Dispute over Rutter and Schopler (1987) article.
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Biomedical subjects
Publications and source records attributed to E R Ritvo.
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The effects of long term (70 days) fenfluramine treatment on selected physiological and behavioral measures were examined in four adult male vervet monkeys (Cercopithecus aethiops sabaeus). Relative to pretreatment baseline values, whole blood serotonin (WBS) and cerebrospinal fluid 5-hydroxyindole acetic acid (5-HIAA) were reduced, cerebrospinal fluid homovanillic acid (HVA) was unaltered, and aggressive and locomotor behavior were increased. Both physiological and behavioral effects were reversible: all measures returned to baseline values in the 35 day post-treatment period, with WBS resuming pretreatment values more rapidly than CSF 5-HIAA. At the relatively low doses (1-4 mg/kg/day) employed in the present study fenfluramine produced behavioral effects similar to those resulting from PCPA and opposite to those following tryptophan administration. Thus the behavioral effects of long-term fenfluramine may involve reductions in serotonergic transmission.
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Fenfluramine was administered to eight autistic outpatients in a double-blind study to determine its effects on symptomatic behavior, developmental scores, blood serotonin levels and platelet counts. Two children benefited substantially according to academic and cognitive tests, parental and teacher reports and the principal investigator's clinical impressions. They also manifested behavioral and mood swings. The remaining six children showed varying degrees of response; one was withdrawn during the study by his parents. The greatest improvement occurred in children with an IQ above 40; the more severely retarded improved little, and primarily in the motor sphere.
As part of an autopsy research project, the brains of four autistic subjects were examined and compared with those of three comparison subjects without CNS pathology and one with phenytoin toxicity. The cerebellum was selected for initial investigation because pathognomonic symptoms and neurophysiological measures suggest that pathology may exist in the cerebellar-vestibular axis in certain patients. Total Purkinje cell counts were significantly lower in the cerebellar hemisphere and vermis of each autistic subject than in the comparison subjects.
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The UCLA Registry for Genetic Studies in Autism was established in 1980 to test the hypothesis that genetic factors may be etiologically significant in subsets of patients. To date 61 pairs of twins have enrolled and 40 meet research diagnostic criteria for autism. The authors found a concordance for autism in these 40 pairs of 95.7% in the monozygotic twins (22 of 23) and 23.5% in the dizygotic twins (four of 17).
The authors ascertained 46 families with multiple incidences of autism (41 with two and five with three autistic probands). Classical segregation analyses revealed a maximum likelihood estimate of the segregation ratio of p = 0.19 +/- 0.07. This is not significantly less than 0.25, the expected value for autosomal recessive inheritance. However, it is significantly less than 0.50, the expected value for autosomal dominant inheritance. The polygenic threshold model was tested and rejected over a full range of values of heritability and ascertainment probability for these families. These results are most consistent with the hypothesis of autosomal recessive inheritance in this subset of 46 families with multiple incidences of autism.
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Fenfluramine was administered to 14 outpatient children with the syndrome of autism to determine whether previously produced decreases in blood serotonin concentrations and clinical improvements could be reinstituted. A double-blind medication-placebo crossover design was used. Each patient received fenfluramine 1.5 mg/kg daily (0.75 mg/kg twice daily) for 8 months, followed by placebo for 2 months. Blood serotonin levels promptly fell approximately 49% regardless of baseline levels. Clinical improvement returned, and on some scales gains after 8 months exceeded those noted after only 4 months of treatment. Significant correlations emerged among the amount of clinical response, initially high verbal IQs, and low blood serotonin concentrations. Compliance was excellent, and no clinically relevant side effects or weight changes occurred. It appears that fenfluramine is effective in ameliorating specific symptoms in certain autistic patients. The extent and mechanism of its action remain to be discovered.
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