MULTIPLE SCLEROSIS AND ALLIED DEMYELINATIVE DISEASESDr. OronceNeurology

DEMYELINATIVE DISEASES

PATHOLOGIC CRITERIA: Destruction of the myelin sheaths of

nerve fibers Relative sparing of the other elements

of nervous tissue, i.e., of axis cylinders, nerve cells, and supporting structures

Infiltration of inflammatory cells in a periventricular distribution

Particular distribution of lesions, often perivenous and primarily in white matter, either in multiple small disseminated foci or in larger foci spreading from one or more centers

Relative lack of wallerian degeneration or secondary degeneration of fiber tracts

CLASSIFICATION:I. Multiple sclerosis (disseminated sclerosis)o Chronic relapsing encephalomyelitiso Acute multiple sclerosiso Diffuse sclerosis of Schilder and

concentric sclerosis of Balo II. Neuromyelitis optica (Devic)III. Acute disseminated encephalomyelitis

o Post-infectious: chickenpox, smallpox, mumps, rubella, influenza; viral and bacterial infections

o Post-vaccinal: rabies or smallpoxIV. Acute and subacute necrotizing hemorrhagic encephalitiso Acute hemorrhagic

leukoencephalopathyo Subacute necrotic myelopathy

MULTIPLE SCLEROSIS Among the most venerable of

neurologic diseases and one of the most important by virtue of its frequency, chronicity and tendency to attack young adults

Episodes of focal disorder of the optic nerves, spinal cord and brain which remit to a varying extent and recur over a period of many years

Classic features: motor weakness, paraparesis, paresthesias, impaired vision, diplopia, nystagmus, intention tremor, ataxia, impairment of deep sensation, and bladder dysfunction

Long period of latency (1 to 10 years) between a minor initial symptom

In most cases, the initial manifestations improve partially or completely, to be followed after a variable interval by the recurrence of the same abnormalities or the appearance of new ones in other parts of the nervous system

In as many as 50% of patients, intermittently progressive or sometimes, steadily progressive

Diagnosis of MS is not secure unless there is a history of remission and relapse and evidence on examination of more than one discrete lesion of the CNS

PATHOLOGIC FINDINGS: Lesions (plaques) affect principally

the white matter of the brain and spinal cord and do not extend beyond the root zones of the cranial and spinal nerves

Periventricular location: adjacent to the bodies and atria of the lateral ventricles

Other favored sites: optic nerves and chiasm, spinal cord

Lesions destroy myelin sheaths but leave the nerve cells essentially intact

Recent lesions show a partial or complete destruction and loss of myelin

Variable but slight degeneration of oligodendroglia, a neuroglial (astrocytic) reaction, and perivascular and para-adventitial infiltration with mononuclear cells and lymphocytes

Macrophages infiltrate the lesions, and astrocytes in and around the lesions increase in number and size

Long-standing lesions are composed of thickly matted, relatively acellular fibroglial tissue,

Page 1 of 10

with only occasional perivascular lymphocytes and macrophages

In old lesions with interruption of axons, there may be descending and ascending degeneration of long fiber tracts in the spinal cord

Exceptionally, a few of the older lesions undergo cavitation, indicating that not only myelin and axons have been affected but also supporting tissues and blood vessels as well

ETIOLOGY AND EPIDEMIOLOGY: 15% of MS patients have an

affected relative, with the highest risk of concurrence (5%) observed in the patient’s siblings

34% (monozygotic twins); 4% (dizygotic twins)

Certain histocompatibility antigens (HLAs) more frequent in patients with MS: DR locus on the 6th chromosome, HLA-DR2,-DR3,-B7,-A3 (markers for an MS susceptibility gene)

Two to three times higher in women; incidence in children: 0.3 to 0.4%; age of onset between 20-40 years old

Greater among rural than urban dwellers, in the higher socioeconomic groups

PATHOGENESIS:1. Viral Infection

Alterations in humoral and cell-mediated immunity to viral agents though no virus has been isolated from tissues of patients with MS

Chlamydia pneumoniae and herpes virus 6 have been implicated but their participation in the disease is no more compelling than that for any other infectious agent

Some secondary factor after the viral or other infection must be operative

This secondary mechanism is an autoimmune reaction, attacking some components of myelin and destroying tissue elements, including axons

