The next step is to attempt to arouse the patient with verbal stimuli and, if it fails, painful stimuli (Figure 14.1). One of the most useful techniques is to pinch the skin on the medial aspect of the elbows and knees between your fingernails. A normal response is abduction of the limbs away from the painful stimulus; an abnormal response is adduction of the limbs towards the painful stimulus or extension of the limbs. Before testing the response to painful stimuli in front of the family, explain to them that it is the way to test when someone is unconscious. The family should also be warned that this technique may leave bruises.

FIGURE 14.1 Methods of A applying painful stimuli to the limbs, B testing the nasal and corneal reflexes and C testing eye movements using the doll’s eye procedure

The brainstem reflexes are then examined. The region tested is shown in brackets.

• The pupil responses – the afferent pathway is the 2nd nerve; the efferent pathway is the parasympathetic pathway on the surface of the 3rd nerve (midbrain and 3rd nerve)

• Doll’s eye reflexes – spontaneous and head movement-evoked eye movements (vertical eye movements = midbrain, horizontal eye movements = pons) (Figure 14.1)

• The corneal and nasal tickle reflexes – the afferent pathway is the 5th cranial nerve; the efferent pathway is the 7th nerve (pons) (Figure 14.1)

• The gag reflex – the afferent pathway is the 9th cranial nerve; the efferent pathway is the 10th cranial nerve (medulla)

Note: This reflex is not as useful as the others because many healthy people may not have a gag reflex.

Normal pupil responses, doll’s eye testing and corneal or nasal tickle reflexes indicate that the brainstem is intact and that the cause of the coma is either in the cerebral hemispheres or due to a diffuse problem. A 3rd or 6th nerve palsy does not necessarily indicate brainstem involvement. A 3rd can occur with a hemisphere lesion with downward herniation, and a 6th can occure with raised intracranial pressure as a false localising sign.

Response to pain

If the patient abducts or withdraws the limb away from the painful stimulus applied to the medial aspect of the elbow or knee, this implies that the motor pathway is intact. On the other hand, if the patient does not withdraw the limb, but the arm or leg moves towards the painful stimulus or it straightens, this indicates that the motor pathway is damaged.

Decorticate and decerebrate rigidity are two terms used to describe certain postures that may occur in the comatose patient and were formerly thought to provide localising value, although this is now in question. Decorticate rigidity refers to flexion of the elbows and wrists and supination of the arms and was said to indicate bilateral damage above (rostral) to the midbrain; decerebrate rigidity consists of extension of the elbows and wrists with pronation of the forearms indicating damage to the motor pathways in the midbrain or lower part (caudal) of the diencephalon (thalamus and hypothalamus). Similarly, the pattern of respiration is not of great localising value. For example, the cyclic breathing with periods of apnoea referred to as Cheyne–Stokes respiration can occur with bilateral hemisphere damage or metabolic suppression of the conscious state.

The pupil responses

The response of the pupils to a bright light is one of the most important aspects of the examination (see Figure 14.2). It may be necessary to use a magnifying glass to see slight reactions. The size of the pupil and the reaction to light are used to exclude or localise pathology in or affecting the midbrain and pons of the brainstem.

FIGURE 14.2 Abnormal pupil responses in the comatose patient Reproduced from Diagnosis of Stupor and Coma. 2nd edn, by F Plum, JB Posner, 1972, FA Davis.

• Bilateral normal size (2.5–5mm) and reactive pupils:

• Essentially excludes midbrain damage

• Unilateral dilated (> 6 mm) and non-reactive pupil + contralateral weakness:

• Compression of the ipsilateral 3rd cranial nerve with herniation due a mass lesion (tumour, haemorrhage, oedema related to a cerebral infarct) in the cerebral hemisphere

• Bilateral dilated and non-reactive pupils:

• Bilateral midbrain pathology

• Bilateral small (1–2.5 mm) and reactive pupils:

• Metabolic encephalopathy or bilateral deep hemisphere lesions

• Bilateral pinpoint pupils that react to light:

• Pontine haemorrhage, narcotic or barbiturate overdose

The eye movements

In normal patients the eyes may be divergent in sleep.

• Spontaneous movements of the eyes, referred to as ‘roving eyes’, exclude damage to the midbrain and pons.

• If the eyes are deviated to one side, this is either due to an ipsilateral hemisphere lesion, where the eyes look to the side of the lesion and away from the side of the paralysis, or alternatively may indicate pontine pathology, where the eyes look away from the side of the lesion and towards the side of the paralysis or hemiparesis. One exception to this rule is that with irritating hemisphere lesions the eyes may be deviated away from the side of the lesion and towards the side of the paralysis.

• Ocular bobbing indicates bilateral pontine damage, most often seen with basilar artery thrombosis. It consists of the absence of horizontal eye movements and a characteristic brisk downward movement of both eyes and then a slow upward movement to return to the normal position.

Eyes that spontaneously deviate away from the side of the paralysis indicate a hemisphere lesion on the side opposite to the paralysis; eyes that deviate to the side of the paralysis indicate a brainstem lesion on the side opposite the paralysis.

In the absence of these spontaneous ocular signs, the brainstem can be tested using the technique referred to as the oculocephalic reflex or doll’s eye test (see Figure 14.1C).

• The head is moved rapidly horizontally and then vertically while the movement of the eyes in the opposite direction to the movement of the head is observed.

• When the head is turned to the right, the eyes deviate fully left and vice versa.

• If the eye movement is full, i.e. the eyes move in the orbits to their full extent so that no sclera can be seen, this indicates that the brainstem is intact and therefore not the site of the pathology causing the impaired consciousness.

• If the eyes fail to move, this suggests damage to the ipsilateral brain stem nuclei.

• In patients with severe depression of the conscious state due to drug overdose, the oculocephalic reflexes may be abnormal and not indicate any structural damage to the brainstem. In this latter setting the pupils would usually be of normal size and react to light, something that would not occur in destructive brainstem lesions.

More intense stimulation of the oculocephalic reflex can be produced with caloric stimulation, where either warm or cold water is used to irrigate the external ear canal (ensure that the external ear canal is not occluded by wax before performing this test). Tonic deviation of the eyes with nystagmus to the opposite side with cold water and to the same side with warm water indicates that the brainstem is intact. If the eyes fail to deviate this indicates brainstem damage.

The corneal and nasal tickle reflexes

The cornea of the eye or the nostril is stimulated using cotton wool (not tissue paper as this may damage the cornea), and reflex closure of the eyes indicates that the pons is intact. Absent reflexes may occur with hemisphere lesions, drug overdose or structural brainstem lesions and, thus, absent corneal reflexes are not particularly useful for localising the problem.

ASSESSMENT OF THE CONFUSED OR DEMENTED PATIENT

Confusion, delirium and dementia

Students often have difficulty understanding the difference between delirium and dementia because of the similar symptoms. Patients with delirium develop it quickly, become agitated, and can go in and out of consciousness over time. Delirium is usually reversible and memory problems are usually short-term. Dementia develops more gradually, and the effects on memory are more permanent.

CONFUSION AND DELIRIUM

Delirium is an acute and relatively sudden (developing over hours to days) decline in attention–focus, perception and cognition. The patient appears out of touch with their surroundings and is spontaneously producing evidence of this confusion, such as a lack of clear and orderly thought and behaviour, disorientation with muttering, restlessness, rambling and shouting (often offensively and continuously) with evidence of delusion and hallucinations. It is not synonymous with drowsiness and may occur without it. Other features of delirium can include: depression, memory problems, difficulty writing or finding words and disturbances of the sleep–wake cycle.

The International Classification of Diseases, 10th edition [2], defines delirium as:

• impairment of consciousness and attention;

• global disturbance of cognition (including illusions, hallucinations, delusions and disorientation);

• psychomotor disturbances;

• disturbance of the sleep–wake cycle;

• emotional disturbances.

