Clinical Neuroscience - Multiple Sclerosis

Wichtige Krankheitsbilder der Neurowissenschaften - MS

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This flashcard set provides an in-depth look at multiple sclerosis (MS) at a university level, focusing on its pathology, diagnosis, and treatment. It covers key aspects such as the role of T-cells, B-cells, and autoimmune factors, as well as the progression and stages of the disease. The set also explores genetic and environmental factors contributing to MS, along with common symptoms and diagnostic criteria. Medical professionals and students will find this flashcard set valuable for understanding the complexities of MS and its management.

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MS - SCELROSIS = hardening of tissue caused by replace-ment of the normal organ-specific tissue with connective tissue. What are the key facts about multiple sclerosis?

Autoimmune disease of the CNS

Onset in young adults (20-40 years)

INLFAMMATION dominates in relapsing-remitting stage (CD4+ mediated)

DEMYELINATION is domonating in progressive stage

females are not affected more than male (f/m3-2:1)

Which are the 4 main types of MS?

CIS – Clinically isolated syndrome (repeated relapses in diff. severity/length)

RR – Relapsing-remitting (relapses with slight progression onset)

SP – Secondary progressive (progression after relapses)

PP – Primary progressive (no relapses but constant progression)

there are no other forms of MS

What is true about the DIAGNOSIS in MS?

No absolute speficic diagnostic sign or symptom: MS based on clinical presentation

Relapsing/Remitting nature of signs/symptoms

STREUUNG (Dissemination): 1.) relapse = temporal 2.) neurological systems affected = spatial

MRI: lesions in MS-typical locations in brain and spinal cord --> McDonald criteria

CSF: Oligoclonal Ig bands (OCBs) = inflammation

Which are the most common EARLY symptoms in MS?

Hypoesthesia (reduced sense of touch or sensation)

Nystagmus (involuntary eye movement)

Optic neuritis (inflammation of potic nerve leading to (partial) loss of vision)

Ataxia (lack of voluntary coordination of muscle movements)

LATE symptoms can't be EARLY symptoms

Which are the most common LATE symptoms in MS?

all EARLY symptoms/signs

90%: Hypoesthesia, Paresis (unvollständige Lähmung), Spasticity

bladder dysfunction

depression

headache

What is true about the EDSS?

EDSS = Expanded Disability Status Scale

Stage 1-5: RR-MS Ability to walk @ least 200m w/o helpbut not able to fully perform job

Stage 6: SP-MS after this stage no medicament is able to reduce progression; person needs walking aid

Stage 7-10: wheelchair prerequisite --> death in consequnce of MS

stage 11: death

Etiology of MS?

Etiology = study factors coming together to cause an illness/disorder

3 factors mainly define the etiology of an AUTOIMMUNE DISEASE

Immune Regulation

Genetics

Environment

What is true about the genetic factor in MS?

not complex

HLA DRB1 und DRB5 are the major risk for MS in terms of genetics (10-60%)

<100 further risk alleles and >50 genetic risk factors identified (act in concert)

Prevalence (rate of a population found to have the condition) 100-200:100.000

First degree relatives: 20-40 fold risk

What is true about the Immune regulation and environment factor?

IRF: MS is defined as autoimmune disease--> immune system attacks body‘s own cells, tissues and organs!

IRF: Organ-specific tissue in MS is CNS

EF: Infection with EBV: 4 fold risk for MS(100% of MS patients have EBV-titer)

EF: Higher risk with lack in vitamine D

smoking is no environmental factor

Which pathology is an evidence in autoimmune diseases?

Inflammation

Inflammation manifested in: Different composition of infiltrates (pattern I-IV) varying in CD3-Tcells, Plasma cells and mφ

Demyelination

Demyelination is not defined by sharp lesion edges

Axonal/Neuronal damage

Bcells and autoantibodies are evidence for the presence of MS/autoimmune disease.

Oligoclonal IgG Bands (OCBs) in CSF show antigenic drive and are found in MS lesions

It is know against which antigens IgGs are targeted

ABs bind to neurons: maybe to contactin-2/TAG-1

targeting or clearence of autoABs (therapy)

depletion of Bcells can stop relapsing in some MS patients

T-cells are an evidence for presence of autoimmune disease. What is true in MS?

Autoreactive Tcells are found in MS lesions (CD4+, CD8+, Th1, Th17 , Tregs)

Naive Tcells or memory Tcells can be activated towards autoreactive Tcells which cause lesions

EAE-model: MS is transferred by myelin specific CD4+ or induced by myelin protein

HLA-DRB1/5 risk genes serve primarily as recognition receptors for CD4+ Tcells

prior event is always infection with EBV

CD4+ cells in MS?

The frequency of high avidity myelin-specific CD4+ T cells is elevated in MS and directed at several myelin peptides (MBPs)

these MBPs bind suboptimal to TRC --> central tolerance compromised

Autoreactive T cells are activated by foreign triggers = molecular mimicry

CD4+ Treg function and thymic output appear to be compromised

autoreactive T cells (in peripherie) are not able pass the BBB

What is true about CD8+ in MS?

HLA-class I alleles contribute to MS risk independently of HLA-DR/DQ.

CD8+ T-cells are not involved in MS

CNS parenchymal infiltrates are dominated by CD8+ Tcells

CD8+ T cells can directly damage axons/neurons

What belongs to the Pathomechanim of MS?

Inflammation (Tcells) dominating in relapse-remitting stage

CNS tissue repair decreasing with progression

Neurodegeneration with progression

Chronic microglia activation

adaptive immune system dominates in reaction toward ongoing progression

What is true about autologous HSC therapy?

HSC = Hematopoeic Stem Cells and autologous = take patients own stem cells

Idea: Reduce CD3 diversity and removal of autoreactive Tcells

63% PFS = progression-free survival

37% progression remains

Death rate 1%

What are the major steps in HSCT?

Mobilization: G-CSF stimulates release of hematopoetic stem cells from BM into bloodstream

HSC-CD34 collection --> Cryopreservation

Conditioning regimen: Radiation to destroy patients whole population of immune cells

HSC-infusion (depleted Tcells!)

Engraftment & Recovery

What is standard treatment in (RR) MS?

FIRST line treatment (EDSS 0-4):fingolimod, fumaric acid, teriflunomide-- > suppress inflammation & relapses

SECOND lime treatment: (inbetween)natalizumab, alemtuzumab (anti-CD25)-- > clearence of autoABs

THIRD line treatment (EDSS 4-7)aHSCT (severe) and second line

Treatment for Progressive MS: unknown

first line treatment is not able to suppress inflammation & relapses

Which are the unmet medical needs in MS?

Highly effective immunomodulatory treatments with minimal side effects

Target cause of disease

Neuro/Myelin-protection

Treatments of major signs/symptoms

Regenerative therapies

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Clinical Neuroscience - Multiple Sclerosis

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