Handbook of clinical neurology最新文献

Autoimmune autonomic disorders are common, though often under-recognized, and suboptimally understood. Autonomic nervous system impairment may result from immune-mediated damage to central or peripheral autonomic pathways, and typically involve both sympathetic and parasympathetic systems, as well as the enteric nervous system. Various autoimmune conditions may primarily involve the autonomic nervous system, as in autoimmune autonomic ganglionopathy associated with ganglionic nicotinic acetylcholine receptor antibodies or may involve autonomic systems as part of a multisystem neurologic process with or without underlying malignancy, or autonomic nerves may be targeted in systemic autoimmunity as is seen with Sjögren's syndrome. A careful history and diagnostic evaluation is necessary to determine the type, distribution, and severity of dysautonomia; which may be generalized or more restricted in nature. An understanding of potential autonomic features in the various autoimmune autonomic disorders can help to provide diagnostic clarity, and recognition of autonomic signs and symptoms is necessary to direct symptomatic and immunotherapeutic decisions in these patients.

Stiff-person syndrome (SPS) is increasingly recognized as the prototypic and most common autoimmune neuronal hyperexcitability disorder that presents with stiffness in the limbs and axial muscles, stiff gait with uncontrolled falls, and episodic painful muscle spasms triggered by anxiety, task-specific phobias and startle responses, collectively leading to disability. Recent publicity has increased SPS awareness among patients and physicians, generating concerns about diagnosis, misdiagnoses, pathomechanism, and the most successful or promptly applied therapies. The paper addresses the evolving diagnostic challenges within the overlapping SPS-spectrum disorders, focusing on the progress made in SPS pathophysiology and the underlying autoimmunity; addresses the significance of antibodies against glutamic acid decarboxylase or other inhibitory synaptic antigens and the fundamentals of autoimmune neuronal hyperexcitability; and elaborates on the rationale of target-specific therapeutic interventions based on γ-aminobutyric acid -enhancing drugs and immunotherapies, stressing the need for early immunotherapy initiation to halt disability progression. The challenges of current therapies in late-onset SPS are also highlighted and an updated therapeutic scheme is provided for present and upcoming immunotherapeutic interventions for refractory disease. Finally, the challenges of applying suitable therapeutic scales in capturing the fundamentals of SPS symptomatology and objectively assessing responses to novel therapeutic trials are discussed.

B cells have an ever-increasing role in the etiopathology of a number of autoimmune neurologic disorders, acting, in addition to their autoantibody-secreting role, as antigen-presenting cells but also as sensors, coordinators, and regulators of the immune response. B cells can regulate the immune response, including T-cell activation through antigen presentation, production of proinflammatory cytokines (either as a bystander activation or suppression), and contribution to ectopic lymphoid aggregates. Such important functions make therapeutic depletion of B cells an attractive treatment strategy. The last decade, anti-B-cell therapies targeting B-cell surface molecules, have evolved into a rational approach for successfully treating autoimmune neurologic disorders, even when T cells seem to be the main effector cells, providing an invaluable therapeutic criterion for appreciating the key role of B cells in neurologic autoimmunities. The chapter is focused on the basic aspects of B-cell biology, addresses the different roles of B cells and autoantibodies in the pathogenesis of autoimmune and inflammatory neurologic disorders and highlights how the currently available or in the developmental stage anti-B-cell therapeutics exert their action. It specifically examines the autoantibodies of different IgG-isotypes and IgG-subclasses stressing the uniqueness of IgG4-neuroautoimmunities, and summarizes the current status of the rapidly evolving B-cell therapeutics, including CD19-CAR-T cell therapies, in multiple sclerosis, neuromyelitis-spectrum disorders, autoimmune encephalitis, stiff-person syndrome spectrum disorders, chronic autoimmune neuropathies, myasthenia gravis, and inflammatory myopathies.

