are characterised by progressive degeneration of groups of muscles without involvement of the nervous system.
Clinical features
Wasting and weakness are usually symmetrical, there is no fasciculation and no sensory loss and, except in dystrophia myotonica, tendon reflexes are preserved until a late stage. Differential diagnosis is based on the age at onset, the distribution of affected muscles and the pattern of inheritance (see Box 22.75).
Investigations
22.75 DIAGNOSTIC FEATURES IN MUSCULAR DYSTROPHY
Dystrophy Chromosome involved Inheritance Age at onset (yrs) Muscles affected
Duchenne X X-linked recessive 3-10 Proximal legs and arms, then general
Limb girdle (Probably multiple) Autosomal recessive 10-30 Pelvic girdle, shoulder girdle or both
Facioscapulohumeral 4 Autosomal dominant 10-40 Facial, shoulder girdle, serratus anterior
Dystrophia myotonica 19 Autosomal dominant Any age Temporalis, facial, sternomastoid, distal limbs, myotonia
The diagnosis of muscular dystrophy can be confirmed by EMG and muscle biopsy. Creatine kinase is markedly elevated in Duchenne muscular dystrophy, but is normal or only moderately elevated in the other types.
Dystrophia myotonica may be diagnosed clinically by the distribution of muscle weakness and other features including myotonia (slow relaxation of muscle), cataracts, ptosis, frontal baldness and gonadal atrophy. It is caused by expansion of a trinucleotide repeat on chromosome 19, and diagnosis is now possible by measuring the number of repeats. The genetic defects of Duchenne dystrophy and facioscapulohumeral dystrophy have been mapped to chromosomes Xp21 and 4q35, respectively. DNA analysis may allow early diagnosis and pre-natal testing in these conditions, as in dystrophia myotonica.
Management
There is no specific therapy for these conditions, although advice from the physiotherapist and occupational therapist may help the patient to cope with disability. Genetic counselling is important.
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Prognosis
Most patients with Duchenne dystrophy die within 10 years of diagnosis, while the lifespan in limb girdle and facioscapulohumeral dystrophies is normal. Premature death due to respiratory or cardiac failure in early middle age is the usual outcome in dystrophia myotonica, although patients are affected very variably.
METABOLIC AND ENDOCRINE MYOPATHY
Muscle weakness may develop in a range of metabolic and endocrine disorders and is usually reversible. The causes are listed in Box 22.76.
Clinical features
The weakness is often acute and generalised in metabolic disorders, while a proximal myopathy predominantly affecting the pelvic girdle is a feature of some endocrine disorders. This may develop without other manifestations of hormonal disturbance. Hypo- and hyperkalaemia may occur in the familial periodic paralyses, which are inherited conditions characterised by attacks of profound weakness lasting for several hours, often precipitated by eating or exertion.
Muscle pain on exercise is the characteristic feature of myophosphorylase deficiency (McArdle's syndrome) and a number of other rare recessively inherited disorders of metabolism (see Box 22.77).
22.76 METABOLIC AND ENDOCRINE CAUSES OF MUSCLE WEAKNESS
Acute muscle weakness
Hypokalaemia
Hyperkalaemia
Hypocalcaemia
Hypercalcaemia
Proximal myopathy
Hyperthyroidism
Hypothyroidism
Cushing's syndrome
Addison's disease
22.77 RARE DISORDERS OF MUSCLE METABOLISM
Myophosphorylase deficiency (McArdle's syndrome)
Muscle pain on exercise
Increased glycogen in muscle
Failure of blood lactate to rise on exercise
Reduced myophosphorylase (muscle biopsy)
Phosphofructokinase deficiency
Similar to above, but reduced phosphofructokinase (muscle biopsy)
Carnitine-palmityl transferase (CPT) deficiency
Muscle pain after prolonged exercise
Increased lipid in muscle on biopsy
Reduced CPT (muscle biopsy)
INFLAMMATORY MYOPATHY OR POLYMYOSITIS
See page 1038.
CONGENITAL MYOPATHY
This is rare and presents in infancy with muscular weakness and limpness. Serum enzymes may be normal or slightly elevated and the EMG is usually myopathic. The syndrome may be caused by a number of specific conditions that have a variable inheritance, and are defined by the type of structural abnormality present in skeletal muscle fibres. Most patients have a slowly progressive disease and there is no specific therapy.
TOXIC MYOPATHY
A wide variety of drugs may cause disorders of muscle, including carbenoxolone, thiazide diuretics, zidovudine, statins and steroids. Alcohol may cause a spectrum of muscle disease varying from a mild proximal weakness to severe muscle necrosis. Avoidance of the offending agent usually results in recovery of muscle function.
DISORDERS OF THE SPINE AND SPINAL CORD
The spinal cord and spinal roots may be affected by intrinsic disease or by disorders of the surrounding meninges and bones. The clinical presentation of these conditions depends on the anatomical level at which the cord or roots are affected as well as the nature of the pathological process involved. It is important to recognise when emergency surgical intervention is necessary and therefore to plan investigations to identify such patients.
COMPRESSION OF THE SPINAL CORD
Acute spinal cord compression is one of the most common neurological emergencies encountered in clinical practice and the common causes are listed in Box 22.78.
22.78 CAUSES OF SPINAL CORD COMPRESSION
Site Frequency Causes
Vertebral (extradural) 80% Trauma
Intervertebral disc prolapse
Metastatic carcinoma (e.g. breast, prostate, bronchus)
Myeloma
Tuberculosis
Meninges (intradural extramedullary) 15% Tumours (e.g. meningioma, neurofibroma, ependymoma, metastasis, lymphoma, leukaemia)
Epidural abscess
Spinal cord (intradural intramedullary) 5% Tumours (e.g. glioma, ependymoma, metastasis)
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A space-occupying lesion within the spinal canal may damage nerve tissue either directly by pressure or indirectly by interfering with blood supply. Oedema from venous obstruction impairs neuronal function, and ischaemia from arterial obstruction may lead to necrosis of the spinal cord. The early stages of damage are reversible but severely damaged neurons do not recover; hence the importance of early diagnosis and treatment.
Clinical features
The onset of symptoms of spinal cord compression is usually slow (over weeks), but can be acute as a result of trauma or metastases, especially if there is associated arterial occlusion. The symptoms are shown in Box 22.79.
22.79 SYMPTOMS OF SPINAL CORD COMPRESSION
Pain
Localised over the spine or in a root distribution, which may be aggravated by coughing, sneezing or straining
Sensory
Paraesthesia, numbness or cold sensations, especially in the lower limbs, which spread proximally, often to a level on the trunk
Motor
Weakness, heaviness or stiffness of the limbs, most commonly the legs
Sphincters
Urgency or hesitancy of micturition, leading eventually to urinary retention
Pain and sensory symptoms occur early, while weakness and sphincter dysfunction are usually late manifestations. The signs vary according to the level of the cord compression and the structures involved. There may be tenderness to percussion over the spine if there is vertebral disease, and this may be associated with a local kyphosis. Involvement of the roots at the level of the compression may give dermatomal sensory impairment and corresponding lower motor signs. Interruption of fibres in the spinal cord causes sensory loss (see p. 1140) and upper motor neuron signs below the level of the lesion, and there is often disturbance of sphincter function. The distribution of these signs varies with the level of the lesion, as shown in Box 22.80.
The Brown-Séquard syndrome (see Fig. 22.15E, p. 1141) results if damage is confined to one side of the cord; the findings are explained by the anatomy of the sensory tracts (see Fig. 22.16, p. 1141). On the side of the lesion there is a band of hyperaesthesia with loss of proprioceptive sense and upper motor neuron signs below it. On the other side there is loss of spinothalamic sensation (pain and temperature). With compressive lesions there is usually a band of pain at the level of the lesion in the distribution of the nerve roots subject to compression.
Investigations
Patients with a short history of a progressive spinal cord syndrome should be investigated urgently. Investigations necessary are listed in Box 22.81.
22.80 SIGNS OF SPINAL CORD COMPRESSION
Cervical, above C5
Upper motor neuron signs and sensory loss in all four limbs
Cervical, C5 to T1
Lower motor neuron signs and segmental sensory loss in the arms; upper motor neuron signs in the legs
Thoracic cord
Spastic paraplegia with a sensory level on the trunk
Conus medullaris
Lesions at the end of the spinal cord cause sacral loss of sensation and extensor plantar responses
Cauda equina
Spinal cord ends at approximately the T12/L1 spinal level and spinal lesions below this level can only cause lower motor neuron signs by affecting the cauda equina
22.81 INVESTIGATION OF ACUTE SPINAL CORD SYNDROME
Plain radiographs of spine
Chest radiographs
MRI of spine or myelography
CSF
Serum B12
Plain radiographs may show bony destruction and soft-tissue abnormalities and are an essential initial investigation (see Fig. 22.43). Routine investigations, including chest radiograph, may provide evidence of systemic disease. MRI of the spine is the investigation of choice (see Fig. 22.44); myelography also localises the lesion and, with CT in suitable cases, defines the extent of compression and associated soft-tissue abnormality (see Fig. 22.45). CSF should be taken for analysis at the time of myelography. In cases of complete spinal block this shows a normal cell count with a very elevated protein causing yellow discoloration of the fluid (Froin's syndrome). Acute deterioration may develop after myelography and it is preferable to alert the neurosurgeons before such procedures are undertaken. Needle biopsy is required prior to radiotherapy to establish the histological nature of the tumour.
Management
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Figure 22.43 Plain radiographs of the spine. A Loss of vertebral pedicle (arrow) by bony erosion of an osteolytic metastasis. B An osteosclerotic metastasis (arrow).
Figure 22.44 Axial MRI of thoracic spine. A A meningioma is compressing the spinal cord and emerging in a 'dumbbell' fashion through the vertebral foramen into the paraspinal space. B Line diagram illustrating major structures.
Figure 22.45 CT myelogram of cervical spine at the level of C2 showing bony erosion of vertebra by a metastasis (arrow).
Treatment and prognosis depend on the nature of the underlying lesion. Benign tumours should be surgically excised, and a good functional recovery can be expected unless a marked neurological deficit has developed before diagnosis. Extradural compression due to malignancy is the most common cause of spinal cord compression in developed countries and has a poor prognosis, although useful function can be regained if treatment is initiated within 24 hours of the onset of severe weakness or sphincter dysfunction. Surgical decompression may be appropriate in some patients, but has a similar outcome to radiotherapy. Spinal cord compression due to tuberculosis is common in some areas of the world, and requires surgical treatment if seen early. This should be followed by appropriate antitubercular chemotherapy (see p. 538) for an extended period. Traumatic lesions of the vertebral column require specialised treatment in a neurosurgical centre.
CERVICAL SPONDYLOSIS
In the cervical spine, some degree of degenerative change is a normal radiological finding in the middle-aged and elderly. Degeneration of the intervertebral discs and secondary osteoarthrosis (cervical spondylosis) is often asymptomatic, but may be associated with neurological dysfunction. The C5/6, C6/7 and C4/5 vertebral levels and C6, C7 and C5 roots, respectively, are most commonly affected (see Fig. 22.46).
