Jörg Kraus

The increasing incidence and prevalence of female multiple sclerosis—A critical analysis of potential environmental factors

Multiple sclerosis (MS) is the most common acquired inflammatory demyelinating disorder of the central nervous system (CNS). Not unlike many inflammatory diseases with a presumed autoimmune pathogenesis, it has been established that there is a female preponderance in prevalence. While in the past it was shown that there are two women for every man with a diagnosis of MS, recent serial cross-sectional assessments provide compelling evidence for an increase of the female to male sex ratio in patients with relapsing-remitting MS over the last decades. An understanding of this phenomenon might provide key insights into the pathogenesis of the disease but also may have implications for health-care strategies and further research efforts. We review possible etiologies for the gender disparity in MS, and we discuss possible underlying causes. We determined that the biologically most plausible explanations for a disproportional increase of MS among women in some population may be the role of vitamin D in MS pathogenesis. Decreased sun exposure may be a critical factor in diminished vitamin D levels in many recent cohort studies. Vitamin D insufficiency or deficiency has been shown to affect T cell differentiation and regulation, which may affect cellular immune responses against autoantigens and pathogens that have been associated with the etiology of MS. Vitamin D also appears to impact B cell activation and differentiation, another cell type that has been implicated in the inflammatory cascade underlying CNS autoimmune disease.

Current therapies in ischemic stroke. Part A. Recent developments in acute stroke treatment and in stroke prevention.

Stroke is the third leading cause of death with an increasing prevalence. In previous years many important achievements and new therapeutic strategies have been established. This article provides an overview on recent developments and is an update to the article of Green et al. that was published in 2004. As this article is a comprehensive review we divided it in two parts. In this Part A of our review, recent developments in acute stroke treatment and in stroke prevention are described. In Part B we will reflect on neuroprotection.

Current therapies in ischemic stroke. Part B. Future candidates in stroke therapy and experimental studies

Stroke still remains a major healthcare problem. The growing understanding of the mechanism of cell death in ischemia leads to new approaches in stroke treatment. The aim of neuroprotection is to reduce the post-stroke impairment and the overall costs that are accompanied in patients with severe disability. Despite encouraging data from experimental animal models, almost all neuroprotective therapies have, to date, not been established in clinical routine. In this part B of our review on stroke therapies we provide an overview on future candidates in stroke therapy and neuroprotective agents that are under investigation.

Natalizumab saturation: biomarker for individual treatment holiday after natalizumab withdrawal?

More and more patients with multiple sclerosis (MS) switch from natalizumab to fingolimod because of the risk of progressive multifocal leukoencephalopathy. The duration of the treatment holiday is still under debate referring to a possible recurrence of disease activity.

Cholinergic dysfunction and amnesia in patients with Wernicke–Korsakoff syndrome: a transcranial magnetic stimulation study

The specific neurochemical substrate underlying the amnesia in patients with Wernicke–Korsakoff syndrome (WKS) is still poorly defined. Memory impairment has been linked to dysfunction of neurons in the cholinergic system. A transcranial magnetic stimulation (TMS) protocol, the short latency afferent inhibition (SAI), may give direct information about the function of some cholinergic pathways in the human motor cortex. In the present study, we measured SAI in eight alcoholics with WKS and compared the data with those from a group of age-matched healthy individuals; furthermore, we correlated the individual SAI values of the WKS patients with memory and other cognitive functions. Mean SAI was significantly reduced in WKS patients when compared with the controls. SAI was increased after administration of a single dose of donezepil in a subgroup of four patients. The low score obtained in the Rey Complex Figure delayed recall test, the Digit Span subtest of the Wechsler Adult Intelligence Scale—Revised (WAIS-R) and the Corsi’s Block Span subtest of the WAIS-R documented a severe impairment in the anterograde memory and short-term memory. None of the correlations between SAI values and these neuropsychological tests reached significance. We provide physiological evidence of cholinergic involvement in WKS. However, this putative marker of central cholinergic activity did not significantly correlate with the memory deficit in our patients. These findings suggest that the cholinergic dysfunction does not account for the memory disorder and that damage to the cholinergic system is not sufficient to cause a persisting amnesic syndrome in WKS.

Treatment strategies for vasculitis that affects the nervous system

Vasculitis is a rare but severe disease. It is diagnostically challenging because patients present with nonspecific symptoms. The definitive diagnosis is therefore complicated, because many diagnostic procedures have to be performed. Currently, several systemic types are known that have a secondary affect on the nervous system; an isolated primary central nervous system (CNS) vasculitis also occurs. In this review, we highlight new developments in medical treatment and provide an overview of the various combination strategies regarding the most significant types of vasculitis.

