Multiple Sclerosis
Multiple Sclerosis
Overview
Multiple sclerosis is 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.
We cover important details of multiple sclerosis presentation, diagnosis, and treatment in the Multiple Sclerosis whiteboard tutorial.
Acute MS Attacks
Time-course
- 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).
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).
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).
Incoordination/Ataxia
- Intention tremor, especially identifiable on finger-to nose testing.
- Ataxia, which can involve a patient’s gait, trunk, and/or limbs.
Cognitive Deficits
- Fatigue and memory loss can simply be an early symptom of MS or a consequence of chronic disease.
Basics of Demyelination/Remyelination
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.
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.
Common Demyelinating Lesions
Dawson's fingers
- Periventricular, ovoid lesions, called Dawson’s fingers, 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
- Brainstem, cerebellar parenchymal, and cerebellar peduncular lesions are 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 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."
Chronic MS Pharmacotherapeutics
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 cover comprehensive details of multiple sclerosis pathophysiology in the Multiple Sclerosis Pharmacology whiteboard tutorial.
Clinical Management Vignettes
Symptom Management
Vignette
22-year-old with vision loss