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CERVICAL SPONDYLOTIC RADICULOPATHY
Compression of a nerve root occurs when a disc prolapses laterally. This may develop acutely, or more gradually due to osteophytic encroachment of the intervertebral foramina.
Clinical features
The patient complains of pain in the neck that may radiate in the distribution of the affected nerve root. The neck is held rigidly and neck movements may exacerbate pain. Paraesthesia and sensory loss may be found in the affected segment and there may be lower motor neuron signs, including weakness, wasting and reflex impairment (see Box 22.82).
22.82 PHYSICAL SIGNS IN CERVICAL ROOT COMPRESSION
Root Muscle weakness Sensory loss Reflex loss
C5 Biceps, deltoid, spinati Upper lateral arm Biceps
C6 Brachioradialis Lower lateral arm, thumb, index finger Supinator
C7 Triceps, finger and wrist extensors Middle finger Triceps
Investigations
Plain radiographs, including lateral and oblique views, should be obtained to confirm the presence of degenerative changes and to exclude other conditions, including destructive lesions. If surgery is contemplated, MRI is appropriate. Electrophysiological studies rarely add to the clinical examination, but may be necessary if there is doubt about the differential diagnosis between root and peripheral nerve lesions.
Management
Conservative treatment with analgesics and a cervical collar results in resolution of symptoms in the great majority of patients, but a few require surgery in the form of foraminotomy or disc excision.
CERVICAL SPONDYLOTIC MYELOPATHY
Dorsomedial herniation of a disc and the development of transverse bony bars or posterior osteophytes may result in pressure on the spinal cord or the anterior spinal artery which supplies the anterior two-thirds of the cord (see Fig. 22.46).
Clinical features
Figure 22.46 MRI showing cervical cord compression (arrow) in cervical spondylosis.
The onset of symptoms is usually insidious and painless, but acute deterioration may occur after trauma, especially hyperextension injury. Upper motor neuron signs develop in the limbs, with spasticity of the legs usually appearing before the arms are involved. Sensory loss in the upper limbs is common, producing tingling numbness and proprioception loss in the hands, with progressive clumsiness. Sensory manifestations in the legs are much less common. The neurological deficit usually progresses gradually and disturbance of micturition is a very late feature.
Investigations
Plain radiographs confirm the presence of degenerative changes, and MRI or myelography may be indicated if surgical treatment is being considered. MRI may also show areas of high signal within the spinal cord at the level of compression. Imaging of the cervical spine should be considered if there is diagnostic doubt or if surgery is contemplated.
Management
Surgical procedures, including laminectomy and anterior discectomy, may arrest progression of disability but may not result in neurological improvement. The judgement as to whether surgery should be undertaken may be difficult. Manipulation of the cervical spine is of no proven benefit and may precipitate acute neurological deterioration.
Prognosis
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The prognosis of cervical myelopathy is variable. In many patients the condition stabilises or even improves without intervention, but if progressive disability does develop, surgical decompression should be considered.
LUMBAR DISC HERNIATION
In Western countries low back pain ('lumbago') is the most common medical cause of inability to work (see p. 981). In the great majority of patients it is due to abnormalities of joints and ligaments in the lumbar spine rather than herniation of an intervertebral disc. Pain in the distribution of the lumbar or sacral roots ('sciatica') is often due to disc protrusion, but can be a feature of other rare but important disorders including spinal tumour, malignant disease in the pelvis and tuberculosis of the vertebral bodies.
Acute lumbar disc herniation is often precipitated by trauma, usually by lifting heavy weights while the spine is flexed. The nucleus pulposus may bulge or rupture through the annulus fibrosus, giving rise to pressure on nerve endings in the spinal ligaments, changes in the vertebral joints or pressure on nerve roots.
Clinical features
The onset may be sudden or gradual. Alternatively, repeated episodes of low back pain may precede sciatica by months or years. Constant aching pain is felt in the lumbar region and may radiate to the buttock, thigh, calf and foot. Pain is exacerbated by coughing or straining and may be relieved by lying flat.
The altered mechanics of the lumbar spine result in loss of lumbar lordosis and there may be spasm of the paraspinal musculature. Root pressure is suggested by limitation of flexion of the hip on the affected side if the straight leg is raised (Lasègue's sign). If the third or fourth lumbar roots are involved, Lasègue's sign may be negative, but pain in the back may be induced by hyperextension of the hip (femoral nerve stretch test). The roots most frequently affected are S1, L5 and L4; the signs of root pressure at these levels are summarised in Box 22.83.
Investigations
Plain radiographs of the lumbar spine are of little value in the diagnosis of lumbar disc disease although they may show other conditions such as malignant infiltration of a vertebral body. CT, especially using spiral scanning techniques, can provide helpful images of the disc protrusion and/or narrowing of the exit foramina. MRI is the investigation of choice if available, since soft tissues are well imaged.
22.83 PHYSICAL SIGNS IN LUMBAR ROOT COMPRESSION
Disc level Root Sensory loss Weakness Reflex loss
L3/L4 L4 Inner calf Inversion of foot Knee
L4/L5 L5 Outer calf and dorsum of foot Dorsiflexion of hallux/toes Hamstring
L5/S1 S1 Sole and lateral foot Plantar flexion Ankle
Management
Some 90% of patients with sciatica recover with conservative treatment with analgesia and early mobilisation; there is little evidence that bed rest helps recovery. The patient should be instructed in back-strengthening exercises and advised to avoid physical manoeuvres likely to strain the lumbar spine. Injections of local anaesthetic or steroids may be useful adjunctive treatment if symptoms are due to ligamentous injury or joint dysfunction.
Surgery may have to be considered if there is no response to conservative treatment or if progressive neurological deficits develop. Central disc prolapse with bilateral symptoms and signs and disturbance of sphincter function requires urgent surgical decompression.
LUMBAR CANAL STENOSIS
This is due to a congenital narrowing of the lumbar spinal canal, exacerbated by the degenerative changes that commonly occur with age.
Clinical features
The patients, who are usually elderly, characteristically develop exercise-induced weakness and paraesthesia in the legs (cauda equina claudication). These symptoms progress with continued exertion, often to the point that the patient can no longer walk, but are quickly relieved by a short period of rest. Physical examination at rest shows preservation of peripheral pulses with absent ankle reflexes. Weakness or sensory loss may only be apparent if the patient is examined immediately after exercise.
Investigations
Myelography, CT or MRI will demonstrate narrowing of the lumbar canal.
Management
Extensive lumbar laminectomy often results in complete relief of symptoms and recovery of normal exercise tolerance.
SYRINGOMYELIA
In this condition a fluid-filled cavity (or cavities) develops near the centre of the spinal cord, usually in the cervical segments (see Fig. 22.47). The expanding cavity disrupts second-order spinothalamic neurons (see Fig. 22.16, p. 1141), may extend laterally to damage the anterior horn cells, and may compress the long fibre tracts. Slit-like cavities may appear in the medulla in association with syringomyelia, producing brain-stem dysfunction (syringobulbia).
Aetiology
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Figure 22.47 MRI scan showing syrinx (arrows A), with herniation of cerebellar tonsils (arrow B).
Many patients have some obstruction to the flow of CSF at the foramen magnum. In some this is associated with congenital herniation of the cerebellar tonsils (Chiari type I malformation, see Fig. 22.47), and in others with basal arachnoiditis. It is assumed that the disturbed CSF dynamics cause the development of the syrinx but the mechanism is not clear. Cavities may also develop in the spinal cord following trauma or in association with an intrinsic spinal cord tumour.
Clinical features
Patients usually present in the third or fourth decade; symptoms are of insidious onset and slowly progressive. Pain in the neck or shoulder is common and patients may seek advice because of sensory loss in the upper limbs. The most characteristic physical sign is dissociated sensory loss (impaired pain and temperature sensation with preservation of dorsal column modalities), which has an upper and a lower level in a mantle or hemi-cape distribution (see Fig. 22.15F, p. 1141). Loss of protective sensory function leads to trophic lesions such as painless burns or ulcers on the hands, and sometimes painless deranged joints (Charcot joints-see p. 1046) in the upper limbs. Kyphoscoliosis is frequently present and wasting of the small hand muscles is a common early feature, with loss of reflexes in the arms. Upper motor neuron signs develop in the legs as the condition progresses. Syringobulbia leads to dysarthria, palatal palsy, Horner's syndrome, nystagmus and sensory loss on the face.
Investigations
Plain radiographs may demonstrate congenital anomalies around the foramen magnum or expansion of the cervical canal. The most sensitive and least invasive investigation is MRI (see Fig. 22.47).
Management
Surgical decompression of the foramen magnum or the syrinx itself may arrest progression of the neurological deficit and often alleviates pain. The results of surgery are, however, often disappointing and in some patients the condition continues to progress slowly over long periods.
pages 1180 - 1192
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Home > 2 SYSTEM-BASED DISEASES > 22 Neurological disease > INFECTIONS OF THE NERVOUS SYSTEM
INFECTIONS OF THE NERVOUS SYSTEM
The clinical features of nervous system infections depend upon the location of the infection (in the meninges or in the brain/spinal cord parenchyma), the causative organism (virus, bacteria or parasite), and whether the infection is acute or chronic. The major infections of the nervous system are listed in Box 22.84. The frequency of these varies somewhat geographically. Helminthic infections such as cysticercosis and hydatid disease are described in Chapter 1.
22.84 INFECTIONS OF THE NERVOUS SYSTEM
Bacterial infections
Meningitis
Suppurative encephalitis
Brain abscess
Tuberculosis
Paravertebral (epidural) abscess
Neurosyphilis
Leprosy (peripheral nerves)
Diphtheria (peripheral nerves)
Tetanus (motor cells)
Viral infections
Meningitis
Encephalitis
Transverse myelitis
Poliomyelitis
Rabies
HIV infection
Slow virus/prion infections
Creutzfeldt-Jakob disease
Kuru
Subacute sclerosing panencephalitis
Progressive multifocal leucoencephalopathy
Protozoal infections
Malaria
Toxoplasmosis (in immunosuppressed)
Trypanosomiasis
Amoebic abscess
Helminthic infections
Schistosomiasis (spinal cord)
Cysticercosis
Hydatid disease
Strongyloidiasis
Fungal infections
Cryptococcal meningitis
Candida meningitis or brain abscess
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22.85 CEREBROSPINAL FLUID INDICES IN MENINGITIS*
Condition Cell type Cell count Glucose Protein Gram stain
Normal Lymphocytes 0-4 per mm3 > 60% of blood glucose Up to 0.45 g/l -
Viral Lymphocytes 10-2000 Normal Normal -
Bacterial Polymorphs 1000-5000 Low Normal/elevated +
Tuberculous Polymorphs/lymphocytes/mixed 50-5000 Low Elevated Often -
Fungal Lymphocytes 50-500 Low Elevated ±
Malignant Lymphocytes 0-100 Low Normal/elevated -
* See also Box 22.3, page 1115.
