Multiple sclerosis and Guillain-Barré

Question 1

Progressive neurodegenerative diseases:

Answer 1

Question 2

main non-infectious neurodiseases / disorders

Answer 2

Progressive neurodegenerative diseases
Neuropsychiatric disorders

Question 3

Neuropsychiatric disorders

Answer 3

• Depression
• Schizophrenia

Question 4

Diseases of motor neurons and NMJ (properties)

Answer 4

Question 5

Diseases of motor neurons and NMJ (examples)

Answer 5

Question 6

Secondary neurodegenerative diseases

Answer 6

know cause and know not intrinsic

Question 7

muscular dystrophies vs diseases of motor neurons and NMJ

Answer 7

not the same - issue is with muscles not with

Question 8

GBS affects

Answer 8

Motor nerve axons, from spinal cord to muscles - PNS

Guillain-Barré syndrome

Question 9

GBS is the most common

Answer 9

acute paralytic neuropathy
> 100,000 cases yearly

can affect anybody

Question 10

GBS is a syndrome not

Answer 10

a disease - various subtypes

Spectrum of presentations, from very mild to very severe/fatal

Question 11

GBS subtypes

Answer 11

Axonal subtype most severe

Question 12

GBS is a reaction to

Answer 12

immune stimulation
- vaccines
- sickness/ infection

Question 13

GBS develops

Answer 13

days/weeks after infection or vaccination

Molecular mimicry

Question 14

Molecular mimicry is defined as

Answer 14

structural similarity between antigens coded by different genes

(definition in disease - Similarities between the antigens of a microbe and a host.)

Question 15

GBS severity vs time

Answer 15

Question 16

___ patients recover spontaneously in ___

Answer 16

Most
in 3 – 4 weeks
~70 % recover completely
~30 % retain residual weakness

Question 17

___ develop into severe cases (GBS)

Answer 17

20 – 30 %

complete paralysis, including respiratory muscles

Rapid progression after onset, 3 – 4 days

Question 18

GBS has strong evidence relating GBS with ___ bacteria

Answer 18

C. jejuni infection

LOS (lipooligosaccharides) in outer membrane = gangliosides in PNS axons

Question 19

GBS associated with ____ viruses

Answer 19

flu, Zika, CMV (Cytomegalovirus), Epstein-Barr

Question 20

Antibody production in GBS

Answer 20

is random!

Correlations seen, still it is a sporadic disorder!

Question 21

GBS Immunopathology

Answer 21

mostly an humoral driven pathogenesis - Driven by serum (humoral - antibody- mediated) rxn. NOT cellular rxn.

antibodies against:
Against gangliosides in axonal membrane
(exposed at nodes of Ranvier)

Against broad range of myelin sheet
proteins (moesin was suggested)

Question 22

GBS Humoral effects

Answer 22

antibody deposits
complement activation
macrophage recruitment

Question 23

GBS prognosis

Answer 23

Potentially life-threatening disease, early diagnosis = better recovery

Question 24

GBS treatments

Answer 24

1) IV Ig infusion: addition of normal antibodies overcomes effect of autoreactive antibodies (many mechanisms, most end up reducing inflammation)

2) Plasma exchange: removal of autoreactive antibodies and other damaging humoral factors

Question 25

Severe cases ___ can achieve complete recovery

Answer 25

with physical therapy

Question 26

GBS in low income countries

Answer 26

these treatments are too expensive, so unavailable - new therapeutics are urgently needed 10 – 15 % of patients die - lack of treatment and medical support (in US more like 1-3%)

Question 27

MS is the most common __ also known as ___

Answer 27

autoimmune-mediated disease of the CNS disseminated encephalomyelitis

Question 28

Global distribution of MS

Answer 28

~350,000 cases in US; 2.5 – 3 million worldwide

Question 29

MS age

Answer 29

Can strike at any age, but mostly 20 – 40 years old Most common cause of permanent disability in young adults (stroke in older adults)

Question 30

MS telltale signs

Answer 30

Clinical spectrum (a lot of overlap) but (SW S N P V) sudden-onset muscle weakness loss of sensation numbness pain vision problems - unique + CNS

Question 31

MS epidemiology

Answer 31

geographically, diet age (20-40) women

Question 32

Men vs Women MS

Answer 32

Women 3X more likely pregnancy is protective - hormonal effect? Or immunity? not clear why - if have MS then get pregnant symptoms go away - when pregnant immunocompromised and ms is over immune rxn.

Question 33

MS Clinical presentation

Answer 33

1. Relapsing-remitting MS 2. Secondary-progressive MS 3. Primary-progressive MS 4. Progressive-relapsing MS 3-4 vary rare

Question 34

Ultimately MS becomes

Answer 34

steadily progressive After 15 – 25 years of RRMS (relapsing-remitting), it turns into SPMS (secondary- progressive)

Question 35

Relapsing vs progressive MS manifestation

Answer 35

Relapsing - autoimmune inflammation Progressive - neurodegeneration

Question 36

MS history

Answer 36

important - recurrence of isolated neurological symptoms

Question 37

MS MRI

Answer 37

best way to see lesions (an aggregation of immune cells) Presence of lesions predicts MS development with > 80% accuracy Size and number of lesions DO NOT correlate with severity – location most critical – however, steady increase correlates with severity Use of contrast enhancing media shows BBB breaches due to inflammation

Question 38

Why does MS occour

Answer 38

don't know what initially starts it but is due to chronic inflammation

Question 39

MS progression pathology

Answer 39

White matter early on (mylen), then spread to grey matter does not stop until pathogen (antigen/olog.) is gone

Question 40

Why MS is such a chronic disease with months of no symptoms between attacks?

Answer 40

Immune does not stop until pathogen (antigen/olog.) is gone - when gone Olig can regenerate - attack again Is permanent is because the immune response is generated against self-antigens

Question 41

When myelin is destroyed in MS, the axon

Answer 41

redistributes the ion channels and switches to continuous signaling rather than saltatory conduction

Question 42

MS remylenation ocours because

Answer 42

OPCs (NG2 - oligodendroyte precusor cells) can generate oligodendrocytes

Question 43

As MS progresses, remission periods are

Answer 43

shorter and fewer - Correlates with decline in remyelination - With less remyelination, axon eventually dies - OPCs ability to differentiate declines with age - Once axonal death starts, progression into advanced MS is inevitable

Question 44

MS treatments

Answer 44

Current disease-modifying drugs targets the immune reaction, not the actual causative pathology - axonal destruction No cure – but increasing arsenal of drugs makes it manageable - Sadly, one of the leading causes of death in MS is suicide Supportive treatments - Amelioration of acute attack symptoms - Anti-inflammatory agents Very expensive – average costs per single dose is $60,000! Many make you immunosuppressed, so susceptible to infections!

Question 45

MS and prions

Answer 45

MS excellent example that not all neurodegenerative diseases involve a prion-like component 1) Its all genetics and environment, and chance - (like) cancers 2) The 2 hits theory - applicable to many autoimmune diseases (2 hit - also in cancers)