There are many causes of delirium and often it is multifactorial in origin. Even after extensive investigation it is not always possible to define the particular aetiology in all patients and in such patients the delirium usually resolves spontaneously. Delirium in the absence of any clearly definable alternative explanation is not uncommon in hospital in the postoperative period following prolonged anaesthesia. Delirium occurs more commonly in patients with mild cognitive impairment and it can be precipitated by a chest or urinary tract infection, electrolyte disturbances, cardiac, liver or renal failure, drug toxicity and drug withdrawal.

It is important to review all medications, particularly those that have recently been commenced or ceased. Clinical signs of chronic liver disease and the characteristic odour on the breath referred to as ‘fetor hepaticus’ (the breath of the dead where the breath has a sweet or fecal smell related to mercaptans, ammonia and ketones) identifies patients with portal hypertension and hepatic encephalopathy. Patients with a metabolic encephalopathy due to any cause may also have an abnormality referred to as asterixis: a short, flapping tremor elicited by having the patient hold their arms out in front of them with their wrists extended. Asterixis is also seen in patients with hypercapnia (elevated carbon dioxide) and anticonvulsant overdose. A tremor together with myoclonic jerks may be seen in patients with renal failure or patients exposed to antipsychotic drugs. Delirium may also be a manifestation of hypoxia in the setting of cardiac or respiratory failure or a chest infection.

Patients with delirium should have a full workup for sepsis, including looking for fever and tachycardia, examining the chest for evidence of infection, palpating the abdomen to look for tenderness that might suggest abdominal pathology and checking for neck rigidity by flexing the neck. Check the urine with a dip stick to look for evidence of infection (protein, blood and nitrites) and request a full blood examination, ESR, CRP and urine, blood and, if appropriate, sputum cultures. In the absence of obvious infection, assessments of hepatic and renal function, blood gases and electrolytes (in particular sodium, calcium and magnesium) should be undertaken. Very rarely, delirium may be the presenting feature of meningitis or encephalitis and a lumbar puncture may be necessary.

One clue is that patients with confusion and delirium are usually restless and agitated, whereas patients with symptoms related to parietal lobe pathology are not as a rule agitated.

This is particularly so for problems in the dominant parieto-temporal lobe with fluent dysphasia, word salad, literal and verbal paraphasic errors and

It is not uncommon for patients with hemisphere lesions affecting the parietal lobes to be diagnosed with confusion or delirium.

neologisms (see Chapter 5, ‘The cerebral hemispheres and cerebellum’) or non-dominant parietal lobe lesions with patients ‘lost in space’. A quick screening examination (if the patient can cooperate) with double simultaneous stimuli in the visual fields and asking the patient to hold their arms out could detect the visual inattention and parietal drift that would alert one to focal rather than diffuse brain pathology.

MANAGEMENT of DELIRIUM

The main goal in managing delirium is keeping each patient comfortable and safe. Place the patient in a quiet, well-lit room with familiar people and objects, a visible clock and wall calendar.

Alcohol withdrawal or delirium tremens, ‘the DT’s’, is a common cause of delirium. Benzodiazepines are the treatment of choice. A meta-analysis of nine prospective controlled trials [3] concluded that sedative-hypnotic agents (diazepam, chlordiazepoxide, pentobarbital paraldehyde and barbital) are more effective than neuroleptic agents (chlorpromazine, promazine and thioridazine) in reducing duration of delirium and mortality. Adequate doses should be used to maintain light somnolence for the duration of delirium. Coupled with comprehensive supportive medical care, this approach is highly effective in preventing morbidity and mortality. In general it is best to use one drug at a time, using the minimal effective dose, increasing the dose as required and reviewing the treatment on a regular basis [4]. The atypical antipsychotics such as risperidone and olanzapine have the advantage of producing less sedation and are less likely to be associated with extrapyramidal side effects.

For patients with delirium unrelated to alcohol withdrawal, there are no randomised trials but most clinicians would follow the same principles of management used in treating patients with delirium tremens [5]. Imaging in the form of a CT or MRI scan is often performed but rarely rewarding.

DEMENTIA

Dementia is derived from the Latin ‘de-’, meaning apart or away, + ‘mens’ (genitive mentis), meaning mind. It consists of a progressive global deterioration of intellectual and cognitive function with defects in orientation, memory, intellect, judgement and affect. Dementia is often associated with depression and apathy. As cognitive function declines the patient loses the ability to be independent with regard to all activities of daily living.

There are many causes of dementia; the more common include Alzheimer’s disease (AD), vascular dementia, alcoholism and Parkinson’s disease.

Potentially treatable causes of dementia include:

• hypothyroidism

• vitamin B₁ or vitamin B₁₂ deficiency

• normal pressure hydrocephalus

• subdural haematoma

• drug intoxication

• cerebral vasculitis

• heavy metal intoxication

• brain tumours

• chronic infections or inflammation such as syphilis, meningitis related to tuberculosis, cryptococcus, sarcoidosis and the extremely rare entity of Whipple’s disease.

It is anticipated that future discoveries will lead to even more cases of treatable dementia.

Do not to miss the treatable causes of ‘dementia’.

Alzheimer’s disease: Alzheimer’s disease is the commonest cause of dementia and, at the time of writing this textbook, the definitive diagnosis still requires histopathological demonstration of sufficient numbers of amyloid plaques and neurofibrillary tangles and is therefore not usually possible in life. The risk of Alzheimer’s increases with advancing age and 20–40% of patients over the age of 85 will have Alzheimer’s disease. A positive family history is not uncommon. Patients with Down syndrome (trisomy 21) have an increased risk of Alzheimer’s disease after the age of 40.

Most patients with Alzheimer’s disease will present with the insidious onset over many years of memory impairment, particularly short-term memory. As cognitive function declines the patient develops increasing difficulties with daily activities and it is this difficulty that differentiates mild cognitive impairment from true dementia. A reversal of the sleep cycle with patients sleeping during the day and wandering at night is not uncommon. Some patients with Alzheimer’s disease are unaware of their cognitive impairment and it is concerned relatives that urge them to seek medical attention. Patients may cope well in their home environment, but often the dementia is unmasked when they are admitted to hospital or when they travel and are placed in an unfamiliar environment. As the disease relentlessly progresses, patients become lost when they go for walks or when they are driving, and they have difficulty with finances, housekeeping, shopping and following instructions. Leaving the stove on is a common complaint. Walking becomes difficult and patients may develop a characteristic disorder of gait referred to as the apraxic gait (see Chapter 13, ‘Abnormal movements and difficulty walking due to central nervous system problems’). Language function deteriorates with difficulty naming objects, comprehension and then subsequently the development of aphasia. In advanced Alzheimer’s patients are no longer able to care for themselves in terms of dressing, bathing and feeding and eventually lose control of bladder and bowels.

Depression can present with many of the clinical features of dementia that resolve with treatment of the depression and this is referred to as ‘pseudodementia’. It is the intellectual impairment in patients with a primary psychiatric disorder, in which the features of intellectual abnormality resemble, at least in part, those of a neuropathologically induced cognitive deficit. These patients often complain of memory disturbance and yet are often able to recant the history of their ‘cognitive decline’ without much difficulty. The correct diagnosis may only reveal itself when the patient improves with treatment for depression. Reynolds et al [6] in a small study found that significantly greater pretreatment early morning awakening, higher ratings of psychological anxiety and more severe impairment of libido were features of pseudodementia whereas patients with dementia showed significantly more disorientation to time, greater difficulty finding their way about familiar streets or indoors and more impairment with dressing.

