Handbook of clinical neurology最新文献

Migraine is estimated to affect 959 million people worldwide and has a female preponderance of 3:1. This is thought to be due to the influence of female hormones as before puberty both sexes are affected equally. The prevalence is highest in women of childbearing age at 24%. It is, therefore, important to have a good understanding of how pregnancy influences migraine and how to advise and manage women with migraine during pregnancy and lactation.

Dizziness is a common symptom among patients in primary care, general neurology, and headache clinic practices. Vestibular migraine is conceptualized as a condition of recurrent attacks of vestibular symptoms attributed to migraine. It is now considered the most common cause of spontaneous episodic vertigo. Persistent postural-perceptual dizziness (PPPD) has more recently been defined based on four previous clinical entities as a syndrome of chronic daily dizziness, unsteadiness, or nonspinning vertigo that fluctuates and is exacerbated by postural, motion, or visual factors. Although PPPD is more often precipitated by other conditions causing vertigo, unsteadiness, or dizziness, it is discussed at length in this chapter because vestibular migraine is among the most common triggers for development of PPPD. Pathophysiology of each is incompletely understood, and with lack of biomarkers, the diagnosis of each rests on consensus-derived, symptom-based criteria. Areas of uncertainty exist regarding some overlapping symptoms that may create potential diagnostic confusion between the conditions. This chapter provides a comprehensive review of the current state of vestibular migraine and PPPD, including diagnostic and management guidance for when they occur separately, together, or along with other common comorbidities.

Paraneoplastic neurologic syndromes are rarely associated with hematologic malignancies. In their rarity, lymphomas are the diseases with more frequent paraneoplastic neurologic syndrome. High-risk antibodies are absent in most lymphoma-associated paraneoplastic neurologic syndromes, with the exception of antibodies to Tr/DNER in paraneoplastic cerebellar degeneration, mGluR5 in limbic encephalitis, and mGluR1 in some cerebellar ataxias. Peripheral nervous system paraneoplastic neurologic syndromes are rare and heterogeneous, with a prevalence of demyelinating polyradiculoneuropathy in non-Hodgkin lymphoma. Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) is a rare, paraneoplastic syndrome due to an underlying plasma cell disorder. The diagnosis is based on defined criteria, and vascular endothelial growth factor (VEGF), not an antibody, is considered a reliable diagnostic marker that also mirrors therapy response. As with the paraneoplastic neurologic syndromes in solid tumors, therapies rely on cancer treatment associated with immunomodulatory treatment with better response in PNS with antibodies to surface antigens. The best outcome is generally present in Ophelia syndrome/limbic encephalitis with anti-mGluR5 antibodies, with frequent complete recovery. Besides patients with isolated osteosclerotic lesions (where radiotherapy is indicated), hematopoietic stem-cell transplantation is the therapy of choice in patients with POEMS syndrome. In the paraneoplastic neurologic syndromes secondary to immune checkpoint inhibitors, discontinuation of the drug together with immunomodulatory treatment is recommended.

New onset movement disorders are a common clinical problem in pediatric neurology and can be infectious, inflammatory, metabolic, or functional in origin. Encephalitis is one of the more important causes of new onset movement disorders, and movement disorders are a common feature (~25%) of all encephalitis. However, all encephalitides are not the same, and movement disorders are a key diagnostic feature that can help the clinician identify the etiology of the encephalitis, and therefore appropriate treatment is required. Movement disorders are a characteristic feature of autoimmune encephalitis such as anti-NMDAR encephalitis, herpes simplex virus encephalitis-induced autoimmune encephalitis, and basal ganglia encephalitis. Other rarer autoantibody-associated encephalitis syndromes with movement disorder associations include encephalitis associated with glycine receptor, DPPX, and neurexin-3 alpha autoantibodies. In addition, movement disorders can accompany acute disseminated encephalomyelitis with and without myelin oligodendrocyte glycoprotein antibodies. Extremely important infectious encephalitides that have characteristic movement disorder associations include Japanese encephalitis, dengue fever, West Nile virus, subacute sclerosing panencephalitis (SSPE), and SARS-CoV-2 (COVID-19). This chapter discusses how specific movement disorder phenomenology can aid clinician diagnostic suspicion, such as stereotypy, perseveration, and catatonia in anti-NMDAR encephalitis, dystonia-Parkinsonism in basal ganglia encephalitis, and myoclonus in SSPE. In addition, the chapter discusses how the age of the patients can influence the movement disorder phenomenology, such as in anti-NMDAR encephalitis where chorea is typical in young children, even though catatonia and akinesia is more common in adolescents and adults.

