신경과 강의록

Transcription

1 ISSN J 제 29 권 부 록 년 OURNAL OF THE K OREAN N EUROLOGICAL A SSOCIATION 2011 October Volume 29 Supplement 년도 제30차 추 계 학 술 대 회 10 월 [ 1 ~ th Annual Meeting of the Korean Neurological Association ] -강의록- 대 한 신 경 과 학 회

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21 6 th October, 2011(Thuday) Early-bird Workshop: Learning from Video Epilepsy 2 Partial epilepsy 서대원 ( 성균관의대 ) 4 Generalized epilepsy 조양제 ( 연세의대 ) Abnormal ocular motility in brainstem disorders 8 Medulla 최광동 ( 부산의대 ) 12 Pons 이승한 ( 전남의대 ) 17 Midbrain 김현아 ( 계명의대 ) Integrated Educational Course/PSY Atrial fibrillation (AF) & stroke 25 Overview of AF: evaluation and management 최기준 ( 울산의대심장내과 ) 32 Conventional anticoagulation 김대현 ( 동아의대 ) 38 New anticoagulants 권형민 ( 서울의대 ) Consultation neurology 43 Cognitive impairment and behavioral disturbance 박경원 ( 동아의대 ) 50 Movement disorders 김상진 ( 인제의대 ) 55 Neuromuscular disorders 김병조 ( 고려의대 ) Memorial Lecture 61 Lambert-eaton myasthenic syndrome: UAB experience Shin J. Oh (Univ. Alabama) 18

22 Scientific Session I & PSY Chronic aquired immune-mediated polyneuropathy 64 Spectrum and differentiation Shin J. Oh (Univ. Alabama) 66 Therapeutic considerations 김대성 ( 부산의대 ) Scientific Session II & PSY Epilepsy in the elderly 74 Characteristics 이서영 ( 강원의대 ) 75 Antiepileptic drug selection 김지현 ( 고려의대 ) 81 Cognitive change 박성파 ( 경북의대 ) 7 th October, 2011(Friday) Scientific Session III & PSY Acute visual loss 84 Inflammatory optic neuropathy 오선영 ( 전북의대 ) 91 Ischemic optic neuropathy 박지윤 ( 순천향의대 ) 99 Cerebral visual loss 김선혜 ( 부산의대 ) Plenary Lecture 107 A novel retino-thalamo-cortical pathway mediating migraine-type photophobia Rami Burstein (Harvard Medical School) PSY Accompanying symptoms of migraine 108 Understanding the mechanism of migraine-type photophobia Rami Burstein (Havard Medical School) 19

23 109 Photo-/phono-/osmophobia 주민경 ( 한림의대 ) 115 Nausea & vomiting 조수진 ( 한림의대 ) 117 Dizziness 김병건 ( 을지의대 ) Neuroinfection 120 Blood brain barrier and immune privilege in CNS 박재현 ( 인제의대 ) 124 Neuroimaging in CNS infections 이승구 ( 연세의대영상의학과 ) 129 Antimicrobial therapy for CNS infections 장현하 ( 경북의대감염내과 ) Neurocritical care and brain damage 137 Neurocritical care in post arrest patients 고임석 ( 국립중앙의료원 ) 142 Neurosonology in neurocritical care 이준홍 ( 국립건강보험공단일산병원 ) 148 Brain death: recent views and updates 이광수 ( 가톨릭의대 ) 20

24 2011 년대한신경과학회제 30 차학술대회 2011년 10월 6일 ( 목요일 ) - 첫째날 -

25 특수상황에서의간질환자치료 : 고찰및증례부분간질 성균관대학교의과대학삼성서울병원신경과서대원 Partial epilepsy Dae-Won Seo, MD, PhD Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 우선간질과발작과의관계를보면돌발적증상을보이는간질환자는독립하나의간질로진단되며, 그진단하에다양한임상유형인간질발작을가지게된다. 이러한간질발작은환자의상태와질환의경과에따라변화할수있다. 임상적으로는간질발작, 뇌파, 뇌영상, 혈액검사등을통해간질을진단하게된다. 또한최근에는비디오- 뇌파를통한발작유형, 뇌영상, 뇌면역학, 유전학의발전으로다양한질환들이특징적인간질발작을나타내는경향을보인는것을알수있게되었다. 이러한특정간질에대한특이적효과를보는약물치료, 수술치료들이개발되었다. 따라서과거간질증후군원발성, 속발성, 증후성과단순분류보다는최근의발전된임상개념을포괄하는분류가필요하게되었다. 간질에대한 2010 년 ILAE 보고에따른새로운분류에서는과거에사용한전신간질과국소간질이라는용어는더이상쓰기않고전기임상증후군 (electroclinic syndromes), 명확집합군 (distinct constellations), 구조-대사원인간질 (epilepsies attributed to and organized by structural-metabolic causes), 원인미상증후군 (epilepsies of unknown case) 으로명확히하였다. 또한원발성, 속발성, 증후성이라는말대신에유전성, 구조 / 대사적, 원인미상과같이명확한용어를사용하여구분하게되었다. 우선간질의분류인전기임상증후군 (electroclinic syndromes), 명확집합군 (distinct constellations), 구조- 대사원인간질 (epilepsies attributed to and organized by structural-metabolic causes), Figure 1. Semiological seizure classification. 원인미상증후군 (epilepsies of unknown case) 의네가지구분하였다. 본강의에서도이전분류에서는부분간질이지만위의분류에따라재분류하여간질발작을살표보겠다 (Table 1). 또한이에대한편측화국소화에도움을줄수있는소견을분석할수있는 semiological seizure classification에대해서도살펴보겠다 (Fig.1). Dae-Won Seo, MD, PhD Department of Neurology, Samsung Medical Center, 50 Irwon-dong, Gangnam-gu, Seoul , Korea Tel: Fax: daewon@skku.edu 2 대한신경과학회지제 29 권부록 2, 2011

26 부분간질 Table 1. Electroclinical syndromes and other epilepsies Electroclinical syndromes arranged by age at onset a Neonatal period Benign familial neonatal epilepsy (BFNE) Early myoclonic encephalopathy (EME) Ohtahara syndrome Infancy Epilepsy of infancy with migrating focal seizures West syndrome Myoclonic epilepsy in infancy (MEI) Benign infantile epilepsy Benign familial infantile epilepsy Dravet syndrome Myoclonic encephalopathy in nonprogressive disorders Childhood Febrile seizures plus (FS+) (can start in infancy) Panayiotopoulos syndrome Epilepsy with myoclonic atonic (previously astatic) seizures Benign epilepsy with centrotemporal spikes (BECTS) Autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) Late onset childhood occipital epilepsy (Gastaut type) Epilepsy with myoclonic absences Lennox-Gastaut syndrome Epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) b Landau-Kleffner syndrome (LKS) Childhood absence epilepsy (CAE) Adolescence-Adult Juvenile absence epilepsy (JAE) Juvenile myoclonic epilepsy (JME) Epilepsy with generalized tonic-clonic seizures alone Progressive myoclonus epilepsies (PME) Autosomal dominant epilepsy with auditory features (ADEAF) Other familial temporal lobe epilepsies Less specific age relationship Familial focal epilepsy with variable foci (childhood to adult) Reflex epilepsies Distinctive constellations Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE with HS) Rasmussen syndrome Gelastic seizures with hypothalamic hamartoma Hemiconvulsion-hemiplegia-epilepsy Epilepsies that do not fit into any of these diagnostic categories can be distinguished first on the basis of the presence or absence of a known structural or metabolic condition (presumed cause) and then on the basis of the primary mode of seizure onset (generalized vs. focal). Epilepsies attributed to and organized by structural-metabolic causes Malformations of cortical development (hemimegalencephaly, heterotopias, etc.) Neurocutaneous syndromes (tuberous sclerosis complex, Sturge-Weber, etc.) Tumor Infection Trauma Angioma Perinatal insults Stroke Etc. Epilepsies of unknown cause Conditions with epileptic seizures that are traditionally not diagnosed as a form of epilepsy per se Benign neonatal seizures (BNS) Febrile seizures (FS) a The arrangement of electroclinical syndromes does not reflect etiology. b Sometime referred to as Electrical Status Epilepticus during Slow Sleep (ESES). J Korean Neurol Assoc Volume 29 Suppl. 2,

27 특수상황에서의간질환자치료 : 고찰및증례특발성전신성간질의임상양상 연세대학교의과대학신경과학교실조양제 Clinical Features of Idiopathic Generalized Epilepsy Yang-Je Cho, MD Department of Neurology, Yonsei University College of Medicine, Seoul, Korea Idiopathic generalizedepilepsy (IGE) comprises several spectrum of clinical syndromes. The pathophysiology of the IGE is not fully understood; it is evident that typical absences are the result of abnormal oscillations between the thalamus and cerebral cortex. Genetic influence may play animportant role in its development and many efforts are in progress to elucidate this. The clinical and electroencephalographic (EEG) features of the each syndrome are distinct; however, some cases are difficult to discriminate as one specific syndrome, and their clinical spectrum frequently overlaps among the syndromes. A precise diagnosis is based upon accurate interpretation of both clinical and EEG features, and will be a key-stone for best treatment strategies, for best predictor of outcome, and a strong basis for future genetic study. Key Words: Epilepsy classification, Idiopathic generalizedepilepsy, Electroencephalography, Semiology. 서 론 특발성전신성간질 (idiopathic generalized epilepsy, IGE) 이란특별한선행원인없이, 아마도유전적원인에기인할것으로생각되는전신성간질을일컫는간질증후군이며 1989 년에제정된 International League Against Epilepsy (ILAE) epilepsy classification 에서처음기술되었다. 1-3 일부예외는있으나대개소아기나청소년기에발병한다. 현재간질분류의경향은전신성간질과부분성간질이라는이분법적분류에서벗어나려는경향이있으나, 현재까지도대부분의임상에서사용되고있는 1989 년 ILAE 분류에따르면특발성전신성간질은다음과같이분류할수있다. 4 영아기양성근간대성간질 (benign myoclonic epilepsy in infancy, BMEI), 열성발작을동반한전신성간질 (generalized epilepsy with febrile seizures plus, GEFS + ), 근간대성결신발작을동반한간질 (epilepsy with myoclonic Yang-Je Cho, MD Department of Neurology, Yonsei University College of Medicine, Severance Hospital, 50 Yonsei-ro, Seodaemun-gu, Seoul Korea Tel: Fax: choyj@yuhs.ac absences, EMA), 근간대성무정위발작을동반한간질 (epilepsy with myoclonic-astatic seizures), 소아결신간질 (childhoodabsence epilepsy, CAE), 연소성결신간질 (juvenile absence epilepsy, JAE), 연소성근간대성간질 (juvenile myoclonic epilepsy, JME), 그리고전신긴장간대발작만을동반한간질 (epilepsy with generalized tonic-clonic seizures on awakening, EGTCSA) 이그예이다. 이러한간질의분류에대해여러논란이있기는하다. 연구자에따라이렇듯정확히간질증후군을분류하여각각의분류에따른정확한임상양상, 진단, 치료및예후를기술함으로써, 각각의간질증후군의서로다른유전적, 신경생물학적차이를규명하려는그룹이있는반면, 그와반대로이러한특발성전신성간질을하나의질환으로보는그룹도존재한다. 이들은좀더실제적으로임상에서적용되는관점에서, 이러한특발성간질은하나의공통된병태생리적기전을가지고있으며, 따라서각각의환자들은단지좀더특출한임상적증상에의해분류될뿐이라는것이다. 이에따라이환자들은대체로공통된치료원칙에따라치료할수있으며, 각각개인의환자특성에맞춰치료해야한다는것이다. 1,2,5 이러한원칙은특히신경과에서많이다루는 JAE, JME, 그리고 EGTCSA 에서그러한경향이많으며, 실제임상적인특성이서로혼재되어 4 대한신경과학회지제 29 권부록 2, 2011

28 특발성전신성간질의임상양상 있다. 여기서는임상에서주로보는특발성전신성간질에대해특징적임상양상, 뇌파소견, 치료, 예후들에대해간략히다룰것이다. 1. 소아결신간질 (childhood absence epilepsy, CAE; pyknolepsy) 소아결신간질의발생연령은 3-12 세이며, 대부분 4-8세에서발병한다. 연간발생률은 6-8/100,000 로추산되고있으며, 여아에서조금더많고유전적경향이있다. 이러한유전적소인은단일유전자가아닌다인성이며, 아직그기전이정확히밝혀지지않았다. 6 결신발작은치료하지않을때많게는하루에백번이상도할수있으며, 멍하니무반응을보이는발작이약수초간지속되고대개 15초내외이다. 특징적인 3Hz 전신성극서파복합체가나타나면서바로하던일을멈추고눈을멍하니뜨게되며, 입을오물거린다던지손을움직인다던지하는약한자동증 (automatism) 이적지않게동반되어관찰된다. 때로는얼굴에 clonic jerking 이관찰될수있고, 근육의긴장도가소실되거나또는반대로긴장하게되면서목이나팔다리가힘없이쳐지거나아니면뻣뻣하게뒤로넘어지는경우도때때로관찰할수있다. 7 이러한결신발작은갑작스럽게 (abruptly) 시작하여갑작스럽게끝나므로하던일을잠시멈추었다가다시수초내로바로시작하는증상을흔히볼수있다. 과호흡에의해흔히유발된다. 소아결신간질은대부분의증상이결신발작이라는점에서, 비슷하지만다른증상이좀더동반되는 EMA, JAE, JME, 그리고 frontal dialeptic seizure 와차이가있으나, 실제감별진단이어려울수가있으므로주의하여야한다. 약 40% 의소아결신간질환자가전신성긴장간대발작을나타내며, 8세이후에발병하거나결신발작이잘조절되지않을때, 그리고남아에서좀더많이발생하는것으로알려져있다. 근간대성발작은약 3-8% 정도의환자에서볼수있다. 지능은대부분정상이나, 잦은결신발작이나항간질약물로인해집중력저하를보일수있다. 뇌파는정상배경뇌파와함께전신성또는좌우대칭적인 3Hz 극서파복합체가나타나며, 갑작스런시작과끝이그특징이다. 때로약 2Hz 정도로느리게끝날수있으며, 다극파 (polyspike) 형태도가끔관찰된다. 과호흡에의해잘유발되며 (~95%), 약 20% 의환자에서는광과민성반응을관찰할수있다. 8 수면에의해이러한뇌파형태의변형이관찰될수있으므로각성상태의뇌파를관찰하는것이좀더중요하다. Valproic acid와 ethosuximide 가치료에효과적이며, 약 70% 의환자에서완전한발작관해를기대할수있다. 발작이잘조절되지않는경우, lamotrigine, clonazepam, topiramate 등을추가할수있다. 예후는좋아서청소년기에들면서서서히줄게되고어른이되면약 80-90% 의환자가발작의관해를보이고약을끊을수있게된다. 2. 연소성결신간질 (juvenile absence epilepsy, JAE) 연소성결신간질은소아결신간질의약 4분의 1 정도의발생률을가지고남녀차이는별로없다. 대개 10세를전후해서발생하는것으로알려져있다. 약 3분의 1의환자가가족력이있다. 1,2,6 소아결신간질에비해결신발작의횟수는적으나, 좀더길게발생하고불완전의식소실을보이는경우가많다. 뒤로넘어지는증상은적게나타나나, 근간대성발작은좀더많아서약 16-20% 정도로보고되고있다. 약 80% 정도의환자가전신성긴장간대발작을경험하며, 대부분 (75%) 아침에일어나면서하는경우가많다. 결신발작과전신성긴장간대발작의선후관계를명확히알기힘든경우가많아서, 이경우 EGTCSA 와의감별진단이어려울수있다. 7 뇌파는정상배경뇌파와함께전신성극서파또는다극서파복합체가특징이다. 하지만소아결신간질보다좀더빨라서, 3-4 Hz 의속도를보이며끝날무렵느려지는경우가많다. 역시과호흡과수면박탈에의해잘유발되며, 10-20% 정도의광과민성이보고되고있다. 8 치료는소아결신간질과마찬가지로 valproic acid 와 ethosuximide 가일차약물이다. 전신성긴장간대발작이나, 근간대성발작이동반된경우 valproic acid 가일차고려대상이된다. 예후는좋아서약 80% 의환자가약물에잘조절된다. 하지만약물중단이힘든경우가많은것으로여겨지고있는데, 소아결신간질이약을끊고약 10% 정도만이재발하는반면, 연소성결신간질은 80-90% 가재발하는연소성근간대성간질보다는적으나상당수가재발하는것으로여겨지고있다. 2,9 3. 연소성근간대성간질 (juvenile myoclonic epilepsy, JME; Janz syndrome) 연소성근간대성간질은비교적흔한증후군으로전체간질의약 5-10%, 특발성전신간질의약 20-27% 를차지하는것으로알려져있다. 역시유전적경향이있으나, 단일유전자형은아닌것으로알려져있다. 6 호발연령은 세이며주로전신성긴장간대발작으로병 J Korean Neurol Assoc Volume 29 Suppl. 2,

29 조양제 원을찾게되나, 자세히병력청취를해보면대개아침에발생하는근간대성발작이수개월에서수년선행했던경우가많다. 결신발작, 근간대성발작, 전신성긴장간대발작을다동반하며, 대개 10세경에결신발작, 4-5 년후근간대성발작, 그 1-2 년후전신성긴장간대발작을경험한다고알려져있다. 근간대성발작은대개상지에호발하며, 일측성또는양측성, 근위부혹은원위부다발생할수있다. 의식의변화는없으며대개아침에기상할때발생한다. 흔히수전증으로오인하거나대수롭지않게무시되고컵을떨어뜨리거나칫솔을놓치는등의증상으로기억된다. 때때로전신성긴장간대발작으로진행한다. 결신발작은소아결신발작과유사하나, 자동증이드물고불완전의식소실이많다. 10 잠을못자거나술을마시면잘유발된다. 광과민성은약 50% 의환자에서보고되고있다. 지능은대개정상이다. 뇌파소견은정상배경뇌파와함께 4-6 Hz의다극서파복합체를보인다. 시작부에서가장빠르고대개불규칙적인형태를보인다. 과호흡에의해잘유발되고약 50% 의광과민성이보고된다. 약 30-50% 에서국소극파나예파, 비대칭적전신간질파를보일수있어해석에주의를요한다. 11 Valproic acid 가일차치료약물이며, 약 80% 에서잘조절된다. 근간대성발작의조절을위해 clonazepam 을추가로쓸수도있다. 전신성긴장간대발작의조절을위해, lamotrigine, topiramate, levetiracetam 등을추가할수있다. 예후는좋아서약 90% 의환자가약에잘들으나, 약을중단할경우약 90% 에서재발할가능성이있다. 1,2,6 4. 전신긴장간대발작만을동반한간질 (epilepsy with generalized tonic-clonic seizures on awakening, EGTCSA) 정확한발병률은알기힘들다. 이는 EGTCSA 와아침에생기는다른이차성전신발작또는특발성전신발작과구분이쉽지않기때문이다. 약 10% 에서가족력이있다 세에가장호발하고, 9-25 세로발병연령의폭이넓다. 50% 의환자가결신발작을동반하고 30% 의환자가근간대성발작을보이는것으로보고되고있다. 일반적으로기상후 2시간내에발작이발생할때로정의하는경우가많다. 수면박탈이나, 술에의해악화되며, 다른신경학적이상은없다. 연소성근간대성간질과의감별이때로매우어려운데, 실제로는먼저발생하는발작유형에따라구분하는경우가많다. 이역시특발성전신성간질이일종의공통된병인을가지는하나의질환군으로해석할수있는근거가된다. 1 뇌파소견은 Hz 다극서파복합체가관찰되며, 과호흡에의해항진된다. 광과민성은 15% 정도에서관찰된다. 12 역시 valproic acid 가일차치료약물로흔히선택되며, 다른광범위항간질약을추가할수있다. 예후역시연소성근간대성간질과비슷하여 70% 정도가약물에좋은반응을보이나약을중단하면 80% 이상에서재발하는것으로알려져있다. 결 론 특발성전신성간질은 20대이전에발병하는유전적소인을가진전신성간질이며, 여러가지특징적임상양상을가진증후군들로나뉘어져있다. 결신발작, 근간대성발작, 전신성긴장간대발작등의발작유형이각각의증후군에따라특징적으로나타나나, 때론그구분이모호할수있으며, 이는특발성전신성간질을여러임상범주를보이는하나의공통된병인을가진간질로이해하는근거가된다. 간질약물치료에좋은반응을보이나, 질환에따라약물중단후, 재발하는빈도는각각의증후군에따라다르다. 특발성전신성간질의여러유형에따른그특징적임상양상, 뇌파소견및치료, 예후에대해잘알아야할것이다. Refernces 1. Duncan JS.Idiopathic generalized epilepsies with typical absences. J Neurol 1997; 244: Nordli DR Jr. Idiopathic Generalized Epilepsies Recognized by the InternationalLeague Against Epilepsy. Epilepsia 2005;46: Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification ofepilepsies and epileptic syndromes. Epilepsia 1989;30: Engel J, Jr. A proposed diagnostic scheme for people with epilepticseizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia 2001;42: Berkovic SF, Andermann F, AndermannE, Gloor P. Concepts ofabsence epilepsies: discrete syndromesor biological continuum? Neurology 1987; 37: Beck-Mannagetta G, Janz D, Hoffmeister G, Behl I. Scholz G. Morbidity risk for seizures andepilepsy in offspring of patients withpilepsy. In: Beck-Mannagetta G, AndersonVE,Doose H, Janz D (eds) Geneticsof the epilepsies. Springer, Berlin Heidelberg New York, 1989; Panayiotopoulos CP, Obeid T, WaheedG. Differentiation of typical absencesin epileptic syndromes. A video-eeg study of 224 seizures in 20 patients. Brain 1989;112: Wolf P, Goosses R. Relation ofphotosensitivity to epileptic syndromes. J Neurol Neurosurg Psychiatry 1986;49: Sato S, White BG, Penry JK, Dreifuss FE, Sackellares JC, Kupferberg HJ. Valproic acid versus ethosuximidein the treatment of absenceseizures. Neurology 1982;32: 대한신경과학회지제 29 권부록 2, 2011

30 특발성전신성간질의임상양상 10. Panayiotopoulos CP, Obeid T, Tahan A. Juvenile myoclonic epilepsy:a 5-year prospective study. Epilepsia 1994;35: Panayiotopoulos CP, Chroni E, Daskopoulos C, Baker A, RowlinsonS, Walsh P. Typical absenceseizures in adults: clinical, EEG, vide-eeg findings and diagnostic/syndromicconsiderations. J Neurol Neurosurg Psychiatry 1993;55: Wolf P. Epilepsy with grand malon awakening. In: Roger J, Bureau M,Dravet C, Dreifuss FE, Perret A, WolfP (eds).epileptic syndromes in infancy,childhood and adolescence, 2nd ed. Libbey, London, 1992; J Korean Neurol Assoc Volume 29 Suppl. 2,

31 특수상황에서의간질환자치료 : 고찰및증례숨골병변에서의신경안과적이상 부산대학병원신경과 a, 분당서울대학병원신경과 b 최재환 a 최광동 a 김지수 b Neuro-Ophthalmologic Findings in Medullary Lesions Kwang-Dong Choi, MD a, Jae-Hwan Choi, MD a, Ji Soo Kim, MD, PhD b Department of Neurology, Pusan National University Hospital, Pusan National University College of Medicine a, Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine b The medulla contains nuclei and tracts that are important in the control of eye movements, including the vestibular nuclei, perihypoglossal nuclei, medullary reticular formation, inferior olivary nuclei, and inferior cerebellar peduncle. Various patterns of ocular motor abnormalities, such as spontaneous or gaze-evoked nystagmus, ocular lateropulsion, and ocular-tilt reaction, can be found in medullary lesions by involvements of these structures. The exact understanding for ocular motor abnormalities in medullary lesion would provide valuable information for the mechanism in the control of eye movements. Key Words: Medulla, Eye movement, Nystagmus, Lateropulsion, Ocular-tilt reaction 뇌줄기에는안구운동을담당하는뇌신경및신경핵들이위치하며, 이들과안구운동의핵상 (supranuclear) 조절을담당하는구조물들을연결하는신경섬유들이치밀하게얽혀있으므로, 모든부위의뇌줄기병변에서안구운동장애가관찰될수있다. 1 뇌줄기에서가장아래부위에위치한숨골 (medulla) 에서는전정신경핵 (vestibular nucleus), 설하주위신경핵 (perihypoglossal nuclei) 및아래올리브핵 (inferior olive) 등이안구운동에관여하는주요구조물로알려져있다 (Fig. 1). 전정신경핵의병변은현훈증상과더불어다양한중추성안진을발생시킨다. 안쪽전정신경핵및설하전신경핵 (nucleus prepositus hypoglossus) 은신경적분체 (neural integrator) 로서시선유지에중요한역할을하며, 이곳에병변이생기면시선유발안진 (gaze-evoked nystagmus) 이발생한다. 아래올리브핵은오름섬유 (climbing fiber) 를통해소뇌로정보를입력하며, 전정안반사의적응 (adaptation) 에관여하는것으로알려져있다. 본장에서는숨골에서관찰될수있는다양한안구운동장애에대하여설명하고자한다. 1. 안진 가쪽숨골증후군 (Lateral medullary syndrome) 가쪽숨골증후군에서자발안진은다양하게관찰될수있다. 안진의수평성분은흔히병변반대쪽을향하나 (pseudovestibular nystagmus), 윗쪽숨골이침범될때에는병변쪽을향하는경우가더흔하다. 2 수직성분은주로위쪽을향하며, 회선안진은어느방향으로도발생할수있다. 3 두진후안진은대부분에서병변쪽으로발생하며, 병변반대편으로자발안진이있는환자에서도두진후에는안진의방향이바뀌어나타나는경우가흔하다. 2 수평안진에동반되는눈꺼풀의떨림을눈꺼풀안진 (lid nysatagmus) 이라하며, 눈모음에의해눈꺼풀안진이유발되는경우를 Pick 징후 (Pick s sign) 라한다. 환자에게병변의반대쪽을계속해서쳐다보게하면 1분정도발작적으로지속되는안진및현훈이발생할수있다. Kwang-Dong Choi, MD Department of Neurology, College of Medicine, Pusan National University, 1-10 Ami-dong, Seo-gu, Busan , Korea Tel: Fax: kdchoi@medimail.co.kr 2. 눈가쪽쏠림 (Lateropulsion) 안구운동범위에는제한이없으면서양안이병변쪽으로몰리는현상으로, 환자에게눈을감았다뜨게하면양쪽눈이병변 8 대한신경과학회지제 29 권부록 2, 2011

32 숨골병변에서의신경안과적이상 A B C D Figure 1. Medullary structures involved in ocular motor control. ACN; accessory cuneate nucleus, CF; climbing fibers, CN; cuneate nucleus, CRF; central reticular formation, CST; corticospinal tract, DVN; dorsal vagal nucleus, FN; facial nucleus, GN; gracile nucleus, HN; hypoglossal nucleus, ICP; inferior cerebellar peduncle, IVN; inferior vestibular nucleus, IO; inferior olivary nucleus, ML; medial lemniscus, MLF; medial longitudinal fasciculus, MVN; medial vestibular nucleus, NI; nucleus intercalatus, NPR; nucleus prepositus, NR; nucleus of Roller, NST; nucleus of the solitary tract, PMT; cell groups of the paramedian tract, RA; nucleus raphes, STN; spinal trigeminal nucleus, STT; spinothalamic tract, TST; tectospinal tract, TT; spinal trigeminal tract. 쪽으로쏠려있거나, 쏠려있다가다시중앙으로되돌아오는것을관찰할수있다. 이러한긴장성편위 (tonic deviation) 는수직안구운동에도영향을미쳐, 환자에게위나아래를쳐다보게하면환자의눈이곧바로위아래를향하지못하고병변쪽으로비스듬히움직인후다시중앙으로향하는양상을보인다. 홱보기는병변쪽으로향할때는겨냥과다 (hypermetria), 병변반대쪽으로는겨냥부족 (hypometria) 을보이며 (ipsipulsion), 병변반대편으로의부드런따라보기장애도관찰된다. 4-5 눈가쪽쏠림의정확한기전은모르나, 반대편아래올리브핵에서소뇌로가는오름섬유가가쪽숨골에서침범되어소뇌의 Purkinje 세포가과활성화되기때문이라는주장이있다. 일반적으로 Purkinje 세포는동측의꼭지핵 (fastigial nucleus) 을억제하므로 Purkinje 세포가과활성화되면꼭지핵에의해서흥분되는반대편정중곁다리뇌그물체 (paramedian pontine reticular formation, PPRF) 가억제되어긴장성불균형 (tonic imbalance) 가생긴다는것이다 (Fig. 2). 이외에도이석신경로 (otolithic pathway) 또는꼭지핵에서뇌줄기로정보입력을중개하는 juxtarestiform body 등의관련성이제기된바있다. 3. 눈기울임반응 (Ocular tilt reaction, OTR) OTR 은관상회전면 (roll plane) 에서의전정안반사이상에의해발생하며, 1) 머리기울임 (head tilt), 2) 스큐편위 (skew deviation), 3) 안구회선 (cyclotorsion) 의 3가지반응으로이루어진다 6 (Fig. 3A). OTR 은말초전정에서부터중뇌- 사이핵접합부의 Cajal 사이질핵 (interstitial nucleus of Cajal) 및안쪽세로다발입쪽사이질핵 (rostral interstitial nucleus of medial longitudinal fasciculus, rimlf) 에이르는모든부위의병변 J Korean Neurol Assoc Volume 29 Suppl. 2,

33 최재환최광동김지수 A B Figure 2. Hypothetical scheme for lateropulsion of saccades. Interruption of climbing fibers originating from the inferior olivary nucleus may occur prior to their crossing in the medulla or as they enter the inferior cerebellar peduncle (in lateral medullary syndrome). Loss of climbing fiber inputs to Purkinje cells in the dorsal vermis causes the latter to inhibit the fastigial nucleus, which causes ipsipulsion of saccades. Interruption of crossed fastigial nucleus outputs in the superior cerebellar peduncle causes contrapulsion. ION; inferior olivary nucleus, PC; Purkinje cell, FN; fastigial nucleus, UF; uncinate fasciculus, SCP; superior cerebellar peduncle, PPRF; paramedian pontine reticular formation. 에서발생할수있다. 일반적으로 OTR 의방향은머리가기울어지는방향으로정한다. OTR 에서안구회선은머리가기울어지는방향으로발생하고, 스큐편위도머리가기울어진쪽눈이아래에위치한다. 관상회전면에서의전정안반사는수직반고리관및이석기관 (otolithic organ) 에의해감지되어전정신경핵으로전달되고, 전정신경핵에서통합된정보는하부다리뇌에서반대편으로건너간뒤, 안쪽세로다발 (medial longitudinal fasciculus, MLF) 을따라 Cajal 사이질핵으로가므로, 하부다리뇌아래쪽의병변에서는병변쪽으로, 위쪽의병변에서는병변반대편으로 OTR 이발생한다 (Fig. 3B). 가쪽숨골증후군에서는병변쪽으로 OTR 이발생하며, 그중안구회선은한쪽눈에서만관찰될수도있다. 1. 안진 안쪽숨골증후군 (Medial medullary syndrome) 안쪽숨골증후군에서안구운동장애는비교적드무나, 병변이 Figure 3. (A) Ocular tilt reaction (OTR) to the left with leftward head tilt, left skew deviation (SD) (hypotropic left eye), and ocular torsion (OT). (B) Utricular projections from the vestibular nuclei cross the midline and ascend in the medial longitudinal fasciculus. Interruption of utricular projection before crossing cause ipsilesional OTR, while interruption of crossed fibers give rise to contralesional OTR. 숨골의피개부위를침범하면특징적인안구운동이상을보일수있다. 7-8 자발안진은주로병변쪽을향하며, 시선유발안진도병변쪽을바라볼때더강하게유발된다. 병변쪽을향하는자발안진이나시선유발안진은설하전핵 (nucleus prepositus hypoglossi) 이손상되어발생한다. 설하주위핵 (perihypoglossal nuclei) 의가장아래쪽부위인사이질핵 (nucleus intercalatus) 이침범되면드물게상방안진이발생할수있다. 9 그러나, 한환자에서양측성병변에서관찰되던상방안진이한쪽병변이소실되면서반시소안진 (hemiseesaw nystagmus) 로변하였던것으로미루어상방안진이양측앞반고리관에서기원하는전정안반사로침범되어발생할수있을것으로생각된다 눈가쪽쏠림 안쪽숨골증후군에서는아래올리브핵에서소뇌로가는오름섬유가교차전에침범되어병변반대편소뇌의 Purkinje 세포가과활성화되기때문에, 가쪽숨골증후군과는달리양안이병변반대쪽으로쏠리게된다 (contrapulsion). 따라서, 홱보기는병변쪽으로향할때는겨냥부족 (hypometria), 병변반대쪽으로는겨냥과다 (hypermetria) 을보이며, 병변쪽으로의부드런따라보기장애도관찰된다 3. 눈기울임반응 안쪽숨골증후군에서는병변반대편에서교차되어온전정안반사의손상으로인해병변반대편으로눈기울임반응이발생 10 대한신경과학회지제 29 권부록 2, 2011

34 숨골병변에서의신경안과적이상 한다. 눈입천장떨림 (Oculopalatal myoclonus) 2-3 Hz 주기의시계추안진 (pendular nystagmus) 이입천장떨림 (palatal tremor) 과함께관찰되며심한진동시 (oscillopsia) 를일으킨다. 11 치아핵-적색핵 -아래올리브핵삼각로 (dentatorubro-olivary pathway, Guillain-Mollaret triangle) 의손상에뒤따르는아래올리브핵 (inferior olivary nucleus) 의가성비후 (pseudohypertrophy) 에동반되나정확한발병기전은알지못한다. 12 눈입천장떨림은중심피개로 (central tegmental tract) 를침범하는뇌줄기부위뇌졸중에서수개월의잠복기를두고발생하는것이일반적이나, 드물게는손상후 24 시간이내에수직방향의시계추안진이발생하기도한다. 13 Refernces 1. Bogousslavsky J, Meienberg O. Eye-movement disorders in brain-stem and cerebellar stroke. Arch Neurol 1987;44: Choi KD, Oh SY, Park SH, et al. Head-shaking nystagmus in lateral medullary infarction: patterns and possible mechanisms. Neurology 2007;68: Morrow MJ, Sharpe JA. Torsional nystagmus in the lateral medullary syndrome. Ann Neurol 1988;24: Baloh RW, Yee RD, Honrubia V. Eye movements in patients with Wallenberg's syndrome. Ann N Y Acad Sci 1981;374: Kim JS, Moon SY, Park SH, et al. Ocular lateropulsion in Wallenberg syndrome. Neurology 2004;62: Brandt T, Dieterich M. Vestibular syndromes in the roll plane: topographic diagnosis from brainstem to cortex. Ann Neurol 1994;36: Kim JS, Moon SY, Kim KY, et al. Ocular contrapulsion in rostral medial medullary infarction. Neurology 2004;63: Kim JS, Choi KD, Oh SY, et al. Medial medullary infarction: abnormal ocular motor findings. Neurology 2005;65: Munro NA, Gaymard B, Rivaud S, et al. Upbeat nystagmus in a patient with a small medullary infarct. J Neurol Neurosurg Psychiatry 1993;56: Choi KD, Jung DS, Park KP, et al. Bowtie and upbeat nystagmus evolving into hemi-seesaw nystagmus in medial medullary infarction: possible anatomic mechanisms. Neurology 2004;62: Moon SY, Park SH, Hwang JM, et al. Oculopalatal tremor after pontine hemorrhage. Neurology 2003;61: Kim JS, Moon SY, Choi KD, et al. Patterns of ocular oscillation in oculopalatal tremor: imaging correlations. Neurology 2007;68: Keane JR. Acute vertical ocular myoclonus. Neurology 1986;36: J Korean Neurol Assoc Volume 29 Suppl. 2,

35 특수상황에서의간질환자치료 : 고찰및증례뇌간병변에서관찰되는안구운동장애 : 교뇌 전남대학교의과대학신경과학교실이승한 Abnormal Ocular Motility in Brainstem Disorders: PONS Seung-Han Lee, MD Department of Neurology, Chonnam National University Medical School, Gwangju, Korea Regarding generation and control of eye movements, the pons contains important neural structures such as abducens nucleus, paramedian pontine reticular formation (PPRF), and medial longitudinal fasciculus (MLF). Abducens nucleus contains two types of neurons. Abducens motoneurons innervate the ipsilateral lateral rectus muscle, and abducens internuclear neurons cross the midline and ascend in the MLF to innervate the contralateral oculomotor neurons. MLF also carry vestibular and smooth pursuit signals from the vestibular nuclei to midbrain nuclei connected with vertical gaze. Lesions affecting the MLF cause internuclear ophthalmoplegia. Clinical lesions restricted to the abducens nucleus are rare, and then combined lesions with the MLF are more common. PPRF itself is thought as a generator of the saccadic eye movement, and omnipause neuron in the nucleus raphe interpositus inhibit all horizontal and vertical burst neuron except during saccades. Lesions of the above structures cause various horizontal and vertical eye movements disorders. Key Words: Pons, Abducens nucleus, Paramedian pontine reticular formation, Medial longitudinal fasciculus 서 론 외전신경핵병변 교뇌는안구운동에관여하는여러가지중요한구조물들을포함하고있어서, 이곳을손상시키는여러질환들은침범하는해부학적인구조물에따라다양한안구운동의장애를초래할수있다. 교뇌에존재하는대표적인구조물로서는외전신경핵 (abducens nucleus), 흥분성돌발신경원 (excitatory burst neurons, EBN), 억제성돌발신경원 (inhibitory burst neurons, IBN), 범정지신경원 (omnipuase neuron, OPN) 을포함하여방정중교뇌망상체 (paramedian pontine reticular formation, PPRF), 안쪽세로다발 (medial longitudinal fasciculus, MLF), 교뇌피개그물핵 (nucleus reticularis tegmenti pontis, NRTP) 등이있다. 본원고에서는상기교뇌의구조물을중심으로하여, 임상에서흔히발생하는교뇌이상에따른안구운동장애를살펴보고자한다. Seung-Han Lee, MD Department of Neurology, Chonnam National University Medical School, 671 Jaebongro, Dong-gu, Gwangju , Korea Tel: Fax: nrshlee@chonnam.ac.kr 외전신경핵의병변은동측으로수평공액주시 (horizontal conjugate gaze) 의장애를일으킨다. 병변측눈의외전뿐만아니라반대측눈의내전까지, 즉양안의운동이모두장애를보이는데, 이는외전신경핵이운동신경원 (motoneuron) 과핵간신경원 (internuclear neuron) 두가지신경원으로구성되어있기때문이다. 운동신경원은동측의외직근을지배하며, 핵간신경원은반대측의 MLF 를타고올라가서 3번신경핵에도달하여최종적으로반대측내직근을지배한다. 외전신경핵병변이있는경우에이향운동 (vergence) 을시켰을때반대측눈의내전은대부분보존되는데, 이는이향운동의경우외전신경핵을거치지않고 3번신경핵의내직근신경원으로바로전달되기때문이다. 신속운동 (saccade), 원활추종운동 (smooth pursuit), 시운동성 (optokinetic), 전정안운동 (vestibular movement) 등대부분의안구운동의경우병변측시야를향하는경우에결손을보이나, 반대측시야로향하는경우에는보존된다. 예를들어좌측외전신경핵병변때중앙에서우측으로, 즉병변반대측으로향하는신속운동은보존된다. 이운동은정상적인우측 PPRF 의 EBN 으로부터신호를받는우측외전신경핵으로부터지배를 12 대한신경과학회지제 29 권부록 2, 2011

36 뇌간병변에서관찰되는안구운동장애 : 교뇌 받기때문이다. 우측으로부터중앙을향하는, 즉병변측을향하는신속운동의경우속도가느려지는데, 이안구운동은정상적인우측외전신경핵의지배를받긴하지만좌측연수망상체 (medullary reticular formation) 의 IBN 으로부터신호를받는다. 따라서작용근 (agonist) 의수축이라기보다는길항근 (antagonist) 의이완에의한것이므로신속운동의속도는다소느려지는것으로해석된다. 또한가지나타날수있는안구운동의이상으로는수평성분의주시유발안진 (gaze-evoked nysatgmus, GEN) 이다. 예를들면좌측외전신경핵의병변이있을경우우측을볼때 GEN 이나타날수있다. 이때 GEN 이발생하는기전은반대측외전신경핵으로안구위치에대한신호를전달하는내측전정신경핵 (medial vestinular nucleus, MVN) 으로부터들어오는신경섬유의차단, 또는외전신경핵의입구쪽끝에위치하는 PMT (paramedian tracts) 로부터의신경섬유차단에기인하는것으로생각된다. 1 임상적으로외전신경핵에국한된병변이발생하는것은드물고, 1,2 대신인접한 MLF 나 PPRF 등피개 (tegmentum) 의구조물과같이손상되는경우가더흔하다. 또한동측안면신경의슬상구조부위가같이침범됨으로써안면신경마비가외전신경핵병변과동반되는경우가있다. 뇌경색이나탈수초성병변에의해양측성병변이발생하는경우양측성수평운동마비가발생하기도하지만, 3 이러한경우는근무력증, 보툴리누스중독 (botulism), 밀러피셔증후군 (Miller Fisher syndrome), 베르니케뇌병증 (Wernicke s encephalopathy), 약물중독등을감별해야한다. 4 방정중교뇌망상체 (PPRF) 병변 우선적으로 PPRF 의병변은동측으로의수평성분의신속운동의장애를일으킨다. 그외에도 PPRF 는신속운동의생성에관여하는몇가지다른종류의신경원들을포함하고있고, 또한여기를통과하는안구운동에관여하는신경섬유들이같이손상되기도하므로다른종류의수평및수직안구운동도영향을받을수있다. EBN 은 nucleus pontis centralis caudalis 의등안쪽부위에위치하고, 외전신경핵의상방에위치한다. 또한 EBN 은동측의외전신경핵으로신호를전달한다. 5 거대솔기핵 (raphe interpositus nucleus, RIP) 은외전신경핵높이에위치하는데, OPN 은 RIP 와그들의수상돌기구조물의정중앙에위치하며신속운동시를제외하고모든수평과수직돌발신경원을억제하고있다. IBN 은외전신경핵의하방, 상부연수의등안쪽피개에위치하고있는데, 이는동측의 EBN 으로부터신호를받고, 반대측외전신경핵으로신호를보낸다. 또다른구조물로는 PMT cell group 이있는데이는 PPRF 주변에위치하면서안구운동을조절하는신경원으로서소뇌편엽 (flocculus) 으로신호를보낸다. 6 전정안운동, 원활추종운동, 주시유지에관여하는신호를외전신경핵으로전달하는축색다발또한 PPRF 주변의교뇌를통과한다. 일측성 PPRF 병변은병변측으로의공액수평운동의마비를초래한다. 대체로모든종류의안구운동이다문제가되지만, 전정안운동이나원활추종운동은때때로보존되기도한다. 7,8 또한급성기에는안구가병변반대측으로편위된다. 안진도관찰될수있는데, 병변반대측을주시할때안진의빠른성분이주시방향을향하는양상 ( 즉, 병변반대측을향하는양상 ) 으로나타나고이는암실에서더욱증강된다. 병변측을향하는신속운동과안진의빠른성분이작고느려지며, 이들안구운동은대개정중선을통과하지못한다. 병변측으로향하는신속운동의속도저하는, 정상측시야에서이루어졌을때 ( 예, 우측 PPRF 의병변일때좌측에서중앙으로향하는신속운동 ), 반대측외전신경원으로신호를보내는 IBN 이침범되었는지여부에달려있다. 이는동측으로의신속운동을일으키는신호는동측 PPRF 의 EBN 으로부터오는반면, 신속운동을억제시키는신호는반대측연수의 IBN 으로부터오는점과연관된다. 위에서언급했듯이동측의외전신경원에만병변이국한되어있다면, 건측시야로부터중앙을향하는신속운동은발생할수있으나느려진다. 이는길항근 ( 동측내직근과반대측외직근 ) 의억제는정상이기때문이다. 대부분의 PPRF 병변 ( 특히하방부위를포함하여 PPRF 가광범위하게손상된경우 ) 에서는이러한길항근의억제또한장애를보이게되어외전신경원에국한된경우와는달리병변측으로향하는모든신속운동들은소실되게된다. 1 병변반대측을향하는빠른신속운동은정상적으로보인다. 수직신속운동은약간느려질수있고, 비정상적인수평성분때문에병변측으로부터비스듬히멀어지는현상도관찰할수있다. 9 원활추종운동이나시운동성안진의느린성분은정상적인운동범위내에서양측으로보존될수있다. 그러나이들안구운동역시통상적으로는정중선을넘어가진못한다. 때때로수평원활추종운동이나시운동성안진은비대칭적으로손상되기도한다. 보다더상방의뇌간병변은동측으로의원활추종운동장애를유발하고, 하방의뇌간병변은반대측으로의원활추종운동손상을유발하는것으로알려져있다. 10 Basis pontis 의병변은병변측또는양측으로원활추종운동의장애를유발한다. 11 뇌간은대뇌로부터내려오고또소뇌로연결되는복잡한원활추종운동의통로이기때문에뇌간병변에서원활추종운동의이상으로병변부위를편측화하기는어렵다. 12 일부환자에서는전정자극이안구를정중선을넘게한다. 이러한경우 PPRF 병변은 J Korean Neurol Assoc Volume 29 Suppl. 2,

37 이승한 보다윗쪽의교뇌이고, 또동측의외전신경핵자체와이로부터전정신경핵까지의경로는보존된경우로생각해볼수있다. 7,13 전정자극이오직반대로부터내전하는눈만병변측시야로움직이게하는경우도있는데, 이러한경우는 PPRF 와함께동측의외전신경에병변이있으면서, 외전신경원은보존된경우로생각해볼수있다. PPRF 에만국한된양측성병변은매우드물다. 불연속적인뇌경색, 종양등은원활추종운동이나전정안반사는보존되면서선택적으로신속운동만을손상시킬수있다. 14 이러한경우신속운동을일으키는돌발신경원에선택적인손실이나이상기능및원활추종이나전정안반사를전달하는신경섬유는보존됨을시사한다. 실험적으로원숭이의 PPRF 에리도카인을투여했더니신속운동이느려짐을확인할수있었다. 15 또한원숭이에서 neurotoxin 을이용하여신경섬유의통과는보존시킨채 PPRF 만손상시킨경우또한유사한소견을보였다. 16 수평주시마비로부터회복기에있는환자들은손상된내전운동을대신하여폭주 (convergence) 를사용하기도하며, 이에뒤따르는교차주시 (cross-fixation) 를통해시야를좀더넓혀주는역할을한다. 불수의적인협동성 (synkinetic) 개산 (divergence) 와폭주가뇌혈관질환등에의한양측성주시마비의회복기에서수평또는수직주시때에나타날수있다. 17 양측성교뇌병변은모든수평안구운동을소실시킬수는있지만, 종양처럼만성적인병변인경우에는전정안운동은보존되는경우도있다. 8 양측성교뇌병변은수직안운동의장애도일으킬수있는데, 주로신속운동의장애를유발한다. 14 다발성의양측성교뇌경색환자 14,18 및실험적으로 neurotoxin 에의해양측 PPRF 가손상된원숭이에서느린수직신속운동이보고되어있다. 16 OPN이수평운동의돌발신경원과중뇌에위치한수직운동의돌발신경원으로신호를보내기때문에 OPN 을포함한교뇌병변은수평및수직신속운동에장애를보일수있다. 만약수직전정안운동및원활추종운동이같이손상된경우라면 MLF 와함께다른상향경로의장애를생각할수있다. 배측면신경핵 (dorsolateral) 을침범하는교뇌병변에서동측으로의원활추종운동이이상을보일수있다. NRTP 를침범하는병변의경우이향운동의장애를초래할수있다. 안쪽세로다발 (MLF) 의병변 MLF 를침범하는병변은핵간안근마비 (internuclear ophthalmoplegia, INO) 를초래한다. MLF 는 INO 의발생기전으로서잘알려져있듯이외전핵간신경핵으로부터수평안구운동에대한정보를반대측동안신경핵의내직근아핵으로전달하는것뿐만 아니라, 전정안운동과원활추종운동에대한정보를전정신경핵으로부터중뇌의수직운동관련신경핵으로전달하기때문에 MLF 병변이있을때수평과수직안구운동모두영향을받을수있다. 이단락에서는 INO 의임상적소견, 원인, 병태생리학적인기전 (pathophysiology) 에대해살펴보려한다. 1. INO 의임상적특징 INO 의전형적인증상은공액주시때병변측눈의내전장애다. 이렇게손상된내전운동은완전마비로부터좀더경한형태로내전시신속운동의속도만느려진경우까지다양하게나타날수있다. 따라서임상적인진단은양안의수평신속운동의공액주시운동을평가하여내전지체 (adduction lag) 라불리는상대적으로느려진내전운동을확인함으로써이루어진다. 또한흔히동반되는병변반대측외전안에서관찰되는안진을확인하는것이진단에도움이된다. 다시한번정리하면느려진내전운동과더불어반대측눈에서일측성으로관찰되는해리성안진 (dissociated nystagmus) 이 INO 를시사하는중요한소견이된다. 폭주 (convergence) 는보존되기도하고경우에따라서는손상되기도한다. 급성기때는내사위 (esophoria) 가동반되기도하는데이는증가된이향운동의긴장도 (vergence tone) 를시사한다. 19 비대칭적인수직전정안반사는빠른머리회전에서뚜렷한데, 예를들어우측 INO 의경우좌측후반고리관자극에의한수직전정안반사는결함을보일수있고, 좌측전반고리관자극에의한것은보존될수있다. 20 INO 에서작은진폭의 saccadic intrusion 이주시를방해할수있다. 또한 INO 는복시와진동시의원인이될수있다. 2. INO 의원인 INO 를초래했던다양한원인들이보고되어있다. 21 그러나일반적으로는일측성 INO 는 ( 물론반대측도약간침범될수는있지만 ) 허혈성뇌경색에흔히동반된다. 22 일부환자에서는하나의 paramedian perforating pontine artery 가양측 MLF 를모두지배하기때문에뇌졸중에의해양측성 INO 가나타날수있다. 23 물론모든경우가양측성인것은아니지만, MS 와이와연관된탈수초성질환은양측성 INO 의흔한원인으로알려져있다. INO 환자에서 MRI 로 MLF 의병변을확인하는것이가능하긴하지만, 병변이잘안보이는경우도종종있으므로진단율을높이기위해서는 thin section 의횡단 (axial) 과시상 (sagittal) 영상이필요하다. 그외에도드물지만다양한 INO 의원인들도 14 대한신경과학회지제 29 권부록 2, 2011

38 뇌간병변에서관찰되는안구운동장애 : 교뇌 Table 1. Etiology of internuclear ophthalmoplegia Brainstem infarction (commonly unilateral), including vasculitis and hemorrhage Multiple sclerosis (commonly bilateral); post-irradation demyelination Brainstem and fourth ventricular tumors Arnold-Chiari malformation abd associated hydrocephalus and syringobulbia Infection: bacterial, viral, and other forms of meningoencephalitis Hydrocephalus, subdural hematoma Nutritional disorders: Wernicke's encephalopathy, pernicious anemia Metabolic disorders: hepatic encephalopathy, maple syrup urine disease, Fabry's disease Drug intoxications: phenothiazines, tricyclic antidepressants, narcotics, lithium, barbiturates Cancer: carcinomatous infiltration, remote effect 보고되어있다 (Table 1). 21 통상 INO 는절반정도의환자에서오래지속된다고알려져있으며, 일반적으로탈수초성원인인경우좀더예후가좋고, 24 뇌경색에동반된경우는회복이더느린것으로알려져있다 INO 에서동반되는기타이상안구운동 1) 스큐편위 (skew deviation) 일측성 INO 에서스큐편위가자주관찰된다. 보통내전장애를보이는눈이상사시를보이게된다. 스큐편위는기전적으로이석기관으로부터 MLF 를통해중추로올라가는경로가차단됨으로써나타나게된다. 상사시를보이는눈이내회선 (incyclotorsion) 되는소견은 4번신경마비와의감별점이된다. 3번신경마비때에도내전마비와더불어안구의수직편위를보일수있으나, 이경우에는대부분이환된쪽눈에서눈이하사시를보이고동반되는안검하수나동공변화로서감별이가능하다. 2) INO에동반되는수직회선안진일측성 INO 에서병변측에서는하향안진과함께병변반대측눈에서는회선안진성분이더큰양상의해리성수직안진이또한관찰될수있다. 이는수직전정안반사를매개하는경로의차단에기인하는것으로생각해볼수있다. 25 대표적으로후반고리관은 MLF 를통하여흥분성정보를전달한다. 그러나전반고리관은상황이좀다르다. 실험적으로리도카인에의해유발된일측성 INO 에서병변측의상사시와일측에뚜렷한하향안진이관찰되었다. 26 또한일측성 INO 환자에서는회선안진이관찰될수있는데, 주로병변측을향하여회선하는안진이나타난다. 3) 양측성 INO 양측에서 MLF 가손상된경우양측내전장애가초래되고, 양측에서외전안진이발생하며, 이러한경우수직전정안운동및원활추종운동도장애를일으키는것으로되어있다. 실험적으로나임상적으로양측성 MLF 의병변을가지는경우 INO 와함께수직안구운동에도이상을보이는것으로알려져있다. 27 상향과하향의전정안반사모두이득이감소하며, 안구의속도는머리의속도보다느려진다. 수직시운동성안진또한장애를보이며, 수직시운동후안진 (optokinetic after-nysatgmus) 역시소실되는것으로알려져있다. 20 수직원활추종운동또한중등도의장애를보이는것으로되어있는데, eye-head tracking 에서전정안반사의 cancellation 이이루어지지않는다. 수직주시유지 (gaze-holding) 도장애를보인다. 그러나 INO 나 NPH/MVN 병변에서부분적으로수직주시유지가보존되는점은 INC 가수직안구운동의신경적분체로서역할을뒷받침하는소견으로볼수도있다 INO 와동반된공액주시장애 : 1과 1/2증후군외전신경원또는 PPRF 와인접한동측의 MLF 의복합병변은병변측으로의수평공액주시마비와더불어 INO 를초래한다. 이때보존된수평안구운동은반대측눈의외전뿐이다. 이러한임상적인특징때문에 1과 1/2 증후군으로명명된다. 13,29 이러한환자는통상정면을주시할때병변반대측의눈이외측으로치우치는양상의외사시를보일수있다. 이러한사시증상은 Frenzel 안경등에의해주시가차단된경우에보다뚜렷해진다. 보존된병변반대측눈의외전신속운동은중심을향해끌려가는 drift 가뒤따르는데, 마치 INO 에서해리성안진과유사한양상을보인다. 때때로병변측을향하는수의적인안구운동이소실된상태에서도전정안구운동은나타나는경우가있는데, 13,29 이는외전신경원으로들어가는전정신경으로부터경로가보존되었음을의미한다. 이향운동이보존되는경우가있고, ocular bobbing 이 1과 1/2증후군에동반되기도한다. 1과 1/2 증후군의병변측에서말초성안면신경마비가나타나는경우는대개외전신경핵과안면신경의 genu, 인접한 MLF 의병변을시사한다. 30 중심피개로 (central tegmental tract) 를침범한경우는향후안구개진전 (oculopalatal tremor) 의원인이된다. 1과 1/2 증후군은뇌경색, 다발성경화증, 종양, 뇌출혈, 외상, 감염등의원인에의해발생할수있다. 29 앞서언급한대로통상 1과 1/2증후군은일측의외전신경원이나 PPRF 병변과반대측외전핵간신경원으로부터넘어온축색 (MLF) 이손상되면서나타나는것으로설명한다. 또다른가능한기전으로는하나 J Korean Neurol Assoc Volume 29 Suppl. 2,

39 이승한 의 paramedian pontine tegmental artery 가외전신경원높이에서분지하면서양측의 MLF 를모두혈류를공급할수있는데, 이로인해양측 MLF 가손상이되고외전신경원은일측에서손상되면서양측성 INO 와일측성주시마비가나타나는것으로설명하기도한다. 23 요 약 교뇌이상에동반된안구운동장애는주로수평안구운동의장애가많은것으로나타나는데이는수평안구운동의돌발성신경원인 PPRF 와역시수평안구운동에중요한역할을담당하고있고운동신경원과핵간신경원으로구성된외전신경원이교뇌에위치하기때문이다. MLF는외전핵간신경원으로부터 3번신경원까지수평안구운동에관한정보를제공하는것외에도, 전정안운동및이석기관으로부터신호를상부뇌간로전달해주는역할을하므로이곳에이상이생길경우안구의내전장애외에도다양한안구운동장애가동반될수있다. References 1. Müri RM, Chermann JF, Cohen L, Rivaud S, Pierrot-Deseilligny C. Ocular motor consequences of damage to the abducens nucleus area in humans. J Neuro-ophthalmology 1996;16: Hirose G, Furui K, Yoshioka A, Sakai K. Unilateral conjugate gaze palsy due to a lesion of the abducens nucleus. J Clin Neuro-ophthalmol 1993;13: Milea D, Napolitano M, Dechy H, Le Hoang P, Delattre JY, Pierrot- Deseilligny C. Complete bilateral horizontal gaze paralysis disclosing multiple sclerosis. J Neurol Neurosurg Psychiatry 2001;70: Muni RH, Wennberg R, Mikulis DJ, Wong AM. 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40 특수상황에서의간질환자치료 : 고찰및증례중뇌병변에의한안구운동이상 계명대학교의과대학신경과학교실김현아 Ocular Motor Syndromes Caused by Lesions in the Midbrain Hyun-Ah Kim, MD Department A of Neurology, Brain Research Institute, Keimyung University School C of Medicine, Daegu, Korea The rostral midbrain is the critical site of prenuclear (supranuclear) vertical and torsional eye motion control. At this level, the rostral interstitial nucleus of the medial longitudinal fasciculus (rimlf), the interstitial nucleus of Cajal (INC), and the posterior commissure (PC) are the anatomical structures mediating vertical-gaze inputs to the oculomotor nuclei. Whereas the rimlf is the immediate premotor structure for vertical and torsional saccade generation, the INC is considered a major part of the neural integrator for vertical and torsional eye movements. In company with impairment of vertical or torsional eye movement or disturbance of vergence eye movement from the lesion of dorsal midbrain including rimlf or INC, gaze palsy from ocular motor nucleus or fasciculus or medial longitudinal fasciculus (MLF) lesion can come in making various manifestations in midbrain lesions. Key Words: Midbrain, Eye Movement Disorders 내측세로다발의입쪽간질핵 (rostral interstitial nucleus of the medial longitudinal fasciculus, rimlf), 카할간질핵 (interstitial nucleus of Cajal, INC), 그리고뒤맞교차 (posterior commissure) 는안구운동핵으로가는수직주시신호를매개하는해부학적구조물들로이들부위의손상이중뇌병변시안구운동이상의주원인이된다. 1 이외에도동안신경핵 (oculomotor nucleus) 과활차신경핵 (trochlear nucleus) 그리고이들에서나오는신경속 (fasciculus) 과내측세로다발 (medial longitudinal fasciculus, MLF) 등도중뇌병변시안구운동이상을일으킬수있다. 중뇌에서안구운동에관여하는각각의구조물과이들을침범했을때발생할수있는안구운동이상에관해동영상을보며살펴보기로한다. 중뇌의내부구조 (Internal Structure of Midbrain) 중뇌를수평단면으로보았을때중뇌수도관 (cerebral aqueduct) Hyun-Ah Kim, MD Department of Neurology, Keimyung University School of Medicine, 56 Dalseong-ro, Jung-gu, Daegu , Korea Tel: Fax: kha0206@dsmc.or.kr 를중심으로뒤쪽은덮개 (tectum), 앞쪽은피개 (tegmentum) 와대뇌각 (cerebral peduncles) 으로이루어져있다. 수직단면으로보았을때는상구 (superior colliculus) 와하구 (inferior colliculus) 를중심으로상부 (rostral) 와하부 (caudal) 로나눌수있다. 중뇌병변에서안구운동이상을일으킬수있는부위중내측세로다발의입쪽간질핵, 뒤맞교차는상부피개중에서도가장위쪽인간뇌-중뇌접합부에위치하며바로아래에카할간질핵이, 중간부피개에동안신경핵이위치한다. 활차신경핵과내측세로다발은하부피개에위치한다 (Fig. 1-A). 중뇌와간뇌의이행부에위치한내측세로다발의입쪽간질핵은동안신경핵의상부, 적핵 (red nucleus) 의뒤쪽안쪽에위치하며중외수도관주위회색질 (periaqueductal gray matter) 의앞쪽에위치한다 (Fig. 1-B). 내측세로다발의입쪽간질핵의바로아래에카할간질핵이위치하며이는에딩거 -베스트팔핵 (Edinger-Westphal nucleus) 의뒤쪽외측, 중뇌수도관주위회색질의바로바깥쪽에위치한다 (Fig. 1-C). 2 동안신경핵은중뇌상부상구를지나는수평단면에서중뇌수도관주위회색질의앞쪽에위치해있으며, 활차신경핵의위쪽끝부분에서중뇌의위쪽끝부분까지뻗어있다 (Fig. 1-D). 내직근, 하사근, 하직근아핵으로부터기시하는신경섬유는동측의외안근을지배하는데, 상직근아핵에서기시하는신경섬유는동안신경핵내에서 J Korean Neurol Assoc Volume 29 Suppl. 2,

41 김현아 A B C D Figure 1. A sagittal view of the midbrain showing the location of structures that essential for the control of eye movements and gaze. The dashed lines in Figure 1-A indicate the levels of the transverse sections shown in Figures 1-B~D. Abbreviations: 3N, oculomotor nucleus; 4N, trochlear nucleus; CeCa, central caudal nucleus; fr, fasciculus retroflexus; InC, interstitial nucleus of Cajal; mlf, medial longitudinal fasciculus; MMC, medial mammillary nucleus; mt, mammillothalamic tract; pc, posterior commissure; RPC, red nucleus; RI, rostral interstitial nucleus of the medial longitudinal fasciculus; SC, superior colliculus. 교차하여반대쪽으로건너간다음동안신경을따라주행하여반대편상직근에도달하게된다. 미측중심핵 (caudal central nucleus) 은반대쪽으로건너가는신경섬유와건너가지않는신경섬유모두를가지고있어서양측의눈꺼풀올림근을지배하게된다. 동안신경핵복합체에서기시된동안신경속은내측종속을통과하여적핵, 흑질 (substantia nigra), 대뇌다리의내측모서리 (medial edge) 를통해지주막하공간으로빠져나온다. 활차신경핵은중뇌하부하구를지나는수평단면에서나타나며, 내측세로다발섬유내에위치해있고동안신경핵바로아래에위치한다. 활차신경핵은내측세로다발내에있는데비해, 동안신경핵은내측세로다발뒤에위치하고있다. 활차신경핵신경원의축삭은활차신경 (trochlear nerve) 을형성하여중뇌수도관을돌아교뇌와중뇌의이행부에서반대편으로교차하여뇌간밖 으로나온다. 중뇌의혈관공급 (Blood Supply of Midbrain) 기저동맥 (basilar artery), 후뇌동맥 (posterior cerebral artery), 상소뇌동맥 (superior cerebellar artery) 이중뇌에서겹쳐지며혈액을공급하며동맥의분포정도는중뇌의어느부위인가하느냐에따라다르다. 기저동맥에서바로나오는 paramedian artery 는앞쪽정중옆부위에혈액을공급한다. posterior thalamo-subthalamic artery 는후대뇌동맥의제 1 분지에서갈라져나와내측세로다발의입쪽간질핵, 안쪽입쪽적색핵과일부시상핵에혈액을공급한다. 하나의후대뇌동맥에서 18 대한신경과학회지제 29 권부록 2, 2011

42 중뇌병변에의한안구운동이상 Figure 2. Schematic template showing arterial territories of mesencephalon. 분지되는단일의 posterior thalamo-subthalamic artery 가중앙을통과하여반대측중뇌까지혈액공급을하기도한다. 후대뇌동맥의제2분지로부터오는 Peduncular artery 는직접적으로가쪽상부중뇌로간다. 중뇌를감아돌고있는상소뇌동맥의 short circumferential artery는가측등쪽부위의하부 2/3 부위에혈액을공급한다 (Fig. 2). 3,4 내측세로다발의입쪽간질핵과카할간질핵그리고핵상수직주시마비 (rimlf, INC and Supranuclear vertical gaze palsy) 단속성안구운동계의방출에는방출세포와범휴지기세포등 두가지형태의신경원이중요한역할을한다. 방출세포는안구의관성을극복하고빠른속도의안구운동을발생시키기위하여조용히있다가단속성안구운동직전폭발적으로흥분한다. 방출세포의활성화 (pulse) 는외안근을지배하는안구운동핵으로전달되어단속성안구운동이발생한다. 수직성단속성안구운동의방출세포는내측세로다발의입쪽간질핵에위치하는것으로알려져있다. 따라서내측세로다발의입쪽간질핵이손상되면위, 아래쪽을쳐다보는수직주시를할수없게된다. 이핵은대뇌피질의전두엽안구영역 (frontal eye field) 과상전정핵 (superior vestibular nucleus) 에서기원되는구심섬유를받으며, 중심옆교뇌그물형성체 (PPRF) 와서로연결되어있다. 각각의내측세로다발의입쪽간질핵으로가는신호는상구, 뒤맞교 J Korean Neurol Assoc Volume 29 Suppl. 2,

43 김현아 차핵 (nucleus of the posterior commissure), 반대측내측세로다발의입쪽간질핵, 소뇌의꼭지핵 (fastigial nucleus) 과대뇌반구에서온다. 각각의내측세로다발의입쪽간질핵으로부터중뇌수도관의앞쪽으로교차하여양눈의수직운동을조절하는안구근육의아핵으로신호가전달된다. 1,2,5,6 반면에회전단속운동을조절에대한신호는교차하지않는다. 7-9 양측내측세로다발의입쪽간질핵병변에서는수직, 회전성단속운동이모두되지않으나추적운동이나전정안반사는정상이며주시유지나수평단속운동도이상이생기지않는다. 상방운동을담당하는신호는내측세로다발의입쪽간질핵으로부터안구운동핵으로양방향으로전달되나하방운동을담당하는신호는동측성이다. 1,8 따라서일측성내측세로다발의입쪽간질핵병변에서는하향단속운동만약간느려지고반대측으로회전성안구편향이생길수있으며동측으로회전하는빠른안구운동의위상이사라지고병변반대방향으로의회전성안진이관찰될수있다 (video). 1,10,11 방출세포의활성화에의해단속성안구운동이발생하여안구운동이발생한후안구자체의탄성력에의해안구가원래의중앙으로되돌아오려하는힘이안구운동의역방향으로발생하는데이런현상을방지하고이동된위치에안구를유지시키기위해서는지속적인외안근의수축이필요하다. 외안근의지속적수축에대한유지명령 (step) 을내리는기관이신경적분체 (neural integrator) 이다. 수직및회선방향의단속성안구운동에대한신경적분체는카할간질핵이다. 신경적분체에이상이생기면안구가중앙으로흐르게되어이를교정하기위한주시유발안진등이발생한다. 카할간질핵은대뇌피질의전두엽안구영역 (frontal eye field) 과덮개앞부분 (pretectal area) 에서내려오는구심섬유를받으며, 내측세로다발을통해상전정핵 (superior vestibular nucleus) 과내측전정핵 (medial vestibular nucleus) 에서상행섬유를받는다. 소뇌의꼭지핵에서기원되는섬유도이핵에종지한다. 간질핵의원심섬유는척수, 동안신경핵, 활차신경핵, 중심옆교뇌그물형성체, 전정핵 (vestibular nuclei) 등으로이어진다. 카할간질핵은뒤맞교차를경유하여 3, 4번뇌신경의반대측핵의운동신경과반대측카할간질핵으로신호를보낸다. 1,12,13 카할간질핵으로가는신호는내측세로다발의입쪽간질핵과하부뇌간구조물에서주로 MLF 를경유하여오는데카할간질핵은수직추적운동과수직전정안구운동에도관여한다. 14 따라서카할간질핵의양측병변에서는수직방향의단속, 추적운동과전정안반사가모두이상을보이나단속운동의속도는정상인소견을보이고상방안진이관찰될수있다. 카할간질핵의일측병변에서는동측방향으로의회전성안진이관찰될수있으며수직, 회전성주시유지가되지않는다. 또한카할간질핵은눈기울임반응 (ocular tilt reaction, OTR) 에도관여하여카할간질핵 에병변이있을때병변반대편으로눈기울임반응이일어난다. 이는관상회전면에서중력에대한전정안반사가수직반고리관및이석기관에의해감지되어전정신경핵으로전달되며, 전정신경핵에서통합된정보는하부교뇌에서반대편으로건너간후내측세로다발을따라카할간질핵으로향하기때문이다. 1,10,11 카할간질핵으로부터의신경섬유는뒤맞교차에서교차하여수직주시에관여하는반대편구조물로건너가게되고수직주시에중요한역할을하는뒤맞교차핵의신경섬유도뒤맞교차를지나반대편내측세로다발의입쪽간질핵과카할간질핵으로연결된다. 따라서양측성상방주시마비가흔히뒤맞교차병변에의해발생할수있다 (video). 15 또한편측의상부중뇌의병변또한입쪽간질핵를침범함과동시에뒤맞교차를통해서반대쪽으로넘어오는신경경로를침범하여양측성상방주시마비를일으킬수있다 그러나하방운동을담당하는신호는동측성이므로상방뿐만아니라하방주시마비도같이발생하는경우는양측입쪽간질핵의병변으로만설명이될수있다. 이렇게양측입쪽간질핵의병변으로수직주시마비가일어나는경우수직전정안반사는정상이다 (video). 2,19 그러나양측입쪽간질핵과함께양측동안신경핵의일부가침범된경우나양쪽카할간질핵병변으로인한수직주시마비의경우는수직전정안반사의이상을보일수있다 (video). 양측의입쪽간질핵이나카할간질핵병변의경우하나의후대뇌동맥에서분지되어반대측중뇌까지혈액공급을하는단일의 posterior thalamosubthalamic artery 가막히는경우에가능할것이다. 파리노드증후군 (Parinaud s Syndrome) 파리노드증후군은등쪽중뇌의덮개앞부위의손상으로인한질환으로덮개앞증후군 (pretectal syndrome) 혹은등쪽중뇌증후군 (dorsal midbrain syndrome) 으로도불린다. 이부위에있는내측세로다발의입쪽간질핵, 카할간질핵, 뒤맞교차손상에의해여러가지안구운동장애가나타날수있다. 파리노드증후군은앞에언급된핵상수직주시마비외에눈모음후퇴안진및빛-접근반사해리, 병적눈꺼풀후퇴 (Collier's sign) 를특징으로하며그외에도 pretectal V-pattern pseudo-bobbing, setting sun sign, pseudo-abducens palsy, 시소안진 (seesaw nystagmus), vertical one and a half 등의증상이동반될수있다. 송과체종양, 수두증, 다발성경화증, 중뇌수도관확대로인한뒤맞교차의압박, 뇌출혈, 뇌경색및중뇌의감염성질환등이원인이될수있다 눈모음- 후퇴안진이란실제진짜안진은아니고불규칙하게발생하는이명성 (dysjunctive) 안구운동으로초기의눈모음에 20 대한신경과학회지제 29 권부록 2, 2011

