Ipsilateral Vestibular Schwannoma after Cochlear Implantation.

OBJECTIVE: The vestibular schwannoma incidence rate is approximately 4.2 per 100,000/year. Thus far, about 700,000 cochlear implantations have been performed worldwide; therefore, the occurrence of vestibular schwannoma postcochlear implantations can be assumed to be infrequent. Recent developments allow safe observation and surveillance of the implanted-side internal auditory canal (IAC) and cochlea by magnetic resonance imaging (MRI), even after cochlear implantation. Patients. A 71-year-old woman with sudden hearing loss and a contralateral vestibular schwannoma without clinical and genetic signs of neurofibromatosis type II. Intervention(s). Ipsilateral cochlear implantation and contralateral vestibular schwannoma extirpation with regular tumor follow-up. Main Outcome Measure(s). Comparison of ipsilateral pre and postcochlear implantation 3T MRI T1 GAD. RESULTS: We observed a tumor growing at the fundus of the internal auditory canal 1 year after cochlear implantation on the ipsilateral side. Although first detected after cochlear implantation beside a known vestibular schwannoma on the contralateral side, a scan slice thickness of 2 mm cannot fully exclude the preoperative persistence of a small tumor. Based on the clinical findings and after genetic exclusion of NFII, the patient was classified as a NFII mosaic type. CONCLUSION: Even after cochlear implantation, tumors in the IAC causing vertigo, facial palsy, and affecting the audiologic outcome can be detected by MRI. The MRI slice thickness used before cochlear implantation should be under 2 mm.

Bevacizumab treatment for symptomatic spinal ependymomas in neurofibromatosis type 2.

BACKGROUND: Neurofibromatosis type 2 (NF2) is a tumor suppressor syndrome associated with vestibular schwannomas, meningiomas, and spinal ependymomas. There have been anecdotal reports of radiographic response of spinal ependymomas in NF2 patients being treated for progressive vestibular schwannomas with bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF). AIMS: The aim of this study was to review the clinical effects of bevacizumab treatment for symptomatic, NF2-associated ependymomas METHODS: We conducted a retrospective review of all patients with NF2 treated with bevacizumab for symptomatic ependymoma at three NF2 specialty centers. Tumor size was evaluated by linear measurements; radiographic response was defined as >20% reduction in tumor size. We also performed immunohistochemical evaluation of NF2-associated symptomatic ependymomas from five patients, including two from this clinical series. RESULTS: Eight patients with NF2 and symptomatic ependymoma were treated with bevacizumab. All patients had subjective clinical improvement with bevacizumab, although only five of eight patients evaluated had radiographic response. All tumors expressed VEGF-R2. Four of five evaluated ependymomas expressed VEGF-R1; one without VEGF-R1 expression was from a patient who showed clinical but not radiographic response. CONCLUSIONS: Treatment using bevacizumab improved symptoms related to NF2-associated ependymomas, often without concurrent radiographic response. This treatment effect may be related to VEGF-R1 expression in NF2-associated ependymoma.

Growth in neurofibromatosis 1 microdeletion patients.

Microdeletions of the entire NF1 gene and surrounding genomic region occur in about 5% of patients with neurofibromatosis 1 (NF1). NF1 microdeletion patients usually have more cutaneous and plexiform neurofibromas and a higher risk of developing malignant peripheral nerve sheath tumors than other people with NF1. Somatic overgrowth has also been observed in NF1 microdeletion patients, an observation that is remarkable because most NF1 patients are smaller than average for age and sex. We studied longitudinal measurements of height, weight, and head circumference in 56 patients with NF1 microdeletions and 226 NF1 patients with other kinds of mutations. Although children with NF1 microdeletions were much taller than non-deletion NF1 patients at all ages after 2 years, the lengths of deletion and nondeletion NF1 patients were similar in early infancy. NF1 microdeletion patients tended to be heavier than other NF1 patients, but height or weight more than 3 standard deviations above the mean for age and sex was infrequent in children with NF1 microdeletions. Head circumference and age of puberty were similar in deletion and non-deletion NF1 patients. The pattern of growth differs substantially in deletion and non-deletion NF1 patients, but the pathogenic basis for this difference is unknown.

Multimodal Imaging in Neurofibromatosis Type 1-associated Nerve Sheath Tumors.

