Search

Catatonia is a debilitating psychomotor disorder. Previous neuroimaging studies have used small samples with inconsistent results. The authors aimed to describe the structural neuroradiological abnormalities in clinical magnetic resonance imaging (MRI) brain scans of patients with catatonia, comparing them with scans of psychiatric inpatients without catatonia. They report the largest study of catatonia neuroimaging to date.In this retrospective case-control study, neuroradiological reports of psychiatric inpatients who had undergone MRI brain scans for clinical reasons were examined. Abnormalities were classified by lateralization, localization, and pathology. The primary analysis was prediction of catatonia by presence of an abnormal MRI scan, adjusted for age, sex, Black race-ethnicity, and psychiatric diagnosis.Scan reports from 79 patients with catatonia and 711 other psychiatric inpatients were obtained. Mean age was 36.4 (SD=17.3) for the cases and 44.5 (SD=19.9) for the comparison group. Radiological abnormalities were reported in 27 of 79 cases (34.2%) and in 338 of 711 in the comparison group (47.5%) (odds ratio [OR]=0.57, 95% confidence interval [CI]=0.35, 0.93; adjusted OR=1.11, 95% CI=0.58, 2.14). Among the cases, most abnormal scans had bilateral abnormalities (N=23, 29.1%) and involved the forebrain (N=25, 31.6%) and atrophy (N=17, 21.5%).Patients with catatonia were commonly reported to have brain MRI abnormalities, which largely consisted of diffuse cerebral atrophy rather than focal lesions. No evidence was found that these abnormalities were more common than in other psychiatric inpatients undergoing neuroimaging, after adjustment for demographic variables. Study limitations included a heterogeneous control group and selection bias in requesting scans.

Background: Neuropsychiatric symptoms are common and important to people with Parkinson’s disease (PD), but their etiology is poorly understood. Plasma neurofilament light (NfL) and p-tau181 are biomarkers of neuro-axonal degeneration and tau pathology respectively, which have yet to be explored in association with the affective and psychotic symptoms in PD. Objective: To investigate the relationship between plasma NfL and p-tau181 with the affective and psychotic symptoms in PD. Methods: We assessed the baseline concentration of plasma NfL and p-tau181 in a cohort of 108 patients with PD and 38 healthy controls. A subgroup of patients (n = 63) were assessed annually with clinical measures for up to 7 years. Psychotic symptoms were assessed using the Non-Motor Symptom Scale and affective symptoms were measured in the Hospital Anxiety and Depression Scale. Results: Baseline plasma NfL was a significant predictor of psychotic symptoms longitudinally across the study adjusted for age, Hoehn and Yahr stage, duration of follow up, duration of disease, baseline levodopa and dopamine agonist medication, and baseline cognition: (OR 8.15 [95% CI 1.40–47.4], p = 0.020). There was no association between NfL concentration and the cumulative prevalence of affective symptoms. Plasma p-tau181 concentration was not associated with psychotic or affective symptoms. Conclusion: These findings suggest psychotic symptoms are associated with greater neurodegeneration in PD. Further studies are needed to explore NfL as a potential biomarker for psychosis in PD.

Synopsis Many patients with COVID-19 will experience acute or longer-term neuropsychiatric complications. The neurobiological mechanisms behind these are beginning to emerge, however the neurotropic hypothesis is not strongly supported by clinical data. The inflammatory response to SARS-CoV-2 is likely to be responsible for delirium and other common acute neuropsychiatric manifestations. Vascular abnormalities such as endotheliopathies contribute to stroke and cerebral microbleeds, with their attendant neuropsychiatric sequelae. Longer-term neuropsychiatric syndromes fall into two broad categories: neuropsychiatric deficits occurring after severe (hospitalised) COVID-19, and ‘long COVID’, which occurs in many patients with a milder acute COVID-19 illness.

Encephalitis is associated with psychiatric symptoms in the acute and post-acute stages, and many survivors experience long-term sequelae. Despite this, the breadth and severity of mental health symptoms in survivors of encephalitis has not been systematically reported. We recruited adults who had been diagnosed with encephalitis of any aetiology to complete a web-based questionnaire assessing a wide range of mental health symptoms and disorders. In total, 445 respondents from 31 countries (55.1% UK, 23.1% USA, 2.2% low-and middle-income countries) completed the survey, with a median seven years since encephalitis diagnosis; 84.7% were diagnosed by a neurologist or infectious diseases doctor. Infectious encephalitis constituted 65.4% of cases, autoimmune 29.7%. Mean age was 50.1 years (SD 15.6); 65.8% were female. The most common self-reported psychiatric symptoms were anxiety (75.2%), sleep problems (64.4%), mood problems (62.2%), unexpected crying (35.2%), and aggression (29.9%). Rates of self-reported psychiatric diagnoses following encephalitis were high: anxiety (44.0%), depression (38.6%), panic disorder (15.7%), and post-traumatic stress disorder (PTSD, 21.3%); these rates were broadly consistent with the results of a validated self-report measure, the Psychiatric Diagnostic Screening Questionnaire (PDSQ). Severe mental illnesses such as psychosis (3.3%) and bipolar affective disorder (3.1%) were also reported. Many respondents also felt they had symptoms of disorders including anxiety (37.5%), depression (28.1%), PTSD (26.8%), or panic disorder (20.9%) which had not been diagnosed by a professional. Overall, rates of major self-reported psychiatric diagnoses and symptoms did not significantly differ between autoimmune and infectious encephalitis. In total, 37.5% of respondents had thought about suicide, and 4.4% had attempted suicide since their encephalitis diagnosis. Over half (53.5%) reported that they either had no, or substandard, access to appropriate care for their mental health. High rates of sensory hypersensitivities (>75%) suggest a previously unreported association between encephalitis and this distressing symptom cluster. This large international survey indicates that psychiatric symptoms following encephalitis are common, and that mental healthcare provision to this population may be inadequate, highlighting a need for increased provision of proactive psychiatric care for these patients.

Background There has been much speculation about untoward effects of the Covid-19 pandemic on psychological symptoms. OCD may be expected to be especially impacted. Our aim was to distil the current evidence base on relationships between the pandemic and obsessive-compulsive symptoms, in patients, and general population samples. Methods We conducted a rapid scoping review, in the form of a systematic literature search, coupled with narrative review. 32 relevant papers were identified. Results and interpretation (1) A sizable proportion of people with OCD (but not all) experienced/reported symptom worsening during the pandemic, especially during initial restrictions (approximately 20–65 % of cases in longitudinal studies); (2) contamination/washing symptoms appeared particularly susceptible; and (3) OCD symptoms in general population samples were associated with trait compulsivity and pandemic-related-stress. The literature was heterogeneous with various methodological issues being commonplace. Future directions The review identified important unaddressed issues: how should exposure based therapy be adapted during pandemics? How can we minimise harm from exacerbation of OCD in vulnerable individuals arising from public health messaging? Why do some but not all OCD patients experience worsening? And does Covid-19 infection affect (or lead to) OCD symptoms?

Functional neurological disorder (FND) is a core neuropsychiatric condition. To date, promising yet inconsistently identified neural circuit profiles have been observed in patients with FND, suggesting that gaps remain in our systems-level neurobiological understanding. As such, other important physiological variables, including autonomic, endocrine, and inflammation findings, need to be contextualized for a more complete mechanistic picture.The investigators conducted a systematic review and meta-analysis of available case-control and cohort studies of FND. PubMed, PsycINFO, and Embase databases were searched for studies from January 1, 1900, to September 1, 2020, that investigated autonomic, endocrine, and inflammation markers in patients with FND. Sixty-six of 2,056 screened records were included in the review, representing 1,699 patients; data from 20 articles were used in the meta-analysis.Findings revealed that children and adolescents with FND, compared with healthy control subjects (HCs), have increased resting heart rate (HR); there is also a tendency toward reduced resting HR variability in patients with FND across the lifespan compared with HCs. In adults, peri-ictal HR differentiated patients with functional seizures from those with epileptic seizures. Other autonomic and endocrine profiles for patients with FND were heterogeneous, with several studies highlighting the importance of individual differences.Inflammation research in FND remains in its early stages. Moving forward, there is a need for the use of larger sample sizes to consider the complex interplay between functional neurological symptoms and behavioral, psychological, autonomic, endocrine, inflammation, neuroimaging, and epigenetic/genetic data. More research is also needed to determine whether FND is mechanistically (and etiologically) similar or distinct across phenotypes.

