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Neuroimmunology Flashcards

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1
Q

What is transverse myelitis?

A

Inflammation of the spinal cord - typically affecting a level

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2
Q

What’s the difference between myelitis and myelopathy?

A

Myelitis is the Inflammation of the spinal cord

Myelopathy is damage of the spinal cord
- Extrinsic or intrinsic

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3
Q

List causes of myelitis

A

1) Infection
- HSV, VZV, HTLV1, HIV, syphilis, TB, mycoplasma

2) Autoimmune
- MS, NMO, Sarcoid, GFAP

3) Paraneoplastic - CRMP5, amphiphysin

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4
Q

List causes of myelopathy - think extrinsic and intrinsic

A

1) Extrinsic
> Tumour
> Trauma
> Compression - disc herniation, epidural mets, epidural abscess

2) Intrinsic
> Vascular 
- Cord infarct (anterior spinal artery) 
- Spinal dural AVF 
- Syrinx
> Genetic 
- Hereditary spastic paraparesis
- Leukodystrophies
> Tumour
> Nutritional - copper, B12, vitamin E 
> Drugs and toxins - nitric oxide
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5
Q

List primary causes of transverse myelitis

A

MS
Neuromyelitis optica (NMO)
Acute demyelinating encephalomyelitis (ADEM)
Post vaccine

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6
Q

List systemic causes of transverse myelitis

A

1) Systemic inflammatory conditions
SLE
Behcets
Sarcoid (Heerfordt syndrome)

2) Infectious
Syphilis, TB, HIV, HTLV1`, mycoplasma, HSV, VZV

3) Paraneoplastic - CRMP-5 ab, anti-amphyphysin ab

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7
Q

What’s Heerfordt syndrome?

A

Transverse myelitis secondary to sarcoid

Get facial palsy + uveitis + fever + parotid enlargement + transverse myelitis

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8
Q

How to differentiate between optic neuritis and optic neuropathy?

A

Both cause visual loss

Optic neuritis causes pain on eye movement
Optic neuropathy is painless

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9
Q

How does optic neuritis present?

A

Pain on eye movement
Decreased visual acuity and colour vision
Sparkles of light (photopsia)
Cecocentral scotoma (a central scotoma that joins up with a blind spot)
RAPD positive
Optic disc swelling if there is anterior inflammation of the optic nerve (comes out to make optic disc).
No optic nerve swelling if its retrobulbar inflammation (posterior section of optic nerve). Progresses to optic nerve disc pallor.

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10
Q

List causes of optic neuritis

A

1) Infection - Bartonella (cat scratch disease), syphilis
2) Autoimmune - MS, NMO, sarcoid
3) Paraneoplastic - CRMP 5

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11
Q

List causes of optic neuropathy

Think extrinsic and intrinsic

A

1) Extrinsic
- Compression by Tumour
- Compression by raised intracranial pressure (bilateral optic nerve compression)
- Trauma

2) Intrinsic
- Vascular - non-arteritic ischaemic optic neuropathy (NAION), arteritic ischaemic optic neuropathy (AION), central retinal vein occlusion (CRVO)
- Genetic - Leber’s ON
- Metabolic
- Nutritional - copper, B12, B1, folate deficiency
- Drugs and toxins - methanol, ethambutol, linezolid, amiodarone

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12
Q

What’s non-arteritic ischaemic optic neuropathy (NAION)?

A

Problem with blood vessel.
Classically small vessel disease risk factors e.g. hypertension, DM

When you stand up, you drop your BP, and you get loss of blood flow to the optic nerve and painless vision loss

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13
Q

What’s arteritic ischaemic optic neuropathy (AION)?

A

Giant cell arteritis –> loss of blood flow to the optic nerve –> painless vision loss

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14
Q

What’s Leber’s optic neuropathy?

A

Bilateral sequential (sometimes at the same time) painless vision loss
Progressive
Due to mitochondrial loss
Genetics, positive FHx

Rx: steroids, IVIG

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15
Q

What’s the cause of bilateral optic disc swelling?

