[Show abstract][Hide abstract] ABSTRACT: Fingolimod, an oral sphingosine 1-phosphate (S1P) receptor modulator, is approved for the treatment of relapsing forms of multiple sclerosis (MS). The interference with S1P signaling leads to retention particularly of chemokine receptor-7 (CCR7) expressing T cells in lymph nodes. The immunological basis of varicella zoster virus (VZV) infections during fingolimod treatment is unclear. Here, we studied the dynamics of systemic and intrathecal immune responses associated with symptomatic VZV reactivation including cessation of fingolimod and initiation of antiviral therapy. Key features in peripheral blood were an about twofold increase of VZV-specific IgG at diagnosis of VZV reactivation as compared to the previous months, a relative enrichment of effector CD4+ T cells (36% versus mean 12% in controls), and an accelerated reconstitution of OPEN ACCESS Int. J. Mol. Sci. 2015, 16 21833 absolute lymphocytes counts including a normalized CD4+/CD8+ ratio and reappearance of CCR7+ T cells. In cerebrospinal fluid (CSF) the lymphocytic pleocytosis and CD4+/CD8+ ratios at diagnosis of reactivation and after nine days of fingolimod discontinuation remained unchanged. During this time CCR7+ T cells were not observed in CSF. Further research into fingolimod-associated VZV reactivation and immune reconstitution is mandatory to prevent morbidity and mortality associated with this potentially life-threatening condition.
International Journal of Molecular Sciences 09/2015; 16(9):21832-21845. DOI:10.3390/ijms160921832 · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Incidence and mortality of ischemic stroke in Croatia is significantly higher than in many other developed European countries. Here, we aimed to evaluate underlying conditions of this unacceptably high ischemic stroke burden. An observational prospective cohort study of ) first-ever ischemic stroke patients identified in a population-based incidence study (N=751) (study 1, S1) and a concurrent case-control trial (215 patients, 125 controls, S2) were conducted in the country of Varazdin from 2007-2010. Atrial fibrillation (AF) was common (36.1% in S1, 40.9% in S2) and mostly (>50%) unrecognized before the index event. In a multivariate analysis, odds of stroke increased with tobacco smoking (OR=3.95, 95%CI 1.33-10.8), unhealthy diet (OR=2.12, 1.12-4.01) and AF (OR=9.40, 4.01-22.0), and decreased with higher education (OR=0.33, 0.11-0.98), moderate alcohol consumption (OR=0.48, 0.25-0.93), higher fasting HDL (OR=0.14, 0.07-0.30) and pre-stroke use of anticoagulants (OR=0.09, 0.01-0.59), antihypertensive drugs (OR=0.52, 0.27-1.00) and statins (OR=0.29, 0.12-0.69. Fourteen-day case fatality was 10.8% (S1) and 6.1% (S2) and the risk was higher with AF, cardioembolic stroke, older age, higher fasting serum glucose, and lower with acute aspirin. Among the acute phase survivors, 30.9% died over the subsequent 1-3 years (p<0.05). We conclude that the incidence of ischemic stroke in Croatia is related to conventional risk factors and largely due to a high rate of unawareness and inadequate treatment of predisposing morbidity.
Current neurovascular research 07/2015; 12(4). DOI:10.2174/1567202612666150731105554 · 2.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Reduced working capability is one of the most devastating consequences of multiple sclerosis (MS). We aimed to study working capability and related variables in Swiss MS patients.
Materials and methods:
A cross-sectional analysis of employment status and risk factors for reduced working capability among MS patients treated at our outpatient clinic. A questionnaire was mailed to 644 MS patients and returned by 69.7%. 405 patients (66% female, mean age 44.2 years (SD ± 10.2), median EDSS 3.0 (SD ± 1.8)) were eligible for subsequent analysis.
After a mean disease duration of 12.3 years (SD ± 8.25), full or part time employment was declared by 26.7% and 25.7%, respectively. Incapacity to work was reported by 27.1%. A total of 52.8% specified MS as the cause for altered working capability, whereas 20.5% cited reasons unrelated to the disorder. Even with minimal disability (EDSS < 3) a significant proportion of patients (24%) reported reduced working capability. Among the MS-specific restricting factors were fatigue (47.6%), sensorimotor deficits (31.1%), impaired vision (3.3%) and pain (2.8%).
MS continues to takes its toll on the professional life of the patients early in the course. While complete incapacity becomes relevant with moderate to severe disability, many patients scale down to part-time even with minimal impairment.
PLoS ONE 04/2015; 10(4):e0121856. DOI:10.1371/journal.pone.0121856 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The future occupations and interests of the medical profession have to be in some respects different from those of the past, and they have to be more various.(1</SUP)
[Show abstract][Hide abstract] ABSTRACT: Objective:
To assess the general interest in and motivation for cross-border mobility among residents and junior neurologists from member states of the European Union and neighboring countries.
Questionnaire-based paper survey among 118 participants of a neurology course.
