Low CSF gamma-aminobutyric acid levels in Parkinson's Disease. Effect of levodopa and carbidopa.

Levels of gamma-aminobutyric acid (GABA) in CSF were measured in patients with Parkinson's disease (n = 14) and sex-matched controls (n = 14). One patient underwent a spinal tap before and after treatment. The mean (+/- SD) CSF GABA levels were 200 +/- 70 pmole/mL in controls and 121 +/- 52 pmole/mL in patients with Parkinson's disease. In the untreated patients with Parkinson's disease, the CSF GABA level was 95 +/- 31 pmole/mL (n = 7) and in those who were treated with levodopa and carbidopa the level was 144 +/- 53 pmole/mL (n = 8). No significant difference was seen in plasma GABA levels between the controls and patients with Parkinson's disease. The decreased GABA level in CSF, which was elevated by levodopa, supports the concept that in Parkinson's disease, the GABA-dopamine interaction in the substantia nigra may be an important compensatory mechanism counteracting the dopamine neuronal loss.

Cerebrospinal fluid amino compounds in Parkinson's disease. Alterations due to carbidopa/levodopa.

Employing a triple-column ion-exchange/fluorometric procedure, 29 amino compounds, including amino acid neurotransmitters, were measured in lumbar cerebrospinal fluid (CSF) from two groups of patients with idiopathic Parkinson's disease de novo (n = 6) and those who were treated with carbidopa/levodopa (n = 6), and from neurologically normal controls (n = 10). Consideration was given to in vivo and in vitro factors known to influence levels of various CSF constituents. Results showed statistically significant decreases in the levels of gamma-aminobutyric acid, homocarnosine, phosphoethanolamine, and threonine, and elevation of ornithine levels, in the CSF of de novo patients with Parkinson's disease compared with controls. These changes "normalized" following treatment with carbidopa/levodopa. This study suggests that Parkinson's disease may be characterized by defects in specific amino compound metabolic pathways, resulting in central nervous system amino compound imbalances that may contribute to the pathophysiology of this disorder. Carbidopa/levodopa therapy tends to "normalize" these amino compound imbalances.

Clinical implications of enzyme-mediated alterations of gamma-aminobutyric acid content in human CSF.

Pooled samples of lumbar CSF from nine patients with neurologic disorders were aliquoted and subjected to the differential influence of temperature for four hours. The determination of the gamma-amino-butyric acid (GABA) levels in CSF by ion-exchange-fluorometric analysis before and after incubation showed a progressive increase in GABA content of CSF as a function of temperature, reaching a maximum at 50 degrees C. However, no increases in GABA level were noted in CSF incubated at 80 degrees C or 100 degrees C. These in vitro increases in the GABA content of untreated CSF appear to be entirely secondary to enzyme action, subject to individual and temperature variability, and necessitate standardization of clinical CSF protocols.

Cerebrospinal fluid as a reflector of central cholinergic and amino acid neurotransmitter activity in cerebellar ataxia.

Cerebrospinal fluid (CSF) amino acid neurotransmitters, related compounds, and their precursors, choline levels, and acetylcholinesterase activity were measured in the CSF of patients with cerebellar ataxia during a randomized, double-blind, crossover, placebo-controlled clinical trial of physostigmine salicylate. The CSF gamma-aminobutyric acid, methionine, and choline levels, adjusted for age, were significantly lower in patients with cerebellar ataxia compared with controls. Physostigmine selectively reduced the level of CSF isoleucine and elevated the levels of phosphoethanolamine. No change occurred in CSF acetylcholinesterase activity and in the levels of plasma amino compounds in patients with cerebellar ataxia when compared with controls. Median ataxia scores did not statistically differ between placebo and physostigmine nor did functional improvement occur in any of the patients.

Central nervous system gamma-aminobutyric acid activity in man. Relationship to age and sex as reflected in CSF.

