摘要
人工耳蜗植入(cochlear implantation，CI)是一种治疗和康复重度和极重度感音神经性耳聋的有效方法，我国已开展CI约4000例，但对这部分患者的耳聋病因研究，尤其是分子发病机制的研究尚不系统；各种遗传性致病因素对耳蜗植入疗效的影响也不十分明确。本研究重点是进行CI术前听神经及神经通路完整性的评估；接受CI的患者的耳聋分子发病机制的研究，明确致聋的遗传学病因，对明确诊断的遗传性聋患者及家属进行遗传咨询，减少此类家庭再出现相同的遗传性聋；探讨不同遗传性聋的耳蜗植入疗效，为聋病基因诊断来预测耳蜗植入效果奠定基础；探讨CI并发症的产生原因、处理方法和预后，并规范手术知情同意书。本研究分四部分：
第一部分人工耳蜗植入术前听力学和影像学评估
目的探讨听力学和影像学检查对于确定CI的适应证和禁忌证的意义。方法对1997年3月～2007年1月在我科接受CI手术的262例患者的术前听力学和影像学资料做回顾性分析。听力学检测包括纯音测听或行为测听、声导抗、耳声发射、听性脑干诱发反应闽值、40Hz听觉事件相关电位闽值、听觉稳态反应和鼓岬电刺激；影像学检查包括计算机断层摄影术和磁共振成像。结果246例患者至少一项有听觉反应；16例患者未引出明确听觉反应，无法初步判断听神经及神经通路是否完整。CT和MRI检查发现内耳畸形38例，耳蜗部分纤维化1例，内听道狭窄1例。上述听力学检查无反应的16例中的14例MRI检查提示内听道和听神经结构形态正常。结论CI术前判定听神经及神经通路的完整性是非常必要的，结合听力学与影像学检查资料才能做出较准确的判定，CI的病例选择要注意适应证和禁忌证。
第二部分人工耳蜗植入患者耳聋分子发病机制的研究
目的探讨接受CI的耳聋患者的聋病分子发病机制。方法对接受CI的127例患者进行聋病重点致病基因筛查，GJB2基因、SLC26A4(PDS)基因、线粒体DNAA1555G突变和GJB3基因。应用线粒体DNAA1555G突变试剂盒检测线粒体DNAA1555G突变，SLC26A4(PDs)基因检测先用变性高效液相色谱法筛查，再对可疑峰的行基因序列测序，GJB2基因和GJB3基因采用全基因序列测序。结果127例患者中检测出31例GJB2基因突变，其中1例为新发现突变；有3例mtDNA A 1555G突变；10例大前庭水管综合征(Large vestibular aqueduct syndrome，LVAS)中检测出9例SLC26A4基因突变，突变分布在外显子Exon 7+8、Exon10、Exon19、Exon17、Exon5。IVS7-2 A＞G突变为最常见的SLC26A4突变。GJB3基因检测出4种基因多态；发现1例可疑基因变异719G＞A(R240H)。结论接受CI的患者中约33.9％的为常染色体隐性遗传性耳聋。GJB2基因突变是接受CI人群中耳聋的主要致病因素；其次为SLC26A4基因突变的LVAS和线粒体DNA A1555G突变，GJB3基因突变较少见。
第三部分遗传性聋人工耳蜗植入疗效分析
目的探讨不同遗传性聋(GJB2基因突变、LVAS)患者人工耳蜗植入的效果。方法对不同遗传性聋(GJB2基因突变、LVAS)行人工耳蜗植入的患者进行疗效评估，评价内容包括声场人工耳蜗助听听阈、言语测听、意义听觉整合量表测试、听觉行为分级标准和言语可懂度分级标准。比较GJB2基因突变和LVAS患者疗效与对照组有无差异。结果GJB2基因突变和LVAS患者CI术后人工耳蜗助听听阈平均约30 dB HL，与对照组相同(P＞0.05)。听觉语言康复效果和问卷评价结果提示：各遗传性聋组也与对照组接近(P＞0.05)。结论CI适用于上述常染色体隐性遗传性耳聋的患者，术后听力及语言康复效果满意。
第四部分人工耳蜗植入的并发症和知情同意书填写情况分析
目的探讨CI并发症的产生原因、处理方法和预后。总结CI手术知情同意书填写情况，规范手术知情同意书。方法总结262例接受CI患者的并发症及其处理和预后情况。同时对手术知情同意书的填写内容做回顾性分析，在此基础上设计完整详细的手术知情同意书。结果本组262例CI患者中有49例(18.7％)患者发生不同程度的并发症。严重手术并发症有4例(1.5％)；轻度手术并发症有40例(15.3％)；与人工耳蜗装置相关的并发症11例(4.2％)。所有手术并发症经保守治疗或手术干预，预后良好。11例与人工耳蜗装置相关的并发症，9例患者得到圆满解决，1例植入体取出，1例未处理。262例手术知情同意书均存在填写内容不完整、不规范的问题。结论CI是相对安全的手术，大部分手术并发症为轻度，预后良好。应规范知情同意书的内容和格式。
Cochlear implantation (CD is one of effective method for severe and profound sensory deafness. CI has been used successfully to restore hearing in more than 4000 deafness in China, but there is no systematical study on the etiological factors of these patients, especially on the molecule pathogenesis. Besides, the influence of various hereditary etiological factors on the curative effect of CI is not extremely definite. This study will evaluate the integrity of cochlear nerve and nervous pathway, and investigates the molecule pathogenesis of deafness. At the same time, we offer the hereditary deafness patients and their families the genetic counseling, in order to decrease the cases of hereditary deafness. We discuss the difference of curative effect between different hereditary deafness and control group. Part one: Evaluation of audiology and imageology data of patients before CI
Objective To investigate the effect of preoperative audiology and imageology data in anticipating indication and contraindication of CI. Methods Retrospectively study the preoperative audiology and imageology data of CI recipients in our department. Results Of 246 cases, at least one of Audiological tests has auditory response, but 16 cases do not induce definite auditory response so that can not judge the integrity of the cochlear nerve and nervous pathway .There are 38 cases with inner ear malformation in CT and MRI films. There are one case with inner acoustic meatus narrow and one case with fibrous degeneration partially in Cochlea after trauma. 16 cases have no response to audiological test, and MRI films indicate that configuration of inner acoustic meatus and cochlear nerve is normal in 14 cases. Conclusion We can judge correctly by binding audiological tests with imageology data. Part two: Study of the molecule pathogenesis of deafness in CI recipients
