Henning Pflugrad

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.

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.

Active at night, sleepy all day - Sleep disturbances in patients with hepatitis C virus infection

BACKGROUND & AIMS More than 50% of patients with chronic hepatitis C with only mild liver disease complain about chronic fatigue, daytime sleepiness and poor sleep quality. The aim of the present study was to characterize and objectify the sleep disturbances in hepatitis C virus-infected patients. METHODS Twenty-five women who had been infected with hepatitis C virus contaminated anti-D immunoglobulin in 1978/79 and 22 age-matched female healthy controls underwent actigraphy over a period of 5 days to measure motor activity and thereby sleep-wake-rhythm and in addition completed questionnaires for depression, health-related quality of life, fatigue and sleep, and a sleep diary. Liver cirrhosis, a history of neurological or psychiatric disease, history of intravenous drug abuse, shift work, or current medication with effect upon the central nervous system were exclusion criteria. RESULTS The patients achieved higher scores for depression, fatigue and sleep disturbances and lower quality of life scores than the healthy controls. Actigraphy showed higher nocturnal activity and worse sleep efficiency in the patients, while the 24-h activity level did not differ between groups. Fatigue and quality of life scores correlated with bad sleep quality and daytime sleepiness. CONCLUSIONS Our data indicate that chronic fatigue is associated with bad sleep quality and increased nocturnal activity in HCV-infected patients suggesting an alteration of sleep architecture behind fatigue in HCV-associated encephalopathy.

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. Liver Transpl 20:807–814, 2014.

Cerebral microglia activation in hepatitis C virus infection correlates to cognitive dysfunction.

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 [11C]‐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 [11C]‐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.

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. Liver Transpl 21:224‐232, 2015.

The temporal dynamics of plasma fractalkine levels in ischemic stroke: association with clinical severity and outcome

BackgroundThe chemokine fractalkine (CX3CL1, FKN) is involved in neural-microglial interactions and is regarded as neuroprotective according to several in vivo studies of inflammatory and degenerative states of the brain. Recently, an association with outcome in human ischemic stroke has been proposed. In this study, we aimed to investigate the temporal pattern of FKN levels in acute ischemic stroke in relation to stroke severity and outcome.MethodsFKN levels were measured in plasma specimens of fifty-five patients with acute ischemic stroke. Blood was available for time points 6 hours (h), 12 h, 3 days (d), 7 d and 90 d after stroke onset. Clinical outcome was evaluated using the modified Rankin Scale (mRS) at 7 d and 90 d.ResultsThe time course of FKN significantly differs depending on stroke severity, with higher FKN levels linked to a lower severity. FKN levels in patients with moderate to severe strokes differ significantly from controls. In outcome analysis, we found an association of dynamics of FKN with clinical outcome. Decrease of FKN is pronounced in patients with worse outcome. Multivariate analysis including stroke severity and stroke etiology revealed that deltaFKN between 6 h and 3 d is independently associated with mRS at 90 d. In addition deltaFKN is inversely correlated with the extent of brain damage, as measured by S100B.ConclusionsFKN dynamics are independently associated with stroke outcome. Further studies might give insight on whether FKN is actively involved in the inflammatory cascade after acute ischemic stroke.

Apolipoprotein E-ε4 deficiency and cognitive function in hepatitis C virus-infected patients.

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.

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

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.

Longterm calcineurin inhibitor therapy and brain function in patients after liver transplantation

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 = 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.