Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults.

More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications. We aimed to identify predictors of seizure recurrence after starting postoperative antiseizure medication withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started antiseizure medication withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting antiseizure medication withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of antiseizure medication withdrawal were focal non-motor aware seizures after surgery and before withdrawal [adjusted hazard ratio (aHR) 5.5, 95% confidence interval (CI) 2.7-11.1], history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of antiseizure medication withdrawal (aHR 0.9, 95% CI 0.8-0.9) and number of antiseizure medications at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative antiseizure medication withdrawal. These multicentre-validated models may assist clinicians when discussing antiseizure medication withdrawal after surgery with their patients.

Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants.

Coordinated programs of gene expression drive brain development. It is unclear which transcriptional programs, in which cell-types, are affected in neuropsychiatric disorders such as schizophrenia. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. We identify transcriptional programs expressed during early neurogenesis in vitro and in human foetal cortex that are down-regulated in DLG2-/- lines. Down-regulation impacted neuronal differentiation and maturation, impairing migration, morphology and action potential generation. Genetic variation in these programs is associated with neuropsychiatric disorders and cognitive function, with associated variants predominantly concentrated in loss-of-function intolerant genes. Neurogenic programs also overlap schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways active during prenatal cortical development may also be associated with mature neuronal dysfunction. Our data from human embryonic stem cells, when combined with analysis of available foetal cortical gene expression data, de novo rare variants and GWAS statistics for neuropsychiatric disorders and cognition, reveal a convergence on transcriptional programs regulating excitatory cortical neurogenesis.

Do foetal transplant studies continue to be justified in Huntington's disease?

Early CNS transplantation studies used foetal derived cell products to provide a foundation of evidence for functional recovery in preclinical studies and early clinical trials. However, it was soon recognised that the practical limitations of foetal tissue make it unsuitable for widespread clinical use. Considerable effort has since been directed towards producing target cell phenotypes from pluripotent stem cells (PSCs) instead, and there now exist several publications detailing the differentiation and characterisation of PSC-derived products relevant for transplantation in Huntington's disease (HD). In light of this progress, we ask if foetal tissue transplantation continues to be justified in HD research. We argue that (i) the extent to which accurately differentiated target cells can presently be produced from PSCs is still unclear, currently making them undesirable for studying wider CNS transplantation issues; (ii) foetal derived cells remain a valuable tool in preclinical research for advancing our understanding of which products produce functional striatal grafts and as a reference to further improve PSC-derived products; and (iii) until PSC-derived products are ready for human trials, it is important to continue using foetal cells to gather clinical evidence that transplantation is a viable option in HD and to use this opportunity to optimise practical parameters (such as trial design, clinical practices, and delivery strategies) to pave the way for future PSC-derived products.

Protocol for an open label: phase I trial within a cohort of foetal cell transplants in people with Huntington's disease.

Huntington's disease is a progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric symptoms. Currently, no disease-modifying therapies are available to slow or halt disease progression. Huntington's disease is characterized by relatively focal and specific loss of striatal medium spiny neurons, which makes it suitable for cell-replacement therapy, a process involving the transplantation of donor cells to replace those lost due to disease. TRIal DEsigns for delivery of Novel Therapies in neurodegeneration is a phase I Trial Within a Cohort designed to assess safety and feasibility of transplanting human foetal striatal cells into the striatum of people with Huntington's disease. A minimum of 18 participants will be enrolled in the study cohort, and up to five eligible participants will be randomly selected to undergo transplantation of 12-22 million foetal cells in a dose escalation paradigm. Independent reviewers will assess safety outcomes (lack of significant infection, bleeding or new neurological deficit) 4 weeks after surgery, and ongoing safety will be established before conducting each subsequent surgery. All participants will undergo detailed clinical and functional assessment at baseline (6 and 12 months). Surgery will be performed 1 month after baseline, and transplant participants will undergo regular clinical follow-up for at least 12 months. Evaluation of trial processes will also be undertaken. Transplant participants and their carers will be interviewed ∼1 month before and after surgery. Interviews will also be conducted with non-transplanted participants and healthcare staff delivering the intervention and involved in the clinical care of participants. Evaluation of clinical and functional efficacy outcomes and intervention costs will be carried out to explore plausible trial designs for subsequent randomized controlled trials aimed at evaluating efficacy and cost-effectiveness of cell-replacement therapy. TRIal DEsigns for delivery of Novel Therapies in neurodegeneration will enable the assessment of the safety, feasibility, acceptability and cost of foetal cell transplants in people with Huntington's disease. The data collected will inform trial designs for complex intra-cranial interventions in a range of neurodegenerative conditions and facilitate the development of stable surgical pipelines for delivery of future stem cell trials. Trial Registration: ISRCTN52651778.