In very rare instances dementia may begin with focal neurological deficits [7–10] and a number of syndromes have been identified, such as posterior cortical atrophy (PCA), corticobasal syndrome (CBS), behavioural variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia (PNFA) (or a mixed aphasia) and semantic dementia (SD). In some instances these patients will have the pathological features of Alzheimer’s disease. These focal syndromes may remain pure for many years before the subsequent appearance of other signs of dementia. The underlying neuropathology does not uniquely associate the clinical syndromes with distinctive patterns of pathological markers. A detailed discussion of these entities is beyond the scope of this textbook [7, 9, 10].

Rapidly progressive dementia (RPD): Rapidly progressive dementias can develop subacutely over months, weeks or even days and be quickly fatal. Prion disease (Creutzfeldt–Jakob disease) is the commonest cause, but some cases of frontotemporal dementia (FTD), corticobasal degeneration (CBD), Alzheimer’s disease, dementia with Lewy bodies (DLB) and progressive supranuclear palsy may sometimes present in a fulminant form with death occurring in less than 3 years [11].

Antibody-mediated limbic encephalitis (LE) associated with cancer (paraneoplastic) or occurring without cancer (non-paraneoplastic) and Hashimoto’s encephalopathy (HE) with associated antineuronal antibodies are potentially treatable causes of RPD. Multiple sclerosis and neurosarcoidosis may also cause rapidly progressive dementia.

Limbic encephalitis presents with rapid memory loss, depression, anxiety and changes in personality followed by impaired cognitive function and seizures. Anti-neuronal antibodies may be found in the serum or cerebrospinal fluid and hyponatraemia due to the syndrome of inappropriate anti-diuretic hormone secretion may also be present.

Creutzfeldt–Jakob disease (CJD) presents with cerebellar ataxia and behavioural disturbances in addition to the rapid dementia. There is a variant form of vCJD, ‘mad-cow disease’, where the initial manifestations are major psychiatric symptoms with the ataxia and dementia associated with chorea and myoclonus occurring later in the course.

Forgetfulness or early dementia: Forgetfulness or absent-mindedness is a feature of the ageing process. Most patients over the age of 70 complain of problems with memory and many patients seek medical attention concerned about the possibility of dementia. It can be very difficult in the early stages to differentiate between these two processes [12]. Episodic memory loss precedes widespread cognitive decline in early AD [13].

DIAGNOSIS and MANAGEMENT of ALZHEIMER’S DISEASE

Magnetic resonance imaging including volumetric studies can detect specific changes in patients with minimal cognitive disturbance that may predict progression to dementia [14].

Apo E was the first gene demonstrated to increase the risk of Alzheimer’s disease and a point mutation in APP results in the early onset of Alzheimer’s disease that is inherited in an autosomal dominant pattern. Presenelin-1 on chromosome 14 and presenelin-2 on chromosome 1 have been associated with extremely rare instances of familial Alzheimer’s disease of early onset.

There are a number of cholinesterase inhibitors that provide symptomatic benefit and may decrease the rate of cognitive decline in the first few years. The management of patients with Alzheimer’s disease is predominantly providing support for the family and the patient, treatment of depression and treatment of seizures if they occur. In the early stages patients can be instructed to write lists or put up little reminders where they will see them of what they need to do that day. It is also helpful if patients with Alzheimer’s develop a daily routine including physical exercise. Caring for patients with Alzheimer’s disease is very demanding day in and day out, and organising a period of family relief where the patient is admitted to an interim care facility while the supportive family member has a break will often enable the patient to remain at home for a longer period of time.

DISORDERS OF MUSCLE AND THE NEUROMUSCULAR JUNCTION

Diseases of muscle and conditions affecting the neuromuscular junction are very rare. For example, the prevalence of inflammatory muscle disease is estimated to be 1 in 100,000 and of myasthenia gravis is 8 in 100,000. A complete discussion of all disorders of muscle is well beyond the scope of this text and interested readers will find many excellent reviews, textbooks and websites [15–18].

Although symptoms such as myalgia (muscle pain), muscle cramps, muscle stiffness, fatigue and exercise intolerance occur in patients with muscle disease, many of these are somewhat non-specific. Patients should be suspected of suffering from muscle disease when they complain of weakness with or without wasting of muscles in the absence of other neurological symptoms. The weakness will develop very slowly over years in most of the disorders, of muscle other than the inflammatory myopathies although, even in the inflammatory myopathies where the weakness usually evolves over weeks to months, occasionally the onset may also be more gradual. As many muscle diseases are hereditary, there will often be a positive family history.

• Muscle pain or myalgia, apart from (therapeutic) drug-induced muscle pain, is rare in muscle diseases and more often relates to rheumatological, psychiatric or orthopaedic disorders, although it may occur in patients with congenital or endocrine myopathies and myositis. It is important to question about the use of prescription and non-prescription medications when a patient presents with muscle pain.

For a recent review on drug-induced myopathies, refer to Klopstock [19].

• Fatigue is also a very non-specific symptom. Patients with depression, for example, often complain of fatigue; however, fatigue in the form of exercise intolerance may point to involvement of the neuromuscular junction with conditions such as myasthenia gravis and the Lambert–Eaton syndrome. Fatigue is also a prominent symptom in patients with motor neuron disease.

• Muscle cramps are seen with hyponatraemia, renal failure, hypothyroidism and many other conditions that affect peripheral nerves.

• Myotonia is the inability to relax a muscle after forced voluntary contraction, for example gripping an object with the hands. It is seen in some of the hereditary disorders of muscle such as myotonic dystrophy and Thompson’s disease as well as acquired disorders such as neuromyotonia (Isaac’s syndrome).

There are many approaches to patients with suspected muscle disease; one is shown in Figure 14.3.

FIGURE 14.3 An approach to patients with suspected muscle disease
Note: The uncommon diseases are in italics.
^∗A ‘negative’ family history does not exclude inherited disorders of muscle. ‘Other’ pattern refers to patterns of weakness other than proximal or distal, for example fascioscapulohumeral.
ICU = intensive care unit; LGMD = limb-girdle muscular dystrophy

1. The initial step is to establish if there is a family history, as many diseases of muscle, such as the muscular dystrophies and the congenital, metabolic and mitochondrial myopathies, are inherited disorders of muscle and there will be another member of the family affected. It is important to remember that a negative family history does not exclude hereditary disorders of muscle. Some patients are so mildly affected that they are not aware of the problem or have not sought medical attention. This is not uncommon in patients with muscular dystrophy.

2. The age of onset can provide another clue, e.g. congenital myopathies may be present at birth, the muscular dystrophies often develop in the first few years of life and inclusion body myositis is predominantly seen in elderly patients.

3. Consider the rapidity of onset of the weakness. Many disorders of muscle, particularly the inherited disorders of muscle, develop gradually over many, many years; most of the acquired disorders of muscle, for example the inflammatory myopathies, on the other hand progress rapidly over months. Patients with congenital myopathies may not progress at all. Fluctuating weakness suggests disorders of the neuromuscular junction, such as myasthenia gravis and the Lambert–Eaton syndrome. Recurrent attacks of weakness are a feature of the periodic paralyses and certain glycolytic pathway disorders.

4. Define the pattern of weakness. Many conditions of muscle have been labelled according to the pattern of weakness, for example limb-girdle muscular dystrophy or fascioscapulohumeral dystrophy. This may be less important in the future. As the underlying genetic bases for the muscle diseases are defined, it is increasingly apparent that there is great variability in the phenotypic expression (the pattern of weakness), reflecting the severity of the underlying the genetic defect. For example, with mutations in the dysferlin gene, patients can present with the pattern of a limb-girdle muscular dystrophy, a distal anterior compartment myopathy or the classic Miyoshi myopathy with multifocal weakness and wasting [20]. The term ‘dysferlin deficient muscular dystrophy’ has replaced the term ‘Miyoshi myopathy’. The classification of the limb-girdle dystrophies continues to be revised on the basis of the elucidation of the underlying protein and genetic abnormalities [21]. In everyday clinical practice, other than a proximal muscle weakness, the ‘proximal myopathy’ that is probably the most common pattern and distal weakness in the forearms, most of the other disorders of muscle are extremely rare.

