MS (and Other Demyelinating Disorders)

Question 1

What is MS?

Answer 1

• MS is a presumed autoimmune demyelinating disorder of the CNS
  
  • ​lesions are in the brain/SC, get SECONDARY effects elsewhere due to that injury
• It affects at least 400K Americans (likely greatly underestimated)
• Early cases (1395)-MS has been around for a VERY long time
  
  • well described in medical lit
  • *CHARCOT’s Triad (1868)-all due to multiple lesions+ commented on axonal and demyelinting features and gray matter involvement:
    
    • Nystagmus
    • intention tremor
    • scanning speech

Question 2

MS Epidemiology

Answer 2

• Generallyoccurs in younger females (20-50 yo) of Northern European descent
• Female:male ratio of 2:1 or 3:1 (rate is increasing)
• However…
  
  • Pediatric MS (<18) may be under-diagnosed (symptoms get better….get clinical attacks and then it resolves, so it is missed when pt returns a few wks later)
  • Those over 50 incorrectly believed “cannot get it”
  • Those at “lower risk” may be “higher risk” for severe disease
    
    • men or Africa/Asain descent may have worst manifestation
• Genetic contribution but not a “genetic disease”
  
  • Certain HLA markers and single nucleotide polymorphisms (SNPs) increase risk
  • No genetic or prenatal tests are recommended
  • Lifetime risk of MS: 0.1-0.2%
  • Absolute risk to a child or full sibling: 2-4%
  • Even in identical twins the risk is “only” 25%

Note: “MS clusters with the so-called complex genetic diseases, a group of multifactorial disorders characterized by modest disease risk heritability driven primarily by allelic variants relatively common in the population.”

Question 3

MS Risk Factors

Answer 3

• MULTIFACTORIAL!
  
  • Triple G: geography, genetics, germs!
• Risk seems to increase with distance from the equator
  
  • May be related to lower Vitamin D levels due to sun exposure (or lack thereof)
  • May acquire that risk early in life (geographic risk established by age 15-where you live UP TO this age)
  • BUT, epidemiologic data is changing for a variety of reasons:
    
    • population moving south
    • increased hygiene standards internationally
    • more MRI scanners
• Suspected environmental triggers
  
  • Viral Exposures
    
    • EBV most commonly implicated in pediatric MS (but high in general-very common in the US)
    • Canine distemper virus (Faroe Islands)
  • Are CMV, HSV and even HIV protective?
  • Tobacco exposure-STOP SMOKING
  • Obesity and Diet
• Vaccines are safe and DO NOT cause MS.
• Hygiene Hypothesis
  
  • The relative lack of exposure to infectious agents early in life may lead to defects in immune tolerance.
  • There is some data the parasitic infection may decrease the risk of MS.
    
    • parasites release anti-inflamm for themselves

Question 4

MS Pathogenesis

Answer 4

1. APCs possibly traveling from the cranial vault, present some signal to & activate primed “autoreactive” T-cells residing within LN
2. Activated T-cells leave the LN
3. Activated T-cells enter the peripheral blood stream looking for that target (which is presumably “found” in the CNS)
4. T-cells attach to, break down and cross the BBB
5. Release interleukins that cause inflammatory response and disrupt the BBB
6. Secrete pro-inflammatory cytokines leading to myelin destruction and neuronal death
7. Cell may become “chronically active” within the CNS over time leading to progressive neurodegeneration

Question 5

MS Pathogenesis: End Result

Answer 5

demyelinated region of medulla due to MS

A. acute demyelination causes conduction block

B. with repeated damage axon dies, get no message when gets to the other end, debilitation with age

C. degenerated axon no longer sends message

Question 6

MS: Impact of DE-myelination

Answer 6

• The disease is characterized by clinical relapses (NEW neurologic signs/symptoms lasting >24 hours–usually last days to weeks) due to CNS demyelination followed by remission (complete or partial improvement in symptoms)
• The frequency of relapses varies but averages one every 1-2 years for the first 5-10 years of the illness after disease onset (more attacks=more progressive disease)
• Over time, patients develop progressive symptoms without clear clinical relapses or new lesions

Question 7

Syndromes HIGHLY suggestive of MS (A): Optic Neuritis

Answer 7

• “fuzzy or absent in the middle of my visual field, I can only see out the sides”
• Decreased monocular vision
  
  • Often involving central vision
• Pain with eye movement
• Decreased red/green color (looks grey or DE-saturated)
• ****Clinically associated with an afferent pupillary defect (APD or Marcus-Gunn pupil)
  
  • shine light in bad eye, will NOT get constriction
• Uhthoff phenomenon (heat intolerance)
  
  • -or- is phyisologically stressed/sick=MS symptoms recurred b/c myelinated axons are temp modulated–Ex: overheated compy no work as well
  • “Hot bath test”
    
