Percepção auditiva e desenvolvimento de linguagem oral após cirurgia de implante auditivo de tronco encefálico: uma revisão de escopo / Auditory perception and oral language in brainstem auditory implant users: a scoping review

RESUMO Objetivo mapear as evidências atuais em relação à percepção auditiva da fala e desenvolvimento de linguagem oral em usuários de implante auditivo de tronco encefálico (auditory brainstem implant - ABI), para responder à seguinte questão norteadora: "O que se sabe sobre a habilidade de percepção auditiva da fala e de linguagem oral em indivíduos usuários de implante auditivo de tronco encefálico?" Estratégia de pesquisa a busca foi realizada nas bases de dados BVSalud, PubMed e SciELO e, para literatura cinzenta, utilizou-se a fonte de informação Google Acadêmico, por meio dos descritores: implante auditivo de tronco encefálico (auditory brainstem implantation), linguagem (language), audição (hearing) e percepção auditiva (auditory perception). Critérios de seleção foram incluídos estudos nos quais foram aplicados testes para avalição da percepção auditiva ou para verificar desenvolvimento de linguagem oral em crianças e/ou adultos usuários de ABI. Foram incluídos artigos publicados nos últimos cinco anos e excluídos estudos secundários. Resultados Foram encontrados 1767 artigos nas bases de dados e fonte de informação, dos quais, 27 foram incluídos na revisão. Observou-se que a maioria dos usuários de ABI torna-se capaz de perceber alguns sons ambientais, alguns tornam-se capazes de reconhecer vocábulos, porém, poucos atingem o reconhecimento de frases. Conclusão a maioria dos usuários de ABI não avança para a habilidade de reconhecimento auditivo em conjunto aberto e há unanimidade na recomendação de métodos de comunicação visual para esses indivíduos.

ABSTRACT Purpose This scope review aims to map current evidence in relation to auditory perception of speech and oral language development in users of Auditory Brainstem Implant - ABI, to answer the following guiding question: "what do we know about the ability of auditory perception of speech and oral language in auditory brainstem implants users?" Research strategy The search was performed in the BVSalud, PubMed and SciELO databases and for gray literature the source of information Google Academic, using the descriptors: auditory brainstem implantation , language, hearing and auditory perception. Selection criteria Studies were included in which tests were applied to assess auditory perception or to verify oral language development in children and/or adults using ABI. Articles published in the last five years were included and secondary studies were excluded. Results 1767 articles were found in the databases and source of information, of which 27 studies were included. It was observed that most users of ABI become able to perceive some environmental sounds, some become able to recognize words, but few reach the recognition of sentences. Conclusion Most ABI users do not advance towards the open set auditory recognition skill and there is unanimity in recommending visual communication methods for these individuals.

Epidemiological features of meningiomas: a single Brazilian center's experience with 993 cases.

BACKGROUND: Meningiomas are the most frequent primary central nervous system (CNS) tumors. Their geographical and ethnic characteristics need to be known, in order to enable rational treatment. OBJECTIVE: To investigate clinical and epidemiological aspects in a series of patients with meningiomas. METHODS: Retrospective analysis on the demographic profile, location and histopathology of 993 patients with meningiomas (768 operated and 225 not operated). RESULTS: Meningiomas represented 43.8% of the primary CNS tumors; 6.8% were multiple tumors (14.7% with neurofibromatosis 2) and 0.6% were radiation-induced tumors. The mean ages were 53.0 and 63.9 years for operated and non-operated patients and the female/male ratios were 3.2:1 and 6.3:1. Diagnosis was made later among females. The peak incidences were in the 6th and 7th decades respectively for operated and non-operated patients. The incidence was low at early ages and higher among patients aged 70+ years. The meningiomas were intracranial in 96.5% and most were WHO grade I (88.9%) and transitional. In the spinal canal (3.5%), they occurred mainly in the dorsal region (all grade I; mostly transitional). The racial distribution was 1.0% in Asian-Brazilians, 87% in Caucasians and 12% in African-Brazilians. 83.4% and 51.6% of the patients were estimated to be recurrence-free at 10 and 20 years, and the mortality rate was 3%. CONCLUSIONS: Most of the demographic data were similar to what has been observed in other western centers. Differences were higher incidence of meningiomas, female and older predominance in non-operated patients, predominance in Caucasian, and higher association with neurofibromatosis 2.

