Multiple Sclerosis

DEMYELINATING DISEASES

Dr. BASHAR SHAKER

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 100 000 of the population, with an annual incidence of around 7 per 100 000. 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, indicating that environmental exposure during growth and development are impotant.

Aetiology

The prevalence has also been found to correlate with various environmental factors, such as sunlight exposure, vitamin D and exposure to EBV,although it is unclear exactly how all of these factors interact to cause the disease. An immune mechanism is suggested by increased levels of activated T lymphocytes in the CSF, and increased immunoglobulin synthesis within the central nervous system .

Aetiology

The risk of familial recurrence is 15%, with highest being for first-degree relatives (age-adjusted risk: 4 -5 %for siblings2-3% for parents or offspring) and a monozygotic twin concordance of 30%. The inheritace appears to be polygenic, with influences from the HLA regional, IL-7 R (interleukine -7 receptor ), IL – 2 R (interleukine – 2 receptor),CLEC16A( C- type lectin domain family 16 member A ).

Pathology

An attack of central nervous system inflammation in multiple sclerosis starts with the entry of activated T lymphocytes through the blood-brain barrier. These recognise myelin-derived antigens on the surface of the nervous system's antigen-presenting cells, the microglia, and undergo clonal proliferation. The resulting inflammatory cascade releases cytokines and initiates destruction of the oligodendrocyte-myelin unit by macrophages.

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 .

Pathophysiology

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 efficiency of impulse propagation or causes complete conduction block, which impairs the efficiency of central nervous system functions. Inflammatory mediators released during the acute attack (particularly nitrous oxide) probably also initiate axonal damage, which is a feature of the latter stages of the disease.

Pathophysiology

In established multiple sclerosis there is progressive axonal loss, probably due to direct damage to axonal integrity by the inflammatory mediators released in acute attacks and subsequently the loss of neurotrophic factors from oligodendrocytes. This axonal loss is the cause of the phase of the disease in which there is progressive and persistent disability .

Clinical features

Demyelinating lesions cause symptoms and signs that usually come on subacutely over days or weeks and resolve over weeks or months, although rarely a stroke-like presentation may occur. After a variable interval there may be a recurrence, often within 2 years. Frequent relapses with incomplete recovery indicate a poor prognosis, and in many patients a phase of secondary progression, caused by secondary axonal degeneration, supersedes the phase of relapse and remission. In a minority of patients, there may be an interval of years or even decades between attacks, and in some, particularly if optic neuritis is the initial manifestation, there is no recurrence. Some presentations, such as optic neuritis with purely sensory relapses, have a good prognosis .

Clinical features

The physical signs observed in multiple sclerosis depend on the anatomical site of demyelination. Combinations of spinal cord and brain-stem signs are common, may be with evidence of previous optic neuritis in the form of an afferent pupillary deficit. Significant intellectual impairment is unusual until late in the disease, when loss of frontal functions and impairment of memory are common

Course

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.

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

Optic neuritis

In about 25 percent of all MS patients (and in a larger proportion of children), the initial manifestation is an episode of optic neuritis. Characteristically, over a period of several days, there is partial or total loss of vision in one eye. Many patients, for a day or two before the visual loss, experience pain within the orbit, worsened by eye movement or palpation of the globe. Usually a scotoma involving the macular area and blind spot (cecocentral) can be demonstrated, but a wide variety of other field defects may occur, rarely even hemianopic involvement sometimes homonymous).

Optic neuritis

In some patients, both optic nerves are involved, either simultaneously or, more commonly, within a few days or weeks of one another . Papillitis vs Retrobulbar neuritis About half of patients with optic neuritis recover completely, and most of the remaining ones improve significantly, even those who present initially with profound visual loss and, later, pallor of the optic disc. One-half or more of adult patients who present with optic neuritis will eventually develop other signs of MS.

Relapsing and remitting sensory symptoms

Transient facial hypesthesia or anesthesia Dull aching pain in the low back Sharp, burning, poorly localized, or lancinating-radicular pain, localized to a limb or discrete part of the trunk Paresthesias or numbness of an entire arm or leg

Spinal cord lesionTransverse Myelitis

Symmetrical or asymmetrical paraparesis or paraplegia, ascending paresthesias, loss of deep sensibility in the feet, a sensory level on the trunk, sphincteric dysfunction, and bilateral Babinski signs.

