Epidemiological and Evolutionary study of Vestibular Schwannoma after different types of treatment

UNIVERSITY OF SANTIAGO DE COMPOSTELA FACULTY OF MEDICINE AND DENTESTRY Department of Dermatology and Otolaryngology DOCTORAL THESIS "EPIDEMIOLOGICAL AND EVOLUTIONARY STUDY OF VESTIBULAR SCHWANNOMAS AFTER DIFFERENT TYPES OF TREATMENT" Jamol ERGASHEV Academic year 2013 / 2014 Directors: Prof. Dr. Sofía Santos Pérez Prof. Dr. Andrés Soto Varela Prof. Dr. Torcuato Labella Caballero 1 Dissertation Comittee: SOFÍA SANTOS PÉREZ, Professor, Head of Dermatology and Otolaryngology Department, Staff Physician of Otolaryngology division of Santiago de Compostela University Hospital; ANDRÉS SOTO VARELA, Professor of Otolaryngology and Staff Physician of Otolaryngology division of Santiago de Compostela University Hospital; TORCUATO LABELLA CABALLERO, Honored Professor, Former Chairman of Otolaryngology division of Santiago de Compostela University Hospital; CERTIFIES: That Jamol ERGASHEV has realized the work entitled: "”Epidemiological and Evolutionary study of Vestibular Schwannoma after different types of treatment”under our direction for the degree of Doctor of Medicine fulfilling the requisites for “European Doctor”mention, and that mentioned work is ready to be presented from the present day. Signed: Prof. Torcuato Labella Prof. Sofía Santos Prof. Andrés Soto ………………………… ………………….…. …………………….. November 7th, 2013 Departamento de Dermatologia y Otorrinolaringologia Facultad de Medicina Rua San Francisco s/n 15705 Santiago de Compostela Telf. 981563100, ext 12385 Correo electronico:[email protected] 2 Dedication I dedicate this dissertation to my parents for their unconditional love and support. I also dedicate it to the memory of my first school teacher Juraboy NISHONOV, who would have been happy to see my achievements. 3 Acknowledgement Foremost, I offer my sincerest gratitude to my mentor and thesis supervisor, Prof. Sofía Santos Pérez, who supported me with her encouragement, patience, knowledge and endless advice throughout my courses for my PhD at the University of Santiago de Compostela. I attribute my PhD degree to her and am ever thankful for her encouragement, effort and friendly attitude. Without her guidance and persistent help, this thesis would not have been possible. My sincere thanks also goes to Prof. Andrés Soto, a punctual person and a great scientist who was always at my disposal in spite of his having a tight schedule. Especially in my difficult moments, he spared no efforts to support me and always stood with me, shoulder to shoulder, helping me to bring my thesis to the light of day. I have received generous support from Professor Torcuato Labella and appreciated the friendly countenance he often expressed towards me as I was in my home country hospital during his chairmanship at the Department Otolaryngology and Head & Neck surgery of the CHUS. Thanks to him, I did not have any difficulties in collecting primary source materials for my PhD thesis. Also, I have learned many things from the lectures of Prof. Labella and in the surgeries in which I assisted him. He is a great mentor. In my daily work, I have been blessed with a friendly and cheerful group of otolaryngologists, residents, nurses and administrative personnel. I appreciate the feedback offered by Dr. María del Río, who helped me in refreshing patient data with new audiologic tests performed by her. Also to Dr. Crisanto Castro, who always motivated me and consistently asked how I was going with my papers in the last three years, I am ever grateful. Ana Burés and Begoña Rey helped me in obtaining primary source materials and in repeating the vestibular tests for VS patients. I would like to thank Dr. Pilar Gayoso and university professor, Xosé Luis Otero, who is a great teacher, for their valuable support, in my most difficult times, as I worked on the statistical part of my thesis. 5 TABLE OF CONTENTS DISSERTATION COMITTEE..............................................................................................1 DEDICATION.......................................................................................................................2 ACKNOWLEDGEMENT.....................................................................................................3 TABLE OF CONTENTS.......................................................................................................5 LIST OF ABBREVIATIONS..............................................................................................10 LIST OF FIGURES .............................................................................................................13 RESUMEN (español)...........................................................................................................17 1 INTRODUCTION......................................................................................................31 1.1 Anatomy of Vestibulocochlear nerve (CN VIII)...................................................31 1.2 Anatomic relationship of CN VIII ........................................................................34 1.3 Physiology of CN VIII..........................................................................................42 1.3.1 Physiology of the cochlear nerve...................................................................42 1.3.2 Physiology of superior and inferior vestibular nerves...................................51 1.3.3 Schwannoma of Vestibulocochlear nerve......................................................58 1.3.4 Explorations of hearing impairments in Vestibular Schwannoma ................70 1.4 Explorations of balance dysfunctions in Vestibular Schwannoma.......................85 1.4.1 Posturography. ...............................................................................................85 1.4.2 Craniocorpography ........................................................................................89 1.4.3 Caloric testing................................................................................................91 1.4.4 Vestibular Evoked Myogenic Potentials........................................................96 1.5 Neurologic examinations in Vestibular Schwannoma ..........................................98 1.6 Diagnostic Imaging in Vestibular Schwannoma.................................................101 6 1.6.1 Magnetic Resonance Imaging (MRI)...........................................................101 1.6.2 Computed Tomography imaging (CT) ........................................................107 1.7 The natural Evolution of Vestibular Schwannoma .............................................111 1.8 Treatment modalities of Vestibular Schwannoma ..............................................115 1.8.1 Follow up or observation with serial MRI...................................................115 1.8.2 Conventional neurosurgery..........................................................................118 1.8.3 Radiosurgery with Gamma Knife................................................................122 1.9 Complications of Vestibular Schwannoma treatment.........................................124 1.9.1 Complications conventional microsurgery ..................................................124 1.9.2 Complications of Gamma Knife Radiosurgery............................................128 1.10 Tumour Recurrence.............................................................................................131 2 OBJECTIVES ..........................................................................................................135 3 MATERIALS AND METHODS ............................................................................139 3.1 Materials..............................................................................................................139 3.1.1 Patients.........................................................................................................139 3.1.2 Technical support.........................................................................................139 3.2 Methods...............................................................................................................142 3.2.1 Audiometric testing......................................................................................142 3.2.2 Testing of balance with Dynamic Craneocorpography ...............................143 3.2.3 Computerized Dynamic Posturography (CDP) ...........................................144 3.2.4 Caloric testing with Videonystagmography (VNG) ....................................145 3.2.5 Otoacoustic emissions..................................................................................146 3.2.6 Auditory Brainstem Response (ABR) audiometry......................................146 3.2.7 Vestibular Evoked Myogenic Potentials (VEMP) testing ...........................147 3.2.8 Magnetic Resonance Imaging......................................................................148 7 4 RESULTS .................................................................................................................153 4.1.1 Demographic and Epidemiological characteristics of patients with VS......153 4.1.2 Gender..........................................................................................................153 4.1.3 Age...............................................................................................................153 4.2 Clinic Characteristics of patients with VS ..........................................................154 4.2.1 Primary symptom.........................................................................................154 4.2.2 Symptoms at the time of diagnosis..............................................................154 4.2.3 Localization of VS.......................................................................................156 4.3 Exploration..........................................................................................................158 4.3.1 Audiologic Testing.......................................................................................158 4.3.2 Vestibular and Balance Testing ...................................................................165 4.3.3 Imaging Tests...............................................................................................171 4.4 Treatment ............................................................................................................173 4.4.1 Wait-and-watch............................................................................................173 4.4.2 Radiosurgery................................................................................................173 4.4.3 Conventional neurosurgery..........................................................................174 4.4.4 Association between the wait-and-watch and radiosurgery groups.............174 4.5 Complications of treatment.................................................................................177 4.6 Follow up.............................................................................................................178 4.6.1 Size of the tumor..........................................................................................180 4.6.2 Auditory function (PTA)..............................................................................184 4.7 Results of exploration of VS patient due to NF2 ................................................192 5 DISCUSSION ...........................................................................................................196 5.1 Population characteristics and epidemiological considerations of VS................196 5.1.1 Sex distribution............................................................................................196 14 Figure 33. Parameters of Evaluation of VEMPs................................................................ 97 Figure 34. VEMPs showing 87% asymmetry rate in patient with VS............................... 97 Figure 35. MRI scanner MAGNETOM Symphony Maestro Class (CHUS)................... 102 Figure 36. Axial fast spin echo T2 and gadolinium T1images of VS patient ............... 103 Figure 37. High-resolution T2-weighted images of MRI showing IAC.......................... 105 Figure 38. An extraaxial, enhancing image showing a meningioma.. ............................. 106 Figure 39. T1and T2-weighted images of a CPA arachnoid cyst.................................. 106 Figure 40. A VS with high resolution computed tomography......................................... 108 Figure 41. A Polytef in the CPA cistern........................................................................... 109 Figure 42. The Air cisternogram shows the infilling of IAC ........................................... 110 Figure 43. A chart showing the rate of growth of a VS during the follow-up years........ 112 Figure 44. Image shows the growth of a VS after 1,5 years of observation .................... 116 Figure 45. Selection criteria for the surgical approach .................................................... 119 Figure 46. The suboccipital approach .............................................................................. 120 Figure 47. Drawing illustrates the translabyrinthine approach ........................................ 121 Figure 48. Schematic of stereotactic Radiosurgery with the Gamma Knife®.................. 123 Figure 49. Image of a CSF leak following suboccipital resection of a VS.. .................... 126 Figure 50. CSF wound leak. Axial nonenhanced CT scane............................................. 127 Figure 51. VEMP software............................................................................................... 141 Figure 52. The Craneocorpography device...................................................................... 143 Figure 53. Chart showing the distribution of patients by gender..................................... 153 Figure 54. Distribution of presenting symptoms and localization of the tumor............... 157 Figure 55. Shows the initial size of the VSs in regard to the age of the patients............. 172 Figure 56. The value of MRI and PTA in three treatment groups ................................... 175 Figure 57. The average initial size of VS in 3 different treatment groups....................... 176 Figure 58. The dynamics of follow up of 106 VS patients .............................................. 179 Figure 59. The evolution of VS size in the wait-and-watch group .................................. 182 Figure 60. Chart showing variations in tumor size in a group of patients under GKR.... 183 Figure 61. Variations in tumor size in the wait-and-watch and radiosurgery groups ...... 184 Figure 62. A chart showing the evolution of the PTA (wait-and-watch)......................... 185 Figure 63. The evolution of a PTA overall (GKR) .......................................................... 187 Figure 64. Image of the comparison of the mean PTA between groups.......................... 188 Figure 65. The survival rate of the wait-and-watch approach (Kaplan-Meir) ................. 191 15 LIST OF TABLES Table 1. An analysis of 100 translabyrinthine operations................................................... 68 Table 2. Percentage of cases with a VS growth and a review of literature....................... 112 Table 3. Incidence of CSF fistulae following VS surgery................................................125 Table 4. Published results of GKR for VS........................................................................129 Table 5. The normal value of waves in ABR (CHUS) ..................................................... 147 Table 6. Distribution of VS patients by gender ................................................................153 Table 7. Distribution of patients regarding the type of presenting symptoms of a VS..... 154 Table 8. Distribution of symptoms which brought the patient to a physician..................155 Table 9. Distribution of VS patients regarding gender and localization of a VS .............156 Table 10. The results of early conventional audiometry of patients with a VS................158 Table 11. Type of audiometric configuration in a group of VS patients..........................159 Table 12. Comparative data of hearing loss at diagnosis and gender of the patients.......160 Table 13. The value of PTA regarding the localization of a VS.......................................161 Table 14. The results of ABR waveform latencies...........................................................162 Table 15. The prevalence of abnormal ABR regarding the gender.................................. 163 Table 16. Female and male proportion and results of IT5................................................163 Table 17. Tumor size by ABR Interval Latency Difference for wave V..........................164 Table 18. Distribution of VS patients according to results of OAE ................................. 165 Table 19. Results of CCG testing regarding the gender of the patients............................165 Table 20. Association of CCG with clinical picture of VS ..............................................166 Table 21. Descriptive statistics of SOT ............................................................................167 Table 22. Overall balance and CDP conditions regarding the gender.............................. 168 Table 23. Distribution of patients according to caloric testing results .............................169 Table 24. Association between VEMPs, PTA regarding the localization of VS.............. 170 Table 25. The size of tumor regarding the gender of the patient...................................... 171 Table 26. The overall average PTA and size of VS in wait-and-watch group .................173 Table 27. The overall average PTA and size of VS in the GK Radiosurgery group........173 Table 28. The overall average PTA and size of VS in neurosurgery group.....................174 Table 29. Comparative characteristics of wait-and-watch and GK radiosurgery groups 175 Table 30. Duration of overall follow up times in different treatment groups...................178 Table 31. The variation of tumor size in wait-and-watch group.......................................181 Table 32. The average size of the tumor in radiosurgery group....................................... 182 16 Table 33. Variations in the overall average PTA in the wait-and-watch group............... 185 Table 34. Variations of the PTA average in GKR group ................................................. 186 Table 35. The rate of changes of the average PTA and/or hearing deterioration............. 188 Table 36. Outcome results of useful hearing preservation............................................... 189 Table 37. Outcome results of PTA and Size of the VS.................................................... 190 Table 38. Summary of the recent series of VSs managed with the wait-and-watch........ 211 Table 39. Summary of recent series of VSs managed with GK Radiosurgery ................ 213 Table 40. The plus signs show factors which influence VS treatment options................ 218 Abstract 17 Resumen "Estudio epidemiológico y evolutivo de los schwanomas vestibulares tras distintos tipos de tratamiento" 1. Antecedentes Los schwanomas vestibulares (SVs) son tumores intracraneales benignos que se originan en las células de Schwann del nervio cócleo-vestibular; suponen el 80-90% de las masas localizadas en el ángulo pontocerebeloso1,3,8,12,20,22,32. El estudio histopatológico de los SV determina la existencia de dos tipos celulares, Antoni “A” y Antoni “B”. Rubinstein (1989) describió que los cambios mucinosos y microquísticos tienden a suceder en las células Antoni B20. A medida que el tumor crece, lo hace en la dirección de menor resistencia, medialmente en el APC o hacia el oído interno (formando un cordón en el CAI). Por ello, los SV pueden tener componente extracanalicular, intra-extracanalicular o exclusivamente intracanalicular. El SV bilateral es poco frecuente y se asocia generalmente con la Neurofibromatosis tipo 2 (NF2). La aparición de SVs esporádicos y NF2 parece estar asociado con una mutación de un gen supresor tumoral en el cromosoma 22q12. La base biológica que explique los diferentes patrones de crecimiento permanece desconocida. La presentación clínica de un SV es muy variable; incluye hipoacusia neurosensorial unilateral en frecuencias agudas, acúfenos, desequilibrio, presión ótica, otalgia y vértigo. Todos son resultado de la presión ejercida por el tumor sobre las ramas coclear y vestibular del VIII par craneal. La hipoacusia es el hallazgo más frecuente; ocurre en más del 95% de los pacientes en el transcurso de la evolución.35 Según algunas publicaciones, la incidencia de los SVs está aumentando52,53 mientras que el tamaño del tumor en el momento del diagnóstico es cada vez menor y la edad media al diagnóstico se mantiene estable130,132. Este incremento en la incidencia probablemente se deba a un uso generalizado de la RM en la práctica clínica. Abstract 18 Las modalidades de tratamiento incluyen vigilancia, radiocirugía (Gamma Knife or Cyber Knife) y cirugía convencional. La elección de una u otra alternativa depende de muchos factores: tamaño, edad del paciente y estado general, severidad de la hipoacusia, presencia de síntomas neurológicos y preferencia del paciente. 