CONTINUUM Lifelong Learning in Neurology最新文献

Objective: Autoimmune neurologic disorders encompass a broad category of diseases characterized by immune system attack of the central, peripheral, or autonomic nervous systems. This article provides information on both acute and maintenance immunotherapy used to treat autoimmune neurologic disorders as well as a review of symptomatic management and special considerations when caring for patients with these diseases.

Latest developments: Over the past 20 years, more than 50 antibodies have been identified and associated with autoimmune neurologic disorders. Although advances in diagnostic testing have allowed for more rapid diagnosis, the therapeutic approach to these disorders has largely continued to rely on expert opinion, case series, and case reports. With US Food and Drug Administration (FDA) approval of biologic agents to treat neuromyelitis optica spectrum disorder (NMOSD) and myasthenia gravis as well as ongoing clinical trials for the treatment of autoimmune encephalitis, the landscape of immunotherapy options continues to expand. Consideration of the unique pathogenesis of individual autoimmune neurologic disorders as well as the mechanism of action of the diverse range of treatment options can help guide treatment decisions today while evidence from clinical trials informs new therapeutics in the future.

Essential points: Recognizing patients who have a clinical history and examination findings concerning for autoimmune neurologic disorders and conducting a thorough and directed imaging and laboratory evaluation aimed at ruling out mimics, identifying specific autoimmune syndromes, and screening for factors that may have an impact on immunotherapy choices early in the clinical course are essential to providing optimal care for these patients. Providers must consider immunotherapy, symptomatic treatment, and a multidisciplinary approach that addresses each patient's unique needs when treating patients with autoimmune neurologic disorders.

Objective: This article reviews the clinical presentations, neural antibody associations, and oncologic accompaniments of paraneoplastic neurologic syndromes and neurologic autoimmunity in the context of immune checkpoint inhibitor (ICI) cancer immunotherapy.

Latest developments: Neural antibody discovery has improved the diagnosis of paraneoplastic neurologic syndromes. Neural antibodies also delineate the underlying disease pathophysiology and thus inform outcomes and treatments. Neural antibodies specific for extracellular proteins have pathogenic potential, whereas antibodies specific for intracellular targets are biomarkers of a cytotoxic T-cell immune response. A recent update in paraneoplastic neurologic syndrome criteria suggests high- and intermediate-risk phenotypes as well as neural antibodies to improve diagnostic accuracy in patients with paraneoplastic neurologic syndromes; a score was created based on this categorization. The introduction of ICI cancer immunotherapy has led to an increase in cancer-related neurologic autoimmunity with distinct clinical phenotypes.

Essential points: Paraneoplastic neurologic syndromes reflect an ongoing immunologic response to cancer mediated by effector T cells or antibodies. Paraneoplastic neurologic syndromes can present with manifestations at any level of the neuraxis, and neural antibodies aid diagnosis, focus cancer screening, and inform prognosis and therapy. In patients with high clinical suspicion of a paraneoplastic neurologic syndrome, cancer screening and treatment should be undertaken, regardless of the presence of a neural antibody. ICI therapy has led to immune-mediated neurologic complications. Recognition and treatment lead to improved outcomes.

Objective: Antibodies against glutamic acid decarboxylase (GAD), originally associated with stiff person syndrome (SPS), define the GAD antibody-spectrum disorders that also include cerebellar ataxia, autoimmune epilepsy, limbic encephalitis, progressive encephalomyelitis with rigidity and myoclonus (PERM), and eye movement disorders, all of which are characterized by autoimmune neuronal excitability. This article elaborates on the diagnostic criteria for SPS and SPS spectrum disorders, highlights disease mimics and misdiagnoses, describes the electrophysiologic mechanisms and underlying autoimmunity of stiffness and spasms, and provides a step-by-step therapeutic scheme.

