Differential Diagnosis of Autism and other Neurodevelopmental Disorders

The diagnostic criteria for autism spectrum disorder (ASD) have changed considerably over time.¹ Here, we present the current criteria as they are outlined in both the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, text revision,² as well as in the International Classification of Diseases, 11^th version (ICD-11).³

As shown in Box 1, the DSM-5-TR has substantial overlap, but not complete alignment, with the ICD-11, both in terms of diagnostic coding and description of diagnoses. In the DSM-5-TR, ASD is one of seven different categories of neurodevelopmental disorders, along with intellectual developmental disorder (which includes 6 different codes), communication disorders (including 5 different diagnoses), attention-deficit hyperactivity disorder (with 5 presentation codes), specific learning disorder (with 3 separate designations for specific impairments), motor disorders (with 2 separate diagnoses), and tic disorders.² The “other neurodevelopmental disorders” section includes 2 additional codes, “other specific neurodevelopmental disorder” and “unspecified neurodevelopmental disorder”, which can be used when full criteria are not met for ASD and a specific reason is described, or not described, respectively. One additional diagnosis in the ICD-11 is secondary neurodevelopmental syndrome (code 6E60), which is included in the section on secondary mental or behavioral syndromes associated with disorders or diseases classified elsewhere. This is a diagnosis that may be used when symptoms of ASD develop after the early developmental period, such as in the case of autoimmune encephalitis, or when criteria person meets some but not all criteria for ASD and/or another neurodevelopmental disorder, such as in the context of a specific genetic condition.³

Box 1. Substantial Overlap Between DSM-5-TR and ICD-11.

DSM-5-TR (APA, 2022)

1. Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history (examples are illustrative, not exhaustive, see text; APA, 2022):

   • Deficits in social-emotional reciprocity, ranging, for example, from abnormal social approach and failure of normal back- and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions.
   • Deficits in nonverbal communicative behaviors used for social interaction, ranging, for example, from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or deficits in understanding and use of gestures; to a total lack of facial expressions and nonverbal communication.
   • Deficits in developing, maintaining, and understanding relationships, ranging, for example, from difficulties adjusting behavior to suit various social contexts; to difficulties in sharing imaginative play or in making friends; to absence of interest in peers.
2. Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at least two of the following, currently or by history (examples are illustrative, not exhaustive, see text):

   • Stereotyped or repetitive motor movements, use of objects, or speech (e.g., simple motor stereotypes, lining up toys or flipping objects, echolalia, idiosyncratic phrases).
   • Insistence on sameness, inflexible adherence to routines, or ritualized patterns of verbal or nonverbal behavior (e.g., extreme distress at small changes, difficulties with transitions, rigid thinking patterns, greeting rituals, need to take same route or eat same food every day).
   • Highly restricted, fixated interests that are abnormal in intensity or focus (e.g., strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interests).
   • Hyper- or hyporeactivity to sensory input or unusual interest in sensory aspects of the environment (e.g., apparent indifference to pain/temperature, adverse response to specific sounds or textures, excessive smelling or touching of objects, visual fascination with lights or movement).

3. Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities, or may be masked by learned strategies in later life).

4. Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning.

5. These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication should be below that expected for general developmental level.

ICD-11 (WHO, 2019):

Persistent deficits in initiating and sustaining social communication and reciprocal social interactions that are outside the expected range of typical functioning given the individual’s age and level of intellectual development. Specific manifestations of these deficits vary according to chronological age, verbal and intellectual ability, and disorder severity. Manifestations may include limitations in the following:

• Understanding of, interest in, or inappropriate responses to the verbal or non-verbal social communications of others.

• Integration of spoken language with typical complimentary non-verbal cues, such as eye contact, gestures, facial expressions and body language. These non-verbal behaviours may also be reduced in frequency or intensity.

• Understanding and use of language in social contexts and ability to initiate and sustain reciprocal social conversations.

• Social awareness, leading to behaviour that is not appropriately modulated according to the social context.

• Ability to imagine and respond to the feelings, emotional states, and attitudes of others.

• Mutual sharing of interests.

• Ability to make and sustain typical peer relationships.

Neurodevelopmental disorders (NDDs) are generally conceptualized as representing qualitative impairments resulting from the extreme ends of developmental domains, such as social communication, cognition, and attention, as examples. NDDs share a number of overlapping features, which can make differential diagnosis challenging. Thus, it may be particularly challenging to determine when symptoms of a second or third neurodevelopmental disorder are subthreshold or meet criteria for an additional diagnosis. In relation to ASD specifically, other NDDs are prevalent among the many co-occurring conditions that are often present.⁴

Due to the complexities of ASD diagnosis, its behavioral nature, its many diagnostic differentials (see below), comorbidities, and its early childhood onset, diagnosis of ASD requires a thorough, systematic assessment by a trained expert.⁵ Such a professional (or team) must be well-versed in use of diagnostic instruments, their limitations, and how to apply them to individuals with different characteristics that may influence administration and/or interpretation.⁶ Pediatricians play a critical role in ASD surveillance, and mounting evidence underscores the importance of active screening practices for facilitating timely referrals.⁷ Some pediatricians may also seek additional, specialized training in diagnostic assessment of ASD, but this requires training beyond what is provided in pediatric residency. Further, given the complexities of differential diagnosis (see below), even those with additional training may not feel equipped to make or rule out diagnoses of ASD (and/or other NDDs) in all cases. While this chapter will not delve into the full listing of tests available, nor details of all of the best practices for diagnosis, we refer the reader to other training materials, including several provided by the American Academy of Pediatrics.^8–12 We will also not provide an exhaustive review of factors that may affect diagnostic assessment of ASD– these include chronological age, developmental and language level, sex and gender, cultural and linguistic differences, and other societal influences, including access to diagnosticians and services. However, we will try to highlight a few, and provide exemplars of issues to consider.

Those involved in making diagnoses of ASD or other NDDs must acquire deep understanding of typical child development, manifestations of autism across development, and commonly co-occurring conditions. However, general practitioners and pediatric providers can develop the skills to discern when cases should be referred for specialty assessment.¹³ Indeed, equipping some pediatric providers with necessary training to identify children at particularly high likelihood for ASD could significantly reduce wait times and increase timely access to diagnostic services, thereby opening the doorway to appropriate supports and interventions.¹³ In addition to consulting the aforementioned training materials provided by the AAP, and the information presented in this chapter, pediatricians should consider seeking training programs or shadowing seasoned diagnosticians in order to increase their competencies in the diagnostic arena.¹³ Training models such as ECHO Autism¹⁴ have also been developed with the specific purpose of increasing capacity among pediatricians to identify likely ASD cases and are quickly gaining popularity across the US and abroad.¹⁵

When should a child be evaluated for ASD? Before answering this, we will discuss when a child should receive surveillance and screening for ASD, which should lead a child and family down a path towards a diagnostic evaluation if results of screeners indicate concern. Surveillance is the process of monitoring children to be able to identify those showing developmental concerns.¹⁶ Screening is an active process that should occur at certain timepoints. Screening should assess for general developmental concerns, followed by ASD-specific concerns, per instruction of the American Academy of Pediatrics.¹⁶ Screening results may necessitate a referral for a diagnostic evaluation. While this process has mostly been studied and promoted with respect to young children,¹⁷ it is increasingly apparent that there are many autistic adolescents and adults who were not diagnosed as children.^18,19 As such, a variation on this process may also be relevant for older children and adolescents presenting with concerns in social-communication and/or other developmental domains.²⁰

The American Academy of Pediatrics recommends that in addition to general developmental screening at 9, 18 and 30 months of age, pediatricians use validated instruments to screen children for ASD specifically at 18 and 24 months of age.²¹ Screening can also occur at any age when concerns arise. One reason for the repeated screenings is that, for some children, regression or loss of skills may be a feature of autism symptom onset, so a child may “pass” an earlier screener but fail a later one. Caregiver questionnaires and interviews are often used as “level 1” screeners, but pediatricians may also be trained in “level II” screeners that can involve brief and often structured direct observation measures, which require reliability training for coding. In particular, providers could seek training in level II screeners such as the Rapid Interactive Screening Test for Autism in Toddlers (RITA-T) or the Screening Tool for Autism in Toddler and Young Children (STAT) to support implementation of models where those who fail these screeners are expedited for referrals for comprehensive evaluations.²²

Once a child is referred for comprehensive diagnostic evaluation of ASD, best practices include several elements: a parent/caregiver interview to determine history and pervasiveness of symptoms; an in-person portion with direct observation and interaction with the individual; and outside corroboration of the impaired functioning (e.g., collateral information from teachers).⁵ The developmental history is critical for ascertaining whether Criterion C are met, that is, that symptoms are present in the early developmental period (i.e., before age 5). In addition, cognitive or developmental testing is necessary to determine whether any observed deficits in social-communication and/or play are beyond what would be expected based on an individual’s developmental level (i.e., to consider all criteria, including Criterion E of DSM-5 criteria for ASD).²³ The best-practice components of an assessment may be carried out by a sole provider, or as part of a multidisciplinary team (e.g., including pediatric providers, speech-language pathologists, psychologists and others). As opposed to many other diagnoses that pediatric providers make, the diagnosis of ASD or any other NDD cannot be made based on results from any particular test.^1,6 There are no definitive diagnostic biomarkers, and there is no behavioral test that is sufficiently accurate on its own to diagnose ASD. Further, individuals present with extremely variable constellations of symptoms, which also change within individuals over time, meaning that clinical expertise is another critical component of the diagnostic assessment process.⁶ The process of administering standardized diagnostic instruments can improve diagnostic decision-making by eliciting diagnostically salient information to inform expert clinical judgment.⁶ However, mis-use of these instruments, including overreliance on scores and classifications, likely contributes to high rates of misdiagnosis,²⁴ especially because sensitivity and specificity of these instruments varies significantly based on developmental and behavioral factors.²⁵

Because of the extreme phenotypic heterogeneity characteristic of ASD, a major focus of the comprehensive assessment is to describe the individual’s profile in sufficient detail to meaningfully inform treatment planning. Thus, the DSM-5-TR includes specifiers to encourage clinicians to go beyond the simple consideration of whether ASD is present, which could be the case for individuals with any level of language or cognitive ability or other differences. Specifiers are a convention of the DSM to define subgroups within a disorder for individuals who share features. There are several specifiers available in the ASD diagnosis, including indication for intellectual and/or language impairment. However, even within these specifiers, there is huge variability. Specifiers are also used to indicate whether there are known medical and/or genetic factors, and/or co-occurring diagnoses (including other NDDs). Importantly, though, clinicians should also assign independent diagnoses whenever applicable. This means that even in an individual diagnosed with ASD with accompanying intellectual impairment or language impairment, an additional DSM-5 diagnosis of intellectual disability and/or language disorder might also be appropriate.

The DSM-5 further includes specifiers to indicate the level of support required for core ASD-related impairments (i.e., social-communication deficits and restricted and repetitive behaviors).² This represents another attempt to explicitly acknowledge the wide range of symptom severity among people with ASD. These categorical designations include level 1: requiring support, level 2: requiring substantial support, and level 3: requiring very substantial support. Unfortunately, these categories were never field tested, nor is there any evidence regarding their validity or reliability. Based on studies of other measures of ASD ‘severity,’ it is unlikely that such designations provide meaningful information beyond what can be conveyed by an individual’s current developmental and language level.^26,27 By developmental level we generally mean nonverbal mental age, which can be gleaned from developmental tests or cognitive tests, or estimated based on knowledge of the individual’s adaptive functioning in various developmental areas. Given the degree of intra-individual change, especially in young children with ASD, it is also not clear what, if any, prognostic value these designations have. Without more explicit guidance about how they should be operationalized (i.e., to capture symptom severity beyond what is attributable to cognitive and/or language level), or at what point in development they can be reliably assigned, these severity levels are unlikely to provide meaningful information to providers or families. Further, they may have the potential to do more harm than good (e.g., if insurance providers attempt to limit coverage for individuals with “level 1 ASD”).^1,28,29 There is also no comparable metric in the ICD-11.

In contrast to the DSM-5 support specifiers and other potentially misleading terms for describing an individual with ASD (e.g., “low” vs. “high” functioning),³⁰ detailed information about an individual’s specific profile across developmental and behavioral domains is much more helpful for treatment planning. This includes language, attention, motor function, as well as various areas of cognition, including memory and executive functioning, and the broader context of psychiatric symptoms that may occur over time. As mentioned above, because “ASD” is used to describe individuals with such a wide range of symptom profiles, the diagnostic label does not convey information about which types of supports are needed for that individual. Specific therapies are often necessary to promote adaptive functioning and allow participation in developmentally appropriate learning opportunities, and these therapies will vary significantly between individuals. Specific therapies may include speech therapy, occupational therapy, or home or center-based behavioral therapies that focus on various aspects of adaptive functioning (e.g., communication, daily living skills). Educational support needs will also vary widely, and some individuals with a medical diagnosis of ASD may not meet criteria for an educational classification of autism if their ASD symptoms do not interfere with their ability to access the curriculum. However, even if a child with ASD is excelling academically, it is important to consider whether they require support to improve social functioning in the school setting.³¹

Regardless of the treatment plan developed from a comprehensive diagnostic assessment, it is critical to remember that treatment needs change over time as a function of both age and the degree and rate of developmental progress.³² In addition, transient or chronic medical, behavioral, psychiatric, and/or educational concerns that arise may require various specialized assessment, management, and treatment services.³³ This underscores the importance of periodic re-evaluations, as would be recommended with any chronic condition, to evaluate changes that are needed to the treatment plan.^32,34 Further, as it becomes available, it is important to communicate information to individuals and their families regarding expectations for the future.³⁵ If applicable, information about co-occurring diagnoses such as intellectual disability should also be clearly communicated.^36,37

Importantly, there is no one behavioral feature that is universal to all individuals with ASD, just as there is no symptom that is entirely specific to ASD.² This significantly complicates diagnosis, because children with various NDDs or psychiatric diagnoses may present with symptoms that appear very similar to ASD. Increasingly, children with social challenges are referred for diagnostic assessment of ASD, but as described in more detail below, children can experience social difficulties for myriad reasons, some of which are not related to ASD. These may include other symptoms of other NDDs, such as inattention or impulsivity, or a variety of other behavioral or emotional issues, or even experiences they are having (e.g., bullying, trauma).^38,39 Thus, it is only after careful consideration of a child’s complete developmental and behavioral profile that a diagnosis of ASD should be considered.

Associated conditions and differential diagnoses with autism:

The following sections focus on conditions that show significant symptom overlap with ASD and are also commonly co-occurring. All of these conditions may also need to be considered as differential diagnoses with autism depending on the clinical presentation.

Attention Deficit / Hyperactivity Disorder (ADHD):

Attention Deficit / Hyperactivity Disorder (ADHD) is characterized by attention dysregulation, and/or by the presence of hyperactive and impulsive behaviors that cause impairments in at least two settings (e.g., school and home).² ADHD commonly co-occurs with ASD, with rates as high or higher than 40%, and it may also be mistaken for autism or vice versa.^40,41 While DSM-IV did not allow for the additional diagnosis of ADHD to be made when ASD was present, this restriction was lifted in DSM-5. This decision was made due to growing recognition that many individuals with ASD do present with additional ADHD symptoms that are not fully accounted for by ASD, and these individuals might benefit from evidence-based treatments for ADHD.⁴² Still, the question about whether an additional diagnosis of ADHD is warranted must be considered carefully, especially in children with ASD who are young and/or with global developmental delays or intellectual disability. For these individuals, symptoms of inattention, impulsivity, and/or hyperactivity may be largely explained by lower developmental level. Similar to Criterion E for ASD, the DSM-5 diagnostic criteria for ADHD indicate that inattention and hyperactivity must be inappropriate for developmental level in order to be considered symptoms.² Related, some children with ASD may appear to be inattentive and/or hyperactive because of social disinhibition and reduced ability to modify behaviors appropriately to the social situation (e.g., frequently leaving group classroom activities due to disinterest/lack of engagement; not attending to others’ conversational attempts).⁴³ Thus, providers making diagnoses of ADHD in the context of ASD must be trained in assessment and diagnosis of both conditions.⁴³

Differential diagnosis of ASD versus ADHD is also challenging, because while social challenges are not a core diagnostic feature of ADHD (as they are in ASD), individuals with ADHD commonly experience social problems. Therefore, especially in verbal school-aged children and adolescents with intact cognitive abilities, it can be unclear whether social difficulties arise from ASD-related and/or ADHD-related symptoms (or both). Further, children with ADHD are likely to receive elevated scores on ASD screening and diagnostic instruments,⁴⁴ which underscores the importance of careful attention to and specific training in this complex differential diagnosis.

Deficits in basic social communication skills (such as nonverbal communication), is a key distinguishing factor between ADHD and ASD. However, much like children with ASD, children with ADHD commonly experience rejection by peers, and they tend to have fewer friendships and poorer friendship quality than neurotypical peers.⁴⁵ Many of these characteristic social challenges in ADHD are likely attributable to impulsivity and its associated costs (e.g., frequent interruption, difficulty waiting one’s turn, etc. ).⁴⁶ Whereas children with ASD often lack social knowledge, studies suggest that children with ADHD show intact social knowledge despite difficulty with social interactions and forming friendships.^{46,47 46} As such, identifying specific sources of social difficulties can be useful for distinguishing lack of interest or engagement related to ASD symptoms from difficulty participating successfully in social interactions due to symptoms of ADHD (or if both apply).

Language Disorders:

Language Disorders are defined by deficits in acquiring and using language (spoken, signed, or written)² due to reduced vocabulary, limited sentence structure (i.e., putting words together according to rules of grammar), and impairments in discourse (i.e., having conversations or describing topics).² To qualify for a language disorder diagnosis, language abilities must be below age expectations, and there must be evidence of functional impairments in communication, socialization, academic achievement, or occupational performance. Onset of symptoms must occur early in development and language difficulties cannot be attributable to sensory impairment, motor dysfunction, another neurological condition, or intellectual disability.²

The estimated prevalence of language disorders in school age children is ~7.5% (not including children with language delays in the presence of other NDDs).⁴⁸ For children with other neurodevelopmental disorders such as ASD or ADHD, the prevalence of language disorder is estimated at 30 – 50%.^48–50 In order to distinguish between ASD and Language Disorder, it is necessary to consider aspects of social communication that are not associated with language level.⁵¹ Communication behaviors including showing, directing attention, and coordinating gaze, facial expressions, and gestures, do not depend on language level and are, by definition, limited or absent in ASD.^2,51 Thus, a child with Language Disorder in the absence of ASD would be expected to show many such compensatory communication strategies. Further, symptoms such as lack of imitation and limitations in pretend play are much more prevalent in ASD than Language Disorder.^52–55 Additionally, when differentiating between ASD and Language Disorder in early childhood, parent report indicating delays in social and self-help skills may be more indicative of concern for ASD than Language Disorder.⁵⁶

Social Pragmatic Communication Disorder:

Social Pragmatic Communication Disorder (SPCD) is defined by deficits in pragmatic language. These encompass social aspects of language including taking turns in conversation, using and understanding figurative language, greeting others, etc.² To meet diagnostic criteria for SPCD, these pragmatic language deficits cannot be accompanied by the presence of restricted and repetitive behaviors or interests associated with ASD, structural language disorders, or intellectual disability.² Symptoms of SPCD overlap with some of the social-communication deficits of ASD, but are more confined. Although data are limited, the estimated prevalence of SPCD is less than 1%.^57,58 Further, there has been ongoing debate regarding the validity of the SPCD diagnosis, as social pragmatic deficits rarely occur in the absence of ASD.⁵⁷ Implementation of SPCD diagnosis is challenging due to the lack of established assessment measures and the high rates of overlap between SPCD and other disorders, including ADHD, conduct disorder, and genetic conditions.⁵⁹ Given the diagnostic confusion and lack of diagnostic utility, many have argued that challenges associated with SPCD should be considered as a set of symptoms that cuts across multiple neurodevelopmental disorders.⁵⁹

Intellectual Developmental Disorder (Intellectual Disability):

