Demyelinating disorders

Demyelinating disorders

Definition Demyelinating disorders are characterized by inflammation and selective destruction of central nervous system (CNS) myelin and the peripheral nervous system (PNS) is spared, and most patients have no evidence of an associated systemic illness.

MULTIPLE SCLEROSISDefinition-Characterized by a triad of inflammation, demyelination, and gliosis (scarring) with lesions typically disseminated in time and location.

Etiopathogenesis Although the precise mechanism is unknown but there some evidence suggesting that multiple sclerosis is caused by interplay of multiple genetic and environmental factors. Multiple sclerosis is more common higher socioeconomic people and in western countries than Asian countries. There is an inflammatory process against self molecules in the white matter of the brain and spinal cord mediated by CD4 T cells. These cells entry brain through the blood-brain barrier. These CD 4 cells recognize myelin-derived antigens on the surface of the nervous system's antigen-presenting cells, the microglia, and undergo clonal proliferation.

Characteristic lesion is a plaque of inflammatory demyelination occurring most commonly in the periventricular regions of the brain, brainstem and its cerebellar connections, the optic nerves and cervical spinal cord (corticospinal tracts and posterior columns). Plaques vary in size from 1 or 2 mm to several centimeters.

After acute attack of demyelination there is stage of remission during which there is remyelination of nerves, but if when damage is severe, secondary permanent axonal destruction occurs. Nerve conduction in myelinated axons occurs in a saltatory manner; this produces considerably faster conduction velocities. When there is demyelination this salutatory conduction is lost resulting in significant reduction in the conduction velocities.Clinical features The age of onset is typically between 20 and 40 years and twice as common in women as in men. Symptoms and signs are sub acute in nature presenting over days or weeks and resolve over weeks or months. MS may present with four different types of patterns1. Relapsing and remitting MS (80-90%)

2. Primary progressive MS (10-20% of cases)

3. Secondary progressive MS - this follows on from relapsing/remitting disease

4. Progressive/relapsing MS.

The physical signs observed in multiple sclerosis depend on the anatomical site of demyelination.

Optic nerves,brainstem and cerebellum spinal cord are most frequently involved.

a) optic nerves

Acute optic neuritis is one of the most important presentations. Patient may present with retro bulbar neuritis i.e. the lesion is several millimeters behind the disc there are often no ophthalmoscopic abnormalities but patient complains of loss of vision. Blurring of vision in one eye develops over hours or days. In a few weeks the vision improves, but the residual damage to the nerve manifests in some degree of optic atrophy. A relative afferent pupillary defect in optic neuropathy is often found, and persists after recovery.

b) Brainstem demyelination

Common manifestations of brain stem lesion include diplopia, vertigo, facial numbness/weakness, dysarthria or dysphagia.

Diplopia in MS is produced by many lesions like a sixth nerve lesion and internuclear opthalmoplegia (lesion in medial longitudinal faciculus causing ipsilateral adduction palsy and contralateral abducting eye with Nystagmus). Pyramidal signs in the limbs occur when the corticospinal tracts are involved.

c) Cerebellar lesions

Ataxia is one of the common manifestations of multiple sclerosis. Usually affects gait and coordination of limbs.

d) Spinal cord lesions

Weakness of one or more limbs is a common symptom. Weakness is often associated with spasticity, hyperreflexia, and Babinski signs. Subjective sensory symptoms, especially tingling and numbness are frequent. Impairment of position and joint sense results from a lesion in the posterior columns of the spinal cord.

As a result of the plaque in the posterior columns of the cervical cord, an electric current-like sensation may radiate through the body on flexion of the neck (Lermittes sign). Urinary incontinence is very common manifestation.e) Other symptoms

Fatigue is present in 90% of the patients and is exacerbated by elevated temperature, depression. Elevated temperature can worsen many symptoms of multiple sclerosis.

Other symptoms of multiple sclerosis include sexual dysfunction, cognitive dysfunction.Differential Diagnosis Acute disseminated encephalomyelitis

Antiphospholipid antibody syndrome

Stroke Vasculitis leukodystrophiesINVESTIGATIONS There is no diagnostic test for MS

a) Demonstrate other sites of involvement

Magnetic resonance imaging (MRI) is very sensitive in picking up the lesions of multiple sclerosis. Lesions typical of MS, seen best on T-2 weighted MRI images, are circumscribed or confluent, mainly periventricular plaques, fewer plaques in other locations, and involvement of the corpus callosum.

