Neurology 2(A) - MS Flashcards
What is transverse myelitis, and its symptoms?
inflammatory, demyelinating disease of the spinal cord
subacute non-compressive myelopathy
What are causes of transverse myelitis?
Parainfectious (40%) CMV, EBV, Mycoplasma, HTLV, HIV etc Cord ischaemia (12%) MS associated 20-30% Idiopathic 21-60%
Sx evolve over hours to 1-2 weeks
Improve over weeks to months
What is the primary pathology of MS?
demyelination and axonal loss
What proportion of MS patients develop visual involvement?
80% will have at some stage.
20-50% will have optic neuritis as their presenting Sx
What are the Sx of optic neuritis?
acute or subacute unilateral eye pain - on eye movement 90%
central scotoma/red vision loss
RAPD or marcus Gunn pupil
Disc oedema - fundus usually normal as retrobulbar defect
Overt bilateral and simultaneous is rare - but subclinical involvement is noted in 70%
rarely progressive after 2 weeks - if >1/12, other pathology likely
What is the prognosis of optic neuritis?
90% regain vision over 2-6/12 15yr risk of permanent vision loss = 1% Risk of progression to MS - 0 lesions 25% risk at 15y 1 lesion 50% 15yr risk >=3 lesions 78% risk at 15y
In patients w optic neuritis, who are at lowest risk of MS?
No MRI lesions
Male
atypical features (papilloedema, severe visual loss, no pain)
Risk 4% over 15y
what proportion of patients have abnormal visual evoked responses?
unilateral conduction delay - abnormal in 85 of patients with CDMS (2 or more relapses)
can be used to detect subclinical disease or silent previous attack
What is the classical finding on CSF in MS?
oligoclonal bands (evidence of intrathecal IgG) - NOT in serum
>95% are positive in CDMS
adds prognostic value - 25% risk of 2nd attack (CDMS) at 3 years, only 5% if MRI, OGB negative
8% of general pop has OCB - vasculitis (1mary, 2ndary), CNS infections, paraneoplastic disorders, CIDP etc.
What are features of CIS or FDE?
40% optic neuritis (85% have single symptom) 30% Transverse myelitis 20% Brainstem, cerebellum 10% - paroxysmal stiffness/limb spasm - bladder - cognitive - pseudo-radiculopathy/trigeminal neuralgia - episodic fatigue L'Hermitte's Uhtoff's phenomenin sexual dysfunction
What are features of relapsing remitting MS?
90% initially F:M 2-3:1 Benign disease in 25% Extremely aggressive in 5% (relapsing progressive) Relapses reduce after 1st 5 years
What are features of secondary progressive MS?
50-75% wtihin median of 15y
with relapses 1/3
w/o 2/3
What are features of primary progressive MS?
10% overall, 20% males
on average behaves exactly like SPMS
gradual but continous neruological decline
Progressive relapsing MS?
What progresses from CIS to CDMS?
Presence of OCB 1.7 RR for recurrent attack
In general - MRI normal 10-30% risk over 3-5y
If MRI abnormal 60-90% risk over 3-5 years.
In Radiologically isolated syndromes - 33% will develop Sx over 1-10y (med 5.4)
high risk of clinical Sx if spinal cord lesions are present
What are features of benign MS?
Dx can only be made in retrospect! Treat all pts the same
only 50% remain benign, 21% needed walking stick, 23% had SPMS.
Defn is weighted towards motor deficits - cognitive, psychological and social challenges still significant.
80% of untreated patients go on to further attacks, and 50% go on to SPMS and increased disability
What effect does interferons or glatiramer and teriflunomide have on CIS?
delays onset of CDMS by 45% at 2-3y
Reduced MRI activity
No effect on disability at 5 years
Reduced cerebral atrophy
What are the 4 principles of Dx MS?
1) Typical Sx and signs
2) Dissemination in space and time
3) MRI criteria can be used as substitute for clinical eps
4) Exclusion of alternative causes with paraclinical tests if needed
What is the dissemination in space criteria in McDonald 2010?
Clinical: symptoms/signs in >=2 functional systems of CNS
Radiological: lesions in >=2 regions of the CNS
- periventricular
- juxtacortical
- infratentorial
- spinal cord
- all lesions in symptomatic region excluded in brainstem and spinal cord lesions
What is the dissemination in time criteria in McDonald 2010?
Clinical: >=2 relapses at least 1 month apart
Radiological: a new lesion on follow-up MRI brain (irrespective of timing) OR simultaneous non-enhancing AND contrast enhancing lesion
What are the Dx criteria for primary progressive MS?
- 1y of disease progression (retro/prosp determined)
- plus 2/3 of the following criteria:
a) evidence of DIS in the brain based on >=1 T2 lesions in at least one area characteristic of MS (periventricular, juxtacortical or infratentorial)
b) evidence of DIS in the spinal cord based on >=2 T2 lesions in the cord
c) positive CSF for oligoclonal bands/Inc IgG index)
What conditions must be excluded pre Dx of MS?
