Demyelinating Diseases Roop/Raja Flashcards
A 35 year-old-woman visits her primary physician with a CC of difficulty in walking. She said this occurred for five days last month, and she has experienced pain and prickly sensations that come and go, as well as occasional muscle weakness. Vital signs show: Temp.= 97.7 °F, Pulse= 70/min, Resp. = 15/min, BP = 124/80 mmHg, BMI = 27. Physical exams appears w/ muscle strength testing = normal, deep tendon reflexes = normal, patellar tendon reflexes = normal, when asked to walk, she had difficulty in balancing and maintaining a normal gait. What other lab studies would you order to be done on this patient?
Electromyography and nerve conduction velocity test
Edrophonium Test (Tensilon)
CSF analysis
MRI
A 35 year-old-woman visits her primary physician with a CC of difficulty in walking. She said this occurred for five days last month, and she has experienced pain and prickly sensations that come and go, as well as occasional muscle weakness. Vital signs show: Temp.= 97.7 °F, Pulse= 70/min, Resp. = 15/min, BP = 124/80 mmHg, BMI = 27. Physical exams appears w/ muscle strength testing = normal, deep tendon reflexes = normal, patellar tendon reflexes = normal, when asked to walk, she had difficulty in balancing and maintaining a normal gait. A number of lab studies were done: electromyography test= normal, nerve conduction velocity test = normal, Edrophonium Test (Tensilon ) test= normal, CSF analysis had oligoclonal IgG bands. What are oligoclonal bands and what do they primarily indicate?
Oligoclonal bands are proteins called immunoglobulins. The presence of these proteins indicates inflammation of the CNS
Useful aid in diagnosis of MS (primarily), herpes simplex, encephalitis, bacterial meningitis, neurosyphilis, lupus, etc
A 35 year-old-woman visits her primary physician with a CC of difficulty in walking. She said this occurred for five days last month, and she has experienced pain and prickly sensations that come and go, as well as occasional muscle weakness. Vital signs show: Temp.= 97.7 °F, Pulse= 70/min, Resp. = 15/min, BP = 124/80 mmHg, BMI = 27. Physical exams appears w/ muscle strength testing = normal, deep tendon reflexes = normal, patellar tendon reflexes = normal, when asked to walk, she had difficulty in balancing and maintaining a normal gait. A number of lab studies were done: electromyography test= normal, nerve conduction velocity test = normal, Edrophonium Test (Tensilon ) test= normal, CSF analysis had oligoclonal IgG bands, MRI – Gadolinium-enhancing brain lesions. What is Gadolinium?
A naturally occurring element used to enhance certain lesions
ex: cancer has vasculature so it uptakes GAD, whereas a cyst that does not uptake GAD
MS is an immune-mediated inflammatory disease that attacks ____________ axons in the CNS
myelinated
What is the hallmark of MS?
symptomatic episodes that occur months or years apart affecting different anatomic locations
MS most commonly begins between ______ years of age, and is more common in ____________
20-40, women
MS has localized areas of demyelination called _________ with destruction of oligodendrocytes, primarily in the white matter
plaques
MS has perivascular inflammation & chemical changes in the ________ and _______ components of myelin
lipid, protein
In MS, what is damaged?
axons and cell bodies
What does scleroses mean?
hardening
A 35 year-old-woman visits her primary physician with a CC of difficulty in walking. She said this occurred for five days last month, and she has experienced pain and prickly sensations that come and go, as well as occasional muscle weakness. Vital signs show: Temp.= 97.7 °F, Pulse= 70/min, Resp. = 15/min, BP = 124/80 mmHg, BMI = 27. Physical exams appears w/ muscle strength testing = normal, deep tendon reflexes = normal, patellar tendon reflexes = normal, when asked to walk, she had difficulty in balancing and maintaining a normal gait. A number of lab studies were done: electromyography test= normal, nerve conduction velocity test = normal, Edrophonium Test (Tensilon ) test= normal, CSF analysis had oligoclonal IgG bands, MRI – Gadolinium-enhancing brain lesions. What does this pt most likely have?
MS
What happens to the neuron speed of transmission in MS patients?
Wouldn’t have saltatory conduction
-Saltatory conduction → action potential jumping from the nodes of Ranvier (bc of this we have synchronized movements like walking)
-if damaged, then it can lead to muscle weakness or even paralysis
What are the classic signs and symptoms of MS?
-sensory loss (early in disease)
-spinal cord symptoms (motor): muscle cramping secondary to spasticity
-spinal cord symptoms (autonomic): bladder, bowel, and sexual dysfunction
-cerebellar triad/symptoms: dysarthria (slurred speech), nystagmus, and intentional tremor
-optic neuritis (inflammation of optic nerve)
-trigeminal neuralgia
-heat intolerance
-fatigue (70% of cases)
-dizziness
-carpal tunnel early on can actually indicate MS
How many categories of MS are there? What are they?