MENINGITIS
Acute infection of the meninges presents with the characteristic combination of pyrexia, headache and meningism. Meningism, which can occur in other situations (such as after subarachnoid haemorrhage) consists of stiffness of the neck, often with other signs of meningeal irritation: Kernig's sign (with the hip joint flexed, extension at the knee causes spasm in the hamstring muscles) and Brudzinski's sign (passive flexion of the neck causes flexion of the thighs and knees). The severity of these features varies somewhat according to the causative organism, as does the presence of other features such as a skin rash. Abnormalities in the CSF (see Box 22.85) are very helpful in distinguishing the cause of meningitis. Causes of meningitis are listed in Box 22.86.
22.86 CAUSES OF MENINGITIS
Infective
Bacteria (see Box 22.87)
Brucella
Viruses
Enteroviruses (echo, Coxsackie, polio)
Mumps
Influenza
Herpes simplex
Varicella zoster
Epstein-Barr
HIV
Lymphocytic choriomeningitis
Protozoa and parasites
Toxoplasma
Amoeba
Cysticercus
Fungi
Cryptococcus neoformans
Candida
Histoplasma
Blastomyces
Coccidioides
Sporothrix
Non-infective ('sterile')
Malignant disease
Breast cancer
Bronchial cancer
Leukaemia
Lymphoma
Inflammatory disease (may be recurrent)
Sarcoidosis
SLE
Behçet's disease
Mollaret's meningitis
VIRAL MENINGITIS
Viral infection is the most common cause of meningitis, and usually results in a benign and self-limiting illness requiring no specific therapy. It is a much less serious illness than bacterial meningitis unless there is associated encephalitis, which is rare. A number of viruses can cause meningitis (see Box 22.86), the most common being echoviruses and, where specific immunisation is not employed, the mumps virus.
Clinical features
The condition occurs mainly in children or young adults, with acute onset of headache and irritability and the rapid development of meningism. In viral meningitis the headache is usually the more severe feature. There may be a high pyrexia, but focal neurological signs do not occur since there is seldom parenchymal involvement of the brain.
Investigations
The CSF contains an excess of lymphocytes, but glucose and protein levels are normal. It is extremely important to verify that the patient has not received antibiotics (for whatever cause) prior to the lumbar puncture, as this picture can also be found in partially treated bacterial meningitis.
Management
There is no specific treatment and the condition is usually benign and self-limiting. The patient should be treated symptomatically in a quiet environment. Recovery usually occurs within days, although a lymphocytic pleocytosis may persist in the CSF.
Meningitis may also occur as a complication of a viral infection primarily involving other organs: for example, in mumps, measles, infectious mononucleosis, herpes zoster and hepatitis. Complete recovery without specific therapy is the rule.
PYOGENIC BACTERIAL MENINGITIS
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22.87 BACTERIAL CAUSES OF MENINGITIS
Age of onset Common Less common
Neonate Gram-negative bacilli (Escherichia coli, Proteus etc.)
Group B streptococci Listeria monocytogenes
Pre-school child Haemophilus influenzae
Neisseria meningitidis
Streptococcus pneumoniae Mycobacterium tuberculosis
Older child and adult Neisseria meningitidis
Streptococcus pneumoniae Listeria monocytogenes
Mycobacterium tuberculosis
Cryptococcus neoformans (in immunosuppressed)
Staphylococcus aureus (skull fracture)
Haemophilus influenzae
Many bacteria can cause meningitis but some do so more frequently than others (see Box 22.87). Bacterial meningitis is usually secondary to a bacteraemic illness, although infection may result from direct spread from an adjacent focus of infection in the ear, skull fracture or sinus. Bacterial meningitis has become less common but the mortality and morbidity remain significant despite the availability of an increasing range of antibiotics. An important factor in determining prognosis is early diagnosis and the prompt initiation of appropriate therapy.
The meningococcus (Neisseria meningitidis) is the most common cause of bacterial meningitis in Britain, whilst in the USA Haemophilus influenzae is more common. Spread is by the air-borne route, but close contact is necessary. Epidemics occur, particularly in cramped living conditions or where the climate is hot and dry, e.g. areas of Africa. The organism invades through the nasopharynx, producing septicaemia that is usually associated with pyogenic meningitis. Complications of meningococcal septicaemia are listed in Box 22.88. Chronic meningococcaemia is a rare condition in which the patient can be unwell for weeks or even months with recurrent fever, sweating, joint pains and transient rash. It usually occurs in the middle-aged and elderly.
In pneumococcal and Haemophilus infections there may be an associated otitis media. Pneumococcal meningitis may be associated with pneumonia and occurs especially in older patients and alcoholics, as well as in patients without functioning spleens. Listeria monocytogenes has recently emerged as an increasing cause of meningitis and rhombencephalitis (brain-stem encephalitis) in the immunosuppressed, diabetics, alcoholics and pregnant women (see p. 42). It can also cause meningitis in the neonatal period.
Pathology
22.88 COMPLICATIONS OF MENINGOCOCCAL SEPTICAEMIA
Meningitis
Rash (morbilliform, petechial or purpuric)
Shock
Intravascular coagulation
Renal failure
Peripheral gangrene
Arthritis (septic or reactive)
Pericarditis (septic or reactive)
The pia-arachnoid is congested and infiltrated with inflammatory cells. A thin layer of pus forms and this may later organise to form adhesions. These may cause obstruction to the free flow of CSF leading to hydrocephalus, or they may damage the cranial nerves at the base of the brain. The CSF pressure rises rapidly, the protein content increases, and there is a cellular reaction that varies in type and severity according to the nature of the inflammation and the causative organism. An obliterative endarteritis of the leptomeningeal arteries passing through the meningeal exudate may produce secondary cerebral infarction. Pneumococcal meningitis is often associated with a very purulent CSF and a high mortality, especially in older adults.
Clinical features
Headache, drowsiness, fever and neck stiffness are the usual presenting features. In severe bacterial meningitis the patient may be comatose and later there may be focal neurological signs. Meningococcal meningitis may present very rapidly, with abrupt onset of obtundation due to cerebral oedema, probably as a result of endotoxin and/or cytokine release. There may be a purpuric skin rash and circulatory collapse.
Figure 22.48 The investigation of meningitis.
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Investigations
Lumbar puncture is mandatory unless there are contra-indications (see p. 1114). Particularly if the patient is drowsy with focal neurological signs or seizures it is wise to obtain a CT to exclude a mass lesion (such as a cerebral abscess) before lumbar puncture because of the risk of coning, but this should not delay treatment of a presumptive meningitis. If lumbar puncture is deferred or omitted, it is essential to take diagnostic specimens and to start empirical treatment (see Fig. 22.48).
22.89 TREATMENT OF PYOGENIC MENINGITIS OF UNKNOWN CAUSE
Patients with a typical meningococcal rash
Benzylpenicillin 2.4 g i.v. 6-hourly
Adults aged 18-50 years without a typical meningococcal rash
Cefotaxime 2 g i.v. 6-hourly
or
Ceftriaxone 2 g i.v. 12-hourly
Patients in whom penicillin resistant pneumococcal infection is suspected
As for (2) but add: Vancomycin 1 g i.v. 12-hourly
or
Rifampicin 600 mg i.v. 12-hourly
Adults aged over 50 years and those in whom Listeria monocytogenes infection is suspected
(e.g. brain-stem signs, immunosuppression, diabetic, alcoholic)
As for (2) but add: Ampicillin 2 g i.v. 4-hourly
or
Co-trimoxazole 50 mg/kg i.v. daily in two divided doses
Patients with a clear history of anaphylaxis to ß-lactams
Chloramphenicol 25 mg/kg i.v. 6-hourly plus vancomycin 1 g i.v. 12-hourly
In bacterial meningitis the CSF is cloudy (turbid) due to the presence of many neutrophils (often > 1000 cells/mm3), the protein content is significantly elevated and the glucose reduced. Gram film and culture may allow identification of the organism. Blood cultures may be positive. Polymerase chain reaction (PCR) techniques can be used on both blood and CSF to identify bacterial DNA. These methods are useful in detecting meningococcal infection and in typing the organism.
Management
If meningococcal disease is suspected the patient should be given parenteral benzylpenicillin (intravenous is preferable to intramuscular) before admission to hospital. The only contraindication is a history of penicillin anaphylaxis. Recommended empirical therapy before the cause of meningitis is known is given in Box 22.89. The antibiotic regimen may be modified after CSF examination, depending on the infecting organism. Guidance as to the preferred antibiotic is given in Box 22.90 if the organism is known and in Box 22.89 if the organism has not been identified. Adjunctive steroid therapy, though useful in children (see EBM panel), has not been adequately evaluated in adults.
EBM
ADJUNCTIVE DEXAMETHASONE THERAPY FOR BACTERIAL MENINGITIS IN CHILDREN-and reduction in severe hearing loss
'The available evidence on adjunctive dexamethasone therapy confirms benefit for H. influenzae type B meningitis and, if commenced with or before parenteral antibiotics, suggests benefit for pneumococcal meningitis in childhood. Limiting dexamethasone therapy to 2 days may be optimal.'
McIntyre PB, Berkey CS, King SM, et al. Dexamethasone as adjunctive therapy in bacterial meningitis. A meta-analysis of random clinical trials since 1988. JAMA 1997; 278:925-931.
Coyle PK. Glucocorticoids in central nervous system bacterial infection. Arch Neurol 1999; 56:796-801.
Further information: www.clinicalevidence.org
22.90 CHEMOTHERAPY OF BACTERIAL MENINGITIS WHEN THE CAUSE IS KNOWN
Pathogen Regimen of choice Alternative agent(s)
N. meningitidis Benzylpenicillin 2.4 g i.v. 4-hourly for 5-7 days Cefuroxime, ampicillin
Chloramphenicol*
Strep. pneumoniae (sensitive to ß-lactams, minimum inhibitory concentration (MIC) < 1 mg/l) Cefotaxime 2 g i.v. 6-hourly or ceftriaxone 2 g i.v. 12-hourly for 10-14 days Chloramphenicol*
Strep. pneumoniae (resistant to ß-lactams) As for sensitive strains but add vancomycin 1 g i.v. 12-hourly or rifampicin 600 mg i.v. 12-hourly Vancomycin plus rifampicin*
H. influenzae Cefotaxime 2 g i.v. 6-hourly or ceftriaxone 2 g i.v. 12-hourly for 10-14 days Chloramphenicol*
Listeria monocytogenes Ampicillin 2 g i.v. 4-hourly plus gentamicin 5 mg/kg i.v. daily Ampicillin 2 g i.v. 4-hourly plus co-trimoxazole 50 mg/kg daily in two divided doses
*For patients with a history of anaphylaxis to ß-lactam antibiotics.
