Showing papers by "Franz Fazekas published in 2018"

Neurofilaments as biomarkers in neurological disorders

Abstract: Neuroaxonal damage is the pathological substrate of permanent disability in various neurological disorders. Reliable quantification and longitudinal follow-up of such damage are important for assessing disease activity, monitoring treatment responses, facilitating treatment development and determining prognosis. The neurofilament proteins have promise in this context because their levels rise upon neuroaxonal damage not only in the cerebrospinal fluid (CSF) but also in blood, and they indicate neuroaxonal injury independent of causal pathways. First-generation (immunoblot) and second-generation (enzyme-linked immunosorbent assay) neurofilament assays had limited sensitivity. Third-generation (electrochemiluminescence) and particularly fourth-generation (single-molecule array) assays enable the reliable measurement of neurofilaments throughout the range of concentrations found in blood samples. This technological advancement has paved the way to investigate neurofilaments in a range of neurological disorders. Here, we review what is known about the structure and function of neurofilaments, discuss analytical aspects and knowledge of age-dependent normal ranges of neurofilaments and provide a comprehensive overview of studies on neurofilament light chain as a marker of axonal injury in different neurological disorders, including multiple sclerosis, neurodegenerative dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis and Parkinson disease. We also consider work needed to explore the value of this axonal damage marker in managing neurological diseases in daily practice.

MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset

Abstract: Background Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase. Methods In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale ...

ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis:

Abstract: Background:Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years There is a need for a reference tool compiling current data to aid professionals in trea

ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis.

Abstract: Background and purpose: Multiple sclerosis (MS) is a complex disease of the central nervous system. As new drugs are becoming available, knowledge on diagnosis and treatment must continuously evolve. There is therefore a need for a reference tool compiling current data on benefit and safety, to aid professionals in treatment decisions and use of resources across Europe. The European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have joined forces to meet this need. The objective was to develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS to guide healthcare professionals in the decision-making process. Methods: This guideline has been developed using the GRADE methodology and following the recently updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. An exhaustive literature search up to December 2016 was performed for each question and the evidence is presented narratively and, when possible, combined in a meta-analysis using a random-effects model. The quality of evidence for each outcome was rated into four categories – very high, high, low and very low − according to the risk of bias. GRADE evidence profiles were created using GRADEprofiler (GRADEpro) software (Version 3.6). The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk−benefit balance. Consensus between the panellists was reached by use of the modified nominal group technique. Results: A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency at the time of publication. A total of 20 recommendations were agreed by the guideline working group members after three rounds of consensus.

The current role of MRI in differentiating multiple sclerosis from its imaging mimics

Abstract: MRI red flags proposed over a decade ago by the European Magnetic Resonance Network in MS (MAGNIMS) have guided clinicians in the diagnosis of multiple sclerosis (MS). However, the past 10 years have seen increased recognition that vascular disease can coexist and possibly interact with MS, improvements in the reliability of ways to differentiate MS from novel antibody-mediated CNS disorders (such as anti-aquaporin-4 antibody and myelin-oligodendrocyte glycoprotein antibody-associated diseases) and advances in MRI techniques. In this Review, MAGNIMS updates the imaging features that differentiate the most common mimics of MS, particularly age-related cerebrovascular disease and neuromyelitis optica, from MS itself. We also provide a pragmatic summary of the clinically useful MRI features that distinguish MS from its mimics and discuss the future of nonconventional techniques that have identified promising disease-specific features.

Systematic Review: Syndromes, Early Diagnosis, and Treatment in Autoimmune Encephalitis.

Abstract: In recent years, new antibodies have been discovered which mediate autoimmune encephalitis This immunological response can be triggered by an infection or a tumor Classical onconeuronal antibodies are directed against intracellular neuronal agents but recently, a novel group of antibodies to neuronal cell-surface and synaptic antigens associated with different CNS-syndromes, has been discovered Interestingly, the syndromes in this group can be successfully treated with immunotherapy and frequently do not have underlying tumors The aim of this review is to describe the current state of knowledge about autoimmune encephalitis, in order to provide clinicians with a concise, up-to-date overview Thus, a comprehensive literature search was performed in medical databases The literature was carefully studied and new findings focusing on the symptoms, diagnosis and treatment were summarized and interpreted Even though it might be challenging in some cases, the awareness of certain symptom constellations and demographic information, in combination with laboratory- and MRI-results, allows clinicians to make the diagnosis of probable autoimmune encephalitis at an early stage Treatment can therefore be initiated faster, which significantly improves the outcome Further investigations could define the underlying pathogenic mechanisms Randomized controlled trials, paired with increasing clinical experience, will be necessary to improve the identification of affected patients, treatment strategies, and outcomes in the years to come

