How To Know If You Have Multiple Sclerosis

Transcription

1 Dr Paul Timmings Neurologist and Senior Lecturer University of Auckland School of Medicine 16:30-17:25 WS #71: Current New Therapies for MS 17:35-18:30 WS #81: Current New Therapies for MS (Repeated)

2 Multiple Sclerosis A Rapidly Evolving Landscape What You Need to Know What your Patients want to Know Dr Paul Timmings MBChB MD FRACP. Neurologist, Anglesea Clinic Hamilton

3 Case: A 27yr old previously well man presents with weakness and tingling in both legs, imbalance and urinary hesitancy 2 weeks after respiratory infection. Family Hx: Paternal grandmother had MS Examination shows mild leg weakness, slight gait ataxia and subjective sensory change below the costal margin. What might be the cause?? Differential? What other clinical information will be helpful

4 Questions Diagnosis A. Guillian Barre B. New onset MS C. CIS D. NMO E. ADEM What else to look at Limb exam Cranial nerves CXR CBC & CRP

5 Case: Leg reflexes are brisk, certainly not reduced. Need to check the arms, cranial nerves & visual acuity. MRI spine shows cord lesion MRI brain shows 3 lesions: periventricular, juxtacortical and callosal CSF shows 1RBC, 7WBC, Pr 0.3, & OGB +ve What is the likely diagnosis? What is the actual diagnosis?

6 Case 1: MRI scans

7 Question - Repeated Diagnosis Guillian Barre New onset MS CIS NMO ADEM

8 Clinically Isolated Syndrome: Differs from Case to Case CIS is the patient s first episode of CNS inflammation & demyelination Presentations and outcomes vary widely CIS may convert to MS

9 A Word or Two about CIS:

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11 What is MS? MS 101 : A wee catch up Pathologically Multiple focal areas of myelin loss (plaques) within the CNS. With variable gliosis & inflammation and blood-brain barrier damage. Initially axons are relatively preserved and will thinly remyelinate. Dissemination in the CNS is common: Predilection for optic nerve, sub-pial spinal cord, brainstem, cerebellum and juxta-cortical white matter. Historically described as a disorder of white matter: But. Imaging and pathology also show demyelination in cortical grey matter. Popescu & Luchinetti. Ann Rev Pathol. 2012;7: Calabrese et al. Nat Rev Neurol. 2010;6:

12 Pathology & Immunopathogenesis

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14 What is MS? Immunologically A genetically & environmentally modified dysregulated immunological response: An Immuno-genetic Disease Genetic Twin studies HLA DR2 (Ag presenting cells) GWA (>100 alleles) Immunologic IL-2Ra (regulatory T cells) IL-7Ra (memory T cells) Environmental Demographics / Epidemics Microbial agents EBV Vitamin D Smoking Salt BMI Microbiome Popescu & Luchinetti. Ann Rev Pathol. 2012;7: Calabrese et al. Nat Rev Neurol. 2010;6:

15 What is MS? Clinically Relapsing & Remitting (80-85%) Episodes of acute or sub-acute new or recurrent focal neurologic deficit (attributed to lesion[s] in the CNS), followed by partial or complete recovery % of R&R patients convert to Secondary Progressive MS after an average of 20yrs. Relapses may continue, superimposed on progressive disease. Primary Progressive (10-15%) Insidious onset with gradual progression over time. Rovaris et al. Lancet Neurol. 2006;5:

16 What is MS? The 2010 McDonald Criteria for Diagnosis of MS Diagnostic Criteria Polman et al, Ann Neurol 2011;69:

17 What is MS: Diagnostic Criteria in Essence The 2010 McDonald Criteria for Diagnosis of MS Polman et al, Ann Neurol 2011;69:

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19 Case: Progress Had steroid course (Methyl prednisolone 1g/d po 5/7). Became fully well. No ongoing Rx 18 months later presented with painful blurred vision Left VA 6/60 & R arm weak Repeat MRI (brain & C spine) >20 new brain lesions, swollen L optic nerve, new C & T cord lesions? Diagnosis? Differential What other test should we do? Review Cervical cord scan?. Was Gad given in scan?

20 Case: Progress; MRI 18 months

21 NMO: Neuromyelitis Optica (NMO), Devic's Disease A CNS demyelinating auto-immune disease Optic nerves and spinal cord are primarily affected Optic neuritis &/or cord lesions can occur years apart Usually there are only few T2-lesions in the brain. NMO typically demonstrates extensive spinal cord lesions (>3 segments) with low T1-signal intensity and swelling of the cord. Antibodies against Aquaporin-4 (AQP4) receptors are usually present Standard MS DMTs usually don t work and may aggravate

22 Could this be NMO?

23 MS: Definition An immune-mediated inflammatory disease that attacks central nervous system myelinated axons, destroying the myelin and the axon in variable degrees. Leading to significant physical disability within years in more than 30% of patients. The hallmark of MS is recurrent symptomatic episodes of neurological malfunction, lasting days to months, occurring months or years apart, affecting different anatomic locations in the CNS.

24 Prognostic factors: Age of onset: Older = worse Smoking. Vitamin D deficiency: Supplement studies underway. Number of lesions on initial MRI: More = worse. Number of active lesions: More = worse. Number of relapses in first 2 yrs: More = worse. Early disability. Progressive disease within first 2 yrs.

25 MRI in MS: How can it help us help? MRI allows earlier diagnosis and treatment decisions MRI helps assess aggressiveness of the disease and so helps choose best treatment MRI helps measure disease activity MRI assists with assessing Rx efficacy MRI helps predict clinical outcomes

26 MRI: Predicts Treatment Effect, Relapses and EDSS Worsening Treatment effect on MRI lesions predicts treatment effect on relapse rate. 1yr MRI lesion relapse activity predicts treatment effect and EDSS change at 2yrs. Gadolinium enhancing lesions seen during IFN-ß Rx (indicating continued disease activity), predict poor outcome at 15yr follow-up. Sormani MP et al. Lancet Neurol. 2003;12: Sormani MP et al. Neurology. 2011;77: Bermel RA et al. Ann Neurol. 2013;73:95-103

27 Measuring Patient Status: EDSS Examine every neurological Sub-System. Score 1 for signs without symptoms. Score 2 for signs and symptoms in 1 area. Score 3 for signs and symptoms in 2 or more areas (abridged). Combine all scores via agreed chart to arrive at an overall disability score (EDSS). Expanded Disability Status Scale (EDSS): Important cut points (edited): No disability, minimal signs in one System Minimal disability in one System, may have signs in other Systems. Moderate disability in one System, or mild disability in three or four Systems. No impairment of walking Significant disability but self-sufficient and up and about some 12 hours a day. Able to walk without aid or rest for 500m Requires a walking aid - cane, crutch, etc - to walk about 100m with or without resting Unable to walk beyond 5m even with aid. Essentially restricted to wheelchair Death due to MS Kurtzke JF. Neurology 1983;33(11):

28 Clinical Progress Predicts Outcomes Incomplete recovery from relapse Predicts future progression Predicts higher risk of conversion to SPMS Motor relapses predict more disability than sensory relapses Relapses without recovery or periods of progression unrelated to relapse indicate aggressive disease Aggressive MS Definition: EDSS 4 by 6 months, or progression of 2 EDSS points in 2 yrs Scott TF & Schramke CJ. J Neurol Sci. 2010;292: Skoog B et al MS Relat Disord. 2014:3; Scott TF. Clin Neurol Neurosurg. 2014:127;86-92

29 MRI useful in Lesion Assessment Lesion location does not predict response to treatment Lesion location has marked effect on function & disability Spinal cord, brainstem and cerebellar lesions have more impact Periventricular and subcortical lesions have less impact Total lesion volume correlates with disease activity. Can help determine how aggressively to treat Wybrecht D et al. Multiple Sclerosis. 2012;18:

30 Understanding MS Progression and Evolution: Topographical Model The model illustrates: Topographical lesions distribution, relapse frequency, severity, recovery and progression rate. The CNS is depicted as a pool, with a shallow end and a deep end. Water depth equates to functional reserve. The water s surface represents clinical threshold. Clinical progression is made up of prior relapses & lesions which incrementally appear above the threshold as the water level recedes. Krieger SC et al. ECTRIMS 2015 e-poster:p270

31 What is our treatment target? NEDA In the context of the model, clinical assessment alone may be too bland. MRI reveals subclinical lesions Can we aim for NEDA (No Evidence of Disease Activity)? Need regular MRI scans MRI s are improving What s the relevance of underlying new but clinically silent lesions?