    • pts placed in hot tubs and then examined for recurrence of an APD
• On exam: swollen/blurred disc

Question 8

Syndromes HIGHLY suggestive of MS (B): Brainstem Syndromes

Answer 8

• Internuclear ophthalmoplegia (MLF syndrome)
• MLF lesion between CN3&6
• Oculomotor dysfunction
• Ataxia
• Trigeminal Neuralgia
• Facial nerve palsy
• CST (cortical spinal tract)/UMN involvement
• Note:
  
  • MS lesions tend to hug the periphery of the brainstem, like to be at the SURFACE.
  • Vascular lesions (stroke) tend to be internal/deep midline; buried in the blood vessels.

Question 9

Syndromes HIGHLY suggestive of MS (C): SC Syndrome

Answer 9

• If at sensory level they are numb in torse: form chin to hip=SC lesion until proven otherwise!!
• Partial myelopathy
• Lhermitte’s “sign” (electric shock sensation with the neck flexed; neck to chest)
• Numbness/sensory level
• Deafferented hand
• Urinary urgency, incontinence, erectile dysfunction (do not occur with GBS (should never be this high!—commonly misdiagnosed)
• Progressive asymmetric spastic paraplegia

Question 10

Syndromes HIGHLY suggestive of MS (D): Romberg Sign

Answer 10

• Romberg sign: a sign indicating loss of proprioceptive control in which increased unsteadiness occurs when standing with eyes closed
  
  • does NOT localize to the central or peripheral nervous system—it is a marker of proprioceptive dysfunction
• Lesions affecting the pial surface of the SC; MS lesions LOVE the dorsal colums
• sensation from feet travels up legs and enters the SC at the dorsal root, then travels up the dorsal columns in the medial aspect–fall over when they try to wash hair in the shower (or have to hold onto something)

Question 11

“Silent” Symptoms of MS

Answer 11

• nonspecific, from hundred of lesions that increase energy need (causing things like fatigue an spasticity)
• Fatigue 65%-97% (increased energy demand)
• Bladder dysfunction 52%-97%
• Sexual dysfunction 40%-90%
• Spasticity 40%-85%
• Pain 29%-86%
• Cognitive impairment 40%-70%
• Bowel dysfunction 35%-68%

Question 12

MS Diagnosis: SCHUMACHER (OG) Criteria (1965)=”SIX Essential Criteria for ‘Definite MS’”

Answer 12

***MS is a CLINICAL DIAGNOSIS!!***

1. Objective abnormalities on examination; symptoms alone not acceptable
2. Evidence on exam or hx of 2 or more separate parts of the CNS (has to be more than one lesion)
3. Objective evidence must reflect predominantly white matter involvement
   * fiber tract damage; more than a minor proportion of brainstem findings disqualified pts for studies
4. Involvement of the neuroaxis must occur temporally:

• Risk of REOCCURENCE is key finding
• 2 or more episodes of worsening separated by one month or more
  
  • ​each episode lasting at least 24 hrs
• Slow or step-wise progression of s/s over a period of 6 months

5. Age 10-50 (misnomer for trials!–its a bell curve!!)
6. Cannot be better explained by another process

Question 13

MS Diagnosis: 2010 McDONALD Criteria (*MRIs)

Answer 13

YAY, MRIs-can make diagnosis from ONE attack!

• Diagnosis rests on the objective demonstration of CNS white matter lesions—based on clinical and radiographic grounds—that are disseminated in time & space for which there is no better alternative diagnosis
• There is no single test that “confirms” MS—it is ultimately a clinical diagnosis with radiographic corroboration

Question 14

MS: Radiographic Diagnosis

Answer 14

A. Dissemination in Space

• At least one T2 lesion—that is characteristic in appearance for MS—in at least two out of four locations considered characteristic for MS: (JIPS)
  
  • juxtacortical-interface of grey/white matter
  • periventricular-most classic; easy for immune cells to attack blood vessels and cross over near the lesions; lined up right against tip of lateral ventricles
  • infratentorial-below tentorium cerebelli, by middle cerebellar peduncle
  • spinal cord

B. Dissemination in Time

• A new T2 and/or GdE lesion on follow up MRI, irrespective of the timing of the baseline MRI (because it is a RELAPSING disease)
• Can diagnose off of a single MRI

Question 15

MS: Typical Lesion

Answer 15

• Lesions >3mm
• lesions like to line up against the corpus callosum
• Optic radiation lesions (at back of the ventricles)
• Brainstem lesion abutting the 4th ventricle or aqueduct
• Incomplete/partial enhancement (sometimes a U-shape facing the ventricle-typical of an active lesion)
• T1 “Black Holes” (atrophy over time, sign of chronic/repeated damage)
• ***DAWSON’S FINGERS***
  
  • essentially pethognomonic for MS
  • perpendicular oriented periventricular lesions (BOOM! MS!–get a SAGGITAL view!!)

