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1 종설 영남대학교의과대학신경과학교실 Posterior Reversible Encephalopathy Syndrome Se-Jin Lee, MD, PhD Department of Neurology, Yeungnam University College of Medicine, Daegu, Korea Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic state with distinct clinical and radiological features. It is characterized by headache, vomiting, altered mentality, seizures, and visual disturbances. PRES typically consists of reversible vasogenic edema in the posterior circulation territories, although irreversible cytotoxic edema and atypical lesion locations have also been described. Most patients are markedly hypertensive at presentation, although some have only mildly elevated or even normal blood pressure. Many known causative factors of PRES have been elucidated, but its underlying pathophysiology remains poorly defined. This review summarizes the etiologies, presumed pathophysiology, histopathologic findings, basic and advanced imaging features, clinical symptoms of presentation, and treatment of PRES. J Korean Neurol Assoc 34(4): , 2016 Key Words: Posterior reversible encephalopathy syndrome, Etiology, Pathophysiology, Differential diagnosis, Treatment 서 론 고혈압뇌병증, 자간또는장기이식후사이클로스포린 (cyclosporine) 치료를받은환자에서두통, 경련, 시력소실혹은의식저하같은신경계증상이발생하였다가 7일가량지나면대부분회복되고, 뇌영상검사에서양쪽후두두정측두엽에가역뇌병변이나타난증례들이보고되었다. Hinchey 등 1 은이러한환자에서주로후방대뇌백질에국한된혈관부종이발생하고추적뇌영상검사에서대부분의병변이사라지는것을확인한후에가역후백질뇌병증 (reversible posterior leukoencephalopathy syndrome) 으로명명하였다. 이후 Casey 등 2 은뇌백질뿐만아니라피질에도병변이관찰되었기때문에 (posterior reversible encephalopathy syndrome, PRES) 으로개명하였다. 물론 PRES에서혈관부종뿐만아니라세포독부종이관찰되는경우도많고, 이가운데일부는추적검 Received February 10, 2015 Revised March 31, 2015 Accepted March 31, 2015 Address for correspondence: Se-Jin Lee, MD, PhD Department of Neurology, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea Tel: Fax: sejinmayo@ynu.ac.kr 사에서뇌경색으로진행하기때문에반드시가역적인것은아니다. 3-7 아울러대뇌후방뿐만아니라전두엽, 뇌간, 소뇌, 기저핵또는시상에도병변이발생하기때문에 PRES라는명칭이적절한지에대한논란이있다. 2,4-7 PRES는여러질환에의하여유발되고임상증상이비특이적이며발생기전이아직명확하게밝혀지지않았지만자기공명영상 (magnetic resonance imaging, MRI) 에서특징적인병변이발견되면쉽게진단할수있으며국내에서도가역후백질뇌병증혹은으로여러증례를보고하였다. 이종설에서는문헌고찰을통하여 PRES의원인, 발생기전, 병리소견, 임상양상, 영상소견, 치료와예후에대하여자세히알아보고자한다. 본론 1. 원인 연구대상에따라서원인질환의빈도가다르지만고혈압이가장흔하여 PRES 환자의약 75% 에서동반되고 25% 에서는혈압이정상이거나약간상승되어있다. 1,2,4-9 장기이식후면역억제제에의한경우가다음으로흔한데사이클로스포린과타크로리무스 (tacro- J Korean Neurol Assoc Volume 34 No. 4,

2 limus) 가대표적이다 (Table 1). 면역억제제뿐만아니라항암제도 PRES를유발할수있는데고용량을투여하거나여러가지약물을동시에투여할때발생빈도가높은것으로알려져있다. 7 전신홍반루푸스, 결절다발동맥염, 피부경화증, Wegener 육아종증, 혈전혈 Table 1. Conditions at risk for PRES Hypertension Toxemia of pregnancy (preeclampsia/eclampsia) Post-transplantation Allogenic bone marrow transplantation Solid organ transplantation Immune suppression Cyclosporine, Tacrolimus (FK-506) Infection/sepsis/shock Systemic inflammatory response syndrome Multiorgan dysfunction syndrome Autoimmune diseases Systemic lupus erythematosus Systemic sclerosis (scleroderma) Wegener s granulomatosis Polyarteritis nodosa Thrombotic thrombocytopenic purpura Hypothyroidism Crohn's disease Ulcerative colitis Primary sclerosing cholangitis Rheumatoid arthritis Grave disease Hashimoto thyroiditis Sjögren syndrome Autoimmune hepatitis Anti-phospholipid syndrome Anti-glomerular BM antibody disease Status-post cancer chemotherapy Combination high-dose chemotherapy Reported miscellaneous drugs cytarabine, cisplatin, gemcitabine, bevacizumab (Avastin), tiazofurin, kinase inhibitor BAY Acute intermittent porphyria Miscellaneous reported associations Alcohol withdrawal/intoxication Anaphylaxis Cocaine Methamphetamine Hypomagnesemia Hypercalcemia Hypocholesterolemia Intravenous immunoglobulin Pancreatitis Guillain-Barré syndrome Ephedra overdose Dislysis/erythropoietin Triple-H therapy Tumor lysis syndrome Hydrogen peroxide Dimethyl sulfoxide stem cells BM; basement membrane, PRES; posterior reversible encephalopathy syndrome. 소판감소자색반병같은자가면역질환과자간또는신장질환에서도 PRES가발생한다. 1,2,4-7 감염, 폐혈증또는쇼크환자에서도 PRES가발생할수있는데 86% 가그람양성균이었고 40% 에서는혈압이정상혹은약간상승되었다. 10 Cyclosporine 치료중에저콜레스테롤혈증이발생하였던환자, 갑상선기능항진증에의한고칼슘혈증이나저마그네슘혈증환자에서도발생하였으므로혈중전해질농도와콜레스테롤을확인하여야한다. 이밖에급성간헐포르피린증, 수혈, 알코올중독혹은알코올금단, 자율신경침범에의하여급성고혈압이발생한길랭-바레증후군, 면역글로불린요법을받은길랭-바레증후군, 만성신부전으로투석을받는환자에게에리트로포이에틴요법, 벌침치료또는췌장염등에의한경우도있었다. 2. 병태생리와병리 PRES의발병기전은아직도명확하게규명되지않았으며중요한세가지가설은다음과같다. 1) 과관류현재까지가장유력한가설이며고혈압과자간환자에서 PRES 가많이발생하기때문에제시되었던기전이다. 뇌혈관자동조절의범위를벗어나는수준까지혈압이상승하면세동맥이확장되어모세혈관망에과관류가초래되고이어서적혈구, 거대분자및액체가혈관밖으로유출되어혈관부종이발생한다는가설이다. 11,12 일반적으로피질은혈액뇌장벽이치밀하게연결되어있기때문에부종이잘생기지않는데 PRES에서는부종이피질에서먼저시작되고이어서피질하백질까지파급된다. 2 초기연구에서 PRES 의병변이주로피질하백질에발생된다고오인하였는데이것은시간이경과하였거나중등도이상의 PRES 환자에서주로피질하백질에병변이나타났기때문이다. 두정엽과후두엽에는혈관의교감신경이적게분포하기때문에이부위에병변이잘생기는것으로추정된다. 13 PRES 환자에서고혈압이동반되는경우가많고고혈압을치료하면증상이호전되고뇌관류영상에서과관류가확인되었던증례 14 가있었는데이는과관류가설을뒷받침하고있다. 그러나약 25% 의환자에서는혈압이정상이거나약간높은상태에서도 PRES가발생할뿐만아니라 1,2,4-9 뇌부종의정도와혈압은서로반비례한다는보고가있었다. 10,15,16 아울러혈압이뇌혈관자동조절의상한선을넘는경우는거의없고, 15,17 병변에서관류저하가있었던연구결과 15,18 도있으므로과관류가설만으로 PRES의발생기전을모두설명하기는어렵다. 278 대한신경과학회지제 34 권제 4 호, 2016

3 2) 저관류 PRES의발생기전에대한초기가설인데혈압이상승하면뇌혈관자동조절기능에의하여뇌혈관이수축된다. 과도한뇌혈관의수축으로인하여뇌조직에허혈이발생하면혈액-뇌장벽이손상되고혈관부종과점상출혈이발생한다는가설인데경계부위 (watershed) 에이러한손상이심하게발생하였다. 19 자간 / 전자간환자의뇌혈관촬영에서큰뇌혈관의수축이발견되었기때문에이러한가설이제기되었다. 20 일부환자에서허혈과뇌경색이발견되었고최근에는임신중독환자의단일양자방출단층촬영에서관류저하를확인하였으며 MR (magnetic resonance) 관류영상에서도관류저하가있었는데이러한결과는저관류이론을뒷받침한다. 15,18 그러나고혈압이없는환자에서 PRES가발생하는것과 T세포활성과시토카인방출현상은관류저하로설명할수없다. 7 3) 혈관내피손상과관류혹은관류저하단독으로 PRES의병태생리를정확하게설명하기어렵다. 최근에분자생물학의발달에힘입어 혈관내피손상 이라는새로운가설이제기되었는데혈관내피손상은여러원인에의한 PRES에서공통적으로나타나는현상이며면역반응에의하여혈액뇌장벽손상이발생하는병리기전이다 (Fig. 1). 사이클로스포린과타크로리무스혹은항암제와같은독성물질에노출되거나자가면역질환, 자간, 감염 / 폐혈증 / 쇼크또는장기이식과같은상황에서는혈관내피가활성화되어종양괴사인자-α (TNF-α), 인터루킨-1(IL-1) 또는인터페론-γ와같은시토카인, 케모카인, 집락자극인자 (colony stimulating factors) 혹은엔도텔린 (endothelin) 을분비하고면역체계 (T세포) 가활성화된다. 16,21-24 혈관내피에서분비되는엔도텔린은강력한혈관수축제이므로혈압을상승시키고뇌혈관을수축시켜조직의허혈을유발할수있다. TNF-α와 IL-1은세포간부착분자-1 (intercellular adhesion molecule-1, ICAM-1) 과혈관세포부착분자-1 (vascular cell adhesion molecule-1, VCAM-1) 의발현을증가시키고이는백혈구와반응하여활성산소 (reactive oxygen species) 와단백분해효소를발생시킴으로써혈관내피가손상된다. 22 아울러 TNF-α와 IL-1은성상세포에작용하여혈관내피성장인자 (vascular endothelial growth factor, VEGF) 의생산을증가시키는데혈관내피성장인자는뇌혈관의치밀이음부 (tight junction) 를약화시키고수포공포소기관 (vesiculo-vacuolar organelle) 을활성화시켜부종을일으킨다. 이러한혈관내피기능저하설이 PRES의발병기전과부합되고고혈압이동반되지않는경우, 독성물질또는자가면역질환에의하여 PRES가발생하는것도설명이가능하다. 4,6,7 이러한과정은혈압의변화에의하여영향을받을수있는데, 혈압이상승하면뇌혈관자동조절기능이과민하게반응하여혈관이심하게수축된다. 그래서고혈압을치료하면혈관수축자동조절기능이감소하여혈관이확장됨으로써관류가개선될수있다. 16 아울러혈액뇌장벽이손상되면조영증강이일어날수있는데이것역시혈관내피의기능저하를시사한다. 혈관내피의손상과혈관의수축은뇌관류를감소시켜서뇌조직의저산소증을초래하고, 저산소증으로인하여저산소증유발인자 1-α (hypoxia-induced factor 1-α) 가발현되면 VEGF가더욱증가되어치밀이음부가약화되어부종이악화된다. 미세혈관의내피가손상되거나수축하면적혈구가손상을받거나파괴될수있으며 ( 미세혈관병증용혈 ), 실제로다양한원인에의한 PRES에서미세혈관병증용혈이확인되었다. 24 PRES 환자의 3/4에서고혈압이동반되지만 PRES를유발하는중요원인이라기보다는 PRES를유발하는병리기전에의한결과로보아야한다는주장이제기되었다. 24 첫째, 혈관내피의기능저하로인하여혈관확장제인산화질소 (nitric oxide) 의생성이감소하면 Figure 1. Molecular basis of endothelial damage in PRES. PRES-related conditions cause the activation of the immune system and the release of cytokines such as TNF-a and IL-1. TNF-a and IL-1 induce the expression of the adhesion molecules ICAM-1 and VCAM-1 which interact with leukocytes, making them produce ROS and proteases leading to endothelial damage and consequent fluid leakage. TNF-a and IL-1 can also induce astrocytes production of VEGF which weakens the tight junction of brain vasculature and activates the VVO, thus contributing to edema formation (This figure was kindly provided by Dr. Marra A). PRES; posterior reversible encephalopathy syndrome, TNF; tumor necrosis factor, IL; interleukin; ICAM; intercellular adhesion molecule, VCAM; vascular cell adhesion molecule, ROS; reactive oxygen species, VVO; Vesiculo-Vacuolar Organelle, VEGF; vascular endothelial growth factor. J Korean Neurol Assoc Volume 34 No. 4,

4 혈관이수축하여혈압이상승할수있으며혈관영상에서보이는혈관수축의원인이될수있다. 둘째, 혈관내피의활성화로인하여엔도텔린이분비되면혈관의수축이발생하고혈관에세포유착이증가하는데이로인하여혈압이상승할수있다. 4) 병리급성기에조직생검을하였던보고에의하면병변에내피세포의활성화, 광범위한혈관부종, 반응성성상세포또는반응성소교세포가나타났지만염증반응은없었다. 25 CD4와 CD8을포함하는비특이적 T세포의부착은발견되었으나 B세포, 다형핵백혈구, 단핵구, 대식세포또는임파구침윤은없었다. 혈관의손상에대한보고도있었는데간이식환자의조직생검에서혈관염증과같은급성혈관병이나타났다. 26 급성기를지나고상당한시간이경과한후에하였던부검결과에의하면병변부위에탈수초, 허혈, 신경세포손상, 층형태 (laminar) 괴사혹은출혈이발견되었다. 혈관에는내막비후, 부분협착, 내막박리, 기질화혈전 (organized thrombus) 이보였다. 27 5) 생물표지자젖산탈수소효소 (lactate dehydrogenase, LDH) 는뇌, 신장, 간, 폐, 심근, 비장, 적혈구, 백혈구혹은혈소판에분포한다. 세포내에주로분포하기때문에혈청보다세포내에서농도가 500배가량높다. PRES 환자에서뇌조직의손상혹은용혈이발생하면 LDH 혈청농도가상승하기때문에생물표지자로사용할수있다. 28,29 자간또는전자간환자에서 LDH의혈청농도와뇌부종사이에는상관관계가없었지만 30 PRES 증상이발생하기전에 LDH 혈청농도가먼저상승하므로 PRES 발생을예측하는데도움이될수있다. 30,31 혈관내피활성의표적자인 ICAM-1 과 VCAM-1뿐만아니라 TNF-α와 VEGF도 PRES의생물표지자로사용될수있으나현실적으로임상에서활용하기는부적절하고연구에주로이용된다 임상양상대규모연구결과에의하면발생빈도는자간혹은전자간에의하여여성에서약간많은편이고 50대중반에호발한다. 5,6,9,32-34 대부분환자에서임상증상은비특이적이며병변위치와정도에따라서다를수있다. 경련이발생하면급성으로발현하지만경련이동반되지않으면며칠에걸쳐서서서히의식저하를보이는아급성으로시작된다. 5,6 가장흔한초기증상인발작은 43-92% 에서발생하는데첫 24시간이내에발생하는전신강직간대발작이대부분이며약 2/3에서단발성이었다. 뇌전증지속상태는드물지만 Fugate 등 6 의연구에의하면 18% 에서발생하였는데뇌병변의범위와정도와는상관관계가없었다. 그리고발작이발생하였던대부분의환자에서피질침범이없었기때문에발작과피질병변은연관성이없는것으로볼수있다. 급성기에발작이발생하더라도만성적인뇌전증으로이행하는경우는거의없는것으로나타났지만 35 뇌경색또는뇌출혈의동반여부에따라서차이가있을것으로추정된다. 뇌파에서국소극파가나타날수있지만드문것으로알려져있다. 다음으로흔한초기증상은의식장애 (30-60%), 심한두통 (18-50%), 시력저하혹은시야장애 (10-50%), 구토, 실어증의순서이다. 1,2,5,6,9,32-35 의식장애는 PRES 경과중에대부분의환자에서다양하게나타나는데착란, 졸음, 혼미혹은혼수가나타날수있다. 시각증상은후두엽과시각부챗살침범으로발생하며시력감소, 반맹, 피질시각상실또는환시가나타날수있다. 4. 뇌영상 1) 병변의위치와분포전형적인병변은뇌의후방부에좌우비대칭혹은대칭으로피질, 피질하백질또는심부백질에발생하는혈관부종이다 (Fig. 2). T2-강조영상, 액체감쇠역전회복 (fluid attenuation inversion-recovery, FLAIR) 영상, 겉보기확산계수지도에서는고신호강도로나타나고확산강조영상에서는동신호강도로나타난다. 1,2,4 세포독성부종이동반되면확산강조영상에서고신호강도, 겉보기확산계수지도에서는저신호강도로나타난다. 세포독성부종과조영증강은흔하지않으며있더라도일부분에국한된다. 혈관부종은시간이지나면서대부분저절로좋아진다. 초기에는피질이손상되고시간이경과하면서심부백질이침범되기때문에 MRI 촬영시점과정도에따라서병변의위치가다를수있다. 2 경미한경우에는주로피질에병변이나타나지만중등도인경우에는부종이피질뿐만아니라피질하백질과심부백질에도나타되고심한경우에는피질에서뇌실주변부에이르기까지혈관부종이광범위하게생길수도있다. 과거연구에서는시간이경과한후에혹은증상이심한경우에 MRI를촬영하였기때문에피질하백질에만병변이발생하는것으로오인되었다. 부종이심하거나출혈이동반되어뇌척수액경로를압박함으로써수두증을유발하거나, 종괴효과로인하여중심선이동 (midline shift) 또는이차적인뇌탈출이발생할수도있다. 2,7, 대한신경과학회지제 34 권제 4 호, 2016

5 A B C D Figure 2. Typical Parietal-occipital pattern of PRES. FLAIR images (A) and DWI (B), and ADC maps (C) demonstrate vasogenic edema in the cortex and subcortical white matter of the parietal and occipital lobes. There is slight leptomeningeal enhancement in the posterior area (D). PRES; posterior reversible encephalopathy syndrome, FLAIR; fluid attenuation inversion-recovery, DWI; diffusion weighted images, ADC; apparent diffusion coefficient. 병변위치는두정후두엽 (94-98%) 이가장흔하고전두엽 (77-79%), 측두엽 (64-68%), 소뇌 (33%), 뇌간 (12-20%), 기저핵 (12-20%) 의순서이며뇌간과기저핵이모두침범되는경우는 10% 가량되고자가면역질환에서는소뇌침범이유의하게많았다. 1,6,8 패혈증혹은감염환자에서는피질침범이유의하게많았다. 6 병변의위치와범위는고혈압또는자간의유무와상관관계가없는것으로나타났지만 6,37 자간환자에서병변의숫자가더많고기저핵침범이더많았다는보고가있었다. 37 Bartynski 4 는 MRI 결과를분석하여대뇌반구를침범하는유형에따라서 3가지로나누었다. 첫째, 두정엽과후두엽에만병변이국한 되는특징적이고전형적인유형인데실제로 22% 에불과하였다 (Fig. 2). 둘째, 상전두구 (superior frontal sulcus) 유형은 27% 를차지하였는데상전두구의중반부와후반부피질, 피질하백질과심부백질에병변이발생하는데전두극부분은침범하지않았다 (Fig. 3). 셋째, 전반구분수계 (holohemispheric watershed) 유형은 23% 에서나타났는데전두엽, 두정엽그리고후두엽의분수계에병변이나타났다 (Fig. 4). 이러한 3가지유형에서도병변이일부분혹은비대칭으로나타나기도하고두가지유형이혼재되어있는경우도있다. 최근에비전형적인 PRES를보고하였는데 4-5% 에서는전형적인뇌후방부병변없이뇌간, 기저핵, 시상, 소뇌또는뇌실주위 J Korean Neurol Assoc Volume 34 No. 4,

6 Figure 3. Superior frontal sulcus pattern of PRES. FLAIR images demonstrate high signal intensity lesions involving the cortex and subcortical white matter of the frontal and parietal lobes extending along the middle and posterior portions of the superior frontal sulci. PRES; posterior reversible encephalopathy syndrome, FLAIR; fluid attenuation inversion-recovery. Figure 4. Holohemispheric pattern of PRES. FLAIR images demonstrate high signal intensity lesions in the frontal, parietal, and occipital lobes, with lesser involvement of the temporal lobes. The anterior poles of the frontal lobes are spared. PRES; posterior reversible encephalopathy syndrome, FLAIR; fluid attenuation inversion-recovery. 백질에병변이있었다 (central-variant PRES) (Fig. 5). 2,8,38-42 두정엽-후두엽에전형적인병변이있으면진단에어려움이없지만뇌간, 기저핵또는시상과같은중심영역에만병변이있는경우에는진단이어려울수있다. 4 이외에후방속섬유막과섬 (insular) 의백질에도병변이나타날수있으며미세출혈이약절반에서동반되지만조영증강과세포독성부종은잘동반되지않는다고한다. 38 드물지만뇌간, 소뇌, 기저핵, 시상, 대뇌반구에광범위한병변이나타나는경우도있다 (Fig. 6). 약 5% 에서는광범위한혈관부종이한쪽에만생기는경우도있는데종괴효과로인하여뇌종양과감별이필요한경우 (tumefactive PRES) 도있다. 5 2) 세포독부종세포독성부종은 11-27% 에서나타나는데대부분크기가작은반점 (patchy) 또는점 (punctate) 모양이거나국소뇌이랑형태로나타난다. 3,6,8,34 이러한세포독성부종은시간이지나면서회복되는경우가많지만뇌경색으로진행하면뇌위축과신경계증상이후유증으로남을수있다. 3) 출혈출혈은 5-27% 에서발생한다. 5,6,9,34 Hefzy 등 17 의체계적인연구 에의하면 15% 에서출혈이동반되었고유형은 5 mm 미만의점상출혈, 구 (sulcus) 의거미막하출혈또는뇌실질혈종이있었다. 이가운데점상출혈이가장많았고한환자에서여러종류의출혈이있는경우도있었다. 면역억제요법을받고있는환자에서출혈빈도가높았는데고형장기이식보다는동종이형골수이식을받은환자에서더높았다. 항응고치료를받는환자에서뇌출혈발생빈도가높았지만혈압은뇌출혈과상관관계가없었다. 감수성강조 (susceptibility-weighted) 영상을이용한 McKinney 등 43 의연구에의하면 65% 에서출혈이있었고 T2*-기울기에코영상보다민감도가더높았다. 점상출혈이 90% 를차지하였고환자당평균 3개의점상출혈이있었다. 점상출혈은뇌부종의정도, 세포독부종과조영증강의유무와상관관계가없었고추적검사에서변화가없었다. 4) 조영증강일반적으로조영증강은잘되지않는것으로알려져있지만 21-38% 에서나타났다. 6,9,34 대개경미하고이랑, 연수막혹은피질에조영증강이나타나지만심부백질과경막에조영증강을보이는경우는드물다. 조영증강은뇌부종의범위와정도와는상관이없었다. 282 대한신경과학회지제 34 권제 4 호, 2016

7 A B C Figure 5. Central-variant pattern of PRES. A 80-year-old man presented with altered mental status, acute pyelonephritis, and recent history of mild head trauma. FLAIR images (A) and DWI (B) show vasogenic edema in the bilateral pons, cerebellum, thalami, and basal ganglia with subdural hygroma and hemorrhage. Follow-up FLAIR imaging (C) at 7 days later shows almost resolution of the vasogenic edema and altered mental status of the patient recovered completely within 10 days. PRES; posterior reversible encephalopathy syndrome, FLAIR; fluid attenuation inversion-recovery, DWI; diffusion weighted images. 5) 혈관영상 Bartynski 등 15 의연구에의하면카테터혈관조영술에서는 9명가운데 8명에서이상이있었고 MRA에서는 43명가운데 30명 (70%) 에서혈관의불규칙한확장과수축이중등도이상수준으로나타났지만추적 MRA를했던 11명가운데 9명은혈관이정상으로회복되었다. 감염, 패혈증또는쇼크에의한 PRES 환자를대상으로시행하였던 Bartynski 등 10 의다른연구에서는급성기에 MRA를하였던 10명가운데 9명 (90%) 에서혈관협착혹은말단분지폐색이있었다. 그러나 Fugate 등 6 의연구에서는 MRA (32명), 컴퓨터단층혈관조영술 (1명), 카테터혈관조영술 (4명) 을하였던 37명가운데혈관수축은 4명 (11%), 말단부분지폐색은 1명 (2.7%), 국소후대뇌동맥협착은 1명 (2.7%), 척추동맥박리는 1명 (2.7%) 에서발견되었다. 이처럼혈관촬영결과는연구마다상당한차이가있었다. 혈관병은시간 이경과하면서임상증상과 MRI 결과가호전되면대부분회복된다. 6) 관류 PRES 환자에서관류가증가된다는증례 14 가있었지만최근연구에의하면자간, 자가면역질환또는항암화학요법을받은환자에서관류가감소한다는보고도있었다. 15,18 MR 관류영상을이용한 Bartynski 등 15 의연구에의하면병변부위에서피질과피질하영역의국소뇌혈액량은 59명가운데 51명 (86%) 에서감소하였다. 5. 치료위험인자를신속하게찾은후에이를교정하거나원인약물을중단하는것이가장중요하며뇌부종의악화와후유증을예방할수있다. 1,2,4,6 상황에따라원인이되는면역억제제혹은항암제의 J Korean Neurol Assoc Volume 34 No. 4,

8 A B C Figure 6. Severe PRES. A 58-year-old woman, suffered from systemic lupus erythematosus, presented with seizures. FLAIR images (A, B) demonstrate extensive high signal intensity lesions involving the cortex, subcortical region, and deep white matter throughout much of both cerebral hemispheres. There is also vasogenic edema in the bilateral pons, basal ganglia, and cerebellar hemispheres. On a follow-up FLAIR imaging (C) performed 1 week later, most of the previous lesions were resolved. PRES; posterior reversible encephalopathy syndrome, FLAIR; fluid attenuation inversion-recovery. 중단, 자간또는전자간환자에서는제왕절개를통한분만, 혈액투석이필요할수있다. 만약혈압이높다면즉시혈압을정상으로낮추어야하는데산모는혈압을너무많이감소시키면태반의혈류가감소될수있으므로주의하여야한다. 44 발작혹은뇌전증지속상태가발생하면즉시항경련제를투여하여발작을중단시켜야한다. 산모에서발작이발생하면마그네슘황산 (magnesium sulfate) 을투여하는것이좋다. 44 발작이발생하면급성기에항경련제를투여하지만증상과 MRI 병변이좋아지면항경련제를중단하는것이바람직하다. 급성기를지나면항경련제를중단하더라도발작이재발하는경우는드물고뇌전증으로이행하는경우는거의없다고한다. 35 그러나급성기를지나서발작이재발하는경우에는장기간항경련제치료가필요하며뇌출혈혹은뇌경색의유무와연관성이있을것으로추정된다. 양쪽소뇌에걸친광범위한뇌부종에의하여뇌간이압박되고 제4뇌실이눌려서수두증이발생한환자에서뇌실문합과개두술을하였던증례보고가있다. 36 내피세포를활성화시키는 TNF-ɑ와치밀이음부를약화시켜혈액-뇌장벽에손상을유발하는 VEGF의수용체를억제하거나항체를투여하면이러한손상을차단할수있을것으로추정된다. 24 글루코코르티코이드는혈관내피에직접작용하여이를안정시키고혈관투과성을감소시키는것으로알려져있다. PRES 의병변이주로혈관부종이고혈관내피의손상으로발생하므로스테로이드치료가도움이될수있지만효과에대한임상연구가없었고일반적으로추천하지않는다. 6. 예후원인질환을치료하거나유발약물을중단하면신경계증상은대부분 6-8일이내에회복된다. 5,9 그러나신속한진단이이루어지지않아 284 대한신경과학회지제 34 권제 4 호, 2016

9 치료가지연되면영구적인후유증혹은사망을초래할수있다. PRES 자체에의한사망은드물고다발기관부전의유무와정도또는원인질환에의하여결정된다. 환자의 20% 가량에서는 MRI에서세포독부종이관찰되고약 10% 에서는뇌실질에큰혈종이동반되는데이러한경우에는신경계후유증의발생위험성이높다. 뇌출혈은발작의위험인자로작용하기때문에발작의위험성이증가하는데연구에의하면미세출혈이동반된환자의 5-8% 에서는다른증상이회복 된후에도 1개월이상발작의위험성이높은것으로나타났다. 7. 재발재발은흔하지않지만 % 정도이며점차증가하는추세이다. 6,9,45,46 유발요인이다시나타날때재발할수있는데만성신부전환자에서고혈압위기에의한경우가가장많았고, 첫발병후 30일 A B C D E Figure 7. MRI of acute toxic leukoencephalopathy. DWI (A), ADC maps (B), and FLAIR images (C) demonstrate abnormal cytotoxic edema in the bilateral deep white matter and corpus callosum symmetrically. On a follow-up DWI (D) and FLAIR images (E) performed 1 week later, all of the previous lesions except splenium of the corpus callosum were resolved. MRI; magnetic resonance imaging, DWI; diffusion weighted images, ADC; apparent diffusion coefficient, FLAIR; fluid attenuation inversion-recovery. J Korean Neurol Assoc Volume 34 No. 4,

10 에서 2년후에발생하였으며재발이거듭될수록시간이짧아지는경우도있었다. 33,44,47 여러가지위험인자가동반되면재발가능성이높아지므로고혈압이있으면적극적인혈압조절이필요하다. 48,49 8. 감별진단 1) 독성백질뇌병증 (toxic leukoencephalopathy) 독성백질뇌병증은항암치료, 면역억제제, 약물남용, 환경독성물질, 감염에의하여뇌백질에손상이발생하는질환이다. 50 PRES는사이클로스포린과타크로리무스또는항암제에의하여주로발생하지만독성백질뇌병증을일으키는많은원인도 PRES를유발할수있다. PRES 에서는혈관의내피세포가주로손상되지만독성백질뇌병증은백질에분포하는소동맥이주로손상된다. 7 이러한차이로인하여 PRES는피질과피질하백질의손상이먼저발생하고독성백질뇌병증은심부백질에서손상이시작된다 (Fig. 7). 51 독성백질뇌병증은주로세포독부종이발생하기때문에 PRES보다예후가나쁘다. 2) 가역뇌혈관수축증후군 (reversible cerebral vasoconstriction syndrome, RCVS) RCVS는뇌혈관의수축이발생하는가역비염증질환으로서대부분반복되는벼락두통으로발현하고구역, 구토, 시각증상, 눈부심, 소리공포증이흔히동반되고경련, 일시적인신경계증상, 뇌졸중, 비동맥류성거미막하출혈이발생할수있다. 52 PRES를일으키는원인 ( 자간, 폐혈쇼크, 면역글로불린, 수혈, 고칼슘혈증, 포르피린 ) 가운데 RCVS를유발하는것도있다. RCVS 환자의 8-38% 에서는가역혈관부종이나타나는데대개 1개월이내에회복되지만거미막하출혈, 뇌출혈혹은뇌경색과동반되어발생하는경우가많다 (Fig. 8). 52,53 국제두통학회의 RCVS 진단기준에는수축된뇌혈관이 3개월이내에회복되어야하는것으로명시되었으며 PRES 와비교하면 RCVS에서는비동맥류성거미막하출혈이더빈번하고뇌혈관촬영에서다발성뇌혈관수축이현저한것으로보고되었다. 이처럼 PRES와 RCVS의유발요인, 가역혈관부종과가역뇌혈관수축이서로동일하거나유사한부분이많으므로동일한기전에의하여발생하는스펙트럼질환으로추정된다. 성부종이병변전체에생기지않고일부분에국한되기때문에대부분감별이가능하다. PRES 에서는후두엽의정중앙옆부분과새발톱 (calcarine) 부위는잘침범하지않기때문에감별에도움이된다. 1 증상에대한자세한병력청취를통하여 PRES의증상을확인하고혈관촬영에서동맥의폐색과추적 MRI에서뇌연화혹은뇌위축을확인함으로써감별할수있다. 4) 급성저산소-허혈뇌병증 (acute hypoxic-ischemic encephalopathy, HIE) PRES에서는세포독성부종이작은점혹은국소이랑형태로발생하고 FLAIR 영상과비교하면병변의일부분에지나지않지만 HIE에서는훨씬심하고광범위한세포독성부종이피질에다발성으로나타난다. 7 HIE에서는후두엽뿐만아니라섬, 피각, 해마, 소뇌에도세포독부종이관찰된다. 5) 삼투탈수초증후군 (osmotic demyelination syndrome) 교뇌를침범하지만다른부위에병변이없는 (central variant) PRES는중심교뇌수초용해증과감별이필요하다 (Fig. 5). 54 중심교뇌수초용해증에서교뇌의중심부가침범되지만바깥쪽은보존되기때문에병변이박쥐날개 (bat-wing) 모양으로나타나고세포독부종과조영증강이일어날수있다 (Fig. 9). 교뇌외수초용해증에서는시상, 기저핵, 외측무릎체또는드물게피질과해마도침범될수있으므로역시 PRES와구분하여야한다. 저나트륨혈증을빨리교정하였거나, 전해질이상, 알코올중독, 심한화상, 장기이식또는영양실조의병력이있는지확인이필요하다. 전해질이상없이 PRES 유발요인이있고가벼운의식저하와교뇌의경미한혈관부종이나타났다가며칠이내에의식이회복되고혈관부종이사라지는경우에는중심교뇌수초용해증보다는 PRES의가능성이높다. 40 6) 급성간뇌병증 (acute hepatic encephalopathy) 만성간질환의병력이있으면서 MRI T1-강조영상에서기저핵에고신호강도의병변이나타난다. 양쪽시상, 후방속섬유막또는뇌실주변백질에 FLAIR에서고신호강도, DWI에서저신호강도의병변이보인다. 55,56 피질과피질하백질도침범될수있지만후두엽에는병변이잘생기지않는다. 3) 뇌경색급성뇌경색에의한병변은세포독부종이지만 PRES는주로혈관부종이므로감별에어려움이없다. 두정후두엽에아급성뇌경색이양쪽에발생하면구분이어려울수있지만 PRES에서는세포독 7) 뇌종양대부분에서뇌종양과감별은어렵지않지만한쪽에발생하는종양형태 (tumefactive) 의 PRES에서는조영증강이되지않기때문에낮은등급의신경교종과감별이필요하다. 7 뇌간의신경교종은급 286 대한신경과학회지제 34 권제 4 호, 2016

11 A C B Figure 8. MRI of reversible cerebral vasoconstriction syndrome. A 33-year-old woman presented with thunderclap headache, vomiting, weakness of right leg, and blindness. DWI (A) and ADC maps (B) demonstrate cytotoxic edema, consistent with infarcts, in the bilateral parieto-occipital regions. MRA (C) shows stenosis of the left anterior cerebral artery (long arrow) and multiple irregular constriction and dilatation of bilateral posterior cerebral arteries (short arrows). Follow-up MRI showed subacute stage of infarcts in the same area of (A) and (B), and MRA showed almost resolved state of arteries (not shown here). MRI; magnetic resonance imaging, DWI; diffusion weighted images, ADC; apparent diffusion coefficient, FLAIR; fluid attenuation inversion-recovery, MRA; magnetic resonance angiography. A B C Figure 9. MRI of central pontine myelinolysis. DWI (A) and FLAIR images (C) showing high signal intensity in the central pons with sparing of periphery. ADC maps (B) showing isosignal intensity and subtle low signal intensity in the same area of (A) and (C). MRI; magnetic resonance imaging, DWI; diffusion weighted images, FLAIR; fluid attenuation inversion-recovery. J Korean Neurol Assoc Volume 34 No. 4,

12 성으로발병하지않고증상이서서히시작되며젊은나이에서생기고 PRES의원인질환이없으며증상이호전되지않고악화된다. 결 론 PRES는다양한원인에의하여의식저하, 경련, 두통또는시각증상이발생하였다가 7일가량지나면회복되고 MRI에서가역혈관부종이나타나는질환이다. 비전형적인증례가많이있기때문에이를고려하여야한다. 혈관부종이여러부위에나타나면서전형적인병변이없는경우에는추적 MRI를하고임상경과를주의깊게확인하여 PRES를감별하여야한다. 아울러 PRES의유발요인이있는경우에는발생가능성을염두에두고 PRES의증상이나타나면즉시 MRI를촬영하여야한다. 향후병태생리에대한연구가활발히이루어져발생기전을밝힘으로써 PRES에의한손상을조기에차단할수있을것이다. 기존영상기법뿐만아니라확산텐서영상, 확산텐서경로술 (tractography) 과뇌관류영상에대한연구는 PRES의병인, 진단및치료에더많은도움을줄수있을것으로예상된다. REFERENCES 1. Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996; 334: Casey SO, Sampaio RC, Michel E, Truwit CL. Posterior reversible encephalopathy syndrome: utility of fluid-attenuated inversion recovery MR imaging in the detection of cortical and subcortical lesions. AJNR Am J Neuroradiol 2000;21: Covarrubias DJ, Luetmer PH, Campeau NG. Posterior reversible encephalopathy syndrome: prognostic utility of quantitative diffusion-weighted MR images. 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