NMDAR encephalitis presenting with "behavioral changes and some autistic features"

Anti N-methyl-D-aspartate (anti-NMDA) receptor encephalitis is yet again (see here) the blogging topic today, as I bring the case report published by Yasmin Khundakji and colleagues [1] to your attention. It's an important case report because, in keeping with the primary focus of this blog, the words 'autistic features' also appear in the Khundakji account. This follows quite a bit of other independent research where autism or autistic features has been mentioned in the context of NMDA receptor encephalitis (see here and see here).

The details? "The patient was a healthy girl" ('was' being the operative word). Some time before she was 2 years of age, she experienced some really quite sudden and stark behavioural changes "manifesting as bouts of irritability, aggression, inconsolable crying, and self-mutilatory behavior (self-biting)." A fever brought about various other somatic symptoms, as eye contact was lost and insomnia set in. "In addition, she developed a progressive regression in gross and fine motor skills and an inability to swallow" with seizures following. Things were getting really serious.

Various tests were carried out which in the most part came up within typical reference ranges (including a "brain MRI"). Someone had their suspicions that NMDA receptor encephalitis *might* fit with the presented profile. Lo and behold, following testing a positive result was received albeit "one month later" (samples had to be sent out of country for analysis). Interventions were put in place ("intravenous immunoglobulin (IVIg) and intravenous methylprednisolone... plasma exchange... rituximab") with some being more successful than others. Of particular note: "A dramatic improvement in her social skills and irritability appeared within hours following plasma exchange." Interesting. Things did eventually improve for the young girl at the centre of the Khundakji paper as we are told that: "Apart from mild speech delay, her neurological exam and developmental milestones are normal."

What lessons can be learned from such case reports? How about starting with the idea that rapid onset childhood regression that includes 'autistic features' should always be investigated as a sign of unmet medical need such as a response to infection (see here)? Perhaps also acknowledge that the presentation of autism or autistic features is not a life-long, immutable, set-in-stone scenario for some people (see here and see here and see here)? And as for the effects of plasmapheresis (plasma exchange) on this particular young child linked to a "dramatic improvement in her social skills and irritability", I'm wondering whether there is a research study or two to be designed and conducted on this topic (with due care)?

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[1] 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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"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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Results "provides support for the possibility that some children with ASD may benefit from IVIG": but do they?

I had high hopes for the paper by Kathleen Connery and colleagues [1] titled: "Intravenous immunoglobulin for the treatment of autoimmune encephalopathy in children with autism." It talked about screening for various "brain-targeted autoantibodies" under the label of autoimmune encephalopathy (AIE) and the use of intravenous immunoglobulin (IVIG) as an intervention, all in the context of autism. Important and timely issues.

Unfortunately, after having read the paper a few times, high hopes dissipated somewhat in terms of some of the methodology employed and the 'support' provided by some of the test results obtained for using something like IVIG...

AIE covers quite a bit of diagnostic ground. First and foremost, it represents a disease where a person's own immune system starts to recognise 'self' as 'other' and starts attacking healthy brain cells, leading to inflammation of the brain. AIE is a serious condition that in some cases leads to death. Other symptom manifestations include seizures accompanied by various cognitive, behavioural and psychiatric consequences. In short, it is not something that anyone would want. It also requires prompt identification and treatment. If you need a good example of this, type in the words 'brain on fire' into your search engine and read on...

I've talked quite a bit on this blog about encephalitis (brain inflammation) in the context of autism (see here and see here for examples). Indeed, some big names in autism research are coming around the idea that brain inflammation in the context of some autism is a very real concept (see here). Although correlation does not necessarily equal causation, the coincidence of autistic signs and symptoms appearing alongside cases of encephalitis is hard to ignore. Particularly when some authors have talked about an 'autistic regression' [2] in the context for example, of N‐methyl‐d‐aspartate receptor antibodies (NMDAR‐Ab) encephalitis. In the same breath, some of those peer-reviewed documented cases of encephalitis and autism co-occurring have also talked about treatment. And in some cases, the treatment of choice was immunotherapy including IVIG.

So, back to the Connery paper. Some 80 children diagnosed with an autism spectrum disorder (ASD) were included for study. They were all evaluated at a "multispecialty clinic for AIE." They were (variably) screened for various autoantibody markers "by several panels." This included "antineuronal nuclear, anti-glial nuclear, Purkinje cytoplasmic, P/Q and N-type calcium, and VGKC antibodies as well as GAD65, AMPA, NMDA, and GABA-B receptor antibodies" headed under the term 'Paraneoplastic panel'. Something called the 'Cunningham panel' was also undertaken: "antidopamine D1 receptor (D1R), antidopamine D2L receptor (D2R), anti-lysoganglioside GM1, anti-tubulin, CaMKII." I believe that one of the authors on the Connery paper was also an inventor of this Cunningham panel. I should also reiterate that participants were 'variably' screened using the different panels. What this means is that not every child received the total panel of screening available

Results: perhaps most importantly we are told that within this cohort: "very few demonstrated autoantibodies usually associated with AIE in children." Having already focused in on NMDA receptor encephalitis, researchers observed that none of their cohort (who were tested) showed a positive result for NMDA receptor autoantibodies: "NMDA receptor autoantibodies were negative in all of the 34 patients in which it was tested."

