-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Gut 01/2013; · 10.11 Impact Factor
-
Milani Deb,
Stefan Gerdes,
Meike Heeren,
Jürgen Lambrecht,
Hans Worthmann, Annemarie Goldbecker,
Anita Blanka Tryc,
Svjetlana Lovric,
Walter Schulz-Schaeffer,
Almuth Brandis,
Reinhard Dengler,
Karin Weissenborn,
Marion Haubitz
[show abstract]
[hide abstract]
ABSTRACT: 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.
Journal of neurology, neurosurgery, and psychiatry 12/2012; · 4.87 Impact Factor
-
Anita B Tryc, Annemarie Goldbecker,
Georg Berding,
Stefan Rümke,
Kambiz Afshar,
Golschan Hamidi Shahrezaei,
Henning Pflugrad,
Hannelore Barg-Hock,
Christian P Strassburg,
Hartmut Hecker,
Karin Weissenborn
[show abstract]
[hide abstract]
ABSTRACT: 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 to analyze 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 striatatal 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 the 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. CONCLUSION: 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.
Journal of Hepatology 12/2012; · 9.26 Impact Factor
-
Shufen Chen,
Jens Martens-Lobenhoffer,
Karin Weissenborn,
Jan T Kielstein,
Ralf Lichtinghagen,
Milani Deb,
Na Li,
Anita B Tryc, Annemarie Goldbecker,
Qiang Dong,
Stefanie M Bode-Böger,
Hans Worthmann
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Elevated levels of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are accompanied by endothelial dysfunction and predict adverse outcome after ischemic stroke. Via induction of oxidative stress, dimethylarginines are possibly linked to the inflammatory cascade after stroke that is known to considerably contribute to secondary progression of brain injury. We sought to investigate the association between dimethylarginines and inflammatory mediators in patients with acute ischemic stroke. METHODS: Plasma levels of ADMA and SDMA were measured in prospectively collected blood samples of 58 patients with acute ischemic stroke. Blood samples were taken at 6 hours, 12 hours, 24 hours, 3 days and 7 days after onset of symptoms. Analyses of ADMA and SDMA were done by high-performance liquid chromatography-tandem mass spectrometry. 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 S100B as markers of inflammation and brain damage were determined by commercially available immunometric assays. Patient data were compared with control data from 32 age-adjusted healthy volunteers. Baseline stroke severity was evaluated by the National Institutes of Health Stroke Scale (NIHSS) (NIHSS 0 to 1: mild stroke; NIHSS 2 to 8: moderate stroke; NIHSS >=9: severe stroke). RESULTS: Plasma ADMA and SDMA levels significantly correlated with blood levels of inflammatory mediators up to day 7 after stroke. On multiple stepwise linear regression analysis ADMA correlated with TIMP-1 at 6 hours, 24 hours, 3 days and 7 days, MMP-9 at 12 hours and IL-6 at 7 days (P <0.05) while SDMA correlated with MCP-1 at 6 hours, 24 hours, 3 days and 7 days as well as IL-6 at 3 days and 7 days (P <0.05). CONCLUSIONS: The levels of the vasoactive compound ADMA as well as levels of its structural isomer SDMA are associated with levels of inflammatory mediators after acute ischemic stroke. Further studies need to elucidate the cause and effect relationship of these crucial players.
Journal of Neuroinflammation 11/2012; 9(1):251. · 3.83 Impact Factor
-
Munir Rababah,
Hans Worthmann,
Milani Deb,
Anita B Tryc,
Yue Tao Ma,
Omnia M El Bendary,
Hartmut Hecker, Annemarie Goldbecker,
Meike Heeren,
Korbinian Brand,
Karin Weissenborn,
Ralf Lichtinghagen
[show abstract]
[hide abstract]
ABSTRACT: Matrix metalloproteinase-9 (MMP-9) represents a promising marker for acute stroke management. In clinical studies MMP-9 has been quantified by ELISA using differing protocols. We aimed to establish a valid protocol by evaluation of preanalytics.
Blood from stroke patients (n=28) and healthy controls (n=28) was drawn into tubes containing different anticoagulants (EDTA, citrate, lithium-heparin (heparin) and heparin with proteinase inhibitors) and processed after 0, 60 and 240 min. MMP-9 plasma protein and mRNA from mononuclear leukocytes were determined.
In regard to anticoagulants used, samples showed different MMP-9 protein baseline values and kinetics. Stable MMP-9 protein concentrations were only measured from EDTA samples. Particularly in samples with proteinase inhibitors protein and mRNA concentrations increased over time. Kinetics did not differ between patients and controls.
Preanalytics plays a key role for determination of MMP-9. EDTA seems to be a valid anticoagulant for MMP-9 protein measurement.
