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ISSN 2093-2952 Journal of Multiple Sclerosis 3(1):6-12, 2012 REVIEW ARTICLE 고려대학교의과대학신경과학교실 Benign Multiple Sclerosis Jae Hong Jang, MD, Byung-Jo Kim, MD, PhD Department of Neurology, Korea University Medical Center, Seoul, Korea ABSTRACT Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. The clinical course of MS is variable case by case. Patients with low levels of disability after a course of 10 or 15 years may be considered benign MS. In the past, the level of disability was determined by Expanded Disability Status Scale, so non-motor symptoms were less reflected. At the last decade, the studies of non-motor symptoms and magnetic resonance image suggest the need of a new definition. In the future, through the long term studies about neuropsychological test and magnetic resonance image, the truly benign multiple sclerosis may be determined. Journal of Multiple Sclerosis 3(1):6-12, 2012 Key Words: Benign multiple sclerosis, Neuropsychological test, Magnetic resonance image 서론 다발성경화증 (multiple sclerosis, MS) 은재발과완화를특징으로하는중추신경계탈수초성질환이다. 시간이경과함에따라병의재발혹은진행은중추신경계의여러부위에손상을일으켜신경학적결손이점차진행되지만그경과는다양하다. 극단적으로 Marburg s disease와같이사망으로급격히진행하는경우도있지만생전에증상이나징후없이부검에서발견되는무증상의 MS (subclinical multiple sclerosis) 도가능하다. 그중에서처음발병하여 MS로진단받고 10년혹은 15년이지나도질병의진행이경미하고장애가미미한경우를 (Benign multiple sclerosis, BMS) 이라고한다. 이차진행다발성경화증 (secondary progressive multiple sclerosis, SPMS) 환자에서재발- 완화다발성경화증 (relapsing- remitting multiple sclerosis, RRMS) 환자에비해질환조절치료에반응이낮다는점과 MS 환자에서질환의초기에축삭손상의변화들이발생한다는연구보고들은 MS 환자에서조기치료의중요성을시사한다. 1-4 최근에는 CIS 환자를조기치료했을때질환의진행을지연시킨다는결과는 CIS 환자에서도조기치료의필요성을제시하였다. 5 하지만이러한치료를받지않고도양호한경과를겪는 BMS 환자의존재는모든 MS 환자에서조기치료를하는것이타당한지에대해의문을제기하게된다. 아직까지 BMS에대하여평가기준, 질병기간, 그리고유병률에대하여일치된기준은없지만최근의연구들은새로운정의의필요성을제기하고있다. 6 본고에서는 BMS에대하여최근의연구들을중점적으로분석하여유병률, 정의, 그리고평가방법에대하여논의하고자한다. Received February 2, 2012 / Revised February 16, 2012 / Accepted February 16, 2012 Address for correspondence: Byung-Jo Kim Department of Neurology, Korea University Medical Center, 126-1, Anam-dong 5ga, Seongbuk-gu, Seoul 136-705, Korea Tel: +82-2-920-6619, Fax: +82-2-925-2472, E-mail: nukbj@korea.ac.kr 6

본론 1. 유병률 BMS의발병률은적게는 5% 에서많게는 64% 까지다양하다. 7-14 이에대한원인은먼저연구방법에서 BMS의정의가각각다르며, 대부분의경우병원에내원한환자를대상으로조사하였으며, 연구기간이다양하고, 대부분후향적으로연구하였기때문으로생각한다. 따라서 20년이상의연구기간과인구집단을대상으로비교적환자의소실없이 20년이상전향적으로시행한연구들은살펴볼필요가있다. Benedikz 등은 Iceland에서전체인구를대상으로 50 년간시행한전향적연구결과를 2002년에보고하였다. 10 이연구를통해 1950년부터 1999년까지 MS환자 372명의 50년간질병경과를알수있었다. 초기 15년까지 70% 의환자가 EDSS 4.0 미만의경증의장애를보였으며발병 30년뒤에도 52% 의환자가 EDSS 4.0 미만의경증장애상태였다. 저자들은타지역에비해보다양호한경과를보인다고보고하였고이러한원인으로유전적혹은환경적요인의차이와발달된의료제공환경에대한가능성을제시하였다. Pittock 등은 Olmsted에서기존의 10년간추적관찰결과를토대로이후 1991년부터 2001년까지의추적기간을추가하여연구한결과를 2004년에발표하였다.11 162명의 MS환자중에서 28명이 1991년당시 EDSS 2.0 이하의 BMS에해당하였다. 