Background Studies have reported elevated rates of dissociative symptoms and comorbid dissociative disorders in functional neurological disorder (FND); however, a comprehensive review is lacking. Aims To systematically review the severity of dissociative symptoms and prevalence of comorbid dissociative disorders in FND and summarise their biological and clinical associations. Method We searched Embase, PsycInfo and MEDLINE up to June 2021, combining terms for FND and dissociation. Studies were eligible if reporting dissociative symptom scores or rates of comorbid dissociative disorder in FND samples. Risk of bias was appraised using modified Newcastle–Ottawa criteria. The findings were synthesised qualitatively and dissociative symptom scores were included in a meta-analysis (PROSPERO CRD42020173263). Results Seventy-five studies were eligible (FND n = 3940; control n = 3073), most commonly prospective case–control studies (k = 54). Dissociative disorders were frequently comorbid in FND. Psychoform dissociation was elevated in FND compared with healthy (g = 0.90, 95% CI 0.66–1.14, I2 = 70%) and neurological controls (g = 0.56, 95% CI 0.19–0.92, I2 = 67%). Greater psychoform dissociation was observed in FND samples with seizure symptoms versus healthy controls (g = 0.94, 95% CI 0.65–1.22, I2 = 42%) and FND samples with motor symptoms (g = 0.40, 95% CI −0.18 to 1.00, I2 = 54%). Somatoform dissociation was elevated in FND versus healthy controls (g = 1.80, 95% CI 1.25–2.34, I2 = 75%). Dissociation in FND was associated with more severe functional symptoms, worse quality of life and brain alterations. Conclusions Our findings highlight the potential clinical utility of assessing patients with FND for dissociative symptomatology. However, fewer studies investigated FND samples with motor symptoms and heterogeneity between studies and risk of bias were high. Rigorous investigation of the prevalence, features and mechanistic relevance of dissociation in FND is needed.

Background and purpose Functional neurological disorder (FND) is common, and symptoms can be severe. There have been no international large-scale studies of patient experiences of FND. Methods A patient questionnaire was created to assess FND patient characteristics, symptom comorbidities and illness perceptions. Respondents were recruited internationally through an open access questionnaire via social media and patient groups over a month-long period. Results In total, 1048 respondents from 16 countries participated. Mean age was 42 years (86% female). Median FND symptom duration was 5 years, and median time from first symptom to diagnosis was 2 years. Mean number of current symptoms (core FND and associated) was 9.9. Many respondents had associated symptoms, for example fatigue (93%), memory difficulties (80%) and headache (70%). Self-reported psychiatric comorbidities were relatively common (depression, 43%; anxiety, 51%; panic, 20%; and post-traumatic stress disorder, 22%). Most respondents reported that FND had multiple causes, including physical and psychological. Conclusions This large survey adds further evidence that people with FND typically have high levels of multiple symptom comorbidity with resultant distress. It also supports the notion that associated physical symptoms are of particular clinical significance in FND patients. Dualistic ideas of FND were not supported by respondents, who generally preferred to conceptualize the disorder as one at the interface of mind and brain. The need for a broad approach to this poorly served patient group is highlighted. Potential selection and response biases due to distribution of the survey online, mostly via FND patient groups, are a key limitation.

ObjectivesNeuropsychiatric presentations of monkeypox (MPX) infection have not been well characterised, Despite evidence of nervous system involvement associated with two relatedOrthopoxviruses, in the case of smallpox infection (with the variola virus) and smallpox vaccination (which contains live vaccinia virus). In this systematic review and meta-analysis, we aim to determine the prevalence and describe the spectrum of neurological and psychiatric presentations of MPX.DesignSystematic review and meta-analysisData sourcesMEDLINE, EMBASE, PsycINFO, AMED and pre-print server (MedRxiv) searched up to 31/05/2022Eligibility criteria for study selection and analysisAny study design of humans infected with MPX that reported neurological or psychiatric presentation. Studies which included more than ten individuals, and symptoms that were reported in a minimum of two separate studies were eligible for meta-analysisData synthesisResults were pooled with random-effects meta-analysis to calculate generalised linear mixed models and corresponding 95% confidence intervals for each prevalence outcome. Heterogeneity was measured with the I2statistic. All included studies are summarised through a narrative synthesis. Risk of bias was assessed with the Newcastle Ottawa Scale and the Joanna Briggs Institute quality assessment tool.ResultsFrom 1,702 unique studies, we extracted data on 19 eligible studies (1,512 participants, 1,031 with confirmed infection using CDC criteria or PCR testing) most of which were cohort studies and case series with no controlled populations. Study quality was generally moderate. Six clinical features were eligible for meta-analysis, of which the most prevalent were myalgia in 55.5% [95%CI 12.1-91.9%], headache 53.8% [30.6-75.4%], fatigue 36.2% [2.0-94.0%], seizure 2.7% [0.6-10.2%], confusion 2.4% [1.1-5.2%] and encephalitis 2.0% [0.5-8.2%]. Heterogeneity significantly varied across clinical features (I2=0%-98.7%). Other reported presentations not eligible for meta-analysis included sensory-perceptual disturbance (altered vision, dizziness, and photophobia) and psychiatric symptoms (anxiety and depression).ConclusionsThere is preliminary evidence for a range of neurological and psychiatric presentations of MPX, ranging from commonly reported and nonspecific neurological symptoms (myalgia and headache) to rarer but more severe neurological complications, such as encephalitis and seizures. There is less evidence regarding the psychiatric sequelae of MPX, and although there are multiple reports of anxiety and depression the prevalence of these symptoms is unknown. MPX-related nervous system presentations may warrant surveillance within the current MPX outbreak, with prospective longitudinal studies evaluating the mid to long-term sequelae of the virus. Robust methods to evaluate the potential causality of MPX with these clinical features are required at an individual and epidemiological level.Systematic review registrationPROSPERO ID 336649SUMMARY BOXWhat is already known on this topicNeuropsychiatric symptoms can be highly disabling and have a detrimental effect on quality of life.Neuropsychiatric manifestations of monkeypox virus infection have not been well characterised, however, there is evidence of nervous system involvement with the related smallpox virus and vaccinia vaccine.What this study addsPreliminary evidence for a range of neurological and psychiatric presentations of monkeypox infection, ranging from commonly reported and nonspecific neurological symptoms (myalgia and headache) to rarer but more severe neurological complications, such as encephalitis and seizures.There is less evidence regarding the psychiatric sequelae of monkeypox infection, and although there are multiple reports of anxiety and depression the prevalence of these symptoms is unknown.This preliminary suspicion that there are monkeypox-related nervous system manifestations may warrant both surveillance within the current monkeypox outbreak and robust methods to evaluate the potential causality.

