Initial experience using middle meningeal artery embolisation for patients with recurrent and high-recurrence-risk chronic subdural haematoma.

Recurrence rates following surgical management of chronic subdural haematoma (CSDH) range from 5 to 33 %. There is growing evidence which suggests middle meningeal artery embolisation (MMAe) may reduce recurrence rates when used as surgical adjunct or standalone treatment. In this study we described our experience of this new procedure in the our UK institution. Patients with recurrent CSDH or CSDH at high risk of recurrence were selected for MMAe on a case-by-case basis following MDT discussion. A departmental database was used to identify patients treated. 26 CSDH were embolised in 20 patients; 9 CSDH were de-novo and 17 were recurrent. 10/26 CSDH were treated with MMAe only. No procedural mortality, access site or thrombo-embolic complications occurred. One patient experienced symptomatic collection growth 12 h following MMAe and required surgical drainage. 15 (75 %) of patients were living at home at follow-up (mean 14 months). On imaging follow-up 15/18 showed CSDH volume reduction or resolution, 1/18 remained stable requiring no further treatment, 2/18 patients suffered recurrent CSDH requiring treatment. In both recurrent cases incomplete embolisation was noted on procedural imaging (posterior division of MMA not embolised). Persistent posterior MMA division filling was significantly associated with collection recurrence (p = 0.002). Our results suggest MMAe as a stand-alone or adjuvant therapy can be performed safely in a UK neuroscience setting and is associated with high rates of symptomatic CSDH size reduction or resolution in problematic CSDH that have either recurred or are prone to recurrence.

The use of cerebral computed tomographic angiography as an ancillary investigation to support a clinical diagnosis of death using neurological criteria: a consensus guideline.

This multidisciplinary consensus statement was produced following a recommendation by the Faculty of Intensive Care Medicine to develop a UK guideline for ancillary investigation, when one is required, to support the diagnosis of death using neurological criteria. A multidisciplinary panel reviewed the literature and UK practice in the diagnosis of death using neurological criteria and recommended cerebral CT angiography as the ancillary investigation of choice when death cannot be confirmed by clinical criteria alone. Cerebral CT angiography has been shown to have 100% specificity in supporting a diagnosis of death using neurological criteria and is an investigation available in all acute hospitals in the UK. A standardised technique for performing the investigation is described alongside a reporting template. The panel were unable to make recommendations for ancillary testing in children or patients receiving extracorporeal membrane oxygenation.

The mitochondrial RNA granule modulates manganese-dependent cell toxicity.

Prolonged manganese exposure causes manganism, a neurodegenerative movement disorder. The identity of adaptive and nonadaptive cellular processes targeted by manganese remains mostly unexplored. Here we study mechanisms engaged by manganese in genetic cellular models known to increase susceptibility to manganese exposure, the plasma membrane manganese efflux transporter SLC30A10 and the mitochondrial Parkinson's gene PARK2. We found that SLC30A10 and PARK2 mutations as well as manganese exposure compromised the mitochondrial RNA granule composition and function, resulting in disruption of mitochondrial transcript processing. These RNA granule defects led to impaired assembly and function of the mitochondrial respiratory chain. Notably, cells that survived a cytotoxic manganese challenge had impaired RNA granule function, thus suggesting that this granule phenotype was adaptive. CRISPR gene editing of subunits of the mitochondrial RNA granule, FASTKD2 or DHX30, as well as pharmacological inhibition of mitochondrial transcription-translation, were protective rather than deleterious for survival of cells acutely exposed to manganese. Similarly, adult Drosophila mutants with defects in the mitochondrial RNA granule component scully were safeguarded from manganese-induced mortality. We conclude that impairment of the mitochondrial RNA granule function is a protective mechanism for acute manganese toxicity.

Quantitative EEG (qEEG) guided transcranial magnetic stimulation (TMS) treatment for depression and anxiety disorders: An open, observational cohort study of 210 patients.

