MultipleSclerosis:Current&Emerging Treatments Personalized Strategies

1. MultipleSclerosis:Current&Emerging Treatments Personalized Strategies Dr. Suhail Al-Shammri Associate Professor& Head Division of Neurology, Mubark Al Kabir Hospital

2. Overview • The diagnostic criteria of multiple sclerosis( MS) • Classification of idiopathic inflammatory demyelinating disorders • Clinical course of MS • Current and emerging MS therapies

3. Idiopathic CNS Demyelinating Diseases • Typical CNS demyelinating Diseases: • Radiologically isolated syndrome (RIS) • Clinically isolated syndrome (CIS) • Relapsing –remitting multiple sclerosis (RRMS) • Secondary progressive MS (SPMS) • Primary progressive MS (PPMS)

4. Atypical CNS Demyelinating Diseases • Acute disseminated encephalomyelitis (ADEM) • Acute hemorrhagic leukoencephalitis (AHLE) • Tumefactive MS • Balo’s concentric sclerosis • Marburg

5. Radiologically Isolated Syndrome (RIS) • No typical symptoms of CNS demyelination • No formally accepted diagnostic criteria • MRI : Typical MS lesions • CSF abnormalities • Clinical MS Attack: • 35% over 5 years • MRI progression: • 59-83% in 2 years • DMT is initiated only in case of clinical/MRI progression Okuda DT et al, Neurology2011:76()8, 686-692

6. Diagnostic Criteria for MS • An effort to make the diagnostic process more objective • Formal criteria were devised to codify the typical MS features into indisputable diagnostic criteria • The primary driving force is identification of patients for research trials. ”a consensus on which patient has MS” • Criteria are designed to be specific • There are patients with MS who do not meet those criteria • “A patient has MS when an an experienced neurologist says he or she has MS”

7. Schumacher Criteria- 1965 • Onset of symptoms between 10 and 50 years • Objective abnormalities on neurologic examination • The signs and symptoms indicate CNS white matter damage • The lesions are disseminated in space ( 2 or more separate lesions) • The lesions are disseminated in time (2 attacks at least 1 month apart) • No better explanation

9. The Mc Donald Criteria • ‘the world consists of three types of person: those who have multiple sclerosis; those who do not; and those who might’. PolmanCH et al,Ann Neurology, 2001

10. Dissemination in Space Polman CH et al, Ann Neurol 2011; 69:292–302

11. Dissemination in Time Polman CH et al, Ann Neurol 2011; 69:292–302

12. MRI Brain DIS

13. MRI Cervical spine: DIS

14. MRI Brain T2WI

15. MRI Brain Enhanced T1WI:DIT

16. CASE • On 18/3/08 patient complained of ocular pain on moving the left eye with blurred vision. • 2 days later she developed left frontal headache. • Seen by the ophthalmologist who diagnosed her as optic neuritis and advised to be on neurobion. • She had several attacks of Rt. Upper limb heaviness in the last 2 years, each was lasting for a week. • Her cousin has MS .

17. CASE : Examination • Her vision was 20/200 in the left eye and 20/40 in the right eye. There was a central scotoma, and red and blue colors were less intense in the left eye. • RAPD on the left • Left fundus: disc is congested and swollen. • Central Scotoma • Treated with pulse IV methylprednisolone for 3 days and improved followed by short prednisolone taper

18. Case 1: Fundoscopy

19. Case : MRI Brain

20. Case 2: MRI Spine

21. Case : CSF Oligoclonal bands

22. Clinically Isolated Syndrome (CIS) • Single characteristic clinical attack of CNS demyelination: • Optic neuritis • Acute partial myelitis • Brain stem syndrome • Cortical

23. Clinically Isolated Syndrome (CIS) • MRI: • Low risk: 1 or no other asymptomatic brain lesion • High risk: 2 or > asymptomatic lesions • Treatment approved for high risk patients • IFN-B, GA reduces second attack: ARR 15%

24. Baseline MRI and Risk of CDMS for Monofocal onset CIS (BENEFIT Placebo N=93)

26. TOPIC Key inclusion criteria: • Patients 18 to 55 years of age with a first acute/subacute neurologic event consistent with demyelination. • MS symptom onset within 90 days of randomization. • Screening MRI scan with 2 T2 lesions 3 mMdiameter that are characteristic of MS. Placebo(n=197) Randomized n=618 Teriflunomide 7 mg (n=205) Screened(N=846) Long-Term Extension R Primary end point:Conversion to CDMS (as defined by the occurrence of a relapse) Teriflunomide 14 mg (n=216) 108-Week Treatment Phase Miller A. Plattform presentation  ECTRIMS 2013

27. Primary / Key Secondary Endpoint Primary Endpoint: Time to Clinically Definite MS (CDMS) Gd-enhancing T1 Lesions) 21%p=0.4366 59% p=0.0008 43% Safety / Tolerability:Adverse events observed in the trial were consistent with previous clinical trials with Aubagio. Miller A. Plattform presentation  ECTRIMS 2013

28. CIS: When To Initiate Therapy? • Patients with normal MRI or with fewer than 2 • Low risk of developing early clinical attacks • Clinical and MRI monitoring • Without immediately commencing immunotherapy (DMT) • Those with abnormal MRI with2or> lesions consistent with MS or with evidence of intrathecal synthesis of antibodies should be considered for DMT, • Patients with atypical clinical or MRI presentation require further diagnostic evaluation.