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In meningococcal disease mortality is doubled if the patient presents with features of septicaemia rather than meningitis. Certain patients are likely to require intensive care facilities and expertise, including those with cardiac, respiratory or renal involvement, and those with CNS depression prejudicing the airway. Early endotracheal intubation and mechanical ventilation protect the airway and may prevent the development of the acute respiratory distress syndrome (ARDS, see p. 198). Adverse prognostic features include hypotensive shock, a rapidly developing rash, a haemorrhagic diathesis, multisystem failure and an age of more than 60 years.
EBM
CHEMOPROPHYLAXIS FOR MENINGOCOCCAL INFECTION-does it reduce the incidence of clinical disease among contacts?
'There are no RCTs examining the effects of antibiotics on the incidence of meningococcal disease among contacts. Observational data suggest that antibiotics reduce the risk of disease. There is no good evidence to address the question of which contacts should be treated.'
Hart C. Meningococcal disease. Clinical Evidence 2000; 3:350-357.
Cooke RPD, Riordan T, Jones DM, Painter MJ. Secondary cases of meningococcal infection among close family and household contacts in England and Wales, 1984-7. BMJ 1989; 298:555-558.
Further information: www.clinicalevidence.org
www.phls.co.uk/facts/meni.htm
Prevention of meningococcal infection
Household and other close contacts of patients with meningococcal infections, especially children, should be given 2 days of oral rifampicin (age 3-12 months 5 mg/kg 12-hourly, > 1 year 10 mg/kg 12-hourly, adults 600 mg 12-hourly). In adults a single dose of 500 mg of ciprofloxacin is an alternative. If not treated with ceftriaxone the index case should be given similar treatment to clear infection from the nasopharynx before hospital discharge. Vaccines are available for the prevention of disease caused by meningococci of groups A and C, but not group B which is the most common serogroup isolated in many countries, including Britain.
TUBERCULOUS MENINGITIS
Now rare in the Western world in previously healthy individuals, tuberculous meningitis remains common in developing countries and is seen more frequently as a secondary infection in patients with AIDS.
Pathology
Tuberculous meningitis occurs most commonly shortly after a primary infection in childhood or as part of miliary tuberculosis. The usual local source of infection is a caseous focus in the meninges or brain substance adjacent to the CSF pathway. The brain is covered by a greenish, gelatinous exudate, especially around the base, and numerous scattered tubercles are found on the meninges.
Clinical features
The clinical features are listed in Box 22.91.
22.91 CLINICAL FEATURES OF TUBERCULOUS MENINGITIS
Symptoms
Headache
Vomiting
Low-grade fever
Lassitude
Depression
Confusion
Behaviour changes
Signs
Meningism (may be absent)
Oculomotor palsies
Papilloedema
Depression of conscious level
Focal hemisphere signs
Investigations
The CSF is under increased pressure. It is usually clear but, when allowed to stand, a fine clot ('spider web') may form. The fluid contains up to 500 cells/mm3, predominantly lymphocytes. There is a rise in protein and a marked fall in glucose. Detection of the tubercle bacillus in a smear of the centrifuged deposit from the CSF may be difficult. The CSF should be cultured but as this result will not be known for up to 6 weeks, treatment must be started without waiting for confirmation. Brain imaging may show hydrocephalus, brisk meningeal enhancement on enhanced CT, and/or an intracranial tuberculoma.
Management
As soon as the diagnosis is made or strongly suspected, chemotherapy should be started using one of the regimens including pyrazinamide described on page 538. The use of steroids in addition to antituberculous therapy is controversial but may be indicated to treat raised intracranial pressure. Surgical ventricular drainage may be needed if obstructive hydrocephalus develops. Skilled nursing is essential during the acute phase of the illness and measures must be taken to maintain adequate hydration and nutrition.
Prognosis
Untreated tuberculous meningitis is fatal in a few weeks but complete recovery is the rule if treatment is started before the appearance of focal signs or stupor. When treatment is started at a later stage the recovery rate is 60% or less and the survivors show permanent neurological deficit.
OTHER FORMS OF MENINGITIS
Fungal meningitis (especially cryptococcosis-see p. 95) usually occurs in patients who are immunosuppressed and is a recognised complication of HIV infection (see p. 124). The CSF findings are similar to those of tuberculous meningitis, but the diagnosis can be confirmed by microscopy or specific serological tests.
In some areas meningitis may be caused by spirochaetes (leptospirosis, Lyme disease and syphilis-see pp. 20, 21 and 96), rickettsiae (typhus fever-see p. 62) or protozoa (amoebiasis-see p. 45).
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Meningitis can also be due to non-infective pathologies. This is seen in recurrent aseptic meningitis due to SLE, Behçet's disease or sarcoidosis, as well as a condition of unknown origin known as Mollaret's syndrome in which the recurrent meningitis is associated with epithelioid cells in the spinal fluid ('Mollaret' cells). Meningitis can also be seen due to direct invasion of the meninges by neoplasm ('malignant meningitis'-see Box 22.86, p. 1193).
PARENCHYMAL VIRAL INFECTIONS
Infection of the substance of the nervous system will produce symptoms of focal dysfunction (focal deficits and/or seizures) with general signs of infection depending upon the acuteness of the infection and the type of organism.
VIRAL ENCEPHALITIS
A range of viruses can cause encephalitis but only a minority of patients have a history of recent viral infection. In Europe, the most common cause of viral encephalitis is herpes simplex (see p. 30), which probably reaches the brain via the olfactory nerves. The development of effective therapy for some forms of encephalitis has enhanced the importance of clinical diagnosis and virological examination of the CSF. In some parts of the world viruses transmitted by mosquitoes and ticks (arboviruses) are an important cause of encephalitis. The epidemiology of some of these infections is changing. Japanese encephalitis (see p. 93) has spread relentlessly across Asia to Australia, and there have been outbreaks of West Nile encephalitis in Romania, Israel and New York. Acute encephalitis illness may occur in HIV infection, occasionally at the time of infection, but more commonly as a manifestation of AIDS (see p. 122).
Pathology
Inflammation can occur in the cortex, white matter, basal ganglia and brain stem, and the distribution of lesions varies with the type of virus. In herpes simplex encephalitis the temporal lobes are usually primarily affected. Inclusion bodies may be present in the neurons and glial cells and there is an infiltration of polymorphonuclear cells in the perivascular space. There is neuronal degeneration and diffuse glial proliferation, often associated with cerebral oedema.
Clinical features
Viral encephalitis presents with acute onset of headache, with fever, focal neurological signs (aphasia and/or hemiplegia) and seizures. Disturbance of consciousness ranging from drowsiness to deep coma supervenes early and may advance dramatically. Meningism occurs in many patients. Rabies presents a distinct clinical picture and is described below.
Investigations
CT of the head, which should precede lumbar puncture, may show low-density lesions in the temporal lobes. MRI is more sensitive in detecting early abnormalities. The CSF usually contains excess lymphocytes, but polymorphonuclear cells may predominate in the early stages. Occasionally, the CSF is normal. The protein content may be elevated but the glucose is normal. The EEG is usually abnormal in the early stages, especially in herpes simplex encephalitis, with characteristic periodic slow-wave activity in the temporal lobes. Virological investigations of the CSF, including PCR for viral DNA, may reveal the causative organism but the initiation of treatment should not await this.
Management
Anticonvulsant treatment is often necessary (see p. 1127) and raised intracranial pressure is treated with dexamethasone 8 mg 12-hourly. Herpes simplex encephalitis responds to aciclovir 10 mg/kg i.v. 8-hourly for 2-3 weeks. This should be given early to all patients suspected of suffering from viral encephalitis.
Even with optimum treatment, mortality is 10-30% and significant proportions of survivors have residual epilepsy or cognitive impairment. For details of post-infectious encephalomyelitis, see page 1172.
BRAIN-STEM ENCEPHALITIS
This presents with ataxia, dysarthria, diplopia or other cranial nerve palsies. The CSF is lymphocytic, with a normal glucose. The causative agent is presumed to be viral. However, Listeria monocytogenes may cause a similar syndrome with meningitis (and often a polymorphonuclear CSF pleocytosis) and requires specific treatment with ampicillin 500 mg 6-hourly (see Box 22.90).
RABIES
Rabies is caused by a rhabdovirus which infects the central nervous tissue and salivary glands of a wide range of mammals, and is usually conveyed by saliva through bites or licks on abrasions or on intact mucous membranes. Humans are most frequently infected from dogs. In Europe the maintenance host is the fox.
The incubation period varies in humans from a minimum of 9 days to many months but is usually between 4 and 8 weeks. Severe bites, especially if on the head or neck, are associated with shorter incubation periods.
Clinical features
At the onset there may be fever, and paraesthesia at the site of the bite. A prodromal period of 1-10 days, during which the patient is increasingly anxious, leads to the characteristic 'hydrophobia'. Although the patient is thirsty, attempts at drinking provoke violent contractions of the diaphragm and other inspiratory muscles. Delusions and hallucinations may develop, accompanied by spitting, biting and mania, with lucid intervals in which the patient is markedly anxious. Cranial nerve lesions develop and terminal hyperpyrexia is common. Death ensues, usually within a week of the onset of symptoms.
Investigations
During life the diagnosis is usually made on clinical grounds but rapid immunofluorescent techniques can detect antigen in corneal impression smears or skin biopsies.
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Management
A few patients with rabies have survived. All received some post-exposure prophylaxis, and needed intensive care with facilities to control cardiac and respiratory failure. Otherwise, only palliative treatment is possible once symptoms have appeared. The patient should be heavily sedated with diazepam 10 mg 4-6-hourly, supplemented by chlorpromazine 50-100 mg if necessary. Nutrition and fluids should be given intravenously or through a gastrostomy.
Prevention
Pre-exposure prophylaxis is required by those who by profession handle potentially infected animals, those who work with rabies virus in laboratories and those who live at special risk in rabies-endemic areas. Protection is afforded by two intradermal injections of 0.1 ml human diploid cell strain vaccine, or two intramuscular injections of 1 ml, given 4 weeks apart, followed by yearly boosters.
Post-exposure prophylaxis
The wounds should be thoroughly cleaned, preferably with a quaternary ammonium detergent or soap; damaged tissues should be excised and the wound left unsutured. Rabies can usually be prevented if treatment is started within a day or two of biting. Delayed treatment may still be of value. For maximum protection hyperimmune serum and vaccine are required.
The safest antirabies antiserum is human rabies immune globulin; the dose is 20 i.u./kg body weight. Half is infiltrated around the bite and half is given intramuscularly at a different site from the vaccine. The dose of hyperimmune animal serum is 40 i.u./kg; hypersensitivity reactions, including anaphylaxis, are common.
The safest vaccine, free of complications, is human diploid cell strain vaccine; 1.0 ml is given intramuscularly on days 0, 3, 7, 14, 30 and 90. In developing countries, where human rabies globulin may not be obtainable, 0.1 ml of vaccine should be given intradermally into eight sites on day 1, with single boosters on days 7 and 28. Where human products are not available and when risk of rabies is slight (licks on the skin, or minor bites of covered arms or legs) it may be justifiable to delay starting treatment for up to 5 days while observing the biting animal or awaiting examination of its brain rather than use the older vaccine.
