Poul Jennum

Epidemiology of sleep apnoea/hypopnoea syndrome and sleep-disordered breathing

Epidemiological studies have revealed a high prevalence of sleep-disordered breathing in the community (up to 20%). A subset of these patients has concurrent symptoms of excessive daytime sleepiness attributable to their nocturnal breathing disorder and is classified as having obstructive sleep apnoea/hypopnoea syndrome (4–5% of the middle-aged population). There is strong evidence for an association of sleep apnoea with cardiovascular and cerebrovascular morbidity, as well as adverse public health consequences. Treatment and diagnosis have remained largely unchanged over the past 25 yrs. In moderate-to-severe obstructive sleep apnoea/hypopnoea syndrome, treatment with continuous positive airway pressure has been shown to be effective. Questions remain as to how to screen patients with sleep-disordered breathing. Should time-consuming diagnostic procedures with high sensitivity and specificity be employed, or should simpler methods be applied for screening populations at risk, e.g. in the primary care sector?

The standardization of terminology in nocturia: report from the standardization subcommittee of the International Continence Society

P. VAN KER REBROECK 1 , P. ABRAMS 2 , D. CHAIKIN 3 , J. DONOVAN 4 , D. FONDA 5 , S. JACKSON 6 , P. JENNUM 7 , T. JOHNSON 8 , G.R. LOSE 9 , A. MATTIASSON 10 , G.L. ROBER TSON 11 and J. WEISS 12 1 Chairman of the International Continence Society Standardization Committee, Department of Urology, University Hospital Maastricht, the Netherlands, 2 Bristol Urological Institute, Southmead Hospital, Bristol, UK, 3 Morristown Memorial Hospital, Morristown NJ, and Department of Urology, Weill Medical College of Cornell University, USA, 4 Department of Social Medicine, University of Bristol, Bristol, UK, 5 Aged Care Services, Caulfield General Medical Centre, Victoria, Australia, 6 Department of Gynaecology, John Radcliffe Hospital, Oxford, UK, 7 Department of Clinical Neurophysiology, University of Copenhagen and Sleep Laboratory, Glostrup, Denmark, 8 Rehabilitation Research and Development Center, Atlanta VA Medical Centre, Georgia, USA, 9 Department of Obstetrics and Gynaecology, Glostrup County Hospital, University of Copenhagen, Denmark, 10 Department of Urology, Lund University Hospital, Lund, Sweden, 11 Northwestern University Medical School, Chicago, USA, 12 Department of Urology, Weill Medical College of Cornell University and The New York Presbyterian Hospital, New York, NY, USA

Speech localization using repetitive transcranial magnetic stimulation

To evaluate whether repetitive transcranial magnetic stimulation (RTMS) may be used for speech localization, we compared the results from RTMS with the intracarotid amobarbital test (IAT) in 21 patients undergoing surgical treatment (amygdalohippocampectomy or anterior temporal lobe resection) for medically intractable partial epilepsy. None of the patients had aphasia. We stimulated the temporal and frontal cortex on each side at a frequency of 30 Hz for 1 second and increased the intensity until speech was inhibited. A list of words and forward and backward counting were used to test speech function. The IAT was performed on the hemisphere of proposed surgery by unilateral injection and simultaneous regional cerebral blood flow (rCBF) recordings. In one patient, there was doubt about hemisphere dominance and a second bilateral IAT was performed. Fifteen patients had left-sided speech dominance; one, left-sided dominance and a moderate right-sided speech inhibition; two, right-sided speech dominance; and one, bilateral speech representations (bilateral injection at the IAT) with both techniques. One patient showed bilateral with right-sided speech dominance by RTMS and showed right-sided speech inhibition with right-sided injection only at the IAT procedure. One patient differed from the rest, showing bilateral representation with right-sided speech dominance with RTMS and left-sided speech inhibition by IAT with left-sided injection only. The concordance was 95%. None of the patients had seizures provoked by the procedure. We conclude that speech localization with RTMS shows a high concordance with the results from the IAT and may be useful in addition to traditional techniques in speech localization. RTMS is noninvasive, can be repeated, carries little or no risks, and does not require that the patients be hospitalized.