5. Look for associated phenomena that may help differentiate one condition from another.

• Muscle hypertrophy

• Duchenne and Becker muscular dystrophy

• Hypothyroidism

• Respiratory failure:

• Myotonic dystrophy

• Centronuclear myopathy

• Nemaline myopathy

• Acid maltase deficiency

• Cardiac disease:

• Myotonic dystrophy

• Duchenne or Becker muscular dystrophies

• Limb-girdle muscular dystrophies 1B, 2I, 2C–F, 2G

• Emery–Dreifuss muscular dystrophy

• Hepatomegaly: metabolic or alcoholic myopathies

• Central nervous system involvement may occur in patients with mitochondrial myopathies [15]

6. Blood tests

• Measure the creatinine kinase (CK). CK is elevated in most but not all disorders of muscle and in itself is not a particularly useful test to differentiate one disorder of muscle from another; however, a markedly elevated CK is seen with Duchenne muscular dystrophy and the dysferlinopathies.

• Thyroid function tests and electrolytes should be routine and parathyroid hormone and human immuno-deficiency virus (HIV) in selected cases.

• Inflammatory myopathies can be associated with connective tissue diseases such as systemic lupus erythematosus and rheumatoid arthritis; thus an antinuclear factor (ANF), double-stranded DNA and rheumatoid factor tests should be performed in these patients.

7. The urine should be examined for myoglobinuria in patients with exercise-induced muscle pain.

8. A forearm ischaemic lactate test is performed in patients suspected of having a metabolic myopathy; a less than threefold increase in the lactate is abnormal.

9. Perform nerve conduction studies and in particular electromyography. Nerve conduction studies are normal in patients with muscle disease (exceptions include mitochondrial disorders, myotonic dystrophy and inclusion body myositis). Electromyography (EMG) can confirm the presence of a myopathy with the demonstration of brief small amplitude polyphasic potentials (BSAPPs) and a full recruitment pattern with minimal effort; exclude other conditions such as motor neuron disease, peripheral neuropathy and disorders of the neuromuscular junction. Occasionally the nerve conduction studies and EMG can be completely normal in patients with muscle disease. The presence of fibrillation potentials and positive sharp waves with the myopathic changes described above indicate a likely inflammatory myositis such as polymyositis, dermatomyositis or inclusion body myositis. The sound of a motorbike or dive bomber on EMG is seen with myotonia in myotonic and congenital muscular dystrophies.

10. Biopsy an affected muscle. This can be performed using an open biopsy procedure or a needle biopsy; the latter is less invasive and multiple samples can be taken but the size of the individual samples is small. It is important to remember that pathological changes may be focal and thus a normal biopsy does not exclude muscle disease. It is more rewarding to biopsy an affected muscle, but not one that is so severely affected that the likely pathology will be non-diagnostic end-stage muscle. It is also important not to biopsy a muscle at the site of EMG as the EMG needle will cause abnormal pathology. Increasingly sophisticated pathological methods, such as immunohistochemical staining with a panel of antibodies, quantitative analysis of proteins by western blotting and DNA analysis, are now a routine part of the pathological examination of muscle and help to determine the cause of muscle weakness in most patients.

Note: The unravelling of the genome is in some instances already replacing muscle biopsy with non-invasive molecular genetics studies in the hereditary muscle diseases [15, 22]. DNA analysis is becoming the gold standard for the diagnosis.

In everyday clinical practice there are two common clinical presentations of patients with muscle disease: proximal weakness (referred to as the proximal myopathy) and distal weakness.

Proximal limb weakness, ‘the proximal myopathy’

Patients with proximal muscle weakness complain of difficulty sitting in and getting out of chairs, getting up off the floor, climbing up and down stairs, lifting objects above their head or brushing their hair. The term ‘proximal myopathy’ is very non-specific and both hereditary and acquired conditions will result in weakness of the proximal muscles (shoulder abduction and hip flexion). The list is very extensive and includes limb-girdle muscular dystrophy, endocrine and metabolic disturbances, drugs and infections, osteomalacia and hyperparathyroidism, polymyositis and dermatomyositis, corticosteroids, HIV, Cushing’s disease and hyperthyroidism. The commonest causes would be iatrogenic corticosteroid use, critical illness or ICU myopathy, the inflammatory myopathies and thyroid disease, although with early detection of thyroid disease weakness is increasingly uncommon.

Muscle diseases causing distal weakness in the arms

Patients with distal weakness will complain of difficulty opening jars, turning the key in the lock or doing up buttons. Distal weakness in the legs related to muscle disease is extremely rare and is more common in patients with peripheral neuropathies. If present, distal weakness in the legs causes patients to complain of difficulty walking on uneven ground often associated with tripping due to catching their toe due to a foot drop.

Although there are many causes of distal weakness in the arms [16], myotonic dystrophy and inclusion body myositis are the two commonest conditions that result in distal weakness in the forearms. Some of the limb-girdle muscular dystrophies may involve distal as well as proximal weakness [21].

TREATMENT of MUSCULAR DYSTROPHIES

At present there is no established therapy that can cure muscular dystrophy. Corticosteroids have a defined role in patients with Duchenne muscular dystrophy, but not in other muscular dystrophies [23].

The inflammatory myopathies

POLYMYOSITIS AND DERMATOMYOSITIS

Polymyositis and dermatomyositis should be suspected in patients who develop weakness over a period of months. The weakness is symmetrical and affects proximal muscles in the limbs with weakness of shoulder abduction and hip flexion; associated neck flexion weakness is a clue to the diagnosis. Rarely, the bulbar (muscles innervated by the 9th, 10th and 12th cranial nerves) and respiratory muscles may be affected. Patients with dermatomyositis have characteristic skin changes such as the heliotrope rash resulting in violaceous discoloration of the eyelids, scaly erythema over the joints on the dorsal aspect of the hands, macular erythema on the posterior neck and shoulders or on the anterior neck and chest or a violaceous erythema associated with increased pigment and telangiectasia on the anterior neck, chest, posterior shoulders, back and buttocks.

TREATMENT of POLYMYOSITIS and DERMATOMYOSITIS

Treatment of polymyositis and dermatomyositis is largely empirical. Corticosteroids remain the agent of first choice, despite the lack of randomised controlled data [24]. Other immunosuppressive agents are recommended for patients who fail to respond to corticosteroids or are used in combination with corticosteroids to reduce the incidence of side effects from the steroids.

• The initial dose of prednisolone is 1–2 mg/kg body weight for 2–4 weeks, slowly reducing the dose over a period of 6 months and changing to an alternate day regimen as maintenance therapy.

• If the response to corticosteroids is suboptimal at 3 months, other immunosuppression is recommended [25]. Azathioprine (it may take 3–6 months before seeing any benefit), cyclophosphamide [26], cyclosporine and methotrexate [27] have all been advocated in corticosteroid-resistant cases.

• Plasmapheresis was not shown to be of any benefit in a randomised controlled trial [28].

• A randomised controlled trial has confirmed the efficacy of intravenous immunoglobulin in corticosteroid-resistant polymyositis [29] and is currently recommended by the European Federation of Neurological Societies [30]. Treatment may need to continue for 1–3 years to prevent relapse.

