Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics.

The authors studied the pharmacokinetics of levodopa (LD) with and without pramipexole (PPX) in men and postmenopausal women with PD. Patients on stable dose of carbidopa/LD were randomized to receive escalating doses of placebo or PPX over 7 weeks. LD and PPX pharmacokinetics were performed after a single test dose 25/100 of carbidopa/LD, before initiation of PPX or placebo, at 1.5 mg/d and 4.5 mg/d of PPX or placebo. Compared to men, women had greater LD bioavailability. PPX did not alter LD bioavailability, and PPX pharmacokinetics were equivalent in men and women.

Toward an understanding of violence: neurobehavioral aspects of unwarranted physical aggression: Aspen Neurobehavioral Conference consensus statement.

OBJECTIVE: Violence is a global problem that poses a major challenge to individuals and society. This document is a consensus statement on neurobehavioral aspects of violence as one approach to its understanding and control. BACKGROUND: This consensus group was convened under the auspices of the Aspen Neurobehavioral Conference, an annual consensus conference devoted to the understanding of issues related to mind and brain. The conference is supported by the Brain Injury Association and by individual philanthropic contributions. Participants were selected by conference organizers to represent leading opinion in neurology, neuropsychology, psychiatry, trauma surgery, nursing, evolutionary psychology, medical ethics, and law. METHODS: A literature review of the role of the brain in violent behavior was conducted and combined with expert opinion from the group. The major goal was to survey this field so as to identify major areas of interest that could be targeted for further research. Additional review was secured from the other attendees at the Aspen Neurobehavioral Conference. RESULTS: The group met in the spring of 1998 and 1999 for two 5-day sessions, between which individual assignments were carried out. The consensus statement was prepared after the second meeting, and agreement on the statement was reached by participants after final review of the document. CONCLUSIONS: Violence can result from brain dysfunction, although social and evolutionary factors also contribute. Study of the neurobehavioral aspects of violence, particularly frontal lobe dysfunction, altered serotonin metabolism, and the influence of heredity, promises to lead to a deeper understanding of the causes and solution of this urgent problem.

Neurologic evaluation of violent juveniles.

Any juvenile who has acted violently requires a systematic, meticulous neurologic evaluation. There is no substitute for an adequate medical, family, and social history, the latter focusing on abuse and neglect. Evaluation should include a full physical and a conventional neurologic examination. Additionally, the physical, neurologic examination must include tests of cerebral-cortical function. The history and physical examination usually will indicate the diagnosis. A neuropsychologic evaluation of higher cerebral functions, including tests of frontal functions, should also be done in most cases. Some specific causes of brain disease can be identified by appropriate blood and urine tests, waking and sleep EEGs, and neuroimaging investigations. In general, positive findings are more significant than negative findings. If the physical examination and psychological tests are negative and the MR imaging shows a brain tumor, the patient has a brain tumor. If the neurologic or neuropsychological examinations demonstrate brain dysfunction, the patient has brain dysfunction, even if MR imaging is normal.

Objective documentation of child abuse and dissociation in 12 murderers with dissociative identity disorder.

OBJECTIVE: The skepticism regarding the existence of dissociative identity disorder as well as the abuse that engenders it persists for lack of objective documentation. This is doubly so for the disorder in murderers because of issues of suspected malingering. This article presents objective verification of both dissociative symptoms and severe abuse during childhood in a series of adult murderers with dissociative identity disorder. METHOD: This study consisted of a review of the clinical records of 11 men and one woman with DSM-IV-defined dissociative identity disorder who had committed murder. Data were gathered from medical, psychiatric, social service, school, military, and prison records and from records of interviews with subjects' family members and others. Handwriting samples were also examined. Data were analyzed qualitatively. RESULTS: Signs and symptoms of dissociative identity disorder in childhood and adulthood were corroborated independently and from several sources in all 12 cases; objective evidence of severe abuse was obtained in 11 cases. The subjects had amnesia for most of the abuse and underreported it. Marked changes in writing style and/or signatures were documented in 10 cases. CONCLUSIONS: This study establishes, once and for all, the linkage between early severe abuse and dissociative identity disorder. Further, the data demonstrate that the disorder can be distinguished from malingering and from other disorders. The study shows that it is possible, with great effort, to obtain objective evidence of both the symptoms of dissociative identity disorder and the abuse that engenders it.

