Multiple Sclerosis Presentation (PDF)

School of Pharmacy MULTIPLE SCLEROSIS Dr Suha Dadou [email protected] Sensitive topic Copyright University of Reading LIMITLESS POTENTIAL...

School of Pharmacy MULTIPLE SCLEROSIS Dr Suha Dadou [email protected] Sensitive topic Copyright University of Reading LIMITLESS POTENTIAL | LIMITLESS LIMITLESS POTENTIALOPPORTUNITIES | LIMITLESS | LIMITLESS OPPORTUNITIES IMPACT | LIMITLESS IMPACT Learning Outcomes LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Multiple Sclerosis (MS) An autoimmune disease of the central nervous system (brain & spinal cord) MS typically affects young adults (onset between 20 & 40 years) and females Affects function in cognitive, emotional, motor, sensory, or visual areas LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Incidence and prevalence Incidence: 3-7 new cases per year per 100,000 population 2 500 000 affected people worldwide >130,000 in the UK (2018)  The incidence of MS has increased significantly over the past century  Primary cause of non-traumatic disability in young adult  Second - Alzheimer  There are remarkable differences in incidence between continents and countries LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Incidence and prevalence England 190 per 100,000 Adapted from Filippi et al, 2018 Scotland 290 per 100,000 Female to male ration 3:1 (it was 2:1 in 1950s) LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Environmental factors Sunlight – Vit D Tobacco exposure Pierrot- Deseilligny & Souberbielle, 2017 Healy et al, 2009 D has a modularity effect on MS Obesity Olsson et al, 2017 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Environmental factors Viral Exposure Science, 2022 (Epstein Barr Virus) Haahr et al, 2004 Samples from 801 people who developed MS. Compared these to samples from more than 1,500 matched controls (people with similar characteristics who did not develop MS). A much higher rate of EBV infection among people who developed MS than among controls People infected with EBV were 32 times as likely to develop MS as uninfected people. This was the first study providing compelling evidence of causality LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Genetic factors  There is an increased risk linked to close family members developing the disease Prevalence of familiar MS is about 13% for all MS phenotypes (Harirchian et al, 2017) 1st degree relatives (parent, children, sibling) have risk 2.5-5% developing MS An identical twin with MS raises the risk to 20-25%  Genome wide association study identified further immune related genes – 200 genetic factors (Baranzini & Oksenberg, 2017) LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Pathology Inflammation in the brain and spinal cord – demyelination Why it is important? Inflammatory infiltrates mainly consist of lymphocytes and macrophages The initial cause of inflammation in MS is not clear, and may be multifactorial LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Pathology Loss of myelin sheaths (‘demyelination’) Immune cell (lymphocytes – macrophages) cross BBB – attack neuron cells Axonal damage and neuronal loss Lesion LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Pathology Pathology Consequences: a) acute loss of function b) repairable damage - remission c) chronic damage In primary progressive MS, 5% of the spinal cord cross sectional area can be lost annually Chronic lesions in paralysed MS patients show an average loss of 68% (45-84%) of axons Axonal degeneration is a major cause of irreversible deficit with no effective therapy LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Clinical presentation A key aspect of MS is the relationship between relapsing and remitting disease, and progressive disease. About 20% of patients with MS present with a progressive form of the disease from the start (primary progressive) However individuals with a relapsing/remitting form of MS can go on to develop a progressive disorder (secondary progressive) LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Clinical presentation Common symptoms with other diseases – difficult to diagnose Specific symptoms Uhthoff’s phenomenon Symptoms take a huge turn for the worse upon an increase in body temperature (e.g. upon immersion in a hot bath) Lhermitte’s sign Electrical sensation running down the spine upon neck flexion LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Diagnosis MRI: to detect white matter abnormalities and spinal lesions McDonald diagnostic criteria LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Diagnosis Diagnosis is a combination of time-course for clinical episodes, lesions detected by MRI and cerebrospinal fluid (CSF) markers Adapted from Compston and Coles (2008) LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Treatments MS can improve or stabilise by being treated with medicines early in the course of the disease. Treatments will be different for each person depending on the severity of the disease and symptoms. No cure for MS, treatment can reduce symptoms, prevent further relapses and improve quality of life. Disease-modifying treatments (DMT) Symptomatic treatments LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Treatments NICE - June 2022 Stoppable Repairable Unrepairable but