Short-term benefit from oral vancomycin treatment of regressive-onset autism.

In most cases symptoms of autism begin in early infancy. However, a subset of children appears to develop normally until a clear deterioration is observed. Many parents of children with "regressive"-onset autism have noted antecedent antibiotic exposure followed by chronic diarrhea. We speculated that, in a subgroup of children, disruption of indigenous gut flora might promote colonization by one or more neurotoxin-producing bacteria, contributing, at least in part, to their autistic symptomatology. To help test this hypothesis, 11 children with regressive-onset autism were recruited for an intervention trial using a minimally absorbed oral antibiotic. Entry criteria included antecedent 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. These included coded, paired videotapes scored by a clinical psychologist blinded to treatment status; these noted improvement in 8 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, as it might lead to greater pathophysiologic insight and meaningful prevention or treatment in a subset of children with autism.

Secretin and autism: a two-part clinical investigation.

Recent anecdotal reports have touted the gastrointestinal (GI) hormone secretin as a treatment modality for autism, though there is little clinical evidence or literature to support its viability. We undertook a two-part clinical trial to investigate these claims. Fifty-six patients (49 boys, 7 girls, mean age = 6.4 years, SD = 2.7) enrolled in an open-label trial of secretin, during which they received one injection of the hormone (2 IU/kg). All subjects were evaluated by their parents at baseline and follow-up visits (3-6 weeks later, M = 3.7, SD = 1.4 weeks) with Childhood Autism Rating Scales (CARS). Thirty-four patients were labeled with Pervasive Developmental Disorder Not Otherwise Specified, and 22 met diagnostic criteria for Autistic Disorder. Forty-five patients were concurrently on other drug treatments. At follow-up, some reported minimal but potentially significant improvements including changes in GI symptoms, expressive and/or receptive language function, and improved awareness and social interactions. No adverse effects were reported or observed. Subsequently, 17 of the most responsive patients from Study 1 began a double-blind trial that also included 8 newly enrolled patients. Patients in this second study were alternatively entered into one of two groups and received injections of secretin or placebo with crossover at 4 weeks. Patients from Study 1 entered into Study 2 at an average of 6.5 (SD = 0.8) weeks after beginning Study 1. Results of both inquiries indicate that although treatment with secretin was reported to cause transient changes in speech and behavior in some children, overall it produced few clinically meaningful changes when compared to children given placebo injections.

Verbal memory impairment resulting from hippocampal neuron loss among epileptic patients with structural lesions.

We recently demonstrated statistically significant correlations between presurgical memory impairment and hippocampal volumetric cell densities (in CA3 and the hilar area only) for patients with idiopathic left temporal lobe epilepsy who exhibited marked hippocampal neuron loss. In the present research we determine whether the same relationship exists for patients with structural lesions, in whom hippocampal neuron loss was minimal. Rank-order correlations of verbal memory test results (ie, Long Term Retrieval score of the verbal Selective Reminding Test, Percent Retention index of the Logical Memory subtest of the Wechsler Memory Scale) and hippocampal volumetric cell densities (subfields CA1, CA2, CA3, the hilar area, and the granule layer of area dentata) were computed for 22 patients with structural lesions and medically refractory epilepsy of temporal lobe onset (11 left, 11 right). There were statistically significant correlations between Long Term Retrieval and the volumetric cell density of CA1 (r = 0.62, p < 0.05) and between percent retention and the volumetric cell density of CA2 (r = 0.60, p < 0.05) for patients with left hemisphere lesions. No other correlations were found for patients with left or right temporal lobe lesions.

Right hemisphere mediation of verbal learning and memory in acquired right hemisphere speech dominant patients.

Forty-eight patients with temporal lobe epilepsy completed measures of narrative recall and list learning prior to surgery. The intracarotid amytal procedure (IAP) established that 13 patients were right hemisphere dominant for speech and 35 (18 left foci, 17 right foci) were left hemisphere dominant. Hippocampal volumetric neuron densities were measured after surgery. The left hippocampal neuron densities in subfields CA3 and the hilar area were significantly correlated with list learning ability and percent retention for narrative recall only for left hemisphere speech dominant patients with left seizure foci. No significant correlations between measures of neuron volume and memory were found for the left hemisphere speech dominant patients with right seizure foci or the right hemisphere speech dominant patients with left seizure foci. This suggests that the right hemisphere of right speech dominant patients mediates verbal memory as well as speech. This conclusion is supported by patterns of correlations among measures of verbal memory that differed for patients undergoing resection of the dominant hemisphere versus those undergoing resection of the nondominant hemisphere. However, it is premature to conclude that the cerebral organization of cognitive functions of right hemisphere speech dominant patients is equivalent albeit reversed from that of left hemisphere speech dominant patients. Right hemisphere speech dominant patients with left temporal foci differed from left hemisphere speech dominant patients with right temporal foci with respect to the patterns of correlations between measures of verbal memory and intelligence as well as the level of intellectual ability that they demonstrated.

General cognitive ability following unilateral and bilateral fetal ventral mesencephalic tissue transplantation for treatment of Parkinson's disease.

