Multiple Sclerosis

Question 1

Multiple sclerosis is an autoimmune demyelinating disorder of central nervous system, characterised by (3):

List the predilection for CNS sites (4)

Answer 1

Autoimmune demyelinating disorder
Central nervous system

Characterised by:
1. Upper motor neuron lesions
2. Separated in both time and space
3. Non-specific distribution: unilateral or bilateral

Predilection for:
1. Optic nerve
2. Brainstem (periventricular white matter)
3. Cerebellum
4. Spinal cord

Question 2

What are your expected findings of the common CNS sites involved in MS?

Answer 2

1. Optic nerve - optic atrophy, RAPD
2. Brainstem - INO, facial sensory loss, UMNL facial weakness, rubral tremor, diplopia
3. Cerebellum - ataxia, dysarthria
4. Spinal cord
   - Corticospinal tract - pyramidal spastic weakness, with hyperreflexia
   - Dorsal columns - loss of vibration, proprioception, Lhermitte’s sign, pseudoathetosis

Question 3

Examination findings of MS

Answer 3

Cranial Nerves
1. Internuclear ophthalmoplegia (MLF lesion)
- Ipsilateral eye adduction weakness
- Nystagmus on contralateral eye abduction
- Dissociation of conjugate eye movement, resolves when contralateral eye is covered

2. Ocular dysmetria - hypo/hypermetric saccades, broken pursuit, nystagmus towards site of lesion
3. Optic atrophy (from optic neuritis)
   - RAPD
   - Reduced visual acuity
   - Central scotoma
4. Any cranial nerves can be affected, with difficulty in neurolocalisation
   - Motor nerves will show UMNL pattern
   - Sensory loss
5. Cerebellar syndrome
   - Staccato speech
   - Dysdiadochokinesia, impaired finger-nose
   - Impaired heel shin test
   - Intention tremor

Upper and Lower Limbs
6. UMNL pattern pyramidal weakness
- Contracture (early) or disuse atrophy wasting (late)
- Hypertonia
- Hyperreflexia
- Weakness of extensors > flexors
- Unilateral or bilateral

7. Dorsal column sensory loss
   - Vibration, proprioception loss
   - Pseudoathetosis (choreographic writhing movement of fingers when eyes closed)
   (Rarely affecting spinothalamic tract - pain, temperature)
8. Scissoring gait, wide based and ataxic
9. Romberg test positive (DCML loss)

Question 4

What are the other (non-neurological) clinical features of multiple sclerosis?

Answer 4

1. Depression
2. Urinary retention or incontinence
3. Impotence
4. Bowel problems
5. Uthoff’s phenomenon - symptoms worse after a hot bath or exercise

Question 5

What are the causes/pathophysiology of multiple sclerosis?

Answer 5

1. Unknown - genetic and environmental factors
   - Environment: increasing latitude, EBV, HHV6, Chlamydia
   - Genetic: HLA-DR2, interleukin 2 and 7
2. Autoantigens prime T-lymphocytes to cross BBB and activate macrophages
   - Eg: proteolipid, myelin oligodendrocyte glycoprotein, myelin basic protein
3. Inflammation and demyelination, with relatively sparing of axons
   (Studies do show axonal damage in acute attacks)

Question 6

Clinical classification of MS

Answer 6

1. Relapsing-remitting (80-85%)
   - Short acute attacks with periods of remissions and steady baseline state in between
2. Secondary progressive (30-40%)
   - Gradual progressive deterioration with relapsing-remitting state
3. Primary progressive (10-15%)
   - Progressive deterioration from onset of symptoms
4. Progressive relapsing (5-10%)
   - Primary progressive with superimposed relapses

Question 7

What is Lhermitte’s sign?
What are the possible causes of this sign?

Answer 7

Neck flexion causes rapid tingling or electric shock feeling, passing down the spine into arms and legs

Causes of Lhermitte’s sign:
1. Multiple sclerosis
2. Cervical myelopathy
3. Cervical cord tumour
4. Subacute combined degeneration of cord

Question 8

What is Uhtoff’s phenomenon?