Intellectual Disability (ID) is defined by deficits in intellectual and adaptive functioning.² It can range in severity from mild to profound. These severity levels represent distinct diagnostic entities, and are important to designate given their vastly different symptom profiles and associated support needs and prognoses.⁶⁰ Individuals with mild ID (the most frequent type) often live and work independently with minimal supports needed at various times, whereas individuals with profound ID continue to require 24-hour supervision throughout their lives given basic support needs.^60,61

ID also commonly co-occurs with ASD. Earlier studies showed it to be present in the majority of ASD cases,⁶² and as a result, issues in differential diagnosis of ID and ASD were historically a focal point of the assessment literature, where discussion was largely focused on how to differentiate whether ASD was present in the context of ID. However, the distribution has shifted such that now a minority of individuals with ASD are diagnosed with ID.⁶³ Given this shifting prevalence of combined ID and ASD,^64,65 many newly trained clinicians are much less experienced in differential diagnosis of ID and ASD. Consequently, there are growing concerns that ASD may be over-diagnosed in ID, especially in developmentally or medically complex populations such as those with genetic conditions that require special expertise.^66–68

To diagnose ASD in the context of ID, or global developmental delay for younger children, challenges in social communication, and the presence of restrictive/repetitive behaviors/interests, need to be beyond what would be expected for developmental age.^2,67,68 Therefore, developmental or cognitive testing is a critical component of any diagnostic evaluation, because it is impossible to evaluate the presence of social communication deficits without establishing an individual’s expected level of social communication ability. If direct cognitive or developmental testing is not possible, clinicians may consider using cognitive measures that rely heavily on parent report of cognitive skills (e.g., the cognitive subtest of the Developmental Profile or the Developmental Assessment of Young Children, Second Edition – DAYC-2).^69–71 However, clinicians should be aware of the limitations of using parent-report measures to estimate cognitive ability, and this method should only be used as a measure of last resort as it does not adhere to recommended best practices in ASD diagnostic assessment.⁷² Requesting reports from school Individualized Education Plan evaluations is another strategy for obtaining estimates of developmental level, which can then be used to determine whether observed deficits in social communication are beyond what would be expected based on overall developmental level.

Among children identified as having global developmental delays or ID, assessing for differences in more basic/early-emerging social communication behaviors, such as eye contact, joint attention, and showing can help distinguish ASD from ID, as these skills are likely to be better developed in individuals without ASD even at very low mental ages.²³ Standardized instruments that quantify these behaviors based on direct observation and parent report are helpful in gathering information about deficits or capacities in basic social communication behaviors, but to appropriately interpret results of these tests, the assessor must still exercise judgment about what would be expected for an individual’s developmental level. Early development may also hold clues relevant to differential diagnosis. Although some children with ASD show delays from early on, these are often subtle, transient and not detected without intensive assessment. Further, the majority of children with ASD achieve early motor milestones like sitting and walking on time, which may contribute to the impression that they are developing normally during the first years of life.^73,74 In contrast, clinically identifiable motor delays are common in children with ID when ASD is not present. Regardless of whether a child is diagnosed with ASD and/or ID, identifiable delays in early motor milestones are likely to signal a potential genetic etiology and should prompt referral for genetic testing.^73,75

As noted in DSM-5-TR criterion E and ICD-11 diagnostic criteria, the diagnosis of ASD in individuals with Intellectual Disability is particularly difficult, and requires in-depth and sometimes longitudinal assessments.^2,3 Individuals with visual, hearing, and motor impairments, which commonly occur in the context of severe to profound ID and genetic conditions, have been excluded from ASD diagnostic instrument validation samples. This exclusion limits the availability of data on differential diagnosis of ASD and ID within these conditions, as well as the availability of tools that can be validly employed for such purposes.^23,76,77 The issue is so complex that Kanner actually excluded these children from his initial descriptions of ASD, claiming that these children’s symptoms did not align with other descriptions of ASD.⁷⁸ However, to avoid diagnostic overshadowing, it is important to emphasize that an additional diagnosis of ASD should be made if skills in social reciprocity and communication are significantly impaired relative to the individual’s general level of intellectual ability.^2,3,23

Anxiety Disorders:

Anxiety Disorders are generally characterized by excessive fear or worry and avoidance of feared situations or stimuli. Differential diagnosis of autism and anxiety is nuanced and can be difficult. The challenges in differential diagnosis are somewhat related to symptom overlap between autism and anxiety.⁷⁹ Autism and anxiety also frequently co-occur.^80,81 Social Anxiety Disorder (SAD) very commonly co-occurs with ASD.^82–84 SAD is characterized by fear of negative evaluation by others, resulting in avoidance of social situations, possibly impacting school, work, and social life.² Both SAD and ASD are characterized by difficulty with social communication, leading some youth with SAD to receive elevated scores and/or score above cut-offs on ASD screening tools.⁸² Thus, clinicians must consider not only the sensitivity of ASD screeners (i.e., how likely they are to identify ASD in a child diagnosed with ASD), but also their specificity (i.e., how likely they are to NOT identify ASD in a child who is not diagnosed with ASD). Age of onset can be useful in distinguishing between SAD and ASD, as ASD is present early in the developmental period whereas SAD more commonly emerges in early adolescence.^82,85 Youth with ASD can be expected to show overall greater generalized impairments in social function compared to youth with SAD.

Youth with selective mutism (SM) are also likely to score above cut-offs on some ASD screeners.⁸⁶ Both SM and autism are characterized by communication challenges. Selective mutism is an anxiety disorder defined by the lack of speaking in specific settings (e.g., school) despite the ability to speak in other settings (e.g., home).² It commonly co-occurs with other anxiety disorders, and SAD in particular.⁸⁷ Selective mutism can start at any age, although it most often presents in early childhood.⁸⁸ Selective mutism cannot currently be diagnosed in the context of ASD, although some argue that the two conditions can co-occur.^2,87 One key distinguishing feature between SM and ASD is the pervasiveness of communication difficulties. In contrast to ASD, communication challenges associated with SM are not present in all settings. In addition, whereas symptoms of ASD are present in early childhood, anxiety disorders tend to arise in later childhood and adolescence.⁸² Thus, gathering a careful and comprehensive developmental history including detailed information about if, how, and when symptoms present across settings, is necessary for differentiating ASD from selective mutism and other anxiety disorders that may have symptom overlap with ASD.

Obsessive Compulsive Disorder:

Obsessive Compulsive Disorder is defined by the presence of obsessions (i.e., intrusive, unwanted thoughts, images, or urges), and compulsions (repetitive behaviors or mental acts).^2,3 The difficulty in differentiating between OCD and ASD typically relates to distinguishing ASD-associated repetitive motor behaviors from compulsions, and distinguishing ASD-associated restricted interests or insistence on sameness from OCD-related obsessions, as they may appear very similar at first glance.⁸⁹ Compulsions in the context of OCD typically relieve anxiety caused by obsessive thoughts.^2,90 For example, hand washing is a common compulsion that relieves anxiety associated with contamination-related obsessive thoughts. Although they may bring relief from anxiety, compulsions are generally distressing to people with OCD, whereas repetitive behaviors in the context of ASD are often enjoyed.⁹¹ When differentiating between repetitive thoughts and behaviors that are ASD-related vs. OCD-related, it is important to consider that individuals (including children) can lack insight into their symptoms, so this can make it more difficult to assess for the presence of ego dystonic distress associated with symptoms (characteristic of OCD, but not ASD).⁹¹

Depressive Disorders:

Depressive disorders, generally, are characterized by persistent feelings of sadness, hopelessness, and lack of interest or pleasure in activities.^2,3 Depressive symptoms can also include changes in sleep and appetite and difficulty concentrating. Depression has well-documented impacts on social function. In particular, youth with depression may show reduced interest in social activities and can also display flattened facial and vocal affect.⁹² As is the case with other differential diagnoses, a detailed clinical and developmental history is helpful for distinguishing whether flattened affect and increased withdrawal from social activities are attributable to depression vs. ASD, or depression in the context of ASD. As with anxiety disorders, the age of onset for depressive disorders tends to occur in adolescence or adulthood, differentiating it from ASD’s early developmental period onset. Although they can be persistent, depressive disorders are often episodic. Thus, considering one’s social behavior in the absence of a mood-related depressive episode will be important for distinguishing between social impairment due to ASD vs. depression. Importantly, depression and autism commonly co-occur, especially in adolescence and adulthood, and screening for mood disturbance is important in the context of ASD.^93–95

Schizophrenia Spectrum Disorders:

Schizophrenia and autism have a history of diagnostic confusion. Prior to the first description of autism by Leo Kanner in 1943, “autism” was a term used to describe a symptom of schizophrenia.^78,96 Autism was not formally recognized as a separate disorder from childhood onset schizophrenia until 1980 with the publication of the DSM III.⁹⁶ Schizophrenia Spectrum Disorder (SSD) is a chronic disorder involving cognitive, behavioral, and emotional symptoms, and perceptual abnormalities associated with psychosis (e.g., hallucinations).^2,3 Although not included in the neurodevelopmental disorder section of the DSM, schizophrenia is often considered a neurodevelopmental disorder.⁹⁷ Because SSD typically emerges in late adolescence and/or early adulthood, it has been considered at least nosologically distinct from other neurodevelopmental disorders. However, there is increasing evidence that SSD, like other childhood neurodevelopmental disorders, develops after early neurobiological insults causing perturbations in typical brain developmental patterns.⁹⁸ Both ASD and SSD are characterized by impairments in social behavior and cognition, but the impairments differ qualitatively.^2,3 Although they have distinguishable features (e.g., presence of psychotic features), there is significant phenotypic overlap between SSD and ASD. In addition to phenotypic overlap in social cognition, SSD and ASD also have some shared genetic features.⁹⁹

While frank symptom onset in SSD typically occurs in late adolescence or early adulthood,² individuals later diagnosed with schizophrenia often show atypical early developmental patterns similar to those commonly observed in autism (e.g., speech and motor delay, social impairments).¹⁰⁰ Given that SSD and ASD are both associated with atypical early social development, clinicians may still be unclear regarding the differential between SSD and ASD after obtaining a detailed early developmental history. Additionally, as with most other disorders discussed, ASD and SSD can co-occur.¹⁰¹ Further, Childhood Onset Schizophrenia, characterized by onset prior to age 13 years, is very rare, although is an appropriate diagnosis for some children (estimated prevalence ~1/40,000).¹⁰²