INCLUSION BODY MYOSITIS

Inclusion body myositis (IBM) is a sporadic condition seen predominantly in patients over the age of 50. IBM has a pathognomonic pattern of weakness affecting the quadriceps muscle with severe weakness of knee extension resulting in frequent falls as the knees give way in addition to the distal weakness in the forearms and hands with weakness of flexion of the fingers. Hip flexion weakness is much less severe than the knee extension weakness. Dysphagia is common but involvement of the respiratory muscles is rare [31]. The muscle biopsy demonstrates inflammatory cells and vacuoles in muscle fibres.

TREATMENT OF INCLUSION BODY MYOSITIS

Many immunosuppressive drugs have been tried in IBM, including corticosteroids, azathioprine, cyclosporine, methotrexate and intravenous immunoglobulin and interferon-beta-1a, all to no avail. Current recommendations encourage exercise for patients with IMB [32].

Drug-induced myopathies

Side effects from the use of drugs are rare and occur in less than 0.5% of patients. They include muscle pain that can be mild and not require cessation of the drug or severe and associated with fatigue and elevation of the CK to more than 10 times the upper limit of normal (ULN). Other complications include a proximal muscle weakness or rhabdomyolysis which at times is fatal. Myopathy is more common in patients on multiple therapeutic agents and may relate to drug–drug interactions. Although the CK is usually elevated, a normal value does not exclude a drug-induced myopathy [33]. The myopathy may take months or even years to develop, and symptoms may persist for some time after cessation of the drug [34].

Statins, fibrates, antidepressants, antipsychotic drugs, benzodiazepines, calcium channel blockers, corticosteroids, alcohol, cocaine, amphetamines, colchicines and heroin are some of the drugs that can produce myopathy including rhabdomyolysis.

Weakness and fatigue

MYASTHENIA GRAVIS AND LAMBERT–EATON SYNDROME

The term ‘myasthenia’ literally means muscle weakness and is derived from the Latin ‘myos’, meaning muscle, and the Greek ‘asthenes’, meaning a- (without) + sthenos (strength).

Disorders of the neuromuscular junction should be suspected in patients who have weakness that is associated with fatiguability.

The two currently recognised disorders that affect the neuromuscular junction (NMJ) are myasthenia gravis [35] and the Lambert–Eaton syndrome, also referred to as the Lambert–Eaton myasthenic syndrome [36]. Patients with myasthenia gravis observe that their weakness is exacerbated by exercise, whereas patients with the Lambert–Eaton syndrome complain of weakness and fatigue unrelated to exercise. Patients with amyotrophic lateral sclerosis (motor neuron disease) may also complain of a significant exacerbation of weakness with exercise, but the severe fixed weakness, wasting and fasciculations seen in motor neuron disease are not seen in the disorders of the NMJ [37].

Both are immune-mediated disorders.¹ Lambert–Eaton syndrome is often associated with malignancy, particularly small cell carcinoma of the lung [40], but may also occur as an autoimmune disease in the absence of malignancy [41]. Myasthenia gravis may be associated with a tumour of the thymus [42], either benign or malignant; this is more common in elderly patients and younger patients tend to have thymic hyperplasia or aplasia of the thymus.

Myasthenia gravis is classified as either ocular if it just affects the ocular muscles (including the eyelids) or generalised if it affects the facial, bulbar and limb muscles. The characteristic feature is the exacerbation of the weakness with exercise or prolonged use of the muscles. Variable ptosis (drooping of the eyelid) and variable diplopia with a mixture of horizontal and vertical diplopia at different times occur with ocular myasthenia gravis, although the occasional patient does not observe variable diplopia leading to the incorrect diagnosis of a 3rd, 4th or 6th nerve palsy or an internuclear ophthalmoplegia (a lesion of the median longitudinal fasciculus in the brainstem).² The ocular muscles may also be affected in patients with generalised myasthenia gravis. Patients with generalised myasthenia may complain of difficulty holding their head up while watching television due to weakness of the extensor muscles of the neck, increasing dysarthria the more they speak; problems with chewing or swallowing food, again worse with prolonged chewing; increasing weakness leading to difficulty holding the arms up above the head when washing the hair or putting clothes on the clothes line. Patients have to rest momentarily before they can continue this activity. During the examination increasing degrees of ptosis and diplopia can be elicited by asking the patient to look up for a prolonged period of time; fatiguable weakness in the limbs can be elicited with repetitive exercise. A quick test in patients with suspected ocular myasthenia is to place ice on the eyelid and see the temporary resolution of the ptosis [43]. Changes in the degree of diplopia with the ice test should be interpreted with caution [44].

The reflexes are normal and are not influenced by exercise. There are a number of diagnostic tests for myasthenia gravis with variable sensitivity but high specificity (see Table 14.1).

TABLE 14.1

Sensitivity and specificity of diagnostic tests in myasthenia gravis

Test	Sensitivity (%) (95% CI)	Specificity (%) (95% CI)
Tensilon test [45]	92 (83–100%)	97 (91–100)
Ice test [43]	95 (87–100)	97 (90–100)
ACHR antibody^∗ [46]	54 (44–63)	98 (96–100)
Repetitive nerve stimulation [47]	26 (15–44)	95 (94–100)
SFEMG [48]	89 (83–95)	88 (78–96)

Note: These figures were calculated from the table in the article entitled ‘A systematic review of diagnostic studies in myasthenia gravis’ [49]. Benatar assessed the quality of the studies as well as the reported results of sensitivity and specificity. The individual figures from each of the studies quoted were summed and divided by the number of studies to obtain the sensitivity, specificity and 95% confidence intervals quoted in this table.

^∗The figures for the ACHR antibody assay are at variance with the accepted figure of approximately 85% sensitivity [50] and the explanation for this is unclear.

Diagnostic tests:

THE TENSILON TEST: The tensilon (edrophonium hydrochloride) test demonstrates transient improvement lasting 30–60 seconds.

1. The patient should be pre-treated with atropine 600 μg to reduce the gastrointestinal side effects of the edrophonium hydrochloride.

2. 10 mg of edrophonium is mixed with 9 mL of normal saline (1 mg of edrophonium per mL).

3. Initially 2 mg is injected; if the patient fails to respond to 2 mg, the other 8 mg is injected.

4. Observe the patient for at least 3 minutes after the injection (longer in older patients due to a slower circulation time).

In some patients 2 mg is too much and in other patents 8 mg may be insufficient [51]. In normal patients the tensilon test does not produce any change in strength.

ACETYLCHOLINE RECEPTOR ANTIBODIES: Acetylcholine receptor (ACHR) antibodies are positive in 85% of patients with myasthenia gravis [50]. ACHR antibodies may be detected with repeat testing in some patients with myasthenia gravis in whom they are initially negative [52]. It is likely that further antibodies will be discovered in the sero-negative (the ACHR antibody negative) patients with myasthenia gravis.

Musk antibodies are an IgG antibody against the muscle-specific kinase (MuSK). The presence of antibodies against MuSK appears to define a subgroup of patients with sero-negative myasthenia gravis who have predominantly localised, in many cases bulbar, muscle weaknesses (face, tongue, pharynx etc) and reduced response to conventional immunosuppressive treatments [53].

Anti-titin antibodies may identify patients with a thymoma [39].

NERVE CONDUCTION STUDIES: Nerve conduction studies can differentiate between myasthenia gravis and Lambert–Eaton syndrome.

A repetitive stimulation study is where the nerve is stimulated at 3 per second for 8 impulses immediately before exercise, 20 seconds after sustained exercise and then at intervals of 1 minute for several minutes. The test may demonstrate a decremental response (the 5th response is of lower amplitude compared to the 1st response) in patients with myasthenia gravis and an incremental response in patients with the Lambert–Eaton syndrome.

Single fibre electromyography (SFEMG) can demonstrate instability at the neuromuscular junction (referred to as increased jitter) but cannot differentiate between Lambert–Eaton syndrome and myasthenia gravis. Increased jitter is also seen in motor neuron disease.

