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Neurology > Multiple Sclerosis and Demyelinating Disorders > Flashcards

Multiple Sclerosis and Demyelinating Disorders Flashcards

1
Q

Multiple sclerosis

Pathogenesis and Immunology

A

Pathogenesis
* ****Inflammation, demyelination and axon degeneration in multiple sites of CNS - brain, spinal cord, optic nerve
* Most widely accepted theory -> inflammatory autoimmune disorder mediated by autoreactive lymphocytes - later dominated by microglial activation and chronic neurodegeneration
* Other theories -> immune due to chronic viral infection, nonimmune non-inflammatory etiology due to genetically determined neuroglial degenerative process

Epidemiology
* ****F: M = 3:1
* Usually ages 15-50. 5% MS population < 18 years
* Genetics - HLA DRB1
* Risk factors -> lack of sun exposure, low vitamin D levels, EBV and other viruses, temperate latitude, smoking (increased relapse rates in smokers), obesity, early adulthood, female sex
* 2-4% risk if first degree relative affected
* Concordance in monozygotic twins 30-50%

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2
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Clinical features multiple sclerosis

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Commonest = sensory symptoms in limbs (31%), then visual loss (14%)
* * Internuclear ophthalmoplegia
* Optic neuritis - 50% chance of developing MS by 15 years
○ Fundoscopy - reduction in visual acuity, pappilitis, optic atrophy, scotomata (usually central)
* RAPD
* Upper motor neurone weakness
* Cerebellar signs
* Posterior column sensory loss
* Faecal/urinary incontinence
* Lhermitte’s sign
○ Electric shock like sensation in the limbs or trunk following neck flexion
○ Also seen in subacute combined degeneration of the cord, cervical spondylosis, cervical cord tumours, foramen magnum tumours, nitrous oxide abuse, mantle irradiation
* Uhthoff’s phenomenon
○ Worsening symptoms in the setting of hotter temperatures or exercise
§ Common in MS - also occurs in peripheral disorders like myasthenia gravis

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3
Q

Notes on clinically isolated syndrome in multiple sclerosis

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  • First clinical episode suggestive of MS - thought of as a precursor in MS
  • Monophasic clinical episode, acute or subacute onset lasting > 24 hours
  • Resembles typical MS relapse, with symptoms and objective findings reflecting focal or multifocal inflammatory demyelinating event in CNS
  • No evidence of previous episodes of demyelination from patient history
  • Develop over hours - days, remit over weeks to months
  • Typical syndromes include (also typical for relapse) -> unilateral optic neuritis, painless diplopia, brainstem/cerebellar syndrome, partial transverse myelitis - often predominantly sensory, Lhermitte symptom, sphincter/erectile dysfunction

**Risk of progression to MS
**if abnormal MRI - 70-90% develop MS
Normal MRI - 10% will develop MS
Gadolinium enhancing lesions - higher risk of progression
MRI better predictor of development of MS than CSF or evoked potentials

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4
Q

Notes on multiple sclerosis and optic neuritis

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  • First presenting symptom of MS in 21% cases
  • Probability of developing MS by 15 years after onset of optic neuritis 50%
    • Strongly related to presence of lesions on a baseline MRI
    • No lesions - 25% probability during follow up period, risk very low after ten years
    • 1 or more lesions - 72% probability, risk substantial even after ten years
    • Increased risk of progression to MS: females, younger adults > adults or children, abnormal brain MRI, recurrence, retinal perivenous sheathing, CSF oligoclonal bands, severe papillitis
    • Note simultaneous bilateral ON - lower MS risk

**Symptoms
**Monocular, central visual loss, pain (particularly on eye movement), altered colour vision e.g. red -> dark/bleached, red-green more affected in late phase , phosphenes, uhthoff phenomenon, reduced contrast sensitivity

Recovery: 90% vision 6/12 or better at one year
Poorer prognosis: moer severe visual loss at presentation, longer lesion in optic nerve, african-american heritage, children
Recurrence: 35% at 10 years

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5
Q

Notes on eye movement abnormalities in MS

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**Gaze abnormalities
**Internuclear ophthalmoplegia
One-and-a-half syndrome
Dorsal midbrain syndrome
Skew deviation

**Nystagmus
**Horizontal, vertical, pendular

**Slowed smooth pursuit movements
Ocular motor nerve palsies (uncommon)

**One and a half syndrome
**Horizontal gaze palsy on looking to one side plus impaired adduction on looking to the opposite side
Other features - turning out (exotropia) of the eye opposite the lesion
If ilsiplateral LMN facial nerve weakness = 8 and a half syndrome
Dorsal pons lesion - stroke, MS