Acute brain-stem syndrome

Diplopia Myokymia or paralysis of facial muscles, Deafness, tinnitus,vertigo Cerebellar signs

Test for visual field defects (confrontation test)

Temporal disc atrophy

Sensory disturbances

Other symptoms and syndromes suggestive of CNS demyelination


INO

Paroxysmal symptoms  (trigeminal neuralgia)

Ataxia &Incoordination

Motor disturbances(central paresis, spasticity,abnormal fatigability)

Central paresis(right hyperreflexia)

Autonomic dysfunctionurinary/fecal incontinence, sexualdysfunction

Behavioral changes

Investigations


There is no specific test for multiple sclerosis, and the results of investigation are taken in conjunction with the clinical picture in making a diagnosis of varying probability. The clinical diagnosis of multiple sclerosis should be supported by investigations to exclude other conditions, provide evidence for an inflammatory disorder and identify multiple sites of neurological involvement



CSF


The cerebrospinal fluid (CSF) is commonly abnormal, with mild lymphocytosis or a slightly increased protein concentration, especially if examined soon after an acute relapse. CSF protein electrophoresis shows the presence of discrete bands in the immunoglobulin G (IgG) region ( oligoclonal bands) in 70 - 90% of patients between attacks. The antigens responsible for these antibodies are not known. Oligoclonal bands are not specicfic to MS but denote intra thecal inflammation.


CSF

Evoked PotentialsEP

If clinical evidence of a lesion exists at only one site in the central nervous system, a diagnosis of multiple sclerosis cannot properly be made unless other regions have been affected subclinically, as detected by the electrocerebral responses evoked by one or more of the following: monocular visual stimulation with a checkerboard pattern (visual evoked potentials - VEP); monaural stimulation with repetitive clicks ( brainstem auditory evoked potentials - BAEP); and electrical stimulation of a peripheral nerve (somatosensory evoked potentials - SSEP).

VEP measurement

VEP

BAEP

SSEP


MRI may also detect subclinical lesions and has become nearly indispensible in confirming the diagnosis


MRI

Other investigations

CXRSerum angiotensin converting enzyme( ACE) SarcoidosisSerum B12Antinuclear Antibodies – SLEAntiphospholipid Antibodies


CSF positive for oligoclonal bandsandDissemination in 'space' and 'time' on MRI and/or abnormal VERor Continued progression for a year
Insidious neurological progression suggestive of MS
MRI demonstration of dissemination in 'space' and 'time' (as above) or Two or more MRI-detected lesions with CSF showing oligoclonal bands and dissemination in time, demonstrated by MRIor Await further (second) clinical attack at different anatomical site
One attack with clinical evidence of only one lesion (clinically isolated syndrome)


Dissemination in 'time', demonstrated by serial MRI scans (looking for a new lesion developing at least 3 months after the inital presentation)or Await further (second) clinical
One attack with objective clinical evidence of two or more lesions in different parts of the CNS (i.e. dissemination in 'space')

MRI demonstrates dissemination in 'space' (multiple lesions in several different sites ) or Two or more MRI-detected lesions consistent with MS and oligoclonal bands in CSFor Await further clinical attack at different anatomical si
Two or more attacks separated in 'time' and 'space', but with objective clinical evidence for only one lesion
None
Two or more attacks separated in 'time' (at least 3 months apart) and 'space' (involving different parts of the CNS) with objective clinical evidence of two or more lesions
Additional evidence required for diagnosis of MS
Clinical presentation

THE MACDONALD CRITERIA FOR THE DIAGNOSIS OF MULTIPLE SCLEROSIS

Management


This involves treatment of the acute episode,prevention of future relapses,treatment of complications and management of the patient disability.

The acute episode

In a function threatening exacerbation of MS pulses of high dose methylprednisolone , either I.V. (1 gm daily for 3 days or orally (500 mg daily for 5 days),shorten the duration of the episode.

The acute episode

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.Prophylaxis to prevent the occurrence of steroid –induced osteoporosis should be considered.

Preventing relapses

Immunosuppressive agents including azathioprine appear to reduce the risk of 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 ; glatiramer acetate has similar effects. Glatiramer is a polymer of 4 aminoacids found inMBP which is thought possibly to act as a decoy for the immune reponse in patients with MS.

Preventing relapses

The most common side effects of interferons are a flu-like syndrome and (in the case of interferon b-1b) injection site reactions. Glatiramer acetate is generally tolerated well, but it may produce erythema at the sites of injection, and about 15% of patients experience transient episodes of flushing, dyspnea, chest tightness, palpitations, and anxiety after injections. All three of these agents are approved for use in relapsing-remitting multiple sclerosis and are available by prescription. They are expensive, but their cost must be balanced against the reduced need for medical care and reduced time lost from work that follows their use.

Preventing relapses

The recently introduced agent natalizumab is probably somewhat more effective than both but is usually preserved for patients with more aggressive disease, along with the less proven therapies as mitoxantrone and cyclophosphamide. Special diets including gluten-free, linoleic acid supplements or hyperbaric oxygen therapy are popular with patients, but are of no proven benefit.

Management

Appropriate treatment of primary or secondary progressive multiple sclerosis is less well established. Recent studies suggest that interferon b-1b (and probably interferon b-1a) are effective in reducing the progression rate as determined clinically and by MRI in secondary progressive disease, but there is only limited experience with glatiramer acetate in this setting. Treatment with cyclophosphamide, azathioprine, methotrexate, cladribine, or mitoxandrone may help to arrest the course of secondary progressive disease, but studies are inconclusive. Pulse therapy with high-dose intravenous methylprednisolone (1 g/d once a month) is also sometimes effective and may carry a lower risk of long-term complications than the cytotoxic drugs.

Early trials in aggressive disease (no proven benefit in RCTs)

Immune suppression (cytotoxic)
Mitoxantrone
Occasionally used in aggressive disease. Not recommended for widespread use (no proven benefit in RCTs)
Immune suppression (cytotoxic)
Cyclophosphamide
Similar efficacy to interferon beta (RCT evidence)
Immune suppression
Azathioprine
Similar efficacy to interferon beta (RCT evidence)
Immune modulation
Glatiramer acetate
In widespread use for reducing relapse rate (RCT evidence)
Immune modulation
Interferon beta
Comment
Mode of action
Treatment


DISEASE-MODIFYING TREATMENTS IN MS

Encouraging experimental results (no proven efficacy in RCTs)

Immune suppression (lymphocyte depletion)
Monoclonal antibodies to lymphocyte epitopes (e.g. campath1-H)
Encouraging experimental results (no proven efficacy in RCTs)
Immune modulation (lymphocyte entry into CNS)
Monoclonal antibodies to beta-integrins (e.g. natalizumab)
Occasionally used in aggressive disease
Immune modulation
Intravenous immunoglobulin
Occasionally used in aggressive disease (no proven efficacy in RCTs)
Immune modulation
Plasmapheresis
Comment
Mode of action
Treatment

DISEASE-MODIFYING TREATMENTS IN MS

Carbamazepine 200-1800 mgGabapentin 900-2400 mgPhenytoin 200-400 mgAmitriptyline 10-100 mg
Dysaesthesia
Isoniazid 600-1200 mgClonazepam 2-8 mg
Ataxia
PhysiotherapyBaclofen 15-100 mg (oral)Intrathecal baclofenTizanidine 18-32 mgLocal (i.m.) injection of botulinum toxinChemical neuronectomy
Spasticity
Treatment
Complication

TREATMENT OF COMPLICATIONS OF MULTIPLE SCLEROSIS

Sildenafil 50-100 mg/24 hours
Impotence
Amantadine 100-300 mg Amitriptyline 10-50 mg Modafinil 100-400 mg
Fatigue

Bladder symptoms

Treatment
Complication

TREATMENT OF COMPLICATIONS OF MULTIPLE SCLEROSIS

Prognosis


The outlook is difficult to predict with confidence in any individual patient, especially early in the disease. Furthermore, the ability to diagnose disease at an earlier stage means that older studies may not reliably reflect the outcome of those diagnosed with modern techniques. 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.

Prognosis

Features that tend to imply a more favorable prognosis include Female sex, Onset before age 40, and Presentation with visual or somatosensory, rather than pyramidal or cerebellar dysfunction.

ACUTE DISSEMINATED ENCEPHALOMYELITIS

This is an acute, usually monophasic, demyelinating condition in which there are areas of perivenous demyelination widely disseminated throughout the brain and spinal cord. The illness may apparently occur spontaneously but often occurs a week or so after a viral infection, especially measles and chickenpox, or following vaccination, suggesting that it is immunologically mediated.

Clinical features

Headache, vomiting, pyrexia, confusion and meningism may be presenting features, often with focal or multifocal brain and spinal cord signs. Seizures or coma may occur. A minority of patients who recover have further episodes.

Investigations

Management


The disease may be fatal in the acute stages but is otherwise self-limiting. Treatment with high-dose intravenous methylprednisolone, using the same regimen as for a relapse of multiple sclerosis, is recommended.

Neuromyelitis optica

The concurrence of transverse myelitis and bilateral optic neuritis in some patients has been recognized in some patients,and these clinical manifestations are more common in MS which occurs in Asia. The majority of these cases are associated with an antibody to water channel,aquaporin 4, which is found in cells near the ventricular system of the brain.

Neuromyelitis optica

Patients typically have brain MRI scans which are either normal or have high signal lesions restricted to the region of the ventricular system.Spinal MRI scans show lesions which are typically longer than 3 spinal segments(unlike the lesions of ms).Clinical deficits tend to recover less well than those of MS,and the disease may be more aggressive with more frequent relapses.Teatment with immunosuppressive agents such as steroids,azathioprine or cyclophosphamide and or plasmapheresis seems to be more effective than in MS.

ACUTE TRANSVERSE MYELITIS

Transverse myelitis is an acute, often monophasic, inflammatory demyelinating disorder affecting the spinal cord over a variable number of segments. Patients may be of any age and present with a subacute paraparesis with a sensory level, often with severe pain in the neck or back at the onset. MRI is needed to distinguish this from a compressive lesion of the spinal cord. CSF examination shows cellular pleocytosis, often with polymorphs at the onset, and oligoclonal bands are usually absent. Treatment is with high-dose intravenous methylprednisolone. The outcome is variable; in some cases, near-complete recovery occurs despite a severe initial deficit. Some patients who present with acute transverse myelitis go on to develop multiple sclerosis in later years.