胎儿酒精谱系障碍综合征与癫痫_Journal of Epilepsy

Authors：

王克玲 ,  施荣富

海南省儿童医院神经内科（海口 570206）;

Corresponding author：

施荣富, Email: srf.111@126.com

Keywords：

酒精; 胎儿酒精谱系障碍; 癫痫

DOI：

10.7507/2096-0247.20180012

Video：

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以往研究资料显示胎儿酒精谱系障碍（Fetal alcohol spectrum disorders，FASD）合并有较高的癫痫发生率，FASD 高发癫痫的机制尚不十分清楚，现有的研究认为其机制有下面几个方面原因：① 酒精作用于胎儿脑组织引起代谢和形态学改变，而导致功能改变，诱发癫痫；② 酒精降低了神经元的兴奋阈值；③ 通过突触机制；④ 或非突触路径引发癫痫。研究资料还显示酒精暴露对胎儿脑组织的损伤具有时效性，不同时间暴露酒精，损害的部位不一样，造成的不良事件也不一样；癫痫也是 FASD 常见的不良事件之一。快速发育中的脑组织对酒精尤其敏感。目前对 FASD 及合并的癫痫还没有安全有效的治疗方法，有学者在动物实验中尝试用雷帕霉素和神经干细胞注射治疗 FASD 合并的癫痫和其它神经功能障碍，并显示了一定效果，但安全性和有效性有待进一步认证。FASD 合并癫痫在我国的研究较少，现将相关研究进行综述分析。

Citation： 王克玲, 施荣富. 胎儿酒精谱系障碍综合征与癫痫. Journal of Epilepsy, 2018, 4(1): 49-52. doi: 10.7507/2096-0247.20180012 Copy

1.	Waja T, Ebrahim J, Yohannis Z, et al. Prevalence of alcohol use disorders and associated factors among people with epilepsy attending Amanuel Mental Specialized Hospital, Addis Ababa, Ethiopia. Neuropsychiatr Dis Treat, 2016, 12: 2989-2996.
2.	Johnson JL, Leff M. Children of substance abusers: overview of research findings. Pediatrics, 1999,103(5 Pt 2): 1085-1099.
3.	Bell SH, Stade B, Reynolds JN, et al.The remarkably high prevalence of epilepsy and seizure history in fetal alcohol spectrum disorders. Alcohol Clin Exp Res, 2010, 34(6): 1084-1089.
4.	O'Malley KD, Rich SD. Clinical implications of a link between fetal alcohol spectrum disorders (FASD) and autism or asperger's disorder - a neurodevelopmental frame for helping understanding and management. edn. 2013, INTECH Open Access Publisher.
5.	Sampson PD, Bookstein FL, Barr HM, et al. Prenatal alcohol exposure, birthweight, and measures of child size from birth to age 14 years. Am J Public Health, 1994, 84(9): 1421-1428.
6.	Sampson PD, Streissguth AP, Bookstein FL,et al.Incidence of fetal alcohol syndrome and prevalence of alcohol-related neurodevelopmental disorder. Teratology, 1997, 56(5):317-326.
7.	Sokol RJ, Delaney-Black V, Nordstrom B. Fetal alcohol spectrum disorder. JAMA , 2003, 290(22):2996-2999.
8.	Chudley AE, Conry J, Cook JL, et al. Fetal alcohol spectrum disorder: canadian guidelines for diagnosis. CMAJ, 2005, 3(1): 172.
9.	May PA, Gossage JP, Kalberg WO, et al. Prevalence and epidemiologic characteristics of FASD from various research methods with an emphasis on recent in-school studies. Dev Disabil Res Rev, 2009, 15(3): 176-192.
10.	Iosub S, Fuchs M, Bingol N, et al. Fetal alcohol syndrome revisited. Pediatrics, 1981, 68(4): 475-497.
11.	O’Malley K, Barr H. Fetal Alcohol syndrome and seizure disorder. Can J Psychol, 1998, 43(10): 1051.
12.	Spohr H, Steinhausen H. Follow-up studies of children with fetal alcohol syndrome. Neuropediatrics, 1987, 18(1): 13-17.
13.	Liang J, Shen Y, Shao XM, et al. Dihydromyricetin prevents fetal alcohol exposure-induced behavioral and physiological deficits: the roles of GABAA receptors in adolescence. Neurochem Res, 2014, 39(6): 1147-1161.
14.	Bonthius DJ, Pantazis NJ, Karacay B, et al. Alcohol exposure during the brain growth spurt promotes hippocampal seizures, rapid kindling, and spreading depression. Alcohol Clin Exp Res, 2001, 25(5): 734-745.
15.	Fernandes Y, Gerlai R. Long-term behavioral changes in response to early developmental exposure to ethanol in zebrafish. Alcohol Clin Exp Res, 2009, 33(4): 601-609.
16.	Tanguay RL, Reimers MJ. Analysis of ethanol developmental toxicity in zebrafish. Methods Mol Biol, 2008, 447: 63-74.
17.	Carvan MJ, Loucks E, Weber DN, et al. Ethanol effects on the developing zebrafish: neurobehavior and skeletal morphogenesis. Neurotoxicol Teratol, 2004, 26(6): 757-768.
18.	Strömland K, Pinazo-Durán MD. Ophthalmic involvement in the fetal alcoholsyndrome: clinical and animal model studies. Alcohol Alcohol, 2002, 37(1): 2-8.
19.	Kashyap B, Pegorsch L, Frey RA, et al. Eye-specific gene expression following embryonic ethanol exposure in zebrafish: roles for heat shock factor 1. Reprod Toxicol, 2014, 43: 111-124.
20.	Boronat S, Vicente M, Lainez E, et al. Seizures and electroencephalography findings in 61 patients with fetal alcohol spectrum disorders. Eur J Med Genet, 2017, 60(1): 72-78.
21.	Church MW, Holloway JA. Audiogenic seizure susceptibility in mature rats with fetal alcohol syndrome. Alcohol Clin Exp Res, 1981, 5: 145.
22.	胡建, 杨德森. 酒精中毒所致大脑损害的病因与神经生化研究. 国外医学精神病分册, 1998, 25(1): 31-34.
23.	Hirai K, Yoshioka H, Kihara M, et al. Effects of ethanol on neuronal migration and neural cell adhesion molecules in the embryonic rat cerebral cortex: A tissue culture study. Dev Brain Res,1999, 118(1-2): 205-210.
24.	Ikonomidou C, Bittigan P, Ishimaru MJ, et al. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science, 2000, 287(5455): 1056-1060.
25.	West JR, Hodges CA, Black AC. Prenatal exposure to ethanol alters the organization of hippocampal mossy fibers in rats. Science, 1981, 211(4485): 957-959.
