Romana Höftberger

Antibodies to nodal/paranodal proteins in paediatric immune-mediated neuropathy

REF: Link zur Originalpublikation

Autoren: Desiree De Simoni, Gerda Ricken, Michael Winklehner, Inga Koneczny, Michael Karenfort, Ulf Hustedt, Ulrich Seidel, Omar Abdel-Mannan, Pinki Munot, Simon Rinaldi, Claudia Steen, Michael Freilinger, Markus Breu, Rainer Seidl, Markus Reindl, Julia Wanschitz, Cinta Lleixà, Günther Bernert, Klaus-Peter Wandinger, Ralf Junker, Luis Querol, Frank Leypoldt, Kevin Rostásy, Romana Höftberger


Background: The identification of autoantibodies against epitopes at the node of Ranvier in peripheral immune-mediated neuropathies has led to new insights and therapeutic implications in Guillain-Barré-syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Their relevance in pediatric immune-mediated neuropathies is unclear.

Objective: To report clinical features and frequency of nodal/paranodal antibodies in a cohort of 54 pediatric patients with immune-mediated neuropathy.

Methods: We reviewed clinical and paraclinical data of 54 children with GBS (n=42) and CIDP (n=12) that were referred to our center for autoantibody testing from hospitals in Germany, Austria, and Croatia between 2006 and 2018. All serum samples were screened for autoantibodies against neurofascin155 (NF155), NF186, NF140, contactin-1 (CNTN1), contactin-associated protein1 (CASPR1), and gangliosides (GM1, GD1a, GD1b, GQ1b) using tissue- and cell-based assays, and ELISAs.

Results: Five/12 children with CIDP but none of the 42 GBS patients had nodal/paranodal antibodies: 2 pan-neurofascin (NF155/NF186/NF140 triple-positive), 1 NF155, and 2 CNTN1-antibodies. Mean age was 7.9 years (range 3-11), the male:female ratio was 3:2. Median duration of hospitalization was 13 days (range 2-28). One child had an acute onset, the other four a prolonged atypical disease course. All children had ataxia, four neuropathic pain (all except 1 panneurofascin) and three (2 CNTN1, 1 pan-neurofascin) tremor. One had a preceding infection. At peak of disease, three children needed a walking aid (Hughes 3) and two were bedridden (Hughes 4). Three/5 patients significantly improved after rituximab treatment, whereas none of the children sufficiently responded to IVIG, steroids and/or plasma exchange.

Conclusion: Paranodal antibodies need to be taken into account in the diagnostic work-up of children with CIDP and atypical/prolonged disease course with high Hughes score (>2), sensory ataxia, prominent neuropathic pain, and tremor, in which IVIG may be insufficient and patients may benefit from rituximab.

Michael Guger

Real life data from the Austrian MS Treatment Registry

REF: Link zur Originalpublikation

Autoren: Michael Guger, Christian Enzinger, Fritz Leutmezer, Jörg Kraus, Stefan Kalcher, Erich Kvas, Thomas Berger, Austrian MS Treatment Registry (AMSTR)


OBJECTIVES: To compare the efficacy of natalizumab (NTZ) and fingolimod (FTY) in the treatment of relapsing-remitting multiple sclerosis (MS) in sequential use in common and as a function of transition periods in a nationwide observational cohort using prospectively collected data from a real-life setting.

MATERIALS AND METHODS: We included 195 patients from the Austrian MS Treatment Registry, who had started treatment with NTZ at any time since 2006 and stayed on NTZ for at least 24 months, switched afterwards within 1 year to FTY and stayed on FTY for at least another 12 months. Transition periods between NTZ and FTY were grouped into three different intervals: < 3 months (135 patients), 3-6 months (44 patients), and 6-12 months (16 patients).

RESULTS: Estimated mean annualized relapse rates (ARR) over a mean treatment period of 44 months were 0.26 for NTZ and 0.32 for FTY (p = 0.381) over 46 months. In the treatment gap, differences were found concerning the relapse probability, seven (5.2%) patients in the < 3 months group, six (13.6%) in thef 3-6 months group, and seven (43.8%) in the 6-12 months group (p < 0.001). After this treatment gap, no significant differences concerning ARR, EDSS change, EDSS progression, and regression were observed regardless the proceeding transition periods. Significantly higher efficacy of NTZ compared to FTY in sequential use was found regarding EDSS change, EDSS progression, and EDSS regression sustained for 12 and 24 weeks.