Toll-like receptor linked cytokine profiles in cerebrospinal fluid discriminate neurological infection from sterile inflammation.

Rapid determination of an infective aetiology causing neurological inflammation in the cerebrospinal fluid can be challenging in clinical practice. Post-surgical nosocomial infection is difficult to diagnose accurately, as it occurs on a background of altered cerebrospinal fluid composition due to the underlying pathologies and surgical procedures involved. There is additional diagnostic difficulty after external ventricular drain or ventriculoperitoneal shunt surgery, as infection is often caused by pathogens growing as biofilms, which may fail to elicit a significant inflammatory response and are challenging to identify by microbiological culture. Despite much research effort, a single sensitive and specific cerebrospinal fluid biomarker has yet to be defined which reliably distinguishes infective from non-infective inflammation. As a result, many patients with suspected infection are treated empirically with broad-spectrum antibiotics in the absence of definitive diagnostic criteria. To begin to address these issues, we examined cerebrospinal fluid taken at the point of clinical equipoise to diagnose cerebrospinal fluid infection in 14 consecutive neurosurgical patients showing signs of inflammatory complications. Using the guidelines of the Infectious Diseases Society of America, six cases were subsequently characterized as infected and eight as sterile inflammation. Twenty-four contemporaneous patients with idiopathic intracranial hypertension or normal pressure hydrocephalus were included as non-inflamed controls. We measured 182 immune and neurological biomarkers in each sample and used pathway analysis to elucidate the biological underpinnings of any biomarker changes. Increased levels of the inflammatory cytokine interleukin-6 and interleukin-6-related mediators such as oncostatin M were excellent indicators of inflammation. However, interleukin-6 levels alone could not distinguish between bacterially infected and uninfected patients. Within the patient cohort with neurological inflammation, a pattern of raised interleukin-17, interleukin-12p40/p70 and interleukin-23 levels delineated nosocomial bacteriological infection from background neuroinflammation. Pathway analysis showed that the observed immune signatures could be explained through a common generic inflammatory response marked by interleukin-6 in both nosocomial and non-infectious inflammation, overlaid with a toll-like receptor-associated and bacterial peptidoglycan-triggered interleukin-17 pathway response that occurred exclusively during infection. This is the first demonstration of a pathway dependent cerebrospinal fluid biomarker differentiation distinguishing nosocomial infection from background neuroinflammation. It is especially relevant to the commonly encountered pathologies in clinical practice, such as subarachnoid haemorrhage and post-cranial neurosurgery. While requiring confirmation in a larger cohort, the current data indicate the potential utility of cerebrospinal fluid biomarker strategies to identify differential initiation of a common downstream interleukin-6 pathway to diagnose nosocomial infection in this challenging clinical cohort.

Improving the Predictions of Computational Models of Convection-Enhanced Drug Delivery by Accounting for Diffusion Non-gaussianity.

