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Identification of autism in cognitively able adults with epilepsy: A narrative review and discussion of available screening and diagnostic tools

Published:November 26, 2022DOI:https://doi.org/10.1016/j.seizure.2022.11.004

      Highlights

      • Screening for Autism in cognitively able adults with epilepsy.
      • Diagnostic tools for Autism in cognitively able adult patients with epilepsy.
      • Autism characteristics in cognitively able adult patients with epilepsy.

      Abstract

      The recent NICE epilepsy Guideline (NG217; 2022) recommends that epilepsy professionals need to be alert to autism when considering mental health presentations, behavioural difficulties and as a marker for referral for whole genome sequencing for those patients with epilepsy of unknown cause. However, this relies upon the existence of valid autism screens for people with epilepsy (PWE). We found few studies of autism in cognitively able PWE. This represents an important gap in the literature. We describe different autism screening and diagnostic tools; two screening tools have been used specifically for adult PWE who are cognitively able (AQ, SRS-AS). The AQ is more psychometrically robust, but there may be an overlap between these screening questions and questions relevant to some psychiatric disorders. Formal gold-standard diagnostic tools (module 4 of ADOS-2, ADI-R or 3Di or 3Di-Adult) would benefit from studies of their application to cognitively able PWE. More research is needed to understand the characteristics of autism in cognitively able PWE and to ascertain the appropriate screening and diagnostic tools for this cohort.

      Keywords

      1. Autism and epilepsy

      1.1 Historical perspective

      The relationship between autism and epilepsy has been studied for more than fifty years, ever since Kanner's observations in 1943 of children with autism, where one child had a history of seizures and an abnormal EEG [
      • Kanner L.
      Autistic disturbances of affective contact.
      ]. The Diagnostic Statistical Manual – 5th Edition (DSM-5; [
      American Psychiatric Association
      Diagnostic and statistical manual of mental disorders.
      ]) defines autism spectrum disorder as “persistent difficulties with social communication and social interaction” and “restricted and repetitive patterns of behaviours, activities or interests” (this includes sensory behaviour). Symptoms must be present since early childhood, to the extent that these “limit and impair everyday functioning”. It is noteworthy that the diagnostic criteria for autism have widened over the last twenty years and individuals with higher cognitive function and less severe traits of autism would now be diagnosable under the current criteria, potentially representing Simon Baron Cohen's “lost generation” whose autism may not have been previously detected. We use the term ‘autism’ in this article to refer to both autism and autistic spectrum disorder (ASD).
      Taft and Cohen made observations on the relationship between infantile spasms and autism [
      • Taft L.
      • Cohen H.
      Hypsarrhythmia and infantile autism: a clinical report.
      ] and subsequent prevalence studies showed that a significant proportion of children with infantile spasms later developed autism [
      • Riikonen R.
      • Amnell G.
      Psychiatric disorders in children with earlier infantile spasms.
      ]. Gillberg and Schaumann [
      • Gillberg C.
      • Schaumann H.
      Epilepsy presenting as infantile autism? Two case studies.
      ] highlighted the close correlation between autism, epilepsy and intellectual disability [
      • Gillberg C.
      • Schaumann H.
      Epilepsy presenting as infantile autism? Two case studies.
      ].
      The epilepsy syndrome is a key indicator of the likelihood of co-existing autism; autism is more frequent in individuals who have a history of infantile spasms, but less common in those who have some forms of later-onset epilepsy. This may be due to the developmental sequelae of seizures early in life, that increase the risk for developing autism as suggested by Saemundsen and collaborators [
      • Saemundsen E.
      • Ludvigsson P.
      • Hilmarsdottir I.
      • Rafnsson V.
      Autism spectrum disorders in children with seizures in the first year of life – a population-based study.
      ,
      • Saemundsen E.
      • Ludvigsson P.
      • Rafnsson V.
      Risk of autism spectrum disorders after infantile spasms: A population-based study nested in a cohort with seizures in the first year of life.
      ,
      • Saemundsen E.
      • Magnusson P.
      • Georgsdottir I.
      • Egilsson E.
      • Rafnsson V.
      Prevalence of autism spectrum disorders in an Icelandic birth cohort.
      ]. Strasser, Downes, Kung, Cross and Haan, [
      • Strasser L.
      • Downes M.
      • Kung J.
      • Cross J.H.
      • Haan M.D.
      Prevalence and risk factors for autism spectrum disorder in epilepsy: a systematic review and meta-analysis.
      ], in their systematic review of nineteen studies, found a pooled prevalence autism rate of 6.3% in people with epilepsy (PWE). Just one year later, Lukmanji et al [
      • Lukmanji
      • Manji S.
      • Kadhim S.
      • Wirrel E.
      • Kwon C.
      • Jetté N
      The co-occurrence of epilepsy and autism: a systematic review.
      ] showed a median pooled prevalence of 9% but with a range of 0.60-41%. There were methodological differences across studies, including epilepsy diagnosis, the presence and definition of intellectual disability, the age at testing, the gender ratio, and the method and criteria of autism diagnosis, with broadening diagnostic criteria for autism after 2013. Nevertheless, the studies show an increased prevalence of autism in PWE.
      PWE who have autism and intellectual disability can usually access support through their learning disability service. However, a cohort that has been historically neglected, are those who are cognitively more able. They may fall between services; not cognitively disabled enough to meet criteria for learning disability services from which they might benefit and/or not having severe mental health difficulties to access to their community mental health team (CMHT). Having a diagnosis of autism may provide access to appropriate services or charities, greater understanding of the self and by others and so that reasonable adjustments are made in service provision. However, identification relies upon the existence of valid autism screens for PWE.

