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1 ISSN Journal of Multiple Sclerosis 1(2):31-37, 2010 REVIEW ARTICLE 충남대학교병원신경과 Update in Multiple Sclerosis Eun Hee Sohn, MD Department of Neurology, Chungnam National University Hospital, Daejeon, Korea ABSTRACT Multiple sclerosis (MS) is a chronic, potentially disabling, immune-mediated inflammatory demyelinating disease of the central nervous system. The earlier intervention of MS results in the better prognosis. Recently there have been lots of trials to detect MS in the early stage and to treat it properly. Disease modifying agents, immune-suppressive agents, monoclonal antibodies, and combination of these agents are leading therapies. I will talk about the way to detect MS in clinically isolated patients and the marker of disease progression in MS patients. Also I will discuss the recent therapeutic methods of MS. Journal of Multiple Sclerosis 1(2):31-37, 2010 Key Words: Multiple sclerosis, Diagnosis, Clinically isolated syndrome, Retinal nerve, Treatment 서론 다발성경화증은반복적으로재발과완화를반복하면서결국에는장애를남겨사회적, 경제적으로큰소실을초래하는만성면역반응매개질환이다. 최근까지여러연구들을통해다발성경화증의병인과진단및치료에관한사실들이밝혀지고있지만, 향후더많은연구가이루어져야할분야이기도하다. 본고에서는현재까지발표되어온여러연구중진단과치료에중점을두어최신지견에대해정리해보고자한다. 진단 1. 임상적단독증후군 (clinically isolated syndrome, CIS) 을진단하기위한 MRI 기준 다발성경화증은재발과완화를반복하는과정을거치 며, 특히시신경염이나척수염처럼중추신경계중한부분의탈수초성병변으로시작하는경우가흔하다. 이처럼첫번째중추신경계에발생한탈수초성질환을 CIS라지칭한다. 다발성경화증을초기에진단하기위한여러진단기준이개발되어왔으며, 특히다발성경화증의초기단계인 CIS에서다발성경화증을진단하여조기치료하기위한여러가지노력들이있어왔다. 다발성경화증을진단하기위해서는한가지의질환특이적인검사방법은없으며, 대부분의진단기준은다발성경화증의병변이시간과 (dissemination in time, DIT) 공간 (dissemination in space, DIS) 에걸쳐여러번재발했음을밝히는것을기본으로한다. 과거주로사용되었던 Poser 진단기준은확실히두번이상의재발이있었을때다발성경화증을임상적으로확정진단내릴수있으며, 그외의경우뇌척수액검사와 MRI 등을사용하여진단민감도를높이도록제시하고있다. 1 McDonald 진단기준은이전 Received August 10, 2010 / Accepted August 20, 2010 Address for correspondence: Eun Hee Sohn Department of Neurology, Chungnam National University Hospital, 33 Moonhwha-ro Jung-gu, Daejeon , Korea Tel: , Fax: , seh337@hanmail.net Journal of Multiple Sclerosis Vol. 1, No. 2,

2 에사용되던진단기준과달리 MRI만으로도 DIT와 DIS를증명하여초기에다발성경화증을진단할수있는기준을제시하였다. 2 이진단기준에서사용한 MRI 기준은 Barfhof 3 가제시하고 Tintoré 4 에의해수정된것을사용하였다 (Table 1). Barkhof-Tintoré 기준은너무엄격해서이를사용하는경우다발성경화증을초기에진단하지못하는경우가많았고, 특히아시아인에서흔한척수병변에대한기준이미비하여아시아인에서사용시진단율이감소하였다. 이를보완하기위해 2005년에개정 McDonald 진단기준을제시하였다 (Table 1). 5 개정된기준에서는 1) 척수병변을천추막하병변과동일하게보았고, 2) 뇌병변의개수를측정할때척수병변도동일하게사용함으로써, DIS 를증명하기위해척수병변을더유용하게사용할수있도록하였다. 또한 DIT를밝히기위해 3) 처음 MRI를촬영후 30일에다시 MRI를시행해서 T2 영상에서새로운병변이있는경우를인정함으로써이전진단기준보다더초기에다발성경화증을진단할수있게되었다. 