Search

In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors. Between January 1998 and June 2018, we identified 111 patients with genetically determined mitochondrial disease who developed stroke-like episodes. Post-mortem cases of mitochondrial disease (n = 26) were identified from Newcastle Brain Tissue Resource. The primary outcome was to interrogate the clinico-radiopathological correlates and prognostic indicators of stroke-like episode in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). The secondary objective was to develop a multivariable prediction model to forecast stroke-like episode risk. The most common genetic cause of stroke-like episodes was the m.3243A>G variant in MT-TL1 (n = 66), followed by recessive pathogenic POLG variants (n = 22), and 11 other rarer pathogenic mitochondrial DNA variants (n = 23). The age of first stroke-like episode was available for 105 patients [mean (SD) age: 31.8 (16.1)]; a total of 35 patients (32%) presented with their first stroke-like episode ≥40 years of age. The median interval (interquartile range) between first and second stroke-like episodes was 1.33 (2.86) years; 43% of patients developed recurrent stroke-like episodes within 12 months. Clinico-radiological, electrophysiological and neuropathological findings of stroke-like episodes were consistent with the hallmarks of medically refractory epilepsy. Patients with POLG-related stroke-like episodes demonstrated more fulminant disease trajectories than cases of m.3243A>G and other mitochondrial DNA pathogenic variants, in terms of the frequency of refractory status epilepticus, rapidity of progression and overall mortality. In multivariate analysis, baseline factors of body mass index, age-adjusted blood m.3243A>G heteroplasmy, sensorineural hearing loss and serum lactate were significantly associated with risk of stroke-like episodes in patients with the m.3243A>G variant. These factors informed the development of a prediction model to assess the risk of developing stroke-like episodes that demonstrated good overall discrimination (area under the curve = 0.87, 95% CI 0.82–0.93; c-statistic = 0.89). Significant radiological and pathological features of neurodegeneration were more evident in patients harbouring pathogenic mtDNA variants compared with POLG: brain atrophy on cranial MRI (90% versus 44%, P < 0.001) and reduced mean brain weight (SD) [1044 g (148) versus 1304 g (142), P = 0.005]. Our findings highlight the often idiosyncratic clinical, radiological and EEG characteristics of mitochondrial stroke-like episodes. Early recognition of seizures and aggressive instigation of treatment may help circumvent or slow neuronal loss and abate increasing disease burden. The risk-prediction model for the m.3243A>G variant can help inform more tailored genetic counselling and prognostication in routine clinical practice.

We investigated the phenotypes and genotypes of a cohort of 'long-surviving' individuals with motor neuron disease (MND) to identify potential targets for prognostication.Patients were recruited via the Clinical Audit Research and Evaluation for MND (CARE-MND) platform, which hosts the Scottish MND Register. Long survival was defined as 8 years from diagnosis. 11 phenotypic variables were analysed. Whole genome sequencing (WGS) was performed and variants within 49 MND-associated genes examined. Each individual was screened for C9orf72 repeat expansions. Data from ancestry-matched Scottish populations (the Lothian Birth Cohorts) were used as controls.58 long survivors were identified. Median survival from diagnosis was 15.5 years. Long survivors were significantly younger at onset and diagnosis than incident patients and had a significantly longer diagnostic delay. 42% had the MND subtype of primary lateral sclerosis (PLS). WGS was performed in 46 individuals: 14 (30.4%) had a potentially pathogenic variant. 4 carried the known SOD1 p.(Ile114Thr) variant. Significant variants in FIG4, hnRNPA2B1, SETX, SQSTM1, TAF15, and VAPB were detected. 2 individuals had a variant in the SPAST gene suggesting phenotypic overlap with hereditary spastic paraplegia (HSP). No long survivors had pathogenic C9orf72 repeat expansions.Long survivors are characterised by younger age at onset, increased prevalence of PLS and longer diagnostic delay. Genetic analysis in this cohort has improved our understanding of the phenotypes associated with the SOD1 variant p.(Ile114Thr). Our findings confirm that pathogenic expansion of C9orf72 is likely a poor prognostic marker. Genetic screening using targeted MND and/or HSP panels should be considered in those with long survival, or early-onset slowly progressive disease, to improve diagnostic accuracy and aid prognostication.