      1.2 Epilepsy and autism

      It has been established that PWE with intellectual disability are more likely to have autism. In a meta-analysis of twenty-four reports from Amiet and collaborators [
      • Amiet C.
      • Gourfinkel-An I.
      • Bouzamondo A.
      • Tordjman S.
      • Baulac M.
      • Lechat P.
      • Cohen
      Epilepsy in autism is associated with intellectual disability and gender: evidence from a meta-analysis.
      ], the prevalence of epilepsy was 21% in patients with autism and intellectual disability, and 8% in people without intellectual disability. Based on a systematic review of twenty-one studies [
      • Berg A.
      • Plioplys S.
      Epilepsy and autism: are there a special relationship?.
      ], a wider gap was noted, with an autism prevalence of 38.9% in the epilepsy population with intellectual disability and 5.2% in those without intellectual disability. As these studies were conducted before the broader DSM-5 diagnostic criteria of 2013, the prevalence may well be higher in those diagnosed after 2013.
      There is a dearth of studies analysing adult PWE with an IQ>80 who have autism or features of autism [
      • Tuchman R.
      • Cuccaro M.
      Epilepsy and autism: neurodevelopmental perspective.
      ], despite this population being more ‘at risk’ than the general population [
      • Amiet C.
      • Gourfinkel-An I.
      • Bouzamondo A.
      • Tordjman S.
      • Baulac M.
      • Lechat P.
      • Cohen
      Epilepsy in autism is associated with intellectual disability and gender: evidence from a meta-analysis.
      ]. Wakeford, Hinvest, Ring, and Brosnan [
      • Wakeford S.
      • Hinvest N.
      • Ring H.
      • Brosnan M.
      Autistic characteristics in adults with epilepsy.
      ], examined autism traits in people with and without epilepsy, neither of whom had been formally diagnosed with autism. Autism traits such as difficulties in social skills, mental flexibility, imagination, attention to detail and difficulties with communication were surveyed by the Autism Spectrum Disorder Quotient (AQ; [
      • Baron-Cohen S.
      • Wheelwright S.
      • Skinner R.
      • Clubley J.M.
      The autism-spectrum quotient (AQ): evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians.
      ]). The ability to make accurate social inferences was estimated using the Intuitive Physics Test [
      • Baron-Cohen S.
      • Wheelwright S.
      • Hill J.
      • Raste Y.
      • Plumb I.
      The "Reading the Mind in the Eyes" test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism.
      ]. The Adult Eyes Task-Revised [
      • Baron-Cohen S.
      • Wheelwright S.
      • Hill J.
      • Raste Y.
      • Plumb I.
      The "Reading the Mind in the Eyes" test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism.
      ] was used to assess the ability to correctly recognize facial expressions of emotion from eyes. PWE produced higher scores than people without epilepsy, suggesting they had more autism traits. There was no difference between the two groups on the Intuitive Physics Test and the Adult Eyes Task-Revised tests. The authors [
      • Wakeford S.
      • Hinvest N.
      • Ring H.
      • Brosnan M.
      Autistic characteristics in adults with epilepsy.
      ] argue that this suggests that PWE may have symptoms that resemble features of autism but with a different aetiology.
      The study was limited by the small sample size and use of only one scale for measurement of autism characteristics (i.e., the AQ). The follow-up study by Wakeford, Hinvest, Ring and Brosnan [
      • Wakeford S.
      • Hinvest N.
      • Ring H.
      • Brosnan M.
      Autistic characteristic in adults with epilepsy and perceived seizure activity.
      ] evaluated PWE using the Social Responsiveness Scale-Shortened (SRS-S) as a measure of social ability and the Repetitive Behaviour Scale-Revised (RBS-R) as a measure of restricted repetitive behaviours [
      • Barrett S.
      • Uljarevic M.
      • Baker E.
      • Richdale A.
      • Jones C.
      • Leekam S.R.
      The adult repetitive behaviours questionnaire-2 (RBQ-2A): a self-report measure of restricted and repetitive behaviours.
      ]. The results obtained were consistent with the 2014 study [
      • Wakeford S.
      • Hinvest N.
      • Ring H.
      • Brosnan M.
      Autistic characteristics in adults with epilepsy.
      ]. PWE without a formal diagnosis of autism had a higher score on the SRS-S, indicating more difficulties, compared to the control group. Moreover, they had more difficulties with social responsiveness (as derived by SRS-S scores) during self-perceived seizure activity. Repetitive behaviours on the RBS-R were unimpaired. However, neither study thoroughly evaluated autism with formal diagnostic tools such as the ADOS [
      • Lord C.
      • Rutter M.
      • DiLavore C, P.
      • Risi S.
      ] and ADI-R [
      • Lord C.
      • Rutter M.
      • Counter A.L.
      Autism Diagnostic Interview - revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders.
      ]. These tools are considered the “gold standard” in diagnostic assessment for autism, particularly when combined with clinical judgment. It is of interest that the PWE did not exhibit sameness, restrictive/rigid and repetitive behaviours, suggesting that PWE may represent a different phenotype. As the authors suggest, further studies are needed to examine psychosocial factors and autism traits using different screening and diagnostic tools on a large sample of PWE [
      • Wakeford S.
      • Hinvest N.
      • Ring H.
      • Brosnan M.
      Autistic characteristic in adults with epilepsy and perceived seizure activity.
      ].
      People with PWE frequently experience psychiatric disorders including anxiety, depression, and obsessive-compulsive disorder (OCD) [
      • Kaplan P.W.
      Epilepsy and obsessive-compulsive disorder.
      ]. Seizure location, and living with uncertainty and disability may contribute [
      • Kaplan P.W.
      Epilepsy and obsessive-compulsive disorder.
      ]. Stigmatization, social isolation, and loneliness may be confounders of autism diagnosis, due to their chronic effects on communication and social interaction [
      • Lai M.
      • Baron-Cohen S.
      Identifying the lost generation of adults with autism spectrum condition.
      ].
      Females with epilepsy have been reported to have a higher rate of autism [
      • Besag FM.
      Epilepsy in patients with autism: links, risks and treatment challenges.
      ] although this may be related to them being more likely to have intellectual disability [
      • Besag FM.
      Epilepsy in patients with autism: links, risks and treatment challenges.
      ]. Other epilepsy syndrome factors that may increase the risk of autism are focal epilepsy [
      • Levisohn P.M.
      The autism-epilepsy connection.
      ], presence of a genetic syndrome [
      • Tuchman R.
      • Cuccaro M.
      • Alessandri M.
      Autism and epilepsy: historical perspective.
      ] and the severe epileptic encephalopathies [
      • Srivastava S
      • Sahin M.
      Autism spectrum disorder and epileptic encephalopathy: common causes, many questions.
      ].
      A timely and accurate diagnosis of autism is crucial to enabling PWE to receive appropriate treatment and support [
      • Koegel L.
      • Koegel R.
      • Ashbaugh K.
      • Bradashaw J.
      The importance of early identification and intervention for children with or at risk for autism spectrum disorders.
      ]. It is imperative that clinicians have access to appropriate screening tools to flag whether further referral for diagnostic assessment is required. However, to date, very few autism screens are validated in adult PWE. This paper will describe the different screening and diagnostic tools that may be considered.

      2. Screening tools

      2.1 Autism-Spectrum and Quotient (AQ;
      • Allison C.
      • Auyeung B.
      • Baron-Cohen S.
      Toward brief “red flags” for autism screening: the Short Autism Spectrum Quotient and the Short Quantitative checklist for autism in toddlers in 1000 cases and 3000 controls.
      ])

      This is a self-rating questionnaire, published in 2001 by Simon Baron-Cohen and his colleagues at the Autism Research Centre in Cambridge, UK. The original extended version of the AQ includes fifty questions divided into five subscales, each consisting of ten items that investigate “domains of cognitive strengths and difficulties related to autism: communication, social skills, imagination, attention to detail and attention switching” [
      • Ruzich E.
      • Allison C.
      • Watson P.
      • Auyeung B.
      • Ring H.
      • Baron-Cohen S.
      Measuring autistic traits in the general population: a systematic review of the Autism-Spectrum Quotient (AQ) in a nonclinical population sample of 6,900 typical adult males and females.
      ]. Individuals respond to each of the items with one of four choices: ‘definitely agree’, ‘slightly agree’, ‘slightly disagree’, and ‘disagree’. Responses are scored using a binary system [
      • Ruzich E.
      • Allison C.
      • Watson P.
      • Auyeung B.
      • Ring H.
      • Baron-Cohen S.
      Measuring autistic traits in the general population: a systematic review of the Autism-Spectrum Quotient (AQ) in a nonclinical population sample of 6,900 typical adult males and females.
      ]. The original fifty item questionnaire takes ten minutes to complete while the abbreviated version (AQ10) which retains the predictive validity, takes two to five minutes. It is also available translated into several languages.
      In a systematic review of the literature, Baghdadli, Russet and Mottron [
      • Baghdadli A.
      • Russet F.
      • Mottron L.
      Measurement properties of screening and diagnostic tools for autism spectrum adults of mean normal intelligence: a systematic review.
      ] reviewed diagnostic and screening tools for autism in adult patients without intellectual disability, analysing eighteen studies to verify the validity of this tool. The internal consistency was analysed using Cronbach's alpha, to measure the reliability and to verify the reproducibility over time of the results that psychometric tests provide. In general, high-reliability values are to be considered for those from 0.70 upwards.
      Sensitivity and specificity were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) and the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist. They found evidence for internal consistency and satisfactory test-retest reliability (r>0.70). The same values were also verified for the shortened version of ten items (AQ-10).
      Frequently used by general practitioners and brief to use, a disadvantage of the AQ-10 is the items may overlap between different neurological or mental health disorders [
      • Baghdadli A.
      • Russet F.
      • Mottron L.
      Measurement properties of screening and diagnostic tools for autism spectrum adults of mean normal intelligence: a systematic review.
      ]. Furthermore, the scoring is printed on the questionnaire; if patients can view this, it can bias their responses. Nonetheless, the Wakeford [
      • Wakeford S.
      • Hinvest N.
      • Ring H.
      • Brosnan M.
      Autistic characteristics in adults with epilepsy.
      ] study found this a valuable screening tool in adult PWE.

