University of Manchester



Expert Review of Neurotherapeutics An update on the diagnosis and treatment of vestibular schwannomaHalliday J1, Rutherford SA1, McCabe M2, Evans DG3.Department of Neurosurgery, Salford Royal NHS Foundation Trust, Stott Lane, Salford, Manchester, M6 8HDDivision of Cancer Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PL Manchester Centre for Genomic Medicine, MAHSC, Division of Evolution and Genomic Science, University of Manchester, 6th Floor, Saint Mary's Hospital, Oxford Road, Manchester, M13 9WLAuthor Information:Halliday J (MB BChir, MA(Cantab), MSc, FRCS (Neuro.Surg) is a UK senior Neurosurgical Trainee in the Department of Neurosurgery, Salford Royal NHS Foundation Trust. Rutherford SA (MBChB, FRCSEd (Neuro.Surg)) is a ?Consultant Neurosurgeon at Salford Royal Foundation Trust, specialising in Skull Base Neurosurgery. McCabe M (MB BChir, PhD, FRCPCH) is a Clinical Senior Lecturer in Paediatric, Teenage and Young Adult Cancer at the University of Manchester, and an Honorary Consultant Paediatric and Young Adolescent Oncology at the Christie Hospital, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX. Evans DG (MB BS MRCP MD FRCP) is a Professor in Medical Genetics and Cancer Epidemiology at the University of Manchester. He is also a consultant in Medical Genetics and Cancer Epidemiology, at the Central Manchester Hospitals NHS Foundation Trust and The Christie NHS Foundation TrustCorresponding Author:Miss Jane HallidayDepartment of NeurosurgerySalford Royal NHS Foundation TrustStott Lane, SalfordManchester M6 8HDE-Mail: jane.halliday@Tel: 07912657675Fax: N/AAbstractIntroduction:Vestibular schwannomas (VS) account for approximately 85% of tumours in the cerebello-pontine angle, with a lifetime incidence of approximately 1 in 1000. Most are sporadic, with approximately 5% related to the tumour predisposition syndrome Neurofibromatosis Type 2 (NF2). The mainstay of management strategies are observation, surgery, radiosurgery/radiotherapy and, for patients with NF2 and rapidly growing tumours or deteriorating neurology the targeted therapy bevacizumab. While morbidity and mortality rates related to treatment of VS have improved dramatically over the last decades, there are still significant improvements that could be made, in particular with regards to long-term facial nerve and hearing outcomes. Areas covered: The epidemiology and diagnosis of VS are discussed, followed by the different management strategies and outcomes of those for both sporadic and NF2 related tumours. An extensive literature review has been performed to inform this review article using Pubmed and Google Scholar. Expert commentary: The future direction of VS management lies in obtaining longer-term follow-up data for patients with treated VS, and in improved understanding of cellular pathways and targeted therapies. Keywords: long-term outcomesneurofibromatosis type 2observationradiosurgerysurgerytargeted therapyvestibular schwannomaIntroductionVestibular schwannomas (VS) are benign tumours that arise from Schwann cells of the vestibular portion of the vestibulocochlear nerve inside the internal auditory canal (intracanalicular). As they grow they fill and extend beyond the internal auditory canal into the cerebello-pontine (CP) angle (extracanalicular). VS result from genetic abnormalities on chromosome of 22q12 (the Neurofibromatosis Type 2 (NF2) gene (coding for the tumour suppressor Merlin)). Approximately 5% of cases occur as part of the tumour predisposition syndrome NF2, and very rarely as part of the tumour predisposition syndrome Schwannomatosis ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"19ngudo92i","properties":{"formattedCitation":"[1]","plainCitation":"[1]"},"citationItems":[{"id":442,"uris":[""],"uri":[""],"itemData":{"id":442,"type":"article-journal","title":"Vestibular schwannomas occur in schwannomatosis and should not be considered an exclusion criterion for clinical diagnosis","container-title":"American Journal of Medical Genetics Part A","page":"215-219","volume":"158A","issue":"1","source":"CrossRef","DOI":"10.1002/ajmg.a.34376","ISSN":"15524825","language":"en","author":[{"family":"Smith","given":"Miriam J."},{"family":"Kulkarni","given":"Anjana"},{"family":"Rustad","given":"Cecilie"},{"family":"Bowers","given":"Naomi L."},{"family":"Wallace","given":"Andrew J."},{"family":"Holder","given":"Susan E."},{"family":"Heiberg","given":"Arvid"},{"family":"Ramsden","given":"Richard T."},{"family":"Evans","given":"D. Gareth"}],"issued":{"date-parts":[["2012",1]]}}}],"schema":""} [1] (caused by inactivating mutations in the tumour suppressor genes?SMARCB1?and?LZTR1). The remainder are thought to be sporadic due to acquired loss of NF2 gene function ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"191q1vjb1b","properties":{"formattedCitation":"[2]","plainCitation":"[2]"},"citationItems":[{"id":382,"uris":[""],"uri":[""],"itemData":{"id":382,"type":"article-journal","title":"The Genetics of Vestibular Schwannoma","container-title":"Current Otorhinolaryngology Reports","page":"226-234","volume":"2","issue":"4","source":"CrossRef","DOI":"10.1007/s40136-014-0061-x","ISSN":"2167-583X","language":"en","author":[{"family":"Hexter","given":"Adam T."},{"family":"Evans","given":"D. Gareth"}],"issued":{"date-parts":[["2014",12]]}}}],"schema":""} [2]. The most common presenting symptoms are progressive hearing loss (90%) and tinnitus (>60%). Imbalance, dizziness, vertigo, facial paraesthesia and headache secondary to hydrocephalus can occur with larger VS due to brainstem and trigeminal nerve compression. Up to 12% of patients can present with facial paraesthesia due to involvement of the trigeminal nerve, and up to 17% can present with facial nerve palsy; again these symptoms occur in patients with larger VS ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2394u6oamc","properties":{"formattedCitation":"[3]","plainCitation":"[3]"},"citationItems":[{"id":380,"uris":[""],"uri":[""],"itemData":{"id":380,"type":"article-journal","title":"Management of 1000 vestibular schwannomas (acoustic neuromas): the facial nerve--preservation and restitution of function","container-title":"Neurosurgery","page":"684-694; discussion 694-695","volume":"40","issue":"4","source":"PubMed","abstract":"OBJECTIVE: Although the rate of reported facial nerve preservation after surgery for vestibular schwannomas continuously increases, facial nerve paresis or paralysis is a frequent postsurgical sequelae of major concern. The major goal of this study was to define criteria for the right indication, timing, and type of therapy for patients with palsies despite anatomic nerve continuity and those with loss of anatomic continuity.\nMETHODS: One thousand vestibular schwannomas were surgically treated at the Department of Neurosurgery at Nordstadt Hospital from 1978 to 1993. Of 979 cases of complete removal and 21 cases of deliberately partial removal, the facial nerve was anatomically preserved in 929 cases (93%). The rate of preservation is increasing, as is evidenced in the most recent cases, and preservation is supported by special electrophysiological monitoring. The facial nerve was anatomically severed in 60 cases (6%). It was anatomically lost in previous operations that were performed elsewhere in 11 cases (1%). In case of nerve discontinuity (42 cases), immediate nerve reconstruction by one of three available intracranial procedures (within the cerebellopontine angle, intracranial-intratemporal, intracranial-extracranial) was performed in the same surgical setting. In case of loss of the proximal facial nerve stump at the brain stem, early reanimation by combination with the hypoglossal nerve was achieved in most patients within weeks after tumor surgery. In a few patients with anatomic nerve continuity but absence of reinnervation for 10 to 12 months, a hypoglossal-facial combination was applied. All the patients with partial or with complete palsies were treated in a special follow-up program of regular controls and of modulation of physiotherapeutic treatment every 3 to 6 months.\nRESULTS: In intracranial nerve reconstruction at the cerebellopontine angle, 61 to 70% of patients regained complete eye closure and an overall result equivalent to House-Brackmann Grade 3. Hypoglossal-facial reanimation led to Grade 3 in 79%. The duration between the onset of paralysis and the reconstructive procedure is decisive for the quality of the outcome. These data are discussed in view of other treatment options and certain parameters influencing outcome.\nCONCLUSIONS: This management contains three major principles as follows: 1) preservation of facial nerve continuity in function by the aid of intraoperative monitoring, 2) early nerve reconstruction in case of lost continuity, and 3) scheduled follow-up program for all patients with incomplete or complete palsies.","ISSN":"0148-396X","note":"PMID: 9092841","shortTitle":"Management of 1000 vestibular schwannomas (acoustic neuromas)","journalAbbreviation":"Neurosurgery","language":"eng","author":[{"family":"Samii","given":"M."},{"family":"Matthies","given":"C."}],"issued":{"date-parts":[["1997",4]]},"PMID":"9092841"}}],"schema":""} [3] . The lifetime risk of developing a VS is estimated at approximately 1 in 1000, including sporadic and NF2 related tumours ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2efprvcivq","properties":{"formattedCitation":"[4]","plainCitation":"[4]"},"citationItems":[{"id":378,"uris":[""],"uri":[""],"itemData":{"id":378,"type":"article-journal","title":"Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period: higher incidence than previously thought","container-title":"Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology","page":"93-97","volume":"26","issue":"1","source":"PubMed","abstract":"OBJECTIVE: To determine the incidence of vestibular schwannoma (VS) in sporadic, neurofibromatosis type 2 (NF2) germ-line and mosaic form in a 10-year period.\nSTUDY DESIGN: Review of all incident cases of VS presenting to the four main neurosurgical centers for a population of 4.1 million from 1990 to 1999 and cross-referencing with the regional cancer registry.\nSETTING: Population based.\nPATIENTS: All patients presenting with VS detected on magnetic resonance imaging scan.\nRESULTS: A total of 419 sporadic and 64 NF2-related VS were identified over the study period. This represented an incidence of 10.4 per million per year for sporadic VS and 11.8 per million per year including NF2-related tumors. The incidence rose to 14 per million per year in the latter 5 years. The NF2 patient diagnoses represent an estimated birth incidence of 1 in 25,000, and 7% of the patients with VS had NF2, which is higher than previous estimates.\nCONCLUSIONS: The incidence of VS is rising almost certainly due to increasing diagnosis in the magnetic resonance imaging era. At current rates, 1 per 1,000 individuals will be diagnosed with VS in their lifetime. More VS than previously thought are due to NF2, which may be because of recognition of mosaic forms of the disease.","ISSN":"1531-7129","note":"PMID: 15699726","shortTitle":"Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period","journalAbbreviation":"Otol. Neurotol.","language":"eng","author":[{"family":"Evans","given":"D. Gareth R."},{"family":"Moran","given":"Anthony"},{"family":"King","given":"Andrew"},{"family":"Saeed","given":"S."},{"family":"Gurusinghe","given":"Nihal"},{"family":"Ramsden","given":"Richard"}],"issued":{"date-parts":[["2005",1]]},"PMID":"15699726"}}],"schema":""} [4] ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"10p9sjl9sb","properties":{"formattedCitation":"[5]","plainCitation":"[5]"},"citationItems":[{"id":383,"uris":[""],"uri":[""],"itemData":{"id":383,"type":"article-journal","title":"Vestibular schwannomas in the modern era: epidemiology, treatment trends, and disparities in management: Clinical article","container-title":"Journal of Neurosurgery","page":"121-130","volume":"119","issue":"1","source":"CrossRef","DOI":"10.3171/2013.1.JNS121370","ISSN":"0022-3085","shortTitle":"Vestibular schwannomas in the modern era","language":"en","author":[{"family":"Babu","given":"Ranjith"},{"family":"Sharma","given":"Richa"},{"family":"Bagley","given":"Jacob H."},{"family":"Hatef","given":"Jeffrey"},{"family":"Friedman","given":"Allan H."},{"family":"Adamson","given":"Cory"}],"issued":{"date-parts":[["2013",7]]}}}],"schema":""} [5]. The incidence appears to be increasing, thought largely due to the incidental diagnosis of asymptomatic lesions with the increasing use of magnetic resonance imaging (MRI) and, to a much lesser extent, computed tomography (CT) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1v3p5kpsu3","properties":{"formattedCitation":"[6]","plainCitation":"[6]"},"citationItems":[{"id":376,"uris":[""],"uri":[""],"itemData":{"id":376,"type":"article-journal","title":"The prevalence of \"incidental\" acoustic neuroma","container-title":"Archives of Otolaryngology--Head & Neck Surgery","page":"241-244","volume":"131","issue":"3","source":"PubMed","abstract":"OBJECTIVE: To estimate the prevalence of \"incidental\" acoustic neuromas (ANs) in the population at large.\nDESIGN: An intracranial magnetic resonance imaging (MRI) database of 46 414 patients presenting to the University of California, San Francisco (UCSF), without known audiovestibular complaints was searched retrospectively from July 1995 to February 2003. Seventy percent of these MRIs included gadolinium, and none was specifically targeted through the internal auditory canal. A medical chart review of 688 patients with acoustic neuromas presenting to UCSF between 1980 and 1999 was searched for sex distribution.\nSETTING: Tertiary care university medical center.\nRESULTS: Eight patients with incidental AN were discovered. This figure suggests that undiagnosed ANs may be present in at least 0.02% of the population. Three patients were found to have audiovestibular symptoms on inquiry after diagnosis. Audiometry revealed asymmetry at 4 kHz in only 3 of 7 patients, with an otherwise symmetric audiogram in the remaining patients. Tumor size in this population ranged from 3 to 28 mm. Incidental ANs were more common in men, but ANs were more common in women overall.\nCONCLUSIONS: The prevalence of incidental AN appears to be roughly 2 in 10,000 people. This figure indicates that AN may be less prevalent than suggested in previously reported temporal bone studies and more prevalent than suggested by epidemiologic studies.","DOI":"10.1001/archotol.131.3.241","ISSN":"0886-4470","note":"PMID: 15781765","journalAbbreviation":"Arch. Otolaryngol. Head Neck Surg.","language":"eng","author":[{"family":"Lin","given":"Doris"},{"family":"Hegarty","given":"Joseph L."},{"family":"Fischbein","given":"Nancy J."},{"family":"Jackler","given":"Robert K."}],"issued":{"date-parts":[["2005",3]]},"PMID":"15781765"}}],"schema":""} [6]. Linn et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"d4nnhak1","properties":{"formattedCitation":"[6]","plainCitation":"[6]"},"citationItems":[{"id":376,"uris":[""],"uri":[""],"itemData":{"id":376,"type":"article-journal","title":"The prevalence of \"incidental\" acoustic neuroma","container-title":"Archives of Otolaryngology--Head & Neck Surgery","page":"241-244","volume":"131","issue":"3","source":"PubMed","abstract":"OBJECTIVE: To estimate the prevalence of \"incidental\" acoustic neuromas (ANs) in the population at large.\nDESIGN: An intracranial magnetic resonance imaging (MRI) database of 46 414 patients presenting to the University of California, San Francisco (UCSF), without known audiovestibular complaints was searched retrospectively from July 1995 to February 2003. Seventy percent of these MRIs included gadolinium, and none was specifically targeted through the internal auditory canal. A medical chart review of 688 patients with acoustic neuromas presenting to UCSF between 1980 and 1999 was searched for sex distribution.\nSETTING: Tertiary care university medical center.\nRESULTS: Eight patients with incidental AN were discovered. This figure suggests that undiagnosed ANs may be present in at least 0.02% of the population. Three patients were found to have audiovestibular symptoms on inquiry after diagnosis. Audiometry revealed asymmetry at 4 kHz in only 3 of 7 patients, with an otherwise symmetric audiogram in the remaining patients. Tumor size in this population ranged from 3 to 28 mm. Incidental ANs were more common in men, but ANs were more common in women overall.\nCONCLUSIONS: The prevalence of incidental AN appears to be roughly 2 in 10,000 people. This figure indicates that AN may be less prevalent than suggested in previously reported temporal bone studies and more prevalent than suggested by epidemiologic studies.","DOI":"10.1001/archotol.131.3.241","ISSN":"0886-4470","note":"PMID: 15781765","journalAbbreviation":"Arch. Otolaryngol. Head Neck Surg.","language":"eng","author":[{"family":"Lin","given":"Doris"},{"family":"Hegarty","given":"Joseph L."},{"family":"Fischbein","given":"Nancy J."},{"family":"Jackler","given":"Robert K."}],"issued":{"date-parts":[["2005",3]]},"PMID":"15781765"}}],"schema":""} [6] retrospectively analysed 46,414MRI scans performed for reasons other than suspected VS, and identified eight, suggesting that undiagnosed VS may be present in at least 0.02% of the population. Mean age of presentation is 50-55 years, with no significant difference in incidence by gender ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2pm1o3bfbm","properties":{"formattedCitation":"[4]","plainCitation":"[4]"},"citationItems":[{"id":378,"uris":[""],"uri":[""],"itemData":{"id":378,"type":"article-journal","title":"Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period: higher incidence than previously thought","container-title":"Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology","page":"93-97","volume":"26","issue":"1","source":"PubMed","abstract":"OBJECTIVE: To determine the incidence of vestibular schwannoma (VS) in sporadic, neurofibromatosis type 2 (NF2) germ-line and mosaic form in a 10-year period.\nSTUDY DESIGN: Review of all incident cases of VS presenting to the four main neurosurgical centers for a population of 4.1 million from 1990 to 1999 and cross-referencing with the regional cancer registry.\nSETTING: Population based.\nPATIENTS: All patients presenting with VS detected on magnetic resonance imaging scan.\nRESULTS: A total of 419 sporadic and 64 NF2-related VS were identified over the study period. This represented an incidence of 10.4 per million per year for sporadic VS and 11.8 per million per year including NF2-related tumors. The incidence rose to 14 per million per year in the latter 5 years. The NF2 patient diagnoses represent an estimated birth incidence of 1 in 25,000, and 7% of the patients with VS had NF2, which is higher than previous estimates.\nCONCLUSIONS: The incidence of VS is rising almost certainly due to increasing diagnosis in the magnetic resonance imaging era. At current rates, 1 per 1,000 individuals will be diagnosed with VS in their lifetime. More VS than previously thought are due to NF2, which may be because of recognition of mosaic forms of the disease.","ISSN":"1531-7129","note":"PMID: 15699726","shortTitle":"Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period","journalAbbreviation":"Otol. Neurotol.","language":"eng","author":[{"family":"Evans","given":"D. Gareth R."},{"family":"Moran","given":"Anthony"},{"family":"King","given":"Andrew"},{"family":"Saeed","given":"S."},{"family":"Gurusinghe","given":"Nihal"},{"family":"Ramsden","given":"Richard"}],"issued":{"date-parts":[["2005",1]]},"PMID":"15699726"}}],"schema":""} [4]. Over 90% of tumours are unilateral, equally affecting left and right, with bilateral VS almost exclusively occurring in patients with NF2. Environmental risk factors to developing VS continue to be studied. Radiation (ionising or gamma rays) is however consistently identified ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2e6odousmo","properties":{"formattedCitation":"[7]","plainCitation":"[7]"},"citationItems":[{"id":391,"uris":[""],"uri":[""],"itemData":{"id":391,"type":"article-journal","title":"Neurilemomas and salivary gland tumors of the head and neck following childhood irradiation","container-title":"Cancer","page":"2159-2163","volume":"51","issue":"12","source":"PubMed","abstract":"In a program to contact and examine 4180 individuals with a history of childhood irradiation treatment for enlarged tonsils and adenoids, the authors have discovered 29 neurilemomas, two neurofibromas, and one ganglioneuroma in the 2311 subjects who have been found. Ten of these presented as acoustic neuromas, 21 presented as cervical mass lesions, and one was found in the superior posterior mediastinum. Because of their numbers and their strict localization to the area of treatment, it was concluded that they were radiation-induced. Analysis of the latency of these tumors indicates that they continue to occur for at least 30 years after the radiation exposure. In the same group of individuals, there have been 54 confirmed salivary gland tumors, 40 benign and 14 malignant. These tumors are also continuing to occur many years after the radiation exposure.","ISSN":"0008-543X","note":"PMID: 6850504","journalAbbreviation":"Cancer","language":"eng","author":[{"family":"Shore-Freedman","given":"E."},{"family":"Abrahams","given":"C."},{"family":"Recant","given":"W."},{"family":"Schneider","given":"A. B."}],"issued":{"date-parts":[["1983",6,15]]},"PMID":"6850504"}}],"schema":""} [7], with conflicting data on the risk of mobile phones and noise exposure.Morbidity and mortality rates associated with the management of patients with VS have improved dramatically over the past decade. At the 1913 International Conference of Medicine in London mortality rates of greater than 50% were reported, with similarly high rates of morbidity in those who survived ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2nga3c9ggk","properties":{"formattedCitation":"[8]","plainCitation":"[8]"},"citationItems":[{"id":375,"uris":[""],"uri":[""],"itemData":{"id":375,"type":"chapter","title":"History of Vestibular Schwannoma Surgery","container-title":"Progress in Neurological Surgery","publisher":"KARGER","publisher-place":"Basel","page":"6-23","volume":"21","source":"CrossRef","event-place":"Basel","URL":"","ISBN":"978-3-8055-8370-1","note":"DOI: 10.1159/000156555","language":"en","editor":[{"family":"Régis","given":"J."},{"family":"Roche","given":"P.-H."}],"author":[{"family":"Pellet","given":"William"}],"issued":{"date-parts":[["2008"]]},"accessed":{"date-parts":[["2017",9,3]]}}}],"schema":""} [8]. 104 years on from then mortality rates are now well under 1%, with similar significant improvements in morbidity rates too. Early detection, the development and use of operating microscopes and the use of intraoperative neurophysiological monitoring are thought to have been the largest contributors to this. Once diagnosed there are a range of management options for VS management: 1. observation with serial MRI’s, 2. surgery, 3. radiosurgery/radiotherapy, and 4. targeted therapies. Treatment choice depends on the patient age, diagnosis of NF2, health status, symptoms, tumour size, patient preference and institutional and physician biases. BodyDiagnosisThe diagnosis of VS is often made incidentally, during the investigation of other complaints, or as a consequence of patients presenting with otological or neurological symptoms related to VS. These most commonly are hearing loss, and tinnitus. Otological symptoms almost always precede other neurological compromise. Hearing loss is sensorineural and typically progressive, thought to occur due to combination of compression of the cochlear nerve by the tumour and ischaemia ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1v1bap8kbe","properties":{"formattedCitation":"[9]","plainCitation":"[9]"},"citationItems":[{"id":386,"uris":[""],"uri":[""],"itemData":{"id":386,"type":"article-journal","title":"Mechanisms of hearing loss in acoustic neuroma: an otoacoustic emission study","container-title":"Acta Oto-Laryngologica","page":"375-381","volume":"115","issue":"3","source":"PubMed","abstract":"Evoked otoacoustic emissions (EOAE) are active mechanical responses from the cochlea which provide information about the integrity of the preneural cochlear receptor mechanisms. It may be hypothesised, therefore, that if a hearing impairment is neural in origin, normal EOAEs may be obtained from the cochlea, which, although dissociated, is functioning normally. This study examined the status of the cochlea with EOAE in patients with cochlear (Meniere's disease) and neural (surgically proven acoustic neuroma) disease. In patients with presumed cochlear lesions, no emissions were present with mean hearing worse than 40 dB across a frequency range of 0.5 to 4 kHz. Similarly, an EOAE was not present in any of the 26 acoustic neuroma patients studied when the average (0.5 to 4 kHz) hearing was greater than 40 dB. We conclude that dissociation of the cochlea in patients with acoustic neuroma appears to be rare and, in fact, cochlear involvement occurs in most cases. Possible mechanisms responsible for the effect on the cochlea in this group include degenerative changes due to chronic partial obstruction of the blood supply by the tumour, biochemical alterations in the inner ear fluids, loss of efferent control of active mechanical tuning, and hair cell degeneration secondary to neuronal loss in the eighth nerve.","ISSN":"0001-6489","note":"PMID: 7653257","shortTitle":"Mechanisms of hearing loss in acoustic neuroma","journalAbbreviation":"Acta Otolaryngol.","language":"eng","author":[{"family":"Prasher","given":"D. K."},{"family":"Tun","given":"T."},{"family":"Brookes","given":"G. B."},{"family":"Luxon","given":"L. M."}],"issued":{"date-parts":[["1995",5]]},"PMID":"7653257"}}],"schema":""} [9]. Despite their origin on the vestibular nerve it is rare for patients with VS to present with imbalance as their primary symptom. This is thought to occur due to compensation of the vestibular system to the gradual loss of function that typically occurs with VS, due to the slow growing nature of these tumours. Neurological symptoms include sensory trigeminal impairment, facial nerve impairment, headache and imbalance related to brainstem compression and hydrocephalus. These symptoms as presenting symptoms are far rarer than otological symptoms. Unilateral hearing loss, tinnitus and vertigo are common presenting symptoms in patients attending Ear, Nose and Throat (ENT) clinics; VS as a cause of these symptoms is uncommon. It is estimated that up to 20% of patient presenting to ENT clinics have symptoms that could be attributed to a lesion in the CP angle ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"16eflqpeuf","properties":{"formattedCitation":"[10]","plainCitation":"[10]"},"citationItems":[{"id":388,"uris":[""],"uri":[""],"itemData":{"id":388,"type":"article-journal","title":"The incidence of symptoms consistent with cerebellopontine angle lesions in a general ENT out-patient clinic","container-title":"The Journal of Laryngology and Otology","page":"518-522","volume":"113","issue":"6","source":"PubMed","abstract":"To quantify the potential burden for screening for cerebellopontine angle lesions, all adult new patients attending the ENT outpatient department of a district general hospital were documented to see if their presenting symptom(s) could be consistent with the presence of a cerebellopontine angle lesion. Of the patients, 19.7 per cent were found to be potential candidates for screening. A 15 decibel asymmetry at one frequency was found in 11.8 per cent of patients. The burden of screening with a variety of audiological and symptomatic protocols was quantified. Effective age limits to reduce the burden for screening were found to be either 65 or 75 years of age. With such a large potential pool of patients for further investigation, the results of this study could be used to suggest protocols which are likely to produce a load of cases, which matches local resources for screening.","ISSN":"0022-2151","note":"PMID: 10605580","journalAbbreviation":"J Laryngol Otol","language":"eng","author":[{"family":"Harcourt","given":"J. P."},{"family":"Vijaya-Sekaran","given":"S."},{"family":"Loney","given":"E."},{"family":"Lennox","given":"P."}],"issued":{"date-parts":[["1999",6]]},"PMID":"10605580"}}],"schema":""} [10]. For this reason local guidelines have been created to guide clinicians as to when patients should be investigated for suspected VS. For example the ‘Oxford Guideline’ is to investigate in patients who have 15 dB asymmetry between mean thresholds of tested frequencies and unilateral tinnitus with normal hearing, and the ‘Northern Guideline’ to investigate those with 20 dB asymmetry between two contiguous frequencies and unilateral tinnitus ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"3b4ub5jh9","properties":{"formattedCitation":"[11]","plainCitation":"[11]"},"citationItems":[{"id":390,"uris":[""],"uri":[""],"itemData":{"id":390,"type":"article-journal","title":"The Agreement between Protocols for the Investigation of Asymmetrical Audiovestibular Symptoms","container-title":"The Journal of International Advanced Otology","page":"98-100","volume":"12","issue":"1","source":"CrossRef","DOI":"10.5152/iao.2016.1581","ISSN":"13087649, 21483817","author":[{"family":"Nash","given":"Robert"},{"family":"Majithia","given":"Anooj"},{"family":"Singh","given":"Arvind"}],"issued":{"date-parts":[["2016",6,20]]}}}],"schema":""} [11]. Patients reporting symptoms that could be attributed to a CP angle lesion should undergo audiometry (pure tone and speech) as an initial screening laboratory test. Typically patients with VS will have an asymmetrical sensorineural hearing loss, with the speech discrimination score typically much lower than the measured hearing loss. Brainstem-evoked response audiometry can be used as a further screening test, and prior to MRI imaging was the most accurate screening tool for suspected VS. However with a false negative rate as high as 30% with small vestibular schwannomas, and a 10% false positive rate?it is no longer used as a first line investigation ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2147q4m4ui","properties":{"formattedCitation":"[12]","plainCitation":"[12]"},"citationItems":[{"id":395,"uris":[""],"uri":[""],"itemData":{"id":395,"type":"article-journal","title":"Is there still a role for auditory brainstem response audiometry in the diagnosis of acoustic neuroma?","container-title":"Archives of Otolaryngology--Head & Neck Surgery","page":"232-234","volume":"125","issue":"2","source":"PubMed","ISSN":"0886-4470","note":"PMID: 10037293","journalAbbreviation":"Arch. Otolaryngol. Head Neck Surg.","language":"eng","author":[{"family":"Doyle","given":"K. J."}],"issued":{"date-parts":[["1999",2]]},"PMID":"10037293"}}],"schema":""} [12]. The gold standard imaging test is magnetic resonance imaging (MRI) with gadolinium contrast and fine sections through the internal auditory meatus.?If a patient cannot tolerate MRI, high resolution CT scanning with and without contrast is an alternative although this will miss small intracanalicular tumours. Fast spin echo MRI has been investigated as a screening test; it is low cost compared to gadolinium MRI, non-invasive and has been found to have high sensitivity and specificity ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1m20k04jt6","properties":{"formattedCitation":"[13]","plainCitation":"[13]"},"citationItems":[{"id":393,"uris":[""],"uri":[""],"itemData":{"id":393,"type":"article-journal","title":"Accuracy of fast spin echo magnetic resonance imaging in the diagnosis of vestibular schwannoma","container-title":"American Journal of Otolaryngology","page":"211-216","volume":"20","issue":"4","source":"PubMed","abstract":"PURPOSE: An ideal screening test is noninvasive, inexpensive, and has a high specificity and sensitivity. Auditory brain-stem response testing has been the usual screening test for the diagnosis of vestibular schwannoma, although its accuracy in diagnosing small vestibular schwannomas has caused its effectiveness as a screening test to be questioned. Magnetic resonance imaging (MRI) with gadolinium has a high sensitivity and specificity for the diagnosis of vestibular schwannoma. Its use as a screening test for vestibular schwannoma has been limited due to its high cost. Fast spin echo MRI is a technique that provides T2-weighted images with excellent contrast between fluid and neural structures, and its cost is a fraction of a gadolinium MRI scan. This study compares the accuracy of fast spin echo MRI to gadolinium MRI in the diagnosis of vestibular schwannoma.\nMATERIALS & METHODS: Twenty-five patients (50 ears) in whom there was a clinical suspicion of vestibular schwannoma were scanned with both modalities. All studies were read independently and scored as positive, negative, or indeterminate.\nRESULTS: There were 11 true positives and 39 true negatives. There were no false positives or negatives, resulting in a sensitivity of 100% and a specificity of 100%.\nCONCLUSION: Fast spin echo MRI appears to be an excellent choice as a screening test for vestibular schwannoma due to its low cost, noninvasiveness, and high sensitivity and specificity.","ISSN":"0196-0709","note":"PMID: 10442772","journalAbbreviation":"Am J Otolaryngol","language":"eng","author":[{"family":"Marx","given":"S. V."},{"family":"Langman","given":"A. W."},{"family":"Crane","given":"R. C."}],"issued":{"date-parts":[["1999",8]]},"PMID":"10442772"}}],"schema":""} [13].Patients with vestibular schwannomas and an underlying diagnosis of NF2 or schwannomatosis tend to present at a younger age and in NF2 with bilateral vestibular schwannomas (about 85% of NF2 are bilateral at presentation). The current clinical diagnosis of NF2 is based on the following ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1630kgu2lt","properties":{"formattedCitation":"[14]","plainCitation":"[14]"},"citationItems":[{"id":443,"uris":[""],"uri":[""],"itemData":{"id":443,"type":"article-journal","title":"Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis","container-title":"Neurology","page":"87-92","volume":"88","issue":"1","source":"PubMed","abstract":"OBJECTIVE: To determine the specificity of the current clinical diagnostic criteria for neurofibromatosis type 2 (NF2) relative to the requirement for unilateral vestibular schwannoma (VS) and at least 2 other NF2-related tumors.\nMETHODS: We interrogated our Manchester NF2 database, which contained 205 individuals meeting NF2 criteria who initially presented with a unilateral VS. Of these, 83 (40.7%) went on to develop a contralateral VS. We concentrated our genetic analysis on a group of 70 who initially fulfilled NF2 criteria with a unilateral vestibular schwannoma and at least 2 additional nonintradermal schwannomas.\nRESULTS: Overall, 5/70 (7%) individuals with unilateral VS and at least 2 other schwannomas had a pathogenic or likely pathogenic LZTR1 mutation. Twenty of the 70 subsequently developed bilateral disease. Of the remaining 50, 5 (10%) had a germline LZTR1 mutation, equivalent to the number (n = 5) with a germline NF2 mutation.\nCONCLUSIONS: The most common etiology for unilateral VS and 2 additional NF2-associated tumors in this cohort was mosaic NF2. Germline LZTR1 and germline NF2 mutations were equally common in our cohort. This indicates that LZTR1 must be considered when making a diagnosis of NF2 in the presence of unilateral VS in individuals without a germline NF2 mutation.","DOI":"10.1212/WNL.0000000000003418","ISSN":"1526-632X","note":"PMID: 27856782\nPMCID: PMC5200853","journalAbbreviation":"Neurology","language":"eng","author":[{"family":"Smith","given":"Miriam J."},{"family":"Bowers","given":"Naomi L."},{"family":"Bulman","given":"Michael"},{"family":"Gokhale","given":"Carolyn"},{"family":"Wallace","given":"Andrew J."},{"family":"King","given":"Andrew T."},{"family":"Lloyd","given":"Simon K. L."},{"family":"Rutherford","given":"Scott A."},{"family":"Hammerbeck-Ward","given":"Charlotte L."},{"family":"Freeman","given":"Simon R."},{"family":"Evans","given":"D. Gareth"}],"issued":{"date-parts":[["2017",1,3]]},"PMID":"27856782","PMCID":"PMC5200853"}}],"schema":""} [14]:Any one of: bilateral vestibular schwannomas before age 70 years or unilateral vestibular schwannoma before age 70 years and first-degree relative with NF2;Any two of: meningioma, non-vestibular schwannoma, neurofibroma, glioma, cerebral calcification, cataract and a first-degree relative with NF2 or unilateral vestibular schwannoma and negative?LZTR1?testing; Multiple meningiomas and unilateral vestibular schwannoma or any two of the: non-vestibular schwannoma, neurofibroma, glioma, cerebral calcification, cataract;Constitutional or mosaic pathogenic?NF2?gene mutation from the blood or by the identification of an identical mutation from two separate tumours in the same individual. These criteria were recently changed to add an age limit as bilateral VS can occur by chance particularly after 70 years of age ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"173ebqgiul","properties":{"formattedCitation":"[15]","plainCitation":"[15]"},"citationItems":[{"id":499,"uris":[""],"uri":[""],"itemData":{"id":499,"type":"article-journal","title":"Bilateral vestibular schwannomas in older patients: NF2 or chance?","container-title":"Journal of Medical Genetics","page":"422-424","volume":"52","issue":"6","source":"PubMed","abstract":"BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant condition with high spontaneous mutation rate which predisposes to the development of multiple nerve sheath tumours (schwannomas), meningiomas and ependymoma. The cardinal feature and main diagnostic criterion for the diagnosis of NF2 remains the development of bilateral vestibular schwannoma (BVS). With increasing use of MRI screening the possibility of a 'chance' diagnosis of BVS has been mooted with a potential frequency of one in two million people in their lifetime. Until now, however, no evidence for such an event has been published. We aimed to demonstrate that chance occurrence can occur and to estimate its frequency among those with just BVS late in life.\nMETHODS: Two vestibular schwannomas from the same patient were DNA sequenced and underwent loss of heterozygosity analysis.\nRESULTS: We show that a man who developed BVS, at ages 52 and 67 years developed these tumours sporadically by demonstrating that there were no molecular events in common between the two tumours. Furthermore from a database of over 1200 patients with NF2, we have estimated that ~25% of cases of BVS over 50 years and 50% over 70 years of age where no other features of NF2 are present represent a chance occurrence rather than due to an underlying mosaic or constitutional NF2 mutation.\nCONCLUSIONS: Patients presenting with BVS later in life should be appraised of the potential likelihood they may not have NF2 and the resultant further reduction in risks of transmission to offspring.","DOI":"10.1136/jmedgenet-2014-102973","ISSN":"1468-6244","note":"PMID: 25725045","shortTitle":"Bilateral vestibular schwannomas in older patients","journalAbbreviation":"J. Med. Genet.","language":"eng","author":[{"family":"Evans","given":"D. G."},{"family":"Freeman","given":"S."},{"family":"Gokhale","given":"C."},{"family":"Wallace","given":"A."},{"family":"Lloyd","given":"S. K."},{"family":"Axon","given":"P."},{"family":"Ward","given":"C. L."},{"family":"Rutherford","given":"S."},{"family":"King","given":"A."},{"family":"Huson","given":"S. M."},{"family":"Ramsden","given":"R. T."},{"literal":"Manchester NF2 service"}],"issued":{"date-parts":[["2015",6]]},"PMID":"25725045"}}],"schema":""} [15]. LZTR1 mutations have also been identified in 5 of 50 individuals with unilateral VS and two or more other schwannomas but no meningioma or other NF2 feature [14], thus the need to exclude LZTR1.ManagementThe principle of VS management is to reduce mass effect, as required for larger tumours, and maintain long term tumour control, while preserving facial nerve function, and hearing where possible. The management of patients with NF2-related VS differs from those patients with sporadic VS, and therefore will be discussed separately. Sporadic Vestibular SchwannomaFirstly in a patient with very early onset apparently sporadic VS consideration needs to be given to the possibility of NF2 or LZTR1 related schwannomatosis. The chances of NF2 in an apparently sporadic VS under 20 years of age has been previously estimated to be 20% (half of these mosaic) and between 20-29 at 5% (only 1% chance of non-mosaic) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2jv5gou6tn","properties":{"formattedCitation":"[16]","plainCitation":"[16]"},"citationItems":[{"id":501,"uris":[""],"uri":[""],"itemData":{"id":501,"type":"article-journal","title":"What are the implications in individuals with unilateral vestibular schwannoma and other neurogenic tumors?","container-title":"Journal of Neurosurgery","page":"92-96","volume":"108","issue":"1","source":"CrossRef","DOI":"10.3171/JNS/2008/108/01/0092","ISSN":"0022-3085","language":"en","author":[{"family":"Evans","given":"D. Gareth R."},{"family":"Ramsden","given":"Richard T."},{"family":"Shenton","given":"Andrew"},{"family":"Gokhale","given":"Carolyn"},{"family":"Bowers","given":"Naomi"},{"family":"Huson","given":"Susan M."},{"family":"Wallace","given":"Andrew J."}],"issued":{"date-parts":[["2008",1]]}}}],"schema":""} [16]. More recently four of 106 people (3.8%) with a cranial schwannoma aged <25 years were identified with a germline LZTR1 mutation (3 were vestibular schwannomas and 1 was a non-vestibular schwannoma), and 9 (8.5%) had an NF2 mutation identified ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5snjaleoo","properties":{"formattedCitation":"[17]","plainCitation":"[17]"},"citationItems":[{"id":502,"uris":[""],"uri":[""],"itemData":{"id":502,"type":"article-journal","title":"Association of Genetic Predisposition With Solitary Schwannoma or Meningioma in Children and Young Adults","container-title":"JAMA Neurology","page":"1123","volume":"74","issue":"9","source":"CrossRef","DOI":"10.1001/jamaneurol.2017.1406","ISSN":"2168-6149","language":"en","author":[{"family":"Pathmanaban","given":"Omar N."},{"family":"Sadler","given":"Katherine V."},{"family":"Kamaly-Asl","given":"Ian D."},{"family":"King","given":"Andrew T."},{"family":"Rutherford","given":"Scott A."},{"family":"Hammerbeck-Ward","given":"Charlotte"},{"family":"McCabe","given":"Martin G."},{"family":"Kilday","given":"John-Paul"},{"family":"Beetz","given":"Christian"},{"family":"Poplawski","given":"Nicola K."},{"family":"Evans","given":"D. Gareth"},{"family":"Smith","given":"Miriam J."}],"issued":{"date-parts":[["2017",9,1]]}}}],"schema":""} [17]. As such all patients with an apparently isolated VS under 30 years should be evaluated for NF2 and schwannomatosis including molecular testing.The three major treatment options for patients with a sporadic vestibular schwannoma are surgery, radiation therapy, and observation (wait and watch policy). ObservationObservation, i.e. a ‘watch and wait’ policy with serial MRI’s, is an accepted form of management of diagnosed small VS due to their typically slow growth, and the lack of significant symptoms and neurology with small VS. A typical ‘wait and watch’ scanning regime is as follows: initial scan at presentation; a first follow-up scan at 6 months (to detect the small proportion of more rapidly growing VS); further scans at 1 year intervals for a further 3 years; followed by further scans every 2 years for a minimum surveillance period of 10 years in total. The premise of continued watch and rescan is tumour stability, although very slowly growing tumours can continue to be monitored rather than actively treated if this is the patient’s preferenceIn a study of conservatively managed VS that included 386 patients, 59% of patients had an annual tumour growth rate of less than 1?mm per year ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"11nm7jh8co","properties":{"formattedCitation":"[18]","plainCitation":"[18]"},"citationItems":[{"id":397,"uris":[""],"uri":[""],"itemData":{"id":397,"type":"article-journal","title":"Conservative management of 386 cases of unilateral vestibular schwannoma: tumor growth and consequences for treatment","container-title":"Journal of Neurosurgery","page":"662-669","volume":"110","issue":"4","source":"PubMed","abstract":"OBJECT: The object of this study was to evaluate the natural history, pattern, and occurrence of tumor growth and its consequences for treatment of small-sized vestibular schwannomas (VSs).\nMETHODS: From 1990 to 2005, 386 patients underwent conservative management for VS because of the following: age > 60 years, poor health/medical risks, risk of deterioration of good hearing, small tumor size, minimal or no incapacitating symptoms, and/or patient preference. Tumor size was measured by MR imaging according to the guidelines of the Committee on Hearing and Equilibrium. The first MR imaging study was performed 1 year after diagnosis, and subsequent imaging was performed yearly or every 2 years depending on the appearance of new symptoms, tumor growth, or both.\nRESULTS: Sixty-one patients were lost to follow-up the first year after presentation. Of the 325 patients for whom 1-year follow-up data were available, 39 showed tumor growth > or = 3 mm. Conservative management was discontinued for these 39 patients. The patients who returned for follow-up were evaluated at 1- or 2-year intervals depending on tumor growth. The authors extrapolated to obtain data for 2-year intervals, yielding data for 160, 56, 21, and 8 patients at 3, 5, 7, and 9 years after initial presentation, respectively. The overall mean tumor growth rate (+/-standard deviation) was 1.15 +/- 2.4 mm/year. This rate was estimated by pooling all values of tumor growth that had been determined for all patients and dividing by the total number of \"events,\" with each assessment constituting an event. In 58.6% of patients, the annual tumor growth rate was < 1 mm/year; in 29.2%, 1-3 mm/year; and in 12.2%, > or = 3 mm/ year. The growth rates of intrameatal (1.02 +/- 1.8 mm/year) and extrameatal (1.40 +/- 3.1 mm/year) tumors did not differ significantly. No significant association was found between tumor growth rate and sex, age, initial hearing status, or initial tumor grade. Delay in diagnosis was the only significant factor associated with tumor growth rate. During follow-up, conservative management was discontinued for 77 (23.7%) of the 325 patients for whom at least 12-month follow-up data were available; surgery was performed in 60 (77.9%) and radiation therapy in 17 (22.1%).\nCONCLUSIONS: The results of this study support the role of a conservative \"wait-and-scan\" policy of management for small-sized VSs because most have a slow growth rate. Long-term neuroimaging follow-up is needed even with non-growing tumors.","DOI":"10.3171/2007.5.16836","ISSN":"0022-3085","note":"PMID: 19099381","shortTitle":"Conservative management of 386 cases of unilateral vestibular schwannoma","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"Bakkouri","given":"Wissame El"},{"family":"Kania","given":"Romain E."},{"family":"Guichard","given":"Jean-Pierre"},{"family":"Lot","given":"Guillaume"},{"family":"Herman","given":"Philippe"},{"family":"Huy","given":"Patrice Tran Ba"}],"issued":{"date-parts":[["2009",4]]},"PMID":"19099381"}}],"schema":""} [18], thus supporting a conservative wait and watch policy of management in appropriate patients. The Manchester group studied a group of 436 patients with VS, including patients with NF2. They found that two-thirds of VS did not grow, over an average follow-up period of 3.6 years. The mean growth rate for sporadic tumours was 1.1mm/year diameter, and for NF2 tumours 1.7mm/year ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1a9v2sj8e","properties":{"formattedCitation":"[19]","plainCitation":"[19]"},"citationItems":[{"id":405,"uris":[""],"uri":[""],"itemData":{"id":405,"type":"article-journal","title":"Vestibular schwannoma: role of conservative management","container-title":"The Journal of Laryngology and Otology","page":"251-257","volume":"124","issue":"3","source":"PubMed","abstract":"OBJECTIVE: To assess the outcome of conservative management of vestibular schwannoma.\nSTUDY DESIGN: Observational study.\nSETTING: Tertiary referral centre.\nPATIENTS: Four hundred and thirty-six patients with vestibular schwannoma (490 tumours), including 327 sporadic tumours and 163 tumours in 109 patients with neurofibromatosis type two.\nMAIN OUTCOME MEASURES: The relationship of tumour growth to tumour size at presentation, and to certain demographic features.\nRESULTS: The initial tumour size was significantly larger in the neurofibromatosis type two group (11 mm) than in the sporadic vestibular schwannoma group (5.1 mm). In both groups, 68 per cent of tumours did not grow during follow up (mean 3.6 years; range one to 14 years). The mean growth rate was 1.1 mm/year (range 0-15 mm/year) for sporadic tumours and 1.7 mm/year (range 0-18 mm/year) for neurofibromatosis type two tumours. The tumour growth rate correlated positively with tumour size in the sporadic tumour group, and correlated negatively with age in the neurofibromatosis type two group.\nCONCLUSION: Two-thirds of vestibular schwannomas did not grow. Radiological surveillance is an acceptable approach in carefully selected patients. Once a sporadic vestibular schwannoma reaches 2 cm in intracranial diameter, it is likely to continue growing. We do not recommend conservative management for sporadic tumours with an intracranial diameter of 1.5 cm or more. Vestibular schwannoma management is more complex in patients with neurofibromatosis type two.","DOI":"10.1017/S0022215109992362","ISSN":"1748-5460","note":"PMID: 20003606","shortTitle":"Vestibular schwannoma","journalAbbreviation":"J Laryngol Otol","language":"eng","author":[{"family":"Suryanarayanan","given":"R."},{"family":"Ramsden","given":"R. T."},{"family":"Saeed","given":"S. R."},{"family":"Aggarwal","given":"R."},{"family":"King","given":"A. T."},{"family":"Rutherford","given":"S. A."},{"family":"Evans","given":"D. G."},{"family":"Gillespie","given":"J. E."}],"issued":{"date-parts":[["2010",3]]},"PMID":"20003606"}}],"schema":""} [19]. Smouha et al performed a retrospective literature search of conservatively managed VS, including 21 studies. Across these studies with an average follow-up of 3.2 years, they found that 51% of tumours remained stable, 43% grew and 6% regressed without treatment. Only 20% of patients required treatment due to tumour and/or symptom progression. Tschudi et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"15f46n827i","properties":{"formattedCitation":"[20]","plainCitation":"[20]"},"citationItems":[{"id":400,"uris":[""],"uri":[""],"itemData":{"id":400,"type":"article-journal","title":"Conservative management of unilateral acoustic neuromas.","container-title":"American Journal of Otology","page":"722-728","volume":"21","author":[{"literal":"Tschudi DC"},{"literal":"Linder T"},{"literal":"Fisch U."}],"issued":{"date-parts":[["2000"]]}}}],"schema":""} [20], in their study of observed VS, found that growth in the first year following diagnosis was predictive of continued future growth. Patients identified at increased risk of further growth are those with a greater extracanalicular than intracanalicular component, extracanalicular component of diameter greater than 20mm, young age, and diagnosis of NF2 ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"pf27pv342","properties":{"formattedCitation":"[19]","plainCitation":"[19]"},"citationItems":[{"id":405,"uris":[""],"uri":[""],"itemData":{"id":405,"type":"article-journal","title":"Vestibular schwannoma: role of conservative management","container-title":"The Journal of Laryngology and Otology","page":"251-257","volume":"124","issue":"3","source":"PubMed","abstract":"OBJECTIVE: To assess the outcome of conservative management of vestibular schwannoma.\nSTUDY DESIGN: Observational study.\nSETTING: Tertiary referral centre.\nPATIENTS: Four hundred and thirty-six patients with vestibular schwannoma (490 tumours), including 327 sporadic tumours and 163 tumours in 109 patients with neurofibromatosis type two.\nMAIN OUTCOME MEASURES: The relationship of tumour growth to tumour size at presentation, and to certain demographic features.\nRESULTS: The initial tumour size was significantly larger in the neurofibromatosis type two group (11 mm) than in the sporadic vestibular schwannoma group (5.1 mm). In both groups, 68 per cent of tumours did not grow during follow up (mean 3.6 years; range one to 14 years). The mean growth rate was 1.1 mm/year (range 0-15 mm/year) for sporadic tumours and 1.7 mm/year (range 0-18 mm/year) for neurofibromatosis type two tumours. The tumour growth rate correlated positively with tumour size in the sporadic tumour group, and correlated negatively with age in the neurofibromatosis type two group.\nCONCLUSION: Two-thirds of vestibular schwannomas did not grow. Radiological surveillance is an acceptable approach in carefully selected patients. Once a sporadic vestibular schwannoma reaches 2 cm in intracranial diameter, it is likely to continue growing. We do not recommend conservative management for sporadic tumours with an intracranial diameter of 1.5 cm or more. Vestibular schwannoma management is more complex in patients with neurofibromatosis type two.","DOI":"10.1017/S0022215109992362","ISSN":"1748-5460","note":"PMID: 20003606","shortTitle":"Vestibular schwannoma","journalAbbreviation":"J Laryngol Otol","language":"eng","author":[{"family":"Suryanarayanan","given":"R."},{"family":"Ramsden","given":"R. T."},{"family":"Saeed","given":"S. R."},{"family":"Aggarwal","given":"R."},{"family":"King","given":"A. T."},{"family":"Rutherford","given":"S. A."},{"family":"Evans","given":"D. G."},{"family":"Gillespie","given":"J. E."}],"issued":{"date-parts":[["2010",3]]},"PMID":"20003606"}}],"schema":""} [19] ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"nb979e55t","properties":{"formattedCitation":"[21]","plainCitation":"[21]"},"citationItems":[{"id":419,"uris":[""],"uri":[""],"itemData":{"id":419,"type":"article-journal","title":"The growth rate of acoustic neuromas","container-title":"Acta Oto-Laryngologica. Supplementum","page":"157-163","volume":"487","source":"PubMed","abstract":"Growth rate of acoustic neuromas (AN) was studied in 43 patients. The growth rate was analyzed using tumor increasing size (IS) and tumor volume doubling time (VDT). The growth rate of unilateral AN was lower than that of bilateral AN associated with neurofibromatosis2 (NF2). The growth rate of recurrent tumors was higher than that of non-operative tumors. The relationships between growth rate and age and tumor size were also analyzed. The younger the patient or the greater the tumor size, the higher the growth rate. Several factors, i.e. age and sex of patients, tumor pathology and tumor size, should be considered together for predicting the growth rate on AN.","ISSN":"0365-5237","note":"PMID: 1843579","journalAbbreviation":"Acta Otolaryngol Suppl","language":"eng","author":[{"family":"Ogawa","given":"K."},{"family":"Kanzaki","given":"J."},{"family":"Ogawa","given":"S."},{"family":"Yamamoto","given":"M."},{"family":"Ikeda","given":"S."},{"family":"Shiobara","given":"R."}],"issued":{"date-parts":[["1991"]]},"PMID":"1843579"}}],"schema":""} [21]. Thus, in larger tumours, observation is associated with the risk of tumour progression, and therefore the need to proceed with treatment. It is also associated with a risk of progressive hearing loss. Studies on the natural history of small vestibular schwannomas have helped to define the risk factors for further hearing loss. A study of hearing outcomes in conservatively managed vestibular schwannomas found that those patients with tumour growth rates of greater than 2.5mm per year had a significantly higher rate of hearing loss compared with those with growth rates less than that, 75% versus 32%, over a follow-up period ranging from 26 to 52 months ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1nqlpqp3j3","properties":{"formattedCitation":"[22]","plainCitation":"[22]"},"citationItems":[{"id":401,"uris":[""],"uri":[""],"itemData":{"id":401,"type":"article-journal","title":"The natural history of untreated sporadic vestibular schwannomas: a comprehensive review of hearing outcomes","container-title":"Journal of Neurosurgery","page":"163-167","volume":"112","issue":"1","source":"PubMed","abstract":"OBJECT: Observation is an important consideration when discussing management options for patients with vestibular schwannoma (VS). Most data regarding clinical outcomes after conservative management come from modestsized series performed at individual centers. The authors performed an analysis of the published literature on the natural history of VSs with respect to hearing outcome. Their objective was to provide a comprehensive and unbiased description of outcomes in patients whose disease was managed conservatively.\nMETHODS: The authors identified a total of 34 published studies containing hearing outcome data in patients with VSs < 25 mm in largest diameter who underwent observation management. The effects of initial tumor size and tumor growth rate on hearing function at latest follow-up were analyzed. Data from individual and aggregated cases were extracted from each study. Patients with poorer hearing (American Association of Otolaryngology-Head and Neck Surgery Classes C or D, or Gardner-Robertson Classes III, IV, or V) at the time of presentation were excluded.\nRESULTS: A total of 982 patients met the inclusion criteria for this analysis, with a mean initial tumor size of 11.3 +/- 0.68 mm. The mean growth rate was 2.9 +/- 1.2 mm/year. The length of follow-up for these studies ranged from 26 to 52 months. Patients with preserved hearing at latest follow-up had a statistically larger initial tumor size than those whose hearing declined during the observation period (11.5 +/- 2.3 mm vs 9.3 +/- 2.7 mm, p < 0.0001), but the 2-mm difference of means was at the limit of imaging resolution and observer reliability. In contrast, patients with lower rates of tumor growth (<or= 2.5 mm/year) had markedly higher rates of hearing preservation (75 vs 32%, p < 0.0001) compared with patients with higher tumor growth rates. Interestingly, the authors' analysis found no difference in the rate of reported intervention for patients in either group (16 vs 18%, p = not significant).\nCONCLUSIONS: These data suggest that a growth rate of > 2.5 mm/year is a better predictor of hearing loss than the initial tumor size for patients undergoing observation management of VSs < 25 mm in largest diameter.","DOI":"10.3171/2009.4.JNS08895","ISSN":"1933-0693","note":"PMID: 19538047","shortTitle":"The natural history of untreated sporadic vestibular schwannomas","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"Sughrue","given":"Michael E."},{"family":"Yang","given":"Isaac"},{"family":"Aranda","given":"Derick"},{"family":"Lobo","given":"Khadja"},{"family":"Pitts","given":"Lawrence H."},{"family":"Cheung","given":"Steven W."},{"family":"Parsa","given":"Andrew T."}],"issued":{"date-parts":[["2010",1]]},"PMID":"19538047"}}],"schema":""} [22]. Even slow growing tumours are therefore associated with hearing loss. As a consequence, if hearing preservation is important to a patient, this should be factored into the decision as to how appropriate it is to conservatively manage them. There is evidence that hearing preservation outcomes are improved in patients with pre-treatment serviceable hearing ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1b92cs3mek","properties":{"formattedCitation":"[23]","plainCitation":"[23]"},"citationItems":[{"id":403,"uris":[""],"uri":[""],"itemData":{"id":403,"type":"article-journal","title":"Predictors of hearing preservation after stereotactic radiosurgery for acoustic neuroma: clinical article","container-title":"Journal of Neurosurgery","page":"863-873","volume":"119 Suppl","source":"PubMed","abstract":"OBJECT: Many patients with acoustic neuromas (ANs) have hearing function at diagnosis and desire to maintain it. To date, radiosurgical techniques have been focused on conformal irradiation of the tumor mass, with less attention to inner ear structures for which there was scant radiobiological information. The authors of this study evaluated tumor control and hearing preservation as they relate to tumor volume, imaging characteristics, and nerve and cochlear radiation dose following stereotactic radiosurgery (SRS) using the Gamma Knife.\nMETHODS: Seventy-seven patients with ANs had serviceable hearing (Gardner-Robertson [GR] Class I or II) and underwent SRS between 2004 and 2007. This interval reflected more recent measurements of inner ear dosimetry during the authors' 21-year experience. The median patient age was 52 years (range 22-82 years). No patient had undergone any prior treatment for the ANs. The median tumor volume was 0.75 cm3 (range 0.07-7.7 cm3), and the median radiation dose to the tumor margin was 12.5 Gy (range 12-13 Gy). At diagnosis, a greater distance from the lateral tumor to the end of the internal auditory canal correlated with better hearing function.\nRESULTS: At a median of 20 months after SRS, no patient required any other additional treatment. Serviceable hearing was preserved in 71% of all patients and in 89% (46 patients) of those with GR Class I hearing. Significant prognostic factors for maintaining the same GR class included (all pre-SRS) GR Class I hearing, a speech discrimination score (SDS) ≥ 80%, a pure tone average (PTA) < 20 dB, and a patient age < 60 years. Significant prognostic factors for serviceable hearing preservation were (all pre-SRS) GR Class I hearing, an SDS ≥ 80%, a PTA < 20 dB, a patient age < 60 years, an intracanalicular tumor location, and a tumor volume < 0.75 cm3. Patients who received a radiation dose of < 4.2 Gy to the central cochlea had significantly better hearing preservation of the same GR class. Twelve of 12 patients < 60 years of age who had received a cochlear dose < 4.2 Gy retained serviceable hearing at 2 years post-SRS.\nCONCLUSIONS: As currently practiced, SRS with the Gamma Knife preserves serviceable hearing in the majority of patients. Tumor volume and anatomy relate to the hearing level before radiosurgery and influence technique. A low radiosurgical dose to the cochlea enhances hearing preservation.","ISSN":"1933-0693","note":"PMID: 25077316","shortTitle":"Predictors of hearing preservation after stereotactic radiosurgery for acoustic neuroma","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"Kano","given":"Hideyuki"},{"family":"Kondziolka","given":"Douglas"},{"family":"Khan","given":"Aftab"},{"family":"Flickinger","given":"John C."},{"family":"Lunsford","given":"L. Dade"}],"issued":{"date-parts":[["2013",12]]},"PMID":"25077316"}}],"schema":""} [23]. We can see from the literature that observation with serial scans is an acceptable management approach for patients with small tumours (<2cm), elderly patients in whom it is well recognised that treatment of VS is associated with higher morbidity and mortality rates than in younger patients, for those patients who prefer a conservative approach where possible, and for those patients with medical conditions that significantly increase the risk of operation. It is clearly less appropriate for patients with larger tumours with mass effect. Conservatively managed patients should be counselled that they may well require treatment at some point, and with regards to the potential risk of worsened hearing loss should they require future treatment. There is a role for more frequent interval scanning of patients identified at higher risk of further growth. SurgeryThe first recorded operation for VS removal was in 1884 by Sir Charles Balance ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"19vshphvqe","properties":{"formattedCitation":"[24]","plainCitation":"[24]"},"citationItems":[{"id":411,"uris":[""],"uri":[""],"itemData":{"id":411,"type":"book","title":"Tumors of the Nervus Acousticus and the Syndrome of the Cerebellopontine Angle","publisher":"WB Saunders","publisher-place":"Philadelphia","event-place":"Philadelphia","author":[{"literal":"Cushing, H"}],"issued":{"date-parts":[["1917"]]}}}],"schema":""} [24], with recorded mortality rates of up to 84%. In the 1990s expert opinion was that surgery was the most appropriate form of treatment for all patients with VS, regardless of their size ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"3crl4b145","properties":{"formattedCitation":"[25]","plainCitation":"[25]"},"citationItems":[{"id":407,"uris":[""],"uri":[""],"itemData":{"id":407,"type":"article-journal","title":"Intracanalicular acoustic neuromas: the case for early surgery","container-title":"Clinical Otolaryngology and Allied Sciences","page":"1-2","volume":"19","issue":"1","source":"PubMed","ISSN":"0307-7772","note":"PMID: 8174293","shortTitle":"Intracanalicular acoustic neuromas","journalAbbreviation":"Clin Otolaryngol Allied Sci","language":"eng","author":[{"family":"Ramsden","given":"R. T."},{"family":"Moffat","given":"D. A."}],"issued":{"date-parts":[["1994",2]]},"PMID":"8174293"}}],"schema":""} [25]. As we can see from the discussions earlier in the paper, opinion has shifted on the role of surgery for management of all VS. There does however, remain an extremely important role for surgical management of VS. The retrosigmoid and translabyrinthine surgical approaches predominate in the UK. Less frequently employed operations are the middle fossa, the extended middle fossa and transotic approaches. The translabyrinthine approach is typically performed as a joint procedure between neurosurgeons and ENT surgeons. The incision is typically retroauricular extending behind the mastoid tip. A mastoidectomy and labyrinthectomy gives exposure of the internal acoustic canal (IAC), and the dura of the middle and posterior fossa, allowing identification of the facial nerve by stimulation and visualisation, and the tumour. The main advantage of the translabyrinthine approach is that it allows early identification of the facial nerve. It also provides a good access to a wide range of tumour sizes, avoids the need for cerebellar retraction and is associated with low rates of post-operative CSF leaks and headache. Its major disadvantage is that it does not allow for preservation of hearing, thus making the ideal surgical group, for this approach, those patients with absent or non-serviceable hearing pre-operatively ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"81diaateq","properties":{"formattedCitation":"[26]","plainCitation":"[26]"},"citationItems":[{"id":409,"uris":[""],"uri":[""],"itemData":{"id":409,"type":"article-journal","title":"Surgical approaches for resection of vestibular schwannomas: translabyrinthine, retrosigmoid, and middle fossa approaches","container-title":"Neurosurgical Focus","page":"E9","volume":"33","issue":"3","source":"PubMed","abstract":"Surgical removal remains one of the key treatment modalities for vestibular schwannomas. A team approach between a neurotologist and a neurosurgeon offers the patient the expertise of both specialties and maximizes the chances for an optimal outcome. Vestibular schwannomas can typically be resected through 1 of 3 main surgical approaches: the translabyrinthine, the retrosigmoid, or the middle fossa approaches. In this report and videos, the authors describe and illustrate the indications and surgical techniques for the removal of these tumors.","DOI":"10.3171/2012.6.FOCUS12190","ISSN":"1092-0684","note":"PMID: 22937860","shortTitle":"Surgical approaches for resection of vestibular schwannomas","journalAbbreviation":"Neurosurg Focus","language":"eng","author":[{"family":"Chamoun","given":"Roukoz"},{"family":"MacDonald","given":"Joel"},{"family":"Shelton","given":"Clough"},{"family":"Couldwell","given":"William T."}],"issued":{"date-parts":[["2012",9]]},"PMID":"22937860"}}],"schema":""} [26]. For the retrosigmoid approach a suboccipital craniotomy is performed, exposing the edges of the transverse and sigmoid sinuses. After dural opening the tumour is exposed by gentle retraction of the cerebellum. Drilling of the posterior lip of the IAC gives a 180° exposure of the IAC. After dividing the vestibular nerves the tumour is carefully dissected off the facial and cochlear nerves, and tumour debulking performed. Sometimes due to tumour size partial debulking has to be performed before the nerves can be clearly identified ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2j0q7qaluc","properties":{"formattedCitation":"[26]","plainCitation":"[26]"},"citationItems":[{"id":409,"uris":[""],"uri":[""],"itemData":{"id":409,"type":"article-journal","title":"Surgical approaches for resection of vestibular schwannomas: translabyrinthine, retrosigmoid, and middle fossa approaches","container-title":"Neurosurgical Focus","page":"E9","volume":"33","issue":"3","source":"PubMed","abstract":"Surgical removal remains one of the key treatment modalities for vestibular schwannomas. A team approach between a neurotologist and a neurosurgeon offers the patient the expertise of both specialties and maximizes the chances for an optimal outcome. Vestibular schwannomas can typically be resected through 1 of 3 main surgical approaches: the translabyrinthine, the retrosigmoid, or the middle fossa approaches. In this report and videos, the authors describe and illustrate the indications and surgical techniques for the removal of these tumors.","DOI":"10.3171/2012.6.FOCUS12190","ISSN":"1092-0684","note":"PMID: 22937860","shortTitle":"Surgical approaches for resection of vestibular schwannomas","journalAbbreviation":"Neurosurg Focus","language":"eng","author":[{"family":"Chamoun","given":"Roukoz"},{"family":"MacDonald","given":"Joel"},{"family":"Shelton","given":"Clough"},{"family":"Couldwell","given":"William T."}],"issued":{"date-parts":[["2012",9]]},"PMID":"22937860"}}],"schema":""} [26]. Removal of a wide range of sizes of tumour is possible via the retrosigmoid approach, and it offers the significant advantage of potential hearing preservation. The main disadvantages of the approach are the need for cerebellar retraction, and reduced access to the facial and cochlear nerves in the IAC, which increases the potential for nerve damage and leaving residual tumour. The approach is often preferred by surgeons for tumours with significant mass effect and for those patients who have serviceable hearing and wish to try and preserve this. The middle fossa approach is not commonly used in UK practice now as it is limited to small tumours of the IAC in patients in whom hearing preservation is important. It is a less favoured approach as it places the tumour between surgeon and facial nerve, necessitating blind dissection in some cases ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1mlsdjlf7r","properties":{"formattedCitation":"[27]","plainCitation":"[27]"},"citationItems":[{"id":414,"uris":[""],"uri":[""],"itemData":{"id":414,"type":"article-journal","title":"Is the entire fundus of the internal auditory canal visible during the middle fossa approach for acoustic neuroma?","container-title":"The American Journal of Otology","page":"382-388","volume":"21","issue":"3","source":"PubMed","abstract":"HYPOTHESIS: To determine the degree to which the fundus of the internal auditory canal (IAC) can be visualized during the middle fossa approach (MFA).\nBACKGROUND: Conventional wisdom states that the MFA provides excellent access to the IAC from the porus acusticus to the fundus. On the basis of observations derived from a substantial surgical experience, it became obvious that a variable fraction of the fundus lies obscure from the surgeon's line of sight during the MFA because of (1) the overhand of the transverse crest and/or (2) the immobility of the facial nerve at its entry into the fallopian canal.\nMETHODS: Intraoperative measurements were performed in ten cases to determine the typical angle of view to the fundus of the IAC in the MFA. This angle of view was projected onto coronal computed tomography scans of 40 temporal bones. Measurements of the IAC were made to determine the amount of fundus that could not be directly visualized during a MF exposure.\nRESULTS: On the basis of a surgical line of sight, the fraction of the inferior compartment of the canal that could not be directly visualized because of overhand of the transverse crest ranged from 14% to 34% (median 25%).\nCONCLUSIONS: Complete resection of IAC tumors involving the fundus via the MFA requires some degree of blind dissection. Specialized tools and techniques are required to minimize the risk of neural injury during this indirect dissection. Inspection of the fundus with either mirror or endoscope is often necessary to exclude the possibility of retained tumor fragments.","ISSN":"0192-9763","note":"PMID: 10821552","journalAbbreviation":"Am J Otol","language":"eng","author":[{"family":"Driscoll","given":"C. L."},{"family":"Jackler","given":"R. K."},{"family":"Pitts","given":"L. H."},{"family":"Banthia","given":"V."}],"issued":{"date-parts":[["2000",5]]},"PMID":"10821552"}}],"schema":""} [27], requires temporal lobe retraction which increases the risk of seizures, and provides limited views of the cerebello-pontine angle (CPA). It has been found however to have improved hearing outcomes for patients with intracanalicular tumours compared with the retrosigmoid approach ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1qs7d1shvd","properties":{"formattedCitation":"[28]","plainCitation":"[28]"},"citationItems":[{"id":412,"uris":[""],"uri":[""],"itemData":{"id":412,"type":"article-journal","title":"Hearing preservation in patients undergoing vestibular schwannoma surgery: comparison of middle fossa and retrosigmoid approaches","container-title":"Journal of Neurosurgery","page":"840-845","volume":"88","issue":"5","source":"PubMed","abstract":"OBJECT: The goal of this retrospective study was to evaluate hearing preservation after surgery for vestibular schwannoma in which the middle fossa (MF) or retrosigmoid (RS) approaches were used. Hearing preservation in vestibular schwannoma surgery can be achieved by using either the MR or RS approach. Comparative outcome data between these approaches are lacking, and, as a result, selection has generally been determined by the surgeon's preference.\nMETHODS: The authors have compared removal of small vestibular schwannomas via MF and RS approaches with regard to hearing preservation and facial nerve function. The study group was composed of consecutively treated patients with vestibular schwannoma, 48 of whom underwent operation via an MF approach and 50 of whom underwent the same number of RS operations. Tumors were divided into size-matched groups. Hearing results were recorded according to the American Academy of Otolaryngology-Head and Neck Surgery criteria, and facial nerve outcome was recorded as the House-Brackmann grade. Overall, 26 (52%) of the patients treated via the MF approach achieved a Class B or better hearing result compared with seven (14%) of the RS group. Some hearing was preserved in 32 (64%) of the patients in the MF group and in 17 (34%) of the RS group. The results obtained by using the MF approach were superior for intracanalicular tumors (p=0.009, t-test), and for tumors with a cerebellopontine angle (CPA) component measuring 0.1 to 1 cm (p=0.006, t-test). For tumors in the CPA that were 1.1 to 2 cm in size, our data were inconclusive because of the small sample size. Facial weakness was seen more frequently after MF surgery in the early postoperative period, but results were equal at 1 year.\nCONCLUSIONS: The results of this study have demonstrated a more favorable hearing outcome for patients with intracanalicular tumors and tumors extending up to 1 cm into the CPA that were removed via the MF when compared with the RS approach.","DOI":"10.3171/jns.1998.88.5.0840","ISSN":"0022-3085","note":"PMID: 9576251","shortTitle":"Hearing preservation in patients undergoing vestibular schwannoma surgery","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"Irving","given":"R. M."},{"family":"Jackler","given":"R. K."},{"family":"Pitts","given":"L. H."}],"issued":{"date-parts":[["1998",5]]},"PMID":"9576251"}}],"schema":""} [28].The outcomes of surgery for VS can be analysed in terms of hearing outcomes, facial nerve preservation, extent of tumour resection and of complications, namely CSF leak, headache, major neurological complications and mortality. Hearing preservation: Ansari et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"24lgemcbnl","properties":{"formattedCitation":"[29]","plainCitation":"[29]"},"citationItems":[{"id":416,"uris":[""],"uri":[""],"itemData":{"id":416,"type":"article-journal","title":"Surgery for vestibular schwannomas: a systematic review of complications by approach","container-title":"Neurosurgical Focus","page":"E14","volume":"33","issue":"3","source":"CrossRef","DOI":"10.3171/2012.6.FOCUS12163","ISSN":"1092-0684","shortTitle":"Surgery for vestibular schwannomas","language":"en","author":[{"family":"Ansari","given":"Shaheryar F."},{"family":"Terry","given":"Colin"},{"family":"Cohen-Gadol","given":"Aaron A."}],"issued":{"date-parts":[["2012",9]]}}}],"schema":""} [29], who undertook a literature review of outcomes of VS surgery that included 35 studies and a total of 5064 patients, found that hearing preservation rates were similar for intracanalicular tumours operated via middle fossa and retrosigmoid approaches (40.6% vs 44.3%, p = 0.492). Hearing preservation rates for tumours of less than 1.5cm were significantly better when operated via a middle fossa approach rather than a retrosigmoid approach (43.6% vs 64.3%; p < 0.001). For larger tumours of greater than 1.5cm hearing loss rates are significantly higher, but improved with retrosigmoid rather than middle fossa approaches (71.6% vs 82.7% hearing loss post-operatively).Facial nerve function: Facial nerve function is graded by means of the House-Brackmann Scale ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2qrpm3rgkq","properties":{"formattedCitation":"[30]","plainCitation":"[30]"},"citationItems":[{"id":417,"uris":[""],"uri":[""],"itemData":{"id":417,"type":"article-journal","title":"Facial nerve grading system","container-title":"Otolaryngology--Head and Neck Surgery: Official Journal of American Academy of Otolaryngology-Head and Neck Surgery","page":"146-147","volume":"93","issue":"2","source":"PubMed","DOI":"10.1177/019459988509300202","ISSN":"0194-5998","note":"PMID: 3921901","journalAbbreviation":"Otolaryngol Head Neck Surg","language":"eng","author":[{"family":"House","given":"J. W."},{"family":"Brackmann","given":"D. E."}],"issued":{"date-parts":[["1985",4]]},"PMID":"3921901"}}],"schema":""} [30]. In its simplified form grade 1 is normal, grade 2 slight weakness/asymmetry, grade 3 obvious weakness with movement but absence of disfigurement at rest and intact ability to close the eye, grade 4 obvious weakness with movement and disfigurement at rest and an inability to fully close the eye, grade 5 barely perceptible movement and grade 6 no movement. Rates of facial nerve function have been examined in relation to factors such as tumour size and surgical approach. It has been found that tumour size is the most significant predictor of post-operative facial nerve outcomes. For example Surghrue et al, in their extensive literature review ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2mddsfbv1u","properties":{"formattedCitation":"[31]","plainCitation":"[31]"},"citationItems":[{"id":421,"uris":[""],"uri":[""],"itemData":{"id":421,"type":"article-journal","title":"Beyond audiofacial morbidity after vestibular schwannoma surgery","container-title":"Journal of Neurosurgery","page":"367-374","volume":"114","issue":"2","source":"PubMed","abstract":"OBJECT: Outcomes following vestibular schwannoma (VS) surgery have been extensively described; however, complication rates reported in the literature vary markedly. In addition, the majority of reports have focused on outcomes related to cranial nerves (CNs) VII and VIII. The objective of this study was to analyze reported morbidity unrelated to CNs VII and VIII following the resection of VS.\nMETHODS: The authors performed a comprehensive search of the English language literature, identifying and aggregating morbidity and death data from patients who had undergone microsurgical removal of VSs. A subgroup analysis based on surgical approach and tumor size was performed to compare rates of CSF leakage, vascular injury, neurological deficit, and postoperative infection.\nRESULTS: One hundred articles met the inclusion criteria, providing data for 32,870 patients. The overall mortality rate was 0.2% (95% CI 0.1-0.3%). Twenty-two percent of patients (95% CI 21-23%) experienced at least 1 surgically attributable complication unrelated to CNs VII or VIII. Cerebrospinal fluid leakage occurred in 8.5% of patients (95% CI 6.9-10.0%). This rate was markedly increased with the translabyrinthine approach but was not affected by tumor size. Vascular complications, such as ischemic injury or hemorrhage, occurred in 1% of patients (95% CI 0.75-1.2%). Neurological complications occurred in 8.6% of cases (95% CI 7.9-9.3%) and were less likely with the resection of smaller tumors (p < 0.0001) and the use of the translabyrinthine approach (p < 0.0001). Infections occurred in 3.8% of cases (95% CI 3.4-4.3%), and 78% of these infections were meningitis.\nCONCLUSIONS: This study provides statistically powerful data for practitioners to advise patients about the published risks of surgery for VS unrelated to compromised CNs VII and VIII.","DOI":"10.3171/2009.10.JNS091203","ISSN":"1933-0693","note":"PMID: 19943734","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"Sughrue","given":"Michael E."},{"family":"Yang","given":"Isaac"},{"family":"Aranda","given":"Derick"},{"family":"Rutkowski","given":"Martin J."},{"family":"Fang","given":"Shanna"},{"family":"Cheung","given":"Steven W."},{"family":"Parsa","given":"Andrew T."}],"issued":{"date-parts":[["2011",2]]},"PMID":"19943734"}}],"schema":""} [31], found that patients with operated tumours greater than 2cm in size had overall rates of preservation of facial nerve function of 67%, while those with operated tumours less than 2cm had overall rates of 90%. Bloch et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2577f95erm","properties":{"formattedCitation":"[32]","plainCitation":"[32]"},"citationItems":[{"id":425,"uris":[""],"uri":[""],"itemData":{"id":425,"type":"article-journal","title":"Factors associated with preservation of facial nerve function after surgical resection of vestibular schwannoma","container-title":"Journal of Neuro-Oncology","page":"281-286","volume":"102","issue":"2","source":"CrossRef","DOI":"10.1007/s11060-010-0315-5","ISSN":"0167-594X, 1573-7373","language":"en","author":[{"family":"Bloch","given":"Orin"},{"family":"Sughrue","given":"Michael E."},{"family":"Kaur","given":"Rajwant"},{"family":"Kane","given":"Ari J."},{"family":"Rutkowski","given":"Martin J."},{"family":"Kaur","given":"Gurvinder"},{"family":"Yang","given":"Isaac"},{"family":"Pitts","given":"Lawrence H."},{"family":"Parsa","given":"Andrew T."}],"issued":{"date-parts":[["2011",4]]}}}],"schema":""} [32] examined facial nerve outcomes of 624 patients who underwent surgery for VS and similarly found that tumour size is the most significant predictor of post-operative facial nerve function. Their results suggested that surgical approaches, extent of resection and patient age are not independent predictors of post-operative facial palsy. This result does vary in the literature however, with, for example, Ansari et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1td22460gk","properties":{"formattedCitation":"[29]","plainCitation":"[29]"},"citationItems":[{"id":416,"uris":[""],"uri":[""],"itemData":{"id":416,"type":"article-journal","title":"Surgery for vestibular schwannomas: a systematic review of complications by approach","container-title":"Neurosurgical Focus","page":"E14","volume":"33","issue":"3","source":"CrossRef","DOI":"10.3171/2012.6.FOCUS12163","ISSN":"1092-0684","shortTitle":"Surgery for vestibular schwannomas","language":"en","author":[{"family":"Ansari","given":"Shaheryar F."},{"family":"Terry","given":"Colin"},{"family":"Cohen-Gadol","given":"Aaron A."}],"issued":{"date-parts":[["2012",9]]}}}],"schema":""} [29] reporting a significant difference in post-operative rates of facial nerve dysfunction between the different surgical approaches for patients with tumours less than 1.5cm in diameter (3.3% via the middle cranial fossa approach, 7.2% via a retrosigmoid approach, and 11.5% via a translabyrinthine approach). For tumours larger than 1.5cm there was no statistical significance in the rates of facial nerve dysfunction post-operatively for the different surgical approaches. For larger tumours facial nerve outcomes are improved with subtotal and near-total resections, where the decision to accept such an outcome is guided by a concern for facial nerve preservation ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"43n5aeq32","properties":{"formattedCitation":"[33]","plainCitation":"[33]"},"citationItems":[{"id":440,"uris":[""],"uri":[""],"itemData":{"id":440,"type":"article-journal","title":"The behavior of residual tumors and facial nerve outcomes after incomplete excision of vestibular schwannomas: Clinical article","container-title":"Journal of Neurosurgery","page":"1278-1287","volume":"120","issue":"6","source":"CrossRef","DOI":"10.3171/2014.2.JNS131497","ISSN":"0022-3085","shortTitle":"The behavior of residual tumors and facial nerve outcomes after incomplete excision of vestibular schwannomas","language":"en","author":[{"family":"Chen","given":"Zhengnong"},{"family":"Prasad","given":"Sampath Chandra"},{"family":"Lella","given":"Filippo","non-dropping-particle":"Di"},{"family":"Medina","given":"Marimar"},{"family":"Piccirillo","given":"Enrico"},{"family":"Taibah","given":"Abdelkader"},{"family":"Russo","given":"Alessandra"},{"family":"Yin","given":"Shankai"},{"family":"Sanna","given":"Mario"}],"issued":{"date-parts":[["2014",6]]}}}],"schema":""} [33]. Cerebrospinal Fluid (CSF) Leak: Patients who suffer post-operative CSF leak typically require re-operation and repair, and are at increased risk of developing meningitis. There is a significant variability in reported rates of CSF rates post VS surgery in the literature. Mangus et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2kbght1kl9","properties":{"formattedCitation":"[34]","plainCitation":"[34]"},"citationItems":[{"id":426,"uris":[""],"uri":[""],"itemData":{"id":426,"type":"article-journal","title":"Management of Cerebrospinal Fluid Leaks After Vestibular Schwannoma Surgery:","container-title":"Otology & Neurotology","page":"1525-1529","volume":"32","issue":"9","source":"CrossRef","DOI":"10.1097/MAO.0b013e318232e4a4","ISSN":"1531-7129","shortTitle":"Management of Cerebrospinal Fluid Leaks After Vestibular Schwannoma Surgery","language":"en","author":[{"family":"Mangus","given":"Brannon D."},{"family":"Rivas","given":"Alejandro"},{"family":"Yoo","given":"Mi Jin"},{"family":"Alvarez","given":"JoAnn"},{"family":"Wanna","given":"George B."},{"family":"Haynes","given":"David S."},{"family":"Bennett","given":"Marc L."}],"issued":{"date-parts":[["2011",12]]}}}],"schema":""} [34] quoted rates of, on average 10% post operative CSF leaks, and reported that there was no significant difference in rates of CSF leaks between retrosigmoid, translabyrinthine and middle fossa approaches in their series of 1,922 operated patients. ?In another study post-operative CSF leaks are quoted as 8.5% and as occurring more frequently in patients operated via a translabyrinthine approach ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2ebanekma3","properties":{"formattedCitation":"[31]","plainCitation":"[31]"},"citationItems":[{"id":421,"uris":[""],"uri":[""],"itemData":{"id":421,"type":"article-journal","title":"Beyond audiofacial morbidity after vestibular schwannoma surgery","container-title":"Journal of Neurosurgery","page":"367-374","volume":"114","issue":"2","source":"PubMed","abstract":"OBJECT: Outcomes following vestibular schwannoma (VS) surgery have been extensively described; however, complication rates reported in the literature vary markedly. In addition, the majority of reports have focused on outcomes related to cranial nerves (CNs) VII and VIII. The objective of this study was to analyze reported morbidity unrelated to CNs VII and VIII following the resection of VS.\nMETHODS: The authors performed a comprehensive search of the English language literature, identifying and aggregating morbidity and death data from patients who had undergone microsurgical removal of VSs. A subgroup analysis based on surgical approach and tumor size was performed to compare rates of CSF leakage, vascular injury, neurological deficit, and postoperative infection.\nRESULTS: One hundred articles met the inclusion criteria, providing data for 32,870 patients. The overall mortality rate was 0.2% (95% CI 0.1-0.3%). Twenty-two percent of patients (95% CI 21-23%) experienced at least 1 surgically attributable complication unrelated to CNs VII or VIII. Cerebrospinal fluid leakage occurred in 8.5% of patients (95% CI 6.9-10.0%). This rate was markedly increased with the translabyrinthine approach but was not affected by tumor size. Vascular complications, such as ischemic injury or hemorrhage, occurred in 1% of patients (95% CI 0.75-1.2%). Neurological complications occurred in 8.6% of cases (95% CI 7.9-9.3%) and were less likely with the resection of smaller tumors (p < 0.0001) and the use of the translabyrinthine approach (p < 0.0001). Infections occurred in 3.8% of cases (95% CI 3.4-4.3%), and 78% of these infections were meningitis.\nCONCLUSIONS: This study provides statistically powerful data for practitioners to advise patients about the published risks of surgery for VS unrelated to compromised CNs VII and VIII.","DOI":"10.3171/2009.10.JNS091203","ISSN":"1933-0693","note":"PMID: 19943734","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"Sughrue","given":"Michael E."},{"family":"Yang","given":"Isaac"},{"family":"Aranda","given":"Derick"},{"family":"Rutkowski","given":"Martin J."},{"family":"Fang","given":"Shanna"},{"family":"Cheung","given":"Steven W."},{"family":"Parsa","given":"Andrew T."}],"issued":{"date-parts":[["2011",2]]},"PMID":"19943734"}}],"schema":""} [31]. This finding is reflected in other studies too; it is suggested that the rate of this complication can be reduced by modification of technique ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2agrbm17t","properties":{"formattedCitation":"[35]","plainCitation":"[35]"},"citationItems":[{"id":432,"uris":[""],"uri":[""],"itemData":{"id":432,"type":"article-journal","title":"No cerebrospinal fluid leaks in translabyrinthine vestibular schwannoma removal: reappraisal of 200 consecutive patients","container-title":"The American Journal of Otology","page":"660-666","volume":"20","issue":"5","source":"PubMed","abstract":"OBJECTIVE: The objective of this study was to validate measures taken to reduce the number of cerebrospinal fluid (CSF) leaks after removal of vestibular schwannomas to 0.\nSTUDY DESIGN: This study was a retrospective case review.\nSETTING: The study was conducted at an otology/neurotology tertiary referral center (Gruppo Otologico, Piacenza, Italy).\nPATIENTS: Three hundred thirty-one vestibular schwannoma patients were studied.\nINTERVENTIONS: The enlarged translabyrinthine approach (TLA) was used in all cases, with a number of modifications in the last 200 patients. It was extended in 22 patients with blind sac closure of the external meatus, removal of the posterior bony canal wall, and obliteration of the Eustachian tube and middle ear.\nMAIN OUTCOME MEASURES: Whether patients had a leak through the wound, the nose (rhinoliquorrhea), or the ear (otoliquorrhea) was assessed.\nRESULTS: In an early group, the percentage of CSF leaks was 6.9%. On the basis of the evaluated causes, as time went by, technical modifications evolved. They consisted of 1) the total conservation of the fascioperiosteal flap, 2) obliteration of all petrosal cells possibly communicating with the middle ear, 3) removing the incus in a correct way, 4) closing the attic with periosteum, 5) obliterating the surgical cavity, leaving strips of abdominal fat with their medial ends inside the cerebellopontine angle, 6) suturing the musculo-periosteal layer in a correct way, and 7) fixing the skin flap to the underlying surface. The application of these modifications resulted in a total absence of CSF leaks in 200 consecutive patients thereafter. Also, no cases of meningitis were encountered.\nCONCLUSIONS: To our knowledge, this is the first series of 200 consecutive vestibular schwannoma patients operated by means of the enlarged TLA without a single CSF leak. When the appropriate measures are taken, the number of CSF leaks after removing tumors through the enlarged TLA must and can be reduced to 0.","ISSN":"0192-9763","note":"PMID: 10503591","shortTitle":"No cerebrospinal fluid leaks in translabyrinthine vestibular schwannoma removal","journalAbbreviation":"Am J Otol","language":"eng","author":[{"family":"Falcioni","given":"M."},{"family":"Mulder","given":"J. J."},{"family":"Taibah","given":"A."},{"family":"Donato","given":"G.","non-dropping-particle":"De"},{"family":"Sanna","given":"M."}],"issued":{"date-parts":[["1999",9]]},"PMID":"10503591"}}],"schema":""} [35]. Postoperative Headache: Postoperative headache is common after VS surgery, as high as 75% in the immediate post-operative period and 16.5% in the longer term (>6 months post operatively). Rates have been found to be highest in patients undergoing surgery from a retrosigmoid approach, particularly in the short term. There are numerous suggestions as to why this is, including the size of muscle incision and retraction and the presence of intracranial bone dust ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1asvag9ra2","properties":{"formattedCitation":"[36]","plainCitation":"[36]"},"citationItems":[{"id":429,"uris":[""],"uri":[""],"itemData":{"id":429,"type":"report","title":"Headache Associated with Acoustic Neuroma Treatment","URL":"","author":[{"literal":"Acoustic Neuroma Society"}],"issued":{"date-parts":[["2012",6]]}}}],"schema":""} [36]. Residual tumour and recurrence rates: The decision to leave residual tumour is typically conscious to preserve facial nerve function where it would otherwise be felt to be at risk, or to simply decompress the brainstem in patients with significant comorbidity and/or to attempt to preserve hearing ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"108pqv99pd","properties":{"formattedCitation":"[3]","plainCitation":"[3]"},"citationItems":[{"id":380,"uris":[""],"uri":[""],"itemData":{"id":380,"type":"article-journal","title":"Management of 1000 vestibular schwannomas (acoustic neuromas): the facial nerve--preservation and restitution of function","container-title":"Neurosurgery","page":"684-694; discussion 694-695","volume":"40","issue":"4","source":"PubMed","abstract":"OBJECTIVE: Although the rate of reported facial nerve preservation after surgery for vestibular schwannomas continuously increases, facial nerve paresis or paralysis is a frequent postsurgical sequelae of major concern. The major goal of this study was to define criteria for the right indication, timing, and type of therapy for patients with palsies despite anatomic nerve continuity and those with loss of anatomic continuity.\nMETHODS: One thousand vestibular schwannomas were surgically treated at the Department of Neurosurgery at Nordstadt Hospital from 1978 to 1993. Of 979 cases of complete removal and 21 cases of deliberately partial removal, the facial nerve was anatomically preserved in 929 cases (93%). The rate of preservation is increasing, as is evidenced in the most recent cases, and preservation is supported by special electrophysiological monitoring. The facial nerve was anatomically severed in 60 cases (6%). It was anatomically lost in previous operations that were performed elsewhere in 11 cases (1%). In case of nerve discontinuity (42 cases), immediate nerve reconstruction by one of three available intracranial procedures (within the cerebellopontine angle, intracranial-intratemporal, intracranial-extracranial) was performed in the same surgical setting. In case of loss of the proximal facial nerve stump at the brain stem, early reanimation by combination with the hypoglossal nerve was achieved in most patients within weeks after tumor surgery. In a few patients with anatomic nerve continuity but absence of reinnervation for 10 to 12 months, a hypoglossal-facial combination was applied. All the patients with partial or with complete palsies were treated in a special follow-up program of regular controls and of modulation of physiotherapeutic treatment every 3 to 6 months.\nRESULTS: In intracranial nerve reconstruction at the cerebellopontine angle, 61 to 70% of patients regained complete eye closure and an overall result equivalent to House-Brackmann Grade 3. Hypoglossal-facial reanimation led to Grade 3 in 79%. The duration between the onset of paralysis and the reconstructive procedure is decisive for the quality of the outcome. These data are discussed in view of other treatment options and certain parameters influencing outcome.\nCONCLUSIONS: This management contains three major principles as follows: 1) preservation of facial nerve continuity in function by the aid of intraoperative monitoring, 2) early nerve reconstruction in case of lost continuity, and 3) scheduled follow-up program for all patients with incomplete or complete palsies.","ISSN":"0148-396X","note":"PMID: 9092841","shortTitle":"Management of 1000 vestibular schwannomas (acoustic neuromas)","journalAbbreviation":"Neurosurgery","language":"eng","author":[{"family":"Samii","given":"M."},{"family":"Matthies","given":"C."}],"issued":{"date-parts":[["1997",4]]},"PMID":"9092841"}}],"schema":""} [3]. Recurrences are thought to occur where there have been small fragments of tumour left, or deliberate partial resection ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1et8fcmkks","properties":{"formattedCitation":"[37]","plainCitation":"[37]"},"citationItems":[{"id":436,"uris":[""],"uri":[""],"itemData":{"id":436,"type":"article-journal","title":"Long-term control of vestibular schwannoma after a translabyrinthine complete removal","container-title":"Neurosurgery","page":"693-698; discussion 693-698","volume":"57","issue":"4","source":"PubMed","abstract":"OBJECTIVE: The goal of this study was to determine the rate of recurrent vestibular schwannoma after a total removal via the translabyrinthine approach.\nPATIENTS: Between 1973 and 1995, 346 patients were operated on by a translabyrinthine approach. Ninety-one patients were included in a retrospective study for follow-up of 5 years or longer.\nRESULTS: The mean follow-up period for magnetic resonance imaging (MRI) examination was obtained after mean of 11 years in 91 patients. None of the 91 patients experienced a recurrent vestibular schwannoma on MRI.\nCONCLUSION: The translabyrinthine approach is a safe procedure for total definitive removal of a vestibular schwannoma and permitted the absence of tumoral recurrence in our series of 91 patients. A single gadolinium-enhanced MRI scan 5 years after surgery is advised in case of total removal. In case of any doubt about the quality of the tumoral removal, a proposed MRI follow-up schedule within 2 years and 5 years of surgery is an initial baseline pattern, and possibly thereafter repeated MRI examinations on clinical grounds.","ISSN":"1524-4040","note":"PMID: 16239881","journalAbbreviation":"Neurosurgery","language":"eng","author":[{"family":"Schmerber","given":"Sébastien"},{"family":"Palombi","given":"Olivier"},{"family":"Boubagra","given":"Kamel"},{"family":"Charachon","given":"Robert"},{"family":"Chirossel","given":"Jean-Paul"},{"family":"Gay","given":"Emmanuel"}],"issued":{"date-parts":[["2005",10]]},"PMID":"16239881"}}],"schema":""} [37], although a recurrence rate of 0.3% for completely resected tumours has been reported by one author ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"58mk0m5dr","properties":{"formattedCitation":"[38]","plainCitation":"[38]"},"citationItems":[{"id":438,"uris":[""],"uri":[""],"itemData":{"id":438,"type":"article-journal","title":"Unilateral acoustic tumors: how often do they recur after translabyrinthine removal?","container-title":"The Laryngoscope","page":"958-966","volume":"105","issue":"9 Pt 1","source":"PubMed","abstract":"Unilateral acoustic tumors rarely recur after total translabyrinthine removal. Review of the patient records of the House Ear Clinic revealed five recurrent tumors, for an approximate incidence of 0.3%. A questionnaire was mailed to 857 patients who were at least 9 years postoperative and failed to find any additional recurrent tumors. No preoperative or intraoperative factors were identified to predict recurrence. The average time interval from initial removal to recurrence was approximately 10 years. Flow cytometric analysis did not reveal any fundamental differences between the recurrent acoustic tumor group and a larger group of 112 acoustic tumors. Based on observed growth rates of the recurrent acoustic tumors, a single gadolinium-enhanced magnetic resonance image 5 years after surgery is advised. To prevent recurrence, a margin of normal-appearing proximal eighth cranial nerve should be removed and the nerve stump cauterized.","DOI":"10.1288/00005537-199509000-00016","ISSN":"0023-852X","note":"PMID: 7666732","shortTitle":"Unilateral acoustic tumors","journalAbbreviation":"Laryngoscope","language":"eng","author":[{"family":"Shelton","given":"C."}],"issued":{"date-parts":[["1995",9]]},"PMID":"7666732"}}],"schema":""} [38]. There is evidence of growth in a proportion of patients who have residual tumour, with a small proportion requiring further treatment in the form of surgery or SRS ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"27biis6prk","properties":{"formattedCitation":"[33]","plainCitation":"[33]"},"citationItems":[{"id":440,"uris":[""],"uri":[""],"itemData":{"id":440,"type":"article-journal","title":"The behavior of residual tumors and facial nerve outcomes after incomplete excision of vestibular schwannomas: Clinical article","container-title":"Journal of Neurosurgery","page":"1278-1287","volume":"120","issue":"6","source":"CrossRef","DOI":"10.3171/2014.2.JNS131497","ISSN":"0022-3085","shortTitle":"The behavior of residual tumors and facial nerve outcomes after incomplete excision of vestibular schwannomas","language":"en","author":[{"family":"Chen","given":"Zhengnong"},{"family":"Prasad","given":"Sampath Chandra"},{"family":"Lella","given":"Filippo","non-dropping-particle":"Di"},{"family":"Medina","given":"Marimar"},{"family":"Piccirillo","given":"Enrico"},{"family":"Taibah","given":"Abdelkader"},{"family":"Russo","given":"Alessandra"},{"family":"Yin","given":"Shankai"},{"family":"Sanna","given":"Mario"}],"issued":{"date-parts":[["2014",6]]}}}],"schema":""} [33]. Bennett et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"uqifloc7m","properties":{"formattedCitation":"[39]","plainCitation":"[39]"},"citationItems":[{"id":441,"uris":[""],"uri":[""],"itemData":{"id":441,"type":"article-journal","title":"Postoperative imaging of vestibular schwannomas","container-title":"Otolaryngology-Head and Neck Surgery","page":"667-671","volume":"138","issue":"5","source":"CrossRef","DOI":"10.1016/j.otohns.2008.01.012","ISSN":"0194-5998, 1097-6817","language":"en","author":[{"family":"Bennett","given":"Marc L."},{"family":"Jackson","given":"C. Gary"},{"family":"Kaufmann","given":"Ryan"},{"family":"Warren","given":"Frank"}],"issued":{"date-parts":[["2008",5]]}}}],"schema":""} [39] studied the need and timing for post-operative imaging and concluded that initial imaging should be performed at 1 year post-op, with only those patients with enhancement, subtotal resections, or neurofibromatosis type II needing serial imaging. This policy understandably varies between Neurosurgical Units. Morbidity and Mortality: Mortality rates, once over 84% are now quoted as 0.2% ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2qrjcdc2q2","properties":{"formattedCitation":"[31]","plainCitation":"[31]"},"citationItems":[{"id":421,"uris":[""],"uri":[""],"itemData":{"id":421,"type":"article-journal","title":"Beyond audiofacial morbidity after vestibular schwannoma surgery","container-title":"Journal of Neurosurgery","page":"367-374","volume":"114","issue":"2","source":"PubMed","abstract":"OBJECT: Outcomes following vestibular schwannoma (VS) surgery have been extensively described; however, complication rates reported in the literature vary markedly. In addition, the majority of reports have focused on outcomes related to cranial nerves (CNs) VII and VIII. The objective of this study was to analyze reported morbidity unrelated to CNs VII and VIII following the resection of VS.\nMETHODS: The authors performed a comprehensive search of the English language literature, identifying and aggregating morbidity and death data from patients who had undergone microsurgical removal of VSs. A subgroup analysis based on surgical approach and tumor size was performed to compare rates of CSF leakage, vascular injury, neurological deficit, and postoperative infection.\nRESULTS: One hundred articles met the inclusion criteria, providing data for 32,870 patients. The overall mortality rate was 0.2% (95% CI 0.1-0.3%). Twenty-two percent of patients (95% CI 21-23%) experienced at least 1 surgically attributable complication unrelated to CNs VII or VIII. Cerebrospinal fluid leakage occurred in 8.5% of patients (95% CI 6.9-10.0%). This rate was markedly increased with the translabyrinthine approach but was not affected by tumor size. Vascular complications, such as ischemic injury or hemorrhage, occurred in 1% of patients (95% CI 0.75-1.2%). Neurological complications occurred in 8.6% of cases (95% CI 7.9-9.3%) and were less likely with the resection of smaller tumors (p < 0.0001) and the use of the translabyrinthine approach (p < 0.0001). Infections occurred in 3.8% of cases (95% CI 3.4-4.3%), and 78% of these infections were meningitis.\nCONCLUSIONS: This study provides statistically powerful data for practitioners to advise patients about the published risks of surgery for VS unrelated to compromised CNs VII and VIII.","DOI":"10.3171/2009.10.JNS091203","ISSN":"1933-0693","note":"PMID: 19943734","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"Sughrue","given":"Michael E."},{"family":"Yang","given":"Isaac"},{"family":"Aranda","given":"Derick"},{"family":"Rutkowski","given":"Martin J."},{"family":"Fang","given":"Shanna"},{"family":"Cheung","given":"Steven W."},{"family":"Parsa","given":"Andrew T."}],"issued":{"date-parts":[["2011",2]]},"PMID":"19943734"}}],"schema":""} [31]. Morbidity rates, in terms of major neurological complications such as stroke, injury to lower cranial nerves and/or trigeminal nerve, persistent cerebellar dysfunction and seizures, are reported at rates between 1.8-2.6% ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"s4f0qudrb","properties":{"formattedCitation":"[29]","plainCitation":"[29]"},"citationItems":[{"id":416,"uris":[""],"uri":[""],"itemData":{"id":416,"type":"article-journal","title":"Surgery for vestibular schwannomas: a systematic review of complications by approach","container-title":"Neurosurgical Focus","page":"E14","volume":"33","issue":"3","source":"CrossRef","DOI":"10.3171/2012.6.FOCUS12163","ISSN":"1092-0684","shortTitle":"Surgery for vestibular schwannomas","language":"en","author":[{"family":"Ansari","given":"Shaheryar F."},{"family":"Terry","given":"Colin"},{"family":"Cohen-Gadol","given":"Aaron A."}],"issued":{"date-parts":[["2012",9]]}}}],"schema":""} [29], and do not vary significantly between the different surgical approaches. Infection rates, namely of meningitis, are quoted at 4% ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"psivnced9","properties":{"formattedCitation":"[31]","plainCitation":"[31]"},"citationItems":[{"id":421,"uris":[""],"uri":[""],"itemData":{"id":421,"type":"article-journal","title":"Beyond audiofacial morbidity after vestibular schwannoma surgery","container-title":"Journal of Neurosurgery","page":"367-374","volume":"114","issue":"2","source":"PubMed","abstract":"OBJECT: Outcomes following vestibular schwannoma (VS) surgery have been extensively described; however, complication rates reported in the literature vary markedly. In addition, the majority of reports have focused on outcomes related to cranial nerves (CNs) VII and VIII. The objective of this study was to analyze reported morbidity unrelated to CNs VII and VIII following the resection of VS.\nMETHODS: The authors performed a comprehensive search of the English language literature, identifying and aggregating morbidity and death data from patients who had undergone microsurgical removal of VSs. A subgroup analysis based on surgical approach and tumor size was performed to compare rates of CSF leakage, vascular injury, neurological deficit, and postoperative infection.\nRESULTS: One hundred articles met the inclusion criteria, providing data for 32,870 patients. The overall mortality rate was 0.2% (95% CI 0.1-0.3%). Twenty-two percent of patients (95% CI 21-23%) experienced at least 1 surgically attributable complication unrelated to CNs VII or VIII. Cerebrospinal fluid leakage occurred in 8.5% of patients (95% CI 6.9-10.0%). This rate was markedly increased with the translabyrinthine approach but was not affected by tumor size. Vascular complications, such as ischemic injury or hemorrhage, occurred in 1% of patients (95% CI 0.75-1.2%). Neurological complications occurred in 8.6% of cases (95% CI 7.9-9.3%) and were less likely with the resection of smaller tumors (p < 0.0001) and the use of the translabyrinthine approach (p < 0.0001). Infections occurred in 3.8% of cases (95% CI 3.4-4.3%), and 78% of these infections were meningitis.\nCONCLUSIONS: This study provides statistically powerful data for practitioners to advise patients about the published risks of surgery for VS unrelated to compromised CNs VII and VIII.","DOI":"10.3171/2009.10.JNS091203","ISSN":"1933-0693","note":"PMID: 19943734","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"Sughrue","given":"Michael E."},{"family":"Yang","given":"Isaac"},{"family":"Aranda","given":"Derick"},{"family":"Rutkowski","given":"Martin J."},{"family":"Fang","given":"Shanna"},{"family":"Cheung","given":"Steven W."},{"family":"Parsa","given":"Andrew T."}],"issued":{"date-parts":[["2011",2]]},"PMID":"19943734"}}],"schema":""} [31]. These morbidity and mortality rates are relatively low, but even uncomplicated procedures represent a significant trauma to patients, with Pritchard reporting that one-third of patients were unable to work following surgery for at least six months. He calculated that the mean loss of income to patients undergoing VS surgery as ?11,220. Post-operatively 75% of patients were anxious that they wouldn’t ‘ever be normal again’ and 39% reported depression. RadiotherapyA number of approaches are used for patients with VS; stereotactic radiosurgery, stereotactic radiotherapy and proton beam therapy. In England tumours less than 3.5cm in extracanalicular diameter with no clinical signs of brainstem compression can be considered for stereotactic radiosurgery, and tumours less than 2.5cm for stereotactic radiotherapy ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2pqe3vg4gt","properties":{"formattedCitation":"[40]","plainCitation":"[40]"},"citationItems":[{"id":127,"uris":[""],"uri":[""],"itemData":{"id":127,"type":"article","title":"Transforming participation in health and care.","URL":"england.nhs.uk/ wp-content/uploads/2013/09/trans-part-hc-guid1. pdf","author":[{"family":"NHS England","given":""}],"issued":{"date-parts":[["2013"]]},"accessed":{"date-parts":[["2015",9,17]]}}}],"schema":""} [40], although there is an increasing body of evidence to suggest they can be used in larger tumours ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"19hir0mfl","properties":{"formattedCitation":"[41]","plainCitation":"[41]"},"citationItems":[{"id":507,"uris":[""],"uri":[""],"itemData":{"id":507,"type":"article-journal","title":"Multisession stereotactic radiosurgery for large vestibular schwannomas","container-title":"Journal of Neurosurgery","page":"818-824","volume":"122","issue":"4","source":"PubMed","abstract":"OBJECT: Microsurgery is not the only option for larger vestibular schwannomas (VSs); recent reviews have confirmed the feasibility and efficacy of radiosurgery for larger VSs. This study illustrates the outcomes of a series of large VSs after multisession stereotactic radiosurgery (SRS).\nMETHODS: A series of 33 VSs larger than 8 cm(3) (range 8-24 cm(3), mean 11 cm(3), median 9.4 cm(3)) were treated using the CyberKnife from 2003 to 2011 with the multisession SRS technique in 2-5 fractions (14-19.5 Gy). Five patients had undergone surgical removal and 5 had ventriculoperitoneal shunts. Nine patients were eligible for but refused surgery. Twelve patients were older than 70 years and 5 were younger than 40 years. Two female patients had neurofibromatosis.\nRESULTS: The follow-up period ranged from 12 to 111 months (median 48 months); radiological growth control was achieved in 94% of cases: 19 tumors (58%) displayed no size variation or reduction in tumor diameter; 12 (36%), after a transient enlargement, presented with arrested growth or shrinkage. Seven patients had a volume reduction of more than 50%. Two patients (6%) needed debulking and 2 were treated with ventriculoperitoneal shunts. Actuarial progressionfree survival rates at 1 year and 5 years were 97% and 83%, respectively. Hearing was retained in 7 of the 8 patients with serviceable baseline hearing. Adverse events were limited to 1 case each of vertigo, tongue paresthesia, and trigeminal neuralgia.\nCONCLUSIONS: The good control rate obtained with multisession SRS deepens the controversy of the radiobiology of VSs and may extend the indication of radiation therapy (fractionated or SRS) for large VSs to include patients without symptoms of mass effect. The limited number of cases and short follow-up period do not provide sufficient support for widespread application of multisession SRS in young patients. Further studies with multisession SRS are warranted.","DOI":"10.3171/2014.11.JNS131552","ISSN":"1933-0693","note":"PMID: 25594321","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"Casentini","given":"Leopoldo"},{"family":"Fornezza","given":"Umberto"},{"family":"Perini","given":"Zeno"},{"family":"Perissinotto","given":"Egle"},{"family":"Colombo","given":"Federico"}],"issued":{"date-parts":[["2015",4]]},"PMID":"25594321"}}],"schema":""} [41]. All these methods have the goal of arresting tumour growth while minimising the risk to adjacent structures. Its use is not widespread in patients with larger tumours, symptoms secondary to mass effect, or those with brainstem compression.Stereotactic radiosurgery (SRS) delivers a single high dose of radiation to a tumour by utilisation of multiple convergent beams. This therefore minimises injury to adjacent structures including the trigeminal and facial nerves. Gamma Knife radiosurgery uses 201 fixed Cobalt-60 sources to deliver highly focused gamma rays. The linear accelerator delivers highly focused x-rays by using a single source rotated about the target in radiation arcs. SRS usually uses a single isocentre prescription technique and requires targets with spherical shape and maximum diameter less than 3?cm ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1b6rohct10","properties":{"formattedCitation":"[42]","plainCitation":"[42]"},"citationItems":[{"id":459,"uris":[""],"uri":[""],"itemData":{"id":459,"type":"article-journal","title":"Radiotherapy for vestibular schwannoma: Review of recent literature results","container-title":"Reports of Practical Oncology & Radiotherapy","page":"399-406","volume":"21","issue":"4","source":"CrossRef","DOI":"10.1016/j.rpor.2016.02.002","ISSN":"15071367","shortTitle":"Radiotherapy for vestibular schwannoma","language":"en","author":[{"family":"Apicella","given":"Giuseppina"},{"family":"Paolini","given":"Marina"},{"family":"Deantonio","given":"Letizia"},{"family":"Masini","given":"Laura"},{"family":"Krengli","given":"Marco"}],"issued":{"date-parts":[["2016",7]]}}}],"schema":""} [42]. Early users of SRS used treatment doses of up to 22Gy, which showed over 95% tumour control rates with up to 10 years of follow-up but had high rates of cranial nerve toxicity with hearing preservation rates of 40% at two years and trigeminal and facial nerve palsies in 33% of patients ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1jjhv30fm0","properties":{"formattedCitation":"[43]","plainCitation":"[43]"},"citationItems":[{"id":446,"uris":[""],"uri":[""],"itemData":{"id":446,"type":"article-journal","title":"Gamma knife radiosurgery for acoustic tumors: multivariate analysis of four year results","container-title":"Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology","page":"91-98","volume":"27","issue":"2","source":"PubMed","abstract":"In order to evaluate the results of radiosurgery for acoustic tumors and to identify optimum treatment parameters, an analysis of tumor control, as well as incidences of hearing loss, facial and trigeminal neuropathies was undertaken. Between August 1987 and August 1991, 134 patients with 136 acoustic tumors received stereotactic gamma knife radiosurgery at the University of Pittsburgh. Median follow-up was 24 months (range: 6-56 months). Tumor volumes ranged from 0.10 to 17.00 cm3 (median = 2.75 cm3). From one to ten isocenters were utilized per tumor treated (median = 3). Minimum tumor doses varied from 12 to 20 Gy (median = 17 Gy). The 4-year actuarial tumor control rate was 89.2 +/- 6.0%. Some degree of hearing (by pure tone audiometry) was preserved in 71.0 +/- 4.4% of patients. The actuarial rates for preservation of either pretreatment hearing level or useful hearing were 34.4 +/- 6.6% and 35.1 +/- 97% respectively. Respectively, the actuarial incidences of postradiosurgery facial and trigeminal neuropathies were 29.0 +/- 4.4% and 32.9 +/- 4.5%, respectively. No significant factors affecting tumor control were identified. Multivariate analysis identified a significantly increased risk of hearing loss in patients with neurofibromatosis (p = 0.0003) as well as decreased risks of facial and trigeminal neuropathies with both decreasing tumor diameter (p = 0.001) and increasing number of isocenters treated (p = 0.003). Radiosurgery is a safe and effective treatment for acoustic neuromas with acceptable morbidity that may be lowered by the use of multiple isocenter treatment techniques and by earlier treatment of small tumors.","ISSN":"0167-8140","note":"PMID: 8356233","shortTitle":"Gamma knife radiosurgery for acoustic tumors","journalAbbreviation":"Radiother Oncol","language":"eng","author":[{"family":"Flickinger","given":"J. C."},{"family":"Lunsford","given":"L. D."},{"family":"Linskey","given":"M. E."},{"family":"Duma","given":"C. M."},{"family":"Kondziolka","given":"D."}],"issued":{"date-parts":[["1993",5]]},"PMID":"8356233"}}],"schema":""} [43]. Therefore more recently this dose has been reduced to 12-13Gy in most centres giving local control rates of 91-100% at 10 years and trigeminal or facial nerve complication rates of below 5% ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1ribt4eejq","properties":{"formattedCitation":"[44]","plainCitation":"[44]"},"citationItems":[{"id":448,"uris":[""],"uri":[""],"itemData":{"id":448,"type":"article-journal","title":"Radiotherapy for vestibular schwannomas: a critical review","container-title":"International Journal of Radiation Oncology, Biology, Physics","page":"985-997","volume":"79","issue":"4","source":"PubMed","abstract":"Vestibular schwannomas are slow-growing tumors of the myelin-forming cells that cover cranial nerve VIII. The treatment options for patients with vestibular schwannoma include active observation, surgical management, and radiotherapy. However, the optimal treatment choice remains controversial. We have reviewed the available data and summarized the radiotherapeutic options, including single-session stereotactic radiosurgery, fractionated conventional radiotherapy, fractionated stereotactic radiotherapy, and proton beam therapy. The comparisons of the various radiotherapy modalities have been based on single-institution experiences, which have shown excellent tumor control rates of 91-100%. Both stereotactic radiosurgery and fractionated stereotactic radiotherapy have successfully improved cranial nerve V and VII preservation to >95%. The mixed data regarding the ideal hearing preservation therapy, inherent biases in patient selection, and differences in outcome analysis have made the comparison across radiotherapeutic modalities difficult. Early experience using proton therapy for vestibular schwannoma treatment demonstrated local control rates of 84-100% but disappointing hearing preservation rates of 33-42%. Efforts to improve radiotherapy delivery will focus on refined dosimetry with the goal of reducing the dose to the critical structures. As future randomized trials are unlikely, we suggest regimented pre- and post-treatment assessments, including validated evaluations of cranial nerves V, VII, and VIII, and quality of life assessments with long-term prospective follow-up. The results from such trials will enhance the understanding of therapy outcomes and improve our ability to inform patients.","DOI":"10.1016/j.ijrobp.2010.10.010","ISSN":"1879-355X","note":"PMID: 21353158","shortTitle":"Radiotherapy for vestibular schwannomas","journalAbbreviation":"Int. J. Radiat. Oncol. Biol. Phys.","language":"eng","author":[{"family":"Murphy","given":"Erin S."},{"family":"Suh","given":"John H."}],"issued":{"date-parts":[["2011",3,15]]},"PMID":"21353158"}}],"schema":""} [44]. Those patients with post-treatment tumour growth are managed by observation, further radiotherapy or surgery. Hearing preservation rates, even with lower radiation doses, are reported to decline to approximately 25% at 10 years ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1go3aj0tkh","properties":{"formattedCitation":"[45]","plainCitation":"[45]"},"citationItems":[{"id":450,"uris":[""],"uri":[""],"itemData":{"id":450,"type":"article-journal","title":"Long-term safety and efficacy of stereotactic radiosurgery for vestibular schwannomas: evaluation of 440 patients more than 10 years after treatment with Gamma Knife surgery","container-title":"Journal of Neurosurgery","page":"557-565","volume":"118","issue":"3","source":"PubMed","abstract":"Object Little is known about long-term outcomes, including tumor control and adverse radiation effects, in patients harboring vestibular schwannomas (VSs) treated with stereotactic radiosurgery > 10 years previously. The aim of this study was to confirm whether Gamma Knife surgery (GKS) for VSs continues to be safe and effective > 10 years after treatment. Methods A total of 440 patients with VS (including neurofibromatosis Type 2) treated with GKS between May 1991 and December 2000 were evaluable. Of these, 347 patients (79%) underwent GKS as an initial treatment and 93 (21%) had undergone prior resection. Three hundred fifty-eight patients (81%) had a solid tumor and 82 (19%) had a cystic tumor. The median tumor volume was 2.8 cm(3) and the median marginal dose was 12.8 Gy. Results The median follow-up period was 12.5 years. The actuarial 5- and ≥ 10-year progression-free survival was 93% and 92%, respectively. No patient developed treatment failure > 10 years after treatment. According to multivariate analysis, significant factors related to worse progression-free survival included brainstem compression with a deviation of the fourth ventricle (p < 0.0001), marginal dose ≤ 13 Gy (p = 0.01), prior treatment (p = 0.02), and female sex (p = 0.02). Of 287 patients treated at a recent optimum dose of ≤ 13 Gy, 3 (1%) developed facial palsy, including 2 with transient palsy and 1 with persistent palsy after a second GKS, and 3 (1%) developed facial numbness, including 2 with transient and 1 with persistent facial numbness. The actuarial 10-year facial nerve preservation rate was 97% in the high marginal dose group (> 13 Gy) and 100% in the low marginal dose group (≤ 13 Gy). Ten patients (2.3%) developed delayed cyst formation. One patient alone developed malignant transformation, indicating an incidence of 0.3%. Conclusions In this study GKS was a safe and effective treatment for the majority of patients followed > 10 years after treatment. Special attention should be paid to cyst formation and malignant transformation as late adverse radiation effects, although they appeared to be rare. However, it is necessary to collect further long-term follow-up data before making conclusions about the long-term safety and efficacy of GKS, especially for young patients with VSs.","DOI":"10.3171/2012.10.JNS12523","ISSN":"1933-0693","note":"PMID: 23140152","shortTitle":"Long-term safety and efficacy of stereotactic radiosurgery for vestibular schwannomas","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"Hasegawa","given":"Toshinori"},{"family":"Kida","given":"Yoshihisa"},{"family":"Kato","given":"Takenori"},{"family":"Iizuka","given":"Hiroshi"},{"family":"Kuramitsu","given":"Shunichiro"},{"family":"Yamamoto","given":"Takashi"}],"issued":{"date-parts":[["2013",3]]},"PMID":"23140152"}}],"schema":""} [45]. A recent systemic review comparing Gamma Knife radiosurgery with microsurgical resection in VS eligible for both treatments demonstrated better outcome after Gamma Knife radiosurgery? ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2ndjnbc3hi","properties":{"formattedCitation":"[46]","plainCitation":"[46]"},"citationItems":[{"id":452,"uris":[""],"uri":[""],"itemData":{"id":452,"type":"article-journal","title":"What intervention is best practice for vestibular schwannomas? A systematic review of controlled studies","container-title":"BMJ open","volume":"3","issue":"2","source":"PubMed","abstract":"OBJECTIVE: Largely, watchful waiting is the initial policy for patients with small-sized or medium-sized vestibular schwannoma, because of slow growth and relatively minor complaints, that do not improve by an intervention. If intervention (microsurgery, radiosurgery or fractionated radiotherapy) becomes necessary, the choice of intervention appears to be driven by the patient's or clinician's preference rather than by evidence based. This study addresses the existing evidence based on controlled studies of these interventions.\nDESIGN: A systematic Boolean search was performed focused on controlled intervention studies. The quality of the retrieved studies was assessed based on the Sign-50 criteria on cohort studies.\nDATA SOURCES: Pubmed/Medline, Embase, Cochrane Central Register of Controlled Trials and reference lists.\nSTUDY SELECTION: Six eligibility criteria included a controlled intervention study on a newly diagnosed solitary, vestibular schwannoma reporting on clinical outcomes. Two prospective and four retrospective observational, controlled studies published before November 2011 were selected.\nDATA ANALYSIS: Two reviewers independently assessed the methodological quality of the studies and extracted the outcome data using predefined formats.\nRESULTS: Neither randomised studies, nor controlled studies on fractionated radiotherapy were retrieved. Six studies compared radiosurgery and microsurgery in a controlled way. All but one were confined to solitary tumours less than 30 mm in diameter and had no earlier interventions. Four studies qualified for trustworthy conclusions. Among all four, radiosurgery showed the best outcomes: there were no direct mortality, no surgical or anaesthesiological complications, but better facial nerve outcome, better preservation of useful hearing and better quality of life.\nCONCLUSIONS: The available evidence indicates radiosurgery to be the best practice for solitary vestibular schwannomas up to 30 mm in cisternal diameter.","DOI":"10.1136/bmjopen-2012-001345","ISSN":"2044-6055","note":"PMID: 23435793\nPMCID: PMC3586173","shortTitle":"What intervention is best practice for vestibular schwannomas?","journalAbbreviation":"BMJ Open","language":"eng","author":[{"family":"Wolbers","given":"John G."},{"family":"Dallenga","given":"Alof Hg"},{"family":"Mendez Romero","given":"Alejandra"},{"family":"Linge","given":"Anne","non-dropping-particle":"van"}],"issued":{"date-parts":[["2013"]]},"PMID":"23435793","PMCID":"PMC3586173"}}],"schema":""} [46]. However, given that radiation can affect neurologic function even after many years while surgery results in immediate neurological deficit, the length of follow-up in the various studies does influence the incidence of neurologic impairment after radiation treatment. Longer-term data (>10years) on lower dose stereotactic radiosurgery are lacking, particularly relevant to younger patients treated by this method. Post-radiation tumour expansion, otherwise known as pseudo progression, is well reported following SRS, at rates of up to 23%, onset at 6 months and typically regression by 24 months post treatment ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"192k86ei0e","properties":{"formattedCitation":"[47]","plainCitation":"[47]"},"citationItems":[{"id":456,"uris":[""],"uri":[""],"itemData":{"id":456,"type":"article-journal","title":"Tumor pseudoprogression following radiosurgery for vestibular schwannoma","container-title":"Neuro-Oncology","page":"87-92","volume":"14","issue":"1","source":"CrossRef","DOI":"10.1093/neuonc/nor171","ISSN":"1522-8517, 1523-5866","language":"en","author":[{"family":"Hayhurst","given":"C."},{"family":"Zadeh","given":"G."}],"issued":{"date-parts":[["2012",1,1]]}}}],"schema":""} [47]. Tumour progression beyond this time is therefore likely to be treatment failure, and therefore further intervention should be considered only at this stage, unless there is a clinical need to intervene before due to mass effect. Delayed cyst formation has been reported in 2% of patients at a median of 6 years after SRS that required surgical management ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"23l969ct46","properties":{"formattedCitation":"[45]","plainCitation":"[45]"},"citationItems":[{"id":450,"uris":[""],"uri":[""],"itemData":{"id":450,"type":"article-journal","title":"Long-term safety and efficacy of stereotactic radiosurgery for vestibular schwannomas: evaluation of 440 patients more than 10 years after treatment with Gamma Knife surgery","container-title":"Journal of Neurosurgery","page":"557-565","volume":"118","issue":"3","source":"PubMed","abstract":"Object Little is known about long-term outcomes, including tumor control and adverse radiation effects, in patients harboring vestibular schwannomas (VSs) treated with stereotactic radiosurgery > 10 years previously. The aim of this study was to confirm whether Gamma Knife surgery (GKS) for VSs continues to be safe and effective > 10 years after treatment. Methods A total of 440 patients with VS (including neurofibromatosis Type 2) treated with GKS between May 1991 and December 2000 were evaluable. Of these, 347 patients (79%) underwent GKS as an initial treatment and 93 (21%) had undergone prior resection. Three hundred fifty-eight patients (81%) had a solid tumor and 82 (19%) had a cystic tumor. The median tumor volume was 2.8 cm(3) and the median marginal dose was 12.8 Gy. Results The median follow-up period was 12.5 years. The actuarial 5- and ≥ 10-year progression-free survival was 93% and 92%, respectively. No patient developed treatment failure > 10 years after treatment. According to multivariate analysis, significant factors related to worse progression-free survival included brainstem compression with a deviation of the fourth ventricle (p < 0.0001), marginal dose ≤ 13 Gy (p = 0.01), prior treatment (p = 0.02), and female sex (p = 0.02). Of 287 patients treated at a recent optimum dose of ≤ 13 Gy, 3 (1%) developed facial palsy, including 2 with transient palsy and 1 with persistent palsy after a second GKS, and 3 (1%) developed facial numbness, including 2 with transient and 1 with persistent facial numbness. The actuarial 10-year facial nerve preservation rate was 97% in the high marginal dose group (> 13 Gy) and 100% in the low marginal dose group (≤ 13 Gy). Ten patients (2.3%) developed delayed cyst formation. One patient alone developed malignant transformation, indicating an incidence of 0.3%. Conclusions In this study GKS was a safe and effective treatment for the majority of patients followed > 10 years after treatment. Special attention should be paid to cyst formation and malignant transformation as late adverse radiation effects, although they appeared to be rare. However, it is necessary to collect further long-term follow-up data before making conclusions about the long-term safety and efficacy of GKS, especially for young patients with VSs.","DOI":"10.3171/2012.10.JNS12523","ISSN":"1933-0693","note":"PMID: 23140152","shortTitle":"Long-term safety and efficacy of stereotactic radiosurgery for vestibular schwannomas","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"Hasegawa","given":"Toshinori"},{"family":"Kida","given":"Yoshihisa"},{"family":"Kato","given":"Takenori"},{"family":"Iizuka","given":"Hiroshi"},{"family":"Kuramitsu","given":"Shunichiro"},{"family":"Yamamoto","given":"Takashi"}],"issued":{"date-parts":[["2013",3]]},"PMID":"23140152"}}],"schema":""} [45]. Malignant transformation is rare, estimated at 0.3% after SRS ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5dts9k1a8","properties":{"formattedCitation":"[45]","plainCitation":"[45]"},"citationItems":[{"id":450,"uris":[""],"uri":[""],"itemData":{"id":450,"type":"article-journal","title":"Long-term safety and efficacy of stereotactic radiosurgery for vestibular schwannomas: evaluation of 440 patients more than 10 years after treatment with Gamma Knife surgery","container-title":"Journal of Neurosurgery","page":"557-565","volume":"118","issue":"3","source":"PubMed","abstract":"Object Little is known about long-term outcomes, including tumor control and adverse radiation effects, in patients harboring vestibular schwannomas (VSs) treated with stereotactic radiosurgery > 10 years previously. The aim of this study was to confirm whether Gamma Knife surgery (GKS) for VSs continues to be safe and effective > 10 years after treatment. Methods A total of 440 patients with VS (including neurofibromatosis Type 2) treated with GKS between May 1991 and December 2000 were evaluable. Of these, 347 patients (79%) underwent GKS as an initial treatment and 93 (21%) had undergone prior resection. Three hundred fifty-eight patients (81%) had a solid tumor and 82 (19%) had a cystic tumor. The median tumor volume was 2.8 cm(3) and the median marginal dose was 12.8 Gy. Results The median follow-up period was 12.5 years. The actuarial 5- and ≥ 10-year progression-free survival was 93% and 92%, respectively. No patient developed treatment failure > 10 years after treatment. According to multivariate analysis, significant factors related to worse progression-free survival included brainstem compression with a deviation of the fourth ventricle (p < 0.0001), marginal dose ≤ 13 Gy (p = 0.01), prior treatment (p = 0.02), and female sex (p = 0.02). Of 287 patients treated at a recent optimum dose of ≤ 13 Gy, 3 (1%) developed facial palsy, including 2 with transient palsy and 1 with persistent palsy after a second GKS, and 3 (1%) developed facial numbness, including 2 with transient and 1 with persistent facial numbness. The actuarial 10-year facial nerve preservation rate was 97% in the high marginal dose group (> 13 Gy) and 100% in the low marginal dose group (≤ 13 Gy). Ten patients (2.3%) developed delayed cyst formation. One patient alone developed malignant transformation, indicating an incidence of 0.3%. Conclusions In this study GKS was a safe and effective treatment for the majority of patients followed > 10 years after treatment. Special attention should be paid to cyst formation and malignant transformation as late adverse radiation effects, although they appeared to be rare. However, it is necessary to collect further long-term follow-up data before making conclusions about the long-term safety and efficacy of GKS, especially for young patients with VSs.","DOI":"10.3171/2012.10.JNS12523","ISSN":"1933-0693","note":"PMID: 23140152","shortTitle":"Long-term safety and efficacy of stereotactic radiosurgery for vestibular schwannomas","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"Hasegawa","given":"Toshinori"},{"family":"Kida","given":"Yoshihisa"},{"family":"Kato","given":"Takenori"},{"family":"Iizuka","given":"Hiroshi"},{"family":"Kuramitsu","given":"Shunichiro"},{"family":"Yamamoto","given":"Takashi"}],"issued":{"date-parts":[["2013",3]]},"PMID":"23140152"}}],"schema":""} [45]. Stereotactic photon radiotherapyFractionated stereotactic radiotherapy (FSRT) delivers focused doses of radiation given over a series of treatment sessions. The intent of this method of treatment is to control tumour growth while reducing radiation injury to critical neural structures such as the facial nerve. Its main advantage over SRS is for irregularly shaped tumours, where it allows more conformal dose distributions and a more homogeneous dose deposition than SRS. It does not have a radiobiological advantage compared to SRS as the nature of VS (slow growing non-hypoxic tumours) means that there is no biological benefit from fractionation and a larger total dose of radiation is delivered. A large series of patients with VS treated with FSRT of 18Gy in 3 sessions, showed tumour control rates of 99% at 3 years and 96% at 5 years. Serviceable hearing preservation rate was 76%, there was no case of post-FSRT facial weakness and 1% of patients suffering permanent trigeminal dysfunction ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1tulpnu8t7","properties":{"formattedCitation":"[48]","plainCitation":"[48]"},"citationItems":[{"id":460,"uris":[""],"uri":[""],"itemData":{"id":460,"type":"article-journal","title":"Multisession stereotactic radiosurgery for vestibular schwannomas: single-institution experience with 383 cases","container-title":"Neurosurgery","page":"1200-1209","volume":"69","issue":"6","source":"PubMed","abstract":"BACKGROUND: Single-session stereotactic radiosurgery (SRS) treatment of vestibular schwannomas results in excellent tumor control. It is not known whether functional outcomes can be improved by fractionating the treatment over multiple sessions.\nOBJECTIVE: To examine tumor control and complication rates after multisession SRS.\nMETHODS: Three hundred eighty-three patients treated with SRS from 1999 to 2007 at Stanford University Medical Center were retrospectively reviewed. Ninety percent were treated with 18 Gy in 3 sessions, targeting a median tumor volume of 1.1 cm3 (range, 0.02-19.8 cm3).\nRESULTS: During a median follow-up duration of 3.6 years (range, 1-10 years), 10 tumors required additional treatment, resulting in 3- and 5-year Kaplan-Meier tumor control rates of 99% and 96%, respectively. Five-year tumor control rate was 98% for tumors < 3.4 cm3. Neurofibromatosis type 2-associated tumors were associated with worse tumor control (P = .02). Of the 200 evaluable patients with pre-SRS serviceable hearing (Gardner-Robertson grade 1 and 2), the crude rate of serviceable hearing preservation was 76%. Smaller tumor volume was associated with hearing preservation (P = .001). There was no case of post-SRS facial weakness. Eight patients (2%) developed trigeminal dysfunction, half of which was transient.\nCONCLUSION: Multisession SRS treatment of vestibular schwannomas results in an excellent rate of tumor control. The hearing, trigeminal nerve, and facial nerve function preservation rates reported here are promising.","DOI":"10.1227/NEU.0b013e318222e451","ISSN":"1524-4040","note":"PMID: 21558974","shortTitle":"Multisession stereotactic radiosurgery for vestibular schwannomas","journalAbbreviation":"Neurosurgery","language":"eng","author":[{"family":"Hansasuta","given":"Ake"},{"family":"Choi","given":"Clara Y. H."},{"family":"Gibbs","given":"Iris C."},{"family":"Soltys","given":"Scott G."},{"family":"Tse","given":"Victor C. K."},{"family":"Lieberson","given":"Robert E."},{"family":"Hayden","given":"Melanie G."},{"family":"Sakamoto","given":"Gordon T."},{"family":"Harsh","given":"Griffith R."},{"family":"Adler","given":"John R."},{"family":"Chang","given":"Steven D."}],"issued":{"date-parts":[["2011",12]]},"PMID":"21558974"}}],"schema":""} [48]. In another large series patients received doses of 25Gy in five fractions or 30Gy in 10 fractions. Over an average follow-up of 5 years, 3% had progressive growth requiring surgical intervention, 1.6% had new facial weakness, 2.8% had new trigeminal paraesthesias and 0.9% had hydrocephalus. 0.5% of patients in the series had possible, but not confirmed, radiation-induced tumours.A recent systematic review comparing SRS and FSRT that included 19 case series concluded that tumour control rates were similar between the two modalities, that the risk of facial and trigeminal nerve deterioration was less for patients treated by SRS and that there was no significant difference in preserved hearing between the two groups. The authors of this review acknowledged that in forming this comparison of treatments they could only identify 2 studies reporting on long-term tumour control after FSRT ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"27a2vueesq","properties":{"formattedCitation":"[49]","plainCitation":"[49]"},"citationItems":[{"id":462,"uris":[""],"uri":[""],"itemData":{"id":462,"type":"article-journal","title":"Stereotactic radiosurgery vs. fractionated radiotherapy for tumor control in vestibular schwannoma patients: a systematic review","container-title":"Acta Neurochirurgica","page":"1013-1021","volume":"159","issue":"6","source":"CrossRef","DOI":"10.1007/s00701-017-3164-6","ISSN":"0001-6268, 0942-0940","shortTitle":"Stereotactic radiosurgery vs. fractionated radiotherapy for tumor control in vestibular schwannoma patients","language":"en","author":[{"family":"Persson","given":"Oscar"},{"family":"Bartek","given":"Jiri"},{"family":"Shalom","given":"Netanel Ben"},{"family":"Wangerid","given":"Theresa"},{"family":"Jakola","given":"Asgeir Store"},{"family":"F?rander","given":"Petter"}],"issued":{"date-parts":[["2017",6]]}}}],"schema":""} [49]. Proton beam therapyProton beam therapy delivers targeted high energy protons to target tissue, damaging the DNA of the cells they are targeting. Most of the damage is thought to be indirect through the production of oxygen radicals rather than by direct collision with protons. All protons of a given energy have a certain range, meaning that very few penetrate beyond that distance, with the dose delivered to tissue being maximised over the last few millimetres of its range (called the Bragg peak) which minimises the dose to surrounding tissues. There are few papers studying the use of proton beam therapy for treatment of VS. Weber et al conducted a study that included 88 patients treated by proton beam SRS , and a follow-up period of 5 years, giving a dose of 160-MeV protons in 2-4 convergent beams ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1va6cq35ud","properties":{"formattedCitation":"[50]","plainCitation":"[50]"},"citationItems":[{"id":463,"uris":[""],"uri":[""],"itemData":{"id":463,"type":"article-journal","title":"Proton beam radiosurgery for vestibular schwannoma: tumor control and cranial nerve toxicity","container-title":"Neurosurgery","page":"577-586; discussion 586-588","volume":"53","issue":"3","source":"PubMed","abstract":"OBJECTIVE: We sought to determine the tumor control rate and cranial nerve function outcomes in patients with vestibular schwannomas who were treated with proton beam stereotactic radiosurgery.\nMETHODS: Between November 1992 and August 2000, 88 patients with vestibular schwannomas were treated at the Harvard Cyclotron Laboratory with proton beam stereotactic radiosurgery in which two to four convergent fixed beams of 160-MeV protons were applied. The median transverse diameter was 16 mm (range, 2.5-35 mm), and the median tumor volume was 1.4 cm(3) (range, 0.1-15.9 cm(3)). Surgical resection had been performed previously in 15 patients (17%). Facial nerve function (House-Brackmann Grade 1) and trigeminal nerve function were normal in 79 patients (89.8%). Eight patients (9%) had good or excellent hearing (Gardner-Robertson [GR] Grade 1), and 13 patients (15%) had serviceable hearing (GR Grade 2). A median dose of 12 cobalt Gray equivalents (range, 10-18 cobalt Gray equivalents) was prescribed to the 70 to 108% isodose lines (median, 70%). The median follow-up period was 38.7 months (range, 12-102.6 mo).\nRESULTS: The actuarial 2- and 5-year tumor control rates were 95.3% (95% confidence interval [CI], 90.9-99.9%) and 93.6% (95% CI, 88.3-99.3%). Salvage radiosurgery was performed in one patient 32.5 months after treatment, and a craniotomy was required 19.1 months after treatment in another patient with hemorrhage in the vicinity of a stable tumor. Three patients (3.4%) underwent shunting for hydrocephalus, and a subsequent partial resection was performed in one of these patients. The actuarial 5-year cumulative radiological reduction rate was 94.7% (95% CI, 81.2-98.3%). Of the 21 patients (24%) with functional hearing (GR Grade 1 or 2), 7 (33.3%) retained serviceable hearing ability (GR Grade 2). Actuarial 5-year normal facial and trigeminal nerve function preservation rates were 91.1% (95% CI, 85-97.6%) and 89.4% (95% CI, 82-96.7%). Univariate analysis revealed that prescribed dose (P = 0.005), maximum dose (P = 0.006), and the inhomogeneity coefficient (P = 0.03) were associated with a significant risk of long-term facial neuropathy. No other cranial nerve deficits or cancer relapses were observed.\nCONCLUSION: Proton beam stereotactic radiosurgery has been shown to be an effective means of tumor control. A high radiological response rate was observed. Excellent facial and trigeminal nerve function preservation rates were achieved. A reduced prescribed dose is associated with a significant decrease in facial neuropathy.","ISSN":"0148-396X","note":"PMID: 12943574","shortTitle":"Proton beam radiosurgery for vestibular schwannoma","journalAbbreviation":"Neurosurgery","language":"eng","author":[{"family":"Weber","given":"Damien C."},{"family":"Chan","given":"Annie W."},{"family":"Bussiere","given":"Marc R."},{"family":"Harsh","given":"Griffith R."},{"family":"Ancukiewicz","given":"Marek"},{"family":"Barker","given":"Fred G."},{"family":"Thornton","given":"Allan T."},{"family":"Martuza","given":"Robert L."},{"family":"Nadol","given":"Joseph B."},{"family":"Chapman","given":"Paul H."},{"family":"Loeffler","given":"Jay S."}],"issued":{"date-parts":[["2003",9]]},"PMID":"12943574"}}],"schema":""} [50]. They treated tumours up to 35mm in diameter. 5-year tumour control rate was 93.6%, 33% of patients with pre-treatment serviceable hearing retained their hearing, and 5 year facial and trigeminal nerve function rates were 91.1% and 89.4% respectively. It is clear that further studies are required to explore this method more fully, including the effects of altering dose as has been performed in studies of gamma knife SRS. The shortage of proton beam facilities and extra costs may make this modality unworkable at present for VS treatment in many countries.Neurofibromatosis Type 2 and Vestibular Schwannoma ManagementPatients with VS secondary to NF2 require a different management strategy from those patients with sporadic VS, with the goal of management being preservation of function and quality of life. When tumours are detected the risks of treatment versus the risks of observation have to be carefully balanced. Strategies for managing patients with NF2 and VS are observation, surgery, stereotactic radiosurgery and radiotherapy and targeted therapies, particularly the VEGF inhibitor bevacizumab.. The complexity of decision making for this group of patients is highlighted by their proven improved outcomes when managed in specialty treatment centres ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"mrcqi9e94","properties":{"formattedCitation":"[51]","plainCitation":"[51]"},"citationItems":[{"id":473,"uris":[""],"uri":[""],"itemData":{"id":473,"type":"article-journal","title":"Predictors of the risk of mortality in neurofibromatosis 2","container-title":"American Journal of Human Genetics","page":"715-723","volume":"71","issue":"4","source":"PubMed","abstract":"To evaluate clinical and molecular predictors of the risk of mortality in people with neurofibromatosis 2 (NF2), we analyzed the mortality experience of 368 patients from 261 families in the United Kingdom NF2 registry, using the Cox proportional-hazards model and the jackknife method. Age at diagnosis, intracranial meningiomas, and type of treatment center were informative predictors of the risk of mortality. In Cox models, the relative risk of mortality increased 1.13-fold per year decrease in age at diagnosis (95% confidence interval [CI] 1.08-1.18) and was 2.51-fold greater in people with meningiomas compared with those without meningiomas (95% CI 1.38-4.57). The relative risk of mortality in patients treated at specialty centers was 0.34 compared with those treated at nonspecialty centers (95% CI 0.12-0.98). In a separate model, the relative risk of mortality in people with constitutional NF2 missense mutations was very low compared with those with other types of mutations (nonsense or frameshift mutations, splice-site mutations, and large deletions), but the CI could not be well quantified because there was only one death among people with missense mutations. We conclude that age at diagnosis, the strongest single predictor of the risk of mortality, is a useful index for patient counseling and clinical management (as are intracranial meningiomas). To ensure optimal care, we recommend that people with NF2 be referred to specialty treatment centers.","DOI":"10.1086/342716","ISSN":"0002-9297","note":"PMID: 12235555\nPMCID: PMC378530","journalAbbreviation":"Am. J. Hum. Genet.","language":"eng","author":[{"family":"Baser","given":"Michael E."},{"family":"Friedman","given":"J. M."},{"family":"Aeschliman","given":"Dana"},{"family":"Joe","given":"Harry"},{"family":"Wallace","given":"Andrew J."},{"family":"Ramsden","given":"Richard T."},{"family":"Evans","given":"D. Gareth R."}],"issued":{"date-parts":[["2002",10]]},"PMID":"12235555","PMCID":"PMC378530"}}],"schema":""} [51]. The indications for conversion from observation to treatment in patients with VS and NF2 are brainstem compression, risk of brainstem compression, deterioration in facial nerve function and deterioration in serviceable hearing ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"jma37i5s6","properties":{"formattedCitation":"[52]","plainCitation":"[52]"},"citationItems":[{"id":465,"uris":[""],"uri":[""],"itemData":{"id":465,"type":"article-journal","title":"Neurofibromatosis 2 [Bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II]","container-title":"Genetics in Medicine: Official Journal of the American College of Medical Genetics","page":"599-610","volume":"11","issue":"9","source":"PubMed","abstract":"Neurofibromatosis 2 is a dominantly inherited tumor predisposition syndrome caused by mutations in the NF2 gene on chromosome 22. Affected individuals inevitably develop schwannomas typically affecting both vestibular nerves leading to deafness. Rehabilitation with brainstem implants is improving this outcome. Schwannomas also occur on other cranial nerves, on spinal nerve roots, and on peripheral nerves. Meningiomas and ependymomas are other tumor features. In excess of 50% of patients represent new mutations and as many as one third are mosaic for the underlying disease causing mutation. Although truncating mutations (nonsense and frameshifts) are the most frequent germline event and cause the most severe disease, single and multiple exon deletions are common. A strategy for detection of the latter is vital for a sensitive analysis. NF2 represents a difficult management problem with most patients facing substantial morbidity and reduced life expectancy. Surgery remains the focus of current management, although watchful waiting and occasionally radiation treatment have a role. In the future, the development of tailored drug therapies aimed at the genetic level are likely to provide huge improvements for this devastating, life limiting condition.","DOI":"10.1097/GIM.0b013e3181ac9a27","ISSN":"1530-0366","note":"PMID: 19652604","journalAbbreviation":"Genet. Med.","language":"eng","author":[{"family":"Evans","given":"D. Gareth R."}],"issued":{"date-parts":[["2009",9]]},"PMID":"19652604"}}],"schema":""} [52]. Surgery, while still the most accepted form of intervention, is more complicated in patients with NF2. Pathologically VS in NF2 differ from sporadic VS in that they tend to be more lobular in shape (mainly due to multifocality) and grow more quickly ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1tgulshl8i","properties":{"formattedCitation":"[53]","plainCitation":"[53]"},"citationItems":[{"id":469,"uris":[""],"uri":[""],"itemData":{"id":469,"type":"article-journal","title":"Vestibular (acoustic) schwannomas: histologic features in neurofibromatosis 2 and in unilateral cases","container-title":"Journal of Neuropathology and Experimental Neurology","page":"106-113","volume":"52","issue":"2","source":"PubMed","abstract":"Unilateral vestibular schwannomas (VS) differ from those in patients with neurofibromatosis 2 (NF-2) clinically and by in situ appearance. To determine whether there are histopathologic differences, the presence of each of 16 histologic features was compared in first surgical resection specimens of 48 VS from 39 NF-2 patients and 293 unilateral VS. Antoni A and B areas, nuclear atypia, whorls, scarring, chronic inflammation, and sheets of macrophages were found equally in both groups. Vestibular schwannomas in NF-2 had more Verocay bodies, foci of high cellularity, and lobular growth patterns, the latter possibly correlating with in situ appearance. Ten NF-2 VS specimens had either meningiomas or microscopic meningeal cell proliferations removed with the VS from the same area, whereas none of the patients with a unilateral VS had these findings. Unilateral VS had more hyalinized and malformed vessels, recent and old thromboses and hemosiderin deposits. The differences could not be attributed to patient ages because there were similar differences between the VS in NF-2 and the unilateral VS of 40 patients age-matched to the NF-2 patients. There were more female patients in both groups, but gender did not influence the occurrence of any histologic features. There were nine additional patients with apparently unilateral VS but in whom the diagnosis of NF-2 was suggested by additional findings; six of the VS from these patients had lobular patterns.(ABSTRACT TRUNCATED AT 250 WORDS)","ISSN":"0022-3069","note":"PMID: 8440992","shortTitle":"Vestibular (acoustic) schwannomas","journalAbbreviation":"J. Neuropathol. Exp. Neurol.","language":"eng","author":[{"family":"Sobel","given":"R. A."}],"issued":{"date-parts":[["1993",3]]},"PMID":"8440992"}}],"schema":""} [53]. They may also envelop adjacent cochlear and facial nerves (again due to multifocality) rather than displacing them as do sporadic VS, which makes finding cleavage planes more complex ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"r6o1vkdkv","properties":{"formattedCitation":"[54]","plainCitation":"[54]"},"citationItems":[{"id":467,"uris":[""],"uri":[""],"itemData":{"id":467,"type":"article-journal","title":"Interface between the facial nerve and large acoustic neurinomas. Immunohistochemical study of the cleavage plane in NF2 and non-NF2 cases","container-title":"Journal of Neurosurgery","page":"541-547","volume":"80","issue":"3","source":"PubMed","abstract":"In acoustic neurinoma surgery, the surgeon is required to find a cleavage plane between the facial nerve and the tumor, and with the aid of the operating microscope this is usually achieved by fine dissection. A histological specimen of the nerve-tumor interface is available only if the facial nerve was hopelessly adherent to the tumor (usually a large or giant neoplasm) and the surgeon decided to sever the nerve to obtain a complete removal. The authors have examined immunohistochemically the nerve-tumor interface of 20 such facial nerves (six cases of neurofibromatosis 2 (NF2) and 14 of non-NF2) in a series of 351 acoustic neurinomas. The largest extrameatal dimension of the 20 tumors ranged from 20 to 51 mm (median 39 mm). In all of these 20 instances the nerve-tumor contact area was at least partially devoid of a clear-cut histological cleavage plane. Where the facial nerve trunk was attached to the surface of the tumor, nerve fibers of the contact areas either abutted directly against tumor cells or nerve fibers were seen to penetrate into the tumor tissue. Frank embedding of nerve fibers was more frequent in NF2.","DOI":"10.3171/jns.1994.80.3.0541","ISSN":"0022-3085","note":"PMID: 8113868","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"J??skel?inen","given":"J."},{"family":"Paetau","given":"A."},{"family":"Pyykk?","given":"I."},{"family":"Blomstedt","given":"G."},{"family":"Palva","given":"T."},{"family":"Troupp","given":"H."}],"issued":{"date-parts":[["1994",3]]},"PMID":"8113868"}}],"schema":""} [54]. Schwannomas of the facial and cochlear nerves can also co-exist with the VS. Surgically this means that VS in NF2 patients are more difficult to remove, and the risks of facial nerve dysfunction and hearing loss post-operatively are higher than their sporadic VS counterparts. These higher risks are particularly important to consider, especially for patients with bilateral disease. A recent study ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ujack8582","properties":{"formattedCitation":"[55]","plainCitation":"[55]"},"citationItems":[{"id":471,"uris":[""],"uri":[""],"itemData":{"id":471,"type":"article-journal","title":"Outcome of translabyrinthine surgery for vestibular schwannoma in neurofibromatosis type 2","container-title":"British Journal of Neurosurgery","page":"446-453","volume":"27","issue":"4","source":"PubMed","abstract":"OBJECTIVES: To analyse the long-term outcome of translabyrinthine surgery for vestibular schwannoma (VS) in neurofibromatosis type 2 (NF2). RESEARCH TYPE: Retrospective cohort study.\nSETTING: Two tertiary referral NF2 units.\nPATIENTS: One hundred and forty eight translabyrinthine operations for patients with VS were performed. Preoperative stereotactic radiotherapy had been performed on 12(9.4%) patients.\nRESULTS: Mean tumour size was 3.1 cm. Total tumour excision was achieved in 66% of cases, capsular remnants were left in 24% of cases, and subtotal excision was achieved in 5% and partial removal was achieved in 5%. The radiological residual/recurrence rate was 13.9%. The perioperative mortality was 1.6%. At 2 years postoperatively, facial function was expressed in terms of House-Brackmann score (HB): HB 1 in 53.4%, HB 1/2 in 61.3%, HB 1-3 in 83.2% and HB 4-6 in 16.8%. All nine patients who underwent surgery following failed stereotactic radiotherapy had HB 3 function or better. Among 9.5% of the cases, 14 facial nerves were lost during surgery and repaired using direct anastomosis or grafting. There was no tinnitus present preoperatively in 27% of the cases, and 22% of patients developed tinnitus postoperatively. In patients with preoperative tinnitus, 61% remained the same, 17% got it resolved and only in 21% it worsened. The preoperative hydrocephalus rate was 26%, and among 15% of the cases five ventriculo-peritoneal (VP) shunts were performed. The cerebrospinal fluid leak rate was 2.5%. Fifty-six patients underwent auditory brainstem implantation (ABI) and two patients had cochlear implant (CI) sleepers inserted.\nCONCLUSIONS: The management of patients with NF2 presents the clinician with a formidable challenge with many patients still presenting themselves late with the neurological compromise and a large tumour load. There is still an argument for the management by observation until the neurological compromise dictates interventional treatment particularly with the option of hearing rehabilitation with ABI or CI. The translabyrinthine approach provides a very satisfactory means of reducing the overall tumour volume.","DOI":"10.3109/02688697.2013.771143","ISSN":"1360-046X","note":"PMID: 23472624","journalAbbreviation":"Br J Neurosurg","language":"eng","author":[{"family":"Moffat","given":"D. A."},{"family":"Lloyd","given":"S. K. W."},{"family":"Macfarlane","given":"R."},{"family":"Mannion","given":"R."},{"family":"King","given":"A."},{"family":"Rutherford","given":"S."},{"family":"Axon","given":"P. R."},{"family":"Donnelly","given":"N."},{"family":"Freeman","given":"S."},{"family":"Tysome","given":"J. R."},{"family":"Evans","given":"D. G."},{"family":"Ramsden","given":"R. T."}],"issued":{"date-parts":[["2013",8]]},"PMID":"23472624"}}],"schema":""} [55] reporting the outcomes of translabyrinthine surgery for VS in NF2 achieved total tumour excision in 66%, near total excision in 24%, subtotal excision in 5% and partial removal in 5%, with a radiological recurrence rate of 13.9%. 83.6% of patients had facial nerve function of House-Brackmann (HB) score of 1-3, and 53.4% had a HB score of 1 post-operatively. 15% of patients required shunts for post-operative hydrocephalus, and 21% of patients reported worsened post-operative tinnitus. The mortality rate was 1.6%. Hearing rehabilitation was attempted in many patients, with fifty-six patients undergoing auditory brainstem implantation (ABI). It is clear from these outcomes, from centres specialising in the management of patients with NF2, that VS in NF2 are rather different from sporadic VS and require special consideration. Radiosurgery and fractionated radiotherapy are felt to have a role in management of VS in NF2 patients, particularly for those who have aggressive tumours, are high-risk surgical candidates, are more elderly or for those who refuse surgery. Outcomes for radiosurgery and fractionated radiotherapy vary in the literature for VS in NF2 as they do for sporadic VS. Tumour control rates for NF2 VSs are reported at 85, 81, and 81% at 5, 10, and 15 years, respectively, with tumour volume being a significant predictor of control ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"69nclq6v1","properties":{"formattedCitation":"[56]","plainCitation":"[56]"},"citationItems":[{"id":475,"uris":[""],"uri":[""],"itemData":{"id":475,"type":"article-journal","title":"Stereotactic radiosurgery for vestibular schwannomas in patients with neurofibromatosis type 2: an analysis of tumor control, complications, and hearing preservation rates","container-title":"Neurosurgery","page":"460-468; discussion 468-470","volume":"60","issue":"3","source":"PubMed","abstract":"OBJECTIVE: Vestibular schwannomas present significant management challenges in patients with neurofibromatosis Type 2 (NF2). We evaluated the results of gamma knife radiosurgery for the management of these tumors, focusing on tumor response, hearing preservation, and other factors affecting outcomes.\nMETHODS: Stereotactic radiosurgery was performed to manage 74 schwannomas in 62 patients. Ipsilateral serviceable hearing was present in 35% of tumors before the procedure. The mean tumor volume was 5.7 cm3. The mean margin and maximum dose used were 14 and 27.5 Gy, respectively. Cox regression analyses were performed to identify factors affecting outcomes.\nRESULTS: The median follow-up period was 53 months, and two patients were lost to follow-up. Actuarial local control rates at were 85, 81, and 81% at 5, 10, and 15 years, respectively. Tumor volume was significant as a predictor of local control. Since 1992, using current radiosurgery techniques (magnetic resonance imaging scan targeting and reduced margin dose to 14 Gy or less), the actuarial serviceable hearing preservation rate is 73% at 1 year, 59% at 2 years, and 48% at 5 years after radiosurgery. Facial neuropathy occurred in 8% of tumors, trigeminal neuropathy occurred in 4%, and vestibular dysfunction occurred in 4%. Radiation dose and tumor volume were predictive of development of new deficits. No radiosurgery-associated secondary tumors or atypical or malignant changes were noted.\nCONCLUSION: Stereotactic radiosurgery is a safe and effective management modality for neurofibromatosis Type 2 vestibular schwannomas. Although results do not seem to be as good as for patients with sporadic unilateral tumors, gamma knife radiosurgery results seem favorable and indicate that radiosurgery should be strongly considered for primary tumor management in selected patients.","DOI":"10.1227/01.NEU.0000255340.26027.53","ISSN":"1524-4040","note":"PMID: 17327790","shortTitle":"Stereotactic radiosurgery for vestibular schwannomas in patients with neurofibromatosis type 2","journalAbbreviation":"Neurosurgery","language":"eng","author":[{"family":"Mathieu","given":"David"},{"family":"Kondziolka","given":"Douglas"},{"family":"Flickinger","given":"John C."},{"family":"Niranjan","given":"Ajay"},{"family":"Williamson","given":"Richard"},{"family":"Martin","given":"Juan J."},{"family":"Lunsford","given":"L. Dade"}],"issued":{"date-parts":[["2007",3]]},"PMID":"17327790"}}],"schema":""} [56]. In the same study serviceable hearing preservation rate was reported as 73% at 1 year and 48% at 5 years, facial palsy in 8% and trigeminal neuropathy in 4%. A larger study of 122 VS from 96 patients showed a complete tumour control rate of only 50% at 8 years ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"t7f8up314","properties":{"formattedCitation":"[57]","plainCitation":"[57]"},"citationItems":[{"id":503,"uris":[""],"uri":[""],"itemData":{"id":503,"type":"chapter","title":"Radiosurgery for Type II Neurofibromatosis","container-title":"Progress in Neurological Surgery","publisher":"KARGER","publisher-place":"Basel","page":"176-182","volume":"21","source":"CrossRef","event-place":"Basel","URL":"","ISBN":"978-3-8055-8370-1","note":"DOI: 10.1159/000156907","language":"en","editor":[{"family":"Régis","given":"J."},{"family":"Roche","given":"P.-H."}],"author":[{"family":"Rowe","given":"Jeremy"},{"family":"Radatz","given":"Matthias"},{"family":"Kemeny","given":"Andras"}],"issued":{"date-parts":[["2008"]]},"accessed":{"date-parts":[["2017",9,11]]}}}],"schema":""} [57]. There are significant concerns, particularly in younger patients requiring treatment, of increased risk of secondary malignancies, both with stereotactic radiosurgery ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gicbjfspe","properties":{"formattedCitation":"[58]","plainCitation":"[58]"},"citationItems":[{"id":477,"uris":[""],"uri":[""],"itemData":{"id":477,"type":"article-journal","title":"Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes","container-title":"Journal of Medical Genetics","page":"289-294","volume":"43","issue":"4","source":"PubMed","abstract":"In recent years the use of radiation treatment for benign tumours has increased with the advent of stereotactic delivery and, in particular, single high dose gamma knife therapy. This has been particularly true for benign CNS (central nervous system) tumours such as vestibular schwannoma, meningioma, pituitary adenoma, and haemangioblastoma. While short term follow up in patients with isolated tumours suggests this treatment is safe, there are particular concerns regarding its use in childhood and in tumour predisposing syndromes. We have reviewed the use of radiation treatment in these contexts with particular regard to malignant transformation and new tumour induction. This review indicates that much more caution is warranted regarding the use of radiation treatment for benign tumours in childhood and in tumour prone conditions such as the neurofibromatoses.","DOI":"10.1136/jmg.2005.036319","ISSN":"1468-6244","note":"PMID: 16155191\nPMCID: PMC2563223","shortTitle":"Malignant transformation and new primary tumours after therapeutic radiation for benign disease","journalAbbreviation":"J. Med. Genet.","language":"eng","author":[{"family":"Evans","given":"D. G. R."},{"family":"Birch","given":"J. M."},{"family":"Ramsden","given":"R. T."},{"family":"Sharif","given":"S."},{"family":"Baser","given":"M. E."}],"issued":{"date-parts":[["2006",4]]},"PMID":"16155191","PMCID":"PMC2563223"}}],"schema":""} [58] and radiotherapy ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1vrbmvjo1d","properties":{"formattedCitation":"[59]","plainCitation":"[59]"},"citationItems":[{"id":481,"uris":[""],"uri":[""],"itemData":{"id":481,"type":"article-journal","title":"Radiation-induced rhabdomyosarcoma of the brainstem in a patient with neurofibromatosis type 2","container-title":"Journal of Neurosurgery","page":"81-87","volume":"112","issue":"1","source":"PubMed","abstract":"Neurofibromatosis Type 2 (NF2) is a rare autosomal dominant disorder characterized by the development of benign tumors of the peripheral nervous system and the CNS, including schwannomas, meningiomas, and ependymomas. The gene responsible for the development of NF2 acts as a tumor suppressor gene. Stereotactic radiotherapy (SRT) or single-fraction stereotactic radiosurgery has been increasingly used in the past decades to treat benign tumors in patients with NF2. These radiotherapy methods are less invasive and can be potentially used to treat multiple tumors in a single session. The risk of inducing malignancy is unclear. Few reports exist of malignant peripheral nerve sheath tumors, meningiomas, or ependymomas occurring after SRT or stereotactic radiosurgery in patients with NF2. The authors present the first documented case of rhabdomyosarcoma following SRT for multiple NF2-associated schwannomas. Compared with patients with sporadic tumors, NF2 patients having a germline tumor suppressor gene defect may be more prone to secondary malignancies after treatment involving radiation therapy.","DOI":"10.3171/2009.6.JNS09105","ISSN":"1933-0693","note":"PMID: 19575577","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"Carlson","given":"Matthew L."},{"family":"Babovic-Vuksanovic","given":"Dusica"},{"family":"Messiaen","given":"Ludwine"},{"family":"Scheithauer","given":"Bernd W."},{"family":"Scheithauer","given":"Bernd B."},{"family":"Neff","given":"Brian A."},{"family":"Link","given":"Michael J."}],"issued":{"date-parts":[["2010",1]]},"PMID":"19575577"}}],"schema":""} [59]. Patients should be counselled appropriately. Surgery, at present, is favoured over radiotherapy for patients with NF2 that have a VS requiring intervention ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2olasd0gi5","properties":{"formattedCitation":"[60]","plainCitation":"[60]"},"citationItems":[{"id":504,"uris":[""],"uri":[""],"itemData":{"id":504,"type":"article-journal","title":"Management of the patient and family with neurofibromatosis 2: a consensus conference statement","container-title":"British Journal of Neurosurgery","page":"5-12","volume":"19","issue":"1","source":"PubMed","abstract":"A consensus conference on neurofibromatosis 2 (NF2) was held in 2002 at the request of the United Kingdom (UK) Neurofibromatosis Association, with particular emphasis on vestibular schwannoma (VS) surgery. NF2 patients should be managed at specialty treatment centres, whose staff has extensive experience with the disease. All NF2 patients and their families should have access to genetic testing because presymptomatic diagnosis improves the clinical management of the disease. Some clinical manifestations of NF2, such as ocular abnormalities, can be detected in infancy; therefore, clinical screening for at-risk members of NF2 families can start at birth, with the first magnetic resonance (MRI) scan at 10-12 years of age. Minimal interference, maintenance of quality of life, and conservation of function or auditory rehabilitation are the cornerstones of NF2 management, and the decision points to achieve these goals for patients with different clinical presentations are discussed.","DOI":"10.1080/02688690500081206","ISSN":"0268-8697","note":"PMID: 16147576","shortTitle":"Management of the patient and family with neurofibromatosis 2","journalAbbreviation":"Br J Neurosurg","language":"eng","author":[{"family":"Evans","given":"D. G. R."},{"family":"Baser","given":"M. E."},{"family":"O’Reilly","given":"B."},{"family":"Rowe","given":"J."},{"family":"Gleeson","given":"M."},{"family":"Saeed","given":"S."},{"family":"King","given":"A."},{"family":"Huson","given":"S. M."},{"family":"Kerr","given":"R."},{"family":"Thomas","given":"N."},{"family":"Irving","given":"R."},{"family":"MacFarlane","given":"R."},{"family":"Ferner","given":"R."},{"family":"McLeod","given":"R."},{"family":"Moffat","given":"D."},{"family":"Ramsden","given":"R."}],"issued":{"date-parts":[["2005",2]]},"PMID":"16147576"}}],"schema":""} [60].Progress in cellular research has enhanced understanding with regard to pathways in which the NF2 gene product interacts, and this has led to the trial and subsequent use of targeted therapies in NF2 patients. Three of the most studied targeted therapies in NF2 and VS are bevacizumab, everolimus and lapatinib. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF), thought to be of benefit in the treatment of growing VS because it prunes and regularises tumour vasculature or has a direct antibody effect on overexpressed VEGF, thus halting tumour growth. One of the first trials of bevacizumab was in 2009, when 6 of the 10 patients treated had hearing improvement or greater than 20% reduction in tumour volume ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1h77m5b6","properties":{"formattedCitation":"[61]","plainCitation":"[61]"},"citationItems":[{"id":483,"uris":[""],"uri":[""],"itemData":{"id":483,"type":"article-journal","title":"Hearing improvement after bevacizumab in patients with neurofibromatosis type 2","container-title":"The New England Journal of Medicine","page":"358-367","volume":"361","issue":"4","source":"PubMed","abstract":"BACKGROUND: Profound hearing loss is a serious complication of neurofibromatosis type 2, a genetic condition associated with bilateral vestibular schwannomas, benign tumors that arise from the eighth cranial nerve. There is no medical treatment for such tumors.\nMETHODS: We determined the expression pattern of vascular endothelial growth factor (VEGF) and three of its receptors, VEGFR-2, neuropilin-1, and neuropilin-2, in paraffin-embedded samples from 21 vestibular schwannomas associated with neurofibromatosis type 2 and from 22 sporadic schwannomas. Ten consecutive patients with neurofibromatosis type 2 and progressive vestibular schwannomas who were not candidates for standard treatment were treated with bevacizumab, an anti-VEGF monoclonal antibody. An imaging response was defined as a decrease of at least 20% in tumor volume, as compared with baseline. A hearing response was defined as a significant increase in the word-recognition score, as compared with baseline.\nRESULTS: VEGF was expressed in 100% of vestibular schwannomas and VEGFR-2 in 32% of tumor vessels on immunohistochemical analysis. Before treatment, the median annual volumetric growth rate for 10 index tumors was 62%. After bevacizumab treatment in the 10 patients, tumors shrank in 9 patients, and 6 patients had an imaging response, which was maintained in 4 patients during 11 to 16 months of follow-up. The median best response to treatment was a volumetric reduction of 26%. Three patients were not eligible for a hearing response; of the remaining seven patients, four had a hearing response, two had stable hearing, and one had progressive hearing loss. There were 21 adverse events of grade 1 or 2.\nCONCLUSIONS: VEGF blockade with bevacizumab improved hearing in some, but not all, patients with neurofibromatosis type 2 and was associated with a reduction in the volume of most growing vestibular schwannomas.","DOI":"10.1056/NEJMoa0902579","ISSN":"1533-4406","note":"PMID: 19587327\nPMCID: PMC4816642","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Plotkin","given":"Scott R."},{"family":"Stemmer-Rachamimov","given":"Anat O."},{"family":"Barker","given":"Fred G."},{"family":"Halpin","given":"Chris"},{"family":"Padera","given":"Timothy P."},{"family":"Tyrrell","given":"Alex"},{"family":"Sorensen","given":"A. Gregory"},{"family":"Jain","given":"Rakesh K."},{"family":"Tomaso","given":"Emmanuelle","non-dropping-particle":"di"}],"issued":{"date-parts":[["2009",7,23]]},"PMID":"19587327","PMCID":"PMC4816642"}}],"schema":""} [61]. The same group has subsequently analysed the outcomes of 31 patients with NF2 and VS managed with bevacizumab and found that 88% of patients had stable or decreased tumour size at 3 years, 54% at 5 years. 90% of patients had stable or improved hearing after 1 year, and 61% at 3 years ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1a0e16qc8","properties":{"formattedCitation":"[62]","plainCitation":"[62]"},"citationItems":[{"id":495,"uris":[""],"uri":[""],"itemData":{"id":495,"type":"article-journal","title":"Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2: a retrospective review of 31 patients","container-title":"Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology","page":"1046-1052","volume":"33","issue":"6","source":"PubMed","abstract":"OBJECTIVE: Early studies suggest that bevacizumab treatment can result in tumor shrinkage and hearing improvement for some patients with neurofibromatosis type 2 (NF2). The aim of this study was to report extended follow-up in a larger cohort of similarly treated patients.\nSTUDY DESIGN: Retrospective study.\nSETTING: Tertiary referral center\nPATIENTS: Thirty-one consecutive NF2 patients who received bevacizumab for progressive vestibular schwannomas.\nMAIN OUTCOME MEASURE: Hearing improvement, defined as an improvement in word recognition score above the 95% critical difference compared with baseline, and radiographic response, defined as a 20% or greater decrease in tumor volume compared with baseline.\nRESULTS: The median age was 26 years (range, 12-73 yr). The median volumetric tumor growth rate before treatment was 64% per year. At the time of analysis, the median duration of treatment was 14 months (range, 6-41 mo) with a total of 47 patient-years of follow-up. A hearing response occurred in 57% (13/23) of evaluable patients and a radiographic response in 55% (17/31) of target vestibular schwannomas. The median time to response was 3 months for both end points. The only clinical or radiographic feature at baseline that correlated with change in tumor volume at 3 months was the mean apparent diffusion coefficient value, a radiologic marker of edema (p = 0.036). Ninety percent of patients had stable or improved hearing after 1 year of treatment and 61% at 3 years; 88% of patients had stable or decreased tumor size after 1 year of treatment and 54% at 3 years. Overall, treatment was well tolerated.\nCONCLUSION: Bevacizumab treatment was followed by hearing improvement and tumor shrinkage in more than 50% of progressive vestibular schwannomas in NF2 patients. Stable or improved hearing was retained in the majority of patients.","DOI":"10.1097/MAO.0b013e31825e73f5","ISSN":"1537-4505","note":"PMID: 22805104","shortTitle":"Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2","journalAbbreviation":"Otol. Neurotol.","language":"eng","author":[{"family":"Plotkin","given":"Scott R."},{"family":"Merker","given":"Vanessa L."},{"family":"Halpin","given":"Chris"},{"family":"Jennings","given":"Dominique"},{"family":"McKenna","given":"Michael J."},{"family":"Harris","given":"Gordon J."},{"family":"Barker","given":"Fred G."}],"issued":{"date-parts":[["2012",8]]},"PMID":"22805104"}}],"schema":""} [62]. These findings have led to bevacizumab being funded in the UK by the National Specialised Commissioning Team (NSCT) (NHS England). To be treated patients must have a schwannoma that is growing by at least 4mm/year (or 60% by volume), in whom the potential benefits of treatment outweigh the risks (for example of hypertension and altered renal and liver function) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1acj66j","properties":{"formattedCitation":"[63]","plainCitation":"[63]"},"citationItems":[{"id":485,"uris":[""],"uri":[""],"itemData":{"id":485,"type":"report","title":"Bevacizumab (Avastin) in NF2","URL":"","author":[{"literal":"The Neuro Foundation"}]}}],"schema":""} [63]. Treatment must be decided by a patient’s NF2 “hub” centre (Cambridge, London, Manchester or Oxford) as well as by a partner centre, or in the case of children, by all four centres ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"q54e8rdrk","properties":{"formattedCitation":"[64]","plainCitation":"[64]"},"citationItems":[{"id":506,"uris":[""],"uri":[""],"itemData":{"id":506,"type":"article-journal","title":"Bevacizumab in neurofibromatosis type 2 (NF2) related vestibular schwannomas: a nationally coordinated approach to delivery and prospective evaluation","container-title":"Neuro-Oncology Practice","page":"281-289","volume":"3","issue":"4","source":"CrossRef","DOI":"10.1093/nop/npv065","ISSN":"2054-2577, 2054-2585","shortTitle":"Bevacizumab in neurofibromatosis type 2 (NF2) related vestibular schwannomas","language":"en","author":[{"family":"Morris","given":"Katrina A."},{"family":"Golding","given":"John F."},{"family":"Axon","given":"Patrick R."},{"family":"Afridi","given":"Shazia"},{"family":"Blesing","given":"Claire"},{"family":"Ferner","given":"Rosalie E."},{"family":"Halliday","given":"Dorothy"},{"family":"Jena","given":"Raj"},{"family":"Pretorius","given":"Pieter M."},{"literal":"the UK NF2 Research group"},{"family":"Evans","given":"D. Gareth"},{"family":"McCabe","given":"Martin G."},{"family":"Parry","given":"Allyson"}],"issued":{"date-parts":[["2016",12]]}}}],"schema":""} [64]. Sixty-one patients with the rapid required growth showed high rates of tumour control/shrinkage and hearing preservation when treated with bevacizumab. The toxicities of bevacizumab have been reported widely in older cancer populations. Significant rates of hypertension and proteinuria have been reported with increasing cumulative bevacizumab doses in the NF2 population ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2n2pa1t2rk","properties":{"formattedCitation":"[65]","plainCitation":"[65]"},"citationItems":[{"id":509,"uris":[""],"uri":[""],"itemData":{"id":509,"type":"article-journal","title":"Toxicity profile of bevacizumab in the UK Neurofibromatosis type 2 cohort","container-title":"Journal of Neuro-Oncology","page":"117-124","volume":"131","issue":"1","source":"PubMed","abstract":"Bevacizumab is considered an established part of the treatment strategies available for schwannomas in patients with Neurofibromatosis type 2 (NF2). In the UK, it is available through NHS National Specialized Commissioning to NF2 patients with a rapidly growing target schwannoma. Regrowth of the tumour on suspension of treatment is often observed resulting in prolonged periods of exposure to bevacizumab to control the disease. Hypertension and proteinuria are common events with bevacizumab use and there are concerns with regards to the long-term risks of prolonged treatment. Dosing, demographic and adverse event (CTCAE 4.03) data from the UK NF2 bevacizumab cohort are reviewed with particular consideration of renal and cardiovascular complications. Eighty patients (48 male:32 female), median age 24.5 years (range 11-66 years), were followed for a median of 32.7 months (range 12.0-60.2 months). The most common adverse events were fatigue, hypertension and infection. A total of 19/80 patients (24?%) had either a grade 2 or grade 3 hypertension event and 14/80 patients (17.5?%) had proteinuria. Of 36 patients followed for 36 months, 78?% were free from hypertension and 86?% were free of proteinuria. Logistic regression modeling identified age and induction dosing regime to be independent predictors of development of hypertension with dose of 7.5?mg/kg 3 weekly and age >30years having higher rates of hypertension. Proteinuria persisted in one of three patients after cessation of bevacizumab. One patient developed congestive heart failure and the details of this case are described. Further work is needed to determine optimal dosing regimes to limit toxicity without impacting on efficacy.","DOI":"10.1007/s11060-016-2276-9","ISSN":"1573-7373","note":"PMID: 27796735","journalAbbreviation":"J. Neurooncol.","language":"eng","author":[{"family":"Morris","given":"Katrina A."},{"family":"Golding","given":"John F."},{"family":"Blesing","given":"Claire"},{"family":"Evans","given":"D. Gareth"},{"family":"Ferner","given":"Rosalie E."},{"family":"Foweraker","given":"Karen"},{"family":"Halliday","given":"Dorothy"},{"family":"Jena","given":"Raj"},{"family":"McBain","given":"Catherine"},{"family":"McCabe","given":"Martin G."},{"family":"Swampillai","given":"Angela"},{"family":"Warner","given":"Nicola"},{"family":"Wilson","given":"Shaun"},{"family":"Parry","given":"Allyson"},{"family":"Afridi","given":"Shazia K."},{"literal":"UK NF2 research group"}],"issued":{"date-parts":[["2017",1]]},"PMID":"27796735"}}],"schema":""} [65].This finding raises some concern in a population of largely young patients on long-term bevacizumab treatment.Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1). The mTOR signalling pathway has been identified as a major mediator of the tumour suppressor activity of merlin and therefore is an attractive therapeutic target in NF2 ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ku4vcut99","properties":{"formattedCitation":"[66]","plainCitation":"[66]"},"citationItems":[{"id":486,"uris":[""],"uri":[""],"itemData":{"id":486,"type":"article-journal","title":"Consensus recommendations to accelerate clinical trials for neurofibromatosis type 2","container-title":"Clinical Cancer Research: An Official Journal of the American Association for Cancer Research","page":"5032-5039","volume":"15","issue":"16","source":"PubMed","abstract":"PURPOSE: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder associated primarily with bilateral schwannomas seen on the superior vestibular branches of the eighth cranial nerves. Significant morbidity can result from surgical treatment of these tumors. Meningiomas, ependymomas, and other benign central nervous system tumors are also common in NF2. The lack of effective treatments for NF2 marks an unmet medical need.\nEXPERIMENTAL DESIGN: Here, we provide recommendations from a workshop, cochaired by Drs. D. Gareth Evans and Marco Giovannini, of 36 international researchers, physicians, representatives of the biotechnology industry, and patient advocates on how to accelerate progress toward NF2 clinical trials.\nRESULTS: Workshop participants reached a consensus that, based on current knowledge, the time is right to plan and implement NF2 clinical trials. Obstacles impeding NF2 clinical trials and how to address them were discussed, as well as the candidate therapeutic pipeline for NF2.\nCONCLUSIONS: Both phase 0 and phase II NF2 trials are near-term options for NF2 clinical trials. The number of NF2 patients in the population remains limited, and successful recruitment will require ongoing collaboration efforts between NF2 clinics.","DOI":"10.1158/1078-R-08-3011","ISSN":"1078-0432","note":"PMID: 19671848\nPMCID: PMC4513640","journalAbbreviation":"Clin. Cancer Res.","language":"eng","author":[{"family":"Evans","given":"D. Gareth"},{"family":"Kalamarides","given":"Michel"},{"family":"Hunter-Schaedle","given":"Kim"},{"family":"Blakeley","given":"Jaishri"},{"family":"Allen","given":"Jeffrey"},{"family":"Babovic-Vuskanovic","given":"Dusica"},{"family":"Belzberg","given":"Allan"},{"family":"Bollag","given":"Gideon"},{"family":"Chen","given":"Ruihong"},{"family":"DiTomaso","given":"Emmanuelle"},{"family":"Golfinos","given":"John"},{"family":"Harris","given":"Gordon"},{"family":"Jacob","given":"Abraham"},{"family":"Kalpana","given":"Ganjam"},{"family":"Karajannis","given":"Matthias"},{"family":"Korf","given":"Bruce"},{"family":"Kurzrock","given":"Razelle"},{"family":"Law","given":"Meng"},{"family":"McClatchey","given":"Andrea"},{"family":"Packer","given":"Roger"},{"family":"Roehm","given":"Pamela"},{"family":"Rubenstein","given":"Allan"},{"family":"Slattery","given":"William"},{"family":"Tonsgard","given":"James H."},{"family":"Welling","given":"D. Bradley"},{"family":"Widemann","given":"Brigitte"},{"family":"Yohay","given":"Kaleb"},{"family":"Giovannini","given":"Marco"}],"issued":{"date-parts":[["2009",8,15]]},"PMID":"19671848","PMCID":"PMC4513640"}}],"schema":""} [66]. Studies have revealed that loss of merlin activates mTORC1 signalling, which is proven to reduce the growth of merlin-deficient arachnoidal, meningioma, and schwannoma cells ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"10r4v7h5lo","properties":{"formattedCitation":"[67]","plainCitation":"[67]"},"citationItems":[{"id":488,"uris":[""],"uri":[""],"itemData":{"id":488,"type":"article-journal","title":"NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth","container-title":"Molecular and Cellular Biology","page":"4250-4261","volume":"29","issue":"15","source":"PubMed","abstract":"Inactivating mutations of the neurofibromatosis 2 (NF2) gene, NF2, result predominantly in benign neurological tumors, schwannomas and meningiomas, in humans; however, mutations in murine Nf2 lead to a broad spectrum of cancerous tumors. The tumor-suppressive function of the NF2 protein, merlin, a membrane-cytoskeleton linker, remains unclear. Here, we identify the mammalian target of rapamycin complex 1 (mTORC1) as a novel mediator of merlin's tumor suppressor activity. Merlin-deficient human meningioma cells and merlin knockdown arachnoidal cells, the nonneoplastic cell counterparts of meningiomas, exhibit rapamycin-sensitive constitutive mTORC1 activation and increased growth. NF2 patient tumors and Nf2-deficient mouse embryonic fibroblasts demonstrate elevated mTORC1 signaling. Conversely, the exogenous expression of wild-type merlin isoforms, but not a patient-derived L64P mutant, suppresses mTORC1 signaling. Merlin does not regulate mTORC1 via the established mechanism of phosphoinositide 3-kinase-Akt or mitogen-activated protein kinase/extracellular signal-regulated kinase-mediated TSC2 inactivation and may instead regulate TSC/mTOR signaling in a novel fashion. In conclusion, the deregulation of mTORC1 activation underlies the aberrant growth and proliferation of NF2-associated tumors and may restrain the growth of these lesions through negative feedback mechanisms, suggesting that rapamycin in combination with phosphoinositide 3-kinase inhibitors may be therapeutic for NF2.","DOI":"10.1128/MCB.01581-08","ISSN":"1098-5549","note":"PMID: 19451225\nPMCID: PMC2715803","journalAbbreviation":"Mol. Cell. Biol.","language":"eng","author":[{"family":"James","given":"Marianne F."},{"family":"Han","given":"Sangyeul"},{"family":"Polizzano","given":"Carolyn"},{"family":"Plotkin","given":"Scott R."},{"family":"Manning","given":"Brendan D."},{"family":"Stemmer-Rachamimov","given":"Anat O."},{"family":"Gusella","given":"James F."},{"family":"Ramesh","given":"Vijaya"}],"issued":{"date-parts":[["2009",8]]},"PMID":"19451225","PMCID":"PMC2715803"}}],"schema":""} [67]. In addition, targeting mTORC1 may inhibit production of vascular endothelial growth factor (VEGF) and therefore reduce tumour angiogenesis ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"22tgtb07g7","properties":{"formattedCitation":"[68]","plainCitation":"[68]"},"citationItems":[{"id":490,"uris":[""],"uri":[""],"itemData":{"id":490,"type":"article-journal","title":"mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor","container-title":"Clinical Cancer Research: An Official Journal of the American Association for Cancer Research","page":"1612-1622","volume":"15","issue":"5","source":"PubMed","abstract":"PURPOSE: Comparison of the antiangiogenic/vascular properties of the oral mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and the vascular endothelial growth factor receptor (VEGFR) inhibitor vatalanib (PTK/ZK).\nEXPERIMENTAL DESIGN: Antiproliferative activity against various tumor histotypes and downstream effects on the mTOR pathway were measured in vitro. In vivo, antitumor activity, plasma, and tumor RAD001 levels were measured. Activity in several different angiogenic/vascular assays in vitro and in vivo was assessed and compared with PTK/ZK.\nRESULTS: RAD001 inhibited proliferation in vitro (IC50 values<1 nmol/L to >1 micromol/L), and in sensitive and insensitive tumor cells, pS6 kinase and 4E-BP1 were inhibited. Activity in vitro did not correlate with activity in vivo and significant responses were seen in tumors with IC50 values>10-fold higher than tumor RAD001 concentrations. In vitro, RAD001 inhibited the proliferation of VEGF-stimulated and fibroblast growth factor-stimulated human endothelial cells but not dermal fibroblasts and impaired VEGF release from both sensitive and insensitive tumor cells but did not inhibit migration of human endothelial cells. In vivo, in tumor models derived from either sensitive or insensitive cells, RAD001 reduced Tie-2 levels, the amount of mature and immature vessels, total plasma, and tumor VEGF. RAD001 did not affect blood vessel leakiness in normal vasculature acutely exposed to VEGF nor did it affect tumor vascular permeability (Ktrans) as measured by dynamic contrast-enhanced magnetic resonance imaging. However, the pan-VEGFR inhibitor PTK/ZK inhibited endothelial cell migration and vascular permeability but had less effect on mature vessels compared with RAD001.\nCONCLUSIONS: VEGFR and mTOR inhibitors show similar but also distinct effects on tumor vascular biology, which has implications for their clinical activity alone or in combination.","DOI":"10.1158/1078-R-08-2057","ISSN":"1078-0432","note":"PMID: 19223496","journalAbbreviation":"Clin. Cancer Res.","language":"eng","author":[{"family":"Lane","given":"Heidi A."},{"family":"Wood","given":"Jeanette M."},{"family":"McSheehy","given":"Paul M. J."},{"family":"Allegrini","given":"Peter R."},{"family":"Boulay","given":"Anne"},{"family":"Brueggen","given":"Joseph"},{"family":"Littlewood-Evans","given":"Amanda"},{"family":"Maira","given":"Sauveur-Michel"},{"family":"Martiny-Baron","given":"Georg"},{"family":"Schnell","given":"Christian R."},{"family":"Sini","given":"Patrizia"},{"family":"O’Reilly","given":"Terence"}],"issued":{"date-parts":[["2009",3,1]]},"PMID":"19223496"}}],"schema":""} [68]. Results so far are mixed. Karajannis et al in their study of 10 patients did not see a volumetric or hearing response to everolimus ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2n7m6me72q","properties":{"formattedCitation":"[69]","plainCitation":"[69]"},"citationItems":[{"id":492,"uris":[""],"uri":[""],"itemData":{"id":492,"type":"article-journal","title":"Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas","container-title":"Neuro-Oncology","page":"292-297","volume":"16","issue":"2","source":"CrossRef","DOI":"10.1093/neuonc/not150","ISSN":"1523-5866, 1522-8517","language":"en","author":[{"family":"Karajannis","given":"Matthias A."},{"family":"Legault","given":"Geneviève"},{"family":"Hagiwara","given":"Mari"},{"family":"Giancotti","given":"Filippo G."},{"family":"Filatov","given":"Alexander"},{"family":"Derman","given":"Anna"},{"family":"Hochman","given":"Tsivia"},{"family":"Goldberg","given":"Judith D."},{"family":"Vega","given":"Emilio"},{"family":"Wisoff","given":"Jeffrey H."},{"family":"Golfinos","given":"John G."},{"family":"Merkelson","given":"Amanda"},{"family":"Roland","given":"J. Thomas"},{"family":"Allen","given":"Jeffrey C."}],"issued":{"date-parts":[["2014",2]]}}}],"schema":""} [69]. Similarly Goutagny et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"oq6ll9t1k","properties":{"formattedCitation":"[70]","plainCitation":"[70]"},"citationItems":[{"id":498,"uris":[""],"uri":[""],"itemData":{"id":498,"type":"article-journal","title":"Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas","container-title":"Journal of Neuro-Oncology","page":"313-320","volume":"122","issue":"2","source":"CrossRef","DOI":"10.1007/s11060-014-1710-0","ISSN":"0167-594X, 1573-7373","language":"en","author":[{"family":"Goutagny","given":"Stéphane"},{"family":"Raymond","given":"Eric"},{"family":"Esposito-Farese","given":"Marina"},{"family":"Trunet","given":"Stéphanie"},{"family":"Mawrin","given":"Christian"},{"family":"Bernardeschi","given":"Daniele"},{"family":"Larroque","given":"Béatrice"},{"family":"Sterkers","given":"Olivier"},{"family":"Giovannini","given":"Marco"},{"family":"Kalamarides","given":"Michel"}],"issued":{"date-parts":[["2015",4]]}}}],"schema":""} [70] studied the response of 10 patients to everolimus, and found that 40% of patients had progressive disease and 50% had stable disease. There was a reduced annual growth rate from 67% per year pre-treatment to 0.5%per year during treatment, with resumed growth after treatment had stopped. More studies are clearly needed. Lapatinib is an EGFR/ErbB2 inhibitor, and abnormal activation of these growth factor receptors in NF2 patients is thought to be important in tumour development in patients with NF2 ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2208olheem","properties":{"formattedCitation":"[71]","plainCitation":"[71]"},"citationItems":[{"id":493,"uris":[""],"uri":[""],"itemData":{"id":493,"type":"article-journal","title":"Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas","container-title":"Neuro-Oncology","page":"1163-1170","volume":"14","issue":"9","source":"CrossRef","DOI":"10.1093/neuonc/nos146","ISSN":"1523-5866, 1522-8517","language":"en","author":[{"family":"Karajannis","given":"Matthias A."},{"family":"Legault","given":"Geneviève"},{"family":"Hagiwara","given":"Mari"},{"family":"Ballas","given":"Marc S."},{"family":"Brown","given":"Krysten"},{"family":"Nusbaum","given":"Annette O."},{"family":"Hochman","given":"Tsivia"},{"family":"Goldberg","given":"Judith D."},{"family":"Koch","given":"Kevin M."},{"family":"Golfinos","given":"John G."},{"family":"Roland","given":"J. Thomas"},{"family":"Allen","given":"Jeffrey C."}],"issued":{"date-parts":[["2012",9]]}}}],"schema":""} [71]. It was found to have anti-tumour activity in pre-clinical trials ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2e0m9aci74","properties":{"formattedCitation":"[72]","plainCitation":"[72]"},"citationItems":[{"id":494,"uris":[""],"uri":[""],"itemData":{"id":494,"type":"article-journal","title":"ErbB/HER receptor activation and preclinical efficacy of lapatinib in vestibular schwannoma","container-title":"Neuro-Oncology","page":"834-843","volume":"12","issue":"8","source":"CrossRef","DOI":"10.1093/neuonc/noq012","ISSN":"1522-8517, 1523-5866","language":"en","author":[{"family":"Ammoun","given":"S."},{"family":"Cunliffe","given":"C. H."},{"family":"Allen","given":"J. C."},{"family":"Chiriboga","given":"L."},{"family":"Giancotti","given":"F. G."},{"family":"Zagzag","given":"D."},{"family":"Hanemann","given":"C. O."},{"family":"Karajannis","given":"M. A."}],"issued":{"date-parts":[["2010",8,1]]}}}],"schema":""} [72] and a good safety profile, and has therefore been trialled on NF2 patients with VS. Matthias et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"64t3poe1g","properties":{"formattedCitation":"[71]","plainCitation":"[71]"},"citationItems":[{"id":493,"uris":[""],"uri":[""],"itemData":{"id":493,"type":"article-journal","title":"Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas","container-title":"Neuro-Oncology","page":"1163-1170","volume":"14","issue":"9","source":"CrossRef","DOI":"10.1093/neuonc/nos146","ISSN":"1523-5866, 1522-8517","language":"en","author":[{"family":"Karajannis","given":"Matthias A."},{"family":"Legault","given":"Geneviève"},{"family":"Hagiwara","given":"Mari"},{"family":"Ballas","given":"Marc S."},{"family":"Brown","given":"Krysten"},{"family":"Nusbaum","given":"Annette O."},{"family":"Hochman","given":"Tsivia"},{"family":"Goldberg","given":"Judith D."},{"family":"Koch","given":"Kevin M."},{"family":"Golfinos","given":"John G."},{"family":"Roland","given":"J. Thomas"},{"family":"Allen","given":"Jeffrey C."}],"issued":{"date-parts":[["2012",9]]}}}],"schema":""} [71] in their study of 21 eligible patients found volumetric and audiological response rates of 23.5% and 30.8% respectively over a treatment course of 12 months. In responders the reduction in VS volumes ranged from ?15.74% to ?23.9%. Therefore Lapatinib shows promise, but again more studies are required. ConclusionVestibular schwannomas account for 85-90% of tumours in the cerebello-pontine angle in adults. Most are sporadic, typically detected incidentally or during the investigation of hearing loss, tinnitus and headache while approximately 5% develop as part of the tumour predisposition syndrome NF2, and a much smaller number as a consequence of the tumour predisposition syndrome schwannomatosis. The incidence of incidentally diagnosed VS is increasing with increased scanning rates for often-unrelated problems. Audiometry and MRI scans with gadolinium are the gold standard investigations for patients with suspected vestibular schwannoma. In those in whom NF2 is suspected, genetic testing must be conducted. Once detected there are a number of strategies for management of VS. These differ for sporadic and NF2 related tumours. For sporadic tumours recommended strategies include observation (two-thirds of VS have been found not to grow, over an average follow-up of 3.6 years ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"o96k8udl","properties":{"formattedCitation":"[19]","plainCitation":"[19]"},"citationItems":[{"id":405,"uris":[""],"uri":[""],"itemData":{"id":405,"type":"article-journal","title":"Vestibular schwannoma: role of conservative management","container-title":"The Journal of Laryngology and Otology","page":"251-257","volume":"124","issue":"3","source":"PubMed","abstract":"OBJECTIVE: To assess the outcome of conservative management of vestibular schwannoma.\nSTUDY DESIGN: Observational study.\nSETTING: Tertiary referral centre.\nPATIENTS: Four hundred and thirty-six patients with vestibular schwannoma (490 tumours), including 327 sporadic tumours and 163 tumours in 109 patients with neurofibromatosis type two.