Recent advances in the treatment of cerebellar ataxias.
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Cerebellar Ataxia↗
Biomedical subjects
B V Manyam
Publications and source records attributed to B V Manyam.
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.
Adult↗
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.
Aging↗
Further characterization of in vitro conditions appropriate for GABA determination in human CSF: impact of acid deproteinization and freeze/thaw.
Recently established standardized protocols for collection, handling, and storage of CSF for measurement of gamma-aminobutyric acid (GABA) have proven valuable in the characterization of various CNS disorders. In response to two recent reports which may have an impact on certain widely used protocols, we have, using the confirmed ion-exchange/fluorometric procedure, systematically evaluated the effects of deproteinization with various concentrations of sulfosalicylic acid (SSA) ranging from 0 to 10% (100 mg/ml), as well as the effects of freeze/thaw (F/T) on CSF GABA levels. Results of F/T studies documented that levels are stable to freezing and thawing. Acid deproteinization studies revealed the presence of an equilibrium between strictly free GABA, demonstrable only in acid-free CSF, and a very loosely bound form of GABA, fully demonstrable only in CSF deproteinized with concentrations of SSA above 1% (10 mg/ml). The relationship between GABA concentrations in undeproteinized and acid-deproteinized CSF revealed a highly significant (p less than .001) correlation, suggesting that alterations of central GABAergic activity would be reflected by either the level of strictly free GABA or free plus loosely bound GABA. This hypothesis was upheld in studies of patients with Parkinson's disease (PD) and Huntington's disease (HD), two neurologic disorders in which dysfunctions of the GABA system have been implicated. Results indicated that CSF GABA levels are significantly reduced in both PD and HD patients compared with neurologically normal controls, whether the measurement is of free GABA or free plus loosely bound GABA. Thus, we conclude that the level of strictly free GABA is stable to freezing and thawing and can only be accurately determined in nonacidified CSF; however, existing protocols employing deproteinization in 5% SSA yield data that provide an equally good reflection of central GABAergic transmission.
Adult↗
Isoniazid-induced reduction of serum cholesterol.
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Adult↗
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.
Adult↗
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.
Aged↗
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.
Enzymes↗
Isoniazid-induced elevation of CSF GABA levels and effects on chorea in Huntington's disease.
A randomized, double-blind, crossover, placebo-controlled clinical trial of oral isoniazid was undertaken in eight men with known Huntington's disease. Six completed the trial. Overall chorea scores indicated some amelioration, but clinical improvement was noticed in only two patients and was mild. Side effects included anorexia and elevation of liver enzyme levels. Cerebrospinal fluid (CSF) and plasma gamma-aminobutyric acid (GABA) concentrations were measured simultaneously. Mean CSF GABA increased threefold following treatment with isoniazid (414 +/- 52 SEM pmol/ml) compared to placebo (120 +/- 11 pmol/ml). No significant changes occurred in plasma GABA levels between the placebo and drug treatment phases. Reversal of central GABA deficiency appears not to correct extrapyramidal symptoms in Huntington's disease.
Adult↗
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.
Adult↗
Epilepsy in ancient India.
The ancient Indian medical system, Ayurveda, meaning science of life, is the oldest system of medicine in the world. Epilepsy is defined as Apasmara: apa, meaning negation or loss of; smara, meaning recollection or consciousness. Aura was recognized and was called Apasmara Poorva Roopa. A large number of symptoms indicative of aura were listed. Worthy of mention are subjective sensation of sounds, sensation of darkness, feeling of delusion, and dream-like state. An actual attack of Apasmara includes falling down; shaking of the hands, legs, and body; rolling up of the eyes; grinding of the teeth; and foaming at the mouth. Four major types of epilepsy based on the disturbance of doshas (humors) that govern the physiological and physiochemical activities of the body are mentioned. Apasmara is considered a dangerous disease that is chronic and difficult to treat. Several causes are mentioned. Treatment included correcting the etiological factors and dietary regimen and avoiding dangerous places that may result in injuries.
Epilepsy↗
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.
Brain Chemistry↗
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.
Adult↗
Practical guidelines for management of Parkinson disease.
BACKGROUND: This article describes a specialist's perspective on the challenge of caring for patients with Parkinson disease in a changing American health care environment that places increasing responsibility on primary care physicians. METHODS: Guidelines were developed by drawing from a combination of personal experience at a large university Parkinson disease clinic, literature review, presentations at various family practice continuing medical education conferences, and involvement as investigator in various clinical trials of drugs used in Parkinson disease treatment. RESULTS AND CONCLUSIONS: From a therapeutic standpoint, Parkinson disease can be divided into three stages--early, nonfluctuating, and fluctuating. Although the same drugs, namely, carbidopa-levodopa preparations, dopamine agonists, and anticholinergic medications, are usually prescribed, their pattern of use, including frequency and dosing, varies depending on the nature of the dominant symptoms and stage of the disease. Management of Parkinson disease requires familiarity with both the disease-related and drug-related components. Optimal functional efficiency for the patient is gained through striking a delicate balance between the drug regimen and the disease-related components.
Aged↗