From Pediatric to Adult Brain Cancer: Exploring Histone H3 Mutations in Australian Brain Cancer Patients.

Genetic histone variants have been implicated in cancer development and progression. Mutations affecting the histone 3 (H3) family, H3.1 (encoded by HIST1H3B and HIST1H3C) and H3.3 (encoded by H3F3A), are mainly associated with pediatric brain cancers. While considered poor prognostic brain cancer biomarkers in children, more recent studies have reported H3 alterations in adult brain cancer as well. Here, we established reliable droplet digital PCR based assays to detect three histone mutations (H3.3-K27M, H3.3-G34R, and H3.1-K27M) primarily linked to childhood brain cancer. We demonstrate the utility of our assays for sensitively detecting these mutations in cell-free DNA released from cultured diffuse intrinsic pontine glioma (DIPG) cells and in the cerebral spinal fluid of a pediatric patient with DIPG. We further screened tumor tissue DNA from 89 adult patients with glioma and 1 with diffuse hemispheric glioma from Southwestern Sydney, Australia, an ethnically diverse region, for these three mutations. No histone mutations were detected in adult glioma tissue, while H3.3-G34R presence was confirmed in the diffuse hemispheric glioma patient.

Somatostatin receptor expression and clinical outcome of multilineage pituitary tumours expressing PIT1 and SF1.

The application of transcription factor immunohistochemistry to pituitary neuroendocrine tumour (PitNET) assessment has allowed identification of tumours that do not conform to a single lineage. Multilineage pituitary transcription factor 1 (PIT1) and steroidogenic factor 1 (SF1) PitNETs are a rare and relatively newly described tumour subtype. These tumours express both transcription factors and may also express combinations of hormones corresponding to both lineages. Histological and clinical characteristics can vary, and overall clinical behaviour and prognosis is not known. We describe the clinical outcomes and somatostatin receptor status (SSTR) of a series of nine cases identified from our cohort of pituitary tumours at Westmead Hospital. Eight PitNETs (88.9%) expressed growth hormone and caused acromegaly at presentation. Of the seven macrotumours that caused acromegaly, one had cavernous sinus invasion. The Ki-67 labeling index score ranged from 0.6% to 3.6%. About 88% of tumours that secreted excess growth hormone exhibited strong immunostaining for SSTR 2 and all tumours displayed weak immunoreactivity for SSTR5. In 62.5% of patients with acromegaly, cure was achieved after surgical resection. Somatostatin receptor ligands resulted in clinical remission in cases where medical treatment was initiated. There was no new tumour recurrence or regrowth over an overall mean follow-up period of 62.5 months.

Successful stereoelectroencephalography re-evaluation in epilepsy patients after failed initial subdural grid evaluation.

OBJECTIVE: Epilepsy surgery success is dependent on accurate localization of the epileptogenic zone. Despite the use of invasive EEG using subdural grids and strips, surgical failures can occur. In this series, we explore the utility of a second evaluation with stereoelectroencephalography in patients whose initial invasive evaluation with subdural grid electrodes was unsuccessful in localizing seizure origin. METHODS: We conducted a retrospective review of patients who underwent subdural grid evaluation (SDE) at our center and identified patients who underwent a re-evaluation with stereoelectroencephalography (SEEG). RESULTS: We identified three patients who had both subdural and SEEG electrodes in the region of the identified epileptogenic zone in whom the initial SDE evaluation failed to make the patients seizure-free. Two of these patients underwent a second resection and became seizure-free. SIGNIFICANCE: Stereoelectroencephalography can be useful in the re-evaluation and re-operation of patients who previously had surgical failure using SDE.

Endovascular and microsurgical management of blister aneurysms: a multi-centre review.

