常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病癫痫发作的研究进展_Journal of Epilepsy

Authors：

保建见 , 杨兴隆 , 吴崇民 , 王芳 , 朱永云 ,  任惠

昆明医科大学第一附属医院老年神经内科（昆明 650032）;

Corresponding author：

任惠, Email: rh-3338@163.com

Keywords：

常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病; 癫痫; 遗传性疾病

DOI：

10.7507/2096-0247.20200057

Video：

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常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病（Genetic cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy，CADASIL）是一种中青年期发病的常染色体显性遗传的小动脉病，主要病变基因是位于 19 号染色体上的 NOTCH3 基因，主要临床表现有先兆偏头痛、反复发作的脑缺血事件、血管性痴呆、精神症状以及癫痫，具有较高的致残率、致死率。约 10% 的患者在疾病过程可能会发生癫痫，大部分与脑缺血性事件有关。然而，少部分患者在病程早期即出现癫痫，甚至以癫痫为首发症状，提示其可能与 CADASIL 的发病机制有关。关于 CADASIL 患者的癫痫发作在国内外均有报道，但目前临床医师对其认识不足以及癫痫复杂的病理生理学机制，极大影响了对此病与癫痫发作关系的认识。文章就 CADACIL 患者癫痫发作的研究，包括临床表现、病理学、发病机制、诊断、治疗等作一综述，以期提高临床认识 CADASIL 患者癫痫发作提供参考。

Citation： 保建见, 杨兴隆, 吴崇民, 王芳, 朱永云, 任惠. 常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病癫痫发作的研究进展. Journal of Epilepsy, 2020, 6(4): 350-353. doi: 10.7507/2096-0247.20200057 Copy