1.1 Planteamiento del problema. La tasa de crecimiento de los SVs es variable y difícil de predecir. El tamaño del tumor puede permanecer estable, aumentar o disminuir. Cuando crece, habitualmente lo hace de forma lenta. Sin embargo, algunos SVs se comportan de un modo distinto y pueden causar signos neurológicos incluso mortales por compresión del tronco encefálico. Es necesario identificar los tumores que representen una amenaza frente a los que no. La ventaja principal de la cirugía convencional es la posibilidad de conseguir una extirpación completa. Sin embargo, implica morbilidad potencial por complicaciones como fístula de LCR, meningitis, daño en el nervio facial y lesiones vasculares.171,173,224 El tratamiento con radioterapia es cada vez más preciso, al mejorar las técnicas de administración y disminuir las dosis de radiación. Aunque es generalmente bien tolerado, persisten los interrogantes sobre el control del tumor a largo plazo y la morbilidad potencial, incluyendo hipoacusia permanente, parálisis facial, hidrocefalia y daño del tronco cerebral; su incidencia es menor que con cirugía convencional.139,190, 196,231. 2. Objetivos Nuestro estudio tiene como objetivo comparar la actitud vigilante frente a la radiocirugía, para ayudar en la toma de decisiones en el tratamiento conservador del SV. Planteamos los siguientes objetivos específicos: 1. Realizar un análisis epidemiológico de los pacientes con VS diagnosticados en nuestro Servicio. 2. Evaluar la utilidad de diferentes pruebas audiológicas y vestibulares en el diagnóstico del SV. 3. Analizar la historia natural del SV, tanto en aspectos morfológicos como funcionales. Abstract 19 4. Comparar la eficacia de dos estrategias terapéuticas diferentes (vigilancia y radiocirugía) en el manejo SVs pequeños. 5. Establecer un protocolo terapéutico para SVs pequeños. 3. Material y métodos Desarrollamos un estudio retrospectivo observacional de 107 casos consecutivos de SV diagnosticados en el Servicio de Otorrinolaringología del Complexo Hospitalario Universitario de Santiago de Compostela, desde febrero de 1992 hasta febrero de 2013. La duración media del seguimiento fue de 56.52±10.79 (rango 25.02-71.74) meses. 57 pacientes (53.8%) eran mujeres y 50 (46.2%) varones; uno de los varones (0.9%) presentaba un SV bilateral por NF2. Se empleraron los siguientes equipos diagnósticos: Audiómetro - “Audiotest 340” Craneocorpógrafo (CCG) - Eymasa CCG600SE® Posturógrafo dinámica computerizado (PD) - Neurocom® Videonistagmógrafos - Nicolet Instrumental®,“Veonys”from Biodigital® y VNG de “Intracoustics®”. Otoemisiones acústicas (OEA) - TEOAE “ILO 292 Potenciales evocados auditivos (PEA) - “Nicolet Viking IV P System”de Nicolet Biomedical, Inc. Potenciales evocados miogénicos vestibulares (VEMPs) - “Intelligent Hearing Systems” Resonancia magnética (MRI) - magnetom symphony maestro class, siemens. 4. Resultados En nuestra serie, el número de mujeres fue ligeramente mayor al de varones. En la mayoría de los casos, 68 (64.1%), el síntoma principal fue hipoacusia, mientras que en 24 (22,1 %) fue un acúfeno. En 11 (16,1%) de los 68 que debutaron con hipoacusia, ésta fue el único síntoma en el momento del diagnóstico. Pero en 54 (59.0%) de los pacientes con hipoacusia, los acúfenos y los síntomas vestibulares estaban también presentes. Sólo en un caso (0.94%) de los 106 pacientes, el acúfeno fue el único síntoma al debut. Por el Abstract 20 contrario, en 23 (21.6%) casos, la hipoacusia o los síntomas vestibulares se asociaban al acúfeno. El vértigo y la inestabilidad no se presentaron nunca como único síntoma de debut. Sin embargo, en un enfermo (0,94%), el mareo fue el único síntoma inicial. No se encontró una asociación entre el lado afecto y el sexo (p=0.87, test de Chicuadrado). Entre los pacientes con SV intracanalicular, había 27 (65.8%) mujeres y 14 (34.1%) varones. No encontramos correlación entre la localización del tumor y el sexo (p=0.09, Chi-cuadrado). Pero sí hallamos relación estadísticamente significativa entre los síntomas iniciales y la localización del SV (p=0.01, Pearson y Spearman). En las pruebas audiométricas, 51 (53.1%) mujeres tenían un umbral auditivo medio (PTA) de 64.93 dB y 45 (46.8%) varones de 60.96 dB. Diez (8.4%) pacientes presentaban una audición normal. El PTA medio fue menor en pacientes menores de 40 años (49.94±32.69 (Rango 12.50-120)) que en los mayores de esa edad (60.54±28.07 (Rango 13-120)). La mayoría de los pacientes (63.5%) presentaban inicialmente una hipoacusia neurosensorial con caída de graves a agudos, mientras que el 5.0% mostraban una mejora de graves a agudos. Se observó hipoacusia pantonal en el 25 % de los casos. Otros patrones audiométricas se hallaron en el 6,3 % de los pacientes. Los valores medios del PTA no difieren significativamente entre hombres y mujeres (p=0.47). Sin embargo, sí hubo diferencias significativas en función de la localización (p=0.014, ANOVA). Asimismo, hubo diferencias estadísticamente significativas entre las localizaciones intracanalicular e intra-extracanalicular (p=0.016, Bonferroni). Entre los grupos extracanalicular e intra-extracanalicular (p=0.750) y entre los intracanaliculares y extracanaliculares (p=0.200), no hubo diferencias significativas. En los PEA, más del 80% de los pacientes presentaban alteraciones en las latencias I-V y IIII (83.7%); encontramos una fuerte correlación entre el tamaño del tumor y el IT5 (p < 0.001, Chi-cuadrado). En las OEA, los siete pacientes (6.5%) en los que estaban ausentes tenían un SV mayor de 20 mm, con localización extracanalicular o intra-extracanalicular; su PTA media fue 70.22 ±28.66 (Rango 30-120) dB. Abstract 21 El tamaño medio de los SV con craneocorpografía tipo IV era mayor que el de los que tienen una craneocropografía tipo I (normal). No se encontró asociación significativa entre localización y tamaño del SV, y la CCG. Tampoco entre la CCG y las manifestaciones clínicas. La PD era normal en 38 pacientes (63.3), siendo patológico el equilibrio medio en 22 (36.6%). Encontramos diferencia significativa entre hombres y mujeres en la condición 6 (p= 0.005) (t-Student). En 67 pacientes (63.2%) se habían realizado pruebas calóricas. La mayoría de los que tenían pruebas anormales (78.3%) correspondían a SVs intracanaliculares o intraextracanaliculares; su PTA media era 67,24±32.66 (Rango 12.50-120) dB. El tamaño medio era de 16.82±10.02 (Rango 4-50 mm). Los pacientes con pruebas calóricas normales tenían una PTA media de 49.13±21.78 (3.75-88.78) dB y un tamaño tumoral significativamente menor (13.77 ±7.96 (2-32.50)). En cuatro casos (5.9%), las pruebas calóricas mostraron arreflexia vestibular. En 12/21 (57.14%) pacientes, los VEMPs estaban presentes en el lado afecto y en nueve (42.8%) ausentes. No encontramos asociación entre VEMPs y localización del SV. En cuanto a la RM, el tamaño medio del tumor es algo mayor en los varones (17.37 mm (±9.05)) que en las mujeres (14.96 (±10.16)). Esta diferencia fue más pronunciada en pacientes ≤40 años (21,7 ±12.21 (6-50 mm)). Las pruebas estadísticas (t-Student) no mostraron diferencia significativa en el tamaño entre los dos sexos. 4.1. Grupos de tratamiento. En 67 pacientes (63.2%) se realizó vigilancia del SV. 36 (53.2%) eran mujeres y 31 (46.3%) varones. La edad media era 59.21±14.35 (Rango 24-85) y el tamaño medio 12.68 ±6.76 (Rango 2-35). El valor medio de la PTA era 57,30 ±28,53. 35 (52.2%) eran intracanaliculares, 10 (14.9%) extracanaliculares y 22 (32.8) intra-extracanaliculares. De los 27 (25.5%) pacientes sometidos a radiocirugía, 15 (55.67%) eran mujeres y 12 (44.4%) varones. El PTA promedio era 59.80±26,86; el tamaño medio, 16,13±7,56. La edad media fue 56.82±14.30. El tamaño fue levemente mayor en las mujeres (14,86±8,06) que en los varones (17,7±6,88) (p=0.064). La localización del SV en este grupo fue: 7 Abstract 22 intracanaliculares (25.9%), 9 extracanaliculares (33.3%) y 11 (40.74%) intraextracanaliculares. El grupo de 12 (11.32%) pacientes sometido inicialmente a cirugía convencional, incluía 6 (50.0%) mujeres y 6 (50.0%) varones. La edad media era 43.78 ±9.28 (Rango 29.16– 57.85) años. La PTA promedio fue 66.40±35.84 y el tamaño medio 30.04±11.37. Cinco (41.6%) pacientes presentaban SVs extracanaliculares y 7 (58.3%) intra-extracanaliculares. 4.2. Asociación entre grupos de tratamiento Entre los grupos de vigilancia y radiocirugía, encontramos una diferencia estadísticamente significativa en el tamaño tumoral (p=0.002), pero no en la PTA (p=0,33). Comparados globalmente, las diferencias entre grupos fueron significativas (p<0.001, ANOVA). El tamaño medio en el grupo de vigilancia (12.68±6.76) fue menor que en el de radiocirugía (16.13±7.56) (p= 0.014). El tamaño medio del grupo de cirugía convencional (30.04 ±11.37) fue significativamente mayor que el de los otros dos (p<0.001, Bonferroni). 4.2.1. Complicaciones del tratamiento. Las complicaciones tras cirugía convencional son evidentes; por ello, hemos analizado exclusivamente las complicaciones de la radiocirugía. Basándonos en los datos de anamnesis y exploración en la primera revisión (un mes tras la radiocirugía), el 61.90% (26/42) no presentaron ninguna complicación. Sin embargo, el 38.1% (16/42) sí. Entre éstos, el 11.09% (5/42) sufrieron paresia facial, el 2.3% (1/42) parálisis facial, el 6.9% (3/42) cofosis, el 2.3% (1/42) hipoacusia significativa (>10dB) y el 4.76% (2/42) vértigo (que no presentaban previamente). El 4.76% (2/42) referían incremento del acúfeno. Un enfermo (2.3%) aquejó de cefalea holocraneal continua una semana tras la radiocirugía, presentando posteriormente atrofia del hemisferio cerebeloso. 4.3. Seguimiento La primera consulta de seguimiento tras el diagnóstico se realizó a los seis meses; las siguientes, al año, tres años y cinco años. El seguimiento medio fue de 56,52±10,79 meses (vigilancia: 55,30±11,92; radiocirugía: 58,60±9,22; cirugía convencional: 58,70±5,7). Abstract 23 En doce casos fue necesario cambiar la opción terapéutica a lo largo del seguimiento, por aumento del tamaño tumoral o empeoramiento clínico. Concretamente, cinco pacientes pasaron del grupo de vigilancia al de cirugía convencional y ocho del grupo de vigilancia al de radiocirugía; cinco de ellos lo hicieron por empeoramiento de la clínica, aún sin incremento en el tamaño. En tres casos, el cambio de opción de tratamiento se debió al deseo del paciente, pese a mantenerse estable la situación clínica y el tamaño tumoral. 4.3.1. Resultados de la exploración en el paciente con NF2. Los síntomas iniciales fueron hipoacusia, acúfenos, inestabilidad y cefalea holocraneal. La audiometría mostró hipoacusia neurosensorial derecha (PTA: 51,25dB) y cofosis izquierda (PTA: 120dB). LA RM detectó múltiples meningiomas intracraneales y SVs extranaliculares puros bilaterales (tamaño máximo: 11mm en el lado derecho y 20mm en el izquierdo). En febrero de 2006, recibió radiocirugía bilateral con una dosis única de 12Gy, permaneciendo estable el tamaño tumoral en los siguientes controles. Sin embargo, en junio de 2010 el paciente refería acúfeno, empeoramiento de los síntomas vestibulares y parálisis facial izquierda. La RM mostró un crecimiento del SV hacia el CAI, por lo que fue remitido al Servicio de Neurocirugía. En marzo de 2013, fue intervenido con un abordaje retrosigmoideo. En el control postoperatorio en Otorrinolaringología, presentaba atrofia de la hemilengua izquierda y parálisis del hipogloso izquierdo, con parálisis del tensor del velo del paladar. 5. Discusión 5.1. Población y características clínicas. En nuestra serie, hay una ligera diferencia en cuanto al sexo, con 57 (53.8%) mujeres frente a 49 (46.2%) varones. Otros estudios con mayor tamaño muestral sugieren una ligera predilección por el sexo femenino. En una serie de 1000 SV intervenidos, Samii (1997) describe una distribución de 54.0% de mujeres y 46.0% de hombres. La edad media al diagnóstico fue 57.0 años (rango 24-86). A pesar de que es infrecuente el diagnóstico en la tercera década,236-240 hay estudios que comunican que los SVs se diagnostican entre los 30 y los 68 años.246 En nuestra serie, sólo 4 (3.0%) pacientes se Introduction 31 1 Introduction Anatomy of Vestibulocochlear nerve (CN VIII)1.1 The vestibulocochlear nerve or acoustic nerve is the eighth of twelve cranial nerves, and is responsible for transmitting sound and equilibrium (balance) information from the inner ear to the brain. It consists of the cochlear and the vestibular nerves which relay sensory input regarding hearing and balance, respectively.1-3 The cochlear and the vestibular nerves courses together until they reach their respective nuclei in the brain stem. Their entire pathway is discussed from peripheral to central. 3 The vestibular apparatus contains two sack-like structures, the utricle and saccule, and three semicircular canals: superior, lateral, and posterior that are joined together in the same fluid environment.4 The special sensory receptors are the hair cells. Signals from hair cells in the macula of the utricle and from hair cells on the cristae of the superior and lateral semicircular canals travel first to the superior vestibular ganglion. Impulses from hair cells of the macula of the saccule and hair cells on the cristae of the posterior semicircular canal travel to the inferior vestibular ganglion. The superior and inferior vestibular ganglia (Scarpa's) is located in the vestibule.1, 3 Postganglionic fibers from Scarpa's ganglia become the superior and inferior vestibular nerves that traverse the internal acoustic canal (IAC) in the posterosuperior and posteroinferior compartments, respectively. Cadaveric investigations show that the superior vestibular nerve is usually larger than the inferior vestibular nerve.2,4 The cochlear nerve usually represents the most inferior part of the vestibulocochlear nerve near the brain stem.2In some occasions, even the superior vestibular nerve lies completely separated from the remaining portion of the vestibulocochlear nerve.1,4 At the porus acousticus, the medial IAC, the superior and inferior vestibular nerves and cochlear nerves are more fused are sometimes seen as a crescent shape.1,3-4 The cochlear and vestibular nerves are usually separated about 3 to 4 mm from the lateral end of the internal auditory canal (e.g. see fig 1).3The relationship between the cochlear and vestibular nerves Introduction 32 changes from the lateral end of the IAC to the cerebellopontine angle (CPA); the two nerves rotate 90° from the labyrinth to the brainstem. 3-4 Most of the rotation occurs within the IAC. 4Some histological researches show that if there is complete separation between the two nerves, the cochlear nerve contains the variable number of vestibular fibers that are characterized by a larger diameter.4They course through the CPA cistern as two distinct nerves surrounded by cerebrospinal fluid and enter its root entry zone in the brainstem at a slight angle.1-4. The cochlear division is separated from the vestibular division by the cerebellar peduncle.4 Figure 1. Internal aspect of temporal bone and contents of IAC Source: http://www.studmed.ru/4/129.htm (11.11.2013) In the brain stem, the vestibular nerves course medially to the root of the inferior cerebellar peduncle located at the pontomedullary junction along the lateral floor of the fourth ventricle. Just medial to the cerebellar peduncle, the vestibular nerve branches and terminates in one of the four vestibular nuclei that make up the “vestibular nuclear complex”or the flocculonodular lobe of the cerebellum. Axons from there nuclei travel in the following ways: via the vestibulocerebellar tract to aid in coordination, via the vestibulospinal tracts along the length of the spinal cord to modulate muscle tone, to the Introduction 33 reticular formation to regulate consciousness, and via the medial longitudinal fasciculus in the brain stem and upper cervical cord to the paired nuclei of cranial nerves III, IV, and VI, thus, controlling the extraocular muscles.1 The nerve fibers originated from hair cells of the organ of Corti of the cochlea composed to the cochlear nerve the central portion of which forms at the cochlear apex. From the apex to the base of the cochlea, outer fibers converge centrally and complete the formation of the nerve. Nerve fibers course toward the medial IAC where the cochlear and vestibular portions of the vestibulocochlear nerve occupy anteroinferior and posterosuperior portions of the canal, respectively and unite with the superior and inferior vestibular nerves and become the vestibulocochlear nerve bundle. In the Magnetic Resonance Image (MRI) image the nerve complex in this part is seen as a crescent shape.1, 4. The cochlear nerve traverses the CPA cistern heading toward the brain stem at a slightly oblique angle. The nerve enters the anterolateral brain stem at the pontomedullary junction. Here the primary sensory neurons bifurcate and terminate in secondary cochlear neurons, the dorsal and ventral cochlear nuclei. They lie superficially on the dorsal surface of the upper medulla immediately lateral to the restiform body.2From this point, the ascending hearing pathway becomes complicated because there are multiple decussations at all levels. Most nerve fibers from the ventral cochlear nucleus cross the midline and form the trapezoid body, the major acoustic pathway decussation, located in the pontine tegmentum. Neurons from the trapezoid body synapse with the contralateral superior olivary nucleus (lateral pons) and lateral lemniscus. Most neurons from the dorsal cochlear nucleus tend to extend directly to the contralateral lateral lemniscus. A few auditory fibers ascend in the ipsilateral lateral lemniscus.4 Neurons from the dorsal cochlear nucleus tend to extend directly to the contralateral lateral lemniscus. From the lateral lemniscus, neurons ascend into the tectal plate to the inferior colliculus in the lower midbrain.7 At the inferior colliculus, some fibers cross back to the original side but the majority continue upward to the medial geniculate body, located posterolaterally at the level of the superior colliculus immediately lateral to the ambient cisterns. From the medial geniculate body, the acoustic radiations ascend through the thalamus and sublenticular internal Introduction 34 capsule and terminate in the transverse temporal gyry of Heschl of the superior temporal gyrus (Brodmans area 41 and 42), the primary auditory cortex, and central processing area where the conscious perception of sound occurs. Associative areas (Brodmans area 22) are located nearby in the posterior transverse and superior temporal gyri.1 A small number of neurons from the superior olivary complex extend to the facial nucleus, which provide for reflex contraction of the stapedius muscle. Anatomic relationship of CN VIII1.2 The vestibulocochlear nerve travels from the brainstem towards the inner ear and passes through CPA and IAC and makes up the vicinity with the important anatomic structures like brain tissue, nerves and vessels. Therefore the anatomic considerations are divided into sections dealing with the topographic relationships (e.g. see fig. 2, and 3). In general, in the IAC, the facial nerve has a close relationship with the three components of the vestibulocochlear nerve as the facial and vestibulocochlear nerves always run together from the brain stem to the internal auditory canal. . Figure 2. Spatial anatomical relationship between the nerves traveling through the internal auditory canal is shown. Source: http://emedicine.medscape.com/article/835286-overview#showall (11.11.2013) Introduction 35 In general in the IAC, the facial nerve has a close relationship with the three components of the vestibulocochlear nerve as the facial and vestibulocochlear nerves always run together from the brain stem to the internal auditory canal. The average number of fibres forming vestibular, cochlear, and facial nerves was not constant during their courses within the IAC. The superior and the inferior vestibular nerves showed an increase in the number of nerve fibres from the inner ear end towards the brainstem end of the IAC, whereas the facial and the cochlear nerves show reduction in the number of fibres (e.g. see fig. 3). Source: Bhuta S, Hsu Ch, Kwan G. The Course of the Facial & Vestibulo-Cochlear Nerves through the Temporal Maze: A Gazeinto Embryology, Anatomy& Common Pathology 2011; Power point presentation. At the IAC in most of cases the facial nerve occupies the superior and anterior position to the vestibulocochlear nerve or its branches and maintains its tubular shape throughout its course in the canal.1, 5 Close to the transverse crest the facial and cochlear nerves moves are farther anterosuperiorly and anteroinferiorly, respectively.3 Figure 3. MRI views of Facial and vestibulocochlear nerves within the IAC Introduction 36 Figure 4. Posterior view to CN VIII, IX and X. Internal acoustic meatus drilled and dura mater removed. Source: Seker Askin, Kilic Turker. Atlas of anatomical dissections: The Cerebellopontine angle. Marmara University, Turkey, http://nsa.marmara.edu.tr/anatomy/6/Serebellopontin-Aci (11.11.2013). Accordingly, in the lateral part of the IAC there are facial, cochlear and the inferior and superior vestibular nerves. The position of the nerves is most constant in the lateral portion of the canal, which is divided into a superior and an inferior portion by a horizontal ridge, called either the transverse crest or the falciform crest.4The facial and the superior vestibular nerves are superior to the crest. The facial nerve is anterior to the superior vestibular nerve and is separated from it at the lateral end of the canal by a vertical ridge of bone, called the vertical crest. The vertical crest is also called Bill's bar in recognition of William House's role in focusing on the importance of this crest in identifying the facial nerve in the lateral end of the canal.3The cochlear and inferior vestibular nerves run below the transverse crest, with the cochlear nerve being located anteriorly. Thus, the lateral meatus can be considered to be divided into four portions, with the facial nerve being anterior superior, the cochlear nerve anterior inferior, the superior vestibular nerve being posterior superior, and the inferior vestibular nerve being posterior inferior. In the CPA, the filaments of the nervus intermedius are also stretched around the fibers of the vestibulocochlear nerve (e.g. see fig. 4). The nervus intermedius is divisible into three parts: a proximal segment that adheres closely to the vestibulocochlear nerve, an intermediate segment that lies free between the eighth nerve and the motor root of the facial nerve, and a distal segment that joins the motor root to form the facial nerve.7 Introduction 37 Some nerves adhere to the eighth nerve throughout in the posterior cranial fossa and can be found as a separate structure only after opening the internal acoustic meatus. In most instances, the nerve is a single trunk, but in some cases, it is composed of two to four rootlets.3The nerve most frequently arises at the brain stem anterior to the superior vestibular nerve as a single large root and in the meatus, lies anterior to the superior vestibular nerve. When multiple rootlets are present, they may arise along the whole anterior surface of the eighth nerve; however, they usually converge immediately proximal to the junction with the facial motor root to form a single bundle that lies anterior to the superior vestibular nerve.4 The vestibulocochlear nerve in the level of brainstem makes up the vicinity with the consistent set of neural, arterial and venous vessels which facilitate identification of the nerves on the medial side of the tumour. In the medial side the pons, medulla, and cerebellum are also closely related to the vestibulocochlear nerve. These structures are helpful in guiding the junction of the facial nerve with the brain stem are the pontomedullary sulcus; the junction of the glossopharyngeal, vagus and accessory nerves with the medulla, the foramen of Luschka and its choroid plexus and the flocculus.6 Figure 5. Topographical relationship of the facial and vestibulocochlear nerves at four levels. 