Paul Bronzlik

Immunoadsorption Therapy for Steroid-Unresponsive Relapses in Patients with Multiple Sclerosis

Background: Therapeutic plasma exchange (TPE) in steroid-unresponsive relapses of patients with multiple sclerosis (MS) is an established therapy with response rates of up to 70%. Immunoadsorption (IA) specifically removes immunoglobulins from the patient’s plasma. It is hypothesized that IA therapy might be better tolerated than and as effective as TPE in the treatment of MS relapses. Experiences with IA therapy of steroid-unresponsive MS relapses are limited. Methods: We report our experiences with IA therapy in a series of 10 patients with steroid-unresponsive MS relapses. Results: A marked to moderate clinical response with clear gain of function was observed in 66% of our patients. IA therapy was well tolerated. Conclusions: IA therapy is an effective and well-tolerated therapeutic option for steroid-unresponsive MS relapses.

Level and localization of polysialic acid is critical for early peripheral nerve regeneration.

PolySia, the most striking post-translational modification of the neural cell adhesion molecule, is down-regulated during postnatal development. After peripheral nerve lesion, polySia is located on neuronal and glial cells normally not synthesizing polySia. However, structural consequences of reduced polySia content for peripheral nerve regeneration have not yet been clear. Furthermore, the contribution of sialyltransferases ST8SiaII and ST8SiaIV for the up-regulation of polySia has not been studied so far. In order to investigate the impact of polySia on regeneration processes of myelinated axons, we examined mouse mutants retaining only one functional sialyltransferase allele. In the absence of ST8SiaII, quantification of myelinated axons revealed a significant decrease in number and size of regenerated fibers without impairment of remyelination. In contrast, St8SiaIV deficiency resulted in increased fiber outgrowth and axonal maturation. Western blot analysis demonstrated that both ST8SiaII and St8SiaIV direct up-regulation of polySia. Cell-specific induction of polySia in myelinating Schwann cells and on regenerated axons in the presence of ST8SiaIV, but not ST8SiaII, indicates that not only the amount of polySia but also its cellular localization has a high impact on the regeneration progress of peripheral nerves.

Polysialyltransferase overexpression in Schwann cells mediates different effects during peripheral nerve regeneration

The polysialic acid (PSA) moiety of the neural cell adhesion molecule (NCAM) has been shown to support dynamic changes underlying peripheral nerve regeneration. Using transgenic mice expressing polysialyltransferase ST8SiaIV under control of a glial-specific (proteolipid protein, PLP) promoter (PLP-ST8SiaIV-transgenic mice), we tested the hypothesis that permanent synthesis of PSA in Schwann cells impairs functional recovery of lesioned peripheral nerves. After sciatic nerve crush, histomorphometric analyses demonstrated impaired remyelination of regenerated axons at the lesion site and in target tissue of PLP-ST8SiaIV-transgenic mice, though the number and size of regenerating unmyelinated axons were not changed. This was accompanied by slower mechanosensory recovery in PLP-ST8SiaIV-transgenic mice. However, the proportion of successfully mono-(re)innervated motor endplates in the foot pad muscle was significantly increased in PLP-ST8SiaIV-transgenic mice when compared with wild-type littermates, suggesting that long-term increase in PSA levels in regenerating nerves may favor selective motor target reinnervation. The combined negative and positive effects of a continuous polysialyltransferase overexpression observed during peripheral nerve regeneration suggest that an optimized time- and differentiation-dependent control of polysialyltransferase expression in Schwann cells may further improve recovery after peripheral nerves injury.