1.	王蓓蓓, 石正洪. 常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病诊断的研究进展. 中国全科医学, 2015, 18(30): 3736-3740+3744.
2.	万灿, 尤劲松. 伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病的研究进展. 中风与神经疾病杂志, 2019, 36(04): 367-369.
3.	Sonninen V, Savontaus ML. Hereditary multi-infarct dementia. Eur Neurol, 1987, 27(4): 209-215.
4.	汪志云, 王纪佐, 潘旭东. 脑常染色体显性遗传脑动脉病伴皮质下硬化及脑白质脑病. 天津医药, 2006, 34(5): 346-347.
5.	Coupland K, Lendahl U, Karlström H. Role of NOTCH3 mutations in the cerebral small vessel disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke, 2018, 49(11): 2793-2800.
6.	Wang MM. CADASIL. Handb Clin Neurol, 2018, 148: 733-743.
7.	Di Donato I, Bianchi S, De Stefano N, et al. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects. BMC Med, 2017, 15(1): 41.
8.	Cramer J, White ML. Cerebral autosomal dominant arteriopathy (CADASIL), in StatPearls. StatPearls Publishing, 2020.
9.	Drazyk AM, Tan RYY, Tay J, et al. Encephalopathy in a large cohort of British cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients. Stroke, 2019, 50(2): 283-290.
10.	Chan TLH, Sharma M, Burneo JG. Focal epilepsy secondary to juxtacortical lesions in cerebral autosomal dominant arteriopathy with subacute infarcts and leukoencephalopathy. Can J Neurol Sci, 2018, 45(4): 462-463.
11.	Haddad N, Ikard C, Hiatt K, et al. Recurrent status epilepticus as the primary neurological manifestation of CADASIL: A case report. Epilepsy Behav Case Rep, 2015, 3: 26-29.
12.	Velizarova R, Mourand I, Serafini A, et al. Focal epilepsy as first symptom in CADASIL. Seizure, 2011, 20(6): 502-504.
13.	Valko PO, Siccoli MM, Schiller A, et al. Non-convulsive status epilepticus causing focal neurological deficits in CADASIL. J Neurol Neurosurg Psychiatry, 2007, 78(11): 1287-1289.
14.	Dichgans M, Mayer M, Uttner I, et al. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol, 1998, 44(5): 731-739.
15.	Baudrimont M, Dubas F, Joutel A, et al. Autosomal dominant leukoencephalopathy and subcortical ischemic stroke. A clinicopathological study. Stroke, 1993, 24(1): 122-125.
16.	Chen BS, Cleland J, King RI, et al. CADASIL presenting with focal and generalised epilepsy due to a novel NOTCH3 mutation. Seizure, 2019, 66: 36-38.
17.	Zhu S, Nahas SJ. CADASIL: imaging characteristics and clinical correlation. Curr Pain Headache Rep, 2016, 20(10): 57.
18.	He D, Chen D, Li X, et al. The comparisons of phenotype and genotype between CADASIL and CADASIL-like patients and population-specific evaluation of CADASIL scale in China. J Headache Pain, 2016, 17: 55.
19.	Haan J, Lesnik Oberstein SA, Ferrari MD. Epilepsy in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Cerebrovasc Dis, 2007, 24(2-3): 316-317.
20.	张新庆, 刘伟, 李颜宏, 等. 脑卒中后癫痫与血管性痴呆相关性分析. 中国临床康复, 2002, 6(13): 1932.
21.	张慧如, 陈永明. 卒中后癫痫发作及其发病机制的研究进展. 中国脑血管病杂志, 2020, 17(2): 86-91.
22.	Lénárt N, Brough D, Dénes Á. Inflammasomes link vascular disease with neuroinflammation and brain disorders. J Cereb Blood Flow Metab, 2016, 36(10): 1668-1685.
23.	Paudel YN, Shaikh MF, Shah S, et al. Role of inflammation in epilepsy and neurobehavioral comorbidities: Implication for therapy. Eur J Pharmacol, 2018, 837: 145-155.
