NEURO 410 - Lecture 14: Molecular Mechanisms Underlying Multiple Sclerosis

What is the average age of MS diagnosis?

31.7

What is the age range at which you can receive an MS diagnosis?

5-71

What type of symptoms do MS patients present with?

neurological symptoms related to CNS dysfunction

What are 7 neurological symptoms related to CNS dysfunction that MS patients may present with?

weakness

numbness

vision abnormalities

imbalance

incoordination

speech issues

vertigo

What is the term used to describe symptom progression in MS?

subacute - symptoms progress over days to weeks

Which gender is MS dominant in?

75% of MS patients are female

What is the prevalence of MS in Canada? In Alberta?

Canada: 1:400

Alberta: 1:340

Use one word to describe the disease severity of MS.

variable

Use one word to describe the disease course of MS.

variable

What are the two extremes of MS symptom severity?

1. patients develop mild symptoms that don't affect function

2. others develop severe symptoms that require hospitalization

What are the two extremes of recovery from MS symptoms?

1. some recover quickly and completely

2. others left with significant impairment

What are the two extremes of the incidence of attacks in MS patients?

1. some have few attacks over a lifetime

2. some have many attacks over a few short years

Describe the 3 possible varieties in MS disease course.

1. attacks of symptoms from which they improve or recover

2. progressive or ever worsening disease from onset

3. initially have attacks, later develop more progressive disease

What are the 5 subtypes of MS?

1. relapsing remitting MS (RRMS)

2. primary progressive MS (PPMS)

3. radiologically isolated syndrome (RIS)

4. clinically isolated syndrome (CIS)

5. secondary progressive MS (SPMS)

What is the main requirement for a patient to have relapsing remitting MS?

attacks must be disseminated (widely spread) in time and space

What % of MS patients have RRMS at onset?

90%

What is the main requirement for a patient to have primary progressive MS?

attacks must be disseminated (widely spread) in time and space

What % of MS patients have PPMS at onset?

10%

What does dissemination in time refer to?

2nd demyelinating event (a new attack/relapse/lesion) at a time separate from the 1st demyelinating clinical episode

What does dissemination in space refer to?

MS lesion must be present in different regions within brain or spinal cord

In what case would an MS patient be diagnosed with radiologically isolated syndrome (RIS)?

when their MRI meets the criteria for MS, but they have no clinical symptoms of the disease (lesions are disseminated in time and space, but have no clinical symptoms)

In what case would an MS patient be diagnosed with clinically isolated syndrome (CIS)?

when patient meets criteria for dissemination in space, but not dissemination in time (at first demyelinating event, had both MRI lesions and clinical symptoms, but upon further testing did not have MRI lesions OR clinical symptoms)

In what case would an MS patient be diagnosed with secondary progressive MS (SPMS)?

when patient initially meets criteria for RRMS, then later develops more progressive symptoms

What are the 4 steps taken to diagnose MS?

1. confirm patient has clinical symptoms attributable to the CNS

2. confirm patient has a time course consistent with MS

3. obtain MRI - ensure meets criteria + rule out other diagnoses

4. additional testing as needed (ex. CSF) - rule out other diagnoses

What is a diagnostic biomarker?

detects or confirms the presence of a disease

What protein can be used as a biomarker in the CSF of MS patients?

immunoglobulins

Why are immunoglobulins a good biomarker for MS?

because they are barely present in the CSF of healthy people (are mainly present in the blood of healthy people)

How can you detect immunoglobulin in CSF?

oligoclonal bands - look for elevations in a limited number of immunoglobulin subclasses

What are two reasons why MS patients have increased immunolgobulins in their CSF?

1. disruption of BBB

2. intrathecal production of IgG

Which MS diagnostic criteria can CSF biomarkers of the disease fulfill? How does it help us fulfill this criteria with only one CSF sample?

dissemination in time - IgG in the CSF is an independent predictor of a second attack

What are the 4 clinical applications of biomarkers for disease?

diagnostic

prognostic

predictive

disease monitoring

What are the 2 clinical insights that oligoclonal bands as a biomarker in MS provide?

diagnosis

prediction

Why can't oligoclonal bands be used for MS monitoring or to determine MS prognosis?

no evidence for their use in disease monitoring or for response to therapy, controversial findings on how their presence or number is helpful in prognosis

What are the 3 defined aspects of an MS MRI lesion?

lesion size

location

numbers

How does the number of MRI lesion in an MS patient correlate with patient function?

it doesn't

How does the total number of MRI lesions in an MS patient correlate with future disease severity?

total lesions burden = predicts future disease severity

How can we monitor MS progression using MRI as a biomarker?

presence of gadolinium enhancing lesions indicates new lesions, which means disease has worsened or treatment has failed

How can we predict MS time course with MRI as a biomarker?

presence of gadolinium enhancing lesions predicts future relapses, however their are no MRI measures that can predict response to therapy

How can we provide MS patients with a prognosis by using MRI as a biomarker?

gadolinium enhancing lesions at baseline = poorer prognosis of clinical disability, correlate with relapse rate, and predict development of secondary progressive MS

What are the 3 defining characteristics of MS?

demyelinating disease

disease of the CNS

immune mediated

What is a demyelinating disease?

disease where the myelin sheath surrounding neurons is damaged

What is a CNS disease?

affects brain, optic nerves and spinal cord (spares peripheral nerves)

What is an immune-mediated disease?

thought to be caused by the immune system

What is the clinical correlate of the fact that MS is a disease of the CNS?

patterns of symptoms seen can be attributed to the CNS: vertigo and diplopia from brainstem lesion, bilateral leg numbness and urinary symptoms from sc lesions, unilateral vision loss from optic nerve lesion

What are the 3 clinical correlates of the fact that MS is a demyelinating disease?