A
  • Raised intracranial pressure
  • Hypertension
  • Bilateral optic neuritis/neuropathy - NMO spectrum disorder
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16
Q

Define papilloedema

A

Bilateral optic disc swelling secondary to raised intracranial pressure

If no raised intracranial pressure, then its just bilateral disc swelling

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17
Q

How do people get MS?

A

Genetic susceptibility + environmental trigger

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18
Q

What genes predispose you to MS?

A

HLA-DRB1*15

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19
Q

What environmental factors can trigger MS?

A

Smoking
EBV
Further away from the equator (immigrants who migrate before adolescence acquire the risk of the new country)
Sunlight exposure and vitamin D protective

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20
Q

Pathophysiology of MS

A
  • Demyelination (damage to oligodendrocytes) +/- re-myelination
  • Axonal loss/atrophy (neurodegeneration)
  • White matter and grey matter lesions
  • T cell and B cells involved
  • Progression starts from the onset of disease
  • CNS intrinsic or extrinsic antigen activates T and B cells –> come through BBB –> damage CNS tissue –> further releases antigen into peripheral –> further priming of lymphocytes –> continuous cycle
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21
Q

What are plaques in MS?

A

Focal demyelination

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22
Q

How long does an MS attack typically last?

A

It an “itis” - progression over days
Nadir within 2 weeks, resolution within 4 weeks
Lasting greater than 24-48h
May not return to baseline

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23
Q

How does MS present?

What are some common symptoms?

A

Symptoms depends on location of lesion and functional reserve (if it was in an area that had large functional reserve, may not get symptoms and vice versa)

Common symptoms

  • Cognitive impairment
  • Fatigue
  • Sensation changes - numbness, paraesthesia, pain, MS hug (feeling of tightness around chest or stomach), proprioceptive loss
  • Weakness
  • Optic neuritis (first clinical event in 20%; occurs in 50% of all MS)
  • Cerebellum - ataxia, tremor, dysmetria
  • Brainstem - INO (bilateral highly specific), ophthalmoplegia, vertigo, trigeminal neuralgia
  • Spinal cord - bladder and bowel dysfunction (urge incontinence, neurogenic bladder, constipation), myelitis
  • Lhermitte’s sign (shock like sensation shooting down when you bend your neck)
  • Uhthoff’s phenomenon ie pseudorelapse
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24
Q

What is a clinically isolated syndrome?

A

1st event of MS or once off event
Duration of at least 24h
With or without recovery