UNLABELLED: Neurofibromatosis type 1 (NF1) is a neurogenetic disorder. Individuals with NF1 may develop a variety of benign and malignant tumors of which peripheral nerve sheath tumors represent the most frequent entity. Plexiform neurofibromas may demonstrate a locally destructive growth pattern, may cause severe symptoms and may undergo malignant transformation into malignant peripheral nerve sheath tumors (MPNSTs). Whole-body magnetic resonance imaging (MRI) represents the reference standard for detection of soft tissue tumors in NF1. It allows for identification of individuals with plexiform neurofibromas, for assessment of local tumor extent, and for evaluation of whole-body tumor burden on T2-weighted imaging. Multiparametric MRI may provide a comprehensive characterization of different tissue properties of peripheral nerve sheath tumors, and may identify parameters associated with malignant transformation. Due to the absence of any radiation exposure, whole-body MRI may be used for serial follow-up of individuals with plexiform neurofibromas. (18)F-fluorodeoxyglucose positron-emission-tomography (FDG PET/CT) allows a highly sensitive and specific detection of MPNST, and should be used in case of potential malignant transformation of a peripheral nerve sheath tumor. PET/CT provides a sensitive whole-body tumor staging. The use of contrast-enhanced CT for diagnosis of peripheral nerve sheath tumors is limited to special indications. To obtain the most precise readings, optimized examination protocols and dedicated radiologists and nuclear medicine physicians familiar with the complex and variable morphologies of peripheral nerve sheath tumors are required. KEY POINTS: Individuals with NF1 may develop benign and malignant nerve sheath tumors. Whole-body MRI is the reference standard to identify nerve sheath tumors in NF1. MRI provides a comprehensive characterization of the growth pattern, growth dynamics and extent of nerve sheath tumors. (18)F-FDG PET/CT provides a sensitivity of 100% and a specificity of 77-95% for detection of malignant transformation.

Cardiac characterization of 16 patients with large NF1 gene deletions.

The aim of this study was to characterize cardiac features of patients with neurofibromatosis 1 (NF1) and large deletions of the NF1 gene region. The study participants were 16 patients with large NF1 deletions and 16 age- and sex-matched NF1 patients without such deletions. All the patients were comprehensively characterized clinically and by echocardiography. Six of 16 NF1 deletion patients but none of 16 non-deletion NF1 patients have major cardiac abnormalities (p = 0.041). Congenital heart defects (CHDs) include mitral insufficiency in two patients and ventricular septal defect, aortic stenosis, and aortic insufficiency in one patient each. Three deletion patients have hypertrophic cardiomyopathy. Two patients have intracardiac tumors. NF1 patients without large deletions have increased left ventricular (LV) diastolic posterior wall thickness (p < 0.001) and increased intraventricular diastolic septal thickness (p = 0.001) compared with a healthy reference population without NF1, suggestive of eccentric LV hypertrophy. CHDs and other cardiovascular anomalies are more frequent among patients with large NF1 deletion and may cause serious clinical complications. Eccentric LV hypertrophy may occur in NF1 patients without whole gene deletions, but the clinical significance of this finding is uncertain. All patients with clinical suspicion for NF1 should be referred to a cardiologist for evaluation and surveillance.

Accumulation of non-compressive fascicular lesions underlies NF2 polyneuropathy.

A distinct polyneuropathy (PNP) syndrome affects up to 66 % of patients with neurofibromatosis II (NF2). Whether this is primarily a diffuse PNP or due to single, surgically amenable mass lesions has not yet been conclusively demonstrated. We aimed to solve this question by investigating the pathomorphological MR imaging correlate of this rare disorder. Eight patients with NF2-PNP were characterized by clinical examination, electrophysiological studies, and genetic analysis. All patients additionally underwent extended peripheral nerve imaging by a novel protocol of large-coverage high-resolution MRI. Quantitative analyses were performed by separately evaluating cross-sectional images, and by categorizing lesions into non-compressive fascicular microlesions (<2 mm), intermediate lesions (2-5 mm), and compressive macrolesions (>5 mm). The predominant imaging findings were non-compressive fascicular microlesions and intermediate lesions. Proximal-to-distal cumulative lesion burden of these lesions correlated strongly with the severity of clinical symptoms of NF2-PNP. In contrast, compressive macrolesions were not found at all in several symptomatic extremities. We conclude that proximal-to-distal accumulation of non-compressive fascicular lesions instead of compressive mass lesions predominantly underlies the clinical manifestation and severity of NF2-associated PNP. Diagnostic management may now be assisted by large-coverage high-resolution imaging of plexus and peripheral nerves. Additionally, the results underscore the feasibility of this new method, which may open up new diagnostic and investigative possibilities for other disseminated disorders of the peripheral nervous system.

Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions.

