REVIEW online ML Comm J Neurocrit Care 2008;1:1-11 ISSN 2005-0348 급성허혈성뇌졸중치료패러다임의전환 연세대학교의과대학신경과학교실, 뇌졸중및신경 혈관집중치료실, 뇌연구소 신수정 조경주 김현우 김경환 Breaking a Paradigm in Treatment of Acute Ischemic Stroke Soo Jeong Shin, MD, Kyoung Joo Cho, MS, Hyun-Woo Kim, BSc and Gyung Whan Kim, MD Department of Neurology, Stroke and Neurocritical Care Section, Yonsei University College of Medicine, Brain Research Institute, Seoul, Korea Stroke is the second leading cause of death in Korea and responsible for serious long-term disability. Although rt-pa is an approved drug, only 1-3% of stroke patients are receiving the treatment because of its limited 3 hour time window. In this review, we will overview the basic molecular mechanism of acute ischemic stroke and current stroke treatment then discuss about current issue in Korea. Basic concept of stroke treatment is focused on saving the ischemic penumbra; area that is at risk of cell death but potentially salvageable. Apoptosis are believed to play critical roles in ischemic damage, especially in the penumbral zone. Apoptosis is an active form of cell death as a strategy to preserve genomic stability from DNA damage. If DNA damage is overwhelming the capacity of DNA repair, cells that harbor DNA damage are removed from the population by death. Execution of apoptosis is preceded rapidly by activation of complex signal pathways like caspase-dependent and caspase-independent pathways. By turning off the death signal which is activated by massive DNA damage, initiation of apoptosis can be stopped and this concept can be a new therapeutic target of acute ischemic stroke. Reperfusion therapy and neuroprotective agent are two main streams for treatment of acute ischemic stroke. Although, many clinical trials have been done, rt-pa is the only FDA approved medical therapy for patients who can be treated within 3 hours of stroke onset. Emerging endovascular mechanical reperfusion device (clot retrieval device or MERCI) is approved by FDA and its results of recent clinical trials are promising. Neuroprotective agents were successful in animal models of ischemia, they have been unsuccessful in human trials. Clinical trials of NXY-059, one of promising neuroprotective agents, fail to widen the therapeutic window. So far, treatments of acute ischemic stroke have been based on epidemiological approach, not molecular pathophysiology. Introduction of neurocritical care, which will provide more professional, true meaning of treatment, is urgent. And paradigm of treatment of acute ischemic stroke should be focused on repairing damaged neuron by ischemia, not preventing further damage by reperfusion or neuroprotective agent. J Neurocrit Care 2008;1:1-11 KEY WORDS: Stroke MERCI Neurocritical care. 급성허혈성뇌졸중의임상적중요성 뇌졸중은악성신생물에이어우리나라사망원인 2위를차지하는질환으로단일장기로는 1위를차지한다. 