0648 Autism Spectrum Disorders (3)...Autism Spectrum Disorders - Medical Clinical Policy B ulletins | Aetna Page 79 of 138 . Ng and associates (2019) stated that ASD is a complex developmental

Autism Spectrum Disorders - Medical Clinical Policy Bulletins | Aetna Page 1 of 138

(https://www.aetna.com/)

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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http://www.aetna.com/)


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).



educational intervention.



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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http://ClinicalTrials.gov


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.


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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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

Proprietary


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

Proprietary


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

Proprietary


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

Proprietary


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

Proprietary


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

Proprietary


% 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


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


Proprietary


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


Proprietary


+ 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


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


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


Proprietary


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)


Proprietary


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)


70546 without contrast material(s), followed by

contrast material(s) and further sequences


Proprietary


70551 Magnetic resonance (e.g., proton) imaging,

brain (including brain stem); without contrast

material


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


81417 re-evaluation of previously obtained exome

sequence (eg, updated knowledge or unrelated

condition/syndrome)


Proprietary


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


Proprietary


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)


Proprietary


Proprietary


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


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]


Proprietary


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


Proprietary


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


Proprietary


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)


Proprietary


+ 95967 for evoked magnetic fields, each additional

modality (e.g., sensory, motor, language, or

visual cortex localization) (List separately in


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


Proprietary


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


97140 Manual therapy techniques (e.g.,

mobilization/manipulation, manual lymphatic

drainage, manual traction), one or more

regions, each 15 minutes


Proprietary


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


Proprietary


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


Proprietary


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


Proprietary


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


Proprietary


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:


Proprietary


F84.0 -

F84.9

Pervasive developmental disorders

Z13.41 Encounter for autism screening


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

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Completed. Birmingham, UK: University of

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http://www.bham.ac.uk/arif/autism

glutenfreediets.htm. Accessed October 17, 2003.

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auditory integration therapy (AIT) on the plasma levels

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(GDNF) in autism spectrum disorder. J Mol Neurosci.

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efficacy of memantine in children with autism:

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(5):403-412.

6. American Academy of Allergy, Asthma and

Immunology (AAAAI) Website. Position Statement

Proprietary

http://www.bham.ac.uk/arif/autismglutenfreediets.htm

http://www.bham.ac.uk/arif/autismglutenfreediets.htm


(ARCHIVED). The appropriate use of intravenously

administered immunoglobulin (IGIV). January 2005.

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treatment of autism. June 15, 2002.


(AACAP) Website. Policy Statement. Screening children

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algorithm for developmental surveillance and

screening. July 2006.

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2012.

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Proprietary

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http://www.caslpo.com/english_site/m_mempositfac.asp


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benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

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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

http://www.aetnabetterhealth.com/pennsylvania

0648 Autism Spectrum Disorders (3)...Autism Spectrum Disorders - Medical Clinical Policy B ulletins | Aetna Page 79 of 138 . Ng and associates (2019) stated that ASD is a complex developmental

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