Reduced temporal muscle thickness predicts shorter survival in patients undergoing chronic subdural haematoma drainage.

BACKGROUND: Chronic subdural haematoma (CSDH) drainage is a common neurosurgical procedure. CSDHs cause excess mortality, which is exacerbated by frailty. Sarcopenia contributes to frailty - its key component, low muscle mass, can be assessed using cross-sectional imaging. We aimed to examine the prognostic role of temporal muscle thickness (TMT) measured from preoperative computed tomography head scans among patients undergoing surgical CSDH drainage. METHODS: We retrospectively identified all patients who underwent CSDH drainage within 1 year of February 2019. We measured their mean TMT from preoperative computed tomography scans, tested the reliability of these measurements, and evaluated their prognostic value for postoperative survival. RESULTS: One hundred and eighty-eight (122, 65% males) patients (median age 78 years, IQR 70-85 years) were included. Thirty-four (18%) patients died within 2 years, and 51 (27%) died at a median follow-up of 39 months (IQR 34-42 months). Intra- and inter-observer reliability of TMT measurements was good-to-excellent (ICC 0.85-0.97, P < 0.05). TMT decreased with age (Pearson's r = -0.38, P < 0.001). Females had lower TMT than males (P < 0.001). The optimal TMT cut-off values for predicting two-year survival were 4.475 mm for males and 3.125 mm for females. TMT below these cut-offs was associated with shorter survival in both univariate (HR 3.24, 95% CI 1.85-5.67) and multivariate (HR 1.86, 95% CI 1.02-3.36) analyses adjusted for age, ASA grade and bleed size. The effect of TMT on mortality was not mediated by age. CONCLUSIONS: In patients with CSDH, TMT measurements from preoperative imaging were reliable and contained prognostic information supplemental to previously known predictors of poor outcomes.

Pain and functional neurological disorder: a systematic review and meta-analysis.

BACKGROUND: Functional neurological disorder (FND) is characterised by neurological symptoms, such as seizures and abnormal movements. Despite its significance to patients, the clinical features of chronic pain in people with FND, and of FND in people with chronic pain, have not been comprehensively studied. METHODS: We systematically reviewed PubMed, Embase and PsycINFO for studies of chronic pain in adults with FND and FND in patients with chronic pain. We described the proportions of patients reporting pain, pain rating and timing, pain-related diagnoses and responsiveness to treatment. We performed random effects meta-analyses of the proportions of patients with FND who reported pain or were diagnosed with pain-related disorders. RESULTS: Seven hundred and fifteen articles were screened and 64 were included in the analysis. Eight case-control studies of 3476 patients described pain symptoms in a higher proportion of patients with FND than controls with other neurological disorders. A random effects model of 30 cohorts found that an estimated 55% (95% CI 46% to 64%) of 4272 patients with FND reported pain. Random effects models estimated diagnoses of complex regional pain syndrome in 22% (95% CI 6% to 39%) of patients, irritable bowel syndrome in 16% (95% CI 9% to 24%) and fibromyalgia in 10% (95% CI 8% to 13%). Five studies of FND diagnoses among 361 patients with chronic pain were identified. Most interventions for FND did not ameliorate pain, even when other symptoms improved. CONCLUSIONS: Pain symptoms and pain-related diagnoses are common in FND. Classification systems and treatments should routinely consider pain as a comorbidity in patients with FND.

Care and three-year outcomes of children with Benign Epilepsy with Centro-Temporal Spikes in England.

PURPOSE: Benign Epilepsy with Centro-Temporal Spikes (BECTS) is a pediatric epilepsy with typically good seizure control. Although BECTS may increase patients' risk of developing neurological comorbidities, their clinical care and short-term outcomes are poorly quantified. METHODS: We retrospectively assessed adherence to National Institute for Health and Care Excellence (NICE) guidelines relating to specialist referral, electroencephalogram (EEG) conduct and annual review in the care of patients with BECTS, and measured their seizure, neurodevelopmental and learning outcomes at three years post-diagnosis. RESULTS: Across ten centers in England, we identified 124 patients (74 male) diagnosed with BECTS between 2015 and 2017. Patients had a mean age at diagnosis of 8.0 (95% CI = 7.6-8.4) years. 24/95 (25%) patients were seen by a specialist within two weeks of presentation; 59/100 (59%) received an EEG within two weeks of request; and 59/114 (52%) were reviewed annually. At three years post-diagnosis, 32/114 (28%) experienced ongoing seizures; 26/114 (23%) had reported poor school progress; 15/114 (13%) were diagnosed with a neurodevelopmental disorder (six autism spectrum disorder, six attention-deficit/hyperactivity disorder); and 10/114 (8.8%) were diagnosed with a learning difficulty (three processing deficit, three dyslexia). Center-level random effects models estimated neurodevelopmental diagnoses in 9% (95% CI: 2-16%) of patients and learning difficulty diagnoses in 7% (95% CI: 2-12%). CONCLUSIONS: In this multicenter work, we found variable adherence to NICE guidelines in the care of patients with BECTS and identified a notable level of neurological comorbidity. Patients with BECTS may benefit from enhanced cognitive and behavioral assessment and monitoring.

Reversal of cell, circuit and seizure phenotypes in a mouse model of DNM1 epileptic encephalopathy.

Dynamin-1 is a large GTPase with an obligatory role in synaptic vesicle endocytosis at mammalian nerve terminals. Heterozygous missense mutations in the dynamin-1 gene (DNM1) cause a novel form of epileptic encephalopathy, with pathogenic mutations clustering within regions required for its essential GTPase activity. We reveal the most prevalent pathogenic DNM1 mutation, R237W, disrupts dynamin-1 enzyme activity and endocytosis when overexpressed in central neurons. To determine how this mutation impacted cell, circuit and behavioural function, we generated a mouse carrying the R237W mutation. Neurons from heterozygous mice display dysfunctional endocytosis, in addition to altered excitatory neurotransmission and seizure-like phenotypes. Importantly, these phenotypes are corrected at the cell, circuit and in vivo level by the drug, BMS-204352, which accelerates endocytosis. Here, we demonstrate a credible link between dysfunctional endocytosis and epileptic encephalopathy, and importantly reveal that synaptic vesicle recycling may be a viable therapeutic target for monogenic intractable epilepsies.

Survival and complications following supra- and infratentorial brain metastasis resection.

OBJECTIVE: 15-30% of primary cancers metastasise to the brain. Of these, 10-25% involve the posterior fossa. It remains unclear whether patients undergoing resection for infratentorial brain metastases experience poorer prognosis than those with supratentorial lesions. We compare the post-operative outcomes of these two groups. METHODS: We searched the electronic health records of all patients undergoing brain metastases resection at our regional neurosurgical centre between February 2014 and August 2019. Clinical data was collected on 85 consecutive patients (61 supratentorial, 24 infratentorial metastases). Outcome measures included overall survival, post-operative complications, and performance status. Patients were followed up until 21/04/2020. RESULTS: Median post-operative survival of patients with supratentorial metastases was 323 days (95% CI 235-411), compared to 277 days (95% CI 195-359) for those with infratentorial metastases. These two groups experienced comparable survival (log rank = 0.276, p = 0.60) on univariate analysis. Infratentorial metastasis location was not associated with a change in survival using a Cox proportional hazards model incorporating age, sex and extracranial disease activity (HR = 1.39, 95% CI 0.777-2.486) (p = 0.27). However, neurological and non-neurological post-operative complications were more frequent in patients with infratentorial metastases (neurological = 21% vs 13%, non-neurological = 25% vs 2%, p = 0.002). CONCLUSION: Patients with supra- and infratentorial metastases experienced comparable post-operative survival but posterior fossa metastasis location was associated with a 2.5 times higher risk of neurological and/or non-neurological post-operative complications. A better understanding of the precise indications for safe and effective surgical intervention for posterior fossa metastases is required.

Blood-CNS barrier dysfunction in amyotrophic lateral sclerosis: Proposed mechanisms and clinical implications.

There is strong evidence for blood-brain and blood-spinal cord barrier dysfunction at the early stages of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Since impairment of the blood-central nervous system barrier (BCNSB) occurs during the pre-symptomatic stages of ALS, the mechanisms underlying this pathology are likely also involved in the ALS disease process. In this review, we explore how drivers of ALS disease, particularly mitochondrial dysfunction, astrocyte pathology and neuroinflammation, may contribute to BCNSB impairment. Mitochondria are highly abundant in BCNSB tissue and mitochondrial dysfunction in ALS contributes to motor neuron death. Likewise, astrocytes adopt key physical, transport and metabolic functions at the barrier, many of which are impaired in ALS. Astrocytes also show raised expression of inflammatory markers in ALS and ablating ALS-causing transgenes in astrocytes slows disease progression. In addition, key drivers of neuroinflammation, including TAR DNA-binding protein 43 (TDP-43) pathology, matrix metalloproteinase activation and systemic inflammation, affect BCNSB integrity in ALS. Finally, we discuss the translational implications of BCNSB dysfunction in ALS, including the development of biomarkers for disease onset and progression, approaches aimed at restoring BCNSB integrity and in vitro modelling of the neurogliovascular system.

Role of the glymphatic system in idiopathic intracranial hypertension.

This review discusses the potential significance of glymphatic system dysfunction in the pathophysiology of idiopathic intracranial hypertension (IIH). IIH is a clinical syndrome characterised by signs and symptoms which arise from raised intracranial pressure (ICP), in the absence of a clear primary cause of intracranial hypertension. The underlying pathophysiological mechanisms driving IIH remain unclear and raised cerebrospinal fluid (CSF) secretion, reduced fluid drainage, and elevated cerebral venous sinus pressure do not fully explain the condition's aetiology. There is a growing literature which implicates the glymphatic system, a mechanism by which fluid moves into the brain parenchyma via peri-arterial channels and out via perivenous spaces and brain lymphatics, in IIH pathogenesis. We propose that aquaporin-4 (AQP4) changes, neurogliovascular unit disruption, a pro-inflammatory CSF profile and impaired glymphatic outflow are the main mechanisms driving glymphatic dysfunction in IIH. However, it remains unclear which of these mechanisms are primary causes and which are secondary effects. Further studies using CSF tracers, electron microscopy, and immunohistochemistry are needed to better evaluate the cellular and molecular pathology associated with IIH at different timepoints in the disease course, which will help elucidate the mechanistic role of the glymphatic system in the condition's pathogenesis.