Ninety-seven (82%) participants returned the survey. Most of them had at one point considered relocating within or to the European Union for postgraduate education (87%) or employment (71%). Common motivations were superior prospects for clinical training (85%), resources at work and academic environment (both 80%), and remuneration (70%). Barely half of the surveyed intended to return to their home country. The attractiveness of Europe as a destination for migration was ranked over other continents. The most common reasons that reduce enthusiasm for relocation were the loss of family connection (55%) and uncertain future prospects (41%), whereas language barriers were less relevant (21%).
There is keen interest of the upcoming generation of neurologists to relocate within and to the European Union. The motives include regional differences in training and career opportunities as well as economic welfare. Appropriate steps toward the harmonization of educational and career prospects are urgently required to ensure adequate provision of neurology service and patient care throughout Europe.
[Show abstract][Hide abstract] ABSTRACT: The clinical spectrum of viral hepatitis ranges from asymptomatic and inapparent to fulminant and fatal acute infection. Both acute and chronic liver dysfunction can lead to hepatic encephalopathy. Further neurological manifestations of hepatic viruses include various disorders of the central and peripheral nervous system (CNS and PNS, respectively). These can develop either as an isolated complication or in the setting of other extrahepatic manifestations. Alternatively, neurological signs and symptoms precede hepatitis, develop in the post-acute phase, or occur with anicteric hepatitis. This chapter summarizes the current knowledge of neurological manifestations of hepatic viruses and also covers conditions related to neurotoxicity caused by different antiviral drugs.
Handbook of Clinical Neurology 07/2014; 123C:647-661. DOI:10.1016/B978-0-444-53488-0.00031-6
[Show abstract][Hide abstract] ABSTRACT: Around the world, there are marked differences in neurology training, including training duration and degree of specialization. In the United States, adult neurology residency is composed of 1 year of internal medicine training (preliminary year) and 3 years of neurology-specific training. Child neurology, which is not the focus of this article, is 2 years of pediatrics and 3 years of neurology training. The route to adult neurology residency training in the United States is standardized and is similar to most other US specialties. Whereas US medical graduates often receive stepwise guidance from their medical school regarding application for residency training, international graduates often enter this complex process with little or no such assistance. Despite this discrepancy, about 10%-15% of residency positions in the United States are filled by international medical graduates.(1,2) In adult neurology specifically, 35% of matched positions were filled by international graduates in 2013, 75% of whom were not US citizens.(1) In an effort to provide a preliminary understanding of the application process and related terminology (table 1) and thereby encourage international residency applicants, we describe the steps necessary to apply for neurology residency in the United States.
[Show abstract][Hide abstract] ABSTRACT: Background and purposeThe neurological outcome of acute encephalitis can be devastating and early prognosis remains difficult. Biomarkers that quantify the extent of early brain injury are needed to improve the prognostic accuracy and aid patient management. Our objective was to assess whether cerebrospinal fluid (CSF) protein biomarkers of neuroaxonal and glial cell injury are elevated in distinct forms of acute encephalitis and predictive of poor outcome.Methods
This was a prospective study of patients presenting with acute encephalitis to three teaching hospitals in London, UK. Levels of neurofilament heavy chain (NfH, SMI35) and S100B were quantified in CSF using enzyme-linked immunosorbent assay. The outcome was assessed by the Glasgow Outcome Scale (GOS).ResultsFifty-six patients with acute encephalitis were recruited and classified into the following diagnostic categories: infectious (n = 20), inflammatory (n = 14) and unknown etiology (n = 22). Pathological levels of NfH and S100B were observed in 24/56 (43%) and 54/56 (96%), respectively. Patients with infectious encephalitis had significantly higher NfH levels compared with the other two groups (P < 0.05). A poor outcome (GOS < 5) was associated with significantly higher CSF NfH levels within samples taken 2 weeks after symptom onset.Conclusions
This study suggests that longitudinal CSF NfH levels are of superior prognostic value compared with CSF S100B levels. Prolonged release of NfH, a marker of neuroaxonal damage, was associated with poor outcome. Potentially there is a window of opportunity for future neuroprotective treatment strategies in encephalitis.
European Journal of Neurology 03/2014; 21(6). DOI:10.1111/ene.12390 · 4.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Natalizumab-neutralizing antibodies (NABs) occur in 9% of natalizumab-treated multiple sclerosis (MS) patients. Loss of clinical and biological efficacy in patients with persisting NABs requires termination of natalizumab treatment. Because high-titer NABs are strongly associated with persistence of NABs, we investigated if determination of natalizumab saturation levels of α-4 integrins by flow cytometry has the potential to identify patients early with NABs.
Cell-bound natalizumab and natalizumab saturation of α-4 integrins on T cells were detected by flow cytometry using a monoclonal anti-human IgG4 antibody. Peripheral blood mononuclear cells were enriched from venous blood collected at the start (baseline) and every 4 weeks immediately before subsequent infusions until up to 9 months from natalizumab-treated patients with NABs (n=4) and at the start and after 1 (n=15), 2 (n=14), 3 (n=9), 6 (n=7), and 9 months (n=3) from natalizumab-treated patients without NABs. Natalizumab saturation levels (in %) of T cells were determined by relating median fluorescence intensities (MFIs) of in vivo bound natalizumab to MFIs after in vitro incubation with saturating amounts of natalizumab. Determination of serum NABs was performed by ELISA.
