OBJECTIVE: To report on a rare case of Neurofibromatosis type 2 (NF2) manifesting as oculomotor nerve palsy and explore its genetic basis. METHODS: A patient with NF2 who had presented at Beijing Ditan Hospital Affiliated to Capital Medical University on July 10, 2021 was selected as the study subject. Cranial and spinal cord magnetic resonance imaging (MRI) was carried out on the patient and his parents. Peripheral blood samples were collected and subjected to whole exome sequencing. Candidate variant was verified by Sanger sequencing. RESULTS: MRI revealed bilateral vestibular Schwannomas, bilateral cavernous sinus meningiomas, popliteal neurogenic tumors, and multiple subcutaneous nodules in the patient. DNA sequencing revealed that he has harbored a de novo nonsense variant of the NF2 gene, namely c.757A>T, which has replaced a codon (AAG) encoding lysine (K) at position 253 with a stop codon (TAG). This has resulted in removal of the Merlin protein encoded by the NF2 gene from position 253 onwards. The variant was not found in public databases. Bioinformatic analysis suggested that the corresponding amino acid is highly conserved. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as pathogenic (PVS1+PS2+PM2_Supporting+PP3+PP4). CONCLUSION The heterozygous nonsense variant c.757A>T (p.K253*) of the NF2 gene probably underlay the disease in this patient with an early onset, atypical but severe phenotype.
Male ; Humans ; Neurofibromatosis 2/genetics* ; Genes, Neurofibromatosis 2 ; Oculomotor Nerve Diseases/genetics* ; Computational Biology ; Genomics ; Mutation

Objective: To explore the value of electrically evoked auditory brainstem response (EABR) monitoring combined with brainstem auditory evoked potential (BAEP) and compound action potential (CAP) monitoring during vestibular schwannoma resection for the protection of the cochlear nerve. Methods: Clinical data from 12 patients with vestibular schwannomas who had useful hearing prior to surgery were analyzed at the PLA General Hospital from January to December 2021. Among them, there were 7 males and 5 females, ranging in age from 25 to 59 years. Before surgery, patients underwent audiology assessments (including pure tone audiometry, speech recognition rate, etc.), facial nerve function evaluation, and cranial MRI. They then underwent vestibular schwannoma resection via the retrosigmoid approach. EABR, BAEP, and CAP were simultaneously monitored during surgery, and patients' hearing preservation was observed and analyzed after surgery. Results: Prior to surgery, the average PTA threshold of the 12 patients ranged from11 to 49 dBHL, with a SDS of 80% to 100%. Six patients had grade A hearing, and six patients had grade B hearing. All 12 patients had House-Brackman grade I facial nerve function prior to surgery. The MRI indicated tumor diameters between 1.1 and 2.4 cm. Complete removal was achieved in 10/12 patients, while near-total removal was achieved in 2/12 patients. There were no serious complications at the one-month follow-up after surgery. At the three-month follow-up, all 12 patients had House-Brackman grade I or II facial nerve function. Under EABR with CAP and BAEP monitoring, successful preservation of the cochlear nerve was achieved in six of ten patients (2 with grade B hearing, 3 with grade C hearing, and 1 with grade D hearing). Successful preservation of the cochlear nerve was not achieved in another four patients (all with grade D hearing). In two patients, EABR monitoring was unsuccessful due to interference signals; however, Grade C or higher hearing was successfully preserved under BAEP and CAP monitoring. Conclusion: The application of EABR monitoring combined with BAEP and CAP monitoring during vestibular schwannoma resection can help improve postoperative preservation of the cochlear nerve and hearing.
Male ; Female ; Humans ; Adult ; Middle Aged ; Neuroma, Acoustic/complications* ; Hearing/physiology* ; Evoked Potentials, Auditory, Brain Stem/physiology* ; Cochlear Nerve ; Hearing Loss, Sensorineural/etiology* ; Retrospective Studies ; Postoperative Complications/prevention & control*