BACKGROUND: Large deletions of the NF1 gene region occur in approximately 5% of patients with neurofibromatosis type-1 (NF1) and are associated with particularly severe manifestations of the disease. However, until now, the genotype-phenotype relationship has not been comprehensively studied in patients harbouring large NF1 gene deletions of comparable extent (giving rise to haploinsufficiency of the same genes). METHOD: We have performed the most comprehensive clinical/neuropsychological characterisation so far undertaken in NF1 deletion patients, involving 29 patients with precisely determined type-1 NF1 (1.4 Mb) deletions. RESULTS: Novel clinical features found to be associated with type-1 NF1 deletions included pes cavus (17% of patients), bone cysts (50%), attention deficit (73%), muscular hypotonia (45%) and speech difficulties (48%). Type-1 NF1 deletions were found to be disproportionately associated with facial dysmorphic features (90% of patients), tall stature (46%), large hands and feet (46%), scoliosis (43%), joint hyperflexibility (72%), delayed cognitive development and/or learning disabilities (93%) and mental retardation (IQ<70; 38%), as compared with the general NF1 patient population. Significantly increased frequencies (relative to the general NF1 population) of plexiform neurofibromas (76%), subcutaneous neurofibromas (76%), spinal neurofibromas (64%) and MPNSTs (21%) were also noted in the type-1 deletion patients. Further, 50% of the adult patients exhibited a very high burden of cutaneous neurofibromas (N>or=1000). CONCLUSION: These findings emphasise the importance of deletion analysis in NF1 since frequent monitoring of tumour presence and growth could potentiate early surgical intervention thereby improving patient survival.

High bone turnover and accumulation of osteoid in patients with neurofibromatosis 1.

UNLABELLED: Although it is known that neurofibromatosis 1 (NF1) patients suffer from vitamin D deficiency and display decreased bone mineral density (BMD), a systematic clinical and histomorphometrical analysis is absent. Our data demonstrate that NF1 patients display high bone turnover and accumulation of osteoid and that supplementation of vitamin D has a beneficial effect on their BMD. INTRODUCTION: Neurofibromatosis 1 results in a wide range of clinical manifestations, including decreased BMD. Although it has been reported that NF1 patients have decreased vitamin D serum levels, the manifestation of the disease at the bone tissue level has rarely been analyzed. METHODS: Thus, we performed a clinical evaluation of 14 NF1 patients in comparison to age- and sex-matched control individuals. The analysis included dual X-ray absorptiometry osteodensitometry, laboratory parameters, histomorphometric and quantitative backscattered electron imaging (qBEI) analyses of undecalcified bone biopsies. RESULTS: NF1 patients display significantly lower 25-(OH)-cholecalciferol serum levels and decreased BMD compared to control individuals. Histomorphometric analysis did not only reveal a reduced trabecular bone volume in biopsies from NF1 patients, but also a significantly increased osteoid volume and increased numbers of osteoblasts and osteoclasts. Moreover, qBEI analysis revealed a significant decrease of the calcium content in biopsies from NF1 patients. To address the question whether a normalization of calcium homeostasis improves BMD in NF1 patients, we treated four patients with cholecalciferol for 1 year, which resulted in a significant increase of BMD. CONCLUSION: Taken together, our data provide the first complete histomorphometric analysis from NF1 patients. Moreover, they suggest that low vitamin D levels significantly contribute to the skeletal defects associated with the disease.

Bone health and fracture rate in individuals with neurofibromatosis 1 (NF1).

BACKGROUND: Patients with neurofibromatosis 1 (NF1) are shorter than expected and often have low bone mineral density (BMD), but the pathogenesis of these bony problems is poorly understood. METHODS: We performed an exploratory study of BMD, 18 laboratory measures of bone metabolism, and fracture history in 72 adult NF1 patients. RESULTS: Eight of the 18 clinical biochemical measures of bone health had at least 10% of NF1 patients outside the standard reference range. Serum 25-hydroxy-vitamin D concentrations were low in 56% of the NF1 patients, serum parathyroid hormone (PTH) concentrations were high in 34%, and urine deoxypyridinoline cross-link concentrations were high in 50%. Mean serum 25-hydroxy-vitamin D concentrations were significantly lower in people with NF1 than in season matched controls in both summer (p = 0.008) and winter (p<0.001). 36 (50%) of the 72 people with NF1 studied had BMD consistent with osteopenia, and 14 (19%) had BMD consistent with osteoporosis. High serum PTH concentration, high serum bone tartrate resistant acid phosphatase concentration, and high serum calcium concentration were associated with lower BMD among the NF1 patients. Males were more likely than females to have low BMD. The reported frequency of fractures in individuals with NF1 was much higher than in their unaffected siblings and spouses (p<0.001), and pathological fractures were reported only in NF1 patients. CONCLUSION: People with NF1 often have a generalised abnormality of bone metabolism. Further studies are needed to determine the biochemical and molecular basis of this abnormality.

