Autism spectrum disorder (ASD) is a neurodevelopmental condition, characterized by social interaction and communication difficulties, repetitive and restricted interests, and sensory behaviours (DSM-5, 2013). On the other hand, chronic fatigue syndrome (CFS), also referred to as myalgic encephalomyelitis (ME), is a complex disease involving widespread inflammation and dysregulation of the central nervous system (CNS) and immune system (Carruthers et al, 2011). There is evidence to suggest that people with ASD and CFS share overlapping clinical characteristics, including fatigue, low mood, anxiety, and reduced self-efficacy, which impacts upon their overall functioning (Rogers et al, 2017). It has been reported that unexplained chronic fatigue and increased sensitivity to pain are common in both ASD and CFS (Forde et al, 2022, Mariman et al, 2013 and Keville et al, 2021). In addition, sleep difficulties, brain fog and variable deficits in emotional awareness have also been observed in both groups (Maroti et al, 2017, Mariman et al, 2013, Devnani et al, 2015, and Ocon, 2013).
However, some recent explorations have ruled out a direct link between ASD and CFS (Bileviciute-Ljungar et al, 2018). Although CFS and ASD are distinct diagnoses, certain situations can be challenging; for instance, when a person with social interaction difficulties presents with unexplained fatigue at a young age. Although autism typically presents in early childhood (DSM-5, 2013) and CFS usually affects middle-aged adults (Chu et al, 2019 and Bakken et al, 2014), it is not uncommon for a fatigued, emotionally detached CFS patient to be referred for an ASD assessment. On the other hand, patients with ASD are often evaluated in physical health clinics to assess for a CFS co-morbidity that could explain their chronic mental and physical fatigue.
There is currently very limited data on the association between ASD and CFS. The aim of this review is to gather evidence and examine potential associations between autism and chronic fatigue syndrome and explore the possibility of shared genetic influences and similar neuropathology between the two conditions. Additionally, the study also aims to review recent findings around the possible role of anti-inflammatory drugs in the treatment of ASD and CFS considering the role of inflammatory processes involved in the pathogenesis of both conditions.
Literature search was performed on databases PUBMED, MEDLINE and Google Scholar. Eligibility criteria included all studies that looked at the association between autism spectrum disorder (ASD) and chronic fatigue syndrome (CFS). Exclusion criteria included 1) studies that reported on autism and chronic fatigue syndrome separately 2) studies that evaluated the association of autism with conditions other than CFS and 3) and studies that looked at the association of CFS with conditions other than autism. Studies published in a language other than English were also excluded.
On PUBMED, searching with MeSH terms "autism"[MeSH] AND "chronic fatigue syndrome"[MeSH] yielded 47 articles. After applying filters for English language, full text availability and search field (abstract/title), 28 articles were short listed. Out of those, only 4 articles met the eligibility criteria. Full text was not available for 1 article. This completed the search with 3 articles. Further advanced search on PUBMED using key words “autism spectrum disorder”, “autism spectrum condition” and “myalgic encephalomyelitis” did not yield any additional results. On MEDLINE, search was conducted using the key words “autism” AND “chronic fatigue syndrome”. The initial search yielded 26 results. After applying the inclusion/exclusion criteria, search was narrowed down to 3 articles, out of which only 2 were new searches. Google Scholar was searched using key words “autism spectrum condition” AND “chronic fatigue syndrome”. Initial search yielded 79 results. No additional articles were retrieved after searching with MeSH terms “autism”[MeSH] AND “myalgic encephalomyelitis”[MeSH] and after applying advanced search filters for time (anytime), relevance, and type of articles (any type). 7 articles were shortlisted after excluding books and applying inclusion/exclusion criteria. Out of these, 4 were new searches, and full text was available for only 3 articles, which were added to the search. This concluded the literature search with a total of 8 articles for review (see Figure 1. Flow chart). No systematic reviews or meta-analyses on the topic of interest were identified during the literature search.
Search strategy for selection of studies Flowchart
The review was conducted in a responsible and respectful manner, ensuring transparency, honesty and integrity of the research process. Although no direct patient data was collected for the purpose of this review, all efforts were made to ensure that the publicly available data and published papers were collected and reviewed ethically.
