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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several toxic factors have been implicated in the pathogenesis of hepatic encephalopathy (PSE) among which ammonia plays a dominant role. More recently, the gamma-aminobutyric acid (GABA) hypothesis in which an increase in the GABA-ergic tone and the presence of one or more GABA/benzodiazepine receptor ligands which interact with that receptor, has been proposed. We investigated the levels of GABA and ammonia in plasma of patients with acute PSE to test the hypothesis that elevated plasma GABA levels would be found in acute encephalopathy and that GABA levels would correlate with the degree of hepatic encephalopathy. We measured plasma levels of GABA and ammonia during an acute episode of PSE, spontaneous or precipitated by gastrointestinal bleeding or sepsis, and performed assessments of PSE by the PSE index. Patients were evaluated before and two days after standard treatment with lactulose. We also measured plasma GABA levels in the hepatic vein of a selected group of patients undergoing hemodynamic studies. Plasma GABA levels were significantly higher in patients with acute PSE (458 +/- 108 pmol/mL) when compared with normal subjects (110 +/- 23 pmol/mL) (p < 0.01) although no correlation was found between plasma GABA concentration and the degree of PSE. Changes in plasma ammonia, however, correlated with improvements in the PSE index (r = 0.56; p < 0.02) and with abnormalities in the EEG (r = 0.65; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Association of plasma ammonia and GABA levels and the degree of hepatic encephalopathy]. 148 27

The binding characteristics of gamma-aminobutyric acid-A (GABA-A) receptors and the kinetic characteristics of the target enzyme of GABA synthesis in nerve terminals, glutamic acid decarboxylase (GAD), were studied in a dog model of portal-systemic encephalopathy obtained by porta-caval shunt performed in dimethylnitrosamine pretreated animals. Furthermore the properties of dopamine receptors and the levels of catecholamines of encephalopathic dogs were investigated. The mild stage of encephalopathy was characterized by an up-regulation of the inhibitory GABA-A receptors probably related to a decrese of GABA in nerve terminals since GAD was decreased and by a slight decrease of catecholamines and by an increased synthesis of octopamine associated with a decreased affinity of dopamine receptors. In the severe stage there was a selection of high affinity GABA-A receptors with an increased number of benzodiazepine recognition sites which were supersensitive to GABA stimulation, a decreased number of Dopamine D-2 receptors and a marked reduction of catecholamines. These data seem to suggest that the neurological disturbances of experimental portal-systemic encephalopathy might be the result of an imbalance between inhibitory and excitatory systems leading to a prevalence of the first one.
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PMID:Alterations of GABA-A and dopamine D-2 brain receptors in dogs with portal-systemic encephalopathy. 184 16

Organic acidemias are disorders of intermediary metabolism that lead to accumulation of organic acids in biologic fluids, disturb acid-base balance, and derange intracellular biochemical pathways. Their clinical presentation reflects the resultant systemic disease and progressive encephalopathy. While in some organic acidemias, disturbed acid-base metabolism is the predominant presenting feature, in others it is less prominent or even absent. The etiologies of the more than 50 different phenotypes include impaired metabolism of branched-chain amino acids, vitamins, glucose, lipids, glutathione, and gamma-aminobutyric acid and defects of oxidative phosphorylation. Most organic acidemias present with neurologic manifestations, which include acutely or subacutely progressive encephalopathy that involves different parts of the nervous system. The age of presentation and the associated systemic, hematologic, and immune findings provide additional guidelines for differential diagnosis. We summarize major organic acidemias, while emphasizing their usual and unusual neurologic presentations.
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PMID:Organic acidurias: a review. Part 1. 187 22

A 13-year-old boy was the victim of attempted strangulation. His condition had returned to normal by the sixth day after the assault; however, from the seventh day, choreoathetosis, dystonia, and marked pseudobulbar paralysis developed in the boy. The computed tomographic scans and T2-weighted magnetic resonance images that were obtained at this time revealed low-density and high-signal intensities in the region of the bilateral putamen and caudate nucleus. These symptoms and the changes in his computed tomographic scans and magnetic resonance images subsided gradually during a 2-month period. Sequential analysis of the cerebrospinal fluid for gamma-aminobutyric acid and dopamine concentrations during his illness revealed reciprocal changes with normal recovery. Because of the delayed onset of neurological changes and the cerebrospinal fluid showing reversible symptoms, the delayed encephalopathy after strangulation had been related to the biochemical alterations that followed anoxia in the vulnerable basal ganglia.
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PMID:Delayed postanoxic encephalopathy after strangulation. Serial neuroradiological and neurochemical studies. 189 66