Different viruses (rubeola, rubella and varicella) could cause autoimmunization of T-

lymphocytes against myelin basic protein (MBP)

This means that the T-lymphocyte recognizes an identical structure in the virus and myelin sheath

Molecular mimicry (a shared antigen between the virus and CNS myelin or the oligodendrocyte) has been invoked as a mechanism

2. Humoral Factors The presence in the CSF of

oligoclonal immune proteins, which are produced by B-lymphocytes within the CNS

Damage the myelin, inhibit remyelination and block axonal conduction

Antibodies to oligodendrocytes are present in the serum of up to 90% in patients

3. Cellular Factors T-lymphocytes which regulate

humoral immune responses are found in abundance within MS plaques

They are either potentiators (T-helper cells) or inhibitors (T-suppressor cells) of immunoglobulin production by the B-lymphocytes

T-cell receptors respond to antigens presented by major histocompatibility complex, or MHC class II molecules and macrophages and astrocytes

Such interaction is thought to stimulate T-cell proliferation and the secretion of cytokines

Breakdown of the blood-brain barrier, destruction of oligodendrocytes and myelin

A reduction in T-cells, both helper and suppressor subsets, or an increase in helper-suppressor rations, appears to be associated with increasing disability in patients with MS

MS as a T-cell-mediated disease is supported by evidence that T-cells initiate the lesions of experimental allergic encephalomyelitis

Intense T-cell stimulation is in itself sufficient to induce demyelination

Page 2 of 10

Still, the immune mechanisms that are operative in the genesis of MS cannot as yet be specified

PHYSIOLOGIC EFFECTS OF DEMYELINATION

Impedes saltatory electrical conduction from one node of Ranvier, where sodium channels are concentrated, to the next node

Resulting failure of electrical transmission underlies most of the abnormalities of function from demyelinating disease of both central and peripheral nerve fibers

Extreme sensitivity of conduction in demyelinated nerve fibers to elevated temperature (temporary reduction of symptoms by heat or exercise)

Hyperventilation slows conduction of the visual evoked potential; smoking, fatigue are all capable of briefly worsening neurologic functioning and are easily confused with relapses of MS

PRECIPITATING FACTORS: Most common are infection,

trauma and pregnancy; however, none has been convincingly related to an increased risk of new attacks of MS

Respiratory or gastrointestinal viral infections that precede the onset of exacerbations of MS varies from 5-50%

Endogenous infections (labial or genital herpes) have regularly preceded an attack of MS

No significant correlation between traumatic episodes and exacerbation of MS

CLINICAL MANIFESTATIONS: Fatigue, lack of energy, weight loss

and vague muscle and joint pains before the onset of neurologic symptoms

20%: neurologic symptoms fully developed in a matter of hours

30%: symptoms evolve more slowly (a day or more); another 30%: weeks to months; 10%: insidious onset and slow, steady or

intermittent progression over months and years

Relapsing-remitting pattern appears in patients less than 40 years old

Early Symptoms and Signs:o Weakness or numbness is the

initial symptom in 50%o Tingling of the extremities,

tight band-like sensations around the trunk or limbs commonly associated

o Dragging or poor control of one or both legs; spastic or ataxic paraparesis

o Tendon reflexes become hyperactive; abdominal reflexes disappear

o Variable degrees of deep and superficial sensory loss

o Symptoms in one leg but with signs in both: adage in patients with MS

o Weakness, incoordination, or numbness or tingling in one leg but with bilateral Babinski signs

o Lhermitte sign: tingling, electric-like feeling down the shoulders, back and anterior thighs on passive flexion of the neck (increased sensitivity of demyelinated axons to the stretch or pressure on the spinal cord)

o Dull, aching low back pain; sharp burning, poorly localized, or lancinating-radicular pain in a limb or trunk

o Cerebellar ataxia and brainstem symptoms (vertigo, facial pain, numbness, dysarthria, diplopia, disorders of micturition)

Optic Neuritis:o Initial manifestation in about

25% of all MS patientso Partial or total loss of vision in

one eye; pain within the orbit, worsened by eye movement or palpation of the globe

o Scotoma involving the macular area and blind spot (cecocentral) or other field defects

