Wilkinson. Essential Neurology 2005

Fig. 10.7 Common causes of peripheral neuropathy in the UK.

In developed countries the commonest identifiable causes of peripheral neuropathy are alcohol and diabetes. In other parts of the world, vitamin deficiency and leprosy cause more disease, although this is gradually changing. In both settings, many cases of peripheral neuropathy remain unexplained. Figure 10.7 lists some of the most important causes of peripheral neuropathy.

Alcoholic neuropathy

Alcoholic neuropathy is common and usually more sensory than motor. How much it is caused by the direct toxic effect of alcohol on the peripheral nerves, and how much it is due to coexistent vitamin B1 deficiency, is not completely known.

Vitamin B12 deficiency

Vitamin B12 deficiency is not a common cause of neuropathy, but is an important one to recognize because of its reversibility. Every effort should be made to reach the diagnosis before the irreversible changes of subacute combined degeneration of the spinal cord become established.

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Diabetes mellitus

Diabetes mellitus is probably the commonest cause of peripheral neuropathy in the Western world. It occurs in both juvenile-onset insulin-requiring diabetes and maturity-onset diabetes. It may be the first clinical suggestion of the presence of diabetes. Excellent diabetic control has been shown to prevent neuropathy, but does not reverse it once it has developed.

The commonest form of neuropathy in diabetes is a predominantly sensory one. The combination of neuropathy and atherosclerosis affecting the nerves and arteries in the lower limbs very strongly predisposes the feet of diabetic patients to trophic lesions, which are slow to heal.

There are a few unusual forms of neuropathy that may occur in patients with diabetes:

•painful weakness and wasting of one proximal lower limb, so-called diabetic lumbosacral radiculo-plexopathy or diabetic amyotrophy;

•involvement of the autonomic nervous system giving rise to abnormal pupils, postural hypotension, impaired cardioacceleration on changing from the supine to the standing position, impaired bladder, bowel and sexual function, and loss of normal sweating;

•a tendency for individual nerves to stop working quite abruptly, with subsequent gradual recovery. Common nerves to be involved are the 3rd and 6th cranial nerves and the common peroneal nerve in the leg. Involvement of several individual nerves in this way constitutes the clinical syndrome of multifocal neuropathy.

Hereditary motor and sensory neuropathy

(HMSN, also known as Charcot–Marie–Tooth disease)

There are several forms of this, with a complex genetic classification. One of the more common, HMSN type I, is due to a duplication in the gene for peripheral myelin protein 22; this and some other forms can be diagnosed with a genetic test. The illness is usually evident in teenage life and very slowly worsens over many years. Motor involvement predominates, with lower motor neurone signs appearing in the feet and legs (especially in the anterolateral muscle compartments of the calves), and in the small muscles of the hands. Pes cavus and clawing of the toes are very common consequences. Sometimes, the pathology primarily involves the axons, but more often there is demyelination and remyelination to be found in the peripheral nerves.

CHAPTER 10

Key features of HMSN

•Pes cavus

•Distal wasting (‘champagne bottle legs’)

•Distal weakness

•Absent reflexes

•Mild distal sensory loss

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Management of myasthenia gravis

The management of myasthenia gravis includes:

1.The use of oral anticholinesterase drugs, pyridostigmine and prostigmine. These are prescribed at intervals during the day, and work quite effectively. Abdominal colic and diarrhoea, induced by the increased parasympathetic activity in the gut, can be controlled by simultaneous use of propantheline.

2.Immunosuppression by prednisolone or azathioprine. In patients with disabling symptoms inadequately controlled by oral anticholinesterase therapy, suppression of the autoantibody can radically improve muscle strength.

3.Thymectomy. Remission or improvement can be expected in 60–80% of patients after thymectomy, and must be considered in all patients. It may make the use of immunosuppressive drugs unnecessary, which is obviously desirable.

4.Plasma exchange to remove circulating auto-antibody to produce short-term improvement in seriously weak patients.

