Cost-Effectiveness of Newborn Screening for Spinal Muscular Atrophy in England.

INTRODUCTION: We sought to evaluate the cost-effectiveness of newborn screening (NBS) versus no NBS for 5q spinal muscular atrophy (SMA) in England. METHODS: A cost-utility analysis using a combination of decision tree and Markov model structures was developed to estimate the lifetime health effects and costs of NBS for SMA, compared with no NBS, from the perspective of the National Health Service (NHS) in England. A decision tree was designed to capture NBS outcomes, and Markov modeling was used to project long-term health outcomes and costs for each patient group following diagnosis. Model inputs were based on existing literature, local data, and expert opinion. Sensitivity and scenario analyses were conducted to assess the robustness of the model and the validity of the results. RESULTS: The introduction of NBS for SMA in England is estimated to identify approximately 56 (96% of cases) infants with SMA per year. Base-case results indicate that NBS is dominant (less costly and more effective) than a scenario without NBS, with a yearly cohort of newborns accruing incremental savings of £62,191,531 and an estimated gain in quality-adjusted life-years of 529 years over their lifetime. Deterministic and probabilistic sensitivity analyses demonstrated the robustness of the base-case results. CONCLUSIONS: NBS improves health outcomes for patients with SMA and is less costly compared with no screening; therefore, it is a cost-effective use of resources from the perspective of the NHS in England.

Cost-Effectiveness of Newborn Screening for Spinal Muscular Atrophy in The Netherlands.

OBJECTIVES: Spinal muscular atrophy (SMA) is a rare genetic disorder that causes progressive muscle weakness and paralysis. In its most common and severe form, the majority of untreated infants die before 2 years of age. Early detection and treatment, ideally before symptom onset, maximize survival and achievement of age-appropriate motor milestones, with potentially substantial impact on health-related quality of life. Therefore, SMA is an ideal candidate for inclusion in newborn screening (NBS) programs. We evaluated the cost-effectiveness of including SMA in the NBS program in The Netherlands. METHODS: We developed a cost-utility model to estimate lifetime health effects and costs of NBS for SMA and subsequent treatment versus a treatment pathway without NBS (ie, diagnosis and treatment after presentation with overt symptoms). Model inputs were based on literature, local data, and expert opinion. Sensitivity and scenario analyses were conducted to assess model robustness and validity of results. RESULTS: After detection of SMA by NBS in 17 patients, the number of quality-adjusted life-years gained per annual birth cohort was estimated at 320 with NBS followed by treatment compared with treatment after clinical SMA diagnosis. Total healthcare costs, including screening, diagnostics, treatment, and other healthcare resource use, were estimated to be €12 014 949 lower for patients identified by NBS. CONCLUSIONS: NBS for early identification and treatment of SMA versus later symptomatic treatment after clinical diagnosis improves health outcomes and is less costly and, therefore, is a cost-effective use of resources. Results were robust in sensitivity and scenario analyses.

Nusinersen for Spinal Muscular Atrophy in the United States: Findings From a Retrospective Claims Database Analysis.

