An Introduction to the Medical Aspects of Autism

Medical definition What Is Autism? Biologic conditions associated with Autism Prevalence

Genetics Differential diagnosis Diagnostic studies Related medical conditions/problems

Use of behavior modifying drugs Other medical/nutritional therapies References

prepared by: Joanna S. Dalldorf, M.D.; TEACCH Pediatric Consultant; Revised September, 2002

Medical Aspects of Autism

      The following material has been prepared to address the medically related questions about autism which are most frequently raised in the TEACCH programs.

      The Diagnostic Statistical Manual of Mental Disorders (DSM IV, l994) places Autistic Disorder under the broader category of Pervasive Developmental Disorders, which includes not only Autistic Disorder, but also Rett's Disorder, Childhood Disintegrative Disorder, Asperger's Disorder, and PDD not otherwise specified. The following discussion will use the term autism and will primarily refer to Autistic Disorder and Asperger's Disorder. There is currently uncertainty whether Asperger's Disorder represents high functioning autism or a more specific entity with different biologic origins.

What is Autism?

      From a pediatrician's viewpoint, autism is a developmental disorder caused by either structural or neurochemical alterations in central nervous system functioning. Studies have not yet clarified why autistic persons have their particular processing and behavioral characteristics. Theories abound, including suggestions of left cerebral hemisphere dysfunction, cerebellar pathology, and limbic system pathology.

      I do not think we will have an answer until there are many studies of active brain processing, as might be obtainable through the PET (positron emission tomography) scanning procedure, the SPECT (single photon emission computed tomography), modifications of the MRI (magnetic resonance imaging), modifications of electroencephalography (for instance, the BEAM), and studies of neurotransmitter metabolism.

      Eventually, we may know what central nervous system deficits separate autism from other developmental disorders. These deficits, however, will only prove to be the final common denominator since we already know that a variety of organic and metabolic conditions can produce autism, e.g., tuberous sclerosis, phenylketonuria, congenital rubella syndrome.

What are Some of the Documented Biologic Conditions Associated with Autism?

l)  Tuberous Sclerosis - This is a genetically determined (autosomal dominant) condition commonly associated with characteristic skin abnormalities (facial nodular lesions, depigmented spots, coffee-colored spots, leathery skin patch), growths in brain and kidneys, seizures, mental retardation. This condition varies in terms of its severity and progression. There is no specific treatment.

2)  Congenital Rubella Syndrome - This condition is due to placental transfer of the "German Measles" (rubella) virus. The unborn child may sustain severe damage to many organ systems, or he may sustain more selective deficits such as cataracts, sensorineural hearing loss, a central auditory processing problem. The degree of impairment partly depends upon the timing of the rubella infection. There is no specific treatment. Prevention depends upon immunization of susceptible mothers.

3)  Phenylketonuria - This is a genetically determined (autosomal recessive) condition, an inborn error of metabolism in which phenylalanine (an amino acid) is not properly metabolized, leading to elevated phenylalanine levels in the general circulation and in the brain. Phenylketonuria (PKU) victims usually have mental retardation and seizures. The treatment, which must be started shortly after birth for good results, is the provision of a low phenylalanine diet. This diet should probably be continued for life. Most babies born in the US in the past 20 years have been screened for PKU by an automated blood test.

4)  Fragile X Syndrome - This syndrome is due to a structural abnormality of an X chromosome. Theoretically, this condition should be more serious in affected males because they have only one X chromosome. However, Fragile X syndrome is an exception; men and women with Fragile X syndrome can both exhibit mild to severe effects.

      The major features of Fragile X syndrome, which tend to be more evident in boys, are elongated or prominent ears, large head circumference, prominent forehead, high arched palate, long face, large testes (a more consistent finding after puberty), hyperextensible joints ("double-jointed"), mental retardation; a heart condition (mitral valve prolapse) may also exist.

      The diagnosis of Fragile X syndrome used to be made by studying the chromosomes in the blood lymphocytes; a special culture media (folic acid deficient) had to be used. The technique was laborious, and the results were frequently inconclusive. Diagnosis is now made by DNA analysis. DNA analysis is quite accurate; it can be used, with some exceptions, to identify carriers as well as affected persons and for prenatal diagnosis.

      There is no specific treatment, although folic acid therapy may be of help in younger affected children. The genetic implications will vary. If a child demonstrates evidence of Fragile X syndrome, he or she has inherited the Fragile X gene from his/her mother. Inheritance of the Fragile X carrier state is more complicated. A child with Fragile X syndrome could have affected brothers and sisters. The family history and molecular studies on other family members would be necessary to clarify the situation.

      The Fragile X syndrome is an important chromosomal cause of mental retardation. Children with Fragile X syndrome frequently have some autistic characteristics, e.g., gaze avoidance, language disorder, atypical mannerisms. However, it currently appears that only about 5 percent of autistic children have Fragile X syndrome.

5)  Viral Infections - Autism has followed cerebral infection with certain viruses, such as herpes simplex. Dr. M.Coleman, who has done a variety of studies on a large group of autistic children, found suggestive evidence of past infection with herpes simplex in some of her subjects.

6)  Other Possible Causes - Autism has also been associated with Down's syndrome, deLange syndrome, Williams syndrome, Noonan syndrome, infantile spasms (a form of seizures), abnormalities in purine metabolism, abnormalities in intestinal absorption (of gluten), and an increased number of minor physical anomalies.

      In other words, there are many possible originating factors for autism. There are few in which therapy would be specific.

Prevalence of Autism

       Current prevalence rates indicate an incidence of 1 in 1000 for autism and 2 in 1000 if all forms of autism spectrum disorder are included.

       The sense of an increased frequency of autism may relate to changes in diagnostic criteria, earlier identification, and overall improved recognition. Several factors have been proposed to account for a possible true increased prevalence: 1) Measles-mumps-rubella (MMR) vaccine 2) effects of migration of parents (see Gillberg, 1999) 3) increased survival rate of low birth weight/premature infants 4) pollution and other adverse environmental factors. Recent surveys do not support an association between MMR vaccine and autism. The other three possibilities have yet to be fully assessed.

Is Autism Inherited?

      10% of cases of autism are due to known medical conditions, many of which have a known inheritance pattern. Tuberous sclerosis and Fragile X syndrome would be the most likely conditions in this category. Genetic counseling would then be very exact.

      The remaining 90% of cases of autism also appear to be associated with some hereditary factors. Ongoing research suggests that a combination of abnormal genes may result in autism. Genetic material on chromosomes 2, 7, 13, 15, 16, and 19 is of current interest. It is uncertain to what extent genetic and environmental factors interact.

      When the specific cause for autism is unknown, the risk of recurrence is calculated at 5% (3-8%) for a family with one autistic child. There is a risk of about 15% for other developmental problems in siblings of an autistic child.

What Other Conditions Would a Pediatrician Exclude in Evaluating a Child for Autism?

l)  Hearing Loss - It is unlikely that a hearing loss would produce the classical autistic features, since the hearing impaired child would still have considerable communication intent and appropriate interpersonal relationships. However, there are exceptions. For instance, children with high frequency hearing losses (which may be the consequence of early central nervous system infections) will seemingly "hear," but their understanding will be compromised--their atypical responses could be misinterpreted. In addition, children with severe generalized hearing impairments may, on occasion, choose to "withdraw" into a world of their own making.

2)  Severe Visual Impairment - Again, it is unlikely that a severe visual impairment would produce full blown autism. However, the visually impaired child who has not received appropriate stimulation might withdraw or develop atypical mannerisms. However, his language would not be as distorted as it is in autism.

3)  Early Severe Deprivation - Severe deprivation can cause irreversible effects on central nervous system functioning. There may be developmental delays and a withdrawn and passive demeanor. However, typical autism would be an unlikely consequence, and some resolution in the delays and behavioral disturbances should follow improved environmental circumstances.

4)  Multihandicapping Conditions - A child with a combination of sensory impairments (e.g., deafness, blindness), mental retardation, and/or cerebral palsy could be so impaired in his ability to interpret or react to his environment that a repertoire of atypical mannerisms and interactions might ensue. In evaluating a multihandicapped child, every effort would have to be made to determine the extent of each handicap before adding the term autism to the diagnostic confusion.

5)  Epileptic Aphasia (Landau-Kleffner Syndrome) - This is a rather rare condition, usually with onset between ages 3 to 7 years, with some seizures, loss or diminished language comprehension, and then diminished expressive language as well. The EEG will be abnormal with discharges from the temporal lobe area. The extent of the language disorder may wax and wane, and anticonvulsant therapy can be of help. This condition should be considered in cases of rather abrupt change in language skills, particularly if other seizure forms coexist. Anticonvulsant therapy, corticosteroid therapy and a specialized neurosurgical technique have been reported as helpful in some instances.

