Pathophysiologisch-serologische, bildgebende und klinische Charakteristika der Neuromyelitis Optica

Hintergrund: Neuromyelitis optica-Spektrum-Erkrankungen (NMOSD) stellen eine Gruppe neuroinflammatorischer Erkrankungen dar, die mit dem klinischen Auftreten von Myelitiden und/oder Optikusneuritiden (ON) einhergeht. Aufgrund zahlreicher überlappender klinischer und paraklinischer Eigenschaften beim Nachweis verschiedener Antikörper, vor allem auch in Abgrenzung zur Multiplen Sklerose (MS), besteht weiterhin der Bedarf nach neuen Biomarkern. Methodik: In zwei Studien wurden NMOSD-Patienten mit positivem Nachweis für Aquaporin-4-Antikörper (AQP-4-Ak) mittels 7 Tesla (T) Magnetresonanztomografie (MRT) hinsichtlich der I) periventrikulären Venendichte (PVA) in T2*-gewichteten Aufnahmen und II) der Phasenverschiebung in suszeptibilitätsgewichteten Sequenzen untersucht. Als Vergleich dienten die Ergebnisse von Patienten mit MS und gesunden Kontrollen (HC). In einer dritten Arbeit (III) erfolgte eine retrospektive Auswertung visueller Parameter im Vergleich von AQP-4-Ak-positiven Patienten und Patienten mit Antikörpern gegen das Myelin-Oligodendrozyten-Glykoprotein (MOG) mittels Optischer Kohärenztomografie (OCT), Visuell Evozierter Potenziale (VEP) und der Fernvisus-Messung. Ergebnisse: Bildmorphologisch zeigte sich in den 7T-T2* gewichteten Aufnahmen bei Patienten mit AQP-4-Ak-positiver NMOSD eine normal große PVA (AQP-4-Ak: PVA = 133 mm2; MS: PVA = 117 mm2; HC: PVA =144 mm2) und überwiegend fehlende paramagnetische Phasenverschiebungen (107 von 112 Läsionen, 96%) in den SWI-Sequenzen. Hinsichtlich des Vergleichs von MOG-Ak- gegenüber von AQP4-Ak-positiven Patienten fiel eine größere absolute Schubrate (Mittelwert, Spannweite, MOG-Ak: 4.5, 1 - 13; APQ4-Ak: 2, 1 -4; p = 0.012), bei insgesamt ähnlichem Verlust der im OCT gemessenen peripapillären retinalen Nervenfaserschicht (pRNFL) der AQP-4-Ak-positiven NMOSD im Vergleich zu den MOG-Ak-positiven Patienten auf (Mittelwert Standardabweichung, MOG-Ak: 59 ± 23 µm, AQP-4-Ak: 59 ± 21 µm). Jedoch waren die Werte der pRNFL nach dem Erstereignis einer ON bei den Patienten mit AQP-4-Ak deutlich stärker reduziert, als bei den MOG-Ak-positiven Patienten (AQP-4-Ak: pRNFL-Verlust = 32.8 μm (p<0.001); MOG-Ak: pRNFL-Verlust = 12.8 μm (p=0.001)). Schlussfolgerung: Mit Hilfe von modernen diagnostischen Verfahren, wie dem Ultrahochfeld-MRT und dem OCT wird die bessere Charakterisierung von phänotypisch ähnlichen neuroinflammatorischen Krankheitsentitäten ermöglicht. Die hierfür zugrundeliegenden unterschiedlichen Pathomechanismen sind bisher nicht vollständig verstanden und bedürfen weiterer Untersuchungen.Introduction: Different neuroinflammatory entities define the group of Neuromyelitis optica spectrum disorders (NMOSD) and are usually associated with the presentation of myelitis and/or optic neuritis. Although various antibodies were verified, there is still the challenge of overlapping clinical and paraclinical phenotypes which ask for further new diagnostic parameters. Methods: By using 7 Tesla (T) magnetic resonance imaging (MRI) patients with aquaporin-4-antibodies (AQP-4-ab) were investigated concerning a) the periventricular venous area (PVA) at T2*-weighted images and b) the phase changes within brain lesions at susceptibility-weighted (SWI)-images. The findings were compared to patients with Multiple Sclerosis (MS) and healthy controls (HC). Further patients with AQP-4-ab and antibodies against myelin oligodendrocyte glycoprotein (MOG-ab) were faced by using retrospective data of retinal optical coherence tomography (OCT), visual acuity and visual evoked potentials (VEP). Results: Patients with AQP-4-ab presented equal results like HC concerning the PVA (AQP-4-ab: PVA = 133 mm2; MS: PVA = 117 mm2; HC: PVA =144 mm2) and predominantly missing phase changes in brain lesions at SWI-images (107 of 112 lesions, 96%). Both, AQP-4-ab- and MOGab-positive patients, presented a loss in peripapillary nerve fiber layer (pRNFL) thickness at the same extend (mean ± standard deviation, MOG-ab: 59 ± 23 ±m, AQP4-ab: 59 ± 21 ±m), while the number of episodes of optic neuritis (ON) was lower in AQP4-ab-positive patients (mean, range, MOG-ab: 4.5, 1 - 13; APQ4-ab: 2, 1 -4; p = 0.012). However, the loss of pRNFL thickness after the first episode of ON was greater in patients with AQP-4-ab (AQP-4-ab: pRNFL-loss = 32.8 µm (p<0.001); MOG-ab pRNFL-loss = 12.8 µm (p=0.001). Conclusion: With the help of novel diagnostic tools, like the ultrahighfield-MRI and OCT, it is possible to distinguish between neuroinflammatory entities with similar phenotypes. For a better understanding of the underlying pathomechanisms further investigations are still needed

Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

The authors acknowledge the support of the Barts and the London Charity, the Multiple Sclerosis Society of Great Britain and Northern Ireland, the National Multiple Sclerosis Society, USA, notably the National Centre for the Replacement, Refinement & Reduction of Animals in Research, and the Wellcome Trust (grant no. 092539 to ZA). The siRNA was provided by Quark Pharmaceuticals. The funders and Quark Pharmaceuticals had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Electroretinographic Changes in Multiple Sclerosis Patients with Abnormal Visual Evoked Potentials

Purpose: Multiple Sclerosis (MS) is a disease of nervous system which is accompanied by degeneration of visual pathway in certain cases. Magnetic Resonance Imaging (MRI) and Visual Evoked Potentials (VEP) are among the diagnostic techniques in detecting this disease. The aim of the present study was to evaluate the possible electroretinography (ERG) changes among these patients. Patients and Methods: Thirty eyes of the patients with definite diagnosis of multiple sclerosis and delay in latency of visual evoked potential P100 peak entered the present prospective case control study as the case group. Latency and amplitude of ERG b-wave peak were measured in each eye. The result was compared with normal eyes thirty from age and sex marched individuals to evaluate the possible differences between the two groups. Results: There was no statistically significant difference regarding the demographic data (age, UCVA) between the case and control groups. The b-wave latency did show a statistically significant difference between patients with MS and normal controls (P &lt; 0.001). The ERG b-wave amplitude did not show statistically significant difference between patients with MS and the control group. Conclusion: From the result of the present study it seems that the latency of b-wave in flash ERG might be used as an indicator to evaluate the retinal dysfunction in MS patients with abnormal VEP pattern.Keywords:  Multiple sclerosis; retinal changes; flash electroretinograph

Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study

Background Currently available treatments for secondary progressive multiple sclerosis(SPMS) have limited efficacy and/or safety concerns. Adipose-mesenchymal derived stem cells(AdMSCs) represent a promising option and can be readily obtained using minimally invasive procedures. Go to: Patients and methods In this triple-blind, placebo-controlled study, cell samples were obtained from consenting patients by lipectomy and subsequently expanded. Patients were randomized to a single infusion of placebo, low-dose(1x106cells/kg) or high-dose(4x106cells/kg) autologous AdMSC product and followed for 12 months. Safety was monitored recording adverse events, laboratory parameters, vital signs and spirometry. Expanded disability status score (EDSS), magnetic-resonance-imaging, and other measures of possible treatment effects were also recorded. Go to: Results Thirty-four patients underwent lipectomy for AdMSCs collection, were randomized and thirty were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized patients were not infused because of karyotype abnormalities in the cell product. Only one serious adverse event was observed in the treatment arms (urinary infection, considered not related to study treatment). No other safety parameters showed changes. Measures of treatment effect showed an inconclusive trend of efficacy. Conclusion Infusion of autologous AdMSCs is safe and feasible in patients with SPMS. Larger studies and probably treatment at earlier phases would be needed to investigate the potential therapeutic benefit of this technique

Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome

Background A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Objective To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes. Methods Retrospective multicenter study. Results The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80% (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40% (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36%) and markedly impaired ambulation due to paresis or ataxia (25%) as the most common long-term sequelae. Functional blindness in one or both eyes was noted during at least one ON attack in around 70%. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70%). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44%. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70%, oligoclonal bands in only 13%, and blood-CSF-barrier dysfunction in 32%. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9%). Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28%, 32%, 15%, 33%, respectively; MS had been suspected in 36%. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases. Conclusion Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis

The multiple sclerosis visual pathway cohort: understanding neurodegeneration in MS

BACKGROUND: Multiple Sclerosis (MS) is an immune-mediated disease of the Central Nervous System with two major underlying etiopathogenic processes: inflammation and neurodegeneration. The latter determines the prognosis of this disease. MS is the main cause of non-traumatic disability in middle-aged populations. FINDINGS: The MS-VisualPath Cohort was set up to study the neurodegenerative component of MS using advanced imaging techniques by focusing on analysis of the visual pathway in a middle-aged MS population in Barcelona, Spain. We started the recruitment of patients in the early phase of MS in 2010 and it remains permanently open. All patients undergo a complete neurological and ophthalmological examination including measurements of physical and disability (Expanded Disability Status Scale; Multiple Sclerosis Functional Composite and neuropsychological tests), disease activity (relapses) and visual function testing (visual acuity, color vision and visual field). The MS-VisualPath protocol also assesses the presence of anxiety and depressive symptoms (Hospital Anxiety and Depression Scale), general quality of life (SF-36) and visual quality of life (25-Item National Eye Institute Visual Function Questionnaire with the 10-Item Neuro-Ophthalmic Supplement). In addition, the imaging protocol includes both retinal (Optical Coherence Tomography and Wide-Field Fundus Imaging) and brain imaging (Magnetic Resonance Imaging). Finally, multifocal Visual Evoked Potentials are used to perform neurophysiological assessment of the visual pathway. DISCUSSION: The analysis of the visual pathway with advance imaging and electrophysilogical tools in parallel with clinical information will provide significant and new knowledge regarding neurodegeneration in MS and provide new clinical and imaging biomarkers to help monitor disease progression in these patients

Validity of low-contrast letter acuity as a visual performance outcome measure for multiple sclerosis.

Low-contrast letter acuity (LCLA) has emerged as the leading outcome measure to assess visual disability in multiple sclerosis (MS) research. As visual dysfunction is one of the most common manifestations of MS, sensitive visual outcome measures are important in examining the effect of treatment. Low-contrast acuity captures visual loss not seen in high-contrast visual acuity (HCVA) measurements. These issues are addressed by the MS Outcome Assessments Consortium (MSOAC), including representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. MSOAC goals are acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are clinically meaningful. This review shows that MS and disease-free controls have similar median HCVA, while MS patients have significantly lower LCLA. Deficits in LCLA and vision-specific quality of life are found many years after an episode of acute optic neuritis, even when HCVA has recovered. Studies reveal correlations between LCLA and the Expanded Disability Status Score (EDSS), Multiple Sclerosis Functional Composite (MSFC), retinal nerve fiber layer (RNFL) and ganglion cell layer plus inner plexiform layer (GCL + IPL) thickness on optical coherence tomography (OCT), brain magnetic resonance imaging (MRI), visual evoked potential (VEP), electroretinogram (ERG), pupillary function, and King-Devick testing. This review also concludes that a 7-point change in LCLA is clinically meaningful. The overall goal of this review is to describe and characterize the LCLA metric for research and clinical use among persons with MS