Multiple Sclerosis (MS) Dr Oliver Lily Consultant Neurologist Leeds General Infirmary

Transcription

1 Multiple Sclerosis (MS) Dr Oliver Lily Consultant Neurologist Leeds General Infirmary

2 Multiple sclerosis What is MS? What causes MS? Symptoms and signs of MS Making the diagnosis Investigations Treatments

3 Case Study: Ms A 20 year old medical student Presented with 3 day history of pain in the right eye with blurred vision On examination: Reduced colour vision (Ishihara chart) Reduced pupillary light responses (RAPD) Hole in visual field (scotoma)

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7 Case Study: Ms A Next day, awoke to find vision completely gone in right eye! Diagnosis?

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9 Optic Neuritis Inflammation of the optic nerve Causes pain and loss of vision Frequently not visible (retrobulbar) Good prognosis: 95% return to visual acuity of 6/12 or greater within 12 months High dose steroids speed up rate of recovery but have no effect on final acuity 50% go on to develop MS within 10 years

10 Case Study: Ms A Eye completely better within 3 months with no treatment. Well for 2 years Week of medical finals, complained of tingly numbness starting in both feet and gradually ascending to level around chest like a tight band. Felt unsteady walking and fatigued easily. Electric shock sensations running down body whenever she bent her head What is the diagnosis now?

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12 Transverse myelitis Inflammation inside the spinal chord Often mild with good prognosis Often pure sensory Lhermittes phenomenon May affect bladder 50% go on to develop Multiple Sclerosis

13 Diagnosing MS Clinical diagnosis Relies on dissemination in time and place Macdonald Criteria 2010 (2 nd revision)? Is this MS

14 Diagnosing MS Clinically Definite MS Optic neuritis and transverse myelitis at different times Not definite MS Clinically isolated syndrome (CIS) Myelitis and optic neuritis at the same time Recurrent myelitis Recurrent or sequential optic neuritis

15 Supporting investigations

16 Outcome: Ms A Treated with intravenous methylprednisolone 1g daily for 3 days Improved to normal over next 6 weeks Told she had diagnosis of relapsingremitting multiple sclerosis Started on treatment with beta-interferon 1a injections

17 What is MS? MS is the most common cause of neurological disability in young adults in the UK 792 people with MS in Leeds 40 new cases of MS / year

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20 What is MS? MS is a disease of the central nervous system (CNS) An inflammatory reaction in the CNS causes loss of myelin and slowing of nerve conduction Areas of demyelination Loss of axons

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23 Disease modifying treatments Interferon beta 1-b Interferon beta 1-a Glatiramer acetate Teriflunamide Dimethyl Fumarate Fingolimod Natalizumab (Tysabri) Alemtuzumab (Lemtrada) Mitoxantrone

24 LOG frequency of serious adverse events % reduction in relapse rate vs placebo Copaxone 100 Rebif-44 Fingolimod Alemtuzumab Mitoxantrone Tysabri Teriflunamide Dimethylfumarate -6

25 Interferon beta Reduces the number of relapses by a third Effective early in the disease course No evidence on long-term effect on disability

26 Disease-modifying drugs Site of injection Betaferon 1b Avonex 1a Rebif 1a sc im sc sc Frequency Alt days Once week Side effects Flu-like symptomsi SR FLS 3 times /week FLS, ISR Glatiramer acetate Daily Acute reaction

27 The case of Dr A: 6 months later Dr A is admitted to hospital with ataxia, diplopia and vomiting. A repeat MRI scan shows new brain lesions with gadolinium enhancement. She is treated with intravenous methylprednisolone and begins to recover.? What to do now

28 TYSABRI, the first humanized monoclonal antibody approved for the treatment of MS, inhibits adhesion molecules on the surface of immune cells. Research suggests TYSABRI works by preventing immune cells from migrating from the bloodstream into the brain where they can cause inflammation and potentially damage nerve fibers and their insulation.

29 VCAM-1 = vascular cell adhesion molecule-1. Lobb RR et al. J Clin Invest. 1994;94: Natalizumab

30 1. Cannella B et al. Ann Neurol. 1995;37: von Andrian UH et al. N Engl J Med. 2003;348: TYSABRI (natalizumab) US Prescribing information, 2004.

31 Examples of Therapeutic Monoclonal Antibodies Name Antigenic target Clinical use Muromomab CD3 Transplant rejection Daclizumab CD25 Transplant rejection/ms Rituximab/Ocrilizumab CD20 B-cell lymphoma/ms Infliximab TNF Crohn s disease, RA Alemtuzumab CD52 CLL Adalimumab TNF RA Efalizumab CD11a Psoriasis Natalizumab ABT integrin Anti IL-12 MS, Crohn s disease Not yet identified No candidate CD40L, CD154 Not yet identified No candidate Non Fc-binding Not yet identified No candidate Anti-CD3 Not yet identified No candidate Anti-cytokines Not yet identified

32 Elan shares dive on drug setback Shares in Irish drugmaker Elan have plummeted once more after a third case of disease linked to Tysabri, its multiple sclerosis treatment. Elan suspended the drug after two patients were found to have caught the rare disease Progressive Multifocal Leukoencephalopathy (PML), one of whom later died. The newly revealed case - which also ended with the death of the patient - could mean Tysabri never makes it back onto the market, analysts warned. By the close of trading, Elan shares were down 56% to 2.43 euros. The initial cases had involved patients taking both Tysabri and US firm Biogen Idec's drug Avonex, and Elan had hoped that the problem was due to an unexpected problem with the combination. The latest, however, involves Tysabri alone. Biogen's shares were down 11% by 1600 GMT.

