Defined by the core features of social communication issues and the presence of restricted and/or repetitive behaviours that variably but significantly impact on quality of life, autism spectrum disorder (ASD) represents a clinical diagnosis currently based solely on the observation of overt behaviours and developmental history (1). To describe ASD as a heterogeneous label does not do justice to the wide range of presentations that the condition entails. The current system of classification stretches from those who are profoundly disabled by ASD and require round-the-clock care and support to meet their daily needs, to those who are seemingly able to independently navigate the social world with only minimal day-to-day support requirements.

ASD rarely appears in a diagnostic vacuum (2). A multitude of cognitive, behavioural and/or psychiatric conditions are over-represented in ASD (3) many of which can and do significantly impact on quality of life. Diagnoses such as learning disability, attention-deficit hyperactivity disorder (ADHD) and schizophrenia spectrum disorder (SSD) are over-represented in ASD. Issues such as depression, anxiety and various eating disorders can also co-occur with ASD and are commonplace. Various physical health conditions also frequently accompany ASD (4). Most notably, epilepsy and/or seizure disorders and gastrointestinal (GI) disorders (both functional and pathological) can and do affect the expression of ASD, alongside sleeping issues, motor and gait problems and a myriad of other health complications. All these somatic issues have the propensity to affect both the presentation of the core symptoms of ASD and life experiences. For many people diagnosed with ASD, “autism plus” is the rule not the exception (5).

Among the various important debates on the aetiology, presentations, prognosis, and mechanisms underlying ASD (6), the assumptions that (a) ASD is solely an innate condition with universal presentation during the earliest times of development and (b) ASD is a lifelong condition for everyone, continue to be challenged. Various strands of evidence point to differing developmental trajectories in terms of onset patterns and clinical course in ASD. Evidence includes many examples of “acquired autism” where clinically relevant symptoms occur following periods of typical development and subsequent behavioural regression. Similarly, studies of longitudinal ASD presentation show that for some, there is such a significant reduction in symptoms that diagnostic thresholds for ASD are no longer met having previously done so (7).

Historically described as a rare condition, the estimated prevalence of ASD has steadily increased in recent decades, reaching estimates approaching 7% of school-aged children in some regions at the time of writing (8). The reasons for this increase are not yet fully understood. Factors such as increased awareness and diagnostic substitution are probably involved but do not seem to fully account for the sustained increase in numbers of people being diagnosed (9). This increase lends weight to the hypothesis that external (non-genetic) variables may contribute to the onset of ASD.

Various causes of ASD have been identified including syndromic autism (10) (appearing as part of a known genetic condition), ASD accompanying inborn errors of metabolism (11, 12) such as phenylketonuria (PKU) (13), ASD onset following prenatal exposure to specific medications such as sodium valproate (14) and following exposure to infectious diseases such as rubella (15). There have also been many reports of core symptoms and hallmarks of autism emerging as a consequence of viral (16) and bacterial encephalitis (17) in previously developmentally typical children and even adults. There are multiple examples of cases that demonstrate a link between infection and ASD, ranging from developmental and behavioural changes following herpes encephalitis (18, 19) to HIV infection (20–22), where so-called “paediatric NeuroAIDS” patients develop all the core symptoms of ASD as well as numerous accompanying behaviours and presentations (23).

It is instructive to consider the links between autism and infection in light of multiple reports suggestive of a genetic (24, 25) and non-genetic (26) propensity toward issues with immune function in cases of ASD. Despite the heterogeneity of the ASD label, there is evidence for both under- and over-activity of the immune system in ASD. This is exemplified by research reporting abnormalities in immune behaviour in relation to allergy and mast cell functions (27) and inflammatory processes (28) in ASD. Inflammation, and the many and varied inflammatory responses, are the focus of continuing scientific discussion and debate (29, 30) reflective of multiple lines of evidence indicating an important connection. Other literature also highlights the increased risk of autism in the offspring of mothers with poorly controlled immune-related issues in pregnancy (31). An over-exaggerated response to an immune trigger seemingly mirrors the complexity of sensory hypersensitivities and dysautonomia seen in ASD including an increased physiological response to stress (tachycardia, hypertension and raised cortisol/adrenaline levels) (32). Such a physiological response demands much of the metabolic reserve. The “Warburg effect” (aerobic glycolysis) (33) may be relevant, detailing how an exaggerated immune trigger switches oxidative phosphorylation to glycolysis in the race to meet the metabolic demands of an “over-primed” immune system.