44 중뇌병변에의한안구운동이상 이어제일안위로향하는눈벌림 (divergence) 이관찰된다 (video). 초기눈모음시기에는안구가안와의뒤쪽으로밀려들어가는현상 (retraction) 이동반된다. 추종운동은비교적유지가되나신속운동의장애가발생하여상향신속운동을하려고할때상전근작용에장애가생기고, 길항근인하전근의억제에도장애가생기며양안내직근이동시에활성화되면서눈모음후퇴안진이일어난다는가설과이향운동 (vergence) 의이상에의해발생한다는설도있으나아직명확히밝혀지지않은상태이다. 눈모음 -후퇴안진은자연적으로발생하여지속적으로관찰될수있으나, 대부분은상방주시에의해시선이동이일어날때동반 Figure 3. Setting sun sign in premature infants with intraventricular hemorrhage. 된다. 20,22,23 Pretectal V-pattern pseudo-bobbing은 ocular bobbing 처럼빠른하방운동이후서서히제자리로향하는안구운동을보이지만하향하면서내측으로향하여 V자를만드는것을말한다. 이는눈모음안진의변형으로생각되고있다. 24,25 시소안진 (seesaw nystagmus) 은양쪽눈이반대방향의수직성벡터 (disconjugate vertical vector) 를갖는회선성진자양안진이다. 한쪽눈은올라가면서내회선되고반대편눈은떨어지면서외회선되는양상의안진이양쪽눈에서교대로나타난다 (video). 간뇌 -중뇌부위의병변에서드물게방향의역전없이한쪽방향으로만안진이관찰될수있으며 ( 반시소안진, hemi-seesaw nystagmus) (video) 시소안진의정확한발생기전은밝혀지지않았으나안구운동양상이안기울기반응 (ocular tilt reaction, OTR) 에서보이는것과유사하기때문에, 중추성이석신경로의주기적동요가원인기전으로제기된바있다 Vertical one and a half 는단안상전마비를동반한핵상하향주시마비혹은단안하전마비를동반한핵상상향주시마비이다. 단안상전마비를동반한핵상하향주시마비의경우내측세로다발의입쪽간질핵으로부터나오는양측신경섬유와반대측상직근아핵동측하사근아핵으로가는신경섬유가뒤맞교차에서교차전혹은후에손상을받았을때발생한다. 반면에단안하전마비를동반한핵상상향주시마비의경우마찬가지로내측세로다발의입쪽간질핵으로부터나오는양측신경섬유와동측하직근아핵반대측상사근아핵으로가는신경섬유가뒤맞교차에서손상을받아발생하게된다 Figure 4. Pseudoabducens palsy shows bilateral abduction deficits without abducens nerve palsy. J Korean Neurol Assoc Volume 29 Suppl. 2,

45 김현아 Setting sun sign 은뇌실내출혈을보이는미숙아에서관찰할수있으며하방으로안구편위를보이면서눈꺼풀후퇴를보이는것이다 (Fig. 3). Pseudoabducens palsy 는 6번뇌신경의이상없이안구의외전장애가일어나는것으로눈모음의증가가그원인이라고생각된다. 시상이나간-중뇌접합부의병변에의해눈모음의하향억제로가손상되거나직접적인눈모음신경원의손상으로외전장애와함께일측혹은양측내사시 (esotropia) 를보일수있다 (Fig. 4). 이향운동의하향피질로는정중옆시상을통과하고중뇌에서반대측동향운동원을억제한다. 이운동원은이후동측에있는 3번뇌신경핵의내직근아핵으로투사한다. 상부중뇌에서이전운동신경원은동안신경핵의뒤쪽과뒤쪽가쪽에위치한다. 이신경섬유의손상은중뇌에서반대쪽이향운동원으로가는억제를감소시켜신경활동성을증가시키고결국눈모음을증가시키고내편위 (esodeviation) 를가져온다. 31 이전의문헌에서는시상경색이특징적인내측하방으로의안구편위를보이며이를 peering at the tip of the nose 라고불렀다. 이러한현상은시상위치에서의하향하는눈모음신경의손상에의한것으로생각된다. 32 동안신경핵과활차신경핵그리고신경속병변 (Oculomotor Nucleus, Trochlear Nucleus and Fascicular Lesion) 3번뇌신경이신경핵혹은신경다발의문제를보이는경우중간부중뇌의문제인경우가대부분이며기저동맥에서나오는 paramedian artery 의폐쇄가원인이된다. 동안신경핵의병변이있는경우동안신경핵내에서상직근의교차가이루어지기때문에완전동안신경마비와함께반대쪽상직근마비, 부분적인양측안검하수를보일수있다 (video). 33,34 중뇌의동안신경핵이나신경속을침범하는병변에의해부분적인동안신경마비가발생할수있는데특히동안신경속병변은 3번뇌신경병변과임상적으로매우비슷하여구별하기힘들다. 이때앞쪽중뇌내의동안신경속의배열에따라다른임상양상을보이게된다. 수직평면상에는동공으로가는신경섬유는가장위쪽과내측에위치하고그외측과미측부에하직근으로가는신경섬유가위치하며동안신경섬유속의가장외측과미측부에하사근이위치하고그바로내측에상직근이위치하게된다. 그리고하사근과하직근사이에내직근이위치하며그미부에상안검거근이위치하게된다 (Fig. 5) 이러한동안신경속병변과더불어반대측편마비, 불수의적운동, 실조등이있을때웨버증후군 (Weber's syndrome, 베네딕트증후군 (Benedikt's Figure 5. Schematic figure showing the fascicular arrangement of oculomotor nerve. syndrome) 클로드증후군 (Claude syndrome) 노트나겔증후군 (Nothnagel's syndrome) 등으로부르게된다. 38 활차신경은상사근을지배하여안구를내측으로회전시키고아래쪽외측으로움직이는역할을하므로, 활차신경핵이손상되면아래쪽외측을볼때복시가나타난다. 활차신경핵에서나온활차신경은교뇌와중뇌의이행부에서반대편으로교차하여뇌간밖으로나온다. 활차신경핵혹은교차전의활차신경병변의경우반대편상사근마비가, 교차후의활차신경병변의경우동측의상사근마비가일어난다. 39 내측세로다발의병변 (Lesion in Medial Longitudinal Fasciculus) 내측세로다발이손상되면핵간안구운동마비 (internuclear ophthalmoplegia) 가나타난다. 또상부중뇌병변이있는경우양측내측세로다발과내직근아핵의침범으로인해양눈이각각벌어져반대편을바라보게되는 WEBINO 증후군 (Wall Eyed Bilateral INO syndrome) 이발생할수있다 (video). 40 결 론 중뇌병변에서는여러가지다양한안구운동장애가나타날수있지만내측세로다발의입쪽간질핵이나카할간질핵과관련된수직혹은회전성안구운동장애나눈모음과관련된안구운동장애와연관되어나타나는경우가많다. 이러한증상을보이는환자를진찰할때반드시중뇌병변을염두에두는것이중요하겠다. 22 대한신경과학회지제 29 권부록 2, 2011

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47 특수상황에서의간질환자치료 : 고찰및증례심방세동의평가와치료 울산대학교의과대학서울아산병원심장내과최기준 Overview of AF: Evaluation and Management of AF Kee-Joon Choi, MD, PhD Department of Cardiology, Asan Medical Center, Medical College of Ulsan University, Seoul, Korea 심방세동은치료를요하는지속성부정맥중에서가장흔한질환이다. 전체성인에서 % 에서발견되며, 연령이증가함에따라발병빈도가증가하여 60대에서의유병율은 2-3%, 75세이상에서는 9-10% 를넘을정도로흔한질병이다. 의학의발달과함께평균수명이증가하여노년층에서의의료수요가점차증가하며이에따라치료를요하는심방세동환자도증가하고있다. 또한최근전극도자절제술을비롯한새로운치료법이개발되면서많은관심을받고있는부정맥이다. 심방세동의진단과분류 환자는보통심계항진이나가슴답답함, 경미한현기증을주소로의사를찾거나혹은건강진단등에서우연히발견하게되는데, 촉진이나청진시환자의맥이아주불규칙한것이특징이다. 확진은심전도를측정하면쉽게진단할수있는데, 심전도에서는뚜렷한 P파를발견할수없고 RR 간격이아주불규칙하게변화하는양상을보인다. 이는심방의여러부위에서분당 회정도의빠른속도로맥을생성해내고, 이러한맥이방실결절의불응기에걸려심실로불규칙하게전달되기때문이다. 심방세동의분류는치료방향을결정하는데있어중요하다. 심방세동증상이경미하거나증상이없는경우심방세동이언제발생하였는지결정하기어려운경우가많은데, 내원시처음 에심방세동을보이는경우에시작시기나관련증상여부및중증도에관계없이처음진단된 (first diagnosed) 심방세동으로분류한다. 발작성 (paroxysmal) 심방세동은자연적으로소실되고유발되는양상이발작적으로반복되는데지속기간이 7 일이내인유형으로, 대부분은 48시간내에소실된다. 이후에는동율동으로자발적전환가능성이낮고항응고요법이고려된다. 지속성 (persistent) 심방세동은 7일이상지속되는유형으로약제나전기충격에의한 cardioversion 으로동율동전환이필요하며, 장시간지속성 (long-standing persistent) 심방세동은 1년이상지속되는유형으로이경우에도동율동조절전략이가능하다. 영속성 (permanent) 심방세동은심방세동이지속되는유형으로지속기간에관계없이환자나의사에의해더이상동율동전환이시도되지않는것으로받아들여지는 (accepted) 시점을일컫는분류로, 일반적으로동율동전환요법의시도에도실패하거나 24시간이내에재발하여더이상동율동조절전략을 Kee-Joon Choi, MD, PhD Department of Cardiology, Asan Medical Center, Medical College of Ulsan University, Poongnap-dong, Songpa-gu, Seoul , Korea Tel: Fax: kjchoi@amc.seoul.kr Figure 1. 심방세동의분류 (2010 년 ESC guideline). 24 대한신경과학회지제 29 권부록 2, 2011

48 심방세동의평가와치료 고려하지않는경우는영속성으로분류한다. 임상에서는지속성과영속성의구분이모호하여만성 (chronic) 심방세동이라는표현을사용하기도한다 (Fig. 1). 심방세동의원인과유발조건 심방세동의원인은크게두가지로나누어생각할수있는데심장이원인인경우와심장외적인원인으로생기는경우이다. 대부분의경우심방세동은심혈관질환과연관되어있는데, 특히고혈압, 관동맥질환, 심근병증, 판막질환 ( 특히승모판막질환 ) 환자에서흔히발생한다. 또한심장수술, 심근염, 심낭염에합병되어발생하기도한다. 심방세동이 WPW증후군에서발생될수도있는데이경우, 우회로로빠른전도가일어나심박동수가 200 회이상으로빨라져서실신이나돌연사에이르는등치명적일수있다. 다른유발조건으로는많은양의알코올섭취, 갑상선기능항진증, 호흡기질환 ( 폐색전증도포함 ), 고령등을들수있다. 수면무호흡증, 미주신경이나교감신경의항진도모두심방세동의발생과연관될수있다. 원인이되는기저질환이없는경우를 고립성 (lone) 심방세동 이라부른다. 심방세동환자에서필요한검사는? 환자의병력, 신체검사를통하여심방세동의원인에대하여찾아보아야한다. 특히갑상선기능항진증과같이가역적인원인이있는경우에는그원인을교정하여주면심방세동이치료되는경우가있으므로중요하다. 심방세동환자에게최소한의검사로 12유도심전도, 흉부방사선, 심초음파, 일반혈액검사와갑상선검사가필요하다. 심초음파검사를통하여판막의이상유무, 심장특히심방의크기, 심근비후여부, 심낭질환등을알수있다. 그외에운동부하검사를통하여환자의증상이운동과연관이있는지, 운동중심박동수가어떻게변하는지를확인할수있고, 24시간홀터검사를시행하여발작성유무, 일상활동에서의심박동수의조절정도를확인할수있다. 동율동전환전에는경식도초음파를시행하여좌심방내의혈전유무를확인하여야한다. 임상적중요성 1. 빠른심박수 고빠른심실박동과이로인한심계항진, 혈압저하, 폐울혈, 협심증과불안증을초래하게된다. 또한이러한빠른심실반응이오랫동안지속되면빈맥자체에의한빈맥유발성심근증 (Tachycardia-induced cardiomyopathy) 을유발할수있다. 2. 심박출량의감소심방수축이없어짐으로인하여 20-25% 정도의심박출량감소를유발하게되는데이로인해전신무기력감과호흡곤란, 어지러움증등의증상이생길수있다. 특히좌심실기능이떨어져있거나심근비후가심한심비대환자, 판막질환, 관동맥질환환자에서는빠른심실반응과심방수축의소실로인해혈역학적으로불안정한상태, 즉저혈압, 실신, 또는심부전이초래될수있다. 3. 혈전의생성및색전증심방내혈류흐름이저하됨으로써혈전의생성을촉진하고, 뇌졸중및전신색전증의원인이된다. 뇌졸중의연간발생율은 5-9% 로다양한데, 위험도는발작성심방세동과지속성심방세동의경우가동일하다고보고되고있다. 4. 사망률의증가심방세동은다른인자와독립적으로사망의상대위험도가 배정도증가한다. 심방세동의동율동유지 vs. 심박수조절 심방세동의기본적인치료원칙으로는심방세동을정상동율동으로전환하여유지하는동율동유지방법과심방세동이있는상태에서혈전색전증예방을같이병행하면서심박수가빠르지않도록조절하는심박수조절방법두가지가대표적이다. 이두가지방법중어느방법이더좋은가에대하여는오랫동안연구되어왔으나서로장단점이있고, 각환자의상황에따라그우수성이달라아직확실한결론을내기에는어려움이있으나각치료방법의약제및장단점과대규모연구결과에대하여알아보겠다. 1. 동율동유지 심박수조절기능의소실과함께 회정도의불규칙하 기본적으로대부분의의사들은항부정맥약제를이용하여비 J Korean Neurol Assoc Volume 29 Suppl. 2,

49 최기준 정상적인심방세동을정상적인동율동으로유지하는것을더선호한다. 이는당연히동율동을유지하는것이증상완화나혈전색전증의위험및항응고요법필요성의감소, 나아가장기적으로사망률이감소할것이라고생각하기때문이다. 일단지속성 (persistent) 심방세동의경우전기적으로혹은약제를이용하여동율동전환을시도하여야한다. 일반적으로전기적동율동전환의성공율이 75-93% 로더우수하다. 가장큰단점은동율동전환후심방세동의즉시 (immmediate) 혹은조기 (early, 대개 2주이내 ) 재발인데, 이를줄이기위하여동율동전환전에항부정맥제를단독으로혹은 verapamil 이나 ARB(angiotensin receptor blocker) 제재와병용으로사용하기도한다. 7일이내의짧은기간의심방세동인경우, 항부정맥약제를이용한동율동전환의성공율도높은편이다. 약제는우리나라에서사용가능한 flecainide 나 propafenone( 우리나라에서는사용이불가능한 dofetilide, ibutilide) 을선택할수있다. 이런짦은기간의심방세동의동율동전환의경우저절로동율동으로전환되는경우와의구별을위해약을투여후 1-2 시간내에전환되는효과를측정하기도하는데 amiodarone 의경우작용시간이늦기때문에이약제의사용은주로오래된심방세동이나다른약제로전환이되지않은경우주로사용된다. 일단동율동으로전환되면항부정맥제를이용한동율동유지가중요하다 ( 발작성심방세동의경우에는심방세동발생빈도를감소시킴 ). 이목적을위해서는 amiodarone, flecainide, propafenone, sotalol 을사용할수있다. Class IC 약제인 flecainide 나 propafenone 의경우, 구조적인심장질환이있는경우에는 부정맥유발성 (proarrhythmia) 의위험도때문에사용을제한하여야하지만, 구조적인심장질환이없는경우에는부작용이심하지않아흔히사용되고있다. IC 약제로동율동유지가어렵거나구조적심질환이있는경우에는 amiodarone 을사용하게되는데, Canadian Trial of Atrial Fibrillation (CTAF) 연구에서는 amiodarone 이다른약제에비해효과가우 수하여대조군에비해재발율을 60-70% 정도감소시키는효과를보였다. 그러나장기간사용할경우부작용율이높은것이약점이다. 간기능이상, 갑상선기능이상 ( 기능항진혹은저하 ), 피부색변화, 폐섬유화등이대표적인데, 특히폐섬유화는늦게발견되면사망에이르는치명적일수있는부작용이다. Sotalol 의경우 amiodarone 에비해효과는조금떨어지나, 베타차단제의효과가있어심방세동시심박수의감소효과가뚜렷하고허혈성심질환환자에게사용하기에장점이있다. 그러나이약제로인한 QT 간격의연장과동반되어 Torsades des Pointes 라는심실빈맥이드물긴하지만치명적인부작용으로나타날수있으므로약물투여초기에 QT 간격이비정상적으로증가하는경우 ( 대부분교정 QT 간격 520 msec 이상 ), 약제를중단하는것이안전하다. 심부전의증상이있거나심하게수축력이저하된환자에서는 amiodarone 과 dofetilide 를제외한항부정맥제는수축능저하효과가있어사용하기어렵다. 최근출시된 dronedarone 이라는새로운항부정맥제는 amiodarone 의부작용을많이감소시킨약제로심한심부전환자외에는어느정도의심장병이있어도사용이가능하나아직보험적용이안되어경제적부담이크다. 2. 심박수조절과거디곡신만으로심방세동을치료하던시대에비해이후여러가지새로운항부정맥약제들이개발되면서많은의사들이동율동유지치료법을선호하게되었지만, 항부정맥제치료효과의한계점과부작용들이알려지면서다시심박수조절방법이일차치료방법으로대두되었다. 또한비타민 K 길항제인와파린이심방세동환자에서의혈전색전증의예방에효과적으로작용한다는점이알려지면서, 항응고요법과병합요법으로심박수조절치료가힘을받게되었다. 사용가능한약제로는디곡신, 베타차단제, 그리고 nondihydropyridine 계칼슘길항제 Table 1. 심방세동환자에서동율동유지와심박수조절방법의대표적인비교연구 Study (n) Study Characteristic Follow-Up (years) Treatment Protocol, Rate vs. Rhythm AFFIRM (4060) Paroxysmal and persistent AF High risk for stroke and death 3.5 (mean) RACE (522) Persisent AF 1 or 2 prewious ECVs 2.3 (mean) PIAF (252) Persisten AF Symptoms of AF 1 STAF (200) HOT-CAFE (205) Persistent AF Moderate to high risk of recurrent arrhythmia Persistent AF Age: years (mean) Rate: BBL, CCB, digoxin; alone or in combination Rhythm: AAD and ECV, if necessary Rate: BBL, CCB, digoxin; alone or in combination Rhythm: serial ECV and AAD 26 대한신경과학회지제 29 권부록 2, 2011

50 심방세동의평가와치료 인 verapamil 과 diltiazem 이있고, 비약물요법으로는방실결절절제술후의심박동기삽입술이있다. 심방세동환자에서심박수조절의목표치는연구자마다조금씩차이가있기는하지만, 안정시분당 80회이하, 적당한운동시분당 회이하로잡고있다. 중요한점은안정시의심박수뿐만아니라운동시의심박수도적절히조절되어야하며이를위해운동부하검사나 24시간생활심전도검사가필요하다. 디곡신은심박수조절에효과적이긴하지만운동시의심박수조절이잘안되는경우가흔하여젊은환자나활동이많은환자에서는다른베타차단제나칼슘길항제와같이사용하는경우가많다. 하지만활동이많지않은고령의환자나심부전이동반된환자에서는효과적이다. 이에비하여베타차단제나칼슘길항제는큰부작용없이효과적으로사용된다. 또한추가적으로혈압강하효과도있다. 허혈성심질환환자, 심기능이저하되었거나심부전을앓았던환자에서는베타차단제가우선적으로처방된다. 하지만두가지약제모두서맥을유발할수있으므로유의하여야하며, 일반적으로서맥의유발정도는베타차단제가더강하다. 그리고칼슘길항제는심실수축력저하효과가있어심기능이저하된환자에서주의를요하는데, 이러한효과는 dilatiazem 이 verapamil 에비하여덜한편이다. 7개의연구중대상군이조금상이한 PAF2 ( 발작성심방세동군 ) 과 CRAAFT ( 류마티스심장병환자군 ) 을제외한 5개연구의종합분석에서는심박수조절이동율동유지치료와비교하여출혈, 뇌졸중등의혈전색전증, 사망률에차이가없음을보여주었다. 이연구중 AFFIRM 연구는대상환자수 (4060 명 ) 가가장많고추적관찰기간 ( 평균 3.5 년 ) 도길었는데, 동율동유지군에서통계적으로유의하지는않았지만사망률의증가추세를보였고, 또한동율동유지군에서항응고요법이필요없다고생각되어항응고요법을중단한환자군에서는혈전색전증의부작용율이높았다. 이는아마도무증상의심방세동이영향을미쳤다고생각한다. 전반적으로심박수조절법도상당히효과적이라고할수있겠으며, 특히지속적인심방세동환자에서증상이심하지않고혈전색전증의위험도가높은고령의환자라면심박수조절방법이일차치료법으로선택될수있겠고, 이방법은 ( 동율동유지방법에비하여 ) 약의부작용이적고, 입원횟수도적으며, 저비용의장점이있다. 그러나 AFFIRM 연구의소집단분석에따르면울혈성심부전이있는환자에서는동율동유지치료가심박수조절에비하여더유리한것으로발표되어, 이에대해 AF-CHF 연구가진행되 3. 대규모연구에서의비교결과 심방세동의치료에서동율동유지방법과심박수조절방법, 이두가지치료방법중어느것이더우월한지에대한비교연구로는 PIAF, PAF2, AFFIRM, RACE, STAF, HOT CAF, CRAAFT 7가지연구가발표되었다. 전체적으로 5,000 여명의환자를대상으로한이연구들을종합해보면심박수조절방법이, 동율동유지방법에비해적어도뒤지지는않는다는결론이다. 특히고령이면서지속성심방세동의경우에는더뚜렷했다. Figure 2. 심방세동환자에서동율동유지를위한항부정맥약제의선택 (ESC guideline, 2010). Figure 3. AFFIRM 연구의사망률의위험도에대한소집단분석 J Korean Neurol Assoc Volume 29 Suppl. 2,

51 최기준 었으나뚜렷한효과를보이지못했다. 그러나 65세이하의젊은환자군에서는동율동유지법의장점이있었다 (Fig 2). 이제까지의대규모연구결과에서한가지유의하여야할점은대부분의대규모연구의환자군의연령이다. 심방세동이고령의환자에서많이발생하는것은잘알려져있지만위에서분석한 5개연구의평균연령은 세 ( 가장대규모연구인 AFFIRM 연구의평균연령은 70세 ) 이므로비교적젊은연령대의환자군에서도이연구결과를적용할수있는가는아직확실하지않다. 그리고 PIAF, HOT CAFÉ연구에서는전체삶의질에는두방법간에차이가없었으나, 동율동유지환자군에서운동능력이더우월함을보여주었다. 또한 AFFIRM 연구의분석에의하면결과적으로동율동이유지된환자군에서사망율이 47% 정도감소되는것으로나타났다. 결국동율동유지가사망율감소에중요하긴하나현재의항부정맥제로는약제의부작용이적지않아그효과가상쇄되어결과적으로이득이없게되는것이다. 따라서부작용이훨씬적은동율동유지방법이있다면분명히사망률감소에기여할수있을것이고, 전극도자절제술이합병증만최소화할수있다면가장가능성높은방법으로제시되고있다. 이에대해서는더많은연구가필요한실정이다. 4. 동율동유지치료가이드라인 Canadian Cardiovascular Society (CCS) 가이드라인에서는발작성심방세동, 증상이심한심방세동, 65세이하의젊은연령의환자군, 심부전이동반된환자군에서는동율동유지치료가장점이더많고, 반대로재발되는지속성심방세동, 65세이상의고령의환자, 심부전이동반되지않은고혈압혹은허혈성심질환, 항부정맥제치료에실패한환자군에서는심박수조절치료가더유리하다고추천하였다 년에발표된 ACC/AHA/ESC 가이드라인에서는수주이상지속된심방세동의경우우선항응고요법과심박수조절 을시도하고, 심박수조절에도증상이호전되지않는경우에는동율동전환을목표로한다. 이경우 48시간이상지속된심방세동의경우동율동전환시도전에반드시항응고요법을추천한다. 반면심박수조절로증상이완화되고고령이라면반드시동율동전환을고려할필요는없다. 그리고 CCS 가이드라인과비슷하게고령의지속성심방세동인경우에는심박수조절을, 그리고젊은환자나발작성심방세동이면서다른심장질환이없는경우동율동유지요법을우선적으로고려하도록추천하고있다. 또한 AFFIRM 연구에서동율동유지군에서항응고요법의조기중단으로혈전색전증이많이발생하였기때문에혈전색전증의고위험군에서는동율동유지에관계없이항응고요법이필수적이다. 심방세동의비약물적치료 심방세동환자에서약물치료만으로정상동율동으로의전환이나심실반응수의조절이잘안되는경우이거나심방세동에동반한심한서맥이있어약물치료자체가적응이되지않는경우에비약물적치료가효과적인치료법이다. 심방세동의치료로이용되고있는비약물적요법은 1) 전기적요법으로심방세동의동율동으로의전환, 2) 방실결절의절제후심박동기를이용해심방세동의빠른심박수조절, 3) 심방세동의발생부위에대한치료법등으로나누어생각할수있다. 1. 심방세동의전기적동율동전환직류전기 (Direct current, DC) 에의한전기적동율동전환은약제에의한동율동전환에비해효과적이고안전한방법으로성공율은평균 80-95% 정도이다. 성공율에영향을주는주된인자는심장의기능저하나판막질환등심장질환여부와 Table 2. 심방세동환자에서동율동유지와심박수조절방법의비교연구를토대로한장단점비교 Pros Cons Rate Control Not inferior to rhythm control for the majority of patients with AF Preservation of left ventricular function Lower costs of treatment Lower costs of treatment Less hospitalizations Target heart rate is unknown Not as easy to achieve as assumed Not attractive in highly symptomatic AF Persistence of an irregular heart beat Need for permanent anticoagulation Rhythm Control Improved quality of life with maintenance of sinus rhythm Improvement of left ventricular function and functional capacity Nobenefit in terms of morbidity and mortality Demanding approach for doctor and patient, time-consuming Adverse effects of antiarrhythmic drugs High recurrence rate of AF Need for permanent anticoagulation even with maintenance of sinus rhythm 28 대한신경과학회지제 29 권부록 2, 2011

52 심방세동의평가와치료 심방세동의지속기간이며, 좌심방의크기는정상동율동으로의유지여부를결정짓는중요한인자이다. 전기적동율동전환요법시행전충분한기간동안항부정맥제로전처치하고시도하면성공율을향상시키기도한다. 48시간이상지속된심방세동의경우에는시행전 3주동안과시행후 3-4 주간은항응고요법을시행하여야한다. 시행전경식도초음파를시행하여좌심방에혈전이없는것을확인하면충분한항응고요법을생략할수도있다. 그러나이때에도동율동으로전환된뒤에는적절한항응고요법을시행하여야한다. 일반적으로흔히사용하는최초에너지양은단상파형 (monophasic) 인경우 J, 이상파형 (biphasic) 에너지인경우 100J 이다. 2. 방실결절의절제후심박동기를이용한심박수의조절방실결절절제후심박동기삽입시술 (ablate and pace) 은약물에의해서심실반응수가적절히조절되지않고증상이심한심방세동환자에서증상과심실기능의악화예방이나개선에효과적이므로외국에서는많이시행되고있다. 그러나심방세동자체는그대로이기때문에혈전색전증의위험은남는다는점과심박동기에대한의존성이생긴다는단점이있어우리나라에서는널리이용되고있지는않다. 그러나심방세동으로인한증상의개선과생활의질향상에는심박동기요법이약물치료보다우수하다는보고가많다. 3. 심방세동의발생부위에대한비약믈적치료 1) 심방세동의수술적치료수술적치료로는변형된 Maze 수술 (Modified Maze surgery) 이가장널리이용되고있는데, 이수술은좌우심방을마치미로와같이여러구획으로나누어심방세동의유지에필요한심방내파형이잘생성되지않도록하는시술이다. 성공율은 80-90% 정도이고상당수의환자에서심방의기능회복이이루어지긴하지만, 개흉술을하여야하는부담이있어심방세동만으로수술을하는경우는많지않고주로는판막질환의수술과같이시행하는경우가많다. 하지만최근로봇수술을이용한최소침습법수술의도입과심외막도자절제술의도입등으로그유용성이증가될가능성이있다. 2) 심방세동의고주파도자절제술치료대규모임상연구인 AFFIRM 연구결과에서심방세동환자의치료시항부정맥제를이용한정상동율동유지요법이단순심박수조절요법에비해우수하지않다는결과가보고되긴하였 지만, 이는전환된동율동에의한이로운효과가동율동유지를위해투여한항부정맥제의부작용에의해상쇄된결과로분석된다. 따라서부작용을최소화한비약물요법에의한동율동유지를고려하게되었고전극도자절제술이가장적합한대안으로대두되게되었다. 전극도자절제술은경험이축적되고새로운기술이개발됨에따라다양한임상상의심방세동환자, 특히발작성심방세동환자에서비교적높은완치율을보이고있는치료법으로서점차시술의범위가확대되어가고있다 년심방세동의치료에관한미국심장학회 (AHA/ACC) 의지침에의하면전극도자절제술은모든종류의심방세동에서일차항부정맥제에반응하지않을경우다음단계로고려할수있는치료법으로권유되고있다. 그러나심방세동의전극도자절제술을원활하게시행하기위해서는 3차원영상지도화장비등고가의전문화된장비가필요하고, 오랜시술시간, 20-40% 정도의재발율및높은재시술율, 중대한합병증의가능성등제한점이많아보편적인치료법으로선택하는데에는아직은문제점이있다. 따라서심방세동의전극도자절제술은증상이있는심방세동이 1-2 가지이상의항부정맥약제를사용함에도불구하고증상조절이충분치않은경우에고려해볼수있다. 심방세동의도자절제법 심방세동의촉발기전으로조기수축이주요원인이고, 이러한조기수축의원인부위중빈도가가장높은곳이폐정맥이라는사실이알려지면서페정맥에대한절제술이시작되었다. 처음에는페정맥내부에서생기는조기수축을국소적으로제거하는방법을사용하였으나, 페정맥내의다른부위에서의재발율이높고페정맥협착등의합병증발생가능성이높아, 폐정맥을좌심방으로부터완전히전기적으로분리 (Electrical pulmonary vein (PV) isolation) 시키는방법으로발전하였다. 이러한 PV isolation 도처음에는페정맥입구부위에서부분적절제법 (segmental ablation) 을사용하다가최근에는폐정맥의 1-2 cm 근위부주위로원형선상절제법 (circumferential ablation) 이재발율을줄일수있어더많이사용되는추세이다. 또한페정맥이외의장소 ( 상대정맥, 좌심방후벽, 관정맥동개구부등 ) 도필요에따라절제술을시행하여야한다. 최근에는이러한 PV isolation 방법과는별도로혹은추가적으로폐정맥부위이외의부위에서 CFAE(complex fractionated atrial electrogram) 가기록되는부위가회귀파의주요부위라는가정하에이부위를선택적으로절제함으로써심방세동의유지를억제하는방법도시도되고있다. 그리고발작성심방세동의경우시술후심방조 J Korean Neurol Assoc Volume 29 Suppl. 2,

53 최기준 율로심방세동이유발되는경우나만성심방세동의경우에는좌심방내에승모판협부 (mitral isthmus) 나좌심방상벽 (roof) 부위에선형도자절제술 (linear ablation) 을시도하여좌심방의기질변형 (substrate modification) 을유도하여재발빈도를줄이는방법도많이사용된다. 그러나이러한선형도자절제술은불완전한경우오히려좌심방내에심방조동을조장할수있으므로시도한다면가능한한완벽하게전기적차단이이루어지도록만드는것이중요하다. 현재아직은모두가인정하는통일된우세한방법이없이여러가지방법으로시술을하고있기때문에, 성공율도경험과병원에따라큰차이가있기는하지만, 발작성심방세동의경우 70-90%, 지속성및아주오래되지않은만성심방세동의경우 50-80% 의성공율을보인다. 1) 빈맥 -서맥증후군에동반된심방세동의전극도자절제술심방세동이소실되면서 3초이상의긴동정지가관찰되는빈맥-서맥증후군환자에서심방세동의전극도자절제술이효과적인치료법이될수있다. 이전에는이러한환자에서영구형심박동기를삽입한후항부정맥제를쓰는것이표준치료법이었으나, 심방세동의전극도자절제술치료로심방세동이재발하지않는경우, 심방세동의치료를통해심박동기수술없이도서맥을예방할수있으므로전극도자절제술을우선적으로고 려할수있다. 그러나유의해야할점은동정지가심방세동종료직후나타나는동정지의형태일때에는전극도자절제술의효과가좋으나심방세동과관계없이동율동중에나타나는동정지가주된원인일경우에는효과가없다는점이다. 2) 심방세동전극도자절제술의합병증심방세동전극도자절제술에따른중대한합병증의빈도는대개 2-5% 정도이다. 가장문제시되는흔한합병증이폐정맥협착증이었으나, 3차원영상시스템을이용하여폐정맥-좌심방접합부부위에서원형선상절제법을이용하면서그빈도가 1% 미만으로많이감소하였다. 또한뇌색전증이 1% 정도에서발생할수있으므로이의예방을위하여시술전 2개월이상항응고요법으로 INR 2-3 을유지하는것이필요하며, 시술전경식도초음파로좌심방내혈전이없음을확인하여야하고, 시술중헤파린을지속적으로투여하여 ACT 를 초정도로유지하는것이좋다. 또한시술도중심낭압전 (cardiac tamponade) 이 1% 정도발생할수있다. 대부분은심낭천자로회복되지만일부환자에서는심장수술을요할수있다. 원형도자 (circular mapping catheter) 가승모판하부조직이나폐정맥의분지에고정되어빠지지않아수술을요하는경우도있다. 또드물기는하지만가장치명적인합병증으로높은사망률을보이는좌심방- 식도누공 (fistula) 도보고되고있다. 30 대한신경과학회지제 29 권부록 2, 2011

54 특수상황에서의간질환자치료 : 고찰및증례심방세동환자에서전통적항혈전치료 동아대학교의과대학신경과학교실김대현 Conventional Antithrombotic Therapy in Patients with Atrial Fibrillation Dae-Hyun Kim, MD, PhD Department of Neurology, College of Medicine, Dong-A University, Busan, Korea Nonvalvular atrial fibrillation is an important cause of disabling stroke whose incidence can be reduced by using antithrombotic prophylaxis. Adjusted-dose warfarin and antiplatelet agents are effective in the primary and secondary prevention of systemic embolism in patients with atrial fibrillation. Warfarin is substantially more efficacious (by approximately 40%) than antiplatelet therapy. The desired level of anticoagulation is an Internation Normalized Ration (INR) of 2-3. However, bleeding is the most important complication of warfarin and a major concern for both physicians and patients. For patients with transient ischemic attack and ischemic stroke of cardiac origin due to atrial fibrillation, warfarin are highly effective in preventing recurrent ischemic stroke but have important limitations and are thus underused. In this review several aspects for the benefit and limitation of warfarin use in the patients with atrial fibrillation are discussed. Key Words: Atrial fibrillation, Warfarin, Anticoagulation 서 론 심방세동환자에서뇌졸중발생을예방하기위한목적으로항혈전치료요법이필요하다. 항혈전요법에는항혈소판제와항응고제로분류할수있는데항혈소판제는항응고제보다뇌졸중예방효과가미약하다. 대표적인항응고제인와파린은지난 50여년동안심뇌혈관질환자들에게사용되어오면서그효능을충분히인정받아왔으며특히심방세동을포함한심장색전성뇌경색과정맥혈전색정증예방에는최선의약물로알려져왔다. 그러나와파린은출혈이라는치명적위험성을항상내재하고있어서양날의칼을가진약이기도하다. 와파린을처방하는의사들은출혈위험에대한부담뿐만아니라적절한국제응고기준 (INR) 수치를유지하기가어렵고, 약물이나음식물과와파린상호작용에대한환자교육까지담당해야한다. Dae-Hyun Kim, MD Department of neurology, College of Medicine, Dong-A University, 3-Ga Dongdaeshin-dong, Seo-gu, Busan , Korea Tel: Fax: kdh6542@hanmail.net 현재까지알려진심방세동환자에서항혈전치료의전반적인용법과임상연구들에대한근거들을분석해보고자한다. 본론 1. 와파린의기전 와파린은응고인자 Ⅱ, Ⅶ, Ⅸ, Ⅹ, 항응고단백질 C, S 등비타민 K 억제응고요소들을종합적으로억제한다. 투여후 24시간안에효과가나타나지만, 적정 INR 수치에도달하기까지는 시간이걸릴수있다. 와파린은이미형성된혈전에는영향을주지않고이미혈전증이발생했을경우항응고제의목적은추가적인혈전생성의억제와이차혈전색전증합병증의예방을위함이다. 2. 심방세동환자에서항혈전치료독일의해부병리학자 Virchow 는혈전으로인해경색증이나타나는혈전색전증의주요요인으로혈관내피손상 (endothelial injury), 혈액저류 (circulatory stasis), 혈액과응고 (hypercoa- J Korean Neurol Assoc Volume 29 Suppl. 2,

55 김대현 gulability) 를지적하였는데심방세동환자에서는이런위험성을모두가지고있어서뇌경색예방을위해서적극적인항혈전치료가필요하다. 11 현재까지심방세동환자의생존율을높일수있는치료로는항혈전치료 (antithrombotic treatment) 가유일하다. 항혈전치료약물로는항응고제와항혈소판제로나누어지는데위약과대비해서와파린투여시 64%, 아스피린의경우 22% 뇌졸중위험을감소시킨다고알려져있다. 2 따라서심방세동환자에서는항응고제를우선적으로고려해야하며그렇지못한상황에서는항혈소판제를투여한다. 1) 항혈소판제의뇌졸중예방효과 년에시행되었던 7개의임상연구결과를종합해보면심방세동환자 3,990 명을대상으로아스피린 50-1,200 mg 을투여했을때 1개의연구를제외하고는모두아스피린의뇌졸중예방효과를입증하지못하였다. 메타분석에서도상대적뇌졸중감소율은 19% 였지만 95% 신뢰구간이 1-35% 로유의성 을보이지않았다. 대신디피리다몰또는디피리다몰과아스피린복합제를포함한전체항혈소판제투여군과위약 / 대조군비교에서는항혈소판제가 22% 정도뇌졸중을감소시키는것으로나타났다 (Fig. 1). 그러나한건의뇌졸중예방을위해항혈소판제를투여해야하는환자수가너무많아서그효과는그리높지않는것으로생각된다. 2 최근와파린을투여할수없는상황이거나환자가와파린을거부하는경우에아스피린단독투여보다다른항혈소판억제기능을가진클로피도그렐을병용하는것이뇌경색예방에더도움이될것인가에관한 ACTIVE-A 연구가진행되었다. 약 7,500 명의환자를대상으로 4년간진행된연구발표에서 1차종료점인연간주요혈관성사건은아스피린단독군에서병합요법군에비해더많이발생하였다 (6.8% vs. 7.6%, p < 0.001). 이효과는주로뇌경색예방에의해서이루어졌고 (1.9% vs. 2.8%/year) 뇌출혈의발생에서는차이가없었다. 따라서뇌졸중의위험도가높은환자에서와파린을투여할수없는경우에 Figure 1. Relative effects of antithrombotic therapies on all stroke from randomized trials in patients with atrial fibrillation. 32 대한신경과학회지제 29 권부록 2, 2011

56 심방세동환자에서전통적항혈전치료 두가지항혈소판제의동시투여를고려해볼수있을것이다. 그러나, 주요출혈위험성은아스피린과클로피도그렐의복합투여군에서연간 2.0%, 아스피린군에서 1.3% 로복합투여군에서약 1.57 배정도더높아서출혈고위험군에서는주의가필요하다. 3 2) 항응고제의뇌졸중예방효과 년에심방세동환자를대상으로시행된 6개의와파린임상연구를메타분석한결과, 대조군에비해와파린투여군에서뇌졸중발생이 64% 정도감소하는것으로나타났다 (Fig. 1). 이런뇌졸중예방효과는과거뇌졸중발생유무와상관없이유의하게나타났는데전체적으로보면 32명의환자에게와파린을 1년간치료하면뇌졸중발생을한건예방하는효과를가진다. 2 항응고제복용시 PT (INR) 이 3 이상이면출혈의위험성은급격히상승하게되고 2 이하이면뇌졸중예방효과는감소하게된다. 따라서적절한뇌졸중예방과함께출혈부작용을줄이기위해서는 INR 을 2-3 으로유지하는것이좋다. 인공판막수술을받은환자에서는 INR 을 정도로목표로한다. 그러나, 여러임상연구에서규칙적인모니터링을하면서와파린을투약하더라도적정한 PT (INR) 범위를유지하는환자는 63% 에불과할정도로안정적인약물효과를거두기가어렵다. 4 3) 항응고제와항혈소판제의효과비교현재까지알려진와파린과항혈소판제단독요법을통한뇌졸중예방효과에관한연구들을종합해보면와파린은항혈소판제에비해상대적뇌졸중예방효과는약 37% 정도더우수하다고이야기할수있다 (Fig. 1). 두가지항혈소판제를이용한복합요법이와파린과비슷한항혈전치료효과를보인다면와파린의단점을극복하면서편리하게뇌졸중예방을기대해볼수있다. 이에관한해답을얻기위해서심방세동환자를대상으로아스피린과클로피도그렐복합투여군과와파린투여군에서뇌졸중예방효과를비교한연구가진행되었다. 그러나아스피린 mg 과클로피도 그렐 75 mg 을함께투여한환자는와파린투여환자보다뇌졸중발생률이 1.7 배정도높았고주요출혈의위험도와파린군에비해낮지않아서이연구는중간분석후조기종료되었다. 4 이상의연구들을종합애보면심장색전증에의한뇌졸중예방을위해서는심장내혈전의발생기전과맞지않는아스피린또는두가지항혈소판제를사용하는것보다와파린을투여하고 INR 을잘조정하는것이더중요하다는것을알수있다. 4) 항혈소판제와항응고제의동시투여심방세동환자에서와파린에의한출혈의위험성을줄이기위해서와파린투여후 INR 을 로유지하면서아스피린을추가한환자들과와파린투여후 INR 2-3 으로적정하게유지하게한환자를비교한 SPAF Ⅲ 연구결과에의하면적절한 INR 을유지한와파린단독투여환자가병용투여환자에비해뇌졸중과전신색전증발생률이 74% 감소한다는결과를보였다. 5 이연구를통해서적절한용량의와파린단독투여가다른어떤치료보다우수한뇌졸중예방효과를보인다는것을다시한번보여주는결과로생각된다. 한편심방세동환자에서와파린을투여하여뇌졸중위험도에따라 INR 수준을 또는 로맞추도록하면서트리플루살을추가한경우와와파린을단독으로투여하면서 INR 을 2-3 으로유지한경우를비교했을때항응고제와트리플루살복합투여군에서뇌졸중예방효과가더뛰어나다는연구도있어서재발위험성이높은뇌경색환자에서복합치료를고려해볼수도있을것이다 뇌졸중위험의평가도구심방세동환자에서뇌졸중발생위험도를예측하는몇가지평가도구가알려져있는데주로 CHADS 2 점수를통한위험도평가후항응고제사용을결정하는권고안이주로통용되고있다 (Table 1). 7 CHADS 2 란울혈성심부전, 고혈압, 75세이상, 당뇨병이있는경우 1점, 과거뇌졸중또는일과성허혈발작이있는경우는 2점을부여하는방식이다. CHADS 2 점수가 0점이 Table 1. Nonvalvular atrial fibrillation risk stratification and treatment recommendations: Risk stratification by CHADS 2 scheme CHADS2 score Risk level Adjusted stroke rate (%/y, 95% CI) Treatment recommendations 0 Low 1.9 (1.2 to 3.0) Aspirin (75 mg-325 mg/day) 1 Low-moderate 2.8 (2.0 to 3.8) Warfarin INR 2-3 or aspirin (75 mg-325 mg/day) 2 Moderate 4.0 (3.1 to 5.1) Warfarin INR High 5.9 (4.6 to 7.3) Warfarin INR Very high 8.5 (6.3 to 11.1) Warfarin INR 2-3 J Korean Neurol Assoc Volume 29 Suppl. 2,

57 김대현 면아스피린, 2점이상이면와파린을투여하고 1점이면아스피린또는와파린을투여한다. CHADS 2 점수시스템은 0-2 점사이에너무많은환자가분포하여아스피린을투여할지와파린을사용할지잘구분되지않는단점이있는데, 최근에는유럽심장병학회에서 CHA 2DS 2-VASc (Congestive heart failure/poor LV function, Hypertension, Age >75, Diabetes mellitus, Stroke, Transient ischemic stroke, or systemic embolism, Vascular disease, Age 65-74, Sex category) 점수를이용할것을제시하고있는데 (Table 2), 이에따르면 CHA 2DS 2-VASc 점수는총점이 9점이되며 2점이상이면항응고제를투여하고, 1점인경우는항응고제투여또는아스피린 mg을투여할수있으나되도록항응고제를선호하고, 0점인경우는특별한치료가필요없거나아스피린을투여할수있는것으로되어있다. 이시스템은 CHADS 2 점수보 Table 2. Risk factor-based approach expressed as a point based scoring system, with the acronym CHA 2DS 2-VASc Risk factor Score Congestive heart failure/lv dysfunction 1 Hypertension 1 Age 75 2 Diabetes mellitus 1 Stroke/TIA/thrombo-embolism 2 Vascular disease (prior MI, PAD, aortic plaque) 1 Age Sex category (i.e. female sex) 1 Maximum score 9 LV; left ventricular, TIA; transient ischemic attack, MI; myocardial infarction, PAD; peripheral artery disease. 다심방세동환자에대한위험도를보다세분화하고더적극적으로항응고제를사용할것을권고하고있다 항응고제사용과출혈위험심방세동환자에서와파린을이용한뇌졸중예방효과는충분히입증되어있지만출혈의위험성이높다. 특히뇌출혈은가장치명적인출혈합병증인데뇌출혈도와파린투여환자에서더높다고알려져있다. 따라서와파린뇌경색예방효과와뇌출혈을포함한출혈위험성을충분히고려하여고위험환자를대상으로적절한용량의와파린을사용해야한다. 대략적으로와파린으로인한평균출혈발생률은치명적출혈은연간 0.6%, 주요출혈은 3% 이외전체출혈은 9.6% 로알려져있다. 심방세동환자에게항혈전치료를시행한임상연구에서출혈과연관된여러인자들이알려져있는데이를바탕으로출혈의위험도를계산하는여러평가도구들이개발되어있다. 최근유럽심장병학회권고안에서는 HAS-BLED 점수를이용하여출혈위험도를평가할것을권고하고있는데총점 8점중 3점이상인경우고위험군으로분류하고항응고제치료를할때더욱주의를기울여야한다 (Table 3). 8,9 5. 그밖의항응고제단점와파린의사용에서적정치료가능범위가 INR 2-3 으로좁고개인에따른검사차이가매우큰것으로알려져있어서와파린을처방할때마다정기적인혈액검사를해야하는번거로움이있다. 또한와파린은혈액내단백질과의결합이많고, cytochrome Table 3. Clinical characteristics comprising the HAS-BLED bleeding risk score Letter Clinical characteristic Points awarded H Hypertension 1 A Abnormal renal and liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding 1 L Labile INRs 1 E Elederly (e.g. age >65 years) 1 D Drugs or alcohol (1 points each) 1 or 2 Maximum 9 points Hypertension is defined as systolic blood pressure. 160 mmhg. Abnormal kidney function is defined as the presence of chronic dialysis or renal transplantation or serum creatinine 200 mmol/l. Abnormal liver function is defined as chronic hepatic disease (e.g. cirrhosis) or biochemical evidence of significant hepatic derangement (e.g. bilirubin. 2 upper limit of normal, in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase. 3 upper limit normal, etc.). Bleeding refers to previous bleeding history and/or predisposition to bleeding, e.g. bleeding diathesis, anemia, etc. Labile INRs refers to unstable/high INRs or poor time in therapeutic range (e.g., 60%). Drugs/alcohol use refers to concomitant use of drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse, etc. 34 대한신경과학회지제 29 권부록 2, 2011

58 심방세동환자에서전통적항혈전치료 P450 을통해서분해되므로비타민 K를포함한음식물, 다양한약제들과약물학적상호작용이많아서출혈의위험성을포함해서환자및보호자교육이반드시필요하다. 와파린은투여시작시에작용이느리게나타나고드물지만약제투여초기에단백질 C, S를먼저억제하여오히려혈전증을촉진할수있다. 반대로수술, 조직검사등의시술때문에와파린을중단해야하는경우에약효가사라지는데 3-4 일이걸리는단점이있다. 출혈의위험을포함한상기언급한여러가지단점때문에심방세동환자에서의사의와파린처방율은 15-44% 로낮고, 10 와파린을복용하고있는환자라고하더라도 INR 이 2-3 으로유지되는경우는임상연구에서 50-60% 정도이고 4 실제임상에서는절반이하일것으로추정된다 일차예방 심방세동환자에서항응고제사용의국내권고안 IV, 권고수준GPP). 3) 적절한항응고제치료를받던심방세동환자에서허헐뇌졸중또는일과성허혈발작이재발한경우, INR 로치료목표를높이거나항혈소판제병용투여를고려할수있다 ( 근거수준 IV, 권고수준C). 결론 현재까지심방세동환자에서사용가능한항혈전치료제로는와파린과항혈소판제가있으나효과적인면에서와파린이훨씬뛰어나다. 와파린은장기간의사용을통해서효과에대한근거가확실하며약값이저렴하다는강점을가지고있지만출혈의위험성이높고, 적절한약물레벨을맞추기가어려우며, 약물상호작용에민감하다는약점을가지고있는약이다. 향후새롭게개발된항응고제들이많은임상연구를통해약물의효과와안정성이확보되어향후뇌졸중예방에큰기여를할수있을것으로생각한다. 1) 판막질환이동반된- 특히기계판막치환술을시행받은- 심방세동환자에게는뇌졸중의일차예방을위해항응고치료를해야한다 ( 근거수준Ia, 권고수준A). 2) 비판막성심방세동환자에게뇌졸중예방을위해항혈전치료 ( 와파린또는아스피린 ) 를해야하는데, 이는개개인의위험도, 출혈가능성, 환자의선호도및주기적인항응고효과검사가능여부등을고려하여판단한다 ( 근거수준Ia, 권고수준A). 3) 항응고치료에심각한부적응증이없는고위험도 (1년뇌졸중위험도 4% 이상 ) 심방세동환자에서와파린 (INR ) 사용이추천된다 ( 근거수준Ia, 권고수준A). 4) 75세이상고령의심방세동환자에서도뇌졸중의일차예방목적으로와파린 (INR ) 사용이추천된다 ( 근거수준 Ib, 권고수준A). 2. 이차예방 1) 지속또는발작심방세동을가진허혈뇌졸중또는일과성허혈발작환자에서, 특별한금기가없는한 INR 목표의와파린치료가권장된다 ( 근거수준 Ia, 권고수준A). 2) 항응고제를투여할수없다면, 아스피린을투여할수있다 ( 근거수준Ia, 권고수준A). 적절한아스피린용량으로는하루 325 mg가권장되나, 우리나라에서는실제처방가능한용량인하루 300 mg 을고려할수있다 ( 근거수준 References 1. Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow's triad revisited. Lancet 2009;373: Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146: Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M, Chrolavicius S. et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360: Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S. et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events (ACTIVE W): A randomised controlled trial. Lancet 2006;367: Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke prevention in atrial fibrillation Ⅲ randomised clinical trial. Lancet 1996;348: Perez-Gomez F, Alegria E, Berjon J, Iriarte JA, Zumalde J, Salvador A. et al. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation: A randomized multicenter study. J Am Coll Cardiol 2004;44: Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD. et al. Primary prevention of ischemic stroke: A guideline from the american heart association/american stroke association stroke council: Cosponsored by the atherosclerotic peripheral vascular disease interdisciplinary working group; cardiovascular nursing council; clinical cardiology council; nutrition, physical activity, and metabolism council; and the quality of care and outcomes research interdisciplinary working group: The american academy of neurology affirms the value of this guideline. Stroke 2006;37: Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S. et al. J Korean Neurol Assoc Volume 29 Suppl. 2,

59 김대현 Guidelines for the management of atrial fibrillation: The task force for the management of atrial fibrillation of the European society of cardiology (ESC). Eur Heart J 2010;31: Lip GY, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly) score. J Am Coll Cardiol 2011;57: Bungard TJ, Ghali WA, Teo KK, McAlister FA, Tsuyuki RT. Why do patients with atrial fibrillation not receive warfarin? Arch Intern Med 2000;160: McCormick D, Gurwitz JH, Goldberg RJ, Becker R, Tate JP, Elwell A. et al. Prevalence and quality of warfarin use for patients with atrial fibrillation in the long-term care setting. Arch Intern Med 2001;161: 대한신경과학회지제 29 권부록 2, 2011

60 특수상황에서의간질환자치료 : 고찰및증례새로운항응고제 보라매병원신경과권형민 New Anticoagulants Hyung-Min Kwon, MD, PhD SMG-SNU Boramae Medical Center, Seoul, Korea Atrial fibrillation is the major cause of cardioembolic stroke and warfarin has been prescribed for a long time to prevent such cardioemobolic stroke. Though there are clear benefits of warfarin anticoagulation, there is also comparable number of drawbacks - such as major bleeding, narrow range of therapeutic window, and variable dose response. Thus the efforts to find the new anticoagulants were continuously attempted through various studies. Recently, three novel anticoagulants have gathered much attention from clinicians. Oral thrombin (factor IIa) inhibitor, dabigatran, and factor Xa inhibitor, apixaban and rivaroxaban succeeded in showing non-inferiority in primary efficacy and safety outcomes compared to dose-adjusted warfarin therapy. New anticoagulants have quite predictable pharmacokinetic properties and minimal interactions with food and other drugs. Thus they do not need to monitor INR throughout regular blood sampling. However the exact therapeutic windows are not clearly described yet. In addition to that, there are no antidotes to reverse the anticoagulant effect in cases of emergency. Thus we need to understand thoroughly their exact mechanisms, characteristics, benefits, side effects in advance of adopting widespread clinical uses of them. Key Words: Anticoagulants, Warfarin, Dabigatran, Apixaban, Rivaroxaban 서 론 심장색전성뇌졸중 (cardioembolic stroke) 은전체허혈성뇌졸중의약 20% 를차지하는것으로알려져있으며, 이중반수이상은심방세동에기인한다. 1 이러한심장색전성뇌졸중은다른허혈성뇌졸중에비해재발이흔하고발생시중증도나후유장애가심한편으로알려져있다. 2 또한심방세동은나이가증가할수록유병율이증가하는질환으로노령화가빠르게진행되고있는한국사회에서새로운보건문제로대두되고있다. 1 이러한심장색전성뇌졸중에대한국내진료지침은뇌졸중임상연구센터에서제안한바에따르면항응고치료에심각한부적응증이없는이상고위험도 (1년뇌졸중위험도 4% 이상 ) 인심방 Hyung-Min Kwon, MD, PhD Department of Neurology, Seoul National University College of Medicine, Stroke Center/Neurology, SMG-SNU Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul Korea Tel: Fax: hmkwon@snu.ac.kr 세동환자의경우와파린 (warfarin) 사용이추천된다고언급하고있다. 또한심방세동환자들을위한유럽심장협회치료지침에서도심방세동환자에게서이전의뇌졸중병력이나기타위험인자들을 CHADS2 점수 (C=congestive heart failure, H=hypertension, A=age >75 years, D=diabetes, S=stroke) 로환산하여향후뇌졸중고위험군을선별하고이러한환자들에게 prothrombin time (PT) international normalized ratio (INR) 에맞춰용량을조절한와파린치료를권유하고있다. 3 와파린은 1930 년대개발된경구용항응고제로서간에서비타민 K 길항제로작용하여응고인자 II, VII, IX, X의합성을억제함으로써항응고효과를보인다 년이전까지 6개의임상연구가뇌졸중고위험군심방세동환자총 2,900 명을대상으로이루어졌다. 4 와파린은위약과비교하여뇌졸중및전신색전증을 62% 까지감소시키는것으로확인된반면 aspirin 의경우 22% 에그쳤다. 와파린에대한임상연구의메타분석결과를보면뇌졸중의상대발생률을 68% 가량감소시키고, 연간뇌졸중발생률은 4.5% 에서 1.4% 로감소시켰으며, 출혈성부작용은 J Korean Neurol Assoc Volume 29 Suppl. 2,

61 권형민 와파린군에서연간 1.3% 로아스피린군의 1% 에비해의미있는차이를보이지않았다. 1 그러나와파린은다양한음식및약제와상호작용을보이고, 적정약물농도범위 (therapeutic window) 가좁고환자마다용량 -반응(dose response) 이다양하여적정혈중농도를유지하기위해정기적으로채혈을통해 INR 수치를확인해야하는등임상에서사용하기에어려운문제를가지고있다. 또한전체환자의약 60% 정도에서만적정치료농도로알려져있는 INR 사이의농도를유지할수있는것으로알려져실제임상에서의와파린사용에한계를실감할수있다. 5 실제로와파린치료가필요한뇌졸중고위험군의심방세동환자의약 50% 정도는와파린을복용하고있지않거나, 부작용으로인해중단했다는연구결과도있다. 6 이러한단점으로인해와파린을대체할수있는새로운약물개발에대한필요성이꾸준히대두되어왔다. 실제대규모임상시험에서 oral direct thrombin inhibitor인 ximelagatran 과 long-acting factor Xa inhibitor 인 idraparinux 등이혈전색전성뇌졸중을줄일수있음이확인되었으나간독성및심한출혈성부작용으로인해실제임상에서사용되지는못했다. 최근들어주목받고있는약제로 dabigatran, apixaban, rivaroxaban 등을꼽을수있는데본론에서각약물의기전및주요임상시험결과등을살펴보도록하겠다. 본론 세가지대표적인임상연구 (RE-LY, AVERROES, ROCKET-AF) 결과가최근에발표되면서앞서언급한새로운항응고제의역할이주목을받고있다. 세연구모두뇌졸중발생위험성이높은고위험군환자들을대상으로하였고목표 INR 으로조절한와파린과비교해비열등성을증명하고자하였다. 각연구에서보다엄밀한비교를위해와파린치료군의치료순응도를적절하게평가할필요가있었는데저자들은연구기간중치료적정농도에도달한총시간분율과중도탈락률로나누어제시하였다. 세연구들에서와파린치료적정농도에도달한기간은총연구기간의 58-68% 였고, 중도탈락률은 8-24% 였다. 중도탈락률의경우와파린군에서신약군에비해비슷하거나더적은편이었다 Dabigatran (RE-LY) Dabigatran etexilate는 dabigatran의전구약물 (prodrug) 로서활성형으로전환된후선택적, 가역적으로 thrombin (factor IIa) 을억제하게된다. 유리형 (free form) 및혈전결합형 (clot- bound) thrombin 모두에효과가있으며, 전구약물에서활성형으로의전환이 cytochrome P-450 와독립적인 serum esterase 에의해이루어지기때문에 verapamil 이나 amiodarone, quinidine 등일부 P-glycoprotein inhibitor 계열의약물들이 dabigatran 의혈중농도를증가시킬수있는것으로알려진것외에와파린처럼음식이나다수의약물, 유전적다형성 (genetic polymorphism) 의영향을덜받게되어 INR monitoring 이나용량조절이필요없는장점이있다. 7 최대혈장농도도달시간은 시간이며최대효과는 2시간만에나타나게된다. 반감기는 12시간이다 % 가변화없이신장으로배설되게되며, 나머지 5-10% 는담즙을통해배설된다. 혈장단백결합이 35% 로낮기때문에과다복용이나심한출혈시혈액투석으로 rapid reversal 을시도할수있다. PT (INR) 와 aptt가연장되기는하지만임상적으로의미있는약물농도변화를찾아내기에는위의수치들은적절하지않다. 항응고효과의정량화를위해서는 Thrombin Clotting Time (TT) and Ecarin Clotting Time (ECT) 이적합한것으로알려져있다 년도에발표된 RE-LY (Randomized Evaluation of Long-term anticoagulation therapy) 9 연구는총 18,113 명의고위험군심방세동환자를대상으로 dabigatran 과기존와파린의효능및부작용을비교하였다. 환자들은심방세동외에도적어도하나이상의뇌졸중위험인자를가지고있는경우만포함하였고평균 CHADS2 점수는 2.1 점이었다. Dabigatran 은맹검법으로, 와파린은 open-label 로투약하였고 2년간추적관찰하였다. Primary endpoint 는뇌졸중또는전신색전증이었으며 primary safety outcome 은주요출혈성부작용이었다. Dabigatran 두가지용량 (110 mg bid, 150 mg bid) 과목표 INR 에맞춘와파린을비교하였을때, primary outcome 은 dabigatran 150 mg 군에서연간 1.11% 로 110 mg 군의 1.53% 나와파린군의 1.69% 보다우수한성적을보였고비출혈성뇌졸중 ( 허혈성및 unspecified) 에대해서도각각 0.92%, 1.34%, 1.20% 로 150 mg dabigatran 군에서우수한성적을나타내었다. 와파린과비교하여 150 mg 의 dabigatran 을사용하였을때비출혈성뇌졸중환자한명을줄이기위한 NTT (number to treatment) 는 357 명이었다. 와파린환자군의경우총연구기간중 64% 에서치료범위안에서 INR이조절되었고이는기존의다른와파린관련연구와비슷한수치였다. 특히 79% 의기간동안 INR 이치료범위안에있었던환자들의경우 dabigatran 150 mg 군과비슷한정도의뇌졸중예방효과를보였고, INR 이치료범위안에서잘조절된환자들만따로분석할경우사망률면에서 dabigatran 보다유리한경향성을보였으나 10 실제임상에서이와같은조절을기대하기는어려운것이실정이다. 38 대한신경과학회지제 29 권부록 2, 2011

62 새로운항응고제 부작용에있어서는심근경색이와파린군에비해 dabigatran 군에서보다많이나타났고 (0.72%, 0.74% with 110 mg and 150 mg of dabigatran, respectively, 0.53% with warfarin) dyspepsia 또한 dabigatran 군에서많았으며특이후자는연구도중중도탈락되는데중요한원인으로작용했다 (11.8%, 110 mg group; 11.3%, 150 mg group; 5.8%, warfarin; second year dropout rate: dabigatran 21%, warfarin 16.6%). 그러나 ximelagatran 에서문제가되었던정상기준 3배이상의간수치상승은 dabigatran 군에서 2% 정도로 warfarin 군과비교시큰차이가없었고중등도이상의간담도계질환으로입원을요한경우도양군사이에유의한차이는보이지않았다. 그러나연구기간이 2년이었던점을감안하면장기간의효과에대해서는추적관찰이필요한상태이며초기에얼마나자주간수치를확인해야하는지에대한구체적인기준이없는상태로해석에주의를요한다. 정리하자면와파린에비해 dabigatran 150 mg 은출혈성부작용의비율은비슷하면서보다효과적으로뇌졸중을예방할수있었고, 110 mg 은뇌졸중예방효과는 warfarin 과비슷하였으나출혈성부작용이더적어앞서언급한심장혈관계의특정약물을복용하고있는경우에는 110 mg 이선호될수있다. 때문이다. 뇌졸중및전신색전증등의 primary efficacy outcome 은 aspirin 군과 apixaban 군에서각각 3.7%, 1.6% 로확인되었다 (hazard ratio with apixaban, 0.45; 95% CI, ; P < 0.001). 주요출혈성부작용의경우각각연간 1.2% 1.4% 로확인되었다 (hazard ratio with apixaban, 1.13; 95% CI, ; P=0.57). 뇌내출혈의경우 apixaban 에서 11명, aspirin 에서 13명발생하였다. 와파린과의직접적인비교를위해고위험심방세동환자에서뇌졸중등혈전색전성질환발생률을비교하는이중맹검, 비열등성디자인의 ARISTOTLE (Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation) 12 연구는 2011 년 4월에마지막환자를등록하여그결과를최근유럽심장학회에서발표하였는데, 심방세동과한가지이상의뇌졸중위험인자를가지고있는 18,000 여명의환자를무작위배정하여평균 1.8 년간추적관찰하였다. 연구결과 apixaban 은와파린에비해의미있게뇌졸중과전신색전증을감소시키고 (21%) 주요출혈사건을덜일으키며 (31%) 더낮은사망률 (11%) 을보였다 Rivaroxaban (ROCKET-AF) 2. Apixaban (AVERROES, ARISTOTLE) Apixaban 은선택적, 가역적인 direct factor Xa inhibitor 로서혈중최고농도도달시간은 30분에서 2시간, 반감기는 8시간에서 15시간으로알려져있다. CYP450 계통의 CYP3A4 에의해대사되며 30% 는신장으로, 70% 는대변으로대사된다. 유리형 factor Xa 보다는혈전에결합되어있는factor Xa 를주로억제하며 thrombin 합성에대해서도억제효과가있다. 용량의존적으로 aptt 와 modified PT 변화를유도하지만치료용량에서는 INR 이나 aptt를변화시키지않는다. 8 음식과의상호작용은없는것으로보고되어있다. 8 Apixaban 의경우대표적인임상연구는 AVERROES (Apixaban VERsus acetylsalicylic acid to prevent strokes) 이다. 11 와파린사용이불가능한 5,599 명의고위험군심방세동환자를대상으로수행된이연구에서 apixaban (5 mg bid) 과아스피린을이중맹검법으로비교하였고, 뇌졸중및전신색전증여부를 primary efficacy outcome 으로, 주요출혈성부작용을 primary safety outcome 으로설정하였다. AVERROES 는 2010 년유럽심장학회에서조기중단을발표하였는데이는예비결과에서 apixaban 이 aspirin 에비해약 50% 의상대위험도감소를보였고주요출혈성부작용이나간독성의증가도보이지않았기 Rivaroxaban 은선택적, 가역적인 factor Xa direct inhibitor 로서최대혈장농도도달시간은 30분에서 3시간이고, 반감기는 3-9 시간으로알려져있다. CYP450 계통의 CYP3A4 로대사되며 70% 는신장으로, 30% 는대변으로배설된다. Transport 단백질인 P-glycoprotein 의기질로작용하기때문에이를공유하는다른약제들과상호작용을보일수있다. Rivaroxaban 은사용되는시약에따라 INR 을연장시킬수있기에항응고효과의평가를위해서는 factor Xa 억제정도가적절한 surrogate marker 로사용될수있다. 8 RE-LY 연구에연이어발표된연구가 ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) 14 로 14,000 명의고위험군비판막성심방세동환자에서혈전색전성질환의발생을주요결과변수로삼아와파린과 rivaroxaban 을비교한이중맹검, 위약대조군, 비열등성연구이다. 참여자들은 INR 로치료농도를조절한와파린군과 rivaroxaban (20 mg qd) 군으로무작위배정되었고이중맹검법을유지하기위해 rivaroxaban 군에서도 INR 감시를시행하고 sham INR 결과를통보하였다. 24개월동안의뇌졸중및전신색전증을일차결과변수로잡은 ROCKET-AF 의특이한점은결과분석에있어서 per-protocol, J Korean Neurol Assoc Volume 29 Suppl. 2,

