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Biomedical subjects

G Kircheis

Publications and source records attributed to G Kircheis.

16 recordsLinked to original sources
PubMed2006

1H-MR spectroscopy, magnetization transfer, and diffusion-weighted imaging in alcoholic and nonalcoholic patients with cirrhosis with hepatic encephalopathy.

PURPOSE: Mild swelling of astrocytes is proposed as a key event in the pathogenesis of hepatic encephalopathy. Proton MR spectroscopy ((1)H-MR spectroscopy), diffusion-weighted imaging (DWI), and magnetization transfer imaging were performed in patients with alcoholic and nonalcoholic liver cirrhosis and correlated with different clinical stages of hepatic encephalopathy to assess alterations in cerebral water metabolism in different subgroups of patients with cirrhosis. MATERIAL AND METHODS: Forty-five patients (26 alcoholics, 19 nonalcoholics [due to hepatitis C (n = 9), hemochromatosis (n = 2), primary chronic cholangitis (n = 2), hepatitis B (n = 1), Wilson disease (n = 1), cryptogenic cirrhosis (n = 4)]) and 18 controls underwent (1)H-MR spectroscopy, magnetization transfer imaging, and DWI of the basal ganglia and normally appearing occipital white matter (NAWM). N-acetylaspartate (NAA), choline (Cho), myo-inositol (mIns), and glutamine/glutamate (Glx) relative to creatine (Cr), the apparent diffusion coefficients (ADC), and the magnetization transfer ratios (MTR) were correlated to the neuropsychologic status, which was assessed by computerized psychometry and mental state grading, according to the West Haven criteria. RESULTS: Compared with controls, nonalcoholic subjects exhibited a gradual increase of Glx/Cr in the basal ganglia and NAWM; a decrease in mIns/Cr; a significant decrease of MTR in the thalamus, the putamen, the pallidum, and NAWM; and an increase in the ADC of the NAWM with increasing hepatic encephalopathy severity. In alcoholics, mIns/Cr of the basal ganglia and the NAWM, Cho/Cr of the basal ganglia, and MTR of all assessed regions were decreased. Glx/Cr of the basal ganglia and of the NAWM was increased, compared with that of controls; but no correlation to the clinical hepatic encephalopathy grading was found. ADC did not change significantly between the groups. CONCLUSIONS: Apart from a typical pattern of (1)H-MR spectroscopy alterations in hepatic encephalopathy, a gradual decrease in MTR and an increase of ADC was found correlating to clinical grading of hepatic encephalopathy in nonalcoholic patients with cirrhosis. In alcoholic patients with hepatic encephalopathy, there was no such correlation. Abnormalities detected by MR imaging may hint at different pathways of brain damage in alcohol-induced liver disease.

Diffusion Magnetic Resonance Imaging↗
PubMed2005

Deficits in cortico-striatal synaptic plasticity and behavioral habituation in rats with portacaval anastomosis.

Hepatic encephalopathy is characterized by disturbances of motor and cognitive functions involving the basal ganglia. So far no standards for assessment of neuropsychiatric abnormalities (disorders of sleep, mood, anxiety and personality) in subclinical hepatic encephalopathy have been defined. Using an animal model of mild (subclinical) hepatic encephalopathy we investigated now striatum-related behaviors and cortico-striatal synaptic plasticity in rats 2 months after introduction of a portacaval shunt and sham-operated matched controls. In a novel open field portacaval shunt rats displayed less locomotor activity; unlike controls they also showed no habituation to the field and no recall of the field environment after 24 h, indicative of cognitive deficit. The elevated-plus maze test indicated no differences in fear/anxiety in the portacaval shunt animals. Tetanic stimulation of cortical afferents in magnesium-free solution evoked an N-methyl-D-aspartate-dependent long-term potentiation in sham-operated animals. In portacaval shunt animals long-term potentiation was significantly impaired. Histamine, a potent modulator of cortico-striatal transmission, induced a larger long-term depression of field potentials in control compared with portacaval shunt rats. In conclusion, a combination of electrophysiological and behavioral approaches has revealed functional changes in cortico-striatal transmission. These data are relevant for understanding the mechanisms of motor and cognitive dysfunctions in hepatic encephalopathy patients and for the development of precise psychometric tests, evaluating cognitive deficits in subclinical hepatic encephalopathy.

