IMPORTANCE: There is limited information about health care use and costs in patients with functional neurological disorders (FNDs). OBJECTIVE: To assess US emergency department (ED) and inpatient use ...and charges for FNDs. DESIGN, SETTING, AND PARTICIPANTS: This economic evaluation used Healthcare Cost and Utilization Project data to assess all-payer (1) adult (age, ≥18 years) hospitalizations (2008-2017), (2) pediatric (age, 5-17 years) hospitalizations (2003, 2006, 2009, 2012, and 2016), and (3) adult and pediatric ED evaluations (2008-2017). International Classification of Diseases, Ninth Revision, Clinical Modification code 300.11 (conversion disorder) or 306.0 (musculoskeletal malfunction arising from mental factors) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Clinical Modification codes for conversion disorder/functional neurological symptom disorder (F44.4 to F44.7) were used to conservatively define FNDs and to compare them with other neurological disorders that are associated with high levels of health care use. Analysis was performed between January 2019 and July 2020. MAIN OUTCOMES AND MEASURES: Admission traits (eg, demographic characteristics of patients, length of stay, and discharge disposition) and hospital charges. RESULTS: Compared with other neurological disorders in 2017, emergency FND evaluations of 36 359 adults (25 807 women 71.0% and 3800 children (2733 girls 71.9%) more frequently resulted in inpatient admissions (22 895 adult admissions 69.2% female and 1264 pediatric admissions 73.4% ). These FND admissions had a shorter mean (SEM) hospital length of stay (5.21 0.15 days vs 6.03 0.03 days, P < .001) but higher workup rates than admissions for comparable neurological diagnoses. Admissions for FNDs had low rates of inpatient physical therapy, occupational therapy, speech and language pathology, and psychiatric consultation. The total annual costs (a proxy for total costs in 2017 US dollars) were $1066 million (95% CI, $971-$1160 million) for adult FND inpatient charges in 2017 compared with $1241 million (95% CI, $1132-$1351 million) for anterior horn cell disease; $75 million (95% CI, $57-$92 million) for pediatric FND inpatient charges in 2012 compared with $86 million (95% CI, $63-$108 million) for demyelinating diseases; and $163 million (95% CI, $144-$182 million) for adult and pediatric ED visits in 2017 compared with $135 million (95% CI $111-$159 million) for refractory epilepsy. Total charges per admission for ED care of FNDs were higher than the other comparison groups in adults. Total costs and costs per admission for FNDs increased from 2008 to 2017 at a higher rate than that of other neurological disorders. CONCLUSIONS AND RELEVANCE: This economic evaluation found that the more than $1.2 billion and increasing annual costs for ED and inpatient care of FNDs were similar to other investigation-intensive and pharmacologically demanding neurological disorders. Unnecessary investigations and iatrogenic harm inflate costs at the expense of necessary but neglected psychiatric and rehabilitative treatments.
The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into ...plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic–molecular cohorts.
Essential pitfalls in “essential” tremor Espay, Alberto J.; Lang, Anthony E.; Erro, Roberto ...
Movement disorders,
March 2017, Letnik:
32, Številka:
3
Journal Article
Within the broad spectrum of movement disorders, tics and functional tic-like movements belong to a particular clinical category. Both types of movements are within the range of normal movement ...kinematics and muscle synergies, but appear repetitive and without appropriate context embedment. Historically, there have been many attempts to separate the 2 types of movements, but because of their phenomenological overlap, clinical distinction may be prone to error, and misdiagnoses may often occur. Most importantly, the 2 types of movement may coexist. Here, we review the available literature on the 2 types of motor phenomena and demonstrate some of the difficulties in distinguishing tics from functional tic-like movements on clinical grounds. We also highlight similarities and differences in pathophysiologic characteristics, documenting the significance of action monitoring, attentional allocation, and behavioral reinforcement in both types of movements, as well as in their risk factors. We discuss the overlap of current behavioral treatments for tics and functional tic-like movements and emphasize implications of diagnostic mislabeling. Such implications include the need to tailor behavioral treatment approaches to individual phenomenological profiles and guiding decision making for severe patients requiring invasive interventions, such as deep brain stimulation. A deeper insight from clinicians with respect to persisting challenges in classifying and differentiating these motor phenomena could accelerate the development of reliable clinical and physiologic markers (i.e., next generation phenotyping) and a neurobiology-driven therapeutic approach for these motor phenomena.
Keywords: Parkinson's disease; REM sleep behavior disorder Article Note: Relevant conflicts of interest/financial disclosures: None. Byline: Conor Fearon, Anthony E. Lang, Alberto J. Espay
The process of protein aggregation involves the transformation of soluble peptides into insoluble cross-beta amyloids. In Parkinson's disease (PD), soluble monomeric α-synuclein transforms into the ...amyloid state known as Lewy pathology. Monomeric (functional) α-synuclein depletes as the fraction of Lewy pathology increases. We examined the allocation of disease-modifying projects in the PD therapeutic pipeline classified based on whether they aimed to reduce directly or indirectly the insoluble or increase the soluble α-synuclein. A project was defined as a drug development program that may include more than one registered clinical trial, according to the Parkinson's Hope List, a database of therapies under development for PD. Of 67 projects, 46 aimed to reduce α-synuclein, 15 (22.4%) directly and 31 (46.3%) indirectly, amounting to 68.7% of all disease-modifying projects. No projects explicitly aimed to increase soluble α-synuclein levels. Altogether, α-synuclein is the target of more than two-thirds of the disease-modifying pipeline, with treatments aimed at reducing or preventing an increase in its insoluble fraction. As no treatments aim to restore soluble α-synuclein levels within a normal range, we propose rebalancing the therapeutic PD pipeline.
•In Parkinson's, as soluble α-synuclein depletes, insoluble Lewy pathology increases.•69% of disease-modifying projects in the pipeline aim at reducing α-synuclein.•No projects explicitly aimed to increase soluble α-synuclein levels.•A rebalancing of the therapeutic PD pipeline is proposed.
The clinicopathologic model that defines neurodegenerative disorders has remained unchanged for over a century. According to it, clinical manifestations are defined and explained by a given ...pathology, that is, by the burden and distribution of selected proteins aggregated into insoluble amyloids. There are two logical consequences from this model: (1) a measurement of the disease-defining pathology represents a biomarker of that disease in everyone affected, and (2) the targeted elimination of that pathology should end that disease. But success in disease modification guided by this model has remained elusive. New technologies to probe living biology have been used to validate rather than question the clinicopathologic model, despite three important observations: (1) a disease-defining pathology in isolation (without other pathologies) is an exceptional autopsy finding; (2) many genetic and molecular pathways converge on the same pathology; (3) the presence of pathology without neurological disease is more common than expected by chance. We here discuss the rationale for abandoning the clinicopathologic model, review the competing biological model of neurodegeneration, and propose developmental pathways for biomarker development and disease-modifying efforts. Further, in justifying future disease-modifying trials testing putative neuroprotective molecules, a key inclusion criterion must be the deployment of a bioassay of the mechanism corrected by the therapy of interest. No improvements in trial design or execution can overcome the fundamental deficit created by testing experimental therapies in clinically defined recipients unselected for their biologically suitability. Biological subtyping is the key developmental milestone needed to launch precision medicine for patients living with neurodegenerative disorders.
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