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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, I 2 = 70%) and neurological controls (g = 0.56, 95% CI 0.19-0.92, I 2 = 67%). Greater psychoform dissociation was observed in FND samples with seizure symptoms versus healthy controls (g = 0.94, 95% CI 0.65-1.22, I 2 = 42%) and FND samples with motor symptoms (g = 0.40, 95% CI −0.18 to 1.00, I 2 = 54%). Somatoform dissociation was elevated in FND versus healthy controls (g = 1.80, 95% CI 1.25-2.34, I 2 = 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.

Funder: Cambridge NIHR Biomedical Research Centre, Funder: Addenbrooke’s Charities Trust, Funder: NIHR Biomedical Research Centre (BRC), Funder: Maudsley NHS Foundation Trust, Funder: King’s College London, In November 2021, the COVID-19 pandemic death toll surpassed five million individuals. We applied Mendelian randomization including >3,000 blood proteins as exposures to identify potential biomarkers that may indicate risk for hospitalization or need for respiratory support or death due to COVID-19, respectively. After multiple testing correction, using genetic instruments and under the assumptions of Mendelian Randomization, our results were consistent with higher blood levels of five proteins GCNT4, CD207, RAB14, C1GALT1C1, and ABO being causally associated with an increased risk of hospitalization or respiratory support/death due to COVID-19 (ORs = 1.12-1.35). Higher levels of FAAH2 were solely associated with an increased risk of hospitalization (OR = 1.19). On the contrary, higher levels of SELL, SELE, and PECAM-1 decrease risk of hospitalization or need for respiratory support/death (ORs = 0.80-0.91). Higher levels of LCTL, SFTPD, KEL, and ATP2A3 were solely associated with a decreased risk of hospitalization (ORs = 0.86-0.93), whilst higher levels of ICAM-1 were solely associated with a decreased risk of respiratory support/death of COVID-19 (OR = 0.84). Our findings implicate blood group markers and binding proteins in both hospitalization and need for respiratory support/death. They, additionally, suggest that higher levels of endocannabinoid enzymes may increase the risk of hospitalization. Our research replicates findings of blood markers previously associated with COVID-19 and prioritises additional blood markers for risk prediction of severe forms of COVID-19. Furthermore, we pinpoint druggable targets potentially implicated in disease pathology.

World History Connected, Vol. 19 No. 2: Summer 2022

Encephalopathy, a common condition among patients hospitalized with COVID-19, can be a challenge to manage and negatively affect prognosis. While encephalopathy may present clinically as delirium, subsyndromal delirium, or coma and may be a result of 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 (with or without cerebrovascular involvement), demyelination, or seizures, which may be disproportionate to COVID-19 severity and require specific management. Given the large number of patients hospitalized with severe acute respiratory syndrome coronavirus-2 infection, even these relatively unlikely complications are increasingly recognized and are particularly important because they require specific management. Therefore, the aim of this review is to provide pragmatic guidance on the management of COVID-19 encephalopathy through consensus agreement of the Global COVID-19 Neuro Research Coalition. A systematic literature search of MEDLINE, medRxiv, and bioRxiv was conducted between January 1, 2020, and June 21, 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 recommendations and the supporting evidence. This review presents analysis of contemporaneous evidence for the definition, epidemiology, and pathophysiology of COVID-19 encephalopathy and practical guidance for clinical assessment, investigation, and both acute and long-term management.