2005년도개정진단기준을사용함으로써 2001년도진단기준과비교시민감도는높이면서 (60% vs. 47%) 특이도는유지할수 (88% vs. 91%) 있었다. 6 최근초기진단을위한연구들에서는모두 MRI를이용한진단기준을제시하고있다. MRI 를이용한 DIS 기준은진단민감도가낮기때문에 DIT가증명되기전까지 DIS 만으로다발성경화증을진단하기는어렵다. 6 즉, 다발성경화증진단을위해서는 DIS보다 DIT가더중요하다고하겠다. 2005년개정된 McDonald 기준에따르면 CIS 환자가다발성경화증으로진단받기위해서는최소 30일이후추적 MRI 검사가필요하다. 즉, 추적검사까지시간이지연되어그만큼진단이지연된다고생각할수있다. McDonald 진 단기준에서제시한 MRI 기준과달리한번의 MRI 검사에서무증상조영증강되는병변은 DIT를의미하며, 2 따라서한번의 MRI 검사에서 DIS를만족할만한병변이있으면서무증상조영증강되는병변이있다면다발성경화증으로진단할수있다. 또한 2006년에 DIS 기준에대한연구에서 Barfhof 진단기준보다더적은숫자의병변으로도 DIS를만족할수있다는보고가있었다. 7 유럽다발성경화증 MRI 연구공동체에서 (MAGNIMS) 이새로운두가지 DIS와 DIT 기준을이용하여 CIS 환자를초기에다발성경화증으로진단하기위한새로운 MRI 기준을제시하였다 (Table 1). 8 이기준에서는 MRI상 1) 피질근접부위, 2) 뇌실주위, 3) 천막하부위, 4) 척수의네곳중 2개이상의무증상 T2 영상병변이관찰되면 DIS를증명할수있고, 무증상조영증강되는병변과조영증강되지않는병변이같이있는경우또는추적검사기간과관계없이시행한 MRI에서새로운 T2 병변이관찰되는경우 DIT를증명할수있다. 향후이진단기준의민감도와특이도에대한연구가필요하다. 2. Retinal nerve fiber thickness 시력저하는다발성경화증에서흔하게동반되는증상이다. 9 다발성경화증은단순한탈수초성병변뿐만아니라축삭손상으로인해환자의최종적인장애를유발한다. 10 Optical coherence tomography (OCT) 는비침습적으로망막신경섬유의두께를측정하는방법이며, 이를통해측정한망막신경섬유두께는다발성경화증환자에서주요한축삭손상의지표로생각되고있다. 11 다발성경화증환자에서 OCT를이용하여측정한망막신경섬유두께는대조군 Table 1. MRI criteria for dissemination in space and time for multiple sclerosis DIS (on either baseline or follow-up MRI) DIT McDonald 2001 McDonald 2005 MAGNIMS protocol 3 or more of: 3 or more of: 1 lesions in each of 2 characteristic locations: 9 T2 lesions or 1 Gd-enhancing 9 T2 lesions or 1 Gd-enhancing lesion PV lesion 3 PV lesions 3 PV lesions JC 1 JC lesions 1 JC lesions PF 1 PF lesions 1 PF lesions or SC lesion SC 1 cord lesion can replace 1 brain lesion Any number of cord lesions can be included All lesions in symptomatic regions excluded in total lesion count in BS and SC syndromes 1) 1 Gd-enhancing lesion at least 1) 1 Gd-enhancing lesion at least 3months 1) Simultaneous presence of asymptomatic 3months after CIS onset (if not after CIS onset (if not related to CIS) Gd-enhancing and nonenhancing lesions related to CIS) at any time 2) A new T2 lesion with reference to a prior scan obtained at least 3 months after CIS onset 2) A new T2 lesion with reference to a baseline scan obtained at least 30 days after CIS onset 2) A new T2 and/or Gd-enhancing lesion on follow-up MRI irrespective of timing of baseline scan DIS; dissemination in space, Gd; gadolinium, PV; periventricular, JC; juxtacortical, PF; posterior fossa, SC; spinal cord, BS; brainstem, DIT; dissemination in time. 32 대한다발성경화증학회지제 1 권제 2 호, 2010

