Handbook of clinical neurology最新文献

Cases of paraneoplastic neurologic disease were described as early as the 1800s; despite two centuries of impressive progress in our understanding of immunity, autoimmunity, and paraneoplastic antibodies, we still have a lot to learn about these rare and devastating diseases. This chapter focuses on the history of paraneoplastic neurologic diseases of the central, peripheral, and autonomic nervous systems. Rather than attempting an exhaustive chronicle of every antibody discovered to date, we discuss key discoveries and concepts which laid the groundwork for our current understanding of paraneoplastic neurologic disease as a whole. The work of the pioneers described in this chapter, as well as many others, provides the foundation upon which future work in this field will be built. Reflecting on the incremental nature of scientific discovery, the critical observations which allowed for paradigm shifts, and the gaps in our current knowledge provides valuable lessons for future directions in this field.

B lymphocytes are essential to the adaptive immune system with several key functions involving antibody production, pro- and anti-inflammatory cytokine production, and antigen presentation to CD4+ T cells. These functions are critical in promoting downstream effector mechanisms underlying the pathogenesis of many autoimmune neurologic disorders. Inhibiting B cells with monoclonal antibodies has been successful in a variety of autoimmune neurologic disorders, including diseases thought to be primarily T-cell mediated. B-cell depletion is now commonly utilized in clinical practice with approved medications for multiple sclerosis and aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder. Moreover, clinical trials are underway involving several other disorders including autoimmune encephalitis. Their effectiveness has led to the development of a variety of B-cell targeting treatments that differ by antigenic target, form (humanized or chimeric), route of administration, and dosing frequency. Additionally, there has been an increase in their affordability via biosimilars, allowing for increased accessibility globally. With their increasing use, it is important to be aware of their side-effect profile, associated risk of infection, and their use in special populations. Anti-B-cell therapies have revolutionized our therapeutic approach to autoimmune disorders of the central nervous system and their high efficacy has led to an overall benefit in patients afflicted by these conditions.

Behavioral interventions are now recommended within evidence-based treatment guidelines as an alternative or adjunct to medication for the management of tic disorders (TD). The behavioral model of TD conceptualizes tics as neurologic based yet modifiable behaviors that are influenced by internal and external contextual antecedents and tic-contingent consequences. The behavioral interventions with the strongest empirical support are habit reversal training (HRT), an expanded version of HRT referred to as comprehensive behavioral intervention for tics (CBIT), and a version of exposure and response prevention (ERP) adapted from an evidence-based cognitive-behavioral intervention for obsessive-compulsive disorder. Each of these interventions involves teaching volitional tic suppression and environmental modifications aimed at reducing contextual worsening of tics. In this chapter, we review the behavioral model of TD, the core components of HRT, CBIT, and ERP, and discuss their supporting evidence base. We then briefly review several persistent and unfounded concerns and misunderstandings regarding behavior interventions for TD that inhibit adoption among some professionals and patients. Finally, despite evidence supporting their efficacy, access to behavior therapies for TD remains limited. We conclude with a review of existing and emerging approaches aimed at increasing dissemination and implementation and future directions for research.

Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder characterized by multiple motor tics and at least one vocal tic lasting for more than a year. It is a complex, polygenic, and multifactorial disorder. In this chapter, we briefly discuss the early genetic studies on TS, and then provide a detailed overview of current efforts to uncover common and rare variants contributing to TS susceptibility. We also summarize pathway analyses which combine information from multiple loci to identify converging cellular processes and pathways associated with TS pathogenesis. Since TS is highly comorbid with other psychiatric disorders, we highlight the cross-disorder studies exploring the shared genetic basis of TS and these disorders, as well as the phenome-wide association study which revealed associations of multiple phenotypes with TS genetic risk. We provide an overview of the efforts to investigate the contribution of environmental factors and gene-environment interactions on TS development. Finally, we discuss some future directions that we believe the genetic research on TS will follow.

Support associations specifically for tic disorders, such as Tourette syndrome (TS), have the potential to profoundly impact individuals, families, and general awareness. This chapter explores the multifaceted roles of support associations, as well as their evolution - from small groups formed by individuals with a vested interest to large organizations managing multimillion-dollar research funding. Support associations face many challenges, making collaboration within and between countries essential. People with lived experience, clinicians, and researchers each bring valuable expertise to efforts aimed at improving the quality of life for those affected by tics and TS. Support associations serve as a vital nexus, connecting stakeholders and facilitating collaboration to drive meaningful progress.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, with both genetic and environmental risk factors. While traditionally, a relapsing and progressive disease course has been distinguished, it has increasingly become evident that elements of progression are the dominant factor for accumulating MS-related neurologic disability across all clinical courses and can be detected throughout the full disease trajectory in patients with MS. Therefore, defining the dominant pathophysiologic processes driving progression has become indispensable. Pathologic hallmarks of progressive MS include a compartmentalized inflammation within the central nervous system as well as associated neurodegenerative processes, finally leading to neuroaxonal and synaptic loss. Growing understanding of the pathophysiology has led to the development of an increasing number of targeted immunomodulatory treatment approaches for progressive MS. With the development of novel clinical trial designs and the evolution of clinical and paraclinical measures allowing accurate and rapid assessment of progression, new opportunities for personalized treatment regimens are likely to emerge.