Further: Using pre-defined criteria for being positive, "the Cunningham panel was positive in 44 (57%) of the 77 patients in which it was performed." I don't know too much about the Cunningham panel outside of what the company who offer it say about it on their website. I did happen upon one study [2] which looked at its use for potentially diagnosing Pediatric Acute Neuropsychiatric Syndrome (PANS) and concluded that 'must do better' was the best opinion to be given; also observing that "pathological Cunningham Panel results were present in 18 of 21 healthy controls." To provide some balance, there was some further correspondence linked to the Hesselmark/Bejerot paper (see here) regarding incorrect methodology being used. But even after this, the authors still concluded that: "Our results indicate that the [Cunningham] panel does not contribute to correct diagnosis in a clinical setting."

No mind, IVIG was eventually recommended for 49 participants (60% of the cohort). Those autoantibody panels were not however, the only route to receiving an IVIG recommendation, as authors also mention that "patients with severe behavioral or medical symptoms including drug-resistance epilepsy and/or immunodeficiency were considered candidates for IVIG treatment." In all, results are reported for 31 children who received IVIG under the watchful eye of the authors' care team.

So what happened when IVIG was given? Well, this is perhaps also where the Connery paper has perhaps over-stretched itself in terms of what results are presented. Various cognitive and behavioural outcomes are reported on as a function of 'before' and 'after' use of IVIG. The authors for example, talk about use of the SRS - "for measuring the social aspects of ASD" - and observed evidence of statistically significant differences. But one needs to bear in mind that this was not a blinded trial and therefore to say that any gains were present as a direct result of IVIG treatment is pushing it a little. I'm also left slightly unimpressed with the idea of 'best responders' on the basis of such immunological and behavioural results too on the basis of this study alone. At least however, the authors don't shy away from the quite frequently reported adverse effects *correlating* with IVIG use: "Sixty-five percent (20/31) of patients reported adverse effects, most commonly headaches and vomiting" and the need for caution when considering IVIG in the context of some autism.

As I said, I did initially have high hopes for the Connery results and indeed, there are some important research directions they raise which need appropriate follow-up. One of them is the possibility that PANS *might* be something not uncommon to the autism spectrum (see here). I did however come away less than impressed with elements of the design of their study and some of their interpretations of their findings. I don't want to poo-poo the idea that some manifestations of autism might be linked to the presence of AIE or that IVIG might be an intervention option for some. Unfortunately however, the Connery paper does not really provide the ideal evidence for either concept, which is a pity...

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[1] Connery K. et al. Intravenous immunoglobulin for the treatment of autoimmune encephalopathy in children with autism. Transl Psychiatry. 2018 Aug 10;8(1):148.

[2] Hesselmark E. & Bejerot S. Biomarkers for diagnosis of Pediatric Acute Neuropsychiatric Syndrome (PANS) - Sensitivity and specificity of the Cunningham Panel. J Neuroimmunol. 2017 Nov 15;312:31-37.

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"A pilot study of high-dose intravenous immunoglobulin 5% for autism"

Intravenous immunoglobulin (IVIG), the treatment of choice for "patients with antibody deficiencies" [1] has some research history when it comes to autism (see here).

Quite a few years back, I remember some chatter about the use of IVIG for at least a subset of children/adults diagnosed with autism [2]. Interest in IVIG subsequently waxed and waned, partly as a result of some politics 'accompanying' research but also because of things like the cost of such an intervention.

Judging by the recent results published by Isaac Melamed and colleagues [3] however, it looks however, like IVIG *might* be coming back into research fashion...

So: "we investigated the efficacy and tolerability of intravenous immunoglobulin (IVIG) infusion in children with ASD [autism spectrum disorder]." The words "immune dysregulation" and "neuroinflammation" are mentioned a few times in the Melamed paper so you can probably work out the reason(s) why IVIG was examined. I might add that this study appears to have been registered with ClinicalTrials.gov too (see here).

This was a pilot study so, of course, one always needs to be a little bit cautious when it comes to the study and any findings. But, from what I can see, the authors put in place quite a few 'primary' and 'secondary' endpoints covering various aspects of behaviour - "Children's Communication Checklist [CCC-2], Social Responsiveness Scale [SRS], Aberrant Behavior Checklist [ABC], Clinical Global Impressions-Severity [CGI-S] and -Improvement [CGI-I], Autism Diagnostic Observation Schedule [ADOS], and Peabody Picture Vocabulary Test [PPVT]" - and also some 'experimental' biomarkers of immune function in this study. That's quite a comprehensive battery all-in-all.

Based on the use of a "high-dose intravenous immunoglobulin" (1g/kg dose of Gammaplex 5%) for ten 21-day treatment cycles with some 14 research participants diagnosed with autism, researchers reported some signs of 'effect'. Behaviourally speaking, they talk about significant improvements in core areas such as reciprocal social interaction, communication and repetitive and/or stereotyped behaviours being observed. This, alongside significant reductions in "numerous secondary outcomes of immunological biomarkers indicative of neuroinflammation." In short, IVIG seemed to show effects and, importantly: "no subjects withdrew due to an adverse event" providing some well needed 'first, do no harm' data.

One study - an open label study at that - does not an evidence base make. Not even close, and that's despite other open label studies also being published [3] in this area. One also needs to bear in mind that IVIG is a blood product typically derived from more than one donor which, although screened for various infectious diseases, might still leave some people a little nervous about its use.

But... results such as the ones from Melamed cannot be easily ignored. Not least set within the context of a growing interest in immune function being *related* to some autism (see here for example) and specifically where 'regression' seems to be part and parcel of symptom onset (see here and see here), further [controlled] investigations are required. And that includes what happens to any behavioural / immunological gains / changes as and when IVIG intervention is stopped too...

