[Note: Shared for #AutisticHistory archive purposes. This is NOT An Autistic Ally.]
What’s New, What’s Old and What’s Next?
1998-2000: Overview of Autism Research
By Portia Iversen
After forty years in the desert, major change has been underway in the field of autism research. The past two years in particular, have seen a major increase in autism research. Significant new data are beginning to accumulate, laying the ground work for discovering the causes, treatments and a cure for autism. Autism research is increasing, both in the number of studies being conducted and in their scope and variety of approaches. We expect to see this trend continue and as scientific efforts continue to accelerate, we will experience the first medical breakthroughs in our understanding of the causes of autism and the development of treatments and a cure. The following is a sampling of important autism research conducted over the past two years, which may be of particular interest to parents.
Note: The inclusion or omission of any study in this review does not constitute an opinion as to its relevance, importance or validity.
Continued Evidence of Serotonin Involvement in Autism
Dr. Diane Chugani* of Wayne State University, Detroit has provided us with important new information through the use of PET scanning techniques on the abnormal capacity for serotonin synthesis in the brains of autistic children and adults. While the children appear to have decreased serotonin levels, adults show increased levels. This data suggest that humans undergo a period of high brain serotonin synthesis capacity during childhood and that the developmental process may be disrupted in autistic children.
In a striking finding, Marion Leboyer* from the Faculte Jussieu in Paris reports on whole blood serotonin and plasma beta-endorphin in autistic probands and their first-degree relatives. Whole blood serotonin is known to be elevated in autistic subjects and could be a possible marker of genetic liability to autism. The author confirms the previously reported familiality of hyperserotoninemia in autism as mothers (51%), fathers (45%) and siblings (87%) have elevated levels of serotonin and mothers (53%) also show elevated levels of C-ter-beta-EP-ir.
In other serotonin-related research, Robert DeLong of Duke University has completed a study on the use of low-doses of serotonin reuptake inhibitors (SSRI) in young children with autism. Twenty-two of the 37 children who underwent fluoxetine treatment had a beneficial treatment response that was sustained during continuing treatment for 13 – 33 months (mean 21 months). Those children with positive response showed behavioral, language, cognitive, affective and social improvements.
In still another study involving SSRIs, Dr. D. Branford of the Southern Derbyshire Mental Health Trust in Derby, England undertook a retrospective case-note analysis of 37 adults with autism. The subjects were prescribed one of two selective serotonin re-uptake inhibitor antidepressants (fluoxetine or paroxetine). The SSRIs proved to be of no benefit for 15 subjects (40%) and led to a deterioration in nine additional cases (25%). However, some reduction of perseverative and maladaptive behaviors was achieved in 13 cases (35%).
A number of other pharmaceuticals have recently been under investigation for use in autism. Risperidone was investigated by Dr. R. Nicolson of the University of Toronto in his study titled, “An open trial of risperidone in young autistic children.” Eight of the 10 children were considered to be responders. Dr. C.J. McDougle of Indiana University School of Medicine conducted a 12-week double-blind placebo-controlled study of risperidone in 31 adults with autistic spectrum disorders. This study concluded that risperidone was superior to the placebo in reducing repetitive behavior, aggression, anxiety or nervousness, depression, irritability and the overall behavioral symptoms of autism. Nine (60%) of 15 patients who received treatment with open-label risperidone following the double-blind placebo phase responded. In another recent report, Dr. A. Zuddas from the University of Cagliari, Italy, reports that risperidone is an effective and relatively safe drug for long-term treatment of behavioral disruption in autistic children and adolescents.
Dr. Eric Hollander,* from the Seaver Autism Research Center at the Mount Sinai School of Medicine, N.Y. conducted an open, retrospective clinical study with venlafaxine and evaluated its effect on core symptoms of autism as well as associated features of ADHD. He reports that Venlafaxine was effective in low dosages (mean, 24.37 mg/day; range, 6.25 to 50 mg/day) and was well tolerated. Improvement was noted in repetitive behaviors and restricted interests, social deficits, communication and language function, inattention, and hyperactivity. Venlafaxine is both a serotonin and norepinephrine reuptake inhibitor.
