MS

Learning Objectives

  • to gain understanding of the pathology and pathogenesis of MS

  • understand prevalence and risk factors

  • recognise the multiple categories of MS and its progressing symptoms and diagnosis

  • recall forms of therapy available for MS and their mechanism of actions

Introduction

Multiple Sclerosis (MS – “sclerosis” meaning hardening of tissue

  • Chronic, inflammatory, autoimmune neurological disease that causes the degeneration of the myelin sheath and axons of healthy neurons in Central Nervous System

  • Early onset is common and progressive neurological symptoms are seen, varying from movement to vision

  • Disease-modifying therapies have been approved but no cure exists – non-fatal disease

  • MRI scan of a 35-year-old MS patient showing large white matter lesions in top right corners and a small matter in bottom right

Incidence and Prevalence (Epidemiology)

Estimated 2.8 million people worldwide with MS

  • = 35.9/100,000 people prevalence – this is high, why?

  • Prevalence has increased over time, why?

  • Incidence = 2.1/100,000 per year

  • Mean age of diagnosis = 32yrs (but can be any age)

  • Females 2-3x more likely to be diagnosed, why?

Aetiology (causes)

  • The exact cause of MS (if there is one) is unknown

There are 3 leading hypotheses as to this cause:

  • Immune Factors

  • Environmental Risk Factors

  • Genetic Risk Associations

  • It’s most likely it’s a combination of one or more of these that triggers the disease – a “multi-step hypothesis”

Immune Factors

  • An auto-immune attack, or multiple, is the leading hypothesis

  • An unknown antigen (protein recognised by our antibodies) may activate th1 + th17 pro-inflammatory T cells

  • These may then bind to and cross the Blood-Brain Barrier

  • Then cause a cross-reactive immune attack to the CNS

  • This may recur and lead to further CNS damage

1) autoantigens/pathogens engulfed by antigen presenting cell

2) fragments released by APC are detected by CD4 and T cells and bind to activate T cell and releases differentiating cytokines

  • Th1 - protects against intracellular pathogens - autoimmunity

  • Th2 - protection against extracellular pathogens: allergy/asthma

  • Th17 - protect against extracellular pathogens - autoimmunity

Environmental Factors

  • not one definitive causative environmental agent

  • multiple factors correlate with increases incidence e.g.,

1) vit D deficiency - no neuroprotection

2) eptein-barr virus - crosses BBB

3) obesity and smoking - neurodegenerative

  • so mix of genetic and environmental factors are likely

Genetic Risk Factors

What about hereditary risk?

  • Patients with biological relatives with MS have heightened risk

  • General population risk is roughly 0.1% over lifetime

  • Having a 1st-degree relative with MS increases risk to 2-4%

  • Monozygotic twin concordance = ~20-30%, dizygotic = ~5%

What could account for this increase?

  • human leukocyte antigen (HLA) DRB1*1501 allele shows highest correlation with diagnosis (produces a protein which presents foreign antigens to the leukocytes (white blood cells, see on right)

Common correlating gene variants

  • Immunity-related genes: HLA-DR, IL2RA, IL4, IL6, IL12B, IL17R, IRF5, CD24, CD58, and EVI5 (autoimmune)

  • Vitamin D metabolism: VDR and CYP27B1 (neuroprotective)

  • Certain genes in mitochondrial DNA (female prevalence)

  • Fibrinolysis: PAI-1 (failure to break down clots can lead to BBB dysfunction)

  • CNS function and repair: ApoE and DPP6 (prevents excitotoxicity)

Presentation/Diagnosis

Symptoms can relate to any part of the CNS

  • Symptoms will mirror the area of nervous damage

  • These can be sensory or motor symptoms

  • Symptoms in the periphery (neural pathways controlling muscle) are only due to central nervous damage further up the chain

  • Symptoms will appear below the area(s) of damage

Common initial symptoms + diagnosis

symptoms can imitate other conditions so differentials are important

  • usually by seeing localised symptoms vs multiple across the body

initial symptoms include:

  • loss/blurriness of vision

  • sensory or motor weakness/stiffness

  • urinary symptom

  • reduced muscle tone

  • cerebellar symptoms

diagnosis given by presence of multiple common initial symptoms plus history/evidence of neurological disorder

  • MRI to assess lesions to aid diagnosis

Common mimics (misdiagnosis)

Other conditions may present similarly but have localised or much more progressive symptoms, These include

  • Optic neuritis (inflammation of the optic nerve)

  • Meningitis (meninges inflammation)

  • Transverse myelitis (spinal cord inflammation)

