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名古屋大学博士学位論文 学位の種類 : 博士(医学)(課程) 学位授与年月日:平成22年9月28日 山崎雅弘氏の博士論文として提出された

Following vestibular schwannoma excision, a subset of cases has been reported in which hearing is present immediately after surgery, but is lost in the early postoperative period. Such cases have rarely been reported, and the postoperative audiological data collected from patients in these cases lacks the time resolution necessary to determine the pathophysiological mechanism responsible for the pattern of hearing loss. The present study aimed to more clearly define delayed hearing loss by collecting detailed data documenting changes in behavioural and electrophysiological auditory responses following vestibular schwannoma surgery. In particular, we aimed to use this data to determine the time course of changes in auditory function and to identify whether the site of impairment was cochlear or neural. Preoperative and daily postoperative monitoring of auditory function was performed in 19 patients undergoing vestibular schwannoma excision via the retrosigmoid approach at Christchurch Public Hospital. The pre- and postoperative assessment battery included pure-tone and speech audiometry, tympanometry, tone decay, distortion product otoacoustic emissions (DPOAEs), and auditory brainstem response (ABR) measurement. Intraoperative ABR was performed in four cases in which clear preoperative waveforms were present. Transtympanic electrocochleography (ECochG) was carried out if wave I was lost in the early postoperative period. Thirteen of the 19 patients suffered immediate anacusis following surgery and six had measurable hearing postoperatively. The behavioural and electrophysiological data collected in each case is discussed with regard to the likely pathophysiology of pre- and postoperative hearing loss. No patients demonstrated behavioural evidence of delayed hearing loss, however a gradual deterioration of ABR in the early postoperative period was observed in Case 16. ECochG and DPOAEs in this case indicated the presence of cochlear function although the patient presented with immediate postoperative anacusis in the ipsilateral ear. These results are consistent with postoperative retrograde degeneration of the cochlear nerve.

Following vestibular schwannoma excision, a subset of cases has been reported in which hearing is present immediately after surgery, but is lost in the early postoperative period. Such cases have rarely been reported, and the postoperative audiological data collected from patients in these cases lacks the time resolution necessary to determine the pathophysiological mechanism responsible for the pattern of hearing loss. The present study aimed to more clearly define delayed hearing loss by collecting detailed data documenting changes in behavioural and electrophysiological auditory responses following vestibular schwannoma surgery. In particular, we aimed to use this data to determine the time course of changes in auditory function and to identify whether the site of impairment was cochlear or neural. Preoperative and daily postoperative monitoring of auditory function was performed in 19 patients undergoing vestibular schwannoma excision via the retrosigmoid approach at Christchurch Public Hospital. The pre- and postoperative assessment battery included pure-tone and speech audiometry, tympanometry, tone decay, distortion product otoacoustic emissions (DPOAEs), and auditory brainstem response (ABR) measurement. Intraoperative ABR was performed in four cases in which clear preoperative waveforms were present. Transtympanic electrocochleography (ECochG) was carried out if wave I was lost in the early postoperative period. Thirteen of the 19 patients suffered immediate anacusis following surgery and six had measurable hearing postoperatively. The behavioural and electrophysiological data collected in each case is discussed with regard to the likely pathophysiology of pre- and postoperative hearing loss. No patients demonstrated behavioural evidence of delayed hearing loss, however a gradual deterioration of ABR in the early postoperative period was observed in Case 16. ECochG and DPOAEs in this case indicated the presence of cochlear function although the patient presented with immediate postoperative anacusis in the ipsilateral ear. These results are consistent with postoperative retrograde degeneration of the cochlear nerve.

