Handbook of clinical neurology最新文献

Over the last three decades, immunotherapies targeting T cells, cytokines, and intracellular molecules have been explored extensively in clinical trials in multiple sclerosis (MS). These studies resulted in the approval of several therapies for the treatment of relapsing-remitting MS, and secondary and primary progressive MS. However, many treatment approaches were unsuccessful but provided important insights into pathomechanisms driving disease activity and progression in MS. Additional treatment strategies are currently evaluated in phase II and III trials in MS and are likely to improve the treatment of relapsing and progressive MS in the future. Some of the established treatment strategies in MS paved the way for the development of treatment strategies in other autoimmune diseases of the central nervous system, in particular neuromyelitis optica spectrum disorders (NMOSD) and myelin-oligodendrocyte glycoprotein-associated disorders. As a result, the first drugs for the treatment of NMOSD were recently approved and are now available to alter the course of this disease. Overall, T cell and cytokine-targeting treatment approaches have proven less successful in neuroinflammatory diseases than strategies targeting B cells. A better understanding of the pathomechanisms underlying MS and related diseases will facilitate the successful development of specific therapies targeting T cells, cytokines, and intracellular molecules in the future.

While Tourette syndrome (TS) is defined by tics, comorbidities are very much part of the clinical presentation - 90% of patients having a least one associated condition, most prominently obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD), but also learning disabilities, anxiety, depression, rage outbursts, autism spectrum disorder, sensory hypersensitivities, and sleep difficulties. Moreover, the associated symptoms often are more problematic than tics, or interact with the tics such that the different symptoms exacerbate each other, adding complexity to the clinical picture. Thus, to provide optimal care to patients with TS, it is essential that clinicians consider and address associated symptoms as part of their management. In this chapter, we review the treatment of the common neuropsychiatric comorbidities in TS, focusing especially on OCD and ADHD. We describe cognitive, behavioral, and pharmacologic interventions, with the aim of making these clear and applicable for the nonspecialist clinician. The goal is for clinicians to provide holistic care that includes understanding the impact of various symptoms and collaboratively prioritizing targets for intervention while favoring conservative approaches, in order to improve the quality of life of patients with TS.

The co-occurrence of tic disorders and ADHD (attention-deficit/hyperactivity disorder) is common; however, the significant overlap in their symptoms and underlying mechanisms frequently poses questions for diagnosis and treatment. The interaction between tic disorders and ADHD involves intricate genetic and neurobiologic factors, particularly related to inhibitory processes and cortico-striato-thalamic pathways in the brain. While both conditions present shared and specific challenges, studies suggest that ADHD symptoms often pose a greater burden on patients than tics. Therefore addressing ADHD symptoms alongside tics is essential for achieving optimal outcomes and those may differ with respect to the developmental stage and/or age of the individual. Psychoeducation, as well as behavioral and psychopharmacologic treatment strategies, have evolved during the last decade, demonstrating that managing both conditions concurrently can be done safely and effectively. This approach involves comprehensive evaluations and prioritizing treatments that target both tic symptoms and those of ADHD. By focusing on therapies that address these overlapping issues, individuals may experience improved overall outcomes.

Gilles de la Tourette syndrome (GTS) is a childhood-onset neurodevelopmental disorder characterized by motor and vocal tics and commonly associated with comorbid psychiatric and behavioral symptoms. Medication or behavioral therapies are effective for treating GTS in most cases; however, a proportion of individuals experience treatment-refractory tics. Deep brain stimulation (DBS) is an invasive surgical therapy reserved for select individuals with severe, treatment-refractory GTS. DBS has been targeted to several brain regions involved in the basal ganglia-thalamo-cortical networks implicated in GTS pathophysiology, including medial thalamic regions, the anteromedial (limbic) globus pallidus internus, and the posteroventrolateral (sensorimotor) globus pallidus internus, among others. Evidence from case studies, open-label studies, randomized controlled trials, and multicenter retrospective studies has suggested that DBS can be effective for improving tics, comorbidities, and quality of life. However, outcomes have been variable across individuals, and challenges remain regarding selecting individuals who are most likely to benefit from DBS, identifying effective target(s) for each individual, and determining optimal postoperative stimulation strategies. Progress has been made toward addressing these challenges through multicenter collaborations, neuroimaging, and neurophysiology; however, further prospective studies, clinical trials, and regulatory approvals will be needed to advance DBS as a more widely adopted therapy for treatment-refractory GTS.

Tic disorders (TD) present considerable challenges in research due to their intricate and multifaceted nature. Their primary symptoms, tics, often co-occur with other comorbid conditions that overlap with other psychiatric and movement disorders. Tic development and expression are associated with alterations in different neurotransmitter systems, genetic factors, and environmental influences. However, the current understanding regarding the underlying causes and mechanism remains limited, with the available treatments lacking specificity and efficacy. To address these complexities, numerous animal models have been developed using diverse approaches. Some models focus on studying the neural mechanisms underlying tic expression, while others are designed to investigate the therapeutic effects on the various comorbid symptoms. The objective of this chapter is to systematically review the animal models for TD. We will discuss the commonly used criteria for assessing the experimental model validity and evaluate the unique properties of each model based on its ability to address specific aspects of the disorder. Thus, the diverse spectrum of animal models will be established in a complementary form to enable the utilization of these models for the wide range of therapeutic and scientific purposes presented by tic disorders.

