Central nervous system demyelinating diseases - Multiple sclerosis -

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1 Central nervous system demyelinating diseases - Multiple sclerosis - Amilton Antunes Barreira Department of Neurology Faculdade de Medicina and Hospital das Clínicas de Ribeirão Preto - USP

2 Diseases of myelin Autoimmune Acute hemorrhagic leukoencephalopathy Multiple sclerosis Infectious Progressive multifocal leukoencephalopathy Toxic/metabolic Carbon monoxide Vitamin B 12 deficiency Mercury intoxication (Minnamata disease) Alcohool/tobacco amblyopia Central pontine myelinolysis Machiafava-Bignami syndrome Hypoxia Radiation

3 Vascular Binswanger s disease (chronic microvascular leukoencephalopathy) Hereditary disorders of myelin metabolism Adrenoleukodystrophy Metachromatic leukodystrophy Krabbe s disease Alexander s disease Canavan-van-Bogaert disease Pelizaeus-Merzbacher disease Phenylketonuria Multiple sclerosis

4 Diseases of myelin Autoimmune Acute hemorrhagic leukoencephalopathy

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10 Diseases of myelin Vascular Binswanger s disease

11 Diseases of myelin Infectious Progressive multifocal leukoencephalopathy

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13 Diseases of myelin Hereditary disorders of myelin metabolism Canavan-van-Bogaert disease

14 Deficiency of the enzyme aspartoacylase and the accumulation ofn-acetylaspartic acid lead to a severe leukodystrophy and spongy degeneration of the brain, Canavan disease (McKusick ).

15 Epidemiology

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17 1,1 million people with MS worldwide 2/3 experiment the first symptom between the age of 20 and 40 For a minority MS starts in late adult life Women are committed 1.4 to 3.1 times more In temperate zones MS is five times more common than in the tropics

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19 In Brazil: 20 cases per inhabitants ( cases) In Uruguay: cases for a population of inhabitants In United States: cases

20 MS in first degree relatives is 20 times higher than in general populations Monozygotic twin studies show the concordance rate of 30% Dizygotic twins show concordance rate of less than 5%

21 PATHOLOGY

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35 MRI IMAGES

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40 Signs and symptoms

41 Visual loss Ocular motility Diplopia Trigeminal neuralgia Equilibrium alterations Ataxia Pyramidal signs Monoplegia Paraplegia Hemiplegia Sphincter disturbances Cognitive commitments

42 Course

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44 DIAGNOSTIC CRITERIA

45 The Poser criteria are: Clinically definite MS 2 attacks and clinical evidence of 2 separate lesions 2 attacks, clinical evidence of one and paraclinical evidence of another separate lesion Laboratory supported Definite MS 2 attacks, either clinical or paraclinical evidence of 1 lesion, and cerebrospinal fluid (CSF) immunologic abnormalities 1 attack, clinical evidence of 2 separate lesions & CSF abnormalities 1 attack, clinical evidence of 1 and paraclinical evidence of another separate lesion, and CSF abnormalities Clinically probable MS 2 attacks and clinical evidence of 1 lesion 1 attack and clinical evidence of 2 separate lesions 1 attack, clinical evidence of 1 lesion, and paraclinical evidence of another separate lesion Laboratory supported probable MS 2 attacks and CSF abnormalities

46 An exacerbation (relapse) is defined as: the appearance of a new clinical Sign/Symptom or the clinical worsening of a previous sign/symptoms that had been stable for at least the previous 30 days and which persisted for a minimum of 24 hours.