Control of spread
Human rabies is a rare disease even in endemic areas. However, because it is usually fatal, major efforts are directed to limiting its spread and preventing its importation into uninfected countries such as Britain.
POLIOMYELITIS
Aetiology and pathology
The disease is caused by one of three polioviruses, which are a subgroup of the enteroviruses. It is much less common in developed countries following the widespread use of oral vaccines but is still a major problem in the developing world. Infection usually occurs through the nasopharynx.
The virus causes a lymphocytic meningitis and infects the grey matter of the spinal cord, brain stem and cortex. There is a particular propensity to damage anterior horn cells, especially in the lumbar segments.
Clinical features
The incubation period is 7-14 days. Figure 22.49 illustrates the various features of the infection. Many patients recover fully after the initial phase of a few days of mild fever and headache. In others, after a week of well-being, there is recurrence of pyrexia, headache and meningism. Weakness may start later in one muscle group and can progress to widespread paresis. Respiratory failure may supervene if intercostal muscles are paralysed or the medullary motor nuclei are involved.
Investigations
The CSF shows a lymphocytic pleocytosis, a rise in protein and a normal sugar content. Poliomyelitis virus may be cultured from CSF and stool.
Management
In the early stages bed rest is imperative because exercise appears to worsen the paralysis or precipitate it. At the onset of respiratory difficulties a tracheostomy and ventilation are required. Subsequent treatment is by physiotherapy and orthopaedic measures.
Prognosis
Figure 22.49 Poliomyelitis. Possible consequences of infection.
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Epidemics vary widely in their incidence of non-paralytic cases and in mortality rate. Death occurs from respiratory paralysis. Muscle weakness is maximal at the end of the first week and gradual recovery may then take place for several months. Muscles showing no signs of recovery by the end of a month probably will not regain useful function. Second attacks are very rare but occasionally patients show late deterioration in muscle bulk and power many years after the initial infection.
Prevention
Prevention of poliomyelitis is by immunisation with live (Sabin) vaccine.
HERPES ZOSTER (SHINGLES)
Herpes zoster is the result of reactivation of the varicella zoster virus that has lain dormant in a nerve root ganglion following chickenpox earlier in life. Reactivation may be spontaneous (as usually occurs in the middle-aged or elderly) or be due to immunosuppression (as in patients with diabetes, malignant disease or AIDS). Full details are given on page 32.
SUBACUTE SCLEROSING PANENCEPHALITIS
This is a rare, chronic, progressive and eventually fatal neurological disease caused by the measles virus, presumably as a result of an inability of the nervous system to eradicate the virus. It occurs in children and adolescents, usually many years after the primary virus infection. The onset is insidious, with intellectual deterioration, apathy and clumsiness followed by myoclonic jerks, rigidity and dementia.
The CSF may show a mild lymphocytic pleocytosis and the EEG is distinctive, with periodic bursts of triphasic waves. Although there is persistent measles-specific IgG in serum and CSF, antiviral therapy is ineffective and death ensues within years.
PROGRESSIVE MULTIFOCAL LEUCOENCEPHALOPATHY
This was originally described as a rare complication of lymphoma, leukaemia or carcinomatosis. Nowadays it occurs more frequently as a feature of AIDS (see p. 123). It is an infection of oligodendrocytes by human polyomavirus JC, which causes widespread demyelination of the white matter of the cerebral hemispheres. Clinical signs include dementia, hemiparesis and aphasia which progress rapidly, usually leading to death within weeks or months. Areas of low density in the white matter are seen on CT but MRI is more sensitive, showing diffuse high signal on T2-weighted images.
PARENCHYMAL BACTERIAL INFECTIONS
CEREBRAL ABSCESS
Bacteria may enter the cerebral substance through penetrating injury, by direct spread from paranasal sinuses or the middle ear, or by haematogenous spread from septicaemia. The site of abscess formation and the likely causative organism are both related to the source of infection (see Box 22.92).
Initial infection leads to local suppuration followed by loculation of pus within a surrounding wall of gliosis, which in a chronic abscess may form a tough capsule. Multiple abscesses may occur, particularly with haematogenous spread.
Clinical features
22.92 AETIOLOGY AND TREATMENT OF BACTERIAL CEREBRAL ABSCESS
Site of abscess Source of infection Likely organisms Recommended treatment
Frontal lobe Paranasal sinuses
Teeth Streptococci
Anaerobes Cefuroxime 1.5 g i.v. 8-hourly plus metronidazole 500 mg i.v. 8-hourly
Temporal lobe Middle ear Streptococci
Enterobacteriaceae Ampicillin 2-3 g i.v. 8-hourly plus metronidazole 500 mg i.v. 8-hourly plus either ceftazidime 2 g i.v.
Cerebellum Sphenoid sinus Pseudomonas spp. Anaerobes 8-hourly or gentamicin* 5 mg/kg i.v. daily
Any site Penetrating trauma Staphylococci Flucloxacillin 2-3 g i.v. 6-hourly or cefuroxime 1.5 g i.v. 8-hourly
Multiple Metastatic and cryptogenic Streptococci Anaerobes Benzylpenicillin 1.8-2.4 g i.v. 6-hourly if endocarditis or cyanotic heart disease
Otherwise cefuroxime 1.5 g i.v. 8-hourly plus metronidazole 500 mg i.v. 8-hourly
*Monitor gentamicin levels.
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Figure 22.50 Right temporal cerebral abscess (arrows), with surrounding oedema and midline shift to the left. A Unenhanced CT image. B Contrast-enhanced CT image.
A cerebral abscess may present acutely with fever, headache, meningism and drowsiness, but more commonly presents over days or weeks as a cerebral mass lesion with little or no evidence of infection. Seizures, raised intracranial pressure and focal hemisphere signs occur alone or in combination, and distinction from a cerebral tumour may be impossible on clinical grounds.
Investigations
Lumbar puncture is potentially hazardous in the presence of raised intracranial pressure and CT should always precede lumbar puncture. CT shows single or multiple low-density areas, which show ring enhancement with contrast, and surrounding cerebral oedema (see Fig. 22.50). There may be an elevated white blood cell count and ESR in patients with active local infection. The possibility of cerebral toxoplasmosis secondary to HIV infection should always be considered.
Management
Antimicrobial therapy is indicated once the diagnosis is made. The likely source of infection should guide the choice of antibiotic (see Box 22.92). Surgical treatment by burr-hole aspiration or excision may be necessary, especially where the presence of a capsule may lead to a persistent focus of infection. Anticonvulsants are often necessary, as epilepsy frequently develops acutely or in the recovery phase.
Prognosis
The mortality rate remains at 10-20% despite an improvement in available surgical and medical treatments, and in some patients this is related to delay in diagnosis and initiation of treatment.
SUBDURAL EMPYEMA
This is a rare complication of frontal sinusitis, osteomyelitis of the skull vault, or middle ear disease. A collection of pus in the subdural space spreads over the surface of the hemisphere, causing underlying cortical oedema or thrombophlebitis. Patients present with severe pain in the face or head and pyrexia, often with a history of preceding paranasal sinus or ear infection. The patient then becomes drowsy with seizures and focal signs such as a progressive hemiparesis.
The diagnosis rests on a strong clinical suspicion in patients with a local focus of infection. Careful assessment of a head CT (with contrast) or MRI may show a subdural collection with underlying cerebral oedema. Management requires aspiration of pus via a burrhole and appropriate parenteral antibiotics. Any local source of infection must be treated to prevent reinfection.
SPINAL EPIDURAL ABSCESS
The characteristic clinical features are pain in a root distribution and progressive transverse spinal cord syndrome with paraparesis, sensory impairment and sphincter dysfunction. Infection is usually haematogenous but a primary source of infection is easily overlooked.
Plain radiographs of the spine may show osteomyelitis but such changes are often late. MRI or myelography should precede urgent neurosurgical intervention. Decompressive laminectomy with draining of the abscess relieves the pressure on the dura. This, together with appropriate antibiotics, may prevent complete and irreversible paraplegia. Organisms may be cultured from the pus or blood.
TETANUS
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This disease results from infection with Clostridium tetani, which is a commensal in the gut of humans and domestic animals and is found in soil. Infection enters the body through wounds, often trivial. It is rare in Britain, occurring mostly in gardeners and farmers. By contrast, the disease is common in many developing countries, where dust contains spores derived from animal and human excreta. If childbirth takes place in an unhygienic environment, Tetanus neonatorum may result from infection of the umbilical stump, or the mother may develop the disease. Tetanus is still one of the major killers of adults, children and neonates in developing countries, where the mortality rate can be nearly 100% in the newborn and around 40% in others.
In circumstances unfavourable to the growth of the organism, spores are formed and these may remain dormant for years in the soil. Spores germinate and bacilli multiply only in the anaerobic conditions which occur in areas of tissue necrosis or if the oxygen tension is low as a result of the presence of other organisms, particularly aerobic ones. The bacilli remain localised but produce an exotoxin with an affinity for motor nerve endings and motor nerve cells.
The anterior horn cells are affected after the exotoxin has passed into the blood stream and their involvement results in rigidity and convulsions. Symptoms first appear from 2 days to several weeks after injury-the shorter the incubation period, the more severe the attack and the worse the prognosis.
Clinical features
Much the most important early symptom is trismus-spasm of the masseter muscles, which causes difficulty in opening the mouth and in masticating, hence the name 'lockjaw'. Lockjaw in tetanus is painless, unlike the spasm of the masseters due to dental abscess, septic throat or other causes, which is painful. Conditions that can mimic tetanus include hysteria and phenothiazine overdosage.
In tetanus, the tonic rigidity spreads to involve the muscles of the face, neck and trunk. Contraction of the frontalis and the muscles at the angles of the mouth gives rise to the so-called 'risus sardonicus'. There is rigidity of the muscles at the neck and trunk of varying degree. The back is usually slightly arched ('opisthotonus') and there is a board-like abdominal wall.
In the more severe cases violent spasms lasting for a few seconds to 3-4 minutes occur spontaneously, or may be induced by stimuli such as moving the patient or making a noise. These convulsions are painful, exhausting and of very serious significance, especially if they appear soon after the onset of symptoms. They gradually increase in frequency and severity for about 1 week and the patient may die from exhaustion, asphyxia or aspiration pneumonia. In less severe illness convulsions may not commence for about a week after the first sign of rigidity and in very mild infections they may never appear. Autonomic involvement may cause cardiovascular complications such as hypertension.
Rarely, the only manifestation of the disease may be 'local tetanus'-stiffness or spasm of the muscles near the infected wound-and the prognosis is good if treatment is commenced at this stage.
22.93 TREATMENT OF TETANUS
Neutralise absorbed toxin
I.v. injection of 3000 i.u. of human tetanus antitoxin
Prevent further toxin production
Débridement of wound
Benzylpenicillin 600 mg i.v. 6-hourly (metronidazole if allergic to penicillin)
Control spasms
Nurse in a quiet room
Avoid unnecessary stimuli
I.v. diazepam-if spasms continue paralyse patient and ventilate
General measures
Maintain hydration and nutrition
Treat secondary infections
Investigations
The diagnosis is made on clinical grounds. It is rarely possible to isolate the infecting organism from the original locus of entry.
