Multiple sclerosis is the commonest demyelinating disorder and usually presents with recurrent attacks of focal neurological defects involving various parts of the central nervous sysem (optic nerves, spinal cord, brain stem and cerebrum). The attacks occur, remit and recur over a number of years producing a chronic disabling disorder of the central nervous system.
It is an autoimmune disease which begins with an infection of the central nervous system probably by a viral agent and the exposure to this agent occur early in life generally below the age of 15 years. The immune system is stimulated by the viral antigen which produces some degree of inflammatory demyelination.
Destruction of myelin sheath occurs when T cells release cytokines. Besides these genetic and environmental factors are also important in the aetiology of Multiple sclerosis. Blood relatives of Multiple sclerosis patients have fifteen fold increased risk of developing the disease. Among whites certain FILA antigens (HLA-B7, HLA-A3 and DW 2) occur with increased frequency in patients of Multiple sclerosis.
Incidence and prevalence
Multiple sclerosis predominantly affects people in temperate zones. Prevalence is greatest in U.K. Westem Europe, northern United States and Southern Canada. It is rare in Africans and Asians and almost unknown in Polynesian people. There is progressive increase in prevalence of the disease as the person moves away from the equator.
If the person emigrates from an area of high prevalence to one of low prevalence before the age of 15, the risk of developing Multiple sclerosis falls while those who migrate after the age of 15, the risk is similar to that of their country of origin.
Women are more commonly affected than men (Female to male ratio 1.8:1). Average age of onset of the disease is between the ages of 30-50 years though presentation at younger age may occur.
The characteristic picture is the formation of discrete areas of demyclination (Plaque), grey pink sharply defined areas varying in size from 2-10 mm, scattered all over the grey and white matter of the brain and spinal cord.
These typically occur in the paraventricular areas of the cerebrum and within the brain stem and its cerebellar connections, optic nerves and spinal, cord. Brain may show slight atrophy and there may be greyish depressed areas on the surface of pons and spinal cord. The peripheral nerves are not affected.
Many plaques may remain silent. Remyelination occurs rarely and if it does occur it is limited (shadow plaques).
Multiple sclerosis is heterogeneous in its clinical presentation and no single sign or symptom is diagnostic. The most common mode of onset is parasthesia and numbness which spreads and evolve over three to four days accompanied by tiredness and fatigue. Often the first attack is so mild that it may escape notice. Second attack may not appear for another 10-15 years.
But when attack occurs, symptoms get worse over a period of days to weeks and then remit. Remission may be complete initially but subsequently attacks follow with increasing frequency leading to progressive neurological deficit.
A second attack may occur after several years. Most attacks occur without any precipitating factor though there is increased risk for an attack following viral infection, injury arid even emotional upsets.
Common presentation of Multiple sclerosis include optic neuropathy and neurologic dysfunction arising from brainstem, cerebeilar and spinal cord lesions.
Episodes of optic neuropathy is the commonest mode of presentation. Patient presents with blurring or loss of vision in one eye usually associated with pain on movement of eye. There are disturbances of color perception and a wide range of field defects. There is evidence of inflamed optic nerve (papihitis) and when the lesion develops in the optic nerve head, optic neuritis results.
In cases where demyelination is developing some distance behind the nerve head, retrobulbar neuritis develops. There are usually no residual symptoms following an attack of optic neuritis but one third patients may develop optic atrophy.
Brain stem demyelinition produces diplopia because of 3rd, 4th or sixth cranial nerve pathways involvement or due to intranuclear opthalmoplegia. Vertigo, vomiting, nystagmus and facial hypesthesia are other features. Less commonly there is complaint of deafness. Involvement of cerebellum and its connections produces ataxia and scanning speech.
Lesions of spinal cord produce a number of symptoms ranging from spastic parapresis (upper motor neuron dysfunction) loss of joint position, vibration sense (Post column lesion) to diminution of pain and temperature sensations (spino thalamic tract involvement).
Symptoms of bladder dysfunction (Hesistancy, uigency, frequency and incontinence) are common as well as bowel dysfunction (Constipation).
Other feature include tonic spasms of the limbs, trigeminal neuralgia, epilepsy and an electric shock like sensation on flexon of the neck (hermitte’s sign). Depression, psendobulbar palsy and dementia are other manifestations.
Course of the Multiple sclerosis
It is unpredictable. On the basis of its natural course, Multiple sclerosis has been grouped into 4 subtypes.
(a) Relapse remit-tent type: Between 80-90% of patients have initial relapsing remitting course. A relapse is defined as an episode of neurological impairment lasting more than 24 hours. The relapse rate is an average of 0.1 to 1.0 episode per year. In this group there are clear relapses followed by periods of full recovery or recovery with sequale. There is no progress of disease between two relapses.
(b) Progressive relapsing type. Half of patients with relapsing-remitting course develop progressive disease with or without recovery. Between the two relapses there is continued progression of the disease leading to decline in neurological function over a period ranging from 10-25 years.