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6
Q

Notes on bladder/bowel/sexual dysfunction in MS

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7
Q

Notes on paroxysmal symptoms in MS

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8
Q

Notes on radiologically isolated syndrome in multiple sclerosis

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  • Incidental white matter lesions
  • Clinical MS develops in up to 50% of people with RIS, sometimes with a primary progressive course
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9
Q

Notes on MRI in multiple sclerosis

A
  • FLAIR very sensitive
  • MRI shows more active MS lesions than those that produce clinical disease
  • Difficulties in patients > 50 as ischaemic changes can mimic MS lesions
  • **Dissemination in space - **see attached slide
  • **Dissemination in time: **simultaneous contrast enhancging and non-enhancing lesions, or new lesions on follow-up MRI. Sensitivity 72-85%, specificity 67-92%
  • **Spinal lesions - **short segement transverse myelitis. If LETM - think NMO. Cord lesions in MS most common in cervical spine.
  • **Optic neuritis - **Fat-suppressed MRI or orbits: enhancement of the right optic nerve
  • Dawson’s fingers = lesions radiating out from corpus callosum

**Gadolinium
**Enhancement indicates “active” lesions and usually persists for < 1month, may last > 8 weeks
Decreases after steroid treatment
The more gad you use the more lesions you see

**Hypointense T1 lesions
**Black holes - suggest axonal loss
Especially common in SPMS
Correlate better than active lesions with disability and cognitive impairment and progression of disease

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10
Q

Notes on blood and CSF testing in multiple sclerosis

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11
Q

Notes on visual evoked potentionals testing in multile sclerosis

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12
Q

McDonald Criteria for diagnosis of MS

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13
Q

Notes on relapsing-remitting MS

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-Clearly defined attacks, due to recurrent demyelination within the CNS
-Either full or incomplete recovery
-Minimal disease progression between relapses, though severe disability may result from a relapse
-Diagnosis depends on demonstration of dissemination in time and in space
-Differentiate pseudorelapses from true relapses

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14
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Notes on progressive MS

A

**SPMS: initial relapsing-remitting course followed by gradual worsening
**May have occasional relapses, minor remission and plateaus
Transition from RRMS to SPMS occurs at a median of 12 years from diagnosis and 19 years from first symptom
Disease modifying treatment available for active sPMS with relapses

**PPMS: progressive accumulation of disability from disease onset
**Often progressive spastic parapareiss or ataxia, rarely cognitive, visual or brainstem
May have relapses, temporary minor improvement and occasional plataeus
Males= females. Mean age of onset = 40 years

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15
Q

Multiple sclerosis

Treatment of acute relapses

A
  • 3-7 day course IV methyprednisolone (500-100mg daily) +/- short prednisone taper
    • 3-7 days course prednisone (625-1250mg daily) +/- short taper
      ○ Lots of tablets
      ○ Small RCTs - no difference in benefits oral vs IV
      § Exception optic neuritis - oral steroids increased risk of recurrent ON
    • Plasma exchange considered for acute, severe neurological deficits cause by MS attacks showing poor response to high dose glucocorticoids
      ○ Patients with gadolinium-enhancing lesions on MRI before treatment had best response to PLEX
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16
Q

General treatment approach for MS

A

Favour “induction” therapy now - higher efficacy therapies e.g. MABS from the onset of treatment

17
Q

Notes on disease modifying therapies in MS

Beta-interferon

A
  • Antiviral, immunomodulatory (likely mechanism of benefit in MS), antiproliferative actions
    ○ IFN B1b SC alternate days, IFN B1a weekly or 3x weeks IM
    ○ PEG IFN B1a more stable - given fortnightly
    • Adverse effects - flu like symptoms, injection issues, worsening mood, migraines
    • Requires periodic monitoring LFTs, CBC
    • Relatively contraindicated in pregnancy/lactation
18
Q

Notes on disease modifying therapies in MS

Glatiramer Acetate

A
  • Copolymer of amino acids - glutamic acid, lysine, alanine, tyrosine - loosely mimics structure of myelin basic protein
    • Exact mechanism unclear - T cell modulation likely
      ○ Daily SC injection - newer formulation 3x week
    • Adverse effects - injection site reactions, transient flushing, anxiety/panic attacks
      One of the safer drugs in pregnancy
19
Q

Notes on disease modifying therapy in multiple sclerosis

Natalizumab

A
  • Monoclonal antibody against a4-integrin
    ○ Prevents leucocytes binding to VCAMs and crossing BBB
    • Monthly infusion
    • Rare infusion reactions/anaphylaxis
    • Risk of progressive multifocal leukoencephalopathy
      ○ 1/500 arising >2 years on treatment
      ○ Increased risk if JC antibody, longer time on treatment - would try to avoid natalizumab in JC positive patients
    • Reduces severity of relapses
      ○ Faster recovery and less residual disability from relapse
    • NEDA achieved 5-16x more relative to placebo
20
Q

