BIOC 095 Multiple Sclerosis: Treatment Throughout A Lifetime

Question 1

13 Oct, 2017

Noon - 1pm

Answer 1

• University of Vermont School of Medicine - Hill Panitch Lectureship
• John R. Corboy, MD

Question 2

Goal of MS therapy

Answer 2

• Life-long
• Brain / spine
• Health

Question 3

Approach to MS

Answer 3

• avoid developing it, i.e. Find cause and stop it
• alter immune sys function
  protect nerves frm degeneration
• enhance normal repair in CNS
• replace damaged cells in CNS
• good behaviors

Question 4

Natural progression of MS

Answer 4

• Life-long time
• Relapsing forms:
  1. Subclinical
  2. Mono-symptomatic- initial demeaning event
  3. Relapsing remitting - clinically definite MS
  4. Secondary progressive - relapse
• increase lv of disability over time & accumulated MRI lesion burden
• increase cognitive dysfunction
• decrease in brain volume

Question 5

Gray matter lesions in MS

Answer 5

1. Leukocrotical
2. Intracortical
3. Subpial, superficial

Question 6

Meninges B-cell follicles

Answer 6

• Meningeal inflammation > widespread

- link to cortical pathology in MS

Question 7

Affect activity (survey in women patients)

Answer 7

• General activity level diminish after MS diagnosis

Question 8

Radiologically isolated syndrome

Answer 8

• 1/3 will develop clinical MS over 2-5yrs
• 91% develop radio graphic dissemination over 6-30months
• Male > female
• Smaller total brain volume and cortical volume

Question 9

Risk factors in early MS rise MS

Answer 9

• Genetic (>200) & env risk factors (EBV, smoking, obesity, Vit D)
• 1st degree relatives w/ 10-20 fold increase risk
• Study:
  
  1. 300 asymptomatic FDRs of MS patients, 18-30
  2. Env screen, blood (E8V, Vit D, HLA, SNP, immunological & neuronal damage markers); activity monitor
  3. Brief screening MRI, brain & C spine
  4. Compare those w/ vs those w/o MRI c/w MS
• Similar to GEMS (Genes & environment in MS)

Question 10

Treatment

Answer 10

• 1st attack: damage > similar to radiologically

- Associate w/ NfL lvl

Question 11

Treatment effect on brain atrophy correlates w/ treatment effect on disability in MS

Answer 11

• High correlation

Question 12

Net change in expanded disability status scale (EDSS) score frm before an exacerbation to aft

Answer 12

• 42.4% increase 0.5+
• 28.1% increase 1+
  > Relapse has significant relationship w/ disabilities
  > Relapse in early age influences increase

Question 13

Vocab

Answer 13

DSS 3, DSS 6, DSS 8

Question 14

DMT benefits

Answer 14

Decrease:
- relapses
- new /active MRI lesions
- brain volume loss *esp important
- disability progress due to attacks
- no. Failing NEDA
- can't ognitive deterioration
- all approved and effective in RRMS
  - approved in CIS
 - Only ocrelizumab approved for progressive MS
    (Some benefits documented w/ other DMTs)
* DMTs are less efficacious as people age

Question 15

Mean age in MS treatment

Answer 15

• Ocrelizumab OPERA I/II Hauser 2017: mean age = 36

- Another Ocrelizumab: mean age = 47

Question 16

Vocab

Answer 16

• dimethyl fumarate

- natalizumab v Pb

Question 17

EU vs NA treatment difference

Answer 17

• NA almost no diff. btw placebo gp & treatment gp
• EU > diff (becoz EU = younger, early onset, relapses more
  > gain benefits
• W/ relapses> benefit
• <51 age + Gad lesions > gain more benefits

Question 18

Is it safe to discontinue DMTs in MS?

Answer 18

• Outcomes: % with new relapse or T2/FLAIR lesion,
  % w/ EDSS change, patient reported outcomes
  > Safe to DC

Question 19

Progressive MS

Answer 19

• May b thought of as aging transplanted onto MS
• Possibly due to loss of cellular energy production & oxidative stress of cells
• Early studies w/ Biotin (Vitamin B-7), alpha-lipoid acid, & Zocor

Question 20

Chronic

Answer 20

• Increase energy demand & sodium accumulation in the atonal cytoplasm
• Increase exposure to toxic species

Question 21

Ref: 2016 PMID:27889191

Answer 21

Targeting demyelination & virtual hypoxia w/ high-dose biotin as treatment

Question 22

Myelin / atonal damage

Answer 22

• Oxidation
  
  • anti-oxidants e.g. A lipoid acid, sim a station
• Microglial active > destructive pro-inflammmatory cytokines
• Dysfunction of voltage-gate channels
• Use Biotin as a co-enzyme in Krebs cycle

Question 23

Neuroprotective effects of lipoid acid in SPMS

Results of a placebo-controlled pilot trial

Answer 23

• LA = an inexpensive, oral antioxidant > water & fat-soluble
• 2 year RCT of lipoid acid 1200 mg daily vs placebo
• % change brain volume 66% reduction

Question 24

Conclusions

Answer 24

• Protect the cells frm die > good way to treat MS patients
• Younger patient benefits
• • Good behaviors (no smoking, regular exercises)
• Imunotherapy ??? In late progression (Age)