이환자군에서이후 10년뒤의경과에서암으로사망한 1예를제외하면 18명에서 EDSS 2.0 이하, 25명에서 EDSS 3.0 이하의양성경과가관찰되었다. 이에저자들은 BMS 정의를 10년간 EDSS 2.0 이하로정의하는것이이후의 10년뒤에도 93% 의확률로양성의경과를겪는다고하였고이러한기준을적용하여 BMS의유병률을 17% (28/162) 로보고하였다. Andersen 은 Gothenburg에거주하는 MS환자를 50년간전향적방법으로환자의누락없이임상경과에대해 2010년보고하였다. 편파적이지않은집단 (unbiased cohort) 에서대략 10% 의 MS환자가최소한의신경학적, 신경심리학적장애를보인다고보고하였다. 15 하지만비교적유사한방법으로시행하였어도연구마다상당한차이를보이고있는데대상지역의환경적요인과대상지역인구의유전적요인에의해발생했을것으로생각한다. 따라서현시점에서정확한유병률을예측할수없으며몇몇의이상적인방법에의한연구결과를토대로하여도지역별차이를보이고있어타지 역에적용하기는어렵다고생각한다. 다만전체 MS환자군에서무시할수없는수의환자가 15년에서 20년이후에도치료없이양성경과를보이는반면에초기 10 년혹은 15년간은양성경과를보였지만이후에질병의활성도가높아져더이상 BMS라고할수없는경우들도많다는점은주목할만하다. 2. BMS 의정의와평가기준 양성경과의 MS환자에대한기술은초기부터있었다. 1996년 Lublin과 Reingold는질병발생 15년뒤에도모든신경계의기능이온전히유지되는경우를 BMS로정의하였다. 16 이후에 Kurtzke Disability Scale (DSS) 과 EDSS 가소개되면서 BMS의정의가보다구체화되었다. 가장폭넓게사용되는정의는발병후최소 10년이지난상태에서 EDSS 3.0 이하인경우이다. 8,9,13,17,18 하지만 EDSS에의한정의는환자의운동기능에초점이맞춰져있으며특히보행에의해주로좌우되며일상생활에영향을주는주요요소들, 즉인지기능, 피로, 우울, 통증등에관한평가는부족하였다. 따라서질병상태의변화에대한반영이부족하여전체적인신뢰도가떨어진다. 앞서 BMS의유병률을조사한연구에서도발병기간이경과함에따라장애정도가갑자기진행하는환자들이있다는사실은이러한환자들을조기에감별하여보다적극적인치료를해야할필요성을제기한다. 최근 10여년간 BMS환자에서 EDSS와통상적인뇌MRI 이외에도일상생활에영향을주는임상양상들과새로운 MRI 평가방법들이보고되었고 EDSS가악화되기이전에비운동증상과영상검사를통해변화가관찰된환자들이이후에장애가악화되는사실들이보고되어보다폭넓은평가방법과새로운 BMS의정의에대한필요성이대두되고있다. 특히 MRI상에 T2 병변의축척정도는많지않고, EDSS의점수와잘연관되는것으로알려진 T1 영상에서의 black hole도많지않지만, 전반적으로뇌부피가감소하는것을볼때, 에서운동기능의장애에비해인지기능의장애가두드러지게발견되는것이피질병변에의한뇌부피의감소에의한것이라는주장이있다 (Fig. 1). 1) 비운동증상에대한평가 (1) 피로감피로감은 MS환자에서흔한증상이며장애를악화시킬수있으며일상활동을제한하여삶의질을감소시킬 Journal of Multiple Sclerosis Vol. 3, No. 1, 2012 7

A B C D E F Figure 1. Brain FLAIR (A, D), and T1-weighted (B, C, E, F) images in a patient with multiple sclerosis, who has an EDSS score 1.0 with a disease duration of 10 years. Brain images in upper row (A-C) performed at the initial onset time and images in lower row (D-F) at 9 years later. While no black hole in brain white matter are shown on images at initial and follow-up times, brain volume is generally decreased which is suggested by widened sulci, enlarged ventricles and cistern, and decreased pontine volume at follow-up images. 수있다. 19 BMS에서피로감에대한연구는 Fatigue Severity Scale 혹은 Modified Fatigue Impact Scale을통해평가하였고약 40% 정도로보고되고있다. 20,21 전체 MS환자에서피로감은실제 EDSS와연관성이관찰되지않았지만 BMS환자내에서피로감과 EDSS 연관성이한연구에서관찰되었고 BMS로정의된환자중에서이후에지속적인양성경과를보이는환자와진행된환자사이에서피로도는유의한차이가관찰되었다. 21-23 이러한사실은오랜기간동안낮은 EDSS의양성경과를겪는 MS환자의경우병리적피로감의발생으로부터다소보호되기때문으로생각한다. 21 (2) 우울감 MS환자에서약 50% 정도로보고되고있는흔한증상이다. BMS환자에대한연구는 Montgomery and Asberg Depression Rating Scale 혹은 BeckDepression Inventory를통해평가하였고약 20% 의환자에서중등도이상의우울감이보고되었다. 20,21 EDSS와의연관성은연구결과에따라아직다르게보고되고있어추후연구가필요한상태이다. (3) 인지기능장애인지기능은고용상태, 사회적기능, 삶의질에부정적인영향을준다. 24-27 전체 MS환자의 40-65% 가인지기능장애를보이고질병경과에서상대적으로초기에발생한다. 24,28-32 BMS환자의경우 19-45% 에서인지기능장애가나타나며인지기능장애는주의력지속, 집중력, 집행기능과단어유창성에서두드러진저하가발견된다. 20,33-35 BMS환자에서정상적인인지상태가이후의양호한경과와 MRI소견을예측할수있어 BMS의정의에추가항 8

목으로포함시킬것을제시하고있다. 33-35 인지기능상태가이처럼 BMS환자를평가하는데중요한요소이지만일반적인대면진찰에서이상여부를파악하기힘들다. 따라서신경심리검사를 BMS환자평가의한요소로서시행하여야한다. 이용할수있는대표적인선별검사로는 Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) 나 Paced Auditory Serial Addition Test (PASAT) 이있다. 36,37 MSNQ는 15개의항목으로구성되어있으며소요되는시간이 5분미만으로짧지만설문을위해서환자본인과보호자모두가필요하다. 환자본인과보호자가시행한 MSNQ 점수는모두정상인과차이를보였으며인지기능장애와우울감척도와연관성이관찰되었다. 자가 (self-report) MSNQ 점수는인지기능상태보다는우울감과보다더상관관계가관찰되었고보호자 MSNQ 점수는우울감보다는인지기능장애와보다더연관성이관찰되었다. 따라서 MSNQ 는유용한선별검사이지만자가 MSNQ 점수가우울한환자에서보다나쁘게평가되거나심한인지기능장애가있는환자에서보다경미하게나올수있다는점을고려해야한다. PASAT은오디오나컴퓨터를이용하여반복하여한자리수를감산하는검사로써 Brief Repeatable Neuropsychological Battery for MS (BRNB) 나 Minimal Assessment of Cognitive Function in MS (MACFIMS) 의일부분으로포함되어있고이미많은외국의병원에서시행하고있다. 검사시간은 5분에서 10분정도소요되며 MS 환자에서처리속도 (processing speed) 의지연이흔히나타나는인지장애이므로 PASAT은처리속도와작업기억을검사하여 MS환자에서인지기능장애를선별할수있다. 38 물론이러한검사들이신경심리평가결과 와완전히연관되지는않지만비교적적은노력으로인지장애가있는환자를발견할수있다. 선별검사를시행하여인지기능저하가의심되는경우에신경심리검사로서 BRNB나 MACFIMS를고려할수있다 (Table 1). 39,40 BRNB는 MS환자에서신경심리학적연구를위해고안되었으며 40분정도가소요된다. 다섯가지검사를통해언어적기억및지연회상, 시공간기억및지연회상, 지속적주의력및집중력, 그리고의미회상에대한기능을평가한다. MACFIMS는보다광범위한검사로 MS환자에대한임상적평가와연구를위한최소한의신경심리검사를목적으로개발되었고 90분정도소요된다. 7개의검사로이루어져있으며처리속도, 작업기억, 학습및기억, 집행기능, 시공간처리, 단어회상에대하여평가한다. 하지만현재까지이러한선별검사및신경심리검사에대해국문평가판이마련되지않아앞으로이에대한논의가필요할것으로생각한다. 2) 영상을통한평가통상적인 MRI를시행한경우장애정도의차이에도불구하고 BMS환자와 RRMS 혹은 SPMS환자사이의 T2 병변들의수는유의한차이가없었다. 41-43 이러한모순에대하여세가지의이유로설명하고있다. 첫째, 증상발현, 특히운동기능과연관된부위에대한침범이적다는점이다. 평균적인 T2 병변의정도는 BMS환자와 RRMS환자사이에차이가없었으나피질내병변의수는 BMS환자에서유의하게적게관찰되었으 며경추병변의빈도와평균크기역시 SPMS 환자보다 BMS 환자에서적었다. 44,45 또한전체뇌위축의정도가 Table 1. Tests included in the Brief Repeatable Neuropsychological Battery for MS (BRNB) and Minimal Assessment of Cognitive Function in MS (MACFIMS) battery BRBN MACFIMS Test Domain Test Domain Selective Reminding Test Verbal learning and memory Controlled Oral Word Association Test Language 10/36 Spatial Recall Test Visuospatial learning and delayed recall Judgment of Line Orientation Test Spatial processing Symbol Digit Modalities Test Sustained attention and concentration California Verbal Learning Test New learning and memory Paced Audiotry Serial Addition Test Sustained attention and information processing Brief Visuospatial Memory Test New learning and memory Word List Generation Test Semantic verbal fluency Symbol Digit Modalities Test Sustained attention and concentration Paced Audiotry Serial Addition Test Delis Kaplan Executive Function System Sorting Test Sustained attention and information processing Executive function Journal of Multiple Sclerosis Vol. 3, No. 1, 2012 9

BMS환자와 SPMS환자사이에서차이를보이지않았지만천막하부위축, 회색질위축, 소뇌위축그리고경추위축이 SMPM환자에서보다두드러지게나타났다. 43,46-49 둘째, 병변의축적되는속도가 BMS환자에서보다낮다는점이다. 20년간추적관찰연구에서 BMS환자에비해 SPMS환자에서 T2 병변부피의증가율이더높았다. 50 또한 6개월의경과관찰연구에서는 BMS환자에비해 RRMS환자에서조영증강되는새로운병변의발생률이더높았다. 51 BMS환자에서통상적인용량의조영제와세배의조영제를각각사용하여비교했을때통상적인용량을사용한군의 35%, 세배의용량을사용한군의 50% 환자에서조영증강되는병변이관찰되어 BMS환자의염증정도가가볍고균등하지않다는점을시사하였다. 52 셋째, BMS환자에서뇌손상이후의보상기전이효과적으로발생한다는점이다. 기능적 MRI를통한연구에서 BMS환자는정상인에비해인지망 (cognitive network) 의여러부위에서뚜렷한활성화와이러한부위사이에연결강도가보다두드러지게관찰되었다. 이러한기능적피질의변화는특정뇌구조물의손상이후적응반응을시사한다. 53 최근 10년간새로운 MRI 방법, 즉자화전이 (magnetic transfer), 자기공명분광법 (magnetic resonance spectroscopy), 확산텐서자기공명영상 (diffusion tensor MRI) 등을통해 BMS환자와 RRMS 혹은 SPMS환자사이의차이를보고하였다. 34,54,55 특히, 인지기능저하가있는 BMS환자의경우자화전이측정과확산 MRI를통해 T2 및 T1 병변의부피와피질손상이인지기능이정상인 BMS환자에비해보다높게나타났다. 34,56 또한인지기능저하와커진 T1 병변의부피가이후 5년간추적관찰에서 BMS환자의임상소견의진행과관련이있어인지기능평가와 MRI 측정법 (metrics) 이 BMS환자의진행을예측할수있다는점을시사하였다. 35 결론 2010년 MS에대한진단기준으로사용되는 McDonald 기준이개정되었지만이러한 BMS에대해서는기준이제시되지않았고연구자들사이에서도일치점을찾지못하고있다. 57 현재까지의연구들을종합해보면임상양상, 검사소견, 그리고유전적요인중그어떤것으로도정확하게 BMS환자의예후를예측할수는없다. EDSS 를기준으로하는 BMS의정의는 MS 질병양상의일부만을주로반영한것으로진정한 BMS를평가하는데제 한적이다. 인지기능과영상소견이 BMS환자의예후를예측할수있고더나아가진정한 BMS를구분하는역할을할수있기때문에이에대한추가연구와이를통해 BMS에대한새로운평가기준과정의가필요하다고생각한다. REFERENCES 1. Kappos L, Polman C, Pozzilli C, Thompson A, Beckmann K, Dahlke F. Final analysis of the European multicenter trial on IFNbeta-1b in secondary-progressive MS. Neurology 2001;57: 1969-1975. 2. Panitch H, Miller A, Paty D, Weinshenker B. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 2004;63:1788-1795. 3. Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002; 125:2202-2212. 4. De Stefano N, Narayanan S, Francis GS, Arnaoutelis R, Tartaglia MC, Antel JP, et al. Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 2001;58:65-70. 5. Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, et al. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 2007;370:389-397. 6. Pittock SJ. Does benign multiple sclerosis today imply benign multiple sclerosis tomorrow?: implications for treatment. Neurology 2007;68:480-481. 7. Poser S, Bauer H. Clinical data and the identification of special forms of multiple sclerosis in 1271 cases studied with a standardized documentation system. J Neurol Sci 1979;40: 159-168. 8. Thompson AJ, Hutchinson M, Brazil J, Feighery C, Martin E. A clinical and laboratory study of benign multiple sclerosis. Q J Med 1986;58:69. 9. Hawkins SA, McDonnell GV. Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors. J Neurol Neurosurg Psychiatry 1999;67: 148-152. 10. Benedikz J, Stefansson M, Guomundsson J, Jonasdottir A, Fossdal R, Gulcher J, et al. The natural history of untreated multiple sclerosis in Iceland. A total population-based 50 year prospective study. Clin Neurol Neurosurg 2002;104:208-210. 11. Pittock SJ, McClelland RL, Mayr WT, Jorgensen NW, Weinshenker BG, Noseworthy J, et al. Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study. Ann Neurol 2004;56:303-306. 12. Sayao AL, Devonshire V, Tremlett H. Longitudinal follow-up of "benign" multiple sclerosis at 20 years. Neurology 2007; 68:496-500. 13. Costelloe L, Thompson A, Walsh C, Tubridy N, Hutchinson M. Long-term clinical relevance of criteria for designating multiple sclerosis as benign after 10 years of disease. J Neurol 10

Neurosurg Psychiatry 2008;79:1245-1248. 14. Glad S, Aarseth J, Nyland H, Riise T, Myhr KM. Benign multiple sclerosis: a need for a consensus. Acta Neurol Scand Suppl 2010;122:44-50. 15. Andersen O. Natural history of multiple sclerosis: 50 years of follow-up. Mult Scler 2010;16:S36. 16. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996;46:907-911. 17. Ramsaransing GS, De Keyser J. Benign course in multiple sclerosis: a review. Acta Neurol Scand 2006;113:359-369. 18. Glad S, Nyland H, Myhr KM. Benign multiple sclerosis. Acta Neurol Scand Suppl 2006;183:55-57. 19. Bakshi R. Fatigue associated with multiple sclerosis: diagnosis, impact and management. Mult Scler 2003;9:219-227. 20. Amato MP, Zipoli V, Goretti B, Portaccio E, De Caro MF, Ricchiuti L, et al. Benign multiple sclerosis: cognitive, psychological and social aspects in a clinical cohort. J Neurol 2006;253:1054-1059. 21. Sayao AL, Bueno AM, Devonshire V, Tremlett H. The psychosocial and cognitive impact of longstanding 'benign' multiple sclerosis. Mult Scler 2011;17:1375-1383. 22. Fisk JD, Pontefract A, Ritvo PG, Archibald CJ, Murray TJ. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci 1994;21:9-14. 23. Bakshi R, Shaikh ZA, Miletich RS, Czarnecki D, Dmochowski J, Henschel K, et al. Fatigue in multiple sclerosis and its relationship to depression and neurologic disability. Mult Scler 2000;6:181-185. 24. Amato MP, Ponziani G, Pracucci G, Bracco L, Siracusa G, Amaducci L. Cognitive impairment in early-onset multiple sclerosis: pattern, predictors, and impact on everyday life in a 4-year follow-up. Arch Neurol 1995;52:168. 25. Beatty WW, Blanco CR, Wilbanks SL, Paul RH, Hames KA. Demographic, clinical, and cognitive characteristics of multiple sclerosis patients who continue to work. J Neuro Rehab 1995;9:167-173. 26. Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. Neurology 1991;41:692-696. 27. Rao SM, Leo G, Haughton VM, Aubin-Faubert PS, Bernardin L. Correlation of magnetic resonance imaging with neuropsychological testing in multiple sclerosis. Neurology 1989;39: 161-161. 28. Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis: I. Frequency, patterns, and prediction. Neurology 1991. 29. Bobholz JA, Rao SM. Cognitive dysfunction in multiple sclerosis: a review of recent developments. Curr Opin Neurol 2003;16:283. 