24.	Rana A, Musto AE. The role of inflammation in the development of epilepsy. J Neuroinflammation, 2018, 15(1): 144.
25.	Emsley HCA, Parkes LM. Seizures in the context of occult cerebrovascular disease. Epilepsy Behav, 2020, 104(Pt B): 106396.
26.	Lee J, Sohn EH, Oh E, et al. Characteristics of Cerebral Microbleeds. Dement Neurocogn Disord, 2018, 17(3): 73-82.
27.	方圆, 陈文武. 脑出血与癫痫. 河南大学学报(医学版), 2016, 35(03): 153-156.
28.	Malandrini A, Carrera P, Ciacci G, et al. Unusual clinical features and early brain MRI lesions in a family with cerebral autosomal dominant arteriopathy. Neurology, 1997, 48(5): 1200-1203.
29.	Vigdorovich N, Ben-Sira L, Blumkin L, et al. Brain white matter abnormalities associated with copy number variants. Am J Med Genet A, 2020, 182(1): 93-103.
30.	Sokic DV, Stojsavljevic N, Drulovic J, et al. Seizures in multiple sclerosis. Epilepsia, 2001, 42(1): 72-79.
31.	Atmaca MM, Gurses C. Status epilepticus and multiple sclerosis: A case presentation and literature review. Clin EEG Neurosci, 2018, 49(5): 328-334.
32.	Mayer SA, Tatemichi TK, Hair LS, et al. Hemineglect and seizures in Binswanger's disease: clinical-pathological report. J Neurol Neurosurg Psychiatry, 1993, 56(7): 816-819.
33.	Yang GS, Zhou XY, An XF, et al. Mild hypothermia inhibits the Notch 3 and Notch 4 activation and seizure after stroke in the rat model. Pathol Res Pract, 2018, 214(7): 1008-1016.
34.	Dziewulska D, Sulejczak D, Wężyk M. What factors determine phenotype of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)? Considerations in the context of a novel pathogenic R110C mutation in the NOTCH3 gene. Folia Neuropathol, 2017, 55(4): 295-300.
35.	Sha L, Wu X, Yao Y, et al. Notch signaling activation promotes seizure activity in temporal lobe epilepsy. Mol Neurobiol, 2014, 49(2): 633-644.
36.	Kim KC, Lee DK, Go HS, et al. Pax6-dependent cortical glutamatergic neuronal differentiation regulates autism-like behavior in prenatally valproic acid-exposed rat offspring. Mol Neurobiol, 2014, 49(1): 512-528.
37.	Imfeld P, Bodmer M, Schuerch M, et al. Seizures in patients with Alzheimer's disease or vascular dementia: a population-based nested case-control analysis. Epilepsia, 2013, 54(4): 700-707.
38.	程小华, 吴乐霞. 老年人迟发性癫痫发作 53 例临床分析. 中国临床保健杂志, 2005, 8(2): 133-134.
39.	Mancuso M, Arnold M, Bersano A, et al. Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology. Eur J Neurol, 2020, [Epub ahead of print].
40.	Martikainen MH, Roine S. Rapid improvement of a complex migrainous episode with sodium valproate in a patient with CADASIL. J Headache Pain, 2012, 13(1): 95-97.
41.	Wang J, Li J, Kong F, et al. Bipolar II disorder as the initial presentation of CADASIL: an underdiagnosed manifestation. Neuropsychiatr Dis Treat, 2017, 13: 2175-2179.
42.	Pedroso I, Lourdusamy A, Rietschel M, et al. Common genetic variants and gene-expression changes associated with bipolar disorder are over-represented in brain signaling pathway genes. Biol Psychiatry, 2012, 72(4): 311-317.

