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Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019
| Contributor Information
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Image from Dr. John Zajicek/Science Source.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS) that is characterized pathologically by inflammation, demyelination, and, ultimately, axonal loss. Diagnosis of MS is based on the concept of the disease's dissemination in both space and time. Although MS can be diagnosed on clinical grounds alone, magnetic resonance imaging (MRI) can be used to support or establish the diagnosis, as well as to track disease progression.
The colored scanning micrograph above shows microglial cells (yellow) ingesting branched oligodendrocyte cells (purple). Microglia normally ingest cell debris and bacteria as part of the immune response; in MS, they attack oligodendrocytes, which form insulating myelin sheaths around nerve axons in the CNS.
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
A previously healthy 35-year-old woman presents with an episode of gait imbalance that worsens over the course of several days. MRI of the brain is performed (shown). A diagnosis of MS is considered.
With regard to location, which of the following lesions are typical of MS?
Juxtacortical/cortical lesions
Periventricular lesions
Corpus callosal lesions
Brainstem and cerebellar lesions
All of the above
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
Answer: E. All of the above.
As shown in this slide, typical locations of MS lesions include juxtacortical/cortical (yellow arrows) and periventricular (red arrows) white matter, as well as the white matter of the brainstem, cerebellum, and spinal cord.[1] Periventricular lesions are frequently located along the callosal-septal interface and are perpendicularly oriented to the long axis of the corpus callosum. Although it was previously thought that cortical gray matter was spared, there is pathologic evidence of gray-matter involvement in MS[2] and cortical lesions can be seen, especially when using advanced imaging sequences. The 2017 McDonald criteria for MS changed the term juxtacortical to juxtacortical/cortical to reflect this.[3]
Image from Wikimedia Commons | Marvin 101.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
Macroscopic lesions seen on MRI correspond pathologically to areas of demyelination (ie, plaques). Acutely, these plaques are characterized by inflammatory T-cell infiltrate and myelin destruction.[1] The microscopic section pictured in this slide shows an acute plaque centered around a venule, with the absence of blue myelin stain and the presence of lymphocytic infiltrate.
Image from Medscape.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
MRI of this same patient also revealed an asymptomatic enhancing lesion in the right occipital corona radiata (shown).
Which of the following should be done before the patient is started on disease-modifying therapy (DMT)?
Await a second clinical event
Obtain a repeat MRI scan in 3 months to assess for development of new lesions
Perform a lumbar puncture to assess for oligoclonal bands (OCBs) and immunoglobulin G (IgG) index
See if the patient's symptoms fail to improve with a short course of intravenous (IV) methylprednisolone
None of the above; no delay in starting DMT is necessary
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
Answer: E. None of the above; no delay in starting DMT is necessary.
Even though this patient has had only one clinical attack, she meets the diagnostic criteria for dissemination in space (in this case, at least one periventricular lesion and one juxtacortical lesion) and in time (in this case, a nonenhancing lesion and an enhancing lesion).[3] DMT should be started as soon as possible to prevent a second clinical attack.
It is important to start DMT early in the course of MS, ideally when neurologic examination results are normal. These therapies do not affect existing impairments; rather, they are aimed at preventing new clinical and radiologic activity. Guidelines published in April 2018 by the American Academy of Neurology (AAN) advise consideration of early treatment. The AAN recommends discussion of the benefits and risks of DMT with adults who have had "a single clinical demyelinating event with 2 or more brain lesions that have imaging characteristics consistent with MS" and prescribing DMT if such patients then decide to undergo this treatment.[4,5]
Clinical relapses may either remit completely or leave a residual neurologic deficit. Over time, relapsing disease may transition into a secondary progressive course characterized by gradual accrual of disability in the absence of acute relapses.[6] The most typical MS course (shown) begins with a period of relapsing disease that is followed by a period of secondary progression. The ability of DMT to prevent the secondary progressive phase is hotly debated.
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
MRI of the cervical spine (shown) is obtained in a young woman who presents with tingling down her spine into her arms when she flexes her neck. MRI of the brain shows a few lesions, including several callosal and periventricular lesions. Her neurologist suspects clinically isolated syndrome with a high risk of conversion to clinically definite MS, but as part of a workup to exclude other possible causes, lumbar puncture and cerebrospinal fluid (CSF) analysis are performed.