1. improvement of symptoms following relapse (neurons not damaged, myelin is)

2. ephaptic transmission

3. Uthoff's phenomenon

Describe the phenomenon of ephaptic transmission, and how it correlates to a demyelinating disease pathogenesis.

electric field generation by a neuron alters the excitability of neighboring neurons as a result of their proximity - loss of myelin = loss of insulation, causes easier electric generation in neighboring neurons (ex. try to move one mm and get spasm of whole leg)

Describe Uthoff's phenomenon and how it correlates to a demyelinating disease pathogenesis.

when an increase in body temp causes a worsening of symptoms - thin myelin has less effective transmission at higher temps

What are the 2 clinical consequences of the fact that MS is an immune-mediated disease?

1. close association with other immune mediated conditions

2. fatigue

What was MS pathophysiology historically thought to be mediated by?

T cells

What are the 4 pieces of evidence for the pathophysiology of MS being due to T cells?

1. the major cell population present in areas of oligodendrocyte damage was CD4+ T helper population Th17

2. shuttling of Th1/Th17 between cervical lymph nodes and CNS

3. Th1 cells drive microglia towards inflamm phenotype

4. Th22 cells promote BBB dysfunction

What are the two types of pathological samples collected that caused them to believe MS was a T cell mediated disease?

1. active demyelinating lesions

2. CSF

What did treatment trials reveal about the pathophysiology of MS?

told us that MS is not a fully T cell mediated disease, and that B cells must play a role because B cell therapies are effective

What is the name of the first drug that targeted B cells and was effective in MS?

rituximab

What is rituximab?

anti-CD 20 monoclonal Ab targeting B cells

What are the names of the 3 B cell therapies that are approved for the treatment of MS?

rituximab

ocrelizumab

ofatumumab

After finding that B cell therapies effectively treat MS, what did they find in active autopsy studies of active MS lesions?

B cells found around central inflamed vein

Where were B cells found in MS patients with SPMS?

meninges

Although B cell therapies effectively treat MS disease symptoms, what did they find that showed B cells cannot be the whole story of MS pathophysiology?

B cell depletion therapy does not relsolce chronic active MS lesions, which are important for disease symptoms

Why would B cell depletion therapy be a risk for people receiving vaccines?

because B cells are the memory of your immune system, so can your immune system generate a memory against the vaccine if it doesn't have B cells?

What did they find the effect of B cell therapy on vaccine efficacy to be?

B cell therapy blunts vaccine response - cannot generate antibodies

How did they prove that the Covid vaccine does not increase the risk of developing MS, or the risk of an MS relapse?

saw that the combined incidence rate ratio for MS relapse after covid vaccine was 0.97, showing that the incidence of MS in those who received a vaccine was the same as the incidence of MS in those who did not get vaccinated

When they examined the incidence of EBV and MS in the US military, what did they find?

risk of MS increased 32-fold after EBV infection, but was not increased after infection with other viruses

What are the 3 things that have taught us about MS pathophysiology ?

treatment

epidemiological studies

compare to similar disease

What are the 2 diseases we can learn about MS from?

NMOSD: neuromyelitis optic spectrum disorder

MOGAD: myelin oligodendrocyte glycoprotein antibody disease

What are NMOSD and MOGAD?

antibody mediated CNS demyelinating diseases

Why are NMOSD and MOGAD now considered diseases separate from MS?

unique clincal features

presence of pathogenic antibodies

Describe how NMOSD is antibody mediated and how it leads to demyelination.

complement activation in NMOSD is produced by the binding of AQP4-IgG autoantibodies to AQP4 channels on astrocytes, which leads to inflammation and demyelination

What are the two components of NMOSD that are necessary to cause CNS injury characteristic of NMOSD?

AQP4-IgG

complement

What is the evidence that there is bystander injury to neurons in NMOSD?

there is deposition of membrane attack complex on neurons, but not C1q - C1q is only seen on astrocytes

What is the complement component that activates neutrophils?

C5a

What does C5a neutrophil activation result in?

- shift to reactive astrocytes

- produces multiple pro-inflammatory cytokines and chemokines

What did NMOSD pathophysiology tell us about MS?

since NMOSD is complement mediated, researchers looked to see if MS was as well, and we found that it was not because there are normal plasma complement levels in MS patients

How do MS and NMOSD differ in terms of recovery from relapses?

MS: typically good recovery from relapses

NMOSD: poor recovery after relapses