Acute pulmonary edema caused by a multiple sclerosis relapse

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) [1]. In the majority of patients, MS begins with a relapsing–remitting course. It is characterized by unpredictable relapses followed by periods of months to years of clinical remission. MS relapses entail various clinical symptoms depending on the location of the inflammatory lesion within the CNS. Besides the common symptoms of optic neuritis, paresis, paraesthesia, and ataxic gait disorders, in some rare cases a relapse may alter cardiovascular and autonomic function [1]. Clinical studies have shown that acute cerebral lesions (e.g., stroke, hemorrhage) may induce changes in cardiac and respiratory function including hypertension, arrhythmias, myocardial necrosis, and sudden death [2, 3]. Moreover, experimental and clinical studies indicate that damage of the brainstem is likely to cause disturbances in either sympathetic or parasympathetic autonomic function with subsequent cardiac and respiratory dysfunction [4–6]. Neurogenic pulmonary edema (NPE) is usually defined as an acute pulmonary edema occurring shortly after various injuries of the central nervous system [7]. The most important vasomotor centers for NPE development are nuclei of the solitary tract, the dorsal motor vagus nucleus in the medulla oblongata and the medial reticulated nucleus. On the other hand, brainstem damage in the region of the solitary tract nuclei may result in a transient cardiomyopathy [8]. The exact mechanisms remain poorly understood because of the complexity of its pathophysiologic mechanisms, involving both hemodynamic and inflammatory aspects. There are two possible explanations: one presumes that neurological damage directly involves the pulmonary and cardiac vascular bed with disconnection of the central nervous system vasomotor centers. However, there are also data that brainstem dysfunction can cause changes of sympathetic vasomotor tone [7]. This case study describes a rare initial presentation of a MS relapse with pulmonary edema caused by left ventricular failure. A 48-year-old woman, diagnosed with clinically definite relapsing–remitting MS 3 years previously with a preexisting expanded disability status scale (EDSS) of 3.5, presented with increasing dyspnea and cough without chest pain to a department of internal medicine. She was on immunomodulatory treatment with glatiramer acetate. No clinically apparent atherosclerotic disease was known. On admission, laboratory testing showed that high-sensitivity troponin T was slightly elevated. An electrocardiogram showed no signs of myocardial infarction. In a coronary computed tomography angiogram, no significant changes in the coronary arteries were found. The next day, increases in high-sensitivity troponin T, C-reactive protein (CRP), and a massive increase of B-type natriuretic peptide (proBNP) were observed (Table 1). Pulmonary edema was initially not diagnosed (Fig. 1a) and according to the assumption of pneumonia the patient was treated with antibiotic therapy (amoxicillin) and furosemide. Due to the further worsening of respiratory conditions, intubation and mechanical respirator treatment became necessary. An echocardiogram showed acute left ventricular failure with apical wall motion abnormalities and a left ventricular ejection fraction of 35% in this patient without a history of cardiac disease. No abnormalities concerning the right ventricle and the atria were seen. With regard to her P. Wipfler (&) G. Pilz E. Broussalis S. M. Golaszewski A. Kunz E. Trinka J. Kraus Christian-Doppler-Klinik, University Hospital of Neurology, Paracelsus Medical University and Salzburger Landesklinken, Ignaz Harrerstrasse 79, 5020 Salzburg, Austria e-mail: p.wipfler@salk.at

Hyponatremic encephalopathy mimicking hypoxic-ischemic encephalopathy.

Hyponatremia, defined as serum Na+ concentration < less than 130 mEq/l, is one of the most common electrolyte disturbances in hospitalized patients with a wide variety of medical problems [1]. Magnetic resonance imaging (MRI) findings in hypoxic-ischemic encephalopathy are very characteristic: brain swelling, cortical laminar necrosis, signal hyperintensity of basal ganglia at the beginning, followed by white-matter degeneration and, later, by atrophy. The mechanisms of neuronal damage in hypoxic-ischemic encephalopathy are not clearly understood. To the best of our knowledge, similar MRI abnormalities have never been described in patients with hyponatremic encephalopathy without evidence of hypoxia or respiratory failure. We report the case of a schizophrenic patient with psychogenic polydipsia, who suffered from severe hyponatremia without any history of a hypoxic-ischemic event. Case Report

From natalizumab to fingolimod in eight weeks - Immunological, clinical, and radiological data in quest of the optimal switch.

Natalizumab (NZB) discontinuation during a treatment change is associated with recurrence of disease activity in a significant proportion of multiple sclerosis (MS) patients. The immunological basis why disease reactivation occurs in selected patients is unresolved. In search of a prognostic biomarker for a safe and effective transition from NZB to fingolimod, we monitored five parameters related to pharmacokinetic and pharmacodynamic effects of the two drugs in 12 MS patients until six months on fingolimod. Clearance of free and cell-bound NZB, re-expression of alpha-4, and fingolimod-mediated changes on CD8+ and CD4+ T cell subsets showed pronounced interindividual variability. Higher frequencies of memory CD8+ T cells after six months on fingolimod were the sole association with disease reactivation. None of the investigated parameters thus had potential as prognostic biomarker for the outcome of the switch. Our findings rather support the thesis of broad interindividual differences in the immunopathogenesis of MS.

Usability and Potential of Geostatistics for Spatial Discrimination of Multiple Sclerosis Lesion Patterns

In multiple sclerosis (MS) the individual disease courses are very heterogeneous among patients and biomarkers for setting the diagnosis and the estimation of the prognosis for individual patients would be very helpful. For this purpose, we are developing a multidisciplinary method and workflow for the quantitative, spatial, and spatiotemporal analysis and characterization of MS lesion patterns from MRI with geostatistics.