Explosive outbursts, often referred to as "rage attacks," affect a significant number of individuals with Tourette syndrome (TS) and chronic tic disorders (CTDs), and are associated with increased disorder-related morbidity and psychosocial impairment. Tic severity, psychiatric comorbidity, psychosocial and other factors appear relevant. This chapter provides an overview of the phenomenology, possible neurobiologic and environmental underpinnings, and evaluation and treatment of explosive outbursts in TS. Existing literature on explosive outbursts, rage attacks, impulsive anger and aggression, and episodic dyscontrol in TS/CTD was reviewed and summarized. Explosive outbursts are common transdiagnostic symptoms and occur with increased frequency in individuals with TS/CTD. The etiology of these symptoms in TS/CTD is still unknown, appears multifactorial, and may reflect factors that are intrinsic to tic disorders, associated with their common neuropsychiatric comorbidities, and/or extrinsic influences. At present, evidence-based treatments for explosive outbursts in TS/CTD are limited. There remains an urgent need to advance the investigation of these disabling symptoms in TS/CTD. Use of consistent terminology and standardized assessment tools for studying and treating explosive outbursts in TS and CTDs are much needed.

After a year spent working for Jean-Martin Charcot, Georges Gilles de la Tourette published an article in 1885 that would become a seminal work, reporting on nine cases of tic disease. However, only four observations meet the current criteria of the eponym, including echolalia and coprolalia, the latter term coined by Gilles de la Tourette. In 1886, Charcot asked Georges Guinon to complete the clinical picture by adding obsessional disorders temporary control of tics, and the premonitory sensation leading to their occurrence. In 1888, Charcot presided over the jury for Grégoire Breitman's thesis, then in 1890 for Jacques Catrou's thesis; both theses covered Gilles de la Tourette disease and were prepared with the namesake's help. Gilles de la Tourette put the finishing touch on the disease's description in 1900, which implicitly credited Guinon with completing the clinical picture and naming the disease at the time: "la maladie des tics convulsifs" (convulsive tic disease). That said, Gilles de la Tourette did not give much importance to his own nosographic contribution to neurology. After having been nearly forgotten, it was not until the 1960s that this pathology was definitively resurrected and validated by Arthur and Elaine Shapiro under the name of Gilles de la Tourette syndrome. This was a testament to its significant prevalence and its treatment possibilities.

Movement disorder definitions that include the clinical characteristics "sudden, rapid, repetitive, brief, and involuntary" are not limited to motor tic disorders. Hence, it is essential that caregivers be aware of other relatively common conditions that could be confused with the diagnosis of tics. Included in this differential are entities such as repetitive and restricted behaviors (RRBs), habits, body-focused repetitive behaviors (BFRBs), and motor stereotypies. The importance of separation of these individual conditions is further emphasized by the recognition that they can be coexisting problems in individuals with tic disorders, and thus therapeutic approaches may differ. For example, some individuals diagnosed with Tourette syndrome have co-occurring complex motor stereotypies or recurring skin picking, nail biting, and hair pulling. This chapter reviews the definition of a movement disorder and the evolving entity labeled as RRBs. It also contains a more in-depth review of our knowledge regarding the clinical features, etiology, pathophysiology, and therapeutic approaches for the more specific diagnoses including habits, BFRBs, and stereotypies.

Autologous hematopoietic stem cell transplantation (HSCT) for multiple sclerosis (MS) is the technique of administrating a short immunosuppressive regimen over 4-6 days (depending on the drug regimen) followed by intravenous infusion of one's own hematopoietic stem cells to hasten hematopoietic recovery. The toxicity and efficacy of the procedure depend on the regimen and on patient selection and, to a lesser extent, on center experience. MS-specific nonmyeloablative regimens are less toxic and safer than myeloablative regimens that were initially developed for cancer. To date, there have been no randomized trials comparing the different regimens. HSCT like all immune-based therapy is more effective for the inflammatory phase of MS. It is effective for relapsing-remitting MS, less effective for active secondary progressive MS (SPMS), and almost ineffective for nonactive SPMS and primary progressive MS. Effectiveness and superiority of HSCT have been reported in a phase III randomized trial against the best available disease-modifying therapies at that time (mostly natalizumab) and in large meta-analyses. Compared to disease-modifying therapies, HSCT demonstrates posttransplant drug-free meaningful improvement of neurologic disability and quality of life for prolonged long-term follow-up in most patients.

Autoimmune inflammatory myopathies (AIM) constitute a heterogeneous group of acquired myopathies with endomysial inflammation as a shared feature highlighting a potentially autoimmune inflammatory process amenable to immunotherapies. The disorders can be best classified as dermatomyositis, necrotizing autoimmune myositis, antisynthetase syndrome-overlap myositis, and inclusion body myositis. Because of clinical and immunohistologic heterogeneity but often overlapping pathophysiologic features among all major subsets, a correct diagnosis is critical from the outset to apply the most suitable and subset-specific immunotherapy. Advances in the immunopathologic characterization of autoimmune inflammatory myopathies have identified potentially mechanism-specific disease subsets that promise the application of targeted immunotherapies for better clinical outcomes. A number of recent clinical trials with biologic agents and monoclonal antibodies, regardless of the clinical outcome considering that several were negative, have collectively expanded our knowledge on the main pathogenic markers of autoimmunity associated with each AIM subset including the role of T-cell or B-cell factors, key cytokines, complement and various associated antibodies, or innate immunity factors. The paper summarizes the main clinical and histopathologic features of each myositis subtype, including overlapping or unique concepts of their immunopathogenic mechanisms, being mainly focused on applied immunotherapies and relevant controlled clinical trials discussing evidence-based efficacy according to the currently evolved therapeutic algorithm. The ongoing trials are also discussed highlighting those with promising future, if applied early in the disease, and the new immunotherapeutic interventions for the refractory AIM subsets.