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[1] Jolles S. et al. Clinical uses of intravenous immunoglobulin. Clinical and Experimental Immunology. 2005;142(1):1-11.

[2] Gupta S. Treatment of children with autism with intravenous immunoglobulin. J Child Neurol. 1999 Mar;14(3):203-5.

[3] Melamed IR. et al. A pilot study of high-dose intravenous immunoglobulin 5% for autism: Impact on autism spectrum and markers of neuroinflammation. Autism Res. 2018 Feb 10.

[4] Boris M. et al. Improvement in children with autism treated with intravenous gamma globulin. Journal of Nutritional & Environmental Medicine. 2005; 15.

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"Autoimmune epilepsy is an underrecognized condition..."

"Among adult patients with epilepsy of unknown etiology, a significant minority had detectable serum Abs [autoantibodies] suggesting an autoimmune etiology."

So said the findings reported by Divyanshu Dubey and colleagues [1] continuing a research theme previously discussed on this blog (see here) on how epilepsy / seizure-type disorder(s) for some might have more to do with immune function than many people might think.

OK, a brief bit of background: epilepsy is a blanket term covering a wide variety of different presentations that affect the brain and specifically, 'the electrics' of the brain. Seizures are the most common symptom. Treatment typically comes in the form of anti-epileptic medicines (although other options are being considered for some). It's been known for a while that outside of the 'brain' focus of epilepsy, other biological systems might also play a role in the development/maintenance of the condition(s); specifically the immune system and quite often in cases where traditional anti-epileptic medicines don't seem to be able to control seizures effectively. The details are still a little sketchy but studies like the one from Dubey et al are trying to put some scientific flesh on to the bones of what facets of the immune system are potentially involved, specifically under 'autoimmune' conditions where the body fails to recognise 'self' as self and mounts an immune response against the body's own tissue(s).

Dubey and colleagues looked at a group of participants "presenting to neurology services with new-onset epilepsy or established epilepsy of unknown etiology" and tested donated serum samples "for Abs reported to be associated with autoimmune epilepsy (NMDAR-Ab, VGKCc-Ab, leucine-rich glioma-inactivated protein 1 [LGI1] Ab, GAD65-Ab, γ-aminobutyric acid type B receptor [GABAB] Ab, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor [AMPAR] Ab, antineuronal nuclear antibody type 1 [ANNA-1 or anti-Hu] Ab, Purkinje cell cytoplasmic antibody type 2 [PCA-2] Ab, amphiphysin Ab, collapsin-response mediator protein 5 [CRMP-5] Ab, and thyroperoxidase [TPO] Ab)." Quite a lot of those autoantibodies probably sound like gibberish to the lay reader but some of them have been discussed in other contexts on this blog (see here and see here for examples).

Results: some (15) of the 127 participants initially enrolled in the study were "subsequently excluded after identification of an alternative diagnosis." This in itself is interesting, as diagnoses such as "hypoxic or anoxic injury following cardiac arrest" and "ischemic stroke" are mentioned, illustrating how several different roads can lead to epilepsy and/or the presentation of seizures.

Then: "Serum Abs suggesting a potential autoimmune etiology were detected in 39 (34.8%) cases." Over a third of the cohort showed serological evidence of autoantibodies and some presented with more than one type of autoantibody as being present. Breaking down those serologically positive participants, we are told that: "19 patients (48.7%) had new-onset epilepsy and 20 patients (51.3%) had established epilepsy." The authors did also subsequently limit their findings to those cases excluding TPO-Ab and low-titer GAD65-Ab (autoantibodies where a specific role to epilepsy is unclear or not specific) but even then reported that: "23 patients (20.5%) with unexplained epilepsy had positive serologic findings strongly suggestive of an autoimmune cause of epilepsy." There is also a final part to the Dubey paper which also merits mention: "Among the 23 patients who were seropositive, 15 (65.2%) received some sort of immunotherapy. Better seizure outcome was associated with use of immunomodulatory therapy... especially with use of intravenous methylprednisolone... or plasmapheresis."

Alongside other (independent) studies in this area, the peer-reviewed evidence does seem to growing to suggest that within the wide (and heterogeneous) 'spectrum' that is epilepsy, at least some of that epilepsy might have an important immune component to it. To quote again from Dubey: "The data presented here suggest that autoimmune encephalitis may explain at least 20% of adult-onset epilepsies of unknown etiology." Aside from the importance of screening for said autoantibodies when certain cases of epilepsy appear at clinic, there are a few other potentially important points that could be raised about such data. Autism is area that I would be interested to see some further investigations carried out on with the Dubey findings in mind. Epilepsy is an important comorbidity 'over-represented' when it comes to autism (see here) and given the suggestions down the years that immune function (specifically autoimmunity) might be a facet of 'some' autism (see here for example) it's not beyond the realms of possibility that comorbid epilepsy might be a further facet of any autoimmune processes. Birds of an autoimmune feather tend to stick together and all that (see here). Add in the findings specifically talking about 'anti-NMDA-receptor encephalitis "mimicking an autistic regression"' (see here) and how methlyprednisolone might not be an uncommon medicine for some types of (autoimmune-related autistic presentation) and the hypotheses to be tested are laid out in front of you. By saying that, I don't want to take anything away from the more typical forms of epilepsy that can present (either alone or alongside autism) but rather point to the expanding knowledge base suggesting that immune functions may extend much further than just protecting the host from infection et al...