1. Near the brainstem; 2. At the CPA; 3. At the IAC; 4. At the midportion of the IAC. TNtrigeminal nerve; Cbll - cerebellum. Source: Kim Hyun-Sook, Kim Dong-Ik, Chung In-Hyuk, Lee Won-Sang, Kim Kyo. Topographic relationship of the Facial and Vestibulocochlear Nerves in the Suparachnoid Space and Internal Auditory Canal. Am J Neuroradiol 1998; 19:1155-1161 Introduction 38 The facial nerve arises from the brain stem near the lateral end of the pontomedullary sulcus. This sulcus extends along the junction of the pons and the medulla, and ends immediately in front of the foramen of Luschka and the lateral recess of the fourth ventricle. The facial nerve arises in the pontomedullary sulcus 1 to 2 mm anterior to the point at which the vestibulocochlear nerve joins the brain stem at the lateral end of the sulcus. The interval between the vestibulocochlear and facial nerves is greatest at the level of the pontomedullary sulcus and decreases as these nerves approach the meatus.2-3 Mean distances between the exits of the VIIth and VIIIth are 4.7 ± 0.9 mm (e.g. see fig. 6), between the VIIth and IXth 6.2 ± 1.2 mm and between the VIIIth and IXth 5.5 ± 1.0 mm. 10 Figure 6. The neighboring structures of a CN VIII at CPA Source: Seker Askin, Kilic Turker. Atlas of anatomical dissections: The Cerebellopontine angle. Marmara University, Turkey, http://nsa.marmara.edu.tr/anatomy/6/Serebellopontin-Aci (11.11.2013). The structures related to the lateral recess of the fourth ventricle which have a consistent relationship to the facial and vestibulocochlear nerves are the foramen of Luschka and its choroid plexus and the flocculus. The foramen of Luschka is situated at the lateral margin of the pontomedullary sulcus, just dorsal to the junction of the glossopharyngeal nerve with the brain stem, and immediately posteroinferior to the junction of the facial and vestibulocochlear nerves with the brain stem. The foramen of Luschka is infrequently well visualized.7,10 However, there is a consistently identifiable tuft of choroid plexus which hangs out of the foramen of Luschka and sits on the posterior surface of the Introduction 39 glossopharyngeal and vagus nerves just inferior to the junction of the facial and vestibulocochlear nerves with the brain stem. 11 Another structure related to the lateral recess is the flocculus. It is a fan-shaped cerebellar lobule that projects from the margin of the lateral recess into the CPA. The flocculus, together with the nodule of the vermis, forms the primitive flocculonodular lobe of the cerebellum.10,11 The flocculus is attached to the rostral margin of the lateral recess and foramen of Luschka. It continues medially with the inferior medullary velum, a butterflyshaped sheet of neural tissue which forms on the surface of the nodule and sweeps laterally above the tonsil to form part of the inferior half of the roof of the fourth ventricle. The lateral part of the inferior medullary velum narrows to a smaller bundle, the peduncle of the flocculus, which fuses to the rostral margin of the lateral recess and foramen of Luschka.11-12 The flocculus projects from the peduncle of the flocculus into the cerebellopontine angle just posterior to the site at which the facial and vestibulocochlear nerves join the pontomedullary sulcus. At the CPA, among the other structures, the blood vessels are closely related to facialvestibulocochlear complex 5. The arteries crossing the cerebellopontine angle, especially the anterior inferior cerebellar artery, have a consistent relationship with the facial and vestibulocochlear nerves, foramen of Luschka and the flocculus. After coursing near, and sending branches to the nerves entering the acoustic meatus and the choroid plexus protruding from the foramen of Luschka, the anterior inferior cerebellar artery passes around the flocculus to reach the surface of the middle cerebellar peduncle and terminates by supplying the lips of the cerebellopontine fissure and the petrosal surface of the cerebellum.5, 6 The anterior inferior cerebellar artery usually bifurcates near the facial and vestibulocochlear nerves to form a rostral trunk and a caudal trunk. The rostral trunk courses along the middle cerebellar peduncle to supply the upper part of the petrosal surface, and the caudal trunk passes near the lateral recess and supplies the lower part of the petrosal surface 6. Introduction 46 The first two factors affect the modes of vibrations of the skull whereas the third depends on the type and quality of the ear occlusion. The last factor dramatically affects the effectiveness of the outer ear compression.14 The neural activity of the inner ear is dependent on electro-chemical processes and initial electric potentials between the fluids occupying the various structures of the inner ear. An electric potential is created when there is a difference in the electric charge between two different locations. The area of higher charge is said to be positively polarized while the area of lower charge is said to be negatively polarized. In a biological system, such as the human ear, a difference in chemical charge between two areas is called the bioelectric potential.11 When the two polarized areas are connected, the charged particles move from one area to another. This occurs because of the electromotive force that is created by the difference in electrical charge. Commonly charged particles in the human ear include positively-charged potassium ions (K+), negatively-charged chloride ions (Cl-), positivelycharged sodium ions (Na+) and positively-charged calcium ions (Ca2+). In the inner ear, the endolymph contains a large amount of potassium ions and the perilymph contains a large amount of sodium ions. A static bioelectric potential that involves the separation of charged particles by a cell membrane is called a resting potential. The resting potential of the endolymph in the scala media, called the endocochlear potential (EP), is + 80 millivolts (mV) in reference to the resting potential of the perilymph in the two other cochlear channels. The resting potential of the inner hair cells is -40 mV and of the outer hair cells is -70 mV compared with the perilymph. 15 Therefore, the difference in potential between the endolymph and the inner hair cell is 120 mV and between the endolymph and the outer hair cell is 150 mV. This 150-mV potential is a biological battery that supports all inner ear processes. It is a very efficient system that consumes only approximately 14 microwatts (μW) of power while carrying out the equivalent of approximately one billion floatingpoint operations per second. 12, 13, 15 A dynamic bioelectrical potential that involves the movement of charged particles from one area to another in response to a stimulus is called a stimulus related potential. There are three stimulus related potentials that are commonly observed in the inner ear in response to an auditory stimulus. The three stimulus related potential are the summating potential (SP), cochlear microphonic (CM), and the compound action potential (CAP). The Introduction 47 former SP and CM are generated by the hair cells and CAP is generated by the vestibulocochlear nerve.11, 12, 15 The SP is a direct current potential that causes a positive or negative change in the endocochlear potential for the duration of a signal. It is the driving force for moving the charged ions through the stereocilia and membrane separating hair cell from the surrounding endolymph. Both the CM and CAP are alternating current potentials which vary in polarity based on changes in the phase of the signal. The CM is a pre-neural electric potential that mimics the incoming sound signal; it is considered to be a reflection of receptor currents flowing through the hair cells. The CAP is the actual event related potential (ERP) that is generated when the auditory nerve “fires”(transmits a signal) in response to a stimulus. The CAP results from the firing of the auditory portion of the vestibulocochlear nerve in response to the release of the neurotransmitters from the hair cells.13 Various ERPs and their changes in time and space can be measured in the central nervous system using electroencephalography (EEG). One example of these measurments is the mismatch negativity (MMN) potential generated in the auditory cortex and having a latency of 150 to 250 ms post-stimulus. The MMN is a negative, task independent neural potential generated in response to an infrequent change in a repetitive sound sequence.15 Up and down movement of the basilar membrane causes a shearing force to act on the cilia of the hair cells of the organ of the Corti. The shearing force is a result of different points of attachment of the basilar membrane and the tectorial membrane to the cochlear wall. The force bends the cilia to the left and to the right of the basilar membrane axis.1 The stereocilia of a hair cell have gradually changing height and are held together by tipto-side links that cause the whole bundle to move together when stimulated.14 Tilting movements of the stereocilia affect the tension on the fiber in the tip link. When the stereocilia are bent toward the largest stereocilium, the tip-to-side links cause mechanically-gated ion channels in the stereocilia membranes to open. The opening of the ion gates allows positively-charged ions (K+) of potassium, which are the main cations in the endolymph, to flow from the positively-charged endolymph into the negativelycharged hair cell.15 As the fiber tension increases, the flow of ions into the hair cell also increases. When the stereocilia bundle is bent in the direction away from the largest stereocilium, the ion channels close and the excess of K+ in the cell is pushed out of the Introduction 48 cell through a semipermeable membrane via active pumping processes restoring natural negative polarization of the cell (Geisler, 1998). 7,14 However, the effects of stereocilia bending and the in-and-out flow of K+ ions are different in the inner hair cells and the outer hair cells. When the K+ ions enter the inner hair cell, they depolarize the content of the cell, that is, they change to zero the difference in electric potentials between the areas inside and outside the cell. As a result, when the gates are open, the cell becomes depolarized (excited), and when the gates are closed, the cell becomes hyperpolarized or inhibited (e.g. see fig. 9). Figure 9. The inner hair cells response to the bending of the steriocilia. Source: Emanuel D, Maroonroge S, Letowski T. The Hearing System 2009. Chapter 9. Physiology and Function of the Hearing System p320 The transduction of the mechanical actions of the shearing of the stereocilia to the electrochemical signal transmitted by the nervous system begins when a neurotransmitter is released from the base of the inner hair cell. 17 This neurotransmitter crosses the synaptic cleft and binds to specialized receptor sites located on the post-synaptic membrane of the peripheral processes of the nerve fibers connecting the inner ear with the brainstem. The bundle of nerves connecting the inner ear with the brainstem is called the auditory nerve. If a sufficient amount of neurotransmitters are released, the afferent nerve fibers will fire in response, sending an electric signal down the length of the auditory nerve towards the brainstem. 16, 17 Introduction 49 The response of single auditory nerve fibers to different stimuli has been measured in many experiments. Most of them performed experimentally in which a microelectrode placed in the nerve trunk to isolate the activity myelinated nerve fibers.17,20 The auditory nerve has approximately 30,000 fibers in humans and there are approximately 50,000 auditory nerve fibers in cats. Perhaps one of the most important research findings was the observation that 90% to 95% of neurons (type I radial fibers) innervate to the outer hair cells, whereas 5% to 10% (type II, outer radial fibers) innervate to the outer hair radial cells. The radial cells have bipolar cell bodies in the spiral ganglion. Outer spiral fibers are monopolar and unmyelinated.15,16,17 On the base of spontaneous discharge, the nerve fibers have been classified into the following three categories: high (18 to 20 spikes per second), medium (0,5 to 18 spikes per second), and low (0 to 0,5 spikes per second). Fibers with high rates of spontaneous activity respond to auditory signals at low levels better than do the fibers with medium or low rates that have thick dendrites which tend to determinate on the side of the inner hair cells facing the outer hair cells. Fibers with low and medium spontaneous rates have thin dendrites on the side of the inner hair cells facing the modeolus.11 According to some ongoing studies, the fibers with high rates of spontaneous activity have different terminations in the auditory CNS (cochlear nucleus) than do fibers with low rates of spontaneous activity. In other words, spontaneous activity of nerve fibers is not random but is proving to be anatomically and functionally significant.11 The tuning curve of the single auditory nerve fiber is perhaps the most basic measure of auditory nerve function. When effectively stimulated by sound, the cochlear afferent responds with an increase in the rate of discharge. At low stimulus intensities, such rate increases are evoked only by a narrow range of stimulus frequencies.18 Auditory nerve fibers arrive at the brainstem by forming synapses with large groups of neurons in the cochlear nuclei located in the border between the pons and medulla.The fibers from each ear terminate on the nucleus located on the same (ipsilateral) side of the brainstem from where most of the fibers cross to the opposite (contralateral) side of the brainstem, and either connects to contralateral superior olivary complex or ascends directly to contralateral inferior colliculus in the midbrain. Type I nerve fibers with large Introduction 50 myelinated neurons are responsible for transporting the coded auditory signal from the peripheral to the central nervous system. The function of the smaller and less numerous type II fibers is still largely unknown.16,18 The neural cells in the cochlear nuclei have several complex firing patterns and wider dynamic ranges than the neurons in the auditory nerve. In response to simple tonal stimuli, several response patterns have been recorded in the various cells of the cochlear nuclei. These response patterns include the following patterns: 1) a “primary”pattern that is similar to that of the auditory nerve (“primary-like”neurons), 2) a “chopper”pattern that consists of repeated bursts of firing followed by short pauses (“chopper”neurons). The periodicity does not match the periodicity of the stimulus. 3) an “on”pattern, in which the cell fires only when a stimulus begins “on”neurons, and 4) a “pauser”pattern in which the cell fires only at the onset of the stimulus, pauses, and then continues until the stimulus is turned off (“pauser”neurons).20 Examples of peristimulus (PST) histograms, i.e., the histograms of the times at which neurons fire, as a function of latency following tonal stimuli (e.g. see fig. 10). The firing patterns shown in figure 10 are the most commonly reported firing patterns. However, there also are other firing patterns observed in response to simple stimuli. Further, there are reports of many different subcategories of firing patterns under each of the main categories, and the response of the cochlear nucleus to complex stimuli varies from the response to simple stimuli. The type of response recorded from the neurons in the cochlear nucleus depends on a number of physical features associated with the cells (e.g. characteristics of the membrane, type of cell), the connection between the auditory nerve and the cochlear nucleus cells (e.g. many or few axon endings contacting many or few dendrites), and the presence of inhibitory input from other cells. For example, in the anterior ventral cochlear nucleus (AVCN), the most common cell types are the global and spherical bushy cell. These cells receive very few axonal connections from auditory nerve fibers from a localized frequency area of the cochlea and are the most likely contributors to the primary response pattern seen in the cochlear nucleus. Their frequency specificity may also be enhanced by their function as coincidence detectors, which reduce the random noise level from spontaneous activity of the auditory nerve.18,19 Other cells may specialize in transmitting intensity of Introduction 51 sound (multipolar cells) or temporal order of sound events (octopus cell). In the posterior ventral cochlear nucleus (PVCN), the octopus cell is a common cell type, so-called because these cells resemble an octopus with long tentacle-like dendrites. These dendrites receive many more connections, across a broader frequency range of the cochlea, compared with the AVCN bushy cells, and they are thus more broadly tuned. These cells have been reported to respond well to amplitude modulated tones and clicks, but have a reduced activity in response to steady state noise. In some species, the dorsal cochlear nucleus (DCN) has been recorded to respond to spectral differences that may indicate they provide some coding in response to monaural localization cues in a vertical plane.17,18 Figure 10. PST histograms illustrating different types of neuron firing patterns in the cochlear nucleus. Source: Pfeiffer R. Classification of response patterns of spike discharges for units in the cochlear nucleus: Tone-burst stimulation. Experimental Brain Research 1966, Volume 1, Number 3, 220-235. Physiology of superior and inferior vestibular nerves1.3.2 The vestibular nerves as a sensory nerve conducts vestibular information from the inner ear to the brain.1,3,7,11 The peripheral vestibular system includes the paired vestibular sensory end organs of the semicircular canals (SCC) and the otolithic organs (Fig. 11). These receptors are found Introduction 52 within the fluid-filled bony channels of the otic capsule and are responsible for perception of both the sense of position and motion. 