Expanding the phenotypic spectrum of CLCN2-related leucoencephalopathy and ataxia.

Mutations in CLCN2 are a rare cause of autosomal recessive leucoencephalopathy with ataxia and specific imaging abnormalities. Very few cases have been reported to date. Here, we describe the clinical and imaging phenotype of 12 additional CLCN2 patients and expand the known phenotypic spectrum of this disorder. Informed consent was obtained for all patients. Patients underwent either whole-exome sequencing or focused/panel-based sequencing to identify variants. Twelve patients with biallelic CLCN2 variants are described. This includes three novel likely pathogenic missense variants. All patients demonstrated typical MRI changes, including hyperintensity on T2-weighted images in the posterior limbs of the internal capsules, midbrain cerebral peduncles, middle cerebellar peduncles and cerebral white matter. Clinical features included a variable combination of ataxia, headache, spasticity, seizures and other symptoms with a broad range of age of onset. This report is now the largest case series of patients with CLCN2-related leucoencephalopathy and reinforces the finding that, although the imaging appearance is uniform, the phenotypic expression of this disorder is highly heterogeneous. Our findings expand the phenotypic spectrum of CLCN2-related leucoencephalopathy by adding prominent seizures, severe spastic paraplegia and developmental delay.

Feasibility of comparing medical management and surgery (with neurosurgery or stereotactic radiosurgery) with medical management alone in people with symptomatic brain cavernoma - protocol for the Cavernomas: A Randomised Effectiveness (CARE) pilot trial.

INTRODUCTION: The top research priority for cavernoma, identified by a James Lind Alliance Priority setting partnership was 'Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?' This pilot randomised controlled trial (RCT) aims to determine the feasibility of answering this question in a main phase RCT. METHODS AND ANALYSIS: We will perform a pilot phase, parallel group, pragmatic RCT involving approximately 60 children or adults with mental capacity, resident in the UK or Ireland, with an unresected symptomatic brain cavernoma. Participants will be randomised by web-based randomisation 1:1 to treatment with medical management and with surgery (neurosurgery or stereotactic radiosurgery) versus medical management alone, stratified by prerandomisation preference for type of surgery. In addition to 13 feasibility outcomes, the primary clinical outcome is symptomatic intracranial haemorrhage or new persistent/progressive focal neurological deficit measured at 6 monthly intervals. An integrated QuinteT Recruitment Intervention (QRI) evaluates screening logs, audio recordings of recruitment discussions, and interviews with recruiters and patients/parents/carers to identify and address barriers to participation. A Patient Advisory Group has codesigned the study and will oversee its progress. ETHICS AND DISSEMINATION: This study was approved by the Yorkshire and The Humber-Leeds East Research Ethics Committee (21/YH/0046). We will submit manuscripts to peer-reviewed journals, describing the findings of the QRI and the Cavernomas: A Randomised Evaluation (CARE) pilot trial. We will present at national specialty meetings. We will disseminate a plain English summary of the findings of the CARE pilot trial to participants and public audiences with input from, and acknowledgement of, the Patient Advisory Group. TRIAL REGISTRATION NUMBER: ISRCTN41647111.

Nitrous oxide-induced myeloneuropathy: a case series.

BACKGROUND: Nitrous oxide (N2O) is the second most common recreational drug used by 16- to 24-year-olds in the UK. Neurological symptoms can occur in some people that use N2O recreationally, but most information comes from small case series. METHODS: We describe 119 patients with N2O-myeloneuropathy seen at NHS teaching hospitals in three of the UK's largest cities: London, Birmingham and Manchester. This work summarises the clinical and investigative findings in the largest case series to date. RESULTS: Paraesthesia was the presenting complaint in 85% of cases, with the lower limbs more commonly affected than the upper limbs. Gait ataxia was common, and bladder and bowel disturbance were frequent additional symptoms. The mid-cervical region of the spinal cord (C3-C5) was most often affected on MRI T2-weighted imaging. The number of N2O canisters consumed per week correlated with methylmalonic acid levels in the blood as a measure of functional B12 deficiency (rho (ρ)=0.44, p=0.04). CONCLUSIONS: Preventable neurological harm from N2O abuse is increasingly seen worldwide. Ease of access to canisters and larger cylinders of N2O has led to an apparent rise in cases of N2O-myeloneuropathy in several areas of the UK. Our results highlight the range of clinical manifestations in a large group of patients to improve awareness of risk, aid early recognition, and promote timely treatment.

Volume maximised glycerol rhizolysis for trigeminal neuralgia: a single centre analysis of outcomes.

