Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness. Responding to this, a ...weekly virtual coronavirus disease 19 (COVID-19) neurology multi-disciplinary meeting was established at the National Hospital, Queen Square, in early March 2020 in order to discuss and begin to understand neurological presentations in patients with suspected COVID-19-related neurological disorders. Detailed clinical and paraclinical data were collected from cases where the diagnosis of COVID-19 was confirmed through RNA PCR, or where the diagnosis was probable/possible according to World Health Organization criteria. Of 43 patients, 29 were SARS-CoV-2 PCR positive and definite, eight probable and six possible. Five major categories emerged: (i) encephalopathies (n = 10) with delirium/psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or partial recovery with supportive care only; (ii) inflammatory CNS syndromes (n = 12) including encephalitis (n = 2, para- or post-infectious), acute disseminated encephalomyelitis (n = 9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis (n = 1). Of these, 10 were treated with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial recovery, and one patient died; (iii) ischaemic strokes (n = 8) associated with a pro-thrombotic state (four with pulmonary thromboembolism), one of whom died; (iv) peripheral neurological disorders (n = 8), seven with Guillain-Barré syndrome, one with brachial plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with miscellaneous central disorders who did not fit these categories. SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to determine the underlying pathobiological mechanisms that will guide treatment. Longitudinal follow-up studies will be necessary to ascertain the long-term neurological and neuropsychological consequences of this pandemic.
BackgroundAndersen-Tawil Syndrome (ATS) is a rare channelopathy caused by mutations in the KCNJ2 gene that encodes the ubiquitously expressed Kir2.1 potassium channel.MethodsIn our paper, we describe ...key findings in a large UK cohort of 52 patients, pertinent to the diagnosis and management of ATS. We report a new point prevalence of 0.105 per 100 000 (increased from 0.08 per 100 000).ResultsWhile ATS has historically been considered a triad of episodic weakness, cardiac arrhythmias and dysmorphic features, we show that there is considerable variability to this phenotype. Pure cardiac or muscle phenotypes may exist. The absence of dysmorphic features does not exclude the diagnosis. Similarly, a normal long exercise test was seen in five patients.Importantly, we identify that the phenotype includes a significant risk of cardiac morbidity and mortality with 13% of our cohort requiring cardiac defibrillator or pacemaker insertion and an additional 23% reporting syncope. Syncope has been recently associated with an increased risk of life threatening arhythmic events in this cohort. Severe fixed myopathy was seen in a quarter of our cohort with 14% requiring a wheelchair or gait aid.ConclusionsThis is the largest multi-system study in ATS and provides key clinical insights to improve diagnosis, as well as management recommendations to address the potential for severe muscle weakness and cardiac morbidity and mortality.
Subacute combined degeneration of the spinal cord is a potentially reversible myelopathy typically associated with vitamin B12 deficiency. There is predominant involvement of spinal cord posterior ...and lateral tracts, and manifestations include peripheral paraesthesia, impaired proprioception, gait disturbance, neuropathy and cognitive changes. Motor neuron disease (MND) is an unremittingly progressive neurodegenerative disorder involving upper and lower motor neurons with an average prognosis of 2-3 years. The diagnosis is clinical and may be supported by electromyography. A subset of MND occurs concurrently with frontotemporal dementia (FTD-MND) and may be initially misdiagnosed as a primary psychotic disorder.
We describe a 57-year-old Caucasian woman who presented with confusion and dysarthria. Low vitamin B12 levels and MRI findings led to an initial diagnosis of subacute combined degeneration of the spinal cord. Despite treatment, persistent dysarthria and presence of both upper and lower motor neuron signs on clinical examination prompted further assessment. Electromyography supported the diagnosis of MND. Comorbid chronic paranoid schizophrenia complicated the diagnostic process. We discuss overlapping features between B12 deficiency and MND as well as the neuropsychiatric overlap of B12 deficiency, FTD-MND and chronic schizophrenia.
Firstly, variability in neurocognitive and imaging manifestations of B12 deficiency can limit delineation of other pathologies. Failure to improve following correction of nutritional deficiencies warrants further investigation for an alternate diagnosis. Secondly, re-evaluation of patients with comorbid mental health conditions is important in reaching timely and accurate diagnoses.
A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies ...in COVID-19 neurology remains unclear.