19 The vestibular nerves are the afferent connection to the brainstem nuclei for the peripheral vestibular system. Figure 11. Anatomic organization of the peripheral vestibular system (vestibular end-organs and the vestibular nerve). Source: http://otorrinos2do.wordpress.com/2009/12/08/physiology-of-the-vestibular-system/ The cells bodies of vestibular nerve afferents are located in the superior or inferior divisions of Scarpa's ganglia, which lie within the internal auditory canal near the emergence of the vestibular nerve into the cerebellopontine angle. 16 From the vestibular labyrinth, the afferent information travels ipsilateral in 1 of 2 branches of the vestibular nerve. The superior vestibular nerve innervates the lateral and anterior SCC as well as the utricle. The inferior vestibular nerve innervates the posterior SCC and the saccule (e.g. see fig. 11). Variation of nerve fiber counts among studies appears to be a function of age, although rate of decline of the number of afferent fibers also appears to be variable. The branches of the vestibular nerve travel together into the pontomedullary junction where they bifurcate.16 Primary vestibular afferents in the superior division of the vestibular nerve include axons that synapse in the superior and medial vestibular nuclei or the uvula, nodulus, flocculus, or fastigial nucleus of the cerebellum. 16-17 Primary vestibular afferents from the inferior branch synapse with neurons in either the medial, lateral, or inferior vestibular nuclei, which, along with the superior vestibular nuclei and other subnuclei, comprise the vestibular nuclear complex.16 Introduction 53 Perception of angular accelerations is chiefly the responsibility of the three paired SCCs (superior, posterior, and lateral). Within the ampullated portion of the membranous labyrinth are the end-organs of the cristae, containing specialized hair cells that transduce mechanical shearing forces into neural impulses. Histologically the hair cells of the ampulla are located on its surface. Their cilia extend into a gelatinous matrix better known as the cupula, which acts like a hinged gate between the vestibule and the canal itself (e.g. see fig. 12). The otolithic organs of the utricle and the saccule are found within the vestibule. Chiefly responsible for the perception of linear accelerations (eg, gravity, deceleration in a car), their end-organs consist of a flattened area, rich in hair cells, in the macular area whose cilia project into a similar gelatinous matrix. The matrix, however, differs from the matrix associated with the SCCs in its support of a blanket of calcium carbonate crystals better known as otoliths, which have a mean thickness of approximately 50 μm Information from the vestibular end-organs is transmitted along the superior (which receives information from the superior, horizontal SCCs and utricle) and inferior (which receives information from the posterior SCC and saccule) divisions of the vestibular nerve. Although its role is primarily afferent in the transmission of electrical activity to the central vestibular nuclei of the brainstem, an efferent system does exist that probably serves to modify end-organ activity. Each vestibular nerve consists of approximately 25,000 bipolar neurons whose cell bodies are located in a structure known as Scarpa’s ganglion, which is typically found within the IAC.17, 20 Figure 12. A stylized representation of the crista with the angular acceleration receptor Source: http://otorrinos2do.wordpress.com/2009/12/08/physiology-of-the-vestibular-system/ Introduction 54 Type I neurons of the vestibular nerve derive information from corresponding type 1 hair cells, whereas type II neurons derive information from corresponding type 2 hair cells at its simplest. The cristae ampullares convey information approximately angular in acceleration of the head to the central nervous system. The maculae convey information about linear acceleration and head position relative to gravity. 18 The utricular macula is oriented horizontally and the saccular macula is oriented vertically. Tilting the head to the side stimulates the saccular macula and titling the head forward or to the back stimulates the utricular macula.15 All these sensory organs contain hair cells with their stereocillia responding to the head motion analogous to the way the inner hair cells in the cochlea respond to the acoustic signal. Depending on the head position and the direction of the head movement, the endolymph flow in the semicircular canals and the vestibule stimulates the hair cells of the organs which control balance.18 For example, the cilia of the maculae are embedded in the gelatinous membrane containing a relatively heavy amount of calcium carbonate (otoconia); movements of the head cause the otoliths to bend the cilia, causing depolarization/hyperpolarization of the hair cells, depending on the direction of movement.14,18 The signals from the organs which control balance are transmitted through the vestibular portion of the vestibulocochlear nerve to four vestibular nuclei within the brainstem and further to the brain.18 The fibers from the vestibular nuclei also crossover to the contralateral nuclei from which they project, among others, to oculomotor nuclei that drive eye muscle activity, resulting in a vestibule-ocular reflex that helps maintain fixation of the eyes on the object moving, in relation to the head position. In this way, the fibers are responsible for a complex coordination between the vestibular system, visual system, proprioceptors, and structures within the cerebellum, brainstem, and the whole cortex.18 Primary vestibular afferents enter the brainstem dividing into ascending and descending branches. Within the brainstem there appears to exist a nuclear region with four distinct anatomic types of second-order neurons that have been traditionally considered to constitute the vestibular nuclei. It appears, however, that not all these neurons receive input from the peripheral vestibular system. The main nuclei are generally recognized as the superior (Bechterew’s nucleus), lateral (Deiters’nucleus), medial (Schwalbe’s nucleus), Introduction 55 and descending (spinal vestibular nucleus). Functionally, in primate models, the superior vestibular nucleus appears to be a major relay station for conjugate ocular reflexes mediated by the SCCs. 14, 15, 18 The lateral vestibular nucleus appears to be important for control of ipsilateral vestibulospinal (the so-called “righting”) reflexes. The medial vestibular nucleus, because of its other connections with the medial longitudinal fasciculus, appears to be responsible for coordinating eye, head, and neck movements. The descending vestibular nucleus appears to have an integrative function with respect to signals from the vestibular nuclei, the cerebellum, and an amorphous area in the reticular formation postulated to be a region of neural integration. Commonly referred to as the “neural integrator” among neurophysiologists, the nucleus is responsible for the ultimate velocity and position command for the final common pathway for conjugate versional eye movements and position.16 The vestibular nerve in part also projects directly to the phylogenetically oldest parts of the cerebellum namely, the flocculus, nodulus, ventral uvula, and the ventral paraflocculus on its way directly through the vestibular nucleus. Better known as the vestibulocerebellum, this area also receives input from other neuronal pathways in the central nervous system (CNS) responsible for conjugate eye movements, especially smooth-pursuit eye movements, which, in addition to the VOR, are responsible for holding the image of a moving target within a certain velocity range on the fovea of the retina. 1315 The Purkinje’s cells of the flocculus are the main recipients of this information, of which some appears to be directed back toward the ipsilateral vestibular nucleus for the purposes of modulating eye movements in relation to gaze (eye in space) velocity with the head still or during combined eye–head (vestibular signal-derived) tracking. 15 Important for cancelling the effects of the vestibule-ocular reflex (VOR) on eye movement when it is not in the best interest of the individual (think of twirling ballet dancers or figure skaters and how they can spin without getting dizzy), the vestibulocerebellum is also important in the compensation process for a unilateral vestibular loss. Introduction 62 cautiously retracted, several small blood vessels crossing from the brainstem or cerebellum are brought into view and doubly ‘clipped’and the vessel divided.” 28 Previously, Horsley had advocated blunt finger removal of an intact large tumour, and Cushing had favored subtotal enucleation of VS as an adjunct to osseous suboccipital decompression. Dandy took the next step in the history of VS surgery by performing extensive intracapsular decompression followed by meticulous tumour capsule excision and careful management of surrounding vasculature to respect important vessels and avoid postoperative hemorrhage. 24 In this 1922 report, however, Dandy failed to mention any of Cushing’s 1917 monograph, and so Cushing promptly wrote a letter attacking his manners and professional ethics and dismissed Dandy’s success.26 Rather than considering Dandy’s new approach, Cushing rigidly maintained his belief that the high mortality rates of total VS resection would make it irresponsible even to attempt such an approach. He considered Dandy’s method to be inconsistent with the standard of care. Some neurosurgeons that had been trained by Cushing followed his recommendations. 21 In Europe the modern viewpoints of VS has been dominated by the efforts of House, Yasargil and Fisch (1969), Glasscock (1973), Sterkers (1979), King and Morrison (1980), Samii and Wigand (1992).26 Particularly, surgeons from England, France, Germany and Denmark have made great contribution to the development of knowledge of VS and management of patients with VS. In Denmark, two CPA tumours were operated on via the translabyrinthine approach by the otologist, EC Schmiegelow, who operated on two patients at the National Hospital, Rigshospitalet, in 1914. 21 It was a huge step forward in VS surgery When William House developed the translabyrinthine approach in 1960. Nevertheless, it resulted in a 20% cerebrospinal fluid leak. But after microsurgical techniques were introduced by M Tos in 1976, who removed a medium size VS via the translabyrinthine approach in the Department of Otolaryngology, Gentofte University Hospital. 23 Even this approach later termed as a Danish VS model, where Tos and Thomsen in close cooperation with the neurosurgeons J Riishede, G Thornval and A Harmsen established one team to manage VS in Denmark.23 Introduction 63 The invention of the Gamma Knife Machine for the management of patients with VS has revolutionized tumor control. The Gamma Knife Surgery for VS was first conducted by professor Leksell in Sweden in 1969. In 1986, the Leksell Gamma Knife type “B”was introduced. But the worldwide interest in GKS roused only after 1991, when results of GKS for VS were reported at the first international conference on VS held in Copenhagen.26 GKS was spotlighted as an ideal treatment for patients with a high risk for surgery, old patients, and patients who refused to undergo an operation. Since then, many medical centers have reported good results of GKS for a VS.28 Over the years, starting from 2000, the Leksell Gamma Knife type “C”with a robotic automatic positioning system and an automatic helmet changer was introduced, which allowed for more convenient and rapid treatment, and this is still being used today. 28, 30 In 2004, the Leksell Gamma Knife type “4C”was introduced. It features new Leksell Gamma Plan software, provides the ability to co-register non-stereotactic images, allows planning from various image sources such as computed tomography, magnetic resonance image, and positron emission tomography (PET), and sharing the remote images from the center where a gamma knife is not available.29 1.3.3.2 Histopathology of Vestibular Schwannoma In a majority of literature, different markers in an SV have been revealed such as Luse bodies, fibrous collagen bundles, myelin sheath irregularities, and subepithelial nerve fiber losses and all were observed in the vestibule. But histopathological examinations of VS always detects two tissue types, Antoni “A”and Antoni “B”. The Antoni A and Antoni B types are termed after the the Swedish pathologist Antoni.20 It is the distal part of the eighth nerve, with Schwann cells enclosing the axons, where an overproliferation of Schwann cells leads to the formation of VS. As a result, acoustic schwannoma cells can survive and proliferate in the absence of axon-derived growth factors, in a similar manner to mature, denervated Schwann cells. 32 The tumours have a remarkably diffuse yellow appearance and as described by Sandiford with it a firm Introduction 64 consistency. When compared to other benign intracranial tumours, VS have the least proliferative status. 30, 31 Antoni type “A” tissue is type usually described as densely packed cells with small spindle-shaped densely staining nuclei and Antoni “B” refers to a looser cellular aggregation of vacuolated pleomorphic cells. 20 In any particular VS, one tissue type may predominate (e.g. see fig. 15). The cells are dispersed randomly around blood vessels, microcysts, collections of xanthomatous cells and sites of previous hemorrhage. Lymphocytes attest to antecedent degenerative events within Antoni B tissue. The degree of nuclear pleomorphism varies considerably among acoustic neurinomas as well as between different areas within the same tumor. This pleomorphism often contributes to a random population of large and bizarre nuclei that taunt the pathologist with thoughts of anaplasia; however, fortunately, malignant transformation is of a rarity that permits individual case reports. Mitotic figures are most infrequent. Necrosis is commonly present but most often testifies to the meagerness of native blood vessels and their compression by tumor expansion within a restricted compartment.20, 21 Figure 15. Atoni type A (On the left) is a VS with a thick concentration of cells and the Antoni type B (On the right) is schwannoma. The pattern is a loose texture of cells with a honeycomb appearance. The accumulation of lipids within the cells gives it its characteristic look. Source: http://www.otopathology.com/acoustic.htm Introduction 65 Schwann cells possess a basement membrane that lies external to the plasma membrane. This feature distinguishes Schwann cells from fibroblasts. In addition, the presence of widely spaced collagen validates this identification. The histological features of a vestibular schwannoma are generally diagnostic, and the assessment of anaplasia or malignancy has already been resolved in favor of benignity by the natural history of this neoplasm. Russell & Rubinstein (1989) described that mucinous and microcystic changes are especially prone to occur in Antoni B tissue. When confluent, the changes presumably result in the production of large cysts. 20 In some literature the cystic elements in VS have been reported as a degenerative “A” tissue especially it refers to large and old tumours. But in other literatures this theory has been neglected and criticized along with stating that the distinctive types of Schwann cells could be cultured from “A”and “B”types of human schwannomas. 20Tumors derived from type “B”tissue had a more pronounced liquificative action upon the culture media than those composed of “A”tissue. VSs can reach sizes of up to several centimeters in diameter and thus, most of the cells comprising a tumor are not adjacent to the axon. As a result, vestibular schwannoma cells can survive and proliferate in the absence of axon-derived growth factors, and in a similar manner will mature into denervated Schwann cells.32 A VS receives its arterial blood supply primarily from the branches of the basilar arteries, as well as from branches of the vertebral arteries.29 Of course, as the tumor grows, it follows the direction of least resistance, often medially into the CPA, at which stage it may be of considerable size. As a result, a tumor often consists of two parts, the stalk within the IAC and the main portion occupying the CPA. Schwann cells are multivalent neuro-ectodermal cells, which are considered homologous to oligodendroglia of the central nervous system, both of which form and maintain the myelin sheath.33 The immunohistochemical identification of nuclear antigen associated with cellular proliferation offered a very promising approach to the measurement of growth fraction in a VS.20 The occurrence of both sporadic VSs and those associated with Introduction 66 Neurofibromatosis NF appears to be associated with an aberration of a tumor suppressor gene on chromosome 22q12. The biological background and reason for the diverse growth patterns of a VS is, however, largely unknown and the natural history of the VS remains enigmatic. Growth of any solid tumor with a volume of more than 2 or 3mm requires angiogenesis in demand of sufficient tissue supply of oxygen and nutrients through diffusion. Angiogenesis is defined as a process of new blood vessel formation from preexisting vasculature and is characterized by a cascade of processes, during which the vessel basal membrane and the surrounding tissue stroma is degraded by endothelial cell proliferation and migration. Established hypoxia induces paracrine secretion of proangiogenetic factors from the tumor cells, thus activating adjacent endothelial cells, which proliferate and migrate.34 The most potent proangiogenetic factor among the several is Vascular Endothelial Growth factor-A (VEGF). VEGF causes vasodilatation, increases vascular permeability, induces angiogenesis through endothelial cell proliferation and migration, and thus plays an important role in regulating angiogenesis. It promotes extravasation of plasma proteins from tumour vessels to form a new and provisory extravascular matrix favoring inward migration and the proliferation of endothelial cells.34 1.3.3.3 Clinical manifestations of Vestibular Schwannoma The clinical presentations of a VS is highly variable and includes unilateral high frequency sensoneural hearing loss, tinnitus, disequilibrium, pressure in the ear, otalgia, and occasionally vertigo, which result from pressure exerted by the tumor upon the cochlear and vestibular portions of the eighth cranial nerve. But hearing loss is the most common finding, occurring in more than 95% of patients over the course of this disease.35 While hearing loss is common in a VS there are plenty of other causes of hearing loss. Approximately 10% of cases of unilateral progressive hearing loss are caused by a VS33 and one out of 100 patients with otologic symptoms will actually have a VS.1 Introduction 67 The sudden hearing loss occurs in about 25% of patients with a VS. However, because a VS is a rare condition, sudden hearing loss attributable to an acoustic tumor occurs in only 1-5 percent of patients with sudden hearing loss, as there are many more common causes.38 Even a sudden hearing loss with complete recovery can be caused by a VS.35 The mechanism of hearing loss is related to the direct compression of the cochlear nerve. Hearing loss occurs in VS patients as a symptom may be of several years’duration prior to diagnosis.33, 36, 37 The average time from onset of symptoms to clinical diagnosis has been shown to range from approximately 4 to 7.3 years.33 But in some occasions, this time could last much longer.36 Nevertheless, as many as 5 to 12 percent of patients with a newly diagnosed VS have normal hearing, in part as a result of the detection of smaller tumors by means of an MRI. In most cases, the onset of hearing loss is gradual, but in 15 percent of cases, it may be sudden if compression of the internal auditory artery occurs.33 The subjective tinnitus is another very common consequence of vestibular schwannoma or cochlear nerve dysfunction, it usually presents with concomitant hearing loss which is unilateral and confined to the affected ear. Tinnitus may even be the first symptom of a VS, without the person experiencing hearing loss. Like hearing loss, tinnitus is also present mostly in the high-frequency range. Most of those affected with tinnitus are usually severely impacted. According to Kim et al.,48 tinnitus is associated with 71% of a VS at presentation. Unlike hearing loss, tinnitus has a low impact on patient functioning; therefore, it rarely serves as the impetus to seek medical attention.48 Nonetheless, unilateral tinnitus without obvious cause warrants investigation of the auditory brainstem response (ABR) or MR imaging. Tinnitus in the absence of hearing loss is extremely rare.10 The pathophysiology of tinnitus associated with a VS is thought to be similar to that of hearing loss, that is, neural or vascular compression. Unlike the asymmetric hearing loss, the tinnitus has low specificity in the diagnosis of a VS. Approximately 50 percent of all patients with a VS have vestibular symptoms like vertigo and disequilibrium.49 Introduction 68 Frequency of Symptoms at Presentation of VS. Symptoms Percent Sensorineural hearing loss 96 Unsteadiness 77 Tinnitus 71 Headache 29 Mastoid pain/otalgia 28 Facial numbness 7 Diplopia 7 Table 1. An analysis of 100 translabyrinthine operations. Source: Kim Louis, Klopfenstein Jeffrey, Porter Randall, Syms Mark. Acoustic neuroma: Symptoms and diagnosis. Barrow quarterly. Vol 20 No.4.2004. 