Clinical UM Guideline

This document addresses various tools used in the testing of individuals with suspected Autism Spectrum Disorders (ASDs) and Rett syndrome. ASDs, as defined in the fifth edition of the American Psychiatric Association's (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM-5), include disorders previously referred to as:

• Atypical autism
• Asperger’s disorder
• Childhood autism
• Childhood disintegrative disorder
• Early infantile autism
• High-functioning autism
• Kanner’s autism
• Pervasive developmental disorder not otherwise specified

NOTE: Please see the following related documents for additional information:

• CG-BEH-02 Adaptive Behavioral Treatment for Autism Spectrum Disorder
• CG-BEH-15 Activity Therapy for Autism Spectrum Disorders and Rett Syndrome
• CG-GENE-13 Genetic Testing for Inherited Diseases
• CG-MED-75 Medical and Other Non-Behavioral Health Related Treatments for Autism Spectrum Disorders and Rett Syndrome

Medically Necessary:

Assessment for ASDs and Rett syndrome is considered medically necessary when any of the following criteria A through C and both criteria D and E have been met:

1. Presence of any of the following signs or symptoms in infants or young children:
   1. No babbling by 12 months; or
   2. No gesturing (for example, pointing, waving bye-bye) by 12 months; or
   3. No single words by 16 months; or
   4. No 2-word spontaneous (not just echolalic) phrases by 24 months; or
   5. Any loss of any language or social skills at any age; or
   6. None-to-little mutual gaze or joint attention;
      or
2. Persistent deficits in social communication and social interaction across multiple contexts, as manifested by any of the following:
   1. Deficits in social-emotional reciprocity; or
   2. Deficits in nonverbal communicative behaviors used for social interaction; or
   3. Deficits in developing, maintaining and understanding relationships;
      or
3. Restricted, repetitive patterns of behavior, interests, or activities as manifested by the following
   1. Stereotyped or repetitive motor movements, use of objects, or speech; or
   2. Insistence on sameness, inflexible adherence to routines, or ritualized patterns of verbal or nonverbal behavior; or
   3. Highly restricted, fixated interests that are abnormal in intensity or focus; or
   4. Hyper- or hypoactivity to sensory inputs or unusual interest in sensory aspects of the environment;
      and
4. 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 learning strategies in later life);
   and
5. Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning.

Note: The following services may be included in the assessment of the individuals with suspected ASDs and Rett syndrome:

1. Medical evaluation (complete medical history and physical examination).
2. Evaluation by speech-language pathologist.
3. Parent and/or child interview (including siblings of children with ASDs).
4. Audiological hearing evaluation including frequency-specific brainstem auditory evoked response.
5. Measurement of blood lead level if the child exhibits developmental delay and pica, or lives in a high-risk environment. Additional periodic lead screening can be considered if the pica persists.
6. Neuropsychological evaluation including developmental testing in the areas of social skills, intellect, adaptation and an ASD specific screening tool.
7. Selective metabolic testing if the child exhibits any of the following:
   1. Clinical and physical findings suggestive of a metabolic disorder (for example, lethargy, cyclic vomiting, or early seizure); or
   2. Dysmorphic or coarse features; or
   3. Evidence of intellectual developmental disorder; or
   4. Intellectual developmental disorder cannot be ruled out; or
   5. Occurrence or adequacy of newborn screening for a birth defect is questionable; or
   6. History of developmental regression.
8. Sleep-deprived EEG study only if the child exhibits any of the following conditions:
   1. Clinical seizures; or
   2. High suspicion of subclinical seizures; or
   3. Symptoms of developmental regression (clinically significant loss of social and communicative function) at any age, but especially in toddlers and pre-schoolers.

Not Medically Necessary:

The following tests/tools are considered not medically necessary for the assessment of ASDs and Rett syndrome:

1. Allergy testing (including but not limited to food allergy for gluten, casein, Candida, and other molds).
2. Erythrocyte glutathione peroxides studies.
3. Event-related brain potentials (other than frequency-specific brainstem auditory evoked response, as noted above).
4. Hair analysis for trace elements.
5. Intestinal permeability studies.
6. Stool analysis.
7. Tests for celiac antibodies.
8. Tests for immunologic or neurochemical abnormalities.
9. Tests for metabolic markers in the blood, urine, tissue, or other biologic materials (also known as metabolomics), including but not limited to Amino Acid Dysregulation Metabotype (ADDM) testing.
10. Tests for micronutrients such as vitamin levels.
11. Tests for mitochondrial disorders including lactate and pyruvate.
12. Tests for urinary peptides.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for situations designated in the Clinical Indications section as not medically necessary, including the following services

In May 2013, the American Psychiatric Association (APA) released the 5^th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). This edition of the DSM includes several significant changes over the previous edition, including combining several previously separate diagnoses under the single diagnosis of “autism spectrum disorder” (ASD). This diagnosis included the following disorders, previously referred to as: atypical autism, Asperger’s disorder, childhood autism, childhood disintegrative disorder, early infantile autism, high-functioning autism, Kanner’s autism, and pervasive developmental disorder not otherwise specified. All of these conditions are now considered under one diagnosis, ASD. It should be noted that Rett syndrome is not included in the new DSM-5 ASD diagnostic group but is included in this discussion due to similar condition presentations and diagnostic work up.

The DSM-5 described the essential diagnostic features of autism spectrum disorders as both a persistent impairment in reciprocal social communication and restricted and repetitive patterns of behavior, interest or activities. These attributes are present from early childhood and limit or impair everyday functioning. Parents may note symptoms as early as infancy, and the typical age of onset is before 3 years of age. Symptoms may include problems with using and understanding language; difficulty relating to or reciprocating with people, objects, and events; lack of mutual gaze or inability to attend events conjointly; unusual play with toys and other objects; difficulty with changes in routine or familiar surroundings, and repetitive body movements or behavior patterns. Children with childhood disintegrative disorder are an exception to this description, in that they exhibit normal development for approximately 2 years followed by a marked regression in multiple areas of function.

Children with ASD vary widely in abilities, intelligence, and behaviors. Some children do not speak at all, others speak in limited phrases or conversations, and some have relatively normal language development. Repetitive play skills, resistance to change in routine and inability to share experiences with others, and limited social and motor skills are generally evident. Unusual responses to sensory information, such as loud noises and lights, are also common. Children unaffected by ASDs can exhibit unusual behaviors occasionally or seem shy around others sometimes without having ASD. What sets children with ASD apart is the consistency of their unusual behaviors. Symptoms of the disorder have to be present in all settings, not just at home or at school, and over considerable periods of time. With ASD, there is a lack of social interaction, impairment in nonverbal behaviors, and a failure to develop normal peer relations. A child with an ASD tends to ignore facial expressions and may not look at others; other children may fail to respect interpersonal boundaries and come too close and stare fixedly at another person.

The exact causes of autism are unknown, although genetic factors are strongly implicated. A study released by the Center for Disease Control and Prevention (2014) indicates that the incidence of ASD was as high as 1 in 68.

In 2014, the American Academy of Child and Adolescent Psychiatry (AACAP) published their practice parameter for the assessment and treatment of children and adolescents with ASDs. They made the following recommendations for the assessment of children with ASDs:

• Recommendation 1. The developmental assessment of young children and the psychiatric assessment of all children should routinely include questions about ASD symptomatology [CS].
• Recommendation 2. If the screening indicates significant ASD symptomatology, a thorough diagnostic evaluation should be performed to determine the presence of ASD [CS].
• Recommendation 3. Clinicians should coordinate an appropriate multidisciplinary assessment of children with ASD [CS].

These recommendations are based on “clinical standard” or “CS”, which they state is applied to recommendations based on rigorous empirical evidence and/or overwhelming clinical consensus.

ASDs are felt to be a heterogeneous group of disorders arising from a variety of different genetic, metabolic and environmental factors. There have been many different tests proposed for the assessment of ASDs, including allergy testing, stool analysis, antibody testing, testing for immunologic or neurochemical abnormalities, testing for metabolic markers (metabolomics), evaluation of micronutrients, and others. Currently, there are no reliable diagnostic biomarkers for ASD although a variety are under study. There appear to be different biological forms of ASD for which different diagnostic and treatments strategies will be needed.

One type of metabolic testing under investigation looks for dysregulation of branch chain amino acid metabolism (Smith, 2019). The purpose of this study was to determine if detection of dysregulation of branch chain amino acids using the NeuroPointDX test (Stemina Biomarker, Inc.; Madison, Wisconsin) may explain the behavioral characteristics of ASD. Dysregulation of amino acid metabolism was identified by comparing plasma metabolites from 516 children with ASD with those from 164 unaffected age-matched children recruited into the CAMP study. Subjects were stratified into subpopulations based on shared metabolic phenotypes (metabotypes) associated with branch chain amino acid (BCAA) dysregulation. The authors reported that they identified groups of amino acids that were negatively correlated with branch chain amino acid levels in ASD. Imbalances between these two groups of amino acids identified three ASD associated Amino Acid Dysregulation Metabotypes (AADM). The combination of glutamine, glycine, and ornithine AADMs identified dysregulation in branch chain amino acid metabolism in 16.7% of the CAMP ASD subjects. The investigators do caution that the specificity of ADDM for ASD is unclear and that further longitudinal studies are needed to determine if AADMs are stable over time.

The investigators propose the results of the CAMP study provide a mechanism for stratifying children with ASD and may enable a more targeted approach to understanding the etiology of specific subsets of individuals with ASD. They concluded that identification of these metabotypes may potentially result in an earlier diagnosis and targeted therapeutic interventions for a subset of individuals with ASD. However, further study is needed to establish the clinical utility of amino acid dysregulation metabotype testing in the diagnosis and treatment of ASDs.

The specific DSM-5 diagnostic criteria for ASD are provided below:

DSM-5 Criteria for Autism Spectrum Disorder*

Diagnostic criteria

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 DSM- 5 text);
   1. 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.
   2. 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 communications.
   3. Deficits in developing, maintaining and understanding relationships, ranging, for example, from difficulties adjusting behavior to suit various social context; to difficulties in sharing imaginative play or in making friends; to absence of interest in peers.
      Specify current severity:
      Severity is based on social communication impairments and restricted, repetitive patterns of behavior (See table 2).
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);
   1. Stereotyped or repetitive motor movements, use of objects, or speech (e.g., simple motor stereotypes, lining up toys or flipping objects, echolalia, idiosyncratic phrases).
   2. 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).
   3. 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.
   4. Hyper- or hypoactivity to sensory inputs 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 or objects, visual fascination with lights or movement).
      Specify current severity:
      Severity is based on social communication impairments and restricted, repetitive patterns of behavior (See table 2).
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 learning 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.

Note: Individuals with a well-established DSM-IV diagnosis of autistic disorder, Asperger’s disorder, or pervasive developmental disorder not otherwise specified should be given the diagnosis of autism spectrum disorder. Individuals who have marked deficits in social communication, but whose symptoms do not otherwise meet criteria for autism spectrum disorder, should be evaluated for social (pragmatic) communication disorder.

Specify current severity:

With or without accompanying intellectual impairment
With or without accompanying language impairment
Associated with a known medical or genetic condition or environmental factor (Coding note: Use additional code to identify the associated medical or genetic condition)
Associated with another neurodevelopmental, mental, or behavioral disorder (Coding note: Use additional code[s] to identify the associated neurodevelopmental, mental, or behavioral disorder)
With catatonia (refer to the criteria for catatonia associated with another mental disorder, pp. 119-120 for definition). (Coding note: Use additional code 293.89 [F06.1] catatonia associated with autism spectrum disorder to indicate the presence of the comorbid catatonia)

* From: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. DSM-5. American Psychiatric Association. Washington, DC. May 2013. Page 50-51.

*From: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. DSM-5. American Psychiatric Association. Washington, DC. May 2013. Page 52.

Rett syndrome is a disorder of the nervous system that leads to regression in development, especially in the areas of expressive language and hand use. In most cases, it is caused by a genetic mutation on the X chromosome in the gene that contains instructions for creating methyl-CpG-binding protein 2 (MeCP2). Rett syndrome may be misdiagnosed as autism or cerebral palsy.

A child affected with Rett syndrome normally follows a standard developmental path for the first 5 months of life. After that time development in communication skills and motor movement in the hands seems to stagnate or regress. After a short period, stereotyped hand movements, gait disturbances, and slowing of the rate of head growth become apparent. Other problems may also be associated with Rett syndrome, including seizures, disorganized breathing patterns while awake and apraxia/dyspraxia (the inability to program the body to perform motor movements). Apraxia/dyspraxia is a key symptom of Rett syndrome and it results in significant functional impairment, interfering with body movement, including eye gaze and speech.

Asperger's Syndrome: A developmental disorder that affects the parts of the brain that control social interaction and communications.

Assessment instruments: Specialized and standardized diagnostic test used to evaluate an individual’s performance in specific areas of functioning (for example, learning and communications skills, social interaction, etc.). Examples of this type of instrument include Verbal Behavior Milestones Assessment and Placement Program (VB-MAPP), the Vineland Adaptive Behavior Scale, the Autism Diagnostic Interview-Revised (ADI-R), the Gilliam Autism Rating Scale - Second Edition (GARS-2), etc.

Autism Spectrum Disorders: A collection of associated developmental disorders that affect the parts of the brain that control social interaction and verbal and non-verbal communication.

Childhood Disintegrative Disorder: A developmental disorder characterized by marked regression in multiple areas of functioning following a period of at least 2 years of apparently normal development.

Dysmorphic: A characteristic that is abnormally formed.

Echiolaic: A symptom of some medical conditions characterized by an individual repeating things they hear.

Pica: A symptom of some medical conditions characterized by eating earth, clay or chalk.

Rett syndrome: A developmental disorder that affects the parts of the brain that control social interaction, communications, and motor function.

Peer Reviewed Publications:

1. Smith Am, King JJ, West PR, et al. Amino acid dysregulation metabotypes: potential biomarkers for diagnosis and individualized treatment for subtypes of autism spectrum disorder. Biological Psychiatry. 2019; 85 (4): 345-354.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. DSM-5. Washington, DC. May 2013.
2. Centers for Disease Control and Prevention. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2010. Morbidity and Mortality Weekly Report (MMWR). 2014; 3(SS02):1-21.
3. Filipek PS, Accardo PJ, Ashwal S, et al. American Academy of Neurology and the Child Neurology Society. Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society. Neurology. 2000; 55(4):468-479. Guideline-reaffirmed 07/28/2006.
4. Shevell M, Ashwal S, Donley D, et al. Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2003; 60(3):367-380. Guideline reaffirmed 10/15/2005.
5. Volkmar F, Siegle M, Woodbury-Smith M, et al.; American Academy of Child and Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI). Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry, 2014; 53(2):237-257.

Asperger’s Syndrome
Autism
Autism Spectrum Disorder
NeuroPointDX
Pervasive Developmental Disorder (PDD)