Answer 8

Exacerbation of symptoms when body temperature rises (exercise, sauna, hot bath or shower)
- Due to heat induced conduction block or partially demyelinated fibres

Question 9

Internuclear ophthalmoplegia

Answer 9

MLF starts below posterior commissures and ends in upper cervical cord
- Conjugate eye movement: connects ipsilateral CN 3 (MR - adduction) with contralateral CN 6 nucleus (LR - abduction)

Lesion of MLF:
- Impaired ipsilateral adduction
- Abduction of contralateral eye causes divergence, with abducting eye flicks back towards nose for correction (nystagmus)

Causes:
1. Multiple sclerosis
2. Brainstem lesions - infarct, tumour, aneurysms
3. Wernicke’s encephalopathy
4. SLE
5. Miller Fisher syndrome
6. Drug overdose (TCA, phenytoin, barbiturates)

Question 10

What are the diagnostic criteria for multiple sclerosis?

Answer 10

Central nervous system demyelination causing neurological impairment that is disseminated in both space and time

Question 11

How would you investigate a patient with suspected multiple sclerosis?

Answer 11

Multiple sclerosis is a clinical diagnosis with history of lesions separated by time and space

1. MRI of brain and spinal cord:
   - T2 hyperintense periventricular white matter plaques
   - T1 hypointense axonal damage and gliosis, or new lesion with oedema
2. Lumbar puncture and CSF analysis:
   - Oligoclonal IgG bands
   - Lymphocytosis
   - Normal to slight increase in protein
   - Normal glucose
3. Visual evoked potentials: delayed velocity but normal amplitude, suggests previous optic neuritis

Question 12

What are the causes of CSF oligoclonal bands?

Answer 12

1. Multiple sclerosis and neuromyelitis optica (NMOSD)
2. Neurosarcoidosis
3. Neurosyphilis
4. CNS lymphoma
5. Meningoencephalitis
6. Acute disseminated encephalitis
7. SLE
8. Subacute sclerosing panencephalitis
9. Guillain-Barre syndrome and Miller Fisher syndrome
10. Progressive multifocal leukoencephalopathy
11. Behcet’s disease
12. Subarachnoid haemorrhage

Question 13

Management of multiple sclerosis

Answer 13

General
1. Multidisciplinary team involvement - ICU, Neurology, PT, OT

Acute attacks and induction
1. IV methylprednisolone
2. Plasmapharesis for steroid unresponsive patients

Maintenance of remission
1. Interferon beta (s/e: flu-like symptoms, myalgia, neutralising antibodies)
2. Glatiramer acetate
3. Mitoxantrone (s/e: cardiotoxicity)
4. Natalizumab
(Reduces relapse rates by 35%, 50% reduction in inflammatory activity on MRI)

Symptomatic and supportive treatments
1. Spasticity: baclofen, tizanidine, gabapentin, dantrolene
2. Depression: SSRIs, TCA
3. Fatigue: amantadine, modafinil, SSRI
4. Pain: carbamazepine, TCAs
5. Bladder dysfunction: self catheterisation, anti-cholinergic, alpha antagonists
6. Erectile dysfunction: sildenafil
(Anti-spasmodics, laxatives, SSRIs, pain control, self catheterisation and bladder control, psychologist)

Question 14

Neuromyelitis optica spectrum disorder (NMOSD) is also known as Devic’s disease, due to idiopathic inflammatory demyelination disease of CNS affecting optic nerves and spinal cord.

NMOSD has (3):

Treatment (3):

Answer 14

Devic’s disease
Idiopathic inflammatory demyelination disease of CNS
Optic nerves and spinal cord

1. More severe attacks
2. Larger centrally located spinal cords
3. Positive for NMO-IgGs - Aquaporin-4

IV steroids, plasmapharesis, ISTs

Question 15

Acute disseminated encephalomyelitis is a monophasic demyelinating disorder of CNS
Commonly affects children (age group), with up to 75% occur post-infectious or post-immunisation (exposure).

Pathogenesis: autoreactive T cells crosses BBB and targets myelin antigens

MRI brain and spinal cord reveals widespread, extensive, multifocal white matter lesions, with no T1 hypointense lesion (no time dissemination)

Treatment (3)

Answer 15

Monophasic demyelinating disorder of CNS
Children
Post-infectious or post-immunisation

Autoreactive T cells -> myelin antigens

Widespread, extensive, multifocal white matter lesions, with no T1 hypointense lesion (no time dissemination)

Treatment:
1. IV methylprednisolone with prolonged oral steroid
2. Plasmapharesis or IVIG
3. IV cyclophosphamide