The functional activity of the gamma-aminobutyric acid (GABAA) receptor-chloride ionophore complex was studied in rats with hepatic encephalopathy (HE) secondary to thioacetamide-induced fulminant hepatic failure (FHF). Muscimol stimulation and benzodiazepine potentiation of GABA receptor-mediated 36Cl- uptake into cerebral cortical synaptoneurosomes was compared in HE and control rats. [3H]Flumazenil binding assays were conducted to determine whether the levels of endogenous benzodiazepine-like ligands in extracts of cortex were increased with stages of encephalopathy in this animal model of HE. In both control and HE rats maximal uptake of 36Cl- via the GABAA receptor complex occurred at muscimol concentrations of 30 microM. Potentiation of muscimol-stimulated 36Cl- uptake into synaptoneurosomes by diazepam (5 microM) was equivalent in both groups. Aqueous extracts of proteolytically digested homogenates of cerebral cortices prepared from control and HE rats were effective in stimulating 36Cl- uptake into synaptoneurosomes. Alkaline organic extracts of proteolytically digested homogenates of cerebral cortices from HE rats were more effective than corresponding extracts from controls at inhibiting the binding of [3H]flumazenil. Inhibition of [3H] fumazenil binding by organic extracts derived from the cerebral cortices of HE rats did not increase with progression of encephalopathy. The results show that muscimol-stimulated 36Cl- uptake into synaptoneurosomes and, consequently, GABAA receptor-mediated chloride channel function are not significantly altered in the model of HE studied and are consistent with the hypothesis that HE results in an increased availability of one or more endogenous ligands which can augment GABA receptor-gated chloride conductance.
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PMID:Gamma-aminobutyric acid (GABAA) receptor-function in a rat model of hepatic encephalopathy. 196 8

Environmental and occupational exposure to lead still generates concern, and recent studies have focused such concern on the role of body burden of lead during the fetal/neonatal period, especially in the genesis of disturbed central nervous system development. This discussion provides some comparative observations on the neurotoxicity of inorganic and organic lead species. The characteristics acute, predominantly cerebellar encephalopathy associated with neonatal high lead exposure contrasts to the subtle, axo-dendritic disorganization shown to be associated with low-level neonatal inorganic Pb2+ exposure. There is a preferential involvement of the hippocampus in both low-level inorganic Pb2+ and organolead exposure, and the clinical syndromes of irritability, hyperactivity, aggression, and seizures are common features of disturbed hippocampal function. Neurotransmitter system abnormalities have been described with inorganic Pb2+, but recent attention has focused on the abnormalities in glutamate, dopamine and/or gamma-aminobutyric acid (GABA) uptake, efflux, and metabolism. Abnormalities of GABA and glutamate metabolism are also found with the organolead species. While the pathogenesis is still unclear, the interactive role of Pb2+ on mitochondrial energy metabolism, Ca2+ uptake, intracellular Ca2+ homeostasis, and neurotransmitter influx/efflux is considered. Consideration is given to low-dose inorganic Pb2+ and organolead effects on mitochondrial and/or plasmalemmal membranes inducing either Cl-/OH- antiport-linked depolarization, inhibition of intracellular ATP biosynthesis and transduction. and/or abnormalities induced due to the preferential affinity of Pb2+ for intracellular Ca2(+)-cytoplasmic protein, e.g. calmodulin. Testable hypotheses are presented that may provide an understanding of the pathogenesis underlying dystrophic neuronal development under the influence of inorganic or organolead intoxication.
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PMID:Comparative observations on inorganic and organic lead neurotoxicity. 198 34

Quantitative autoradiography was used to assess the densities of gamma-aminobutyric acid (GABAA) receptors in the brains of rats with a portacaval end-to-side shunt (PCA). The shunt alone induced only mild encephalopathy with ataxia and decreased locomotion. Aggravation of the encephalopathy was achieved by gavage feeding of packed erythrocytes or by induction of severe hyperammonemia by intraperitoneal injection of urease. Gavage feeding of erythrocytes led to severe encephalopathy in about 50% of the animals with PCA. The combination of PCA and urease treatment caused severe encephalopathy in every animal. The serum ammonia concentration increased 5 times normal by PCA alone, 20 times normal by gavage feeding of erythrocytes and more than 30 times normal by urease-treatment of the PCA-animals. For autoradiography, coronal slices were cut at the level of the hippocampal formation and through the cerebellum. Radioligand binding was measured using as a ligand 3H-muscimol, a specific GABAA receptor agonist. The specific binding of 3H-muscimol was assessed densitometrically in several microregions of cerebral cortex, hippocampus and cerebellar cortex. No significant differences were observed between the magnitude of ligand binding to specific microregions of brains from normal animals, animals with PCA without overt encephalopathy and animals with severe encephalopathy induced by a combination of PCA and gavage feeding of erythrocytes or urease treatment.
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PMID:[Autoradiography determination of the GABA(A) receptor density in the brain of rats with portacaval shunt]. 216 Jul 60

