MULTIPLE SCLEROSIS
Prof Akram Al.Mahdawi CABM,MRCP,FRCP,FACP,FAANWhat is demyelination disease How would you diagnose MS What are the different treatment options
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 1849. It was Jean-Martin Charcot who is credited with giving us the first signs and symptoms of Multiple Sclerosis.Piere Marie Charcot
This Disease (MS) without his name is meaningless! His students are Babinski Zigmond feroidIt 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.
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 pathogenesisWomen 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
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 CNSentry of activated T lymphocyte Recognized antigen-presenting cell(microglia). Inflammatory cascade lead to release cytokines and initiate destruction of oligodendrocyte-myelin unit by macrophage
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
Conduction abnormalities-(delay, blocked, Impairment) lead to negative symptoms & signs (visual loss.weakness,ataxia, numbness) Emphatic conduction-postive signs and symptoms (pain, paroxysmal syndrome)
COMMON INITIAL SYMPTOMS
Optic neuritis RR sensory symptoms Subacute painless SC lesion Acute brain-stem syndrome Subacute dorsal column deficit 6th nerve palsyA 20-year –old male. He had three episodes of neurological symptoms including1-an episode of hemiparesis lasting 3 weeks2-one episode of optic neuritis in left eye lasting 2 weeks3-episode of paresthesias of both legs and lower abdomen with reduce bladder sensation with residual symptoms
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 disturbanceWeakness 90% Sensory disturbance Ataxia Bladder Fatigue Cramps Diplopia Visual loss 50%
Dysarthria 30% Vertigo Psychatric symptoms Dysphagia Loss of consciousness Loss of taste 6%
SENSORY DISTURBANCES
Ascending numbness starting in feetBilateral hand numbnessHemiparesthesia/dysesthesiaGeneralized heat intoleranceDorsal column signsLoss of vibration/proprioceptionLhermitte’s signVISUAL 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)MOTOR DISTURBANCES
Weakness Increased spasticity Pathologic signs (Babinski, Hoffman)Crebellar signs
Nystagmus Dysarthria Tremor Dysmetria Titubation Stance and gaitOTHER CLINICAL SIGNS
Urinary incontinence, incomplete emptying Cognitive and emotional abnormalities (depression, anxiety, emotional lability) Fatigue Sexual dysfunctionDIFFERENTIAL DIAGNOSIS
Connective tissue diseasesPrimary CNS vasculitisPostinfectious encephalomyelitisLyme diseaseBehcet’s syndromeSarcoidosis / Sjogren’s diseaseB12 deficiency / tertiary syphylisLeukodystrophiesMacdonald 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
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)
MRI FINDINGS
Patchy areas of white matter in paraventricular cerebral areas Lesions in cerebellum/brainstem/ cervical and thoracic spinal cord Gadolinium enhancement identifies active lesionsMRI
**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
ABNORMAL MRI--CEREBELLUM
ABNORMAL MRI—OPTIC NERVEABNORMAL MRI—CEREBRAL HEMISPHERES CEREBRUM
CSF
Increased immunoglobulin concentration in >90% of patientsIgG index (CSF/serum) elevatedOligoclonal bands—85%Elevated protein—50%Modest increase in mononuclear cells
EVOKED POTENTIALS
VER (visual evoked response)—75% abnormal regardless of optic neuritis hxBAER (brainstem auditory evoked response)—30% abnormalSSER (somatosensory evoked response) – 80% abnormalHelps distinguish peripheral from central lesionsRelapse-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.
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 onsetR 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.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 ).
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 monthsAdverse 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 hepatitisSymptomatic therapy
Spasticity-physiotherpy,baclofen,tizanidine,benzodiazepine,dantrolen,Botulinm toxin type AFatigue-amantadine,Modafinil,SSRIsDepression –SSRIs,TADAnxaiety-alprazolamAtaxia –isoniazid,clonazepamDysthesia-carbamazepine,gabapentinCont
Paroxysmal disordersl.evetiracetam, carbamazepine Trigeminal neuralgia.carbamazepine levetiracetam Tonic spasms-anticonvulsant,baclofen Cerebellar dysfunction-levetiracetam,INH,carbamazepineNeurogenic 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 controlBreakthrough Relapsing
An increase in NO of relapses coupled with increase No of T2 hypertense and or T1 enhancing lesion on MRIApproach –Switch to another agentRestoring conduction in area of demyelination
Dalfampridine ( ampyria ) is a broad- spectrum K channel blocker that increase conduction of action potential in area of demyelinationCounselling: 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.
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
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.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