Epidemiology. Geographical distribution: Average onset age: years

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2 Multiple sclerosis chronical disease, characterized by multiple areas of inflamation and demielination in the CNS One of the major causes of disability in the young adult Variable clinical picture and evolution

3 Epidemiology Geographical distribution: Average onset age: years Rarely under 10 or after 60 years old In females disease starts 5 years earlier Relapsing remiting form: years Primary progressive: 40-44years F>M (2-3:1) Prevalence: (temperate climate )? 80/ loc. (Northern europe)

4 The most widelly accepted hypothesis: An autoimmune disease that is triggered by un unknown environmental factor in genetically susceptible persons

5 Demielination is due to an autoimmune reaction

6 Patogenical aspects Brain-blood barrier breakdown Inflamation Demielination Oligodendrocyte loss Reactive gliosis Degeneration and axonal loss

7 INFLAMATION DEGENERATION Relapse Acute clinical presentation Cronic signs; increase of disability

8 Chronic lesions Plaques Different degrees of inflammation Perivascular hyperintense on T2-weighted and FLAIR images and hypointense on T1- weighted scans

9 Clinical presentation in MS Motor Sensory Cerebellar Brainstem Visual Sfincterian Cognitive Functional damage is evaluated by the EDSS (Kurtzke Expanded Disability Status Scale): Scale from 0 to 10 0 no signs/simptoms 10 dead 6 loss of gait autonomy Monitoring of disease evolution and treatment efficiency

10 Relapse Sudden onset of new symptoms or exacerbation of preexistent clinical symptoms At least 24 hours More than 30 days from previous relape Duration can extend from days to weeks Demyelination areas appear

11 McDonald diagnostic criteria Clinical =2 relapses + =2 clinical lesions =2 relapses + 1 clinical lesion 1 relapse + =2 clinical lesion 1relapse + 1 clinical lesion (Clinical isolated syndrome) Slow progression of clinical picture Additional data No IRM +/- oligoclonal bands in LCR MRI or wait for second relapse MRI +/- oligoclonal bands ANDtime dissemination (a second relapse or new MRI Progression changes) for more than 1 year AND MRI + VEP or oligoclonal bands

12 Updated McDonald criteria(2005) Changes regarding: Space dissemination: spinal lesions on MRI are accepted Time dissemination: new T2 lesions, gadolinofile lesions accepted at 1 month interval from baseline Allow a more timely diagnosis Clinical criteria remain accepted

13 Clinical types of MS Relapsing/Remitting RRMS Secondary progressive (SPMS) Progresive with relapses (PRMS) Primary Progressive (PPMS)

14 Relapsing/Remitting (RRMS) 85% Twice more in females Relapses followed by remission

15 Secondary Progressive (SPMS) Approx 50 % of the RRMS patients will change to this form after many years of evolution In time recovery after relapses is less complete, leading to progressive aggravation

16 Progressive Relapsing/Remitting (PRMS) Relapses and remissions exist During remission there is a slow progression of symptoms Approximativelly 5% of cases.

17 Primary Progressive (PPMS) No relapses/remission Gradual aggravation of symptoms Usually begins during the end of the 3 rd decade Man=woman 10% of the total MS patients

18 MS - onset Clinical isolated syndrome (CIS) firs neurological symptoms that last for more than a day, caused by inflamation/demyelination in one or more sites in the CNS monofocal only one lesion, only one type of clinical damage multifocal more than one symptoms, caused by multiple lesions Usually more lesions on the MRI exist at the time of clinical onset

19 Clinical picture Motor (pyramidal)involvement Sensory Cerebellar Brainstem Visual Sphincterian Higher functions

20 Cerebellar syndrome Ataxia, gait trouble Limb coordination problems Tremor Dysmetria Dysartria

21 Pyramidal syndrome Upper motor neuron syndrome: Paraparesis Hemiparesis Tetraparesis

22 Vestibular Syndrome Static and dynamic balance problems Nystagmus

23 Visual problems Optic neuritis Diplopia / internuclaer oculomotricity paresis

24 Optic neuritis Retrobulbar Pain, sight loss Scotoma -> blindness Usually unilateral

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26 Sfincterian abnormalities Retention/incontinence Disuria Constipation

27 Cognitive Depression Euphoria Memory impairment Fatigue In more advanced stades, as degeneration and atrophy occur, more severe cognitive problems may appear

28 Multiple sclerosis Impossible to predict evolution on an individual scale MRI lesions and clinical symptoms may not coincide on a temporal scale Clinical picture may take different aspects, depending on the location of the lesions

