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.

BACKGROUND: Hepatic encephalopathy is a common severe complication of liver cirrhosis that, however, so far is not considered as an indication for organ allocation to patients on the transplant waiting list. Multiple psychometric tests have been developed to detect hepatic encephalopathy. However, there is only rare data about the predictive value of psychometric test results regarding mortality in patients with liver cirrhosis. This retrospective analysis of prospective data determined the predictive value of the Inhibitory Control Test (ICT), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Portosystemic Encephalopathy Syndrome-Test and the Critical Flicker Frequency (CFF) assessment in regard to mortality in patients on the waiting list for liver transplantation. METHODS: 143 patients awaiting liver transplantation were included. They underwent a test battery including the Inhibitory Control Test, the Repeatable Battery for the Assessment of Neuropsychological Status, the Portosystemic Encephalopathy Syndrome-Test which provides the psychometric hepatic encephalopathy score (PHES) and the Critical Flicker Frequency assessment at study inclusion. The PHES was available for all patients (n = 143), the RBANS scores for n = 115, the ICT results for n = 99, and the CFF results for n = 136 patients. Basic characteristics (age, gender, underlying liver disease, accompanying diseases) and Model for End-stage Liver Disease (MELD) -Score at the time of study inclusion were documented. Follow-up was done for 5 years. Patients who either received a liver transplantation or dropped out of the study during the observation period were censored. The five-year survival rate was analyzed with the Kaplan-Meier curve. RESULTS: Patients with abnormal PHES had a significantly higher mortality risk than patients with a normal PHES ( P < 0.0001). Also patients with an abnormal RBANS result had a significantly higher risk to die than patients with a normal RBANS result ( P = 0.018), but the difference was less significant compared to the PHES. Mortality risk did not significantly differ between patients with normal or abnormal CFF or ICT results. (CFF: P = 0.412; ICT: P = 0.202). In a binary logistic regression analysis the MELD-Score and diabetes were independent prognostic factors for mortality risk (MELD: P = 0.003; diabetes: P = 0.008). The MELD-Score turned out to have significant impact on the test results regarding the PHES ( P < 0.0001), but not concerning the other tests (CFF: P = 0.903; RBANS: P = 0.065; ICT: P = 0.139). CONCLUSIONS: An abnormal PHES result is an indicator for an increased mortality risk, though less predictive than the MELD-Score.

BACKGROUND: Cognitive dysfunction caused by hepatic encephalopathy in patients with acute or chronic liver failure improves within the first year after liver transplantation. However, cognitive restitution seems to be incomplete in a subset of patients. Furthermore, a new-onset cognitive decline after liver transplantation was described. This prospective study analyzed whether a history of hepatic encephalopathy before liver transplantation had an impact on the long-term outcome of cognitive function after liver transplantation and if patients who underwent liver transplantation up to 5 five years before showed worse cognitive function than adjusted healthy controls. METHODS: 34 patients with liver cirrhosis on the waiting list for liver transplantation underwent a psychometric test battery and questionnaires assessing health-related quality of life 3.4 ± 3.1 months (T1) before liver transplantation. Further 33 patients were included directly after liver transplantation. After transplantation all patients (n = 67) underwent psychometric testing and completed questionnaires at 8.9 ± 3.6 months (T2) and at 62.1 ± 12.2 months (T3) thereafter. The psychometric test battery consisted of the Portosystemic Encephalopathy Syndrome-Test which provides the psychometric hepatic encephalopathy score (PHES), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Inhibitory Control Test and the Critical Flicker Frequency. All patients were asked to complete the self-reporting questionnaires Hospital Anxiety and Depression Scale, Beck Depression Inventory, Fatigue Impact Scale and Short Form 36 health survey to assess health-related quality of life. Patients were divided into 2 groups: Patients with and without hepatic encephalopathy before liver transplantation. Test results were compared to those of 55 adjusted healthy controls. RESULTS: Patients tested before liver transplantation performed significantly worse than controls in the psychometric tests (RBANS total scale mean 92.6 ± 13.3 vs 99.9 ± 12.0, P < 0.001; PHES median 0 (interquartile range (IQR) −3; 1) vs 1 (IQR 0; 2), P < 0.01). About 1 year after liver transplantation patients with a history of hepatic encephalopathy still showed cognitive impairment compared to controls (RBANS total scale mean 89.5 ± 15.6 vs 99.9 ± 12.0, P = 0.001; PHES median 0 (IQR −2; 1) vs 1 (IQE 0; 2), P < 0.01) while patients without a history of hepatic encephalopathy did not. 5 years after liver transplantation both patient groups did not differ from healthy controls (Table 1). Health-related quality of life improved significantly in both patient groups after transplantation. CONCLUSIONS: Cognitive impairment associated to hepatic encephalopathy seems to be reversible within 5 years 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.