CONCLUSIONS: First, we here show an increased short-time risk for relapses during the treatment gap between NTZ and FTY therapy, dependent on the length of transition time. Second, the disease course after switching to FTY remained stable in the long-term evaluation. Therefore, switching from NTZ to FTY in a real-world setting appears efficacious and safe, but this data advocate for a short switching gap of 3 months or less.

Patrick Altmann

Increased serum neurofilament light chain concentration indicates poor outcome in Guillain-Barré syndrome

REF: Link zur Originalpublikation

Autoren: Altmann P, De Simoni D, Kaider A, Ludwig B, Rath J, Leutmezer F, Zimprich F, Hoeftberger R, Lunn MP, Heslegrave A, Berger T, Zetterberg H, Rommer PS.


BACKGROUND: Guillain-Barré syndrome (GBS) is an autoimmune disease that results in demyelination and axonal damage. Five percent of patients die and 20% remain significantly disabled on recovery. Recovery is slow in most cases and eventual disability is difficult to predict, especially early in the disease. Blood or cerebrospinal fluid (CSF) biomarkers that could help identify patients at risk of poor outcome are required. We measured serum neurofilament light chain (sNfL) concentrations from blood taken upon admission and investigated a correlation between sNfL and clinical outcome.

METHODS: Baseline sNfL levels in 27 GBS patients were compared with a control group of 22 patients with diagnoses not suggestive of any axonal damage. Clinical outcome parameters for GBS patients included (i) the Hughes Functional Score (HFS) at admission, nadir, and discharge; (ii) the number of days hospitalised; and (iii) whether intensive care was necessary.

RESULTS: The median sNfL concentration in our GBS sample on admission was 85.5 pg/ml versus 9.1 pg/ml in controls. A twofold increase in sNfL concentration at baseline was associated with an HFS increase of 0.6 at nadir and reduced the likelihood of discharge with favourable outcome by a factor of almost three. Higher sNfL levels upon admission correlated well with hospitalisation time (rs = 0.69, p < 0.0001), during which transfer to intensive care occurred more frequently at an odds ratio of 2.4. Patients with baseline sNfL levels below 85.5 pg/ml had a 93% chance of being discharged with an unimpaired walking ability.

CONCLUSIONS: sNfL levels measured at hospital admission correlated with clinical outcome in GBS patients. These results represent amounts of acute axonal damage and reflect mechanisms resulting in disability in GBS. Thus, sNfL may serve as a convenient blood-borne biomarker to personalise patient care by identifying those at higher risk of poor outcome.

Gabriel Bsteh

Serum neurofilament levels correlate with retinal nerve fibre layer thinning in multiple sclerosis

REF: Link zur Originalpublikation

Autoren: Bsteh G, Berek K, Hegen H, Teuchner B, Buchmann A, Voortman MM, Auer M, Wurth S, Zinganell 2, Di Pauli F, Deisenhammer F, Khalil M, Berger T.


BACKGROUND: Serum neurofilament light chain levels (sNfL) and peripapillary retinal nerve fiber layer (pRNFL) are both emerging biomarkers of neuro-axonal damage in MS. However, data on the relation between sNfL and pRNFL are scarce.

OBJECTIVE: We aimed to determine the relation of sNfL levels with pRNFL thinning in a large cohort of relapsing-remitting (RR)-MS patients.

METHODS: We identified 80 patients from a prospective, 3-year observational study on retinal changes in RRMS with annual blood samples available. sNfL was measured using single molecule array (SimoaTM) assay. Annualized pRNFL thinning rates (aLpRNFL) were determined by individual linear regression models. Correlations between single and repeated sNfL levels and aLpRNFL were analyzed using multivariate linear regression and mixed-effect models.

RESULTS: After correction for sex, age and baseline sNfL, a sNfL increase of 10pg/ml was associated with an aLpRNFL of -0.7µm (95% CI: [-1.3 – -0.2], p<0.001). Patients with ≥2 sNfL measurements >75th percentile displayed higher aLpRNFL (2.2µm, SD 0.6) compared to patients with no sNfL measure >75th percentile (0.4µm, SD 0.2, p<0.001). Between 15-20% of the aLpRNFL variance could be predicted from sNfL levels.

CONCLUSIONS: sNfL contributes to the prediction of retinal thinning in patients with RRMS strengthening its value as biomarker of neuro-axonal damage.

Markus Leitinger

Epidemiology of status epilepticus in adults: A population-based study on incidence, causes, and outcomes

REF: Link zur Originalpublikation

Autoren: Leitinger M, Trinka E, Giovannini G, Zimmermann G, Florea C, Rohracher A, Kalss G, Neuray C, Kreidenhuber R, Höfler J, Kuchukhidze G, Granbichler C, Dobesberger J, Novak HF, Pilz G, Meletti S, Siebert U


OBJECTIVE: In 2015, the International League Against Epilepsy (ILAE) proposed a new definition of status epilepticus (SE): 5 minutes of ongoing seizure activity to diagnose convulsive SE (CSE, ie, bilateral tonic-clonic SE) and 10 minutes for focal SE and absence SE, rather than the earlier criterion of 30 minutes. Based on semiology, several types of SE with prominent motor phenomena at any time (including CSE) were distinguished from those without (ie, nonconvulsive SE, NCSE). We present the first population-based incidence study applying the new 2015 ILAE definition and classification of SE and report the impact of the evolution of semiology and level of consciousness (LOC) on outcome.

METHODS: We conducted a retrospective population-based incidence study of all adult patients with SE residing in the city of Salzburg between January 2011 and December 2015. Patients with hypoxic encephalopathy were excluded. SE was defined and classified according to the ILAE 2015.

RESULTS: We identified 221 patients with a median age of 69 years (range 20-99 years). The age- and sex-adjusted incidence of a first episode of SE, NCSE, and SE with prominent motor phenomena (including CSE) was 36.1 (95% confidence interval [CI] 26.2-48.5), 12.1 (95% CI 6.8-20.0), and 24.0 (95% CI 16.0-34.5; including CSE 15.8 [95% CI 9.4-24.8]) per 100 000 adults per year, respectively. None of the patients whose SE ended with or consisted of only bilateral tonic-clonic activity died. In all other clinical presentations, case fatality was lower in awake patients (8.2%) compared with patients with impaired consciousness (33%).

SIGNIFICANCE: This first population-based study using the ILAE 2015 definition and classification of SE found an increase of incidence of 10% compared to previous definitions. We also provide epidemiologic evidence that different patterns of status evolution and LOCs have strong prognostic implications.

Aljoscha Thomschewski

Localization of the Epileptogenic Zone Using High Frequency Oscillations

REF: Link zur Originalpublikation

Autoren: Aljoscha Thomschewski, Ana-Sofía Hincapié, Birgit Frauscher


For patients with drug-resistant focal epilepsy, surgery is the therapy of choice in order to achieve seizure freedom. Epilepsy surgery foremost requires the identification of the epileptogenic zone (EZ), defined as the brain area indispensable for seizure generation. The current gold standard for identification of the EZ is the seizure-onset zone (SOZ). The fact, however that surgical outcomes are unfavorable in 40–50% of well-selected patients, suggests that the SOZ is a suboptimal biomarker of the EZ, and that new biomarkers resulting in better postsurgical outcomes are needed. Research of recent years suggested that high-frequency oscillations (HFOs) are a promising biomarker of the EZ, with a potential to improve surgical success in patients with drug-resistant epilepsy without the need to record seizures. Nonetheless, in order to establish HFOs as a clinical biomarker, the following issues need to be addressed. First, evidence on HFOs as a clinically relevant biomarker stems predominantly from retrospective assessments with visual marking, leading to problems of reproducibility and reliability. Prospective assessments of the use of HFOs for surgery planning using automatic detection of HFOs are needed in order to determine their clinical value. Second, disentangling physiologic from pathologic HFOs is still an unsolved issue. Considering the appearance and the topographic location of presumed physiologic HFOs could be immanent for the interpretation of HFO findings in a clinical context. Third, recording HFOs non-invasively via scalp electroencephalography (EEG) and magnetoencephalography (MEG) is highly desirable, as it would provide us with the possibility to translate the use of HFOs to the scalp in a large number of patients. This article reviews the literature regarding these three issues. The first part of the article focuses on the clinical value of invasively recorded HFOs in localizing the EZ, the detection of HFOs, as well as their separation from physiologic HFOs. The second part of the article focuses on the current state of the literature regarding non-invasively recorded HFOs with emphasis on findings and technical considerations regarding their localization.  

