Background:Recent evidence has demonstrated a tight relationship between neuronal activity and glioblastoma (GBM) growth, involving novel mechanisms such as neuron-glioma synapses and tumor microtube networks. Seizure activity and antiepileptic drug (AED) usage are highly prevalent among GBM patients. In this study, we investigate the impact of AEDs and their mechanism of action on overall survival (OS) in a cohort of patients treated for GBM. Methods:We performed a retrospective, single-center study of a cohort of histopathologically proven GBM patients at a tertiary center. Multivariate analyses were performed at 4 different timepoints by (1) patients who did and did not use AEDs, (2) use of individual AEDs, and (3) use of AEDs with the same mechanism of action. Results:A total of 236 patients were included in the analysis, 178 of which were on anti-epileptics (75.4%). There was no significant impact of AEDs overall in OS-median survival was 16.2 months for patients taking AEDs and 13.8 months for patients not. Being on a voltage-gated sodium channel (VGNC) blocker seemed to confer a significant survival advantage at 24 months when compared with patients not on AEDs (hazard ratio [HR] = 0.67, P = .045). This significance was, however, lost when corrected for covariates (multivariable HR = 1.01, confidence interval [CI] = 0.67-1.54, P = .953). While patients on adjuvant treatment had a higher OS, this was only the case in patients -taking AEDs. Conclusion:There was no significant effect of AEDs on OS, VGNC blockers trended toward significance at 24 months. However, a link may exist between AEDs and the impact of adjuvant treatments.

INTRODUCTION:New neurological symptoms in neuro-oncology patients are usually attributed to the tumor or its treatment. A diagnosis of functional neurological disorder (FND) is often only considered when investigations do not reveal a cause and medical management fails. The consequences to neuro-oncology patients of comorbid FND have not been elaborated. METHODS:We performed a single-center retrospective case study of adult neuro-oncology patients with an intracranial tumor who presented acutely with FND and required expedited investigations. Data recorded were tumor type, investigations, adverse life events, medical interventions, and outcomes. This was combined with a systematic literature review. RESULTS:Ten patients met our study criteria. Six had functional seizures, two had functional hemiparesis, and two had functional speech disorders. FND symptoms started prior to tumor diagnosis in three patients; between diagnosis and tumor treatment in three patients; and after treatment commenced in four patients. Two patients were thrombolyzed for a presumed stroke. Three patients had either their tumor surgery or chemoradiotherapy delayed. Diagnosis and management of FND enabled tumor treatment to restart. The systematic review identified 43 patients. Thirty-nine had functional seizures, and four had motor FND. All FNDs except one started after tumor treatment commenced. CONCLUSION:Acute FND can occur at any stage of a brain tumor illness. The FND may lead to unnecessary medical interventions and can disrupt tumor treatment. Although acute FND improved with diagnosis and explanation, many neuro-oncology patients require a multidisciplinary tumor-FND pathway to manage acute FND and avoid delays to tumor treatment.

We investigated stroke in patients with either benign or malignant primary intracranial tumours to give insights into how malignant and non-malignant intracranial tumours affect stroke and to provide evidence for stroke guidelines for these patients. We conducted a retrospective cohort study of patients with benign or malignant primary intracranial tumours admitted with stroke (2011–2022) to a single centre with regional stroke and neuro-oncology units. Data collected included: stroke aetiology, stroke timing relative to tumour diagnosis, pre-stroke disability, post-stroke disability, stroke recurrence and treatment. We identified 258 patients who had an index stroke (120 haemorrhagic, 135 ischaemic, three coincident haemorrhagic/ischaemic) at or after the diagnosis of their primary intracranial tumour (71

