Leitner Dominique F, Faustin Arline, Verducci Chloe, Friedman Daniel, William Christopher, Devore Sasha, Wisniewski Thomas, Devinsky Orrin
Comprehensive Epilepsy Center, NYU Grossman School of Medicine, New York, NY, USA.
Department of Neurology, NYU Langone Health and School of Medicine, New York, NY, USA.
Brain Commun. 2021 Aug 23;3(3):fcab192. doi: 10.1093/braincomms/fcab192. eCollection 2021.
Sudden unexpected death in epilepsy is the leading category of epilepsy-related death and the underlying mechanisms are incompletely understood. Risk factors can include a recent history and high frequency of generalized tonic-clonic seizures, which can depress brain activity postictally, impairing respiration, arousal and protective reflexes. Neuropathological findings in sudden unexpected death in epilepsy cases parallel those in other epilepsy patients, with no implication of novel structures or mechanisms in seizure-related deaths. Few large studies have comprehensively reviewed whole brain examination of such patients. We evaluated 92 North American Sudden unexpected death in epilepsy Registry cases with whole brain neuropathological examination by board-certified neuropathologists blinded to the adjudicated cause of death, with an average of 16 brain regions examined per case. The 92 cases included 61 sudden unexpected death in epilepsy (40 definite, 9 definite plus, 6 probable, 6 possible) and 31 people with epilepsy controls who died from other causes. The mean age at death was 34.4 years and 65.2% (60/92) were male. The average age of death was younger for sudden unexpected death in epilepsy cases than for epilepsy controls (30.0 versus 39.6 years; = 0.006), and there was no difference in sex distribution respectively (67.3% male versus 64.5%, = 0.8). Among sudden unexpected death in epilepsy cases, earlier age of epilepsy onset positively correlated with a younger age at death ( = 0.0005) and negatively correlated with epilepsy duration ( = 0.001). Neuropathological findings were identified in 83.7% of the cases in our cohort. The most common findings were dentate gyrus dysgenesis (sudden unexpected death in epilepsy 50.9%, epilepsy controls 54.8%) and focal cortical dysplasia (FCD) (sudden unexpected death in epilepsy 41.8%, epilepsy controls 29.0%). The neuropathological findings in sudden unexpected death in epilepsy paralleled those in epilepsy controls, including the frequency of total neuropathological findings as well as the specific findings in the dentate gyrus, findings pertaining to neurodevelopment (e.g. FCD, heterotopias) and findings in the brainstem (e.g. medullary arcuate or olivary dysgenesis). Thus, like prior studies, we found no neuropathological findings that were more common in sudden unexpected death in epilepsy cases. Future neuropathological studies evaluating larger sudden unexpected death in epilepsy and control cohorts would benefit from inclusion of different epilepsy syndromes with detailed phenotypic information, consensus among pathologists particularly for more subjective findings where observations can be inconsistent, and molecular approaches to identify markers of sudden unexpected death in epilepsy risk or pathogenesis.
癫痫猝死是癫痫相关死亡的主要类型，其潜在机制尚未完全明确。危险因素可能包括近期有全面性强直阵挛发作病史且发作频繁，这可在发作后抑制脑活动，损害呼吸、觉醒及保护性反射。癫痫猝死病例的神经病理学发现与其他癫痫患者相似，在与癫痫发作相关的死亡中未发现新的结构或机制。很少有大型研究对这类患者的全脑检查进行全面综述。我们对92例北美癫痫猝死登记病例进行了全脑神经病理学检查，由对判定的死亡原因不知情的经过委员会认证的神经病理学家进行检查，平均每例检查16个脑区。这92例病例包括61例癫痫猝死（40例确诊、9例确诊加疑似、6例可能、6例疑似）和31例癫痫对照者（死于其他原因）。平均死亡年龄为34.4岁，65.2%（60/92）为男性。癫痫猝死病例的平均死亡年龄低于癫痫对照者（30.0岁对39.6岁；P = 0.006），性别分布无差异（男性分别为67.3%对64.5%，P = 0.8）。在癫痫猝死病例中，癫痫发病年龄越早与死亡年龄越年轻呈正相关（P = 0.0005），与癫痫病程呈负相关（P = 0.001）。在我们的队列中，83.7%的病例有神经病理学发现。最常见的发现是齿状回发育异常（癫痫猝死50.9%，癫痫对照者54.8%）和局灶性皮质发育不良（FCD）（癫痫猝死41.8%，癫痫对照者29.0%）。癫痫猝死的神经病理学发现与癫痫对照者相似，包括总的神经病理学发现频率以及齿状回的具体发现、与神经发育相关的发现（如FCD、异位）和脑干的发现（如延髓弓形或橄榄体发育异常）。因此，与之前的研究一样，我们未发现癫痫猝死病例中更常见的神经病理学发现。未来对更大规模的癫痫猝死和对照队列进行神经病理学研究，纳入不同癫痫综合征并提供详细表型信息、病理学家之间达成共识（特别是对于更主观的发现，因为观察结果可能不一致）以及采用分子方法来识别癫痫猝死风险或发病机制的标志物将大有裨益。