Epidemiological features of meningiomas: a single Brazilian center's experience with 993 cases / Características epidemiológicas de meningiomas: experiência de um centro único brasileiro com 993 casos

ABSTRACT Background: Meningiomas are the most frequent primary central nervous system (CNS) tumors. Their geographical and ethnic characteristics need to be known, in order to enable rational treatment. Objective: To investigate clinical and epidemiological aspects in a series of patients with meningiomas. Methods: Retrospective analysis on the demographic profile, location and histopathology of 993 patients with meningiomas (768 operated and 225 not operated). Results: Meningiomas represented 43.8% of the primary CNS tumors; 6.8% were multiple tumors (14.7% with neurofibromatosis 2) and 0.6% were radiation-induced tumors. The mean ages were 53.0 and 63.9 years for operated and non-operated patients and the female/male ratios were 3.2:1 and 6.3:1. Diagnosis was made later among females. The peak incidences were in the 6th and 7th decades respectively for operated and non-operated patients. The incidence was low at early ages and higher among patients aged 70+ years. The meningiomas were intracranial in 96.5% and most were WHO grade I (88.9%) and transitional. In the spinal canal (3.5%), they occurred mainly in the dorsal region (all grade I; mostly transitional). The racial distribution was 1.0% in Asian-Brazilians, 87% in Caucasians and 12% in African-Brazilians. 83.4% and 51.6% of the patients were estimated to be recurrence-free at 10 and 20 years, and the mortality rate was 3%. Conclusions: Most of the demographic data were similar to what has been observed in other western centers. Differences were higher incidence of meningiomas, female and older predominance in non-operated patients, predominance in Caucasian, and higher association with neurofibromatosis 2.

RESUMO Antecedentes: Meningiomas são os tumores mais frequentes do sistema nervoso central (SNC). Suas características étnicas e geográficas precisam ser conhecidas para o seu tratamento racional. Objetivo: Investigar aspectos clínicos e epidemiológicos de uma série de pacientes com meningiomas. Métodos: Análise retrospectiva demográfica de 993 pacientes com meningiomas (768 operados e 225 tratados conservadoramente) Resultados: Meningiomas constituíram 43.8% dos tumores primários do SNC. 0.8% deles eram múltiplos (14,7% com neurofibromatose 2) e 0,6% eram radioinduzidos. A idade média e o índice mulheres/homens foram respectivamente 53,0 e 63,9 anos e 3.2:1 e 6.3:1 para pacientes operados e não operados. O diagnóstico foi mais tardio em mulheres. Ocorreram picos de incidências na 6ª e na 7ª décadas respectivamente para pacientes operados e não operados. A incidência foi menor na infância e maior após 70 anos. Meningiomas predominaram no crânio (96.5%), a maioria grau I da OMS, subtipo transicional. Do total, 3.5% ocorreram no canal raquídeo, principalmente na região torácica, todos grau I, a maioria transicional. Em relação à distribuição racial, 1.0% dos meningiomas ocorreu em amarelos, 87% em brancos e 12% em negros. As taxas de sobrevida sem recorrência foram 83.4% e 51.6% em 10 e 20 anos e a mortalidade operatória foi 3%. Conclusões: A maioria dos dados demográficos observados foi similar aos de outros centros ocidentais. As diferenças observadas foram maior incidência, predominância em mulheres e idosos nos pacientes não operados e em caucasianos, e maior associação com neurofibromatose 2.

Síndrome de pseudo-Duane secundario a Schwannoma de nervio abducens: Reporte de caso y revisión / Pseudo-Duane syndrome secondary to abducens nerve schwannoma: Case report and review

Reporte de caso de síndrome de pseudo-Duane asociado a schwannoma de nervio abducens y neurofibromatosis tipo 2 (NF2). Este síndrome es raro, caracterizado por limitación en abducción, retracción ocular, disminución de hendidura palpebral en abducción y restricción del recto medial ipsilateral en test de ducción forzada. La NF2 es también una enfermedad infrecuente caracterizada por tumores de sistema nervioso central y periférico. Los schwannomas de nervio abducens son también poco frecuentes, y se presentan comúnmente con diplopia. Se revisan brevemente estas enfermedades. Es el primer caso reportado de pseudo-Duane secundario a schwannoma de nervio abducens y NF2 según nuestro conocimiento.