Sustained, over-responsive immune signalling-a risk factor for autoimmunity where self is not recognised as self by the immune system, and results in an immune response to the body's own tissues-is also strongly implicated in ASD (34, 35). Findings range from the over-representation of a family history of autoimmune issues as a recognised risk factor for ASD (36), to exposure and reaction to maternal autoantibodies and maternal immune activation during critical periods of gestation (37, 38). Some authors have even gone as far as to talk about “an immune subtype of the autism spectrum” (39) as being a specific type of autoimmune disorder.

Consolidating many of the immune system findings in ASD, the specific notion of neuroinflammation as a feature of at least some ASD (40) holds particular importance given the nature of encephalitis, characterised by inflammation of the brain or surrounding tissue. The related use of immune modulating agents in ASD is also gaining recognition (41, 42). Primary immunomodulatory agents such as intravenous immunoglobulin (IVIG) (43), corticosteroids (44, 45), adrenocorticotropic hormone (ACTH) (46) and celecoxib (47) as possible treatments for core autism symptoms have garnered research attention, alongside recognition that other medications widely used in ASD, such as the atypical antipsychotic risperidone for example, have immunomodulatory actions (48).

For all the reasons previously outlined, our first aim is to review the current literature on AE and ASD. Secondly, we review the literature on autoimmune psychosis (AP) and the preliminary evidence of a psychosis-linked subtype of ASD.

Despite sound scientific evidence that various immune system irregularities are a feature of ASD and that early-life infection exposure to infections and inflammatory mediators can cause ASD or ASD-like features, or contribute to the severity of symptoms and presentations, there remains some hesitancy toward viewing ASD as a biological condition. Although past psychological explanations in relation to ASD have been roundly dismissed and all-encompassing psychological models on the nature of ASD are in retreat, entrenched views about the label persist. None more so than the assumptions that (a) ASD is solely and universally inborn and innate, and (b) that a diagnosis is immutable and lifelong (7). Such viewpoints are flawed on the basis of various factors, not least the enormous heterogeneity that ASD encompasses, and the emerging data on regression, acquired ASD as well as a significant minority of ASD cases where diagnostic symptom thresholds are no longer met. Such observations are also pertinent when exploring the overlap between ASD and AE.

Complicating the clinical picture on the overlap between AE and ASD is an additional area with the potential for further misdiagnosis: autoimmune psychosis (AP) vs. AE. AP (84) represents a relatively new label characterised by the presence of psychotic behaviours (hallucinations, delusions, incoherent thinking, disorganised behaviour) coupled with positive immunological findings for neuronal antibodies of the type used to diagnose types of AE. Screening and intervention options also mimic those used in AE as opposed to more traditional antipsychotic pharmacotherapy. Whether AP is entirely distinguishable from AE remains a source of debate. For the purpose of this article we accept the separative model as valid based on the currently available evidence. As with the potential for misdiagnosis of ASD in cases of AE and issues around related conditions such as autoimmune epilepsy, there is a requirement for careful screening for AP in cases of sudden onset psychosis (84).