7-13. Although, the usual origin of a VS is the inferior vestibular nerve50 vertigo prior to surgery is not common, occurring in only about 20 percent of persons with a VS.42 Vertigo may be related to the available compensation of vestibular functions or nerve resistance to the compression. However, it occurs in later stages of the diseases. According to Timothy et al, the hyperventilation induced nystagmus (HVIN) may be far more specific for a VS.42,43,50 Evaluation of HVIN requires more sophisticated equipment than is available in most offices. It also requires the examiner to be familiar with this condition, and it is somewhat obscure.50 Furthermore, the above mentioned signs, in a VS course, may present any symptoms related to any intracranial mass such as sensory changes on the face or tongue, decreased corneal reflex, direction-changing nystagmus, ipsilateral numbness of the face, facial nerve motor dysfunction, a slurring of speech, ataxia, gait disturbance, an incoordination of one or both upper extremities, numbness or tingling of the malar eminence, and occasionally long tract signs.48 Dysfunction of a facial nerve also can be counted as a symptom presenting in later stages of a VS and/or large VS. For example the facial nerve numbness occurs in 50 percent of cases with the tumor size > 2 cm.42 Facial twitching, also known as facial synkinesis or hemifacial spasm, occurs in about 10 percent of the patients with a VS.50 Decreased or absent corneal reflex is a consequence of trigeminal nerve dysfunction, although this deficit is rarely noticed by patients.33 Trigeminal nerve dysfunction is, however, responsible for the more common complaint of numbness or tingling of the malar eminence. Brainstem compressive symptoms include Introduction 69 ipsilateral upper or lower extremity dysfunction,and cerebellar symptoms include ataxia and gait disturbance.33 Usually these symptoms occur in late stages of a VS course and are observed in large-sized tumors. Symptoms from hydrocephalus related to tumor obstruction of the fourth ventricle include headache, nausea, vomiting, diplopia, papilledema, and changes in mental status. The incidence of hydrocephalus in VS patients is low, occurring in 4% of cases according to a University of California-San Francisco series. Significant tumor growth is usually required to produce obstructive hydrocephalus.49 Symptoms, like raised intracranial pressure, headaches, nausea, vomiting, and dullness of mental faculties are gradual and persistent symptoms. The symptoms are also characteristic of the later stage of the disease. These symptoms appear gradually and are persistent. An onset of headaches as a symptom of a VS is typically a sequela of hydrocephalus. It occurs prior to surgery in roughly 40 percent of those with large tumors.39 Therefore, the symptoms of a VS are highly dependent upon the size of the tumor. Patients with small tumors present with unilateral hearing loss and symptoms of vestibular nerve compression.39 Patients with larger tumors present with symptoms of trigeminal nerve dysfunction, facial nerve dysfunction, and increased intracranial pressure. Finally, continued growth of the tumor are evident in symptoms related to brainstem and cerebellar compression.33 Introduction 70 Explorations of hearing impairments in Vestibular Schwannoma1.3.4 1.3.4.1 Conventional Audiometry The hearing loss is a most frequent initial sign and most common symptom of VS. Over the years the Audiometry became a time-tested useful tool in diagnosis vestibular schwannoma as 95% of all VS patients at early or late stages of the disease would have a hearing loss. 48 It usually develops over month to year and it associated with impairment of speech disproportionate to the pure tome. In 10% of cases, sudden hearing loss occurs and it attributable to the vascular interruption of the internal auditory artery. 49,50 A complete audiologic test includes pure-tone audiometry,acoustic reflex testing with a measurement of reflex decay and speech reception audiometry. Figure 16. Figure 16. Audiometry room and audiometry equippment “Audiotest 340”(Our photo) Introduction 71 The most frequent hearing impairment in patients with VS has been found to be asymmetrical high-frequency sensorineural hearing loss (SNHL). Although, it should be taken into account that no more than 1 out of 20 patients with large tumours have symmetry within 15 dB at 4000 hz, but only about 1 in 1000 patients with hearing asymmetry have VS.42 (Figure 17.). In general, it has been estimated that 5 percent of persons with sensorineural hearing loss have a VS.48 But in reality, perhaps this number is much higher with a prevalence of VS than is commonly accepted. Usually, the speech reception (SRT) is normal in many patients with small tumors. According to some trials, there are many cases of a VS being registered with symmetrical hearing but with a large VS on one side. Approximately 50% of all VS patients with small tumors normally have excellent speech discrimination, and one third of patients with large tumors still have near-normal (> 80%) speech discrimination.42 Although a small percentage of patients with asymmetric hearing impairment end up having a VS, a missed early diagnosis of VS may jeopardize hearing and may have legal implications.51,52 Figure 17. A simple audiogram and tympanogram of a patient with a left-sided vestibular schwannoma (Our photo) Introduction 78 The ABR sensitivity in the diagnosis of CN VIII tumours by size according to several studies is as follows: In a 1994 study by Dornhoffer, Helms, and Hoehmann, the sensitivity was 93% for tumours smaller than 1 cm. 100 In 1997, Zappia, O'Connor, Wiet, and Dinces reported a sensitivity of 89% for small tumours smaller than 1 cm, 98% for medium tumours 1.1-2 cm, and 100% for tumours larger than 2 cm. The overall sensitivity was 95%.102 In a 1995 study, Chandrasekhar, Brackmann, and Devgan reported a sensitivity of 83.1% for tumours smaller than 1 cm and a sensitivity of 100% for tumours larger than 3 cm. Overall sensitivity was 92%.103 In 1995, Gordon and Cohen reported the following sensitivities: 69% for tumours smaller than 9 mm, 89% for tumours 1-1.5 cm, 86% for tumours 1.6-2 cm, and 100% for tumours larger than 2 cm.103, 104 In a 2001 report by Schmidt, Sataloff, Newman, Spiegel, and Myers, the sensitivity was 58% for tumours smaller than 1 cm, 94% for tumours 1.1-1.5 cm, and 100% for tumours larger than 1.5 cm. The overall sensitivity was 90%.105, 106 In a large prospective study that compared ABR with contrast-enhanced MRI (the criterion standard) in 312 patients with asymmetric sensorineural hearing loss, Cueva found that ABR yielded a sensitivity and specificity of 71% and 74%, respectively, in revealing the cause of lesions for asymmetric sense and oral hearing loss (including, but not limited to, vestibular schwannoma). The ABR-positive predictive value was only 23%, whereas its negative predictive value was 96%. Seven of 31 positive cases had other lesions that ABR could not identify as a cause of the hearing loss. 106 Although traditional ABR measures decrease in sensitivity as a factor of tumour size, recent studies have shown that by using a new stacked derived-band ABR that measures amplitude, very small tumours may be detected more accurately. 100, 108 This new technique, combined with traditional ABR audiometry, may soon make possible the detection of very small tumours with accuracy approaching 100% using ABR audiometry. Other applications of ABR continue to evolve as some reviewed literatures suggests that although the overall ABR wave latencies are within normal limits in patients with tinnitus, Introduction 79 those patients have longer latencies than control patients without tinnitus.107 It almost means that ABR may be useful in monitoring and understanding tinnitus. They are variety of scientific viewpoints and opinions regarding diagnostic value of ABR. The results of individual trials are also controversial. Several investigators have reported the sensitivity of ABRs testing as 93% or greater. 119, 120, 121 However some other authors stated that in their trial 85% of VS patients had abnormal ABRs. 122 Of course the tumour size and nerve of origin is important factors affecting the ABR sensitivity. Wilson DF at all, states that in their group of patients one of 25 patients with extracanalicular tumours had normal ABRs for a false-negative rate of 4%; however, 5 of 15 patients with intracanalicular tumours had normal ABRs for a false-negative rate of 33%. 118 Figure 22. Figure 22. Sensitivity of ABR testing by tumour size Source: Wilson DF. Talbot JM, Mills L. The sensitivity of auditory brainstem response testing in small VSs. Laryngoscope. 1992 Sep; 102(9):961-964 The ABR was less sensitive in detecting intracanalicular VS than in detecting extracanalicular VS. 118 Introduction 80 1.3.4.4 Otoacoustic emissions (OAE) testing An otoacoustic emission is a low-level sound emitted by the cochlea either spontaneously or evoked by an auditory stimulus. Specifically, OAEs provide information related to the function of the outer hair cells. 62, 66 Over the past 20 years, their use in routine audiological assessments has increased significantly. Today, OAEs are used commonly in the audiological assessment of difficult to test patients, such as persons who cannot or will not volunteer reliable behavioral responses. Otoacoustic emissions were first reported by Kemp in 1978. The primary purpose of OAE tests is to determine cochlear status, specifically hair cell function. 57, 58 Present OAEs in an ear indicate many things about the auditory system. First, a present OAE tells us that the conductive mechanism of the ear is functioning properly. This includes proper forward and reverse transmission, no blockage of the external auditory canal, normal tympanic membrane movement, and a functioning impedance matching system. Present OAEs also indicate that outer hair cells (OHC) function is normal, which, in most cases, correlates with normal hearing sensitivity. OAE testing does have some limitations. OAE testing does not evaluate the inner hair cells, CN VIII, ascending central auditory pathway, or auditory processing function. 67,80 Understanding the cochlear anatomy and physiology must exist to understand OAEs. Generally speaking, OAEs are waves generated by movement of the basilar membrane and are measured in the external auditory canal.80 However, with an in-depth understanding of cochlear anatomy and physiology, OAEs can be directly related to OHC function. There are many events leading up to this. First, there is a stimulus delivered to the ear. This stimulus invokes movement of the basilar membrane, which in turn causes the OHCs to move, or be deflected. 80, 83 When the OHCs move, their stereocilia bend in one direction or the other. Ions rush in and rush out, changing the membrane potential within the hair cell. The changes in voltage across the plasma membrane lead to OHC length changes, which are called electromotility. The electromotility of the OHCs has a feedback effect on the basilar membrane, causing it Introduction 81 to vibrate. Therefore, the electromotility of the OHCs is thought to be the mechanism which underlies OAEs. Furthermore, research studies over the past 25 years have demonstrated that when the OHC electromotility is blocked, OAEs are absent, which solidifies the relationship between OHC motility and OAEs. 80, 83 This information can be used to screen hearing, partially estimate hearing sensitivity within a limited range, differentiate between the sensory and neural components of sensorineural hearing loss, and test for functional hearing loss. 62,63 The information can be obtained from patients who are sleeping or even comatose because no behavioral response is required. 61-63 The normal cochlea does not just receive sound and produces low-intensity OAEs. These emissions are produced most probably, by the cochlear outer hair cells as they expand and contract. 61 The presence of cochlear an emission was hypothesized in the 1940s on the basis of mathematical models of cochlear nonlinearity. 63 However, OAEs could not be measured until the late 1970s, when technology created the extremely sensitive low-noise microphones needed to record these responses (e.g. see figure 23). Figure 23. TEOAE software “ILO 292”; Contents: Ear probe, Small speaker, Microphon and Response Analyzer connected to computer (Our photo) Introduction 82 The 4 types of otoacoustic emissions are as follows: - Spontaneous otoacoustic emissions (SOAEs) - Sounds emitted without an acoustic stimulus (ie, spontaneously) - Transient otoacoustic emissions (TOAEs) or transient evoked otoacoustic emissions (TEOAEs) - Sounds emitted in response to an acoustic stimuli of very short duration; usually clicks but can be tone-bursts - Distortion product otoacoustic emissions (DPOAEs) - Sounds emitted in response to 2 simultaneous tones of different frequencies - Sustained-frequency otoacoustic emissions (SFOAEs) - Sounds emitted in response to a continuous tone. 62, 67 The PTA measures throughout the outer ear, middle ear, cochlea, cranial nerve (CN) VIII, and central auditory system. However, OAEs measure only the peripheral auditory system, which includes the outer ear, middle ear, and cochlea. The response only emanates from the cochlea, but the outer and middle ear must be able to transmit the emitted sound back to the recording microphone. 66, 68 OAE testing often is used as a screening tool to determine the presence or absence of cochlear function, although analysis can be performed for individual cochlear frequency regions. 61 OAEs cannot be used to fully describe an individual's auditory thresholds, but they can help question or validate other threshold measures or they can provide information about the site of the lesion. 65,66 Using current technology, most researchers and clinicians find a correlation between frequency-specific analysis of TOAEs/DPOAEs and cochlear hearing loss. However, at this juncture, the correlation cannot fully describe auditory threshold. Naturally, a correlation would not be expected for noncochlear hearing loss. 65, 67, 68 Multiple responses are averaged. All OAEs are analyzed relative to the noise floor; therefore, reduction of physiologic and acoustic ambient noise is critical for good recordings. Because no behavioral response is required, OAEs can be obtained even from patients who are comatose. For a quiet and cooperative patient, recordings usually require less a few minutes per ear. 78, 80 For uncooperative or noisy patient, recordings may take significantly longer or may be impossible to obtain on a given visit. Introduction 83 In spontaneous otoacoustic emissions (SOAE) This nonevoked response is usually measured in narrow bands (< 30 Hz bandwidth) of frequencies recorded in the external ear canal. No stimulus is required. Obtain multiple recordings to ensure replicability and to distinguish the response from the noise floor. SOAE recordings usually span the 500-Hz to 7000-Hz frequency range. 82,84 In transient otoacoustic emissions cicks are the most commonly used stimuli, although tone-burst stimuli may be used. Most commonly, 80to 85-dB sound pressure level (SPL) stimuli are used clinically. The stimulation rate is less than 60 stimuli per second. TOAEs are generally recorded in the time domain over approximately 20 milliseconds. Alternating responses are stored in alternating computer memory banks, A and B. Data that correlate between the 2 memory banks are considered a response. 80 Data that do not correlate are considered noise. When present, TOAEs generally occur at frequencies of 500-4000 Hz. Data in the time domain then are converted to the frequency domain, usually in octave band analysis.82 In Distortion product otoacoustic emissions the stimuli consist of 2 pure tones at 2 frequencies (ie, f1, f2 [f2>f1]) and 2 intensity levels (ie, L1, L2). The relationship between L1-L2 and f1-f2 dictates the frequency response. An f1/f2 ratio yields the greatest DPOAEs at 1.2 for low and high frequencies and at 1.3 for medium frequencies. To yield an optimal response, set intensities so that L1 equals or exceeds L2. Lowering the absolute intensity of the stimulus renders the DPOAEs more sensitive to abnormality. A setting of 65/55 dB SPL L1/L2 is frequently used 88, 89 (e.g. figure 24). Figure 24. An example of DPOAEs recorded from 80 year old female patient with left sided VS (Our photo) Introduction 84 Responses are usually most robust and recorded at the emitted frequency of 2 f1–f2; however, they generally are charted according to f2 because that region approximates the cochlear frequency region generating the response. 80, 90 But anyway, most investigators believe that otoacoustic emissions whether they be spontaneous, product distortion, or evoked are present in healthy cochleae. 96, 97 Studies have shown that TEOAEs are lost on the lesioned side in a variable number of patients with VS, probably because of cochlear vascular damage 90, 95 According to Singh et al 94 the presence of TEOAEs on the lesioned side in 63 patients with VS who were surgically treated with the aim of saving hearing function was a favorable prognostic factor for hearing preservation, probably as a result of better cochlear vascularization. An Otoacoustic emission testing is regarded as the only test capable of demonstrating the function of the organ of Corti, especially in the outer hair cells, in an objective, noninvasive, and reproducible way. There is also a consensus that different noxious factors that can affect the cochlea such as ototoxics and acoustic disorders diminish or eliminate otoacoustic emissions. 94, 96 It is accepted that otoacoustic emissions are modified by stimulation of the efferent auditory system, as contralateral acoustic stimuli reduce distortion product and evoked emissions.98 For these reasons, the use of otoacoustic emissions testing is widely acknowledged as useful for making auditory assessments of newborns and patients who have been exposed to ototoxics or environmental noise, and for controlling cortipathy that is, damage to or a lesion in the organ of Corti.98 In cases of a VS and other central auditory system disorders, the OAEs presents but ABR altered. Interestingly, a number of reviewed literatures have indicated that OAEs (TEOAES or DPOAEs)can be both affected and unaffected by the presence of a VS.54,57 An explanation for such data can be derived from information of how the growth of the tumor affects the vascular supply of the cochlea or how the growth of the tumors induces mechanical pressure alterations on the vascular supply and the cochlea itself. The OAEbased measures can provide information on the sensory component of any hearing disorder; thus, they can provide precise indexes of evaluating sensorineural hearing impairment cases which can play an important role in the detection of a VS.57 Introduction 85 Explorations of balance dysfunctions in Vestibular Schwannoma1.4 Posturography.1.4.1 Posturography is a general term that covers all the techniques used to quantify postural control in an upright stance, in either static or dynamic conditions. Among those techniques is computerized dynamic posturography (CDP), also called test of balance (TOB). 200-201 CDP is a non-invasive specialized clinical assessment technique used to quantify the central nervous system adaptive mechanisms involved in the control of posture and balance, both in normal and abnormal conditions (e.g. see fig. 25) Figure 25. Assessment of VS patient with Computerized Dynamic Posturography equipment from “Smart Balance Master Neurocom®”(Our photo) Due to the complex interactions among the sensory, motor, and central processes involved in posture and balance, CDP requires different protocols to differentiate among the many defects and impairments, which may affect a subject's postural control system. CDP challenges that system by using several different combinations of visual and support Introduction 86 surface stimuli and parameters. It has been proven effective in assessing vestibular as well as some neuromuscular disorders affecting balance. 202 Computerized Dynamic Posturography is an integral component in the diagnostic workup of imbalance or dizziness when used to identify the underlying sensory (vestibular, visual, somatosensory) and motor control impairments. CDP is not considered to be a site-oflesion test nor is it pathonomonic for vestibular disease.24 Balance and dizziness disorders often have multiple causes that cannot be isolated to a single localized pathology. Clinical evidence indicates that an impairment reduction strategy is the most effective way to reduce the symptoms associated with imbalance and dizziness with multiple causes.23. 