Management
This should be begun as soon as possible. The essentials are shown in Box 22.93.
Prevention
Active immunisation must be given. Contaminated injuries are treated by débridement. The immediate danger of tetanus can be greatly reduced by the injection of 1200 mg of penicillin followed by a 7-day course of oral penicillin. For those who are allergic to penicillin, erythromycin should be used. When the risk of tetanus is judged to be present, an injection of 250 units of human tetanus antitoxin should be given along with an intramuscular injection of toxoid which should be repeated 1 month and 6 months later. For those already immunised only a booster dose of toxoid is required.
LYME DISEASE
See page 21.
NEUROSYPHILIS
Neurosyphilis may present as an acute or chronic process and may involve the meninges, blood vessels and/or parenchyma of the brain and spinal cord. In developed countries syphilis is now most commonly seen in patients with AIDS. The clinical manifestations are diverse and, although the condition is now rare, early diagnosis and treatment remain important.
Clinical features
The clinical and pathological features of the three most common presentations are summarised in Box 22.94.
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22.94 CLINICAL AND PATHOLOGICAL FEATURES OF NEUROSYPHILIS
Type Pathology Clinical features
Meningovascular (5 years)* Endarteritis obliterans
Meningeal exudate
Granuloma (gumma) Stroke
Cranial nerve palsies
Seizures/mass lesion
General paralysis of the insane (5-15 years)* Degeneration in cerebral cortex/cerebral atrophy
Thickened meninges Dementia
Tremor
Bilateral upper motor signs
Tabes dorsalis (5-20 years)* Degeneration of sensory neurons
Wasting of dorsal columns
Optic atrophy Lightning pains
Sensory ataxia
Visual failure
Abdominal crises
Incontinence
Trophic changes
*Interval from primary infection.
Neurological examination reveals signs appropriate to the anatomical localisation of lesions. Delusions of grandeur suggest general paresis of the insane, but more commonly there is simply progressive dementia. The pupillary abnormality described by Argyll Robertson may accompany any neurosyphilitic syndrome, but most commonly tabes dorsalis; the pupils are small and irregular, and react to convergence but not directly to light.
Investigations
Routine screening for syphilis is warranted in the great majority of neurological patients. Serological tests (see pp. 98-99) are positive in the serum in most patients, but CSF examination is essential if neurological involvement is suspected. Active disease is suggested by an elevated cell count, usually lymphocytic, and the protein content may be elevated to 0.5-1.0 g/l with an increased gammaglobulin fraction. Serological tests in the CSF are usually positive, but progressive disease can occur with negative CSF serology.
Management
The essential part of the treatment of neurosyphilis of all types is the injection of procaine benzylpenicillin (procaine penicillin) and probenecid for 17 days (see Box 1.73, p. 100). Further courses of penicillin must be given if symptoms are not relieved, if the condition continues to advance or if the CSF continues to show signs of active disease. The cell count returns to normal within 3 months of completion of treatment, but the elevated protein takes longer to subside and some serological tests may never revert to normal. Evidence of clinical progression at any time is an indication for renewed treatment.
PRION DISEASES: TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Transmissible spongiform encephalopathies (TSEs) include a number of conditions affecting both animals and humans which are characterised by the histopathological triad of spongiform change, neuronal cell loss, and gliosis in the grey matter of the brain. Associated with these changes, there is deposition of amyloid made up of an altered form of a normally occurring protein, the prion protein. These diseases can be transmitted by inoculation; the precise nature of the infective agent is not yet clear but almost certainly involves the abnormal prion protein. They may also occur spontaneously or as an inherited disorder. Diseases affecting animals include bovine and feline spongiform encephalopathies (BSE and FSE). In humans, the most common TSE is Creutzfeldt-Jakob disease (CJD). This occurs sporadically, with a world-wide incidence of approximately 1/1 000 000, but can also be transmitted by inoculation (e.g. via depth EEG electrodes, corneal grafts, neurosurgery (especially when cadaveric dura mater grafts were used), and by the use of pooled cadaveric growth hormone), and some 10% of cases arise due to a mutation in the gene coding for the prion protein. A variant form of CJD has recently been described which is probably due to the same agent which causes BSE. Other extremely rare inherited human TSEs include Gerstmann-Sträussler-Scheinker disease, fatal familial insomnia and kuru. Kuru occurred only in members of a cannibalistic New Guinea tribe and was probably transmitted by eating the brains of dead tribal members. Clinical features involved progressive ataxia and dementia.
CREUTZFELDT-JAKOB DISEASE (CJD)
Sporadic CJD usually occurs in middle-aged to elderly patients. Clinical features usually involve a rapidly progressive dementia, with myoclonus and a characteristic EEG pattern (repetitive slow wave complexes), though a number of other features such as visual disturbance or ataxia may also be seen. These are particularly common in CJD transmitted by inoculation. Death occurs after a mean of 4-6 months. There is as yet no known treatment.
Variant CJD
A variant of CJD (vCJD) has been described in a small number of patients, mostly in the UK. The agent which causes it appears to be identical to that causing BSE in cows, and it has been suggested that the disease appeared in humans as a result of the epidemic of this disease in the UK which started in the late 1980s. Patients affected by vCJD are typically younger than those with sporadic CJD and present with neuropsychiatric changes and sensory symptoms in the limbs, followed by ataxia, dementia and death, progressing at a slightly slower rate than patients with sporadic CJD (mean time to death is over a year). Characteristic EEG changes are not present but MRI scans of the head show characteristic high signal changes in the pulvinar in a high proportion of cases. The brain pathology is distinct, with very florid plaques containing the prion proteins. Abnormal prion protein has been identified in tonsil specimens from sufferers of vCJD, leading to the suggestion that the disease could be transmitted by reticulo-endothelial tissue (like TSEs in animals but unlike sporadic CJD in humans). This has caused great concern in the UK, leading to precautionary measures such as leucodepletion of all blood used for transfusion, and the mandatory use of disposable surgical instruments for tonsillectomy and appendicectomy operations. Implications for ophthalmological practice are also being considered.
pages 1192 - 1202
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Home > 2 SYSTEM-BASED DISEASES > 22 Neurological disease > INTRACRANIAL MASS LESIONS AND RAISED INTRACRANIAL PRESSURE
INTRACRANIAL MASS LESIONS AND RAISED INTRACRANIAL PRESSURE
There are many different types of mass lesion in the head (see Box 22.95). In developing countries, tuberculoma is a very common cause, but in developed countries cerebral neoplasms are the most frequent. The clinical features relate to the site of the mass, its nature and its rate of expansion. Symptoms and signs are produced by a number of mechanisms, as listed in Box 22.96.
RAISED INTRACRANIAL PRESSURE
22.95 INTRACRANIAL MASS LESIONS
Traumatic
Subdural haematoma
Vascular
Intracerebral haematoma (see p. 1162)
Infective
Cerebral abscess (pyogenic, Toxoplasma etc.)
Tuberculoma
Cysticercosis
Echinococcosis (as hydatid cysts)
Schistosomiasis
Inflammatory
Sarcoid mass
Neoplastic
Cerebral neoplasm (benign and malignant)
Other
Embryonic dysplastic lesions (e.g. craniopharyngiomas, hamartomas)
Arachnoid cyst
Colloid cyst (in the ventricles)
22.96 CLINICAL FEATURES OF INTRACRANIAL MASS LESIONS
Local effects on adjacent brain tissue (e.g. seizures, focal signs)
Depends on the site of the lesion (see pp. 1146-1148)
Raised intracranial pressure
Headache (see p. 1117)
Impairment of conscious level
Papilloedema
Vomiting, bradycardia, arterial hypertension
False localising signs
Pupillary dilatation (ipsilateral to lesion)
6th cranial nerve lesion (unilateral or bilateral)
Hemiparesis (ipsilateral to lesion)
Bilateral extensor plantar responses
Raised intracranial pressure may be caused by mass lesions (especially tumours), cerebral oedema, obstruction to CSF circulation (causing hydrocephalus) or impaired CSF absorption, as in idiopathic intracranial hypertension (see below) and cerebral venous obstruction.
Clinical features
The major features of raised intracranial pressure are listed in Box 22.96. Impairment of conscious level is related to the level of intracranial pressure. Cerebral mass lesions will obviously tend to increase intracerebral pressure, but the amount by which the pressure is raised depends on the rate of growth of the mass. If it is slow, various compensatory mechanisms may occur, including alteration in the volume of fluid in CSF spaces and venous sinuses, thereby allowing some tumours to achieve considerable size. More rapid growth (as in highly malignant tumours or abscesses) does not allow the compensatory mechanisms to take place, so raised intracranial pressure develops early, especially if the CSF circulation is also obstructed. Papilloedema is not always present, either because raised intracranial pressure has developed too recently, or because of anatomic anomalies of the meningeal sheath of the optic nerve. Vomiting, bradycardia and arterial hypertension develop as late features of raised intracranial pressure and usually parallel the other clinical signs; sudden vomiting may be an early feature of tumours of the cerebellum, especially in children.
Management
The management of raised intracranial pressure is largely dictated by its specific cause, as described later. ICU support may be required (see p. 208).
'CONING' AND FALSE LOCALISING SIGNS
Figure 22.51 Cerebral tumour displacing medial temporal lobe and causing pressure on the mid-brain and 3rd cranial nerve.
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Figure 22.52 Tonsillar cone. Downward displacement of the cerebellar tonsils below the level of the foramen magnum.
The rise in intracranial pressure from a mass lesion is not usually uniform within the cerebral substance and alterations in pressure relationships within the skull may lead to displacement of parts of the brain between its various compartments. Downward displacement of the temporal lobes through the tentorium due to a large hemisphere mass may cause 'temporal coning' (see Fig. 22.51). This may stretch the 3rd and/or 6th cranial nerves, or cause pressure on the contralateral cerebral peduncle (thereby resulting in ipsilateral upper motor neuron signs). Downward movement of the cerebellar tonsils through the foramen magnum may compress the medulla-'tonsillar coning' (see Fig. 22.52). This coning may result in brain-stem haemorrhage and/or acute obstruction of the CSF pathways. As coning progresses, the patient may adopt a decerebrate posture and, unless rapidly treated, death almost invariably ensues. The process may be acutely accelerated if the pressure dynamics are suddenly disturbed by lumbar puncture.
INTRACRANIAL NEOPLASMS
In the developed world cerebral tumours account for 2% of deaths at all ages. The majority are metastatic tumours from malignancies outside the nervous system. Meningiomas account for about one-fifth of intracranial tumours. Benign or malignant neoplasms of central nervous system tissue account for the remainder.
Pathology
Metastases from extracranial primary tumours are usually located in the white matter of the cerebral or cerebellar hemispheres, and common sources are bronchus, breast and gastrointestinal tract. Primary intracerebral tumours are classified by their cell of origin and degree of malignancy, and vary in incidence by age and localisation (see Boxes 22.97 and 22.98). Even when malignant they do not metastasise outside the nervous system.
