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Multiple Sclerosis for the Non-Specialist

Multiple Sclerosis for the Non-Specialist. Keith Cushing, M.D. Board Certified, Neurology JWM Neurology. Disclosures:. None. Topic Outline: Multiple Sclerosis. Epidemiology and Demographics Pathophysiology Diagnosis and Differential Treatment Options. MS: A brief history.

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Multiple Sclerosis for the Non-Specialist

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  1. Multiple Sclerosis for the Non-Specialist Keith Cushing, M.D. Board Certified, Neurology JWM Neurology

  2. Disclosures: None

  3. Topic Outline: Multiple Sclerosis • Epidemiology and Demographics • Pathophysiology • Diagnosis and Differential • Treatment Options

  4. MS: A brief history first described by French neurologist Charcot in 1868: “la sclérose en plaques disséminées” named for the scattered, firm, sclerotic plaques seen post-mortem in the brain and spinal cord

  5. Epidemiology and Demographics more common in women than men mean age of onset 30 years peak age of onset 5 years earlier in women than men Source: Up-to-Date,” Epidemiology and clinical features of multiple sclerosis in adults”

  6. Epidemiology and Demographics incidence and prevalence varies geographically • high prevalence areas • all of Europe, including Russia • southern Canada • northern U.S. • New Zealand • southeast Australia • lowest risk • people of Asian, African, or American Indian origin • supposed latitudinal gradient of MS incidence has been recently challenged Source: Up-to-Date,” Epidemiology and clinical features of multiple sclerosis in adults”

  7. Epidemiology and Demographics no association between vaccines and MS though many viruses, including EBV, have been linked, there is no specific evidence linking them directly to the development of MS Source: Up-to-Date,” Epidemiology and clinical features of multiple sclerosis in adults”

  8. Epidemiology and Demographics Genetic factors appear to contribute to the pathogenesis of MS, particularly variation involving the HLA-DRB1 locus Chronic cerebrospinal venous insufficiency has been reported in some patients with MS but its relationship to MS is controversial Source: Up-to-Date,” Epidemiology and clinical features of multiple sclerosis in adults”

  9. Natural History • Progression of disability due to MS is highly variable, but accumulating evidence suggests that progression in most patients with MS is slow. • At the extreme ends of the severity spectrum, there are benign and malignant forms of MS. Source: Up-to-Date,” Epidemiology and clinical features of multiple sclerosis in adults”

  10. Natural History • Benign MS refers to disease in which the patient remains fully functional in all neurologic systems 15 years after the disease onset. • Malignant MS refers to disease with a rapid progressive course, leading to significant disability in multiple neurologic systems or death in a relatively short time after disease onset Source: Up-to-Date,” Epidemiology and clinical features of multiple sclerosis in adults”

  11. MS Pathophysiology

  12. MS: Pathophysiology the precise etiology of MS has not yet been determined pathologic hallmark is multiplefocal areas of myelin loss within the CNS it is these areas that are referred to as plaques or lesions Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.

  13. Pathophysiology myelin loss is typically accompanied by gliosis and inflammation and by relative preservation of the axons Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.

  14. Pathophysiology active MS lesions are infiltrated by macrophages containing myelin debris Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.

  15. Pathophysiology lymphocytic inflammatory infiltrates in MS are composed mainly of CD8+ cytotoxic T cells less so, CD4+ helper T cells, B cells, and plasma cells Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.

  16. Pathophysiology Gadolinium MRI enhancement characterizes lesions with a damaged blood-brain barrier, which enables the infiltration of inflammatory cells into the CNS Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.

  17. Pathophysiology: Heterogeneity active lesions show a profound pathologic heterogeneity and can be classified into four immunopatterns, suggesting that the targets of injury and the mechanisms of demyelination are distinct in different disease subgroups Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.

  18. Pathophysiology: Axonal Injury • Although demyelination appears to be the dominant process, axonal injury occurs in multiple sclerosis and is most pronounced during active inflammatory demyelination • acute axonal injury occurring in early multiple sclerosis lesions likely contributes to the relapse-related disability observed predominantly during the inflammatory disease phases Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.

  19. Pathophysiology • neurodegeneration is present in demyelinated lesions and is invariably associated with inflammation • in chronic inactive lesions from aged patients with long-standing progressive multiple sclerosis where the inflammatory process has died out, the neurodegeneration is also reduced to levels seen in control patients. Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.

  20. Pathophysiology Extensive remyelination, illustrated by the presence of newly formed myelin sheaths and oligodendrocyte precursor cells, is frequently encountered within active plaques of early multiple sclerosis. Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.

  21. Pathophysiology • Cortical demyelinated lesions are present and common in early multiple sclerosis • these lesions are highly inflammatory • they may represent the pathologic substrate of cognitive impairment and epilepsy in relapsing-remitting multiple sclerosis. Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.

  22. Pathophysiology • The presence of inflammatory cortical demyelination in early multiple sclerosis argues against a primary neurodegenerative process at this stage of disease • this process suggests that neuronal and axonal injury in early cortical demyelination occur on a background of inflammation. Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.