Previous studies have suggested that the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is a key factor in the syndrome of portasystemic encephalopathy. We report the case of a patient with medically intractable portasytemic encephalopathy after portacaval shunt who had marked clinical improvement after creation of an end ileostomy. Plasma GABA and serum ammonia levels were measured before and after ileostomy. Although the clinical syndrome and the EEG improved markedly after the ileostomy, the plasma GABA levels remained markedly elevated. Preoperative and postoperative GABA levels were 865 and 633 pmol/ml, respectively (nl = 100-180 pmol/ml). Our findings confirm previous reports of the efficacy of colonic exclusion in patients with intractable portasystemic encephalopathy. However, our results conflict with the hypothesis that GABA itself is the key mediator of the syndrome.
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PMID:Reversal of chronic hepatic encephalopathy by colonic exclusion: poor correlation with blood GABA levels. 225 33

We examined autopsied brain from 10 patients with end-stage renal failure who had undergone repeated hemodialysis. Eight had classic symptoms, and two had suggestive symptoms of dialysis encephalopathy. Findings were compared with those in autopsied brain from control adults who had never been hemodialyzed. Mean gamma-aminobutyric acid (GABA) contents were significantly reduced in frontal and occipital cortex, cerebellar cortex, dentate nucleus, caudate nucleus, and medial-dorsal thalamus of the hemodialyzed patients, the reduction being greater than 40% in cerebral cortex and thalamus. Choline acetyltransferase activity was reduced by 25-35% in three cortical regions in the hemodialyzed patients. These two abnormalities were observed in the brain of each hemodialyzed patient, regardless of whether or not the patient died with unequivocal dialysis encephalopathy. Pyridoxal phosphate contents were substantially reduced in brains of the hemodialyzed patients, but metabolites of noradrenaline, 3,4-dihydroxyphenylethylamine (dopamine), and 5-hydroxytryptamine (serotonin) were present in normal amounts. Aluminum levels were abnormally high in frontal cortical gray matter in the hemodialyzed patients. Although this study does not clarify the role played by aluminum toxicity in the pathogenesis of dialysis encephalopathy, the abnormalities we found suggest the need for further neurochemical investigations in this disorder.
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PMID:Neurochemical abnormalities in brains of renal failure patients treated by repeated hemodialysis. 241 64

If increased gamma-aminobutyric acid (GABA)-mediated neurotransmission contributes to the mediation of hepatic encephalopathy, it may be possible to induce ameliorations of the syndrome by pharmacologically antagonizing a component of the GABA/benzodiazepine receptor complex. To test this possibility we administered the benzodiazepine receptor antagonist flumazenil by intravenous injection to 14 patients with hepatic encephalopathy complicating cirrhosis. Flumazenil administration induced variable and transient, but distinct, improvements of the mental status in 71% of the patients. The degree of encephalopathy improved from stage IV to stage II in 4 patients and from stage IV to stage III in 2 patients. The mental status of all patients with less advanced encephalopathy (3 with stage III, 1 with stage II) also improved, but these responses were clinically less impressive. The arousal effect occurred within minutes after the injection and lasted for 1 to 2 h. Furthermore, it was associated with a significant increase of the mean electroencephalographic frequency from 4.2 to 5.2 cycle/s. Of the 8 patients who were ultimately discharged from the hospital, 7 had responded to flumazenil. No patient who died within 48 h of receiving flumazenil had shown any arousal effect. These findings strongly favor a prominent pathogenetic role of increased GABAergic tone in hepatic encephalopathy in humans and suggest that a positive response to flumazenil might be of prognostic value in predicting short-term survival in encephalopathic patients with liver disease.
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PMID:Effects of the benzodiazepine receptor antagonist flumazenil in hepatic encephalopathy in humans. 254 50


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