preventable? LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Steroids Acute relapse episode High dose corticosteroid Hospitalisation  oral methylprednisolone, 500 mg daily, 3-5 days  i.v. methylprednisolone, 1g daily, 3-5 days Adapted from Kieger et at, 2014 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Natalizumab Monoclonal antibody which inhibits leucocyte migration into CNS Anti-inflammatory effects Marketed as Tysabri Mechanism of action: binds to a4 subunit of a4b1 and a4b7 integrins, expressed on the surface of activated T-cells Prevents binding of cells to receptors on the endothelium – x BBB Licensed for the treatment of adults with rapidly evolving severe relapsing-remitting multiple sclerosis (NICE TA127) Linked to cases of Progressive multifocal leukoencephalopathy LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Natalizumab Deemed not to be a cost-effective treatment in some groups of MS patients (those who failed to respond to beta interferon) NICE guidelines published August 2007 Natalizumab is administered by intravenous infusion; the recommended dose is 300 mg every 28 days. Natalizumab costs £1130 per 300 mg vial (in 2007), so over a year the cost of the drug is approximately £14,730 per patient. LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Fingolimod Fingolimod (Gileyna) – Sphingosine analogue – Sequesters lymphocytes in lymph nodes Prevents them crossing BBB – Reduces rate of relapse – Reduce inflammatory agents – May become first line treatment? LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Fingolimod Fingolimod is recommended as an option for treatment of highly active relapsing–remitting multiple sclerosis in adults, only if: they have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon, and the manufacturer provides fingolimod with the discount agreed as part of the patient access scheme* Received EMEA license in March, 2011 NICE TA254, April 2012 *The list price of fingolimod is £1470 for 28 capsules equivalent to an annual cost of approximately £19,169 per person. The manufacturer of fingolimod has agreed a patient access scheme with the Department of Health, in which a discount on the list price of fingolimod is offered. LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Dimethyl fumarate Developed by Biogen as anti-MS therapy (as Tecfidera) Thought to act as anti-inflammatory agent NICE TA320 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Both beta interferon and glatiramer acetate have been used in a clinical setting for MS. Current NICE guidelines do not recommend use following cost/benefit analysis (NICE TA527) Some patients may still be prescribed interferon beta if treatment started prior to changes in NICE guidelines LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Alemtuzumab Anti-CD52 antibody CD52: antigens expressed on B and T cells Reduces inflammatory response in early MS Based on clinical trial vs beta interferon, this is now available on the NHS (as of NICE guideline, last update March 2020) (TA312) LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Teriflunomide Once-daily oral immunomodulator (NICE TA303) Teriflunomide inhibits dihydro-orotate dehydrogenase This is required for de-novo pyrimidine synthesis pathway needed by rapidly dividing lymphocytes LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Symptomatic treatments NICE guidelines 2022 – first line baclofen (GABAb receptor agonist, inhibits spinal reflexes) - Second line Gabapentin (calcium channel blocker) (class C substance) THC:CBD spray (4-week trial): when other treatment are not effective tizanidine (alpha2 agonist, muscle relaxant) diazepam, clonazepam (benzodiazepines, GABAa agonists, act at level of spinal cord to cause muscle relaxation) dantrolene (ryanodine receptor agonist, muscle relaxant) Intrathecal baclofen Sativex LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  Pain (NICE guidelines 2022) 80% of MS patients have pain See Pain lecture Cognitive symptoms 60% of MS patients have cognitive symptoms Donepazil sometimes used Cognitive training programmes Fatigue (NICE guidelines 2022) Amantadine – dopamine agonist Modafinil (except pregnant) SSRI Emotional lability Amitriptyline LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Vitamin D Lower incidence of MS in countries with more sunlight Some suggestion that Vitamin D may help prevent MS, leading to the idea that it could be useful in treating MS No clinical trial evidence to support use of Vitamin D, not recommended by NICE as a treatment for MS https://theconversation.com/does-a-lack-of-vitamin-d-put-you-at-greater-risk-of-multiple-scler s-47057 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Future treatment LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT https://www.mssociety.org.uk/ LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT cines Lists (EML); WHO acy including through World MS Day (May 30); RESPONSE with MS, health professionals and MS groups and organizations to stimulate and infor hen health systems to improve the rehabilitation services for people with neurological Endorsed a global action plan on epilepsy and other neurological disorders 2022–2031 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Summary SUMMARY LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT