0648 Autism Spectrum Disorders (3)...Autism Spectrum Disorders - Medical Clinical Policy B ulletins...
Transcript of 0648 Autism Spectrum Disorders (3)...Autism Spectrum Disorders - Medical Clinical Policy B ulletins...
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Autism Spectrum Disorders
Number: 0648
Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.
I. Aetna considers autism spectrum disorder (ASD)
evaluation and diagnosis medically necessary when
developmental delays or persistent deficits in social
communication and social interaction across multiple
contexts have been identified and when the evaluation
is performed by the appropriate certified/licensed
health care professional.
The following services may be included in the assessment
and treatment of the member's condition:
A. ASD specific developmental evaluation
B. Cognitive and adaptive behaviors evaluations
C. Speech, language and comprehensive communication evaluation by speech-language pathologist.
D. Formal audiological hearing evaluation i ncluding frequency-specific brainstem auditory evoked response
(see
CPB 0181 - Evoked Potential Studies
(../100_199/0181.html)
or otoacoustic emissions.
Policy History
Last Review
06/08/2020
Effective: 09/17/2002
Next
Review: 07/22/2021
Review History
Definitions
Ad d i t ion al Information
Clinical Policy Bulletin
Notes
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E. Measurement of blood lead level if the child exhib i ts
developmental delay and pica, or lives in a high-risk
environment
(see CPB 0553 - Lead Testing (../500_599/0553.html)).
Additional periodic lead screening can be considered if
the pica persists.
F. Genetic testing specifically high resolution chromosome
analysis (karyotype) and DNA analysis for fragile X
syndrome in the presence of mental retardation (or if
mental retardation can not be excluded) if there is a
family history of fragile X or mental retardation of
undetermined etiology, or if dysmorphic features are
present
(see CPB 0140 - Genetic Testing (../100_199/0140.html)).
G. Comparative genomic hybridization (CGH), when
medical necessity criteria are met in
CPB 0787 - Comparative Genomic Hybridization
(../700_799/0787.html)
.
H. Medical evaluation (complete medical history and
physical examination, including neurologicevaluation).
I. Parent and/or child interview (including siblings of
children with autism).
J. Quantitative plasma amino acid assays to detect
phenylketonuria.
K. Selective metabolic testing if the child exhibits any of
the following:
1. Clinical and physical findings suggestive of a
metabolic disorder
a. Cyclic vomiting, recurrent vomiting and
dehydration
b. Early seizure,
c. Lethargy;
d. Hearing impairment;
e. Hypotonia;
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f. Visual impairment; or
g. Unusual odor; or
2. Dysmorphic or coarse features; or
3. Evidence of mental retardation or mental retardation
can not be ruled out; or
4. Occurrence or adequacy of newborn screening
for a birth defect is questionable.
L. Genetic counseling for parents of a child with autism
(see
CPB 0189 - Genetic Counseling
(../100_199/0189.html)
M. Electroencephalogram (EEG) for clinical spells that
might represent seizures.
N. Physical therapy (PT) and/or occupational therapy
(OT) evaluations for sensorimotor deficits.
O. 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.
P. Video-EEG when criteria are met in
CPB 0322 - Electroencephalographic (EEG) Video
Monitoring (../300_399/0322.html)
.
Q. Pharmacotherapy for management of co-
morbidities.
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Note: Coverage of pharmacotherapy is subject to the
member's specific benefits for drug coverage. Please
check benefit plan descriptions. Information on
pharmacotherapy options for autism can be found in
the Background section below.
R. Behavior modification, for management of
behavioral co-morbidities.
Note: Interventions for behavioral co-morbidities are
covered under the member's behavioral health
benefits. Please check benefit plan descriptions.
S. Intensive educational interventions* in which the
child is engaged in systematically planned and
developmentally appropriate educational activity
toward identified objectives, including services
rendered by a speech-language pathologist to
improve communication skills.
* Notes:
1. Many Aetna plans exclude coverage of
educational services. Speech therapy provided in
educational settings would be excluded under
these plans. Please check benefit plan
descriptions for details;
2. There is insufficient evidence for the superiority
of any particular intensive educational
intervention strategy (such as applied behavior
analysis, structured teaching, or developmental
models) over other intensive educational
intervention strategies. (see
CPB 0554 - Applied Behavior Analysis
(../500_599/0554.html)
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T. Alternative and augmentative communication aids
(e.g., sign language, flashcards, communication
boards, etc.) if demonstrated as effective for the
individual with PDD. Note : Some plans exclude
coverage of “communication aids.” Please check
benefit plan descriptions for details.
U. Physical and occupational therapy for co-morbid
physical impairments.
V. Medical therapy or psychotherapy, as indicated for
co-morbid medical or psychological conditions.
Note : Psychotherapy is covered under the member's
behavioral health benefits. Please check benefit plan
descriptions.
II. Aetna considers the following procedures and services
experimental and investigational because the peer-
reviewed medical literature does not support the use of
these procedures and services in the assessment and
treatment of autism and other pervasive developmental
disorders:
Assessment
A. Allergy testing (including food allergy for gluten, casein,
candida, and other molds; allergen specific IgG and
IgE)
B. Blood tests for metabolomic analyses (e.g., NPDX
ASD ADM Panel I by NeuroPointDX)
C. Celiac antibody testing
D. Ciliary neurotrophic factor (as a biomarker for ASD)
E. GABA receptor polymorphisms testing
F. Electronystagmography (in the absence of dizziness,
vertigo, or balance disorder)
G. Erythrocyte glutathione peroxidase studies
H. Event-related brain potentials
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I. Genetic panels other than CGH (e.g., the Fulgent ASD
panel, the Greenwood Genetic Center's Syndromic
Autism Panel, and the MitoMed-Autism Assay)
J. Genetic testing for COX10, DRD2, HTR2C, MTHFR,
RELN, SLC25A12 and UGT2B15 for diagnosis of
autism and other pervasive developmental disorders
and their drug treatment
K. Hair analysis for trace elements
(see CPB 0300 - Hair Analysis (../300_399/0300.html))
L. Homocysteine testing
CPB 0763 - Homocysteine Testing
(see (../700_799/0763.html) )
M. Intestinal permeability studies
N. Latent class analysis (for determination of psychosis-
related clinical profiles in children w ith autism spectrum
disorders)
O. Magnetoencephalography/magnetic source imaging
(see
CPB 0279 - Magnetic Source
Imaging/Magnetoencephalography
(../200_299/0279.html) )
P. Measurements of plasma oxytocin (OXT) and
vasopressin (VP) levels
Q. Measurements of plasma central carbon metabolites
(e.g., alpha-ketoglutarate, alanine, lactate,
phenylalanine, pyruvate, and succinate)
R. Micronutrients (ie, trace elements, trace minerals or
vitamin) level testing
S. Neuroimaging studies such as CT, functional MRI
(fMRI), MRI, MRS
(see
CPB 0202 - Magnetic Resonance Spectroscopy (MRS)
(../200_299/0202.html) ),
PET
(see
CPB 0071 - Positron Emission Tomography (PET)
(../1_99/0071.html) ),
and SPECT
(see
CPB 0376 - Single Photon Emission Computed
Tomography (SPECT) (../300_399/0376.html) )
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T. Nutritional testing (e.g., testing for arabinose and
tartaric acid)
U. Olfactory function testing
V. Provocative chelation tests for mercury
W. Saliva analysis (e.g., Clarifi ASD, Quadrant
Biosciences, Inc.)
X. Serum cytokine and growth factor levels
Y. Stool analysis
Z. Tests for amino acids (except quantitative plasma
amino acid assays to detect phenylketonuria), fatty
acids (non-esterified), organic acids, citrate, silica,
urine vanillylmandelic acid
AA. Tests for glutamatergic candidate genes
AB. Tests for heavy metals (e.g., antimony, arsenic,
barium, beryllium, bismuth, mercury)
AC. Tests for immunologic or neurochemical abnormalities
AD. Tests for micronutrients such as vitamin levels
AE. Tests for mitochondrial disorders including lactate and
pyruvate
AF. Tests for single-nucleotide polymorphisms within the
OXT and VP receptor genes
AG. Tests for trace metals (e.g., aluminum, cadmium,
chromium, copper, iron, lead, lithium, magnesium,
manganese, nickel, selenium, zinc)
AH. Thyroid function testing
AI. Tympanometry (in the absence of hearing loss)
AJ. Urinary peptide testing
AK. Whole-exome sequencing
Note : Neuropsychological or psychological testing
(see
CPB 0158 - Neuropsychological and Psychological
Testing (../100_199/0158.html)
beyond standardized parent interviews and direct,
structured behavioral observation is rarely considered
medically necessary for the diagnosis of pervasive
developmental disorders.
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Treatment
A. Acupuncture
B. Anti-fungal medications (e.g., fluconazole, ketoconizole,
metronidazole, nystatin)
C. Anti-viral medications (e.g., acyclovir, amantadine,
famciclovir, isoprinosine, oseltamivir, valacyclovir)
D. Auditory integration training (auditory integration
therapy)
(see
CPB 0256 - Sensory and Auditory Integration Therapy
(../200_299/0256.html)
E. BioMat
F. Chelation Therapy
(see CPB 0234 - Chelation Therapy (../200_299/0234.html))
G. Cognitive rehabilitation
(see
CPB 0214 - Cognitive Rehabilitation
(../200_299/0214.html)
H. Electro-convulsive therapy (for the treatment of autistic
catatonia)
I. Elimination diets (e.g., gluten and milk elimination)
J. Facilitated communication
K. Emotion recognition training
L. Herbal remedies (e.g., astragalus, berberis, echinacea,
garlic, plant tannins, uva ursi)
M. Floor time therapy
N. GABAergic agents (e.g., acamprosate, arbaclofen,
and valproic acid)
O. Hippotherapy (See
CPB 0151 - Hippotherapy (../100_199/0151.html))
P. Holding therapy
Q. Immune globulin infusion
R. Manipulative therapies
S. Massage therapy
T. Music therapy and rhythmic entrainment interventions
U. Memantine
V. Neurofeedback/EEG biofeedback
(see CPB 0132 - Biofeedback (../100_199/0132.html))
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W. Nutritional supplements (e.g., dimethylglycine,
glutathione, magnesium, megavitamins, omega-3 fatty
acids, and high-dose pyridoxine)
X. Nutritional therapy (e.g., casein-free and gluten-free
diets, ketogenic and modified Atkins diets)
Y. Oxytocin
Z. Prebiotic / probiotic therapy
AA. Quantum Reflex Integration
AB. Secretin infusion
AC. Sensory integration therapy
(see
CPB 0256 - Sensory and Auditory Integration Therapy
(../200_299/0256.html)
AD. Stem cell transplantation
AE. Systemic hyperbaric oxygen t herapy (see
CPB 0172 - Hyperbaric Oxygen Therapy (HBOT))
(../100_199/0172.html)
AF. Tomatis sound therapy
AG. Transcranial direct current stimulation
AH. Vestibular stimulation
AI. Vision therapy
(see CPB 0489 - Vision Therapy (../400_499/0489.html))
AJ. Vitamins and minerals (calcium, germanium,
magnesium, manganese, selenium, tin, tungsten,
vanadium, zinc, etc.).
AK. Weighted blankets or vests.
Background
Autism spectrum disorders (ASD) are a group of biologically
based chronic neurodevelopmental disorders characterized by
impairments in two major domains: (i) deficits in social
communication and social interaction and restricted
repetitive patterns of behavior, interests and activities. The
exact cause is unknown, but is believed to have many factors,
including a strong genetic component.
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Signs and symptoms of ASD generally appear prior to three
years of age and include difficulties with language, deficient
social skills and restricted or repetitive body movements and
behaviors. Autism and other autism spectrum disorders
(ASD) may be suspected by the following symptoms: any loss
of any language or social skills at any age; no 2-word
spontaneous (not just echolalic) phrases by 24 months; no
babbling by 12 months; no gesturing (e.g., pointing, waving
bye-bye) by 12 months; or no single words by 16 months.
Autism spectrum disorders (ASD) include autism, Rett
syndrome, childhood disintegrative disorder and Asperger’s
syndrome, and are chronic life-long conditions. Autism has
been estimated to affect approximately 1 in 1,000 children in
the United States, and other pervasive developmental
disorders have been estimated to affect approximately 2 in
1,000 children in the United States. Based on recent
prevalence estimates of 10 to 20 cases per 10,000 individuals,
between 60,000 and 115,000 children under the age of 15
years meet diagnostic criteria for autism.
There is no cure for ASD. However, there is a consensus that
treatment must be individualized depending upon the speci f ic
strengths, weaknesses and needs of the child and family.
Early diagnosis and early intensive treatment have the
potential to affect outcome, particularly with respect to
behavior, functional skills and communication. There is
increasing evidence that intervention is more effective when
initiated as early as possible.
Diagnosis and treatment of ASD may involve a variety of tools.
Developmental screening, usually performed during a routine
well child exam, identifies atypical (unusual) behaviors such as
social, interactive and communicative behaviors that are
delayed, abnormal or absent. Once identified, a
comprehensive multidisciplinary assessment is recommended
in order to make an accurate and appropriate diagnosis.
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Appropriate certified/licensed healthcare professionals for
evaluation and management of autism include the following:
board certified behavioral analyst; developmental
pediatrician; neurologist; occupational therapist; physical
therapist; primary care provider; psychiatrist; psychologist; or
speech-language pathologist and audiologist.
According to the American Academy of Neurology (AAN)'s
practice parameter, Screening and Diagnosis of Autism
(Filipek et al, 2000), autism is characterized by severe
deficiencies in reciprocal social interaction, verbal and non-
verbal communication, and restricted interests. It usually
commences before the age of 3 years and lasts over the
whole lifetime. Early signs that distinguish autism from other
atypical patterns of development include poor use of eye gaze,
lack of gestures to direct other people's attention (especially to
show things of interest), decreased social responsiveness, and
lack of age-appropriate play with toys (especially imaginative
use of toys). A typical symptom of autism is absence of
speech development, observed from infancy, taking the form
of complete mutism at later stages. It has been emphasized
that most pathological symptoms of autism result from altered
perception of external stimuli, which arouse fear and anxiety.
Currently, there are no biological markers for autism and there
is no proven cure for this disorder.
Because there are no biological markers for autism, screening
must focus on behavior. Studies comparing autistic and
typically developing children demonstrated that problems with
eye contact, orienting to one’s name, joint attention, pretend
play, imitation, non-verbal communication, and language
development are measurable by 18 months of age. These
symptoms are stable in children from toddler age through
preschool age. Retrospective analysis of home videotapes
also has identified behaviors that distinguish infants with
autism from other developmental disabilities as early as 8
months of age.
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Current screening methods may not identify children with
milder variants of autism, those without mental retardation or
language delay, such as verbal individuals with high-
functioning autism and Asperger’s disorder, or older children,
adolescents, and young adults.
There are relatively few appropriately sensitive and specific
autism screening tools for infants and toddlers, and this
continues to be the current focus of many research centers.
The Checklist for Autism in Toddlers (CHAT) for 18-month-old
infants, and the Autism Screening Questionnaire for children 4
years of age and older, have been validated on large
populations of children. However, it should be noted that the
CHAT is less sensitive to milder symptoms of autism, as
children later diagnosed with PDD-NOS, Asperger’s, or
atypical autism did not yield positive results on the CHAT at 18
months.
The AAN’s practice parameter noted that specific
neuropsychological impairments can be identified, even in
young children with autism, that correlate with the severity of
autistic symptoms. Performance on tasks that rely on rote,
mechanical, or perceptual processes are typically spared;
deficient performance exists on tasks requiring higher-order
conceptual processes, reasoning, interpretation, integration, or
abstraction. Dissociations between simple and complex
processing are reported in the areas of language, memory,
executive function, motor function, reading, mathematics, and
perspective-taking. However, there is no reported evidence
that confirms or excludes a diagnosis of autism based on
these cognitive patterns alone.
The AAN’s practice parameter recommended that diagnosis of
autism should include the use of standardized parent
interviews regarding current concerns and behavioral history
related to autism, and direct, structured observation of social
and communicative behavior and play. Recommended
instruments for parental interviews include the Gilliam Autism
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Rating Scale, Parent Interview for Autism,Pervasive
Developmental Disorders Screening Test–Stage 3, and Autism
Diagnostic Interview–Revised. Recommended instruments for
observation include the Childhood Autism Rating Scale,
Screening Tool for Autism in Two-Year-Olds, and Autism
Diagnostic Observation Schedule-Generic. The AAN practice
parameter did not recommend that neuropsychological testing
be used for the diagnosis of autism, but insteadshould be
performed as needed, in addition to a cognitive assessment, to
assess social skills and relationships, educational functioning,
problematic behaviors, learning style, motivation and
reinforcement, sensory functioning, and self-regulation.
Similarly, the American Academy of Child And Adolescent
Psychiatry (AACAP)’s practice parameter for the assessment
and treatment of autism recommended neuropsychological
testing only when the clinical context indicates that it may be
helpful. Psychological testing is recommended in the AACAP
practice parameter to assess for cognitive and intellectual
functioning, in order to determine eligibility and plan for
educational and other services.
Mental retardation (IQ less than 70) is associated with 70 % of
cases of autism and seizures with 33 % of cases.
Furthermore, the recurrence risk for siblings is about 3 to 5 %,
corresponding to an incidence 75 times greater than that in the
general population. These features, in conjunction with the
increased number of male patients (3:1 male:female ratio),
suggest a genetic predisposition. On the other hand, parallel
evidence of immune abnormalities in autistic patients argues
for an implication of the immune system in pathogenesis.
Additionally, some neurological disorders such as tuberous
sclerosis, neurofibromatosis, fragile X syndrome, Rett
syndrome and phenylketonuria may also be associated with
autistic features. In these cases, autism is defined as
"secondary".
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The AAN's practice parameter Screening and Diagnosis of
Autism (Filipek et al, 2000) recommended genetic testing in
children with autism, specifically high resolution chromosome
analysis (karyotype) and DNA analysis for fragile X syndrome
in the presence of mental retardation (or if mental retardation
can not be excluded), if there is a family history of fragile X or
undiagnosed mental retardation, or if dysmorphic features are
present. However, there is little likelihood of positive karyotype
or fragile X testing in high-functioning autism.
An assessment prepared for the Agency for Healthcare
Research and Quality (Sun, et al., 2015) on genetic testing for
developmental disability, intellectual disability and autism
spectrum disorders concluded that "little evidence from
controlled studies exists to directly link genetic testing to health
outcomes. Published studies have reported superior
diagnostic yields of newer genetic tests (e.g., aCGH) in
identifying DD-related genetic abnormalities, and some have
identified the impact of the tests on medical management
(e.g., medical referrals, diagnostic imaging, further laboratory
testing). However, these findings are not sufficient for drawing
a conclusion that use of the tests will lead to improved health
outcomes....."
The AAN (Filipek et al, 2000) recommended selective
metabolic testing if the child exhibits clinical and phy sical
findings suggestive of a metabolic disorder such as (i)
lethargy, cyclic vomiting, or early seizure, or (ii) dysmorphic
or coarse features, or (iii) evidence of mental retardation, or
(iv) mental retardation can not be ruled out, or (v)
occurrence or adequacy of newborn screening for a birth
defect is questionable. The AAN also recommended lead
screening if the child exhibits developmental delay and pica.
Epileptiform abnormalities on electroencephalography (EEG)
are common in children with autism spectrum disorders
(ASDs), with reported frequencies ranging from 10 % to 72 %
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(AAP, 2007). Some studies have suggested that epileptiform
abnormalities on EEG and/or epilepsy are more common in
the subgroup of children with ASDs who have a history of
regression, whereas other studies have not demonstrated this
association. Autistic regression with epileptiform abnormalities
on EEG has been compared by analogy with Landau-Kleffner
syndrome and electrical status epilepticus in sleep, but there
are important differences between these conditions, and the
treatment implications are unclear (AAP, 2007). Whether
subclinical seizures have adverse effects on language,
cognition, and behavior is debated, and there is no evidence-
based recommendation for the treatment of children with ASDs
and epileptiform abnormalities on EEG, with or without
regression. A report from the American Academy of Pediatrics
(AAP, 2007) states that universal screening of patients with
ASDs by EEG in the absence of a clinical indication is not
currently supported. The report states, however, that because
of the increased prevalence of seizures in this population, a
high index of clinical suspicion should be maintained, and EEG
should be considered when there are clinical spells that might
represent seizures.
Localized structural and functional brain correlates of PDD
have yet to be established. Structural neuroimaging studies
performed in autistic patients have reported abnormalities
such as increased total brain volume and cerebellar
abnormalities. However, none of these abnormalities fully
account for the full range of autistic symptoms. Functional
neuroimaging has demonstrated temporal lobe abnormalities
and abnormal interaction between frontal and parietal brain
areas. However, the value of functional neuroimaging such as
positron emission tomography (PET), single photon emission
computed tomography (SPECT) and functional magnetic
resonance imaging (fMRI) in diagnosing autism has not been
established. Functional neuroimaging techniques are at the
early stage of identifying abnormalities at the neurotransmitter
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and systems levels. Further studies with well-defined patient
populations and appropriate activation paradigms will better
elucidate the pathophysiology of this disorder.
The AAN (Filipek et al, 2000) stated that there is no clinical
evidence to support the role of routine clinical neuroimaging
(CT, MRI, PET SPECT, and fMRI) in the diagnostic evaluation
of autism, even in the presence of megalocephaly.
Additionally, the AAN stated that there is insufficient evidence
to recommend EEG studies in all individuals with autism.
Sleep-deprived EEG study may be performed if (i) the patient
has clinical seizures or suspicion of subclinical seizures; or
(ii) a history of regression (clinically significant loss of social
and communicative function) at any age, but especially in
toddlers and pre-schoolers. Moreover, the AAN considered
event-related potentials and magnetoencephalography to be
research tools, which have no evidence of routine clinical utility
(Filipek et al, 2000).
Philip and colleagues (2012) stated that recent years have
seen a rapid increase in the investigation of ASD through the
use of fMRI. These investigators performed a systematic
review and ALE meta-analysis of fMRI studies of ASD. A
disturbance to the function of social brain regions is among the
most well replicated finding. Differences in social brain
activation may relate to a lack of preference for social stimuli
as opposed to a primary dysfunction of these regions.
Increasing evidence points towards a lack of effective
integration of distributed functional brain regions and
disruptions in the subtle modulation of brain function in relation
to changing task demands in ASD. The authors stated that
limitations of the literature to date include the use of small
sample sizes and the restriction of investigation to primarily
high-functioning males with autism.
The AAN (Filipek et al, 2000) also found inadequate
supporting evidence of the following procedures in the
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management of autism: (i) allergy testing (especially food
allergy for gluten, casein, candida, and other molds), (ii)
erythrocyte glutathione peroxidase studies, (iii) hair
analysis, (iv) intestinal permeability studies, (v) stool
analysis, and (vi) tests for celiac antibodies, immunologic or
neurochemical abnormalities, micronutrients such as
vitamin levels, mitochondrial disorders including lactate
and pyruvate, thyroid function, and urinary peptides.
Hair Analysis is a test in which a sample of an individual's hair,
typically from the back of the neck, is sent to a laboratory for
measurement of its mineral content. The AAN (Filipek et al,
2000) found inadequate supporting evidence for hair analysis
for treatment of autism.
Autistic patients may suffer from gastrointestinal disturbances
such as abdominal pains, diarrhea, and the so-called leaky-gut
syndrome. Secretin, a hormone produced by the pancreas to
stimulate the production of gastric juices, has been used to aid
digestion before intestinal biopsy or endoscopy. Secretin is a
hormone made in the duodenum which causes the stomach to
make pepsin, the liver to make bile and the pancreas to make
a digestive juice. Early case studies suggested that secretin
improved gastrointestinal symptoms as well as behavior, eye
contact, alertness, and expressive language in autistic
children. However, such claims are not borne out by recent well-
designed studies.
A randomized, double blind, placebo-controlled, cross-over
study (Corbett et al, 2001) investigated the effect of a single
intravenous dose of porcine secretin on autistic children. The
authors found that significant differences were not observed
on the majority of the dependent variables. Statistically
significant differences were observed on measures of positive
affect and activity level following secretin infusion. In general,
autistic children did not demonstrate the improvements
described in the initial retrospective report. This is in
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agreement with the findings of Owley and colleagues (2001)
who reported that there was no evidence for efficacy of
secretin in a multi-center, randomized, placebo-controlled,
double-blind trial. In a single-blinded, prospective, open-label
study, Lightdale and associates (2001) reported that
intravenous secretin had no effects in a 5-week period on the
language and behavior of 20 children with autism and
gastrointestinal symptoms.
The National Academy of Sciences (NAS) (2001) has stated
that there is no known cure for autism, and that “[e]ducation,
both directly of children, and of parents and teachers, is
currently the primary form of treatment for autistic spectrum
disorders.” The National Academy of Sciences recommends
that educational services begin as soon as a child is
suspected of having autistic spectrum disorder, and that those
services should include a minimum of 25 hours a week, 12
months a year, in which the child is engaged in systematically
planned and developmentally appropriate educational activity
toward identified objectives. Brasic (2003) has stated that,
while parents may choose to utilize a variety of experimental
treatments including medication, they should concurrently
utilize intensive individual special education by an educator
familiar with instructing children with autistic disorder and
related conditions.
The NAS report concluded that “there is little evidence
concerning the effectiveness of discipline-specific therapies,
and there are no adequate comparisons of different
comprehensive treatments. However, there is substantial
research supporting the effectiveness of many specific
therapeutic techniques and of comprehensive programs in
contrast to less intense, nonspecific interventions.” “The
consensus across programs is generally strong concerning the
need for: early entry into an intervention program; active
engagement in intensive instructional programming for the
equivalent of a full school day, including services that may be
offered in different sites, for a minimum of 5 days a week with
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full-year programming; use of planned teaching opportunities,
organized around relatively brief periods of time for the
youngest children (e.g., 15- to 20-minute intervals); and
sufficient amounts of adult attention in one-to-one or very
small group instruction to meet individualized goals.”
The NAS report concluded that functional communication
training has been shown to be effective in treatment of autism:
“There is strong empirical support for the efficacy of functional
communication training to replace challenging behaviors. This
approach includes a functional assessment of the particular
behavior to determine its function for a child (e.g., desire for
tangible or sensory item, attention, or to escape a situation or
demand) and teaching communication skills that serve
efficiently and effectively as functional equivalents to
challenging behaviors, a method that has been documented to
be the most effective for reductions in challenging behavior
(Horner et al, 1990; see Horner et al, 2000).”
The NAS report also concluded that there is evidence to
support the use of augmentative and alternative
communication strategies (AAC) in children with autism. “For
children with autism who do not acquire functional speech or
have difficulty processing and comprehending spoken
language, augmentative and alternative communication (AAC)
and assistive technology (AT) can be useful components of an
educational program.” “AAC is defined as ’an area of clinical
practice that attempts to compensate (either temporarily or
permanently) for the impairment and disability patterns of
individuals with severe expressive communication
disorders’ (American Speech-Language-Hearing Association,
1989). AAC may involve supporting existing speech or
developing independent use of a non-speech symbol system,
such as sign language, visual symbols (pictures and words)
displayed on communication boards, and voice output devices
with synthesized and digitized speech. AT is any commercial,
hand-made, or customized device or service used to support
or enhance the functional capabilities of individuals with
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disabilities. AT includes computer-assisted instruction,
mobility devices, high and low technology adaptations and
AAC.”
