Multiple Sclerosis

Question 1

Definition of MS

Answer 1

Inflammatory demyelinating disease characterised by the presence of episodic neurological dysfunction in at least two areas of the central nervous system (brain, spinal cord, and optic nerves) separated in time and space

Question 2

When is MS commonly diagnosed?

Answer 2

between 20 and 40 years old. However, it can occur in the paediatric age group to as young as 2 years, where it may be confused for acute disseminated encephalomyelitis. It is occasionally diagnosed in individuals in their sixth or seventh decade who may have been asymptomatic for years.

Question 3

What is the sex ratio of MS?

Answer 3

There is a significantly skewed sex ratio, with a female to male ratio of around 3:1, and the disparity appears to be increasing

Question 4

What genes are involved in MS susceptibility?

Answer 4

While the genetics of this condition are multifactorial, genes in the human leukocyte antigen (HLA) region and interleukin region are likely to be involved

Question 5

What environmental factors are involved in MS?

Answer 5

toxins, viral exposures, and sunlight exposure (and its effect on vitamin D metabolism)

Question 6

Which virus has the greatest link to increased risk of MS?

Answer 6

Epstein-Barr

Question 7

What other factors are involved in MS relapses?

Answer 7

Relapses are sometimes triggered by infections or postnatal hormonal changes. Surgical procedures may also trigger relapses, and some literature suggests that acute trauma or stressful events may be precipitants, although this is controversial.

Question 8

What are the two phases of MS?

Answer 8

inflammatory and degenerative

Question 9

Describe the inflammatory phase of MS

Answer 9

• Lymphocytes with encephalitogenic potential are activated in the periphery by factors such as infection or other metabolic stress
• These activated T cells seek entry into the central nervous system (CNS) via attachment to a receptor on endothelial cells.
• This interaction, mediated by production of matrix metalloproteinases, allows a breach in the blood-brain barrier, leading to further upregulation of endothelial adhesion molecules and additional influx of inflammatory cells.
• The T cells produce inflammatory cytokines that cause direct toxicity and also attract macrophages that contribute to demyelination.
• Epitope spread occurs early and contributes to the complexity of the immunopathology

Question 10

Describe the degenerative phase of MS

Answer 10

• reflect axonal degeneration and loss.
• Demyelination disrupts axonal support and leads to destabilisation of axonal membrane potentials, which causes distal and retrograde degeneration over time.
• There is also a suggestion that inflammatory cells, antibodies, and complement may contribute to axonal injury.
• Axonal damage has been identified in regions of active inflammation, indicating that it begins early in the disease process.

Question 11

What are the pathological characteristics of MS?

Answer 11

multifocal areas of demyelination, loss of oligodendrocytes, and astrogliosis with loss of axons primarily in the white matter of the CNS, although cortical lesions may also play a significant role

Question 12

How does inflammatory and degenerative processes differ in different MS presentations?

Answer 12

Relapsing-remitting MS shows the most inflammatory activity, followed by early secondary progressive MS. Primary progressive MS is thought to be a primarily degenerative process, although some patients do have relapses and/or enhancing lesions

Question 13

How do inflammatory and degenerative processes manifest differently?

Answer 13

Acute relapses of MS with disturbance of CNS function such as vision or mobility are thought to be periods of increased inflammatory activity of the immune system and treated accordingly.
Clinical progression, such as the gradual loss of ability to ambulate over several years, and/or poorer recovery from relapses, is believed to be a manifestation of combined on-going chronic low-level inflammation with degenerative processes.

Question 14

How does inflammatory and degenerative processes differ in MRI scans?

Answer 14

Brain and spinal magnetic resonance imaging (MRI) manifestations of inflammation show contrast-enhancing lesions with limited oedema, whereas MRI manifestations of the progressive process show atrophy and T1 hypo intensity (or black holes)

Question 15

What are the two phenotypes of MS?

Answer 15

Relapsing-remitting

Progressive

Question 16

Describe relapsing-remitting disease

Answer 16

• Clinically isolated syndrome (CIS) is a clear-cut syndrome such as optic neuritis, brainstem/cerebellar dysfunction, or partial myelitis and is now considered to be part of the relapsing-remitting MS disease spectrum.
• Relapsing-remitting MS (RRMS) requires magnetic resonance imaging (MRI) evidence of dissemination in space, as well as Gd+ and non-enhancing T2 lesions on a single MRI scan, and/or a subsequent event. Relapsing-remitting MS is also characterised as active or not active within a specified time frame

Question 17

What are the 4 sub-categories of progressive disease?

Answer 17

• Active and with progression (individual has had an attack and is also gradually worsening)
• Active but without progression (e.g., individual has had an attack within a previous specified time frame [i.e., 1 year, 2 years])
• Not active but with progression (e.g., walking speed has decreased)
• Not active and without progression (stable disease).

