Feedback EEG in the detection of subclinical hepatic encephalopathy: a preliminary report

The detection, monitoring, and quantification of subclinical hepatic encephalopathy present difficult problems for the clinician caring for patients with liver disease. Traditionally, pencil and paper tests such as signature-writing have been used at the bed-side to measure early encephalopathy. More recently, the Trail-making test has been employed to detect and quantify encephalopathic changes. While the electroencephalogram has provided information about the extent of clinically-obvious encephalopathy, it has only recently proved useful in the detection of subclinical disease. In these cases, evoked potentials and spectral analysis methods have discriminated between 35 and 62% of patients with subclinical hepatic encephalopathy. The present study used the method of feedback electroencephalography to detect and quantify differences in cortical arousal in 5 cirrhotic patients and 5 normal age-matched controls. Subject were also compared with respect to baseline measures of cortical arousal. Finally, arousal during feedback EEG stimulation was correlated with Trail-making test performance. The data revealed that cirrhotic patients can be discriminated from normal controls by baseline (80% detection) and feedback stimulation conditions (100% detection). In addition, feedback EEG reactivity (cortical arousal) was inversely correlated with Trail-making test performance (-0.86, P less than 0.01). The results indicate that simple features of the conventional EEG can reliably discriminate cirrhotic patients from normals. Clinical application of the feedback method in other metabolic encephalopathies, as well as in hypoaroused states secondary to, for example, narcolepsy, is discussed.     

In vivo hepatic differentiation potential of human cord blood-derived mesenchymal stem cells

Although recent studies have demonstrated the in vitro hepatic differentiation potential of mesenchymal stem cells (MSCs), the evidence supporting the in vivo engraftment of MSCs, hepatic differentiation and improvement of hepatic function is still lacking. We investigated in vivo hepatic differentiation potential and therapeutic effect of cord blood derived-MSCs (CBMSCs) transplantation in a cirrhotic rat model. CBMSCs (2 x 10(6)) were infused in Wistar rats with thioacetamide-induced chronic liver injury. Biochemical markers, liver fibrosis and engraftment of CBMSCs were assessed. Infused CBMSCs were detected in the perivascular or fibrous region of the liver and did not acquire mature hepatic phenotypes. There was no difference in biochemical markers and in the area of liver fibrosis between the experimental and placebo groups. After infusion of CBMSCs in our experimental cirrhotic rat model we did not observe an improvement of liver function and liver fibrosis. Inversely, CBMSCs could have a pro-fibrogenic potential suggesting that a cautious approach is required in future research.     

Anoxic versus traumatic brain injury: amount of tissue loss, not etiology, alters cognitive and emotional function

Research in neuropsychology suggests that the etiology of a neurologic injury determines the neuropathological and neuropsychological changes. This study compared neuropsychological outcome in subjects who had traumatic brain injury (TBI) with subjects who had anoxic brain injury (ABI), who were matched for age, gender, and ventricle-to-brain ratio. There were no group differences for morphologic or neuropsychological measures. Both groups exhibited impaired memory, attention, and executive function, as well as slowed mental processing speed. Intelligence correlated with whole brain volume, and measures of memory correlated with hippocampal atrophy. There was no unique contribution of hippocampal atrophy on neuropsychological outcome between the groups. In the absence of localized lesions, the amount of neural tissue loss, rather than etiology, may be the critical factor in neuropsychological outcome.     

肝硬化患者的神经心理功能障碍研究

目的：探讨肝硬化患者的神经心理功能障碍及其特征,为诊断亚临床肝性脑病提供科学依据和检测手段。方法：采用几种神经心理检测对６９例肝硬化患者、６５例脑肿瘤患者及６２名正常人进行测试。结果：三组被试各测验组间比较均有显著性差异（Ｐ〈０．００１）;组间两两比较显示,绝大多数测验成绩正常组优于其它两组（Ｐ〈０．０５０;而肝病组和脑病组的成绩相比,只有少数几个变量（相似性测验、第四例外的全误、木图测验）肝病组优于脑病组（Ｐ〈０．０５）,其余测验成绩两组比较无显著性差异（Ｐ〉０．０５）。结论：亚临床肝性脑病存在分析综合、抽象概括、概念化思维、心理灵活性、心理运动速度、知觉－运动协调和视觉空间等神经心理功能障碍,其严重程度的许多方面和脑肿瘤患者无明显差异。     