Central nervous system gamma-aminobutyric acid (GABA) activity was demonstrated to be an age- and sex-dependent phenomenon through the study of GABA concentration in lumbar CSF obtained from 87 drug-free normal individuals. Evaluation of the data from homogeneous subgroups of this population disclosed that both the propensity of lumbar CSF GABA levels to decrease with age and the magnitude of the rostrocaudal GABA concentration gradient are more pronounced in females, suggesting possible neuroendocrine involvement. Thus, age and sex are important variables that normally influence central GABAergic activity. Patient populations included in clinical investigations must be age- and sex-matched to avoid invalid conclusions biased by these physiologic variations in CSF GABA concentrations.

A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor.

OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin type A injection in essential tremor of the hand. BACKGROUND: Botulinum toxin type A is an effective treatment for dystonia, spasticity, and other movement disorders and has been found to be useful in open-label studies and one double-masked study of essential hand tremor. METHODS: One hundred thirty-three patients with essential tremor were randomized to low-dose (50 U) or high-dose (100 U) botulinum toxin type A (Botox) or vehicle placebo treatment. Injections were made into the wrist flexors and extensors. Patients were followed for 16 weeks. The effect of treatment was assessed by clinical rating scales, measures of motor tasks and functional disability, and global assessment of treatment. Hand strength was evaluated by clinical rating and by a dynamometer. RESULTS: Both doses of botulinum toxin type A significantly reduced postural tremor on the clinical rating scales after 4 to 16 weeks. However, kinetic tremor was significantly reduced only at the 6-week examination. Measures of motor tasks and functional disability were not consistently improved with botulinum toxin type A treatment. Grip strength was reduced for the low- and high-dose botulinum toxin type A groups as compared with the placebo group. Adverse reactions consisted mainly of dose-dependent hand weakness. CONCLUSION: Botulinum toxin type A injections for essential tremor of the hands resulted in significant improvement of postural, but not kinetic, hand tremors and resulted in limited functional efficacy. Hand weakness is a dose-dependent significant side effect of treatment at the doses used in this study.

Free and conjugated GABA in human cerebrospinal fluid: effect of degenerative neurologic diseases and isoniazid.

gamma-Aminobutyric acid (GABA) was measured in CSF as such and following acid hydrolysis by the ion-exchange/fluorometric method. The conjugated GABA level was obtained by subtracting the free GABA level from the total GABA level. Results showed that at room temperature, while the free GABA level increased, the level of conjugated GABA decreased in a linear fashion during the first 24 h (r = -0.974; P less than 0.001). Aging and CSF conjugated GABA levels were inversely correlated (r = -0.613; P less than 0.05). Unlike free GABA levels, the levels of conjugated GABA were not altered in Huntington's disease, Parkinson's disease, cerebellar ataxias, dementias, epilepsy and multiple sclerosis compared to controls. In patients with Huntington's disease, on administration of isoniazid at 900 mg/day, along with pyridoxine at 100 mg/day, a 4-fold increase of both free (P less than 0.005) and conjugated GABA (P less than 0.0025) was seen. The results indicate that while total GABAergic peptides are not altered in several of the neurologic diseases studied, drugs such as isoniazid and/or pyridoxine can significantly elevate both free and conjugated GABA levels in human CSF.

Isoniazid-induced alteration of CSF neurotransmitter amino acids in Huntington's disease.

During a randomized, double-blind, crossover, placebo-controlled clinical trial of isoniazid (plus pyridoxine) in Huntington's disease (HD), amino acids and related amino compounds were measured in both cerebrospinal fluid (CSF) and plasma utilizing a newly developed high-performance liquid chromatography ion-exchange/fluorometric assay method. Results showed that isoniazid (plus pyridoxine) significantly elevated the mean (+/- S.E.M.) levels of gamma-aminobutyric acid, aspartate, asparagine, homocarnosine, ornithine, histidine, alpha-aminobutyric acid, isoleucine, leucine and alanine in CSF and the levels of beta-alanine in both CSF and plasma. These alterations can be traced to inhibition of decarboxylation and transamination reactions requiring the cofactor pyridoxal phosphate and may be related to the observed equivocal clinical response in the HD patients. The differential influence of isoniazid on plasma and CSF amino acid profiles suggests that alterations of CNS amino acid metabolism may be reflected in CSF, and that isoniazid-induced alterations of amino acid metabolism in the CNS differ from those in the periphery.