A pseudo-Duane syndrome case associated with abducens nerve schwannoma and neurofibromatosis type 2 (NF2) is presented. This syndrome is a rare disease characterised by abduction limitation, ocular retraction, narrowing of the palpebral fissure in abduction, and ipsilateral medial rectus restriction on forced duction test. NF2 is also an uncommon disease which is characterised by peripheral and central nervous system tumours. Abducens nerve schwannomas are also uncommon and presents usually as diplopia. A short review of these diseases is given. This is the first case of pseudo-Duane secondary to abducens nerve schwannoma, to our knowledge.

Vestibular schwannoma: predictive factors of long-term postoperative neurological outcome.

Introduction: Vestibular schwannoma (VS) is a slow-growing, benign tumor that is usually diagnosed when symptoms develop. Surgical management aims to reduce long-term sequelae (LTS) associated with late diagnosis.Objective: Identify predictive factors of LTS after VS surgery and clinical outcome measured by modified Rankin scale (mRS).Methods: This cohort study included patients submitted to VS surgery from 1999 to 2014, with a mean follow-up of 6.4 ± 4.5 years. Disability was assessed across the mRS the primary outcome was defined by scores 3 to 6, which implied poor outcome in neurological recovery. Predictive factors were identified through multivariate logistic regression.Results: A total of 101 patients were included in this study. Fifty-one (50.49%) presented mRS ≥ 3 on the late postoperative period. Men comprise 22.8%, and the mean age was 47.1 ± 16.0 years (range19-80). Patients with mRS ≥ 3 presented larger tumors (3.7 ± 1.1 cm vs. 3.2 ± 1.0 cm, p < .001), less total resection (50% vs. 76.7%, p < .010) and more neurofibromatosis II(NFII) (84.9% vs. 64.3%, p = .023). On multivariate analysis NFII, tumor size and type resection were predictive of degree of autonomy (mRS ≥3: NF II (OR 3.5, 95% CI 1.08-11.36, p = .036) and tumor size (each 1 cm, OR1.51, 95% CI 0.96-2.38, p = .050).Conclusion: Tumor size, presence of NFT II, type of surgical approach and number of surgeries were identified as predictive factors of functional sequelae in long-term follow-up after VS surgery.HighlightsOne-third of our patients presented some degree of disability that impact in autonomy (mRS ≥ 3) in the late postoperative period.Tumor size, NFII, surgical approach were predictive to comprise independency.Considering the cranial nerve monitoring and late diagnosis, our results can give some contribution to understanding the Brazilian profile of VS surgery.Our findings suggests the need to look over what it is well recognized and identify aspects that affect the prognosis such as functional disabilities in VS surgery.

Neurofibromatosis tipo 2, entidad a tener presente durante la práctica clínica / Neurofibromatosis type 2, entity to have present during clinical practice

La neurofibromatosis tipo 2 es un trastorno poco frecuente, que pertenece al grupo de las neurofibromatosis, que se caracterizan por la mayor propensión al desarrollo de tumores. Se presenta con múltiples tumores no malignos del sistema nervioso, incluidos schwannomas, meningiomas, ependimomas y gliomas, siendo los schwannomas vestibulares bilaterales una característica clásica. La mayoría de los casos se diagnostican en la adultez, sin embargo, las características clínicas habitualmente están presentes durante muchos años antes del diagnóstico. Es importante un alto índice de sospecha y un adecuado examen cutáneo y neurológico, ya que es crítico para hacer un diagnóstico correcto y precoz, y así, realizar un tratamiento interdisciplinario adecuado, evitando posibles complicaciones como son la pérdida auditiva y el uso de ayudas técnicas.

