INVITED REVIEW online ML Comm J Neurocrit Care 2008;1:111-116 ISSN 2005-0348 간질중첩증의최신지견 영남대학교의과대학신경과학교실 이세진 Status Epilepticus: Recent Updates Se Jin Lee, MD, PhD Department of Neurology, Yeungnam University College of Medicine, Daegu, Korea Status epilepticus (SE) is an under-recognized neurological emergency which requires rapid and aggressive treatment to prevent neuronal damage, systemic complications, and death. The treatment should be started as soon as possible, particularly in generalized convulsive SE, even before arriving hospital by non-medical personnel, and should include general supportive measures, drugs to suppress epileptic activity, and, whenever possible, treatments aimed at relieving the underlying causative condition. The criterion about the duration of SE has been changed to be shorter, from 30 minutes to 5 minutes, to reduce brain injury and increase the successful control of seizures through starting drug treatment at the early stage. The preferred initial treatment pathway of antiepileptic drug is intravenous adminstration of lorazepam or diazepam directly, followed by phenytoin. Refractory SE needs to be treated with anesthetic doses of midazolam, propofol or pentobarbital; the anesthetics are titrated against an electroencephalographic burst-suppression pattern. Standardized treatment guidelines are believed to improve the quality of emergency care and outcomes. Epileptologists must develop local SE treatment guidelines and protocols that define the specialized roles of resident of neurology, nursing staffs and technician, and educate neurological care teams to reenforce and implement the guidelines. J Neurocrit Care 2008;1:111-116 KEY WORDS: Status epilepticus Treatment Guidelines. 서 론 간질중첩증은신경과적응급질환으로서초기에적극적으로치료함으로써뇌손상, 전신적인합병증및사망률을줄일수있다. 임상적인발작 (clinical seizure) 과뇌파상의발작 (electrical seizure) 모두뇌손상을일으키고, 발작의지속시간이길어질수록조절하기가어려워지므로최대한빨리발작을중지시켜야한다. 최근까지체계적인치료지침들이많이발표되고있으나아직도신속한치료의필요성과중요성에대한인식이부족하고치료가지연되는경우가적지않다. 간질중첩증의발생률은지역과연구자에따라서차이가 Address for correspondence: Se Jin Lee, MD, PhD Department of Neurology, Yeungnam University College of Medicine, 317-1 Daemyeong-dong, Nam-gu, Daegu 705-717, Korea Tel: +82-53-620-3683, Fax: +82-53-627-1688 E-mail: sjlee@med.yu.ac.kr 많은데 9.9~41 명 /100,000 명가량된다. 나이가들수록증가하는데 60세이상이되면 54~86 명 /100,000 명정도이다. 간질중첩증의정의 간질중첩증은 일반적인경련의지속시간이경과한후에도발작이멈추지않고계속되는상태혹은중추신경계의기능이발작이발생하기이전의평소상태로회복되지않은상황에서발작이반복적으로발생하는것 이라고 ILAE 의 Task Force on Classification and Terminology 에서정의하였다. 1 과거에는 30분이상경련이지속되는상태라고정의하였지만최근에는시간을더욱짧게정의하여간질중첩증의범위를확대하였다. 이는동물실험에서 30분이상경련이지속될경우에는신경세포의손상과약물에대한저항성이발생하고, 경련이자가유지 (self-sustaining) 되는경향이관찰되었는데사람에서도초기에경련을조절하지 Copyright c 2008 The Korean Neurocritical Care Society 111
