儿童癫痫中的神经元抗体：临床特征和未经免疫治疗的历史队列远期预后_Journal of Epilepsy

Authors：

SukhvirWright , AdaT Geerts , CorneliaMaria , Jol-van derZijde , 熊维希 , 慕洁

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Keywords：

自身抗体; 儿童癫痫; 电压门控钾通道复合体; N-甲基-D-天冬氨酸受体

DOI：

10.7507/2096-0247.20170054

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神经元细胞表面抗体在自身免疫性脑炎的发病中起着明确的作用；早期诊断和治疗的患者预后更好。在不伴脑炎的儿童癫痫中也见神经元抗体阳性的报道。文章旨在评估神经元抗体对儿童癫痫患者远期预后是否有影响。该前瞻性研究患者来自荷兰儿童癫痫研究(Dutch Study of Epilepsy, DSEC)的4个中心，于1988年-1992年期间招募患者(n=178)，均未接受免疫治疗。以健康且年龄匹配的骨髓捐赠者作为正常对照(n=112)。所有受试者均使用标准方法，检测血清N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate, NMDAR)、α氨基-3-羟基-5-甲基-4-异恶唑丙酸受体、富含亮氨酸胶质瘤失活1蛋白，接触蛋白相关蛋白2(Contactin associated protein like 2, CASPR2)、contactin-2、谷氨酸脱羧酶和电压门控钾通道(Voltage gated potassium channel, VGKC)-复合物抗体。均未使用脑脊液(Cerebrospinal fluid, CSF)样本检测。并将抗体检测结果与随访15年以上的临床资料进行相关性分析。17例患者(9.5%)神经元抗体检测为阳性，分别为VGKC复合物(n=3)，NMDAR(n=7)，CASPR2(n=4) 和contactin-2(n=3)，同时有3名(3/112，2.6%)健康对照者神经元抗体检测为阳性，VGKC复合物(n=1)，NMDAR (n=2)(P=0.03)。虽然抗体滴度相对较低(细胞表面抗体≤ 1：100)，但17例阳性样本中有8例(47%)可与活性海马神经元表面结合，提示具有潜在的致病性。在抗体阳性患者中更多见预先存在的认知障碍(9/17vs.33/161, P=0.01)。14例抗体阳性患者接受了规范的抗癫痫药物(AEDs)治疗。其中3例(17%)为耐药性癫痫，但与161例抗体阴性的患者中16例为耐药性癫痫(16人，10%)相比，不存在统计学差异。在6和/或12个月有随访样本的96例患者中，7例之前抗体阳性患者中6例抗体转阴，相反，另有7例患者在随访时第一次出现了抗体阳性。在9.5%的儿童新发癫痫患者中发现低水平的神经元抗体阳性，虽然抗体不一定会持续存在，但在随访中可见神经元抗体由阴性转为阳性，这表明抗体可能是由于神经元的损伤或炎症的继发反应所产生的。此外，由于抗体阳性的儿童癫痫患者对规范AEDs的反应和远期预后与抗体阴性患者没有差异，提示在儿童癫痫中常规进行神经元抗体检测意义不大。抗体阳性组中预先存在的认知障碍的发生率较高，17例患者中7例患者CASPR2和contactin-2抗体阳性，以及17例血清样品中8例与活性海马神经元的结合表明，即使是继发反应，神经元抗体也可能参与到儿童癫痫的共病发生中。

Citation： SukhvirWright, AdaT Geerts, CorneliaMaria, Jol-van derZijde, 熊维希, 慕洁. 儿童癫痫中的神经元抗体：临床特征和未经免疫治疗的历史队列远期预后. Journal of Epilepsy, 2017, 3(4): 340-347. doi: 10.7507/2096-0247.20170054 Copy