1) Relapsing-remitting MS (most common)
2) Secondary progressive MS (follows the initial relapsing remitting course)
3) Primary progressive MS
4) Progressive-Relapsing MS (rare)
What is the etiology of MS?
-unknown
-genetic & molecular factors
-viral infection: activates T cells against myelin
-environmental factors: lower MS rates in equatorial regions
-Low levels of vitamin D – low sunlight exposure in temperate areas (MS is not as common in tropical areas)
What does the histology look like for MS?
-vacuolation as the myelin is destroyed
-arrows in pic indicate macrophages/microglia with ingested myelin (myelin that has been damaged)
The first step of MS seems to be ____________ molecules interacting with T cells, B cells & macrophages. Later the BBB endothelium is digested away and the cells enter. B cells release immunoglobulins, T cells release inflammatory cytokines/chemokines and _____________ expose axons releasing NO, glutamate & oxygen free radicals.
adhesion, macrophages
Acute demyelination falls into 3 categories. What are they?
1) Phagocytic cells with perivascular & parenchymal T cell infiltration
2) Everything in category 1 + the presence of complement & antibodies.
3) Oligodendrocyte apoptosis (Oligodendrocytes responsible for myelin in CNS, Schwann cells responsible for myelin in PNS)
In ________ MS, what determines remyelination or not, is not well understood.
chronic
In chronic MS, there is remyelination with a ______ myelin sheath
thin
In chronic MS, inflammation resolves without remyelination = _______ _______
chronic inactive
In chronic MS, inflammation does not resolve and there is a slow demyelination = ___________. This is most common in progressive MS.
smoldering
(inflammation is still occurring)
MS has an unknown trigger that sets up the initial focus of inflammation in the brain and _____ becomes locally permeable to leukocytes and blood proteins. T cells specific for CNS antigens and are activated in peripheral lymphoid tissues that reencounter antigen presented on __________ or ______ in brain. Inflammatory reaction occurs in the brain due to mast cell activation, complement activation, Abs, and cytokines. This results in the demyelination of neurons.
BBB, microglia, DCs
What are the risk factors for MS?
-Previous viral infections
»EBV has molecular mimicry and there are Abs against EBV attacking the myelin sheath
»Herpes(HHV-6 specifically)
-Low vitamin D
»over-activating Th cells releasing IFN-gamma
»pushing T cells to become activated
-Genetics
»changes in the HLA-DRB1 gene affects MHC
-brain should be a privileged site, unknown on how MS breaches BBB
-metabolism, diet, and obesity
What are the immune cells involved in the problem
with MS?
-B cells make Abs against myelin sheath
-Th1 produces IFN-gamma which degranulates mast cells and recruits neutrophils
-Th17 produces IL23
-CD8 T cells kill oligodendrocytes when they’re presented by a microglia cell or DC
-GM-CSF (granulocyte-macrophage colony stimulating factor) proliferates activated monocytes, macrophages, and granulocytes
-DCs w/ CCR5 or CCR7 which tells them to migrate
What is the disease progression of MS?
Very early in disease
-Widespread inflammatory infiltrates, populations of CD4+ T cells, CD8+ T cells, B cells and monocytes.
-The subsequent destruction of myelin-producing oligodendrocytes by these cells leads to the formation of acute lesions in early disease stages
-Demyelinated axons and axonal damage will occur, and the neuronal body is also affected. This indicates that neuronal loss, a defining feature of disease progression, is also present in early stages of the disease.
Progressive Disease
-Inflammation in the form of chronic active lesions that exhibit a thinner margin of activated microglia, and few myelin-containing macrophages is still frequent in patients with progressive disease
-Notably, MS-associated inflammation disturbs the protein homeostasis of neurons, resulting in a formation of protein aggregates that directly contribute to neuronal injury. This leads to the progression of neuronal degeneration in MS
What is NMOSD, and what symptoms result in it still being misdiagnosed as MS?
rare inflammatory disease that most often affects the optic nerves and spinal cord. Less often, it affects the brain. It often leads to sudden vision loss, paralysis or both. Symptoms after a first attack usually improve
What is the pathophysiology of NMOSD?
-body produces Abs (anti-AQP4) against aquaporin-4 (AQP4)
-Abs found in approx. 73% of NMOSD pts (not found in MS)
-AQP4 is the most widely expressed water channel in the brain, spinal cord, and optic nerves (also present in the collecting ducts of the kidney, parietal cells of the stomach, airways, secretory glands, and skeletal muscle)
-in the CNS, AQP4 is found primarily in the foot processes of astrocytes
-Abs get through the BBB and bind to AQP4 receptors on the astrocytes and initiate complement and inflammation
-Neutrophils and eosinophils are abundant
-Damaged astrocytes can no longer support neurons or oligodendrocytes and demyelination occurs
-Unlike MS, demyelination is secondary to astrocytic damage
How does NMOSD differ from MS?
NMOSD indirectly demyelinates myelin (secondary to astrocytic damage), while MS is direct demyelination (primary)