Johannes Koren

Early Epileptiform Discharges and Clinical Signs Predict Nonconvulsive Status Epilepticus on Continuous EEG.

REF: Link zur Originalpublikation

Autoren: Koren J, Herta J, Draschtak S, Pötzl G, Fürbass F, Hartmann M, Kluge T, Gruber A, Baumgartner C.


Critical care continuous electroencephalography (CCEEG) represents the gold standard for detection of nonconvulsive status epilepticus (NCSE) in neurological critical care patients. It is unclear which findings on short-term routine EEG and which clinical parameters predict NCSE during subsequent CCEEG reliably. The aim of the present study was to assess the prognostic significance of changes within the first 30 min of EEG as well as of clinical parameters for the occurrence of NCSE during subsequent CCEEG.

METHODS: Systematic analysis of the first 30 min and the remaining segments of prospective CCEEG recordings according to the ACNS Standardized Critical Care EEG Terminology and according to recently proposed NCSE criteria as well as review of clinical parameters of 85 consecutive neurological critical care patients. Logistic regression and binary classification tests were used to determine the most useful parameters within the first 30 min of EEG predicting subsequent NCSE.

RESULTS: The presence of early sporadic epileptiform discharges (SED) and early rhythmic or periodic EEG patterns of “ictal-interictal uncertainty” (RPPIIIU) (OR 15.51, 95% CI 2.83-84.84, p = 0.002) and clinical signs of NCS (OR 18.43, 95% CI 2.06-164.62, p = 0.009) predicted NCSE on subsequent CCEEG. Various combinations of early SED, early RPPIIIU, and clinical signs of NCS showed sensitivities of 79-100%, specificities of 49-89%, and negative predictive values of 95-100% regarding the incidence of subsequent NCSE (p < 0.001).

CONCLUSIONS: Early SED and early RPPIIIU within the first 30 min of EEG as well as clinical signs of NCS predict the occurrence of NCSE during subsequent CCEEG with high sensitivity and high negative predictive value and may be useful to select patients who should undergo CCEEG.

Martin Krenn

Mutations outside the N-terminal part of RBCK1 may cause polyglucosan body myopathy with immunological dysfunction: expanding the genotype-phenotype spectrum.

REF: Link zur Originalpublikation

Autoren: Krenn M, Salzer E, Simonitsch-Klupp I, Rath J, Wagner M, Haack TB, Strom TM, Schänzer A, Kilimann MW, Schmidt RLJ, Schmetterer KG, Zimprich A, Boztug K, Hahn A, Zimprich F


A subset of patients with polyglucosan body myopathy was found to have underlying mutations in the RBCK1 gene. Affected patients may display diverse Symptoms ranging from skeletal muscular weakness, cardiomyopathy to chronic autoinflammation and immunodeficiency. It was suggested that the exact localization of the mutation within the gene might be responsible for the specific phenotype, with N-terminal mutations causing severe immunological dysfunction and mutations in the middle or C-terminal part leading to a myopathy phenotype.

We report the clinical, immunological and genetic findings of two unrelated individuals suffering from a childhood-onset RBCK1-asscociated disease caused by the same homozygous truncating mutation (NM_031229.2:c.896_899del,p.Glu299Valfs*46) in the middle part of the RBCK1 gene. Our patients suffered from a myopathy with cardiac involvement, but in contrast to previous reports on mutations in this part of the gene, also displayed signs of autoinflammation and

Our report suggests that RBCK1 mutations at locations that were previously thought to lack immunological features may also present with
immunological dysfunction later in the disease course. This notably broadens the genotype-phenotype correlation of RBCK1-related polyglucosan body myopathy.