60% will develop MS…risk increased by

  • > 9 T2 lesions on MRI
  • CSF OCBs
  • Low vitamin D
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25
What is the Mcdonalds criteria?
- Identify MS in patients who present with a typical clinically isolated syndrome - Basically shows 2 lesions in time and space - Uses evidence of clinical attack, MRI and CSF oligoclonal bands
26
In those who have a clinically isolated syndrome, what are the risk factors for MS?
``` Young age Large lesion Asymptomatic infratentorial or spinal cord lesion Gadolinium-enhancing lesion Oligoclonal bands in CSF Abnormal visual evoked potentials ```
27
How does optic neuritis in MS look on fundoscopy?
60-90% optic neuritis is retrobulbar so you won't see swollen disc But eventually will progress to optic atrophy so you will see pale/white disc
28
List the 4 classic areas you would see MS plaques
1) paraventricular 2) juxtacortical 3) infratentorial 4) spinal cord
29
How do you see disseminated plaques in time and space on MRI?
Dissemination in space seen when you have T2 lesions in different areas Dissemination in time seen when you have - New T2 or gadolinium enhancing lesions on follow up MRI - Simultaneous enhancing (<1/12 old) and non-enhancing (>1/12 old) lesions
30
Why are oligoclonal bands important in MS?
Basically you run the CSF and the serum through a western blot and you compare how much IgG is in each. In MS, you can have increased IgG as you get intrathecal production but this takes a year to develop. Hence if you have high CSF IgG, this indicates a chronic process = dissemination in time
31
What's a radiologically isolated syndrome in MS?
Looks like MS on MRI but no clinical symptom More likely to get progressive symptoms Currently not treated
32
Acute treatment of MS relapse
1) 3/7 IV methylpred or PO methylpred - Accelerates recovery from MS relapse but does not modify disease progression/disability 2) Plasmapharesis for severe attacks
33
Is early intensive therapy or escalation therapy better in MS?
Early intensive therapy - Longer time to secondary progressive MS and less disability Treatment is more effective in "relapsing" phase when its more inflammatory and contributes to axonal injury, rather than "progressive" phase when its more neurodegenerative. Hence early treatment is best. Time is brain.
34
Natalizumab has been a game changer for MS 1) MOA 2) Side effects 3) Disease modifying? 4) Screening
1) Inhibits leucocyte migration across the BBB by blocking the interaction between alpha4-integrin on leucocytes and vascular cell adhesion molecule-1 on endothelial cells. Keeps it in the blood. 2) - 6% can develop persistent anti-natalizumab neutralising ab - PML - Elevated LFTs - Infection esp herpes - Infusion reactions - Risk of rebound relapse with cessation 3) No 4) JC virus serology every 6 months and pre-screening Strict MRI monitoring (due to PML risk) Bloods
35
Fingolimod in MS 1) MOA 2) Side effects 3) Disease modifying?
1) Sphingosine-1-phosphate receptor modulator Inhibits migration of T cells from lymphoid tissue into the peripheral circulation and CNS 2) - First dose bradycardia (need hospital monitoring; CI in conduction abnormality) - Varicella virus reactivation - Macular oedema especially in diabetes (need OCT monitoring) - LFT derangement - Lymphopenia - Risk of rebound relapse with cessation 3) No
36
What is progressive multifocal leukoencephalopathy (PML)?
Progressive demyelinating process of the CNS secondary to JC virus (indolent virus that gets reactivated when you're immunocompromised)
37
PML is associated with ...
Immunosuppressive states - Organ transplant - HIV - Haematological malignancies - Chemotherapy - Natalizumab**, dimethyl fumarate, fingolimod, rituximab, alemtuzumab
38
PML with natalizumab has a ...% mortality rate
20%
39
The risk of PML increases with natalizumab treatment and ...
- Duration of tx >2 years - Previous exposure to an immunosuppressant particularly natalizumab - JCV serology positive and high titre
40
How does PML present? Include investigations
Subacute Worsening visual, cognitive, motor changes CSF: positive JC virus PCR (80% sensitivity) MRI: Enlarging T2 hyperintensity lesions with minimal or no gadolinium enhancement (no inflammation)
41
Rx PML secondary to natalizumab
- Cease natalizumab - Plasma exchange - remove natalizumab from the blood - Pembrolizumab - PD1 inhibitor - gets rid of PD1 checkpoint --> enhances immune system --> kill JC virus - BK virus specific T cells
42
What's immune reconstitution inflammatory syndrome (IRIS)?