To close, slightly related to some of the content included in this post, the trailer for the film Brain on Fire (from the book of the same name) is out and looking like required viewing.

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[1] Dubey D. et al. Neurological Autoantibody Prevalence in Epilepsy of Unknown Etiology. JAMA Neurol. 2017 Feb 6.

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Dubey D, Alqallaf A, Hays R, Freeman M, Chen K, Ding K, Agostini M, & Vernino S (2017). Neurological Autoantibody Prevalence in Epilepsy of Unknown Etiology. JAMA neurology PMID: 28166327

Psychosis (sometimes) as an immune disorder?

"Some psychosis cases an 'immune disorder'" went the BBC headline with reference to the paper by Belinda Lennox and colleagues [1] talking about the detection of antibodies against the N-methyl-D-aspartate receptor (NMDAR) in cases of first-episode psychosis (FEP).

Although by no means a universal phenomenon, researchers reported that 3% of their 228 participants diagnosed with FEP who provided a blood sample showed the presence of NMDAR antibodies compared with none of the healthy controls (n=105) included for study. As part of the condition known as anti-NMDAR encephalitis, the presence of NMDAR antibodies can indeed include/induce psychotic features [2].

This is interesting work. For anyone that has come across the book 'Brain on Fire' by Susannah Cahalan, there is a growing interest in how the presentation of psychiatric features can, on occasion, include a significant role for the immune system and particularly, the concept of autoimmunity (where the body's own immune system fails to differentiate between 'self' and 'other'). Some of the authors included on the Lennox paper have previously summarised and discussed the idea that NMDAR antibodies might show a connection to some cases of psychosis and conditions manifesting psychosis such as schizophrenia [3]. The current data tally with their previous conclusion that: "A minority of patients with psychosis are anti-NMDA receptor antibody positive" and onwards the idea that there may be many different 'roads' to psychosis in these days of plural conditions (see here).

Where next for this research area I hear you ask? Well, set against the idea that various autoimmune diseases might be over-represented alongside a diagnosis like schizophrenia (see here), one needs to tease out some of the hows-and-whys details. Does, for example, a history of autoimmune disease 'set someone up' for psychosis and/or schizophrenia? Or is the autoimmune element of it something that follows a diagnosis of psychosis and/or schizophrenia? I have some opinions on this based on other findings on how autoimmunity may come about for some (see here for some discussion on HERVs) taking into account other peer-reviewed ideas and data [4]. I don't profess to be right or offer any universal answer but it is interesting that endogenous virus expression does seem to be heightened in a condition like schizophrenia and said elements might be considered important in processes such as molecular mimicry as one mechanism of autoimmunity [5]. There is a research plan to carry out and specifically on the topic of how NMDAR antibodies come about.

The other important 'where next' for this area of investigation is the tantalising prospect that 'treating' said autoimmune reaction might have some important effects on the presentation of something like FEP. There are hints out there in the peer-reviewed literature of possible treatment options being available. I might for example, draw your attention to some overlapping work looking at anti-NMDAR encephalitis ('encephalitis' that is) and cases of autism (see here and see here) where intervention options are discussed. With no medical advice given or intended, methylprednisolone seems to have found therapeutic favour for some. Other, more aggressive treatment options have also been reported but further investigations are required.

I note the words 'immuno-psychiatry' are mentioned in the media reporting of the Lennox findings and I'm happy to see the profile of this area of research being elevated through such work. The idea that immune function(s) might be doing so much more than just identifying and eradicating foreign bodies to maintain our physical health continues to gather pace...

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[1] Lennox BR. et al. Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study. Lancet Psychiatry. 2016. Dec 7.

[2] Dalmau J. et al. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurology. 2011;10(1):63-74.

[3] Pollak TA. et al. Prevalence of anti-N-methyl-D-aspartate (NMDA) receptor [corrected] antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis. Psychol Med. 2014 Sep;44(12):2475-87.

[4] Slokar G. & Hasler G. Human Endogenous Retroviruses as Pathogenic Factors in the Development of Schizophrenia. Frontiers in Psychiatry. 2015;6:183.

[5] Trela M. et al. The role of molecular mimicry and other factors in the association of Human Endogenous Retroviruses and autoimmunity. APMIS. 2016 Jan-Feb;124(1-2):88-104.

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Lennox, B., Palmer-Cooper, E., Pollak, T., Hainsworth, J., Marks, J., Jacobson, L., Lang, B., Fox, H., Ferry, B., Scoriels, L., Crowley, H., Jones, P., Harrison, P., & Vincent, A. (2016). Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study The Lancet Psychiatry DOI: 10.1016/S2215-0366(16)30375-3

Anti-NMDA-receptor encephalitis "mimicking an autistic regression"

Anti-NMDA-receptor encephalitis is not something that I ever envisaged talking about so much on this blog primarily concerned with autism research. Describing an often severe form of encephalitis where the body mounts an immune response against self ("the NR1 subunit of the NMDA receptor"), this condition is more readily associated with the symptoms of psychosis than anything specifically autism-related.

But yet again (see here and see here) I'm talking about peer-reviewed research suggesting that when one talks about the appearance of 'autistic regression' one might consider testing for anti-NMDA-receptor encephalitis just to rule it out as a possible cause. This time around the findings are those reported by Yael Hacohen and colleagues [1] and their description of "two toddlers who presented with developmental regression, particularly of their social communication skills, mimicking an autistic regression, who were found to have NMDAR-Ab [N-methyl-d-aspartate receptor antibodies] in the serum and cerebrospinal fluid." Aside from various "other neurological features" hampering timely diagnosis of anti-NMDA-receptor encephalitis, the authors report that subsequent "immunotherapy was beneficial in both patients, with significant improvement of their language skills and behaviour."