- other 1mary demyelinating diseases of the CNS - Devic’s disease or NMO, ADEM or acute disseminated encephalomyelitis
- secondary demyelinating conditions - SLE, Sjogren’s PAN, Bechet’s, sarcoid
- infections - mycoplasma, EBV, CMV, HIV, HTLV, Rickettsia, Lyme disease
- Tumours
- Psychiatric disorders - conversion disorder, somatisation
What are features of Devic’s Disease?
1% of all MS, 50% in eastern asia Relapsing remitting involvement of optic nerves and or spinal cord Long cord lesions >3 segments without brain lesions on MRI without OCB usually sequential (can be simult) Monophasic in 1/3, relapsin in 2/4 Sp and Sn Ab in anti-Aquaporin 4 Intractable vomiting, hicoughs and narcolepsy can be presenting features
What are features of Anti-Aquaporin antibodies?
aka anti-NMO IgG
Sn and Sp 88 and 83% for Devics vs MS
less Sn with Devics from partial devic’s
12-15% have seronegative NMO - can be +ve for anti-MOG Ab
Directed against AQP4 - spinal cord grey matter, periaqueductal and periventricular regions, astrocytic foot processes, renal medulla, gastric parietal cells, area postrema - vomiting centre
What are features of Acute Disseminated Encephalomyelitis?
AKA post infectious encephalomyelitis
infectious prodrome 1-4 weeks pre
- EBV, mycoplasma pneumonia, strep pyogenes, CMV, Rickettsia, HIV, varicella, corona virus
- encephalopathy with behavioural changes, irritability, confusion, lethargy, drowsiness
- multifocal polysymptomatic neuro deficit
- low grade fevers, seizures, headache common
- most recover completely
What are other MRI features of MS?
Cerebral atrophy - large ventricles, loss of cortex, visible sulci
T1 hypointense lesions or Blackholes - permanent axonal loss, correlates with disability in MS
Loss of GM and WM in MS, GM loss correlates with EDSS
What is PML?
caused by JC virus - polyoma virus
assoc with AIDS in the past, or lymphoproliferative dz
now assoc with natalizumab, rituximab, alemtuzumab and MMF, MTX, AZA
How is PML Dx on imaging?
CT often normal
MRI brain - large >3cm lesions, subcortical, T2/FLAIR/Diffusion hyperintense, T1-hypointense
41% contrast enhancement in eraly PML
Punctate T2 hyperintense lesions in regino of PML lesion
mass effect in 18%
What are features of serology in PML?
55% of normal adults have +ve JCV antibodies
DNA - JCV PCR of CSF is 74-93% Sn, 92-100% Sp
CNS still frequently required
What are treatment options for PML?
Stop immunosuppression immediately
Consider immune reconstitution
- PlEx to remove antibodies (risk of IRIS - treat with hi dose methylpred)
- mirtazepine ? reduction of Ab entry into cells
- ?Mefloquine
- no evidence for cidofovir, cytosine arabinoside
What genetic associations are found in MS?
15-20% have FHx
30% risk with ident twin
HLADR2 (DRB1*1501) 3-4 x risk
Likely IL-7 and IL-2 R polymorphisms
What are environmental risks for MS?
Smoking increases risk by 1.4-1.9 - cessation can delay onset
Sesonal variation - peaks in spring, trough in autumn
Risk after EBV
Measels or mumps after 15y
Insufficient vit D
What are the main cells involved in MS?
oligodendrocytes:
inflammation - focal and global infiltration with T-cells (CD3, CD4, CD8), macrophages (CD68+) and b-cells
Demyelination- Loss of oligodendrocytes
axonal loss - apoptosis and neuronal die back
What T-cell response is favoured in MS?
Th1-Th17
secreted CK and matrix metalloproteinases disrupt BBB and upregulation of adhesion molecules allow T cells to gain entry to CNS
further activation takes place - CD4+ and CD8+ and microlgia becomes involved
Damage to myelin, oligodendrocytes and axons due to cytokine damange, Ab and complement, oxidative stress and mitochondrial dysfucntion
What are 4 hot topics in MS pathogenesis?
1) B-cell dysfunction
2) Mitochondria damage
3) Iron deposition
4) KIR4.1 as therapeutic target
What is occuring in normal white matter in MS (on MRI)?
diffuse axonal injury and wallerian degeneration
diffuse dense lymphocytic infiltration
microglial activation
evidence of decreased N-acety aspartate levels on MR spect, indicating axonal loss
What affects prognosis in MS?
high attack rates and short intervals predict poorer prognosis
large number of MRI spots portend weakly more rapid development of disability
gait related disability once established, progresses at a similar rate in absence of ongoing relapses and at the same rate with Primary and secondary progressive MS
What is life expectancy in MS?
increased mortality rate of 2-3x
22.1% deaths due to MS
treatment with IFN-B reduces hazard rate of death by 46.8%
What effect does methylpred have in MS relapses?
