Multiple Sclerosis and Demyelinating Diseases 1

Question 1

Diseases affecting CNS myelin classification

Answer 1

Dysmyelinating: hereditary disorders

Demyelinating:
Autoimmune
Infectious
Toxic and metabolic
Vascular Processes

Question 2

Which is the most common non-traumatic disabling disorder in young adults?

Answer 2

Multiple Sclerosis

Question 3

Multiple Sclerosis
(Risk factors)

Answer 3

1) Ultraviolet radiation (higher prevlence in northern regions)

2) Vitamin D (higher prevalence in northern regions)

3) Genetics (HLA-DRB1*15:01)

4) Epstein Barr virus

5) Smoking

6) Obesity

7) Microbiome and diet

Question 4

A) Mean age of disease onset

B) Sex distribution

Answer 4

A) The mean age of RRMS MS onset ranges from 28 to 31 years and PPMS is 40 years

B) affects more women than men
2-3:1 in RRMS
1:1 in PPMS

Question 5

Multiple Sclerosis Pathophysiology
(Main factors)

Answer 5

1) impaired regulatory T cell function or resistance of autoreactive cells to suppression

2) B cells

3) Microglia

4) Disruption of the blood-brain barrier

Question 6

Multiple Sclerosis Pathophysiology
(Role of T cells)

Answer 6

Normally, CNS autoreactive immune cells are deleted during development through central tolerance in the thymus (T cells) or bone marrow (B cells). Although some may escape this mechanism and be released into the circulation, peripheral tolerance mechanisms typically prevent them from causing disease.

Mechanisms by which peripheral tolerance can fail include impaired regulatory T cell function or resistance of autoreactive cells to suppression. (A complex interplay between genetic and environmental risk factors may influence function and activation of these autoreactive cells and lead to disease pathogenesis.)

Primary T cell subsets implicated in MS include CD8+ T cells and CD4+ T helper (TH) 1 and TH17 cells.
Autoreactive T cells also produce cytokines that may contribute to MS pathogenesis including interferon gamma, interleukin (IL)-17, and granulocyte-macrophage colony-stimulating factor.

Question 7

Multiple Sclerosis Pathophysiology
(Role of B Cells)

Answer 7

1) In MS, B cells produce proinflammatory cytokines including lymphotoxin-α, IL-6, TNF-α, and granulocyte-macrophage colony stimulating factor.

2) Normally, B cells can also generate anti-inflammatory cytokines including IL-10, IL-35, and transforming growth factor β1, but the production of these in patients with MS may be impaired.

3) B cells may also act as a reservoir for Epstein-Barr virus

4) Other pathologic mechanisms involving B cells in MS include antigen presentation to T cells and secretion of molecules that may be directly toxic to oligodendrocytes

Question 8

Multiple Sclerosis Pathophysiology
(Role of microglia)

Answer 8

Activated microglia and CD8+ T cells lead to :
- myelin destruction
- recruitment of B cells, other T cells, and macrophages
- axon damage
- disruption of the blood-brain barrier.

In progressive MS, activated microglia and macrophages may mediate neurodegeneration by several mechanisms including cytokine release, glutamate release resulting in excitotoxicity, and release of reactive oxygen/nitrogen species resulting in oxidative injury.

Question 9

Multiple Sclerosis Pathophysiology
(Blood Brain Barrier)

Answer 9

Classic acute lesions begin with infiltrates of inflammatory B, T, and plasma cells and macrophages surrounding a central vein

Question 10

Multiple Sclerosis Pathophysiology: Factors contributing in degeneration in progressive forms

Answer 10

• chronic microglial activation (even in normal -appearing white matter)
• impaired ion homeostasis
• mitochondrial injury
• meningeal inflammation

Question 11

Role of Vitamin D in immune system

Answer 11

Effects of vitamin D in adaptive immune cells include:
- inducing differentiation to regulatory T and B cells
- decreased production of proinflammatory cytokines
- increased secretion of anti-inflammatory cytokines
- promoting oligodendrocyte maturation

Question 12

MS most common symptoms

Answer 12

Question 13

Optic Neuritits in MS:
A) Presentation/ Clinical findings
B) Findings in fundoscopy/ mapping of visual fields
C) Prognosis

Answer 13

A) Acute or subacute, pain in the eye accentuated by occular movements, variable degree of visual loss affecting mainly central vision, and sometimes decreased colour vision as well.
Patients with MS might also may report a phenomenon called the Pulfrich phenomenon, which is an illusory perception that an object moving linearly along a two-dimensional plane appears to instead follow an elliptical three-dimensional trajectory.
RAPD is present.

