Multiple faces of multiple sclerosis in the era of highly efficient treatment modalities: Lymphopenia and switching treatment options challenges daily practice.

The expanded treatment landscape in relapsing-remitting multiple sclerosis (MS) has resulted in highly effective treatment options and complexity in managing disease- or drug-related events during disease progression. Proper decision-making requires thorough knowledge of the immunobiology of MS itself and an understanding of the main principles behind the mechanisms that lead to secondary autoimmunity affecting organs other than the central nervous system as well as opportunistic infections. The immune system is highly adapted to both environmental and disease-modifying agents. Immune reconstitution following cell depletion or cell entrapment therapies eliminates pathogenic aspects of the disease but can also lead to distorted immune responses with harmful effects. Atypical relapses occur with second-line treatments or after their discontinuation and require appropriate clinical decisions. Lymphopenia is a result of the mechanism of action of many drugs used to treat MS. However, persistent lymphopenia and cell-specific lymphopenia could result in disease exacerbation, secondary autoimmunity, or the emergence of opportunistic infections. Clinicians treating patients with MS should be aware of the multiple faces of MS under novel, efficient treatment modalities and understand the intricate brain-immune cell interactions in the context of an altered immune system. MS relapses and disease progression still occur despite the current treatment modalities and are mediated either by failure to control effector mechanisms inherent to MS pathophysiology or by new drug-related mechanisms. The multiple faces of MS due to the highly adapted immune system of patients impose the need for appropriate switching therapies that safeguard disease remission and further clinical improvement.

Planimetric and Volumetric Brainstem MRI Markers in Progressive Supranuclear Palsy, Multiple System Atrophy, and Corticobasal Syndrome. A Systematic Review and Meta-Analysis.

BACKGROUND: Various MRI markers-including midbrain and pons areas (Marea, Parea) and volumes (Mvol, Pvol), ratios (M/Parea, M/Pvol), and composite markers (magnetic resonance imaging Parkinsonism Indices 1,2; MRPI 1,2)-have been proposed as imaging markers of Richardson's syndrome (RS) and multiple system atrophy-Parkinsonism (MSA-P). A systematic review/meta-analysis of relevant studies aiming to compare the diagnostic accuracy of these imaging markers is lacking. METHODS: Pubmed and Scopus were searched for studies with >10 patients (RS, MSA-P or CBS) and >10 controls with data on Marea, Parea, Mvol, Pvol, M/Parea, M/Pvol, MRPI 1, and MRPI 2. Cohen's d, as a measure of effect size, was calculated for all markers in RS, MSA-P, and CBS. RESULTS: Twenty-five studies on RS, five studies on MSA-P, and four studies on CBS were included. Midbrain area provided the greatest effect size for differentiating RS from controls (Cohen's d = -3.10; p < 0.001), followed by M/Parea and MRPI 1. MSA-P had decreased midbrain and pontine areas. Included studies exhibited high heterogeneity, whereas publication bias was low. CONCLUSIONS: Midbrain area is the optimal MRI marker for RS, and pons area is optimal for MSA-P. M/Parea and MRPIs produce smaller effect sizes for differentiating RS from controls.

The mTOR Signaling Pathway in Multiple Sclerosis; from Animal Models to Human Data.

This article recapitulates the evidence on the role of mammalian targets of rapamycin (mTOR) complex pathways in multiple sclerosis (MS). Key biological processes that intersect with mTOR signaling cascades include autophagy, inflammasome activation, innate (e.g., microglial) and adaptive (B and T cell) immune responses, and axonal and neuronal toxicity/degeneration. There is robust evidence that mTOR inhibitors, such as rapamycin, ameliorate the clinical course of the animal model of MS, experimental autoimmune encephalomyelitis (EAE). New, evolving data unravel mechanisms underlying the therapeutic effect on EAE, which include balance among T-effector and T-regulatory cells, and mTOR effects on myeloid cell function, polarization, and antigen presentation, with relevance to MS pathogenesis. Radiologic and preliminary clinical data from a phase 2 randomized, controlled trial of temsirolimus (a rapamycin analogue) in MS show moderate efficacy, with significant adverse effects. Large clinical trials of indirect mTOR inhibitors (metformin) in MS are lacking; however, a smaller prospective, non-randomized study shows some potentially promising radiological results in combination with ex vivo beneficial effects on immune cells that might warrant further investigation. Importantly, the study of mTOR pathway contributions to autoimmune inflammatory demyelination and multiple sclerosis illustrates the difficulties in the clinical application of animal model results. Nevertheless, it is not inconceivable that targeting metabolism in the future with cell-selective mTOR inhibitors (compared to the broad inhibitors tried to date) could be developed to improve efficacy and reduce side effects.

