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ABSTRACT: Cerebrospinal fluid (CSF) analysis is of utmost importance to establish an early diagnosis of central nervous system (CNS) infections and to start appropriate therapy. The CSF white cell count, lactate concentration and total protein levels are usually available very quickly even from non-specialized laboratories and the combination of these parameters often provides sufficient information for decision-making in emergency cases. It is, however, not always possible to identify the underlying infective agent despite further CSF analyses, such as bacterial and fungal staining, evaluation of the blood-CSF barrier function, intrathecal immunoglobulin synthesis and oligoclonal IgG bands. Therefore, close communication between the laboratory and the clinician is an important prerequisite to specify additional pathogen-related diagnostic measures for successful confirmation of the diagnosis.
Der Nervenarzt 02/2013; · 0.68 Impact Factor
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Der Nervenarzt 05/2012; 80:30-31. · 0.68 Impact Factor
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ABSTRACT: Die Diagnostik CT-negativer Subarachnoidalblutungen (SAB) stellt eine besondere klinische Herausforderung dar. Die Lumbalpunktion
mit Liquordiagnostik ist hierbei die diagnostische Methode der Wahl. Die Diagnose einer SAB basiert neben dem visuellen Nachweis
eines blutigen bzw. xanthochrom verfärbten Liquors auf der Liquorzytologie mit dem Nachweis von Erythrophagen und Siderophagen.
Andere hierzu komplementäre Untersuchungen wie ein Nachweis eines erhöhten Ferritinspiegels oder ein spektrophotometrischer
Nachweis einer visuell nicht sichtbaren Xanthochromie sind im Rahmen des klinischen Gesamtbildes sinnvoll. Allgemein ist eine
genaue Kenntnis des zeitlichen Ablaufs der Liquorveränderungen nach SAB notwendig, um die Wertigkeit der einzelnen Liquorveränderungen
richtig einordnen zu können.
The diagnostic investigation of CT-negative subarachnoid haemorrhage (SAH) is a particular challenge in clinical neurology.
Cerebrospinal fluid (CSF) analysis via lumbar puncture is the method of choice. The diagnosis of SAH in CSF is based on a
bloody or xanthochromic discoloration of the CSF as well as on findings in non-automated CSF cytology including the detection
of erythrophages and siderophages. The automated determination of CSF ferritin concentrations or spectrophotometric detection
of xanthochromia may contribute to the diagnosis but are only useful with regard to the overall clinical picture. Generally,
the knowledge of the time flow of CSF changes associated with SAH is essential for a correct interpretation of CSF findings.
SchlüsselwörterSubarachnoidalblutung-Liquor cerebrospinalis-Xanthochromie-Zytologie-Ferritin-Spektrophotometrie
KeywordsSubarachnoid haemorrhage-Cerebrospinal fluid-Xanthochromia-Cytology-Ferritin-Spectrophotometry
Der Nervenarzt 04/2012; 81(8):973-979. · 0.68 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The diagnostic investigation of CT-negative subarachnoid haemorrhage (SAH) is a particular challenge in clinical neurology. Cerebrospinal fluid (CSF) analysis via lumbar puncture is the method of choice. The diagnosis of SAH in CSF is based on a bloody or xanthochromic discoloration of the CSF as well as on findings in non-automated CSF cytology including the detection of erythrophages and siderophages. The automated determination of CSF ferritin concentrations or spectrophotometric detection of xanthochromia may contribute to the diagnosis but are only useful with regard to the overall clinical picture. Generally, the knowledge of the time flow of CSF changes associated with SAH is essential for a correct interpretation of CSF findings.
Der Nervenarzt 08/2010; 81(8):973-9. · 0.68 Impact Factor
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ABSTRACT: In neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), CSF biomarkers are increasingly studied to evaluate their relevance for differential diagnosis, disease progression, and understanding of pathophysiologic processes.
To identify a biomarker profile of neuronal and glial CSF proteins to discriminate ALS from other motor neuron diseases (MND) and to assess whether baseline levels of CSF measures in ALS are associated with the course of the disease.