Latest developments: Very-high serum GAD antibody titers are diagnostic for GAD antibody-spectrum disorders and also predict the presence of GAD antibodies in the CSF, increased intrathecal synthesis, and reduced CSF γ-aminobutyric acid (GABA) levels. Low serum GAD antibody titers or the absence of antibodies generates diagnostic challenges that require careful distinction in patients with a variety of painful spasms and stiffness, including functional neurologic disorders. Antibodies against glycine receptors, first found in patients with PERM, are seen in 13% to 15% of patients with SPS, whereas amphiphysin and gephyrin antibodies, seen in 5% of patients with SPS spectrum disorders, predict a paraneoplastic association. GAD-IgG from different SPS spectrum disorders recognizes the same dominant GAD intracellular epitope and, although the pathogenicity is unclear, is an excellent diagnostic marker. The biological basis of muscle stiffness and spasms is related to autoimmune neuronal hyperexcitability caused by impaired reciprocal γ-aminobutyric acid-mediated (GABA-ergic) inhibition, which explains the therapeutic response to GABA-enhancing agents and immunotherapies.

Essential points: It is essential to distinguish SPS spectrum disorders from disease mimics to avoid both overdiagnoses and misdiagnoses, considering that SPS is treatable if managed correctly from the outset to prevent disease progression. A step-by-step, combination therapy of GABA-enhancing medications along with immunotherapies ensures prolonged clinical benefits.

Objective: This article discusses common principles in diagnosing and managing autoimmune neurologic conditions in children.

Latest developments: The key to improving outcomes in all patients with autoimmune neurologic diseases is making an early diagnosis, promptly initiating treatment, and identifying patients who will benefit from long-term maintenance treatment. Some neuroinflammatory syndromes can be diagnosed with an antibody biomarker (eg, aquaporin-4 antibodies, N-methyl-d-aspartate [NMDA] receptor antibodies), whereas others require clinical diagnostic criteria (eg, multiple sclerosis, opsoclonus-myoclonus syndrome). A proportion of children will be labeled as seronegative, and further investigations for other inflammatory or monogenetic etiologies need to be carried out in parallel with treating the central nervous system inflammation. Time to treatment and treatment escalation were shown to correlate with outcomes in many patients with these disorders. The choice and duration of treatment should be evaluated considering side effects and risks in the short and long terms. The presence of a highly inflammatory disease process in children supports the use of highly effective disease-modifying therapies in pediatrics.

Essential points: The phenotypes of pediatric autoimmune neurologic conditions may change across different age groups, as the brain is still actively developing. In general, the presentation in children is more inflammatory, but overall disability is lower, likely because of better neuroplasticity and repair. Convincing evidence has increasingly emerged to support the biological rationale that effective immunosuppressive therapies used in adult neuroimmunology are equally effective in children.

Objective: This article reviews the clinical features, MRI characteristics, diagnosis, and treatment of aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The main differences between these disorders and multiple sclerosis (MS), the most common demyelinating disease of the central nervous system (CNS), are also highlighted.

Latest developments: The past 20 years have seen important advances in understanding rare demyelinating CNS disorders associated with AQP4 IgG and myelin oligodendrocyte glycoprotein (MOG) IgG. The rapidly expanding repertoire of immunosuppressive agents approved for the treatment of AQP4-NMOSD and emerging as potentially beneficial in MOGAD mandates prompt recognition of these diseases. Most of the recent literature has focused on the identification of clinical and MRI features that help distinguish these diseases from each other and MS, simultaneously highlighting major diagnostic pitfalls that may lead to misdiagnosis. An awareness of the limitations of currently available assays for AQP4 IgG and MOG IgG detection is fundamental for identifying rare false antibody positivity and avoiding inappropriate treatments. For this purpose, diagnostic criteria have been created to help the clinician interpret antibody testing results and recognize the clinical and MRI phenotypes associated with AQP4-NMOSD and MOGAD.

Essential points: An awareness of the specific clinical and MRI features associated with AQP4-NMOSD and MOGAD and the limitations of currently available antibody testing assays is crucial for a correct diagnosis and differentiation from MS. The growing availability of effective treatment options will lead to personalized therapies and improved outcomes.