Cerebrospinal fluid acetylcholinesterase and choline measurements in Huntington's disease.

The caudate nucleus has the highest acetylcholinesterase (AChE) activity in the brain and it has been shown that autopsied brain tissue of patients with Huntington's disease (HD) have reduced levels of acetylcholine. Because of these findings, the cholinergic function in HD was studied by measuring cerebrospinal fluid (CSF) choline levels and AChE activity during a randomized, double-blind, cross-over, placebo-controlled clinical trial of isoniazid. While mean choline levels adjusted for age were lower compared with controls (P = 0.0007), AChE activity did not differ between HD patients and normal controls. Treatment with isoniazid had no significant effect on CSF choline levels or CSF AChE activity. CSF AChE activity showed a statistically significant increase with advancing age. The reduced level of choline in CSF of HD patients may reflect either a defect in choline transport into the brain or a decrease of choline-phospholipid output from the brain.

Brain iron in patients with Parkinson disease: MR visualization using gradient modification.

In patients with Parkinson disease, improved visualization of brain iron on a mid-field-strength magnet can be obtained with T2-weighted images and elimination of phase-encoding artifacts. A long echo delay time accentuates the loss of signal from brain iron. However, the long pulse sequence creates phase-encoding artifacts from CSF pulsations at the level of the basal ganglia. These artifacts are eliminated and resolving power increased with additional pulsing in the slice-selective and read gradients. Elimination of motion artifacts enhances visualization of brain iron in three ways: (1) extrapyramidal nuclei containing iron have better definition, (2) abnormalities are better identified, and (3) pseudolesions disappear. Our findings suggest there is significant improvement in the resolving power of brain iron on MR scans made with a mid-field-strength scanner when gradient modification is used.

Visualization of brain iron by mid-field MR.

Brain iron was visualized on a mid-field (0.5 T) scanner using a spin-echo pulse sequence. Methemoglobin was hyperintense on T1- and T2-weighted images. Deoxyhemoglobin, hemosiderin, and ferritin were seen as decreased intensity on T2-weighted images. The spin-echo pulse sequences were improved for identification of deoxyhemoglobin, hemosiderin, and ferritin by prolonging the TR to 3000 msec and the TE to 80-120 msec. Phase-encoding artifacts at the level of the sylvian fissures caused increased noise, obscuring the brain iron in the lentiform nuclei with the TE of 120 msec. This artifact was substantially reduced or eliminated by lowering the TE to 80 msec, changing the phase-encoding gradient to the Y axis, or using additional pulsing in the slice and read gradients. Use of either the improved spin-echo or gradient-echo pulse sequences on a mid-field MR scanner provides improved evaluation of brain iron.

Cerebrospinal fluid GABA measurements: basic and clinical considerations.

The valid measurement of GABA concentration in the CSF for studying in vivo alterations of central nervous system GABAergic activity requires that consideration be given to several factors that affect GABA concentration. These factors include in vivo variables such as the caudocranial concentration gradient in CSF, age, sex, precursor intake, medications, and physical activity, as well as in vitro alterations that can occur during collection, storage, preparation of sample, and analysis. The influence of these factors can be minimized with proper methodology.

Safety of long-term levodopa therapy in malignant melanoma.

Levodopa therapy is contraindicated in malignant melanoma because of its apparent carcinogenic effects reported by physicians in the early 1970s. We discuss the case of a 74-year-old man with Parkinson's disease who was treated with levodopa and whose malignant melanoma was later diagnosed. Before development of malignant melanoma, the patient received an estimated 5.7 kg levodopa over 6 years. Therapy with levodopa was continued for > 10 years, with a total dose of approximately 4.3 kg levodopa (together with carbidopa.) Recurrence of the melanoma was not observed. Based on our experience with this patient and an extensive literature review, we conclude that the natural history of malignant melanoma is not adversely influenced by concurrent levodopa therapy. Levodopa therapy should not be withheld for fear of accelerating malignant melanoma in parkinsonian patients.