A total of 122 consecutive subjects with MND were included in this cross-sectional study (ALS, n = 75; lower motor neuron syndrome, n = 39; upper motor neuron diseases, n = 8). Clinical follow-up included 76 patients. We determined baseline levels of protein tau and astroglial S100beta in CSF and microglial sCD14 in CSF and serum in relation to diagnosis, duration of disease, and survival.
CSF tau was significantly elevated in ALS and upper motor neuron diseases as compared to lower motor neuron diseases and controls. CSF S100beta levels were significantly lower in lower motor neuron diseases as compared to other MND. CSF concentrations of S100beta and sCD14 correlated with the survival time in patients with ALS.
In motor neuron diseases, CSF tau elevation indicates the degeneration of upper motor neurons, while S100 beta and sCD14 may indicate the activation of CNS glial cells. Because S100beta and sCD14 concentrations correlate with survival in amyotrophic lateral sclerosis (ALS), we suppose that the combination of both markers may be useful to obtain prognostic information in patients with ALS.
Neurology 03/2010; 74(12):982-7. · 8.31 Impact Factor
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A Petzold,
M D Chapman,
S Schraen,
N A Verwey,
F Pasquier,
S Bombois, J Brettschneider,
N C Fox,
C A F von Arnim,
C Teunissen,
Y Pijnenburg,
M W Riepe,
M Otto,
H Tumani,
P Scheltens,
L Buee,
M N Rossor
[show abstract]
[hide abstract]
ABSTRACT: Newly proposed diagnostic criteria for Alzheimer's disease include cerebrospinal fluid (CSF) tau levels as one core supportive criterion. The published high sensitivity and specificity figures for CSF tau levels in Alzheimer's disease are offset by the large range of proposed cutoff values (9.6 pg/mL to 1140 pg/mL). This study aimed to provide guidance on how to establish, validate and audit CSF tau cutoff values using an unbiased, two-stage multicentre strategy. Both receiver operator characteristics (ROC) optimised and population-based cutoff values were calculated on a pilot dataset (n=99), validated in a large dataset (n=560) and then compared to the literature. The data suggest using an ROC optimised cutoff level of 323+/-51.7 pg/mL allowing for the published inter-laboratory coefficient of variation of 16%. This cutoff level was confirmed in a prospective audit (n=100). As demand for CSF tau levels will increase globally, the accuracy of local CSF hTau cutoff levels can be compared against this benchmark.
Experimental Neurology 12/2009; 223(2):432-8. · 4.70 Impact Factor
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ABSTRACT: Early predictors of prognosis in Guillain-Barré syndrome (GBS) are needed to identify patients who are likely to make a poor recovery and to guide therapeutic decision-making in the acute phase. Here we investigate whether axonal protein biomarkers released into the cerebrospinal fluid (CSF) following proximal axonal damage improve the early prognostic accuracy in GBS. A prospective multicenter study including 132 patients (38 GBS, 38 neurological controls, 42 headaches, 14 chronic inflammatory demyelinating neuropathy). CSF levels of axonal [neurofilament (NfH) and tau] and glial (S100B and glial fibrillary acidic protein) protein biomarkers were measured on admission. Nerve conduction studies were performed at the time of lumbar puncture and patients were classified according to neurophysiological criteria. Outcome was assessed on the Hughes functional score (F-score). Poor outcome was defined as the inability to walk independently (F-score > or = 3). High NfH levels (>0.73 ng/ml) predicted poor outcome (P = 0.01) with an odds ratio of 7.3 and correlated with the outcome F-score (R = 0.51, P < 0.01), as did hTau levels (R = 0.47, P < 0.01). Patients with poor outcome had significantly higher CSF NfH (median 1.78 ng/ml) when compared to those with good outcome (0.03 ng/ml) or all of the control groups (neurological controls 0.18 ng/ml, headaches 0.06 ng/ml, chronic inflammatory demyelinating neuropathy 0.05 ng/ml). Except for age (P < 0.05) and need for ventilatory support (P < 0.05), none of the other features reliably predicted outcome. Improved prognostic accuracy in the acute phase of GBS seems possible using CSF NfH levels.
