Multiple Sclerosis and Demyelinating Disorders

Question 1

Multiple sclerosis

Pathogenesis and Immunology

Answer 1

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%

Question 2

Clinical features multiple sclerosis

Answer 2

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

Question 3

Notes on clinically isolated syndrome in multiple sclerosis

Answer 3

• 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

Question 4

Notes on multiple sclerosis and optic neuritis

Answer 4

• 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

Question 5

Notes on eye movement abnormalities in MS

Answer 5

**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

Question 6

Notes on bladder/bowel/sexual dysfunction in MS

Answer 6

Question 7

Notes on paroxysmal symptoms in MS

Answer 7

Question 8

Notes on radiologically isolated syndrome in multiple sclerosis

Answer 8

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

Question 9

Notes on MRI in multiple sclerosis

Answer 9

• 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

Question 10

Notes on blood and CSF testing in multiple sclerosis

Answer 10

Question 11

Notes on visual evoked potentionals testing in multile sclerosis

Answer 11

Question 12

McDonald Criteria for diagnosis of MS

Answer 12

Question 13

Notes on relapsing-remitting MS

Answer 13

-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

Question 14

Notes on progressive MS

Answer 14

**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

Question 15

Multiple sclerosis

Treatment of acute relapses

Answer 15

• 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

Question 16

General treatment approach for MS

Answer 16

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

Question 17

Notes on disease modifying therapies in MS

Beta-interferon

Answer 17

• 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

Question 18

Notes on disease modifying therapies in MS

Glatiramer Acetate

Answer 18

• 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

Question 19

Notes on disease modifying therapy in multiple sclerosis

Natalizumab

Answer 19

• 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

Question 20

Notes on disease modifying therapies in multiple sclerosis

Alemtuzumab

Answer 20

• 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

Question 21

Notes on disease modyifying therapies

Ocrelizumab

Answer 21

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

Question 22

Notes on oral disease modifying therapies in multiple sclerosis

Fingolimod

Answer 22

• 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

Question 23

Notes on oral disease modifying therapies in multiple sclerosis

Dimethyl fumarate

Answer 23

• 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

Question 24

Notes on oral disease modifying therapies in multiple sclerosis

Teriflunomide

Answer 24

• 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

Question 25

Notes on oral disease modifying therapies in multiple sclerosis | Cladribine

Answer 25

* 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

Question 26

Notes on progressive multifocal leukoencephalopathy

Answer 26

* 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

Question 27

Role of stem cell transplantation in multiple sclerosis

Answer 27

**See slide attached

Question 28

Management of pregnancy in multiple sclerosis

Answer 28

- 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

Question 29

Notes on Vitamin D and Multiple Sclerosis

Answer 29

Question 30

Differential diagnosis of MS

Answer 30

**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,

Question 31

Poor prognostic factors in MS

Answer 31

**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

Question 32

Principles of NEDA

Answer 32

- 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

Question 33

Notes on Neuromyelitis Optica Spectrum Disorder

Answer 33

- 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

Question 34

Notes on MOGAD

Answer 34

- 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

Question 35

Notes on ADEM

Answer 35

* 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

Question 36

Notes on CLIPPERS

Answer 36

* 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