3 과비교하여시신경염이없는경우에도현저하게감소되어있으며시력저하정도와잘연관된다는연구들이보고되고있다 또한다발성경화증환자에서망막신경섬유두께감소는 MRI를이용하여측정한회색질과백질부피감소와상관관계가있었다. 16 그러나이런연구들은모두단면연구로써장기간추적연구가없었기에, 장기간변화에대한연구가필요하였다. 2010년에발표된 18개월간추적관찰한연구에서는최근 3개월이내에시신경염이없는다발성경화증환자들 299명을대조군과비교하였다. 17 연구결과다발성경화증환자들이대조군에비해망막신경섬유두께가더많이감소하였으며, 시신경염의병력이없는환자에서도같은결과를보였다. 또한추적검사시에도망막신경섬유두께가감소할수록시력저하가심하였으며, 다발성경화증의장애정도와망막신경섬유두께간에의미있는연관성이있었다. 따라서다발성경화증환자에서망막신경섬유두께를측정하고이를추적검사하는것이축삭손상의정도를알고추적관찰하는데에도움이될것으로기대되고있다. 치료 현재까지재발-완화다발성경화증 (relapsing-remitting multiple sclerosis, RRMS) 의치료로인정된면역조절제제는 interferon beta-1a 근육주사 (Avonex ), 피하주사 (Rebif ), interferon beta-1b 피하주사 (Betaseron ), glatiramer acetate (Copaxone ) 이있다 면역조절제제는안전성이입증되어있지만재발과장애진행을막는효과가높지못하다. 치료효과가인정된면역억제제인 natalizumab (Tysabri ) 과 22 mitoxantrone (Novantrone ) 은 23 좀더강력하지만심각한부작용으로치료에많은제약이있다. 최근에는새로운약제의개발과함께여러약제를병합해서사용하는방법에대한연구들이진행중이다. 1. 면역조절제제간의비교연구 Interferon beta 는여러가지기능이있으나특히 T cell의활성도를억제하여그효과를나타내는것으로생각된다. Glatiramer acetate는 myelin basic protein (MBP) 과유사한구조를가지는합성물질로서 MBP에반응하는 T cell을억제하여작용한다. 두가지면역조절제제가다발성경화증치료에가지는효과는이미입증되었다. 최근면역조절제제간의비교연구가진행되어, Rebif 와 Copaxone 을비교한연구 (REGARD) 와 24 Betaseron 과 Copaxone 을비교한연구 (BEYOND) 가 25 발표되었다. REGARD연구에서 RRMS 환자들을대상으로두약제를비교한결과두약제간에첫번째재발까지의시간과 MRI상병변의변화에차이가없었으며, 24 BEYOND 연구에서도재발위험요인, 재발이없는환자의비율, 첫재발까지걸린시간, 장애정도, MRI 병변에두약제간에차이가없었다. 25 따라서현재까지개발된면역조절제제간효과는차이가없는것으로추측된다. 2. Interferon beta-1b 의장기간안전성및치료효과 Interferon beta-1b의장기간안전성을알아보기위해 RRMS 에서효과를입증했던초기연구 18 의대상환자 372명을 16 년후에다시추적진료하였다. 총 372명중 328명을다시인터뷰할수있었으며, 다시인터뷰하게된환자중새로보고된부작용은없었다. 26 중성화항체 (neutralizing antibody, NAbs) 는현저하게감소하여처음 NAbs 양성이었던환자의 76% 가음성으로전환되었다. 또한처음 NAbs 양성이었던환자와음성이었던환자간에장기간예후에는차이가없었다. 즉, interferon beta-1b는 16년간장기간사용시에도그안전성이입증되었다고하겠다. Interferon beta-1b의장기간효과를알아본연구에서는 interferon beta-1b를사용한군이위약군에비해사망률이적고 (5.4% vs. 18.3%), 처음과비교시 16년후재발율이낮아졌으며 (1.6~1.8 vs. 0.3~0.6), interferon beta-1b를사용할수록더낮은장애정도를보였다. 27 그러나 16년기간동안 interferon beta-1b외에다른치료를병행한경우가더많았고, 사망환자수가적어결과해석에주의를요한다. 3. 병합치료 Interferon beta 와스테로이드제제의병합치료에관한여러연구가있었다 (Table 2). Avonex Combination Trial (ACT) 연구에서는 28 methylprednisolone 정맥주사, methotrexate 경구복용과함께 interferon beta-1a를근육주사한군을각각의위약군과비교하였다. MRI 상새로운병변, 재발율, 다발성경화증기능혼합척도 (MS functional composite, MSFC) 점수, 뇌위축정도를비교하였으나각군마다차이가없었으며, methylprednisolone 정맥주사한군에서만 T2 영상에서병변부피가감소하였다. 연구결과 methotrexate는효과가없었으며, 병합치료로인해부작용이더증가하지는않았다. Avonex-Steroids-Azathioprine (ASA) 연구에서는 29 Avonex 만사용한군, Avonex와 azathioprine을사용한군, 세가지약제를모두사용한군을비교하였다. 세군간에재발율, MRI 병변의변화에차이가없었다. 그러나 ASA 연구에서 Journal of Multiple Sclerosis Vol. 1, No. 2,

4 Table 2. Trials of combination therapy with corticosteroids in multiple sclerosis ACT 28 ASA 29 NORMIMS 30 MECOMBIN 31 Platform tx. IFNβ-1a (IM) IFNβ-1a (IM) IFNβ-1a (SC) IFNβ-1a (IM) Group 1 Placebo+no IV methylpd (n=78) Placebo (n=60) Oral methylpd (n=66) Oral methylpd (n=172) Group 2 Methotrexate (n=83) Oral azathioprine+placebo (n=58) Placebo (n=64) Oral placebo (n=169) Group 3 IV methylpd (n=74) Oral azathioprine+pd (n=63) Group 4 Methotrexate+IV methylpd (n=78) Primary endpoints New or enlarging T2 lesions Yearly relapse rate Yearly relapse rate Time to EDSS progression Result Negative Negative Positive Negative Comment Change in T2 lesion volume was the only endpoint to approach significance 1) P<0.06 when comparing triple tx. with monotherapy 2) Significant difference in the change of T2 lesion volume 1) Rate ratio of 0.41 between the methylpd and placebo groups, 2) Significant difference in the proportion of relapse-free 1) Secondary endpoints were significant (relapse rate, T2 lesion volume change, MSFC score) ACT; Avonex Combination Trial, ASA; Avonex-Sterids-Azathioprine trial, IFNβ; interferon beta, IM; intramuscular, IV; intravascular, NORMIMS; Nordic Trial of Oral Methylprednisolone as Add-On Therapy to Interferon beta-1a for the Treatment of Relapsing-Remitting Multiple Sclerosis, MECOMBIN; Methylprednisolone in Combination with Interferon beta-1a trial, SC; subcutaneous. Table 3. Target molecules and function of monoclonal antibodies Monoclonal Ab Targeted molecules Cell expression Alemtuzumab CD52 All T and B cells, NK cells, majority of macrophages, dendritic cells, most granulocytes Daclizumab CD25 (IL-2Rα) Activated T cells, CD56 bright NK cells, activated macrophages, activated dendritic cells, oligodendrocytes Rituximab CD20 B cell (not plasma cells) Natalizumab CD49d (VLA-4) All T and B cells (CD4+T-cell), NK cells, majority of monocytes and macrophages, granulocytes Ab; antibody, NK; natural killer, IL-2Rα; interleukin-2 receptor, VLA-4; very late activating antigen-4. 단독치료를받은군이병합치료를받은군에비해더젊고유병기간이짧아연구결과에영향을주었을것으로생각되며, 약의용량이충분하지않았고, 각군의환자수가적어향후더많은환자를대상으로연구가시행되어야할것으로보인다. Nordic Trial of Oral Methylprednisolone as Add-On Therapy to Interferon beta-1a for the Treatment of Relapsing Remitting Multiple Sclerosis (NORMIMS) 연구에서는 30 methylprednisolon 을사용한군이위약군과비교시재발율이감소하고 T2 영상에서병변의부피가감소하여 methylprednisolone의효과를입증하였다. Methylprednisolone in Combination with Interferon beta-1a (MECOMBIN) 연구에서는 31 methylprednisolone을사용한군에서재발율은감소하였지만, 장애의진행을막지는못하는것으로나타났다. 즉, 여러연구에서아직까지는결론을내릴수없는연구결과들이보고되고있으며, 향후연구가더필요하다. 4. Mitoxantrone RRMS 의치료로 interferon beta, glatiramer acetate, natalizumab 이그효과를인정받고사용되고있지만, 진행성다 발성경화증의치료는아직제한적이다. 현재까지이차진행다발성경화증 (secondary progressive MS, SPMS) 의치료로인정받은약제는 interferon beta-1b 와 mitoxantrone 뿐이다. 32 Mitoxantrone은항암치료목적으로사용되며 T cell, B cell, 대식세포의억제를통해면역억제효과를보인다. 194명의진행성 RRMS 환자를대상으로한 3상임상연구에서 mitoxantrone 12 mg/m 2 으로사용한환자군에서 EDSS 점수, 치료가필요한재발횟수, 첫번째재발까지의시간에더좋은결과를보였다. 33 현재 mitoxantrone은 12 mg/m 2 으로 3 개월간격으로사용하며일생동안축적된용량이 140 mg/m 2 이내로사용하도록추천하고있다 Monoclonal antibodies Monoclonal antibodies (mabs) 는세포막에있는특정항원을공격함으로써고도의선택적치료가가능한약제이다. 주로 T cell, B cell 등의면역체계와연관된세포를공격하는 mabs 가다발성경화증치료로사용되고있다. 다발성경화증치료에사용되는 mabs 의종류와각각의목표가되는면역세포는 Table 3에기술하였다. Nataliumab 은 mabs 중유일하게다발성경화증치료로미국과유럽에서인정받고사용되고있는약제로 α 4 β 1 in- 34 대한다발성경화증학회지제 1 권제 2 호, 2010

5 tegrin에대한 mab이며염증세포의중추신경계침윤을막는다. Natalizumab 단독치료와위약을비교하는이중맹검무작위시험인 AFFIRM 연구에서 35 natalizumab 은위약에비교해재발율을 68% 낮추었고, 2년간장애의진행을 42% 낮추었다. 또한 MRI에서도조영증강되는병변을 92% 까지낮췄다. Natalizumab 과 interferon beta-1a를사용한군과 interferon beta-1a 단독으로사용한군을비교한 SENTINEL 연구에서도 36 재발율을 53% 까지낮추어서그효과가입증되었다. 그러나 2005년도두명의치명적인 progressive multifocal leukoencephalopathy (PML) 환자가보고되면서 36 natalizumab 의사용이중단되었다. 2006년 natalizumab 만단독치료시 PML의위험도가낮다는 (0.1%) 연구보고 37 이후단독치료로주의를요하면서사용하도록재인정받고사용되고있다. 최근에는무증상환자에서도 natalizumab을사용하면서 PML의원인이되는 JC 바이러스가활성화되는비율이높다는연구와 38 그렇지않다는연구가 39 보고되고있어향후추적연구가필요할것으로보인다. Alemtuzumab 은 T cell과 B cell 모두억제하여효과를나타낸다. RRMS 와 SPMS 에서단독치료시재발율을낮추는효과는있었지만장애의진행을막지는못했다. 40 RRMS 환자에서 interferon beta-1a와비교한또다른연구에서도 alemtuzumab 을사용한경우재발율을 74% 감소시키고장애의진행을 71% 낮추었다. 41 현재까지의연구결과들을보면부작용으로 immune-mediated thrombocytopenic purpura, autoimmune thyroiditis만이보고되어안전성이있을것으로추측되며, 비교적초기 RRMS 단계에서효과가있는것으로생각된다. 32 현재진행중인연구를 Table 4에기술하였다. 그외에 daclizumab 42 과 rituximab 이연구되고있으며, 이의작용기전과진행중인연구를각각 Table 3과 Table 4에기술하였다. 6. 경구제제현재까지여러종류의경구제제가개발되어연구되고있다 (Table 5) 특히 fingolimod는 RRMS 에서효과가입증되었다 (Table 5). T cell 수용체에결합하여 T cell 이혈액으로이동하는것을막음으로써효과를나타내며, 피부암과 2명의심각한 herpes 감염의경우외에특이한부작용이보고되지않고있다. Cladribine 도 RRMS 에서효과를보이면서새로운기대를받고있는약제이다. 그외에다른약제들에관한연구를 Table 5에기술하였다. Table 4. Clinical trials of monoclonal antibodies for multiple sclerosis Monoclonal Ab Finished studies Ongoing studies Alemtuzumab Monotherapy in RRMS (phase II alemtuzumab vs Rebif) 41 CARE-MS II (phase III, alemtuzumab vs Rebif, RRMS), CARE-MS I (phase III, Tx-naïve) Daclizumab CHOICE (phase II, add-on to IFN-β, RRMS) 42 Phase II monotherapy in RRMS Rituximab Phase II monotherapy in RRMS, failed in PPMS 32 Natalizumab AFFIRM (phase III, RRMS), 35 SENTINEL (phase III, RRMS) 36 Risk management programs IFN; interferon, PPMS; primary progressive MS. Table 5. Action mechanism and clinical trials of oral therapies in development Agents Mechanism of action Finished studies Ongoing studies Fingolimod (FTY720) Sphingosine-1-phosphate receptor (S1P1) modulator; inhibition of T-cell migration TRANSFORMS (phase III, RRMS) 43 -increased rate of isolated skin malignancies, 2 severe herpes infection Cladribine Purine analogue; depletion of T-cell CLARITY (phase III, RRMS) 44 -lymphopenia Teriflunomide Inhibit dihydro-orolate dehydrogenase; inhibit Phase II in RRMS 45 -good safety pyramidine synthesis; inhibit expansion of lymphocyte FREEDOMS I, II (phase III, RRMS, placebo), INFORMS (PPMS) ONWARD (RRMS add on to IFNβ), ORACLE MS (CIS monotherapy) TEMSO, TOWER (phase III, RRMS, placebo), TENERE (phase III, RRMS, IFN β) Laquinimod Prevents the migration of lymphocytes Phase II in RRMS 46 NCT (phase III, RRMS, placebo), NCT (phase III,, RRMS, IFN β) Dimethyl fumarate (BG00012) Firategrast (SB ) Potent transcription factor activator; neuroprotective effect α4-integrin antagonist; prevent migration of immune cell Phase II in RRMS 47 -good safety DEFINE (phase III, RRMS, placebo), CONFIRM (phase III, RRMS, placebo) NCT (phase II, RRMS) Journal of Multiple Sclerosis Vol. 1, No. 2,

6 7. 신경보호제제 다발성경화증은탈수초병변뿐만아니라축삭의손상도진행하며, 초기에는염증반응에의해병변이발생하지만후기로갈수록신경퇴행 (neurodegeneration) 이진행하는것으로생각된다. 따라서다발성경화증을치료하기위해서는염증반응을억제하는치료외에신경퇴행을막는치료가필요하다. 그러나최근까지연구되고있는약제는주로염증반응을억제하는치료제이며, 최근에는신경보호제제개발에많은관심이기울여지고있다. Sodium 통로억제제인 topiramate, riluzole, lamotrigine 등이연구중에있으며, 면역억제기능과신경보호기능을같이가지고있는 doxycyline, minocycline, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase 억제제도활발히연구되고있다. 48 결론 다발성경화증은탈수초병변과함께초기부터축삭의손상이진행되는신경퇴행성질환이다. 재발이없는상태에서도뇌 MRI를이용하여뇌위축정도를측정함으로써병의진행정도를예측할수있다. 또한최근에는 OCT를이용한망막신경섬유두께를측정함으로써병의진행경과를예측하는데에사용할수있을것으로생각된다. 다발성경화증환자를초기에치료하면더좋은예후를볼수있기때문에 CIS 상태에서빨리진단하기위한다양한노력들이진행되고있으며새로운 MRI 기준이제시되고있다. 다발성경화증의치료로인정되어온 interferon beta 는장기간사용에도새롭게보고된부작용이없었으며, 이전에보고되었던부작용도감소하는경향을보였다. 면역조절제제사용에도진행하는다발성경화증의치료를위해여러면역억제제와병합요법및경구제제가개발중이나아직까지는더많은연구가필요한상태이다. REFERENCES 1. Poser CM, Paty DW, Sceinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13: McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50: Barfhof F, Filippi M, Miller HD, Scheltens P, Campi A, Polman CH, et al. Comparison of MR imaging criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997;120: Tintoré M, Rovira A, Martínez MJ, Rio J, Díaz-Villoslada P, Brieva L, et al. Isolated demyelinating syndrome: comparison of different MR imaging criteria ro predict conversion to clinically definite multiple sclerosis. Am J Neuroradiol 2000;21: Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald Criteria. Ann Neurol 2005;58: Swanton JK, Rovira A, Tintoré M, Altmann DR, Barkhof F, Filippi M, et al. MRI criteria for multiple sclerosis in patients presenting with clinically isolated syndromes: a multicenter retrospective study. Lancet Neurol 2007;6: Swanton JK, Fernando K, Dalton CM, Miszkiel KA, Thompson AJ, Plant GT, et al. Modification of MRI criteria for multiple sclerosis in patients with clinically isolated syndrome. J Neurol Neurosurg Psychiatry 2006;77: Montalban X, Tintoré M, Swanton J, Barkhof F, Fazekas F, Filippi M, et al. MRI criteria for MS in patients with clinically isolated syndrome. Neurology 2010;74: Mowry EM, Loguidice MJ, Danielas AB, Jacobs DA, Markowitz CE, Galetta SL, et al. Vision related quality of life in multiple sclerosis: correlation with new measures of low and high contrast letter acuity. J Neurol Neurosurg Psychiatry 2009;80: Compston A, Coles A. Multiple sclerosis. Lancet 2008;372: Sepulcre J, Murie-Fernandez M, Salinas-Alaman A, García-Layana A, Bejarano B, Villoslada P. Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS. Neurology 2007; 68: Fisher JB, Jacobs DA, Markowitz CE, Galetta SL, Volpe NJ, Nano-Schiavi ML, et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology 2006;113: Pulicken M, Gordon-Lipkin E, Balcer LJ, Frohman E, Cutter G, Calabresi PA. Optical coherence tomography and disease subtype in multiple sclerosis. Neurology 2007;69: Costello F, Hodge W, Pan YI, Freedman M, DeMeulemeester C. Differences in retinal nerve fiber layer atrophy between multiple sclerosis subtypes. J Neurol Sci 2009;281: Kolappan M, Henderson AP, Jenkins TM, Wheeler-Kingshott CA, Plant GT, Thompson AJ, et al. Assessing structure and function of the afferent visual pathway in multiple sclerosis and associated optic neuritis. J Neurol 2009;256: Gordon-Lipkin E, Chodkowski B, Reich DS, Smith SA, Pulicken M, Balcer LJ, et al. Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis. Neurology 2007;69: Talman LS, Bisker ER, Sackel DJ, Long DA Jr, Galetta KM, Ratchford JN, et al. Longitudinal study of vision and retinal nerve fiber layer thickness in multiple sclerosis. Ann Neurol 2010; 67: The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43: PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomized double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352: Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al. The Multiple Sclerosis Collaborative Research 36 대한다발성경화증학회지제 1 권제 2 호, 2010

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