      2.2 Ritvo Autism Asperger Diagnostic Scale - Revised (RAADS-R)

      Ritvo et al. [
      • Ritvo R.
      • Ritvo E.
      • Guthrie D.
      • Ritvo M.
      • Hufnagel D.H.
      • McMahon W.
      • Eloff T.A.
      The Ritvo autism asperger diagnostic scale-revised (RAADS-R): a scale to assist the diagnosis of autism spectrum disorder in adults: an international validation study.
      ,
      • Eriksson J.
      • Andersen L.
      • Bejerot S.
      RAADS-14 screen: validity of a screening tool for autism spectrum disorder in an adult psychiatry population.
      ]. This questionnaire was originally a scale consisting of 80 items measuring symptoms based on the DSM-4-TR and ICD-10 [
      World Health Organization
      ICD-10: international statistical classification of diseases and related health problems: tenth revision.
      ]. This must be administered with the clinician [
      • Ritvo R.
      • Ritvo E.
      • Guthrie D.
      • Ritvo M.
      • Hufnagel D.H.
      • McMahon W.
      • Eloff T.A.
      The Ritvo autism asperger diagnostic scale-revised (RAADS-R): a scale to assist the diagnosis of autism spectrum disorder in adults: an international validation study.
      ] and takes up to thirty minutes to complete. The authors report that RAADS-R is a highly specific (100%) and sensitive (97%) instrument, useful as an adjunct clinical diagnostic tool [
      • Ritvo R.
      • Ritvo E.
      • Guthrie D.
      • Ritvo M.
      • Hufnagel D.H.
      • McMahon W.
      • Eloff T.A.
      The Ritvo autism asperger diagnostic scale-revised (RAADS-R): a scale to assist the diagnosis of autism spectrum disorder in adults: an international validation study.
      ]. These results were confirmed by further studies conducted in Sweden [
      • Andersen L.M.
      • Naswall K.
      • Manouilenko I.
      • Nylander L.
      • Edgar J.
      • Ritvo R.
      • Bejerot S.
      The Swedish version of the Ritvo autism and asperger diagnostic scale: revised (RAADS-R). A validation study of a rating scale for adults.
      ] and ten years later in France [
      • Picot M.
      • Michelon C.
      • Bertet H.
      • Pernon E.
      • Flard D.
      • Coutelle R.
      • et al.
      The French version of the revised Ritvo autism and asperger diagnostic scale: a psychometric validation and diagnostic accuracy study.
      ].
      Picot and collaborators [
      • Picot M.
      • Michelon C.
      • Bertet H.
      • Pernon E.
      • Flard D.
      • Coutelle R.
      • et al.
      The French version of the revised Ritvo autism and asperger diagnostic scale: a psychometric validation and diagnostic accuracy study.
      ] argue that as with any screening tool, this instrument may give rise to false positives of autism and may not discriminate enough from those with comorbid psychiatric disorders. They argue that further studies are needed to assess the sensitivity and specificity of the RAADS-R those with other psychiatric DSM-5 diagnoses such as obsessive-compulsive-disorder (OCD), social anxiety disorder, severe personality disorder, and schizophrenia.
      The same results were verified for the Ritvo Autism Asperger Diagnostic Scale- 14 Screen (RAADS-14) [
      • Baghdadli A.
      • Russet F.
      • Mottron L.
      Measurement properties of screening and diagnostic tools for autism spectrum adults of mean normal intelligence: a systematic review.
      ]. The RAADS-14 has proven to be a good screening tool as it maps onto the full version of RAADS-R, takes less than five minutes to complete and is easy to score. However, as with the full RAADS-R, no studies have analysed this tool in PWE.

      2.3 Sensory Reactivity Scale (SR-AS)

      Elwin et al. [
      • Elwin M.
      • Schroder A.
      • Ek L.
      • Kjellin L.
      Development and pilot validation of a sensory reactivity scale for adults with high functioning autism spectrum conditions: sensory reactivity in autism spectrum (SR-AS).
      ]. This self-report questionnaire surveys sensory reactivity [
      • Elwin M.
      • Schroder A.
      • Ek L.
      • Kjellin L.
      Development and pilot validation of a sensory reactivity scale for adults with high functioning autism spectrum conditions: sensory reactivity in autism spectrum (SR-AS).
      ]. It reports good internal consistency and discriminatory power, accurately distinguishing patients with autism from controls. The authors comment that they did not acquire enough data to make accurate conclusions regarding test-retest reliability. Accordingly, as the authors suggest, due to the relatively small standardisation sample of 162, further studies are needed to establish the validity and reliability of the SR-AS, with a greater number of patients in different clinical settings [
      • Elwin M.
      • Schroder A.
      • Ek L.
      • Kjellin L.
      Development and pilot validation of a sensory reactivity scale for adults with high functioning autism spectrum conditions: sensory reactivity in autism spectrum (SR-AS).
      ].

      2.4 Reading the Mind in the Eyes Test [
      • Baron-Cohen S.
      • Wheelwright S.
      • Hill J.
      • Raste Y.
      • Plumb I.
      The "Reading the Mind in the Eyes" test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism.
      ]

      This cognitive test measures the ability to recognize facial expressions from the eyes. Consisting of thirty-six black and white photos of peoples’ faces, there are four possible answers: panicked, arrogant, jealous or hateful, with only one being correct [
      • Baron-Cohen S.
      • Wheelwright S.
      • Hill J.
      • Raste Y.
      • Plumb I.
      The "Reading the Mind in the Eyes" test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism.
      ]. Farrant and colleagues [
      • Farrant A.
      • Morris R.
      • Russel T.
      • Elwes R.
      • Akanuma N.
      • Alarcon G.
      Social cognition in frontal lobe epilepsy.
      ] showed that PWE who also exhibit autism traits, demonstrated an impairment of facial emotion recognition. The intellectual ability of participants was not stated, which may have been a contributory factor in recognising complex emotions. It varies in its completion time, taking from two to twenty minutes to complete, with people with autism generally taking longer to complete the test.

      2.5 Gazefinder [
      • Fujioka T.
      • Inohara K.
      • Okamoto Y.
      Gazefinder as a clinical supplementary tool for discriminating between autism spectrum disorder and typical development in male adolescents and adults.
      ]

      Reduced eye gaze has been noted in adults with autism [
      • Klin A.
      • Micheletti M.
      • Klaiman C.
      • Shultz S.
      • Constantino J.N.
      • Jones W.
      Affording autism an early brain development re-definition.
      ]. Gazefinder is purported to be a clinical supplementary measure to distinguish autism; in the 2016 study Gazefinder measured the percentage of eye fixation time allocated to objects or people depicted in movies, in twenty-six patients with autism and thirty-five age-matched males with typical development. The participants’ eye positions were examined using infrared light. The group of patients with autism gazed less at eyes in human face stimuli than the control group. From the analyses carried out in this research, Gazefinder results measure the single gaze fixation pattern. However, it does not predict the degree of social deficit. Further studies are necessary, because, although it has high sensitivity and specificity, Gazefinder measures only a part of the wide range of autism traits. Furthermore, patients with psychiatric disorders may also have low gaze fixation. It will be necessary to examine Gazefinder in PWE who present with autism traits and different mental psychiatric conditions to identify its specificity.

      2.6 Adult Social Behaviour Questionnaire (ASBQ)

      Kan et al. [
      • Horwitz E.
      • Schoevers R.
      • Ketelaars C.
      • Kan C.
      Clinical assessment of ASD in adults using self- and other report: Psychometric properties and validity of the adult social behavior questionnaire (ASBQ).
      ]. This questionnaire is adapted from the Children Social Behaviour Questionnaire, and is designed to quantitatively measure autism traits in adult patients. It consists of ‘self’ and ‘other’ reports for relatives, friends, or people who know the patient well. The forty-four questions are in line with DSM-5 criteria for the diagnosis of autism and shows good discrimination properties [
      • Baghdadli A.
      • Russet F.
      • Mottron L.
      Measurement properties of screening and diagnostic tools for autism spectrum adults of mean normal intelligence: a systematic review.
      ]. However, Horwitz, Schoevers, Ketelaars, Kan et al [
      • Horwitz E.
      • Schoevers R.
      • Ketelaars C.
      • Kan C.
      Clinical assessment of ASD in adults using self- and other report: Psychometric properties and validity of the adult social behavior questionnaire (ASBQ).
      ] comment that diagnostic validity was limited, as the gold standard module 4 of the ADOS-2 was not used to reliably identify autism. However, it presents good data on structural validity and intermediate internal consistency. As pointed out in the study: “as a questionnaire it is not intended for purposes of diagnostic classification on its own, but rather as one of the sources to assist clinicians in the diagnostic and assessment process of ASD in adults” [
      • Horwitz E.
      • Schoevers R.
      • Ketelaars C.
      • Kan C.
      Clinical assessment of ASD in adults using self- and other report: Psychometric properties and validity of the adult social behavior questionnaire (ASBQ).
      ]. We did not find studies of its use with adult PWE.

      2.7 Adult Repetitive Behaviours Questionnaire-2 (RBQ-2A; [
      • Barrett S.
      • Uljarevic M.
      • Baker E.
      • Richdale A.
      • Jones C.
      • Leekam S.R.
      The adult repetitive behaviours questionnaire-2 (RBQ-2A): a self-report measure of restricted and repetitive behaviours.
      ])

      This self-report screening questionnaire consists of 20 items derived from the Diagnostic Interview for Social and Communication Disorders (DISCO; [
      • Wing L.
      • Leekam S.
      • Libby S.
      • Gould J.
      • Larcombe M.
      The diagnostic interview for social and communication disorders: background, inter-rater reliability and clinical use.
      ]). It surveys one of the core diagnostic features of autism; that of restricted and repetitive behaviours. It is divided into insistence on sameness, such as finding comfort in routines and consistency and repetitive motor behaviours. It takes five to ten minutes and is suitable for those with average or higher intelligence. Barrett and collaborators [
      • Barrett S.
      • Uljarevic M.
      • Baker E.
      • Richdale A.
      • Jones C.
      • Leekam S.R.
      The adult repetitive behaviours questionnaire-2 (RBQ-2A): a self-report measure of restricted and repetitive behaviours.
      ] found that those with autism scored higher than the control group. A good internal consistency was confirmed, and the results obtained supported its diagnostic capabilities with further validity confirmed [
      • Barrett S.L.
      • Uljarević M.
      • Jones C.R.G.
      • et al.
      Assessing subtypes of restricted and repetitive behaviour using the adult repetitive behaviour questionnaire-2 in autistic adults.
      ]. However, clinical experience suggests people with psychiatric conditions such as anxiety and obsessive-compulsive disorder (OCD) may score higher on this scale. Further research is required to examine its validity in PWE and its discriminative properties with psychiatric conditions.

      2.8 The  Social Responsivenes Scale for Adults (SRS-A; [
      • Constantino J.N.
      • Todd R.D.
      Intergenerational transmission of subthreshold autistic traits in the general population.
      ])

      This questionnaire surveys social responsiveness and social behaviour in individuals aged 19 to 89 and can be used as a self or other report. It comprises 65 items related to five domains: social awareness, social information processing, capacity for reciprocal social communication, social anxiety/avoidance, and autistic preoccupations and mannerisms. In subsequent studies conducted in 2012 and 2014 by Bölte and Takei, the values of sensitivity and specificity were satisfactory, over 0.80. In the Wakeford study [
      • Wakeford S.
      • Hinvest N.
      • Ring H.
      • Brosnan M.
      Autistic characteristic in adults with epilepsy and perceived seizure activity.
      ] the shortened version of the scale (SRS-AS) was used to verify autism features in PWE, with higher scores found in PWE than in controls. More validation studies in adult PWE are needed.

      3. Diagnostic tools

      3.1 Adult Asperger Assessment (AAA [
      • Baron-Cohen S.
      • Wheelwright S.
      • Robinson J.
      • Woodbury-Smith M.
      The adult Asperger assessment (AAA): a diagnostic method.
      ])

      This face-to-face interview consists of four Sections (A–D), each describing a group of autism features presented in the DSM-4. Section A of the AAA is “Qualitative impairment in social interaction”; Section B is “Restricted, repetitive and stereotyped patterns of behaviour, interests and activities”; Section C, “Qualitative impairments in verbal or non-verbal communication”, and Section D, “Impairments in imagination”. Each area is probed by the clinician, in order to collect a range of examples from self and/or other report. It also includes two self-report questionnaires: The Autism Spectrum Quotient (AQ) and the Empathy Quotient (EQ). In a systematic review of the literature ([
      • Baghdadli A.
      • Russet F.
      • Mottron L.
      Measurement properties of screening and diagnostic tools for autism spectrum adults of mean normal intelligence: a systematic review.
      ] its validity is confirmed with a sensitivity =of 0.92 and a specificity = 1.00. We could not find application of this tool to PWE in the literature.

      3.2 Autism Diagnostic Observation Schedule 2/ module 4 (module 4 of ADOS-2) [
      • Lord C.
      • Risi S.
      • Lambrecht L.
      • Cook J.E.
      • Leventhal B.
      • DiLavore P.
      The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with spectrum of autism.
      ]

      Considered to be the gold standard to reliably identify autism, the ADOS is an observational face-to-face assessment involving the clinician spending time interacting with the patient. It requires specific training and attendance at reliability coding sessions. It can take an hour or just over to complete. Kupper, Stroth, and collaborators [
      • Kupper C.
      • Stroth S.
      Identifying predictive features of autism spectrum disorders in a clinical sample of adolescents and adults using machine learning.
      ] described the tool as follows: “the ADOS is a standardized semi-structured diagnostic observational schedule (interview and interaction between the patient and the clinician) designed to assess important social-communicative behaviours as well as stereotypic and repetitive behavioural features”. The ADOS includes four different modules for different age and language levels. For each module, there is a diagnostic algorithm for the classification of autism or non-autism [
      • Kupper C.
      • Stroth S.
      Identifying predictive features of autism spectrum disorders in a clinical sample of adolescents and adults using machine learning.
      ]. Baghdadli, Russet and Mottron [
      • Baghdadli A.
      • Russet F.
      • Mottron L.
      Measurement properties of screening and diagnostic tools for autism spectrum adults of mean normal intelligence: a systematic review.
      ] reported that internal consistency and discriminant validity for module 4 of the ADOS-2 were satisfactory; however, these data are limited as only the COSMIN checklist was used.
      There have been several analytical studies of the module 4 of the ADOS-2 ([
      • Bastiaansen J.
      • Meffert H.
      • Hein S.
      • Huizinga P.
      • Ketelaars C.
      • Pijnenborg M.
      Diagnosing autism spectrum disorders in adults: the use of autism diagnostic observation schedule (ADOS) module 4.
      ,
      • Hus V.
      • Lord C.
      The autism diagnostic observation schedule, module 4: revised algorithm and standardized severity scores.
      ]). Nevertheless, sensitivity and specificity appear to vary depending on the studies and methodologies used to verify its validity. To date, no studies have addressed this tool in adults PWE and verifying its use with adult PWE will be essential.

      3.3 The Autism Diagnostic Interview Revised (ADI-R; [
      • Rutter M.
      • Couteur A.L.
      • Lord C.
      Autism diagnostic interview-revised (ADI-R).
      ])

      The ADI-R is a structured informant interview, obtaining a full range of past and current information to diagnose autism. It requires specific training and can take 1-2 h to complete. It was designed to be used in conjunction with the Autism Diagnostic Observation Schedule 2 (ADOS-2). The ADI-R focuses on the systematic and standardized observation of behaviours rarely found in non-clinical subjects, and mainly on three areas of functioning: language and communication, mutual social interaction, stereotypical behaviours and narrow interests. The ADI-R is divided into an interview protocol and five algorithms, which can be used at different ages and is recommended by the NICE No. CG142 autism guidelines (2012) “To aid more complex diagnosis and assessment for adults, consider using a formal assessment tool, such as: ADI-R”. Further validation studies in adult PWE are required.

      3.4 The Asperger Syndrome (High Functioning Autism) Diagnostic Interview (ASDI) [
      • Gillberg C.
      • Gillberg C.
      • Rastam M.
      • Wentz E.
      The Asperger syndrome (and high-functioning autism) diagnostic interview (ASDI): a preliminary study of a new structured clinical interview.
      ]

      The ASDI is a brief structured interview for informants. It consists of twenty open-ended questions divided into six broader areas of autism characteristics. The clinician needs to have a comprehensive developmental and clinical history of the patient to conduct the interview. A study conducted by Gillberg, and collaborators [
      • Gillberg C.
      • Gillberg C.
      • Rastam M.
      • Wentz E.
      The Asperger syndrome (and high-functioning autism) diagnostic interview (ASDI): a preliminary study of a new structured clinical interview.
      ] reported: that “inter-rater reliability and test-retest stability may be excellent, with kappa's exceeding 0.90 in both instances” [
      • Gillberg C.
      • Gillberg C.
      • Rastam M.
      • Wentz E.
      The Asperger syndrome (and high-functioning autism) diagnostic interview (ASDI): a preliminary study of a new structured clinical interview.
      ]. This is a shorter interview than others, Further validation studies are needed in adult PWE.

      3.5 Developmental, Dimensional and Diagnostic Interview (3Di; [
      • Skuse D.
      • Warrington R.
      • Bishop D.
      • Chowdhury U.
      • Lau J.
      • Mandy W.
      • Place M.
      The developmental, dimensional and diagnostic interview (3di): a novel computerized assessment for autism spectrum disorders.
      ]) and the adult version 3Di-adult; [
      • Mandy W.
      • Clarke K.
      • McKenner M.
      • Strydom A.
      • Crabtree J.
      • Lai M.
      • Skuse D.
      Assessing autism in adults: an evaluation of the developmental, dimensional and diagnostic interview-adult version (3Di-Adult).
      ])