A few more details are worthy of discussion: Case 1 talks about a 2-year old girl who following a typical developmental profile experienced an "acute onset of behavioural change, disrupted sleep, and loss of motor, language and social communication skills." Even after some investigation for "an organic brain syndrome" everything came out as within typical ranges despite her continuing to regress after initial discharge. Following a second admission, during which time "she was mute and had orofacial and right hand sterotypies" she was found to have positive NMDAR-Ab and treatment was initiated in the form of methylprednisolone. We are told: "At follow-up, aged 4 years, 2 years from symptom onset, she is well, has age-appropriate language acquisition, no behaviour and psychiatric concerns, and remains relapse-free."

Case 2 was another young girl also aged 2 years who following a similar pattern to case 1 followed a typical pattern of development that was quite suddenly replaced with "abnormal behaviour" including a loss of speech, biting, pinching and "banging her head." Again, most parameters were in the typical zone when it came to assessments, although her sleep EEG "revealed occasional focal and generalized epileptiform discharges." Those NMDAR-Ab were detected and treatment initiated. Interestingly, authors reported that methlyprednisolone only provided short-term improvements for this child and so more aggressive treatment (rituximab and then mycophenolate mofetil) was put in place. The longer-term prospect for this child also did not seem to mirror case 1 as we are told that despite improvements in speech for example, "she continues to suffer from ongoing behavioural concerns and sleep disruption."

Combined with those other reports that dot the autism research literature, anti-NMDA-receptor encephalitis does seem to be at least one probable 'cause' of autistic regression. The important idea that one can screen for the presence of those antibodies (although looking in cerebrospinal fluid is quite invasive) also opens up a role for medicine and investigation when such a clinical outcome presents. 

And then there is the idea that when detected alongside certain autistic or autistic-like symptoms this type of encephalitis might be 'treatable'. No matter what your views are on autism or which 'kingdom' you subscribe to, I don't think anyone would truly suggest that a medical diagnosis of encephalitis should not be treated in an appropriate and timely manner. Indeed, various interventions could be indicated for such encephalitic cases [2] including the use of IVIg and methylprednisolone, all under appropriate medical supervision (I say this without any medical or clinical advice given or intended). Corticosteroid 'therapy' for regressive autism for example, has been previously discussed in the peer-reviewed literature (see here) so there may be quite a bit more research to do in this area. I might also add that none of the treatments discussed in the Hacohen paper are without potential side-effects so caution and medical input is a must.

Regression occurring in cases of autism is, at last, moving out of the shadows and becoming more readily accepted these days. I would hope that reports such as the one from Hacohen and colleagues are finally moving the conversation on in terms of what might cause instances of regression (see here for another example) and what interventions might be possible, all set within the context of the very plural and very heterogeneous autisms.

I will leave you with a few final sentences from Hacohen et al: "NMDRAR-Ab should be tested in cases of regression of social and communication skills with additional neurological symptoms such as movement disorder or seizures. Unlike autism, early diagnosis and treatement of NMDAR-Ab encephalitis is associated with much improved outcome." Make of that what you will...

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[1] Hacohen Y. et al. N-methyl-d-aspartate (NMDA) receptor antibodies encephalitis mimicking an autistic regression. Developmental Medicine & Child Neurology. 2016. June 3.

[2] Luca N. et al. Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Newly Recognized Inflammatory Brain Disease in Children. Arthritis and rheumatism. 2011;63(8):2516-2522. 

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Hacohen Y, Wright S, Gadian J, Vincent A, Lim M, Wassmer E, & Lin JP (2016). N-methyl-d-aspartate (NMDA) receptor antibodies encephalitis mimicking an autistic regression. Developmental medicine and child neurology PMID: 27255282

Anti-NMDA-receptor encephalitis and autism: research ascendancy

The paper by Reza Kiani and colleagues [1] (open-access available here) detailing the presence of anti-N-methyl-d-aspartate (NMDA) receptor encephalitis in two people "with autism and intellectual disability presenting with neuropsychiatric symptoms of catatonia and neuroleptic malignant syndrome" caught my eye recently.

Having previously talked about anti-NMDA-receptor encephalitis and autism in a previous blog post (see here) back in 2013 with the emphasis on a possible link to 'autistic regression', I've been intrigued by the rise and rise of peer-reviewed material on this subject in the intervening years. Subsequent descriptions such as the one from González-Toro and colleagues [2] again talking about children diagnosed with anti-NMDA receptor encephalitis after suffering a "regression of previously acquired abilities that developed into autism" further adds to my interest in this potentially important connection. That also there may be several roads leading to a diagnosis of autism is also an important take-away point from such work.

Kiani et al continue with the idea that there may be an "aetiological role of the immune system in the pathogenesis of various psychiatric disorders" on the back of various studies looking at anti-NMDA receptor encephalitis. On this occasion, they detail two case reports where autism and learning (intellectual) disability were already diagnosed but deteriorations in behaviour were noted. The first case report of a woman in her early-30s who "presented with social withdrawal and a persistently low mood" that subsequently led into "objective evidence of hallucinations" illustrates how various tests followed various symptoms ultimately leading the authors to suspect anti-NMDA receptor encephalitis. Importantly, they detail how psychotropic medication was the first choice of intervention and how, only after this 'failed', did they look for anti-NMDA-receptor antibodies. Of importance to the female presentation of anti-NMDA receptor encephalitis were the further investigations looking for any signs of "an underlying tumour, particularly an ovarian teratoma" given previous suggestions of a possible link [3].