Dr. P. G. Rossi, from the Neurological Institute, University of Bologna, Italy, reports promising results in its study of Niaprazine, a histamine H1-receptor antagonist with marked sedative properties. Niaprazine was administered at 1 mg/kg/day for 60 days to 25 subjects with autistic disorder. A positive effect was found in 52% of patients, particularly on hyperkinesia, unstable attention, resistance to change and frustration, mild anxiety signs, heteroaggressiveness, and sleep disorders. No side effects were observed. Because of its sedative effects and good tolerability, niaprazine can be used as a first-choice drug to improve behavior and sleep disorders in patients with autistic disorder.
In another study, McDougle and colleagues published results of a clinical trial of Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders. Eight patients with autistic disorder or PDD were given olanzapine in an open-label, prospective fashion for 12 weeks. Seven of eight patients completed the 12-week trial, and six of the completers were deemed clinical responders. Significant improvements in overall symptoms of autism, motor restlessness or hyperactivity, social relatedness, affectual reactions, sensory responses, language usage, self-injurious behavior, aggression, irritability or anger, anxiety, and depression were observed. Significant changes in repetitive behaviors were not observed for the group. A daily dose of olanzapine was 7.8 +/- 4.7 mg/day was given. No evidence of extrapyramidal side effects or liver function abnormalities was seen. Preliminary results suggest that olanzapine may be an effective and well-tolerated drug in targeting core and related symptoms of PDDs in children, adolescents, and adults.
Dr. Michael Chez* published the results of a depakote (anticonvulsant) and steroid trial. This was an open-label trial on a small group of children with autism and PDD, many with EEG abnormalities. His paper suggests that this may be a useful intervention in a subset of children with autism. His data show that a subset of children with autism (which may be as high as 50%) show abnormal EEG activity during sleep. In an earlier study, Dr. Isabel Rapin* has attempted to further distinguish a subset of children with autism who experience sudden and acute developmental and language regression and to relate this phenomena to epileptiform activity.
Additional Biochemical Studies Emerge
Brain metabolites in the hippocampus-amygdala region and cerebellum in autism were reported in an 1H-MR spectroscopy study by Dr. H. Otsuka and co-investigators working at the University of Tokushima, Japan. They examined 27 autistic patients and 10 normal children, using the STEAM sequence. The N-acetyl aspartate (NAA) concentration was significantly lower (P = 0.042) in autistic patients than in normal children.
In the further work of Chugani* from Wayne State University School of Medicine, Detroit, she has published data that show that in autistic children, N-acetyl-aspartate (NAA)levels are reduced compared to controls. Plasma lactate levels were higher in the 15 autistic children.
Sulphation deficit in “low-functioning” autistic children was the subject of a pilot study by Drs. Alberti and Waring. Alberti is located at the Oasi Institute for Research on Mental Retardation and Brain Aging in Troina, Italy. Waring is located in the U.K. The researchers investigated a group of 20 autistic children and age-matched controls. Utilizing the biochemical characteristics of paracetamol (tylenol) they evaluated by high-performance liquid chromatography, the urine paracetamol-sulfate/paracetamol-glucuronide ratio in all subjects following administration of this drug. The PS/PG ratio in the group of autistic subjects gave a significantly lower result than the control group.
Ted Page,* of the University of California, San Diego published two separate reports over the past two years describing different purine-related metabolic defects in subgroups of autistic patients. In the first paper, Page and his colleague Nyhan, report: “A syndrome of seizures and pervasive developmental disorder associated with excessive cellular nucleotidase activity.” This syndrome presents with lack of language and social interaction, truncal ataxia and seizures. It is treatable with oral administration of uridine. It is currently unknown what degree of overlap may exist between these patients and the autistic population. CAN has funded the development of a rapid-screening tool. Page and Colemen* report on purine metabolism abnormalities in a hyperuricosuric subclass of autism, in their recent paper describing a subclass of patients with classic infantile autism who have uric acid excretion, which is >2 standard deviations above the normal mean. They state these hyperuricosuric autistic individuals may comprise approximately 20% of the autistic population. Their experiments show that de novo purine synthesis is increased approximately four-fold in the hyperuricosuric autistic patients. Although an enzyme defect responsible for the accelerated purine synthesis was not identified, the abnormal ratio of adenine to guanine nucleotides suggests a defect in purine nucleotide interconversion.
A recently released study by J. Zhang et al, describes results of analysis of compounds in the urine of autistic children with HPLC and mass spectrometry. This study was the joint effort of Repligen Corporation and University of Maryland School of Medicine, Baltimore. Urine samples were collected from 40 autistic children aged 3-12 and 44 healthy children and analyzed by HPLC-MS/MS. The most significant difference in the two groups was a significant fraction (47%) of the autistic patients with undetectable levels of 7-methylxanthine in their urine. In a double-blind, placebo-controlled, crossover clinical study in 20 children the effect of placebo vs. secretin was evaluated on urinary metabolites. There was a significant increase in urinary 7-methylxanthine following secretin, which was not observed following placebo administration. Four autistic children who had no detectable levels of 7-methylxanthine at the beginning of the study showed an increase of greater than 100-fold following secretin.
On the Immunology Front
S. Mesahel, University of Birmingham U.K., published the results of a study titled: Urinary Levels of Neopterin and Biopterin in Autism. Increased neopterin levels are known to be associated with activation of the cellular immune system. Reduced biopterins are essential for neurotransmitter syntheses. In this study, both urinary neopterin and biopterin were raised in the autistic children compared to controls and the siblings showed intermediate values.
Serum auto-antibodies to brain in Landau-Kleffner variant (LKSV), autism and other neurological disorders (OND) were reported by Anne Connolly of St. Louis Children’s Hospital. Connolly’s results show lgG anti-brain autoantibodies present in 45% of sera from children with LKSV, 27% with autism and 10% with ONDs compared with 2% in healthy children. lgM autoantibodies were present in 36% of sera from children with autism, 9% with LKSV and 15% with ONDs compared with 0% of control sera. The author concludes that the presence of these antibodies raises the possibility that automimmunity plays a role in the pathogenesis of language and social developmental abnormalities in a subset of children with these disorders.
Andrew Zimmerman and Anne Comi of John Hopkins Hospital report on familial clustering of autoimmune disorders in autism. This research group surveyed the families of 61 autistic patients and 46 healthy controls using questionnaires. The mean number of autoimmune disorders was greater in families with autism. 46% had two or more members with autoimmune disorders. Zimmerman purports that the increased number of autoimmune disorders suggests that in some families with autism, immune dysfunction could interact with various environmental factors to play a role in autism pathogenesis.
Gina DelGiudice-Asch* reports B lymphocyte antigen D8/17 (which can be associated with a constellation of repetitive behaviors, sometimes referred to as PANDAS: pediatric autoimmune neuropsychiatric disorder associated with streptococcus), to be higher in 18 autistic patients than in 14 medically ill controls. The frequency of individuals with higher than normal levels of D8/17-positive cells was significantly greater in the autistic patients (78%) than controls (21%). The researchers believe that elevated D8/17 expression may serve as a marker for compulsion severity with autism.
Dr. Sudhir Gupta* located at the University of California, Irvine, is still completing his double blind study of intravenous immunoglobulin (IVIG) treatment in autistic children and we await the outcome of this important study. In a related study, Audreyus Plioplys reported a positive response rate of only 10% in the autistic children treated with IVIG. In their brief report, “A pilot open clinical trial of intravenous immunoglobulin in childhood autism,” Gina DelGiudice-Asch and Eric Hollander* also investigated IVIG treatment in autistic children in a small scale study.
Koraly Horvath, whose practice is at the Maryland School of Medicine in Baltimore, published a study in which 36 children with autism underwent upper GI endoscopy with biopsies, intestinal and pancreatic enzyme analyses and bacterial and fungal cultures. Histologic examination revealed grade I or II reflux esophagitis in 25 (69.4%), chronic gastritis in 15 and chronic duodenitis in 24. 75% of the autistic children had an increased pancreatico-biliary fluid output after intravenous secretin administration. In another study, Horvath reports improved social and language skills after secretin administration in patients with autism. This study included three children with autism who underwent upper GI endoscopy and intravenous administration of secretin. Within five weeks of the secretin infusion, a significant amelioration of the children’s gastrointestinal symptoms was observed, as was a dramatic improvement in their behavior. Horvath’s most recent study examined the intestinal permeability of 25 autistic children and measured the changes following a single secretin injection. The effect of secretin on intestinal permeability in autistic children was evaluated in a double-blind, placebo-controlled study. Analysis of urine samples from 20 children demonstrated a significant decrease in the level of intestinal permeability at the end of the trial.
J.R. Lightdale, Children’s Hospital, Boston, evaluated the gastrointestinal symptoms in autistic children before and following secretin infusion. This study enrolled 20 autistic children for an open-label trial of secretin. Clinical observations confirmed parental reports that 16/20 (80%) of the children were documented to have >2 loose stools during the 24-hour period. A 3 CU/Kg dose of porcine secretin (Ferring) was then administered. At the one-week follow-up visit, 7/16 (44%) of children with previously noted diarrhea brought diapers containing formed stool to the clinic. A majority of the parents (15/20) also reported fewer and more formed stools during the 5-week follow-up period.
In a study by Dr. C.K. Schneider, from the Southwest Autism Research Center, Phoenix, AZ, efficacy of synthetic human secretin in the treatment of PDD was assessed using a double-blind, placebo controlled design in which participants were followed for 12 weeks after a single infusion of secretin or saline placebo. Thirty autistic children were randomly assigned to one of three groups to receive either high dose (0.4 mg/kg) secretin, low dose (0.2mg/kg) secretin, or saline placebo. Psychological and language assessments and gastrointestinal histories were obtained at baseline and at three, six, and 12 weeks post-infusion. The average scores on the Childhood Autism Rating Scale, Vineland Adaptive Behavior Scales, Gilliam Autism Rating Scale, and the Preschool Language Scale-3 improved over time in all three treatment groups.
Dr. Sockolow, Winthrop-University Hospital, Mineola, NY has published a paper titled: “Safe Use of Intravenous Secretin in Autistic Children.” This study assesses the safety of secretin in 34 autistic children for immediate clinical reactions and post injection side effects within the six weeks following two doses of porcine secretin (Ferring). There were no immediate life-threatening side effects. Analysis of blood samples showed that 25 of the 34 had low secretin levels just before the first dose. None had secretin antibodies before or after the secretin injection. The authors conclude that two doses of intravenous secretin is safe to use in children provided that they are observed for at least one hour.
Ed Cook,* reports no significant difference between those who received placebo and those who received secretin treatment in a double-blind study at University of Chicago. In similar results, Dr. Michael Chez* pediatric neurologist, Lake Forest Hospital, Illinois, reports that overall, secretin produced few clinically meaningful changes when compared to children given placebo injections. A. D. Sandler, located at the Thoms Rehabilitation Hospital, Asheville, N.C., conducted a double-blind, placebo-controlled trial of a single intravenous dose of synthetic human secretin in 60 children with autism. The authors concluded that a single dose of synthetic human secretin is not an effective treatment for autism or pervasive developmental disorder.
Neouroimaging and Neuropatholgy Studies
Jeffrey LeWine* working at the University of Utah has published a study which describes evidence of abnormal auditory processing that he continues to study using MEG scan technology. He reports that one-third of autistic children experience one or more seizures by adolescence and epileptiform activity may play a causal role in some cases of autism. MEG identified epileptiform activity in 41 of the 50 (82%) children with autism.
At the Institute of Psychiatry in London, Dr. Anthony Bailey describes abnormal neuropathology in the post mortem brains of three autistic adults and one child. His findings contradict earlier suggestions of prenatal brain insult. Unidentified inclusion bodies (abnormal material found in brain tissue), were described in the child’s brain, but not the adult brains. The inclusion bodies appeared similar to those more commonly associated with diseases of aging.
