MULTIPLE SCLEROSIS (MS)
MS is a chronic inflammatory disorder of the CNS. There are multiple plaques of
demyelination within the brain and spinal cord. Plaques are disseminated both in time
and place.
Prevalence
Varies widely, being directly proportional to distance of residence from the equator.
At latitudes of 50-65° N prevalence is 60-100 per 100 000; at latitudes less than 30° N
prevalence is below 10 per 100 000. At the equator MS is a rarity. Dietary factors, e.g.
high animal fat consumption, have been suggested for this geographical distribution
but there is little evidence for this. In the southern hemisphere this trend is similar -
increasing prevalence with distance from the equator. In Europe and North America
MS is a common neurological disease of young adults.
Etiology and pathogenesis
Although the precise mechanism is unknown, there is an inflammatory process in
the white matter of the brain and cord mediated by CD4 T cells. In active lesions
(plaques) there is an increase in inflammatory cells, active myelin degradation and
phagocytosis. The integrin is a regulator of immune cell activation.
Antibody-mediated demyelination, probably develops early in MS.
Familial incidence, HLA linkage and migration
First-degree relatives of a patient have an increased chance of developing MS,
without a clear-cut pattern of inheritance. The concordance rate is 31% in
monozygotic twins.
In Caucasians in northern Europe and the USA, there is a weak association
between MS and antigens HLA-A3, B7, D2 and DR2.
Immigrants from low to high prevalence zones (e.g. from the equator to
northern Europe) acquire the prevalence of their destination, provided they
arrive before the age of 10, irrespective of racial origin.
Infection: No known links exist between MS and any infection. However,
Increased titres of serum and CSF antibodies to many common viruses, particularly
measles were noticed. Chlamydia has been questioned as a cause.
Pathology
Plaques of demyelination, initially 2-10 mm in size, are the cardinal features.
Plaques are perivenular with a predilection for distinct CNS sites: optic nerves, the
periventricular region, the brainstem and its cerebellar connections and the cervical
cord (corticospinal tracts and posterior columns).
Acute relapses are caused by focal inflammatory demyelination, which causes
conduction block. Remission follows as inflammation subsides and remyelination
occurs, helping recovery. When damage is severe, secondary permanent axonal
destruction occurs. In the cord, plaques rarely destroy large groups of anterior horn
cells, thus focal muscle wasting (e.g. small hand muscles) is unusual. Plaques are not
seen in myelin sheaths of peripheral nerves.
Clinical features
The commonest age of onset is between 20 and 45 years; diagnosis before puberty
or after 60 is rare. MS is more common in women. No single group of signs or
symptoms is diagnostic.
MS is often recognizable clinically by different patterns:
Relapsing and remitting MS (80-90%)
Primary progressive MS (10-20%)
secondary progressive MS - this follows on from relapsing/remitting disease
Occasionally (<10%) MS runs a fulminating course over some months
(fulminant MS).
Three characteristic common presentations of relapsing and remitting MS are
optic neuropathy, brainstem demyelination and spinal cord lesions.
Optic neuropathy (ON)
Blurring of vision in one eye to severe unilateral visual loss develops over hours or
days, but rarely complete blindness. Mild ocular pain is usual. Recovery occurs,
typically within 2 months. Bilateral ON can occur.
The optic disc appearance depends upon the site of the plaque within the optic
nerve. When the lesion is in the nerve head there is disc swelling (optic neuritis). If
the lesion is behind the disc there are no abnormalities. This is retrobulbar neuritis.
Worsening of vision in ON during a fever, hot weather or after exercise is known as
Uthoff's phenomenon - central conduction is slowed by an increase in body
temperature.
Disc swelling from optic neuritis causes early visual acuity loss, thus distinguishing it
from disc swelling from raised intracranial pressure.
A relative afferent pupillary defect is often found, and persists after recovery.
Late sequelae of optic neuropathy
There is often no residual loss of vision, but small scotomata and defects in colour
vision can be found. Following optic neuropathy, disc pallor can develop (optic
atrophy), first on the temporal side. Visual evoked responses (VER) remain abnormal
Brainstem demyelination
This causes combinations of diplopia, vertigo, facial numbness/weakness, dysarthria
or dysphagia. Pyramidal signs in the limbs occur when the corticospinal tracts are
involved. A typical picture is sudden diplopia, and vertigo with nystagmus, but
without tinnitus or deafness. This lasts for some weeks before recovery. Diplopia is
produced by many lesions - a 6th nerve lesion and internuclear ophthalmoplegia
(INO) are examples.