McDonald Criteria 2010 and 2005 Compared: Persistence of High Oligoclonal Band Prevalence Despite Almost Doubled Diagnostic Sensitivity

The 2010 McDonald criteria were developed to allow a more rapid diagnosis of relapsing-remitting multiple sclerosis (MS) by only one MRI of the brain. Although cerebrospinal fluid (CSF) is not a mandatory part of the latest criteria, the evidence of an intrathecal humoral immunoreaction in the form of oligoclonal bands (OCB) is crucial in the diagnostic workup. To date, the impact of the 2010 McDonald criteria on the prevalence of OCB has not been investigated. We retrospectively evaluated data of 325 patients with a clinical relapse suggestive of demyelination that were treated in a German university hospital between 2010 and 2015. One hundred thirty-six patients (42%) were diagnosed with MS and 189 patients with CIS when the criteria of 2010 were applied. The criteria of 2005 allowed only 70 patients (22%) to be designated as MS. In contrast, the prevalence of OCB was marginal affected in MS patients with 96% for the criteria of 2010 and 98.5% for the criteria of 2005. In conclusion, OCB are prevalent in most MS patients and reflect the chronic inflammatory nature of the disease. We recommend CSF examination to exclude alternative diagnoses and reevaluation of the diagnosis MS in patients with negative OCB.

Detection of Normal Aging Effects on Human Brain Metabolite Concentrations and Microstructure with Whole-Brain MR Spectroscopic Imaging and Quantitative MR Imaging

BACKGROUND AND PURPOSE: Knowledge of age-related physiological changes in the human brain is a prerequisite to identify neurodegenerative diseases. Therefore, in this study whole-brain 1H-MRS was used in combination with quantitative MR imaging to study the effects of normal aging on healthy human brain metabolites and microstructure. MATERIALS AND METHODS: Sixty healthy volunteers, 21–70 years of age, were studied. Brain maps of the metabolites NAA, creatine and phosphocreatine, and Cho and the tissue irreversible and reversible transverse relaxation times T2 and T2′ were derived from the datasets. The relative metabolite concentrations and the values of relaxation times were measured with ROIs placed within the frontal and parietal WM, centrum semiovale, splenium of the corpus callosum, hand motor area, occipital GM, putamen, thalamus, pons ventral/dorsal, and cerebellar white matter and posterior lobe. Linear regression analysis and Pearson correlation tests were used to analyze the data. RESULTS: Aging resulted in decreased NAA concentrations in the occipital GM, putamen, splenium of the corpus callosum, and pons ventral and decreased creatine and phosphocreatine concentrations in the pons dorsal and putamen. Cho concentrations did not change significantly in selected brain regions. T2 increased in the cerebellar white matter and decreased in the splenium of the corpus callosum with aging, while the T2′ decreased in the occipital GM, hand motor area, and putamen, and increased in the splenium of the corpus callosum. Correlations were found between NAA concentrations and T2′ in the occipital GM and putamen and between creatine and phosphocreatine concentrations and T2′ in the putamen. CONCLUSIONS: The effects of normal aging on brain metabolites and microstructure are region-dependent. Correlations between both processes are evident in the gray matter. The obtained data could be used as references for future studies on patients.

Physiological neuronal decline in healthy aging human brain — An in vivo study with MRI and short echo-time whole-brain 1H MR spectroscopic imaging

Knowledge of physiological aging in healthy human brain is increasingly important for neuroscientific research and clinical diagnosis. To investigate neuronal decline in normal aging brain eighty-one healthy subjects aged between 20 and 70years were studied with MRI and whole-brain (1)H MR spectroscopic imaging. Concentrations of brain metabolites N-acetyl-aspartate (NAA), choline (Cho), total creatine (tCr), myo-inositol (mI), and glutamine+glutamate (Glx) in ratios to internal water, and the fractional volumes of brain tissue were estimated simultaneously in eight cerebral lobes and in cerebellum. Results demonstrated that an age-related decrease in gray matter volume was the largest contribution to changes in brain volume. Both lobar NAA and the fractional volume of gray matter (FVGM) decreased with age in all cerebral lobes, indicating that the decreased NAA was predominantly associated with decreased gray matter volume and neuronal density or metabolic activity. In cerebral white matter Cho, tCr, and mI increased with age in association with increased fractional volume, showing altered cellular membrane turn-over, energy metabolism, and glial activity in human aging white matter. In cerebellum tCr increased while brain tissue volume decreased with age, showing difference to cerebral aging. The observed age-related metabolic and microstructural variations suggest that physiological neuronal decline in aging human brain is associated with a reduction of gray matter volume and neuronal density, in combination with cellular aging in white matter indicated by microstructural alterations and altered energy metabolism in the cerebellum.

