Background Concerns regarding potential neurological complications of COVID-19 are being increasingly reported, primarily in small series. Larger studies have been limited by both geography and specialty. Comprehensive characterisation of clinical syndromes is crucial to allow rational selection and evaluation of potential therapies. The aim of this study was to investigate the breadth of complications of COVID-19 across the UK that affected the brain. Methods During the exponential phase of the pandemic, we developed an online network of secure rapid-response case report notification portals across the spectrum of major UK neuroscience bodies, comprising the Association of British Neurologists (ABN), the British Association of Stroke Physicians (BASP), and the Royal College of Psychiatrists (RCPsych), and representing neurology, stroke, psychiatry, and intensive care. Broad clinical syndromes associated with COVID-19 were classified as a cerebrovascular event (defined as an acute ischaemic, haemorrhagic, or thrombotic vascular event involving the brain parenchyma or subarachnoid space), altered mental status (defined as an acute alteration in personality, behaviour, cognition, or consciousness), peripheral neurology (defined as involving nerve roots, peripheral nerves, neuromuscular junction, or muscle), or other (with free text boxes for those not meeting these syndromic presentations). Physicians were encouraged to report cases prospectively and we permitted recent cases to be notified retrospectively when assigned a confirmed date of admission or initial clinical assessment, allowing identification of cases that occurred before notification portals were available. Data collected were compared with the geographical, demographic, and temporal presentation of overall cases of COVID-19 as reported by UK Government public health bodies.

SummaryBackgroundLithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS.MethodsThe lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31.FindingsBetween May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank χ2 on 1 df=1·64; p=0·20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0·71 (95% CI 0·40–1·24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event.InterpretationWe found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments.FundingThe Motor Neurone Disease Association of Great Britain and Northern Ireland.

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 15000 people with amyotrophic lateral sclerosis. 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.

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As the COVID-19 pandemic progresses neurological complications are increasingly being reported. Posterior reversible encephalopathic syndrome (PRES) is a clinico-radiological syndrome characterised by headache, visual loss, encephalopathy and seizures, and the development of vasogenic white matter lesions in a classically parieto-occipital distribution. The pathophysiology of PRES is incompletely understood, but both hyperperfusion secondary to hypertension, and endothelial dysfunction leading to vasogenic oedema have been implicated. Here we present a case series of 2 hospitalised COVID-19 patients with markedly different disease severity, both of whom developed PRES. Patient 1 presented with confusion and headache without significant systemic features, on a background of known hypertension. Patient 1 had a single generalised seizure and was managed with levetiracetam and antihypertensives, and showed complete clinical recovery. In contrast, patient 2 presented with respiratory distress, metabolic disturbance and encephalopathy requiring critical care admission. Patient 2 had a protracted admission, developing marked visual disturbance and generalised seizures requiring multiple agents. In both cases initial CT/MRI showed characteristic posterior PRES-like leukoencephalopathy with resolution on follow-up imaging, and CSF biochemistry, cytology and virology were normal. This case series highlights the potential for neurological complications in COVID-19 patients across the spectrum of disease severity.Philip.hayton@nhs.net

A 57–year–old male presented with a six–year history of cramps in the left thumb, which initially occurred exclusively when playing the bass guitar. Examination revealed no focal wasting or fasciculations, and all reflexes were depressed. There was no tremor or dystonic posturing of neck, trunk or limbs, and writing was unaffected. When playing the guitar he developed sustained contraction of the left thumb, limiting his ability to play for long periods of time, but this did not occur in other positions or tasks. Nerve conduction studies showed normal motor, sensory and F–wave responses, but after–discharges were seen after 10 Hz repetitive stimulation. Needle EMG showed frequent fasciculations in distal upper and lower limb muscles, with no signs of active denervation. Antibodies to the voltage–gated potassium channel (VGKC) complex were positive (>100 pM), while CT thorax showed no evidence of thymoma. Botulinum toxin injections to left opponens pollicis relieved the cramps, but caused thumb weakness. Other drug treatments were ineffective or poorly tolerated. Peripheral nerve hyperexcitability has rarely been reported to cause abnormalities resembling focal dystonia, but this is the first case to our knowledge where the initial presentation was suggestive of task–specific dystonia. This case expands the phenotype of neurological syndromes associated with antibodies to the VGKC complex.

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