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Kovacs G.G.,Medical University of Vienna | van der Zee J.,Neurodegenerative Brain Diseases Group | van der Zee J.,University of Antwerp | Hort J.,Charles University | And 9 more authors.
Neuropathology | Year: 2016

There is a strong genetic influence on the clinicopathological phenotypes associated with frontotemporal lobar degeneration (FTLD) and frontotemporal dementia (FTD). Intracellular deposition of TDP-43 is the phenotypical hallmark of a frequent subgroup of cases. Mutations in the sequestosome 1 (SQSTM1) gene have rarely been found in individuals with FTD. Here we provide a comprehensive clinicopathological description of two cases with a SQSTM1 mutation. The clinical phenotype of patient 1 (mutation p.Glu396*) was compatible with the behavioural variant (bv) of FTD. TDP-43 pathology was consistent with the features of type B of FTLD-TDP pathology. However, prominent neuronal granular cytoplasmic TDP-43 immunoreactivity and abundant oligodendroglial inclusions, proven by colocalization with the oligodendroglial-marker TPPP/p25, were also seen. The clinical phenotype of patient 2 was compatible with bvFTD associated with parkinsonism and bulbar symptoms in the later stage. Genetic testing of patient 2 identified a C9orf72 repeat expansion mutation together with a missense mutation (p.Arg212Cys) in SQSTM1. TDP-43 pathology was characterized by neuritic profiles compatible mostly with type A. In contrast to patient 1, p62 pathology was seen to a greater extent as TDP-43 immunoreactivity in neurons. Using an antibody that detects poly(GP) peptides produced via repeat associated non-ATG translation associated with expanded hexanucleotide repeat in the C9orf72 gene, we confirmed the presence of pathognomonic inclusions. The present study supports previous observations on amyotrophic lateral sclerosis (ALS) that SQSTM1 mutations consistently associate with TDP-43 pathology. The co-presence of C9orf72 mutation may influence the phenotype, thus finding one FTLD (or ALS) related mutation does not exclude the presence of further influential genetic alterations. Oligodendroglial TDP-43 pathology is considerable in some forms of FTLD-TDP, thus their evaluation might be considered to be included in classification systems. © 2016 Japanese Society of Neuropathology.


Hansen K.,Copenhagen University | Crone C.,Copenhagen University | Kristoferitsch W.,Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders
Handbook of Clinical Neurology | Year: 2013

Lyme neuroborreliosis (LNB) designates the nervous system disorders caused by the tick-borne spirochete Borrelia burgdorferi (Bb). The clinical syndromes are usually distinct and are classified as early and the rare late or chronic LNB. Early LNB occurs 3-6 weeks after infection most frequently as a lymphocytic meningoradiculoneuritis (LMR). Symptoms are mainly due to a painful sensory radiculitis and a multifocal motor radiculo-neuritis. Fifty percent have cranial nerve involvement predominantly uni- or bilateral facial nerve palsies. Meningitic symptoms occur primarily in children. Nerve biopsies, autopsies, animal models, and nerve conduction studies showed that the pathology is a lymphocytic perineuritis leading to multisegmental axonal injury of nerve roots, spinal ganglia, and distal nerve segments. Due to meningeal and root inflammation cerebrospinal fluid (CSF) shows lymphocytic inflammation. The only evidence that Bb causes peripheral neuropathy without CSF inflammation is seen in patients with acrodermatitis chronica atrophicans (ACA), a chronic dermatoborreliosis. In the rare chronic or late LNB the pathology and thus the clinical presentation is primarily due to chronic meningitis and meningovascular CNS involvement, whereas the peripheral nervous system is not primarily affected. In early and late LNB the diagnosis is based on a characteristic clinical appearance and CSF inflammation with Bb-specific intrathecal antibody production. Both conditions, but not the ACA-associated neuropathy, respond to antibiotic therapy. © 2013 Elsevier B.V.


Kornek B.,Medical University of Vienna | Aboul-Enein F.,Medical University of Vienna | Rostasy K.,Innsbruck Medical University | Steiner I.,Center for Medical Statistics | And 12 more authors.
JAMA Neurology | Year: 2013

Importance: Given the high frequency of failure of firstline therapies, there is an urgent need for second-line treatment strategies for pediatric patients with multiple sclerosis (MS). Objective: To report the use of natalizumab in pediatric MS. Natalizumab, a humanized monoclonal antibody targeting α4 integrin, is effective against active relapsingremitting MS in adults. Design: Retrospective study. Setting: Eleven centers for neurology and pediatric neurology in Germany and Austria. Participants: A total of 20 pediatric patients with MS who started treatment with natalizumab prior to 18 years of age. These patients underwent magnetic resonance imaging as clinically indicated, despite the fact that 19 of these 20 patients were undergoing first-line diseasemodifying therapy. The mean (SD) age at initiation of natalizumab therapy was 16.7 (1.1) years, and the mean (SD) pretreatment period was 18 (10) months. Intervention: Natalizumab, 300 mg every 4 weeks. Main Outcome Measures: Annualized relapse rates, Expanded Disability Status Scale scores, number of new T2/fluid-attenuated inversion recovery lesions and contrastenhancing lesions on magnetic resonance imaging, number of adverse events, the prevalence of neutralizing antibodies against natalizumab, and serum JC virus-antibody status. Results: Treatment with natalizumab was associated with reductions in mean annualized relapse rates (3.7 without treatment vs 0.4 with treatment; P<.001), median Expanded Disability Status Scale scores (2 without treatment vs 1 with treatment; P<.02), and mean number of new T2/fluid-attenuated inversion recovery lesions per year (7.8 without treatment vs 0.5 with treatment; P<.001). Two patients developed high-titer neutralizing antibodies against natalizumab and had to stop therapy. Adverse events included headaches, asthenia, infections, and hypersensitivity. Abnormal laboratory results were found for 8 patients. JC virus antibodies were found in 5 of 13 patients. After the discontinuation of natalizumab therapy, relapse activity occurred in 6 of 8 patients within 6 months. Conclusions and Relevance: Our data indicate that natalizumab may be safe and effective against MS in pediatric patients with breakthrough disease. © 2013 American Medical Association. All rights reserved.


Presslauer S.,Wilhelminenspital | Milosavljevic D.,FH Campus Wien, University of Applied Sciences | Aboulenein-Djamshidian F.,Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders | Deisenhammer F.,Innsbruck Medical University | And 3 more authors.
Multiple Sclerosis | Year: 2016

Background: Kappa free light chains (KFLCs) have been proposed as a diagnostic biomarker in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS). Objective: The objective of this paper is to validate the diagnostic accuracy of intrathecal KFLC synthesis in a multicenter study. Methods: KFLCs were measured by nephelometry under blinded conditions in cerebrospinal fluid (CSF) and serum sample pairs of patients with CIS (n = 60), MS (n = 60) and other neurological diseases (n = 60) from four different MS centers. The upper normal limit for intrathecal KFLC concentrations depending on blood-CSF barrier function was previously calculated in a cohort of 420 control patients. Results: Diagnostic sensitivity of intrathecal KFLC synthesis, IgG synthesis according to Reiber, IgG index and oligoclonal bands (OCBs) was 95%, 72%, 73% and 93% in patients with MS and 82%, 47%, 43% and 72% in patients with CIS. Specificity of intrathecal KFLC synthesis was 95% and 98% for all other measures. Conclusion: These findings further support the diagnostic value of intrathecal KFLC synthesis in CIS and MS patients and demonstrate a valid, easier and rater-independent alternative to OCB detection. © SAGE Publications.


Katzenschlager R.,Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders
Journal of Neurology | Year: 2014

While a curative treatment for Parkinson's disease remains elusive, our understanding of disease mechanisms as well as preclinical and pre-motor early manifestations has improved greatly over the past years. An agent with proven disease modifying properties has not yet been identified but symptomatic treatment options for affected patients have improved. For patients with motor complications, this includes invasive approaches such as deep brain stimulation and continuous device-aided drug delivery. The many facets of non-motor problems patients are faced with have finally been fully recognized and have become the target of treatment trials, as have been non-pharmacological approaches. © 2014 Springer-Verlag.

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