63 권형민 as-treated test 를통해비열등성검사를수행했다는점이고, 그결과 rivaroxaban 이와파린에비해효능이떨어지지않음을증명하였다 (1.71 vs events per 100 patient-years, P < 0.001). 저자들은 intention-to-treat analysis 를통해 superiority 역시증명하고자하였으나원하는결과를얻지는못했다 (P = 0.117). 안전성분석에서주요출혈성부작용의 composite 는양군간에차이가없었으나뇌내출혈과출혈성뇌경색은 rivaroxaban 군에서유의하게적게나타났다 (0.5% vs. 0.7%, P =0.02). 이는 RE-LY trial 에서 dabigatran 110 mg 치료군에서도확인할수있었던결과이다. 이러한결과의원인에대해서는확언할수없지만다양한 target 을가지는와파린에비해두가지신약모두항응고경로의단일 target 을통해작용을나타낸다는점에주목할필요가있다. 5,15 그러나혈색소 (Hb) 가 2 g/dl 이상감소하여수혈이필요한환자들은 rivaroxaban 군에서유의하게많았다. 저자들은안전성분석에있어서도 intention-to-treat analysis 가아닌 as-treated population safety 를확인함으로써해석에주의를요하는면이있다. 결론적으로 rivaroxaban 은고위험군심방세동환자에서와파린과필적할만한효용성과안전성을보이는것으로볼수있다. RE-LY trial 과 ROCKET-AF 를해석할때주의할점한가지는두연구에서와파린치료효과를반영하기위한치료적정농도에도달한총시간분율인데 ROCKET-AF 에서는 55%, RE-LY 에서는 64% 로확인되어 dabigatran 과 rivaroxaban 과비교대상이되었던와파린치료군의특성에대해독자들이주의를기울일필요가있다. 5 앞서언급한대로 INR 이비교적오랜기간동안치료적정농도범위안에서유지되었던일부와파린군의환자들의경우비교대상이되었던신약투약군보다뇌졸중예방효과나사망률면에서유리한경향성을보이는경우도있었다. 10 위의세가지약제들을정리하면 dabigatran etexilate 는 150 mg 제형의경우뇌졸중및전신색전증을와파린보다효과적으로줄이면서출혈성부작용은비슷한정도로확인되었다. Apixaban 의경우저용량 aspirin 과비교할때와파린을사용할수없는심방세동환자에서출혈위험성을증가시키지않으면서뇌졸중발생위험도는감소시키는것으로확인되었고, 와파린과비교해서도더나은효과를보여주고있다. Rivaroxaban 의경우와파린과비교하여뇌졸중과전신색전증의예방에있어비열등성을증명하였고, 주요출혈성부작용은양군간에차이가없었으며, 뇌출혈은 rivaroxaban 군에서더적은것으로나타났다. 결 론 Dabigatran, apixaban, rivaroxaban 모두와파린을대체할만한훌륭한신약으로서주목을받고있다. 음식이나약물간상호작용이적은점이나복용의편리성, 예측가능한약동학적특성으로인해 INR 등 monitoring 이필요없다는점이강력한이점으로여겨지고있다. 따라서순응도가좋지않거나 INR 조절이어려운환자들의경우위와같은약제들이도움이될수있을것이다. 그러나용량에비례하여특정 coagulation test 결과를연장시키는점과정확한치료농도영역이아직까지알려져있지않다는점을고려하여야한다. 8 특히아직까지세가지약제모두효과를즉각적으로반전시킬수있는해독제가알려져있지않다는점을주지할필요가있다. 또한 dabigatran 및 rivaroxaban 의경우 P-glycoprotein 상호작용효과가분명하여 amiodarone, verapamil, clarithromycin 등 P-glycoprotein 를억제하는약물들로인해항응고효과가상승할수있어주의를요한다. 8 또한신약으로서높은약값또한실제임상에적용할때걸림돌이될수있는부분이다. 이렇게최근주목받고있는새로운항응고제들의작용기전과약동학적특성, 임상연구에서의효능및부작용들에대해숙지하고있다면곧상용화될신약들을도움이필요한환자들에게적절하게사용하는데있어큰도움이될것이다. References 1. 대한뇌졸중학회. 뇌졸중. 이퍼블릭, Stewart RA. Clinical trials of direct thrombin and factor Xa inhibitors in atrial fibrillation. Curr Opin Cardiol 2011;26: Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the european society of cardiology (ESC). Eur Heart J 2010;31: Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131: Del Zoppo GJ, Eliasziw M. New options in anticoagulation for atrial fibrillation. N Engl J Med DOI: /NEJMe Go AS, Hylek EM, Borowsky LH, Phillips KA, Selby JV, Singer DE. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann Intern Med 1999;131: Gage BF. Can we rely on RE-LY? N Engl J Med 2009;361: Galanis T, Thomson L, Palladino M, Merli GJ. New oral anticoagulants. J Thromb Thrombolysis 2011;31: Poller L, Jespersen J, Ibrahim S. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: ; author reply Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of 40 대한신경과학회지제 29 권부록 2, 2011

64 새로운항응고제 dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010;376: Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364: Lopes RD, Alexander JH, Al-Khatib SM, et al. Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J 2010;159: ARISTOTLE: efficacy and safety of apixaban compared to warfarin for prevention of stroke and systemic embolism in 18,202 patients with atrial fibrillation: primary results of the ARISTOTLE trial. 28 August 2011, ESC congress Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med DOI: / NEJMoa Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011; 123: J Korean Neurol Assoc Volume 29 Suppl. 2,

65 특수상황에서의간질환자치료 : 고찰및증례인지장애및이상행동으로의뢰된환자의임상적접근 동아대학교의과대학신경과학교실, 동아대학교병원신경과기억장애ㆍ치매클리닉 박경원 Practical Approach to Patients with Cognitive Impairment and Behavior Disturbance Kyung Won Park, MD, PhD Department of Neurology, Dong-A University College of Medicine, Memory Disorders and Dementia Clinic, Dong-A University Medical Center Generally, causes of cognitive impairment and behavior disturbance in elderly patients are various, it is difficult to identify the exact underlying disorders. To differentiate a number of diverse disorders of cognitive impairment, thorough evaluations such as, detailed history taking, physical and neurological examination, neuropsychological assessment, laboratory test and neuroimaging study should be performed. It is very important to classify the conditions derived by transient delirium or by secondary cause of pathologic disease in patients with old age. In addition, to ascertain the course of disease, such as, acute onset with rapid deterioration or insidious onset with slow progression is also essential on practical approach in elderly patients with referral to neurology department. Key Words: Cognitive impairment, Behavior disturbance, Dementia, Delirium 서 론 우리나라는세계에서가장빠른속도로노령화되고있다. 젊은사람들의출산율을급격히떨어지고, 수명은가파르게증가하고있기때문이다. 65세이상노인의비율이 7% 를넘는고령화사회로이미 1999 년에진입했고, 2022 년에는그비율이전인구의 14% 가넘는고령사회로들어갈것으로예상된다. 1 노인인구가급속히증가하는시점에서인지기능저하혹은성격변화나이상행동을보이는환자의빈도도점차증가추세에있다. 인지장애및이상행동을일으키는원인질환은매우다양하기때문에, 이들의원인질환을정확하게진단하기는쉽지않다. 더구나노인환자에서인지장애혹은이상행동을보일때일시적인섬망상태인지병적인질환에의한이차적인증상인지를구분하여적절한치료를하는것은신경과의사로서매우 Kyung Won Park, MD, PhD Department of Neurology, Dong-A University College of Medicine, 1 Dongdaesin-dong 3-ga, Seo-gu, Busan , Korea Tel: Fax: neuropark@dau.ac.kr 중요한영역이라할수있다. 따라서인지장애혹은이상행동으로인해타과에서신경과에의뢰되는경우가비교적흔하므로이에대한임상적접근법을숙지하는것은매우중요하다. 본장에서는인지장애및이상행동을보이는환자가의뢰되었을때신경과의사가반드시감별진단해야할질환들, 병력청취, 신경학적진찰, 검사실검사및영상검사등에대해서기술하고자한다. 노인에서인지장애및이상행동을야기하는원인질환 1. 급성경과를보이는원인질환 1) 섬망섬망 (delirium) 은노인환자에서갑자기발생하고의식의변동이심한가역적상태를총칭한다. 의식의혼탁이동반되면서하루중에변동하는데, 특히밤에심한경향을보인다. 섬망환자는불안, 초조, 환시, 환청이있을때맥박수가올라가고땀이나는등자율신경계의이상이동반된다. 섬망은의식의장애, 42 대한신경과학회지제 29 권부록 2, 2011

66 인지장애및이상행동으로의뢰된환자의임상적접근 주의력저하뿐만아니라정동, 사고, 언어등인지기능전반의장애와정신병적증상을유발하는급성기질환이다. 발생시간은통상수시간내지수일에걸쳐급격하게발생하며, 하루중에도증상의기복을보이는것이특징이다. 섬망은발생빈도가매우흔하여전체병원재원환자의 10-15% 가섬망을경험하며, 특히수술후또는노인 ( 특히 80세이상 ) 환자에서매우흔하다. 섬망유발인자로는치매, 골절, 전신감염, 마약성혹은항정신병약물복용등이있다. 섬망이흔히나타나는원인질환으로는감염, 열병, 저산소증, 저혈당증, 약물중독, 약물금단, 간성뇌증등과같은대사장애와뇌졸중, 외상성뇌손상, 경련발작후상태등과같은중추신경계이상이있다. 섬망은선행되는요인이동반되고원인이제거되면 3-7 일이내대부분사라지지만원인인자가남아있는한계속된다. 섬망의발생에관여하는신경전달물질로는 serotonin, glutamate, GABA 등이알려져있지만, 일반적으로는내인성도파민활성의증가와아세틸콜린활성의감소가중요한역할을담당하는것으로알려져있다 2. 섬망환자는기억력과지남력등인지기능의장애를동반하며기억력은최근기억에대한장애가가장분명하며, 지남력은시간및장소에대한장애가흔하다. 사람에대한지남력, 특히자신에대한지남력은대개유지되며, 환각등의지각장애도동반하는데주로시각적인환각이나착각이많다. 그외산만하거나지리멸렬한언어, 비논리적인사고, 피해망상, 의심, 연상이완등사고장애를보이는경우도흔히있다. 따라서노인환자에서치매와반드시감별해야하며, 급성기로나타나는인지장애및이상행동의가장흔한원인이라고할수있다 (Table 1). 2) 급성기뇌경색에의한치매기억력및인지기능과관련된신경회로는 Papez 신경회로 (Papez circuit) 와전두엽-피질하신경회로 (Frontal subcortical circuit) 등이있는데이들의주요구조물이나연결하는백색질에급성기뇌경색병변이있을경우기억장애를포함한인지장애및행동변화가발생할수있다. Papez 신경회로의주요구조물로는해마 (hippocampus), 뇌궁 (fornix), 유두체 (mammilla body), 전시상핵 (anterior thalamic nucleus), 대상회 (Cingulate gyrus), 해마곁이랑 (parahippocampus) 등이있는데, 이들은주로기억을저장하는역할을하기때문에이회로에병변이생기면기억회상에장애를나타낼수있다 3. 미상핵 (caudate nucleus) 및내포 (internal capsule) 의무릎 (genu) 부위에뇌경색이생겨도심한인지장애가유발될수있다. 3) 일과성건망증일과성건망증 (transient global amnesia, TGA) 은주로격한운동이나심한스트레스를받은후갑자기발생한다. 기억장애는매우심하지만, 의식과다른인지기능에는장애가없기때문에외형상으로는못느낄수있다. 하지만시간과장소에대한인식이없어서주위사람들에게물어보게되고, 심한전향기억상실 (anterograde amnesia) 이발생하기때문에이러한질문을반복함으로써주위사람들이알아차리게된다. 24시간내에기억장애는사라지는데주로 2-8 시간지속된다. 예후는좋은데, 재발확률은매년 6% 미만이고, 일과성건망증이치매의발생, 장기적인예후에영향을주지못하는것으로알려져있다. 4) 약물과연관된인지장애약물에의한급성기인지기능장애는매우흔하게경험할수있는데, 특히약물의분해능이낮고, 신장기능이떨어져있는노인환자에서의식변화및인지장애의원인으로서많은비중을차지한다. 노인환자에게흔하게처방되는약물계열로는 1) 수면제, 2) 안정제및항정신병약, 3) 진통제등을들수있으며 Table 1. Differential diagnosis between delirium and dementia Delirium Dementia 발병 급성 만성 경과 변동적 서서히진행및악화 기간 보통 1개월이내 수개월에서수년이상 지남력상실 초기 중기에서후기 의식 혼미 명료 수면-각성주기 시간별변화보임 낮-밤주기로변화보임 환각 초기에나타남 후기에주로나타남 행동장애 과잉행동이초기에나타남 후기에주로나타남 J Korean Neurol Assoc Volume 29 Suppl. 2,

67 박경원 이런약의과다복용은치매와유사한인지장애및이상행동을유발시키고, 치매환자의증상을악화시키기도한다. 많은약제들중항콜린성분이강한항우울제와마약성진통제, 항간질제및항불안제등이주요원인으로알려져있다. 따라서노인환자에서이유없이비교적급성기로인지장애가초래되면약물과연관된증상을의심하고반드시약물에관한복용력을확인하고, 혼자사는노인인경우에는주위이웃이나도우미를통해조사하여야한다. 2. 만성경과를보이는질환 1) 알츠하이머병 65세이상노인인구를대상으로한인구대상연구에의하면치매가심장병, 뇌졸중, 암과더불어가장강력한사망위험인자로알려져있다. 알츠하이머병은노인인구에서치매를유발하는가장흔한질환이다. 4 65세에서 85세범위내에서는나이가 5세증가할때마다알츠하이머병의발병률이 2배씩높아진다. 알츠하이머병환자는서서히기억력이감퇴되고언어구사및다른사람들과의대화가힘들어지며점차간단한일상업무수행이어려워진다. 시간, 장소에대한개념이흐려지며학습을통하여새로운지식을습득하지못하고어떤일을미루어생각하거나판단하는능력이떨어짐은물론간단한계산조차못하게된다. 병이더진행되면성격변화를동반한행동심리증상 (behavioral and psychological symptoms of dementia, BPSD) 이나타나며결국에는아주단순한일상생활능력마저유지하기힘들며자기자신을돌볼수없게되어대ㆍ소변을가리지못하는경우도있다. 알츠하이머병환자들은각환자마다서로다른임상양상을나타내는데이러한임상적발현의차이점은발생연령, 병전성격, 육체적건강, 치매의가족력, 문화적, 인종적배경등여러가지요소에의해결정된다. 알츠하이머병의확진시병리소견은노인성판 (senile plaque) 과신경섬유농축제 (neurofibrillary tangle) 의두병변의분포정도가알츠하이머병을확진하는기준이되어왔다. 임상적진단을위해서는기억장애를포함한두가지이상의다발성인지장애가신경심리학적으로확인되어야하며이로인해일상생활장애가초래되어야한다. 56 이전에는치매를유발할수있는모든원인질환을배제한후에알츠하이머병을진단할수있었으나최근에는특징적임상경과와특이적검사소견등표준화된진단검사기준에의해진단을한다. 2) 경도인지장애경도인지장애란연령에비해인지기능, 특히기억력이떨어 져있는상태로일상생활수행능력은보존돼있어아직치매는아닌상태를의미하는것으로정상노화와치매의중간단계라고할수있다. 경도인지장애의개념은 1990 년대초부터나왔지만, 1999 년에 Petersen 등에의해비교적명확한기준이제시되었다. 7 경도인지장애를진단하기위해서는환자가기억장애를호소하고, 신경심리학적평가에서그사람의나이와교육수준을고려했을때 1.5 표준편차이하로기억력장애를보여야한다. 또한, 다른정보제공자가보기에도장애가있어야하며, 일상생활능력 (activity of daily living) 과전반적인인지기능도정상이어야한다. 경도인지장애는치매의전임상단계로파악되고있다. 적용한진단기준이나평가도구의차이등에의해서경도인지장애환자가알츠하이머병으로이행하는전환율은연구마다다르지만, 기억상실성경도인지장애환자군만을대상으로한경우의연구들을보면대체적으로 1년에 10-15% 정도로서, 65세이상정상인에서의전환율인 1-2% 에비하면상당히높음을알수있다. 8 3) 피질하혈관성치매혈관성치매란뇌혈관질환에의하여뇌세포가손상되고, 이로인하여치매가발생하는증후군을말한다. 알츠하이머병과함께가장흔한치매의원인질환이다. 뇌혈관질환은크게뇌출혈과뇌경색으로나눌수있는데, 두질환모두치매를일으킬수있다. 혈관성치매를진단하려면먼저치매가있어야하고, 이치매가뇌혈관질환 ( 뇌졸중 ) 과연관이있어야한다. 9 뇌졸중과관련된국소신경학적증상과징후로는시야장애, 안구운동장애, 발음장애, 삼킴장애, 안면마비, 편측마비, 감각이상, 심부건반사의증가, 병적반사양성, 근긴장도증가, 서동증 (bradykineisia), 보행장애등이있다. 알츠하이머병과혈관성치매를감별하기위하여하친스키허혈점수 (Hachinski ischemia scale) 를많이사용해왔으나이중 1) 인지기능이갑자기나빠짐, 2) 계단식으로인지기능이나빠짐, 3) 고혈압의기왕력이있음, 4) 뇌졸중의기왕력이있음, 5) 국소신경증상이있음, 6) 국소신경징후등이혈관성치매를시사하는중요한요인으로꼽히고있다. 혈관성치매를일으키는위험요소는고혈압, 당뇨, 심장질환, 고지혈증, 흡연, 비만또는운동부족등을들수있다. 혈관성치매를치료함에있어서이와같은위험인자를제거하는것이급선무이다. 혈관성치매의원인이뇌경색인경우에는항혈소판제나항응고제를투여하게된다. 최근에는혈관성치매환자에서알츠하이머병이합병되어혼합성치매형태로흔하게나타난다는보고가있다 대한신경과학회지제 29 권부록 2, 2011

68 인지장애및이상행동으로의뢰된환자의임상적접근 4) 전두측두치매전두측두치매는알츠하이머병다음으로흔한뇌퇴행성질환중하나이다. 전두측두치매는크게임상양상에따라 1) 전두측두치매 (frontotemporal dementia, FTD), 2) 의미치매 (semantic dementia), 3) 진행성비유창성실어증 (progressive nonfluent aphasia) 으로분류한다. 11 전두측두치매 (FTD) 는전두엽과측두엽의손상에의한증상으로변별될수있는데이중에서도전두엽손상에의한증상이더두드러지게나타나는편이다. 전두측두치매의가장큰특징중의하나는질병초기에 성격변화 가기억장애보다먼저온다는것이다. 따라서기억력장애소견이없이성격변화나이상행동을보여타과에서의뢰될수있다. 의미치매의병변은병의초기에측두엽의전방부에국한되어있고병변이매우비대칭적이다. 즉어떤환자는주병변이좌측측두엽이고, 어떤환자는우측측두엽이다. 전자의경우, 단어를잘말하지못하거나단어의정확한의미를잘알지못하는언어장애로시작하고, 후자의경우에는얼굴을잘알아보지못하는증상으로시작한다. 비유창성진행성실어증은초기에우성반구의실비우스주위피질 ( 전두엽의하부와측두두정엽의경계부 ) 에비대칭적인위축을보인다. 5) 파킨슨병을동반한치매파킨슨병은흑질에서의도파민신경세포의소실로떨림증과근육이뻣뻣해지고동작이느려지며자세불안정및걸음걸이의장애등과같은운동증상과함께치매를비롯한여러가지비운동증상을동반하는신경계의대표적인퇴행성질환이다. 보고자들마다조금씩다르나파킨슨병환자의약 30% 에서치매가동반되는것으로알려져있다. 파킨슨증상과치매가공존하는대표적인질환인파킨슨병치매 (Parkinson's disease dementia) 와루이체치매 (dementia with Lewy bodies) 를들수있다. 파킨슨병에서관찰되는치매는나이가많을수록그리고파킨슨병이진행될수록또한이전에환각을경험한경우가있을때가그렇지않은경우에비하여발생될가능성이커진다. 파킨슨병의초기에치매가동반되는경우는매우드물다. 파킨슨병에서치매가동반될수있는병리학적인근거로서파킨슨병의가장중요한병리소견인루이체가흑질이있는중뇌에만국한되지않고뇌의피질부위등에도생김으로써인지기능의장애가초래될것으로생각된다 12. 루이체치매는노인들에서관찰되는퇴행성질환중알츠하이머병다음으로흔한치매의원인질환으로알려져있다. 일반적으로파킨슨병에선행해서치매의증상이나타나거나파킨슨병의운동증상이시작된후 12개월이내에치매증상이있으면 반드시루이체치매의가능성을생각해야한다 13. 루이체치매의주요증상인인지기능의변화와환각증상은파킨슨병의초기에는거의관찰되지않는증상들이다. 루이체치매에서관찰되는파킨슨병의운동증상은근육의경직 (rigidity) 과행동이느려지는증상 (bradykinesia) 이주이며안정시진전은상대적으로드물다. 인지장애및이상행동을보이는환자의진단및평가방법 1. 병력청취및신경학적검사 인지장애혹은이상행동으로내원한환자에서는병력청취가매우중요할뿐아니라다른인지장애를흔히동반하고있는경우가많기때문에이들에대한병력청취가진단을위해매우중요하다. 1) 기억력을포함한인지장애환자나보호자에게언제어떠한증상이생겼는지구체적인예를들게한다. 기억장애가있다면, 그기억장애가언제생겼는지, 본인이나가족도언제부터인지모르게생겼는지, 아니면어느날갑자기생겼는지를물어봐야한다. 갑자기생겼다고할경우에는정확한날짜와그때상황에대해서물어봐야한다. 기억장애발생후진행상황에대해서도확인을해야한다. 서서히진행을하는지, 계단식으로나빠졌는지, 아니면중간에호전이된적이있는지물어보아야한다. 점점심해졌다면현재는어떤상태인지를파악해야한다. 예를들어, 오전에있었던일을오후에알지못하는정도인지또는너무심해서수분전의일을전혀기억하지못하거나돌아서면잊어버리는정도인지를알아야한다. 또한기억장애에대해환자가병식이있는지를물어보아야한다. 또한자기의기억장애를심각하게받아들이고있는지, 아니면부정하는지를살펴야한다. 기억장애와흔히동반될수있는인지장애로는언어장애, 시공간능력저하, 계산능력의감소, 성격변화등이같이나타날수가있다. 언어장애의가장흔한형태는하고싶은표현이금방나오지않거나물건이름을금방대지못하여머뭇거리는증상이다. 그밖에읽기, 쓰기장애가있고, 환자의말수가갈수록감소하는증상도있을수있다. 시공간능력이저하된결과로서방향감각이떨어지거나길을잃고헤맬수가있다. 계산능력의감소때문에돈관리에실수가생기고, 계산을기피하는지를물어보아야한다. J Korean Neurol Assoc Volume 29 Suppl. 2,

69 박경원 2) 성격변화및이상행동성격변화에대해서는과거에의욕적이던사람이만사를귀찮아하고하루종일잠만잔다든가, 또는과거에매우활동적이고사교적이던사람이모임에나가는것을싫어하거나남과의대화를피한다거나, 과거에는전혀화를내지않던사람이쉽게화를내거나, 과거에는매우까다롭고구두쇠였는데이제는관대해졌다던가등에대한질문을해야한다. 인지장애환자들중에는이상행동을함께나타나는경우가흔히있다. 이와같은이상행동은약물로많은도움을받을수있다. 현재개발된선별설문지나평가지를통해망상이나, 환각, 초조 / 공격성, 우울증등과같은다양한증상이동반되어있는지확인해야한다 (Table 2). 14 3) 일상생활능력인지장애가있는환자는대개일상생활의영향을받고, 기억장애의가장흔한원인질환인치매의진단기준에일상생활능력이들어가므로이에대한평가가이루어져야한다. 환자의일상생활을알기위해서는환자나보호자에게하루일과에대해서물어보아야하고, 직업을가지고있는경우에는직장동료에게전화하여직장생활에대해서자세하게물어볼수도있다. 매우기본적인기능으로서양치질, 식사, 화장실사용, 목욕하기등이있고, 좀더복잡한기능으로서설거지, 빨래, 요리 ( 김치, 찌개, 밥 ), 돈관리, 외출, 취미생활 ( 화투, 바둑, 장기 ), 종교모임, 계모임등이있다. 4) 과거력과가족력인지장애의원인질환을찾기위해서는과거력에대한철저한조사가필요하다. 고혈압, 당뇨병, 고지혈증, 심장병, 과거뇌졸중등혈관성위험인자들은혈관성치매뿐만아니라알츠하이머병의위험인자이므로이에대해진단을받은적이있는지약물복용을하고있는지를확인해야한다. 청력감소로인해정보를제대로전달받지못하는노인들을기억력이떨어져있다고호소하는보호자들도있다. 우울증은기억장애와비슷한양상을보일수도있고, 기억장애에직접영향을줄수도있으며, 또한항우울제도기억장애에영향을줄수있으므로이에대한정확한문진이필요하다. 드물게는간질에의해서도이와비슷한양상을호소할수있다. 항우울제 (amitriptyline), 항정신병약, 항간질제 (topiramate), 수면제 (triazolam), 멀미약등도이와비슷한증상을유발하기때문에이에대한주의도필요하다. 5) 신경학적진찰신경학적이상유무는인지장애혹은이상행동의원인질환을찾는데매우중요하다. 따라서발음장애, 삼킴장애, 안면마비, 편마비, 보행장애, 심부건반사이상유무, 병적반사유무, Parkinson 증후군등이있는지를면밀히확인해야한다. Table 2. Appropriate assessment of behavioral and psychological symptoms 14 Obtain a focused history from the patient, nursing staff and/or family Describe behavioral and psychological symptoms in detail Include the frequency, duration, intensity, time of day Look for patterns or triggers Think about environmental or psychosocial reasons Review medications Physical examination Vital signs including pulse oximetry General physical examination Neurological examination Depression assessment Laboratory tests Targeted by current medications or history or physical results May include electrolytes, urinalysis, serum drug levels, chest X-ray Most important causes to eliminate Discomfort, pain Delirium Acute illness such as urinary tract infection or pneumonia Urinary retention Medication side effect Constipation or fecal impaction Environmental factors Depression 2. 인지장애및이상행동의평가방법인지장애의일반적인선별검사로서가장흔하게사용되는것은간이정신상태검사 (MMSE) 15 로서 1976 년 Folstein 등에의해서고안되어전세계적으로가장널리사용되고있다. 이검사는장소나시간지남력검사, 단어를불러주고나서기억여부를확인하는언어기억력검사, 계산능력검사, 언어검사, 도형을그리는구성력검사등으로구성되어있고모두 30 점만점으로평가된다. 총검사시간은대략 10분정도이며, 간편한인지검사이므로치매의선별검사로사용될수있으나, 확진검사법은아니다. 언어기능및학력에영향을많이받는단점이있고, 시각적평가부분및판단력을포함한전두엽기능검사항목이부족하다. MMSE 외에 1분안에동물이름대기 (category fluency test) 를시행하여 15개이상이름을댈수있는지유무를통해전두엽기능평가를할수있다. 시공간기능검사 (Visuoperception) 검사와집행기능을함께볼수있는가장간단하고도유용한검사로는시계그리기방법이있다. 인지장애유무를정확하게진단하기위해서는이를객관적 46 대한신경과학회지제 29 권부록 2, 2011

70 인지장애및이상행동으로의뢰된환자의임상적접근 으로증명할수있는종합적인검사가필요하다. 기억력저하와함께다른인지장애가흔히동반될수있으므로이에대한검사들이같이필요한데, 신경심리검사총집을이용하는것이좋다. 우리나라에서는 SNSB (Seoul Neuropsychological Screening Battery), 16,17 CERAD-K (Consortium to Establish a Registry for Alzheimer Disease-Korea) 18 등이있다. 의뢰된노인환자에서나타난이상행동및성격변화를적절히평가하기위해서는대체로 table 2에제시한순서를따라평가하는것이좋다. 그외에 CGA-NPI (Caregiver-administered Neuropsychiatric Inventory) 나 NPI-Q (Neuropsychiatric Inventory-Questionnaire) 와같은검사도구를이용하여망상 (deluision), 환각 (hallucination), 초조 / 공격성 (agitation/aggression), 우울증 (depression), 불안 (anxiety), 다행감 (euphoria), 무감동 (apathy), 탈억제 (disinhibition), 쉽게화냄 (irritability), 반복적인행동 (repetitive motor behavior), 불면증 (sleep disorder), 식습관의변화 (appetite/eating change) 등에대해빈도및정도등을평가할수있다. 3. 혈액검사인지장애를보이는환자에게서혈액검사는중요하다. 혈액검사의목적은 1 공존질환이나합병증, 2가능한위험인자, 3 자주반복되는혼돈상태원인, 4 드물게는치매의일차적인원인을찾는데있다. 특히환자가혼돈상태를보이거나, 빠른진행양상, 비전형적인증상을보이는경우혈액검사가진단적가치가있어환자를치료하는데도움을줄수있다. 일반적으로제안되고있는검사로는혈액검사, 전해질, 칼슘, 당, 신기능, 간기능, 갑상선자극호르몬, 비타민 B 12 및엽산수치, 매독, HIV 등이있다. 4. 뇌영상검사일반적인뇌영상의기능은인지장애의가역적인원인을배제하는용도로이용된다. 최근에는인지장애의원인질환들인알츠하이머병, 혈관성치매, 전두측두치매, 헌팅톤병 (huntington s disease), 크로이츠펠트 -야콥병 (creutzfeldt Jakob disease, CJD), 정상압수두증 (normal pressure hydrocephalus, NPH) 등을감별진단하는데중요한보조적도구로이용된다. 또한뇌 MRI 는특정치매의중요한생물학적표지자로도이용이된다. 즉, 알츠하이머병환자에서의해마용적, 뇌위축정도, 아밀로이드영상 19 과함께피질하혈관성치매환자에서의백질변성 (white matter hyperintensities), 열공성뇌경색 (lacunes), 미세출혈 (microbleeds) 등은위질환들을진단하는데도움을준다. 결 론 노인환자에서인지장애및이상행동을일으키는원인질환은매우다양하기때문에, 이들의원인질환을정확하게진단하기는쉽지않다. 기억장애의다양한원인질병들을감별하기위해서문진, 신경학적진찰, 신경심리검사, 혈액검사, 뇌영상검사등을철저히시행해야한다. 더구나노인환자에서인지장애혹은이상행동을보일때일시적인섬망상태인지병적인질환에의한이차적인증상인지를구분하여적절한치료계획을수립하는것이중요하다. 인지장애혹은이상행동으로인해타과에서신경과에의뢰되는경우가비교적흔하므로이러한환자를감별진단할때 갑자기생긴인지장애인지? 서서히진행하는인지장애인지? 를파악한후그와관련된질환들을순차적으로확인하는것이감별진단하는데도움이될수있고, 이에대한임상적접근법을숙지하는것이매우중요하다. References 1. 통계청. 한국의사회지표 Kaplan & Sandock. Kaplan & sandock's comprehensive textbook of psychiatry. 9th ed. vol. 1, pg Park KW, Ha BL, Cha JK, Kim SH, Kang DY, Kim JW. Strategic infarct dementia: Clinical features, neuroimaging and neuropsychological findings. J Korean Neurol Assoc 2003;21: Ebly EM, Hogan DB, Parhad IM. Cognitive impairment in the nondemented elderly. results from the canadian study of health and aging. Arch Neurol 1995;52: American Psychiatric Association. Diagnostic and statistical manual of mental disorders McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of alzheimer's disease: Report of the NINCDS- ADRDA work group under the auspices of department of health and human services task force on alzheimer's disease. Neurology 1984;34: Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256: Feldman HH, Jacova C. Mild cognitive impairment. Am J Geriatr Psychiatry 2005;13: Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, et al. Vascular dementia: Diagnostic criteria for research studies. report of the NINDS-AIREN international workshop. Neurology 1993;43: Kirshner HS. Vascular dementia: A review of recent evidence for prevention and treatment. Curr Neurol Neurosci Rep 2009;9: Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 1998;51: J Korean Neurol Assoc Volume 29 Suppl. 2,

71 박경원 12. Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, et al. Clinical diagnostic criteria for dementia associated with parkinson's disease. Mov Disord 2007;22: ; quiz McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, et al. Diagnosis and management of dementia with lewy bodies: Third report of the DLB consortium. Neurology 2005;65: Buhr GT, White HK. Difficult behaviors in long-term care patients with dementia. J Am Med Dir Assoc 2007;8:e Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12: Kang Y, Na DL, Hahn S. A validity study on the korean mini-mental state examination (K-MMSE) in dementia patients. J Korean Neurol Assoc 1997;15: Kang Y, Na DL. Seoul neuropsychological screening battery Lee JH, Lee KU, Lee DY, Kim KW, Jhoo JH, Kim JH, et al. Development of the korean version of the consortium to establish a registry for alzheimer's disease assessment packet (CERAD-K): Clinical and neuropsychological assessment batteries. J Gerontol B Psychol Sci Soc Sci 2002;57:P Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in alzheimer's disease with pittsburgh compound-b. Ann Neurol 2004;55: 대한신경과학회지제 29 권부록 2, 2011

72 특수상황에서의간질환자치료 : 고찰및증례자문의뢰받은이상운동질환환자의임상적접근 인제대학교의과대학신경과학교실김상진 Consultation Neurology: Movement Disorders Sang Jin Kim, MD, PhD Department of Neurology, Inje University, Busan Paik Hospital, Busan, Korea Movement disorders consultations are requested by other services in in-patients and out-patients. The first section of this article reviews the perioperative management of patients who have known movement disorders and are undergoing surgery. Parkinsonism is a major risk factor for postoperative complication such as respiratory disease or paralytic ileus, and it is difficult to manage these patients after major surgery. Furthermore, most antiparkinsonian medications must be withheld until the patient is able to resume oral intake and the resulting rigidity and akinesia as well as alterations in gastrointestinal motility, respiratory function, and swallowing mechanism predisposes these patients to numerous postoperative complications. Drug-induced movement disorders which are among the most frequent observed iatrogenic neurologic disorders and some acute movement disorders then are reviewed. Key Words: Perioperative management, Drug-induced, Acute, Movement disorders 서 론 본 론 한연구에서 3차병원내에서신경과에자문의뢰를가장많이낸임상과는내과 (39%) 와정신과 (13%) 이고자문의뢰된환자의증상은신경학적결손 (32%), 발작 (18%), 의식장애 (12%) 순이었고최종진단은간질 (20%), 뇌혈관질환 (15%), 이상운동질환 (11%) 순으로많았다고보고하여 1 적지않은이상운동질환환자들이자문의뢰됨을알수있다. 다른과에서신경과의사에게자문의뢰되는운동저하증이나운동과다증의종류와원인은다양하다. 본종설에서는먼저파킨슨증이나운동과다증을가진환자들의대수술시관리를알아보고자문의뢰되는이상운동질환의많은원인을차지하는약물에의한경우와급성파킨슨증과사경에대해서살펴보겠다. Sang Jin Kim, MD, PhD Department of Neurology, Inje University, Busan Paik Hospital, Gaegeum-dong, Busanjin-gu, Busan , Korea Tel: Fax: jsk120@hanmail.net 1. 이상운동질환환자의수술시관리 1) 파킨슨병파킨슨병은모든연령에서발생가능하지만특히고령에서흔한데 60세이상에서는 1% 정도가파킨슨병을앓게된다. 수술기법과치료수단의발전으로외과적수술을받는고령의파킨슨병환자들의수가계속해서증가하고있다. 파킨슨병환자들은서동및경직, 연하곤란, 구강및호흡기계분비물배출기능의악화로인하여흡인성폐렴과심부정맥혈전증과같은수술후합병증이발생할확률이더높다. 상기도횡문근기능장애는수술후호흡부전의원인으로작용할수있고항파킨슨제의중단으로인하여신경이완제악성증후군이발생할수있어파킨슨병환자들의외과적수술시에는특별한처치가필요하다. 2,3 파킨슨병과연관된여러가지호흡기계이상소견은레보도파에반응을보이지만, 장기간의레보도파치료를받은파킨슨병환자에서보이는운동증상변동과비슷한양상으로호흡기능 J Korean Neurol Assoc Volume 29 Suppl. 2,

73 김상진 변동이발생할수있다. 뿐만아니라동반되어발생하는호흡근이상운동증 (respiratory dyskinesia) 은호흡장애를더악화시킬수있다. 따라서파킨슨병환자는경직및서동에의한호흡기능의변화뿐만아니라운동증상변동과약물유발운동이상증으로인하여추가적인호흡기능장애가발생하게된다. 4 수술후에발행할수있는위장관계합병증은타액분비증가와연하장애, 위배출장애등이있는데즉각적인항파킨슨제투여로마비성장마비나복부팽만을예방하거나개선하고간호를용이하게하고환자의불편을덜어줄수있다. 5 진행된파킨슨병, 특히 OFF 기간동안에배뇨장애가합병될수있다. 수술전후기간에뇨정체의예방과요흐름의개선은환자의불편을개선킬뿐만아니라방관팽만으로인한급성혼돈상태를나타내고수술의회복을어렵게하는방관대뇌증후군 (cystocerebral syndrome) 을예방할수있다. 6 감각및자율신경계장애, 인지기능장애, 정신장애뿐만아니라호흡곤란, 협착음 (stridor), 운동저하증, 호흡근의경직등의 OFF 기간의여러증상들이수술후치료를어렵게만들고, 특히수술후에당분간경구약물섭취가안되는경우에는대부분의사용가능한항파킨슨제가경구로만투여가능하기때문에환자관리가더힘들어진다. 7 지속적인정맥내레보도파주입과피하또는정맥내 apomorphine 이나 lisuride 주사가몇몇논문에서보고되었지만이러한약제들은국내에서는사용할수없다. 하지만최근에수술로경구약물을복용할수없는파킨슨병환자들에서 amantadine 정맥투여가안전하고유용하게사용될수있다는보고가있고 8 조만간국내에도입될것으로예상되는 rotigotine 패취도수술기간에사용하여만족할만한결과를얻었다는보고가있어 9 파킨슨병환자의수술시관리가이전보다는용이해질것으로기대된다. 3) 운동과다성이상운동질환대부분의운동과다성이상운동장애는수면이나깊은마취동안에는사라진다. 무도병, 근긴장이상증, 간대성근경련이나다른운동과다성이상운장장애환자의수술후관리에대한문헌은많지않다. 수술을받은몇몇의헌팅턴병환자에서 barbiturate 와 suxamethonium 의가성콜린분해효소효과에대하여민감성을보였다는보고가있고 11 틱환자에서전신마취없이도 midazolam 정맥내투여만으로틱증상을조절되었다는보고가있다. 12 근긴장이상증환자에서감압적척수수술이필요한경우에는수술후안정화를돕기위하여 halo vest 나단단한경부보호대를이용하면견고한결합및좋은결과를얻을수있고수술전의 botulinum toxin 주사는수술직후에근긴장이상증을줄여줌으로서척추간결합을촉진시킬수있다. 13,14 2. 약물유발성이상운동질환환자의임상적접근 1) 급성근긴장이상반응급성근긴장이상반응은항정신성신경이완제나항구토제같은도파민수용체차단제사용후에나타난다. 급성근긴장이상반응은전형적으로입, 얼굴, 눈, 목부위근육에침범하여목후굴, 등아치 (arch), 몸통의측굴, 입벌림장애, 혀돌출, 안구의상측또는편측편위등의증상으로나타난다. 급성근긴장이상반응의 50% 이상은도파민수용체차단제사용후 1일이내에발생하고 90% 는 5일이내에발생한다. 급성근긴장이상반응의정확한발병기전은불명확하지만가설들은도파민수용체차단제에의해강화된도파민회전율이도파민수용체의과민성을일으킴으로써발생하는데초점을맞추고있다. 15 정맥내 diphenhydramine 이나 benztropin, diazepam 투여로호전된다. 2) 다계통위축증다계통위축증환자들은전형적으로발기부전, 요실금, 발한장애, 기립성저혈압등의현저한자율신경증상및징후나타내고상기도폐색에따른급사의위험을가지고있다. 협착음 (stridor) 은전형적으로성대의벌림근기능이상때문에발생하는데처음에는주로밤중에간헐적으로시작하게되는데벌림근마비로인하여성대는모아진채로유지된다. 조금이라도벌림근마비의증거가있는환자들은급사의위험성이높은데호흡부전및순환허탈을방지하기위하여수술후에는세심한모티터가필요하다. 10 2) 신경이완제악성증후군신경이완제악성증후군은도파민수용체차단제투여나도파민성약제의중단으로발생할수있는급성반응이다. 가장흔한발생시기는도파민수용체차단제치료를시작하거나증량후 1개월이내이다. 증상은발열, 근육경직, 자율신경불안정, 혼란이나의식변화들이나타난다. 전형적으로혈청 creatine kinase 와백혈구증가같은진단검사적이상이동반된다. 가장두드러지는이상운동장애는경직인데종종체간에나타나고활모양강직 (opisthotonus) 을보일수도있다. 발생기전은도파민수용체차단으로생각되는데파킨슨병에서갑자기레도파도를중단하거나헌팅톤병치료에서도파민감소제사용후에나타나는동일한증상으로뒷받침된다. 치료는증상을유발하는 50 대한신경과학회지제 29 권부록 2, 2011

74 자문의뢰받은이상운동질환환자의임상적접근 신경이완제나다른유발약제의중단과 bromocriptine 과 dantrolen 의투여이다. 16,17 3) 세로토닌증후군이름에서의미하듯이이증후군은한가지이상의세로토닌성약제를투여받는환자에서발생한다. 세로토닌증후군의임상적징후는신경이완제악성증후군과비슷하지만세로토닌증후군에서근간대성경련과반사항진이더심하고동공산대가흔하며오한, 구역, 설사등의증상은세로토닌증후군에서만나타난다. 세로토닌증후군에서 creatine kinease 증가가나타날수있지만신경이완제악성증후군에서보이는것처럼심하지는않다. 치료는모든세로토닌성약제의중단이다. 일반적으로약제의중단만으로 24시간이내에증상이회복되지만이런치료에저항성을보이거나증상이심각할때세로토닌길항제를고려해볼수있다. 18 4) 약물유발성급성파킨슨증약물유발성파킨슨증은특발성파킨슨병과매우비슷한증상을보인다. 증상및징후의대칭성이파킨슨병에비해서흔하지만비대칭적으로나타날수도있다. 안정시떨림의발생률은약물유발성파킨슨증에서 50% 이상으로보고되고있다. 파킨슨병과약물유발성파킨슨증의다른감별점은남녀발생비가약물유발성파킨슨증에서 2:1 이며, 항콜린성약제에반응이파킨슨병보다더두드러진다는점이다. 일부에서는저빈도고진폭의입주변떨림이나타날수도있다. 약물유발성파킨슨증의증상은보통유발약제의투여시작으로부터 1개월이내에발생한다. 다양한약제들이약물유발성파킨슨증을일으킬수있는데전형적신경이완제, 항구토성도파민차단제, 도파민감소제, valproic acid, fluoxetine, SSRI, 일부칼슘채널차단제가포함된다. 가장효과적인약물유발성파킨슨증의치료는유발약제의중단이다. 대부분의환자들에서 1-2 개월내에증상회복을보인다. 하지만일부환자에서는완전한회복까지 1년이상의시간이필요하기도한다. 회복되지않는소수의환자에서는도파민차단제투여로증상이악화된특발성파킨슨병의가능성을고려해야한다. 19 5) 좌불안석증 (akanthisia) 좌불안석증은사지, 얼굴, 몸통, 목소리, 호흡근에침범하여발두드림, 손휘젓기, 손흔들기, 걷기등의반복적인상동동작을나타나는데억제할수없는움직임에대한충동이특징이다. 환자는자신내면의안절부절과이러한내부적불안감를완화시키려는움직임에대한충동을인지하고있다. 증상은전형적으 Table 1. Drugs commonly associated with tremor, chorea or myoclonus Tremor Lithium Caffeine Valproic acid Amphetamines Theophylline Corticosteroids Cyclosporine or tacrolimus Marijuana Chorea Levodopa and dopamine agonists Phenytoin Dopamine blocking agent(td) Myoclonus SSRIs Methylphenidate SSRIs TCAs Levodopa Carbamazepine Morphine Thyroid hormone TCAs Amiodarone Phenytoin Lamotrigine a-adrenergic agents Alcohol H1 and H2 antihistamines Anticholinergics Amphetamines Oral contraceptives Cocaine Lithium Bismuth containing agents Valproic acid Phenytoin SSRI: Selective serotonin re-uptake inhibitor; TCA: Tricyclic antidepressant; TD: Tardive dyskinesia 로도파민차단제투여시에나타나지만세로토닌흡수억제제같은몇몇비신경이완성약제에서도좌불안석증이나타날수있다. 급성좌불안석증에서가장효과적인치료는유발약제의중단이다. 유발약제의지속적인투여가필수적인환자에서가장효과적인약물치료는 propranolol 이며대체치료로서 amantadine 과 benzodiazepine 이있다. 6) 운동과다성이상운동증떨림, 무도증, 근간대성경련은다양한약제에의하여유발될수있다 (Table 1). 유발약제의감량이나중단으로증상이완화될것이다. 18 7) 지연이상운동증지연이상운동증은최근에장기간의신경이완제치료나다른도파민차단제에노출된환자에서보이는다양한불수의적이상운동증이다. 고전적또는무도병형태의지연이상운동증은초기에입과볼의저작근및혀에두드러지는침범을특징으로한다. 시간이지남에따라, 혀의움직임은입안에서더욱두드러지고결국혀는간헐적으로돌출된다. 껌씹는시늉과입맛다시기등의아랫턱과관련된이상운동또한매우흔하다. 고전적무도병성지연이상운동증의감별진단으로무도병형태의이상운동을유발시키는대부분의질환이포함된다. 임상적으로 J Korean Neurol Assoc Volume 29 Suppl. 2,

75 김상진 는지연이상운동증과구별이안되는이상운동증이신경학적으로건강한사람에서자발적으로발생할수있으며, 특히치아가없거나고령에서생긴다. 비슷한이상운동이치료받지않은정신분열병환자나정신지체환자에서도자발적으로발생할수있다. 신경이완제의조기중단이나최소필요용량을투여함으로써지속적인관해와임상적장해를감소시킬수있다. 다른선택으로는 clozapine 이나 olanzapine 같은지연이상운동증을덜일으키는비전형적신경이완제로의약물변경이있다. 유발약제를중단또는변경이불가능하거나효과가없는경우에는 reserpine 과 tetrabenazine 같은도파민감소약제을고려할수있다 급성이상운동질환환자의임상적접근 1) 급성파킨슨증신경이완제나항구토제에의한파킨슨증을제외하면급성파킨슨증은매우드물다. 감별진단에는급속발병근긴장이상 - 파킨슨증, 독소나항암치료, 바이러스성감염, 흑질선조체경로를침범하는구조적병변등이포함된다. 많은독소가급성파킨슨증을일으킬수있는데 MPTP, 유기인계살충제, 일산화탄소, 시안화물, 메탄올등이포함된다. 이러한물질에노출된후의파킨슨증의임상증상은전형적으로떨림이없고레보도파에대한반응이떨어진다. 파킨슨증은흑질을침범하는바이러스감염후에도발생할수있다. 급성파킨슨증을유발시키는바이러스로는일본 B형뇌염, 홍역, 콕사키 B12 형, 서부형말 (western equine), 회색질척수염 (poliomyelitis), 거대세포바이러스, HIV, 인플루엔자 A형바이러스등이다. 도파민성자극에대한반응은부작용으로인하여불충분하거나제한적이다. 급성파킨슨증은항암치료후에매우드물게나타날수있다. 흑질선조체의구조적인압박으로매우드물지만가역적인급성파킨슨증이발생할수있다. 16,17,20 2) 악성긴장증 (malignant catatonia) 긴장증은다양한신경학적, 약물유발성, 정신의학상태와관련되어발생할수있는현저한운동및행동이상으로나타나는증후군이다. 긴장증의정도는단순또는양성의경미한형태로부터중증의악성형태까지다양하다. 악성긴장증을가진환자는도파민차단제에대한노출이없더라도신경이완제악성증후군와유사한증상및징후를나타낼수있다. 대개는강한초조함, 긴장증, 상동증, 정신병, 자율신경불안정으로시작된다. 증상시작으로부터평균 8일이지나면체온이 43.4 도까지상승할수있고심한파킨슨증과혼미가동반되고결국은사망 에까지이를수있다. 악성긴장증은뇌졸중, 사이뇌 (diencephalic) 종양, 뇌염, 쿠싱병, 베르니케뇌증에서나타날수있다. 어떤의미에서, 신경이완제악성증후군은악성긴장증의의인성형태이기도하며, 환자에대한정보가제한적이라면이두질환을구별하기어려울수도있다. 전기경련치료에반응이좋다는보고가있다. 17,21 3) 소아환자에서발생하는급성사경소아에서갑자기발생하는사경은세심한관찰을필요로하는징후이다. 원인으로는급성감염, 척수종양, 고리중쇄불완전탈구 (atanto-axial subluxaton) 등이포함된다. 비외상성급성사경을보이는모든소아에서두경부의염증성변화를염두해두어야한다. 초기관리에서경부고정이포함되어야한다. CT 또는 MRI 는고리중쇄관절을확인하기위하여필요하며경부의공간점유병변을확인하는추가적인이점이있다. 급성사경을보이는모든환자에서다른질환이확인되기전까지는고리중쇄불완전탈구를의심해야한다. 22 결 론 파킨슨증환자의수술시에는호흡기질환이나위장관장애같은수술후합병증의위험성이상대적으로높고대부분의항파킨슨약물이경구복용을해야하므로경구섭취가가능할때까지약물투여가중단될수있어이로인해경직과서동악화, 호흡및연하기능의저하로여러가지합병증에노출될가능성이많다. 하지만최근에국내에서도사용가능한 amantadine 정맥투여나조만간국내에도입될 rotigotine 패취가파킨슨증환자의수술기간중에안정하고유용하게사용될수있다는보고가있어이전보다는파킨슨증환자의수술후관리가용이해질것으로기대된다. 약물에의한이상운동질환은가장흔하게접하는신경학적질환중의하나이고자문의뢰받는이상운동질환환자의많은원인을차지하고있어이상운동질환을유발하거나악화시킬수있는약물에대한충분한숙지가필요하다. 급성파킨슨증을유발할수있는원인으로는약물이외에도독소와항암화학요법, 흑질선조체경로를침범하는바이러스감염및구조적병변등이있고소아에서발생하는급성사경의원인으로는두경부감염성질환, 척수종양, 고리중쇄불완전탈구가있다. References 1. Garcia-Ramos R, Garcia-Morales I, Vela A, Galan L, Serna C, Matias- Guiu J. Analysis of hospital consultations to Neurology in a tertiary 52 대한신경과학회지제 29 권부록 2, 2011

76 자문의뢰받은이상운동질환환자의임상적접근 hospital. Neurologia 2009;24: Mueller MC, Juptner U, Wuellner U, et al. Parkinson's disease influences the perioperative risk profile in surgery. Langenbecks Arch Surg 2009;394: Holland J. Care of patients with Parkinson's disease in the operating department. J Perioper Pract 2010;20: Herer B, Arnulf I, Housset B. Effects of levodopa on pulmonary function in Parkinson's disease. Chest 2001;119: Fujii T, Nakabayashi T, Hashimoto S, Kuwano H. Successful perioperative management of patients with Parkinson's disease following gastrointestinal surgery: report of three cases. Surg Today 2009;39: Riley DE, Lang AE. The spectrum of levodopa-related fluctuations in Parkinson's disease. Neurology 1993;43: Galvez-Jimenez N, Lang AE. The perioperative management of Parkinson's disease revisited. Neurol Clin 2004;22: Kim YE, Kim HJ, Yun JY, Jeon BS. Intravenous amantadine is safe and effective for the perioperative management of patients with Parkinson's disease. J Neurol Wullner U, Kassubek J, Odin P, et al. Transdermal rotigotine for the perioperative management of Parkinson's disease. J Neural Transm 2010;117: Frucht SJ. Movement disorder emergencies in the perioperative period. Neurol Clin 2004;22: Mitra S, Sharma K, Arora S, Deva C, Gombar KK. Repeat anesthetic management of a patient with Huntington's chorea. Can J Anaesth 2001;48: Yoshikawa F, Takagi T, Fukayama H, Miwa Z, Umino M. Intravenous sedation and general anesthesia for a patient with Gilles de la Tourette's syndrome undergoing dental treatment. Acta Anaesthesiol Scand 2002; 46: Loher TJ, Barlocher CB, Krauss JK. Dystonic movement disorders and spinal degenerative disease. Stereotact Funct Neurosurg 2006;84: Wong AS, Massicotte EM, Fehlings MG. Surgical treatment of cervical myeloradiculopathy associated with movement disorders: indications, technique, and clinical outcome. J Spinal Disord Tech 2005;18 Suppl: S Rodnitzky RL. Drug-induced movement disorders. Clin Neuropharmacol 2002;25: Kipps CM, Fung VS, Grattan-Smith P, de Moore GM, Morris JG. Movement disorder emergencies. Mov Disord 2005;20: Poston KL, Frucht SJ. Movement disorder emergencies. J Neurol 2008;255 Suppl 4: Rodnitzky RL. Drug-induced movement disorders in children and adolescents. Expert Opin Drug Saf 2005;4: Bondon-Guitton E, Perez-Lloret S, Bagheri H, Brefel C, Rascol O, Montastruc JL. Drug-induced parkinsonism: A review of 17 years' experience in a regional pharmacovigilance center in France. Mov Disord Robottom BJ, Weiner WJ, Factor SA. Movement disorders emergencies. Part 1: Hypokinetic disorders. Arch Neurol 2011;68: Tousi B. Movement disorder emergencies in the elderly: recognizing and treating an often-iatrogenic problem. Cleve Clin J Med 2008;75: Robottom BJ, Factor SA, Weiner WJ. Movement disorders emergencies Part 2: hyperkinetic disorders. Arch Neurol 2011;68: J Korean Neurol Assoc Volume 29 Suppl. 2,

77 특수상황에서의간질환자치료 : 고찰및증례협진신경학 : 신경근육질환 고려대학교의과대학신경과학교실장재홍김병조 Consultation Neurology: Neuromuscular Disorders Jae Hong Jang, MD, Byung-Jo Kim, MD, PhD Department of Neurology, Korea University College of Medicine, Seoul, Korea The consultation neurology is an important part of clinical medicine, because it can suggests indispensability of neurologist to other physicians and patients. Of neurology, the neuromuscular disorder requires not only laboratory studies, but also clinical assessment to diagnosis. Knowledge and experience of it is necessary to physician to appropriate decision making. For this consideration, we reviewed the performed consultation in our center during last year to examine the consultation of neuromuscular disorder. The neuromuscular disorder is about 11% of all consultation. Oncology was the specialty making the most requests, followed by infectious disease, gastroenterology. Sensory symptom was the most chief complain of patients, followed by motor or sensorimotor symptom, symptoms due to cranial nerve dysfunction, and orthostatic dizziness or syncope. Systemic disease, medication and surgery can cause diverse manifestation of neuromuscular disorder. Neurologist should be familiar with this presentation for pertinent evaluation and diagnosis. Key Words: Consultation neurology, Neuromuscular disorder 서 론 국내에서신경과학회가설립된것은약 30년전이다. 타과에비해짧은역사이지만현재의신경과의위상을살펴보면연구와진료에서신경과의사들이얼마나많은노력을기울여왔는지추측할수있다. 협진은병원내에서과의위상과환자및보호자에게신경계질환에대한전문진료의필요성을호소한다는점에서중요한진료분야이다. 특히여러영상의학적검사방법이있는뇌질환에비해말초신경및근육질환은임상양상및전기생리학적검사를통해주로진단이이루어지므로진단에있어보다체계적인의학적지식과경험이필요하다. 지난 1년간고려대학교안암병원에입원한환자중신경과에협진을의뢰한경우는총 1549 건이었다. 이들중약 11% 가말초신경및근육질환에대한의뢰였다. 협진을많이요청한과들순서로나열하면, 종양내과, 감염내과, 소화기내과, 호흡기내과, Byung-Jo Kim, MD, PhD Department of Neurology, Korea University College of Medicine, Anam-dong 5-ga, Seongbuk-gu, Seoul , Korea Tel: Fax: nukbj@korea.ack.kr 순환기내과, 일반외과, 가정의학과, 신장내과, 내분비내과, 신경외과, 재활의학과, 정형외과, 이비인후과, 산부인과, 그외과들로대부분의협진의뢰가내과계열에서있었다. 주요의뢰사유를증상별로구별해보면, 통증을포함한다양한감각장애가가장많았고, 그다음이근력저하, 자율신경계증상을시사하는기립성어지럼증및실신, 안면마비, 시력저하, 복시및안검하수순으로나타났다. 본고에서는저자의병원에실제의뢰되었던건들의증상별로그원인이규명된경우를기술하고, 임상적접근에대하여정리하였다. 1. 각각의증상에따른분석 1) 감각증상감각증상에는무감각 (numbness), 감각이상 (paresthesia), 감각불쾌 (dysesthesia), 통증 (pain) 등이있다. 협진을의뢰한원인들중가장흔한증상이였고과별로는내과계열에서외과계열보다압도적으로많이의뢰되었다. 내과계열에서는양측발혹은양측손및다리의감각증상을호소한환자에서당뇨병성신경병증, 항암제와관련된다발성신경병증 (cisplatin, paclitaxel), 결핵약 (isoniazid) 과연관된다발성신경병증을진단하였다. 54 대한신경과학회지제 29 권부록 2, 2011

78 협진신경학 : 신경근육질환 편측상지혹은하지의감각증상이있는경우신경근병증 (radiculopathy) 이관찰되었으며편측하지에움직임에의해유발되는통증을호소한환자는장골근 (iliacus muscle) 농양으로진단되었다. 양측손의감각증상에서는수근관증후군이관찰되었다. 외과계열에서는수술후편측대퇴부저림증을호소한환자에서외측대퇴피신경병증 (lateral femoral cutaneous neuropathy), 팔꿈치에서척골신경병증 (ulnar neuropathy at the elbow) 을진단하였다. 주로수술중마취상태에서발생한압박에의한것들로생각되는경우들이었다. 양측손, 발의저림을호소하여신경외과에서의뢰된환자에서외상성경추척수병증을진단하였고양측하지의감각증상을호소한안과의시신경염환자는시신경척수염으로진단되었다. 산부인과에서편측하지의저림때문에의뢰된자궁경부암환자는암의직접적인침범에의한편측요천추신경총병증 (lumbosacral plexopathy) 으로진단되었다. 2) 근력저하혹은근력저하및감각증상근력저하혹은근력저하와감각증상이동반된경우로의뢰되었다. 호흡기내과에서폐렴으로중환자실치료를받은환자에서사지의근력저하를호소한경우중증질환다발성신경병증을진단하였다. 신장내과의당뇨, 신부전환자에서사지말단부의근력저하및감각증상을호소한경우다발성신경병증이관찰되었고횡문근융해증환자에서양하지의근력저하로의뢰된경우약제 (simvastatin) 에의한근병증을진단하였다. 혈액내과에서사지의근력저하로의뢰된경우다발성골수종환자에서만성염증성탈수초성다발성신경병증을진단하였고, 양하지의근력저하로의뢰된다발성골수종의침범으로인한척수병증이관찰되었다. 소화기내과의간세포암환자에서경동맥화학색전술후양하지의근력저하및감각증상, 배뇨장애를호소한경우척수경색을진단하였다. 그외양하지의근력저하로의뢰된환자에서급성횡단성척수염, 해면성혈관종 (cavernous hemangioma) 으로인한척수병증이있었다. 편측상지의근력저하혹은근력저하및감각증상을호소한환자에서상완신경총병이관찰되었으며기저질환으로담관암종, 비소세포폐암, 림프종이이환된상태였다. 혈액내과의림프종환자에서편측하지의근력저하를호소한환자에서대퇴신경병증이관찰되었다. 그외편측하지의근력저하혹은감각증상을호소한경우요추신경근병증이관찰되었다. 3) 뇌신경증상복시, 안검하수, 시력저하, 안면근력약화및감각증상들과같은뇌신경장애가주로의뢰되는원인들이었으며그중안면 신경마비로의뢰된경우가가장많았다. 종양내과의흉선암종환자에서안검하수를호소한경우중증근무력증을진단하였고대장암환자에서편측의안검하수와복시를호소한경우뇌하수체의암전이를진단하였다. 혈액내과의비강내림프종환자에서편측시력저하가발생하였고이후양측의안면신경마비가순차적으로발생한환자에서림프종침범에의한다발뇌신경병증을진단하였다. 안면통증을호소한환자에서삼차신경통에대한약물조절을위해의뢰된경우가있었으며당뇨혹은림프종에이환된환자에서대상포진후신경통에대해진료하였다. 안면신경마비는내과및외과를포함한여러과에서의뢰되었고대부분벨마비이였지만 Ramsay-Hunt syndrome 과림프종에의한안면신경마비및전두부종괴로발현된경우도있었다. 4) 기립성어지럼증및실신대부분의경우혈관미주신경성실신혹은체위성기립성빈맥증후군이관찰되었다. 소화기내과의췌장암환자에서항암제 (gemcitabine, capecitabine) 와관련된다발성신경병증및자율신경병증이있었으며산부인과의난소암환자에서도항암제 (paclitaxel, carboplatin) 와관련된다발성신경병증및자율신경병증이관찰되었다. 그외내분비내과의당뇨환자에서자율신경병증을진단하였다. 5) 기타호흡기내과및감염내과에서호흡곤란및흡인성폐렴으로치료중인경우많은수가근육병이나운동신경원질환을진단받은말기환자들이었다. 2. 각질환별임상적접근 1) 말초신경계질환에대한접근감별진단을좁히기위해자세한병력청취와진찰을시행하여야한다. 기본적으로침범된신경섬유유형, 감각증상의양상, 말초신경계이상의분포, 발생과진행에있어시간적변화, 가족력에대한사항을고려해야한다. 1-4 또한특정전신질환은말초신경병증을유발할수있어내과적질환에대한병력청취가중요하다. 당뇨, 갑상선기능저하증, 신부전, 간질환, 흡수장애, 종양, 후천성면역결핍증등내과질환과복용약물, 음주습관및비타민과다복용등에대한병력청취가시행되어야한다. 협진의뢰를분석한결과에서도당뇨, 종양, 복용약제, 수술시자세와관련된말초신경병증혹은신경뿌리병증이관찰되었다. 비교적대칭성말단부에현저한감각장애를호소하지만심부건반사의저하도없고근전도검사에서도이상이없는경우 J Korean Neurol Assoc Volume 29 Suppl. 2,

79 장재홍김병조 Table 1. Characteristics of Chemotherapy Related Neuropathy Clinical Feature Drug Pathophysiology Reversibility Sensory Motor Autonomic Vincristine Axonopathy 57%, sensorimotor More than 1/3, constipation common Usually Paclitaxel Axonopathy 59-78%, mild Uncommon, mild distal weakness Rare Usually Cisplatin Neuronopathy 38%, pain common Normal Rare Usually Bortezomib Axonopathy 33%, mild to moderate Normal Rare Mostly Ixabepilone Axonopathy 60%, mild to severe, Uncommon Rare Mostly Thalidomide Axonopathy 40%, mild to moderate Normal Rare Minimally 에는세섬유신경병증을고려해볼수있다. 이때는교감성피부반응 (sympathetic skin response), 정량적발한축삭반응검사 (quantitative sudomotor axonal reflex), 혹은피부생검과같이세섬유신경의기능을평가할수있는검사들이도움이될수있다. 원인적조사에는당뇨의병력이없다하더라도공복혈당이나경구포도당부하검사 (oral glucose tolerance test) 를시행하여당뇨전단계 (prediabetic state) 가아닌지확인이필요하다. 5 당뇨전단계신경병증 (prediabetic neuropathy) 은선택적으로세섬유신경을손상시켜통증을동반한감각증상을유발하며자율신경계이상도흔하게나타난다. 6 당내인성 (impaired glucose intolerance) 과관련된신경병증에대한치료연구는없지만, 당내인성에대한표준치료는식이조절과운동이다. 당내인성신경병증의장기간예후는밝혀지지않았지만치료를하지않을경우상당수가당뇨로진행될수있다. 5 중환자실에서치료를받은환자들중중증질환다발성신경병증혹은근병증이발생할수있다. 중증질환다발성신경병증의경우말단부에더심한이완마비가전신에나타나며, 심부건반사가감소되지만, 근위축은 1/3 의환자에서나타나지않고뇌신경침범도드물다. 7 패혈증과다발성장기부전으로중환자실에서 2주이상치료받은환자중적어도 50% 이상에서축삭성다발성신경병증을시사하는전기진단학적소견이관찰되었다. 7 중증질환근병증은대개정맥내코르티코스테로이드혹은비탈분극성신경근육차단제를투여한급성호흡부전증후군이나심한천식환자에서발생한다. 임상적으로중증질환신경병증과근병증은감별이어려우며전기진단학적검사를통해구별할수있지만함께이환되는경우도있다. 8 중증질환신경병증이나근병증을진단하기전에중환자실입원을초래할수있는기존의신경근육질환과신경근전달차단제가체내에남아있어발생한신경근전달장애를배제하여야한다. 중증질환신경병증과근병증의예후는기저질환에의해좌우되며기저질환에서생존한경우예후는양호하다. 9,10 2) 암환자에서말초신경계질환항암치료의발전으로암환자의생존기간이늘어남에따라삶의질을중요하게생각하게되었으며, 특히말초신경병증은삶의질에영향을줄수있는주요요인들중하나로고려되고있다. 11,12 임상양상만으로는 2% 에서 16% 까지보고되었으나전기생리학적검사를시행한경우약 30% 에서 40% 의환자에서말초신경병증을시사하는이상이보고되었다. 암환자에서말초신경병증이의심될때는원발성혹은전이암의신경계침범, 다발성신경근을침범하는뇌수막전이, 신경에대한암의원격효과, 심한악액질상태에서포착성신경병증, 항암제혹은방사선치료에의한신경병증을고려하여야하지만, 암환자에서말초신경병증의가장흔한원인은항암제에의한독성말초신경병증이다. 13,14 특히말초신경병과연관성이많게알려진약제들은주로감각신경에영향을주는약제들로 bortezomib, cisplatin, oxaliplatin, thalidomide 등이있으며운동신경에도영향을줄수있는약제들은 ixabepilone, paclitaxel, suramin, vincristine 등이있다 (Table 1) 대부분항암제사용이중단된이후에는회복이되지만, 훗날암의재발로인해다시항암제를사용하게되었을때는더이른시기에증상이발현되고, 또한회복도늦으며영구히후유증이남을수있다. 암환자에서발생한말초신경계증상을조사하는경우도있지만, 순수감각장애를호소하는환자들에서신경전도검사에서감각신경활동전위의진폭만이선택적으로작아져있는감각신경원병 (sensory neuronopathy) 가확인된경우에는반드시부종양증후군의가능성을고려해서잠재된악성종양, 특히폐암에대한검사가필요하다 (Table 2) ) 삼차신경통및안면신경마비안면신경마비의경우벨마비외에도외상이나감염, 종양등에의해서도유발될수있다. 진행경과에따라 2주이내의급성, 56 대한신경과학회지제 29 권부록 2, 2011

