"NMDAR-antibody encephalitis might best be described as a mixed mood-psychosis syndrome"

Every once in a while a paper comes along with the potential to 'really shift opinions'. I'm gonna place the publication by Adam Al-Diwani and colleagues [1] in that category, and their (pre-registered) systematic review around the topic of N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis.

NMDAR-antibody encephalitis reflects a condition characterised by the immune system failing to identify self as self. For whatever reason, the immune system starts treating specific cells of the body as 'enemy' and mounts an immune attack against them. This results in the formation of specific antibodies - "against the NR1 subunit of the NMDA receptor" [2] - also typically resulting in "psychiatric features before progressing to seizures, a complex movement disorder, autonomic dysfunction, and hypoventilation." The book and film 'Brain on Fire' is about as good an education as you might need on the personal costs and effects of NMDAR-antibody encephalitis.

As Al-Diwani et al mention, things are getting rather interesting for NMDAR-antibody encephalitis in psychiatric circles. Awareness of the condition is growing, albeit with further 'flesh on the bones' required in terms of clinical features to look out for which could accompany the biological testing for the condition. Researchers sought to do just that: "the psychopathology of NMDAR-antibody encephalitis needs to be clearly defined to encourage accurate clinical identification and prompt treatment."

They trawled the peer-reviewed scientific literature looking for mention of NMDAR-antibody encephalitis, and eventually settled on over 300 records describing 1100 people in total. Over 460 of those people were identified with "definite NMDAR-antibody encephalitis according to consensus criteria" and their psychiatric features were examined. "The authors extracted 50 lower-level psychiatric features reported in these 464 patients, defined their frequency, and grouped them into eight higher-level features." Further comparisons were made leading to them assessing "whether individual patients were best described by one or by several psychiatric diagnoses" used as comparators.

Various features were potentially important: "The most common higher-level features were behaviour (316 [68%]), psychosis (310 [67%]), mood (219 [47%]), catatonia (137 [30%]), and sleep disturbance (97 [21%]), and these features frequently coexisted in individual patients." Various interesting graphs and figures are presented by the authors to illustrate their findings. The end result was the description of NMDAR-antibody encephalitis as "polymorphic and not to respect traditional psychiatric classifications." That being said, the notion of a "mixed mood-psychosis syndrome" represents as good a description as any based on the Al-Diwani findings.

Other details? "Overall, the age and sex distribution centred around young women, and the frequency of cases was greatly reduced after 40 years of age." Important information there about a potentially vulnerable group. Also: "139 (30%) of 464 cases were associated with ovarian teratoma, seven (2%) with previous herpes simplex virus encephalitis, and 24 (5%) with pregnancy." Ovarian teratoma is described as a rare cancer categorised as a 'germ cell tumour'. The *link* between ovarian teratoma and NMDAR-antibody encephalitis is something that has been of interest for a few years [3] and perhaps provides a clue for further investigation.

I do stand by my 'game-changer' type comment of the Al-Diwani paper. There is of course more to do in this area (including examining a curious link between NMDAR-antibody encephalitis and 'an autistic-like regression' in some children which is becoming all the more prominent in the research literature [4]). Putting all the various features identified by the authors into a useful set of diagnostic criteria is also a next step...

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[1] Al-Diwani A. et al. he psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data. The Lancet Psychiatry. 2019. Feb 11.

[2] Finke C. A transdiagnostic pattern of psychiatric symptoms in autoimmune encephalitis. The Lancet Psychiatry. 2019. Feb 11.

[3] Acién P. et al. Ovarian teratoma-associated anti-NMDAR encephalitis: a systematic review of reported cases. Orphanet J Rare Dis. 2014;9:157.

[4] Khundakji Y. et al. Anti-NMDA receptor encephalitis in a toddler: A diagnostic challenge. International Journal of Pediatrics and Adolescent Medicine. 2018; 5: 75-77.

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Childhood lead (Pb) exposure and "greater psychopathology across the life course"

I've talked about the effects of lead (Pb) on cognition, behaviour and psychology before on this blog (see here and see here for examples). A (heavy) metal with no confirmed biological function, lead represents something that pretty much everyone should be avoiding exposure to, despite it still being used in everything from roofing materials to batteries. The findings reported by Aaron Reuben and colleagues [1] add further to the 'avoid lead' sentiments, and specifically how: "Childhood lead exposure may have long-term consequences for adult mental health and personality."

