Hepatic Encephalopathy Is Reversible in the Long Term After Liver Transplantation.

Cognitive dysfunction caused by hepatic encephalopathy (HE) improves within the first year after liver transplantation (LT). However, cognitive restitution seems to be incomplete in a subset of patients and after LT a new-onset cognitive decline was described. Data about the longterm development of cognitive function after liver transplantation (LT) are sparse. This prospective study analyzed whether a history of hepatic encephalopathy (HE) before LT had an impact on the longterm outcome of cognitive function after LT and if patients who underwent LT 5 years earlier showed worse cognitive function than healthy controls. The cognitive function of 34 patients was assessed before LT and at 1 year and 5 years after LT by psychometric tests, including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the portosystemic encephalopathy syndrome test, which provides the psychometric hepatic encephalopathy score (PHES). Furthermore, patients completed surveys to assess health-related quality of life (HRQOL). An 22 additional patients were included after LT. Patients were subdivided by having a history of HE before LT. The control group consisted of 55 healthy patients adjusted for age and education. Before LT, patients performed significantly worse than controls in the psychometric tests: RBANS Total Scale (TS), mean ± standard deviation (SD), 92.6 ± 13.3 versus 99.9 ± 12.0, P = 0.01; and PHES, median (interquartile range [IQR]), 0 (-3 to 1) versus 1 (0-2), P < 0.001. At 1 year after LT, patients with a history of HE still showed cognitive impairment compared with controls: RBANS TS, mean ± SD, 89.8 ± 15.1 versus 99.9 ± 12.0, P < 0.01; and PHES, median (IQR), 0 (-2 to 1.25) versus 1 (0-2), P = 0.03. At 5 years after LT, patients with and without a history of HE showed normal cognitive function and improved HRQOL. In conclusion, HE-associated cognitive impairment seems to be reversible within 5 years after LT.

Cerebral metabolite alterations in patients with posttransplant encephalopathy after liver transplantation.

BACKGROUND: In the first weeks after liver transplantation about 30% of the patients develop a posttransplant encephalopathy. A posttransplant encephalopathy comprises metabolic-toxic caused symptoms such as disorientation, confusion, hallucinations, cognitive dysfunction and seizures. We hypothesize that alterations of cerebral metabolites before liver transplantation predispose posttransplant encephalopathy development after liver transplantation. METHODS: 31 patients with chronic liver disease underwent magnetic resonance spectroscopy (MRS) before liver transplantation to assess glutamine/glutamate (Glx), myo-Inositol (mI), choline (Cho), creatine/phosphocreatine- and N-acetyl-aspartate/N-acetyl-aspartate-glutamate concentrations in the thalamus, lentiform nucleus and white matter. Of these, 14 patients underwent MRS additionally after liver transplantation. Furthermore, 15 patients received MRS only after liver transplantation. Patients' data were compared to 20 healthy age adjusted controls. RESULTS: Patients showed significantly increased Glx and decreased mI and Cho concentrations compared to controls before liver transplantation (p≤0.01). The MRS values before liver transplantation of patients with posttransplant encephalopathy showed no significant difference compared to patients without posttransplant encephalopathy. Patients after liver transplantation showed increased Glx concentrations (p≤0.01) compared to controls, however, patients with and without posttransplant encephalopathy did not differ. Patients with posttransplant encephalopathy who underwent MRS before and after liver transplantation showed a significant mI increase in all three brain regions (p<0.04) and Glx decrease in the lentiform nucleus after liver transplantation (p = 0.04) while patients without posttransplant encephalopathy only showed a mI increase in the thalamus (p = 0.04). CONCLUSION: Patients with and without posttransplant encephalopathy showed no significant difference in cerebral metabolites before liver transplantation. However, the paired sub-analysis indicates that the extent of cerebral metabolite alterations in patients with liver cirrhosis might be critical for the development of posttransplant encephalopathy after liver transplantation.

Hepatic encephalopathy before and neurological complications after liver transplantation have no impact on the employment status 1 year after transplantation.

