John M. Shneerson

Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis

Objective To evaluate the risk of narcolepsy in children and adolescents in England targeted for vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine (Pandemrix) from October 2009. Design Retrospective analysis. Clinical information and results of sleep tests were extracted from hospital notes between August 2011 and February 2012 and reviewed by an expert panel to confirm the diagnosis. Vaccination and clinical histories were obtained from general practitioners. Setting Sleep centres and paediatric neurology centres in England. Participants Children and young people aged 4-18 with onset of narcolepsy from January 2008. Main outcome measures The odds of vaccination in those with narcolepsy compared with the age matched English population after adjustment for clinical conditions that were indications for vaccination. The incidence of narcolepsy within six months of vaccination compared with the incidence outside this period measured with the self controlled cases series method. Results Case notes for 245 children and young people were reviewed; 75 had narcolepsy (56 with cataplexy) and onset after 1 January 2008. Eleven had been vaccinated before onset; seven within six months. In those with a diagnosis by July 2011 the odds ratio was 14.4 (95% confidence interval 4.3 to 48.5) for vaccination at any time before onset and 16.2 (3.1 to 84.5) for vaccination within six months before onset. The relative incidence from the self controlled cases series analysis in those with a diagnosis by July 2011 with onset from October 2008 to December 2010 was 9.9 (2.1 to 47.9). The attributable risk was estimated as between 1 in 57 500 and 1 in 52 000 doses. Conclusion The increased risk of narcolepsy after vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine indicates a causal association, consistent with findings from Finland. Because of variable delay in diagnosis, however, the risk might be overestimated by more rapid referral of vaccinated children.

Health-related quality of life in narcolepsy

Narcolepsy is a chronic sleep disorder characterised by symptoms of excessive daytime sleepiness and cataplexy. The aim of this study was to describe the health‐related quality of life of people with narcolepsy residing in the UK. The study comprised a postal survey of 500 members of the UK narcolepsy patient association, which included amongst other questions the UK Short Form 36 (SF‐36), the Beck Depression Inventory (BDI), and the Ullanlinna Narcolepsy Scale (UNS). A total of 305 questionnaires were included in the final analysis. The results showed that the subjects had significantly lower median scores on all eight domains of the SF‐36 than normative data, and scored particularly poorly for the domains of role physical, energy/vitality, and social functioning. The BDI indicated that 56.9% of subjects had some degree of depression. In addition, many individuals described limitations on their education, home, work and social life caused by their symptoms. There was little difference between the groups receiving different types of medication. This study is the largest of its type in the UK, although the limitations of using a sample from a patient association have been recognised. The results are consistent with studies of narcolepsy in other countries in demonstrating the extensive impact of this disorder on health‐related quality of life.

Sleep and Circadian Rhythm Regulation in Early Parkinson Disease

IMPORTANCE Sleep disturbances are recognized as a common nonmotor complaint in Parkinson disease but their etiology is poorly understood. OBJECTIVE To define the sleep and circadian phenotype of patients with early-stage Parkinson disease. DESIGN, SETTING, AND PARTICIPANTS Initial assessment of sleep characteristics in a large population-representative incident Parkinson disease cohort (N=239) at the University of Cambridge, England, followed by further comprehensive case-control sleep assessments in a subgroup of these patients (n=30) and matched controls (n=15). MAIN OUTCOMES AND MEASURES Sleep diagnoses and sleep architecture based on polysomnography studies, actigraphy assessment, and 24-hour analyses of serum cortisol, melatonin, and peripheral clock gene expression (Bmal1, Per2, and Rev-Erbα). RESULTS Subjective sleep complaints were present in almost half of newly diagnosed patients and correlated significantly with poorer quality of life. Patients with Parkinson disease exhibited increased sleep latency (P = .04), reduced sleep efficiency (P = .008), and reduced rapid eye movement sleep (P = .02). In addition, there was a sustained elevation of serum cortisol levels, reduced circulating melatonin levels, and altered Bmal1 expression in patients with Parkinson disease compared with controls. CONCLUSIONS AND RELEVANCE Sleep dysfunction seen in early Parkinson disease may reflect a more fundamental pathology in the molecular clock underlying circadian rhythms.

Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived?

