Thomas Berger

Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain

About 30% of patients with chronic upper motor neuron syndrome (UMNS) suffer from disabling spasticity-related pain not sufficiently correctable by conventional treatment. Delta9-tetrahydrocannabinol (Δ9-THC) was reported to add benefit in the treatment of pain in patients with multiple sclerosis (MS). The question arose whether synthetic cannabinoids with lower potential for psychotropic side effects could be effective as well. To evaluate the safety and efficacy of low dose treatment with the synthetic cannabinoid Nabilone (1xa0mg per day) on spasticity-related pain a placebo-controlled double-blind crossover trial was performed.11 out of 13 included patients completed the study. The 11-Point-Box-Test showed a significant decrease of pain under Nabilone (pxa0<xa00.05), while spasticity, motor function and activities of daily living did not change. 5 patients reported side effects: one moderate transient weakness of the lower limbs (Nabilone phase, drop out), three mild drowsiness (two Nabilone, one placebo) and one mild dysphagia (placebo). One patient was excluded from the study due to an acute relapse of multiple sclerosis (Nabilone phase, drop out).Nabilone 1xa0mg per day proved to be a safe and easily applicable option in the care of patients with chronic UMNS and spasticity-related pain otherwise not controllable.

Serum and cerebrospinal fluid antibodies to Nogo-A in patients with multiple sclerosis and acute neurological disorders

Nogo-A is a protein associated with central nervous system (CNS) myelin thought to impair regenerative responses and to suppress sprouting and plastic changes of synaptic terminals. In this study, we report that serum IgM autoantibodies to the recombinant large N-terminal inhibitory domain of Nogo-A are a frequent finding in multiple sclerosis (MS) and acute inflammatory (IND) and non-inflammatory neurological diseases (OND), but not in neurodegenerative diseases (ND), systemic inflammatory disease and healthy controls. Furthermore, we demonstrate intrathecal production of anti-Nogo-A antibodies measured by increased IgG indices. Intrathecal anti-Nogo antibodies were significantly more frequent in patients with relapsing-remitting as compared to chronic progressive (CP) MS. We also found a highly significant negative correlation of these antibody responses with age indicating that they are more frequent in younger patients. We finally demonstrate that human anti-Nogo-A antibodies recognize native Nogo-A in brain extracts, oligodendrocytes and cells expressing human Nogo-A.

Increased intrathecal production of apolipoprotein D in multiple sclerosis.

Apolipoprotein D (apoD) is a small glycoprotein responsible for the local transport of small hydrophobic ligands. Within the nervous system, apoD may be an acute phase protein that is upregulated in a variety of neuropathological conditions and is involved in the removal of lipids during nerve cell degeneration and provision of lipids during the regenerative phase. In this study, we measured cerebrospinal fluid (CSF) and serum apoD levels in patients with multiple sclerosis (MS), chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barré Syndrome (GBS), infectious inflammatory neurological diseases (IND) and non-inflammatory neurological diseases (NND). We found that mean CSF apoD levels are significantly increased in patients with CIDP/GBS reflecting an acute blood-nerve barrier leakage. In contrast, MS is characterized by an increased intrathecal apoD release as measured by the apoD index. Thus, the results of our study provide the first evidence of an increased intrathecal production of apoD in MS. Moreover, we demonstrate that mean apoD indices are highest in MS patients at the time of their first clinical exacerbation. CSF apoD levels and apoD indices correlate with MS disease duration but not with disability or age. Finally, we found that corticosteroid treatment resulted in significantly elevated CSF apoD levels.

A critical comparison of frequently used methods for the analysis of tumor necrosis factor-α expression by human immune cells

A variety of methods have been developed for the measurement of tumor necrosis factor (TNF)-alpha synthesis by immune cells. Here we have compared the results of the most common used methods, including in vitro stimulation of whole blood or peripheral blood mononuclear cell (PBMC) cultures with phytohaemagglutinin (PHA) or lipopolysaccharide (LPS) and RT-PCR analysis of TNF-alpha transcription in unstimulated PBMC. When we used EDTA treated blood samples we observed a significant correlation between the PHA and LPS stimulated TNF-alpha responses in whole blood or PBMC cultures. In contrast, TNF-alpha concentrations obtained from PHA and LPS stimulated whole blood cultures from citrate-treated blood did not show a correlation. We also found that the PHA stimulated TNF-alpha response was significantly higher in PBMC than in whole blood cultures, whereas the highest LPS stimulated TNF-alpha response was observed in citrate-treated blood. Moreover, the TNF-alpha response in both, citrate and EDTA treated whole blood cultures was significantly higher after LPS than after PHA stimulation. In contrast, in PBMC cultures the PHA stimulated TNF-alpha response was significantly higher than the LPS stimulated response. The results of RT-PCR analysis revealed a significant correlation with the PHA stimulated TNF-alpha response, both in whole blood assays and in PBMC cultures. In addition our results demonstrate that these different methods can only be compared when the influence of external factors such as the immediate processing of blood samples or the use of an appropriate anticoagulant and stimulant is considered.

Comparison of the Specificity of Implantable Dual Chamber Defibrillator Detection Algorithms

The aim of the study was to compare the specificity of dual chamber ICDs detection algorithms for correct classification of supraventricular tachyarrhythmias derived from clinical studies according to their size to detect an impact of sample size on the specificity. Furthermore, the study sought to compare the specificities of detection algorithms calculated from clinical data with the specificity calculated from simulations of tachyarrhythmias. A survey was conducted of all available sources providing data regarding the specificity of five dual chamber ICDs. The specificity was correlated with the number of patients included, number of episodes, and number of supraventricular tachyarrhythmias recorded. The simulation was performed using tachyarrhythmias recorded in the electrophysiology laboratory. The range of the number of patients included into the studies was 78–1,029, the range of the total number of episodes recorded was 362–5,788, and the range of the number of supraventricular tachyarrhythmias used for calculation of the specificity for correct detection of these arrhythmias was 100 (Biotronik) to 1662 (Medtronic). The specificity for correct detection of supraventricular tachyarrhythmias was 90% (Biotronik), 89% (ELA Medical), 89% (Guidant), 68% (Medtronic), and 76% (St. Jude Medical). There was an inverse correlation (r =−0.9, P = 0.037) between the specificity for correct classification of supraventricular tachyarrhythmias and the number of patients. The specificity for correct detection of supraventricular tachyarrhythmias calculated from the simulation after correction for the clinical prevalence of the simulated tachyarrhythmias was 95% (Biotronik), 99% (ELA Medical), 94% (Guidant), 93% (Medtronic), and 92% (St. Jude Medical). In conclusion, the specificity of ICD detection algorithms calculated from clinical studies or registries may depend on the number of patients studied. Therefore, a direct comparison between different detection algorithms based on clinical data is difficult. In contrast, simulation of supraventricular tachyarrhythmias using a uniform database may be a better tool for direct comparison of the specificity of ICD detection algorithms. (PACE 2004; 27:976–982)

Serial contrast-enhanced magnetic resonance imaging and spectroscopic imaging of acute multiple sclerosis lesions under high-dose methylprednisolone therapy

To evaluate biochemical changes in contrast-enhancing multiple sclerosis (MS) lesions, we examined 14 patients with relapsing-remitting MS at acute clinical exacerbation with the help of contrast-enhanced magnetic resonance imaging (MRI) and 1H magnetic resonance spectroscopic imaging (1H MRSI). Using a 1.5-tesla MR system (Magnetom Vision, Siemens, Germany), we followed 29 contrast-enhancing and 24 nonenhancing MS lesions as well as normal-appearing white matter (NAWM) before and during high-dose methylprednisolone (HDMP) therapy. Metabolite ratios of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and lactate (Lac) were calculated. A transient decrease in contrast enhancement under HDMP therapy was observed. Both groups of MS lesions showed significantly decreased NAA to Cr ratios compared to NAWM with no changes in time. Baseline 1H MRSI revealed significantly increased Cho to Cr ratios in the contrast-enhancing MS lesions (1.13 +/- 0.25) compared to the nonenhancing MS lesions (0.85 +/- 0.26, P < 0.001) and NAWM (0.97 +/- 0.22, P = 0.015). Both the contrast-enhancing and the nonenhancing MS lesions exhibited a significant increase in Cho to Cr ratios from the second to the third 1H MRSI. We identified resonances of lactate in both groups of MS lesions and NAWM without any significant group differences or changes over time. 1H MRSI provides additional information that help to estimate macrophages activity, cell membrane activation, and neuronal impairment within MS lesions. We believe that combined contrast-enhanced MRI and 1H MRSI may help to further investigate inflammatory processes within active MS lesions and should be employed more frequently to the research on therapy effects in MS.

Antibody response to myelin oligodendrocyte glycoprotein and myelin basic protein depend on familial background and are partially associated with human leukocyte antigen alleles in multiplex families and sporadic multiple sclerosis

We investigated the association of the antibody response to myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) with human leukocyte antigen (HLA) class II alleles in 41 patients with sporadic multiple sclerosis (MS) and 12 multiplex MS families. We found significantly increased antibody response to MOG and MBP in MS patients without any difference to asymptomatic relatives. HLA DRB1*04 was associated with IgM reactivity to MOG in MS patients, and DRB1*15 and DRB5 with anti-MOG IgA among asymptomatic relatives. We conclude that antibody responses to MOG and MBP depend on familial background. Moreover, the humoral immune reactivity against MOG is partially under control of certain HLA class II alleles.

Autoimmunity and inflammation in the peripheral nervous system

Peripheral Nerve Society Biennial Meeting, organized in conjunction with the Austrian Federal Ministry of Education, Research and Culture, held at Telfs, Tyrol, Austria from 8-12 September 2001.

Biomarkers in Multiple Sclerosis: Role of Antibodies

The first international workshop on “Biomarkers in Multiple Sclerosis” was organized by B. Bielekova, R. Hohlfeld, R. Martin and U. Utz from April 14–16, 2004, in Washington, DC. The workshop intended to discuss the current status and potential applicability of biological markers for the understanding of the pathogenesis, diagnosis, and therapy of multiple sclerosis. The present review summarizes the presentation on the potential role of antibodies as biomarkers for diagnosis, disease activity, classification and prediction of clinical courses in multiple sclerosis.

Emergence of antibodies as biomarkers in multiple sclerosis

Rather than being a homogenous disease entity, multiple sclerosis (MS) represents a family of heterogenous inflammatory-demyelinating CNS diseases. The heterogeneity is demonstrated by various well known clinical disease courses and, more importantly, by inhomogenous and unpredictable therapeutic effects. Recent neuropathological evidence has initiated a process of re-evaluation of the immunopathogenetic concepts in MS. The heterogeneity of MS claims to subtype our patients more distinctively in the future by genetic, clinical, neuroradiological and neuroimmunological parameters. Therefore, the importance of identifiying biological markers in MS has evolved over the pastxa0few years. This review discusses the current status and potential applicability of antibodies as biological markers for the diagnosis, classification, disease activity and prediction of clinical courses in MS. Antibodies serving as biomarkers will create the future path for establishing a differential therapeutic concept in MS, which will...