AIM: To investigate the impact of hepatic encephalopathy before orthotopic liver transplantation (OLT) and neurological complications after OLT on employment after OLT. METHODS: One hundred and fourteen patients with chronic liver disease aged 18-60 years underwent neurological examination to identify neurological complications, neuropsychological tests comprising the PSE-Syndrome-Test yielding the psychometric hepatic encephalopathy score, the critical flicker frequency and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), completed a questionnaire concerning their occupation and filled in the short form 36 (SF-36) to assess health-related quality of life before OLT and 12 mo after OLT, if possible. Sixty-eight (59.6%) patients were recruited before OLT, while on the waiting list for OLT at Hannover Medical School [age: 48.7 ± 10.2 years, 45 (66.2%) male], and 46 (40.4%) patients were included directly after OLT. RESULTS: Before OLT 43.0% of the patients were employed. The patients not employed before OLT were more often non-academics (employed: Academic/non-academic 16 (34.0%)/31 vs not employed 10 (17.6%)/52, P = 0.04), had more frequently a history of hepatic encephalopathy (HE) (yes/no; employed 15 (30.6%)/34 vs not employed 32 (49.2%)/33, P = 0.05) and achieved worse results in psychometric tests (RBANS sum score mean ± SD employed 472.1 ± 44.5 vs not employed 443.1 ± 56.7, P = 0.04) than those employed. Ten patients (18.2%), who were not employed before OLT, resumed work afterwards. The patients employed after OLT were younger [age median (range, min-max) employed 47 (42, 18-60) vs not employed 50 (31, 29-60), P = 0.01], achieved better results in the psychometric tests (RBANS sum score mean ± SD employed 490.7 ± 48.2 vs not employed 461.0 ± 54.5, P = 0.02) and had a higher health-related quality of life (SF 36 sum score mean ± SD employed 627.0 ± 138.1 vs not employed 433.7 ± 160.8; P < 0.001) compared to patients not employed after OLT. Employment before OLT (P < 0.001), age (P < 0.01) and SF-36 sum score 12 mo after OLT (P < 0.01) but not HE before OLT or neurological complications after OLT were independent predictors of the employment status after OLT. CONCLUSION: HE before and neurological complications after OLT have no impact on the employment status 12 mo after OLT. Instead younger age and employment before OLT predict employment one year after OLT.

Central nervous system complications after liver transplantation: common but mostly transient phenomena.

Although central nervous system complications (CNSCs) are common after orthotopic liver transplantation (OLT), standardized prospective studies are still lacking. This prospective study was aimed at determining the incidence of CNSCs, describing their clinical presentations, and establishing predicting factors. One hundred thirty-six adult patients who underwent OLT at Hannover Medical School between December 2008 and June 2011 were included. Weekly examinations were performed by a neurologist during the hospital stay after OLT. Patient data, donor data, and operative and postoperative variables were collected. Patients with cerebral dysfunction after OLT underwent a diagnostic work-up, which included brain imaging and, if necessary, cerebrospinal fluid analysis. Patients with central nervous system (CNS) symptoms but negative imaging and cerebrospinal fluid results and patients with pontine myelinolysis or posterior reversible encephalopathy syndrome were placed in a metabolic-toxic CNSC group, and patients with strokes, intracranial hemorrhaging, or CNS infections were placed in a nonmetabolic CNSC group. Multiple regression analysis was used to identify independent risk factors for the development of metabolic-toxic CNSCs. After excluding two patients that died after OLT without regaining consciousness, forty-four (32.8%) patients developed CNSCs: 37 of these patients (27.6%) had metabolic-toxic CNSCs, and 7 (5.2%) had nonmetabolic CNSCs. Acute-on-chronic liver failure, the number of subsequent surgeries, and primary sclerosing cholangitis were identified as independent predictors for the development of metabolic-toxic CNSCs. Metabolic-toxic CNSCs were associated with prolonged hospital stays, and nonmetabolic CNSCs were associated with higher mortality. In conclusion, CNSCs are common and relevant complications after OLT. Patients after OLT, especially with risk factors, should undergo a regular standardized neurological examination that would allow early detection of these complications.

Cerebral white matter lesions in patients with cirrhosis - causative for hepatic encephalopathy or bystanders?

BACKGROUND & AIMS: Focal white matter lesions mimicking microvascular lesions were connected to the development of hepatic encephalopathy (HE) in patients with cirrhosis. This study aims to assess the relationship between cerebrovascular risk factors and the prevalence and extent of these lesions in patients with cirrhosis, as well as their impact upon cognitive function. METHODS: 55 cirrhotic patients underwent neurological examination, psychometric testing and magnetic resonance imaging. T2-weighted images were reviewed for white matter lesions by a neuroradiologist and a neurologist, independently. Patients were allocated into three groups: (i) no or <5, (ii) 6-15 and (iii) more than 15 lesions. Allocation was confirmed by a senior neuroradiologist blinded for the clinical data. The patient groups were compared concerning age, underlying liver disease, mortality, MELD Score, history of HE, treatment for HE, cerebrovascular risk factors and psychometric test results. Regression analysis was performed to identify risk factors for the presence and extent of white matter lesions. RESULTS: Patient groups 2 and 3 were older and showed worse results in the psychometric tests than group 1 (P < 0.05). Correlation analyses showed a significant relationship between the number of white matter lesions and the grade of HE (P < 0.001) and cognitive function (P < 0.05), but no interrelationship between the lesions and cerebrovascular risk factors or other factors tested. CONCLUSIONS: Focal white matter lesions in patients with cirrhosis do not represent cerebrovascular small-vessel disease but are related to the pathology of HE. Further studies are needed to clarify the mechanisms behind in detail.

New-onset cognitive dysfunction impairs the quality of life in patients after liver transplantation.

Patients after orthotopic liver transplantation (OLT) may show cognitive dysfunction. To date, it has not been clear whether this dysfunction is due to residual hepatic encephalopathy (HE) or new-onset cognitive disturbances. Just as little is known about the course and clinical significance. In this prospective, observational study, 50 patients on the waiting list for OLT were examined in an outpatient setting before OLT and 6 and 12 months after OLT with the Psychometric Hepatic Encephalopathy Score, the Inhibitory Control Test, and the critical flicker frequency for the diagnosis of HE; in addition, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used as a tool for the measurement of global cognitive function. The Short Form 36 health survey was used to assess health-related quality of life. Twelve months after OLT, cognitive dysfunction characteristic of HE had resolved, but a secondary cognitive decline became apparent and had features different from those known with HE. Approximately 70% of the patients deteriorated in at least 1 cognitive domain of RBANS. This cognitive decline was related to neither a history of HE nor a history of alcohol abuse, but it was accompanied by a decline in the quality of life. In conclusion, OLT improves HE but is frequently followed by new-onset cognitive dysfunction, which can interfere with the quality of life.

Comparison of the most favoured methods for the diagnosis of hepatic encephalopathy in liver transplantation candidates.

OBJECTIVE: Hepatic encephalopathy (HE) is a common complication of liver insufficiency. While there is widespread acceptance of its importance, there is no consensus on how best to diagnose and monitor HE. OBJECTIVE: To compare the four most favoured methods for the diagnosis of HE. DESIGN: 170 patients who were on the waiting list for liver transplantation as well as 86 healthy controls were included in the study. All patients and controls underwent the portosystemic encephalopathy syndrome test yielding the psychometric hepatic encephalopathy score (PHES), the repeatable battery for the assessment of neuropsychological status (RBANS), the inhibitory control test (ICT) and critical flicker frequency (CFF) measurement. RESULTS: PHES and ICT targets had the best sensitivity (85.7% vs 85.7%) and specificity (96.5% vs 97.6%) for the diagnosis of overt HE. CFF showed inferior sensitivity (40.9%) for the diagnosis of HE and dependency from previous alcohol abuse (p=0.015). Multiple regression analysis showed that all test results apart from PHES were influenced by secondary diagnoses such as diabetes mellitus and renal insufficiency. CONCLUSIONS: In the German population of patients awaiting liver transplantation, PHES is the most robust method for the diagnosis and follow-up of HE.

Cirrhosis-related Parkinsonism: prevalence, mechanisms and response to treatments.