Clinical features
Headache
Headache is not an invariable manifestation of cerebral tumour. If present, it may have characteristics suggesting raised intracranial pressure, or be caused by traction on the pain-sensitive intracranial structures (see p. 1117). The site of the headache often does not correlate with the site of the tumour, although posterior fossa tumours often cause pain in the occiput or neck.
Local effects
22.97 PRIMARY MALIGNANT INTRACRANIAL TUMOURS
Histological type Common site Age
Glioma (astrocytoma) Cerebral hemisphere
Cerebellum
Brain stem Adulthood
Childhood/adulthood
Childhood/young adulthood
Oligodendroglioma Cerebral hemisphere Adulthood
Medulloblastoma Posterior fossa Childhood
Ependymoma Posterior fossa Childhood/adolescence
Cerebral lymphoma (microglioma) Cerebral hemisphere Adulthood
22.98 PRIMARY BENIGN INTRACRANIAL TUMOURS
Histological type Common site Age
Meningioma Cortical dura
Parasagittal
Sphenoid ridge
Suprasellar
Olfactory groove Adulthood
Neurofibroma Acoustic neuroma Adulthood
Craniopharyngioma Suprasellar Childhood/adolescence
Pituitary adenoma Pituitary fossa Adulthood
Colloid cyst Third ventricle Any age
Pineal tumours Quadrigeminal cistern Childhood (teratomas) Young adulthood (germ cell)
In general the focal deficits produced by a cerebral tumour are of slow onset and progressive. Tumours may present at an early stage in some areas, such as the brain stem where structural disturbance quickly results in a neurological deficit. In other regions, especially the frontal lobe, a tumour may be quite large before symptoms occur. The clinical features of dysfunction in the various lobes of the brain are outlined in Box 22.39, page 1148. Occasionally, localised oedema in the brain tissue surrounding a tumour will cause a rapid progression of symptoms. Rarely, haemorrhage into a tumour presents like an acute stroke.
Seizures
Infiltration by tumour cells of an area of cerebral cortex often excites seizure activity. The resulting seizures may be generalised or partial in nature, and the development of focal seizures in adult life should always suggest the possibility of a tumour.
Investigations
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CT or MRI of the head is the definitive investigation, allowing accurate localisation of the tumour and providing some guidance as to the likely histological type (see Fig. 22.53). MRI is of particular value in the investigation of tumours of the posterior fossa and brain stem (see Fig. 22.54) and in delineating the nature and extent of tumours prior to surgery, largely replacing angiography. Distortion of intracranial structures and the size of the ventricular system can be assessed and may provide accurate evaluation of the extent of the tumour. Plain skull radiographs are rarely of diagnostic value except in pituitary tumours. Chest radiography is an important investigation and may provide evidence of a primary pulmonary tumour or other systemic malignancy.
Figure 22.53 MRI showing meningioma in frontal lobe (arrow A) with associated oedema (arrow B).
Figure 22.54 MRI of an acoustic neuroma (arrows) in the posterior fossa compressing the brain stem. A Axial image. B Coronal image.
Management
Medical
Relief of raised intracranial pressure is often required when surgery is not possible or when life is threatened before investigation has revealed the diagnosis. Dexamethasone, 8 mg 12-hourly either orally or by injection, is used to lower intracranial pressure by resolving the reactive oedema around a tumour. A striking improvement in conscious level is often produced and focal disabilities may regress. In severe and acutely raised intracranial pressure 16-20 mg of dexamethasone may be given intravenously or 200 ml of a 20% solution of mannitol may be infused.
Prolactin- or growth hormone-secreting pituitary tumours (see p. 741) may respond to treatment with the dopamine agonists bromocriptine, cabergoline or quinagolide.
Surgical
Surgery is the mainstay of treatment, although only partial excision may be possible if the tumour is inaccessible or if its removal is likely to cause unacceptable brain damage. Biopsy by a direct or stereotactic technique should be considered even if the tumour cannot be removed, since the histological diagnosis has important implications for management and prognosis.
Meningiomas and acoustic neuromas offer the best prospects for complete removal without unacceptable damage to surrounding structures. Meningiomas can recur, particularly those of the sphenoid ridge when partial excision is often all that is possible. Pituitary adenomas can often be removed by a trans-sphenoidal route, thereby avoiding the necessity for a craniotomy.
Radiotherapy and chemotherapy
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EBM
BRAIN TUMOUR-role of cranial irradiation in the prevention of intracerebral secondaries from small-cell lung cancer
'Prophylactic cranial irradiation significantly reduces the incidence of cerebral secondaries and improves survival in patients with small-cell lung cancer in complete remission.'
Prophylactic Cranial Irradiation Overview Collaborative Group. Cranial irradiation for preventing brain metastases of small cell lung cancer in patients in complete remission (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.cochrane.co.uk
Radiotherapy and chemotherapy have only a marginal effect on survival in cerebral metastases and malignant gliomas in adults (see EBM panel), but their combination has greatly improved the prognosis in medulloblastoma in children. Radiotherapy reduces the risk of recurrence of pituitary adenoma after surgery and may also be helpful as an adjunct to operative treatment in those meningiomas whose anatomical site precludes complete excision or whose histology suggests an increased tendency to recurrence. Ependymomas, some pineal tumours and low-grade gliomas in children and young adults are often radiosensitive.
Prognosis
Gliomas are rarely completely excised, as infiltration spreads beyond the radiologically evident boundaries of the tumour. Recurrence is therefore common, even if the mass of the tumour is apparently completely removed. Partial excision ('debulking') may be useful in alleviating raised intracranial pressure, but survival in highly malignant gliomas is poor even if such a decompressive procedure is attempted. Prognosis is related to histological grade; the better grades (I-II) may survive many years, whilst only 20% of patients with grade IV gliomas (glioblastoma multiforme) survive 1 year.
The prognosis for benign tumours is good, provided complete surgical excision can be achieved. Ependymomas and medulloblastomas can often be excised with minimal residual disability, but may recur with seeding of the tumour via the CSF. Oligodendrogliomas are often slow-growing and relatively benign in the early stages, but may transform to a more malignant form and behave as gliomas.
NEUROFIBROMATOSIS
22.99 TYPES OF NEUROFIBROMATOSIS
Type 1 Peripheral form (> 70% of cases)
Multiple cutaneous neurofibromas
'Soft' papillomas
Café au lait patches
Axillary freckling
Iris fibromas
Plexiform neurofibromas
Spinal neurofibromas
Aqueduct stenosis
Scoliosis
Endocrine tumours
Type 2 Central form
Few or no cutaneous lesions
Bilateral acoustic neuromas
Cerebral and optic nerve gliomas
Meningiomas
Spinal neurofibromas
Figure 22.55 A café au lait spot (arrow A) and subcutaneous nodules (arrows B) on the forearm of a patient with neurofibromatosis type 1.
This is a disorder of autosomal dominant inheritance due to an abnormal gene on chromosome 17 (q11.2, type 1 neurofibromatosis, NF1) or 22 (q12.2, type 2 neurofibromatosis, NF2). Multiple fibromatous tumours develop from the neurilemmal sheaths of peripheral and cranial nerves. Most of the lesions are benign but sarcomatous change may occur. In NF1 (von Recklinghausen's disease) there are characteristic cutaneous manifestations and other extracranial manifestations (see Box 22.99).
Patients with NF1 are easily recognised because of the cutaneous lesions (see Fig. 22.55) which increase in number throughout life. Investigation and treatment are only indicated if there are symptoms of cerebral or spinal involvement, or if malignant change is suspected.
Patients with NF2 present with acoustic neuromas, often bilateral, and/or other central neoplasms, and have fewer, if any, cutaneous lesions. A family history of cerebral or spinal tumours should be noted with care, since relatives of patients with NF2 may require screening for acoustic neuromas.
ACOUSTIC NEUROMA
This is a benign tumour of Schwann cells of the 8th cranial nerve, which may arise in isolation or as part of NF2 (see above). As an isolated finding, an acoustic neuroma occurs after the third decade and is more frequent in females. The tumour commonly arises near the nerve's entry into the medulla or in the internal auditory meatus, usually on the vestibular division. Such schwannomas of the 8th nerve make up 80-90% of tumours at the cerebello-pontine angle.
Clinical features
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These depend somewhat on the site of the tumour along the acoustic or vestibular nerve. (Similar tumours arise rarely from the trigeminal nerve.) Hearing loss is almost invariable, although it may not be the presenting feature. Sensory symptoms in the face and vertigo are also common symptoms at presentation. Distortion of the brain stem and/or cerebellar peduncle may cause ataxia and/or cerebellar signs in the limbs. Distortion of the fourth ventricle and cerebral aqueduct may cause hydrocephalus, which may be the presenting feature (see p. 1208). Facial weakness is unusual at presentation, but facial palsy may follow surgical removal of the tumour.
Investigations
MRI is the investigation of choice (see Fig. 22.54), CT being less useful in this region of the posterior fossa.
Management
This involves surgical removal. If this is complete, the prognosis is excellent. Deafness and facial weakness, if not present before surgery, usually result from the operation.
VON HIPPEL-LINDAU DISEASE
This is a dominantly inherited disease due to a defective gene on chromosome 3p25-26, characterised by the combination of retinal and intracranial (typically cerebellar) haemangiomas and haemangioblastomas. There may be associated extracranial hamartomatous lesions, which may undergo malignant change. About 10% of posterior fossa tumours are cerebellar haemangioblastomas. Von Hippel-Lindau disease needs to be considered in patients with such lesions, so that screening for other lesions and, if necessary, of family members can be instituted.
PARANEOPLASTIC NEUROLOGICAL DISEASE
Neurological disease may occur with systemic malignant tumours in the absence of metastases. Mild degrees of myopathy and neuropathy are quite frequent with the common malignancies. Much rarer are certain disabling, and often fatal, paraneoplastic syndromes which often have an inflammatory basis, with associated autoantibodies which cross-react with neural and tumour antigens (see Box 22.100). In the case of the Lambert-Eaton myasthenic syndrome the autoantibodies have a functional effect on neuromuscular transmission (see p. 1185).