The aim of the Reuben paper was to conduct "the longest and largest psychiatric follow-up to date in a cohort of adults who were lead exposed and lead tested as children." Participants and their data came from "the Dunedin Multidisciplinary Health and Development Study, a longitudinal investigation of health and behavior in a birth cohort." This study specifically drew on data from over 500 Dunedin study members who were tested for lead exposure around age 11 years and were followed up until their late 30s. A range of psychometric measures were employed in adulthood to complement participants' blood lead test results during childhood, including "(1) repeated clinical interviews assessing psychopathology symptoms across adulthood up to 38 years of age; (2) comprehensive, dimensional measures of psychopathology that account for severity, comorbidity, and reoccurrence; and (3) a broad measure of adult personality (Big Five Personality Inventory)... that did not rely on self-report." Importantly, researchers relied on a sample where "the extent of children's exposure to lead was unrelated to their socioeconomic origins."

Results: most of the cohort (over 90%) had tested blood lead levels above the 5 μg/dL level that the US CDC currently describes as a "reference value for clinical attention." This threshold value replaced the 10 μg/dL level that used to be thought to be important. Indeed within the Reuben cohort: "The mean (SD) blood lead level was 11.08 (4.96) μg/dL."

Researchers also observed that: "After adjusting for covariates, each 5-μg/dL increase in childhood BLL was associated with a 1.34-point increase... in general psychopathology." Covariates included "family socioeconomic status, maternal IQ, and family history of mental illness." This seemingly dose-dependent relationship looked to be quite important.

Onward: "study members with higher BLLs [blood lead levels] at 11 years of age were viewed in adulthood by their informants as more neurotic..., less agreeable..., and less conscientious" than those with lower levels. Personality it seems *might* also be affected by childhood lead exposure (at least partially). These and other factors lead Reuben et al to conclude that: "the association between lead exposure and psychopathology may begin to manifest broadly well before adulthood" and "early-life lead exposure in the era of leaded gasoline experienced by individuals who are currently adults may have contributed to subtle, lifelong differences in emotion and behavior that are detectable at least up to 38 years of age."

I know there are caveats to this type of observational work - "there was only one time point of lead testing" - and even controlling for some potential covariates does not mean that the total spread of covariates has been covered in this study. Personally, I'm not overly enthused by the whole personality types bit either; particularly in light of further revelations about some of the historical proponents of such an idea (see here). But taken as part of a wider series of research on lead exposure and psychopathology, the Reuben work is in line with other results on how an environmental factor can seemingly affect both development and psychopathology. And minus any sweeping generalisations about psychopathology and crime, the so-called 'lead-crime hypothesis' under the guise of biosocial criminology for example, doesn't exactly suffer as a result of the Reuben findings...

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[1] Reuben A. et al. Association of Childhood Lead Exposure With Adult Personality Traits and Lifelong Mental Health. JAMA Psychiatry. 2019. Jan 23.

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Autistic traits assessed between 5 and 8 years old are 'primarily stable'

The findings reported by Hideyuki Haraguchi and colleagues [1] (open-access available here) provide the [brief] blogging fodder today and their conclusion that: "total and two subdomain-related autistic trait scores remained primarily stable in males and females" in the general population. Further that "assessing autistic traits before school entrance may aid in predicting later autistic traits as well as other co-occurring social and emotional problems."

Autistic traits were measured "by a mother-reported quantitative measure, the Social Responsiveness Scale, at age 5 and 8 years." The Social Responsiveness Scale or SRS has some good history with autism in mind both from a research and clinical perspective. In this case the Japanese version of the SRS was used, and data from total scores and "Social Communication and Interaction (SCI)" and "restricted and repetitive behaviors (RRBs)" domains also reported on in approaching 170 "Japanese community-based children."

Results: "We found that although autistic traits assessed by the SRS decreased slightly from age 5 to 8, the extent of this change did not reach statistical significance in this sample, indicating that autistic traits are primarily stable during this transition period at the group level."

This is an important finding. Whilst one has to be careful of any sweeping generalisations that for example, the expression of autistic traits by individual children or smaller subgroups might not be as stable as you think (see here and see here), the results do have implications for various areas. Not least those areas connected to the idea that autistic traits might have some subsequent important 'influence' on later psychopathology (or indeed, a subsequent diagnosis of autism). I say this in several important contexts covering the presence of depression and anxiety (see here) and also in relation to other 'overlapping' spectrums (see here and see here) and what this *could* mean for some potentially life-threatening risks (see here and see here).

The next stage of such research? Look beyond the late childhood years and into adulthood with autistic traits in mind.


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[1] Haraguchi H. et al. Stability of Autistic Traits from 5 to 8 Years of Age Among Children in the General Population. J Autism Dev Disord. 2018 Oct 5.

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