Browsing by Author "Schmidt, H."

Neurological manifestations in Whipple's disease are highly variable and tend to occur at later stages of the disease. However, isolated, focal neurological symptoms are reported to be rare. Here we describe the successful treatment of a case of cerebral Whipple's disease initially presenting solely with isolated myoclonic jerks of the left hand and forearm evolving to a segmental myoclonus at a later stage. Additionally, we present - to our knowledge - a novel treatment by administration of immunomodulatory therapy (IVIg) in addition to established antibiotics.

Primary central nervous system (pCNS) posttransplant lymphoproliferative disorder (PTLD) is a complication of solid organ transplantation characterized by poor outcome. In contrast to systemic PTLD, Epstein-Barr virus (EBV)-association of pCNS PTLD is almost universal, yet viral and cellular data are limited. To identify differences in the pattern of EBV-association of pCNS and systemic PTLD, we analyzed the expression of latent and lytic EBV transcripts and the viral and cellular microRNAome in nine pCNS (eight EBV-associated) and in 16 systemic PTLD samples (eight EBV-associated). Notably although 15/16 EBV-associated samples exhibited a viral type III latency pattern, lytic transcripts were also strongly expressed. Members of the ebv-miR-BHRF1 and ebv-miR-BART clusters were expressed in virtually all EBV-associated PTLD samples. There were 28 cellular microRNAs differentially expressed between systemic and pCNS PTLD. pCNS PTLD expressed lower hsa-miR-199a-5p/3p and hsa-miR-143/145 (implicated in nuclear factor kappa beta and c-myc signaling) as compared to systemic PTLD. Unsupervised nonhierarchical clustering of the viral and cellular microRNAome distinguished non-EBV-associated from EBV-associated samples and identified a separate group of EBV-associated pCNS PTLD that displayed reduced levels of B cell lymphoma associated oncomiRs such as hsa-miR-155, -21, -221 and the hsa-miR-17-92 cluster. EBV has a major impact on viral and cellular microRNA expression in EBV-associated pCNS PTLD. The microRNA expression profile of primary central nervous system posttransplant lymphoproliferative disorders that develop in solid organ transplant recipients significantly differs from its systemic counterparts, suggesting that both entities result from distinct pathogenic mechanisms.

The human MDM2 oncogene, well known as the tumor suppressor gene p53's partner, plays an important role in tumorigenesis whether it is dependent on or independent of TP53. In this study, we investigated in a PCR-sequencing analysis the exon 11 of the human MDM2 gene for gene alterations. A MboII polymorphism occurs in 8% of normal blood donors (8 out of 100 probands) and in 13% of the soft tissue sarcoma patients (11 out of 82 patients). Of note was that two STS patients carried the gene alteration only in the tumor specimens heterozygously but not in normal tissue. In a Kaplan-Meier analysis, patients without the polymorphism, indicated a median survival rate of 57 months, whereas, patients with the polymorphism survived on average only 38 months. We suggest that this polymorphism might be associated with an increased cancer susceptibility. (C) 2000 Elsevier Science B.V. All rights reserved.

A 74-year-old man presented in a pulmonary clinic with symmetrically ascending tetraparesis. Physical and neurophysiological examinations suggested Guillain-Barre syndrome. The patient was treated with an initial course of 7s immunoglobulins without success. His state worsened until he was unable to walk. Severe eosinophilia (41%) was later noted in the differential white blood cell count. Combined with the onset of asthma-like symptoms, this prompted us to suspect Churg-Strauss syndrome. Despite treatment with high-dose corticoids, the palsy did not improve. It was only after immunosuppression with cyclophosphamide that the patient began to recover. The subgroup of necrotising vasculitides must be considered as differential diagnosis of rapidly progressive, symmetrical neuropathy with ascending course. Early identification and treatment are essential, since early immunosuppressive therapy is often successful, whereas delayed initiation of treatment may lead to a fatal outcome.