1.	Irani SR, Gelfand JM, Al-Diwani A, et al. Cell-surface central nervoussystem autoantibodies: clinical relevance and emerging paradigms. Ann Neurol, 2014, 76(2): 168-184.
2.	Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies. Ann N Y Acad Sci, 2014, 1338(7): 94-114.
3.	Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1protein and contactin-associated protein-2 in limbic encephalitis.Morvan's syndrome and acquired neuromyotonia. Brain, 2010, 133(11): 2734-2748.
4.	Lai M, Huijbers MG, Lancaster E, et al. Investigation of LGI1 as theantigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol, 2010, 9(2): 776-785.
5.	Irani SR, Bera K, Waters P, et al. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain, 2010, 133(7): 1655-1667.
6.	Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptorencephalitis: case series and analysis of the effects of antibodies. Lancet Neurol, 2008, 7(2): 1091-1098.
7.	Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizuresprecede Lgi1 antibody limbic encephalitis. Ann Neurol, 2011, 69(4): 892-900.
8.	Irani SR, Stagg CJ, Schott JM, et al. Faciobrachial dystonic seizures:the influence of immunotherapy on seizure control and prevention ofcognitive impairment in a broadening phenotype. Brain, 2013, 136(8): 3151-3162.
9.	Majoie HJ, de Baets M, Renier W, et al. Antibodies to voltage-gatedpotassium and calcium channels in epilepsy. Epilepsy Res, 2006, 71(10): 135-141.
10.	McKnight K, Jiang Y, Hart Y, et al. Serum antibodies in epilepsy andseizure-associated disorders. Neurology, 2005, 65(6): 1730-1736.
11.	Brenner T, Sills GJ, Hart Y, et al. Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy. Epilepsia, 2013, 54(5): 1028-1035.
12.	Suleiman J, Wright S, Gill D, et al. Autoantibodies to neuronal antigens in children with new-onset seizures classified according to therevised ILAE organization of seizures and epilepsies. Epilepsia, 2013, 54(11): 2091-2100.
13.	Quek AM, Britton JW, McKeon A, et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol, 2012, 69(9): 582-593.
14.	Bien CG. Value of autoantibodies for prediction of treatment responsein patients with autoimmune epilepsy: review of the literature andsuggestions for clinical management. Epilepsia, 2013, 54(Suppl. 2): 48-55.
15.	Arts WF, Geerts AT, Brouwer OF, et al. The early prognosis of epilepsy in childhood: the prediction of a poor outcome. The dutch study of epilepsy in childhood. Epilepsia, 1999, 40(7): 726-734.
16.	Arts WF, Brouwer OF, Peters AC, et al. Course and prognosis of childhood epilepsy: 5-year follow-up of the dutch study of epilepsy in childhood. Brain, 2004, 127(8): 1774-1784.
17.	Hauser WA, Anderson VE, Loewenson RB, et al. Seizurerecurrence after a first unprovoked seizure. N Engl J Med, 1982, 307(10): 522-528.
18.	Callenbach PM, Jol-Van Der Zijde CM, Geerts AT, et al.Immunoglobulins in children with epilepsy: The dutch study of epilepsy in childhood. Clin Exp Immunol, 2003, 132(12): 144-151.
19.	Stroink H, Brouwer OF, Arts WF, et al. The first unprovoked, untreated seizure in childhood: a hospital based study of the accuracy of the diagnosis, rate of recurrence, and long term outcome after recurrence. Dutch study of epilepsy in childhood. J Neurol Neurosurg Psychiatry, 1998, 64(7): 595-600.
20.	Geerts A, Brouwer O, Stroink H, et al. Onset of intractability and its course over time: the Dutch study of epilepsy in childhood. Epilepsia, 2012, 53(4): 741-751.
21.	Paterson RW, Zandi MS, Armstrong R, et al. Clinical relevance of positive voltage-gated potassium channel (VGKC)-complex antibodies: experience from a tertiary referral centre. J Neurol Neurosurg Psychiatry, 2014, 85(7): 625-630.
22.	Hacohen Y, Singh R, Rossi M, et al. Clinical relevance of voltagegated potassium channel-complex antibodies in children. Neurology, 2015, 85(2): 967-975.
23.	Beaudoin GM III, Lee SH, Singh D, et al. Culturing pyramidal neurons from the early postnatal mouse hippocampus and cortex. Nat Protoc, 2012, 7(3): 1741-1754.
24.	Kaech S, Banker G. Culturing hippocampal neurons. Nat Protoc, 2006, 1(4): 2406-2415.
25.	Zandi MS, Paterson RW, Ellul MA, et al. Clinical relevance of serum antibodies to extracellular N-methyl-D-aspartate receptor epitopes. J Neurol Neurosurg Psychiatry, 2015, 86(3): 708-713.
26.	Hacohen Y, Wright S, Waters P, et al. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system auto antigens. J Neurol Neurosurg Psychiatry, 2013, 84(4): 748-755.
27.	Ramanathan S, Wong CH, Rahman Z, et al. Myoclonic status epilepticus as a presentation of caspr2 antibody-associated autoimmune encephalitis. Epileptic Disord, 2014, 16(3): 477-481.
28.	Hacohen Y, Deiva K, Pettingill P, et al. N-methyl-D-aspartate receptor antibodies in post-herpes simplex virus encephalitis neurological relapse. Mov Disord, 2014, 29(2): 90-96.
29.	Mohammad SS, Sinclair K, Pillai S, et al. Herpes simplex encephalitis relapse with chorea is associated with auto antibodies to N-Methyl-Daspartate receptor or dopamine-2 receptor. Mov Disord, 2014, 29(7): 117-122.
30.	Hegde M, Lowenstein DH. The search for circulating epilepsy biomarkers. Biomark Med, 2014, 8(2): 413-427.

