Patho of MS Flashcards
multiple sclerosis
-immune-mediated inflammatory disorder
-destruction of myelin sheath
-sclerosis = scar/plaque of white matter
Charcot’s Triad (key MS signs)
-nystagmus
-intention tremor
-telegraphic speech
-also cognitive defects
MS common symptoms
-visual (optic nerve)
-numbness/tingling
-fatigue, motor weakness (corticospinal tract)
-gait problems, falls, ataxia (cerebellum)
-pain (sensory pathways)
-spasticity
-dizziness, vertigo (vestibular pathways)
-sexual dysfunction
-bladder probs, constipation
-emotional changes, depression
Less common MS sx
-tremor/seizures
-itching (pruritis), pins and needles
-speech/swallowing probs
-breathing probs
-headache
-hearing loss
MS etiology
-infections may inc risk by activating autoreactive immune cells
=autoimmune response in genetically susceptible individuals
-inc IgG in CNS of MS pt
-inc antibody titers to certain viruses
-childhood infection may inc risk
-EBV
Epstein-Barr Virus (EBV) in MS
-seq similarities between EBV and self-peptides result in activation of autoreactive T or B cells (molecular mimicry)
-pt w certain HLA phenotype have inc risk of MS when they also have anti-EBNA antibodies (gene-environment reaction)
Different clinical forms of MS
-Relapsing-remitting MS (RRMS)
-Secondary progressive MS (SPMS)
-Primary progressive MS (PPMS)
Relapsing-remitting MS (RRMS)
-85% of cases
-relapses of neurological dysfunction lasting weeks/months
-multifocal areas of damage in white matter (MRI)
-initial sx disappear but less remission w each relapse
-most cases eventually enter a phase of SPSMS when underlying progression crosses clinical threshold
Secondary progressive MS
-less inflammation than RRMS (no episodes on graph?)
-slowly progressive neurological decline and CNS damage
-little remission
-cytodegeneration of myelin, axons, oligodendrocytes
Primary progressive MS
-15%
-Resembles SPMS at initial stage of disease
-mean age of onset is LATER than RRMS (by abt 10 years)
-inflammatory episodes are occuring but don’t pass threshold so they go unnoticed until SPSM
Clinically isolated syndrome (CIS)
-initial episode of neurologic sx more than 24h
-inflammation and demyelination in optic nerve, cerebrum, cerebellum, brainstem, spinal cord
-most progress to MS
Overall clinical presentation of MS
-determined by combo of underlying degeneration AND the host’s immune reaction to it
-see graph 8!!
MS phases
-autoimmune
-degenerative
-unclear which phase is the trigger
Autoimmune phase of MS
-antigens from CNS or cross-reactive foreign antigens are presented to B and T cells in lymph
-B and T cells expand and migrate to CNS where they reencounter antigen and are activated
-activated B and T cells carry out immune functions at CNS site
Degenerative phase of MS
-CNS damage triggered by activated B and T cells or other insults (infection/stroke)
-antigens released from damaged sites in CNS further prime immune cells in periphery = vicious cycle
Autoimmune response in MS
-dendritic cells w antigen activate T cell in peripheral lymph
-activated B and T cells penetrate BBB via a4-integrin-mediated binding
-after encountering antigen in CNS, B cells mature to plasma cells = release IgG antibodies
-T cells interact with antigen presented by oligodendrocytes, neurons, or microglia on MHC molecules
-T cell activation = cytokine release and macrophage stimulation = damage to myelin sheath
T cell autoimmune reaction in MS
-CD8 T cells engage oligodendrocytes (MHCI complex)
-release cytokines IFN-y, TNF-a, perforin, granzyme (punches holes)
=oligodendrocyte destruction
B cell autoimmune reaction MS
-antibodies trigger complement (C5-9) on oligodendrocyte membranes
=pore formation and cell damage
Macrophage autoimmun reaction in MS
-recruited
-release toxic agents (ROS, nitrogen species, GLUTAMATE)
-harm oligodendrocytes
-also harm MYELIN SHEATH via phagocytosis
Action potentials in demyelinated regions in MS
-travel slower bc NO insulation
=leaks out
-amount of current generated at node of ranvier insufficient to depolarize membrane
Nodes of Ranvier
-demylenated parts of axons
-has voltage-gated Na channels that replenish the action potentials that have leaked out
-not sufficient enough in MS
Remyelination
-recruitment of OPCs to the lesion and differentiation into myelin-producing olidodendrocytes
-fails in MS bc lack of OPCs or failure to differentiate
Astrogliosis
-invasion and propogation of astrocytes in demylenated tissue
=irreversible formation of gliotic plaques or scars
Key steps of remyelination
-demyelination activates MICROGLIA and ASTROCYTES
=release PRO-MIGRAORTY factors and MITOGENS that RECRUIT OPCs to the lesion and stimulate proliferation
-macrophages eliminate myelin debris
-OPCs differentiate into OLIGODENDRYTES by a process that involves axon and myelin sheath formation (KEY STEP WHERE THIS FAILS IN MS)
Why remyelination fails in MS
-myelin sheaths that result from remyelination are shorter and thinner (only partial recovery)
-inflammation
-demyelinated axons and neurons undergo degeneration
Which of the following molecular phenomena is (are) thought to
be less pronounced in SPMS compared to RRMS?
(A) T cell priming in the peripheral lymphoid tissue
(B) infiltration of B cells in the CNS
(C) axon degeneration
(D) A and B
(E) A, B, and C
-A and B
-T cell and B cell
Rationale for MS therapies
-immunotherapies:
-interfere w T or B cell activation (APC interactions), proliferation, movement
-inhibition of a4-integrin
-rescue strat: remyelination (OPC recruitment/differentiation)
Gadolinium
-contrast agent in MRI
-marks regions where BBB is compromised
=active lesions
-lesions can grow or recede
Guillain-Barre syndrome
-acute, inflammatory neuropathy
-preceded by GI or respiratory infection in half of pt
-weakness in distal muscles that moves inwards
-can progress to total paralysis (death from respiratory failure)
-peak 10-14 days
-autoimmune attack on peripheral nerves (demyelination)
-slow recovery but most survive
-tx: ventilation, plasmapheresis, IV Ig admin