TREATMENT of MYASTHENIA GRAVIS

Treatment of myasthenia gravis is influenced by the presence or absence of a thymic tumour. Most authorities would recommend thymectomy [54] in patients with thymic tumours as it is difficult to differentiate between benign and malignant tumours prior to surgery. Thymic tumours are locally malignant, invading the lung and/or pericardium; they do not metastasise.

In patients with isolated ocular myasthenia gravis, the treatment options include nothing, pyridostigmine ³ or other anticholinesterase drugs to provide symptomatic relief or full immunosuppressive treatment. In patients with generalised myasthenia gravis the options include immunosuppression or thymectomy in the presence of thymic hyperplasia.

In generalised myasthenia gravis corticosteroids are often the first drug of choice and limited evidence from randomised controlled trials has demonstrated short-term benefit [56]. Small randomised controlled trials suggest that cyclosporine, as monotherapy or with corticosteroids, or cyclophosphamide with corticosteroids significantly improve myasthenia gravis. Azathioprine, either as monotherapy or with steroids, has not been shown to be of benefit in randomised controlled trials. Mycophenolate mofetil (as monotherapy or with either corticosteroids or cyclosporine) or tacrolimus (with corticosteroids or plasma exchange) has also been advocated in resistant cases [57]. Although intravenous immunoglobulin has been shown to be superior to placebo but no different to plasma exchange, the ease of use means that intravenous immunoglobulin is regarded by most as the treatment of choice for a myasthenic crisis or preoperatively in patients undergoing thymectomy or other surgery if the myasthenia is unstable at the time. Pyridostigmine may provide some symptomatic benefit, but gastrointestinal upset and the fact that an excess dose can cause similar symptoms to worsening myasthenia gravis makes this a difficult drug to use. Excess salivation and abdominal discomfort with diarrheoa are the two clues that there may be an excess of pyridostigmine.

Currently corticosteroids, azathioprine, plasmapheresis, intravenous immunoglobulins and 3,4-diaminopyridine are used in treatment of Lambert–Eaton myasthenic syndrome with limited success. Some evidence from randomised controlled trials shows that either 3,4-diaminopyridine or intravenous immunoglobulin improves muscle strength scores and compound muscle action potential amplitudes in patients with Lambert–Eaton myasthenic syndrome [58]. 3,4 diaminopyridine works by blocking K⁺ channel efflux in nerve terminals so that action potential duration is increased. Ca²⁺ channels thus remain open for a longer period of time, which allows greater acetylcholine release to stimulate the muscle at the end plate.

³ First described by Mary Walker who administered prostigmin [neostigmine] and performed the ‘miracle of St Alfeges’ [55]; until then myasthenia gravis was regarded as an incurable progressive neurological disease.

CHRONIC FATIGUE OR POST-VIRAL FATIGUE SYNDROME

The post-viral fatigue syndrome is very common. It was initially described at the Royal Free Hospital [59] and was referred to as benign myalgic encephalomyelitis [60]. The aetiology remains obscure, although a similar syndrome of fatigue and depression is common following infectious mononucleosis [61], suggesting a possible viral aetiology and thus the term post-viral fatigue syndrome.

Although post-viral fatigue can occur in epidemics, it is usually sporadic. It occurs at any age but is more common in young and middle-aged females. The overwhelming complaint is one of severe fatigue with muscle aches and pains developing after a flu-like illness. Depression and excessive sleep are common, as are complaints of poor memory and difficulty concentrating [62].

MANAGEMENT of POST-VIRAL FATIGUE

There is at this stage no specific test. The diagnosis is a clinical one and requires the presence of a definite viral infection followed by severe fatigue. There is no specific treatment but fortunately it is a self-limiting illness in most patients, although some may be troubled for months or even years.

MULTIPLE SCLEROSIS

After more than a century of study (multiple sclerosis was first described by the French pathologist Charcot in 1868), the aetiology of multiple sclerosis (MS) remains unknown. There is no gold standard test to confirm the diagnosis and there is no curative treatment. It is highly likely that everything written in this section will very rapidly be out of date.

Currently the diagnosis is based on the clinical features, the results of MRI, analysis of the cerebral spinal fluid and visual evoked potentials [63] (see Tables 14.2–14.4). These criteria have been modified on several occasions and are likely to change in the future. The diagnosis of MS can be very difficult as there are a number of conditions that can result in multifocal involvement of the central nervous system and thus mimic MS. These include central nervous system or systemic vasculitis including systemic lupus erythematosus, acute disseminated encephalomyelitis, antiphospholipid antibody syndrome, sarcoidosis, Wilson’s disease, paraneoplastic syndromes and central nervous system lymphoma.

TABLE 14.2

Primary tumours of the nervous system named according to their cell of origin

Central nervous system	Cell of origin	Name of tumour
	Astrocytes	Astrocytoma^∗
	Ependyma	Ependymoma^∗
	Oligodendrocytes	Oligodendrogliomas^∗
	Neuroectoderm	Medulloblastoma, pinealoblastoma
	Meninges	Meningioma
	Schwann cell	Neurofibroma
Peripheral nervous system
	Schwann cell	Neurofibroma
	Neuroectoderm	Ewing’s sarcoma

Note: All these tumours can be either malignant or benign.

^∗Astrocytomas, ependymomas and oligodendrogliomas are referred to as gliomas.

TABLE 14.3

Central nervous system paraneoplastic syndromes

Clinical syndrome	Antibodies	Underlying malignancy
Carcinoma-associated retinopathy	Antirational	SCLC, melanoma, gynaecologic
Limbic encephalitis	Anti-Hu, anti-Ma2	SCLC, testicular
Brainstem encephalitis	Anti-Ma1, anti-Ma2	Lung, testicular
Encephalomyelitis	Anti-amphiphysin, anti-PCA-2, anti-CRMP5, ANNA-3, anti-NMDA-receptor	SCLC, breast, thymoma, ovarian
Cerebellar degeneration	Anti-Yo, anti-Hu, anti-Tr anti-Ma1, anti-mGluR1, anti-PCA-2, anti-CRMP5	SCLC, ovarian, breast, bladder, Hodgkin’s lymphoma
Opsoclonus–myoclonus	Anti-Ri	Ovarian, breast, bladder, lung
Chorea	Anti-CRMP5 (anti-CV2)	SCLC, breast, thymoma
Necrotising myelopathy	None identified	Not specific
Stiff-person syndrome	Anti-amphiphysin	SCLC, breast

SCLC = small cell lung cancer

Compiled from Darnell and Posner [71], Dalmau [72] and Anderson and Barber [73]

TABLE 14.4

Peripheral nervous system paraneoplastic syndromes

Clinical syndrome	Antibodies	Underlying malignancy
Dorsal root ganglionopathy	Anti-Hu, anti-CRMP5 (anti-CV2), ANNA-3	Lung, SCLC, thymoma
Peripheral neuropathy	Anti-MAG	Waldenstrom’s
Autonomic neuropathy	Anti-Hu, anti-nicotinic AchR	SCLC, bladder, thyroid
Myasthenia gravis	AchR, anti-titin	Thymoma
Lambert–Eaton syndrome	Anti-VGCC, anti-PCA-2	SCLC
Dermatomyositis	None identified	Ovarian, breast, lung
Necrotising myopathy	None identified	No specific neoplasm
Neuromyotonia	Anti-VGKC	SCLC, thymoma
Stiff-person syndrome	Anti-amphiphysin	SCLC, breast

SCLC = small cell lung cancer

Compiled from Darnell and Posner [71], Dalmau [72], Rudnicki [74] and Anderson and Barber [73]

MS as it is currently defined is more common in women and in younger patients between the ages of 15 and 50, with a mean age of onset of 29–33 years. It can occur in children or in adults over the age of 50. There is probably a genetic predisposition [64]. The natural history is highly variable from the very benign, where it is accidentally discovered at autopsy in old age, to the very malignant with death within the first few years of onset. This variability makes it very difficult to assess therapeutic interventions. In general, at 10 years 50% of patients with MS will have a neurological deficit requiring the use of a cane to walk while 15% will be in a wheelchair [65].