J Neurocrit Care 2008;1:111-116 못하면간질중첩증으로이행할가능성이높고치료가힘들어지기때문이다. 2,3 통상적인전신강직성-간대성발작의지속시간이 2분을넘지않기때문에최근에는 generalized convulsive status epilepticus(gcse) 의기준을발작이 5분이상지속되는경우로하여야한다는주장이제기되었다 (operational definition). 4,5 Non-convulsive status epilepticus(ncse) 의진단기준에대해서는현재까지지속시간에대한뚜렷한규정이없다. 간질중첩증의치료 병원에도착하기전치료유럽에서는충분히교육을받은응급구조사가 GCSE 환자에한하여직장으로벤조디아제핀 (benzodiazepine: BDZ) 을투여할수있도록하고있으나아직국내에서는이러한교육이시행되지않고있다. BZD를병원에도착하기전에투여한군과투여하지않는군을비교한연구결과에의하면 BDZ를미리투여하면간질중첩증의지속시간이유의하게짧아진다고보고되었다. 6,7 병원에도착한후치료기본적으로호흡과혈압을유지하고기본적인혈액및혈청검사, 간기능및신장기능, 크레아틴키나제, 독성물질, 항경련약제의혈중농도, 혈당, thiamine 농도를측정한다. 일단발작이조절되면 CT를촬영하여뇌병변의유무를확인하고뇌수막염이나뇌염이의심되면뇌척수액검사를시행한다. 간질중첩증에대한약물치료는 1970년대까지는체중과상관없이단순히페니토인 (phenytoin: PHT) 을 1,000 mg을주사하였다. 그러다가 Cranford 등 8 에의하여혈압과심전도를모니터하면서 PHT를 18 mg/kg, 50 mg/min 이하의속도로투여하는지침이발표되었다. 미국간질협회- Working Group on Status Epilepticus에서 1993년간질중첩증의치료지침을발표한이후로많은나라에서치료지침을정하였다. 9 대표적인치료지침은다음과같다. 1) Status Epilepticus Working Party(Appleton) 10 2) National Institute for Health and Clinical Excellence(NICE)-guideline(UK) 11 3) Scottish Intercollegiate Guidelines Network (SI- GN)- guideline(scotland) 12 4) Italian League Against Epilepsy-guideline(Minicucci) 13 5) Finnish Evidence Evidence Based Guidelines for Prolonged Seizure and Status Epilepticus 14 병원에도착하기전응급구조사에의한 BDZ 투여를치료지침에포함시켰다. 6) European Federation of Neurological Societiesguideline(Meierkord) 15 문헌고찰과그룹토의를통해서충분한근거가부족하지만치료에유익하다는전문가들의의견일치가명확한경우에는 good practide points(gpp) 로기술하였다. 간질중첩증의치료지침들은원칙적으로큰차이가없으며요약하면 Table 1과같다. 전통적인간질중첩증의치료단계는먼저 BDZ를정맥으로반복해서투여한후에도발작이계속되면 PHT 를정맥으로투여한다. 치료자에따라서는페노바르비탈 (phenobarbital: PB) 을정맥투여하는경우도있다. 이후에도발작이지속되면난치성간질중첩증 (refractory status epilepticus: RSE) 에해당되며전신마취제인 midazolam, propofol, pentobarbital(thiopental) 가운데한가지를투여한다. 이러한약물치료와동시에간질중첩증의원인을찾기위하여검사를실시하며근본적인원인을차단함으로써발작을중단시키고뇌손상을줄일수있다. 간질중첩증에대한약물치료가운데대표적인무작위임상시험의결과는 Table 2에요약하였다. Treiman 등 16 의연구에서는 NCSE 의진단기준에제한을두지않았는데 overt GCSE 상태에서약물치료후에 NCSE 상태로호전된경우도모두포함시켰기때문에원발성 NCSE의치료결과와는차이가있을것이다. 간질중첩증환자에서 BDZ, PHT 혹은 PB의투여에의하여발작이조절될가능성은 30~50% 가량된다. Midazolam, propofol 혹은 pentobarbital을투여하여도 8~21% 에서는발작이완전히조절되지않는다. 그리고발작이조절되면대개 24시간이후에전신마취제의용량을서서히감소시키는데전신마취제감량후에발생할수있는발작의재발을막기위하여다른항경련제를투여한다. 난치성간질중첩증 RSE의정의에대해서는아직까지적절한기준이마련되지않았지만일반적으로 BDZ와 PHT를포함하여 2가지혹은 3가지의항경련제에 1시간혹은 2시간이상발작이조절되지않는상태로규정하고있다. RSE에대한전통적인치료지침은전신마취제를사용하여뇌파에서돌발파- 억제양상 (burst-suppression pattern) 이나타날때까지 112
Status Epilepticus: Recent Updates SJ Lee TABLE 1. Protocol for drug treatment, general measures, and emergency investigations of convulsive status epilepticus as function of time from the onset the seizure Prolonged epileptic seizure: Premonitory stage/out-of-hospital (non-medical personnel) Drug treatment General measures Emerg. investigations Time Adults Children Airway, Breathing 5 min Diazepam 10 mg rectally Diazepam 0.5 mg/kg rectally Circulation safety Repeat once if necessary If Seizure continues, proceed Early status epilepticus First stage/out-of or in-hospital (medical personnel) Glucometer Time Drug treatment General measures Emerg. investigations 