Multiple Sclerosis

Question 1

Histopathology of MS lesions:

Answer 1

• perivascular cuffing and parenchymal infiltration with T lymphocytes and macrophages
• loss of oligodendrocytes –> primary demyelination
• axonal transection, axonal degeneration –> gliosis (secondary demyelination)

Question 2

What is the difference between primary and secondary demyelination?

Answer 2

Primary demyelination: demyelination by damage to oligodendrocytes, but axon remains intact.
As axons cannot regenerate but myelin can, this means there is potential for improvement / recovery.

Secondary demyelination: transection of axon –> axon distal to transaction degenerates, as does myelin sheath –> gliosis (scarring).

Both processes can occur in MS.

Question 3

Typical sites of MS lesions:

Answer 3

1. Cerebrum:
   - Periventricular (juxtacortical)
   - Corpus callosum
   - Juxtacortical
2. Brainstem
3. Cerebellum
4. Optic nerve
5. Spinal cord

RR-MS: lesions tend to be in white matter, periventricular
PP-MS: lesions tend to affect cerebral and cerebellar cortices

Question 4

MS is a CNA chronic inflammatory demyelinating disease.

Pathogenesis remains uncertain and is probably multifactorial.

Features that suggest implicate primary autoimmunity are:

Answer 4

1. HLA association
   - DRB11501
   - DQA10102
   - DQB1*0602
2. Increased occurrence of other AI diseases in MS patients / families
3. similarities with animal model (EAE experimental autoimmune encephalomyelitis)
4. MS patients have increased T-cell reactivity to myelin antigens
5. Increased anti-myelin and anti-ganglioside Abs
6. Response to high-dose corticosteroids and immunotherapy

Question 5

Temporal profile of MS:
Relapsing remitting
Primary progressive
Secondary progressive

Answer 5

Relapsing remitting:
Typical attack - time from onset to maximum deficit is days to weeks.

Primary progressive
Secondary progressive

Question 6

Pathogenesis of MS - how would EBV contribute to the development of MS?

Answer 6

Postulated that EBV infection is a prerequisite for the development of MS.

Autoimmune genes 
(→ ↓CD8 cells that regulate EBV)
\+
Genetic predisposition 
(eg. HLA-DR15)
\+
Late EBV infection
↓
MS

Mechanism: EBV → infects autoreactive
B cells → seed CNS → pathogenic autoantibodies and provide survival signals to autoreactive T cells.

Question 7

Pathophysiology of MS:

Explain conduction block:

Answer 7

Loss of myelin → loss of saltatory conduction → leak / dissipation of electrical signal → conduction block.

If occurring in enough fibres in a nerve → will see effect on function
(eg. optic nerve: visual loss)

Question 8

Pathophysiology of MS:

Explain why conduction block can increase with increased body temperature.

Answer 8

Reduction current generated at each node of Ranvier with increasing temperature due to shortening of action potential (all people).

In demyelination the decreased current may not be sufficient to allow conduction → conduction block.

With cooling function may improve.

Known as Uhtoff’s phenomenon in MS.

Question 9

Pathophysiology of MS: Mechanisms of recovery from conduction block

Answer 9

Conduction block occurs when nerve fibre conduction is halted due to demyelination (impulses dissipate due to lack of insulation).

Over time:
1. Redistribution of Na+ channels along axon (instead of only at nodes of Ranvier) → conduction occurs, but slowly

2. Remyelination can occur → recovery of saltatory conduction and normal function.

Question 10

Symptoms and signs of optic neuritis (common in MS):

Answer 10

Optic neuritis:

• pain with EOM
• reduced VA
• desaturation of colour vision
• RAPD (Marcus Gunn pupil)
• scotoma

Question 11

Symptoms and signs of MS:

Answer 11

Optic neuritis

SC involvement:

• UMN deficits of limbs
• sensory deficits of limbs
• bladder and bowel dysfunction

Brainstem involvement:

• CN symptoms: diplopia, vertigo, facial weakness, facial pain
• Long tract signs - sensory and motor
• Cerebellar signs

Cerebellar involvement:

• ataxia
• nystagmus
• dysarthria

Cerebral involvement:

• hemiparesis (eg. internal capsular lesion)
• epilepsy
• cognitive impairment (multiple lesions)

Question 12

Diagnosis of MS:

Answer 12

Dissemination of CNS lesions (that are typical of MS) in time and space.

