Scott A. Rutherford

A comparison of Ktrans measurements obtained with conventional and first pass pharmacokinetic models in human gliomas

To compare in a group of patients with cerebral gliomas the estimates of Ktrans between a conventionally established pharmacokinetic model and a recently developed first pass method.

Rates of loss of heterozygosity and mitotic recombination in NF2 schwannomas, sporadic vestibular schwannomas and schwannomatosis schwannomas

Biallelic inactivation of the NF2 gene occurs in the majority of schwannomas. This usually involves a combination of a point mutation or multiexon deletion, in conjunction with either a second point mutation or loss of heterozygosity (LOH). We have performed DNA sequence and dosage analysis of the NF2 gene in a panel of 239 schwannoma tumours: 97 neurofibromatosis type 2 (NF2)-related schwannomas, 104 sporadic vestibular schwannomas (VS) and 38 schwannomatosis-related schwannomas. In total, we identified germline NF2 mutations in 86 out of 97 (89%) NF2 patients and a second mutational event in 77 out of 97 (79%). LOH was by far the most common form of second hit. A combination of microsatellite analysis with either conventional comparative genomic hybridization (CGH) or multiplex ligation-dependent probe amplification (MLPA) identified mitotic recombination (MR) as the cause of LOH in 14 out of 72 (19%) total evaluable tumours. Among sporadic VS, at least one NF2 mutation was identified by sequence analysis or MLPA in 65 out of 98 (66%) tumours. LOH occurred in 54 out of 96 (56%) evaluable tumours, but MR only accounted for 5 out of 77 (6%) tested. LOH was present in 28 out of 34 (82%) schwannomatosis-related schwannomas. In all eight patients who had previously tested positive for a germline SMARCB1 mutation, this involved loss of the whole, or part of the long arm, of chromosome 22. In contrast, 5 out of 22 (23%) tumours from patients with no germline SMARCB1 mutation exhibited MR. High-resolution Affymetrix SNP6 genotyping and copy number (CN) analysis (Affymetrix, Santa Clara, CA, USA) were used to determine the chromosomal breakpoint locations in tumours with MR. A range of unique recombination sites, spanning approximately 11.4u2009Mb, were identified. This study shows that MR is a mechanism of LOH in NF2 and SMARCB1-negative schwannomatosis-related schwannomas, occurring less frequently in sporadic VS. We found no evidence of MR in SMARCB1-positive schwannomatosis, suggesting that susceptibility to MR varies according to the disease context.

Cranial meningiomas in 411 neurofibromatosis type 2 (NF2) patients with proven gene mutations: clear positional effect of mutations, but absence of female severity effect on age at onset

Background Meningiomas have been reported to occur in approximately 50% of neurofibromatosis type 2 (NF2) patients. The NF2 gene is commonly biallelically inactivated in both schwannomas and meningiomas. The spectrum of NF2 mutations consists mainly of truncating (nonsense and frameshift) mutations. A smaller number of patients have missense mutations, which are associated with a milder disease phenotype. Methods This study analysed the cumulative incidence and gender effects as well as the genotype–phenotype correlation between the position of the NF2 mutation and the occurrence of cranial meningiomas in a cohort of 411 NF2 patients with proven NF2 mutations. Results and conclusion Patients with mutations in exon 14 or 15 were least likely to develop meningiomas. Cumulative risk of cranial meningioma to age 50u2005years was 70% for exons 1–3, 81% for exons 4–6, 49% for exons 7–9, 56% for exons 10–13, and 28% for exons 14–15. In the cohort of 411 patients, no overall gender bias was found for occurrence of meningioma in NF2 disease. Cumulative incidence of meningioma was close to 80% by 70u2005years of age for both males and females, but incidence by age 20u2005years was slightly increased in males (male 25%, female 18%; p=0.023). Conversely, an increased risk of meningiomas in women with mosaic NF2 disease was also found.

The Surgical Management and Outcomes for Spheno-orbital Meningiomas: A 7-year Review of Multi-disciplinary Practice

Aims/Purpose: Spheno-orbital meningiomas account for 9% of all adult intracranial meningiomas. Complete resection is extremely difficult with this condition. We report on our experience in the surgical management of spheno-orbital meningiomas. Methods: A retrospective review was performed of all patients with spheno-orbital meningiomas who underwent joint neurosurgical and ophthalmic procedures between January 2000 and December 2007. Radiological findings, presenting clinical signs, indications for surgery, surgical approach, histopathological findings, surgical complications and post-operative results were recorded. Results: Twelve patients were included in the study. Visual function deterioration was the main indication for surgery. Six patients underwent an optic canal decompression along with their initial tumour resection and all 12 patients underwent an extensive lateral orbital wall decompression. Post-operatively 6 patients had reduced proptosis. Two patients had an improvement in their visual acuity, 5 patients had a stable visual acuity and 5 patients had a progressive deterioration in visual acuity following surgery. Six patients maintained a stable visual field. Cranial nerve palsy was the commonest post-operative complication. Three patients required postoperative fractionated radiotherapy. Three patients required further surgery. Conclusion: Spheno-orbital meningiomas are difficult tumours to manage. Surgical resection can reduce the degree of proptosis and stabilise visual function in patients with failing vision, although sustained improvement is difficult to achieve if the tumour behaves in an aggressive manner. The risk of post-operative visual loss is considerable, either due to surgery or tumour progression. Outcomes from surgical decompression may not necessarily be better than the natural history of these tumours.

Geniculate neuralgia: a systematic review

OBJECTIVEnTo systematically summarise the peer-reviewed literature relating to the aetiology, clinical presentation, investigation and treatment of geniculate neuralgia.nnnDATA SOURCESnArticles published in English between 1932 and 2012, identified using Medline, Embase and Cochrane databases.nnnMETHODSnThe search terms geniculate neuralgia, nervus intermedius neuralgia, facial pain, otalgia and neuralgia were used to identify relevant papers.nnnRESULTSnFewer than 150 reported cases were published in English between 1932 and 2012. The aetiology of the condition remains unknown, and clinical presentation varies. Non-neuralgic causes of otalgia should always be excluded by a thorough clinical examination, audiological assessment and radiological investigations before making a diagnosis of geniculate neuralgia. Conservative medical treatment is always the first-line therapy. Surgical treatment should be offered if medical treatment fails. The two commonest surgical options are transection of the nervus intermedius, and microvascular decompression of the nerve at the nerve root entry zone of the brainstem. However, extracranial intratemporal division of the cutaneous branches of the facial nerve may offer a safer and similarly effective treatment.nnnCONCLUSIONnThe response to medical treatment for this condition varies between individuals. The long-term outcomes of surgery remain unknown because of limited data.

Multiple synchronous sites of origin of vestibular schwannomas in neurofibromatosis Type 2.

Background Neurofibromatosis Type 2 (NF2) is a dominantly inherited tumour syndrome with a phenotype which includes bilateral vestibular (eighth cranial nerve) schwannomas. Conventional thinking suggests that these tumours originate at a single point along the superior division of the eighth nerve. Methods High resolution MRI was performed in children genetically proven to have NF2. The superior vestibular nerve (SVN) and inferior vestibular nerve (IVN) were visualised along their course with points of tumour origin calculated as a percentage relative to the length of the nerve. Results Out of 41 patients assessed, 7 patients had no identifiable eighth cranial nerve disease. In 16 patients there was complete filling of the internal auditory meatus by a tumour mass such that its specific neural origin could not be determined. In the remaining 18 cases, 86 discrete separate foci of tumour origin on the SVN or IVN could be identified including 23 tumours on the right SVN, 26 tumours on the right IVN, 18 tumours on the left SVN and 19 tumours on the left IVN. Discussion This study, examining the origins of vestibular schwannomas in NF2, refutes their origin as being from a single site on the transition zone of the superior division of the vestibular nerve. We hypothesise a relationship between the number of tumour foci, tumour biology and aggressiveness of disease. The development of targeted drug therapies in addition to bevacizumab are therefore essential to improve prognosis and quality of life in patients with NF2 given the shortcomings of surgery and radiation treatments when dealing with the multifocality of the disease.

Outcome from surgery for vestibular schwannomas in children.