5-20 min. Adults Children Lorazepam i.v. 4 mg bolus or Diazepam i.v. 10 mg Lorazepam i.v. 0.1 mg/kg (max. 4) or Diazepam i.v. 0.3 mg/kg (max. 10) Airway: oxygen Blood pressure Regular monitoring: ECG, SpO2, BP iv glucose, thiamine pyridoxine (children) Treat acidosis Glucose, Na, K, Ca, Levels of AEDs Toxicology screening Kidney and liver function test If seizure continues, proceed Established status epilepticus, second stage/emergency department Time Drug treatment General measures Emerg. investigations 20-60 min Phenytoin i.v. 15-18 mg/kg at max. rate of 50 mg/min or in children Phenobarbital i.v. 15-20 mg/kg at max. rate of 100 mg/min Cardiorespiratory monitoring ECG, BP, SpO2 Identify & treat medical complication CT scan for etiology CSF for CNS infection EEG for pseudo-status If seizure continues, proceed Refractory status epileptics, third stage/intensive care unit Time Drug treatment General measures Emerg. Investigations >60 min General anesthesia Intensive care Continuous EEG electrical seizures, depth of anesthesia (burst-suppression) Thiopental 3-5 mg/kg bolus, Increased ICP Monitor then 3-5 mg/kg/h measure & treat or Pentobarbital 10-15 mg/kg, then 0.5-1 mg/kg/h or Anesthesia for 12-24h after last clinical or electrical seizure levels of AEDs K +, Na +, glucose & lactate Midazolam 0.2 mg/kg bolus (max. 2) then 0.05-2 mg/kg/h or only in adults: Propofol 1-2 mg/kg bolus (max. 10), then 2-10 mg/kg/h Modified from Finnish guideline. Epilepsia 2007;48(Suppl 8):99-102 Optimize maintenance of AED treatment 약물을증량하는것이다. 그러나전신마취제의투여로인한호흡저하, 혈압하강, 의식저하, 면역기능저하등과같은부작용이발생할수있기때문에근래에와서는발프론산 (valproic acid: VPA) 혹은 PB와같은비전신마취제 (non-anesthetising) 항경련제사용이증가하고있다. Mayer 등 18 의후향적연구에의하면약 50% 의 RSE 환자에서 PB나 VPA와같은비전신마취제항경련제에의하여발작이조절되었지만 GCSE 혹은 NCSE 를구분하지않았다 (Class IV). 미국과 19 유럽에서 20 시행된전문가설문조사결과에의하면약 70~80% 에서는비전신마취제항경련제를먼저투여하는데 PHT보다 PB를더선호하는것으로나타났는데미국의조사에서는 GCSE와 NCSE 를구분하지않았다. 유럽에서는전신마취제를먼저투여한다는 의견이 GCSE 35%, NCSE 16% 로나타났다. 약 75% 에서복합부분발작간질중첩증 (complex partial SE: CPSE) 환자에게는절대로전신마취제를투여하지않겠다고응답하였지만 GCSE 환자에게는특정시점에서필요하다면모든응답자가전신마취제를사용하겠다고하였다. 전신마취제의투여시기도차이가있는데 CPSE 환자에게는 1시간이후에사용하겠다는응답자가 60% 였지만 GCSE 환자에게는 80% 에서 1시간이내에전신마취제를투여할것이라고응답하였다. 전신마취제와비전신마취제항경련제의치료결과를직접비교한연구는없기때문에어느것이효과가더우수하다거나, 먼저투여하여야한다고주장할수없다. 간질중첩증의원인과종류, 환자의나이와상태, 동반질환등을고려 113
J Neurocrit Care 2008;1:111-116 TABLE 2. The results of clinical trials for the treatment of status epilepticus No. of patients Type of AEDs Efficacy Side effects 1. GCSE Treiman (1998) 16 384 LZP 0.1 mg/kg i.v.