Demyelinating Disorders - Cochran, Dittel, Walsh

Question 1

Recall the morphology and distribution of oligodendrocytes.

What products do they produce?

In what disease may these be targeted?

Answer 1

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.

Question 2

Compare and contrast the myelination of nerve fibers in the CNS and PNS.

Answer 2

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.

Question 3

What is the difference between a demyelinating disorder and a dysmyelination disorder?

Answer 3

Demyelination is destruction of normal myelin.

Dysmyelination is abnormal formation of myelin (also known as a leukodystrophy).

Question 4

Describe the epidemiology of multiple sclerosis.

Answer 4

Hits mostly “Northern climate” young women, with some familaial clustering.

Question 5

Describe the gross morphology of MS. Where is it seen?

Describe the microscopic morphology of MS. Distinguish between the three plaque types.

Answer 5

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.

Question 6

Who classically gets acute disseminated encephalomyelitis (ADEM)?

Describe its pathology.

How is its outcome?

Answer 6

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.

Question 7

Describe the epidemiology of neuromyelitis optica.

Describe its pathology (note its most distinctive feature)

Answer 7

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.

Question 8

Central pontine myelinolysis is caused by _______, which can be seen in conditions such as _______.

Answer 8

Overcorrection of hyponatremia, seen in burns/alcoholism/malnutrition.

Question 9

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.

Answer 9

According to our lecture, all three of these are true.

Question 10

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.

Answer 10

M2 (stimulated by IL-4/13)

Foxp3

B-1, B-2, marginal zone, follicular, memory.

Question 11

What cell populations are responsible for destruction of myelin in multiple sclerosis?

What cell is being targeted?

Answer 11

CD4+, CD8+ T-lymphocytes.

Oligodendroglia

Question 12

How do CD4+ T-cells localize to the CNS in MS?

Describe the mechanisms they employ to destroy myelin.

Answer 12

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.

Question 13

Describe the mechanisms by which CD8+ cells destroy myelin.

Answer 13

Perforins (form a pore in the target cell membrane)

Granzymes (enter the target cell cytoplasm, induce apoptosis)

FasL and presumably several other molecules…

Question 14

Describe the structure and organization of chemokines.

Answer 14

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.

Question 15

Oligodendrocytes may also be destroyed by mechanisms including Excitotoxicity, Oxidative stress, and Antibody-mediated death.

Briefly describe these three mechanisms.

Answer 15

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)

Question 16

Name 4-5 classic symptoms of MS.

How apt are they to present at initial onset?

Answer 16

Sensory disturbance, weakness, visual problems, ataxia, bladder dysfunction.

Fewer symptoms at onset. Weakness & sensory disturbance are most common.

Question 17

Recall and contrast the four clinical courses of MS.

Answer 17

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?

Question 18

Describe the diagnostic criteria for MS.

Answer 18

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)

Question 19

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)

Answer 19

Clinically isolated syndrome (CIS)

If lesions are present on MRI, 88% risk of developing MS. Otherwise, 19% risk.

Question 20

How is MS treated?

Answer 20

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.

Question 21

Contrast demyelinating optic neuritis (DON) with MS and neuromyelitis optica.

Answer 21

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.

Question 22

Describe the ocular signs seen in DOM.

Answer 22

Vision loss (acuity, color, visual fields, pupil reflex) with phosphenes

Pain (worse with movement).

Question 23

What role do steroids play in the treatment of DOM?

Answer 23

They can increase the rate of recovery, but also the risk of recurrence. Yet, they also seem to be briefly protective against MS.

Question 24

What will an MRI reveal in a child with ADEM?

CSF?

Answer 24

Bilateral involvement (both hemispheres), potentially also involving the deep grey matter, optic nerves, and spinal cord.

Some leukocytosis on CSF.

Question 25

How is ADEM diagnosed?

How is it treated?

Answer 25

Diagnosis of exclusion. Biopsy could be helpful, but you don’t want to do that.

High dose steroids (IV, then oral)

Question 26

Briefly define Transverse Myelitis.

What symptoms are prevalent?

Answer 26

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.

Question 27

Describe the significant differences between complete and incomplete transverse myelitis.

Answer 27

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.

Question 28

What else is central pontine myelinolysis known as?

What symptoms may it present with?

Answer 28

Osmotic demyelination syndrome.

Neuropsych symptoms, neurologic deficits (weakness, gaze/speech abnormality, dysphagia). Coma and death in the worst-case.

Question 29

What structures are involved in neuromyelitis optica?

Is it monophasic or relapsing?

Is this a necrotic or simply demyelinating disease?

Answer 29

The optic disc/nerves/chiasm/tracts as well as the spinal cord.

NMO can be either monophasic or relapsing.

Necrotic, though demyelination understandably follows.

Question 30

Recall the diagnostic criteria for neuromyelitis optica (NMO).

Answer 30

Optic neuritis AND acute myelitis, plus 2/3 of:

1. Spinal cord lesion > 3 vertebral segments
2. Brain MRI not consistent with MS
3. IgG seropositivity against AQP4.