Abstract AIMS People with primary CNS tumours are at increased risk of stroke. However, there is little guidance on stroke management. We investigated the types and timing of stroke in primary brain and meningeal tumours to inform their treatment. METHOD Patient data on stroke aetiology, timing, management and outcomes was collected from electronic medical records at King’s College Hospital between April 2012 to April 2022. A primary brain tumour was defined using the 2021 World Health Organisation Classification of Tumours of the Central Nervous System. RESULTS We identified 244 patients with a brain tumour and a stroke with a total of 317 strokes in the 10-year period (male:female = 48:52; median age, 62 years [IQR 51 – 74]). The most common brain tumours were meningiomas (43%) and glioblastomas (21%). 56% of strokes were ischaemic. Ischaemic strokes were most frequent within 30 days of brain tumour surgery (38%). Haemorrhages were more common in malignant tumours (p=4.7 x10 35% of haemorrhages were intratumoural. Strokes in malignant tumours: occurred closer to diagnosis (p=0.032); caused greater functional loss (mean Modified Rankin Scale change 2.00 vs 1.17, p 0.001); and had a higher mortality rate (HR 5.87, CI 3.41 - 10.11, p=1.8x10 Recurrent strokes occurred in 64 (26%) patients and were associated with tumour malignancy (p=0.016), radiotherapy (p=0.023) and chemotherapy (p=0.009). CONCLUSION Strokes in malignant brain tumours are more lethal, disabling and often recurrent in patients undergoing chemo and radiotherapy. Clinical trials are needed to improve outcomes of stroke in neuro-oncology patients.

ABSTRACTBACKGROUNDMalignant primary intracranial tumours are associated with stroke. Knowing how stroke differs in patients with either benign or malignant primary intracranial tumours would give insights into how intracranial tumours affect stroke and would help to improve the limited stroke guidelines for these patients.METHODSWe conducted a retrospective cohort study of patients with benign or malignant primary intracranial tumours admitted with stroke (2011 - 2022) to a single centre with regional stroke and neuro-oncology units. Data collected included: stroke aetiology, stroke timing relative to tumour diagnosis, pre-stroke disability, post-stroke disability, stroke recurrence and treatment.RESULTSWe identified 258 patients who had an index stroke (120 haemorrhagic, 135 ischaemic, three coincident haemorrhagic/ischaemic) at or after the diagnosis of their primary intracranial tumour (71% benign, 29% malignant). Symptomatic intracranial haemorrhage was more commonly associated with malignant primary intracranial tumours. Patients with a malignant primary intracranial tumour were 2.7 times more likely to have a stroke than patients with a benign intracranial tumour. We estimated that the risk of ischaemic stroke and symptomatic intracranial haemorrhage within six months of diagnosis of a benign primary intracranial were respectively 2.5 and 5.0 times that of the general population. In-hospital mortality and level of disability at hospital discharge (median modified Rankin scale score, 4) were similar for patients with benign or malignant primary intracranial tumours. Stroke recurrence was 22% at one year. Statins were associated with reduced stroke recurrence.Patients with malignant tumours and high post-stroke disability were less likely to receive chemotherapy after hospital discharge.CONCLUSIONSOur findings suggest that stroke is a wider issue for patients with primary intracranial tumours than commonly recognised. Our data indicated that statins may help to prevent stroke recurrence. Despite concerns about intracranial haemorrhage, antiplatelet agents should be considered after ischaemic stroke.

Abstract AIMS Poor seizure control is a common problem for brain tumour patients. Epilepsy surgery is considered in patients with seizures not caused by a brain tumour when trials of two anticonvulsants given in therapeutic doses fail. There are no clear guidelines on when epilepsy surgery should be considered for brain tumour patients. Given the high burden on quality of life, preventing recurrent seizures is essential. METHOD Retrospective data collection of patients seen in the Low-Grade Glioma and Joint Neurology-Oncology clinics of a regional Neuro-oncology service between January – June 2023. Data were analysed within STATA 18. RESULTS We identified 121 patients (61 male, 60 female; age range 20-84 yrs). The majority (93/121) were diagnosed with a low-grade glioma. [GF1] 44 patients had tumour-related epilepsy. Of these, 31/44 (70%) patients presented clinically with seizure(s) and 13/44 (30%) patients had their first seizure 3 - 2421 days post diagnosis. All patients were started on anticonvulsant medication, commonly Levetiracetam (70%). Tumour surgery was performed on 28/44 (63%) patients. Recurrent seizures occurred in 22/44 (50%) patients. Seizures were not controlled in 12 (29%) patients after trying two or more anticonvulsants. Four patients were considered for epilepsy surgery. CONCLUSION Recurrent seizures are a common clinical problem in patients with low-grade gliomas. Surgery to treat brain tumour-related epilepsy may be performed as a last option. Brain tumour patients may benefit from earlier consideration of surgery to treat both the epilepsy and the brain tumour.

