Schizophrenia and idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome)]

Idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome, GS) is a relatively common congenital hyperbilirubinemia occurring in 3-7% of the world's population. It has been recognized as a benign familial condition in which hyperbilirubinemia occurs in the absence of structural liver disease or hemolysis, and the plasma concentration of conjugated bilirubin is normal. Recently, it was reported that unconjugated bilirubin exhibited neurotoxicity in the developing nervous system. The 'neurodevelopmental hypothesis' of schizophrenia proposes that an as yet unidentified event occurs in utero or during early postnatal life. We have observed that patients suffering from schizophrenia frequently present an increased unconjugated bilirubin plasma concentration when admitted to the hospital. Therefore, we noticed a relation between unconjugated bilirubin and the etiology of and vulnerability to schizophrenia. Our reported findings suggest that there are significant biological and clinical character differences between schizophrenic patients with and without GS. From the viewpoint of the heterogeneity of schizophrenia, there may be a poor outcome for the subtype of schizophrenia with GS.     

Schizophrenia-associated idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome)

BACKGROUND: Idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome) is a benign hyperbilirubinemia found in the general population. There has been only 1 previous report of Gilbert's syndrome occurring in schizophrenic patients. The present study was conducted to determine the frequency of Gilbert's syndrome in schizophrenic patients relative to patients with other psychiatric disorders. METHOD: Plasma bilirubin concentrations of every patient admitted to the psychiatric hospital during a 3-year period were collected, and patients were examined to exclude all other causes of hyperbilirubinemia. In addition, the psychiatric symptoms of schizophrenic patients (ICD-10 criteria) with hyperbilirubinemia were evaluated by the Positive and Negative Syndrome Scale (PANSS). RESULTS: Schizophrenic patients showed a significantly higher incidence of hyperbilirubinemia (p < .05) relative to patients suffering from other psychiatric disorders, and schizophrenic patients with hyperbilirubinemia showed significantly higher scores on the positive and general psychiatric subscales of the PANSS (p < .0001) than patients without hyperbilirubinemia. CONCLUSION: The apparently higher frequency of Gilbert's syndrome in schizophrenic patients may reflect a relationship between hyperbilirubinemia and schizophrenic psychosis. Hypothetical explanations, such as a possible genetic disposition for Gilbert's syndrome, an increased vulnerability of red cell membranes, and the role of estrogens in schizophrenic patients, are discussed.     

Schizophrenia and idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome)

Idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome, or GS) is a relatively common congenital hyperbilirubinemia occurring in 3-7% of the world's population. It has been recognized as a benign familial condition in which hyperbilirubinemia occurs in the absence of structural liver disease or hemolysis, and the plasma concentration of conjugated bilirubin is normal. Recently, it has been reported that unconjugated bilirubin exhibited neurotoxicity in the developing nervous system. The 'neurodevelopmental hypothesis' of schizophrenia proposes that an as-yet-unidentified event occurs in utero or during early postnatal life. We have observed that patients suffering from schizophrenia frequently present with an increased unconjugated bilirubin plasma concentration when admitted to the hospital. As a result, we noticed a relationship between unconjugated bilirubin and the etiology of, and vulnerability to, schizophrenia. Our reported findings suggest that there are significant biological and clinical character differences between schizophrenic patients with and without GS. From the viewpoint of the heterogeneity of schizophrenia, there may be a poor outcome for the subtype of schizophrenia with GS.     

Fluid-attenuated inversion-recovery MR imaging in schizophrenia-associated with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome).

BACKGROUND: Patients with schizophrenia show a significantly higher frequency of hyperbilirubinemia the patients suffering from other psychiatric disorders and the general healthy population. The objective of the current study was to determine whether patients with schizophrenia-associated idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome, GS) have specific changes in signal intensities on fluid-attenuated inversion-recovery (FLAIR) magnetic resonance (MR) images. METHODS: Axial 5-mm-thick FLAIR MR images from schizophrenia patients with GS (n=18) and schizophrenia patients without GS (n=18), all diagnosed according to DSM-IV criteria, were compared with age- and sex-matched non-psychiatric controls (n=18). Signal intensities in the hippocampus, amygdala, caudate, putamen, thalamus, cingulate gyrus, and insula were graded relative to cortical signal intensity in the frontal lobe. RESULTS: Compared to both schizophrenia patients without GS and normal controls, the schizophrenia patients with GS showed significantly increased signal intensities in almost all regions studied. CONCLUSION: Patients with schizophrenia-associated GS have specific changes of signal intensities on FLAIR MR images, suggesting that schizophrenia with GS produces changes in the fronto-temporal cortex, limbic system, and basal ganglia.     