Tim von Oertzen

Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery

REF: Link zur Originalpublikation

Autoren: Ingmar Blumcke, M.D., Roberto Spreafico, M.D., Ph.D., Gerrit Haaker, M.D., Roland Coras, M.D., Katja Kobow, Ph.D., Christian G. Bien, M.D., Margarete Pfäfflin, M.Sc., Christian Elger, M.D., Guido Widman, M.D., Johannes Schramm, M.D., Albert Becker, M.D., Kees P. Braun, M.D., Frans Leijten, M.D., Johannes C. Baayen, M.D., Eleonora Aronica, M.D., Ph.D., Francine Chassoux, M.D., Hajo Hamer, M.D., Hermann Stefan, M.D., Karl Rössler, M.D., Maria Thom, M.D., Matthew C. Walker, M.D., Sanjay M. Sisodiya, F.R.C.P., John S. Duncan, M.D., Andrew W. McEvoy, M.D., Tom Pieper, M.D., Hans Holthausen, M.D., Manfred Kudernatsch, M.D., H. Joachim Meencke, M.D., Philippe Kahane, M.D., Ph.D., Andreas Schulze-Bonhage, M.D., Josef Zentner, M.D., Dieter H. Heiland, M.D., Horst Urbach, M.D., Bernhard J. Steinhoff, M.D., Thomas Bast, M.D., Laura Tassi, M.D., Giorgio Lo Russo, M.D., Cigdem Özkara, M.D., Buge Oz, M.D., Pavel Krsek, M.D., Silke Vogelgesang, M.D., Uwe Runge, M.D., Holger Lerche, M.D., Yvonne Weber, M.D., Mrinalini Honavar, M.D., José Pimentel, M.D., Ph.D., Alexis Arzimanoglou, M.D., Adriana Ulate-Campos, M.D., Soheyl Noachtar, M.D., Elisabeth Hartl, M.D., Olaf Schijns, M.D., Renzo Guerrini, M.D., Carmen Barba, M.D., Thomas S. Jacques, F.R.C.Path., Ph.D., J. Helen Cross, F.R.C.P.C.H., Ph.D., Martha Feucht, M.D., Angelika Mühlebner, M.D., Thomas Grunwald, M.D., Ph.D., Eugen Trinka, M.D., Peter A. Winkler, M.D., Antonio Gil-Nagel, M.D., Ph.D., Rafael Toledano Delgado, M.D., Thomas Mayer, M.D., Martin Lutz, Ph.D., Basilios Zountsas, M.D., Kyriakos Garganis, M.D., Felix Rosenow, M.D., Anke Hermsen, M.Sc., Tim J. von Oertzen, M.D., Thomas L. Diepgen, M.D., Ph.D., and Giuliano Avanzini, M.D., for the EEBB Consortium*


BACKGROUND: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy.

METHODS: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%).

RESULTS: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients.

CONCLUSIONS: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.)

Christoph Waiß

CXCL-13 as a biomarker in the diagnostics of neuroborreliosis

REF: Link zur Originalpublikation

Autoren: Waiß C.,Kindler W., Ströbele B., Aspöck C., Oberndorfer S.


BACKGROUND: The chemokine CXCL-13 is a potential intrathecal biomarker for neuroborreliosis (NB). According to the literature the sensitivity of CXCL-13 in the diagnostics of NB varies between 88% and 100% and the specificity between 63% and 99.7%. The objective of this study was to analyze the sensitivity and specificity of CXCL-13 in the diagnosis of NB in an endemic area of Borrelia burgdorferi.

MATERIAL AND METHODS: In a retrospective analysis of data from August 2014 to August 2016, 63 patients with clinically suspected NB were identified. The diagnosis of NB was based on the guidelines of the German Society of Neurology (DGN).

RESULTS: In 10 patients a definitive diagnosis of NB could be established (CXCL-13 min. 254 pg/ml /max. >900 pg/ml). The criteria for a probable NB were fulfilled by 2 patients (CXCL-13 concentration 8 pg/ml and 69 pg/ml, respectively), 9 patients had a chronic inflammatory demyelinating disease (CXCL-13 min. 10 pg/ml/max. 649 pg/ml) and 42 patients had other neurological diagnoses. Out of these, elevated intrathecal CXCL-13 concentrations were detected in 8 patients (e. g. tuberculosis, syphilis and anti-RI antibody positive paraneoplastic syndrome).

CONCLUSION: By increasing the CXCL-13 cut-off level from 20 pg/ml to 200 pg/ml, the diagnostic sensitivity for NB remains 100% and consequently the specificity increases from 69.8% to 92.4%. Moreover, a CXCL-13 cut-off set at 200 pg/ml would exclude NB in the 2 patients with probable NB. We conclude from these results that CXCL-13 represents a valuable biomarker for the exclusion of untreated NB, although with limited specificity.