5.Great care of the myasthenic patient with severe weakness who is already on treatment. The muscle strength of such patients may change abruptly, and strength in the bulbar and respiratory muscles may become inadequate for breathing. The correct place for such patients is in hospital, with anaesthetic and neurological expertise closely to hand. There may be uncertainty as to whether such a patient is undertreated with anticholinesterase (myasthenic crisis), or overtreated so that the excessive acetylcholine at the neuromuscular junction is spontaneously depolarizing the postsynaptic membrane, i.e. depolarization block (cholinergic crisis). Fasciculation may be present when such spontaneous depolarization is occurring. Tensilon may be used to decide whether the patient is underor overdosed, but it is essential to perform the Tensilon test with an anaesthetist present in these circumstances. If the weak state is due to cholinergic crisis, the additional intravenous dose of anticholinesterase may produce further critical paralysis of bulbar or respiratory muscles.

CHAPTER 10

Management of myasthenia gravis

•Anticholinesterase

•Immunosuppression

•Thymectomy

•Plasma exchange

•Crisis management

Fig. 10.10 Classification of muscle diseases.

Inherited

1Muscular dystrophies, whose genetic basis is increasingly understood in terms of gene and gene product identification.

2Muscle diseases in which an inherited biochemical defect is present.

Specific enzyme deficiencies occur which disrupt the pathways of carbohydrate or fat oxidation, often with accumulation of substrate within the muscle cell. The enzyme deficiency may be within the muscle cell cytoplasm, interfering with the utilization of glycogen or glucose, or it may be within the mitochondria of muscle cells (and cells of other organs) blocking the metabolism of pyruvate, fatty acids or individual elements of Krebs cycle.

In other diseases of this sort, there is uncoupling of the electrical excitation of muscle fibres and their contraction.

This is the case in McArdle's syndrome, and in malignant hyperpyrexia where sustained muscle contraction may occur in the absence of nerve stimulation.

Acquired

1 Immunologically mediated inflammatory disease, e.g. polymyositis

dermatomyositis

2 Non-inflammatory myopathy, e.g. corticosteroids thyrotoxicosis

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Duchenne dystrophy

Duchenne dystrophy is the most serious inherited muscular dystrophy. The X-linked recessive inheritance gives rise to healthy female carriers and affected male children. The affected boys usually show evidence of muscular weakness before the age of 5 years, and die of profound muscle weakness (predisposing them to chest infections), or of associated cardiomyopathy, in late teenage life. In the early stages, the weakness of proximal muscles may show itself by a characteristic way in which these boys will ‘climb up their own bodies with their hands’ (Gower’s sign) when rising from the floor to the standing position. They also show muscle wasting, together with pseudohypertrophy of the calf muscles (which is due to fat deposition in atrophied muscle tissue).

The affected boys have elevated levels of creatine kinase muscle enzyme in the blood, and the clinically unaffected carrier state in female relatives is often associated with some elevation of the muscle enzymes in the blood. The gene locus on the X chromosome responsible for Duchenne dystrophy, and its large gene product, dystrophin, have been identified. Molecular genetic diagnosis of affected patients and female carriers is possible, as is prenatal diagnosis.

This same region of the X chromosome is also implicated in the inheritance of a more benign variant of Duchenne dystrophy (later in onset and less rapidly progressive), known as Becker’s musclar dystrophy.

The combination of family history, clinical examination, biochemical and genetic studies allows the detection of the carrier state, and the prenatal detection of the affected male fetus in the first trimester of pregnancy. Genetic counselling of such families has reached a high degree of accuracy. As a single gene disorder, Duchenne muscular dystrophy is one of the conditions in which gene therapy is being considered.

CHAPTER 10

Key features of Duchenne muscular dystrophy

•Young

•Male

•Generalized weakness

•Muscle wasting

•Calf pseudohypertrophy

•Gower’s sign