Clinical neurophysiology constitutes a relevant tool for clinicians in movement disorders since it expands their characterization beyond clinically observable features and supports their diagnosis. Although the field has yet to identify a specific neurophysiologic marker for the diagnosis of tics, neurophysiology serves as a valuable tool for clinicians in differentiating tics from other hyperkinetic disorders. Beside diagnosis, recent years have witnessed the emergence of two primary domains in which neurophysiology plays a pivotal role in the realm of tic disorders: investigating the pathophysiologic foundations of tics, in an attempt to unravel the neural mechanisms that give rise to this complex movement disorder, and the application of noninvasive brain stimulation (NIBS) techniques as an avenue for therapeutic intervention. The two domains are inherently connected, as the development of noninvasive treatment methods is grounded in the mechanisms believed to underlie tics. Although the precise neurobiology of tic disorders remains incompletely understood, growing evidence implicates dysfunction within cortical-striatal-thalamic-cortical circuits as a key contributor to their pathophysiology. In this context, NIBS has been explored as a potential therapeutic approach aimed at modulating pathologic cortical hyperexcitability in specific regions, thereby enhancing inhibitory circuit engagement and ultimately alleviating tics. An intriguing alternative to transcranial stimulation is peripheral electrical nerve stimulation, which offers a distinct yet complementary mechanism of action. For instance, studies have demonstrated that rhythmic stimulation of the median nerve within the alpha frequency band can entrain neuronal oscillations in the sensorimotor cortex, leading to a measurable reduction in tic frequency and intensity. In this chapter, we will first present a comprehensive overview of clinical neurophysiology studies that have significantly contributed to our understanding of the pathophysiology of tics, and then we will offer a brief synopsis of the application of noninvasive stimulation for the treatment of tics, illustrating that clinical neurophysiology is a powerful tool that provides valuable insights into the neural underpinnings of tics and holds potential as adjunct therapy for tic management.

This chapter provides a review of obsessive-compulsive disorder (OCD), as it manifests in primary tic disorders and Gilles de la Tourette syndrome (GTS). We examine the clinical features of OCD in GTS, focusing on how these symptoms diverge from typical OCD presentations, often blending with or mimicking tics. Key pathophysiologic mechanisms are explored, with an emphasis on the neurobiologic substrates that underlie this unique OCD subtype and distinctions from tics. Finally, the chapter discusses therapeutic approaches specifically adapted for this population, highlighting both established and emerging treatments. This chapter aims to deepen understanding of the complex interplay between OCD and GTS, offering insights into more effective clinical management and therapeutic strategies for affected individuals.

Tourette syndrome (TS) is a neuropsychiatric and a neurodevelopmental disorder often presenting alongside other neurodevelopmental conditions such as attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), learning difficulties, and dyspraxia. TS shares genetic and neurobiologic features with ASD and ADHD, suggesting common underlying mechanisms. Recent diagnostic frameworks such as the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, APA, 2013) allow for multiple co-occurring diagnoses, reflecting the complex overlap among neurodevelopmental disorders. Whilst there are several studies stating high rates of TS in ASD and vice versa, the data about the nature of tics in those with ASD is sparse; nevertheless, it shows that they are probably not different in nature to tics present in TS. Tics in individuals with ASD can be diagnostically challenging due to overlapping motor behaviors like stereotypies. Intellectual disability (ID) further complicates tic identification, given communication difficulties and co-occurring behaviors. A pragmatic, needs-focused clinical approach is recommended, emphasizing prioritisation of presenting problems over an accumulation of diagnostic labels. This strategy facilitates targeted interventions where needed. In children with ID, differentiating between tics and stereotypies is important to avoid inappropriate management.