Which of the following findings from CSF analysis would not be consistent with a diagnosis of MS?
White blood cell (WBC) count of 200/µL
Elevated IgG index
Presence of OCBs in CSF but not in serum
Slightly elevated protein
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
Answer: A. White blood cell (WBC) count of 200/µL.
The MRI scan of the cervical spine on slide 7 shows a single T2-hyperintense lesion at the C4 level with associated enhancement. The differential diagnosis of acute myelitis includes MS and other primary demyelinating diseases, such as neuromyelitis optica (NMO) and acute disseminated encephalomyelitis (ADEM), as well as infectious and rheumatologic processes. If no cause for the myelitis is found, a diagnosis of idiopathic myelitis can be made. A normal to minimally elevated CSF WBC count (≤20/µL) would be consistent with a diagnosis of MS; in contrast, dramatic pleocytosis in the range of 200/µL would instead suggest infection. A normal to minimally elevated protein level and an elevated IgG index are also CSF findings consistent with MS. The presence of OCBs in the CSF but not in serum (shown) is a sensitive but nonspecific marker for MS. In the most recent iteration of the MS diagnostic criteria, OCBs can be used as a proxy to establish dissemination in time.[3]
Image from Wikimedia Commons | Mick lucas (left); Medscape (right).
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
A 29-year-old man with relapsing-remitting MS develops right-side periorbital pain with eye movement, followed by blurry vision in the right eye the next day. He describes a darkened cloud over the center of his visual field (left image). After 3 days, the patient's vision is still blurry and he visits an ophthalmologist, who documents a visual acuity of 20/40 in the right eye and 20/20 in the left. The results of funduscopic examination appear normal. Visual field testing demonstrates a central scotoma of the right eye (right image).
Image from Medscape.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
MRI is performed and shows a contrast-enhancing lesion of the intracanalicular portion of the right optic nerve. A diagnosis of acute optic neuritis is made. Funduscopic examination at this time shows normal optic discs (shown). The patient is treated with a 5-day course of IV methylprednisolone, and partial improvement of his vision is noted.
Funduscopic examination performed 3 months later will most likely reveal which of the following?
Optic nerve swelling
Optic nerve pallor
Small-vessel hemorrhages
A and B
Image from Medscape.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
Answer: B. Optic nerve pallor.
In a case of acute retrobulbar optic neuritis, funduscopic examination usually reveals a normal-appearing optic disc (left). In the less frequent instance of acute bulbar optic neuritis, funduscopic examination may show optic disc edema. During the months following acute inflammation, the optic nerve thins, and this thinning manifests on funduscopic examination as a pale optic nerve head (arrow, right).
Image from Wikimedia Commons | Samir.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
A 25-year-old woman with no prior medical history presents with a complaint of acute-onset, painless double vision on leftward gaze; her vision is normal on rightward and primary gaze. She reports no other neurologic symptoms. Oculomotor examination reveals normal primary and rightward gaze. On leftward gaze, the patient is unable to adduct the right eye and has nystagmus of the abducting eye (shown).
Which of the following areas is the site of the lesion responsible for this patient's symptoms?
Splenium of the corpus callosum
Red nucleus
Left tegmentum
Right medial longitudinal fasciculus
Right third cranial nerve nucleus
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
Answer: D. Right medial longitudinal fasciculus.
Internuclear ophthalmoplegia with impaired ipsilateral adduction and contralateral abduction nystagmus is frequently seen in MS patients. This phenomenon results from demyelination in the medial longitudinal fasciculus, which is the white-matter tract connecting the nucleus of the third cranial nerve to that of the contralateral sixth cranial nerve, mediating lateral conjugate gaze. The image in this slide shows an acutely enhancing medial longitudinal fasciculus lesion (red arrow).
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
The MRI scan of this patient's brain also shows a few other characteristic MS lesions, and the decision is made to initiate DMT. The patient starts treatment and subsequently has no further neurologic events. MRI of her brain is repeated 1 year later; the T1 sequence with contrast is shown in this slide.
Which of the following is the most appropriate next course of action?