Abstract AIMS There is a gap in supporting patients with sexual relationships and intimacy. The aim of this study is to establish if patients with a brain tumour feel they are able to ask questions and concerns about sex, relationships and intimacy following diagnosis; is there an unmet need and how can this be addressed. METHOD An anonymous survey was sent to patients known to a neuro-oncology team. Questions were in relation to their experiences of sex relationships and intimacy. Patients were asked if they had concerns about changes in their relationships since their diagnosis. They were also asked for their comments on the subject so we can better understand how as a service we can improve to ensure holistic care. RESULTS There are 40 responses. The majority of respondents had concerns about their relationship since diagnosis and that their relationships have changed. 57% were concerned about a physical relationship with a partner/ future partners. 50% agreed their physical relationship had changed. 45% of people agreeing their emotional relationships have changed. 38 out of the 40 people questioned, had not asked their clinical team for advice about sex and relationships. 46% suggested clinicians initiating these conversations. CONCLUSION Sex relationships and intimacy are significant for most adult populations, encompassing connection with their loved ones, self esteem and psychological and emotional well-being. With brain tumour diagnosis this part of people’s lives can hugely impacted. Historically clinicians have found this a difficult subject to discuss. Further work is required to understand the barriers initiating this subject

Abstract Aims Signs and symptoms that develop in people with brain tumours are often attributed to their tumour. The prevalence and management of functional neurological symptoms in brain tumour patients have received little attention. This is surprising because functional neurological symptoms complicate management greatly and misdiagnosis can lead to inappropriate treatment and iatrogenic side-effects. Therefore, we investigated the presentation, diagnosis and management of functional neurological disorders (FND) in patients who had a brain or meningeal tumour. Method A retrospective case review was performed from 2017 - 2021 to identify adult brain tumour patients who developed a functional neurological disorder that caused significant disability necessitating expedited investigations. All patients attended a regional neuro-oncology centre. We recorded type of brain tumour and diagnostic investigations. The onset of functional symptoms was divided into three time windows: before tumour diagnosis, after diagnosis and before treatment or after tumour treatment. A neuropsychological review looked for evidence of previous adverse life events. Therapeutic interventions for functional neurological disorder and their outcomes were documented. The case review was combined with a systematic review of the literature to identify the published presentations of functional neurological disorder in the adult brain tumour population. MEDLINE, EMBASE and PsycINFO databases were searched for studies published between January 1980 and February 2021. Results Six patients (5 female, 1 male) were identified from the case review with a median age of 41 (range 29 - 56) years old. Four patients had non-epileptic attack disorder, which was diagnosed with videotelemetry of habitual attacks. One patient had a functional hemiparesis with normal central motor conduction time. One patient had a functional speech disorder with normal EEG. Half of these patients had functional neurological symptoms prior to surgery/oncological treatment. Five patients (83%) were referred for further neuropsychiatric or psychological evaluation. A history of significant psychological trauma prior to the brain tumour diagnosis was elicited in four (66%) patients. Conclusion Patients with either a brain or meningeal tumour may develop functional neurological symptoms. Our findings suggest the possibility that diagnosis of a brain tumour may precipitate a debilitating functional neurological disorder. The neurobiological basis for functional neurological disorders is being actively investigated. There are suggestions in the literature that some brain diseases increase the risk of developing a functional neurological disorder. Further work is needed to determine whether this is true for patients with brain tumours. Increased awareness of functional neurological disorders will improve management. Withdrawal of unnecessary treatment, such as anticonvulsant drugs, reduces the risk of iatrogenic side effects. Initiation of multi-disciplinary care pathways, e.g. physiotherapy, speech and language therapy and psychological treatments, promotes recovery. Collectively, these interventions improve our patients’ quality of life.

