원저 연세대학교의과대학신경과학교실 Differential Diagnostic Value of Transient Increase of Plasma Ammonia Level in Seizure and Syncope Yun Ho Choi, MD, Ji Hwa Kim, MD, Won Ko, MD, Hye Ihn Kim, MD, Won-Joo Kim, MD, PhD Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea Background: Differential diagnosis between a generalized tonic-clonic seizure and syncope may be difficult due to similar clinical features. The need for a biological marker to distinguish a seizure from syncope has been emphasized from past studies. Transient hyperammonemia could be an indicator of recent convulsive seizure. The purpose of this study is to review the use of plasma ammonia level in the differential diagnosis of seizure and syncope. Methods: Adult patients who were admitted to the Department of Neurology at Gangnam Severance Hospital with final diagnosis of a generalized tonic-clonic seizure or syncope were eligible for this study. Plasma ammonia levels were checked within 8 hr after an insult. Results: Among the patients with a loss of consciousness who underwent analysis of plasma ammonia level, diagnoses were made with a seizure (n=65) and syncope (n=38). The seizure group had 7.29±7.86 μmol/l and the syncope group had 28.37±1.27 μmol/l of ammonia level, respectively. The seizure group presented with a significantly increased plasma ammonia (p<.5) compared to the syncope group. The cut-off value with the reliable diagnostic level was defined as 36 μmol/l (=61.38 μg/dl) with a sensitivity of.65 and specificity of.8 by receiver operating characteristic (ROC) curve analysis. Conclusions: Plasma ammonia measurement during acute post-ictal period may be a useful test for the identification and the differential diagnosis of seizures and syncope. J Korean Neurol Assoc 3(4):279-283, 212 Key Words: Ammonia, Hyperammonemia, Seizure, Syncope 서론 의식소실은발작과실신모두에서발생하지만, 이두가지는원인, 치료, 예후가다르므로정확히진단하는것이매우중요하다. 1 임상증상이전형적이라면, 이둘을구분하고진단하는것이그리어려운일은아니다. 2,3 하지만의식소실당시목격자가없거나특징적인임상증상이없을경우에는병력청취만으 Received April 19, 212 Revised June 7, 212 Accepted June 7, 212 *Won-Joo Kim, MD, PhD Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 135-72, Korea Tel: +82-2-219-3324 Fax: +82-2-3462-594 E-mail: kzoo@yuhs.ac 로감별하는것이매우어렵다. 3 실신환자도혀를깨물거나요실금같은증상이드물지않으며, 가장오진하기쉬운근간대움찔현상도약 15% 에서나타날수있다고알려져있다. 1,2,4 이러한이유로뇌파, 24시간심전도검사, 기립경사검사, 심초음파같은의식소실과연관있는검사를하지만한계가있다. 발작간뇌파의위음성률이높으며, 1 부정맥, 서맥, 저혈압같은심장문제가발작과동반하여나타날수있기때문이다. 2,3 따라서발작과실신의감별을위해보다객관적이고적절한검사지표가필요하다. 프로락틴, 크레아틴인산활성효소 (creatine phosphokinase, CK) 수치는이전부터널리연구되어왔으며, 5-1 최근음이온차이 (anion gap) 와대사산증 (metabolic acidosis), 뉴런특이에놀라아제 (neuron-specific enolase, NSE) 같은유용한지표가소개되었으나, 11,12 아직임상에서널리사용되지못하고있다. J Korean Neurol Assoc Volume 3 No. 4, 212 279
이와더불어, 발작후일시적인암모니아상승이보고되었다. 13-18 이전부터의식소실로응급실에온환자에게원인을찾기위해혈장암모니아를확인해왔다. 암모니아상승은별아교세포 (astrocyte) 의구조와기능변성을일으키고뇌부종을야기하는것으로알려져있으며, 간성뇌병증, 패혈증같은다양한질환과관련이있기때문이다. 19-21 하지만, 실제발작과실신감별을위해임상지표로암모니아를사용하는것이적절한지에대해서는아직연구가부족하다. 이에저자들은발작에서일시적암모니아상승을확인하고, 발작과실신을감별하기위한수단으로암모니아수치의임상적유용성을알아보고자본연구를하였다. 대상과방법 28년 1월 1일부터 211년 2월 28일까지의식소실때문에강남세브란스병원응급실을방문한 16세이상의성인환자를연구대상으로하였다. 모든환자에게병력청취와의무기록, 신경계진찰을신경과의사두명이하였으며, 신뢰할수있는성인목격자가없는경우는대상에서제외하였다. 혈액은암모니아검사를위해응급실에도착한직후바로채취하였으며, 의식소실 8시간이후에채취된경우에는제외하였다. 혈장암모니아수치분석은 COBAS INTEGRA 8 (Roche Diagnostics Limited, Rotkreuz, Switzerland) 를이용하였다. 이후뇌파, 뇌영상검사, 심전도, 24시간심전도검사, 기립경사검사, 심초음파를하였다. 첫발작이의심되는경우는수막뇌염감별을위해뇌척수액검사를추가로하였다. 급성뇌경색, 뇌출혈, 저산소증, 중추신경계감염이있는경우는대상에서제외하였고, 의식소실에영향을줄수있을만한내과적문제나간수치증가 (AST/ALT> UI/L), 혈소판감소 (<,/ul), 만성간질환의과거력이있는경우도제외하였다. 발작진단은병력청취, 목격자진술, 진찰검사결과를토대로신경과의사가하였다. 발작군은전신강직간대발작으로제한하였으며, 국소부분발작, 복합부분발작이나뇌전증지속상태는제외하였다. 따라서강직간대발작운동과발작후혼동과수면증상이있으며, 뇌파에서이와관련된뇌전증모양방전과국소서파가나타난경우를대상으로하였다. 이전에같은발작과발작후증상으로뇌전증이진단된경우는대상에포함하였다. 실신은어지러움, 쓰러질것같은느낌, 발한같은증상이있은후온몸이이완된상태로의식소실이있으나발작후혼동과같은증상이없는경우로, 이와관련된분명한혈압저하가있거나 Isoproterenol을사용한기립경사검사에서증상이유도되거나 24시간심전도검사에서심실빈맥혹은기타부정맥이나타 나는경우를대상으로하였다. 통계분석은 SPSS 윈도우용 18. 버전 (SPSS Inc., Chicago, IL, USA) 을이용하였다. 각군의연령, 증상발생으로부터암모니아채취시간, 혈장암모니아수치에대한검정은독립적인 t-test를이용하였고성별에대해서는카이제곱검정을하였다. 군간차이를보이는성별과연령을보정한후다중로지스틱회귀분석 (multiple logistic refression analysis) 을이용하여암모니아수치와채취시간교차비 (odds ratio) 를추정하였다. 혈장암모니아의수치와검체채취시간의관계를분포도로살펴보았으며, 발작군에서이둘의상관관계를알아보기위하여스피어만상관계수를구하였다. 암모니아수치를통하여발작과실신을예측하기위하여 ROC (receiver operating characteristic) 곡선분석을하였다. 암모니아의최적절단값을결정하기위하여두군의 ROC 곡선분석을통해민감도 (sensitivity) 가 1이고특이도 (specificity) 가 1 인지점과제일가까운거리를구하는 Euclidean distance와민감도와특이도가가장큰점을찾는 Youden index (= 민감도 + 특이도 1) 를이용하였다. 암모니아수치의다중 ROC 곡선분석을수행하여 AUC (area under the ROC curve) 값이가장큰경우를최적절단값으로결정하였다. 9 8 7 6 4 3 2 1 7.29 28.37 Seizure (65) Syncope (38) Mean ± standard error Numbers in parentheses are numbers of tested patients Figure 1. Plasma ammonia level. 결과 대상환자는총 13명으로발작군 (65명), 실신군 (38명) 이었다. 발작군의평균연령은 35.75±14.81세 (17-86세) 로남자 49명 (75.4%), 여자 16명 (24.6%) 이었고실신군의평균연령은 46.74± 28 대한신경과학회지제 3 권제 4 호, 212
21.17세 (16-89세) 로남자 2명 (52.6%), 여자 18명 (47.4%) 이었다. 평균혈장암모니아수치는발작군은 7.29±7.86 μmol/l, 실신군은 28.37±1.27 μmol/l로의미있게발작군에서높았다 (p<.1)(fig. 1). 증상발생으로부터암모니아채취시간은두군간에의미있는차이가없었으나, 평균연령과성별이차이가있었다 (Table 1). 다중로지스틱회귀분석 (multiple logistic regression analysis) 을하여교차비 (odds ratio) 를구하고각변수를보정한후에도평균암모니아수치는교차비 1.64로의미있게발작군에서더높았다 (p=.25)(table 2). 발작군에서혈장암모니아수치와검체채취시간의관계를본분포도에서빨리채취할수록암모니아수치가높았으며 (Fig. Table 1. The comparison of characteristics between seizure and syncope Clinical character Seizure (n=65) Syncope (n=38) p-value Sex (n) (M : F) 49:16 2:18.18 Mean age (yr) 35.75±14.81 46.74±21.17.7 Sampling time (min) 97.54±81.59 121.32±84.87.163 Plasma NH3 (μmol/l) a 7.29±7.86 28.37±1.27 <.1 Mean ± standard deviation. Numbers in parentheses are numbers of tested patients. a US units (μg/dl) = Sl units (μmol/l) 1.73. Table 2. Results of multiple logistic regression analysis Odds ratio 95% Wald confidence interval p-value Sex.588.214 1.616.33 Age.958.932.985.22 Sampling time 1..997 1.2.9481 NH3 1.64 1.22 1.18.25 4 3 3 2 2 1 4 3 3 2 2 1 Seizure (65) 6 12 18 24 3 36 Sampling time (min) Syncope (38) 6 12 18 24 3 36 Sampling time (min) Figure 2. Correlation between plasma ammonia level and sampling time. Numbers in parentheses are numbers of tested patients. 2), 스피어만상관계수는 -.26이었다. 발작과실신의감별을위한암모니아최적절단값을결정하기위하여두군의 ROC 곡선분석을하여구한 Euclidean distance와 Youden index 모두에서 36 μmol/l (=61.38 μg/dl) 가최적절단값이었으며, 이때의민감도는.65, 특이도는.8이었다 (Fig. 3). 또한, 각암모니아수치의다중 ROC 곡선분석을수행하여가장큰 AUC 값을찾는방법에서도같은암모니아값이최적절단값이었다 (Fig. 4). 고찰 의식소실의원인은다양하다. 원인을밝히기에앞서매우중요한일이발작과실신을구분하는것이며, 이에따라원인, 치료, 예후가모두달라진다. 이를감별하기위하여다양한임상지표와객관적인검사를하지만한계가많다. NH3 Sensitivity Specificity Euclidean Youden *36.6476.8.4567.4476 *36.6476.8.4567.4476 *36.6476.8.4567.4476 *36.6476.8.4567.4476 35.67647.75.4887.42647 35.67647.75.4887.42647 35.67647.75.4887.42647 35.67647.75.4887.42647 33.7259.7.4996.4259 34.7588.7.4213.4588 Figure 3. ROC curve analysis of plasma ammonia level between seizure and syncope groups for different cut-off points. Euclidean distance: the straight-line distance between two points on a plane. Youden's index = sensitivity + specificity 1. NH3 AUC 31.77 32.698 33.71 34.73 35.713 *36.724 37.714 38.699 39.69 4.69 Figure 4. Multiple ROC curve analysis of each plasma ammonia level for different cut-off points. AUC; area under the ROC curve. J Korean Neurol Assoc Volume 3 No. 4, 212 281
뇌파는발작을진단하기위해발작활동을직접기록할수있는주요검사이나, 일반적으로단기의식소실로응급실에오는환자에게발작과동시에뇌파를기록할수있는경우는매우드물다. 한연구에서 4세이상의첫발작환자에게뇌파를찍었을때발작간뇌파의위음성률이약 93% 에달한다고보고하였으며, 1 첫기본뇌파의민감도는 2-55% 정도로낮다. 22,23 따라서응급실에서적절한생화학지표가필요하고, 프로락틴과 CK 수치가전신간대강직발작과정신성비뇌전증발작의감별에유용한지표가될수있다고알려져있다. 5-1 특히, 프로락틴의경우성인에서전신간대강직발작을구별하는데민감도약 6%, 특이도는약 96% 를보인다. 7 하지만이는증상발생후 1-2분이라는짧은시간에만의미가있으며, 실신과발작을구분할수는없다. 6,7 CK 수치는정신성비뇌전증발작이나혈관미주신경실신과발작을구별하는데유용하지만, CK의상승시기가응급실도착당시부터 48시간사이로폭넓게분포하고있어적절한채취시간을결정하기에는어려움이있었다. 8-1 최근발작과실신감별에음이온차이와대사산증, NSE가유용한지표로소개되었으나, 11,12 아직검증이더필요한상황이다. 이에반해, 혈장암모니아수치는발작과실신감별에장점이많은지표이다. 첫째, 혈장암모니아는의식소실이생긴환자에게흔히측정하는검사이다. 혈액내암모니아는주로장과근육에서분해되는단백질을통해생성되며, 고암모니아혈증은암모니아의과잉생산이나대사감소로인해나타난다. 과잉생산으로는지나친질소섭취, 장시간의심한운동으로인한근단백질분해, 위장출혈, 변비또는요소- 분열병원체를포함한병적인과정을통해이루어진다. 19-21,24-27 혈장암모니아상승을동반하는질환에는간경화증과전격간염, 바드- 키아리증후군 (Budd-Chiari syndrome), 선천요소회로이상 (congenital urea cycle disorder), 신세관산증 (renal tubular acidosis), 레이증후군 (Reye s syndrome), 요로감염또는기형, 다발골수종, 백혈병이있다. 19-21,28 따라서의식소실의원인감별을위해서라도암모니아수치확인이필요하다. 둘째, 발작후혈장암모니아상승이일시적이며응급상황에대처가능한시기라는것이다. 발작에서혈장암모니아상승은극심한근육수축이푸린뉴클레오티드회로 (purine nucleotide cycle) 에서일인산아데노신 (adenosine monophosphate) 의탈아미노화를일으킴으로써암모니아생성을증가시킨다. 14,24,25,29,3 따라서일시적인극심한경련이발작후암모니아상승을일으키게되고, 이는자발적으로수시간이내에하강하는것으로알려져있다. 한연구에서고암모니아혈증이있는발작군에서대조군에비해 1-3시간후측정한암모니아값이의미있게하강 하는것을확인하였고, 16 다른연구에서는발작후고암모니아혈증이 3-8시간정도지속되며이후정상으로회복되었다고보고하여본연구에서도의식소실후 8시간이내에혈장암모니아수치를측정한환자만을대상으로하였다. 17 본연구에서혈장암모니아수치를각개인마다연속적으로측정하지는못하였으나, 빨리검사할수록암모니아수치가더높았다. 따라서앞서나열한혈장암모니아의상승을일으킬수있는원인이배제된다면고암모니아혈증에대한치료는별도로필요하지않으며, 31-33 의식소실이있는환자에서일시적인암모니아상승을확인하여발작진단에도움을줄수있을것이다. 이런생화학지표가임상진단에도움을주기위해서는, 최적절단값을결정하는것이매우중요하다. 따라서우리는가장정확한진단가치를알아보기위하여 ROC 곡선분석을이용한세가지방법으로최적절단값을구하였으며, 세방법모두에서 36 μmol/l (=61.38 μg/dl) 이최적절단값이었고이때의민감도는 65%, 특이도는 8% 였다. 이결과는최근경련과비경련군을비교한후향연구에서보고된 65 μg/dl ( 민감도 53%, 특이도 9%) 의최적절단값과도유사한결과이다. 18 본연구는의식소실환자를발작과실신군으로나누어혈장암모니아수치를측정한전향연구로, 몇가지제한점이있다. 먼저본원응급실에온성인만을대상으로하고 16세미만의청소년은배제된것이다. 또한, 발작군이실신군보다남자가많고연령이낮았다는것인데, 발작군이근육량이더많고이것이암모니아수치에영향을줄수있을것이라는것이다. 하지만, 본연구에서이러한차이에대한변수를조정한후에도혈장암모니아에차이가있었다. 결론적으로, 의식소실환자에게응급실에서혈장암모니아수치가일시적으로상승하면발작과실신을감별하는데도움이될것이다. REFERENCES 1. McKeon A, Vaughan C, Delanty N. Seizure versus syncope. Lancet Neuroly 26;5:171-18. 2. Bergfeldt L. Differential diagnosis of cardiogenic syncope and seizure disorders. Heart 23;89:353-358. 3. Britton JW, Benarroch E. Seizures and syncope: anatomic basis and diagnostic considerations. Clin Auton Res 26;16:18-28. 4. Sheldon R, Rose S, Ritchie D, Connolly SJ, Koshman ML, Lee MA, et al. Historical criteria that distinguish syncope from seizures. J Am Coll Cardiol 22;4:142-148. 5. Bauer J. Epilepsy and prolactin in adults: a clinical review. Epilepsy Res 1996;24:1-7. 6. Chen DK, So YT, Fisher RS; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Use of serum 282 대한신경과학회지제 3 권제 4 호, 212
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