INTRODUCTION: Spinal muscular atrophy (SMA) is a rare, genetic neuromuscular disorder caused by deletion/mutation of the survival motor neuron 1 gene, characterized by progressive loss of motor neurons, resulting in increasing muscular weakness, deteriorating motor function, and, in its most severe form, death before 2 years. Nusinersen, an antisense oligonucleotide that increases expression of the functional SMN protein, was approved for SMA by US and European regulatory agencies in 2016 and 2017, respectively. The indicated regimen requires intrathecal injections every 4 months, following the first four injections during the loading phase. Adherence is integral to treatment success. Adherence to nusinersen may pose particular challenges as most patients with SMA are young children who require complex multidisciplinary care (including ongoing intrathecal treatment administration and potential specialized anesthetic and surgical procedures) at specialized centers. However, real-world data on adherence to nusinersen are limited. METHODS: We conducted a retrospective claims database analysis from December 23, 2016, to November 20, 2019, to study nusinersen adherence and discontinuation/persistence in US patients with SMA types 1-3 who completed the loading phase, and to determine the impact of non-adherence or treatment discontinuation on SMA-related comorbidities, health care resource utilization (HCRU), and costs. RESULTS: We identified 23 patients with SMA type 1, 41 patients with SMA type 2, and 260 patients with SMA type 3 who had completed the loading phase. Deviations from the indicated nusinersen treatment schedule were frequent in real-world usage, with most patients receiving ≥1 dose outside the scheduled interval. Across SMA types, non-adherent patients were more likely to have had SMA-related comorbidities (e.g., feeding difficulties, dyspnea and respiratory anomalies, and muscle weakness) and greater HCRU. Persistence rates 12 months after treatment initiation for patients with SMA types 1, 2, and 3 were 55.2%, 42.4%, and 54.6%, respectively. Patients who discontinued nusinersen and those who did not had generally similar comorbidity profiles. Discontinuation was associated with greater health care costs across SMA types. CONCLUSION: Our analysis of claims data indicated that discontinuation and non-adherence to nusinersen treatment were prevalent, and associated with greater frequency of comorbidities, greater HCRU, and increased costs for patients.

Matching-adjusted indirect treatment comparison of onasemnogene abeparvovec and nusinersen for the treatment of symptomatic patients with spinal muscular atrophy type 1.

OBJECTIVE: Onasemnogene abeparvovec, a one-time intravenous gene replacement therapy, and nusinersen, an antisense oligonucleotide that requires ongoing intrathecal administration, have been evaluated as treatments for spinal muscular atrophy (SMA) type 1 in separate Phase III trials, but no head-to-head comparison studies have been conducted. Onasemnogene abeparvovec was compared with nusinersen using a matching-adjusted indirect comparison (MAIC) to estimate the treatment effect of onasemnogene abeparvovec relative to nusinersen for the treatment of symptomatic patients with SMA type 1 for up to 24 months of follow-up. METHODS: In the absence of studies for both onasemnogene abeparvovec and nusinersen with a common comparator, a Bayesian naïve indirect treatment comparison (ITC) and MAIC between onasemnogene abeparvovec and nusinersen were conducted to compare efficacy and safety of onasemnogene abeparvovec with nusinersen. Outcomes of interest were event-free survival (EFS), overall survival (OS), and motor milestone achievements (independent sitting and independent walking). Relative treatment effects were expressed as relative risk (RR) and risk difference. RESULTS: Pooled and weighted patient-level data illustrated a favorable effect toward onasemnogene abeparvovec, suggesting longer EFS for patients compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.19 [95% CI: 0.07-0.54; 99% CI: 0.05-0.74]). At 24 months of follow-up, patients receiving onasemnogene abeparvovec were statistically significantly more likely to achieve the motor milestone of sitting independently compared with patients treated with nusinersen. Although statistically significant differences were not observed at 6 to 18 months between treatment options, the likelihood of sitting independently at 12 and 18 months numerically favored onasemnogene abeparvovec. A numerically greater likelihood of walking by 18 and 24 months was also observed for patients treated with onasemnogene abeparvovec compared with nusinersen. Onasemnogene abeparvovec therapy was also associated with a favorable (but statistically nonsignificant) outcome for OS and may be associated with prolonged survival compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.35 [95% CI: 0.09-1.32; 99% CI: 0.06-2.01]). Bayesian naïve ITC results were similar to the MAIC analysis for EFS, OS, and motor milestone achievements. Small sample size limited covariate matching to baseline CHOP INTEND and nutritional support requirement, leading to wider CIs and statistically inconclusive outcomes for some of the results. CONCLUSIONS: Despite limitations of the current MAIC analysis (mainly a small sample size for statistical testing, even for the pooled onasemnogene abeparvovec trials, and potential differences in prognostic and predictive factors between studies), the relative treatment effects in EFS, OS, and motor milestone achievement indicate that onasemnogene abeparvovec may offer continued benefit compared with nusinersen through 24 months of follow-up.