B) Most have a normal fundoscopy, rarely papilitis may be seen.
Later the optic disc becomes pale as a result of axonal loss and resultant gliosis.

C) 90% of patients regain normal vision typically over a period of 2-6 months

Question 14

Causes of bilateral simultaneous optic neuritis

Answer 14

• Leber hereditary optic neuropathy
• Toxic optic neuropathy
• NMO
• anti-MOG associated ON
• MS (rare)

Question 15

Clinical features of more common optic neuropathies

Answer 15

Question 16

Causes of optic neuropathy

Answer 16

https://www.uptodate.com/contents/image?imageKey=NEURO%2F75945&topicKey=NEURO%2F5244&search=optic%20neuritis&source=outline_link

Question 17

Chronic relapsing inflammatory optic neuropathy (CRION)

Answer 17

• rare, relapsing autoimmune optic neuritis in which no other known systemic disease can be found; these patients do not have sarcoidosis, lupus, MS, neuromyelitis optica, or other cause
• On first presentation, the clinical features are those of optic neuritis, including enhancement of the optic nerve on MRI.
• In contrast to patients with optic neuritis, tapering glucocorticoid therapy leads to a clinical relapse.
• In order to stay in remission, patients with CRION require chronic immunosuppression with steroid-sparing agents such azathioprine, methotrexate, cyclophosphamide, or intravenous immune globulin
• Diagnostic work-up should exclude other systemic, metabolic, toxic, or paraneoplastic causes of optic neuropathy, including serum myelin oligodendrocyte glycoprotein and aquaporin 4 immunoglobulin G antibody tests.

Question 18

Visual evoked potentials in MS

Answer 18

Abnormalities (P100 wave prolongation) are detected in over 90% of patients with a history of optic neuritis

Question 19

What can OCT show in MS patients?

Answer 19

Can be used to noninvasively quantify axonal damage following an ON event
It can be used to measure the thickness of the retinal nerve fiber layer, which is reduced in most patients (85 percent) with optic neuritis.
Optic nerve or optic tract demyelination leads to retrograde degeneration of unmyelinated retinal nerve fiber layer axons. Retinal nerve fiber layer loss becomes evident with OCT approximately three months after optic neuritis

(The retinal nerve fiber layer lacks myelin and contains axons)

It is not used in MS diagnosis at this point of time

Question 20

Internuclear Opthalmoplegia in MS: Presentation, localization

Answer 20

Abnormal horizontal ocular movements with lost ot impaired adduction and horizontal nystagmus of the abducting eye.
Convergence is preserved!

Lesion of the medial longitudinal fasciculus on the side of diminished adduction.

Question 21

How to distinguish INO from isolated third nerve palsy

Answer 21

Convergence is preserved!

Question 22

Order of frequency of occular nerves involvement in MS

Answer 22

Decreasing order
VI, III, IV

Question 23

Which kind of nystagmus is characteristic in MS? Presentation, localization

Answer 23

Acquired pendular nystagmus (εκκρεμοειδής)
Rapid, small-amplitude pendular oscillations of the eyes in the primary position. Most often bilateral but can also be unilateral.
Consequent of an optic neuropathy, involvement in the cerebellum or dorsal pontine tegmentum.