Continue the current treatment
Begin a course of IV methylprednisolone
Change the DMT
Test for urinary tract infection
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
Answer: C. Change the DMT.
This patient has multiple enhancing lesions (red arrows), which indicate that disease activity is ongoing despite treatment. Clearly, the current treatment is suboptimal, and continuation therefore is not warranted. There is no evidence supporting the use of steroids to treat asymptomatic enhancing lesions.
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
A 60-year-old man has had MS for 30 years. He has never taken disease-modifying agents. Since his last relapse, which occurred 15 years ago, he has experienced a continuous decline in function; for the past 10 years, he has had to use a wheelchair.
Which of the following MRI findings is/are indicative of long-standing or degenerative aspects of MS?
Whole-brain atrophy
T1-weighted hypointensities
Gadolinium enhancement
A and B
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
Answer: D. A and B.
Whole-brain atrophy is seen in many neurodegenerative processes, including long-standing MS. Persistent hypointensities on T1 sequences—so-called black holes (red arrows)—indicate axonal loss and neuronal tissue destruction. Gadolinium enhancement occurs during active inflammation, when there is destruction of the blood-brain barrier.[7]
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
A 41-year-old man with a history of relapsing MS develops acute left lower quadrantanopia and left-side numbness. MRI of the brain is performed (shown).
Which of the following is the most appropriate next step in management?
Give a course of IV steroids, and repeat imaging shortly thereafter
Perform a biopsy of the lesion as soon as possible to obtain a tissue diagnosis
Change the DMT
Repeat MRI in 1 year
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
Answer: A. Give a course of IV steroids, and repeat imaging shortly thereafter.
The brain MRI scans on slide 18 revealed a large enhancing right parieto-occipital lesion with associated edema (T2 fluid-attenuated inversion recovery [FLAIR] and T1 with contrast sequences). MS lesions can occasionally appear tumefactive and can be very difficult to distinguish from true malignancies. Ideally, biopsy of demyelinating lesions should be avoided whenever possible, because it can lead to permanent neurologic deficits. The best next step in this particular case would be to administer IV steroids and to follow the MRI closely to ensure resolution of the enhancement and associated edema. If the lesion does prove to be a tumefactive MS lesion, changing the DMT may be reasonable; however, assessing for malignancy would be the first priority.
Accordingly, a course of IV steroids is administered, and the patient experiences significant improvement in his symptoms. MRI performed 6 weeks later reveals reduction in the size of the lesion and resolution of contrast enhancement (shown), which would not be seen if the lesion were a malignant brain tumor.
Image courtesy of Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
A 45-year-old man with no prior medical history presents with complaints of gait impairment and increased tingling and tightness in both legs. He reports that the tingling and tightness developed about 5 years ago and has been getting progressively worse. He also reports gradual progression of weakness in his legs, most noticeably during the last 12 months, when he started using a cane. His neurologic exam shows increased tone and mild to moderate weakness in both lower extremities. MRI of the brain and cervical spine is performed and shows a few periventricular and juxtacortical lesions, as well as lesions in the cervical spine. As part of a diagnostic workup, lumbar puncture and CSF analysis are carried out, revealing the presence of 10 OCBs.
What is the most appropriate course of action for this patient?
Start treatment with ocrelizumab
No treatment is indicated in this case
Start treatment with glatiramer acetate
Start treatment with fingolimod
Image courtesy of Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
Answer: A. Start treatment with ocrelizumab.
This patient meets the 2010 McDonald Criteria for the diagnosis of primary progressive MS: 1 year of disease progression, dissemination in space in the brain and spinal cord (blue arrows), and the presence of OCBs in the CSF. The most appropriate action in his case is to start ocrelizumab.
In 2017, ocrelizumab, a humanized anti-CD20 antibody that selectively depletes CD20-expressing B cells, became the first agent approved by the US Food and Drug Administration (FDA) for the treatment of primary progressive MS.[8] The FDA approval was based on the results of the phase 3 ORATORIO trial, which showed lower rates of clinical and MRI progression with ocrelizumab versus placebo treatment.[9] Neither glatiramer acetate nor fingolimod, which were assessed in the PROMISe and INFORMS trials, have shown positive results in primary progressive MS.[10,11]
Image courtesy of Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
The course of primary progressive MS is shown in the above graph.
