CNS II - MS (Exam 2 Material)

What are the 3 main characteristics of Multiple Sclerosis (MS)?

• Sclerosis: Stiffening of tissue or anatomical feature

  • REMEMBER: S for stiffening, S for sclerosis

• Demyelinating disease: Acquired condition characterized by damage to previously healthy myelin

• Autoimmune disease: Immune system attacks own myelin

What is the epidemiology of MS?

• Most common demyelinating disorder

• 1 in 1000 individuals in the U.S. have MS

  • ~1 million in the U.S., 2.8 million worldwide

• More common in females (~75% of people with MS are female)

• Most people are diagnosed between ages of 20 and 50

  • Mean age of diagnosis is 32

  • REMEMBER: Disease of YOUNG ADULTS

What are the genetic factors of MS?

• Family history increases risk

• Not familial/monogenic (not Mendelian - not autosomal dominant/recessive)

  • MS has genetic susceptibility, but is NOT a familial/monogenic disease (not caused by a single inherited gene).

• Genetics (over 200 genes identified → complex gene disorder = genes + environmental factors)

  • HLA-DRB1

  • IL-2 and IL-7 receptors

  • Shared genetics with other autoimmune disorders → involved in the immune system

What are the environmental risks factors of MS?

• Infection/abnormal immune activation:

• Environmental Factors:

  • Geography: More frequent when you’re farther from the equator

    • Due to less sun/Vitamin D

  • Vitamin D: Low levels are associated with the risk of MS

  • Smoking: Associated with increased risk of disease and more rapid disease progression

    • Stopping smoking will cause slower progression of disease

  • Obesity specifically in childhood or adolescence: associated with increased risk and more MS activity in those already diagnosed with MS

What are the (5) most common clinical symptoms of MS?

• Fatigue

• Numbness or weakness in one or more limbs that typically occurs on one side of your body at a time

• Mobility issues: Lack of coordination, unsteady gait or inability to walk

• Vision problems: Partial or complete loss of vision, usually in one eye at a time, often with pain during eye movement; prolonged double vision; blurry vision

• Pain: Neuropathic and musculoskeletal

What are the 4 clinical presentations of Multiple Sclerosis (MS)? 🟠

[CIS, RRMS, SPMS, PPMS]

1. Clinically Isolated Syndrome (CIS)

• First episode of neurological symptoms lasting ≥24 hours

• Occurs only once initially; may or may not progress to MS

2. Relapsing-Remitting MS (RRMS): Most common form

• Relapse: New OR existing neurological symptoms suddenly worsen.

• Remission: Symptoms partially or completely improve

• Characterized by repeated relapses followed by periods of remission

3. Primary Progressive (MS)

• Progressively worsens from disease onset (like when the disease starts, the symptoms just become worse and worse with no stop)

4. Secondary Progressive MS:

• Initially begins as RRMS

• Symptoms steadily worsen, even without relapses (progressively just gets worse)

• "I used to have episodes where I got worse and then better, but now I'm gradually getting worse over time, even without new attacks."

Memory trick:

• RRMS = Relapse and Recover

• SPMS = Starts as RRMS then Progresses

• PPMS = Progresses from the beginning.

What are the clinical manifestations of Clinically Isolated Syndrome (CIS) in MS? 🟠

1. Optic Nerve Involvement (Frequent First Manifestation)

• Optic neuritis: Inflammation of the optic nerve

  • Causes unilateral visual impairment (vision problems in one eye)

• ~10-50% of people with optic neuritis develop MS

Remember: Optic neuritis is a frequent first manifestation of MS, but not everyone who develops optic neuritis will develop MS.

2. Brainstem involvement → produces cranial nerve-related signs

• Ataxia: Poor coordination and balance

• Nystagmus: Involuntary eye movements

• Internuclear ophthalmoplegia (INO): Damage to pathways coordinating eye movements → eyes don’t move together properly → double vision

3. Spinal Cord Lesions

• Cause motor and sensory impairment of the trunk and limbs

• Spasticity: Increased muscle stiffness/tone

• Loss of bladder control: Difficulty controlling urination

4. Cognitive changes:

• Changes in cognitive function may occur

• Often milder than the motor and sensory symptoms described

How is MS diagnosed? What are the three main diagnostic tests for MS? 🟠

• No specific tests for MS but can rule out other diseases by blood test or test CSF (cerebrospinal fluid) to rule out infection