Question 24

Impairment of cranial nerves in MS (other than ocular motor nerves)

Answer 24

Impairment of facial sensation
Trigeminal neuralgia (uncommon presenting symptom - later in course)
Facial myokymia
Unilateral facial paresis
Hearing loss (uncommon)
Isolated dysfunction in taste
Pseudobulbar syndrome (later in course)
Vertigo (30-50% of patients)

Question 25

distinguishing between a spastic and denervated bladder in MS

Answer 25

The volume of postvoiding residual urine measured
either by catheterization or by ultrasound

Urodynamic studies may be helpful

Question 26

Most common initial bladder symptom in MS and cause

Answer 26

Urinary urgency caused by uninhibited detrusor (εξωστήρας μυς) contraction

Question 27

Bladder symptoms caused by sacral involvement in MS

Answer 27

Bladder hypoactivity (decreased urinary flow, interrupted micturition, incomplete bladder emptying)

Question 28

Neurogenic bladder dysfunction in MS categorization

Answer 28

●Detrusor overactivity (ie, overactive bladder), leading to failure of the bladder to store urine.
The resulting symptoms include urgency, frequency, and urge incontinence.
Detrusor overactivity is the most common urologic abnormality affecting patients with MS, and is typically caused by cortical demyelinating lesions that impair the detrusor reflex at the level of the frontal cortex.

●Detrusor sphincter dyssynergia, the term used to describe detrusor contraction without urethral sphincter relaxation, leading to functional bladder outlet obstruction and failure to empty, typically caused by lesions involving the pontine micturition center or spinal cord lesions above the sacral parasympathetic centers.
Associated symptoms include hesitancy, interrupted stream, and incomplete voiding.

●Inefficient bladder contractility, leading to failure of the bladder to empty, and attributed to spinal cord lesions that disrupt coordination with the pontine micturition center.
Related symptoms include incomplete emptying, residual urine, and frequency.

●Abnormal sensation and bladder hypoactivity due to involvement of sacral segments of the spinal cord, leading to failure to empty (ie, an atonic dilated bladder that empties by overflow); this condition results from loss of perception of bladder fullness, and it is usually associated with urethral, anal, and genital hypesthesia, and sensory deficits in the sacral dermatomes.
Symptoms include urinary retention, interrupted micturition, and incomplete bladder emptying.

Question 29

Cause of bladder overflow in MS

Answer 29

Loss of perception of bladder fulness.
Commonly associated with urethral, genital, anal hypoesthesia and sensory deficits in the sacral dermatomes

Question 30

Cognitive impairment in MS: most common features

Answer 30

Cognitive impairment may be common even at the onset of MS.
The most frequent abnormalities are in attention, executive functioning, abstract conceptualization, short term memory, word recall, and speed of information processing.

Question 31

Causes of constipation in MS

Answer 31

Spinal cord involvement
Decreased general mobility
Dietary issues
Fluid restriction by patients

Question 32

Paroxysmal symptoms in MS

Answer 32

Paroxysmal attacks of motor or sensory phenomena can occur with demyelinating lesions.
These symptoms are characterized by brief, almost stereotypic, events occurring frequently and often triggered by movement or sensory stimuli.
They are likely caused by ephaptic transmission of nerve impulses at sites of previous disease activity.

Within the brainstem, lesions may cause paroxysmal diplopia, facial paresthesia, trigeminal neuralgia, ataxia, and dysarthria.
Motor system involvement results in painful tonic spasms of muscles of one or two (homolateral) limbs, trunk, and occasionally the face, but these only rarely occur in all four limbs or the trunk.

These paroxysmal attacks typically respond to low doses of carbamazepine and frequently remit after several weeks to months, usually without recurrence.

