Epileptiform Electrographic Patterns After Cardiac Arrest: Give Up or Treat?

Andrea O. Rossetti, MD, FAES1; Sarah Benghanem, MD, PhD2,3

2024년 11월 11일

JAMA Neurol. 2025;82(2):119-120.

doi:10.1001/jamaneurol.2024.3831

Viewpoint

  For decades, electroencephalogram (EEG) has been a cornerstone for prognostication of comatose patients after cardiac arrest. Along with clinical examination, somatosensory evoked potentials (SSEP), serum biomarkers, and brain imaging, “highly malignant patterns” (suppressed or burst-suppressed background with or without periodic discharges) are routinely used to identify patients with poor functional prognosis.1 About one-third of patients may show epileptiform abnormalities—spikes, sharp waves, or spike waves—in the first days, often taking a periodic or rhythmic pattern (RPP, along the ictal-interictal continuum) or even fulfilling criteria for electrographic seizures. These patterns have traditionally been considered to herald poor prognosis and may be coupled with myoclonic jerks in two-thirds of patients.2,3

  However, several reports have described patients who awoke from coma despite epileptiform abnormalities on EEG,4,5 challenging the historical pessimism and suggesting that pharmacological interventions treating epileptiform abnormalities under video EEG monitoring may be beneficial. While advocates of this strategy underscore the necessity of attempting to save each patient, others argue that systematically allocating limited resources to patients with a low likelihood of recovery is inefficient, generates unrealistic expectations among caregivers and relatives, and may increase the proportion of patients with severe neurological deficits, including unresponsive wakefulness, which is observed relatively frequently in environments that culturally do not foresee limitation of maximal care. The clinical community has struggled to reconcile these differing perspectives.

  The Treatment of Electroencephalographic Status Epilepticus after Cardiopulmonary Resuscitation (TELSTAR) trial2 was established to build, for the first time, a stronger evidence base to guide clinicians in these challenging scenarios. Comatose patients with RPP on continuous EEG within 3 days of cardiac arrest were randomized to standard care vs aggressive antiseizure medication treatment with levetiracetam, phenytoin, or valproate, combined with propofol or midazolam, and escalation to high-dose barbiturates if needed to suppress RPP for 48 hours. Cerebral performance categories (CPCs) at 3 months represented the primary outcome, dichotomized into favorable (CPC 1-2, representing no to moderate disability) vs unfavorable (CPC 3-5, representing several disabilities, unresponsive wakefulness, or death).2 Among 172 patients, 79 of 88 patients in the treatment group (90%) and 77 of 84 control group patients (92%) had an unfavorable outcome (95% CI of the difference, −7% to 11%; P = .68), demonstrating that prognosis at 3 months in that cohort was unaffected by EEG-guided treatment, thus reinforcing the view that treating epileptiform EEG patterns is futile in this setting.

  However, a prespecified subgroup analysis showed that among 36 patients with electrographic seizures or evolving, rhythmic EEG patterns, 6 of 20 patients randomized to the pharmacologic treatment group (30%) had a favorable outcome compared to 0 of 16 patients randomized to standard care. While the study was underpowered to examine this subgroup and this difference was nonsignificant, for some observers, this finding (in addition to other issues within the trial design) challenges the simple, pessimistic conclusions from the primary analysis.

  While the TELSTAR investigators used multicenter recruitment to enroll a clinically diverse population, about 80% of participants displayed generalized periodic discharges, which have been shown to be poorly responsive to treatment,5 likely diluting the potential treatment effect (ie, inclusion bias). Additionally, the trial included patients with certain types of EEG patterns not belonging to the ictal-interictal continuum (such as generalized rhythmic delta) that most specialists would not consider justifying antiseizure treatment. Roughly one-third of patients displayed suppressed or burst-suppressed EEG backgrounds, which are widely regarded as “highly malignant” patterns strongly related to unfavorable outcomes, especially if lacking background reactivity.6 Furthermore, including patients solely according to EEG results, without considering other routinely recommended ancillary prognostic tests,1 may have reduced the sensitivity to detect favorable outcomes. Finally, the use of phenytoin could aggravate myoclonus in this population at high risk, thus possibly reducing favorable outcomes.