47 International Panel Criteria (McDonald Criteria) for Diagnosis MS Clinical Presentation Two or more attacks; objective clinical evidence of 2 or more lesions Two or more attacks; objective clinical evidence of 1 lesion One attack; objective clinical evidence of 2 or more lesions One attack; objective clinical evidence of 1 lesion (clincally isolated syndrome) Insidious neurological progression suggestive of MS None a Additional Data Needed for MS Diagnosis Dissemination in space demonstrated by: MRI b, or 2 or more MRI lesions consistent with MS plus positive CSF c, or await further clinical attack implicating a different site. Dissemination in time demonstrated by: MRI b, or second clinical attack. Dissemination in space demonstrated by: MRI b, or 2 or more MRI lesions consistent with MS plus positive CSF c And dissemination in time, demonstrated by: MRI b, or Second clinical attack Positive CSF c, and dissemination in space, demonstrated by: 1) 9 or more T2 lesions in brain, or 2) 2 or more lesions in spinal cord, or 3) 4-8 brain lesions plus 1 spinal cord lesion; or Abnormal visual evoked potentials with MRI demonstrating 4-8 brain lesions, or fewer than 4 brain lesions plus 1 spinal cord lesion; and Dissemination in time demonstrated by MRI b ; or Continued progression for 1 year

48 MRI Criteria for Brain Abnormality: Space and Time Dissemination MRI lesions disseminated in space: At least three of the following criteria must be met: 1.One gadolinium-enhancing lesion or nine T2-hyperintense lesions if there is no gadolinium-enhancing lesion 2.At least one infratentorial lesion 3.At least one juxtacortical lesion 4.At least three periventricular lesions MRI lesions disseminated in time: At least one criterion must be met: 1.If MRI is more than 3 months after clinical event, then a gadolinium-enhancing lesion at a site different from the original clinical event is sufficient; if there is no gadolinium enhancement, then a follow-up scan is required (usually > 3 months later). A new T2 or gadolinium-enhancing lesion on this second or subsequent MRI fulfills the requirement. 2.If first MRI scan occurs less than 3 months after the onset of the clinical event, then a second scan > 3 months later showing a new gadolinium-enhancing lesion fulfills requirement. If no gadolinium enhancement is seen at this second scan, a further scan not less than 3 months after the first scan that shows a new T2 lesion or an enhancing lesion will suffice.

49 Pathogenesis

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58 Specific pharmacologic Treatment

59 MS The dimension of the problem August patients in São Paulo state use IFN-β -CEREM of HC de Ribeirão Preto 140 patients are using IFN-β -CEREMs of SP city More than 200 pacientes in each center are in IFN-β

60 MS The dimension of the problem US in 1991: - U$ ,00 US in 2001: 50%: MS chronic progressive (MSCP) US in 2006: 70% will have EMCP US in 2016: 85% will have o EMCP

61 MS The dimension of the problem Malignant form (1 a 3% dos pacientes): - Loss of walk in weeks or months - Life expectancy for MS patients: 10 years less than the general population

62 MS The dimension of the problem What is the real cost of the incapacities? How many working ours are lost? What is the dimension of the human suffering?

63 Specific treatment for MS Relapses Pulsotherapy with metyil-prednisolone Different regimens: 250mg (IV) each 6 hours in 1g EV in 4 to 6 hours Plasmapheresis

64 Specific treatment for MS Interfere in the course of MS Preventing or attenuating the relapses intensity Possible reduction in the course velocity

65 Specific treatment for MS Intérferons β-interferons Glatiramer acetate Mitoxantrone

66 Action of the medicines used for MS Intérferon β Glatiramer acetate - change the MHC expression; - Inhibits the cell trafficking; -lessens the hemato-encephalic barrier permeability; - change the balance between pro and antiinflammatory cytokines - Blockade of the T cells antigen receptors Mitoxantrone - cytotoxicity

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68 Collateral effects -reversible mielotoxicity; - transitory amenorrhea ; Mitoxantrone - nausea; - alopecia; - Cardio toxicity ( cardio myopathy cumulative effect)

69 Collateral effects Intérferon β (discrete or moderated) - influenza; -local inflammation (injection); - worsening of the previous depression; -do not approved for use during pregnancy; -leucopenia, hepatitis, hipo or hypertirheodism; -uncommon: worsening or starting of asthma or Raynaud phenomenon, -myastenia gravis, psoriasis, urticaria, cerebral hemorrhage; -Hepatic necrosis, anaphylaxis. Glatiramer -local pain in the site of injection; - thoracic pain; -death sensation; - lynphadenopaty; - do not approved for use during pregnancy.

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71 EMPP: there is no specific treatment (?)

72 Thank you very much for your attention!!!!

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