BACKGROUND & AIMS: Extrapyramidal and cerebellar symptoms belong to the most prominent features of episodic hepatic encephalopathy, and usually decrease upon ammonia-lowering therapy. Rapidly progressing parkinsonian symptoms, which are unresponsive to treatment of hepatic encephalopathy, indicate cirrhosis-related Parkinsonism. This study aims at analyzing the prevalence of cirrhosis-related Parkinsonism in patients with liver cirrhosis, and to study the functional status of the striatal dopaminergic system in these patients. METHODS: 214 patients with liver cirrhosis who were consecutively seen at the out-patient clinic for liver transplant candidates and/or at the transplantation wards at Hannover Medical School, between August 1, 2008 and March 31, 2011, underwent a standardized neurological examination while on the waiting list or immediately after liver transplantation. Single photon emission computer tomography (SPECT) using (123)I-beta-CIT, for the evaluation of the striatal dopamine transporter function, and (123)I-IBZM for the evaluation of the striatal dopamine D2 receptor availability, was performed in 6 patients with cirrhosis-related Parkinsonism. RESULTS: Cirrhosis-related Parkinsonism was diagnosed in 9 of 214 patients (4.2%). SPECT revealed significantly decreased dopamine receptor availability in 5 of 6 patients studied, and significantly decreased dopamine transporter availability in 3. Levodopa improved motor dysfunction in two of four patients treated, although only temporarily. Incomplete recovery was observed in two patients after liver transplantation. CONCLUSIONS: Cirrhosis-related Parkinsonism is more frequent than presumed. The presented data suggest pre- and postsynaptic alteration of striatal dopaminergic neurotransmission as a possible cause of cirrhosis-related Parkinsonism and reveal the limited effects of dopaminergic therapy.

Circulating endothelial cells as potential diagnostic biomarkers in primary central nervous system vasculitis.

OBJECTIVE: Histological evidence is considered the only proof of primary central nervous system vasculitis (PCNSV). However, brain biopsy is often omitted or delayed because of the invasiveness and possible complications of the procedure. Circulating endothelial cells (CEC) were shown to be elevated in patients with active antineutrophil cytoplasmic antibody-associated vasculitis. We hypothesise that CEC are also elevated in patients with active PCNSV and may contribute to the diagnosis. METHODS: CEC were assessed in 18 patients, 3 of whom had biopsy-proven PCNSV and 15 clinical, cerebrospinal fluid and imaging data, highly suggestive of PCNSV. In 3 of these 15 patients CEC assessment was performed after initiation of successful immunosuppressive therapy. CEC numbers of all patients were compared to those of 16 healthy volunteers and 123 subjects with cerebrovascular risk factors and/or ischaemic stroke, who had been studied in our group before. CEC were assessed by immunomagnetic isolation from peripheral blood. RESULTS: In patients with proven and suspected active PCNSV, CEC were extremely elevated (>400 cells/ml in most of the patients) and significantly higher than in healthy and disease controls (p≤0.01 for each group). CEC significantly decreased with immunosuppressive treatment. CONCLUSIONS: For the first time it is shown that CEC are significantly elevated in patients with active PCNSV in contrast to other pathologies associated with brain infarction and correlate with disease activity. Sensitivity and specificity of the method for diagnosing PCNSV and the use of the method for treatment monitoring should be addressed in future prospective studies with a larger patient group.

Association of dimethylarginines and mediators of inflammation after acute ischemic stroke.

