Multiple sclerosis

Key concepts

An idiopathic demyelinating disease of the CNS producing exacerbating and remitting symptoms disseminated in space and time

Classic clinical findings

Optic neuritis
Paresthesias
INO
Bladder symptoms

Diagnostic criteria (McDonald criteria) use clinical and/or lab results (MRI, CSF…) to stratify patients as

MS
Probable MS
Not MS

Multiple usually enhancing lesions involving optic nerves & white matter of brain (especially periventricular white matter), cerebellum and spinal cord

Definition

An idiopathic demyelinating disease (thus affecting only white matter) of the cerebrum, optic nerves, and spinal cord (especially the corticospinal tracts and the posterior columns).

Does not affect peripheral myelin.
Pathologically produces multiple plaques of various age in diffuse locations in the CNS, especially in the periventricular white matter.
Lesions initially evoke an inflammatory response with monocytes and lymphocytic perivascular cuffing, but with age settle down to glial scars.

Numbers

Age of onset: 10–59 years

Greatest peak between ages 20–40 years.

F : M incidence is 2:1.27

Prevalence varies with latitude,

<1 per 100,000 near the equator,
≈ 30–80 per 100,000 in the northern U.S. and Canada.

Classification

Clinical categories

Category	Definition
Relapsing-remitting	Episodes of acute worsening with recovery and a stable course between relapses
Secondary progressive	Gradual neurologic deterioration ± superimposed acute relapses in a patient who previously had relapsing-remitting MS
Primary progressive	Gradual, nearly continuous neurologic deterioration from the onset of symptoms
Progressive relapsing	Gradual neurologic deterioration from the onset of symptoms, but with subsequent superimposed relapses

Common symptoms: visual disturbances (diplopia, blurring, field cuts or scotoma), spastic paraparesis, and bladder disturbances.

Nomenclature for the time course of MS is shown in

Relapsing-remitting MS

Most common pattern (≥ 70%) at onset
Has the best response to therapy
But >50% of cases eventually become secondary progressive MS.

Primary progressive MS

Only 10%
These patients tend to be older at onset (40–60 years) and frequently develop progressive myelopathy

Progressive relapsing MS is very uncommon

Deficits present > 6 months usually persist

Clinical signs and symptoms

Visual disturbances

Due to optic or retrobulbar neuritis

Presenting symptom of MS in 15% of cases
Occurs at some time in 50% of MS patients
The percentage of patients with an attack of optic neuritis and no prior attack that will go on to develop MS ranges from 17–87%
Symptoms: acute visual loss in one or both eyes with mild pain (often on eye movement).

Diplopia

May be due to internuclear ophthalmoplegia (INO) from a plaque in the MLF.

INO is an important sign because it rarely occurs in other conditions besides MS or brainstem stroke.

Motor findings

Extremity weakness (mono, para, or quadriparesis) and gait ataxia are among the most common symptoms of MS.

Spasticity of the LEs is often due to pyramidal tract involvement.

Scanning speech results from cerebellar lesions.

Tremor

Pathophysiology

Lesions in the cerebellum or cerebellar peduncles or cerebello-thalamo-cortical pathways based on its co-occurrence with other signs and symptoms such as dysarthria, dysmetria, dysdiadochokinesia, and dystonia

Sensory findings

Posterior column involvement often causes loss of proprioception.

Paresthesias of extremities, trunk, or face occur.

Lhermitte’s sign

Electric shock-like pain radiating down the spine on neck flexion
Common, but is not pathognomonic.

Trigeminal neuralgia occurs in ≈ 2%,

More often bilateral
Occurs at a younger age than the population in general.

Mental disturbances

Euphoria (la belle indifference) and depression occur in ≈ 50% of patients.

Reflex changes

Hyperreflexia and Babinski signs are common.

Abdominal cutaneous reflexes disappear in 70–80%.

GU symptoms

Urinary frequency, urgency, and incontinence are common.

