Screening for viral nucleic acids in vestibular schwannoma.

To investigate if viruses are involved in the pathogenesis of vestibular schwannomas (VS), we have screened biopsies from VS patients using different molecular techniques. Screening for the presence of known viruses using a pan-viral microarray assay (ViroChip) indicated the presence of several viruses including human endogenous retrovirus K (HERV-K) and human herpes virus 2 (HHV2). But with the exception of HERV-K, none of the findings could be verified by other methods. Whole transcriptome sequencing showed only the presence of HERV-K transcripts and whole genome sequencing showed only the presence of Epstein-Barr virus, most likely originating from infiltration of lymphocytes. We therefore conclude that it is less likely that viruses are involved in the pathogenesis of vestibular schwannomas.

Lack of association between human herpesvirus and vestibular schwannoma: analysis of 121 cases.

OBJECTIVE: To assess for the presence of human herpesvirus (HHV) using immunohistochemical and polymerase chain reaction (PCR) assay in surgically excised vestibular schwannoma (VS) samples. STUDY DESIGN: Cross-sectional study. SETTING: A retrospective laboratory-based study of tumors from patients with vestibular schwannoma. SUBJECTS AND METHODS: Tissue microarrays (TMAs) representing sporadic and NF2-associated VS from 121 patients, as well as appropriate positive and negative controls, were studied. TMA sections were immunostained using antibodies directed against HHV-1, HHV-2, HHV-3, HHV-4, HHV-5, and HHV-8. PCR was used for the detection of all 8 known human herpesviruses. RESULTS: There was no detectable HHV (HHV-1, HHV-2, HHV-3, HHV-4, HHV-5, HHV-8) by immunohistochemistry in any of the 121 cases of sporadic and NF2 cases analyzed. These data were further validated by DNA sequence analyses using PCR in a subset of the VS samples, all of which were found to be negative for all HHV. CONCLUSIONS: The data offer no support for an association between HHV and the development of sporadic or NF2-associated VS in humans.

Herpes and acoustic neuromas: is there a cause and effect to observe?

Acoustic neuromas are a result of damage to the affected nerve function and can potentially press surrounding tissues. Although some sources suggest that observation is the treatment of choice for only those over 65 years of age and those unable to tolerate undergoing surgery or radiosurgery, most affected individuals should strongly consider not doing any aggressive therapies. Herpes has already been shown to mimic acoustic neuroma clinically, but growing evidence suggests that it is likely the cause of most cases of this entity.

Bioluminescent imaging of intracranial vestibular schwannoma xenografts in NOD/SCID mice.

HYPOTHESIS: Intracranial vestibular schwannoma xenografts can be successfully established and followed with bioluminescent imaging (BLI). BACKGROUND: Transgenic and xenograft mouse models of vestibular schwannomas have been previously reported in the literature. However, none of these models replicate the intracranial location of these tumors to reflect the human disease. Additionally, traditional imaging methods (magnetic resonance imaging, computed tomography) for following tumor engraftment and growth are expensive and time consuming. BLI has been successfully used to longitudinally follow tumor treatment responses in a noninvasive manner. BLI's lower cost and labor demands make this a more feasible approach for tumor monitoring in studies involving large numbers of mice. METHODS: Patient excised vestibular schwannomas were cultured and transduced with firefly luciferase expressing lentivirus. One million cells were stereotactically injected into the right caudate nucleus of 21 nonobese diabetic/severe combined immunodeficient mice. Schwannoma engraftment and growth was prospectively followed for 30 weeks after injection with BLI. After animal sacrifice, the presence of human tumor cells was confirmed with fluorescent in situ hybridization. RESULTS: Eight (38%) of 21 mice successfully engrafted the schwannoma cells. All of these mice were generated from 4 (67%) of the 6 patient excised tumors. These 8 mice could be differentiated from the nonengrafted mice at 21 weeks. The engrafted group emitted BLI of greater than 100,000 photons/s (range, 142,478-3,106,300 photons/s; average, 618,740 photons/s), whereas the nonengrafted group were all under 100,000 photons/s (range, 0-76,010 photons/s; average, 10,737 photons/s) (p < 0.001). Fluorescent in situ hybridization analysis confirmed the presence of viable human schwannoma cells in much greater numbers in those mice with stable or growing tumors compared with those whose tumors regressed. CONCLUSION: We have successfully established an intracranial schwannoma xenograft model that can be followed with noninvasive BLI. We hope to use this model for in vivo testing of schwannoma tumor therapies.

Lack of association of herpesviruses with brain tumors.

Gliomas are the most frequent primary brain tumors in humans. Many studies have been carried out on their etiology; however, the only confirmed risk factors are hereditary predisposing conditions and high dose of ionizing radiation. Recently, human cytomegalovirus (HCMV) gene products and nucleic acids were reported to be present in all of 27 glioma samples investigated in contrast to other brain tissues, and it was hypothesized that HCMV might play a role in glioma pathogenesis. To evaluate these findings, samples of 40 gliomas, 31 meningiomas, and 6 acoustic neurinomas (ACNs) were analyzed for the presence of HCMV macromolecules using polymerase chain reaction (PCR) and immunohistochemistry. Additionally, corresponding blood samples from 72 patients were analyzed for the presence of HCMV DNA to check for a possible contamination of tumor tissues with HCMV-infected blood cells. No HCMV DNA sequences were found, neither in brain tumor tissues nor in corresponding blood samples. Immunohistochemistry did not detect HCMV-specific proteins. Addressing a possible role of other herpesviruses as has been suggested in seroepidemiological studies, seroprevalence of antibodies to HCMV, herpes simplex virus (HSV), Epstein-Barr virus (EBV), and varicella-zoster virus (VZV) were determined by enzyme-linked immunosorbent assay (ELISA). Serological analyses of brain tumor patients showed no significant differences in the prevalences of antibodies to HCMV, HSV, EBV, or VZV compared to the general population. Thus, the data of the present study do not support the hypothesis of an association of herpesviruses with the development of primary brain tumors.

Viral titers and delayed facial palsy after acoustic neuroma surgery.

OBJECTIVE: Delayed facial palsy (DFP) after acoustic neuroma surgery has been reported to occur in up to one third of cases. Reactivation of latent virus has been proposed as an etiology for DFP. However, only retrospective case reports and case series have offered data to support this theory. The objective of this study was to correlate DFP with change in viral titers. PATIENTS AND METHODS: Twenty consecutive patients who underwent acoustic neuroma surgery were prospectively evaluated for viral titers immediately preoperatively and at 3 weeks postoperatively. Viral titers measured included herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), and varicella zoster virus (VZV) and included both IgG and IgM titers. The status of facial nerve function was documented preoperatively and throughout the postoperative period. Patients were categorized according to the presence or absence of DFP. RESULTS: Seven patients developed DFP after acoustic neuroma surgery, while the remaining 13 patients did not. There was no difference in preoperative and 3-week postoperative IgG titers for any of the 3 viruses tested. However, IgM titers were much higher postoperatively in DFP patients for all 3 viruses tested. The average HSV-1 IgM titer rose 92% in DFP patients compared with only 4.5% in the patients who did not develop DFP. Average HSV-2 IgM titers rose 70% compared with a decline of 8.5% in non-DFP patients. Most strikingly, VZV IgM titers rose an average 495% postoperatively among DFP patients compared with a decline of 14% in the non-DFP patients. CONCLUSION: Elevation of the IgM titers of the viruses measured in this study implies that recrudescence of the virus has occurred. The absence of this rise among patients who did not develop DFP implies that viral recrudescence plays a role in the etiology of DFP. These findings support treatment or prophylaxis of DFP with antiviral therapy.

Delayed facial palsy after acoustic neuroma resection: the role of viral reactivation.

Delayed facial palsy after acoustic neuroma resection may occur in up to 15% of cases. Prognosis is generally good if the palsy does not progress to total paralysis. However, a delayed palsy with subsequent total paralysis has a more variable final outcome, which ranges from normal function to permanent total paralysis. This delayed paralysis has been attributed to edema from surgical manipulation of the facial nerve. Steroids and intraoperative decompression of the meatal foramen have been used with some success, but some cases remain refractory to these measures. Herpes simplex virus and varicella-zoster virus are ubiquitous in the population and remain in a latent state in neural ganglia. These viruses are reactivated during times of stress. Trigeminal nerve surgery (partial sensory rhizotomy and microvascular decompression) stimulates reactivation of herpes simplex with manifestations in the sensory distribution of the trigeminal nerve in 38-94% of procedures. Prevention of this reactivation has been demonstrated in placebo-controlled trials by using prophylactic acyclovir. We present a patient who underwent translabyrinthine resection of an intracanalicular acoustic neuroma and in whom developed otalgia, vesicles on the ear canal and the ipsilateral buccal mucosa, and progressive facial palsy the week after surgery. Serologic evaluation confirmed the diagnosis of herpes zoster oticus. Reactivation of latent virus apparently occurred as a result of surgical manipulation of the facial nerve. This parallels viral reactivation seen in trigeminal nerve surgery. We propose a new theory for an additional cause of delayed facial palsy after acoustic neuroma resection-reactivation of latent herpesvirus resulting from surgical trauma. Acyclovir should be evaluated in clinical trials for a prophylactic role in patients undergoing acoustic neuroma resection or a therapeutic role in patients in whom a delayed postoperative facial palsy develops.