Although MS has historically been regarded as a T-cell disease, the contribution of B cells in MS pathology, including progressive disease, has become more prominently recognized. The proposed role of B cells in MS pathology includes antigen presentation, autoantibody production, and presence in the areas of meningeal inflammation. These areas, characteristic of chronic MS, may suffer cortical demyelination and neurodegeneration, prominent features of progressive disease.
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
A 23-year-old woman presents with upper-back pain, lower-extremity weakness and tingling, and urinary retention that developed over 2 days. In the emergency department (ED), a Foley catheter is inserted, and 2 L of urine is drained. MRI of the spine and brain is performed (shown).
Which of the following would constitute the most appropriate next step?
Check serum for aquaporin-4 antibody
Begin IV methylprednisolone
Begin interferon beta
A and B
A, B, and C
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
Answer: D. A and B.
The spinal MRI scan reveals an intramedullary lesion extending from T1 to T5 (red arrows); the brain MRI scan is normal. Longitudinally extensive cord lesions and optic neuritis (unilateral or bilateral, often severe) are characteristic of the demyelinating condition NMO. NMO is humorally mediated, characterized by the presence of a highly specific autoantibody against the aquaporin-4 water channel (known as NMO IgG Ab).[12] Accordingly, testing the serum for aquaporin-4 antibody is warranted in this case. As with MS, acute relapses may respond to treatment with steroids. To prevent relapses, immunosuppressive agents such as mycophenolate mofetil, rituximab, and azathioprine are typically used, rather than MS DMT. However, large well-controlled studies proving the efficacy of these agents are lacking.
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
One week after a viral upper respiratory tract infection, a 12-year-old boy presents to the ED with a history of several days of confusion and left-side weakness. T2 FLAIR MRI of his brain is performed (shown). Contrast T1 sequences show enhancement of the lesions.
Which of the following statements constitutes the most accurate assessment of this patient's prognosis and the most appropriate recommendation regarding DMT at this time?
The patient is likely to have benign MS and should not receive DMT
The patient is likely to experience relapses for many years before developing progressive disease and should be started on DMT
The patient is likely to have severe, progressive disease and should not receive DMT
The patient has a good chance of never experiencing another attack and should not receive DMT
Image courtesy of Rebecca Farber, MD, and Sylvia Klineova, MD, MS.
Multiple Sclerosis and Other Enemies of Myelin
Rebecca Farber, MD; Sylvia Klineova, MD, MS | June 18, 2019 | Contributor Information
Answer: D. The patient has a good chance of never experiencing another attack and should not receive DMT.
The patient probably has ADEM. This condition occurs most frequently in children, often after vaccination or infection, and typically presents in a polysymptomatic fashion that includes encephalopathy. MRI shows large confluent lesions, additional examples of which are shown above. The factors noted help to differentiate ADEM, which is typically monophasic, from a first attack of MS;[13] this patient should not receive DMT unless there is evidence of a second attack in the future.
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Multiple sclerosis (MS) is an immune-mediated inflammatory disease that attacks myelinated axons in the central nervous system, destroying the myelin and the axon in variable degrees and producing significant physical disability within 20-25 years in more than 30% of patients.Diseases/Conditions, May 2019
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Contributor Information
Rebecca Farber, MD
Assistant Professor of Neurology
Multiple Sclerosis Clinical Care and Research Center
Columbia University Irving Medical Center
New York, NY
Disclosure: Rebecca Farber, MD, has disclosed no relevant financial relationships.
Sylvia Klineova, MD, MS
Assistant Professor of Neurology
The Corinne Goldsmith Dickinson Center for Multiple Sclerosis
Icahn School of Medicine at Mount Sinai
New York, NY
Disclosure: Sylvia Klineova, MD, MS, has disclosed the following relevant financial relationships: has received compensation for advisory board work for Teva, Genentech, and Biogen Idec and has given nonpromotional lectures with Biogen Idec.
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References
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Thompson AJ, Banwell BL, Barkhof F et al. Diagnosis of multiple sclerosis: 2017 revisions to the McDonald criteria. Lancet Neurol. 2018; 17(2):162-173 PMID: 29275977
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