Clinical biochemistry 02/2012; 45(6):483-9. · 2.02 Impact Factor
-
Meike Heeren,
Karin Weissenborn,
Dimitrios Arvanitis,
Martin Bokemeyer, Annemarie Goldbecker,
Argyro Tountopoulou,
Thomas Peschel,
Julian Grosskreutz,
Hartmut Hecker,
Ralph Buchert,
Georg Berding
[show abstract]
[hide abstract]
ABSTRACT: Patients with hepatitis C virus (HCV) infection frequently show neuropsychiatric symptoms. This study aims to help clarify the neurochemical mechanisms behind these symptoms and to add further proof to the hypothesis that HCV may affect brain function. Therefore, 15 patients who reported increasing chronic fatigue, mood alterations, and/or cognitive decline since their HCV infection underwent neurologic and neuropsychological examination, magnetic resonance imaging, (18)F-fluoro-deoxy-glucose positron emission tomography of the brain, and single photon emission tomography of striatal dopamine and midbrain serotonin transporter (SERT) availability. None of the patients had liver cirrhosis. Patients' data were compared with data of age-matched controls. In addition, regression analysis was performed between cognitive deficits, and mood and fatigue scores as dependent variables, and cerebral glucose metabolism, dopamine, or SERT availability as predictors. Patients showed significant cognitive deficits, significantly decreased striatal dopamine and midbrain SERT availability, and significantly reduced glucose metabolism in the limbic association cortex, and in the frontal, parietal, and superior temporal cortices, all of which correlated with dopamine transporter availability and psychometric results. Thus, the study provides further evidence of central nervous system affection in HCV-afflicted patients with neuropsychiatric symptoms. Data indicate alteration of dopaminergic neurotransmission as a possible mechanism of cognitive decline.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 06/2011; 31(11):2199-208. · 5.46 Impact Factor
-
Hans Worthmann,
Tibor Kempf,
Christian Widera,
Anita B Tryc, Annemarie Goldbecker,
Yue T Ma,
Milani Deb,
Argyro Tountopoulou,
Jürgen Lambrecht,
Meike Heeren,
Ralf Lichtinghagen,
Kai C Wollert,
Karin Weissenborn
[show abstract]
[hide abstract]
ABSTRACT: Growth differentiation factor 15 (GDF-15) is a stress-responsive cytokine that is induced after experimental brain injury. We hypothesized that the circulating levels of GDF-15 are increased and associated with neurological outcome in patients with ischemic stroke.
Serial blood samples were obtained between 6 h and 7 days after symptom onset in 57 consecutive patients with acute ischemic stroke (n = 51) or transient ischemic attack (n = 6). GDF-15 was measured by immunoradiometric assay. Neurological outcome using the modified Rankin Scale (mRS) at 7 and 90 days was classified as favorable (mRS 0 or 1) or unfavorable (mRS >1).
Six hours after symptom onset, GDF-15 levels were abnormally high (>1,200 ng/l) in 68% of the patients. They declined by 8% over the course of 7 days (p < 0.001). GDF-15 levels were correlated with the circulating levels of the inflammatory marker interleukin-6 and the glial protein S100 calcium binding protein B, and with carotid intima-media thickness. Ischemic stroke patients with an mRS score >1 at 7 or 90 days had higher circulating levels of GDF-15 at all preceding sampling time points compared to patients with an mRS score of 0 or 1 (p ≤ 0.002). Similarly, in a logistic regression analysis, GDF-15 levels measured between 6 h and 7 days after symptom onset were associated with mRS at 7 and 90 days.
These data show for the first time that the circulating levels of GDF-15 are elevated and associated with neurological outcome in patients with ischemic stroke.
Cerebrovascular Diseases 05/2011; 32(1):72-8. · 2.72 Impact Factor
-
Hans Worthmann,
Shufen Chen,
Jens Martens-Lobenhoffer,
Na Li,
Milani Deb,
Anita Blanka Tryc, Annemarie Goldbecker,
Qiang Dong,
Jan Thomas Kielstein,
Stefanie Margarethe Bode-Böger,
Karin Weissenborn
[show abstract]
[hide abstract]
ABSTRACT: 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.
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.
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.
An increase of both ADMA and SDMA plasma levels within the first 72 hours after the onset of ischemic stroke predicts a poor outcome.
Journal of atherosclerosis and thrombosis 05/2011; 18(9):753-61. · 2.69 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Journal of Neuro-Oncology 05/2011; 103(1):163-6. · 3.21 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
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.
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.
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.
Nephrology Dialysis Transplantation 01/2011; 26(8):2635-41. · 3.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We report the case of a 50-year-old female patient with non-active sarcoidosis and no kind of immunosuppression, admitted to our hospital because of increasing confusion and focal neurological deficits. Initially a tumor, herpes encephalitis, or neurosarcoidosis were suspected, but surprisingly biopsy revealed progressive multifocal leukoencephalopathy, additionally confirmed by JC-positive PCR in cerebrospinal fluid. Cases of sarcoidosis and progressive multifocal leukoencephalopathy have been reported before. This is the first case of a patient with no sign of active sarcoidosis and without immunosuppressive therapy who recovered spontaneously with a follow-up time of nearly 3 years.
International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 09/2010; 14 Suppl 3:e313-6. · 2.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Increased blood-brain barrier (BBB) permeability for ammonia is considered to be an integral part of the pathophysiology of hepatic encephalopathy (HE) in patients with liver cirrhosis. Increased glutamate-/glutamine-signal intensity in magnetic resonance spectroscopic studies of the brain in cirrhotic patients was explained as a consequence of increased cerebral ammonia uptake. As similar spectroscopic alterations are present in patients with liver fibrosis, we hypothesized that BBB permeability for ammonia is already increased in liver fibrosis, and thereby contributing to the development of HE. To test this hypothesis, cerebral perfusion and ammonia metabolism were examined through positron emission tomography with (15)O-water, respectively, (13)N-ammonia in patients with Ishak grades 2 and 4 fibrosis, cirrhosis, and healthy controls. There were neither global nor regional differences of cerebral blood flow, the rate constant of unidirectional transport of ammonia from blood into brain tissue, the permeability surface area product of the BBB for ammonia, the net metabolic clearance rate constant of ammonia from blood into glutamine in brain, or the metabolic rate of ammonia. The hypothesis that increased permeability of the BBB for ammonia in patients with liver fibrosis contributes to the later development of HE could not be supported by this study.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 03/2010; 30(7):1384-93. · 5.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Metabolic Brain Disease 02/2009; 24(1):197-210. · 2.20 Impact Factor