Spinal cord lesions
Spastic paraparesis developing over days or weeks is a typical result of a plaque in the
cervical or thoracic cord, causing difficulty in walking and lowers limb numbness.
Lhermitte's sign may be present. Urinary symptoms are common.
Unusual presentations
Epilepsy and trigeminal neuralgia are more commonly in MS than in the general
population. Tonic spasms (brief spasms of one limb) are other unusual presentations.
Organic psychosis is occasionally seen in early MS.
End-stage multiple sclerosis
Severe disability with spastic tetraparesis
Ataxia, optic atrophy, nystagmus
brainstem signs (e.g. bilateral INO), pseudobulbar palsy
Urinary incontinence.
Dementia is common.
Death follows from uraemia and/or bronchopneumonia.
Differential diagnosis and course
Few other neurological diseases have a similar relapsing and remitting
course. Thromboembolism typically causes events with more sudden onset.
Other degenerative conditions, such as Friedreich's ataxia, are gradually
progressive.
Following an isolated neurological event that is possible MS, it is often unclear, even
with MR imaging, whether or not MS is the cause. The pattern and imaging
appearance of subsequent lesions establishes the diagnosis. Remissions length is
unpredictable and the mechanism of relapse and remission unknown. Infection
sometimes appears to provoke a relapse. Trauma as a cause has no evidence.
Individual plaques (e.g. in optic nerve, brainstem or cord) must be distinguished
from mass, vascular or other inflammatory lesions. Of the latter, CNS sarcoidosis,
SLE and Behçet's syndrome may mimic relapsing MS. Adrenoleukodystrophy can
cause a progressive paraparesis identical to chronic progressive MS.
Investigations
1. MRI of brain and cord is the definitive structural investigation. And shows
lesions in 85% cases with clinical M.S
the periventricular region
corpus callosum
cerebellar peduncles
juxtacortical posterior fossa
Brainstem and cervical cord. Lesions are elliptical in shape with discrete
borders and lack of a mass effect. Typical lesions are multifocal (2 mm to 2
cm), with 10 or more lesions. Gadolinium can enhance active lesions. Plaques
are rarely visible on CT.
2. CSF examination is often unnecessary with suggestive MR imaging and a
compatible clinical picture. CSF analysis shows oligoclonal IgG bands in 80%
of cases but these are not specific. The CSF cell count may be raised (5-60
mononuclear cells/mm3).
3. Evoked responses. Evoked potentials become delayed when these pathways
have been damaged. Peripheral nerve studies are normal and EEGs unhelpful.
4. Blood/urine tests are unhelpful.
Management and prognosis
The course of MS is unpredictable.
Many forms of treatment have been marketed, None has been shown to improve
outcome.
Acute relapses. Short courses of steroids, such as i.v. methylprednisolone 1
g/day for 3 days or high-dose oral steroids, may reduce severity. They do not
influence long-term outcome.
Preventing relapse and disability. Beta-interferon (both INF-β1/b & a) is used
in relapsing and remitting disease. This is defined as at least two attacks of
neurological dysfunction over the previous 2 or 3 years followed by a
reasonable recovery. IFN-β1b is used for secondary progressive MS.
Interferon certainly reduces relapse rate in some patients and prevents an
increase in lesions seen on MRI. Unwanted effects are flu-like symptoms and
irritation at injection sites.
Immunosuppressants and antineoplastic drugs (azathioprine,
cyclophosphamide, Mitoxantrone and others) .
Glatiramer acetate, an immunomodulator, reduces relapse frequency in
ambulatory patients with relapsing remitting MS - similar to beta-interferon.
Natalizumab is a monoclonal antibody which inhibits migration of leucocytes
into the central nervous system by inhibitory α-4 integrins found on the
surface of lymphocytes and monocytes. It is useful in severe, relapsing
remitting MS that is unresponsive to other treatments. It is associated with a
risk of progressive multifocal leucoencephalopathy (PML) and all patients
need close surveillance for this and hypersensitivity reactions.
The rehabilitative approach in MS
All infections should be treated. Urinary infection frequently exacerbates symptoms.
Urinary incontinence may be helped by oxybutinin and/or intermittent self-
catheterization.
Physiotherapy is of particular value in reducing pain and discomfort of spasticity,
particularly lower limb flexor spasms. Muscle relaxants (e.g. Baclofen,
Benzodiazepines, Dantrolene and Tizanidine) are sometimes helpful. Injected
botulinum toxin is used for severe spasticity. Cannabis is used by many patients for
painful spasms. Cannabis extracts and synthetic cannabinoids are also used.
Prevention of pressure sores is vital. Amantadine is sometimes used for general
fatigue.
