1. MULTIPLE SCLEROSIS
Prof Akram Al.Mahdawi CABM,MRCP,FRCP,FACP,FAAN

2. What is demyelination disease
How would you diagnose MS
What are the different treatment options

3. 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.

4. Piere Marie Charcot This Disease (MS) without his name is meaningless!
His students are
Babinski
Zigmond feroid

5. 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.

6. 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

7. 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

8. 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

9. 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

10. 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

11. Conduction abnormalities-(delay, blocked, Impairment) lead to negative symptoms & signs (visual loss.weakness,ataxia, numbness) Emphatic conduction-postive signs and symptoms (pain, paroxysmal syndrome)

12. COMMON INITIAL SYMPTOMS
Optic neuritis
RR sensory symptoms
Subacute painless SC lesion
Acute brain-stem syndrome
Subacute dorsal column deficit
6th nerve palsy

13. 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

14. 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

15. 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%

16. 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

17. 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)

18. MOTOR DISTURBANCES Weakness Increased spasticity
Pathologic signs (Babinski, Hoffman)

19. Crebellar signs Nystagmus Dysarthria Tremor Dysmetria Titubation
Stance and gait

20. OTHER CLINICAL SIGNS Urinary incontinence, incomplete emptying
Cognitive and emotional abnormalities (depression, anxiety, emotional lability)
Fatigue
Sexual dysfunction

21. DIFFERENTIAL DIAGNOSIS
Connective tissue diseases
Primary CNS vasculitis
Postinfectious encephalomyelitis
Lyme disease
Behcet’s syndrome
Sarcoidosis / Sjogren’s disease
B12 deficiency / tertiary syphylis
Leukodystrophies

22. 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

23. 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)

24. 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

25. 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

26. ABNORMAL MRI--CEREBELLUM

27. ABNORMAL MRI—OPTIC NERVE

28. ABNORMAL MRI—CEREBRAL HEMISPHERES
CEREBRUM

29. CSF Increased immunoglobulin concentration in >90% of patients
IgG index (CSF/serum) elevated
Oligoclonal bands—85%
Elevated protein—50%
Modest increase in mononuclear cells

30. 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

31. 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.

32. 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

33. 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.

34. 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 ).

35. 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

36. 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

37. 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

38. Cont Paroxysmal disordersl.evetiracetam, carbamazepine
Trigeminal neuralgia.carbamazepine
levetiracetam
Tonic spasms-anticonvulsant,baclofen
Cerebellar dysfunction-levetiracetam,INH,carbamazepine

39. 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

40. 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

41. 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

42. 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.

43. 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

44. 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.

45. 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

46. 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

47. 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)

48. 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