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1 Korean J Gastroenterol Vol. 64 No. 3, pissn eissn CASE REPORT 5-Fluorouracil 을투여한대장암환자에서총정맥영양공급치료중에발생한베르니케뇌병증 2 예 조경표, 이재성, 성지석, 우용문, 조영준, 정범진, 손지훈 1, 김수정 1 서울적십자병원내과, 서울대학교병원공공보건의료사업단 1 Two Cases of Wernicke s Encephalopathy That Developed during Total Parenteral Nutrition in Colon Cancer Patients Treated with 5-Fluorouracil-based Chemotherapy Kyung Pyo Cho, Jae Sung Lee, Ji Seok Seong, Yong Moon Woo, Young Jun Cho, Beom Jin Jeong, Jee Hoon Sohn 1 and Su-Jung Kim 1 Department of Internal Medicine, Seoul Red Cross Hospital, Division of Public Health Medical Service, Seoul National University Hospital 1, Seoul, Korea Wernicke s encephalopathy (WE) caused by thiamine deficiency is an acute neurological disorder. Clinically, the classic triad of WE consists of ophthalmoplegia, ataxia, and mental status changes. Thiamine deficiency is known to occur commonly in chronic alcoholic patients. Sometimes, it can occur in patients after gastrointestinal surgery and in those with malabsorption. In addition, patients undergoing renal dialysis, suffering from hyperemesis gravidarum, receiving total parenteral nutrition (TPN), and being treated with chemotherapeutic agents are also prone to develop thiamine deficiency. Herein, we report two cases of WE that developed following simultaneous 5-fluorouracil (5-FU) chemotherapy and TPN in colon cancer patients which was successfully treated with thiamine administration. (Korean J Gastroenterol 2014;64: ) Key Words: Wernicke encephalopathy; Thiamine; Total parenteral nutrition; Fluorouracil; Colonic neoplasms 서론 베르니케뇌병증은 1881년칼베르니케에의해처음으로기술된질환으로 thiamine 결핍이원인으로알려져있으며, 안구진탕, 의식변화, 보행실조의세가지증상을특징으로하는급성대사성뇌병증이다. Thiamine 결핍은주로성인만성알코올중독환자에서흔히발생하지만위장관수술, 혈액투석, 임신오조, 장기간의금식, 영양결핍, 항암제사용등과도관련이있으며 1970년이후 thiamine 결핍과이에따른임상양상의관계가알려지게되었다. 1 암환자는소화기원발병소로인한위장관수술, 식욕저하및구토등으로인한영양실조, 항암제사용등으로 thiamine 결핍의호발조건을가지 고있으나, 지금까지국내에서는암환자에서발생한베르니케뇌병증에대한보고는드물며, 5-fluorouracil (5-FU) 항암제치료로발생한베르니케뇌병증은국내에 2예가보고되었다. 2,3 저자들은대장암환자에서 5-FU를포함한항암제치료와동반하여지속적인총정맥영양공급치료를하던중발생한베르니케뇌병증 2예를경험하였기에보고하는바이다. 증례 1. 증례 1 60세남자가내원 5일전부터발생한의식변화와보행장애를주소로내원하였다. 이환자는고혈압이외다른병력은 Received December 16, Revised March 1, Accepted March 3, CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 교신저자 : 김수정, , 서울시종로구대학로 101, 서울대학교병원공공보건의료사업단 Correspondence to: Su-Jung Kim, Division of Public Health Medical Service, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul , Korea. Tel: , Fax: , annie8012@naver.com Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 64 No. 3, September