A total of eight articles explored the association between autism spectrum disorder and chronic fatigue syndrome. Research indicates that autistic individuals have a higher prevalence of co-occurring medical conditions compared to the general population (Grant et al, 2022), however, the underlying mechanisms are not well understood. There is evidence to suggest that central sensitivity syndromes (CSS), which include chronic fatigue syndrome (CFS), are more prevalent among people with autism (Grant et al, 2022). Grant et al (2022) investigated the occurrence of CSS diagnoses and symptoms in autistic individuals using a Central Sensitization Inventory (CSI). They reported that in a large sample of 973 participants, about 4.5% of people with autism reported a co-occurring diagnosis of CFS. Although higher scores on the CSI appeared to be related to stronger autistic traits, the path analysis suggested that this relationship was mediated by sensory sensitivity and anxiety, implying that these two variables could increase the vulnerability to conditions like CFS, rather than autism per se (Grant et al, 2022).
Kentrou et al (2024) explored the frequency of perceived psychiatric misdiagnoses in autistic individuals before receiving an autism diagnosis. They reported that about 4% of autistic individuals who had received a diagnosis of CFS prior to autism diagnosis, perceived it as a misdiagnosis. It is interesting to note that most patients were diagnosed with autism after the age of 18; this was attributed to autistic traits being potentially misinterpreted as symptoms of other conditions like anxiety disorders, CFS/burnout-related disorders and fibromyalgia etc (Kentrou et al, 2024).
Keville et al captured the mothers’ experiences of co-occurring fatigue in children with autism spectrum disorder (Keville et al, 2021). They analyzed semi-structured interviews from mothers of children with ASD aged 4–19 who also had severe levels of co-occurring fatigue. Mothers reported that their children’s fatigue was mostly a result of culmination of everyday life, social interactions and sensory demands (Keville et al, 2021). It is interesting to note that even when the child had a formal diagnosis of CFS, their mother continued to seek their own explanations for fatigue and did not agree with the diagnosis (Keville et al, 2021). The study reported that children with ASD experienced excessive tiredness and intense day time fatigue which was more unusual than the general population and significantly affected the children’s ability to function (Keville et al, 2021). They argued that the autistic fatigue was different from the fatigue seen in CFS and that individuals diagnosed with CFS (in the absence of a known medical explanation for fatigue) did not show autistic traits (Bileviciute-Ljungar et al,2018 and Keville et all, 2021).
Bileviciute-Ljungar et al (2018) examined whether there was an association between ASD and CFS and whether individuals with CFS would score higher on the autism-spectrum quotient (AQ) when compared to healthy controls. They found that patients with ASD scored significantly higher on the AQ as compared to the CFS and control groups. However, no differences in AQ scores were found between patients with CFS and healthy controls (Bileviciute-Ljungar et al, 2018).
Konyenburg (2006), on the other hand, studied the genetic susceptibility and similarities between autism and CFS including shared immune response pathways. He reported that glutathione metabolism, through its impact on redox environment, exerts a significant impact on neuroinflammation and neural apoptosis in both ASD and CFS, thus providing a link between both conditions and glutathione depletion. Similar findings have been validated by other studies (Bjørklund et al, 2020 and Paul et al, 2021).
Theoharides and Tsilioni (2018) also studied the neuroimmune and genetic link between ASD and CFS and aimed to explore the inflammatory processes involved in the pathogenesis of both conditions. They reported that ASD and CFS both involve focal inflammation in hypothalamus and amygdala which could explain most symptoms in both conditions (Theoharides and Tsilioni, 2018). They reported that neuropeptides and cytokine stimulation of mast cells and microglia during early development adversely affects the brain in ASD and that similar neuroimmune dysfunction and neuroinflammation has also been proposed in CFS (Theoharides and Tsilioni, 2018). Since intranasal administration of anti-inflammatory drugs has shown to reduce inflammation in mice models (Sun et al, 2010 and Zhuang et al, 2011), they proposed treatment with tetramethoxyluteolin, a mast-cell inhibitor, which could potentially reduce inflammation by directly reaching the diencephalon through the cribriform plexus. Theoharides and Tsilioni (2018) also reported that tetramethoxyluteolin has shown to improve attention and sociability in children with ASD. They quoted evidence that treatment with flavonoids/luteolin has improved symptoms of ASD in children (Taliou et al, 2013) and has also shown to reduce symptoms of CFS in experimental models (Sachdeva et al, 2009 and Kuo et al, 2009). However, because of limited data on its use in humans, they did not draw definite conclusions rather suggested it as an area of further research in future.