      The 3Di is a standardized, diagnostic tool which can be used face-to-face or as a telephone interview. It is an informant report to identify autism in children and adolescents and it has an adult version
      • Mandy W.
      • Clarke K.
      • McKenner M.
      • Strydom A.
      • Crabtree J.
      • Lai M.
      • Skuse D.
      Assessing autism in adults: an evaluation of the developmental, dimensional and diagnostic interview-adult version (3Di-Adult).
      ]. It is a collaborative interview to clarify responses and requires specific training. It can take from thirty minutes to an hour to complete. It is recommended to use alongside a specific diagnostic tool such as the module 4 of the ADOS-2. Studies in 2004 [
      • Skuse D.
      • Warrington R.
      • Bishop D.
      • Chowdhury U.
      • Lau J.
      • Mandy W.
      • Place M.
      The developmental, dimensional and diagnostic interview (3di): a novel computerized assessment for autism spectrum disorders.
      ], in 2018 [
      • Mandy W.
      • Clarke K.
      • McKenner M.
      • Strydom A.
      • Crabtree J.
      • Lai M.
      • Skuse D.
      Assessing autism in adults: an evaluation of the developmental, dimensional and diagnostic interview-adult version (3Di-Adult).
      ], and confirmed in 2020 [
      • TjaardA I.C.
      • Skuse D.
      • Greaves-Lord K.
      Developmental, dimensional and diagnostic interview (3Di).
      ] showed good test-retest reliability, current validity and discriminative power. This diagnostic tool has never been used in PWE. As reported by Mandy et al [
      • Mandy W.
      • Clarke K.
      • McKenner M.
      • Strydom A.
      • Crabtree J.
      • Lai M.
      • Skuse D.
      Assessing autism in adults: an evaluation of the developmental, dimensional and diagnostic interview-adult version (3Di-Adult).
      ] the “Translation and validation of the 3Di-Adult in other cultures will provide a reliable, valid, and resource-efficient way in helping the lost generation of adults with ASD who are currently lacking a formal diagnosis and therefore appropriate treatment” [
      • Mandy W.
      • Clarke K.
      • McKenner M.
      • Strydom A.
      • Crabtree J.
      • Lai M.
      • Skuse D.
      Assessing autism in adults: an evaluation of the developmental, dimensional and diagnostic interview-adult version (3Di-Adult).
      ].
      Tables 1 and 2 show tools for cognitively able PWE with strengths, weaknesses and relevant studies.
      Table 1Screening instruments.
      Screening InstrumentsAuthorsStrengthsWeaknessesUse in adult PWE?Methods of assessment
      Autism-Spectrum Quotie (AQ and AQ-10)[
      • Allison C.
      • Auyeung B.
      • Baron-Cohen S.
      Toward brief “red flags” for autism screening: the Short Autism Spectrum Quotient and the Short Quantitative checklist for autism in toddlers in 1000 cases and 3000 controls.
      ]
      High internal consistency and test-retest reliability.

      Valuable screening tool in adult patients with epilepsy without intellectual disability

      Available in several languages

      AQ10 is brief
      Possible overlapping between autism and other neurological or psychiatric conditions

      Scoring on the patient form may bias responses
      YesSelf-report questionnaire (2–5 min)
      Ritvo Autism Asperger Diagnostic Scale – Revised (RAADS-R and RAADS-14)[
      • Eriksson J.
      • Andersen L.
      • Bejerot S.
      RAADS-14 screen: validity of a screening tool for autism spectrum disorder in an adult psychiatry population.
      ,
      • Ritvo R.
      • Ritvo E.
      • Guthrie D.
      • Ritvo M.
      • Hufnagel D.H.
      • McMahon W.
      • Eloff T.A.
      The Ritvo autism asperger diagnostic scale-revised (RAADS-R): a scale to assist the diagnosis of autism spectrum disorder in adults: an international validation study.
      ]
      Good reliability and diagnostic validity in different populations (Sweden and French)Autism misdiagnoses and the questions may overlap with psychiatric disordersNoInteraction with the patient (30 min of assessment)
      Sensory Reactivity Scale (SR-AS)[
      • Elwin M.
      • Schroder A.
      • Ek L.
      • Kjellin L.
      Development and pilot validation of a sensory reactivity scale for adults with high functioning autism spectrum conditions: sensory reactivity in autism spectrum (SR-AS).
      ]
      High internal consistency (0.96), accurately distinguishes between patients with autism and other comorbid mental disordersTest-retest reliability data neededNoQuestionnaire – informant 15–20 min
      Adult Social Behaviour Questionnaire (ASBQ)[
      • Horwitz E.
      • Schoevers R.
      • Ketelaars C.
      • Kan C.
      Clinical assessment of ASD in adults using self- and other report: Psychometric properties and validity of the adult social behavior questionnaire (ASBQ).
      ]
      In line with the DSM-5 diagnostic system; Good data on structural validity and internal consistency; good discrimination propertiesNot clear if it reliably maps onto autism diagnosisNoQuestionnaire 5-10 min
      Adult Repetitive Behaviours Questionnaire-2 (RBQ-2A)[
      • Barrett S.
      • Uljarevic M.
      • Baker E.
      • Richdale A.
      • Jones C.
      • Leekam S.R.
      The adult repetitive behaviours questionnaire-2 (RBQ-2A): a self-report measure of restricted and repetitive behaviours.
      ]
      Good internal consistency and diagnostic validityLow discrimination properties between autism and OCD or anxiety disorderNoQuestionnaire 5-10 min
      The Social Responsiveness Scale for Adults (SRS-A)[
      • Constantino J.N.
      • Todd R.D.
      Intergenerational transmission of subthreshold autistic traits in the general population.
      ]
      High sensitivity and specificity; satisfactory diagnostic data;Moderate evidence for test-retest reliability.