Convection-enhanced delivery (CED) is an innovative method of drug delivery to the human brain, that bypasses the blood-brain barrier by injecting the drug directly into the brain. CED aims to target pathological tissue for central nervous system conditions such as Parkinson's and Huntington's disease, epilepsy, brain tumors, and ischemic stroke. Computational fluid dynamics models have been constructed to predict the drug distribution in CED, allowing clinicians advance planning of the procedure. These models require patient-specific information about the microstructure of the brain tissue, which can be collected non-invasively using magnetic resonance imaging (MRI) pre-infusion. Existing models employ the diffusion tensor, which represents Gaussian diffusion in brain tissue, to provide predictions for the drug concentration. However, those predictions are not always in agreement with experimental observations. In this work we present a novel computational fluid dynamics model for CED that does not use the diffusion tensor, but rather the diffusion probability that is experimentally measured through diffusion MRI, at an individual-participant level. Our model takes into account effects of the brain microstructure on the motion of drug molecules not taken into account in previous approaches, namely the restriction and hindrance that those molecules experience when moving in the brain tissue, and can improve the drug concentration predictions. The duration of the associated MRI protocol is 19 min, and therefore feasible for clinical populations. We first prove theoretically that the two models predict different drug distributions. Then, using in vivo high-resolution diffusion MRI data from a healthy participant, we derive and compare predictions using both models, in order to identify the impact of including the effects of restriction and hindrance. Including those effects results in different drug distributions, and the observed differences exhibit statistically significant correlations with measures of diffusion non-Gaussianity in brain tissue. The differences are more pronounced for infusion in white-matter areas of the brain. Using experimental results from the literature along with our simulation results, we show that the inclusion of the effects of diffusion non-Gaussianity in models of CED is necessary, if reliable predictions that can be used in the clinic are to be generated by CED models.

VCath: a tablet-based neurosurgery training tool.

VCath is a neurosurgery training tool for the catheterization of the lateral ventricle that has been designed for use on tablet devices. We believe this is the first use of a tablet (iPad) for this purpose and demonstrates future utility for this approach, particularly for Objective Structured Clinical Exams (OSCEs). This paper outlines the implementation and use of VCath.

Transsylvian selective amygdalohippocampectomy in children with hippocampal sclerosis: seizure, intellectual and memory outcome.

PURPOSE: This study investigates the efficacy of transylvian selective amygdalohippocampectomy (TS SAH) in children with medically intractable epilepsy due to unilateral hippocampal sclerosis. Post-surgical seizure control, intellectual and memory outcomes are examined. METHOD: This study reports on pre- and post-surgical clinical data from 10 patients who underwent TS SAH between 2002 and 2010 after 24 months follow-up. Pre- and post-operative change in seizure frequency, AED use, intellect and memory are compared. RESULTS: At 12 months and 24 months post-surgery, 9/10 (90%) and 7/8 (87.5%) patients respectively, were seizure free (Engel I). No patients were classed as Engel III or IV. No significant improvement or decline at a group level was found on measures of intellect or verbal or visual memory. One hundred per cent improved or remained within 1 SD of their pre-operatives score on verbal and perceptual reasoning learning and reasoning measures. Significant improvement was found post-operatively for both immediate and delayed facial memory. CONCLUSION: Our findings of good post-surgical seizure control and favourable cognitive outcome provides evidence against previous findings that SAH in children may not be effective.

A-Disintegrin and Metalloprotease (ADAM) 10 and 17 promote self-renewal of brain tumor sphere forming cells.

It has been proposed that gliomas contain a subpopulation of 'Brain Tumor Stem Cells' (BTSCs), which demonstrate resistance to conventional therapies. A potential component of the environment governing the behavior of these BTSCs is a class of transmembrane proteins with structural and signaling functions, the A-Disintegrin And Metalloproteases (ADAMs). In this study we confirm overexpression of ADAM10 and 17 in human glioma tissue compared to human controls, and especially in tumor sphere cultures thought to enrich for BTSCs. Inhibition of ADAM10/17 function impairs the growth of tumor spheres with evidence of depletion of the sphere forming cell population. This results from a combination of reduced proliferation, cell death and a switch of sphere-forming cells away from symmetric self-renewal division towards neuronal differentiation. A developing appreciation of the role of ADAMs in BTSC promises insights into pathophysiology and potential therapeutic avenues in this intractable group of tumors.

Seizure-induced miosis.

Ictal autonomic pupillary dilation is common; however, miosis is rare. We describe a case of focal seizures secondary to cortical dysplasia presenting with bilateral pupillary miosis, rendered seizure free by resective surgery. The seizure-onset zone was localized within the left middle parietal gyrus by intracranial electrographic recording. Seizure onset was coincident with focal left centroparietal fast spike activity on electroencephalography (EEG). A large region of the left frontocentral cortical dysplasia was demonstrated on magnetic resonance imaging (MRI). Complete resection of the area of cortical dysplasia and additional cortical regions of ictal activity, identified using intracranial EEG, rendered the patient seizure free.

Very good inter-rater reliability of Engel and ILAE epilepsy surgery outcome classifications in a series of 76 patients.

The inter-rater reliability, expressed as kappa score, k, of the Engel and International League Against Epilepsy (ILAE) classifications of epilepsy surgery seizure outcome has not previously been evaluated. In a consecutive series of 76 patients (40 male; 25 children), 75 undergoing resective and 1 disconnective surgery at a mean age of 27.5 years (13 months-62 years), one observer classified 88% (n=67) and a second observer classified 87% (n=66) of patients as either Engel I or II (free from or rare disabling seizures) after a median follow up of 36 months (range 12-92 months); comparably, both observers classified 84% (n=64) as ILAE 1-3. Correlation for Engel versus ILAE for observer 1 was 0.933 (p<.0005) and for observer 2 was 0.931 (p<.0005). Both ILAE (k 0.81, 95% confidence intervals 0.69, 0.91) and Engel (k 0.77, 95% CI 0.65, 0.87) classifications have very acceptable inter-rater reliability as well as significant correlation.

Stem cells in the adult human brain.

The rapidly advancing field of stem cell research holds great promise for regenerative medicine. Regenerating brain tissue, while technically the most challenging application of stem cell biology, is also likely to reap the most reward for patients. Here, we review the current state of stem cell research in the field of human neuroscience and highlight aspects that will be of relevance to neurosurgeons.

Maternal low-protein diet during mouse pre-implantation development induces vascular dysfunction and altered renin-angiotensin-system homeostasis in the offspring.

Environmental perturbations during early mammalian development can affect aspects of offspring growth and cardiovascular health. We have demonstrated previously that maternal gestational dietary protein restriction in mice significantly elevated adult offspring systolic blood pressure. Therefore, the present study investigates the key mechanisms of blood pressure regulation in these mice. Following mating, female MF-1 mice were assigned to either a normal-protein diet (NPD; 18 % casein) or an isocaloric low-protein diet throughout gestation (LPD; 9 % casein), or fed the LPD exclusively during the pre-implantation period (3.5 d) before returning to the NPD for the remainder of gestation (Emb-LPD). All offspring received standard chow. At 22 weeks, isolated mesenteric arteries from LPD and Emb-LPD males displayed significantly attenuated vasodilatation to isoprenaline (P = 0.04 and P = 0.025, respectively), when compared with NPD arteries. At 28 weeks, stereological analysis of glomerular number in female left kidneys revealed no significant difference between the groups. Real-time RT-PCR analysis of type 1a angiotensin II receptor, Na+/K+ ATPase transporter subunits and glucocorticoid receptor expression in male and female left kidneys revealed no significant differences between the groups. LPD females displayed elevated serum angiotensin-converting enzyme (ACE) activity (P = 0.044), whilst Emb-LPD males had elevated lung ACE activity (P = 0.001), when compared with NPD offspring. These data demonstrate that elevated offspring systolic blood pressure following maternal gestational protein undernutrition is associated with impaired arterial vasodilatation in male offspring, elevated serum and lung ACE activity in female and male offspring, respectively, but kidney glomerular number in females and kidney gene expression in male and female offspring appear unaffected.

NPY augments the proliferative effect of FGF2 and increases the expression of FGFR1 on nestin positive postnatal hippocampal precursor cells, via the Y1 receptor.

We have shown that neuropeptide Y (NPY), a peptide neurotransmitter released by hippocampal interneurons, is proliferative for hippocampal neural stem progenitor cells (NSPCs) via the Y1 receptor. Fibroblast growth factor (FGF) 2, released predominantly by astrocytes, is also a powerful mitogen for postnatal and adult NSPCs, via the FGFR1 receptor. Knockout studies show that NPY and FGF2 are individually necessary, but not sufficient, for seizure-induced neurogenesis, suggesting a possible interaction. Here, we examined for interactions between NPY and FGF2 on NSPCs from the postnatal hippocampus and report that the combination of NPY and FGF2 significantly shortens the cell cycle time of nestin positive NSPCs, more than either factor alone. This augmentation of proliferation rate is NPY Y1 receptor mediated, and Y1 receptor activation increases both FGFR1 mRNA and protein in NSPC cultures. NSPCs immunostain for both Y1 and FGFR1 receptors and the interaction is specific for dentate NSPCs. This is the first report of a proliferative factor that augments the proliferative effect of FGF2 and is the first evidence of a positive proliferative interaction between a glial growth factor and a neuronal transmitter, identifying a novel neural activity driven mechanism for modulating the proliferation of hippocampal NSPCs.