PURPOSE: To develop an algorithm in order to establish a consensus on how oculomotor nerve schwannomas should be treated by reviewing results from reported cases in the literature. Given the rarity of oculomotor nerve schwannomas, there is no agreed upon criteria for when a surgical or a nonsurgical intervention would be indicated. By reviewing former cases of oculomotor nerve schwannomas, our study proposes a flowchart for physicians to follow for optimal management. METHODS: The review of reported oculomotor nerve schwannoma cases involved 51 cases. From the 51 cases, data was tabulated including age, patient symptoms, symptom duration, tumor size, tumor location, treatment, post operative results, and follow up time. The cases were then divided in to surgical subgroup and a nonsurgical subgroup. Each case was also grouped based on post operative oculomotor function into improved, no change, and worsened groups. Our collaboration with Tufts Medical center also yielded 4 unreported cases of oculomotor nerve schwannoma that are described and compared to the previous 51 cases from the literature review. RESULTS: The review of the 51 reported cases yielded a few statistically significance differences between the surgical and nonsurgical subgroups. The surgical subgroup was older with a mean age of 35 years than the nonsurgical subgroup with a mean age of 15.8 years. The surgical group also had larger tumors with a mean tumor diameter of 29.5 mm versus the nonsurgical subgroup's 4.5 mm mean tumor diameter. The surgical subgroup also experienced shorter symptom durations as well. The mean duration of symptoms in the surgical subgroup was 17.8 months versus the 140 month mean symptom duration for the nonsurgical cases. Finally, the majority of surgically treated cases experienced a worsening of residual oculomotor function (20/38), while the majority of nonsurgically treated cases experienced little to no change in oculomotor function (11/13). CONCLUSION: Given the high likelihood of complete third nerve palsy after surgery, this study advocates a conservative approach to oculomotor nerve schwannomas that do not present with any life threatening symptoms or acutely deteriorating symptoms. The cases that are presented in this study also corroborate previous studies' findings on the efficacy of stereotactic radiosurgery in managing schwannoma size without resorting to more invasive interventions.

Os tumores extra-axias do sistema nervoso são de localização extra-cerebral e na maioria das vezes benignos; meningiomas, schwanomas e metástases fazem parte deste grupo. O aparecimento de um tumor ocorre a partir do acúmulo de alterações genéticas e epigenéticas nas células. Para entender o mecanismo molecular da progressão tumoral e a formação de metástases é indispensável identificar os genes que acumulam essas alterações. Sendo assim, este trabalho teve como objetivo analisar o perfil de metilação dos genes TP16, TP53, DAL-1, GSTP-1, MEN-1, NDRG2 e das DNA metiltransferases 3A, 3B e 3L e sua associação com os tumores extra-axiais e ainda, avaliar, através de um estudo caso-controle, a influência dos SNPs TP53 Pro47Ser e Arg72Pro, EGF + 61, GSTP-1 Ile105Val e WRN Cys1367Arg no desenvolvimento e prognóstico desses tumores. A técnica utilizada para a análise de hipermetilação foi a MSP, e através dela observamos que a atividade das DNMTs não está associada à metilação dos tumores extra-axiais e ainda, os perfis de metilação das DNMTs de novo não estão associados com alterações no padrão de metilação dos genes TP16, TP53, DAL-1, GSTP-1, MEN- 1 e NDRG2. Observamos que a metilação do gene TP53 está associada principalmente aos tumores de maior grau de malignidade, a uma deficiência na resposta a tratamentos e, conseqüentemente, a um maior número de óbitos. A metilação do gene TP16 está envolvida mais freqüentemente na formação de schwanomas e a de NDRG2 na progressão dos meningiomas. A análise de polimorfismos foi realizada através da técnica de PCR-RFLP e observamos diferenças nas distribuições genotípicas entre pacientes e controles nos SNPs TP53 Pro47Ser e Arg72Pro, EGF + 61 e GSTP-1 Ile105Val, onde as variantes Ser47, Pro72, EGF G61 e Val105 foram observadas com maior freqüência entre os portadores de tumores extra-axiais. Dessa forma, estas variantes podem ser fatores de susceptibilidade para o desenvolvimento dos tumores. / The extra-axial brain tumors have extra-brain localization and in most of the time they are benign, meningiomas, schwannomas and metastasis are included in this group. The appearance of a tumor occurs because of the accumulation of genetic and epigenetic alterations in the cells. In order to understand the molecular mechanism of the tumor progression and the metastasis formation it is important to identify the genes that accumulate the alterations. Thereby, the objective of this study was to analyze the methylation profile of the genes TP16, TP53, DAL-1, GSTP-1, MEN-1, NDRG2 and the DNA methyltransferases 3A, 3B and 3L and their association with the extra-axial brain tumors. Another purpose was to determine, in a case-control study, the roles of the TP53 Pro47Ser and Arg72Pro, EGF + 61, GSTP-1 Ile105Val and WRN Cys1367Arg SNPs in the development and prognosis of these tumors. We used the MSP to screen the hypermethylation profile and we observed no association between the DNMTs activity and the hypermethylation of the tumors. We also did not find association between the methylation of the DNMTs de novo and alterations in the methylation profile of the genes TP16, TP53, DAL-1, GSTP-1, MEN-1 and NDRG2. We observed that TP53 hypermethylation was associated with the high grade tumors, a poor response to the treatments and, consequently, the high number of obits. The TP16 methylation was involved with the shwannomas formation and the NDRG2 gene was involved in the meningiomas progression. For the polymorphism analysis, we used the PCR-RFLP technique and we observed differences in the genotype distributions between cases and controls of TP53 Pro47Ser and Arg72Pro, EGF + 61 and GSTP-1 Ile105Val SNPs, where the variants Ser47, Pro72, EGF G61 and Val105 were more frequent in patients than in controls. Thus, these variants can be important factors of susceptibility to the tumor development.

