Multiple Sclerosis

Question 1

Major demyelinating diseases

Answer 1

• Multiple sclerosis
• Neuromyelitis optica (NMO)
• Acute disseminated encephalomyelitis (ADEM)
• Optic neuritis
• Transverse myelitis

Question 2

Epidemiology of multiple sclerosis

Answer 2

• Occurs more commonly in young women
• more prevalent further from the equator

Question 3

Natural history of multiple sclerosis

Answer 3

• demyelinating disease of the CNS
• In its most common clinical course, patients have multiple flares of symptoms at multiple time points, and recover from these attacks to varying degrees (relapsing-remitting MS)
• Later in the disease, patients with a relapsing-remitting course may enter a period of progressive decline, a scenario referred to as secondary progressive MS
• Primary progressive MS is the least common clinical phenotype of MS, and is typically a spinal cord predominant illness with steady clinical decline
• Marburg variant, tumefactive demyelination, or Balo’s concentric sclerosis presents rather with large tumor-like lesions

Question 4

Initial presentation of typical MS

Answer 4

• Focal neurologic deficits that emerge and evolve over hours to days and usually resolve completely or near completely in subsequent days to weeks
• Can include a region of paresthesias and/or weakness, diplopia, vertigo, optic neuritis, transverse myelitis, ataxia, and/or trigeminal neuralgia

Question 5

MS patients between flares

Answer 5

Between flares of MS, the accumulation of subclinical lesions may cause cognitive symptoms, neuropsychiatric symptoms, and/or fatigue, but progression of focal neurologic deficits between attacks is uncommon in relapsing-remitting MS.

Question 6

On neurologic examination, patients often demonstrate ___ signs

Answer 6

On neurologic examination, patients often demonstrate upper motor neuron signs, which makes sense given that MS primarily affects the CNS.

These signs may appear even outside of regions of new or prior clinical symptoms due to subclinical lesions that have caused CNS damage without having caused clinical flares.

Question 7

Classic symptoms and signs of MS include

Answer 7

• Uthoff’s phenomenon
• L’hermitte’s sign
• Internuclear ophthalmoplegia
• Afferent pupillary defect

Question 8

Uthoff’s phenomenon

Answer 8

Recurrence or emergence of neurologic symptoms with heat (due to environmental temperature in the summer, hot bath, or exercise).

Question 9

L’hermitte’s sign

Answer 9

Electrical sensation down the spine with forward flexion of the neck.

This can occur in any type of cervical myelopathy and is not specific to MS

Question 10

Internuclear ophthalmoplegia

Answer 10

Due to disruption of the medial longitudinal fasciculus (MLF)

Question 11

Afferent pupillary defect

Answer 11

Due to prior optic neuritis.

An afferent pupillary defect may be present even in patients who have not had a clear clinical episode of optic neuritis

Question 12

Neuroimaging of MS

Answer 12

• Key diagnostic test for MS
• Classic radiologic features of MS are small, ovoid T2/FLAIR hyperintensities that are perpendicularly oriented to the lateral ventricles and corpus callosum.
• Acute lesions may demonstrate enhancement with gadolinium, often in an open ring (as compared to the complete ring of contrast enhancement seen with tumor and abscess)
• The damage caused by lesions over time can lead to T1 hypointensities at sites of prior demyelination (T1 black holes).

Question 13

Clinically isolated syndrome

Answer 13

• When a patient presents with a first demyelinating event typical of MS (e.g., optic neuritis, transverse myelitis, or another focal symptom with suggestive imaging correlate)
• If a patient has normal brain imaging in the setting of a first attack of optic neuritis or transverse myelitis, the risk of future development of MS is two to three times lower but is still in the range of 10%–30%
• Based on evidence that vitamin D deficiency may be associated with an increased risk of the development of MS, many practitioners initiate vitamin D supplementation in patients with CIS.

Question 14

Oligoclonal Bands

Answer 14

• The presence of oligoclonal bands in the CSF that are not present in the serum indicates intrathecal IgG synthesis
• Nonspecific and can be seen in CNS infections and other CNS inflammatory conditions

Question 15

Visual Evoked Potentials

Answer 15

• Examine a particular EEG of visual stimulation (P100) to evaluate conduction along the visual pathway.
• If the latency of P100 between the two eyes is significantly different, this suggests slowed conduction in one optic nerve, a sign of optic nerve dysfunction
• In cases of possible MS, abnormal VEPs can suggest prior optic neuritis.
• The optic nerve can also be examined by optical CT to look for prior damage to the nerve.

Question 16

Radiologically Isolated Syndrome

Answer 16

• MRI performed for a different reason incidentally finds radiographic features of MS
• Such patients should be evaluated for other evidence of possible MS and other causes of CNS white matter disease (cerebrovascular disease, systemic inflammatory disease)
• This evaluation is commonly unremarkable
• Such patients are typically followed clinically and with serial imaging.
• About one third of patients with RIS will eventually develop MS and have presumably been discovered in the preclinical stage
• Empiric vitamin D supplementation recommended to reduce risk

Question 17

Fulminant Demyelinating Disease

Answer 17

• Marburg variant MS, tumefactive demyelination, and Balo’s concentric sclerosis are names given to differing radiologic and pathologic appearances of these entities
• Biopsy is necessary for diagnosis as radiologic apperance may appear similar to other pathologies
• If steroids are ineffective in treating fulminant demyelination, patients may be treated with IVIg or plasma exchange. If these are ineffective, cyclophosphamide and/or rituximab may be considered.

Question 18

Treating MS

Answer 18

• Acute attack rescue medications:
  
  • 3–5 day course of IV methyprednisolone
• Preventative medications:
  
  • Diethyl fumarate, fingolimod, and teriflunomide are all convenient oral preventative agents, often first-line for prevention
  • Natalizumab (second line, mAb, anti-α​4 integrin subunit)
  • Injectable treatments IFN β and glatiramer acetate are favored for chronic disease
    *

Question 19

Fingolimod

Answer 19

S1P receptor agonist

Downregulates S1P receptor within the lymphatic system, preventing T cells from following the chemotactic gradient and egressing. In effect, fingolimod decreases the cycle frequency of T cells and increases the lymphatic T cell storage at any given moment.

Bradycardia and macular edema are sometimes seen. Baseline electrocardiogram (ECG) and cardiac monitoring are required with the first dose. Baseline ophthalmologic examination and subsequent periodic ophthalmologic monitoring are also necessary.

Question 20

Teriflunomide

Answer 20

Inhibitor of pyrimidine biosynthesis.

Decreases lymphocyte proliferation.

Hepatotoxicity and teratogenicity are notable side effects. Liver function monitoring is required, and women planning to conceive require elimination of teriflunomide with cholestyramine

Question 21

Natalizumab

Answer 21

Anti-α4 integrin subunit. Prevents T cell recruitment to regional lymph nodes.

Progressive multifocal leukoencephalopathy is a common consequence of use. PML is an opportunistic CNS viral infection caused by the John Cunningham Virus. The risk of developing PML with natalizumab treatment is related to three factors:

1. Whether the patient has antibodies to the JC virus
2. Whether the patient has received prior immunosuppressive therapy
3. Length of treatment with natalizumab beyond 2 years

anti-JC antibody screening required. In patients who are not found to have JC virus antibodies, the risk of developing PML is exceedingly low. Given these risks, JC virus antibody–negative patients on natalizumab therapy must be screened for JC virus antibody every 6 months to evaluate for seroconversion

Question 22

Symptomatic Management in Multiple Sclerosis

Answer 22

• Fatigue: amantadine, modafinil
• Gait: dalfampridine (contraindicated if seizures or renal failure)
• Spasticity: baclofen, tizanidine, botulinum toxin
• Bladder dysfunction: anticholinergics (e.g., oxybutynin), alpha-blockers (e.g., terazosin)
• Depression: psychiatric/psychological care, selective serotonin reuptake inhibitors (SSRIs)

Question 23

John Cunningham virus

Answer 23

One of the two major polyomaviruses.

Causes progressive multifocal leukoencephalopathy. In this disease, patients develop CNS white matter damage. May cause memory loss, poor speech, and impaired coordination.

Question 24

Risk factors for developing MS

Answer 24

• Hypovitaminemia D
• Previous EBV infection
• Obesity
• Genetics (20-40% concordance rate)

Question 25

On MRI, lesions that enhance with administration of gadolinium are. . .

Answer 25

. . . new.

They appeared some time between 2 and 6 weeks prior to the imaging.

Question 26

Workup for apparent clinical optic neuritis

Answer 26

• Test cranial nerves
• Test visual acuity
• Test detection of red saturation
• Test for MS signs (L’hemertte, Uthoff, afferent pupillary defect)

Question 27

Findings on a patient’s acuity exam are OD 20/100 and OS 20/20. Which eye does the patient have a problem with?

Answer 27

The right eye!

OD means dextral, or right

OS means sinistral, or left

Question 28

Why do vision tests only go up to 20/200?

Answer 28

20/200 is the cutoff for blindness, according to the legal/technical definition.

Question 29

Testing sense of red saturation

Answer 29

Have a red object. Have the patient cover one eye at a time, and ask if the object appears more red with either eye.

Question 30

What diagnostic test do you perform if you suspect MS?

Answer 30

MRI with contrast (if patient has good kidney function and no hypersensitivity)

If patient cannot tolerate gadolinium contrast, MRI is still the technique, but without contrast you do lose enhancement of the acute demyelinating regions, making it slightly less sensitive.