30. Amato MP, Zipoli V, Portaccio E. Multiple sclerosis-related cognitive changes: a review of cross-sectional and longitudinal studies. J Neurol Sci 2006;245:41-46. 31. Achiron A, Barak Y. Cognitive impairment in probable multiple sclerosis. J Neurol Neurosurg Psychiatry 2003;74:443. 32. Patti F, Amato M, Trojano M, Bastianello S, Tola M, Goretti B, et al. Cognitive impairment and its relation with disease measures in mildly disabled patients with relapsing-remitting multiple sclerosis: baseline results from the Cognitive Impairment in Multiple Sclerosis (COGIMUS) study. Mult Scler 2009;15:779-788. 33. Rovaris M, Barkhof F, Calabrese M, De Stefano N, Fazekas F, Miller D, et al. MRI features of benign multiple sclerosis. Neurology 2009;72:1693-1701. 34. Amato MP, Portaccio E, Stromillo ML, Goretti B, Zipoli V, Siracusa G, et al. Cognitive assessment and quantitative magnetic resonance metrics can help to identify benign multiple sclerosis. Neurology 2008;71:632-638. 35. Portaccio E, Stromillo ML, Goretti B, Zipoli V, Siracusa G, Battaglini M, et al. Neuropsychological and MRI measures predict short-term evolution in benign multiple sclerosis. Neurology 2009;73:498-503. 36. Benedict RHB, Cox D, Thompson LL, Foley F, Weinstock- Guttman B, Munschauer F. Reliable screening for neuropsychological impairment in multiple sclerosis. Mult Scler 2004;10:675-678. 37. Fischer JS, Rudick RA, Cutter GR, Reingold SC. The Multiple Sclerosis Functional Composite Measure (MSFC): an integrated approach to MS clinical outcome assessment. National MS Society Clinical Outcomes Assessment Task Force. Mult Scler 1999;5:244-250. 38. DeLuca J, Chelune GJ, Tulsky DS, Lengenfelder J, Chiaravalloti ND. Is speed of processing or working memory the primary information processing deficit in multiple sclerosis? J Clin Exp Neuropsychol 2004; 26:550-562. 39. Boringa J, Lazeron RHC, Reuling IEW, Ader H, Pfennings LEMA, Lindeboom J, et al. The brief repeatable battery of neuropsychological tests: normative values allow application in multiple sclerosis clinical practice. Mult Scler 2001;7: 263-267. 40. Benedict RHB, Cookfair D, Gavett R, Gunther M, Munschauer F, Garg N, et al. Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). J Int Neuropsychol Soc 2006;12:549-558. 41. Koopmans RA, Li DK, Grochowski E, Cutler PJ, Paty DW. Benign versus chronic progressive multiple sclerosis: magnetic resonance imaging features. Ann Neurol 1989;25:74-81. 42. Filippi M, Barker GJ, Horsfield MA, Sacares PR, MacManus DG, Thompson AJ, et al. Benign and secondary progressive multiple sclerosis: a preliminary quantitative MRI study. J Neurol 1994;241:246-251. 43. Filippi M, Campi A, Mammi S, Martinelli V, Locatelli T, Scotti G, et al. Brain magnetic resonance imaging and multimodal evoked potentials in benign and secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 1995;58:31-37. 