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.

One of the most disabling symptoms of hepatitis C virus (HCV) infection is chronic fatigue. While this is accepted for HCV polymerase chain reaction (PCR)-positive patients, a relationship between HCV infection and chronic fatigue is questioned after successful virus eradication. As fatigue is a subjective criterion, we aimed to evaluate in addition mood alterations and cognitive function in HCV-exposed patients with only mild liver disease and to assess a) possible interrelationships between these factors and health-related quality of life and b) the impact of viremia and former interferon treatment. One hundred and fifty-nine anti-HCV-positive individuals without advanced liver disease answered health-related quality of life (HRQoL), fatigue and depression questionnaires and underwent a battery of attention and memory tests. Accompanying diseases which could distort the results of the study such as HIV co-infection or drug addiction were exclusion criteria. The patients were subdivided into four groups according to their viremia status and interferon treatment history. Patients' data were evaluated with respect to norms given in the respective test manuals and in addition compared to those of 33 age-matched healthy controls. Eighty-five per cent of the patients had chronic fatigue, 50-60% mild depression or anxiety, 45% memory deficits and 30% attention deficits, irrespective of their HCV viremia status or treatment history. HRQoL correlated negatively with chronic fatigue (P<.001), while cognitive deficits-especially memory function-were independent from fatigue and depression. HCV infection may cause long-standing cerebral dysfunction that significantly impairs HRQoL and may even persist after clearance of the virus.

Summary Hepatitis C virus ( HCV ) causes not only liver damage in certain patients but can also lead to neuropsychiatric symptoms. Previous studies have shown that the type 4 allele of the gene for apolipoprotein E ( APOE ) is strongly protective against HCV‐induced damage in liver. In this study, we have investigated the possibility that APOE genotype is involved in the action of HCV in brain. One hundred HCV‐infected patients with mild liver disease underwent a neurological examination and a comprehensive psychometric testing of attention and memory function. In addition, patients completed questionnaires for the assessment of fatigue, health‐related quality of life and mood disturbances. Apolipoprotein E gene genotyping was carried out on saliva using buccal swabs. The APOE ‐ε4 allele frequency was significantly lower in patients with an impairment of working memory, compared to those with a normal working memory test result ( P = 0.003). A lower APOE ‐ε4 allele frequency was also observed in patients with definitely altered attention ability ( P = 0.008), but here, the P ‐value missed the level of significance after application of the Bonferroni correction. Our data suggest that the APOE ‐ε4 allele is protective against attention deficit and especially against poor working memory in HCV ‐infected subjects with mild liver disease. Considering the role of apolipoprotein E in the life cycle of the virus, the findings shed interesting new light upon possible pathomechanisms behind the development of neuropsychiatric symptoms in hepatitis C infection.