(c) Secondary progressive. Here the initial part of the disease course follows the relapse remitting pattern and most common presentation is progressive parapresis due to spinal cord involvement.
(d) Primary progressive. About 10 per cent of patients have a primary progressive course in which there are no relapses but a gradual decline. There are no real remissions and patient follows a down hill course. This most likely occurs in patients of multiple sclerosis who present in middle age.
It is difficult to say as to what will happen to a case of Multiple sclerosis. About 30 per cent of patient have a benign course in which progression does not occur or appears late. Of those with progressive symptoms, 50 per cent are disabled after 10 years. Rarely Multiple sclerosis may be fulminant and prove fatal within short periods ranging from weeks to months.
Diagnosis of Multiple sclerosis is based on clinical presentation and laboratory aids.
1. CSF shows slight rise in protein content with little or no rise in cell count. There is increase in IgG immunoglobulins and this increase is greatest in long standing cases with severe neurological deficit. Oligo clonal IgO bands can be demonstrated in over 90% of patients. During acute attack of disease myelin debris as well as myelin basic protein can be found in CSE
2. Electrophysiological tests: Conduction of nerve impulses is slowed. There is delay in visual evoked responses (VER) in patients with optic neuropathy. Besides this somatosensory evoked potential, brain stem auditory evoked potential and central motor conduction time are helpful in detecting clinically silent cases.
3. Imaging computed tomography (CT) may reveal low density lesions within white matter usually in paraventricular or subcortical regions. Cortical atrophy with enlarged ventricles may be found in some patiens with chronic disease. MRI is the most sensitive test to detect Multiple sclerosis and is superior to CT. Multifocal lesions are seen best on T-2 weighted MRI images. I.V. administration of gadolinium DTPA can enhance detection of active lesions. Proton weighted images can demonstrate brain stem and cerebellar lesions better. Serial studies on MRI have shown progress of the disease.
A case of M.S. has a bizarre presentation and can mimic a number of disorder such as lupus, Behcets disease and other connective tissue disorders, Fluctuating course of the disease may have to be differentiated from spino cerebellar ataxias, Tuberculosis and neurosyphilis. Vascular lesions, tumours and other compression lesions of the spinal cord are also to be considered in differential diagnosis. But diagnosis of Multiple sclerosis is mainly clinical though CSF. Examination (oligoclonal bands, Rise in IgG) evoked potentials and MRI are the mainstay in making the diagnosis.
Management of Multiple sclerosis
It primarily consists of drugs and supportive treatment.
There is no effective treatment for Multiple sclerosis. For an acute attack or relapse glucocorticoids are the most commonly used therapeutic agent. Dose is I/V methylprednisolone acetate (500-1000 mg/day) for 5 days.
The drug is given in 100 ml of normal saline over an hour, A five day course is followed by 15 to 30 day period of 60 mg prednisolone daily. This is tapered off over a period of 15 to 30 days. AternativelyACTfl can be given (80 units I/M) daily over 2 to 3 weeks.
Immunosuppressive agents (Azathioprine, Cyclophosphamide) have been employed to reduce the number of relapses. Other drugs of benefit are interferons, copolymer I and methotrexate.
Interferon interferes with and inhibits subsequent viral replication. These are disease modifying agents and are of use in some relapsing remitting patients.
Interferone Beta I-B is administered subcutaneously every other day in the dosage of 1.6- 8 million / 1 units for 3 years. Flu-like symptoms, injection site reactions and lymphopenia are the side effects of the drug. Interferon beta-I-alpha is given intramuscularly 6 million I units in a weekly dose.
There is significant decrease in exaceberation frequency and godlonium enhaning lesions in the MRI. Adverse reactions include flu like symptoms and mild anaemia. Copolymer-I is again effective in relapsing remitting type.
Dose is 20 mg daily given subcutaneously for 2 years. This treatment has no effect on progressive multiple sclerosis. Methotrexate in dose of 7.5 mg orally weekly is also tried in chronic progressive disease, Benefit occurs within 6 months and may be sustained for 2 years.
Symptomatic treatment consists of use of muscle relaxants (baclofen, dantrolene and diazepam) for reducing pain and discomfort of spasticity when there are flexor spasms.
Bladder dysfunction is managed by use of intermittent self catheterization. For hesitancy probanthine is useful. For mood disorders (Anxiety / Depression) transquilizers and anti-depressants are indicated.
In short a case of multiple sclerosis shall require approach on all fronts.
Prognosis of Multiple sclerosis
It is unpredictable. Factors associated with favourable prognosis include young age of onset of the disease, rapid resolution of first attack and long duration between first and second attacks. Presentation with sensory symptoms or optic neuritis carries good prognosis.
Prognosis is poor in patients who have incomplete recovery from attacks, have high frequency of early relapse and go into a progressive disease course. Female sufferers from Multiple sclerosis have good prognosis as compared to men.