2 Cho KP, et al. Two Cases of Wernicke s Encephalopathy in Colon Cancer Patients 159 Fig. 1. Brain magnetic resonance images. T2 weighted images and fluid attenuated inversion recovery (FLAIR) images show (A) high signal intensity in both medial thalamus and (B) high signal intensity in mamillary body (arrows) and dorsal midbrain (arrowheads). 없었고, 4개월전대장암을진단받고저위전방직장절제술을시행하였으며이후재발하여복막파종으로인한장마비가발생하면서금식및총정맥영양공급치료를유지하였다. 고식적항암화학요법으로 5차의 FOLFOX를투여한후촬영한복부컴퓨터단층촬영에서복막파종및악성복수는호전되는추세를보여보존적치료를위해타병원으로전원되었다. 환자는내원 4개월전부터총정맥영양공급치료수액을유지한상태였으며, 거동이가능하였고인지기능에문제는없었다. 내원 4일전부터환자는혼잣말을하는모습을보이고, 이름, 나이에대한질문에대답을하지못하였고, 부인이외에는다른가족은잘알아보지못하였으며, 다리를후들거리며벌리고걷는모습을보였다. 섬망의심하에 quetiapine을복용하며 3일간지켜보던중증상호전이없어본원으로내원하였다. 환자는과거매일소주 1병씩 10년간의음주력이있었으나 1년전중지하였고, 흡연력은없었다. 의식변화등으로내원시혈압은 100/69 mmhg, 맥박및호흡수는 108회 / 분, 18회 / 분이었으며, 체온은 37.3 o C였다. 신경학적검사에서의식은기면상태 (drowsy) 였고, Glasgow coma scale E3V6M4이었다. 양측동공은동일하였고, 대광반사는정상이었으며, 안구검사에서양측방향으로안진 (nystagmus) 이있었고, 손가락- 코시험 (finger to nose test), 빠른교대운동 (rapid alternative movement) 검사에서운동실조소견을보였으나사지근력은정상이었다. 말초혈액검사에서백혈구 2,900/mm 3, 혈색소 9.1 g/dl, 혈소판 88,000/mm 3 의소견을보였고, 생화학검사에서 LDH 207 IU/L, AST 17 IU/L, ALT 7 IU/L, BUN 35 mg/dl, creatinine 1.0 mg/dl, high-sensitivity CRP (hscrp) 7.45 mg/l ( 참고치 : mg/l) 였고, 전해질검사에서 Na meq/l, K meq/l, Cl - 83 meq/l였다. 매독반응검사와간염항원, 항체검사결과는모두음성이었으며혈액응고수치는정상이었고, 요검사에서잠혈및단백뇨모두음성이었다. 갑 상선기능검사에서 free T ng/dl ( 참고치 : ng/dl), thyroid stimulating hormone (TSH) 0.75 IU/mL ( 참고치 : IU/mL) 로정상소견을보였다뇌척수액검사에서백혈구수는 0이었고, 당은 57 mg/dl ( 참고치 : mg/dl), 단백 56 mg/dl ( 참고치 : mg/dl), LDH 18 IU/L였다. 그외에세포검사에서악성세포는없었으며 India ink 및그람염색, 결핵균및바이러스, 진균배양검사에서도모두음성을보였다. 뇌전이및기질적인병변을배제하기위해뇌자기공명영상을시행하였고, T2강조자기공명영상에서양측내측시상 (both medial thalamus), 유두체 (mamillary body), 등쪽중뇌 (dorsal midbrain) 의고음영증강이확인되었으며, 뇌전이나뇌출혈등의소견은보이지않았다 (Fig. 1). 신경학적증상및 4개월이상의총정맥영양공급치료의과거력, 뇌자기공명영상소견을바탕으로하여베르니케뇌병증으로진단하였으며, thiamine을하루 3회, 2일간정맥주사로투여하였다. 3일후 thiamine (1일 500 mg) 근육주사치료로바꾸었고, 환자의안진증상과의식변화는호전되었으며이후외래에서추적관찰하기로하였다. 2. 증례 2 35세남자가내원전일발생한구음장애와내원일발생한의식변화를주소로내원하였다. 환자는 3개월전복막암종증이동반된구불결장암으로진단되어전결장절제술과그물막절제술및회장-직장문합술을시행받았고, 고식적항암제치료로 FOLFOX와 bevacizumab 병용요법을투여받으며경과관찰중이었으며, 복막파종으로인한장마비로타병원에서 80일간금식및총정맥영양공급치료수액을유지하였다. 내원 2일전환자는발음이다소어눌해진것같다고말하였고, 다음날아침지속적으로자는모습을보이고꼬집으면서깨워도점점반응없는모습을보여내원하였다. Vol. 64 No. 3, September 2014