\nMAIN OUTCOME MEASURES: The relationship of tumour growth to tumour size at presentation, and to certain demographic features.\nRESULTS: The initial tumour size was significantly larger in the neurofibromatosis type two group (11 mm) than in the sporadic vestibular schwannoma group (5.1 mm). In both groups, 68 per cent of tumours did not grow during follow up (mean 3.6 years; range one to 14 years). The mean growth rate was 1.1 mm/year (range 0-15 mm/year) for sporadic tumours and 1.7 mm/year (range 0-18 mm/year) for neurofibromatosis type two tumours. The tumour growth rate correlated positively with tumour size in the sporadic tumour group, and correlated negatively with age in the neurofibromatosis type two group.\nCONCLUSION: Two-thirds of vestibular schwannomas did not grow. Radiological surveillance is an acceptable approach in carefully selected patients. Once a sporadic vestibular schwannoma reaches 2 cm in intracranial diameter, it is likely to continue growing. We do not recommend conservative management for sporadic tumours with an intracranial diameter of 1.5 cm or more. Vestibular schwannoma management is more complex in patients with neurofibromatosis type two.","DOI":"10.1017/S0022215109992362","ISSN":"1748-5460","note":"PMID: 20003606","shortTitle":"Vestibular schwannoma","journalAbbreviation":"J Laryngol Otol","language":"eng","author":[{"family":"Suryanarayanan","given":"R."},{"family":"Ramsden","given":"R. T."},{"family":"Saeed","given":"S. R."},{"family":"Aggarwal","given":"R."},{"family":"King","given":"A. T."},{"family":"Rutherford","given":"S. A."},{"family":"Evans","given":"D. G."},{"family":"Gillespie","given":"J. E."}],"issued":{"date-parts":[["2010",3]]},"PMID":"20003606"}}],"schema":""} [19]), surgery and radiosurgery/fractionated radiotherapy. Treatment is recommended for large tumours presenting with mass effect and small but growing tumours. Radiosurgery and radiotherapy are limited to tumours 3.5cm or less in diameter ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"208ol5v2ah","properties":{"formattedCitation":"[40]","plainCitation":"[40]"},"citationItems":[{"id":127,"uris":[""],"uri":[""],"itemData":{"id":127,"type":"article","title":"Transforming participation in health and care.","URL":"england.nhs.uk/ wp-content/uploads/2013/09/trans-part-hc-guid1. pdf","author":[{"family":"NHS England","given":""}],"issued":{"date-parts":[["2013"]]},"accessed":{"date-parts":[["2015",9,17]]}}}],"schema":""} [40], but for eligible patients, tumour growth control rates are reported at 91-100% at 10 years with trigeminal or facial nerve complication rates of below 5%. Surgery has mortality rates of less than 0.2%, and facial nerve preservation rates of up to 90% ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2io1dobtj4","properties":{"formattedCitation":"[31]","plainCitation":"[31]"},"citationItems":[{"id":421,"uris":[""],"uri":[""],"itemData":{"id":421,"type":"article-journal","title":"Beyond audiofacial morbidity after vestibular schwannoma surgery","container-title":"Journal of Neurosurgery","page":"367-374","volume":"114","issue":"2","source":"PubMed","abstract":"OBJECT: Outcomes following vestibular schwannoma (VS) surgery have been extensively described; however, complication rates reported in the literature vary markedly. In addition, the majority of reports have focused on outcomes related to cranial nerves (CNs) VII and VIII. The objective of this study was to analyze reported morbidity unrelated to CNs VII and VIII following the resection of VS.\nMETHODS: The authors performed a comprehensive search of the English language literature, identifying and aggregating morbidity and death data from patients who had undergone microsurgical removal of VSs. A subgroup analysis based on surgical approach and tumor size was performed to compare rates of CSF leakage, vascular injury, neurological deficit, and postoperative infection.\nRESULTS: One hundred articles met the inclusion criteria, providing data for 32,870 patients. The overall mortality rate was 0.2% (95% CI 0.1-0.3%). Twenty-two percent of patients (95% CI 21-23%) experienced at least 1 surgically attributable complication unrelated to CNs VII or VIII. Cerebrospinal fluid leakage occurred in 8.5% of patients (95% CI 6.9-10.0%). This rate was markedly increased with the translabyrinthine approach but was not affected by tumor size. Vascular complications, such as ischemic injury or hemorrhage, occurred in 1% of patients (95% CI 0.75-1.2%). Neurological complications occurred in 8.6% of cases (95% CI 7.9-9.3%) and were less likely with the resection of smaller tumors (p < 0.0001) and the use of the translabyrinthine approach (p < 0.0001). Infections occurred in 3.8% of cases (95% CI 3.4-4.3%), and 78% of these infections were meningitis.\nCONCLUSIONS: This study provides statistically powerful data for practitioners to advise patients about the published risks of surgery for VS unrelated to compromised CNs VII and VIII.","DOI":"10.3171/2009.10.JNS091203","ISSN":"1933-0693","note":"PMID: 19943734","journalAbbreviation":"J. Neurosurg.","language":"eng","author":[{"family":"Sughrue","given":"Michael E."},{"family":"Yang","given":"Isaac"},{"family":"Aranda","given":"Derick"},{"family":"Rutkowski","given":"Martin J."},{"family":"Fang","given":"Shanna"},{"family":"Cheung","given":"Steven W."},{"family":"Parsa","given":"Andrew T."}],"issued":{"date-parts":[["2011",2]]},"PMID":"19943734"}}],"schema":""} [31]. It can be performed through a number of approaches, typically the translabyrinthine route for patients with reduced or non-serviceable hearing, and the retrosigmoid approach for those with serviceable hearing who wish to try and preserve this if possible ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"uku3p4kk2","properties":{"formattedCitation":"[26]","plainCitation":"[26]"},"citationItems":[{"id":409,"uris":[""],"uri":[""],"itemData":{"id":409,"type":"article-journal","title":"Surgical approaches for resection of vestibular schwannomas: translabyrinthine, retrosigmoid, and middle fossa approaches","container-title":"Neurosurgical Focus","page":"E9","volume":"33","issue":"3","source":"PubMed","abstract":"Surgical removal remains one of the key treatment modalities for vestibular schwannomas. A team approach between a neurotologist and a neurosurgeon offers the patient the expertise of both specialties and maximizes the chances for an optimal outcome. Vestibular schwannomas can typically be resected through 1 of 3 main surgical approaches: the translabyrinthine, the retrosigmoid, or the middle fossa approaches. In this report and videos, the authors describe and illustrate the indications and surgical techniques for the removal of these tumors.","DOI":"10.3171/2012.6.FOCUS12190","ISSN":"1092-0684","note":"PMID: 22937860","shortTitle":"Surgical approaches for resection of vestibular schwannomas","journalAbbreviation":"Neurosurg Focus","language":"eng","author":[{"family":"Chamoun","given":"Roukoz"},{"family":"MacDonald","given":"Joel"},{"family":"Shelton","given":"Clough"},{"family":"Couldwell","given":"William T."}],"issued":{"date-parts":[["2012",9]]},"PMID":"22937860"}}],"schema":""} [26]. The current treatment options and potential indications in sporadic VS and NF2 and are outlined in tables 1 and 2. Treatment OptionsPotential IndicationsObservation “wait and watch”small stable tumours (<2cm)elderly patientshigh surgical risk due to co-morbiditypatient preferenceRadiosurgerysmall growing tumours (<2cm)no brainstem compressionpatient desire for serviceable hearing preservation if possible elderly patients/patients with significant co-morbidities with growing tumours that cannot undertake surgical riskspatient preferenceRadiotherapysmall tumours (<2cm) with an irregular outline no brainstem compressionpatient desire for serviceable hearing preservation if possibleSurgerylarge (>2cm) tumours not suitable for observation or radiosurgery/radiotherapysmall growing tumours (<2cm)brainstem compressionsymptoms and signs secondary to mass effectpatient preferenceTable 1: Treatment options for patients with sporadic VS and potential indications for each. Treatment OptionsPotential IndicationsObservation “wait and watch”small tumours with no mass effect and no growth or slow growthpatients with small tumours and serviceable hearingpatient preferenceBevacizumabtumour growing by at least 4mm/year (or 60% by volume)potential benefits of treatment outweigh the risks agreement for appropriateness of treatment at ‘hub’ centre and partner centre for adults, all four ‘hub’ centres for children.Surgerylarge tumours with brainstem compressionrapidly growing tumours with a high risk of developing brainstem compressiondeterioration in facial nerve function deterioration in serviceable hearingRadiosurgery/radiotherapysmall tumours without mass effect but demonstrable growthmore elderly patients with mild phenotypepatient is a high risk surgical candidatepatient preferenceTable 2: Treatment options for patients with VS and NF2 and potential indications for each.A national audit of UK practice in the management of patients with sporadic VS showed that 69% of patients with VS are observed, 19% of patients undergo surgery and 12% undergo radiotherapy ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"e9417bbng","properties":{"formattedCitation":"[73]","plainCitation":"[73]"},"citationItems":[{"id":497,"uris":[""],"uri":[""],"itemData":{"id":497,"type":"article-journal","title":"Trends In Acoustic Neuroma Management: A 20-Year Review of the Oxford Skull Base Clinic","container-title":"Journal of Neurological Surgery Part B: Skull Base","page":"194-200","volume":"74","issue":"04","source":"CrossRef","DOI":"10.1055/s-0033-1342919","ISSN":"2193-6331, 2193-634X","shortTitle":"Trends In Acoustic Neuroma Management","language":"en","author":[{"family":"MacKeith","given":"Samuel"},{"family":"Kerr","given":"Richard"},{"family":"Milford","given":"Chris"}],"issued":{"date-parts":[["2013",4,1]]}}}],"schema":""} [73]. There are differences in practices between units however, a reflection perhaps of the absence of clear long-term data as yet as to the most beneficial intervention for patients that require treatment for their VS. In the UK patients with NF2 and VS are managed through one of four NF2 centres based in Manchester, Oxford, London and Cambridge. Management strategies in this group of patients should focus on quality of life, rather than tumour treatment per se. They include observation, with different parameters for intervention than patients with sporadic tumours, surgery, radiosurgery/radiotherapy and targeted therapies, of which bevacizumab is commissioned for use in the UK at present due to its good safety profile and tumour and hearing response rates ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"23gi8i0qgo","properties":{"formattedCitation":"[62]","plainCitation":"[62]"},"citationItems":[{"id":495,"uris":[""],"uri":[""],"itemData":{"id":495,"type":"article-journal","title":"Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2: a retrospective review of 31 patients","container-title":"Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology","page":"1046-1052","volume":"33","issue":"6","source":"PubMed","abstract":"OBJECTIVE: Early studies suggest that bevacizumab treatment can result in tumor shrinkage and hearing improvement for some patients with neurofibromatosis type 2 (NF2). The aim of this study was to report extended follow-up in a larger cohort of similarly treated patients.\nSTUDY DESIGN: Retrospective study.\nSETTING: Tertiary referral center\nPATIENTS: Thirty-one consecutive NF2 patients who received bevacizumab for progressive vestibular schwannomas.\nMAIN OUTCOME MEASURE: Hearing improvement, defined as an improvement in word recognition score above the 95% critical difference compared with baseline, and radiographic response, defined as a 20% or greater decrease in tumor volume compared with baseline.\nRESULTS: The median age was 26 years (range, 12-73 yr). The median volumetric tumor growth rate before treatment was 64% per year. At the time of analysis, the median duration of treatment was 14 months (range, 6-41 mo) with a total of 47 patient-years of follow-up. A hearing response occurred in 57% (13/23) of evaluable patients and a radiographic response in 55% (17/31) of target vestibular schwannomas. The median time to response was 3 months for both end points. The only clinical or radiographic feature at baseline that correlated with change in tumor volume at 3 months was the mean apparent diffusion coefficient value, a radiologic marker of edema (p = 0.036). Ninety percent of patients had stable or improved hearing after 1 year of treatment and 61% at 3 years; 88% of patients had stable or decreased tumor size after 1 year of treatment and 54% at 3 years. Overall, treatment was well tolerated.\nCONCLUSION: Bevacizumab treatment was followed by hearing improvement and tumor shrinkage in more than 50% of progressive vestibular schwannomas in NF2 patients. Stable or improved hearing was retained in the majority of patients.","DOI":"10.1097/MAO.0b013e31825e73f5","ISSN":"1537-4505","note":"PMID: 22805104","shortTitle":"Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2","journalAbbreviation":"Otol. Neurotol.","language":"eng","author":[{"family":"Plotkin","given":"Scott R."},{"family":"Merker","given":"Vanessa L."},{"family":"Halpin","given":"Chris"},{"family":"Jennings","given":"Dominique"},{"family":"McKenna","given":"Michael J."},{"family":"Harris","given":"Gordon J."},{"family":"Barker","given":"Fred G."}],"issued":{"date-parts":[["2012",8]]},"PMID":"22805104"}}],"schema":""} [62]. Studies are on-going as to the efficacy of other targeted therapies such as everolimus ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1njgs4icf5","properties":{"formattedCitation":"[69]","plainCitation":"[69]"},"citationItems":[{"id":492,"uris":[""],"uri":[""],"itemData":{"id":492,"type":"article-journal","title":"Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas","container-title":"Neuro-Oncology","page":"292-297","volume":"16","issue":"2","source":"CrossRef","DOI":"10.1093/neuonc/not150","ISSN":"1523-5866, 1522-8517","language":"en","author":[{"family":"Karajannis","given":"Matthias A."},{"family":"Legault","given":"Geneviève"},{"family":"Hagiwara","given":"Mari"},{"family":"Giancotti","given":"Filippo G."},{"family":"Filatov","given":"Alexander"},{"family":"Derman","given":"Anna"},{"family":"Hochman","given":"Tsivia"},{"family":"Goldberg","given":"Judith D."},{"family":"Vega","given":"Emilio"},{"family":"Wisoff","given":"Jeffrey H."},{"family":"Golfinos","given":"John G."},{"family":"Merkelson","given":"Amanda"},{"family":"Roland","given":"J. Thomas"},{"family":"Allen","given":"Jeffrey C."}],"issued":{"date-parts":[["2014",2]]}}}],"schema":""} [69] and lapatinib ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"28npl8efdd","properties":{"formattedCitation":"[71]","plainCitation":"[71]"},"citationItems":[{"id":493,"uris":[""],"uri":[""],"itemData":{"id":493,"type":"article-journal","title":"Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas","container-title":"Neuro-Oncology","page":"1163-1170","volume":"14","issue":"9","source":"CrossRef","DOI":"10.1093/neuonc/nos146","ISSN":"1523-5866, 1522-8517","language":"en","author":[{"family":"Karajannis","given":"Matthias A."},{"family":"Legault","given":"Geneviève"},{"family":"Hagiwara","given":"Mari"},{"family":"Ballas","given":"Marc S."},{"family":"Brown","given":"Krysten"},{"family":"Nusbaum","given":"Annette O."},{"family":"Hochman","given":"Tsivia"},{"family":"Goldberg","given":"Judith D."},{"family":"Koch","given":"Kevin M."},{"family":"Golfinos","given":"John G."},{"family":"Roland","given":"J. Thomas"},{"family":"Allen","given":"Jeffrey C."}],"issued":{"date-parts":[["2012",9]]}}}],"schema":""} [71]. Response rates to treatment, both surgery and radiosurgery/radiotherapy are worse for patients with NF2 than sporadic tumours, with higher rates of neurological dysfunction, tumour recurrence and mortality in this group of patients ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"h7l3ng2lb","properties":{"formattedCitation":"[55]","plainCitation":"[55]"},"citationItems":[{"id":471,"uris":[""],"uri":[""],"itemData":{"id":471,"type":"article-journal","title":"Outcome of translabyrinthine surgery for vestibular schwannoma in neurofibromatosis type 2","container-title":"British Journal of Neurosurgery","page":"446-453","volume":"27","issue":"4","source":"PubMed","abstract":"OBJECTIVES: To analyse the long-term outcome of translabyrinthine surgery for vestibular schwannoma (VS) in neurofibromatosis type 2 (NF2). RESEARCH TYPE: Retrospective cohort study.\nSETTING: Two tertiary referral NF2 units.\nPATIENTS: One hundred and forty eight translabyrinthine operations for patients with VS were performed. Preoperative stereotactic radiotherapy had been performed on 12(9.4%) patients.\nRESULTS: Mean tumour size was 3.1 cm. Total tumour excision was achieved in 66% of cases, capsular remnants were left in 24% of cases, and subtotal excision was achieved in 5% and partial removal was achieved in 5%. The radiological residual/recurrence rate was 13.9%. The perioperative mortality was 1.6%. At 2 years postoperatively, facial function was expressed in terms of House-Brackmann score (HB): HB 1 in 53.4%, HB 1/2 in 61.3%, HB 1-3 in 83.2% and HB 4-6 in 16.8%. All nine patients who underwent surgery following failed stereotactic radiotherapy had HB 3 function or better. Among 9.5% of the cases, 14 facial nerves were lost during surgery and repaired using direct anastomosis or grafting. There was no tinnitus present preoperatively in 27% of the cases, and 22% of patients developed tinnitus postoperatively. In patients with preoperative tinnitus, 61% remained the same, 17% got it resolved and only in 21% it worsened. The preoperative hydrocephalus rate was 26%, and among 15% of the cases five ventriculo-peritoneal (VP) shunts were performed. The cerebrospinal fluid leak rate was 2.5%. Fifty-six patients underwent auditory brainstem implantation (ABI) and two patients had cochlear implant (CI) sleepers inserted.\nCONCLUSIONS: The management of patients with NF2 presents the clinician with a formidable challenge with many patients still presenting themselves late with the neurological compromise and a large tumour load. There is still an argument for the management by observation until the neurological compromise dictates interventional treatment particularly with the option of hearing rehabilitation with ABI or CI. The translabyrinthine approach provides a very satisfactory means of reducing the overall tumour volume.","DOI":"10.3109/02688697.2013.771143","ISSN":"1360-046X","note":"PMID: 23472624","journalAbbreviation":"Br J Neurosurg","language":"eng","author":[{"family":"Moffat","given":"D. A."},{"family":"Lloyd","given":"S. K. W."},{"family":"Macfarlane","given":"R."},{"family":"Mannion","given":"R."},{"family":"King","given":"A."},{"family":"Rutherford","given":"S."},{"family":"Axon","given":"P. R."},{"family":"Donnelly","given":"N."},{"family":"Freeman","given":"S."},{"family":"Tysome","given":"J. R."},{"family":"Evans","given":"D. G."},{"family":"Ramsden","given":"R. T."}],"issued":{"date-parts":[["2013",8]]},"PMID":"23472624"}}],"schema":""} [55] ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1hbb8t7co2","properties":{"formattedCitation":"[56]","plainCitation":"[56]"},"citationItems":[{"id":475,"uris":[""],"uri":[""],"itemData":{"id":475,"type":"article-journal","title":"Stereotactic radiosurgery for vestibular schwannomas in patients with neurofibromatosis type 2: an analysis of tumor control, complications, and hearing preservation rates","container-title":"Neurosurgery","page":"460-468; discussion 468-470","volume":"60","issue":"3","source":"PubMed","abstract":"OBJECTIVE: Vestibular schwannomas present significant management challenges in patients with neurofibromatosis Type 2 (NF2). We evaluated the results of gamma knife radiosurgery for the management of these tumors, focusing on tumor response, hearing preservation, and other factors affecting outcomes.\nMETHODS: Stereotactic radiosurgery was performed to manage 74 schwannomas in 62 patients. Ipsilateral serviceable hearing was present in 35% of tumors before the procedure. The mean tumor volume was 5.7 cm3. The mean margin and maximum dose used were 14 and 27.5 Gy, respectively. Cox regression analyses were performed to identify factors affecting outcomes.\nRESULTS: The median follow-up period was 53 months, and two patients were lost to follow-up. Actuarial local control rates at were 85, 81, and 81% at 5, 10, and 15 years, respectively. Tumor volume was significant as a predictor of local control. Since 1992, using current radiosurgery techniques (magnetic resonance imaging scan targeting and reduced margin dose to 14 Gy or less), the actuarial serviceable hearing preservation rate is 73% at 1 year, 59% at 2 years, and 48% at 5 years after radiosurgery. Facial neuropathy occurred in 8% of tumors, trigeminal neuropathy occurred in 4%, and vestibular dysfunction occurred in 4%. Radiation dose and tumor volume were predictive of development of new deficits. No radiosurgery-associated secondary tumors or atypical or malignant changes were noted.\nCONCLUSION: Stereotactic radiosurgery is a safe and effective management modality for neurofibromatosis Type 2 vestibular schwannomas. Although results do not seem to be as good as for patients with sporadic unilateral tumors, gamma knife radiosurgery results seem favorable and indicate that radiosurgery should be strongly considered for primary tumor management in selected patients.","DOI":"10.1227/01.NEU.0000255340.26027.53","ISSN":"1524-4040","note":"PMID: 17327790","shortTitle":"Stereotactic radiosurgery for vestibular schwannomas in patients with neurofibromatosis type 2","journalAbbreviation":"Neurosurgery","language":"eng","author":[{"family":"Mathieu","given":"David"},{"family":"Kondziolka","given":"Douglas"},{"family":"Flickinger","given":"John C."},{"family":"Niranjan","given":"Ajay"},{"family":"Williamson","given":"Richard"},{"family":"Martin","given":"Juan J."},{"family":"Lunsford","given":"L. Dade"}],"issued":{"date-parts":[["2007",3]]},"PMID":"17327790"}}],"schema":""} [56].It is clear that at present there is no single best treatment for every patient with VS, either sporadic or related to NF2. Patients must be fully informed as to their treatment options, and decisions made on a case-by-case basis. Since the early reports of VS surgery, with mortality rates of over 50% ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"pn8msfsfp","properties":{"formattedCitation":"[8]","plainCitation":"[8]"},"citationItems":[{"id":375,"uris":[""],"uri":[""],"itemData":{"id":375,"type":"chapter","title":"History of Vestibular Schwannoma Surgery","container-title":"Progress in Neurological Surgery","publisher":"KARGER","publisher-place":"Basel","page":"6-23","volume":"21","source":"CrossRef","event-place":"Basel","URL":"","ISBN":"978-3-8055-8370-1","note":"DOI: 10.1159/000156555","language":"en","editor":[{"family":"Régis","given":"J."},{"family":"Roche","given":"P.-H."}],"author":[{"family":"Pellet","given":"William"}],"issued":{"date-parts":[["2008"]]},"accessed":{"date-parts":[["2017",9,3]]}}}],"schema":""} [8], VS management has come a long way and continues to do so. While it is clear that surgery will remain an essential method of managing patients with VS, there is a growing role for non-surgical treatment and this is likely to continue into the future. Expert CommentaryOne of the key weaknesses of VS management so far is the lack of long-term outcome data available for the different treatment modalities, in particular the non-surgical modalities such as radiosurgery and radiotherapy. This is particularly relevant to younger patients diagnosed with VS, in whom it would be extremely valuable to understand the long-term (10 year plus) outcomes for. Data on the role and outcomes of proton beam therapy is particularly lacking and further research should be directed towards this in the management of VS. There is also a wide variability in published outcomes for patients managed with non-surgical therapies; it would be helpful to have a clearer understanding of why these differ to accordingly aid decision-making for patients. Future research holds potential in two main avenues. One is further clinical research to help better define long term outcomes of the available treatment modalities, and to better understand and hopefully reduce the variability in reported outcomes that exist. The second avenue is further exploration of the cellular pathways that lead to VS occurrence and growth, for both sporadic VS and those related to tumour predisposition syndromes such as NF2 and Schwannomatosis. So far cellular research has enhanced understanding with regard to pathways in which the NF2 gene product interacts, and has led to the trial and subsequent use of targeted therapies in NF2 patients. It has, as we can see from the discussions above, a long way to go. Further research would be helpful in exploring if targeted therapies could be of value in sporadic VS too, as well as further exploring their use in NF2 patients with VS. Furthermore, an ability to predict which tumours hold growth potential and those that respond well to non-surgical therapies including targeted therapies would be of great value in the management of VS. It is, therefore, cellular research and targeted therapies that hold the most interest to us at present. Five-year viewWe believe that in 5 years we will have more long term data on non-surgical therapies, a greater understanding of cellular pathways that lead to development and growth of VS, and further targeted therapies, both for sporadic and NF2-related VS. We believe that there will be a continued improvement in outcomes for patients with VS, both in terms of long-term tumour control rates, and also the morbidity associated with treatments for this tumour. Key issuesThe incidence of diagnosed VS is increasing worldwide.There is still a lack of clear consensus between units on the most appropriate management strategies for patients with VS, both sporadic and those related to tumour predisposition syndromes.Life expectancies are increasing.Long-term data for non-surgical management strategies are lacking, and there is still a significant variability in reported outcomes between different studies. Outcomes for patients with VS secondary to NF2 remain significantly worse than for those patients with sporadic tumours. Significant progress has been made on understanding cellular pathways that lead to development of VS, particularly for patients with NF2, which has led to the trial and use of targeted therapies. These are still at the early stages of use and investigation, and much work is still to be done to explore the uses and potential value of targeted therapies for patients with both sporadic and NF2-related VS. Funding:There has been no funding for this review article.Conflicts of Interest:The authors report no conflicts of interest. References ADDIN ZOTERO_BIBL {"custom":[]} CSL_BIBLIOGRAPHY [1] Smith MJ, Kulkarni A, Rustad C, et al. Vestibular schwannomas occur in schwannomatosis and should not be considered an exclusion criterion for clinical diagnosis. Am. J. Med. Genet. A. 2012;158A:215–219.[2] Hexter AT, Evans DG. The Genetics of Vestibular Schwannoma. Curr. Otorhinolaryngol. Rep. 2014;2:226–234.[3] Samii M, Matthies C. Management of 1000 vestibular schwannomas (acoustic neuromas): the facial nerve--preservation and restitution of function. Neurosurgery. 1997;40:684–694; discussion 694–695.[4] Evans DGR, Moran A, King A, et al. Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period: higher incidence than previously thought. Otol. Neurotol. Off. Publ. Am. Otol. Soc. Am. Neurotol. Soc. Eur. Acad. Otol. 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The Laryngoscope. 1995;105:958–966.[39] Bennett ML, Jackson CG, Kaufmann R, et al. Postoperative imaging of vestibular schwannomas. Otolaryngol.-Head Neck Surg. 2008;138:667–671.[40] NHS England. Transforming participation in health and care. [Internet]. 2013 [cited 2015 Sep 17]. Available from: england.nhs.uk/ wp-content/uploads/2013/09/trans-part-hc-guid1. pdf.[41] Casentini L, Fornezza U, Perini Z, et al. Multisession stereotactic radiosurgery for large vestibular schwannomas. J. Neurosurg. 2015;122:818–824.[42] Apicella G, Paolini M, Deantonio L, et al. Radiotherapy for vestibular schwannoma: Review of recent literature results. Rep. Pract. Oncol. Radiother. 2016;21:399–406.[43] Flickinger JC, Lunsford LD, Linskey ME, et al. Gamma knife radiosurgery for acoustic tumors: multivariate analysis of four year results. Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol. 1993;27:91–98.[44] Murphy ES, Suh JH. Radiotherapy for vestibular schwannomas: a critical review. Int. J. Radiat. 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