Objective: This article focuses on the clinical features and diagnostic evaluations that accurately identify patients with ever-expanding forms of antibody-defined encephalitis. Forms of autoimmune encephalitis are more prevalent than infectious encephalitis and represent treatable neurologic syndromes for which early immunotherapies lead to the best outcomes.

Latest developments: A clinically driven approach to identifying many autoimmune encephalitis syndromes is feasible, given the typically distinctive features associated with each antibody. Patient demographics alongside the presence and nature of seizures, cognitive impairment, psychiatric disturbances, movement disorders, and peripheral features provide a valuable set of clinical tools to guide the detection and interpretation of highly specific antibodies. In turn, these clinical features in combination with serologic findings and selective paraclinical testing, direct the rationale for the administration of immunotherapies. Observational studies provide the mainstay of evidence guiding first- and second-line immunotherapy administration in autoimmune encephalitis and, whereas these typically result in some clinical improvements, almost all patients have residual neuropsychiatric deficits, and many experience clinical relapses. An improved pathophysiologic understanding and ongoing clinical trials can help to address these unmet medical needs.

Essential points: Antibodies against central nervous system proteins characterize various autoimmune encephalitis syndromes. The most common targets include leucine-rich glioma inactivated protein 1 (LGI1), N-methyl-d-aspartate (NMDA) receptors, contactin-associated proteinlike 2 (CASPR2), and glutamic acid decarboxylase 65 (GAD65). Each antibody-associated autoimmune encephalitis typically presents with a recognizable blend of clinical and investigation features, which help differentiate each from alternative diagnoses. The rapid expansion of recognized antibodies and some clinical overlaps support panel-based antibody testing. The clinical-serologic picture guides the immunotherapy regime and offers valuable prognostic information. Patient care should be delivered in conjunction with autoimmune encephalitis experts.

Objective: This article reviews autoimmune neuromuscular disorders and includes an overview of the diagnostic approach, especially the role of antibody testing in a variety of neuropathies and some other neuromuscular disorders.

Latest developments: In the past few decades, multiple antibody biomarkers associated with immune-mediated neuromuscular disorders have been reported. These biomarkers are not only useful for better understanding of disease pathogenesis and allowing more timely diagnosis but may also aid in the selection of an optimal treatment strategy.

Essential points: Recognition of autoimmune neuromuscular conditions encountered in inpatient or outpatient neurologic practice is very important because many of these disorders are reversible with prompt diagnosis and early treatment. Antibodies are often helpful in making this diagnosis. However, the clinical phenotype and electrodiagnostic testing should be taken into account when ordering antibody tests or panels and interpreting the subsequent results. Similar to other laboratory investigations, understanding the potential utility and limitations of antibody testing in each clinical setting is critical for practicing neurologists.

Objective: This article reviews the clinical and antibody spectrum of autoimmune cerebellar ataxia and other autoimmune movement disorders. It highlights characteristic phenotypes and red flags to the diagnosis and how these rare, but treatable, disorders are integrated into a differential diagnosis.

Latest developments: An increasing number of neuronal antibodies have been identified in patients with cerebellar ataxia, for example, against Kelch-like protein 11 (KLHL11), seizure-related 6 homolog-like 2, septin-3 and septin-5, or tripartite motif containing protein 9 (TRIM9), TRIM46, and TRIM67. Ig-like cell adhesion molecule 5 (IgLON5) antibody-associated syndromes have emerged as an important alternative diagnostic consideration to various neurodegenerative diseases such as Huntington disease or atypical parkinsonism. Opsoclonus-myoclonus syndrome emerged as the most relevant parainfectious movement disorder related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Essential points: Autoimmune cerebellar ataxia and other autoimmune movement disorders encompass a broad spectrum of different clinical syndromes, antibodies, and immunopathophysiologic mechanisms. Clinical acumen is key to identifying the cases that should undergo testing for neuronal antibodies. Given the overlap between phenotypes and antibodies, panel testing in serum and CSF is recommended.