In retrospektiv angelegten Untersuchungen soll der Einfluss unterschiedlicher Operationsstrategien auf die Morbidität bei der Behandlung des Akustikusneurinoms aufgezeigt werden. In einer ersten Untersuchung wurde der Einfluss eines doppelten Verschlusses der Dura mater nach subokzipitaler Kraniotomie zur mikrochirurgischen Exstirpation eines Akustikusneurinoms im Hinblick auf die Vermeidung einer Liquorfistel analysiert. Hier wurden zwei Patientengruppen miteinander verglichen. Zum einen Patienten mit einem einfachen Duraverschluss, Duranaht plus alloplastisches Material epidural. Zum anderen Patienten mit einem doppelten Duraverschluss. Hier epidurales und subdurales alloplastisches Material plus Duranaht. Untersucht wurden das Auftreten von Liquorfisteln sowie die Häufigkeit von Wundheilungsstörungen. Es konnte keine signifikante Überlegenheit einer Operationstechnik zur Vermeidung von postoperativen Liquorfisteln gezeigt werden. In einer zweiten Untersuchung wurde der Zusammenhang einer inkompletten Resektion des Tumors (Belassen eines Kapselrestes) mit dem Ziel der Schonung des Nervus facialis untersucht. Hierzu wurden die postoperative Facialisfunktion sowie ein möglicherweise erhöhtes Rezidivrisiko im Verlauf betrachtet. Die postoperative Funktion des N. facialis wurde zwischen den Patientengruppen mit Kapselrest (inkomplette Entfernung) und ohne Kapselrest (komplette Entfernung) verglichen. Es zeigte sich bei vergleichbarer postoperativer Facialisfunktion kein signifikanter Unterschied im Auftreten von Rezidiven nach inkompletter Resektion. Nur gut ein Drittel der inkomplett resezierten Tumore zeigten im Nachbeobachtungszeitraum (im Mittel 52 Monate) überhaupt ein Wachstum.