27 Whereas traditional site-of-lesion tests are designed to confirm the presence and anatomical location of pathology, CDP, in contrast, documents the physiological impairments that are the functional manifestations of pathology. Because the balance system is highly adaptive, patients with similar pathology can present with different impairments, depending on the stage (progression) of the disease or disorder. 123 In many patients with chronic balance disorders, no anatomical pathology can be identified that accounts for the patient's symptoms and impairments. Because of the "disconnect" between pathology and impairments, CDP and traditional site-of-lesion tests provide complementary rather than redundant information in the diagnostic workup of the dizzy and/or unsteady patient.128 The Sensory Organization Test (SOT) objectively identifies problems with postural control by assessing the patient's ability to make effective use of (or suppress inappropriate) visual, vestibular, and proprioceptive information. 200 During the SOT, useful information delivered to the patient's eyes, feet and joints is effectively eliminated through calibrated "sway referencing" of the support surface and/or visual surround. The support surface and/or visual surround tilt to directly follow the patient's anteroposterior body sway, eliminating orientation information. By controlling the usefulness of the sensory (visual and proprioceptive) information through sway referencing and/or eyes open/closed conditions, the SOT protocol systematically eliminates useful visual and/or support surface information and creates sensory conflict situations. These conditions isolate vestibular balance control, as well as stress the adaptive responses of the central nervous system. In Introduction 87 short, patients may display either an inability to make effective use of individual sensory systems, or inappropriate adaptive responses, resulting in the use of inaccurate sense. 202 The CDP has become an increasingly popular modality for evaluating balance function. Most clinicians and researchers use the equipment, protocol, and normative values developed by NeuroCom International of Clackamas, Ore., as the standard for testing and comparison. 200 A central aspect of the CDP protocol is SOT and it helps the physician evaluate how visual, somatosensory, and vestibular inputs affect a patient's ability to maintain functional balance. This objective test measures the extent of a patient's sway while standing on a force platform during six conditions (e.g. see fig. 26-27). Figure 26. Test conditions SOT 1 to 6 (Our photo) Condition 1 is a simulation of a common, normal state. With eyes open, and the platform and visualsurround are stable; In condition 2, the platform and visual surround are both still fixed, but the patient's eyes are shut; In condition 3, the eyes are open and the platform is fixed, but the visual surround tilts in the direction of the patient's sway, thereby delivering inaccurate visual information about orientation in space; Conditions 4, 5, and 6 are the same as conditions 1, 2, and 3, respectively, except that the platform moves. The sway-referenced platform tilts with the patient's sway, thereby altering somatosensory Introduction 94 Directional preponderance (right beating - left-beating/total) should be 35% or less. There is little if any clinical value in DP. Unilateral paresis or RVR, RVR = (RC+RW-LC+LW)/TR. This is called "Jongkee's formula". It should be 25% or less. If all responses are appropriately directed (see commentary on TR above), one can simply take the sum of the absolute values of responses due to the right ear, subtract the sum of the absolute responses due to the left, and normalize to the sum of the absolute values of all responses. An upward change in the middle ear temperature above the body temperature causes the endolymph to move upwards, generating an endolymphatic current within the canal towards the ampulla. If the stimulus temperature is lower than the bodily temperature, there is the opposite movement, which generates an ampullary current towards the canal, away from the ampulla. The action of these convection currents on the ampullary crest alters the action potential of this sensory receptor, stimulating or inhibiting these currents. Stimulation initiates the VOR, a simple reflex arc from the vestibular nucleus to the oculomotor nuclei, which generates the vestibular nystagmus. The nystagmographic response is evaluated and compared with a normal standard. Caloric testing does not assess the function of the sacculus or the utricle of the vertical canals. 203-204 In the literature there are almost no work has been done regarding the results of VNG in a group of patients with VS, except ENG. Kirtane et al 207, studied 30 cases, 16 were found to have large schwannomas compressing the cerebellum or brainstem as proved on surgical exploration or at autopsy. The ENG showed evidence of a central lesion in these patients in the form of an abnormal pendular eye tracking test, an abnormal gaze test, failure of visual fixation suppression or hyperactive contralateral caloric response. 206 The pendular eye tracking test, if abnormal, indicates a central lesion. They observed to occur in 10 patients, each of whom had large VS compressing the cerebellum and/or the brain stem. Significant spontaneous nystagmus was recorded in only 12 patients (40%). Linthicum et al 209, reported recordable SN in only 10% of their cases. However in series Introduction 95 of patients studied by Kirtane et al 207, the direction of the spontaneous nystagmus beat was nonlocalising, beating towards the side of the tumour in 5 cases and away from the tumour in 6 cases. The results of bithermal caloric test seem to be most important and valuable test of the entire ENG test battery. 207 Kirtane and his colleagues twenty seven patients (90%) had the anticipated ipsilateral, hypoactive, warm and cold, caloric responses. Attention, however, must be paid to the caloric responses elicited from the normal ear. Normal contralateral caloric responses are to be expected. They were seen in 11 cases (36.7%), all of whom had small or moderate-sized schwannomas. 207,208 Interestingly, in their group of patients, 10 cases (33.3%) demonstrated hyperactivity of both warm and cold caloric responses on the contralateral side. These patients were found to have fairly large neuromas compressing the brain stem which probably caused compression of the cerebello-vestibular fibers to the contralateral vestibular nuclei. These cerebello-vestibular fibers passing through the inferior cerebellar peduncle cross in the midline close to the restiform body and are mainly inhibitory. A lesion in these fibers as is caused by a large VS leads to a release of the contralateral vestibular nuclei from the inhibitory influences of the cerebellum, thus explaining the noninhibition of the contralateral caloric responses. 207,209 Nowadays the VNG testing is considered the new standard for testing inner ear functions over ENG, because VNG measures the movements of the eyes directly through infrared cameras, instead of measuring the mastoid muscles around the eyes with electrodes like the previous ENG version. VNG testing is more accurate, more consistent, and more comfortable for the patient. Bilateral hypoactivity in their series was found in 9 patients (30%). Of these, only 2 patients had bilateral VSs. A schwannoma situated medial to the porus acousticus and arising from the inferior vestibular or cochlear nerve may give a normal caloric response since the impulses resulting from lateral semicircular canal stimulation pass in the superior vestibular nerve which may yet be free from compression. This occurred in 3 of their patients (10%).209 Thus, in conjunction with audiological and radiological findings, ENG is a valuable aid in establishing a definitive diagnosis of a VS and in evaluating its probable size and extent. Introduction 96 Hence the complete ENG test battery should be performed in every case suspected to have VS. 207, 210 Vestibular Evoked Myogenic Potentials1.4.4 The Vestibular Evoked Myogenic Potentials (VEMPs) is a diagnostic tool in the process of which investigated patients with specific vestibular disorders. Basically, the VEMP is a biphasic response elicited by loud clicks or tone bursts recorded from the tonically contracted sternocleidomastoid muscle, being the only resource available to assess the function of the saccule and the lower portion of the vestibular nerve. It is known to be inhibitory electrical potentials generated after a sound stimulus (clicks or pure tones), originated in the saccule and conducted by the lower portion of the vestibular nerve all the way to the CNS, generating inhibitory electrical responses picked up by electrodes placed on the sternocleidomastoid muscle (SCM).211 The patients are put in a chair, seated and instructed to turn their heads to the opposite side of the sound stimulus, in order to contract the contralateral SCM muscle. VEMPs are read by electrodes placed on the patient’s SCM (ipsilateral to the sound stimulus), the positive electrode is placed on the upper third of the muscle, while the negative electrode is placed on the muscle tendon, just above the clavicle. 212 (e.g. see fig. 32). Figure 32. VEMPS software and electrode placement (Our photo) Introduction 97 The electrical responses from these potentials are made up of two biphasic waves, the first is positive, with a latency around 13ms, known as p13; followed by another wave, this time negative, with a latency around 23ms, known as n23 (e.g. see fig. 33-34). Figure 33. Parameters of Evaluation of VEMPs (Our photo) Figure 34. VEMPs showing 87% asymmetry rate in patient with right sided VS (Our photo) These responses are present in most of the normal individuals studied, differently from a second biphasic complex known as n34-p44, which according to Colebatch would be absent in 40% of the normal individuals studied, while Robertson described that this second complex would be present in 68% of normal individuals. 211,212 Introduction 98 In spite of several conducted studies there are still exist some controversial points regarding the VEMPs. One of those controversies is the relationship observed between the electrical response amplitudes and the level of contraction of the muscles tested (usually the SCM). Because it becomes very hard to be able to compare the test of an elderly patient with that from a young athlete, who very likely has a much higher level of muscle contraction. Following important controversy regarding VEMPs could be the index of sound stimulus generated through clicks or tone bursts.212 As we know that VEMPs neural pathways involve lower portion of the vestibular nerve, so it can be used in diagnosis of vestibular schwannomas. Some studies in the literature already show this important contribution of VEMPs, such as the one developed by Murofushi et al. in 1998, who observed 80% of altered VEMPs in 17 patients with established diagnosis of vestibular schwannoma. In 2001, Takeichi et al. performed a similar study in which he observed altered VEMPs in 13 of 18 patients diagnosed with vestibular schwannoma confirmed by MRI. In a general way, VEMPs can contribute to the diagnosis of vestibular tumors, but must not be used as the sole diagnostic method, because it only assesses the function of the inferior vestibular nerve. Nonetheless, when performed together with MRI, the ABR, audiometry and caloric test, they may help in the exact location of the tumor in the vestibular pathways.212 Neurologic examinations in Vestibular Schwannoma1.5 Neurological examination plays an important role in diagnosing acoustic tumours. Because it assesses motor and sensory skills, the functioning of one or more cranial nerves, hearing and speech, vision, coordination and balance, mental status, and changes in mood or behavior, among other abilities. Items including a tuning fork, flashlight, reflex hammer, ophthalmoscope, and needles are used to help diagnose brain tumours.133 Otoneurologic testing includes otoscopy, exploration of muscular strength, sensibility, cranial nerves, cerebellar testing, and exploration of spontaneous or induced nystagmus Introduction 99 with head shaking, absence of saccadic movements by Halmagy testing, Romberg and Unterberger Testing. Usually the VS is a cause of positive otoneurological findings such as pathologic nystagmus, positive pastpointing and postural instability, a conclusion regarding the involvement of the vestibular system can usually be reached on bedside examination. Moreover, the presence or absence of signs of brainstem or cerebellar dysfunction, are sometimes sufficient to determine the nature of the disturbance without any need to conduct laboratory tests.124,138 Examinations of patients in otoneurology room can be performed in following order. First of all the examiner will check the eye movements of patient via asking the patient to keep their head perfectly still directly in front of examiner. The patient will follow the finger of examiner without head movements. It is important to ask patient if the patient experiences any double vision and if so when is it worse. This is to check the oculomotor nerve function.133 Following the trigeminal nerve function can be assisted. It has sory supply to the face and motor supply to the muscles of mastication. Initially test the sensory branches by lightly touching the face with a piece of cotton wool and then with a blunt pin in three places on each side –around the jawline, on the cheek and on the forehead.11 The corneal reflex would also be examined as the sensory supply to the cornea is from this nerve. This is done by lightly touching the cornea with the cotton wool. This should cause the patient to shut their eyelids. So we will ask the patient to look in the other direction, so we will not be testing the blink reflex. Then gently but firmly will touch the cornea at its junction with the sclera. Sensitivity to pain increases medially from this point and decreases laterally. The junction of the cornea and sclera is a good compromise between causing pain to the patient and obtaining the reflex.133 There is a rapid blink of the eye being tested and a consensual blink of the other eye. If there is seventh nerve weakness on the side being tested, then observe the consensual reflex.The patient will close his/her eyes tightly and the examiner will look for Introduction 100 completeness of eye closure. Also the nasolabial folds and mouth will be observed while the patient is concentrating on the eyes.134 As the orbicularis oculi contract tightly, there are milder associated contractions of muscles about the mouth and nose; these milder contractions are better suited to displaying slight weakness than when these muscles are tested directly.124 Additionally it can be asked a patient to smile, show you teeth, or pull back the corners of the mouth. Look for asymmetry about the mouth. The most subtle signs of mild facial weakness are the blink reflex and incomplete lid closure. More often we in otoneurology practice will ask to patient to get out the tongue and move to right and left side. To test the sensory fibers of the facial nerve, we can apply sugar, salt, or lemon juice on a cotton swab to the lateral aspect of each side of the tongue and have the patient identify the taste. Taste is often tested only when specific pathology of the facial nerve is suspected.4 The eighth cranial nerve carries two special sensory afferent fibers, one for audition and one for vestibular function. The cochlear division of CN 8 is tested by screening for auditory acuity. This can be done by the examiner lightly rubbing his fingers together next to each of the patient's ears and comparing the left and right side responses. 124 In addition, the Rinne and Weber tests are easy to perform and can help differentiate conductive deficits from neurosensory lesions. The Weber test consists of placing a vibrating tuning fork on the middle of the forehead and asking if the patient feels or hears it best on one side or the other. The normal patient will say that it is the same on both sides. The Rinne test consists of comparing bone conduction, assessed by placing the tuning fork on the mastoid process behind the ear, versus air conduction, assessed by holding the tuning fork in air near the front of the ear. Normally, air conduction volume is greater than bone conduction sound volume. For neurosensory hearing loss, air conduction volume is still greater than bone conduction, but for conduction hearing loss, bone conduction sound volume will be greater than air conduction volume.133 Introduction 101 Diagnostic Imaging in Vestibular Schwannoma1.6 Imaging has become a sensitive method of evaluating patients with possible VS.130 MRI continues to evolve but is already considered the preferred imaging study for the evaluation of a patient with suspected VS. Other imaging techniques remain as useful tools in certain clinical settings, but many techniques, considered state of the art less than a decade ago, have faded into almost complete obsolescence. 29. 131 Because of the increasing acceptance of MRI as the imaging procedure of choice, much of discussions deal with MRI. Other modalities, such as CT, are discussed where appropriate. It should be remembered that either gadolinium enhanced MRI or contrast-enhanced CT can demonstrate almost any VS.132 The usual clinical situation, however, is that the clinician is trying to ensure that the patient does not have an VS, and so the most desirable test is the one that is the most sensitive. Magnetic Resonance Imaging (MRI)1.6.1 MRI has largely replaced other radiological and clinical investigations in the screening of patients with audio-vestibular symptoms for the presence of vestibular schwannoma. Smaller tumours can now be detected, leading to earlier surgical intervention with improved rates of hearing preservation. 132 Since the introduction of MR imaging technology, the number of patients with relatively small, incidentally found, asymptomatic VS has increased. A recent study estimates the incidence of VS at 0.2% of all scans done in asymptomatic patients. 137 There has been a significant increase in the incidence of VS over the past 30 years, from 5 tumours per million per year in 1976 to just under 20 per million per year in 2001.52, 53 Much of this increase in incidence is due to the advent of better noninvasive diagnostic techniques, especially MRI. 53 Introduction 102 Noncontrast high-resolution MRI, the recommended method for diagnosis of VS, enables accurate evaluation of the cranial nerves within the cochlea, labyrinth, internal auditory canal, and cerebellopontine angle. Furthermore, the incidence of giant tumours has recently dropped, whereas that of small and medium-sized tumours has increased.52 Thus, in some occasions the CT may not visualize the intracanalicular region well, and it is here that MRI establishes its advantage 130 (e.g. see fig 35). Figure 35. MRI scanner MAGNETOM Symphony Maestro Class (CHUS) (Our photo) Thin section fast spin echo T2 weighted sequences are capable of clearly demonstrating the auditory nerves and, on the basis of small studies, this unenhanced MRI sequence has been advocated as a screening technique for detecting vestibular schwannoma 133 (e.g. see fig 36). Introduction 103 Figure 36. Axial fast spin echo T2 weighted (top) and gadolinium enhanced T1weighted (bottom) images from one patient. On the left the fast spin echo images clearly demonstrate a 3 mm intracanalicular intracanalicular VS Source: O'Rourke B, Wallace R. Imaging of VSs. Barrow Quarterly 2004,Vol 20, (4) However, the presence of audiovestibular symptoms and studies with large numbers of patients are required for the proper assessment of alternatives to gadolinium enhanced imaging for VS screening. The vestibular schwannoma is a soft tissue tumour. Although the lesion can certainly come into contact with the brain, the role of imaging is usually to try to contrast the lesion against the CSF. It may be difficult to appreciate VS on CT done without contrast administration because the density differences are insufficient for consistent visualization of a tumour. 22 MRI, on the other hand, gives excellent soft tissue visualization but does not show the bony detail nearly as well as CT. Cortical bone gives a lack of signal or signal void on MRI. Air also is seen as a lack of signal on the MRI scan. In a normal situation, therefore, the observer is not able to differentiate the otic capsule from the air filled middle ear. Both appear black. The petrous apex often contains fat, which is seen as bright signal on the T1weighted (short TR/TE) image. 130 Introduction 110 Figure 42. The Air cisternogram shows the infilling of the internal auditory canal (IAC), with air outlining the nerves. Note that the air passes all the way to the extreme lateral portion of the IAC Source: Curtin HD, Hirsch WL Jr. Imaging of acoustic neuromas. 