Neurofibromatosis type 2 is a rare disorder, belonging to the group of neurofibromatosis, which are characterized by the propensity for tumor development. The usual presentation are multiple non-malignant tumors of the nervous system, including schwannomas, meningiomas, ependymomas, and gliomas, with bilateral vestibular schwannomas being a classic feature. Most cases are diagnosed in adulthood; however, the clinical features are usually present for many years before diagnosis. A high index of suspicion and an adequate skin and neurological examination are important, since it is critical to make a correct and early diagnosis, so an appropriate interdisciplinary treatment can be performed, avoiding possible complications such as hearing loss and use of technical aids.

Neurofibromatosis tipos 1 y 2 / Neurofibromatosis type 1 and 2

La neurofibromatosis (NF) comprende un grupo de enfermedades genéticas de herencia autosómica dominante, que se clasifican de la siguiente manera: neurofibromatosis tipo 1 (NF1), neurofibromatosis tipo 2 (NF2) y schwannomatosis (también conocida como neurofibromatosis tipo 3). Esta última es una enfermedad muy infrecuente, con una prevalencia aproximada de 1/126 000 personas, por lo que solo profundizaremos las dos primeras. La NF1, también conocida como la enfermedad de Von Recklinghausen, es la más frecuente de las tres y afecta principalmente la piel y el sistema nervioso periférico. Se caracteriza por la presencia de máculas "café con leche", pecas axilares o inguinales, nódulos de Lisch (hamartomas en el iris) y neurofibromas (tumores de la vaina de nervios periféricos). Otras manifestaciones menos frecuentes, aunque de mayor gravedad, incluyen gliomas del nervio óptico, meningiomas, neurofibromas malignos, escoliosis y displasia de la tibia. Su diagnóstico se suele realizar al nacimiento o durante los primeros años de vida, y se estima que un 50% de quienes la padecen presenta dificultades cognitivas. No hay datos concluyentes sobre la mortalidad en los pacientes con NF1, aunque se sabe que la expectativa de vida es menor que en la población general. La NF2 tiene una prevalencia considerablemente menor que la NF1 y su inicio es más tardío, afectando principalmente a adultos jóvenes. La presentación clínica típica se caracteriza por acúfenos, hipoacusia y ataxia en contexto de la presencia de schwannomas vestibulares bilaterales. Otros hallazgos menos frecuentes incluyen schwannomas de nervios periféricos, meningiomas, ependimomas o astrocitomas. La esperanza de vida es de unos 36 años, con una supervivencia media desde el momento del diagnóstico de 15 años. (AU)

Neurofibromatosis (NF) includes a group of genetic diseases with an autosomal-dominant inheritance pattern, and they are classified as follows: Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and Schwannomatosis (also known as neurofibromatosis type 3). This last one is a very rare disease, with an approximate prevalence of 1/126000, so we will only deepen in the first two. NF1, also known as von Recklinghausen disease, is the most frequent, and mainly affects the skin and peripheral nervous system. Its typical manifestations are the presence of café-au-lait macules, axillary or inguinal freckles, Lisch nodules (hamartomas in the iris) and neurofibromas (peripheral nerve sheath tumors). Less frequent manifestations, although more serious, include optic nerve gliomas, meningiomas, malignant neurofibromas, scoliosis and tibial dysplasia. The diagnosis is usually made at birth or during the first years of life, and approximately 50% of patients present cognitive difficulties. There is no conclusive data on mortality in patients with NF1, although it is known that life expectancy is lower than in general population. NF2 has a considerably lower prevalence than NF1, and its onset is later in life, mainly affecting young adults. Its typical clinical presentation is characterized by tinnitus, hearing loss and ataxia in the context in the presence of bilateral vestibular schwannomas. Less frequent findings include peripheral nerve schwannomas, meningiomas, ependymomas or astrocytomas. Life expectancy is about 36 years old, with a median survival from the moment of diagnosis of 15 years. (AU)

Ocular alterations, molecular findings, and three novel pathological mutations in a series of NF2 patients.