When you give plasma exchange for PML, you mop up all the natalizumab and the immune system recovers. However it comes back too full on, resulting in inflammation and you get paradoxical deterioration in clinical status. = New contrast enhancement in PML lesions consistently with inflammatory breakdown of BBB
43
Rx for immune reconstitution inflammatory syndrome (IRIS)
Rx: steroids
44
When does immune reconstitution inflammatory syndrome (IRIS) occur after plasma exchange?
Typically 2-5 weeks after plasma exchange but can persist for several months
45
Alemtuzumab is a game changed for MS 1) MOA 2) AEs 3) Disease modifying? 4) Monitoring
1) Targets CD52 on lymphocytes --> profound lymphopenia Shifts autoimmunity away from MS (depletes and repopulates lymphocytes) 2) Induces autoimmune disease - ITP (1%; serious), Graves disease (34%), anti-GBM disease i.e. GN Increased infection - URTI, herpes (aciclovir cover) 3) No 4) Thyroid function, monthly serum Cr and urine protein (GN)
46
Ocrelizumab is a game changer for MS 1) MOA 2) AEs 3) Disease modifying? 4) Monitoring
1) anti-CD20 - B cell depleting therapy Similar to rituximab 2) Really safe 3) yes - slows progression 4) Monitor WCC and immunoglobulins (can drop with time)
47
Siponimod is a game changer for MS 1) MOA 2) AEs 3) disease modifying? 4) PBS criteria
1) Sphingosine 1-phosphate (S1P) receptor modulator 2nd generation fingolimod 2) 1st dose bradycardia, varicella virus dissemination, macular oedema, HTN, LFT derangement, lymphopenia ~Similar AE profile to fingolimod 3) Yes - slows progression 4) Only for secondary progressive on PBS
48
Ofatumumab is a game changer for MS 1) MOA 2) AEs 3) Disease modifying? 4) Monitoring
1) Anti-CD20 2) URTI, UTI, nasopharyngitis, decreased immunoglobulin levels 3) No 4) FBC (WCC), immunoglobulin levels Once monthly subcut injection - super easy!
49
What happens to MS in pregnancy?
Reduced relapses during pregnancy, but increases relapse post-partum so they even out Post-partum relapses are usually severe and associated with risk of disability Best predictor of post-partum relapse is the frequency of relapses before pregnancy
50
What to do with medications pre-conception? | What is the best medication to use in highly active disease?
Stop 4 months pre-conception Best option is rituximab/ocrelizumab - Usually dose every 6/12, but the effects of the drug last 9-12 months hence if you stop the drug 4/12 before conception, you should be covered for most of the pregnancy
51
Drugs to avoid in pregnancy in MS
Fingolimod | Teriflunomide (Useless drug)
52
Pathophysiology of neuromyelitis optica spectrum disorder (NMOSD)
Relapsing B cell mediated disease --> ab targets astrocytes
53
Classic presentation of NMOSD
- Bilateral optic neuritis - Longitudinal transverse myelitis (longitudinally extensive often spanning over 3 vertebral segments, centrally located, necrotic spinal cord) Others - Unexplained hiccups or N&V (lesion in medulla) - Acute brainstem syndrome
54
Prognosis of NMOSD
Horrendous disease Attacks are likely to result in permanent neurological deficit with low change of recovery 50% of NMO patients are blind in at least 1 eye or require ambulatory assistance within 5 years of disease onset
55
How to diagnose NMOSD?
Serum AQP4 antibody - >99% specific for NMOSD, 80% sensitive Serum MOG antibody - 50% positive of all AQP4 negative cases - Positive in chronic inflammatory optic neuritis, ADEM, NMOSD <30% have CSF oligoclonal bands, high WCC in CSF NMOSD is a peripheral problem, therefore ab found in serum
56
Rx NMOSD 1) Acute 2) Long-term therapy
1) 5/7 IV methylpred or PLEX or IVIG 2) Azathioprine, mycophenolate Rituximab If AQPA4 positive, can use eculizumab, inebilizumab, satralizumab (game changer)
57
Which part of the brain does acute dissemination encephalomyelitis (ADEM) affect?
Brain and spinal cord | Large demyelinating lesions on MRI but will generally resolve with time
58
Which age group does ADEM affect?
Children or young adults
59
How do you get ADEM?
Usually after a viral infection or other systemic infection
60
Prognosis of ADEM
Excellent prognosis. Usually resolves by 3 months.
61
ADEM has a risk of progressing into...
25% will develop MS later in life
62
Optic neuritis in MS Clinical features Exam Rx Prognosis
Not always caused by MS and doesn't always progress to MS 1 eye affected Blurred vision, reduced colour vision, painful eye movement, reduced visual acuity Fundoscopy: pale optic disc Exam: red desaturation/ishihara, enlarged blind spot/scotoma, visual field detect Rx: steroid to reduce duration of symptoms Complete clinical recovery or blindness in some cases