26.	Bouilleret V, Ridoux V, Depaulis A, et al. Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice. Electroencephalography, histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy. Neuroscience, 1999, 89(3): 717-729.
27.	Chen WJA, Parnell SE, West JR. Effects of alcohol and nicotine on developing olfactory bulb: Loss of mitral cells and alterations in neurotransmitter levels. Alcohol Clin Exp Res, 1999, 23(1): 18-25.
28.	Bailey CD, Brien JF, Reynolds JN. Altered GABA(A)-benzodiazepine receptor number and pharmacology in the adult guinea pig cerebral cortex after chronic prenatal ethanol exposure. Alcohol Clin Exp Res, 1999, 23(11): 1816-1824.
29.	Baulac M, Laplane D. Alcohol and epilepsy. Rev Prat, 1990,40(4): 307-311.
30.	Bonthius DJ, Woodhouse J, Bonthius NE, et al. Reduced seizure threshold and hippocampal cell loss in rats exposed to alcohol during the brain growth spurt. Alcohol Clin Exp Res, 2001, 25(1): 70-81.
31.	Thomas JD, Goodlett CR, West JR. Alcohol-induced Purkinje cell loss depends on developmental timing of alcohol exposure and correlates with motor performance. Dev Brain Res, 1998, 105(2): 159-166.
32.	董志霞, 陆伦根. 酒精戒断综合征的机制、临床特点及治疗进展. 现代医药卫生, 2017, 33(1): 12-14.
33.	Carlson SL, O'Buckley TK, Thomas R, et al. Altered GABAA receptor expression and seizure threshold following acute ethanol challenge in mice lacking the RIIβ subunit of PKA. Neurochem Res, 2014, 39(6): 1079-1087.
34.	Fox JE, Bikson M, Jefferys JG. Tissue resistance changes and the profile of synchronized neuronal activity during ictal events in the low calcium model of epilepsy. J Neurophysiol, 2004, 92(1): 181-188.
35.	Santos LE, da Silveira GA, Costa VD,et al.Alcohol abuse promotes changes in non-synaptic epileptiform activity with concomitant expression changes in cotransporters and glial cells. PLoS ONE, 2000, 8(11): e78854.
36.	Anton RF, Randall CL. Central nervous system prostaglandins and ethanol. Alcohol Clin Exp Res, 2006, 11(1): 10-18.
37.	Morales-Aza BM, Chilingworth NL, Payne JA, et al. Inflammation alters cation chloride cotransporter expression in sensory neurons. Neurobiol Dis, 2004, 17(1): 62-69.
38.	de Almeida AC, Rodrigues AM, Scorza FA, et al. Mechanistic hypotheses for nonsynaptic epileptiform activity induction and its transition from the interictal to ictal state: computational simulation. Epilepsia, 2008, 49(11): 1-17.
39.	Goodlett CR, Eilers AT. Alcohol-induced Purkinje cell loss with a single binge exposure in neonatal rats: a stereological study of temporal windows of vulnerability. Alcohol Clin Exp Res, 1997, 21(4): 738-744.
40.	Maier SE, Miller JA, Blackwell JM, et al. Fetal alcohol exposure and temporal vulnerability: Regional differences in cell loss as a function of the timing of binge-like alcohol exposure during brain development. Alcohol Clin Exp Res, 1999, 23(4): 726-734.
41.	Cartwright MM, Smith SM. Stage dependent effects of ethanol on cranial neural crest cell development: partial basis for the phenotypic variations observed in fetal alcohol syndrome. Alcohol Clin Exp Res, 1995, 19(6): 1454-1462.
42.	Kotch LE, Sulik KK. Experimental fetal alcohol syndrome: Proposed pathogenic basis for a variety of associated focal and brain anomalies. Am J Med Genet, 1992, 44(2): 168-176.
43.	Goodlett CR, Johnson TB. Neonatal binge ethanol exposure using intubation: timing and dose effects on place learning. Neurotoxicol Teratol, 1997, 19(6): 435-446.
44.	Fu X, Guo Z, Gao C, et al. Long-term alcohol-Induced activation of mammalian target of rapamycin is a key risk factor of epilepsy. Med Sci Monit, 2016, 25(22): 3975-3980.
45.	Yoshinaga T, Hashimoto E, Ukai W, et al. Neural stem cell transplantation in a model of fetal alcohol effects. Neural Transm Suppl, 2007, 72: 331-337.
46.	Shirasaka T, Ukai W, Yoshinaga T, et al. Promising therapy of neural stem cell transplantation for FASD model-neural network reconstruction and behavior recovery. Nihon Arukoru Yakubutsu Igakkai Zasshi, 2011, 46(6): 576-584.
47.	Lippert T, Gelineau L, Napoli E, et al. Harnessing neural stem cells for treating psychiatric symptoms associated with fetal alcohol spectrum disorder and epilepsy. Prog Neuropsychopharmacol Biol Psychiatry, 2018, 3(80):10-22.

1. Waja T, Ebrahim J, Yohannis Z, et al. Prevalence of alcohol use disorders and associated factors among people with epilepsy attending Amanuel Mental Specialized Hospital, Addis Ababa, Ethiopia. Neuropsychiatr Dis Treat, 2016, 12: 2989-2996.
2. Johnson JL, Leff M. Children of substance abusers: overview of research findings. Pediatrics, 1999,103(5 Pt 2): 1085-1099.
3. Bell SH, Stade B, Reynolds JN, et al.The remarkably high prevalence of epilepsy and seizure history in fetal alcohol spectrum disorders. Alcohol Clin Exp Res, 2010, 34(6): 1084-1089.
4. O'Malley KD, Rich SD. Clinical implications of a link between fetal alcohol spectrum disorders (FASD) and autism or asperger's disorder - a neurodevelopmental frame for helping understanding and management. edn. 2013, INTECH Open Access Publisher.
5. Sampson PD, Bookstein FL, Barr HM, et al. Prenatal alcohol exposure, birthweight, and measures of child size from birth to age 14 years. Am J Public Health, 1994, 84(9): 1421-1428.
6. Sampson PD, Streissguth AP, Bookstein FL,et al.Incidence of fetal alcohol syndrome and prevalence of alcohol-related neurodevelopmental disorder. Teratology, 1997, 56(5):317-326.
7. Sokol RJ, Delaney-Black V, Nordstrom B. Fetal alcohol spectrum disorder. JAMA , 2003, 290(22):2996-2999.
8. Chudley AE, Conry J, Cook JL, et al. Fetal alcohol spectrum disorder: canadian guidelines for diagnosis. CMAJ, 2005, 3(1): 172.
9. May PA, Gossage JP, Kalberg WO, et al. Prevalence and epidemiologic characteristics of FASD from various research methods with an emphasis on recent in-school studies. Dev Disabil Res Rev, 2009, 15(3): 176-192.
10. Iosub S, Fuchs M, Bingol N, et al. Fetal alcohol syndrome revisited. Pediatrics, 1981, 68(4): 475-497.
11. O’Malley K, Barr H. Fetal Alcohol syndrome and seizure disorder. Can J Psychol, 1998, 43(10): 1051.
12. Spohr H, Steinhausen H. Follow-up studies of children with fetal alcohol syndrome. Neuropediatrics, 1987, 18(1): 13-17.
13. Liang J, Shen Y, Shao XM, et al. Dihydromyricetin prevents fetal alcohol exposure-induced behavioral and physiological deficits: the roles of GABAA receptors in adolescence. Neurochem Res, 2014, 39(6): 1147-1161.
14. Bonthius DJ, Pantazis NJ, Karacay B, et al. Alcohol exposure during the brain growth spurt promotes hippocampal seizures, rapid kindling, and spreading depression. Alcohol Clin Exp Res, 2001, 25(5): 734-745.
15. Fernandes Y, Gerlai R. Long-term behavioral changes in response to early developmental exposure to ethanol in zebrafish. Alcohol Clin Exp Res, 2009, 33(4): 601-609.
16. Tanguay RL, Reimers MJ. Analysis of ethanol developmental toxicity in zebrafish. Methods Mol Biol, 2008, 447: 63-74.
17. Carvan MJ, Loucks E, Weber DN, et al. Ethanol effects on the developing zebrafish: neurobehavior and skeletal morphogenesis. Neurotoxicol Teratol, 2004, 26(6): 757-768.
18. Strömland K, Pinazo-Durán MD. Ophthalmic involvement in the fetal alcoholsyndrome: clinical and animal model studies. Alcohol Alcohol, 2002, 37(1): 2-8.
19. Kashyap B, Pegorsch L, Frey RA, et al. Eye-specific gene expression following embryonic ethanol exposure in zebrafish: roles for heat shock factor 1. Reprod Toxicol, 2014, 43: 111-124.
20. Boronat S, Vicente M, Lainez E, et al. Seizures and electroencephalography findings in 61 patients with fetal alcohol spectrum disorders. Eur J Med Genet, 2017, 60(1): 72-78.
21. Church MW, Holloway JA. Audiogenic seizure susceptibility in mature rats with fetal alcohol syndrome. Alcohol Clin Exp Res, 1981, 5: 145.
22. 胡建, 杨德森. 酒精中毒所致大脑损害的病因与神经生化研究. 国外医学精神病分册, 1998, 25(1): 31-34.
23. Hirai K, Yoshioka H, Kihara M, et al. Effects of ethanol on neuronal migration and neural cell adhesion molecules in the embryonic rat cerebral cortex: A tissue culture study. Dev Brain Res,1999, 118(1-2): 205-210.
24. Ikonomidou C, Bittigan P, Ishimaru MJ, et al. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science, 2000, 287(5455): 1056-1060.
25. West JR, Hodges CA, Black AC. Prenatal exposure to ethanol alters the organization of hippocampal mossy fibers in rats. Science, 1981, 211(4485): 957-959.