Cerebral white matter lesions in patients with cirrhosis – causative for hepatic encephalopathy or bystanders?

Focal white matter lesions mimicking microvascular lesions were connected to the development of hepatic encephalopathy (HE) in patients with cirrhosis. This study aims to assess the relationship between cerebrovascular risk factors and the prevalence and extent of these lesions in patients with cirrhosis, as well as their impact upon cognitive function.

Clinically Isolated Syndrome According to McDonald 2010: Intrathecal IgG Synthesis Still Predictive for Conversion to Multiple Sclerosis

While the revised McDonald criteria of 2010 allow for the diagnosis of multiple sclerosis (MS) in an earlier stage, there is still a need to identify the risk factors for conversion to MS in patients with clinically isolated syndrome (CIS). Since the latest McDonald criteria were established, the prognostic role of cerebrospinal fluid (CSF) and visual evoked potentials (VEP) in CIS patients is still poorly defined. We conducted a monocentric investigation including patients with CIS in the time from 2010 to 2015. Follow-ups of 120 patients revealed that 42% converted to MS. CIS patients with positive oligoclonal bands (OCB) were more than twice as likely to convert to MS as OCB negative patients (hazard ratio = 2.6). The probability to develop MS was even higher when a quantitative intrathecal IgG synthesis was detected (hazard ratio = 3.8). In patients with OCB, VEP did not add further information concerning the conversion rate to MS. In patients with optic neuritis and negative OCB, a significantly higher rate converted to MS when VEP were delayed. In conclusion, the detection of an intrathecal IgG synthesis increases the conversion probability to MS. Pathological VEP can help to predict the conversion rate to MS in patients with optic neuritis without an intrathecal IgG synthesis.

Cerebrospinal Fluid Findings in Neurological Diseases Associated with Sjögren's Syndrome

Background: Sjögrens syndrome is a chronic autoimmune-mediated disease that can cause a variety of neurological manifestations. Methods: This study investigated characteristics of clinical and cerebrospinal fluid (CSF) features in patients with neurological diseases associated with Sjögrens syndrome. Eighty-two patients were examined separately according to the presence of Sjögrens syndrome alone or in combination with other autoimmune diseases. Results: In the 47 patients with primary Sjögrens syndrome, peripheral neuropathy (57%) was found most frequently, followed by the involvement of the central nervous system (CNS; 17%), cranial neuropathy (15%), and myalgia (11%). These patients did not display consistent signs of inflammation in the CSF. Slight pleocytosis of 8-107 cells/µL was found in patients with peripheral neuropathy (9%), cranial neuropathy (20%), and CNS involvement (25%). Oligoclonal bands indicating intrathecal IgG synthesis occurred in 26% of patients with peripheral neuropathy, 20% of patients with cranial neuropathy, and 25% of patients with CNS involvement. Conclusions: In patients with Sjögrens syndrome and neurological manifestations, inflammatory CSF changes were rarely found and did not show a characteristic pattern irrespective of peripheral or central genesis of neurological deficits. Analysis of the CSF presents therefore an important diagnostic procedure to exclude other autoimmune and infectious diseases.

Effects of Aging on the Human Brain: A Proton and Phosphorus MR Spectroscopy Study at 3T: H- and P-MRS Study of Aging Effects

To investigate accumulative aging effects on neurometabolism in human brain and to collect a reference dataset.