A structured evidence assessment of interventions in
alternative and augmentive communication (ACC) (training to
compensate for the impairment and disability patterns) in
persons with severe expressive communication disorders
(including autism, mental retardation, and other disabilities)
concluded that ACC interventions are effective in terms of
behavior change, generalization, and, to a lesser degree,
maintenance (Schlosser and Lee, 2000).
A number of discipline-specific intensive intervention programs
have been advocated for the treatment of autism, including
Lovaas therapy, the Rutgers Program, the LEAP Program, the
Denver Program, the Autism Pre-school Program, and
TEACCH Program. The objectives of treatment are to improve
the child's early social communication and social interaction
skills, leading to the potential development of play and
flexibility of behavior. The NAS (2001) concluded that,
although there is substantial research supporting the
effectiveness of comprehensive programs in contrast to less
intense, non-specific interventions, “there is little evidence
concerning the effectiveness of discipline-specific therapies,
and there are no adequate comparisons of different
comprehensive treatments.”
Lovaas therapy is a method of early behavioral intervention for
the treatment of PDD. It entails the employment of intensive
teaching techniques designed to reinforce appropriate social
behaviors in children with autism and related disorders. Every
task (trial) consists of a directive to the patient, a response
from the patient, and a reaction from the therapist. The patient
learns to respond in a manner that generates reinforcement
reaction from the therapist. Lovaas therapy is usually
practiced 30 to 40 hours a week.
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Lovaas therapy was based on a study by Lovaas published in
1987; however, the study had several problems which include
(i) choice of outcome measure, (ii) criteria for subject
selection and the intellectual level of the subjects, and (iii)
method for assigning subjects to control groups. These
methodological problems made it difficult to ascertain the
effects of early behavioral intervention on autistic children.
Recent reviews suggested that there is no available treatment
that meets criteria for well-established or probably efficacious
treatment; and that more research is needed to refine current
behavioral treatment approaches.
Delprato (2001) compared discrete trial training (Lovaas
Therapy) and normalized behavioral language intervention for
young children with autism. The author reported that in
studies with language criterion responses, normalized
language training was more effective than discrete trial
training. Furthermore, in studies that assessed parental affect,
normalized treatment yielded more positive affect than discrete
trial training.
Boyd and Corley (2001) reported the outcome survey of early
intensive behavioral intervention (EIBI) programs for young
children with autism in a community setting. Based on both
individual case reviews and parent questionnaires, they found
that these programs failed to support any instances of
"recovery", but yielded a high degree of parental satisfaction.
Moreover, a follow-up inquiry into the type of services each
child was receiving in his or her post-EIBI setting documented
continued dependence on extensive educational and related
developmental services, suggesting that the promise of future
treatment sparing did not materialize. The authors concluded
that there is a need for further research designed to document
the effectiveness of services provided to young children with
autism.
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The Alberta Heritage Foundation for Medical Research
(AHFMR) evaluated the effectiveness of intensive intervention
programs for children with autism (Ludwig and Harstall, 2001).
These programs range from strict operant discrimination
learning such as Lovaas therapy to broader applied behavior
analysis such as the Rutgers Program to more
developmentally oriented programs such as the Denver
Program and the Treatment and Education of Autistic and
Communication Handicapped Children (TEACCH) Program.
Furthermore, these treatment programs vary in their intensity
from 40 hours per week for Lovaas Therapy and the Rutgers
Program to a range of 15 hours per week for the LEAP
Program.
The evaluation by AHFMR was primarily based on the results
of 3 systematic evidence reviews, including those by ECRI
(2000) and the British Columbia Office of Health Technology
Assessment (BCOHTA) (Bassett, 2000). Two of the critical
findings of this assessment are as follows: (i) studies on
Lovaas therapy were methodologically flawed. ECRI
concluded that Lovaas Therapy appears to increase scores
on IQ tests and behavioral adaptation, at least in some
children with autism. However, given the designs and
methodological flaws of the studies, it could not be
determined if the changes in IQ and functional parameters
could be attributed to the Lovaas therapy. BCOHTA
concluded that the original Lovaas study as well as other
follow-up studies were still inadequate to establish the
degree to which this form of therapy resulted in "normal"
children, and (ii) there is insufficient evidence to establish a
relationship between amount (intensity and duration) of
any intensive intervention treatment program and
outcomes measures (intelligence tests, language
development, adaptive behavior tests).
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Smith (1999) evaluated the evidence supporting intensive
intervention programs for autism. Smith noted that most
reports of major gains made by children with autism have
“withered under scrutiny”. Smith emphasized the need to
validate the long-term benefits of these intervention programs.
Smith noted that most studies of specific intensive intervention
programs do not provide data on the children’s progress
following termination of treatment. Smith noted that this is a
critical omission because even if treatment is successful while
ongoing, the benefits may not be durable. Smith concluded
that methodological weaknesses in the research hinder us
from drawing conclusions from existing early intervention
studies.
An assessment of intensive intervention programs for autism
by the Canadian CoordinatingOffice for Health Technology
Assessment (CCOHTA) (McGahan, 2001) concluded that
“there are few published controlled primary studies regarding
the efficacy of behavioral interventions; most have
methodological flaws that make interpretation of results
difficult. Study design in this area could benefit from the
inclusion of an adequate control group and the application of
consistent outcome measures used for all children enrolled in
a study, administered by the same, blinded assessor at the
beginning and end of the study.”
In assessing the evidence supporting specific intensive
intervention programs for children with autism, the NAS (2001)
concluded that “[a]s a group, these studies show that intensive
early interventions with children with autistic spectrum
disorders makes a clinically significant difference for many
children …. However, each of the studies has methodological
weaknesses, and most of the reports were descriptive rather
than evaluations with controlled experimental research
designs. There are virtually no data on the relative merit of
one model over another, either overall or as related to
individual differences in children …. In sum, it appears that a
majority of children participating in comprehensive behavioral
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interventions made significant progress in at least some
developmental domains, although methodological limitations
preclude definitive attributions of that progress to specific
intervention procedures”.
A New Zealand Health Technology Assessment (Doughty,
2004) reviewed the conclusions of 5 recently published
systematic evidence reviews of intensive behavioral
interventions for autism-spectrum disorders. The assessment
found that all of these systematic evidence reviews draw
attention to the lack of well-conducted research on early
intervention for autism in young children. The assessment
found that all of the systematic evidence reviews reached the
same conclusion, that “to date there is insufficient evidence to
allow conclusions to be drawn about best practice.
Furthermore, researchers have yet to establish a relationship
between the amount (per day and total duration) of any form of
early comprehensive treatment programme and overall
outcome.” The New Zealand Health Technology Assessment
also reviewed recently published primary research on
intensive behavioral interventions for autism. The assessment
found that, despite the relatively large volume of studies
published and extent of interest of a variety of stakeholders in
the effectiveness of interventions for young children with
autism, only 5 primary studies published since 2000 met
selection criteria for relevance and methodological quality.
The assessment concluded that these studies provide
preliminary evidence suggesting that early intervention (note
this includes different types of behavioral intervention, across
different settings) may lead to selected gains in a number of
specific domains. The report concluded, however, that “further
research is required to address the methodological limitations
of existing studies and replicate their findings. In particular
studies with larger sample sizes (from multisite collaborations
using identical methods and outcome measures) are required
to provide greater statistical power and more precise estimates
of effectiveness.”
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A position statement on early intervention for autism from the
Canadian Paediatric Society (2004) reviewed the published
literature on intervention programs, and concluded that the
evidence for these programs is "weak" and "suboptimal".
More recently, an assessment by the Scottish Intercollegiate
Guidelines Network (SIGN, 2007) stated that "[a]ll studies
included in this review [of applied behavior analysis] were
marked by considerable methodological flaws and there was
also a concern that many had enrolled high functioning
children with autism, making it difficult to generalise from the
conclusions". The review concluded that a causal relationship
can not be established between a particular program of
intensive behavioral intervention and the achievement of
"normal functioning". SIGN concluded that "[t]he Lovaas
programme should not be presented as an intervention that
will lead to normal functioning". SIGN also noted that a
comprehensive literature search did not find any good quality
evidence for other intensive behavioral interventions.
A systematic evidence review and metanalysis
found inadequate evidence that applied behavior intervention
programs have better outcomes than standard care for
children with autism (Spreckley and Boyd, 2009). The authors
reviewed systematic reviews and randomized or
quasirandomized controlled trials of applied behavioral
interventions delivered to preschool children with autism
spectrum disorder. Quantitative data on cognitive, language,
and behavior outcomes were extracted and pooled for meta-
analysis. The authors reported that thirteen studies met the
inclusion criteria. Six of these were randomized comparison
trials with adequate methodologic quality. Meta-analysis of 4
studies concluded that, compared with standard care, applied
behavioral intervention programs did not significantly improve
the cognitive outcomes of children in the experimental group.
There was no additional benefit over standard care for
expressive language, for receptive language, or adaptive
behavior. The authors concluded that there is inadequate
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evidence that applied behavioral interventions have better
outcomes than standard care for children with autism. The
authors stated that appropriately powered clinical trials with
broader outcomes are required.
An special report on applied behavior analysis for autism
spectrum disorders by the BlueCross BlueShield Association
Technology Evaluation Center (BCBSA, 2009) found that the
strongest evidence of effectiveness came from 2 randomized
controlled clinical trials (Smith et al, 2000; Sallows and
Graupner, 2005); however, weaknesses in research design,
differences in the treatments and outcomes compared, and
inconsistent results mean that the impact of applied behavior
analysis versus other treatments on outcomes for children with
autism can not be determined. The report stated that, given
the lack of a definitive evidence on the relative effectiveness of
applied behavior analysis, one can not answer the question of
whether there are characteristics of children that predict a
greater likelihood of success. The assessment also stated that
the findings on whether more intense treatment leads to better
outcomes were inconsistent, and no conclusions can be
drawn.
The BlueCross BlueShield Association's special report on
"Early Intensive Behavioral Intervention Based on Applied
Behavior Analysis among Children with Autism Spectrum
Disorders" (2010) stated that overall, the quality and
consistency of results of this body of evidence are weak.
Consequently, no conclusions can be drawn from this
literature on how well early intensive behavioral intervention
(based on applied behavior analysis or ABA; hereafter referred
to as “EIBI”) works. Weaknesses in research design and
analysis, as well as inconsistent results across studies,
undermine confidence in the reported results. It is important to
distinguish between certainty about ineffectiveness and
uncertainty about effectiveness. Based on the weakness of
the available evidence, we are uncertain about the
effectiveness of EIBI for autism spectrum disorders (ASDs).
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Furthermore, the authors stated that the variability of
presentation and progression among children with ASDs, as
well as potential differences in delivery of behavioral
interventions, make this topic challenging to study.
Nevertheless, given the importance of caring for children with
ASDs, additional research is needed to identify those
characteristics of treatment -- content, technique, intensity,
starting and ending age, etc. -- that maximize its
effectiveness. Because of the challenges in launching a very
large randomized controlled trial (RCT) and the ethical
necessity to provide some treatment to the control group, this
body of research needs to be built piece by piece, with a
series of studies that investigate different components of the
larger research question. For this to be effective, however, the
overall quality of studies needs to be improved, including a
greater emphasis on RCTs, where at all possible; substantially
larger sample sizes; uniformity of outcomes evaluated and
instruments used to measure them; and consistent treatments
that do not vary widely within treatment groups (i.e.,
experimental or control group).
The cost of continuing the current course of assuming that
EIBI works may not be obvious. EIBI is costly financially for
society and requires a large time commitment from children,
their families, and their teachers or therapists. However, these
programs may not appear to pose any harm for the children
themselves. Nevertheless, the opportunity costs could be
high, indeed, of providing sub-optimal care to these children,
simply because we as a society do not know what works best.
The children may be treated with an intervention that is not as
effective as the alternatives. And if we accept an intervention
because it seems to work, without solid evidence, research on
the alternatives or on how it can be improved is likely to be
stifled.
Other interventions that have little or insufficient evidence of
effectiveness in the treatment of children with autism are
auditory integration training (also referred to auditory
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integration therapy, [AIT]), cognitive rehabilitation, facilitated
communication, gluten and milk elimination diets, holding
therapy, immune globulin therapy, music therapy, nutritional
supplements (e.g., megavitamins, high-dose pyridoxine and
magnesium, dimethylglycine), sensory integration therapy, and
vision therapy.
Facilitated Communication is a method of providing assistance
to a nonverbal individual by typing words using a typewriter,
computer keyboard or other communication device. An
assessment of interventions for autism conducted by the NAS
(2001) concluded that there is insufficient evidence of the
effectiveness of facilitated communication (FC) for autism.
The NAS report stated: “There are over 50 research studies of
FC with 143 communicators. Based on these research
studies, the American Speech-Language-Hearing Association
(1994) has stated that there is a lack of scientific evidence
validating FC skills and a preponderance of evidence of
facilitator influence on messages attributed to communicators
(ASHA Technical Report, 1994). Thus, there is now a large
body of research indicating that FC does not have scientific
validity.”
The AAP (2001) stated that available information does not
support the claims of proponents that FC is effective in the
treatment of autism, and considered it experimental. In a
review on autism, Levy and colleagues (2009) stated that
popular biologically based treatments include anti-infectives,
chelation medications, gastrointestinal medications, hyperbaric
oxygen therapy, off-label drugs (e.g., secretin), and
intravenous immunoglobulins. Non-biologically based
treatments include AIT, chiropractic therapy, cranio-sacral
manipulation, FC, interactive metronome, and transcranial
stimulation. However, few studies have addressed the safety
and effectiveness of most of these treatments.
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Chelation Therapy is treatment that aims at lowering levels of
mercury, lead or other heavy metals in the body. Medication is
taken on a regular schedule that chelates (binds with) the
metal to lessen its toxic effect on the body. In a review on
autism, Levy and colleagues (2009) found that few studies
have addressed the safety and effectiveness of chelation
therapy for autism
Sensory Integration Therapy is a method to improve the way
the brain processes and organizes external stimuli, such as
touch, movement, body awareness, sight and sound. The NAS
report (2001) concluded that there is insufficient evidence of
the effectiveness of sensory integration therapy for autism. By
focusing a child on play, sensory integration therapy
emphasizes the neurological processing of sensory
information as a foundation for learning of higher-level skills.
The goal is to improve subcortical (sensory integrative)
somatosensory and vestibular functions by providing
controlled sensory experiences to produce adaptive motor
responses. The hypothesis is that, with these experiences,
the nervous system better modulates, organizes, and
integrates information from the environment, which in turn
provides a foundation for further adaptive responses and
higher-order learning. The NAS report states, however, that
“[t]here is a paucity of research concerning sensory integration
treatments in autism …. These interventions have also not yet
been supported by empirical studies.” In addition, the AAP
(2001) stated that research data supporting the effectiveness
of sensory integration therapy in managing autistic children is
scant.
Vision therapy is a primarily optometric treatment method that
focuses on neurological and muscular function and the brain-
eye connection for developing efficient visual skills and
processing. Orthoptics is a component of vision therapy.
Orthoptics is therapy limited in scope to eye muscle training,
typically for straightening eye gaze so that both eyes appear to
be looking toward the same direction. After initial training, the
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individual performs the eye exercises at home. The NAS
concluded that there is insufficient evidence of the
effectiveness of vision therapy for autism. “A variety of visual
therapies (including oculomotor exercises, colored filters, i.e.,
Irlen lenses, and ambient prism lenses) have been used with
children with autism in attempts to improve visual processing
or visual spatial perception. There are no empirical studies
regarding the efficacy of the use of Irlen lenses or oculomotor
therapies specifically in children with autism …. As with
auditory integration therapy, studies have not provided clear
support for either its theoretical or its empirical basis.”
Other therapies involving sensory stimulation have insufficient
evidence of effectiveness for treatment of autism, including
holding therapy and vestibular stimulation. Holding Therapy is
a practice that consists of forced holding by a therapist or
parent until the child stops resisting, eye contact is made or a
fixed time period has elapsed. Vestibular Stimulation is the
input the body receives when experiencing movement or
gravity.
Bell (2004) assessed the evidence for the effectiveness of
music therapy for autism for the Wessex Institute for Health
Research and Development, and concluded that there is
insufficient evidence to support its use. The assessment
concluded that children with autism may demonstrate slight
improvements in speech and imitation during music therapy
sessions, but the clinical importance of these changes may be
negligible. The assessment found that the impact of music
therapy on behavior and social functioning is unclear, and the
long-term effects are uncertain. The assessment also stated
that it is unclear whether music therapy is better than other
forms of behavioral therapy for children with autism. The
assessment stated that these conclusions are limited by the
poor quality of the evidence, in particular the biased selection
of the children, the small numbers involved, the contamination
effect of the crossover design of many of the studies, the
uncertain relevance of many of the outcome measures and the
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short follow-up. The assessment concluded “[w]ithout further
research, no recommendation about the clinical effectiveness
of music therapy for autism can be made.”
The AAP stated that speech therapy and physical therapy play
important roles in the comprehensive, interdisciplinary
management of children with autistic spectrum disorder
(2001). An assessment by the National Initiative for Autism:
Screening and Assessment (NIASA) (National Autistic Society,
2003) stated that children with co-morbid specific
developmental disorders will require additional therapeutic
services. “These services include speech and language
therapy for augmented communication programmes,
physiotherapy and occupational therapy for visual perceptual
problems, fine and gross motor co-ordination difficulties
including with writing, unusual sensory responses, self-care
skills and provision of equipment and environmental
adaptations.” However, there is a lack of high-quality evidence
for speech/language therapy for autism. The evidence for the
effectiveness of speech/language therapy for autism is derived
from case reports, single-case research designs, small-scale
studies, and anecdotal reports.
Physical therapy for children with autistic spectrum disorders
focuses on developing strength, coordination and movement
(CARD, 2001). Therapists work on improving gross motor
skills, such as running, reaching, and lifting. This therapy is
concerned with improving function of the body's larger muscles
through physical activities including exercise and massage.
Occupational therapists commonly focus on improving fine
motor skills, such as brushing teeth, feeding, and writing, or
sensory motor skills that include balance (vestibular system),
awareness of body position (proprioceptive system), and touch
(tactile system).
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Immune globulin infusions are concentrated antibodies
administered intravenously to treat certain infectious diseases
or boost the immune system response. The AAP (2001) has
concluded that there is no scientific evidence to justify the use
of infusions of immune globulin in treating autism.
Cognitive Rehabilitation is a systematic, goal oriented
treatment program to improve cognitive (mental/intellectual)
function and functional abilities (memory, judgment, perception
and reasoning). The bulk of the evidence supporting cognitive
rehabilitation for autism comes from case studies, anecdotal
evidence and expert opinion. The effectiveness of cognitive
rehabilitation in treating autism has not been critically
evaluated in well-designed studies.
In a Cochrane review on the use of music therapy for the
treatment of autistic spectrum disorders, Gold et al (2006)
stated that published studies were of limited applicability to
clinical practice. However, the findings indicate that music
therapy may help children with autistic spectrum disorder to
improve their communicative skills. The authors noted that
more research is needed to examine whether the effects of
music therapy are enduring, and to investigate the effects of
music therapy in typical clinical practice.
In a Cochrane review, Millward et al (2008) noted that it has
been suggested that peptides from gluten and casein may
have a role in the origins of autism and that the physiology and
psychology of autism might be explained by excessive opioid
activity linked to these peptides. Research has reported
abnormal levels of peptides in the urine and cerebrospinal fluid
of people with autism. These investigators examined the
effectiveness of gluten and/or casein free diets as an
intervention to improve behavior, cognitive and social
functioning in individuals with autism. The authors concluded
that research has shown of high rates of use of
complementary and alternative therapies for children with
autism including gluten and/or casein exclusion diets.
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However, current evidence for the effectiveness of these diets
is poor. They stated that large scale, good quality randomized
controlled trials are needed. This is in agreement with the
observations of Curtis and Patel (2008) who stated that larger
studies are needed to determine optimum multi-factorial
treatment plans for autism and attention deficit hyperactivity
disorder involving nutrition, environmental control, medication,
as well as behavioral/education/speech/physical therapies.
The Tomatis sound therapy has been used to improve
language skills in children with autism. It entails the use
classical music that includes complex rhythms, melodies and
harmonic relationships known to create improved brain
function. The music is filtered with a device that Dr. Alfred
Tomatis invented and called the Electronic Ear. The filtering or
"gating", which the Electronic Ear provides, creates a
gymnastic program that activates and rehabilitates the middle
ear muscles and the whole auditory system. Programs are
progressively filtered to gradually awaken the ear and auditory
system to the full range of high frequencies.
Corbett et al (2008) examined the effects of the Tomatis sound
therapy on language skills in children with autism utilizing a
randomized, double-blind, placebo-controlled, cross-over
design. The results indicated that although the majority of the
children demonstrated general improvement in language over
the course of the study, it did not appear to be related to the
treatment condition. The percent change for Group 1
(placebo/treatment) for treatment was 17.41 %, and placebo
was 24.84 %. Group 2 (treatment/placebo) showed -3.98 %
change for treatment and 14.15 % change for placebo. The
results reflect a lack of improvement in language using the
Tomatis sound therapy for children with autism.
Hyperbaric Oxygen Therapy is a mode of treatment in which
an individual breathes 100% oxygen at greater than normal
atmospheric pressure. Rossignol and associates (2009)
performed a multi-center, randomized, double-blind, controlled
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trial to evaluate the effectiveness of hyperbaric treatment in
children with autism. A total of 62 children with autism were
recruited from 6 centers, aged 2 to 7 years (mean of 4.92 +/-
1.21 years). Subjects were randomly assigned to 40 hourly
treatments of either hyperbaric treatment at 1.3 atmosphere
(atm) and 24 % oxygen (treatment group, n = 33) or slightly
pressurized room air at 1.03 atm and 21 % oxygen (control
group, n = 29). Outcome measures included Clinical Global
Impression (CGI) scale, Aberrant Behavior Checklist (ABC),
and Autism Treatment Evaluation Checklist (ATEC). After 40
sessions, mean physician C GI scores significantly improved in
the treatment group compared to controls in overall functioning
(p = 0.0008), receptive language ( p < 0.0001), social
interaction (p = 0.0473), and eye contact (p = 0.0102); 9/30
children (30 %) in the treatment group were rated as "very
much improved" or "much improved" compared to 2/26 (8 %)
of controls (p = 0.0471); 24/30 (80 %) in the treatment group
improved compared to 10/26 (38 %) of controls (p = 0.0024).
Mean parental CGI scores significantly improved in the
treatment group compared to controls in overall functioning (p
= 0.0336), receptive language ( p = 0.0168), and eye contact (p
= 0.0322). On the ABC, significant improvements were
observed in the treatment group in total score, irritability,
stereotypy, hyperactivity, and speech (p < 0.03 for each), but
not in the control group. In the treatment group compared to
the control group, mean changes on the ABC total score and
sub-scales were similar except a greater number of children
improved in irritability (p = 0.0311). On the ATEC,
sensory/cognitive awareness significantly improved (p =
0.0367) in the treatment group compared to the control group.
Post-hoc analysis indicated that children over the age of 5
years and children with lower initial autism severity had the
most robust improvements. Hyperbaric treatment was safe
and well-tolerated. The authors concluded that children with
autism who received hyperbaric treatment at 1.3 atm and 24 %
oxygen for 40 hourly sessions had significant improvements in
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overall functioning, receptive language, social interaction, eye
contact, and sensory/cognitive awareness compared to
children who received slightly pressurized room air.
Moreover, the authors stated that because this study was not
designed to measure the long-term outcomes of hyperbaric
treatment in children with autism, additional studies are
needed to determine if the significant improvements observed
in this study last beyond the study period. It is possible that
ongoing treatments would be necessary to maintain t he
improvements observed, but this study was not designed to
examine that possibility. These findings suggest that
additional hyperbaric treatments beyond 40 t otal sessions may
lead to additional improvements; however, further studies are
needed to formally validate these observations. Finally, this
study was not designed to determine if higher hyperbaric
treatment parameters (higher atmospheric pressure and
oxygen levels, which can only be provided in a clinic setting)
would lead to better or more long-lasting results. Additional
studies are needed to investigate that possibility.
It is interesting to note that Yildiz and colleagues (2008) stated
that neither the Undersea Hyperbaric Medical Society nor the
European Committee for Hyperbaric Medicine "approves"
autism as an indication for hyperbaric oxygen therapy. The
authors concluded that there is insufficient evidence to support
the use of hyperbaric oxygen therapy in the treatment of
children with autism.
It has been claimed that weighted blankets are beneficial
for patients with autism since they "calm" the nervous system
so afflicted individuals can relax and sleep. It is believed that
weighted blanket leads to releases of melatonin, which plays a
role in the body and brain’s sensory processing. Melantonin
has been used for autistic children with sleep disorders despite
insufficient evidence of its effectiveness in this population.
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Moreover, there is a lack of evidence regarding the clin ica l
benefits of weighted blankets for individuals with autism or
other pervasive developmental disorders.
Stephenson and Carter (2009) noted that therapists who use
sensory integration therapy may recommend that children
wear weighted vests as an intervention strategy that they claim
may assist in remediating problems such as inattentiveness,
hyperactivity, stereotypic behaviors and clumsiness. These
investigators reviewed 7 studies on weighted vests. The
authors concluded that while there is only a limited body of
research and a number of methodological weaknesses, on
balance, indications are that weighted vests are ineffective.
There may be an arguable case for continued research on this
intervention but weighted vests can not be recommended for
clinical application at this point.
Floor time therapy is a series of 20- to 30-min periods during
which parents interact and play with their autistic child on the
floor. The aim of the interaction is to promote social and
communicative abilities. A British Medical Journal Clinical
Evidence systematic assessment on autism (Parr, 2006)
concluded that the effectiveness of floor time therapy for
autism is unknown.
Ichim and colleagues (2007) stated that ASDs are a group of
neurodevelopmental conditions whose incidence is reaching
epidemic proportions, afflicting approximately 1 in 166
children. Autistic disorder, or autism is the most common form
of ASD. Although several neurophysiological alterations have
been associated with autism, immune abnormalities and
neural hypo-perfusion appear to be broadly consistent. These
appear to be causative since correlation of altered
inflammatory responses, and hypo-perfusion with
symptomatology was reported. Mesenchymal stem cells
(MSC) are in late phases of clinical development for treatment
of graft versus host disease and Crohn's Disease, 2 conditions
of immune dysregulation. Cord blood CD34+ cells are known
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to be potent angiogenic stimulators, having demonstrated
positive effects in not only peripheral ischemia, but also in
models of cerebral ischemia. Additionally, anecdotal clinical
cases have reported responses in autistic children receiving
cord blood CD34+ cells. These researchers proposed the
combined use of MSC and cord blood CD34+cells may be
useful in the treatment of autism.