MS may present as a clinically isolated syndrome, a relapsing/remitting course with or without secondary progressive MS or primary progressive MS where progression to disability occurs without remission.

OPTIC OR RETROBULBAR NEURITIS

Unilateral blurring of vision associated with pain on movement of the eye evolving over hours to days is a very typical initial presentation and represents optic or retrobulbar neuritis. As described in Chapter 4, ‘The cranial nerves and understanding the brainstem’, patients with optic neuritis will have markedly impaired visual acuity with a swollen optic disc and an afferent pupillary defect with or without impairment of colour vision, whereas patients with retrobulbar neuritis will have the same features but without the optic disc swelling.

Not all patients with optic neuritis will subsequently develop MS.

TRANSVERSE MYELITIS

Weakness commencing in the lower limbs that may spread to affect the upper limbs or an ascending sensory disturbance once again commencing in the lower limbs and spreading up onto the trunk and sometimes into the arms represents involvement of the spinal cord and is referred to as transverse myelitis. Sphincter disturbance is common in patients with spinal cord involvement. This may manifest as either acute urinary retention or incontinence of either urine or faeces.

Not all patients with transverse myelitis will develop MS.

It is important to remember that transverse myelitis is a syndrome and not a diagnosis. Although MS is a common cause of transverse myelitis, transverse myelitis also occurs with infectious and post-infectious diseases, as a paraneoplastic phenomenon and in collagen vascular diseases. Patients with transverse myelitis and a normal MRI scan of the brain have a low risk of developing clinically definite MS [66].

NEUROMYELITIS OPTICA

The term neuromyelitis optica (NMO) is used to describe an entity where severe attacks of optic neuritis and transverse myelitis occur either simultaneously or in succession. Although a monophasic form exists, the tendency is for recurrent optic neuritis and transverse myelitis. The original description was of transverse myelitis with bilateral optic neuritis or bilateral retrobulbar neuritis. MS, systemic lupus erythematosus, acute disseminated encephalomyelitis and Behçet’s can present with clinical features resembling NMO. Some authorities regard NMO as a distinct disorder separate from MS [67]. On MRI there are extensive longitudinal central spinal cord T2 lesions over several segments. Oligoclonal bands are usually negative in the cerebral spinal fluid and 70% will have a unique biomarker in the serum, the NMO-IgG or aquaporin [67]. In contrast, in patients with MS the spinal cord abnormality on MRI usually involves fewer than two segments, is asymmetrical and in the peripheral aspect of the spinal cord. Patients with NMO often succumb to respiratory failure. The pathogenesis of NMO is likely to be different to that of MS.

BILATERAL INTERNUCLEAR OPHTHALMOPLEGIA

Another classical presentation is with horizontal diplopia with or without vertigo due to involvement of the brainstem. The diplopia results from involvement of the median longitudinal fasciculus and this causes ipsilateral failure of adduction (looking towards the nose) and leading eye nystagmus in the opposite eye, the so-called internuclear ophthalmoplegia. Bilateral internuclear ophthalmoplegia is regarded as almost pathognomonic of MS. Pseudo-internuclear ophthalmoplegia can occur with the Miller Fisher variant of acute inflammatory demyelinating peripheral neuropathy, myasthenia gravis and thyroid eye disease, although in these conditions other signs are the clue to the diagnosis.

SPHINCTER DISTURBANCE

Neurologists are often asked to see young patients with disturbances of micturition and, although this can be a presenting symptom in a very small number of patients with MS, most of these patients do not have MS.

UHTHOFF’S PHENOMENON

Transient worsening of symptoms in patients with MS is not uncommon in the setting of excessive heat or an infection that causes fever. This is referred to as Uhthoff’s phenomenon. Patients with established MS will often confuse this with a relapse of their MS; the clue is that it is a transient worsening of preexisting symptoms and signs rather than the appearance of new symptoms or signs that would indicate involvement of a different part of the nervous system. Uhthoff’s phenomenon may be the only symptom of, for example, a urinary tract infection in patients with MS.

L’HERMITTE’S PHENOMENON

Electric shock-like sensations that radiate from the neck down the body and into the limbs with neck flexion is referred to as the L’Hermitte’s phenomenon. Although characteristic of MS it is not pathognomonic and can occur with severe cervical cord compression.

TRIGEMINAL NEURALGIA IN YOUNG PATIENTS

Although trigeminal neuralgia (see Chapter 4, ‘The cranial nerves and understanding the brainstem’) can occur in patients with MS, MS is rarely the cause.

Investigation in suspected multiple sclerosis

MRI has revolutionised the management of patients with MS, both in terms of diagnosis and also as a surrogate endpoint in therapeutic trials. The current McDonald criteria [63] used for the diagnosis of MS rely heavily on the MRI scan findings. The criteria are given in Appendix I.

The MRI scan must not be used in isolation to diagnose MS; the findings must be carefully correlated with the clinical presentation.

MALIGNANCY AND THE NERVOUS SYSTEM

Neurological problems are very common in patients with malignancy. The symptoms may relate to:

1. direct effects of the malignancy on the central nervous system – patients present with focal neurological deficits, seizures or headache

2. remote effects of the malignancy, the paraneoplastic syndrome – patients present with diffuse neurological problems

3. complications of therapy (chemotherapy or radiotherapy) for the malignancy

4. an entirely separate problem and unrelated to either the malignancy or its treatment.

Just because a patient has malignancy it does not mean they cannot develop an unrelated neurological problem.

Direct effects of malignancy

PRIMARY TUMOURS OF THE NERVOUS SYSTEM

Primary tumours of the nervous system can affect the brain, spinal cord or rarely the peripheral nervous system and they are named according to their cell of origin (see Table 14.2). Tumours can develop from:

• Glial cells

• Astrocytes

• Ependyma (inner lining of the brain)

• Oligodendrocytes

• Neuroectoderm (external lining of the brain)

• Meninges

• Schwann cell

• Pituitary gland

Classifications of tumours of the nervous system, such as that of the World Health Organization [68, 69], will continue to evolve with new discoveries [70].

Primary central nervous system tumours declare themselves with seizures, headache or the development of a progressive focal neurological deficit. Gliomas can affect any part of the nervous system but are less common in the brainstem or spinal cord. They can infiltrate the corpus collosum, spreading to both hemispheres and forming a butterfly glioma, or they can infiltrate throughout the entire brain rather than forming a discrete mass and this is referred to as gliomatosis cerebri.

Tumours of the pituitary gland represent about 10% of primary central nervous system tumours. Symptoms arise from pituitary tumours in three ways:

1. a direct result of the tumour (visual loss due to compression of the optic chiasm or optic nerves and headache)

2. destruction of the pituitary gland and loss of hormone function, in particular hypothyroidism and amenorrhoea

3. excess hormone secretion, e.g. growth hormone causing either gigantism or acromegaly or prolactin causing galactorrhoea.

Most pituitary tumours are macroadenomas whereas hormone-secreting tumours such as prolactinomas can be microadenomas.

Secondary tumours of the nervous system

In non-central nervous system malignancy the neurological manifestations may be the presenting symptom of that malignancy or they may develop in a patient with an established diagnosis. Any tumour can potentially metastasise to the brain, but the common ones are lung and breast, while the paired organs (thyroid, lung, breast, kidney and prostate) metastasise to the spinal column. Secondaries tend to occur in patients between the ages of 40 and 60. Spinal cord compression due to malignancy is discussed in Chapter 13, ‘Abnormal movements and difficulty walking due to central nervous system problems’.