OBJECTIVE: To contrast the neuropsychological profiles of Parkinsonian patients, before and after fetal ventral mesencephalic tissue transplantation. DESIGN: Case series of personally examined patients. SETTING: Patients were evaluated by neurologists, neurosurgeons, and neuropsychologists as outpatients at a university hospital. PATIENTS: Fetal mesencephalic tissue was implanted in the right caudate nucleus of three patients and both nuclei of one patient. These patients were evaluated prior to surgery and at 12, 24, and 26 months postoperatively. RESULTS: Factor analysis of the test battery identified four statistically orthogonal test clusters. No statistically significant changes were identified postoperatively for clusters assessing verbal cognitive ability, nonverbal cognitive ability, and information-processing speed. An improvement of verbal memory cluster index was observed 12 months after surgery, and the improvement reached the level of statistical significance at 24 months after surgery. However, the verbal memory of all patients declined between 24 and 36 months after surgery. CONCLUSIONS: Fetal tissue transplantation to one or both caudate nuclei did not permanently arrest cognitive dysfunction. Although there is some evidence of improved cognitive ability after transplantation, it is improbable that normal cognitive function can be restored by this procedure because the impairments of cognitive ability associated with Parkinson's disease do not appear to originate solely from dopamine deficiency.

Degree of hippocampal neuron loss determines severity of verbal memory decrease after left anteromesiotemporal lobectomy.

Fifty-eight left speech dominant adults with medically refractory epilepsy originating from the temporal lobe (28 left, 30 right) were examined using the verbal Selective Reminding Test before and after anteromesiotemporal lobectomy. After neuron density in the excised hippocampal tissue was established, a median split procedure was performed to distinguish patients with severe neuron loss (13 left, 16 right) from those with only mild or moderate neuron loss (15 left, 14 right). The memory of patients with severe left hippocampal neuron loss did not decrease significantly postoperatively. Patients with mild or moderate left hippocampal neuron loss experienced significant verbal memory decrease postoperatively. The magnitude of the verbal memory decrease was not related to recurrence of seizures after operation. Patients undergoing right anteromesiotemporal lobectomy exhibited significant improvements in verbal memory, regardless of the condition of the excised hippocampal tissue. The degree of hippocampal neuron loss determines to a great extent the severity of the verbal memory decrease that follows dominant anteromesiotemporal lobectomy.

Time-dependent effects of PCPA on social aggression in chicks.

We investigated the effects of para-chlorophenylalanine (PCPA), a serotonin (5-HT) antagonist, on social aggression and brain neurochemistry in young domestic chickens (Gallus domesticus). In Experiment 1, the effects of four different doses of PCPA (0, 100, 200, and 400 mg/kg) were examined for 3 days after injection. Immediately after PCPA injection, aggressive pecking was low and then increased over the 3-day test period. PCPA significantly decreased 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), and 5-HT turnover. In addition, the frequency of aggression was negatively correlated with levels of 5-HIAA. In Experiment 2, the time-dependent effects of a single 400-mg/kg dose of PCPA were examined for 5 and 7 days after drug exposure. PCPA-treated chicks observed for 5 days after injection had significantly greater frequencies of aggression 4 days following drug exposure and significantly reduced 5-HT levels when measured on the next day. Similarly, chicks observed for 7 days exhibited significantly elevated aggression 5 days after injection, after which their pecking decreased to control levels on days 6 and 7. Coinciding with this behavioral pattern, 5-HT levels from these PCPA-treated chicks when assessed 7 days after drug exposure were the same as those for control birds. We concluded that PCPA increased social aggression in birds, an effect that diminished as brain 5-HT levels recovered over a 1-week period.

Cerebral dominance for speech and handwriting of patients with cortical vascular malformations.

Lateralization of speech dominance was established using amobarbital for 22 patients with vascular malformations lateralized to the left cerebral hemisphere. Patients' histories were negative for clinically evident neurological events (e.g., seizures or hemorrhage) prior to adulthood. The vascular lesions were categorized as high flow arteriovenous malformations (AVMs) (n = 4), low flow AVMs (n = 6), cavernous hemangiomas (n = 10), or venous angiomas (n = 2) by reviewing angiographic findings and surgical pathology for those patients whose lesions were excised. Three of the malformations encroached upon primary language areas. The frequency of right hemisphere speech dominance was not significantly elevated in comparison with the normal population, even though the incidence of nonright-handedness was. Ninety-five percent of the patients were left hemisphere dominant for speech: only one patient, with a parietal lobe cavernous hemangioma, was found to be right hemisphere dominant for speech. This malformation did not involve the primary language areas. These findings suggest that vascular malformations do not affect speech dominance as readily as other neurological diseases, but frequently affect manual dominance.

Long-term consequences of minimal brain injury: loss of consciousness does not predict memory impairment.

This study evaluated the memory and intellectual function of 32 adults following minimal brain injury. All patients had a Glasgow Coma Scale score of 15 upon evaluation in the Emergency Room, negative findings on radiographic examination, and negative history of prior neurologic disease or injury. Seventeen of these had experienced a loss of consciousness. Patients suffering a loss of consciousness postinjury obtained significantly lower mean verbal intelligence quotients than those obtained by patients who remained conscious following their accidents. Both groups exhibited memory impairments. This could indicate that loss of consciousness predicts intellectual impairment, but not degree of memory dysfunction. An alternative interpretation of these data is that patients referred for examination after a head injury that did not involve a loss of consciousness included a disproportionate number of patients from upper socioeconomic levels who have greater access to medical delivery systems or greater sophistication regarding cognitive function.