The role of astrocytes in the development of hepatic encephalopathy

Thioacetamide (TAA), a hepatotoxin used to ascertain the role of astrocytes in hepatic encephalopathy, was administered to prepare four experimental groups of rats. (The TAA1D, TAA1.5D, TAA2D, and TAA2.5D group rats were perfusion fixated with formalin at 1, 1.5, 2, and 2.5 days, respectively, after initial administration of TAA. In addition, TAA was readministered to the TAA2D and TAA2.5D rats 24 h after the first dose.) Abnormalities of higher brain function and equilibrium that progressed with time were apparent in the rats receiving TAA. On the other hand, innate reflexes (e.g. pupillary reflex) were similar to those in the normal control group. Astrocyte cell areas in the hippocampus, neocortex, hypothalamus, cerebellum, and basal ganglia (striatum) from the TAA rats were significantly larger than in corresponding sites from the normal rats (maximum in TAA1D and TAA1.5D groups). However, there were no differences with respect to the midbrain. Any morphological difference was not observed in neurons between the hepatic encephalopathy and normal rats. Administration of TAA caused hepatic tissue injury that progressed over time. Surprisingly, encephalopathy was apparent even when hepatic injury was mild. These findings suggest that abnormalities in astrocytes, which precede any abnormal change in neurons, play a role in the development of hepatic encephalopathy.     

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.     

暴发性肝损伤肝性脑病大鼠血浆及脑游离氨基酸变化的相关分析

本文测定了D-氨基半乳糖所致暴发性肝损伤肝性脑病大鼠血浆及脑勺浆游离氨基酸含量的变化,并作相应的相关分析。结果表明,正常大鼠血浆及脑内各种氨基酸含量间均无相关。肝性脑病大鼠血浆及脑勺浆多种氨基酸水平均有增高,脑内大多数氨基酸含量与血浆相应氨基酸的变化无相关关系,但一些与肝性脑病发生相关的氨基酸水平与其相应的血浆含量呈显著相关。提示肝性脑病的发生与血脑屏障氨基酸转运功能选择性改变有关。     

纳洛酮治疗亚临床型肝性脑病疗效观察

目的探讨纳洛酮治疗亚临床型肝性脑病(SHE)的疗效。方法69例SHE按双盲法随机分为治疗组及对照组二组,分别给予纳洛酮0.4mg、0.9%氯化钠静脉推注,连用5-10天,用药前后分别作数字连接试验(NCT)、数字符号试验(DS)、脑干诱发电位(BAEP),并随访有否发性临床型肝性脑病。结果治疗组治疗后各项指标均较治疗前有明显改善,且随访无一例发生肝性脑病,对照组治疗前后各项指标改善不明显,且随诊有3例发生临床型肝性脑病。结论纳洛酮是一种对SHE治疗有效的药物。     

Dietary intake and clinical, anthropometric and biochemical indices of malnutrition in elderly demented patients and non-demented subjects

Anthropometric and biochemical indices of nutritional status and weighed dietary intake have been studied in hospitalized patients with senile dementia, demented patients living in the community and age-matched control subjects who were not cognitively impaired. Demented patients were lighter than control subjects, and had a lower body mass index, skinfold thickness, mid-arm circumference and arm muscle bulk. The hospitalized patients were more seriously affected than those living in the community, and body weight was significantly negatively correlated with duration of hospitalization. Over a 6-month period the hospitalized patients showed a further weight loss, while those living in the community did not. Both groups of demented patients had higher intakes of energy, protein, vitamins and minerals than the control subjects. The diet of the hospitalized patients was slightly, but not significantly, superior to that of the patients living in the community. Biochemical evidence of specific vitamin inadequacy was equally prevalent in all three groups of subjects, and there were no significant correlations between the degree of cognitive impairment or behavioural disorder and any of the indices of nutritional state. Clinical signs suggestive of malnutrition were not correlated with either biochemical evidence of deficiency or cognitive impairment and behavioural disturbance.     

Distribution of cerebral atrophy assessed by magnetic resonance imaging reflects patterns of neuropsychological deficits in Alzheimer's dementia

Neuropsychological deficits were investigated with respect to regional distribution of cerebral atrophy as assessed by volumetric magnetic resonance imaging (MRI) in 50 patients with Alzheimer's dementia (AD; NINCDS-ADRDA criteria) and 20 healthy volunteers. When compared between groups, test performance of all investigated neuropsychological domains including declarative memory, language, praxia, psychomotor speed, as well as attention and concentration was significantly impaired. These deficits were differentially correlated with regional atrophic changes. In particular, volumes of the right amygdala-hippocampus complex correlated with declarative memory performance, whereas volumes of the left temporo-parietal regions correlated with performance in naming and praxia. Furthermore, left frontal lobe atrophy was associated with verbal fluency. Our data confirm the central role that medial temporal atrophy plays for declarative memory deficits in AD and indicate that additional changes in the parietal, temporal and frontal lobes are responsible for further neuropsychological deficits characteristic of this disorder.     

Relationship between hepatic morphology and clinical and biochemical findings in morbidly obese patients

This study was undertaken to determine the interrelations between clinico-biochemical parameters and hepatic morphology in markedly obese patients. One hundred and sixty-six women and 52 men comprise this series. There was a statistically significant association of carbohydrate metabolism disturbance with increasing age and corpulence and, in women, with hyperuricaemia and morphological alterations of the liver. Menstrual irregularities also correlated well with hepatic morphology. The livers frequently exhibited steatosis, but other morphological changes were mild. Compared with women, men had higher triglyceride values, more severe hepatic involvement, and poorer correlation of carbohydrate disturbances with hepatic histology. The results indicate a central role of the impaired carbohydrate utilization in the biochemical and hepatic alterations of obesity.     

Vinyl chloride-induced hepatic coproporphyrinuria with transition to chronic hepatic porphyria

Summary A chronic hepatic disorder of prophyrin metabolism was found in 36 workers with vinyl chloride (VC)-induced hepatic injury following long-time industrial exposure. Pathologic porphyrinuria, especially secondary coproporphyrinuria with transition to subclinical chronic hepatic porphyria, is a consistent pathobiochemical parameter for the recognition of VC hepatic lesions. The porphyrinuria is of diagnostic value for the incipient toxic phase. Erythrocyte uroporphyrinogen decarboxylase activity studied in six cases with initial chronic hepatic porphyria was normal, suggesting that VC affects only this enzyme in the liver.This study is dedicated to Hans Popper, M.D., Ph.D., Dr. (hon.) mult., Gustave L. Levy Distinguished Service Professor, Mount Sinai School of Medicine, New York, on the occasion of his 80th birthday on Nov. 24th, 1983.This investigation has been supported by the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg (Grant Do 134)     

Acetylcholinesterase activity in an experimental rat model of Type C hepatic encephalopathy

Patients with liver malfunction often suffer from hepatic encephalopathy, a neurological complication which can affect attention and cognition. Diverse experimental models have been used to study brain alterations that may be responsible for hepatic encephalopathy symptoms. The aim of the study was to determine whether cognitive impairment found in cirrhosis could be due to disturbance of acetylcholinesterase activity. Acetylcholinesterase activity was assessed in the brains of Wistar rats with thioacetamide-induced cirrhosis. The cirrhotic group displayed up-regulation of acetylcholinesterase levels in the entorrhinal cortex, anterodorsal and anteroventral thalamus and accumbens, whereas down-regulation was found in the CA1, CA3 and dentate gyrus of the hippocampus. Our results indicate that the experimental model of hepatic encephalopathy by chronic administration of thioacetamide presents alterations of acetylcholinesterase activity in brain limbic system regions, which play a role in attention and memory.     

暴发性肝损伤肝性脑病大鼠脑糖胺多糖含量的变化

本文应用硫代乙酰胺灌胃复制暴发性肝损伤肝性脑病大鼠模型,检测了实验大鼠大脑、脑干、小脑糖胺多糖含量的变化。结果表明肝性脑病发生时大脑、脑干糖胺多糖含量较正常大鼠显著降低,而小脑糖胺多糖含量并无变化。说明肝性脑病发生时大脑及脑干部位伴有糖胺多糖的变化,提示肝性脑病的发生与脑内神经细胞外基质成份糖胺多糖等的变化有关。     

The pathogenesis of hepatic encephalopathy

Hepatic encephalopathy remains a complex clinicopathological problem. Much is known about the biochemical derangements in liver, blood, and brain. The precise pathogenetic mechanism for central nervous system dysfunction remains to be determined. Ammonia continues to be considered as an important neurotoxin and may act synergistically with other toxic substances. Disturbances of amino acid balance may result in a disproportion of inhibitory and excitatory neurotransmitters in the brain. Alternatively, some amino acids may act as false neurotransmitters. Recent clinical and laboratory data have advanced the hypothesis that gamma-aminobutyric acid (GABA) absorbed from the gut may enter the brain and exert a profound inhibitory effect. Drugs which antagonize the GABA-benzodiazepate receptor may offer symptomatic improvements in hepatic encephalopathy.     

Familial cognitive deficits in schizophrenia.

Susceptibility to schizophrenia is considered familial, but the mechanism for transmission has not been found. Since widespread cognitive deficits have been found in patients with schizophrenia, several of these have been proposed as candidate familial endophenotypes that may or may not be predictive of who develops the illness. The current study examines these candidates in individuals from 32 families with at least 2 members having the diagnosis of chronic schizophrenia and normal comparison subjects using an extensive neuropsychological battery. Consistent with previous literature, family members with schizophrenia were significantly impaired on all measures compared with controls. Well relatives demonstrated significantly worse performance on a measure of verbal learning, delayed visual recall, perceptual-motor, and pure motor speed. Expressive and receptive language, but not other functions, were highly correlated within both concordant for schizophrenia and discordant sibling pairs, suggesting that they are familial vulnerability endophenotypes, but not predictive of whom becomes ill. On the other hand, some measures of perceptual-motor, pure motor speed, and frontal/executive functioning were significantly correlated in concordant, but not discordant pairs. These latter correlations suggest that some cognitive measures may be genetically related to the illness.     

Protective influence of diphenyl-p-phenylenediamine on hydrazine induced lipid peroxidation and hepatic injury

Previous studies have demonstrated the ability of water soluble and/or lipid soluble antioxidants to reduce the toxicity as well as the biochemical, functional, and pathological changes induced by a variety of hepatotoxic agents. To further determine the ability of diphenyl-p-phenylenediamine (DPPD) to modify chemical induced hepatic injury, the influence of DPPD on hydrazine-induced hepatic toxicity was assessed. The administration of hydrazine to rats significantly increased liver triglycerides. Significant inhibition of triglyceride accumulation occurred in the DPPD-treated group. Hydrazine also caused an increase in hepatic lipid peroxidation as reflected by malonaldehyde (MDA) formation. The enhancement in MDA formation was prevented by DPPD treatment. In contrast to the profound hepatic necrosis observed following hydrazine, livers from DPPD treated rats which received hydrazine showed only mild architectural alterations. The hypoglycemia and retention of BSP which developed upon hydrazine administration was not modified by DPPD. The ability of the lipid soluble antioxidant, DPPD, to significantly inhibit hydrazine-induced fatty infiltration, necrosis, and lipid peroxidation further accents the potential of employment of appropriate antioxidants in the prevention of chemical-induced hepatic injury.     

Serotonergic and cognitive impairment in impulsive aggressive personality disordered offenders: are there implications for treatment?

BACKGROUND: Reduced serotonin (5-HT) function and deficits on neuropsychological tasks have been separately reported in antisocial populations. We investigated whether these impairments are independent or associated factors underlying impulsivity in aggressive personality disordered (PD) offenders and healthy controls and whether there are associated changes in quantitative brain measures. METHODS: This study reports on the findings from a sample of 51 PD offenders and 24 controls, recruited from maximum security psychiatric hospitals, who were characterized using the Special Hospital Assessment of Personality and Socialisation (SHAPS). Subjects underwent assessment of 5-HT function (prolactin response to D-fenfluramine challenge), neuropsychological testing and had a diagnostic MRI scan. Of this sample 19 controls and 24 patients also had quantitative measurement of frontal and temporal lobe volumes on magnetic resonance imaging (MRI). RESULTS: Non-psychopathic (low-impulsive) aggressive PDs had enhanced 5-HT function compared with controls and highly impulsive aggressive psychopaths. Primary and secondary psychopaths had poorer executive/frontal, but not memory/temporal neuropsychological function than controls and non-psychopaths. There were no significant group differences in frontal or temporal lobe brain volumes. Although impulsivity and aggression are correlated constructs impulsivity appeared to be related to both executive function and 5-HT function, while aggression only correlated inversely with executive/frontal and memory/temporal function. 5-HT did not directly correlate with frontal or temporal volume or function. CONCLUSION: Impulsivity appears to be contributed to by both impaired neuropsychological function and 5-HT function. Impaired neuropsychological function alone makes a contribution to aggression. Treatment needs to take account of the neuropsychological and biochemical deficits in this challenging population.     

Role of endotoxin on hypoglycaemia in acute hepatic failure. Relationship between hypoglycaemia and hepatic injury following endotoxaemia in diabetic and nondiabetic rats

To clarify the relation of endotoxaemia to hypoglycaemia and consequent death in acute hepatic failure, the interrelationship between the degree of hepatic injury, blood glucose level and mortality following endotoxaemia were examined in streptozotocin-induced diabetic and nondiabetic rats. Endotoxin hepatotoxicity was not enhanced in diabetic state. Blood glucose level was markedly reduced after endotoxin administration in the nondiabetic rats, and the reduction of blood glucose level closely correlated with the degree of hepatic injury (serum transaminase activities), namely, the more severe the hepatic injury, the lower the blood glucose level. Hypoglycaemia due to endotoxaemia occurred also in the diabetic rats when the hepatic injury was severe, but the reduction of blood glucose level was slight when it was mild. The mortality for endotoxaemia in diabetic rats was significantly lower than that in the nondiabetic rats. These experimental data suggest that endotoxaemia may play a role in the development of hypoglycaemia in acute hepatic failure, and that the diabetic state may lower the mortality for endotoxaemia.     

Effect of ursodeoxycholic acid on experimental hepatic porphyria induced by griseofulvin.

Griseofulvin(GF) has become the drug of choice as an antifungal agent for patients who suffer from many kinds of fungal infection. In order to clarify hepatic injury by griseofulvin(GF) overload and the effect of UDCA on GF-induced hepatic injury, the authors carried out biochemical, histologic, and ultrastructural studies of liver following treatment with griseofulvin and ursodeoxycholic acid(UDCA) in mice. Urine porphobilinogen excretion in the group treated with GF alone was significantly increased and reached the highest level in the 4th week and declined thereafter. Biochemical studies of the liver function showed no remarkable changes of serum bilirubin levels throughout the experimental period in all groups, except for SGPT and alkaline phosphatase activities which were significantly elevated and reached the highest level in the second week. Then they slightly decreased in GF treated groups(GF alone and GF plus UDCA) in comparison with the control group. Pathologic findings in the group treated with GF alone include focal liver cell necrosis(esp, zone 3), Mallory bodies in hepatocytes(esp, zone 1), Kupffer cell activation, and brown protoporphyrin pigments in the hepatocytes, bile canaliculi and interlobular bile ducts with a marked inflammatory cell infiltration in the portal tracts. Under the polarizing light microscope, bile ductular and canalicular thrombi showed a "Maltese cross" birefringence in mice treated with GF alone. There is no definite finding of fatty change in hepatocyte. Under the microscope, the liver appeared normal with an intact lobular architecture in the GF plus UDCA treated group. Electron microscopically, GF-induced changes include swelling of mitochondria, globular protoporphyrin crystals in the hepatocyte cytoplasm, markedly dilated bile cannaliculi and bile ducts and the formation of a Mallory hyaline bodies in the hepatocytes. There were no noticeable structural changes in the GF plus UDCA-treated group. Therefore the results suggest that GF causes hepatic injury, namely porphyria and cholestasis, and the treatment of UDCA may have cytoprotective and choleretic effects on GF-induced hepatic injuries.