Impotence in males and reduced libido in either sex is often seen.

Red flag symptoms to be excluded include:

Sensory changes, deafness, difficulty achieving pain control, poor response to carbamazepine, history of skin or oral malignancy that could lead to perineural spread, symptoms in ophthalmic distribution (more likely herpes zoster), under age of 40, symptoms suggestive of optic neuritis, family history of MS.

Differential diagnosis

Acute disseminated encephalomyelitis (ADEM): generally monophasic. May also have CSF-OCB. Corpus callosum involvement is uncommon

CNS lymphoma

Other closely related demyelinating diseases: e.g. Devic syndrome (p.1489)

Vasculitis

Encephalitis: patients are usually very ill

Chronic white matter changes: seen in older patients

Diagnostic criteria

Diagnosing MS after a single, acute remitting clinically isolated syndrome (CIS) is very risky. 50–70% of patients with a CIS suggestive of MS will have multifocal MRI abnormalities characteristic of MS.

The presence of these MRI abnormalities increases the risk of developing MS in 1–3 years (with greater prognostic significance than CSFOCB).

The more MRI lesions, the higher the risk.

Summary of 2017 McDonald criteria

Requires elimination of more likely diagnoses
Requires demonstration of dissemination of lesions in the central nervous system in space and time

Clinical presentation	Additional criteria to make MS diagnosis
…In a person who has experienced a typical attack/CIS at onset	ㅤ
- 2 or more attacks and clinical evidence of 2 or more lesions; OR - 2 or more attacks and clinical evidence of 1 lesion with clear historical evidence of prior attack involving lesion in different location	None. DIS and DIT have been met.
- 2 or more attacks and clinical evidence of 1 lesion	DIS shown by one of these criteria - Additional clinical attack implicating different CNS site - 1 or more MS-typical T2 lesions in 2 or more areas of CNS: periventricular, cortical, juxtacortical, infratentorial or spinal cord
- 1 attack and clinical evidence of 2 or more lesions	DIT shown by one of these criteria - Additional clinical attack - Simultaneous presence of both enhancing and non-enhancing MS-typical MRI lesions, or new T2 or enhancing MRI lesion compared to baseline scan (without regard to timing of baseline scan) - CSF oligoclonal bands
- 1 attack and clinical evidence of 1 lesion	DIS shown by one of these criteria - Additional attack implicating different CNS site - 1 or more MS-typical T2 lesions in 2 or more areas of CNS: periventricular, cortical, juxtacortical, infratentorial or spinal cord AND DIT shown by one of these criteria - Additional clinical attack - Simultaneous presence of both enhancing and non-enhancing MS-typical MRI lesions, or new T2 or enhancing MRI lesion compared to baseline scan (without regard to timing of baseline scan) - CSF oligoclonal bands
…In a person who has steady progression of disease since onset	ㅤ
1 year of disease progression (retrospective or prospective)	DIS shown by at least two of these criteria - 1 or more MS-typical T2 lesions (periventricular, cortical, juxtacortical or infratentorial) - 2 or more T2 spinal cord lesions - CSF oligoclonal bands

DIT = dissemination in time; DIS = dissemination in space; CNS = central nervous system; CSF = cerebrospinal fluid; T2 lesion = hyperintense lesion on T2-weighted MRI

Definitions

Attack (exacerbation, relapse)

Neurologic disturbance lasting > 24 hrs typical of MS when clinicopathological studies determine that the cause is demyelinating or inflammatory lesions
Each attack should be separated from another one by at least one month

Remission

≥ 30 days should separate the onset of the first attack from the onset of a second

Historical information

Reporting of symptoms by the patient (confirmation by observer desirable), adequate to locate a lesion of MS, and has no other explanation (i.e., manifestations must not be attributable to another condition)

Clinical evidence (signs)

Neuro dysfunction recorded by competent examiner

Paraclinical evidence

Tests or procedures demonstrating CNS lesion which has not produced signs; e.g. Uhthoff phenomenon or sign (worsening of symptoms with hot bath or shower), BAER, imaging procedures (CT, MRI), expert urological assessment

Typical of MS

Signs & symptoms known to occur frequently in MS. Thus excludes gray matter lesions, peripheral nervous system lesions, and non-specific complaints such as H/A, depression, convulsive seizures, etc.