Notes on disease modifying therapies in multiple sclerosis

Alemtuzumab

A
  • First approved induction treatment
    • Humanised monoclonal antibody to CD52 - depletion of B and T lymphocytes - long lasting changes in adaptive immunity
    • Annual course over 3-5 days for 2 years
      ○ Infusion related events - hypotension, rigors, fever, bronchospasm
      ○ Autoimmune disease - thyroidistis (30%), haemolytic anaemia, ITP (1%)
      ○ Serious infections, cancers (breast, melanoma)
    • Monthly monitoring - CBC, U&Es, TSH
21
Q

Notes on disease modyifying therapies

Ocrelizumab

A
  • Humanised anti-CD20 monoclonal antibody - similar to rituximab
    • Breakthrough therapy designation or PPMS - has since been approved for RRMS also
22
Q

Notes on oral disease modifying therapies in multiple sclerosis

Fingolimod

A
  • Primary MOA - activity at sphingosine-1-phosphate receptor 1
  • Also - cannabinoid receptor antagonist, and ceramide synthase inhibitor
  • Immunomodulator - sequesters lymphocytes in lymph nodes
  • Side effects - heart block, bradycardia, zoster (need to check immunity +/- vaccinate), HSV, macular oedema
    • Contraindicated in recent MI, heart blocks etc
    • Regular eye checks - macular oedema as side effect
    • 1st dose reactions common - often need to admit for first 6 hours after dose
    • Cases of PML reported
23
Q

Notes on oral disease modifying therapies in multiple sclerosis

Dimethyl fumarate

A
  • Antiinflammatory, immunomodulatory, cytoprotective effects
  • BD dosing - reduces ARR and 12 week disability progession and increases NEDA
  • Side effects
    • LFT derangement, lymphopenia - monitor FBC, LFTs
      Can get anaphlaxis and angiodema
24
Q

Notes on oral disease modifying therapies in multiple sclerosis

Teriflunomide

A
  • Active metabolite of leflunomide
  • Antimetabolite, inhibits pyrimidine synthesis and subsequent reduced T cell proliferation
  • OD dosing
  • Reduces mean attack rate by 31%, new T2 lesions by 70%
  • Teratogenic, LFT derangement, alopecia, flu, pharnygitis
  • Need baseline TB testing prior to starting
25
Q

Notes on oral disease modifying therapies in multiple sclerosis

Cladribine

A
  • Synthetic purine nucleoside analgue, reduces T cell population
    • Responsible for antiinflammatory effect
    • Lymphopenia common
  • Second line oral agent - two treatment courses >43 weeks apart
  • May cause increased ancer risk - contraindicated with current malignancy
  • Contraindicated in pregnancy
    • Contraception during and up to 6 months after treatment both men and women
  • Risk of PML, liver injury, lymphopenia, Herpes prophylxis
  • Monitor FBC, LFTs
26
Q

Notes on progressive multifocal leukoencephalopathy

A
  • Complication seen in immunocompromised e.g. AIDS
    • A/W JC virus infection
    • Features
      ○ Cognitive decline/confusion
      ○ Paralysis
      ○ Incoordination
    • MRI - demyelinting lesions in cerebral hemispheres - in white matter and at grey-white junctions
    • Biopsy and immunohistochemical staining - JC virus in oligodendrocytes
    Agents A/W PML
    - Cladribine
    - Natalizumab
    - Fingolimod
    - Dimethyl fumarate
27
Q

Role of stem cell transplantation in multiple sclerosis

A

**See slide attached

28
Q

Management of pregnancy in multiple sclerosis

A
  • Needs to be discussed early - previously many women deferred treatment until family completed. Move toward earlier treatment now
  • Stopping DMTs during pregnancy has risks of flare and disability progression.
  • Natural relapse reduction in pregnancy may not control disease activity. Increase in relapses in 6 months post partum, breastfeeding reduces risk but not as effective as restarting DMTs
  • Withdrawing highly effective DMTs can cause rebound MS
  • MS does not affect fertility - caution in using GnRH protocols for IVF in women as may increase relapse rate

**Counselling
**Do not stop DMTs if pregnant or planning pregnancy - talk to doctor first
- Take Vitamin D in pregnancy and when breastfeeding
- Relapses in pregnancy treated with steroids
- MRI not contraindicated in pregnancy, avoid GAD
- Obstetrics - not automatically high risk, should not influence delivery/analgesia
- Breastfeeding encouraged