Hyperbilirubinemia-related behavioral and neuropathological changes in rats: A possible schizophrenia animal model

Background

Patients with schizophrenia show a significantly higher frequency of hyperbilirubinemia than patients suffering from other psychiatric disorders and the general healthy population. We examined the hyperbilirubinemia on behavioral and neuropathological changes in rats as a possible animal model of schizophrenia.

Methods

Gunn rats with severe hyperbilirubinemia (j/j), Gunn rats without severe hyperbilirubinemia (+/j), and Wistar rats were examined by open-field, social interaction, and prepulse inhibition tests. TUNEL, AgNOR and Ki-67 were also assayed on paraffin-embedded brain sections of these rats.

Results

Compared to Wistar rats, both Gunn j/j and +/j rats showed hyperlocomotion, high sniffing scores, and low defecation scores. They showed significantly more aggressive behaviors and impaired prepulse inhibition. The numbers of Ki-67-labeled cells and AgNOR were lower and the number of TUNEL-positive cells was higher than that of Wistar rats.

Conclusions

These results might support the neurodevelopmental hypothesis of schizophrenia. Both Gunn j/j and +/j rats may be a useful animal model and provide clues to the role of hyperbilirubinemia in schizophrenia.     

Urokinase antigen in plasma of patients with liver cirrhosis and hepatoma

Plasma urokinase antigen levels were studied in 78 patients suffering from liver diseases. Blood was drawn before any specific medication was initiated. Impairment of liver function was comparable in all patients. In both groups of cirrhotic liver disease (alcoholic and non-alcoholic), normal levels of plasma urokinase antigen were found as compared to age-matched control groups. In both groups of patients with hepatomas (with or without a history of liver cirrhosis), however, significantly increased plasma urokinase antigen levels could be determined. These data indicate that an increase in plasma urokinase antigen might rather relate to malignant growth in liver disease than to impaired liver function.     

ELECTRON MICROSCOPIC STUDY OF INTRANUCLEAR SPHERES OF BOUTEILLE TYPE-III IN ASTROCYTES WITH SPECIAL REFERENCE TO LIVER CARCINOMA

Astrocytic intranuclear spheres of Bouteille type-III were studied with the electron microscope in the neocortex of 29 patients dying from various causes. The numbers of laminate whorls in these spheres in patients with carcinoma involving the liver were found statistically to be significantly more numerous than the whorls in the spheres of patients who did not have carcinoma of the liver. This second group included patients who were suffering from carcinoma of other organs or from cirrhosis of the liver. The frequency of cases with the spheres increased with age. The numbers of spheres found in people with liver carcinoma, carcinoma of other organs and cirrhosis were the same as the numbers found in people dying from other diseases. The possibility that the increase in numbers of whorls found in people with liver carcinoma was related to a raised metabolic activity of the astrocytes resulting from reduced catabolism of hormones or metabolites by the liver is briefly discussed.     

Clinical utility of electrophysiological evaluation in Crigler-Najjar syndrome

We evaluated the neurological and neurophysiological features in ten patients with genetically characterized Crigler-Najjar (CN) syndrome: four with typical type I CN had undergone orthotopic liver transplantation (OLT); six had type II CN, and three of them developed severe hyperbilirubinemia with a limited response to phenobarbital leading to an intermediate phenotype I/II. Clinical neurological and multimodal electrophysiological evaluations [electroencephalogram (EEG), visual (VEPs), motor (MEPs) and brainstem auditory (BAEPs) evoked potentials] were performed. Neurological examinations showed mild hand tremor in four patients (one pre-OLT and one post-OLT type I, two type I/II). EEG revealed high voltage paroxysmal discharges in four patients (three type I/II, and one type I with a marked improvement after OLT). VEPs showed P100 wave increased latency in five patients (three type I, and two type I/II considered for OLT evaluation). MEPs showed prolonged central motor conduction time in five patients (two type I; one type I/II; two type II). Only EEG and VEPs findings showed a correlation with high bilirubin levels. BAEPs were normal. In conclusion, VEPs and EEG contribute to identify and monitor bilirubin neurotoxic effects, and may play a decisional role in some cases of severe hyperbilirubinemia without overt neurologic damage.     