80 협진신경학 : 신경근육질환 Table 2. Paraneoplastic neuromuscular disorder Syndrome Clinical presentation Associated antibodies Associated cancer Diagnostic studies Lambert-eaton syndrome Lower extremity proximal weakness, diaphragmatic weakness, bulbar symptoms Anti-VGCC (P/Q type) Small cell lung cancer, lymphoma Repetitive nerve stimulation test with low and high rate Myasthenia gravis Neuromyotonia Motor neuron disease Subacute sensory neuronopathy Fatigable weakness, diaphragmatic weakness Continous undulating muscle twitching, painful cramp worsened by attempted contraction Progressive weakness in the limbs or dysarthria and dysphagia with evidence of upper or lower motor neuron sign Asymmetric pain and paresthesia with sensory ataxia and pseudoathetoid movement of the hands Inflammatory myopathies Subacute muscle weakness with easy fatigability Anti-AchR, anti-titin, anti-ryanodine Anti-VGKC, anti-hu(anna-1) Anti-Hu(ANNA-1), anti-yo(pca-1), anti-mag Thymoma Thymoma, Hodgkin disease, small cell lung cancer Ovarian cancer, small cell lung cancer, breast cancer, lymphoproliferative disorder Repetitive nerve stimulation test Electromyography Electromyography Anti-Hu(ANNA-1) Small cell lung cancer Nerve conduction study Anti-Jo-1, anti-mi-2 Non-hodgkin lymphoma, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer bladder cancer Serum level of creatine kinase, electromyography, muscle biopsy VGCC; voltage-gated calcium channels, VGKC; voltage-gated potassium channels, ANNA; antineuronal nuclear antibody, PCA; purkinje cell autoantibody, MAG; myelin-associated glycoprotein, CRMP; collapsing response mediator protein. 2주이후에도악화되거나 4개월이상이완성마비가지속되는경우만성으로분류할수있다. 급성의경우벨마비, 람세헌트증후군, 외상, 중이염, 길랑바레증후군 (Guillain-Barre syndrome), 유육종증 (sarcoidosis) 등을고려할수있으며만성의경우원발성종양혹은전이암의경우를고려할수있다. 51 삼차신경통의경우대부분삼차신경의감각신경근이동맥에의한압박에의해발생하지만종양, 정맥압박, 동정맥기형, 다발성경화증, 뇌수종등에의해서도발생할수있다. 52 따라서내과적평가가필요하며자기공명영상을시행하여신경 -혈관압박과다른원인에대한감별을시행한다. 4) 기립성어지럼증및실신실신은그발생원인에따라신경중개성실신, 기립성저혈압, 심장성실신으로구분할수있다. 53 먼저의식소실이실신에의한경우라면병력청취와양상에따라실신의원인을추정하고검사를시행한다. 심장질환유무, 실신의과거병력, 실신발생전동반증상, 실신유발상황, 저혈압을유발할수있는약물복용, 자율신경병증혹은파킨슨증후군에대한병력, 돌연사에대한가족력등을통해실신의원인을추정할수있다. 특히기립성저혈압의경우다양한약물과내분비혹은대사성질환과연관되어발생할수있다. 54 항고혈압제, 이뇨제, 혈관확장제가흔히기립성저혈압을유발할수있으며신경안정제, 진정제, 수면제, 항우울제도가능하다. 항암제중에서도 vincristine 이기립성저혈압을유발할수있으며 55 bortezomib, paclitaxel 에서도드물게관찰되었다. 31,56,57 당뇨뿐만아니라에디슨병, 뇌하수체저하증, 갑상선중독증, 갈색세포종 (pheochromocytoma), 카르시노이드증후군 (carcinoid syndrome), 저칼륨혈증에서도발생할수있어이러한전실질환에대한병력청취를고려해야한다. 5) 근전도를의뢰받은경우전기진단학적검사는신경-근육질환에대한진단과추적관찰에있어중요한검사이다. 어떠한근전도소견도특정질환에특징적이지않으며표준혹은규격화된전기진단학적검사는없다. 따라서적절한병력청취와진찰소견에따라전기진단학적검사를계획하고임상적소견에따라검사결과를분석해야한다. 58,59 전기진단학적검사가의뢰된경우의뢰한의사의소견이중요하고이에따라협진의방향을결정해야하지만모든협진의시작점은환자의주소이며정확한병력청취와진찰소견을통해종합적이고집중된검사를계획할수있다. 60 전기진단의학에대한협진도다른진료분야의협진과같이병력청취, 진찰소견, 특수검사, 검사종합소견, 추정진단, 앞으로의진료계획그리고추적관찰에대한권유로이루어진다. 모든검사를시행한뒤이에대한결과를간결하며이해하기쉽게 J Korean Neurol Assoc Volume 29 Suppl. 2,

81 장재홍김병조 전달하는것도중요하다. 결 론 신경근육질환은신경학의각세부분과들중가장다양한병태생리를가지고있고, 다양한질환들과연관되어발병할수있기때문에특히많은빈도의협진이의뢰될수있다. 대부분협진이의뢰된경우에는우선적으로기저질환과연관되었을가능성을고려하여감별진단을수행하는것이필요하다. 신경근육질환들은특정검사결과에의해확진을하기보다는임상증상들과여러검사결과들을종합하여가장적절한진단을내리는경우가대부분이기때문에협진을의뢰받은경우에는특히충분한문진과진찰을통해진단에도움이될만한검사를선별하는과정이반드시선행되어야한다. 신경학에관련된지식뿐만아니라기타의학분야에대한지식도충분히갖추고있어야만자문의뢰에대한적절한답변이가능할수있기때문에현재신경학이다양한세부분과로나누어지고있는것처럼협진신경학혹은자문신경학이라는분야도독립된세부분과로발전할가능성도있지않을까생각해본다. References 1. Barohn RJ. Approach to peripheral neuropathy and neuronopathy. Semin Neurol 1998;18: Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol 1981; 10: Dyck PJ, Chalk CH. The 10 P's: a mnemonic helpful in characterization and differential diagnosis of peripheral neuropathy. Neurology 1992; 42: Smith AG, Bromberg MB. A rational diagnostic approach to peripheral neuropathy. J Clin Neuromuscul Dis 2003;4: Smith AG, Singleton JR. Impaired glucose tolerance and neuropathy. Neurologist 2008;14: Singleton JR, Smith AG, Bromberg MB. Painful sensory polyneuropathy associated with impaired glucose tolerance. Muscle Nerve 2001;24: Visser LH. Critical illness polyneuropathy and myopathy: clinical features, risk factors and prognosis. Eur J Neurol 2006;13: De Jonghe B, Sharshar T, Lefaucheur JP, Authier FJ, Durand-Zaleski I, Boussarsar M, et al. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA 2002;288: Hund EF, Fogel W, Krieger D, DeGeorgia M, Hacke W. Critical illness polyneuropathy: clinical findings and outcomes of a frequent cause of neuromuscular weaning failure. Crit Care Med 1996;24: Zochodne DW, Bolton CF, Wells GA, Gilbert JJ, Hahn AF, Brown JD, et al. Critical illness polyneuropathy. A complication of sepsis and multiple organ failure. Brain 1987;110 ( Pt 4): Kim BJ, Park HR, Roh HJ, Jeong DS, Kim BS, Park KW, et al. Chemotherapy-related polyneuropathy may deteriorate quality of life in patients with B-cell lymphoma. Qual Life Res 2010;19: Doorduijn J, Buijt I, Holt B, Steijaert M, Uyl-de Groot C, Sonneveld P. Self-reported quality of life in elderly patients with aggressive non- Hodgkin's lymphoma treated with CHOP chemotherapy. Eur J Haematol 2005;75: Amato AA, Collins MP. Neuropathies associated with malignancy. Semin Neurol 1998;18: Rudnicki SA, Dalmau J. Paraneoplastic syndromes of the peripheral nerves. Curr Opin Neurol 2005;18: Argyriou AA, Iconomou G, Kalofonos HP. Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood 2008;112: Grunberg SM, Sonka S, Stevenson LL, Muggia FM. Progressive paresthesias after cessation of therapy with very high-dose cisplatin. Cancer Chemother Pharmacol 1989;25: Thompson SW, Davis LE, Kornfeld M, Hilgers RD, Standefer JC. Cisplatin neuropathy. Clinical, electrophysiologic, morphologic, and toxicologic studies. Cancer 1984;54: Strumberg D, Brugge S, Korn MW, Koeppen S, Ranft J, Scheiber G, et al. Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer. Ann Oncol 2002;13: Park SB, Goldstein D, Lin CS, Krishnan AV, Friedlander ML, Kiernan MC. Acute abnormalities of sensory nerve function associated with oxaliplatin-induced neurotoxicity. J Clin Oncol 2009;27: Grothey A. Oxaliplatin-safety profile: neurotoxicity. Semin Oncol 2003;30: Matthews SJ, McCoy C. Thalidomide: a review of approved and investigational uses. Clin Ther 2003;25: Corso A, Zappasodi P, Barbarano L, Petrucci MT, Palumbo A, Caravita T, et al. Long-term outcome in relapsed and refractory multiple myeloma treated with thalidomide. Balancing efficacy and side-effects. Leuk Res 2009;33:e Mazumder A, Jagannath S. Thalidomide and lenalidomide in multiple myeloma. Best Pract Res Clin Haematol 2006;19: Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, et al. Efficacy and safety of ixabepilone (BMS ) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol 2007;25: Goel S, Goldberg GL, Kuo DY, Muggia F, Arezzo J, Mani S. Novel neurosensory testing in cancer patients treated with the epothilone B analog, ixabepilone. Ann Oncol 2008;19: Wilkes G. Peripheral neuropathy related to chemotherapy. Semin Oncol Nurs 2007;23: Chaudhry V, Rowinsky EK, Sartorius SE, Donehower RC, Cornblath DR. Peripheral neuropathy from taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies. Ann Neurol 1994;35: Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. J Peripher Nerv Syst 2008;13: Chaudhry V, Eisenberger MA, Sinibaldi VJ, Sheikh K, Griffin JW, Cornblath DR. A prospective study of suramin-induced peripheral neuropathy. Brain 1996;119 ( Pt 6): Legha SS. Vincristine neurotoxicity. Pathophysiology and management. Med Toxicol 1986;1: Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. 58 대한신경과학회지제 29 권부록 2, 2011

82 협진신경학 : 신경근육질환 J Neurol 2002;249: Wirtz PW, Smallegange TM, Wintzen AR, Verschuuren JJ. Differences in clinical features between the Lambert-Eaton myasthenic syndrome with and without cancer: an analysis of 227 published cases. Clin Neurol Neurosurg 2002;104: Sanders DB. Lambert-eaton myasthenic syndrome: diagnosis and treatment. Ann N Y Acad Sci 2003;998: Lang B, Waterman S, Pinto A, Jones D, Moss F, Boot J, et al. The role of autoantibodies in Lambert-Eaton myasthenic syndrome. Ann N Y Acad Sci 1998;841: Keesey JC. Clinical evaluation and management of myasthenia gravis. Muscle Nerve 2004;29: Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest 2006;116: Evoli A. Clinical aspects of neuromuscular transmission disorders. Acta Neurol Scand Suppl 2006;183: Toepfer M, Schroeder M, Unger JW, Lochmuller H, Pongratz D, Muller-Felber W. Neuromyotonia, myocloni, sensory neuropathy and cerebellar symptoms in a patient with antibodies to neuronal nucleoproteins (anti-hu-antibodies). Clin Neurol Neurosurg 1999;101: Mygland A, Vincent A, Newsom-Davis J, Kaminski H, Zorzato F, Agius M, et al. Autoantibodies in thymoma-associated myasthenia gravis with myositis or neuromyotonia. Arch Neurol 2000;57: Lahrmann H, Albrecht G, Drlicek M, Oberndorfer S, Urbanits S, Wanschitz J, et al. Acquired neuromyotonia and peripheral neuropathy in a patient with Hodgkin's disease. Muscle Nerve 2001;24: Maddison P. Neuromyotonia. Clin Neurophysiol 2006;117: Khwaja S, Sripathi N, Ahmad BK, Lennon VA. Paraneoplastic motor neuron disease with type 1 Purkinje cell antibodies. Muscle Nerve 1998; 21: Verma A, Berger JR, Snodgrass S, Petito C. Motor neuron disease: a paraneoplastic process associated with anti-hu antibody and small-cell lung carcinoma. Ann Neurol 1996;40: Forsyth PA, Dalmau J, Graus F, Cwik V, Rosenblum MK, Posner JB. Motor neuron syndromes in cancer patients. Ann Neurol 1997;41: Rowland LP, Sherman WH, Latov N, Lange DJ, McDonald TD, Younger DS, et al. Amyotrophic lateral sclerosis and lymphoma: bone marrow examination and other diagnostic tests. Neurology 1992;42: Gordon PH, Rowland LP, Younger DS, Sherman WH, Hays AP, Louis ED, et al. Lymphoproliferative disorders and motor neuron disease: an update. Neurology 1997;48: Molinuevo JL, Graus F, Serrano C, Rene R, Guerrero A, Illa I. Utility of anti-hu antibodies in the diagnosis of paraneoplastic sensory neuropathy. Ann Neurol 1998;44: Oh SJ, Gurtekin Y, Dropcho EJ, King P, Claussen GC. Anti-Hu antibody neuropathy: a clinical, electrophysiological, and pathological study. Clin Neurophysiol 2005;116: Alexanderson H, Lundberg IE. Inflammatory muscle disease: clinical presentation and assessment of patients. Curr Rheumatol Rep 2007;9: Hill CL, Zhang Y, Sigurgeirsson B, Pukkala E, Mellemkjaer L, Airio A, et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet 2001;357: Hauser WA, Karnes WE, Annis J, Kurland LT. Incidence and prognosis of Bell's palsy in the population of Rochester, Minnesota. Mayo Clin Proc 1971;46: Hughes RAC. Disease of the fifth cranial nerve. In: Dyck PJ, Thomas PK, Griffen JW. Peripheral Neuropathy. 3rd ed. Philadelphia: W.B. Saunders. 1992; Brignole M, Alboni P, Benditt DG, Bergfeldt L, Blanc JJ, Thomsen PE, et al. Guidelines on management (diagnosis and treatment) of syncopeupdate Executive Summary. Eur Heart J 2004;25: Brignole M. Diagnosis and treatment of syncope. Heart 2007;93: Aminoff MJ. Postural Hypotension. In: Aminoff MJ. Neurology and general medicine : the neurological aspects of medical disorders. 2nd ed. New York: Churchill Livingstone. 1995; Gupta S, Pagliuca A, Devereux S, Mufti GJ, Schey S. Life-threatening motor neurotoxicity in association with bortezomib. Haematologica 2006;91: Jerian SM, Sarosy GA, Link CJ Jr, Fingert HJ, Reed E, Kohn EC. Incapacitating autonomic neuropathy precipitated by taxol. Gynecol Oncol 1993;51: Oh SJ. Electrophysiologic tests in neuromuscular disease. In: Pourmand R. Neuromuscular diseases: expert clinicians' views. Boston: Butterworth- Heinemann. 2001; Oh SJ. Electromyography in peripheral nerve injuries: when to consider it; what it can tell you. Med Times 1980;108:94-98, Dumitru D, Zwarts MJ. The Electrodiagnostic Medicine Consultation: Approach and Report Generation. In: Dumitru D, Amato AA, Zwarts MJ. Electrodiagnostic medicine. 2nd ed. Philadelphia: Hanley & Belfus. 2002; J Korean Neurol Assoc Volume 29 Suppl. 2,

83 특수상황에서의간질환자치료 : 고찰및증례 Lambert-eaton Myasthenic Syndrome: UAB Experience Shin J. Oh, MD Distinguished Professor of Neurology, The University of Alabama at Birmingham Lambert-Eaton Myasthenic Syndrome (LEMS) is an autoimmune disease clinically characterized by easy fatigability, proximal leg weakness, paucity of oculobulbar symptoms, and hyporeflexia. The main defect in this disorder is the insufficient release of ACh at the pre-synaptic membrane, possibly induced by the antibodies against voltage-gated calcium channels (VGCC). A recent study showed that this antibody was found in 52% of LEMS patients for the N type and in 90% of LEMS patients for the P/Q type. The clinical, electrophysiological, and pharmacological differences between MG and LEMS are given in Table. The most common symptoms are easy fatigability and leg weakness. The classic clinical triad of LEMS includes proximal leg weakness, hyporeflexia or areflexia, and cholinergic dysautonomia (dry mouth, impotence, and orthostatic hypotension). A transient improvement in muscle strength and reflexes immediately after brief exercise is classically observed in LEMS. These findings, if observed, are pathognomonic of LEMS. LEMS is a pivotal example of a paraneoplastic neurological syndrome. From the first description of LEMS, its association with SCLC has been well known. As noted previously, an Table. Differences between MG and LEMS Myasthenia gravis LEMS Sex F:M=2:1 F:M=2: 3 Presenting signs Weakness of ocular, bulbar & facial muscles Weakness of proximal leg muscles Exertion Exertional weakness Transient improvement after brief exercise followed by weakness Reflexes Normal Reduced or absent Tumor Thymoma in 16% of cases Small cell carcinoma of lung in 55 % of cases Basic defect Post-synaptic defect Pre-synaptic defect RNS test: CMAP at rest Normal Low after exercise No change Marked increase Low rate stimulation Decremental response Decremental response High rate stimulation Normal or decrement Incremental response Antibodies AChR-ab (+) in 85% VGCC-ab (+) in 90% Drugs AChEIs Guanidine, aminopyridine Immunotherapies Steroids, immunosuppressives, plasmapheresis, & IVIG in both Thymectomy Effective Not indicated 60 대한신경과학회지제 29 권부록 2, 2011

84 Lambert-Eaton Myasthenic Syndrome earlier study showed that 75% of LEMS patients had SCLC, whereas a more recent study showed this association in only 50% of cases, suggesting a trend toward a lower tumor frequency in recent years. LEMS is a disease of the elderly, with the most common age of onset of symptoms being about 60 years of age. Paraneoplastic LEMS typically develops in the middle-aged to elderly and was originally seen more commonly in men. Usually the discovery of LEMS preceded that of cancer by several months to years. In all cases, cancer developed within 4 years following diagnosis of LEMS. Thus, it is important to do a work-up for occult cancer, especially SCLC, at the time of diagnosis of LEMS and serially thereafter, as noted. There are no clinical and electrophysiological differences which distinguish paraneoplastic LEMS from autoimmune LEMS. The diagnosis of LEMS can only be confirmed by the RNS test. The RNS test is essential in confirming the diagnosis of this disease. The RNS test in LEMS is characterized by a pre-synaptic NMT block: (a) low CMAP, (2) dramatic PEF, (3) decremental response at LRS, (4) marked incremental response at HRS, and (5) prominent PTF but less prominent PTE..Low CMAP has been noted in 95% of cases in this disorder. In many patients, it is extremely low. The most dramatic increase in the CMAP amplitude after exercise (PEF) has been noted in this disease. A more than 100% increase in the CMAP amplitude after exercise is considered to be typical of LEMS. In almost all cases, a decremental response has been noted at LRS. In our series, a decremental response was present in 93% of cases..the most dramatic facilitation at HRS wasseen in this disease. In all cases, there was an incremental response at HRS, ranging from 100% to 4000%. A more than 100% incremental response at HRS is almost pathognomonic of LEMS. Our recent study showed that a more than 60% response in PEF or at HRS is sufficient for the diagnosis of LEMS. Our recent study also showed that the RNS test is more typical of LEMS and more abnormal in the seropositive LEMS group, and that the classic triad (low CMAP amplitude, decrement at LRS, and increment at PEF or HRS) is rare in the seronegative group. General guidelines of therapeutic management of LEMS Once the diagnosis of LEMS is established, 3,4-DAP is the drug of choice for symptomatic treatment (class I). This will virtually always produce symptomatic improvement. If 3,4-DAP is not available, certainly guanidine HCl is an alternative choice of drug, usually along with a liberal dose of pyridostigmine (Class VI; label B). Some LEMS patients find that the addition of pyridostigmine to 3,4 DAP treatment is beneficial. The next important work-up at the time of diagnosis of LEMS is to confirm the SCLC because it is found in half the LEMS patients at the time of or within 2 years following diagnosis. The best diagnostic test for SCLC is a highresolution chest CTscan and possibly also a bronchoscopy and PDG-PET scan if the CT scan is negative. This is especially important for patients with a high risk of SCLC (history of smoking and older patients). Follow-up should be continued with a CT scan every 6 months for at least 4 years. Once the diagnosis of SCLC is established, treatment of cancer will be implemented in its own right, but an added benefit is that it induces an improvement of LEMS symptoms. Chemotherapy is the first choice in SCLC because it has an additional immunosuppressive effect. The presence of LEMS in a patient with SCLC is known to improve survival. If symptomatic treatment is insufficient, the next step is immunosuppressive therapy, usually with high-dose steroid (class IV) regardless of whether the patient has SCLC. When remission has been obtained in LEMS, the prednisone dose should be tapered to the minimum required to maintain remission. As a long-term immunsuppressive medication, AZA is the first choice for autoimmune LEMS (Class IV). However, for paraneoplastic LEMS, this agent is not recommended because of the concern about the carcinogenic property of AZA. In this connection, MM may be an alternative (level C). For the second-line choice for long-term immunosuppressive medication, onecan choose IVIG (intermittent use) (Class I). CsA and MM are other alternatives. However, this recommendation is based on MG, not on LEMS. Personally, none of my patients has needed CsA or MM for the longterm immunosuppression. For patients with severe LEMS, IVIG is the treatment of choice since it is shown to be beneficial in short-term cases J Korean Neurol Assoc Volume 29 Suppl. 2,

85 Shin J. Oh (class I). PE may be an alternative treatment if IVIG is not effective (class IV). Respiratory and bulbar muscle weakness, rare in LEMS, can occasionally be life-threatening in LEMS patients. In patients with such severe weakness, PE can produce a short-term benefit when given as a 5-day course (Class IV). 62 대한신경과학회지제 29 권부록 2, 2011

86 특수상황에서의 Electrophysiological 간질환자 Criteria 치료 : of 고찰 Demyelination: 및증례 Its Relevance to Immune-Mediated Neuropathies Shin J. Oh, MD Distinguished Professor of Neurology, The University of Alabama at Birmingham It is logical to classify a peripheral neuropathy according to the predominant pathological involvement of axon and myelin: axonal degeneration and segmental demyelination. Nerve conduction test is the best way to differentiate axonal neuropathy from demyelinating neuropathy. The hallmarks of nerve conduction abnormalities in segmental demyelination are: 1. Conduction block.this is usually applied to motor nerve conduction. 2. Abnormal temporal dispersion. This is usually applied to the CMAP in the motor nerve conduction and to the CNAP in the near-nerve sensory nerve conduction. 3. Marked slowing in the NCV. These hallmarks of demyelination are classically recognized in motor nerve conduction study. The following findings are typical of segmental demyelination: 1. Normal or reduced amplitude of the CMAP. Substantial slowing of the NCV in the presence of a normal amplitude is indicative of segmental demyelination. When the amplitude is reduced, this reduction is proportional to the degree of temporal dispersion of the CMAP and conduction block. 2. Abnormal temporal dispersion or "dispersion phenomenon" (abnormal CMAP with multiple phases and prolonged duration). This is judged in comparison either with the normal CMAP or with the CMAP at the distal site. We prefer the term "dispersion phenomenon" when comparing with the normal CMAP and "abnormal temporal dispersion". when comparing with the CMAP at he distal site. Abnormal temporal dispersion or dispersion phenomenon is typical of segmental demyelination. 3. Marked prolongation of the terminal latency. The terminal latency is prolonged by more than 50% of the normal mean. Terminal latencies longer than 6 ms in the median nerve and longer than 10 ms in the peroneal nerve are indicative of segmental demyelination. 4. Markedly slow NCV. Slowing of the NCV depends on the degree of segmental demyelination. NCV slowing by more than 40% below the normal mean is indicative of segmental demyelination. Motor NCVs below 35 m/s in the median nerve and below 30 m/s in the peroneal nerve are indicative of segmental demyelination. 5. Conduction block. The amplitude is somewhat lower with stimulation at more proximal sites in normal subjects. Conduction block is defined as being present when there is a greater than 50% reduction of CMAP amplitude and area with normal duration with proximal stimulation as compared with distal stimulation. Demyelinating Polyneuropathy In GBS, nerve conduction abnormalities are present in almost all cases and evidence of demyelination in 80% of cases. Demyelination in GBS can be either expressed as marked NCV slowing, temporal dispersion, or conduction block. It is important to remember that in 20% of cases, NCV is minimally slow, in the range of "axonal neuropathy"due to mild demyelination. Sensory GBS, a sensory variant of GBS, can only be recognized by the electrophysiological evidence of demyelination in nerve conduction study, mostly in the motor nerve conduction. J Korean Neurol Assoc Volume 29 Suppl. 2,

87 Shin J. Oh In CIDP, the most helpful objective diagnostic finding is the typical pattern of nonuniform demyelinating neuropathy. Without this pattern, it is impossible to make the diagnosis of CIDP. The nerve conduction test in this disorder shows findings typical of extensive segmental demyelination: marked slowing in NCV, condubtion block, and dispersion phenomenon. The nerve conduction abnormalities are diffuse, involving the distal and proximal segments of the nerve. All nerves are affected in this disorder, although the degree of abnormality varies from nerve to nerve. Motor nerve conduction is universally abnormal in CIDP, showing evidence of demyelination. Sensory CNAPs are either absent or low in amplitude, and the F-wave and H-reflex are either absent or markedly prolonged in latencies. Compared with GBS, CIDP is characterized by more typical and severe evidence of demyelination. CSDN is an entity recently described by us and is characterized by subacute or chronic progression over months or years, pure sensory neuropathy (no motor weakness), high spinal fluid protein in most cases, electrophysiological evidence of demyelination affecting motor and sensory nerve fibers, demyelination on sural nerve biopsy, and good response to immunotherapy in the progressive phase of disease. In our experience, CSDN is the most common treatable form of neuropathy among the sensory neuropathies.. We believe that this entity represents a CIDP presenting as pure sensory neuropathy. The most important diagnostic test in CSDN is the motor nerve conduction study, which is usually the first objective clue suggestive of demyelinating neuropathy. In some patients, the near-nerve needle sensory nerve conduction study is needed to make a definite diagnosis. MAG (myelin-associated glycoprotein)-positive neuropathy has distinct features: predominantly sensory neuropathy, IgM paraprotein, high CSF protein, and unsatisfactory response to immunotherapies. Nerve conduction study showed findings typical of demyelinating neuropathy. The most conspicuous finding in MAG-positive neuropathy is a disproportionate distal slowing of motor conduction expressed by markedly prolonged terminal latency in comparison to the degree of slow NCV in the proximal segment of nerves. MMN (multifocal motor neuropathy) has emerged as a distinct entity in the recent years which can be confused with ALS because of pure motor involvement, frequent fasciculation, preserved or brisk reflexes, and frequent onset of weakness in the arms. This neuropathy is characterized clinically by pure motor mononeuropathy multiplex, immunologically by a strong association with the anti-gm1 antibody, and therapeutically by a lack of steroid response but a fair response to cyclophosphamide and IVIg treatment. Electrophysiological hallmark of this disorder is multifocal motor conduction block with sparing of sensory nerve conduction. Many claimed that without conduction block one can not make the diagnosis of this disorder. According to our experience, one can make the diagnosis of MMN without motor conduction block and minor sensory nerve conduction abnormalities are not uncommon. MMSDN (multifocal motor-sensory demyelinating neuropathy; Lewis-Summer syndrome) resembles MMN because it is a multifocal neuropathy, involves the arms predominantly, and shows demyelination in the NCS. However, it is different from MMN because of the presence of sensory deficits, sensory nerve conduction abnormalities, good response to immunotherapies, and absence of GM1 antibody. This entity is characterized by subacute or chronic motorsensory mononeuropathy multiplex, high CSF protein in 60% of patients, demyelination in the nerve biopsy, and good response to the immunotherapies. Electrophysiological characteristic of this disorder are evidence of demyelination in multifocal nerves and frequent sensory nerve conduction abnormalities. In one case of MSDN (multifocal sensory demyelinating neuropathy), the routine NCS showed essentially nomral findings except a low sensory CNAP amplitude in the left median and ulnar nerves. Near-nerve needle study in the ulnar nerve showed "conduction block" and temporal dispersion in the above-elbow and axilla segment. 64 대한신경과학회지제 29 권부록 2, 2011

88 특수상황에서의간질환자치료 : 고찰및증례만성염증탈수초성다발척수근말초신경병증의치료 부산대학교의학전문대학원신경과학교실김대성 Treatment of Chronic Inflammatory Demyelinating Polyradiculoneuropathy Dae-Seong Kim, MD, PhD Department of Neurology, Pusan National University School of Medicine, Yangsan, Korea Chronic acquired demyelinating polyneuropathies are a group of diseases caused by autoimmune reaction against the peripheral nerve myelin sheath, and cause a dysfunction of peripheral nerve which produce significant disabilities in affected patients if untreated. Currently, there are many different therapeutic methods including corticosteroids, intravenous immune globulin (IVIG), plasmapheresis, chemotherapeutic agents, and agents for selective immunotherapy. In classical chronic inflammatory demyelinating polyradiculopathy (CIDP), either corticosteroid, IVIG, or plasmapheresis can be used as a first line treatment. About 2/3 of the patients with CIDP will respond to one of them. However, 1/3 of patients with CIDP respond to none of them, and other therapies including chemotherapy or selective immunotherapy should be considered. In mutifocal motor neuropathy, IVIG is the treatment of choice, and corticosteroid or plasmaphereis is not effective. Many patients with anti-myelin associated glycoprotein neuropathy are refractory to the treatment by corticosteroid, IVIG, or plasmapheresis. It is also important for the physicians who are taking care of the patients with chronic acquired demyelinating polyneuropathies to learn the therapeutic effects and side effects of each agent, because the risk of toxic side effects often overweigh the therapeutic effects in some patients. Key Words: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), Corticosteroid, Intravenous immune globulin, Plasmapheresis 본고에서는만성후천성탈수초성신경병증 (chronic acquired demyelinating polyneuropathy) 으로분류되는질환들인만성염증탈수초성다발척수근말초신경병증 (chronic inflammatory demyelinating polyradiculoneuropathy, classic CIDP), 다초점성운동신경병증 (multifocal motor neuropathy, MMN), anti-myelin associated glycoprotein neuropathy (anti-mag neuropathy) 등에서사용되는치료법및치료약제들에관해논하고자한다. 이질환들은모두말초신경항원에대해형성된자가항체에의해발병하는자가면역병이므로여러가지다양한면역조절요법 (immune modulating therapy) 으로증상이호전될수있다. 하지만치료법에따라다양한부작용이발생할수있고, 질 Dae-Seong Kim, MD, PhD Department of Neurology Pusan National University Yangsan Hospital, Beomo-ri, Mulgeum-eup, Yangsan , Korea Tel: Fax: dskim@pusan.ac.kr 병에따라서특정치료법이효과적인경우와그렇지않은경우가있으므로이를잘알고있는것이치료방법과방침을결정하는데도움이된다. 본고에서는우선각치료법의작용기전과효과, 용법, 주요부작용, 사용시에주의할점등을우선기술한후각질환별로어떤치료법이효과적인지를기술하고자한다. 사용되는치료법들 1. 부신피질호르몬 (corticosteroid) 글루코코르티코이드 (glucocorticoid) 는세포질글루코코르티코이드수용체와결합한후핵으로이동하여 DNA 의특정부위에결합하여특정유전자의발현을조절함으로써염증반응을억제하는효과를나타낸다. 글루코코르티코이드는대식세포, T 임파구등에작용하여세포매개면역을광범위하게억제하지만 B 임파구와체액면역 (humoral immunity) 에대한작용은거의 J Korean Neurol Assoc Volume 29 Suppl. 2,

89 김대성 없다. 1 비록 CIDP 환자들을대상으로이중맹검무작위배정임상시험이시행된적은없지만위약을사용한무작위배정임상시험에서부신피질호르몬제제가 CIDP 환자들의기능을향상시키는효과가있음이증명된바있고, 경험적으로도그치료효과가인정되어 CIDP 의치료에널리사용되어지고있으며대략 60-70% 정도의 CIDP 환자가경구혹은경정맥부신피질호르몬치료에반응하는것으로알려져있다. 2-5 치료용법은다양하게사용되지만경구부신피질호르몬의경우 mg/kg 의 prednisone 혹은 prednisolone 의고용량으로시작하여 2-4 주간유지하다가임상적인호전이지속되거나유지되면이를감안하며수주혹은수개월간격으로서서히감량하는방법이일반적으로사용되는데사용용량이낮아질수록감량하는속도를더늦추어주어야한다. 3 경정맥코르티코스테로이드펄스치료 (intravenous corticosteroid pulse therapy) 는경구요법에비해부작용을감소시킬수있다고알려져있으며그용법은 1개월간격으로 4일간 dexamethasone 40mg/day 를투여하는방법과 5 methylprednisolone 1g/day 를첫 3-5 일간투여하여시작한후첫 1개월간은 2주에 1회씩, 그리고이후에는 2-12 주간격으로 1회씩감량해나가는방법 6 등이소개된바있다. 코르티코스테로이드는 classic CIDP 뿐만아니라 LSS, neuropathy with MGUS 등에도뛰어난치료효과를보이지만 anti-mag neuropathy 에서는효과가떨어지며 MMN 에는치료효과가없고오히려증상이악화되기도한다. 3 코르티코스테로이드를오랜기간사용하면거의모든환자들에게다양한부작용이발생하는데주요부작용들로는고혈당, 고혈압, 위염, 위장관출혈, 골다공증, 골절, 대퇴골두무혈성괴사, 녹내장, 백내장, 상처치유지연, 근력저하, 비만, 감염증에대한감수성증가, 어린이의성장장애, 우울증, 조증, 불면증, 시상하부 -뇌하수체 -부신축의억제등을들수있다. 이러한부작용, 특히시상하부 -뇌하수체-부신축의억제를피할목적으로격일제로코르티코스테로이드를투여하기도하는데 (alternate day regimen), 처음에는고용량코르티코스테로이드를매일투여하다가점차그용량을줄여가며격일요법으로바꾸어나가는경우가일반적이지만처음부터격일요법으로시작할수도있다. 하지만아직 CIDP 에서매일요법과격일요법의효과를비교한임상연구결과는없다. 장기간코르티코스테로이드를복용하여야하는환자들에게는매일칼슘 1,000 mg, 비타민 D 800 IU을보충해주는것이좋고, 주기적으로골밀도를검사하여야하며탄수화물과염분이적게함유하는식단을제공하고주기적인근력운동을실시할것을권고하여야한다. 3 Bisphosphonate 는골밀도의감소를예방함으로써골절의발병율을낮추어주는효과가있으므로매일 5 mg 이상의코르티코스테로이드를 3개월이상복용하여야하는환자, 오랫동안코르티코스테로이드를복용하면서골밀도가정상의 1SD 이하로저하되어있는환자, 그리고골다공증에의한골절이발생한환자들에게는반드시처방하여야한다 경정맥면역글로불린 (intravenous immune globuln, IVIG) IVIG 는 3,000-5,000 명의공여자로부터얻은인간혈청으로만드는데, 혈청을효소처리 (enzymatic treatment) 후분획 (fractionation), 크로마토그래피하여정제한후응집 (aggregation) 을억제하기위해 sucrose, maltose, glucose, sorbitol, albumin 등을첨가하여안정화시키며간염바이러스등을불활성화시키기위해용제나세제를첨가한다. 8 IVIG 는 IgG 가 95% 이상, IgA 가 2.5% 이하이며, 기타혈장에있는면역기능관련물질들이미량존재하는데이러한미량물질로인해일부부작용이유발된다. 9 IVIG 는합동자극과항원인식 (costimulation and antigen recognition), 자가항체 (autoantibody), 케모카인 (chemokines), 부착분자 (adhesion molecules) 와그수용체, 병원성시토카인 (cytokines), 보체 (complement), 대식세포 (macrophages) 등에작용하는다양한면역조절기능을가지며, 개개의자가면역질환에서나타나는치료효과의기전은각기다를것으로추측된다. 3 치료시작시에사용하는용법은다양하지만하루 400 mg/kg 씩 5일간에걸쳐총량 2 g/kg 를투여하는방법이가장많이사용된다. 일반적인투여속도는시간당 200 ml 이내이며심장이나신장질환이있는환자에게는그이상의속도로투여하지않는것이좋다. IVIG 의반감기는 18일에서 32일사이이므로증상재발을방지하기위해유지요법을시행하는경우 1 g/kg 의용량을 1개월에한번, 혹은 500 mg/kg 씩매 2주마다한번정주하는방법을권고하고있다. 8 비록모든환자들에게효과적인것은아니지만 IVIG 는다수의 classic CIDP 환자들을대상으로시행된무작위배정이중맹검임상시험들에서그치료효과가입증된바있다 또한 IVIG 는 MMN 에서도무작위배정이중맹검임상시험들에서그뛰어난치료효과가입증되어일차선택약제로인정받고있다 반면 MGUS neuropathy 에서시행된 IVIG 의무작위배정이중맹검임상시험에서는 20% 정도의환자에서만치료효과를보였다. 16 IVIG 치료시에발생하는부작용의대부분은주입 (infusion) 66 대한신경과학회지제 29 권부록 2, 2011

90 만성염증탈수초성다발척수근말초신경병증의치료 과관련되어발생하며오한, 오심, 근육통, 두통등이다. 이런증상들은대부분저절로좋아지지만지속되는경우소염제혹은경정맥 hydrocortisone 등을투여하면증상을경감하거나없앨수있다. 비록드물긴하지만 IVIG 는다음과같은심각한부작용을수반할수있으므로주의하여야한다. 1) 아나필락시스 (anaphylaxis) IVIG 에대한아나필락시스는 common variable immune deficiency 및 selective IgA deficiency 환자에게서만보고되었다. 17 Selective IgA deficiency 는 1,000명중 1명에게서만발견되며, 설령 IgA 결손이있더라도대개아나필락시스가발생하지않으며, IgA 에대한항체가양성인환자에게 IVIG 를투여하여도아나필락시스가없었다는보고등이있어 IVIG 투여전에 IgA 의정량검사를반드시할필요는없다. 17,18 과부하에의해발생하는특징적인병변이다. 23 따라서 IVIG 사용으로인한신기능장애의발병을최소화하기위해서는치료전후에신기능평가를반드시하여야하며, 투여속도를너무빨리하지않는것이좋으며, 혈량저하증 (hypovolemia) 이있다면교정하여야하고, 신독성이있는약물과병용하여사용하지않는것이좋으며, sucrose 가포함되어있지않은 IVIG 제형을사용하는것이좋다. 22 6) 피부발진피부발진은약 6% 의환자들에게발생하는데국소적으로발생하거나같은부위에반복적으로발생한다면항히스타민제나국소적으로코르티코스테로이드를도포함으로써쉽게해결할수있지만전신에발진이발생하거나정도가심하면경구혹은경정맥코르티코스테로이드를사용하여야한다. 18 2) 혈전증 (thrombosis) 그발병기전은불분명하지만 IVIG 치료후에 0-3% 의환자에서뇌졸중, 심근경색, 중심정맥폐색증, 심부정맥혈전증, 폐색전증등심각한혈전증이발생할수있다. 8 3) 가역성혈관경련수축 (reversible vasospasm) 3명의길랑-바레증후군환자들에서 IVIG 치료를받는중, 혹은수일후에가역성뇌증 (reversible encephalopathy) 가발병한보고가있다. 모든환자들에서시력장애와의식혼돈이발생하였으며 MRI 에서후두엽백질에서고신호강도의병변이관찰되었다. 이중한명에서 TCD 검사에서혈관수축경련이관찰되었으며 IVIG 를중단한후모두회복되었다 ) 두통두통은 IVIG 치료후에비교적흔하게발생하는것으로알려져있는데, 대개소염제를투여하거나투입속도를줄임으로써호전된다. 예방적으로스테로이드를경정맥투여하여두통발생을막을수도있다. 18 무균성뇌막염이발병하여심한두통을유발하기도하는데편두통의병력이있는경우빈발하며 2-5 일정도지속된다. 3 5) 신장기능장애 IVIG 의부작용으로신부전증이발생하기도한다. 신부전이발생하는환자의대부분은이전부터경한신기능장애를가지고있으며 sucrose 가첨가된제형을사용한후발병한다. 22 신장생검에서는근위요세관 (proximal tubule) 상피세포에부종과공포화 (vacuolization) 가관찰되는데이는 sucrose 같은용질의 7) 울혈성심부전울혈성심부전은대부분심장질환을가지고있는환자에게 IVIG 를투여할때용적과부하 (volume overload) 가초래됨으로써발병하며, 특히투여속도가빠를때흔히발생하므로주의하여야한다. 18 8) 혈액학적이상일시적인백혈구감소증 (leucopenia) 이흔히발생하며드물게중성구감소증 (neutropenia) 도발생하지만모두자연적으로회복된다. 18 9) 감염체의전파 IVIG 사용으로인한 HIV 감염사례는아직보고된바없다. 하지만과거용제및세제를사용하지않고제조된 IVIG 제형에의해 C형바이러스에감염된사례가있었으며 24 parvovirus 감염증례가 1예보고된적이있다 혈장분리교환술 (plasma exchange) 혈장분리교환술은혈중항체 (circulating antibodies), 면역복합체 (immune complex), 시토카인및기타면역매개체들을제거함으로써치료효과를나타내는것으로알려져있다. 26 1회의혈장분리교환술로전체혈장용적에해당되는용적을교환하면전체 IgG 의 60%, IgM 의 45% 가제거된다. 27 대개혈장분리교환술은 2주간에걸쳐 4-6 회를시행하게되는데이렇게하면 IgG의 70-90% 가제거된다. 28,29 혈장분리교환술은 CIDP 환자들을대상으로시행된 2건의무 J Korean Neurol Assoc Volume 29 Suppl. 2,

91 김대성 작위배정이중맹검임상시험에서그치료효과가입증된바있는데, 단독으로사용하면다른치료법을병행하는것보다재발율이높다는단점이있다. 30,31 혈장분리교환술은 anti-mag neuropathy 환자에서도 40-50% 의반응율을보이지만 32,33 MMN 에는대개치료효과가없으며오히려증상을악화시킬수있다. 34,35 부작용과합병증은시술의 3-17% 에서발생하는데카테터감염, 기흉, 혈관천공, 저혈압, 전해질불균형, 출혈, 혈전증, 저칼슘혈증등을들수있다 화학요법 (Chemotherapy) 1) Cyclosporin Cyclosporin, tacrolimus 등은인산분해효소인 calcineurin 의억제제로서활성화된 T 임파구의 nuclear factor 가핵으로이동되는과정을방해함으로써인터류킨-2 와다른시토카인의유전자가발현되는것을억제하는작용기전을가진다. 1 Cycyclosporin, tacrolimus 등은일부 CIDP, MMN 환자들에서치료효과를보이기도하지만간이식후에 tacrolimus 를사용하던중에 CIDP 가발병하였던증례도보고된바있다. 36 Cyclosporin 은간에서시토크롬 P450 을거쳐대사되므로다른약물과의상호작용이흔하고이로인해진전, 고혈압, 신기증장애등의독성증상을유발할수있으며, 피부및임파선암을유발할수있으므로주의하여야한다. 1,37 2) Cyclophosphomide Cyclophosphomide 는알킬화약물 (alkylating agent) 로서증식이빠른세포인임파구를억제하는작용기전을가지고있으며, CIDP 와같은자가면역병에사용하는경우경구로는대개매일 2 mg/kg, 경정맥투여로는매달 1-3 g/m 2 의용량이사용된다. CIDP, MMN, anti-mag neuropathy 등에서도효과가있음이보고된적이있다. 3 하루 400 mg/kg 의고용량 cyclophosphamide 를 4일간사용하는충격요법 (cyclophosphamid pulse therapy) 을다른약물에잘반응하지않는난치성 CIDP 및 MMN 환자들에게사용하여장기간의완해 (long-term remission) 가이루어졌다는보고가있다 Cyclophosphamide 충격요법을시행하면대략 5일후부터중성구감소증 (neutropenia) 이발생하여 1-2 주간지속되다가회복되는데, 이때말초혈액의 T 및 B 임파구가거의모두소실되었다가회복됨으로써강력한면역억제작용을발휘하게된다. 3 Cyclophosphamide 의주요부작용으로는골수억제, 출혈성 방광염, 탈모, 구토, 불임, 기형유발등이있으며혈액및방광암의발병이증가된다. 1 특히 Cyclophosphamide 의투여총량이 80 g을초과 ( 경구투여시특히 ) 하면암의발병율이증가되므로주의가필요하다. 41 3) Azathioprine Azathioprine 은 purine 계대사억제제로서 CIDP 환자들에서의치료효과가보고된바있다. 42 주요부작용은백혈구감소증, 혈소판증가증, 감염위험증가, 탈모, 간독성, 암발병율증가등이다. 1 4) Fludarabine Fludarabine 은 DNA 및 RNA 내로삽입되어 DNA polymerase, DNA primase, ligase 등의기능을억제하는대사억제제의일종으로서 anti-mac neuropathy 환자의치료에효과를보인바있다. 43,44 5) Mycophenolate mofetill Mycophenolate mofetill 은 inosine monophosphate dehydrogenase 의가역적억제제로서임파구의증식과이동, 부착분자 (adhesion molecule) 의합성등을억제하는기전을가지고있다. 45 Mycophenolate mofetill은일부난치성 CIDP 및 anti-mac neuropathy 환자의일부에서증상개선효과가있다. 46,47 주요부작용으로는오심, 설사, 혈구감소증, 감염감수성증가등이며임파선암의발병율이증가된다 인터페론 (Interferon) 인터페론은 T 세포의증식억제, 항염증작용을가지는 Th2 시토카인의증가, 억제 T 세포기능의항진, MHC II 분자및케모카인 (chemokine) 과그수용체의발현감소등의다양한기전에의해면역억제작용을발휘한다. 1 알파및베타인터페론은 CIDP 환자들을대상으로한소규모의임상연구에서치료효과가있음이시사된바있지만대규모의무작위이중맹검위약대조임상시험에서는특별한이점이없는것으로연구된바있다. 3,48 6. 선택적면역요법 (Selective immunotherapy) 1) Etanercept Etanercept 는인간 IgG1 의 Fc 조각 (Fc fragment) 에재조합 TNF 수용체 (recombinant TNF receptor) 를접합시켜만든것 68 대한신경과학회지제 29 권부록 2, 2011

92 만성염증탈수초성다발척수근말초신경병증의치료 으로서전구염증성시토카인 (proinflammatory cytokine) 인 TNF-α과반응하여그기능을억제한다. 49 대개 25 mg씩 1주일에 2회피하주사하며 CIDP 환자들에게치료효과가있다고보고된바있다. 49 주요부작용으로는주사부위반응과감염감수성증가등이있다. 1 또한울혈성심부전환자에서사망률을증가시키며중추신경계의탈수초성병변을유발할수있으므로주의하여야한다. 50,51 2) Rituximab Rituximab 은 IgG1-κ 동형 (isotype) 의인간- 마우스키메라단클론성항체 (chimeric monoclonal antibody) 로서 B 세포계통에만존재하는 CD20 에작용하여보체매개세포독성 (complement-mediated cytotoxicity) 과항체의존성세포매개세포독성 (antibody-dependant cell-mediated cytotoxicity) 을모두유도한다. 52 일반적인치료용법은 375 mg/m 2 을주 4회경정맥투여하며, anti-mag neuropathy 및 MMN 에서효과가있음이보고되었다. 53,54 Rituximab 의치료효과는 2-8 개월후부터나타나며, 1년이경과하면 50% 정도의환자에서다시증상이재발하므로재치료가필요하다. 54 Rituximab 의부작용으로는피부발진, 발열, 오한, 혈압저하, 호흡곤란등을들수있으며, 55 진행다초점백질뇌증 (progressive multifocal leukoencephalopathy) 이발생할수있다. 56 3) Alentuzumab Alentusumab 은 IgG1-κ 동형 (isotype) 의재조합인간화단클론성항체 (recombinant humanized monoclonal antibody) 로서대부분의 B 및 T 임파구, 대식세포, 단핵구등의표면에위치한 CD52 항원이표적이다. 즉, alentuzumab 은 CD52 항원에부착하여이들세포의파괴를유도함으로써작용한다. 3 Alentuzumab 30 mg 을 5일간정주한후 18개월간완해가된 CIDP 환자가보고된바있다. 57 부작용은주로발열, 오한, 혈압강하, 피부발진등이지만진행다초점백질뇌증, 자가면역성감상선염, 특발성혈소판감소성자반병 (idiopathic thrombocytopenic purpura) 등이발생할수있다. 58,59 CIDP 각아형에서의치료방법의선택 CIDP 각아형에서사용할수있는치료법과그효과는표에간략하게정리하였다. 1. Classical CIDP Classical CIDP 에서는현재부신피질호르몬, IVIG, 혈장분리교환술의 3가지치료가 1차선택치료법으로사용되고있다. 치료에대한반응율은세가지방법이거의비슷하지만특정방법에반응하지않지만다른방법에반응을보일수있다. 따라서일차치료는이세가지방법중환자의순응도, 사회경제학적측면, 부작용의정도등을감안하여한가지방법을선택하여시행한후치료효과가부족하거나부작용등으로인해지속적인사용이곤란하다면제2, 제3의방법을차례로시도해보는것이좋겠다. Classical CIDP 환자의 2/3 정도는상술한세가지방법중적어도한가지방법에의해효과적으로치료할수있다. 60 또한현재 CIDP 의범주에속하는아형이라고간주되고있는 Lewis-Sumner 증후군 (multifocal acquired demyelinating sensory and motor neuropathy, MADSAM neuropathy), idiopathic distal acquired demyelinating symmetrical neuropathy (DADS-I neuropathy), sensory CIDP, 그리고 IgG 혹은 IgA 단클론성항체가동반된 CIDP 등도 classic CIDP 와치료에대한반응이대동소이한것으로알려져있으므로같은방법으로치료하도록권고되고있다. 3,61,62 일부 CIDP 환자들은가벼운이상감각만을가지고있거나무증상인경우가있는데이런경우에는별다른치료를하지않아도무방하다. 또한일부환자들은별다른치료없이도증상이저절로호전되어별다른치료를하지않아도일상생활에불편을느끼지않고생활하기도한다. 하지만대부분의환자들은치료를하지않으면증상이지속되거나악화되어정상적인생활을하기힘들게되므로지속적인치료가필요하다. 3 치료는그효과가최대로발휘될때까지지속되어야하며, 일단치료효과가완전히나타나기시작하면부신피질호르몬의용량이나 IVIG 및혈장분리교환술의빈도와횟수를조금씩조정하여최소의치료로최대의효과를유지할수있도록조정하는것이좋다. 63 일부환자들에서는치료효과가즉시, 혹은수주이내에빨리나타나기도하지만여러가지이유로치료효과가더디게나타나는경우도흔하다. 따라서부신피질호르몬과 IVIG 는 3개월, 그리고혈장분리교환술은 2개월이상치료를지속하여도반응이없는경우에만특정치료법에반응이없는것으로간주하여야한다. 38,64 하지만재발이반복되어증상이오래지속되게되면이차적인축색손상이진행되면서불가역적인변화가발생하게되므로질병이재발하여기능장애가초래되기를기다려치료를하는것보다는증상재발을방지할수있도록꾸준히치료를지속하는것이권고된다. 65 J Korean Neurol Assoc Volume 29 Suppl. 2,

93 김대성 Table. Therapeutic agents and their effects in the treatment of chronic acquired demyelinating polyneuropathies Therapy Classical CIDP MMN Anti-MAG neuropathy Corticosteroids IVIG Plasmapheresis Chemotherapy Cyclosporin Cyclophosphamide + +? Azathioprine ++? + Fludarabine?? + Mycofenolate mofetill ++?? Interferons + +? Selective immunotherapy Etanercept +?? Rituximab Alentuzumab +?? CIDP; chronic inflammatory demyelinatinf polyradiculoneuropathy, MMN; multifocal motor neuropathy, Anti-MAG neuropathy; neuropathy associated with anti-myelin associated glycoprotein antibodies, IVIG; intravenous immune globulin, +++; first line therapy, ++; second line therapy, +; add on therapy, -; no effect,?; not tested. 2. MMN IVIG 가 MMN 의일차선택치료이다. 부신피질호르몬이나혈장분리교환술은효과가없으며심지어는증상악화를가져올수있으므로시도하지않는편이좋다. 66 IVIG 치료에반응이좋지않은경우다양한화학요법을고려하여야한다 Anti-MAG neuropathy Anti-MAG neuropathy 의경우이중맹검무작위위약대조임상연구에서 rituximab 의뛰어난치료효과가증명된바있어일차선택약제로권고되고있으며, 53 일부환자에서는혈장분리교환술이나화학요법이효과가있다. Anti-MAG neuropathy 에서는 IgM 이치료전수치의 25% 까지떨어져야치료효과가나타난다고한다. 33 한편상당수의 anti-mag neuropathy 환자들은증상이그리심하지않고양호한경과를보이므로치료에의한부작용이치료효과를상회하는경우가있다. 32 References 1. Goodman & Gilman s pharmacological basis of therapeutics. New York: McGraw-Hill; Dyck PJ, O Brien PC, Oviatt KF, Dinapoli RP, Daube JR, Bartleson JD, et al. Prednisone improves chronic inflammatory demyelinating polyradiculoneuropathy more than no treatment. Ann Neurol 1982;11: Brannagan TH 3rd. Current treatments of chronic immune-mediated demyelinating polyneuropathies. Muscle Nerve 2009;39: McCombe PA, Pollard JD, McLeod JG. Chronic inflammatory demyelinating polyradiculoneuropathy. A clinical and electrophysiological study of 92 cases. Brain 1987;110: Molenaar DS, van Doorn PA, Vermeulen M. Pulsed high dose dexamethasone treatment in chronic inflammatory demyelinating polyneuropathy: a pilot study. J Neurol Neurosurg Psychiatry 1997;62: Lopate G, Pestronk A, Al Lozi M. Treatment of chronic inflammatory demyelinating polyneuropathy with high-dose intermittent intravenous methylprednisolone. Arch Neurol 2005;62: American College of Rheumatology Ad Hoc Committee on Glucocorticoid- Induced Osteoporosis. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. Arthritis Rheum 2001;44: Brannagan TH 3rd. Intravenous gammaglobulin (IVIg) for treatment of CIDP and related immune-mediated neuropathies. Neurology 2002; 59(suppl):S33-S Blasczyk R, Westhoff U, Grosse-Wilde H. Soluble CD4, CD8, and HLA molecules in commercial immunoglobulin preparations. Lancet 1993;341: Hahn AF, Bolton CF, Zochodne D, Feasby TE. Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. 70 대한신경과학회지제 29 권부록 2, 2011

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Effect of longterm immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporine regimens. Lancet 1998;351: Brannagan TH 3rd, Pradhan A, Heiman-Patterson T, Winkelman AC, Styler MJ, Topolsky DL, et al. High dose cyclophosphamide without stem-cell rescue for refractory CIDP. Neurology 2002;58: Gladstone DE, Prestrud AA, Brannagan TH 3rd. High-dose cyclophosphamide results in long-term disease remission with restoration of a normal quality of life in patients with severe refractory chronic inflammatory demyelinating polyneuropathy. J Peripher Nerv Syst 2005;10: Brannagan TH 3rd, Alaedini A, Gladstone DE. High-dose cyclophosphamide without stem cell rescue for refractory multifocal motor neuropathy. Muscle Nerve 2006;34: Radis CD, Kahl LE, Baker GL, Wasko MC, Cash JM, Gallatin A, et al. Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid-arthritis. A 20-year follow-up-study. 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95 김대성 Psychiatry 1999;66: Chaudhry V, Cornblath DR, Griffin JW, O'Brien R, Drachman DB. Mycophenolate mofetil: a safe and promising immunosuppressant in neuromuscular diseases. Neurology 2001;56: Umapathi T, Hughes R. Mycophenolate in treatment-resistant inflammatory neuropathies. Eur J Neurol 2002;9: Gorson KC, Amato AA, Ropper AH. Efficacy of mycophenolate mofetil in patients with chronic immune demyelinating polyneuropathy. Neurology 2004;63: Gorson K, Hughes R, Cros D. Efficacy of interferon beta-1a in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Neurology 2008;70:A Chin RL, Sherman WH, Sander HW Hays AP, Latov N. Etanercept (Enbrel) therapy for chronic inflammatory demyelinating polyneuropathy. J Neurol Sci 2003;210: Coletta AP, Clark AL, Banarjee P, Cleland JG. Clinical trials update: RENEWAL (RENAISSANCE and RECOVER) and ATTACH. Eur J Heart Fail 2002;4: Khanna D, McMahon M, Furst DE. Safety of tumour necrosis factor-alpha antagonists. Drug Safety 2004;27: Maloney DG, Smith B, Rose A. Rituximab: mechanism of action and resistance. Semin Oncol 2002;29: Dalakas MC, Rakocevic G, Salajegheh M, Dambrosia JM, Hahn AF, Raju R, et al. Placebo-controlled trial of rituximab in IgM anti-myelinassociated glycoprotein antibody demyelinating neuropathy. Ann Neurol 2009;65: Pestronk A, Florence J, Miller T, Choksi R, Al-Lozi MT, Levine TD. Treatment of IgM antibody associated polyneuropathies using rituximab. J Neurol Neurosurg Psychiatry 2003;74: Grillo-López AJ, Hedrick E, Rashford M, Benyunes M. Rituximab: ongoing and future clinical development. Semin Oncol 2002;29: Molloy ES, Cabrese LH. Progressive multifocal leukoencephalopathy in patients with rheumatic diseases: are patients with systemic lupus erythematosus at particular risk? Autoimmun Rev 2008;8: Hirst C, Raasch S, Llewelyn G, Robertson N. Remission of chronic inflammatory demyelinating polyneuropathy after alemtuzumab (Campath 1H). J Neurol Neurosurg Psychiatry 2006;77: Coles AJ, Wing MG, Molyneux P, Paolillo A, Davie CM, Hale G, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 1999;46: Martin SI, Marty FM, Fiumara K, Treon SP, Gribben JG, Baden LR. Infectious complications associated with alemtuzumab use for lymphoproliferative disorders. Clin Infect Dis 2006;43: Gorson KC, Allam G, Ropper AH. Chronic inflammatory demyelinating polyneuropathy: clinical features and response to treatment in 67 consecutive patients with and without a monoclonal gammopathy. Neurology 1997;48: Di Troia A, Carpo M, Meucci N, Pellegrino C, Allaria S, Gemignani F, et al. Clinical features and anti-neural reactivity in neuropathy associated with IgG monoclonal gammopathy of undetermined significance. J Neurol Sci 1999;164: Magy L, Chassande B, Maisonobe T, Bouche P, Vallat JM, Léger JM. Polyneuropathy associated with IgG/IgA monoclonal gammopathy: a clinical and electrophysiological study of 15 cases. Eur J Neurol 2003;10: Barohn RJ, Kissel JT, Warmolts JR, Mendell JR. Chronic inflammatory demyelinating polyradiculoneuropathy. Clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol 1989;46: Reid VA, Black KR, Menkes DL. Chronic inflammatory demyelinating polyradiculoneuropathy: diagnosis and management. In: Cros D, editor. Peripheral neuropathy-a practical approach to diagnosis and management. Philadelphia: Lippincott, Williams & Wilkins; 2001; Nagamatsu M, Terao S, Misu K, Li M, Hattori N, Ichimura M, et al. Axonal and perikaryal involvement in chronic inflammatory demyelinating polyneuropathy. J Neurolog Neurosurg Psychiatry 1999;66: Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of multifocal motor neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society-first revision. J Peripher Nerv Syst 2010; 15: 대한신경과학회지제 29 권부록 2, 2011

96 특수상황에서의간질환자치료 : 고찰및증례노인간질의특성 강원대학교의학전문대학원신경과학교실이서영 Characteristics of Epilepsy in the Elderly Seo-Young Lee, MD, PhD Department of Neurology, Kangwon National University College of Medicine, Chuncheon, Korea The incidence of epilepsy increases with age after the age of 50. Epilepsy in the elderly has unique features. Complex partial seizures presenting with episodic confusion and memory loss are predominant in elderly population. Aura and automatism are less common. Postictal confusion is more prolonged, lasting for hours to weeks. These atypical features and the frequent occurrence of other neurologic symptoms in the elderly make the differentiating seizures from other diseases, such as transient ischemic attack, transient global amnesia, dementia, metabolic encephalopathy, syncope and simple falls, difficult. Seizure manifestations change with age in preexisting epilepsy. In partial epilepsy, seizures become briefer and secondary generalized tonic-clonic seizures decrease as patients aged. Absence seizure tends to remit with puberty, although it can persist into old age. Re-emergence of seizures in old age in patients with idiopathic generalized epilepsy that seemed to have remitted for many years can occur. Elderly onset epilepsy is predominantly partial and symptomatic, although etiology is unfound in almost half of elderly onset epilepsy. Generalized epilepsy rarely starts in old age. Stroke accounts for one third of elderly onset epilepsy. Moreover, some of cryptogenic elderly onset epilepsies probably can be explained by silent stroke. Conversely, the risk of subsequent stroke increases in those who had elderly onset epilepsy. Neurodegenerative diseases account for 10-20% of elderly onset epilepsy. Seizures more likely to occur in advanced stage, but can occur at any stage. Acute symptomatic seizures are also more frequent in elderly persons, because of acute stroke, traumatic injury, and metabolic disturbances. Acute symptomatic seizures usually do not lead to epilepsy, although they raise the risk of development of epilepsy. Seizures tend to be infrequent and well controlled by monotherapy in elderly onset epilepsy. Seo-Young Lee, MD, PhD Department of Neurology, Kangwon National University Hospital, Hyoja-dong, Chuncheon , Korea Tel: Fax: leeseoyoung@kangwon.ac.kr J Korean Neurol Assoc Volume 29 Suppl. 2,

97 특수상황에서의간질환자치료 : 고찰및증례노인뇌전증환자에서의항경련제선택 고려대학교의과대학신경과학교실김지현 Antiepileptic Drug Selection in Elderly Patients Ji Hyun Kim, MD, PhD Department of Neurology, Korea University College of Medicine, Seoul, Korea The elderly are the most rapidly growing segment of the population, and the incidence of new-onset epilepsy is higher among the elderly than in any other age group. New-onset seizures in elderly patients are typically symptomatic or cryptogenic partial seizures that require long-term medical treatment. Because these seizures in the elderly patients are often readily controlled, considerations of safety, adverse events, tolerability, and pharmacokinetics of the antiepileptic drug (AED) as well as the potential for drug interactions may be as important as efficacy in the selection of an AED. Among the older AEDs, phenytoin is the most widely used AED in the treatment of partials seizures, but its higher protein-binding capacity and hepatic enzyme induction, as well as nonlinear pharmacokinetics, are of particular disadvantages for the elderly patients. Because of their potential effects on cognitive functions, sedating AEDs such as phenobarbital and primidone are not generally recommended in the treatment of new-onset seizures in elderly patients. Carbamazepine also is an enzyme-inducing agent with significant potential for serious adverse events and drug interactions. The newer AEDs introduced during the past two decades offer many advantages over older AEDs in regards to safety, tolerability, and drug interactions. Among the newer AEDs, gabapentin and levetiracetam have good safety and cognitive effect profiles and do not interact with other drugs, and lamotrigine offers many of the same benefits. Oxcarbazepine has better tolerability than carbamazepine, and topiramate and zonisamide, although they have more cognitive side effects than the other new AEDs, can be considered for some elderly patients. Recent data from the prospective clinical trials and converging opinions of the expert epileptologists are likely to provide support for the use of selected newer AEDs as the first-line agents for the treatment of epilepsy in elderly patients. Key Words: Elderly epilepsy, Older antiepileptic drug, Newer antiepileptic drug, Safety and tolerability, Pharmacokinetics and drug interaction Introduction 근래에사회가노령화됨에따라노년층에서발생하는뇌전증환자수도급증하는추세로뇌전증은뇌졸중과치매다음으로노년층에서흔하게발생하는뇌질환이다. 최근의역학연구에의하면인구 10만명당연발생빈도는 세에서는 87 명, 70 대에는 147 명, 80대에는 159 명으로고령인구로갈수록뇌전증의발생률이높아지는것을알수있다. 65세이상의노령인구에서의뇌전증의유병율은약 1% 정도이고 75세이상에서는유 Ji Hyun Kim, MD, PhD Department of Neurology, Korea University Medical Center, 80 Guro-dong, Guro-gu, Seoul , Korea Tel: Fax: jhkim.merrf@gmail.com 병률이약 1.5% 로소아또는젊은성인층에서의유병율의 2배정도로추산된다. 1-3 노인에서발작이반복적으로발생하는경우발작후혼돈도소아에비해길게지속되며발작으로인한심각한두부외상과골절등의치명적인위험을초래할수있어조기에정확한진단과항경련제치료가매우중요하다. 노인에서발생하는뇌전증의가장흔한원인은뇌경색과뇌출혈이고그다음으로뇌종양, 두부외상, 간질환, 신장질환과같은대사성질환, 중추신경계감염, 알코올또는약물유발성, 치매와파킨슨병과같은뇌퇴행성질환등이있다. 그러므로노인뇌전증환자의치료시이러한기저질환의유무를반드시파악하여항경련제선택시유의하여야한다. 또한노인은소아나젊고건강한성인과달리간기능과신장기능이저하되어있기때문에항경련제선택시반드시고려하여야하며약역학 (pharmacodynamics) 과약동학 74 대한신경과학회지제 29 권부록 2, 2011

98 노인뇌전증환자에서의항경련제선택 (pharmacokinetics) 의변화도약물선택시유의하여야한다. 또한위에서열거한기저질환또는동반된질환에서사용되는다른약물과의관계도고려되어야하며특히노령층에서의인지기능에대한영향도고려하여약물을선택해야한다. 다음에서노인에서발생하는약역학과약동학의변화와각항경련제선택시고려해야하는사항들에대하여알아본다. Special considerations in the elderly patients 1. Pharmacokinetic changes 노인뇌전증환자에서항경련제의종류와용량을결정할때나이에따른생리학적인변화의위험성이높을수있음을숙지하여야한다. 그러나약물에대한이러한생리적변화가모든노인환자들에서일괄적으로예측이가능하지는않고개인별로다를수있으므로약물선택시더욱주의를요한다. 4 나이에따른변화는대략연령이높아질수록많아지는경향을보이며동반된내과적질환들이존재할때더욱변화를예측하기어렵다. 약역학의변화에영향을미칠수있는다른원인들로는개인의건강상태, 약물의순응도, 식습관, 그리고복용하는다른약물등이있다. 5 1) Absorption 항경련제의흡수는약물의용해능과비례하고흡수되는정도는대부분위산분비에의해결정되는데이위산분비는노인에서저하될수있다. 또한위배출시간 (gastric emptying time) 의증가, intestinal transit time 의증가, 장간막의혈류감소, 약물을흡수하는장벽의표면적감소등노인에서발생할수있는변화는약물의흡수정도를예측하기어렵게한다. 전체적으로상기변화들로인해노인에서는약물의흡수능이저하되고이로인해약물의생체이용률 (bioavailability) 이감소하게된다. 더구나노인들이자주복용하는제산제도항경련제, 특히 phenytoin 의흡수를저해하며주로소장에서흡수되는 gabapentin 의경우소장의생리적인변화에매우민감하게반응한다. 6 2) Protein binding 노인환자들은급성전신질환이발생하는위험이다른연령층에비해상대적으로높은데이경우혈청내알부민농도가급격히감소하며영양상태가불량할경우도역시알부민농도의저하를유발한다. 이렇게저하된알부민농도로인해단백결합을많이하는항경련제의단백결합을하지않는유리분획 (free fraction) 이 증가하게된다. 이경우혈액내총약물농도는변화가없어도증가된약물의유리분획으로부작용의발생빈도와정도가높아지게되고심할경우적은용량에서도위험한독성을유발할수도있다. 그러므로알부민감소가예상되는간질환, 신장질환의경우이들약물의총농도와유리분획을반드시측정하여약물의용량을결정하여야한다. 단백결합이많은항경련제에는 phenytoin, valproate, carbamazepine, diazepam, clonazepam, clobazam 등이있다. 3) Hepatic clearance 간용적과간혈류는나이에따라감소하여 65세이상의경우간의용적이젊은사람에비해 25% 정도적다. 대부분의약물은간의 cytochrome P450 system 으로대사가되는데나이가증가하면서이시스템의기능도저하되게되어약물의간청소율은감소하는경향을보이나때로는예측불가능하게감소할수도있다. 주로 Cytochrome P450 system으로대사되는항경련제에는 carbamazepine, ethosuximide, oxcarbazepine, phenytoin, phenobarbital, primidone, zonisamide 등이있으며 topiramate, valproate 등도부분적으로이경로로통해대사된다. Glucuronidation conjugation 기능도나이에따로감소하는데이경로를통해대사되는약물에는 lamotrigine 과 valproate가있다. 4 그러므로노인환자에서는젊은성인보다항경련제의용량을적게처방하고천천히증량하는것이일반적으로권장되며같은용량이라도부작용발생의빈도가높다는점을염두에두어야한다. Table 1. Average changes in apparent oral clearance of older and newer AEDs in elderly patients 4 Antiepileptic drug Effect of old age on drug clearance Carbamazepine Decrease by 25-40% Felbamate Decrease by 10-20% Gabapentin Decrease by about 30-50% Lamotrigine Decrease by about 35% Levetiracetam Decrease by about 20-40% Oxcarbazepine Decrease by 25-35% Phenobarbital Decrease by about 20% Phenytoin Decrease by about 25% Tiagabine Decrease by about 30% Topiramate Decrease by 20% Valproic acid Decrease by about 40% Vigabatrin Decrease by 50-85% Zonisamide No data available J Korean Neurol Assoc Volume 29 Suppl. 2,

