Seminars in Neurology最新文献

Circadian rhythms (CRs) are entrainable endogenous rhythms that respond to external stimuli and regulate physiological functions. The suprachiasmatic nucleus (SCN) in the hypothalamus is the mammalian master clock that synchronizes all other tissue-specific peripheral clocks, primarily through gamma-aminobutyric acid (GABA) and vasoactive intestinal polypeptide (VIP). The SCN follows Earth's 24-hour cycle by light entrainment through the retinohypothalamic tract. At the cellular level, the core clock genes CLOCK, BMAL1, PER1-PER3, CRY1, and CRY2 regulate CRs in a negative feedback loop. The circadian disruption of the sleep-wake cycle manifests in at least six distinct clinical conditions. These are the circadian rhythm sleep-wake disorders (CRSWDs). Their diagnosis is made by history, sleep diaries, and actigraphy. Treatment involves a combination of timed light exposure, melatonin/melatonin agonists, and behavioral interventions. In addition, CR disturbances and subsequent misalignment can increase the risk of a variety of illnesses. These include infertility and menstrual irregularities as well as diabetes, obesity, fatty liver disease, and other metabolic syndromes. In addition, a disruption in the gut microbiome creates a proinflammatory environment. CR disturbances increase the risk for mood disorders, hence the utility of light-based therapies in depression. People with neurodegenerative disorders demonstrate significant disturbances in their CRs, and in their sleep-wake cycles. Circadian realignment therapies can also help decrease the symptomatic burden of these disorders. Certain epilepsy syndromes, such as juvenile myoclonic epilepsy (JME), have a circadian pattern of seizures. Circadian disturbances in epilepsy can be both the consequence and cause for breakthrough seizures. The immune system has its own CR. Disturbances in these due to shift work, for instance, can increase the risk of infections. CR disturbances can also increase the risk of cancer by impacting DNA repair, apoptosis, immune surveillance, and cell cycle regulation. Moreover, the timing of chemotherapeutic agents has been shown to increase their therapeutic impact in certain cancers.

While pediatric epilepsy shares some features with adult epilepsy, the growing and developing brain during childhood is associated with differences in epilepsy etiologies, syndromes, comorbidities, management, and outcomes. We must also consider the long-term effects of epilepsy and treatments. This section highlights unique considerations for pediatric epilepsy. These include pediatric onset electroclinical syndromes that commonly resolve prior to adulthood, treatment duration of self-limited pediatric epilepsy syndromes, pediatric-onset epilepsy with etiology-specific treatment, and therapies used more commonly in the pediatric population. In addition, pediatric-onset epilepsy is associated with a higher risk for developmental, psychiatric, and behavioral comorbidities in a bidirectional fashion. Family dynamics are affected by a child with epilepsy, and transitioning to the adult clinic is a particular challenge for this population. Finally, there are special issues that occur in pediatric epilepsy, including the lack of pediatric FDA approvals for newly available therapies and the need for sedation for investigations.

Ketogenic diet therapies are an increasingly utilized treatment option for adult and pediatric patients with drug-resistant epilepsy. The two most common are the classic ketogenic diet, following a ratio of fat to combined protein and carbohydrates (typically 4:1), and the modified Atkins diet, limiting total carbohydrates to 10 to 30 g per day. Based on high-quality studies in pediatric patients, the classic ketogenic and modified Atkins diets show >50% reduction in seizure frequency in approximately 40 to 50% of patients. Although there are fewer overall and high-quality studies in adults, they show similar seizure efficacy rates, but notably high rates of noncompliance. In addition to improved seizure outcomes, ketogenic diet therapies have been associated with improved cognitive and quality of life measures. Ketogenic diet therapies are generally safe but require monitoring to ensure adequate growth and tolerance. The core of a ketogenic diet program is a well-trained multidisciplinary team, supported by operational and evidence-based protocols.