      Low discrimination properties.
      Yes – shortened version SRS-SQuestionnaire 10 min shorter version 5 min
      Table 2Diagnostic instruments.
      Diagnostic InstrumentsAuthorsStrengthsWeaknessesUse in adult PWE?Methods of assessment
      Adult Asperger Assessment (AAA)[
      • Baron-Cohen S.
      • Wheelwright S.
      • Robinson J.
      • Woodbury-Smith M.
      The adult Asperger assessment (AAA): a diagnostic method.
      ]
      Two self -questionnaire AQ and Empathy Quotient; high sensitivity and specificityLow discrimination properties between autism and comorbid psychiatric conditionsNoQuestionnaire and in interview with the patient (3 h of direct interview)
      Autism Diagnostic Observation Schedule Module 4 (ADOS-4)[
      • Lord C.
      • Risi S.
      • Lambrecht L.
      • Cook J.E.
      • Leventhal B.
      • DiLavore P.
      The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with spectrum of autism.
      ]
      Consist of different level for age and language; good discrimination properties between autism and other psychiatric conditions; good internal consistencySensitivity and specificity variabilityNoInterview and interaction with the patient (1 hr or just over)
      The Autism Diagnostic Interview Revised (ADI-R)[
      • Rutter M.
      • Couteur A.L.
      • Lord C.
      Autism diagnostic interview-revised (ADI-R).
      ]
      Observation of behaviours that are difficult to find in non-clinical subjects; suitable for those without intellectual disabilityOverlapping properties between autism and comorbid psychiatric conditionsNoInterview with the patient (1-2 h of assessment)
      The Asperger Syndrome (High functioning autism) Diagnostic Interview (ASDI)[
      • Gillberg C.
      • Gillberg C.
      • Rastam M.
      • Wentz E.
      The Asperger syndrome (and high-functioning autism) diagnostic interview (ASDI): a preliminary study of a new structured clinical interview.
      ]
      Good inter-rater reliability and good diagnostic validityOverlapping properties between autism and comorbid psychiatric conditionsNoInformant structured interview (30 min)
      Developmental, Dimensional and Diagnostic Interview (3Di and 3Di-Adult)[
      • Skuse D.
      • Warrington R.
      • Bishop D.
      • Chowdhury U.
      • Lau J.
      • Mandy W.
      • Place M.
      The developmental, dimensional and diagnostic interview (3di): a novel computerized assessment for autism spectrum disorders.
      ,
      • Mandy W.
      • Clarke K.
      • McKenner M.
      • Strydom A.
      • Crabtree J.
      • Lai M.
      • Skuse D.
      Assessing autism in adults: an evaluation of the developmental, dimensional and diagnostic interview-adult version (3Di-Adult).
      ]
      Excellent test-retest reliability and validity; good discrimination propertiesTranslation and validation in other cultures neededNoInterview with the patient (1 h)

      4. Integration and critical analysis

      The gold standard tools for screening and formally diagnosing autism in cognitively able adult patients reported in the NICE (CG142; 2012) [
      National Institute of Health and Care Excellence
      Autism spectrum disorder in adults: diagnosis and management. Clinical guideline.
      ] guidelines are the Autism Spectrum Quotient (AQ), the Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R), the Adult Asperger Assessment (AAA), the Autism Diagnostic Observation Schedule 2 Module 4 (module 4 of the ADOS-2), the Autism Diagnostic Interview-Revised (ADI-R), and the Asperger Syndrome (High functioning Autism) Diagnostic Interview (ASDI). We could only find studies using the AQ with adult PWE. It should be noted that the AQ is a screen for autism symptoms and is not formally diagnostic. Other tools that may be useful are the Sensory Reactivity Scale (SR-AS), the Reading the Mind in the Eyes Test, the Adult Social Behaviour Questionnaire (ASBQ), the Adult Repetitive Behaviour Questionnaire-2 (RBQ -2A), the Social Responsiveness Scale for Adults (SRS-A) and the Developmental, Dimensional and Diagnostic Interview (3Di- and 3Di-Adult). Of these, the Social Responsiveness Scale (shortened version SRS-AS) described specific use in adult PWE, but further research is needed. To date, the formal gold standard diagnostic tools (module 4 of the ADOS-2, ADI-R or 3Di or 3Di- Adult) would benefit from being applied specifically to cognitively able PWE to check their feasibility and acceptability.
      Considering the strong association epilepsy and autism can have with psychiatric disorders such as anxiety and depression, screening and diagnostic tools must be capable of discriminating between these conditions. Of the tools we identified, the Sensory Reactivity Scale (SR-AS), the Adult Social Behaviour Questionnaire (ASBQ), the Autism Diagnostic Observation Schedule 2 Module 4 (module 4 of the ADOS-2) and the Developmental, Dimensional and Diagnostic Interview (3Di) have been found to accurately discriminate between ASD and other comorbid psychiatric disorders. Further studies are needed to examine the test-retest reliability of the Sensory Reactivity Scale, the diagnostic validity of the Adult Social Behaviour Questionnaire (ASBQ), and sensitivity and specificity of the module 4 of the ADOS-2.

      5. Limitations

      This narrative review is limited in its search of only English and Italian articles. Few studies examine autism in cognitively able PWE, and the studies used small, heterogeneous populations and different methods. Importantly this also prohibits stratifying results by clinical characteristics.

      6. Conclusion

      Cognitively able PWE may represent a patient cohort that has been historically neglected from a diagnosis of autism but the high rate of psychiatric conditions in PWE may be confounders for diagnosis. Accurate identification relies on the existence of valid autism screens for use with PWE. We identified two screening tools used with cognitively able PWE (AQ, SRS-AS). The AQ is more psychometrically robust but there may be an overlap between these screening questions and questions relevant to some psychiatric disorder, other screening tools such as the RAADS-14 may be valuable and validation of their use in PWE is needed. Formal gold standard diagnostic tools (module 4 of the ADOS-2, ADI-R or 3Di or 3Di-Adult) would benefit from studies of their application to cognitively able PWE. More research is needed to shed light on the characteristics of autism in cognitively able PWE and to validate appropriate screening and diagnostic tools in this cohort.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors

      Declaration of Competing Interest

      The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

      Acknowledgments

      The authors are extremely grateful for the support of Dr Lina Nashef Consultant Neurologist from the Neurology Department, Kings College Hospital for insightful discussions about the project and for many useful suggestions.

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