Increased middle cerebral artery mean blood flow velocity index after stroke thrombectomy indicates increased risk for intracranial hemorrhage

Abstract: Background and purpose Cerebral hyperperfusion has been related to the risk of intracranial hemorrhage (ICH) in stroke patients after vessel recanalization therapy. We hypothesized that after successful mechanical thrombectomy for acute anterior circulation stroke, hemodynamics detectable by transcranial Duplex (TCD) sonography would vary, and that increased blood flow velocities would be associated with ICH. Methods We retrospectively identified all ischemic stroke patients with successful endovascular recanalization for anterior circulation vessel occlusion (Thrombolysis in Cerebral Infarction 2b–3) between 2010 and 2017. We reviewed their postinterventional TCD examinations for mean blood flow (MBF) velocities of the recanalized and contralateral middle cerebral artery (MCA) and searched for an association with postinterventional ICH and clinical outcome. Results 123 stroke patients (mean age 63±14 years, 40% women) with successful anterior circulation thrombectomy were analyzed. Of those, 18 patients had postinterventional ICH. ICH patients had an increased MCA MBF velocity index (=MBF velocity of the recanalized divided by the contralateral MCA) compared with non-ICH patients (1.32±0.39 vs 1.02±0.32, P Conclusions A high MCA MBF velocity index on TCD after successful recanalization therapy for anterior circulation stroke indicates a risk for postinterventional ICH and worse prognosis.

Effects of concentration and vendor specific composition of formalin on postmortem MRI of the human brain.

Abstract: Purpose Formalin fixation prevents tissue autolysis by crosslinking proteins and changes tissue microstructure and MRI signal characteristics. Previous studies showed high variations in MR relaxation time constants of formalin fixed brain tissue, which has been attributed to the use of different formalin concentrations. Our investigations confirmed the influence of formalin concentration on relaxation times and unexpectedly revealed an influence of vendor specific formalin composition, which has not been investigated so far. Methods We systematically analyzed relaxation times of human brain tissue fixed with 4% and 10% formalin compared with unfixed condition at 3 Tesla MRI. Furthermore, we assessed relaxation times of nine formalin solutions from different vendors and performed comparisons of their magnetic susceptibility by SQUID (superconducting quantum interference device) magnetometry. Results Tissue relaxation times decreased approximately twice as fast using 10% than in 4% formalin fixation. The vendor specific composition of the formalin solutions and concentration dependent paramagnetic effects showed a substantial contribution to differences in relaxation times of formalin. Conclusion Our study demonstrates that differences of the formalin composition have substantial effects on MRI signal characteristics after fixation, which can explain the divergence of reported relaxation times beyond the effect of differences in formalin concentration. Magn Reson Med 79:1111-1115, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Abnormal Blood Flow on Transcranial Duplex Sonography Predicts Poor Outcome After Stroke Thrombectomy.

Abstract: Background and Purpose— Hemodynamic changes following mechanical thrombectomy for large vessel occlusion stroke could be associated with complications and might affect prognosis. We investigated po...

Contactin-1 and contactin-2 in cerebrospinal fluid as potential biomarkers for axonal domain dysfunction in multiple sclerosis.

Abstract: BackgroundContactin-1 and contactin-2 are important for the maintenance of axonal integrity.ObjectiveTo investigate the cerebrospinal fluid levels of contactin-1 and contactin-2 in multiple scleros...

Management of multiple sclerosis patients in central European countries: current needs and potential solutions.

Abstract: Multiple sclerosis (MS) experts in Europe are facing rapidly rising demands of excellence due to the increasing complexity of MS therapy and management. A central European expert board of MS experts met to identify needs and obstacles with respect to raising quality of MS care in central and Eastern European countries. There are substantial variations across countries regarding delivery of care and its cost structure, as well as access to treatment. To date, Eastern European countries are often less able to afford reimbursement of immunomodulatory agents than Western countries. Overall, approximately 40% of working-age patients are not working due to MS. Costs rise steeply with increasing disability; indirect costs constitute the bulk of the financial burden in patients with severe MS. Magnetic resonance imaging (MRI) assessment is meanwhile obligatory as the diagnostic interface in the management of MS patients. Recommended measures directed at improving quality of care include the collection of patient data in registries, enhanced education of healthcare professionals, implementation of national strategies aiming at reducing regional variation, optimization of approval processes, and removal of administrative barriers. Local partnerships with authorities such as those that represent the interests of employees can contribute to leverage the importance of epidemiological data. The need for education extends to (neuro)radiologists who are responsible for reporting MRI findings in expert quality. Dissemination of the Magnetic Resonance Imaging in MS (MAGNIMS) protocol would be an important step in this context. Also, clinical freedom of choice is rated as essential. Physicians should have access to a range of treatment options due to the complexity of disease. Guidelines such as the upcoming EAN-ECTRIMS clinical practice guideline also aim at providing a basis for argumentation in negotiations with national health authorities.