Question 33

Epilepsy in MS: percentage and most common type

Answer 33

2-3% of patients

Approximately two-thirds of seizures in patients with MS are primary or secondary generalized seizures, while the remaining one-third are partial

Question 34

How common is sexual dysfunction in MS?
Causes

Answer 34

40-80% of patients
Direct effects of lesions on the motor, sensory and autonomic pathways within spinal cord
Depression

Question 35

Which is th most commonly used index for characterizing MS disability

Answer 35

Expanded disability status scale (EDSS)

Question 36

Main clinical course phenotypes

Answer 36

Question 37

Percent of MS starting as a relapsing disease

Answer 37

80-90%

Question 38

MS relapse definition

Answer 38

The acute or subacute onset of clinical dysfunction usually reaching its peak in days to several weeks followed by a remission during which the symptoms and signs usually resolve partially or completely
The minimum duration of relapse has been established at 24h

Question 39

Typical presentations of MS

Answer 39

Typical presentations include the following:

●Unilateral optic neuritis, manifesting with painful, monocular visual loss consisting of visual blurring or scotoma

●Painless diplopia due to internuclear ophthalmoplegia (occasionally bilateral) or, less commonly, a sixth nerve palsy

●Brainstem or cerebellar syndrome, such as diplopia described above, ataxia with gaze-evoked nystagmus, vertigo, facial numbness, or paroxysmal episodes of dysarthria or vertigo

●Partial transverse myelitis, usually with predominant sensory symptoms, including a partial Brown-Sequard syndrome, or Lhermitte sign; other manifestations can include sphincter symptoms, with bladder involvement (eg, urge incontinence) more common than bowel, and erectile dysfunction

Question 40

Clinically isolated syndrome: definition, prognosis

Answer 40

Patients who present with an event that is clinically consistent with MS and accompanied by typical multifocal white-matter lesions on MRI, yet the MRI does not meet criteria for dissemination in space and time.
In CIS there is no evidence of previous episodes of demyelination from the patient’s history or examination

A clinically isolated syndrome is the first clinical episode that is suggestive of MS, as characterized by the following features:

●Presents as a monophasic clinical episode with symptoms and objective findings that reflect a focal or multifocal inflammatory demyelinating event in the central nervous system

●Develops acutely or subacutely, with a duration of at least 24 hours, with or without recovery

●Occurs in the absence of fever or infection

●Resembles a typical MS relapse (attack and exacerbation) but occurs in a patient not known to have MS

The long-term likelihood of progression to clinically definite MS for patients with a CIS is 60-80 percent if the baseline brain MRI reveals demyelinating lesions suggestive of MS, and approximately 20 percent if the MRI is normal.

(a patient with a single clinical demyelinating event will be diagnosed with MS if their MRI shows both enhancing and non-enhancing brain or spinal cord lesions, indicative of inflammation separated in space and time)

Question 41

Clinically isolated syndrome management

Answer 41

Disease-modifying treatment is suggested for patients with a CIS who do not fulfill McDonald criteria for a diagnosis of MS but have an abnormal brain MRI with one or more hyperintense T2 lesions that are characteristic of MS in at least two of four MS-typical regions at presentation or within three to six months of the event.

Most DMTs approved for relapsing forms of MS are also approved in the United States for the treatment of CIS. These are:

●Platform injection therapies: Interferons and glatiramer acetate
●Oral therapies
*Fumarates: Dimethyl fumarate
*Teriflunomide
*Sphingosine-1-phosphate receptor modulators: Fingolimod, siponimod, ozanimod, and ponesimod
●Monoclonal antibodies: Natalizumab, ocrelizumab, and ofatumumab

Question 42

Radiologically isolated syndrome definition, prognosis, management and follow up

Answer 42

Incidental brain or spinal cord MRI findings that are highly suggestive of MS in a patient lacking any history, symptoms, or signs of MS.

Patients with an RIS have an increased risk of subclinical MS if one or more of following features are present:

●Age <35 years
●Male sex
●Cervical or thoracic spinal cord lesions on MRI
●Dissemination in time on MRI (gadolinium-enhancing and/or new T2 lesions)
●High T2 lesion load on MRI
●Cortical and/or juxtacortical lesions on MRI
●Presence of oligoclonal bands in the cerebrospinal fluid
●Abnormal visual evoked potentials
●Deficits of specific cognitive functions (ie, information processing speed, complex attention, episodic memory, and executive functions)

Currently, there is no clear indication for the use of disease-modifying treatment for patients with RIS (ie, asymptomatic but with incidental MRI findings suggestive of MS)

For patients with an RIS who remain asymptomatic, a repeat brain MRI at 6 to 12 months and then at yearly intervals for up to five years is suggested.

