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 120 per of the population, with an annual incidence of around 7 per The lifetime risk of developing multiple sclerosis is about 1 in 400. The incidence is higher in temperate climates and in Northern Europeans, and the disease is about twice as common in women as men.

Aetiology Epidemiological and genetic evidence suggests that multiple sclerosis is caused by an interplay of multiple genetic and environmental factors. The incidence varies with latitude, being low in equatorial areas and higher in the temperate zones of both hemispheres, with people retaining the risk of the zone in which they grew up. However, no specific environmental factors such as exposure to viral infections have so far been correlated with an increased risk. The risk of familial recurrence is 15%, with highest being for first-degree relatives (age-adjusted risk: 2-3%) and a monozygotic twin concordance of 35%. An immune mechanism is suggested by increased levels of activated T lymphocytes in the CSF, and increased immunoglobulin synthesis within the central nervous system.

Pathology 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). 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 corticosteroids 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).

Clinical features 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 (dorsal column deficit) 6th cranial nerve palsy

Other symptoms and syndromes suggestive of CNS demyelination Afferent pupillary defect and optic atrophy (previous optic neuritis) Lhermitte's symptom (tingling in spine or limbs on neck flexion) Progressive non-compressive paraparesis Partial Brown-Séquard syndrome) Internuclear ophthalmoplegia with ataxia () Postural ('rubral', 'Holmes') tremor) Trigeminal neuralgia () under the age of 50 Recurrent facial palsy

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). The peak age of onset is in the fourth decade, with onset before puberty or after the age of 60 years being rare. There are a number of clinical symptoms and syndromes suggestive of multiple sclerosis, some of which may occur at presentation while others may develop in the course of the illness).

Investigations Following the first clinical event, investigations may help prognostically in confirming the disseminated nature of the disease. Visual evoked potentials) 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) and in excluding other causes of the neurological deficit. However, the MRI appearances in multiple sclerosis may be confused with 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 conditions such as infection, vitamin B 12 deficiency and spinal cord compression.

Management The management of multiple sclerosis involves treatment of the acute relapse, prevention of future relapses, treatment of complications and management of the patient's disability. Acute relapse In a function-threatening relapse, pulses of high-dose methylprednisolone, either intravenously (1 g daily for 3 days) or orally (500 mg daily for 5 days), shorten the duration of the relapse but do not affect long-term outcome (Pulsed 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 steroids can be given up to three times in a year but their administration should be restricted to those with significant function-threatening deficits.

Preventing relapses Immunosuppressive agents including azathioprine have some 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 (and); glatiramer acetate has similar effects. The effects of other immune modulation therapies) may be of some use in severely affected patients..

The treatment of the complications of multiple sclerosis is. Of prime importance is a careful explanation of the nature of the disease and its outcome, along with support of patients and their relatives when disability occurs. Periods of physiotherapy and occupational therapy may improve functional capacity in those patients who become disabled, and can provide guidance in the provision of aids at home, reducing handicap. Care of the bladder is particularly important. Urgency and frequency may be treated pharmacologically but this may lead to a degree of retention that promotes the development of infection; this needs appropriate treatment. Retention can be managed initially by intermittent urinary catheterisation (by the patient, if possible), but an in-dwelling catheter may become necessary. Sexual dysfunction is a frequent source of distress. Sildenafil helps impotence in men, and skilled counselling and prosthetic aids are often useful.

Prognosis 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, rising to about 50% after 15 years.