Page 3 of 10

o Evidence of swelling or edema of the optic nerve head (papillitis) in about half the patients

o Papillitis:severe and acute visual loss

o About 2/3 of patients with optic neuritis recover completely; improvement begins within 2 weeks of onset, perhaps sooner with corticosteroid treatment

o 50% or more of adult patients with optic neuritis will eventually develop other signs of MS (74% in women, 34% in men by the 15th year after the optic neuritis)

o Most do so within 5 years of the original attack

o Uveitis and sheathing of the retinal veins are other disorders that have a higher than expected incidence in patients with MS

Acute Myelitis (Transverse Myelitis)o In MS, the spinal cord signs are

asymmetrical and incomplete and involve only the long ascending and descending tracts

o Rapidly evolving paraparesis, symmetrical or asymmetrical paraparesis, a sensory level on the trunk, sphincteric dysfunction, and bilateral Babinski signs

o 1/3 of patients report an infectious illness in the weeks preceding the onset of neurologic symptoms (monophasic postinfectious demyelinating disease)

Other Patterns of MS:o Unsteadiness in walking,

brainstem symptoms (diplopia, vertigo, vomiting), paresthesias or numbness of an arm or leg, facial pain, disorders of micturition

o Slowly progressive cervical myelopathy with weakness and ataxia: in elderly women

o Nystagmus and ataxia with or without weakness and spasticity of the limbs

o Cerebellar ataxia: scanning speech, rhythmic instability of the head and trunk, intention tremor of the arms and legs, incoordination of voluntary movements and gait

o Charcot’s triad: nystagmus, scanning speech, intention tremors

o Diplopia: internuclear ophthalmoplegia (involves the medial longitudinal fasciculus); paresis of the medial rectus on attempted lateral gaze with a coarse nystagmus in the abducting eye

o Bilateral internuclear ophthalmoplegia in a young adult virtually diagnostic of MS

o Myokymia or paralysis of facial mucles, deafness, tinnitus

o Transient facial hypesthesia or anesthesia or of trigeminal neuralgia in a young adult should suggest the diagnosis of MS

Established Stage of the Disease:o 50%: mixed or generalized

type (involves optic nerves, brainstem, cerebellum, and spinal cord)

o 30 to 40%: spinal form (spastic ataxia and deep sensory changes in the extremities)

o 5%: cerebellar or pontocerebellar form

o Symptoms of bladder dysfunction (hesitancy, urgency, frequency and incontinence) occur commonly with spinal cord involvement; in males, often associated with impotence

o Abrupt attacks of neurologic deficits (few seconds or minutes) many times daily are well-recognized features of MS

o The attacks occur during the relapsing and remitting phase of the illness

Page 4 of 10

o Consists of dysarthria and ataxia, paroxysmal pain, dysesthesia in a limb, flashing lights, paroxysmal itching or tonic seizures

o Attributed to ephaptic transmission (“cross-talk”) between adjacent demyelinated axons within a lesion

o Severe fatigue, often transient, is more likely to occur in febrile states or with evidence of disease activity

o Typical tic douloureux in young patients; bibrachial, thoracic or lumbosacral pain (thermal and algesic dysesthesias)

o 3% have focal seizures; coma during relapse

o Confusional psychosis with drowsiness; slow intellectual decline with slight cerebellar ataxia

o Rapid onset of ascending paralysis of legs, bladder and bowel and trunk with severe pain in sacral parts and areflexia

VARIANTS OF MS:1. Acute Multiple Sclerosis:

o Combination of cerebral, brainstem, and spinal manifestations

o Few weeks: stupor, coma, or decerebrate posturing with prominent cranial nerve and corticospinal abnormalities

o Has typical of the acute plaques of MS, however, many plaques are of the same age and the confluence of many perivenous demyelination is more obvious

o Main consideration in differential diagnosis is a CNS vasculitis

2. Neuromyeltis Opticao Devic Disease; Necrotic

Myelopathyo Simultaneous or successive

involvement of optic nerves and spinal cord

o An acute to subacute onset of blindness in one or both eyes, preceded or followed by a transverse or ascending myelitis

o Spinal cord lesions often necrotizing rather than purely demyelinative

o Stands apart from MS: failure to develop brainstem, cerebellum or cerebral demyelinative lesions and normal MRI of the cerebral white matter

o Stands apart from MS: almost uniform absence of oligoclonal bands and other abnormalities of IgG in the spinal fluid; necrotizing and cavitary nature of the spinal cord lesion, affecting white and gray matter alike, with prominent thickening of vessels but without inflammatory infiltrates

o Differential diagnosis: arteriovenous malformation and infarction of the cord

o Treatment has been largely unsuccessful despite aggressive therapy with corticosteroids and cyclophosphamide

