Journal Article Annotations
2020, 2nd Quarter

Neuropsychiatry

Nicholas Kontos, MD and Franklin King IV, MD
June, 2020

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic.
Serum and CSF Anti-NMDAR Antibody Testing in Psychiatry.

PUBLICATION #1 — Neuropsychiatry

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic.

Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli P, Zandi MS, Lewis G, David AS.

Abstract: Lancet Psychiatry. 2020 Jul;7(7):611-627. doi: 10.1016/S2215-0366(20)30203-0. Epub 2020 May 18.

BACKGROUND
Before the COVID-19 pandemic, coronaviruses caused two noteworthy outbreaks: severe acute respiratory syndrome (SARS), starting in 2002, and Middle East respiratory syndrome (MERS), starting in 2012. We aimed to assess the psychiatric and neuropsychiatric presentations of SARS, MERS, and COVID-19.

METHODS
In this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature databases (from their inception until March 18, 2020), and medRxiv, bioRxiv, and PsyArXiv (between Jan 1, 2020, and April 10, 2020) were searched by two independent researchers for all English-language studies or preprints reporting data on the psychiatric and neuropsychiatric presentations of individuals with suspected or laboratory-confirmed coronavirus infection (SARS coronavirus, MERS coronavirus, or SARS coronavirus 2). We excluded studies limited to neurological complications without specified neuropsychiatric presentations and those investigating the indirect effects of coronavirus infections on the mental health of people who are not infected, such as those mediated through physical distancing measures such as self-isolation or quarantine. Outcomes were psychiatric signs or symptoms; symptom severity; diagnoses based on ICD-10, DSM-IV, or the Chinese Classification of Mental Disorders (third edition) or psychometric scales; quality of life; and employment. Both the systematic review and the meta-analysis stratified outcomes across illness stages (acute vs post-illness) for SARS and MERS. We used a random-effects model for the meta-analysis, and the meta-analytical effect size was prevalence for relevant outcomes, I² statistics, and assessment of study quality.

FINDINGS
1963 studies and 87 preprints were identified by the systematic search, of which 65 peer-reviewed studies and seven preprints met inclusion criteria. The number of coronavirus cases of the included studies was 3559, ranging from 1 to 997, and the mean age of participants in studies ranged from 12·2 years (SD 4·1) to 68·0 years (single case report). Studies were from China, Hong Kong, South Korea, Canada, Saudi Arabia, France, Japan, Singapore, the UK, and the USA. Follow-up time for the post-illness studies varied between 60 days and 12 years. The systematic review revealed that during the acute illness, common symptoms among patients admitted to hospital for SARS or MERS included confusion (36 [27·9%; 95% CI 20·5-36·0] of 129 patients), depressed mood (42 [32·6%; 24·7-40·9] of 129), anxiety (46 [35·7%; 27·6-44·2] of 129), impaired memory (44 [34·1%; 26·2-42·5] of 129), and insomnia (54 [41·9%; 22·5-50·5] of 129). Steroid-induced mania and psychosis were reported in 13 (0·7%) of 1744 patients with SARS in the acute stage in one study. In the post-illness stage, depressed mood (35 [10·5%; 95% CI 7·5-14·1] of 332 patients), insomnia (34 [12·1%; 8·6-16·3] of 280), anxiety (21 [12·3%; 7·7-17·7] of 171), irritability (28 [12·8%; 8·7-17·6] of 218), memory impairment (44 [18·9%; 14·1-24·2] of 233), fatigue (61 [19·3%; 15·1-23·9] of 316), and in one study traumatic memories (55 [30·4%; 23·9-37·3] of 181) and sleep disorder (14 [100·0%; 88·0-100·0] of 14) were frequently reported. The meta-analysis indicated that in the post-illness stage the point prevalence of post-traumatic stress disorder was 32·2% (95% CI 23·7-42·0; 121 of 402 cases from four studies), that of depression was 14·9% (12·1-18·2; 77 of 517 cases from five studies), and that of anxiety disorders was 14·8% (11·1-19·4; 42 of 284 cases from three studies). 446 (76·9%; 95% CI 68·1-84·6) of 580 patients from six studies had returned to work at a mean follow-up time of 35·3 months (SD 40·1). When data for patients with COVID-19 were examined (including preprint data), there was evidence for delirium (confusion in 26 [65%] of 40 intensive care unit patients and agitation in 40 [69%] of 58 intensive care unit patients in one study, and altered consciousness in 17 [21%] of 82 patients who subsequently died in another study). At discharge, 15 (33%) of 45 patients with COVID-19 who were assessed had a dysexecutive syndrome in one study. At the time of writing, there were two reports of hypoxic encephalopathy and one report of encephalitis. 68 (94%) of the 72 studies were of either low or medium quality.

INTERPRETATION
If infection with SARS-CoV-2 follows a similar course to that with SARS-CoV or MERS-CoV, most patients should recover without experiencing mental illness. SARS-CoV-2 might cause delirium in a significant proportion of patients in the acute stage. Clinicians should be aware of the possibility of depression, anxiety, fatigue, post-traumatic stress disorder, and rarer neuropsychiatric syndromes in the longer term.