Neurologic abnormalities in murderers.

Thirty-one individuals awaiting trial or sentencing for murder or undergoing an appeal process requested a neurologic examination through legal counsel. We attempted in each instance to obtain EEG, MRI or CT, and neuropsychological testing. Neurologic examination revealed evidence of "frontal" dysfunction in 20 (64.5%). There were symptoms or some other evidence of temporal lobe abnormality in nine (29%). We made a specific neurologic diagnosis in 20 individuals (64.5%), including borderline or full mental retardation (9) and cerebral palsy (2), among others. Neuropsychological testing revealed abnormalities in all subjects tested. There were EEG abnormalities in eight of the 20 subjects tested, consisting mainly of bilateral sharp waves with slowing. There were MRI or CT abnormalities in nine of the 19 subjects tested, consisting primarily of atrophy and white matter changes. Psychiatric diagnoses included paranoid schizophrenia (8), dissociative disorder (4), and depression (9). Virtually all subjects had paranoid ideas and misunderstood social situations. There was a documented history of profound, protracted physical abuse in 26 (83.8%) and of sexual abuse in 10 (32.3%). It is likely that prolonged, severe physical abuse, paranoia, and neurologic brain dysfunction interact to form the matrix of violent behavior.

Unilateral destruction of dopamine pathways increases ipsilateral striatal serotonin turnover in rats.

In order to evaluate the influence of dopaminergic transmission on regional brain utilization of serotonin (5HT), the effects of the destruction of the ascending dopamine (DA) pathways on regional brain 5HT metabolism in the rat were examined. Complete unilateral lesions of the nigrostriatal DA pathways (> 90% DA loss) were made by infusing the neurotoxin 6-hydroxy-dopamine into either the left medial forebrain bundle (MFB) or the left substantia nigra (SN). At 6 weeks after the lesions, levels of 5HT and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA), were determined bilaterally in the striatum, frontal cortex, and hypothalamus. In the striatum of the lesioned hemisphere, the 5HT level decreased by more than 50%, while the ratio of 5HIAA:5HT (an index of 5HT turnover) increased by more than 90%. In the same rats, cortical and hypothalamic 5HT, 5HIAA, and 5HT turnover were not changed as a result of the MFB or SN lesions. These results suggest that the loss of DA innervation in the striatum triggers an increase in 5HT turnover and a net depletion of 5HT in the striatum. To verify that the loss of DA was responsible for the observed striatal 5HT changes, we examined the effect of intracerebral implantation of DA-containing pellets into one group of MFB-lesioned rats. The lesioned rats with placebo pellets did not differ from lesioned rats without pellets, whereas the implantation of DA pellets reversed the lesion-induced changes in the 5HT levels and 5HIAA:5HT ratios.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspartame use in Parkinson's disease.

The artificial sweetener aspartame (NutraSweet) is hydrolyzed in the gut as phenylalanine (PA), a large neutral amino acid (LNAA). LNAAs compete with levodopa for uptake into the brain. To determine the effect of aspartame on levodopa-treated Parkinson's disease (PD) patients, we studied 18 PD patients with protein-sensitive motor fluctuations by administering in a double-blind and single-crossover design, on alternate days, aspartame (600 or 1,200 mg) and placebo. Every hour, we performed a motor examination and drew blood to estimate plasma LNAA, PA, and levodopa levels. Six-hundred mg of aspartame had no effect on plasma PA or motor status. Although 1,200 mg of aspartame significantly increased plasma PA, motor performance did not deteriorate. Aspartame consumption in amounts well in excess of what would be consumed by heavy users of aspartame-sweetened products has no adverse effect on PD patients.

Protein redistribution diet remains effective in patients with fluctuating parkinsonism.

Forty-three carbidopa-levodopa (Sinemet)-treated parkinsonian patients with protein-sensitive motor fluctuations were started on the protein redistribution diet within the past 48 months. Thirty patients (70%) are still using the diet successfully after more than 12 months (mean duration, 33.6 months; range, 12 to 48 months). The diet was discontinued in the other 13 cases. In 10 of these 13 patients, the protein redistribution diet was discontinued for a variety of reasons, despite continued sensitivity to dietary protein; in only three patients (7%), those with the most severe and complicated disease, was the protein redistribution diet stopped because of its limited therapeutic benefit. The protein redistribution diet is a simple adjunct to the treatment of Parkinson's disease that can significantly prolong the efficacy of levodopa therapy in many fluctuating "end-stage" patients.

