Handbook of clinical neurology最新文献

Leukodystrophies are heritable disorders with white matter abnormalities observed on central nervous system magnetic resonance imaging. Pediatric leukodystrophies have long been known for their classically high, "unsolved" rate. Indeed, these disorders provide a diagnostic dilemma for many clinicians as over 100 genetic disorders alone may present with white matter abnormalities, with this figure not taking into account the substantial number of infectious agents, toxicities, and acquired disorders that may affect the white matter of the brain. Achieving a diagnosis may be the single most important step in the clinical course of a leukodystrophy-affected individual, with important implications for care and quality of life. For certain disorders, prompt recognition can direct therapeutic intervention with significant implications and requires urgent recognition. In this review, we cover newborn screening efforts, standard-of-care testing methodologies, and next generation sequencing approaches that continue to change the landscape of leukodystrophy diagnosis. Early studies have shown that next generation sequencing approaches, particularly exome and now genome sequencing have proven to be powerful in helping resolve many cases that were refractory to a single gene or linkage analysis approach. In addition, other methods are required for cases that remain persistently unsolved after next generation sequencing methods have been used. In the past more than half of affected individuals never achieved an etiologic diagnosis, and when they did, the reported times to diagnosis were >5 years although molecular testing has allowed this to be reduced to closer to 16 months. For affected families, next generation sequencing technologies have finally provided a way to fill gaps in diagnosis.

Hypomyelination is defined by the evidence of an unchanged pattern of deficient myelination on two MRIs performed at least 6 months apart in a child older than 1 year. When the temporal criteria are not fulfilled, and the follow-up MRI shows a progression of the myelination even if still not adequate for age, hypomyelination is excluded and the pattern is instead consistent with delayed myelination. This can be mild and nonspecific in some cases, while in other cases there is a severe delay that in the first disease stages could be difficult to differentiate from hypomyelination. In hypomyelinating leukodystrophies, hypomyelination is due to a primary impairment of myelin deposition, such as in Pelizaeus Merzabcher disease. Conversely, myelin lack is secondary, often to primary neuronal disorders, in delayed myelination and some condition with hypomyelination. Overall, the group of inherited white matter disorders with abnormal myelination has expanded significantly during the past 20 years. Many of these disorders have only recently been described, for many of them only a few patients have been reported and this contributes to make challenging the diagnostic process and the interpretation of Next Generation Sequencing results. In this chapter, we review the clinical and radiologic features of rare and lesser known forms of hypomyelination and delayed myelination not mentioned in other chapters of this handbook.

The hallmark neuropathologic feature of all leukodystrophies is depletion or alteration of the white matter of the central nervous system; however increasing genetic discoveries highlight the genetic heterogeneity of white matter disorders. These discoveries have significantly helped to advance the understanding of the complexity of molecular mechanisms involved in the biogenesis and maintenance of healthy white matter. Accordingly, genetic discoveries and functional studies have enabled us to firmly establish that multiple distinct structural defects can lead to white matter pathology. Leukodystrophies can develop not only due to defects in proteins essential for myelin biogenesis and maintenance or oligodendrocyte function, but also due to mutations encoding myriad of proteins involved in the function of neurons, astrocytes, microglial cells as well as blood vessels. To a variable extent, some leukodystrophies also show gray matter, peripheral nervous system, or multisystem involvement. Depending on the genetic defect and its role in the formation or maintenance of the white matter, leukodystrophies can present either in early childhood or adulthood. In this chapter, the classification of leukodystrophies will be discussed from the cellular defect point of view, followed by a description of known neuropathologic alterations for all leukodystrophies.