Functional neurological (conversion) disorder (FND) is a neuropsychiatric condition whereby individuals present with sensorimotor symptoms incompatible with other neurological disorders. Early-life maltreatment (ELM) is a risk factor for developing FND, yet few studies have investigated brain network-trauma relationships in this population. In this neuroimaging-gene expression study, we used two graph theory approaches to elucidate ELM subtype effects on resting-state functional connectivity architecture in 30 patients with motor FND. Twenty-one individuals with comparable depression, anxiety, and ELM scores were used as psychiatric controls. Thereafter, we compared trauma endophenotypes in FND with regional differences in transcriptional gene expression as measured by the Allen Human Brain Atlas (AHBA). In FND patients only, we found that early-life physical abuse severity, and to a lesser extent physical neglect, correlated with corticolimbic weighted-degree functional connectivity. Connectivity profiles influenced by physical abuse occurred in limbic (amygdalar-hippocampal), paralimbic (cingulo-insular and ventromedial prefrontal), and cognitive control (ventrolateral prefrontal) areas, as well as in sensorimotor and visual cortices. These findings held adjusting for individual differences in depression/anxiety, PTSD, and motor phenotypes. In FND, physical abuse also correlated with amygdala and insula coupling to motor cortices. In exploratory analyses, physical abuse correlated connectivity maps overlapped with the AHBA spatial expression of three gene clusters: (i) neuronal morphogenesis and synaptic transmission genes in limbic/paralimbic areas; (ii) locomotory behavior and neuronal generation genes in left-lateralized structures; and (iii) nervous system development and cell motility genes in right-lateralized structures. These circuit-specific architectural profiles related to individual differences in childhood physical abuse burden advance our understanding of the pathophysiology of FND.

BackgroundCatatonia, a severe neuropsychiatric syndrome, has few studies of sufficient scale to clarify its epidemiology or pathophysiology. We aimed to characterise demographic associations, peripheral inflammatory markers and outcome of catatonia.MethodsElectronic healthcare records were searched for validated clinical diagnoses of catatonia. In a case–control study, demographics and inflammatory markers were compared in psychiatric inpatients with and without catatonia. In a cohort study, the two groups were compared in terms of their duration of admission and mortality.ResultsWe identified 1456 patients with catatonia (of whom 25.1% had two or more episodes) and 24 956 psychiatric inpatients without catatonia. Incidence was 10.6 episodes of catatonia per 100 000 person-years. Patients with and without catatonia were similar in sex, younger and more likely to be of Black ethnicity. Serum iron was reduced in patients with catatonia [11.6 v. 14.2 μmol/L, odds ratio (OR) 0.65 (95% confidence interval (CI) 0.45–0.95), p = 0.03] and creatine kinase was raised [2545 v. 459 IU/L, OR 1.53 (95% CI 1.29–1.81), p < 0.001], but there was no difference in C-reactive protein or white cell count. N-Methyl-d-aspartate receptor antibodies were significantly associated with catatonia, but there were small numbers of positive results. Duration of hospitalisation was greater in the catatonia group (median: 43 v. 25 days), but there was no difference in mortality after adjustment.ConclusionsIn the largest clinical study of catatonia, we found catatonia occurred in approximately 1 per 10 000 person-years. Evidence for a proinflammatory state was mixed. Catatonia was associated with prolonged inpatient admission but not with increased mortality.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the aetiologic agent of the coronavirus disease 2019 (COVID-19), is now rapidly disseminating throughout the world with 147,443,848 cases reported so far. Around 30-80% of cases (depending on COVID-19 severity) are reported to have neurological manifestations including anosmia, stroke, and encephalopathy. In addition, some patients have recognised autoimmune neurological disorders, including both central (limbic and brainstem encephalitis, acute disseminated encephalomyelitis [ADEM], and myelitis) and peripheral diseases (Guillain-Barré and Miller Fisher syndrome). We systematically describe data from 133 reported series on the Neurology and Neuropsychiatry of COVID-19 blog ( https://blogs.bmj.com/jnnp/2020/05/01/the-neurology-and-neuropsychiatry-of-covid-19/ ) providing a comprehensive overview concerning the diagnosis, and treatment of patients with neurological immune-mediated complications of SARS-CoV-2. In most cases the latency to neurological disorder was highly variable and the immunological or other mechanisms involved were unclear. Despite specific neuronal or ganglioside antibodies only being identified in 10, many had apparent responses to immunotherapies. Although the proportion of patients experiencing immune-mediated neurological disorders is small, the total number is likely to be underestimated. The early recognition and improvement seen with use of immunomodulatory treatment, even in those without identified autoantibodies, makes delayed or missed diagnoses risk the potential for long-term disability, including the emerging challenge of post-acute COVID-19 sequelae (PACS). Finally, potential issues regarding the use of immunotherapies in patients with pre-existent neuro-immunological disorders are also discussed.

Adverse life events precede the onset of functional neurological disorder (FND, also known as conversion disorder) more commonly than other neuropsychiatric conditions, but their aetiological role is unclear. We conducted a systematic review and quantitative analysis of the type, timing and number of life events preceding the onset of FND in adults, and a meta-analysis of the proportions of types of events in controlled studies. Fifty-one studies of different designs, covering 4247 patients, were eligible for inclusion. There was no clear majority of any type of preceding event. Family problems were the most common category of events, followed by relationship problems. Females were more likely to experience preceding family/relationship problems than males, who reported more work problems. Family problems were the commonest type of preceding event in studies in developing countries, whereas family and health problems were equally common in developed countries. Abuse was associated with early symptom onset, while patients with later onset were more likely to report family problems. The median number of events was one, and the events occurred closer to onset than in controls. Meta-analysis found that family, relationship and work events were all relatively more common in patients than pathological controls, as were events where symptoms might provide a solution to the stressor. In conclusion, although a range of events precede the onset of FND, they do not appear to do so uniformly. This may support a different aetiological role for stressors than in other disorders, although the support is indirect and the quality generally low.

Objectives/AimsDissociation is a potential mechanism in FND. Although scientific studies report elevated rates of dissociative symptoms in FND, a systematic assessment of the biological and clinical correlates of dissociation in FND is lacking. We aimed to systematically review the current evidence describing dissociative symptoms and disorders in functional neurological disorder (FND), and additionally conduct a meta-analysis of dissociative symptom severity in FND. We also aimed to synthesise the existing data on biological and clinical correlates of dissociation in FND.MethodsWe systematically searched Embase, PsycINFO, and Medline, combining terms for FND and dissociation. Studies were eligible for inclusion if reporting on dissociative symptom scale scores or rates of dissociative disorder in FND samples. Studies were appraised for methodological quality using modified Newcastle-Ottawa criteria. Findings pertaining to dissociative symptoms or disorders, as well as biological and clinical correlates of dissociation in FND samples, were synthesised qualitatively. Dissociative symptom scores were included in a meta-analysis using random and mixed effects models.ResultsTwo-thousand and eighty-eight records were screened and seventy-nine studies were included in the final review. Dissociative symptoms were elevated in FND. The meta-analysis demonstrated a significant elevation in dissociation in FND samples relative to neurological and healthy controls, but not psychiatric controls. Dissociative disorders were frequently co-morbid in FND samples. Psychoform (cognitive) dissociation was more prominent in FND-seizures, whereas somatoform (physical) dissociation tended to be more prominent in FND-motor symptom samples. Dissociation was associated with FND symptom severity or frequency, general psychopathology, and reduced quality of life. Biological correlates of elevated dissociation included structural and functional brain alterations in regions that have previously been implicated in FND, such as the anterior cingulate cortex.ConclusionsDissociative symptoms and disorders are common in FND, and different FND subgroups appear to endorse varying degrees of psychoform or somatoform dissociation. Presence of dissociative symptoms in FND is associated with adverse clinical features; there is therefore a clinical need to assess patients with FND for dissociative symptomatology and to address these symptoms during treatment. Future research should examine dissociation further in different FND subgroups, using measures that distinguish between different types of dissociation, alongside measures of underlying pathophysiology.

