MS

Multiple Sclerosis - Pathology, Current Treatments, and Challenges

Presenter Information

  • Dr. Hugh Kearney

    • Qualifications: MB BCh BAO, FRCPI, PhD

    • Role: Consultant Neurologist at St James’s Hospital, Senior Clinical Lecturer at Trinity College Dublin

Dr. Kearney's Background

  • Affiliation with key institutions:

    • Queen Square MS Centre

    • Candidate for significant contributions in multiple sclerosis (MS) research and treatment.

Overview of the Presentation

  • Main Topics Covered:

    • Pathology of Multiple Sclerosis

    • Current Treatment Options

    • Challenges in MS Management

Understanding Multiple Sclerosis

  • Definition:

    • Multiple Sclerosis (MS) is an immune-mediated chronic inflammatory disorder that affects the central nervous system (CNS).

  • Key Characteristics:

    • Involves inflammatory demyelination of both the brain and spinal cord.

    • Recognized as the second leading cause of physical disability in young adults in the western world.

Epidemiology

  • World Distribution of Multiple Sclerosis:

    • Risk varies geographically:

    • Areas marked with varying degrees of risk from high to low according to latitude.

    • Adapted from the work of McAlpine et al. (1965).

Risk Factors Associated with MS

  1. Epstein-Barr Virus

    1. Smoking

  2. Low Serum Vitamin D

  3. Genetics: HLA DRB1*1501

  4. Adolescent Obesity

Scientific Evidence Related to EBV and MS

  • Studies Indicating High Prevalence of EBV in MS Patients:

    • Reference: K. Bjornevik et al. (2022), published in Science.

    • Noteworthy Findings:

    • Analysis showed higher levels of seropositivity in MS patients compared to non-MS controls.

Pathological Features of Multiple Sclerosis

  • Lesion Formation:

    • Lesions typically form around blood vessels.

    • Perivascular inflammation is an early pathological feature.

  • Demyelination Locations:

    • Grey and white matter demyelination established in both regions of the CNS.

Symptoms Associated with MS

  • General Symptoms:

    • Fatigue, heat intolerance (Uthoff’s phenomenon), depression, neuropathic pain, urinary frequency, ambulatory dysfunction, spasms, and spasticity.

  • Specific Symptoms:

    • Optic Neuritis:

    • Unilateral visual loss, red vision affected first, pain on eye movement which typically resolves within two weeks.

    • Brain Stem/Cerebellar Symptoms:

    • Facial palsy, ataxia, diplopia, trigeminal neuralgia, nystagmus, and signs indicative of brain stem syndrome.

    • Spinal Cord Symptoms:

    • Lhermitte’s symptom, numbness, urinary urgency, fecal incontinence, sexual dysfunction, spastic paraplegia, and increased muscle tone.

Differential Diagnosis for MS

  • Considerations Include:

    • Ischaemia, inflammatory diseases (e.g., sarcoidosis, lupus), infections (e.g., syphilis, listeria), nutritional deficiencies (e.g., B12), and genetic conditions (e.g. Fabry’s disease).

Subtypes of Multiple Sclerosis

  1. Relapsing-Remitting MS (RRMS)

  2. Secondary-Progressive MS (SPMS)

  3. Primary-Progressive MS (PPMS)

Clinical Diagnosis of RRMS

  • Diagnosis Criteria:

    • Based on documentation of dissemination in time and dissemination in space linked to history of relapses suggestive of demyelination.

    • Physical examination must corroborate findings.

Diagnostic Techniques for MS

  • Use of MRI in Diagnosis:

    • MRI applied post-clinical diagnosis for confirmations based on McDonald criteria.

  • Criteria for Dissemination in Space and Time:

    • Dissemination in Space: At least one T2 lesion observed in at least two of the four specified areas of CNS:

    • Periventricular, juxtacortical, infratentorial, and spinal cord.

    • Dissemination in Time:

    • Established via follow-up MRI demonstrating new lesions compared to baseline or indication of simultaneous existence of asymptomatic enhancing and non-enhancing lesions.

Current Treatment Strategies

  1. Interferon Beta:

    • Mechanism of action (MOA) is unclear, indicated to reduce relapses by ~1/3, administered via s/c or i.m. injection.

    • Side effects: headache, flu-like symptoms, elevated liver function tests (LFT), leukopenia.

    • Notable high number needed to treat (NNT).

  2. Glatiramer Acetate:

    • Functions by mimicking myelin, also reducing relapses by ~1/3 via s/c injection.

    • Side effects include injection site reactions and rare occurrences of anaphylaxis.

  3. Sphingosine Phosphate Receptor Inhibitors:

    • Fingolimod, ponesimod, ozanimod, Siponimod: administered orally, reduce relapses by ~50%.

    • Caution needed due to side effects including bradycardia, heart block, macular edema, raised LFTs, lymphopenia, and risk for progressive multifocal leukoencephalopathy (PML).

  4. Fumarates (Dimethyl Fumarate):

    • Oral administration with ~40% reduction in relapses; side effects include flushing, gastrointestinal issues, PML, lymphopenia, elevated LFTs, and reactivation of tuberculosis.

  5. Cladribine:

    • Administered orally or s/c, recommended in five-day intervals, for immune reconstitution therapy with ~60% reduction in relapses.

    • Side effects include reactivation of TB or Hepatitis B, increased malignancy risk, lymphopenia, hepatotoxicity, and nausea.

  6. Natalizumab:

    • Delivered via IV every four weeks, indicated for ~60% reduction in relapses, with PML as a significant risk assessed through JC virus status monitoring.

  7. Anti-CD20 Monoclonal Antibodies:

    • Includes ocrelizumab, ofatumumab, ublituximab, and rituximab.

    • Administered via IV or s/c based on specific protocols, with ~50-60% reduction in relapses, and risk of upper respiratory tract infections, herpes infections, reactivation of Hepatitis B or tuberculosis, and PML.

  8. Anti-CD52 Monoclonal Antibodies (Alemtuzumab):

    • Administered in two infusions one year apart; with ~55% reduction in relapses and considered for immune reconstitution therapy.

    • Notable side effects include headaches, infusion reactions, risk of Graves' disease, immune thrombocytopenic purpura (ITP), stroke, and increased risk of malignancy.

Challenges in MS Treatment

  • Current Treatment Limitations:

    • Not all patients benefit; for every individual helped, a considerably higher number experience no improvement (NNT statistics).

  • Effects of Disease-Modifying Therapies (DMTs):

    • Impact on the natural history of MS suggest nuanced outcomes with patients diagnosed later experiencing delayed disability milestones.

    • Need for advancements toward addressing neuroprotection and remyelination remains pivotal for future therapies.

Future Perspectives on Treatment Strategies

  • Development of mRNA vaccines aimed at addressing implications of EBV infection in relation to MS.

  • Continued research essential for identifying efficient therapeutics that mitigate long-term complications and enhance patient quality of life.

Conclusions

  • MS is established as an autoimmune disease strongly linked with prior Epstein-Barr virus infections.

  • Existing therapies primarily focus on immunosuppression/immunomodulation to control relapses, with future treatment discoveries required to effectively address disease progression.

Acknowledgements

  • Research collaborators include Ms. Aoife Kirwan - MS Ireland, Dr. Jean Dunne, Prof. Jim Meaney, Prof. Matthew Campbell, and Prof. Niall Conlon.

Contact Information

  • Dr. Hugh Kearney

    • St James’s Hospital, Trinity College Dublin, The University of Dublin, Dublin, Ireland.