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35 The case of Dr A Dr A tests positive for the JC virus in the blood. She has Tysabri infusions for 24 months before changing to oral Fingolimod. She remains relapse free

36 New Oral Treatments for MS Fingolimod Teriflunomide Dimethyl Fumarate

37 Isaria sinclairii

38 Fingolimod Sphingosine 1-phosphate (S1P) receptor modulator T cell S1P receptor FTY720-P Fingolimod results in internalisation of the receptor S1P1 This blocks lymphocyte egress from lymph nodes while sparing immune surveillance by circulating memory T cells LN Prevents T cell invasion of CNS Fingolimod traps circulating lymphocytes in peripheral lymph nodes

39 Fingolimod TRANSFORMS Phase 3 Trial (n=1292) 52% reduction in relapse rate compared to IM Interferon 1a 2 incidences of fatal Herpes virus infection (type 1 encephalitis and disseminated Zoster) Troublesome bradycardia after first dose

40 Patient reads information and signs consent form. Bloods PT, FBC, LFTs, Zoster Abs (if not immune) Baseline ECG must be entirely normal. Arrange baseline OCT if uveitis/diabetes. Day unit admission arranged Continuous ECG monitoring for 6 hours, with hourly pulse and BP recording If any abnormality, SHO to review. If new heart block, bradycardia<45 or QTc interval >500 msec then urgent referral to Cardiology SpR on-call for overnight telemetry. ECG post 6-hours and SHO review prior to discharge FBC, LFT at 1, 3, 6 and 9 months Retinal Screening at 3 months

41 Single Disabling relapse Or Treatment Failure Lemtrada Positive Patient Choice: Avonex Copaxone Betaferon Rebif-22 Teriflunamide Dimethyl Fumarate Fingolimod 5 At least 2 significant relapses in past 2 years 1 >2 disabling relapses per year 2 Negative Tysabri for 1-2 years MRI 2 : New GAD lesion Significant increase in T2 lesions JC virus serology >2 disabling relapses/year At least 6 months after Mitox 1. ABN NICE MIMS Spilker et al NICE 2012 Rapidly-progressive MS EDSS increasing by >1 point per year With or without relapses (3) Within 12 years of first symptoms (4) START Mitoxantrone Usually 1 year Follow-on: Copaxone Rebif-44 Azathioprine

42 Walter Schweckendieck 1959

43 Dimethylfumarate (BG-12) Dimethyl fumarate (DMF) is the methyl ester of fumaric acid. DMF combined with three other fumaric acid esters (FAE) was licensed in Germany as oral therapy for psoriasis (Fumaderm). Glutathione depletion and subsequent induction of the anti-inflammatory stress protein HO-1 is thought to be one of the mechanisms responsible for the immunomodulatory actions of DMF

44 N Engl J Med Sep 20;367(12): Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K, Novas M, Sweetser MT, Viglietta V, Dawson KT; CONFIRM At 2 years, Study the annualized relapse rate was significantly lower Investigators. with twice-daily BG-12 (44%), thrice-daily BG-12 (51%), and glatiramer acetate (29%) than with placebo.

45 The case of Dr A Now working as a GP 34 years old Noticing that when she walks, after a mile or so her left leg tingles and begins to drag. If she stops for a few minutes she can carry on normally. Referred for physiotherapy Returns two years later. Is limping on left leg and carries a walking stick. Right leg also feels stiff and wooden. Noticed urinary urgency and occasional spasms in the legs

46 Case of Dr A On examination has weakness of flexors more than extensors worse on the left, with a left sided foot drop. There is increased tone and sustained clonus in both legs with very brisk reflexes and upgoing plantars. Spastic paraparesis suggests a spinal chord problem? diagnosis

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48 Axonal loss in MS Disability Time

49 Axonal loss in MS Disability Axonal loss Inflammation Time

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51 The case of Dr A Over the next five years walking becomes more difficult and she has to start using two elbow crutches and then a wheelchair Her fingolimod is stopped but she continues with regular physiotherapy She gets more forgetful, and eventually retires from the health service aged 42 15% of MS patients are confined to a wheelchair within 10 years of diagnosis

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54 Targets for Neuroprotection Inflammatory mechanisms: 1.Nitric oxide 2.CD8 cytotoxicity 3.TNF, PGE2 4.Proinflammatory cytokines 5.Antibodies 6.Oedema Excitotoxic mechanisms: 1.Glutamate overactivation 2.Ca++ influx 3.Na+ influx Energy depletion: 1. Mitochondrial dysfunction 2. Free radicals Demyelination induced: 1.Increased vulnerability to damage of demyelinated axons 2.Dying back mechanism Genetic determination: 1. Genetic programme 2. Degeneration Depletion of growth factors: 1.Depletion of stem cells 2.Lack of inflammatory cells which may produce GF Apoptotic mechanisms: 1.Caspase pathway 2.Other

55 Current Problems in MS Management We don`t know if treating the relapsing phase aggressively helps delay or prevent the progressive phase. Still no effective treatment for progressive multiple sclerosis There is no way of telling benign patients at the start of their disease

56 Summary MS is common and becoming more common in the western world It affects young adults mostly women It is autoimmune and treatable (but not curable) There is a relapsing phase followed by a progressive phase in most cases