BACKGROUND:Lower-grade gliomas may be indolent for many years before developing malignant behavior. The mechanisms underlying malignant progression remain unclear. METHODS:We collected blocks of live human brain tissue donated by people undergoing glioma resection. The tissue blocks extended through the peritumoral cortex and into the glioma. The living human brain tissue was cut into ex vivo brain slices and bathed in 5-aminolevulinic acid (5-ALA). High-grade glioma cells avidly take up 5-ALA and accumulate high levels of the fluorescent metabolite, Protoporphyrin IX (PpIX). We exploited the PpIX fluorescence emitted by higher-grade glioma cells to investigate the earliest stages of malignant progression in lower-grade gliomas. RESULTS:We found sparsely distributed "hot-spots" of PpIX-positive cells in living lower-grade glioma tissue. Glioma cells and endothelial cells formed part of the PpIX hotspots. Glioma cells in PpIX hotspots were IDH1 mutant and expressed nestin suggesting they had acquired stem-like properties. Spatial analysis with 5-ALA-conjugated quantum dots indicated that these glioma cells replicated adjacent to blood vessels. PpIX hotspots were formed in the absence of angiogenesis. CONCLUSION:Our data show that PpIX hotspots represent microdomains of cells with high-grade potential within lower-grade gliomas and identify locations where malignant progression could start.

Abstract Aims Primary central nervous system lymphoma (PCNSL) is a rare form of non–Hodgkin lymphoma with exclusive manifestations in the central nervous system, leptomeninges and eyes. It forms around 5% of all primary brain tumours. It is an aggressive tumour which has a poor prognosis if left untreated. It is imperative that diagnosis is made timely so treatment can be started promptly. Therefore, we performed an audit looking into the speed of diagnostic process of PCNSL in our tertiary Neuro–oncology Unit. Method Single-centre retrospective review of PCNSL cases referred to a tertiary Neuro–Oncology Unit over a six month period from June to November 2020. Results A total of 1309 cases were discussed in the Neuro–oncology MDT meeting over the study period. Fourteen cases (6 male, 8 female; median age [range] 66 [59–83] years) were identified as highly likely PCNSL. Neuroimaging suggested PCNSL as the likely diagnosis in twelve patients. Twelve patients were started on steroids after CT or MRI brain scans. Nine patients had a surgical target and proceeded to have diagnostic brain biopsy. Two patients had different working diagnoses and three patients were deemed unsuitable for brain surgery. One patient required repeat brain biopsy. A tissue diagnosis was made in twelve patients. One patient deteriorated rapidly and one patient had a brain lesion that was deemed too high risk for surgery. The median time between neuroimaging and biopsy was 25 days. The median time taken from first investigation to the pathological confirmation of PCNSL was 36 days (range 6–86 days). Conclusion The chief reason for delay in diagnosis of PCNSL was that patients were started on steroids before diagnostic investigations were completed. Steroids caused the brain lesions to become smaller or disappear. Accordingly, time was needed to allow withdrawal of steroids before diagnostic investigations could be repeated. Diagnostic delays may have been exacerbated by logistical issues associated with COVID–19. We propose that there needs to be greater awareness of how early introduction of steroids can markedly delay the diagnosis of PCNSL.