Object. A review of sporadic and NF2-related vestibular schwannoma surgery in children (under 18 years of age) with a specific interest in resection rates, recurrence, facial nerve outcomes, hearing preservation, hearing rehabilitation and genetic analysis. Methods. A retrospective analysis of prospectively collected data of 35 consecutively operated vestibular schwannomas in 29 paediatric patients that underwent 38 operations between 1992 and 2007. Pre- and post-operative radiology, facial nerve function, pure tone audiogram and speech discrimination tests were performed with a mean follow-up of 4.5 years. Tumour and blood mutations were analysed in 86% of patients. Results. Total resection was achieved in all sporadic cases and 68% of NF2 cases. Near total resection led to tumour recurrence in 5 out of 10 cases. The facial nerve was anatomically preserved in 92%. Facial nerve function was excellent to good (Grades 1–3) in 88% with outcome related to tumour size. Hearing preservation was successful in 3 of 11 cases. Conclusions. Surgery with complete resection results in excellent tumour control, but it is more difficult to attain total resection in NF2 with a relatively high recurrence rate of persistently growing tumours. A better facial outcome is associated with smaller tumours, near-total resection and first time surgery. Hearing preservation is possible in a minority. Hearing rehabilitation can be successful by utilising cochlear implants and auditory brain stem implants (ABI) as appropriate. Overall there is a low complication rate and results are comparable with adult series.

Pediatric intracranial clear cell meningioma associated with a germline mutation of SMARCE1: a novel case.

PurposeIntracranial clear cell meningioma (CCM) represents a rare and potentially more aggressive subgroup of meningioma that is observed more frequently in children and adolescents. Despite its characterization as a histological entity, there is little evidence identifying tumorigenic etiologies. Recently, a novel mutation in SMARCE1, encoding a subunit of the SWI/SNF chromatin remodeling complex, was identified in a cohort of spinal CCMs. To date, no intracranial CCM has been subjected to analysis.MethodsWe report the case of an isolated intracranial CCM in a 14-year-old girl. Gross total resection was achieved following a two-stage approach with no evidence of tumor recurrence 8xa0months following presentation.ResultsExon sequencing identified a germline mutation in SMARCE1, which was also present in tumor DNA. Extensive literature review confirmed our study is the first to seek and report a genetic anomaly for childhood intracranial CCMs outside of the NF2 gene locus, and the first to make an association between a germline SMARCE1 mutation and childhood intracranial CCMs.ConclusionsTogether with the previous description of SMARCE1 mutations in spinal CCMs, our report suggests that SMARCE1 aberrations may be implicated in establishing a clear cell histology irrespective of meningioma location. We would advocate that, where feasible, genetic sequencing is performed on future new cases of childhood neuraxial CCMs and includes interrogation of the SMARCE1 gene.

The management of cochlear nerve deficiency

Abstract The assessment process is critical in deciding whether a profoundly deaf child with cochlear nerve deficiency (CND) will be suitable for a cochlear or auditory brainstem implant (ABI). Magnetic resonance imaging (MRI) using submillimetric T2 weighted gradient echo or turbo spin echo sequences is mandatory for all profoundly deaf children to diagnose CND. Evidence of audition on behavioural or electrophysiological tests following both auditory and electrical stimulation sometimes allows identification of significant auditory tissue not visible on MRI. In particular electric auditory brainstem response (EABR) testing may allow some quantification of auditory tissue and help decide whether a cochlear implant will be beneficial. Age and cognitive development are the most critical factors in determining ABI benefit. Hearing outcomes from both cochlear implants and ABIs are variable and likely to be limited in children with CND. A proportion of children will get no benefit. Usually the implants would be expected to provide recognition of environmental sounds and understanding of simple phonetics. Most children will not develop normal speech and they will often need to learn to communicate with sign language. The ABI involves a major neurosurgical procedure and at present the long term outcomes are unknown. It is therefore essential that parents who are considering this intervention have plenty of time to consider all aspects and the opportunity for in depth discussion.

Rare giant frontal sinus osteoma mimicking fibrous dysplasia.

OBJECTIVEnTo present the first report of a giant frontal sinus osteoma treated by excision and single-stage reconstruction with custom-made titanium cranioplasty and left orbital roof prostheses.nnnCASE REPORTnA 31-year-old man with a history of chronic frontal sinusitis presented with a deforming, painless, midline forehead swelling of 11 years duration, which had been treated unsuccessfully in Nigeria. Differential diagnosis included both benign and malignant bony tumours. Computerised tomography revealed a giant bony frontal sinus tumour extending beyond the sinus roof and breaching the left orbit, consistent with fibrous dysplasia. Given the extent of the tumour, open craniectomy was performed for surgical extirpation. Histological analysis identified multiple osteomas. This surgical approach achieved excellent cosmesis, with no evidence of recurrence at 12-month follow up.nnnCONCLUSIONnForehead swelling may pose diagnostic and management dilemmas for the ENT surgeon; however, effective management is facilitated by a multidisciplinary approach.