lecture 35 Flashcards
rochet - pathophysiology of ms
what is charcot’s triad?
nystagmus
intention tremor
telegraphic speech
three key signs of MS
what are common symptoms of MS?
visual problems
numbness, tingling (often an early symptom)
fatigue, motor weakness
difficulty walking, gait problems, falls, ataxia
pain
spasticity
dizziness, vertigo
sexual dysfunction
bladder problems, constipation
emotional or cognitive changes; depression
what are examples of visual problems that occur in MS and what is a root cause?
double vision
monocular blindness due to damage in optic nerve
when a person with MS experiences fatigue/motor weakness, what area has been disturbed?
corticospinal tract
when a person with MS experiences ataxia, what area has been disturbed?
cerebellum
when a person with MS is experiencing generic pain, what area is disturbed?
sensory pathways
when a person with MS is experiencing vertigo, what area is disturbed?
vestibular pathways
what are less common symptoms associated with MS?
tremors, seizures
itching (pruritis), feeling of pins and needles
speech and swallowing issues
breathing problems (chest muscles affected by nerve damage)
HA
hearing loss
what is molecular mimicry?
activation of auto reactive T or B cells due to sequence similarities between Epstein-Barr Virus (EBV) and self-peptides
what process can explain gene-environment interactions in MS?
individuals with a particular HLA phenotype have an increased risk of developing MS when they also have anti-EBNA (epstein-barr nuclear antigen) antibodies
how can viral or bacterial infections affect MS?
may increase the risk of MS by activating autoreactive immune cells, leading to an autoimmune response in genetically susceptible individuals
what is evidence that supports the relationship between viral/bacterial infections and MS?
increased IgG synthesis in the CNS of MS patients
increased antibody titers to certain viruses
epidemiological data suggesting that childhood infections increase MS risk
what is CIS?
clinically isolated syndrome
an initial episode of neurologic symptoms lasting over 24h
involves inflammation and demyelination in the optic nerve, cerebellum, cerebrum, brain stem or spinal cord
most cases progress to MS
what is the progressive phase?
involves cytodegeneration (loss of myelin, axons, oligodendrocytes)
occurs within a similar rate in different forms of MS
associated with thick blue line on graphs
how is the clinical presentation of MS determined?
by the combination of the underlying degeneration (uniform, progressive) and the host’s immune reaction to it (intermitten, variable)
determiend by dashed blue/orange lines on graph
what is the difference between the autoimmune and degenerative phases?
autoimmune phase - antigens activate B and T cells, moving to CNS sites and carrying out immune functions
degenerative phase - CNS damage by activated B and T cells and antigens released from these damaged sites prime immune cells in the periphery
unclear what phase is the disease trigger
what are the roles of dendritic cells in MS?
present CNS antigens
activate T-cell responses in the peripheral lymphoid tissue
how do activated B and T cells proliferate and infiltrate the CNS?
through a4-integrin-mediated binding and penetration of the BBB
what are the steps to autoimmune response in MS?
dendritic cells activate T cells –> activated B/T cells proliferate –> infiltrate the CNS through a4-integrin-mediated binding and penetration of BBB –> B cells mature to plasma cells while T cells interact with target ligands –> release of cytokines and macrophage stimulation –> damage to myelin sheath
what do mature B cells do?
also known as plasma cells
release IgG antibodies that target the antigen on expressing cells
what do T cells do once in the CNS?
interact with target ligands resulting in cytokine release and macrophage stimulation –> leading to damage to the myelin sheath
what is remyelination?
myelin repair
involves the recruitment of OPCs to the lesion and the differentiation into myelin-producing oligodendrocytes
does remyelination happen in MS?
typically fails due to lack of OPCs or failure of OPCs to differentiate
what is astrogliosis?
involves the invasion and propagation of astrocytes –> forms irreversible gliotic plaques or scares
what are the steps of remyelination?
demyelination –> activates microglia and astrocytes –> release pro-migratory factors and mitogens –> recruit OPCs to lesion and stimulate proliferation –> OPCs differentiate into oligodendrocytes
how do recruited OPCs differentiate into oligodendrocytes?
via a process involving axon engagement and myelin sheath formation
what molecular phenomenas are though to be less pronounced in SPMS compared to RRMS?
t cell priming in the peripheral lymphoid tissue
infiltration of B cells in the CNS
what is the MOA of immunomodulatory therapies?
interference with T/B cell activation
inhibition of T/B cell proliferation or movement into the CNS
inhibition of a4-integrin mediated binding and penetration of the BBB, or enzymatic breakdown of the BB
what is MOA of rescue strategies?
remyelination in agents that facilitate OPC recruitment or promote OPC differentiation
what are symptoms of Guillian-Barre syndrome?
weakness beginning in distal muscles and lower extremities then ascending to proximal muscles and upper extremities
progress to total paralysis with death from respiratory failure in days
when does Guillain-Barre syndrome peak?
10-14 days
what is the pathophysiology of GB syndrome?
autoimmune attack on peripheral nerves by circulating antibodies, resulting in demyelination
what is the treatment of GB syndrome?
ventilation, plasmapheresis, IV Ig administration
