Potential of Sodium MRI as a Biomarker for Neurodegeneration and Neuroinflammation in Multiple Sclerosis

In multiple sclerosis (MS), experimental and ex vivo studies indicate that pathologic intra- and extracellular sodium accumulation may play a pivotal role in inflammatory as well as neurodegenerative processes. Yet, in vivo assessment of sodium in the microenvironment is hard to achieve. Here, sodium magnetic resonance imaging (23NaMRI) with its non-invasive properties offers a unique opportunity to further elucidate the effects of sodium disequilibrium in MS pathology in vivo in addition to regular proton based MRI. However, unfavorable physical properties and low in vivo concentrations of sodium ions resulting in low signal-to-noise-ratio (SNR) as well as low spatial resolution resulting in partial volume effects limited the application of 23NaMRI. With the recent advent of high-field MRI scanners and more sophisticated sodium MRI acquisition techniques enabling better resolution and higher SNR, 23NaMRI revived. These studies revealed pathologic total sodium concentrations in MS brains now even allowing for the (partial) differentiation of intra- and extracellular sodium accumulation. Within this review we (1) demonstrate the physical basis and imaging techniques of 23NaMRI and (2) analyze the present and future clinical application of 23NaMRI focusing on the field of MS thus highlighting its potential as biomarker for neuroinflammation and -degeneration

Pengaruh Facilitated Tucking Dan Musik Terhadap Respon Nyeri Bayi Prematur Ketika Pengambilan Darah

Manajemen nyeri yang tidak terkontrol pada bayi akan mempengaruhi pertumbuhan dan perkembangan selanjutnya. Salah satu tindakan manajemen nyeri non-farmakologi yang aman bagi bayi prematur adalah facilitated tucking dan pemberian musik. Penelitian ini untuk mengidentifikasi pengaruh kombinasi fasilitated tucking dan musik dalam mengurangi respon nyeri dan durasi menangis bayi prematur saat pengambilan darah. Rancangan kuasi eksperimen dengan pos-ttest control group design dipilih. Sampel penelitian ini adalah 60 bayi prematur yang dirawat di rumah sakit dan dilakukan pengambilan darah. Uji hipotesis menggunakan independent t-test. Kelompok intervensi diberikan facilitated tucking dan musik ketika pengambilan darah. Pengukuran nyeri menggunakan Premature Infant Pain Profile (PIPP) dan durasi menangis diukur dalam detik. Hasil penelitian menunjukkan bahwa rata-rata skor nyeri bayi adalah 7,03 pada kelompok intervensi dan 12,4 pada kelompok kontrol. Rata-rata durasi menangis bayi pada kelompok intervensi adalah 68,5 detik dan kelompok kontrol adalah 105 detik. Uji t menunjukkan perbedaan yang bermakna skor nyeri p 0,000 (α=0,05) dan durasi menangis 0,009 (α=0,05) bayi premature antara kelompok intervensi dan kelompok kontrol. DIsimpulkan bahwa facilitated tucking dan musik telah mengurangi respon nyeri dan durasi tangisan bayi prematur ketika pengambilan darah

Effects of a single-nucleotide-polymorphism in the adiponectin-gene on pathogenesis and clinical manifestations of systemic sclerosis