BACKGROUND: Elevated levels of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are accompanied by endothelial dysfunction and predict adverse outcome after ischemic stroke. Via induction of oxidative stress, dimethylarginines are possibly linked to the inflammatory cascade after stroke that is known to considerably contribute to secondary progression of brain injury. We sought to investigate the association between dimethylarginines and inflammatory mediators in patients with acute ischemic stroke. METHODS: Plasma levels of ADMA and SDMA were measured in prospectively collected blood samples of 58 patients with acute ischemic stroke. Blood samples were taken at 6 hours, 12 hours, 24 hours, 3 days and 7 days after onset of symptoms. Analyses of ADMA and SDMA were done by high-performance liquid chromatography-tandem mass spectrometry. Monocyte chemotactic protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), interleukin-6 (IL-6), C-reactive protein (CRP) and S100B as markers of inflammation and brain damage were determined by commercially available immunometric assays. Patient data were compared with control data from 32 age-adjusted healthy volunteers. Baseline stroke severity was evaluated by the National Institutes of Health Stroke Scale (NIHSS) (NIHSS 0 to 1: mild stroke; NIHSS 2 to 8: moderate stroke; NIHSS ≥9: severe stroke). RESULTS: Plasma ADMA and SDMA levels significantly correlated with blood levels of inflammatory mediators up to day 7 after stroke. On multiple stepwise linear regression analysis ADMA correlated with TIMP-1 at 6 hours, 24 hours, 3 days and 7 days, MMP-9 at 12 hours and IL-6 at 7 days (P <0.05) while SDMA correlated with MCP-1 at 6 hours, 24 hours, 3 days and 7 days as well as IL-6 at 3 days and 7 days (P <0.05). CONCLUSIONS: The levels of the vasoactive compound ADMA as well as levels of its structural isomer SDMA are associated with levels of inflammatory mediators after acute ischemic stroke. Further studies need to elucidate the cause and effect relationship of these crucial players.

Anticoagulants affect matrix metalloproteinase 9 levels in blood samples of stroke patients and healthy controls.

OBJECTIVES: Matrix metalloproteinase-9 (MMP-9) represents a promising marker for acute stroke management. In clinical studies MMP-9 has been quantified by ELISA using differing protocols. We aimed to establish a valid protocol by evaluation of preanalytics. DESIGN AND METHODS: Blood from stroke patients (n=28) and healthy controls (n=28) was drawn into tubes containing different anticoagulants (EDTA, citrate, lithium-heparin (heparin) and heparin with proteinase inhibitors) and processed after 0, 60 and 240 min. MMP-9 plasma protein and mRNA from mononuclear leukocytes were determined. RESULTS: In regard to anticoagulants used, samples showed different MMP-9 protein baseline values and kinetics. Stable MMP-9 protein concentrations were only measured from EDTA samples. Particularly in samples with proteinase inhibitors protein and mRNA concentrations increased over time. Kinetics did not differ between patients and controls. CONCLUSIONS: Preanalytics plays a key role for determination of MMP-9. EDTA seems to be a valid anticoagulant for MMP-9 protein measurement.

Cerebral glucose utilisation in hepatitis C virus infection-associated encephalopathy.

Patients with hepatitis C virus (HCV) infection frequently show neuropsychiatric symptoms. This study aims to help clarify the neurochemical mechanisms behind these symptoms and to add further proof to the hypothesis that HCV may affect brain function. Therefore, 15 patients who reported increasing chronic fatigue, mood alterations, and/or cognitive decline since their HCV infection underwent neurologic and neuropsychological examination, magnetic resonance imaging, (18)F-fluoro-deoxy-glucose positron emission tomography of the brain, and single photon emission tomography of striatal dopamine and midbrain serotonin transporter (SERT) availability. None of the patients had liver cirrhosis. Patients' data were compared with data of age-matched controls. In addition, regression analysis was performed between cognitive deficits, and mood and fatigue scores as dependent variables, and cerebral glucose metabolism, dopamine, or SERT availability as predictors. Patients showed significant cognitive deficits, significantly decreased striatal dopamine and midbrain SERT availability, and significantly reduced glucose metabolism in the limbic association cortex, and in the frontal, parietal, and superior temporal cortices, all of which correlated with dopamine transporter availability and psychometric results. Thus, the study provides further evidence of central nervous system affection in HCV-afflicted patients with neuropsychiatric symptoms. Data indicate alteration of dopaminergic neurotransmission as a possible mechanism of cognitive decline.

Growth differentiation factor 15 plasma levels and outcome after ischemic stroke.