Muscle & Nerve 07/2009; 40(1):42-9. · 2.37 Impact Factor
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H Tumani,
V Lehmensiek,
D Rau,
I Guttmann,
G Tauscher,
H Mogel,
C Palm,
V Hirt,
S D Suessmuth,
I Sapunova-Meier,
A C Ludolph, J Brettschneider
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ABSTRACT: Cerebrospinal fluid (CSF) is a promising source of biomarkers in clinically isolated syndrome (CIS), which frequently presents as a first episode of multiple sclerosis (MS). Using the two-dimensional difference in gel electrophoresis (2-D DIGE), we compared CSF samples from patients with CIS that remained CIS (CIS-CIS, n=8) over a follow-up time of 2 years and from patients with CIS that developed definite MS of the relapsing-remitting subtype (CIS-RRMS, n=8) over the same period. Protein spots that showed significant differences between patients and controls were selected for further analysis by MALDI-TOF mass spectrometry. For validation of identified spots ELISA experiments were performed. We identified one protein that was upregulated in CIS-RRMS (serin peptidase inhibitor) and eight proteins (alpha-1-B-glycoprotein, Fetuin-A, apolipoprotein A4, haptoglobin, human Zinc-alpha-2-glycoprotein (ZAG), Retinol-binding protein, superoxid dismutase 1, transferrin) that were down-regulated in CIS-RRMS vs. CIS-CIS. For Fetuin-A, our findings could be confirmed by ELISA. The pathophysiological role as well as clinical relevance of these candidate proteins in CIS remains to be further clarified by future studies.
Neuroscience Letters 04/2009; 452(2):214-7. · 2.11 Impact Factor
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ABSTRACT: Amnestic Mild Cognitive Impairment (MCI) is a condition with an increased risk for developing Alzheimer's disease (AD). Presently, gender differences are neglected in the assessment of MCI and AD.
We examined verbal and visuospatial episodic memory in 143 subjects diagnosed as healthy controls (HC; N = 48, Mini-Mental State Examination (MMSE) 29.2 +/- 1.0 (mean +/- standard deviation)), MCI (N = 43,MMSE 28.5 +/- 1.4), and AD (N = 49, MMSE 25.1 +/- 2.2).
Female HC and MCI subjects performed better on verbal episodic memory tasks than males. In contrast, visuospatial episodic memory was better in male than female AD patients.
We interpret the results in light of a gender-specific cognitive reserve and conclude that the gender-specificity of neuropsychological performance needs to be accounted for in clinical diagnosis of Alzheimer's disease.
Journal of Neurology 02/2008; 255(1):117-22. · 3.47 Impact Factor
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ABSTRACT: Cerebrospinal fluid (CSF) proteins may provide important information about the pathomechanisms present in multiple sclerosis (MS). Although diagnostic criteria for early MS are available, there is still a need for biomarkers, predicting disease subtype and progression to improve individually tailored treatment. Using the two-dimensional difference gel electrophoresis (2-D-DIGE) technology for comparative analysis, we compared CSF samples from patients with MS of the relapse-remitting type (RRMS, n = 12) and from patients with clinically isolated syndrome (CIS, n = 12) suggestive of a first demyelinating attack with neurologically normal controls. Protein spots that showed more than two-fold difference between patients and controls were selected for further analysis with MALDI-TOF mass spectrometry. Immunoblot analysis was performed to confirm the validity of individual candidate proteins. In RRMS, we identified 1 up-regulated and 10 down-regulated proteins. In CIS, 2 up-regulated and 11 down-regulated proteins were identified. One of these proteins (Apolipoprotein A1) was confirmed by immunoblot. Though the pathophysiological role of these proteins still remains to be elucidated in detail and further validation is needed, these findings may have a relevant impact on the identification of disease-specific markers.