Immunopathology of Tumefactive Demyelinating Lesions-From Idiopathic to Drug-Related Cases.

Tumefactive demyelinating lesions (TDL) represent a diagnostic dilemma for clinicians, and in rare atypical cases a collaboration of a neuroradiologist, a neurologist, and a neuropathologist is warranted for accurate diagnosis. Recent advances in neuropathology have shown that TDL represent an umbrella under which many different diagnostic entities can be responsible. TDL can emerge not only as part of the spectrum of classic multiple sclerosis (MS) but also can represent an idiopathic monophasic disease, a relapsing disease with recurrent TDL, or could be part of the myelin oligodendrocyte glycoprotein (MOG)- and aquaporin-4 (AQP4)-associated disease. TDL can appear during the MS disease course, and increasingly cases arise showing an association with specific drug interventions. Although TDL share common features with classic MS lesions, they display some unique features, such as extensive and widespread demyelination, massive and intense parenchymal infiltration by macrophages along with lymphocytes (mainly T but also B cells), dystrophic changes in astrocytes, and the presence of Creutzfeldt cells. This article reviews the existent literature regarding the neuropathological findings of tumefactive demyelination in various disease processes to better facilitate the identification of disease signatures. Recent developments in immunopathology of central nervous system disease suggest that specific pathological immune features (type of demyelination, infiltrating cell type distribution, specific astrocyte pathology and complement deposition) can differentiate tumefactive lesions arising as part of MS, MOG-associated disease, and AQP4 antibody-positive neuromyelitis optica spectrum disorder. Lessons from immunopathology will help us not only stratify these lesions in disease entities but also to better organize treatment strategies. Improved advances in tissue biomarkers should pave the way for prompt and accurate diagnosis of TDL leading to better outcomes for patients.

Experimental hypogonadism: insulin resistance, biochemical changes and effect of testosterone substitution.

Background We sought to clarify the role of testosterone substitution in terms of insulin resistance and metabolic profile dysregulation in hypogonadism. Methods Twenty-nine male Wistar rats aged 11-12 weeks were divided in three groups: control (C, n = 10), sham operation; orchiectomy (ORX, n = 9); and orchiectomy + testosterone substitution (ORX+T, n = 10). Blood samples were obtained at day 1 (operation), after 10 days (intramuscular T injection 100 µg/100 g b.w.), 25 days (second T injection) and 40 days (sacrifice). Results Hormonal replacement significantly attenuated the negative effect of orchiectomy on insulin resistance as indicated by the successive changes in both insulin levels (1.44 ± 2.94 vs. 4.10 ± 2.47 vs. 1.78 ± 0.68 ng/mL, for D1, D10 and D40, respectively; p = 0.028 and p = 0.022, respectively) and HOMA-IR index (1.36 ± 2.75 vs. 3.68 ± 1.87 vs. 1.74 ± 0.69 ng/mL, for D1, D10 and D40, respectively; p = 0.024 and p = 0.026, respectively) in the ORX+T group. Irisin levels peaked at the 10th postoperative day and were decreased at the end of the experiment (0.27 ± 0.11 vs. 0.85 ± 0.54 vs. 0.02 ± 0.07 ng/mL for D1, D10 and D40, respectively; p = 0.028 in both cases), whereas resistin levels did not differ. Experimental hypogonadism results in an unfavorable lipid profile and insulin resistance, which is not observed when the ORX animals are substituted for T.