SARS-CoV-2 is associated with new-onset neurological and psychiatric conditions. Detailed clinical data, including factors associated with recovery, are lacking, hampering prediction modelling and targeted therapeutic interventions. In a UK-wide cross-sectional surveillance study of adult hospitalized patients during the first COVID-19 wave, with multi-professional input from general and sub-specialty neurologists, psychiatrists, stroke physicians, and intensivists, we captured detailed data on demographics, risk factors, pre-COVID-19 Rockwood frailty score, comorbidities, neurological presentation and outcome. A priori clinical case definitions were used, with cross-specialty independent adjudication for discrepant cases. Multivariable logistic regression was performed using demographic and clinical variables, to determine the factors associated with outcome. A total of 267 cases were included. Cerebrovascular events were most frequently reported (131, 49%), followed by other central disorders (95, 36%) including delirium (28, 11%), central inflammatory (25, 9%), psychiatric (25, 9%), and other encephalopathies (17, 7%), including a severe encephalopathy (n = 13) not meeting delirium criteria; and peripheral nerve disorders (41, 15%). Those with the severe encephalopathy, in comparison to delirium, were younger, had higher rates of admission to intensive care and a longer duration of ventilation. Compared to normative data during the equivalent time period prior to the pandemic, cases of stroke in association with COVID-19 were younger and had a greater number of conventional, modifiable cerebrovascular risk factors. Twenty-seven per cent of strokes occurred in patients 60 years old, the younger stroke patients presented with delayed onset from respiratory symptoms, higher rates of multi-vessel occlusion (31%) and systemic thrombotic events. Clinical outcomes varied between disease groups, with cerebrovascular disease conferring the worst prognosis, but this effect was less marked than the pre-morbid factors of older age and a higher pre-COVID-19 frailty score, and a high admission white cell count, which were independently associated with a poor outcome. In summary, this study describes the spectrum of neurological and psychiatric conditions associated with COVID-19. In addition, we identify a severe COVID-19 encephalopathy atypical for delirium, and a phenotype of COVID-19 associated stroke in younger adults with a tendency for multiple infarcts and systemic thromboses. These clinical data will be useful to inform mechanistic studies and stratification of patients in clinical trials., Ross Russell et al. report novel details of COVID-19 neurological complications: multiple overlapping diagnoses in the same patients, a severe encephalopathy atypical for delirium, and a lowered threshold for stroke in younger adults. Higher age, pre-morbid frailty score and white cell count predicted clinical outcome., Graphical Abstract Graphical Abstract

The COVID-19 pandemic death toll now surpasses two million individuals and there is a need for early identification of individuals at increased risk of mortality. Host genetic variation partially drives the immune and biochemical responses to COVID-19 that lead to risk of mortality. We identify and prioritise blood proteins and biomarkers that may indicate increased risk for severe COVID-19, via a proteome Mendelian randomization approach by collecting genome-wide association study (GWAS) summary statistics for >4,000 blood proteins. After multiple testing correction, troponin I3, cardiac type (TNNI3) had the strongest effect (odds ratio (O.R.) of 6.86 per standard deviation increase in protein level), with proteinase 3 (PRTN3) (O.R.=2.48), major histocompatibility complex, class II, DQ alpha 2 (HLA-DQA2) (O.R.=2.29), the C4A-C4B heterodimer (O.R.=1.76) and low-density lipoprotein receptor-related protein associated protein 1 (LRPAP1) (O.R.=1.73) also being associated with higher odds of severe COVID-19. Conversely, major histocompatibility complex class I polypeptide-related sequence A (MHC1A) (O.R.=0.6) and natural cytotoxicity triggering receptor 3 (NCR3) (O.R.=0.46) were associated with lower odds. These proteins are involved in heart muscle contraction, natural killer and antigen presenting cells, and the major histocompatibility complex. Based on these findings, it may be possible to better predict which patients may develop severe COVID-19 and to design better treatments targeting the implicated mechanisms.

ObjectivesThere is accumulating evidence of the neurological and neuropsychiatric features of infection with SARS-CoV-2. In this systematic review and meta-analysis, we aimed to describe the characteristics of the early literature and estimate point prevalences for neurological and neuropsychiatric manifestations.MethodsWe searched MEDLINE, Embase, PsycInfo and CINAHL up to 18 July 2020 for randomised controlled trials, cohort studies, case-control studies, cross-sectional studies and case series. Studies reporting prevalences of neurological or neuropsychiatric symptoms were synthesised into meta-analyses to estimate pooled prevalence.Results13,292 records were screened by at least two authors to identify 215 included studies, of which there were 37 cohort studies, 15 case-control studies, 80 cross-sectional studies and 83 case series from 30 countries. 147 studies were included in the meta-analysis. The symptoms with the highest prevalence were anosmia (43.1% [35.2—51.3], n=15,975, 63 studies), weakness (40.0% [27.9—53.5], n=221, 3 studies), fatigue (37.8% [31.6—44.4], n=21,101, 67 studies), dysgeusia (37.2% [30.0—45.3], n=13,686, 52 studies), myalgia (25.1% [19.8—31.3], n=66.268, 76 studies), depression (23.0 % [11.8—40.2], n=43,128, 10 studies), headache (20.7% [95% CI 16.1—26.1], n=64,613, 84 studies), anxiety (15.9% [5.6—37.7], n=42,566, 9 studies) and altered mental status (8.2% [4.4—14.8], n=49,326, 19 studies). Heterogeneity for most clinical manifestations was high.ConclusionsNeurological and neuropsychiatric symptoms of COVID-19 in the pandemic’s early phase are varied and common. The neurological and psychiatric academic communities should develop systems to facilitate high-quality methodologies, including more rapid examination of the longitudinal course of neuropsychiatric complications of newly emerging diseases and their relationship to neuroimaging and inflammatory biomarkers.

Background: Neurological COVID-19 disease has been reported widely, but often without using standard case definitions or detailed diagnostic work up. Several meta-analyses, based on such reports, describe the neurological diagnoses but give little information on outcomes and risk factors. Methods: We conducted an individual patient data meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute, and extracted aggregate data from published reports. We analysed features associated with poor outcome (moderate to severe sequelae or death, 3-6, on the modified Rankin scale) using multivariable models. Findings: We identified 381 studies (31 unpublished) describing 4443 patients with COVID-19 and neurological disease: 83 of these provided IPD for 1979 (45%) patients. Encephalopathy (978 [49%]) and cerebrovascular events (506 [26%]), were the most common diagnoses in the IPD database and aggregate data. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41] overall), and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-Dimer. Overall, 30-day mortality was 30% (27-32). The hazard of death was reduced for patients in the WHO European region, but increased in low- and lower-middle-income countries. Interpretation: Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission. Funding This study was funded by the UK Medical Research Council’s Global Effort on COVID-19 Programme (MR/V033441/1); UK National Institute for Health Research (NIHR)-funded Global Health Research Group on Acute Brain Infections (17/63/110); and the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections (NIHR200907), at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (Grant Nos. IS-HPU-1112-10117 and NIHR200907). Declaration of Interests: BS reports a grant from UKRI/DHSC Global Effort on COVID-19 Research (Medical Research Council) and non-financial support from UK National Institute for Health Research Global Health Research Group on Brain Infections. SL and TS are supported by a grant from the EU Zika Preparedness Latin American Network consortium (ZikaPLAN). ZikaPLAN has received funding from the EU's Horizon 2020 research and innovation programme under grant agreement number 734584. LCG reports non-financial support from Pfizer, non-financial support from Gilead. LB reports grants from GlaxoSmithKline, Research England and Wellcome Trust. AMBM reports grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico CNPq/Brazil, and Sao Paulo Research Foundation FAPESP/Brazil. AP reports personal fees from ZAMBON, UCB , BIOMARIN, and ABBvie pharma. TS was an adviser to the GlaxoSmithKline Ebola Vaccine programme, chaired a Siemens Diagnostics clinical advisory board, and advises the WHO Brain Health Unit Forum on Neurology and COVID-19; TS has also previously filed a patent for a test for bacterial meningitis based on a blood test (GB 1606537.7, April 14, 2016), and has grants from the UK Medical Research Council and National Institute for Health Research. All other authors declare no conflict of interest

