Lancet neurology
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Spinal muscular atrophy was the most common inherited cause of infant death until 2016, when three therapies became available: the antisense oligonucleotide nusinersen, gene replacement therapy with onasemnogene abeparvovec, and the small-molecule splicing modifier risdiplam. These drugs compensate for deficient survival motor neuron protein and have improved lifespan and quality of life in infants and children with spinal muscular atrophy. Given the lifelong implications of these innovative therapies, ways to detect and manage treatment-modified disease characteristics are needed. ⋯ Adults with spinal muscular atrophy report stabilisation of disease and less fatigue with treatment. These subjective benefits need to be weighed against the high costs of the drugs to patients and health-care systems. Clinical consensus is required on therapeutic windows and on outcome measures and biomarkers that can be used to monitor drug benefit, toxicity, and treatment-modified disease characteristics.
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Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease rather than as clinical syndromes. This major shift from a clinical to a biological definition of Parkinson's disease and dementia with Lewy bodies takes advantage of the availability of tools to assess the gold standard for diagnosis of neuronal α-synuclein (n-αsyn) in human beings during life. ⋯ A biological definition of neuronal α-synuclein disease and an NSD-ISS research framework are essential to enable interventional trials at early disease stages. The NSD-ISS will evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated. Presently, the NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate.
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Review
A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria.
With the hope that disease-modifying treatments could target the molecular basis of Parkinson's disease, even before the onset of symptoms, we propose a biologically based classification. Our classification acknowledges the complexity and heterogeneity of the disease by use of a three-component system (SynNeurGe): presence or absence of pathological α-synuclein (S) in tissues or CSF; evidence of underlying neurodegeneration (N) defined by neuroimaging procedures; and documentation of pathogenic gene variants (G) that cause or strongly predispose to Parkinson's disease. ⋯ We emphasise the initial application of these criteria exclusively for research. We acknowledge its ethical implications, its limitations, and the need for prospective validation in future studies.
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Globally, up to 1·5 million individuals with ischaemic stroke or transient ischaemic attack can be newly diagnosed with atrial fibrillation per year. In the past decade, evidence has accumulated supporting the notion that atrial fibrillation first detected after a stroke or transient ischaemic attack differs from atrial fibrillation known before the occurrence of as stroke. ⋯ Patients with ischaemic stroke or transient ischaemic attack can be classified in three categories: no atrial fibrillation, known atrial fibrillation before stroke occurrence, and atrial fibrillation detected after stroke. This classification could harmonise future research in the field and help to understand the role of prolonged cardiac monitoring for secondary stroke prevention with application of a personalised risk-based approach to the selection of patients for anticoagulation.
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Immune checkpoint inhibitors, a class of oncological treatments that enhance antitumour immunity, can trigger neurological adverse events closely resembling paraneoplastic neurological syndromes. Unlike other neurological adverse events caused by these drugs, post-immune checkpoint inhibitor paraneoplastic neurological syndromes predominantly affect the CNS and are associated with neural antibodies and cancer types commonly found also in spontaneous paraneoplastic neurological syndromes. Furthermore, post-immune checkpoint inhibitor paraneoplastic neurological syndromes have poorer neurological outcomes than other neurological adverse events of immune checkpoint inhibitors. ⋯ Importantly, the neural antibodies found in patients with post-immune checkpoint inhibitor paraneoplastic neurological syndromes are sometimes detected before treatment, indicating that these antibodies might help to predict the development of neurological adverse events. Experimental and clinical evidence suggests that post-immune checkpoint inhibitor paraneoplastic neurological syndromes probably share immunological features with spontaneous paraneoplastic syndromes. Hence, the study of post-immune checkpoint inhibitor paraneoplastic neurological syndromes can help in deciphering the immunopathogenesis of paraneoplastic neurological syndromes and in identifying novel therapeutic targets.