Repeated Endovascular Treatment of Early Recurrent Proximal Middle Cerebral Artery Occlusion: Case Report and Brief Review of the Literature.

Abstract: Mechanical thrombectomy (MT) is the gold standard treatment for large vessel occlusion (LVO) stroke of the anterior circulation. Whether MT can also be effectively and safely performed in early recurrent LVO is largely unclear. We present the case of a middle-aged patient who was successfully treated by MT for right proximal middle cerebral artery (MCA) occlusion with excellent outcome. One day after discharge (nine days after the first MT), the patient was readmitted with wake-up stroke. MRI again revealed right proximal MCA occlusion with severe diffusion-perfusion mismatch. Repeat MT was performed and once more led to almost full recovery. The recurrent strokes were attributed to exulcerated non-stenosing plaques in the ipsilateral internal carotid artery which prompted thromboendarterectomy. In an 18-months follow-up period, no further vascular events occurred. In conclusion, repeated MT for early recurrent LVO appears feasible in carefully selected patients. The collection of similar cases via registries would be desirable.

Predictors of gait speed and its change over three years in community-dwelling older people.

Abstract: We aimed to assess whether and how changes in brain volume and increases in white matter hyperintensity (WMH) volume over three years predict gait speed and its change independently of demographics, vascular risk factors and physical status We analyzed 443 individuals from the Lothian Birth Cohort 1936, at mean age 73 and 76 years Gait speed at age 76 was predicted by age, grip strength and body mass index at mean age 73, three-year brain volume decrease and WMH volume increase, explaining 261% of variance Decline in gait speed to age 76 was predicted by the same five variables explaining 409% of variance In both analyses, grip strength and body mass index explained the most variance A clinically significant decline in gait speed (≥ 01 m/s per year) occurred in 244% These individuals had more structural brain changes Brain volume and WMH changes were independent predictors of gait dysfunction and its three-year change, but the impact of malleable physical factors such as grip strength or body mass index was greater

Assessment of ferritin content in multiple sclerosis brains using temperature‐induced R*2 changes

Abstract: Purpose Current MRI techniques cannot reliably assess iron content in white matter due to the confounding diamagnetic effect of myelin. The purpose of this study was to validate with histology a novel iron mapping technique that uses the temperature dependency of the paramagnetic susceptibility in multiple sclerosis (MS) brains, where white matter has been reported to show significant variations in iron content. Methods We investigated post mortem brain tissue from three MS patients and one control subject. Temperature-dependent R2* relaxometry was performed between 4°C and 37°C. The resulting temperature coefficient ( TcR2*) maps were compared with immunohistochemical stains for ferritin light chain. Results Good agreement between TcR2* maps and ferritin staining was found by way of visual comparison and quantitative analysis. The highest iron concentrations were detected at the edge of MS lesions and in the basal ganglia. For all regions, except the subcortical U-fibers, there was a significant negative correlation between the TcR2* values and the ferritin count. Conclusion This study provides further evidence that TcR2* may be a reliable measure of white matter iron content due to the elimination of myelin-induced susceptibility changes and is well suited for further research into neurological diseases with distortions of the iron homeostasis. Magn Reson Med 79:1609-1615, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

The effect of disease modifying therapies on CD62L expression in multiple sclerosis

Abstract: BackgroundThe increasing armamentarium of disease-modifying therapies in multiple sclerosis is accompanied by potentially severe adverse effects The cell-adhesion molecule CD62L, which facilitates

Stroke Referrals from Nursing Homes: High Rate of Mimics and Late Presentation.