Thompson and colleagues (2010) summarized data from a
review of neurofeedback (NFB) training with 150 patients with
Asperger's syndrome (AS) and 9 patients with ASD seen over
a 15-year period in a clinical setting. The main objective was
to examine if NFB (also known as EEG biofeedback) made a
significant difference in patients diagnosed with AS. A further
aim of the current report was to provide practitioners with a
detailed description of the method used to address some of
the key symptoms of AS in order to encourage further
research and clinical work to refine the use of NFB
plus biofeedback in the treatment of AS. All charts were
included for review where there was a diagnosis of AS or ASD
and pre- and post-training testing results were available for
one or more of the standardized tests used. Patients received
40 to 60 sessions of NFB, which was combined with training in
meta-cognitive strategies and, for most older adolescent and
adult patients, with biofeedback of respiration, electrodermal
response, and, more recently, heart rate variability. For the
majority of patients, feedback was contingent on decreasing
slow wave activity (usually 3 to 7 Hz), decreasing beta
spindling if it was present (usually between 23 and 35 Hz), and
increasing fast wave activity termed sensorimotor rhythm
(SMR) (12 to 15 or 13 to 15 Hz dependingon assessment
findings). The most common initialmontage was referential
placement at the vertex (CZ) for children and at FCz (midway
between FZ and CZ) for adults, referenced to the right ear.
Meta-cognitive strategies relevant to social understanding,
spatial reasoning, reading comprehension, and math were
taught when the feedback indicated that the patient was
relaxed, calm, and focused. Significant improvements were
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found on measures of attention (T.O.V.A. and IVA), core
symptoms (Australian Scale for Asperger's Syndrome,
Conners' Global Index, SNAP version of the DSM-IV criteria
for ADHD, and the ADD-Q), achievement (Wide Range
Achievement Test), and intelligence (Wechsler Intelligence
Scales). The average gain for the Full Scale IQ score was 9
points. A decrease in relevant EEG ratios was also observed.
The ratios measured were (4 to 8 Hz)(2)/(13 to 21 Hz)(2), (4 to
8 Hz)/(16 to 20 Hz), and (3 to 7 Hz)/(12 to 15 Hz). The
positive outcomes of decreased symptoms of Asperger's and
attention deficit hyperactivity disorder (including a decrease in
difficulties with attention, anxiety, aprosodias, and social
functioning) plus improved academic and intellectual
functioning, provided preliminary support for the use of NFB as
a helpful component of effective intervention in people with
AS.
Massage involves manipulation of tissues (as by rubbing or
kneading) with the hand or an instrument for therapeutic
purposes. Lee et al (2011) examined the effectiveness of
massage as a treatment option for autism. These
investigators searched the following electronic databases
using the time of their inception through March 2010:
MEDLINE, AMED, CINAHL, EMBASE, PsycINFO, Health
Technology Assessment, Cochrane Central Register of
Controlled Trials, Cochrane Database of Systematic Reviews,
Database of Abstracts of Reviews of Effects, Psychology and
Behavioral Sciences Collection, 6 Korean medical databases
(KSI, DBpia, KISTEP, RISS, KoreaMed, and National Digital
Library), China Academic Journal (through China National
Knowledge Infrastructure), and 3 Japanese medical databases
(Journal@rchive, Science Links Japan, and Japan Science &
Technology link). The search phrase used was "(massage or
touch or acupressure) and (autistic or autism or Asperger's
syndrome or pervasive developmental disorder)". The
references in all located articles were also searched. No
language restrictions were imposed. Prospective controlled
clinical studies of any type of massage therapy for autistic
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patients were included. Trials in which massage was part of a
complex intervention were also included. Case studies, case
series, qualitative studies, uncontrolled trials, studies that
failed to provide detailed results, and trials that compared one
type of massage with another were excluded. All articles were
read by 2 independent reviewers, who extracted data from the
articles according to predefined criteria. Risk of bias was
assessed using the Cochrane classification. Of 132 articles,
only 6 studies met inclusion criteria. One RCT found that
massage plus conventional language therapy was superior to
conventional language therapy alone for symptom severity (p
< 0.05) and communication attitude (p < 0.01). Two RCTs
reported a significant benefit of massage for sensory profile (p
< 0.01), adaptive behavior (p < 0.05), and language and social
abilities (p < 0.01) as compared with a special education
program. The fourth RCT showed beneficial effects of
massage for social communication (p < 0.05). Two non-RCTs
suggested that massage therapy is effective. However, all of
the included trials have high risk of bias. The main limitations
of the included studies were small sample sizes, predefined
primary outcome measures, inadequate control for non
specific effects, and a lack of power calculations or adequate
follow-up. The authors concluded that limited evidence exists
for the effectiveness of massage therapy as a symptomatic
treatment of autism. Because the risk of bias was high, firm
conclusions can not be drawn. They stated that future, more
rigorous RCTs are warranted.
The Agency for Healthcare Research and Quality's report
on comparative effectiveness of therapies for children
with ASDs (AHRQ, 2011) has the following conclusions:
▪ Early intensive behavioral and developmental
interventions such as the UCLA/Lovaas Model improve
cognitive, language, and adaptive outcomes in certain
subgroups of children (Low confidence scale).
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▪ The evidence is insufficient to understand the
effectiveness, benefits, or adverse events from any
other behavioral interventions.
▪ Secretin does not improve language, cognition,
behavior, communication, autism symptom severity, or
socialization (High confidence scale).
▪ The evidence is insufficient to understand the
effectiveness, benefits, or adverse events from any
educational intervention.
▪ The evidence is insufficient to understand the
effectiveness, benefits, or adverse events from any
allied health or complementary and alternative
medicine intervention.
In a Cochrane review, Sinha et al (2011) examined the
effectiveness of AIT or other methods of sound therapy in
individuals with ASDs. For this update, these
investigators searched the following databases in September
2010: CENTRAL (2010, Issue 2), MEDLINE (1950 to
September week 2, 2010), EMBASE (1980 to Week 38, 2010),
CINAHL (1937 to current), PsycINFO (1887 to current), ERIC
(1966 to current), LILACS (September 2010) and the
reference lists of published papers. One new study was found
for inclusion. Randomized controlled trials involving adults or
children with ASDs were reviewed. Treatment was AIT or
other sound therapies involving listening to music modified by
filtering and modulation. Control groups could involve no
treatment, a waiting list, usual therapy or a placebo
equivalent. The outcomes were changes in core and
associated features of ASDs, auditory processing, quality of
life and adverse events. Two independent review authors
performed data extraction. All outcome data in the included
papers were continuous. They calculated point estimates and
standard errors from t-test scores and post-intervention
means. Meta-analysis was inappropriate for the available
data. These researchers identified 6 RCTs of AIT and 1 of
Tomatis therapy, involving a total of 182 individuals aged 3 to
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39 years. Two were cross-over trials; 5 trials had fewer than
20 participants. Allocation concealment was inadequate for all
studies. Twenty different outcome measures were used and
only 2 outcomes were used by 3 or more studies. Meta-
analysis was not possible due to very high heterogeneity or
the presentation of data in unusable forms. Three studies
(Bettison 1996; Zollweg 1997; Mudford 2000) did not
demonstrate any benefit of AIT over control conditions. Three
studies (Veale 1993; Rimland 1995; Edelson 199 9) reported
improvements at 3 months for the AIT group based on the
Aberrant Behaviour Checklist, but they used a total score
rather than subgroup scores, which is of questionable v alidity,
and Veale's results did not reach statistical significance.
Rimland (1995) also reported improvements at 3 months in
the AIT group for the Aberrant Behaviour Checklist subgroup
scores. The study addressing Tomatis therapy (Corbett 2008)
described an improvement in language with no difference
between treatment and control conditions and did not report on
the behavioral outcomes that were used in the AIT trials. The
authors concluded that there is no evidence that AIT or other
sound therapies are effective as treatments for ASDs. As
synthesis of existing data has been limited by the disparate
outcome measures used between s tudies, there is insufficient
evidence to prove that this treatment is ineffective. However,
of the 7 studies including 182 participants that have been
reported to date, only 2 (with an author in common), involving
a total of 35 participants, reported statistically significant
improvements in the AIT group and for only 2 outcome
measures (Aberrant Behaviour Checklist and Fisher's Auditory
Problems Checklist). As such, there is no evidence to support
the use of AIT at this time.
Alcantara and associates (2011), using 8
databases, performed a systematic review of the literature on
the effectiveness of chiropractic care in patients with ASD.
Eligibility criteria for inclusion included: (i) the study was a
primary investigation/report published in an English peer-
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reviewed journal; (ii) the study involved patients less than
or equal to 18 years; and (iii) patients are diagnosed with
autism, Asperger's Syndrome, Pervasive Developmental
Disorder-Not Otherwise Specified (PDD-NOS), or ASD.
Review of the literature revealed a total of 5 articles consisting
of 3 case reports, 1 cohort study and 1 randomized
comparison t rial. The literature is lacking on documenting
chiropractic care of children with ASD. These researchers
stated that at the heart of the core symptoms of ASD (i.e.,
impaired social interactions, deficits in communication and
repetitive or restricted behavioral patterns) is abnormal
sensory processing. Preliminary studies indicated that
chiropractic adjustment may attenuate sensorimotor
integration based on somatosensory evoked potentials
studies. The authors concluded that they encourage further
research for definitive studies on chiropractic's effectiveness
for ASD.
In a Cochrane review, James et al (2011) examined the
efficacy of omega-3 fatty acids for improving core features of
ASD (e.g., social interaction, communication, and stereotypies)
and associated symptoms. These investigators searched the
following databases on June 2, 2010: CENTRAL (2010, Issue
2), MEDLINE (1950 to May Week 3 2010), EMBASE (1980 to
2010 Week 21), PsycINFO (1806 to current), BIOSIS (1985 to
current), CINAHL (1982 to current), Science Citation Index
(1970 to current), Social Science Citation Index (1970 to
current), metaRegister of Controlled Trials (November 20,
2008) and ClinicalTrials.gov (December 10, 2010).
Dissertation Abstracts International was searched on
December 10, 2008, but was no longer available to the
authors or editorial base in 2010. All RCTs of omega-3 fatty
acids supplementation compared t o placebo i n individuals with
ASD were reviewed. Three authors independently selected
studies, assessed them for risk of bias and extracted relevant
data. They conducted meta-analysis of the included studies
for 3 primary outcomes (social interaction, communication, and
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stereotypy) and 1 secondary outcome (hyper-activity). These
researchers included 2 t rials with a total of 37 children
diagnosed with ASD who were randomized i nto groups that
received either omega-3 fatty acids supplementation or a
placebo. They excluded 6 trials because they were either non-
RCTs, did not contain a control group, or the control group did
not receive a placebo. Overall, there was no evidence that
omega-3 supplements had an effect on social interaction
(mean difference (MD) 0.82, 95 % confidence interval [CI]:
-2.84 to 4.48, I(2) = 0 %), communication (MD 0.62, 95 % CI:
-0.89 to 2.14, I(2) = 0 %), stereotypy (MD 0.77, 95 % CI: -0.69
to 2.22, I(2) = 8 %), or hyper-activity (MD 3.46, 95 % CI: -0.79
to 7.70, I(2) = 0 %). The authors concluded that to date there
is no high quality evidence that omega-3 fatty acids
supplementation is effective for improving c ore and associated
symptoms of ASD. Given the paucity of rigorous studies in
this area, there is a need for large well-conducted RCTs that
examine both high- and low-functioning individuals with ASD,
and that have longer follow-up periods.
Wuang et al (2010) examined the effectiveness of a 20-week
Simulated Developmental Horse-Riding Program (SDHRP) by
using an innovative exercise equipment (Joba) on the motor
proficiency and sensory integrative functions in 60 children
with autism (age of 6 years, 5 months to 8 years, 9 months).
In the 1st phase of 20 weeks, 30 children received the
SDHRP in addition to their regular occupational therapy while
another 30 children received regular occupational therapy
only. The arrangement was reversed in the 2nd phase of
another 20 weeks. Children with autism in this study showed
improved motor proficiency and sensory integrative functions
after 20-week SDHRP (p < 0.01). In addition, the therapeutic
effect appeared to be sustained for at least 24 weeks (6
months). This study utilized Joba, an exercise equipment that
served as simulated horseback riding; not conventional
horseback riding.
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Kern et al (2011) noted that anecdotal reports and some
studies suggested that equine-assisted activities may be
beneficial in ASD. These investigators examined the effects of
equine-assisted activities on overall severity of autism
symptoms using the Childhood Autism Rating Scale (CARS)
and the quality of parent-child interactions using the
Timberlawn Parent-Child Interaction Scale. In addition, this
study examined changes in sensory processing, quality of life,
and parental treatment satisfaction. Children with ASD were
evaluated at 4 time-points: (i) before beginning a 3-to-6
month waiting period, (ii) before starting the riding
treatment, (iii) after 3 months, and (iv) 6 months of riding. A
total of 24 participants completed the waiting list period and
began the riding program, and 20 participants completed the
entire 6 months of riding. Pre-treatment was compared to post-
treatment with each child acting as his or her own control. A
reduction in the severity of autism symptoms occurred with the
therapeutic riding treatment. There was no change in CARS
scores during the pre-treatment baseline period; however, there
was a significant decrease after treatment at 3 months and 6
months of riding. The Timberlawn Parent-Child Interaction
Scale showed a significant improvement in Mood and Tone at
3 months and 6 months of riding and a marginal improvement in
the reduction of Negative Regard at6 months of riding. The
parent-rated
quality of life measure showed improvement, including the pre-
treatment waiting period. All of the ratings in the Treatment
Satisfaction Survey were between good and very good. The
authors concluded that these results suggested that children
with ASD benefit from equine-assisted activities. The findings
of this small study need to be validated by well-designed
studies.
An UpToDate review on “Autism spectrum disorder in children
and adolescents: Overview of management” (Weissman and
Bridgemohan, 2013a) does not mention the use of
hippotherapy as a management tool. Furthermore, an
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UpToDate review on “Autism spectrum disorders in children
and adolescents: Complementary and alternative
therapies” (Weissman and Bridgemohan, 2013b) states that
“The use of therapeutic horseback riding (hippotherapy) for
children with ASD is based upon the hypothesis that
therapeutic horseback riding stimulates multiple domains of
functioning (e.g., cognitive, social, gross motor). In a
nonrandomized study, 19 children with autism who
participated in 12 weeks of therapeutic horseback riding
(hippotherapy) demonstrated improvements in attention,
distractibility, and social motivation compared with 15 wai t- l ist
controls. Additional studies are necessary before this therapy
can be recommended”.
In a Cochrane review, Williams et al (2013) determined if
treatment with a selective serotonin reuptake inhibitor (SSRI):
(i) improves the core features of autism (social interaction,
communication and behavioral problems); (ii) improves
other non-core aspects of behavior or function such as self-
injurious behavior; (iii) improves the quality of life of adults
or children and their carers; (iv) has short- and long-term
effects on outcome; and (v) causes harm. These
investigators searched the following databases up until March
2013: CENTRAL, Ovid MEDLINE, Embase, CINAHL,
PsycINFO, ERIC and Sociological Abstracts. They also
searched ClinicalTrials.gov and the International Clinical Trials
Registry Platform (ICTRP). This was supplemented by
searching reference lists and contacting known experts in the
field. Randomized controlled trials of any dose of oral SSRI
compared with placebo, in people with ASD were selected for
analysis. Two authors independently selected studies for
inclusion, extracted data and appraised each study's risk of
bias. A total of 9 RCTs with 320 participants were included.
Four SSRIs were evaluated: fluoxetine (3 studies),
fluvoxamine ( 2 studies), fenfluramine (2 studies) and
citalopram (2 studies). Five studies included only children and
4 studies included only adults. Varying inclusion criteria were
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used with regard to diagnostic criteria and intelligence quotient
of participants; 18 different outcome measures were reported.
Although more than 1 study reported data for Clinical Global
Impression (CGI) and obsessive-compulsive behavior (OCB),
different tool types or components of these outcomes were
used in each study. As such, data were unsuitable for meta-
analysis, except for 1 outcome (proportion improvement). One
large, high-quality study in children showed no evidence of
positive effect of citalopram; 3 small studies in adults showed
positive outcomes for CGI and OCB; 1 study showed
improvements in aggression, and another in anxiety. The
authors concluded that there is no evidence of effect of SSRIs
in children and emerging evidence of harm. There is limited
evidence of the effectiveness of SSRIs in adults from small
studies in which risk of bias is unclear.
Furthermore, an UpToDate review on “Autism spectrum
disorder in children and adolescents: Pharmacologic
interventions” (Weissman and Bridgemohan, 2014) lists SSRI
as one of the potential treatments for repetitive behaviors,
stereotypies, and rigidity in children with ASD. The review also
notes that “When used in children and adolescents with
depression, SSRI have been associated with increased
suicidal ideation. Increased suicidal ideation has not been
demonstrated in studies of SSRI in individuals with ASD.
However, most studies did not assess suicidal ideation and
included too few subjects to detect rare adverse effects, such
as suicidal ideation”.
In an open-label study, Erickson et al (2014) evaluated the
safety, tolerability, and effectiveness of arbaclofen, a selective
GABA-B agonist, in non-syndromic ASD. This study enrolled
32 children and adolescents with either autistic disorder or
PDD-not otherwise specified, and a score greater than or
equal to 17 on the ABC-Irritability subscale. Arbaclofen was
generally well-tolerated. The most common adverse events
were agitation and irritability, which typically resolved without
dose changes, and were often felt to represent spontaneous
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variation in underlying symptoms. Improvements were
observed on several outcome measures in this exploratory
trial, including the ABC-Irritability (the primary end-point) and
the Lethargy/Social Withdrawal subscales, the Social
Responsiveness Scale, the CY-BOCS-PDD, and CGI scales.
The authors concluded that placebo-controlled study of
arbaclofen is needed.
Acupuncture
In a systematic review and meta-analysis, Lee and associates
(2018) evaluated the available evidence regarding the safety
and efficacy acupuncture for children with ASD. These
investigators searched 13 databases for studies published up
to December 2016; RCTs evaluating the efficacy of
acupuncture for children with ASD were included. Outcome
measures were the overall scores on scales evaluating the
core symptoms of ASD and the scores for each symptom,
such as social communication ability and skills, stereotypies,
language ability, and cognitive function; effect sizes were
presented as MD. A total of 27 RCTs with 1,736 subjects were
included. Acupuncture complementary to behavioral and
educational intervention significantly decreased the overall
scores on the CARS (MD -8.10, 95 % CI: -12.80 to -3.40) and
ABC (MD -8.92, 95 % CI -11.29 to -6.54); however, it was
unclear which of the ASD symptoms improved. Acupuncture
as a monotherapy also reduced the overall CARS score. The
reported adverse events (AEs) were acceptable. The authors
concluded that the findings of this review suggested that
acupuncture may be safe and effective for pediatric ASD.
However, these researchers stated that it is not conclusive due
to the heterogeneity of the acupuncture treatment methods
used in the studies.
Liu and colleagues (2019a) stated that ASD is a
neurodevelopment disorder without definitive cure. Previous
studies have provided evidence for the safety and efficacy of
scalp acupuncture in children with ASD. However, the efficacy
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of scalp acupuncture treatment (SAT) in children with ASD has
not been evaluated systematically. In a systematic review and
meta-analysis, these researchers examined the efficacy of
SAT in children with ASD. Information from 6 databases,
including Medline, Embase, Cochrane database, AMED,
China National Knowledge Infrastructure, and Wanfang D ata,
were retrieved from the inception of each database f rom 1980
through September 2018; RCTs evaluating the efficacy of SAT
for patients with ASD were included. The primary outcome
measures were the CARS and ABC; secondary outcome
measures were Psychoeducational Profile (3rd Edition)
(PEP-3) scores. Risk of bias assessment and data synthesis
were conducted with Review Manager 5.3 software.
Methodological quality was assessed with the Cochrane risk of
bias tool. A total of 14 trials with 968 subject were conducted
and 11 of the trials were suitable for meta-analysis. Compared
with behavioral and educational interventions, SAT
significantly decreased the overall CARS scores for children
under 3 years of age (MD = 3.08, 95 % CI: -3.96 to -2.19, p < 0.001)
and above 3 years old (MD = 5.29, 95 % CI: -8.53 to
-2.06, p < 0.001), ABC scores (MD = 4.70, 95 % CI: -6.94 to
-2.79, p < 0.001). Furthermore, SAT significantly improved PEP
3 scores in communication (MD = 3.61, 95 % CI: 2.85 to 4.37,
p < 0.001), physical ability (MD = 2.00, 95 % CI: 1.16 to 2.84,
p < 0.001), and behavior (MD = 2.76, 95 % CI: 1.80 to 2.71,
p < 0.001). The authors concluded that SAT may be an effective
treatment for children with ASD. Moreover, these researchers
stated that given the heterogeneity and number of subjects,
RCTs of high quality and design are needed before widespread
application of this therapy.
Auditory Integration Therapy
Auditory Integration Training (AIT) is a procedure for reducing
painful hypersensitivity to sound. The NAS report (2001)
concluded that there is insufficient evidence of the
effectiveness of AIT in autism. Proponents of auditory
integration therapy suggest that music can “massage” the
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middle ear (hair cells in the cochlea), reduce hyper-sensitivities
and improve overall auditory processing ability. The NAS
concluded that “auditory integration therapy has received more
balanced investigation than has any other sensory approach to
intervention, but in general studies have not supported either
its theoretical basis or the specificity of its effectiveness.”
Based on a lack of clearly demonstrated effectiveness, the
AAP (2001) also recommended against the use of AIT for
autism.
A Cochrane review (Sinha et al, 2011) reviewed the evidence
for AIT and other sound therapies for autism, and concluded
that there is “no evidence that auditory integration therapy or
other sound therapies are effective as treatments for autism
spectrum disorders.” The evidence review identified 6
relatively small studies of AIT and one of Tomatis therapy met
the inclusion criteria for AIT. These largely measured different
outcomes and reported mixed results. The report found that,
of the seven studies including 182 participants that have been
reported to date, only two (with an author in common),
involving a total of 35 participants, report statistically significant
improvements in the auditory integration therapy group and for
only two outcome measures.
Al-Ayadhi and colleagues (2019) stated that neurotrophic
factors, including the glial cell line-derived neurotrophic factor
(GDNF), are of importance for synaptic plasticity regulation,
intended as the synapses' ability to strengthen or weaken their
responses to differences in neuronal activity. Such plasticity is
essential for sensory processing, which has been shown to be
impaired in ASD. This study was the first to examine the
impact of AIT of sensory processing abnormalities in autism on
plasma GDNF levels. A toal of 15 ASD children, aged
between 5 and 12 years, were enrolled and underwent the
present research study; AIT was carried out throughout 10
days with a 30-min session twice-daily. Before and after AIT,
CARS, SRS, and Short Sensory Profile (SSP) scores were
calculated, and plasma GDNF levels were assayed by an EIA
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test. A substantial decline in autistic behavior was observed
after AIT in the scaling parameters used. Median plasma
GDNF level was 52.142 pg/ml before AIT. This level greatly
increased immediately after AIT to 242.05 pg/ml (p < 0.001).
The levels were depressed to 154.00 pg/ml and 125.594 pg/ml
1 month and 3 months later, respectively, but they were still
significantly higher compared with the levels before the
treatment (p = 0.001, p = 0.01, respectively). There was an
improvement in the measures of autism severity as an effect of
AIT that induced the up-regulation of GDNF in plasma. The
authors concluded that further research, on a large scale, is
needed to evaluate if the cognitive improvement of ASD
children following AIT is related or not connected to the up-
regulation of GDNF.
Ciliary Neurotrophic Factor (CNTF) as a Biomarker for ASD
Brondino and colleagues (2018) stated that ciliary neurotrophic
factor (CNTF) is a neurotrophin that could signal neuronal
suffering and at the same time acts as a neuroprotective
agent. These researchers evaluated C NTF serum levels in
ASD. They noted that considering the role of CNTF as a
neuronal damage signal and the role of neuro-inflammation,
excito-inhibitory imbalance and excito-toxicity in the
pathogenesis of ASD, a possible alteration of CNTF in ASD
could be hypothesized. These investigators recruited 23
individuals with ASD and intellectual disability (ID), 20 ID
subjects and 26 typical adults. A complete medical and
psychopathological characterization of the participants was
performed; CNTF serum levels were measured with ELISA.
Serum levels of CNTF were significantly higher in the ASD+ID
group compared to ID (p < 0.001) or typically developed
subjects (p < 0.001). The authors concluded that CNTF may
be considered as a potential biomarker candidate for ASD in
the context of severe ID. They stated these findings support
the hypothesis of neurotrophic imbalance in ASD.
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Electro-Convulsive Therapy
DeJong et al (2014) performed a systematic review to examine
the effectiveness of a range of treatments for autistic
catatonia. The review identified 22 relevant papers, reporting
a total of 28 cases including both adult and pediatric patients.
Treatments included electro-convulsive therapy (ECT),
medication, behavioral and sensory interventions. Quality
assessment found the standard of the existing literature to be
generally poor, with particular limitations in treatment
description and outcome measurement. The authors
concluded that there was some limited evidence to support the
use of ECT, high dose lorazepam and behavioral interventions
for people with autistic catatonia; however, there is a need for
controlled, high-quality trials. They also noted that reporting of
side effects and adverse events should also be improved, in
order to better evaluate the safety of these treatments.
Emotion Recognition Training for the Treatment of Autism Spectrum Disorder
Berggren and colleagues (2018) evaluated the generalizability
of findings from RCTs evaluating emotion recognition training
(ERT) for children and adolescents with ASD. These
investigators presented a systematic review and narrative
synthesis of the determinants of external validity in RCTs on
ERT. Generalizability of the findings across situations,
populations, settings, treatment delivery, and intervention
formats was considered. These researchers identified 13
eligible studies. Participants were predominantly boys with
ASD in the normative IQ range (IQ over 70), with an age span
from 4 to 18 years across studies. Interventions and outcome
measures were highly variable. Several studies indicated that
training may improve ER, but it is still largely unknown to what
extent training effects are translated to daily social life. The
authors concluded that the generalizability of findings from
currently available RCTs remains unclear.
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FDA-Approved Pharmacotherapy for Autism
As of 2017, there were two FDA-approved medications on the
market for the treatment of irritability associated with autistic
disorder, risperidone and aripiprazole.
In 2006, the U.S. Food and Drug Administration (FDA)
approved Risperdal (risperidone) for the treatment of irritability
associated with autistic disorder, including symptoms of
aggression, deliberate self-injury, temper tantrums, and quickly
changing moods, in children and adolescents aged 5 to 16
years. This was noted to be the first FDA-approved medication
for use in children and adolescents with autism (BioSpace,
2006). The drug is marketed by Janssen, L.P, a subsidiary of
Johnson & Johnson.
In a systematic review on novel and emerging treatments for
ASD, Rossignol (2009) stated that risperidone was FDA-
approved for the treatment of ASD. The use of novel,
unconventional, and off-label treatments for ASD is common,
with up to 74 % of children with ASD using these treatments;
however, treating physicians are often unaware of this usage.
The author performed a systematic review of electronic
scientific databases to identify studies of novel and emerging
treatments for ASD, including nutritional supplements, diets,
medications, and non-biological treatments. A grade of
recommendation ("Grade") was then assigned to each
treatment using a validated evidence-based guideline as
outlined in this review: Grade A: Supported by at least 2
prospective randomized controlled trials (RCTs) or 1
systematic review; Grade B: Supported by at least 1
prospective RCT or 2 non-RCTs; Grade C: Supported by at
least 1 non-RCT or 2 case series;and Grade D: Troublingly
inconsistent or inconclusive studies or studies reporting no
improvements. Potential adverse effects for each treatment
were also reviewed. Grade A treatments for ASD include
melatonin, acetylcholinesterase inhibitors, naltrexone, and
music therapy. Grade B treatments include carnitine,
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tetrahydrobiopterin, vitamin C, alpha-2 adrenergic agonists,
hyperbaric oxygen treatment, immunomodulation and anti-
inflammatory treatments, oxytocin, and vision therapy. Grade
C treatments for ASD include carnosine, multi-vitamin/mineral
complex, piracetam, polyunsaturated fatty acids, vitamin
B6/magnesium, elimination diets, chelation, cyproheptadine,
famotidine, glutamate antagonists, acupuncture, AIT,
massage, and neurofeedback. The author concluded that the
reviewed treatments for ASD are commonly used, and some
are supported by prospective RCTs. Promising treatments
include melatonin, antioxidants, acetylcholinesterase
inhibitors, naltrexone, and music therapy. All of the reviewed
treatments are currently considered off-label for ASD and
some have adverse effects. The author stated that further
studies exploring these treatments are needed.
