1
Q
What genetic and environmental factors predispose to MS?
A
Genetic Factors:
- Presence of HLADRB1*15 (HLADR2) allele increases the risk of MS especially in Northern Europeans
- Presence of HLA-A*02 allele appears to be protective against MS
- 35% disease concordance among monozygotic twins
- 3–4% disease concordance among first-degree relatives
Environmental RF:
- Pathogens: EBV, HHV6
- Cigarette smoking
- Low Vit D - sunlight exposure and vit D protective for MS
- Obesity early in life.
- Latitude - effect has decreased over years
Living further away from equator
Those who migrate before adolescence acquire the risk of the new country, those who migrate later keep risk of initial country
2
Q
What does CSF oligoclonal bands mean?
A
Oligoclonal bands in CSF indicate antibody production in CNS
Oligoclonal bands are a form of IgG.
3
Q
What does the pathophysiology of MS consist of.
A
Characterised by autoimmune inflammation, demyelination and axonal degeneration.
Activation of autoreactive T-lymphocytes→ inflammatory processes → focal demyelination with partial preservation of axons (acute plaques) → loss of axons and atrophy of oligodendrocytes (chronic plaques) → gliosis → inadequate remyelination
4
Q
What is the function of oligodendrocytes.
A
Oligodendrocytes produce the myelin sheath insulating neuronal axons (analogous to Schwann cells in the peripheral nervous system),
5
Q
What are the clinical types of MS?
A
- Clinically isolated: first clinical episode Demyelinating attack: - subacute progression of symptoms - >24-28 hours - Nadir within 2 weeks - Resolution by 4 weeks - May not return to baseline - Pseudorelapse: due to infections, electrolytes
- Radiologically Isolated MS
Presence of demyelinating lesions characteristic for MS in an asymptomatic individual - ovoid well circumscribed focus. Leads to increase risk of developing primary progressive MS - Relapsing Remitting: clearly defined attacks due to recurrent demyelination within CNS with either full/incomplete recovery - minimal disease progression during relapses though severe disability may result from a relapse.
- Secondary progressive: initially relapsing remitting followed by gradual worsening of symptoms in between exacerbations.
- Primary progressive: progressive accumulation of disability from disease onset. Diagnosis requires positive oligoclonal bands.
6
Q
Definition of exacerbation in MS
A
- New symptoms or significant worsening of existing symptoms, both of which last at least 24 hours and preceded by at least 30 day of clinical stability.
7
Q
What are the earliest clinical manifestations for MS?
A
Optic neuritis
- Typically unilateral
- Can be painful - pain on eye movement
- Mononuclear central vision loss
- Impaired vision and colour blindness
- Relative afferent pupillary defect
- Retrobulbar (have no optic nerve swelling)
- Will progress to optic atrophy
Pale optic disc, red desaturation/ishihara, enlarged blind spot/scotoma, visual field defects
Tx: steroids
8
Q
Characteristic of internuclear ophthalmoplegia?
A
- Occurs due to damage to MEDIAL LONGITDUINAL FASCICULUS (the connection between the abducens nucleus, CN VI in pons and the oculomotor nucleus, CN III on the other side in the midbrain)
- Ipsilateral medial rectus weakness but an intact convergence reflex
- Disconjugate lateral gaze nystagmus in the contralateral eye - affected eye shows impairment of adduction and abducted eye shows nystagmus
- More frequently bilateral than unilateral
Internuclear ophthalmoplegia (INO) is characterized by Impaired adduction of the eye ipsilateral to the lesion and Nystagmus on the Opposite side!
9
Q
Lhermitte sign
A
Shooting electric sensation that travels down the spine upon flexion of neck. Indicate demyelination of spinal cord tracts.
Also seen in cervical spondylosis, tranverse myelitis, b12 deficiency, chiari malformation
10
Q
Uhthoff phenomenon
A
Reversible exacerbation of neurological symptoms following an increase in body temperature, eg: physical exertion, a warm bath or fever
Heat sensitivity: small increase in body temperature worsens signs and symptoms
11
Q
What other dysfunction is common in MS?
A
- Bladder, bowel and sexual dysfunction.