  While awaiting a larger trial on a selected cohort with electrographic seizures, how should clinicians manage comatose patients after cardiac arrest with epileptiform abnormalities or RPP on EEG (Figure)? As clinical situations are virtually never absolute, a pragmatic approach should avoid generalized assumptions and instead be informed by multimodal assessments including, but not limited to, EEG. In assessing EEG results, diffuse, high-voltage poly-spikes that are time-locked with myoclonus, superimposed on a suppressed background, strongly correlate with poor prognosis, while lower-voltage, midline spikes on a continuous background may represent early forms of Lance-Adams posthypoxic myoclonus, which is treatable.7 Additional EEG characteristics, such as the timing of the appearance of epileptiform abnormalities (the earlier the worse, despite routine administration of γ-aminobutyric acid [GABA]-mediated agents that are also anticonvulsants), background continuity (the earlier the better, reflecting a timely recovery of brain function),8 and the presence of a reactive background (ie, better prognosis) should also be considered. These aspects have been summarized in a validated EEG score.3 After assessing other ancillary tests, it seems reasonable to initiate antiseizure treatment in patients with results compatible with favorable prognosis rather than poor outcome, such as patients with preserved brainstem reflexes, intact cortical SSEP, and low serum NSE, and those without widespread alterations in diffusion-weighted magnetic resonance imaging.9,10 In the absence of high-level evidence, we recommend antimyoclonic compounds (eg, intravenous levetiracetam or valproate or perampanel, topiramate, or zonisamide through the nasogastric tube), escalating to general anesthetics if needed.9 Treating these patients for at least a few days and up to 2 to 3 weeks seems reasonable, following the clinical evolution (awakening to follow command on sedation weaning) and the EEG (limitation or resolution of epileptiform features).5,9 For patients with results not compatible with favorable prognosis, antiseizure treatment may be warranted for symptomatic relief and comfort to mask the clinical manifestations of seizures and myoclonus, without aiming at prolonging life. Above all, a patient-tailored approach should consider family preferences and beliefs, premorbid conditions, and directives.

  Further research is clearly needed in this challenging field. An ideal randomized clinical trial should at least initially enroll an adequate cohort of comatose cardiac arrest survivors showing epileptiform EEG patterns with or without clinical counterparts, excluding those fulfilling criteria of “highly malignant” features (ie, unreactive, suppressed, or burst-suppressed background) and/or those with ancillary tests that herald poor prognosis (eg, absent brainstem reflexes, lack of cortical SSEP, markedly elevated serum markers, or severe alterations on brain imaging) to focus on the population that may be amenable to meaningful clinical improvement.

요약

• 소개 : 심정지 후 혼수상태 환자의 예후를 예측하기 위해 뇌파(EEG)는 오랫동안 중요한 역할을 해왔다. EEG에서 간헐적 방전(주기적 또는 리드미컬한 패턴)이나 발작 형태가 나타나면 전통적으로 불량한 예후로 간주되었지만, 일부 연구에서는 이러한 이상이 있어도 회복하는 사례가 보고되었다. 이에 따라, EEG 이상을 보이는 환자에게 항경련 치료를 시행하는 것이 회복 가능성에 영향을 미치는지에 대한 논란이 지속되어 왔다.

  
  

• 연구 방법 :

  TELSTAR 무작위 대조 시험은 심정지 후 3일 이내에 EEG에서 리드미컬한 패턴(RPP)을 보이는 성인 혼수 환자 172명을 대상으로 진행되었다.

  • 치료군 : 항경련 치료(levetiracetam, phenytoin, valproate, combined with propofol or midazolam, and escalation to high-dose barbiturates)

  • 대조군 : 표준 치료만 시행

  주요 임상 결과는 3개월 후의 뇌 기능 평가(뇌 성능 카테고리, CPC)로, 12는 양호한 회복, 35는 중증 장애나 사망으로 구분하였다.

• 결과 :3개월 후, 치료군 90%와 대조군 92%가 불량한 예후를 보였으며, 두 그룹 간에 유의한 차이는 없었다(P = .68). 그러나 전기발작 패턴(EEG에서 발작적 양상)을 보인 하위군 분석에서 치료군의 30%(6/20명)는 양호한 결과를 보인 반면, 대조군에서는 회복 사례가 없었다.

  
  

• 결론 및 의의 : EEG에서 높은 전압의 다극성 스파이크와 억제성 배경이 동반된 경우는 불량한 예후와 강하게 연관된다. 반면, 연속적인 배경에서 중간 전압의 중심부 스파이크가 나타나는 경우는 저산소성 발작 후 근간대성 경련(Lance-Adams syndrome)의 초기 징후일 수 있으며, 치료 가능성이 있다.

  치료 여부는 EEG 소견뿐만 아니라 뇌 영상, 혈청 신경 특이적 에놀라아제(NSE), 뇌간 반사 소실 여부 등 다각적 평가를 통해 결정해야 한다. TELSTAR 연구는 심정지 후 혼수상태 환자에게 EEG 이상만으로 항경련 치료를 적용하는 것이 전반적으로 유의미한 예후 개선을 가져오지 못함을 보여주었다. 그러나 발작적 EEG 패턴을 보이는 하위군에서 긍정적인 경향이 관찰된 만큼, 추후 대규모 연구를 통해 특정 환자군에서의 치료 효과를 검증할 필요가 있다.