BACKGROUND: Growth differentiation factor 15 (GDF-15) is a stress-responsive cytokine that is induced after experimental brain injury. We hypothesized that the circulating levels of GDF-15 are increased and associated with neurological outcome in patients with ischemic stroke. METHODS: Serial blood samples were obtained between 6 h and 7 days after symptom onset in 57 consecutive patients with acute ischemic stroke (n = 51) or transient ischemic attack (n = 6). GDF-15 was measured by immunoradiometric assay. Neurological outcome using the modified Rankin Scale (mRS) at 7 and 90 days was classified as favorable (mRS 0 or 1) or unfavorable (mRS >1). RESULTS: Six hours after symptom onset, GDF-15 levels were abnormally high (>1,200 ng/l) in 68% of the patients. They declined by 8% over the course of 7 days (p < 0.001). GDF-15 levels were correlated with the circulating levels of the inflammatory marker interleukin-6 and the glial protein S100 calcium binding protein B, and with carotid intima-media thickness. Ischemic stroke patients with an mRS score >1 at 7 or 90 days had higher circulating levels of GDF-15 at all preceding sampling time points compared to patients with an mRS score of 0 or 1 (p ≤ 0.002). Similarly, in a logistic regression analysis, GDF-15 levels measured between 6 h and 7 days after symptom onset were associated with mRS at 7 and 90 days. CONCLUSIONS: These data show for the first time that the circulating levels of GDF-15 are elevated and associated with neurological outcome in patients with ischemic stroke.

High plasma dimethylarginine levels are associated with adverse clinical outcome after stroke.

AIM: Increased levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been observed in patients with cardiovascular risk factors and atherosclerosis and in patients with a history of stroke. The role of ADMA and its analogue symmetric dimethylarginine (SDMA) in acute ischemic stroke is yet unclear. We hypothesized that plasma dimethylarginine levels increase in the hyper-acute phase after ischemic stroke and that their time course is related to stroke outcome. METHODS: Plasma dimethylarginines ADMA and SDMA and L-arginine levels were measured in 67 patients at 6, 12, 24 hours, as well as 3 and 7 days after stroke onset using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS). Data were compared to control data from 32 age-adjusted healthy volunteers. Clinical outcome was assessed using the modified Rankin Scale (mRS) at 90 days after stroke. RESULTS: At baseline, plasma ADMA levels were higher in stroke patients than in controls, whereas plasma SDMA and L-arginine levels did not differ from control subjects. The time courses of ADMA and SDMA were related to the clinical outcome. Binary logistic regression analysis showed that ADMA levels of ≥ 0.566 µmol/L at day 3, ≥ 0.530 µmol/L at day 7 and SDMA levels of ≥ 0.59 µmol/L at 24 hours predicted an unfavorable clinical outcome. CONCLUSIONS: An increase of both ADMA and SDMA plasma levels within the first 72 hours after the onset of ischemic stroke predicts a poor outcome.

Cerebral metabolic alterations and cognitive dysfunction in chronic kidney disease.

BACKGROUND: The diagnosis of uraemic encephalopathy is considered if patients with end-stage renal disease present with neuropsychiatric symptoms. However, cognitive deficits may occur in patients with chronic kidney disease (CKD) long before any overt neurological symptoms can be observed. We hypothesized that cognitive dysfunction in patients with CKD both, treated and untreated by haemodialysis, may correspond to metabolic changes in distinct brain regions. METHODS: We performed magnetic resonance spectroscopy (MRS) ((1)H-MRS) of the brain in 23 non-dialysed patients with CKD (Stages 4-5) and in 15 haemodialysed patients. Healthy controls (n = 63) adjusted for age and education were recruited from the social environment of the patients' population. Attention, learning and memory were assessed by psychometric testing. RESULTS: MRS alterations were predominantly found in the white matter. Concentrations of creatine-containing compounds (Cr) were decreased in dialysed and non-dialysed patients. Choline concentration (Cho) and combined N-acetylaspartate and N-acetylaspartylglutamate concentration (NAx) were reduced only in dialysed patients. Disturbance in memory and learning ability as well as attention deficits were observed in both patient groups. Of note, attention deficits were more severe in dialysed patients. MRS results correlated with attention deficits in dialysed patients. CONCLUSIONS: CKD patients without clinical signs of uraemic encephalopathy showed metabolic disturbances in distinct brain regions as well as cognitive impairments. Haemodialysis was accompanied with more severe cognitive dysfunction and metabolic alternations than CKD alone. Although the small sample size limits the interpretation of the data, a negative impact of haemodialysis on cognitive function must be considered.