Other GI-Related Research
Andrew Wakefield from the School of Medicine, London, published a study titled, “Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children,” in which he investigated children with chronic enterocolitis and regressive developmental disorder. The study included 12 children (nine had the diagnosis of autism), who were referred with a history of normal development followed by loss of acquired skills including language, together with diarrhea and abdominal pain. The author reports that onset of behavioral symptoms was associated, by the parents, with the MMR vaccination in eight of the 12 children. All 12 children had intestinal abnormalities. Abnormal laboratory results were significantly raised urinary methylmalonic acid compared with age-matched controls (p=0.003), low hemoglobin in four children, and low serum IgA in four children.
In a subsequent study, Wakefield, in collaboration with Kawashima and colleagues from Tokyo Medical University, report “Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism.” In this study, the investigators carried out detection of measles genomic RNA in peripheral mononuclear cells (PBMC) in eight patients with Crohn’s disease, three patients with ulcerative colitis, and nine children with autistic enterocolitis. One of eight patients with Crohn’s disease, one of three patients with ulcerative colitis, and three of nine children with autism, were positive. Controls were all negative. The sequences obtained from the patients with Crohn’s disease shared the characteristics with wild-strain virus. The sequences obtained from the patients with ulcerative colitis and children with autism were consistent with being vaccine strains.
In a study reporting negative correlation between autism and MMR vaccine, Taylor, et al, University College London, undertook an epidemiological study to investigate whether measles, mumps, and rubella (MMR) vaccine may be causally associated with autism. Children with autism born since 1979 were identified from special needs/disability registers and special schools in eight North Thames health districts. Information from clinical records was linked to immunization data. The investigators looked for evidence of a change in trend in incidence or age at diagnosis associated with the introduction of MMR vaccination to the U.K. in 1988. While there was a steady increase in cases by year of birth, there appeared to be no sudden “step-up” or change in the trend line after the introduction of MMR vaccination. There was no difference in age at diagnosis between the cases vaccinated before or after 18 months of age and those never vaccinated. There was no temporal association between onset of autism within one or two years after vaccination with MMR. Developmental regression was not clustered in the months after vaccination. This group’s analyses did not support a causal association between MMR vaccine and autism.
Bolte, Finegold and Sandler* report short-term benefit from oral vancomycin treatment of regressive-onset autism in their recently published paper of the same title. Eleven children with regressive-onset autism were recruited for an intervention trial using the minimally absorbed oral antibiotic, vancomycin. Entry criteria included previous broad-spectrum antimicrobial exposure followed by chronic persistent diarrhea, deterioration of previously acquired skills, and then autistic features. Short-term improvement was noted using multiple pre- and post-therapy evaluations. Improvement was noted in eight of 10 children studied. Unfortunately, these gains had largely waned at follow-up. Although the protocol used is not suggested as useful therapy, these results indicate that a possible gut flora-brain connection warrants further investigation.
There have been a number of genome screens reported in the past two years, including those conducted by Monaco (IMGSAC), Gillberg* (PARISS group), Reisch (Stanford group), Pericek-Vance (Duke group), Folstein (Hopkins group), the recent genome scan from Finland and the recently completed genome scan done by Conrad Gilliam,* at Columbia University, N.Y. Amongst these studies, two “hot spots” have emerged, one on chromosome 7q and the other on 15q. Additional genomic regions producing significant LOD scores are also of interest. Researchers are currently fine mapping these hot spots. For an excellent overview of recent autism genome screen and linkage studies please see J. A. Lamb’s April 2000 study titled: “Autism: recent molecular genetic advances” in the May 2000 issue of Human Molecular Genetics.
We are very pleased to report that a number of top gene hunters have been able to become active autism researchers as a direct result of the availability of DNA samples from the CAN-funded Autism Genetic Resource Exchange (AGRE). Since the release of the first AGRE catalog in November 1999, over 30 new researchers have requested and received DNA and/or serum samples from AGRE–many of these are investigators who are new to the field of autism, while others are established autism researchers who have been able to extend and expand their research with the addition of these samples. AGRE currently offers access to DNA samples, serum and cell lines from 358 well characterized families with two or more members affected by autism. This resource is available to the entire scientific community. Clinical and genetic information may be accessed online at http://www.agre.org
In an interesting recent report of a single case by Graf, et al, these researchers report autism associated with the mitochondrial DNA transfer RNA(Lys) mutation. The authors conclude that this observation suggests certain mitochondrial point mutations could be the basis for autism in some individuals.
