Multiple Sclerosis

Question 1

Etiology/risk factors

Answer 1

• multifactorial
• genetic predisposition
  
  • e.g. HLA allele for MHC Class 2 (on APC’s), 100s of other immune system-related loci ID’d
• immunogenic triggers:
  
  • viruses (EBV, HHV6)
  • autoimmunity
• vitamin D deficiency
  
  • certain alleles for genes involving Vit D metabolism assoc w/ increased risk for MS
• temperate latitudes
  
  • environmental –> acquire risk of are you move to when young

Question 2

Clinical presentations (3 types)

Answer 2

• Relapsing-remitting pattern (85%)
  
  • –> Secondary progressive MS (when neurological deficits persist and progress instead of passing
• Progressive-relapsing
• Primary progressive

Question 3

Signs and symptoms (10)

Answer 3

1. Focal weakness –> UMN pattern, weakness in progravity mm (elevators, flexors), monoparesis, hemiparesis, paraparesis –> ** can be subtle
2. Focal numbness/paresthesias –> often bilateral, band-like sensation, tingling
3. Optic neuritis –> painful inflammation of optic nerve, +/- scotoma (blind spot in eye)
4. Speech difficulty –> dysarthria/slurring
5. Lhermitte’s –> flexion of neck causes paraesthesia
6. Uhthoff’s –> symptoms excerbated by overheating
7. Coordination/Gait/Balance issues
8. Bladder spasticity, frequency
9. Spasticity –> especially in legs
10. Internuclear ophthalmoparesis (MLF white matter tract demyelination)

** typical symptoms of white matter dysfunction

Question 4

MRI findings

Answer 4

• White matter enhancing lesions (T2/FLAIR)
  
  • Dawson’s fingers
  • periventricular and/or perivenular
  • Increased water signal where myelin has been disrupted
  • acute or chronic lesions
• Hypointense “black holes” (T1)
  
  • chronic demyelinating lesions w/ localized areas of axonal loss, astrocytosis
  • associated w/ MS disability
• Gadolinium enhancement of lesions
  
  • BBB breakdown – acute lesions
• Brain atrophy - over time, assoc w/ MS disability
• Spinal cord enhancing lesions MRI (FLAIR)
  
  • Short white lesions

Question 5

Course of MS for relapsing-remitting type

Answer 5

• starts as a primarily immune-mediated process
• can take several decades to progress to “secondary progressive” phase
• Secondary progressive phase is more difficult to treat symptoms effectively –> use combinations of existing drugs or more potent drugs, new drugs in pipeline
• over time, MS becomes neurodegenerative –> a secondary neurodegerative disease
• brain volume atrophy is accelerated in MS, treatment helps slow this down

Question 6

Pathogenesis

Answer 6

• Immune-mediated inflammatory disease of CNS
• WBCs cross BBB & secrete cytokines
  
  • T and B cells, macrophates –> autoimmune attack against myelin antigens –> due to molecular mimicry (?)
  • T lymphocytes form perivascular infiltrate (white lesions on MRI)
• Results:
  
  • Demyelination
  • Axonal Injury – correlates with neurologic disability
  • Brain atrophy
  • Damage doesn’t respect vascular boundaries

Question 7

Clinical criteria for MS diagnosis

Answer 7

• neurological symptoms and signs attributd to myelin dysfunction in different regions of the CNS (dissemination in space) and at different times (dissemination in time)
• Adjunct studies (MRI, lumbar puncture, evoked potentials)
• No other explanation:
  
  • lyme sarcoid, B-12 deficiency, HIV, small strokes

Question 8

Adjunct tools to support diagnosis

Answer 8

• MRI
• Oligoclonal IgG bands (Lumbar puncture)
  
  • inflammation
  • thought to represent B cell expansion in CNS in response to demyelination (antigen not known)
  • Pleocytosis NOT common
  • 80% of individuals w/ MS
• Evoked potentials
  
  • test for impulse conduction delays

Question 9

Treatment strategies for MS

Answer 9

• type 1 IFN
• antibodies to immune-related proteins
• trap T cells in lymph nodes
• block proliferation of activated B and T cells
• immunosuppressives
• ** most act to prevent immune activation/inflammation @ periphery