1. Irani SR, Gelfand JM, Al-Diwani A, et al. Cell-surface central nervoussystem autoantibodies: clinical relevance and emerging paradigms. Ann Neurol, 2014, 76(2): 168-184.
2. Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies. Ann N Y Acad Sci, 2014, 1338(7): 94-114.
3. Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1protein and contactin-associated protein-2 in limbic encephalitis.Morvan's syndrome and acquired neuromyotonia. Brain, 2010, 133(11): 2734-2748.
4. Lai M, Huijbers MG, Lancaster E, et al. Investigation of LGI1 as theantigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol, 2010, 9(2): 776-785.
5. Irani SR, Bera K, Waters P, et al. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain, 2010, 133(7): 1655-1667.
6. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptorencephalitis: case series and analysis of the effects of antibodies. Lancet Neurol, 2008, 7(2): 1091-1098.
7. Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizuresprecede Lgi1 antibody limbic encephalitis. Ann Neurol, 2011, 69(4): 892-900.
8. Irani SR, Stagg CJ, Schott JM, et al. Faciobrachial dystonic seizures:the influence of immunotherapy on seizure control and prevention ofcognitive impairment in a broadening phenotype. Brain, 2013, 136(8): 3151-3162.
9. Majoie HJ, de Baets M, Renier W, et al. Antibodies to voltage-gatedpotassium and calcium channels in epilepsy. Epilepsy Res, 2006, 71(10): 135-141.
10. McKnight K, Jiang Y, Hart Y, et al. Serum antibodies in epilepsy andseizure-associated disorders. Neurology, 2005, 65(6): 1730-1736.
11. Brenner T, Sills GJ, Hart Y, et al. Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy. Epilepsia, 2013, 54(5): 1028-1035.
12. Suleiman J, Wright S, Gill D, et al. Autoantibodies to neuronal antigens in children with new-onset seizures classified according to therevised ILAE organization of seizures and epilepsies. Epilepsia, 2013, 54(11): 2091-2100.
13. Quek AM, Britton JW, McKeon A, et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol, 2012, 69(9): 582-593.
14. Bien CG. Value of autoantibodies for prediction of treatment responsein patients with autoimmune epilepsy: review of the literature andsuggestions for clinical management. Epilepsia, 2013, 54(Suppl. 2): 48-55.
15. Arts WF, Geerts AT, Brouwer OF, et al. The early prognosis of epilepsy in childhood: the prediction of a poor outcome. The dutch study of epilepsy in childhood. Epilepsia, 1999, 40(7): 726-734.
16. Arts WF, Brouwer OF, Peters AC, et al. Course and prognosis of childhood epilepsy: 5-year follow-up of the dutch study of epilepsy in childhood. Brain, 2004, 127(8): 1774-1784.
17. Hauser WA, Anderson VE, Loewenson RB, et al. Seizurerecurrence after a first unprovoked seizure. N Engl J Med, 1982, 307(10): 522-528.
18. Callenbach PM, Jol-Van Der Zijde CM, Geerts AT, et al.Immunoglobulins in children with epilepsy: The dutch study of epilepsy in childhood. Clin Exp Immunol, 2003, 132(12): 144-151.
19. Stroink H, Brouwer OF, Arts WF, et al. The first unprovoked, untreated seizure in childhood: a hospital based study of the accuracy of the diagnosis, rate of recurrence, and long term outcome after recurrence. Dutch study of epilepsy in childhood. J Neurol Neurosurg Psychiatry, 1998, 64(7): 595-600.
20. Geerts A, Brouwer O, Stroink H, et al. Onset of intractability and its course over time: the Dutch study of epilepsy in childhood. Epilepsia, 2012, 53(4): 741-751.
21. Paterson RW, Zandi MS, Armstrong R, et al. Clinical relevance of positive voltage-gated potassium channel (VGKC)-complex antibodies: experience from a tertiary referral centre. J Neurol Neurosurg Psychiatry, 2014, 85(7): 625-630.
22. Hacohen Y, Singh R, Rossi M, et al. Clinical relevance of voltagegated potassium channel-complex antibodies in children. Neurology, 2015, 85(2): 967-975.
23. Beaudoin GM III, Lee SH, Singh D, et al. Culturing pyramidal neurons from the early postnatal mouse hippocampus and cortex. Nat Protoc, 2012, 7(3): 1741-1754.
24. Kaech S, Banker G. Culturing hippocampal neurons. Nat Protoc, 2006, 1(4): 2406-2415.
25. Zandi MS, Paterson RW, Ellul MA, et al. Clinical relevance of serum antibodies to extracellular N-methyl-D-aspartate receptor epitopes. J Neurol Neurosurg Psychiatry, 2015, 86(3): 708-713.
26. Hacohen Y, Wright S, Waters P, et al. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system auto antigens. J Neurol Neurosurg Psychiatry, 2013, 84(4): 748-755.
27. Ramanathan S, Wong CH, Rahman Z, et al. Myoclonic status epilepticus as a presentation of caspr2 antibody-associated autoimmune encephalitis. Epileptic Disord, 2014, 16(3): 477-481.
28. Hacohen Y, Deiva K, Pettingill P, et al. N-methyl-D-aspartate receptor antibodies in post-herpes simplex virus encephalitis neurological relapse. Mov Disord, 2014, 29(2): 90-96.
29. Mohammad SS, Sinclair K, Pillai S, et al. Herpes simplex encephalitis relapse with chorea is associated with auto antibodies to N-Methyl-Daspartate receptor or dopamine-2 receptor. Mov Disord, 2014, 29(7): 117-122.
30. Hegde M, Lowenstein DH. The search for circulating epilepsy biomarkers. Biomark Med, 2014, 8(2): 413-427.

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儿童癫痫中的神经元抗体：临床特征和未经免疫治疗的历史队列远期预后

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