Functional neurological disorder (FND), also known as conversion disorder, is characterised by a loss of voluntary control over parts of the nervous system (Espay et al., 2018). Examples of FND subtypes include paralysis, dystonia, seizures, and sensory abnormalities. Despite being the second most common disorder in neurology outpatient clinics (A. Carson & Lehn, 2016; Stone et al., 2010) and causing similar physical disability to multiple sclerosis and Parkinson’s disease (Alan Carson et al., 2011), FND has been relatively neglected by research. Current treatment options are limited, and many patients have severe long-term symptoms despite best-available treatment (Nicholson et al., 2020). There is a pressing need for better understanding of the neurobiology of the disorder (Perez et al., 2021). FND patients have shown increased connectivity in brain regions which comprise the default mode network (DMN), such as the posterior cingulate cortex (Cojan et al., 2009; de Lange et al., 2007, 2008, 2010), and the medial prefrontal cortex (Marapin et al., 2020). The increased DMN connectivity in patients with FND may be a correlate of abnormal predictions (otherwise known as over-weighted priors) about the body, for example that one cannot move one’s limb (Edwards et al., 2012). Patients with FND have also shown heightened limbic-motor cortex connectivity (Baizabal-Carvallo et al., 2019) and temporo-parietal junction (TPJ) aberrations (Marapin et al., 2020). Evidence from structural neuroimaging is heterogenous, although morphometric alterations have been seen in limbic and frontal cortices (Begue et al., 2019). There are some studies (albeit not always replicated) which have shown increased amygdala volumes in mixed FND cohorts, consistent with the idea that FND is a threat-related disorder (Maurer et al., 2018; Perez et al., 2017). Leading neurobiological theories of FND symptom generation have implicated regions associated with limbic-motor and limbic-frontal cortical connectivity, such as the cingulate cortex, orbitofrontal cortex, and insula (Pick et al., 2018). Patients with functional weakness have also been shown to have reduced left thalamic volume (unrelated to the laterality of symptoms) (Atmaca et al., 2006; Nicholson et al., 2014), which fits with structural imaging of patients with amputated limbs – conditions linked by loss of use of a limb - who also show reduction in thalamic volumes (Draganski et al., 2006). Structural neuroimaging in other causes of limb weakness with peripheral causes – namely motor neurone disease – have shown decreased grey matter volume in the motor cortex (Devine et al., 2015). A mega-analysis of all available structural neuroimaging data would (i) allow determination of morphometric alterations with increased statistical power clarifying inconsistencies in the literature (ii) allow grouping of participants my presentation phenomenology (iii) allow the inclusion of potential confounding factors (e.g. mood symptoms) in the analysis and (iv) allow the exploration of correlations with clinical features (e.g. frequency of seizures). 5-HT2A receptors are found throughout the cortex, especially so in high-level associative cortices (such as the DMN). It is thought that 5-HT2A receptors are upregulated in response to stress and may enhance plasticity and learning in response to stressors (Murnane, 2019), a hypothesis which is supported by data from mouse models of stress (Murnane, 2019). Although childhood adversity has been removed as a qualifier for the diagnosis of FND in the Diagnostic and Statistical Manual 5 (DSM-V), many patients do have a history of past or current stressors (Keynejad et al., 2019), indicating a possibility of increased cortical 5-HT2A receptor expression in this patient population.

Introduction: Encephalitis is typically caused by infection or autoimmunity. Most survivors suffer complex neurological and psychiatric sequelae. Standardised outcome measures are needed for accurate interpretation of observational studies and clinical trials. Step one in this process is understanding the strengths and weaknesses of those in use.\ud \ud Methods: We performed a systematic literature review searching six databases. One reviewer screened titles and abstracts, and two reviewers determined if shortlisted full-text articles met inclusion criteria. Key data were extracted from these papers and presented as a narrative summary.\ud \ud Results: Thirty-seven outcome measures were used for 3,133 patients across the 35 included papers, of which, only one was developed for encephalitis. The outcome measures used in most patients were the Glasgow Outcome Score used in 1,436 (46%), Barthel Index used in 1,173 (37%), Euro-QoL-5D used in 1,107 (35%) and modified Rankin Scale used in 1,034 (33%).\ud \ud Conclusion: Most of the 37 measures assessed a single category of sequelae using 5–8-point scales and were not validated for use in encephalitis. Research is needed to develop a composite outcome measure for use in clinical practice and a core-outcomes set for use in clinical trials. For now, the Liverpool Outcome Score offers a good choice for clinicians.