PURPOSE: To evaluate ophthalmological and molecular findings in eight patients with a clinical diagnosis of neurofibromatosis type 2 (NF2). New pathological mutations are described and variability in the ophthalmic phenotype and NF2 allelic heterogeneity are discussed. METHODS: Eye examination was performed in eight NF2 patients, and it included the measurement of the visual acuity, biomicroscopy, dilated fundus examination, color fundus photography, infrared photography, and spectral domain optical coherence tomography (SD-OCT). Molecular analysis was performed with whole-exome sequencing using DNA derived from peripheral blood mononuclear cells from each individual. RESULTS: Ophthalmological features were present in all patients, ranging from subtle retinal alterations identified only using SD-OCT to severe ocular damage present at birth. Six mutations were observed: two patients with stop codon mutation as shown on table 1 and result section, three patients with frameshift mutation as shown on table 1 and result section. Three novel mutations were found among them. CONCLUSIONS: It is a descriptive study of a rare disease, with poor previous literature. Clinical and genetic data are shown, reviving the need to further studies to clarify the genotype-phenotype correlations in NF2.

Clinical and molecular characterization of neurofibromatosis in southern Brazil.

OBJECTIVES: Neurofibromatoses (type 1: NF1; type 2: NF2) are autosomal dominant tumor predisposition syndromes mostly caused by loss-of-function mutations in the tumor suppressor genes NF1 and NF2, respectively. Genotyping is important for correct diagnosis of these diseases. The authors aimed to characterize NF1 and NF2 variants in patients from Southern Brazil. METHODS: Ninety-three unrelated probands with NF1 and 7 unrelated probands with NF2 features were recruited from an Oncogenetics center in Southern Brazil. Two next generation sequencing panels were customized to identify point mutations: NF1 (NF1, RNF135, and SUZ12 genes) and NF2 (NF2 and SMARCB1 genes). Large rearrangements were assessed by Multiplex Ligation-dependent Probe Amplification. RESULTS: Sixty-eight heterozygous NF1 variants were identified in 75/93 probands (80%) and 3 heterozygous NF2 variants were identified in 3/7 probands (43%). In NF1, 59 (87%) variants were pathogenic (4 large rearrangements - 6%), 6 (9%) were likely pathogenic, 3 (4%) were variants of uncertain significance and 28 (41%) were novel. In NF2, all variants were pathogenic. No novel genotype-phenotype correlations were observed; however, previously described correlations were confirmed in our cohort. CONCLUSION: The clinical and molecular characterization of neurofibromatoses in different populations is very important to provide further insights into the pathogenesis of these diseases.

Frequency of the Loss of Heterozygosity of the NF2 Gene in Sporadic Spinal Schwannomas.

BACKGROUND/AIM: Individuals with type 2 Neurofibromatosis are predisposed for the appearance of schwannomas. In the present study we analyzed the loss of heterozygosity and mutations in the NF2 gene in patients with sporadic Schwannoma without Neurofibromatosis type 2. MATERIALS AND METHODS: We analyzed 39 patients with sporadic spinal schwannoma. We quantified the number of alleles by FISH and sequenced the NF2 gene. RESULTS: We identified 16/39 patients with point mutations and/or LOHs in the tumor samples analyzed. The LOHs were found in 7/39 patients. Two homozygous mutations were detected in 4/39 tumors, and the presence of the mutation in heterozygosis was revealed in 3/39 patients. In two tumors, we detected the loss of one allele of the NF2 gene, with no mutation. CONCLUSION: The genetic alterations observed in the NF2 gene indicated that spinal schwannomas are associated with genetic alterations also found in other schwannomas and type 2 Neurofibromatosis, which reinforces the etiological role of this gene.

Concomitant Occurrence of Vestibular Schwannoma and Epidermoid Cyst in Neurofibromatosis: Case description and Review of the Literature

We report a case of a 16-year-old female patient harboring neurofibromatosis type 2 who presented with bilateral hearing impairment, which was on the left side, as well as facial paresis (House-Brackmann grade III) and ataxic gait. A magnetic resonance imaging (MRI) exam evidenced bilateral lesions in the cerebellopontine angles (CPAs) with extension into the internal acoustic meatus, and an additional lesion in the right CPA with radiological characteristics of an epidermoid cyst. The patient was submitted to microsurgical resection, confirming a collision of a vestibular schwannoma and an epidermoid cyst in the right CPA. In the present case report, we describe the first case reported in the literature with preoperative diagnostic work-up, intraoperative findings, postoperative course of the patient, as well as a detailed literature review of these specific coinciding pathologies, denoting the importance of further genomic studies regarding multiple central nervous system (CNS) lesions.

