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Multiple Sclerosis

Multiple Sclerosis

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Basics of Demyelination/Remyelination
Demyelination
First, let’s illustrate what is meant by demyelination.
  • Myelin (formed by oligodendrocyte) is chewed up and broken down, hence it’s “de-myelinated”.
  • On histopathology, we see regions of pale, demyelination.
    • With Luxol fast blue staining (turns myelin blue) and Periodic acid-Schiff (PAS) (turns gray matter pink), the contrast with the rest of the myelin is much easier to appreciate when it is stained in this way.
Remyelination
  • Remyelination forms thin sheaths of myelin.
  • Regions of remyelination are called shadow plaques, due to the faint nature of their myelin compared to unaffected surrounding myelinated regions.
    • 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
Overview
  • 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.
Cerebrum
  • On gross pathology, we show 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
In addition to the periventricular predominate cerebral MS plaques that occur, the spinal cord (especially the cervical spinal cord) is often affected.
  • 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.
  • We 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 of Demyelination & Oligoclonal Bands
FLAIR (Fluid Attenuated Inversion Recovery) Sequence
  • We focus on the FLAIR sequence, since FLAIR (Fluid Attenuated Inversion Recovery) is the best sequence for viewing white matter pathology.
  • With FLAIR imaging, show that gray matter is a light gray; white matter is a dark gray; and CSF is dark.
    • It is essentially the same as the T2 sequence with one very important difference: the CSF is dark instead of bright; this helps distinguish the bright white matter lesions from normal CSF.
    • At the present time, MRI is the best test for the diagnosis of MS.
Key MRI Sequences:
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
  • We show periventricular, ovoid lesions, called Dawson’s fingers.
  • 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
  • We show 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.
  • Brainstem and cerebellar parenchymal lesions are also common given their large amounts of white matter.
Mimickers
Common non-autoimmune causes for white matter hyperintensities, including small vessel disease, migraine with aura, and large perivascular spaces (Virchow-Robin spaces).
  • 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 with aura is an important common cause of deep white matter lesions and infratentorial central pontine lesions.
  • 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.
CSF Oligoclonal Bands
  • CSF oligoclonal bands and elevated IgG synthesis measurements are characteristic CSF findings, albeit not exclusive to MS.
Acute Pathophysiology
Acute MS Attacks
Time-course
  • That these attacks generally occur over hours to days and recover (completely or incompletely) over weeks to months.
Retrobulbar optic neuritis
  • Retrobulbar optic neuritis is the presenting symptoms of MS in up to 40% of cases of MS.
  • In optic neuritis, the nerve, itself, is swollen. The optic nerve head itself is typically normal in MS optic neuritis: the neuritis lies behind the eye.
  • 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.
  • 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.
  • 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 in part 2, and more commonly non-arteritic anterior ischemic optic neuropathy (NA-AION).
Optic Neuritis Mimicker: Ischemic Optic Neuropathy
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
  • Internuclear ophthalmoplegia 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.
  • For example, 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
  • Transverse myelitis 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.
  • In MS it 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 is common finding: it’s a shock-like, electric sensation down the spine, which was at one time thought to be pathognomonic for MS.
  • 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, there is a reduction in attack frequency during pregnancy (although a rebound MS flare is also common postpartum).
Demyelination
  • MS plaques or lesions refer to areas of active demyelination.
  • The blood-brain barrier serves to separate the brain, immunologically, from the rest of the body (called immunologic privilege).
    • Thus, inflammatory mediators from the periphery must break-down the blood-brain barrier in order to attack the CNS.
Molecular Mimicry: Peripheral vs Central
Overview
  • There are two leading schools of thought regarding the molecular mimicry that triggers the formation of autoreactive lymphocytes:
Peripheral Hypothesis
  • The peripheral hypothesis is that peptides derived from infections, such as HSV, EBV, or influenza and trigger autoreactive T-cells towards myelin proteins, such as: myelin basic protein (MBP), proteolipid protein, and myelin oligodendrocyte glycoprotein (MOG).
Central Hypothesis
  • The central hypothesis is that CNS auto-antigens pass into regional lymph nodes and induce a peripheral immune response, which triggers a CNS attack.
Key Immune-Mediators in MS
Adaptive Immune System
  • From the adaptive immune system: B-cells and T-cells are recruited into the CNS via break-down in the blood brain barrier. Note that in MS, CD8+ T-cells are more numerous than CD4+ T-cells.
Innate Immune System
  • From the periphery, monocytes and macrophages are recruited to the CNS.
  • Within the CNS, microglia, are activated.
Pathogenesis
  • These key cellular mediators exert their pathogenesis, namely, via: phagocytosis, cytokine emission, and antibody secretion:
Phagocytosis