Symptoms of schizophrenia are divided into two categories: negative symptoms refer to the absence of typical social communication behaviors associated with SSD, including flat affect, lack of speech apathy, anhedonia, and inattentiveness; and positive symptoms refer to the presence of atypical symptoms (e.g., hallucinations/delusions). Notably, much of the phenotypic overlap between SSD and ASD is in the negative symptoms category (e.g., lack of eye contact, reduced use of gesture, limited range of facial expressions), as positive symptoms tend to me more disorder specific.¹⁰³ Given the potential behavioral overlap between SSD and ASD, especially in adolescence and adulthood, it is unsurprising that administration of the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2)¹⁰⁴ in adolescents and adults with schizophrenia results in a high rate of false positives (i.e., exceeding cut-offs for an ADOS-2 classification of “ASD”).^{103 97}This further illustrates the dangers of over-reliance on scores for making diagnoses, rather than considering multiple sources of information including expert clinical judgment, especially in situations involving complex differential diagnostic questions.

Stereotypic Movement Disorder:

Motor stereotypies are repetitive, non-functional motor behaviors that are commonly observed in both autistic and non-autistic youth.^2,3,105 Stereotypic motor movements commonly present before age 3 and can continue into adulthood.^2,106 These predictable movements include arm flapping, hand flapping, and rocking back and forth, among many other repetitive movements.^105,106 Although they are most often described in the context of ASD and/or ID, motor stereotypies are also very common in children without other neurodevelopmental conditions.¹⁰⁷ They are also common in typically developing children, with prevalence estimates for simple motor stereotypies such as nail or lip biting and hair twirling ranging from 20% – 70% in children older than age 3.¹⁰⁶ Motor stereotypies are also commonly observed in children with anxiety, OCD, ADHD, and tic disorders.¹⁰⁶

In order to meet DSM-5 criteria for stereotypic movement disorder, movements must interfere with daily activities and may result in self-injury.^2,106,108 Stereotypic movement disorder, unlike ASD, is not characterized by the presence of deficits in social communication.^2,3 As such, if stereotypic movements are interfering and unaccompanied by the presence of deficits in social communication, it is more likely the child has stereotypic movement disorder than ASD. There is very little data on the prevalence of stereotypic movement disorder, especially in children without other neurodevelopmental disorders. However, the DSM-5 does indicate these types of movements are more common in individuals with intellectual disability.

Genetic Conditions:

While the previous differentials described are behaviorally-defined diagnoses included in DSM-5-TR, genetic condition are diagnosed based on genetic testing or screening for the presence of characteristic phenotypes. Many genetic syndromes and single gene variants are associated with increased likelihood of ASD,^109,110 however, this is almost always in the context of other neurodevelopmental concerns, often including intellectual disability. For instance, in conditions that confer significant risk for intellectual disability, such as Fragile X, Down Syndrome, and Tuberous Sclerosis, individuals are also more likely to have ASD than those in the general population.^111,112 As mentioned above, it can be especially challenging to determine the presence of ASD in the context of a genetic condition and severe to profound intellectual disability (ID).^23,113 However, even in the context of mild or moderate ID, it is important for clinicians to carefully consider and ensure that difficulties in social communication and the presence of RRBs are not better explained by intellectual disability or global developmental delay.²

On the other hand, as with all individuals with ID and/or complex medical profiles, it is important to avoid diagnostic overshadowing of ASD in the context of a genetic condition. For example, Down syndrome was historically believed to be a clearly contrasting condition to ASD, but it is now recognized that a subset of children with Down syndrome do meet criteria for ASD, and it is important that these children are afforded specialized treatment for their relative deficits in social communication. Indeed, recent estimates of prevalence of ASD in the context of Down Syndrome range from 16% to 42%.^112,114,115

For youth with genetic condition who have ID, differential diagnosis is also complicated because of the common presence of RRBs.¹¹⁶ It is important to consider the degree to which RRBs interfere with social interaction when making a differential diagnosis.¹¹⁷ Rett syndrome, a genetic condition associated with neurodevelopmental disorder caused by variants in the MeCP2 gene, shares some phenotypic overlap with ASD, including hand stereotypies in some cases.¹¹⁶ Clinically, Rett syndrome is characterized by regression in motor skills, loss of spoken language, gait abnormalities, and hand stereotypies.¹¹⁸ While it was previously considered alongside autism as a pervasive developmental disorder in DSM-IV, since a gene was identified and because there are many conditions with similar circumstances, it was removed from DSM-5 except as a potential specifier (e.g., ASD with Rett syndrome). It also remains as a medical diagnosis in the ICD-11 along with many other genetic conditions.

