Meike Dirks

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.

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.

Neurological Sequelae in Adults After E coli O104: H4 Infection-Induced Hemolytic-Uremic Syndrome.

AbstractIn an outbreak of shiga toxin-producing Escherichia coli infections and associated hemolytic-uremic syndrome (STEC O104:H4) in Germany in the year 2011 neurological complications in adult patients occurred unexpectedly frequent, ranging between 48% and 100% in different patient groups. Few is known about the long-term effects of such complications and so we performed follow-up exams on 44 of the patients treated for STEC-HUS at Hannover Medical Scool in this observational study. Standardized follow-up exams including neurological and neuropsychological assessments, laboratory testing, magnetic resonance imaging (MRI), and EEG were carried out. Subgroups were examined 2 (n = 34), 7 (n = 22), and 19 (n = 23) months after disease onset. Additionally, at the 19-month follow-up, quality of life, sleep quality, and possible fatigue were assessed.Nineteen months after disease onset 31 patients were reassessed, 22 of whom still suffered from symptoms such as fatigue, headache, and attention deficits. In the neuropsychological assessments only 39% of the patients performed normal, whereas 61% scored borderline pathological or lower. Upon reviewal, the follow-up data most prominently showed a secondary decline of cognitive function in about one-quarter of the patients. Outcome was not related to treatment or laboratory data in the acute phase of the disease nor length of hospitalization. Prognosis of STEC-HUS associated brain dysfunction in adults with regard to severity of symptoms is mostly good; some patients however still have not made a full recovery. Patients’ caretakers have to be aware of possible secondary decline of brain function as was observed in this study.

ADAMTS-13 Activity Predicts Outcome in Acute Ischaemic Stroke Patients Undergoing Endovascular Treatment

BACKGROUND Endovascular treatment improves outcome in patients with acute ischaemic stroke due to large vessel occlusion in general. But outcome in some of these patients is jeopardized by recanalization failure or bleeding. OBJECTIVES This study aimed to determine a possible association of mediators of inflammation and haemostasis (C-reactive protein, interleukin-6, matrix metalloproteinase-9, monocyte chemoattractant protein-1, asymmetric dimethylarginine [ADMA], symmetric dimethylarginine, von Willebrand factor and a disintegrin and metalloproteinase with a thrombospondin type 1 motif 13 [ADAMTS-13]) with the post-intervention grade of reperfusion, complications and clinical outcome in patients who underwent endovascular treatment of ischaemic stroke. PATIENTS/METHODS Forty-one patients with acute ischaemic stroke due to large vessel occlusion were prospectively enrolled into the study. Peripheral venous blood was taken prior to treatment and 24 hours and 3, 7 and 90 days after symptom onset. The post-intervention grade of reperfusion was determined using the modified Treatment in Cerebral Infarction (mTICI) score. Clinical outcome on day 90 was assessed using the modified Rankins scale (mRS). RESULTS Low ADAMTS-13 activity (p = 0.009) and missing of statin therapy (p = 0.038) on admission were independently associated with unfavourable outcome (mRS: 5-6). Patients with unsuccessful reperfusion (mTICI: 0-1) showed higher ADMA levels on admission (p = 0.018). However, this association could not be confirmed in the binary logistic regression analysis. CONCLUSION Low ADAMTS-13 activity is a predictor of unfavourable outcome in patients with ischaemic stroke undergoing endovascular therapy. Further studies are warranted to elucidate the clinical and potential therapeutic role of ADAMTS-13 in acute ischaemic stroke.

Systemic inflammation and immune cell phenotypes are associated with neuro-psychiatric symptoms in patients with chronic inflammatory liver diseases

Chronic inflammatory liver diseases are frequently associated with neuropsychiatric and cognitive dysfunctions. We hypothesized that symptomatic patients may show altered levels of soluble inflammatory mediators (SIMs) as well as changes in immune cell phenotypes.

Neuropsychiatric symptoms in hepatitis C patients resemble those of patients with autoimmune liver disease but are different from those in hepatitis B patients

Chronic fatigue, mood alterations and cognitive impairment are frequent accessory symptoms of HCV infection. Fatigue and mood alterations have also been observed in autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), but not in hepatitis B virus (HBV)‐infection, thus indicating an autoimmune response as possible cause of HCV infection‐associated encephalopathy. Data, however, are sparse. This study aimed to prove that HCV patients feature similar to those with autoimmune liver disease but contrary to HBV patients regarding neuropsychiatric symptoms. A total of 132 noncirrhotic patients (HCV: 46, HBV: 22, AIH: 27, PBC: 29, AIH/PBC: 8) completed questionnaires addressing the domains mentioned above. Eighty‐eight underwent a comprehensive neuropsychological assessment. Patient groups were compared among each other and to 33 healthy controls. Fatigue, anxiety and depression scores were significantly increased, and the SF‐36 mental score significantly decreased in all patient groups compared to controls. Fatigue was significantly more pronounced in HCV than in HBV patients. HCV patients scored significantly worse than HBV patients but not AIH and PBC patients in the SF‐36. HCV, AIH and PBC but not HBV patients did significantly worse than controls in word learning. Recognition of words was impaired in HCV, AIH and PBC patients and recognition of figures in HCV patients, exclusively (P ≤ 0.002). HCV patients did also worse than controls and HBV patients concerning alertness and working memory (P ≤ 0.001). The neuropsychiatric profiles of HCV patients are similar to those of AIH and PBC patients but differ from those of HBV patients, suggesting an autoimmune response as a possible cause for these differences.

Response to letter to the editor: Persistent neuropsychiatric impairment in HCV patients - or educational mismatch?!

First, we would like to thank Dr. Gade for his interest in our study. Obviously Dr. Gade wonders if our findings in HCV patients are an artifact due to systematic bias based on a neglect of the study subjects’ education. In his opinion “patients with HCV have almost invariably been more poorly educated than comparison groups”. We can assure him that his statement does not fit in respect to our study group as most of the patients were infected via blood transfusion or application of blood products. HCV infection is not inevitably associated with poor education (see table 1). This article is protected by copyright. All rights reserved.