99 김지현 4) Renal clearance 나이가증가함에따라비교적일관되게발생하는변화는신기능의감소이다. 신용적의감소, 사구체소실, 혈청크레아티닌감소등의변화는사구체여과율을감소시키고이로인해약물이나독성물질의신장을통한청소율이저하된다. 신장을통해주로배설되는항경련제에는 gabapentin, levetiracetam, vigabatrin, pregabalin 등이있고 felbamate, topiramate, zonisamide 등도부분적으로신장을통해배설된다. 각항경련제의노인환자들에서의청소율의변화는표1 에정리되어있다 Pharmacodynamic changes 노인에서는약동학의변화외에도세포단위에서이루어지는약역학의변화를분명하게보인다. 그러므로젊은환자에서는부작용이나타나지않을정도의적은용량에서도의식의혼돈, 감정변화, 행동장애, 인지기능장애등예기치못한중추신경계부작용이잘나타나고반대로젊은성인환자들보다적은용량에서발작이잘조절될수도있다. 또한약물의효과와독성을예측하게해주는적정약물농도 (therapeutic window) 의범위가노인에서는소아나젊은성인보다좁아지게된다 (Fig. 1). 7 그리고현재사용되는각항경련제의적정약물농도범위는대부분건강한젊은성인을대상으로정립된것이기때문에위에서설명한노인에서의변화들에맞추어생각하면이범위가전반적으로하향조정되어노인뇌전증환자들에게적용되어야한다. 3. System side-effects and compliance Phenytoin, carbamazepine, lamotrigine 과같은 membranestabilizing 약물은특히노인에서부정맥과저혈압을유발할 Figure 1. Effect of age on therapeutic ranges. The elderly typically have a narrower therapeutic window, the range between the lowest effective concentration and the maximal tolerated concentration. 7 수있으므로주의해야한다. Phenytoin, carbamazepine, phenobarbital, valproate 등은골밀도를감소시켜골절을유발할수있는데이정도는특히노인에서위험성이증가하므로역시주의를요한다. Phenytoin, carbamazepine 은특히당뇨병이동반된노인환자들에서심각한자율신경이상을유발할수있고, carbamazepine 은항콜린효과가있어요정체 (urinary retention) 을일으킬수있다. 노인환자들에서발생할수있는기억력저하, 경미한의식의혼돈등으로약물복용의순응도가떨어질수있으므로약물복용에대한철저한지도가요구된다. 순응도를높이기위해서는되도록한가지의항경련제를복용하기간편한복용요법으로처방해야하고이를문서화하여환자들이쉽게알아볼수있도록하며가능하면보호자와간호사가상시전화를하여약물의복용여부를확인하는것이좋다. Antiepileptic drug choice 1. General principles 노인뇌전증환자에게처방되는항경련제의이상적인조건은다음과같다 (Table 2). 7 그러나이조건들을모두만족시키는항경련제는없으므로환자맞춤형으로선택을해야한다. 현재상용화되어있는모든항경련제들은부분발작의치료에있어서비슷한효과를보인다. 그러므로약동학과약역학의변화, 동반된질환여부, 복용중인약물과의관계등을정확히파악하여부작용과순응도를우선고려하여처방하여야한다. 일반적으로약물치료를시작하기전에간기능과신기능에대한평가가반드시시행되어야 Table 2. Desirable features of an AED for use in the elderly 7 No interactions with other medications No interactions with other AEDs Can be introduced at therapeutic doses No metabolism No protein binding Once- or twice-daily dosing Laboratory monitoring not necessary Excellent safety record Good side-effect profile High therapeutic index Little effect on cognitive function Psychoactive benefits 76 대한신경과학회지제 29 권부록 2, 2011

100 노인뇌전증환자에서의항경련제선택 하고젊은성인환자들보다적은용량으로시작해야하며증량하는기간도길게갖는것이부작용을줄일수있는방법이다. 또한가능하면 2가지이상의복합요법보다는단일요법이권장되며순응도를높이기위해하루한번또는두번복용하는요법으로처방하는것이좋다. 2. Older antiepileptic drugs Phenytoin, phenobarbital, primidone, valproate, carbamazepine 등의고전적항경련제는모두부분발작의치료에비슷한효과를보이나 8,9 특히노인환자들에서여러심각한부작용을초래할수있어때로는이상적인선택이아닐수있다. Phenobarbital 과 primidone 은진정효과가강하고인지기능을심각하게저하시킬수있을뿐만아니라장기간복용시심한우울증의발생빈도가증가한다. 더구나강력한간효소유도체로작용하기때문에복용중인다른약물들의농도를저하시킬수있고골밀도감소의부작용까지있어노인환자에서일차선택약으로는적합하지않다. 9 Phenytoin 은부분발작의치료에가장많이사용되는약물이나노인환자에서는여러불리한점들이있다. 우선 phenytoin 은 nonlinear kinetics 의특성을가지고있는데노령층에서는이곡선의기울기가가파르게변하고약물의적정범위가좁아지게되어용량이조금만증가하여도독성이나타나기쉽다 (Fig.2). 7 또한간을통한약물의대사와청소율이저하되고여러조건에의해체내단백농도가감소하면약물의유리분획이증가하여결국부작용이나타나기쉽다. 강력한간효소유도체로서간에 서대사되는다른약물과의상호작용이많고예측하기어려운경우가많은데 amiodarone, cimitidine, isoniazid, trazodone 등의약물에의해 phenytoin 농도가증가할수있고 warfarin, estrogen, theophylline, carbamazepine, statin agents 등의약물은 phenytoin 과병용투여시그혈청농도가감소할수있다. 골다공증을유도할수있어 phenytoin 역시노인환자에서일차선택약으로권장되지않는다. 7 Valproate 는 90% 단백결합을하고간효소억제제로작용하기때문에다른약물들과의상호작용이나타날수있다. 고용량의 valproate 복용시활동떨림 (action tremor) 이발생할수있고드물게는고암모니아혈증뇌병증과파킨슨병증상이유발되기도하므로주의해야한다. 10,11 Valproate 는심각한인지기능장애, 정동장애, 중추신경계독성등의부작용이매우드물기때문에위에서열거한부작용만나타나지않는다면노인뇌전증환자의일차치료제로좋은선택이다. Carbamazepine은 phenytoin 에서의 nonlinear kinetics 와관련된문제들을야기하지는않으나역시간에서주로대사가되고간효소유도제로약물상호작용이많은편이다. Fluoxetine, diltiazem, cimetidine, isoniazid, erythromycin, verapamil 등의약물에의해 carbamazepine 의혈중농도가증가할수있으므로이들약물과병용투여시혈중농도에대한주기적인검사가요구된다. Carbamazepine 은항이뇨호르몬부적절분비증후군 (SIADH) 을유발하여저나트륨혈증이발생할수있는데특히노인층에서그위험성이증가하므로각별한주의를요한다. 12 Carbamazepine 은노인환자들에서비교적안전하고유지율이높은약이다. 3. Newer antiepileptic drugs Figure 2. Nonlinear kinetics of phenytoin. The transition to zeroorder nonlinear kinetics occurs at therapeutically relevant doses. In the elderly this transition is much steeper than in children or non-elderly adults. 7 Gabapentin, pregabalin, oxcarbazepine, topiramate, zonisamide, lamotrigine, levetiracetam 등의근래에개발된 2세대항경련제들은 1세대항경련제들에비해부작용과안전성면에서우수한특성을보인다. Lamotrigine 은심각한부작용의위험이상대적으로적고졸림을유발하지않으며인지기능의저하를유도하지않아노인환자들에게안전하게사용할수있는약이다. 간효소유도의작용이없으며단백결합의정도가낮아다른약물과의상호작용이적은장점이있다. 60세이후에새롭게진단된뇌전증환자들에서 lamotrigine 과 carbamazepine 을비교한전향적인연구가 2개시행되었는데, 발작예방효과는두약제군사이에차이가없었던반면 carbamazepine 군에비해 lamotrigine 군에서약물의중단을초래하는부작용의발현이적었고약물의 J Korean Neurol Assoc Volume 29 Suppl. 2,

101 김지현 유지율도높았다. 13,14 이연구들의결과에서 lamotrigine 이 carbamazepine 보다노인뇌전증환자들에서안전하게사용될수있는약임을알수있다. 또한 lamotrigine 은인정된기분안정제로양극성우울증의치료에흔히사용되므로 15 우을증이동반된노인환자들에게는좋은선택약이다. 16 그러나 lamotrigine 은심각한피부발진의부작용을줄이기위해서매우천천히증량시켜야하며 valproate 와병용사용시약물의농도와반감기가약 2-3 배증가하므로주의해야한다. 17 Gabapentin 과 pregabalin 도심각한부작용이적어비교적안전하게사용될수있는항경련제다. 두약물모두신장으로배설되고인지능력에는거의영향을미치지않는다. 또한간효소유도또는억제의기능이없으며단백결합도하지않아다른약물과의상호적용이적다. 그러나두약물모두반감기가 5-7 시간으로짧아하루에 3번투여해야하는불편함이있으며신기능이저하된환자들에서는반드시감량하여투여해야한다. Topiramate 와 zonisamide 도간효소유도의작용이없고단백결합의비율이낮아다른약물과의상호작용이적다. 그러나두약물은졸림을유발하기쉽고인지기능의저하를유발할수있어노인환자들에게조심스럽게사용해야하며부작용을줄이기위해천천히증량하고다소적은용량을투여해야한다. 또한주로신장으로배설되므로신기능이저하된노인들에서감량하여투여해야하며요로결석이발생할수있으므로이에대한주기적인검사가요구된다. 두약물은식욕을억제하여체중을감량시킬수있어식욕부진등으로저체중의노인환자들에는적절하지않으나반대로과체중으로인한수면무호흡증을가진환자들에게는좋은선택약일수있다. Carbamazepine 의 10-keto 유사체인 oxcarbazepine 은 carbamazepine 에비해백혈구감소증과재생불량성빈혈발생의부작용이적고약물상호작용이작아노인환자들에게상대적으로안전하게사용할수있다. 그러나 carbamazepine 과마찬가지로, 소아와젊은성인에서보다노인환자에서저나트륨혈증을잘유발할수있는데, 소아에서는 125 meq/l 이하의저나트륨혈증의발생확률은 0.1% 미만인데비해노인에서는 6-7% 정도로발생하기때문에사용시주의가요구된다. 또한나트륨을저하시키는이뇨제등의항고혈압약제나 selective serotonin reuptake inhibitor (SSRI) 를복용하는환자에서저나트륨혈증이자주발생하므로가급적 oxcarbazepine 의사용을피하는것이좋다. 18 노인환자에게는 900 mg/day 의용량이적정하며젊은성인보다천천히증량하면부작용을줄일수있다. Levetiracetam 은 SV2A 단백에결합하여항경련효과를나타내는약물로간에서대사되지않고신장으로배설되며단백결합을하지않아약물상호작용이없어여러약물을복용하 는노인환자들에사용하기적합하다. 19 또한혈중최고농도에이르는시간이 1-2 시간으로짧고초기용량부터항경련작용이빠르게나타날수있다는장점이있다. 인지기능에는부정적인영향이없으나졸림을유발할수있고적게는우울증, 조증, 과격한행동과같은기분장애, 행동장애를유도할수있기때문에이러한부작용의발생에주의를기울여야한다. 그러나아직 levetiracetam 복용으로인한행동, 기분장애가노인에서더흔하게발생한다는증거는없다. Conclusions 급증하는노인뇌전증환자들에서항경련제치료는불가피하다. 대부분의노인뇌전증은항경련제에대한반응이좋으므로발작예방효과와더불어안전성과부작용에대하여유의하여야한다. 노인들은소아나젊은성인에비해약동학적변화가잘일어나고부작용의발생빈도가높고다른약물과의상호작용이많이일어나므로항경련제선택시각약물의특성, 대사경로, 병용되는다른약물들과의관계를반드시고려하여야한다. 일반적으로고전적항경련제는부작용과약물상호작용이노인들에서증가하므로노인뇌전증환자에서는상대적으로이러한특성이적은새로운항경련제가선호되는추세이다. 그러나아직노인환자들에서새로운항경련제를사용한약물연구가충분히시행되지않았으므로이에대한추가적인연구를통한검증이요구된다. References 1. de la Court A, Breteler MM, Meinardi H, Hauser WA, Hofman A. Prevalence of epilepsy in the elderly: the Rotterdam Study. Epilepsia 1996;37: Olafsson E, Ludvigsson P, Gudmundsson G, Hesdorffer D, Kjartansson O, Hauser WA. Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome classification: a prospective study. Lancet Neurol 2005;4: Hauser WA, Annegers JF, Kurland LT. Prevalence of epilepsy in Rochester, Minnesota: Epilepsia 1991;32: Perucca E, Berlowitz D, Birnbaum A, et al. Pharmacological and clinical aspects of antiepileptic drug use in the elderly. Epilepsy Res 2006;68 Suppl 1:S Hammerlein A, Derendorf H, Lowenthal DT. Pharmacokinetic and pharmacodynamic changes in the elderly. Clinical implications. Clin Pharmacokinet 1998;35: Lackner TE, Cloyd JC, Thomas LW, Leppik IE. Antiepileptic drug use in nursing home residents: effect of age, gender, and comedication on patterns of use. Epilepsia 1998;39: Bergey GK. Initial treatment of epilepsy: special issues in treating the elderly. Neurology 2004;63:S 대한신경과학회지제 29 권부록 2, 2011

102 노인뇌전증환자에서의항경련제선택 8. Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. N Engl J Med 1992;327: Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313: Zaret BS, Beckner RR, Marini AM, Wagle W, Passarelli C. Sodium valproate-induced hyperammonemia without clinical hepatic dysfunction. Neurology 1982;32: Jamora D, Lim SH, Pan A, Tan L, Tan EK. Valproate-induced Parkinsonism in epilepsy patients. Mov Disord 2007;22: Van Amelsvoort T, Bakshi R, Devaux CB, Schwabe S. Hyponatremia associated with carbamazepine and oxcarbazepine therapy: a review. Epilepsia 1994;35: Brodie MJ, Overstall PW, Giorgi L. Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group. Epilepsy Res 1999;37: Rowan AJ, Ramsay RE, Collins JF, et al. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology 2005;64: Hahn CG, Gyulai L, Baldassano CF, Lenox RH. The current understanding of lamotrigine as a mood stabilizer. J Clin Psychiatry 2004; 65: Gilliam FG, Santos J, Vahle V, Carter J, Brown K, Hecimovic H. Depression in epilepsy: ignoring clinical expression of neuronal network dysfunction? Epilepsia 2004;45 Suppl 2: Gidal BE, Sheth R, Parnell J, Maloney K, Sale M. Evaluation of VPA dose and concentration effects on lamotrigine pharmacokinetics: implications for conversion to lamotrigine monotherapy. Epilepsy Res 2003;57: Kutluay E, McCague K, D'Souza J, Beydoun A. Safety and tolerability of oxcarbazepine in elderly patients with epilepsy. Epilepsy Behav 2003;4: Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs-best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008;49: J Korean Neurol Assoc Volume 29 Suppl. 2,

103 특수상황에서의간질환자치료 : 고찰및증례노인에서뇌전증 : 인지변화 경북대학교의학전문대학원신경과학교실박성파 Epilepsy in the Elderly: Cognitive Change Sung-Pa Park, MD, PhD Department of Neurology, School of Medicine, Kyungpook National University, Daegu, Korea People with chronic epilepsy are exposed to many risk factors demonstrated to be associated with abnormal cognitive and brain aging in the general population, with many of these risk factors present in people with chronic epilepsy as early as midlife. Many researches will be needed to identify and treat known modifiable risk factors in order to protect and promote cognitive and brain health in the elderly patients. Antiepileptic drugs should be cautiously chosen in those patients to minimize cognitive impairment and drug interactions. Key Words: Elderly, Epilepsy, Cognition 서 론 만성뇌전증의인지기능에대한영향 뇌전증환자들에서인지기능저하는잘알려져있다. 1 하지만만성뇌전증을가진 65세이상의노인에게인지기능의변화가어떠한지에관한연구는드물다. 단지만성뇌전증을가진젊은환자들의인지장애, 신경영상이상, 정신질환동반이잘알려져있고, 이문제점들이중년까지진행한다는증거들은있다. 인지기능의악화를유발하는인자들로는항경련제투여로인한콜레스테롤, 엽산및당대사의장애, 혈관질환위험인자의증가, 사회생활및신체적활동의감소같은생활방식의변화, 염증표지자의증가를생각할수있다. 실제일반인에대한전향적연구들에서도이런인자들과혈관성치매및알쯔하이머병이연관성을가진다고확인한바있다. 그러나만성뇌전증에서이런인자들이관여하여인지기능을악화시키는지에대한연구는아직시도되지않고있다. 따라서본강의는현재까지연구된몇개의결과들을토대로이문제점에접근하고자한다. Sung-Pa Park, MD, PhD Department of Neurology, School of Medicine, Kyungpook National University, 101 Dongin-dong 2ga, Jung-gu, Daegu , Korea Tel: Fax: sppark@mail.knu.ac.kr 만성뇌전증환자에서 IQ 와기억력의손상이광범위한신경심리단면연구를통해증명되었고, 이는조기발병및발작빈도와밀접한관계가있다고하였다. 2 따라서만성약물불응성뇌전증이시간이경과함에따라지속적인인지기능장애를보이는지에대한관심도높아지게되었다. 몇개의조절전향연구에서는뇌전증의특정환자군에서그런현상이목격되었다고보고하였다. 즉만성측두엽뇌전증환자는기억력을포함한인지기능의장애가 4년뒤추적검사에서건강인에비해더많이감소함을보고하였다. 3 이는환자의나이가많을수록, 질병이환기간이길수록, 지능이낮을수록, 뇌 MRI 상뇌부피의이상이있을수록뚜렷하다고하였다. 한편만성측두엽뇌전증의신경영상연구에서도해마, 측두엽및외측두엽부위 ( 전두엽및소뇌 ), 피질하구조물 ( 미상핵및시상 ) 의이상뿐만아니라뇌백질부및피질의부피감소가병의진행에따라관찰됨을보고하였다. 4-6 이처럼만성뇌전증이서서히인지기능을악화시키고뇌구조의이상을초래한다는보고는많으나환자가노인연령에접어들어이러한현상이어떻게진행할지에대한연구는아직없는실정이다. 또한만성측두엽뇌전증환자는일반인에비해서 DSM-IV Axis I 장애, 특히기분장애의발생빈도가 4년간의추적조사로더증가함을밝혔으나, 7 이것역시노인환자 80 대한신경과학회지제 29 권부록 2, 2011

104 노인에서뇌전증 : 인지변화 들에서는어떠한경과를보일지에대한조사는되어있지않다. 최근에노인뇌전증환자의인지기능과기분상태에대한환자대조단면연구에서는환자군이같은나이의건강대조군에비해인지기능이저하되고, 우울및불안증이더높은것으로밝혀졌으며인지기능저하는환자가복용하는항경련제나기분상태와무관하다고하였다. 8 이는노인연령에서도인지기능저하와기분장애가지속됨을보여주는간접적자료로서추후전향적추적조사가필요함을제시하였다. 노인뇌전증환자에서인지기능저하에대한잠재적인위험인자 측두엽뇌전증에서신경병리연구와노인뇌전증환자에서지적변화의선별검사를통해만성뇌전증환자의인지기능변화에관심이증가하게되었다. 여기서는현재까지밝혀진연구결과들을토대로인지기능저하에대한잠재적인위험인자를살펴보면모두 8가지로요약할수있는데, 첫째는만성뇌전증에서뇌전증수술후얻은측두엽뇌조직에서활성화된아밀로이드전구단백, 노년판 (senile plaque) 및 corpora amylacea 축적을발견한것이며, 9-11 둘째는신경심리학적검사를통해기억상실형경도인지장애 (amnestic MCI) 를가진노인과만성부분뇌전증을가진노인들의기억력과수행력을비교한결과기억력은양군에서유사하게장애가있었으며, 수행력은오히려만성뇌전증환자에서더감소되고추적조사에서의미있게나빠졌고, 12,13 셋째는인구집단연구를통해뇌전증환자들의동반질환을조사한결과일반인에비해약 4배정도알쯔하이머병을가질수있고, 14 비유발발작이치매가없는노인들보다알쯔하이머병환자들에서더많이발생하여 15 뇌전증과치매는서로밀접한관계가있다는것이며, 넷째는인구집단연구에서뇌전증환자들이일반인에비해고혈압, 허혈성심질환, 당뇨및뇌졸중의동반빈도가더높았고, 14 그들이복용하는항경련제로의부작용으로인한인슐린분비장애나비만, 엽산대사장애에의한고호모시스테인혈증, 고콜레스테롤혈증을통해혈관질환위험인자가인지기능저하에중요한역할을할것이며, 다섯째는뇌전증환자의 44-73% 가경동맥의여러부위의내중막두께 (intima media thickness) 가일반인에비해더두꺼워져있고, 이들모두다양한혈관질환위험인자를가지고있었다는것이며, 20 여섯째는만성측두엽뇌전증환자에서나이에따라가속화되는노년판형성과 21 만성뇌전증환자의나이에따른기억장애의가속화가 APOE epsilon4 의존재와연관성이있다는단면적연구가있었으며, 22 일곱째는만성뇌전증에서도알쯔하이머병의인지장애를유발하는염증반응이발생하였다고보고하 였는데예를들어환자의혈청, 뇌척수액, 뇌표본에서염증지표인 IL-6 가강직간대발작직후증가되어있었다고한다. 23 마지막여덟째로는인지기능장애에생활방식요인이관여할것이라추정되는데뇌전증환자의경우규칙적인육체활동이부족하고, 이로인한체중증가가발생하며, 사회참여나여가활동이부족하여정신활동이위축되는것이다. 24 이상의잠재적인위험인자들은특히중년에서향후인지기능을결정짓는데매우중요하다고한다. 또한중년의인지장애는말년의정신상태를결정짓는매우중요한예측인자라고한다. 25 하지만아직까지만성간질환자가이러한잠재적인위험인자를통해노인이되어심각한인지장애를일으키거나치매환자가되는지에대한연구는거의없는실정이므로향후지속적인연구가필요하고, 추가적으로항경련제치료나간질수술이노년의인지기능에미치는영향또한연구되어야할중요한과제가될것이다. 최근만성측두엽뇌전증환자들의인지기능변화에대한단면연구를보면정상인에비해조기에 learning peak 에도달하며나이에따른인지기능감소정도는양군에서차이가없었으므로발병초기에적극적인발작조절을시도하여인지기능감퇴를예방하는것이중요하다고하였다. 26 노인에서항경련제의인지기능영향및항경련제선택 노인에서뇌기능의비축 (reserve) 이감소하거나알쯔하이머병처럼퇴행성질환이있는경우에는약간의인지장애가일상생활에큰영향을줄수있다. 따라서인지장애가의심되는노인뇌전증환자에게는인지기능에악영향을끼치는항경련제는피해야한다. 구세대항경련제로는 benzodiazepine, phenobarbital, primidone 이, 그리고신세대항경련제로는 topiramate, zonisamide 가기억력과집중력에악영향을주는것으로알려져있고, 인지기능에영향을주지않는항경련제로는 gabapentin, levetiracetam, lamotrigine, pregabalin이있다. 27 노인환자의인지기능은항경련제의선택뿐만아니라약물의적정속도, 약물용량, 다자요법에의해영향을받으므로이또한투여시고려하여야할요소이다. 한편부검으로입증된알쯔하이머병환자의 10-17% 는발작을경험한다고한다. 28 따라서이런환자들에게항경련제를투여할수있는데주의할점은그들이복용하는약물과의상호작용이다. 특히 cholinesterase inhibitors 의혈중농도는간대사효소유발제재인 phenytoin, carbamazepine, phenobarbital 에의해감소하는것으로알려져있으므로주의하여야하고, 신세대항경련제중에 oxcarbazepine 도같은영향을주는것으로알려져있다. 29 J Korean Neurol Assoc Volume 29 Suppl. 2,

105 박성파 결 론 현재까지의결과들을종합해보면만성뇌전증이인지기능, 뇌구조및정신건강에영향을주는것으로추정되며여기에는잠재적인위험인자가작용할것으로생각된다. 하지만이런변화가노인이되어서도지속되고이것이궁극적으로치매에도달하게될지에관해서는더많은연구가필요하다. 만성뇌전증노인환자들에게사용되는항경련제는인지기능에영향이없는것이좋으며타약제와상호작용이없어야한다. References 1. Motamedi G, Meador K. Epilepsy and cognition. Epilepsy Behav 2003; 4 Suppl 2:S Elger CE, Helmstaedter C, Kurthen M. Chronic epilepsy and cognition. Lancet Neurol 2004;3: Hermann BP, Seidenberg M, Dow C, Jones J, Rutecki P, Bhattacharya A, et al. Cognitive prognosis in chronic temporal lobe epilepsy. Ann Neurol 2006;60: Liu RS, Lemieux L, Bell GS, Hammers A, Sisodiya SM, Bartlett PA, et al. Progressive neocortical damage in epilepsy. Ann Neurol 2003;53: Hermann B, Seidenberg M, Sears L, Hansen R, Bayless K, Rutecki P, et al. Cerebellar atrophy in temporal lobe epilepsy affects procedural memory. Neurology 2004;63: Bernasconi N, Duchesne S, Janke A, Lerch J, Collins DL, Bernasconi A. Whole-brain voxel-based statistical analysis of gray matter and white matter in temporal lobe epilepsy. Neuroimage 2004;23: Jones JE, Bell B, Fine J, Rutecki P, Seidenberg M, Hermann B. A controlled prospective investigation of psychiatric comorbidity in temporal lobe epilepsy. Epilepsia 2007;48: Haut SR, Katz M, Masur J, Lipton RB. Seizures in the elderly: impact on mental status, mood, and sleep. Epilepsy Behav 2009;14: Sheng JG, Boop FA, Mrak RE, Griffin WS. Increased neuronal beta-amyloid precursor protein expression in human temporal lobe epilepsy: association with interleukin-1 alpha immunoreactivity. J Neurochem 1994;63: Gouras GK, Relkin NR, Sweeney D, Munoz DG, Mackenzie IR, Gandy S. Increased apolipoprotein E epsilon4 in epilepsy with senile plaques. Ann Neurol 1997;41: Radhakrishnan A, Radhakrishnan K, Radhakrishnan VV, Mary PR, Kesavadas C, Alexander A, et al. Corpora amylacea in mesial temporal lobe epilepsy: clinico-pathological correlations. Epilepsy Res 2007;74: Griffith HR, Martin RC, Bambara JK, Marson DC, Faught E. Older adults with epilepsy demonstrate cognitive impairments compared with patients with amnestic mild cognitive impairment. Epilepsy Behav 2006;8: Griffith HR, Martin RC, Bambara JK, Faught E, Vogtle LK, Marson DC. Cognitive functioning over 3 years in community dwelling older adults with chronic partial epilepsy. Epilepsy Res 2007;74: Tellez-Zenteno JF, Matijevic S, Wiebe S. Somatic comorbidity of epilepsy in the general population in Canada. Epilepsia 2005;46: Amatniek JC, Hauser WA, DelCastillo-Castaneda C, Jacobs DM, Marder K, Bell K, et al. Incidence and predictors of seizures in patients with Alzheimer s disease. Epilepsia 2006;47: Luef GJ, Waldmann M, SturmW, Naser A, Trinka E, Unterberger I, et al. Valproate therapy and nonalcoholic fatty liver disease. Ann Neurol 2004;55: Sheth RD. Metabolic concerns associated with antiepileptic medications. Neurology 2004;63:S24-S Tamura T, Aiso K, Johnston KE, Black L, Faught E. Homocysteine, folate, vitamin B-12 and vitamin B-6 in patients receiving antiepileptic drug monotherapy. Epilepsy Res 2000;40: Hamed SA, Nabeshima T. The high atherosclerotic risk among epileptics: the atheroprotective role of multivitamins. J Pharmacol Sci 2005;98: Hamed SA, Hamed EA, Hamdy R, Nabeshima T. Vascular risk factors and oxidative stress as independent predictors of asymptomatic atherosclerosis in adult patients with epilepsy. Epilepsy Res 2007;74: Gouras GK, Relkin NR, Sweeney D, Munoz DG, Mackenzie IR, Gandy S. Increased apolipoprotein E epsilon4 in epilepsy with senile plaques. Ann Neurol 1997;41: Busch RM, Lineweaver TT, Naugle RI, Kim KH, Gong Y, Tilelli CQ, et al. APOE-epsilon4 is associated with reduced memory in longstanding intractable temporal lobe epilepsy. Neurology 2007;68: Peltola J, Laaksonen J, Haapala AM, Hurme M, Rainesalo S, Keranen T. Indicators of inflammation after recent tonic-clonic epileptic seizures correlate with plasma interleukin-6 levels. Seizure 2002;11: Steinhoff BJ, Neusüss K, Thegeder H, Reimers CD. Leisure time activity and physical fitness in patients with epilepsy. Epilepsia 1996; 37: Kawas CH, Corrada MM, Brookmeyer R, Morrison A, Resnick SM, Zonderman AB, et al. Visual memory predicts Alzheimer s disease more than a decade before diagnosis. Neurology 2003;60: Helmstaedter C, Elger C. Chronic temporal lobe epilepsy: a neurodevelopmental or progressively dementing disease? Brain 2009;132: Park SP, Kwon SH. Cognitive effects of antiepileptic drugs. J Clin Neurol 2008;4: Mendez M, Lim G. Seizures in elderly patients with dementia: epidemiology and management [review]. Drugs Aging 2003;20: Jenssen S, Schere D. Treatment and management of epilepsy in the elderly demented patient. Am J Alzheimers Dis Other Demen 2010;25: 대한신경과학회지제 29 권부록 2, 2011

106 글락소스미스클라인

107 한국에자이주식회사

108 한국오츠카제약

109 대웅제약

110 머크주식회사

111 고려제약

112 종근당

113 ( 주 ) 온세메디칼

114 2011 년대한신경과학회제 30 차학술대회 2011년 10월 7일 ( 금요일 ) - 둘째날 -

115 특수상황에서의간질환자치료 : 고찰및증례염증성시신경염 전북대학교의학전문대학원신경과학교실, 전북대학교병원임상의학연구소 오선영 Inflammatory Optic Neuropathy Sun-Young Oh, MD Department of Neurology and Research Institute of Clinical Medicine, Chonbuk National University College of Medicine, Jeonju, Korea Inflammatory optic neuropathies are common in clinical practice and a wide variety of illnesses produce inflammation of the optic nerves, i.e., optic neuritis (ON). Monosymptomatic optic neuritis has important implications for the development of multiple sclerosis. In the patient presenting with monosymptomatic optic neuritis, MR imaging provides critical prognostic information concerning the development of MS. The Optic Neuritis Treatment Trial (ONTT) has provided valuable insights into both the natural history and clinical course of demyelinating ON with respect to treatment. Oral prednisone alone is contraindicated in the treatment of optic neuritis because of its association with increased recurrence rate of optic neuritis. Intravenous methylprednisolone remains a viable treatment option to slightly increase the rate of recovery and provide a degree of short-term protection against the subsequent development of MS. Other inflammatory optic neuropathies include NMO (neuromyelitis optica, Devic's disease), sarcoidosis, and neuroretinitis with each possessing distinct clinical characteristics and treatment approaches. Key Words: Optic neuritis, Multiple sclerosis (MS), Neuromyelitis optica (NMO), Management 시신경수초의염증이나탈수초화로인한시신경의질환을염증성시신경병증이라하며, 여기에는여러가지원인의염증성시신경병증이포함된다 (Table 1). 본장에서는전형적인염증성시신경병증, 즉시신경염 (optic neuritis) 의임상적인특징과진단검사, 치료를포함하여비전형적시신경염으로시신경척수염 (NMO, neuromyelitis optica) 과기타시신경염을유발하는질환들에대해살펴보고자한다. 전형적인탈수초성시신경염 (Idiopathic demyelinating optic neuritis) 전형적인시신경염의경우 20대에서 50대사이에호발하며, 여자에게많고, 급성단안성의시력감소를주증상으로한다. 시 Sun-Young Oh, MD Department of Neurology, College of Medicine, Chonbuk National University, Gumam-dong, Jeonju , Korea Tel: Fax: ohsun@jbnu.ac.kr 력저하뿐아니라시야의감소, 색각의감소, 대비감도의감소등시기능저하를보일수있으며그중환자가느끼는가장흔한증상은시력의갑작스런감소이다 (Table 2). 1-3 전형적인탈수초성시신경염환자에서의시력감소는 2,3 일간에걸쳐일어나는것이대부분이고조금길면 7일에서 10일에걸쳐발생한다. 시력감소의정도는정상시력부터무광각까지다양하며성인의경우보통단안성인경우가많지만증상이없는반대쪽눈에도검사상시기능장애를보이기도한다. 섬광증상이시력저하가발생하기전에나타날수있고시신경염이치료된후에도지속되기도하는데, 시신경염에서의섬광증상은수평안구운동시잘나타나는특징을가지고있다. 시신경염에서특징적인증상은안통인데안통은크게안운동과상관없는안구주위의통증과안운동에의해악화되는안통으로나눌수있는데, 시신경염에만나타나는특이한증상은아니지만다른시신경병증과의감별에유용한증상이다. 섬광증상과마찬가지로시력저하가나타나기전에먼저안통이나타나기도한다. 색각이상이다양하게나타날수있는데이는시력저하보다 84 대한신경과학회지제 29 권부록 2, 2011

116 염증성시신경염 더심한것이보통이다. 또불의밝기가정상눈에비해어둡게보이고대비감도의장애도나타난다. 시신경염에서나타나는전형적인시야장애는중심암점이다. 하지만실제로중심암점을보이기보다는다양한다른형태의시야장애가나타나는경우가더많다. 중심부근암점, 궁상암점, Table 1. Classification of inflammatory optic neuropathy 1. Optic neuritis associated with demyelinating disease - Idiopathic optic neuritis - Optic neuritis as a manifestation of - Multiple sclerosis - NMO - ADEM 2. Optic neuritis associated with infectious diseases - Bacterial infections: syphilis, cat scratch diseases - Viral infections: herpes zoster, herpes simplex, HIV, EBV - Parasitic infections: toxoplasmosis, systicercosis - Fungal infections: cryptococcosis, aspergillosis 3. Postvaccination optic neuritis - Hepatitis B virus, rabies virus, tetanus toxoid 4. Optic neuritis associated with other inflammatory disorders - Sarcoidosis - Systemic lupus erythematosus - Sjogren syndrome - Polyarteritis nodosa - Wegener granulomatosis - Inflammatory bowel disease - Behcet - Bee and wasp stings 5. Isolated recurrent optic neuritis (autoimmune optic neuritis) 교호성암점, 중심부맹점암점, 비측계단, 주변부위축등이나타날수있고드물게반맹이나타나는경우도있다. ONTT (Optic neuritis treatment trial) 에의하면성인의시신경염은여자에서더많고 (77%), 평균연령이 31.8 세이고, 75% 에서단안성이며시신경부종은 35% 에서발생하였다고하였다. 보통 20대에서 40대의성인여자가안운동에의해악화되는안통을동반하면서한눈의시력이며칠사이에감소한경우를전형적인시신경염이라고할수있다. 하지만시력감소가양안성인경우, 2주이상진행하는시력저하, 안통이없는경우, Table 2. Common symptoms in optic neuritis Decreased vision Visual field defects Reduced color vision Uhthoff s symptom Decreased depth perception Pain Phosphenes ; movement-induced, sound-induced Table 3. Common examination findings in optic neuritis Visual acuity loss Dyschromatopsia Reduced contrast sensitivity Reduced stereoacuity Visual field loss Afferent pupillary defect Normal or swollen optic nerve A B Figure 1. Optic fundus findings in patients with optic neuritis. Mild (A) and diffuse (B) prominent disk swelling without hemorrhages, cotton-wool spots, and exudates. J Korean Neurol Assoc Volume 29 Suppl. 2,

117 오선영 환자의나이가 50세이상, 망막출혈이나삼출물등의망막병변이함께있는경우, 안구내염증소견, 시력감소가시작된지 4-6 주가지나도시력의개선이없는경우, 시야결손이비전형적인경우등은다른원인에의한시신경염을의심해야한다. 특히양안성인경우혈관염이나, 전신적인결합조직질환과동반가능성이있고특히시신경척수염등에서의시신경염과감염성질환의위험등도있으므로혈액검사등이필요하다. 시신경염의진단을위해어떠한검사를시행할것인지는표 1에서처럼원인면에서전형적인탈수초성시신경염인지아니면다른원인에의한비전형적증상을보이는지에따라결정된다. 일단기본적인신경안과검사로시력, 색각, 시야, 동공반응검사, 안저검사, 시유발전위검사등을시행하고 (Table 3) 뇌 와안와의자기공명영상촬영과척수검사를고려하는데, 척수검사는전형적인탈수초성시신경염이의심될때는필수적인검사는아니지만뇌자기공명영상검사는향후다발성경화증의발생여부를판단하고압박성병변의발견및다른원인의시신경병증등을배제하기위해시행하는것이추천된다. 시신경염의진단을위해자기공명영상촬영을할때는조영제 (Gadolinium) 를주입하여조영증강을하는것이좋은데조영제는정상적인뇌- 혈관장벽을통과하지못하지만염증이있는시신경에서는뇌혈관장벽을통과하여신호증강으로보일수있어서진단에도움이되기때문이다. 시신경염에서고해상도자기공명영상촬영을했을때시신경의조영증강은환자의 85% 까지나타날수있으며 (Fig. 2-A, B), 이러한조영증강은시신경염이발생한후 3주 A B C D E Figure 2. A-B. Axial T1-weighted, fat suppressed, gadolinium-enhanced orbital MRIs in patients with acute optic neuritis. The MRI demonstrates focal enhancement of the left optic nerve (A), and in another patient more diffuse enhancement of the right optic nerve (B) is seen. C-D. FLAIR MRI of the brain in a patient with optic neuritis but no known history of multiple sclerosis (clinically isolated syndrome). Numerous high signal abnormalities in the cerebral white matter consistent with demyelination are visible. Characteristic lesions in the corpus callosum (C) and periventricular white matter (D) are seen. 86 대한신경과학회지제 29 권부록 2, 2011

118 염증성시신경염 에서 4주이내에잘나타난다. 또한조영증강의양상으로시력의예후도어느정도알수있는데조영증강이나타날때병변의길이가긴경우시력의회복이늦거나불완전할수있다고하였고병변의위치가시신경관내나시신경교차부근처, 즉뒤쪽시신경에있을수록시력의회복이늦어질수있다는보고가있다. 따라서 MRI 상에서이를확인하는것이시력회복의예측하는데도움이될수있을것으로생각된다. 또한다발성경화증발생의예측을위해서확인해야할사항은 T2-weighted image 에서고신호를보이는병변이있는지확인하고, 조영증강 T1-weighte image 에서조영증강이되는병변이있는지, 또병변의위치가뇌실주변인지, 피질주변인지 (juxtacortical), infratentorial 에있는지확인하는것도추후다발성경화증의진단과발생예측에도움이된다 (Fig. 2-C-E). 비전형적인시신경염의증상을보일때는세밀한신경학적진찰과추가적인검사들을시행할수있는데뇌, 안와와척추자기공명영상촬영을필수적으로시행하는것이좋고그밖에척수검사, 혈청검사를시행하여 antinuclear antibldy test (ANA), Fluorescent treponemal antibody absorbtion (FTA- ABS), angiotensin-converting enzyme (ACE) level, Lyme titer, Chest X-ray 등을시행하고, 망막의병변과시신경의병변을구별하기위해안과적인검사로 Optical coherence tomography (OCT), Electroretinogram (ERG) 등을시행할수있겠다. 모든시신경염환자에서유두부종 (Fig. 1) 이관찰되는것은아닌데, 구후시신경염 (retrobulbar optic neuritis) 에서는안저검사상시신경유두부종이보이지않고정상적으로보인다. 이를 OCT 를이용하여시신경유두주위에시신경두께를측정한연구에의하면구후성시신경염이있는눈에서반대쪽정상안에비해시신경의두께가증가하였다고하였으며안저검사상정상으로보이는구후성시신경염에서경미한시신경유두부종을발견할수있다고하였다. 4 다른연구에서는다발성경화증환자에서보이는뇌실질의위축과축삭의손상정도를 OCT 를이용하여신경섬유층두께를측정함으로써간접적으로알수있다고보고한연구도있다. 5 시신경염의치료는아직까지확실하게적립되어있지않다. 하지만탈수초성시신경염의주된치료는 ONTT 의연구결과를바탕으로고용량부신피질호르몬의정맥주사요법이시행되어지고있다. ONTT 에서탈수초성시신경염환자를 3개의그룹으로나누어치료효과를비교하였는데첫번째그룹은경구스테로이드 (1 mg/kg/day for 14days with 4day taper) 를투여한군, 두번째그룹은정맥내 methylprednisolone (250 mg every 6hous for 3 days followed by oral prednisone(1 mg/kg/day) for 11days with 4-day taper) 를투여한군, 세번째그룹은위약을 투여한군으로나누어비교하였다. 결과에의하면 methylprednisolone 정맥주사를한환자들에서시력의회복속도가빨랐고, 시력저하발생 2주째에다른그룹의환자에비해시력회복을경험하는빈도가많았다고한다. 하지만 1년이지난후에는시력의차이는세그룹에서보이지않았다. 이는다른연구들에서도어느정도증명되어졌고따라서현재시신경염의치료는시신경염발병 8일이내에정맥내로 methylprednisolone 1 g/day 을 3일간투여하고경구스테로이드를 1 mg/kg/day 로 11일간투약한다음 4일일정으로감량하는데 20 mg 을첫째날주고, 둘째날은 10 mg, 하루건너뛰고넷째날 10 mg을투약하는것이일반적이다. 경구스테로이드만투여했던그룹은다른그룹에비해재발률을 2배정도높인다고하여경구스테로이드만투약한것은현재추천되지않는다. 그밖에정맥내고용량스테로이드치료는시력회복속도를빠르게하는효과이외에안통의회복을빠르게하고추후 2,3 년내에다발성경화증이발생하는것을어느정도예방하는효과가있다고 ONTT 는밝히고있다. 최근에는스테로이드에반응하지않는심한임상증상을보이는시신경염의환자에서혈장교환술을시행하여효과를보았다는연구도있고, 면역글로불린을정맥주사로치료하였다는보고도있다. 6,7 시신경염이발병이추후다발성경화증의발생과의연관성을보기위한가장좋은방법은뇌MRI 에서 T2-signal 에서의회백질이상병변의유무를확인하는것이다 (Fig. 2-C-E). ONTT 에의하면뇌 MRI 에 3mm 이상크기의병변이 1개이상있으면 5년후에다발성경화증이발생할확률이 51%, 10년후에는 56%, 15 년후에는 72% 라고하였고, 뇌병변이없을때 5년후에다발성경화증이발생할확률은 16%, 10년후에는 22%, 15년후에는 25% 로낮아진다고하였다. 또 ONTT 에의하면뇌병변이없는시신경염환자에서추후다발성경화증의발생가능성이낮음을시사하는임상인자로서, 남자환자, 시신경유두부종이동반되어있을때등이고특히안구통이동반되지않았을때, 무광각인시력, 시신경유두부종이아주심할때, 시신경유두출혈이동반됐을때, 망막삼출물등을보일때등은단한명에서도다발성경화증이발생하지않았다고하였다. 시신경염이발생당시의 MRI 와비교해서 3개월후에찍은 MRI 상에서새로운 T2병변이발생하였다면추후다발성경화증발생의가능성이높고, 8 시신경염발생 1년후의 MRI 상에조영제로증강되는병변이존재하면추후다발성경화증이발생할가능성이높아진다는연구도있다. 9 또한뇌 MRI 상에 T2 병변이보이고동시에 CSF 내에 oligoclonal band 가양성이면추후다발성경화증발생의가장정확한예측인자가될수있다는보고가있다. J Korean Neurol Assoc Volume 29 Suppl. 2,

119 오선영 비전형적시신경염 비전형적시신경염이란일차적인탈수초성염증반응에의한것이아니라이차적으로감염이나자가면역질환, 결체조직질환등의전신질환과관련되어발생한경우이다. 시신경염을동반하는자가면역질환들로는시신경척수염 (NMO), 전신성홍반성루푸스 (SLE), Antiphosphoid syndrome, 유육종 (Sarcoidosis), 쇼그렌증후군, 베쳇병 (Behcet s disease), 전신경화증등이알려져있다. 감염성질환은주로신경망막염 (Neuroretinitis) 의형태로나타나며 Bartonella henselae, 결핵 (Tuberculosis) 의원인균인 Mycobacterium tuberculosis, 브루셀라병 (brucellosis) 의원인이되는 brucellae, 라임병 (lyme disease) 을일으키는 Borrelia burgdorferi, 매독 (syphilis) 을일으키는 Treponema pallidum, 록키산열병의원인균이었던 rickettsia rickettsii 등이시신경염을일으킬수있고, Adenovirus, Coxachie virus, Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Human immune deficiency virus (HIV), Measles, Mumps, Rubeola, Rubella, Varicella and Herpes Zoster, Hepatitis A, B, C 등의바이러스도시신경을직접침범하거나간접적으로면역반응을촉진하여시신경염증을일으킬수있다. 1. 시신경척수염 (Neuromyelitis optica, NMO) 시신경척수염은과거 Devic disease 라고도알려진, 자가항체에의해 ( 아 ) 급성의단안또는양안의시신경염 (Fig. 3-A) 과횡단성척수염 (Fig. 3-C) 을동반하는중추신경계의탈수초질 A B C D E Figure 3. (A) Bilateral optic neuritis with optic nerve swelling and severe visual loss from neuromyelitis optica (NMO). (B) Fluid attenuated inversion recovery (FLAIR) MRI shows hyperintensities in the lesion from dorsomedial pons and the left medial frontal area. (C) Sagital T2-weighted cervical spine MRI showing an extensive hypersignal consistent with myelitis. 88 대한신경과학회지제 29 권부록 2, 2011

120 염증성시신경염 Table 4. Revised diagnostic criteria for NMO (Wingerchuk et al. 2006) Two absolute criteria: optic neuritis myelitis At least two of three supportive criteria: Presence of a contiguous spinal cord MRI lesion extending over three or more vertebral segments MRI criteria not satisfying the revised McDonald diagnostic criteria for MS NMO-IgG in serum 환의하나다. 횡단성척수염은시력소실을선행해서또는뒤따라발생할수있다. 전형적인다발성경화증과임상증상이비슷하고감별이어려웠지만, 최근중추신경계의수분통로인 aquaporin-4 (AQP-4) 에대한자가항체가발견되면서 NMO 의발병기전과임상특징에대한이해가증가되었다. 또한과거에는정상뇌영상을진단기준으로여겨져왔으나최근 AQP-4 항체와연관한뇌영상소견이알려지면서새로운진단기준이제시되고 (Table 4 and Fig. 3-B) NMO 진단기준을모두만족하지않더라도척수염이나시신경염의일부증상, 또는다른자가면역질환에서 AQP-4 항체를보이기도하여이를 NMO spectrum disorder 로따로분류하기도한다. 다발성경화증과비슷한증상을보이지만일반적으로더심한시력소실을보이며, 시신경염은양안에동시에발병하거나 1개월이내에연속적으로시신경염이발생하는경우다발성경화증보다는 NMO 의가능성이더높겠다. 10 다발성경화증에비해망막섬유두께의감소가심하며이는더광범위한축삭손상을시사하며좋지않은예후를설명해준다. 예후는일반적으로다발성경화증보다좋지못한것으로알려졌으며, 영구또는심한시력소실과사지마비등을동반할수있다. 치료는주로급성기에고용량의스테로이드정맥주사를하지만시력소실이심하고사지마비를보이는경우에혈장혈장교환시행하는것이추천되고있다. 재발방지를위해장기적으로면역억제치료를해야하며이를위해경구스테로이드나 11 azathioprine 을투여할수있다. Rituximab 은 B 림파구에특이적인단클론항체로서기존의약제에반응이없는환자에사용해볼수있겠다. 그외이차약제로서 Cyclophosphamide 정주나 Mitoxantrone 정주, 또는 Mycophenolate mofetil 의경구투여를고려할수있다. 면역글로불린 (IVIG) 이효과적이라는보고도있다. 다발성경화증에서예방치료로사용되는인터페론이 NMO 환자에서는연간재발률의감소를보이지못했고, 일부환자에서는오히려증상의악화또는광범위한뇌병변을일으키기도하였다고보고하고있어, NMO 에서인터페론의예방치료는추천되지않고있다 매독시신경염 (Syphilitic optic neuritis) 시신경염은이차또는삼차매독에흔한증상으로대부분림파구성뇌수막염과동반되어신경매독의하나의증상으로발현한다. 이에뇌압항진과유두부종이동반하는경우가많으며, 림파구성뇌수막염환자에서뇌압항진에의한유두부종과시신경염을보이면매독에대한검사 (RPR; rapid plasma regain, FTA-ABS; fluorescent treponemal antibody absorption) 가필요하다. 혈액검사가양성이면뇌척수액검사를통한뇌압측정과 VDRL (venereal disease research laboratories) 검사, 그리고 HIV 검사를실시해야하겠다. 매독시신경염은신경매독에준하여치료를하며대개시기능에대한예후는양호한편이다. 3. 유육종성시신경염 (Sarcoid optic neuritis) 유육종 (sarcoidosis) 은여러장기에육아종성염증반응을일으키는자가면역질환으로유육종성시신경염은독립적으로발생하거나, 신경유육종 (neurosarcoidosis) 의한형태로발현할수있다. 5,15 진단을위해서폐 X-RAY 와 CT 를찍고혈청 angiotensin converting enzyme (ACE) level, 또는 gallium scan, FDG-PET (fluorodeoxyglucose positron emission tomography) scan 을측정한다. 유육종에서시신경염은신경유육종에서동반하는림프구성뇌수막염의결과로초래될수있다. 뇌압항진시단안또는양안의시신경부종을관찰할수있으며, 또한시신경두부에대한육아종성침습으로시신경의상승을동반할수있다. 대부분의경우시신경병증은스테로이드치료에대한반응이좋으며때로스테로이드의존을보이기도하며, 장기간면역억제제로 azathioprine, methotrexate 등의투여가필요하기도하다. 4. 기타자가면역질환에의한시신경염전신성홍반성루푸스 (SLE) 는만성전신적면역관련결체조직질환이고시각증상은망막, 안검피부, 시신경을침범하여나타날수있고그중망막혈관을가장잘침범한다. 망막에면화반, 망막출혈등이발생할수있고중심망막정맥폐쇄, 중심망막동맥폐쇄, 분지망막정맥폐쇄등도나타날수있다. SLE 에서시신경염은비교적드물게나타나는데, 시신경염의기전은아직불확실하지만비교적가벼운시신경염은허혈과, 탈수초등이관여하고심한시신경염은허혈에의한축삭괴사가관여할것이라고보고된바있다. 16 쇼그렌증후군 (Sjogren`s syndrome) J Korean Neurol Assoc Volume 29 Suppl. 2,

121 오선영 은단핵구의침착으로타액선과누액선이파괴되는자가면역질환으로 20-34% 의환자에서척수에침범하여횡단성척수염을일으킬수있다. Sjogren`s syndrome 에서의시신경염은단독으로나타날수도있고횡단성척수염과동반될수도있다. 척수염과시신경염이동반되는 Neuromyelitis Optica (NMO) 환자에서전신적인 Sjogren`s syndrome 이있는지검사하는것이좋다. 진단을위해서혈청 aquaporin (AQP)-4 autoantibody, anti SS-A, anti SS-B antibody 를검사해야한다. 결 론 갑작스런시력소실을보이는시신경병증환자에서다양한감별질환들을고려해야하는데기저원인에따라시신경병증의경과나치료효과, 예후등이결정되기때문이다. 이를위해통상적인신경학적, 안과적검사외에전신증상에대해꼼꼼히살피면서혈청학적검사, 뇌척수액검사나영상검사등발현증상에기본한맞춤검사로서감별질환들을좁혀가야하겠다. 감별에도움이되는임상적인특징들, 즉시력소실의발생이급성 ( 허혈성이나염증성 ) 인지진행성 ( 독성이나압박성시신경병증 ) 인지, 색각은정상인지, 허혈성시신경염인경우에는보존되고염증성시신경염인경우는매우심하게이환되며, 안운동과연관한통증이수반되는지 ( 염증성원인 ) 를살펴야하겠다. 그외에형광안저촬영과망막소견 ( 신경망막증의감별 ) 도중요한정보를줄수있다. 임상소견으로시신경병증이의심된다면동반하는증상을찾고시신경병증의국재화 (localization), 즉 anterior, posterior in the orbit, orbital apex, intracranial 병변인지를가리기위한노력이필요하다. 또한원인적인진단을위해앞서기술한영상검사와혈청학적검사를실시해야함으로써정확한진단에이를수있겠다. References 1. Balcer LJ. Optic neuritis. N Engl J Med 2006;354: Ebers GC. Optic neuritis and multiple scle-rosis. Arch Neurol 1985; 42: Rizzo JF, Lessell S. Risk of developing mul-tiple sclerosis after uncomplicated optic neu-riti: A long term prospective study. Neurology 1988;38: Pro MJ, Pons ME, Liebmann JM, et al. Imaging of the optic disc and retinal nerve fiber layer in acute optic neuritis. J Neurol Sci 2006;250: Sieger M, Dziegielewski K, Jasek L, et al. Optical coherence tomography in multiple sclerosis: thickness of the retinal nerve fiber as a potential measure of axonal los and brain atrophy. J Neurol 2008; 255: Ruprecht K, Klinker E, Dintelmann T, et al. Plasma exchange for severe optic neuritis: treatment of 10 patennts. Neurology 2004;63: Tselis A, Perumal J, Caon C, et al. Treatment of corticosteroid refractory optic neuritis in multiple sclerosis patients with intravenous immunoglobulin. Eur J Neurol 2008;15: Brex PA, Miszkiel KA, O`Riordan JI, et al. Assessing the risk of early multiple sclerosis in patients with clinically isolated syndromes: the role of a follow up MRI. J Neurol Neurosurg Psychiatry 2001;70: Kappos L, Moeri D, Radue EW, et al. Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability of impairment in multiple sclerosis: a meta-analysis. Lancet 1999;353: Merle H, Olindo S, Bonnan M, et al. Natural history of the visual impairment of relapsing neuromyelitis optica. Ophthalmology 2007;114: Watanabe S, Misu T, Miyazawa I, Nakashima I, Shiga Y, Fujihara K, Itoyama Y. Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis. Multiple Sclerosis 2007;13: Warabi Y, Matsumoto Y, Hayashi H. Interferon beta-1b exacerbates multiple sclerosis with severe optic nerve and spinal cord demyelination. J Neurol Sci 2007;252: Shimizu Y, Yokoyama K, Misu T, et al. Development of extensive brain lesions following interferon beta therapy in relapsing neuromyelitis optica and longitudinally extensive myelitis. J Neurol 2008;255: Tanaka M, Tanaka K, Komori M. Interferon-beta(1b) treatment in neuromyelitis optica. Eur Neurol 2009;62: Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up. Arch Neurol 2008;65: Asherson RA, Merry P, Acheson JF, Hughes GR. Antiphospholipid antibodies: a risk factor for occlusive ocular vascular disease in systemic lupus erythematosus and the primary antiphospholipid synhdrome. ANN Rheum Dis 1989;48: 대한신경과학회지제 29 권부록 2, 2011

122 특수상황에서의간질환자치료 : 고찰및증례허혈시신경병 순천향대학교의과대학신경과학교실, 부천순천향대학병원신경과 박지윤 Ischemic Optic Neuropathy Ji-Yun Park, MD, Tae-Kyeong Lee, MD, PhD Department of Neurology, College of Medicine, Soonchunhyang University, Soonchunhyang University Bucheon Hospital, Bucheon, Korea Ischemic optic neuropathy may be classified into two types: anterior ischemic optic neuropathy (AION) presenting pale edema of the optic disc and posterior ischemic optic neuropathy (PION) manifesting no remarkable changes on the optic disc during the acute stage. AION results from ischemic damage to the anterior portion of the optic nerve, which is primarily supplied by the posterior ciliary artery circulation. AION is generally divided into two types: arteritic AION (AAION), resulting from ischemia secondary to vasculitis (usually from giant cell arteritis, GCA), and non arteritic AION (NAION), resulting from noninflammatory small-vessel infarction of anterior optic nerve. PION is much less common than AION and also is divided into arteritic and nonarteritic conditions. PION generally occurs in either the perioperative setting or in the setting of GCA or other vasculitides and should be differentiated from any retrobular optic nerve pathology including compressive, inflammatory, and infiltrative optic neuropathies. While the management of arteritic ischemic optic neuropathy is relatively straightforward with steroids, various therapeutic trials for nonarteritic type has been applied but not established yet. In addition to ischemic optic neuropathy, central retinal artery occlusion (CRAO) and branch retinal artery occlusion (BRAO) can also result in sudden, catastrophic visual loss. Intraarterial thrombolysis for acute CRAO may produce superior visual outcomes compared with conventional treatments in certain situations. Key Words: Ischemic optic neuropathy, Optic nerve disease, Giant cell arteritis 서론 허헐시신경병은시신경염과더불어성인에서신경성시력상실의가장흔한원인중하나이다. 두질환은치료방침과예후가달라임상적으로두질환을감별하는것은중요하기때문에임상적인특징을숙지하고있어야한다 (Table 1). 허혈시신경병증은거대세포동맥염 (gaint cell arteritis, GCA) 을제외하면대부분급성으로발생하여통증없이일측의시신경을침범하고색각 (color vision) 이보존되는것이특징이다. 허혈시신경병은시신경유두의부종에따라앞허혈시신경병 (anterior ischemic optic neuropathy, AION) 과뒤허혈시신경병 (posterior ischemic optic neuropathy, PION) 으로나뉘며, 발생원인에따라동맥염성 (arteritic) 과비동맥염성 (non-arteritic) 으로다시세분되고, 침범된혈관에따라망막중심동맥폐쇄 (central retinal artery occlusion, CRAO), 망막분지동맥폐쇄 (branch retinal artery occlusion, BRAO), 망막정맥폐쇄 (retinal vein occlusion) 로분류하기도한다. 본고에서는안구의혈류공급에대한해부학적지식및허혈시신경병을분류하여살펴보고자한다. 시신경의혈관분포 Tae-Kyeong Lee, MD, PhD Department of Neurology, College of Medicine, Soonchunhyang University, Bucheon Hospital, 1174 Jung-dong, Wonmi-gu, Bucheon , Korea Tel: Fax: xorudoc@schmc.ac.kr 눈동맥 (ophthalmic artery) 은내경동맥 (internal carotid artery) 의경막내분지 (intradural branch) 중가장먼저분리되어앞으로진행한후시신경관 (optic canal) 으로들어와시신경의아래에분포한다 (Fig. 1). 1 눈동맥은눈확내부위 (intraobital portion) 에서시신경과교차하며망막중심동맥 (central retinal artery, J Korean Neurol Assoc Volume 29 Suppl. 2,

123 박지윤이태경 Table 1. Clinical Characteristics of Common Optic Neuropathies Optic Neuritis NAION AAION PION Heredity Papilledema Age Younger 60 (mean) 70 (mean) Any age Younger Any age Laterality Unilateral Unilateral Uni or bilateral Uni or bilateral Bilateral Bilateral Visual loss Rapidly progressive Acute, up to 61%>20/200 Pain Orbital pain frequent Infrequent with eye movement Acute, up to 76%<20/200 Headache, scalp tenderness, jaw claudication Acute Subacute (LHON); progressive (DOA) Acuity preserved until late Infrequent Absent Headache (raised ICP) Color vision abnormal Variably spared Variably spared Variably spared Abnormal Preserved until late Visual field Central defect Altitudinal defect (inferior) Optic disc (acute) Normal or disc edema Disc edema +/- small cup-to-disc ratio Altitudinal defect Altitudinal defect Cecocentral scotoma Peripheral constriction chalky-white optic disc swelling Normal disc Pseudoedema in LHON Disk edema (late) Temporal pallor Segmental pallor Pallor Pallor Pallor Pale swelling Visual prognosis Systemic disease Good Risk of multiple sclerosis Improvement in up to 43%, Fellow eye in <30% Vascular risk factors :DM,HTN Improvement rare, Improvement up to Fellow eye in up to 34%, Fellow eye in 95% 50-55% GCA, elevated ESR,CRP Vascular risk factor, GCA Poor Mitochondrial disease, DIDMOAD syndrome Reversible if treated early Any cause of raised ICP Figure 1. Schematic drawings of the blood supply of the optic nerve. (A) The ophthalmic artery provides major blood supply to the optic nerve. In the optic canal, the ophthalmic artery gives rise to the pial vasculature and pierces the optic nerve sheath becoming the central retinal artery. The central retinal artery does not contribute directly to the circulation of the optic nerve head. Instead, the major blood flow to the optic nerve head is derived from short posterior ciliary arteries, peripapillarychoroidal arteries and circle of Zinn-Haller. The short posterior ciliary arteries send branches to the circle of Zinn-Haller, peripapillarychoroidal arteries, and the pial vasculature. The central retinal vein parallels the course of the central retinal artery (Reproduced from Saden AA., Wang MY., 2011). CRA) 과외측후섬모체동맥 (lateral posterior ciliary artery) 으로분지하고이후눈물샘동맥 (lacrimal artery), 내측후섬모체동맥 (medial posterior ciliary artery), 후벌집동맥 (posterior ethmoid artery), 눈확위동맥 (supraorbital artery), 앞벌집동맥 (anterior ethmoid artery), 내측눈꺼풀동맥 (medial palpebral artery) 으로분지된후앞으로진행하여등쪽코분지 (dorsal nasal branch) 와도르래위동맥 (supratrochlear artery) 으로나뉘게된다. 시신경과의교차는 80% 가신경아래에서 20% 가신경의윗부분에서이루어지고, CRA 는신경집 (nerve sheath) 을뚫고지주막하공간 (subarachnoid space) 에서 1-3 mm 정도진행한후시신경으로들어가시신경의중앙으로진행하여시신경유두에서위측두쪽 (superior temporal), 위코쪽 (superior nasal), 아래측두쪽 (inferior temporal), 아래코쪽 (inferior nasal) 등네개의분지를낸다. 후섬모체동맥은다양하게분포하는데주로 2-3 개정도주요분지를낸후다시여러개의분지로나뉜후공막 (sclera) 을뚫고시신경주위에서진씨고리 (circle of Zinn-Haller) 라는연결고리 (anastomotic ring) 를형성하는짧은후섬모체동맥 (short posterior ciliary artery) 과공막내에서안와의내부구조들의혈류를공급하는긴후섬모체동맥 (long posterior ciliary artery) 으로나뉘게된다. 시신경유두는 CRA 에의해서직접적으로혈액공급을받는것이아니라짧은후섬모체동맥에의해형성되는진씨고리에의해혈액공급을받는다. 정상적으로안저검사상시신경유두주위에서 4개의 CRA 분지가관찰되고, 50% 에서는짧은섬모체동맥에서분지된섬모체막망동맥 (cilioretinal artery) 이관찰되기도한다. 92 대한신경과학회지제 29 권부록 2, 2011

124 허혈시신경병 비동맥염성앞허혈시신경병 (Nonarteritic Anterior Ischemic Optic Neuropathy, NAION) 비동맥염성앞허혈시신경병 (Nonarteritic anterior ischemic optic neuropathy, NAION) 은 50대이후발생하는시신경병증의가장흔한원인이다. 남녀의차이는없고, 발생평균연령은 세로고령에많이분포되어있으나 11세에서 90세까지다양한연령에서발생할수있으므로주의가필요하다. 2-4 대부분통증없이급격한시력저하를호소하고 10% 정도에서안구주위의둔통을호소하나전형적인시신경염에서호소하는눈을움직일때발생하는통증과는구분된다. 3 또한 IONDT (ischemic optic neuropathy decompression trial research group) 에따르면 42% 는기상후 2시간이내 42% 는오후에발생한다고알려져있어특정시간과의연관성은적다. 고혈압과당뇨병이 NAION 의위험인자로잘알려져있으나흡연, 고지혈증, 과트리글리세라이드혈증 (hypertriglyceridemia), 고호모시스틴혈증 (hyperhomocysteinemia), 야간저혈압 (nocturnal hypotension), 백내장수술등도위험인자로알려져있다. 백인종은흑인종이나라틴계에비해 NAION의빈도가높은것으로알려져있으며이는시신경이눈으로빠져나오는공막입구 (scleral opening) 가작아 ( 작은 cup-to-disc ratio), 즉시신경의밀도가높아시신경이쉽게손상받기때문으로추측된다. NAION의색각이상은상대적으로심한시신경염과달리시력소실과비례하여손상되므로비교적색각기능이보존되어있다 % 에서특징적인수평반맹 (altitudinal field defect) 이보고되고있으며특히아래쪽이더많다고알려져있으나시신경이상과관련된어떤시야결손에서도발생할수있다. 6 급성기안저검사에서는유두부종 (disc edema), 유두주위화염상망막출혈 (peripapillary flameshaped retinal hemorrhage) 이관찰될수있으며 4-6 주후에는이차적시신경위축을동반한광범위혹은부분적창백 (diffuse or segmental pallor with secondary atrophy) 이관찰될수있다 (Fig. 2). NAION 은 AAION보다시력소실이심하지않아 58-66% 에서 0.1 이상으로시력이유지되고대부분시력악화가진행하지않는다. 특별한치료를하지않아도시력은 41% 에서, 시야는 25% 에서 6개월까지회복을기대할수있으나이후에는더이상의호전을기대하기어렵다. 7 아직까지 NAION 의확립된치료는없으나시도되었던치료들은다음과같다. 3,8 이전에시신경초감압술 (optic nerve sheath decompression) 이시신경주위의조직을느슨하게하여압력을줄여줌으로써시력를호전시킨다는주장이있었으나, 9 최근에는시신경초감압술이효과적이지않을뿐아니라위험할수있다고알려져있다. 10 증상발생 2주이내심한시각소실 ( 시력 20/70 이하, 초기에심한시야장애 ) 을보이는경우 2주간 prednisolone 80 mg 경구치료를통해 6개월, 12개월후시력, 시야를호전시킨다는보고가있다. 7 이는급성기스테로이드치료가유두부종을감소시켜시신경앞쪽 (optic nerve head) 의모세혈관의혈액순환을호전시키기때문이라고추측하고있으나아직까지무작위통제된연구결과가없고스테로이드의부작용을고려해야하므로효과를판단하기어렵다. 반면에아스피린경구투여는 NAION 발생이후시력의회복에영향을미치지못한다고알려져있으나, 11 정상눈의이차적 NAION의발생을예방하기위해고려해볼수있다 명의 NAION 환자의후향적코호트연구결과 2년후정상눈의 NAION 발생을효과적으로감소시켰으나, 5년후는큰차이없는결과를보였는데 12 향후효과적인예방법을찾기위한연구가필요하다. 최근동물실험에서신경보호효과를가지고있는 topialbrimonidine 이효과 A B C Figure 2.Fundus photographs and Goldman visual field (GVF) of the nonarteritic anterior ischemic optic neuropathy (NAAION). (A) The hyperemetic disc edema is more prominent superiorly. Focal surface telangiectasia of disc vessels is seen superotemporally(arrows) (B) The disc, 2 months after onset, is segmentally atrophic superiorly (arrows), with sparing and resolving edema inferiorly. (C) GVF shows inferior altitudinal visual field defect (Reproduced from Arnold AC.,2009). 45 J Korean Neurol Assoc Volume 29 Suppl. 2,

125 박지윤이태경 가있다고알려졌으나. 13 임상시험에서 0.2% brimonidine tartrate 가효과가없는것으로밝혀졌다. 14,15 그외에 bevacizumab 유리체강내주입이신생혈관생성을억제하여부종을호전시켜효과가있다는연구가있으나아직까지치료가확립되지못했다. 16 그외항응고제, 17 diphenylhydantoin, 18 레보도파 (levodopa), 19 노르에피네프린정맥주입, 20,21 헤파린유발저밀도지단백 / 섬유소원침전혹은혈액희석 (heparin-induced low-density lipoprotein/ fibrinogen precipitation or hemodilution) 22 등이시도되었으나뚜렷한효과를입증하지못했다. 결론적으로 NAION 의확립된치료는없지만, 급성기심한시각소실시심한유두부종이관찰된다면경구스테로이드치료를고려해볼수있고, 장기적으로정상측눈에재발을방지하기위해항혈소판제의복용을고려하고혈관위험인자를조절하는것이무엇보다중요하다. 동맥염성허혈시신경병 (Arteritic Anterior Ischemic Optic Neuropathy, AAION) AAION 의대부분의원인인거대세포동맥염 (gaint cell arteritis, GCA) 은 50대이상에서새롭게발생하거나두통의양상이바뀌었을때의심해야하며특징적으로적혈구침강속도 (erythrocyte sedimentation rate, ESR) 와 C반응단백 (C-reactive protein, CRP) 수치가크게증가되어있다. 50세이후에연령이증가하면서발생빈도도현저히증가하여 60대에비해 70대에서약 9배, 90대에서 22배나증가한다. GCA 는백인종에서흔하게발생하나, 아프리카계아메리카인 (Africa-American) 과라틴계, 아시안에서는드물다고알려져있다. ICHD-II 의진단기준은 Table 2 와같으며가장흔한증상인두통은 70% 이상에서동반되고그외전신증상으로이마관자부위통증, 체중감소, 몸살, 식은땀등이동반되거나씹거나턱을많이움직일때허혈로인한통증이유발되는턱파행 (jaw claudication) 및시신경에혈액을공급하는혈관들이침범되어시력소실이발생할수있다. 시력소실은 대부분처음에일측으로발생하지만, 치료하지않으면수일내에 30% 까지양측으로발생할수있으므로빠른진단과치료가중요하다. 23 영구적인시력소실은일시적인시력소실이나턱파행의기왕력이있는경우증가하고간기능수치의상승이나열, 체중감소등전신증상이있는경우감소한다 AAION은안저검사에서백묵같이흰유두부종 (chalky-white optic disc swelling), 양측침범, 면모반 (cotton-wool spots) 이나망막경색 (retinal infarction) 같은동반된망막혹은맥락막동맥허혈 (concurrent signs of retinal or choroidal circulation ischemia) 등이관찰될수있다 (Fig. 3). 잘알려진대로대부분의 GCA 에서 ESR 의상승이관찰된다. ESR 의정상범위를정확히알수없으나일반적으로남성의경우나이를절반으로나눈값을여성의경우나이에 10을더한후절반으로나눈값을최대정상범위로정하여사용하고있다. 27 생검으로진단된 GCA 의 8% 에서 22% 까지 ESR이정상범위일수있으므로 ESR 이정상범위이더라도강력히 GCA 가의심된다면관자동맥생검을시행해야한다. 28,29 CRP 의민감도는 ESR( 민감도92%) 에비해높아 100% 까지보고되기도한다. 30 또한급성기에 ESR 보다빠르게상승하고효과적인치료에빠르게감소하므로임상에서유용하게사용될수있다. 30 이외에혈소판증가나 interleukin-6 의상승이관찰될수있다. GCA 의확진을위해얕은관자동맥 (superficial temporal Table 2. Gaint cell arteritis-international Headache Society Diagnostic criteria Headache attributed to giant cell arteritis A Any new persisting headache fulfilling criteria C and D B C D At least one of the following 1. Swollen tender scalp artery with elevated erythrocyte sedimentation rate (ESR) and/or C reactive protein (CRP) 2. Temporal artery biopsy demonstration giant cell arteritis Headache develops in close temporal relation to other symptoms and signs of giant cell arteritis Headache resolves or greatly improve within 3 days of high-dose steroid treatment Figure 3.Fundus photograph of the arteritic anterior ischemic optic neuropathy (AAION). The optic disc demonstrates diffuse chalky white optic disc edema during the initial stages (Reproduced from Hayreh et al., 2009) 대한신경과학회지제 29 권부록 2, 2011