The second case report focused on a middle-aged man "with moderate intellectual disability, autism and a history of affective psychosis in remission." Again, antipsychotic medication was the first thing to be reached for when "his condition deteriorated and he displayed aggressive outbursts and insomnia." Alas, this did not improve his state and neuroleptic malignant syndrome (NMS) was eventually diagnosed as a result of such intervention. Anti-NMDA-receptor encephalitis was finally considered when "further investigations revealed positive anti-NMDA-receptor antibodies."

Of note for both these individuals was the effect of treating anti-NMDA receptor encephalitis. This involved the use of methylprednisolone, an anti-inflammatory compound, normally administered for various autoimmune conditions. Interestingly, as a corticosteroid, prednisolone (the un-methylated version of methylprednisolone) has been talked about with 'regressive autism' in mind before in the peer-reviewed literature (see here). Kiani et al note that delivery of methylprednisolone was associated with a gradual recovery in behavioural symptoms "with no evidence of psychosis or cognitive deficit."

"In both patients the diagnosis was made with delay owing to the complexity of their presentation." This is an important sentence from Kiani and colleagues. Not only in respect to the various behavioural and somatic issues that were present (including comorbid diagnoses) but also insofar as issues with communication for example. I've talked about similar things before on this blog (see here). Further, the authors reiterate "the complex presentation of anti-NMDA-receptor encephalitis in... patients with intellectual disability and autism" and how further research is required to see whether diagnostic conditions such autism and/or learning disability "are more prone to develop this type of encephalitis or have a worse prognosis in comparison with the rest of the population." I struggle to disagree with such sentiments.

Music: Hozier - Take Me To Church.

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[1] Kiani R. et al. Anti-NMDA-receptor encephalitis presenting with catatonia and neuroleptic malignant syndrome in patients with intellectual disability and autism. BJPsych Bull. 2015 Feb;39(1):32-5.

[2] González-Toro MC. et al. Anti-NMDA receptor encephalitis: two paediatric cases. Rev Neurol. 2013 Dec 1;57(11):504-8.

[3] Dabner M. et al. Ovarian teratoma associated with anti-N-methyl D-aspartate receptor encephalitis: a report of 5 cases documenting prominent intratumoral lymphoid infiltrates. Int J Gynecol Pathol. 2012 Sep;31(5):429-37.

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Kiani R, Lawden M, Eames P, Critchley P, Bhaumik S, Odedra S, & Gumber R (2015). Anti-NMDA-receptor encephalitis presenting with catatonia and neuroleptic malignant syndrome in patients with intellectual disability and autism. BJPsych bulletin, 39 (1), 32-5 PMID: 26191422

Psychiatry and inflammation (again)

I'd like to bring two papers to your attention in today's very quick post.

"The Death Star plans are not in the main computer"

First up is the article by Kahn & Sommer [1] (open-access) titled: 'The neurobiology and treatment of first-episode schizophrenia'. It's about as good a read as we have so far on the topic of "brain changes in the first phase of schizophrenia" and the various management options for first-episode schizophrenia. Outside of the very important fact that "It is highly unlikely that the pathogenesis of all patients with schizophrenia will be uniform", the authors make mention of the growing interest that "the signs and symptoms of schizophrenia is an increased proinflammatory status of the brain".

Continuing on the topic of inflammation and psychiatry, which has been mentioned previously on this blog, the article by Friedrich [2] (open-access) is also worth a read which also covers anti-inflammatory treatment in schizophrenia. This paper has also been talked about with reference to inflammatory mechanisms potentially related to cases of autism (see here for some commentary).

Cumulatively, these papers do a good job of bringing immune involvement in psychiatry to the forefront. The recent publication [3] suggestive of common genetic variants linked to schizophrenia and in particular "loci found in areas of the genome associated with the immune system" ties in well with the increased interest in issues like inflammation in relation to schizophrenia. The next question is 'where next?'.

Music from a local band to finish: Frankie and the Heartstrings with Hunger. They also run quite a nice shop/store too (see here).

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[1] Kahn RS. Sommer IE. The neurobiology and treatment of first-episode schizophrenia. Mol Psychiatry. 2014. July 22.

[2] Friedrich MJ. Research on Psychiatric Disorders Targets Inflammation. JAMA 2014. July 23.

[3] Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014; 511: 421-427.

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Kahn RS, & Sommer IE (2014). The neurobiology and treatment of first-episode schizophrenia. Molecular psychiatry PMID: 25048005




Friedrich MJ (2014). Research on Psychiatric Disorders Targets Inflammation. JAMA : the journal of the American Medical Association PMID: 25054339

Regression and autism continued (yet again)

I noticed a few weeks back that the topic of regression - developmental regression - with autism in mind resurfaced during a few media reports (see here and here). That last report by Jennifer Richler, who knows more than most about the research around regression and autism [1] particularly took my attention, and the implication that perhaps we need a little more investigation into this area with a focus on developmental trajectories and the small details which might reflect onset of the regressive phenotype(s) and indeed, any pre-regressive presentation. Whether also a history of developmental regression might affect age at diagnosis might be another question to be asked in light of the study findings from Mishaal and colleagues [2].

