Restless Legs Syndrome and Periodic Limb Movements of Sleep: From Neurophysiology to Clinical Practice.

SUMMARY: This article summarizes restless legs syndrome (RLS), periodic limb movements of sleep, and periodic limb movement disorder. RLS is a common sleep disorder with a prevalence of 5% to 15% in the general population. RLS can present in childhood, and incidence increases with age. RLS can be idiopathic or secondary to iron deficiency, chronic renal failure, peripheral neuropathy, and medications such as antidepressants (with higher rates for mirtazapine and venlafaxine, while bupropion may reduce symptoms at least in the short term), dopamine antagonists (neuroleptic antipsychotic agents and antinausea medications), and possibly antihistamines. Management includes pharmacologic agents (dopaminergic agents, alpha-2 delta calcium channel ligands, opioids, benzodiazepines) and nonpharmacologic therapies (iron supplementation, behavioral management). Periodic limb movements of sleep are an electrophysiologic finding commonly accompanying RLS. On the other hand, most individuals with periodic limb movements of sleep do not have RLS. The clinical significance of the movements has been argued. Periodic limb movement disorder is a distinct sleep disorder that arises in individuals without RLS and is a diagnosis of exclusion.

Sleep and Breathing After Nusinersen Therapy in a Child With Spinal Muscular Atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) type 3 is an autosomal recessive neurological disorder associated with a deletion/mutation in the survival motor neuron gene, with gradually progressive degeneration of the motor neurons of the spinal cord and brainstem, which causes muscle weakness responsible for impairment of swallowing, breathing, and mobility. REPORT OF CASE: We report an 11-year-old girl with SMA type 3 with moderate to severe obstructive sleep apnea (OSA) syndrome refractory to adenotonsillectomy and noninvasive ventilatory support. She was started on nusinersen, which is a novel disease modifying therapy for SMA. This new treatment led to improvement of the OSA in a short period, likely from better respiratory muscle function. CONCLUSIONS: The improvement in OSA supports the role of nusinersen in sleep-related upper respiratory muscle function in SMA type 3.

Postoperative outcomes in patients with treatment-emergent central sleep apnea: a case series.

PURPOSE: Treatment-emergent central sleep apnea (TECSA) is a central sleep-related breathing disorder, characterized by either the persistence or emergence of central sleep apnea during the initiation of positive airway pressure therapy for obstructive sleep apnea. The purpose of this study was to review the perioperative course of patients diagnosed with TECSA. METHODS: We reviewed medical records of patients with TECSA who had a procedure or surgery with general anesthesia between January 1, 2009 and May 1, 2018. We describe postoperative outcomes including respiratory complications, unplanned intensive care unit (ICU) admissions, and other postoperative outcomes. RESULTS: We identified 150 (116 male, 34 female) patients with TECSA. Of these, 39 (26%) had their anesthesia recovery associated with moderate to profound sedation, 22 (14.7%) required unplanned transfer to ICU (8 for hypoxemia). Compared to patients without ICU admissions, patients with unplanned ICU admissions had higher rates of cardiovascular disease, Charlson comorbid scores, and perioperative benzodiazepines. Within the first 30 postoperative days there were 23 (16%) hospital re-admissions, and 7 (4.6%) deaths. CONCLUSION: Patients with TECSA have high rates of postoperative complications, characterized by an increased rate of unplanned intensive care admissions and both high 30-day readmission and mortality rates. When dealing with these patients perioperative physicians should implement an increased level of respiratory monitoring, and early postoperative use of their home prescribed non-invasive ventilation devices.

Frequency and outcomes of primary central sleep apnea in a population-based study.