An updated cost-utility model for onasemnogene abeparvovec (Zolgensma®) in spinal muscular atrophy type 1 patients and comparison with evaluation by the Institute for Clinical and Effectiveness Review (ICER).

Background: Recent cost-utility analysis (CUA) models for onasemnogene abeparvovec (Zolgensma®, formerly AVXS-101) in spinal muscular atrophy type 1 (SMA1) differ on key assumptions and results. Objective: To compare the manufacturer's proprietary CUA model to the model published by the Institute for Clinical and Economic Review (ICER), and to update the manufacturer's model with long-term follow-up data and some key ICER assumptions. Study design: We updated a recent CUA evaluating value for money in cost per incremental Quality-adjusted Life Year (QALY) of onasemnogene abeparvovec versus nusinersen (Spinraza®) or best supportive care (BSC) in symptomatic SMA1 patients, and compared it to the ICER model. Setting/Perspective: USA/Commercial payer Participants: Children aged <2 years with SMA1. Interventions: Onasemnogene abeparvovec, a single-dose gene replacement therapy, versus nusinersen, an antisense oligonucleotide, versus BSC. Main outcome measure: Incremental-cost effectiveness ratio and value-based price using traditional thresholds for general medicines in the US. Results: Updated survival (undiscounted) predicted by the model was 37.60 years for onasemnogene abeparvovec compared to 12.10 years for nusinersen and 7.27 years for BSC. Updated quality-adjusted survival using ICER's utility scores and discounted at 3% were 13.33, 2.85, and 1.15 discounted QALYs for onasemnogene abeparvovec, nusinersen, and BSC, respectively. Using estimated net prices, the discounted lifetime cost/patient was $3.93 M for onasemnogene abeparvovec, $4.60 M for nusinersen, and $1.96 M for BSC. The incremental cost per QALY gained for onasemnogene abeparvovec was dominant against nusinersen and $161,648 against BSC. These results broadly align with the results of the ICER model, which predicted a cost per QALY gained of $139,000 compared with nusinersen, and $243,000 compared with BSC (assuming a placeholder price of $2 M for onasemnogene abeparvovec), differences in methodology notwithstanding. Exploratory analyses in presymptomatic patients were similar. Conclusion: This updated CUA model is similar to ICER analyses comparing onasemnogene abeparvovec with nusinersen in the symptomatic and presymptomatic SMA populations. At a list price of $2.125 M, onasemnogene abeparvovec is cost-effective compared to nusinersen for SMA1 patients treated before age 2 years. When compared to BSC, cost per QALY of onasemnogene abeparvovec is higher than commonly used thresholds for therapies in the USA ($150,000 per QALY).

A Cost-Utility Analysis of Lisdexamfetamine Versus Atomoxetine in the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and Inadequate Response to Methylphenidate.

BACKGROUND: An economic analysis from the perspective of the UK National Health Service (NHS) evaluated the cost effectiveness of lisdexamfetamine dimesylate (LDX) compared with atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder who have had an inadequate response to methylphenidate. METHODS: A 1-year decision-analytic model was constructed, with the health outcomes "response", "nonresponse", and "unable to tolerate". Clinical data were taken from a head-to-head, randomized controlled trial in inadequate responders to methylphenidate. Response to treatment was defined as a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impression-Improvement subscale. Tolerability was assessed by discontinuation rates owing to adverse events. Utility weights were identified via a systematic literature review. Healthcare resource use estimates were obtained via a survey of clinicians. Daily drug costs were derived from British National Formulary 2012 costs and mean doses reported in the trial. One-way and probabilistic sensitivity analyses (PSAs) were performed. RESULTS: The comparison of LDX with atomoxetine resulted in an estimate of an incremental cost-effectiveness ratio of £1802 per quality-adjusted life-year (QALY). The result was robust in a wide range of sensitivity analyses; results were most sensitive to changes in drug costs and efficacy. In the PSA, assuming a maximum willingness to pay of £20,000 per QALY, LDX versus atomoxetine had an 86 % probability of being cost effective. In 38 % of PSA runs, LDX was more effective and less costly than atomoxetine. CONCLUSIONS: From the perspective of the UK NHS, LDX provides a cost-effective treatment option for children and adolescents who are inadequate responders to methylphenidate.