Relatamos o caso de uma paciente de 16 anos de idade com neurofibromatose tipo II com deficiência auditiva bilateral, pior no ouvido esquerdo, assim como paresia facial (HouseBrackmann grau III) e ataxia. Estudo de ressonância magnética comprovou lesão bilateral nos ângulos cerebelopontinos (ACPs) com extensão ao meato acústico interno, e uma lesão adicional no ACP direito com características radiológicas de um cisto epidermoide. A paciente foi submetida a ressecção microcirúrgica, confirmando a colisão de um schwannoma vestibular com um cisto epidermoide no ACP direito. No presente estudo, descrevemos o primeiro caso relatado na literatura com trabalho diagnóstico pré-operatório, resultados intraoperatórios, evolução da paciente no pós-operatório, assim como revisão detalhada da literatura específica sobre essas patologias, demonstrando a importância de mais estudos genômicos sobre as múltiplas lesões do sistema nervoso central (SNC).

Cervicomedullary Junction Ependymoma Associated with Neurofibromatosis Type II: Case Report and Literature Review

Neurofibromatosis type II (NF2) is a rare autosomal dominant inherited disease caused by a mutation in chromosome 22q12 and associated with multiple central nervous system tumors. In this paper, we describe a rare case of cervicomedullary junction ependymoma associated with NF2 in a 25-year-old man who underwent surgical treatment with total resection and had a good clinical outcome. We discussed the nuances of the surgical resection and the literature concerning this rare form of presentation of NF2.

Neurofibromatose tipo II (NF2) é uma doença autossômica dominante provocada por uma mutação no cromossomo 22q12, e que está relacionada ao surgimento de múltiplos tumores do sistema nervoso central. Neste artigo, é descrito um caso raro de um paciente com 25 anos de idade submetido ao tratamento cirúrgico de um ependimoma da junção cervicobulbar, com ressecção total "en bloc" e bom resultado clínico. Discutimos as nuances da ressecção cirúrgica, bem como a literatura sobre o tratamento destas lesões raras.

Spectral-Domain Optical Coherence Tomography Findings in Neurofibromatosis Type 2.

PURPOSE: Neurofibromatosis type 2 (NF2) is an autosomal-dominant disease, characterized by bilateral vestibular schwannomas, multiple central nervous system (CNS) tumors, skin tumors, and juvenile cataract. The present study assessed retinal abnormalities using spectral-domain optical coherence tomography (SD-OCT) in a case series of NF2 patients. METHODS: Nine NF2 patients from the neurofibromatosis outpatient reference center of the Federal University of Minas Gerais, in Brazil, were submitted to a complete anamnesis and a detailed ophthalmic evaluation, including SD-OCT, to detect retinal lesions. RESULTS: Of the nine NF2 patients evaluated, five had an early onset (<20 years) of NF2, and four patients had a late onset (>20 years) of symptoms. SD-OCT scans revealed retinal abnormalities in every patient with early onset (EOS) and in two patients with late onset (LOS) of the disease. In the EOS group, SD-OCT scans revealed flame-shaped epiretinal membranes (ERM) with peculiar characteristics in four eyes of three patients. Two patients had fine undulations of the inner retinal surface with a subtle ERM. Retinal hamartomas were present in four eyes of three patients with EOS; in two eyes, they were subclinical and were detected only by SD-OCT scans. In two patients with LOS and one patient with EOS, SD-OCT scans revealed retinal tufts of a nerve fiber layer. CONCLUSIONS: SD-OCT revealed ERM in most patients with NF2, therefore it may be a valuable exam for evaluating NF2 patients. Epiretinal membranes in NF2 has unique features, distinguishing it from idiopathic ERM or membranes associated with other diseases. We suggest that flame-shaped ERM seems to be specific for NF2 and that ERM can be considered as an important diagnostic sign of NF2.