3. Diffuse Cerebral Sclerosis of Schildero Schilder Disease; Encephalitis

Periaxialis Diffusao Cerebrum is the site of

massive demyelination occurring in multiple foci or as a single large focus

o More frequent in childhood and adolescence

o Case report of a 14-year-old girl with progressive mental deterioration and signs of increased intracranial pressure, that terminated fatally in 19 weeks

o Nonfamilial; runs a progressive course. either steady and unremitting or punctuated by a series of episodes of rapid worsening

Page 5 of 10

o Dementia, homonymous hemianopia, cerebral blindness and deafness, varying degrees of hemiplegia, and pseudobulbar palsy

o CSF without oligoclonal bands; instead, large quantities of myelin basic protein in the CSF

o Large, sharply outlined, asymmetrical focus of myelin destruction often involving an entire lobe or cerebral hemisphere

o Concentric sclerosis of Balo: variant of Schilder disease; resembles in its clinical aspects and the overall distribution of lesions

4. Concentric Sclerosis of Balo:o Distinguishing feature:

alternating bands of destruction and preservation of myelin in a series of concentric rings

5. MS in Conjunction with Peripheral Neuropathyo Polyneuropathy or

mononeuropathy multiplexo An autoimmune

demyelination incited in both spinal cord and peripheral nerve

o Takes the form of a chronic inflammatory paolyradiculoneuropathy (CIDP)

LABORATORY FINDINGS:1. Cerebrospinal Fluid:

o With acute onset or exacerbation, moderate mononuclear pleocytosis

o Increased CSF proteino Increased CSF gamma

globulin (IgG): > 12% of the total protein

o Presence of oligoclonal bands (abnormal discrete populations of gamma globulin)

o Presence of oligoclonal bands in a first attack of MS is

predictive of chronic relapsing MS

o Myelin Basic Protein (MBP): increased during acute exacerbations of MS, normal in slowly progressive MS and during remissions

2. MRI in MS:o Most helpful ancillary

examination in the diagnosis of MS (ability to reveal asymptomatic plaques in cerebrum, brainstem, optic nerves, and spinal cord)

o MS plaques are hypointense (white) on T2-weighted images and more strikingly obvious on FLAIR images

o T2 weighted image: several asymmetrical, well-demarcated lesions immediately adjacent to the ventricular surface

o Diagnostic: oval or linear regions of demyelination, oriented perpendicular to the ventricular surface and corresponding to the radially oriented fiber bundles of the white matter and periventricular veins

3. Evoked Potentials and Other Tests:o Abnormal visual evoked

responses in 70% of patients with the clinical features of

Page 6 of 10

definite MS and in 60% with probable or possible MS

o Somatosensory evoked responses: 69% (definite MS); 51% (probable or possible MS)

o Brainstem auditory evoked responses: 47% (definite MS); 20% (possible or probable MS)

o CT scan may also demonstrate cerebral lesions; acute plaques may simulate abscess or tumor and some contrast-enhanced periventricular lesions become radiologically inevident after steroid treatment

CLINICAL COURSE AND PROGNOSIS: Some patients will have a complete

clinical remission after the initial attack, or rarely, a series of exacerbations each with complete remission

Relapse rate: 0.3 to 0.4 attacks/year; interval between the opening symptom and the first relapse is highly variable: 1, 2, 5-9, 10-30 years

After a number of years, there is an increasing tendency for the patient to enter a phase of slow, steady or fluctuating deterioration of neurologic function

In about 10% of cases, the clinical course is almost evenly progressive from the beginning.

