Multiple Sclerosis (MS)

Sections

General Information
Pathophysiology
MRI Imaging in MS
Clinical Conditions
Diagnostic Modalities
Treatment
References

Multiple Sclerosis

General Information

Overview

Definition

Multiple sclerosis pathology involves inflammatory attacks of central nervous system demyelination that are separated in time and space.

MS can ultimately evolve into a chronic state of inflammation and neurodegeneration of both gray and white matter.

Thus, it can start as a disease of isolated motor/sensory attacks and end as a disabling, progressive dementia.

Relapsing-Remitting vs Progressive

The disease has a relapsing-remitting pattern in roughly 85% of cases and a progressive pattern in the other 15%.

Progressive disease can be primary, meaning it starts out that way, or it can be secondary, meaning it transforms from relapsing-remitting to progressive. Note that you may also see the term: relapsing-progressive.

As a helpful heuristic, we can think of relapsing-remitting disease as being secondary to demyelination and progressive disease as being caused by axonal damage.

Clinically Isolated Syndrome

Clinically isolated syndrome is a single clinical attack.

Radiographically Isolated Syndrome

Radiographically isolated syndrome refers to a situation wherein there are white matter lesions that fulfill certain diagnostic criteria for MS but there's no history of a clinical attack.

In essence, this condition fulfills dissemination in space but not in time.

Pathophysiology

Demyelination

Demyelination

Show a neuron and an oligodendrocyte wrapping myelin around the axon; much of the myelin appears chewed up and broken down, hence it's "de-myelinated".

Show a coronal section through a section of brain stained with:

• Luxol fast blue, which turns myelin blue.
• Periodic acid-Schiff (PAS), which turns gray matter pink.

Within it, draw a region of pale, demyelination: the contrast with the rest of the myelin is much easier to appreciate when it is stained in this way.

Remyelination

Remyelination

Our goal is for demyelinated axons to become remyelinated.

Draw an oligodendrocyte wrapping around an axon but here show that it's covered in thin sheaths of myelin.

As a correlative, redraw our coronal section and show a pale blue in the former region of demyelination.

Shadow plaques

Regions of remyelination are called a shadow plaques, due to the faint nature of their myelin compared to unaffected surrounding myelinated regions.

Uhthoff's phenomenon

We can remember that the remyelinated plaques are more faint when we consider that physiological stress can re-exacerbate old MS lesions, called Uhthoff's phenomenon.

Gross Pathology

Neurodegeneration

Multiple sclerosis is broadly considered a CNS demyelinating disorder wherein inflammatory events (for still unknown reasons) trigger a demyelinating process that ultimately evolves into chronic inflammation and neurodegeneration of both gray and white matter.

Gray matter atrophy / Demyelinating Plaques

On gross pathology, draw a coronal section through a shrunken, atrophic brain that bears just a thin layer of gray matter and is riddled with numerous demyelinated plaques: we draw them as yellowish in color and they are soft in texture. This is the unfortunate end-outcome of multiple sclerosis when the disease is aggressive and uncontrolled: neurodegeneration occurs in addition to the underlying demyelination (ie, patients can suffer a gradual deterioration of both gray and white matter).

Note that the range of disease is wide and MS can be a very benign disorder with limited worsening over many decades. Thus, goals of therapy are a chronic reduction in inflammation, augmentation of remyelination, and a suppression of neurodegeneration.

Spinal cord lesions (esp. cervical & thoracic)

In addition to the periventricular predominate cerebral MS plaques that occur, the spinal cord, especially the cervical spinal cord (and to a lesser extent the thoracic cord) is often affected. Remember that within the cervical spinal cord, all of the descending motor white matter tracts are present and then compiling ascending sensory white matter tracts are present, so the white matter to gray matter ratio is large. As opposed to the lumbar spine cord where the opposite is true.

Show distinct, multifocal regions of demyelination within the white matter and also show that the neurodegeneration also extends into the gray matter (albeit to a lesser extent).

MRI Imaging in MS

White Matter Hyperintensities

FLAIR

We'll focus on the FLAIR sequence, since FLAIR (Fluid Attenuated Inversion Recovery) is the best sequence for viewing white matter pathology.

