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MULTIPLE SCLEROSIS Prof Akram Al.Mahdawi CABM,MRCP,FRCP,FACP,FAAN
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What is demyelination disease
How would you diagnose MS What are the different treatment options
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History of disease Multiple Sclerosis, also known as MS, was given its name, multiple because of the numerous sites of demyelination and ‘sclerosis’ which means scarring. “There are accounts of probable MS dating back to the 14th century but the history of the disease really begins in the 19th century with the first illustrations and clear clinical description of the disease beginning to appear in 1838”. the first actual case was first diagnosed in It was Jean-Martin Charcot who is credited with giving us the first signs and symptoms of Multiple Sclerosis.
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Piere Marie Charcot This Disease (MS) without his name is meaningless!
His students are Babinski Zigmond feroid
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It is an Auto Immune Disease .
It is a life-long disease with no cure. MS, the body attacks and destroys myelin that insulates an axon/nerve ( demyelination ) If damage is severe it can also destroy the nerve/axon itself. MS affects the central nervous system and inflames the white matter in the brain which creates plaques.
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MULTIPLE SCLEROSIS Most common disabling condition in young adults
Most common demyelinating disorder Chronic disease of the CNS Progresses to disability in majority of cases Unpredictable course / variety of signs and symptoms. Current theory favors immunologic pathogenesis
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Women 2 to 3 times as men It is rare in the pediartric MS is rare after age of 60 Ms is uncommon in equatorial climates but increase with northern distance from equator
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pathophysiology Both genetic and eniviroment
Low near the equator and increase in temperate Sunlight,Vit D,EBV Familial 15%,monozygotic twins 30% Polygenic Immunological-T lympocyte in CSF and increase immunoglobulin synthesis in CNS
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entry of activated T lymphocyte
Recognized antigen-presenting cell(microglia). Inflammatory cascade lead to release cytokines and initiate destruction of oligodendrocyte-myelin unit by macrophage
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Damage myelin associated with inflammatory infiliterate of lymphocyte,macrophage,antibody,complement depostion,activated microglia and oligodendroglia cell. inflammation+demylination=plaque=gliosis Mainly select periventricular,optic nerve, subpial region of spinal cord
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Conduction abnormalities-(delay, blocked, Impairment) lead to negative symptoms & signs (visual loss.weakness,ataxia, numbness) Emphatic conduction-postive signs and symptoms (pain, paroxysmal syndrome)
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COMMON INITIAL SYMPTOMS
Optic neuritis RR sensory symptoms Subacute painless SC lesion Acute brain-stem syndrome Subacute dorsal column deficit 6th nerve palsy
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A 20-year –old male. He had three episodes of neurological symptoms including 1-an episode of hemiparesis lasting 3 weeks 2-one episode of optic neuritis in left eye lasting 2 weeks 3-episode of paresthesias of both legs and lower abdomen with reduce bladder sensation with residual symptoms
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Condition suggestive of MS ?
Afferent pupillary defect and optic atrophy Lhermitts symptom INO Rubral,holmes tremor Trigeminal neuralgia under the age of 50 Recurrent V11 palsy Urinary sphincter disturbance
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Weakness 90% Sensory disturbance Ataxia Bladder Fatigue Cramps Diplopia Visual loss 50%
Dysarthria 30% Vertigo Psychatric symptoms Dysphagia Loss of consciousness Loss of taste 6%
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SENSORY DISTURBANCES Ascending numbness starting in feet
Bilateral hand numbness Hemiparesthesia/dysesthesia Generalized heat intolerance Dorsal column signs Loss of vibration/proprioception Lhermitte’s sign
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VISUAL DISTURBANCES Unilateral or bilateral partial/complete intranuclear ophthalmoplegia CN VI paresis Optic neuritis Central scotoma, headache, change in color perception, retroorbital pain with eye movement)
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MOTOR DISTURBANCES Weakness Increased spasticity
Pathologic signs (Babinski, Hoffman)
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Crebellar signs Nystagmus Dysarthria Tremor Dysmetria Titubation
Stance and gait
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OTHER CLINICAL SIGNS Urinary incontinence, incomplete emptying
Cognitive and emotional abnormalities (depression, anxiety, emotional lability) Fatigue Sexual dysfunction
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DIFFERENTIAL DIAGNOSIS
Connective tissue diseases Primary CNS vasculitis Postinfectious encephalomyelitis Lyme disease Behcet’s syndrome Sarcoidosis / Sjogren’s disease B12 deficiency / tertiary syphylis Leukodystrophies
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Macdonald criteria Two or more relapses,objective clinical evidence of two or more lesions. Two or more relapses,objective clinical evidence of one lesion (Need dissemination in space) One relapse,objective clinical evidence of two or more lesions (dissemination in time). CIS
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Exclude other structural disease and identify plaques of demylination
Demonstrate other site of involvement (MRI,VER,) Demonstrate inflammatory nature of lesions (CSF,cellcount,oligoclonal bands) Exclude other condions(B12, CTS, CXR,ACE)
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MRI FINDINGS Patchy areas of white matter in paraventricular cerebral areas Lesions in cerebellum/brainstem/ cervical and thoracic spinal cord Gadolinium enhancement identifies active lesions
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MRI **Caveat: ** Abnormal MRI without clinical evidence is not sufficient to confirm dx of MS… …Absence of abnormal MRI in clinically definite MS doesn’t disprove diagnosis
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ABNORMAL MRI--CEREBELLUM
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ABNORMAL MRI—OPTIC NERVE
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ABNORMAL MRI—CEREBRAL HEMISPHERES
CEREBRUM
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CSF Increased immunoglobulin concentration in >90% of patients
IgG index (CSF/serum) elevated Oligoclonal bands—85% Elevated protein—50% Modest increase in mononuclear cells
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EVOKED POTENTIALS VER (visual evoked response)—75% abnormal regardless of optic neuritis hx BAER (brainstem auditory evoked response)—30% abnormal SSER (somatosensory evoked response) – 80% abnormal Helps distinguish peripheral from central lesions
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Relapse-remitting MS (RRMS): Here you have an attack, go into complete or partial remission, then have the symptoms return. Primary-progressive MS (PPMS): Here you continually decline and have no remissions. A few patients have malignant MS which is where they have a quick decline which leaves them severely disabled or even lead to death. Secondary-progressive MS (SPMS): This stage of MS starts with RRMS symptoms and continues on to show signs of PPMS. Progressive-relapsing MS (PRMS): This is a rare form but here it takes a progressive route made worse by acute attacks. 20% of the people with MS have a benign form. Here they show little progression after the first attack.
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FAVORABLE PROGNOSTIC FACTORS
Female gender Low rate of relapses per year Complete recovery from 1st attack Long interval between 1st and 2nd attack Younger age of onset Later cerebellar involvement Low disability 2-5 years from onset
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R of relapse attack Methylprednisolone -500 to 1000 mg /daily for 5 days. may be followed by tapering oral steroid PE,IV immune globulin for fulminate disease.
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Interferon-beta ---Immune modulation --- widespread use for reducing relapse rate (RCT evidence).
Glatiramer acetate --Immune modulation --Similar efficacy to interferon-beta (RCT evidence) . Fingolimod --Immune modulation --Superior efficacy to interferon-beta in RCTs . Monoclonal antibody to alpha4-integrin (natalizumab) --Immune modulation. Possibly more effective than other drugs. Teriflunomide (AUBAGO). Dimethyl fumarate (Tecfidera ).
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When Interferon beta therapy is initiated
Liver function tests and CBC at baseline. Lab tests should then be repeated in 1,3,6 months during initiation of therapy. Monitoring can then be performed every 3 to 6 months thereafter. TFT are recommended in patients with history of thyroid dysfunction every 6 months
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Adverse events Inflammation at site of injection.
Headache, 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
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Symptomatic therapy Spasticity-physiotherpy,baclofen,tizanidine,benzodiazepine,dantrolen,Botulinm toxin type A Fatigue-amantadine,Modafinil,SSRIs Depression –SSRIs,TAD Anxaiety-alprazolam Ataxia –isoniazid,clonazepam Dysthesia-carbamazepine,gabapentin
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Cont Paroxysmal disordersl.evetiracetam, carbamazepine
Trigeminal neuralgia.carbamazepine levetiracetam Tonic spasms-anticonvulsant,baclofen Cerebellar dysfunction-levetiracetam,INH,carbamazepine
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Neurogenic bladder Atonic –lesion in conus medullaris,root and nerve(loss of detrusor contraction,difficult in intiation,bladder distension with overflow) Hypertonic(UMN) lesion in spinal cord and brainstem(urgency and urge incontinence,incoplete emptying) Cortical-precentral,postcentral ,frontal(loss of awareness,difficult in intiation,,inappropriate micturatin,loss of social control
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Breakthrough Relapsing
An increase in NO of relapses coupled with increase No of T2 hypertense and or T1 enhancing lesion on MRI Approach –Switch to another agent
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Restoring conduction in area of demyelination
Dalfampridine ( ampyria ) is a broad- spectrum K channel blocker that increase conduction of action potential in area of demyelination
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Counselling: provision of pre-conception counselling is best practice
Relapse risk: endocrine effects on the immune system ensure that relapse risk drops during pregnancy. • Disease-modifying drugs: risk of teratogenicity means that all disease-modifying drugs should ideally be stopped 6–8 wks before conception and recommenced after. breastfeeding has stopped. • Post-partum relapse rate: rebound of immune system activity means that the highest risk of relapse is in the first year after delivery.
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Clinically isolated Syndrome
An episode of symptoms of demylinating affecting the optic nerve, spinal cord, brain stem in isolation. 85% of MS patients, onset is heralded by single episode. Early treatment with interferon can delay progression to CDMS after CIS presentation guidelines give beta interferon a level A recommendation for use in CIS. Early initiation of treatment can delay progression to CDMS
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MS & NMO The two conditions were long thought to represent variations of same disease. Neuropathologic differences as well as the recent identification of an autoantibody to the aquaporin-4 water channel (NMO-IgG) in patients with NMO suggest is pathologically distinct from MS.
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Acute bilateral optic neuritis should suggest the diagnosis of NMO.
The vision loss in NMO also tends to be more sever and recovary is less complete than in MS. Spinal cord lesion extending over at least three segment,. Absence of oligoclonal band in the CSF. Strong associationb with other autoimmune disease. Paucity or absence of brain lesions on MRI Presence of NMO-IgG antibody
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Treatment ON IV MP was associated at 6 months with a significantly faster recovery. Short-term improvements with corticosteroid use have been demonstrated in several studies. IV MP is often given at a dose of 500mg to 1000 mg for 3 to 5 days ,sometimes followed by an oral prednisone taper for 10 to 14 days. Other therapy include plasma exchange and IVIG,Rituximab,anti-CD-20 monoclonal antibody, azathioprin in combination with long-term prednisone
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ADEM Occurs n children and young adult
Typically follows febrile illness or vaccination Low grade fever, headache and meningism followed by encephalopathy Muti-focal deficit and seizure Diagnosis depend on history,clincal findings,CSF,MRI(extensive,large ,multifocal lesion)
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contiue Usually monophasic illness,recovary occurs in 50-70%
Recurrent or multiphase occur in20% Neurological squeal in 1/3 Treatment,supportive,antiviral medication, high dose IV MP followed by tapering oral steroid
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