Dihydrocodeine is metabolized to dihydromorphine, dihydrocodeine-6-O-, dihydromorphine-3-O- and dihydromorphine-6-O-glucuronide, and nordihydrocodeine. The current study was conducted to evaluate the affinities of dihydrocodeine and its metabolites to mu-, delta- and kappa-opioid receptors. Codeine, morphine, d,l-methadone and levomethadone were used as controls. Displacement binding experiments were carried out at the respective opioid receptor types using preparations of guinea pig cerebral cortex and the specific opioid agonists [H-3]DAMGO (g-opioid receptor), [H-3]DPDPE (8-opioid receptor) and [H-3]U69,593 (K-opioid receptor) as radioactive ligands at concentrations of 0.5, 1.0 and 1.0 nmol/l, respectively All substances had their greatest affinity to the mu-opioid receptor. The affinities of dihydromorphine and dihydromorphine-6-O-glucuronide were at least 70 times greater compared with dihydrocodeine (K-i 0.3 mumol/1), whereas the other metabolites yielded lower affinities. For the 6-opioid receptor, the order of affinities was similar with the exception that dihydrocodeine-6-O-glucuronide revealed a doubled affinity in relation to dihydrocodeine (K-i 5.9 mumol/1). In contrast, for the K-opioid receptor, dihydrocodeine-6-O- and dihydromorphine-6-O-glucuronide had clearly lower affinities compared to the respective parent compounds. The affinity of nordihydrocodeine was almost identical to that of dihydrocodeine (K-i 14 mumol/1), whereas dihydromorphine had a 60 times higher affinity. These results suggest that dihydromorphine and its 6-O-glucuronide may provide a relevant contribution to the pharmacological effects of dihydrocodeine. The O-demethylation of dihydrocodeine to dihydromorphine is mediated by the polymorphic cytochrome P450 enzyme CYP2D6, resulting in different metabolic profiles in extensive and poor metabolizers. About 7% of the caucasian population which are CYP2D6 poor metabolizers thus may experience therapeutic failure after standard doses.

Aquaporins facilitate water transport through cell membranes. Due to the localization of AQP1 and AQP4 in the brain, they might contribute to cerebral edema. Our study aimed to determine whether AQP1 and AQP4 can be measured in cerebrospinal fluid (CSF), and whether there is a difference in AQP1 and AQP4 concentration between patients with bacterial meningitis (BM) and healthy controls. AQP1 and AQP4 concentrations in CSF from 35 patients with BM and 27 controls were analyzed using a commercial ELISA. The mean concentration of AQP1 in CSF was significantly elevated in patients with BM (BM: 3.8 +/- 3.4 ng/ml, controls: 0.8 +/- 0.5 ng/ml; p < 0.001). AQP4 had a tendency to be increased, however the difference was not significant (BM: 1.8 +/- 3.1 ng/ml, controls: 0.1 +/- 0.2 ng/ml; p = 0.092). AQP1 and AQP4 in CSF of BM patients were inversely correlated (r = -0.47, p = 0.004). We could not find any other correlation between concentration of AQP1 or AQP4 in CSF and CSF leukocytes, lactate, protein, albumin CSF/serum ratio, age, a prediction score, an outcome score or the Glasgow Coma Scale at admission in patients with BM. Control patients displayed a correlation between AQP1 and the albumin CSF/serum ratio (r = 0.390, p = 0.040). This is the first study that detected AQP1 and AQP4 in CSF. Whether the significant elevation of AQP1 is due to a higher expression and subsequent shedding into CSF or a BM-induced cell damage needs to be determined. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

The chemical composition of the cerebrospinal fluid (CSF) is age-dependent. Routine CSF parameters, the indications for lumbar puncture (LP), and the most frequent complications were retrospectively studied in patients older (n = 167) and younger (n = 36) than 65 years. In the absence of meningeal inflammation, the mean CSF lactate level of patients older than 65 years was slightly but significantly higher than the mean CSF lactate level of younger patients. The lactate level of patients with otherwise normal CSF findings correlated significantly with the age of the patients. In the absence of meningeal inflammation, the CSF-to-serum albumin ratio (Q(Albumin)) was significantly higher in older patients than in younger ones. The most frequent indication for LP, suspected infection of the central nervous system (CNS) (n = 110), was confirmed in 12.7% of patients. The only LP complication documented was headache in two patients. Elevations of Q(Albumin) and CSF lactate levels appear to be nonspecific findings in elderly patients. Suspected infections, the most frequent indication for LP, were confirmed by CSF analysis in more than 10% of patients. The very low complication rate of LP makes it a very valuable tool in the diagnostic routine for older patients with CNS diseases.

Normal pressure hydrocephalus (NPH) is characterised by gait disturbance, urinary incontinence and dementia. Even though dementia is a cardinal symptom of NPH, there is few data available concerning cognitive functioning. The aim of this observational case-control study was to evaluate the use of neuropsychological (NPSY) tests prior and after spinal tap test, which might be helpful for diagnosis, treatment and as a prognostic factor for shunt surgery. 15 patients with NPH and 18 controls were examined with eleven different tests covering all neuropsychological domains on two consecutive days. The second examination in NPH patients was 1 day after a spinal tap of 30-50 ml cerebrospinal fluid. A significant difference between NPH and controls in the change between baseline and 1 day after spinal tap was only observed in MMSE. In the domains of visuo-constructive function and attention, controls performed slightly better at day one compared to baseline, which could be interpreted as a learning effect, but after adjusting for multiple testing none of the P values were significant. In contrast to other reports, the MMSE seems to provide a sensitive evaluation of the response to spinal tap in NPH patients and might therefore be included into the routine work up of NPH patients. All other NPSY tests showed less prominent changes within 1 day after spinal tap.