Hintergrund und Ziele Die systemische Sklerose (SSc) ist eine Bindegewebserkrankung unbekannter Ursache, welche in ihrem klinischen Krankheitsbild stark variiert und deren pathogenetische Hauptmerkmale Entzündung, Vaskulopathie und Fibrose darstellen. Bisher wurden in genetischen Untersuchungen über 1.800 Suszeptibilitätsgene der SSc festgestellt, die zu einem beträchtlichen Teil über Analysen von Einzel-Nukleotid-Polymorphismen (SNP) identifiziert wurden. Das Protein Adiponectin (ADIPOQ) wurde in ähnlicher Weise bisher meist im Zusammenhang mit Faktoren des metabolischen Syndroms untersucht und assoziiert. Da es aber nachgewiesene Wirkung auf Entzündung, Fibrosierung und Vaskulopathie, also wichtigen Pathogenese-Faktoren der SSc, hat, wurde in dieser Arbeit der SNP +45T>G (rs2241766) im Exon 2 des ADIPOQ-Gens auf Korrelation mit Pathogenese und klinischer Manifestation der SSc hin untersucht. Unterschiede der auftretenden Genotypen GG, TG und TT bei SSc-Patienten und gesunden Kontrollpersonen könnten dabei auf erhöhte oder erniedrigte Suszeptibilität für SSc hinweisen. Methoden In zwei voneinander unabhängigen Fall-Kontroll-Studien wurde genetisches Material von SSc Patienten und gesunden Kontrollpersonen mit Hilfe der Real-Time-Polymerasekettenreaktion (TaqMan-RealTime-PCR) durch allelische Diskrimination hinsichtlich der verschiedenen Genotypen analysiert. Dabei wurde DNA-Material aus Blut von 188 SSc-Patienten und 634 Kontrollen in der Erlanger Kohorte, sowie von 1.012 SSc-Patienten und 998 Kontrollen in der Kohorte der Université Descartes Paris isoliert und auf Assoziation mit SSc, dcSSc, fibrosierender Alveolitis, pulmonal-arterieller Hypertonie, digitalen Ulzerationen, sowie ACA und Anti-Scl70-Antikörpern hin überprüft. Ergebnisse und Beobachtungen In unserer Untersuchung war keiner der möglichen Genotypen GG, TG oder TT des SNP +45T>G im ADIPOQ-Gen signifikant mit der SSc, den klinischen Merkmalen dcSSc, fibrosierender Alveolitis, pumonal-arterieller Hypertonie, digitalen Ulzerationen oder positivem Antikörper-Status bezüglich Anti-Scl70 und ACA assoziiert. Praktische Schlussfolgerungen Unsere Analyse erbrachte keinen Zusammenhang zwischen SNP rs2241766 im Adiponectin-Gen und der SSc. Um abschließend den Einfluss von Adiponectin auf die Systemische Sklerose beurteilen zu können, sollten dennoch weitere Studien auf DNA-Ebene erfolgen, da es nicht ausgechlossen ist, dass andere SNPs im ADIPOQ-Gen mit SSc assoziiert sind und gegebenenfalls zur veränderten Expression und Wirkung des Adiponectin beitragen.Objective Systemic Sclerosis is a connective tissue disease of unknown origin, which is quite variable in its clinical appearance and whose pathogenetic hallmarks are inflammation, vasculopathy and fibrosis. Former genetic studies revealed more than 1.800 genes with an increased susceptibility for SSc, which were mainly based on analysis of single-nucleotide-polymorphisms (SNP). The protein adiponectin (ADIPOQ) was analyzed similarly, but, thus far, more often its association to the metabolic syndrome was investigated and found to be significantly associated with it. Because of its proven effect to fibrosis, inflammation and vasculopathy, important factors of the pathogenesis of SSc, we studied the influence of SNP +45T>G in exon 2 of the ADIPOQ-gene to pathogenesis and clinical manifestation of SSc. Differences of frequencies for the investigated genotypes GG, TG and TT between SSc-patients and healthy controls could indicate an increased or lowered susceptibility for SSc. Methods Genetic material of SSc-patients and healthy controls was analyzed in two independent case-control-studies by Real-Time-polymerase-chain-reaction (TaqMan-RealTime-PCR) and allelic discrimination for the different genotypes. Therefore, DNA from blood of 188 SSc-patients and 634 controls in the cohort of Erlangen plus 1.012 SSc-patients and 998 controls in the cohort of the Université Descartes Paris was isolated and tested for association with SSc, dcSSc, fibrosing alveolitis, pulmonary hypertension, digital ulcerations as well as ACA and Anti-Scl70-autoantibodies. Results Our investigation failed to show a significant association of the possible genotypes GG, TG or TT in the SNP +45T>G with SSc, the clinical signs dcSSc, fibrosing alveolitis, pulmonary hypertension, digital ulcerations or ACA- and Anti-Scl70-antibody-status. Conclusion Our analysis did not reveal any coherence between SNP rs2241766 in the ADIPOQ-gene and SSc. To finally evaluate the influence of adiponectin to SSc, further investigations based on SNP-analysis have to be performed, especially to find out if other polymorphisms in the ADIPOQ-gene are associated with SSc, which cannot be excluded so far

Pneumococcal-meningitis associated acute disseminated encephalomyelitis (ADEM) – case report of effective early immunotherapy

