Neuroimmunology Flashcards
Epidemiology of MS:
Genetic susceptibility + environmental exposure:
Genetics:
- HLA-DR2 (HLA-DRB1*15) ub Northern Europeans
- Female > male
Environment:
- EBV (HHV4)
- Smoking
- Increasing latitude
- Sunlight and Vit D protective
Pathophysiology of MS:
Not well understood.
Genetics + Environmental exposure –> auto-reactive lymphocytes which target CNS specific antigen (unknown)
Formation of MS Plaques (focal demyelination) –> axonal loss.
- Variable extend of re-myelination
Classical description of T cell mediated, pure demyelination, pure white matter, relapsing followed by progression is not entirely accurate.
Feature of MS clinical presentation:
- Sub-acute presentation of symptoms over 24-48 hours
- Nadir within 2 weeks
- Resolution by 4 weeks by may not be complete
pseudo-relapse - same symptoms as previous attack.
- heat, fever, infection, stress.
Uhthoffs phenomenon - heat leads to worsening of symptoms (slows conduction)
Lhermittes - bending neck, leads to pain down spine.
Risk of disease progression with CIS (and risk factors)
Overall 64% of progression to MS. Higher risk with:
- younger age
- higher lesion load
- spinal cord lesions
- GAD enhancing lesions
- OCB in CSF
- Abnormal visual evoked potentials
Radiological features of MS
Characteristics: T2 hyperintense (demyelination), T1 hypointense (axonal loss)
GAD enhancing if acute (within 1 month).
Dissemination in space requires at least 1 T2 lesions in 2 or more locations:
- Periventricular
- Juxtacortical
- Infratentorial
- Spinal cord
Dissemination in time may be evidenced by GAD enhancing and non-enhancing lesions.
McDonalds Criteria:
2 lesions in time and space:
Time:
- 2 separate attacks
- MRI with enhancing and non-enhancing lesions
-Presence of OCB in CSF
Space:
- 2 difference locations on MRI or through clinical evidence.
- BUT optic nerve lesions does not count currently
Significance of oligoclonal Bands
Bands of IgG in the CSF but not in serum, evidence of intra-thecal production.
Increased risk of progression from CIS or RIS to MS.
But not specific and will also be present with conditions causing BBB disruption - CNS infection, autoimmune/paraneoplastic CNS conditions.
Acute treatment of MS attack
3 days of corticosteroid. Oral non-inferior to IV. No role for prolonged course or taper.
Plasmapheresis if severe
Teriflunomide
Class: Antimetabolite - inhibits pyrimidine synthesis (cytosine, thymine, uracil)
AED: hair loss, GI upset, teratogenic
Fingolimod / Siponimod
MOA: Sphingosine-1-phosphate receptor modulator (S1P inhibitor). Inhibits migration of lymphocytes from lymphoid tissue into peripheral circulation.
AED: First dose bradycardia, varicella reactivation, macula oedema, risk of rebound with cessation.
Very poor response to vaccination
Siponimod contraindicated with CYP2C93/3
Cladribine
MOA: purine antimetabolite that cause lymphocyte depletion followed by lymphocyte reconstitution.
Given 5 day course, repeat 1 month later, repeat 1 year later.
AED: headache, lymphopenia, herpes zoster reactivation
Natalizumab
MOA: alpha 1 integrin inhibitor - prevents migration of lymphocytes into CNS
High efficacy
AED:
- pharyngitis, peripheral oedema, infusion related symptoms.
- progressive multifocal leukoencephalopathy
Alemtuzumab
MOA: mAb to CD-52 (on B and T cells), rapid depletion of lymphocytes and then repopulation.
(causes a shift in autoimmunity towards other organs - ITP, graves, anti-GBM)
Yearly infusion for 2 years
AED: infusion reactions, ITP, Graves disease, Anti-GBM, increase infections
Ocrelizumab, Ofatumumab
Anti-CD 20 (like rituximab)
Increased risk of severe COVID
Dampens response to vaccination
MS and Pregnancy
Reduced risk of relapse intra-partum, increased risk post-partum.
Management - most drugs are ceased 4 months prior to conception if possible.
If poorly controlled, best drugs to use are:
- Interferon beta
- Glatiramer acetate
- Rituximab / Ocrelizumab
Drugs to avoid:
- Fingolimod
- Teriflunamide
PML Pathology
Sub-acute progressive demyelinating process caused by reactivation of the John Cunningham Virus (JC virus)
Indolent virus that lays dormant in kidney and bone marrow, present in 50-60% of population, reactivated with immunosuppression.
Toxic to oligodendrocytes, causes demyelination however is not an inflammatory process –> no enhancing MRI lesions.
Presents with progressive neurological deficits, gradually enlarging T2 hyper-intensities on MRI with minimal GAD enhancement.
PML and Natalizumab
Increased risk of PML with > 2 years exposure, previous exposure to immunosuppression (any), JCV serology positive and high titre.
With 6 years of treatment, and titre > 1.5, risk if > 1 in 100
Eculizumab
C5 inhibitor
AED: High risk of disease from encapsulated organisms - High risk of invasive meningococcal disease (need to have both vaccines)
Neuromyelitis Optica Spectrum Disorders
Epidemiology: Asian and African decent, female to male 9:1
Path: B cell mediated disease, targeting astrocytes in CNS
Key features: optic neuritis, acute myelitis (with longitudinal lesions >3 vertebral bodies), area postrema syndrome (hiccups, nausea and vomiting), symptomatic narcolepsy
More severe than MS with individual attacks more likely to result in permanent disability.
Diagnosis of NMO:
Serology:
- AQP-4 antibody (serum)
- MOG Ab - 50% of AQP-4 negative cases. MOGAD steroid responsive, less responsive to rituximab.
Management of NMOSD
Acute - IV MP or PLEX
Chronic:
- AZA or MMF
- Rituximab
- Eculizumab
- Ineblizumab CD-19 depletion
- Satralizumab - anti-IL 6
difference between management of NMO/MOG and MS
MS: PO is as good as IV. Only 3 days, no role for longer.
NMO/MOG: Treat aggressively with IV MP and consider PLEX