Bevacizumab (BZM) en Neurofibromatosis tipo 2 (NF2) / Bevacizumab (BZM) in Neurofibromatosis type 2 (NF2)

INTRODUCCIÓN Y CONTEXTO: Un paciente presentó en el Ministerio de Salud de la Nación (MSN) un pedido de autorización para el uso del Bevacizumab (BZM) por su caso de Neurofibromatosis tipo 2. El MSN pide opinión a la ANMAT. (Expediente MSN 1-2002-30984-15-5, Nota ANMAT: 197/2016) En el expediente consta que el paciente padece una neurofibromatosis tipo 2. (NF2) según criterios internacionales de diagnóstico de la enfermedad. (Manchester y NNFF - National Neurofibromatosis Foundation). Presenta varios informes de TAC y RMI de cerebro desde diciembre 2012 hasta julio 2015. Los informes no encuentran progresión de las lesiones durante ese tiempo de aproximadamente 30 meses. Si bien hay un certificado de hipoacusia bilateral neuroperceptiva progresiva, no hay en el expediente, un estudio completo de audiometría y logoaudiometría para evaluar la evolución funcional, ni el grado de la misma. Este parámetro resulta de extrema importancia como punto de partida, para saber si el paciente tiene o no capacidad de mejora en el reconocimiento de la palabra, dado que es una de las variables que determinan el uso y la exposición al BZM. Además, falta un Consentimiento Informado completo, firmado por el paciente, aceptando el uso de la droga. Sin embargo, expresa conocer los beneficios dudosos según cada caso y los efectos adversos del BZM que se detallan en el expediente y coinciden con el prospecto y la Disposición ANMAT. En este contexto, la Administración de ANMAT solicitó un informe ultrarrápido de ETS para saber si había evidencia suficiente para dar opinión sobre el uso de BZM fuera de ficha técnica del producto en la NF2. La NF2 es una enfermedad compleja que se caracteriza por el desarrollo de múltiples neuromas / schwannomas, especialmente schwannomas vestibulares, así como otros tipos de tumores benignos en otros nervios craneales, espinales o periféricos. También meningiomas y ependimomas espinales y gliomas del SNC. La carga tumoral finalmente termina siendo importante. Debido a su naturaleza multisistémica, la gestión de la NF2 requiere un enfoque multidisciplinario. La NF2 es causada por mutaciones en el gen supresor NF2 en el cromosoma 22q12, que codifica para una proteína llamada "merlin" o "schwannomin" y otras mutaciones que la hacen más compleja y heteromorfa cuando se expresa antes de la pubertad. Esta alteración produce desinhibición y crecimiento de neuromas. Basados en los datos de estudios in vitro y en animales en la vía Merlin, se permitieron estrategias de tratamiento dirigidas biológicamente (empleando lapatinib, erlotinib, everolimus, picropodofilina, OSU.03012, imatinib, sorafenib y bevacizumab), destinadas a la detención o regresión del tumor y la mejoría funcional. Una de las recomendaciones más importantes se refiere a que dada la rareza de su presentación, se deben centralizar y estandarizar la evaluación de los pacientes y cooperar para llevar adelante y acelerar estudios experimentales, fase 0 y fase 2, seleccionando con precisión que pacientes incorporar primero según evolución y condición física, realizándolos sin placebo y sin azar. TECNOLOGÍA: El BZM es un anticuerpo monoclonal humanizado IgG1 dirigido contra el factor de crecimiento vascular endotelial (VEGF) y es utilizado como droga antiangiogénica aprobada por la ANMAT cuyas características e indicaciones figuran en su prospecto. OBJETIVO: Eficacia, seguridad y efectividad del BZM para el tratamiento de la NF2. RESUMEN DE LOS RESULTADOS DE LOS ESTUDIOS SELECCIONADOS: Existe un estudio Fase II ya concluido que incluyó a 14 pacientes, cuyos resultados no están disponibles aún. La evidencia disponible, es de baja calidad y pocos casos. No solamente porque la enfermedad es muy poco frecuente, sino porque los criterios para incluir pacientes en BZM también restringen aún más la población a tratar. Del análisis surge que los tratamientos recomendados pueden durar a lo sumo un año. El NHS/Oxford recomienda seis meses. La