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35 ABC s: [Avonex, Betaferon, Copaxone] Treatments have similar efficacy and are safe (but weak). Approx 30% reduction in relapse rates and progression rate O connor P et al. Lancet Neurology. 2009;8:

36 New MS Treatments in NZ: Teriflunomide, Fingolimod, Dimethyl Fumarate, Natalizumab More potent = Better disease modification, but more risk Target disease mechanism(s) more accurately Suppress immune response more effectively So. Risk of opportunistic infections JCV & PML. HSV Contra-indicated in pregnancy Unexpected immune surveillance effects Specific side effects differ with each agent

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39 Teriflunomide: Safety & Tolerability Pregnancy exposure concerns (animal studies) Enters semen Hepatic monitoring (ALT may rise).. Monitor monthly for 6 months Rare neutropenia TB reactivation Hypertension Peripheral neuropathy Hair thinning GI disturbance, - diarrhoea Can be removed with cholestyramine Miller A. Clin Ther. 2015;37:

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41 Fingolimod: Efficacy & Safety

42 Fingolimod: Patient Management

43 Dimethyl Fumarate (DMF)

44 Dimethyl Fumarate: Efficacy

45 Dimethyl Fumarate: Tolerability & Safety

46 Natalizumab

47 Natalizumab: Efficacy & Safety

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51 Choosing Therapy in NZ Treatment Entry Criteria: NZ A. MS diagnosis must be confirmed by a neurologist. Diagnosis must include MRI confirmation. And B. Clinically Definite Relapsing Remitting MS with or without underlying progression. And C. EDSS score And D. At least 1 significant relapse of MS in the previous 12 months or 2 significant relapses in the past 24 months. And E. Evidence of new inflammatory activity on an MR scan within the past 24 months as evidenced by: i) Gadolinium enhancing MRI lesion; or ii) Diffusion Weighted Imaging positive lesion; or iii) T2 MRI lesion with associated local swelling; or iv) Prominent T2 lesion that is clearly responsible for the clinical features of a recent relapse; or v) New T2 MRI scan lesions

52 How to Quantify Progress on Treatment When to Change Treatment? Modified Rio Score: Uses MRI & relapse rate. Predicts 4 yr disability progression after 1yr of treatment with 69% accuracy Non-Responders, who might benefit from treatment change or escalation are Identified from modified Rio Score Sormani M, Rio J. et al. Mult Scler 2012;19: Sormani M. et al. Nat Rev Neurol. 2013:

53 Can Stable Patients Stop Treatment? At what Risk? 36% of stoppers had relapses within 5yrs Relapse rate was similar for stayers and stoppers Relapse was more likely in young less-disabled Stoppers showed more disability progression Conclusion: Stopping DMT after 5years of no relapse does not increase probability of relapse Kister et al. ECTRIMS; 2015:Poster#261

54 Steroid Protocols for Acute Relapses 199 MS patients with relapse <15 days duration Randomised to Oral vs IV methyl-prednisolone 1000mg daily for 3 days. IV or oral 81% vs 80% improved by 4 weeks Similar adverse effects, more insomnia in oral group (77 vs 64%) Bottom line: Oral methyl-prednisolone is just as effective as IV Le Page et al. Lancet. 2015;

55 MS Pathophysiology & Treatment: The Bottom Line(s) MS is an immunologically driven CNS disease New mechanistic understandings are bringing many new therapies New treatments work because they target the immune mechanisms New Treatments have uncommon but serious immunological (and other) adverse effects because they work! Treatment efficacy has a lag phase measured in years MRI shows treatment efficacy (or likely failure) earlier Vigilance and patient buy in with full disclosure and an eyes wide open approach is needed.

