MULTIPLE SCLEROSIS

Dr.Raed Ahmed MBChB , FIBMSNeurologist

Lec. 810.00 AMMarch /15 / 2015

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WHAT IS MULTIPLE SCLEROSIS ?

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Multiple Sclerosis (MS)

A chronic neurological disorder that affects the central nervous system,

in which myelin is destroyed in the brain and

spinal cord and

causes scarring at multiple sites in the CNS.

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MULTIPLE SCLEROSIS

Most common disabling condition in young adultsMost common demyelinating disorderProgresses to disability in majority of casesUnpredictable course / variety of signs and symptoms; sometimes mistaken for psych dxCurrent theory favors immunologic pathogenesis

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J.M CharcotThis Disease (MS) without his name is meaningless!first who described MS in 1868.

Yet, after more than 140 years of research , much remains a mystery.

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MULTIPLE SCLEROSIS

Leading cause of neurologic disability in young adult.

Over 1 million individual worldwideFocal demylination is patholgic

hallmarkPlaque,discreate area of damage

myelinNo known cause, and as yet,No cure

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“saltatory conduction”

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Abnormal Conduction

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WHO GETS THE DISEASE ?

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>Predominant age: 20-40

MULTIPLE SCLEROSIS AFFECT:0.1%Worldwide incidence

MS is more common in temperate regions, such as northern Europe and North America, but much rarer in the tropics.

The ratio is increasing

now

people in US have MS

400, 000 onset before puberty or after the age of 60 years is rare.

worse prognosis

Highly variable and unpredictable

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WHAT CAUSES MULTIPLE SCLEROSIS?

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Genetic susceptibility

•15% to 20% of patients have history of familial MS.

•Twin studies : monozygotic twins (30%) than dizygotic twins (5%).

•3–5% in first degree relatives

The exact cause remains unknown, but

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• HLA class II region, particularly (HLADRB1*15 and HLA-DQB1*06 —chromosome 6p21 )associated with 3X to 4x fold increased risk of MS.

Environmental factors• Geographic variation in prevalence• Epstein-Barr virus, insufficient vitamin D

intaked and smoking.

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WHAT IS PATHOPHYSIOLOGY ?

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When brain is inflammed –lymphocytes cross BBB

Activated T lymphocytes recognise myelin-derived antigens & secrete cytokines

initiates destruction of the oligo -dendrocyte–myelin unit by macrophages.

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HOW TO CLASSIFY MS?

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Clinically isolated syndromes(CIS)First acute episode suggestive of CNS demyelination,

and it may be the first presentation of MS.

The average risk of developing MS ( 30%-70%)

unilateral ON have a lower risk of converting to multiple sclerosis.

Abnormal MRI at first presentation shown to confer a higher risk of conversion to MS than if MRI is normal.

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WHAT ARE THE CLINICAL FEATURES?

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INITIAL SYMPTOMS

Double vision / blurred visionNumbness/weakness in extremitiesInstability while walkingProblems with bladder controlHeat intoleranceMotor weakness

“All symptoms can be precipitated by heat”

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SENSORY DISTURBANCES

Ascending numbness starting in feetBilateral hand numbnessHemiparesthesia/dysesthesiaGeneralized heat intoleranceDorsal column signs Loss of vibration/proprioception Lhermitte’s sign

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VISUAL DISTURBANCES

Unilateral or bilateral partial/complete intranuclear ophthalmoplegiaCN VI paresisOptic neuritis Central scotoma, headache, change

in color perception, retroorbital pain with eye movement)

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MOTOR DISTURBANCES

Weakness (mono-, para-, hemi- or quadriparesis)Increased spasticityPathologic signs (Babinski, Chaddock, Hoffman)Dysarthria

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Crebellar signs

NystagmusDysarthriaTremorDysmetriaTitubationStance and gait

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OTHER CLINICAL SIGNS

Urinary incontinence, incomplete emptying Set up for UTI’s

Cognitive and emotional abnormalities (depression, anxiety, emotional lability)FatigueSexual dysfunction

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MCDONALD DIAGNOSTIC CRITERIA FOR MS

2 or more relapses, objective clinical evidence of 2 or more lesions.2 or more relapses,objective clinical evidence of 1 lesion (Need dissemination in space)1 relapse,objective clinical evidence of 2 or more lesions (dissemination in time).CIS

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DIAGNOSTIC TESTS DIAGNOSTIC TESTS

MRI Evoked potentials CSF

Blood and urine

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MRI findings in MS

T2

T2 T2T1 Post CT2 T2

C

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T1 Post C

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EVIDENCE FOR DIS1 or more T2 lesion in at least 2 out of 4

areas of CNS : periventricular, juxtacortical , infratentorial, or spinal cord

EVIDENCE FOR DITSimultaneous presence of asymptomatic Gd-enhancing and non enhancing lesion at any time ORA new T2 and/or Gd-enhancing lesion(s) on follow-up MRI irrespective of the timing of baseline MRI scan

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RED FLAGS FOR OTHER DIAGNOSES

Onset before age 10 or after age 50Absence of sensory or genitourinary symptomsDeficit developing within minutesSeizuresRigidity Cortical deficits

(aphasia, apraxia, alexia, neglect)

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DISORDERS THAT CAN MIMIC MS (DDx) =

VITAMINS

Auto-immune

Traumati

c

Psychiatri

c

Neoplastic

Idiopathi

c Metaboli

c

Vascular

Infectious

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Natural History Of MS

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Management A.Treatment of acute attacks

Relapse should be differentiated from a pseudoexacerbation

Glucocorticoid treatment is usually administered as i.v. methylprednisolone

Monitering side effects ST need Plasma exchange

TREATMENTACUT ATTACK

TREATMENTACUT ATTACK

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B.Treatment with disease-modifying agents

For relapsing form of MS (RRMS, SPMS with exacerbations.