Common variants in P2RY11 are associated with narcolepsy

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3′ untranslated region of P2RY11, the purinergic receptor subtype P2Y11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10−10, odds ratio = 1.28, 95% CI 1.19–1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8+ T lymphocytes (72% reduced, P = 0.003) and natural killer (NK) cells (70% reduced, P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.

Rapid eye movement sleep disturbances in Huntington disease.

BACKGROUND Sleep disorders including insomnia, movements during sleep, and daytime sleepiness are common but poorly studied in Huntington disease (HD). OBJECTIVE To evaluate the HD sleep-wake phenotype (including abnormal motor activity during sleep) in patients with various HD stages and the length of CAG repeats. Because a mild hypocretin deficiency has been found in the brains of some patients with HD (hereinafter referred to as HD patients), we also tested the HD patients for narcolepsy. DESIGN AND PATIENTS Twenty-five HD patients (including 2 premanifest carriers) underwent clinical interview, nighttime video and sleep monitoring, and daytime multiple sleep latency tests. Their results were compared with those of patients with narcolepsy and control patients. RESULTS The HD patients had frequent insomnia, earlier sleep onset, lower sleep efficiency, increased stage 1 sleep, delayed and shortened rapid eye movement (REM) sleep, and increased periodic leg movements. Three HD patients (12%) had REM sleep behavior disorders. No sleep abnormality correlated with CAG repeat length. Reduced REM sleep duration (but not REM sleep behavior disorders) was present in premanifest carriers and patients with very mild HD and worsened with disease severity. In contrast to narcoleptic patients, HD patients had no cataplexy, hypnagogic hallucinations, or sleep paralysis. Four HD patients had abnormally low (< 8 minutes) daytime sleep latencies, but none had multiple sleep-onset REM periods. CONCLUSIONS The sleep phenotype of HD includes insomnia, advanced sleep phase, periodic leg movements, REM sleep behavior disorders, and reduced REM sleep but not narcolepsy. Reduced REM sleep may precede chorea. Mutant huntingtin may exert an effect on REM sleep and motor control during sleep.

The incidence of narcolepsy in Europe: Before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns

BACKGROUND In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification. METHODS We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000-2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom. RESULTS Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90-0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women>men) and around 60 years of age. In the age group 5-19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1-3.1) in Denmark, 6.4 (95% CI: 4.2-9.7) in Finland and 7.5 (95% CI: 5.2-10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time. CONCLUSIONS The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail.

Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15–25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 × 10−8). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 × 10−43) and DRB1*1301-DQB1*0603 (P < 3 × 10−7). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 × 10−14). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.

ImmunoChip Study Implicates Antigen Presentation to T Cells in Narcolepsy

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

Epidemiology of snoring and obstructive sleep apnoea in a Danish population, age 30-60.

SUMMARY  Several epidemiological studies have estimated the prevalence of obstructive sleep apnoea syndrome (OSAS). As many of those suffering from sleep apnoea may be asymptomatic, the occurrence of sleep apnoea may be underestimated. The epidemiology of self‐reported snoring, sleep apnoea and OSAS, and their relationships with various symptoms, were evaluated in 1504 randomly selected males and females, aged 30, 40, 50 and 60 years. Nocturnal respiration was determined in 748 participants using inductive plethysmography.

A single-question screen for rapid eye movement sleep behavior disorder: A multicenter validation study†

Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia that is an important risk factor for Parkinsons disease (PD) and Lewy body dementia. Its prevalence is unknown. One barrier to determining prevalence is that current screening tools are too long for large‐scale epidemiologic surveys. Therefore, we designed the REM Sleep Behavior Disorder Single‐Question Screen (RBD1Q), a screening question for dream enactment with a simple yes/no response.