Closes BBB
reduces inflammatory oedema
suppresses inflammation (t-cell apoptosis, dowreg of endothelial adhesion molecules)
rapid resolution of Sx compared to placebo
What should be considered in refractory relapses?
further IV methylpred pulse after 4-8 weeks
consider plasma exchange
Which treatment is safest wrt AEs, pregnancy and breastfeeding?
glatiramer acetate
Which treatments for MS have the best compliance?
fingolimod and natalizumab
What are the most significant issues with natalizumab?
PML, JCV
What are the most significant issues with fingolimod?
lymphopenia, HTN, liver function tests, macular oedema
What are the most significant issues with alemtuzumab?
graves disease, patients turning up for FBE, UEC monthly for 5 years
What are the most significant issues with glatiramer?
local site reactions
What are the most significant issues with terliflunomide?
har loss, liver function derangement
what are the most significant issues with interferon?
flu like symptoms, early LFT derangement
What are the most significant issues with dimethyl fumarate?
gud - diarrhoea, nausea, lymphocyte counts and PML
What are features of glatiramer acetate?
synthetic polypeptide cont myelin basic protein (MBP)
may promote Th2 proliferation
alters macrophage function
equivalent to interferon
daily injection, reactions at site
rare post injection reaction with palpitations, chest pain and dyspnoea
What are features of natalizumab?
m-Ab to alpha-4-integrin (VCAM1)
inhibits tissue migration of lymphocytes and monocytes
Relapse risk reduction of 67%
PML, infusion reactions, transaminitis
What are main risk factors for PML?
duration of exposure >2y
Methotrexate, AZA, Cyclosporine (previous exposure)
JCV serology positive
If all 3 RFs - risk is 10/1000 (1%)
What factors are associated with decreased survival of PML?
Older age higher EDSS pre PML longer time from Sx onset to Dx Widespread PML extension on MRI Higher JC viral load at Dx
What is the MoA of fingolimod?
S1P receptor modulator
selectively retains ciculating lymphocytes in lymphoid organs (internalisation of S1P-r leads to retention of CCR7+ t-naive and TCM (incl Th17 cells)
TEM are spared effect due to lack of CCR7
How efficacious os fingolimod?
superior wrt to relapses vs std of care
superior wrt disability vs placebo
superior rt MRI inflammation
reduces brain atrophy vs std care
What are significant AEs in fingolimod?
mild symptomatic bradycardia post dose (6hrs) elevated liver enzymes macular oedema - 0.4% of patients infections pregnancy 3 cases of PML reported
What is the MoA of dimethyl fumarate?
anti-inflamatory via atten of proinflamm CK, reg of NFkB, reduced activation of microglia/macrophages/astrocytes
Shift Th1/Th2/Th17 balance
Cytoprotective - enhanced antioxidant capacity, regulation of stress induced Ca++ acucmulation, enhanced mitochondrial function, protective against neurodegenerative stimuli
(ox stress, demyelination, excitotoxicity)
What is the efficacy of dimethyl-fumarate?
reduced relapses, risk of disability, reduced lesions T2 and gad compared to placebo
What are common AEs with dimethyl-fumarate?
flushing headache nausea upper abdo pain 4 cases of PML (all with lymphopenia)
What is the MOA and AEs of terliflunomide?
active metabolite of leflunomide
interferes w lymphocyte proliferation - inhibits pyrimidine synthesis, reduces tyrosine kinase activity
may prevent interaction of lymphocytes and antigen presenting cells
serious hepatic disoders, infections
pregnancy category X - requires cholestryramine washout
What is the MoA of alemtuzumab?
lysing Anti-CD52 antibody - lyses B and T cells, but B cells more than T (5 day infusion once yearly)
75% relapse reduction, 65% reduction in disab progression
ITP concern, 15% graves disease, goodpastures syndrome in one case
When should mitoxantrone be considered?
EDSS score 3.0 - 7.0 IF two severe relapses in last 12 months or EDSS decline 1 point in last 18 months and ongoing inflammatory activity
C/I in primary progressive MS, secondary progressive MS w/o relapses or clear cut CNS inflammatory activity
what are SEs of mitoxantrone?
amenorrhoea (10-20% permanent) - se GnRH agonist for ovarian protection nausea and vomiting cytopenia and urosepsis cardoitoxic -echo pre and post 5th dose LFT abnormalities AML or APML risk 0.33%
What symptoms of MS impact QoL?
Depression Fatigue Spasticity Cognitive dysfunction Urinary frequency Neuropathic pain Sexual dysfunction
What is the MoA and outcome and AEs of famipridine?
blocks K channels and prolongs APs, increasing NT release at synapse
Improves walking speed (Symptomatic therapy only)
causes seizures in some patients
What are features of depression in MS?
50% of MS patients
10x suicide risk of population
SSRI/SNRI
What are common cognitive problems in MS?
40-70% of MS patients
frank dementia uncommon (
What are common bladder problems in MS?
bladder hyperreflexia - inc tone, small vol, hyperreflexia (causes - urgency, urge incontinence, nocturia)
Bladder weakenss - causes:
- difficult starting, double voiding
- residual volume
What is treatment of urgency, frequency and nocturia in MS?
anticholinergic meds
- oxybutinin
- probanthine
- imipramine