- For bladder: urge incontinence and then overflow incontinence.
Urge incontinence develops first due to loss of CNS inhibition of detrusor contraction in the bladder. Later, detrusor muscle becomes weak, atonic and dilate and thus overflow incontinence occurs.
12
Q
Most common symptom in MS?
A
Fatigue (90%) Walking difficulties (76%) Numbness/tingling (70%) Pain (64%) Muscle spasms (61%) Headache, depression, emotional changes (54%) Bladder dysfunction (51%) Cognitive impairment Optic neuritis Internuclear ophthalmoplegia (bilateral highly specific) Lhermittes + Uhthoof
- Cognitive impairment
- Fatigue
- Weakness
- Visual pathways: optic neuritis
- Cerebellum: ataxia, dysmetria, tremor
- Brainstem - THINK INO (BILATERALY HIGHLY SPECIFIC), ophthalmoplegia, vertigo, trigeminal neuralgia
- Spinal Cord: bladder bowel dysfunction (urge incontinence, neurogenic bladder, constipation)
- Numbness, parathesia
- Lhermitte + Uthoff
13
Q
Common areas of the brain affected in MS
A
Periventricular
Juxtacortical/cortical
Infratentorial
Spinal cord
Dissemination in space requires lesions in at least 2/4 areas
14
Q
Ix for MS
A
- MRI: looking for lesions separated in time and space
White matter lesions best sein on T2 FLAIR (T2 hyperintense, T1 hypointense)
Contrast enhancement on post gadolinium T1 weighted imaging - CSF: oligoclonal bands only in CSF, lymphocytic pleocytosis.
- Can also do evoked potentials
- VER (visual evoked): slow means demyelination
- SER (somatosensory)
- MER (motor)
15
Q
Characteristics of neuromyelitis optica (NMO)
A
- Relapsing B cell mediated disease against astrocytes characterised by longitudinally extensive, centrally located necrotic spinal cord.
- Central nervous system disorder and autoimmune disorder that attacks the optic nerves (optic neuritis) and the spinal cord (myelitis)
- More severe disease than MS, individual attacks are more likely to result in a permanent neurological deficit with less chance of recovery
- Leads to bilateral optic neuritis
- Transverse myelitis: symmetric paraplegia, sensory loss, bladder dysfunction
- Antibody-mediated inflammation directed at aquaporin-4 antibody channels in the CNS that results in inflammatory demyelination in the optic nerve and spinal cord. Can be differentiated from MS by NMO lgG antibody testing and by its lack of significant brain involvement, large and longitudinally extensive spinal cord lesions, and profound CSF leukocytosis
- In people with NMO who test negative for anti-AQP4 antibodies, up to a third may be positive for auto-antibodies directed against a component of myelin called myelin oligodendrocyte glycoprotein (MOG). People with anti-MOG related NMO similarly have episodes of transverse myelitis and optic neuritis, but recovery after attacks appears to be better than anti-AQP4 related disease.
- Hanna Pearl: If MOG is negative - indicate NMO spectrum disorder which is associated with sjogrens and sarcoid
MRI Spine Findings: MS vs NMO
- MS: short segments, partial lesions
- NMO: LETM (longitudinally extensive transverse myelitis), often whole extent of cord
Longitudinally extensive, centrally located, necrotic spinal cord
16
Q
Diagnosis of MS
A
- Dissemination of lesions in time and space
Dissemination in time: appearance of new lesions over time confirmed by one of the following
- 2 or more exacerbations occurring at least 30 days apart
- MRI showing 2 separate lesions
- Positive CSF oligoclonal bands
Dissemination in space: presence of lesions in different regions of CNS
- Presence of 2 or more lesions with objective clinical evidence
- Presence of one or more hyperintense lesions in at least 2 of the following: periventricular, juxtacortical, infratentorial, spinal
McDonalds Criteria
- 2 lesions in space and time
Time:
- 2 separate attacks or even a history of an attack
- MRI with contrast enhancement of a lesion and non enhancement of another
- Oligoclonal bands
Space
- 2 different locations in the CNS through objective clinical evidence
- 2 different locations in the CNS through MRI
17
Q
Ab associate with Neuromyelitis optica (NMO)
A
- Anti aquaporin 4
- Anti MOG (myelin oligodendrocyte glycoprotein (MOG).