Worldwide SARS-CoV-2 vaccination campaigns for prevention of COVID-19 are currently underway. In clinical trials and in open-label monitoring the vaccines have shown efficacy against COVID-19 and there have been limited and transient side effects. Previous vaccination campaigns have taught us that neurological adverse events to vaccinations can occur. In this review, we summarise what is already known about neurological and neuropsychiatric adverse events of COVID-19 vaccinations, and place this in the context of historical vaccination campaigns. There have been a number of neurological and neuropsychiatric adverse events following immunisation (AEFI) in association with SARS-CoV-2 vaccinations, however in each case there is either no definitive evidence currently to support causality or recognised adverse events are extremely rare. Causality assessment aids such as the Causality Assessment of an Adverse Event Following Immunization from the World Health Organisation and the Bradford Hill criteria may help us better understand potential neurological and neuropsychiatric adverse events to COVID-19 vaccinations. Functional neurological disorder (FND) can be precipitated by the process of vaccination and has previously been noted to potentially spread between individuals, particularly in younger communities. Importantly FND does not implicate the vaccine constituents and therefore should not hamper ongoing vaccination campaigns. Although neurological and neuropsychiatric AEFI may occur after SARS-CoV-2 vaccinations, at present there are no common causally associated neurological adverse events. It is likely that some patients will develop FND in response to vaccination, although this does not implicate vaccine constituents. In cases of future serious neurological or neuropsychiatric AEFIs, judicious and rapid assessment of causality must occur. In general, the benefits of ARS-CoV-2 vaccination at present outweigh the risks from a neurological standpoint, although in specific situations the risk-benefit ratio will vary depending on geographic and demographic factors as well as population risk factors. Ensuring as minimal disruption as possible to ongoing swift worldwide vaccination campaigns is essential to establish the herd immunity required to end the COVID-19 pandemic.

Encephalopathy is a common complication of COVID-19 that can both be a challenge to manage and also negatively impacts prognosis. Whilst encephalopathy may be due to common systemic causes, such as hypoxia, COVID-19 has also been associated with more prolonged encephalopathy due to less common but nevertheless severe complications, such as inflammation of the brain parenchyma, cerebrovascular involvement and seizures, which may be disproportionate to COVID-19 severity and which require specific management. The aim of this review is to provide pragmatic guidance on the management of COVID-19 encephalopathy through a consensus agreement of the Global COVID-19 Neuro-Research Coalition. A systematic literature search of Medline, MedRxiv, and BioRx was conducted between 1st January 2020 and 11th June 2021 with additional review of references cited within the identified bibliographies. A modified Delphi-approach was then undertaken to develop recommendations along with a parallel approach to score the strength of both the recommendation and the supporting evidence. This manuscript presents analysis of contemporaneous evidence for definition, epidemiology, and pathophysiology of COVID-19 encephalopathy and practical guidance for clinical assessment, investigation, and acute and long-term management.

ObjectivesTranscranial magnetic stimulation (TMS) has been used therapeutically for functional (conversion) motor symptoms but there is limited evidence for its efficacy and the optimal protocol. We examined the feasibility of a novel randomised controlled trial (RCT) protocol of TMS to treat functional limb weakness.DesignA double-blind (patient, outcome assessor) two parallel-arm, controlled RCT.SettingSpecialist neurology and neuropsychiatry services at a large National Health Service Foundation Trust in London, UK.ParticipantsPatients with a diagnosis of functional limb weakness (Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition). Exclusion criteria included comorbid neurological or major psychiatric disorder, contraindications to TMS or previous TMS treatment.InterventionsPatients were randomised to receive either active (single-pulse TMS to primary motor cortex (M1) above resting motor threshold) or inactive treatment (single-pulse TMS to M1 below resting motor threshold). Both groups received two TMS sessions, 4 weeks apart.Outcome measuresWe assessed recruitment, randomisation and retention rates. The primary outcome was patient-rated symptom change (Clinical Global Impression–Improvement scale, CGI-I). Secondary outcomes included clinician-rated symptom change, psychosocial functioning and disability. Outcomes were assessed at baseline, both TMS visits and at 3-month follow-up.ResultsTwenty-two patients were recruited and 21 (96%) were successfully randomised (active=10; inactive=11). Nineteen (91%) patients were included at follow-up (active=9; inactive=10). Completion rates for most outcomes were good (80%–100%). Most patients were satisfied/very satisfied with the trial in both groups, although ratings were higher in the inactive arm (active=60%, inactive=92%). Adverse events were not more common for the active treatment. Treatment effect sizes for patient-rated CGI-I scores were small-moderate (Cliff’s delta=−0.1–0.3, CIs−0.79 to 0.28), reflecting a more positive outcome for the active treatment (67% and 44% of active arm-rated symptoms as ‘much improved’ at session 2 and follow-up, respectively, vs 20% inactive group). Effect sizes for secondary outcomes were variable.ConclusionsOur protocol is feasible. The findings suggest that supramotor threshold TMS of M1 is safe, acceptable and potentially beneficial as a treatment for functional limb weakness. A larger RCT is warranted.Trial registration numberNCT51225587.

Reply by the current author to the comments made by Mark A Oldham et al (see record 2020-79526-008) and Dorothy Wade et al (see record 2020-79526-009) on the original article (see record 2020-71085-023) We thank Dorothy Wade and colleagues and Mark Oldham and colleagues for their recognition of the cross-speciality effort of members of the UK's major professional neuroscience bodies who undertook this challenging UK-wide study during the exponential phase of the COVID-19 pandemic We also welcome the involvement of geriatricians and psychologists in future research We agree that delirium is common, especially in severe infections and in the intensive care unit As stated in our Article, we acknowledge that the study might have not recorded all such cases Changes in mental status with clear and recognised risk factors were not the focus of this study We agree that if such commonly observed complications were included, they might have substantially increased the number of patients recruited, mirroring the situation in other critical illnesses In this situation, the burden of CNS complications arising from COVID-19 would be even greater than we found in our study (PsycInfo Database Record (c) 2020 APA, all rights reserved)

Functional neurological (conversion) disorder (FND) is a prevalent and disabling condition at the intersection of neurology and psychiatry. Advances have been made in elucidating an emerging pathophysiology for motor FND, as well as in identifying evidenced-based physiotherapy and psychotherapy treatments. Despite these gains, important elements of the initial neuropsychiatric assessment of functional movement disorders (FND-movt) and functional limb weakness/paresis (FND-par) have yet to be established. This is an important gap from both diagnostic and treatment planning perspectives. In this article, the authors performed a narrative review to characterize clinically relevant variables across FND-movt and FND-par cohorts, including time course and symptom evolution, precipitating factors, medical and family histories, psychiatric comorbidities, psychosocial factors, physical examination signs, and adjunctive diagnostic tests. Thereafter, the authors propose a preliminary set of clinical content that should be assessed during early-phase patient encounters, in addition to identifying physical signs informing diagnosis and potential use of adjunctive tests for challenging cases. Although clinical history should not be used to make a FND diagnosis, characteristics such as acute onset, precipitating events (e.g., injury and surgery), and a waxing and waning course (including spontaneous remissions) are commonly reported. Active psychiatric symptoms (e.g., depression and anxiety) and ongoing psychosocial stressors also warrant evaluation. Positive physical examination signs (e.g., Hoover's sign and tremor entrainment) are key findings, as one of the DSM-5 diagnostic criteria. The neuropsychiatric assessment proposed emphasizes diagnosing FND by using "rule-in" physical signs while also considering psychiatric and psychosocial factors to aid in the development of a patient-centered treatment plan.