Abstract: In a double-blind, parallel groups study, 60 healthy student volunteers (29 men and 31 women, aged 19-22 years) were randomly allocated to receive placebo, 100 or 200 mg modafinil. Two hours later, in the early evening, they completed an extensive cognitive battery. The 3 groups did not differ in self-ratings of sleepiness or tiredness before the testing session, and there were no treatment-associated changes in these or in mood ratings during the tests. Modafinil was without effect in several tests of reaction time and attention, but the 200-mg group was faster at simple color naming of dots and performed better than placebo in the Rapid Visual Information Processing test of sustained attention. Modafinil was without effect on spatial working memory, but the 100-mg group performed better in the backward part of the digit span test. Modafinil was without effect on verbal short-term memory (story recall), but 100 mg improved digit span forward, and both doses improved pattern recognition, although this was accompanied by a slowing of response latency in the 200-mg group. There were no significant effects of modafinil compared with placebo in tests of long-term memory, executive function, visuospatial and constructional ability, or category fluency. These results suggest that the benefits of modafinil are not clearly dose-related, and those from 100 mg are limited to the span of immediate verbal recall and short-term visual recognition memory, which is insufficient for it to be considered as a cognitive enhancer in non-sleep-deprived individuals.

The cognitive-enhancing properties of modafinil are limited in non-sleep-deprived middle-aged volunteers

Modafinil is a selective wakefulness-promoting agent that has been shown to enhance cognitive performance under conditions of sleep deprivation but which has equivocal effects in normal young volunteers. In a double-blind parallel group design study, 45 non-sleep-deprived middle-aged volunteers (20 men and 25 women, aged 50-67 years) were randomly allocated to receive two capsules containing placebo, 100 or 200 mg modafinil, and 3 h later they completed 100 mm visual analogue scales of mood and bodily symptoms, before and after an extensive battery of cognitive tests [pen and paper and the Cambridge Neuropsychological Test Automated Battery (CANTAB)]. There were no significant treatment-associated changes in ratings of mood or bodily symptoms and no significant effects on most of the cognitive tests used in this study. The group treated with modafinil (200 mg) was significantly faster in a simple colour naming of dots and also significantly better in a test of constructional ability (Clock Drawing Test) compared with the placebo group. However, subjects in the 200-mg group also made significantly more total errors in the Intra/Extradimensional Set Shift (ID/ED) task than both the other groups. Thus, this study found limited evidence of cognitive-enhancing properties of modafinil in healthy middle-aged volunteers.

A Comprehensive Study of Clinical, Biochemical, Radiological, Vascular, Cardiac, and Sleep Parameters in an Unselected Cohort of Patients With Acromegaly Undergoing Presurgical Somatostatin Receptor Ligand Therapy

CONTEXT Attainment of safe GH and IGF-1 levels is a central goal of acromegaly management. OBJECTIVE The aim of this study was to determine the extent to which reductions in GH and IGF-1 concentrations correlate with amelioration of radiological, metabolic, vascular, cardiac, and respiratory sequelae in a single unselected patient cohort. STUDY DESIGN This was a prospective, within-subject comparison in 30 patients with newly diagnosed acromegaly (15 women and 15 men: mean age, 54.3 years; range, 23-78 years) before and after 24 weeks of lanreotide Autogel (ATG) therapy. RESULTS Reductions in GH and IGF-1 concentrations and tumor volume were observed in all but 2 patients (median changes [Δ]: GH, -6.88 μg/L [interquartile range -16.78 to -3.32, P = .000001]; IGF-1, -1.95 × upper limit of normal [-3.06 to -1.12, P = .000002]; and pituitary tumor volume, -256 mm(3) [-558 to -72.5, P = .0002]). However, apnea/hypopnea index scores showed highly variable responses (P = .11), which were independent of ΔGH or ΔIGF-1, but moderately correlated with Δweight (R(2) = 0.42, P = .0001). Although systolic (P = .33) and diastolic (P = .76) blood pressure were unchanged, improvements in arterial stiffness (aortic pulse wave velocity, -0.4 m/s [-1.2 to +0.2, P = .046]) and endothelial function (flow mediated dilatation, +1.73% [-0.32 to +6.19, P = .0013]) were observed. Left ventricular mass index regressed in men (-11.8 g/cm(2) [-26.6 to -1.75], P = .019) but not in women (P = .98). Vascular and cardiac changes were independent of ΔGH or ΔIGF-1 and also showed considerable interindividual variation. Metabolic parameters were largely unchanged. CONCLUSIONS Presurgical ATG therapy lowers GH and IGF-1 concentrations, induces tumor shrinkage, and ameliorates/reverses cardiac, vascular, and sleep complications in many patients with acromegaly. However, responses vary considerably between individuals, and attainment of biochemical control cannot be assumed to equate to universal complication control.