  • Lyme disease (bacterial tick-borne disease can cause neurological symptoms)

  • And many others

Biomarkers

  • Diagnosis can be aided by measuring of concentrations of proteins taken from cerebrospinal fluid samples (CSF) taken by lumbar puncture (spinal tap)

Biomarkers include:

  • Oligoclonal bands (representative of IgGs – antibodies – to suggest inflammation or autoimmune attack in the CSF)

  • Neurofilament light (NfL) – suggests neurodegeneration

  • Glial Fibrillary Acid Protein (GFAP) – suggest glial cell dysfunction (astrocytes support neurons)

Categories of MS

Relapsing-remitting (RR): This initial onset is observed in 70% to 80% of multiple sclerosis patients and. New or recurrent neurological symptoms that are consistent with multiple sclerosis

  • Symptoms lasting 24 to 48 hours

  • Symptoms developing over days to weeks

Primary progressive (PP): This course presents in 15% to 20% of patients and shows a gradual deterioration from onset without relapses.

Secondary progressive (SP): Following an initial relapsing-remitting course, this course is marked by a more gradual neurological decline. Superimposed relapses can occur but are not mandatory.

Progressive-relapsing (PR): This course involves gradual deterioration with superimposed relapses and is seen in 5% of patients.

Rare categories of MS

  • Clinically isolated syndrome: This is often classified as a single episode of inflammatory CNS demyelination.

  • Fulminant: This is characterized by severe multiple sclerosis with multiple relapses and rapid progression toward disability.

  • Benign: This features an overall mild disability course with rare relapses.

MS Progression

most people present with relapsing remitting ms

  • new or worsening symptoms with periods of partial/complete recovery

most people eventually reach secondary progressive MS

  • symptoms gradually worsen over time with increased disability

  • can be influenced by treatments - DMTs

  • few people die of MS but can lead to complications of bed bound or dysphagia

Expanded Disability Status Scale (EDSS)

  • 1 - normal neurological function

  • 2 - no disability but minimal functions

  • 3 - minimal disability

  • 4 - significant disability but no walking impairments

  • 5 - unable to perform daily activities

  • 6 - aid is required to walk

  • 7 - needs wheelchair to get around

  • 8 - requires assistance with wheelchair

  • 9 - bedridden and unable to communicate

  • 10 - death due to MS

Prognosis

Not considered a terminal disease

  • Patients die with MS, not of it (in most cases)

Longevity = 5-10 years reduced relative to those without MS

  • Prognosis depends on category, and progression through stages of disability and speed reaching Secondary Progressive Phase

  • This varies greatly, dependent on treatment, age of onset, aetiology

  • Long Term Treatment of Multiple Sclerosis with Interferon-?? May Be Cost Effective

Pathophysiology of MS

Primarily affects the CNS

  • Grey matter, white matter, optic nerve, spinal nerve, cerebellum, meninges all affected

2 Fundamental processes:

  • Focal inflammation results in macroscopic plaques (lesions) and injury to the blood-brain barrier.

  • Neurodegeneration involves microscopic damage to various components of the CNS, such as axons, neurons, and synapses.

Further pathophysiology

  • chief components of plague pathology - myelin loss, oedema and axonal injury

  • disruptions of BBB corresponds to enhancement observed on MRI scans

  • inflammatory process subsides over time - leads to formations of astrocytic scar

Pharmacotherapy of MS

  • immediate treatment upon diagnosis is crucial for multiple sclerosis

  • short term goals focusing on decreasing MRI lesion activity

  • long term goals are preventing secondary progression

Forms of MS therapy

  • can be drug based

  • physiotherapy to help retain muscle function and reduce neurological symptoms

  • cannabis can be help with spasms and stiffness - difficult in UK

  • acupuncture, pilates, yoga etc

HSCT therapy for MS

  • Haematopoietic Stem Cell Therapy (HSCT) aims to treat the auto-immune aspect of MS

  • Immune stem cells (HSCs) are removed and stored, while chemotherapy and other biologics degrade the patient’s immune system (a “reset”)

  • Infusion of autologous HSCs has been shown to reduce or remove relapses and progression to secondary progressive stage

Disease Modifying Therapies for MS

  • DMTs are treatments that target the underlying cause of a disease

  • Multiple are approved for use in MS treatment, though no cure exists

  • Patients with aggressive, secondary MS often experience neurodegenerative symptoms and thus DMTs can inhibit neuronal loss and symptom progression

Interferon beta

a cytokine in the interferon family used to treat multiple sclerosis

interferon injections may result in an 18–38% reduction in the rate of MS relapses.

MoA: multiple mechanisms:

  • Modulation of T- and B-cell function

  • Alters cytokine expression

  • BBB recovery

  • Injected subcutaneously or intramuscularly

expression of immune response genes

  • natural IFN beta type 1 is secreted primarily by fibroblasts

  • IFN binds to the interferon receptor to mediate effects in multiple tissues

  • activating interferon stimulated genes

Natalizumab

  • IV-administered monoclonal antibody

  • Prevents adhesion of leukocytes to the vascular endothelium (BBB)

  • Prevents invasion of immune cells into the CNS

  • Reduces auto-immune activity and subsequent neuronal damage

Fingolimod

  • First orally approved medication

  • Specifically modulates phosphate receptors in the lymphatic system

  • This prevents leukocytes from exiting lymph nodes (where they are stored) to join an autoimmune response

  • Reduces the size of auto-immune damage to prevent relapse and limit neuronal damage

QUESTIONS

Part 1: Single Best Answer (SBA) Questions

1.

What is the primary pathological process that underpins the formation of the characteristic lesions (plaques) seen on MRI scans in Multiple Sclerosis?

a) A primary, degenerative loss of neurons in the cerebral cortex.

b) An autoimmune-mediated inflammatory attack on the myelin sheath and axons within the Central Nervous System (CNS).

c) A bacterial or viral infection that directly destroys oligodendrocytes.

d) A vascular event causing ischemia and necrosis of white matter tracts.

Answer:

b) An autoimmune-mediated inflammatory attack on the myelin sheath and axons within the Central Nervous System (CNS).

MS is defined as a chronic, inflammatory, autoimmune disease that causes demyelination and axonal damage in the CNS. This focal inflammation is what creates the plaques visible on MRI.

2.

A 28-year-old woman presents with a two-day history of blurred vision in one eye and new-onset numbness in her left leg. An MRI shows multiple white matter lesions in different regions of the brain and spinal cord. This clinical presentation is most characteristic of which category of MS?

a) Primary Progressive MS (PPMS)

b) Secondary Progressive MS (SPMS)

c) Relapsing-Remitting MS (RRMS)

d) Benign MS

Answer:

c) Relapsing-Remitting MS (RRMS)

The acute onset of new neurological symptoms (optic neuritis, sensory deficit) with dissemination in space (multiple CNS lesions) is classic for a relapse in RRMS, which is the most common initial presentation.

3.

Which of the following is a key environmental risk factor strongly associated with an increased incidence of MS?

a) High dietary intake of saturated fats

b) Vitamin D deficiency

c) Excessive caffeine consumption

d) High-altitude living

Answer:

b) Vitamin D deficiency

Low vitamin D levels are a well-established environmental correlate with increased MS risk, thought to relate to its neuroprotective and immunomodulatory roles.

4.

What is the primary mechanism of action of Natalizumab, a Disease-Modifying Therapy (DMT) for MS?

a) It modulates sphingosine-1-phosphate receptors to sequester lymphocytes in lymph nodes.

b) It is a cytokine that broadly alters the expression of immune response genes.

c) It is a monoclonal antibody that prevents immune cells from crossing the blood-brain barrier.

d) It acts as a chemotherapeutic agent to ablate the existing immune system.

Answer:

c) It is a monoclonal antibody that prevents immune cells from crossing the blood-brain barrier.

Natalizumab is an IV-administered monoclonal antibody that blocks the adhesion of leukocytes to vascular endothelial cells, thereby preventing their migration across the BBB into the CNS to cause inflammation.

5.

When diagnosing MS, the presence of Oligoclonal Bands (OCBs) in the cerebrospinal fluid (CSF) is a useful biomarker because it indicates:

a) A specific bacterial infection mimicking MS.

b) Evidence of intrathecal IgG synthesis, suggesting an inflammatory/autoimmune process within the CNS.

c) Acute axonal damage and neurodegeneration.

d) Dysfunction of the astrocytes that support neurons.

Answer:

b) Evidence of intrathecal IgG synthesis, suggesting an inflammatory/autoimmune process within the CNS.

OCBs represent immunoglobulins (IgG) produced by plasma cells within the CNS, indicating a localized immune response. This supports the diagnosis of an inflammatory condition like MS.

Part 2: Extended Matching Questions (EMQ)

Questions 6-8:

Match the Disease-Modifying Therapy (DMT) to its correct mechanism of action.