Background Gliomas are composed of multiple clones of tumor cells. This intratumor heterogeneity contributes to the ability of gliomas to resist treatment. It is vital that gliomas are fully characterized at a molecular level when a diagnosis is made to maximize treatment effectiveness. Methods We collected ultrasonic tissue fragments during glioma surgery. Large tissue fragments were separated in the operating theater and bathed continuously in oxygenated artificial cerebrospinal fluid to keep them alive. The ex vivo tissue fragments were transferred to a laboratory and incubated in 5-aminolevulinic acid (5-ALA). 5-ALA is metabolized to Protoporphyrin IX (PpIX), which accumulates in glioma cells and makes them fluorescent. The molecular and neuropathological features of the PpIX fluorescent ultrasonic tissue fragments were studied. Results We show that PpIX fluorescence can rapidly identify tissue fragments infiltrated by glioma in the laboratory. Ultrasonic tissue fragments from the tumor core provided molecular and neuropathological information about the glioma that was comparable to the surgical biopsy. We characterized the heterogeneity within individual gliomas by studying ultrasonic tissue fragments from different parts of the tumor. We found that gliomas exhibit a power relationship between cellular proliferation and tumor infiltration. Tissue fragments that deviate from this relationship may contain foci of more malignant glioma. The methylation status of the O-6-methylguanine DNA methyltransferase gene promoter varied within each glioma. Conclusions Ex vivo ultrasonic tissue fragments can be rapidly screened for glioma infiltration. They offer a viable platform to characterize heterogeneity within individual gliomas, thereby enhancing their diagnosis and treatment.

Abstract Gliomas often present clinically with seizures. Tumour-associated seizures can be difficult to control with medication. A deeper understanding of the cellular mechanisms underlying tumour-associated seizures would provide a basis for developing new treatments. Here, we investigate epileptic discharges in peritumoral cortex using living human brain tissue donated by people having a craniotomy for glioma resection (REC approval, 18/SW/002). The brain tissue was cut into thin slices, which preserved the architecture of the glioma and the adjacent healthy brain. The brain slices were incubated in 5-aminolevulinic acid to make the glioma cells fluorescent. This enabled us to make electrophysiological recordings of brain activity across the boundary between glioma and brain. We recorded from brain slices of 5 participants with glioblastoma and 4 participants with oligodendroglioma (WHO grade II – III). Spontaneous “seizure-like” discharges were recorded in brain slices from 5/8 participants (3 GBM, 2 oligodendroglioma) who reported seizures and from one participant (GBM) who had not had any clinical seizures. Further analysis of the seizure-like discharges revealed that they could be subdivided into two distinct types based on the major frequencies in the discharge. We concluded that human brain slices from people with either a low-grade or a high-grade glioma can generate spontaneous seizure-like discharges. The living human brain tissue preparation gives us a platform to study the mechanisms of tumour-associated seizures and how abnormal neural activity affects glioma growth.

We aimed to characterize the demographics of adults with dissociative (nonepileptic) seizures, placing emphasis on distribution of age at onset, male:female ratio, levels of deprivation, and dissociative seizure semiology.

BackgroundConditions such as primary CNS lymphoma (PCNSL) or demyelinating/inflammatory diseases may present with similar clinical and neuroradiological features to gliomas. These ‘glioma mimics’ are commonly diagnosed with brain biopsy, but this is not always possible. We aim to optimize the contribution of less invasive investigations to the diagnostic pathway.MethodRetrospective review of the diagnostic process of glioma mimics between September to November 2018 in a tertiary Neuro–oncology unit.ResultsThe Neuro-oncology MDT gave 558 opinions excluding post –operative reviews. Twelve cases were identified as glioma mimics. 6/12 were new cases. Further investigations in five new cases took 2.5 – 11 weeks to complete. Two patients deteriorated during diagnostic workup and had expedited brain biopsies which confirmed PCNSL. One proceeded with chemotherapy and one was referred to palliative care.ConclusionDiagnostic tests prior to brain biopsy were not performed in all glioma mimic cases. This was because test results excluding brain biopsy were not available to start treatment before the patient deteriorated clinically. We anticipate that the frequency of glioma mimics will increase due to the greater use of immunomodulatory therapies. A dedicated protocol to achieve rapid diagnosis of glioma mimics is imperative to facilitate early, appropriate treatment.