Preferential accumulation within tumors and in vivo imaging by functionalized luminescent dendrimer lanthanide complexes.

We have created a dendrimer complex suitable for preferential accumulation within liver tumors and luminescence imaging by substituting thirty-two naphthalimide fluorophores on the surface of the dendrimer and incorporating eight europium cations within the branches. We demonstrate the utility and performance of this luminescent dendrimer complex to detect hepatic tumors generated via direct subcapsular implantation or via splenic injections of colorectal cancer cells (CC531) into WAG/RijHsd rats. Luminescence imaging of the tumors after injection of the dendrimer complex via hepatic arterial infusion revealed that the dendrimer complex can preferentially accumulate within liver tumors. Further investigation indicated that dendrimer luminescence in hepatic tumors persisted in vivo. Due to the incorporation of lanthanide cations, this luminescence agent presents a strong resistance against photobleaching. These studies show the dendrimer complex has great potential to serve as an innovative accumulation and imaging agent for the detection of metastatic tumors in our rat hepatic model.

A review of methods used in long-term cost-effectiveness models of diabetes mellitus treatment.

Diabetes mellitus is a major healthcare concern from both a treatment and a funding perspective. Although decision makers frequently rely on models to evaluate the long-term costs and consequences associated with diabetes interventions, no recent article has reviewed the methods used in long-term cost-effectiveness models of diabetes treatment. The following databases were searched up to April 2008 to identify published economic models evaluating treatments for diabetes mellitus: OVID MEDLINE, EMBASE and the Thomson's Biosis Previews, NHS EED via Wiley's Cochrane Library, and Wiley's HEED database. Identified articles were reviewed and grouped according to unique models. When a model was applied in different settings (e.g. country) or compared different treatment alternatives, only the original publication describing the model was included. In some cases, subsequent articles were included if they provided methodological advances from the original model. The following data were captured for each study: (i) study characteristics; (ii) model structure; (iii) long-term complications, data sources, methods reporting and model validity; (iv) utilities, data sources and methods reporting; (v) costs, data sources and methods reporting; (vi) model data requirements; and (vii) economic results including methods to deal with uncertainty. A total of 17 studies were identified, 12 of which allowed for the conduct of a cost-effectiveness analysis and a cost-utility analysis. Although most models were Markov-based microsimulations, models differed with respect to the number of diabetes-related complications included. The majority of the studies used a lifetime time horizon and a payer perspective. The DCCT for type 1 diabetes and the UKPDS for type 2 diabetes were the trial data sources most commonly cited for the efficacy data, although several non-randomized data sources were used. While the methods used to derive the efficacy data were commonly reported, less information was given regarding the derivation of the utilities or the costs. New interventions were generally deemed cost effective based on ten studies presenting results. Authors relied mostly on univariate sensitivity analyses to test the robustness of their models. Although diabetes is a complex disease, several models have been developed to predict the long-term costs and consequences associated with diabetes treatment. Combined with previous findings, this review supports the development of a reference case that could be used for any new diabetes models. Models could be enhanced if they had the capacity to deal with both first- and second-order uncertainty. Future research should continue to compare economic models for diabetes treatment in terms of clinical outcomes, costs and QALYs when applicable.

A review of health utilities across conditions common in paediatric and adult populations.