The various syndromes of autoimmune encephalitis, with an estimated prevalence of 14 per 100,000, although discovered and better defined during the last 15 years, have left an impactful footprint on autoimmune neurology and have been shaping the novel field of autoimmune neuropsychiatry. Many patients presenting with altered mental status and behavioral aberrations of subacute onset and initially treated with antipsychotic medications turn out to have autoimmune conditions caused by autoantibodies against CNS antigens that respond dramatically to immunotherapy. This chapter describes the different clinical syndromes connected to different autoantibodies and discusses general principles of autoimmunity in connection with intracellular or antisynaptic antibodies as well as different aspects of the evolving concept of autoimmune neuropsychiatry. Further, the chapter summarizes evidence of autoantibody pathogenicity and of potential triggers for this kind of autoimmunity including infections, neoplasms, and immune checkpoint inhibitors. Finally, it analyzes therapeutic maneuvers as well as prognosis. Overall, the chapter stresses the paramount importance of early recognition and diagnosis leading to targeted immunotherapy and improved outcomes.

Myasthenia gravis (MG) is the most common disease of the neuromuscular junction. Conventional immunotherapy based on corticosteroids and immunosuppressants has been in use for several decades and has greatly contributed to the improvement of the disease prognosis. In recent years, several new agents, mostly monoclonal antibodies, have proved effective in randomized controlled trials and are in clinical use. Other biologics are currently under evaluation. Novel therapies, that offer the advantage of more selective effects on the immune system, are not devoid of potentially serious adverse effects. MG subgrouping based on associated autoantibodies is a prerequisite for personalized treatment. Patient-specific selection is especially relevant and includes MG-specific IgG subclasses and B-cell subsets responsible for antibody production. While ever-growing knowledge of the disease pathogenicity and advances in technology have made such therapeutic advances possible, lack of biomarkers of disease activity complicates treatment decisions. On the other hand, treatment of Lambert-Eaton myasthenic syndrome (LEMS) has scarcely changed in recent decades and biologics have been tried in very few patients to date. Its rarity and association with cancer have likely discouraged the exploration of new immunotherapies for LEMS despite disease-related disability.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, and its application in neuroimmunologic autoimmune diseases is now emerging as a promising therapeutic avenue. Neuroimmunologic diseases such as multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disorder, and stiff-person syndrome have shown varying degrees of response to traditional immunomodulatory therapies, but a significant proportion of patients remain refractory to treatment. In recent studies, anti-CD19 CAR T cells have shown encouraging results in targeting B cells, a key driver of autoimmune pathogenesis. CAR T-cells can penetrate the central nervous system and overcome the limitations of conventional B-cell depleting therapies such as rituximab, particularly in accessing ectopic lymphoid follicles that maintain compartmentalized inflammation. In early clinical cases, CAR T-cell treatment has resulted in marked clinical improvements, including significant reductions in symptoms and durable disease remission, with manageable side-effects. In addition, advances in allogeneic CAR T cell constructs and chimeric autoantibody receptor T cells offer additional avenues for precision-targeted therapies. These developments underscore the potential of CAR T cells to reshape the treatment landscape for refractory neuroimmunologic autoimmune diseases and warrant further controlled trials and regulatory exploration.

Tics are the most common hyperkinetic manifestations during development. The clinical phenomenology of motor tics ranges from mild twitches affecting a single facial muscle to orchestrated contractions of different muscular districts resembling purposeful behaviors. Likewise, the repertoire of vocal tics (also called phonic tics) covers the whole spectrum between isolated grunting noises and meaningful strings of words. Simple and complex tics arguably sit on a continuum of symptom severity and respond to the same treatment interventions. The diagnosis of Gilles de la Tourette syndrome (GTS) is based on the presence of multiple motor tics plus at least one vocal tic, with onset before the age of 18 years and chronic course. It has been argued that the different tic disorders belong to a spectrum of increasing complexity, from the transient form (provisional tic disorder), through persistent motor or vocal tic disorder, to GTS. However, the clinical phenotype of GTS stands out because of the frequent association with specific behavioral problems, ranging from tic-related obsessive-compulsive disorder to other neurodevelopmental conditions. The diagnosis of tic disorders is based on clinical observation and requires expertise. The recent outbreak of functional tics, documented across several countries during the COVID-19 pandemic, introduced unprecedented challenges to the differential diagnosis of neurodevelopmental tics.