Introduction Unvaccinated patients with history of splenectomy are prone to fulminant courses of Streptococcus pneumoniae-associated bacterial meningitis. Besides direct brain damage those patients may additionally suffer from parainfectious syndromes, notably vasculitis and acute disseminated encephalomyelitis (ADEM). Differentiation and treatment of these immunological reactions is challenging. Methods Case report. Results A 61 year-old woman with history of splenectomy without vaccination for S. pneumoniae presented with progressive headache and meningism. CSF-analysis revealed pleocytosis with microbiological evidence for pneumococcal meningitis. After unsuspicious initial cranial CT imaging and initiation of appropriate antibiotic therapy, MRI two days later showed widespread FLAIR- and T2-hyperintense white matter lesions that further progressed upon follow-up MRI and that fulfilled imaging criteria of ADEM. Meanwhile the patient deteriorated and required mechanical ventilation. Cranial angiography showed no signs of vasculitis or vasospasms. Screening for autoimmune diseases remained negative, however oligoclonal bands turned positive. Brain biopsy mainly revealed perivascular CD4+ T-cells and demyelinated areas. Despite ongoing acute meningitis, a 10-day corticosteroid-pulse was initiated followed by steroid-tapering. Within 4 weeks, clinical and MRI findings ameliorated. In an one-year follow-up visit, the patient significantly recovered, MRI lesions were markedly reduced and no further relapses occurred. Conclusion Acute pneumococcal meningitis in unvaccinated splenectomized patients may be complicated by a monophasic course of parainfectious ADEM that can be controlled with high-dose corticosteroids. Parainfectious vasculitis or cerebritis are important differential diagnoses and exact differentiation of these entities is important to initiate early appropriate immunotherapy

No evidence of disease activity status over 3 years in a real-world cohort of relapsing remitting MS patients in Germany

Background: Over the last decade, therapy of relapsing remitting multiple sclerosis (RRMS) has evolved with the approval of several new treatment concepts. Thus, treatment goals have become more ambitious aiming at "no evidence of disease activity" (NEDA). As NEDA-3, this concept comprises freedom of clinical disease progression and relapses as well as inflammatory MRI activity. So far, data on NEDA status mainly stem from post-hoc analyses of drug approval studies. Yet, less is known about the significance of NEDA in "real-world" clinical settings. Hence, our study aims at investigation of NEDA in a heterogeneous cohort of relapsing MS patients. Methods: This is a retrospective single-center study at the Department of Neurology of the University Hospital Erlangen, Germany, including data of 306 patients with relapsing forms of MS (RMS) or clinical isolated syndrome (CIS) from 2009 to 2016. Inclusion required sufficient clinical information and in house cranial MRI follow-up data sets at baseline and at follow-up after one year with a potential extension to two and three year follow-up, if possible. NEDA-3 status, its correlation to clinical features, associated medication and NEDA failure (EDA) were analyzed. Results: In a cohort of RMS patients at the early stages of the disease (median EDSS 1.5, mean disease duration 30 months) at baseline, 45% retained NEDA-3 status after one year. This percentage decreased in year two (29%) and three (21%) of follow-up. MRI criteria were responsible for loss of NEDA status in 64% of cases and CIS patients were more likely to sustain NEDA status. Therapy with monoclonal antibodies appeared superior in sustaining NEDA status as compared to injectables or oral treatment options. Discussion: In our real-world analysis, we confirm the potential of NEDA for the evaluation and surveillance of MS disease activity, progression and therapy efficacy. Despite highly efficient immunomodulatory treatment, NEDA-3 was only preserved in a minority of patients. Monoclonal antibodies may yield best NEDA rates. Further studies are warranted to evaluate the value of the NEDA concept in real-world settings beyond standardized clinical studies

Real world application of ocrelizumab in multiple sclerosis: Single-center experience of 128 patients

Background: Pivotal trials showed good clinical efficiency of the monoclonal antibody ocrelizumab while being well tolerated and manageable in multiple sclerosis (MS). However, data on adverse events in everyday practice are scarce. Hence, our study aims at investigating short-term tolerability of ocrelizumab in a "real-world" setting. Methods: In this retrospective cohort study, data of 128 (86 relapsing-remitting, 42 progressive) MS patients at initiation of ocrelizumab were analyzed at the MS center of the University of Erlangen, Germany. Additionally, follow-up data of 68 patients at 6-months retreatment were analyzed. Structured phone interviews were applied after ocrelizumab initiation to report undocumented side effects. Results: Patients predominantly switched from monoclonal antibodies (46%), orals (20%), injectables (10%), steroids or immunosuppressants (each 8%), with a mean interval of 9.0 months after the last application of the previous immunotherapy. Applying a combined premedication with steroids, antihistamines and antipyretics for> 90% of patients, ocrelizumab treatment was well tolerated and mainly comprised mild (n = 59/128 at initiation, n = 5/68 at 6 months retreatment) and rarely moderate (n = 7/128 at initiation, n = 2/68 at 6 months) side effects. Predominantly mild infusion related reactions (IRR) were reported with a declining percentage over the follow-up applications. Infections occurred rarely. No severe side effects were observed. Secondary, treatment appeared efficient when looking at clinical surrogates of stable disease. Discussion: Our study delineates good short-term tolerability of ocrelizumab in a miscellaneous "real-world" MS cohort. Additional studies are warranted to confirm these beneficial findings and to reveal safety concerns in the longer-term follow-up