Objective To analyze the molecular pathogenesis of deafness in 127 CI recipients. Methods The molecule pathogenesis of 127 CI recipients from our department was analyzed, including mtDNA A1555G mutation, PDS gene, GJB2 (Cx26) gene and
GJB3 (Cx31) gene for mutations. Results: Among 127 deaf patients, 31 cases were found to have GJB2 mutation. Three patients were found to carry mtDNA A1555G mutation. Among 10 patients with large vestibular aqueduct, 9 cases were found to have mutation. One novel mutation, GJB2 235delC/598G>A was identified in this study. The GJB3 (Cx31) was the only gene without detecting any mutation, but with 4 kinds of polymorphism. Conclusions The first most frequently occurring mutations were found in the Cx26 (31/127, 24.4%).GJB2 gene mutations were the major cause for autosomal recessive non-syndromic hearing impairment (NSHI). Part three: The curative effect of CI in patients with autosomal recessive NSHI.
Objective To analyze the curative effect of CI in patients with autosomal recessive NSHI, including GJB2 (Cx26) gene mutation and large vestibular aqueduct syndrome. Method The evaluations of curative effect include auditory threshold with CI. The postoperative outcomes of these cases with autosomal recessive NSHI were compared patients with negative results of screening of gene mutation (control group). Result The postoperative outcomes of CI with GJB2 (Cx26) gene mutation and LVAS had no significant difference in comparison with control group (P>0.05). Conclusion CI could be performed in the patients with GJB2 (Cx26) gene mutation and LVAS. Postoperative outcomes of hearing and speech in the patients with GJB2 (Cx26) gene mutation and LVAS were satisfied.
PART FOUR: Complications and their management and analysis of contents of informed consent in CI
Objective To study the complications and the management and sequelae of each complication encountered in 262 CI recipients. To study contents of informed consent of 262 CI recipients, and to design a new reasonable informed consent used for CI. Methods Retrospectively study the complications and the contents of informed consent of CI recipients in our department. Results There were 4 major surgical complications (e.g., persistent eardrum perforation, facial paralysis, leakage of cerebrospinal fluid with meningitis). There were 40 minor surgical complications, respectively. These complications were managed with conservative treatment or minor intervention. The 9 of 11 CI device complications have been managed with
revision or reimplantation. While the complications contents in the informed consents of the CI were not complete and normative. Conclusion CI is a relatively safe surgical operation. Most surgical complications are minor and can be treated with conservative treatment or minor surgical intervention. It is very important to choose patients according to the indication of CI. It is very important to normalize the contents and format of CI surgical informed consents.