Seven such agents are approved by the U.S. FDA:

(1) IFN-β-1a (Avonex ), (2) IFN-β-1a (Rebif ), (3) IFN-β-1b (Betaseron), (4) Glatiramer acetate (Copaxone), (5) Natalizumab (Tysabri), (6) Fingolimod (Gilenya), and (7) Mitoxantrone - (cytotoxic) (Novantrone).

DISEASE MODIFYING TREATMENT

DISEASE MODIFYING TREATMENT

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The first six agents were approved for RRMS, and mitoxantrone is indicated for worsening forms of MS and for SPMS.

For PPMS : No therapies but symptomatic measures.

The three IFN-β drugs and Glatiramer reduce the relapse rate by approximately one third.

DISEASE MODIFYING TREATMENT

DISEASE MODIFYING TREATMENT

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Interferon- β

(1) Downregulating expression of MHC molecules on antigen-presenting cells, (2) Inhibiting proinflammatory and increasing regulatory cytokine levels, (3) Inhibition of T cell proliferation, and (4) limiting the trafficking of inflammatory cells in the CNS.

DISEASE MODIFYING TREATMENT

DISEASE MODIFYING TREATMENT

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Interferon- β : SE sInflammation at site of injection.Flu-like symptoms(myalgia,fever, rigor, rhinitis and fatigue).Rare side effects

Depression, suicide, epileptic events Thyroid abnormalities , lymphopenia,

thrombocytopenia, asymptomatic elevated liver transaminase levels and rarely symptomatic hepatitis

DISEASE MODIFYING TREATMENT

DISEASE MODIFYING TREATMENT

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Glatiramer acetate A synthetic, random polypeptide designed to mimic myelin basic proteinReduces the attack rate in RRMS. (Similar efficacy to interferon-beta)Erythema, pain, mild swelling.Chest tightness, dyspnea, tachycardia, palpitation occur seconds to minutes of injection

DISEASE MODIFYING TREATMENT

DISEASE MODIFYING TREATMENT

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Fingolimod A sphingosine-1-phosphate (S1P) inhibitor.Trapping of lymphocytes in the periphery, preventing them reaching the brain. Reduces the attack rate (superior efficacy to interferon-beta)Administered orally each daySE : Mildly elevated liver function tests or lymphopenia , first-dose bradycardia, macular edema, and respiratory infections.

DISEASE MODIFYING TREATMENT

DISEASE MODIFYING TREATMENT

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C.Treatment of Specific Symptoms

healthy lifestyleSpasticity :physical therapy, baclofen, Local (IM) injection of botulinum toxin

For severe spasticity, a baclofen pumpAtaxia often intractable. Clonazepam,ST IsoniazidWeakness potassium channel blockers such as dalfampridine

MANAGE MS SYMPTOMS

MANAGE MS SYMPTOMS

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Bladder dysfunction Urodynamic testings oxybutynin, tamsulosin, Bethanechol for an atonic bladder, but intermittent catheterization is often required.

UTIs should be treated promptlyPsychosocial

prompt Dx and Rx of Depression, Fatique Sexual Dysfunction

MANAGE MS SYMPTOMS

MANAGE MS SYMPTOMS

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FAVORABLE PROGNOSTIC FACTORS

Female gender Onset before age 40Visual or somatosensory, rather than pyramidal or cerebellar dysfunction.Low rate of relapses per yearComplete recovery from early attacksLong interval between 1st and 2nd attackMinimal impairment after 5 years of disease onset

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Acute Disseminated EncephaloMyelitis (ADEM): An acute monophasic demyelinating condition

Widely disseminated throughout the brain and spinal cord.

Spontaneously but often occurs a week or so after a viral infection,or following vaccination,

Immunologically mediated response to MBP (Molecular mimicry)

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Clinical features ADEM is more common in children

Mean age of onset 5–8 years. it is more common in males

History of recent vaccination or viral illness.

Headache, vomiting, pyrexia, confusion and meningism may be presenting features . Seizures or coma may occur.

ADEM evolves rapidly over hours to days.

ADEMADEM

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InvestigationsMRI shows multiple high-signal areas in a

pattern similar to that of MSCSF may be normal or show an increase in

protein and lymphocytes

ManagementICU, with adequate hydration ,pyrexia,

seizures High-dose i.v methylprednisolone, If unresponsive to steroids, plasmapheresis

or IVIG may be considered.

ADEMADEM

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 Neuromyelitis optica (also known as Devic’s disease)

an inflammatory demyelinating disease of the CNS distinct from multiple sclerosisyoung adults (mean age 40), Predominantly female (4 : 1). Commonly in Asian and African.Antibody to a neuronal membrane channel, aquaporin 4. (autoantibody, NMO-IgG)

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Clinical features

Severe episodes of transverse myelitis and optic neuritis without clinical involvement of other parts of the CNS. Contiguous spinal cord MRI lesion extending over ≥3 vertebral segments. Brain MRI not meeting diagnostic criteria for multiple sclerosis. NMO-IgG seropositive status.

 

NMONMO

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Management

Acute attacks of high dose i.v gluco- corticoids for 5–10 days followed by a prednisone taper.Unresponsive to high-dose steroids, the next line is plasma exchange.In relapsing NMO long-term immunosuppression is indicated.

NMONMO

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THANK YOU

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