Multiple Sclerosis

Question 1

DDx for MS

Answer 1

1. Paraneoplastic syndrome
2. CNS neoplasm - symptoms are usually progressive
3. Vitamin B12 deficiency
4. CNS vasculitis
5. SLE - can cause white matter changes on MRI & encephalopathy
6. Sarcoidosis
7. HIV and Syphilis
8. Migraine
9. Somataform disorders

Question 2

Diagnosis of MS

Answer 2

Usually begins with an episode of acute neurological disturbance, which is called a ‘clinically isolated syndrome’.
Clinical diagnosis requires at least 2 Neurological events separate by time and place in the CNS

Question 3

Course of MS

Answer 3

1. Relapsing-remitting: relapses with or without complete recovery but stable between episodes - disease modifying therapy
2. Secondary progressive MS: gradual progression of symptoms without distinct episodes
3. Primary progressive MS: increasing symptoms without distinct episodes from the start
4. Progressive relapsing: gradual worsening with episodes of deterioration occurring later in the illness

Question 4

Presenting symptoms of MS

Answer 4

1. Episodes of spastic paraparesis, hemiparesis or tetraparesis
2. Episodes of limb parasthesia
3. Episodes of visual disturbance - loss of acuity, pain on eye movement, loss of central visual field (optic neuritis), diploplia
4. Episodes of ataxia, dysarthria and tremor - Charcot’s triad (cerebellar or posterior column involvement)
5. Band sensations around trunk or limbs
6. Urinary urgency, incontinence of faeces

Question 5

Less common symptoms of MS

Answer 5

Vertigo, symptoms of cranial nerve disorders
Erectile dysfunction 
Depression
Euphoria
Dementia 
Seizures 
Bulbar dysfunction

Question 6

Factors that worsen symptoms in MS

Answer 6

Heat (baths) - Uhthoff’s phenomenon
Infection 
Fever
Pregnancy 
Exercise

Question 7

MS History

Answer 7

Presenting symptoms
Factors that worsen symptoms
Family history
Social disability- inc sexual function, ability to work, financial problems
Place of birth (temperate vs tropical regions)
Smoking history
Treatments

Question 8

DDx of multiple CNS lesions

Answer 8

SLE
Sjögren’s syndrome 
Behçet’s disease
Small vessel ischemia
Acute disseminated encephalomyelitis
Meningovascular syphilis
Paraneoplastic effects of carcinoma 
Sarcoidosis
Lyme disease 
Multiple emboli from any source

Question 9

Sites of demyelinating lesions on MRI

Answer 9

corpus callosum 
Juxtacortical white matter
Spinal cord
Optic nerve
Periventricular white matter
Pons, cerebellar peduncles & cerebellum

Question 10

Cerebrospinal fluid in MS

Answer 10

Contains IgG bands (70%) & altered IgG:albumin ratio
Myelin base protein may be elevated in acute demyelination
Acute severe demyelination may result in WCC >100 / mL

Question 11

Treatment of MS

Answer 11

Interferon Beta1a & interferon beta1b
Glatiramer acetate
Natalizumab (monoclonal antibody to alpha4-integrity)
Fingolimod
Teriflunomide
Dimethyl fumarate
Alemtuzumab (monoclonal antibody against CD52)

Question 12

Interferon Beta1a & Interferon Beta1b

Answer 12

Reduce frequency of exacerbation by 1/3 when used at an early stage of disease
Reduces accumulation of white CNS white matter lesions
More effective for relapsing forms of MS
Evidence they improve survival
SE: hepatotoxicity ; leukopenia

Question 13

Glatiramer Acetate

Answer 13

Stimulates regulatory T cells that resemble myelin-reactive T cells in having a propensity for CNS migration
Takes up to a year to provide benefit
SE: non-cardiac chest pain, SOB, Bradycardia

Question 14

Natalizumab

Answer 14

GAME CHANGER - reduction in annual relapse rate, disability progression & MRI lesions
Monoclonal antibody to alpha4-integrin
Inhibits the leukocyte migration across the blood-brain barrier
Main risk: 1 in 600 patients treated develop progressive multifocal leuckoencephalopathy (PML) from brain infection with Jakob-Creuztfeld agent
SE: anxiety, pharyngitis, peripheral oedema, infusion related symptoms
6% patients develop persistent anti-natalizumab-neutralising Ab
Risk of rebound relapse with cessation

Question 15

Fingolimod

Answer 15

Works via the sphingosine-1-phosphate receptor to prevent lymphocyte tracking through lymph nodes
Causes reversible lymphopenia
More effective than interferon
SE: macular oedema, First-dose bradycardia, HTN, LFT derangement, lymphopenia
Main risk: Varicella reactivation - should not be given to patients without varicella immunisation or known previously exposure or immunity
Patients should be screened for herpes simplex, hepatitis & TB

Question 16

Teriflunomide

Answer 16

Antimetabolite that interferes with the de novo synthesis of pyrimidines
SE: hair loss, GI upset, teratogenic
Monitor for skin malignancy

Question 17

Dimethyl furmate

Answer 17

unknown mechanism - lowers lymphocyte count

SE: flushing, gut upset (diarrhoea, nausea, abdo pain)

Question 18

Alemtuzumab

Answer 18

Monoclonal antibody against CD52
B-cell-mediated autoimmunity a- problem in early phase post dose:
- autoimmune thyroid disease
- GBM glomerulonephritis (Good Pastures Syndrome)
- ITP

Question 19

Acute treatment of MS

Answer 19

Corticosteroids - accelerates recovery from relapse
Oral methylprednisolone
Plasmapheresis (severe attacks)

Question 20

MS drugs that can be used in pregnancy

Answer 20

Interferon Beta
Glatiramer Acetate
Natalizumab (but generally not used as increased risk of rebound relapse if stopped)
Alemtuzumab
Rituximab / Ocrelizumab
- best option; dose prior to conception; avoid in 2nd and 3rd trimester

Question 21

Ocrelizumab / Rituximab

Answer 21

Reduction of number & function of CD20
SE: minimal
Takes 3 months to work

Question 22

MS

Answer 22

Demyelinating disorder of the CNS
Acute MS plaques develop when primed t-lymphocytes cross the blood-brain barrier and activate macrophages
This inflammatory process results in demyelination & the axons lose the ability for salutatory conduction

Question 23

Internuclear ophthalmoplegia

Answer 23

Due to a lesion in the medial longitudinal fasciculus
Results in weakness of ADduction of the ipsilateral eye, with nystagmus on ABduction of the contralateral eye = dissociation of conjugate eye movements
ADduction becomes normal when the contralateral (ABducting) eye is covered

Question 24

MS eye signs

Answer 24

Internuclear opthalmoplegia
Cerebellar eye signs - ocular dysmetria (hypo- or hypermetric saccades), broken pursuit & nystagmus towards the site of the cerebellar lesion
Optic atrophy (results from optic neuritis)

Question 25

Demyelinating plaques in MS have a predilection for what areas of the CNS

Answer 25

• Optic nerve: optic atrophy, relative afferent pupillary defect
• brain stem: internuclear opthalmoplegia, facial sensory loss, facial weakness (UMN), rub real tremor, diploplia
• Cerebellum: ataxia, dysarthria
• Spinal cord (corticospinal tracts): pyramidal weakness
• spinal cord (dorsal columns): loss of vibration and proprioception, Lhermitte’s signs

Question 26

Lhermitte’s sign

Answer 26

Neck flexion results in rapid tingling or electric shock-like feeling that passes down the spine into the arms and legs. Indicates dorsal column involvement of a the cervical spinal cord