Longitudinal study of neurofibromatosis 1 associated plexiform neurofibromas.

BACKGROUND: Plexiform neurofibromas are benign tumours that occur in more than half of people with neurofibromatosis 1 (NF1). These tumours can cause serious complications and can also progress to malignant peripheral nerve sheath tumours (MPNSTs), one of the leading causes of death among NF1 patients. Plexiform neurofibromas are clinically heterogeneous, and knowledge of their natural history is limited. In order to characterise the growth of plexiform neurofibromas better, we performed serial magnetic resonance imaging (MRI) in NF1 patients with such tumours. METHODS: MRI was done on 44 plexiform neurofibromas in 34 NF1 patients (median age 10 years; range 1-47 years). Each tumour was measured in two dimensions from the MRI scan, and the area and growth rate were calculated. The median length of follow-up was 6 years, with an average interval of 3 years between scans. RESULTS: 36 tumours remained stable in size throughout the period of follow-up. 8 tumours increased in size; all occurred in patients who were under 21 years of age when first studied. The single exception was a man who developed rapid tumour growth and pain in a plexiform neurofibroma that had been followed for 10 years. Biopsy showed the presence of an MPNST. CONCLUSION: Longitudinal MRI is a valuable means of monitoring the growth of plexiform neurofibromas in individuals with NF1.

Clinical relevance of positron emission tomography and magnetic resonance imaging in the progression of internal plexiform neurofibroma in NF1.

Neurofibromatosis type 1 (NF1) is a frequent and inherited disease with a predisposition for malignant peripheral nerve sheath tumor (MPNST) development. MPNST are soft tissue sarcomas that arise from peripheral nerves, being one of the most aggressive malignancies in humans with extremely poor prognosis. MPNST frequently arise from a previously undetected plexiform neurofibroma (PNF). The malignant transformation of an internal PNF to an MPNST is difficult to assess and requires advanced imaging techniques like magnetic resonance imaging or positron emission tomography. Despite the high quality of current diagnostics, the changing tumor biology inside a plexiform neurofibroma cannot currently be visualized accurately. We report 4 cases of NF1 patients with PNF who showed imaging findings suspicious for malignant degeneration, but proved to have MPNST in only one case. Three tumors might represent an intermediate type between PNF and MPNST. Ablative surgery and complete histological work-up of specimens is the only way to clarify tumor status, thereby enabling provision of adequate local treatment.

Malignant peripheral nerve sheath tumors (MPNST) in NF1-affected children.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) constitute a heterogeneous group of malignant tumors that probably arise from cells of the peripheral nerve sheath. Association of MPNST with neurofibromatosis type 1 (NF1) is frequently reported. MPNST contribute significantly to the reduced life-span of NF1-patients. At present there are only sparse data on MPNST in NF1-children. The aim of this study was to determine the outcome of children affected with NF1 who developed an MPNST. MATERIALS AND METHODS: Over the period of 1985 to 2005, we followed 52 NF1 patients with MPNST at our outpatient department. All patients were diagnosed and re-evaluated according to the updated NIH diagnostic criteria for NF1. RESULTS: Out of this cohort, 8 patients with MPNST were aged 1 to 17 years at the time of MPNST diagnosis (mean age: 12 years; 5 girls and 3 boys). We noticed the following characteristics: MPNST arose from plexiform neurofibromas (PNF) with invasive or displacing growth pattern on MRI. Many patients reported pain and neurological deficits at the time of presentation. Diagnosis of MPNST in this age group took longer compared to adults. This cohort did not show longer survival periods than adults with MPNST. Adjunctive treatment with chemotherapy or radiation had no lasting effect. The overall survival time of this small cohort was 30.5 months. Those children who died showed a median survival time after diagnosis of 20 months. The longest survival of 112 months was achieved for a girl who presented with MPNST of the distal upper arm and underwent amputation. The NF1 mutation analysis in the MPNST pediatric age group revealed the same mutational spectrum as the adult group. CONCLUSION: Our data reveal MPNST in children with NF1. Children cannot verbalize physical alterations adequately; therefore the correct diagnosis might be hampered in these patients. Unresolved complaints of children with NF1 should be investigated thoroughly due to the risk for malignancy in NF1.

Vitamin D deficiency associated with number of neurofibromas in neurofibromatosis 1.