Multiple Sclerosis 09/2007; 13(7):840-9. · 4.26 Impact Factor
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ABSTRACT: We used two-dimensional difference in-gel electrophoresis (2-D-DIGE) for proteome analysis of cerebrospinal fluid (CSF) in Guillain-Barré syndrome (GBS). Spots showing >2-fold difference between GBS and controls were analysed using MALDI-TOF mass spectrometry. Proteins that were up-regulated in GBS included haptoglobin, serine/threonine kinase 10, alpha-1-antitrypsin, SNC73, alpha II spectrin, IgG kappa chain and cathepsin D preprotein, while transferrin, caldesmon, GALT, human heat shock protein 70, amyloidosis patient HL-heart-peptide 127aa and transthyretin were down-regulated. Some of these proteins are reported in CSF of GBS for the first time. Accordingly, the 2-D-DIGE technology may be useful to identify disease-specific proteins in patients with GBS.
Journal of Neuroimmunology 05/2007; 185(1-2):190-4. · 2.96 Impact Factor
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ABSTRACT: Clinically isolated syndrome (CIS) represents the earliest phase of multiple sclerosis (MS). This study tested whether biomarkers for axonal degeneration can improve upon sensitivity and specificity of magnetic resonance imaging (MRI) parameters in predicting conversion from CIS to MS. Patients with CIS (n = 52), relapsing-remitting MS (RRMS, n = 38) and age-matched controls (n = 25) were included. Cerebrospinal fluid (CSF) levels of tau and neurofilaments (NfHSMI35) were measured using ELISA. The MRI T2-lesion load and the Expanded Disability Status Scale (EDSS) were recorded. CSF tau and NfHSMI35 were elevated in CIS compared to controls (P<0.05). RRMS patients with acute relapse had higher NfHSMI35 levels than stable patients. Tau and NfHSMI35 levels correlated with EDSS in CIS and RRMS. In RRMS, the number of T2-lesions correlated with tau levels (R = 0.53, P = 0.01). The sensitivity predicting the conversion from CIS to MS was higher for the combination of CSF markers (either tau or NfHSMI35 elevated) than for MRI (40 versus 34%), but could be further increased to 60% if CSF and MRI criteria were combined. Similarly, the combination of tau and NfHSMI35 showed higher specificity (94%) than MRI (82%). Tau and NfHSMI35 are valuable biomarkers for axonal damage in the CIS patients. Predicting conversion from CIS to MS can be improved if CSF markers are combined with MRI.
Multiple Sclerosis 04/2006; 12(2):143-8. · 4.26 Impact Factor
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ABSTRACT: To test whether biomarkers for axonal degeneration correlated with clinical subtypes and were of use in predicting progression of ALS.
Patients with ALS (n = 69), patients with Alzheimer disease (AD; n = 73), and age-matched controls (n = 33) were included in this prospective study. CSF levels of tau protein and neurofilaments (NfHSMI35) were measured using ELISA. In 49 patients with ALS, follow-up data were available (median follow-up 7 months).
CSF levels of NfHSMI35 were five times higher in patients with ALS (1.7 ng/mL) than in controls (0.3 ng/mL, p < 0.001) and 10 times higher than in patients with AD (0.14 ng/mL, p < 0.001). NfHSMI35 values were also higher in patients with upper motor neuron-dominant ALS than in patients with typical ALS (upper motor neuron + lower motor neuron) at p = 0.02. Values of NfHSMI35 were higher in ALS of more rapid progression. The values of NfH and tau did not correlate with CSF protein content.
The authors propose that axonal damage markers in CSF may discriminate between subtypes of ALS and that they could be used as markers for therapeutic trials. CSF NfH was superior to tau in these discriminations.
Neurology 03/2006; 66(6):852-6. · 8.31 Impact Factor
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ABSTRACT: An isolated dysfunction of the blood-CSF barrier is characterised by an abnormal elevation of the albumin CSF/serum concentration ratio (Q(alb)) without any other pathological CSF findings. Although common in routine CSF analysis, the clinical significance of an isolated barrier dysfunction frequently remains unclear. We examined neurological disorders associated with an isolated elevation of Q(alb) to identify possible determinants of blood-CSF barrier dysfunction.
367 patients (124 women, 243 men, median age 60. 0 years) out of 3,873 patients receiving diagnostic lumbar puncture at the University Hospital of Ulm (Germany) showed an isolated dysfunction of the blood-CSF barrier. Clinical data as well as MRI findings of these patients were analysed.