Journeys... @ Wikipedia 

It is therefore timely that the paper by Kern and colleagues [3] (open-access here) also appeared in my inbox recently talking about regression in relation to autism based on parental reports. The quote: "82 children (60.7%) were reported to have R[egressed]" was interesting because this seemed to be quite a high figure bearing in mind the participant group size (N=135).

My previous post on the topic of regression and autism highlighted the meta-analysis paper by Barger and colleagues [4] which at most set parent-reported regression in autism at around 40% of cases, bearing in mind how one goes about defining regression. Indeed, the recent paper by Goin-Kochel and colleagues [5] similarly found the rate to be around the 40% mark (36.9% overall) in their cohort of over 2000 children. Allowing for the assumption that rates of regression in cases of autism are a static entity and not subject to changes over time, the disparity between the figures is interesting.

I'm not on this occasion going to go through the Kern paper in excruciating detail because it is open-access. It is not altogether dissimilar from the earlier Richler paper in that parental report forms the crux of the observations and factors such as gastrointestinal (GI) issues were also included in the research mix. Where the two results separate is on a few main points: (a) Richler and colleagues included a control group; Kern et al did not, (b) Richler talks about: "no evidence that onset of autistic symptoms or of regression was related to measles-mumps-rubella vaccination"; Kern suggests: "The majority of parents reported that the regression was preceded by or was associated with vaccinations (57.3%) or another medically related event (11.0%)", and (c) Richler talks about children "who lost skills" had "more gastrointestinal symptoms than children with ASD and no regression"; Kern by contrast reports: "no significant relationship between the children’s age, gender, race, severity, or GI symptoms, and their membership in the D[elayed], DR [delayed and later regressed], or R[egressed] groups". I don't want to head too far into the discussions surrounding point (b) but will draw your attention to the paper by Woo and colleagues [6], who looking at data from the US VAERS (Vaccine Adverse Event Reporting System) observed that "The proportion of VAERS cases of autism with regression was greater than that reported in population-based studies, based on the subset of VAERS cases with medical record confirmation". I wonder if this might have something to do with the high rate of regression reported by Kerns et al also?

I was particularly interested in the differing results reported as a consequence of the presence of GI factors comorbid to core autism presentation with regression in mind. I note in the paper by Valicenti-McDermott and colleagues [7], they reported that "children with language regression more frequently exhibited an abnormal stool pattern" assuming that one equates abnormal stool pattern[s] as being the same as GI symptoms; well, functional GI symptoms at least. The paper from Mady Hornig and colleagues [8] (open-access here) adds to this sentiment with their observation that "Autism with GI disturbances is associated with elevated rates of regression in language or other skills and may represent an endophenotype distinct from other ASD". All of this kinda puts a new slant on the recent papers confirming an over-representation of GI issues in cases of autism (see here).

I'm intrigued by the notion that combined regression and GI issues might be a distinguishing endophenotype (sub-group) in the growing plurality of autism. Autism research is still feeling its way through the concept of regression outside of something like Heller's syndrome / CDD (and anti-NMDA receptor encephalitis and other viral infections in mind) and how such reports fit into the grand scheme of how and why autism comes about. As per some recent chatter on the early [behavioural] identification of autism, regression occurring in cases of autism is also a potential fly in the ointment for establishing very early indicators of autism, further compounded by the start-stop that accompanies child development. And then there is the issue of racial differences in the reported rates of regression in autism... already covered by some media just to complicate matters further.

More to do methinks.

To close, although Europe is braced for that annual get-together that is the Eurovision Song Contest tomorrow (Saturday 10th May 2014) I'm not gonna post to any of the past or present songs. Instead, some very motivational lyrics from Kiss. Thank God.

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[1] Richler J. et al. Is there a 'regressive phenotype' of Autism Spectrum Disorder associated with the measles-mumps-rubella vaccine? A CPEA Study. J Autism Dev Disord. 2006 Apr;36(3):299-316.

[2] Mishaal RA. et al. Age of autism spectrum disorder diagnosis is associated with child's variables and parental experience. Res Autism Spect Disord. 2014; 8: 873-880.

[3] Kern JK. et al. Evaluation of regression in autism spectrum disorder based on parental reports. N Am J Med Sci. 2014 Jan;6(1):41-7.

[4] Barger BD. et al. Prevalence and onset of regression within autism spectrum disorders: a meta-analytic review. J Autism Dev Disord. 2013 Apr;43(4):817-28.

[5] Goin-Kochel R. et al. Developmental regression among children with autism spectrum disorder: Onset, duration, and effects on functional outcomes. Res Autism Spec Disord. 2014; 8: 890-898.

[6] Woo EJ. et al. Developmental regression and autism reported to the Vaccine Adverse Event Reporting System. Autism. 2007 Jul;11(4):301-10.

[7] Valicenti-McDermott MD. et al. Gastrointestinal symptoms in children with an autism spectrum disorder and language regression. Pediatr Neurol. 2008 Dec;39(6):392-8.

[8] Hornig M. et al. Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS One. 2008 Sep 4;3(9):e3140.

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Kern JK, Geier DA, & Geier MR (2014). Evaluation of regression in autism spectrum disorder based on parental reports. North American journal of medical sciences, 6 (1), 41-7 PMID: 24678477

Anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis and autistic regression

Regression as part of the presentation of autism is still a topic which has the ability to create discussion and fuel controversy. I've talked about it a few times on this blog (see here and here) and how, after a bit of a laboured start, modern day autism research has finally come around to acknowledging that regression can occur in cases of autism.