1. 王蓓蓓, 石正洪. 常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病诊断的研究进展. 中国全科医学, 2015, 18(30): 3736-3740+3744.
2. 万灿, 尤劲松. 伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病的研究进展. 中风与神经疾病杂志, 2019, 36(04): 367-369.
3. Sonninen V, Savontaus ML. Hereditary multi-infarct dementia. Eur Neurol, 1987, 27(4): 209-215.
4. 汪志云, 王纪佐, 潘旭东. 脑常染色体显性遗传脑动脉病伴皮质下硬化及脑白质脑病. 天津医药, 2006, 34(5): 346-347.
5. Coupland K, Lendahl U, Karlström H. Role of NOTCH3 mutations in the cerebral small vessel disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke, 2018, 49(11): 2793-2800.
6. Wang MM. CADASIL. Handb Clin Neurol, 2018, 148: 733-743.
7. Di Donato I, Bianchi S, De Stefano N, et al. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects. BMC Med, 2017, 15(1): 41.
8. Cramer J, White ML. Cerebral autosomal dominant arteriopathy (CADASIL), in StatPearls. StatPearls Publishing, 2020.
9. Drazyk AM, Tan RYY, Tay J, et al. Encephalopathy in a large cohort of British cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients. Stroke, 2019, 50(2): 283-290.
10. Chan TLH, Sharma M, Burneo JG. Focal epilepsy secondary to juxtacortical lesions in cerebral autosomal dominant arteriopathy with subacute infarcts and leukoencephalopathy. Can J Neurol Sci, 2018, 45(4): 462-463.
11. Haddad N, Ikard C, Hiatt K, et al. Recurrent status epilepticus as the primary neurological manifestation of CADASIL: A case report. Epilepsy Behav Case Rep, 2015, 3: 26-29.
12. Velizarova R, Mourand I, Serafini A, et al. Focal epilepsy as first symptom in CADASIL. Seizure, 2011, 20(6): 502-504.
13. Valko PO, Siccoli MM, Schiller A, et al. Non-convulsive status epilepticus causing focal neurological deficits in CADASIL. J Neurol Neurosurg Psychiatry, 2007, 78(11): 1287-1289.
14. Dichgans M, Mayer M, Uttner I, et al. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol, 1998, 44(5): 731-739.
15. Baudrimont M, Dubas F, Joutel A, et al. Autosomal dominant leukoencephalopathy and subcortical ischemic stroke. A clinicopathological study. Stroke, 1993, 24(1): 122-125.
16. Chen BS, Cleland J, King RI, et al. CADASIL presenting with focal and generalised epilepsy due to a novel NOTCH3 mutation. Seizure, 2019, 66: 36-38.
17. Zhu S, Nahas SJ. CADASIL: imaging characteristics and clinical correlation. Curr Pain Headache Rep, 2016, 20(10): 57.
18. He D, Chen D, Li X, et al. The comparisons of phenotype and genotype between CADASIL and CADASIL-like patients and population-specific evaluation of CADASIL scale in China. J Headache Pain, 2016, 17: 55.
19. Haan J, Lesnik Oberstein SA, Ferrari MD. Epilepsy in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Cerebrovasc Dis, 2007, 24(2-3): 316-317.
20. 张新庆, 刘伟, 李颜宏, 等. 脑卒中后癫痫与血管性痴呆相关性分析. 中国临床康复, 2002, 6(13): 1932.
21. 张慧如, 陈永明. 卒中后癫痫发作及其发病机制的研究进展. 中国脑血管病杂志, 2020, 17(2): 86-91.
22. Lénárt N, Brough D, Dénes Á. Inflammasomes link vascular disease with neuroinflammation and brain disorders. J Cereb Blood Flow Metab, 2016, 36(10): 1668-1685.
23. Paudel YN, Shaikh MF, Shah S, et al. Role of inflammation in epilepsy and neurobehavioral comorbidities: Implication for therapy. Eur J Pharmacol, 2018, 837: 145-155.
24. Rana A, Musto AE. The role of inflammation in the development of epilepsy. J Neuroinflammation, 2018, 15(1): 144.
25. Emsley HCA, Parkes LM. Seizures in the context of occult cerebrovascular disease. Epilepsy Behav, 2020, 104(Pt B): 106396.
26. Lee J, Sohn EH, Oh E, et al. Characteristics of Cerebral Microbleeds. Dement Neurocogn Disord, 2018, 17(3): 73-82.
27. 方圆, 陈文武. 脑出血与癫痫. 河南大学学报(医学版), 2016, 35(03): 153-156.
28. Malandrini A, Carrera P, Ciacci G, et al. Unusual clinical features and early brain MRI lesions in a family with cerebral autosomal dominant arteriopathy. Neurology, 1997, 48(5): 1200-1203.
29. Vigdorovich N, Ben-Sira L, Blumkin L, et al. Brain white matter abnormalities associated with copy number variants. Am J Med Genet A, 2020, 182(1): 93-103.
30. Sokic DV, Stojsavljevic N, Drulovic J, et al. Seizures in multiple sclerosis. Epilepsia, 2001, 42(1): 72-79.
31. Atmaca MM, Gurses C. Status epilepticus and multiple sclerosis: A case presentation and literature review. Clin EEG Neurosci, 2018, 49(5): 328-334.
32. Mayer SA, Tatemichi TK, Hair LS, et al. Hemineglect and seizures in Binswanger's disease: clinical-pathological report. J Neurol Neurosurg Psychiatry, 1993, 56(7): 816-819.
33. Yang GS, Zhou XY, An XF, et al. Mild hypothermia inhibits the Notch 3 and Notch 4 activation and seizure after stroke in the rat model. Pathol Res Pract, 2018, 214(7): 1008-1016.
34. Dziewulska D, Sulejczak D, Wężyk M. What factors determine phenotype of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)? Considerations in the context of a novel pathogenic R110C mutation in the NOTCH3 gene. Folia Neuropathol, 2017, 55(4): 295-300.
35. Sha L, Wu X, Yao Y, et al. Notch signaling activation promotes seizure activity in temporal lobe epilepsy. Mol Neurobiol, 2014, 49(2): 633-644.
36. Kim KC, Lee DK, Go HS, et al. Pax6-dependent cortical glutamatergic neuronal differentiation regulates autism-like behavior in prenatally valproic acid-exposed rat offspring. Mol Neurobiol, 2014, 49(1): 512-528.
37. Imfeld P, Bodmer M, Schuerch M, et al. Seizures in patients with Alzheimer's disease or vascular dementia: a population-based nested case-control analysis. Epilepsia, 2013, 54(4): 700-707.
38. 程小华, 吴乐霞. 老年人迟发性癫痫发作 53 例临床分析. 中国临床保健杂志, 2005, 8(2): 133-134.
39. Mancuso M, Arnold M, Bersano A, et al. Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology. Eur J Neurol, 2020, [Epub ahead of print].
40. Martikainen MH, Roine S. Rapid improvement of a complex migrainous episode with sodium valproate in a patient with CADASIL. J Headache Pain, 2012, 13(1): 95-97.
41. Wang J, Li J, Kong F, et al. Bipolar II disorder as the initial presentation of CADASIL: an underdiagnosed manifestation. Neuropsychiatr Dis Treat, 2017, 13: 2175-2179.
42. Pedroso I, Lourdusamy A, Rietschel M, et al. Common genetic variants and gene-expression changes associated with bipolar disorder are over-represented in brain signaling pathway genes. Biol Psychiatry, 2012, 72(4): 311-317.

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常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病癫痫发作的研究进展

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