Coagulation activation in liver diseases.

In liver disorders alterations of the coagulation system are mainly due to a reduced synthesis of coagulation proteins. In addition, an enhanced intravascular consumption of coagulation factors is discussed controversely in liver diseases. By measuring factor IXiAT- and TAT-complexes we tried to find out, whether coagulation activation in liver patients leads to activation of the complete coagulation cascade followed by DIC or whether in some diseases a futile partial coagulation activation develops. In all liver diseases examined, elevated factor IXiAT-complexes were demonstrated, while TAT-complexes were only elevated in chronic active hepatitis, metabolic decompensated liver cirrhosis and in patients suffering from end stage liver disease. We conclude that all liver diseases examined lead to an activation of the coagulation cascade. A complete activation followed by DIC only occurs in patients with very severe liver disorders.     

Suicide amongst Alzheimer's disease patients: a 10-year survey

Suicide is a major public health problem with advancing age being one of the factors associated with increased risk. It has been suggested that most DSM axis-I disorders contribute to increased suicidal risk while dementia is one of the few exceptions. We conducted a 10-year retrospective analysis of all elderly patients suffering from dementia admitted to a large urban mental health center. Between 1991 and 2000 there were 1,551 admissions to our center who were 65 years or older. Of these, 341 were diagnosed (DSM-IV criteria) as suffering from dementia and 215/341 as suffering from Alzheimer's disease (AD). Sixteen AD patients (7.4% of all AD patients) were admitted immediately following a suicide attempt. The control group consisted of the next admission of an elderly AD patient matched for age and gender. The index group (suicidal patients) differed from controls in Clinical Dementia Rating scores (p = 0.017) and higher frequency of previous suicide attempts (p = 0.022). Lifetime psychopathology was not associated with higher rates of suicide attempts (p = 0.068). Physicians should be aware that suicide attempts are not rare in elderly AD patients. Higher level of daily functioning and previous suicide attempts are associated with increased suicidal risk.     

Linear and non-linear measures indicate gastric dysmotility in patients suffering from acute schizophrenia

Cardiac autonomic dysfunction has been reported in patients suffering from schizophrenia. The aim of the present study was to evaluate gastric electrical activity in unmedicated patients suffering from acute schizophrenia in relation to their symptoms.Electrogastrography was performed before and after test meal ingestion in 26 patients suffering from schizophrenia and 26 matched controls. The non-linear measure approximate entropy (ApEn) was calculated for the first time from the obtained signal in addition to standardized measures. Results were correlated with the scales for the assessment of positive symptoms and negative symptoms. In addition, autonomic and abdominal symptoms were assessed by the autonomic symptom score.We found a significantly increased amount of tachygastria and arrhythmia within the signal of the activity of the gastric pacemaker before and after test meal digestion in patients compared to controls, indicating increased sympathetic modulation within the enteric nervous system. A significant difference was observed for slow wave, which represents the dominant frequency of gastric pacemaker activity, indicating gastric dysmotility in our patients. The elevated ApEn measure points to increased complexity and dysregulation. In addition, we have observed a correlation between delusions and tachygastria.Sympathetic function seems to be altered in the enteric nervous system of patients suffering from schizophrenia. Future studies need to explore the influence of the disease on different branches of the autonomic nervous system and clinical consequences of enteric dysfunction. Our findings point to a possible systemic autonomic imbalance that needs to be studied in respect to the neurobiology of schizophrenia.     

Gastric dysmotility in healthy first-degree relatives of patients with schizophrenia

Gastric dysmotility has been reported in patients suffering from major depression or schizophrenia. An increased sympathetic activity modulating the gastric pacemaker located in the antrum of the stomach has been suggested as the underlying pathology. Similar to patients suffering from schizophrenia, their first-degree relatives showed alterations in cardiac autonomic modulation. Here we aimed to investigate gastric myoelectrical activity in healthy relatives of patients suffering from paranoid schizophrenia.     