* 65% no difference among AEDs Class I PB 15 mg/kg i.v. 58% DZP 0.15 mg/kg i.v. 56% +PHT 18 mg/kg i.v. PHT 18 mg/kg i.v. 44% Alldredge (2001) 7 205 LZP 2mg i.v. 59% 11% Class I pre-hospital Tx DZP 5mg i.v. 43% 10% Placebo 21% 23% Leppik (1983) 17 78 LZP 4mg i.v. 89% 13% Class I (81 episodes) DZP 10mg i.v. 76% 12% 2. NCSE Treiman (1998) 15 134 LZP 0.1 mg/kg i.v. 18% Class I PB 18 mg/kg i.v. 24% DZP 0.15 mg/kg i.v. 08% +PHT 18 mg/kg i.v. PHT 18 mg/kg i.v. 08% *LZP vs PHT, P=0.002, DZP+PHT or PB vs PHT, P=0.02, LZP or DZP vs Placebo, P=0.001, not significant. AEDs: antiepileptic drugs, DZP: diazepam, GCSE: generalized convulsive status epilepticus, LZP: lorazepam, NCSE: non-convulsive status epilepticus, No.: number, PB: phenobarbital, PHT: phenytoin 하여약제의종류를결정하는것이바람직하다. 나이가많으면전신마취제의위험성이더욱높아지기때문에가급적피하는것이좋다. NCSE 환자에서는발작으로인한뇌손상의상대적인위험성이 GCSE보다는낮기때문에비전신마취제항경련제를먼저투여하고조절이안되면전신마취제를투여하는것이합리적이다. 난치성간질충첩증에사용되는 3차약제비전신마취제항경련제 PB는일차약제로포함되어있지만요즈음은 3차약제로분류되는경향이있으며 3차약제로서의효과에대해서는충분한연구결과가없다. PB의부과용량은 20 mg/kg 이며 30~50 mg/min 이하의속도로투여한다. RES 환자에서 VPA의역할은아직명확하게규명되지않았지만의식저하, 저혈압및호흡억제등과같은부작용이없고 NCSE 와 GCSE에모두효과가있는것으로보고되었다 (Class IV). 21 Limdi 등 22 의후향적연구에의하면간질중첩증환자의 63% 에서발작이중단되었다. 부과용량으로 25~45 mg/kg 을투여하는데 6 mg/kg/min 의빠른속도로정맥주입가능하다고보고되었지만 PHT보다우수하다는연구결과는현재까지없으므로 PHT를대신하여일차약제로 VPA를먼 저사용할만한근거는없다. 23,24 전신마취제 Pentobarbital, midazolam, propofol이주로사용되며 (Class IV) 이들의효과를서로비교한무작위-대조군임상연구 (randomized controlled trials) 는현재까지없다. 후향적연구결과들을분석한자료에의하면발작의억제효과는 pentobarbital 이가장우수한것으로나타났지만 pentobarbital 은돌발파-억제양상이나타날때까지투여하였고 midazolam 과 propofol 은뇌파에서발작이없어질때까지투여하였기때문에이들약제의효과를직접적으로비교하기는어렵다. 25 저혈압, 의식장애등과같은부작용은 pentobarbital 이훨씬높게나타났으며 (77% vs 34%), 전체사망률이 48% 였지만약물에따른차이는없었다. 저체온요법 (Hypothermia) Corry 등 26 은 midazolam 혹은 pentobarbital에조절되지않는 RSE 환자에게저체온요법을실시하여발작을완전히조절하였다. 체온을정상화시킨후에도 2명은발작이더이상없었으며나머지 2명에서도발작의횟수가현저히감소하였다. 저체온요법은항경련효과와함께신경세포보호효과도기대할수있으며동물실험에서도확인되었다. 114
Status Epilepticus: Recent Updates SJ Lee 약물에더이상조절되지않는 RES 환자에서마지막으로시도해볼수있는치료법이다. 치료의문제점과해결책오래전부터간질중첩증의치료에대한여러지침들이발표되고있지만후향적연구결과에의하면이러한치료지침들이실제임상진료에는제대로적용되지않는것으로나타났다. Davis 등 27 은 SIGN guideline 이제대로지켜지지않는중요한원인으로다음사항들을지적하였다. 첫째, 개인적인치료패턴을바꾸지않으며, 둘째, 치료지침의자세한내용에대한지식이부족하거나심지어치료지침이있는지도모르는경우가있다. 셋째, 인력부족으로인하여실제로적용하기가어려운경우가많으며, 넷째, 자주인력이교체되기때문에치료지침에대한정기적인교육이필요하다. 간질중첩증의예후 간질중첩증의예후를좌우하는가장중요한인자는발생원인이다. 일반적으로발작이멈추지않고 1시간이상지속되는경우, 저산소증, 뇌졸중, 중추신경계감염성질환및대사성질환으로인한이차성간질중첩증, 노인인경우에는예후가불량한것으로알려져있다. 항경련제의갑작스러운중단으로인한경우, 알코올중독, 외상에의한뇌손상으로발생한간질중첩증은대개예후가좋다. 13 사망률간질중첩증으로인한사망률은약 20% 가량되지만연구자에따라서 1~22% 로다양하게나타났다. 이러한차이는발생원인, 간질중첩증의유형, 환자의나이, 동반질환의유무, 초기의적절한치료등의차이에기인한다. 생존하더라도인지기능의저하가많이발생하며만성간질로이행할가능성이높다. 만성간질의발생소아에서간질중첩증후 2년이내에만성간질로이행할가능성은 25~40% 가량된다. 28,29 소아에서첫번째비유발성 (first unprovoked) 발작이후에간질이발생할가능성은 37% 이므로간질중첩증과첫번째비유발성발작후에발생하는만성간질의위험성은별다른차이가없음을알수있다. 30 그러므로소아에서의간질중첩증은간질의발생 (epileptogenesis) 에큰영향을미치지못함을의미하며소아의뇌는간질중첩증이나질병에의한손상을적게받 음을알수있다. 성인을대상으로한연구에서는잘조절되는간질중첩증환자보다난치성간질중첩증환자에서만성간질의발생이훨씬많았으며만성간질의종류는부분간질이많았다. 31 Hesdorfer 등 32 의연구결과에의하면첫번째증후성 (first symptomatic) 발작에비하여증후성간질중첩증후에만성간질로이행할가능성은훨씬높게나타났다 (42% vs 13%). 대사성질환에의한간질중첩증과첫번째증후성발작의비교에서도간질중첩증에서유의하게높았다 (29% vs 8%, P=0.02). 이러한사실은소아와는달리성인에서의간질중첩증은간질의발생에많은영향을미치고있음을알수있다. 그리고만성간질의발생에영향을미치는인자로는간질중첩증의원인뿐만아니라발생당시의연령도중요하다는사실을알수있다인지기능저하과거의연구결과에의하면이차성 GCSE 후에인지기능장애는 8~26% 에서발생하는것으로보고되었다. 그러나과거의연구들은대부분신경심리검사결과를바탕으로하지않았을뿐만아니라후향적으로의무기록이나면담에의거하여연구하였기때문에결과를신뢰하기어렵다. 최근의연구결과에의하면인지기능의저하를결정하는인자에는간질중첩증의종류, 원인, 발작의정도 ( 난치성 ) 와발병당시의나이가중요한것으로알려져있다. 간질중첩증환자에서발작으로인한인지기능의저하는대부분시간이지나면서회복된다. 그러므로발작자체는인지기능의저하에큰영향을미치지못하지만간질중첩증을일으키는기질적뇌손상의정도에비례하여인지기능의저하가발생하는것으로보고되었다. 33 결론 간질중첩증은조기에적극적으로치료하지않으면높은사망률과심각한합병증을남길수있는응급질환이지만이에대한중요성이과소평가되고있다. 각병원의여건과상황에맞는치료지침을설정하고이것이실제간질중첩증의치료에잘활용될수있도록교육과훈련이필요하다. 국내에서도병원에도착하기전부터응급구조사를통하여치료가시작될수있도록지침과제도를마련하여초기에발작을중단시켜야할것이다. GCSE가 BDZ와 PHT에조절되지않아난치성간질중첩증상태가되었을때환자의상태가양호하다면전신마취제를사용하더라도최대한빨리발작을조절하여야한다. 반면에 NCSE 는난치성간질중첩 115
J Neurocrit Care 2008;1:111-116 증으로이행하더라도전신마취제보다는먼저 VPA와 PB 를투여하여발작을조절하고실패할경우에한하여전신마취제의사용을고려하는것이바람직하다. REFERENCES 1. Blume WT, Luders HO, Mizrahi E, Tassinari C, van Emde Boas W, Engel J Jr. Glossary of descriptive terminology for ictal semiology: report of the ILAE tast force on classification and terminology. Epilepsia 2001;42:1212-8. 2. Nevander G, INgvar M, Auer R, Siesjo BK. Status epilepticus in well-oxygenated rats causes neuronal necrosis. Ann Neurol 1985;18: 281-90. 3. Smith BJ. Treatment of status epilepticus. Neurol Clin 2001;19:347-69. 4. Lowenstein DH, Bleck T, Macdonald RL. It s time to revise the definition of status epilepticus. Epilepsia 1999;40:120-2. 5. Lowenstein DH, Alldredge BK. Status epilepticus. NEJM 1998;338: 970-6. 6. Alldredge BK, Wall DB, Ferriero DM. Effect of prehospital treatment on the outcome of status epilepticus in children. Pediatr Neurol 1995;12:213-6. 7. Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epileticus. NEJM 2001;345:631-7. 8. Cranford RE, Leppik IE, Patrick B, Anderson CB, Kostick B. Intravenous phenytoin: clinical and pharmacokinetic aspects. Neurology 1978;28:874-80. 9. EFA Working Group on Status Epilepticus. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America s Working Group on status epilepticus. JAMA 1993;270:854-9. 10. Appleton R, Choonara I, Martland T, Phillips B, Scott R, Whitehouse W. The treatment of convulsive status epilepticus in children. Arch Dis Childhood 2000;83:415-9. 11. NICE guideline Epilepsy. (2004) www.nice.org.uk/cg020 (accessed May, 2008). 12. SIGN guideline Diagnosis and Management of Epilepsy in Adults (2003) www.sign.ac.uk/pdf/sign70.pdf (accessed May, 2008). 13. Minicucci F, Muscas G, Perucca E, Capovilla G, Vigevano F, Tinuper P. Treatment of status epilepticus in adults: guidelines of the Italian league against epilepsy. Epilepsia 2006;47(Suppl 5):9-15. 14. Finnish national guidelines for the treatment of prolonged seizures and status epilepticus. (2005) Summary by Kälviäinen R in English. In Evidence-Based Medicine Guidelines by Duodecim Medical Publications Editor-Chief Kunnamo I. Wiley, Cichester, West Sussex, England. Full text in Finnish in http://www.kaypahoito.fi (accessed May, 2008). 