FUNDING
Wellcome Trust, UK National Institute for Health Research (NIHR), UK Medical Research Council, NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London.

PMID: 32437679

PMCID: PMC7234781

DOI: 10.1016/S2215-0366(20)30203-0

Annotation

Findings
Delirium is a frequent intra-illness accompaniment of SARS and MERS with between ¼ and 1/3 of acute (hospitalized) cases experiencing delirium despite a mean patient age of about 40. In a smaller total sample size, intra-illness rates of delirium in COVID-19 patients in the ICU was nearly 2/3. Not surprisingly, high rates of agitation and of dysexecutive syndrome at the time of discharge were also found in these COVID-19 patients. Depressive and anxiety symptoms are common among SARS and MERS survivors, with PTSD found to have a striking point-prevalence of about 1/3 of patients.

Strengths & Weaknesses
While studies and reports of the neuropsychiatric accompaniments and sequelae of COVID-19 are being published at a steady clip, this is an unusually rigorous attempt to combine existing data on similar viruses and recent data on COVID-19 to generate data based on the maximum numbers of subjects from relatively well-designed studies. This report does rest somewhat on (acknowledged) educated assumptions about commonalities of coronaviruses, so it remains to be seen if these assumptions prove to be well-founded. Another necessary limitation is that reports used for gathering COVID-19 data are no more recent than March 2020.

Relevance to Consultation-Liaison Psychiatrists
Consultation-liaison psychiatrists are currently called upon to assess and treat neuropsychiatric symptoms encountered in the setting of COVID-19 infected patients and may soon be doing the same for survivors of the diease. Some sense of the incidence of neuropsychiatric presentations in these groups is the first step in providing quality care and may be a good starting point for those attempting further research in this area.

PUBLICATION #2 — Neuropsychiatry

Serum and CSF Anti-NMDAR Antibody Testing in Psychiatry.

Warren N, Swayne A, Siskind D, O’Gorman C, Prain K, Gillis D, Blum S.

Abstract: J Neuropsychiatry Clin Neurosci. 2020 Spring;32(2):154-160. doi: 10.1176/appi.neuropsych.19030079. Epub 2019 Sep 18.

OBJECTIVE
The authors examined and compared the clinical presentation of CSF positive and negative N-methyl-d-aspartate receptor (NMDAR) antibody.

METHODS
The investigators performed a retrospective chart review of NMDAR-antibody-positive cases (serum or CSF) involving patients presenting to psychiatric services from 2010 to 2018 in Queensland, Australia. Presentation, progress, investigations, and efficacy of treatment are detailed.

RESULTS
There were 24 serum or CSF NMDAR-antibody-positive cases and three equivocal serum results. High rates of prodromal cognitive deficits, catatonia, speech disturbance, and antipsychotic sensitivity were observed in the 16 CSF NMDAR-antibody-positive case patients and two CSF NMDAR-antibody-negative case patients, all evident before neurological deterioration with seizures, movement disorder, and autonomic disturbance occurring in the weeks following admission. The majority of these patients (N=17) were treated successfully with immunomodulatory therapy. The nine remaining patients, who were CSF NMDAR antibody negative or equivocal, did not demonstrate any of these features and improved with psychiatric care alone.

CONCLUSIONS
These findings suggest that traditional psychiatric care may be appropriate for patients with isolated psychiatric symptoms who have positive serum NMDAR testing when CSF is negative and there are no key clinical features such as cognitive deficits, catatonia, speech disturbance, and antipsychotic sensitivity. However, if these key features are present, a trial of immunomodulatory treatment should be considered with repeated examination of CSF for neuronal antibodies.

KEYWORDS
Autoimmune; Catatonia; Encephalitis; NMDA; Psychosis

PMID: 31530118

DOI: 10.1176/appi.neuropsych.19030079

Annotation

Findings
Among patients initially presenting with solely psychiatric symptoms and found to be serum positive for anti-NMDAR antibodies, CSF anti-NMDAR positivity was associated with prodromal cognitive, catatonic, language disturbances and/or antipsychotic sensitivity and subsequent neurological deterioration. Among those with initial serum anti-NMDAR positivity and CSF negativity, subsequent neurological deterioration occurred in a small minority of patients within weeks. When neither CSF positivity nor neurological deterioration occurred, patients responded to psychiatric care without immunotherapy.

Strengths & Weaknesses
Providing a fairly comprehensive clinical review and clarly addressing a significant clinical dilemma are the main strengths of this study. Selection bias almost certainly skewed the tested population towards young psychotic patients. A relatively low number of patients (27) divided into subgroups makes the findings preliminary, and hopefully multi-center studies will be completed to replicate or refute these findings.

Relevance to Consultation-Liaison Psychiatrists
Despite well over a decade of clinical and academic attention, anti-NMDA-R encephalitis remains an area of concern, worry, and even dispute in individual clinical cases. This study provides CL psychiatrists with some guidance for making and justifying decisions about pursuing CSF testing and prognosticating “purely psychiatric” versus immunological treatment responses.