Options:

A. Modulates sphingosine-1-phosphate receptors to sequester lymphocytes in lymph nodes.

B. A cytokine that alters T/B-cell function and cytokine expression.

C. A monoclonal antibody that blocks leukocyte adhesion and migration across the BBB.

D. Resets the immune system via chemotherapy followed by autologous stem cell infusion.

6.

Fingolimod

Answer:

A. Modulates sphingosine-1-phosphate receptors to sequester lymphocytes in lymph nodes.

Fingolimod is an oral S1P receptor modulator that traps lymphocytes in lymph nodes, preventing them from reaching the CNS.

7.

Interferon-beta

Answer:

B. A cytokine that alters T/B-cell function and cytokine expression.

Interferon-beta is an immunomodulatory cytokine with multiple mechanisms, including shifting the immune response away from pro-inflammatory pathways.

8.

Haematopoietic Stem Cell Therapy (HSCT)

Answer:

D. Resets the immune system via chemotherapy followed by autologous stem cell infusion.

HSCT uses high-dose chemotherapy to ablate the autoreactive immune system, which is then rebuilt using the patient's own (autologous) stem cells.

Questions 9-10:

For each genetic factor, select its proposed role in MS susceptibility.

Options:

A. Highest genetic risk association; involved in antigen presentation.

B. Implicated in vitamin D metabolism and neuroprotection.

C. Involved in preventing excitotoxicity and CNS repair.

D. Associated with failure to break down clots, potentially affecting BBB integrity.

9.

HLA-DRB1*1501 allele

Answer:

A. Highest genetic risk association; involved in antigen presentation.

This HLA allele is the single strongest genetic risk factor for MS. HLAs are critical for presenting antigens to T-cells, linking to the autoimmune hypothesis.

10.

Plasminogen Activator Inhibitor-1 (PAI-1) gene

Answer:

D. Associated with failure to break down clots, potentially affecting BBB integrity.

Variants in the PAI-1 gene, involved in fibrinolysis (clot breakdown), may contribute to BBB dysfunction, a key step in MS pathogenesis.

Part 3: Clinical Scenarios (OSCE/Patient Style)

Scenario 1: Explaining the Diagnosis

A patient has just been diagnosed with Relapsing-Remitting MS after an episode of optic neuritis. They ask, "What is actually happening inside my body to cause these symptoms?"

How would you explain the core pathophysiology in simple terms?

* Use an Analogy: "Think of the nerves in your brain and spinal cord like electrical wires. They have a protective coating called myelin, similar to the plastic insulation on a wire."

* Explain the Attack: "In MS, your body's own immune system mistakenly attacks and damages this insulation. This is called inflammation. When the insulation is damaged, the electrical signals that carry messages—like 'see' from your eye or 'move' to your leg—get slowed down, garbled, or blocked entirely."

* Link to Symptoms: "The recent problem with your vision was because this inflammation happened on the nerve connecting your eye to your brain. The MRI spots we saw are like scars (plaques) left from these areas of damage."

Scenario 2: Counselling on DMT Options

A patient with active RRMS is discussing starting a Disease-Modifying Therapy. They are trying to choose between an injectable (Interferon-beta), an oral medication (Fingolimod), and an IV infusion (Natalizumab).

What is a key mechanistic difference you would highlight between Fingolimod and Natalizumab?

* Fingolimod's Mechanism: "Fingolimod works like a 'lock-in' signal for specific immune cells in your lymph nodes. It stops them from leaving and traveling to your brain and spinal cord to cause damage in the first place."

* Natalizumab's Mechanism: "Natalizumab works right at the 'gate' to your brain—the blood-brain barrier. It blocks the immune cells, preventing them from actually crossing over from your blood into your nervous system to attack it."

* Key Difference: "So, Fingolimod acts upstream by keeping the cells in the lymph nodes, while Natalizumab acts at the final barrier itself. Both aim to reduce inflammatory attacks, but they do it at different geographical points in the body."

Part 4: Monitoring & Prognosis

Question 11: Using the EDSS Scale

On the Expanded Disability Status Scale (EDSS), a score of 6.0 indicates which level of disability?

Answer:

A score of 6.0 means the patient requires intermittent or unilateral constant assistance (cane, crutch, brace) to walk about 100 meters with or without resting. It signifies "aid is required to walk."

Question 12: Long-Term Prognosis

Why is MS generally described as a disease that patients "die with" rather than "die of"?

Answer:

MS itself is rarely the direct cause of death. The reduced life expectancy (by 5-10 years) is primarily due to complications of severe disability, such as infections (e.g., pneumonia from being bedbound), dysphagia leading to aspiration, or complications related to immobility. The disease burden is chronic disability, not acute fatality.