OBJECTIVES: Glycerol rhizotomy is an established treatment for medically refractory trigeminal neuralgia in select cases where microvascular decompression is contraindicated or not preferred. The standard approach is to inject a fixed volume of glycerol using Hartel's technique into Meckel's cave. We discuss a 'volume-maximised' technique of measuring the volume of Meckel's cave using intra-operative fluoroscopy and injecting an equivalent volume of glycerol such that every patient receives a tailored quantity of glycerol dependent on the volume of Meckel's cave. The safety and efficacy of this approach is analysed. METHODS: A retrospective analysis of 53 procedures where volume-maximised glycerol rhizolysis was utilised over a 7-year period (2012 -2018) at a single centre by the senior author was carried out. The incidence and duration of pain freedom and complications incurred over a median follow-up period of 8 years were analysed. RESULTS: 37 procedures were carried out for typical trigeminal neuralgia, 13 for secondary trigeminal neuralgia, and 3 for atypical trigeminal neuralgia. Overall, pain freedom was achieved in 85% cases, and 92% in patients with typical trigeminal neuralgia. Median duration of pain freedom in patients with typical trigeminal neuralgia was 63 months, versus 6 months in those with secondary trigeminal neuralgia (p < 0.00001). 14 procedures (26.4%) resulted in mild and temporary complications. 54.7% of cases experienced hypoaesthesia in a distribution similar to or less extensive than the distribution of trigeminal neuralgia. The presence of hypoaesthesia post-procedure was highly predictive of longer pain freedom (95 months versus 8 months median pain freedom (p = 0.00003)). CONCLUSIONS: Volume-maximised glycerol injection is safe and effective when compared to literature-reported outcomes post-standard volume glycerol injections. The duration of pain freedom achieved exceeds most literature-reported studies, with hypoaesthesia outcomes being comparable with previous studies. Pain freedom outcomes are more favourable in those with post-procedure hypoaesthesia.

Nitrous oxide-induced subacute combined degeneration of the cord: diagnosis and treatment.

Recreational use of nitrous oxide (N2O) has increased rapidly in recent years and is now the second most commonly used recreational drug among young people in the UK. There has been a corresponding rise in cases of nitrous oxide-induced subacute combined degeneration of the cord (N2O-SACD), a pattern of myeloneuropathy usually associated with severe vitamin B12 deficiency. This can cause serious and permanent disability in young people but, if recognised early, may be effectively treated. All neurologists should be aware of N2O-SACD and its treatment; however, there are currently no agreed guidelines. Based on our experience in East London, an area of high N2O use, we provide practical advice on its recognition, investigation and treatment.

The prognostic value of resting-state EEG in acute post-traumatic unresponsive states.

Accurate early prognostication is vital for appropriate long-term care decisions after traumatic brain injury. While measures of resting-state EEG oscillations and their network properties, derived from graph theory, have been shown to provide clinically useful information regarding diagnosis and recovery in patients with chronic disorders of consciousness, little is known about the value of these network measures when calculated from a standard clinical low-density EEG in the acute phase post-injury. To investigate this link, we first validated a set of measures of oscillatory network features between high-density and low-density resting-state EEG in healthy individuals, thus ensuring accurate estimation of underlying cortical function in clinical recordings from patients. Next, we investigated the relationship between these features and the clinical picture and outcome of a group of 18 patients in acute post-traumatic unresponsive states who were not following commands 2 days+ after sedation hold. While the complexity of the alpha network, as indexed by the standard deviation of the participation coefficients, was significantly related to the patients' clinical picture at the time of EEG, no network features were significantly related to outcome at 3 or 6 months post-injury. Rather, mean relative alpha power across all electrodes improved the accuracy of outcome prediction at 3 months relative to clinical features alone. These results highlight the link between the alpha rhythm and clinical signs of consciousness and suggest the potential for simple measures of resting-state EEG band power to provide a coarse snapshot of brain health for stratification of patients for rehabilitation, therapy and assessments of both covert and overt cognition.

Covert Speech Comprehension Predicts Recovery From Acute Unresponsive States.