Immune checkpoint inhibitors (ICIs) are cancer immunotherapies that enhance the body's own immune system to treat cancer. ICI treatment, however, can cause immune-related adverse events (irAEs) that can affect any organ, resulting in significant morbidity and mortality. Neurologic irAEs (nirAEs) are rare and can affect the peripheral nervous system more commonly than the central nervous system. Treatment is dependent on the severity of the neurologic manifestations and often includs discontinuation of the ICI and initiation of steroid therapy as the first line; other treatments have also been used. NirAEs and cardiac irAEs have higher fatality rates underlying the importance of early recognition and appropriate management. This chapter reviews the clinical manifestations of neurologic immune-related adverse events associated with ICI treatment as well as diagnostic and therapeutic modalities.

An adaptive immune response in less than 1% of people who develop cancer produces antibodies against neuronal proteins. These antibodies can be associated with paraneoplastic syndromes, and their accurate detection should instigate a search for a specific cancer. Over the years, multiple systems, from indirect immunofluorescence to live cell-based assays, have been developed to identify these antibodies. As the specific antigens were identified, high throughput, multi-antigen substrates such as line blots and ELISAs were developed for clinical laboratories. However, the evolution of assays required to identify antibodies to membrane targets has shone a light on the importance of antigen conformation for antibody detection. This chapter discusses the early antibody assays used to detect antibodies to nuclear and cytosolic targets and how new approaches are required to detect antibodies to membrane targets. The chapter presents recent data that support international recommendations against the sole use of line blots for antibody detection and highlights a new antigen-specific approach that appears promising for the detection of submembrane targets.

Paraneoplastic neurologic syndromes (PNSs) are a group of diseases affecting the central and/or peripheral nervous system caused by immune-mediated processes directed toward antigens with shared expression in tumor and neural tissue. Germ cell tumors (GCTs) are associated with PNSs with varied clinical phenotypes. Early diagnosis of PNS is vital to potentially uncover and treat underlying tumors, improving the chances of recovery, and preventing permanent neurologic complications. In this chapter, we outline the pathophysiology and epidemiology of PNS. We briefly provide a summary of GCTs in males and females. We review the neural-specific autoantibodies and PNSs associated with GCTs and their clinical and radiologic accompaniments. We also provide an overview of the treatment and prognosis of these disorders.

"Vanishing white matter" (VWM) is a leukodystrophy caused by autosomal recessive pathogenic variants in the genes encoding the subunits of eukaryotic initiation factor 2B (eIF2B). Disease onset and disease course are extremely variable. Onset varies from the antenatal period until senescence. The age of onset is predictive of disease severity. VWM is characterized by chronic neurologic deterioration and, additionally, episodes of rapid and major neurologic decline, provoked by stresses such as febrile infections and minor head trauma. The disease is dominated by degeneration of the white matter of the central nervous system due to dysfunction of oligodendrocytes and in particular astrocytes. Organs other than the brain are rarely affected, with the exception of the ovaries. The reason for the selective vulnerability of the white matter of the central nervous system and, less consistently, the ovaries is poorly understood. eIF2B is a central regulatory factor in the integrated stress response (ISR). Genetic variants decrease eIF2B activity and thereby cause constitutive activation of the ISR downstream of eIF2B. Strikingly, the ISR is specifically activated in astrocytes. Modulation of eIF2B activity and ISR activation in VWM mouse models impacts disease severity, revealing eIF2B-regulated pathways as potential druggable targets.

Approaches to repair the brain around the loss of the nigrostriatal dopaminergic pathways in Parkinson disease (PD) are not new and have been attempted over many years. However, of late, the situation has moved forward in two main ways. In the case of cell therapies, the ability to make large numbers of authentic midbrain dopaminergic neuroblasts from human pluripotent stem cell sources has turned what was an interesting avenue of research into a major area of investment and trialing, by academics in conjunction with Pharma. In the case of gene therapies, their use around dopamine replacement has waned, as the interest in using them for disease modification targeting PD-specific pathways has grown. In this chapter, we discuss all these developments and the current status of cell and gene therapies for PD.

Despite the enormous advancements seen in recent years, curative therapies for patients with genetic leukoencephalopathies are available for only a relatively small number of disorders. Therefore, symptomatic treatment and preventive management of the multiple clinical manifestations of patients with genetic leukoencephalopathies are critical in their care. The goals of the symptomatic treatment are to improve patients' quality of life, increase their survival, and reduce the impact on medical resources and related expenses. The coordinated work of a multidisciplinary team, including all specialists involved in the care of these patients, is the gold standard approach to manage and treat their complex and evolving clinical picture. Along with a multidisciplinary team, the relationship and close collaboration with the patient and their caregivers are essential. Their insight into the disease manifestations and management of the different issues should be integrated with the assessments of the multidisciplinary team to prevent clinical complications and preserve the quality of life of patients and their caregivers. Genetic leukoencephalopathies are very heterogeneous in terms of age of onset, clinical features, and disease course. However, many clinical features and problems are shared by most forms. Consequently, common therapeutic strategies apply to the majority of these diseases. This chapter presents the symptomatic approach for shared core clinical features presented by patients with genetic leukoencephalopathies divided by systems and, for each system, the specificities of some genetic leukoencephalopathies.