Blister aneurysms (BA) are high-risk cerebrovascular lesions accounting for 1% of intracranial aneurysms. The defective vessel wall and broad-based neck make this clinical entity difficult to treat, with high rates of re-rupture and mortality in patients presenting with acute subarachnoid haemorrhage. Blister aneurysms pose substantial challenges for both endovascular and microsurgical management. The objective of this study is to evaluate endovascular and microsurgical outcomes in intracranial blister aneurysm management across two tertiary hospitals. A review of two tertiary hospitals with a systematic imaging database search for term of "blister" in modalities from January 2010 to October 2022 was conducted. Operation reports were screened for the 5-year period since cerebral angiogram reports transitioned to surgical database. Identified reports were screened and reviewed for confirmed diagnosis by consultant neuroradiologist. A total of 21 cases of blister aneurysms managed at respective facilities were included. Sixteen cases (76%) were managed endovascularly. Four cases (19%) were managed surgically-2 with primary clipping, and 2 wrap and clipping. One case was managed conservatively (5%). Clinical outcomes were discharge disposition, aneurysm exclusion and post-operative complications. BAs have challenging considerations with high mortality and morbidity. Endovascular treatment offers a less invasive modality with lower rates of intraoperative rupture and morbidity. Mortality rates and patients discharged home were comparable. Commencement of dual anti-platelet therapy was safe in patients with flow diversion stents despite sub-arachnoid blood volume. Management of blister aneurysms is complex. Endovascular treatment shows promise for acute management but careful collaborative consideration of antithrombotic regime and requirement for further surgery should be considered.

Aneurysmal Bone Cyst of the Orbit With USP6 Gene Rearrangement.

PURPOSE: Aneurysmal bone cyst (ABC) of the orbit is a very rare tumor, occurring mostly in the pediatric population, and can result in sight threatening complications and disfigurement. This review discusses previously reported cases with a focus on evolving treatment options and molecular genetics. METHODS: We report the youngest case of an orbital ABC with a confirmed gene fusion: a 17-month-old girl, with confirmed FGFR-UPS6 (Fibroblast Growth Factor Receptor 1-ubiquitin specific peptidase 6/tre-2). A literature search for relevant publications on the topic was performed via Medline and PubMed, with the appropriate data extracted. RESULTS: Thirty-two cases of orbital aneurysmal bone cyst were identified in the literature. Presentations are varied and can include pain, proptosis, decreased vision, and extraocular motility disturbance. Typical imaging and histopathology findings are discussed, in particular the usefulness of identifying USP6 gene arrangements. Treatment modalities are reviewed including surgery, embolization, and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors. Recurrences can occur, usually within 2 years. CONCLUSIONS: Orbital ABC is a neoplasm that presents unique diagnostic and treatment challenges. Gene rearrangements can confirm primary ABC and rule out other underlying pathology. Disfigurement and sight threatening complications can occur due to both the disease process and with treatment. Outcomes may be improved with the use of systemic therapy.

Predictors of longitudinal seizure outcomes after epilepsy surgery in childhood.

There is a paucity of data on longitudinal seizure outcome of children undergoing epilepsy surgery. All children (n = 132) who underwent resective epilepsy surgery from January 1998 to December 2015 were identified. Relevant clinical, neurophysiological, imaging, surgical and seizure outcome data were extracted. Multivariable logistic regression analysis and Kaplan-Meier survival with Cox proportional hazard modelling were performed. The mean age at surgery was 7.8 years (range 0.2-17.9). 71% were seizure-free at a mean follow up of 5.3 ± 2.7 years. Of those who were seizure-free, 65 patients were able to completely wean off anti- seizure medications successfully. Using survival analysis, the probability of Engel Class I outcome at one year after surgery was 81% (95% confidence interval [CI] 87%-75%). This dropped to 73% at two years (95% CI 81%-65%), 58% at five years (95% CI 67.8%-48%), and 47% at ten years. Proportional hazard modelling showed that the presence of moderate to severe developmental disability (HR 6.5; p = 0.02) and lack of complete resection (HR 0.4; p = 0.02) maintain association as negative predictors of seizure-free outcome. Our study demonstrates favorable long-term seizure control following pediatric epilepsy surgery and highlights important predictors of seizure outcome guiding case selection and counseling of expectations prior to surgery.

Investigating the Precise Localization of the Grasping Action in the Mid-Cingulate Cortex and Future Directions.

Objective: To prospectively study the cingulate cortex for the localization and role of the grasping action in humans during electrical stimulation of depth electrodes. Methods: All the patients (n = 23) with intractable focal epilepsy and a depth electrode stereotactically placed in the cingulate cortex, as part of their pre-surgical epilepsy evaluation from 2015 to 2017, were included. Cortical stimulation was performed and examined for grasping actions. Post-implantation volumetric T1 MRIs were co-registered to determine the exact electrode position. Results: Five patients (male: female 4:1; median age 31) exhibited contralateral grasping actions during electrical stimulation. All patients had electrodes implanted in the ventral bank of the right cingulate sulcus adjacent to the vertical anterior commissure (VAC) line. Stimulation of other electrodes in adjacent regions did not elicit grasping. Conclusion: Grasping action elicited from a localized region in the mid-cingulate cortex (MCC) directly supports the concept of the cingulate cortex being crucially involved in the grasping network. This opens an opportunity to explore this region with deep brain stimulation as a motor neuromodulation target for treatment in specific movement disorders or neurorehabilitation.