29 Evolution

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31 MRI CSF analysis Evoked potentials

32 MRI Multiple lesions Hyperintense in Ts and FLAIR, hypointense in T1 Round/ovalar, well defined margins >85% perivenular Periventricular, calososeptal, subcortical, brainstem, spinal chord

33 MRI Aspect patognomonic

34 MRI Spinal chord lesions

35 MRI Localizari infratentoriale

36 MRI gadolinium enhancement T1 + contrast: ring shaped or nodular enhancement

37 IRM 6&/ ( 5 2 =$ 0 8 / 7,3/ A Best imagistic method for white matter evaluation MRI aspect allows MS diagnosis Gadolinium enhancement allows lesion activity evaluation New MRI tehniques bring more information, allowing for a better clinicalimagistic corelation

38 CSF analysis Important for differential diagnostic Oligoclonal bands accesory diagnostic criteria

39 Evoked potentials VEP AEP SSEP MEP Ascending (AEP, VEP, SSEP) and descending pathways (MEP) Demyelinations leads to slower conduction and increased latencies Functional and not structural information Longer pathways improved sensitivity

40 Motor evoked potential Motor treshold. Amplitude and latency Central conduction time Other TMS techniques transcallosal inhibition

41 Differential diagnosis Other inflamatory diseases (infectious and non infectious) Cranio cerebral or spinal structural abnormalities Metabolic and endocrine disorders Neoplasic diseases Genetic and neurodegenerative disorders O. Bajenaru: Ghiduri de diagnostic si tratament in neurologie 2005

42 Treatment DISEASE MODIFYING THERAPIES IMUNOMODULATORY IMUNOSUPRESANT RELAPSE TREATMENT SYMPTOMATIC AND REHABILITATION THERAPY

43 Imunommodulatory treatment Beta interferons: interferon beta l a (REBIF) s.c. 3 times/week interferon beta l a (AVONEX) i.m. 1/week interferon beta l b (BETAFERON) s.c., e.a.d. Glatiramer acetate ( COPAXONE ), s.c., daily Natalizumab

44 ?eta interferons RRMS SPMS (in patient with relapses) CSI with high risk to developp MS

45 Efect: Decrease of relapse rate Decrease of disease severity Decrease of disability progression rate

46 Adverse events Flu-like syndrome; skin reactions Depression (Ifn beta 1 b) Liver function abnormalities

47 B. Glatiramer acetate (Copaxone): : Decrease of relapse rate Decrease of disease severity Decrease of disability progression rate

48 Contraindications Unclear diagnosis Primary progressive MS Depression Pregnancy Severe diseases (haematological, liver, neoplasms) Intolerance Therapeuthic failure: 2-3 relapses in 6 months or at least 4 relapses in one year

49 Monoclonal antibodies Natalizumab IV, 1/month Better efficiency Potentially very severe adverse events (LMP)

50 Imunosupressants: Approved: mitoxantrone (Novantrone, Onkotrone) other imunosuppresants: off label, in special cases azathioprin, metrothrexate, ciclophosphamide, cladribine, ciclosporine, etc.

51 Relapse treatment methil prednisolone mg/day 3-5 days, i.v. Improvement of post relapse recovery No effect on overall long time disability progression

52 Rehabilitation and symptomatic treatment Adresses specific clinical conditions in MS patients Improvement of quality of life Adapted for the clinical stage of the disease and the disabilities of each patient Possibly a diminishment of disability

53 Friedreich s disease

54 Degeneration of the long spinal pathways (both ascending and descending) and the peripheral nerve fibers

55 Clinical presentation Gait abnormalities Ataxia Speech disorders Nistagmus Hyporeflexia Trophic changes High plantar arches (pes cavus deformity of the foot) Sensory disturbance Babinski sign

56 Clinical presentation Symptoms typically begin sometime between the ages of 5 to 15 years, scoliosis Diabetes (about 20% of people with Friedreich's ataxia develop carbohydrate intolerance and 10% develop diabetes mellitus) Heart disorders (e.g., atrial fibrillation, and resultant tachycardia (fast heart rate) and hypertrophic cardiomyopathy ) These symptoms are slow and progressive. Long-term observation shows that many patients reach a plateau in symptoms in the patient's early adulthood.

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58 Genetics Autosomal recesive disorder Mutation of frataxin gene (9q13-q21) Long arm of cromosome 9 Prevalence 1 : Genetic counselling!

59 Treatment Physical therapy Nerve and muscle trophic drugs Treatment of complications Treatment of heart disorders