56 MS Treatment: Messages to the Patient DMT s are largely invisible treatment They have delayed benefit The treatment benefit delay may be measured in years Patients need to understand the rationale for treatment They need to partner in treatment decisions Remember: DMT s are generally well tolerated, safe and effective Side effects are manageable, but vigilance is needed

57 Other Treatments Biotin 16 of 18 unblinded patients with PPMS or SPMS improved with biotin mg/day. Unblinded 15% of 103 patients showed less disability at 24 months, (open label) Vit D deficiency linked to increased risk of MS, but is hyper supplementation helpful? we don t know yet! Diet (VLCA s, Microbiome, BMI) Exercise Meditation & awareness of self, Cognitive training Lifestyle

58 MS: A Changing Landscape Questions and Discussion Thank You Paul Timmings Neurologist, Anglesea Clinic Hamilton

59 MS lesion (arrow) in corpus callosum on Sagittal FLAIR imaging is not easily seen on T2-weighted imaging.

60 Dimethyl Fumarate and Lymphopaenia

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62 Figure 3. Probability of disability progression from the first year since interferon treatment started (3 years, (a)) and over the follow-up period (4 years, (b)), according to application of the modified Rio score on the validation set (Barcelona study data). MP Sormani et al. Mult Scler 2012;19:

63 Take home slides

64 Take home slides Multiple Sclerosis A Rapidly Evolving Landscape What You Need to Know What your Patients want to Know Dr Paul Timmings MBChB MD FRACP. Neurologist, Anglesea Clinic Hamilton

65 Clinically Isolated Syndrome: Differs from Case to Case CIS is the patient s first episode of CNS inflammation & demyelination Presentations and outcomes vary widely CIS may convert to MS

66 A Word or Two about CIS:

67 What is MS? MS 101 : A wee catch up Pathologically Multiple focal areas of myelin loss (plaques) within the CNS. With variable gliosis & inflammation and blood-brain barrier damage. Initially axons are relatively preserved and will thinly remyelinate. Dissemination in the CNS is common: Predilection for optic nerve, sub-pial spinal cord, brainstem, cerebellum and juxta-cortical white matter. Historically described as a disorder of white matter: But. Imaging and pathology also show demyelination in cortical grey matter. Popescu & Luchinetti. Ann Rev Pathol. 2012;7: Calabrese et al. Nat Rev Neurol. 2010;6:

68 What is MS? Immunologically A genetically & environmentally modified dysregulated immunological response: An Immuno-genetic Disease Genetic Twin studies HLA DR2 (Ag presenting cells) GWA (>100 alleles) Immunologic IL-2Ra (regulatory T cells) IL-7Ra (memory T cells) Environmental Demographics / Epidemics Microbial agents EBV Vitamin D Smoking Salt BMI Microbiome Popescu & Luchinetti. Ann Rev Pathol. 2012;7: Calabrese et al. Nat Rev Neurol. 2010;6:

69 What is MS? Clinically Relapsing & Remitting (80-85%) Episodes of acute or sub-acute new or recurrent focal neurologic deficit (attributed to lesion[s] in the CNS), followed by partial or complete recovery % of R&R patients convert to Secondary Progressive MS after an average of 20yrs. Relapses may continue, superimposed on progressive disease. Primary Progressive (10-15%) Insidious onset with gradual progression over time. Rovaris et al. Lancet Neurol. 2006;5:

70 What is MS: Diagnostic Criteria in Essence The 2010 McDonald Criteria for Diagnosis of MS Polman et al, Ann Neurol 2011;69:

71 MS: Definition An immune-mediated inflammatory disease that attacks central nervous system myelinated axons, destroying the myelin and the axon in variable degrees. Leading to significant physical disability within years in more than 30% of patients. The hallmark of MS is recurrent symptomatic episodes of neurological malfunction, lasting days to months, occurring months or years apart, affecting different anatomic locations in the CNS.