• clinical
• MRI

Exclude other causes.

Question 13

LP is not usually required in diagnosis of MS, but can be used in difficult cases. What would be seen in MS?

Answer 13

Abnormal IgG bands in CSF but not in serum.
Oligoclonal B cell expansion in CSF.

Typical of MS but DDx: subacute sclerosing panencephalitis, neuro-berylliosis

Question 14

Visual evoked responses - when to perform:

Answer 14

1. If looking for second lesion (separated in space) - will show slowing of conduction in optic pathway, suggestive of demyelination.

But need to exclude ocular or retinal pathology before attributing to demyelination.

2. If visual symptoms suspected to be functional (ie. to rule out optic neuritis)

Question 15

Neuromyelitis optica (NMO) / Devic’s disease is a variant of MS. What are the diagnostic criteria?

Answer 15

1. Transverse myelitis and optic neuritis
2. At least 2 of:
   - Brain MRI non-Dx for MS
   - SC lesion extending ≥3 vertebral segments
   - seropositive for NMO IgG
   (directed against aquaporin 4 water channel - affects atsrocytes that form BBB)

Question 16

Disease-modifying treatments in relapsing-remitting MS:

Answer 16

Dr Pender’s Approach:

Mild attack (no effect on ADLs): no treatment, as usually spontaneously resolve

Mod-severe attack (interfering with ADLs, lasting days): IV high-dose methylprednisolone (1g/day) for 3 days.

Relapse within 2 years:
1st line: Interferon β (IFN-β)
2nd line: Glatiramer acetate (copaxone)
3rd line: Natalizumab or possibly fingolimod

These reduce the frequency of relapses.
Natalizumab also reduces progression of disability.

Question 17

Disease modifying treatment of SP-MM or PP-MS:

Answer 17

NO safe, effective disease-modifying treatment therapy for primary- or secondary- progressive MS.

However, in recent acceleration deterioration, can use IV high-dose methylprednisolone.

Question 18

What is Natalizumab (used in MS)?

Answer 18

Mab against α4β1 integrin → INHIBITS ENTRY OF CIRCULATING LYMPHOCYTES AND MONOCYTES INTO CNS
(both autoreactive and anti-viral)

Potent effects on brain lesions (MRI), clinical relapse and progression of disability.

Question 19

What is the main side effect of concern with Natalizumab (used in MS)?

Answer 19

Natalizumab has potent side effects:

• PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
  = opportunistic infection of JC polyoma virus
  = demyelination in subcortical white matter due to destruction of oligodendrocytes.
• Others: Hypersensitivity reactions, liver injury, possible ↑ malignant melanoma

Question 20

What is rituximab? Is it useful in MS?

Answer 20

Mab that selectively depletes CD20+ B cells.

2008 NEJM: reduced relapse rate and MRI brain lesions in RR-MS.

Question 21

Alemtuzumab in MS (not on PBS):
Teriflunomide in MS (not on PBS):
Fingolimod

Answer 21

…

…

Question 22

Symptomatic management of MS: Troublesome spasticity

Answer 22

Treatment of spasticity:

• baclofen
• diazepam

Question 23

Symptomatic management of MS: persistent neurogenic pain (non-paroxysmal)

Answer 23

Treatment of neurogenic pain:

• amitriptyline
• gabapentin

Question 24

Symptomatic management of MS: paroxysmal symptoms, eg. trigeminal neuralgia, tonic spasms

Answer 24

Treatment of paroxysmal symptoms of MS:
- carbamazepine
- phenytoin
NOTE: Small doses only . Block sodium channels - so can worsen neurological deficits.

Question 25

Symptomatic management is important in MS. | Symptoms in MS requiring management:

Answer 25

1. Spasticity 2. Neurogenic pain (persistent) 3. Paroxysmal syndromes (eg. trigeminal neuralgia, tonic spasms) 4. Bladder dysfunction: Get urological consult 5. Depression: psychiatric consultation and antidepressants 6. Epilepsy: levetiracetam, sodium valproate (avoid sodium channel blocking agents a will worsen symptoms) 7. Persistent fatigue (not due to depression): amantadine