Movement and Sensory Related Disorders Reported
Philip Teitlebaum* of the University of Florida, Gainesville published his study, “Movement analysis in infancy may be useful for early diagnosis of autism.” All of the 17 autistic children studied in the paper showed disturbance of movement that with Teitlebaum’s methods could be detected clearly at the age of four to six months, and sometimes even at birth. Disturbances were revealed in the shape of the mouth and in some or all of the milestones of development including lying, righting, sitting, crawling and walking. Teitlebaum’s findings support the view that movement disturbances play an intrinsic part in the phenomena of autism, that they are present at birth, and that they can be used to diagnose the presence of autism in the first few months of life.
In related reports, Werner and Dawson,* University of Washington, Seattle, issued a brief report: “Recognition of autism spectrum disorder before one year of age: a retrospective study based on home videotapes.” And in related studies, Grace Baranek,* University of North Carolina, published: “Autism during infancy: a retrospective video analysis of sensory-motor and social behaviors at 9-12 months of age.”
Steve Edelson, of the Autism Research Institute in San Diego, reports on the behavioral and physiological effects of deep pressure on children with autism in his pilot study evaluating the efficacy of Temple Grandin’s hug machine. Arousal was measured behaviorally with the Conners Parent Rating Scale and physiologically with galvanic skin response (GSR) readings. Behavioral results indicated a significant reduction in tension and a marginally significant reduction in anxiety for children who received the deep pressure compared with the children who did not.
More With Cure Autism Now
The Autism Community Is Not The Autistic Community
Autistic people have fought the inclusion of ABA in therapy for us since before Autism Speaks, and other non-Autistic-led autism organizations, started lobbying legislation to get it covered by insurances and Medicaid.
ABA is a myth originally sold to parents that it would keep their Autistic child out of an institution. Today, parents are told that with early intervention therapy their child will either be less Autistic or no longer Autistic by elementary school, and can be mainstreamed in typical education classes. ABA is very expensive to pay out of pocket. Essentially, Autism Speaks has justified the big price tag up front will offset the overall burden on resources for an Autistic’s lifetime. The recommendation for this therapy is 40 hours a week for children and toddlers.
The original study that showed the success rate of ABA to be at 50% has never been replicated. In fact, the study of ABA by United States Department of Defense was denounced as a failure. Not just once, but multiple times. Simply stated: ABA doesn’t work. In study after repeated study: ABA (conversion therapy) doesn’t work.
What more recent studies do show: Autistics who experienced ABA therapy are at high risk to develop PTSD and other lifelong trauma-related conditions. Historically, the autism organizations promoting ABA as a cure or solution have silenced Autistic advocates’ opposition. ABA is also known as gay conversion therapy.
The ‘cure’ for Autistics not born yet is the prevention of birth.
The ‘cure’ is a choice to terminate a pregnancy based on ‘autism risk.’ The cure is abortion. This is the same ‘cure’ society has for Down Syndrome.
This is eugenics 2021. Instead of killing Autistics and disabled children in gas chambers or ‘mercy killings’ like in Aktion T4, it’ll happen at the doctor’s office, quietly, one Autistic baby at a time. Different approaches yes, but still eugenics and the extinction of an entire minority group of people.
Fact: You can’t cure Autistics from being Autistic.
Fact: You can’t recover an Autistic from being Autistic.
Fact: You can groom an Autistic to mask and hide their traits. Somewhat. … however, this comes at the expense of the Autistic child, promotes Autistic Burnout (this should not be confused with typical burnout, Autistic Burnout can kill Autistics), and places the Autistic child at high risk for PTSD and other lifelong trauma-related conditions.
[Note: Autism is NOT a disease, but a neurodevelopmental difference and disability.]
Fact: Vaccines Do Not Cause Autism.