In 2009, Bristol-Myers Squibb Company announced the FDA
approval of Abilify (aripiprazole) for the treatment of irritability
associated with autistic disorder in pediatric patients ages 6 to
17 years, including symptoms of aggression towards others,
deliberate self-injuriousness, temper tantrums,and quickly
changing moods (BMS, 2009).
Approval was based on two 8-week, randomized, double-
blind, placebo-controlled ,Phase III trials in pediatric patients (6
to 17 years of age) who met the DSM-IV criteria for autistic
disorder and demonstrated behaviors such as tantrums,
aggression, self-injurious behavior, or a combination of these
problems. Efficacy was evaluated using two assessment
scales: the Aberrant Behavior Checklist (ABC) and the Clinical
Global Impression-Improvement (CGI-I) scale. The primary
outcome measure in both trials was the change from baseline
to endpoint in the Irritability subscale of the ABC (ABC-I). The
ABC-I subscale measured symptoms of irritability in autistic
disorder. Results of the first 8-week trial, contained 98 children
and adolescents with autistic disorder. The participants
received daily doses of placebo or Abilify 2 to 15 mg/day.
Abilify, starting at 2 mg/day with increases allowed up to 15
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mg/day based on clinical response, significantly improved
scores on the ABC-I subscale and on the CGI-I scale
compared with placebo. The mean daily dose of Abilify at the
end of 8week treatment was 8.6 mg/day (Otsuka, 2016).
The second 8-week trial contained 218 children and
adolescents with autistic disorder. Three fixed doses of Abilify
(5 mg/day, 10 mg/day, or 15 mg/day) were compared to
placebo. Abilify dosing started at 2 mg/day and was increased
to 5 mg/day after one week. After a second week, it was
increased to 10 mg/day for patients in the 10 and 15 mg dose
arms, and after a third week, it was increased to 15 mg/day in
the 15 mg/day treatment arm (Study 2 in Table 29). All three
doses of Abilify significantly improved scores on the ABC-I
subscale compared with placebo (Otsuka, 2016).
Abilify is available as oral tablets, orally-disintegrating tablets,
and oral solution for treatment of irritability associated with
autistic disorder. According to prescribing information (Otsuka,
2016), it is not known if Abilify is safe or effective in children
under 6 years of age with irritability associated with autistic
disorder.
GABAergic Agents
Brondino et al (2016) stated that it has been hypothesized that
autism may result from an imbalance between excitatory
glutamatergic and inhibitory GABAergic pathways. Commonly
used medications such as valproate, acamprosate, and
arbaclofen may act on the GABAergic system and be a
potential treatment for people with ASD. These investigators
evaluated the state-of-the-art of clinical trials of GABA
modulators in autism. The authors concluded that there is
insufficient evidence to suggest the use of these drugs in
autistic subjects, even if data are promising. They stated that
short-term use of all the reviewed medications appeared to be
safe; however, future well-designed trials are needed to
elucidate these preliminary findings.
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GABA Receptor Polymorphisms Testing
Mahdavi and colleagues (2018) noted that previous studies
have reported the association of GABA receptor subunits B3,
A5, and G3 single-nucleotide polymorphisms (SNPs) in
chromosome 15q11-q13 with ASDs. However, the currently
available results are inconsistent. These investigators
examined t he association between A SD and the GABA
receptor SNPs in chromosomal region 15q11-q13. The
association was calculated by the overall OR with a 95 % CI.
These researchers used sensitivity analyses and the
assessment of publication bias in their meta-analysis. A total
of 8 independent case-control studies involving 1,408 cases
and 2,846 healthy controls were analyzed, namely, 8 studies
for GABRB3 SNPs as well as 4 studies for GABRA5 and
GABRG3 polymorphisms. The meta-analysis showed that
GABRB3 polymorphisms in general were not significantly
associated with autism (OR = 0.846; 95 % CI: 0.595 to 1.201,
I2 = 79.1 %). Further analysis indicated that no associations
were found between GABRB3 SNPs and autism on rs2081648
(OR = 0.84; 95 % CI: 0.41 to 1.72, I2 = 89.2 %) and rs1426217
(OR = 1.13; 95 % CI: 0.64 to 2.0, I2 = 83 %). An OR of 0.95;
95 % CI: 0.77 to 1.17 was reported; I2 = 0.0 %) for GABRA5
SNPs and an OR of 0.96; 95 % CI: 0.24 to 3.81 was obtained
from GABRG3 SNPs; I2 = 97.8 %). The authors concluded
that the findings of this meta-analysis provided strong
evidence that different SNPs of GABA receptor B3, A5, and
G3 subunit genes located on chromosome 15q11-q13 are not
associated with the development of autism spectrum diseases
in different ethnic populations.
Genetic Testing for DRD2, HTR2C, MTHFR, RELN, SLC25A12 and UGT2B15
Wang and associates (2014) noted that the reelin gene
(RELN), which plays a crucial role in the migration and
positioning of neurons during brain development, has been
strongly posed as a candidate gene for ASD. Genetic variants
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in RELN have been investigated as risk factors of ASD in
numerous epidemiologic studies but with inconclusive results.
To clearly discern the effects of RELN variants on ASD, these
researchers conducted a meta-analysis integrating case-
control and transmission disequilibrium test (TDT) studies
published through 2001 to 2013. Odds ratios (ORs) with 95 %
CIs were used to estimate the associations between 3 RELN
variants (rs736707, rs362691, and GGC repeat variant) and
ASD. Overall, the summary ORs for rs736707, rs362691, and
GGC repeat variant were 1.11 [95 % CI: 0.80 to 1.54], 0.69 (95
% CI: 0.56 to 0.86), and 1.09 (95 % CI: 0.97 to 1.23),
respectively. Besides, positive result was also obtained in
subgroup of broadly-defined ASD for rs362691 (OR = 0.67, 95
% CI: 0.52 to 0.86). The authors concluded that the findings of
this meta-analysis revealed that the RELN rs362691, rather
than rs736707 or GGC repeat variant, might contribute to ASD
risk.
Liu and colleagues (2015) noted that the solute carrier family
25 (aspartate/glutamate carrier), member 12 gene
(SLC25A12) has been suggested as a candidate gene for
ASD given its role in mitochondrial function and adenosine
triphosphate (ATP) synthesis. Evidence is growing for the
association between SLC25A12 variants (rs2056202 and
rs2292813) and ASD risk, but the results are inconsistent. To
clarify the effect of these 2 variants on ASD, these researchers
performed a meta-analysis integrating case-control and TDT
studies. The PubMed, Embase, Cochrane Library, Web of
Science, Chinese BioMedical Literature, Wanfang, and
Chinese National Knowledge Infrastructure databases were
systematically searched to identify relevant studies published
up to May 2014; ORs and 95 % CIs were calculated to assess
the strength of association. A total of 775 cases, 922 controls,
and 1,289 families available from 8 studies concerning
rs2056202, and 465 cases, 450 controls, and 1,516 families
available from 7 studies concerning rs2292813 were finally
included. In the overall meta-analysis, the rs2056202 T allele
and rs2292813 T allele were both significantly associated with
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a decreased risk of ASD (rs2056202: OR = 0.809, p = 0.001,
95 % CI: 0.713 to 0.917, I(2) = 0.0 %, and p (heterogeneity) =
0.526; rs2292813: OR = 0.752, p < 0.001, 95 % CI: 0.649 to
0.871, I(2) = 0.0 %, p (heterogeneity) = 0.486). Besides,
subjects with T-T haplotype of rs2056202-rs2292813 had a
significantly reduced risk of ASD (OR = 0.672, p < 0.001, 95 %
CI: 0.564 to 0.801, I(2) = 0.0 %, p (heterogeneity) = 0.631).
Sensitivity analysis, cumulative meta-analysis, and publication
bias diagnostics confirmed the reliability and stability of these
results. The authors concluded that the findings of this meta-
analysis suggested that rs2056202 and rs2292813 in
SLC25A12 may contribute to ASD risk.
Aoki and Cortese (2016) stated that mitochondrial dysfunction
has been reported to be involved in the pathophysiology of
ASD. Studies investigating the possible association bet ween
ASD and polymorphism in SLC25A12, which encodes the
mitochondrial aspartate/glutamate carrier, have yielded
inconsistent results. These researchers conducted a
systematic review and meta-analysis of such studies to
elucidate if and which SLC25A12 s ingle nucleotide
polymorphisms (SNPs) are associated with ASD. They
searched PubMed, Ovid, Web of Science, and ERIC
databases through September 20, 2014; ORs were
aggregated using random effect models. Sensitivity analyses
were conducted based on study design (family-based or case-
control); 15 out of 79 non-duplicate records were retained for
qualitative synthesis. These investigators pooled 10 datasets
from 9 studies with 2,001 families, 735 individuals with ASD
and 632 typically developing ( TD) individuals for the meta-
analysis of rs2292813, as well as 11 datasets from 10 studies
with 2,016 families, 852 individuals with ASD and 1,058 TD
individuals for the meta-analysis of rs2056202. They found a
statistically significant association bet ween A SD and variant in
rs2292813 (OR = 1.190, 95 % CI: 1.052 to 1.346, p = 0.006) as
well as in rs2056202 (OR = 1.206, 95 % CI: 1.035 to 1.405,
p= 0.016) .Sensitivity analyses including only studies with family-
based design demonstrated significant association between
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ASD and polymorphism in rs2292813 (OR = 1.216, 95 % CI:
1.075 to 1.376, p = 0.002) and rs2056202 (OR = 1.267, 95 %
CI: 1.041 to 1.542, p = 0.018). In contrast, sensitivity analyses
including case-control design studies only failed to find a
significant association. The authors concluded that further
research on the role of SLC25A12 and ASD may pave the way
for potential innovative therapeutic interventions.
Long and Goldblatt (2016) noted that a polymorphism is a
variant within a gene that does not necessarily affect its
function, unlike a pathogenic mutation. Genetic testing for 2
common polymorphisms in the methylenetetrahydrofolate
reductase gene (MTHFR), 677C>T and 1298A>C, is being
accessed by general practitioners (GPs) and alternative
medicine practitioners (based on in-house records from
referrals), and promoted through some pharmacies in Western
Australia (based on the authors' personal communication).
Due to the large, varied and often conflicting data reported on
MTHFR, these polymorphisms have been weakly associated
with multiple conditions, including autism, schizophrenia,
cardiac disease, fetal neural tube defects, poor pregnancy
outcomes and colorectal cancer. These investigators
explained the difficulty in translating inconclusive results -- and
results of uncertain clinical relevance -- of genetic-association
studies on common polymorphisms into clinical practice. They
explored why testing for polymorphisms needs to be re-
considered in a diagnostic clinical setting. The authors
concluded that on the basis of the available scientific
evidence, they proposed that there are very limited clinical
indications for testing for the 677C>T and the 1298A>C
polymorphisms in the MTHFR gene, and that testing is not
indicated as a non-specific screening test in the asymptomatic
general population.
Ziegler and colleagues (2017) noted that ASD is a highly
heritable neural development disorder characterized by social
impairment. The earlier the diagnosis is made, the higher are
the chances of obtaining relief of symptoms. A very early
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diagnosis uses molecular genetic tests, which are also offered
commercially. These investigators performed a systematic
search of databases PubMed, Medline, Cochrane, Econlit and
the NHS Center for Reviews and Dissemination for articles in
English and German from January 1, 2000 to December 31,
2015. Original articles published in peer-reviewed journals
were screened in a 2-step process:
(i) they focused their search on economic evaluations of
genetic tests for ASD, and (ii) they searched for any
economic evaluation (EE) of genetic tests. These
researchers identified 185 EE of genetic tests for various
diseases. However, not a single EE of genetic tests has been
found for ASD. The outcomes used in the EE of the genetic
tests were heterogeneous, and results were generally not
comparable. The authors concluded that there is no evidence
for cost-effectiveness of any genetic diagnostic test for ASD,
although such genetic tests are available commercially. They
stated that cost-effectiveness analyses for genetic diagnostic
tests for ASD are needed; there is a clear lack in research for
EE of genetic tests.
Furthermore, an UpToDate review on “Autism spectrum
disorder: Diagnosis” (Augustyn, 2017) does not mention
testing for the DRD2, HTR2C, MTHFR, RELN, SLC25A12 and
UGT2B15 genes.
Latent Class Analysis
Kyriakopoulos et al (2015) stated that in children with ASD,
high rates of idiosyncratic fears and anxiety reactions and
thought disorder are thought to increase the risk of psychosis.
The critical next step is to identify whether combinations of
these symptoms can be used to categorize individual patients
into ASD subclasses, and to test their relevance to psychosis.
In this study, all patients with ASD (n = 84) admitted to a
specialist national inpatient unit from 2003 to 2012 were rated
for the presence or absence of impairment in affective
regulation and anxiety (peculiar phobias, panic episodes,
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explosive reactions to anxiety), social deficits (social
disinterest, avoidance or withdrawal and abnormal attachment)
and thought disorder (disorganized or illogical thinking, bizarre
fantasies, over-valued or delusional ideas). Latent class
analysis of individual symptoms was conducted to identify ASD
classes. External validation of these classes was performed
using as a criterion the presence of hallucinations. Latent
class analysis identified 2 distinct classes. Bizarre fears and
anxiety reactions and thought disorder symptoms
differentiated ASD patients into those with psychotic features
(ASD-P: 51 %) and those without (ASD-NonP: 49 %).
Hallucinations were present in 26 % of the ASD-P class but
only 2.4 % of the ASD-NonP. Both the ASD-P and the ASD-
NonP class benefited from inpatient treatment although
inpatient stay was prolonged in the ASD-P class. The authors
concluded that the findings of this study provided the first
empirically derived classification of ASD in relation to
psychosis based on 3 underlying symptom dimensions,
anxiety, social deficits and thought disorder. They stated that
these results can be further developed by testing the
reproducibility and prognostic value of the identified classes.
Measurements of Plasma Central Carbon Metabolites for Evaluation of Autism Spectrum Disorder
UpToDate reviews on “Autism spectrum disorder in children
and adolescents: Overview of management” (Weissman,
2019), “Autism spectrum disorder: Screening tools” (Augustyn,
2019), “Autism spectrum disorder: Clinical features” (Augustyn
and von Hahn, 2019a), and “Autism spectrum disorder:
Evaluation and diagnosis” (Augustyn and von Hahn, 2019b) do
not mention measurements of plasma central carbon
metabolites as a management option.
Measurements of Plasma Oxytocin and Vasopressin for Evaluation of Autism Spectrum Disorder
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Zhang and associates (2016) stated that ASD is defined by
impairments of social interaction and the presence of
obsessive behaviors. The "twin" nonapeptides oxytocin (OXT)
and arginine-vasopressin (AVP) are known to play regulatory
roles in social behaviors. However, the plasma levels and
behavioral relevance of OXT and AVP in children with ASD
have seldom been examined. It is also unclear if mothers of
children with ASD have abnormal plasma peptide levels. By
means of well-established methods of neuropeptide
measurement and a relatively large sample size, these
researchers determined the plasma levels of these 2
neuropeptides in 85 normal children, 84 children with ASD,
and 31 mothers from each group of children. As expected,
children with ASD had lower plasma OXT levels than gender-
matched controls (p = 0.028). No such difference was found
for plasma AVP concentrations. Correlation analysis showed
that ASD children with higher plasma OXT concentrations
tended to have less impairment of verbal communication (Rho
= -0.22, p = 0.076), while those with higher plasma AVP levels
tended to have lower levels of repetitive use of objects (Rho =
-0.231, p = 0.079). Unlike the findings in children, maternal
plasma OXT levels showed no group difference. However,
plasma AVP levels in the mothers of ASD children tended to
be lower than in the mothers of normal children (p = 0.072).
The authors concluded that these findings suggested that the
OXT system was dysregulated in children with ASD, and that
OXT and AVP levels in plasma appeared to be associated with
specific autistic symptoms. The plasma levels of OXT or AVP
in mothers and their ASD children did not appear to change in
the same direction.
The authors stated that this study had several drawbacks. It
remained unclear whether peripheral OXT or AVP levels
represent the central neuropeptide levels and activities. Some
studies in pregnant women, adult suicide attempters, and adult
patients undergoing surgical procedures have indicated a lack
of correlation between OXT concentrations in plasma and
cerebrospinal fluid (CSF).However, a recent study on children
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and adult patients have reported a positive correlation o f OXT
levels between the 2 compartments and this relationship was
stronger when only children were included in the analysis.
Also in studies with children, higher peripheral OXT levels had
been shown to correspond with greater interaction s kills in
normal individuals. Recently-published studies on human
neonates and children had also suggested that plasma AVP
was a surrogate for brain AVP activity and a biomarker of
social functioning in children with ASD. All these findings
indicated that a correlation between O XT/AVP levels in plasma
and CSF was more likely to occur in pediatric populations.
The subjects in this study were all children, thus, these
researchers speculated that plasma OXT or AVP
concentrations, to some extent, represented brain
neuropeptide l evels. Subsequent work, if possible, should
focus on OXT and AVP levels in CSF, which were more
directly relevant to behavioral effects or psychopathology.
Wilczyński and colleagues (2019b) noted that ASD is a
neurodevelopmental disorder characterized by deficits in
social interactions, communication, and the presence of
stereotyped, repetitive behaviors; OXT and AVP are
neuropeptides produced in hypothalamus and they are related
to processing emotions and social behavior. In the light of a
growing number of scientific reports related to this issue, these
2 neurohormones started to be linked with the basis of
neurodevelopmental disorders, including t he ASD. In a
systematic review, these investigators examined studies
regarding the differences in OXT and AVP levels in ASD and
neurotypical persons. Literature r eview focused on
publications in the last 10 years located via the
Medline/PubMed database as well as the Google Scholar
browser. Selection was made by assumptive criteria of
inclusion and exclusion. From the 487 studies qualified to the
initial abstract analysis, 12 met the 6 inclusion criteria and
were included in the full-text review. The authors concluded
that currently, available studies still do not provide unequivocal
answers as to the differences in concentrations of those
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neuropeptides between children with ASD and neurotypical
control. Thus, it is necessary to continue the research taking
into account necessity of proper homogenization of study
groups, utilization of objective and quantifiable tools for ASD
diagnosis and broadening the range of biochemical and
molecular factors analyzed.
Memantine for the Treatment of Autism Spectrum Disorder
In a prospective,12-week, open-label, clinical trial, Joshi and
colleagues (2016) evaluated the tolerability and effectiveness
of memantine for the treatment of core social and cognitive
deficits in adults with high-functioning ASD. Measures for
assessment of therapeutic response included the Social
Responsiveness Scale-Adult Research Version (SRS-A),
disorder-specific Clinical Global Impression scales, Behavior
Rating Inventory of Executive Functioning-Adult Self-Report,
Diagnostic Analysis of Nonverbal Accuracy Scale, and
Cambridge Neuropsychological Test Automated Battery. A
total of 18 adults (mean age of 28 ± 9.5 years) with high-
functioning ASD (SRS-A raw score, 99 ± 17) were treated with
memantine (mean dose of 19.7 ± 1.2 mg/day; range of 15 to
20 mg), and 17 (94 %) completed the trial. Treatment with
memantine was associated with significant reduction on
informant-rated (SRS-A, -28 ± 25; p < 0.001) and clinician-
rated (Clinical Global Impression-Improvement subscale ≤ 2,
83 %) measures of autism severity. In addition, memantine
treatment was associated with significant improvement in
ADHD and anxiety symptom severity. Significant improvement
was noted in nonverbal communication on the Diagnostic
Analysis of Nonverbal Accuracy Scale test and in executive
function per self-report (Behavior Rating Inventory of Executive
Functioning-Adult Self-Report Global Executive Composite, -6
± 8.8; p < 0.015) and neuropsychological assessments
(Cambridge Neuropsychological Test Automated Battery).
Memantine treatment was generally well-tolerated and was not
associated with any serious adverse events (AEs). The
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authors concluded that treatment with memantine appeared to
be beneficial for the treatment of ASD and associated
psychopathology and cognitive dysfunction in intellectually
capable adults. Moreover, they stated that future placebo-
controlled trials are needed.
In a 12-week, randomized, placebo-controlled, study with a 48-
week open-label extension, Aman and associates (2017)
examined t he safety, tolerability, and effectiveness of
memantine (once-daily extended-release [ER]) in children with
autism. A total of 121 children aged 6 to 12 years with
Diagnostic and Statistical Manual of Mental Disorders, 4th ed.,
Text Revision (DSM-IV-TR)-defined autistic disorder were
randomized (1:1) to placebo or memantine ER for 12 weeks;
104 children entered the subsequent extension trial.
Maximum memantine doses were determined by body weight
and ranged from 3 to 15 mg/day. There was 1 serious adverse
event (SAE) (affective disorder, with memantine) in the 12
week study and 1 SAE (lobar pneumonia) in the 48-week
extension; both were deemed unrelated to treatment. Other
AEs were considered mild or moderate and most were
deemed not related to treatment. No clinically significant
changes occurred in clinical laboratory values, vital signs, or
electrocardiogram (ECG). There was no significant between-
group difference on the primary effectiveness outcome of
caregiver/parent ratings on the SRS, although an improvement
over baseline at week 12 was observed in both groups. A
trend for improvement at the end of the 48-week extension
was observed. No improvements in the active group were
observed on any of the secondary end-points, with 1
communication measure s howing s ignificant worsening with
memantine compared with placebo (p = 0.02) after 12 weeks.
The authors concluded that this trial did not demonstrate
clinical effectiveness of memantine ER in autism; however, the
tolerability and safety data were reassuring. They noted that
these findings could inform future trial design in this population
and may facilitate the investigation of memantine ER for other
clinical applications.
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Furthermore, the largest RCT study of memantine for ASD,
conducted by Forrest Pharmaceuticals, had negative results.
Since this was a negative trial, the results have not been
published but are posted on ClinicalTrials.gov.
Metabolomic Analyses of Blood Samples (as a Biomarker for ASD)
Metabolomics is the large-scale study of small molecules,
commonly known as metabolites, within cells, biofluids, tissues
or organisms. Collectively, these small molecules and their
interactions within a biological system are known as the
metabolome.
NeuroPointDX, the neurological disorders division of Stemina
Biomarker Discovery, announced that it has validated a first-
generation autism diagnostic blood test panel in the Children’s
Autism Metabolome Project (CAMP), its clinical study (Smith et
al.; article in press).
Smith et al [article in press] stated Autism Spectrum Disorder
(ASD) is behaviorally and biologically heterogeneous and
likely represents a series of conditions arising from different
underlying genetic, metabolic, and environmental factors.
There are currently no reliable diagnostic biomarkers for ASD.
Based on evidence that dysregulation of branch chain amino
acids (BCAA) may contribute to the behavioral characteristics
of ASD, the authors tested whether dysregulation of amino
acids (AA) was a pervasive phenomenon in individuals with
ASD. This is the first paper to report results from the Children’s
Autism Metabolome Project (CAMP, ClinicalTrials.gov
Identifier: NCT02548442), a large-scale effort to define autism
biomarkers based on metabolomic analyses of blood samples
from young children. Dysregulation of AA metabolism was
identified by comparing plasma metabolites from 516 children
with ASD with those from 164 age-matched typically-
developing ( TYP) children recruited into CAMP. ASD subjects
were stratified into subpopulations based on shared metabolic
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phenotypes associated with BCAA dysregulation. The authors
identified groups of AAs with positive correlations that were, as
a group, negatively correlated with BCAA levels in ASD.
Imbalances between these two groups of AAs identified three
ASD associated Amino Acid Dysregulation Metabotypes
(AADM). The combination of glutamine, glycine, and ornithine
AADMs identified a dysregulation in AA/BCAA metabolism that
is present in 16.7% of the CAMP ASD subjects and is
detectable with a specificity of 96.3% and a PPV of 93.5%.
The authors concluded that identification and utilization of
metabotypes of ASD can lead to actionable metabolic tests
that support early diagnosis and stratification for targeted
therapeutic interventions.
West et al (2014) stated the diagnosis of autism spectrum
disorder (ASD) at the earliest age possible is important for
initiating optimally effective intervention. In the United States
the average age of diagnosis is 4 years. Identifying metabolic
biomarker signatures of ASD from blood samples offers an
opportunity for development of diagnostic tests for detection of
ASD at an early age. The objective of this study was to
discover metabolic features present in plasma samples that
can discriminate children with ASD from typically developing
(TD) children. The ultimate goal is to identify and develop blood
based ASD biomarkers that can be validated in larger clinical
trials and deployed to guide individualized therapy and
treatment. Blood plasma was obtained from children aged 4 to
6, 52 with ASD and 30 age-matched TD children. Samples
were analyzed using 5 mass spectrometry-based methods
designed to orthogonally measure a broad range of
metabolites. Univariate, multivariate and machine learning
methods were used to develop models to rank the importance
of features that could distinguish ASD from TD. A set of 179
statistically significant features resulting from univariate
analysis were used for multivariate modeling. Subsets of these
features properly classified the ASD and TD samples in the
61-sample training set with average accuracies of 84% and
86%, and with a maximum accuracy of 81% in an independent
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21-sample validation set. The authors concluded that this
analysis of blood plasma metabolites resulted in the discovery
of biomarkers that may be valuable in the diagnosis of young
children with ASD. The results will form the basis for additional
discovery and validation research for:
(i) determining biomarkers to develop diagnostic tests to
detect ASD earlier and improve patient outcomes, (ii)
gaining new insight into the biochemical mechanisms of
various subtypes of ASD, (iii) identifying biomolecular
targets for new modes of therapy, and (iv) providing the
basis for individualized treatment recommendations.
In June 1998, the National Institutes of Health Autism
Coordinating C ommittee (NIH/ACC) invited representatives of
13 major medical and other professional academies and
associations and six national autism parent research
organizations to review research data on screening and
diagnosis of autism spectrum disorders. Ten review papers
and more than 4,000 publications were consulted in this effort.
This paper highlights some promising areas for research
identified in this process. One of the highest priorities is the
search for the ultimate diagnostic indicator, a biological marker
(s), for example, genetic, metabolic, immunologic, neurologic,
that will distinguish autism unequivocally from other
developmental disabilities. In the interim, research on infant
screening and diagnosis might lower the threshold age for
diagnosis to 8-12 months. The role of sensory-motor disorders
in early diagnosis needs further research. Earlier and better
diagnosis of co-occurring, potentially treatable disorders,
including epileptic and epileptiform disorders, has implications
both for diagnosis and treatment. Pharmacogenetic and
pharmacogenomic research strategies could help diagnose
subtypes and responders versus nonresponders to potential
treatments. Better endpoints and outcome measures are
needed, including improved pr ocedures for cognitive and
neuropsychological testing, more knowledge about verbal and
nonverbal communication m ilestones, and less invasive and
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more sensitive neuroimaging measures. Critical questions
remain regarding regression after apparently normal
development, and about possible environmental precipitants.