OBJECTIVE: Patients with traumatic brain injury who fail to obey commands after sedation-washout pose one of the most significant challenges for neurological prognostication. Reducing prognostic uncertainty will lead to more appropriate care decisions and ensure provision of limited rehabilitation resources to those most likely to benefit. Bedside markers of covert residual cognition, including speech comprehension, may reduce this uncertainty. METHODS: We recruited 28 patients with acute traumatic brain injury who were 2 to 7 days sedation-free and failed to obey commands. Patients heard streams of isochronous monosyllabic words that built meaningful phrases and sentences while their brain activity via electroencephalography (EEG) was recorded. In healthy individuals, EEG activity only synchronizes with the rhythm of phrases and sentences when listeners consciously comprehend the speech. This approach therefore provides a measure of residual speech comprehension in unresponsive patients. RESULTS: Seventeen and 16 patients were available for assessment with the Glasgow Outcome Scale Extended (GOSE) at 3 months and 6 months, respectively. Outcome significantly correlated with the strength of patients' acute cortical tracking of phrases and sentences (r > 0.6, p < 0.007), quantified by inter-trial phase coherence. Linear regressions revealed that the strength of this comprehension response (beta = 0.603, p = 0.006) significantly improved the accuracy of prognoses relative to clinical characteristics alone (eg, Glasgow Coma Scale [GCS], computed tomography [CT] grade). INTERPRETATION: A simple, passive, auditory EEG protocol improves prognostic accuracy in a critical period of clinical decision making. Unlike other approaches to probing covert cognition for prognostication, this approach is entirely passive and therefore less susceptible to cognitive deficits, increasing the number of patients who may benefit. ANN NEUROL 2021;89:646-656.

Enlarged and Enhancing Optic Nerves in Advanced Glial Fibrillary Acidic Protein Meningoencephalomyelitis.

A 36-year-old woman presented with intermittent fever, nausea and vomiting, generalized polyarthralgias, and bilateral optic disc swelling. She had a history of difficult-to-control myasthenia gravis since the age of 18 years. Lumbar puncture demonstrated a normal opening pressure; cerebrospinal fluid (CSF) was remarkable for high protein, low glucose, and a mononuclear pleocytosis. Although initial MRI of the brain was normal, a repeat study 8 weeks later revealed enlarged and enhancing bilateral intraorbital and intracranial optic nerves. After a nondiagnostic brain biopsy, a CSF sample tested positive for antibodies to glial fibrillary acidic protein (GFAP). Findings in this case indicate that optic nerve swelling encountered in GFAP meningoencephalomyelitis is more likely due to optic nerve inflammation rather than elevated intracranial pressure.

Association Between Hospital Volume and Mortality in Status Epilepticus: A National Cohort Study.

OBJECTIVES: In various medical and surgical conditions, research has found that centers with higher patient volumes have better outcomes. This relationship has not previously been explored for status epilepticus. This study sought to examine whether centers that see higher volumes of patients with status epilepticus have lower in-hospital mortality than low-volume centers. DESIGN: Cohort study, using 2010-2015 data from the nationwide Case Mix Programme database of the U.K.'s Intensive Care National Audit and Research Centre. SETTING: Greater than 90% of ICUs in United Kingdom, Wales, and Northern Ireland. PATIENTS: Twenty-thousand nine-hundred twenty-two adult critical care admissions with a primary or secondary diagnosis of status epilepticus or prolonged seizure. INTERVENTIONS: Annual hospital status epilepticus admission volume. MEASUREMENTS AND MAIN RESULTS: We used multiple logistic regression to evaluate the association between hospital annual status epilepticus admission volume and in-hospital mortality. Hospital volume was modeled as a nonlinear variable using restricted cubic splines, and generalized estimating equations with robust SEs were used to account for clustering by institution. There were 2,462 in-hospital deaths (11.8%). There was no significant association between treatment volume and in-hospital mortality for status epilepticus (p = 0.54). This conclusion was unchanged across a number of subgroup and sensitivity analyses, although we lacked data on seizure duration and medication use. Secondary analyses suggest that many high-risk patients were already transferred from low- to high-volume centers. CONCLUSIONS: We find no evidence that higher volume centers are associated with lower mortality in status epilepticus overall. It is likely that national guidelines and local pathways in the United Kingdom allow efficient patient transfer from smaller centers like district general hospitals to provide satisfactory patient care in status epilepticus. Future research using more granular data should explore this association for the subgroup of patients with refractory and superrefractory status epilepticus.

Clinical outcomes of VNS therapy with AspireSR® (including cardiac-based seizure detection) at a large complex epilepsy and surgery centre.

PURPOSE: To compare the efficacy of AspireSR® to preceding VNS battery models for battery replacements, and to determine the efficacy of the AspireSR® for new implants. METHODS: Data were collected retrospectively from patients with epilepsy who had VNS AspireSR® implanted over a three-year period between June 2014 and June 2017 by a single surgeon. Cases were divided into two cohorts, those in whom the VNS was a new insertion, and those in whom the VNS battery was changed from a previous model to AspireSR®. Within each group, the seizure burden was compared between the periods before and after insertion of AspireSR®. RESULTS: Fifty-one patients with a newly inserted AspireSR® VNS model had a significant reduction in seizure frequency (p < 0.001), with 59% (n = 30) reporting ≥50% reduction. Of the 62 patients who had an existing VNS, 53% (n = 33) reported ≥50% reduction in seizure burden when the original VNS was inserted. After the battery was changed to the AspireSR®, 71% (n = 44) reported a further reduction of ≥50% in their seizure burden. The size of this reduction was at least as large as that resulting from the insertion of their existing VNS in 98% (61/62) of patients. CONCLUSION: The results suggest that approximately 70% of patients with existing VNS insertions could have significant additional benefit from cardiac based seizure detection and closed loop stimulation from the AspireSR® device. For new insertions, the AspireSR® device has efficacy in 59% of patients. The 'rule of thirds' used in counseling patients may need to be modified accordingly.