BACKGROUND: Cost-utility analyses are commonly used in economic evaluations of interventions or conditions that have an impact on health-related quality of life. However, evaluating utilities in children presents several challenges since young children may not have the cognitive ability to complete measurement tasks and thus utility values must be estimated by proxy assessors. Another solution is to use utilities derived from an adult population. To better inform the future conduct of cost-utility analyses in paediatric populations, we reviewed the published literature reporting utilities among children and adults across selected conditions common to paediatric and adult populations. METHODS: An electronic search of Ovid MEDLINE, EMBASE, and the Cochrane Library up to November 2008 was conducted to identify studies presenting utility values derived from the Health Utilities Index (HUI) or EuroQoL-5Dimensions (EQ-5D) questionnaires or using time trade off (TTO) or standard gamble (SG) techniques in children and/or adult populations from randomized controlled trials, comparative or non-comparative observational studies, or cross-sectional studies. The search was targeted to four chronic diseases/conditions common to both children and adults and known to have a negative impact on health-related quality of life (HRQoL). RESULTS: After screening 951 citations identified from the literature search, 77 unique studies included in our review evaluated utilities in patients with asthma (n = 25), cancer (n = 23), diabetes mellitus (n = 11), skin diseases (n = 19) or chronic diseases (n = 2), with some studies evaluating multiple conditions. Utility values were estimated using HUI (n = 33), EQ-5D (n = 26), TTO (n = 12), and SG (n = 14), with some studies applying more than one technique to estimate utility values. 21% of studies evaluated utilities in children, of those the majority being in the area of oncology. No utility values for children were reported in skin diseases. Although few studies provided comparative information on utility values between children and adults, results seem to indicate that utilities may be similar in adolescents and young adults with asthma and acne. Differences in results were observed depending on methods and proxies. CONCLUSIONS: This review highlights the need to conduct future research regarding measurement of utilities in children.

Cost-effectiveness of drug-eluting stents in a US Medicare setting:a cost-utility analysis with 3-year clinical follow-up data.

BACKGROUND: There is only limited information about cost-effectiveness of drug-eluting compared with bare metal stents (BMS) over a time horizon of more than 1 year. METHODS AND RESULTS: We developed a Markov model based on clinical outcome data from a meta-analysis including 17 randomized controlled trials comparing drug-eluting versus BMS with a minimum follow-up of 1 (n = 8221) and a maximum follow-up of 3 years (n = 4105) in patients with chronic coronary artery disease. Costs were obtained as reimbursement rates for diagnosis related groups from the US Centers for Medicare and Medicaid Services. All costs and effects were discounted at 3% annually. All costs are reported in US dollars of the financial year 2007. The incremental effects are 0.002 (95% confidence interval −0.039 to 0.041) quality-adjusted life-years (QALYs) for the sirolimus- and −0.001 (−0.040 to 0.038) QALYs for the paclitaxel-eluting stents (PES). The incremental costs are $2790 for the sirolimus- and $3838 for the PES. The incremental cost-effectiveness ratio is >$1,000,000 per QALY for the sirolimus-eluting stent. PES are dominated by BMS (i.e., less effective and more costly). Among various sensitivity analyses performed, the model proved to be robust. CONCLUSIONS: Our analysis from a US Medicare perspective suggests that drug-eluting stents are not cost-effective compared with BMS when implanted in unselected patients with symptomatic ischemic coronary artery disease.

Approaches for economic evaluations of health care technologies.