1 2006 년 Truelsen 등이유럽각국의뇌졸중발생률및유병률을각국의이상적인인구집단과비교한역학연구에따르면 Address for correspondence: Gyung Whan Kim, MD Department of Neurology, College of Medicine, Yonsei University, 134 Sinchon-dong, Seodaemun-gu, Seoul 120-752, Korea Tel: +82-2-2228-1609, Fax: +82-2-393-0705 E-mail: gyungkim@yuhs.ac 우리나라의경우발생률, 유병률모두영국, 프랑스, 이탈리아보다높게나타났다. 질병관리본부, 건강보험심사평가원이발표한자료에따르면 2004년우리나라뇌졸중의발생률은인구 10만명당 216 건으로발병률은남녀모두나이가증가함에따라증가하였고남자가여자보다높았다. 2 전세계적으로뇌졸중이사회경제에미치는영향이커지고있으며이는노년층으로갈수록두드러진다. 뇌졸중은한번발생하면영구적인장애를가져오기때문에환자뿐만아니라가족, 나아가사회전반에걸쳐정신적, 감정적인문제뿐만아니라사회경제적인문제를낳는다. 3 WHO 의발표 Copyright c 2008 The Korean Neurocritical Care Society 1
J Neurocrit Care 2008;1:1-11 에따르면 2020년에이르면뇌졸중은관상동맥질환과함께건강한삶을저해하는 (loss of healthy life year) 가장중요한원인이될것이다. 4 통계청과질병관리본부의보고서를이용하여미래의우리나라뇌졸중발생건수를추정하면 2030년에는 35만건으로증가될것으로추정되며이는인구의빠른노령화에의할것으로여겨진다. 2 뇌졸중이인성, 지능, 추리력, 감정, 집중력과같이삶을살아가는데있어필수적인기능을관장하는부위에발생하지않은경우에는큰문제가되지않지만그렇지않은경우기본적인삶을영위하는데어려움이있고따라서다른사람의도움을필요로하며이는사회적인문제로이어진다. 미국의뇌졸중치료지침인 American Heart Association(AHA) guideline에서는 multiple randomized clinical trial 로효과가입증된 Class I, Level of Evidence A의치료는증상발생 3시간이내의환자에적용되는 rt-pa 뿐이다. 5 그러나 rt-pa 의짧은 time window와 50% 정도의재개통률 (recanalization), 출혈위험등의부작용에의해 1~3% 의환자만이 rt-pa 에의한재관류치료를받는다. 6 재관류치료를받지못하는대부분의뇌졸중환자의치료를위해 time window를연장하기위한연구가진행되었다. 급성허혈성뇌졸중의치료는두가지의큰연구방향인혈전용해제와신경보호제 (neuroprotective agent) 를사용한동물실험및임상실험이진행되었다. 지난 6년간이주제에대하여 1,000편이상의동물실험논문들이발표되었고 400편이상의임상연구결과들이발표되었다. 그러나이중임상실험에성공한치료 (translational therapy) 는단한건도없다. 7,8 최근에 3상 1차임상실험 (SAINT I trial) 에성공하여관심을끌었던 NXY-059 와 9시간까지치료효과를늘릴것으로기대를모았던 desmoteplase 의연이은실패는많은이들에게회의를안겨주었다. 현재공인된치료법으로인정받는것은 3시간의 time-window를갖는 rt-pa와 48시간내의 aspirin 두가지뿐이다. 그러나 rt- PA는짧은 time-window 로실제적으로 1~3% 의환자만이치료가능하며 aspirin 은뇌졸중의치료보다는재발예방의개념에더가깝다. 9,10 이에최근까지의 molecular biology 의개념에중점을둬서급성허혈성뇌졸중의가능한치료방법들을고찰해보고자한다. 뇌졸중의병태생리, 분자생물학적접근 라신경세포 (neuron) 의전기생리학적변화가일어나는데뇌의혈류공급이 50 ml/100 g/min 이하로감소될경우시냅스에서신경전달물질의전달이차단되고신경세포의기능을하지못하게되며 20 ml/100 g/min 이하로감소될경우이온의항상성이깨지게된다. 11,12 뇌혈류의차단은혈류공급정도에따라 oligemia, penumbra, core로나눌수있다 (Fig. 1). 1) Oligemia 는허혈손상을받은뇌조직의가장바깥쪽에위치한부분으로측부 (collateral) 순환에의해뇌의에너지요구량이충족되고신경세포는정상적인기능을유지한다. 이부분은허혈손상이후에도주로 survive 할것으로예상되는지역이다. 2) Core 는허혈손상의중심에있는지역으로이지역의신경세포는혈액공급이빠른시간내에재개되지않으면항상성을유지할수없게되고세포사망으로이어진다. 혈액공급이완전히차단될경우수초안에신경세포의전기적활동이중단되고수분내에에너지상태가악화되며이온펌프의항상성이깨지게된다. 이러한비가역적인손상은혈액공급이중단된후 5~10분내에일어나게된다. 11 3) Penumbra는전통적으로 core 주변지역을의미한다. 1970년대에행하여진뇌의전기생리학적인관찰을통해 penumbra가정의되었는데시냅스에서신경전달물질의전달은차단되지만 ( 뇌혈류 50 ml/100 g/min 이하 ) 이온의항상성은유지되는 ( 뇌혈류 20 mg/100 g/min 이상 ) 지역을말한다. 시냅스의활동에따른신경학적장애는발생하나세포의모양은유지되고있는상태로뇌혈류가다시공급된다면가역적일수있고임상증상또한호전될수있다. 11,13,14 활성산소로부터세포를보호하는 SOD(superoxide dismutase) 를제거한동물실험을보면허혈손상이후 4(A), 16 Oligemia Penumbra Core 뇌졸중의병태생리뇌졸중으로인한신경학적결함은뇌혈류 (cerebral blood flow: CBF) 의감소에기인한다. 뇌혈류의감소정도에따 FIGURE 1. A schematic diagram showing the three hypoperfused tissue compartments of ischemia: center is the ischemic core; peripheral zone is the oligemia; and the region between core and oligemia is penumbra. 2