Separate lesions

Signs & symptoms cannot be explained on basis of single lesion (optic neuritis of both eyes simultaneously or within 15 days represents single lesion)

Laboratory support

In this study, the only considerations were CSF oligoclonal bands (CSF-OCB) (see below) (OCB must not be present in serum) or increased CSF IgG production (CSF-IgG) (serum IgG must be normal). This assumes that syphilis, SSPE, sarcoidosis, etc. have been ruled out

Imaging

MRI

MRI is the preferred imaging study in evaluating MS and can demonstrate dissemination of lesions in time and space.

MRI criteria for diagnosing MS

See Mcdonald's criteria above
Dissemination in space

Dissemination in space requires ≥1 T2-hyperintense lesions (≥3 mm in long axis), symptomatic and/or asymptomatic, that are characteristic of multiple sclerosis in two or more of the four following locations 5

Periventricular (≥1 lesion, unless the patient is over the age of 50 in which case it is advised to seek a higher number of lesions)
Cortical or juxtacortical (≥1 lesion)
Infratentorial (≥1 lesion)
Spinal cord (≥1 lesion)

Notably, T2-hyperintense lesions of the optic nerve, such as those in a patient presenting with optic neuritis, cannot be used in fulfilling the 2017 revised McDonald criteria.

Dissemination in time

Dissemination in time can be established in one of two ways

A new T2-hyperintense or gadolinium-enhancing lesion when compared to a previous baseline MRI scan (irrespective of timing)
Simultaneous presence of a gadolinium-enhancing lesion and a non-enhancing T2-hyperintense lesion on any one MRI scan

Lesions

Normally >3mm diameter.
Multiple white matter abnormalities in 80% (compared to 29% for CT).

Lesions are high signal
Acute lesions tend to enhance with gadolinium more than old lesions do.

Periventricular lesions

May blend in with the signal from CSF in the ventricles on T2;
These lesions are shown to better advantage on FLAIR
These lesions are ovoid, are oriented perpendicular to the ependymal surface,

Dawson’s fingers

Spinal cord lesions

Normally show little or no swelling
Should be≥ 3mm but < 2 vertebral segments
Occupy only a portion of the cross-section of the cord
Must be hyperintense on T2.

Specificity of MRI is ≈ 94%

However, encephalitis as well as UBOs seen in aging may mimic MS lesions.

Should be normal;
However, plaques can sometimes exhibit “shine through”
The ADC map must be checked to rule out infarct.

Focal tumefactive demyelinating lesions (TDL)

May occur in isolation or, more commonly, in patients with established MS (often blotchy in appearance, but may appear as bull’s-eye targets in Balo’s disease AKA concentric sclerosis of Balo).
TDL may represent an intermediate position between MS and ADEM (Acute Disseminated Encephalomyelitis)
TDLs tend to be symmetric.
TDLs may enhance, and show perilesional edema (but less than MS) and thus be mistaken for neoplasms.
Biopsy results may be confusing.
MRS may not be able to differentiate from neoplasm.

CSF

CSF analysis can support the diagnosis in some cases, but cannot document dissemination of lesions in time or space. The CSF in MS is clear and colourless.

The OP is normal.

Total CSF protein is < 55mg/ dl in ≈ 75% of patients, and<108mg/dl in 99.7% (values near 100 should prompt a search for an alternative diagnosis).

The WBC count is

≤ 5 cells/mcl in 70% of patients,
Only 1% have a count> 20 cells/mcl

High values may be seen in the acute myelitis).