1992. Neurosurg Clin N Am. 2008 Apr;19(2):p202 Almost all VSs will be found by high quality modern CT scanning. Some clinicians prefer CT scanning, especially when the clinical picture is not as clear cut and high quality images of the otic labyrinth are desirable at the same time that the IAC is evaluated. 132, 133 Also CT remains more available in some locations and so becomes the initial study, with MRI reserved for the few cases in which the CT scan is considered equivocal.123 Introduction 111 The natural Evolution of Vestibular Schwannoma1.7 Follow up management is an important part of any pretreatment discussion with patients who have VS, because excision or radiosurgical treatment can potentially compromise function.138, 139, 140 Despite the availability of published data highlighting clinical, radiographic, and biological parameters of significance when managing VS conservatively, deciding between early treatment and expectant management remains a significant challenge for practitioners. 138 Observation management with serial MR images has provided useful information about the variability in natural history of untreated VSs. 141 Increasing utilization of MRI has revealed that the growth rate of VS can vary unpredictably from case to case, and observation of early stage patients in whom no increase in volume was detected over the years (or even decades) has permitted surgical treatment to be deferred and in some cases avoided altogether. According to some authors the difference incidence between its postmortem and clinical diagnosis suggests that in a significant number of cases the tumour’s growth rate can be extremely limited, if not absent. 144 However, the practical implications of this finding have been a cause of controversy: although it has facilitated the planning of increasingly conservative surgical treatment, the specific indications for immediate surgery remain a matter of debate. 143 In order to search for a possible predictive factor of growth rate Modugno 155 et al. performed analysis using 6 clinical variables (tumour size, sex, age, initial symptoms, ABR pattern and duration of the symptoms). According to their results in 30/47(63.8%) cases, no growth was detected during the entire period of follow-up, while in the remaining 17/47 (36.2%) patients, a volumetric increase was recorded. Growth was observed within the first year in 10/17 (58.8%) cases, at 2, 3 and 4 years from diagnosis in 1/17 (5.8%), 3/17 Introduction 112 (17.6%) and 1/17 (5.8%) cases respectively, after 6 years in 2/17 (11.7%) cases (e.g. see fig. 43). Figure 43. A chart showing the rate of growth of a VS during the follow-up years Source: Modugno GC et al. Small VSs: Monitoring the Growth Rate by MRI. Acta Neurochir (Vienna) 1999. 14.141: 1063-1067 The growth rate, according to Modugno155 et.al., expressed in absolute millimetric increase of the greatest axis of the neoplasm, ranged from 1 to 12mm/year with a mean value of 4.0mm/year. In 5/17 (29.4%) cases the growth was < 2mm/year; in 10/17 (58.8%) cases it was between 3 and 6mm/year; in the remaining 2/17(11.7%) cases it was > 9mm/year. In this case the relative increase ranged from a minimum of 11.1% to a maximum of 150%, with a mean value of 55.9%. When growth was recorded, the therapeutic choice varied considering different parameters. The results of comparative analysis of literature, between different works are quite interesting (e.g. see table 2). Author Case (n) Age (Years) F.U years RM No Growth (%) Valvassori (144) 35 16-81 1-2 -43 Thomsen (145) 21 37-79 4,2 -85 Ogawa (148) 36 15-73 4,5 -19 Bederson (146) 70 2,2 - + 47 Sterkers (147) 21 49-79 3,5 - + 47 Nedzelski (149) 50 50-83 3,4 - + 52 Woods (151) 27 55-80 2,1 - + 40 Noren (152) 98 16-82 2,5 - + 30 Rosenberg (153) 16 65-86 4,3 -44 Strasnick (154) 50 40-90 2,6 - + + 32 Charabi (150) 97 <81 3,4 - + 26 Table 2. Percentage of cases with a VS growth and a review of literature. Source: Modugno GC et al. Small VSs: Monitoring the Growth Rate by MRI. Acta Neurochir (Vienna) 1999. 14.141: 1063-1067 Introduction 113 By contrast, Thomsen, et.al.,145 reported no growth in as many as 85% of cases submitted in a longitudinal follow-up study for a mean period of observation of 4.2 years. However, it is noteworthy that in a 5-year multicenter study, which included Thomsen's group, a much lower overall percentage (26%) of cases without growth was reported.2 It is possible to conclude from the literature that in about 45% of the patients with a diagnosis of a VS, the MRI did not reveal any growth for an average period of 2±4 years of follow-up. 155 Several investigators have published their institutional results, but to date, there have been few efforts to combine these experiences to achieve the statistical power needed to determine the suitability of follow-up management for these tumors. Sughrue, et.al.,138 performed a comprehensive review of the literature on the hearing preservation and intervention rates, with special emphasis on tumor growth rates, in a large population of patients with a VS who were treated conservatively. Their results suggest that the patients with tumors that grew < 2.5mm/year had better hearing outcomes than patients with tumors that grew > 2.5mm/year. They did not find a similar relationship between initial tumor size and rate of hearing preservation.139 In fact, patients with preserved hearing had statistically larger tumors on average at presentation, but the 2mm difference in average size must be interpreted within the context of limitations associated with imaging resolution and observer reliability. This suggests that for patients with tumors < 2.5 cm, the tumor growth rate is a more important indicator of who is at risk for progressive hearing loss than tumor size at presentation. The mechanism behind this observation is unclear;138 however, it has been hypothesized that faster growing tumors represent a biologically more aggressive subset of lesions, which are more likely to infiltrate and disable the cochlear nerve, regardless of the initial size of the tumor. Facial nerve outcomes in patients with a VS in whom the disease is managed conservatively, have consistently excellent outcomes throughout the series reports. The patients with faster growing tumors had a nearly identical reported rate of subsequent intervention to that of patients with slow growing tumors, despite poorer hearing Introduction 114 outcomes.138 In literature, some authors performed studies analyzing predictor factors where the mean age of the patients in whom growth was recorded was slightly higher, but the difference did not appear significant. As for the initial symptoms, tinnitus was more frequent in cases with growth, but even this difference was not significant.140 ABR also showed a greater frequency of electrophysiological patterns correlated with a block of the central pathways in the cases with growth, although this difference was not significant. As regards the relation between tumor growth and duration of the symptoms, variance analysis showed only a tendency towards an inverse correlation: the average duration of the symptoms was shorter in patients who presented with tumor growth.150 Regarding growth patterns, in a recent multicenter study, Charabi, et.al.,23,150 recognized the following five different types of behavior: 1) continuous growth (40%), 2) non-visible growth (18%), 3) continuous growth after a variable period of quiescence (18%), 4) a regressive tendency (8%), and 5) irregular growth (16%). The fact that the third subgroup had the longest mean period of observation led Charabi, et.al.,23,150 to argue that, in a percentage of cases with apparently no growth, a volumetric increase could be revealed at a later date (a finding which could be in keeping with the observations of Thomsen, et.al..145 However, the fact that the mean age of the patients with no growth was significantly higher than that of the patients with linear growth, after a period of quiescence, could also suggest the following opposite hypothesis: that patients who do not present any growth could belong to a separate, independent population. A larger series of experiments with longer follow-up periods must therefore be accomplished before any clear conclusions can be drawn. Tumour size, age and sex have been particularly considered in the literature. However, no significant correlation has been found between any of these parameters and tumour growth. Ogawa et al.148 maintain that older age, female sex and bigger tumour size are likely to predict a volumetric increases of the neoplasm, but their data do not reach statistical significance. A different predictive factor was proposed by Charabi et al.23, 150, who found a significant inverse correlation between tumour growth and the reported duration of symptoms before diagnosis. Introduction 115 Treatment modalities of Vestibular Schwannoma1.8 Present day there are 3 treatment modalities or options exists for patients with VS. Watch and Wait; Conventional neurosurgery; Radiosurgery with Gamma Knife. Follow up or observation with serial MRI1.8.1 In recent years, the wide diffusion of the Internet has meant that many patients come to consultation with prior knowledge about the various treatment options, which far from making matters clearer, often mislead patients due to incomplete and biased information. It is very important for all patients to be informed of the 3 treatment modalities. 156 In majority of cases above listed treatment options would be informed or presented to patient to choose the treatment option.145 With the exception of some situations where the choice of treatment is clear, for example observation for a 90-yearold patient with a 3 mm tumour or surgery for a 30-yearold patient with a 5 cm tumour, the decision on the best therapeutic option for patients with VS is very difficult to take. In this case otoneurologist would recommend the best option and the patient would accept ether will look for the second opinion. The ideal situation for such patients could be to consult the ideal situation is for a patient to consult a multidisciplinary team in a center with experience. It is important to take into account that the majority of patients with VS present only hearing loss and/or tinnitus at the time of diagnosis, and disabling symptoms are rare. 23, 150, 156 Thus, the vast majority of preoperative patients have very good quality of life despite having a tumour. 156 After the chosen treatment regardless the type of it, even if there are no serious or unforeseen complications, this quality of life worsens.153 Obviously, this situation is exacerbated if severe complications or sequelae appear.143 That is why it is very important that the patient understands - the goal of VS treatment is to avoid problems derived from the growth of the tumour, which by its nature and location can lead to intracranial hypertension and death. 23, 155, 150, 156 But these problems can appear after many years, so the treatment involves, at the present time, a reduction in the quality Introduction 116 of life to avoid serious complications in an uncertain future.156 Exceptions to this rule are patients with large and symptomatic tumours, in which treatment is imperative, and patients with severe vertigo. In these cases, quality of life may improve after treatment. Follow up or observation/ wait-and-scan treatment approach consists in performing serial MRI, the first one generally 6 months after diagnosis and, if there are no significant changes, every year.156, 155, 149 Along with serial MRI, it is important to perform audiometric test in each review. Even some clinical hospital’s ORL dept. includes otoneurology divisions which equipped with other machines and of course they afford to perform some other tests like Craneocorpography, posturography, Videonystagmography/caloric test etc. In older patients with small tumours where the expected growth of the tumour is not lifethreatening in the years they presumably have left to live, this attitude would be the treatment indicated. 156 In these cases, as long as no significant changes are observed in the symptoms, an annual MRI is carried out (e.g. see fig 44). Figure 44. Image shows the growth of a VS after one and a half years of observation Source: Lassaletta L et al. An update on the treatment of vestibular schwannoma. Acta Otorrinolaringol Esp. 2009;60(2): pp131-140 Advanced age, deterioration of general condition, absence of relevant symptoms, longstanding clinical condition indicating slow growth, are all factors in favor of this waitand-scan treatment. Introduction 117 Age factor and the size of the tumour, hearing level could be predict the exact type of the treatment. If the combination of advanced age and small tumour size is hardly questioned as an indicator for observation, there are other situations which may also indicate the same treatment. But the most case could be a case of young patient with a small tumour and good hearing. In this case, all 3 therapeutic options could be considered: microsurgery to resect the tumour and preserve hearing while the tumour is still small; radiosurgery to control the growth of the tumour, thus avoiding the potential morbidity of surgery, relying on preserving hearing; and observation, as the rate of tumour growth is not initially known and the possibility exists that it may not grow or it does so at a normal rate, in which case the injury will not become life-threatening for many years. And lastly, the slow rate of growth of most tumours makes observation a valid option as an initial approach in almost all tumours, except in very large ones which may become life threatening in the short or medium term. 156 The main advantage of observation is that it avoids the complications of surgery or radiation. A theoretical disadvantage of this wait-and-scan approach is the delay in providing definitive treatment if the growth of the tumour is established, although it has not shown that this delay has a negative impact on the quality of life. Other drawbacks are the need for lifelong imaging tests and the psychological factor, due to knowing that there is an untreated intracranial tumour. 156 Along the recommendation or just when the observation is chosen as a therapeutic option, it is important to inform the patient that it is likely that the hearing loss will increase, even if the tumour does not grow.158 According to several authors the decision of conservative management is not straightforward, although some treatment guidelines have been proposed. An algorithm designed by Smouha et al. (2005) recommends observation in elderly patients, with small tumours, and no symptoms other than hearing loss. 196-197 They define elderly patients as over 45 years and small tumours as less than 25 mm in diameter. Upon observing growth beyond 2 mm/year or changes in symptoms, intervention is indicated. Unfortunately there is little correlation between symptoms and tumour size, and patient quality of life may diminish even without growth. 189 Therefore, treatment may also be indicated when symptoms progress but the tumour size remains static. Concerns about patient compliance have also been voiced, and high attrition rates were noticed in some conservative Introduction 118 management studies.197 Nonetheless, observation remains a practical choice for many patients. 196-197 Conventional neurosurgery1.8.2 The introduction of the microscope, microsurgical techniques, monitoring of the facial nerve, the refinement of anesthesia and the experience acquired at some centers have helped to generate new targets in VS surgery. Present day, the goal is not just excision of the tumour with minimal mortality, but also the preservation of facial function and, where possible, hearing. While mortality has fallen to values below 1%-2% at experienced centers, and preservation of facial function is achieved in most cases, the preservation of hearing is achieved in only a select few. As in other areas of otolaryngology falling between different specialities, there is controversy about which specialist should carry out VS surgery. The answer is usually neurosurgeon, but whether the neurosurgeon or not it should be performed by the person with most experience in it.149 In theory, any otoneurology surgeon or neurology surgeon with enough experience can carry out the complete surgery, although it is rare for a neurosurgeon to have experience in the milling of the IAC. In some medical centers that’s why VS surgery performs by the otolaryngologist and some others it performs in cooperation between otolaryngology specialists and neurosurgeons which has been enriching and brought several advantages: each specialist provides their expertise in different fields, allowing for shifts to be set up so that, in patients with large tumours, dissection of the cranial pairs can be performed more restfully, and all approaches can be used, some of which are not accessible to certain specialist. 156 In conventional neurosurgery there are three different surgical approaches could be applied: Retrosigmoid (RS), translabyrinthine (TL) and the middle cranial fossa (MCF). 156 In many occasions the surgical removal is only treatment for large VSs because stereotactic radiosurgery is not applicable. The translabyrinthine,161-162 retrosigmoid suboccipital, 163-164 and middle fossa approaches165 are the three basic approaches for the removal of these tumours. Recent papers recommend the translabyrinthine approach for the removal of large tumours and have reported good results with this technique. 160 Introduction 119 The selection of surgical approach is based on multiple factors, including pure tone thresholds, speech discrimination score, auditory-evoked responses, tumour size, hearing status of both ears, and patient age and preference. Surgery practices vary in degree of experience and preferred techniques.166 Despite these differences, however, imaging directs preoperative management by addressing tumour size, extent of IAC penetration, cerebellopontine angle involvement, relationship of the tumour to cranial nerves, and relevant anatomic variants. 167 Preoperative MR imaging is generally considered the standard procedure unless contraindications exist. (e.g. see fig 45). Figure 45. Selection criteria for the surgical approach Source: Whittaker CK, Luetje CM Vestibular schwannomas. J Neurosurg 1992;76:897–900 1.8.2.1 The retrosigmoid (suboccipital) approach (RS) The retrosigmoid or suboccipital approach used to attempt hearing preservation. Success rates vary from 30-65% in CPA tumours smaller than 1.5 cm with good hearing and limited involvement of the IAC. However a tumour extending to the fundus is a Introduction 126 Figure 49. Image of a CSF leak following suboccipital resection of a VS. *A craniotomy defect is seen traversing mastoid air cells (arrow), allowing an egress of CSF into the middle ear cavity. Source: Silk PS, Lane JI, Driscoll CL. Surgical Approaches to Vestibular Schwannomas: What the Radiologist Needs to Know. November 2009 RadioGraphics, 29, p1965 Following severe facial nerve injury is uncommon with microscopic techniques, and most tumours are now being removed by experienced teams of neurosurgeons and neurotologists.223 Transient facial nerve palsy is more common with the MCF approach as mentioned earlier. Vascular injury occurs infrequently, but the sigmoid sinus and jugular bulb can be directly compromised or may potentially thromboses after retraction, possibly with devastating consequences.225 It is important to assess for an intact torcula and the potential for adequate contralateral venous flow should there be injury to the sigmoid sinus or jugular bulb. In the rare case of absent flow on the contralateral side, the translabyrinthine approach would be contraindicated. Parenchymal venous injury can also occur as a result of large adherent tumours with complicated dissection. Arterial injuries occur rarely, with the anteroinferior cerebellar artery being most at risk. 169,223,225 Introduction 127 Figure 50. CSF wound leak. Axial nonenhanced CT scan shows changes from suboccipital resection, with a CSF wound leak that resulted in a pseudomeningocele Tinnitus is a most frequent also remaining most challenging issue among postoperative complications of VS. Kameda and colleagues (2010) 174 report their single-institution, retrospective study of tinnitus outcomes after resection of VS via the retrosigmoid approach. Of their 242 patients with VSs, 171 (70.7%) complained of tinnitus before surgery. This symptom disappeared in 25.2%, improved in 33.3%, remained unchanged in 31.6%, and worsened in 9.9% after tumour removal.174 Another study conducted by Levo et al. 227 observed 251 cases of postsurgical VS and according to their results: Preoperatively, 62.6% of the patients had experienced tinnitus. Of those with preoperative tinnitus, 47.4% also had it postoperatively, but of those 93 patients without preoperative tinnitus, 39.8% had tinnitus postoperatively. Tinnitus is one of the primary symptoms of VS, together with hearing impairment and disequilibrium. The risk of postoperative tinnitus is almost 40%, and with preoperative tinnitus, the risk is 7.6% higher. Even though the cochlear nerve was resected in 45 cases, tinnitus later was noted in 3 patients. The status of postoperative tinnitus was not associated