Demyelinating Disorders - Cochran, Dittel, Walsh Flashcards
Recall the morphology and distribution of oligodendrocytes.
What products do they produce?
In what disease may these be targeted?
White matter glial cells with small round dark nuclei and short processes.
Major basic protein (MBP), Myelin oligodendrocyte glycoprotein (MOG), Proteolipid protein (PLP)
Notably MS, but presumably any demyelinating disease of the CNS.
Compare and contrast the myelination of nerve fibers in the CNS and PNS.
In the CNS, this is done by oligodendroglia, which extends processes to wrap around many axons.
In the PNS, this is done by schwann cells, which only surround one internodal region of one axon.
What is the difference between a demyelinating disorder and a dysmyelination disorder?
Demyelination is destruction of normal myelin.
Dysmyelination is abnormal formation of myelin (also known as a leukodystrophy).
Describe the epidemiology of multiple sclerosis.
Hits mostly “Northern climate” young women, with some familaial clustering.
Describe the gross morphology of MS. Where is it seen?
Describe the microscopic morphology of MS. Distinguish between the three plaque types.
Sclerotic, depressed plaques of demyelination can be found in periventricular white matter, as well as in optic, cerebellar, and brainstem tissues. (can be found in gray matter too!)
Active plaques have macrophages, lymphocytes, and reactive astrocytes. Inactive has only fibrillary astrocytes. Shadow plaques show incomplete myelin absence.
Who classically gets acute disseminated encephalomyelitis (ADEM)?
Describe its pathology.
How is its outcome?
Children, following a viral infection or immunization.
Antibody cross-reaction causes perivenous demyelination with congestion of the blood vessels. Neutrophils, then lymphocytes.
Good, if treated promptly with steroids.
Describe the epidemiology of neuromyelitis optica.
Describe its pathology (note its most distinctive feature)
Asian and african women, median age 39yo.
Caused by anti-AQP4 IgG which compromises the BBB. Causes necrosis and demyelination of the optic pathways and spinal cord.
Central pontine myelinolysis is caused by _______, which can be seen in conditions such as _______.
Overcorrection of hyponatremia, seen in burns/alcoholism/malnutrition.
Review of Immunology
T/F: Eosinophils assist in fighting viral infections.
T/F: Basophils assist in fighting ectoparasites.
T/F: Mast cells assist in wound healing.
According to our lecture, all three of these are true.
Review of Immunology
Which macrophage subset promotes tissue repair?
What master transcription factor do T-regulatory cells express?
Name some of the B cell subsets.
M2 (stimulated by IL-4/13)
Foxp3
B-1, B-2, marginal zone, follicular, memory.
What cell populations are responsible for destruction of myelin in multiple sclerosis?
What cell is being targeted?
CD4+, CD8+ T-lymphocytes.
Oligodendroglia
How do CD4+ T-cells localize to the CNS in MS?
Describe the mechanisms they employ to destroy myelin.
Integrin VLA-4.
TNFa (triggers TNFRI to induce apoptosis), FasL (bind Fas to induce apoptosis), TRAIL (cytokine binds DR4/5 to induce apoptosis), plus IFNy/IL-17 and more cytokines.
Describe the mechanisms by which CD8+ cells destroy myelin.
Perforins (form a pore in the target cell membrane)
Granzymes (enter the target cell cytoplasm, induce apoptosis)
FasL and presumably several other molecules…
Describe the structure and organization of chemokines.
Chemokines belong to 1 of 4 families based on their structure. Each immune cell responds to certain chemokines for chemotaxis, though there is abundant cross-activity between receptors.
Oligodendrocytes may also be destroyed by mechanisms including Excitotoxicity, Oxidative stress, and Antibody-mediated death.
Briefly describe these three mechanisms.
Excitotoxicity: Glutamate receptor (NMDA/AMPA) activation increases intracellular calcium, causing ATP depletion and protease activation.