IntroductionWe will use an occupational sample to study the impact of COVID-19 on current staff and postgraduate research students at a large UK university. The cohort study will address some of the key questions about COVID-19 for the international community, while also providing feedback to the employer and educator.Methods and analysisParticipants were recruited via email to their University email address. Administrative records were available to compare the composition of volunteer participants to underlying staff and postgraduate student populations of the University. The study comprises a baseline survey, longitudinal follow-up surveys and a viral antibody study. Baseline information was collected in April 2020 including demographics, working situation, current stresses and worries, mental health and neurological symptoms. Personal experiences of COVID-19, indirect experiences and attitudes towards the pandemic were queried, as well as satisfaction with communication and support at work. Longitudinal surveys will assess changes in COVID-19 exposure and mental health. A viral antibody detection component is being planned and will also be longitudinal in nature.Ethics and disseminationEthical approval has been gained from KCL’s Psychiatry, Nursing and Midwifery Research Ethics Committee (HR-19/20-18247). Participants were provided with information and agreed to a series of consent statements before enrolment. Data are kept on secure servers with access to personally identifiable information limited. Researchers may apply to have access to pseudonymised data. Findings will be disseminated internally to the University and participants, and externally through scientific publications.

OBJECTIVE Altered attentional processing (automatically attending to negative or illness-relevant information) and interpretative biases (interpreting ambiguous information as negative or illness relevant) may be mechanistically involved in functional neurological disorder (FND). Common mechanisms between FND and chronic fatigue syndrome (CFS) have been proposed but not compared experimentally. METHODS We compared the cognitive task performance of FND, CFS, and healthy control (HC) groups. The tasks assessed attentional bias toward illness-relevant stimuli (visual probe task), attentional control (attention network task), and somatic interpretations (interpretative bias task), alongside self-reported depression, anxiety, fatigue, and general health. RESULTS Thirty-seven participants diagnosed with FND, 52 participants diagnosed with CFS, and 51 HC participants were included. Although participants with CFS showed attentional bias for illness-relevant stimuli relative to HC (t = -3.13, p = .002, d = 0.624), individuals with FND did not (t = -1.59, p = .118, d = 0.379). Both the FND (t = 3.08, p = .003, d = 0.759) and CFS (t = 2.74, p = .007, d = 0.548) groups displayed worse attentional control than did the HC group. Similarly, the FND (t = 3.63, p < .001, d = 0.801) and CFS groups (t = 4.58, p < .001, d = 0.909) showed more somatic interpretative bias than did the HC group. CONCLUSIONS Similar attentional control deficits and somatic interpretative bias in individuals with FND and CFS support potential shared mechanisms underlying symptoms. Interpretative bias toward somatic and illness-relevant stimuli in functional disorders may prove a therapeutic target.

Funder: UCLH Biomedical Research Centre; doi: http://dx.doi.org/10.13039/501100012317, Funder: National Institute for Health Research; doi: http://dx.doi.org/10.13039/501100000272, INTRODUCTION: Neuronal antibodies can cause encephalopathy syndromes often presenting with subacute cognitive impairment, sometimes resembling neurodegenerative dementias. METHODS: We searched Medline and Embase for studies reporting associations between neuronal surface antibodies in all-cause dementia versus controls. Random-effects meta-analysis was used to pool adjusted estimates across studies. RESULTS: Six studies were included, all reporting frequency of serum NMDAR antibodies in dementia with four also reporting frequency in atypical dementias. Both IgG [OR = 8.09 (1.51; 56.85), p = 0.036] and IgA/IgM NMDAR antibodies [OR = 42.48 (11.39; 158.52), p < 0.001] were associated with atypical dementia, but neither were associated with all-cause dementia. DISCUSSION: In the first meta-analysis to explore this literature, serum IgG and IgA/IgM NMDAR antibodies were significantly more common in atypical dementias. However, methodological issues and small-sample sizes necessitate caution interpreting this result. Further studies measuring both serum and CSF antibodies are needed to investigate the role of neuronal antibodies in dementia, since evidence of pathogenicity in even a subset of patients could pave the way for novel treatment options.

H.A.B. is funded by a National Institute for Health Research (NIHR) Clinical Lectureship. R.B. is supported by a NIHR Academic Clinical Fellowship. D.J.B. is funded by Alzheimer's Research UK & Rosetrees. D.J.B., M.R. and A.V. acknowledge the support of the National Institute for Health Research Sheffield Biomedical Research Centre (Translational Neuroscience). M.J.E. is funded by NIHR and the Medical Research Council. S.M.F. is funded by the Wellcome Trust & the Royal Society. J.H. is funded by a Wellcome Clinical Research Career Development Fellowship. R.H., N.C.F., J.M.S. and M.N.R. acknowledge the support of the National Institute for Health Research University College London Hospitals Biomedical Research Centre. L.M. receives philanthropic funding from Baillie Gifford. T.R.N. is funded by an NIHR Clinician Scientist Award. C.P. is funded by the Innovative Medicines Initiative, BRACE, and the David Telling Charitable Trust. J.S. is supported by a National Research Scotland Career Researcher Fellowship. This publication presents independent research; the views expressed are those of the authors and not necessarily those of the specified funding bodies.

Antibodies to the voltage-gated potassium channel (VGKC) complex and glutamic acid decarboxylase (GAD) have been reported in some cases of psychosis. We conducted the first systematic review and meta-analysis to investigate their prevalence in people with psychosis and report a case series of VGKC-complex antibodies in refractory psychosis. Only five studies presenting prevalence rates of VGKC seropositivity in psychosis were identified, in addition to our case series, with an overall prevalence of 1.5% (25/1720) compared to 0.7% in healthy controls (12/1753). Meta-analysis established that the pooled prevalence of GAD65 autoantibodies was 5.8% (95% confidence interval [CI]: 2.0-15.6%; I2 = 91%; nine studies) in psychotic disorders, with a prevalence of 4.6% (95%CI: 1.2-15.9%; nine studies; I2 = 89%) and 6.2% (95%CI: 1.2-27.0%; two studies; I2 = 69%) in schizophrenia and bipolar disorder, respectively. People with psychosis were more likely to have GAD65 antibodies than controls (odds ratio [OR], 2.24; 95%CI: 1.28-3.92%; P = 0.005; eight studies; I2 = 0%). Among 21 participants with treatment-resistant psychosis, none had VGKC antibodies. The prevalence of VGKC antibodies is low in psychosis. Our preliminary meta-analysis suggests that GAD autoantibodies are more common in people with psychosis than in controls, although few studies accounted for the possibility of co-existing type 1 diabetes mellitus and the clinical significance of reported GAD titers remains unclear. The paucity of studies reporting thresholds for defining GAD abnormality and rates of comorbid type 1 diabetes mellitus precludes interpretations regarding the influence of GAD antibodies on the development of psychotic disorders and may have led to an overestimate of the prevalence of GAD. Our case series fails to support the hypothesis that VGKC antibodies are linked to treatment resistance in psychosis, but the literature to date is remarkably sparse.