Finally, field trials of the reliability and validity of screening and
diagnosis using the newly developed practice guidelines are
needed.
Music Therapy
Crawford and colleagues (2017) stated that preliminary studies
have indicated that music therapy may benefit children w ith
ASD. In an international, multi-center, 3-arm, single-masked
RCT, including a National Institute for Health Research (NIHR)
-funded center, these researchers examined the effects of
improvisational music therapy (IMT) on social affect and
responsiveness of children with ASD. Randomization was via
a remote service using permuted blocks, stratified by study
site. Subjects were children aged between 4 and 7 years with
a confirmed diagnosis of ASD and a parent or guardian who
provided written informed c onsent. These investigators
excluded children w ith serious sensory disorder and those who
had received music therapy within the past 12 months. All
parents and children received enhanced s tandard care (ESC),
which involved three 60-min sessions of advice and support in
addition to treatment as usual. In addition, they were
randomized to either 1 (low-frequency) or 3 (high-frequency)
sessions of IMT per week, or to ESC alone, over 5 months in a
ratio of 1 : 1 : 2. The primary outcome was measured using the
social affect score derived from the ADOS at 5 months: higher
scores indicated greater impairment; secondary outcomes
included social affect at 12 months and parent-rated social
responsiveness at 5 and 12 months (higher scores indicated
greater impairment). A total of 364 participants were
randomized between 2011 and 2015. A total of 182 children
were allocated to IMT (90 to high-frequency sessions and 92
to low-frequency sessions), and 182 were allocated to ESC
alone. A total of 314 (86.3 %) of the total sample were followed-
up at 5 months [165 (90.7 %) in the intervention
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group and 149 (81.9 %) in the control group]. Among those
randomized to IMT, 171 (94.0 %) received it. From baseline to
5 months, mean scores of ADOS social affect decreased from
14.1 to 13.3 in music therapy and from 13.5 to 12.4 in
standard care [MD: music therapy versus standard care = 0.06,
95 % CI: -0.70 to 0.81], with no significant difference in
improvement. There were also no differences in the parent-
rated social responsiveness score, which decreased from 96.0
to 89.2 in the music therapy group and from 96.1 to 93.3 in the
standard care group over this period (MD: music therapy
versus standard care = -3.32, 95 % CI: -7.56 to 0.91). There
were 7 admissions to hospital that were unrelated to the study
interventions in the 2 IMT arms compared with 10 unrelated
admissions in the ESC group. The authors concluded that
adding IMT to the treatment received by children with ASD did
not improve social affect or parent-assessed social
responsiveness.
In an assessor-blinded, randomized clinical trial, conducted in
9 countries, Bieleninik and associates (2017) examined t he
effects of IMT on generalized social communication skills of
children with ASD. Children aged 4 to 7 years with ASD were
enrolled in this study; they were recruited from November 2011
to November 2015, with follow-up between January 2012 and
November 2016. These researchers compared ESC (n = 182)
versus ESC plus IMT (n = 182), allocated in a 1:1 ratio; ESC
consisted of usual care as locally available plus parent
counseling to discuss parents' concerns and provide
information about ASD. In IMT, trained music therapists sang
or played music with each child, attuned and adapted to the
child's focus of attention, to help children develop affect
sharing and joint attention. The primary outcome was
symptom severity over 5 months, based on the ADOS, social
affect domain (range of 0 to 27; higher scores indicate greater
severity; minimal clinically important difference, 1). Pre-
specified secondary outcomes included par ent-rated social
responsiveness. All outcomes were also assessed at 2 and
12 months. Among 364 participants randomized (mean age of
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5.4 years; 83 % boys), 314 (86 %) completed the primary end-
point and 290 (80 %) completed the last end-point. Over 5
months, participants assigned to IMT received a median of 19
music therapy, 3 parent counseling, and 36 other therapy
sessions, compared with 3 parent counseling and 45 other
therapy sessions for those assigned to ESC. From baseline to
5 months, mean ADOS social affect scores estimated by linear
mixed-effects models decreased from 14.08 to 13.23 in the
IMT group and from 13.49 to 12.58 in the ESC group (MD,
0.06; 95 % CI: -0.70 to 0.81; p = 0.88), with no significant
difference in improvement. Of 20 exploratory secondary
outcomes, 17 showed no significant difference. The authors
concluded that among children with ASD, IMT, compared with
ESC, resulted in no significant difference in symptom severity
based on the ADOS social affect domain over 5 months. They
stated that these findings did not support the use of IMT for
symptom reduction in children with ASD.
Nutritional Therapy
Sausmikat and Smollich (2016) providedevidence-based data
on nutritional interventions for children and adolescents with
ASD, thus enabling practitioners to competently assess these
diets. Applying defined inclusion and exclusion criteria, a
systematic literature research in PubMed, Cinahl and the
Cochrane Library was conducted. Studies published earlier
than 1999 were excluded. Study quality was assessed by
using the CONSORT, STROBE or PRISMA checklist,
respectively. A total of 12 RCTs and 2 non-controlled studies
were included in the evaluation (n = 971). There is no proven
efficacy of the widely used gluten-free and casein-free diets
(GFCF), and no respective predictive marker has been proven
significant. The authors concluded that based on available
data, no evidence-based recommendations regarding
nutritional interventions for children and adolescents with ASD
can be made. They stated that future studies need to clarify
whether particular patients may yet benefit from certain diets.
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Oxytocin Therapy
Tachibana et al (2013) stated that oxytocin (OT) has been a
candidate for the treatment of ASD, and the impact of intra-
nasally delivered OT on ASD has been investigated.
However, most previous studies were conducted by single-
dose administration to adults; and, therefore, the long-term
effect of nasal OT on ASD patients and its effect on children
remain to be clarified. These researchers conducted a singled-
armed, open-label study in which OT was administered intra-
nasally over the long term to 8 male youth with ASD (10 to 14
years of age; intelligence quotient [IQ] 20 to 101). The OT
administration was performed in a step-wise increased dosage
manner every 2 months (8, 16, 24 IU/dose).A placebo period
(1 to 2 weeks) was inserted before each step. The outcome
measures were autism diagnostic observation schedule --
generic (ADOS-G), child behavior checklist (CBCL), and the
aberrant behavior checklist (ABC).
In addition, side effects were monitored by measuring blood
pressure and examining urine and blood samples. Six of the 8
participants showed improved scores on the communication
and social interaction domains of the ADOS-G. However,
regarding the T-scores of the CBCL and the scores of the
ABC, these investigators could not find any statistically
significant improvement, although several subcategories
showed a mild tendency for improvement. Care-givers of 5 of
the 8 participants reported certain positive effects of the OT
therapy, especially on the quality of reciprocal communication.
All participants showed excellent compliance and no side
effects. The authors concluded that although these findings
on the effectiveness of long-term nasal OT therapy still remain
controversial, to the best of these researchers’ knowledge, this
was the first report documenting the safety of long-term nasal
OT therapy for children with ASD. They stated that even
though these data were too preliminary to draw any definite
conclusions about effectiveness, they do suggest this therapy
to be safe, promising, and worthy of a large-scale, double-
blind placebo-controlled study.
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Anagnostou et al (2014) reviewed the literature for OT and
ASD and reported on early dosing, safety and efficacy data of
multi-dose OT on aspects of social cognition/function, as well
as repetitive behaviors and co-occurring anxiety within ASD. A
total of 15 children and adolescents with verbal IQs greater
than or equal to 70 were diagnosed with ASD using the ADOS
and the ADI-R. They participated in a modified maximum
tolerated dose study of intra-nasal OT (Syntocinon). Data
were modeled using r epeated m easures regression analysis
controlling for week, dose, age, and sex. Among 4 doses
tested, the highest dose evaluated, 0.4 IU/kg/dose, was found
to be well-tolerated. No serious or severe adverse events
were reported and adverse events reported/observed were mild
to-moderate. Over 12 weeks of treatment, several measures of
social cognition/function, repetitive behaviors and anxiety
showed sensitivity to change with some measures suggesting
maintenance of effect 3 months past discontinuation of intra
nasal OT. The authors concluded that the findings of this pilot
study suggested that daily administration of intra-nasal OT at
0.4 IU/kg/dose in children and adolescents with ASD is safe
and has therapeutic potential. Moreover, they stated that
larger studies are needed.
Preti et al (2014) noted that little is known about the
effectiveness of pharmacological interventions on ASD. These
investigators performed a systematic review of RCTs of OT
interventions in autism (from January 1990 to September
2013). A search of computerized databases was
supplemented by manual search in the bibliographies of key
publications. The methodological quality of the studies
included in the review was evaluated independently by 2
researchers, according to a set of formal criteria.
Discrepancies in scoring were resolved through discussion.
The review yielded 7 RCTs, including 101 subjects with ASD
(males = 95) and 8 males with Fragile X syndrome. The main
categories of target symptoms tested in the studies were
repetitive behaviors, eye gaze, and emotion recognition. The
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studies had a medium to high risk of bias. Most studies had
small samples (median = 15). All the studies but 1 reported
statistically significant between-group differences on at least 1
outcome variable. Most findings were characterized by
medium effect size. Only 1 study had evidence that the
improvement in emotion recognition was maintained after 6
weeks of treatment with intra-nasal OT. Overall, OT was well-
tolerated and side effects, when present, were generally rated
as mild; however, restlessness, increased irritability, and
increased energy occurred more often under OT. The authors
concluded that RCTs of OT interventions in autism yielded
potentially promising findings in measures of emotion
recognition and eye gaze, which were impaired early in the
course of the ASD condition and might disrupt social skills
learning in developing children. They stated that there is a
need for larger, more methodologically rigorous RCTs in this
area. They noted that future studies should be better powered
to estimate outcomes with medium to low effect size, and
should try to enroll female participants, who were rarely
considered in previous studies; risk of bias should be
minimized. These researchers stated that human long-term
administration studies are needed before clinical
recommendations can be made.
Evans et al (2014) noted that the last decade has seen a large
number of published findings supporting the hypothesis that
intra-nasally delivered OT can enhance the processing of
social stimuli and regulate social emotion-related behaviors
such as trust, memory, fidelity, and anxiety. The use of nasal
spray for administering OT in behavioral research has become
a standard method, but many questions still exist regarding its
action. Oxytocin is a peptide that cannot cross the blood-brain
barrier, and it has yet to be shown that it does indeed reach
the brain when delivered i ntra-nasally. Given the evidence, it
seems highly likely that OT does affect behavior when
delivered as a nasal spray. These effects may be driven by at
least 3possible mechanisms: (i) the intra-nasally delivered OT
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may diffuse directly into the CNS where it directly engages
OT receptors; (ii) the intra-nasally delivered OT may trigger
increased central release via an indirect peripheral
mechanism; and (iii) the indirect peripheral effects may
directly lead to behavioral effects via some mechanism
other than increased central release. Although intra-nasally
delivered OT likely affects behavior, there are conflicting
reports as to the exact nature of those behavioral changes:
some studies suggested that OT effects are not always "pro-
social" and others suggested effects on social behaviors are
due to a more general anxiolytic effect. In this critique, the
authors drew from work in healthy human populations and the
animal literature to review the mechanistic aspects of intra-
nasal OT delivery, and discussed intra-nasal OT effects on
social cognition and behavior. They concluded that future
work should control carefully for anxiolytic and gender effects,
which could underlie inconsistencies in the existing literature.
Quintana et al (2015) stated that accumulating evidence
demonstrated the important role of OT in the modulation of
social cognition and behavior. This has led many to suggest
that the intra-nasal administration of OT may benefit
psychiatric disorders characterized by social dysfunction, such
as ASD and schizophrenia. These investigators reviewed
nasal anatomy and OT pathways to central and peripheral
destinations, along with the impact of OT delivery to these
destinations on social behavior and cognition. The primary
goal of this review is to describe how these identified pathways
may contribute to mechanisms of OT action on social cognition
and behavior (i.e., modulation of social information processing,
anxiolytic effects, increases in approach-behaviors). The
authors proposed a 2-level model involving 3 pathways to
account for responses observed in both social cognition and
behavior after intra-nasal OT administration and suggested
avenues for future research to advance this research field.
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Furthermore, an UpToDate review on “Autism spectrum
disorder in children and adolescents: Pharmacologic
interventions” (Weissman and Bridgemohan, 2015) states that
“Pharmacologic agents that demonstrated potential benefit for
social deficits in individuals with autism spectrum disorder in
small open-label studies include oxytocin, D-cycloserine,
tetrahydrobiopterin, and cognition enhancers used in the
treatment of Alzheimer disease (e.g., galantamine, memantine,
and rivastigmine). Additional controlled studies are necessary
to confirm efficacy and safety before these therapies can be
recommended”.
Owada and colleagues (2019) stated that discrepancies in
efficacy between single-dose and repeated administration of
oxytocin for ASD have led researchers to hypothesize that time-
course changes in efficacy are induced by repeated
administrations of the peptide hormone. However, repeatable,
objective, and quantitative measurement of ASD's core
symptoms are lacking, making it difficult to examine potential
time-course changes in efficacy. These researchers tested
this hypothesis using repeatable, objective, and quantitative
measurement of the core symptoms of ASD. They examined
videos recorded during semi-structured social interaction
administered as the primary outcome in single-site exploratory
(n = 18, cross-over within-subjects design) and multi-site
confirmatory (n = 106, parallel-group design), double-blind,
placebo-controlled 6-week trials of repeated intra-nasal
administrations of oxytocin (48 IU/day) in men with ASD. The
main outcomes were statistical representative values of
objectively quantified facial expression intensity in a
repeatable part of the Autism Diagnostic Observation
Schedule: the maximum probability (i.e., mode) and the
natural logarithm of mode on the probability density function of
neutral facial expression and the natural logarithm of mode on
the probability density function of happy expression. A recent
study by these researchers revealed that increases in these
indices characterized autistic facial expression, compared with
neurotypical individuals. The current results revealed that
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oxytocin consistently and significantly decreased t he increased
natural logarithm of mode on the probability density function of
neutral facial expression compared with placebo i n exploratory
(effect-size, -0.57; 95 % CI: -1.27 to 0.13; p = 0.023) and
confirmatory trials (-0.41; -0.62 to -0.20; p < 0.001). A
significant interaction between time-course ( at baseline, 2, 4,
6, and 8 weeks) and the efficacy of oxytocin on the natural
logarithm of mode on the probability density function of neutral
facial expression was found in confirmatory trial (p < 0.001).
Post-hoc analyses revealed maximum efficacy at 2 weeks (p <
0.001, Cohen's d = -0.78; 95 % CI: -1.21 to -0.35) and
deterioration of efficacy at 4 weeks (p = 0.042, Cohen's d =
-0.46; 95 % CI: -0.90 to -0.01) and 6 weeks (p = 0.10, Cohen's
d = -0.35; 95 % CI: -0.77 to 0.08), while efficacy was
preserved at 2 weeks post-treatment (i.e., 8 weeks) (p < 0.001,
Cohen's d = -1.24; 95 % CI: -1.71 to -0.78). Quantitative facial
expression analyses successfully verified the positive effects
of repeated oxytocin on autistic individuals' facial expressions
and demonstrated a time-course change i n efficacy. The
authors concluded that these findings support further
development of optimization of objective, quantitative, and
repeatable outcome measures for autistic social deficits and to
establish optimized regimen of oxytocin treatment for ASD.
The authors stated that this study had several potential
limitations and methodological considerations that should be
considered. First, subjects in this trials were all adult, male,
Japanese individuals with ASD. Thus, while the uniformity in
subjects’ demographic characteristics enhanced the ability to
detect scientifically sound evidence, it should be noted that the
current findings may not be generalizable to other clinical or
non-clinical populations. Second, since the outcome measure
of current study was developed in the authors’ research team,
the findings should be replicated by other research groups.
The majority of the quantification methods were automatically
conducted and independent of human labor, facilitating the
replication of the current findings. Third, as some autistic
characteristics in facial expression at baseline, such as a high
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mode of neutral facial expression and log-PDF mode of happy
facial expression w ere not significantly improved by oxytocin
treatment, these investigators were unable to conclude that
oxytocin could treat or recover all characteristics of facial
expression in individuals with ASD. Furthermore, these
researchers did not show an association between the effects
of oxytocin on the quantified facial expression and those on
beneficial therapeutic outcomes, such as Clinical Global
Impressions (CGI) or Global Assessment of Functioning
(GAF). Although the effects of oxytocin on the variability of
neutral facial expression exhibited weak correlations with the
neural effect of oxytocin on anterior cingulate activity during a
social judgment task (ρ = −0.56, p = 0.028) and on resting
state functional connectivity between ant erior cingulate and
dorsomedial prefrontal cortices (ρ = −0.60, p = 0.019)
assessed with functional MRI in the exploratory trial, the
current results did not necessarily support the clinically
beneficial effects of oxytocin. Fourth, the possibility of further
improving the method of quantifying facial expressions, the
task used to induce facial expressions in individuals with
autism, and the outcome variables, should be c onsidered.
FaceReader and ADOS are not optimized for longitudinal
facial expression anal yses in individuals with ASD. It could be
useful to validate these tools (and other available s oftware) in
this methodological context using electromyography (EMG),
and/or action unit processing. The outcome variables used
were determined based on the results of the authors’ previous
case-control comparison in a limited sample size.
Prebiotic / Probiotic Therapy
Shaaban and co-workers (2018) noted that there are limited
data on the efficacy of probiotics in children with ASD. In a
prospective, open-label study, these investigators examined
the efficacy and tolerability of probiotics in a cohort of children
with ASD. Gastro-intestinal (GI) flora were assessed by
quantitative real-time PCR of stool samples of 30 autistic
children aged 5 to 9 years; GI symptoms of autistic children
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were assessed with a modified 6-item Gastrointestinal Severity
Index (6-GSI) questionnaire, and autistic symptoms were
assessed with Autism Treatment Evaluation Checklist (ATEC)
before and after 3 months of supplementation of probiotics
nutritional supplement formula (each gram contains 100 × 106
colony forming units of 3 probiotic strains; Lactobacillus
acidophilus, Lactobacillus rhamnosus and Bifidobacteria
longum). After probiotic supplementation, the stool PCR of
autistic children showed increases in the colony counts of
Bifidobacteria and Lactobacilli levels, with a significant
reduction in their body weight as well as significant
improvements in the severity of autism (assessed by the
ATEC), and GI symptoms (assessed by the 6-GSI) compared
to the baseline evaluated at the start of the study. The authors
concluded that probiotics have beneficial effects on both
behavioral and GI manifestations of ASD. Probiotics (a non-
pharmacological and relatively risk-free option) could be
recommended for children with ASD as an adjuvant therapy.
Moreover, these researchers noted that at this study was a
single-center trial with a small number of patients (n = 30);
they stated that additional large-scale RCTs are needed to
confirm the efficacy of probiotics in ASD.
Liu and colleagues (2019b) noted that the therapeutic
potentials of probiotics in ASD remains controversial, with the
only existing systematic review on this topic published in
2015. Results from new trials have become available in recent
years. These researchers conducted an updated systematic
review, to evaluate the efficacy of probiotics in relieving
behavioral symptoms of ASD and GI co-morbidities. This
review included 2 RCTs, which showed improvement of ASD
behaviors, and 3 open-label trials, which exhibited a trend of
improvement; 4 of these trials concluded from subjective
measures that GI function indices showed a trend of
improvement with probiotic therapy. The authors concluded
that additional rigorous trials are needed to evaluate the
effects of probiotic supplements in ASD.
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Ng and associates (2019) stated that ASD is a complex
developmental condition typically characterized by deficits in
social and communicative behaviors as well as repetitive
patterns of behaviors. Despite its prevalence (affecting 0.1 %
to 1.8% of the global population), the pathogenesis of ASD
remains incompletely understood. Patients with ASD are
reported to have more frequent GI complaints. There is some
anecdotal evidence t hat probiotics are able to alleviate GI
symptoms as well as improve behavioral issues in children
with ASD. However, systematic reviews of the effect of
prebiotics/probiotics on ASD and its associated symptoms are
lacking. Using the keywords (prebiotics OR probiotics or
microbiota or gut) and (autism or social or ASD), a systematic
literature search was conducted on PubMed, Embase,
Medline, Clinicaltrials.gov and Google Scholar databases.
The inclusion criteria were original clinical trials, published i n
English between the period January 1, 1988 and February 1,
2019. A total of 8 clinical trials were systematically reviewed; 2
clinical trials examined the use of prebiotic and/or diet
exclusion while 6 involved the use of probiotic
supplementation in children with ASD. Most of these were
prospective, open-label studies. Prebiotics only improved
certain GI symptoms; however, when combined with an
exclusion diet (gluten and casein free) showed a s ignificant
reduction in anti-sociability scores. As for probiotics, there is
limited evidence to support the role of probiotics in alleviating
the GI or behavioral symptoms in children with ASD. The 2
available double-blind, randomized, placebo-controlled trials
found no significant difference in GI symptoms and behavior.
The authors concluded that despite promising pre-clinical
findings, prebiotics and probiotics have demonstrated an
overall limited efficacy in the management of GI or behavioral
symptoms in children with ASD. In addition, there was no
standardized probiotics regimen, with multiple di fferent strains
and concentrations of probiotics, and variable duration of
treatments.
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Saliva Analysis Testing
Quadrant Biosciences, Inc. offers Clarifi autism spectrum
disorder (ASD) saliva test for children with a clinical suspicion
of ASD, such as a positive screen on the modified checklist for
autism in toddlers – revised (MCHAT-R), who are 18 months
through 6 years of age. The Clarifi test is a healthcare provider
administered saliva swab test designed to provide a probability
of an autism diagnosis based on regulatory RNAs and
microbes found in the saliva. There are conditions that have
not been clinically validated and may affect the validity of the
test including, but not limited to, dental caries, fever,
cold/flu/sinus conditions, feeding tubes, known chromosomal
deletions or duplications, epilepsy, and head trauma
(Quadrant Biosciences, 2020).
Hicks et al. (2018) state that ASD relies on behavioral
assessment and that efforts to define biomarkers of ASD have
not resulted in an objective, reliable test. The authors report
that studies have demonstrated that RNA levels in ASD have
potential utility, but have been limited by a focus on single
RNA types, small sample sizes, and lack of developmental
delay controls. Thus, the authors conducted a multi-center
cross-sectional study which included 456 children, ages 19-83
months. Children were either neurotypical (n = 134) or had a
diagnosis of ASD (n = 238), or non-ASD developmental delay
(n = 84). Comprehensive human and microbial RNA
abundance was measured in the saliva of all participants using
unbiased next generation s equencing. Prior to analysis, the
sample was randomly divided into a training set (82% of
subjects) and an independent validation t est set (18% of
subjects). The training set was used to develop an RNA-based
algorithm that distinguished ASD and non-ASD children. The
validation set was not used in model development (feature
selection or training) but served only to validate empirical
accuracy. The authors found that in the training set (n = 372;
mean age 51 months; 51% ASD), a set of 32 RNA features,
identified ASD status with a cross-validated area under the
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curve (AUC) of 0.87 (95% CI: 0.86-0.88). In the completely
separate validation test set (n = 84; mean age 50 months; 60%
ASD), the algorithm maintained an AUC of 0.88 (82%
sensitivity and 88% specificity). Notably, the RNA features
were implicated i n physiologic processes related to ASD (axon
guidance, neurotrophic signaling). The authors concluded t hat
salivary poly-omic RNA measurement represents a novel, non-
invasive approach that can accurately identify children with
ASD. This technology could improve the specificity of referrals
for ASD evaluation or provide objective s upport for ASD
diagnoses. The authors note the study limitations include
reliance on microbial measures for ASD identification which
will require accounting f or features influenced by diet and
geography. The current study enrolled children from multiple
sites and relied on several microbes found in humans
throughout the world (e.g., Lactobacillus). However, validation
of RNA from less common bacteria (e.g., Oenococcus oeni)
will require sample c ollection from diverse sites. In addition,
numerous medical and demographic factors may influence
RNA expression in the oropharynx. The authors state that
because medical and demographic features of their cohort
generally represent childhood ASD populations, they expect
these differences will not impact external validity. Indeed, in
the test set (which was matched on ASD:TD:DD ratios, but not
medical and demographic factors) the RNA panel maintained
predictive accuracy. The authors report that they have
developed an objective, quantitative algorithm based on
salivary RNA abundance that accurately discriminates children
with ASD from peers with DD or TD. This non-invasive test
could augment the accuracy of current ASD assessment, as
an adjunctive tool for children w ith positive M CHAT screening,
or an objective aid in ASD diagnosis.
Kong et al. (2019) state that while most studies agree that the
microbiome composition is different between autistic and
neurotypical populations, these studies have yielded
inconsistent results as to the nature or extent of these GI
bacterial community differences. Compared to the gut, the oral
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microbiome i s understudied, despite dental plaque and saliva
samples being easier to obtain than stool samples. The
authors designed a pilot study to investigate the oral and gut
microbiome s imultaneously in patients with ASD and their first-
degree family members. The first degree-relative matched
design combined with high fidelity 16S rRNA (ribosomal RNA)
gene amplicon s equencing w as used in order to characterize
the oral and gut microbiotas of patients with ASD compared to
neurotypical individuals, and explored the utility of microbiome
markers for ASD diagnosis and subtyping of clinical comorbid
conditions. 20 patients diagnosed w ith ASD were recruited and
compared with 19 family members (parent or sibling) as
neurotypical controls. Exclusion criteria for all subjects
included known genetic conditions, clinically evident serious
infections or inflammatory conditions, history of cancer, severe
dental/periodontal diseases or possession of dental braces.
Subjects who had received probiotic treatment were asked to
stop treatment at least one week prior to sample collection and
subjects were excluded if they had taken antibiotics in the
preceding month. The authors report that their study identified
distinct features of gut and salivary microbiota that differ
between individuals with and without an ASD diagnosis. Given
the emerging role that the human microbiome plays in
systemic diseases, they hope that their analyses will provide
clues for developing microbial markers for diagnosing ASD
and comorbid conditions, and to guide treatment. The authors
pointed out the limitations of their study which include: (1) The
use of both sibling and parental controls, where age could
contribute to the large inter-individual variability. Future studies
should focus on only age-matched sibling controls, if possible.
(2) The small sample size, which likely contributed to high FDR
in the majority of their analyses and the difficulty in
distinguishing true differences from noise. Verification of their
findings with a larger cohort is required. Furthermore, the
current study was not sufficiently powered f or detecting
clinically relevant biomarkers.
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Hicks et al. (2020) conducted a multicenter, prospective, case-
control study to investigate the utility of salivary microRNAs for
differentiating children with ASD from peers with typical
development (TD) and non-autism developmental delay (DD).
The secondary purpose was to explore microRNA patterns
among ASD phenotypes. The study included 443 children (2-6
yrs old) diagnosed with ASD per DSM-5 criteria. Children with
ASD or DD were assessed with the Autism Diagnostic
Observation Schedule II and Vineland Adaptive Behavior
Scales II. MicroRNAs were measured with high-throughput
sequencing. Differential expression of microRNAs was
compared among the ASD (n = 187), TD (n = 125), and DD (n
= 69) groups in the training set (n = 381). Multivariate logistic
regression defined a panel of microRNAs that differentiated
children with ASD and those without ASD. The algorithm was
tested in a prospectively collected naïve set of 62 samples
(ASD, n = 37; TD, n = 8; DD,n = 17).Relations between
microRNA levels and ASD phenotypes were explored. The
authors found 14 microRNAs displayed differential expression
(false discovery rate < 0.05) among ASD, TD, and DD groups.