63
Transverse myelitis in MS Clinical features MRI Rx Prognosis
Not always caused by MS and doesn't always progress to MS Bladder and bowel dysfunction Sexual dysfunction Band like sensation around chest or abdo Short segment on MRI Rx: steroid to reduce duration of symptoms Complete clinical recovery or severe residual disability (death if cervical or BS lesion)
64
Sensory symptoms in MS Classic symptoms
Intermittent parasethesia/tingling! Lasting over 24h in same region and recurrent Isolated sensory symptoms should still be investigated even if they completely resolve
65
INO in MS Clinical features Pathophysiology
When an attempt is made to gaze contralaterally (relative to the affected eye), the affected eye adducts minimally, if at all The contralateral eye abducts however with nystagmus Cause: dysfunction of MLF (brainstem) Common in MS, may be uni or bilateral
66
Uhthoff's phenomenon in MS Clinical features
Worsening of neurological symptoms in MS when the body gets overheated When body temperature normalise, symptoms improve back to baseline
67
Lhermitte's phenomenon Clinical features
Electrical sensation that runs downt the back and limbs elicited by bending/flexing the neck forward Suggests a lesion in the dorsal columns of the C spine or caudal medulla (lower BS) Classic MS finding
68
How do you make an early diagnosis at first clinical presentation in MS?
2 clinical attacks separated in time and space 1 clinical attack and MRI criteria shows dissemination in time and space
69
What's dissemination in space? | Radiological and clinical
>=1 T2 lesion in at least 2 of 4 areas of the CNS Paraventricular Juxtacortical or cortical Infratentorial Spinal cord Clinical E.g. optic neuritis and spinal cord syndrome
70
What's dissemination in time? | Radiological and clinical
1 new T2 and/or gadolinium enhancing lesion(s) on follow up MRI Or Simultaneous presence of asymptomatic gadolinium enhancing and non-enhancing lesion at any time (on single MRI) Clinical E.g. Optic neuritis --> spinal cord syndrome 6/12 later
71
Poor prognostic signs in MS
Age >40 Male Asian or African Initial presentation with motor, cerebellar, sphincter and/or multifocal symptoms Incomplete recovery after initial attacks Short interval between relapses Frequent relapses early in the disease course Rapid disability progression Progressive disease from outset Cognitive impairment from outset Short interval between disease onset and start of progressive phase CSF OGB High lesion burden and/or gadolinium enhancing lesions on initial MRI
72
All DMTs are available on PBS as 1st line for the treatment of relapsing remitting MS except...
Siponimod - secondary progressive only
73
What investigations should be done before starting DMTs for MS?
Exclude mimics - AQP4+ NMO, MOG Ab disease, autoimmune screen For oral and infusions: do pre-immunosuppression screen - hep, VZV, HIV, TB Test JCV before natalizumab or any high efficacy treatments
74
What monitoring should be done for DMTs for MS?
ALL: routine bloods ALL: Annual skin checks, papsmears ALL: MRI monitoring NATA: 6 monthly JCV serology (if negative) Alemtuzumab: heavy burden monitoring for patients and Dr
75
Interferons e.g. betaferon for MS 1) Mode of adminstration 2) Benefits 3) Safety
1) Injections 2) Reduce relapse rate by 35% 3) Long term data available. Rarely any problems. Flu like symptoms, can make depression worse
76
Glutiraemer acetate for MS 1) Benefits 2) Safety
1) 30% efficacy 2) long term safety data really good Immediate post injection reaction (rare)
77
Teriflunomide for MS 1) Benefits 2) AE/safety
1) 30% efficacy, once daily tablet 2) Hair thinning, LFTs derangement, peripheral neuropathy (Rare) Pregnancy X!!
78
Dimethylfumarate for MS 1) Benefits 2) AEs 3) MOA
1) 50% efficacy, twice daily capsule 2) GI upset (loperamide for diarrhoea), flushing (take with food), lymphopenia Rare PML cases 3) Activation of Nrf2 --> reduce inflammatory response
79
Ozanimod for MS 1) MOA 2) Efficacy 3) AE 4) CI
1) S1P agonist 2) Reduces relapse rate by 45% 3) AE similar to fingolimod 4) CI in certain cardiovascular disease and CVA
80
Cladribine for MS 1) MOA 2) Benefits 3) AE
1) Cytotoxic; selective depletion of T and B lymphocytes 2) 2 treatment weeks per course, separated by 4 weeks usually 2) Lymphopenia, infection, HSV, caution with blood transfusion (prevent GVHD), rash
81
Secondary progressive MS best tx
Siponimod | On PBS
82
Primary progressive MS best tx
Ocrelizumab | But not available on PBS

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