Oxidative stress: ROS and RNS produced by immune cells, infectious agents, or inborn metabolism damages protein/lipid/DNA, leading to apoptosis/necrosis.
Antibodies can direct destruction by immune cells (ADCC), or trigger the complement pathways (CDC)
Name 4-5 classic symptoms of MS.
How apt are they to present at initial onset?
Sensory disturbance, weakness, visual problems, ataxia, bladder dysfunction.
Fewer symptoms at onset. Weakness & sensory disturbance are most common.
Recall and contrast the four clinical courses of MS.
Relapsing-remitting (RR): Most common, periods of remission punctuated by periods of acute dysfunction.
Secondary-progressive (SP): Progresses from RR after ~20yrs. Remissions become less frequent and function declines.
Primary progressive (PP): Uncommon; symptoms progressively worsen from onset without remissions.
Progressive relapsing (PR): Rare; progressive from onset with rare relapses?
Describe the diagnostic criteria for MS.
No specific test. Check history, confirm dissemination in:
Time (New lesions on follow-up, or simultaneous presence of enhancing and non-enhancing lesions)
Space (Lesions in at least 2 of 4 CNS areas: Periventricular/Juxtacortical/Infratentorial/Spinal)
A patient presents reporting symptoms of MS (sensory dysfunction, weakness) without any prior history of the illness.
What is this called?
What is her risk of MS? (+/- lesion)
Clinically isolated syndrome (CIS)
If lesions are present on MRI, 88% risk of developing MS. Otherwise, 19% risk.
How is MS treated?
There is no cure, and treatments are only somewhat effective.
Examples include Interferon, natalizumab, and a buttload of other immunosuppressive drugs we probably don’t need to learn now.
Contrast demyelinating optic neuritis (DON) with MS and neuromyelitis optica.
DON is associated with MS and shares the same demography (caucasian women).
DON has a milder visual deficit than neuromyelitis optica, but is associated more closely with pain.
Describe the ocular signs seen in DOM.
Vision loss (acuity, color, visual fields, pupil reflex) with phosphenes
Pain (worse with movement).
What role do steroids play in the treatment of DOM?
They can increase the rate of recovery, but also the risk of recurrence. Yet, they also seem to be briefly protective against MS.
What will an MRI reveal in a child with ADEM?
CSF?
Bilateral involvement (both hemispheres), potentially also involving the deep grey matter, optic nerves, and spinal cord.
Some leukocytosis on CSF.
How is ADEM diagnosed?
How is it treated?
Diagnosis of exclusion. Biopsy could be helpful, but you don’t want to do that.
High dose steroids (IV, then oral)
Briefly define Transverse Myelitis.
What symptoms are prevalent?
A heterogeneous collection of disorders resulting in acute or subacute myelopathy.
Sensory/motor/incontinent defects. Notable are a positive Lhermitte’s sign (dysesthesis of spine on neck flexion) and paroxysmal tonic muscle spasms.
Describe the significant differences between complete and incomplete transverse myelitis.
Complete: Symmetric loss of motor and sensory function. Monophasic but likely to result in residual deficit.
Partial: Partial or patchy involvement with variable asymmetric symptoms. More likely to herald MS.
What else is central pontine myelinolysis known as?
What symptoms may it present with?
Osmotic demyelination syndrome.
Neuropsych symptoms, neurologic deficits (weakness, gaze/speech abnormality, dysphagia). Coma and death in the worst-case.
What structures are involved in neuromyelitis optica?
Is it monophasic or relapsing?
Is this a necrotic or simply demyelinating disease?
The optic disc/nerves/chiasm/tracts as well as the spinal cord.
NMO can be either monophasic or relapsing.
Necrotic, though demyelination understandably follows.
Recall the diagnostic criteria for neuromyelitis optica (NMO).
Optic neuritis AND acute myelitis, plus 2/3 of:
- Spinal cord lesion > 3 vertebral segments
- Brain MRI not consistent with MS
- IgG seropositivity against AQP4.