26. Bouilleret V, Ridoux V, Depaulis A, et al. Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice. Electroencephalography, histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy. Neuroscience, 1999, 89(3): 717-729.
27. Chen WJA, Parnell SE, West JR. Effects of alcohol and nicotine on developing olfactory bulb: Loss of mitral cells and alterations in neurotransmitter levels. Alcohol Clin Exp Res, 1999, 23(1): 18-25.
28. Bailey CD, Brien JF, Reynolds JN. Altered GABA(A)-benzodiazepine receptor number and pharmacology in the adult guinea pig cerebral cortex after chronic prenatal ethanol exposure. Alcohol Clin Exp Res, 1999, 23(11): 1816-1824.
29. Baulac M, Laplane D. Alcohol and epilepsy. Rev Prat, 1990,40(4): 307-311.
30. Bonthius DJ, Woodhouse J, Bonthius NE, et al. Reduced seizure threshold and hippocampal cell loss in rats exposed to alcohol during the brain growth spurt. Alcohol Clin Exp Res, 2001, 25(1): 70-81.
31. Thomas JD, Goodlett CR, West JR. Alcohol-induced Purkinje cell loss depends on developmental timing of alcohol exposure and correlates with motor performance. Dev Brain Res, 1998, 105(2): 159-166.
32. 董志霞, 陆伦根. 酒精戒断综合征的机制、临床特点及治疗进展. 现代医药卫生, 2017, 33(1): 12-14.
33. Carlson SL, O'Buckley TK, Thomas R, et al. Altered GABAA receptor expression and seizure threshold following acute ethanol challenge in mice lacking the RIIβ subunit of PKA. Neurochem Res, 2014, 39(6): 1079-1087.
34. Fox JE, Bikson M, Jefferys JG. Tissue resistance changes and the profile of synchronized neuronal activity during ictal events in the low calcium model of epilepsy. J Neurophysiol, 2004, 92(1): 181-188.
35. Santos LE, da Silveira GA, Costa VD,et al.Alcohol abuse promotes changes in non-synaptic epileptiform activity with concomitant expression changes in cotransporters and glial cells. PLoS ONE, 2000, 8(11): e78854.
36. Anton RF, Randall CL. Central nervous system prostaglandins and ethanol. Alcohol Clin Exp Res, 2006, 11(1): 10-18.
37. Morales-Aza BM, Chilingworth NL, Payne JA, et al. Inflammation alters cation chloride cotransporter expression in sensory neurons. Neurobiol Dis, 2004, 17(1): 62-69.
38. de Almeida AC, Rodrigues AM, Scorza FA, et al. Mechanistic hypotheses for nonsynaptic epileptiform activity induction and its transition from the interictal to ictal state: computational simulation. Epilepsia, 2008, 49(11): 1-17.
39. Goodlett CR, Eilers AT. Alcohol-induced Purkinje cell loss with a single binge exposure in neonatal rats: a stereological study of temporal windows of vulnerability. Alcohol Clin Exp Res, 1997, 21(4): 738-744.
40. Maier SE, Miller JA, Blackwell JM, et al. Fetal alcohol exposure and temporal vulnerability: Regional differences in cell loss as a function of the timing of binge-like alcohol exposure during brain development. Alcohol Clin Exp Res, 1999, 23(4): 726-734.
41. Cartwright MM, Smith SM. Stage dependent effects of ethanol on cranial neural crest cell development: partial basis for the phenotypic variations observed in fetal alcohol syndrome. Alcohol Clin Exp Res, 1995, 19(6): 1454-1462.
42. Kotch LE, Sulik KK. Experimental fetal alcohol syndrome: Proposed pathogenic basis for a variety of associated focal and brain anomalies. Am J Med Genet, 1992, 44(2): 168-176.
43. Goodlett CR, Johnson TB. Neonatal binge ethanol exposure using intubation: timing and dose effects on place learning. Neurotoxicol Teratol, 1997, 19(6): 435-446.
44. Fu X, Guo Z, Gao C, et al. Long-term alcohol-Induced activation of mammalian target of rapamycin is a key risk factor of epilepsy. Med Sci Monit, 2016, 25(22): 3975-3980.
45. Yoshinaga T, Hashimoto E, Ukai W, et al. Neural stem cell transplantation in a model of fetal alcohol effects. Neural Transm Suppl, 2007, 72: 331-337.
46. Shirasaka T, Ukai W, Yoshinaga T, et al. Promising therapy of neural stem cell transplantation for FASD model-neural network reconstruction and behavior recovery. Nihon Arukoru Yakubutsu Igakkai Zasshi, 2011, 46(6): 576-584.
47. Lippert T, Gelineau L, Napoli E, et al. Harnessing neural stem cells for treating psychiatric symptoms associated with fetal alcohol spectrum disorder and epilepsy. Prog Neuropsychopharmacol Biol Psychiatry, 2018, 3(80):10-22.

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