Neurofibromatosis 1 (NF1) is a tumour suppressor gene syndrome characterized by multiple cutaneous and plexiform neurofibromas. Focal osseous abnormalities, short stature, and decreased bone mineral density are also frequent in people with NF1. We measured serum 25-hydroxyvitamin D concentrations in 55 patients with NF1 and 58 healthy controls, and correlated the findings in the patients with NF1 with their estimated number of dermal neurofibromas. Geometric mean (SD) serum 25-hydroxyvitamin D concentration was 14.0 (1.6) ng/mL among the patients with NF1 compared with 31.4 (1.7) ng/mL among healthy controls (p<<0.0001). The serum vitamin D concentration and number of dermal neurofibromas reported by patients with NF1 were inversely correlated (Spearman's rho = -0.572, p<0.00001). The occurrence of low serum vitamin D concentrations in people with NF1, especially those with many dermal neurofibromas, may provide new pathogenic insights and have important therapeutic implications.

MRI growth patterns of plexiform neurofibromas in patients with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an incidence of 1:3000. Approximately 30% of NF1 patients develop plexiform neurofibromas (PNF) which often cause severe clinical deficits. We studied the growth patterns of 256 plexiform neurofibromas (PNF) by magnetic resonance imaging (MRI) and associated disfigurement and functional deficits to determine whether there are definable growth types of these tumors. Retrospectively, we evaluated MRI scans obtained during 1997 to 2003 of 256 plexiform neurofibromas from 202 patients with NF1. Clinical investigation was carried out at the same time as the MRI scans. We identified three growth patterns: superficial in 59, displacing in 76, and invasive growth in 121 tumors. The majority (52%) of invasive PNF were found in the face, head and neck area. While superficial PNF primarily caused aesthetic problems, displacing PNF led in most cases to aesthetic problems and pain, while invasive PNF led mainly to functional deficits and disfigurement. Our study demonstrates that PNF have different growth patterns that are associated with specific clinical features. Classification of PNF may open new opportunities in clinical management, especially regarding decisions and options associated with surgical intervention.

Malignant peripheral nerve sheath tumors (MPNST) in neurofibromatosis type 1 (NF1): diagnostic findings on magnetic resonance images and mutation analysis of the NF1 gene.

UNLABELLED: Plexiform neurofibroma (PNF) is a typical feature of neurofibromatosis 1 (NF1). About 10% of patients with NF1 develop malignant peripheral nerve sheath tumors (MPNST), usually arising from PNF, and this is the major cause of poor prognosis. A better prognosis can be achieved if the tumors are diagnosed at an early stage. Our objective was to establish magnetic resonance imaging (MRI) criteria for MPNST, and to test their usefulness in detecting early malignant changes in PNF and to correlate the findings with the mutations of the NF1 gene. PATIENTS AND METHODS: NF1 outpatients were diagnosed according to the NIH criteria. All patients underwent a complete dermatological, ophthalmological and neurological examination and ultrasound of the abdomen between 1997 and 2002. The study was approved by the Institutional Review Board and all patients gave informed consent to analyze clinical records and tumor material for scientific purposes. MRI was performed with devices at 1.5 Tesla field strength (Siemens Magnetom Symphony) or in some patients at 1.0 Tesla field strength (Siemens Impact Expert). T1- and T2-weighted sequences including STIR-sequences were acquired. Ultra-rapid image sequences with HASTE technique were performed for trunk imaging. In patients with no contraindication for the application of contrast media, Gadolinum-DTPA Magnevist was administered intravenously. RESULTS: MRI was performed on 50 patients with NF1 and nerve sheath tumors, of whom 7 had atypical pain, tumor growth or neurological deficits indicative of malignancy; the other 43 were asymptomatic. On MRI, all 7 symptomatic patients had inhomogeneous lesions, due to necrosis and hemorrhage and patchy contrast enhancement. In one patient, the multiplicity of confluent tumors with inhomogeneous areas in addition to central lesions did not allow the exclusion of malignancy. Only 3 of the 43 asymptomatic patients had comparable changes; the other 40 patients had tumors of relatively homogeneous structure on T1- and T2-weighted images before and after contrast enhancement. All 3 asymptomatic patients with inhomogeneous lesions were shown to have MPNST. Analysis of mutations of the NF1 gene of the 10 MPNST patients revealed a variety of mutations. Concerning the correlation of genetic findings and MPNST in NF1, the sample size of this study group was too small to define genotype-phenotype relations. In this cohort, all types of mutations were found. CONCLUSION: This study provides evidence for certain radiographic findings on MRI in PNF of NF1 patients that have to be considered as signs of malignancy, in particular indicating an MPNST. These findings are especially valuable in the long term follow-up control of patients with large tumors (plexiform neurofibromas).