22.100 PARANEOPLASTIC SYNDROMES
Syndrome Clinical features Antibody Associated tumours Investigations
Retinal degeneration Painless progressive visual loss Antiretinal Small-cell carcinoma of lung
Melanoma Chest radiograph, CT chest
Electroretinogram
Opsoclonus-myoclonus Arrhythmic chaotic rapid eye movements Anti-Ri Ovarian, lung
Neuroblastoma (in children) Chest radiograph, CT chest
Pelvic ultrasound or CT
Sensory neuropathy Limb pain, paraesthesia
Distal numbness Anti-Hu Small-cell carcinoma of lung
Hodgkin's disease Chest radiograph, CT chest
Nerve conduction studies
Limbic encephalitis Memory loss, progressive dementia
Seizures Anti-Hu Small-cell carcinoma of lung
Hodgkin's disease Chest radiograph, CT chest
MRI (head)
CSF (pleocytosis, raised protein)
Myelitis Progressive spinal cord lesion (usually cervical cord) Anti-Hu Small-cell carcinoma of lung Chest radiograph, CT chest
MRI (cord, head)
Cerebellar degeneration Progressive ataxia, nystagmus (down-beating), vertigo Anti-Yo Anti-Hu Small-cell carcinoma of lung
Ovarian
Hodgkin's disease Chest radiograph, CT chest
Pelvic ultrasound or CT
CSF (raised protein, oligoclonal bands)
Subacute motor neuronopathy Subacute, patchy progressive, usually lower limb, weakness and wasting Anti-Hu Hodgkin's disease
Small-cell carcinoma of lung Chest radiograph, CT chest
Nerve conduction studies/EMG
Sensorimotor peripheral neuropathy Mild, non-disabling peripheral limb numbness and paraesthesia Not known Small-cell carcinoma of lung
Breast
Other carcinoma Chest radiograph, CT chest
Nerve conduction studies/EMG
Lambert-Eaton myasthenic syndrome Weakness of proximal limb muscles, fatigue with exertion after initial improvement, areflexia Anti-Ca++ channel Small-cell carcinoma of lung Chest radiograph, CT chest
EMG
Dermatomyositis/polymyositis Proximal limb weakness and pain, heliotrope skin rash, Grotten's papules on knuckles Anti-Jo-1 Lung, breast, ovary Chest radiograph, CT chest
Creatine kinase
EMG, muscle biopsy
Guillain-Barré Ascending weakness, distal paraesthesia Not known Hodgkin's disease Nerve conduction studies/EMG
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Pathology
These syndromes are particularly associated with small-cell carcinoma of the lung, ovarian tumours, and lymphomas. In addition to the presence of autoantibodies in the serum and/or CSF, there is usually a lymphocytic infiltrate of the neural tissue affected.
Clinical features
These are summarised in Box 22.100. In most instances the neurological disease progresses quite rapidly over a few months. In 50% of patients with a paraneoplastic syndrome the neurological disease precedes clinical presentation of the primary neoplasm. Paraneoplastic disease should be considered in the diagnosis of any unusual progressive neurological syndrome.
Investigations
See Box 22.100. The presence of characteristic autoantibodies in the context of a suspicious clinical picture may be diagnostic. The causative tumour may be very small and therefore CT of the chest or abdomen is often necessary to find it. The CSF often shows an increased protein and lymphocyte count with oligoclonal bands.
Management
This is directed at the primary tumour. Occasionally, successful therapy of the tumour is associated with improvement of the paraneoplastic syndrome. Some improvement may occur following administration of intravenous immunoglobulin.
HYDROCEPHALUS
Hydrocephalus (dilatation of the ventricular system) may be due to obstruction of the CSF circulation (see Fig. 22.56). Hydrocephalus is said to be 'communicating' if the obstruction is outside the ventricular system (usually in the basal cisterns). Obstruction within the ventricles is most common in the narrow channels of the third ventricle and aqueduct, and may be caused by tumour or a congenital anomaly such as aqueduct stenosis (see Fig. 22.57). Causes of hydrocephalus are given in Box 22.101.
Diversion of the CSF by means of a shunt procedure between the ventricular system and the peritoneal cavity or right atrium may result in prompt relief of symptoms in obstructive or communicating hydrocephalus.
NORMAL PRESSURE HYDROCEPHALUS
Figure 22.56 The circulation of cerebrospinal fluid. (1) CSF is synthesised in the choroid plexus of the ventricles, and flows from the lateral and third ventricles through the aqueduct to the fourth ventricle. (2) At the foramina of Luschka and Magendie it exits the brain, flowing over the hemispheres (3) and down around the spinal cord and roots in the subarachnoid space. (4) It is then absorbed into the dural venous sinuses via the arachnoid villi.
22.101 CAUSES OF HYDROCEPHALUS
Communicating (obstruction outside ventricular system)
Bacterial meningitis (esp. tuberculous)
Sarcoidosis
Subarachnoid haemorrhage
Head injury
Idiopathic ('normal pressure')
Non-communicating (obstruction within ventricular system)
Tumours
Colloid cyst
Arnold-Chiari malformation
Aqueduct stenosis
Cerebellar abscess
Cerebellar or brain-stem haematoma
In this condition the dilatation of the ventricular system is caused by intermittent rises in CSF pressure, which occur particularly at night. It occurs predominantly in old age and is suggested by the combination of gait apraxia (see p. 1138) and dementia, often with urinary incontinence as an early feature. This cause of dilatation of the ventricles can be very difficult to distinguish from that occurring due to cerebral atrophy, where the cortical sulci are also dilated. The result of shunting procedures for normal pressure hydrocephalus is unpredictable.
IDIOPATHIC INTRACRANIAL HYPERTENSION
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Figure 22.57 MRI of hydrocephalus due to aqueduct stenosis. A Axial image: note the dilated lateral ventricles. B Sagittal image: note the dilated ventricles (top arrow) and narrowed aqueduct (bottom arrow).
This condition, previously known as benign intracranial hypertension, usually occurs in obese young women. Raised intracranial pressure develops without a space-occupying lesion, ventricular dilatation or impairment of consciousness. The aetiology is uncertain but there may be a diffuse defect of CSF reabsorption by the arachnoid villi. The condition can be precipitated by drugs, including tetracycline, the oral contraceptive pill and withdrawal of corticosteroid therapy.
Clinical features
Characteristically, there is a headache, sometimes with transient diplopia and visual obscurations, but few other symptoms. There are usually no signs other than papilloedema, which may be discovered incidentally at a routine visit to an optician, but a 6th nerve palsy may be present.
Investigations
The CT is normal, with normal-sized or small ventricles. Once this has been demonstrated, a lumbar puncture is safe and will allow confirmation of the raised CSF pressure and form part of treatment. MR angiography or cerebral venography will exclude cerebral venous occlusion. True papilloedema may need to be distinguished from other causes of disc swelling by fluorescein angiography.
Management
Any precipitating medication should be withdrawn and a weight-reducing diet instigated, if indicated. The carbonic anhydrase inhibitor, acetazolamide, may help to lower intracranial pressure. Repeated lumbar puncture can be considered, but is often unacceptable to the patient. Patients failing to respond, in whom chronic papilloedema threatens vision, may require optic nerve sheath fenestration or a lumbo-peritoneal shunt.
FURTHER INFORMATION
Aminoff MJ, ed. Neurology and general medicine: neurological aspects of medical disorders. 3rd edn. New York: Churchill Livingstone; 2001.
Bone I, Fuller F, eds. Neurology in practice: stroke. J Neurol Neurosurg Psychiatry 2001; 70(suppl I):i1-22. Medline Similar articles
Bone I, Fuller F, eds. Neurology in practice: sleep and coma. J Neurol Neurosurg Psychiatry 2001; 71(suppl I):i1-27. Medline Similar articles
Bone I, Fuller F, eds. Neurology in practice: epilepsy. J Neurol Neurosurg Psychiatry 2001; 70(suppl II):ii1-27. Medline Similar articles
Bone I, Fuller F, eds. Neurology in practice: multiple sclerosis. J Neurol Neurosurg Psychiatry 2001; 71(suppl II):ii1-27. Medline Similar articles
Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in clinical practice: principles of diagnosis and management. 3rd edn (2 vols). Boston: Butterworth-Heinemann; 2000.
Prusiner S. Neurodegenerative diseases and prions. N Engl J Med 2001; 344:1516-1525. Medline Similar articles Full article
Shakir RA, Newman PK, Poser CM, eds. Tropical neurology. London: WB Saunders; 1996.
http://medweb.bham.ac.uk/http/depts/clin_neuro/teaching/disclaimer.html Neurology teaching pages (from University of Birmingham, UK).
www.bcm.tmc.edu/neurol/index.html Baylor College of Medicine (USA), Department of neurology.
www.medinfo.ufl.edu/year1/bcs/clist/neuro.html Neurological examination (from the University of Florida).
www.ninds.nih.gov/ National Institute of Neurological Disorders and Stroke.
www.toddtroost.com/mylinks2001.html Neuroscience links from the American Neurological Association.
www.wfneurology.org World Federation of Neurology.
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Home > 2 SYSTEM-BASED DISEASES > Appendix
Appendix
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INCUBATION PERIODS, IMMUNISATION SCHEDULES AND NOTIFIABLE DISEASES
23.1 INCUBATION PERIODS OF IMPORTANT INFECTIONS
Infection Maximum range Normal range
Short incubation periods (< 7 days)
Anthrax 2-5 days
Bacillary dysentery 1-7 days
Cholera Hours-5 days 2-3 hours
Diphtheria 2-5 days
Gonorrhoea 2-5 days
Meningococcaemia 2-10 days 3-4 days
Scarlet fever 1-3 days
Intermediate incubation periods (7-21 days)
Amoebiasis 14 days-months 21 days
Chickenpox 14-21 days
Lassa fever 7-14 days
Malaria 8 days-months
Measles 7-14 days 10 days
Mumps 12-21 days 18 days
Poliomyelitis 3-21 days 7-10 days
Psittacosis 4-14 days 10 days
Rubella 14-21 days 18 days
Trypanosoma rhodesiense infection 14-21 days
Typhoid fever 7-21 days
Typhus fever 7-14 days 12 days
Whooping cough 7-10 days 7 days
Long incubation periods (> 21 days)
Brucellosis Days-months
Filariasis 3 months-years
Hepatitis A 2-6 weeks 4 weeks
Hepatitis B 6 weeks-6 months 12 weeks
Leishmaniasis
Cutaneous 1 week-months
Visceral 2 weeks-2 years 2-4 months
Leprosy Years 2-5 years
Rabies Variable 2-8 weeks
Schistosomiasis Weeks-years
Trypanosoma gambiense infection Weeks-years
Tuberculosis Months-years
23.2 NOTIFIABLE INFECTIOUS DISEASES IN BRITAIN
Under the Public Health (Control of Diseases) Act 1984
Cholera
Food poisoning
Plague
Relapsing fever
Smallpox
Typhus
Under the Public Health (Infectious Diseases) Regulations 1988
Acute encephalitis
Acute poliomyelitis
Anthrax
Diphtheria
Dysentery (amoebic or bacillary)
Leprosy
Leptospirosis
Malaria
Measles
Meningitis
Meningococcal septicaemia (without meningitis)
Mumps
Ophthalmia neonatorum
Paratyphoid fever
Rabies
Rubella
Scarlet fever
Tetanus
Tuberculosis
Typhoid fever
Viral haemorrhagic fever
23.3 PERIODS OF INFECTIVITY IN CHILDHOOD INFECTIOUS DISEASES
Disease Infectious period
Chickenpox 5 days before rash to 6 days after last crop
Diphtheria 2-3 weeks (shorter with antibiotic therapy)
Measles From onset of prodromal symptoms to 4 days after onset of rash
Mumps 3 days before salivary swelling to 7 days after
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS 1106 
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