'The great imitator': Neurosyphilis and new-onset refractory status epilepticus (NORSE) syndrome.

New-onset refractory status epilepticus (NORSE) is a syndrome of new-onset drug resistant status epilepticus that often has a catastrophic outcome. A 30-year-old man of Somali origin presented with refractory status to a district general hospital. A clinical diagnosis of NORSE syndrome was made, and he was transferred to the regional epilepsy center for immunomodulatory treatment and consideration for cyclophosphamide treatment. After transfer to the regional epilepsy center, his repeat cerebrospinal fluid tested strongly positive for syphilis, indicating a diagnosis of neurosyphilis, and the patient was treated with high-dose intravenous (IV) benzylpenicillin. His status epilepticus abated 24 h later. New-onset refractory status epilepticus syndrome is a diagnosis of exclusion. Before instigation of potentially harmful neuromodulatory therapies, treatable causes such as neurosyphilis should be considered. We advocate the early transfer of refractory status patients to a specialist epilepsy center for both seizure management and cause determination.

Improving the likelihood of neurology patients being examined using patient feedback.

We aimed to establish whether recall of elements of the neurological examination can be improved by use of a simple patient assessment score. In a previous study we demonstrated that in-patients referred to neurology at two United Kingdom (UK) hospitals were not fully examined prior to referral; we therefore designed a larger quality improvement report with 80% power to detect a 10% increase in tendon hammer or ophthalmoscope use following an educational intervention. In-patients referred to neurology over a four month period (in hospitals in the UK (10), Jordan (1), Sweden (2), and the United Arab Emirates (1)) were asked whether they recalled being examined with a tendon hammer (T), ophthalmoscope (O), and stethoscope (S) since admission. The results were disseminated to local medical teams using various techniques (including Grand Round presentations, email, posters, discounted equipment). Data were then collected for a further four month period post-intervention. Pre-intervention and post-intervention data were available for 11 centres with 407 & 391 patients in each arm respectively. Median age of patients was 51 (range 13-100) and 49 (range 16-95) years respectively, with 44.72% and 44.76% being male in each group. 264 patients (64.86%) recalled being examined with a tendon hammer in the pre-intervention arm, which significantly improved to 298 (76.21%) (p<0.001). Only 119 patients (29.24%) recollected examination with an ophthalmoscope pre-intervention, which significantly improved to 149 (38.11%)(p=0.009). The majority of patients (321 (78.87%)) pre-intervention recalled examination with a stethoscope, which significantly improved to 330 (84.4%) to a lesser extent (p=0.045). Results indicate that most patients are not fully examined prior to neurology referral yet a simple assessment score and educational intervention can improve recall of elements of the neurological examination and thus the likelihood of patients being examined neurologically. This is the largest and - to our knowledge - only study to assess this issue. This has implications for national neurological educators.

Lesson of the month 2: a case of coma in a Parkinson's patient: a combination of fatigue, dehydration and high protein diet over the New Year period?

Although motor fluctuation can often be severe in Parkinson's disease (PD), it is rare for an 'off period' to result in coma. The case presented here is of a patient with longstanding PD who was admitted to our hospital with a Glasgow Coma Scale of three after missing just one or two doses of her medication. Investigation for infective, neurovascular and metabolic causes of coma were negative and the patient recovered very rapidly following reinstitution of dopaminergic therapy via nasogastric tube. This case highlights how florid the presentation of motor fluctuations in PD can be and the importance of restarting treatment as quickly as possible. Guidance is provided on how to administer dopaminergic medications in patients who are unable to swallow.

Biomarker report from the phase II lamotrigine trial in secondary progressive MS - neurofilament as a surrogate of disease progression.

OBJECTIVE: Lamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment. METHODS: SPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12-24 and 0-24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored. RESULTS: Treatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12-24 months p=0.043, Nfh 0-24 months p=0.023). Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand), PASAT, z-score, MSIS-29 (psychological) and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin. CONCLUSIONS: The relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration.