Focused Issue of This Month Multiple Sclerosis Woojun Kim, MDHo Jin Kim, MD Department of NeurologyNational Cancer Center E - mail : hojinkim@ncc.re.kr J Korean Med Assoc 2009; 52(7): 665-676 Abstract Multiple sclerosis (MS) is an inflammatory autoimmune disorder of the central nervous system (CNS) and one of the most common disabling neurological diseases of young adults. Although the exact mechanisms involved in MS pathogenesis remain unclear, MS is believed to be caused by interactions between as yet unidentified environmental factors and susceptibility genes. Symptoms commonly occurred in MS include visual disturbance; weakness; spasticity; sensory disturbances; ataxia; bladder, bowel, and sexual dysfunction; fatigue; affective symptoms; and cognitive impairment. Most patients initially undergo a relapsing-remitting course, however, without treatment, the majority of them make a transition to the secondary progressive form. The clinical diagnosis is based on demonstrating neurological lesions, predominantly in the white matter, that are disseminated over space with the lapse of time. The key to the successful MS management is to prevent disability. Although there is no effective cure for MS, therapies are available that mitigate the course of the disease, treat relapses and improve symptoms, all of which place a significant impact on patients quality of life. Recent clinical trials suggest that early identification and treatment are critical to optimize the treatment benefit. Currently six agents have been specifically approved for mitigating the course of MS. These include three formulations of interferon beta, glatiramer acetate, mitoxantrone, and natalizumab. Recent advances in understanding of immune pathogenesis lead us to new therapeutic approaches focused on precise target mechanisms. Many ongoing clinical trials will provide better treatment protocols in near future. Keywords: Multiple sclerosis; Epidemiology; Immunopathology; Diagnosis; Treatment 665
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Multiple Sclerosis A B C D E APC = antigen presenting cell, IFN = interferon, MBP = myelin basic protein, MHC = major histocompatibility complex, MMP = matrix metalloproteinase, NOI = nitric oxide intermediates, ROI = reactive oxygen intermediates, TCR = T cell receptor, TNF = tumor necrosis factor, VCAM = vascular cell adhesion molecule, VLA = very late antigen. Figure 1. The five key immunopathogenic processes in multiple sclerosis (MS) targeted by MS therapies (10). (A) T cell activation and differentiation into T-helper (Th) -1 cells, (B) interleukin (IL)-2-induced proliferation of activated Th1 cells, (C) recruitment of B cells and monocytes by activated Th1 cells, (D) activated Th1 cell trafficking across the blood- brain barrier (BBB), (E) T cell reactivation and induction of immune cell-mediated demyelination. 667
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Multiple Sclerosis Figure 2. Diagram representing the different types of multiple sclerosis. 669
Kim WKim HJ Table 1. 2005 Revisions to the McDonald Diagnostic Criteria for Multiple Sclerosis (25) Clinical Presentation Two or more attacks a ; objective clinical evidence of two or more lesions Two or more attacksa; objective clinical evidence of one lesion One attack a ; objective clinical evidence of two or more lesions One attack a ; objective clinical evidence of one lesion (monosymptomatic presentation; clinically isolated syndrome) Insidious neurological progression suggestive of MS Additional Data Needed for MS Diagnosis None b Dissemination in space, demonstrated by: MRIc or Two or more MRI- detected lesions consistent with MS plus positive CSF d or Await further clinical attacka implicating a different site Dissemination in time, demonstrated by: MRIe or a Second clinical attack Dissemination in space, demonstrated by: MRIc or Two or more MRI-detected lesions consistent with MS plus positive CSF d and Dissemination in time, demonstrated by: MRIe or a Second clinical attack One year of disease progression (retrospectively or prospectively determined) and two of the following: a. Positive brain MRI (nine T2 lesions or four or more T2 lesions with positive VEP) f b. Positive spinal cord MRI (two focal T2 lesions) c. Positive CSF d If criteria indicated are fulfilled and there is no better explanation for the clinical presentation, the diagnosis is MS; if suspicious, but the criteria are not completely met, the diagnosis is possible MS ; if another diagnosis arises during the evaluation that better explains the entire clinical presentation, then the diagnosis is not MS. a An attack is defined as an episode of neurological disturbance for which causative lesions