A panel of 4 microRNAs (controlling for medical/demographic
covariates) best differentiated children with ASD from children
without ASD in training (area under the curve = 0.725) and
validation (area under the curve = 0.694) sets. Eight
microRNAs were associated (R > 0.25, false discovery rate <
0.05) with social affect, and 10 microRNAs were associated
with restricted/repetitive behavior. The authors concluded that
salivary microRNAs are "altered" in children with ASD and
associated with levels of ASD behaviors. Salivary microRNA
collection is noninvasive, identifying ASD-status with moderate
accuracy. A multi-"omic" approach using additional RNA
families could improve accuracy, leading to clinical application.
An UpToDate review on "Autism spectrum disorder: Screening
tools" (Weissman, 2020) does not mention the utility of saliva
analysis testing as a screening or assessment tool for
diagnosing autism spectrum disorder. An UpToDate review on
"Autism spectrum disorder: Evaluation and
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diagnosis" (Augustyn and von Hahn, 2019) state that tests for
yeast metabolites, gut permeability and micronutrients are not
indicated since there are no empiric data to support such
analyses. There is no mention of the utility of saliva analysis
testing for evaluating and diagnosing children with ASD.
Screening in Young Children
Siu and colleagues (2016) reported on the new US Preventive
Services Task Force (USPSTF) recommendation on screening
for ASD in young children. The USPSTF reviewed the
evidence on the accuracy, benefits, and potential harms of
brief, formal screening instruments for ASD administered
during routine primary care visits and the benefits and
potential harms of early behavioral treatment for young
children identified with ASD through screening. This
recommendation applies to children aged 18 to 30 months
who have not been diagnosed with ASD or developmental
delay and for whom no concerns of ASD have been raised by
parents, other caregivers, or health care professionals. The
USPSTF concluded that the current evidence is insufficient to
assess the balance of benefits and harms of screening for
ASD in young children for whom no concerns of ASD have
been raised by their parents or a clinician. This
recommendation is in agreement with:
(i) American Academy of Family Physicians (2015) which
states that the current evidence is insufficient to assess the
balance of benefits and harms of screening for ASD in
children for whom no concerns of ASD have been raised by
their parents or clinical provider, and (ii) the UK national
Screening Committee (2015), which does not recommend
systematic population screening, citing concerns about the
stability of ASD diagnosis at a young age, lack of data on
positive predictive value, and weakness of the evidence for
the efficacy of treatment.
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Serum Cytokine and Growth Factor Levels
Lochman and colleagues (2018) noted that the immune
system may have a role in the pathogenesis of ASD, including
typical and atypical autism. These researchers examined if a
cytokine and growth factor panel could be identified for the
diagnosis and prognosis in children with ASD, including typical
and atypical autism. This trial enrolled 26 children with ASD
(typical or atypical) and 11 of their siblings who did not have
ASD. A panel of 10 serum cytokines and growth factors were
investigated using addressable laser bead assay (ALBIA) and
enzyme-linked immunosorbent assay (ELISA) kits. Results
were correlated with scores using the CARS and ADOS for the
children with ASD and compared with the findings from their
siblings without ASD. There were no statistically significant
differences in serum cytokine and growth factor levels
between children with ASD and their siblings. The scores
using CARS and ADOS were significantly greater in children
with typical autism compared with children with atypical autism
as part of the ASD spectrum. Serum levels of cytokines and
growth factors showed a positive correlation with CARS and
ADOS scores but differed between children with typical and
atypical autism and their siblings. The authors concluded that
the findings of this study showed that serum measurement of
appropriately selected panels of cytokines and growth factors
might have a role in the diagnosis of ASD.
Testing of Single-Nucleotide Polymorphisms Within the Oxytocin and Vasopressin Receptor Genes
Wilczyński and colleagues (2019a) stated that ASD is found in
virtually all population groups regardless of ethnic or socio-
economic backgrounds. Among others, dominant symptoms
of autism persistent throughout its course of development
include, inter alia, qualitative disorders of social
communication and social interactions. Numerous studies
have been performed on animal models as well as groups of
healthy individuals to examine the potential role of
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oxytocinergic and vasopressinergic systems in normal social
functioning. In a systematic review, these investigators
discussed their potential participation in the development of
social cognition dysfunctions in the course of ASD. This
literature review identified studies examining single-nucleotide
polymorphisms (SNPs) of the OXT and AVP receptor genes
and their differential effects on social cognitive dysfunction in
the development of ASD. These researchers carried out a
systematic review of literature published within the last 10
years and accessible in PubMed, Google Scholar, Cochrane
Library, and APA PsycNET databases by each author
separately. Inclusion criteria required that articles should be
published between January 2008 and August 2018; be
published in English or Polish; be located in periodical
publications; focus on the role of polymorphisms within OXT
and VP receptor genes in autistic population; provide a clear
presentation of the applied methodology; and apply proper
methodology. From the 491 studies qualified to the initial
abstract analysis, 15 met the 6 inclusion criteria and were
included in the full-text review. The authors concluded that the
analysis of available literature appeared to indicate that there
is an association between social cognition dysfunctions in the
course of autism and selected alleles of polymorphisms within
the OXT receptor AVP 1A receptor genes. However, these
researchers stated that previous studies neither specified the
nature of this association in an unequivocal way nor select
genotypes thatwere the basis for this association. They
stated that further research into this field, which will maintain a
more uniform structure of studied groups, is definitely needed,
and in the future, it may help bring a better understanding of
the pathogenesis of social cognitiondysfunctions and their
relation to ASD.
Tests for Glutamatergic Candidate Genes
Chiocchetti and associates (2014) noted that ASD are
neurodevelopmental disorders with early onset in childhood.
Most of the risk for ASD can be explained by genetic variants
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that act in interaction with biological environmental risk
factors. However, the architecture of the genetic components
is still unclear. Genetic studies and subsequent systems
biological approaches described converging functional effects
of identified genes towards pathways relevant for neuronal
signaling. Mouse models suggested an aberrant synaptic
plasticity at the neuropathological level, which is believed to be
conferred by dysregulation of long-term potentiation or
depression of neuronal connections. A central pathway
regulating these mechanisms is glutamatergic signaling.
These researchers hypothesized that susceptibility genes for
ASD are enriched for components of this pathway. To further
understand the impact of ASD risk genes on the glutamatergic
pathway, these investigators performed a systematic review
using the literature database "PubMed" and the "AutismKB"
knowledgebase. They provided an overview of the
glutamatergic system in typical brain function and
development, and summarized findings from linkage,
association, copy number variants, and sequencing studies in
ASD to provide a comprehensive picture of the glutamatergic
landscape of ASD genetics. Genetic variants associated with
ASD were enriched in glutamatergic pathways, affecting
receptor signaling, metabolism and transport. Furthermore, in
genetically modified mouse models for ASD, pharmacological
compounds acting on ionotropic or metabotropic receptor
activity were able to rescue ASD reminiscent phenotypes. The
authors concluded that glutamatergic genetic risk factors for
ASD showed a complex pattern and further studies are
needed to fully understand its mechanisms, before translation
of findings into clinical applications and individualized
treatment approaches will be possible.
Tests for Olfactory Function
Tonacci and colleagues (2017) stated that olfactory function is
a well-known early biomarker for neurodegeneration and
neural functioning in the adult population, being supported by
a number of brain structures that could be dysfunctioning in
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neurodegenerative processes. Evidence has suggested that
atypical sensory and, particularly, olfactory processing is
present in several neurodevelopmental conditions, including
ASDs. These investigators presented data obtained by a
systematic literature review, conducted according to PRISMA
guidelines, regarding the possible association between
olfaction and ASDs, and analyzed them critically in order to
evaluate the occurrence of olfactory impairment in ASDs, as
well as the possible usefulness of olfactory evaluation in such
conditions. The results obtained in this analysis suggested a
possible involvement of olfactory impairment in ASDs,
underlining the importance of olfactory evaluation in the clinical
assessment of ASDs. The authors concluded that this
assessment could be potentially included as a complementary
evaluation in the diagnostic protocol of the condition.
Therapeutic Diets (e.g., Ketogenic Diet and Modified Atkins Diet)
El-Rashidy and colleagues (2017) stated that many diet
regimens were studied for patients with ASD over the past
several years. Ketogenic diet is gaining attention due to its
proven effect on neurological conditions like epilepsy in
children. In a case-control study, a total of 45 children aged 3
to 8 years diagnosed with ASD based on DSM-5 criteria were
enrolled to compare ketogenic diet versus gluten free casein
free diet for the treatment of ASD. Patients were equally
divided into 3 groups, first group received ketogenic diet as
modified Atkins diet (MAD), second group received gluten free
casein free (GFCF) diet, and the third group received balanced
nutrition and served as a control group. All patients were
assessed in terms of neurological examination, anthropometric
measures, as well as Childhood Autism Rating Scale (CARS),
Autism Treatment Evaluation Test (ATEC) scales before and 6
months after starting diet. Both diet groups showed significant
improvement in ATEC and CARS scores in comparison to
control group, yet ketogenic scored better results in cognition
and sociability compared to GFCF diet group. The authors
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concluded that depending on the parameters measured in this
study, modified Atkins diet and gluten free casein free diet
regimens may safely improve autistic manifestations and could
be recommended for children with ASD. Moreover, they noted
that this study was a single-center trial with a small number of
subjects (n = 45); more large-scale prospective studies are
needed to confirm these findings.
Gogou and Kolios (2018) stated that a nutritional background
has been recognized in the pathophysiology of autism and a
series of nutritional interventions have been considered as
complementary therapeutic options. As available treatments
and interventions are not effective in all individuals, new
therapies could broaden management options for these
patients. These investigators provided current literature data
regarding the effect of therapeutic diets on ASD. A systematic
review was conducted by 2 reviewers independently;
prospective clinical and pre-clinical studies were considered.
Therapeutic diets that have been used in children with autism
include ketogenic and gluten/casein-free diet. These
researchers were able to identify 8 studies conducted in
animal models of autism demonstrating a beneficial effect on
neurophysiological and clinical parameters. Only 1 clinical
study was found showing improvement in childhood autism
rating scale after implementation of ketogenic diet. With
regard to gluten/casein-free diet, 4 clinical studies were totally
found with 2 of them showing a favorable outcome in children
with autism. Furthermore, a combination of gluten-free and
modified ketogenic diet in a study had a positive effect on
social affect scores. No serious adverse events (AEs) have
been reported. The authors concluded that despite
encouraging laboratory data, there is controversy regarding
the real clinical effect of therapeutic diets in patients with ASD.
They stated that more research is needed to provide sounder
scientific evidence.
Transcranial Direct Current Stimulation
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Kang and colleagues (2018) noted that ASD is a
heterogeneous neurodevelopmental disorder that affects the
developmental trajectory in several behavioral domains,
including impairments of social communication, cognitive and
language abilities. Transcranial direct current stimulation
(tDCS) is a non-invasive brain stimulation technique, and it
was used for modulating the brain disorders. In this study,
these researchers enrolled 13 ASD children (11 males and 2
females; mean ± SD age of 6.5 ± 1.7 years) to examine the
effects of tDCS on ASD. Each patient received 10 treatments
over the dorsolateral prefrontal cortex (DLPFC) once every 2
days. Also, these investigators enrolled 13 ASD children (11
males and 2 females; mean ± SD age of 6.3 ± 1.7 years)
waiting to receive therapy as controls. A maximum entropy
ratio (MER) method was adapted to measure the change of
complexity of EEG series. It was found that the MER value
significantly increased after tDCS. The authors concluded that
the findings of this study suggested that tDCS may be helpful
in the rehabilitation of children with ASD. Moreover, they
stated that further research is needed to examine the potential
of brain stimulation treatments for ASD and to interpret the
mechanisms of these treatments using neuroimaging
techniques.
The authors stated that this study had several drawbacks.
First, resting-state EEG of ASD children can be influenced by
many factors, including EOG and other movements. Second,
the stimulation region of DLPFC was not confirmed by
neuroimaging but rather by using a slightly less accurate F3
placement of the standard international system. furthermore,
sham stimulation was not obtained in the experiment.
Wh ole-Exome Sequencing
Tammimies and associates (2015) stated that the use
genome-wide tests to provide molecular diagnosis for
individuals with ASD requires more study. These researchers
performed chromosomal microarray analysis (CMA) and
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whole-exome sequencing (WES) in a heterogeneous group of
children with ASD to determine the molecular diagnostic yield
of these tests in a sample typical of a developmental pediatric
clinic. Subjects consisted of 258 consecutively ascertained
unrelated children w ith ASD who underwent evaluations to
define morphology scores based on the presence of major
congenital abnormalities and minor physical anomalies. The
probands were stratified into 3 groups of increasing
morphological severity: (i) essential, (ii) equivocal, and (iii)
complex (scores of 0 to 3, 4 to 5, and greater than or equal
to 6). All probands underwent CMA, with WES performed for
95 proband-parent trios. Main outcome measure was the
overall molecular diagnostic yield for CMA and WES in a
population-based ASD sample s tratified in 3 phenotypic
groups. Of 258 probands, 24 (9.3 %, 95 % CI: 6.1 % to 13.5
%) received a molecular diagnosis from CMA and 8/95 (8.4 %,
95 % CI: 3.7 % to 15.9 %) from WES. The yields were
statistically different between the morphological groups.
Among the children who underwent both CMA and WES
testing, the estimated proportion with an identifiable genetic
etiology was 15.8 % (95 % CI: 9.1 % to 24.7 %; 15/95
children). This included 2 children who received molecular
diagnoses from both tests. The combined yield was
significantly higher in the complex group w hen compared with
the essential group (pair-wise comparison, p = 0.002). The
authors concluded that among a heterogeneous sample of
children with ASD, the molecular diagnostic yields of CMA and
WES were comparable, and the combined molecular
diagnostic yield was higher in children w ith more complex
morphological phenotypes in comparison with the children in
the essential category. They stated that if replicated in
additional populations, these findings may inform appropriate
selection of molecular diagnostic testing for children affected
by ASD. The drawbacks of this study were: (i) a relatively
small sample size as well as possible ascertainment bias
related to the clinical differences that may have existed
between families who consented and declined (less than 10
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% declined to participate in the study after diagnosis in the
developmental pediatric clinics), (ii) only 63.5 % of the
children had brain MRI, which may have skewed the final
morphological classification in favor of the essential group,
and only 49.2 % (127/258) of the study sample underwent
IQ testing, (iii) only 36.8 % (95/258) of the children were
included in the WES analysis, which could have led to an
unmeasured confounding effect on the results, (iv) WES
does not provide equal coverage for all the coding
sequence regions, and lacks sensitivity and specificity for
the detection of structural variants, and (v) the resolution
limits of CMA, the inability to detect the majority of larger
indels (greater than20 base pairs) and smaller CNVs (less
than 20 kilobases).
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":
Code Code Description
CPT codes covered if selection criteria are met:
80047 Basic metabolic panel (Calcium, ionized)
80048 Basic metabolic panel (Calcium, total)
80053 Comprehensive metabolic panel
81228 Cytogenomic constitutional (genome-wide)
microarray analysis; interrogation of genomic
regions for copy number variants (eg, bacterial
artificial chromosome [BAC] or oligo-based
comparative genomic hybridization [CGH]
microarray analysis)
Proprietary
Code Code Description
81229 interrogation of genomic regions for copy
number and single nucleotide polymorphism
(SNP) variants for chromosomal abnormalities
81277 Cytogenomic neoplasia (genome-wide)
microarray analysis, interrogation of genomic
regions for copy number and loss-of-
heterozygosity variants for chromosomal
abnormalities
83655 Chemistry examination; lead
88245 Chromosome analysis for breakage syndromes;
baseline Sister Chromatid Exchange (SCE), 20
- 25 cells
88248 baseline breakage, score 50 - 100 cells,
count 20 cells, 2 karyotypes (e.g., for ataxia
telangiectasia, Fanconi anemia, fragile X)
88249 score 100 cells, clastogen stress (e.g.,
diepoxybutane, mitomycin C, ionizing radiation,
UV radiation)
88261 Chromosome analysis; count 5 cells, 1
karyotype, with banding
88262 count 15 - 20 cells, 2 karyotypes, with
banding
88263 count 45 cells for mosaicism, 2 karyotypes,
with banding
88264 analyze 20 - 25 cells
+90785 Interactive complexity (List separately in
addition to the code for primary procedure)
90832 -
90840
Psychotherapy
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Proprietary
Code Code Description
90845 -
90853
Other psychotherapy [covered for co-morbid
medical or psychological conditions - not
covered for neurofeedback]
92521 Evaluation of speech fluency (eg, stuttering,
cluttering)
92522 Evaluation of speech sound production (eg,
articulation, phonological process, apraxia,
dysarthria)
92523 Evaluation of speech sound production (eg,
articulation, phonological process, apraxia,
dysarthria); with evaluation of language
comprehension and expression (eg, receptive
and expressive language)
92524 Behavioral and qualitative analysis of voice and
resonance
92585 Auditory evoked potentials for evoked response
audiometry and/or testing of the central nervous
system; comprehensive
92586 limited
92605 Evaluation for prescription of non-speech-
generating augmentative and alternative
communication device
92606 Therapeutic service(s) for the use of non-
speech-generating device, including
programming and modification
92607 Evaluation for prescription f or speech-
generating augmentative and alternative
communication device, face-to-face with the
patient; first hour
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Proprietary
Code Code Description
+ 92608 each additional 30 minutes (List separately in
addition to code for primary procedure)
92609 Therapeutic services for the use of speech-
generating device, including pr ogramming and
modification
95812 Electroencephalogram (EEG) extended
monitoring; 41 - 60 minutes [covered for
symptoms that may indicate seizures - not EEG
biofeedback]
95813 greater than one hour [covered for symptoms
that may indicate seizures - not EEG
biofeedback]
95816 Electroencephalogram (EEG); including
recording awake and drowsy [covered for
symptoms that may indicate seizures - not EEG
biofeedback]
95819 including recording awake and as leep
[covered for symptoms that may indicate
seizures - not EEG biofeedback]
95822 recording in coma or sleep only [covered for
symptoms that may indicate seizures - not EEG
biofeedback]
95827 all night recording [covered for symptoms
that may indicate seizures - not EEG
biofeedback]
96127 Brief emotional/behavioral assessment (eg,
depression inventory, attention-
deficit/hyperactivity disorder [ADHD] scale),
with scoring and documentation, per
standardized instrument
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Proprietary
Code Code Description
96156 Health behavior assessment, or re-assessment
(ie, health-focused clinical interview, behavioral
observations, clinical decision m aking)
96158 -
96171
Health behavior intervention
97151 -
97158
Adaptive Behavior Assessments and treatment
97161 -
97168
Physical and occupational therapy evaluation
and re-evaluation
CPT codes not covered for indications listed in the CPB:
SLC25A12, Biomat, Growth factor levels, genetic testing
for COX10, Plasma oxytocin (OXT), Alpha-ketoglutarate,
Alanine, Succinate, testing of single-nucleotide
polymorphisms within the OXT and VP receptor genes -
no specific code
0063U Neurology (autism), 32 amines by LC-MS/MS,
using plasma, algorithm reported as metabolic
signature associated with autism spectrum
disorder [metabolomic analysis of blood
samples]
0111T Long-chain (C20-22) omega-3 fatty acids in red
blood cell (RBC) membranes
0139U Neurology (autism spectrum disorder [ASD]),
quantitative measurements of 6 central carbon
metabolites (ie, a-ketoglutarate, alanine,
lactate, phenylalanine, pyruvate, and
succinate), LC-MS/MS, plasma, algorithmic
analysis with result reported as negative or
positive (with metabolic subtypes of ASD)
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Proprietary
Code Code Description
0170U Neurology (autism spectrum disorder [ASD]),
RNA, next-generation sequencing, saliva,
algorithmic analysis, and results reported as
predictive probability of ASD diagnosis
38205 Blood-derived hematopoietic cell harvesting for
transplantation. per collection; allogeneic
38206 -
38215
Transplant preparation procedures
38230 Bone marrow harvesting for transplantation;
allogeneic
38232 autologous
38240 Hematopoietic progenitor cell (HPC); allogeneic
transplantation per donor
38241 autologous transplantation
70450 Computed tomography, head or brain; without
contrast material
70460 with contrast material(s)
70470 without contrast material, followed by
contrast material(s) and further sections
70496 Computed tomographic angiography, head,
with contrast material(s), including noncontrast
images, if performed, and image
postprocessing
70544 Magnetic resonance angiography, head;
without contrast material(s)
70545 with contrast material(s)
70546 without contrast material(s), followed by
contrast material(s) and further sequences
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Proprietary
Code Code Description
70551 Magnetic resonance (e.g., proton) imaging,
brain (including brain stem); without contrast
material
70552 with contrast material(s)
70553 without contrast material, followed by
contrast material(s) and further sequences
76390 Magnetic resonance spectroscopy
78600 Brain imaging, less than 4 static views
78601 with vascular flow
78605 Brain imaging, minimum 4 static views
78606 with vascular flow
78607 Brain imaging, tomographic (SPECT)
78608 Brain imaging, positron emission tomography
(PET); metabolic evaluation
78609 perfusion evaluation
80178 Lithium
81291 Methylenetetrahydrofolate Reductase
(MTHFR), DNA Mutation
81415 Exome (eg, unexplained constitutional or
heritable disorder or syndrome); sequence
analysis
81416 sequence analysis, each comparator exome
(eg, parents, siblings) (List separately in
addition to code for primary procedure)
81417 re-evaluation of previously obtained exome
sequence (eg, updated knowledge or unrelated
condition/syndrome)
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Proprietary
Code Code Description
82108 Aluminum
82136 Amino acids, 2 to 5 amino acids, quantitative,
each specimen
82139 Amino acids, 6 or more amino acids,
quantitative, each specimen
82180 Ascorbic acid (Vitamin C), blood
82300 Cadmium
82306 Calcifediol (25-OH Vitamin D-3)
82310 Calcium; total
82495 Chromium
82507 Citrate
82525 Copper
82607 Cyancobalamin (Vitamin B-12)
82608 unsaturated binding capacity
82652 Vitamin D; 1, 25 dihydroxy, includes fraction(s),
if performed
82725 Fatty acids, nonesterified
82726 Very long chain fatty acids
82746 Folic acid; serum
82747 RBC
82784 Gammaglobulin; IgA, IgD, IgG, IgM, each [for
celiac antibodies]
82785 Gammaglobulin; IgE
83015 Heavy metal (e.g., arsenic, barium, beryllium,
bismuth, antimony, mercury); screen
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Proprietary
Code Code Description
83018 quantitative, each
83090 Homocysteine
83516 Immunoassay for analyte other than infectious
agent antibody or infectious agent antigen;
qualitative or semiquantitative, multiple step
method
83518 qualitative or semiquantitative, single step
method (eg, reagent strip)
83519 quantitative, by radioimmunoassay (eg, RIA)
83520 not otherwise specified [for celiac antibodies]
83540 Iron
83550 Iron binding capacity
83605 Lactate (lactic acid)
83655 Lead
83735 Magnesium
83785 Manganese
83885 Nickel
83918 Organic acids; total, quantitative, each
specimen
83919 qualitative, each specimen
83921 Organic acid, single, quantitative [not covered
for tartaric acid nutritional testing]
84030 Phenylalanine (PKU), blood
84100 Phosphorus inorganic (phosphate)
84105 urine
84207 Pyridoxal phosphate (Vitamin B-6)
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Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 101 of 138
Proprietary
Code Code Description
84210 Pyruvate
84252
84255
Riboflavin (Vitamin B-2)
Selenium
84285 Silica
84375 -
84379
Sugars [not covered for nutritional or arabinose
testing]
84425 Thiamine (Vitamin B-1)
84443 Thyroid stimulating hormone (TSH)
84446 Tocopherol alpha (Vitamin E)
84479 Thyroid hormone (T3 or T4) uptake or thyroid
hormone binding ratio (THBR)
84585 Vanillylmandelic acid (vma), urine
84588 Vasopressin (antidiuretic hormone, ADH)
84590 Vitamin A
84591 Vitamin, not otherwise specified
84597 Vitamin K
84600 Volatiles (eg, acetic anhydride, diethylether)
84630 Zinc
86001 Allergen specific IgG quantitative or semi-
quantitative, each allergen
86003 Allergen specific IgE; quantitative or semi-
quantitative, each allergen
86005 qualitative, multi-allergen screen (dipstick,
paddle or disk)
86140 C-reactive protein
Code Code Description
86160 Complement; antigen, each component
86161 functional activity, each component
86162 total hemolytic (CH50)
86255 Fluorescent noninfectious agent antibody;
screen, each antibody
86256 titer, each antibody
86332 Immune complex assay
86343 Leukocyte histamine release test (LHR)
86485 Skin test; candida
86628 Antibody; candida
88341 -
88344
Immunohistochemistry or
immunocytochemistry, per specimen
88346 Immunofluorescence, per specimen; initial
single antibody stain procedure
88350 Immunofluorescence, per specimen; each
additional single antibody stain procedure (List
separately in addition to code for primary
procedure
90281 Immune globulin (Ig), human, for intramuscular
use
90283 Immune globulin (IgIV), human, for intravenous
use
90870 Electroconvulsive therapy (includes necessary
monitoring) [for the treatment of autistic
catatonia]
90901 Biofeedback training by any modality
[neurofeedback/EEG biofeedback]
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Proprietary
Code Code Description
92065 Orthopic and/or pleoptic training, with
continuing medical direction and evaluation
92507 Treatment of speech, language, voice,
communication, and/or auditory processing
disorder; individual
92508 group,2 or more individuals
92540 Basic vestibular evaluation, includes
spontaneous nystagmus test with eccentric
gaze fixation nystagmus, with recording,
positional nystagmus test, minimum of 4