Paraneoplastic syndromes

Paraneoplastic syndromes are rare except for myasthenia gravis (thymoma), Lambert–Eaton syndrome (small cell carcinoma of the lung) and the demyelinating peripheral neuropathy associated with the osteosclerotic plasmacytoma.

Paraneoplastic syndromes refer to neurological symptoms and signs in a patient with malignancy that are not the direct result of the tumour but rather an immune-mediated remote effect. Paraneoplastic syndromes are seen in both the central and peripheral nervous systems (see Tables 14.3 and 14.4). Similar clinical syndromes mediated by antibodies may also be seen in the absence of malignancy. Anti-neuronal antibodies that react with the underlying tumour and the target cells within the central nervous system can be detected [71–74].

These neurological syndromes are very severe, often disabling and sometimes fatal. They can develop rapidly over days but more commonly weeks to a few months. The neurological symptoms and signs often but not invariably precede the diagnosis of malignancy for months and sometimes years; in other patients they may herald a recurrence of the tumour. The malignancy may initially elude detection, despite extensive investigations and be diagnosed some time later. It is thought that effective antitumour immunity is associated with autoimmune brain disease [71, 75–81]. Increasing numbers of antibodies are being recognised and the type of malignancy can vary considerably; the ones listed in the tables are the more common (see Tables 14.3 and 14.4). It is now recognised that pure presentations of these syndromes are the exception rather than the rule and it is not uncommon for a patient with malignancy and paraneoplastic phenomena to have multifocal symptoms and signs.

Positron emission tomography (PET) scanning is able to detect malignancy even in patients where a CT scan is negative. In patients with paraneoplastic syndromes, PET scanning has a sensitivity and specificity of 80% and 67%, respectively [82].

Self-examination, mammography, ultrasound, MRI and a new modality termed elasticity imaging are all used to detect breast cancer [83].

INVESTIGATION and MANAGEMENT of PARANEOPLASTIC SYNDROMES

The exact pathogenesis of most paraneoplastic syndromes is currently unknown, and it is possible that both humoral and cell-mediated immunity are involved. In patients suspected of having paraneoplastic syndrome, anti-neuronal antibodies, a whole body PET scan and in females mammography and ultrasound or CT scan of the ovaries are recommended. New anti-neuronal antibodies are being increasingly identified; the particular antibody is often a guide to the site of the underlying malignancy (see Tables 14.3 and 14.4).

The most effective treatment is removal of the antigen by treatment of the underlying malignancy but, as already stated, the tumour may not be detectable at the time of the initial presentation. Unfortunately, many patients are severely disabled at the time of presentation. Myasthenia gravis, the Lambert–Eaton syndrome, peripheral neuropathy associated with osteosclerotic plasmacytoma and opsoclonus–myoclonus may respond to treatment of the underlying malignancy, immunosuppression or both. In most patients treatment consists of immunosuppression.

Complications of therapy

When neurological symptoms develop in a patient undergoing therapy for malignancy it is important to consider the possibility of side effects due to the therapy. There are many recognised complications of radiotherapy and chemotherapy and, with the emergence of newer chemotherapeutic agents including monoclonal antibodies and proteasome inhibitors in recent years, the list of neurological complications is expanding.

COMPLICATIONS OF CHEMOTHERAPY

The most common side effect of chemotherapeutic agents is peripheral neuropathy [84, 85]. The neuropathy is dose-dependent, develops gradually and increases in severity with subsequent doses. It is almost invariably a length-dependent peripheral neuropathy in which patients develop a distal sensory loss in the lower limbs with or without distal weakness. Very rarely the autonomic nervous system may be affected, for example with vincristine. Oxaliplatin has been reported to cause an acute reversible peripheral neuropathy developing within hours of commencing intravenous therapy [86]. Improvement often but not invariably occurs if no further doses are given, although this may be unavoidable in order to treat the malignancy. Peripheral neuropathy is seen with many of the currently employed chemotherapeutic agents, including thalidomide and an analogue of thalidomide, lenalidomide, the vinca alkaloids (vincristine and vinblastine), platinum compounds (cisplatin, carboplatin and oxaliplatin), the taxanes (paclitaxel and docetaxel) and cytarabine.

Cognitive decline may occur with chemotherapy and is referred to as ‘chemobrain’ [85].

COMPLICATIONS OF INTRATHECAL THERAPY

Occasionally drugs, for example methotrexate and cytarabine, are administered via the intrathecal route (into the cerebral spinal fluid via a lumbar puncture). This route of administration can be complicated by chemical meningitis, myelopathy (spinal cord involvement) or seizures Multifocal leucoencephalopathy has been reported with capecitabine [87]. The inadvertent intrathecal administration of vincristine causes a severe myelopathy with tetraplegia that is often fatal [88].

COMPLICATIONS OF RADIOTHERAPY

The neurological complications of radiotherapy can be divided into early and delayed [89]. The early complications are usually mild and transient whereas the delayed complications are often progressive and disabling. Complications occur when central nervous system tumours are irradiated or as a result of incidental damage when the radiation is applied to soft tissue tumours adjacent to the nervous system. The site of the neurological complications will relate directly to the site of radiotherapy. Necrosis resulting in swelling and a mass effect may occur with radiation to the brain. The onset of symptoms usually commences 1–3 years after therapy but may begin as early as 3 months or be delayed for as long as 12 years. The symptoms and signs relate to the mass. At times it can be difficult to differentiate between recurrent tumour and radiation necrosis. Radiation necrosis-induced masses may also, like tumours, enhance with contrast on a CT scan of the brain. Careful correlation with the sight of maximum irradiation may sometimes help to differentiate recurrent tumour from radiation necrosis. MR spectroscopy or computer-assisted stereotactic biopsy is used to differentiate tumour recurrence from radiation necrosis [90, 91].

Immediate radiation damage to the spinal cord is usually transient. A transient myelopathy develops within weeks of radiation with numbness and paraesthesia without weakness or objective neurological signs. These sensory symptoms spread from the site of radiation down into the limbs and are often associated with L’Hermitte phenomena. Symptoms usually resolve within months.

Non-reversible radiation myelopathy can occur acutely, with paraplegia or quadriplegia evolving over days and is thought to relate to arterial occlusion [92]. This acute form of myelopathy is very rare and more common is the chronic progressive myelopathy developing within 1 year, although it may occur as early as 4 months or as late as 13 years after radiation. The patient develops ascending sensory loss and weakness often associated with sphincter disturbance. The symptoms and signs are usually bilateral but may be unilateral. The myelopathy progresses over months, often to severe disability. An MRI scan demonstrates swelling of the spinal cord, focal contrast enhancement, low signal over several segments on T1-weighted images and high signal on T2-weighted images [93, 94].

Radiation injury may also occur to cranial nerves, either single or multiple cranial nerves may be affected. The brachial plexus is another site where radiation damage can occur. It can be difficult to differentiate between radiation injury to the brachial plexus and malignant infiltration; perhaps the only clue is that pain is much more common with the latter.

There is little effective treatment for radiation damage to the nervous system. Treatment with corticosteroids, surgery or antioxidants is often ineffective and the role of anticoagulation remains unclear [95, 96].

INFECTIONS OF THE NERVOUS SYSTEM

Meningitis, which is one of the more common infections of the nervous system, has already been discussed in Chapter 9, ‘Headache and facial pain’. Central nervous system infections, particularly opportunistic infections, are more common in immunocompromised patients such as patients with HIV or those on immunosuppressive therapy. A complete discussion of central nervous system infections is beyond the scope of this book.