MRI Review

T1

• Gray matter – Gray
• White Matter – Light Gray
• CSF – Dark

T2

• Gray matter – Light Gray
• White Matter – Dark Gray
• CSF – Bright

FLAIR

• Gray matter – Light Gray
• White Matter – Dark Gray
• CSF – Dark

Common Demyelinating Lesions

Dawson's fingers

Draw periventricular, ovoid lesions, called Dawson's fingers.

Show that they are perpendicularly oriented to the lateral ventricles; this is because the cerebral veins run in perpendicular to the lateral ventricles.

Perivenular inflammation and blood-brain barrier breakdown is a key aspect of MS pathophysiology (it allows for entry of peripheral immune mediators into the immune-privileged CNS), so these periventricular, perpendicularly-oriented lesions is are common and important.

Fresh, active MS lesions will often contrast enhance due to the active inflammatory breakdown at the site of the venules; thus, the T1 with contrast sequence can help identify acute, contrast enhancing lesions.

Brainstem & Cerebellar Lesions

Draw a middle cerebellar peduncle lesion, which is common in MS because large bundles of white matter motor pathways relay from the cortex into the cerebellum for pre-motor processing.

Draw brainstem and cerebellar parenchymal lesions, as well, which are also common given their large amounts of white matter.

MRI Mimickers

Common non-autoimmune causes for white matter hyperintensities, including small vessel disease, migraine with aura, and large perivascular spaces (Virchow-Robin spaces).

Small vessel disease

White matter hyperintensities due to small vessel disease (arteriosclerosis) are more common than not in individuals 60+. These hyperintensities appear in vascular end-zones and can have a periventricular or central pontine localization.

Migraine

Migraine with aura is an important common cause of deep white matter lesions and infratentorial central pontine lesions.

Perivascular spaces

Perivascular spaces (Virchow-Robin spaces) surround the walls of vessels and can become dilated, which creates an appearance of hyperintensities in spaces where we don't expect to see CSF.

CSF is bright on T2 imaging, so dilated perivascular spaces can give an appearance of white matter lesions, similar to the perivenular inflammation from MS.

FLAIR sequencing helps with this distinction, since CSF is dark on FLAIR. Thus, while MS lesions will be bright on FLAIR, perivascular spaces (filled with CSF) will be dark.

Clinical Conditions

Epidemiology

Female Gender. Temperate Climates.

From an epidemiological standpoint, MS is three times more common in women than in men and that living in a more temperate (northern) climate confers a substantially increased risk of developing the disease.

Disease Terminology

Relapsing-remitting MS (RRMS)

RRMS refers to clearly defined attacks of new or worsening neurologic symptoms: called relapses or exacerbations. Generally, they partial or complete recovery follows the attacks: called remissions. Unfortunately, some symptoms may become permanent. ~ 85% of cases of MS are of the RRMS form at the time of diagnosis.

Clinically Isolated Syndrome (CIS)

CIS is a first episode of CNS demyelination but does not yet meet the criteria for a diagnosis of MS and may or may not go on to ultimately develop MS.

Radiologically Isolated Syndrome (RIS)

RIS represents the finding of MS-like disease on radiographic imaging without having had associated clinical findings. Just as with CIS, patients with RIS may or may not go on to ultimately develop MS.

Secondary progressive MS (SPMS)

SPMS represents a transition from RRMS to a secondary progressive course in which there is a steady worsening and accumulations over time.

Primary progressive MS (PPMS)

PPMS is essentially a progressive accumulation of neurological dysfunction without ever having gone through a period of RRMS. ~ 15% of cases of MS are PPMS form at the time of diagnosis.

MS Attacks

Acute Attacks

Now, that we've seen some of the regions of demyelination, let's look at some common clinical presentations of MS attacks; note that these attacks generally occur over hours to days and recover (completely or incompletely) over weeks to months.

It is important to remember that MS (unlike ADEM, which we'll address in part 2), involves neurological attacks that are separated in TIME and SPACE.

Retrobulbar optic neuritis

First, retrobulbar optic neuritis, which is presenting symptoms of MS in up to 40% of cases of MS.