BACKGROUND: Major depression and anxiety disorders represent a substantial burden of morbidity. Neither antidepressant medication nor psychological interventions are fully effective, the former beset with side effects, interactions and compliance issues, and the latter requiring patient engagement, effort and a degree of psychological mindedness. Both treatments are lengthy. TMS by contrast is virtually free of side effects and compliance issues, relatively brief, and requires no patient effort. Nevertheless, remission rates are only about 1 in 3 with standard left frontal rapid (rTMS) stimulation, and up to 30 treatment sessions may be required. Our aim was to improve the effectiveness of TMS treatment using bespoke as opposed to standard left frontal rTMS, including theta burst stimulation (TBS). METHODS: 210 male and female patients were treated: regions and frequencies of TMS were guided by quantitative EEG analysis (qEEG) to elicit recognisable phenotypes, neuromarkers integral to the genesis of major depression and anxiety disorder, dictating treatment parameters. RESULTS: 98 patients (47%) achieved at least 50% reduction in Hamilton depression rating scale scores, while a further 60 (29%) patients achieved a 30-50% reduction, over a mean of 7.03 ± 0.3 treatment sessions. Theta burst stimulation (TBS) almost halved treatment time within session compared to rTMS. The effect size (Cohen's d) for both treatments was large (>0.8) with rTMS at 1.43 (1.16-1.70) and TBS at 1.87 (1.48-2.25). CONCLUSIONS: qEEG guided TMS treatment is a safe and effective treatment in depression and anxiety disorders.

Electroencephalographic (EEG) features of encephalopathy in the setting of Covid-19: A case series.

OBJECTIVE: The Covid-19 pandemic is a global challenge presenting clinicians with an evolving diagnostic landscape. We sought to describe EEG findings observed from local experience in a typical case series of patients with severe Covid-19. METHODS: Ten cases of Covid-19 were identified in whom EEG recordings had been made during the course of admissions to Bristol hospitals which had required intensive care. Electro-clinical correlation between the EEG and available medical history, imaging and laboratory investigation results was explored. RESULTS: The predominant EEG features in severe Covid-19 are of generalised symmetrical slowing, consistent with encephalopathy. CONCLUSIONS: The presence of focal disturbances or irritative abnormalities may be a pointer away from a pure encephalopathy and warrant further investigation. SIGNIFICANCE: A growing range of neurological sequelae from Covid-19 are now recognised to be common amongst patients hospitalised by with this condition, being seen to affect approximately one third of such cases. Electroencephalography has a unique place in the diagnostic work-up of impaired consciousness, a frequent feature of severe Covid-19. However, there is currently a paucity of literature describing typical EEG findings in this setting.

Compact spatially heterodyned static interferometer.

This paper presents a novel, to the best of our knowledge, and simple technique for achieving a higher spectral resolution in classical static Fourier transform spectrometers. This is achieved by heterodyning the frequency of a standard interferogram to a lower spatial frequency by placing a single transmission grating at the image plane of two mutually coherent beams produced by the interferometer. The grating splits the beams into diffraction orders, which overlap to produce the heterodyned interferogram, similar to that seen in techniques such as spatial heterodyne spectroscopy. The increase in spectral resolution for such a system is shown to be related to the angle between the beams and the groove period of the transmission grating. The theoretical performance of this design is compared with a proof-of-concept system built using off-the-shelf components and tested at visible wavelengths. The experimental results agree well with those produced from a theoretical simulation.

Soluble TNF-R1, VEGF and other cytokines as markers of disease activity in systemic lupus erythematosus and lupus nephritis.

BACKGROUND: Current non-invasive methods of assessing disease activity in systemic lupus erythematosus (SLE) are of limited sensitivity and specificity. Testing includes acute phase markers, autoantibodies and complement levels. Although measurements of dsDNA antibodies and complement C3/C4 levels are routine, they remain of limited value. Improved blood and urine markers may help in early detection of flare, distinction between flare and chronic damage, and monitoring response to therapy. METHODS: A total of 87 patients with SLE were tested for the following cytokines in serum and urine: monocyte chemoattractant protein 1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), soluble tumour necrosis factor receptor 1 (sTNF-R1), interferon-inducible protein 10 (IP-10), monocyte inhibitory protein 1α (MIP-1α) and vascular endothelial growth factor (VEGF). Patients attending the Lupus Unit at St Thomas' Hospital, London, UK were divided into active lupus nephritis (LN), inactive LN and non-renal SLE groups based on their renal pathology and SLE disease activity index (SLEDAI). Cytokine testing was performed using the FIDIS multiplex bead assay. RESULTS: The mean level of serum sTNF-R1 was higher in the active LN group compared with both inactive LN and non-renal SLE groups ( p < 0.001). For urine measurements there were significant differences between active LN and non-renal SLE for VEGF ( p = 0.016), after statistical correction for multiple testing. Both urinary and serum sTNF-R1 and IP-10 levels correlated with SLEDAI scores ( p < 0.001), while serum VEGF correlated weakly with SLEDAI ( p = 0.025). The optimum combination for differentiating active from inactive LN patients was serum VEGF, sTNF-R1, MCP-1 and glomerular filtration rate plus urinary sTNF-R1 and protein-creatinine ratio. CONCLUSION: These results indicate that for active LN, sTNF-R1 could be a useful serum cytokine marker, with potential for VEGF in the urine. This study has confirmed the ability of the multiplex bead technique to detect cytokines in a good analytical range, including very low and high levels, in both serum and urine. Combining serum and urine markers provided additional sensitivity in distinguishing active from inactive LN.