Breaking a Paradigm in Stroke Treatment SJ Shin, et al. A FIGURE 2. Comparison of cerebral infarction 4 or 16 hours after ischemia in Sod 2-/+ mice. A: 4 hours after ischemia. The ischemic core is apparent but ischemic penumbra is not visible, thus the penumbra is still viable. B: 16 hours after ischemia without any treatment, the core extends widely into cortical areas meaning that the penumbra has been recruited. A FIGURE 3. Comparison of morphologic features between normal cells (A) and apoptosis (B). (B) 시간에뇌를관찰하였을때뇌경색의크기가증가함을확인할수있다 (Fig. 2). 이는허혈손상이후 4시간에는세포사망이 core에만일어나고 penumbra는보존되고있으나 (A) 시간이경과할수록 penumbra(16 시간 ) 지역까지세포사망이진행됨을보여준다 (B). 15 PET을이용한연구를보면 6시간까지는 penumbra의 90% 가유지되나 9시간이경과하면 50% 정도가남고 18시간이되면 30% 정도가남아있게된다. 16 따라서뇌졸중의치료는이러한 penumbra 를살리는데초점을맞추었다. Penumbra 의분자생물학적접근오랜시간동안뇌혈류가중단될경우신경세포는에너지의고갈로세포괴사 (necrosis) 에빠지게되며이는주로허혈의중심 (core) 에서관찰된다. 반면에상대적으로짧은시간동안허혈손상을받은경우에는세포괴사에이르지는않으나세포자멸사 (apoptosis) 로진행하는유전자가발현되고 DNA 가분해되게된다. 17,18 이러한형태의지연성세포사망 (delayed cell death) 은주로 penumbra에서나타난다. 이러한분자생물학적관점에서보면단순히뇌혈관폐색후재관류만을한다고해서허혈성 penumbra 지역이뇌경색으로빠지는것을막을수없다. 따라서이러한분자생물학적기전은기초의학자만의개념이아니라임상에서뇌졸중을치료하는모든의사가확실히알아야하는기본개념이다. 세포괴사와세포자멸사는형태학적으로다른특징을갖는다. 세포괴사는세포가팽창, 파열되고세포소기관들이분해되며세포질내단백질이변성되며염증반응을유발한다. 이는주로다형핵백혈구에의해제거된다. 반대로세포자멸사는정상세포 (A) 의세포부피의 60% 까지줄어들며핵이응축된다 (B)(Fig. 3). 세포자멸사는대식세포 (macrophage) 와미세아교세포 (microglia) 의식세포작용 (phagocytosis) 에의해제거된다. 19 분자생물학의발달로허혈손상이후세포의사망 / 생존에관한기전이밝혀지고있다. 동물실험을통해세포괴사의과정에 glutamate 가관여함이밝혀졌고 excitotoxicity 의개념이도입되었다. Glutamate 는뇌와척수에작용하는중요한흥분성신경전달물질로써신경세포가 glutamate 에과다하게노출될경우세포괴사에빠지게되는데이러한 glutamate 의방출은에너지의고갈에의하며 glutamate 의작용에의해 ion channel 의항상성이깨져서 Na+, Ca2+ 가세포내로유입되면서미토콘드리아의 failure 가오고세포사망에이르게된다. 20,21 Penumbra에서의세포사망은 ischemic core에서시작된 spreading depression 에의해서도일어난다. Cortical spreading depression(csd) 은 1944년 Leao에의해처음제시된개념으로 slow moving wave 의형태로나타난다. 외상이나저산소증등에의해시작되어뇌의피질전반에걸쳐전파되면서세포를탈분극시키고시냅스의활동전위를중단시킨다. 22 현재사람에서 CSD가일어난다는증거는아직부족한실정이다. 여러동물실험을통해 penumbra에서의세포사망이일련의과정으로일어나며그기전이밝혀지고있다. 이과정에관여하는 protease를 caspase 라한다. Caspase는 cysteine protease 로평소에는비활성화형태인 pro-caspase 로존재하며활성화될경우다른 caspase 를포함한기질 (substrate) 의아스파르트산기를자르며이를통해다음단계의 caspase를활성화시켜일련의 cascade를진행시킨다. Caspase 는두개의그룹으로나눌수있는데 cascade 상위단계에서시작에관여하는 caspase 8, 9, 10(initiator) 과직접세포기질을분해하여세포를파괴시키는 caspase 3, 6, 7(executioner) 로나눌수있다. Caspase 1, 2, 4, 5, 11, 12는 initiator와 executioner의기능을동시에갖는다. 23 이러한 caspase 에의해일어나는세포사망을 death receptor를통해일어나는 extrinsic pathway 와 mitochondria 를통해일어나는 intrinsic pathway 로나눴다 (Fig. 4). Extrinsic pathway 는세포밖에존재하는 Fas 리간드가세 B B 3
J Neurocrit Care 2008;1:1-11 FIGURE 4. Schematic diagram of the caspase-dependent and caspase-independent cell death signaling pathways in the penumbra following ischemia. Cell death signaling produces DNA fragmentation leading to apoptosis. 포막의 Fas 수용체에결합함으로써수용체가활성화되어시작된다. 24 활성화된수용체는 Fas-associated death domain(fadd) 와 caspase 8을활성화시키고이는 caspase 3의활성화로이어진다. 25 미토콘드리아를통한 intrinsic pathway 는 Bax가미토콘드리아 membrane 으로전좌 (translocation) 되어시작된다. 미토콘드리아내의 cytochrome c를세포질내로방출시키며방출된 cytochrome c는 apoptosis protease-activating factor-1(apaf-1), datp, pro-caspase 9와결합하여 caspase 9를활성화시키고이는 caspase 3를활성화시킨다. 15,26-31 Caspase 3와세포사망의관련성은많은동물모델에서뇌경색이후 caspase 3 가활성화되고 caspase 3의활성을억제할경우뇌경색의크기가감소하였다고보고하고있다. 32-34 Extrinsic/intrinsic pathway 에의해활성화된 caspase 3는 DNA-repairing enzyme poly(adp-ribose) polymerase(parp) 를포함하여여러가지중요한기질을자르며이는 DNA에손상을줘서세포자멸사에이른다. 35,36 Intrinsic pathway 의활성화는 extrinsic pathway 에의해서도일어난다. Extrinsic pathway 에관여하는 caspase 8은 Bcl-2 family 중하나인 Bid를자르고, 잘려진 Bid는미토콘드리아로들어가 cytochrome c를방출시킨다. 37 Bid 와세포사망의관련성은 Bid 가결핍된쥐에서뇌경색의부피가확연히감소한실험결과로입증되고있으며, 이와비슷한다양한연구보고들은뇌경색의 penumbra에서 celldeath receptor 에의한미토콘드리아 pathway 가활성화 됨을의미한다. 38 직접적인세포자멸사의 pathway 에있는 caspase 들외에도간접적으로 caspase 에의한세포자멸사과정에참여하는 molecule 들이있다. 대표적으로 inhibitor of apoptosis (IAP) family의 X-linked inhibitor of apoptosis(xiap) 는세포사망으로의진행을차단하는역할을하는데 caspase 3, 7과같은 caspase cascade 의마지막단계를억제하고 caspase 9/Apaf-1복합체와결합하여세포사망을막는역할을한다. 39,40 이러한 XIAP는미토콘드리아에서방출되는 second mitochondrial activator of caspase/direct IAP binding protein with low pi(smac/diablo) 에의해억제되며세포자멸사로이르게된다. 41,42 Caspase 를차단함으로써세포자멸사를막을수있다는개념하에 caspase inhibitor 를이용한동물실험이시행되었고임상적으로도시도되었다. 그러나결과적으로 caspase 의억제는세포자멸사를막지못하였으며 35,43-45 caspase 와독립적으로세포자멸사를일으키는 pathway 가알려지기시작하였다. 그중대표적인것으로 apoptosis-inducing factor(aif) 가있다. AIF는미토콘드리아에위치하는단백질로세포자멸사의마지막단계에관여한다. 세포자멸사과정에서세포질로유리된 AIF는핵으로들어가염색질을응축시키고 largescale DNA fragmentation 이나타나게하고미토콘드리아에서 cytochrome c를유리시켜세포사망에이르게한다. 46-49 이러한 AIF의활동은 caspase 와무관하게일어 4
Breaking a Paradigm in Stroke Treatment SJ Shin, et al. 나며이를 caspase-independent pathway라한다. 50,51 AIF가미토콘드리아에서핵으로이동하는데 poly(adpribose) polymerase 1(PARP-1) 가관여함이실험을통해보여졌다. 52 PARP-1 은 DNA를 repair 하고단백질을변화시키는효소로핵내에풍부하게존재한다. 53 정상적인환경에서 DNA에손상이오면 PARP-1 은 ADP-ribose polymer 를만들며세포항상성의유지와 genomic stability 에중요한역할을한다. 그러나허혈손상등에의해 DNA damage 가광범위하게발생한경우 PARP-1 은과활성되며이로인해세포내 NAD+, ATP의고갈을일으키고세포괴사를유발한다. 54 이러한작용외에도앞에서언급했듯이 PARP-1 은 AIF를통한세포자멸사에도관여한다. PARP-1 이활성화되면핵에서미토콘드리아로신호를보내 AIF를유리시켜세포자멸사를유발하며이는 PARP-1 의활성화이후수시간후에관찰된다. 55 PARP-1 외에도 DNA repair enzyme 이세포자멸사에관여함을실험을통해알수있다. Ku70 는 DNA repair enzyme 으로세포자멸사의과정에서 caspase 3와관련될것으로여겨지고있다. 30 쥐에서 Ku70가급격히감소될경우뇌병변부위의세포에서는 DNA가 ladder pattern 으로나타나며이를통해전형적인세포자멸사가일어난다고보고되고있다 (Fig. 5). 17 DNA는핵내에위치하며세포에있어서가장중요한물질이다. 세포는내부 / 외부에서가해지는 damage 에대해 DNA내유전정보를보존하고자끊임없이노력한다. DNA 492 369 246 123 MW Con 4H 24H FIGURE 5. DNA laddering was observed as bands 24 hours after ischemia, which suggests DNA fragmentation and apoptosis is underway. MN: molecular weight, con: control. 는 histone을감싸면서 chromatin 이라는단단한구조를이룬다. Histone은 DNA를보호하는데중요한역할을하며구조적특성으로인해 DNA는외부의손상으로부터보호된다. 정상적인환경에서는 DNA가손상될경우 repair enzyme 등에의한 DNA repair mechanism 에의해손상된 DNA를복구한다. 그러나산화독성 (oxidative stress), 발암물질, 전리방사선등과같이병적인환경에놓이면 DNA damage 는 repair 한계를넘게되고이럴경우세포는세포자멸사를택한다. 56-58 세포가세포자멸사를택하는이유는세포자멸사가에너지의고갈을유발하지않으면서식세포작용을통해죽은세포를재활용하는효율적인세포사망과정이기때문이다. 세포자멸사의반대개념의세포사망은세포소기관들의파괴와 PARP-1 의과활성으로에너지의고갈을유발하며세포와세포, 세포와기질사이의신호전달이왜곡되는등개체에게악영향을끼친다. 57 세포는 DNA 의 repair 가불가능할경우 genomic stability 를유지하기위해이러한효율적인세포사망인세포자멸사를택한다. DNA 의손상이세포자멸사로이어지는몇몇특징적 site 가밝혀졌는데 DNA에 O 6 -methylguanine, base에 N- 알킬화, bulky DNA adduct, DNA cross-link, DNA double-strand break 등이일어날경우세포자멸사를유발한다. 이중 DNA double-strand break(dbs) 은세포에치명적으로 check-point 에있는 ATM, ATR에의해발견되며이들은 CHK1, CHK2(check point kinase), p53으로신호를보내며 P53은 FAS, PUMA, BAX와같은 pro-apoptotic gene을활성화시킨다. 59,60 DNA가 oxidative stress에의해 damage를입을경우 base excision repair(ber) 를통해복구된다. BER은손상받은 DNA의 base 를제거하여 AP site 를만들고이 site 는 DNA polymerase 에의해복구되는과정을거친다. 61 이러한 AP site가증가할경우 DNA가잘리고세포자멸사가진행된다. 여기서우리는 AP site가형성된것을복원시켜주면세포자멸사를막을수있지않을까하는의문을갖게되었다. Apurinic/apyrimidinic endonuclease/redox factor-1(ape/ref-1) 는 DNA repair enzyme으로 oxidative stress, ROS 등과같은해로운자극에의해발생하는 DNA apurinic/apyrimidinic(ap) site를 repair한다. 62,63 동물실험에서허혈손상의정도에따라 APE/Ref-1 의발현이달라지는데손상이극심하지않을경우 APE/Ref-1 는증가하며허혈손상에대해보호적인역할을하지만 63-65 손상이극심할경우 APE/Ref-1 은감소하며이는 DNA fragmentation 으로이어진다. 66-68 우리연구에서는허혈손상이후 APE/Ref-1 의감소가세포사망과연관되어있 5
J Neurocrit Care 2008;1:1-11 음에기인하여허혈손상후 APE/Ref-1 를보충하였다. 허혈손상을가한후 1, 4, 8시간에쥐뇌에 APE small peptide를직접투여하고뇌경색의범위를관찰하였다. 그결과 4시간까지는 APE에의해세포사망이감소하고 (Fig. 6) 뇌경색의범위가확연히줄었음을관찰할수있었다 (Fig. 7). 또한 AP site 와 single stranded DNA(ssDNA), DNA fragmentation 도줄어들었다. 이는 APE peptide 에의한 AP site repair 로뇌경색이감소함을직접적으로증명하며 APE 가세포자멸사의시작에관여하는 AP site 를 repair함으로써세포자멸사로의진행을막고뇌졸중을근본적으로치료할수있는가능성을제시하고있다. 재관류치료 (Reperfusion Therapy) Reperfusion therapy의 time window 재관류를통해 penumbra의 core로의진행을막는것이재관류치료의핵심이다. core를살리는것은어려운문제이며잘못하면뇌출혈등의심각한결과를낳을수있다. Relative optical density 30 25 20 15 10 5 0 Veh Cell death assay Post 4 h FIGURE 6. After administration of APE/Ref-1 4 hours after ischemia/reperfusion, cell death assay was done 24 hrs after I/R. The resullt showed decreased cell death, suggesting repairing APE small peptide can resucue cell from cell death. * 또상대적으로혈액공급이좋은 oilgemia 는재관류의관심의대상이아니다. Penumbra라고해서모두같은단계에있는것은아니며측부순환이잘안되면 core 로의진행이빠르고또증상발생이후시간이지날수록더많은지역이 core 로진행되며개개인에따라서도다른양상을보인다. 뇌경색의시간에따른치료는분자생물학적기전에의한병태생리에기초한다. 급성허혈성뇌경색에서 rt-pa 을투여할경우 3시간이내에투여해야만임상양상의호전을기대할수있고 3시간을경과할경우그효과에대해서는일관된결과를얻기어렵다. 69 일과성뇌허혈발작 (TIA) 에서는뇌경색후몇분간은모든뇌조직이 penumbra 단계에있다가우연한기회에의해뇌혈류가재개통되어증상이완전히회복되는과정을겪는다. 일과성뇌허혈발작이있던환자들을분석해보면증상의완전한회복은 2 시간이내에나타나게된다. 70 따라서뇌경색발생이후시간이경과할수록뇌에서일어나는분자생물학적기전에기초한병태생리를알아야만환자의치료에접근할수있다. 최근영상기술의발전으로재관류를통해도움을얻을수있는환자군을선별하는데많은도움이되고있다. 3시간이내의치료방법뇌경색발생 3시간이내의치료방법에대해서는 NINDS 연구에서 rt-pa 의효과에대해밝힌바가있다. 71 1.5시간이내에 rt-pa 를투여한실험군에서가장좋은결과를보였으며 3시간까지는뇌출혈등의합병증에비해이득이더많은것으로나타났다. rt-pa 는뇌출혈의발생을 10 배정도 ( 실험군 6%, 대조군 0.6%) 증가시켰으나이는대부분뇌경색의정도가심한환자군에서발생하였으며이러한환자들은뇌출혈을제외하고서라도좋은결과를기대하기어렵다. rt-pa 를사용한대표적임상실험인 NINDS, ECASS, ATLANTIS의 pooled analysis 를보면증상발 * * 180 160 140 Vehicle Post Tx 4h Post Tx 1h Post Tx 8h Infarct volume (mm 3 ) 120 100 80 60 40 20 0 Vehicle Post 1 h Post 4 h Post 8 h Time FIGURE 7. Comparison of infarction sizes after administrating APE small peptide. The volume of infarction is significantly decreased by APE small peptide given 1, 4 hours after ischemia but not 8 hours. 6
Breaking a Paradigm in Stroke Treatment SJ Shin, et al. 생부터혈전용해제의사용은빠르면빠를수록그결과가좋으나 3시간까지는부작용과비교하였을때뚜렷한효과가있는것으로나타났다. 72 정맥을통한혈전용해제투여의한계혈전용해제는혈관을막고있는혈전전체에작용하기보다는그표면에작용하는데그친다. 혈전의크기는다양하며때로는몇센티미터가되는경우도있으며이러한큰혈전은대부분혈관 proximal 쪽에위치하게된다. 따라서 proximal 에위치한혈전의경우정맥을통한혈전용해제로재개통을기대하기는어렵다. 실재로 TCD를이용하여 rt- PA 사용후재관류정도를본연구에서는 distal MCA에서는 44.2%, proximal MCA는 30%, terminal internal carotid artery 5.9% 로 proximal 에서낮은재개통률을보인다. 73 또한큰혈관에폐색 (occlusion) 이있는경우혈전용해제를사용해재개통이되더라도몇시간후다시폐색되는경우가많다. 중대뇌동맥폐색이있는환자에게 IV rt-pa를투여하였을경우 48% 에서만부분적으로재개통이이루어졌으며 34% 의환자에서는조기에재폐색이되었고 2/3 의환자에서는재폐색에따른임상증상의악화가동반되었다. 74 그러나재폐색이되었다하더라도재관류를시행한군에서그렇지않은군보다나은결과를보였다. 혈전이 proximal 에위치할수록환자는더심각한증상을경험하며혈전용해제의사용으로도재개통률이낮으며재폐색또한높게나타난다. rt-pa 의짧은 time-window 와치료성공률을높이기위해근본적인치료방법이필요하다. 보조적치료초음파 (TCD) 의에너지를이용해혈전용해제의효과를증폭시킬수있다. 초음파에너지는혈전용해제와 plasminogen의혈전내로의침투를증강시키고 fibrin 구조를변화시키며 rt-pa 와 fibrin 의결합을돕는다. CLOTBUST 연구에서 3시간안에 rt-pa 를투여받은환자중초음파치료를지속적으로받은군에서그렇지않은군보다높은호전률을보였다. 75 또, 미세공기방울 (microbubble) 을병합하여사용할경우좀더좋은결과를보였다. 76 현재 400명의환자를대상으로하는 3상연구 (TRUST) 가진행중이다. 뇌졸중발생 3~9 시간이후의치료 Intra-arterial(IA) 을통한혈전용해술뇌혈관촬영술을통해뇌혈류를막은혈전을직접눈으로확인하고혈전에근접하여국소적으로혈전용해제를투여 하는방법은정맥을통한혈전용해제의투여보다매력적인치료법이다. 이러한치료법은독일에서처음시도되었다. 77 Basilar artery occlusion 환자를대상으로 IA urokinase 를투여하였으며그결과 44% 의환자에서재개통된소견을보였다. MCA occlusion 환자를대상으로한 PROACT II연구에서는증상발생 6시간이내의환자에게 IA로 pro-urokinase 를투여하였고연구에참가한모든환자에대해 IV heparin 을투여하였다. 78 IA군은대조군에비해높은재개통률을보였으며 (IA군 66% vs 대조군 18%, P<0.001) 3개월후측정한 mrs도좋은결과를보였으며 (IA군 40% vs 대조군 25%, P=0.04) 사망률도 IA군 25%, 대조군 27% 로나타났다 (P<0.001). 그러나대조군에비해뇌출혈이더빈번하게나타났으며 (IA 군 10% vs 대조군 2%, P=0.06) 이결과로인해 urokinase 는 FDA 의승인은받지못하였다. PROACT 의긍정적인연구결과를바탕으로다른치료가불가능한환자를대상으로 IA를통한접근이실험적으로진행되고있다. Urokinase 뿐만아니라 rt-pa, reteplase 를이용한연구들이진행되고있으며 urokinase 가가장많이사용되고있다. 79 몇몇연구에서는 IA를통한혈전용해제의투여가 IV를통한투여보다효과적이라고보고되고있지만그효과는아직제한적이다. 80 2007년까지 30개의임상실험결과가보고되었으며여기에는 1,000 명이넘는환자가참여하였다. 그러나아직까지는어떤 IA 치료도명확한효과가입증되지는않았다. 79 2007년에발표된 AHA guideline 에서는동맥을통한혈전용해술은증상발생 6시간이내의 MCA 폐색이있는 major stroke 환자에대해서치료의한방법으로제시하고있으며, 환자가 IV rt-pa 의적응증이된다면 rtpa 에우선하여사용해서는안된다고권고하고있다. 5 IV rt-pa 실패후 IA를통한 rt-pa 의투여앞에서언급했듯이정맥을통한 rt-pa 의투여는 distal occlusion 에대해서는높은재개통률을보이지만 proximal vessel 의폐색일경우실패율이높고재폐색의가능성도높다. 73,74 이런높은실패율로인해 IV rt-pa 에실패한환자에대해추가적인치료로 IA를통한혈전용해제투여가시도되고있다. Emergency management of stroke(ems) Bridging study 에서는 3시간이내의환자에서 IV/IA rt-pa 군과 placebo/ia rt-pa군을비교하였다. 이연구에서는두군간의 long term outcome 에는차이가없었으며오히려 IV/ IA군에서사망률이더높게나타났다. 81 Interventional Man- 7
J Neurocrit Care 2008;1:1-11 agement of Stroke(IMS) I study 에서는저용량 (0.6 mg/ kg) IV rt-pa 를투여후혈관촬영술을시행하여폐색이관찰되면 IA로 rt-pa 를투여하였고이를 NINDS trial 의결과와비교하였다. IV/IA 군에서좀더나은 outcome 을보였으며사망률또한낮게나타났다. 82 IMS II study에서도기존의연구와유사한결과를보였다. 83 그러나앞에서언급하였듯이 IA urokinase 는높은출혈률로인하여 FDA의공인을받지못한상태이고 EMS study 결과에서는오히려사망률이높은것으로나타났다. 또한 2007 AHA guideline에서는혈전용해제의병용투여는아직까지명확한근거가없는실정이며임상실험에한해서만적용할것을권고하고있다. 5 따라서우리나라의일부대학병원에서 IV rt-pa 실패후 IA urokinase 를표준화진료지침 (critical pathway) 으로모든환자에의적용하고있는데이는명백한오류이다. 이는미국에서 FDA허가를받지못했을뿐만아니라우리나라의경우도 urokinase 는정맥내주입만이식품의약품안전청허가사항이라 84 urokinase 의동맥내적용과더군다나 IV TPA 후 IA urokinase 의표준화진료지침으로의자동적용은허가사항에없는임의비급여치료로우려되는실정이다. MERCI 약물을이용하여색전을녹이는방법이외에기구를사용하여물리적인방법으로색전을제거하는방법이연구되어왔다. Mechanical embolus removal in cerebral embolism (MERCI) retriever는색전을제거하는기구로주로큰혈관을막고있는색전에동맥을통해접근하여색전을당겨내는기구로 rt-pa 를사용할수없는환자에대해효과적일것으로주목받고있다. 첫 MERCI trial 에서는증상발생 8시간이내의환자중기저동맥, MCA, 내경동맥끝에패색이있는환자를대상으로임상실험을실시하였다. 85 이 trial 에서는 48% 의재개통률을보였으며 IA를통한혈전용해제와동반하여사용할경우 60% 의재개통률을보였다. 또시술 90일후재개통에성공한환자군에서그렇지않은군보다뚜렷한임상양상의호전을보여 (RR= 4.4) FDA의승인을받았다. Multi MERCI trail 에서는 8시간이내의큰혈관폐색환자를대상으로시행되었다. 기존의임상실험보다높은 57.3% 의재개통률을보였으며 IA tpa 등의부가적인요법을병행하였을경우 69.5% 의재개통률을보였다. 또이번임상실험에서는 IV rt-pa 를사용한환자도포함되었는데 IV-rt-PA 를사용하지않은환자와비교하였을때합병증발생에차이가없어 IV rt- PA를사용한환자에서도안전성을입증하였다. 증후성뇌출혈은 9.8% 의환자에서나타났으며시술로인한심각한합병증은 5.5% 의환자에서발생하였다. 86 이치료법은혈전용해제를이용한치료방법외에물리적인방법을사용하여 8시간까지치료시간을넓혔다는데의의가있으며 FDA의공인을받은치료법으로관심을끌고있다. 우리나라에는아직까지는사용되지않고있으나미국 FDA공인을받은 MERCI의도입은조속히이루어져야할것으로사료된다. 이는앞에서언급했듯이우리나라일부대학병원에서무리하게시도되는 IV rt-pa 실패후 IA urokinase 치료의대체치료법으로사용될수있으며이의도입에 neurocritical care 학회의역할이강조된다. 신경보호제 재관류치료이외에급성허혈성뇌졸중의치료로신경보호제가있다. 앞에서언급한데로뇌졸중의치료는허혈성 penumbra가경색으로진행되는것을방지한다는개념으로연구되었다. 하지만분자생물학적인관점에서보면허혈성 penumbra 지역에서도이미세포자멸사는진행되고있기때문에근본적으로효과를기대하기는힘들다. 3상 1차임상실험 (SAINT I trial) 에성공한 free-radical scarvenger인 NXY-059는최근가장주목을받았던신경보호제로 2차임상실험 (SAINT-II) 을시행하였으나 2007년임상실험에실패하였다고발표하였다. 87 SAINT I에서보였던 3개월후 mrs의호전이 SAINT II에서는관찰되지않았으며다른지표도대조군과의차이를보이지못하였고임상실험은중단되었다. Desmoteplase는 plasminogen activator로 time-window 를 9시간까지늘려줄것으로기대를모았다. 2차례의 2 상임상실험 (DIAS) 결과 desmoteplase 는 9시간까지효과가있는것으로보고되었다. 88 그러나 3상임상실험에서높은사망률과뇌출혈을보였고임상실험은조기중단되었다. 씨티콜린 (citicholine) 은인지질의전구체로써신경세포의세포막을이루는지질의합성에관여한다. 씨티콜린을투여한 4개의임상실험의 pooled analysis 를보면 NIHSS 점수 8점이상의환자에서증상발생 24시간이내에투여한경우 3개월 NIHSS, mrs, Rankin scale 에서유의한결과를보였으며 (global recovery 치료군 25.2%, 대조군 20.2%) 다른부작용은관찰되지않았다. 현재다른 3상임상실험 (ICTUS) 이진행중이다. 8 씨티콜린은경구투여가가능하고증상발생 24시간까지효과가있다는점에서주목할만하다. 8
Breaking a Paradigm in Stroke Treatment SJ Shin, et al. 새로운 Paradigm 의필요성 지금까지급성뇌졸중치료에서수많은동물실험들이있어왔고좋은결과들을보였으나실질적인임상분야에서뇌졸중을치료하는데는모두실패하였다. 7,8 미국같은효율적인체제로운영되는뇌졸중치료시스템에서조차 3시간내혈전용해제치료제투여율이 3% 미만인상황이고 6,89 최근보고또한그많은홍보와교육을통해서도이러한급성기뇌졸중환자의혈전용해제투여율은별증가된소견을보이지않는다는절망적인결과를보여주고있다. 89 이는지금까지의기존패러다임으로급성뇌졸중치료를접근하는데에한계가있음을보여주고있으며이는새로운패러다임의필요성을말해주고있다. 고전적인의미의치료란손상받은장기나신체의일부를정상적인상태로돌리는데목적이있다. 물론최근에는예방의학적인면이강조가되면서앞에서언급한재관류치료나신경보호제가넓은의미의치료범위에들어가기는하나진정한의미의치료범위에는들어가지않는다. 지금의 3 시간내뇌혈전용해제치료만하더라도뇌경색이생기지않게예방하는것이목적이지뇌허혈이생겨손상받은신경세포들을치료하는기술은아니다. 따라서손상받은신경세포를치료하는진정한의미의치료기술의개발에지금부터라도나서야한다. 다행히현재많은과학자들의노력에따라허혈성 penumbra지역에서의분자생물학적기전이많이밝혀져있어진정한의미의치료가능성을예상하고있다. 1990년도중반에뇌혈전용해제가개발되기전까지는급성기뇌졸중치료는미비하였으며뇌졸중의분자생물학적인기전도 2000년이후최근에서야확립되었다. 8 따라서기존의뇌졸중치료를담당하는의사들은주로예방적차원의접근법과임상적진단과역학적관점에초점을맞췄으며진정한의미의뇌졸중치료방법에대해서는무지한상태였다. 과거영상기술이발달하지않았을때는뇌졸중의진단이중요하였으나영상기술이발달한현재는뇌졸중의진단을내리는훈련보다는적극적인치료기술의훈련이필요한상황이되었다. 이에미국에서는새로운대안으로진단및역학적개념이주가아닌치료중심의 neurocritical care분야가대두되었고현재급성기뇌졸중분야의치료를 neurocritical care를훈련받은의사들이담당하고고전적의미의뇌졸중전공자들은역학에치중하는체제로바뀌고있는추세이다. 또한최근뇌졸중치료의추세는뇌졸중이라는하나의병명으로개념화해서치료하는데는앞에서언급한대로여러한계가있음이증명되어뇌졸중환자한명당개별화된치료 (personalized treatment) 에중점을두는 치료개념이대두되고있다. 이는우리나라일부대학병원의급성기뇌졸중의표준화진료지침 (critical pathway) 의운영과는대조적이다. 표준화진료지침은뇌졸중의 protocol 혹은매뉴얼과는또다른개념으로환자의최선의치료를위한개념이아니라저운영비용을목적으로보험을운영하는입장에서개발된개념이다. 따라서현재일부병원에서근거중심의료 (evidence based medicine) 에도반하는급성기뇌졸중의표준화진료지침운영은다시한번재고가필요하다고생각된다. 또한최근우리나라에서유행처럼설치하고있는뇌졸중집중치료실은집중치료에대한전문지식이전혀없이고전적인뇌졸중치료개념을갖고있는의료진에운영되고있는현실이다. 90 이에보다전문적인급성기뇌졸중치료를할수있는 neurocritical care 분야의양성과교육이필요하며또한단순한예방적치료와역학적접근이아니라손상된뇌세포를회복혹은복구시키는진정한의미의급성기뇌졸중치료로의패러다임의전환이필요하다. REFERENCES 1. KNSO. Statistical survey of death causes in 2007. Seoul, korea. Korea National Statistical Office. 2007. 2. Bae HJ. Epidemiology of stroke: 2006 update. Korean J Stroke 2006; 9:5-10. 3. Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2003;2:43-53. 4. WHO. The world health report 2000: health systems-improving performance. 2000. 5. Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the american heart association/american stroke association stroke council, clinical cardiology council, cardiovascular radiology and intervention council, and the atherosclerotic peripheral vascular disease and quality of care outcomes in research interdisciplinary working groups: the american academy of neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 2007;38:1655-711. 6. Molina CA, Saver JL. Extending reperfusion therapy for acute ischemic stroke: emerging pharmacological, mechanical, and imaging strategies. Stroke 2005;36:2311-20. 7. Legos JJ, Tuma RF, Barone FC. Pharmacological interventions for stroke: failures and future. Expert Opin Investig Drugs 2002;11:603-14. 8. Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology 2008. 9. van der Worp HB, van Gijn J. Acute ischemic stroke. N Engl J Med 2007;357:572-9. 10. Lees KR. Does neuroprotection improve stroke outcome? Lancet 1998;351:1447-8. 11. Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia-the ischemic penumbra. Stroke 1981;12:723-5. 12. Heiss WD, Rosner G. Functional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol 1983;14:294-301. 13. Muir KW, Buchan A, von Kummer R, Rother J, Baron JC. Imaging of acute stroke. Lancet Neurol 2006;5:755-68. 9
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