Hepatic encephalopathy after treatment with temozolomide.

Temozolomide in combination with radiation has been in use for more than 5 years for the therapy of glioblastoma. Known adverse effects concerning the gastrointestinal system are elevation of liver enzymes. We present the case of a patient treated with temozolomide who developed severe cholestatic liver damage and consecutive hepatic encephalopathy. Neurological symptoms were mistaken as being caused by focal brain damage for more than 9 months. After the correct diagnosis had been made and the treatment had been started, the patient's condition ameliorated. In conclusion, neurological deficits in patients with known brain lesion should not be attributed automatically to the pre-existing damage even if it is progressive but should be examined carefully, also including toxic and metabolic encephalopathies into the differential diagnosis. Furthermore, new side effects of drugs have to be considered. At least this case might lead to a closer monitoring of liver enzymes during temozolomide therapy.

Spontaneous recovery from progressive multifocal leukoencephalopathy in a patient with non-active sarcoidosis.

We report the case of a 50-year-old female patient with non-active sarcoidosis and no kind of immunosuppression, admitted to our hospital because of increasing confusion and focal neurological deficits. Initially a tumor, herpes encephalitis, or neurosarcoidosis were suspected, but surprisingly biopsy revealed progressive multifocal leukoencephalopathy, additionally confirmed by JC-positive PCR in cerebrospinal fluid. Cases of sarcoidosis and progressive multifocal leukoencephalopathy have been reported before. This is the first case of a patient with no sign of active sarcoidosis and without immunosuppressive therapy who recovered spontaneously with a follow-up time of nearly 3 years.

Blood-brain barrier permeability for ammonia in patients with different grades of liver fibrosis is not different from healthy controls.

Increased blood-brain barrier (BBB) permeability for ammonia is considered to be an integral part of the pathophysiology of hepatic encephalopathy (HE) in patients with liver cirrhosis. Increased glutamate-/glutamine-signal intensity in magnetic resonance spectroscopic studies of the brain in cirrhotic patients was explained as a consequence of increased cerebral ammonia uptake. As similar spectroscopic alterations are present in patients with liver fibrosis, we hypothesized that BBB permeability for ammonia is already increased in liver fibrosis, and thereby contributing to the development of HE. To test this hypothesis, cerebral perfusion and ammonia metabolism were examined through positron emission tomography with (15)O-water, respectively, (13)N-ammonia in patients with Ishak grades 2 and 4 fibrosis, cirrhosis, and healthy controls. There were neither global nor regional differences of cerebral blood flow, the rate constant of unidirectional transport of ammonia from blood into brain tissue, the permeability surface area product of the BBB for ammonia, the net metabolic clearance rate constant of ammonia from blood into glutamine in brain, or the metabolic rate of ammonia. The hypothesis that increased permeability of the BBB for ammonia in patients with liver fibrosis contributes to the later development of HE could not be supported by this study.

Hepatitis C virus infection and the brain.

There is growing evidence that hepatitis C virus (HCV)-infection may affect the brain. About half of the HCV-infected patients complain of chronic fatigue irrespective of their stage of liver disease or virus replication rate. Even after successful antiviral therapy fatigue persists in about one third of the patients. Many patients, in addition, report of deficits in attention, concentration and memory, some also of depression. Psychometric testing revealed deficits in attention and verbal learning ability as characteristic for HCV-afflicted patients with normal liver function. Magnetic resonance spectroscopic studies showed alterations of the cerebral choline, N-acetyl-aspartate, and creatine content in the basal ganglia, white matter and frontal cortex, respectively. Recently, pathologic cerebral serotonin and dopamine transporter binding and regional alterations of the cerebral glucose utilisation compatible with alterations of the dopaminergic attentional system were observed. Several studies detected HCV in brain samples or cerebro-spinal fluid. Interestingly, viral sequences in the brain often differed from those in the liver, but were closely related to those found in lymphoid tissue. Therefore, the Trojan horse hypothesis emerged: HCV-infected mononuclear blood cells enter the brain, enabling the virus to reside within the brain (probably in microglia) and to infect brain cells, especially astrocytes.