BACKGROUND: Primary central sleep apnea (PCSA) is believed to be rare and data regarding its prevalence and long-term outcomes are sparse. We used the Rochester Epidemiology Project (REP) resources to identify all Olmsted County, Minnesota, residents with an incident diagnosis of PCSA and their clinical outcomes. METHODS: We searched the REP database for all residents with polysomnography (PSG)-confirmed diagnoses of central sleep apnea (CSA) between 2007 and 2015. From these, we reviewed the PSGs and medical records to find those who had PCSA based upon accepted diagnostic criteria. Data based on detailed review of the medical records, including all clinical notes and tests were recorded for analysis. RESULTS: Of 650 patients identified with CSA, 25 (3.8%; 23 male) had PCSA, which was severe in most patients (n = 16, 64%). Of those, 23 (92%) patients were prescribed and 18/23 (78.2%) adherent to positive airway pressure therapy. Median duration of follow-up was 4.4 years (IQR:4.2). Four (16%) patients were subsequently diagnosed with cardiac arrhythmias, one (4%) with unstable angina, two (8%) with heart failure, five (20%) with mild cognitive impairment (MCI)/dementia and two (8%) with depression. Six (25%) patients died (median time to death = 5 years; IQR:4.8), three of whom had Lewy body dementia. CONCLUSIONS: In this population-based study, PCSA was rare and when present, was severe in a majority of patients. The mortality rate was high. Most frequently observed disorders during follow-up were mild cognitive impairment (MCI)/dementia followed by cardiac arrhythmias; it is possible that these entities were present and not recognized prior to the diagnosis of PCSA.

Facial Weakness and Ophthalmoplegia in a 4-Day-Old Infant.

We present a neonate with neurologic deficits recognized at 4 days of age. A male infant was born at term via emergency cesarian section due to failure to progress and fetal decelerations. He underwent therapeutic hypothermia for hypoxic ischemic encephalopathy. Upon completion of rewarming, he was noted to have left facial palsy, abduction deficit on the left eye past the midline, and nystagmus involving the right eye. Brain magnetic resonance imaging showed a pontine stroke, and computed tomography angiogram revealed basilar artery thrombosis. He was treated with enoxaparin for 3 months, followed by low-dose aspirin. The mechanism of the stroke remains unclear, and there is limited evidence to guide management.

HLA associations with multiple sclerosis in Greece.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system originated by a complex interplay of environmental and genetic factors. The association of MS with the human leukocyte antigen (HLA) class II alleles was investigated in MS patients in northwest Greece, in the geographical region of Epirus. OBJECTIVE: Our aim was to estimate the prevalence of the HLA-DRB1*1501, HLA-DQB1*0602 and HLA-DQA1*0102 alleles, consisting the most common susceptibility haplotype in North European and North American Caucasians. METHODS: We studied 126 MS patients and 93 age and sex matched healthy controls. HLA typing was performed by a polymerase chain reaction (PCR) amplification with sequence-specific primers (PCR-SSP) method. RESULTS: We found that HLA-DRB1*1501, HLA-DQB1*0602 and HLA-DQA1*0102 alleles were significantly more frequent among patients (34% versus 11%, p=0.00015; 69% versus 51%, p=0.01; 76% versus 55%, p=0.002, respectively). HLA-DRB1*1501, HLA-DQB1*0602, HLA-DQA1*0102 haplotype was significantly more common among patients (p=0.00067). HLA-DRB1*1501 and HLA-DQB1*0602 alleles were more frequently detected in patients with initial symptoms from the brainstem or the cerebellum (p=0.024). No significant correlation was observed among these alleles with sex, disease clinical course, or age at onset. CONCLUSION: This is the first study to investigate genetic susceptibility to MS in Greece. Our results are in line with previous reports in North European and North American patients.

Reporting and interpretation of SF-36 outcomes in randomised trials: systematic review.

OBJECTIVE: To determine how often health surveys and quality of life evaluations reach different conclusions from those of primary efficacy outcomes and whether discordant results make a difference in the interpretation of trial findings. DESIGN: Systematic review. DATA SOURCES: PubMed, contact with authors for missing information, and author survey for unpublished SF-36 data. STUDY SELECTION: Randomised trials with SF-36 outcomes (the most extensively validated and used health survey instrument for appraising quality of life) that were published in 2005 in 22 journals with a high impact factor. DATA EXTRACTION: Analyses on the two composite and eight subdomain SF-36 scores that corresponded to the time and mode of analysis of the primary efficacy outcome. RESULTS: Of 1057 screened trials, 52 were identified as randomised trials with SF-36 results (66 separate comparisons). Only eight trials reported all 10 SF-36 scores in the published articles. For 21 of the 66 comparisons, SF-36 results were discordant for statistical significance compared with the results for primary efficacy outcomes. Of 17 statistically significant SF-36 scores where primary outcomes were not also statistically significant in the same direction, the magnitude of effect was small in six, moderate in six, large in three, and not reported in two. Authors modified the interpretation of study findings based on SF-36 results in only two of the 21 discordant cases. Among 100 additional randomly selected trials not reporting any SF-36 information, at least five had collected SF-36 data but only one had analysed it. CONCLUSIONS: SF-36 measurements sometimes produce different results from those of the primary efficacy outcomes but rarely modify the overall interpretation of randomised trials. Quality of life and health related survey information should be utilised more systematically in randomised trials.

