Lancet neurology
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Hereditary optic neuropathies result from defects in the human genome, both nuclear and mitochondrial. The two main and most recognised phenotypes are dominant optic atrophy and Leber hereditary optic neuropathy. ⋯ A unifying feature in the pathophysiology of these disorders appears to involve mitochondrial dysfunction, suggesting that the retinal ganglion cells and their axons are especially susceptible to perturbations in mitochondrial homoeostasis. As we better understand the pathogenesis behind these genetic diseases, aetiologically targeted therapies are emerging and entering into clinical trials, including treatments aimed at halting the cascade of neurodegeneration, replacing or editing the defective genes or their protein products, and potentially regenerating damaged optic nerves, as well as preventing generational disease transmission.
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Traditionally, multiple sclerosis has been categorised by distinct clinical descriptors-relapsing-remitting, secondary progressive, and primary progressive-for patient care, research, and regulatory approval of medications. Accumulating evidence suggests that the clinical course of multiple sclerosis is better considered as a continuum, with contributions from concurrent pathophysiological processes that vary across individuals and over time. ⋯ These observations encourage a new consideration of the course of multiple sclerosis as a spectrum defined by the relative contributions of overlapping pathological and reparative or compensatory processes. New understanding of key mechanisms underlying progression and measures to quantify progressive pathology will potentially have important and beneficial implications for clinical care, treatment targets, and regulatory decision-making.
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Optic neuritis is an inflammatory optic neuropathy that is commonly indicative of autoimmune neurological disorders including multiple sclerosis, myelin-oligodendrocyte glycoprotein antibody-associated disease, and neuromyelitis optica spectrum disorder. Early clinical recognition of optic neuritis is important in determining the potential aetiology, which has bearing on prognosis and treatment. Regaining high-contrast visual acuity is common in people with idiopathic optic neuritis and multiple sclerosis-associated optic neuritis; however, residual deficits in contrast sensitivity, binocular vision, and motion perception might impair vision-specific quality-of-life metrics. ⋯ Key clinical, imaging, and laboratory findings differentiate these disorders, allowing clinicians to focus their diagnostic studies and optimise acute and preventive treatments. Guided by early and accurate diagnosis of optic neuritis subtypes, the timely use of high-dose corticosteroids and, in some instances, plasmapheresis could prevent loss of high-contrast vision, improve contrast sensitivity, and preserve colour vision and visual fields. Advancements in our knowledge, diagnosis, and treatment of optic neuritis will ultimately improve our understanding of autoimmune neurological disorders, improve clinical trial design, and spearhead therapeutic innovation.
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The factor that is most relevant and strongly associated with the clinical course of multiple sclerosis is chronological age. Very young patients exclusively have relapsing remitting disease, whereas those with later onset disease face a more rapid development of permanent disability. For people with progressive multiple sclerosis, the poor response to current disease modifying therapies might be related to ageing in the immune system and CNS. ⋯ Both somatic and reproductive ageing processes might contribute to development of progressive multiple sclerosis. Understanding the role of ageing in immune and neural cell function in patients with multiple sclerosis might be key to halting non-relapse-related progression. The growing literature on potential therapies that target senescent cells and ageing processes might provide effective strategies for remyelination and neuroprotection.
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There is no consensus regarding the classification of optic neuritis, and precise diagnostic criteria are not available. This reality means that the diagnosis of disorders that have optic neuritis as the first manifestation can be challenging. Accurate diagnosis of optic neuritis at presentation can facilitate the timely treatment of individuals with multiple sclerosis, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. ⋯ Our diagnostic criteria are based on clinical features that permit a diagnosis of possible optic neuritis; further paraclinical tests, utilising brain, orbital, and retinal imaging, together with antibody and other protein biomarker data, can lead to a diagnosis of definite optic neuritis. Paraclinical tests can also be applied retrospectively on stored samples and historical brain or retinal scans, which will be useful for future validation studies. Our criteria have the potential to reduce the risk of misdiagnosis, provide information on optic neuritis disease course that can guide future treatment trial design, and enable physicians to judge the likelihood of a need for long-term pharmacological management, which might differ according to optic neuritis subgroups.