  • A selection of these cells especially the macrophages and microglia chew-up myelin proteins.
    • On histopathology, there is such a large ream of macrophages that the appearance bears the name, "sea of macrophages".
Cytokines
  • These cells secrete numerous cytokines (cell signaling proteins), including various interleukins (eg, Il-10, IL-17A, and IL-23), interferons (eg, IFN-gamma), tumor necrosis factor (TNF-alpha, THF-beta), and chemokines (eg, CCR1 through CCR6).
MS Histopathology
Some key histopathologic signatures of MS include:
  • Myelin protein products. Demyelinating plaques comprise varying myelin protein products at different stages: early on, minor myelin proteins are observed, whereas later-on, hydrophobic major myelin proteins are identifiable.
  • Perivascular and parenchymal inflammatory infiltrates.
  • Blood-brain barrier breakdown, which is observable on MRI as gadolinium enhancing lesions.
  • Reactive astrocytes: gemistocytic (plump), eosinophilic, and/or heavily mitotic.
  • Variable oligodendrocyte pathology. In early, active demyelination, there is simply a loss of oligodendrocytes. If degenerated oligodendrocytes are found, their cell bodies (like the astrocytes) are swollen and they tend to have a pale, poorly defined nucleus.
  • Shadow plaques. Oligodendrocytes are replaced during remyelination and the axons become covered with thin sheaths of myelin. Remyelinated lesions are called shadow plaques: due to the faint nature of their myelin compared to unaffected surrounding myelinated regions. We can remember that the remyelinated plaques are more faint when we consider that physiological stress can re-exacerbate old MS lesions, called Uhtoff phenomenon.
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). Repository corticotropin 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.
Efficacy of Immunesuppressants
  • It is important to note that not all MS attacks require treatment, as generally, it is believe that they hasten recovery but do not, necessarily, change the ultimate likelihood of recovery via remyelination. However, the landscape of MS treatment is changing quickly, as we address in part 2, and it's certainly possible that this mentality will change in time, as well.
Chronic Pathophysiology
Chronic Deficits in MS
Note that these can also present acutely, as an MS attack, but more commonly accrue over time.
Neurogenic Bladder
  • Neurogenic bladder can present with urinary retention (an inability to fully empty the bladder) and/or urinary incontinence (urinary leakage).
Cerebellar Deficits
  • The following are classically ascribed to the cerebellum but they can involve more widespread areas, including the brainstem, basal ganglia, and spinal cord.
  • We show a hand tremulously reaching outward in incoordination fashion in finger-to nose testing to illustrate incoordination and tremor.
  • We show a person with a wide-stance, seemingly off-balance to show ataxia, which can involve a patient’s gait, trunk, and/or limbs.
Cognitive Deficits
  • We show 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).
Chronic MS Histopathology
  • Much remains unknown about why neurodegeneration occurs in MS, but over time, in many instances, patients suffer a gradual deterioration of both gray and white matter.
  • On histopathology, we see areas of chronic demyelination, axonal transection, as well as neuronal and glial cell death.
  • Neurodegeneration is believed to either be a primary, separate, process or a secondary process due to chronic inflammation.
  • It's thought that chronic inflammation leads to the production of free radicals (such as reactive oxygen and nitrogen species) that lead to complex biochemical derangements, including oxidative injury, mitochondrial dysfunction, protein misfolding, alterations in ion channel function along axons, and lack of trophic support from myelin – ultimately leading to axon and neuronal death.
    • Neuronal death can occur due to axon pathology that triggers retrograde degeneration or anterograde degeneration that leads to loss of neuronal connectivity.
    • Or it can occur as its own, separate poorly understood process: since neuronal death occurs at regions without underlying demyelination, a separate pathophysiological process makes intuitive sense.
Chronic MS Pharmacotherapeutics
  • 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.
  • With this information as a background, now we can now address the current pharmacotherapeutics of MS, which act via chronic immune modulation.
We'll divide the available medications by their modes of administration:
  • Injectable medications
  • Oral medications
  • Intravenous infusions
Injectable Medications
  • 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 of Action
Interferon-beta (IFN-beta)
  • Down-regulates pro-inflammatory lymphoctyes and up-regulates regulatory T-cells.
Glatiramer acetate (GA)
  • Induces an anti-inflammatory T-cell response.
IFN-beta & GA
  • IFN-beta and GA act on lymphocytes; their mechanisms of action are far more complex than how we simplify them here and still not fully understood.
Side Effects
  • Common side effects for both of these drugs include injection site reactions.
  • Show that IFN-beta tends also can often produce flu-like symptoms, and depression.
  • Whereas indicate that 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
  • GA:
    • No specific monitoring is necessary for GA.
Oral medications
  • Three oral medications are currently available:
    • 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
  • It's too early to report on the side effect profile of ocrelizumab (it only received FDA approval in March of 2017); there is concern that breast cancer may ultimately be considered a potential side effect.
References
  • See the related Multiple Sclerosis tutorials.

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