This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies aCL IgA, IgM, IgG; anti-beta-2 glycoprotein-1 aβ2GPI IgA, IgM, IgG; anti-phosphatidylserine/prothrombin aPS/PT IgM, IgG; and anti-domain I β2GPI (aD1β2GPI) IgG.
There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups (p < 0.001). Moderate-high titre of aPS/PT IgG was found in 2 out of 3 (67%) patients with acute disseminated encephalomyelitis ADEM. aPS/PT IgG titres negatively correlated with oxygen requirement (FiO2R=-0.15 p = 0.040) and was associated with venous thromboembolism (p = 0.043). In contrast, aCL IgA (p < 0.001) and IgG (p < 0.001) was associated with non-neurological COVID-hospitalised controls compared to the other groups and correlated positively with d-dimer and creatinine but negatively with FiO2.
Our findings show that aPS/PT IgG is associated with COVID-19-associated ADEM. In contrast, aCL IgA and IgG are seen much more frequently in non-neurological hospitalised patients with COVID-19. Characterisation of antiphospholipid antibody persistence and potential longitudinal clinical impact are required to guide appropriate management.
This work is supported by UCL Queen Square Biomedical Research Centre (BRC) and Moorfields BRC grants (#560441 and #557595). LB is supported by a Wellcome Trust Fellowship (222102/Z/20/Z). RWP is supported by an Alzheimer's Association Clinician Scientist Fellowship (AACSF-20-685780) and the UK Dementia Research Institute. KB is supported by the Swedish Research Council (#2017-00915) and the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and theUK Dementia Research Institute at UCL. BDM is supported by grants from the MRC/UKRI (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). MSZ, MH and RS are supported by the UCL/UCLH NIHR Biomedical Research Centre and MSZ is supported by Queen Square National Brain Appeal.
Introduction/Aims
Although we have gained insight into coronavirus disease‐2019 (COVID‐19) caused by severe acute respiratory syndrome–coronavirus 2 since the beginning of the pandemic, our ...understanding of the consequences for patients with neuromuscular disorders is evolving. In this study we aimed to study the impact of COVID‐19 and COVID‐19 vaccination on skeletal muscle channelopathies.
Methods
We conducted a survey of patients with genetically confirmed skeletal muscle channelopathies seen at the UK Nationally Commissioned Channelopathy Service.
Results
Thirty‐eight patient responses were received. Six patients had COVID‐19 infection leading to exacerbation of their underlying muscle channelopathy. No major complications were reported. Thirty‐six patients had received one or two COVID‐19 vaccinations and the majority (68%) had no worsening of their underlying channelopathy. Thirty‐two percent reported worsening of their usual symptoms of their muscle channelopathy, but all reported recovery to baseline levels. No serious adverse events were reported.
Discussion
The overall rates of COVID‐19 infection were low in our study and COVID‐19 vaccine uptake rates were high. Our results have been useful to inform patients that a subset of patients have reversible worsening of their channelopathy post–COVID‐19 vaccination. Our study provides information for giving advice to patients with skeletal muscle channelopathies regarding COVID‐19 infection and vaccination.
206 Follow your nose to the diagnosis Li, Vivien; Vivekanandam, Vinojini; Lunn, Michael
Journal of neurology, neurosurgery and psychiatry,
12/2019, Letnik:
90, Številka:
12
Journal Article
Recenzirano
A 47-year-old female presented with episodic cranial neuropathies. Over four years, she had bilateral hearing impairment. Right maxillary distribution pain was attributed to sinusitis, with ...subsequent sinus surgery. She developed bilateral abducens palsies and left optic neuropathy, each lasting several weeks before resolution.She was diagnosed with hypopituitarism and commenced hormonal replacement after prolonged amenorrhoea. She noticed altered smell, and most recently, developed right facial weakness, which resolved with prednisolone.MRI brain demonstrated nodular dural thickening of cranial fossa floor, with symmetrical T2 white matter and basal ganglia hyperintensity. Bloods and CSF were non-diagnostic. FDG-PET showed multifocal uptake particularly involving the upper aerodigestive tract.Differentials included inflammatory or infiltrative aetiologies. Meningeal biopsy was considered, but recent corticosteroids and hydrocortisone replacement would potentially mask tissue appearances. A history of tonsillectomy and sinus surgery four years earlier coinciding with neurological symptoms led to re-review of external histology, showing 40% of IgG-positive plasma cells expressing IgG4. IgG4 disease was diagnosed and immunosuppression commenced, with clinical stability and radiological improvement.This case illustrates the chronic fluctuating presentation of IgG4 disease, and the forensic medicine required to make a diagnosis with relevant historical histology, when both presentation and tissue have been modified by steroid treatment.
