美发表首个院内癫痫发作流行病学研究

根据《美国医学会杂志-神经病学》1月14自在线发表的一项报告，因非癫痫疾病住院患者在住院期间发作的癫痫易于复发，死亡率和发病率风险通常较高，且往往得不到最佳治疗[JAMA Neurol. 2013 Jan. 14 (doi:10.1001/2013.jamaneurol.337)]。

纽约西奈山医学院神经科的Madeline C. Fields博士及其同事报告称，对218例在住院期间发生癫痫的内科、外科或急诊住院患者的回顾性研究结果显示，总死亡或转入临终关怀治疗率为14%。


Madeline Fields博士
 
这项研究旨在考察住院患者癫痫发作的流行病学特点。美国迄今尚未见有关该类研究的报道，也没有可供临床医生参考的诊治指南，抗癫痫药物(AED)的有效性甚至也不明确，但住院患者癫痫发作往往可导致医疗护理和会诊强度加大，患者住院时间延长。

据美国卫生保健研究与质量署(AHRQ)估计，每年大约有140万住院患者出现癫痫发作，约占每年总住院患者的4%。无癫痫史患者癫痫发作的原因通常为脑卒中、感染或代谢紊乱，而有癫痫史患者则为应激、药物、睡眠剥夺、发热或住院加剧潜在癫痫发作的其他因素。

研究者通过查阅纽约市2家医院1年内收治患者的病历资料，确认了218例在住院期间癫痫发作的非癫痫原因住院患者，其中多数为 (64%)无癫痫史患者。在有癫痫史的79例(36%)患者中，16例(20%)在住院期间未服用AED，32例(41%)服用1种AED，32例(39%)服用2种或以上AED。

在纳入研究的所有患者中，多数(61%)在住院期间多次癫痫发作，39%的患者在多天内发作癫痫，而另外22%的患者1天内多次发作。近半数(43%)新发癫痫患者在住院期间复发，癫痫史患者复发率为32%。研究者称，上述高癫痫复发率属首次报告，这或许对于医生治疗这些患者非常重要。

8%的患者出现癫痫持续状态，6%为首次发作。无论是癫痫史患者还是无癫痫史患者，最常见癫痫类型为全面性强制阵挛性惊厥(33%)和复杂部分发作(21%)。除已有癫痫加剧外，癫痫发作最常见原因为脑卒中、代谢紊乱和脑部肿瘤。脑卒中是1天内多次发作患者最常见病因，而代谢异常是多天内单独发作患者的最常见病因。

14%的患者死亡或转入临终关怀医疗。该比例在无癫痫史患者中更高，为19%。住院期间癫痫复发患者上述比例(21%)高于单次发作患者(10%)。

研究者指出，新的AED在其他医疗机构常被推荐用于共病患者。因为与老药相比，它们与其他药物相互作用和不良反应均较小，且没有蛋白结合异常风险。但在这项研究中，患者更多服用老的AED。

半数无癫痫史患者首选苯妥英钠，而有癫痫史患者占28%。此外，苯妥英钠的应用在某种程度上也并不总是与目前标准相一致。患者静脉注射苯妥英钠的负荷剂量通常没有实现个体化给药，导致21%的患者治疗剂量不足，9%的患者治疗剂量过大，而29%的患者没有负荷剂量的记录。此外，26%的患者在出院时开具了苯妥英钠，可能是作为短期用药选择，没有考虑其长期治疗结果。苯妥英钠具有肝酶诱导作用，而这类患者通常同时服用其他药物，苯妥英钠可影响这些合并用药的代谢。

61%的患者首选苯二氮卓类AED，包括25%首次发作为癫痫持续状态的患者。另外24%的无癫痫史患者首选左乙拉西坦。

研究者认为，这项研究为开展随机对照试验提供了初步数据。癫痫复发非常常见，可作为首要结局指标。

按照辉瑞制药与纽约大学综合癫痫中心达成的咨询协议，辉瑞资助该项研究及论文发表。2位作者在研究期间在该中心工作。1位作者报告与Milken基金会、癫痫治疗项目、癫痫研究联盟以及国立神经疾病和脑卒中研究所存在利益关联。

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By: MARY ANN MOON, Internal Medicine News Digital Network

Seizures that occur in patients admitted to the hospital for nonseizure reasons are likely to recur during the hospital stay, usually carry a high risk of mortality and morbidity, and often are not treated optimally, according to a report published online Jan. 14 in JAMA Neurology.