The diagnosis of Creutzfeldt- Jakob disease (CJD) is still made by exclusion of other dementias. We now evaluated lactate dehydrogenase (LDH) in the cerebrospinal fluid (CSF) as a possible additional diagnostic tool. CSF LDH levels of patients with CJD ( n = 26) were compared with those in other dementias ( n = 28). LDH isoenzymes were determined in a subset ( n = 9). Total LDH and isoenzyme LDH-1 were significantly higher, whereas the fractions of LDH-2 and LDH-3 were significantly lower in CJD patients. We conclude that in addition to established CSF parameters, LDH and its isoenzymes might serve as a further help to discriminate between CJD and other dementias. Copyright (C) 2004 S. Karger AG, Basel.

BACKGROUND AND PURPOSE: The structural basis of cognitive sequelae after bacterial meningitis in humans is still poorly understood. In animal models and human autopsy cases, neuronal apoptosis of the hippocampal formation in particular seems to play an important role. Here, we aimed to analyze if BM entails MR imaging structural consequences in humans in vivo. MATERIALS AND METHODS: We applied voxel-based morphometry in a cohort of BM survivors with normal conventional MR imaging after resolution of the acute inflammation to assess morphologic differences. RESULTS: We found clear gray matter volume loss in the limbic system including the hippocampal formation, thalamus, and cingulate gyri bilaterally as well as in the temporal lobe. These results were corroborated by an alternative atlas-based method. CONCLUSIONS: Even in patients with normal routine MR imaging results, clear-cut gray matter atrophy with a mesial temporal/limbic pattern was evident. The anatomic distribution is compatible with the neuropsychological deficit commonly observed in patients after BM. The similarity of the observed atrophy may point to causal link between BM and mesial temporal epilepsy.

High factor VIII (FVIII) levels are known to be a risk factor for deep venous thrombosis, but the mechanisms responsible for high FVIII levels remain unclear. Here, a new phenotype "FVIII level residuum" (FVIII-R) was defined in order to eliminate the impact of common determinants on FVIII levels. We studied 13 families of patients with thrombosis and reproducibly high FVIII levels of unknown origin. Since familial clustering was evident, we looked for a possible genetic basis. A genome scan was performed with 402 evenly spaced microsatellite markers. A quantitative linkage analysis using variance component methods showed suggestive evidence for linkage of FVIII-R with a locus on chromosome 8 (logarithm of odds [LOD] = 2.1). In addition, we performed parametric exploratory linkage analysis of dichotomized FVIII-R, taking a parent-of-origin effect into account. Single-trait-locus MOD-score analysis showed suggestive evidence for linkage under an imprinting model at chromosomes 5 and 11. Furthermore, a 2-traitlocus analysis under a multiplicative model for the loci of chromosomes 5 and 11 yielded a remarkable LOD of 4.44. It confirmed the finding of paternal imprinting, obtained by sing le-trait-locus analysis, at both loci. Our results suggest that high FVIII levels in venous thromboembolism represent a complex trait caused by several genetic factors.

Objective: Neurogenesis is increased in experimental models of bacterial meningitis. In this study, neurogenesis was examined after bacterial infection of the CNS, and after stroke and brain trauma in humans. Methods: Brain sections of patients after death from bacterial meningitis, stroke, or brain trauma and from autopsy cases after death from nonneurologic diseases were investigated by immunohistochemistry. Results: In the dentate gyrus, the density of proliferating cellular nuclear antigen-expressing cells was higher after bacterial meningitis compared to the control group (p = 0.0075). Furthermore, the number of cells expressing the immature neuronal marker proteins TUC-4 and doublecortin were increased in brain sections of patients after death from meningitis compared to control cases (p = 0.0067 and p = 0.045). After stroke and brain trauma, higher densities of proliferating cells were observed (p = 0.031 and p = 0.018), while an increase of TUC-4-expressing cells was detected after stroke only (p = 0.0012 and p = 0.47). Conclusions: The increased proliferation of neural progenitors suggests an endogenous mechanism in response to noxious stimuli. Stimulation of neurogenesis might help to alleviate the consequences of neuronal destruction in bacterial meningitis and other diseases of the brain. Neurology (R) 2009;73:1026-1032