Longitudinal Sodium MRI of Multiple Sclerosis Lesions: Is there Added Value of Sodium Inversion Recovery MRI

Background Sodium enhancement has been demonstrated in multiple sclerosis (MS) lesions. Purpose To investigate sodium MRI with and without an inversion recovery pulse in acute MS lesions in an MS relapse and during recovery. Study Type Prospective. Subjects Twenty-nine relapsing-remitting MS patients with an acute relapse were included. Field Strength/Sequence A 3D density-adapted radial sodium sequence at 3 T using a dual-tuned (Na-23/H-1) head coil. Assessment Full-brain images of the tissue sodium concentration (TSC1, n = 29) and a sodium inversion recovery sequence (SIR1, n = 20) at the beginning of the anti-inflammatory therapy and on medium-term follow-up visits (days 27-99, n = 12 [TSC], n = 5 [SIR]) were measured. Regions of interest (RoIs) with contrast enhancement (T1CE+) and without change in T1-weighted imaging (FL + T1n) were normalized (nTSC and nSIR). To gain insight on the origin of the TSC enhancement at time point 1, it is investigated whether the nTSC enhancement of the lesions is accompanied by a change of the respective nSIR. Potential prognostic value of nSIR1 is examined referring to the nTSC progression. Statistical Tests nTSC and nSIR were compared regarding the type of lesion and the time point using a one-way ANOVA. Pearson's correlation coefficient was calculated for nTSC over nSIR and for nTSC1-nTSC2 over nSIR1. A P-value At the first measurement, all lesion types showed increased nTSC, while nSIR was decreased in the FL + T(1)n and the T1CE+ lesions in comparison to the normal-appearing white matter. For acute lesions, the difference between nTSC at baseline and nTSC at time point 2 showed a significant correlation with the baseline nSIR. Data Conclusion At time point 1, nTSC is increased, while nSIR is unchanged or decreased in the lesions. The mean sodium IR signal at baseline correlates with recovery or progression of an acute lesion. Evidence Level 2 Technical Efficacy Stage

Baseline magnetic resonance imaging of the optic nerve provides limited predictive information on short-term recovery after acute optic neuritis.

BACKGROUND: In acute optic neuritis, magnetic resonance imaging (MRI) may help to confirm the diagnosis as well as to exclude alternative diagnoses. Yet, little is known on the value of optic nerve imaging for predicting clinical symptoms or therapeutic outcome. PURPOSE: To evaluate the benefit of optic nerve MRI for predicting response to appropriate therapy and recovery of visual acuity. METHODS: Clinical data as well as visual evoked potentials (VEP) and MRI results of 104 patients, who were treated at the Department of Neurology with clinically definite optic neuritis between December 2010 and September 2012 were retrospectively reviewed including a follow up within 14 days. RESULTS: Both length of the Gd enhancing lesion (r = -0.38; p = 0.001) and the T2 lesion (r = -0.25; p = 0.03) of the optic nerve in acute optic neuritis showed a medium correlation with visual acuity after treatment. Although visual acuity pre-treatment was little but nonsignificantly lower if Gd enhancement of the optic nerve was detected via orbital MRI, improvement of visual acuity after adequate therapy was significantly better (0.40 vs. 0.24; p = 0.04). Intraorbitally located Gd enhancing lesions were associated with worse visual improvement compared to canalicular, intracranial and chiasmal lesions (0.35 vs. 0.54; p = 0.02). CONCLUSION: Orbital MRI is a broadly available, valuable tool for predicting the improvement of visual function. While the accurate individual prediction of long-term outcomes after appropriate therapy still remains difficult, lesion length of Gd enhancement and T2 lesion contribute to its prediction and a better short-term visual outcome may be associated with detection and localization of Gd enhancement along the optic nerve