29
Q

Notes on Vitamin D and Multiple Sclerosis

A
30
Q

Differential diagnosis of MS

A

**NMOSD & MOGAD
Inflammatory diseases
**SLE, Sjogren’s, PAN, Behcet’s, ADEM
**Infectious diseases
**HIV, HTLV1, PML, Lyme, syphilis
**Granulomatous disease
**Sarcoidosis, Wegener’s granulomatosis
**Disease of myelin
**Adrenoleukodystrophy
**Micellaneous
**Spinocerebellar ataxia, vitamin B12 deficiency, Arnold Chiari malformation, mitochondrial cytopathy, vascular disease, CADASIL,

31
Q

Poor prognostic factors in MS

A

**Demographics:
**Male, onset of disease > 40
**Relapse characteristics
**Frequent relapses early in disease course, multifocal, more severe, short inter-attack interval, poor recovery from relapses
**Disease course
**Rapid disability, progressive rather than relapsing-remitting course
**MRI
**At onset - High T2 lesion load, >=2 GAD enhancing lesions, >1 T1 hypointense lesion, early atrophy, infratentorial
During treatment - new T2 lesions, >1 GAD enhancing lesion
**Clinical features
**Pyramidal weakness, brainstem or cerebellar signs

**Good prognostic factors
**Sensory pathways involvedm cranial nerve dysfunction, optic neuritis

32
Q

Principles of NEDA

A
  • No evidence of disease activity
  1. No relapses
  2. No evidence of new T2 lesions or GAD enhancing lesions
  3. No sustained EDSS progression
  4. Lack of brain atrophy
33
Q

Notes on Neuromyelitis Optica Spectrum Disorder

A
  • Inflammatory disease of CNS
  • Astrocytopathy - AQ4 antibodies (all patients with suspected MS should be tested)
  • 90% women, disproprortionately affects non-Caucasians
  • **Presentation
  • **Often BL optic neuritis
  • LETM
  • 90% recurrent events, may be severe with little improvement
  • **Investigations
  • **CSF - pleocytosis, usually no OCBs
  • **Management
  • **Doesn’t respond to MS DMTs
  • Treatment with steroids, IVIG, PLEX acutely. Azathioprine, mycophenolate, rituximab more long term
  • Relapse rate does not decrease in pregnancy
  • Worse prognosis than MS
34
Q

Notes on MOGAD

A
  • Myelin oligodendrocyte glucoprotein associated disease (IgG antibodies)
    • Type of encephalomyelitis - predominantly involves the pons
    • Relapsing remitting pattern of diplopia, gait ataxia, dysarthira, facial parathesiae
    • MRI
      ○ Punctate, curvilinear gadolinium enhacing lesions of MRI scattered throughout pons - can also get involvement of medulla, cerebellum, midbrain and spinal cord
    • Neuropathology
      ○ Predominantly T cell lymphocytic infiltrate in the perivascular white matter
    • Some patients have oligoclonal bands
    • Generally responsive to glucocorticoids
35
Q

Notes on ADEM

A
  • Autoimmune demyelinating disease of CNS - typically follows a systemic viral infection or less commonly a vaccination
    • Perivascular inflammation, oedema and demyelination within cns
    • Rapid development of focal or multifocal neurologic dysfunction - motor, sensory, cranial nerve, brainstem deficits
      ○ Non specific - headache, malaise, altered mental status
    • Features to help distinguish from MS
      ○ Typically follows a prodromal viral illness (MS may or may not)
      ○ May present with fever and stiff neck (unusual in MS)
      ○ Usually widespread CNS disturbance - often impaired consciousness and/or encephalopathy
      § MS typically monosymptomatic - relapsing remitting course
      ○ MRI features
      § Typically more lesions in ADEM - larger bilateral but assymetric
      § ADEM tend to be poorly defined lesions
      § Brain lesions about the same age more consistent with ADEM - presenve of brain lesions of different ages and/or presence of black holes (hypointense T1 weighted lesion) more consistent with MS
      § Thalamic lesions common ADEM, rare MS
      § Periventricular lesions less common in ADEM than MS
      ○ Oligoclonal bands less common in ADEM than MS
36
Q

Notes on CLIPPERS

A
  • Type of encephalomyelitis - predominantly involves the pons
    • Relapsing remitting pattern of diplopia, gait ataxia, dysarthira, facial parathesiae
    • MRI
      ○ Punctate, curvilinear gadolinium enhacing lesions of MRI scattered throughout pons - can also get involvement of medulla, cerebellum, midbrain and spinal cord
    • Neuropathology
      ○ Predominantly T cell lymphocytic infiltrate in the perivascular white matter
    • Some patients have oligoclonal bands
    • Generally responsive to glucocorticoids

Neurology (9 decks)

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