These data argue for the potential clinical utility of JCV serology for PML risk stratification. However, further investigations of fluctuations in serostatus and of antibody levels for a more precise understanding of the predictive value are warranted.

Pathological and clinical studies implicate antibody-dependent mechanisms in the immunopathogenesis of multiple sclerosis. We tested this hypothesis directly by investigating the ability of patient-derived immunoglobulins to mediate demyelination and axonal injury in vitro. Using a myelinating culture system, we developed a sensitive and reproducible bioassay to detect and quantify these effects and applied this to investigate the pathogenic potential of immunoglobulin G preparations obtained from patients with multiple sclerosis (n = 37), other neurological diseases (n = 10) and healthy control donors (n = 13). This identified complement-dependent demyelinating immunoglobulin G responses in approximately 30% of patients with multiple sclerosis, which in two cases was accompanied by significant complement-dependent antibody mediated axonal loss. No pathogenic immunoglobulin G responses were detected in patients with other neurological disease or healthy controls, indicating that the presence of these demyelinating/axopathic autoantibodies is specific for a subset of patients with multiple sclerosis. Immunofluorescence microscopy revealed immunoglobulin G preparations with demyelinating activity contained antibodies that specifically decorated the surface of myelinating oligodendrocytes and their contiguous myelin sheaths. No other binding was observed indicating that the response is restricted to autoantigens expressed by terminally differentiated myelinating oligodendrocytes. In conclusion, our study identifies axopathic and/or demyelinating autoantibody responses in a subset of patients with multiple sclerosis. This observation underlines the mechanistic heterogeneity of multiple sclerosis and provides a rational explanation why some patients benefit from antibody depleting treatments.

Low vitamin D and remote EBV infection may be associated with clinical MS breakthrough within 2-3 years.

Abstract:Background: The incidence of therapy-related acute leukaemia (TRAL) in mitoxantrone treatment in multiple sclerosis (MS) is controversially discussed. Methods and results:In a retrospective meta-analysis from six centres, we observed six cases of acute myeloid leukaemia (AML) (incidence 0.41% for patients with mean follow up after end of treatment of 3.6 years, n = 1.156; incidence 0.25% for all patients, n = 2.261). Potential influencing factors such as myelotoxic or glucocorticosteroid pretreatment/ cotreatment were present in all but one case of TRAL. Between 1990 and 2010, 11 cases of TRAL were reported to the Drug Commission of the German Medical Association (estimated risk of 0.09-0.13%). Conclusions: Regional differences in reported TRAL incidence may point to confounding cofactors such as administration protocols and cotreatments.

BackgroundIn asthma, mechanisms contributing to chronicity remain to be determined. Recent models of sensitisation with prolonged airway allergen challenges reproduce typical features of chronic asthma. However, the interplay between inflammation, structural changes and lung function is poorly understood. This study was performed to delineate functional, structural and immunological airway changes after cessation of long term challenges to elucidate factors contributing to the development of prolonged lung function changes.Methodology/Principal FindingsMice sensitised systemically were consecutively challenged intranasally with ovalbumin for two or eight weeks. After the end of challenges, lung function, airway inflammation, features of airway remodelling, local T-cell cytokines and systemic ovalbumin-specific antibodies were monitored. Long term challenges resulted in airway hyperresponsiveness lasting 2 weeks and reduced baseline lung function for 6 weeks after their cessation. In contrast, these changes resolved within one week after short term challenges. Prolonged transforming growth factor beta (TGF-β)1 production and marked peribronchial fibrosis were only induced by long term challenges. Importantly, fibrosis became apparent only after the onset of lung function changes and outlasted them. Further, long term challenges led to prolonged and intense airway inflammation with marked lymphocytosis, but moderate eosinophilia, sustained IL-5 production and ovalbumin-specific IgG2a antibodies, the latter suggesting a Th1 component to the immune response. In contrast, following short term challenges airway inflammation was dominated by eosinophils and associated with a strong, but transient IL-13 response.ConclusionsProlonged lung function changes after long term allergen challenges seem to develop and resolve independently of the persistent peribronchial fibrosis. They are more closely associated with intense airway inflammation, marked lymphocytosis, prolonged IL-5 and TGF-β1 production in the airways and a Th1 immune response.

Coebergh et al. agree that the most plausible mechanism for air in the cavernous sinus is a retrograde venous embolism. In reviewing our article, we concur that the discussion may be misleading; we used the term TIA to denote a clinical syndrome which resolved within 1 hour rather than to referring to a proposed mechanism. We know that the patient was sitting upright at the time. Because air is less dense than blood, it is possible that the embolism traveled retrogradely to produce the transient symptoms. On review of the catheter placement seen on chest x-ray at time of admission, the line appears to be placed with the tip in the superior vena cava. We refer to a study 2 that monitored paradoxical emboli in patients with transatrial shunts after central line placements. The head CT shows presence of air in the sinus and makes it more likely that it was retrograde. However, paradoxical air embolism should always be considered in patients with transatrial shunts. We thank Coebergh et al. for raising this important issue.

Central nervous system (CNS) inflammation has been considered to be the main pathological feature of multiple sclerosis (MS). However, the complexity of this autoimmune disorder also comprises neurodegenerative processes that may occur within acute phases of inflammation, yet also temporally independent and outside of inflammatory lesions or even in so-called normal appearing white matter. Measurement strategies for neurodegeneration and neuroprotection include clinical parameters, magnetic resonance imaging and novel instruments such as diffusion tensor imaging or optical coherence tomography. Neurotrophic factors activate endogenous neuroprotective pathways. Their up-regulation by CNS-infiltrating immune cells has led to the concept of neuroprotective autoimmunity. The capacity to enhance this endogenous neuroprotection is a valuable property for therapeutic agents and has in detail been studied for glatirameracetate, laquinimod and dimethylfumarate. Multimodal measurement of neuroprotective properties of established and novel MS therapeutics and further elucidation of neuroprotective pathways within the autoimmune process will be useful to augment our insight into the complexity of the disease and to improve therapy, especially in terms of long-term disability and cognitive decline.

Multiple sclerosis (MS)-related spasticity is associated with disability and impairment in quality of life. We report on a patient with secondary progressive MS and spastic tetraparesis (Expanded Disability Status Scale score 8.5). The right arm exhibited flexor spasticity resulting in functional disability despite multimodal symptomatic treatment. Intrathecal baclofen led to side effects despite decreasing efficacy. Low-dose nabiximols improved spasticity and function with recovery of daily-life activities and spasticity-related symptoms. Reduction of intrathecal baclofen ameliorated adverse drug reactions. Add-on cannabinoid therapy was effective in therapy-refractory spasticity with supra-additive effect in combining intrathecal baclofen and nabiximols, hypothetically explained by mutually complementing mechanisms of action.