In patients without NABs, the median natalizumab saturation level of T cells over 9 months was 75% (confidence interval of 95%: 72–78%). In two of the four patients with NABs, the natalizumab saturation level of T cells only reached approximately 50% after the first infusion and further declined to baseline levels with the second infusion. Low-titer NABs were measured after the first infusion and development of persistent high-titer NABs led to termination of natalizumab treatment after 6 months. In another two patients, the natalizumab saturation level of T cells was 74% and 68% after the first infusion, temporarily decreased to approximately baseline levels and re-increased after approximately 6 months. Transient NABs were detected after 2 and 3 months, which resolved after 5 and 6 months.
Monitoring the natalizumab saturation level on T cells is a fast and reliable method to identify patients with a reduced treatment effect due to NABs. Both high- and low-titer NABs were equally effective in reducing cellular natalizumab saturation levels. We were able to show that monitoring the natalizumab saturation levels by flow cytometry, is a sensitive method for detecting a prolonged NAB-mediated reduced treatment effect because NABs are apparently effective longer than suggested by the detection limit of ELISA.
[Show abstract][Hide abstract] ABSTRACT: Zusammenfassung
Neutralisierende Antikörper gegen Natalizumab (NAB) kommen in 9% der mit Natalizumab behandelten Multiple Sklerose (MS) PatientInnen vor. Dies ist assoziiert mit einer verminderten Wirksamkeit von Natalizumab und in der Folge muss bei PatientInnen mit persistierenden NAB die Behandlung mit Natalizumab beendet werden.
Da hohe Titer an NAB stark mit persistierenden NAB assoziiert sind, haben wir untersucht, ob die durchflusszytometrische Bestimmung der Sättigung des Alpha-4-Integrins mit Natalizumab das Potenzial hat, PatientInnen mit NAB früher zu identifizieren.
Zellgebundenes Natalizumab und Natalizumab-Sättigung des Alpha-4 Integrins auf T-Zellen wurden mittels Durchflusszytometrie unter Verwendung eines monoklonalen anti-human IgG4 Antikörpers nachgewiesen. Mononukleäre Zellen wurden aus venösem Blut angereichert und bei PatientInnen mit NAB (n=4) 9 Monate lang alle 4 Wochen unmittelbar vor der nächsten Infusion und bei PatientInnen ohne NAB vor Beginn der Therapie und nach 1 (n=15), 2 (n=14), 3 (n=9), 6 (n=7) und 9 Monate (n=3) auf gebundenes Natalizumab untersucht. Der Natalizumab-Sättigungsgrad (in%) der T-Zellen wurde durch das ins Verhältnis Setzen von der mittleren Fluoreszenzintensität (MFI) von in vivo gebundenem Natalizumab mit der MFI von mit in vitro mit Natalizumab gesättigten Immunzellen bestimmt. Die Bestimmung der NAB aus dem Serum wurde mittels ELISA durchgeführt.
Bei PatientInnen ohne NAB betrug die mittlere Natalizumab-Sättigung von T-Zellen über einen Zeitraum von 9 Monaten durchschnittlich 75% (95%iges Konfidenzintervall: 72–78%). Bei 2 der 4 PatientInnen mit NAB erreichte die Natalizumab-Sättigung der T-Zellen nach der ersten Infusion ca. 50% und fiel auf die Höhe des Ausgangsniveaus (Natalizumab-Sättigung vor Beginn der Therapie) nach der zweiten Infusion zurück. Im ELISA wurden niedrige NAB-Titer nach der ersten Infusion gemessen und die anschließende Entwicklung von anhaltend hoch titrigen NAB führte nach ca. 6 Monaten zum Abbruch der Therapie mit Natalizumab. Bei den zwei anderen PatientInnen betrug der Natalizumab-Sättigungsgrad der T-Zellen 74% und 68% nach der ersten Infusion, und ging danach vorübergehend auf das Ausgangsniveau zurück. Bei beiden PatintInnen erholten sich die Natalizumab-Sättigungen nach ca. 6 Monaten wieder. NAB wurden nach 2 bzw. 3 Monaten nachgewiesen und waren nach ca. 5 bis 6 Monaten wieder verschwunden.
Die Überwachung der Natalizumab-Sättigung auf T-Zellen ist eine schnelle und zuverlässige Methode, um PatientInnen zu identifizieren, bei denen aufgrund von NAB Natalizumab nur vermindert wirken kann. Beides, hoch- und niedrig titrige NAB, reduzieren gleichermaßen effektiv die zelluläre Natalizumab-Sättigung. Interessanterweise zeigte die mittels Durchflusszytometrie gemessene Natalizumab-Sättigung, dass dieses Verfahren sehr empfindlich ist, da die NAB anscheinend länger wirksam sind, als die Nachweisgrenze des ELISA vermuten lässt.