3 Main Diagnostic Tests for MS:

1. MRI (Brain and spinal cord)

• Detects characteristic MS lesions (areas of demyelination) in the CNS

• A contrast agent may be injected into a vein to highlight active inflammatory lesions

2. Lumbar Puncture (Spinal Tap)

• Collects cerebrospinal fluid (CSF) for analysis

• Examines proteins and inflammatory markers associated with MS

• Helps rule out infections and other diseases that mimic MS

3. Evoked Potential Tests

• Electrodes placed on the skin/scalp measure the nervous system’s electrical responses to stimulation

• Evaluate speed and accuracy of nerve signal transmission

• Demyelination can slow electrical conduction, producing delayed responses

What are the pathological hallmarks of MS?

1. White Matter Lesions (Plaques)

• When myelin is destroyed in a particular area of the CNS, that area becomes a demyelinating lesion or a patch of damaged tissue

• Appears as focal regions of gray discoloration in white matter

  • Certain small areas of the brain's white matter appear gray because myelin has been destroyed

  • White matter contains many myelinated axons, so loss of myelin causes characteristic lesions

    • White matter looks whitish; when white matter destroyed, there’s some gray color

• Caused by demyelination of axons in the CNS (NOT PNS)

• Myelin is destroyed, but axons may initially be preserved (although axonal damage can occur)

2. Immunopathology: Inflammatory cells found in plaques

• Inflammatory immune cells accumulate within MS plaques since autoimmunity occurs (targeting self axons)

• Mainly CD8+ T lymphocytes, microglia, macrophages

  • These cells contribute to inflammation and damage to myelin surrounding axons

3. Reactive Glial Scarring (Gliosis)

• Glial cells, especially astrocytes, respond to demyelination

• Form scar tissue at sites of myelin damage → scarring contributes to sclerosis seen in MS

What is the 3 majors etiologies of MS?

1. Autoimmune Response:

• Immune system mistakenly attacks components of myelin sheath in the CNS

• Leads to inflammation and demyelination

2. Genetic Predisposition

• Inherited genetic variants increase susceptibility to MS

• Increased risk ≠ guaranteed development of MS

3. Environmental Trigger → Epstein-Barr Virus (EBV)

• EBV is strongly associated with MS development

• 30x increased risk

• May contribute to MS through antigenic mimicry (molecular mimicry)

Other:

• In the preclinical face, symptoms exist but not yet diagnosed → some biomarkers exist

How can EBV trigger autoimmunity through antigenic mimicry?

1. EBV Infection: EBV infects the individual

2. Immune Response: The body produces antibodies against an EBV protein called EBNA1 (EBV nuclear antigen 1)

3. Protein similarity: Parts of EBNA1 resemble GlialCAM, a protein associated with glial cells in the CNS

4. Cross-reactivity: Some antibodies against EBNA1 can also recognize GlialCAM

5. Autoimmune response: This cross-reactivity may contribute to inflammation and myelin damage in the CNS

What is the molecular mechanism of Multiple Sclerosis (MS)?

1. Failure of Self-Tolerance:

• Self-tolerance: Normally, the immune system does NOT attack the body’s own antigens, even tho some lymphocytes recognize self-antigens

• In autoimmune diseases: Self-tolerance fails → immune system mistakenly attacks its own tissues

2. Why does self-tolerance fail?

• Genetic susceptibility: Inherited genes (especially HLA genes) increase the likelihood of losing tolerance

• Environmental triggers: Infections, inflammation, or tissue injury can promote immune activation

3. Autoimmune Response Against Myelin

• T helper cells and B cells recognize myelin-related antigens + become activated

• Activated immune cells release cytokines → recruit additional leukocytes

• These inflammatory cells contribute to myelin destruction

What are the symptomatic treatments for Multiple Sclerosis (MS)?

MS has no cure, but treatments can reduce inflammation and manage flare-ups

1. Corticosteroids → first-line treatment

• EX: Oral prednisone and IV methylprednisolone

• Reduce CNS inflammation

• Hasten recovery from acute MS attacks (relapses)

• Do NOT alter the long-term disease outcomes (like it’s more of an immediate action)

2. Plasma Exchange (Plasmapheresis)

• Used for severe MS flare-ups when corticosteroids are ineffective

• Removes and replaces the patient’s plasma, helping eliminate circulating harmful antibodies and inflammatory factors