Question 16

MS: SC Lesions

Answer 16

• Lesions are typically small (<1-2 vertebral levels)
• Located in the cord periphery, especially the DORSAL COLUMNS
  
  • Lesions begin at the pial surface
  • ***Very few other neurologic diseases (esp stroke) cause discrete SC lesions AND brain lesions***

Question 17

Other Tests: CSF

Answer 17

NOT a gold standard. NOT mandatory for diagnosis or even included in the current criteria

everything should be nml!! BUT–may find OLIGOCLONAL BANDS

• Cell count <5/mm3
  
  • Rarely >50/mm3
  • Usually 90% lymphocytes and <5% PMN cells
• Protein normal (2/3rds of pts)
  
  • Rarely >100/dL
  • High levels associated with cord swelling
• Glucose normal
• Oligoclonal bands (90%-95%)
  
  • Provides evidence for intrathecal synthesis and carries the implication of immunological process in the CNS (not specific)
  • Once present are persistent
  • OCBs with optic neuritis or first event (CIS-clinically isolated syndrome; essentially “early MS”) is associated with an increased risk of MS
• IgG abnormalities common
  
  • Intrathecal IgG synthesis is highly characteristic
  • Elevated IgG, IgG index or synthesis rate (80%-90%)

Question 18

Differential Diagnosis

Answer 18

• Keep in Mind: Multiple Sclerosis is a disease of the Central Nervous System that affects discrete areas of White Matter, typically in a relapsing and remitting fashion.
• Big point: consider alternative etiologies (even if MS may be more common)
• A. Neuromyelitis Optica
  
  • MUCH worse/more aggressive than MS
  • CP:
    
    • Longitudinally extensive spinal cord lesion (>3 vertebral segments)
    • Bilateral optic neuritis + transverse myelitis
    • Hic-coughs
    • Normal/minimal brain lesions
  • Tests: NMO IgG Ab positive
  • Path: Starts in medulla then extends to C3 or further, much longer lesion
• B. Acute Disseminated Encephalomyelitis (ADEM)
  
  • Often post-infectious process (ONE-time vs. REOCCURING MS)
  • CP: HA, vomiting, drowsiness and meningism (often initially treated for infectious meningoencephalitis)
  • Large, “fluffy” multifocal lesions (vs small, discrete MS lesions)
  • More common in children than adults
• C. Progressive Multifocal Leukoencephalopathy (PML)
  
  • Opportunistic infection due to the John Cunningham Virus
  • 55% of the US pop has it; opportunistic infection
  • Commonly seen in the HIV population, including as the initial diagnosis
  • Rare side effect that occurs in those on NATALIZUMAB (an MS drug) who are also JC Virus positive
    
    • If treated early, MS pts will have a good recovery
  • Multiple lesions are commonly present
  • CP: change in mental status-cognition, depression
  • Frequently subcortical hemispheric white matter or cerebellar peduncles
  • Can lead to death or severe neurologic injury; better chance of recovery with early detection
  • classical findings: Hyper-intense FLAIR signal in the right middle cerebellar peduncle

Question 19

MS Treatment

Answer 19

• The challenge is no longer the lack of effective treatments. The challenge is in navigating the increasingly complex and effective therapy options
• Selecting a Tx: Considerations

1. Overall Effectiveness

• Reduction in Relapse Rate
• Impact on MRI metrics ({less} T2 lesions, enhancing lesions, T1 black holes)
• Impact on Disability (EDSS)

2. Side Effect Profile
   * Any reason the patient cannot or should not take it?
3. Long Term Safety Profile
   * Usually treating young patients for lengthy periods of time; do we trade today’s problem for tomorrow’s? Answer should be “NO!”
4. Will the patient take it?
   * “No medication works less well than the one you don’t take.”
5. The main goal of treatment is to make life as “normal” as possible
   * “I have MS, MS does not have me”

Question 20

MS: Treating Relapses (New, Focal Symptoms due to Inflammation)

Answer 20

Goal is the speed recovery & limit injury

• ***Steroids (HIGH DOSES)***
  
  • IV methylprednisonle or oral prednisone
    
    • if forced to pick on a test, IV steroids are preferred—even though current data suggests IV and PO are equivalent
  • Far and away the most commonly used for acute relapses
• ACTH
• Plasmapharesis
• IVIg

Future:

• OCRELIZUMAB:
  
  • anti-CD20 monoclonal antibody given every 6 months
  • 89-95% reduction in new lesions
  • 73-80% reduction relapases