The potential role of diffusion weighted imaging in the diagnosis of early carotid and vertebral artery dissection.

PURPOSE: To investigate the role of the diffusion weighted imaging (DWI) in the acute dissection of internal carotid artery (ICA) and vertebral artery (VA) and assessing the length of intramural hematoma (IMH), caused by dissection. METHODS: We analyzed 28 patients presenting with a dissection of the ICA and/or VA with respect to the presence of high signal intensity areas on DWI suggestive of dissection and 20 control subjects without arterial dissection, some with and some without atherosclerotic lesions. ICA or VA dissection was defined by clinical and imaging, computed tomography angiography (CTA), MR angiography (MRA), and digital subtraction angiography (DSA) findings. The length of DWI hyperintensity was compared to length of the occlusion or stenosis on the angiographic examination. RESULTS: In 28 patients, 30 dissected arteries were analyzed. Time intervals from the onset of the first clinical symptoms to the radiological evaluation ranged from 1.5 h to 42 days. In 28 (93%) of the dissections, a high signal intensity of the affected artery was present on DWI. The measurement of the dissection length on DWI compared to DSA showed a mean deviation of 2.7 mm and a standard deviation of 3.7 mm. CONCLUSION: DWI is a highly sensitive and valuable pulse sequence for the detection of dissected cervical arteries even in the first hours after symptom onset. In contrast to CTA and MRA, DWI can be a potential tool for a reliable measurement of the dissection length.

Varying Patterns of CNS Imaging in Influenza A Encephalopathy in Childhood.

PURPOSE: The brain imaging findings in children with neurological complications associated with influenza A infections are presented and analyzed and pathological imaging changes including atypical intracerebral hemorrhages in these patients are discussed. METHODS: Neuroimaging findings in six children with influenza encephalopathy following influenza A infection between 2012-2017 were retrospectively investigated. Of these five underwent magnetic resonance imaging (MRI) and one computed tomography (CT). Gene analysis was performed in two cases with acute necrotizing encephalitis of childhood (ANEC). RESULTS: The MRI findings of one child were concordant with mild encephalopathy with a reversible splenial lesion (MERS); this patient recovered but remained aphasic. In two cases MRI showed typical bilateral thalamic lesions as a feature of ANEC; genetic testing facilitated the diagnosis in one case. One of the patients died, the other showed little improvement. The remaining three patients had multiple diffuse cerebral hemorrhages predominantly affecting the supratentorial white matter after influenza A infection complicated by pneumonia, rhabdomyolysis and sepsis requiring extracorporeal membrane oxygenation (ECMO). CONCLUSION: Neurological complications in children associated with influenza A infection may include MERS and ANEC. Additionally, atypical disseminated intracerebral hemorrhages as a complication of influenza A infection is reported.

Quantitative magnetic resonance imaging indicates brain tissue alterations in patients after liver transplantation.

PURPOSE: To investigate cerebral microstructural alterations in patients treated with calcineurin inhibitors (CNI) after orthotopic liver transplantation (OLT) using quantitative magnetic resonance imaging (qMRI) and a cross-sectional study design. METHODS: Cerebral qMRI was performed in 85 patients in a median 10 years after OLT compared to 31 healthy controls. Patients were treated with different dosages of CNI or with a CNI-free immunosuppression (CNI-free: n = 19; CNI-low: n = 36; CNI-standard: n = 30). T2-, T2*- and T2'- relaxation times, as well as apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in brain gray and white matter by using the regions of interest method. RESULTS: In comparison to controls, patients revealed significantly increased T2, T2*, T2', ADC and reduced FA, predominantly in the frontal white matter, indicating microstructural brain alterations represented by increased free water (increased T2), reduced neuronal metabolism (increased T2') and a lower degree of spatial organization of the nervous fibers (reduced FA). CNI-low and CNI-free patients showed more alterations than CNI-standard patients. Analysis of their history revealed impairment of kidney function while under standard CNI dose suggesting that these patients may be more vulnerable to toxic CNI side-effects. CONCLUSION: Our findings suggest that the individual sensitivity to toxic side effects should be considered when choosing an appropriate immunosuppressive regimen in patients after liver transplantation.

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.

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.

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.

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.

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.

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.