关键词： Immune checkpoint inhibitors   Immune-related adverse events   Neurological disorders   Autoantibody  

摘要： Among diverse neurological immune-related adverse events (irAEs), autoimmune encephalitis, aseptic meningitis, Guillain-Barre syndrome (GBS), myasthenia gravis (MG), and myositis are particularly important. The clinical presentation may be different from that of patients with conditions unrelated to immune checkpoint inhibitors (ICIs). Many of the autoantibodies detected in patients' sera are committed to the pathogenesis, while the clinical significance of such autoantibodies in cases of neurological irAEs is different from the significance in cases of typical neuronal disorders. A broad range of clinical symptoms complicates the diagnosis of autoimmune encephalitis. The clinical features of aseptic meningitis induced by classical drugs are different from those of aseptic meningitis induced by ICIs. Although autoantibodies against synaptic receptors or neuronal cell surface proteins are not detected, anti-Ma2 antibodies, which are onconeural antibodies against intracellular proteins, are detected in patients with autoimmune encephalitis associated with ICIs. GBS induced by ICIs sometimes shows gradual progression and a relapse of symptoms, suggesting chronic inflammatory demyelinating polyneuropathy. Bulbar symptoms and myasthenic crisis are frequently observed in ICI-induced MG. Anti-acetylcholine receptor antibodies are found in only half of patients with MG occurring as an irAE. ICI-induced myositis is accompanied by ocular muscle symptoms, such as ptosis and diplopia, which can suggest MG. Patients receiving ICI treatment present clinical features and laboratory findings that represent a mixture of MG and myositis. Anti-striational antibodies may act as biomarkers in cases in which MG and myositis overlap. A correct understanding of neurological adverse events is required to achieve the best management of patients.

关键词： Cardiac arrest   Coma   Prognosis   Clinical examination   Electroencephalogram   Somatosensory evoked potentials   Neuron specific enolase   Computed tomography   Diffusion magnetic resonance imaging  

摘要： Purpose To assess the ability of clinical examination, blood biomarkers, electrophysiology or neuroimaging assessed within 7 days from return of spontaneous circulation (ROSC) to predict good neurological outcome, defined as no, mild, or moderate disability (CPC 1-2 or mRS 0-3) at discharge from intensive care unit or later, in comatose adult survivors from cardiac arrest (CA). Methods PubMed, EMBASE, Web of Science and the Cochrane Database of Systematic Reviews were searched. Sensitivity and specificity for good outcome were calculated for each predictor. The risk of bias was assessed using the QUIPS tool. Results A total of 37 studies were included. Due to heterogeneities in recording times, predictor thresholds, and definition of some predictors, meta-analysis was not performed. A withdrawal or localisation motor response to pain immediately or at 72-96 h after ROSC, normal blood values of neuron-specific enolase (NSE) at 24 h-72 h after ROSC, a short-latency somatosensory evoked potentials (SSEPs) N20 wave amplitude > 4 mu V or a continuous background without discharges on electroencephalogram (EEG) within 72 h from ROSC, and absent diffusion restriction in the cortex or deep grey matter on MRI on days 2-7 after ROSC predicted good neurological outcome with more than 80% specificity and a sensitivity above 40% in most studies. Most studies had moderate or high risk of bias. Conclusions In comatose cardiac arrest survivors, clinical, biomarker, electrophysiology, and imaging studies identified patients destined to a good neurological outcome with high specificity within the first week after cardiac arrest (CA).

关键词： Intensive / Critical Care Medicine   Anesthesiology   Emergency Medicine   Pneumology/Respiratory System   Pain Medicine   Pediatrics  

关键词： Alzheimer's disease   amyloid processing   APP   beta amyloid   COVID-19  

摘要： SARS-CoV-2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID-19 neurological injury. This is a cross-sectional exploratory prospective biomarker cohort study of 21 patients with COVID-19 neurological syndromes (Guillain-Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID-19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] alpha, interleukin [IL]-6, IL-1 beta, IL-8). Patients with COVID-19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)-alpha (p = 0.004) and sAPP beta (p = 0.03) as well as amyloid beta (A beta) 40 (p = 5.2 x 10(-8)), A beta 42 (p = 3.5 x 10(-7)), and A beta 42/A beta 40 ratio (p = 0.005) compared to controls. Patients with COVID-19 neurological syndromes showed significantly increased neurofilament light (NfL, p = 0.001) and this negatively correlated with sAPPalpha and sAPP beta. Conversely, GFAp was significantly reduced in COVID-19 neurological syndromes (p = 0.0001) and this positively correlated with sAPPalpha and sAPP beta. COVID-19 neurological patients also displayed significantly increased CSF proinflammatory cytokines and these negatively correlated with sAPPalpha and sAPP beta. A sensitivity analysis of COVID-19-associated GBS revealed a non-significant trend toward greater impairment of amyloid processing in COVID-19 central than peripheral neurological syndromes. This pilot study raises the possibility that patients with COVID-19-associated neurological syndromes exhibit impaired amyloid processing. Altered amyloid processing was linked to neuronal injury and neuroinflammation but reduced a

摘要： Several challenges are associated with rare disease drug development in neurology. In this article, we summarize the US Food and Drug Administration's experience with clinical drug development for rare neurological diseases and discuss clinical pharmacology's critical contributions to drug development for rare diseases. We used publicly available information to identify and screen drug products approved for rare neurological indications between 1983 and 2019. We highlighted cases in which clinical pharmacology contributed to the evidence of drug efficacy, dose selection for pivotal clinical trials, dose optimization based on intrinsic and extrinsic factors, pharmacokinetic bridging for formulations, and efficacy bridging across different racial groups. Fifty-one approved drug products were identified since the introduction of the Orphan Drug Act in 1983. Interestingly, the number of approvals in the last few years increased significantly, probably due to advances in genomic research and targeted drug modalities. Evaluation of dose selection in patient populations showed that in 52% of cases, the sponsors did not evaluate efficacy for more than one or two dose levels throughout the development program. Clinical pharmacology studies to evaluate the effect of intrinsic or extrinsic factors were adequately characterized in most of the applications. With the expansion of model informed drug development applications, (e.g., quantitative systems pharmacology and deep learning neural network models), the role and impact of clinical pharmacology is expected to grow exponentially in the next decade and enhance the development of novel treatment modalities for neurological rare diseases.

关键词： Pandemic   COVID-19   Stroke Unit   Acute neurology   Management  

摘要： Background The pandemic implied dramatic changes in public health assets. In Italy, some Stroke Units were transformed into sub-intensive COVID-19 Units, making the management of neurological patients demanding. We described how the flow of neurological emergencies was affected by the pandemic impact. Methods We analyzed accesses to the Emergency Department (ED) of the "Maggiore della Carita" Hospital, Piedmont, Italy, during a period of 8 months (COVID time;March to May 2020 and October 2020 to February 2021) and analyzed the admissions to the Neurology Unit and the underlying diagnosis. We also evaluated potential changes in the treatment of acute ischemic stroke in the same period. These variables were compared with two equivalent periods of time (2019-2020;2018-2019). Results During the COVID time, there was a clear-cut reduction of the total ED accesses compared to NoCOVID times. However, admissions for acute neurological conditions showed a mild but non-significant decrease (6.3%vs.7.3%). The same applied to acute ischemic stroke, which represented the most common condition (47.7%). The proportion of patients who underwent emergent reperfusion therapies remained unchanged. Furthermore, no difference was found in door-to-needle and door-to-groin intervals between COVID time and NoCOVID times. On the contrary, the onset-to-door interval was significantly longer during the COVID time (p value: 0.001). Discussion While the percentage of admissions following an ED access grew dramatically, those to the Neurology Unit showed overall only a slight non-significant decrease. This finding implicitly reflects the serious and urgent nature of many neurological diseases, compelling people to access EDs at any time.

关键词： Ion channel   Venom peptide   Viral vector   Gene therapy   Neurological disease  

摘要： The venoms of arachnids, cone snails, and snakes consist of many peptides that have varieties of physiological activities, e.g., modulation of ion channels. We have recently prepared lentiviral vectors that express spider venom peptides and successfully observed their expression and secretion by the transduced cells. We expect that this expression method can be applied to neurological diseases. Because most neurological and psychiatric symptoms are caused by the dysregulations of neuronal activities and/or synaptic transmission, a single injection of a viral vector that expresses venom peptides would compensate for the dysregulations and thereby exert a therapeutic effect. Here, we discuss the details of application methods, and how and what venom peptide would exert therapeutic potential for a given disorder, e.g., chronic pain, epilepsy, and Parkinson's and Huntington's diseases. We also discuss the potential obstacles, i.e., lack of genetic information, side effects, and immune response, and methods to circumvent them.