6)  Degenerative Organic Brain Syndrome - There are a variety of degenerative diseases, most (fortunately) rare and many genetically determined, which could cause regression in a variety of cognitive, linguistic, motoric, and behavioral processes. Seizures, visual or hearing problems, and non-neurological difficulties might also occur. These conditions should be considered when a child appears to be regressing in several developmental spheres, particularly if there was an initial period of totally normal development, if there are seizures as well, if there are changing neuromotor signs, if the child's growth rate is decreasing, and if there is a family history suggestive of such a condition.

      Rett's syndrome should be considered in girls who present with motor regression, social withdrawal, excessive hand movements (especially hand wringing). It should be noted that the social withdrawal, which generates concerns regarding autism, is primarily evident during the period of developmental regression, usually during the first two years of life.

What Laboratory, Radiographic, or Other Diagnostic Studies Should Be Done in Evaluating an Autistic Child?

      Since we are discussing a condition with a variety of causes, the studies need to be individualized. Some possible studies follow. Most require time, sedation, and patience (on the part of the examiner as well as the child).

1)  Audiologic Evaluation - We are all aware that autistic children may have inconsistent responses to sound stimuli. However, they could also have a conductive hearing loss (particularly if they have had middle ear infections) or a sensorineural hearing loss (particularly if they had been very premature or suffered central nervous system infections or trauma). When in doubt, an audiologic evaluation is essential, although not easy to do. Response to playroom noisemakers is not a valid test because a noisemaker contains many frequencies and the loudness of the noise is difficult to calibrate. Traditional audiometry in a sound suite can be tailored to some autistic children; various sounds and voices can be used as stimuli, and visual reinforcement for responding has proven effective on some occasions. Even if the child cannot be reinforced for responding, it is possible to observe his semi-voluntary responses (breathing rate, eye movement, etc.) in the sound suite environment.

2)  Auditory Brainstem Evoked Response Audiometry (ABR, BER) - If there are serious questions about a child's hearing and the above techniques are not possible, then brainstem evoked responses to auditory stimuli need to be considered. This procedure does not require the cooperation of the child, but he must be adequately sedated and the test is time-consuming (about l hour). ABR measures hearing by extracting the brainstem's responses to sounds from ongoing EEG activity. The test sounds are abrupt clicks, l0-60 per second, delivered through ear phones. The resulting computed wave pattern reflects responses of different stations along the auditory pathway in the brainstem. The degree of response, the speed of response, and the nature of the response at the different points along the pathway are all noted. This test can therefore detect hearing losses, although it is less sensitive to low frequency (up to l500 Hz) hearing losses. It is not a test for higher level auditory disorders, such as a receptive aphasia. Autistic children have been reported to have inconsistent responses and increased latency of response on ABR.

3)  Skull X-rays - Skull X-rays, which do require patient cooperation, are rarely indicated in evaluating the autistic child. They might be considered if the child's head size is unusually small or large, if maldevelopment of the skull is suspected, or if intracranial calcifications are suspected. (Intracranial calcifications can be a sign of intrauterine infections or tuberous sclerosis.)

4)  CT (Computed Tomography) of the Brain - This is the first technique which provided direct imaging of the brain rather than associated tissues and structures. This procedure is generally safe and painless, and it involves a modest amount of radiation exposure. However, adequate sedation is required since the child must lie still for l5-30 minutes with his head encased in a head holding device. Brain CT scans are good at detecting tumors, hydrocephalus, cysts, blood/fluid collections, congenital anomalies. Studies on some autistic children and 2 reported groups of mentally retarded children revealed a fairly low incidence of abnormalities, most of which were non-specific. Brain CT scans should probably only be considered in the evaluation of autistic children if there are signs of increasing intracranial pressure (headaches, vomiting, papilledema -- a change in the retina seen with an ophthalmoscope), if there are progressive focal signs (e.g., one sided weakness or seizures), if there is rapidly increasing head size, or if tuberous sclerosis is being considered.

5)  Magnetic Resonance Imaging (MRI) - formerly known as Nuclear Magnetic Resonance (NMR). This technique produces sectional images similar to those obtained with a brain CT scan. No radiation is involved. Rather, the child is exposed to static magnetic fields and radio frequency waves; this exposure does not appear to be biologically significant. As with brain CT scans, this technique detects structural rather than functional problems, although an adaptation of the MRI technique can be used to demonstrate ongoing physiologic processes.

      MRI brain studies are more effective in detecting small brain tumors, brain stem and cerebellar defects, and defects in myelinization (which could be found in some degenerative processes).