Present in chronic recurrent inflammatory optic neuritis, ADEM, NMOASD
People with anti-MOG related NMO similarly have episodes of transverse myelitis and optic neuritis, but recovery after attacks appears to be better than anti-AQP4 related disease. - Hanna Pearl: If MOG is negative - indicate NMO spectrum disorder which is associated with sjogrens and sarcoid
- Steroid responsive, may be monophasic
- Poorer response to rituximab
<30% have oligoclonal bands
18
Q
Clinical features of NMO (NMO spectrum disorder)
A
- Optic neuritis
- Acute myelitis
- Area postrema (dorsal medulla) syndrome (episodes of intractable nausea, vomiting and/or hiccups)
- Acute brainstem syndrome
- Narcolepsy
- Cerebral syndrome with typical brain lesions
19
Q
Summary of NMO
Diagnostic Criteria
A
- Anti aquaporin 4
- Anti MOG
- Big lesions >3 vertebrae
- Hiccups
Diagnostic Criteria
At least 2 core clinical characteristics + AQP4
- 1 of ON, myelitis or area postrema syndrome
- Dissemination in space
Isolated recurrent ON or recurrent TM do not qualify
- Additional MRI requirements
AP syndrome: dorsal medulla lesion
Myelitis: LETM
ON
20
Q
Treatment for NMO
A
- High dose glucocorticoid for 3-5 days follow by a taper for 2-8 weeks
- Plasmapheresis in severe refractory cases
- Biologic agents approved for use in patients with positive AQP4-IgG ONLY
- Eculizumab: antibody against C5 complement component - blocking of complement activation by IgG1 and IgG3 aquaporin 4 autoantibodies deposited on neural tissue
Need to have meningococcal vaccine prior - Inebilizumab: antibody against CD19
Satrlizumab: against IL6 - Immune modulators used off label (azathioprine, rituximab, mcyopheolate) may reduce risk of acute attacks
- Natalizumab and IFNB (effective MS options) can trigger NMOSD exacerbations,
21
Q
Characteristics of acute disseminated encephalomyelitis (ADEM)
A
type IV hypersensitivity reaction
- Immune mediated demyelinating CNS disease of parainfectious origin (eg: measles) or after vaccinations (less common)
- Monophasic disorder that affects the brain and occasionally the spinal cord
- Majority of cases in children or young adults
- Associated ENCEPHALOPATHY
- Usually preceded by viral infection or other systemic infection
- Usually resolves after 3 months
- 25% will develop MS later in life
- MOG Ab + in subset (especially children)
Monophasic: A disorder that causes only one episode of inflammation in the central nervous system
22
Q
Diagnosis and treatment of acute disseminated encephalomyelitis (ADEM)
A
- LP: lymphocytic pleocytosis, elevated protein
- Spinal/brain MRI: typically multiple, bilateral lesions
High dose IV steroids IVIG/plasma exchange Acyclovir Usually resolves after 3 months 25% will develop MS later in life MOG ab positive in subset
23
Q
What medication in MS is approved for primary progressive MS?