MRI detects numerous asymptomatic lesions. MRI has provided an important tool for assessment of progression of the disease and therapeutic evaluation. Visual evoked potentials and evoked potentials Evoked responses from visual, auditory and somatosensory stimulation have been useful in the demonstration of clinically silent lesionsb) Demonstrate inflammatory nature of lesion-CSF examination Slight elevation of protein and mild mononuclear cell pleocytosis. Oligoclonal IgG bands (immunoglobulins) are present in most patient but they are not diagnostic of multiple sclerosis.

c) Investigations to exclude other conditions. Chest X-ray

Serum B12

Antinuclear antibodies-SLE

Antiphospholipid antibodies Diagnostic criteria for Multiple sclerosis

1. Examination must reveal objective CNS abnormalities2. Involvement must reflect predominantly disease of white-matter long tracts

3. Examination or history must implicate involvement of 2 areas of CNS (MRI and/or evoked response testing).

4. The clinical pattern must consist of 2 separate episodes of worsening involving different sites of the CNS

5. The patients neurological condition cannot be better attributed to another disease. TREATMENT There is no curative treatment. Treatment of multiple sclerosis includes 3 parts 1. Treatment of acute attacks

2. Treatment with disease-modifying agents that reduce the biological activity of MS i.e. treatment to prevent relapse.3. Symptomatic therapy

1) Treatment of acute attacks

Preferred treatment is IV methylprednisolone succinate, given as an infusion (1 g/day) for 5 to 7 days.

Alternatively, ACTH can be given. They do not influence long-term outcome

2) Treatment to prevent relapse

Beta-interferon (both INF-1b and 1a) and glatiramer acetate given as injections are used in relapsing and remitting disease.

Immunosuppressive agents including azathioprine, Cyclophosphamide, Mitoxantrone have some effect in reducing relapses.

3) Symptomatic treatment

Spasticity - Spasticity can be reduced with diazepam or drugs such as baclofen, dantrolene or tizanidine and physiotherapy. Pain and Dysesthesia can treated with anticonvulsants like carbamazepine , phenytoin or gabapentin. Bladder care is important; for urinary urgency and hesitancy probanthine or oxybutynin are useful.NEUROMYELITIS OPTICA Neuromyelitis optica is believed to be a variant of multiple sclerosis. It is characterized by acute or subacute onset and involvement of both optic nerves and spinal cord but episodes of optic neuritis and myelitis occur separately.

Recovery is usually partial and recurrences are quite rare.

The neuromyelitis optica type of presentation of MS is more common in Japan, India.ACUTE DISSEMINATED ENCEPHALOMYELITIS(Postinfectious encephalomyelitis) Definition Acute disseminated encephalomyelitis (ADEM) is characterised by widespread scattered demyelination of the central nervous system following infections, especially exanthematous fevers or vaccination.Etiopathogenesis

ADEM may follow the administration of smallpox and certain rabies vaccines or measles vaccine. The lesions characteristically surround a vein. there is complete or incomplete destruction of myelin sheaths in the lesions and the axons are relatively better preserved.Clinical features The symptoms usually appear after 7 to 14 days of the febrile illness or vaccination. Onset of clinical features is abrupt, and progression rapid (hours to days) and has monophasic course. Fever reappears, and headache, Meningismus, and lethargy progressing to coma may develop.

Signs of disseminated neurological disease are consistently present. Investigations MRI findings include extensive and relatively symmetric white matter abnormalities and Gd enhancement of all abnormal areas. CSF- protein is modestly elevated and lymphocytic pleocytosis may be present. Oligoclonal bands are uncommon. Diagnosis History of recent vaccination or exanthematous illness and simultaneous onset of disseminated symptoms and signs with monophasic course differentiate ADEM from MS. Treatment Initial treatment is with high-dose glucocorticoids as for exacerbations of MS. Patients who fail to respond may benefit from a course of plasma exchange or intravenous immunoglobulin.