are likely to be inflammatory and demyelinating in nature. There should be subjective report (backed up by objective findings) or objective observation that the event lasts for at least 24 hours. b No additional tests are required; however, if tests (MRI, CSF) are undertaken and are negative, extreme caution needs to be taken before making a diagnosis of MS. Alternative diagnoses must be considered. There must be no better explanation for the clinical picture and some objective evidence to support a diagnosis of MS. c MRI demonstration of space dissemination must fulfill the criteria derived from Barkhof and colleagues and Tintoré and coworkers. d Positive CSF determined by oligoclonal bands detected by established methods (isoelectric focusing) different from any such bands in serum, or by an increased IgG index. e MRI demonstration of time dissemination must fulfill the criteria in Table 3. f Abnormal VEP of the type seen in MS. MS = multiple sclerosis, MRI = magnetic resonance imaging, CSF = cerebrospinal fluid, VEP = visual- evoked potential Table 2. MRI criteria to demonstrate brain abnormality and demonstration of dissemination in space Three of the followings: 1 At least one gadolinium- enhancing lesion or nine T2 hyperintense lesions if there is no gadolinium enhancing lesion 2 At least one infratentorial lesion 3 At least one juxtacortical lesion 4 At least three periventricular lesions NOTE: A spinal cord lesion can be considered equivalent to a brain infratentorial lesion: an enhancing spinal cord lesion is considered to be equivalent to an enhancing brain lesion, and individual spinal cord lesions can contribute together with individual brain lesions to reach the required number of T2 lesions. Table 3. MRI criteria to demonstrate dissemination of lesions in time There are two ways to show dissemination in time using imaging: a. Detection of gadolinium enhancement at least 3 months after the onset of the initial clinical event, if not at the site corresponding to the initial event b. Detection of a new T2 lesion if it appears at any time compared with a reference scan done at least 30 days after the onset of the initial clinical event 670
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Kim WKim HJ A Figure 3. Representing MRI of multiple sclerosis. (A) Fluid-attenuated inversion recovery (FLAIR) MRI demonstrates typical multiple perpendicular-axis periventricular white matter lesions called Dawson s fingers. (B) Gadolinium enhanced T1-weighted MRI shows well-enhancing MS plaque. B 672
Multiple Sclerosis Table 4. List of US food and drug administration-approved disease-modifying therapies Disease-modifying Approved indication Dose/Route Frequency Recommended tests agent Glitiramer acetate RR 20 mg/sc q day None (Copaxone ) Inteferon -1a Relapsing forms 30 µg/im q week LFTs and CBCs at baseline, (Avonex ) 1 month, 3 months, 6 months, then periodically in absence of clinical symptoms Consistent with MS TFTs q 6 months in those with thyroid consistent with MS thyroid dysfunction or as clinically indicated Inteferon -1a Relapsing forms 22 µg or 44 µg/sc TIW LFTs and CBCs at baseline, 1 month, (Rebif ) (titration needed) 3 months, 6 months, then periodically in absence of clinical symptoms TFTs q 6 months in those with thyroid dysfunction or as clinically indicated, then periodic intervals in absence of clinical symptoms Inteferon -1b Relapsing forms 250 µg/sc qod LFTs and CBCs at baseline, 1 month, (Betaferon ) (titration needed) 3 months, 6 months, then periodically in absence of clinical symptoms CIS with MRI features TFTs q 6 months in those with thyroid consistent with MS dysfunction or as clinically indicated Natalizumab Relapsing forms 300 mg/iv q 4 weeks MRI with contrast of the brain prior (Tysabri ) to initiation Inadequate response to MRI and CSF testing for JC virus disease-modifying therapies when suspecting PML Monotherapy only Clinical follow-up at 3 and 6 months; then q 6 months thereafter Mitoxantrone Worsening RR, PR, 12 mg/m 2 /IV q 3 months LVEF evaluation at baseline (Novantrone ) or SP and prior to each dose Cumulative lifetime Contraindicated if LVEF <50% dose 140 mg/m 2 LFTs and CBCs at baseline and prior to each dose CBC = complete blood count with platelets, CIS = clinically isolated syndrome, DMT = disease-modifying therapy, LFT = liver function tests, LVEF = left ventricular ejection fraction, MS = multiple sclerosis, PML = progressive multifocal leukoencephalopathy, PR = progressive-relapsing, q = every, qod = every other day, RR = relapsing-remitting, SC = subcutaneous, SP = secondary progressive, TFT = thyroid function tests, TIW = 3 times a week 673
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