Isolated barrier dysfunction occurred most frequently (> 30%) in Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), normal pressure hydrocephalus (NPH), lumbar spinal stenosis, and polyneuropathy (PNP). In patients who showed no other evidence of neurological disease, isolated barrier dysfunction was found in 14. 9% of cases. The extent of barrier dysfunction was most prominent in brain tumours, GBS, and CIDP. There was a significant correlation of Q(alb) with both weight and body mass index (BMI).
Although isolated barrier dysfunction may be found in a variety of neurological diseases, it is especially frequent in GBS, CIDP, NPH, spinal canal stenosis, and PNP. In these patients, disease-related mechanisms contributing to barrier dysfunction are likely. Moreover, barrier function seems to be influenced by disease-independent determinants like weight and BMI.
Journal of Neurology 09/2005; 252(9):1067-73. · 3.47 Impact Factor
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I Uttner,
S Müller,
C Zinser,
M Maier,
S Süssmuth,
A Claus,
B Ostermann,
E Elitok,
D Ecker, J Brettschneider,
R Gold,
H Tumani
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ABSTRACT: Thirty patients with multiple sclerosis were randomized to 500 or 2,000 mg of methylprednisolone (MP) over 5 days. They were prospectively studied neuropsychologically before and at days 6 and 60 after onset of the therapy, using a double-blind study design. Patients showed selective deterioration of declarative memory retrieval at day 6, which was fully reversible at day 60. Although the sample size was small, these effects were independent of the administered MP dose.
Neurology 07/2005; 64(11):1971-3. · 8.31 Impact Factor
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ABSTRACT: Axonal damage has been proposed as the major substrate of permanent clinical disability in multiple sclerosis. Tau protein, a microtubule-associated protein localised in neuronal axons, may serve as a biochemical surrogate marker to evaluate axonal damage in vivo. We intended to determine the extent of axonal damage in different stages and clinical subtypes of MS by investigating cerebrospinal fluid tau concentrations. Tau was measured using an immunoassay in 35 patients with relapsing-remitting MS, eight patients with secondary progressive MS, nine patients with primary progressive MS, 50 patients with clinically isolated syndrome suggestive of early MS and 46 normal controls. Cerebrospinal fluid tau was significantly elevated in MS compared with normal controls (median 206.0 pg/mL versus 152.0 pg/mL; P = 0.002). No significant difference among different subtypes of MS could be detected, although highest levels were found in very early disease stages. There was a significant elevation of CSF tau among patients with gadolinium-enhancing brain lesions in magnetic resonance imaging (P = 0.02) and a tendency towards higher CSF tau levels in patients with pronounced intrathecal IgG synthesis, supporting the notion that axonal damage is influenced by inflammatory activity.
Multiple Sclerosis 07/2005; 11(3):261-5. · 4.26 Impact Factor
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ABSTRACT: In animal models and in vitro studies leptomeninges have been shown to be the origin of neurotrophic substances that support the survival and growth of neuronal cells. Because dementia is associated with neuronal loss, we investigated whether leptomeningeal dysfunction may be involved in the pathogenesis of dementia disorders.
We analysed the cerebrospinal fluid (CSF) concentrations of the leptomeningeal derived beta trace protein, beta2 microglobulin, and cystatin C.
There was a statistically significant difference of the CSF beta trace protein levels among different groups. Patients with idiopathic normal pressure hydrocephalus (NPH) (17.5 (SD 4.3) mg/l) showed significantly lower CSF beta trace protein levels than patients with Alzheimer's disease (23.8 (6.2) mg/l), depression (24.2 (7.3) mg/l), and normal controls (25.3 (4.9) mg/l). To patients with vascular dementia (20.1 (5.6) mg/l) and frontotemporal dementia (21.9 (7.0) mg/l), the difference was not significant. There was no significant difference regarding the CSF and serum concentrations of beta2 microglobulin or cystatin C among the different groups.
We conclude that leptomeningeal dysfunction may be involved in certain types of dementia such as NPH and that reduced CSF beta trace protein levels in patients with NPH may aid in differentiating this difficult to diagnose disorder from other syndromes such as Alzheimer's disease.