Variants of uncertain significance (VUS) remain a huge challenge in genomic medicine. Accurate classi- fication of missense variants is key to clinical practice. In silico predictive tools are ...routinely used to score the pathogenicity of such variants. However, their statistical value is often unclear as they have usually not been validated against robust functional assays. We compare nine routinely utilised in silico predictive tools with detailed cell-based electrophysiology for 126 CLCN1 variants we discovered in patients with the skeletal muscle channelopathy myotonia congenita. Most in silico predictive tools had poor accuracy – the better performing were Mutation Taster (84.58%) and REVEL (ROC 0.89) but had poor specificity. EVE performed better on specificity while maintaining good AUC and sensitivity. Combined methods based on concordance, improved performance but still lacked specificity. We also showed that the statistics for tools varied between genes. Hence, validation to determine the optimal in silico tools for individual genes should be considered. Overall, tools with better specificity are urgently required to tackle the ongoing major challenge that VUS pose to the effective clinical implementation of genetic data.
COVID-19 in a UK neurology hospital Khoo, Anthony; Smyth, Duncan; Vivekanandam, Vinojini
Internal medicine journal,
August 2020, Letnik:
50, Številka:
8
Journal Article
Abstract
Accurate determination of the pathogenicity of missense genetic variants of uncertain significance is a huge challenge for implementing genetic data in clinical practice. In silico ...predictive tools are used to score variants’ pathogenicity. However, their value in clinical settings is often unclear, as they have not usually been validated against robust functional assays. We compared nine widely used in silico predictive tools, including more recently developed tools (EVE and REVEL) with detailed cell-based electrophysiology, for 126 CLCN1 variants discovered in patients with the skeletal muscle channelopathy myotonia congenita. We found poor accuracy for most tools. The highest accuracy was obtained with MutationTaster (84.58%) and REVEL (82.54%). Both of these scores showed poor specificity, although specificity was better using EVE. Combining methods based on concordance improved performance overall but still lacked specificity. Our calculated statistics for the predictive tools were different to reported values for other genes in the literature, suggesting that the utility of the tools varies between genes. Overall, current predictive tools for this chloride channel are not reliable for clinical use, and tools with better specificity are urgently required. Improving the accuracy of predictive tools is a wider issue and a huge challenge for effective clinical implementation of genetic data.
Vivekanandam et al. show that in silico predictive tools for determining pathogenicity of genetic variants in skeletal muscle channelopathies have poor specificity compared to functional prediction. Improved in silico predictive tools are needed.
Introduction/Aims
The periodic paralyses are muscle channelopathies: hypokalemic periodic paralysis (CACNA1S and SCN4A variants), hyperkalemic periodic paralysis (SCN4A variants), and Andersen‐Tawil ...syndrome (KCNJ2). Both episodic weakness and disabling fixed weakness can occur. Little literature exists on magnetic resonance imaging (MRI) in muscle channelopathies. We undertake muscle MRI across all subsets of periodic paralysis and correlate with clinical features.
Methods
A total of 45 participants and eight healthy controls were enrolled and underwent T1‐weighted and short‐tau‐inversion‐recovery (STIR) MRI imaging of leg muscles. Muscles were scored using the modified Mercuri Scale.
Results
A total of 17 patients had CACNA1S variants, 16 SCN4A, and 12 KCNJ2. Thirty‐one (69%) had weakness, and 9 (20%) required a gait‐aid/wheelchair. A total of 78% of patients had intramuscular fat accumulation on MRI. Patients with SCN4A variants were most severely affected. In SCN4A, the anterior thigh and posterior calf were more affected, in contrast to the posterior thigh and posterior calf in KCNJ2. We identified a pattern of peri‐tendinous STIR hyperintensity in nine patients. There were moderate correlations between Mercuri, STIR scores, and age. Intramuscular fat accumulation was seen in seven patients with no fixed weakness.
Discussion
We demonstrate a significant burden of disease in patients with periodic paralyses. MRI intramuscular fat accumulation may be helpful in detecting early muscle involvement, particularly in those without fixed weakness. Longitudinal studies are needed to assess the role of muscle MRI in quantifying disease progression over time and as a potential biomarker in clinical trials.
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