Localisation and stimulation of the parietal eye field.

Localisation of the human parietal eye fields (PEF) has not been as well studied as the human frontal eye fields (FEF). Stimulation studies in rhesus monkeys have suggested the localisation of the PEF to be within the intraparietal sulcus. Functional MRI studies have demonstrated this region to be highly active and potentially connected in saccadic and gaze shifting tasks. Here, we present a case of a patient with left versive seizures evaluated with SEEG, in whom electrical stimulation within the right intraparietal sulcus resulted in horizontal and downward conjugate eye movements contralateral to stimulation. We illustrate clinical differences between the FEF and PEF on cortical stimulation. In addition to the frontal eye field, it is important to recognise other cortical regions involved in eye movement which can cause conjugate contralateral eye movement.

FISH analysis of brain smears obtained at intraoperative diagnosis - An accurate and fast method to detect 1p/19q-codeletion in gliomas.

The importance of molecular testing of gliomas is highlighted in the 2016 revised 4th edition of the WHO Classification of Tumours of the Central Nervous System, which applies an integrated diagnosis of histological and molecular features. In this classification system, oligodendrogliomas (ODG) are defined as IDH-mutant and 1p/19q-codeleted. Fluorescence in situ hybridization (FISH) analysis of formalin-fixed paraffin-embedded (FFPE) tissue is a standard method of determining 1p/19q-codeletion. However, it has several disadvantages, including requiring lengthy pretreatment, truncation artefact and lack of on-site access in many centers. In an effort to address these issues, we analysed FISH performed on smears obtained at intraoperative frozen section on 51 gliomas and compared this to FISH performed on subsequent FFPE sections. Four cases were excluded due to uninterpretable FISH results. Of the remaining 47 cases, 17 were concordant for 1p/19q-codeletion, 29 were concordant for lack of 1p/19q-codeletion, and 1 was discordant with 1p/19q-codeletion found on FFPE tissue but not on intraoperative smears. The discordant case was most likely due to sampling error, as the frozen section had not shown definite tumor. The FISH results on intraoperative smears were received within 24-48 h after the sample was collected, compared with 3-4 days for FFPE tissue. FISH on smears obtained at intraoperative frozen section is an accurate and fast method for determining 1p/19q-codeletion.

Giant aneurysms of the distal posterior inferior cerebellar artery - systematic review.

BACKGROUND: Posterior inferior cerebellar artery (PICA) aneurysms are uncommon and are typically found at the origin or proximal segments of the vessel. Giant aneurysms are uncommon and present unique treatment challenges. Giant distal PICA aneurysms are exceedingly rare and have traditionally been managed via open surgical approaches. METHODS: A total of 207 studies were assessed, identifying 26 cases of giant distal PICA aneurysms from 26 separate publications. One additional case is described followed by a review of presentation, anatomical characteristics, treatment and outcome. RESULTS: Presentation was due to local mass effect in 19 (70%), hydrocephalus in 4 (15%) and acute haemorrhage in 5 (19%). All reported cases were partially (86%) or completely (14%) thrombosed. The telovelotonsillar segment was involved in 18/24 (75%) cases. Two cases (7%) were associated with an arteriovenous malformation. Twenty-two (81%) were managed surgically and 5 (19%) managed endovascularly. Outcome was good in 22 (85%) and poor in one (4%). CONCLUSIONS: Giant distal PICA aneurysms can be managed effectively through a variety of open surgical and endovascular techniques.

Successful epilepsy surgery for tuberous sclerosis complex evaluated by stereoelectroencephalography.

Evaluating the candidacy for epilepsy surgery in patients with tuberous sclerosis can be challenging, particularly when non-invasive investigations do not show a clear epileptogenic zone. Stereoencephalography may be useful in such cases. We present a case in which the primary epileptogenic tuber was successfully identified by stereoencephalography, which resulted in seizure freedom following epilepsy surgery. [Published with video sequences].

Failure of platelet function analyser 200 to demonstrate clinical clopidogrel resistance in a patient undergoing intracranial vascular stenting.