Pregnancy does not have an adverse effect on MS; typically associated with clinical stability or even with improvement

There appears to be an increased risk of exacerbation in the first few months postpartum

Duration of the disease varies; may survive up to 25 years (average duration of the disease is in excess of 30 years)

TREATMENT:Corticosteroids:

On the basis of clinical trials, only adrenocorticotropic hormone (ACTH), methylprednisolone, prednisone, cyclophosphamide and beta-interferon have proved to have

a beneficial effect on the disease and on MRI lesions

IV administration of massive doses of methyprednisolone: bolus of 500-1000 mg/day for 3-5 days

Then, prednisone 60-80 mg/day, tapering the dosage over a 12-day period: generally effective in aborting or shortening an acute or subacute exacerbation of MS or of optic neuritis

If impractical to use parenteral methylprednisolone, may substitute oral: 48 mg/day for 1 week, followed by 24 mg/day for 1 week, then, 12 mg/day for 1 week

Alternate-day steroid treatment offers little benefit

Pulses of high-dose intravenous steroids administered once each month seem to keep some patients from having relapses and are better tolerated than the continuous administration of oral medications

TREATMENT OF OPTIC NEURITIS Intravenous methylprednisolone

followed by oral prednisone speeds the recovery from visual loss

Although at 6 months interval, there is little difference between patients treated in this way and those treated with placebo

Methylprednisolone 500 mg orally for 5 days has beneficial effect on visual functions at 1 and 3 weeks; at 8 weeks, no effect could be shown

Interferon Beta and Copolymer 1: For relapsing-remitting MS Interferon beta-1b (Betaseron):

subcutaneous injection every second day for up to 5 years; decreases the frequency and severity of relapses and the number of new or enlarging MRI lesions

Treatment with interferon beta-1a (Avonex) equally effective: 6.6 million units, intramuscular, once a week

Copolymer 1 (mimics the action of MBP): 20 mg/day, subcutaneous

Side effects: flu-like symptoms, sweating and malaise

Page 7 of 10

Immunosuppressive Drugs: Agents that modify immune

reactivity with limited success Azathioprine, cyclophosphamide,

total lymphoid irradiation seem to have improved the clinical course

Burdensome and potentially serious toxicity – risk of neoplastic change

Other Therapies: No valid studies for the value of

synthetic polypeptides, hyperbaric oxygen, low-fat and gluten-free diets, linoleate supplementation of the diet

Plasma exchange and immunoglobulin in fulminant cases: monthly infusions of IVIG (0.2 g/kg) for 2 years

General Measures: Adequate bed rest, prevention of

excessive fatigue and infection, rehabilitative measures to postpone the bedridden stage

Fatigue during acute attacks: Amantadine 100 mg morning and noon; pemoline 20-75 mg

In urinary retention: bethanecol chloride; intermittent catheterization

Urinary urgency and frequency (spastic bladder): propantheline or oxybutynin may relax the detrusor muscle

Constipation: laxatives, properly spaced enemas

With spastic paralysis and painful flexor spasms of the legs: intrathecal infusion of baclofen

Selective injection of botulinum toxin into the most hypertonic muscles

For severe and disabling tremor: isoniazid 300 to 1200 mg/day plus pyridoxine 100 mg/day; carbamazepine, clonazepam

Enlist the support of physical and occupational therapists, visiting nurses and social workers

ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM)Postinfectious, Postexanthem, Postvaccinal Encephalomyelitis

Represents an acute demyelinative disease, distinguished pathologically by numerous foci of demyelination scattered throughout the brain and spinal cord

Perivenular inflammatory reaction; perivascular spaces are infiltrated with lymphocytes and mononuclear cells

Adjacent regions of white matter are invaded by polymorphic microglia corresponding to the zones of demyelination

A few days of onset of the exanthem of measles, rubella, smallpox and chickenpox; rarely occurs after influenza and mumps

At present, ADEM appears to develop after infections with Epstein-Barr, cytomegalovirus, and Mycoplasma pneumoniae

Grave: significant rate of neurologic defects in patients who survive

In children, recovery from the acute stage is followed by a permanent disorder of behavior, mental retardation or epilepsy

Cerebellitis and ataxia that follow chickenpox and other infections are more benign and normally clear over several months

PATHOGENESIS: The disorder represents an

immune-mediated complication of infection rather than a direct infection of the CNS

An experimental allergic encephalomyelitis has been produced by inoculating animals with sterile brain tissue and adjuvants: perivenular demyelinative and inflammatory lesions that one observes in the human disease

Presumably, the lesions are the result of T-cell-mediated immune reaction to components of myelin or oligodendrocytes

CLINICAL FEATURES: Abrupt onset of confusion,

somnolence, and often convulsions

Page 8 of 10

with headache, fever and varying degrees of neck stiffness

Ataxia, myoclonic movements and choreoathetosis less frequent

In the more severe cases, stupor, coma and decerebrate rigidity occur in rapid succession

In the myelitic form (postinfectious myelitis): partial or complete paraplegia or quadriplegia, diminution or loss of tendon reflexes, sensory impairment and varying degrees of paralysis of bladder and bowel

In postexanthem encephalomyelitis (2-4 days after the rash): convulsions, stupor, and sometimes, coma

Less commonly, hemiplegia or a virtually pure cerebellar syndrome and occasionally, a transverse myelitis, sphincteric disturbance

In less severe cases of postexanthem encephalitis: headaches, confusion and signs of meningeal irritation

CSF: increase in lymphocytes and protein; MRI shows bilateral confluent white matter lesions in both cerebral hemispheres and in the subcortical white matter as well

DIFFERENTIAL DIAGNOSIS/ TREATMENT:

Viral meningoencephalitis Infectious mononucleosis Herpes simplex Mycoplasmal infections Cerebrovascular disease

(thrombophlebitis) Hypoxic encephalopathy Acute toxic hepatoencephalopathy

(Reye syndrome) High-potency steroids the best

choice of treatment Plasma exchange and IV

immunoglobulin successful in some fulminant cases

POSTVACCINAL ENCEPHALOMYELITIS:

Complicates the injection of old rabies vaccine

Evolution of symptoms: subacute (2-4 weeks), demyelinative lesions are macroscopic, composed of confluent perivenous lesions

Encephalomyelitis following vaccination against smallpox has now disappeared

Combination of encephalitic and myelitic features; may involve nerve roots and peripheral nerves

Mortality rate: 30-50%; residual neurologic signs, intellectual impairment, behavioral abnormalities

ACUTE NECROTIZING HEMORRHAGIC ENCEPHALOMYELITISAcute Hemorrhagic Leukoencephalitis of Weston Hurst

Most fulminant form of demyelinative disease; mainly in young adults and children

Almost invariably preceded by a respiratory infection (Mycoplasma pneumoniae)

Headache, fever, stiff neck and confusion; followed by focal seizures, hemiplegia or quadriplegia, pseudobulbar paralysis and progressively deepening coma

CSF under increased pressure; lymphocytes to a polymorphonuclear pleocytosis of

Page 9 of 10

up to 3000 cells/cu mm; increased protein, normal sugar

Most fulminant form of demyelinative disease; mainly in young adults and children

Almost invariably preceded by a respiratory infection (Mycoplasma pneumoniae)

Headache, fever, stiff neck and confusion; followed by focal seizures, hemiplegia or quadriplegia, pseudobulbar paralysis and progressively deepening coma

CSF under increased pressure; lymphocytes to a polymorphonuclear pleocytosis of up to 3000 cells/cu mm; increased protein, normal sugar

CT scan and MRI: bilateral but asymmetrical large, confluent edematous lesions in the cerebral white matter

Terminates fatally in 2-4 days Differential diagnosis: brain

abscess, subdural empyema, local embolic encephalomalacia, herpes simplex virus encephalitis

Pathologic features: white matter of one or both

hemispheres destroyed almost to the point of liquefaction

tissue flecked with multiple small hemorrhages

changes also found in the brainstem, cerebellar peduncles, spinal cord

Histologic examination: widespread necrosis of small blood vessels and brain tissue around the vessels; intense cellular infiltration, multiple small hemorrhages and an inflammatory reaction in the meninges

Histologic features similar to ADEM but with more widespread necrosis and tendency of lesions to form large foci

Etiology: lymphocytes undergo transformation to lymphoblasts in response to a pure encephalitogenic MBP

Delayed hypersensitivity mechanisms are operative

Treatment: corticosteroids, plasma exchange, IV immunoglobulin

__END__

Page 10 of 10