A
Ocrelizumab- targets CD20
Can be used for RRMS and PPMS
24
Q
Treatment for acute exacerbation of MS
A
1st line: IV steroids
2nd line: plasmapheresis for severe attacks
25
Ocrelizumab in MS
- MOA
- Indication
- SE
- Antibody against CD20 which depletes premature and mature B cells
- For RRMS, PPMS (only medication effective for PRIMARY progressive)
- Indication: PPMS with prior oligoclonal bands on CSF
- IV
- SE: URTI, hep B reactivation, immune suppression
Risk of reactivation of Hep B, TB
LFT derangement
Increased risk of URTI
But very well tolerated and safe medication
26
Natalizumab in MS
- MOA
- Indication
- SE
- Antibody against a4-integrin which decreases leukocyte migration across the BBB by blocking interaction between a4-integrin on leukocytes and vascular cell adhesion molecule 1 (VCAM-1) expressed on the vascular endothelial cells in the brain and spinal cord blood vessels, inhibiting inflammation
- RRMS
- IV
SE
- Risk of reactivation of latent JC virus causing progressive multifocal leukoencephalopathy (PML)
- Anxiety, pharyngitis, peripheral oedema
- Risk of rebound relapse on cessation
- Elevated LFTs
- Infections - herpes
27
Characteristics of PML
PML
- Subacute, progressive demyelinating process of the CNS secondary to John Cunningham Virus
- JV virus is a polyomavirus - indolent virus that lies dormant in the kidney and bone marrow in immunocompetent patients
- JC gets reactivated when immunosuppressed where they destroy oligodendrocytes leading to demyelination
- Not an inflammatory process
PML is associated with
- Organ transplant
- HIV positive patients
- Hematologic malignancies
- Anti-neoplastic or haematological maligncancies
- Natalizumab, dimethyl fumarate, fingolimod, rituximab, alemtuzumab
```
PML + Natalizumab
- Increased risk if
Duration of exposure > 2 years
Previous exposure to an immunosuppressant
JCV serology positive and high titre
```
Clinical Features
The most common symptoms are confusion, behavioural change, ataxia, hemiparesis and visual deficits.
Subacute worsening visual, motor or cognitive changes and/or gradually enlarging T2 hyperintensities with minimal gadolinium enhancement
- First symptoms are clumsiness, weakness or difficulty speaking or thinking - may develop dementia and eventually become bedbound
- Ataxia, encephalopathy, visual disturbances
- Focal symptoms: depends on what part of the brain is affected, optic nerves and spinal cord typically not affected
- Seizures
- Impaired vigilance
- Cognitive disorders
- Behavioural changes
Diagnostics:
- MRI: disseminated, non-enhancing white matter lesions without mass effect
- CSF: detection of JC virus DNA in PCR of cerebrospinal fluid
- Brain biopsy and histology: demyelination of axons and intranuclear inclusions
Prognosis: high mortality
Tx
- Cease natalizumab
- Plasma exchange: remove natalizumab from blood
- Can possibly use Pembrolizumab (PD1 inhibitor)
IRIS: immune reconstitution inflammatory syndrome
- Paradoxical deterioration in clinical status attributed to recovery of the immune system is vital for controlling JCV
- New contrast enhancement in PML lesions consistent with inflammatory breakdown of the BBB
- IRIS typically occurs 2-5 weeks after PLEX, can persist for months
Tx: steroids
need to monitor JC virus every 6 months
28
Fingolimod in MS
- MOA
- Indication
- SE
Ozanimod
- Spingosine 1 phosphate analog that decrease lymphocyte invasion of the CNS
- Oral tablet
- RRMS, can be used in children as well
SE:
- First dose bradycardia
- Varicella reactivation
- Macular oedema
- Non melanoma skin cancer (SCC/BCC)
- HTN
- LFT derangement
- Lymphopenia
- Risk of rebound relapse with cessation
- Rare PML cases
Contraindicated in patients with recent MI, unstable angina, heart block.
Useful oral medication
29
Alemtuzumab in MS
- MOA
- Indication
- SE
- Monoclonal ab against the superficial antigen CD52 which is found on the surface of immune cells (T cells/B cells/NK cells/monocytes)
- As a consequence, both B and T cells decrease drastically
- RRMS
- Yearly infusion for 2 years
```
SE
- Induce other autoimmune diseases
ITP
Graves disease - usually occur 6-18 months following alemtuzumab therapy
Anti-GBM
Cancers - breast and melanoma
Infections: herpes, listeria meningitis
```
TSH-receptor antibodies are elevated in 30-40% of patients following Alemtuzumab therapy
30
Interferon Beta in MS
- MOA
- Indication
- SE
Betaferon - Interferon beta 1b, S/C
Rebif - interferon beta 1a, S/C
Avones - Interferon beta-1a, IM
Plegridy - pegylated interferon beta 1a - NEWEST
MOA:
- Suppress T cell activity --> decreased proinflammatory cytokines and decreased lymphocyte invasion of CNS
- Modulates T and B cell function
- Decreases expression of matrix metalloproteinases
- Reverses BBB disruption
- Alters expression of a number of cytokines
Indication:
- All forms of MS
SE:
- Injection site issues, lipoatrophy
- Flu like symptoms - headache, muscle aching, fatigue
- Depression
- Liver dysfunction
- leukopenia
- thyroid disorders
Interferon beta is a cytokine that is released during inflammation so will develop flu like symptoms and can cause uthoff
not very useful medication
31
Glaitramer acetate in MS
- MOA
- Indication
- SE
MOA:
- Subcut injection
- Acts as decoy for T cells instead of neuronal myelin
- Decrease activity of proinflamamtory Th1 lymphocytes
Indication:
- RRMS
- SE: chest pain, lipoatrophy
not very useful medication
32
Dimethyl fumarate in MS
- MOA
- Indication
- SE
- Activation of NRF2, Immunomodulator that protects nerve cells through its anti-inflammatory effect
lowers lymphocyte count
- RRMS - first line
- Oral
SE
- Flushing and diarrhoea (common) - aspirin can help
- Nausea + abdominal pain
- Lymphopaenia
- LFT (rare)
- Rare PML cases
- Safe in pregnancy
Useful oral med
33
For RRMS, which medications are low-intermediate efficacy and which are high efficacy?