positions, with recording, optokinetic
nystagmust test, bidirectional foveal and
peripheral stimulation, with recording, and
oscillating tracking test, with recording
92541 -
92548
Vestibular function tests, with recording (e.g.,
ENG, PENG), and medical diagnostic
evaluation
92550 Tympanometry and reflex threshhold
measurements
92567 Tympanometry (impedance testing)
92568 -
92569
Acoustic reflex testing
92570 Acoustic immittance testing, includes
typanometry (impedance testing), acoustic
reflex threshold testing, and acoustic reflex
decay testing
95004 Percutaneous tests (scratch, puncture, prick)
with allergenic extracts, immediate type
reaction, including test interpretation and report
by a physician, specify number of tests
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 103 of 138
Proprietary
Code Code Description
95017 Allergy testing, any combination of
percutaneous (scratch, puncture, prick) and
intracutaneous (intradermal), sequential and
incremental, with venoms, immediate type
reaction, including test interpretation and report,
specify number of tests
95018 Allergy testing, any combination of
percutaneous (scratch, puncture, prick) and
intracutaneous (intradermal), sequential and
incremental, with drugs or biologicals,
immediate type reaction, including test
interpretation and report, specify number of
tests
95024 Intracutaneous (intradermal) tests with
allergenic extracts, immediate type reaction,
including test interpretation and report by a
physician, specify number of tests
95027 Intracutaneous (intradermal) tests, sequential
and incremental, with allergenic extracts for
airborne allergens, immediate t ype reaction,
including test interpretation and report by a
physician, specify number of tests
95028 Intracutaneous (intradermal) tests with
allergenic extracts, delayed type reaction,
including reading, specify number of tests
95044 Patch or application t est(s) (specify number of
tests)
95052 Photo patch test(s) (specify number of tests)
95056 Photo tests
95060 Ophthalmic mucous membrane tests
95065 Direct nasal mucous membrane tests
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 104 of 138
Proprietary
Code Code Description
95070 Inhalation bronchial challenge testing (not
including necessary pulmonary function tests);
with histamine, methacholine, or similar
compounds
95071 with antigens or gases, specify
95076 Ingestion challenge t est (sequential and
incremental ingestion of test items, eg, food,
drug or other substance); initial 120 minutes of
testing
+95079 Ingestion challenge t est (sequential and
incremental ingestion of test items, eg, food,
drug or other substance); each additional 60
minutes of testing (List separately in addition to
code for primary procedure)
95961 Functional cortical and subcortical mapping by
stimulation and/or recording of electrodes on
brain surface, or of depth electrodes, to
provoke seizures or identify vital brain
structures; initial hour of physician attendance
+ 95962 each additional hour of physician attendance
(List separately in addition to code for primary
procedure)
95965 Magnetoencephalography (MEG), recording
and analysis; for spontaneous brain magnetic
activity (e.g., epileptic cerebral cortex
localization)
95966 for evoked magnetic fields, single modality
(e.g., sensory, motor, language, or visual cortex
localization)
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 105 of 138
Proprietary
Code Code Description
+ 95967 for evoked magnetic fields, each additional
modality (e.g., sensory, motor, language, or
visual cortex localization) (List separately in
addition to code for primary procedure)
96020 Neurofunctional testing selection and
administration during non invasive imaging
functional brain mapping, with test administered
entirely by a physician or other qualified health
care professional (ie, psychologist), with review
of test results and report
96116 -
96125
Neuropsychological testing
96130 -
96131
Psychological testing evaluation s ervices by
physician or other qualified hea lth care
professional, including integration of patient
data, interpretation of standardized test results
and clinical data, clinical decision m aking,
treatment planning and r eport, and interactive
feedback to the patient, family member(s) or
caregiver(s), when performed
96136 -
96137
Psychological or neuropsychological test
administration and scoring by physician or other
qualified hea lth care professional, two or more
tests, any method
96138 -
96139
Psychological or neuropsychological test
administration and scoring by technician, two or
more tests, any method
96146 Psychological or neuropsychological test
administration, with single automated,
standardized instrument via electronic platform,
with automated result only
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 106 of 138
Proprietary
Code Code Description
96902 Microscopic examination of hairs plucked or
clipped by the examiner (excluding hair
collected by the patient) to determine telogen
and anagen counts, or structural hair shaft
abnormality
97124 Therapeutic procedure, one or more areas,
each 15 minutes; massage, including
effleurage, petrissage and /or tapotement
(stroking, compression, percussion)
97127 Therapeutic interventions that focus on
cognitive function (eg, attention, memory,
reasoning, executive function, problem solving,
and/or pragmatic functioning) and
compensatory strategies to manage the
performance of an activity (eg, managing time
or schedules, initiating, organizing and
sequencing tasks), direct (one-on-one) patient
contact
97129 Therapeutic interventions that focus on
cognitive function (eg, attention, memory,
reasoning, executive function, problem solving,
and/or pragmatic functioning) and
compensatory strategies to manage the
performance of an activity (eg, managing time
or schedules, initiating, organizing, and
sequencing tasks), direct (one-on-one) patient
contact; initial 15 minutes
+97130 each additional 15 minutes (List separately in
addition to code for primary procedure)
97140 Manual therapy techniques (e.g.,
mobilization/manipulation, manual lymphatic
drainage, manual traction), one or more
regions, each 15 minutes
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 107 of 138
Proprietary
Code Code Description
97530 Therapeutic activities, direct (one-on-one)
patient contact (use of dynamic activities to
improve functional performance), each 15
minutes
97533 Sensory integrative techniques to enhance
sensory processing and promote adaptive
responses to environmental demands, direct
(one-on-one) patient contact, each 15 minutes
97802 -
97804
Medical nutrition therapy
97810 -
97814
Acupuncture
98925 -
98929
Osteopathic manipulative treatment (OMT)
98940 -
98943
Chiropractic manipulative treatment (CMT)
99183 Physician or other qualified health care
professional attendance and supervision of
hyperbaric oxygen therapy, per session
Other CPT codes related to the CPB:
0362T Behavior identification supporting assessment,
each 15 minutes of technicians' time face-to-
face with a patient, requiring the following
components: administration by the physician or
other qualified health care professional who is
on site; with the assistance of two or more
technicians; for a patient who exhibits
destructive behavior; completion i n an
environment that is customized to the patient's
behavior
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 108 of 138
Proprietary
Code Code Description
0373T Adaptive behavior treatment with protocol
modification, each 15 minutes of technicians '
time face-to-face with a patient, requiring the
following components: administration by the
physician or other qualified health care
professional who is on site; with the assistance
of two or more technicians; for a patient who
exhibits destructive behavior; completion in an
environment that is customized to the patient' s
behavior
97005 -
97006
Athletic training
97010 -
97546
Modalities and therapeutic procedures
98960 Education and training for patient self-
management by a qualified, nonphysician
health care professional using a standardized
curriculum, face-to-face with the patient (could
include caregiver/family) each 30 minutes;
individual patient
99201 -
99215
Office or other outpatient visit
HCP CS codes covered if selection criteria are met:
E1902 Communication board, non-electronic
augmentative or alternative communication
device
E2500 -
E2599
Speech generating devices
V 5008 Hearing screening
V 5362 Speech screening
V 5363 Language screening
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 109 of 138
Proprietary
Code Code Description
HCPCS codes not covered for indications listed in the CPB:
A4575 Topical hyperbaric oxygen chamber, disposable
A9152 Single vitamin/mineral/trace element, oral, per
dose, not otherwise specified [omega-3 fatty
acid supplements]
E0446 Topical oxygen delivery system, not otherwise
specified, includes all supplies and accessories
G0068 Professional services for the administration of
anti-infective, pain management, chelation,
pulmonary hypertension, and/or inotropic
infusion drug(s) for each infusion dr ug
administration calendar day in the individual's
home, each 15 minutes
G0176 Activity therapy, such as music, dance, art or
play therapies not for recreation, related to the
care and treatment of patient's disabling m ental
health problems, per session (45 minutes or
more)
G0277 Hyperbaric oxygen under pressure, full body
chamber, per 30 minute interval
G0461 Immunohistochemistry or
immunocytochemistry, per specimen; first
single or multiplex antibody stain
G0462 each additional single or multiplex antibody
stain (list separately in addition to code for
primary procedure)
G0515 Development of cognitive s kills to improve
attention, memory, problem solving (includes
compensatory training), direct (one-on-one)
patient contact, each 15 minutes
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 110 of 138
Proprietary
Code Code Description
J0600 Injection, edetate calcium disodium, up to 1000
mg
J0610 Injection, calcium gluconate, per 10 ml
J0620 Injection, calcium glycerophosphate and
calcium lactate, per 10 ml
J0133 Injection, acyclovir, 5 mg
J1450 Injection, fluconazole, 200 mg
J1561 Injection, immune globulin,
(Gamunex/Gamunex-C/Gammaked),
nonlyophilized (e.g., liquid), 500 mg
J1566 Injection, immune globulin, intravenous,
lyophilized (e.g., powder), not otherwise
specified, 500 mg
J1568 Injection, immune globulin, (Octagam),
intravenous, nonlyophilized (e.g., liquid), 500
mg
J1569 Injection, immune globulin, (Gammagard liquid),
nonlyophilized, (e.g., liquid), 500 mg
J1572 Injection, immune globulin, (Flebogamma),
intravenous, nonlyophilized (e.g., liquid), 500
mg
J2590 Injection, oxytocin, up to 10 units
J2850 Injection, secretin, synthetic, human, 1mcg
J3415 Injection, pyridoxine HCl, 100 mg
J3475 Injection, magnesium sulphate, per 500 mg
P2031 Hair analysis (excluding arsenic)
S0030 Injection, metronidazole, 500 mg
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 111 of 138
Proprietary
Code Code Description
S8035 Magnetic source imaging
S8040 Topographic brain mapping
S8940 Equestrian/Hippotherapy, per session
S9355 Home infusion therapy, chelation therapy;
administrative services, professional pharmacy
services, care coordination, and all necessary
supplies and equipment (drugs and nursing
visits coded separately), per diem
S9470 Nutritional counseling, dietitian visit
O ther HCPCS codes related to the CPB:
G0151 Services performed by a qualified phy sical
therapist in the home health or hospice setting,
each 15 minutes
G0153 Services performed by a qualified s peech-
language pathologist in the home health or
hospice setting, each 15 minutes
G0161 Services performed by a qualified s peech-
language pathologist, in the home health
setting, in the establishment or delivery of a
safe and effective speech-language pathology
maintenance program, each 15 minutes
S9128 Speech therapy, in the home, per diem
S9129 Occupational therapy, in the home, per diem
S9131 Physical therapy, in the home, per diem
T1029 Comprehensive environmental lead
investigation, not including l aboratory analysis,
per dwelling
ICD-10 codes covered if selection criteria are met:
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 112 of 138
Proprietary
Code Code Description
F84.0 -
F84.9
Pervasive developmental disorders
Z13.41 Encounter for autism screening
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 113 of 138
The above policy is based on the following references:
1. Agency for Healthcare Research and Quality (AHRQ)
Website. Comparative Effectiveness Review.
Interventions for adolescents and young adults with
autism spectrum disorder. August 2014.
2. Aggressive Research Intelligence Facility (ARIF). Gluten
free diets for autism. Requests for Information -
Completed. Birmingham, UK: University of
Birmingham; April 2003. Available at:
http://www.bham.ac.uk/arif/autism
glutenfreediets.htm. Accessed October 17, 2003.
3. Al-Ayadhi L, El-Ansary A, Bjorklund G, et al. Impact of
auditory integration therapy (AIT) on the plasma levels
of human glial cell line-derived neurotrophic factor
(GDNF) in autism spectrum disorder. J Mol Neurosci.
2019;68(4):688-695.
4. Alcantara J, Alcantara JD, Alcantara J. A systematic
review of the literature on the chiropractic care of
patients with autism spectrum disorder. Explore (NY).
2011;7(6):384-390.
5. Aman MG, Findling RL, Hardan AY, et al. Safety and
efficacy of memantine in children with autism:
Randomized, placebo-controlled study and open-label
extension. J Child Adolesc Psychopharmacol. 2017;27
(5):403-412.
6. American Academy of Allergy, Asthma and
Immunology (AAAAI) Website. Position Statement
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 114 of 138
(ARCHIVED). The appropriate use of intravenously
administered immunoglobulin (IGIV). January 2005.
7. American Academy of Child and Adolescent Psychiatry
(AACAP) Website. Policy Statement. Secretin in the
treatment of autism. June 15, 2002.
8. American Academy of Child and Adolescent Psychiatry
(AACAP) Website. Policy Statement. Screening children
for lead: guidelines for children and adolescent
psychiatrists. March 1995.
9. American Academy of Child and Adolescent Psychiatry
(AACAP) Website. Policy Statement. Facilitated
communication. June 2008.
10. American Academy of Child and Adolescent Psychiatry.
Practice parameters for the assessment and treatment
of children, adolescents, and adults with autism and
other pervasive developmental disorders. J Am Acad
Child Adolesc Psychiatry. 1999;38(12 Suppl):32S-54S.
11. American Academy of Pediatrics (AAP) Website. Policy
Statement. Identifying infants and young children with
developmental disorders in the medical home: An
algorithm for developmental surveillance and
screening. July 2006.
12. American Academy of Pediatrics (AAP) Website. Policy
Statement. Sensory integration therapies for children
with developmental and behavioral disorders. May 28,
2012.
13. American Academy of Pediatrics (AAP). Speech
development. Guide to your child's symptoms.
Parenting Book. Elk Grove Village, IL: AAP; 2002.
Available at: http://www.aap.org/pubserv/speech.htm.
Accessed July 9, 2002.
14. American Academy of Pediatrics, Committee on
Children with Disabilities. The pediatrician's role in the
diagnosis and management of autistic spectrum
disorder in children (RE060018). Policy Statement.
Pediatrics. 2001;107(5):1221-1226. Available at:
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 115 of 138
http://www.aap.org/policy/re060018.html. Accessed
July 9, 2002.
15. American Academy of Pediatrics, Committee on
Children with Disabilities. Developmental surveillance
and screening of infants and young children (RE0062).
Pediatrics. 2001;108(1):192-196.
http://www.aap.org/policy/re0062.html. Accessed July
9, 2002.
16. American Academy of Pediatrics, Committee on
Children with Disabilities. Technical report: The
pediatrician's role in the diagnosis and management
of autistic spectrum disorder in children. Pediatrics.
2001;107(5). Available at:
http://www.pediatrics.org/cgi/content/full/107/5/e85.
Accessed July 11, 2002.
17. American Academy of Pediatrics, Committee on
Children with Disabilities. Auditory integration training
and facilitated communication for autism (RE9752).
Policy Statement. Pediatrics. 1998;102(2):431-433.
Available at: http://www.aap.org/policy/re9752.html.
Accessed July 9, 2002.
18. American Speech-Language-Hearing Association
(ASHA). Position statement on facilitated
communication. ASHA. 1995;37(Suppl 14):22. Available
at:
http://www.caslpo.com/english_site/m_mempositfac.asp.
Accessed September 21, 2005.
19. Anagnostou E, Soorya L, Brian J, et al. Intranasal
oxytocin in the treatment of autism spectrum
disorders: A review of literature and early safety and
efficacy data in youth. Brain Res. 2014;1580:188-198.
20. Aoki Y, Cortese S. Mitochondrial aspartate/glutamate
carrier SLC25A12 and autism spectrum disorder: A
meta-analysis. Mol Neurobiol. 2016;53(3):1579-1588.
21. Association for Science in Autism Treatment (ASAT).
Sensory integration. Autism Information. Portland, ME:
ASAT; 2001. Available at:
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 116 of 138
http://www.asatonline.org/autism_info12.html.
Accessed June 25, 2002.
22. Augustovski F, Pichon Riviere A, Alcaraz A, et al.
Usefulness of music therapy in clinical practice
[summary]. Report IRR No. 85. Buenos Aires,
Argentina: Institute for Clinical Effectiveness and
Health Policy (IECS); 2006.
23. Augustyn M. Autism spectrum disorder: Diagnosis.
UpToDate Inc., Waltham, MA. Last reviewed April 2017.
24. Augustyn M. Autism spectrum disorder: Screening
tools. UpToDate Inc., Waltham, MA. Last reviewed
December 2019
25. Augustyn M, von Hahn LE. Autism spectrum disorder:
Clinical features. UpToDate Inc., Waltham, MA. Last
reviewed December 2019a
26. Augustyn M, von Hahn LE. Autism spectrum disorder:
Evaluation and diagnosis. UpToDate Inc., Waltham,
MA. Last reviewed December 2019b.
27. Baird G, Cass H, Slonims V. Diagnosis of autism.
Clinical Review. Br Med J. 2003;327:488-493.
28. Barnard L, Young AH, Pearson J, et al. A systematic
review of the use of atypical antipsychotics in autism. J
Psychopharmacol. 2002;16(1):93-101.
29. Bassett K, Green C J, Kazanjian A. Autism and Lovaas
treatment: A systematic review of effectiveness
evidence. BCOHTA 00:1T. Vancouver, BC: British
Columbia Office of Health Technology Assessment,
Centre for Health Services and Policy Research,
University of British Columbia; July 2000.
30. Bell CM. Music therapy for children with autistic
spectrum disorder. Bazian, Ltd., eds. London, UK:
Wessex Institute for Health Research and
Development, University of Southampton; 2003.
31. Berggren S, Fletcher-Watson S, Milenkovic N, et al.
Emotion recognition training in autism spectrum
disorder: A systematic review of challenges related to
generalizability. Dev Neurorehabil. 2018;21(3):141-154.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 117 of 138
32. Bernstein BE. Pervasive developmental disorder:
Childhood disintegration disorder. eMedicine
Pediatrics Topic 2654. Omaha, NE: eMedicine.com;
updated March 10, 2003. Available at:
http://www.emedicine.com/ped/topic2654.htm.
Accessed April 5, 2004.
33. Best L, Milne R. Auditory integration training in autism.
DEC Report No. 66. Southampton, UK: Wessex Institute
for Health Research and Development (WIHRD),
University of Southampton; 1997.
34. Bieleninik L, Geretsegger M, Mössler K, et al; TIME-A
Study Team. Effects of improvisational music therapy
vs enhanced standard care on symptom severity
among children with autism spectrum disorder: The
TIME-A randomized clinical trial. JAMA. 2017;318
(6):525-535.
35. BioSpace. FDA approves Risperdal (R) for treatment of
irritability associated with autistic disorder. Press
Release. Titusville, NJ: BioSpace; October 2006.
36. BlueCross BlueShield Association (BCBSA), Technology
Evaluation Center (TEC). Special report: Early intensive
behavioral intervention based on applied behavior
analysis among children with autism spectrum
disorders. TEC Assessment Program. Chicago, IL:
BCBSA; February 2009;23(9).
37. BlueCross BlueShield Association (BCBSA), Technology
Evaluation Center (TEC). Special Report: Early intensive
behavioral intervention based on applied behavior
analysis among children with autism spectrum
disorders. TEC Assessments in Press. Chicago, IL:
BCBSA; October 2010. Available at:
http://www.bcbs.com/blueresources/tec/press/special
report-early.html. Accessed September 13, 2011.
38. Boddaert N, Zilbovicius M. Functional neuroimaging
and childhood autism. Pediatr Radiol. 2002;32(1):1-7.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 118 of 138
39. Boyd RD, Corley MJ. Outcome survey of early intensive
behavioral intervention for young children with autism
in a community setting. Autism. 2001;5(4):430-441.
40. Brasic JR. Pervasive developmental disorder: Asperger
syndrome. eMedicine Pediatrics Topic 147. Omaha,
NE: eMedicine.com; updated October 22, 2003.
Available at:
http://www.emedicine.com/ped/topic147.htm.
Accessed April 5, 2004.
41. Brasic JR. Pervasive developmental disorder: Autism.
eMedicine Pediatrics Topic 180. Omaha, NE:
eMedicine.com; updated April 24, 2003. Available at:
http://www.emedicine.com/ped/topic180.htm.
Accessed October 17, 2003.
42. Bristol MM, Cohen DJ, Costello EJ, et al. State of science
in autism: Report to the National Institutes of Health. J
Autism Dev Disord. 1996;26:121-154.
43. Bristol-Myers Squibb Co. (BMS). U.S. Food and Drug
Administration approves Abilify® (aripiprazole) for the
treatment of irritability associated with autistic
disorder in pediatric patients (Ages 6 to 17 Years).
Press Release. Princeton, NJ: BMS; November 2009.
44. Bristol-Power MM, Spinella G. Research on screening
and diagnosis in autism: a work in progress. J Autism
Dev Disord. 1999;29(6):435-438.
45. Broadstock M, Doughty C. The effectiveness of
pharmacological therapies for young people and
adults with autism spectrum disorder (ASD): A critical
appraisal of the literature. Christchurch, NZ: New
Zealand Health Technology Assessment (NZHTA);
2003.
46. Brondino N, Fusar-Poli L, Panisi C, et al.
Pharmacological modulation of GABA function in
autism spectrum disorders: A systematic review of
human studies. J Autism Dev Disord. 2016;46(3):825
839.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 119 of 138
47. Brondino N, Rocchetti M, Fusar-Poli L, et al. Increased
CNTF levels in adults with autism spectrum disorders.
World J Biol Psychiatry. 2018 Jun 5:1-13 [Epub ahead of
print].
48. Canadian Paediatric Society. Early intervention for
autism. Position Statement (PP2004-02). Paediatr Child
Health. 2004;9(4):267-270. Available at:
http://www.cps.ca/english/publications/Psychosocial.htm.
Accessed March 2, 2007.
49. Case-Smith J, Bryan T. The effects of occupational
therapy with sensory integration emphasis on
preschool-age children with autism. Am J Occup Ther.
1999;53(5):489-497.
50. Case-Smith J, Weaver LL, Fristad MA. A systematic
review of sensory processing interventions for children
with autism spectrum disorders. Autism. 2015;19
(2):133-148.
51. Center for Autism & Related Disabilities (CARD).
Diagnosing and evaluating autism: Part 1. CARD Fact
Sheet No. 3. Tampa, FL: University of South Florida;
revised May 2001. Available at: http://card
usf.fmhi.usf.edu/factsheets.asp. Accessed October 17,
2003.
52. Center for Autism & Related Disabilities (CARD).
Diagnosing and evaluating autism: Part 2. CARD Fact
Sheet No. 4. Tampa, FL: University of South Florida;
revised May 2001. Available at: http://card
usf.fmhi.usf.edu/factsheets.asp. Accessed October 17,
2003.
53. Chen Q, Qiao Y, Xu XJ, et al. Urine organic acids as
potential biomarkers for autism-spectrum disorder in
Chinese children. Front Cell Neurosci. 2019;13:150.
54. Cheuk DK, Wong V, Chen WX. Acupuncture for autism
spectrum disorders (ASD). Cochrane Database Syst
Rev. 2011;(9):CD007849.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 120 of 138
55. Chiocchetti AG, Bour HS, Freitag CM. Glutamatergic
candidate genes in autism spectrum disorder: An
overview. J Neural Transm. 2014;121(9):1081-1106.
56. Corbett B, Khan K, Czapansky-Beilman D, et al. A
double-blind, placebo-controlled crossover study
investigating the effect of porcine secretin in children
with autism. Clin Pediatr (Phila). 2001;40(6):327-331.
57. Corbett BA, Shickman K, Ferrer E. Brief report: The
effects of Tomatis sound therapy on language in
children with autism. J Autism Dev Disord. 2008;38
(3):562-566.
58. Coucouvanis J. Behavioral intervention for children
with autism. J Child Adolesc Psychiatr Nurs. 1997;10
(1):37-44.
59. Coury D. Medical treatment of autism spectrum
disorders. Curr Opin Neurol. 2010;23(2):131-136.
60. Crawford MJ, Gold C, Odell-Miller H, et al. International
multicentre randomised controlled trial of
improvisational music therapy for children with autism
spectrum disorder: TIME-A study. Health Technol
Assess. 2017 Oct;21(59):1-40.
61. Curtis LT, Patel K. Nutritional and environmental
approaches to preventing and treating autism and
attention deficit hyperactivity disorder (ADHD): A
review. J Altern Complement Med. 2008;14(1):79-85.
62. Dagg P. Pervasive developmental disorder: Autism.
eMedicine J. 2001;2(10). Available at:
http://www.emedicine.com/med/topic3202.htm.
Accessed July 9, 2002.
63. Dawson G, Watling R. Interventions to facilitate
auditory, visual, and motor integration in autism: A
review of the evidence. J Autism Dev Disord. 2000;30
(5):415-421.
64. DeJong H, Bunton P, Hare DJ. A systematic review of
interventions used to treat catatonic symptoms in
people with autistic spectrum disorders. J Autism Dev
Disord. 2014;44(9):2127-2136.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 121 of 138
65. Delprato DJ. Comparisons of discrete-trial and
normalized behavioral language intervention for
young children with autism. J Autism Dev Disord.
2001;31(3):315-325.
66. Diggle T, McConachie H R, Randle V R L Parent-
mediated early intervention for young children with
autism spectrum disorder. Cochrane Database Syst
Rev. 2002;(2):CD003496.
67. Doughty C. What is the evidence for the effectiveness
of behavioural and skill-based early intervention in
young children with Autism Spectrum Disorder (ASD)?
New Zealand Health Technology Assessment (NZHTA)
Tech Brief Series. Christchurch, NZ: Department of
Public Health and General Practice, Christchurch
School of Medicine and Health Sciences; April 2004;3
(1). Available at:
http://nzhta.chmeds.ac.nz/publications.htm#review.
Accessed April 6, 2005.
68. Dua V and the Autism Spectrum Disorders Standards
and Guidelines Working Group. Standards and
guidelines for the assessment and diagnosis of young
children with autism spectrum disorder in British
Columbia. An Evidence-Based Report prepared for the
British Columbia Ministry of Health Planning. Victoria,
BC: British Columbia Ministry of Health Services;
March 2003.
69. ECRI. Comprehensive programs for the treatment of
children with autism. ECRI Report. Plymouth Meeting,
PA: ECRI; 2000, as cited in Ludwig S, Harstall C.
Intensive intervention programs for children with
autism. Health Technology Assessment. HTA-8: Series
B. Edmonton, AB: Alberta Heritage Foundation for
Medical Research (AHFMR); February 2001.
70. Eikeseth S, Smith T, Jahr E, Eldevik S. Intensive
behavioral treatment at school for 4- to 7-year-old
children with autism. A 1-year comparison controlled
study. Behav Modif. 2002;26(1):49-68.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 122 of 138
71. El-Rashidy O, El-Baz F, El-Gendy Y, et al. Ketogenic diet
versus gluten free casein free diet in autistic children:
A case-control study. Metab Brain Dis. 2017;32
(6):1935-1941.
72. Erickson CA, Veenstra-Vanderweele JM, Melmed RD, et
al. STX209 (arbaclofen) for autism spectrum disorders:
An 8-week open-label study. J Autism Dev Disord.
2014;44(4):958-964.
73. European Molecular Biology Laboratory-European
Bioinformatics Institute (EMBL-EBI). Metabolomics: An
introduction [website]. Hinxton, Cambridgeshire, UK:
EMBL-EBI; updated 2018. Accessed September 26,
2018. Available at:
https://www.ebi.ac.uk/training/online/course/introduction
metabolomics/what-metabolomics.
74. Evans SL, Dal Monte O, Noble P, Averbeck BB.
Intranasal oxytocin effects on social cognition: A
critique. Brain Res. 2014;1580:69-77.
75. Feasby T, Banwell B, Benstead T, et al. Guidelines on
the use of intravenous immune globulin for neurologic
conditions. Transfus Med Rev. 2007;21(2 Suppl 1):S57
S107.
76. Filipek PA, Accardo PJ, Ashwal S, et al. 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.
77. Frank Y, Pavlakis SG. Brain imaging in neurobehavioral
disorders. Pediatr Neurol. 2001;25(4):278-287.
78. Gill AR. Interventions for autism. JAMA. 2001;286
(6):670-671.
79. Gogou M, Kolios G. Are therapeutic diets an emerging
additional choice in autism spectrum disorder
management? World J Pediatr. 2018;14(3):215-223.
80. Gold C, Wigram T, Elefant C. Music therapy for autistic
spectrum disorder. Cochrane Database Syst Rev. 2006;
(2):CD004381.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 123 of 138
81. Goldstein H. Communication intervention for children
with autism: A review of treatment efficacy. J Autism
Develop Disord. 2002;32(5):373-396.
82. Green G, Brennan LC, Fein D. Intensive behavioral
treatment for a toddler at high risk for autism. Behav
Modif. 2002;26(1):69-102.
83. Gresham FM, Macmillan DL. Early Intervention Project:
Can its claims be substantiated and its effects
replicated? J Autism Dev Disord. 1998;28(1):5-13.
84. Harrower JK, Dunlap G. Including children with autism
in general education classrooms. A review of effective
strategies. Behav Modif. 2001;25(5):762-784.