Animals↗
PubMed2004

Pathological oscillatory coupling within the human motor system in different tremor syndromes as revealed by magnetoencephalography.

Whole-head MEG-systems and modern spatial-filter-based analysis tools recently provided new possibilities to analyze non-invasively cerebral networks of human tremor syndromes. We compared tremor syndromes in Parkinsonian patients with a typical resting tremor as well as in patients with hepatic encephalopathy (HE) with a postural tremor called "mini-asterixis". In 6 patients with idiopathic Parkinson's disease (PD) we found strong coherence between the electromyography (EMG) of forearm muscles and activity in the contralateral primary motor cortex (M1) at tremor frequency but also at double tremor frequency. Furthermore, significant coherences were observed between M1 and medial wall areas (CMA/SMA), lateral premotor cortex, diencephalon, SII cortex, posterior parietal cortex and the contralateral cerebellum at tremor and, stronger, at double tremor frequency. In contrast, in 6 patients with "mini-asterixis" and HE due to chronic liver cirrhosis excessive corticomuscular coherence occurred at the individual tremor frequency between EMG and M1 activity. Interestingly, thalamus-M1 coupling was significantly altered towards lower frequencies matching the individual frequency of the mini-asterixis. Cerebro-muscular or cerebro-cerebral coupling at double tremor frequency was not observed. Therefore, "mini-asterixis" reflects most likely a pathologically decelerated and augmented synchronized rhythmical motor cortical output. This could be due to functional alterations in the M1-basal-ganglia-thalamo-cortical loops in severe HE. In summary, tremor syndromes in PD as well as in patients with HE and "mini-asterixis" are characterized by pathological oscillatory activity within cerebral networks of motor areas. However, the present study shows different mechanisms of tremor generation in PD and HE patients.

Evoked Potentials, Motor↗
PubMed2003

Mini-asterixis in hepatic encephalopathy induced by pathologic thalamo-motor-cortical coupling.

Recently, it was shown that a slowed motor cortical drive in hepatic encephalopathy (HE) results in mini-asterixis (MA). During forearm elevation, the authors have now investigated the coupling between motor cortex and thalamic activity using magnetoencephalography in six cirrhotic patients with HE and MA and in six control subjects. HE patients showed thalamo-motor-cortical coupling at a significantly lower frequency than the coupling in control subjects. The pathologic motor cortical drive in HE probably results from altered thalamocortical oscillatory coupling.

Aged↗
PubMed2002

[Hepatic encephalopathy].

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome which develops during chronic or acute liver disease. It is functional in nature and potentially reversible and symptoms range from subtle personality changes to deep coma. Diagnosis of manifest HE is made on a clinical basis, whereas psychometric tests are required to diagnose subclinical HE (SHE). Paper-pencil tests are frequently used for diagnosing SHE, but they may be inferior to measurements of critical flicker frequency, which pick minimal and low grade manifest HE as a continuum. Pathogenetically, HE is seen as clinical manifestation of low grade chronic cerebral edema, which is accompanied by alterations in glioneuronal communication. Different factors such as ammonia, inflammatory cytokines, benzodiazepines and electrolyte imbalances may precipitate or aggravate glia edema, thereby explaining precipitation of HE episodes by a variety of unrelated factors. Recognition and rigorous treatment of these precipitating factors is the most important measure in HE therapy, which may be augmented by dietary and medical approaches.

Combined Modality Therapy↗
PubMed2002

Cortical origin of mini-asterixis in hepatic encephalopathy.

The authors investigated 12 patients with cirrhosis who had hepatic encephalopathy (HE): six with continuous mini-asterixis and six with subclinical HE without asterixis. They studied the coupling between hand-muscle electromyography (EMG) recordings and brain activity recorded by magnetoencephalography. On forearm elevation, patients with tremor developed excessive coupling between activity in the motor cortex (M1) and contralateral hand-muscle EMG recordings at the frequency of mini-asterixis, which was not found in controls. The corticomuscular coupling demonstrates the involvement of M1 in asterixis and may reflect a pathologically slowed and synchronized motor cortical drive.