OBJECTIVE: To explore the biomarkers of tinnitus in vestibular schwannoma patients using electroencephalographic (EEG) microstate technology. METHODS: The EEG and clinical data of 41 patients with vestibular schwannoma were collected. All the patients were evaluated by SAS, SDS, THI and VAS scales. The EEG acquisition time was 10-15 min, and the EEG data were preprocessed and analyzed using MATLAB and EEGLAB software package. RESULTS: Of the 41 patients with vestibular schwannoma, 29 patients had tinnitus and 12 did not have tinnitus, and their clinical parameters were comparable. The average global explanation variances of the non-tinnitus and tinnitus groups were 78.8% and 80.1%, respectively. The results of EEG microstate analysis showed that compared with those without tinnitus, the patients with tinnitus had an increased frequency (P=0.033) and contribution (P=0.028) of microstate C. Correlation analysis showed that THI scale scores of the patients were negatively correlated with the duration of microstate A (R=-0.435, P=0.018) and positively with the frequencies of microstate B (R=0.456, P=0.013) and microstate C (R=0.412, P=0.026). Syntax analysis showed that the probability of transition from microstate C to microstate B increased significantly in vestibular schwannoma patients with tinnitus (P=0.031). CONCLUSION EEG microstate features differ significantly between vestibular schwannoma patients with and without tinnitus. This abnormality in patients with tinnitus may reflect the potential abnormality in the allocation of neural resources and the transition of brain functional activity.
Humans ; Neuroma, Acoustic/complications* ; Electroencephalography ; Patients ; Probability

Objective: To investigate the application of cochlear nerve action potential (CNAP) monitoring in the resection of vestibular schwannoma, especially evaluating its significance for hearing preservation. Methods: From April 2018 to December 2021, 54 patients with vestibular schwannoma who underwent resection via retrosigmoid approach were collected in Chinese PLA General Hospital. Before surgery, all patients had effective hearing (AAO-HNS grade C or above). Brainstem auditory evoked potential (BAEP) combined with CNAP monitoring was performed during surgery. The CNAP monitoring was combined with continuous monitoring and cochlear nerve mapping. And patients were divided into hearing preservation group and non-preserved group according to postoperative AAO-HNS grade. SPSS 23.0 software was used to analyze the differences of CNAP and BEAP parameters between the two groups. Results: A total of 54 patients completed intraoperative monitoring and data collection, including 25 males (46.3%) and 29 females (53.7%), aged 27-71 years with an average age of 46.2 years. The maximum tumor diameter were (18.1±5.9) mm (range 10-34 mm). All tumors were totally removed with preserved facial nerve function (House-Brackmann grade I-II). The hearing preservation rate of 54 patients was 51.9% (28/54). During surgery, the V wave extraction rate of BAEP waveform was 85.2% (46/54) before tumor resection, 71.4% (20/28) in the hearing preservation group after tumor resection, and disappeared in the hearing preservation group (0/26). CNAP waveform was elicited in 54 patients during operation. Differences were found in the distribution of CNAP waveforms after tumor resection. The waveforms of the hearing-preserving group were triphasic and biphasic, while those in the non-preserving group were low-level and positive. For hearing preservation group, the amplitude of N1 wave after tumor resection was significantly higher than that before tumor resection[14.45(7.54, 33.85)μV vs 9.13(4.88, 23.35)μV, P=0.022]; However, for the non-preserved group, the amplitude of N1 wave after tumor resection was significantly lower than that before tumor resection [3.07(1.96, 4.60)μV vs 6.55(4.54, 9.71)μV, P=0.007]; After tumor resection, the amplitude was significantly higher than that of the unreserved group [14.45(7.54, 33.85)μV vs 3.07(1.96, 4.60)μV, P<0.001]. Conclusions: BAEP combined with CNAP monitoring is conducive to intraoperative hearing protection, and the application of cochlear nerve mapping can prompt the surgeon to avoid nerve injury. The waveform and N1 amplitude of CNAP after tumor resection have a certain value in predicting postoperative hearing preservation status.
Female ; Male ; Humans ; Middle Aged ; Neuroma, Acoustic/surgery* ; Action Potentials ; Evoked Potentials, Auditory, Brain Stem ; Cochlea ; Cochlear Nerve

Cochlear Implantation ; Genes, Neurofibromatosis 2 ; Humans ; Neurofibromatosis 2/surgery* ; Neuroma, Acoustic/surgery* ; Sequence Deletion