Co-occurring Conditions that Accompany ASD:

In addition to understanding differential diagnoses, it is important to consider that most individuals diagnosed with ASD are also diagnosed with co-occurring conditions.^119,120 Numerous studies have examined rates, demographics and potential reasons for the generally high comorbidity rates found in individuals with ASD.⁴ Moreover, multimorbidities may be described as the rule, rather than the exception, for neurodevelopmental disorders generally.¹²¹ Diagnoses already discussed in this chapter are among the most frequently co-occurring for youth with ASD, with ADHD currently considered the most prevalent.⁴

Given the co-occurring mental health and behavioral needs among youth with ASD, it is very important for clinicians to screen for the presence of mental health concerns and consider these needs when developing treatment plans.¹¹⁹ As mentioned, it is important that clinicians be aware of diagnostic overshadowing, which could cause them to overlook co-occurring disorders (e.g., attributing emotional symptoms to an established ASD diagnosis rather than the possible presence of a co-occurring mood disorder).¹¹⁹ The presence of mental health concerns that do not fit clearly within the bounds of ASD as defined in DSM-5 (e.g., anxiety, depression, obsessions/compulsions, etc.) should be considered by clinicians as additional diagnostic questions during comprehensive evaluations. Screening for mental health concerns, especially in adolescents and adults with ASD, is extremely important given the high rates of suicide among autistic individuals.¹²² Suicide is estimated to be at least three times as common among autistic individuals as compared to the general population. Suicidal ideation is also thought to occur at very high rates in the autistic adult population (~66%).¹²³ Given the increased risk of suicide among autistic people, including children and adolescents, it is recommended that all people with autism be screened for suicidal ideation and previous attempts.¹²⁴

In addition to mental health, it is also important to consider medical comorbidities among autistic youth. Youth with autism show higher rates of many medical conditions than non-autistic youth, including seizures, eczema, asthma, food allergies, sleep difficulties, and gastrointestinal problems.^4,125 At the time of diagnosis, and certainly if behavioral changes occur later, it is important to consider potential medical contributors and additional diagnoses, especially for younger and/or minimally verbal or non-speaking autistic youth who may do not communicate about their pain verbally. Co-occurring medical conditions could exacerbate symptoms associated with autism and can also contribute to other behavioral challenges.¹²⁶ For example, self-injury can reflect underlying medical problems or pain, in some cases.¹²⁷

Conclusions:

Autism is a behaviorally defined condition with multiple etiologies and heterogeneous clinical presentation. Thus, accurate diagnosis requires expertise in autism and common rule-out conditions. Often an autism diagnosis merits consideration of genetic testing to determine if there is a genetic condition causing or contributing to autism symptoms, especially in the context of co-occurring intellectual disability. Additionally, autistic youth and their families should be offered ongoing monitoring and periodic re-evaluations to identify updated support needs throughout development.

Synopsis:

This chapter covers the diagnostic criteria for Autism Spectrum Disorder (ASD), as well as other neurodevelopmental disorders that may be confused with or co-occur with ASD. ASD also commonly co-occurs with various mental health and medical conditions. Practitioners involved in diagnostic assessment of ASD must be well-versed in the features that differentiate ASD from other conditions, and be familiar with how co-occurring conditions may manifest in the context of ASD. ASD symptoms present differently across development, underscoring the need for training about typical developmental expectations for youth. Periodic re-evaluations throughout development are also important, as support needs for autistic individuals change over time.

Clinics Care Points.

• The diagnosis of autism spectrum disorder is complex, with different challenges depending on the chronological and developmental age of the child or adolescent

• Autism is a behaviorally defined condition associated with many different etiologies, including rare genetic conditions, therefore practitioners need to be aware of the importance of genetic and medical assessment in addition to psychodiagnostic evaluation

• Pediatricians play a key role in providing surveillance and screening for ASD in all children; practitioners who wish to participate in the ASD diagnostic assessment process require additional, specialized training

• Needs and diagnoses for autistic youth can change across time, therefore it is important for youth to have continued monitoring and re-evaluation across different developmental periods

• Even after an ASD diagnosis has been established, clinicians must consider other important elements of management, including the diagnosis of co-occurring medical, genetic, and/or psychiatric conditions that can present at various points throughout development

• Characteristics associated with ASD can be observed in a number of other conditions. Some of the most challenging differential diagnoses from Autism include the following (most of which can also co-occur with ASD):

  • Attention Deficit / Hyperactivity Disorder
  • Language Disorders
  • Social Pragmatic Communication Disorder
  • Intellectual Disability
  • Anxiety Disorders
  • Depressive Disorders
  • Schizophrenia Spectrum Disorders
  • Stereotypic Movement Disorder
  • Genetic Conditions

• Diagnosis of ASD requires a thorough, systematic assessment by a trained expert. A diagnostic evaluation includes both direct observation of the child as well as detailed developmental history obtained from the youth’s caregiver. Clinicians must have both expertise in autism and ample experience in identifying commonly co-occurring conditions

• It is important that clinicians working with autistic youth understand the limitations of current assessment measures especially when evaluating children with genetic conditions and/or other medical issues or sensory differences (e.g., hearing or visual impairments)

Key Points:

• The diagnosis of autism spectrum disorder is complex, with different challenges depending on the chronological age and developmental level of the child or adolescent.

• Clear understanding of an individual’s developmental level, and associated developmental expectations, are critical for differentiating ASD from other conditions that may show significant symptom overlap with ASD.

• Pediatricians play a key role in providing surveillance and screening for ASD, as well as in facilitating appropriate and timely referrals. Some pediatricians may receive specialized training to directly participate in the diagnostic assessment process.

• Comprehensive assessment and management of individuals with ASD should include evaluation of genetic, medical, and mental health conditions that commonly occur in youth with ASD at different points in development.