Adult↗
PubMed2002

Clinical efficacy of L-ornithine-L-aspartate in the management of hepatic encephalopathy.

The clinical efficacy of both oral and parenteral L-ornithine-L-aspartate (OA) was confirmed by randomized, placebo-controlled, double-blind studies in patients with manifest hepatic encephalopathy and hyperammonemia. The drug was able to reduce high blood ammonia levels induced either by ammonium chloride or protein ingestion or existing as a clinical complication of cirrhosis per se. Furthermore, OA improved performance in Number Connection Test-A as well as mental state gradation. In contrast to the positive effects observed in patients with more advanced hepatic encephalopathy, oral OA does not seem to affect minimal hepatic encephalopathy. In a recent trial, OA decreased protein breakdown and stimulated protein synthesis in muscle. The therapy had little side effects, increasing with higher intravenously administered dosages, and was well tolerated after oral and parenteral administration.

Ammonia↗
PubMed1999

L-ornithine-L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure.

Brain edema sufficient to cause intracranial hypertension and brain herniation remains a major cause of mortality in acute liver failure (ALF). Studies in experimental animal models of ALF suggest a role for ammonia in the pathogenesis of both encephalopathy and brain edema in this condition. As part of a series of studies to evaluate the therapeutic efficacy of ammonia-lowering agents, groups of rats with ALF caused by hepatic devascularization were treated with L-ornithine-L-aspartate (OA), an agent shown previously to be effective in reducing blood ammonia concentrations in both experimental and human chronic liver failure. Treatment of rats in ALF with infusions of OA (0.33 g/kg/h, intravenously) resulted in normalization of plasma ammonia concentrations and in a significant delay in onset of severe encephalopathy. More importantly, brain water content was significantly reduced in OA-treated rats with ALF. These protective effects of OA were accompanied by increased plasma concentrations of several amino acids including glutamate, gamma-aminobutyric acid (GABA), taurine, and alanine, as well as the branched-chain amino acids, leucine, isoleucine, and valine. Increased availability of glutamate following OA treatment provides the substrate for the major ammonia-removal mechanism (glutamine synthetase). Plasma (but not cerebrospinal fluid) glutamine concentrations were increased 2-fold (P <.02) in OA-treated rats, consistent with increased muscle glutamine synthesis. Direct measurement of glutamine synthetase activities revealed a 2-fold increase following OA treatment. These findings demonstrate a significant ammonia-lowering effect of OA together with a protective effect on the development of encephalopathy and brain edema in this model of ALF.

Ammonia↗
PubMed1998

Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study.

BACKGROUND/AIMS: In the current state of knowledge of the pathophysiology of hepatic encephalopathy, a reduction in hyperammonemia is the most important evidence of effective treatment. Therefore, the therapeutic efficacy of oral L-ornithine-L-aspartate, which improves impaired ammonia detoxification, was investigated in patients with cirrhosis, hyperammonemia and stable, overt, chronic hepatic encephalopathy, and in subclinical hepatic encephalopathy in a randomized, double-blind, placebo-controlled clinical trial. METHODS: Oral L-ornithine-L-aspartate was administered three times daily at fixed times for 14 consecutive days in a total dose of 18 g per day. The design was chosen to prevent an increase in ammonia induced by a protein meal of 0.25 g/kg body weight, given at the start of the daily treatment period. Efficacy variables were: fasting and postprandial ammonia concentration, Number-Connection-Test time, mental state grades, and a Portosystemic Encephalopathy Index. Analyses were based on the total study sample of 32 placebo- and 34 L-ornithine-L-aspartate-treated patients as well as on the subgroup samples in the overt (20 placebo- and 23 L-ornithine-L-aspartate-treated) and subclinical hepatic encephalopathy (12 placebo- and 11 L-ornithine-L-aspartate-treated) patients. RESULTS: Number Connection Test performance times (p<0.01) as well as fasting (p<0.01) and postprandial (p<0.05) venous blood ammonia concentrations in the L-ornithine-L-aspartate-treated group showed improvement in comparison to placebo. Also, the mental state grade (p<0.05) and the Portosystemic Encephalopathy Index (p<0.01), improved to a much greater degree in the L-ornithine-L-aspartate group than in the placebo group. Adverse events were observed in neither the placebo nor the L-ornithine-L-aspartate-treated patients. CONCLUSION: Oral L-ornithine-L-aspartate is a safe, well-tolerated treatment with a good compliance rate and a beneficial therapeutic effect in patients with cirrhosis and stable, overt, chronic hepatic encephalopathy.

Administration, Oral↗
PubMed1998

L-ornithine-L-aspartate in experimental portal-systemic encephalopathy: therapeutic efficacy and mechanism of action.

Strategies aimed at the lowering of blood ammonia remain the treatment of choice in portal-systemic encephalopathy (PSE). L-ornithine-L-aspartate (OA) has recently been shown to be effective in the prevention of ammonia-precipitated coma in humans with PSE. These findings prompted the study of mechanisms of the protective effect of OA in portacaval-shunted rats in which reversible coma was precipitated by ammonium acetate administration (3.85 mmol/kg i.p.). OA infusions (300 mg/kg/h, i.v) offered complete protection in 12/12 animals compared to 0/12 saline-infused controls. This protective effect was accompanied by significant reductions of blood ammonia, concomitant increases of urea production and significant increases in blood and cerebrospinal fluid (CSF) glutamate and glutamine. Increased CSF concentrations of leucine and alanine also accompanied the protective effect of OA. These findings demonstrate the therapeutic efficacy of OA in the prevention of ammonia-precipitated coma in portacaval-shunted rats and suggest that this protective effect is both peripherally-mediated (increased urea and glutamine synthesis) and centrally-mediated (increased glutamine synthesis).

Ammonia↗
PubMed1997

Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study.

One hundred twenty-six patients with cirrhosis, hyperammonemia (>50 micromol/L), and chronic (persistent) hepatic encephalopathy (HE), which developed spontaneously without the existence of known precipitating factors, were enrolled in a randomized, double-blind, placebo-controlled clinical trial of intravenously administered L-ornithine-L-aspartate (OA). Patients with subclinical (grade 0, West-Haven criteria) hepatic encephalopathy (SHE), characterized by a prolonged number connection test A (NCT-A) time, and manifest HE (grades I and II, West-Haven criteria) were included in the investigation. The trial was planned as a confirmatory clinical trial OA administered in a dose of 20 g/d, as well as placebo, were dissolved in 250 mL of 5% fructose and infused intravenously for a period of 4 hours during 7 consecutive days with a superimposed protein load at the end of the daily treatment period. Primary variables were postprandial venous ammonia and NCT-A performance time measured following OA or placebo infusions to evaluate the net effect of the treatment on the prevention of the protein-induced hyperammonemia, and on parameters such as NCT-A influenced by hyperammonemia. Mental state gradation, portal systemic encephalopathy index (PSEI), and fasting ammonia levels were estimated as additional efficacy parameters. The data presented are based on the total study sample (intent-to-treat analysis), which included 63 patients in the placebo group and 63 patients in the OA group. Of the 126 patients, 114 met all the criteria for inclusion and completed the trial and treatment as outlined in the protocol (treated-per-protocol analysis). During baseline, the placebo and treatment groups were homogeneous with regard to mental states, NCT-A performance time, fasting venous blood ammonia levels, and Child-Pugh criteria. Although a slight improvement occurred in the placebo group, NCT-A performance times (P < .001) and postprandial venous ammonia concentrations in the OA-treated group showed improvements in comparison with placebo. In addition, venous fasting blood ammonia concentration (P < .01), mental state gradation (P < .001), and PSEI (P < .01), which includes the mental state gradation, NCT-A time, and postprandial venous ammonia in this trial, improved to a much higher degree in the OA group than in the placebo group. In subgroups retrospectively classified according to their initial mental state gradation, OA showed differential but uniformly significant efficacies in patients with manifest HE with respect to ammonia-lowering, improvement in NCT times, and mental state gradation. In patients with initial SHE, OA revealed differences between the medications in the psychometric test used. Adverse events consisting of mild gastrointestinal disturbances were observed in 3 of the OA-treated patients (5%). OA infusion appears to be a safe, effective treatment of chronic (persistent) manifest HE in cirrhotic patients. Additional investigations are required to assess the efficacy of OA in patients with SHE, as well as in patients with more severe grades of HE.

Adult↗