From the simple message of ‘I will please’ (Latin placēbō ) encapsulated in a sugar pill, to the famous theatrics of Jean-Martin Charcot’s hypnotic seizure inductions and treatments (figure 1), implicit and explicit narratives of healing and illness have been noted to exert a particularly strong influence on functional neurological disorder (FND). Although the placebo effect is near universal in medicine, and cultural frameworks are relevant for any illness experience, expectancy plays a more central mechanistic role in FND.1 Techniques of suggestion are still occasionally used in neurology practice, specifically to diagnose functional motor deficits by demonstrating reversibility,2 or to provoke dissociative seizures during video electroencephalography monitoring to enable a definitive diagnosis.3 Figure 1 The painting ‘Une lecon clinique a la Salpetriere’ (1887) by Andre Brouillet depicts Jean-Martin Charcot inducing neurological symptoms through hypnotic suggestion. His student Joseph Babinski (pictured holding the patient) later proposed changing the term hysteria to pithiathism (from Ancient Greek peithō , meaning ‘I convince’ ), emphasising the suggestibility of symptoms as a cardinal feature. Source: …

For over 4 months, we have been in the privileged position of witnessing real-time trends in the literature via our weekly curation of The Neurology and Neuropsychiatry of COVID-19 blog.1 There is an emerging recognition of the need to report the severity and outcomes of neurological complications of SARS-CoV-2 infection. Stroke is a rare but well-documented complication, with most prevalence estimates varying slightly around 0.8%.2 It is therefore important to elucidate both those at risk of developing stroke and stratifying those at risk of more severe outcomes when stroke occurs. We were greatly interested to read the letter by Dmytriw et al ,3 which highlighted potential racial disparities in outcomes from ischaemic stroke after COVID-19. Their novel study built on the hypothesis that black and minority ethnic (BAME) individuals have poorer outcomes from COVID-19 in general.4 An editorial commentary by Renieri5 further highlighted the need to elucidate mechanisms that may drive an interaction between stroke and COVID-19 to explain increased mortality in ethnic minorities. Previously also, Katz et al reported that patients with stroke with COVID-19 were more likely to be from a BAME population than patients with stroke without COVID-19. The potential over-representation of BAME individuals in COVID-19 stroke cohorts …

Introduction: We aimed to examine susceptibility to dissociation and the impact of dissociation on interoceptive processing in individuals with functional neurological disorder (FND). We hypothesised that dissociative states would be elevated and interoceptive accuracy and awareness impaired at baseline in people with FND, and that such differences would be exacerbated following acute dissociation. Methods: Nineteen adults with FND were compared to 20 healthy controls. A modified heart-beat tracking task measured interoceptive accuracy and awareness (confidence) before and after a validated dissociation induction procedure. An exteroceptive processing control task was included. Mann–Whitney tests and r-values (effect size) were computed for between-group comparisons. Results: The FND group displayed elevated dissociation at baseline (p = 0.001, r = 0.528) compared to controls which increased following dissociation-induction (p r = 0.663). Interoceptive accuracy did not differ between groups at baseline (p = 0.967, r = 0.009); however, the FND group had lower accuracy scores post-induction (p = 0.021, r = 0.379). A negative correlation (trend) between change scores for dissociation and interoceptive accuracy was noted (rs = −0.411, p = 0.057). Confidence ratings on interoceptive and exteroceptive processing tasks were lower in the FND group (p-values r-values 0.331–0.489). Conclusions: Individuals with FND experienced greater susceptibility to dissociation, metacognitive deficits and impaired interoceptive accuracy than controls after acute dissociation.

The development and selection of optimal outcome measures is increasingly recognized as a key component of evidence-based medicine, particularly the need for the development of a standardized set of measures for use in clinical trials. This process is particularly complex for functional neurological disorder (FND) for several reasons. FND can present with a wide range of symptoms that resemble the full spectrum of other neurological disorders. Additional physical (e.g., pain, fatigue) and psychological (e.g., depression, anxiety) symptoms are commonly associated with FND, which also can be highly disabling with implications for prognosis, and warrant concurrent assessment, despite an unclear etiological relationship with FND. Furthermore, several unique clinical aspects of FND make it likely that the usual prioritization of "objective" (or clinician-rated) over "subjective" (or patient-rated) measures might not be appropriate. Self-report measures may be more clinically meaningful in this patient population. Despite being a common and disabling disorder, there has been little research into outcome measures in FND, and to date trials have largely used measures designed for the assessment of other disorders. An international FND Core Outcome Measure group (FND-COM) has been established to develop a consensus battery of outcomes for FND: a "core outcome set." In this perspective article, the authors reviewed the process of outcome measure development and selection before considering the specific features of FND affecting the development of a core outcome set, as well as a research agenda to optimize outcome measurement in this complex neuropsychiatric disorder.

Objectives/Aims Catatonia is an important neuropsychiatric disorder with a high morbidity and mortality. However, due to a perception that it is very infrequent and because of the acuity of the patients, it has remained poorly studied and research has often been confined to small groups. We aimed to establish the demographic, disease-related variables and blood-based biomarkers for catatonia in a large dataset. Methods We used the Clinical Records Interactive Search (CRIS) system hosted at the NIHR Maudsley Biomedical Research Centre to search the clinical records for patients with catatonia. An initial free-text search was refined by use of a natural language processing app. The results of the app were validated by three of the authors, who included patients in the analysis only if a clinician had made a diagnosis of catatonia and two or more items of the Bush-Francis Catatonia Screening Instrument were in evidence. Demographics, disease-related variables and blood-based biomarkers could then be extracted for these patients and compared, where relevant, to non-catatonic psychiatric patients. Results The natural language processing app extracted the records of 2766 patients with at least one mention of catatonia in their records. The majority of cases identified by the app could be validated by the researchers. A high proportion of patients had more than one episode of catatonia. Full results will be available in time for the presentation. Conclusions This study demonstrates that catatonia is not very rare, even relying on clinician identification. The frequency of recurrence is interesting, as it suggests that catatonia might indicate an underlying trait, rather than merely a transient state.

BackgroundFunctional neurological disorder (FND), previously known as conversion disorder, is common and often results in substantial distress and disability. Previous research lacks large sample sizes and clinical surveys are most commonly derived from neurological settings, limiting our understanding of the disorder and its associations in other contexts. We sought to address this by analysing a large anonymised electronic psychiatric health record dataset.MethodsData were obtained from 322 patients in the South London and Maudsley NHS Foundation Trust (SLaM) who had an ICD-10 diagnosis of motor FND (mFND) (limb weakness or disorders of movement or gait) between 1 January 2006 and 31 December 2016. Data were collected on a range of socio-demographic and clinical factors and compared to 644 psychiatric control patients from the same register.ResultsWeakness was the most commonly occurring functional symptom. mFND patients were more likely to be female, British, married, employed pre-morbidly, to have a carer and a physical health condition, but less likely to have had an inpatient psychiatric admission or to receive benefits. No differences in self-reported sexual or physical abuse rates were observed between groups, although mFND patients were more likely to experience life events linked to inter-personal difficulties.ConclusionsmFND patients have distinct demographic characteristics compared with psychiatric controls. Experiences of abuse appear to be equally prevalent across psychiatric patient groups. This study establishes the socio-demographic and life experience profile of this understudied patient group and may be used to guide future therapeutic interventions designed specifically for mFND.

AimsFunctional neurological disorder (FND), formerly known as conversion disorder, causes a high burden of disability and distress, and is amongst the most commonly encountered conditions in neurology clinics and neuropsychiatry services, yet the therapeutic evidence base is limited. Research into psychedelics such as psilocybin and lysergic acid diethylamide (LSD) is currently being undertaken with significant renewed interest, and in recent studies psychedelics have shown promise in treating a range of psychiatric conditions. Modification of neural circuits associated with self-representation is thought to underlie some of this effect, and as some contemporary theories of FND focus on aberrant somatic self-representation, psychedelics may therefore represent an unexplored treatment option for FND. METHODS: We systematically reviewed studies involving the use of psychedelics in FND. Nine studies published between 1954 – 1967, with a total of 26 patients, were identified. Due to restriction of licencing of psychedelic drugs since this period, no modern studies were identified.ResultsLSD was the most commonly used psychedelic, with some studies also using psilocybin and/or mescaline. The number of therapeutic sessions of psychotherapy ± psychedelic substance administration ranged from one to 26, with descriptions of therapeutic methods used widely varying, and in some cases not described in any detail. Psychedelics were given either orally or intramuscularly, with doses of LSD ranging from 25 to 2,000 micrograms (mcg), and doses of psilocybin ranging from 3 to 15 milligrams (mg). Of those treated, 69% (n=18) were found to have made at least some recovery, with 23% (n=6) having completely recovered after psychedelic therapy. Adverse events were typically mild and transient.ConclusionsStudies were generally of low quality, often lacking control groups and valid outcome measures. Despite this, the degree of improvement is considerable, even if the presumptive bias in favour of the treatment in the studies is taken into consideration. Furthermore, good therapeutic outcomes and lack of adverse events in modern open-label trials utilising psychedelic therapy for neuropsychiatric disorders is encouraging. Advances in the understanding of the neurobiology of FND, as well as further modern clinical research into the therapeutic utility of psychedelics, may help to determine whether psychedelics offer a feasible, safe and effective treatment for FND.

