Demyelinating Disorders Dr. Maitham F.Jalal F.I.B.M.S (neurology) , F.E.B.N

1. Multiple Sclerosis Multiple Sclerosis (MS) is an inflammatory disease of the Central Nervous System (CNS) affecting the brain and spinal cord. Predominantly, it is a disease of the "white matter" tissue. The white matter is made up of nerve fibres which are responsible for transmitting communication signals both internally within the CNS and between the CNS and the nerves supplying rest of the body. Damage starts immediately upon inception, damage is continuous Disease is hetegeneous: each person’s progression to disability is different P. Martini

Myelin Sheath insulating the axon of the nerve fibers ;it is produced in the central nervous system by oligodendrocyte while its production in the peripheral nerves done by Schwann cells It is composed of protein [20%] and lipid of cholestrol fraction acquired defect in the myelin sheath is called demyelinating disease

There are 2 types of fiber Non myelinated 2 . myelinated nerve fibers : the nerve impulse transmitted by saltatory conduction

Prevalence is increased with increased distance from the equator

MULTIPLE SCLEROSIS: AN ELUSIVE ETIOLOGY The causes are enigmatic: interplay between environment and genetic factors Migration < age of 15 years > age of 15 years Low Vitamin D Infection with human Endogenous Retroviral EBV , HHV 6, Environmental factors Infection MS Genes Monozygotic twins 30% Dizygotic twin 5% Relative at 3-5% risk

Disease Overview: Multiple Sclerosis Disease course: MS is an ongoing process of demyelination, remyelination, and eventual neuron loss Results: Repeated attacks characterized by the its tendency for dissemination in the space [involvement of different parts of the CNS] and dissemination in time [involvement of the CNS at different times ] Heterogeneity: Symptoms, severity, and course vary per person and disease seems to follow a distinct progression in each individual pt Relapses & Remissions: Most MS sufferers experience periods of acute exacerbations (flares, relapses) varying in number and severity, followed by periods of remission, where all symptoms spontaneously cease: inflammation damage to CNS is continuous, occurring during flares AND remissions Damage starts immediately upon inception, damage is continuous Disease is hetegeneous: each person’s progression to disability is different P. Martini

Clinical Forms of MS Secondary Progressive (SPMS): 35% Four internationally recognized general categories Relapsing-remitting (RRMS): 55% Secondary Progressive (SPMS): 35% Primary Progressive (PPMS) 9% Progressive Relapsing (PRMS): 1% Clearly defined flare-ups & remissions; inflammatory lesions developing constantly Early 20s & 30s; women 2:1 Initial disease activity in brain (cognitive) Better prognosis: supporting equipment avg. 20 yrs Majority of RRMS pts will develop SPMS (90% in 25-30 years) Relapse frequency decreases but disability increases Less remyelination & more plaques, resulting in steadily progressive disability with less recovery Could represent different, advanced stage of RRMS At onset, steady worsening without relapses or remissions Variations in rates of progression; occasional plateaus or temporary minor improvements Late 30s/early 40s; men as likely as women Initial disease activity in spinal cord (physical disability) Worse prognosis: supporting equipment avg. 6-7 yrs From onset steadily worsening disease with clear acute relapses with or without recovery Unlike RRMS, remission periods contain clinically observable continuing disease progression Familiar with these forms, graphs visually depict disease and disability progression over time – become more meaningful when you take a closer look RR well defined acute attacks with full recovery, residual neurological deficit est over time – at this stage little or no progression between attacks 3. SP Relapses decline 4. PP we see progression PP progressively increasing disiability from the start w/o relapses, 5. SP a hybrid of these two disease forms (hence the two colors), pts exhibiting periods of intense symptoms, with only MINOR remission in between Somewhat controversial, 1% Source: National Multiple Sclerosis Society & NIH estimates

Multiple Sclerosis Clinical Manifestations 1. visual disturbance Optic neuritis : sub acute unilateral reduction in visual acuity over 3 days associated with pain during eye movement

Multiple Sclerosis Clinical Manifestations 2.Sensory manifestations Numbness and tingling Decreased hearing ( sensory neural hearing loss) Chronic neuropathic pain

Multiple Sclerosis Clinical Manifestations 3.Motor manifestations Weakness or paralysis of limbs, trunk, and head -Hemiplegia -paraplegia Diplopia (double vision) Spasticity of muscles

Multiple Sclerosis Clinical Manifestations 4.Cerebellar manifestations Nystagmus Involuntary eye movements Ataxia Dysarthria Lack of coordination in articulating speech Dysphagia