126 허혈시신경병 artery) 의생검이필요한데생검시짧은길이를체취하면비연속적으로동맥염이침범 (skip lesion) 되어있을경우위음성 (false negative) 으로나올수있으므로최소한 3 cm 이상을체취하여야한다. 31 GCA의전형적인병리학적소견은혈관내막의비후 (intimal thickening), 내탄력판의분절 (fragmentation of the internal elastic lamina), 다수의다핵거대세포 (macrophages in the elastic lamina) 가있는육아종성염증이다. 32,33 GCA 가강력히의심되는데관자동맥생검에서위음성이나오는경우반대편관자동맥생검을시도하거나, 경험이많은병리학자에게재의뢰하는것을고려할수있다. 반드시필요한검사는아니지만색도플러영상 (color doppler imaging) 은혈류의이상, 혈관벽의부종등을관찰하여생검부위를확인할때, 34 MRI, MRA 는시신경의조영증강, 얕은관자동맥주변조영증강이나협착등을관찰 하기위해유용하게사용될수있다 조기스테로이드치료가대부분환자의시력소실을막는데효과적이므로 GCA 가의심되는경우고용량의스테로이드치료가되도록빨리시작되어야한다. 38 스테로이드치료후최소 2주동안 GCA 의병리학적소견이지속적으로관찰되므로생검을위해치료를미루어서는안된다. 39,40 Prednisolone 1 g/day 정맥투여를 3-5 일간유지한후고용량의경구 prednisolone 1-2 mg/kg/day 치료를최소 4주이상유지해야하며증상의소실, ESR, CRP 의감소를고려하여치료기간을결정한다. 스테로이드의장기간사용이골다공증, 당뇨병, 쿠싱증후군등부작용을일으킬수있으므로이에대한주의가필요하다. 최근에는스테로이드의용량을줄이기위해혹은스테로이드저항성 GCA인경우 cyclophosphamide, dapsone, methotrexate, azathioprine, infliximab, A B C D Figure 4. Diffusion weighted MRI (A), apparent diffusion coefficient (ADC, B) and fundus views (C,D) of the posterior ischemic optic neuropathy (PION). Diffusion weighted MRI of orbit (A) can reveal abnormal hyperintensity in left optic nerve(white arrow) with the reduced ADC (B, yellow arrow). The optic disc in PION (C) appeared normal in acute stage, but the optic disc becomes pale after 2 months. J Korean Neurol Assoc Volume 29 Suppl. 2,

127 박지윤이태경 저용량 aspirin 의단독혹은추가적치료를고려할수있다. 8 GCA 는안전수지 (count finger) 이하의시력소실이 54% 정도로 26% 정도인 NAION 에비해심한시력소실이관찰된다. 23 또한적절한치료에도불구하고시력의회복은 15% 정도밖에되지않는다. 그러나증상발생 24시간이내치료를시작하는경우 58% 까지시력회복을기대할수있으므로무엇보다조기스테로이드치료가중요하다. 뒤허혈시신경병 (posterior ischemic optic neuropathy, PION) PION 은시신경유두의부종을동반하지않고갑자기발생한시신경병증의경우의심해볼수있으나압박시신경병증, 침윤시신경병증, 유전시신경병증, 독성시신경병증, 외상시신경병증등을먼저배제해야한다. 초기안저검사는정상소견을보이나후에시신경위축 (optic atrophy) 이발생할수있다. PION은수술후혈류공급이저하되거나거대세포염을포함한혈관성질환등에의해발생할수있으므로 PION 이의심된다면이에대한검사가필요하다. 41 PION 에서뇌 MRI 는다른질환을배제하기위해시행하는데, 때때로확산강조영상MRI 에서시신경의이상소견이관찰되기도한다 (Fig. 4). 42 GCA 가원인인경우를제외하고 PION의정립된치료는아직까지없으며빈혈, 저혈압등위험인자를빨리확인하여교정시키는것이중요하다. 급성망막동맥폐색증후군 (Acute retinal arterial occlusive disorders) CRAO 는뇌혈관폐색의일종으로생각할수있으나인구 10만명당 0.85 명정도로빈도가낮고내경동맥에서기원하는혈전과연관성이높다. 43 눈동맥은경동맥에서 90도각도로꺾여서진행하는데심장에서기원한비교적큰붉은혈전 (red thrombi) 은경동맥내부의중심에위치하여이동하므로눈동맥으로진입하기어려우나, 내경동맥에서기원한혈전은크기가작고협착부위에서형성된난기류 (turbulence flow) 에의해혈관벽을돌며이동하다가눈동맥으로들어갈수있다. CRAO 는특징적으로앵두반점 (cherry red spot) 라는안저소견을보이는데이는허혈로인한부종과백색침착이보이는망막내층과섬모체동맥 (ciliary artery) 으로부터혈류공급을받고망막속층이없어상대적으로덜붓고, 엽황소 (xanthophyll) 로인해적갈색으로보이는황반부가대비되어관찰되는소견이다 (Fig. 5). CRAO 는시력예후가매우불량하여대부분 0.1 이하의시력을보이며망막동맥의폐쇄기간과정도가시력회복에연관성을갖는다. 44 안압하강, 혈 Figure 5. Fundus photograph of the left eye with CRAO. Fundal examination showed the cherry-red spot (arrow) with retinal pallor of CRAO (Reproduced from Raja et al., 2009). 47 관확장제, 망막부종감소, 고압산소요법, 항응고제, 항혈소판제등보존적인치료들이시도되었으나현재까지증명된효과적인치료는없었다. 43 CRAO 에대한혈전용해술이아직뚜렸한효과를입증하지못하였으나대부분심각한실명에이르므로증상발생급성기에내원한환자를대상으로동맥내혈전용해술 (intra-arterial thrombolysis) 을시도해볼수있다. 43 동맥내혈전용해술의적응증은 세로증상발생 24 시간이내이고시력이 20/60 이하로소실된경우이다. 반면에 BRAO 이거나섬모체망막혈관이황반의혈류를공급하거나심각한전신질환이있는경우에는시행하지말아야한다. 43 결 론 허혈시신경병은원인에따라치료및예후가다르고때로는응급을요하므로빠르고정확하게원인을찾고자노력해야한다. NAION 는약반이상에서 0.1 이상의시력을유지하고있으며 6개월내시력회복을기대해볼수있다. 또한, 동측눈의재발은적으나정상눈의재발이발생할수있으므로혈관위험인자를확인하여조절해야한다. GCA 는발생빈도가드물지만심각한시력저하를초래하고조기에치료하지않으면수일내에정상눈을침범할수있으므로의심된다면빠른시간내에고용량의스테로이드치료를시작해야한다. CRAO 는대부분심각한실명에이르지만급성기동맥내혈전용해술로시력회복을기대해볼수있으므로숙련된중재시술팀이있다면고려해보아야한다. 96 대한신경과학회지제 29 권부록 2, 2011

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Am J Ophthalmol 1997;123: Lui GT, Volpe NJ, Galetta SL.Neuroophthalmology: diagnosis and management. Philadelphia: Saunder; Rentsch JL, Liedel JL, Bayley NB, Buchanan MR, Goldblatt JC, Warren RJ, et al. Giant cell arteritis (GCA) presenting with severe aortic regurgitation and a normal ESR. Aust N Z J Med 1998;28: Ghanchi FD, Dutton GN. Current concepts in giant cell (temporal) arteritis. Surv Ophthalmol 1997;42: Salvarani C, Silingardi M, Ghirarduzzi A, Lo Scocco G, Macchioni P, Bajocchi G, et al. Is duplex ultrasonography useful for the diagnosis of giant-cell arteritis? Ann Intern Med 2002;137: Morgenstern KE, Ellis BD, Schochet SS, Linberg JV. Bilateral optic nerve sheath enhancement from giant cell arteritis. J Rheumatol 2003; 30: Mitomo T, Funyu T, Takahashi Y, Murakami K, Koyama K, Kamio K. Giant cell arteritis and magnetic resonance angiography. Arthritis Rheum 1998;41: Stanson AW. Imaging findings in extracranial (giant cell) temporal arteritis. 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129 박지윤이태경 40. Guevara RA, Newman NJ, Grossniklaus HE. Positive temporal artery biopsy 6 months after prednisone treatment. Arch Ophthalmol 1998;116: Newman NJ. Perioperative visual loss after nonocular surgeries. Am J Ophthalmol 2008;145: Verma A, Jain KK, Mohan S, Phadke RV. Diffusion-weighted MR imaging in posterior ischemic optic neuropathy. AJNR Am J Neuroradiol 2007;28: Biousse V, Calvetti O, Bruce BB, Newman NJ. Thrombolysis for central retinal artery occlusion. J Neuroophthalmol 2007;27: Hayreh SS, Zimmerman MB. Central retinal artery occlusion: visual outcome. Am J Ophthalmol 2005;140: Arnold AC. Ischemic optic neuropathies. In: Yanoff M., Duker J.(Ed.) Ophthalmology. 3rd ed. Amsterdam: Elseiver 2009; Hayreh SS. Ischemic optic neuropathy. Prog Retin Eye Res 2009;28: Raja MS, Marshall T, Burton BJ. Acute central retinal artery occlusion presenting as CREST syndrome: a case report. Cases J 2009;2:9. 98 대한신경과학회지제 29 권부록 2, 2011

130 특수상황에서의간질환자치료 : 고찰및증례뇌병변에의한시각이상 양산부산대학교병원신경과김선혜 Cerebral Visual Loss Seonhye Kim, MD Department of Neurology, Pusan National University Yangsan Hospital, Yangsan, Korea The symptoms of central visual disturbance depend on the location of disease or injury. Damage to the visual pathway from optic tract to striate cortex is characterized by homonymous visual field loss. Lesion in visual cortex such as V1-V5 area have shown various symptoms including Anton syndrome, blindshigh, riddoch phenomenon, akinetopsia, and cerebral achromatopsia. Two occipitofugal pathways: a ventral occipitogemporal pathway, often called the what pathway, and a dorsal occipitoparietal pathway, often called the where pathway are involved in processing of visual information. Lesion in the dorsal pathway may cause a variety of visuospatial disorders, such as Balint syndrome, hemispatial neglect, and visual allesthesia. Lesion in the ventral pathway may cause a variety of associative defects, including visual alexia, visual agnosia, and visual amnesia. Key Words: Lateral geniculate nucleus, Optic radiation, Striate cortex, Dorsal stream, Ventral stream, Homonymous visual field defect 망막에맺힌상은시신경 (optic nerve), 시신경교차 (optic chiasm), 시신경로 (optic tract), 가쪽무릎핵 (lateral geniculate nucleus), 그리고시각부챗살 (optic radiation) 을거쳐일차시각피질 (primary visual cortex) 로전달된다. 일차시각피질의정보는배쪽경로 (ventral occipitotemporal pathway) 와등쪽경로 (dorsal occipitoparietal pathway) 를통해상위피질시각영역으로연결된다. 여기에서는시신경교차이후의시각경로의해부학적구조와각시각경로의병변에서보일수있는다양한증상을설명하고자한다. 시각과관련된해부학적구조물 망막의신경절세포에서시작되는축삭은시신경을구성하여안와를통과한후시신경교차를이룬다. 시신경에는시신경교차에서반대편으로건너가는교차섬유와동측으로향하는비교차 Seonhye Kim, MD Department of Neurology, Pusan National University Yangsan Hospital, Beomeo-ri, Mulgeum-up, Yangsan , Korea Tel: Fax: antitj@hanmail.net Figure 1. Anatomy of the optic tracts and optic radiations. Appearance of the visual sensory pathway in axial section, viewed from below. Note the position of the optic tracts (black arrow) as they originate from the optic chiasm and diverge to end at the lateral geniculate nuclei. The optic radiations (white arrow) extend as fan-shaped structures from the lateral geniculate nuclei to the visual cortices (From Ghuhbegovic N, Williams TH. The human brain: a photographic guide. Hagerstown, MD, Harper & Row, 1980). J Korean Neurol Assoc Volume 29 Suppl. 2,

131 김선혜 섬유가 53% 대 47%로 구성되어 있다.1 망막에서 동측의 가쪽 리사이공간(interpeduncular space) 앞 부위에서 좌우로 나뉘 무릎핵으로 향하는 비교차섬유는 측두부망막(temporal retina) 어진 뒤 대뇌다리(cerebral peduncle)를 돌아 가쪽무릎핵으로 에서 기인하고, 반대편의 가쪽무릎핵으로 향하는 교차섬유는 코 향한다(Fig. 1). 상부 망막의 섬유는 회전하여 시신경로의 가쪽 쪽망막(nasal retina)에서 기인한다. 교차섬유와 비교차섬유는 에 위치하고, 하부 망막의 섬유는 내측에 위치한다. 그리고 황 시신경교차의 앞쪽에서 나누어지고, 등쪽망막(dorsal retina)으 반부 섬유는 배외측에 위치하고, 상하망막의 주변부 섬유는 각 로 부터의 교차섬유는 배쪽망막(ventral retina)에 비해 좀더 아 2 각 배내측과 복외측에 위치한다. 시신경로 내에서 세포의 기능 래부위에서 시신경교차로 들어간다. 황반부위의 교차섬유는 시 에 따라 섬유들의 부분적인 재배열이 일어나는데, M-망막세포 2 3 절세포의 큰 축삭은 좀더 표면에 위치하고, P-망막세포절세포 신경교차의 중앙과 뒤쪽에서 교차한다. 시신경로는 시신경교차와 가쪽무릎핵 사이 부분으로 대뇌다 3 의 작은 축삭은 연막(pia mater)가까이 위치하게 된다. 동공섬 유는 가쪽무릎핵으로 향하지 않고 시신경로를 떠나 덮개앞영역 (pretectal area)으로 향하고, 일부는 시상하부뇌실주위핵(paraventricular nucleus of hypothalamus)으로 향한다. 시신경로의 혈액공급은 내경동맥의 분지인 앞쪽맥락막동맥(anterior choroidal 4 artery)로 부터 이루어진다. 가쪽무릎핵은 망막과 시피질영역 V1, V2를 연결해주는 시상의 시각중추로 시상의 뒤아래쪽에 위치하고, 시상베개(pulvinar) 의 가쪽에 위치하고 있다. 가쪽무릎핵은 3가지의 하부구조로 나누어지는데, 등쪽핵(dorsal nucleus, dlgn), 무릎전복합체 Figure 2. Schematic diagram of coronal section through the primate lateral geniculate nucleus showing the parvocellular (P), magnocelluar (M), and koniocellular (K) layers. At this plane there are four P layers, two M layers, and six K layers. Lamina 1, 4, and 6 receive input from the contralateral eye; lamina 2, 3, and 5 receive input from the ipsilateral eye. The thin layers ventral to each of the six primary lamina to which the K-retinal gangion cells project are known as intercalated or interlaminar layer. A (pregenculate complex), 그리고 무릎사이소편(intergeniculate leaflet, IGL)이다. 이중 등쪽핵이 가장 크며, 망막과 시각피질을 연결시키는 역할을 한다. 등쪽핵은 6개의 층으로 나누어지는데, 2, 3, 5번 층에는 동측 측두부망막에서 온 섬유들이 도달하고, 2 1, 4, 6번 층에는 반대편 코쪽망막에서 온 섬유들이 도달한다. 1과 2번 층은 M-망막세포절세포로부터의 신호를 받고, 3-6번 5 층은 P-망막세포절세포로부터의 신호를 받는다(Fig. 2). 각 B Figure 3. Representation of the visual field in the lateral geniculate nucleus (LGN) in human. (A) The left homonymous hemifield separated into specific sector deginated by number (top) and latter (buttom). (B) The right LGN in coronal section from behind. Central vision is represented by cells located superiorly in the LGN, upper quadrant of the visual field is represented by cells located laterally in the LGN. 100 대한신경과학회지 제29권 부록 2, 2011

132 뇌병변에의한시각이상 층사이는 K-망막세포절세포로부터의신호를받는다. M-망막세포절세포는고농도의대비와저해상도의정보를전달하는반면색감의전달에는관여하지않아주로움직임에대한분석에관여한다. 6 P-망막세포절세포는저농도의대비와특정파장의신호를전달하여높은공간해상력 (spatial resolution) 과색각정보에관여한다. 6 K-망막세포절세포는파랑- 노랑색의보색정보를전달한다. 등쪽핵은반대편시야절반으로부터의신호를받는다. 가쪽무릎핵에서의신경섬유의분포는망막분포에서내측으로 90도회전한것으로위쪽망막으로부터의섬유는외측으로, 아래쪽망망으로부터의섬유는내측에위치한다. 그리고황반부의섬유는위쪽에위치하고, 가쪽부위의섬유는아래쪽에위치한다 (Fig. 3). 2 가쪽무릎핵의등쪽핵의세포들은축삭을줄무늬피질로보낸다. 가쪽무릎핵의혈류공급은앞, 뒤로나뉘어지는데, 앞쪽은내경동맥의분지인앞쪽맥락막동맥으로부터받고, 뒤쪽은뒤내뇌동맥의분지인가쪽맥락막동맥으로부터혈류공급을받는다. 시각부챗살은무릎새발톱신경로 (geniculocalcarine tract) 로불리며, 가쪽무릎핵으로부터일차시각피질로정보를전달한다. 시각부챗살은위, 아래, 가운데의 3다발로나뉘어지는데, 위와가운데다발은뒤쪽으로측두엽과두정엽을통해후두엽에도달하고, 아래다발은초기에앞쪽으로주행 ( 예, Meyer 고리 ; Meyer s loop) 하였다가가쪽뇌실측두각의위와측부로주행한후시각피질로향한다 (Fig. 4). 2 중심다발은가장크며, 황반부시야를전달한다. 위, 아래다발은각각아래와위시야를포함한다. 시각부챗살의혈류공급은위쪽은주로중대뇌동맥의하지분지에의하고, 아래쪽은후대뇌동맥으로부터공급을받는다. 2 시각피질영역은 V1 (striate cortex, Brodmann 17), V2 (Brodman 18), V3/V3A, V4, V5, and V6/V6A 로구성된다 (Fig. 5). V1영역은일차시각피질로줄무늬피질에해당되고, V2에서 V6 영역은이차시각피질영역으로분류된다. V1영역은후두엽의새발톱틈새 (calcarine fissure) 의위아래둔덕을포함하고, 6개의층으로이루어져있다. 제 I층은가장표면에위치하며, 신경은거의없고섬유성상세포와일부소아교세포, 그리고희소돌기아교세포로구성된다. 7 제 II층은작인피라미드세포를포함하고, 제 III층은 V1에서연합피질 (V2, V5) 로투사하는주요부분이다. 7 제 IV층은시각부챗살 ( 무릎새발톱신경로, geniculocalcarine pathway) 이이어지는부분이다. 이부위에서는 V1이외의시각영역으로신호를보내지는않지만, V1영역내에서의연접에관여한다. 2 IVB층은 Gennari 줄무늬가특징이어서줄무늬피질이라고불린다. 제 V층은다양한크기의피라미드세포를포함하며, 이들은위둔덕 (superior colliculus), 시상베개 (pulvinar) 로신호를보낸다. 8 제 VI층은중간크기의신경세포를포함하며, 이들대부분은위가쪽무릎핵에되먹임작용을한다. 일차시각피질세포의대부분은가쪽무릎핵을통해 P-혹은 M-경로로부터의흥분신호를받는다. V1영역의신경세포들은색깔과음영에반응하여색상의경계를인지하는데중요한역할을하게된다. 일차시각피질대부분은중심시야를담당한다. 실제로중심시야 10도범위를일차시각피질 50-60%, 30 도범위는약 80% 가담당한다 (Fig. 6). 9 황반부를담당하는부 Figure 4. Interpretation of the optic radiation (geniculocalcarine radiation) in human. Meyer s loop is that portion of the optic radiation that projects anteriorly (arrows) before then turning back to extend toward the primary visual cortex. Figure 5. Posterior lateral view of human visual cortex showing several of the visual associative areas. The cerebellum had been removed and the hemispheres have been separated and displaced medial and lateral occipital regions. V1 corresponds to the primary of striate visual cortex. J Korean Neurol Assoc Volume 29 Suppl. 2,

133 김선혜 위는 주로 뒤쪽에 위치하고, 주변시야를 담당하는 부위는 주로 (parastriate cortex)하고 있고, 줄무늬외시각영역(extrastriate 앞쪽에 위치한다(Fig. 6). 후두엽 손상 이후에도 황반부 시야가 visual cortex) 중 가장 넓다. 망막과 시상베개로부터의 신호는 보존되는 경우가 많은데 이는 황반부 시야를 담당하는 부위는 다른 영역에 분포하기 전에 V1을 거쳐 V2영역으로 모인다. V2 중대뇌동맥과 후대뇌동맥으로부터 이중혈류공급을 받기 때문 영역은 전전두엽(prefrontal), 감각, 운동, 청각연합영역, 대뇌 2 이다. V2영역은 Brodmann영역 18로 V1영역에 인접하여 위치 2 섬(insular)과 앞쪽 측두엽으로 신호를 투사하거나 받는다. V2 A B C D Figure 6. The presentation of the visual field in the human striate cortex. (A) Left occipital lobe showing location of striate cortex within the calcarine fissure (between arrows). The boundary (dashed line) between the striate cortex (area V1) and the extrastriate cortex contains the representation of the vertical meridians. (B) View of the striate cortex after opening the lips of the calcarine fissure. The dashed lines indicate the coordinates of the visual field map. The representation of the horizontal meridian runs approximately along the base of the calcarine fissure. The vertical dashed lines mark the isoeccentiricity contours from 2.5 to 4.0. Striate cortex wraps around the occipital pole to extend about 1cm onto the lateral convexity where the fovea is represented. (C) Schematic map showing the projection of the right visual hemifield upon the left visual cortex by transposing the map illustrated in B onto a flat surface. The row of dots indicates approximately where striate cortex folds around the tip of the occipital lobe. The black oval marks the region of the striate cortex corresponding to the blind spot of the contralateral eye. (D) Right visual hemifield plotted with a Goldman perimeter. The strippled region corresponds to the monocular temporal crescent, which is mapped within the most anterior 8-10% of the striate cortex (From Horton JC, Hoyt WF. The representation of the visual field in human striate cortex. A revision of the classic Holmes map. Arch Ophtalmol 1991;109: ) 102 대한신경과학회지 제29권 부록 2, 2011

134 뇌병변에의한시각이상 영역으로부터의신호는동측의 V3, V4, 그리고 V5영역으로신호를보내고, 또한뇌들보 (corpus callosum) 을통해반대편 V2 영역으로도신호를보낸다. 10 V3영역은 Brodmann 영역 18과 19 사이에위치하고있는작은부위로해부학적구성등에대해서는잘알려져있지는않다. V3영역세포의대부분은속도와방향에반응을하고, 50% 에서는색각에반응을한다. 11 V3영역은 V3d와 V3v로나누어지는데, V3d 부위는움직임을감지하는등쪽경로를형성하고, 일부는형태인식에특징적인배쪽경로를이룬다. 12 V1영역이완전히손상된경우 V2와대부분의 V3영역의신경세포는반응이없다. 그러나 V3A의일부에서는 V1 혹은 V2영역이완전히없는상태에서도빛자극에반응을한다. 이는 V1을경유하지않는시각부챗살의신경유입이있음을의미한다. V5영역은 MT (medial temporal) 라고도하는데원숭이에서중간측두엽이랑의꼬리쪽에위치하고, 사람에서는 Brodmann영역 19와 37사이에위치한다. 2 이영역은자극운동의방향을처리하는데있어가장중요한피질부위인것으로생각되며, 전반적인움직임이라기보다각각의시야에서국소적인움직임의정보를전달하는데중요하다. V4영역은물체의모양을시각적으로감지하는데관여하는배쪽경로로 V1, V2를통해유입된정보가 V4로전달된다. V4영역은주로시자극의모양, 색감, 질감에관여한다. V1와 V2영역에서두가지경로인등쪽경로와배쪽경로를통해다른시연합피질로신호를보낸다. 등쪽경로는물체가어디에있는지에관여하고 (where pathway), 배쪽경로는형태를인지하는데관여한다 (what pathway). 등쪽경로는 V1영역에서부터시작하여 V2영역을경유하여 V3, V5로향한다. 배쪽경로는 V1영역에서시작하여 V2와 V4영역을경유하여측두엽의아래쪽, 모이랑 (angular gyrus) 과변연계로향한다. 뇌병변에의한시각이상 중추성시각이상은병변의위치에따라다양한증상을보이게된다. 시각경로와일차시각피질의병변에서는동측시야결손 (homonymous visual field loss) 을보이고, 줄무늬외시각영역들과등쪽경로, 배쪽경로의병변에따라다양한증상이나타난다 (Table 1) 시야결손시야결손은시신경로의이상에서다양하게나타날수있다. 여기에서는시신경교차이후의병변에서나타날수있는시야결손에대하여기술하고자한다. 시신경로병변에서는불일치 (incongruous) 동측반맹 (homonymous hemianopia) 이나암점 (scotoma), 사분맹 (quadrantanopia) 이나타날수있다. 가쪽무릎핵의병변에서는불일치동측시야결손이발생되나, 일치성 (congruous) 동측부채꼴결손 (homonymous sectoranopia) 이나타나기도한다. 가쪽무릎핵의가쪽병변에서는위시야결손이, 안쪽병변에서는아래시야결손이나타난다 (Fig. 3). 시각부챗살의병변에서는병변의위치에따라다른데, 측두엽병변에서는동측위사분맹이주로나타나고, Meyer 고리의손상에서는불일치성동측위사분맹이나타난다. 두정엽병변에서는주로동측아래사분맹이발생한다. 한쪽후두엽앞쪽 Table 1. Syndromes localized to one of the visual cortical areas or fugal pathways Location Area V1 Area V2 and V3 Area V4 Area V5 Dorsal pathway Ventral pathway Syndrome Anton syndrome Blindsight Riddoch phenomenon Transient achromatopsia Visual ataxia Quadrantic homonymous hemianopsia Cerebral achromatopsia Akinetopsia Balint syndrome Hemispatial neglect Visual allesthesia Environment rotation Visual-verbal disconnection: pure alexia, color anomia, object anomia Visual-visual disconnection: prosopagnosia, object agnosia Visual-limbic disconnection: visual amnesia, visual hypoemotionality J Korean Neurol Assoc Volume 29 Suppl. 2,

135 김선혜 의병변에서는반대편한눈의측두부시야의 60에서 90도이르는초승달모양의시야결손 (temporal crescent) 이나타난다. 뒤쪽의병변일수록양안의일치성시야결손을보이게되는데동측반맹, 동측중심암점, 교차사분반맹, 그리고고리암점 (ring scotoma) 도발생될수있다 시피질과연관된증후군 1) Anton 증후군 (Anton syndrome) 일차시각피질의광범위한병변에서나타나는증후군으로보이지않는것을인지하지못하는현상인데, 시각상실을부인하거나이를감추기위해보이는것처럼표현한다. 이는무릎줄무늬경로 (geniculostriate pathway) 의손상외에도시각교차이전병변에서도나타나기도한다. Anton 증후군은시각상실을인지하는뇌의다른부위와의소통이상으로인하여발생하는것으로설명한다. 15 2) 맹시야 (blindsight) 피질시각상실 (cortical blindness) 이있는환자에서무의식적시각 (unconscious vision) 이남아있는것으로, 불빛눈깜박임반사 (photic blink reflex) 와같은시각반사 (visual reflex) 가유지되어있는것을통해확인할수있다. 16 맹시야는무릎줄무늬경로를거치지않는망막덮개시상베개경로 (retino-tentopulvinar-cortical pathway) 를경유하는부시각로에의해나타난다. 17 3) Riddoch 현상 (Riddoch phenomenon) 일차시각피질의병변에의해소실된시야에서물체의움직임을인식할수있는현상을말한다. 18 이러한현상은일차시각피질내기능이남아있는부분이있거나, 줄무늬외시피질특히 V5영역으로의시각정보의전달에의한것으로설명한다. 19 4) 대뇌색맹 (cerebral achromatopsia) 대뇌색맹이란후천성대뇌병변에의해색각이소실되는것을말한다. V4영역은인간색각중추 (human color center) 라불려지는데, 특히방추형이랑 (fugiform gyrus) 과혀이랑 (lingual gyrus) 의병변에서대뇌색맹이관찰된다. 20 환자들은흔히주변물체가흑백 TV를보는것과같다고느끼거나, 물체의색상이선명하지않고빛이바랜것처럼보인다고호소한다. 대뇌색맹은흔히시야장애와얼굴인식불능증 (prosopagnosia) 을동반하며, 시야의전체혹은일부에서관찰될수있다. 절반시야색맹은병변의반대쪽절반시야에서만색맹이나타나는경우로시야장 애를동반하는경우가흔하므로, 환자들도인지하지못할수있고, 자세한검사없이는확인하기힘들다. 양쪽병변에서는완전색맹이생길수있다. 21 5) 시각성실조 (Visual ataxia) 후부엽의손상으로인해동측시야결손이있는경우시야결손이있는방향으로쏠리는느낌이들수있다. 22 이는시각조화운동불능 (optic ataxia) 과는달리균형장애로인한것으로, 시선에의한사지의균형감의소실로발생된다. 6) 운동맹 (akinetopsia) 시각의다른요소인모양, 질감, 색각에대한인식은가능한반면시각적움직임을인식하지못하는경우를운동맹이라한다. 13 운동맹은위측두엽의뒷둑 (posterior bank) 의병변에서발생하는것으로알려져있다. V5영역을포함한편측의후두두정엽병변에서반대편시야에서의움직임에대한인식의결손이관찰되었고, fmri 를이용한연구에서정상인에서움직이는자극을보는동안위측두엽의활성을확인하였다. 23 7) Balint 증후군 (Balint s syndrome) 동시실인증 (simultanagnosia), 안구행위상실증 (ocularmotor apraxia), 시각조화운동불능 (optic ataxia) 의 3가지증상이특징으로, 양측두정후두엽병변에서발생한다. 24 동시실인증은주어진그림에서개별요소를인지하는데문제가없으나, 그것이이루는전체가뜻하는바를알지못하는것으로양측의시각적주의집중이동 (shift visual attention) 의장애에의한것으로여겨진다. 안구행위상실증은불수의적이고반사적인홱보기 (saccade) 는정상적으로할수있으나, 눈을의지대로움직이는못하는것으로후두엽과전두엽의눈운동영역 (frontal eye field) 이연결되지못하거나, 목표물을정확하게국소화하지못하는것이원인으로생각된다. 시각조화운동불능은물체를볼수있으나소뇌기증이상이나근력이상없이그물체를잡을수없는것으로, 물체에이르는동작을계획하는운동중추와후두엽의분리에의한것으로생각된다. 21 8) 시각이상감각 (visual allesthesia) 전형적인시각이상감각은망막중심적시야 (retinotopic visual field) 가회전하거나 (rotation), 뒤집히거나 (flipping), 혹은위아래가바뀌는 (invert) 현상을이르는말로가쪽연수와우측의후두두정엽의병변에의해서발생된다 (Fig. 7-B). 13 경련이나편두통에서도이러한시각이상감각이일시적으로나타날수있다 대한신경과학회지제 29 권부록 2, 2011

136 뇌병변에의한시각이상 A B C Figure 7. Illustrations on the view and orientation looking forward. (A) This figure shows the orientation of the environment that would be seen by a normal person looking forward. (B) This figure illustrates the appearance of the environment that would be seen by a patient with classic visual allesthesia. (C) This figure illustrates the environmental rotation experienced by a patient with right posterior parietal lobe lesion (From Girkin CA, Perry JD, Miller NR. Visual environmental rotation: a novel disorder of visiospatial integration. J Neuroophthalmol 1999;19:13-16). 9) 환경회전 (environmental rotation) 환경회전은시각이상감각에서보이는시야의회전과는달리물체즉환경의회전을보이는경우로실내에서특정물체의위치가바뀌거나회전한것처럼보인다 (Fig. 7-C). 13 이는우측두정엽을지나는뇌실복강션트를시행한정상뇌압수두증환자에서일시적으로실내의물체가회전되어보이는현상을보고하면서알려졌고, 이러한증상은뒤쪽두정엽의자극에의해서발생되는것으로설명하고있다. 26 배쪽경로의이상에서는얼굴인식불능증, 물체인식불능증 (object agnosia), 순수실독증 (pure alexia), 색각명칭실어증 (color anomia), 물체명칭실어증 (object anomia), 시각기억상실등이나타난다. 이외에도시각환상 (visual illusion) 이나시각환시 (visual hallucination) 등도고위시각피질이상에서보일수있다. References 1. Kupfer C, Chumbley L, Downer JC. Quantitative histology of optic nerve, optic tract and lateral geniculate nucleus of man. J Anat 1967;101: Miller NR, Newman NJ. Walsh and Hoyt s clinical neuro-ophthalmology. 6th ed. Baltimore: Williams & Wilkins, Reese BE, Cowey A. Fiber organization of the monkey s optic tract: I. Segregation of functionally distinct optic axons. J Comp Neurol 1990; 295: Carpenter MB, Noback CR, Moss ML. The anterior choroidal artery; its origins, course, distribution, and variations. AMA Arch Neurol Psychiatry 1954;71: von Noorden G, Middleditch P. Histologicall observations in the normal monkey lateral geniculate nucleus. Invest Ophthalmol Vis Sci 1975;14: Livingstone MS, Hubel D. Physiological evidence for separate channels for the perception of form, color, movement, and depth. J Neurosci 1987;7: Braak H. On the striate area of the human isocortex. A Golgi and pigment architectonic study. J Comp Neurol 1976;166: Lund JS, Lund RD, Hendrickson AE, Bunt AH, Fuchs AF. The origin of efferent pathways from the primary visual cortex, area 17, of the macaque monkey as shown by retrograde transport of horseradish peroxidase. J Comp Neurol 1975;164: Horton JC, Hoyt WF. The presentation of the visual field in human striate cortex. A revision of the classic Holmes map. Arch Ophthalmol 1991;109: Abel PL, O Brien BJ, Olavarria JF. Organization of colossal linkages in visual area V2 of macaque monkey. J Comp Neurol 2000;428: Gegenfurtner KR, Kiper DC, Levitt JB. Functional properties of neurons in macaque are V3. J Neurophys Sci 1997;77: Felleman DJ, Burkhalter A, Van Essen DC. Cortical connections of areas V3 and VP of macaque monkey estrastriate visual cortex. J Comp Neurol 1997;379: Girkin CA, Miller NR. Central disorder of vision in human. Surv Ophthalmol 2001;45: 장봉린. 신경안과학. 1st ed. Korea: 일조각 Joseph R. Confabulation an delusional denile: frontal lobe and loateralized influences. J Clin Psychol 1986;42: Hackley SA, Johnson LN. Distinct early and late subcomponents of the photic blink reflex: response characteristics in patients with retrogeniculate lesions. Psychophysiology 1996;33: Weiskrants L. Blindsight revisited. Curr Opin Neurol 1996;6: Mestre DR, Brouchon M, Ceccaldi M, Poncet M. Perception of optical flow in cortical blindness: a case report. Neuropsychologia 1992;30: Riddoch G. Dissociation of visual perceptions due to occipital injuries, with especial reference to appreciation of movement. Brain 1917: Moon SY, Kim JS, Shin DH, Park SH, Kim SY, Han ML, et al. Cerebra hemiachromatopsia. J Korean Neurol Assoc 2004;22: 김지수, 황정민외. 문답으로풀어가는신경안과진료. 1st ed. Korea: Epublic Rondot P, Odier F, Valade D. Postural disturbances due to homo- J Korean Neurol Assoc Volume 29 Suppl. 2,

137 김선혜 nymous hemianoptic visual ataxia. Brain 1992;115 Pt: Livingstone MS, Rosen GD, Drislane FW, Galaburda AM. Physiological and anatomical evidence for a magnocellular defect in developmental dyslexia. Proc Natl Acad Sci US 1991;88: Rizzo M, Hurtig R. Looking but not seeing: attention, perception, and eye movements in simultanagnosia. Neurology 1987;37: Hachinski VC, Porchawka J, Steele JC. Visual symptoms in the migraine syndrome. Neurology 1973;23: Girkin CA, Perry JD, Miller NR. Visual environmental rotation: a novel disorder of visiospatial integration. J Neuroophthalmol 1999;19: 대한신경과학회지제 29 권부록 2, 2011

138 특수상황에서의간질환자치료 : 고찰및증례 A Novel Retino-thalamo-cortical Pathway Mediating Migraine-type Photophobia Rami Burstein, PhD Departments of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center; Department of Neurobiology and the Program in Neuroscience, Harvard Medical School, Boston, MA Historically, photophobia was studied in patients and attempts to explain mechanisms were speculative. Efforts to understand better the neural substrate of photophobia paved way to the development of different animal models and the publication of several articles on the mechanism by which light exacerbates migraine headache. Observations made in blind migraine patients devoid of any visual perception and blind migraine patients capable of detecting light have led tothe discovery of a novel retino-thalamo-cortical pathway that carries photic signal from the retina to thalamic trigeminovascular neurons believed to play a critical role in the perception of headache intensity during migraine. Evidence for modulation ofthe trigeminovascular pathway by light and identification of the pathway through which photic signal converge on the nociceptive pathway that mediate migraine headache provide first set of scientific data on the mechanism by which light intensifies migraine headache. The lecture will provide a neural substrate for migraine-type photophobia and the discussion will focus on identification and development of molecular targets for selective prevention of photophobia during migraine. J Korean Neurol Assoc Volume 29 Suppl. 2,

139 특수상황에서의간질환자치료 : 고찰및증례 The Science Of Migraine Ten Years After Recognizing The Role Central Sensitization And Cutaneous Allodynia Play In The Pathophysiology Of This Malady Rami Burstein, PhD Departments of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center; Department of Neurobiology and the Program in Neuroscience, Harvard Medical School, Boston, MA In recent years, we discovered that the network of neurons that sense pain signals from the dura, changes rapidly during the course of a single migraine attack and that the treatment of an attack is a moving target. We found that if the pain is not stopped within minutes after it starts, the first set of neurons in the network, those located in the trigeminal ganglion, undergo molecular changes that make them hypersensitive to the changing pressure inside the head which explains why migraine headache throbs and is worsen by bending over and sneezing. We found that if the pain is not stopped within minutes, the second group of neurons in the network, those located in the spinal trigeminal nucleus, undergoes molecular changes that convert them from being dependent on sensory signals they receive from the dura by the first set of neurons, into an independent state in which they themselves become the pain generator of the headache. When this happen, patients notice that brushing their hair, taking a shower, touching their periorbital skin, shaving, wearing earrings, etc become painful, a condition called cutaneous allodynia. Based on this scenario, we showed recently that the success rate of rendering migraine patients pain-free increased dramatically if given before the establishment of cutaneous allodynia and central sensitization. The molecular shift from activity-dependent to activity-independent central sensitization together with our recent conclusion that triptans ability to disrupt communications between peripheral and central trigeminovascular neurons (rather than inhibiting directly peripheral or central neurons) explain theirclinical effects. Both our clinical and pre-clinical findings of the last 10 years point to possible short- and long-term advantages in using early-treatment approach in the treatment of acute migraine attacks. 108 대한신경과학회지제 29 권부록 2, 2011

140 특수상황에서의간질환자치료 : 고찰및증례편두통동반증상 : 빛공포증, 소리공포증, 냄새공포증 한림대학교의과대학신경과학교실주민경 Migraine Associated Symptoms: Photophobia, Phonophobia and Osmophobia Min Kyung Chu, MD, PhD Department of Neurology, Hallym University College of Medicine, Anyang, Korea Migraine is a common and disabling headache disorder which is associated with sensory symptoms during attacks. Sensory associated symptoms include photophobia, phonophobia, osmophobia, taste abnormality and allodynia. Though definitions and assessment method of sensory symptoms are not included in ICHD-2, photophobia, phonophonia and osmophobia are included in ICHD-2 or appendix diagnostic criteria for migraine without aura. Recent findings on sensory associated symptoms suggest that enhanced interactions between sensory input and trigeminal nociceptive pathways are key mechanism of sensory associated symptoms. Sensory associated symptoms are painful in addition to headache itself and management of sensory associated symptoms is helpful in reducing sufferings during migraine attacks. This review describes definition, assessment, mechanism and clinical significances of the photophobia, phonophobia and osmophobia, which are typical sensory associated symptoms of migraine. Key Words: Migraine, Photophobia, Phonophobia, Osmophobia, Symptoms 서 론 편두통은특징적인박동성의중등도- 심도의두통과동반증상이함께나타나는원발두통질환이다. 편두통발작기간 (ictal) 중의동반증상으로는구역, 구토등의소화기증상과빛공포증 (photophobia), 소리공포증 (phonophobia), 냄새공포증 (osmophobia), 무해자극통증 (allodynia), 맛이상 (taste abnormality) 등의감각과민증상이있다 (Fig. 1). 특히빛공포증과소리공포증은편두통환자에서발작기간중에흔하게나타나며편두통에비교적특징적인증상으로제2판국제두통질환분류 (the 2 nd edition of international classification of headache disorder, ICHD-2) 의편두통진단기준에동반증상의항목으로포함되어있다 (Table 1). 1 냄새공포증도편두통에비교적특이적인증상이며, 빛공포증, 소리공포증과함께무조짐편두통의 ICHD-2 부록 (appendix) Min Kyung Chu, MD, PhD Department of Neurology, Hallym University College of Medicine, 896 Pyungchon-dong, Dongana-gu, Anyang , Korea Tel: Fax: chumk@hallym.ac.kr 진단기준에포함되어있다 (Table 2). 본종설에서는편두통의특징적인동반증상으로편두통진단기준에포함되어있는빛공포증, 소리공포증그리고냄새공포증에대해고찰하고자한다. 1. 빛공포증 Taste abnormality Osmophobia Allodynia Olfaction Taste Somatosensory 본 론 1) 빛공포증의정의및평가빛공포증은포도막염 (uveitis), 섬모체염 (cyclitis), 홍채염 Sensory associated symptoms Vision Balance Hearing Photophobia Figure 1. The sensory associated symptoms of migraine. Dizziness Phonophobia J Korean Neurol Assoc Volume 29 Suppl. 2,

141 주민경 (iritis), 그리고눈꺼풀염 (blepharitis) 등의눈앞부분질환또는편두통, 수막염, 경질막밑출혈, 거미막밑출혈, 뇌종양과같은두개내질환과동반되어나타난다. 2-5 빛공포증은크게 : (1) 비정상적인빛에대한민감성 (abnormal sensitivity to light) 6 ; (2) 빛자극에의한눈의불편감 (ocular discomfort); (3) 빛에의한두통악화 7 (exacerbation of headache by light) 8 등의서로다른 3가지상태로정의할수있다. ICHD-2 에서는빛공포증평가방법이정해져있지않으며, 빛공포증의정의에따라다르게평가할수있다. 편두통의선별 (screening) 을위해널리사용되는 ID-Migraine에서는빛공포증을 두통없을때에비해두통이있을때밝은곳이나빛에의해더고통스럽다 (light bothers you a lot more than when you don t have headaches) 로정의하고있다. 9 회피행동으로빛공포증을평가한경우에는빛에의한두통악화에비해빛공포증유병률이증가한다고보 Table 1. The ICHD-2 diagnostic criteria for migraine without aura 무조짐편두통 1) 기준 B-D 를만족하는발작이최고한 5 번발생 2) 치료하지않거나치료가불완전한경우두통발작이 4-72 시간지속 3) 두통은최소한두가지이상을가진다. (1) 일측성 (2) 박동성 (3) 중등도또는심도의통증강도 (4) 일상적인신체활동 ( 걷거나계단오르기등의 ) 에의해악화되거나이를회피함 4) 두통이있는동안다음중최소한한가지이상을가진다. (1) 구역또는구토 (2) 빛공포증과소리공포증 5) 다른질환에기인하지않음. 고되었다. 10 편두통발작시의 ; (1) 빛이나특정형태에대한눈부심증상악화 ; (2) 빛에대한회피행동 ; (3) 빛에의한통증악화등다양한빛에대한못견딤상황으로평가하였을때, 한가지정의를사용한경우에비해보다효과적으로빛공포증을평가할수있다 (Table 3). 11 빛공포증은서유럽또는미국에서는인구조사나병원기반조사에서는편두통환자의약 80-90% 에서관찰된다고보고되나, 한국을포함한일본, 대만등의조사에서는 50-60% 로다소낮은빈도를보인다 ) 빛공포증의기전빛공포증은편두통의발작기간동안증가된대뇌피질의과흥분으로두통을인지하는삼차신경과시각중추감각경로의과 Table 2. The appendix diagnostic criteria for migraine without aura 무조짐편두통 1) 기준 B-D 를만족하는발작이최고한 5 번발생 2) 치료하지않거나치료가불완전한경우두통발작이 4-72 시간지속 3) 두통은최소한두가지이상을가진다. (1) 일측성 (2) 박동성 (3) 중등도또는심도의통증강도 (4) 일상적인신체활동 ( 걷거나계단오르기등의 ) 에의해악화되거나이를회피함 4) 두통이있는동안다음중두가지이상이동반됨 (1) 구역 (2) 구토 (3) 빛공포증 (4) 소리공포증 (5) 냄새공포증 5) 다른질환에기인하지않음. Table 3. Questionnaire for photophobia assessment (adapted from reference No. 11 with modification). Q1 Simple glittering sensation 머리가아플때밝은빛을보면유난히더눈이부십니까? During your headache, do you feel a great sense of glare or dazzle in your eyes than usual by bright light? Q2 머리가아플때평소와달리번쩍이는화면, 특정색이나선, 명암이뚜렷한그림등이눈에더 거슬리십니까? During your headache, do flickering lights, glare, specific colours or high contrast striped patterns bother you or your eyes? Q3 Avoiding behavior 머리가아플때는환한것이싫어서불을끄거나커튼을치십니까? During your headache, do you turn off the lights or draw a curtain to avoid bright conditions? Q4 머리가아플때는햇빛이강하지않는날에도선글래스를끼십니까? During your headache, do you have to wear sunglasses even in normal daylight? Q5 Painful photophobic symptoms 머리가아플때는밝은빛을보면눈이더아픕니까? During your headache, do bright lights hurt your eyes? Q6 머리가아플때는밝은빛을보면머리가더아픕니까? Is your headache worsened by bright lights? Q7 Headache triggering 밝은빛을보면머리가아픈것이시작되십니까? Is your headache triggered by bright lights? 110 대한신경과학회지제 29 권부록 2, 2011

142 편두통동반증상 : 빛공포증, 소리공포증, 냄새공포증 다한상호작용에의한것으로생각된다 편두통발작으로인한삼차신경경로의활성화는말초삼차신경계뿐만아니라시각전달경로와상호작용할수있는중추삼차신경계의활성화가유발되어빛공포증을유발한다고생각되고있다. 빛공포증이있는환자의 fmri 연구에서는밝은빛으로자극을할경우민감하게된삼차신경절, 삼차꼬리핵 (trigemical nucleus caudalis), 시상의뒤쪽내측배핵 (ventroposteromedial nucleus), 앞쪽띠이랑 (cingulate gyrus), 등의삼차신경경로와시각피질 (visual cortex) 의활성화가관찰되었다. 22 과거에는편두통발작시의빛공포증은두통의통증경로인삼차신경과시각경로가필수적이라고생각되었다. 그러나상형성 (image forming) 과빛감지 (light perception) 를모두상실한맹인편두통환자에서는빛공포증이관찰되지않으나상형성은상실하였으나빛감지를유지하는맹인편두통환자에서는빛공포증이관찰되어, 상형성보다는빛감지가빛공포증발생에필수적인것으로생각된다. 23,24 편두통발작시의두통은겉질확산억제 (cortical spreading depression) 등에의해경막에서통증유발물질이분비되고경막에분포되어있는삼차신경이통증자극을삼차신경절이있는뇌줄기로전달되고이어서뒤쪽시상 (posterior thalamus) 에위치한경막민감 (dura-sensitive) 신경세포를거쳐대뇌겉질에있는체감각신경세포 (somatosensory neuron) 로통증신호가전달되어나타난다. 25 최근상형성이아닌빛감지신경세포가망막에서직접뒤쪽시상으로연결되는경로가발견되었으며빛자극에노출될때이경로에의해뒤쪽시상에위치한경막민감신경세포의활성이증가함이관찰되었다. 뒤쪽시상의경막민감신경세포의축삭은시각겉질 (visual cortex), 몸감각겉질 (somatosensory cortex) 그리고연합겉질 (association cortex) 로광범위하게투사된다. 24,26 이러한편두통과빛공포증에대한일련의발견으로 : (1) 편두통발작시빛자극에의한두통악화는편두통발작시의두통을감지하고전달하는경막민감신경세포의통증신호가망막에서직접연결되는빛감지경로에의해뒤쪽시상에서상호작용이증가하여나타나는것으로설명되며 ; (2) 편두통발작시의빛에대한비정상적인민감성은뒤쪽시상에서시각겉질로투사되는일부경막민감신경세포에의해삼차혈관경로의활성화가시각겉질의기능에영향을주어유발된다고설명된다. 24,26 편두통환자는편두통발작기뿐만아니라편두통발작사이 (interictal) 기간에도비편두통환자에비해서밝은곳에서눈부심이더심하고, 빗금무늬 (striped pattern) 과같은특정형태에더불편함을많이느끼며, 선글래스를더자주착용하고, 사진촬영시의플래시불빛에더많이깜박인다 편두통환자의발작사이기간의시각자극에대한민감성을발작사이 빛공포증 (interictal photophobia) 라고한다. 편두통환자의발작사이빛공포증은편두통환자의겉질과민 (cortical hyperexcitability) 으로시각자극을포함한환경자극에대한과반응에의한것으로생각된다. 2,20,21,30 발작사이빛공포증과발작기빛공포증은모두병리기전에서편두통에서나타나는겉질과민이밀접하게관련되어있으며최근한연구에서편두통환자의발작사이빛공포증은발작사이빛공포증과밀접하게관련되어있다고보고되었다. 31 3) 빛공포증의임상적의미빛공포증은 ICHD-2 진단기준에동반증상의항목으로포함되며편두통을간단히선별하는선별도구에도포함되는등편두통진단과평가에서중요한증상이다. 편두통발작시에는빛공포증이있는경우빛공포증으로인해두통의악화가나타나며이로인해환자의고통이증가하므로편두통발작시에어두운곳에있든지, 커튼을치는등의빛자극을차단으로두통의악화를줄일수있다. 일부의환자에서는편두통발작이반짝이는빛이나밝은장소에노출될때유발될수있으므로, 빛자극에의한편두통유발여부를확인하고유발인자를회피하도록한다. 발작사이기간에도편두통환자는흔히발작사이빛공포증에의해눈부심이심하고, 빗금무늬등에의해불편감이자주나타나므로선글래스착용, 빗금무늬회피등을교육하도록한다. 2. 소리공포증 1) 소리공포증의정의및평가소리공포증은빛공포증과함께편두통발작시에관찰되는특징적인동반증상으로빛공포증과같이흔히편두통발작시에관찰되는동반증상으로 ICHD-2 진단기준의동반증상의항목으로포함되어있다. ICHD-2 에서는소리공포증에대한구체적인정의및평가방법이포함되어있지않으며, 빛공포증과유사하게편두통발작시에 (1) 비정상적인소리에대한민감성 ; (2) 소리자극에의한두통악화또는불편감등소리에대한여러가지못견딤상황으로평가할수있다. 흔히 두통없을때에비해두통이있을때소리에의해더고통스럽다 (Sound bothers you a lot more than when you don t have headaches) 와같이편두통발작시에소리에의한불편감또는두통악화로평가한다. 회피행동으로평가할경우소리에의한통증악화보다효과적으로소리공포증을평가할수있다고보고되었다. 10 2) 소리공포증의기전소리공포증은빛공포증과같이소리공포증도편두통의발작 J Korean Neurol Assoc Volume 29 Suppl. 2,

143 주민경 기간동안증가된대뇌피질의과흥분으로두통을인지하는삼차신경과청각중추감각경로의과다한상호작용에의한것으로생각된다. 32 그러나구체적으로어떤경로를거쳐서소리에대한민감도가증가하고불편간또는통증의악화가나타나는지는현재정확히밝혀져있지않다. 편두통환자는 (1) 소리에의해불편함을느끼는역치가더낮으며, 32 (2) 듣기유발전위 (auditory evoked potential) 검사에서습관화 (habituation) 가나타나지않으며, (3) 청각자극에대한대뇌피질의반응의증가가관찰되는점들은소리공포증이편두통에서나타나는대뇌피질의과흥분에의해나타나거나밀접히관련됨을시사한다. 36 3) 소리공포증의임상적의미소리공포증은편두통이외에도벨마비 (Bell s palsy), 내이의달팽이관질병 (cochlear disease), 속귀신경 (vestibulrchclear nerve), 등자뼈 (stapes) 질환과같은귀질환과거미막밑출혈, 경막밑출혈등의중추신경계질환에서나타난다. 특히중추신경계질환에서는두통과소리공포증이동반되어나타나므로진단에유의해야한다. 편두통환자에서는 60-85% 에서소리공포증이보고되었다. 소리공포증이동반된경우에는소리에의해두통의악화가나타나서환자의고통이증가하므로편두통발작시에소리자극이차단된조용한곳에있도록한다. 소리공포증이있는경우에는발작이없는기간에도소리자극에민감하고편두통이없는사람들이별로불편하지않은약한강도의소리자극에도불편하거나고통스러울수있으므로편두통환자의평가에서발작기및발작사이기간의소리공포증을평가하고이에적절히대처하도록하여두통의악화와소리자극에의한불편유발을방지하도록한다. 3. 냄새공포증 1) 냄새공포증의정의및평가냄새공포증은편두통발작기간중에후각의이상감각으로냄새가강하게느껴지거나약하게느껴지거나또는다르게느껴지는경우를말한다. 빛공포증, 소리공포증과마찬가지고 ICHD-2 에서는냄새공포증의정의와평가방법이포함되어있지않다. 인구집단에서편두통환자의냄새공포증에대한보고는아직없으나병원기반연구에서는편두통환자의 25-60% 의환자에서냄새공포증이보고되었다 편두통발작시에후각의이상뿐만아니라냄새자극에의해편두통의악화유발도보도된다. 42,43 다른병원기반의연구에서약 45% 의편두통환자가냄새자극에의해편두통발작을경험하며, 냄새자극에의한편두통유발이있는경우냄새공포증의빈도가 61.5% 로 보고되었다. 38,39 화학수용체에의한다른감각인미각의이상도편두통발작중에약 25% 에서나타난다고보고되었다. 39 한국에서병원기반으로조사한연구에서는냄새공포증은편두통환자의 38% 에서냄새공포증이관찰되었으며이중 54.8% 에서는냄새가다르게느껴졌으며, 41.9% 에서는강하게느껴졌고 3.2% 에서는약하게느껴진다고보고되었다. 냄새공포증의기간은대부분편두통기간중에 (83.9%) 나타나며, 90.3% 에서편두통발작의 2/3 이상의빈도로나타났다. 44 2) 냄새공포증의기전냄새공포증의기전에대해서는밝혀진바가적으며, 다른감각이상증상과같이편두통발작중의뇌의과흥분에의한것으로생각되고있다. 편두통발작시의 fmri 연구에서냄새자극을준후발생한편두통발작에서, 냄새자극없이나타난편두통발작에비해편도체 (amygdala), 섬 (insular) 그리고관자극 (temporal pole) 등의둘레엽 (limbic) 과입쪽다리뇌 (rostral pons) 의활성증가가관찰되었다. 그러나발작사이기간에는냄새공포증여부에관계없이둘레엽과입쪽다리뇌의활성화가관찰되지않았다. 45 편두통발작중냄새자극을준후 PET으로뇌활성을조사한연구에서는냄새자극에의해유사하게앞쪽측두엽의활성화가관찰되었다. 46 이러한결과는편두통병리기전에서후각과삼차신경의통증경로가편두통발작에서밀접한상호작용이있음을시사한다. 47 3) 냄새공포증의임상적의의냄새공포증은편두통이외에도뇌손상, 불안, 빠른호흡또는숨찬상태, 구강건조등에서나타난다. 두통이동반된경우에는긴장형두통에서는거의관찰되지않으나편두통환자의 25-75% 의환자에서관찰되는, 편두통에비교적특이한동반증상이다. 37,39,48,49 일차두통질환에서냄새공포증이동반되면편두통일가능성이높다고할수있다. 41 ICHD-2 무조짐편두통진단기준에서동반증상은구역또는구토가나타나거나빛공포증과소리공포증이동시에나타나는경우에진단할수있으나부록진단기준에서는구역, 구토, 빛공포증, 냄새공포증, 소리공포증등 5가지의동반증상중 2가지이상있는경우에진단할수있다 (Table 2). 부록진단기준을 ICHD-2 진단기준과비교했을때민감도는 0.85, 특이도는 1.00으로특이도가매우높았다. 44 편두통환자에서는냄새공포증여부에따라발작횟수, 강도, 임상특성, 두통에의한영향등이특별한차이는없다고보고되었다. 편두통발작시의냄새공포증에의해후각과민또는후각이상으로환자의고통이더증가할수있으며, 냄새공포증을가진 112 대한신경과학회지제 29 권부록 2, 2011

144 편두통동반증상 : 빛공포증, 소리공포증, 냄새공포증 환자의상당수에서냄새자극에의해편두통을유발한다. 환자의편두통발작에의한고통을경감하고편두통발작을감소시키기위해냄새공포증여부를평가하고냄새공포증과편두통발작을유발할수있는악취또는강한냄새를피하도록한다. 결 론 편두통발작시간중에는감각에대한과민증상이나타나며, 특히빛공포증, 소리공포증그리고냄새공포증은편두통발작도중에자주나타나는감각과민증상이다. 빛공포증과소리공포증은편두통 ICHD-2 진단기준에동반증상항목으로포함되어있으나현재그평가방법은규정되어있지않다. 빛공포증, 소리공포증과냄새공포증은편두통발작기간중의대뇌겉질의과흥분과밀접하게관련된것으로생각되고있다. 편두통발작시에두통에의한고통이외에도빛공포증, 소리공포증그리고냄새공포증에의해고통이유발될수있으므로편두통발작시에감각과민이동반된경우에는발작시에과다한자극을차단또는조절함으로써고통을줄일수있다. 일부편두통환자에서는빛, 소리, 냄새자극에의해편두통발작이유발되므로이러한자극에의해편두통이유발되면자극을회피하도록하여발작을방지하도록한다. References 1. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24: Aurora S, Cao Y, Bowyer S, Welch K. The occipital cortex is hyperexcitable in migraine: experimental evidence. Headache: The Journal of Head and Face Pain 1999;39: Kawasaki A, Purvin VA. Photophobia as the presenting visual symptom of chiasmal compression. Journal of Neuro-ophthalmology 2002;22:3. 4. 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145 주민경 Face Pain 2011;in press. 32. Ashkenazi A, Mushtaq A, Yang I, Oshinsky M. Ictal and interictal phonophobia in migraine-a quantitative controlled study. Cephalalgia 2009;29: Afra J, Proietti Cecchini A, Sandor P, Schoenen J. Comparison of visual and auditory evoked cortical potentials in migraine patients between attacks. Clinical Neurophysiology 2000;111: Ambrosini A, Schoenen J. The electrophysiology of migraine. Current Opinion in Neurology 2003;16: Ozkul Y, Uckardes A. Median nerve somatosensory evoked potentials in migraine. European Journal of Neurology 2002;9: Wang W, Timsit-Berthier M, Schoenen J. Intensity dependence of auditory evoked potentials is pronounced in migraine. Neurology 1996;46: De Carlo D, Dal Zotto L, Perissinotto E, Gallo L, Gatta M, Balottin U, et al. Osmophobia in migraine classification: A multicentre study in juvenile patients. Cephalalgia 2010;30: Kelman L. Osmophobia and taste abnormality in migraineurs: a tertiary care study. Headache: The Journal of Head and Face Pain 2004;44: Kelman L. The place of osmophobia and taste abnormalities in migraine classification: a tertiary care study of 1237 patients. Cephalalgia 2004; 24: Saisu A, Tatsumoto M, Hoshiyama E, Aiba S, Hirata K. Evaluation of olfaction in patients with migraine using an odour stick identification test. Cephalalgia Zanchin G, Dainese F, Trucco M, Mainardi F, Mampreso E, Maggioni F. Osmophobia in migraine and tension-type headache and its clinical features in patients with migraine. Cephalalgia 2007;27: Adress-Rothrock D, King W, Rothrock J. An analysis of migraine triggers in a clinic-based population. Headache: The Journal of Head and Face Pain 2010;50: de Lima AM, Sapienza GB, de Oliveira Giraud V, Fragoso YD. Odors as triggering and worsening factors for migraine in men. Arq Neuropsiquiatr 2011;69: Kim J, Chu M, Yu K, Ma H, Kim Y, Kim J, et al. Osmophobia during headache attacks and validation of alternative diagnostic criteria of migraine without aura in Korean headache patients. Korean Journal of Headache 2007;8: Stankewitz A, May A. Increased limbic and brainstem activity during migraine attacks following olfactory stimulation. Neurology 2011;77: Demarquay G, Royet J, Mick G, Ryvlin P. Olfactory hypersensitivity in migraineurs: a H215O PET study. Cephalalgia 2008;28: Grosser K, Oelkers R, Hummel T, Geisslinger G, Brune K, Kobal G, et al. Olfactory and trigeminal event related potentials in migraine. Cephalalgia 2000;20: Blau J, Solomon F. Smell and other sensory disturbances in migraine. Journal of Neurology 1985;232: Zanchin G, Dainese F, Mainardi F, Mampreso E, Perin C, Maggioni F. Osmophobia in primary headaches. The Journal of Headache and Pain 2005;6: 대한신경과학회지제 29 권부록 2, 2011

146 특수상황에서의간질환자치료 : 고찰및증례 편두통의주요한증상인오심과구토 한림대학교의과대학한강성심병원신경과조수진 Nausea and Vomiting, as a Main Symptom of Migraine Soo-Jin Cho, MD, PhD Department of Neurology, Hangang Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea Nausea and vomiting (NV) is the common accompaying symptoms of migraine. The presence of NV implay severity of headache and is important to differenciate migraine from tension-type headache. Pathomechanisms of NV are similar to that of migraine. Various stimuli from gut, blood, vestibular apparatus, brainstem nuclues, and cerebral cortex provoke NV through so-called vomiting center or central pattern generator for vomiting. Currently, nucleus tractus solitarius is considered as a key structure of nausea and dorsal motor nueclus of vagus do cruical role in vomitng. Several neurotranmitters involve in NV: serotonin, histamine, dopamine, neurokinin. NV is important in understanding and management of migraine. Key Words: Nausea, Vomiting, migraine, Serotonin, Solitary nucleus 서 론 오심과구토는독성이의심되는물질을피하거나제거하는자기보호기제이고, 임신, 약물, 수술후, 차멀미등다양한조건에서발생한다. 편두통환자의오심과구토는이러한외부적자극과달리세로토닌등의여러신경전달물질이뇌간의신경핵에작용하여발생한다는점에서독특하다. 1. 오심, 구토의기전 본 론 오심은토할것같은불쾌한느낌으로식욕부진이나구토를동반한다. 척추동물의특별한기능이며, 외부의가능한독성물질에대한효과적인감시장치이지만, 과도하거나불필요한경우 Soo-Jin Cho, MD, PhD Department of Neurology, Hangang Sacred Heart Hospital, Hallym University College of Medicine, 12 Beodnamuro 7 gil, Yeongdeungpo-gu, Seoul , Korea Tel: Fax: dowonc@naver.com 에도작용하여정상적인영양섭취를방해하거나건강에부정적영향을준다. 1 오심의감지와구토의발생에는뇌간의여러신경핵이작용하며, 고립핵, 미주신경의등쪽운동핵등이주요한매개센터로작용한다. 2 오심의자극으로장의이상이나이물질, 혈액성분, 정신적충격, 전정신경계의자극등이있다. 창백, 타액분비, 식은땀등이동반되며, 구토시위와식도, 횡격막근육의수축, 위식도괄약근의이완, 호흡의조절등이조화롭게이루어진다. 3-4 따라서오심과구토는여러신경전달물질이관여하는위장계의과민증상이며, 통증에대한과민증상을동반하는편두통과일맥상통한다. 2. 편두통의오심과구토오심은편두통의가장흔한동반증상으로 91.8% 가경험하며, 약 1/3의환자는매번편두통마다겪는다고한다. 5 그에비하여구토는적은환자가경험하고, 13.2% 의환자에서매번동반된다. 삽화성긴장형두통의진단기준에의하면식욕부진은동반될수있더라도오심이나구토는동반되지않아야하므로주요한감별점이다. 6 오심과구토는연령이나성별에따라다른빈도로동반된다. 여성에서더흔히보고되고, 소아보다는성인이나노인에서흔하다. J Korean Neurol Assoc Volume 29 Suppl. 2,

147 조수진 편두통에서오심과구토가발생하는원인은잘알려져있지않으나, 삼차신경핵에서고립핵으로전달되는정보가중요한역할을하며, 세로토닌등의신경전달물질이관여한다. 2 오심시위장운동이저하된다고추정되며, 구토가심하면섭취자체가어려워진다. 오심과구토만있는편두통아형은소아기주기성증후군에속하며복부편두통과주기성구토가있다. 복부편두통과주기성구토는소아나성인의원인불명위장질환의원인이며, 미토콘드리아이상, 자율신경계이상이관여되고, 편두통예방약물에효과가보고된다 오심, 구토의치료오심과구토를억제하는약물은다양한신경전달물질의수용체에작용한다. 도파민길항제인 metocloporamide와 domperidon 은편두통의보조적치료제로권장된다. 10 다른항구토제는주로수술후증상이나항암제에의한오심, 구토에서그효과가연구되었으며, 항히스타민제, 세로토민길항제, neurokinin 길항제등이있다. 11 Neurokinin 1 길항제인 Lanepitant 는편두통의신경인성염증을감소시켜효과가기대되었으나, 편두통의급성기나예방치료제로효과가관찰되지않았다. 12 세로토닌 3형수용체에대한길항제 ondansetron은두통이주요한부작용이다. 13 결론 오심과구토는편두통의주요한증상으로, 편두통에의한일상생활장애를악화시킨다. 오심과구토의기전은편두통의발생기전과긴밀한연관이추정된다. 편두통의보조치료제로도파 민길항제등의사용이권장되며, 다른항구토제의효과는향후검토될가치가있다. References 1. Horn CC. Why is the neurobiology of nausea and vomiting so important. Appetite 2008;50: Cuomo-Granston A, Drummond PD. Migraine and motion sickness: what is the link? Prog Neurobiol 2010;91: Sanger GJ, Andrews PL. Treatment of nausea and vomiting: gaps in our knowledge. Auton Neurosci 2006;129: Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007;132: Silberstein SD. Migraine symptoms: results of a survey of self-reported migraineurs. Headache 1995;35: Celetano DD, Stewart WF, Linet MS. The relationship of headache symptoms with severity and duration of attacks. J Clin Epidemiol 1990;43: Yang HR. Recent concepts no cyclic vomiting syndrome in children. J Neuroenterol Motil 2010;16: Hejazi RA, McCallum RW. Review article: cyclic vomiting syndrome in adults-rediscovering and redefining an old entity. Aliment Pharmacol Ther 2011;34: Carson L, Lewis D, Tsou M, McGuire E, Surran B, Miller C, et al. Abdominal migraine: an under-diagnosed cause of recurrent abdominal pain in children. Headache 2011;51: Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, et al. EFNS guideline on the drug treatment of migraine-revised report of an EFNS task force. European Federation of Neurological Societies. Eur J Neurol 2009;16: Macgregor GA. Anti-emetics. Curr Med Res Opin 2001;17:s22-s Goldstein DJ, Offen WW, Klein EG, Phebus LA, Hipskind P, Johnson KW, et al. Lanepitant, and NK-1 antagonist, in migraine prevention. Cephalalgia 2001;21: Singh V, Sinha A, Prakash N. Onddansetron-induced migraine-type headache. Can J Anaesth 2010;57: 대한신경과학회지제 29 권부록 2, 2011