Fire @ Wikipedia  

The cause(s) of regression associated with autism has been where a lot of the debate has been had over the years. I've talked for example, about how vitamin B12 deficiency has been associated with cases of Childhood Disintegrative Disorder (CDD) (see here). This being one of the less 'controversial' theories put forward for regression in autism or in an autistic-like presentation as per other papers analysing factors such as thimerosal (thiomersal) exposure* and that-which-should-not-be-mentioned**.

What I take from the collection of literature on this topic is that (a) autism is probably better defined as the autisms insofar as the regression being present or not for example, and (b) there probably isn't just one factor influencing regression where and when it occurs in relation to those autisms. Oh and (c) getting to the bottom of the causes of regression in cases of autism is a mighty difficult task.

For today's post I'm talking about the paper by Ori Scott and colleagues*** describing a case report of a child where anti-N-methyl-D-Aspartate (NMDA) receptor encephalitis was suspected "as the cause of autistic regression".

From the top, anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis is an autoimmune condition whereby a person generates antibodies against self, in particular, antibodies that target NMDA receptors in the brain. As per the paper by Florance and colleagues**** (open-access here) the presentation of the anti-NMDA receptor encephalitis in children and adolescents is not wholly dissimilar from that in adults including behaviour and personality changes albeit including "temper tantrums, behavioral change, agitation, aggression, and progressive speech deterioration as initial symptoms". For those more interested in the adult presentation of the condition, the book 'Brain on Fire' by Susannah Cahalan is probably a good starting point.

Scott and colleagues chart the clinical course of a young boy following "an upper respiratory tract infection" into what would eventually "fit the diagnostic criteria for autistic spectrum disorder". Said anti-NMDA receptor antibodies were detected in cerebrospinal fluid (CSF) and treatment with "intravenous immunoglobulins and steroids" brought about a resolution of some of the behavioural issues. I might add that this is not the first time that anti-NMDA receptor encephalitis has been mentioned with autism in mind***** including that cross-over with CDD.

Taking into account the Scott paper and the writings of Cahalan, I get the impression that luck played a big role in the resolution of both cases. As per the Grauniad (sorry, Guardian) write-up of her book "Cahalan is never in any doubt about the extent of her luck: the luck in finding a sensitive doctor who listened to her, and took her case on its own merits". One can perhaps see that other medics might have not offered a similar diagnosis to the one she was eventually given and upon which treatment was commenced.

The Scott paper also brings into sharp focus how, when presented with cases of "autistic regression", it may be worthwhile undertaking some pretty detailed medical examination to determine whether the source of the regression might just fall into the jurisdiction of something like anti-NMDA receptor encephalitis. This accepting that getting a sample of CSF is not the nicest of procedures although as per other case studies, a full medical work-up is indicated****** (open-access).

That there also may be a medical reason for such a regression to occur is another lesson for autism research as and when it is confronted by children presenting with a fairly rapid regression into autism or autistic-like symptoms. It for example, strikes me that there is a growing respect for anti-NMDA receptor encephalitis when it comes to the presentation of something like delerium******* or even some cases of schizophrenia******** (open-access here) even without seizures being present. So when such a regression occurs in younger children, are they any less deserving of such medical consideration too? Exactly how the Scott report might play into the blanket 'autism is a lifelong condition' is another consideration.

Finally, I have to point out that the Scott paper was a case report and before anyone gets too carried away, does not necessarily mean that every case of regression in autism is due to this factor. That being said, the use of something like IVIg as the chosen treatment method for anti-NMDA receptor encephalitis is not necessarily a stranger to autism research (see here). The use of steroids as immunosuppressive agents, indicated for certain autoimmune conditions, might also offer some clues about certain parts of those autisms (see here) too bearing in mind my caveat on this blog about not giving medical or clinical advice.

Some music to close this post I think. Oasis and Don't Look Back in Anger. "Please [Mr McGee], don't make me angry, you wouldn't like me when I'm angry" (he says hiding behind the sofa).

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* Kern JK. et al. Thimerosal exposure and the role of sulfation chemistry and thiol availability in autism. Int J Environ Res Public Health. 2013 Aug 20;10(8):3771-800.

** Richler J. et al. Is there a 'regressive phenotype' of Autism Spectrum Disorder associated with the measles-mumps-rubella vaccine? A CPEA Study. J Autism Dev Disord. 2006 Apr;36(3):299-316.

*** Scott O. et al. Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: An Unusual Cause of Autistic Regression in a Toddler. J Child Neurol. 2013 Oct 3. [Epub ahead of print]

**** Florance NR. et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol. 2009 Jul;66(1):11-8.

***** Creten C. et al. Anti-NMDA-receptor encephalitis: a new axis-III disorder in the differential diagnosis of childhood disintegrative disorder, early onset schizophrenia and late onset autism. Tijdschr Psychiatr. 2012;54(5):475-9.

****** Chapman MR. & Vause HE. Anti-NMDA Receptor Encephalitis: Diagnosis, Psychiatric Presentation, and Treatment. Am J Psychaitry. 2011; 168: 245-251.

******* Punja M. et al. Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis: an etiology worth considering in the differential diagnosis of delirium. Clin Toxicol (Phila). 2013 Sep;51(8):794-7.

******** Tsutsui K. et al. Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features. BMC Psychiatry. 2012 May 8;12:37.

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Scott O, Richer L, Forbes K, Sonnenberg L, Currie A, Eliyashevska M, Goez HR. (2013). Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: An Unusual Cause of Autistic Regression in a Toddler Journal of Child Neurology DOI: 10.1177/0883073813501875