Question 43

Multiple sclerosis: McDonald criteria (2017 revision)

Answer 43

Question 44

MRI criteria for MS

Answer 44

Question 45

Atypical presentations that may suggest a diagnosis other than MS

Answer 45

Question 46

MRI in MS: red flags mnemonic

Answer 46

Question 47

Laboratory investigations in atypical presentations of MS

Answer 47

Question 48

McDonald criteria 2017: changes comparing to 2010

Answer 48

1) cortical lesions were added as a typical lesion interchangable for juxtacortical lesion

2) for dissemination in time, either simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time, or a new T2 or T1 gadolinium-enhancing lesion on follow-up MRI scan

3) oligoclonal bands can substitute for dissemination in time

Question 49

Which MRI lesions can be considered in the determination of
dissemination in space or time, symptomatic or asymptomatic?

Answer 49

Symptomatic AND asymptomatic MRI lesions can be considered in the determination of dissemination in space or time.

MRI lesions in the optic nerve in a patient presenting with optic neuritis remain an exception

Question 50

Concerning DIS, can evidence from paraclinical tests be used (such as OCT, MRI, VEP) in a patient without a history of optic neuritis?

Answer 50

Despite recognising optic nerve involvement as an important feature of multiple sclerosis, the Panel felt the data concerning the diagnostic sensitivity and specificity of MRI, visual evoked potentials, or optical coherence tomography to demonstrate optic nerve lesions in patients without a clear-cut history or clinical evidence of optic neuritis were insufficient to support incorporation into the McDonald criteria at this time.

Question 51

Primary progressive MS disgnostic criteria

Answer 51

Question 52

What does gadolinium enhancement mean?

Answer 52

Gd crosses the disrupted BBB indicating increased vascular permeability in association with inflammation

Question 53

Which MRI metric correlates most with clinical measures of disability in MS

Answer 53

Atrophy of the spinal cord and especially the central grey matter

Question 54

MRI sign that can distunguish MS from other causes of T2 hyperintense signal change

Answer 54

Central vein sign (venous structure within an area of hyperintense signal change)

Question 55

Acute and chronic lesions in MS imaging characteristics

Answer 55

Acute lesions (less than 12 weeks)
- often show Gd enhancement on T1 (enhancement pattern complete or incomplete ring, patchy, or homogenously enhancement)
- may be associated with bright signal on DWI
- Often associated with bright T2/ Flair signal
- at times may show an associated dark T1 signal

Subacute lesions
May no loner show contrast enhancement but continue to show bright DWI abnormality

Chronic lesions
- appear hyperintense on T2/ Flair
- T1 hypointensities (black holes) usually reflects irreversible tissue damage such as axonal loss and demyelination

Question 56

Rate of brain atrophy in MS

Answer 56

0.6%-1.35% per year

Question 57

Percent of MS patients with spinal cord lesions

Answer 57

Over 90% of MS patients have spinal cord lesions at some point in the course of the disease, and 30% of patients presenting with CIS other than transverse myelitis

• they typically involve fewer than 2 contiguous segments
• they produce neurological symptoms with greater frequency than those in the brain

Question 58

Cerebrospinal fluid in MS

Answer 58

• 15-20% slightly elevated cells (predominantly T-lymphocytes) / usually not greater than 50
• Presence of OCB
• Abnormal IgG index
• levels of protein may be quite increased

Question 59

Percent of clinical definite MS without OCB presence

Answer 59

10-20%

Question 60

Multiple Sclerosis differential diagnosis

Answer 60

2008 Differential diagnosis of suspected multiple sclerosis:
a consensus approach

Question 61

Worsening of previous clinical relapse in MS causes

Answer 61

• Fever
• Infection
• Physical activity
• Metabolic upset

Question 62

Benign and malignant MS

Answer 62

Benign MS: Disease in which the patient remains fully functional in all neurological systems 15 years after the disease onset

Malignant MS: Disease with a rapid progressive course leading to significant disability in multiple neurological systems or death in a relatively short time after disease onset.