Clozapine for the control of hemiballismus.

Pharmacological agents used for the control of ballistic movements include chloral hydrate, barbiturates, paraldehyde, bromides, phenothiazines, progabide, haloperidol, pimozide, reserpine, tetrabenazine, sodium valproate, and dimethylaminoethanol. These agents are believed to act by different mechanisms, including modification of dopaminergic, GABAergic, or cholinergic mechanisms. We report a case where, after failure of haloperidol, phenobarbital, and pimozide, the hemiballistic movements were controlled with clozapine.

Evaluation of equivalent efficacy of sinemet and sinemet CR in patients with Parkinson's disease applying levodopa dosage conversion formula.

We report ease of conversion, effect on equivalent efficacy and frequency of dosing when immediate-release carbidopa/levodopa (Sinemet, IR-CL, DuPont Pharma, Wilmington, DE, U.S.A.) is replaced with controlled-release carbidopa/levodopa (Sinemet CR, CR-CL, DuPont Pharma, Wilmington, DE, U.S.A.) in patients with Parkinson's disease (PD). One-step conversion through the application of a mathematical formula was utilized. Fifty-two patients (35 men, 17 women) with a mean +/- SD age of 72 +/- 8 years participated in this open-label study. All patients were taking IR-CL prior to conversion. The Unified Parkinson's Disease Rating Scale (UPDRS) was used for efficacy assessment. Pharmacokinetic studies were undertaken in five patients while they were on IR-CL, and repeated after they were switched to CR-CL. Dosage adjustment was not required either immediately after converting or during the 6-month follow-up. No significant changes occurred in efficacy scores during follow-up visits, indicating the effectiveness of the conversion. There were substantial differences in the level of plasma DOPA, dopamine, 3-O-methyldopa, homovanillic acid, and dihydroxyphenylacetic acid between patients receiving IR-CL and those receiving CR-CL, but the differences did not correlate with clinical changes, suggesting that plasma levels do not reflect tissue levels at the site of action for levodopa. This study demonstrates that conversion from IR-CL to CR-CL for optimal dosing may be achieved in one step through the application of a mathematical formula with ease of conversion and reduction of number of doses.

Traditional and complementary therapies in Parkinson's disease.

Parkinson's disease has existed in different parts of the world since ancient times. The first clear description is found in the ancient Indian medical system of Ayurveda under the name Kampavata. Traditional therapies in the form of herbal preparations containing anticholinergics, levodopa, and monoamine oxidase inhibitors were used in the treatment of PD in India, China, and the Amazon basin. Scientific reevaluation of these therapies may be valuable, as shown in the case of Mucuna pruriens and Banisteria caapi. Complementary therapies such as massage therapy, biofeedback, and acupuncture may have beneficial effects for patients and deserve further study.

Dementia in Ayurveda.

The ancient Indian medical system, Ayurveda, included geriatrics as 1 of 8 medical divisions. Well-documented evidence exists for treating aging and age-related disorders including dementia. Geriatrics was termed Rasayanatantra. Cognitive function was well recognized and Sanskrit terms existed such as Buddhi for intelligence and Cittanasa (Citta means mind, nasa means loss of) for dementia. A normal human life span was considered to be 100 years. It could be prolonged to 116-120 years through the use of preventive treatments, if they were started during late youth or middle age. Treatments included herbal preparations, diet, exercise, and attention to general mode of life and social behavior. Several herbal formulations are described, including details of their composition and preparation. The mode of action of antiaging drugs was believed to occur at 3 levels. Detailed descriptions of the mode of action of several herbs are provided, and recent research confirms some of this activity.