85. Hicks SD, Carpenter RL, Wagner KE, et al. Saliva
microRNA differentiates children with autism from
peers with typical and atypical development. J AM Acad
Child Adolesc Psychiatry. 2020;59(2):296-308.
86. Hicks SD, Rajan AT, Wagner KE, et al. Validation of a
salivary RNA test for childhood autism spectrum
disorder. Fron Genet. 2018;9:534.
87. Horner RH, Carr EG, Strain PS, et al. Problem
behaviour interventions for young children with
autism: A research synthesis. J Autism Develop Disord.
2002;32(5):423-446.
88. Horvath A, Łukasik J, Szajewska H. ω-3 fatty acid
supplementation does not affect autism spectrum
disorder in children: A systematic review and meta-
analysis. J Nutr. 2017;147(3):367-376
89. Howlin P. Can early interventions alter the course of
autism? Novartis Found Symp. 2003;251:250-265, 281
297.
90. Ichim TE, Solano F, Glenn E, et al. Stem cell therapy for
autism. J Transl Med. 2007;5:30.
91. James S, Montgomery P, Williams K. Omega-3 fatty
acids supplementation for autism spectrum disorders
(ASD). Cochrane Database Syst Rev. 2011;
(11):CD007992.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 124 of 138
92. Janssen Pharmaceuticals, Inc. Risperdal®
(risperidone). Prescribing Information. Titusville, NJ:
Janssen; revised February 2017.
93. Jesner OS, Aref-Adib M, Coren E. Risperidone for
autism spectrum disorder. Cochrane Database Syst
Rev. 2007;(1):CD005040.
94. Johnson CP, Myers SM; Council on Children With
Disabilities. Identification and evaluation of children
with autism spectrum disorders. Pediatrics. 2007;120
(5):1183-1215.
95. Joshi G, Wozniak J, Faraone SV, et al. A prospective
open-label trial of memantine hydrochloride for the
treatment of social deficits in intellectually capable
adults with autism spectrum disorder. J Clin
Psychopharmacol. 2016;36(3):262-271.
96. Kagan-Kushnir T, Roberts SW, Snead OC 3rd. Screening
electroencephalograms in autism spectrum disorders:
Evidence-based guideline. J Child Neurol. 2005;20
(3):197-206.
97. Kang J, Cai E, Han J, et al. Transcranial direct current
stimulation (tDCS) can modulate EEG complexity of
children with autism spectrum disorder. Front
Neurosci. 2018;12:201.
98. Kern JK, Fletcher CL, Garver CR, et al. Prospective trial
of equine-assisted activities in autism spectrum
disorder. Altern Ther Health Med. 2011;17(3):14-20.
99. Koenig K, Scahill L. Assessment of children with
pervasive developmental disorder. J child Adoles
Psychiatr Nurs. 2001;14(4):159-166.
100. Korvatska E, Van de Water J, Anders TF, et al. Genetic
and immunologic considerations in autism. Neurobiol
Dis. 2002;9(2):107-125.
101. Krishnaswami S, McPheeters ML, Veenstra-
Vanderweele J. A systematic review of secretin for
children with autism spectrum disorders. Pediatrics.
2011;127(5):e1322-e1325.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 125 of 138
102. Kyriakopoulos M, Stringaris A, Manolesou S, et al.
Determination of psychosis-related clinical profiles in
children with autism spectrum disorders using latent
class analysis. Eur Child Adolesc Psychiatry. 2015;24
(3):301-307.
103. Lainhart JE, Piven J. Diagnosis, treatment, and
neurobiology of autism in children. Curr Opin Ped.
1995;7:392-400.
104. Lee B, Lee J, Cheon JH, et al. The efficacy and safety of
acupuncture for the treatment of children with autism
spectrum disorder: A systematic review and meta-
analysis. Evid Based Complement Alternat Med.
2018;2018:1057539.
105. Lee MS, Kim JI, Ernst E. Massage therapy for children
with autism spectrum disorders: A systematic review. J
Clin Psychiatry. 2011;72(3):406-411.
106. Levy SE, Mandell DS, Schultz RT. Autism. Lancet.
2009;374(9701):1627-1638.
107. Liu C, Li T, Wang Z, et al. Scalp acupuncture treatment
for children's autism spectrum disorders: A systematic
review and meta-analysis. Medicine (Baltimore).
2019a;98(13):e14880.
108. Liu J, Wan GB, Huang MS, et al. Probiotic therapy for
treating behavioral and gastrointestinal symptoms in
autism spectrum disorder: A systematic review of
clinical trials. Curr Med Sci. 2019b;39(2):173-184.
109. Liu J, Yang A, Zhang Q, et al. Association between
genetic variants in SLC25A12 and risk of autism
spectrum disorders: An integrated meta-analysis. Am J
Med Genet B Neuropsychiatr Genet. 2015;168B(4):236
246.
110. Lochman I, Svachova V, Milkova Pavlíkova K, et al.
Serum cytokine and growth factor levels in children
with autism spectrum disorder. Med Sci Monit.
2018;24:2639-2646.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 126 of 138
111. Long S, Goldblatt J. MTHFR genetic testing: Controversy
and clinical implications. Aust Fam Physician. 2016;45
(4):237-240.
112. Ludwig S, Harstall C. Intensive intervention programs
for children with autism. Health Technology
Assessment. HTA-8: Series B. Edmonton, AB: Alberta
Heritage Foundation for Medical Research (AHFMR);
February 2001.
113. Mahdavi M, Kheirollahi M, Riahi R, et al. Meta-analysis
of the association between GABA receptor
polymorphisms and autism spectrum disorder (ASD). J
Mol Neurosci. 189. 2018;65(1):1-9.
114. Manitoba Speech and Hearing Association (MSHA).
Auditory integration training. Position Statement.
Winnipeg, MB: MSHA; adopted October 16, 1996.
Available at:www.msha.ca/pdf/59_60positionstate.pdf.
Accessed September 21, 2005.
115. Manitoba Speech and Hearing Association (MSHA).
Facilitated communication. Position Statement.
Winnipeg, MB: MSHA; adopted October 16, 1996.
Available at:www.msha.ca/pdf/59_60positionstate.pdf.
Accessed September 21, 2005.
116. McEachin JJ, Smith T, Lovaas OI. Long-term outcome
for children with autism who received early intensive
behavioral treatment. Am J Ment Retard. 1993;97
(4):359-372; discussion 373-391.
117. McGahan L. Behavioural interventions for preschool
children with autism. Technology Report. Issue 18.
Ottawa, ON: Canadian Coordinating Office for Health
Technology Assessment (CCOHTA); August 2001.
118. McPheeters ML, Warren Z, Sathe N, et al. A systematic
review of medical treatments for children with autism
spectrum disorders. Pediatrics. 2011;127(5):e1312
e1321.
119. McQueen JM, Heck AM. Secretin for the treatment of
autism. Ann Pharmacother. 2002;36(2):305-311.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 127 of 138
120. Millward C, Ferriter M, Calver S, Connell-Jones G.
Gluten- and casein-free diets for autistic spectrum
disorder. Cochrane Database Syst Rev. 2008;
(2):CD003498.
121. Moqadem K, Pineau G. The role of hyperbaric oxygen
therapy in the management of autism. AETMIS 07-11.
Montreal, QC: Agence d'Evaluation des Technologies et
des Modes d'Intervention en Sante (AETMIS);
November 2007.
122. Mosheim J. Adults with autism: Meeting the challenges
of a multifaceted life [editorial]. Advance for Speech
Language Pathologists & Audiologists. King of Prussia,
PA: Merion Publications; 2004. Available at:
http://www.advanceforspanda.com/. Accessed March
18, 2004.
123. Mudford OC, Martin NT, Eikeseth S, et al. Parent-
managed behavioral treatment for preschool children
with autism: Some characteristics of UK programs. Res
Dev Disabil. 2001;22(3):173-182.
124. Murray J, Cuckle H, Taylor G, et al. Screening for fragile
X syndrome. Health Technol Assess. 1997;1(4)i-iv, 1-71.
125. Myers SM, Johnson CP; Council on Children With
Disabilities. Management of children with autism
spectrum disorders. Pediatrics. 2007;120(5):1162
1182.
126. National Academy of Sciences, National Research
Council, Division of Behavioral and Social Sciences and
Education, Committee on Educational Interventions
for Children with Autism. Educating Children with
Autism. C Lord, JP McGee, eds. Washington, DC:
National Academies Press; 2001.
127. National Horizon Scanning Centre. Secretin for autism
spectrum disorders - horizon scanning review.
Birmingham, UK: National Horizon Scanning Centre
(NHSC); 2002.
128. National Information Center for Children and Youth
with Disabilities (NICHCY), National Dissemination
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 128 of 138
Center for Children with Disabilities (NDCCD).
Pervasive developmental disorders. Fact Sheet 20.
Washington, DC: NICHCY; updated October 2003.
Available at:
http://www.nichcy.org/pubs/factshe/fs20txt.htm.
Accessed April 5, 2004.
129. National Initiative for Autism: Screening and
Assessment. National autism plan for children (NAPC).
London, UK: National Autistic Society; March 2003.
Available at:
http://www.doh.gov.uk/nsf/children/nationalautisticfrsec.pdf.
Accessed October 15, 2003.
130. National Institute for Health and Care Excellence
(NICE) Website. Autism in adults: diagnosis and
management. May 2014.
131. National Institute for Health and Care Excellence
(NICE) Website. Autism in under 19s: recognition,
referral and diagnosis. August 2014.
132. National Institute for Health and Care Excellence
(NICE) Website. Autism in under 19s: support and
management. August 2013.
133. National Institutes of Health (NIH), National Institute of
Child Health and Human Development. The use of
secretin to treat autism. Rockville, MD: NIH; October
16, 1998.
134. National Institutes of Health (NIH), National Institute of
Neurological Disorders and Stroke (NINDS). Pervasive
Developmental Disorders Information Page [website].
Bethesda, MD: NIH; updated July 15, 2003. Available at:
http://www.ninds.nih.gov/health_and_medical/disorders/pdd.htm.
Accessed April 5, 2004.
135. New York State Department of Health, Early
Intervention Program. Autism / pervasive
developmental disorders. Assessment and
intervention for young children (age 0-3 years). Clinical
Practice Guideline: Report of the Recommendations.
Albany, NY: New York State Department of Health;
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 129 of 138
1999. Available at:
http://www.health.state.ny.us/nysdoh/eip/autism/autism.htm.
Accessed October 17, 2003.
136. Ng QX, Loke W, Venkatanarayanan N, et al. A
systematic review of the role of prebiotics and
probiotics in autism spectrum disorders. Medicina
(Kaunas). 2019;55(5).
137. No authors listed. Autism and Lovaas treatment: A
systematic review of effectiveness evidence. Int J
Technol Assess Health Care. 2001;17(2):252.
138. No authors listed. Autism -- Part II. Harv Ment Health
Lett. 2001;18(1):1-4.
139. Nye C, Brice A. Combined vitamin B6-magnesium
treatment in autism spectrum disorder. Cochrane
Database Syst Rev. 2005;(4):CD003497.
140. Otsuka America Pharmaceutical, Inc. Ability
(aripiprazole). Prescribing Information. Rockville, MD:
Otsuka Pharmaceutical; revised August 2016.
141. Owada K, Okada T, Munesue T, et al. Quantitative
facial expression analysis revealed the efficacy and
time course of oxytocin in autism. Brain. 2019;142
(7):2127-2136.
142. Owley T, McMahon W, Cook EH, et al. Multisite, double-
blind, placebo-controlled trial of porcine secretin in
autism. J Am Acad Child Adolesc Psychiatry.
2001;40(11):1293-1299.
143. Parr J. Autism. In: BMJ Clinical Evidence. London, UK:
BMJ Publishing Group; May 2006.
144. Pelios LV, Lund SK. A selective overview of issues on
classification, causation, and early intensive behavioral
intervention for autism. Behav Modif. 2001;25(5):678
697.
145. Philip RC, Dauvermann MR, Whalley HC, et al. A
systematic review and meta-analysis of the fMRI
investigation of autism spectrum disorders. Neurosci
Biobehav Rev. 2012;36(2):901-942.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 130 of 138
146. Pichon Riviere A, Augustovski F, Alcaraz A, et al. Floor
time therapy in autism [summary]. Report ITB No. 31.
Buenos Aires, Argentina: Institute for Clinical
Effectiveness and Health Policy (IECS); 2007.
147. Prater CD, Zylstra RG. Autism: A medical primer. Am
Fam Physician. 2002;66(9):1667-1674.
148. Prelock P. Understanding autism spectrum disorders:
The role of speech-language pathologists and
audiologists in service delivery. ASHA Leader Online.
Rockville, MD: American Speech-Language-Hearing
Association (ASHA); 2001. Available at:
http://www.asha.org/about/publications/leader
online//leader-online/. Accessed March 18, 2004.
149. Preti A, Melis M, Siddi S, et al. Oxytocin and autism: A
systematic review of randomized controlled trials. J
Child Adolesc Psychopharmacol. 2014;24(2):54-68.
150. Quadrant Biosciences, Inc. Clarifi: Providing a new tool
to aid autism diagnosis. Syracuse, NY: Quadrant
Biosciences. Available at:
https://www.clarifiasd.com/health-care-providers/.
Accessed March 20, 2020.
151. Quintana DS, Alvares GA, Hickie IB, Guastella AJ. Do
delivery routes of intranasally administered oxytocin
account for observed effects on social cognition and
behavior? A two-level model. Neurosci Biobehav Rev.
2015;49:182-192.
152. Rapin I, Katzman R. Neurobiology of autism. Ann
Neurol. 1998;43:7-14.
153. Rapin I. Autism. N Engl J Med. 1997;337(2):97-104.
154. Roberts TP, Schmidt GL, Egeth M, et al.
Electrophysiological signatures:
Magnetoencephalographic studies of the neural
correlates of language impairment in autism spectrum
disorders. Int J Psychophysiol. 2008;68(2):149-160.
155. Rogers SJ. Empirically supported comprehensive
treatments for young children with autism. J Clin Child
Psychol. 1998;27(2):168-179.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 131 of 138
156. Rossignol DA, Rossignol LW, Smith S, et al. Hyperbaric
treatment for children with autism: A multicenter,
randomized, double-blind, controlled trial. BMC
Pediatr. 2009;9:21.
157. Rossignol DA. Novel and emerging treatments for
autism spectrum disorders: A systematic review. Ann
Clin Psychiatry. 2009;21(4):213-236.
158. Sallows GO, Graupner TD. (2005). Intensive behavioral
treatment for children with autism: Four-year
outcomes and predictors. Am J Ment Retard. 2005;110
(6):417-438.
159. Sausmikat J, Smollich M. Nutritional therapy for
children and adolescents with autism spectrum
disorders: What is the evidence?. Klin Padiatr.
2016;228(2):62-68.
160. Schlosser R W, Lee D L. Promoting generalization and
maintenance in augmentative and alternative
communication: A meta-analysis of 20 years of
effectiveness research. AAC: Augmentative and
Alternative Communication. 2000;16(4):208-226.
161. Schneider JH, Glaze DG. Pervasive developmental
disorder: Rett's syndrome. eMedicine Pediatrics Topic
2653. Omaha, NE: eMedicine.com; updated May 3,
2003. Available at:
http://www.emedicine.com/ped/topic2653.htm.
Accessed April 5, 2004.
162. Schopler E, Short A, Mesibov G. Relation of behavioral
treatment to 'normal functioning': Comment on
Lovaas. J Consult Clin Psychol. 1989;57(1):162-164.
163. Scottish Intercollegiate Guidelines Network (SIGN).
Assessment, diagnosis and clinical interventions for
children and young people with autism spectrum
disorders. A National Clinical Guideline. Glasgow,
Scotland: NHS Quality Improvement Scotland; June
2007. Available at:
http://www.sign.ac.uk/pdf/sign98.pdf. Accessed
September 24, 2007.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 132 of 138
164. Shaaban SY, El Gendy YG, Mehanna NS, et al. The role
of probiotics in children with autism spectrum
disorder: A prospective, open-label study. Nutr
Neurosci. 2018;21(9):676-681.
165. Shattock P. The use of gluten and casein free diets
with people with autism. Sunderland, UK: Autism
Research Unit, University of Sunderland, UK; 1995.
Available at:
http://osiris.sunderland.ac.uk/autism/dietinfo.html.
166. Sheinkopf SJ, Siegel B. Home-based behavioral
treatment of young children with autism. J Autism Dev
Disord. 1998;28(1):15-23.
167. Sinha Y, Silove N, Hayen A, Williams K. Auditory
integration training and other sound therapies for
autism spectrum disorders (ASD). Cochrane Database
Syst Rev. 2011;(12):CD003681.
168. Sinha Y, Silove N, Wheeler D, Williams K. Auditory
integration training and other sound therapies for
autism spectrum disorders: A systematic review. Arch
Dis Child. 2006;91(12):1018-1022.
169. Siu AL; US Preventive Services Task Force (USPSTF),
Bibbins-Domingo K, Grossman DC, et al. Screening for
autism spectrum disorder in young children: US
Preventive Services Task Force Recommendation
Statement. JAMA. 2016;315(7):69169-6.
170. Smalley SL, Asarnow RF, Spence MA. Autism and
genetics. A decade of research. Arch Gen Psychiatry.
1988;45(10):953-961.
171. 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. Biol Psychiatry.
2018 [Article in Press].
172. Smith T, Eikeseth S, Klevstrand M, et al. Intensive
behavioral treatment for preschoolers with severe
mental retardation and pervasive developmental
disorder. Am J Ment Retard. 1997;102(3):238-249.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 133 of 138
173. Smith T. Outcome of early intervention for children
with autism. Clinical Psychol. 1999;6(1):33-49.
174. Spreckley M, Boyd R. Efficacy of applied behavioral
intervention in preschool children with autism for
improving cognitive, language, and adaptive behavior:
A systematic review and meta-analysis. J Pediatr.
2009;154(3):338-344.
175. Stathopulu E, Zwi M, York A. Parent-training
intervention in school-aged children with autistic
spectrum disorders (Protocol for Cochrane Review).
Cochrane Database Syst Rev. 2003;(3):CD004255.
176. Stephenson J, Carter M. The use of weighted vests with
children with autism spectrum disorders and other
disabilities. J Autism Dev Disord. 2009;39(1):105-114.
177. Sturmey P. Secretin is an ineffective treatment for
pervasive developmental disabilities: A review of 15
double-blind randomized controlled trials. Res Dev
Disabil. 2005;26(1):87-97.
178. Sun F, Oristaglio J, Levy SE, et al. Genetic testing for
developmental disabilities, intellectual disability, and
autism spectrum disorder. Technical Brief No. 23.
Prepared by the ECRI Institute–Penn Medicine Evidence-
based Practice Center under Contract No. 290-2012
00011-I. AHRQ Publication No.15-EHC024-EF. Rockville,
MD: Agency for Healthcare Research and Quality
(AHRQ); June 2015.
179. Tachibana M, Kagitani-Shimono K, Mohri I, et al. Long
term administration of intranasal oxytocin is a safe
and promising therapy for early adolescent boys with
autism spectrum disorders. J Child Adolesc
Psychopharmacol. 2013;23(2):123-127.
180. Tammimies K, Marshall CR, Walker S, et al. Molecular
diagnostic yield of chromosomal microarray analysis
and whole-exome sequencing in children with autism
spectrum disorder. JAMA. 2015;314(9):895-903.
181. The National Professional Development Center on
Autism Spectrum Disorders Website. Evidence-based
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 134 of 138
practices for children, youth and young adults with
autism spectrum disorder. 2014.
182. Thompson L, Thompson M, Reid A. Neurofeedback
outcomes in clients with Asperger's syndrome. Appl
Psychophysiol Biofeedback. 2010;35(1):63-81.
183. Tonacci A, Billeci L, Tartarisco G, et al. Olfaction in
autism spectrum disorders: A systematic review. Child
Neuropsychol. 2017;23(1):1-25
184. UK National Health Service (NHS). What is the
incidence of autism in UK and USA? What information
is available on music therapy? ATTRACT Database.
Gwent, Wales, UK: NHS; January 27, 2003. Available at:
http://www.attract.wales.nhs.uk/. Accessed October
17, 2003.
185. UK National Health Service, Department for Education
and Skills (DfES). Autism spectrum disorder - Guidance
from the autism spectrum workgroup. DfES Special
Education Needs Publications. London, UK: DfES; July
2002. Available at:
http://www.dfes.gov.uk/sen/viewDocument.cfm?
dID=401. Accessed October 17, 2003.
186. US Preventive Services Task Force (USPSTF) Website.
Recommendation Statement. Screening for autism
spectrum disorder in young children. February 16,
2016.
187. Virues-Ortega J. Applied behavior analytic intervention
for autism in early childhood: Meta-analysis, meta-
regression and dose-response meta-analysis of
multiple outcomes. Clin Psychol Rev. 2010;30(4):387
399.
188. Volkmar FR. Pharmacological interventions in autism:
Theoretical and practical issues. J Clin Child Psychol.
2001;30(1):80-87.
189. Wang Z, Hong Y, Zou L, et al. Reelin gene variants and
risk of autism spectrum disorders: An integrated meta-
analysis. Am J Med Genet B Neuropsychiatr Genet.
2014;165B(2):192-200.
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 135 of 138
190. Warren Z, McPheeters ML, Sathe N, et al. A systematic
review of early intensive intervention for autism
spectrum disorders. Pediatrics. 2011;127(5):e1303
1311.
191. Warren Z, Veenstra-VanderWeele J, Stone W, et al.
Therapies for children with autism spectrum
disorders. Comparative Effectiveness Review No. 26.
Prepared by the Vanderbilt Evidence-based Practice
Center for the Agency for Healthcare Research and
Quality (AHRQ) under contract no. 290-2007-10065-I.
AHRQ Publication No. 11-EHC029-EF. Rockville, MD:
AHRQ; April 2011. Available at:
http://www.effectivehealthcare.ahrq.gov/ehc/products/106/656/CER26_Autism_Report_04
14-2011.pdf. Accessed July 18, 2011.
192. Weiss MJ, Harris SL. Teaching social skills to people
with autism. Behav Modif. 2001;25(5):785-802.
193. Weissman L. Autism spectrum disorder in children and
adolescents: Overview of management. UpToDate Inc.,
Waltham, MA. Last reviewed December 2019.
194. Weissman L. Autism spectrum disorder: Screening
tools. UpToDate [online serial]. Waltham, MA:
UpToDate; reviewed January 2020.
195. Weissman L, Bridgemohan C. Autism spectrum
disorder in children and adolescents: Overview of
management. UpToDate [serial online]. Waltham, MA:
UpToDate; reviewed September 2013a.
196. Weissman L, Bridgemohan C. Autism spectrum
disorder in children and adolescents: Pharmacologic
interventions. UpToDate [serial online]. Waltham, MA:
UpToDate; last reviewed May 2014. (updated May
2015).
197. Weissman L, Bridgemohan C. Autism spectrum
disorders in children and adolescents: Complementary
and alternative therapies. UpToDate [serial online].
Waltham, MA: UpToDate; reviewed September 2013b.
198. Weitlauf AS, McPheeters ML, Peters B, et al. Therapies
for children with autism spectrum disorder: Behavioral
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 136 of 138
interventions update. Comparative Effectiveness
Review No. 137. (Prepared by the Vanderbilt Evidence-
based Practice Center under Contract No. 290-2012
00009-I.) AHRQ Publication No. 14-EHC036-EF.
Rockville, MD: Agency for Healthcare Research and
Quality (AHRQ); August 2014.
199. West PR, Amaral DG, Bais P, et al. Metabolomics as a
tool for discovery of biomarkers of autism spectrum
disorder in the blood plasma of children. PLoS One.
2014;9(11):e112445.
200. Wilczyński KM, Siwiec A, Janas-Kozik M. Systematic
review of literature on single-nucleotide
polymorphisms within the oxytocin and vasopressin
receptor genes in the development of social cognition
dysfunctions in individuals suffering from autism
spectrum disorder. Front Psychiatry. 2019a;10:380
201. Wilczyński KM, Zasada I, Siwiec A, Janas-Kozik M.
Differences in oxytocin and vasopressin levels in
individuals suffering from the autism spectrum
disorders vs general population - a systematic review.
Neuropsychiatr Dis Treat. 2019b;15:2613-2620.
202. Whiteley P. Autism unravelled conference -- 'the
biology of autism--unravelled'. Expert Opin
Pharmacother. 200l;2(7):1191-1193.
203. Williams K, Brignell A, Randall M, et al. Selective
serotonin reuptake inhibitors (SSRIs) for autism
spectrum disorders (ASD). Cochrane Database Syst
Rev. 2013;8:CD004677.
204. Williams K, Wheeler DM, Silove N, Hazell P. Selective
serotonin reuptake inhibitors (SSRIs) for autism
spectrum disorders (ASD). Cochrane Database Syst
Rev. 2010;(8):CD004677.
205. Williams KW, Wray JJ, Wheeler DM. Intravenous
secretin for autism spectrum disorder. Cochrane
Database Syst Rev. 2012;(4):CD003495.
206. Wuang YP, Wang CC, Huang MH, Su CY. The
effectiveness of simulated developmental horse-riding
Proprietary
Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 137 of 138
program in children with autism. Adapt Phys Activ Q.
2010;27(2):113-126.
207. Yamasue H. Promising evidence and remaining issues
regarding the clinical application of oxytocin in autism
spectrum disorders. Psychiatry Clin Neurosci. 2016;70
(2):89-99..
208. Yildiz S, Aktas S, Uzun G. Hyperbaric oxygen therapy in
autism: Is there evidence? Undersea Hyperb Med.
2008;35(6):453-455.
209. Zhang HF, Dai YC, Wu J, et al. Plasma oxytocin and
arginine-vasopressin levels in children with autism
spectrum disorder in China: Associations with
symptoms. Neurosci Bull. 2016;32(5):423-432.
210. Ziegler A, Rudolph-Rothfeld W, Vonthein R. Genetic
testing for autism spectrum disorder is lacking
evidence of cost-effectiveness. A systematic review.
Methods Inf Med. 2017;56(3):268-273.
211. Zwaigenbaum L. Autistic spectrum disorders in
preschool children. Can Fam Physician. 2001;47:2037
2042.
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Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 138 of 138
Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan
benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,
general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care
services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors
in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely
responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is
subject to change.
Copyright © 2001-2020 Aetna Inc.
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AETNA BETTER HEALTH® OF PENNSYLVANIA
Amendment to Aetna Clinical Policy Bulletin Number: 0648
Autism Spectrum Disorders
The following references to benefit coverage do not apply to Pennsylvania Medicaid:
•Interventions for behavioral co‐morbidities are covered under the member's behavioral health benefits. Please check benefit plan descriptions.
•Coverage of pharmacotherapy is subject to the member's specific benefits for drug coverage. Please check benefit plan descriptions.
•Many Aetna plans exclude coverage of educational services. Speech therapy provided in educational settings would be excluded under these plans. Please check benefit plan descriptions for details.
•Some plans exclude coverage of “communication aids.” Please check benefit plan descriptions for details.
Aetna Better Health of Pennsylvania covers all Medically Necessary services for children (under age 21). Some covered services may be provided in a school setting. Behavioral health services, including applied behavioral analysis, are covered by the Behavioral Health Managed Care Organizations. Please contact the Special Needs Unit at us at 1‐866‐638‐1232 if you require assistance.
www.aetnabetterhealth.com/pennsylvania revised 06/08/2020