Indiana University-Purdue University Indianapolis (IUPUI) / Neurofibromatosis type 2 (NF2) is an autosomal dominant cancer predisposition in which loss of heterozygosity at the NF2 gene locus leads to the development of tumors of neural crest derived origin, most commonly bilateral vestibular schwannomas. There are currently no FDA approved chemotherapeutic agents for treatment in patients with NF2. Development of therapeutic agents has been hampered by our incomplete knowledge of how Merlin, the protein product of the NF2 gene, functions as a tumor suppressor. In order develop a deeper understanding for how loss of Merlin leads to oncogenic transformation in Schwann cells we have developed a genetically engineered mouse model (GEMM) of Neurofibromatosis Type 2 in which functional expression of Merlin is lost in Schwann cell precursors. In parallel studies utilizing these mice, we have sought to understand the pathophysiology driving tumor formation in Merlin deficient Schwann cells. In Chapter 1, we explore the role of Merlin as a negative regulator of the Group A p21 activated kinases, PAK1 and PAK2. We demonstrate that PAK1, a previously well established oncogene in solid tumors and Merlin binding partner, is hyperactivated in Merlin deficient schwannomas. Through therapeutic interventions and genetic manipulations we demonstrate that inhibition of PAK1 was capable of reducing tumor formation and alleviating sensorineural hearing loss in our NF2 GEMM. In Chapter 2, we investigate the role of NF-kB inducing kinase (NIK) and NF-kB signaling in the formation and growth of Merlin deficient Schwann cell tumors. Prior work in our lab as well as by others demonstrated elevated NF-kB signaling in Merlin deficient Schwann cell tumors. We observed accumulation of a catalytically active fragment of NF-kB inducing kinase and present data that accumulation of a 55Kd constitutively active fragment of NIK is sufficient trigger wild type Schwann cells to form tumors. In vivo however, Schwann cell intrinsic expression of NIK is not required for tumor formation or growth. / 2 years (2021-05-24)

Background: The use of intraoperative neurophysiological monitoring, including direct nerve stimulation (especially the facial nerve), acoustic evoked potentials (AEP) and somatosensory evoked potentials (SSEP), is a helpful tool in the microsurgery of vestibular schwannoma to prevent nerve injury. Patient characteristics and intraoperative and postoperative variables might also influence the postoperative facial nerve function. The study was performed to investigate these variables and the intraoperative neurophysiological monitoring values. Methods: Seventy-nine patients with vestibular schwannoma were included consecutively into this study. Intraoperative neurophysiological monitoring, including SSEP, AEP, and direct nerve stimulation for facial and trigeminal nerve electromyography, was performed utilizing digital data storage in all cases. The intensity (in volts) of the direct stimulation and the latency (in ms) for the orbicularis oculi and the orbicularis oris muscle and the amplitude (in mV) was measured. Univariate and multivariate statistical analyses concerning the different parameters was performed directly after the operation and in the subsequent follow-ups 3 and 6 months after the operation. Results: The mean intensity was 0.79 V (SD.29). The latency and amplitude for the oris muscle was 5.2ms (SD 2.07) and 0.68mV (SD.57), respectively. The mean latency for the occuli muscle was 5.58ms (SD 2.2) and the amplitude was 0.58mV (SD 1.04). The univariate and multivariate statistical analyses showed significance concerning the postoperative facial nerve function and the amplitude of the direct stimulation of the facial nerve in the orbicularis oris muscle (p = 0.03), so repeated direct nerve stimulation might show FN function deterioration. The mean diameter of the tumors was 24mm (range 10–57mm). Cross total resection and near total was achieved in 76 patients (96%) and subtotal in three patients (4%). The preoperative House–Brakeman score (HBS) 1 was constant in 65 (82%) cases. The mortality in our series was 0%; the overall morbidity was 10%. The HBS was not influenced concerning the extent of resection. The mean follow-up was 28 months (range 6 to 60 months). The limitations of the study might be a low number of patients and the retrospective character of the study. Conclusion: Intraoperative neurophysiological monitoring is crucial in vestibular schwannoma surgery. Repeated direct nerve stimulation and a detected decreased amplitude might show facial nerve function deterioration.

The aim of this diploma thesis is to evaluate spatial orientation in the patients after vestibular schwannoma surgery. In the theoretical part, there are summarized the facts about vestibular system; there is described the clinical picture of unilateral vestibular dysfunction and the field of vestibular schwannoma and spatial orientation in general. In the practical part, we performed the investigation of the spatial orientation using the Blue Velvet Arena System and posturography using the platform Balance Master® System. The purpose of the practical part was to find out, whether unilateral vestibular dysfunction in patients after vestibular schwannoma surgery has the impact on spatial orientation and to what extent is the postural stability influenced in patients identified for surgery and in patients after vestibular schwannoma surgery. Powered by TCPDF (www.tcpdf.org)