Objective/aimsInteroceptive differences have been proposed as an aetiological factor in functional neurological disorder (FND) but there is limited supportive evidence. Previous studies are few, have mixed findings and assessed only (objective) interoceptive accuracy, but not (metacognitive) interoceptive awareness. The aim of this study was to explore interoception in FND in greater detail, by assessing interoceptive accuracy and awareness in individuals with a range of FND presentations. As dissociative symptoms (e.g., depersonalisation, derealisation) are common in FND and could influence interoception, we sought to examine the effects of induced acute dissociation on interoception. We hypothesised that interoceptive accuracy/awareness would be impaired at baseline in FND relative to healthy controls, but that the differences would be exacerbated following dissociation induction.MethodsTwenty adults with FND were recruited from online FND support groups. Diagnosis was confirmed by medical documentation from a relevant healthcare professional. The FND group was compared to a group of 20 healthy controls recruited from online community groups. A modified heart-beat tracking task measured interoceptive accuracy (correct detection of heart beats) and awareness (confidence judgements). A control task involved counting visually presented geometric shapes. Both tasks were completed before and after a validated dissociation induction procedure (mirror-gazing).ResultsThe FND group reported elevated dissociation at baseline relative to controls (pConclusionsIndividuals with FND reported elevated dissociation both before and after a dissociation induction procedure, although this was exacerbated post-dissociation induction. In contrast, interoceptive accuracy was unimpaired at baseline, but impaired following dissociation induction, relative to controls. The FND group showed reduced metacognitive awareness for detection of bodily states and external (visual) stimuli. Future research should better determine the nature of interoceptive deficits in FND and assess the impact of dissociation on a range of cognitive and affective processes relevant to the disorder.

AimsFunctional neurological disorder (FND) is common and often severe. It is poorly understood, and there have been no international large-scale studies of self- management and illness beliefs in FND. We created a patient questionnaire to assess FND demographics, symptom comorbidity, self-management strategies (particularly in relation to prohibited substances), views on novel treatments, and illness beliefs.MethodsThe questionnaire was shared open access over a three-week period.Participants were recruited internationally through social media and patient groups. RESULTS: In total, 1162 respondents from 16 countries took the survey. Of these, 98% reported a formal diagnosis of FND from a consultant neurologist or other suitably trained clinician. Females constituted 86% of respondents, with an average age of 41.7 years (SD=12.50). Mean symptom duration was 7.69 years (SD=9.37) and average time from diagnosis was 2.24 years (SD=3.35), indicating a diagnostic lag of over 5 years. Symptom comorbidity was very high, with respondents reporting current: seizures (50%), gait disturbance (76%), loss of balance (77%), tremors (61%), muscle jerks/spasms (65%), altered sensations (79%), speech difficulties (65%), memory problems (80%), fatigue (93%), and headache (70%). Current psychiatric comorbidities – depression (43%), anxiety (51%), panic (20%), and PTSD (22%) - were also common. Illness beliefs varied, with respondents agreeing most strongly that FND is a combination of physical and stress/trauma-related factors. Respondents rated FND as having a severe effect on their life, with little control felt over their symptoms. Respondents had received a wide range of medical interventions, and many had tried alternative treatments. Prohibited substances such as cannabis, ketamine, and psychedelics had been used by 15% of respondents, with the majority experiencing no or minimal physical (90%) and psychological (95%) sequelae. Many respondents reported that they would be willing to try medically supervised psychedelic therapy if it was found to be safe and effective.ConclusionsThis large international online survey of FND patients indicated a striking co-occurrence of multiple symptoms. As expected, respondents reported that FND severely impacted on their lives, and many had lived with symptoms, which are not well managed by current medical therapies, for years. There was interest in novel putative treatments, such as medically supervised psychedelic therapies, which indicates a strong need to investigate alternative treatments for this poorly served patient group.

Objectives/AimsCatatonia is an important neuropsychiatric disorder with a high morbidity and mortality. However, due to a perception that it is very infrequent and because of the acuity of the patients, it has remained poorly studied and research has often been confined to small groups.We hypothesised that: catatonia would remain a significant clinical problem; catatonic patients would have a longer duration of admission and higher mortality; serum iron would be reduced, reflecting a systemic inflammatory response, and high rates of NMDA receptor antibody serum positivity would be observed.MethodsThis was a prospective cohort study that included patients in a large mental health trust who were diagnosed with catatonia between 2007 and 2016. We used the Clinical Records Interactive Search (CRIS) system hosted at the NIHR Maudsley Biomedical Research Centre to search the clinical records for patients with catatonia. An initial free-text search was refined by use of a natural language processing app. The results of the app were validated by three of the authors, who included patients in the analysis only if a clinician had made a diagnosis of catatonia and two or more items of the Bush-Francis Catatonia Screening Instrument were in evidence.Demographic, clinical and blood-based markers could then be extracted for these patients and compared, where relevant, to non-catatonic psychiatric patients.Results1,456 patients with catatonia (of whom 787 were psychiatric inpatients) and 37,456 psychiatric inpatient controls were identified. There was no evidence for a reduction in the rate of catatonia over time. Patients with catatonia were younger than the controls by 2.52 years (95% CI 1.30 to 3.73) and similar in gender composition. Patients with catatonia were more likely to be black (53.5% vs 24.5%, pConclusionsThis is the largest study of catatonia to date. There is evidence that catatonia is not dying out and confers high morbidity but without affecting mortality. The innate immune system does not seem to be activated, but NMDA receptor antibodies are present at higher rates than in psychiatric controls. We demonstrate that catatonia remains an important clinical problem and may be associated with neuroimmunological dysfunction.

BackgroundFND and migraine are both common disorders that occur in the absence of structural brain damage. Clinically, it is suspected that they might co- occur more often than would be expected by chance. It is important to distinguish them in some clinical situations, especially hemiplegic migraine from migraine that triggers FND with weakness but there are no systematic, and limited narrative reviews of the topic.ObjectivesTo study the association of FND and migraine with a systematic review of the literature.MethodsSearches for relevant literature were performed in July 2018 in MEDLINE and PsycINFO electronic databases without time limitation and augmented by hand searching the reference lists within these papers and the knowledge of literature from selected experts in the fieldResultsFive studies were identified; two from electronic, one from hand searches and two from experts. The total number of the sample size from the included studies was 2385. Findings generally indicated a positive association between migraine and FND. A prospective epidemiological study found that number of FND symptoms reported by migraineurs was 2.2 and 1.1 on controls. In a retrospective review of medical report study functional movement disorders occurred within 6 months or concomitantly with migraine onset in 71% of chronic migraine (CM) & 87.5% episodic migraine (EM) cases and the outcome effect of treating migraine on FND symptoms was a decrease or remission in 91% in CM and by 67% in EM. In a retrospective chart review study in the epilepsy monitoring unit, migraine diagnosis had a predictive value for diagnosing PNES & epilepsy OR=1.83, pConclusionsDespite a limited evidence base, migraine and FND appear to co-occur at elevated rates. It is imperative to explore how treating either migraine or FND impacts on the other. More studies are needed to confirm these findings and to investigate any potential mechanistic overlap.