In a retrospective study of 218 patients who developed seizures when they were inpatients at medical, surgical, or emergency departments at two New York hospitals, the overall rate of death or discharge to hospice care was 14%, said Dr. Madeline C. Fields of the department of neurology at Mount Sinai School of Medicine, New York, and her associates.
 
The investigators undertook this study to describe the epidemiology of hospital-onset seizures because until now, no studies in the United States have done so. No management guidelines are available for clinicians, and even the usefulness of antiepileptic drugs (AEDs) is uncertain. "This is surprising considering that hospital-onset seizures are dramatic events that often lead to increased intensity of medical care, consultations, and prolonged hospital stays," they noted.

The Agency for Healthcare Research and Quality estimates that seizures develop during approximately 1.4 million hospitalizations each year, or about 4% of all annual hospitalizations. When they develop in people with no history of seizure, it is usually because of stroke, infection, or metabolic disturbances. When they develop in people with a history of seizure, it is thought to be because stress, medication, sleep deprivation, fever, or other factors related to the hospitalization exacerbate the underlying seizure disorder.

Dr. Fields and her colleagues reviewed 1 year of medical records from a large nonprofit and a large municipal hospital affiliated with New York University, identifying 218 cases in which adults admitted for nonseizure indications developed hospital-onset seizures. Most of these cases (64%) occurred in patients without a history of seizures.

Among the 79 (36%) patients with a history of seizures, 16 (20%) were not taking AEDs at hospitalization, 32 (41%) were taking a single AED, and 31 (39%) were taking two or more AEDs.

Most patients (61%) in the entire study population had multiple seizures during the hospital stay. A total of 39% had seizures on multiple days, while another 22% had multiple seizures during a single day. Close to half (43%) of the patients who had new-onset seizures had recurrences during the hospital stay, as did 32% of patients who had a history of seizure.

These high rates of seizure recurrence "have never been reported and may be important" for clinicians trying to manage such cases, the researchers said (JAMA Neurol. 2013 Jan. 14 [doi:10.1001/2013.jamaneurol.337]).

Status epilepticus occurred in 8% of patients overall and was the index seizure in 6% overall.

The most common types of seizure were generalized tonic-clonic convulsions (33%) and complex partial seizures (21%). This was true in both patients with no history of seizures and in those with known seizure disorders.

The most frequent identifiable reasons for the seizures, other than exacerbation of an existing seizure disorder, were stroke, metabolic derangement, and brain tumor. Stroke was the most common etiology in patients who had multiple seizures during a single day, whereas metabolic abnormalities were the most common etiology in patients who had isolated seizures on multiple days.

Death or discharge to hospice care was considered "common" in this study, occurring in 14% of patients overall. Among patients with no history of seizures, this rate was even higher at 19%. This outcome occurred more often in patients who had recurrences during their stay (21%) than in those who had only a single seizure while hospitalized (10%).

In other settings, newer AEDs are recommended for patients with comorbidities because they are less likely than are older agents to interact with other medications, less likely to provoke adverse reactions, and do not carry the risk of protein-binding abnormalities that older agents do. However, in this study, older AEDs were much more likely to be prescribed.

Phenytoin was the first-line choice in half of the patients who had no history of seizures, as well as in 28% of those who had a history of seizures.

Moreover, "phenytoin was not always used in a manner commensurate with current standards," Dr. Fields and her associates wrote.

The loading dose of IV phenytoin often was not individualized to the patient, resulting in a subtherapeutic dose in 21% of cases and a supratherapeutic dose in 9%. The loading dose was not checked in another 29% of cases.

In addition, 26% of the patients discharged from the hospital were given prescriptions for phenytoin at that time. It may be that selection of this hepatic-enzyme-inducing drug was "predicated on acute choice rather than consideration of the consequences of long-term therapy in what is most likely an ill population receiving concomitant medications whose metabolism could be affected by phenytoin," the researchers wrote.

Benzodiazepines were the first line choice of AEDs in 61% of patients, including 25% of those whose index seizure was status epilepticus. Levetiracetam was the first line choice in another 24% of patients who had no history of seizures.

"This study provides preliminary data that could be used to plan a randomized controlled trial. Seizure recurrence was common enough that it could be a primary outcome measure," the investigators added.

This study was funded by Pfizer under a paid consultant agreement with the New York University Comprehensive Epilepsy Center, through which the investigators conducted their research and wrote their report. Two of the authors were employees of the center at the time of the study. One author reported ties to the Milken Foundation, the Epilepsy Therapy Project, the Epilepsy Study Consortium, and the National Institute of Neurological Disorders and Stroke.