A patient undergoes intracranial stent insertion for stent-assisted coiling of a basilar tip aneurysm and left middle cerebral artery aneurysm. A flow diverting stent is also placed across an anterior communicating artery aneurysm. Prior to the procedure, the patient takes dual antiplatelet medications, being aspirin and clopidogrel. Because of the concern regarding in-stent thrombus and thromboembolic complications related to intracranial stenting and the high rate of clopidogrel resistance, preoperative platelet function testing (PFT) was undertaken to ensure platelet inhibition. In this case, PFT was performed on a platelet function analyser which demonstrated platelet inhibition. Ten days following the procedure, the patient represented with thromboembolic stroke. Repeat PFT performed with whole blood impedance aggregometry and despite full medication compliance demonstrated clopidogrel resistance. Clopidogrel was then ceased and prasugrel commenced. This case demonstrates the importance of appropriate platelet inhibition in patients with intracranial stents and the controversy surrounding PFT.

The varied semiology of seizures in the context of small anterior temporal encephaloceles.

Small encephaloceles of the anterior temporal pole have been increasingly recognised as an underlying epileptogenic substrate in patients with medically refractory epilepsy. The current report aims to expand on the current knowledge by emphasising that seizure semiology in such patients can vary significantly. Patients were selected from an epilepsy surgery database between 2012 and 2017. Of the 143 patients who underwent epilepsy surgery, six patients had a temporal encephalocele. Four of these patients had stereo-EEG implantation. Of the four patients studied, each had a seizure semiology discordant with an ictal focus in the temporal lobe. Intracranial EEG assessment demonstrated, irrespective of this semiology, seizures originated from the anterior temporal pole. Seizures were observed to rapidly propagate to the orbitofrontal cortex, insula, temporo-occipital junction, and posterior language regions. Engagement of the mesial temporal structures could occur early or late, however, a good surgical outcome was achieved following a focused lesionectomy in either situation. The major finding was that seizures arising from anterior temporal encephaloceles can have an extra-temporal semiology. The varied clinical semiology and the rapid propagation to seemingly distant cortical regions could be explained by the connectivity of the anterior temporal lobe.

Antemortem histopathology and imaging findings in a case of Marchiafava-Bignami disease.

Marchiafava-Bignami disease (MBD) is a rare condition often associated with chronic alcohol abuse. Clinical presentation is diverse. Characteristic magnetic resonance imaging (MRI) changes in the corpus callosum are the mainstay of radiological diagnosis. We present a case of a 54-year-old man with chronic alcoholism and peripherally enhancing lesion in the body of the corpus callosum on MRI Brain. Open biopsy of the lesion showed necrosis and demyelination. He was diagnosed with Marchiafava-Bignami disease based on clinical, radiology and histopathology findings. Our case represents the only case in the literature with antemortem histopathology findings describing MBD.

An alternative technique for pituitary tumour removal: Sequential endoscopic-microscopic pituitary procedure (SEMPP).

Several authors have reported advantages of the purely endoscopic (PE) approach over traditional purely microscopic (PM) techniques for many sinus and anterior skull base procedures. However, in pituitary surgery, the PE approach carries a number of limitations. Experienced microscopically-trained neurosurgeons are required to master the endoscopic technique which has a steep learning curve due to its one-handed nature and optically-distorted 2-dimensional view. We describe our novel technique, the sequential endoscopic and microscopic pituitary procedure (SEMPP) which does not require microscopically-trained neurosurgeons to alter their technique. We compare SEMPP with the PE approach in terms of outcome and safety. Retrospective chart review of consecutive SEMPP cases performed at our institution between January 2010 and December 2013 was conducted. Operative time, gross total resection rate, resolution of endocrine and visual dysfunction, hospital length of stay, cerebrospinal fluid (CSF) leak rate and revision rates were recorded. 32 patients were identified (50% female, mean age 53.0 years), and 33 SEMPP cases. Mean operating time was 132 min (range 90-200). 69% of patients experienced gross total resection. Most patients (81.3%) with preoperative visual deficit either experienced complete resolution or improved symptoms. The remainder experienced no change in vision. 12.5% (n = 4) of patients experienced intraoperative CSF leaks. All were repaired intraoperatively or with conservative management. Two patients (6.3%) experienced epistaxis managed with conservative measures. The SEMPP technique demonstrates comparable outcomes, complication rates and operative time to PE and PM techniques described in the literature.

A study of perfusion changes with Insula Epilepsy using SPECT.