Selective temporal resections and spatial memory impairment: cue dependent lateralization effects.

Patients who had undergone a unilateral trans-sylvian selective amygdalohippocampectomy as treatment for chronic intractable epilepsy were tested in a virtual Morris Water Maze (MWM) task where they were required to locate a hidden platform as a measure of spatial learning. These individuals' performance on spatial tasks was compared to age-matched healthy controls and drug-matched healthy controls. Training occurred in two different maze environments, one with conventional cues such as windows and doors, and another with abstract cues, such as colours and patterns. Participants searched for a hidden platform in the virtual pool, guided by either the conventional or abstract cues. There was a significant impairment in the surgery group compared to the control groups in all environments, however in the abstract environment only the patients with right-sided lesions were significantly worse than the controls. There was no difference between the groups on a control egocentric navigation task. These results suggest that people who have had right-sided surgery are impaired in spatial tasks, and that the level of impairment on the spatial task may be dependent on the characteristics of the cues such as how easily the cues are verbalised. These results support the notion of the functional lateralization of specific elements of spatial memory and functional lateralization, and may shed light on previous inconsistencies in this area of research.

The neurotransmitter VIP expands the pool of symmetrically dividing postnatal dentate gyrus precursors via VPAC2 receptors or directs them toward a neuronal fate via VPAC1 receptors.

The controlled production of neurons in the postnatal dentate gyrus and throughout life is important for hippocampal learning and memory. The mechanisms underlying the necessary coupling of neuronal activity to neural stem/progenitor cell (NSPC) function remain poorly understood. Within the dentate subgranular stem cell niche, local interneurons appear to play an important part in this excitation-neurogenesis coupling via GABAergic transmission, which promotes neuronal differentiation and integration. Here we show that vasoactive intestinal polypeptide, a neuropeptide coreleased with GABA under specific firing conditions, is uniquely trophic for proliferating postnatal nestin-positive dentate NSPCs, mediated via the VPAC(2) receptor. We also show that VPAC(2) receptor activation shifts the fate of symmetrically dividing NSPCs toward a nestin-only phenotype, independent of the trophic effect. In contrast, selective VPAC(1) receptor activation shifts NSPC fate toward granule cell neurogenesis without any trophism. We confirm a trophic role for VPAC(2) receptors in vivo, showing reduced progeny survival and dentate neurogenesis in adult Vipr2(-/-) mice. We also show a specific reduction in type 2 nestin-positive precursors in vivo, consistent with a role for VPAC(2) in maintaining this cell population. This work provides the first evidence of differential fate modulation of neurogenesis by neurotransmitter receptor subtypes and extends the fate-determining effects of neurotransmitters to maintaining the nestin-positive pool of NSPCs. This differential receptor effect may support the independent pharmacological manipulation of precursor pool expansion and neurogenic instruction for therapeutic application in the treatment of cognitive deficits associated with a decline in neurogenesis.

Neuropeptide Y is neuroproliferative for post-natal hippocampal precursor cells.

New neurones are produced in the adult hippocampus throughout life and are necessary for certain types of hippocampal learning. Little, however, is known about the control of hippocampal neurogenesis. We used primary hippocampal cultures from early post-natal rats and neuropeptide Y Y1 receptor knockout mice as well as selective neuropeptide Y receptor antagonists and agonists to demonstrate that neuropeptide Y is proliferative for nestin-positive, sphere-forming hippocampal precursor cells and beta-tubulin-positive neuroblasts and that the neuroproliferative effect of neuropeptide Y is mediated via its Y1 receptor. Immunohistochemistry confirmed Y1 receptor staining on both nestin-positive cells and beta-tubulin-positive cells in culture and short pulse 5-bromo-2-deoxyuridine studies demonstrated that neuropeptide Y has a proliferative effect on both cell types. These studies suggest that the proliferation of hippocampal neuroblasts and precursor cells is increased by neuropeptide Y and, therefore, that hippocampal learning and memory may be modulated by neuropeptide Y-releasing interneurones.