The neuromuscular junction is a prototypic synapse that has been extensively studied and provides a model for smaller and less accessible central synapses. Central to transmission at the neuromuscular synapse is the muscle acetylcholine receptor cation channel. Studies of the genetic disorders affecting the neuromuscular junction, termed congenital myasthenic syndromes, have illustrated how impaired signal transmission may be caused by a variety of mutations both within the ion channel itself and by the context of the ion channel within the synapse. Thus, multiple pathogenic mutations are also identified in proteins affecting the clustering, location, and density of the receptor within the overall synaptic structure. Disease severity ranges from death in childhood to mild disability throughout life. In addition, in utero, fetal akinesia due to impaired neuromuscular transmission may cause developmental abnormalities. Early studies identified mutations in the genes encoding the acetylcholine receptor subunits that impair ion channel gating or reduce the number of endplate receptors or a combination of the two, giving rise to "slow channel," "fast channel," or deficiency syndromes. Subsequently, it became clear that myasthenic syndromes also stem from mutations in proteins involved in neurotransmitter release, the formation and maintenance of the neuromuscular synapse, or glycosylation. This chapter describes the patient phenotypes, the diverse range of molecular mechanisms for synaptic dysfunction, and the corresponding therapeutic strategies, including drug combinations, that can be tailored to the many subtypes.

Median mononeuropathy is common, with carpal tunnel syndrome the most frequently encountered acquired mononeuropathy in clinical practice. However, other disorders of the median nerve and many known anatomical variants can lead to misdiagnosis and unexpected surgical complications if their presence is not correctly identified. A number of inherited and acquired disorders can affect the median nerve proximal to the wrist, alone or accompanied by other affected peripheral nerves. Recognizing other disorders that can masquerade as median mononeuropathies can avoid misdiagnosis and misguided management. This chapter explores median nerve anatomical variants, disorders, and lesions, emphasizing the need for careful examination and electrodiagnostic study in the localization of median neuropathy.

The evidence base for migraine prevention in both episodic and chronic migraine is outlined. The older oral preventatives, including antidepressants, antihypertensives, serotonin antagonists, antiepileptics, and calcium channel antagonists, and newer options including onabotulinumtoxinA and the CGRP monoclonal antibodies are covered. Many of the older oral preventatives were trialed before chronic migraine was defined, and they are used in chronic migraine based on the assumption that episodic migraine and chronic migraine are on a spectrum of the same condition. First- and second-line options are given, and a multicountry perspective is considered.

Nutraceuticals represent substances derived from food or plants that provide medical or health benefits, and are increasingly sought by patients as a means of treating migraine in a natural, effective, and safe manner as conventional therapies often fail, are expensive, and laden with side effects. This chapter reviews various nutraceutical therapies for migraine including phytomedicines (plant-based therapies), diets for migraine management and vitamin, mineral, and supplement-based treatments for migraine with respect to preclinical and clinical evidence. Reviewed herein are a multitude of nutraceutical options for the treatment of migraine including vitamins (e.g., riboflavin), antioxidants, and plants/phytomedicines: feverfew, butterbur, cannabis, St. John's Wort, Rosa x damascena, and Gingko biloba. Dietary interventions for migraine include low lipid, vegan, ketogenic, and DASH (dietary approaches to stop hypertension). Supplements such as polyunsaturated fatty acids (PUFAs) as well as l-carnitine, pre/probiotics, and melatonin are also discussed. Migraine patients and their caregivers have an armamentarium of nutraceutical options to treat headache. While some therapies such as vitamins harbor stronger evidence with more rigorous studies, patients may also choose dietary therapies that may offer more systemic health benefits while also improving migraine. As cannabis legalization spreads worldwide, care providers must be aware of the limited evidence in migraine. Future studies may explore traditional ancient medicines for migraine at basic science and clinical level, while currently adopted and new nutraceutical treatments may benefit from partnership with industry to engage in larger trials in humans.

Retinal migraine is usually characterized by attacks of fully reversible monocular visual loss associated with migraine headache. Retinal migraine is most common in women of child-bearing age who have a history of migraine with aura. In the typical attack, monocular visual features consist of partial or complete visual loss lasting less than 1h. Although the current diagnostic criteria for retinal migraine require fully reversible visual loss, our findings suggest that irreversible visual loss is part of the retinal migraine spectrum. Nearly half of reported cases with recurrent transient monocular visual loss subsequently experienced permanent monocular visual loss.