BACKGROUND: We previously reported the frequent neurofibromatosis 2 (NF2) gene mutations in anaplastic thyroid cancers in association with the BRAF V600E mutation. We aimed to investigate the role of NF2 in thyroid cancer with BRAF mutation. METHODS: To identify the function of NF2 in thyroid cancers, we investigated the changes in cell proliferation, colon formation, migration and invasion of thyroid cancer cells (8505C, BHT101, and KTC-1) with BRAF V600E mutation after overexpression and knock-down of NF2. We also examined how cell proliferation changed when NF2 was mutagenized. Human NF2 expression in papillary thyroid carcinoma (PTC) was analyzed using the The Cancer Genome Atlas (TCGA) data. RESULTS: First, NF2 was overexpressed in 8505C and KTC-1 cells. Compared to control, NF2 overexpressed group of both thyroid cancer cells showed significant inhibition in cell proliferation and colony formation. These results were also confirmed by cell migration and invasion assay. After knock-down of NF2 in 8505C cells, there were no significant changes in cell proliferation and colony formation, compared with the control group. However, after mutagenized S288* and Q470* sites of NF2 gene, the cell proliferation increased compared to NF2 overexpression group. In the analysis of TCGA data, the mRNA expression of NF2 was significantly decreased in PTCs with lateral cervical lymph node (LN) metastasis compared with PTCs without LN metastasis. CONCLUSION: Our study suggests that NF2 might play a role as a tumor suppressor in thyroid cancer with BRAF mutation. More studies are needed to elucidate the mechanism how NF2 acts in thyroid cancer with BRAF mutation.
Cell Movement ; Cell Proliferation ; Colon ; Genes, Neurofibromatosis 2 ; Genes, Tumor Suppressor ; Genome ; Humans ; Lymph Nodes ; Neoplasm Metastasis ; Neurofibromatosis 2 ; RNA, Messenger ; Thyroid Carcinoma, Anaplastic ; Thyroid Gland ; Thyroid Neoplasms

BACKGROUND AND OBJECTIVES: Controversy related to the choice of surgical approach for vestibular schwannoma (VS) resection remains. Whether the retrosigmoid (RS) or translabyrinthine (TL) approach should be performed is a matter of debate. In the context of a lack of clear evidence favoring one approach, we conducted a retrospective study to compare the morbidity rate of both surgical approaches. SUBJECTS AND METHODS: 168 patients underwent surgical treatment (2007-2013) for VS at our tertiary care center. There were no exclusion criteria. Patients were separated into two groups according to the surgical approach: TL group and RS group. Signs and symptoms including ataxia, headache, tinnitus, vertigo and cranial nerve injuries were recorded pre- and postoperatively. Surgical complications were analyzed. Perioperative facial nerve function was measured according to House-Brackmann grading system. RESULTS: Tumor resection was similar in both groups. Facial paresis was significantly greater in RS group patients preoperatively, in the immediate postoperative period and at one year follow-up (p < 0.05). A constant difference was found between both groups at all three periods (p=0.016). The evolution of proportion was not found to be different between both groups (p=0.942), revealing a similar rate of surgically related facial paresis. Higher rate of ataxic gait (p=0.019), tinnitus (p=0.039) and cranial nerve injuries (p=0.016) was found in RS group patients. The incidence of headache, vertigo, vascular complications, cerebrospinal fluid leak and meningitis was similar in both groups. No reported mortality in this series. CONCLUSIONS: Both approaches seem similar in terms of resection efficacy. However, according to our analysis, the TL approach is less morbid. Thus, for VS in which hearing preservation is not considered, TL approach is preferable.
Ataxia ; Cerebrospinal Fluid Leak ; Cranial Nerve Injuries ; Facial Nerve ; Facial Paralysis ; Follow-Up Studies ; Gait ; Headache ; Hearing ; Humans ; Incidence ; Meningitis ; Mortality ; Neuroma, Acoustic ; Postoperative Period ; Retrospective Studies ; Tertiary Care Centers ; Tinnitus ; Vertigo

PURPOSE: To explore the feasibility of maximum diameter as a response assessment method for vestibular schwannomas (VS) after stereotactic radiosurgery or fractionated stereotactic radiotherapy (RT), we analyzed the concordance of RT responses between maximum diameters and volumetric measurements. MATERIALS AND METHODS: Forty-two patients receiving curative stereotactic radiosurgery or fractionated stereotactic RT for VS were analyzed retrospectively. Twelve patients were excluded: 4 did not receive follow-up magnetic resonance imaging (MRI) scans and 8 had initial MRI scans with a slice thickness >3 mm. The maximum diameter, tumor volume (TV), and enhanced tumor volume (ETV) were measured in each MRI study. The percent change after RT was evaluated according to the measurement methods and their concordances were calculated with the Pearson correlation. The response classifications were determined by the assessment modalities, and their agreement was analyzed with Cohen kappa statistics. RESULTS: Median follow-up was 31.0 months (range, 3.5 to 86.5 months), and 90 follow-up MRI studies were analyzed. The percent change of maximum diameter correlated strongly with TV and ETV (r(p) = 0.85, 0.63, p = 0.000, respectively). Concordance of responses between the Response Evaluation Criteria in Solid Tumors (RECIST) using the maximum diameters and either TV or ETV were moderate (kappa = 0.58; 95% confidence interval, 0.32-0.85) or fair (kappa = 0.32; 95% confidence interval, 0.05-0.59), respectively. CONCLUSION: The percent changes in maximum diameter and the responses in RECIST were significantly concordant with those in the volumetric measurements. Therefore, the maximum diameters can be used for the response evaluation of VS following stereotactic RT.
Classification ; Follow-Up Studies ; Humans ; Magnetic Resonance Imaging ; Methods ; Neuroma, Acoustic ; Radiosurgery ; Radiotherapy ; Response Evaluation Criteria in Solid Tumors ; Retrospective Studies ; Tumor Burden