      MRI now seems to be preferred over CT when brain imaging studies are considered for the autistic child. Some MRI studies have revealed poor development (hypoplasia) of specific areas of the cerebellum.

6)  Positron Emission Tomography (PET) - This technique, the newest on the horizon, produces information about actual brain functioning rather than about structural defects. Glucose utilization by the brain is usually used as the indicator of brain activity. The most active brain cells will entrap the most glucose. This procedure has already revealed some interesting findings in epileptic and aphasic children.

      PET scanning has been used in a small number of autistic adults; the results suggested unusual asymmetry of brain activity. A more recent study suggested impaired functional interaction between the frontal and parietal regions, the neostriatum and thalamus.

      There are drawbacks with PET scanning. A radioactive compound must be injected intravenously. This technique is very expensive and will only be available at a limited number of medical centers. It also only shows a single point in a physiologic process and thus repeated studies might be necessary.

      A less expensive variation of PET, single photon emission computed tomography (SPECT), also provides a 3D picture of cerebral blood flow and an indirect measure of brain metabolism. Although SPECT requires less instrumentation, some radiation exposure is still involved.

7)  Brain Electrical Activity Mapping (BEAM) - This technique, which does not seem to be ready for clinical use, involves computer analyzing of EEG and EEG evoked potential data. This displayed data can locate areas of limited or excessive electrical activity. It has been used in studying dyslexics.

8)  Electroencephalography (EEG) - This procedure, again requiring patient cooperation, simply measures changes in electrical activity on the brain surface. There is a higher incidence of nonspecific and diagnostically useless EEG abnormalities in the mentally retarded and autistic population. EEG's can be useful, however, if a seizure disorder is suspected. EEG patterns are affected by age, by state of sleep, and by drug use (including many of the medications used to sedate children for EEG's).

9)  Urine and Blood Studies for Metabolic Disorders - These studies are available at major medical centers and from some diagnostic laboratories. Analyses, depending upon the screening process, can be done for disorders of amino acid metabolism (e.g. phenylketournia), disorders of carbohydrate metabolism, disorders of mucopolysaccharide metabolism (e.g. Hurlers syndrome or gargoylism), disorders of brain lipid metabolism. Most of these disorders are inherited and can be detected in the unborn baby by amniocentesis studies. A few of these disorders can be satisfactorily treated by diet. These tests should be considered if the child appears to have a progressive problem, feeding/vomiting difficulties, seizures. (The majority of babies born in the US are tested for phenylketournia shortly after birth).

10)  Serologic Studies - Blood tests are available to determine if a child has been infected with some of the agents occasionally associated with autism, e.g., herpes simplex, rubella, cytomegalic inclusion disease. There are limitations in the interpretations of these tests. They might provide information about cause but rarely about treatment. Such studies should be considered if the child has a small head, intracranial calcifications, visual or hearing problems.

11)  Blood Lead Level - Chronic lead poisoning can lead to varied neurologic problems, including deterioration in cognition and (theoretically) autism. Lead studies should be considered if several family members are affected, if there is possible exposure to lead (from ingestion of lead based paints, consumption of "moonshine," exposure to industrial sources--e.g., lead batteries, garages). Chronic lead poisoning can be treated, although the effects are not totally reversible.

12)  Chromosome Analysis - This test requires a venous blood sample. The blood lymphocytes (a type of white blood cell) are cultured and subsequently analyzed for the number of chromosomes and the structure of the individual chromosomes. The chromosome makeup is known as the Karyotype. Chromosome studies are time consuming and require competent technical handling. Chromosome studies can be done by major medical centers and some private facilities. Karyotyping should be considered if the mentally retarded/autistic child has multiple congenital anomalies or several dysmorphic features or a clearly suspected known chromosomal abnormality syndrome (e.g., Down's syndrome). These studies are needed to confirm the diagnosis and for genetic counseling purposes. Chromosome studies may also need to be done on the parents. On occasion, chromosome analyses may be done on other tissues, such as skin.

13)  Other - Measurements of cerebral neurotransmitters, such as serotonin, may eventually prove useful. Serotonin, as measured in blood, is elevated in about a third of autistic children, and this finding provided the rationale for fenfluramine drug therapy. I am presently hesitant about obtaining serotonin levels until there is more information about the clinical applicability.

It is of interest that a recent study (see Nelson) revealed an excess of certain neural growth factors in the blood of newborns who were subsequently diagnosed as mentally retarded or autistic.