Factors impacting on technical success in stroke thrombectomy: experience of a UK neuro-interventional unit.

AIM: To investigate factors that could impact on recanalisation and reperfusion in patients undergoing mechanical thrombectomy and to assess the technical success over time. MATERIALS AND METHODS: Two hundred consecutive patients who underwent thrombectomy for a proximal anterior circulation occlusion were dichotomised into equal groups (groups 1 and 2) based on the date that immediate access to emergency general anaesthesia (GA) commenced. RESULTS: Recanalisation success using thrombolysis in cerebral infarction (TICI) 2b/3 or TICI 2c/3 significantly improved in group 2 (67% versus 93%, p<0.0001; 52% versus 78%, p=0.0002). Symptomatic haemorrhage also reduced from 9% to 4%. Despite similar presentation Alberta Stroke Program Early (computed tomography) CT Scores (ASPECTS), post-procedural ASPECTS was significantly increased in group 2 (7; [interquartile range {IQR} 4-9] versus 8 [IQR 7-9]; p=0.0034). The number of patients with a post procedural ASPECTS of 8-10 increased (46% versus 64%, p=0.0155) and the difference in ASPECTS between pre- and post-thrombectomy CT was significantly lower (2 [IQR 1-4] versus 1 [IQR 0-2], p<0.0001). GA use increased from 8% to 56% (p=0.0001) as did use of distal aspiration (59% versus 87%, p=0.0001) mostly in combination with a stent-retriever. Failed access fell from 8% to 3%. When GA was used, successful recanalisation (TICI 2b/3) was achieved more frequently (90.5% versus 76.7%; OR 3.04, 1.2-7.69, p=0.0187). CONCLUSION: Technical results for thrombectomy are improving over time. Technique modification, operator experience, and judicious use of GA may be contributing.

Mortality from Listeria monocytogenes meningoencephalitis following escalation to alemtuzumab therapy for relapsing-remitting Multiple Sclerosis.

We report the case of a patient who died from the rare complication of Listeriosis in the immediate phase following alemtuzumab administration one month after discontinuing dimethyl fumarate (DMF). There is considerable overlap with typical post-infusion symptoms therefore high surveillance and low threshold for empirical or possible prophylactic antibiotic therapy is advocated.

Spinal dural arteriovenous fistula: delay to radiological diagnosis and sources of radiological error.

AIM: To highlight the magnetic resonance imaging (MRI) signs associated with spinal dural arteriovenous fistula (SDAVF) through categorisation of sources of radiological error and investigation of the delay to radiological diagnosis. MATERIAL AND METHODS: This was a retrospective, observational study of cases referred to a neuroscience centre over 11 years. All patients who underwent spinal digital subtraction angiography (DSA) with a subsequent diagnosis of SDAVF were identified. Prior imaging was reviewed and compared with the formal reports issued. RESULTS: Thirty-seven patients with SDAVF were initially imaged in seven institutions. Radiological abnormalities including intradural vessels (37/37, 100%), cord T2 signal change (34/37, 91.9%), and cord expansion (26/37, 70.2%) were present on prior MRI. These signs were not recognised in 22/37 (59.5%), 7/34 (20.5%), and 15/26 (57.7%) of cases, respectively. Increased T2 signal in the cord was the most commonly identified sign (27/34; 79.4%), but prompted either no diagnosis (7/34; 20.5%) or differential diagnoses including ischaemic, inflammatory, or neoplastic aetiologies or a syrinx in 11/34 (32.4%). An appropriate diagnosis was made on initial MRI in 15 patients (40.5%). The time from initial imaging to diagnosis was significantly delayed for those patients who did not have an arteriovenous vascular aetiology included in the initial differential diagnosis (281 (423.3) days versus 22 (15.7) days, p=0.03). CONCLUSION: SDAVF have imaging features that are frequently missed or misinterpreted. This results in a significant delay to definitive diagnosis and therefore treatment.

Common variants in the chromosome 2p23 region containing the SLC30A3 (ZnT3) gene are associated with schizophrenia in female but not male individuals in a large collection of European samples.