44. Calabrese M, Filippi M, Rovaris M, Bernardi V, Atzori M, Mattisi I, et al. Evidence for relative cortical sparing in benign multiple sclerosis: a longitudinal magnetic resonance imaging study. Mult Scler 2009;15:36-41. 45. Bonek R, Orlicka K, Maciejek Z. Demyelinating lesions in the cervical cord in multiple sclerosis 10 years after onset of the disease. Correlation between MRI parameters and clinical course. Neurol Neurochir Pol 2007;41:229-233. Journal of Multiple Sclerosis Vol. 3, No. 1, 2012 11

46. Thompson AJ, Kermode AG, MacManus D, Kendall B, Kingsley D, Moseley I, et al. Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study. BMJ 1990;300:631-634. 47. Fisniku LK, Chard DT, Jackson JS, Anderson VM, Altmann DR, Miszkiel KA, et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol 2008; 64:247-254. 48. Mesaros S, Rovaris M, Pagani E, Pulizzi A, Caputo D, Ghezzi A, et al. A magnetic resonance imaging voxel-based morphometry study of regional gray matter atrophy in patients with benign multiple sclerosis. Arch Neurol 2008;65: 1223-1230. 49. Filippi M, Campi A, Martinelli V, Colombo B, Scotti G, Comi G. Brain and spinal cord MR in benign multiple sclerosis: a follow-up study. J Neurol Sci 1996;143:143-149. 50. Fisniku L, Brex P, Altmann D, Miszkiel K, Benton C, Lanyon R, et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008;131:808. 51. Thompson AJ, Miller D, Youl B, MacManus D, Moore S, Kingsley D, et al. Serial gadolinium-enhanced MRI in relapsing/ remitting multiple sclerosis of varying disease duration. Neurology 1992;42:60-63. 52. Filippi M, Capra R, Campi A, Colombo B, Prandini F, Marciano N, et al. Triple dose of gadolinium-dtpa and delayed MRI in patients with benign multiple sclerosis. J Neurol Neurosurg Psychiatry 1996;60:526. 53. Rocca MA, Valsasina P, Ceccarelli A, Absinta M, Ghezzi A, Riccitelli G, et al. Structural and functional MRI correlates of Stroop control in benign MS. Hum Brain Mapp 2009;30: 276-290. 54. Rigotti DJ, Gonen O, Grossman RI, Babb JS, Falini A, Benedetti B, et al. Global N-acetylaspartate declines even in benign multiple sclerosis. AJNR AM J Neuroradiol 2011; 32:204-209. 55. Benedetti B, Rocca MA, Rovaris M, Caputo D, Zaffaroni M, Capra R, et al. A diffusion tensor MRI study of cervical cord damage in benign and secondary progressive multiple sclerosis patients. J Neurol Neurosurg Psychiatry 2010;81:26. 56. Rovaris M, Riccitelli G, Judica E, Possa F, Caputo D, Ghezzi A, et al. Cognitive impairment and structural brain damage in benign multiple sclerosis. Neurology 2008;71:1521-1526. 57. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69: 292-302. 12