Economic evaluations involve the comparison of alternative courses of action in terms of both their costs and their consequences. In response to increasing health care costs, economic evaluations of competing technologies, including radiologic interventions, are increasingly used to inform resource allocation decisions. It is therefore crucial that radiologists have a thorough understanding of the methods. The objective of this paper is to present a detailed overview of the principles and methods of economic evaluations of health technologies, including recent methodologic developments. For the purpose of this paper, the key elements of an economic evaluation are divided into 5 broad sections: 1) types of economic evaluations (eg, cost-effectiveness analysis, cost-utility analysis), 2) study perspectives (ie, temporal and cost perspectives), 3) analysis of costs and effects (eg, incremental cost-effectiveness ratios, cost-effectiveness planes), 4) conducting economic evaluations alongside trials or using decision-analytic models, and 5) dealing with the different forms of uncertainty in economic evaluations (eg, sampling uncertainty in trials, parameter uncertainty in models). Examples from the recent radiology literature are used to explain the key concepts. This review improves upon the previous educational papers published in radiologic journals, as it covers recent methodologic advances regarding the treatment of uncertainty.

Health technology assessment and primary data collection for reducing uncertainty in decision making.

BACKGROUND: Health care expenditures continue to escalate, and pressures for increased spending will continue. Health care decision makers from publicly financed systems, private insurance companies, or even from individual health care institutions, will continue to be faced with making difficult purchasing, access, and reimbursement decisions. As a result, decision makers are increasingly turning to evidence-based platforms to help control costs and make the most efficient use of existing resources. Most tools used to assist with evidence-based decision making focus on clinical outcomes. HEALTH TECHNOLOGY ASSESSMENT: Health technology assessment (HTA) is increasing in popularity because it also considers other factors important for decision making, such as cost, social and ethical values, legal issues, and factors such as the feasibility of implementation. In some jurisdictions, HTAs have also been supplemented with primary data collection to help address uncertainty that may still exist after conducting a traditional HTA. ROLE OF PRIMARY DATA COLLECTION: The HTA process adopted in Ontario, Canada, is unique in that assessments are also made to determine what primary data research should be conducted and what should be collected in these studies. In this article, concerns with the traditional HTA process are discussed, followed by a description of the HTA process that has been established in Ontario, with a particular focus on the data collection program followed by the Programs for Assessment of Technology in Health Research Institute. An illustrative example is used to show how the Ontario HTA process works and the role value of information analyses plays in addressing decision uncertainty, determining research feasibility, and determining study data collection needs.

Cost-effectiveness of neonatal extracorporeal membrane oxygenation based on 7-year results from the United Kingdom Collaborative ECMO Trial.

OBJECTIVE: To assess the long-term cost-effectiveness of extracorporeal membrane oxygenation (ECMO) for mature newborn infants with severe respiratory failure. METHODS: A prospective economic evaluation was conducted alongside a pragmatic randomized, controlled trial in which 185 infants were randomly allocated to ECMO (n = 93) or conventional management (n = 92) and then followed up to 7 years of age. Information about their use of health services during the follow-up period was combined with unit costs (pound sterling, 2002-2003 prices) to obtain a net cost per child. The cost-effectiveness of neonatal ECMO was expressed in terms of incremental cost per additional life year gained and incremental cost per additional disability-free life year gained. The nonparametric bootstrap method was used to present cost-effectiveness acceptability curves and net benefit statistics at alternative willingness-to-pay thresholds held by decision-makers for an additional life year and for an additional disability-free life year. RESULTS: Over 7 years, neonatal ECMO was effective at reducing known death or severe disability. Mean health service costs during the first 7 years of life were 30,270 pound sterling in the ECMO group and 10,229 pound sterling in the conventional management group, generating a mean cost difference of 20,041 pound sterling that was statistically significant. The incremental cost per life year gained was estimated at 13,385 pound sterling. The incremental cost per disability-free life year gained was estimated at 23,566 pound sterling. At the notional willingness-to-pay threshold of 30,000 pound sterling for an additional life year, the probability that neonatal ECMO is cost-effective at 7 years was estimated at 0.98. This translated into a mean net benefit of 24,362 pound sterling for each adoption of neonatal ECMO rather than conventional management. CONCLUSIONS: This study provides rigorous evidence of the cost-effectiveness of neonatal ECMO during childhood.

