探寻预测急性卒中事件后发生癫痫的生物标记物_Journal of Epilepsy

Authors：

AbrairaL ,  SantamarinaE , CazorlaS , 郭雅静　孟永玲　译 , 薛国芳　审

Corresponding author：

SantamarinaE, Email: esantama@vhebron.net

Keywords：

癫痫发生; 卒中后癫痫; 癫痫发作; 卒中

DOI：

10.7507/2096-0247.20210091

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

血液生物标记物在卒中后癫痫中的作用尚未得到广泛研究。本研究旨在研究急性卒中的临床因素和生物标记物，并经过较长时间的观察分析它们与卒中癫痫发生的关系。对缺血性和出血性卒中的患者进行 14 个血液生物标记物的检测。用 Z-scores 对生物标记物进行规范化和标准化。同时还评估了卒中和癫痫相关变量：卒中严重程度（依据美国国立卫生研究院卒中量表 NIHSS 评分）、卒中类型和病因、从卒中到迟发性癫痫发作的时间以及癫痫发作类型。使用多因素 Cox 回归分析来确定与癫痫相关的独立的临床变量和生物标记物。从 1 115 例患者队列中纳入 895 例。平均年龄为（72.0±13.1）岁，其中有 57.8% 的患者为男性。51 例患者（5.7%）发展为迟发性癫痫，中位时间为 232 天［四分位数间距 IQR（86～491）］。NIHSS 分数≥8［P<0.001，HR=4.013，95%CI（2.123，7.586）］和早发性癫痫发作的病史［P<0.001，HR=4.038，95%CI（1.802，9.045）］是与癫痫发展风险相关的独立因素。预测癫痫的独立生物标记物有：高水平的内皮抑素>1.203［P=0.046，HR=4.300，95%CI（1.028，17.996）］、低水平的 70 kDa 热休克蛋白 8（Hsc70）<2.496［P=0.006，HR=3.795，95%CI（1.476，9.760）］和 S100B<1.364［P=0.001，HR=2.955，95%CI（1.534，5.491）］。当这些生物标记物共同存在时，癫痫风险上升至 17%。临床变量和血液生物标记物联合使用时，预测模型中受试者工作特性（ROC）曲线下的面积比单独一个存在时［68.9%，95%CI（60.3%，77.6%）］的面积大，为［74.3%，95%CI（65.2%，83.3%）］。S100B 和 Hsc70 的下降及内皮抑制素的升高可能有助于预测卒中后癫痫，这为临床危险因素提供了额外信息。此外，这些数据为癫痫发生假说过程提供了一定依据。

Citation： AbrairaL, SantamarinaE, CazorlaS, 郭雅静　孟永玲　译, 薛国芳　审. 探寻预测急性卒中事件后发生癫痫的生物标记物. Journal of Epilepsy, 2021, 7(6): 547-554. doi: 10.7507/2096-0247.20210091 Copy