3 160 조경표등. 대장암환자에서발생한베르니케뇌병증 2 예 Fig. 2. Brain magnetic resonance images. T2 weighted images and fluid attenuated inversion recovery (FLAIR) images show (A) high signal intensity in anterior precentral gyrus, (B) high signal intensity in both medial thalamus, (C) high signal intensity in the walls of the third ventricle (arrowheads), periaqueductal gray matter, and dorsal midbrain (arrows), and (D) high signal intensity in mamillary body. 환자는특이과거력은없었으며, 의식변화로내원시혈압은 141/66 mmhg, 맥박및호흡수는 131회 / 분, 20회 / 분이었고체온은 37.4 o C였다. 신경학적검사에서의식은혼미 (stupor) 하였고, Glasgow coma scale E2V2M3이었다. 양측동공은동일하였고, 대광반사는정상이었으며, 안구검사에서양측방향으로안진이있었다. 말초혈액검사에서백혈구 3,800/mm 3, 혈색소 10.7 g/dl, 혈소판 97,000/mm 3 의소견을보였다. 생화학검사에서 AST 18 IU/L, ALT 4 IU/L, BUN 33 mg/dl, creatinine 1.68 mg/dl, hscrp는 4.52 mg/l ( 참고치 : mg/l) 였고, 전해질검사에서 Na meq/l, K meq/l, Cl - 95 meq/l였으며, 혈액응고수치는정상이었다. 갑상선기능검사에서 free T ng/dl ( 참고치 : ng/dl), TSH 1.57 IU/mL ( 참고치 : IU/mL) 로정상소견을보였다. 뇌척수액검사에서백혈구수는 0이었고, 당은 123 mg/dl ( 참고치 : mg/dl), 단백 64 mg/dl ( 참고치 : mg/dl), LDH 49 U/L였다. 그외에세포검사에서악성세포는없었으며 India ink 및그람염색, 결핵균및바이러스, 진균배양검사에서도모두음성을보였다. 뇌전이및기질적인 병변을배제하기위해뇌자기공명영상을시행하였고, T2강조자기공명영상에서중심전이랑 (anterior precentral gyrus), 양측내측시상, 유두체, 제3뇌실벽주위, 뇌수도관주위의회백질 (periaqueductal gray matter), 숨뇌의등쪽 (dorsal side of medulla) 의고음영증강이확인되었으며, 뇌전이나뇌출혈등의소견은보이지않았다 (Fig. 2). 신경학적증상및 80일이상의총정맥영양공급치료의과거력, 뇌자기공명영상소견을바탕으로하여베르니케뇌병증으로진단하였다. Thiamine (1일 500 mg) 정맥주사치료를투여하면서의식이점차회복되었고, 의식을회복하면서안구운동장애, 안진의호전이관찰되었다. 이후대장암복막전이의호전이관찰되어외과와상의하여비위경관영양을시작하였고점차양을늘리면서경구영양을시작하였다. 환자는현재거동이가능하며의식은정상이고, 안진은아직남아있는상태이나호전추세이며현재추적관찰중이다. 고찰 베르니케뇌병증은탄수화물대사에주요한조효소인 thi- The Korean Journal of Gastroenterology

4 Cho KP, et al. Two Cases of Wernicke s Encephalopathy in Colon Cancer Patients 161 Table 1. Summary of the Reported Cases of Wernicke s Encephalopathy in Gastrointestinal Tract Cancer Patients in Korea Thiamine treatment Outcome Image study Thiamine concentration (ng/ml) Neurologic symptoms Type Operation Chemotherapy Nutritional support Age (yr) /sex Authors Jung et al. 3 48/F Gastric cancer Inoperable Paclitaxel/S-1 TPN Ataxia, diplopia, nystagmus Not done MRI Yes Improved Not done MRI Yes Not improved Jung et al. 3 58/F Gastric cancer Subtotal gastrectomy FOLFOX-4 Oral Ataxia, confusion, disorientation, gaze palsy, seizure Unknown MRI Yes Improved Kweon et al. 6 59/M Gastric cancer Gastrectomy Unknown Oral Seizure, gaze palsy, nystagmus, ataxia 7 MRI Yes Improved Kim et al. 7 65/M Gastric cancer Total gastrectomy Unknown TPN Ataxia, disorientation, dizziness, nystagmus 10 MRI Yes Improved Kim et al. 7 71/F Gastric cancer Subtotal gastrectomy Unknown TPN Confusion, disorientation, nystagmus 28.7 MRI Yes Improved Unknown Oral Disorientation, dizziness, nystagmus, ataxia Esophagectomy and total gastrectomy Park et al. 8 42/F Esophageal cancer and gastric cancer Coma Unknown MRI Yes Partially improved Lee et al. 9 72/M Colon cancer LAR and partial colectomy Unknown Oral and TPN Jung et al /F Gall bladder cancer Total cholecystectomy Capecitabine Oral Ataxia, dysarthria Unknown MRI Yes Improved Present case 60/M Colon cancer LAR FOLFOX TPN Ataxia, disorientation, nystagmus Not done MRI Yes Improved TPN Stupor, nystagmus Not done MRI Yes Improved FOLFOX and bevacizumab Present case 35/M Colon cancer Total colectomy with ileorectal anastomosis and omentectomy M, male; F, female; TPN, total parenteral nutrition; LAR, low anterior resection. amine의결핍에의해발생한다. Thiamine은음식물로부터흡수되는수용성의필수비타민 (vitamin B1) 으로, 십이지장에서흡수되어세포의크렙스회로 (Krebs cycle) 와오탄당인산화반응 (pentose phosphate pathway) 을통해에너지대사에중요한역할을한다. 정상성인에서하루 thiamine 요구량은 1-2 mg 정도이며, thiamine 결핍이약 3주정도지속되면혈중의 thiamine 수치도떨어지게되고적절한 thiamine을보충하지않고포도당을투여하였을경우 thiamine 결핍은더욱악화되고빨라지기쉽다. 4 Thiamine 결핍이지속되면뉴런 (neuron) 과성상세포 (astrocyte) 에젖산 (lactate) 이축적되어산성화가나타나게되고이로인해뉴런의괴사가진행되는데, 초기에 thiamine 을보충하게되면가역적인임상증상의호전을기대할수있으나치료가늦어지는경우부분적으로비가역적인신경학적후유증이남거나사망할수있다. 5 지금까지국내에서소화기암환자에서발생한베르니케뇌병증의보고는드물어 8예가보고되었다 (Table 1) 이번증례를포함한 10개의국내증례중남성과여성이각 5명이었고, 진단당시의나이는 35세에서 72세로나타났다. 6명이위암, 3명이대장암, 1명이담낭암이었으며 10예중 9예에서수술의기왕력이있었다. 베르니케뇌병증의세가지주증상인안구진탕, 의식변화, 보행실조모두를보인경우는 5예 (50%) 로나타났는데이는 Jung 등 3 의연구에서도 9예중 5예 (55.5%) 로, 이번증례와비슷한수치를보였다. 국외의연구중 1986년보고된 Harper 등 11 의연구에서는 97예중 94예 (96.9%) 가알코올중독환자였고, 3예가소장절제술, 1예가위수술환자였으며세가지주증상을모두동반하는경우는 97예중 16예 (16.5%) 로보고되었다. 소화기암환자는타부위의암환자에비해 thiamine 결핍의가능성이높은데위장관수술후흡수면적감소나지속적인장마비또는구토와같은기능적인원인으로인하여 thiamine 결핍이나타날수있다. 12,13 또한총정맥영양공급치료수액은항산화제로사용되는중아황산 (bisulfite) 이 thiamine 을 pyrimidine과 thiazole로분해시켜용액의 ph를상승시키며총정맥영양공급치료수액의안정성에영향을미치기때문에대부분 thiamine이포함되어있지않아원인으로나타날수있다 FU는대장, 직장, 위등의소화기암에주로투여하는항암제로, Yeh와 Cheng 15 의연구에따르면 5-FU를투약하는환자중약 5.6% 에서 5-FU와관련된 encephalopathy가발생한다고하였다 FU와베르니케뇌병증과의관련성에대해서도드물지만보고된바가있다 FU가 thiamine의티아민인산 (thiamine phosphate) 으로의전환과정을막는작용을하기때문에베르니케뇌병증이호발되는것으로생각되며아직정확한기전은밝혀져있지않다. 17 Vol. 64 No. 3, September 2014

5 162 조경표등. 대장암환자에서발생한베르니케뇌병증 2 예 5-FU를투여한암환자서베르니케뇌병증이나타난국내증례는소화기암환자에서이번증례를제외하고 1예이고, 3 코인두암환자에서 1예가보고되었다. 2 Jung 등 3 의연구에서는 5-FU를투여한위암환자에서금식이아닌상태에서발생한베르니케뇌병증에대해보고하였는데, 그환자는 thiamine 투여에도회복을하지못하였다. Cho 등 2 은 5-FU를투여한코인두암환자에서금식이아닌상태에서발생한베르니케뇌병증을보고하였으며 vitamin B12와 thiamine 농도가낮지않았다. 베르니케뇌병증의진단은혈청 thiamine의감소나적혈구 transketolase 활성도를측정하는생화학적방법이있으나검사결과를얻기위해수일이소요될수있으므로빠른치료가필요한상황에서임상적인실용성이제한이있다. 따라서베르니케뇌병증의진단은 thiamine 결핍의병력과특징적인임상증상으로이루어진다. 이번증례에서두환자의 vitamine B12와 thiamine의농도를측정하지못하였으나두환자모두 thiamine 결핍가능성이높았으며, 또한정상범위의 thiamine의농도를보이면서베르니케뇌병증으로진단된보고들이있기때문에치료결정을하는데있어영향을주었다고보기어렵다. 18 국내증례에서도치료전 thiamine 농도를측정한경우는 10예중 3예에불과하였다. 뇌자기공명영상은진단을확인하는유용한검사이다. 특징적으로 T2강조자기공명영상에서시상의뇌실주변부와시상하부, 제4뇌실기저, 소뇌정준선, 유두체의양측에대칭적인고신호강도소견을보이고, 조영증강이될수도있는데민감도는 53%, 특이도가 93% 로다른질환을배제하는데유용하며, 추적관찰시치료효과판정에도중요한역할을하고있다. 19 베르니케뇌병증은적절한 thiamine 투여로증상의빠른회복이가능하며치료가늦어질경우비가역적뇌손상을가져올수있기때문에응급상황시 thiamine을투여한후임상증상의회복여부를확인하는것이중요하다. 5 Thiamine의치료용량및빈도, 경로에대해공통된의견은정립되어있지않으나보통 500 mg의 thiamine을하루 1-3 회, 2-3일동안정맥투여하도록하고있으며, 증상의호전여부를관찰하면서반응을보이는경우증상호전이멈출때까지 250 mg으로유지하도록권고하고있다. 5 일반적으로 thiamine 투여후안구증상이수시간내에호전을보이고, 의식혼란과운동실조등의증상은수일에서수주후에좋아지는것으로알려져있다. 20 이번증례는두예모두대장암환자로, 대장암에대한수술을시행한후복막파종에의한장마비가발생하여금식및장기간의총정맥영양공급치료를유지하면서 thiamine 보충이이뤄지지않았던것과 5-FU를항암제치료로사용하였던것이 thiamine의결핍을일으키고베르니케뇌병증이호발할수있는조건이되었던것으로판단되며, 두환자모두 thiamine을 투여하면서호전을보였다. 진행된암환자에서신경학적증상이나타나는경우섬망이나뇌전이, 부종양수반증후군, 항암제에의한신경독성, 마약성진통제과용등과감별이어려워조기발견이쉽지않은경우가많다. 암환자에서베르니케뇌병증을감별하는기준은아직정해진것이없지만이번증례와같이 thiamine 결핍의가능성이높은환자에서안구운동장애나의식변화, 소뇌기능장애등의증상을보인다면베르니케뇌병증을반드시감별진단으로고려하고, 즉시뇌자기공명영상등의검사를시행하며신속히 thiamine 치료를하여야한다. 또한저자들은고위험군의암환자들에게일일권장량의 thiamine을공급하거나곡류나견과류등 thiamine의함량이높은음식을섭취하게하는등베르니케뇌병증의예방에도주의를기울일것을제언하는바이다. 5 REFERENCES 1. Kumar N. Neurologic presentations of nutritional deficiencies. Neurol Clin 2010;28: Cho IJ, Chang HJ, Lee KE, et al. A case of Wernicke's encephalopathy following fluorouracil-based chemotherapy. J Korean Med Sci 2009;24: Jung ES, Kwon O, Lee SH, et al. Wernicke's encephalopathy in advanced gastric cancer. Cancer Res Treat 2010;42: Thomson AD, Cook CC, Touquet R, Henry JA; Royal College of Physicians, London. The Royal College of Physicians report on alcohol: guidelines for managing Wernicke's encephalopathy in the accident and Emergency Department. Alcohol Alcohol 2002;37: Sechi G, Serra A. Wernicke's encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol 2007;6: Kweon YM, Kim JE, Kwon OD, Do JK, Lee DK. Two cases of wernicke encephalopathy with focal cerebral cortical involvement and convulsive seizure. J Korean Neurol Assoc 2004;22: Kim MH, Baek JM, Sung GY, et al. Wernicke's encephalopathy following gastrectomy in patients with gastric cancer. J Korean Surg Soc 2006;70: Park JC, Park SY, Kim DW. Wernicke-Korsakoff encephalopathy following cancer treatment in a patient with schizophrenia. Korean J Med 2009;77:S1289-S Lee H, Lee EH, Lee SC, Park HP. A case of Wernicke's encephalopathy in a postoperative patient with parenteral nutrition and temporary oral feeding: a case report. Korean J Crit Care Med 2010;25: Jung YH, Yu HA, Youn GJ, Lee JI, Woo IS, Han CW. Case of atypical Wernicke's encephalopathy in a GB cancer patient. Korean J Med 2013;84: Harper CG, Giles M, Finlay-Jones R. Clinical signs in the Wernicke-Korsakoff complex: a retrospective analysis of 131 The Korean Journal of Gastroenterology

6 Cho KP, et al. Two Cases of Wernicke s Encephalopathy in Colon Cancer Patients 163 cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry 1986;49: Pagnan L, Berlot G, Pozzi-Mucelli RS. Magnetic resonance imaging in a case of Wernicke's encephalopathy. Eur Radiol 1998;8: Heier MS, Fosså SD. Wernicke-Korsakoff-like syndrome in patients with colorectal carcinoma treated with high-dose doxifluridine (5'-dFUrd). Acta Neurol Scand 1986;73: Scheiner JM, Araujo MM, DeRitter E. Thiamine destruction by sodium bisulfite in infusion solutions. Am J Hosp Pharm 1981;38: Yeh KH, Cheng AL. High-dose 5-fluorouracil infusional therapy is associated with hyperammonaemia, lactic acidosis and encephalopathy. Br J Cancer 1997;75: Kondo K, Fujiwara M, Murase M, et al. Severe acute metabolic acidosis and Wernicke's encephalopathy following chemotherapy with 5-fluorouracil and cisplatin: case report and review of the literature. Jpn J Clin Oncol 1996;26: Pirzada NA, Ali II, Dafer RM. Fluorouracil-induced neurotoxicity. Ann Pharmacother 2000;34: Davies SB, Joshua FF, Zagami AS. Wernicke's encephalopathy in a non-alcoholic patient with a normal blood thiamine level. Med J Aust 2011;194: Chung SP, Kim SW, Yoo IS, Lim YS, Lee G. Magnetic resonance imaging as a diagnostic adjunct to Wernicke encephalopathy in the ED. Am J Emerg Med 2003;21: Zubaran C, Fernandes JG, Rodnight R. Wernicke-Korsakoff syndrome. Postgrad Med J 1997;73: Vol. 64 No. 3, September 2014

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