Handbook of clinical neurology最新文献

Pediatric skeletal muscle channelopathies include a spectrum of conditions including nondystrophic myotonias and periodic paralyses. They are rare inherited conditions that can cause significant morbidity. They are characterized by episodic stiffness and weakness. While there is significant phenotypic variability, there are distinct diagnostic features. The nondystrophic myotonias encompass myotonia congenita, paramyotonia congenita, and sodium channel myotonia caused by mutations in chloride and sodium channels. The clinical manifestations vary across age groups and a small subset with sodium channel mutations may have severe presentation with fetal akinesia, laryngospasm, or congenital myopathy. The periodic paralyses include hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and Andersen-Tawil syndrome. The phenotypic differences between the groups can be helpful in diagnosis. It is important to review the cardiac phenotype in Andersen-Tawil syndrome due to a risk of life-threatening cardiac arrhythmias. Early and accurate diagnosis utilizing clinical features aided by investigations is important across all the pediatric channelopathies, as effective symptomatic treatment is available and can substantially improve quality of life.

Traumatic spinal cord injury (SCI) may occur across the lifespan and is of global relevance. Damage of the spinal cord results in para- or tetraplegia and is associated with neuropathic pain, spasticity, respiratory, and autonomic dysfunction (i.e., control of bladder-bowel function). While the acute surgical treatment aims at stabilizing the spine and decompressing the damaged spinal cord, SCI patients require neurorehabilitation to restore neural function and to compensate for any impairments including motor disability, pain treatment, and bladder/bowel management. However, the spinal cord has a limited capacity to regenerate and much of the disability may persist, depending on the initial lesion severity and level of injury. For this reason, and the lack of effective drug treatments, there is an emerging interest and urgent need in promoting axonal regeneration and remyelination after SCI through cell- and stem-cell based therapies. This review briefly summarizes the state-of the art management of acute SCI and its neurorehabilitation to critically appraise phase I/II trials from the last two decades that have investigated cell-based therapies (i.e., Schwann cells, macrophages, and olfactory ensheathing cells) and stem cell-based therapies (i.e., neural stem cells, mesenchymal, and hematopoietic stem cells). Recently, two large multicenter trials provided evidence for the safety and feasibility of neural stem cell transplantation into the injured cord, whilst two monocenter trials also showed this to be the case for the transplantation of Schwann cells into the posttraumatic cord cavity. These are milestone studies that will facilitate further interventional trials. However, the clinical adoption of such approaches remains unproven, as there is only limited encouraging data, often in single patients, and no proven trial evidence to support regulatory approval.

Acquired demyelinating syndromes (ADS) represent acute neurologic illnesses characterized by deficits persisting for at least 24hours and involving the optic nerve, brain, or spinal cord, associated with regional areas of increased signal on T2-weighted images. In children, ADS may occur as a monophasic illness or as a relapsing condition, such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Almost all young people with MS have a relapsing-remitting course with clinical relapses. Important strides have been made in delineating MS from other ADS subtypes. Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and aquaporin 4-antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) were once considered variants of MS; however, studies in the last decade have established that these are in fact distinct entities. Although there are clinical phenotypic overlaps between MOGAD, AQP4-NMOSD, and MS, cumulative biologic, clinical, and pathologic evidence allows discrimination between these conditions. There has been a rapid increase in the number of available disease-modifying therapies for MS and novel treatment strategies are starting to appear for both MOGAD and AQP4-NMOSD. Importantly, there are a number of both inflammatory and noninflammatory mimics of ADS in children with implications of management for these patients in terms of treatment.