Multiple Sclerosis Other Clinical Manifestations Emotional manifestations Anger Depression

Multiple Sclerosis Other Clinical Manifestations Bowel and bladder functions Spastic bladder: small capacity for urine results in incontinence Flaccid bladder: large capacity for urine and no sensation to urinate

Multiple Sclerosis Other Clinical Manifestations Sexual dysfunction Erectile dysfunction Decreased libido Difficulty with orgasmic response Painful intercourse Decreased lubrication

Diagnostic Criteria for MS  There is no definitive diagnostic test for MS clinicians must rely on a thorough history and physical examination coupled with a battery of laboratory and imaging investigations 

MRI - Dissemination in space

MRI - Dissemination in Time Gd Gd T2 T2 > 1 month Polman, 2005 22

DIAGNOSTIC WORK UP 1.Brain and Spinal Cord MRI 2.Labs: rule out mimics of MS Connective tissue diseases, infections, metabolic disorders 3.Cerebrospinal Fluid (when clinical and MRI evidence inconclusive) 4.Evoked Potentials: Identify damage to visual, auditory, & touch perception systems Less sensitive than MRI or cerebrospinal fluid 23

CSF Analysis • Most helpful for suggesting an alternative Dx -high protein, marked pleocytosis, PMNs Elevated IgG Index >0.7 Increased CNS IgG synthesis, with normal serum IgG consistent with MS Oligoclonal Bands Presence of 2 distinct bands in CSF is consistent with MS 24

Multiple Sclerosis Treatment Drug Therapy 1. Corticosteroids for relapse Treat acute exacerbations by reducing edema and inflammation at the site of demyelination Do not affect the ultimate outcome or degree of residual neurologic impairment from exacerbation 2. DMT to reduce the rate of relapse

Treatment of relapse 1. Intravenous Methyprednisolone 1 gm daily for 3- 5 days Severe cases: up to 2 gm daily for 7days 2. Severe relapses not responding to steroids 5 to 7 courses done on alternate days for 2 weeks One course takes place over 3 to 4 hours

DMT to reduce relapse in M.S

Symptom Management Baclofen / Dantrium (for spasms) NSAIDS (for flu-like side effects and pain) Analgesics Antidepressants (like Prozac) Beta blockers for tremors (like Inderal) Anticonvulsants for parethesia (like Tegretol) Anticholinergics for bladder dysfunction (Pro-Banthine)

poor prognostic factor 1. Active progression over past several months or frequent severe relapses 2. Age < 40 3. Ambulatory 4. Earlier disease course (RRMS or early SPMS) 5. Incomplete recovery from relapses 6. Frequent relapses leading to disability 7. Persistence of multiple Gd+ MRI lesions

Clinically isolated syndromes Refers to a first acute episode suggestive of CNS demyelination, and it may be the first presentation of multiple sclerosis. The average risk of developing multiple sclerosis following a clinically isolated syndrome has been reported as between 30% and 70% the development of multiple sclerosis to occur in 80% of people with lesions on MRI and in 20% of those with a normal scan

RIS (Radio logically Isolated Syndrome) White matter lesions suggestive of demyelinating disease on MRI Normal neuro exam No medical history compatible with MS Unclear whether RIS is subclinical MS or a separated entity About 33% of subjects with RIS develop a CIS especially with spinal cord lesions

2.ACUTE DISSEMINATED ENCEPHALOMYELITIS [ADEM] 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

Clinical features : Headache Vomiting Pyrexia confusion meningism investigations Headache Vomiting Pyrexia confusion meningism Seizures coma minority of patients who recover have further episodes MRI shows multiple high- signal areas CSF may be normal or show an increase in protein and lymphocytes oligoclonal bands Treatment with high-dose intravenous methylprednisolone, using the same regimen as for a relapse of multiple sclerosis, is recommended

3.ACUTE TRANSVERSE MYELITIS: an acute monophasic, inflammatory demyelinating disorder affecting the spinal cord a subacute paraparesis with a sensory level, severe pain in the neck or back at the onset . MRI to exclude a compressive lesion of the spinal cord. CSF examination shows cellular pleocytosis, often with polymorphs at the onset, oligoclonal bands are usually absent. Treatment is with high-dose intravenous methylprednisolone 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

4.Neuromyelitis optica

Diagnostic criteria for NMO Optic neuritis with myelitis With 2 of 3 1. normal MRI brain 2. > 3 segment spinal cord lesion 3. NMO antibody +ve