with useful hearing preservation (p = 0.153) or tumour size. Introduction 128 Kameda and colleagues 174 conclude that retrosigmoid tumour resection may provide some chance (~ 60%) for improvement of and some risk (10%) of worsening tinnitus. Outcomes of VS surgery depend on the size and adherence of the tumour, the use of cranial nerve monitoring, and of course the skill of the surgical team. According to Acoustic Neuroma Association reports 60% of members have acceptable facial function after surgery. The medical literature reports vary, but overall, facial movement is preserved in 75% and useful hearing is preserved in 20% of patients228, 229. Delayed hearing loss may occur after surgery in 30 to 50% of patients who had useful hearing immediately after surgery. Partial-removal techniques have higher rates of hearing and facial function preservation; however, the long-term results of these techniques are still being investigated.227-229 Complications of Gamma Knife Radiosurgery1.9.2 Complications that are associated with stereotactic radiosurgery for vestibular schwannoma include hearing deficits, facial palsy, hydrocephalus, and brain stem damage, although the incidence of some of these conditions is much lower than with microscopic open surgery.231 In the literature there are many reports on postradiosurgical complications such as cranial neuropathy, cerebellar infarction and edema, cyst enlargement, malignant transformations, intratumoral hemorrhage, and hemifacial spasm in relatively large VS. 139,190, 196 Bush and colleagues looked specifically at Gamma Knife patients who had "useful audition" pretreatment and found that, at a tumor marginal dose of 13.8 Gy mean at the 50% isodose line, 42% maintained useful hearing posttreatment.60 Regarding trigeminal and facial nerve dysfunctions after radiosurgery for VS, Kondziolka et al.160) reported in 1998 that the application of 16.6 Gy marginal dose on average resulted in facial dysfunction 15% and trigeminal dysfunction 16%. Introduction 129 However, many authors reported lower incidence of complication (<4%) with low dose radiosurgery (Table 4). Author, year Number of patients Mean tumor volume, size Mean maximal /marginal dose Mean follow up period Tumor control rate (%) Hearing preserva tion rate (%) Facial palsy (%) Trigemi nal neuropa thy (%) Kandziolka 190 1998 162 Diameter 22 mm (8-39) 32,7 (2450)/16,6 (12-20) 5-10 years 97 47 (G-R* I-III) 15 16 Moller 2000 111 - 40-12 0.25-10 years 96 80 14 4 Prasad 2000 200 0.0218.3cc 34 (1753)/13(920) 4,3years 92 58 2 4 Regis 2004 1000 12.7 mm3-/- - 97 77.8 (GR I) 47.6 (G-R II) 1.3 0.6 Flickinger 2004 313 1.1 ml (0.0421.4) 26 (2026) 13 (12-13) 24 months 93.5 78.6 (GR I,II) 0 4.3 Hasegawa 2005 73 6.3 cm 3 28.4 (1636) / 14.6 (10-18) 135 months 87 37 (G-R I,II) - - Chung 2005 195 4.1 cm 3 21.9(17.134.0)/ 13 (11-18.2) 36 (1110) 93.6 60 (G-R I,II) 1.4 1.1 Lunsford 2005 829 - -/13 (1020) 6 years 98.6 78.60 <1 <3.1 Table 4. Published results of gamma knife radiosurgery for VS. *G-R Gardner Robertson grade Source: Lim YJ, Choi SK. Gamma Knife Radiosurgery for Vestibular Schwannomas. J Korean Neurosurg Soc 2007 (42), p164 In cases of residual or recurred mass after microsurgery, the repeated operation was recommended generally, however, recently radiosurgery is considered as a secondary treatment instead of reoperation. On the other side, in case of increased tumor size due to failed radiosurgery, microsurgery is indispensable. However, many authors reported that it may be difficult to remove the tumor due to fibrosis after radiosurgery.230 Hearing preservation is another important issue to consider in the treatment of vestibular schwannoma with either microsurgery or radiosurgery. The hearing preservation rate following microsurgery was reported to be 40-70% in patients with serviceable hearing (Betchen et al., 2005)231 Introduction 130 Hearing preservation is an important issue in gamma knife radiosurgery as well. As the experience with gamma knife radiosurgery has grown, the radiation dose has decreased. Currently, a marginal dose of 12 or 13 Gy is the standard dose for treating vestibular schwannoma. Regis et al. (Regis et al., 2008) reported a 60% hearing preservation rate in patients in a large study with a mean follow-up of 7 (minimum 3) years. These authors also mentioned that patients who were not treated using gamma knife radiosurgery lost an average of 9-39 dB compared with an average loss of 2 dB at 3 years following radiosurgery, which corresponds with a preservation of hearing functionality of 60-75%. The probability of preserving functional hearing was higher in patients who had initial symptoms that were other than a decrease in hearing, in patients who were younger than 50 years, and in those patients whose cochlea received a dose of less than 4 Gy during treatment. (Tamura, et al., 2009). The mechanism that underlies hearing deterioration following gamma knife radiosurgery is not fully understood. Some of the mechanisms that have been proposed include a temporary expansion of the tumour in the canal, vascular insufficiency of the auditory system, the toxic dispersion of free radicals, among others (Wackym et al., 2010). Hayhurst et al. (Hayhurst, et al., 2011) reviewed the non-auditory complications that were associated with gamma knife radiosurgery in 80 patients who were followed for more than 2 years. Twenty-seven (33.8%) of their patients developed non-auditory adverse radiation effects, and patients with a target volume that exceeded a threshold of 5 cc were more likely to develop complications. Other complication of GKRS can be Hydrocephalus occurring in approximately 14% of cases and in 4% to 6% of cases after gamma knife treatment.232, 233 Although it has been reported that gamma knife radiosurgery may contribute to the development of hydrocephalus, a causal relationship has not been established and remains controversial. 232 Elevated CSF protein levels are thought to then obstruct CSF resorption at the level of the arachnoid granulations.These events are reported to occur in acoustic schwannomas without radiosurgical treatment, though Radiosurgery may exacerbate these events in some patients. 234 Introduction 131 The condition of patients with significant dysequilibrium or recurrent vertigo is not improved and may actually worsen by stereotactic radiation. Patients who are poor candidates for stereotactic radiation should still be informed of the availability of the therapy and be told why they are poor candidates, in the context of the relative risks and benefits of radiotherapy as opposed to microsurgery.235 Tumour Recurrence1.10 After VS surgery, the rate of tumour recurrence is generally very low, ranging from <1% to 9%. 175-177 According to reviewed literature, the most common cause of VS recurrence after surgery is from incomplete tumour removal,when some of the tumour had to be left behind. This usually happens unplanned, and depends on what happens during surgery.177 An increased risk of residual or recurrent tumour is seen with the suboccipital approach due to relatively blind dissection of the IAC fundus. Residual tumour is deliberately left in approximately 1%–2% of patients if dissection is complicated or vital structures such as the facial nerve are at risk for injury. 178 In 2007 Balasubramaniam and colleagues reviewed 20 cases and revealed 10 de novo secondary tumors, of which eight were malignant, with six being malignant gliomas. The majority of thier cases (14 of 20) involved AN, with most being in patients with neurofibromatosis-2 (8 of 14), reflecting the large numbers and long-term use of radiotherapy for AN. Accelerated growth of primary benign VS and subsequent resection with histopathological confirmation of malignant transformation was found in 6 patients, all of whom had NF-2.235 Objectives Objetives 135 2 Objectives 1. To conduct an epidemiologic analysis of patients with Vestibular Schwannoma diagnosed in our Department. 2. To evaluate the utility of different tests for audiologic and vestibular explorations in the diagnosis of Vestibular Schwannoma. 3. To analyze the natural history of Vestibular Schwannomas, both morphologically and in terms of their functional repercussions. 4. To compare the efficacy of two different therapeutic strategies (the wait-and-watch policy and Radiosurgery) in the management of small Vestibular Schwannomas. 5. To establish a therapeutic protocol for small Vestibular Schwannomas. Materials ans Methods 142 Methods3.2 The study included 107 (100, 0%) patients which clinically followed up from July 21.1992 to May 05, 2011, with the mean follow up period 56.52 ±10.79 (range 25.02-71.74) months. This work consists of both retrospective and prospective clinical observations. The retrospective study based on the investigation of patients having undergone treatment for VS. Data were collected from patient records, outpatient consultations, telephone interviews and re-evaluations of MR scans series. Audiometric testing3.2.1 The audiometric testing has been realized for all VS patients at the outpatient department of the Otolaryngology division of Santiago de Compostela University Hospital Clinic from the period between February 21, 1992 and May 05, 2011. The measurement of PTA implemented was done by the adding up the following threshold levels: 500Hz, 1000Hz, 2000Hz and 3000 Hz and dividing the sum of the values by the four and further revealing the mean. The found number expresses the pure tone average in decibels (dB). It can be explained with following simple formula: Threshold value at 500Hz + threshold value at 1000Hz + threshold value at 2000Hz + threshold value at 3000Hz= x / 4 = Pure Tone Average Apart from the calculation of PTA, in each follow up revision, starting from 6 months, one year, two years, until ten years, depending on the remoteness of VS diagnosis of each VS case, we have calculated the Difference of PTA (DPTA) in order to know how the hearing will be changed over time. For example, if the primary PTA of the patient equals 68,75dB and after 5 years it equals 80dB, in this case we will find DPTA by the means of subtraction of primary PTA from the PTA value after 5 years. It can be illustrated with the following expression: PTA at the time of diagnosis (68, 75)-PTA after x (5) years (80dB) =DPTA (-11, 25). Materials and Methods 143 Testing of balance with Dynamic Craneocorpography3.2.2 The CCG testing has been realized in the CCG room of the outpatient department of CHUS. The CCG equipment uses light markers placed on the forehead, the occiput, and both shoulders of a patient, which reflects through a mirror system on the ceiling into a motion recording video camera and on to a computer that receives, analyzes, and prints the result (e.g. see fig. 52). Figure 52. The Craneocorpography device (Our photo) During the realization of the Unterberger stepping test, the camera records the movements of light markers placed on the forehead, the occiput, and both shoulders of a patient. In order to cut off the visual stimuli of the patient, we have used the sleeping mask. In this way, the patient loses contact with the ground while stepping and will maintain balance Materials ans Methods 144 only through the stimuli received from both vestibular systems. The records of the CCG testing have been analyzed according to Claussen which described 4 different types (page 85). Computerized Dynamic Posturography (CDP)3.2.3 In our group of patients the CDP, like other vestibular tests, were initially realized for prediagnostic VS patients and then checked up during each follow up revision. In all cases, the center of gravity was determined under six sensory conditions, the analysis of which makes up the Sensory Organization Test (SOT): 1. Immobile surface, immobile visual surround, eyes open. 2. Immobile surface, eyes closed. 3. Immobile surface, mobile visual surround, eyes open. 4. Mobile surface, immobile visual surround, eyes open. 5. Mobile surface, eyes closed. 6. Mobile surface, mobile visual surround, eyes open. Each of the six conditions was performed in triplicate, giving a total of 18 tests per session and each test lasts 20 seconds. The following parameters were considered in the data analysis: Balance score (0–100%) obtained in each condition, calculated as the arithmetic mean of the three individual test scores. Mean overall balance score (0–100%), calculated as the arithmetic mean of the 18 individual test scores. Somatosensory ratio, SOM= [condition-2 score]/ [condition-1 score]·100; a measure of the patient´s ability to use somatosensory information for maintenance of balance. Visual ratio, VIS= [condition-4 score]/ [condition-1 score] ·100; a measure of the patient´s ability to use visual information for maintenance of balance. Vestibular ratio, VEST= [condition-5 score]/ [condition -1 score] ·100; a measure of the patient´s ability to use vestibular information for maintenance of balance. Materials and Methods 145 Preference ratio, PREF= [condition-2+condition-5 score]/ [condition-3+condition-6 score] ·100; a measure of the patient´s reliance of visual information, even when that information is incorrect. Caloric testing with Videonystagmography (VNG)3.2.4 We realized the VNG for the diagnostic purposes at the time of diagnosis and also for the estimation of vestibular functions of VS patients over the follow-up years. We have revealed the functionality of each ear and if a VS may be the cause of a dizziness or balance problems. To monitor the movements of the eyes, VNG goggles are placed around the eyes to record eye movements during testing. 1. Ocular Mobility; 2. Optokinetic Nystagmus; 3. Positional Nystagmus; 4. Caloric Testing. For the caloric testing, we used 50 cc of water in 44 ºC to 30 ºC with the period of stimuli being 40 seconds following the indications of Bartual;112.first, right ear with 44 ºC of water; second, left ear with 44 ºC of water; third, left ear with 30 ºC of water; fourth, right ear with 30 ºC of water. The interval between the each irrigation was 5 minutes and the patient was placed in the Hallpike position. The evaluation is both qualitative and quantitative, being most useful at slow phase of nystagmus. For the interpretation, we used Jongkee´s213 formula: % Caloric paresis = 100 x [(LC + LW) - (RC + RW)/(LC + LW + RC + RW)]. The strength of left-beating nystagmus to right-beat calculated: % Directional preponderance (DP) = 100 x [(LC + RW) - (RC + LW)/ (LC + LW+RC+RW. Greater than 30% of directional preponderance is considered to be abnormal, although this is a rather nonspecific finding in isolation. The result is said to be normal when this index is lower than 25%. In turn, the vestibular areflexia (100% canalicular paralysis) is considered if there is no response to cold water. Materials ans Methods 146 Otoacoustic emissions3.2.5 As a screening tool to determine the presence or absence of cochlear function in VS patients with different sizes of the VS tumour, we have investigated the results of DPOAEs by the sounds emitted in response to two simultaneous tones of different frequencies. Each test has been performed by the audiologist in a special cabin designed for OAE. The technique of performing of DPOAE starts from inserting a properly sized probe, according to ear canal volume, with a soft flexible tip to obtain a seal. Stimuli consisted of two pure tones at two frequencies (i.e., f1, f2 [f2>f1]) and two intensity levels (i.e., L1, L2). The relationship between L1-L2 and f1-f2 dictates the frequency response. An f1/f2 ratio yields the greatest DPOAEs at 1.2 for low and high frequencies and at 1.3 for medium frequencies. In order to obtain or yield an optimal response, intensities are tuned up so that L1 equals or exceeds L2. Lowering the absolute intensity of the stimulus renders the DPOAEs more sensitive to abnormality. A setting of 65/55 dB SPL L1/L2 is frequently used. Responses are usually most robust and recorded at the emitted frequency of 2 f1–f2; however, they generally are charted according to f2 because that region approximates the cochlear frequency region generating the response. The result we have registered to our database is simple “present”or “absent”of response to stimuli. Auditory Brainstem Response (ABR) audiometry3.2.6 Auditory brainstem response was performed with the Nicolet Viking IV (Nicolet Biomedical Instrument Inc). Active electrodes were attached to the ipsilateral mastoid region and were referenced to a vertex electrode. A ground electrode was placed on the forehead. The latencies of wave I and wave V, the I-V interpeak interval, the interaural latency difference of waves V (ILD V) and I-III, III-V the interaural differences between IV interpeak intervals (ID I-V) were evaluated. The interaural differences were determined by subtracting the value of the left side from the value of the right side (Table 5). Materials and Methods 147 Table 5. The normal value of waves in ABR (CHUS) Results were considered normal if the interaural difference was 0,2 milliseconds (ms) or less for the wave I-V IPLs. Results were considered borderline if the interaural difference for the wave I-V IPLs was between 0.2 and 0.3 ms. If the interaural difference was 0.3 ms or greater for the wave I-V IPLs, ABR results were considered abnormal. Also the absence of wave III-V or the absence of ABR was considered suggestive of retrocochlear pathology. Vestibular Evoked Myogenic Potentials (VEMP) testing3.2.7 The VEMPS has been performed like other tests have been performed in the otolaryngology outpatient department of CHUS. The test records information using an evoked response laptop, a sound generator, and surface electrodes to pick up neck muscle activation or other muscles, if this is of interest. There are different methods of obtaining the VEMP. Our method of obtaining activation is to have patients sit upright with their chin turned over the contralateral shoulder to tense the SCM muscle. Electrode montage for VEMPs records information in the following places: The ground electrode placed on the forehead; The reference electrode placed on the sternum; Active electrodes to the medial third of SCM muscle. We explained to the patient to sit in an upright position and to rotate the chin to the opposite side while trying to tighten the neck muscles. The device has visual feedback that Wave Media DS (±) Wave Media DS (±) I 1.7 0.15 I-II 2.1 0.15 II 2.8 0.17 I-V 4 0.23 III 3.9 0.19 III-IV 1.2 0.16 IV 5.1 0.24 III-V 1.9 0.18 V 5.7 0.25 IV-V 0.7 0.19 VI 7.3 0.24 V-VI 1.5 0.21 Materials ans Methods 148 indicates whether the intensity of muscle contraction is satisfactory (50 - 200μV). An average we have realized is150 stimuli in each ear with clicks at 99 with the duration of 0.1 ms. In interpretation, we have focused primarily on P1/N1 (P13/N23) amplitude measurements or threshold asymmetries between the right and left sides. Side-to-side differences in VEMP amplitude as an asymmetry ratio we have calculated with the following formulas: Asymmetry Ratio = 100 (AL–AR)/(AL+ AR) Where ALequals the peak-to-peak amplitude (P1/N1) on the left side and ARequals the peak-to-peak amplitude on the right side. We have considered normal AR to be less than 35% 211. Magnetic Resonance Imaging3.2.8 Our group of patients were being followed up over the years, therefore in each revision in the ENT department, they were directed to the Radiology Department to perform an MRI scan for comparing the size of the VS with the previous MRI. All MRI scans of the VS patients were performed with gadolinium contrast. According to the radiologists of CHUS, to enable an accurate and consistent comparison of findings on MRI images, tumour size is defined by calculating the mean intracranial diameter according to the measurements along three easily defined axes on Gd-enhanced T1-weighted images. Thus, the maximum anteroposterior and mediolateral distances were measured on axial images, parallel and perpendicular to the sagittal plane. The maximum craniocaudal diameter was determined by assessing coronal images. The mean diameter as well as the greatest intracranial dimension was noted for each tumor. A decrease or increase in size was regarded as significant if the change of mean diameter was at least 2mm. This cutoff was chosen based on limitations in spatial resolution of the standard 1.5-tesla MR imaging used for most follow-up studies. Intracanalicular tumors, without intracranial extension, were measured in all three dimensions, with a change in size being defined as significant if the transverse diameter had decreased or increased 2mm or more. Materials and Methods From the radiologist's report, we always picked up the maximal size of the VS. For example, according to above measurement methods, if they reported the following dimensions: 22x17x14mm in this case as the maximum size of the tumor, in the follow-up revision we registered it to be 22mm. Moreover, by using the previous reports of the radiologists, we compared the size of the VS tumor with current and primary scan. In this way, we had a size difference for each follow-up year. All the information in numbers from the radiologist's reports were downloaded to the Microsoft Excel 2007 file. Results