Journal of Neurology Neurosurgery & Psychiatry 12/2004; 75(11):1614-6. · 4.76 Impact Factor
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J Brettschneider,
D Ecker,
A Bitsch,
D Bahner,
T Bogumil,
A Dressel,
E Elitok,
B Kitze,
S Poser,
F Weber,
H Tumani
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[hide abstract]
ABSTRACT: The soluble form of the CD14 molecule (sCD14), a macrophage activity marker, was measured in the plasma of 17 patients with primary progressive multiple sclerosis (PPMS) and 20 patients with relapsing remitting MS (RRMS). In patients with PPMS, sCD14 levels were determined before and after treatment with interferon beta (IFNB). In both PPMS and in RRMS, sCD14 levels were significantly elevated compared to healthy controls. In patients with PPMS, sCD14 levels increased significantly during the first 3 months of IFNB therapy, then slightly decreased, but still remained elevated compared with levels before therapy. Therefore, the elevated sCD14 levels may be a marker in evaluating biological response to IFNB therapy.
Journal of Neuroimmunology 01/2003; 133(1-2):193-7. · 2.96 Impact Factor
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A. Petzold,
M.D. Chapman,
S. Schraen,
N.A. Verwey,
F. Pasquier,
S. Bombois, J. Brettschneider,
N.C. Fox,
C.A.F. von Arnim,
C. Teunissen,
Y. Pijnenburg,
M.W. Riepe,
M. Otto,
H. Tumani,
P. Scheltens,
L. Buee,
M.N. Rossor
[show abstract]
[hide abstract]
ABSTRACT: Newly proposed diagnostic criteria for Alzheimer's disease include cerebrospinal fluid (CSF) tau levels as one core supportive criterion. The published high sensitivity and specificity figures for CSF tau levels in Alzheimer's disease are offset by the large range of proposed cutoff values (9.6 pg/mL to 1140 pg/mL). This study aimed to provide guidance on how to establish, validate and audit CSF tau cutoff values using an unbiased, two-stage multicentre strategy. Both receiver operator characteristics (ROC) optimised and population-based cutoff values were calculated on a pilot dataset (n = 99), validated in a large dataset (n = 560) and then compared to the literature. The data suggest using an ROC optimised cutoff level of 323 ± 51.7 pg/mL allowing for the published inter-laboratory coefficient of variation of 16%. This cutoff level was confirmed in a prospective audit (n = 100). As demand for CSF tau levels will increase globally, the accuracy of local CSF hTau cutoff levels can be compared against this benchmark.
Experimental Neurology.
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H. Tumani,
V. Lehmensiek,
D. Rau,
I. Guttmann,
G. Tauscher,
H. Mogel,
C. Palm,
V. Hirt,
S.D. Suessmuth,
I. Sapunova-Meier,
A.C. Ludolph, J. Brettschneider
[show abstract]
[hide abstract]
ABSTRACT: Cerebrospinal fluid (CSF) is a promising source of biomarkers in clinically isolated syndrome (CIS), which frequently presents as a first episode of multiple sclerosis (MS). Using the two-dimensional difference in gel electrophoresis (2-D DIGE), we compared CSF samples from patients with CIS that remained CIS (CIS-CIS, n = 8) over a follow-up time of 2 years and from patients with CIS that developed definite MS of the relapsing-remitting subtype (CIS-RRMS, n = 8) over the same period. Protein spots that showed significant differences between patients and controls were selected for further analysis by MALDI-TOF mass spectrometry. For validation of identified spots ELISA experiments were performed. We identified one protein that was upregulated in CIS-RRMS (serin peptidase inhibitor) and eight proteins (alpha-1-B-glycoprotein, Fetuin-A, apolipoprotein A4, haptoglobin, human Zinc-alpha-2-glycoprotein (ZAG), Retinol-binding protein, superoxid dismutase 1, transferrin) that were down-regulated in CIS-RRMS vs. CIS-CIS. For Fetuin-A, our findings could be confirmed by ELISA. The pathophysiological role as well as clinical relevance of these candidate proteins in CIS remains to be further clarified by future studies.
Neuroscience Letters.