Low-intermediate efficacy:
- glatriamer acetate
- IFNB
- Dimethyl fumarate
- Teriflunomide
- Fingolimod
High Efficacy
- Natalizumab
- Ocrelizumab
- Almetuzumab
- Cladribine
- Ofatumumab
34
Cladribine in MS
- MOA
- Indication
- SE
- Synthetic purine nucleoside analogue, reduces T cell population
- Responsible for anti-inflammatory effect
- Cytotoxic to dividing and nondividing lymphocytes - selective depletion of T and B lymphocytes, CD4+ preferentially reduced compared to CD8
- Lymphopenia common
SE:
- Lymphopenia
- Infections
- Herpes
- Cancer ?skin cancer
- Caution with blood transfusion
- - Rash
- May increase cancer risk: contraindicated with current malignancy
- Contraindicated in pregnancy
- Contraception during and up to 6 months after treatment, both M+F
35
Medications for spasticity in MS.
- Baclofen (GABA agonist) and gabapentin are first-line for spasticity in MS
- Other options include diazepam, dantrolene and tizanidine
Intramuscular botulinum toxin is used in severe cases of MS with progressive spasticity that does not respond to first line treatment
36
Bladder dysfunction in MS
- May take the form of urgency, incontinence, overflow
- Guideline stress the importance of getting an US first to assess bladder emptying - anticholinergics may worsen symptoms in some patients
- If significant residual volume - intermittent self catherisation
- If no significant residual volume - anticholinergics may improve urinary frequency eg: oxybutynin, solifenacin
- Continence: treat UTI, oxybutynin, botox
37
Prognostic factor for disease progression
- Male
- Age at onset >40yo
- Multiple symptoms with early motor and cerebellar involvement
- Incomplete recovery after relapses
- High relapse rate in the first 2 years after MS onset
38
Effect of pregnancy on MS
- Reduced relapse rate
- Increased relapse rate in post partum
- Long term clinical course of MS remains unchanged
39
What MS medications are safe in pregnancy?
Most medications are ceased approximately 4 months prior to conception
- Capaxone and IFN B (injectables)
Glatiramer (capaxone) is the safest
- Natalizumab and almetuzamb will need to be used with caution
- Natalizumab: high risk of relapse/rebound if stopped, low absorption in breastfeeding
- Almetuzumab: monitor for autoimmune disease during pregnancy, irradiated blood products
- Rituximab/ocrelizumab: best option for women with highly active disease and dosed prior to conception, avoid in 2nd/3rd trimestr.
Not safe
- Teriflunomide - teratogenic
- Fingolimod - teratogenic
- Dimethyl fumarate
- Dinglimod
- Ocrelizumab
- Cladribine
40
Summary of medications in MS
Injectables
- Interferon beta
- Glatiramer acetate
Orals
- Finglimod
- Teriflunomide
- Dimethyl Fumarate
- Laquinimod
- Cladribine
- Siponimod
Monoclonal Ab
- Natalizumab
- Alemtuzumab
- Ocrelizumab
41
Teriflunomide in MS
- MOA
- Indication
- SE
MOA: derived from leflunomide, inhibits pyrimidine synthesis which has an antiproliferative and anti-inflammatory effect by selectively and reversibly inhibiting dihydroorotate dehydrogenase (DHODH)
DHODH is required for de novo pyrimidine synthesis in proliferating lymphocytes.