Medical Conditions Which Could Enhance Developmental or Behavioral Problems

1)  Seizures - Seizures are unprovoked paroxysmal episodes which might involve abnormal sensory experiences (e.g., smell, sudden pain), motor manifestations, alterations in consciousness or behavior, or a variety of these features. The area of brain neuronal hyperactivity and the amount of spread of these discharges determine the nature of the seizure. A patient may have an aura (a subjective sensation or occurrence) preceding the seizure. He may have a postictal (after-seizure) phase of reduced responsiveness or deep sleep. Autistic children and adults are at higher risk for seizures, but the seizures may be more difficult to identify because of the child's atypical, repetitive, and/or ritualistic behaviors. Seizures should be considered if a child has repetitive rhythmic motor or eyeblinking movements, particularly if they are associated with diminished responsiveness and do not resemble the child's usual behavioral repertoire. EEG's are rarely diagnostic, and therefore, careful observations of suspected seizures are crucial. It is of note that autistic clients may even manifest their first seizures in adolescence. (About l5% of autistic adolescents who were previously seizure free develop seizures. These seizures are usually not serious and are more likely to occur if there is associated mental retardation.)

2)  Middle Ear Infections - Middle ear infections (otitis media) can cause significant pain, a conductive hearing loss, irritability, and further communication and behavior problems for the autistic person. Middle ear infections are treatable, but antibiotic therapy may be required for a prolonged period. Middle ear disease should be considered if the autistic person appears to have a prolonged "cold," if he is more irritable or lethargic, if he seems to have an ear ache (banging head, etc.) or ear drainage, and if he seems to be even less responsive to sounds.

3)  Dental Disease - Dental caries (cavities) can cause pain and add to the behavioral problems of an autistic person. Tooth or gum disease should be considered if tooth decay is obvious, if the gums are swollen or bleeding, if food intake has dropped off, and if the client develops new behaviors focusing on the mouth. A pedodontist should be consulted.

4)  Nutritional Deficiencies - Autistic persons, as well as the average 2-5 year old child, often have unusual food preferences. It is rare that significant nutritional deficiencies would result, and it is unlikely that the deficiencies would be severe enough to affect learning or behavior. However, iron deficiency anemia can cause irritability and poorer learning ability and should be considered if a child has an aversion for all meats, eggs, dark green leafy vegetables. Vitamin deficiencies are rare because of the frequent vitamin fortification of foods. Vitamin D deficiency (rickets) can occur in some children who are taking Dilantin.

5)  Constipation - The uncomfortable passage of hard fecal material can obviously add to the irritability of an autistic person and also lead to stool holding and "paradoxical" diarrhea around the withheld stool. Constipation is usually due to dietary factors. Milk, starch (potatoes, bread, pasta), bananas, and cheese are very constipating. Once a cycle of constipation and stool holding gets started, it can be very difficult to alter the situation. Thus, the parents and therapists of autistic persons should be alert to signs of constipation (prominent hard abdomen, infrequent bowel movements, blood streaked stool). No therapeutic plan will work unless the diet is also altered. The above mentioned constipating foods will have to be reduced and fruit juices, vegetables, some fruits, and bran will have to be pushed. Useful non-cathartic stool softeners include mineral oil and polyethylene glycol (MiraLax). On occasion, a pediatric Fleet Enema will be needed to start the process.

6)  Allergy - A true allergic reaction is defined as an unusual physiologic event caused by an immunologically mediated response. Allergy can cause asthma, "hay fever," hives, food and drug reactions. There is no documentation that allergy causes autism. It is theoretically possible that chronic allergic reactions causing respiratory or gastrointestinal discomfort could exaggerate the behavioral problems of an autistic child.

      An allergist should be consulted if an autistic child seems to have predictable untoward reactions to foods or other environmental factors.

7)  Medications - Many medications can alter an autistic person's temperament. If an autistic person is acting differently, check his medications. Following are some examples:

Decongestants (e.g., Dimetapp, Sudafed, Actifed)	These medications contain various combinations of sympathomimetic agents (potentially stimulating) and antihistamines (potentially sedating). Some parents may even be giving one or two preparations simultaneously.
Antihistamines (e.g., Benadryl, Chlortrimeton)	These medications can cause drowsiness or irritability.
Anticonvulsants
Name	Side Effects
Phenobarbital	irritability, hyperactivity, drowsiness
Primidone (Mysoline)	marked irritability, drowsiness, dizziness, personality changes
Diphenylhydantoin (Dilantin)	drowsiness, personality changes, clumsiness ("drunken" stance and gait), nystagmus (rhythmic jerking eye movements), gum swelling, increased hair growth
Carbamazepine (Tegretol)	drowsiness, dizziness, double vision
Ethosuximide (Zarontin)	fatigue, lethargy, headaches, dizziness, abdominal discomfort
Clonazepam (Clonopin)	drowsiness, irritability, behavior changes
Trimethadione (Tridione)	drowsiness, photophobia, rash, lowered blood count
Valproic Acid (Depakene)	abdominal discomfort, hair loss, increased appetite
Tranxene	drowsiness, marked irritability

8)  Sleep Disturbances - Daytime irritability, inattention, or lethargy may be due to inadequate sleep (Does the child not go to bed? Is he getting caffeine beverages in the evening?) or frequently interrupted sleep (Does he have chronic nasal obstruction?  Are sleep arrangements potentially disruptive?).

Behavior Modifying Medications for Autistic Persons

      Since autism is due to many biologic factors and since a variety of environmental factors might contribute to the client's behavioral problems, drug therapy must be highly individualized. The potential and demonstrated benefits must outweigh the side-effects.

      As of 2002, the choice of medications to help the behavioral difficulties of autistic persons has markedly increased, but there are still no predictably effective agents.

      Antidepressants, especially the selective serotonin reuptake inhibitors (e.g., Prozac, Zoloft) and one tricyclic (clomipramine) are increasingly suggested for ritualistic and obsessive-compulsive behaviors, as well as improving general mood and adaptability. The overall results are encouraging. (Autistic persons may require relatively low doses of these agents.)

      Aggressive/agitated behavior and/or mood instability are most often addressed with anticonvulsants (carbamazepine, valproic acid), lithium, and the major tranquilizers (e.g., Mellaril, Haldol, Risperdal, and Zyprexa). The major tranquilizers are still probably the most predictably helpful, but they also can have significant immediate and long-term side effects. Fortunately, risperidone (Risperdal) and olanzapine (Zyprexa) appear safer.

      The stimulants (e.g., methylphenidate) continue to be surprisingly helpful in higher functioning, restless, impulsive autistic children. Clonidine (Catapres) has also been used for hyperactivity/impulsivity, but it requires very careful monitoring.

      Fenfluramine is not recommended.

      Naltrexone is, on occasion, reported to help attentional problems and self-injurious behavior. The results seem inconsistent.

      The benefits of medication are often not dramatic or sustained. Behavioral and educational techniques are much more important.

      If a long-term psychopharmacologic approach is to be considered, the following guidelines are suggested:

1)   The target behaviors of concern should be identified and incorporated into an ad hoc rating scale, which should be used in evaluating the effects of drug therapy.

2)   The autistic person should have a readily available source of medical care. Although there are now more potentially helpful psychopharmacologic agents for use in autistic persons, multiple and prolonged drug use continues to occur. Whenever more than one medication is used, there is the potential for drug interactions. For instance, the combined use of selective serotonin reuptake inhibitors and major tranquilizers can result in toxic reactions. The prolonged use of drugs, especially at higher doses, can also lead to less recognized but serious conditions; neuroleptic malignant syndrome is associated with major tranquilizer use and toxic serotonin syndrome is associated with SSRI use.

3)   The parents, guardians, and teachers of the client should understand the indications for, side effects of, and limitations of this psychopharmacologic approach.

4)   Some of the medications, particularly tranquilizers and stimulants, should be periodically phased out for a period of at least 4 weeks to determine whether medication does make a difference. (Such withdrawal periods, however, can be very difficult and may require use of short term alternative mediation).

What Other Medical/Nutritional Therapies Have Been or Are Under Investigation?

1)  Megavitamins - There is not one specific megavitamin regimen. Various vitamins have been suggested, usually on the premise that they contribute to some neurochemical reaction. Vitamin combinations have included vitamin C, nicotinamide, pantothenic acid, pyridoxine (vitamin B6). I am unaware of any multivitamin megavitamin approach which has produced persistent documented improvement. However, there are undoubtedly some autistic clients who may respond to some components of the megavitamin approach.

      At present, pyridoxine--particularly in combination with magnesium--is showing some promise for some autistic clients. It is still uncertain why pyridoxine/magnesium may help, which autistic clients would respond, and what the long term side effects would be.

      It should be emphasized that high doses of some vitamins, particularly fat soluble vitamins like vitamin D and vitamin A, can have serious side effects. Therefore, it is not advisable to fashion a vitamin therapy program (e.g., via a health food store) without medical supervision.

2)  DMG - Dimethylglycine is a nontoxic metabolite, once called vitamin Bl5, which, in anecdotal reports, has occasionally improved speech or behavior in autistic children. Little explanation for its use or efficacy is currently available. TMG (Trimethylglycine) is now also being suggested.

3)  Melatonin - Melatonin is a hormone secreted by the pineal gland, located in the brain. The secretion of melatonin is triggered by changes in light, with increasing amounts being released in darkness. Melatonin has been helpful in regulating the sleep cycles of persons with chronic sleep disorders, blindness, and developmental disabilities. It would appear quite safe for short-term use, and it has reportedly helped some autistic persons. Long-term use cannot be supported since melatonin may indirectly affect other biologic rhythms, such as sexual maturation. Melatonin is still available in many grocery and drug stores, but it may become a more regulated prescription-only preparation.

4)  Secretin - Secretin is a hormone normally produced by the intestines to stimulate release of some pancreatic fluids (especially amount of bicarbonate). Secretin is used in gastrointestinal diagnostic studies. In several instances, intravenously administered secretin was noted to improve the social and language skills in patients with autistic spectrum disorder. The mechanism of this improvement is uncertain although it is known that other members of the secretin family do have receptors in the brain. Although investigations are ongoing, the current results, using both porcine and synthetic secretin, do not consistently support the efficacy of secretin therapy for autism.

Suggested Reading

General
American Academy of Pediatrics. The Pediatrician's role in the diagnosis and management of autistic spectrum disorder in children. Pediatrics 2001; 107: 1221-1226.
Bailey, A., Phillips, W. & Rutter, M. Autism: towards an integration of clinical, genetic, neuropsychological and neurobiological perspectives. Journal of Child Psychology & Psychiatry. 1996; 37: 89 - 126.
Bauer, S. Autism and the pervasive developmental disorders. Pediatrics in Review 1995; 16: 130 - 136, 168 - 176.
Cohen, D.J. & Volkmar, F. ed. Handbook of Autism and Pervasive Developmental Disorders New York, Wiley and Sons, 1997
Filipek P.A., Accardo P.J., Ashwal S. et al. Practice parameter: screening & diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology & the Child Neurology Society. Neurology 2000; 55: 468-479.
Mauk, J.E. Autism and pervasive developmental disorders. Pediatric Clinics of N.A. 1993; 40: 567 - 578.
Minshew, N. & Payton, J. New perspectives in autism. Current Problems in Pediatrics 1988; 10 & 11. Chicago, Yearbook Medical Publishers.
Rapin, I. Autism (Current Concepts). N.E.J.M. 1997; 337: 97 - 104
Volkmar, F. & Bristol, M. Special Issue: Autism Research Report from NIH. Journal of Autism & Developmental Disorders 1996; 26: #2
Wing, L. Autistic Children: A Guide for Parents & Professionals. Secaucus, Citadel, 1980.

Neurobiologic Studies
Barton, M. & Volkmar, F. How commonly are known medical conditions associated with autism. Journal of Autism and Developmental Disorders 1998; 28: 273 - 278
Cantor, D. et al. Computerized EEG analyses of autistic children. Journal of Autism and Developmental Disorders 1986; 16: 169 - 187.
Cook, E. Autism: Review of neurochemical investigation. Synapse 1990; 6: 292 - 308
Courchesne, E. et al. Hypoplasia of cerebellar vermal loboles VI & VII in autism. NEJM 1988; 318: 1349 - 1354
Courchesne, E. Neuroanatomic imaging in autism. Pediatrics 1991; 87 (supplement): 781-790
Denckla, M. & James, L.S. An update on autism: a developmental disorder. Pediatrics 1991; 87: Supplement
Gaffney, G. & Tsai, L. Magnetic resonance imaging of high level autism. Journal of Autism and Developmental Disorders 1987; 17: 433 - 438
Garber, H.J. et al. A MRI study of autism: normal 4th ventricle size & absence of pathoogy. American Journal of Psychiatry 1989; 146: 532 - 534
Gillberg, C. & Coleman, M. Autism and medical disorders: a review of the literature. Dev. Med. Child Neurol 1996; 38: 191 - 202
Haas, R. et al. Neurologic abnormalities in infantile autism. Journal of Child Neurology 1996; 11: 84 - 92
Horowitz, B. et al. Interregional correlations of glucose utilization among brain regions in autistic adults. Annals of Neurology 1987; 22: 118
Kemper, T. & Bauman, M. The contribution of neuropathologic studies to the understanding of autism. Neurology Clinics 1993; 11: 175 - 187
Lewine, J.D. et al. Magnetoencephalographic Patterns of epileptiform activity in children with regressive spectrum disorders, Pediatrics 1999; 104: 405-18
Miles, J.H. & Hillman, R., Value of a clinical morphology exam in autism. American Journal of Medical Genetics 2000; 91: 245-253
Minshew, N. Brief Report: Brain mechanisms in autism, functional and structural abnormalities. Journal of Autism and Developmental Disorders 1996; 26: 205- 209
Nelson, K.B., Grether, J.K., et al. Neuropeptides & neurotroophins in neonatal blood of children with autism or mental retardation. Annals of Neurology 2001; 49: 597-604
Rutter, M. et al. Autism and known medical conditions: myth and substance. Journal of Child Psychology and Psychiatry 1994; 35: 311 - 322
Tuchman, R. & Rapin, I. Regressive in Pervasive Developmental Disorders; Seizures & Epileptiform EEG correlates. Pediatrics 1997; 99: 560 - 566

Epidemiology
Fombonne, E. The epidemiology of autism: a review. Psychol. Medicine 1999; 29: 769-786
Gillberg C, Wing L. Autism: Not an extremely rare disorder. Acta Psychiatric Scand. 1999; 99: 399-406

Genetics
Simonoff, E. Genetic counseling in autism and pervasive developmental disorders. J. Autism Dev Disord. 1998; 28: 447-456

Fragile X / Autism
Bregman, J. et al. Fragile X syndrome: genetic predisposition to psychopathology. J. of Autism and Dev. Disorders 1988; 18: 343 - 354
Brown, W.T. et al. Fragile X and Autism: a multicenter survey. Amer. J of Med. Genetics. 1986; 23: 341 - 352
Fisch, G. et al. Autism & Fragile X Syndrome. Am. J. of Psychiatry 1986; 143: 71 - 73
Goldfine, P. et al. Association of Fragile X Syndrome with Autism. Am J. Psychiatry 1985; 142; 108 - 110
Hagerman, R. and Sobesky, W. Psychopathology in Fragile X syndrome. Am J. Orthopsychiat 1989; 59: 142 - 152
Levitas, A., Hagerman, R. et al. Autism and the Fragile X Syndrome. Dev. & Beh. Pediatrics 1983; 4: 151 - 158

Phenylketonuria
Lowe, T., Tanaka, K et al. Detection of phenylketournia in autistic and psychotic children. JAMA 1980; 243: 126 - 128

Rett Syndrome
Haas, R. et al. Rett Syndrome & Autism. Journal of Child Neurology 1988; 3 Supplement
Holm, V.A. Rett syndrome; A progressive developmental disability in girls. Developoment and Behavioral Pediatrics 1985; 6: 32 - 36
Moeschler, J. et al. Rett syndrome: Natural history & management. Pediatrics 1988; 82: 1-10
Olsson, B. & Rett, A. Autism & Rett syndrome: behavioral investigations and differential diagnosis. Dev. Med. Child Neurol 1987; 29: 429 - 441
Percy, A. et al. Rett Syndrome and the autistic disorders. Neurologic Clinics 1990; 8: 659-676
Tsai, L. Rett Syndrome. Child & Adolescent Psychiatric Clinics of N.A. 1994; 3: 105-118

Tuberous Sclerosis
Baker, P., Piven, J., Sato, Y. Autism and tuberous sclerosis complex: prevalence & clinical feature. Journal of Autism & Developmental Disorders 1998; 28: 279-285

Pharmacologic Treatment
Cook, E. & Leventhal, B. Autistic disorder and other pervasive developmental disorders. Child and Adolescent Psychiatric Clinics of N.A. 1995; 4: 381-399
McDougle, C., Price, L., Volkmar, F. Recent advances in the pharmacotherapy of autism and related conditions. Child and Adolescent Psychiatric Clinics of N.A. 1994; 3: 71-89
McDougle, C.J. Psychopharmacology. In: Cohen D.J., Volkmar F.R., eds. Handbook of Autism & Pervasive Developmental Disorders 2nd ed. New York, N.Y.: Wiley & Sons; 1997: 707-729
Research Units of Pediatric Psychopharmacology Autism Network. Risperdone in children with autism & serious behavioral problems NEJM 2002; 347: 314-321

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Joanna S. Dalldorf, M.D.
TEACCH Pediatric Consultant
September 2002

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