In the German population of patients awaiting liver transplantation, PHES is the most robust method for the diagnosis and follow-up of HE.

Background and Purpose-Recently, we reported high seroprevalence (age-dependent up to >19%) of N-methyl-daspartate-receptor subunit NR1 (NMdAR1) autoantibodies in both healthy and neuropsychiatrically ill subjects (N=4236). Neuropsychiatric syndrome relevance was restricted to individuals with compromised blood-brain barrier, for example, apolipoprotein E4 (APOE4) carrier status, both clinically and experimentally. We now hypothesized that these autoantibodies may upon stroke be protective in individuals with hitherto intact blood-brain barrier, but harmful for subjects with chronically compromised blood-brain barrier. Methods-Of 464 patients admitted with acute ischemic stroke in the middle cerebral artery territory, blood for NMdAR1 autoantibody measurements and APOE4 carrier status as indicator of a preexisting leaky blood-brain barrier was collected within 3 to 5 hours after stroke. Evolution of lesion size (delta day 7-1) in diffusion-weighted magnetic resonance imaging was primary outcome parameter. In subgroups, NMdAR1 autoantibody measurements were repeated on days 2 and 7. Results-Of all 464 patients, 21.6% were NMdAR1 autoantibody-positive (immunoglobulin M, A, or G) and 21% were APOE4 carriers. Patients with magnetic resonance imaging data available on days 1 and 7 (N=384) were divided into 4 groups according to NMdAR1 autoantibody and APOE4 status. Groups were comparable in all stroke-relevant presenting characteristics. The autoantibody+/APOE4− group had a smaller mean delta lesion size compared with the autoantibody−/ APOE4-group, suggesting a protective effect of circulating NMdAR1 autoantibodies. In contrast, the autoantibody+/APOE4+ group had the largest mean delta lesion area. NMdAR1 autoantibody serum titers dropped on day 2 and remounted by day 7. Conclusions-dependent on blood-brain barrier integrity before an acute ischemic brain injury, preexisting NMdAR1 autoantibodies seem to be beneficial or detrimental.

Background: Early inflammation has been suggested as an important factor contributing to unfavorable prognosis after acute ischemic stroke. The present study aimed to clarify the temporal dynamics of discrete inflammatory markers/mediators for future mechanism-targeting anti-inflammatory strategies in ischemic brain damage. Methods: Blood samples of 69 patients with transient ischemic attack or ischemic stroke were taken upon admission and at time points 6, 12 and 24 h, as well as 3 and 7 days after symptom onset for analysis of 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 the brain damage marker S100B. Clinical scores (modified Rankin Scale, National Institute of Health Stroke Scale) were assessed on day 90. Results: MCP-1, MMP-9, TIMP-1, IL-6, CRP and S100B showed significantly different time courses depending on stroke outcome. While the levels of IL-6, MCP-1 and MMP-9 increased already a few hours after symptom onset, CRP and S100B gradually rose commencing at 12–24 h. TIMP-1 demonstrated an extended plateau. By multiple linear regression analysis IL-6, MCP-1, TIMP-1 and S100B were determined to be independently related to clinical outcome scores at specific time points. Conclusions: Our data show important differences in the early time course of several potential markers for the complex network of inflammation and brain damage after ischemic stroke depending on stroke outcome. This must be considered for any therapeutical approach using anti-inflammatory treatment.

Calcineurin inhibitors (CNIs) frequently induce neurological complications early after orthotopic liver transplantation (OLT). We hypothesize that longterm CNI therapy after OLT causes dose-dependent cognitive dysfunction and alteration of brain structure. In this study, 85 OLT patients (20 with CNI-free, 35 with CNI low-dose, and 30 with standard-dose CNI immunosuppression) underwent psychometric testing and cerebral magnetic resonance imaging approximately 10 years after OLT to assess brain function and structural brain alterations. A total of 33 healthy patients adjusted for age, sex, and education served as controls. Patients receiving CNI showed a significantly worse visuospatial/constructional ability compared with controls (P £ 0.04). Furthermore, patients on low-dose CNI therapy had an overall impaired cognitive function compared with controls (P 5 0.01). The tacrolimus total dose and mean trough level were negatively correlated to cognitive function. CNI doses had been adjusted in 91% of the patients in the low-dose and CNI-free groups in the past due to CNI-induced kidney damage. Patients treated with CNI showed significantly more white matter hyperintensities (WMH) than patients on CNI-free immunosuppression and controls (P < 0.05). Both the mean cyclosporine A and tacrolimus trough levels correlated significantly with WMH. In conclusion, longterm CNI therapy carries a risk of cognitive dysfunction especially in patients who already showed nephrotoxic side effects indicating an increased susceptibility of these patients against toxic CNI effects. This subgroup of patients might benefit from a change to CNI-free immunosuppression.Liver Transplantation 24 56-66 2018 AASLD.Received August 9, 2017; accepted October 19, 2017. Orthotopic liver transplantation (OLT) requires lifelong immunosuppression, which is usually composed of calcineurin inhibitors (CNIs; cyclosporine or tacrolimus), mycophenolate mofetil, and steroids. (1) The development of immunosuppressive therapy regimens based on CNI led to significantly increased survival rates after OLT. (2) In consequence, longterm adverse effects of CNI therapy gained increased importance. Renal dysfunction, malignancy, and cardiovascular disease are predominantly considered, each affecting approximately 25% of the patients 10 years after OLT. (3) Interestingly, data about the longterm effects of CNI on the central nervous system are sparse although neurotoxic side effects of CNI are known especially for the first weeks after OLT. (4,5) Within the first weeks after OLT, approximately 30% of the patients present with neurological symptoms like disorientation, hallucinations, cognitive dysfunction, alterations of consciousness, and seizures, which are generally considered as being caused by CNI therapy. (6) So far, those few studies that addressed the longterm effect of CNI on the central nervous system

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.