  23. Pathophysiology • Meningeal inflammation is present in early multiple sclerosis and topographically associated with cortical lesions • it may drive the cortical demyelination but also set the stage for subsequent subcortical white matter inflammation and demyelination. Popescu, Bogdan F. Gh. MD, PhD; Pirko, Istvan MD, FAAN; Lucchinetti, Claudia F. MD, FAAN. Pathology of Multiple Sclerosis: Where Do We Stand?. CONTINUUM: Lifelong Learning in Neurology. 2013; 19: (4): 901-921.

  24. MS: Diagnostic Subtypes • relapsing-remitting • primary progressive • secondary progressive

  25. Diagnosis and Differential The majority of patients diagnosed with multiple sclerosis (MS) (80% to 85%) follow an initial relapsing-remitting course characterized by episodes with fairly rapid onset of new or recurrent neurologic deficits followed by partial or complete recovery. Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  26. Diagnosis and Differential: The Bible McDonald Criteria • first published in 2001 • 2005 revision • 2010 revision Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  27. Diagnosis and Differential • All recent formulations of the diagnostic criteria begin with an initial clinical presentation that includes symptoms typical for a multiple sclerosis attack (also called a relapse or exacerbation) • This initial presentation has been termed the “clinically isolated syndrome” (CIS) Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  28. Diagnosis and Differential The McDonald 2010 panel defined an attack as: • patient-reported symptoms or objectively observed signs typical of an acute inflammatory demyelinating event in the CNS • current or historical • with duration of at least 24 hours • in the absence of fever or infection Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  29. Diagnosis and Differential For paroxysmal symptoms (such as paroxysmal dysarthria, tonic spasms, or paroxysmal sensory symptoms) to be considered an attack, symptoms must be recurrent over at least 24 hours. Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  30. Diagnosis and Differential Once multiple sclerosis has been established as the most likely etiology of the symptoms, the clinician must evaluate for evidence of: • dissemination in space, which requires involvement of multiple areas of the CNS • dissemination in time, which requires ongoing disease activity over time. Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  31. Diagnosis and Differential DIS criteria may be satisfied on clinical grounds alone if the patient has: • objective clinical evidence of involvement of at least two CNS sites • or objective clinical evidence of one lesion with reasonable historical evidence of another site being affected. Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  32. Diagnosis and Differential Objective clinical evidence may include: • findings on neurologic examination • abnormal visual evoked potentials in a patient with a history of visual loss • evidence of a demyelinating lesion on MRI that would explain prior symptoms. Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  33. Diagnosis and Differential • If there is only objective clinical evidence of one lesion, DIS may be established by applying the MRI criteria. • The revised McDonald 2010 DIS MRI criteria are based on recommendations from the European multicenter collaborative research network that studies MRI in MS (MAGNetic Resonance In Multiple Sclerosis, or MAGNIMS) Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  34. Diagnosis and Differential Dissemination-in-space MRI criteria now require at minimum only two lesions: at least one T2 lesion in at least two of the four sites typically affected by multiple sclerosis (periventricular, juxtacortical, infratentorial, or spinal cord).

  35. Diagnosis and Differential • DIT criteria may be satisfied on clinical grounds alone if the patient has a history of at least two attacks • If the patient has a history of one attack, MRI criteria may be applied to establish DIT. Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  36. Diagnosis and Differential • Under the 2010 criteria, DIT can be established with the development of a new T2 lesion at any time, compared to a baseline scan performed at any time • In certain cases, DIT can actually be established with a single MRI scan Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  37. Diagnosis and Differential • Dissemination in time can be demonstrated with a single MRI if simultaneous asymptomatic gadolinium-enhancing and nonenhancing lesions are present.

  38. Diagnosis and Differential Primary progressive multiple sclerosis: • characterized by the insidious onset of symptoms followed by gradual deterioration over time • Clinical disease in these patients typically presents as a progressive myelopathy, and less frequently as a brainstem or cerebellar syndrome. Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  39. Diagnosis and Differential Secondary progressive multiple sclerosis: • diagnosed when, after an initial relapsing-remitting course, a patient demonstrates disease progression independent of relapses for at least 6 months. Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  40. Diagnosis and Differential Radiologically isolated syndrome: diagnosed when a patient is incidentally found to have imaging findings suggestive of multiple sclerosis, which are not better explained by another medical condition, in the absence of clinical symptoms.

  41. Diagnosis and Differential if any element of the: • clinical history • examination • imaging is atypical, additional testing to exclude other etiologies is warranted. Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  42. There are no clinical findings that are unique to MS, but some are highly characteristic of the disease

  43. Diagnosis and Differential A classic presentation of a brainstem syndrome suggestive of clinically isolated syndrome is diplopia due to internuclear ophthalmoplegia, which is often bilateral. Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  44. Diagnosis and Differential Patients with optic neuritis related to underlying multiple sclerosis typically present with painful, subacute, unilateral visual loss that manifests as visual blurring or a scotoma.

  45. Diagnosis and Differential Patients with a spinal cord syndrome suggestive of clinically isolated syndrome characteristically present with a partial transverse myelitis, which is usually dominated by sensory symptoms. Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

  46. Diagnosis and Differential On MRI, spinal cord lesions due to multiple sclerosis are typically peripheral, with the dorsolateral cord being the most common plaque location. Multiple sclerosis lesions are usually less than two vertebral segments in length and occupy less than half of the cross-sectional cord area. Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA. Diagnosis and Differential Diagnosis of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology. 2013; 19:(4): 922-943.

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