In multiple sclerosis (MS), inflammation in the central nervous system (CNS) leads to damage of axons and myelin. Early during the clinical course, patients can compensate this damage, but little is known about the changes that underlie this improvement of neurological function. To study axonal changes that may contribute to recovery, we made use of an animal model of MS, which allows us to target inflammatory lesions to the corticospinal tract (CST), a major descending motor pathway. We demonstrate that axons remodel at multiple levels in response to a single neuroinflammatory lesion as follows: (a) surrounding the lesion, local interneurons show regenerative sprouting; (b) above the lesion, descending CST axons extend new collaterals that establish a “detour” circuit to the lumbar target area, whereas below the lesion, spared CST axons increase their terminal branching; and (c) in the motor cortex, the distribution of projection neurons is remodeled, and new neurons are recruited to the cortical motor pool. Behavioral tests directly show the importance of these changes for recovery. This paper provides evidence for a highly plastic response of the motor system to a single neuroinflammatory lesion. This framework will help to understand the endogenous repair capacity of the CNS and to develop therapeutic strategies to support it.
In multiple sclerosis (MS) the structural damage to axons determines the persistent clinical deficit patients acquire during the course of the disease. It is therefore important to test therapeutic strategies that can prevent or reverse this structural damage. The conventional animal model of MS, experimental autoimmune encephalomyelitis (EAE), typically shows disseminated inflammation in the central nervous system, which leads to a clinical deficit that cannot be directly attributed to a defined tract system. For this reason we have developed a localized EAE model, in which large inflammatory lesions are targeted to the dorsal columns of the spinal cord, an area including the corticospinal tract. These lesions show the pathological hallmarks of MS plaques and lead to reproducible and pronounced deficits in hindlimb locomotion. Because of the anatomical specificity of this technique we can now use highly sensitive behavioral tests that assess the functional integrity of specific axonal tracts. We show that these tests are predictive of the site and extent of a given lesion and are more sensitive for assessing the clinical course than the scales commonly used for disseminated EAE models. We believe that this targeted EAE model will become a Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system (CNS).1 Our understanding of the mechanisms that underlie MS has progressed significantly throughout the last years, yet our means for therapeutic intervention are still very limited. It is believed that in MS an autoimmune dysregulation leads to an inflammatory attack on the resident cells of the CNS.1 Recent studies have emphasized that the target of this inflammatory attack is not the myelin sheath alone but rather the entire myelin-axonal unit.2,3 Neuropathological studies have provided evidence that acute structural damage to axons is a prominent feature of MS lesions starting from the very early stages of the disease. 4 -6 The clinical importance of the structural axon damage is further underlined by the close correlation between neuroradiological markers of axon damage and the persistent neurological deficit in a given MS patient. 7,8 It is thus of central importance to develop therapeutic strategies that can prevent or repair axonal damage in MS. The basis for the development and evaluation of such strategies is the availability of suitable animal models, which should both reflect the pathological hallmarks of MS and allow for the quantification of therapeutic effects on axonal damage and repair.
Purpose It is currently unclear whether management and outcomes of critically ill patients differ between men and women. We sought to assess the influence of age, sex and diagnoses on the probability of intensive care provision in critically ill cardio- and neurovascular patients in a large nationwide cohort in Switzerland. Methods Retrospective analysis of 450,948 adult patients with neuro- and cardiovascular disease admitted to all hospitals in Switzerland between 01/2012 and 12/2016 using Bayesian modeling. Results For all diagnoses and populations, median ages at admission were consistently higher for women than for men [75 (64;82) years in women vs. 68 (58;77) years in men, p < 0.001]. Overall, women had a lower likelihood to be admitted to an intensive care unit (ICU) than men, despite being more severely ill [odds ratio (OR) 0.78 (0.76–0.79)]. ICU admission probability was lowest in women aged > 65 years (OR women:men 0.94 (0.89–0.99), p < 0.001). Women < 45 years had a similar ICU admission probability as men in the same age category [OR women:men 1.03 (0.94–1.13)], in spite of more severe illness. The odds to die were significantly higher in women than in men per unit increase in Simplified Acute Physiology Score (SAPS) II (OR 1.008 [1.004–1.012]). Conclusion In the care of the critically ill, our study suggests that women are less likely to receive ICU treatment regardless of disease severity. Underuse of ICU care was most prominent in younger women < 45 years. Although our study has several limitations that are imposed by the limited data available from the registries, our findings suggest that current ICU triage algorithms could benefit from careful reassessment. Further, and ideally prospective, studies are needed to confirm our findings. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06393-3.
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