frecuencia de aplicación del BZM es cada dos o tres semanas. La dosis de la sesión varía entre 5 y 10 mg/kg, administrado en un ámbito adecuado y con un tiempo de duración de la infusión muy controlado. Es muy importante evaluar la respuesta volumétrica de los schawnnomas medidos y seguidos, dado que un criterio muy claro es que se detenga o disminuya su crecimiento más de un 20% de la medida inicial. La medición con criterios otológicos válidos y reproducibles de la interpretación de la palabra en el estudio de audición constituyen criterios estrictos de seguimiento y tardan habitualmente en mejorar desde 3 a 6 meses luego del inicio del tratamiento. Se insiste en que para usar el BZM, no debe haber dudas de que la radiocirugía o la microcirugía no puedan mejorar la oferta de beneficio para el paciente o por lo menos que haya mucho riesgo de defecto residual postcirugía, como suele ocurrir. No se conoce cuánto tiempo dura el efecto antiangiogénico e inhibidor del crecimiento de los neuromas y es, sin lugar a dudas un tratamiento adyuvante y paliativo que retrasa sobre todo la sordera definitiva o la compresión de lugares clave dentro del SNC y sus consecuencias. Según un estudio de 31 pacientes retrospectivo, el tamaño de los tumores medidos permaneció estable en la mitad de los pacientes a tres años. A pesar de ser una débil evidencia, es la única que hay disponible. El efecto antiangiogénico y antiedema del BZM, son postulados como explicación para la mejoría de la capacidad funcional, la atrofia muscular y hasta como radiosensibilizador para el uso de radioterapia a menores dosis. Una revisión narrativa publicada en 2011, intenta sistematizar el uso de las distintas terapéuticas, concluyendo que la radiocirugía parecería mantener el control del tumor durante una cantidad creciente de años de seguimiento. La radioterapia fraccionada, con especial atención a la limitación de la dosis de radiación coclear, parece ofrecer los mejores resultados funcionales para el nervio auditivo. El tratamiento microquirúrgico sigue siendo la mejor terapia citorreductora y aunque no puede lograr los resultados sobre el nervio facial y auditivo de la radiocirugía, sigue siendo el tratamiento de elección para las lesiones grandes que causan efecto de masa y la hidrocefalia obstructiva. El BZM resulta una promesa sustancial para el tratamiento de lesiones progresivas en neurofibromatosis tipo 2. CONCLUSIONES: No hay estudios científicos de calidad que sustenten el tratamiento de NF2 con BZM. No hay estudios científicos de calidad que sustenten la contraindicación del tratamiento de NF2 con BZM. La evidencia disponible sugiere beneficio pero pone en duda su utilidad si se toma en cuenta que los efectos adversos son frecuentes y manejables pero a veces, mortales. Por el propio mecanismo de acción puede saberse cuando comienza el tratamiento pero por ahora no se sabe cuándo termina. El NHS solo lo autoriza por seis meses. Hay una recomendación muy fuerte de que los pacientes elegibles deben cumplir dos condiciones: que los tumores que dan mayor compromiso o síntomas sean de crecimiento volumétrico medido y significativo en el último año de evolución y que el paciente tenga chances de mejorar su audición y entendimiento de la palabra. Por este mismo motivo se recomienda ser cuidadoso en el uso y seguimiento para evitar daños sin mejoría significativa en capacidad funcional, calidad de vida o crecimiento tumoral. Hasta disponer de nueva evidencia, es razonable el uso fuera de ficha técnica de BZM para el NF2 en las condiciones muy controladas antedichas, siempre que se cumplan los criterios de cuidados extremos para la exposición a la droga y cumpliendo con la firma de un consentimiento informado muy completo y la responsabilidad de médico tratante y paciente y familia. Debe tenerse en cuenta que ANMAT según ha expresado en comunicaciones públicas de posición, "enfoque ANMAT", NO autoriza NI prohíbe el uso "off label" de los medicamentos en plaza; siendo esta facultad, de exclusiva responsabilidad del médico tratante.