Question 63

Prognostic factors in MS

Answer 63

Question 64

MS prognosis based on patient characteristics

Answer 64

• Sex: MS may follow a less severe course in women than in men.
• Age at onset: Average is 29–32 years. Onset at an early age is a favorable factor, whereas onset at a later age carries a less-favorable prognosis. RRMS is more common in younger patients, and PPMS and SPMS are more common in the older age group.
• Initial disease course: Relapsing form of the disease is associated with a better prognosis than progressive disease. A high rate of relapses early in the illness and a short first interval between attacks may correlate with shorter time to reach EDSS 6.
• Initial manifestations: Among initial symptoms, impairment of sensory pathways or ON has been found in several studies to be a favorable prognostic feature, whereas pyramidal and, particularly, brainstem and cerebellar symptoms carry a poor prognosis.

In general, when considering disability as measured by the EDSS (which prioritizes ambulatory function), patients with mild disease (EDSS score 0-3) 5 years after diagnosis only uncommonly progress to severe disease (EDSS score 6) by 10 years (7.5% of patients) and 15 years (11.5% of patients).

Question 65

Pregnancy in Multiple Sclerosis

Answer 65

Several retrospective studies reported an overall increase in relapse rate during the postpartum period and a lower relapse rate during pregnancy itself

Question 66

When to use gadolinium in MRI screening?

Answer 66

Guidelines recommend limiting the use of MRI with gadolinium contrast to selected clinical scenarios:

*When detection or confirmation of recent (ie, within one year) clinical disease activity will influence treatment decisions, such as starting or escalating therapy
*When a recent comparable MRI scan is not available
*When assessment of new MRI disease activity is difficult due to a high baseline T2 lesion burden

Repeated contrast-enhanced MRI studies can lead to gadolinium accumulation in brain tissues. Although there are no documented adverse effects of such accumulation, it is prudent to carefully reflect on whether gadolinium is needed with each MRI.

Question 67

When to consider switching DMT

Answer 67

A single relapse of mild severity or a single new MRI lesion within six months of starting DMT is concerning but is usually insufficient to demand a change in therapy.
However, any serious MS relapse, multiple relapses regardless of severity, or a pronounced increase in MRI activity with multiple new T2 lesions, particularly after more than six months on therapy, should prompt a review of treatment options with a predisposition to change the DMT.

Guidelines from the American Academy of Neurology suggest switching to another DMT for people with MS who are adherent to DMT therapy long enough for the treatment to take full effect when they experience one or more relapses, two or more unequivocally new MRI-detected lesions, or increased disability on examination over a one-year period. However, none of the available DMTs are definitively proven to reduce disability progression for patients who appear to have secondary progressive MS. This factor must be considered when deciding whether to switch to another DMT.

Question 68

Secondary progressive MS definition

Answer 68

This subtype of multiple sclerosis evolves from relapsing-remitting multiple sclerosis as the disease over time enters a stage of steady deterioration in function, unrelated to acute attacks. The change from RRMS to SPMS is a gradual process rather than an abrupt transition.

Although a clear consensus is lacking, one definition of SPMS requires that a patient with multiple sclerosis and a history of at least one clinical relapse (ie, RRMS) has a period of continuous disability progression of at least 6 to 12 months that is independent of clinical relapses

Question 69

When to stop DMT in SPMS

Answer 69

For patients with inactive disease (ie, no ongoing relapses or gadolinium-enhancing lesions on MRI of the brain and spinal cord) who have been nonambulatory for at least two years, it is reasonable to discuss stopping DMT.

Question 70

main mechanisms leading to accrual of disability

Answer 70

Relapse-associated worsening (RAW), defined as confirmed disability worsening over three to six months beginning within 90 days from the onset of a relapse (ie, incomplete recovery from a relapse).

Progression independent of relapse activity (PIRA), defined as confirmed disability worsening over three to six months with either no prior relapse or beginning more than 90 days after the start of the last relapse.