Cost-effectiveness of extended venous thromboembolism prophylaxis with fondaparinux in hip surgery patients.

In the Penthifra Plus trial, extended prophylaxis with the synthetic pentasaccharide fondaparinux for 1 month versus 1 week in hip fracture surgery has been shown to reduce the risk of venous thromboembolic events by 96%. The cost-effectiveness of extended prophylaxis with fondaparinux still remains to be determined. The authors developed a decision analytic cost-effectiveness model comparing the use of fondaparinux for 4 weeks with 1 week from a healthcare perspective. The analyses were performed for patients undergoing hip fracture surgery and total hip replacement (THR). Efficacy data were extracted from published randomized controlled trials and natural history data after venous thromboembolic events from observational studies. Cost data were derived from the literature and other published sources. Costs were expressed in 2004 Swiss Francs (CHF) and effects as life-years gained (LYG). In patients undergoing hip fracture surgery, the incremental cost-effectiveness ratio of extended 4-week fondaparinux prophylaxis versus a 1-week regimen was CHF 2801/LYG after 30 days, with cost-savings after 5 years. In patients undergoing THR, the respective incremental cost-effectiveness ratio of extended fondaparninux prophylaxis was CHF 20,294/LYG after 30 days, with cost-savings after 5 years. In the authors' model, the substantial clinical benefit of extended thromboembolism prophylaxis with fondaparinux in major orthopedic surgery translates into favorable cost-effectiveness figures in the short term and cost savings when a 5-year time horizon is used.

Total dream loss: a distinct neuropsychological dysfunction after bilateral PCA stroke.

The term Charcot-Wilbrand syndrome (CWS) denotes dream loss following focal brain damage. We report the first case of CWS, in whom neuropsychological functions, extension of the underlying lesion, and sleep architecture changes were assessed. A 73-year-old woman reported a total dream loss after acute, bilateral occipital artery infarction (including the right inferior lingual gyrus), which lasted for over 3 months. In the absence of sleep-wake complaints and (other) neuropsychological deficits, polysomnography demonstrated an essentially normal sleep architecture with preservation of REM sleep. Dreaming was denied also after repeated awakenings from REM sleep. This observation suggests that CWS (1) can represent a distinct and isolated neuropsychological manifestation of deep occipital lobe damage, and (2) may occur in the absence of detectable REM sleep abnormalities.

The narcoleptic borderland: a multimodal diagnostic approach including cerebrospinal fluid levels of hypocretin-1 (orexin A).

OBJECTIVES: Biological markers of narcolepsy with cataplexy (classical narcolepsy) include sleep-onset REM periods (SOREM) on multiple sleep latency tests (MSLT), HLA-DQB1*0602 positivity, low levels of cerebrospinal fluid (CSF) hypocretin-1 (orexin A), increased body mass index (BMI), and high levels of CSF leptin. The clinical borderland of narcolepsy and the diagnostic value of different markers of narcolepsy remain controversial and were assessed in a consecutive series of 27 patients with hypersomnia of (mainly) neurological origin. METHODS: Diagnoses included classical narcolepsy (n=3), symptomatic narcolepsy (n=1), narcolepsy without cataplexy (n=4), idiopathic hypersomnia (n=5), hypersomnia associated with psychiatric disorders (n=5), and hypersomnia secondary to neurological disorders or of undetermined origin (n=9). Clinical assessment included BMI, Epworth Sleepiness Scale (ESS), Ullanlinna Narcolepsy Scale (UNS), and history of REM-symptoms (sleep paralysis, hallucinations). HLA-typing, electrophysiological studies (conventional polysomnography, MSLT, 1-week actigraphy), and measurements of CSF levels of hypocretin and leptin were also performed. RESULTS: Hypocretin-1 was undetectable in three patients with classic narcolepsy and detectable in the remaining 24 patients. Other narcoleptic markers also frequently found in patients without narcolepsy included ESS>14 (78% of 27 patients), UNS>14 (75%), REM symptoms (30%), sleep latencies on MSLT<5 min (41%), >/=2 SOREM (30%), DQB1*0602 positivity (52%), BMI>25 (52%), and increased CSF leptin (48%). Hypersomnia was documented by an increased time 'asleep' in 41% of patients. Overlapping clinical and electrophysiological findings were seen mostly in patients with narcolepsy without cataplexy, idiopathic hypersomnia, and psychiatric hypersomnia. CONCLUSIONS: (1) Hypocretin dysfunction is not the 'final common pathway' in the pathophysiology of most hypersomnolent syndromes that fall on the borderline for a diagnosis of narcolepsy. (2) The observed overlap among these hypersomnolent syndromes implies that current diagnostic categories are not entirely unambiguous. (3) A common hypothalamic, hypocretin-independent dysfunction may be present in some of these syndromes.