1.	Klein P, Dingledine R, Aronica E, et al. Commonalities in epileptogenic processes from different acute brain insults: Do they translate? Epilepsia, 2018, 59(1): 37-66.
2.	Feyissa AM, Hasan TF, Meschia JF. Stroke-related epilepsy. European journal of neurology, 2019, 26(1): 18-e13.
3.	Beghi E, Carpio A, Forsgren L, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia, 2010, 51(4): 671-675.
4.	Hesdorffer DC, Benn EK, Cascino GD, et al. Is a first acute symptomatic seizure epilepsy? Mortality and risk for recurrent seizure. Epilepsia, 2009, 50(5): 1102-1108.
5.	Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia, 2014, 55(4): 475-482.
6.	Galovic M, Döhler N, Erdélyi-Canavese B, et al. Prediction of late seizures after ischaemic stroke with a novel prognostic model (the SeLECT score): a multivariable prediction model development and validation study. The Lancet Neurology, 2018, 17(2): 143-152.
7.	Pitkänen A, Roivainen R, Lukasiuk K. Development of epilepsy after ischaemic stroke. The Lancet Neurology, 2016, 15(2): 185-197.
8.	Jungehulsing GJ, Heuschmann PU, Holtkamp M, et al. Incidence and predictors of post-stroke epilepsy. Acta neurologica Scandinavica, 2013, 127(6): 427-430.
9.	Zelano J. Poststroke epilepsy: update and future directions. Therapeutic advances in neurological disorders, 2016, 9(5): 424-435.
10.	Vezzani A, Balosso S, Ravizza T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nature reviews Neurology, 2019, 15(8): 459-472.
11.	Henshall DC, Engel T. Contribution of apoptosis-associated signaling pathways to epileptogenesis: lessons from Bcl-2 family knockouts. Frontiers in cellular neuroscience, 2013, 7: 110.
12.	Bustamante A, López-Cancio E, Pich S, et al. Blood Biomarkers for the Early Diagnosis of Stroke: The Stroke-Chip Study. Stroke, 2017, 48(9): 2419-2425.
13.	Bustamante A, Simats A, Vilar-Bergua A, et al. Blood/brain biomarkers of inflammation after stroke and their association with outcome: from C-Reactive protein to damage-associated molecular patterns. Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics, 2016, 13(4): 671-684.
14.	Abraira L, Giannini N, Santamarina E, et al. Correlation of blood biomarkers with early-onset seizures after an acute stroke event. Epilepsy & behavior: E& B, 2020, 104(Pt B): 106549.
15.	Eriksson H, Löwhagen Hendén P, Rentzos A, et al. Acute symptomatic seizures and epilepsy after mechanical thrombectomy. Epilepsy & behavior: E& B, 2020, 104(Pt B): 106520.
16.	Placencia M, Sander JW, Shorvon SD, et al. Validation of a screening questionnaire for the detection of epileptic seizures in epidemiological studies. Brain, 1992, 115(Pt 3): 783-794.
17.	Bamford J, Sandercock P, Dennis M, et al. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet (London, England), 1991, 337(8756): 1521-1526.
18.	Adams HP, Jr., Bendixen BH, Kappelle LJ, et al Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke, 1993, 24(1): 35-41.
19.	Pencina MJ, D'Agostino RB, Pencina KM, et al. Interpreting incremental value of markers added to risk prediction models. American journal of epidemiology, 2012, 176(6): 473-481.
20.	Naylor J, Thevathasan A, Churilov L, et al. Association between different acute stroke therapies and development of post stroke seizures. BMC neurology, 2018, 18(1): 61.
21.	Bentes C, Martins H, Peralta AR, et al. Epileptic manifestations in stroke patients treated with intravenous alteplase. European journal of neurology, 2017, 24(6): 755-761.
22.	Singh RJ, Chen S, Ganesh A, et al. Long-term neurological, vascular, and mortality outcomes after stroke. International journal of stroke: official journal of the International Stroke Society, 2018, 13(8): 787-796.
23.	Jauch EC, Lindsell C, Broderick J, et al. Association of serial biochemical markers with acute ischemic stroke: the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator Stroke Study. Stroke, 2006, 37(10): 2508-2513.
24.	Foerch C, Wunderlich MT, Dvorak F, et al. Elevated serum S100B levels indicate a higher risk of hemorrhagic transformation after thrombolytic therapy in acute stroke. Stroke, 2007, 38(9): 2491-2495.
25.	Van Eldik LJ, Wainwright MS. The Janus face of glial-derived S100B: beneficial and detrimental functions in the brain. Restorative neurology and neuroscience, 2003, 21(3-4): 97-108.
26.	Vezzani A, Granata T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia, 2005, 46(11): 1724-1743.
27.	Vezzani A, Baram TZ. New roles for interleukin-1 Beta in the mechanisms of epilepsy. Epilepsy currents, 2007, 7(2): 45-50.
28.	Ravizza T, Gagliardi B, Noé F, et al. Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiology of disease, 2008, 29(1): 142-160.
29.	Somera-Molina KC, Nair S, Van Eldik LJ, et al. Enhanced microglial activation and proinflammatory cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a 'two-hit' seizure model. Brain research, 2009, 1282: 162-172.
30.	Wu H, Brown EV, Acharya NK, et al. Age-dependent increase of blood-brain barrier permeability and neuron-binding autoantibodies in S100B knockout mice. Brain research, 2016, 1637: 154-167.
31.	Ré DB, Przedborski S. Fractalkine: moving from chemotaxis to neuroprotection. Nature neuroscience, 2006, 9(7): 859-861.
32.	Fassbender K, Schmidt R, Schreiner A, et al. Leakage of brain-originated proteins in peripheral blood: temporal profile and diagnostic value in early ischemic stroke. Journal of the neurological sciences, 1997, 148(1): 101-105.
33.	Yang T, Hsu C, Liao W, et al. Heat shock protein 70 expression in epilepsy suggests stress rather than protection. Acta neuropathologica, 2008, 115(2): 219-230.
34.	Liu T, Daniels CK, Cao S. Comprehensive review on the HSC70 functions, interactions with related molecules and involvement in clinical diseases and therapeutic potential. Pharmacology & therapeutics, 2012, 136(3): 354-374.
35.	Chen S, Brown IR. Translocation of constitutively expressed heat shock protein Hsc70 to synapse-enriched areas of the cerebral cortex after hyperthermic stress. Journal of neuroscience research, 2007, 85(2): 402-409.
36.	Al Ahmad A, Lee B, Stack J, et al. Endostatin binds nerve growth factor and thereby inhibits neurite outgrowth and neuronal migration in-vitro. Brain research, 2010, 1360: 28-39.
37.	Chen H, Xue LX, Cao HL, et al. Endostatin/collagen XVIII is increased in cerebrospinal fluid after severe traumatic brain injury. BioMed research international, 2013, 2013: 402375.
38.	Mueller CA, Schluesener HJ, Fauser U, et al. Lesional expression of the endogenous angiogenesis inhibitor endostatin/collagen XVIII following traumatic brain injury (TBI). Experimental neurology, 2007, 208(2): 228-237.
39.	Deininger MH, Meyermann R, Schluesener HJ. Endostatin/collagen XVIII accumulates in patients with traumatic brain injury. Journal of neurotrauma, 2006, 23(7): 1103-1110.