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2. Cohen NL, Hoffman RA, Stroschein M. Medical or surgical complications related to the Nucleus multichannel cochlear implant [J]. Ann Otol Rhinol Laryngol, 1988, 97: 8-13.
3. Cohen NL, Hoffman RA. Complications of cochlear implant surgery in adults and children [J]. Ann Otol Rhinol Larygol, 1991, 100: 708-711.
4. Gysin C, Papsin BC, Daya H, et al. Surgical outcome after paediatric cochlear implantation: diminution of complications with the evolution of new surgical techniques [J]. J Otolaryngol, 2000, 29: 285-289.
5. Windmill IM, Martinez SA, Nolph MB, et al. Surgical and nonsurgical complications associated with cochlear [J]. Am J otology, 1990, 11(6): 415-420
6. Wootten CT, Backous DD, Haynes DS. Management of cerebrospinal fluid leakage from cochleostomy during cochlear implant surgery [J]. Laryngoscope. 2006, 116(11): 2055-2059.
7．张道行．胡宝华，肖玉丽，等．人工耳蜗植入“井喷”的判断与术中处理的体会[J]．临床耳鼻咽喉科杂志，2006，20(7)：295-296，299．
8. John M, Graham FRCS, Peter MD, et al. Congenital malformations of the ear and cochlear implantation in children: review and emporal bone report of common cavity [J]. J Laryngol Otol, 2000, 114: 1-14.
9. Page EL, Eby TL. Meningitis after cochlear implantation in Mondini malformation [J]. Otolaryngol Head Neck Surg, 1997, 116: 104-106.
10. Mcelveen. Cochlear implantation in common cavity malformations using a transmastoid labyrinthotomy approach [J]. Laryngscope, 1997, 107: 1032.
11. Goin DW, Rasband RW, Mischke RE, et al. Endolymphatic sac surgery in mondini's dysplasia: a report of 16 cases [J]. Laryngoscope, 1984, 94: 343.
12．诸小侬，廉能静，蔡正华，等．内耳先天畸形102例临床分析[J]．中华耳鼻咽喉科杂志，1995，30(3)：157-159．
13．韩东一，武文明，郗昕，等．先天性内耳畸形的人工耳蜗植入[J]．中华耳鼻咽喉科杂志，2004．39(2)：85-88．
14. Valvassori GE. Clemis JD. The large vestibular aqueduct syndrome [J]. Laryngoscope, 1978, 88: 723-728.
15. Jackler PK, De La Cruz A. The large vestibular aqueduct syndrome [J]. Laryngoscope, 1989, 99: 1238-1243.
16．王秋菊，杨伟炎，吴子明，等．X连锁隐性遗传聋哑(deaf2mute)家系的遗传学特征分析．遗传HER EDI TAS (Beijing)2004，26(5)：579-583．
17. de Kok YJ, van der Maarel S M, Bitner Glindzicz M, et al. Association between X-linked mixed deafness and mutationsin the POU domain gene POU3F4 [J]. Science, 1995, 267 (5198): 685～688.
18. Webb RL, Lehnhardt E, Clark GM, et al. Surgical complications with the cochlear multiple-channel intracochlear implant: experience at Hannover and Melbourne [J]. Ann Otol Rhinol Laryngol. 1991; 100(2): 131-136.
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35. Rudnick EF, Chu MW, Sismanis A, Dodson KM, Mitchell RB. Orbital sequelae of rhinosinusitis after cochlear implantation in children [J]. Laryngoscope. 2006; 116(8): 1368-71
36. Gosepath J, Maurer J, Mann WJ. Epidural hematoma after cochlear implantation in a 2.5-year-old boy [J]. Otol Neurotol. 2005; 26(2): 202-204.
37. Cohen NL, Kuzma J. Titanium clip for cochlear implant electrode fixation [J]. Ann Otol Rhinol Laryngol, 1995, 104(9) (Suppl 166): 402-403.