CSF-IgG

Is increased relative to other CSF proteins
In ≈ 90% of patients with MS,
Agarose gel electrophoresis shows a few IgG bands in the gamma region (oligoclonal bands) that are not present in the serum (higher resolution isoelectric focusing can demonstrate 10–15 bands).

CSF-OCB

Are not specific for MS, and can occur in CNS infections and less commonly with strokes or tumors.
CSF criteria for MS

Qualitative assessment of IgG is the most informative analysis and is best performed using IEF with some form of immunodetection (blotting or fixation)

Analysis should be performed on unconcentrated CSF and must be compared to simultaneously run serum sample in the same assay

Runs should use the same amount of IgG from serum and CSF

Each run should contain positive and negative controls

Quantitative analysis should be made in terms of one of the 5 recognized staining patterns for OCB

An individual experienced in the techniques should report the results

All other tests performed on the CSF (including WBC, protein & glucose, lactate) should be taken into consideration

Evaluation using light chains for immunodetection may be helpful in certain cases to resolve equivocal oligoclonal IgG patterns

If clinical suspicion is high but CSF results are equivocal, negative or show only a single band, consider repeating the LP

To measure IgG levels, nonlinear formulas that consider integrity of the blood-CSF barrier should be used (e.g. the ratio of CSF to serum albumin [AKA Qalb] is a measure of leakiness)

Labs analyzing CSF should have internal as well as external quality assessment controls

Quantitative IgG is a complementary test, but is not a substitute for qualitative IgG testing, which has the highest sensitivity and specificity

Treatment

Focused at reducing duration of relapses (acute) and reducing the frequency of relapses (disease modifying drugs) as there is no cure.

For acute relapses high dose steroids (e.g. oral or IV methylprednisolone) may be given for 3-5 days to shorten the length of an acute relapse, although they do not alter the degree of recovery (i.e. whether a patient returns to baseline function

Clinical and imaging features (focal lesion that does not exceed two vertebral segments in length and does not affect more than half the cross-sectional area of the cord) suggest relapsing-remitting MS with plaques in the cervical spinal cord. In general, current evidence suggests starting disease-modifying therapy at the point of diagnosis of relapsing-remitting forms of MS since damage continues to occur (based on MRI studies) even between relapses. As such, disease modifying therapy is used in those with “active” relapsing MS defined either as 2 or more relapses in the last 2 years or one recent relapse and/or signs of new lesions on MRI. Interferon beta 1a or 1b can be used in relapsing remitting MS, secondary progressive MS if there are still significant relapses and clinically isolated syndrome, but is contraindicated with deranged liver function. Glatiramer acetate may act as a myelin decoy for the immune system and is not contraindicated in liver dysfunction. Fingolimod is the only oral drug and is a sphingosine 1 phosphate receptor modulator affecting lymphocyte migration that has been proven to reduce number of relapses and slow the rate of number of new MRI lesions. However, it was also associated with increased incidence of varicella zoster, tumor formation, and progressive multifocal leucoencephalopathy (PML) hence reserved for patients who fail 1st line therapies. Similarly, while natalizumab is effective in modifying multiple sclerosis progression, it is also associated with PML and not considered a 1st line treatment. Mitoxanthrone is a chemotherapy agent that inhibits DNA synthesis and repair, associated with significant cardiotoxicity, reserved as last resort. Other problems may also need symptomatic treatment:

Fatigue—exclude common causes (e.g. anemia, hypothyroid or depression), amantadine, mindfulness training and CBT.

Spasticity—physiotherapy, baclofen, and gabapentin are first-line. Other options include diazepam, dantrolene, and tizanidine. Botox.

Bladder dysfunction—ultrasound first to assess bladder emptying. If significant residual volume → intermittent self-catheterization, whereas if no significant residual volume anticholinergics may improve urinary frequency.

Oscillopsia may respond to gabapentin.