Standard and controlled-release levodopa/carbidopa in patients with fluctuating Parkinson's disease on a protein redistribution diet. A preliminary report.

Ten patients with Parkinson's disease (PD) with motor fluctuations that responded to a protein redistribution diet were studied. All 10 patients were receiving standard Sinemet (levodopa/carbidopa). Five randomly selected patients were changed from standard Sinemet to a controlled-release form of Sinemet. The other five patients continued to receive standard Sinemet. To maintain the same degree of control of PD in the five patients switched to the controlled-release form of Sinemet, the daily levodopa intake increased. While receiving optimal therapy (standard Sinemet or controlled-release Sinemet) and a protein redistribution diet, all 10 patients then underwent hourly videotaping and blood sampling (for plasma levodopa levels) during 2 consecutive days. Videotapes were blindly reviewed for PD disability, dyskinesia, and the time required to walk a measured distance. Comparing the two groups, standard Sinemet with controlled-release Sinemet, respectively, mean levodopa requirements were 505 and 1895 mg, plasma levodopa levels were 6.1 and 17.6 mumol/L, and abnormal involuntary movement scale scores were 14 and 26. Their mean PD disability scores did not differ statistically or clinically. Also no statistically significant differences were noted in either their mean walking times or their mean daily dose frequencies.

Cryptococcal meningitis. False-negative antigen test results and cultures in nonimmunosuppressed patients.

All cases of cryptococcal meningitis at Yale-New Haven (Conn) Hospital seen during a 4 1/2-year period were reviewed to calculate the rate of false-negative antigen test results and cultures preceding diagnosis. Of 13 patients, 9 were immunosuppressed and were diagnosed following the initial lumbar puncture, with both antigen test results and cultures positive in all cases. Among 4 nonimmunosuppressed patients, the rate of false-negative antigen test results was 77%, and of cultures, 89%. The diagnosis was consequently delayed in 3, 2 of whom died despite treatment. Cryptococcal meningitis may be underdiagnosed and undertreated to a significant degree in nonimmunosuppressed patients.

Neuropsychiatric, psychoeducational, and family characteristics of 14 juveniles condemned to death in the United States.

Of the 37 juveniles currently condemned to death in the United States, all of the 14 incarcerated in four states received comprehensive psychiatric, neurological, neuropsychological, and educational evaluations. Nine had major neurological impairment, seven suffered psychotic disorders antedating incarceration, seven evidenced significant organic dysfunction on neuropsychological testing, and only two had full-scale IQ scores above 90. Twelve had been brutally physically abused, and five had been sodomized by relatives. For a variety of reasons the subjects' vulnerabilities were not recognized at the time of trial or sentencing, when they could have been used for purposes of mitigation.

Protein redistribution diet restores motor function in patients with dopa-resistant "off" periods.

Sixteen parkinsonians with acquired drug-resistant "off" periods without dyskinesia were placed on a diet in which virtually all protein was concentrated in the evening meal. Restoration of sensitivity to levodopa resulted in 88%. Ten patients (62%) have continued to comply with the diet for 7 months (mean). Two patients were studied in detail. Immobility correlated with elevated plasma levels of large neutral amino acids (LNAA), normality with low LNAA.

Plasma levels of amino acids correlate with motor fluctuations in parkinsonism.

Seven patients with Parkinson's disease who experienced severe motor fluctuations in response to levodopa were studied in detail with relation to the effect of dietary protein on their motor function. The levodopa dose for each patient was not changed during the period of study, and no other antiparkinsonian drugs were used. Regular and high-protein diets resulted in a marked elevation in the plasma concentrations of large neutral amino acids (LNAAs) that are known to compete with levodopa for transport across the blood-brain barrier. Despite elevated plasma levodopa levels, all patients with elevated LNAA levels experienced parkinsonian symptoms. When the amino acid level dropped while plasma levodopa levels were elevated, patients experienced relief of these symptoms. On a low-protein diet, LNAA levels remained low and all patients were consistently dyskinetic throughout the day, even though the mean plasma levodopa levels were somewhat lower than when the patients consumed a high-protein diet. A redistribution diet that is virtually protein free until supper and then unrestricted until bedtime is tolerated by patients because this simple manipulation permits near-normal daytime motor function.