72 MRI: Predicts Treatment Effect, Relapses and EDSS Worsening Treatment effect on MRI lesions predicts treatment effect on relapse rate. 1yr MRI lesion relapse activity predicts treatment effect and EDSS change at 2yrs. Gadolinium enhancing lesions seen during IFN-ß Rx (indicating continued disease activity), predict poor outcome at 15yr follow-up. Sormani MP et al. Lancet Neurol. 2003;12: Sormani MP et al. Neurology. 2011;77: Bermel RA et al. Ann Neurol. 2013;73:95-103

73 Measuring Patient Status: EDSS Examine every neurological Sub-System. Score 1 for signs without symptoms. Score 2 for signs and symptoms in 1 area. Score 3 for signs and symptoms in 2 or more areas (abridged). Combine all scores via agreed chart to arrive at an overall disability score (EDSS). Expanded Disability Status Scale (EDSS): Important cut points (edited): No disability, minimal signs in one System Minimal disability in one System, may have signs in other Systems. Moderate disability in one System, or mild disability in three or four Systems. No impairment of walking Significant disability but self-sufficient and up and about some 12 hours a day. Able to walk without aid or rest for 500m Requires a walking aid - cane, crutch, etc - to walk about 100m with or without resting Unable to walk beyond 5m even with aid. Essentially restricted to wheelchair Death due to MS Kurtzke JF. Neurology 1983;33(11):

74 Clinical Progress Predicts Outcomes Incomplete recovery from relapse Predicts future progression Predicts higher risk of conversion to SPMS Motor relapses predict more disability than sensory relapses Relapses without recovery or periods of progression unrelated to relapse indicate aggressive disease Aggressive MS Definition: EDSS 4 by 6 months, or progression of 2 EDSS points in 2 yrs Scott TF & Schramke CJ. J Neurol Sci. 2010;292: Skoog B et al MS Relat Disord. 2014:3; Scott TF. Clin Neurol Neurosurg. 2014:127;86-92

75 New MS Treatments in NZ: Teriflunomide, Fingolimod, Dimethyl Fumarate, Natalizumab More potent = Better disease modification, but more risk Target disease mechanism(s) more accurately Suppress immune response more effectively So. Risk of opportunistic infections JCV & PML. HSV Contra-indicated in pregnancy Unexpected immune surveillance effects Specific side effects differ with each agent

76 How to Quantify Progress on Treatment When to Change Treatment? Modified Rio Score: Uses MRI & relapse rate. Predicts 4 yr disability progression after 1yr of treatment with 69% accuracy Non-Responders, who might benefit from treatment change or escalation are Identified from modified Rio Score Sormani M, Rio J. et al. Mult Scler 2012;19: Sormani M. et al. Nat Rev Neurol. 2013:

77 Can Stable Patients Stop Treatment? At what Risk? 36% of stoppers had relapses within 5yrs Relapse rate was similar for stayers and stoppers Relapse was more likely in young less-disabled Stoppers showed more disability progression Conclusion: Stopping DMT after 5years of no relapse does not increase probability of relapse Kister et al. ECTRIMS; 2015:Poster#261

78 Steroid Protocols for Acute Relapses 199 MS patients with relapse <15 days duration Randomised to Oral vs IV methyl-prednisolone 1000mg daily for 3 days. IV or oral 81% vs 80% improved by 4 weeks Similar adverse effects, more insomnia in oral group (77 vs 64%) Bottom line: Oral methyl-prednisolone is just as effective as IV Le Page et al. Lancet. 2015;

79 MS Pathophysiology & Treatment: The Bottom Line(s) MS is an immunologically driven CNS disease New mechanistic understandings are bringing many new therapies New treatments work because they target the immune mechanisms New Treatments have uncommon but serious immunological (and other) adverse effects because they work! Treatment efficacy has a lag phase measured in years MRI shows treatment efficacy (or likely failure) earlier Vigilance and patient buy in with full disclosure and an eyes wide open approach is needed.

80 MS Treatment: Messages to the Patient DMT s are largely invisible treatment They have delayed benefit The treatment benefit delay may be measured in years Patients need to understand the rationale for treatment They need to partner in treatment decisions Remember: DMT s are generally well tolerated, safe and effective Side effects are manageable, but vigilance is needed

81 Other Treatments Biotin 16 of 18 unblinded patients with PPMS or SPMS improved with biotin mg/day. Unblinded 15% of 103 patients showed less disability at 24 months, (open label) Vit D deficiency linked to increased risk of MS, but is hyper supplementation helpful? we don t know yet! Diet (VLCA s, Microbiome, BMI) Exercise Meditation & awareness of self, Cognitive training Lifestyle