Draw a pair of eyes and optic nerves but show that one of the nerves is swollen; note that the optic nerve head itself is typically normal in MS optic neuritis: the neuritis lies behind the eye.

Indicate that retrobulbar optic neuritis commonly presents (> 90%) with periocular or retro-ocular "gritty" pain with eye movement, followed by loss of vision that can be mild to total (no light perception) – visual blurring is commonly described as like a "fogged window pane" or "smudged eyeglasses." Contrast perception and color vision are also commonly affected.

Relative afferent pupillary defect (RAPD)

Indicate that on exam, a relative afferent pupillary defect (RAPD) is commonly found. Note that this is a relative finding and prior injury to the other eye may make both eyes equally poor constrictors. As mentioned, initially, there is most often no optic disc abnormality (the neuritis is behind the eye: "retrobulbar"); however, within several weeks, optic pallor and atrophy develop.

Indicate that by definition, the majority of patients with optic neuritis in MS will recover completely or almost completely.

This is an important differentiating feature from NMO, which we address separately, and more commonly non-arteritic anterior ischemic optic neuropathy (NA-AION).

Ischemic Optic Neuropathies

Non-arteritic anterior ischemic optic neuropathy (NA-AION):
NA-AION is an important vascular cause of vision loss that can mimic MS optic neuritis but has key differentiating features.

It is due to poor perfusion via the posterior ciliary arteries due to a dip in perfusion pressure (most commonly) or an embolism to the posterior ciliary artery (less commonly) and causes painless vision loss with poor recovery.

It typically occurs in patients over the age of 50 versus MS, which typically presents in patients 20 – 50 years old.

Arteritic anterior ischemic optic neuropathy (A-AION):
The the inflammatory counterpart to NA-AION is arteritic anterior ischemic optic neuropathy, which stems from the inflammatory condition giant cell arteritis (also called temporal arteritis because it affects the temporal arteries); A-AION occurs in the elderly (average age of onset: 72).

Internuclear ophthalmoplegia

Next, let's show internuclear ophthalmoplegia, which is one of the most common exam findings in MS and is due to brainstem injury to the medial longitudinal fasciculus (MLF) injury; elsewhere we address this circuitry in detail.

Show that in a left MLF injury, the right eye is able to abduct successfully albeit with horizontal nystagmus (presumably because of the divergence that occurs from the left eye adduction failure) but the left eye is unable to adduct.

Patients experience diplopia and nystagmus as well as visual blurring.

Acute partial transverse myelitis

Now, indicate transverse myelitis, (specifically acute partial transverse myelitis). As we'll learn elsewhere, complete, longitudinally extensive transverse myelitis is more typical for NMO.

Draw a patient with a thoracic level transverse myelitis, which in MS is typically a painless, gradually ascending numbness that rises to the level of the myelitis.

Sensory symptoms commonly include a feeling of "wearing wet socks" or tightening like a cord is synching the abdomen, or like a shot of Novocain all over.

Indicate that in MS in is typically bilateral and with partial sensory modality loss.

Select modalities are more affected than others: especially large-fiber modalities since MS tends to affect the posterior spinal cord more so than the anterior.

L'hermitte's sign

Then, indicate that L'hermitte's sign is common finding: it's a shock-like, electric sensation down the spine, which was at one time thought to be pathognomonic for MS.

Finally, indicate that over time, paraplegia can develop, along with pyramidal tract signs: brisk and pathologic reflexes (presence of Babinski signs) and motor spasticity.

Reduction of Attacks in Pregnancy

Importantly, indicate that it is well known that there is a reduction in attack frequency during pregnancy (although a rebound MS flare is also common postpartum).

Chronic Deficits in MS

Neurogenic bladder

Neurogenic bladder can present with urinary retention (an inability to fully empty the bladder) and/or urinary incontinence (urinary leakage).

Cerebellar deficits

Note that although these findings are classically ascribed to the cerebellum, they can involve more widespread areas, including the brainstem, basal ganglia, and spinal cord.

Show a hand tremulously reaching outward in incoordination fashion in finger-to nose testing to illustrate incoordination and tremor.