Dying dementia patients: too much suffering, too little palliation

Suffering is traditionally viewed as a state encompassing psychological distress, spiritual concerns, and various aspects of physical pain. There is insufficient clinical evidence for suffering in dying dementia patients, which may lead to inappropriate evaluation and insufficient palliative treatment. Our objective was to evaluate the suffering of terminal dementia patients over time, from admission to a geriatric ward to the last day of life. The study included consecutive end-stage dementia patients dying in a general geriatric department of a tertiary hospital. Patients were evaluated weekly by the Mini Suffering State Examination scale (MSSE). Seventy-one patients were studied. Mean survival of patients was 38.0 +/- 5.1 days. MSSE increased during hospital stays from 5.62 +/- 2.31 to 6.89 +/- 1.95 (p < 0. 001). According to the MSSE scale, 63.4 percent and 29.6 percent of patients died with a high and intermediate level of suffering, respectively. Only 7 percent of the patients died with a low level of suffering. In particular, patients were restless (p < 0. 001), had pressure sores (p = 0. 01), and were considered medically unstable (p < 0. 001). We concluded that, despite traditional medical and nursing care, a large proportion of dying dementia patients experienced an increasing amount of suffering as they approached death. New palliative treatment approaches should be developed for these patients.     

Bilirubin-induced neurotoxic and ototoxic effects in rat cochlear and vestibular organotypic cultures

Exposure to high levels of bilirubin in hyperbilirubinemia patients and animal models can result in sensorineural deafness. However, the mechanisms underlying bilirubin-induced damage to the inner ear, including the cochlear and vestibular organs, remain unknown. The present analyses of cochlear and vestibular organotypic cultures obtained from postnatal day 3 rats exposed to bilirubin at varying concentrations (0, 10, 50, 100, or 250 μM) for 24 h revealed that auditory nerve fibers (ANFs) and vestibular nerve endings were destroyed even at low doses (10 and 50 μM). Additionally, as the bilirubin dose increased, spiral ganglion neurons (SGNs) and vestibular ganglion neurons (VGNs) exhibited gradual shrinkage in conjunction with nuclei condensation or fragmentation in a dose-dependent manner. The loss of cochlear and vestibular hair cells (HCs) was only evident in explants treated with the highest concentration of bilirubin (250 μM), and bilirubin-induced major apoptosis most likely occurred via the extrinsic apoptotic pathway. Thus, the present results indicate that inner ear neurons and fibers were more sensitive to, and exhibited more severe damage following, bilirubin-induced neurotoxicity than sensory HCs, which illustrates the underlying causes of auditory neuropathy and vestibulopathy in hyperbilirubinemia patients.     

Impaired function of the auditory brainstem in term neonates with hyperbilirubinemia

Objective: We studied maximum length sequence brainstem auditory evoked response in term neonates with hyperbilirubinemia to further our understanding of hyperbilirubinemia on the neonatal auditory brainstem and to determine if maximum length sequence technique improves detection of brainstem auditory impairment due to bilirubin neurotoxicity. Methods: Maximum length sequence brainstem auditory evoked response was recorded and analysed shortly after confirming total serum bilirubin levels greater than 15 mg/dL in fifty-seven term neonates with hyperbilirubinemia. Results: Most wave latencies and interpeak intervals in maximum length sequence brainstem auditory evoked response in the neonates with hyperbilirubinemia were correlated with the level of total serum bilirubin at some or most click rates used. Compared with age-matched normal term controls, wave V latency in these neonates was increased significantly at all 91–910/s click rates (p < 0.05–0.001). The I–V and I–III interpeak intervals were also increased significantly at all these rates, and the III–V interval increased at 227–910/s clicks (p < 0.05–0.001). The differences between the neonates with hyperbilirubinemia and the controls were more significant at higher than at lower click rates. The slopes of wave V latency-rate function and I–V and III–V interval-rate functions were all significantly increased. By comparison, the abnormalities in conventional BAER were less significant, with only I–III and I–V intervals were increased (both p < 0.05). Conclusions: Functional status of the auditory brainstem is impaired in neonatal hyperbilirubinemia. Maximum length sequence technique at high click rates improves detection of bilirubin neurotoxicity to the neonatal auditory brainstem, particularly for the more rostral regions.     