International ranking systems for universities and institutions: a critical appraisal.

BACKGROUND: Ranking of universities and institutions has attracted wide attention recently. Several systems have been proposed that attempt to rank academic institutions worldwide. METHODS: We review the two most publicly visible ranking systems, the Shanghai Jiao Tong University 'Academic Ranking of World Universities' and the Times Higher Education Supplement 'World University Rankings' and also briefly review other ranking systems that use different criteria. We assess the construct validity for educational and research excellence and the measurement validity of each of the proposed ranking criteria, and try to identify generic challenges in international ranking of universities and institutions. RESULTS: None of the reviewed criteria for international ranking seems to have very good construct validity for both educational and research excellence, and most don't have very good construct validity even for just one of these two aspects of excellence. Measurement error for many items is also considerable or is not possible to determine due to lack of publication of the relevant data and methodology details. The concordance between the 2006 rankings by Shanghai and Times is modest at best, with only 133 universities shared in their top 200 lists. The examination of the existing international ranking systems suggests that generic challenges include adjustment for institutional size, definition of institutions, implications of average measurements of excellence versus measurements of extremes, adjustments for scientific field, time frame of measurement and allocation of credit for excellence. CONCLUSION: Naïve lists of international institutional rankings that do not address these fundamental challenges with transparent methods are misleading and should be abandoned. We make some suggestions on how focused and standardized evaluations of excellence could be improved and placed in proper context.

Pharmacogenetics of the response to beta 2 agonist drugs: a systematic overview of the field.

The response to beta2-agonist treatment shows large repeatability within individuals and may thus be determined by genetic influences. Here we present a systematic overview of the available genetic association and linkage data for beta2-agonist treatment response. Systematic searches identified 66 eligible articles, as of March 2007, pertaining either to B2AR gene polymorphisms and short-acting or long-acting beta2-agonists or to another 29 different genes. We systematize these study results according to gene, agent and type of outcomes addressed. The systematic review highlights major challenges in the field, including extreme multiplicity of analyses; lack of consensus for main phenotypes of interest; typically small sample sizes; and poor replicability of the proposed genetic variants. Future studies will benefit from standardization of analyses and outcomes, hypothesis-free genome-wide association testing platforms, potentially additional fine mapping around new discovered variants, and large-scale collaborative studies with prospective plans for replication among several teams, with transparent public recording of all data.

Genetic predisposition to asthma and atopy.

A large number of studies have tried to identify heritable components in the susceptibility to asthma and atopy phenotypes. This review examines the evidence of multigenetic inheritance for these conditions. We identified in the literature at least 372 gene-disease association studies for asthma and 124 for atopy published in the last 6 years. Gene-environment analyses were performed in 41 and 14 articles, respectively, in the same time period. Many postulated associations have been probed with limited sample sizes and will require more extensive replication and large-scale evidence. Meta-analyses have been performed for polymorphisms in 5 genes and provide modest evidence for genetic association of asthma with ADAM33 and TNFA gene polymorphisms. Meta-analyses of linkage studies show that it is unlikely to detect strong linkage peaks for asthma susceptibility. However, linkage was claimed between loci on chromosomes 2, 4, 6, 9, 10, 11 and 15 and total serum IgE levels. Careful definitions and standardization of phenotypes across teams of investigators are important to endorse. New large-scale testing platforms may offer new opportunities for discovering susceptibility gene variants, but they need to be coupled with careful study design, international collaboration, and possibly also dissection of gene-environment interactions.