Next, show a person with a wide-stance, seemingly off-balance to show ataxia; indicate that it can involve a patient's gait, trunk, and/or limbs.

Cognitive deficits

Draw an atrophic brain and indicate fatigue and memory loss (these findings do not necessitate brain atrophy to occur, however, and can simply be an early symptom of MS).

The goals of therapy are to reduce the inflammatory and degenerative pathophysiology of MS and promote remyelination for recovery; we address these in the MS pathophysiology and pharmacology tutorial.

Diagnostic Modalities

MRI

T2 Hyperintensities

MRI is the gold standard. We look for T2 sequence hyperintensities in characteristic places.

MS diagnostic criteria (so-called McDonald criteria) focus on finding evidence of disease that is disseminated in time and space. This involves assessing attack history, spread and acuity of MRI lesions, and using additional diagnostic modalities.

Additional Modalities

These diagnostic modalities include CSF oligoclonal bands, evoked potentials, and assessing serologies for MS mimickers (see DDx below).

CSF Oligoclonal Bands

An abnormal number of CSF oligoclonal bands and abnormally elevated IgG synthesis measurements are characteristic CSF findings in MS, albeit neither exclusive to MS no sufficient on their own to make the diagnosis of MS.

Differential Diagnosis

Notable Mimickers

Mimickers include rheumatologic illness (eg lupus), infectious disease (eg,), nutritional deficiencies (B12 and Copper deficiency), degenerative disease (eg primary lateral sclerosis), genetic disease (CADASIL), vascular disease (small vessel arteriopathy, Virchow-Robins spaces), and the migraine findings in migraine MRI findings can be very similar to those in MS.

Treatment

General Information

Acute, Symptomatic

Acute, symptomatic treatment involves IV steroids (especially important for optic neuritis -- evidence exists that optic neuritis can be worsened with oral steroids), oral prednisone for select attacks.

Chronic Therapies

Consider that the goals of therapy at this time are a chronic reduction in inflammation, augmentation of remyelination, and suppression of neurodegeneration but that the agents that are available at these time are generally focused on the reduction of chronic inflammation.

We can divide MS therapies into older, low efficacy treatments (interferon-beta, glatiramer acetate) and modern, high efficacy treatments: (such as, oral treatments, such as fingolimod) and IV treatments (eg, ocrelizumab). Note that there has been rapid development of monoclonal antibody treatments in the management of MS.

Symptomatic Management

Finally, note that MS management especially involves symptom-focused treatments such as for urinary incontinence and mental fatigue.

Vitamin D

We need to use Vitamin D supplementation (as mentioned, northern areas that produce vitamin D deficiencies confer an increased risk of MS).

Acute Immune Suppression

Methylprednisolone

The foremost treatment is intravenous methylprednisolone (typically 1 gram per day for 5 days), followed by oral prednisone taper (often for 2 – 3 weeks).

• Side effects of brief, high-dose steroids include: anaphylaxis, osteonecrosis/avascular necrosis, psychosis, severe mood alteration, insomnia, GI distress, and myalgias.

Prednisone

Alternatively, oral prednisone, alone, (starting at 60 – 80 mg/day with a 2 – 3 week taper) is used in less severe attacks.

• Importantly, however, attacks of optic neuritis should not be treated with oral prednisone alone (without a methylprednisolone burst), as this was shown to have deleterious effects in the "Optic Neuritis Treatment Trial."

ACTH (repository corticotropin injection)

Injectable ACTH (repository corticotropin injection) is a first-line treatment in infantile spasms and is used in MS, albeit far less commonly than meythlprednisolone or prednisone, mostly due to cost.

• Repository corticotropin is generally thought to have similar effect to corticosteroids due to its steroidogenesis but may have additional downstream effects, as well.

Specific MS Therapies

Injectables (Older, Lower Efficacy)

Overview

The injectable medications became available were the first to hit the market, they became available in 1993.

• Generally, these are considered the least efficacious of the drugs now used but because they have been available for over twenty-five years and because of their well accepted safety profile, many patients remain on them.