Indication
RRMS - not very useful
```
SE
Alopecia
Diarrehoa
Teratogenic
Asymptomatic increase in ALT levels, liver dysfunction
Peripheral nerve toxicity
```
Washout requires cholesterol + cholestyramine
42
Siponimod in MS
- MOA
- Indication
- SE
- For SECONDARY progressive MS
MOA
- selective sphingosine 1 phosphate receptor 1 and 5 modulator
- 2nd generation of fingolimod
- Readily crosses the BBB and prevent neurodegeneration and promote remyelination
SE
- First dose bradycardia
- Varicella dissemination
- Macular oedema
- HTN
- LFT derangement
- Lymphopenia
Contraindicated in CYP2C9*3/*3 genotype
43
Ofatumumab in MS
- MOA
- Indication
- SE
New medication for RRMS
- Subcut anti CD20 monoclonal ab, monthly injections
SE: site injections, URTI, UTI, nasopharyngitis,
44
What's the enzyme involved in poor response to clopidogrel
A poor response to clopidogrel is due to, in part, genetic variations in the CYP2C19 gene.
45
Features of transverse myelitis
Symptoms and signs depend on part of spinal cord affected
- Bilateral LL +/- UL involvement - maybe asymmetric
- Motor, sensory or both, all or only some sensory modalities
- Abdominal/chest band, ascending sensory symptoms presentation
- Bladder/bowel symptoms
- Sexual dysfunction
Short segments on MRI for MS
Long segments on MRI for NMO
Steroids
46
Features in clinically isolated syndrome which predict risk of developing MS
High Risk:
- If CIS is accompanied by MRI brain lesions with MS features
- Greater number of T2 lesions is associated with a greater risk
Low Risk:
- If CIS is not accompanied by MRI brain lesions with MS features
- 20% chance of MS diagnosis over same period of time
Highest Risk of Developing MS
- CIS +
- >9 T2 MRI brain lesions +
- CSF OCBs present +
- Vitamin D level < median
Oligoclonal bands
- If CIS + OCBs present - more than twice as likely to convert to MS than if OCB negative
47
Disease modifying treatments for MS - SUMMARY
(A) Interferons
- Betaferon (beta 1b, SC), Rebif (SC), Avonex (IM), Plegridy (pegylated beta 1a) - newest
- Suppresses inflammatory responses via multiple mechanisms - controls secretion of pro and anti-inflammatory cytokines, suppress T cell activation, induces differentiation of neural stem cells to oligodendrocytes
(B) Glatiramer acetate (capoxone) - S/C
Shifts T cell population from pproinflammatoryTh1 to regulatory Th2 that suppress inflammatory response
SE: injection site issues, lipoatrophy, immediate post injection reaction (flushing, palpitations, urticaria)
(C) Teriflunomide - PO
Inhibits dihydroorotate dehydrogenase
(D) Dimethyl fumarate - PO
Activation of NrF2
(E) Fingolimod, Spinoimod, Ozanimod (PO)
Sphingosine 1 phosphate receptor agonist
(F) Cladrabine (PO)
Cytotoxic to dividing and nondividing lymphocytes
(G) Natalizumab (IV)
a4 integrin inhibitor
(H) Alemtuzumab (IV)
CD52 inhibitor
(I) Ocrelizumab (IV), Ofatumumab (SC)
CD20
48
New medications in MS
Primary Progressive MS: Ocrelizumab
Secondary Progressive MS: Siponimod
49
NMO vs MS
NMO
- Optic Neuritis: unilateral or bilateral, often severe
- Transverse Myelitis: extensive long lesions
- Course: monophasic (one episode of inflammation) or more often relapsing
- MRI Brain: often normal
- CSF: >50 WCC, >5 PMNLs, no oligoclonal bands
- Favourable response to plasma exchange