Motor impairment in Wilson's disease, I: slowness of voluntary limb movements

Twenty-three patients with Wilson's disease (WD) treated with D-penicillamine underwent clinical examination, as well as laboratory and motor testing. The clinical findings were scored. Laboratory tests included determination of the caeruloplasmine level, the free serum copper level, 24 h urinary copper excretion, liver enzymes and in 10 patients liver copper content of a liver biopsy. Laboratory tests and clinical scores were correlated. To quantify impairment of voluntary movements in WD fastest possible isometric index finger extensions and fastest alternating finger movements were analysed. Eleven patients presented with abnormally slow and 15 with abnormally irregular voluntary movements. Slowness of alternating movements correlated with the clinical score. The clinical score also correlated with the duration of symptoms prior to onset of therapy. Motor testing turned out to be sensitive enough to monitor improvement of neurological symptoms after onset of therapy. Comparison with motor testing in other basal ganglia diseases and cerebellar patients showed differences to patients with Parkinson's and Huntington's disease and similarities to patients suffering from AIDS-related dementia. In a small number of WD-patients similar results as in patients with a degenerative cerebellar disease were found.     

Magnetic resonance imaging findings in patients with severe neonatal indirect hyperbilirubinemia.

The aim of this study was to document the magnetic resonance imaging (MRI) findings of cases with a history of severe neonatal indirect hyperbilirubinemia. Ten cases (eight cases with neurologic findings, two normal cases) with a history of severe neonatal indirect hyperbilirubinemia were studied. Neurologic findings and MRI results were described and correlated. Seven of eight cases with neurologic findings demonstrated symmetric and uniform increased T2 signal changes limited to globus pallidi. MRI scans of two cases without neurologic findings showed no abnormality. Severe neonatal indirect hyperbilirubinemia should be considered in the differential diagnosis of bilateral symmetric hyperintense signal changes in the globus pallidus on MRI. However, high levels of unconjugated bilirubin concentrations in the neonatal period may not always cause such lesions of globus pallidus on MRI despite the presence of neurologic findings.     

Neurophysiological abnormalities in adolescents with type I Crigler-Najjar syndrome.

We report neurophysiological abnormalities in two adolescents with type I Crigler-Najjar syndrome, an autosomal recessive disorder characterized by severe unconjugated hyperbilirubinemia. Electroencephalograms (EEGs) demonstrated frequent generalized single and polyspikes, and background slowing. Normal pattern reversal evoked responses (PRVERs) and normal central brain-stem auditory evoked responses (BAERs) were recorded in both patients. These findings differ from the EEG triphasic wave pattern seen in the EEG in hepatic encephalopathy and the central BAER abnormalities seen in many infants with kernicterus. Thus these findings most likely result from complex multifactorial processes and are not simply the result of the hyperbilirubinemia which is common to all 3 conditions.     

Dantrolene sodium and hepatic injury

This is a report on hepatic adverse events associated with dantrolene therapy. All cases reported to the manufacturer are included, from all sources, through 1987. Of 122 cases containing sufficient data to analyze, 47 patients had asymptomatic transaminase elevations, 12 had additional mild (less than or equal to 2.5 mg/dl) hyperbilirubinemia, 36 had jaundice, and 27 patients died. There is an overrepresentation of women over 35 years and patients with multiple sclerosis in the fatal group compared with the study population as a whole (not statistically significant). Mean dantrolene dose was 582 mg/d in fatal cases and 263 mg/d in the nonfatal group. Generally, at least 2 months of therapy was given before injury occurred. Concomitant drugs and nonhepatic, drug-independent disease were associated with a fatal outcome. Serum bilirubin may be predictive for death (mean of 17.0 mg/dl in the fatal group compared with 6.5 mg/dl in nonfatal cases). Of available biopsy reports, 68% included chronic active hepatitis or precirrhotic/cirrhotic lesions. Physicians should monitor liver function in patients taking dantrolene.     

Cell-mediated immunity to polio and HLA antigens in amyotrophic lateral sclerosis.

Cell-mediated immunity to poliovirus was demonstrated in 21 of 33 patients suffering from amyotrophic lateral sclerosis (ALS), whereas no response to poliovirus was found in patients suffering from other neurologic disorders or in healthy controls. Three of the severe bulbar cases produced a migration inhibition factor (MIF) in the presence of poliovirus, although skin tests to common antigens were negative. An increased incidence (46 percent) of HLA-A3 was found in patients with amytrophic lateral sclerosis. Nine of the 13 patients with HLA-A3 antigen also had a positive index of MIF to poliovirus. These findings suggest a strong linkage between HLA-A3 and poliovirus in the pathogenesis of amyotrophic lateral sclerosis.