Mechanisms

Interferon-beta (IFN-beta) down-regulates pro-inflammatory lymphoctyes and up-regulates regulatory T-cells (simplified mechanism).
Glatiramer acetate (GA) induces an anti-inflammatory T-cell response (simplified mechanism).

Side Effects

Common side effects for both of these drugs include injection site reactions.

• IFN-beta tends also can often produce flu-like symptoms, and depression.
• GA can often cause a systemic allergic response.

Monitoring
Monitoring for IFN-beta includes:

• Intermittent complete blood count (CBC) and Liver function tests (LFTs)
• Thyroid testing
  Monitoring for GA:
• No specific monitoring is necessary for GA.

Oral medications

Overview

Here, we will address:

• Teriflunomide
• Dimethyl fumarate (DMF)
• Fingolimod

On the whole, these medications are considered to be more effective than the injectables; fingolimod, specifically, is the most effective of the three.

As we'll see, however, it has widespread effects throughout the body and, thus, getting patients started on it is more challenging than with teriflunomide or dimethyl fumarate and its side effect profile is more worrisome.

Teriflunomide

Mechanism of Action

Teriflunomide reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase, which is fundamental to the de novo pyrimidine synthesis pathway, thus it targets proliferating lymphocytes.

Side Effects

Teriflunomide is category X (it's highly teratogenic) and its presence in seminal fluid means that warning about its teratogenicity extends to male patients, as well. Additional common side effects are hair thinning and diarrhea.

Monitoring

Prior to starting teriflunomide, the following tests are recommended:

• CBC and CMP
• Pregnancy test
• TB testing.
  LFTs are recommended every 6 months.

Dimethyl fumarate (DMF)

Mechanism of Action

Dimethyl fumarate (DMF) preferentially depletes CD8+ T-cells (more so than CD4+ T-cells). We recall that CD8+ T-cells outnumber CD4+ T-cells in MS, so there is good rationale for its use.

Side Effects

A common side effect is flushing (aspirin can help treat this), along with GI upset, and lymphopenia. DMF does confer a very low risk of progressive multifocal leukoencephalopathy (PML), which we address at the end.

Monitoring

CBC should be checked prior to starting DMF and periodically thereafter.

Fingolimod

Mechanism of Action

Fingolimod prevents lymphocyte egress from lymph nodes via modulation of lymphocyte sphingosine-1-phosphate (S1P) receptors. This causes the lymphocytes to redistribute to secondary lymphoid tissues (eg, tonsils and spleen), out of circulation.

Side Effects

Sphingosine-1-phosphate receptors are common throughout the body, so in combination with the lymphopenia that results from fingolimod, numerous side effects can occur.

• These risks include: varciella-zoster virus (VZV), macular edema, bradyrhythmia, and basal cell carcinoma.
• There is a very low risk of PML with fingolimod, as well, albeit slightly higher than with dimethyl fumarate (we address this in detail at the end).

Monitoring

Because of the side effect profile, testing surrounding fingolimod is quite extensive, as follows:

• CBC and LFTs as screening and periodically while on treatment.
• Varicella zoster IgG (vaccinate patient, if non-immune), as opportunistic infections can arise from the lymphopenia (notably, varicella zoster infection and cryptococcal infection).
• EKG and first-dose heart rate monitoring for bradyrhythmia
• Ocular exam for macular edema as a screening, three months following initiation, and periodically thereafter.
• Skin assessment periodically for basal cell carcinoma.

Intravenous Infusions

Natalizumab

Mechanism of Action

Natalizumab is a human monoclonal antibody to alpha4 integrin. It blocks lymphocyte migration across the blood-brain barrier.

Side Effects

The risk of PML from natalizumab is the highest of the MS drugs that are commonly used and is its most notable side effect.

Monitoring
Prior to initiation and every 3 to 6 months, check:

• Liver function tests (LFTs)
• Anti-JC virus antibody

Ocrelizumab

Mechanism of Action

Ocrelizumab is a human monoclonal antibody to CD20, which causes depletion of B-cells that present the CD20 receptor.

Side Effects

There is concern that breast cancer may ultimately be considered a potential side effect.

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