BACKGROUND AND OBJECTIVES: The suppression head impulse (SHIMP) test has emerged as one of the new vestibular function tests. The SHIMP test is an analysis of anti-compensatory saccadic movements in gazing moving targets as the head moves. In this study, we investigated the accuracy and sensitivity of the test. SUBJECTS AND METHOD: We analyzed the results of SHIMP test (gain, amplitude, and latency) in 24 cases, which included normal, vestibular neuritis, benign paroxysmal positional vertigo (BPPV), Meniere's disease, bilateral vestibular function loss, temporal bone fracture, tuberculosis meningitis and acoustic schwannoma patients. We also carried out a physical exam, audiologic study, video electronystagmography (vENG) and a conventional video head impulse test to evaluate the feasibility of SHIMP test in cases of vesitibulopathy. RESULTS: In patients with vestibulopathy, the analysis of SHIMP test indicated high sensitivity and accuracy, which were supported by accompanying audio-vestibular studies. Patients suspected with BPPV, vestibular neuronitis and Meniere's disease showed low vestibulo ocular reflex (VOR) gain and delayed anticompensatory saccade with smaller and more scattered amplitudes than the control. Patients with bilateral vestibular function loss, temporal bone fracture, tuberculosis meningitis, and acoustic schwannoma showed delayed latency, and small amplitude or few anticompensatory saccades. Finally, changes in the SHIMP test values might be a hint that patients had recovered from vestibular neuronitis and tuberculosis meningitis. CONCLUSION: We found the feasibility of SHIMP test in detecting the pathologic condition of VOR in vestibulopathy patients. We argue that the usefulness of SHIMP test might be extended to evaluating the effectiveness of rehabilitation.
Benign Paroxysmal Positional Vertigo ; Electronystagmography ; Head Impulse Test ; Head ; Humans ; Meniere Disease ; Methods ; Neuroma, Acoustic ; Reflex, Vestibulo-Ocular ; Rehabilitation ; Saccades ; Temporal Bone ; Tuberculosis, Meningeal ; Vestibular Function Tests ; Vestibular Neuronitis

OBJECTIVES: Growth of vestibular schwannomas (VS) causes progressive vestibular symptoms and postural instability. Since the tumor grows slowly, compensation of decaying vestibular input may decrease subjective symptoms of dizziness. This study aims to estimate the relationship of subjective vestibular symptoms and objective postural instability in patients with VS. METHODS: A retrospective review of 18 patients newly diagnosed with VS and with subjective vertigo symptoms was performed. The results of vestibular function tests including the sensory organization test (SOT) using computerized dynamic posturography, caloric test, and self-report measures of subjective dizziness handicap (Dizziness Handicap Inventory) and visual analogue scale were compared according to the onset of vertigo symptoms. RESULTS: In VS patients, SOT showed decreased equilibrium score for all vestibular function related conditions, condition (C) 5 and 6, and composite (COMP) score. COMP scores were not correlated with visual analogue scale or Dizziness Handicap Inventory scores. Acute onset group included six patients and insidious onset group, 12 patients. Equilibrium scores for C5 and C6, and COMP scores were lower for insidious onset group, but the difference was not statistically significant. CONCLUSION: Our findings confirmed postural instability is prevalent in VS patients. SOT parameters did not differ significantly between acute onset and insidious onset groups, but increased tumor size and canal weakness were noted in the insidious onset group. Clinicians should consider that postural instability is likely present even in patients who do not complain of acute vertigo, and appropriate counseling should be discussed with the patients.
Caloric Tests ; Compensation and Redress ; Counseling ; Dizziness ; Humans ; Neuroma, Acoustic* ; Postural Balance ; Retrospective Studies ; Vertigo* ; Vestibular Function Tests