1. Klein P, Dingledine R, Aronica E, et al. Commonalities in epileptogenic processes from different acute brain insults: Do they translate? Epilepsia, 2018, 59(1): 37-66.
2. Feyissa AM, Hasan TF, Meschia JF. Stroke-related epilepsy. European journal of neurology, 2019, 26(1): 18-e13.
3. Beghi E, Carpio A, Forsgren L, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia, 2010, 51(4): 671-675.
4. Hesdorffer DC, Benn EK, Cascino GD, et al. Is a first acute symptomatic seizure epilepsy? Mortality and risk for recurrent seizure. Epilepsia, 2009, 50(5): 1102-1108.
5. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia, 2014, 55(4): 475-482.
6. Galovic M, Döhler N, Erdélyi-Canavese B, et al. Prediction of late seizures after ischaemic stroke with a novel prognostic model (the SeLECT score): a multivariable prediction model development and validation study. The Lancet Neurology, 2018, 17(2): 143-152.
7. Pitkänen A, Roivainen R, Lukasiuk K. Development of epilepsy after ischaemic stroke. The Lancet Neurology, 2016, 15(2): 185-197.
8. Jungehulsing GJ, Heuschmann PU, Holtkamp M, et al. Incidence and predictors of post-stroke epilepsy. Acta neurologica Scandinavica, 2013, 127(6): 427-430.
9. Zelano J. Poststroke epilepsy: update and future directions. Therapeutic advances in neurological disorders, 2016, 9(5): 424-435.
10. Vezzani A, Balosso S, Ravizza T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nature reviews Neurology, 2019, 15(8): 459-472.
11. Henshall DC, Engel T. Contribution of apoptosis-associated signaling pathways to epileptogenesis: lessons from Bcl-2 family knockouts. Frontiers in cellular neuroscience, 2013, 7: 110.
12. Bustamante A, López-Cancio E, Pich S, et al. Blood Biomarkers for the Early Diagnosis of Stroke: The Stroke-Chip Study. Stroke, 2017, 48(9): 2419-2425.
13. Bustamante A, Simats A, Vilar-Bergua A, et al. Blood/brain biomarkers of inflammation after stroke and their association with outcome: from C-Reactive protein to damage-associated molecular patterns. Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics, 2016, 13(4): 671-684.
14. Abraira L, Giannini N, Santamarina E, et al. Correlation of blood biomarkers with early-onset seizures after an acute stroke event. Epilepsy & behavior: E& B, 2020, 104(Pt B): 106549.
15. Eriksson H, Löwhagen Hendén P, Rentzos A, et al. Acute symptomatic seizures and epilepsy after mechanical thrombectomy. Epilepsy & behavior: E& B, 2020, 104(Pt B): 106520.
16. Placencia M, Sander JW, Shorvon SD, et al. Validation of a screening questionnaire for the detection of epileptic seizures in epidemiological studies. Brain, 1992, 115(Pt 3): 783-794.
17. Bamford J, Sandercock P, Dennis M, et al. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet (London, England), 1991, 337(8756): 1521-1526.
18. Adams HP, Jr., Bendixen BH, Kappelle LJ, et al Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke, 1993, 24(1): 35-41.
19. Pencina MJ, D'Agostino RB, Pencina KM, et al. Interpreting incremental value of markers added to risk prediction models. American journal of epidemiology, 2012, 176(6): 473-481.
20. Naylor J, Thevathasan A, Churilov L, et al. Association between different acute stroke therapies and development of post stroke seizures. BMC neurology, 2018, 18(1): 61.
21. Bentes C, Martins H, Peralta AR, et al. Epileptic manifestations in stroke patients treated with intravenous alteplase. European journal of neurology, 2017, 24(6): 755-761.