Background and aims Chronic migraine is a common neurovascular brain disorder with substantial economic costs. We performed a systematic review to identify economic evaluations of pharmacological treatments for adults with chronic migraine. Methods We undertook systematic literature searches using terms for migraine/headache and prophylactic drug interventions, combined with economic/cost terms where appropriate. Using inclusion and exclusion criteria, two reviewers independently assessed the citations and abstracts, and full-text articles were retrieved. A review of study characteristics and methodological quality was assessed. Results Sixteen citations met the inclusion criteria and were model-based cost-utility studies evaluating: Botox (n = 6); Erenumab (n = 8); Fremanezumab (n = 2); and Galcanezumab (n = 1) as the main treatment. They varied in their use of comparators, perspective, and model type. Botox was cost-effective compared to placebo with an incremental cost-effectiveness ratio (ICER) ranging between £15,028 (€17,720) and £16,598 (€19,572). Erenumab, Fremanezumab and Galcanezumab when compared to Botox, was associated with ICERs ranging between £59,712 ($81,080) and £182,128 (€218,870), with the ICERs above the most common willingness-to-pay thresholds (WTPs). But they were cost-effective within the commonly used WTPs among the population for whom the previous treatments including Botox were failed. Three studies compared the cost-effectiveness of Erenumab against the placebo and found that Erenumab was dominant. All studies performed sensitivity analyses to check the robustness of their results. None of the findings from the included articles were generalisable and none of the included studies fulfilled all the criteria mentioned in the CHEERS 2022 reporting checklist and Phillips’s checklist for economic models. Conclusions Evidence to support the cost-effectiveness of pharmacological treatments of chronic migraine in the adult population using Botox and Erenumab were identified. Our findings suggest that both Botox and Erenumab, are cost-effective compared to placebo; although Erenumab had more incremental economic benefits compared to Botox, the ICERs were above the most common willingness-to-pay thresholds. Hence, Erenumab might be an acceptable treatment for chronic migraine for patients whom other treatments such as Botox do not work. Further research is needed to help characterise the data to adequately structure and parameterise an economic model to support decision-making for chronic migraine therapies.

ObjectiveThe COVID-19 pandemic has broadened the use of teleneurology, how this compares with face-to-face (F2F) clinics is unclear. This study compared virtual with F2F new neurological consultations.MethodsWe retrospectively evaluated new outpatient consultations in neurology clinics in Aberdeen Royal Infirmary. We compared sociodemographic data, time to consultation, time to diagnosis, the need for reassessment and re-investigation between traditional F2F and virtual clinics using the web-based Attend Anywhere platform or telephone into patients’ own homes (or chosen location) without a trained assistant. We calculated the relative risk (RR) of the need for reassessment and re-investigation over 6-month periods by the suspected neurological diagnosis.Results73% of consultations were virtual (Attend Anywhere or telephone) between June and October 2020, this was almost non-existent (ConclusionThis study demonstrates that virtual clinics have higher rates of reassessment and re-investigation than F2F clinics. As virtual clinics become a potential consultation alternative, this study should instruct the selection of patients for either consultation type.

Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease-modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of Phase II, Phase II/III and Phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15 000 people with amyotrophic lateral sclerosis. About 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis., Wong et al. reviewed historical approaches to clinical trials in amyotrophic lateral sclerosis. Lack of sensitive outcome measures, limitations in resources and barriers to trial participation were challenges for timely and definitive evaluation of drugs in two-arm trials. They concluded that future trials should be more flexible, scalable and efficient., Graphical Abstract Graphical Abstract

Tele-neurology is a neurological consultation at a distance, or not in person, using various technologies to achieve connectivity, including the telephone and the internet. The telephone is ubiquitous and is a standard part of how we manage patients. Video consulting has been used for a long time in some centres, particularly in those where the geography means that patients have to travel long distances. Various technologies can be used, and with the development of various internet-based video-calling platforms, real-time video consulting has become much more accessible. We have provided a tele-neurology service in the North East of Scotland since 2006 using video conferencing with far-end camera control. More recently, we have complemented this using an internet-based platform (NHS Near Me). Here we outline the practicalities of video consulting in ‘ordinary’ times and comment on its use in the ‘extraordinary’ times of the coronavirus pandemic.

A 48-year-old man presented with severe limb, bulbar, and respiratory weakness requiring intubation and ventilation. Decrement was seen on repetitive nerve stimulation, but tested muscles were too weak for voluntary activation and tetanic stimulation was not tolerated. Positive voltage-gated calcium channel and SOX1 antibodies confirmed Lambert-Eaton myasthenic syndrome (LEMS). Despite corticosteroids, 3,4-diaminopyridine, and plasma exchange, severe bulbar weakness persisted, the patient remained tracheostomy-dependent, and he developed marked tongue atrophy (figure, A). Small cell lung cancer was subsequently confirmed. Radiotherapy 3 months after presentation resulted in recovery of bulbar function, improvement in tongue atrophy, and tracheostomy decannulation with improvement sustained 10 months later (figure, B and C). Tongue atrophy uncommonly occurs in generalized myasthenia gravis1 but has not been previously reported in LEMS. The underlying mechanism may be neurogenic atrophy due to severe neuromuscular junction dysfunction.2

We report a case of a twenty three year old female presenting with status epilepticus due to a rare mutation in a nuclear gene causing mitochondrial dysfunction. She had previously been investigated for an inherited ataxia without a definitive diagnosis being made. She presented as an emergency with focal seizures that rapidly evolved into intractable status epilepticus. Despite prolonged, aggressive treatment in Intensive Care Unit, she remained encephalopathic with persisting seizures. Her younger sister who also has milder symptoms with ataxia visited our hospital on the day of acute admission and revealed some useful information that led us investigate and confirm the diagnosis in our patient. Her younger sister who was a medical student told us that she had been investigated elsewhere and was confirmed to have an autosomal recessive mutation in a nuclear gene named POLG. We tested and confirmed the same POLG mutation in our patient. POLG is a nuclear gene located on long arm of chromosome 15 that encodes the catalytic subunit of mitochondrial DNA polymerase gamma. The defects in this enzyme are associated with disorders of mitochondrial DNA maintenance. POLG mutation has several phenotypes with onset between early childhood to late adulthood. Typical clinical features include ataxia, neuropathy, epilepsy, ophthalmoplegia, myopathy and in some cases liver failure. Liver failure has been associated with treatment with Sodium valproate and this should be avoided in these patients. Prognosis is poor in the presence of epilepsy with mortality rates to be reported to be nearly 80%. After extensive discussions with the family, local ethics team, and medical director, our patient was palliated in the local palliative care hospital where she died peacefully. A clinical intuition is needed for referring these patients to genetic testing and the diagnosis is crucial to inform us the prognosis. We discuss her presentation, management and our patient9s phenotype Mitochondrial Spino–Cerebellar Ataxia and Epilepsy (MSCAE).

Headache is very common. In the United Kingdom, it accounts for 4.4% of primary care consultations, 30% of referrals to neurology services and 0.5-0.8% of alert patients presenting to emergency departments. Primary headache disorders account for the majority of patients and most patients do not require investigation. Warning features (red flags) in the history and on examination help target those who need investigation and what investigations are required. This article summarizes the typical presentations of the common secondary headaches and what neuroimaging and other investigations are appropriate for each headache type.