Previously, we found a significant gender-specific association of schizophrenia, in a UK case/control study, with SLC30A3, a candidate that is consistently down-regulated in schizophrenia in two independent cohorts. In view of the potential significance of this finding, we extended this study to a larger cohort using GWAS data from the Psychiatric Genetic Consortium (PGC). Meta-analysis was performed for the only two SLC30A3 SNP variants (rs11126936 and rs11126929) available in most PGC cohorts. A significant association with schizophrenia was found for both variants. When meta-analysis was performed in male and female case-control subsets, an increased and gender-specific effect of allele on risk of disease was found in females for both SNPs with no significant effect in males, which was further associated with a gender-specific effect on gene expression. In conclusion, using a large European-wide sample we were able to replicate the gender-specific association previously found in a UK cohort.

The emerging age of endovascular treatment of acute ischaemic stroke and the role of CT angiography in patient work-up: a guide for the radiologist.

Recent trial evidence suggests that for patients suffering large-vessel occlusive stroke, endovascular therapy based on the stent-retriever technique is associated with superior clinical outcomes when compared to intravenous thrombolysis alone. The challenge now is how this service is to be delivered. This may involve both centralisation of services around large cities and development of robust networks to receive patients from district general hospitals situated further afield. Both diagnostic and interventional neuroradiology will need to expand. Furthermore, we suggest that it would be advantageous for radiology departments in those hospitals receiving hyperacute stroke patients to perform computed tomography (CT) angiography in addition to non-contrast CT, which also has implications for service delivery in these units. This could swiftly aid identification of patients who might benefit from thrombectomy and improve decision-making through demonstration of occlusive thrombus and of collateral status.

Endovascular treatment of 300 consecutive middle cerebral artery aneurysms: clinical and radiologic outcomes.

BACKGROUND AND PURPOSE: There is controversy as to the best mode of treating MCA aneurysms. We report the results of a large endovascular series of patients treated at our center. MATERIALS AND METHODS: This study was a retrospective analysis of a prospectively acquired data base. All patients with saccular MCA aneurysms treated between November 1996 and June 2012 were included. World Federation of Neurosurgical Societies grade, aneurysm site, size, and aneurysm neck size were recorded, along with clinical outcome assessed with the Glasgow Outcome Scale and radiographic occlusion assessed with the Raymond classification at 6 months and 2.5 years. RESULTS: A total of 295 patients with 300 MCA aneurysms were treated including 244 ruptured aneurysms (80.7%). The technical failure rate was 4.3% (13 patients). Complete occlusion or neck remnant was achieved in 264 (91.4%). Complications included rupture in 15 patients (5%), thromboembolism in 17 patients (5.7%), and early rebleeding in 3 patients (1%). Overall permanent procedural-related morbidity and mortality were seen in 12 patients (7.8%). Of the ruptured aneurysms, 189 (79.4%) had a favorable clinical outcome (Glasgow Outcome Scale score, 4-5). A total of 33 patients (13.6%) died. On initial angiographic follow-up, aneurysm remnant was seen in 18 aneurysms (8.1%). A total of 13 patients (4.3%) were re-treated. CONCLUSIONS: Our experience demonstrates that endovascular treatment of MCA aneurysms has an acceptable safety profile with low rates of technical failure and re-treatment. Therefore, coiling is acceptable as the primary treatment of MCA aneurysms.

Allelic variants in the zinc transporter-3 gene, SLC30A3, a candidate gene identified from gene expression studies, show gender-specific association with schizophrenia.

Previous microarray analysis of gene expression in frontal cortex showed differential expression of genes associated with synaptic function in schizophrenia compared to matched-controls in two independent cohorts. One of these genes validated in both cohorts, SLC30A3, which encodes the Zinc Transporter 3 (ZNT3), is localised to synaptic vesicles in glutamate synapses and known to be involved in cognitive function. In view of the robust depletion of SLC30A3 mRNA in two independent studies and the importance of this gene in cognitive function, we investigated whether single nucleotide polymorphism (SNP) associations with schizophrenia could be detected in a UK case controlled schizophrenia cohort. Four SNPs were selected across this gene and genotyped in a cohort of cases and controls from East UK. We found significant associations with schizophrenia at the allelic (ORs: 1.51 to 1.57), genotype (ORs: 1.46 to 1.53) and haplotype level (P=2.15×10(-4)). These associations proved to be gender-specific with significant effects of allele (ORs: 1.74 to 2.11), genotype (ORs: 1.78 to 2.14) and haplotype (P=3.51×10(-5)) observed in female schizophrenia cases but not males, when split by gender. In conclusion, SNPs in SLC30A3 showed a gender-specific association with schizophrenia in this East UK cohort, which merits further investigation in other population samples.