Karin Weissenborn

Recombinant Human Erythropoietin in the Treatment of Acute Ischemic Stroke

Background and Purpose— Numerous preclinical findings and a clinical pilot study suggest that recombinant human erythropoietin (EPO) provides neuroprotection that may be beneficial for the treatment of patients with ischemic stroke. Although EPO has been considered to be a safe and well-tolerated drug over 2 decades, recent studies have identified increased thromboembolic complications and/or mortality risks on EPO administration to patients with cancer or chronic kidney disease. Accordingly, the double-blind, placebo-controlled, randomized German Multicenter EPO Stroke Trial (Phase II/III; ClinicalTrials.gov Identifier: NCT00604630) was designed to evaluate efficacy and safety of EPO in stroke. Methods— This clinical trial enrolled 522 patients with acute ischemic stroke in the middle cerebral artery territory (intent-to-treat population) with 460 patients treated as planned (per-protocol population). Within 6 hours of symptom onset, at 24 and 48 hours, EPO was infused intravenously (40 000 IU each). Systemic thrombolysis with recombinant tissue plasminogen activator was allowed and stratified for. Results— Unexpectedly, a very high number of patients received recombinant tissue plasminogen activator (63.4%). On analysis of total intent-to-treat and per-protocol populations, neither primary outcome Barthel Index on Day 90 (P=0.45) nor any of the other outcome parameters showed favorable effects of EPO. There was an overall death rate of 16.4% (n=42 of 256) in the EPO and 9.0% (n=24 of 266) in the placebo group (OR, 1.98; 95% CI, 1.16 to 3.38; P=0.01) without any particular mechanism of death unexpected after stroke. Conclusions— Based on analysis of total intent-to-treat and per-protocol populations only, this is a negative trial that also raises safety concerns, particularly in patients receiving systemic thrombolysis.

Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver

The AASLD/EASL Practice Guideline Subcommittee on Hepatic Encephalopathy are: Jayant A. Talwalkar (Chair, AASLD), Hari S. Conjeevaram, Michael Porayko, Raphael B. Merriman, Peter L.M. Jansen, and Fabien Zoulim. This guideline has been approved by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver and represents the position of both associations.

Neuropsychological assessment of hepatic encephalopathy: ISHEN practice guidelines

Low‐grade or minimal hepatic encephalopathy (MHE) is characterised by relatively mild neurocognitive impairments, and occurs in a substantial percentage of patients with liver disease. The presence of MHE is associated with a significant compromise of quality of life, is predictive of the onset of overt hepatic encephalopathy and is associated with a poorer prognosis for outcome. Early identification and treatment of MHE can improve quality of life and may prevent the onset of overt encephalopathy, but to date, there has been little agreement regarding the optimum method for detecting MHE. The International Society on Hepatic Encephalopathy and Nitrogen Metabolism convened a group of experts for the purpose of reviewing available data and making recommendations for a standardised approach for neuropsychological assessment of patients with liver disease who are at risk of MHE. Specific recommendations are presented, along with a proposed methodology for further refining these assessment procedures through prospective research.

Seroprevalence of autoantibodies against brain antigens in health and disease.

We previously reported an unexpectedly high seroprevalence (∼10%) of N‐methyl‐D‐aspartate‐receptor subunit‐NR1 (NMDAR1) autoantibodies (AB) in healthy and neuropsychiatrically ill subjects (N = 2,817). This finding challenges an unambiguous causal relationship of serum AB with brain disease. To test whether similar results would be obtained for other brain antigen‐directed AB previously connected with pathological conditions, we systematically screened serum samples of 4,236 individuals.

Attention, memory, and cognitive function in hepatic encephalopathy.

Deficits in attention and arousal play a major role in the clinical presentation of hepatic encephalopathy. Attention deficits arealso the main components of minimal hepatic encephalopathy. The present paper summarizes some findings about attentional and memory dysfunction in hepatic encephalopathy, with reference to basic knowledgeabout normal attention and memory function and their cerebral representation.

Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4-associated haemolytic uraemic syndrome: a prospective trial

BACKGROUND In May 2011, an outbreak of Shiga toxin-producing enterohaemorrhagic E coli O104:H4 in northern Germany led to a high proportion of patients developing post-enteritis haemolytic uraemic syndrome and thrombotic microangiopathy that were unresponsive to therapeutic plasma exchange or complement-blocking antibody (eculizumab). Some patients needed ventilatory support due to severe neurological complications, which arose 1 week after onset of enteritis, suggesting an antibody-mediated mechanism. Therefore, we aimed to assess immunoadsorption as rescue therapy. METHODS In our prospective non-controlled trial, we enrolled patients with severe neurological symptoms and confirmed recent E coli O104:H4 infection without other acute bacterial infection or raised procalcitonin concentrations. We did IgG immunoadsorption processing of 12 L plasma volumes on 2 consecutive days, followed by IgG replacement (0·5 g/kg intravenous IgG). We calculated a composite neurological symptom score (lowest score was best) every day and assessed changes before and after immunoadsorption. FINDINGS We enrolled 12 patients who initially presented with enteritis and subsequent renal failure; 10 (83%) of 12 patients needed renal replacement therapy by a median of 8·0 days (range 5-12). Neurological complications (delirium, stimulus sensitive myoclonus, aphasia, and epileptic seizures in 50% of patients) occurred at a median of 8·0 days (range 5-15) and mandated mechanical ventilation in nine patients. Composite neurological symptom scores increased in the 3 days before immunoadsorption to 3·0 (SD 1·1, p=0·038), and improved to 1·0 (1·2, p=0·0006) 3 days after immunoadsorption. In non-intubated patients, improvement was apparent during immunoadsorption (eg, disappearance of aphasia). Five patients who were intubated were weaned within 48 h, two within 4 days, and two patients needed continued ventilation for respiratory problems. All 12 patients survived and ten had complete neurological and renal function recovery. INTERPRETATION Antibodies are probably involved in the pathogenesis of severe neurological symptoms in patients with E coli O104:H4-induced haemolytic uraemic syndrome. Immunoadsorption can safely be used to rapidly ameliorate these severe neurological complications. FUNDING Greifswald University and Hannover Medical School.

Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases

These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic; (2) guideline policies covered by the American Association for the Study of Liver Diseases/European Association for the Study of the Liver (AASLD/EASL) Policy on the Joint Development and Use of Practice Guidelines; and (3) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be

Pallidal lesions in patients with liver cirrhosis: clinical and MRI evaluation

Fifty patients with liver cirrhosis underwent neurological, psychometric, electroencephalographic and biochemical examination as well as cranial magnetic resonance imaging (MRI) to study the incidence of pallidal lesions in cirrhotics and their correlation to liver function, as well as to neurological and mental state. In one patient a histopathological study of the brain was performed. The vast majority of the patients with liver cirrhosis (92%) present with bilateral symmetric pallidal hyperintensities in the T1-weighted MR spin echo sequences, while the T2-weighted images are normal. On the whole there was no correlation between the signal intensity of the pallidal lesions and measures of liver function, neurological status or grade of encephalopathy. As could be shown in follow-up examinations the signal intensity of the lesions increased with decreasing liver function and decreased with normalization of liver function after liver transplantation. The substrate of the lesions remains unclear. However, regions which show alterations in the MRI are histopathologically characterized by the appearance of Alzheimer-type-II cells.

The number connection tests A and B: interindividual variability and use for the assessment of early hepatic encephalopathy

BACKGROUND/AIMS The number connection tests A and B are regarded as sensitive psychometric measures for the assessment of early hepatic encephalopathy. Review of the studies dealing with the diagnostic sensitivity of the number connection tests, however, shows that the scoring of the number connection tests results differs between studies. Most groups define the limits of the normal range by studying small control groups. Others use scores given in the literature without ensuring the comparability of the test versions used. Thus, there is a need for normative data for the number connection test results and for re-evaluation of the sensitivity of the tests using valid scores. METHODS In this study the number connection tests A and B were administered to 249 healthy volunteers (age: 18 to 76 years) to analyze the influence of age, education and occupation on their results. In addition, the age-corrected normative data were applied to 169 patients with grade 0-I hepatic encephalopathy. The specificity and sensitivity of age-corrected and age-independent normative data of the number connection tests were compared. RESULTS There was a significant influence of age and education on the number connection test results, but only a negligible effect of occupation. Application of the age-corrected normative data to the test results of the patients with grade I hepatic encephalopathy significantly decreased the sensitivity of the number connection tests for hepatic encephalopathy compared to widely used age-independent normal ranges, but also increased the specificity. CONCLUSION The use of standardized versions of the number connection tests and age-related normative data is recommended.

Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment

Background: The majority of patients with hepatitis C virus (HCV) infection suffer from disabling fatigue, cognitive dysfunction, and quality of life reduction. Meanwhile, there is increasing evidence that HCV infection can affect brain function. Recent studies have shown that fatigue and psychomotor slowing may resolve in patients with hepatitis C after treatment with ondansetron. This observation indicates alteration of serotonergic neurotransmission in HCV infected patients with chronic fatigue. Methods: Data from 20 HCV infected patients who were referred to our clinic because of disabling fatigue and cognitive decline of unknown cause were analysed retrospectively. Patients had undergone a diagnostic programme, including clinical and psychometric examination, electroencephalogram (EEG), magnetic resonance imaging of the brain, cerebrospinal fluid analysis, and I-123-beta-CIT (2β-carbomethoxy-3-β-(4-[123I]iodophenyl)tropane) single photon emission computerised tomography (SPECT) studies of serotonin and dopamine transporter binding capacity. Results: All patients had pathological results on the fatigue impact scale. Two thirds of patients showed pathological attention test results. EEG, magnetic resonance imaging, and cerebrospinal fluid analysis were normal. Pathological dopamine transporter binding was present in 12/20 (60%) patients and pathological serotonin transporter binding in 8/19 (50%) patients. Patients with normal SPECT results did not significantly differ from controls with regard to psychometric test results. Interestingly, patients with both decreased serotonin and dopamine transporter binding showed significantly impaired performance in most of the tests applied. Comorbidity that could have impaired cerebral function was excluded in all patients. Conclusion: Our findings indicate alteration of serotonergic and dopaminergic neurotransmission in HCV infected patients with chronic fatigue and cognitive impairment.