Lintas et al (2011) and Satterfield et al (2010) aimed to explore the association between xenotropic murine leukaemia virus-related virus (XMRV), CFS and autism. They based their study on the evidence that XMRV had been implicated in chronic fatigue syndrome (Lombardi et al, 2009) and queried whether XMRV could be found in individuals with ASD, establishing a link between the two conditions. They screened blood samples from autistic children born to mothers with CFS using PCR and antibody assays but none of the samples found any evidence of XMRV infection in blood cells from patients (Satterfield et al, 2010). Lintas et al (2011) also screened DNA samples from ASD patients but no XMRV or other MLV-related virus was detected in blood and brain samples of ASD patients. Both studies reported that infection with XMRV or other MLV-related viruses was not related to either autism or CFS pathogenesis (Lintas et al, 2011 and Satterfield et al, 2010). Three European studies that tried to validate Lombardi et al (2009) findings also failed to find XMRV in blood or CSF samples (Erlwein et al, 2010, Groom et al, 2010 and van Kuppeveld et al, 2010), refuting the link between the XMRV and CFS and autism. The primary study (Lombardi et al, 2009) was later retracted from the publishing journal because of concerns around the validity of its results and failure to disclose important information pertaining to study methods.
Previous research has shown clinical overlap between autism and various psychiatric and medical conditions (Kentrou et al, 2024). Grant et al (2022) published that 21% of autistic individuals in their study reported having a CSS diagnosis, including CFS. There are several theoretical explanations that link autism and CFS to each other; a core feature common to both autism and CFS is fatigue and sensory sensitivity (Maroti et al, 2017, Grant et al, 2022 and Keville et al, 2021). Established evidence indicates that sensory processing difficulties are a primary feature of autism (Grant et al, 2022), while similar sensory sensitivity/amplification is observed in individuals with CFS (Geisser et al, 2008). However, research indicates that there remains a risk of diagnostic overshadowing as clinicians are often uninformed about co-occurring conditions in autism (Micai et al, 2021); unexplained fatigue is often attributed to autistic masking (Pearson and Rose, 2021) or burnout (Higgins et al, 2021) when actually it could be a symptom of an underlying condition like CFS (Grant et al, 2022). On the other hand, some autistic individuals who were diagnosed with a co-occurring medical condition reported that their symptoms resulted from the challenges of living with undiagnosed autism rather than distinct co-occurring condition (Baron-Cohen et al, 2001). The complex relationship between autism and co-morbid physical health conditions including CFS warrants a thorough assessment of people with ASD to ascertain whether the functional impairment/fatigue is a part of autism itself or could be attributed to a particular co-morbid diagnosis.
On another note, there is growing evidence around the possible role of neuroinflammation in the pathogenesis of both ASD and CFS and the role of anti-inflammatory drugs in treating the two conditions (Theoharides & Tsilioni, 2018). There are currently no FDA approved drugs to treat either CFS or ASD (Tsilioni et al, 2015) however, research has shown that naturally occurring flavonoids have potent anti-inflammatory and neuroprotective actions and have been discussed as a possible treatment of ASD and CFS (Theoharides & Tsilioni, 2018). Tailou et al (2013) conducted an open label trial and reported significant improvements in communication, adaptive functioning and overall behaviours in children with ASD treated with luteolin capsules for 26 weeks. Another open label trial replicated similar results and reported significant improvements in adaptive functioning in autistic children treated with dietary formulation containing luteolin (Tsilioni et al, 2015). However, this is an area of growing research and further RCTs are needed to validate the reported results.
In terms of hierarchy of evidence, reviewed studies indicate low level of evidence (Melnyk et al, 2023) and are of not sufficient significance to make any recommendations or draw definite conclusions around association between ASD and CFS (see Table 1). The lack of randomizedcontrolled trials contributes to the uncertainty regarding the efficacy of emerging anti-inflammatory treatments for ASD and CFS.
This review shows that there is a paucity of data on the association between autism spectrum disorder and chronic fatigue syndrome despite the co-occurrence of physical health conditions like CFS being increasingly seen in autistic children and young people in clinical practice. The review presents a comprehensive overview of existing research on the topic highlighting the need for more extensive and larger scale studies to further explore and establish the association between the two conditions.
The findings highlight the critical need for enhanced training and awareness of mental health practitioners regarding the presentation of autism and the complex relationship between ASD and co-occurring physical health conditions like CFS. Physicians should be aware that these conditions are common in autistic individuals and recognizing and treating overlapping clinical symptoms can significantly improve their quality of life and wellbeing. Additional epidemiological studies based on larger and more representative samples of autistic individuals are needed to replicate current findings and provide more accurate estimates of association between autism and CFS.