关键词： SARS-CoV-2   COVID-19   Vaccine   Thunderclap headache   Myoclonus  

摘要： Objective To describe three cases with neurological symptoms after SARS-CoV-2 vaccination. Methods A case series followed by a review of the literature, describing hypotheses on how neurological symptoms might develop after vaccination. Results The different temporal relationship between the onset or worsening of different neurological symptoms suggests different pathophysiological mechanisms. Progression of post-infectious myoclonus, caused by a previous SARS-CoV-2-infection, shortly after vaccination suggests a renewed auto-immune mediated crossreaction of antibodies to both viral epitopes and central nervous system components. Thunderclap headache after vaccination suggests a similar pathophysiological mechanism to the headache and other flu-like symptoms described after vaccination against other viruses. This might be ascribed to the activation of immunoinflammatory mediators or accompanying fever. Although headache accompanied by encephalopathy and focal neurological deficit might occur as part of a cytokine release syndrome, this is clinically less likely. Conclusions A variety of symptoms, including thunderclap headache, focal deficits and movement disorders, can occur after SARS-CoV-2 vaccination, and an activation or reactivation of the immune system is suggested as most likely cause. However, one should be careful about claiming a direct correlation. It remains important to exclude other causes, such as structural lesions, infections or subarachnoid hemorrhage, and future research is required to understand possible pathophysiological mechanisms and associations with the SARS-CoV-2 vaccine.

关键词： Neurological disorder   COVID-19   Coronavirus   Brain   Neurological manifestation  

摘要： The first case of coronavirus illness was discovered in Wuhan, China, in January 2020 and quickly spread worldwide within the next couple of months. The condition was initially only linked with respiratory disorders. After the evolution of various variants of the SARS-CoV-2, the critical impact of the virus spread to multiple organs and soon, neurological disorder manifestations started to appear in the infected patients. The review is focused on the manifestation of various neurological disorders linked with both the central nervous system and peripheral nervous system. Disorders such as cytokine release syndrome, encephalitis, acute stroke, and Bell's palsy are given specific attention and psychological manifestations are also investigated. For a clear conclusion, cognitive impairment, drug addiction disorders, mood and anxiety disorders, and post-traumatic stress disorder are all fully examined. The association of the SARS-CoV-2 with neurological disorders and pathway is yet to be clear. For better understanding, the explanation of the possible mechanism of viral infection influencing the nervous system is also attempted in the review. While several vaccines and drugs are already involved in treating the SARS-CoV-2 condition, the disease is still considered fatal and more likely to leave permanent neurological damage, which leads to an essential requirement for more research to explore the neurological toll of the COVID-19 disease.

关键词： COVID-19   SARS-CoV-2   Brachial plexopathy   Peripheral neuropathy   Entrapment neuropathy   RA02  

摘要： Background and aims: We highlight the peripheral neurologic complications of coronavirus disease 2019 (COVID19) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an ongoing global health ***: We evaluated twenty-five patients admitted to the COVID-19 Recovery Unit (CRU) at New York Presbyterian Weill Cornell University Medical Center after intensive care hospitalization with confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), whom neurology was consulted for weakness and/ or paresthesias. All patients were clinically evaluated by a neuromuscular neurologist who performed electrodiagnostic (EDX) studies when indicated. Magnetic resonance imaging (MRI) of the affected regions, along with nerve and muscle biopsies were obtained in select patients to better elucidate the underlying ***: We found fourteen out of twenty-five patients with prolonged hospitalization for COVID-19 infection to have peripheral neurological complications, identified as plexopathies, peripheral neuropathies and entrapment neuropathies. The other eleven patients were not found to have peripheral neurologic causes for their symptoms. Patients with peripheral neurological complications often exhibited more than one type of concurrently. Specifically, there were four cases of plexopathies, nine cases of entrapment neuropathies, and six cases of peripheral neuropathies, which included cranial neuropathy, sciatic neuropathy, and multiple ***: We explore the possibility that the idiopathic peripheral neurologic complications could be manifestations of the COVID-19 disease spectrum, possibly resulting from micro-thrombotic induced nerve ischemia.