This introductory chapter describes the evolution of immunotherapies in neurology as witnessed from the late 1970s to early 1980s, when the main therapy for all autoimmune neurologic diseases was only oral and IV steroids, to the present. The growing pains, complexities, challenges, and the very slow pace by which newer immunotherapeutic options were evolving are discussed pointing out that effective new therapies started to evolve many years later in the late 1990s to 2000 with plasmapheresis, IVIg, and β-interferon as the only disease modifying therapy (DMT) for multiple sclerosis. These early therapies were, however, the impetus for a subsequent faster pace of exploring new biologics with both failures and successes that steadily led to the present impressively galloping pace of trials and approvals of various monoclonal antibodies against B cells, cytokines, complement, FcRn, and currently Bruton's Tyrosine Kinase (BTK) inhibitors across the spectrum of all autoimmune neurologic diseases collectively pointing out that neuroimmunotherapy is now a "living process" with evolving therapeutic schemes that continuously change the therapeutic algorithm. The epitome of this successfully rapidly evolving pace is highlighted by the CAR-T cell therapies, currently explored in all refractory neuro-autoimmunities, when they were not even on the list when this volume began. The chapter describes this remarkable 40-year progress and evolution on immunotherapies in every autoimmune neurologic disease, addresses what has been learnt from the success and failures in the conducted therapeutic trials or targeted therapies, and highlights the promising future as currently projected in neuroimmunotherapeutics.

Complement is an effector of innate and adaptive immunity that consists of a multitasking network of plasma and membrane proteins that protects self. It simultaneously kills pathogens but also helps clearing damaged, diseased, or dying self-cells. The complement's complexity is highlighted by three early activation pathways: the relentless nonspecific activation of C3 on guard and the two recognition pathways, the C1q/classical and the MBL/lectin, all converging in activating C3, the fundamental and also most abundant molecule within the complement pathways. In the center of physiology is the alternative pathway (AP) providing the power through its amplification loop (AL) of C3b generation that boosts abundant C3b deposits on pathogens as well as on self-tissue leading eventually to the membrane attack complex (MAC) formation. In autoimmune and autoinflammatory conditions, a derailed complement function or complement misled by pathologic autoantibodies leads to specific cellular destruction. Further, the AL-generated anaphylatoxin and MAC assembly become a source of local inflammation and tissue damage of host cells triggering, or propagating progression of autoimmune neurologic disorders, justifying why targeting complement is an effective means in suppressing neurologic autoimmunities. The chapter highlights key aspects of complement-targeted immunotherapies pointing out the role of new therapeutic agents in the form of monoclonal antibodies, fusion proteins or peptidomimetics, engineered to inhibit specific complement proteins and intercept the downstream events that trigger autoimmunity and neurologic dysfunction. The efficacy or therapeutic potential of the present or evolving anticomplement biologics in ongoing phase I-III clinical trials is discussed as newly available or emerging promising agents in the treatment of autoimmune neurologic conditions poorly responding to current immunotherapies.

The objective of this chapter is to provide a clinically useful review of epidemiologic studies of Tourette syndrome (TS). The viewpoint of this chapter is that there are significant challenges to validity in epidemiologic studies of TS and co-occurring conditions but that, nonetheless, understanding this literature has value for clinicians, educators, and healthcare policymakers. The topics covered in the chapter, following background provided in the introduction, are as follows: (1) prevalence estimates, (2) risk factors, and (3) co-occurring conditions.

Tourette syndrome (TS) and primary tic disorders are increasingly understood as neurodevelopmental conditions arising from dysfunction within the cortico-basal ganglia-thalamo-cortical circuits, which govern motor, cognitive, and affective processes. This chapter reviews current knowledge on the neurochemical underpinnings of TS, drawing on evidence from neuroimaging studies - notably positron emission tomography - genetics, animal models, and neuropathology. Particular emphasis is placed on the roles of dopamine, serotonin, glutamate and γ-aminobutyric acid (GABA). Dopaminergic hyperactivity, especially involving increased D2 receptor sensitivity in the striatum, has been strongly linked to tic expression. Serotonergic dysfunction, though less consistently defined, may contribute to both tics and common comorbidities such as obsessive-compulsive behaviors, anxiety, and depression. However, the exact nature of serotonin's involvement remains unresolved, complicated by the influence of comorbidities and treatment effects. Additionally, glutamate and GABA, the brain's primary excitatory and inhibitory neurotransmitters, respectively, have emerged as crucial in modulating excitatory/inhibitory balance within the cortico-basal ganglia-thalamo-cortical loops. Glutamatergic hyperactivity and GABAergic deficits may lead to the disinhibition of motor outputs, exacerbating tic symptoms, and interact synergistically with dopaminergic circuits. Taken together, these findings underscore the multifactorial and interconnected nature of neurotransmitter abnormalities in TS. Rather than stemming from a single neurochemical deficit, TS likely arises from a complex interplay between multiple systems - dopaminergic, serotonergic, glutamatergic, GABAergic, and others - converging within dysfunctional brain networks that regulate motor and behavioral control.