22. Singh RJ, Chen S, Ganesh A, et al. Long-term neurological, vascular, and mortality outcomes after stroke. International journal of stroke: official journal of the International Stroke Society, 2018, 13(8): 787-796.
23. Jauch EC, Lindsell C, Broderick J, et al. Association of serial biochemical markers with acute ischemic stroke: the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator Stroke Study. Stroke, 2006, 37(10): 2508-2513.
24. Foerch C, Wunderlich MT, Dvorak F, et al. Elevated serum S100B levels indicate a higher risk of hemorrhagic transformation after thrombolytic therapy in acute stroke. Stroke, 2007, 38(9): 2491-2495.
25. Van Eldik LJ, Wainwright MS. The Janus face of glial-derived S100B: beneficial and detrimental functions in the brain. Restorative neurology and neuroscience, 2003, 21(3-4): 97-108.
26. Vezzani A, Granata T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia, 2005, 46(11): 1724-1743.
27. Vezzani A, Baram TZ. New roles for interleukin-1 Beta in the mechanisms of epilepsy. Epilepsy currents, 2007, 7(2): 45-50.
28. Ravizza T, Gagliardi B, Noé F, et al. Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiology of disease, 2008, 29(1): 142-160.
29. Somera-Molina KC, Nair S, Van Eldik LJ, et al. Enhanced microglial activation and proinflammatory cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a 'two-hit' seizure model. Brain research, 2009, 1282: 162-172.
30. Wu H, Brown EV, Acharya NK, et al. Age-dependent increase of blood-brain barrier permeability and neuron-binding autoantibodies in S100B knockout mice. Brain research, 2016, 1637: 154-167.
31. Ré DB, Przedborski S. Fractalkine: moving from chemotaxis to neuroprotection. Nature neuroscience, 2006, 9(7): 859-861.
32. Fassbender K, Schmidt R, Schreiner A, et al. Leakage of brain-originated proteins in peripheral blood: temporal profile and diagnostic value in early ischemic stroke. Journal of the neurological sciences, 1997, 148(1): 101-105.
33. Yang T, Hsu C, Liao W, et al. Heat shock protein 70 expression in epilepsy suggests stress rather than protection. Acta neuropathologica, 2008, 115(2): 219-230.
34. Liu T, Daniels CK, Cao S. Comprehensive review on the HSC70 functions, interactions with related molecules and involvement in clinical diseases and therapeutic potential. Pharmacology & therapeutics, 2012, 136(3): 354-374.
35. Chen S, Brown IR. Translocation of constitutively expressed heat shock protein Hsc70 to synapse-enriched areas of the cerebral cortex after hyperthermic stress. Journal of neuroscience research, 2007, 85(2): 402-409.
36. Al Ahmad A, Lee B, Stack J, et al. Endostatin binds nerve growth factor and thereby inhibits neurite outgrowth and neuronal migration in-vitro. Brain research, 2010, 1360: 28-39.
37. Chen H, Xue LX, Cao HL, et al. Endostatin/collagen XVIII is increased in cerebrospinal fluid after severe traumatic brain injury. BioMed research international, 2013, 2013: 402375.
38. Mueller CA, Schluesener HJ, Fauser U, et al. Lesional expression of the endogenous angiogenesis inhibitor endostatin/collagen XVIII following traumatic brain injury (TBI). Experimental neurology, 2007, 208(2): 228-237.
39. Deininger MH, Meyermann R, Schluesener HJ. Endostatin/collagen XVIII accumulates in patients with traumatic brain injury. Journal of neurotrauma, 2006, 23(7): 1103-1110.

Previous Article
新发难治性癫痫持续状态的诊治研究进展
Next Article
SLC13A5 基因突变致早发幼儿癫痫性脑病 25 型一例并文献复习

Journal of Epilepsy

探寻预测急性卒中事件后发生癫痫的生物标记物

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content