15. Meierkord H, Boom P, Engelsen B, Gocke K, Shorvon S, Tinuper P, et al. EFNS guideline on the management of status epilepticus. Eur J Neurol 2006;13:445-50. 16. Treiman DM, Meyers PD, Walton NY, Collins JF, Colling D, Rowan J, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. NEJM 1998;339:792-8. 17. Leppik IE, Derivan AT, Homan RW, Walker J, Ramsay RE, Patrick B. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983;249:1452-4. 18. Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons BF. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol 2002;59:205-10. 19. Claassen J, Hirsch LJ, Mayer SA. Treatment of status epilepticus: a survey of neurologists. J Neurol Sci 2003;211:37-41. 20. Holtkamp M, Masuhr F, Harms L, Einhaupl KM, Meierkord H, Buchheim K. The management of refractory generalized convulsive and complex partial status epilepticus in three European countries: a survey among epileptologists and critical care neurologists. J Neurol Neurosurg Psychiatry 2003;74:1095-9. 21. Sinha S, Naritoku DK. Intravenous valproate is well tolerated in unstable patients with status epilepticus. Neurology 2000;55:722-4. 22. Limdi NA, Shimpi AV, Faught E, Gomez CR, Burneo JG. Efficacy of rapid IV administration of valproic acid for status epilepticus. Neurology 2005;64:353-5. 23. Venkataraman V, Wheless JW. Safety of rapid intravenous infusion of valproate loading doses in epilepsy patients. Epilepsy Res 1999;35: 147-53. 24. Hodges BM, Mazur JE. Intravenous valproate in status epilepticus. Ann Pharmacother 2001;35:1465-70. 25. Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 2002;43:146-53. 26. Corry JJ, Dhar R, Murphy T, Diringer MN. Hypothermia for refractory status epilepticus. Neurocrit Care 2008 Apr 15 (Epub ahead of print). 27. Davis J, Roberts R, Davidson DL, Norman A, Ogston S, Grimshaw JM, et al. Implementation strategies for a Scottish epilepsy guidelines in primary care: results of a Tayside Implementation of Guidelines in Epilepsy Randomised (TIDER) trial. Epilepsia 2004;45:28-34. 28. Maytal J, Shinnar S, Moshe SL, Alvarez LA. Low morbidity and mortality of status epilepticus in children. Pediatrics 1989;83:323-31. 29. Eriksson KJ, Koivkko MJ. Status epilepticus in children: aetiology, treatment, and outcome. Dev Med Child Neurol 1997;39:652-8. 30. Shinnar S, Berg AT, Moshe SL, O Dell C, Alemany M, Newstein D, et al. The risk of seizure recurrence after a first unprovoked afebrile seizure in childhood: an extended follow-up. Pediatrics 1996;98:216-25. 31. Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry 2005;76:534-9. 32. Hesdorfer DC, Logroscino G, Casino G, Annegers JF, Hauser WA. Risk of unprovoked seizure after acute symptomatic seizure: effect of status epilepticus. Ann Neurol 1998;44:908-12. 33. Helmstaedter C. Cognitive outcome of status epilepticus in adults. Epilepsia 2007;48(Suppl 8):85-90. 116