29. Relapsing-Remitting MS • Subacute repeated onset of CNS dysfunction with resolution ( sometimes incomplete , over days to weeks) • Revised McDonald criteria • MRI: Periventricular, brainstem, juxtacortical prominent T2, often Gad enhancing lesions, T1 hypointense (black holes) • Treatment: Interferon-B, Glatiramer acetate, natalizumab, mitoxantrone

30. Features Consistent With MS • Relapses and remissions • Age Onset between ages 15 and 50 • Optic neuritis • Lhermitte's sign • Internuclear ophthalmoplegia • Fatigue • Uhthoff's phenomenon

31. Features Inconsistent With MS • Steady progression • Onset before age 10 or after age 50 • Cortical deficits such as aphasia, apraxia, alexia, neglect • Rigidity, sustained dystonia • Convulsions • Early dementia • Deficit developing within minutes

32. Secondary Progressive MS • Majority of RRMS many years following onset • Progressive impairment (spastic gait disturbance) between or in absence of attacks • No clear effect of DMT without ongoing attacks or inflammation • Role of DMTs in SPMS patients: • with ongoing relapses • Substantial ongoing accrual on new MRI inflammatory lesions

33. Primary Progressive MS • Presents with progressive myelopathicgait, cerebellar ataxia or cognitive impairment without clear history of any clinical attacks • Clinical progression must be for at least 1 year and accompanied by a combinstion of brain&spinal abnormalities and/or CSF anormalities consistent with MS • Lack of clinical attacks/ relative paucity of MRI lesions • No approved DMTs

34. Multiple Sclerosis (MS) • Multiple Sclerosis is the commonest disabling neurological condition to afflict young adults • MS is an autoimmune disease triggered by environmental agents acting in a genetically susceptible people • Auto-aggresive autoimmune attack on the myelin sheath and other components of CNS • Current&emerging DMTs are based in the above paradigm • Is MS a primary neurodegenerative disease

35. MS: Pathology

36. MS: Pathology

37. Demographic Characteristics of Multiple Sclerosis in Kuwait SD±10.3 Total recruited patients in study: 195 Gender Distribution N(M/F): 195(76/119) Cross sectional or retrospectively included patients:134 Newly diagnosed drug naïve patient:65

38. Clinical Characteristics of Multiple Sclerosis in Kuwaiti Population Presenting symptoms

41. Medication details in studied Kuwaiti MS patients

42. MS Therapy: Deciding on which Medication • Determine Therapeutic Goals • To reduce clinical relapse • To reduce accumulation of new MRI lesions • new T2 lesions • Gadolinium-enhancing lesions • black holes • Brain and spinal cord atrophy • Reduce short-term relapse related disability

43. How To Determine of The Goals are Met? • Compare with baseline relapse rate • Recall bias • Regression to the mean • Assessment of improvement or stability in neurological impairment • Assess functional ambulatory limitation • May indicate progression • MRI ongoing/new inflammatory activity • Serial MRI to assess radiologic stability, worsening or improvement- q12-24 month except

44. How To Determine of The Goals are Met? • If goals of DMT or symptomatic treatment are being met no change in DMT unless problems with medication tolerability • A detailed evaluation of common and idiopathic side effects will be required • Switching of medication based on adherence and tolerability ma be needed

45. What if Goals are not being Met • If pre-therapy relapse rate is not improved • A therapeutic switch may be indicated • Relapse rate is incomplete indicator of ongoing inflammatory disease activity • Cranial and spinal MRI • May show therapy resistant inflammatory disease • Guide switch to a more potent anti-inflammatory medication • Clinical attack or definitive worsening disability is may lacking

46. Case 2 • Mr. A.M.J is a 33 years old Kuwaiti male, diagnosed to have MS in 2008. • In Jan 2008, he developed diplopia, followed by paresthesia in feet, ascending to abdomen, chest and forearms. • These symptoms persisted • By June 2008, he was ataxic and on a wheel chair, when he sought medical advice • MRI was consistent with MS • Marked imrovement was noted in sensory symptoms after pulse steroids.

47. Case 2 • His symptoms showed a rapid progression, by Sept 2008, he had optic neuritis, sphincteric disturbance, and positive Lhermitte’s sign. • In Oct 2008, he started to take Rebif. • His disease remained stable, with no new relapses and no new lesions on MRI till 2011. • In April 2011, he went for CCSVI treatment and discontinued Rebifwithout our knowledge or advice.

48. CASE 1 • Lhermitte’s sign was positive • Cranial nerves were normal • No motor weakness • Mild sensory deficit for light touch and vibration on left side • Plantars were flexor bilaterally • Romberg’s sign was mildly positive • Moderate left sided dysmetria, with tandem ataxia • EDSS :2; AI :1.