Asymptomatic sleep abnormalities are a common early feature in patients with Huntington's disease.

Huntington’s disease (HD) is a fatal neurodegenerative disease characterized by motor, cognitive, and psychiatric disturbance. In this article, we used polysomnography, actigraphy and a variety of validated questionnaires to ascertain the extent to which sleep changes are identifiable and measurable in mild stage HD, and importantly, to see whether patients are negatively impacted by the changes in their sleep. We found significant differences in sleep architecture and sleep efficiency in patients compared with controls using polysomnography. However, patient scores on the Functional Outcomes of Sleep Questionnaire, Medical Outcomes of Sleep Scale, and Epworth Sleepiness Scale were not significantly different to controls. These results suggest that although marked changes in sleep architecture are present in early HD and can be detected using polysomnography, patients do not necessarily recognize or report these abnormalities.

Is the SF 36 sensitive to sleep disruption? A study in subjects with sleep apnoea

SUMMARY  The objectives of this study were to test the sensitivity of the short form 36 health survey questionnaire (SF 36) to sleep disruption in patients with obstructive sleep apnoea (OSA) and assess its use as an outcome measure for treatment with nasal continuous positive airway pressure (CPAP). Two hundred and twenty‐three subjects under investigation for snoring and/or daytime somnolence completed the questionnaire at presentation and again after a six month period. Subjects with OSA requiring treatment scored lower on all dimensions of the SF 36 (P<0.05) than normative scores for the general population. The largest differences were for vitality (24%) and social functioning (27.9%). After six months of treatment with CPAP there was an improvement in all scores and the score for vitality was no longer significantly different from that of the general population. The SF 36 is sensitive to the effects of sleep disruption in subjects with obstructive sleep apnoea, is a useful outcome measure for treatment with CPAP and its value in other sleep disorders should be assessed.

Functional differences in bi-level pressure preset ventilators

The performance of four bilevel positive pressure preset ventilators was compared. The ventilators tested were; BiPAP ST30 (Respironics); Nippy2 (B + D Electrical); Quantum PSV (Healthdyne); and Sullivan VPAP H ST (Resmed). A patient simulator was used to determine the sensitivity of the triggering mechanisms and the responses to a leak within the patient circuit, and to changes in patient effort. Significant differences (p <0.05) between the devices were seen in the trigger delay time and inspiratory trigger pressure. When a leak was introduced into the patient circuit, the fall in tidal volume (VT) was less than ten per cent for each ventilator. The addition of patient effort produced a number of changes in the ventilation delivered. Patient efforts of 0.25 s induced a variable fall in VT. An increase in VT was seen with some ventilators with patient efforts of 1 s but the effect was variable. Trigger failures and subsequent falls in minute volume were seen with the BiPAP and the Nippy2 at the highest respiratory frequency. Differences in the responses of the ventilators are demonstrated that may influence the selection of a ventilator, particularly in the treatment of breathless patients with ventilatory failure.

Phrenic Nerve Stimulation for Central Ventilatory Failure with Bipolar and Four‐Pole Electrode Systems

A multi‐channel phrenic nerve stimulator developed in Tampere has been implanted into seven patients with C2‐etraplegia and into three patients with central sleep apneas. Six bipolar cuff electrodes were implanted bilaterally into the neck. Two four‐pole cuff and 14 four‐pole noncuff electrodes were used in seven patients and to replace one bipolar electrode. Four‐pole electrodes were implanted within the thorax. Seven patients achieved total independence from conventional ventilators within 4 months of implantation, and one for 18 hours each day. Two patients died 12 days and 3 months after implantation and two patients after having achieved independence from mechanical ventilators from causes unrelated to the simulators. Reoperations were necessary because of dislocation of receivers, electrodes, electrode lesions, nerve injuries, and technical failures in seven patients. Most of the problems appeared in two patients with obesity and in three patients with very thin phrenic nerves. Single unit prototypes failed technically more frequently than units of prototype serial fabrication. New electrode design, progress in the manufacture of receivers, and improved implantation technique should help to diminish failures in future.