PURPOSE: The non-invasive localisation of insular lobe epilepsy is a challenge. We aimed to determine if ictal SPECT is a reliable adjunctive test in insular cases and to explore its role in the tailoring of intracranial strategies. METHOD: From a dataset of patients who underwent SEEG between December 2012 and December 2016, we collected patients with focal insular onset epilepsy. We examined semiology, EEG, PET and SPECT hyperperfusion pattern with SISCOM. We also reviewed relevant literature. RESULTS: 5 patients were identified, 4 females, from a dataset of 51 patients. Median age of seizure onset was 8 years old (8 months to 10 years). All patients had an ictal SPECT during pre-surgical work-up: median injection time was 7 s (3-17 sec) from clinical onset, and median seizure duration was 42 s (11-85 sec). Insula cortex showed focal hyperaemia in four patients, all bilateral, with the greatest hyperperfusion contralateral to the ictal onset in two cases, using SISCOM threshold at 1.5 standard deviation. Other sites with hyperaemia included basal ganglia and middle temporal gyrus. The SEEG confirmed insular onset seizures in all the cases. All patients had epilepsy surgery and were seizure free at 21 to 50 months follow up. The results from the literature review showed frequent hyperperfusion in structures outside insula and frequently over the contralateral hemisphere. CONCLUSIONS: This study highlights the technical limitations of SPECT when attempting to assess seizures arising from the insula. Our findings and the literature show ictal SPECT can be localising but falsely lateralising in seizures arising from the insula.

Paediatric mild head injury: is routine admission to a tertiary trauma hospital necessary?

BACKGROUND: Previous studies have shown that children with isolated linear skull fractures have excellent clinical outcomes and low risk of surgery. We wish to identify other injury patterns within the spectrum of paediatric mild head injury, which need only conservative management. Children with low risk of evolving neurosurgical lesions could be safely managed in primary hospitals. METHODS: We retrospectively analysed all children with mild head injury (i.e. admission Glasgow coma score 13-15) and skull fracture or haematoma on a head computed tomography scan admitted to Westmead Children's Hospital, Sydney over the years 2009-2014. Data were collected regarding demographics, clinical findings, mechanism of injury, head computed tomography scan findings, neurosurgical intervention, outcome and length of admission. Wilcoxon paired test was used with P value <0.05 considered significant. RESULTS: Four hundred and ten children were analysed. Three hundred and eighty-one (93%) children were managed conservatively, 18 (4%) underwent evacuation of extradural haematoma (TBI surgery) and 11 (3%) needed fracture repair surgery. Two children evolved a surgical lesion 24 h post-admission. Only 17 of 214 children transferred from peripheral hospitals needed neurosurgery. Overall outcomes: zero deaths, one needed brain injury rehabilitation and 63 needed child protection unit intervention. Seventy-five percentage of children with non-surgical lesions were discharged within 2 days. Eighty-three percentage of road transfers were discharged within 3 days. CONCLUSIONS: Children with small intracranial haematomas and/or skull fractures who need no surgery only require brief inpatient symptomatic treatment and could be safely managed in primary hospitals. Improved tertiary hospital transfer guidelines with protocols to manage clinical deterioration could have cost benefit without risking patient safety.

Microvascular decompression for elderly patients with trigeminal neuralgia.

Microvascular decompression (MVD) has been demonstrated to be an excellent surgical treatment approach in younger patients with trigeminal neuralgia (TN). However, it is not clear whether there are additional morbidity and mortality risks for MVD in the elderly population. We performed a systematic literature review using six electronic databases for studies that compared outcomes for MVD for TN in elderly (cut-off ⩾60, 65, 70years) versus younger populations. Outcomes examined included success rate, deaths, strokes, thromboembolism, meningitis, cranial nerve deficits and cerebrospinal fluid leaks. There were 1524 patients in the elderly cohort and 3488 patients in the younger cohort. There was no significant difference in success rates in elderly versus younger patients (87.5% versus 84.8%; P=0.47). However, recurrence rates were lower in the elderly (11.9% versus 15.6%; P=0.03). The number of deaths in the elderly cohort was higher (0.9% versus 0.1%; P=0.003). Rates of stroke (2.5% versus 1%) and thromboembolism (1.1% versus 0%) were also higher for elderly TN patients. No differences were found for rates of meningitis, cranial nerve deficits or cerebrospinal fluid leak. MVD remains an effective and reasonable strategy in the elderly population. There is evidence to suggest that rates of complications such as death, stroke, and thromboembolism may be significantly higher in the elderly population. The presented results may be useful in the decision-making process for MVD in elderly patients with TN.