Question 18

Describe the neurological history of MS

Answer 18

• A history of transient motor, cerebellar, sensory, gait, or visual dysfunction lasting over 48 hours and not accompanied by fever or other intercurrent illness is suggestive of a demyelinating episode of MS.
• Symptoms are often asymmetric and involve only one side of the body or one limb, although bilateral involvement can occur.
• Patches of odd sensation such as wetness or tingling may occur, and band-like or hemiband-like sensations are pathognomonic for spinal cord lesions

Question 19

What neurological examinations can be carried out?

Answer 19

• Fundoscopy should be performed to view the optic disc, and the ‘swinging flashlight’ test can be used to evaluate for an afferent pupillary defect.
• Colour vision should be assessed to look for red desaturation (a more subtle sign of optic neuritis).
• Eye movements may also be particularly revealing as patients may develop internuclear ophthalmoplegia (INO) or other abnormalities in the absence of symptoms.
• The presence of nystagmus or abnormal saccades may suggest a cerebellar lesion.
• Testing of tone and reflexes in the upper and lower extremities is important to look for upper motor neuron signs, such as spasticity and hyperreflexia.
• The gait must be carefully assessed, preferably by walking the patient at least 7.6 metres (25 feet).
• Signs may include mild dragging of the foot as well as spasticity and balance problems.
• MRI of the cervical spinal cord is also recommended for all patients. It is an extremely valuable and often underused non-invasive test that is helpful both in identifying MS and in eliminating other causes of myelopathic signs and symptoms such as cervical spondylosis

Question 20

What laboratory evaluations could be carried out?

Answer 20

• People with large spinal cord lesions over several segments of spinal cord, poor recovery from optic neuritis, or atypical lesions on MRI brain should be considered for an anti-NMO antibody (anti-aquaporin 4 (AQP4) antibody) to evaluate for neuromyelitis optica (Devic syndrome).[4]
• Lumbar puncture with CSF examination for oligoclonal bands, and CSF IgG index may be done. Due to the invasive nature of lumbar puncture, all other non-invasive tests should be pursued first. Note that the CSF is normal in 10% to 20% of MS cases.

Question 21

What are the common diagnostic factors of MS?

Answer 21

-Visual disturbance in one eye
=Greying or blurring of vision in one eye (can be described as looking through petroleum jelly). May have pain in moving that eye and describe loss of colour discrimination, particularly reds.
-Peculiar sensory phenomena
=Patients often describe odd sensations of a patch of wetness or burning, or hemi body sensory loss or tingling. In particular, banding or hemibanding is associated with spinal cord lesions. Lhermitte’s sign (electric shock-like sensations extending down the cervical spine radiating to the limbs) and trigeminal neuropathy or neuralgia are other possible sensory findings in MS.

Question 22

Other diagnostic factors of MS

Answer 22

• Foot slapping/ dragging
• Leg cramping
• Fatigue
• Urinary frequency/ retention
• Bowel dysfunction/ constipation
• Spasticity/ increased muscle tone
• Increased deep tendon reflexes
• Imbalance/ incoordination= Wide-based gait and/or limb ataxia indicate cerebellar dysfunction

Question 23

What investigations are there for MS?

Answer 23

• MRI Brain= hyperintensities in the periventricular white matter, most sensitive images are sagittal FLAIR
• MRI Body= demyelinating lesions in the spinal cord, particularly the cervical spinal cord; detection of alternate diagnosis, such as cervical spondylosis
• Cerebrospinal fluid evaluation

Question 24

What are the categories of treatment for MS?

Answer 24

management of acute worsening/relapses;
disease-modifying therapy;
symptomatic management

Question 25

When might patients with MS commonly experience worsening of their condition?

Answer 25

during urinary tract infections (which may be asymptomatic), sinusitis, viral infection, cellulitis and other skin infections, or fevers from any cause. Underlying infections should be appropriately treated

Question 26

How might relapse affect function?

Answer 26

decreased or double vision, difficulty walking, or difficulty using a hand due to coordination or weakness problems

Question 27

What is the treatment when relapse affects function?

Answer 27

high-dose methylprednisolone and oral taper can be offered if not contraindicated by infection or poorly controlled diabetes or hypertension
Intravenous administration is the standard route of administration; however, if this is not possible, high-dose oral administration may be considered and is non-inferior to intravenous administration

Question 28

What is the treatment in the case of neuromyelitis optica?

Answer 28

high-dose intravenous corticosteroid treatment is still the first option, but a longer oral taper of 4-6 weeks is required to prevent rebound. Patients with severe or rapidly progressing disability may benefit from plasma exchange or plasma exchange plus intravenous corticosteroids

Question 29

What is the treatment for relapsing-remitting MS?

Answer 29

interferon beta preparations, glatiramer, dimethyl fumarate, and teriflunomide are generally considered ‘first-line’ agents

Question 30

What are the treatments for aggressive disease and/or have not tolerated or responded to previous disease-modifying agents

Answer 30

fingolimod, siponimod, natalizumab, ocrelizumab, cladribine, and alemtuzumab

Question 31

What are the expected mechanisms for the treatments of MS?

Answer 31

interfere with the formation of new demyelinating plaques in the central nervous system