148 특수상황에서의간질환자치료 : 고찰및증례편두통과어지럼 을지의과대학을지병원신경과김병건 Migraine and Dizziness Byung-Kun Kim, MD, PhD Department of Neurology, Eulji University College of Medicine, Eulji Hospital, Seoul, Korea Patients with migraine frequently have hypersensitivity to light, sound, and smell. In addition to these hallmark features of migraine, patients often describe vestibular complaints ranging from true vertigo to less specific symptoms of dizziness, unsteadiness, and head motion intolerance during migraine attack. Migraine may be a most common cause of various forms of episodic vertigo. However the pathophysiological association of episodic vertigo with migraine is still obscure. Key Words: Migraine, Vertigo, Dizziness, Aura, Vestibular migraine 서 론 빛, 소리및냄새에대한과민성은편두통에비교적특이한증상으로편두통의진단기준에도포함되어있다. 1 또한전정에대한과민성도흔하여많게는 70% 이상의편두통환자가어지럼 (dizziness) 이나현훈 (vertigo) 을겪는다. 2 한국을포함한아시아지역의 2782 명두통환자를대상으로시행한연구결과에서도편두통환자의 55% 가어지럼을호소하였다. 3 어지럼은두통의강도와비례하여나타나며, 2 구역 / 구토와함께편두통환자에게큰장애를초래하는동반증상이었다. 3 어지럼은편두통에서매우흔하며큰장애를초래하는동반증상임은잘알려져있지만편두통이반복성어지럼의원인이되는지는아직까지논쟁이있다. 4,5 편두통과어지럼 편두통과연관된다양한어지럼질환은다음 6가지로분류할수있다 (Table 1). 1) 편두통의조짐 (aura) 으로나타나는현훈 Byung-Kun Kim, MD Department of Neurology, Eulji General Hospital, Eulji University College of Medicine, 280-1, Hagye-dong, Nowon-gu, Seoul, , Korea Tel: Fax: kbk1403@eulji.ac.kr ( 기저형편두통 ); 2) 전정편두통 (vestibular migraine), 소아기양성돌발현훈 (benign paroxysmal vertigo in childhood) 같은무두통편두통 (migraine equivalent); 3) 편두통두통의동반증상으로나타나는어지럼이나현훈 ; 4) 가족성편마비편두통 (familial hemiplegic migraine), 삽화실조증2형 (episodic ataxia type 2) 등의 CACNA1A 유전자변이와연관된어지럼 ; 5) 불안장애등의동반이환질환및편두통예방약제와연관된어지럼 ; 6) 편두통과통계적으로연관성이제기되고있으나직접적인인과관계가불분명한메니에르병이나양성돌발체위현훈등의전정질환등이있다. 본문에서는편의상크게세가지로분류하여 ; 1) 편두통과반복성현훈, 2) 편두통발작의동반증상으로나타나는어지럼 3) 편두통에동반이환되는질환이나편두통치료약제와연관되어나타나는비전정성어지럼으로정리하였다. 1. 편두통과반복성현훈국제두통분류에서현훈이진단기준에포함된것은기저형편두통 (Table 2) 과소아기양성돌발현훈 (Table 3) 이다. 기저형편두통에서는 9가지조짐중하나로현훈이포함된반면소아기양성돌발현훈에서는편두통을두통의유무와관련없이반복적현훈의원인으로분류하였다. 소아기양성돌발현훈과마찬가지로성인에서의반복적인현훈을편두통으로분류한것이전정편두통이다. Neuhauser 와 Lempert 는국제두통학회의두통분 J Korean Neurol Assoc Volume 29 Suppl. 2,

149 김병건 Table 1. Classification of migraine related dizziness 1) Vertigo as a migraine aura Basilar migraine 2) Vertigo without migraine headache ( migraine equivalent ) Children : Benign paroxysmal vertigo of childhood Adults : Vestibular migraine 3) Vertigo/Dizziness during migraine attack 4) CACNA1A gene mutation and migraine Familial hemiplegic migraine, episodic ataxia type 2, SCA-6 5) Non-vestibular dizziness in migraine patients. Comorbid psychiatric disease Anti-migraine medication 6) Well defined vertigo syndromes that are not caused by migraine but show a statistical association with migraine Meniere s disease, BPPV Table 2. Basilar-type migraine At least 2 attacks fulfilling criteria B-D Aura consisting of at least two of the following fully reversible symptoms, but no motor weakness: 1. dysarthria 2. vertigo 3. tinnitus 4. hypacusia 5. diplopia 6. visual symptoms simultaneously in both temporal and nasal fields of both eyes 7. ataxia 8. decreased level of consciousness 9. simultaneously bilateral paraesthesias At least one of the following: 1. at least one aura symptom develops gradually over 5 minutes and/or different aura symptoms occur in succession over 5 minutes 2. each aura symptom lasts 5 and 60 minutes a. Headache fulfilling criteria B-D for 1.1 Migraine without aura begins during the aura or follows aura within 60 minutes Not attributed to another disorder 류에맞추어전정편두통의진단기준을제시하였으며 확정적 과 개연적 으로나누어각각특이도와민감도를높였다 (Table 4). 5 하지만편두통이흔히임상에서보는반복적인현훈의원인이되는지는다음과같은이유로회의적이다. 1) 편두통은 50대이후유병율이급격이감소하는반면현훈은고령에서흔하므로편두통이현훈의원인이될가능성은적다. 2) 기저형편두통과같이현훈외에두가지이상의조짐이동반되는전정편두통은드물다. 3) 소아기양성돌발현훈은소아기에두통과상관없이반복적인현훈을보이다가청소년기이후에는현훈은소실되고편두통이주로나타나는반면전정편두통은나이가증가하면서유병율이증가한다. 6 4) 전정편두통의병태생리기전이불명확하다. 또한 CACNA1A 유전자변이에의한가족성편마비편두통과삽화성실조증2 형에서현훈과편두통은흔히나타 Table 3. Benign paroxysmal vertigo of childhood 1. At least 5 attacks fulfilling criterion B 2. Multiple episodes of severe vertigo, occurring without warning and resolving spontaneously after minutes to hours 3. Normal neurological examination and audiometric and vestibular functions between attacks 4. Normal electroencephalogram Table 4. Diagnostic criteria for vestibular migraine Definite vestibular migraine 1. Episodic vestibular symptoms of at least moderate severity 2. Current or previous history of migraine according to the 2004 criteria of the HIS 3. One of the following migrainous symptoms during at least two vertiginous attacks: a) Migrainous headache, b) Photophobia, c) Phonophobia, d) Visual or other auras 4. Other causes ruled out by appropriate investigations Probable vestibular migraine 1. Episodic vestibular symptoms of at least moderate severity 2. One of the following: 3. Current or previous history of migraine according to the criteria of the International Headache Society 4. Migrainous symptoms during vestibular symptoms 5. Migraine-precipitants before vertigo in more than 50% of attacks: food triggers, sleep irregularities, hormonal changes 6. Response to migraine medications in more than 50% of attacks 7. Other causes ruled out by appropriate investigations 나기때문에이유전자는전정편두통의후보유전자로많은연구가시행되었지만현재까지전정편두통과연관된이온통로의유전적결함은발견되지않았다. 2. 편두통발작의동반증상으로나타나는어지럼 약 50-70% 의편두통환자가두통중현훈을포함한다양한어지럼을호소한다. 2,3,7 그러나그중 1/3 미만이회전성어지럼이며, 현훈이편두통의주된또는가장심한증상인경우는단 5-8% 에불과하다. 7,8 차멀미나배멀미같은동요병이긴장형두통환자나정상인에비하여편두통환자에서흔한데이러한현상은조짐편두통과아동기에더뚜렷하다 이것은편두통환자가다른감각기관 ( 청각, 후각, 시각 ) 에도과민성을보이는것과연계하여설명할수있다. 또한비두통기에도정상인에비하여차멀미등동요병을경험하는빈도가높다 편두통과비전정성어지럼 편두통환자에서편두통의병태생리와연관성이없는어지럼이발생하는원인은다음과같은것들이있다. 118 대한신경과학회지제 29 권부록 2, 2011

150 편두통과어지럼 1) 불안장애, 우울증및공황장애등의정신과적이상불안장애, 우울증및공황장애등정신과적이상의동반이환이편두통환자에서흔하다. 어지럼은심계항진과더불어가장흔한공황장애의증상으로진단기준에도포함되어있고불안장애및우울증에서어지럼은흔한동반증상이다 어지럼환자 268 명를대상으로한연구에서공황장애환자가 17.2%, 주요우울증환자가 11.2% 로나타났다. 16 신경과외래를방문한 189 명의어지럼환자에게정신과및신경이과적검진을시행한결과 27% 가기질적어지럼, 52% 가심인성어지럼, 16% 가기질적원인과심인성원인이혼재된것으로나타났다. 17 한편이연구에서심인성어지럼환자와혼재성어지럼환자간에정신과질환의종류에차이가없는것으로나타나정신과적질환의존재만으로기질적원인을배제할수없음을알수있다. 즉정신과질환이어지럼의원인이될수도있지만기질성어지럼이기존의정신과질환에의하여더악화되거나어지럼이불안장애등정신과질환을일으킬수있다는사실은매우중요하다. 2) 편두통치료약제의의한부작용베타차단제, 칼슘통로차단제및삼환계항우울제는기립저혈압을유발할수있다. 또한베타차단제에의한무력감또는삼환계항우울제에의한졸림, 시력장애등을환자는어지럽다고표현할수있다. 결론 편두통환자는흔히어지럼을경험한다. 편두통발작중에발생하는어지럼은구역, 구토, 빛공포증, 소리공포증등과같이편두통에동반되는많은증상중하나로편두통예방약제에의하여조절될수있다. 한편공황장애에나불안장애등의편두통동반이환질환이나편두통치료약제도어지럼을유발시킬수있다는점도고려해야한다. References 1. The international classification of headache disorders: 2nd edition. Cephalalgia 2004;24 Suppl 1: Kelman L, Tanis D (2006). The relationship between migraine pain and other associated symptoms. Cephalalgia 26: Wang SJ, Chung CS, Chankrachang S, et al. Migraine disability awareness campaign in Asia: Migraine assessment for prophylaxis. Headache 2008;48: Phillips J, Longridge N, Mallinson A, Robinson G. Migraine and vertigo:a marriage of convenience? Headache 2010;50: Neuhauser H, Lempert T. Vestibular migraine. Neurol Clin 2009;27: Abu-Arafeh, Russel G. Paroxysmal vertigo as a migraineequivalent in children: a population based study. Cephalalgia 1993;15: Bayazit Y, Yilmaz M, Mumbuc S, Kanlikana M, Assessment of migraine-related cochleovestibular symptoms. Rev Laryngol Otol Rhinol (Bord) 2001;122: Harker LA. Migraine associated vertigo. In Baloh RW, Halmagyi GM (eds). Disorders of the vestibular system. Oxford University Press, Oxford, 1996: Kayan A, Hood JD. Neuro-otological manifestations of migraine. Brain 1984;107 ( Pt 4): Kuritzky A, Ziegler DK, Hassanein R. Vertigo, motion sickness and migraine. Headache 1981;21: Barabas G, Matthews WS, Ferrari M. Childhood migraine and motion sickness. Pediatrics 1983;72: Margraf J, Taylor B, Ehlers A, Roth WT, Agras WS. Panic attacks in the natural environment. J Nerv Ment Dis 1987;175: Breslau N, Schultz LR, Stewart WF, Lipton RB, Lucia VC, Welch KM. Headache and major depression: Is the association specific to migraine? Neurology 2000;54: Breslau N, Schultz LR, Stewart WF, Lipton R, Welch KM. Headache types and panic disorder: Directionality and specificity. Neurology 2001;56: Furman JM, Jacob RG. Psychiatric dizziness. Neurology 1997;48: Persoons P, Luyckx, Desloovere C, Vandenberghe J, Fischler B. Anxiety and mood disorders in otorhinolaryngology outpatients presenting with dizziness: validation of the self administered PRIME-MD Patient Health Questionnaire and epidemilology. Gen Hosp Psychiatry 2003;25: Eckhardt-Henn A, Breuer P, Thomalske C. Anxiety disorders and other psychiatric subgroups in patients complaining of dizziness. J Anxiety Disord 2003;17: J Korean Neurol Assoc Volume 29 Suppl. 2,

151 특수상황에서의간질환자치료 : 고찰및증례 혈액뇌장벽과면역특권 인제대학교상계백병원신경과학교실박재현 Blood-brain barrier and immune privilege Jae Hyeon Park, MD, PhD Department of Neurology, Sanggye Paik Hospital, Inje University, Seoul, Korea The blood-brain barrier (BBB) is a complex and dynamic interface between blood and the central nervous system (CNS) and provides protection for the brain. Central nervous system immune privilege is indispensable for damage limitation during inflammation and BBB plays an important role in maintaining immune privilege. Immune cell invasion across BBB is carefully restricted in general, but the immune privilege of the brain is certainly not absolute but is relative to other organs. Current researches suggest that impairment of BBB and abolition of brain immune privilege might be related with traditional neurological degenerative diseases. Further understanding of the BBB will lead to novel therapies to manipulate CNS inflammatory diseases. Key Words: Blood-brain barrier, Immue privilege 서 론 면역계의중요한역할은바이러스, 세균등외부의미생물로부터인체를보호하는것이다. 이방어작용을유지하기위하여인체는새로생기고, 형태를바꾸는외부면역원들의변화에적절히반응하여감염이진행되지못하게한다. 이를위하여중추신경계에는세균, 바이러스등을포함한병원균, 특정물질등이침입하는것을막는일종의기능적장벽이존재하는데이를혈액뇌장벽이라고한다. 이장벽의존재는 19세기말부터에측되어왔는데실험적방법을사용하여 1908년 Emil Goldmann이존재를증명하였다. 1 그는트리판블루를정맥주사하였을때이염료가다른신체장기에서나타났지만뇌에서는보이지않았으나뇌척수액에주사하였을때에는뇌가염색이되는것을발견하고뇌와혈액사이에트리판블루가투과하지못하는장벽이있다고생각하였다. 중추신경계는오래전부터면역특권기관으로여겨져왔다. Jae Hyeon Park, MD, PhD Department of Neurology, Sanggye Paik Hospital, Inje University, Sanggye 7dong, Nowon-gu, Seoul, Korea Tel: Fax: jhparkmd@paik.ac.kr 면역특권이란항원이인체내로침입하였을때면역반응이일어나지않는인체조직을일컫는말로써대표적으로눈, 뇌, 고환등을들수있으며넓은의미로임신중의태아도이에속한다. 면역반응자체가이들인체조직에손상을일으킬수있으므로면역특권은이를피하기위한인체의적응과정으로여겨져왔다. 중추신경계는다른장기에비하여동종이식면역반응이적게일어나고염증이없는상태에서 MHC class II 분자가존재하지않는다는점들이중추신경계가면역특권이있는조직이라는근거이다. 그러나최근의개념은면역반응이실제중추신경계내에서일어날수있다는것이다. 전통적인개념의염증을일으키는뇌수막염, 뇌염등에서는세균, 바이러스등의병원체가혈액뇌장벽을파괴시키고그결과혈액의면역세포가중추신경계내로진입하게된다. 다발성경화증같은자가면역질환에서도유사한소견이보이는데이때는면역체계가중추신경계의수초관련구조를표적으로하게된다. 이와같은질환에서볼수있는중추신경계의염증반응은뇌등중추신경계에서도면역반응이일어나고있다는것을의미한다. 최근에는알츠하이머씨병, 파킨슨씨병, 헌팅턴씨병등과같은비염증성중추신경계질환에서도만성염증반응이관찰되고있다. 2,3 이때일차적인손상은대사성, 퇴행성변화때문이며이때는혈액뇌장벽의파괴, 활성화된면역세포의중추신경계내의대량진입같은소 120 대한신경과학회지제 29 권부록 2, 2011

152 혈액뇌장벽과면역특권 견보다는미세한면역학적변화가관찰되는데이는이전에는반응성신경교증식증 (reactive gliosis) 이라불렸으며병적소견으로간주되지않았었다. 혈액뇌장벽 뇌를말초조직과구분하는경계에는해부학적인경계와생리적인경계가있는데혈액내의병원체가뇌로들어가기위해서는혈류와중추신경계사이의생리적경계를건너야한다. 중추신경계와혈류의구분은혈액뇌장벽과혈액뇌척수액장벽에의해서나누어지는데이중혈액뇌장벽이 99% 를차지하며나머지 1% 를혈액뇌척수액장벽이차지한다. 혈관과중추신경계사이의혈액뇌장벽은미세혈관의혈관내피, 내피세포와기저막을공유하는혈관주위세포, 성상세포등으로구성되는데이세포는말초조직에있는네피세포와는달리전기저항이커서세포주위의틈이거의없는폐쇠연접 (tight junction) 이있으며, 세포흡수작용 (pinocytic activity) 가거의없어세포횡단전달도거의없게된다 (Fig.). 신경조직에필요한작은분자량의물질들은세포막의운반물질과결합하게된다. 이들의작용에의하여병원체뿐아니라세포, 단백질등이중추신경내로진입하는것이억제된다. 평상시핼액뇌장벽의 Figure. Blood-brain barrier. Schematic outline of a capillary of the blood-brain barrier in a transverse section showing the endothelium with a tight junction, basement membrane, a pericyte, and a astrocyte. The location of a gap junction between end-feet of the astrocyte is conceptually shown. 투과성은폐쇄연접을조절하는성상세포파생요소에의해조절된다. 내피세포간의간격에는일련의세포내단백질과세포막부착단백질이존재한다대표적인세포막부착단백은 claudin과 occludin 등을들수있다. 이밖에 JAMS(junctional adhesion molecules), PECAM(platelet endothelial cell adhesion molecule) 등이알려져있다. 뇌의원활한기능을유지하기위해서는혈액내의단백이뇌실질내로공급되어야하는데이때는수용체등과결합한내포작용 (endocytosis) 에의하여중추신경계내로운반이된다혈액뇌척수액장벽은맥락막총에위치하며맥락막총은투과성이있는모세혈관과소정맥을포함한다. 맥락막총바깥은혈액과뇌척수액의경계를이루며뇌실막층과연속된상피양세포로구성된다. 뇌실막세포의뇌척수액쪽의폐쇄연접은세포, 단백질등의진입을억제하나그정도는혈액뇌장벽보다는약하다. 중추신경계의혈액뇌장벽과면역특권 면역반응은 T 임파구가항원을인지하면서시작된다. 이과정이일어나려면미성숙 T 세포가활성화되어야한다. T 세포는유리된항원을인지하지못하므로항원과 T 세포표면의항원수용체가결합하는과정이필요하고이때 T 세포는항원전달세포 (antigen presenting cell) 의주요조직적합복합체유전저분자에결합되어있는항원을인지한다. 이외에도 T 세포가활성화되려면항원전달세포에서발현된부수자극이필요하다. 항원전달세포와결합된항원을 T 세포가인지하여수시간이경과하면미성숙세포가활성화되어증식, 분화하게된다. 이반응은이차임파조직으로알려진조직에서대량으로일어나게된다. 뇌를포함한중추신경계가말초조직과는다른면역반응을보인다는것은멀게는 1920년대부터이며 4 면역특권의개념은 1950 년대에언급되기시작되었다. 5 이후로중추신경계는항원전달세포가없고임파액의우출이없으며부수자극요소가충분하지않은등의이유로면역학적특권이있는조직으로알려져왔다. 특히혈액뇌장벽의해부학적, 기능적소견이밝혀지고이에대한연구가활발할때에면역특권에대한연구도활발히이루어져서뇌의면역특권은절대적인것이며이는전적으로혈액뇌장벽의존재때문이다라고생각되어왔다. 그러나최근의연구들에의하면혈액뇌장벽의내피세포에서도주요조직적복합체가발현되고 6 대뇌미세혈관주위의교세포, 대식세포등도항원전달세포역할을한다고밝혀져 7,8 이들이혈액뇌장벽에서일어나는면역반응의중요한역할을한다고여겨진다. 또혈액뇌장벽은내피세포를통한백혈구의이동을억제하는기능을통하 J Korean Neurol Assoc Volume 29 Suppl. 2,

153 박재현 여중추신경계에서의면역반응을적절히조정하게되는등중추신경계의면역특권은말초에비하여상대적이라는의미이며혈액뇌장벽은이의일부를책임진다는것이알려졌다. 중추신경계는재생능력이약한신체기관이기때문에염증등의손상을입을수있는상황에서피해를최소화하기위한필수적방어체계이다. 그러나뇌손상시중추신경계의면역특권은약해질수밖에없으며이는혈관뇌장벽의손상에의한면역억제작용의약화, 사이토카인, 케모카인등의영향등때문이다. T 세포이주 T 세포는정상상태에서는중추신경계내로들어가지않고이차임파조직과혈액사이를순환한다. 그러나일단 T 체포가활성화되면 IFN-γ, IL-1, 2, TNF-α 등림포카인, 사이토카인이분비되고이는유착분자, 기질금속단백분해효소의분비를유발시켜 T 세포를염증부위로인도한다. 활성화된 T 세포는항원특이성과관계없이혈액뇌장벽을통과하며중추신경계항원과의특이성이있는 T 세포가뇌실질에남는다고생각된다. 9 T 세포가뇌실질로진입하는것은간단하지않다. 우선백혈구가 selectin과유착분자사이의작용에의하여내피세포에고정, 부착된후 chemokine 에의하여백혈구가자극되어이주되고곧백혈구 integrin 부착분자가활성화되면서혈관내막에발현된 ICAM-1, VCAM-1 등의면역글로부린 superfamily 와부착되어혈관밖으로유출되어조직내로들어간다. 세균성뇌수막염의중추신경계손상기전 뇌척수염은흔하게볼수있는뇌의염증성질환으로세균, 바이러스, 진균등에의하여발생한다. 중증감염인경우사망에이를수도있고회복되어도후유증을남길수있는질환으로이때뇌손상이생기는기전은몇가지가알려져있다. 병원균이뇌수막염을일으키기위해서는우선상부호흡기점막에서증식해야한다. Streptococcus pneumonia의경우상피세포의 immunoglobulin 수용체와결합하고 PavA (pneumococcal adherence and virulence factor A) 는혈관내피세포와결합하도록조정해준다. Pneurmococcus 의다당류캡슐은세균증식을촉진시키고식균작용을억제시켜패혈증으로진행하게한다. Meningococcus는점막의 CD46, CD66과결합하여비인두에서증식한다. 세균은점막에서증식한후혈액뇌장벽을통하여중추신경계로진입한다. 세균이중추신경계로침입하는주요경로는내피세포이다. 내피세포의 laminin 수용체가세균의부착을조절하며세균이분비하는단백질들도내피세포를통과하도록 작용한다. 세균이침입하여분비하는물질들에는 pneumolysin, lipopolysaccharide 등이있는데이들은소교세포를자극하고염증반응을항진시킨다. 세균감염시인체의방어기전이작동되기위해서는우선미생물을인지하고면역계가활성화되어야한다. 미생물침입시후천면역체제가작동하려면수일이상이경과하므로초기감염시에는선천면역체제가작동하게된다. 선천면역체제에는대식세포, 호중성백혈구, 수지상세포등이중요한역할을하는데중추신경계에침입한세균이나바이러스를인지하고이때세포표면에발현되는 TLR가병원균에있는특정분자를인지하면서세포내신호전달과정이촉발된다. 이렇게 TLR가병원균의특정분자를인지하는것을병원균특이적분자유형인식이라하고이를인지하는 TLR을유형인식수용체라한다. TLR 이발현되면사이토카인발현, 부수자극분자발현이증가되어 T 세포가활성화된다. TLR 는현재 TLR 1부터 TLR 10까지 10개가알려져있고다양한미생물산물에의하여활성화되는데 TLR 2는그람양성세균의세포벽산물에의하여활성화되고 TLR 4 는 LPS에의하여활성화된다. TLR 발현은세균성뇌수막염감염시효과적면역반응이일어나는데필수적인과정으로 TLR 발현을선택적으로억제시키는약물을이용한다면세균성뇌수막염의보조치료제로사용될수있을것이다. 수지상세포는중추신경계에서미성숙한상태로존재하면서병원균을감지하여 T세포에항원을제시하는역할을한다. TLR 를통해병원균을인지한후수지상세포는사이토카인발현은중가하지만병원균을포식하는능력은떨어지게되고이전에포식했던병원균을조각내어주요조직적합복합체유전자와함께세포표면에발현하게되어후천면역체계에도관여하게된다. 세균성뇌수막염의신경세포사멸 동물실험과부검결과세균성뇌수막염에서신경세포손실이관찰되는데해마형성체의치아이랑의경우대부분세포사멸때문이며신피질과해마형성체 CA 1-4 구역의경우는괴사의형태이다. 이밖에도소혈관의혈관염, 국소성경색, 정맥혈전증의경과로생기는백질의손상등을볼수있다. 급성기에사망하였을때에는뇌부종도중요한병리소견이다. 이결과뇌수막염에서회복되어도간질, 기억력장애, 운동장애, 청력손실등의후유증이남는경우가있다. 뇌수막염에서볼수있는신경세포손상은보통세균독소에의한경우와 10 인체면역반응 ( 주로호중구 ) 에의해시작되는경우가있다고생각된다. 11 또위에언급한 TLR 9 을경유하고미세아교세포가관여하는신경독성에의하여신경세포의손상이발생한다. 12 세균성뇌수막염의경우초 122 대한신경과학회지제 29 권부록 2, 2011

154 혈액뇌장벽과면역특권 기에적절한항생제를사용하는것이중요하다부신피질호르몬을성인에서초기에사용하는것이좋은결과를보였다는연구도있었지만 년에발표된메타분석결과에서는큰효과가없는것으로알려졌다. 14 전통적인개념으로는외부병원체에의하여중추신경계의염증성질환이발생한다고알려졌지만다발성경화증은물론알츠하이머씨병, 뇌경색같은질환들의병리소견이알려짐에따라이들질환의원인중의하나로염증반응이관심을받고있다. 이때염증반응은신경계의손상에의하여유발되는데만성적으로진행하며싸이토카인이염증반응과면역반응을조절하는중요한역할을한다. 퇴행성뇌질환이나동맥경화증같은질환에서는개인의유전적요소에의하여염증에대한신체적반응이차이가있다고생각되고있다. 15 최근에는저강도로지속되는염증반응이많은만성신경계질환의발병에중요한역할을한다고여겨지므로지속적인저강도의염증상태를알려주는표지자를개발하고이염증반응을떨어뜨려발병을조기발견하고치료하는연구가진행되면좋은경과를볼수있을것으로생각된다. References 1. Goldmann EF. Vitalfarbung am Zentralnervensystem. Berlin: Eimer, Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer s disease. Neurobiol Aging 2000;21: Benner EJ, Mosley RL, Destache CJ, et al. Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson s disease. Proc Natl Acad Sci U S A 2004;101: Shirai Y. On the transplantation of the rat sarcoma in adult heterogenous animals. Jap Med World 1921;1: Billingham RE and Boswell T. Studies on the problem of corneal homografts. Proc R Soc Lond B Biol Sci 1951;141: Male D, Pryce G, Kinetics of gene expression and mrna synthesis in brain endothelium. Immunology 1988;63: Ford AL, Goodsall AL, Hickey WF, Sedgwick JD. Normal adult ramified microglia seperarted from other central nervous system macrophages by flow cytometric sorting. Phenotypic differences defined and directed ex vivo antigen presentation to myelin basic proteinreactive CD4+ T cells compared. J Immunol 1995;154: Tran EH, Hoekstra K, van Rooijen N, Dijkstra CD, Owens T. Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice. J Immunol 1998;161: Hickey WF. Migration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation. Brain Pathol 1991; 1: Braun JS, Sublett JE, Freyer D, et al. Pneumoccocal pneumolysin and H2O2 medicate brain cell apoptosis during meningitis. J Clin Invest 2002;109: Nau R, Bruck W. Neuronal injury in bacterial meningitis: mechanisms and implications for therapy. Trends Neurosci 2002;25: Iliev AI, Stringaris AK, Nau R, Neumann H. Neuronal injury mediated via stimulation of microglia toll-like receptor-9. FASEB J 2004;18: de Gans J, van de Beek D. European dexamethasone in adulthood bacterial meningitis study investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347: van de Beek D, Farrar JJ, de Gans J, et al. Adjunctive dexamethasone in bacterial meningitis: a meta analysis of individual patient data. Lancet Neurol 2010;9: Andreotti F, Porto I, Crea F, et al. Inflammatory gene polymorphisms and ischemic heart disease: a review of population associated studies. Heart 2002;87: J Korean Neurol Assoc Volume 29 Suppl. 2,

155 특수상황에서의간질환자치료 : 고찰및증례중추신경계감염의신경영상 연세대학교의과대학영상의학교실이승구 Neuroimaging of CNS Infection Seung-Koo Lee, MD Department of Radiology, Yonsei University College of Medicine, Seoul, Korea Early phase of CNS infection usually shows non-specific findings on CT and MRI. Detection of abscess, empyema, ventriculitis and other complication is the major role of neuroimaging in CNS infection. Contrast enhanced MRI and diffusion weighted MRI can detect bacterial meningitis, cerebritis and abscess better than CT. Viral encephalitis is usually non-specific but herpes simplex and some etiologies show predilection area. Post-viral immune reaction and demyelination is also an important complication of CNS infection. Parasitic infection is not uncommon and chronic stage usually shows calcification and adjacent brain atrophy. In immunocompromised patients, various fungal infections must be considered in cases of abnormal MR findings. In all cases, adequate application of MRI pulse sequence is essential in accurate diagnosis and therapeutic planning. Key Words: Brain, Infection, MRI 서론 중추신경계감염은그원인에따라세균, 바이러스, 기생충및기타질환으로나눌수있으며, 감염과연관된이차적인탈수초변화나뇌변성까지광범위하게포함할수있다. 전산화단층촬영 (CT) 과자기공명영상 (MRI) 은뇌신경계질환진단의기본수기이며, 항상 MRI 가우선적으로이용된다기보다는경우에따라 CT 가더유용한정보를제공할수있기때문에원인별, 증상별로적절한진단수기를사용해야한다. CT 는응급실에서보다접근성이높기때문에쉽게사용할수있으며, 뇌척수액천자를시행하기전뇌압이높아질수있는가능성을배제하기위해우선적으로이용된다. MRI 보다석회화병변을더잘볼수있다는장점이있어염증후발생한 calcified granuloma 나기생충질환의후유증을평가하는데는더유리하다. MRI 는훨씬좋은연부조직대조도와해상도, 그리고다양한 펄스열에의한진단률상승으로중추신경계감염에없어서는안될진단수기이다. Gadolinium 조영제사용이필수적이며, 국소적혈뇌장벽의파괴에의한조영제의혈관외유출로염증부위에조영증강을보인다. FLAIR 영상은 sulcal space 의 CSF signal 을감쇄시켜미세한뇌막의변화를조금더정확하게검출할수있으며조영증강 FLAIR 영상은더욱예민도를증가시키며 (Fig. 1), diffusion weighted MRI 는 abscess 와 necrotic Seung-Koo Lee, MD Department of Radiology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemungu, Seoul , Korea Tel: Fax: slee@yuhs.ac Figure 1. Sulcal hyperintensity on FLAIR (arrows). Note dense leptomeningeal enhancement on post-gadolinium T1 weighted image (Gd-T1WI). 124 대한신경과학회지제 29 권부록 2, 2011

156 중추신경계감염의 신경영상 tumor를 구별할 수 있게 한다(Fig. 2). MR spectroscopy상 necrotic lesion에서 lactate (1.2 ppm), acetate (1.9 ppm), 1 succinate (2.4 ppm) peak를 볼 수 있다. Bacterial infection 세균성 질환은 급성기 감염으로 acute pyogenic meningitis, cerebritis 및 cerebral abscess가 있으며 만성 감염으로 결핵 균에 의한 chronic granulomatous infection을 들 수 있다. Acute pyogenic meningitis는 주로 혈행성 전파에 의해 감염 이 일어나며 발열, 두통 등 전형적 증상과 CSF 검사 결과로 확 인할 수 있다. 영상은 초기 CT에서 정상을 보이는 경우가 많고, MRI에서도 특별한 이상 소견이 없는 경우가 있다. 진행될 경우 meningeal enhancement를 보이고 FLAIR에서 sulcal space나 2 cisternal space의 신호가 증가한다. 합병증으로 hydrocephalus, subdural effusion, cerebritis, abscess, empyema, ventriculitis, choroid plexitis, venous sinus thrombosis, infarct 등이 올 수 있고 영상검사의 일차적 목적은 이와 같은 합병증 병발 유무 Figure 2. Brain abscess on diffusion weighted image (DWI). High signal on DWI and diffusion restriction on ADC map is the hallmark of brain abscess compared with necrotic or cystic brain tumors. Figure 3. Twenty eight year old female with tuberculosis. Note diffuse leptomeningeal enhancement, thickened cranial nerves and pituitary stalk, and enlarged choroid plexus suggestive of choroid plexitis. J Korean Neurol Assoc Volume 29 Suppl. 2,

157 이승구 10,11 를 조기에 진단하는 데 있다. Cerebritis나 abscess는 혈행성 도 한다. 또는 인접 sinonasal infection의 직접 전파에 의하며 초기 12 encephalitis로 합병증을 일으키는 경우가 많다. 최근 유행하는 hand-foot-mouth disease가 acute cerebritis는 ill defined subcortical T2 hyperintensity로 주 Viral infection의 합병증으로 acute disseminated encepha- 로 나타나고 조영증강은 될 수도, 되지 않을 수도 있다. 시간이 lomyelitis (ADEM)가 올 수 있는데 일종의 autoimmune white 지나면서 thick, irregular rim enhancement를 나타내며 matter demyelination이며 monophasic, self limited disease abscess가 형성이 되면 특징적으로 DWI에서 높은 신호를, ADC 가 임상적 특징이며 white matter와 basal ganglia에 양측성, 1,3,4 map에서 diffusion restriction을 보인다. Chronic granulomatous infection의 대표적인 예가 결핵이 비대칭성으로 여러 개의 병변이 올 수 있고 조영증강이 나타날 13,14 수 있다(Fig. 6). Subacute sclerosing panencephalitis 며 대부분 혈행성으로 전파되고 basal cistern에 gelatinous (SSPE)는 measles virus 감염이 선행된 뒤 3년에서 9년 사이 exudates, granuloma, fibrosis를 형성하여 강한 조영증강을 에 발병하여 서서히 진행되는 각종 신경학적 증상을 보이며 보이고(Fig. 3), 심할 경우 혈관 침범에 의한 infarct이 올 수 periventricular white matter, subcortex, deep gray matter 5 있다. Communicating hydrocephalus, tuberculous granuloma 등에 non-specific T2 hyperintensity를 보일 수 있으며 시간 가 합병증으로 자주 오며 항결핵제를 투여하면서 일시적으로 15 이 가면서 뇌위축이 나타난다. granuloma의 조영증강이나 크기가 증가하는 소견을 보일 때도 Creutzfeldt-Jacob 병은 virus는 아니지만 prion에 의해 생 있다. Viral infection Encephalitis의 대부분은 virus가 원인이고 adenovirus, enterovirus, coxsackievirus 등 URI를 일으키는 대부분의 virus 가 encephalitis도 일으킬 수 있다. 비특이적인 T2 signal change, meningeal enhancement가 주된 영상 소견이며 2차적인 합병 증 유무를 CT, MRI로 검출한다. Herpes simplex는 insula와 temporal lobe을 주로 침범하는 특징이 있고 출혈이 동반되기 6-8 도 한다(Fig. 4). Japanese B virus는 deep gray matter를 대칭적으로 침범하며 간혹 brain stem lesion을 보이기도 한다 9 (Fig. 5). 대부분의 virus는 neuron을 침범하므로 gray matter 에서 병변이 보이나 JC virus는 white matter를 침범, pro- Figure 5. Four year old boy with altered consciousness, fever and was confirmed to have Japanese B encephalitis. Note symmetric involvement of deep gray matter on FLAIR and DWI. gressive multifocal leukoencephalopathy(pml)로 발현하기 Figure 4. Fifty four year old male with fever and seizure. Increased signal and swelling of bilateral mesial temporal lobe, insula and cingulum are the hallmarks of herpes simplex encephalitis. 126 대한신경과학회지 제29권 부록 2, 2011 Figure 6. Twenty three year old male with seizure, previous upper respiratory infection history. Confluent white matter lesions scattered in entire brain and asymmetric distribution is typical finding of acute disseminated encephalomyelitis.

158 중추신경계감염의 신경영상 A B C Figure 7. Different stages of neurocysticercosis. Non-enhancing cyst (vesicular), enhancing cyst (colloidal vesicular) lesions are noted in brain parenchyma and sulcal spaces (A and B). Racemose and ventricular type neurocysticercosis usually does not enhance and enlarged cisternal and ventricular spaces are common findings (C). 기는 감염 질환으로 급속히 진행되는 치매에 비대칭적 cortical signal change가 diffusion MRI에서 보이고, basal ganglia에 서도 관찰되며 임상 검사와 일치할 경우 진단할 수 있다. 21 장된 cisternal space로 관찰되어 주의를 요한다. Paragonimiasis는 급성기에는 조영증강을 보이는 포도송이 병변이 보이다가 만성기에는 석회화와 인접 뇌실질의 위축을 22,23 보인다. Fungal & parasitic infection 진균감염은 주로 immunocompromised patients에서 발생 하며 면역체계의 이상으로 조영증강이 안되는 경우가 많고 영상 소견이 비특이적이어서 진단에 어려움이 많다. Crpytococcosis 는 Indian ink 검사법으로 확진하며 perivascular space를 따 라 cryptococcoma를 형성하거나 multiple enhancing nodule 을 보이기도 한다. Meningitis가 생길 경우 다른 원인에 의 Sparganosis는 불규칙한 조영증강 병변이 각 단면 마다 연결되면서 serpentine structure를 보이며 비교적 오랜 시간동안 생존하기도 하고, 만성기에는 다른 기생충 감염과 마 찬가지로 석회화를 보인다. 원인 불명의 석회과, 주변부 뇌 위 축, 뇌실의 확장이 보이면 거의 대부분 과거의 기생충 감염으로 간주하면 된다. Toxoplasmosis는 면역력이 떨어진 사람에게 감염되며 특히 HIV 환자의 뇌에 발생하는 가장 흔한 기회감염 21 이다. 영상학적으로 lymphoma와의 감별이 중요하다. 한 것과 비슷한 비특이적 소견을 보인다. Aspergillosis는 PNS 결 infection에서 기인할 수 있고 혈관을 자주 침범하여 mycotic 론 19,20 aneurysm을 형성하기도 한다. Cysticercosis는 아직까지도 자주 접하는 질환이며 제대로 익히지 않은 돼지고기를 통해 감염이 이루어진다. Taenia solium의 larva, 즉 cisticercus가 기생하며 뇌신경계와 근골격 계를 주로 침범한다. 유충의 위치에 따라 cisternal, meningeal, parenchymal, ventricular form으로 나뉘고 시기에 따라 vesicular, colloidal vesicular, granular nodular 및 nodular calcified stage로 나뉜다(Fig. 7). Vesicular stage는 아직 larva가 살아 있는 상태이며 내부에 scolex가 보일 수 있다. Viable membrane 이어서 정상조직과 완전 격리, 염증 반응이 없기 때문에 조영증 강이 되지 않는다. Colloidal vesicular stage가 되면 퇴화가 시 작되어 낭종 내용물이 혼탁해져 CSF와는 다른 density 또는 signal intensity를 보인다. 경우에 따라 조영증강 없는 얇은 막으로 구성된 racemose type으로 발현되면 비정상적으로 확 중추신경계의 감염성 질환은 초기에 비특이적 소견을 보이는 경우가 많고, CT에서는 정상으로 관찰되는 경우가 많아 조영제 를 사용한 MRI 검사를 빨리 진행하여 병변의 위치와 원인균에 대한 판단을 통해 조기 치료에 임할 수 있도록 해야 한다. 일부 원인 별로 특징적으로 나타나는 영상소견을 숙지하면 조기 진 단에 도움이 될 수 있다. References 1. Lai PH, Ho JT, Chen WL, et al. Brain abscess and necrotic brain tumor: discrimination with proton MR spectroscopy and diffusion-weighted imaging. AJNR Am J Neuroradiol 2002;23: Splendiani A, Puglielli E, De Amicis R, Necozione S, Masciocchi C, Gallucci M. Contrast-enhanced FLAIR in the early diagnosis of infectious meningitis. Neuroradiology 2005;47: J Korean Neurol Assoc Volume 29 Suppl. 2,

159 이승구 3. Tung GA, Evangelista P, Rogg JM, Duncan JA, 3rd. Diffusionweighted MR imaging of rim-enhancing brain masses: is markedly decreased water diffusion specific for brain abscess? AJR American J Roentgenol 2001;177: Kim YJ, Chang KH, Song IC, et al. Brain abscess and necrotic or cystic brain tumor: discrimination with signal intensity on diffusion-weighted MR imaging. AJR American J Roentgenol 1998;171: Gupta RK, Kohli A, Gaur V, Lal JH, Kishore J. MRI of the brain in patients with miliary pulmonary tuberculosis without symptoms or signs of central nervous system involvement. Neuroradiology 1997;39: Jiang Y, Tang L, Gao P, Qin S, Jiang J. Delayed MRI findings in Herpes simplex encephalitis. Can J Neurol Sci 2011;38: Noguchi T, Yoshiura T, Hiwatashi A, et al. CT and MRI findings of human herpesvirus 6-associated encephalopathy: comparison with findings of herpes simplex virus encephalitis. AJR American J Roentgenol 2010; 194: Tokumaru AM, Horiuchi K, Kaji T, Kohyama S, Sakata I, Kusano S. MRI findings of recurrent herpes simplex encephalitis in an infant. Pediatr Radiol 2003;33: Abe T, Kojima K, Shoji H, et al. Japanese encephalitis. J Magn Reson Imaging 1998;8: Sullivan JM, Hahn FJ, Adickes E, Hahn PY, Badakhsh S. Progressive multifocal leukoencephalopathy (PML): CT, MRI, and histopathology correlation. Nebr Med J 1990;75: Trotot PM, Vazeux R, Yamashita HK, et al. MRI pattern of progressive multifocal leukoencephalopathy (PML) in AIDS. Pathological correlations. J Neuroradiol 1990;17: Wang GH, Yan CY, Bao WG. [Hand-foot-mouth disease complicated by brainstem encephalitis and cerebral edema in a neonate]. Zhongguo Dang Dai Er Ke Za 2011;13: Callen DJ, Shroff MM, Branson HM, et al. Role of MRI in the differentiation of ADEM from MS in children. Neurology 2009;72: Kuperan S, Ostrow P, Landi MK, Bakshi R. Acute hemorrhagic leukoencephalitis vs ADEM: FLAIR MRI and neuropathology findings. Neurology 2003;60: Anlar B, Saatci I, Kose G, Yalaz K. MRI findings in subacute sclerosing panencephalitis. Neurology 1996;47: Chen S, Chen X, Zhang Z, Quan L, Kuang S, Luo X. MRI findings of cerebral cryptococcosis in immunocompetent patients. J Medl Imaging Radiat oncol 2011;55: Miszkiel KA, Hall-Craggs MA, Miller RF, et al. The spectrum of MRI findings in CNS cryptococcosis in AIDS. Clin Radiol 1996;51: Patronas NJ, Makariou EV. MRI of choroidal plexus involvement in intracranial cryptococcosis. J Comput Assist Tomogr 1993;17: Pollack E, Bhaya A, Law M. Differentiating intracranial aspergillosis from a high grade glioma using MRI and MR spectroscopic imaging. J Neuroimaging 2007;17: Gabelmann A, Klein S, Kern W, et al. Relevant imaging findings of cerebral aspergillosis on MRI: a retrospective case-based study in immunocompromised patients. Eur J Neurol 2007;14: Chang KH, Han MH. MRI of CNS parasitic diseases. J Magn Reson Imaging 1998;8: Zhang JS, Huan Y, Sun LJ, Zhang GY, Ge YL, Zhao HT. MRI features of pediatric cerebral paragonimiasis in the active stage. J Magn Reson Imaging 2006;23: Nomura M, Nitta H, Nakada M, Yamashima T, Yamashita J. MRI findings of cerebral paragonimiasis in chronic stage. Clin Radiol 1999; 54: 대한신경과학회지제 29 권부록 2, 2011

160 특수상황에서의간질환자치료 : 고찰및증례중추신경계감염의항생제치료 경북대학교의학전문대학원감염내과장현하 Antimicrobial Treatment of Central Nervous System Infections Hyun-Ha Chang, MD, PhD Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea Central nervous system infections, such as acute bacterial meningitis, nosocomial meningitis and brain abscess, are the most challenging infectious diseases to most clinicians and even infectious diseases specialists throughout the world because of their significant mortality and morbidity, changing of epidemiology and increase of antimicrobial resistance rate of causative organisms. In this review, the etiologic microorganisms of central nervous system infections and the selection of antimicrobial agents for their treatment in Korea were reviewed, and 2011 Korean antimicrobial treatment guideline of central nervous system infections was introduced briefly. Key Words: Central nervous system Infections; Therapeutics; Anti-Bacterial agents 서 론 중추신경계감염은즉각적인적절한항생제치료가반드시필요한중증질환이지만실제임상에서는응급실이나초진당시원인미생물을모르는상태에서최대한빠르게경험적으로항생제를투여하여야만하는질환이다. 중추신경계감염의가장흔하고대표적인급성뇌수막염의경우응급실도착 30분이내에적절한경험적항균제가투여되는것이권장되고있으며, 따라서초기의적절한항생제의선택은매우중요하다. 이때어떤항생제를투여해야가장효과적인적절한항생제인가를결정하는것은환자의나이, 임상양상, 면역저하의여부, 그리고과거병력등이중요한요인으로이에따라가장가능성이높은원인병원체가달라지고, 확실한병원균이동정될때까지의경험적항생제치료 (empirical antibiotic treatment) 도이에맞추어야한다. 급성중추신경계감염의가장대표적인급성뇌수막염의경우환자의나이에따라흔한원인균들이차이가있어환자의나이 Hyun-Ha Chang, MD, PhD Department of Internal Medicine, Kyungpook National University Hospital, 200 Dongduk-ro, Jung-gu, Daegu , Korea Tel: Fax: changhha@knu.ac.kr 는경험적항균제를선택하는데가장기본적으로중요한인자이다. 최근에는급성지역사회획득뇌수막염의주요대표원인균인폐렴사슬알균 (Streptococcus pneumonaie) 와뇌수막알균 (Neisseria meningitidis) 에대한백신이보급되면서아직뇌수막알균백신은많이사용하지않지만폐렴사슬알균백신은소아뿐만아니라성인에서도널리보급되기시작하여백신접종력도경험적항생제를선택할때고려해야하며, 환자가이전에중추신경계의방어에영향을미칠만한두부의손상이나외상이있는지, 그리고수술병력이있는지여부와특히뇌실복강션트 (ventriculoperitoneal shunt) 나뇌실외배액술 (extraventricular drainage) 등의시술이있는지여부에따라환자에게서중추신경계감염을일으킨원인균이크게달라지므로이에따른경험적항균제의선택이필요하다. 더욱이결핵뇌수막염과같이급성으로도나타나지만아급성이나만성경과를보이는중추신경계감염이흔하여자세한병력청취가반드시필요하다. 최근자가면역질환환자나이식환자의증가로면역저하환자의증가로이에따른뇌수막염의경우병원체가달라지므로투여중인면역억제제의종류와특히스테로이드를사용하고있는지확인하고그용량과기간등을확인하는것이필요하다. 이러한환자의면역저하여부는가능한중추신경계감염병원체의범위를훨씬확장시켜경험적으로투여되는항생제를완전히바꾸기도하므로매우중요하다. J Korean Neurol Assoc Volume 29 Suppl. 2,

161 장현하 경험적항균제를시작하고 시간이경과하면뇌척수액검사나혈액배양검사또는혈청학적검사나분자생물학적검사등을통해원인병원체가동정된다. 동정된원인병원체의항생제감수성등의특성에따라확정적항생제 (definitive antimicrobial treatment) 선택과치료기간등을결정하게되며, 이는환자의면역학적특성, 항생제치료에대한반응, 그리고원인병원체의항생제내성여부나균주의특성등에영향을받는다. 본종설에서는중추신경계감염환자에서의적절한항생제의선택에대해주로다루며, 더불어 2011 년대한감염학회, 대한임상미생물학회, 대한화학요법학회, 대한신경과학회, 그리고대한신경외과학회에서기획중인중추신경계감염의임상진료지침의항생제권장에대해간략히기술하고자한다. 1. 항생제선택에서고려해야하는요인들 1) 병인론과임상양상중추신경계감염에선비교적발병기전이잘알려진균혈증 (bacteremia) 은혈액으로균이전파되는대표적인경로로급성뇌수막염을일으키는원인이된다. 특히폐렴사슬알균 (Streptococcus pneumoniae) 의경우폐렴이나다른감염병소를가지고있으면서균혈증을동반하여급성뇌수막염이합병되는경우가있어혈액배양검사를통해보다빠르고정확하게뇌수막염의원인균이동정될수있다. 또한부비동염이나중이염과같은주변의국소감염증이직접파급되어이로인한중추신경계감염이발생하는경우가있어이주변의감염증에대한진단검사와치료가같이필요하며, 이러한일차감염병소에서동정되는원인병원체에따라중추신경계감염의원인병원체를예상하여경험적항균제를선택할수있다. 이는특히뇌농양 (brain absces) 과같은경우에흔하여뇌농양의경험적항생제를선택할때중요하다. 1 2) 시술혹은수술후감염환자가최근중추신경계방어기전에영향을미칠수있는시술을받았거나뇌실외배액술이나뇌실복강션트와같은수술을받은경우지역사회획득감염보다훨씬복잡하고다양한균주에의한감염이가능하다. 특히이러한시술이나수술후감염인경우각지역이나병원에따른원내감염의양상에더욱영향을받게된다. 따라서폐렴사슬알균이나뇌수막알균보다는황색포도알균 (Staphylococcus aureus) 이나혈장응고효소음성포도알균 (coagulase-negative staphylococci), 장알균 (Enterococcus spp.), Pseudomonas aeruginosa, Acinetobacter, 그리고칸디다 (Candida) 등이원인균이될수있다. 2 3) 환자의나이환자의나이에따라급성뇌수막염의원인균의분포가달라짐은잘알려져있다. 0-4주의신생아에서는 Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes, Klebsiella pneumoniae 등이중요원인균이지만 2세에서 18세까지의소아청소년기에는최근백신접종으로인해확연히감소한 Hemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae 등이가장흔한원인균이다 세성인에서는가장대표적인 Streptococcus pneumoniae 가흔하며 Neisseria meningitidis가일부를차지한다. 60세이상의고령의환자에서는역시 Streptococcus pneumoniae가흔하나 Listeria monocytogenes 나그람음성막대균의빈도가증가함이잘알려져있다. 2 5) 면역저하여부특정보체계인자결핍과같은선천성면역결핍환자나장기간고용량스테로이드를투여중인환자나암환자, 장기이식환자등의경우 Streptococcus pneumoniae 가가장대표적인원인균이기는하나이외에도 Neisseria meningitidis나 Listeria monocytogenes, gram-negative bacilli 등에의한감염을고려해야한다. 2 6) 원인균의항생제내성지역사회획득중추신경계감염의경우원인균의항생제내성은크게문제가되지않으나수술이나각종시술에따른병원감염인경우에주로문제가된다. 수술이나시술후감염의주요병원균인포도알균의경우거의대부분의경우 methicillin 내성이므로 vancomycin 이나 linezolid, quinupristin/dalfopristin 등으로항생제선택범위가좁아진다. 특히그람음성막대균의대표적인 Escherichia coli와 Klebsiella pneumoniae 등과같은장내세균과에서 3세대 cephalosporin 내성이증가하여항생제선택의범위를더욱좁게하여문제가되고있고, Pseudomonas aeruginosa 나 Acinetobacter baumanii의경우광범위한다약제내성을보이는경우가흔하여 imipenem 이나 meropenem 과같은 carbapenem 항생제를일차경험적항생제로투여해야하거나 carbapenem 에까지내성을발현하는경우가흔하여 colistin 이외의항생제에는모두내성인경우가있어임상에서문제가되고있다. 3 7) 혈액뇌장벽과항생제투여방법중추신경계는혈액뇌장벽이있어항생제의투과에영향을미치므로이를고려하여항생제를투여해야한다. 일부항생제의 130 대한신경과학회지제 29 권부록 2, 2011

162 중추신경계감염의항생제치료 경우중추신경계감염병에서는다른감염병에사용되는용량보다 2배용량을투여해야하기도하며, 항생제내성균주에대한새로이개발되는항생제중에서도혈액뇌장벽투과성이낮은항생제들이있어용량을높여야하거나뇌실내로직접투여하는방법을고려해야하기도한다. 거미막밑공간 (subarachnoid space) 은숙주방어기전이상당히취약하여중성구나형질세포, 보체시스템과면역글로불린들이혈액뇌장벽을잘통과하지못하여균의탐식작용이원활하지못하고이로인해병원미생물이급속히증식하는특징이있어정균작용의항생제보다는살균작용 (bactericidal effect) 의항생제를선택해야한다. 4 급성세균성뇌수막염과같이거미막의염증은친수성 (hydrophilic) 항생제의투과성을높여거미막밑공간으로더욱많은항생제가투과될수있도록한다. 친지방성 (lipophilic) 항생제는거미막염증에거의영향을받지않고도뇌척수액으로잘침투하여높은농도를유지하는경향을보이는데주로 fluoroquinolones 이나 rifampin, 그리고 chloramphenicol 이이에해당한다. 4 페니실린은능동운반 (active transport) 를통해뇌척수액내로빠르게이동하는장점을가지고있다. 그러나대부분의 beta-lactams 은지방용해성 (lipid solubility) 이낮고이온화가심하여혈액뇌장벽을잘통과하지못하는경우가많으며, 특히병원획득중추신경계감염의주요원인균인 methicillin 내성포도알균감염에주로사용되는 vancomycin 의경우분자량이너무커서염증으로손상된혈액뇌장벽만잘통과하는단점이있어이를고려해야한다. 4 특히급성뇌수막염에서보조적으로투여되는 dexamethasone 이혈액뇌장벽통과를어렵게할수있는데페니실린내성폐렴사슬알균 (penicillin-resistant Streptococcus pneumoniae) 뇌수막염에서 dexamethasone 투여로인해수막염증의감소로뇌척수액내의 vancomycin 농도가저하되는것이동물실험에서알려져있어 5 급성폐렴알균뇌수막염이의심되면경험적항생제로 vancomycin 과 ceftriaxone ( 또는 cefotaxime) 병합요법에 rifampin 을추가하고균동정검사에서 cephalosporin 에감수성이면 rifampin 을중단하는것을권장하기도한다 국내중추신경계감염의임상진료지침의항생제선택권고안 2011 년대한화학요법학회, 대한감염학회, 대한임상미생물학회, 대한신경과학회와대한신경외과학회에서공동으로마련하여준비중인중추신경계감염의임상진료지침안은주로성인급성세균성수막염과뇌농양을중심으로다루고있어아직발표전이지만여기에간략히소개하고자한다. 1) 얼마나빨리항생제를투여해야하는가? 후향적연구들이지만급성뇌수막염환자에서응급실방문후항생제투여가지연되는경우사망률이급격히증가한다는보고들이있어 6 외국의진료지침과마찬가지로급성뇌수막염이의심되는경우가능한빨리신속히항생제를투여할것을권장하고있다. 2) 국내급성세균성뇌수막염의주요원인균과항생제내성현황 1998 년부터 2008 년까지국내 15개병원에서 18세이상성인에서의지역사회획득급성세균성뇌수막염 195 증례를대상으 Table 1. Etiology of community-acquired acute bacterial meningitis in Korean adults Microorganisms (n=195) (n=53) (n=142) Streptococcus pneumoniae 99 (50.8) 30 (56.6) 69 (48.6) Staphylococcus aureus 20 (10.3) 5 (9.4) 15 (10.6) Klebsiella pneumoniae 15 (7.7) 2 (3.8) 13 (9.2) Listeria spp. 13 (6.7) 2 (3.8) 11 (7.7) Group B Streptococcus 6 (3.1) 4 (7.5) 2 (1.4) Neisseria meningitidis 5 (2.6) 1 (1.9) 4 (2.8) Viridans group streptococci 5 (2.6) 1 (1.9) 4 (2.8) β-hemolytic streptococcus 4 (2.1) 0 (0.0) 4 (2.8) Streptococcus sanguinis 3 (1.5) 1 (1.9) 2 (1.4) Pseudomonas aeruginosa 3 (1.5) 2 (3.8) 1 (0.7) Others 22 (11.3) 5 (9.4) 17 (12.0) J Korean Neurol Assoc Volume 29 Suppl. 2,

163 장현하 Table 2. Comparison of the organisms responsible for bacterial meningitis according to age Age Microorganisms (n=32) (n=28) (n=68) 66 (n=67) Streptococcus pneumoniae 16 (50.0) 20 (71.4) 33 (48.5) 30 (44.7) Staphylococcus aureus 2 (6.3) 4 (14.3) 3 (4.4) 11 (16.4) Klebsiella pneumoniae 1 (3.1) 0 (0.0) 8 (11.8) 6 (9.0) Listeria spp. 1 (3.1) 0 (0.0) 6 (8.8) 6 (9.0) Group B Streptococcus 0 (0.0) 1 (3.6) 4 (5.9) 1 (1.5) Neisseria meningitidis 3 (9.4) 1 (3.6) 0 (0.0) 1 (1.5) Viridans group streptococci 1 (3.1) 0 (0.0) 4 (5.9) 0 (0.0) β-hemolytic streptococcus 2 (6.3) 0 (0.0) 2 (2.9) 0 (0.0) Streptococcus sanguinis 0 (0.0) 0 (0.0) 2 (2.9) 1 (1.5) Pseudomonas aeruginosa 1 (3.1) 0 (0.0) 1 (1.5) 1 (1.5) Others 5 (15.6) 2 (7.1) 5 (7.4) 10 (14.9) Table 3. Antibiotics recommended for empirical therapy in patients with suspected bacterial meningitis Group of Patients Recommended Agents Alternative agents Immunocompetent Age, 18 to 50 yr Vancomycin+3rd G cephalosporin a Vancomycin+moxifloxacin b Age, >50 yr Vancomycin+3rd G cephalosporin a +ampicillin Vancomycin+moxifloxacin b +trimethoprim-sulfa methoxazole c Alcoholism, debilitating diseases, and cellular immunity dysfunction Post-neurosurgery, post-head trauma, or ventriculoperitoneal shunt Vancomycin+3rd G cephalosporin a +ampicillin Vancomycin+anti-pseudomonal cephalosporins d a Cefotaxime, ceftriaxone. b Alternative for 3rd generation cephalosporin. c Alternative for ampicillin. d Cefepime, ceftazidime. e Imipenem or ertapenem also could be considered. However imipenem more likely to cause seizure than others. Vancomycin+moxifloxacin b +trimethoprim-sulfa methoxazole c Vancomycin+aztreonam b, ciprofloxacin, or meropenem e 로하여주요원인균을보고한바있다. 7 기존의연구보고들과유사하게 Streptococcus pneumoniae가가장흔하였고 66세이상의고령의환자군에서는 Klebsiella penumoniae나 Listeria monocytogenens이증가하는특징을보였고특히최근에더욱증가하는양상을보였다 (Table 1, 2). 특징적으로이연구에서는외국에서도급격히감소한 Hemophilus influenzae는한건도없었다. 특히군대와같은특수한상황에서는 Neisseria meningitidis를고려해야하며국내에서의발병률은 2.2건 /100,000명 (95% CI, ) 으로알려져있다. 8 급성세균성뇌수막염의경험적항생제선택에영향을미치는폐렴사슬알균은 60.3% 에서페니실린내성을보였고, 40.0% 에서 3세대 cephalosporin 에대한내성을보여내성율이상당히높게나타 났다. 7 병원획득뇌실외배액도관연관감염의경우원인균의분포는연구자에따라차이가많다. 후향적보고들이긴하지만일개대학병원의 19예의뇌실외배액도관연관감염을대상으로한연구에서는 Staphylococcus aureus 와 coagulase-negative staphylococci 가가장흔한원인균 (53%) 으로보고하였으나 9, 본저자의병원에서총 91례의뇌실외배약도관연관감염을대상으로한후향적연구에서는 coagulase-negative staphylococci 가 40.9% 로가장흔하였고, Acinetobacter가 32.5% 로다른연구들과달리두번째로흔하고, 그다음은주요원인균이 Staphylococcus aureus로 12.0% 로다른연구들과달리 Acinetobacter 가주요원인균으로나타났다. 이들션트나뇌실 132 대한신경과학회지제 29 권부록 2, 2011

164 중추신경계감염의항생제치료 배액도관연관감염의경우원인균들의항생제내성이높은것이문제가되는데특히포도알균의경우 methicillin 내성균이흔하여 vancomycin 이투여되어야하는경우가흔하며그람음성균의경우에도흔하게사용되는 3세대 cephalosporin 에내성이점점증가하고있어일차선택약제로 carbapenem 을사용하여야하는경우가증가하고있어문제가되고있다. 3 3) 항생제의선택국내진료지침에서는지역사회획득급성세균성뇌수막염이의심되거나진단된경우우선경험적치료로선택하는항생제는 vancomycin 과 3세대 cephalosporin 의병합요법을권장하고있다 (Table 3). 혈액배양검사결과와뇌척수액배양검사결과가나올때까지정상신기능과간기능을가진환자라면 Vancomycin 은 mg/kg로 12시간마다정맥주사하며 ceftriaxone 2 gram 을 시간마다정맥주사하여병합투여하거나 cefotaxime 2 gram 을 4-6 시간마다정맥주사하여병합투여한다. 10 항생제투여 2내지 3일째에 vancomycin 혈중최저농도를검사하여 microgram/ml 로유지한다. 만일환자가 beta-lactam 항생제에아나필락시스가있는경우에는 cephalosporin 대신에 moxifloxacin 400 mg 을 24시간마다정맥주사하여병합투여하는것을권장하고있다. 50세이상의노인환자이거나알콜남용, 후천성면역결핍증, 면역억제제투여환자, 이식환자와같이면역저하환자의경우 ampicillin 2 gram 을 4시간마다정맥주사하여병합투여하며 11, 만일 beta-lactam 항생제에아나필락시스병력이있어 ampicillin 을사용할수없다면 trimethoprim-sulfamethoxazole 5-10 mg/kg (trimethoprim 용량을기준으로함 ) 를 6-12 시간마다정 맥주사하여병합투여하도록권장하고있다. 기저두개골골절이나관통하는외상이있는환자, 뇌수술후, 뇌실복막션트를가진환자의경우에는지역사회획득감염과다르게 methicillin 내성포도알균과그람음성막대균이주요원인균이므로 vancomycin 과 anti-pseudomonal cephalosporin 을투여하는것을권장하고있다. Vancomycin 의용량은지역사회획득감염시와동일하며 cephalosporin 은주로 ceftazidime 2 gram을 8시간마다정맥주사하거나 cefepime 2 gram을 8시간마다정맥주사하는것을권장하고있다. 만일환자가 beta-lactam 제재에아나필락시스가있어서 cephalosporin 을투여하지못한다면, aztreonam (2 gram iv q 6-8 hours) 이나 ciprofloxacin ( mg iv q 12 hours), 또는 meropenem (2 gram iv q 8 hours) 를 vancomycin 과함께병합투여할것을권장하고있다. 앞서기술한바와같이혈액뇌장벽이라는특수한중추신경계의구조로다른신체부위의감염병과달리항생제를더고용량을투여해야하는경우가많아주의를요하며, 중추신경계감염에사용되는항생제의권장용량은표 4와같다 시간이경과하면혈액배양검사나뇌척수액배양검사결과에따라경험적으로투여된항생제를변경하거나유지하게된다 (Table 5). 지역사회획득급성세균성뇌수막염의가장흔한원인균인폐렴사슬알균은 penicillin 내성과 cephalosporin 내성에따라서항생제선택이달라진다. Penicillin 최저억제농도 (minimal inhibitory concentration, MIC) 가 0.1 mg/l 미만인경우에는 peniciilin G나 ampicillin 을사용하는것을일차적으로권장하며, penicillin MIC 가 0.1 mg/l 이상인경우는 cefotaxime 또는 ceftriaxone 의 MIC 에따라결정하는데 MIC 가 1.0 mg/l 이하이면 3세대 cephalosporin 을투여하고 rifampin Table 4. Recommended dosages of antimicrobial therapy in patients with bacterial meningitis Antibiotics Total daily dose (dosing interval in hours) Antibiotics Total daily dose (dosing interval in hours) Amikacin a 15 mg/kg (8) Meropenem 6 g (8) Ampicillin 12 g (4) Moxifloxacin b 400 mg (24) Aztreonam 6-8 g (6-8) Nafcillin 9~12 g (4) Cefepime 6 g (8) Penicillin G 24 mu (4) Cefotaxime 8-12 g (4-6) Rifampin 600 mg (24) Ceftazidime 6 g (8) Tobramycin a 5 mg/kg (8) Ceftriaxone 4 g (12-24) TMP-SMZ 10~20 mg/kg (6~12) Ciprofloxacin 800-1,200 mg (8-12) Vancomycin c 30~45 mg/kg (8~12) Gentamicin a 5 mg/kg (8) TMP-SMZ; trimethoprim-sulfamethoxazole. a Need to monitor peak and trough serum concentrations. b No data on optimal dosage needed in patients with bacterial meningitis. c Maintain serum trough concentrations of g/ml. J Korean Neurol Assoc Volume 29 Suppl. 2,

165 장현하 Table 5. Recommendations for specific antimicrobial therapy in bacterial meningitis based on isolated pathogen and susceptibility testing Microorganism Standard therapy Alternative therapies Streptococcus pneumoniae Penicillin MIC <0.1 mg/l Penicillin G or ampicillin 3rd G cephalosporin a 0.1 mg/l Cefotaxime or ceftriaxone MIC <1.0 mg/l 3rd G cephalosporin a,b Moxifloxacin (B II), cefepime (B II), or meropenem c (B II) MIC 1.0 mg/l Vancomycin + 3rd G cephalosporin a,b Moxifloxacin (B II) Neisseria meningitidis Penicillin MIC <0.1 mg/l Penicillin G or ampicillin 3rd G cephalosporin a 0.1 mg/l 3rd G cephalosporin a Moxifloxacin, meropenem c Listeria monocytogenes Ampicillin d or penicillin G d Trimethoprim-sulfamethoxazole, meropenem c (B III) Streptococcus agalactiae Ampicillin d or penicillin G d 3rd G cephalosporin a (B III) Escherichia coli and other Enterobacteriaceae 3rd G cephalosporin (A II) Aztreonam, fluoroquinolone e, meropenem, ampicillin, or trimethoprim-sulfamethoxazole Pseudomonas aeruginosa Cefepime d or ceftazidime d (A II) Aztreonam d, ciprofloxacin d,e, or meropenem d Haemophilus influenzae Ampicillin-susceptible Ampicillin 3rd G cephalosporina, cefepime, or fluoroquinolone e Ampicillin-resistant 3rd G cephalosporin (A I) Cefepime (A I), or fluoroquinolone e Staphylococcus aureus Methicillin-susceptible Nafcillin Vancomycin b, or meropenem (B III) Methicillin-resistant Vancomycin b Trimethoprim-sulfamethoxazole, or linezolid b (B III) Enterococcus species Ampicillin-susceptible Ampicillin + gentamicin f Ampicillin-resistant Vancomycin + gentamicin f Ampicillin &vancomycin -resistant Linezolid (B III) ` All recommendations are A III, unless otherwise indicated. a Ceftriaxone or cefotaxime. b Consider addition of rifampin. c Imipenem or ertapenem also could be considered. However imipenem more likely to cause seizure than others. d Addition of an aminoglycoside should be considered. e Ciprofloxacin, moxifloxacin, or levofloxacin should only be utilized for meningitis caused by multi-drug resistant gram-negative bacilli or when patients have not responded to or cannot receive standard antimicrobial therapy. f Susceptibility test should include the presence of high-level resistance to gentamicin (>500 µg/ml) and streptomycin (>2,000 µg/ml). Optimal synergistic antimicrobial therapy is not available for enterococci with high-level resistance to both gentamicin and streptomycin. 134 대한신경과학회지제 29 권부록 2, 2011