Evolution of sleep and sleep EEG after hemispheric stroke.

The evolution of subjective sleep and sleep electroencephalogram (EEG) after hemispheric stroke have been rarely studied and the relationship of sleep variables to stroke outcome is essentially unknown. We studied 27 patients with first hemispheric ischaemic stroke and no sleep apnoea in the acute (1-8 days), subacute (9-35 days), and chronic phase (5-24 months) after stroke. Clinical assessment included estimated sleep time per 24 h (EST) and Epworth sleepiness score (ESS) before stroke, as well as EST, ESS and clinical outcome after stroke. Sleep EEG data from stroke patients were compared with data from 11 hospitalized controls and published norms. Changes in EST (>2 h, 38% of patients) and ESS (>3 points, 26%) were frequent but correlated poorly with sleep EEG changes. In the chronic phase no significant differences in sleep EEG between controls and patients were found. High sleep efficiency and low wakefulness after sleep onset in the acute phase were associated with a good long-term outcome. These two sleep EEG variables improved significantly from the acute to the subacute and chronic phase. In conclusion, hemispheric strokes can cause insomnia, hypersomnia or changes in sleep needs but only rarely persisting sleep EEG abnormalities. High sleep EEG continuity in the acute phase of stroke heralds a good clinical outcome.

Visual and spectral analysis of sleep EEG in acute hemispheric stroke.

BACKGROUND: Reports on the effects of focal hemispheric damage on sleep EEG are rare and contradictory. PATIENTS AND METHODS: Twenty patients (mean age +/- SD 53 +/- 14 years) with a first acute hemispheric stroke and no sleep apnea were studied. Stroke severity [National Institute of Health Stroke Scale (NIHSS)], volume (diffusion-weighted brain MRI), and short-term outcome (Rankin score) were assessed. Within the first 8 days after stroke onset, 1-3 sleep EEG recordings per patient were performed. Sleep scoring and spectral analysis were based on the central derivation of the healthy hemisphere. Data were compared with those of 10 age-matched and gender-matched hospitalized controls with no brain damage and no sleep apnea. RESULTS: Stroke patients had higher amounts of wakefulness after sleep onset (112 +/- 53 min vs. 60 +/- 38 min, p < 0.05) and a lower sleep efficiency (76 +/- 10% vs. 86 +/- 8%, p < 0.05) than controls. Time spent in slow-wave sleep (SWS) and rapid eye movement (REM) sleep and total sleep time were lower in stroke patients, but differences were not significant. A positive correlation was found between the amount of SWS and stroke volume (r = 0.79). The slow-wave activity (SWA) ratio NREM sleep/wakefulness was lower in patients than in controls (p < 0.05), and correlated with NIHSS (r = -0.47). CONCLUSION: Acute hemispheric stroke is accompanied by alterations of sleep EEG over the healthy hemisphere that correlate with stroke volume and outcome. The increased SWA during wakefulness and SWS over the healthy hemisphere contralaterally to large strokes may reflect neuronal hypometabolism induced transhemispherically (diaschisis).