Developmental and epileptic encephalopathies (DEEs) are a group of rare, severe, early-onset epilepsies characterized by pharmacoresistance, marked electroencephalographic abnormalities, and delayed or regressive psychomotor development. DEEs are associated with poor long-term outcomes and increased mortality; however, early recognition and targeted treatment can impact neurodevelopmental outcomes and overall quality of life. Treatment with antiseizure medication is often challenging given drug resistance, chronic polypharmacy, and medication interactions. With advances in genetic testing and increased understanding of the neurobiological mechanisms of DEEs, the treatment approach is evolving and includes repurposed antiseizure medications and targeted therapies, as well as early surgical intervention in select patients. In addition to high seizure burden and neurodevelopmental delay, DEEs are associated with comorbidities affecting a range of body systems; these can include intellectual disability, psychiatric disorders, motor dysfunction, and respiratory and gastrointestinal problems. Over time, these comorbidities increase the complexity of management and have important implications on the disease burden and quality of life for both patients and their caregivers. Multidisciplinary care in DEEs is paramount. We summarize the current evidence on the management of specific DEEs, focusing on targeted therapies and optimizing outcomes.

The incidence of epilepsy is highest at the extremes of age. Drug resistance is present in approximately one-third of people with epilepsy but occurs at higher than average rates in children with seizure onset before age 3 years, owing to a variety of etiologies unique to this age group. Epilepsy surgery is an effective therapeutic option for drug-resistant epilepsy but is vastly underutilized. Epilepsy surgery in children under age 3 comes with distinct clinical challenges related to brain anatomy, evolving developmental maturation, and limitations of evaluation and surgical strategies. However, epilepsy surgery can lead to seizure freedom or significant seizure reduction in this age group. Early seizure control may have a significant positive impact on long-term cognitive development, making urgency of surgical referral of immense importance. This review highlights available evidence on the safety and efficacy of epilepsy surgery in early-life epilepsy, identifying barriers to surgical therapy, describing utilization of available evaluation and surgical strategies, and examining risks and benefits of earlier surgical consideration in this vulnerable population.

Polyneuropathies are common, with the incidence increasing with older age. The causes of polyneuropathies are diverse and numerous, and it can be challenging for clinicians to determine the etiology of a particular patient's neuropathy. In this article, we systematically detail a practical approach to polyneuropathies, beginning with the most important aspects of the workup, the history and physical. We then discuss the limited diagnostic approach required for patients who present with a distal symmetric polyneuropathy and the more comprehensive approach for patients who present with other neuropathy subtypes.

Immune-mediated neuropathies encompass a range of neurological disorders, including chronic inflammatory demyelinating polyradiculoneuropathy, Guillain-Barré syndrome, multifocal motor neuropathy, autoimmune autonomic neuropathies, and paranodal nodopathies. Recognizing clinical patterns is key to narrowing the broad range of differential diagnoses in immune-mediated neuropathies. Electrodiagnostic testing is a useful tool to support the diagnosis of immune-mediated neuropathies. Our understanding of autoimmune demyelinating neuropathies is rapidly advancing, particularly with the discovery of nodal and paranodal antibodies. Recent advances in neuropathy treatment include the utilization of neonatal Fc receptors to reduce antibody recycling, and the development of complement inhibitors to reduce inflammatory damage, offering promising new therapeutic avenues. Timely identification of immune-mediated neuropathies is imperative as delay in diagnosis and treatment may lead to irreversible disability.

This review explores diverse infectious etiologies of peripheral nervous system (PNS) dysfunction, spanning sensory and motor neurons, nerves, and associated structures. Progress in viral and bacterial infections reveals multifaceted mechanisms underlying neuropathies, including viral neurotoxicity and immune-mediated responses. Latest diagnostic advances facilitate early PNS complication detection, with ongoing research offering promising treatment avenues. Emerging pathogens like severe acute respiratory syndrome coronavirus 2, Zika virus, and EV-D68 highlight the evolving infectious neuropathy paradigm. Recognizing characteristic patterns and integrating clinical factors are pivotal for precise diagnosis and tailored intervention. Challenges persist in assessment and management due to varied pathogenic mechanisms. Advancements in understanding pathogenesis have improved targeted therapies, yet gaps remain in effective treatments. Ongoing research is crucial for optimizing approaches and improving patient outcomes.