Neuronal connections form the physical basis for communication in the brain. Recently, there has been much interest in mapping the “connectome” to understand how brain structure gives rise to brain function, and ultimately, to behaviour. These attempts to map the connectome have largely assumed that connections are stable once formed. Recent studies, however, indicate that connections in mammalian brains may undergo rewiring during learning and experience-dependent plasticity. This suggests that the connectome is more dynamic than previously thought. To what extent can neural circuitry be rewired in the healthy adult brain? The connectome has been subdivided into multiple levels of scale, from synapses and microcircuits through to long-range tracts. Here, we examine the evidence for rewiring at each level. We then consider the role played by rewiring during learning. We conclude that harnessing rewiring offers new avenues to treat brain diseases.

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Time is central to cognition. However, the neural basis for time-dependent cognition remains poorly understood. We explore how the temporal features of neural activity in cortical circuits and their capacity for plasticity can contribute to time-dependent cognition over short time scales. This neural activity is linked to cognition that operates in the present or anticipates events or stimuli in the near future. We focus on deliberation and planning in the context of decision making as a cognitive process that integrates information across time. We progress to consider how temporal expectations of the future modulate perception. We propose that understanding the neural basis for how the brain tells time and operates in time will be necessary to develop general models of cognition.SIGNIFICANCE STATEMENT:Time is central to cognition. However, the neural basis for time-dependent cognition remains poorly understood. We explore how the temporal features of neural activity in cortical circuits and their capacity for plasticity can contribute to time-dependent cognition over short time scales. We propose that understanding the neural basis for how the brain tells time and operates in time will be necessary to develop general models of cognition.

Synaptic neurotransmission is modified at cortical connections throughout life. Varying the amplitude of the postsynaptic response is one mechanism that generates flexible signaling in neural circuits. The timing of the synaptic response may also play a role. Here, we investigated whether weakening and loss of an entire connection between excitatory cortical neurons was foreshadowed in the timing of the postsynaptic response. We made electrophysiological recordings in rat primary somatosensory cortex that was undergoing experience-dependent loss of complete local excitatory connections. The synaptic latency of pyramid-pyramid connections, which typically comprise multiple synapses, was longer and more variable. Connection strength and latency were not correlated. Instead, prolonged latency was more closely related to progression of connection loss. The action potential waveform and axonal conduction velocity were unaffected, suggesting that the altered timing of neurotransmission was attributable to a synaptic mechanism. Modeling studies indicated that increasing the latency and jitter at a subset of synapses reduced the number of action potentials fired by a postsynaptic neuron. We propose that prolonged synaptic latency and diminished temporal precision of neurotransmission are hallmarks of impending loss of a cortical connection.

Mature neocortex adapts to altered sensory input by changing neural activity in cortical circuits. The underlying cellular mechanisms remain unclear. We used blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to show reorganization in somatosensory cortex elicited by altered whisker sensory input. We found that there was rapid expansion followed by retraction of whisker cortical maps. The cellular basis for the reorganization in primary somatosensory cortex was investigated with paired electrophysiological recordings in the periphery of the expanded whisker representation. During map expansion, the chance of finding a monosynaptic connection between pairs of pyramidal neurons increased 3-fold. Despite the rapid increase in local excitatory connectivity, the average strength and synaptic dynamics did not change, which suggests that new excitatory connections rapidly acquire the properties of established excitatory connections. During map retraction, entire excitatory connections between pyramidal neurons were lost. In contrast, connectivity between pyramidal neurons and fast spiking interneurons was unchanged. Hence, the changes in local excitatory connectivity did not occur in all circuits involving pyramidal neurons. Our data show that pyramidal neurons are recruited to and eliminated from local excitatory networks over days. These findings suggest that the local excitatory connectome is dynamic in mature neocortex.