Hepatitis C virus (HCV) infection may induce chronic fatigue and cognitive dysfunction. Virus replication was proven within the brain and HCV-positive cells were identified as microglia and astrocytes. We hypothesized that cerebral dysfunction in HCV-afflicted patients is associated with microglia activation. Microglia activation was assessed in vivo in 22 patients with chronic HCV infection compared to six healthy controls using [(11) C]-PK11195 Positron Emission Tomography (PET) combined with magnetic resonance tomography for anatomical localization. Patients were subdivided with regard to their PCR status, Fatigue Impact Scale score (FIS) and attention test sum score (ATS). A total of 12 patients (54.5%) were HCV PCR positive [of which 7 (58.3%) had an abnormal FIS and 7 (58.3%) an abnormal ATS], 10 patients (45.5%) were HCV PCR negative (5 (50%) each with an abnormal FIS or ATS). Patients without attention deficits showed a significantly higher accumulation of [(11) C]-PK11195 in the putamen (P = 0.05), caudate nucleus (P = 0.03) and thalamus (P = 0.04) compared to controls. Patients with and without fatigue did not differ significantly with regard to their specific tracer binding in positron emission tomography. Preserved cognitive function was associated with significantly increased microglia activation with predominance in the basal ganglia. This indicates a probably neuroprotective effect of microglia activation in HCV-infected patients.

Background & AimsFocal 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.Methods55 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.ResultsPatient 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.ConclusionsFocal 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.

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.

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. (C) 2014 AASLD.

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.

A total of 307 people completed the questionnaire: 47 patients, 17 carers, 62 clinicians and 181 public respondents.Overall there was a preference for maintaining the status quo: 52.1 stated a preference for the current system, 38.4 for an unrestricted listing policy and 9.4 for a highly restricted policy.However, preferences differed between groups: an less restrictive listing policy was preferred by the majority of carers and also public respondents, whereas a majority of patients and clinicians preferred the current listing policy (figure 1).However, there were differences between patient subgroups, with those who had been listed being more inclined to favour the current process.The results show for the first time that there is general support amongst relevant groups for a process of selection for liver transplantation.There are some differences in opinion between groups.It is important that the views of these groups are considered when formulating transplant policy.The general support for selection of liver transplant candidates mandates a transparent and rational selection policy.Figure 1.Group preferences.

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 I-123-beta-CIT, for the evaluation of the striatal dopamine transporter function, and I-123-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. (c) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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.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.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.Preanalytics plays a key role for determination of MMP-9. EDTA seems to be a valid anticoagulant for MMP-9 protein measurement.

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.

OBJECTIVE:Fatigue, mood disturbances and cognitive dysfunction are frequent in patients infected with hepatitis C virus (HCV) who have mild liver disease. The reason is still unclear. The present study aims to gain more insight into the pathomechanism by combining an extensive neuropsychological examination with magnetic resonance spectroscopy in four different brain regions in a patient group covering the whole spectrum of neuropsychiatric findings in patients afflicted with HCV who have only mild liver disease.METHODS:53 HCV-positive patients with only mild liver disease and differing degrees of neuropsychiatric symptoms were studied with single-voxel MRS of the parietal white matter, occipital grey matter, basal ganglia and pons. Brain metabolite concentrations were quantitatively analysed by using LCmodel. MRS data were compared to those of 23 healthy controls adjusted for age, and analysed for relationships with the extent of neuropsychiatric symptoms.RESULTS:Choline (p=0.02), creatine (p=0.047) and N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (NN, p=0.02) concentrations in the basal ganglia and choline concentrations in the white matter (p=0.045) were significantly higher in the patients than in controls. Interestingly, the difference was most evident for the patients with low fatigue scores (eg, white matter: choline: p=0.001, creatine: p=0.003, NN: p=0.031). Myo-inositol differed significantly between groups in the white (p=0.001) and grey matter (p=0.003). Fatigue correlated negatively with white matter NN, choline and creatine and myo-inositol levels in white and grey matter and basal ganglia (p<0.01).CONCLUSION:As the increase of choline, creatine and myo-inositol are usually interpreted to indicate glial activation and macrophage infiltration in chronic inflammation and slow virus infections of the brain the present data endorse the hypothesis, that HCV infection may induce neuroinflammation and brain dysfunction. The concomitant increase of NN and the negative correlation to the extent of fatigue suggest a cerebral compensatory process after HCV infection.

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.

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.