Multiple Sclerosis (MS)

Multiple Sclerosis (MS)

• MS is an inflammatory disease of the central nervous system (CNS).
• The pathological hallmark of MS is demyelination, where the myelin sheath surrounding nerve fibers is damaged or destroyed.
• Myelin and the oligodendrocyte cells that produce it are fragile.
• These are the first CNS components affected by inflammation.
• Demyelination slows down nerve conduction and can ultimately lead to its failure.
• Axonal loss occurs from the outset of the disease.
• Symptoms typically manifest over days, sometimes hours or weeks.

MS Overview

• MS involves random inflammation in the CNS, which can sometimes be silent.
• Frequent inflammation leads to demyelination, axonal transection, and plasticity with potential for remyelination.
• Over time, the disease progresses with less frequent inflammation and increased axonal loss.
• All MS cases have both inflammatory and degenerative components.
• The relapsing-remitting form includes autoimmune attacks, months or years apart, that can lead to irreversible damage.
• Secondary progression involves continuing inflammation and persistent demyelination.
• Later stages involve infrequent inflammation, chronic axonal degeneration, and gliosis (scarring in the CNS).
• Low vitamin D levels and/or infection with Epstein-Barr virus (EBV) may cause MS.
• There may be a genetic component as well.

Common MS Symptoms

• Blurring of vision in one eye, often accompanied by pain.
• Numbness in one or both legs that may ascend up the trunk.
• Weakness in one or both legs.
• Clumsy hand with mixed sensory, motor, and coordination deficits.
• Patchy numbness.
• Urinary difficulties.
• Charcot's triad involves dysarthria, intention tremor with weakness, and nystagmus caused by plaques that blur vision, and affect eye movement.

Common Long-Term Issues in MS

• Fatigue unrelated to physical disability.
• Minor cognitive impairment such as reduced thinking ability and problems remembering.
• Difficulty walking.
• Bladder dysfunction.
• Sexual dysfunction.
• Distal numbness.
• Vision is usually not affected in the long term.

MS Diagnosis

• The 2010 McDonald criteria for MS diagnosis are based on:
  • Number of attacks and lesions
  • Additional requirements demonstrated by MRI.
• Criteria for MS Diagnosis:
  • Two or more attacks: requires two or more lesions or none
  • Two or more attacks and one lesion requires dissemination in space demonstrated by MRI or further attack
  • One attack and two or more lesions requires dissemination in time demonstrated by MRI or further attack
  • One attack and one lesion requires dissemination in space and time demonstrated by MRI or further attack
  • No attacks requires progression of one year of disease in one or more attacks: Positive brain MRI, spinal cord MRI or CSF

MRI Findings in MS

• Gadolinium (GAD) enhancing lesions represent a breakdown in the blood-brain barrier and the immune system’s ongoing inflammatory processes.
• Oligoclonal bands in cerebrospinal fluid (CSF) - MS are also indicative
• T2 lesions show demyelinating lesions, with their effects on fatigue symptoms.

Cerebrospinal Fluid (CSF) in MS

• In MS there are oligoclonal bands (OCB) in CSF, but not in serum
• There are total IgG increases and an increased IgG/albumin ratio.
• Total protein, including albumin, may be elevated, indicating CNS damage.

Evoked Potentials

• Used to assess nerve conduction.
• Visual Evoked Potential (VEP) reveals delayed conduction (>10ms).

Cause of Multiple Sclerosis

• MS has multi-factorial causes.
• Multifactorial contributors include genetics, with environmental factors.
• There is no single, definitive cause.
• EBV infection is believed to be essential, but not always sufficient.

MS Aetiology: Genetic Factors

• Genetic factors play a significant role in MS susceptibility.
• λs (lambda s): 16.8.

MS Aetiology: EBV

• EBV is a risk factor for MS.
• OR = 3.5.

MS Aetiology: Smoking

• Smoking is associated with an increased risk of MS.
• OR = 1.2

MS Aetiology: Latitude and Vitamin D Deficiency

• Latitude and vitamin D deficiency are correlated with MS risk.
• OR = 1.5.

MS and Genetics

• MS genetics encompasses multiple genes.
• MS influences key cell signaling pathways, including TH0, TH17, Treg, TH1, TH2, and TFH cells.

Smoking and Disease Progression

• Kaplan-Meier curves show progression-free survival according to smoking status.
• Smoking shortens the time to symptom onset.

Smoking and Disease Progression

• The US military personnel from 1993 to 2013.
• It included >10 million.
• Biennial serum samples.

• 62 million serum sample.

• 955 developed MS and were.
• 801 with serum sample.
• It also sampled and analyzed 1566 controls.
• 1/801 -ve for EBV: EBV has strong role
• HR = 26.5.
• 35 cases -ve EBV on first sample: seronegative on joining.
• 34/35 seroconverted prior to MS onset had become +ve.
• EBV is essential to develop MS, but not sufficient.
• HR 32.4/

MS Prognosis

• Long-term, the prognosis is dire when there is no treatment.
• With current therapies, most people with MS lead a normal life.

Expanded Disability Status Scale (EDSS)

• EDSS ranges from normal neurological examination to death.

Natural History of MS (Pre-Treatment Era)

• Shows the typical progression of the Expanded Disability Status Scale (EDSS) over time in MS patients before effective treatments were available.

Management Following Initial Attack

• Acute treatments for the initial MS attack: IVMP and oral steroids (large doses)
• Long-term therapies: Beta-interferons, glatiramer acetate, oral medications, infusions (mAbs)
• DMARDS (Disease-Modifying Antirheumatic Drugs) - NEED TO STAY ON INDEFINITELY.

Treatments for MS

• Acute Treatments: ACTH, IVMP, Oral MP
• Symptomatic Treatments: Baclofen, Oxybutinin, Amitriptyline and Gabapentin.
• Disease Modifying Therapy: Azathioprine, Natalizumab, Ocrelizumab, Betaferon, Finglemod, Ofatumumab, Avonex, Rebif, Mitoxantrone, Fumarate, Ozanimod, Copaxone, AHSCT, Teriflunomide, Alemtuzumab, and Siponimod.
• 1950s-2020

Multiple Sclerosis (MS) Treatment Options

• Beta-interferon works by targeting Y-receptors, with an efficacy.
• The route of administration is subcutaneous (S/C).
• The main issues include flu-like symptoms.
• Glatiramer acetate acts as an MBP (myelin basic protein) mimic, providing a modest level of effectiveness
• S/C for route of administration - concerns of post injection issues
• Teriflunomide - DHODH (dihydroorotate dehydrogenase) inhibitor, route - Oral - 1 benefit, concern is alopeica.
• Daclizumab-Interleukin-2 receptor MAB, route - S/C. Issue is liver function.
• Dimethyl Fumarate- Nrf2 inhibitor Route is Oral- Concern is lymphopenia ( low levels of lymphocytes), PML( progressive , multifocal, leukoencephalopathy)
• Fingolimod - S-1-P1 inhibitor route- oral concern - low level risks, lymphophenia, muscular oedema
• Natalizumab- works via VLA4 MAP route, Infusion intravenously PML concern
• Ocrelizumab - works via CD21 MAP route - intravenous infusion ,concern of side effects
• Alemtuzumab - CD52 MAP administered monoclonal antibiotics concern of AIDT

Drug Mechanisms

• Mechanisms and actions of drugs to treat MS

Comparative Efficacy and Approaches Used in MS treatment

• Oral and mAb therapy.
• Uses varying routes as well.
• Some are more effective with less adverse affects

Injectable Disease-Modifying Therapies (DMT) for MS

• It helps reduce relapse rated in all .
• All are very safe and works and helps reduce relapse as well
• 21 year survival rate of interferon Beta

Alemtuzumab

• Alemtuzumab reduces the risk by 49% for death
• Adverse affects include autoimmune disorder and those related to long- term effect after.

Age On Efficacy of Treatments

• the average less than 40 have higher effects

Cause of Uthoff's Phenomenon

• The phenomenon of worsening MS stems with an increase in body temp and is linked to raised ambient or temp
• The increase effect is caused by a release of cytokines.
• Uthoff effect is reversible.

Amitriptyline

• The effect on MS
• Depression aid for pain
• Insomnia aid
• newer SSRI better and less evidence

STOP-MS Trial

• World-first large-scale anti-EBV (Epstein-Barr virus) therapy is being conducted
• Involves 300 patients with different areas of the disease.
• Clinical trails include a double blind effect for the EBV and all treatments during
• Main measure includes side effects and patient outcomes

Neuromyelitis Optica (NMO) and its Treatment

• Also known as Devi's disease
• NMO vs MS Research publication includes all information of symptoms, MRI findings and diagnosis criteria 3 licensed therapies have proven to be useful and are approved.

Anti-MOG (myelin oligodendrocyte glycoprotein) Antibody Disease

• Clinical phenotype of all episodes of myelin oligodendrocyte glycoprotein Antibodies involved is treatment and the duration it takes to maintain.
• It also examines maintenance, treatments and therapy effects