166 중추신경계감염의항생제치료 병합투여를고려할수있다. MIC 가 1.0 mg/l 이상인경우에는 vancomycin 과 3세대 cephalosporin 병합투여를권장하며이때도 rifampin 을병합투여할수있다고권장하고있다. Neisseria meningitidis의경우에는 penicillin MIC 가 0.1 mg/l 미만인경우에는 penicillin G나 ampicillin을투여하고, penicillin MIC 가 0.1 mg/l 이상인경우에는 ceftriaxone 이나 cefotaxime 등의 3세대 cephalosporin 을투여하는것을권장하고있다. Listeria monocytogenes나 Streptococcus agalactiae 는 ampicillin 이나 penicillin G를투여하며 aminoglycoside 를병합투여하는것이권장된다. Escherichia coli와같은장내세균과에대해서는 3세대 cephalosporin 이권장되며, Pseudomonas aeruginosa 의경우 cefepime 이나 ceftazidime 과같은 antipseudomonal cephalosporin과 aminoglycoside 의병합요법이권장되고있다. Haemophilus influenzae의경우 ampicillin 에감수성이면 ampicillin 을투여하나, 만일 ampicillin 내성이면 3세대 cephalosporin 을투여하는것을권장하고있다. 황색포도알균 (Staphylococcus aureus) 의경우 methicillin 감수성이면 nafcillin 이일차치료제로권장되며, methicillin 내성이면 vancomycin 이일차항생제로추천되고 rifampin 을같이병합투여할것이권장되고있다. 장알균 (Enterococcus spp.) 의경우 ampicillin 감수성이면 ampicillin과 gentamicin 을병합투여하고, ampicillin 내성이면 vancomycin 과 gentamicin 을병합투여하는것을권장하며, 최근병원감염에서문제가되는 ampicillin 과 vancomycin 둘다에내성인 vancomycin 내성장알균 (vancomycin-resistant enterococci, VRE) 이면 linezolid 를투여하는것이권장되고있다. 4) 항생제투여기간중추신경계감염의치료기간은정확하게얼마동안이라고단정하기는거의불가능하다. 환자의임상경과와동정된원인균, 그리고환자의치료에대한반응경과등을고려하여반드시환자개별상황에맞추어항생제투여기간을결정할것을권장하고있다. 환자가초기항생제치료에잘반응하여임상증상이호전되고검사결과가호전을보인다면 Streptococcus pneumoniae 는 7-10 일, Neisseria meningitidis는 7일, Haemophilus influenzae 는 7 days, Listeria monocytogenes는 21일, 그리고대부분의그람음성막대균의경우에는 21~28 일의장기간의항생제치료를권장하고있다. 5) 뇌농양의항생제치료뇌농양의원인균은매우다양하고다른감염이외의질환과도감별을요하는경우가흔하고, 항생제치료기간이상당히길어서항생제치료전에반드시정확한진단과원인균동정을위해수술이나영상의학적중재시술을통한조직검사등을시행할것을권유하고있다. 앞서기술한바와같이뇌농양의경우그원인에따라주요병원체가달라지므로이를고려해야한다 (Table 6). 12 원발병소가부비동염으로인해시작된경우에는주로혐기성사슬알균, 특히 Streptococcus milleri가흔한원인균이며, 그외에도 Bacteroides, Haemophilus, 그리고 Fusobacterium 등이흔한원인균으로 penicillin 과 metronidazole 병합요법, 또는 cefotaxime 과 metronidazole 병합요법을권장하고있다. 치원성 (odontogenic) 농양인경우에는사슬알균 (streptococci) Table 6. Brain abscess in adults: microbiology and antimicrobial therapy Source of abscess Microbial flora Antimicrobial therapy * Paranasal sinus Otogenic infection Aerobic streptococci (usually Streptococcus milleri group) Anaerobic streptococci Haemophilus species Bacteroides species (non-fragilis) Fusobacterium species Streptococcus species Enterobacteriaceae Bacteroides species (includes B. fragilis) Penicillin + metronidazole or (Cefotaxime +metronidazole) Penicillin + metronidazole + ceftazidime Metastatic spread Depends on source Nafcillin + metronidazole + cefotaxime Penetrating trauma Staphylococcus aureus Clostridium species Enterobacteriaceae Nafcillin + cefotaxime Postoperative Staphylococcus epidermidis Staphylococcus aureus Enterobacteriaceae Pseudomonaceae Vancomycin + ceftazidime * Suggested antimicrobial therapy for initial empiric treatment; antibiotic selection will vary depending on clinical situation and culture results. J Korean Neurol Assoc Volume 29 Suppl. 2,

167 장현하 Table 7. Recommended antibiotic dosage for bacterial brain abscess * Antibiotics Dosage Penicillin G 2-4 million units iv q4h Metronidazole 500 mg iv q6h Cefotaxime 1-2 g iv q4-8h (maximum dose, 12 g/d) Ceftazidime 1-2 g iv q4-8h (maximum dose, 12 g/d) Nafcillin 2 g iv q4h Vancomycin 1 g iv q12h * Recommended dosage for a 70-kg patient (dosing may need adjustment in patients with underlying renal or liver disease). 이외에도장내세균과 (Enterobactericeae) 나 Bacteroides 가흔한원인균으로 penicillin 과 metornidazole 과 ceftazidime 병합요법을권장하고있다. 전이농양 (metastatic abscess) 인경우에는원발병소가어디인지에따라원인균이매우다양하므로원인병소가어디인지자세한병력과신체검사등을통해알아내는것이중요하며경험적으로 nafcillin 과 metronidazole, 그리고 cefotaxime 의병합요법을권장하고있다. 관통상의경우황색포도알균과 Clostridium, 장내세균과등이주요원인균으로 nafcillin 과 cefotaxime 병합요법을권장하고있으며, 수술창상감염인경우 Staphylococcus epidermidis, Staphylococcus aureus, 장내세균과, Pseudomonaceae가흔한원인균으로 vancomycin 과 ceftazidime 의병합투여를권장하고있다. 이러한뇌농양에서사용되는항생제역시혈액뇌장벽을통과해야하므로고용량의항생제가사용되며정상신기능과정상간기능을가진환자에서의항생제투여용량은표 7과같다. 13 항생제치료기간은원인미생물과뇌농양감소정도에따라달라지며, 어느정도의기간이최적인지에대한연구보고는거의없다. 대부분최소한 6~8 주의정맥주사항생제치료를시행하나뇌의노카르디아 (nocardiosis) 나방선균증 (actinomycosis) 의경우 12개월이상의장기항생제치료가필요한경우도있다. 1 따라서각환자에따라치료기간이개별화해야하며, 특히뇌농양은항생제치료뿐만아니라대부분의경우수술배농이필요한경우가많아, 뇌농양의크기와배농을위한수술, 그원인균과내외과적치료에대한반응에따라개별화하여치료할것을권장하고있다. References 1. Brook I, Townsend GC. Brain abscess and other focal pyogenic infections of the central nervous system. In: Cohen J, Powderly WG, Opal SM. Infectious diseases. 3rd ed. Mosby Elsevier. 2010: Van de Beek D. Acute and chronic meningitis. In: Cohen J, Powderly WG, Opal SM. Infectious diseases. 3rd ed. Mosby Elsevier. 2010: Bayston R. infections in hydrocephalus shunt. In: Cohen J, Powderly WG, Opal SM. Infectious diseases. 3rd ed. Mosby Elsevier. 2010: Lutsar I, McCracken GH Jr, Friedland IR. Antibiotic pharmacodynamics in cerebrospinal fluid. Clin Infect Dis 1998;27: Täuber MG, Khayam-Bashi H, Sande MA. Effects of ampicillin and corticosteroids on brain water content, cerebrospinal fluid pressure, and cerebrospinal fluid lactate levels in experimental pneumococcal meningitis. J Infect Dis 1985;151: Lepur D, Barsic B. Community-acquired bacterial meninigitis in adults: antibiotic timing in disease course and outcome. Infection 2007;35: Moon SY, Chung DR, Kim SW, Chang HH, Lee H, Jung DS, Kim YS, Jung SI, Ryu SY, Heo ST, Moon C, Ki HK, Son JS, Kwon KT, Shin SY, Lee JS, Lee SS, Rhee JY, Lee JA, Joung MK, Cheong HS, Peck KR, Song JH. Changing etiology of ommunity-acquired bacterial meningitis in adults: a nationwide multicenter study in Korea. Eur J Clin Microbiol Infect Dis 2010;29: Lee SO, Ryu SH, Park SJ, Ryu J, Woo JH, Kim YS. Meningococcal disease in the Republic of Korea army: incidence and serogroup determined by PCR. J Korean Med Sci 2003;18: Choi JM, Cho DS, Jin SC, Kim SH, Park DB, Kim YR. Ventriculostomy-associated infection: analysis of risk factors and the venue of external ventricular drainage. Korean J Cerebrovasc Surg 2007;9: Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med 1997;336: Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, Whitley RJ. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39: Mathisen GE, Johnson JP. Brain abscess. Clin Infect Dis 1997;25: Honda H, Warren DK. Central nervous system infections: meningitis and brain abscess. Infect Dis Clin North Am 2009;23: 대한신경과학회지제 29 권부록 2, 2011

168 특수상황에서의간질환자치료 : 고찰및증례심정지후환자에서의집중치료 국립중앙의료원신경과학교실고임석 Neurocritical Care in Post Arrest Patients Im-Seok Koh, MD Department of Neurology, National Medical Center, Seoul, Korea Because the pathology caused by complete ischemia and reperfusion after cardiac arrest is unique in that it had a definite cause, time course, and pathologic process, this state is called a new term: post-cardiac arrest syndrome. Post-cardiac arrest syndrome has relatively poor outcome, therefore accurate assessment of current condition and prognostication is important. The managements are the followings; the effective monitoring, early hemodynamic optimization, oxygenation, ventilation, circulatory support, acute coronary syndrome treatment, therapeutic hypothermia, proper sedation and neuromuscular blockade, seizure control and prevention, aggressive fever and glucose control, treatment of adrenal dysfunction, renal function, and infection. There are some prognostic indicators including end-tidal CO 2, clinical examination, electrophysiologic studies, biochemical markers and imaging studies. Key Words: Post-cardiac arrest syndrome, Hypoxic-ischemic brain injury 서론 심폐소생술의눈부신발전으로갑자기발생한심정지에서회생하는환자는증가하고있지만안타깝게도이들의최종예후는과거와비슷하다 년심정지후순환이회복된환자에서단기간내사망률이 50% 이상으로보고된바있는데, 년 19,819 명의성인과 524 명의소아에서의사망률은각각 67%, 55% 이었고, 2 24,132 명을대상으로시행된최근조사에서도 71% 의사망률을보여 50년전과차이가없다. 3 심정지후순환이재개되면신체전반의허혈손상과함께순환복구후의재관류 (reperfusion) 손상이발생하여독특하고다양한병리기전과증상이나타나는데이를 심정지후증후군 (post-cardiac arrest syndrome) 이라고지칭한다. 4 저산소허혈뇌손상 (hypoxicischemic brain injury), 심정지후심근부전 (post-cardiac myocardial dysfunction), 신체전반의허혈및재관류손상 (systemic ischemic/reperfusion response) 등이발생하므로 이에대한적절한진단과치료는물론최초심정지를일으킨근본적인유발원인에대한정확한평가와치료가중요하다. 또한, 많은경우에서치명적인예후를보이므로정확한상태평가를통한예측이중요하다. 예후평가에는심정지의원인과지속시간, 심폐소생술의시작시간등과같은고전적인방법과최근개발되고있는신경학적척도조사, 각종영상학적및임상진단의학적분석들이있다. 기존의연구결과를종합적으로적용시켜보면심정지에서순환이회복되고 72시간이후에도의식회복이없으면예후가나쁠것으로간주했다. 5 72시간이전의평가방법은아직확립되지않았으나, 최근알려진가장중요한인자는저체온요법 (therapeutic hypothermia) 의시행여부이다. 즉저체온요법을시행한경우예후가양호했고이를기준으로한예후평가연구결과들이과거와는다른양상을보여주고있으므로이에대한고려가필요하다. 치료 Im-Seok Koh, MD Department of Neurology, National Medical Center, 18-79, Eulgiro 6ga, Jung-gu, Seoul , Korea Tel: Fax: neukoh@paran.com 허혈손상을받은장기에적절한혈액과산소를공급하고유지하는것이중요하다. 즉각적인혈량의교정이필요하며저장성수액은뇌부종을악화시킬수있으므로가급적사용하지않 J Korean Neurol Assoc Volume 29 Suppl. 2,

169 고임석 는다. 6 급성기치료의정확한목표지표는아직알려져있지않으나중심정맥압 (central venous pressure) 8-12 mmhg, 평균동맥압 (mean arterial blood pressure) mmhg, 연속적중심정맥산소포화도 > 70%, 적혈구용적률 > 30% 또는혈색소 > 8 g/dl, 유산염 (lactate) < 2 mmol/l(18 mg/dl), 소변량 (urine output) > 0.5 ml/kg/h, 산소운반량 > 600 ml/min/m 2 등이일반적으로추천되는수치들이다. 특히대뇌혈류는평균동맥압 50 mmhg 에서 150 mmhg 사이에는자기조절작용으로일정하게유지되나저산소 -허혈손상시자기조절작용이손상되어뇌관류압 (cerebral perfusion pressure) 은혈압에의존하게되므로적절한평균동맥압의유지가중요하다. 또한, 심정지후순환재개시순간적인뇌혈류량증가와뒤이은감소가나타나는 no-reflow 현상이발생할수있는데 7 자기조절능력상실과 no-reflow 등을고려한다면다소높은평균동맥압의유지가필요하다는주장도있다. 8 대부분기계호흡이시행되는데저산소증과과이산화탄소증은피해야하며 100 mmhg 이상초기산소분압 (PaO 2) 을유지하는것이바람직하다는연구결과도있다. 6 뇌부종과뇌압상승을막기위해과호흡이흔히시도되나심각한뇌부종은내재된손상정도를반영하므로실제과호흡이큰도움이되지않으며오히려혈관수축을유발하고허혈손상을악화시키므로주의하여야한다. 갑자기발생하는심정지의가장흔한원인은심근경색과같은관상동맥질환이므로환자가가지고있던심질환의확인과이에대한적극적치료가필요하다. 또한기존의심질환이없었던경우에도순환회복시심근기능부전이흔히발생하며대개 시간지속된후호전되는데이때매우불안정한심박수및혈압이관찰되므로각별한주의를요한다. 심폐소생술에서사용되는약물 (epinephrine, atropine) 등으로인한혈압상승이나빈맥도있으나주로혈압저하가나타나며이경우허혈손상을받은장기가더욱악화될수있으므로적극적인대처가필요하다. 발열은뇌손상을악화시키므로적극적인조절이필요하다. 감염예방을위해무조건적으로광범위항생제를사용하는것은지양해야하나발열시에는반드시원인을찾아야하며우선적으로폐렴, 비뇨기계감염, 패혈증등을고려하여적절한항생제를사용한다. 4 고혈당은심정지후증후군에서자주관찰되며이유는명확하지않으나스트레스호르몬의영향과심폐소생술에서사용되는 epinephrine 및최근의저체온요법도인슐린의분비능과민감도를저하시켜혈당을올리는것으로생각된다. 저혈당과고혈당은모두저산소 -허혈뇌손상을악화시키므로적극적조절이필요하며정상적인식사와영양공급이어려운경우가많 으므로지속형인슐린사용시는저혈당에대한주의가필요하다. 이상적인혈당에관해서는아직밝혀져있지않으며현재대규모임상연구가진행중이다. 심정지후뇌손상을막기위해뇌대사요구량을줄이는약물의사용이시도되고있는데현재까지무작위대규모연구를통해유의한결과가확인된바는없으며부작용과신경학적검사가불가능하다는점등을고려하여불응성뇌압증가와같은특수한상황에서만시도하여야한다. 다양한형태의발작 (seizure) 과근육간대경련 (myoclonus) 이발생가능하며이경우뇌대사요구량과뇌압이증가하고의식회복이늦어지므로항전간제사용을고려할수있으나예방적인사용은근거가충분하지않다. 경련이없는환자라도의식회복이지연되면뇌파검사를시행한다. 심정지후증후군환자에서저체온요법은뇌대사요구량을줄여주는표준화된치료이다. 무작위연구와메타분석이발표되었으며 33 또는 정도로약한저체온치료가 시간정도시행되었고유의한효과가나타났다. 그러나적절한목표온도, 지속시간, 정상체온으로돌려주는속도등의기술적인부분에있어서는아직확실하지않으며추후지속적인연구가필요하다. 9 예후평가 우선적으로고려할사항은예측대상의선정이다. 예후가좋을환자를예측할것인가? 아니면절대회복하지못할환자를예측할것인가? 또는회복된후심각한결손이동반될환자를예측할것인가? 무엇보다도 false pessimistic prediction ( 비관적으로예측을했는데환자가회복될경우 ) 을피하는것이중요하다. 즉섣부른비관적예측으로보호자들이환자를포기하도록만들게하면안되며예후평가에서는높은민감도 (sensitivity) 보다는특이도 (specificity) 와양성예측률 (positive prediction value) 이중요하다. 1. 심정지발생시의인자들심정지발생시의상황만을분석하여예후를예측하기위한연구들로무호흡시간, 심폐소생술지속시간, 심정지의원인 ( 심장탓 vs. 비심장탓 ), 심정지발생시의부정맥유형등이예후와관련이있을것이라고예상했었으나아직까지는확실한연관이있음은증명되지못했다 대한신경과학회지제 29 권부록 2, 2011

170 심정지후환자에서의집중치료 2. 고체온증체온이높은경우예후가나쁘다는것은잘알려져있다. 심정지후첫 48시간이내에고막체온이 37 이상인경우그렇지않은경우에비해사망률과 6개월이후식물상태일위험이 2.26 배로높다는연구가있었으나이에관련된다른인자들이많으므로고체온증이나쁜예후를보여주는독립적인인자인지는불분명하다 신경학적증상및이학소견 Glasgow 혼수척도 (Glasgow coma scale, GCS), Glasgow 혼수척도 -운동영역 (GCS-Motor part), 뇌간반사 (brainstem reflex: 동공반사, 각막만사, 자발안구운동 ) 등의소견과근육간대경련간질지속증과같은신경학적증상을통한예후예측을보면, 심정지 72시간이후에서 Glasgow 혼수척도운동영역점수가 2점이하이거나뇌간반사가소실된경우불량한예후에대한위양성 0 % 라고한다. 10,12,13 Glasgow 혼수척도는대부분의환자가기관지삽관상태로언어영역검사가불가능하고안구검사도평가도구로서의미가적어운동영역만으로평가하는경우가더우월하다고한다. 9 경련특히근육간대경련지속증시예후가나쁜것은잘알려져있었으나근육간대경련의아형에따라예후가달라진다. 근육간대경련은크게무산소후근육간대경련 (postanoxic myoclonus, Lance-Adams syndrome), 근육간대경련지속증 (status myoclonus, more than 30 minutes of myoclonic activity), 근육간대경련성간질지속증 (myoclonic status epilepticus, myoclonic jerks merging with tonic-clonic seizures and lasting over 30 minutes)) 등이있는데일반적으로무산소후근육간대경련이불량한예후와관계가있다고하며단순경련이나국소적인근육간대경련은의미가없는것으로보여진다. 14 결론적으로근육간대경련간질지속증이발생하거나심정지후 3일째에동공반사또는각막반사의소실, GCS- 운동영역 2점이하인경우예후가불량할것으로보여진다. 4. 전기신경생리검사심한뇌손상을의미하는특징적인뇌의전기적활동의변화들이불량한예후와관련을있을것으로간주되나뇌파소견은검사를시행하는시기와혈역학적, 대사적인자들과약물등의다른교란변수들의영향을받는다. 즉뇌파검사단독만으로환자의예후를예측하는것은지양해야하며다른예후인자들과 조합하여사용한다. Somatosensory evoked potentials (SEPs), Brain stem auditory evoked potentials (BAEPs) 등과같은전기신경생리검사에서는 SEPs 상 short latency cortical response (N20) 가양측에서나오지않을경우예후가나쁘다고하나, 13,15-21 대사성원인과약물같은교란변수의영향을받으므로일방적인적용은피해야한다. 22,23 BAEPs 는연구결과가부족하며아직까지는만족스러운결과를보이지못하고있다. 24,25 5. 생화학적표시인자뇌척수액 (Cerebrospinal fluid) creatine kinase BB (CK-BB) isoenzyme activity, serum and CSF neuron-specific enolase (NSE), CSF-Neurofilament, serum S-100 등의측정을통한연구중 CK-BB 는신경세포와성상세포에존재하며심정지발생 시간후에정점에도달하며나쁜예후판정에특이도 100% 와민감도 48% 를가진다고한다. 26 뇌부종을고려한요추천자시행의안전성문제는과거시행한연구들을통해요추천자가별다른영향을미치지는않는다고보고된바있다. 26,27 생화학적표지인자가환자에서예후를예측하는데약물이나다른신경학적질환등에영향을받을수있는 SEP의단점을극복할수있을것으로기대했으나현재까지의결과를분석해보면예후를예측하는데 SEP보다뛰어나지않은것으로나타나고있다. 6. 신경영상학적분석 CT, MRI, MRS, PET 등의영상학적분석을통한예후분석연구는계속시도되고있으나예측에대한유용성이확립된검사는없는상태이다. 28,18 심폐소생술진료지침 : 예후 29 아래내용은 2010 년미국심장학회에서발표한심폐소생술에대한새로운진료지침중최종권고만을요약한것으로심정지후환자의예후판정시참고할수있으나입증된근거만을가지고기술한지침임을고려할때환자상태에따른의사의임상적판단이더욱중요하다. 1) 심정지발생동안의예측 : 호기말이산화탄소분압심정지시호기말이산화탄소에대한정량적측정은심박출량에대한안전하고효과적인비침습적지표가될수있으며기도 J Korean Neurol Assoc Volume 29 Suppl. 2,

171 고임석 삽관환자에서순환회복의가능성에대한조기지표가될수있다. 낮은수치의호기말이산화탄소분압은생존가능성이낮음을예측할수있으나정확한수치자료는충분하지않다. 2) 소생후의예측저체온요법을시행하지않은혼수상태의성인환자의경우심정지 24시간내에는나쁜예후를예측하는확실한신경학적징후는없다. 24시간이후에서는다른혼란변수 ( 진정제나신경근육차단제의사용 ) 가없는상태에서동공반사와각막반사가 72시간이후에도없는것은신뢰할만한예측인자이다. 24시간이후에서의전정안구반사의소실과 72시간이후에도 GCS 운동영역분야 2점미만인경우는신뢰성이떨어지며근육간대경련을포함한다른임상적징후는나쁜결과에대한예측인자로권고되지않는다. 생화학적표지자에대한연구에서저체온요법을시행여부와관계없이심정지후혼수상태환자에서나쁜예후를예측하는확실한증거는아직없다. 현재까지의연구에서는적은표본수와나쁜예후를나타내는컷오프수치의불확실성에대한한계가남아있다. 전기신경생리학적검사의경우첫 24시간이내에결과를예측할만한검사는없으며 24시간이후정중신경자극에대한양측 N20 피질반응의소실은심정지후저체온요법을시행하지않은혼수상태의생존자들에서나쁜결과를예측한다. 진정제, 저혈압, 저체온또는저산소증같은변수가없는상황에서지속적인순환유지후 24시간에서 72시간사이에관찰된뇌파소견을나쁜결과예측에이용하는것도합리적으로생각된다. 심정지환자에서예후를예측하기위한보편적인신경영상검사의사용을뒷받침하거나반대하는증거는아직충분하지않다. 3) 심정지후예측에있어서저체온요법의효과치료권고안으로저체온치료를시행한심정지후환자에서나쁜결과를예측하기위한특정한방법은아직불충분하다. 심정지후 24시간이내에신경학적결과를예측하는데있어서어떠한임상신경학적징후, 전기생리학적검사, 생물학적표지자또는영상검사도신뢰할수없다. 24시간이지난후에는, 저온치료를받은심정지환자에서나쁜신경학적결과를예측하는단독변수는없다. 다만제한된증거에기초하여저체온치료를받은심정지환자에서잠재적으로믿을만한나쁜결과예측인자는심정지 24시간후의체성감각유발전위검사에서양측 N20 의소실이나 36에서 72시간째의비반응성뇌파배경, 그리고심정지 72시간후각막반사와동공반사의소실을포함한다. 제한된증거들은또한지속적인순환재개 3일째의 GCS 운동점수 2점미만과간질지속상태의존재를심정지후저온치료를받은환자들에서나쁜결과를예측하기위한잠재적으로믿을만한인자로제안한다. NSE 같은생화학지표들은저체온요법이시행된환자들의나쁜결과를예측하기위한보조수단으로잠재적인가치가있으며단독예측수단의결과만으로제한된치료를시행해서는안된다. 예후평가시환자상태를정확하게평가하여예후를추정하는것은바람직하나의사자신이예후자체를결정해서는안된다는점을명심하여야한다. 위에서기술한예후평가방법들은통계적인분석이므로일률적으로적용해서는되며, 예후평가에서회생가능성이낮을것으로판단한경우에도뒤늦게회복되는경우가있으므로섣불리불량한예후를가정하여의사스스로나보호자들이환자를포기하도록만들면안된다. References 1. Stephenson HE Jr, Reid LC, Hinton JW. Some common denominators in 1200 cases of cardiac arrest. Ann Surg 1953;137: Nadkarni VM, Larkin GL, Peberdy MA, Carey SM, Kaye W, Mancini ME, et al. First documented rhythm and clinical outcome from in-hospital cardiac arrest among children and adults. JAMA 2006;295: Nolan JP, Laver SR, Welch CA, Harrison DA, Gupta V, Rowan K. Outcome following admission to UK intensive care units after cardiac arrest: a secondary analysis of the ICNARC Case Mix Programme Database. Anaesthesia 2007;62: Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, Bottiger BW, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation 2008;118: Longstreth WT, Jr., Inui TS, Cobb LA, Copass MK. Neurologic recovery after out-of-hospital cardiac arrest. Ann Intern Med 1983; 98: Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 6: advanced cardiovascular life support: section 8: postresuscitation care. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 2000;102:I 대한신경과학회지제 29 권부록 2, 2011

172 심정지후환자에서의집중치료 7. Wright WL, Geocadin RG. Postresuscitative intensive care: neuroprotective strategies after cardiac arrest. Semin Neurol 2006;26: Bell DD, Brindley PG, Forrest D, Al Muslim O, Zygun D. Management following resuscitation from cardiac arrest: recommendations from the 2003 Rocky Mountain Critical Care Conference. Can J Anaesth 2005; 52: Edgren E, Hedstrand U, Kelsey S, Sutton-Tyrrell K, Safar P. Assessment of neurological prognosis in comatose survivors of cardiac arrest. BRCT I Study Group. Lancet 1994;343: Rogove HJ, Safar P, Sutton-Tyrrell K, Abramson NS. Old age does not negate good cerebral outcome after cardiopulmonary resuscitation: analyses from the brain resuscitation clinical trials. The Brain Resuscitation Clinical Trial I and II Study Groups. Crit Care Med 1995;23: Zeiner A, Holzer M, Sterz F, Schorkhuber W, Eisenburger P, Havel C, et al. Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Arch Intern Med 2001;161: Levy DE, Caronna JJ, Singer BH, Lapinski RH, Frydman H, Plum F. Predicting outcome from hypoxic-ischemic coma. JAMA 1985;253: Zandbergen EG, Hijdra A, Koelman JH, Hart AA, Vos PE, Verbeek MM, et al. Prediction of poor outcome within the first 3 days of postanoxic coma. Neurology 2006;66: Han SW. Hypoxic Brain Injury after Cardiac Arrest: What to do During the Critical Period. J Korean Neurol Assoc 2008;26: Chen R, Bolton CF, Young B. Prediction of outcome in patients with anoxic coma: a clinical and electrophysiologic study. Crit Care Med 1996;24: Bassetti C, Bomio F, Mathis J, Hess CW. Early prognosis in coma after cardiac arrest: a prospective clinical, electrophysiological, and biochemical study of 60 patients. J Neurol Neurosurg Psychiatry 1996;61: Young GB, Doig G, Ragazzoni A. Anoxic-ischemic encephalopathy: clinical and electrophysiological associations with outcome. Neurocrit Care 2005;2: Berek K, Lechleitner P, Luef G, Felber S, Saltuari L, Schinnerl A, et al. Early determination of neurological outcome after prehospital cardiopulmonary resuscitation. Stroke 1995;26: Logi F, Fischer C, Murri L, Mauguiere F. The prognostic value of evoked responses from primary somatosensory and auditory cortex in comatose patients. Clin Neurophysiol 2003;114: Madl C, Kramer L, Domanovits H, Woolard RH, Gervais H, Gendo A, et al. Improved outcome prediction in unconscious cardiac arrest survivors with sensory evoked potentials compared with clinical assessment. Crit Care Med 2000;28: Gendo A, Kramer L, Hafner M, Funk GC, Zauner C, Sterz F, et al. Time-dependency of sensory evoked potentials in comatose cardiac arrest survivors. Intensive Care Med 2001;27: Drummond JC, Todd MM, Schubert A, Sang H. Effect of the acute administration of high dose pentobarbital on human brain stem auditory and median nerve somatosensory evoked responses. Neurosurgery 1987;20: Peterson DO, Drummond JC, Todd MM. Effects of halothane, enflurane, isoflurane, and nitrous oxide on somatosensory evoked potentials in humans. Anesthesiology 1986;65: Mutschler V, Chaumeil CG, Marcoux L, Wioland N, Tempe JD, Kurtz D. [Auditory P300 in subjects in a post-anoxic coma. Preliminary data]. Neurophysiol Clin 1996;26: Wang JT, Young GB, Connolly JF. Prognostic value of evoked responses and event-related brain potentials in coma. Can J Neurol Sci 2004;31: Tirschwell DL, Longstreth WT, Jr., Rauch-Matthews ME, Chandler WL, Rothstein T, Wray L, et al. Cerebrospinal fluid creatine kinase BB isoenzyme activity and neurologic prognosis after cardiac arrest. Neurology 1997;48: Vaagenes P, Mullie A, Fodstad DT, Abramson N, Safar P. The use of cytosolic enzyme increase in cerebrospinal fluid of patients resuscitated after cardiac arrest. Brain Resuscitation Clinical Trial I Study Group. Am J Emerg Med 1994;12: Morimoto Y, Kemmotsu O, Kitami K, Matsubara I, Tedo I. Acute brain swelling after out-of-hospital cardiac arrest: pathogenesis and outcome. Crit Care Med 1993;21: Morrison LJ, Deakin CD, Morley PT, Callaway CW, Kerber RE, Kronick SL, et al International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 2010;122:S345-S421. J Korean Neurol Assoc Volume 29 Suppl. 2,

173 특수상황에서의간질환자치료 : 고찰및증례신경집중치료에서의신경초음파검사 국민건강보험공단일산병원신경과이준홍 Neurosonology in Neurocritical Care Jun Hong Lee, MD, PhD Department of Neurology, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea Neurocitical care is rapidly becoming a sought-after subspecialty. The ideal neuromonitor should be non-invasive, continuous, real-time and have a high sensitivity and specificity for predicting both intracranial alterations, therapy success or need for modifications, in addition to long-term clinical outcomes. Along with pressure monitoring, brain oxygen tension, continuous electroencephalography, transcranial Doppler(TCD) ultrasound can allow the prediction of long-term outcome in patients suffering from neurological diseases. Ultrasound can provide valuable information to help supplement clinical decision-making and improve diagnostic and prognostic accuracy. This review provides an overview of the current applications of ultrasound in the intensive care unit (ICU). Specifically, the use of TCD ultrasound in cerebral perfusion and intracranial pressure prediction is reviewed. Additional important ICU applications of ultrasound, such as predicting malignant middle cerebral infarction, intracranial hemorrhage detection and brain death determination, are discussed. Key Words: Ultrasound, Transcranial doppler, Neurocritical care, Subarachnoid hemorrhage, Brain death, Intracranial pressure, cerebral perfusion pressure 서 론 대하여기술하고자한다. 신경계집중치료분야는비교적새롭고빠르게발전하는의학의분야중하나이다 년도경에두개내압 (Intracranial Pressure, ICP) 모니터링기술이도입되기전까지는신경학적진찰에의한진단만가능하였으나 21세기에들어기능이향상된기구와센서가도입되면서많은발전이이루어졌다. 이상적인신경계모니터링은비침습적이고지속적인실시간검사가가능해야할뿐아니라두개내상태의변화에대한높은민감도와특이도를가져야하는데, 이러한특징의일부를가지고있으며비침습적인검사인경두개도플러초음파 (Transcranial Doppler, TCD) 도여러신경계모니터링방법과함께중요한역할을하고있다. 이종설에서는신경계집중치료분야에서초음파의현재역할에 Jun Hong Lee, MD, PhD Department of Neurology, National Health Insurance Corporation Ilsan Hospital, 1232 Baeksok-1dong, Ilsandong-gu, Goyang , Korea Tel: Fax: jhlee@nhimc.or.kr 본론 1. 지주막하출혈후혈관경련에대한 TCD 검사 TCD 는지주막하출혈 (Subarachnoid Hemorrhage, SAH) 후발생하는혈관경련 (vasospasm) 에대한검사로써초창기부터시행되었으며혈관경련의정도와출혈된혈액량그리고 TCD 혈류속도의증가는비례한다. 혈관경련이발생함에따라혈관내부가가늘어지면혈류속도가증가하며이는혈관경련의정도와비례한다 (Table 1) 지주막하출혈후혈관경련이발생하기전에 TCD 검사를시행하여혈류속도의기준치를알고있는것이중요하며, 그이후매일또는이틀마다자주검사를반복하여혈류속도를비교하여야한다. TCD혈류속도의변화는뇌혈관촬영 (Cerebral Angiography) 에서의혈관협착의정도와비례하며특히 MCA 에서가장좋은연관성을보인다. Lindegaard 등 1 은중뇌동맥 (Middle Cerebral Artery, MCA) 의 TCD 혈류속도가 120 cm/s 142 대한신경과학회지제 29 권부록 2, 2011

174 신경집중치료에서의신경초음파검사 Table 1. 혈관경련의단계에따른변화 stage Vessel narrowing TCD velocity CBF DIND ⅰ No ⅱ No ⅲ No ⅳ or Yes =mild, =moderate, =severe, =very severe, =no change. Abbreviations: TCD = transcranial Doppler, CBF=cerebral blood flow, DIND=delayed ischemic neurologic deficit. 이상증가되는경우경한정도의혈관경련을나타내며, 혈관경련이심해질수록혈류속도는증가하여 200 cm/s 이상인경우는 MCA 의내경은 1 mm 까지감소할수있는데참고로정상적인 MCA 의내경은약 3 mm 정도이다. TCD 혈류속도측정은혈관협착의정도, 혈관경련의진행, 그리고보상적으로발생한혈관확장의정도를예측하는데도움이된다. 혈관경련에따른뇌혈류량 (Cerebral Blood Flow, CBF) 의변화는 Single-photon emission computed tomography (SPECT), xenon-enhanced computed tomography (Xe-CT), positron emison tomography (PET) 등을통하여측정할수있는데, TCD 평균혈류속도의변화가 CBF 의변화를그대로의미하는것은아니다. TCD혈류속도는혈관경련이외에도고혈압-혈량과다증 (hypertension-hypervolemia) 등의과역동상태 (hyperdynamic state) 에의해서도증가될수있으므로내경동맥 (Internal Carotid Artery, ICA) 혈류속도도측정하여이들 MCA/ICA 평균혈류속도의비율인 Lindegaard ratio 1 를이용하면혈관경련에의한혈류속도의증가와과혈류상태 (hyperemia) 로인한전반적인혈류속도의증가를감별진단하는데도움이된다. 지주막하출혈후두개내원위혈관만의경련에의한신경학적증상발현은흔치않은것으로알려져있으며 TCD 에서는 M3 또는원위 (distal) M2 MCA 와같은원위혈관의경련을진단하기에는민감도가높지않으나 MCA 의근위 M2 부분까지는검사가가능하다. Xe-CT 또는 SPECT 검사를통한 CBF 측정과함께 TCD검사를통한혈관협착의정도를같이검사하는것은상호보완적인효과를얻을수있으며이는지주막하출혈의초기환자에서중재적 (Interventional) 또는내과 / 외과적치료방법을결정하는데많은도움이될수있다. 2. TCD를이용한뇌혈류역학검사 상뇌손상 (Traumatic brain injury, TBI), 악성뇌경색증과두개내출혈을포함한여러신경계질환의진단과치료에있어필수적이다. CPP 는평균혈압 (Mean arterial pressure, MAP) 에서 ICP 를빼는방법으로계산할수있으며평균 ICP 가 20 mmhg 보다높고 CPP 가지속적으로 55 mmhg 보다낮은환자에서는치사율이높은것으로보고되고있어서뇌외상환자재단지침 (Brain Trauma Foundation s guidelines) 2 에서는 CPP 를적어도 60 mmhg 이상유지할것을권유하고있다. CPP 의측정은통상적으로뇌실질또는뇌실내로기구를침습적으로넣어서측정하는정확한 ICP 모니터를필요로한다. 비록이와같은방법으로정확한측정을할수있지만, 침습적인술기에따른감염, 출혈, 잘못된위치또는비정상적인작용등의위험이없지는않다. 그러므로비침습적으로 CPP 를측정할수있는방법이연구되어왔으며, TCD 를이용한 CPP 측정에대한몇가지방법이보고되었다 년도중반에 Aaslid 3 등의 TCD 혈류속도와혈압의 Fourier 분석 (analysis) 에의하여 CPP 를측정할수있는방법을처음소개하였는데, 이방법은비록 CPP 의변화를민감하게반영하지만절대적인정확성에있어서는한계가있어 95% prediction error 가 ±27 mmhg 정도로범위가넓었다. Czosnyka 4 등은 96명의뇌손상환자에서직접개발한 CPP 계산방법을침습적으로직접측정한방법과 Aaslid 3 의방법등과비교하였는데, 그들의방법은 MCA 의 TCD 평균, 수축기, 확장기혈압의시간평균 (time-averaged) 방법을사용하였는데 Aaslid 3 의방법과비교하였을때 95% 신뢰성한계 (confidence limits) 에있어더나은결과를얻어 (±21 versus ±29 mmhg), 71% 에서침습적인 CPP 측정에비하여 10 mmhg 이하의오차를보였다. 이와같은방법이향후희망적이긴하지만아직까지침습적인측정방법을대치하기에는오차의정도가너무커서추가적인연구가필요하다. 1) TCD 와뇌관류압 (Cerebral perfusion pressure, CPP) 뇌관류압 (Cerebral perfusion pressure, CPP) 의측정은외 2) TCD와 ICP 측정 CPP 를침습적으로직접측정하기보다는 ICP 를 TCD 를사용 J Korean Neurol Assoc Volume 29 Suppl. 2,

175 이준홍 하여비침습적으로측정하여 CPP 를예측하고자하는노력이이루어져왔다. Schmidt 5 등은뇌실질로부터직접얻은침습적인방법의 ICP 측정치와좋은상관관계를보이는비침습적인방법으로측정한 simulated ICP 계산방법를개발하였다. 11명의중환자 (8명은외상뇌손상환자 ) 를대상으로 TCD 혈류속도, 동맥혈압를측정하여 ICP 값을계산할수있는수학적인방식을개발하였는데, 계산된 ICP 와침습적으로측정된 ICP 와의평균차이는 4.0±1.8 mmhg 이었으며이를감안하였을때 11명의환자중 8명의환자에서계산된 ICP 값을기준으로도적절한치료가가능하였다. 또저자들은 adaptive model 를사용한 ICP 계산법을후에발표하였는데, 이는정확도를더높이기위하여뇌혈관자기조절 (Cerebral autoregulation, CA) 상태를공식에적용하였다. 비록 adaptive model 를사용하여정확도를높이긴하였으나아직까지일반적으로임상적적용을하기에는정확도가충분하지않다. 하지만, 모든신경계질환환자가침습적인 ICP 모니터링를할수있는것은아니며, 이들중일부에서는 ICP 상승을알지못하여치료시점을놓칠수있어서, 저자들은이와같이 TCD 를활용한비침습적인 ICP 측정방법이 ICP 상승을초기에진단하는데유용하다고보고하였다. 3) 박동지수 (Pulsatility Index, PI) 와 ICP 박동지수 (Pulsatility Index, PI) 는혈류저항에대한정보를제공하며 TCD 혈류속도측정과는달리음파조사각도 (insonation angle) 의영향을받지않는장점이있다 년에 Gosling 과 King 6 이 PI에대해서처음기술하였으데, 외상뇌손상환자에서뇌부종은말초혈관저항을증가시키며이에따라증가된 PI는 TCD 를사용하여측정할수있고이때 ICP 를내과적또는외과적방법으로낮추면 PI값도낮아진다고보고하였다. Moreno 7 등은 125 명의심한외상뇌손상환자에서입원 24시간내에 TCD 혈류측정을시행하여, 침습적으로직접측정한 ICP 와 TCD 를통하여측정한 PI값의의미있는연관성에대하여보고하였다 (r 2 =0.69, p < ). Bellner 9 등에의한또다른연구에서도 81명의신경외과환자 (21 명은외상뇌손상환자 ) 에서 658 개의 TCD 측정치와침습적인 ICP 측정치를비교한결과 ICP 와 PI간의훌륭한연관성을보고하였다. 이때회기선 (regression line) 은 ICP=11.1 PI-1.43 이었으며, ICP 값이 mmhg 사이인환자에서 ICP > 20 mmhg 을찾아낼수있는민감도와특이도는각각 89%, 92% 였다. 이에저자들은 TCD 로측정한 PI를활용하면집중치료실에서의 ICP 치료에유용하다고보고하였다. TCD 로측정된 PI는외상뇌손상환자에서 CPP 와도좋은연관성이있다고보고되었는데 Chan 10 등은 41명의심한외상뇌 손상환자에서 CPP 가 70 mmhg 이하로내려감에따른 PI 값의점진적인상승을관찰하였다 (r=-0.942, p < ). ICP 측정기구가없는상황또는 ICP 측정이부정확하게되고있다고의심되는상황에서는, TCD 로측정한 PI가낮은 CPP 상태를찾아내는데매우유용하게활용할수있지만, PI 는전체적인혈류역학과혈액내이산화탄소농도등에의하여영향을받을수있기때문에결과판독시에주의가필요하다. 4) TCD 와뇌의자기조절작용 (cerebral autoregulation) 뇌의자기조절작용 (Cerebral autoregulation, CA) 은혈압또는 CPP 의변동이있는상황에서안정적인환경을유지할수있는뇌의능력중하나이다. 예를들어만약 CA가완전하다면평균혈압의감소는보상적으로혈관확장을유발시키고이에따라뇌혈류량이증가하며결국 ICP 가증가된다. 반대로만약 CA 가손상된상태이면혈압의감소가보상적인혈류확장일으키지못하고 ICP 는감소한다. 외상뇌손상환자에서완전한 CA 기능은 2차적인손상으로부터뇌를보호하는역할을한다. TCD 검사방법으로비침습적이며실시간으로 CA의상태를모니터링할수있는데, 악성 MCA 뇌경색환자에서환측과반대측 MCA 의 TCD 혈류속도는환자의머리위치와고혈압과같은상황변화에따라다른정도의자동조절기능을보여준다. 예를들어한연구에서는 8 norepinephrine투여로혈압을 10 mmhg 상승시켰을때환측중뇌동맥혈류속도는 36% 증가하였는데반하여반대측은단지 18% 만증가하였으며이와같은결과는 ICP 가구역별로차이가있을수있음을시사하였다. TCD 를이용하여측정한 CA의이상은나쁜예후와도연관이되어 Czosnyka 4 등은 6명의외상뇌손상환자에서 CPP 는정상이었으나 TCD 를이용하여측정한 CA가손상된환자에서의나쁜예후에대하여보고하였다 3. 임상적예후와 TCD(Clinical outcome prediction and TCD) 1) 외상뇌손상 (Traumatic brain injury, TBI) TBI 환자에서 TCD 는 ICP 를비침습적인방법으로예측할수있게할뿐아니라임상적인예후를예측하는데도도움이된다. 한연구에서는 10 입원당시 TCD 혈류속도가 28 cm/s 이하인경우 80% 의치사율을보고하였으며 6개월뒤예후가좋은환자에서는혈류속도가입원당시 36.2 cm/s 에서퇴원시에는 47.8 cm/s 까지증가한것에반하여예후가나빴던환자에서는혈류속도가낮은그대로유지되었다. Lang 12 등은 TCD 를이용하여 37명의 TBI환자에서 CA를측정하여 TBI 5일후측정된 CA가 144 대한신경과학회지제 29 권부록 2, 2011

176 신경집중치료에서의신경초음파검사 비정상적인것은나쁜예후와연관이된다고보고하였다. Moreno 7 등은 TBI 환자에서 ICP 와 PI의연관성을보고하였는데뇌손상 6개월뒤좋은예후를보인환자의평균 PI는 1.0 이었으나나쁜예후를보인환자에서는평균 PI가 1.6 이었다. 저자들은심한뇌손상환자에서처음 24시간안에측정된 TCD 값은장기예후를예측하는데도움이된다고보고하였다. 2) 뇌내출혈 (Intracerebral hemorrhage, ICH) 비외상성뇌내출혈 (Intracerebral hemorrhage, ICH) 은 30 일치사율이 30% 이상되는심각한질병이다. ICH 후처음몇시간또는며칠이내의치사율은 ICP 의증가와뇌탈출 (herniation) 과연관이있으며 ICP 는 PI를통하여예측할수있으므로 TCD 는 ICH 의예후를예측하는데좋은도구가될수있다. Mayer 13 등은 30명의뇌출혈환자에서 mm 깊이에서 MCA 혈류를 TCD 를이용하여지속적으로측정하였는데환측 - 반대측 PI비율이, 뇌출혈이큰환자에서뇌출혈이작은환자에비하여의미있게높았다 (1.29 versus 1.06 p=0.001). 저자들은환측-반대측 PI의비율이급성기뇌출혈환자에서구역화된종괴효과 (mass effect) 의측정에임상적으로유용하다고보고하였다. 이와같은환자에서전반적인 ICP 의증가가없이도경천막뇌탈출 (transtentorial herniation) 이일어날수있으므로 TCD 모니터링은중요한정보를제공할수있으나, TCD 혈류의비대칭성의예후적중요성에대하여는좀더추가적인연구가필요하다. Marti-Fabregas 14 등은 48명의 ICH 환자에서증상발생후 12시간이내에양측 MCA 에대한 TCD 측정을하여반대측 MCA PI가 30일후의치사율과높은연관성의결과를보여주었다. 반대측 PI 가 1.75 이상일때 80% 민감도, 94% 특이도로나쁜예후를나타내어서저자들은 TCD 로측정한 PI값이 1.75 이상일때뇌출혈환자에서나쁜예후를나타낼수있다고보고하였다. 비록 TCD 를이용한 ICP 측정이이론적으로는일리가있지만, 보편적인사용은아직이루어지지않고있는데이는몇가지다음과같은한계가있기때문이다. 첫째 TCD 검사의가장큰문제점인불충분한청각창 (poor window) 이약 10-15% 환자에서관찰된다. 둘째 TCD 검사는전문적인훈련과경험이필요하여서보편적으로사용되는데는한계가있다. 셋째 TCD 를이용한 ICP 절대값의정확한측정을아직까지는완벽하게이루지는못한상태이다. 마지막으로 TCD 를이용한비침습적인 CPP 또는 ICP 의측정이침습적인방법으로시행한것들과비교하여치료및예후에열등하지않다는결과를보여줄수있는연구들이아직까지는부족한상태이다. 4. Duplex ultrasound imaging 두개내구조의 2차원영상 (Two-dimensional imaging) 을 transcranial color-coded duplex sonography(tccs) 을통하여얻을수있으며뇌실질, 뇌실그리고두개내혈관등을이기술을통하여관찰할수있다. CT검사는중환자를반드시이송하여실시하여야하나이와같은초음파검사는침상옆에서바로실시할수있어빠른임상적결정을하는데도움이된다. 1) 두개내실질검사 (Intracranial parenchymal assessment) 컴퓨터단층촬영 (Cranial computed tomography, CT) 와자기공명영상 (magnetic resonance imaging, MRI) 은뇌졸중환자진료의방사선적진단에있어표준검사로받아들여지고있어, 초음파검사를이용한뇌영상을 CT검사와비교하는연구가진행되고있다. Maurer 15 등은 151 명의급성기뇌졸중환자에서 TCCS 를 CT와비교하였는데이들중 61명의환자는뇌경색이었고 60명은뇌출혈환자이었으며 24명은병변이없었다. 불충분한청각창 (insufficient acoustic bone windows) 때문에초음파검사를할수없었던 12% 의환자를제외한나머지환자의 95% 에서 CT결과와일치된소견을보였으며, 측두엽초음파창의부재로 2명의뇌출혈환자를진단하지못하였지만뇌출혈을진단하는초음파의감수성은 94%, 특이성은 95% 였다. 저자들은 CT검사를쉽게이용할수없을때 TCCS 가급성기뇌졸중환자의진단에도움을줄수있지만, 초음파검사는뇌실질의한정된부분만을보여주고크기가적은뇌출혈과소경색은초음파의해상도를벗어날수있으므로주의를요한다고하였다. 2) 뇌졸중후의종괴효과 (Mass effect after stroke) 점거성세포독성부종 (Space-occupying cytotoxic edema) 으로인한종괴효과 (mass effect) 가뇌간의수평적위치변경을일으키며이로인하여의식장애가발생하는데, 뇌간이 4 mm 이상정중선에서밀리는것은 14일생존율을낮추며악성중뇌동맥뇌경색의치사율을 80% 에이르게한다. 악성중뇌동맥뇌경색증에서반두개절제술 (hemicraniectomy) 는치사율을 50% 감소시킬수있어서한명의사망을방지하기위한 number-neededto-treat 가 2에이르는데, CT로이와같은변화를검사할수있지만또한초음파검사에서도가능하다. Bertram 16 등은 7명의악성중뇌동맥뇌경색과 10명의뇌출혈환자를대상으로 TCCS 와 CT를시행하여비교하였는데, midline shift 의측정은제3 뇌실의깊이로참조한결과 TCCS 와 CT는매우높은연관성을보여주었다. Midline shift 와뇌탈출 (herniation) 이있어도뇌압은정상 J Korean Neurol Assoc Volume 29 Suppl. 2,

177 이준홍 Table 2. 뇌사판정도구들의 pitfalls. Ancillary test Conventional angiography HMPAO SPECT EEG TCD SSEP MRI/MRA, CT/CTA Potential pitfalls Requires transport;invasive; contrast nephrotoxicity; must involve injection of all four major vessels Posterior fossa may be difficult to visualize; uptake may be affected by hypothermia, barbiturates Measures only surface activity; subject to ICU artifacts Absence of signal insensitive to loss of flow; bilateral and anterior and posterior insonation; cannot be used in setting of craniectomy or EVD Questionable specificity; false negatives early after cardiac arrest Not validated; slow flow may appear as absence of flow 인경우침습적인 ICP 측정으로도놓칠수있으나초음파검사는이것을초기에찾아낼수도있다. 이러한환자의경우검사는자주시행하여야하는데 CT검사의경우환자는누운자세 (supine position) 을취해야하는데이것은 ICP 를증가시킬수도있으며또한방사선의잦은노출도문제가될수있다. TCCS 는안전하고비침습적인방법으로점거성 (Space-occupying) 병변을모니터링할수있어 CT검사를어떤경우대체할수도있으리라생각된다. 3) 출혈성변형 (Hemorrhagic transformation) 뇌경색증초기에 TCCS 를이용하여출혈성변형 (hemorrhagic transformation, HT) 을찾아낼수있다. Seidel 17 등은급성중뇌동맥뇌경색증환자 32명에서증상발현 12시간후부터 5일까지반복적인검사를시행하였는데 CT 로 HT 를확진한 11명의환자중 10명에서 TCCS 검사로 HT 를찾아낼수있었어 ( 민감도 91%, 특이도 95%), 저자들은급성기뇌졸중환자에서 HT 를진단하는데초음파검사가아주유용할수있다고하였다. 4) Localization during ICU procedures 초음파검사는병상옆에서경피적배액 (percutaneous drainage), 복막천자술 (paracentesis), 흉강천자술 (thoracentesis), 하대정맥내필터삽입 (inferior venacava filter placement) 등의침습적인시술을시행하는데도움이될수있다. 초음파의도움없이시행하는정통적인방법은실패율이높고부작용발생위험이높아서중심선 (central line) 시술에따른부작용은 0.3~19% 에이른다고알려져있다. 초음파를이용할경우이와같은시술의성공율을높일수있고시술시간을줄일수있으며또한비용효율적이라고할수있다. 뇌수두증환자에서뇌실창냄술 (ventriculostomy) 카테터시술이나 Ommaya reservoir 시술에서도초음파가도움이된다는보고도있다. 그러나이와같은시술에획일적으로초음파를도입하였을때에도실패율과부작용의의미있는감소결과를 나타낼지는추가적인연구가필요하다. 5. 뇌사 (Brain death) TCD 는뇌사판정에있어서연구가많이되었으며현재보조적인도구로사용되고있다. 뇌압상승에따라두개내큰혈관의혈류변화가발생하는데 TCD 혈류변화는초기에 PI가증가하고그이후확장기및평균혈류속도가감소된다. 그리고앞방향확장기혈류가사라지게되면뒷방향확장기혈류가생기면서진동성이상 (oscillating biphasic) 혈류패턴을보이고, 더진행되면확장기혈류가완전히사라지게되며크기가작은확장기스파이크가발견되기도하지만이것이효과적인앞방향혈류를의미하는것은아니다. 뇌사진단에있어 TCD 의민감도는 % 이고특이도는 % 로보고되고있다. 경측두엽 (Transtemporal) 과경후두엽 (suboccipital) 초음파창 (acoustic window) 을통한검사와함께경안와초음파창 (transobital window) 을통한검사를추가로시행하면뇌사판정에더욱도움이될수있다. 위양성결과는드물게보고되었는데 TCD 결과와뇌파결과가일치하지않은경우도있었고약 5-10% 환자에서는기술적인문제로인하여두개내혈관을정확히관찰하지못할수있었다. 위음성결과는비교적자주보고되었는데임상적으로는뇌사상태인환자의 % 에서두개내혈관의혈류가관찰될수있으며, 이와같은뇌사판정초기의위음성결과는 TCD 검사의시행시점, 여성, 교감신경작용제등과연관이있을수있다. TCD 혈류속도는동맥내이산화탄소농도, 적혈구용적률과심박출량등에의하여영향을받을수있으므로숙련된검사자에의한주의깊은검사가요구된다 (Table 2) 결론 신경집중치료에있어초음파는중요한진단과치료방침결정 146 대한신경과학회지제 29 권부록 2, 2011

178 신경집중치료에서의신경초음파검사 에있어안전하고비침습적이며빠르고비용효율적인방법을제공하며방사선노출과조영제부작용에대한염려가높아지고있는최근의료환경에서초음파는중환자진료에있어중요한역할을할수있다. 신경집중치료는전문치료분야로서빠르게발전하고있는데, 위와같은여러가지장점이있는초음파의중요성이강조되고있어이에대한교육이필요하다고생각된다. References 1. Lindegaard KF, Nornes H, Bakke SJ, Sorteberg W, Nakstad P. Cerebral vasospasm after subarachnoid haemorrhage investigated by means of transcranial Doppler ultrasound. Acta Neurochir Suppl (Wien) 1988;42: Brain Trauma Foundation, Americal Association of Neurological Surgeons, Joint Section on Neurotrauma and Critical care. Intracranial pressure treatment thresholds. J Neurotrauma 2000;17: Aaslid R, Lundar T, Lindegaard KF. Estimation of cerebral perfusion pressure from arterial blood pressure and transcranial Doppler recordings. In: Miller JD, Teasdale GM, Rowan JO, et al. Intracranial pressure VI. Berlin: Springer, 1986: Czosnyka M, Matta BF Smielewski P, Kirkptrick PJ, Pickared D. Cerebral perfusion pressure in head-injured patients: a noninvasive assessment using transcranial Doppler ultrasonography. J Neurosurg 1998;88: Schmidt EA, Czosnyka M, Matta BF. Non-invasive cerebral perfusion pressure (ncpp): evaluation of the monitoring methodology in head injured patients. Acta Neurochir Suppl 2000;76: Gosling R G, King DH. Arterial assessment by Doppler-shift ultrasound. Proc R Soc Med 1974;67: Moreno JA, Mesalles E, Gener J. Evaluating the outcome of severe head injury with transcranial Doppler ultrasonography. Neurosurg Focus 2000;8:e8. 8. Seier RW, Grolimund P, Aaslid R. Cerebral vasospasm evaluated by transcranial ultrasound correlated with clinical grade and CT-visualized subarachnoid hemorrhage. J Neurosurg 1986;64: Bellner J, Romner B, Reinstrup P, Kristiansson K-A, Ryding E, Brandt L. Transcranial Doppler sonography pulsatility index (PI) reflects intracranial pressure(icp). Surg Neurol 2004;62:45-51; discussion Chan KH, Miller JD, Dearden NM, Andrews PJD, Midgley S. The effect of changes in cerebral perfusion upon middle cerebral artery blood flow velocity and jugular bulb venous oxygen saturation after severe brain injury. J Neurosurg 1992;77: Berendes E, Scherer R, Schuricht G. Masive natriuresis and polyuria after triple craniocervical subarachnoid hemorrhage: cerebral salt wasting syndrome. Anasthesiol Intensivemed Notfallmed Schmerzther 1992;27: Lang EW, Lagopoulos J, Griffith J, Yip K, Mudaliar Y, Mehdorn HM. Noninvasive cerebrovascular autoregulation assessments in traumatic brain injury: validation and utility. J Neurotrauma 2003;20: Mayer SA, Thomas CE, Diamond BE. Asymmetry of intracranial hemodynamics as an indicator of mass effect in acute intracerebral hemorrhage. A transcranial Doppler study. Stroke 1996;27: Marti-Fabregas J, Belvis R, Guardia E, Cocho D, Munoz J, Marruecos L, et al. Prognostic value of pulsatility index in acute intracerebral hemorrhage. Neurology 2003;61: Maurer M, Shambal S, Berg D, woydt.m. Differentiation between intracerebral hemorrhage and ischemic stroke by transcranial colorcoded duplex-sonography. Stroke 1998;29: Bertram M, Khoja W, Ringleb P. Transcranial colour-coded sonography for the bedside evaluation of mass effect after stroke. Eur J Neurol 2007;7: Seidel G, Cangur H, Albers T. Transcranial sonographic monitoring of hemorrhagic transformation in patients with acute middle cerebral artery infarction. J Neuroimaging 2005;15: J Korean Neurol Assoc Volume 29 Suppl. 2,

179 특수상황에서의간질환자치료 : 고찰및증례뇌사의진단 가톨릭대학교서울성모병원신경과이광수 Brain Death: Recent Views and Updates Kwang-Soo Lee, MD Department of Neurology, Seoul St. Mary s Hospital, The Catholic University of Korea, Seoul, Korea There is a clear difference between vegetative state and brain death. All medical doctors must understand this difference, because brain death means that life support is useless. And brain death is the principal reqiusite for the diagnosis of organs for transplantation. This review focuses on the clinical diagnosis of brain death including the potential confounding factors, and provides an overview of valid confirmatory tests. 서 론 뇌사진찰과뇌사의선언 뇌사의진단은오랜세월인간의죽음은오로지심장사라는고정관념에서벗어나장기이식의획기적인발전을이루는기초가되었다. 이제대부분국가에서뇌사를법적으로인정하고뇌사자의장기이식을활발하게하여수많은생명을구하고있다. 장기이식에는뇌사자로부터제공받은장기이식과생존하고있는가족이나타인으로부터생체이식두가지방법이활발하게환자에게도움을주고있다. 국내에서는생체이식의비율은선진국수준이나뇌사자에서제공되는장기비율은선진국에비해너무열악한실정이다. 뇌사의진단은국가별로조금씩다르지만뇌와뇌간의비가역적인상태를확인하는절차가핵심으로임상적인진찰중무호흡검사 (apnea test) 가가장중요한진단법이며그이외에도뇌 SPECT, PET 검사, 경두개초음파검사 (TCD) 등의뇌혈류검사, 뇌혈관촬영, 자기공명영상, CT 혈관촬영등객관적인검사방법등을이용하여뇌사진단에있어객관적이고한치의오차가없도록노력하고있다. Kwang-Soo Lee, MD Department of Neurology, Seoul St. Mary s Hospital, Banpo-505, Seochogu, Seoul , Korea Tel: Fax: ks1007@catholic.ac.kr 뇌사상태를진찰하고뇌사라고선언할수있는사람은모든의사들이할수있으나임상에서는실질적으로신경과, 신경외과, 소아과, 신경계중환자의학자등이하고있으며대부분의의사들은경험많은신경과의사나신경계중환자관리의사혹은신경외과의사가뇌사에대한진찰과선언을하는것이타당하다고생각하고있다. 국내에서는뇌사위원회에신경과, 신경외과혹은마취과의사가이를담당하도록규정하고있다. 뇌사판정이전에확인사항 뇌사를진단하는데있어서기본조건으로는심한전해질및산-염기불균형상태, 중심체온이 32 이하인심한저체온, 저혈압그리고약물중독과신경근육차단제등의사용근거가없어야한다. CT검사의소견은뇌사진단에매우중요한데뇌부종과덩어리와관련된뇌탈출현상등이일반적이나저산소증이나뇡며등에서는 CT 가정상소견을보일수있어이런경우는뇌척수액검사로확인이필수적이다. 자세한혼수환자의평가에는혼수에대한서술, 뇌간반사의소실에대한확인그리고무호흡검사로이루어진다. 148 대한신경과학회지제 29 권부록 2, 2011

180 뇌졸중최신지견 2010: 임상분야 뇌사진단기준의발전 인공호흡기 (mechanical ventilator) 의발전으로호흡정지가된말기신경계질환환자의치료경과가변하게되었으며뇌의기능이정지된이후에도신체적인활력징후 (vital sign) 은인공적으로유지가능하게되었다 년 Mollaret 와 Goulon 등이의식소실, 뇌간반사소실, 호흡소실그리고뇌파검사상평탄파 (flat EEG) 를보인 23명의혼수환자를 coma depasse ( 비가역적혼수상태 ) 라고처음기술한이후 1968 년하버드의대 ad hoc 위원회에서뇌사의진단기준에대해구체적으로명시하기시작하였다 년영국의학전문위원회에서뇌사란뇌간기능의비가역적소실이다라고정의하고이때부터무호흡검사 (apnea test) 에대한자세한내용을제시하였다 년부터는혼수환자에대한임상관찰을줄이기위한노력으로뇌파검사를비롯한뇌혈관촬영, 경두개도플러검사, 뇌단일양성자방출스캔 (SPECT) 등의객관적인확진검사를이용할것을적극추천하였다. 뇌사판정에반드시필요한테스트 비가역적혼수, 뇌간반사 (brainstem reflex) 의결여그리고무호흡이확실한지에대한신경진찰법으로구성한다. 비가역적혼수란임상적으로치료에불응상태인뇌압상승, 신경외과적 Table 1. Clinical criteria for brain death in adults and children Coma Absence of motor responses Absence of pupillary responses to light and pupils at midposition with respect to dilatation (4-6 mm) Absence of corneal reflexes Absence of caloric responses Absence of gag reflex Absence of coughing in response to tracheal suctioning Absence of sucking and rooting reflexes Absence of respiratory drive at a PaCO 2 that is 60 mm Hg or 20 mm Hg above normal base-line values * Interval between two evaluations, according to patient's age Term to 2 mo old, 48 hr > 2 mo to 1 yr old, 24 hr > 1 yr to <18 yr old, 12 hr 18 yr old, interval optional Confirmatory tests Term to 2 mo old, 2 confirmatory tests > 2 mo to 1 yr old, 1 confirmatory test > 1 yr to <18 yr old, optional 18 yr old, optional * PaCO 2 denotes the partial pressure of arterial carbon dioxide. See Table 2 for descriptions of the available confirmatory tests. Tests may be required by law outside the United States. 수술이나심폐소생술같은신경손상이개선될가능성이없는경우와관련있다. 따라서임상적으로는심한자극에도얼굴을찡그리거나반응이없어야하고동공반사가없어야하며탄소의자극에도호흡유발이안되는조건등이포함되어야한다. 뇌간반사의진찰법은중간뇌, 뇌다리, 연수에서반사경로를측정하는것으로혼수상태의정도는운동반응의통증자극에대한반응유무로확인하는데상안와신경, 측두-하악관절그리고손톱의밑부분등을세게눌러서환자가어떻게반응하는지를관찰한다. 이어서동공을확인하는데동공이난원형모양으로정중앙에위치하고 4-6 mm 정도의크기로빛에반응이없는지를확인한후머리를양쪽혹은위아래로돌려서 oculocephalic 반사가나타나는지를검사하게된다. 이런 oculocephalic 테스트에서반응이없다하더라도칼로릭테스트로안구운동유무를확인해야한다. 그밖의뇌간반사로각막반사와기침반사등이있다 (Table 1, Fig. 1). 무호흡검사 (Apnea test) 방법 무호흡검사는여러가지가있으나가장간단한원리는인공호흡기를제거하고산소를공급하는것이가장많이이용되는방법이다. 그러나때론이방법은심한폐부종, 불안정한혈압그리고높은 PEEP 요구상황등시에는조기에테스트를종료하게된다. 따라서무호흡검사전에산소를충분히공급하고 (10 분간 FIO2 1유지 ) minute ventilation 을감소시킨다. 5분간분당 10 Figure 1. The steps in a clinical examination to assess brain death. J Korean Neurol Assoc Volume 29 Suppl. 2,

181 이광수 Table 2. Confirmatory testing for a determination of brain death Cerebral angiography The contrast medium should be injected under high pressure in both anterior and posterior circulation No intracerebral filling should be detected at the level of entry of the carotid or vertebral artery to the skull. The external carotid circulation should be patent. The filling of the superior longitudinal sinus may be delayed. Electroencephalography A minimum of eight scalp electrodes should be used. Interelectrode impedance should be between 100 and 10,000 Ω The integrity of the entire recording system should be tested. The distance between electrodes should be at least 10 cm. The sensitivity should be increased to at least 2μV for 30 minutes with inclusion of appropriate calibrations. The high0frequency filter setting should not be set below 30 Hz, and the low-frequency setting should not be above 1 Hz. Electroencephalography should demonstrate a lack of reactivity to intense somatosensory or audiovisual stimuli. Transcranial Doppler ultrasonography There should be bilateral insonation. The probe should be placed at the temporal bone above the zygomatic arch or the vertebrobasilar arteries through the suboccipital transcranial window. The abnormalities should include a lack of diastolic or reverberating flow and documentation of small systolic peaks in early systole. A finding of a complete absence of flow may not be reliable owing to inadequate transtemporal windows for insonation. Cerebral scintigraphy (technetium Tc 99m hexametazime) The isotope should be injected within 30 minutes after its reconstitution. A static image of 500,000 counts should be obtained at several time points: immediately, between 30 and 60 minutes late, and at 2 hours. A correct intravenous injection may be confirmed with additional images of the liver demonstrating uptake (optional). Figure 2. No cortical electrical activity in EEG 번의호흡으로감소하면 hypocapnia 를정상화시키는것이충분하다. 테스트이전에기초검사로동맥혈가스검사를시행하여 PaCO mmhg, PaO2 200 mmhg 이상, 정상 PH를확인한후 8-10 분간인공호흡기를제거한다. 이때에산소는기관지를통하여 6-8L로공급한다. PaCO2 가 60 mmhg 이상혹은기준치보다 20 mmhg 이상증가그리고환자가스스로호흡을하려는시도가없는지를확인하고이런경우를테스트양성 ( 호흡결여 ) 이라고판정한다. Figure 3. Reverberating flow in Transcranial Doppler sonography. Figure 4. No intracranial filling of blood by brain-spect. 뇌사확진을위한그밖의객관적검사법들 (Table 2) 1) 뇌혈관조영술 뇌사의경우수추기혈압이두개내안으로 dye 를밀어올릴만큼충분하지않아두개골입구에서두개내뇌혈관이보이지않게된다. 2) MR 혈관조영술 일반뇌혈관조영술과유사한소견을보인다. 3) 뇌파검사 가장객관적이고검증된방법중의하나로 채널의뇌파검사를최소 30분이상기록해야하고 2uV 이상의 electrical activity 가보이지않아야한다. 4) 경두개도플러초음파검사 민감도 91-99%, 특이도 100% 인검사로뇌사인경우 diastolic 혈류가안보이거나 reverberating 혈류가나타난다. 특히뇌수술을받은환자의경우두부에수술과관련된여러장치나상태로뇌파검사에제한을주기때문에이런경우유용한검사로활용할수있다. 5) 핵의학검사 tracer 의두개내흡수가보이지않는다 ( 예, 99Tcm-SPECT). 150 대한신경과학회지제 29 권부록 2, 2011