Hypomyelinating leukodystrophies are a subset of genetic white matter diseases characterized by insufficient myelin deposition during development. MRI patterns are used to identify hypomyelinating disorders, and genetic testing is used to determine the causal genes implicated in individual disease forms. Clinical course can range from severe, with patients manifesting neurologic symptoms in infancy or early childhood, to mild, with onset in adolescence or adulthood. This chapter discusses the most common hypomyelinating leukodystrophies, including X-linked Pelizaeus-Merzbacher disease and other PLP1-related disorders, autosomal recessive Pelizaeus-Merzbacher-like disease, and POLR3-related leukodystrophy. PLP1-related disorders are caused by hemizygous pathogenic variants in the proteolipid protein 1 (PLP1) gene, and encompass classic Pelizaeus-Merzbacher disease, the severe connatal form, PLP1-null syndrome, spastic paraplegia type 2, and hypomyelination of early myelinating structures. Pelizaeus-Merzbacher-like disease presents a similar clinical picture to Pelizaeus-Merzbacher disease, however, it is caused by biallelic pathogenic variants in the GJC2 gene, which encodes for the gap junction protein Connexin-47. POLR3-related leukodystrophy, or 4H leukodystrophy (hypomyelination, hypodontia, and hypogonadotropic hypogonadism), is caused by biallelic pathogenic variants in genes encoding specific subunits of the transcription enzyme RNA polymerase III. In this chapter, the clinical features, disease pathophysiology and genetics, imaging patterns, as well as supportive and future therapies are discussed for each disorder.

OnabotulinumtoxinA is a potent inhibitor of muscle contraction that acts by preventing the release of acetylcholine at the neuromuscular junction. In pain states such as migraine, its mechanism of action is not yet fully elucidated and probably relates to the phenomena of central and peripheral sensitization within the trigeminal system. Migraine is a prevalent and disabling disorder and, especially in its variant of chronic migraine (CM), is associated with relevant symptomatic and socioeconomic burden, the objective of preventive treatment being to reduce the frequency, duration, or severity of migraine attacks. OnabotulinumtoxinA, administered by intramuscular injection, is approved for the prevention of CM and is among the most utilized preventive treatments in CM and fundamental to clinical practice. The efficacy and safety of OnabotulinumtoxinA in the treatment of CM have been verified by the PREEMPT 1 and 2 studies and confirmed by the real-world studies that followed, including the COMPEL, REPOSE, and CM PASS. OnabotulinumtoxinA not only reduces headache days but also leads to improvement in functioning and quality of life, thereby reducing migraine impact. Data about its pathophysiology, efficacy, and its place in CM treatment in the era of CGRP monoclonal antibodies are reviewed and discussed here.

Migraine presents with high prevalence and similar clinical course with different disorders such as neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metabolic-endocrine, and immunological conditions, which can often cooccur themselves. Multifaceted mechanisms subtend these comorbidities with a bidirectional link. First, a shared genetic load can explain the cooccurrence. Second, comorbid pathologies can promote disproportionate energetic needs, thalamocortical network dysexcitability, and systemic transient or persistent proinflammatory state, which may trigger the activation of a broad self-protective network that includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This response results in maintenance of brain homeostasis by modulating subcortical-cortical excitability, energetic balance, osmoregulation, and emotional response. In this process, the CGRP is released in the trigeminovascular system. However, the calcitonin gene-related peptide (CGRP) plays several actions also outside the brain to maintain the homeostatic needs and is involved in the physiological functions of different systems, whose disorders are associated with migraine. This aspect further increases the complexity of migraine treatment, where standard therapies often have systemic adverse effects. On the other hand, some preventives can improve comorbid conditions. In summary, we propose that migraine management should involve a multidisciplinary approach to identify and mitigate potential risk factors and comorbidity and tailor therapies individually.

Ulnar neuropathy at the elbow is the second most common compressive neuropathy. Less common, although similarly disabling, are ulnar neuropathies above the elbow, at the forearm, and the wrist, which can present with different combinations of intrinsic hand muscle weakness and sensory loss. Electrodiagnostic studies are moderately sensitive in diagnosing ulnar neuropathy, although their ability to localize the site of nerve injury is often limited. Nerve imaging with ultrasound can provide greater localization of ulnar injury and identification of specific anatomical pathology causing nerve entrapment. Specifically, imaging can now reliably distinguish ulnar nerve entrapment under the humero-ulnar arcade (cubital tunnel) from nerve injury at the retro-epicondylar groove. Both these pathologies have historically been diagnosed as either "ulnar neuropathy at the elbow," which is non-specific, or "cubital tunnel syndrome," which is often erroneous. Natural history studies are few and limited, although many cases of mild-moderate ulnar neuropathy at the elbow appear to remit spontaneously. Conservative management, perineural steroid injections, and surgical release have all been studied in treating ulnar neuropathy at the elbow. Despite this, questions remain about the most appropriate management for many patients, which is reflected in the absence of management guidelines.