A multiorganism pipeline for antiseizure drug discovery: Identification of chlorothymol as a novel γ-aminobutyric acidergic anticonvulsant.

OBJECTIVE: Current medicines are ineffective in approximately one-third of people with epilepsy. Therefore, new antiseizure drugs are urgently needed to address this problem of pharmacoresistance. However, traditional rodent seizure and epilepsy models are poorly suited to high-throughput compound screening. Furthermore, testing in a single species increases the chance that therapeutic compounds act on molecular targets that may not be conserved in humans. To address these issues, we developed a pipeline approach using four different organisms. METHODS: We sequentially employed compound library screening in the zebrafish, Danio rerio, chemical genetics in the worm, Caenorhabditis elegans, electrophysiological analysis in mouse and human brain slices, and preclinical validation in mouse seizure models to identify novel antiseizure drugs and their molecular mechanism of action. RESULTS: Initially, a library of 1690 compounds was screened in an acute pentylenetetrazol seizure model using D rerio. From this screen, the compound chlorothymol was identified as an effective anticonvulsant not only in fish, but also in worms. A subsequent genetic screen in C elegans revealed the molecular target of chlorothymol to be LGC-37, a worm γ-aminobutyric acid type A (GABAA ) receptor subunit. This GABAergic effect was confirmed using in vitro brain slice preparations from both mice and humans, as chlorothymol was shown to enhance tonic and phasic inhibition and this action was reversed by the GABAA receptor antagonist, bicuculline. Finally, chlorothymol exhibited in vivo anticonvulsant efficacy in several mouse seizure assays, including the 6-Hz 44-mA model of pharmacoresistant seizures. SIGNIFICANCE: These findings establish a multiorganism approach that can identify compounds with evolutionarily conserved molecular targets and translational potential, and so may be useful in drug discovery for epilepsy and possibly other conditions.

UK neurosurgical workforce planning. What changes have occurred in the consultant body 2014-2018?

Introduction: The British Neurosurgery Trainee Association aimed to investigate the amount of trainees qualifying through the British national training scheme and the rate at which potential consultant posts became available from 2014 to 2018.Methodology: A survey was sent to representatives from each neurosurgical unit and deanery across the United Kingdom to ask about the changes in consultant numbers and those who had attained CCT (Completion of Certificate of Training) over 5 years.Results: At the end of 2018, there were 416.5 full-time equivalent consultants in neurosurgical posts, 388.5 in substantive posts; a median of 11 per unit. The rate of vacating substantive posts was 3.04% per year, with 60% doing so due to retirement. There were 119 substantive appointments, 74 of which were expansion posts (an expansion rate of 4.31% per year). 66% of the appointments went to those with a British CCT. 107 trainees achieved CCT over the 5 years. Five separate scenarios are presented to show the potential variation in the future. If current trends continue there will be 666 consultants by 2031 and 102 too few UK-trained trainees to fill consultant posts. If expansion slows to 467 consultants by 2031, there will potentially be 211 post-CCT trainees more than available consultant posts.Conclusion: There is a wide range of outcomes for workforce planning, greatly impacted upon by retirement rates and consultant body expansion; therefore, a workforce planning committee has been created to monitor and respond to the ongoing situation, with representation from the SBNS, BNTA and SAC.

Ventriculitis from a pituitary prolactinoma: bacterial or chemical?

We report the case of a 70-year-old man presenting with pituitary apoplexy from a macroprolactinoma and ventriculitis. It was not possible to distinguish a bacterial or chemical origin, on the basis of his clinical presentation, laboratory studies and imaging, highlighting the importance of prompt imaging and attainment of CSF cultures, in making the diagnosis.

Trigeminal neuralgia from an Arteriovenous malformation: An intra-operative diagnosis.

We report the case of a 72-year-old lady with a magnetic resonance imaging (MRI) occult arteriovenous malformation (AVM) causing trigeminal neuralgia (TN). The possibility of an AVM when managing patients with TN should be borne in mind. Where possible, decompression of the trigeminal nerve should be attempted, as first-line therapy.

Split mesencephalon: diplomyelia of the basicranium.

We report a novel case of congenitally split mesencephalon, in a 3-year old with hydrocephalus. We speculate that the ontogenetic mechanism is shared with split cord malformations (SCM). Our case adds to the two other cases of basicranial SCM which involved more caudal brainstem.

Terson's syndrome diagnosed by CT.

We report a case of Terson's syndrome diagnosed by a CT head scan. The presence of vitreous haemorrhage may not be appreciated clinically in unwell patients with a subarachnoid haemorrhage. Therefore features of vitreous haemorrhage should be sought on CT head imaging in patients presenting with a subarachnoid haemorrhage.

Management of glioblastoma multiforme in pregnancy.

Glioblastoma multiforme presenting during pregnancy presents unique challenges to the clinician. In planning treatment, potential benefits to the mother must be balanced against the risks to the fetus. In addition, evidence relating to timing of surgery and the use of radiotherapy and chemotherapy in pregnancy is limited. Management of peritumoral edema and seizures in pregnancy is also complicated by the potential for drug-related teratogenic effects and adverse neonatal outcomes on the fetus. The general anesthetic used for surgery must factor obstetric and neurosurgical considerations. In this review article, the authors seek to examine the role, safety, and timing of therapies for glioblastoma in the context of pregnancy. This covers the use of radiotherapy and chemotherapy, timing of surgery, postoperative care, anesthetic considerations, and use of anticonvulsant medications and steroids. The authors hope that this will provide a framework for clinicians treating pregnant patients with glioblastomas.

Why the confusion in Hashimoto's encephalopathy?

A 13-year-old girl presented with an afebrile seizure followed by prolonged confusion and visual hallucinations. Initial investigations in the form of blood tests, cerebrospinal fluid analysis and head imaging by CT, were normal. She represented with two further episodes within a period of 3 weeks. Further investigations considering infective, metabolic and some autoimmune causes of encephalopathy were negative. An MRI head scan was normal. Thyroid function testing disclosed primary hypothyroidism and elevated antithyroid antibodies. She responded well to glucocorticoid therapy for presumed Hashimoto's encephalopathy (HE). HE describes patients with various neurological manifestations with elevated titres of antithyroid antibodies. There are no clear criteria for diagnosis, with many cases labelled as HE. Responses to corticosteroid therapy are favourable. In patients with unexplained encephalopathy, HE should be considered given the favourable response to glucocorticoid therapy.