Various intersecting areas unite AE, AP and ASD. Historically, ASD and schizophrenia, a condition that can manifest as psychosis, share important history. Evans (85) detailed the various revisions leading to our modern description of ASD including the important description provided by Creak and colleagues (86) and their nine key features of “schizophrenic syndrome in childhood.” These features were eventually condensed into what we now know as ASD, with descriptions such as “abnormal perceptual experience” previously thought to mean hallucinations, morphing into the neurocognitive sensory domain that is widely discussed in ASD today. The partition of schizophrenia and/or psychosis-linked conditions from ASD, whilst complete in diagnostic terms, is however not completely severed. Various studies have observed elevated rates of both ASD and ASD-associated traits in psychosis (87), while others have reported on the late diagnosis of ASD only after the incidence of psychotic events (88). The rates of comorbid ASD in schizophrenia are also elevated (89). As part of an increasingly vocal dialogue regarding the pluralisation of ASD (90), observations of “a specific subtype of ASD linked to comorbid psychosis” (91) provide important information about the “cross-reactivity” of ASD and psychosis or psychosis-linked diagnoses in clinical presentation.

At the genetic and biological level, there also remain some important similarities between ASD and psychosis-linked diagnoses. Aside from shared neurological findings, the increasing focus on immune function witnessed in relation to ASD is also mirrored in psychosis and schizophrenia spectrum disorders (SSD) (92). Inflammation and the notion of autoimmunity are key findings in psychosis and SSD, alongside discussions on the usefulness of anti-inflammatory strategies as treatment options. The rise of immunopsychiatry continues at pace. Collectively, such findings suggest commonalities between ASD, AP and AE.

Although still an area under investigation, there is sound, evidence-based backing for expanding screening for AE where a previously healthy child or adult experiences a developmental regression resulting in the presentation of ASD or ASD-associated features (59, 93). There is adequate evidence that neuroinflammation and encephalitis are relevant to ASD (94) and that the presentation of AE mirrors the presentation of regressive ASD. Only with appropriate screening, can a diagnosis of AE be considered and appropriate intervention put in place. There are various other examples of such forensic examination in action when ASD presents, particularly where regression of previously acquired skills is a feature (95, 96).

Screening for AE in cases manifesting regressive ASD needs to take account of the possibility that those with autistic regression may form a distinct subgroup on the autism spectrum, akin to a predisposition to autoimmune and “inflammatory activation” (80). Furthermore, clinicians need to consider that a diagnosis of ASD is in no way protective of developing AE, which may also very well worsen pre-existing features of ASD (97). Cumulatively, these and other findings offer important clues about how age and developmental maturity are important to the presentation of AE. Combined with other age-dependent factors such as the increased likelihood of AE being due to an underlying tumour in adults compared to an absence of tumours in paediatric AE, the requirement for forensic and wide-ranging examinations when AE is suspected in children or adults is paramount.

Methods for the analysis of autoantibodies and the subsequent use of immune therapies in cases of suspected or confirmed AE manifesting ASD also require further scientific examination. There is currently no guidance on the routine inspection of autoantibodies more generally in cases where ASD is diagnosed; something which complicates calls for preferential screening for AE related autoantibodies in cases of regressive ASD. Further longitudinal investigation of immune therapy for ASD manifesting AE is also required. Inspection of other related factors such as shared genetic variables overlapping between AE and ASD may also provide important information about who may be most susceptible to AE manifesting ASD and new ways of intervening. Overlapping research on the human leukocyte antigen (HLA) system would be an obvious starting point given markers of possible overlap (98, 99).

There is emerging evidence of a connection between AE and ASD. Multiple reports have described the presentation of ASD and/or autistic features in cases of diagnosed AE. Alongside other important observations of immunological issues being over-represented in ASD and various other types of infection associated with the onset of symptoms, there are important reasons for AE to be treated as a clinical priority in the context of ASD. It can no longer be assumed that regression, for example, is just “a part of autism” without any need for investigations. The cases of ASD appearing alongside AE provide a template for further clinical examination of such regressive onset patterns. There are significant challenges in relation to the assessment and diagnostic pathways toward recognising AE in ASD. Similar challenges are also present with regards to the treatment of AE in this context and in determining whether ASD appearing alongside AE represents a distinct phenotype of ASD or merely a differential diagnosis of ASD.

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

ESPA Research has received funds from the Robert Luff Foundation, some of which contributed to pay for PW time in the preparation of this manuscript. The Foundation played no role in deciding the content or in the production of the final manuscript.

RS has been an advisor to and has received honoraria from Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.