Abstract: Background Stroke has become a treatable condition with increasing evidence of treatment benefits in older people. However, stroke mimics in geriatric patients are especially prevalent, causing incorrect suspicion and consecutive burden to patients and emergency room resources. We therefore examined the dimension of this problem by investigating emergency room admissions from nursing homes for suspected stroke. Methods We performed a retrospective cohort study of all nursing home residents who were admitted to the neurological emergency room of our primary and tertiary care university hospital between 2013 and 2015. Patients were further divided into those with confirmed stroke and stroke mimics after diagnostic stroke work-up. Results Of 419 nursing home patients referred to the emergency room, nearly one third had suspected stroke (n = 126; mean age: 78 ± 14 years, polypharmacy rate: 77%). Of those, 43 (34%) had a confirmed stroke (ischaemic: n = 34; haemorrhagic: n = 9) and 83 (66%) had stroke mimics after diagnostic work-up. Only one patient underwent intravenous thrombolysis, followed by mechanical thrombectomy for middle cerebral artery occlusion. Prehospital delay (47%) and multimorbidity-associated contraindications (27%) were the main reasons for withholding recanalization therapy. Among the stroke-mimicking conditions, infectious diseases (24%) and epileptic seizures (20%) were the most frequent. Multivariate analysis identified focal deficits (OR 16.6, 95% CI 4.3-64.0), atrial fibrillation (OR 3.9, 95% CI 1.5-10.5) and previous stroke (OR 3.2, 95% CI 1.2-8.9) as indicators that were associated with stroke. Conclusions In our region, nursing home referrals for suspected stroke have a high false positive rate and occur delayed, which most often precludes specific stroke treatment in addition to multimorbidity. Such problems may also exist in other centres and highlight the need for targeted educational and organizational efforts. Simple indicators as identified in this study may help to sort out patients with true stroke more efficiently.

Dysphagia in supratentorial recent small subcortical infarcts results from bilateral pyramidal tract damage

Abstract: BackgroundDysphagia occurs in up to 20% of patients with a recent small subcortical infarct, even when excluding brainstem infarcts.AimTo examine the impact of lesion topography and concomitant cer...

Clinical-Pathological Conference Series from the Medical University of Graz : Case No 153: A 55-year-old woman with atypical multiple sclerosis and irritable bowel syndrome.

Abstract: G. J. Krejs, MD, AGAF, MWGO ( ) Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria guenter.krejs@medunigraz.at medical history includes repeated episodes of neurological symptoms, including transitory paresis of the left arm, vertigo and disturbed equilibrium. Once she also experienced transient paresthesia of the left leg. Magnetic resonance imaging (MRI) of the head during the last 10 years revealed slightly progressing white matter lesions. Cerebrospinal fluid (CSF) showed 50 cells/μl (85% lymphocytes, 15% monocytes) and increased concentration of protein (75mg/dl, normal: 15–40mg/dl), but without oligoclonal bands. Based on these findings, atypical multiple sclerosis (MS) was diagnosed. Therapy with glucocorticoids for 9 months had shown a temporary positive effect, but a therapeutic trial with interferon-beta 1a was futile. Formany years the patient suffered fromheadaches, arthralgia, diffuse myalgia and fatigue without signs of inflammation. Several neurological and rheumatological consultations failed to provide a clear diagnosis. At the age of 49 years the patient took premature disability retirement. Arterial hypertension had been treated with lisinopril (5mg per day) for the last 7 years. The dosage of lisinopril was increased to 10mg per day 2 months before admission because the 24h ambulatory blood pressure measurement gave a mean pressure of 150/95mmHg. The patient did not take any other medication. On admission physical examination was without pathological findings except for pain on deep abdominal palpation but there was no guarding or rebound phenomenon. There was no hepatomegaly or splenomegaly. Skin and mucous membranes were unremarkable. Results were normal or negative for extensive laboratory tests, stool cultures, fecal calprotectin, abdominal ultrasonography, chest and ab-

Overview of Promising Rat Models for Cortical Lesion Research- 2006 Until Now

Abstract: Success in developing new drugs for diseases often depends on laboratory research usually involving animal models. For the early disease phases of multiple sclerosis (MS) this prerequisite was given by experimental autoimmune encephalomyelitis (EAE), an animal model which reflects the pathophysiological mechanisms of the disease quite well. Only a few models resemble cellular features of the progressive disease form of MS (like cortical demyelination) and if they do observable lesions are rather sparse and short lived. The lack of suitable animal models delayed and complicated drug development. Recently a few promising animal models reassembling many characteristics of progressive MS have been described aiming at both a better understanding of cellular mechanisms of this disease phase as well as the development of new therapeutic options. The authors of new rat models postulate novel findings of cortical pathology summarized in this article. The models differ in their focus and not all distinct models are reflecting all features of progressive MS but together they allow research on different aspects of the disease and offer the opportunity to expand our knowledge and clear the way for drug development.

Teaching NeuroImages: Convexal subarachnoid hemorrhage accompanied by transient global amnesia.

Abstract: A 55-year-old otherwise healthy woman presented with sudden-onset anterograde amnesia, temporal disorientation, and repetitive questioning, which was associated with moderate intensity headache. Consistent with transient global amnesia (TGA), this clinical symptomatology lasted for 8 hours. Brain imaging showed a convexal subarachnoid hemorrhage1 (cSAH) (figure, A) and—characteristic of TGA2—a punctuate diffusion-weighted imaging positive lesion in the right hippocampus on MRI (figure, B and C). Cerebral microbleeds or cortical superficial siderosis were not evident on acute MRI.