Dev Banerjee

Treatment of Obesity Hypoventilation Syndrome and Serum Leptin

Background: Leptin is a protein produced by adipose tissue that circulates to the brain and interacts with receptors in the hypothalamus to inhibit eating. In obese humans, serum leptin is up to four times higher than in lean subjects, indicating that human obesity is associated with a central resistance to the weight-lowering effects of leptin. Although the leptin-deficient mouse (ob/ob) develops obesity hypoventilation syndrome (OHS), in humans with OHS, serum leptin is a better predictor of awake hypercapnia in obesity than the body mass index (BMI). This suggests that central leptin resistance may promote the development of OHS in humans. We speculated that the reversal of OHS by regular non-invasive ventilation (NIV) therapy decreases leptin levels. Objectives: The aim of this study was to investigate whether ventilatory treatment of OHS would alter circulating leptin concentrations. Method: We measured fasting serum leptin levels, BMI, spirometry and arterial blood gases in 14 obese hypercapnic subjects undergoing a diagnostic sleep study. Results: The average age of the subjects was (mean ± SE) 62 ± 13 years, BMI 40.9 ± 2.2 kg/m2, PaCO2 6.7 ± 0.2 kPa, PaO2 8.9 ± 0.4 kPa and total respiratory disturbance index 44 ± 35 events/hour. Subjects were clinically reviewed after a median of 2.3 years (range 1.6–3) with repeat investigations. Nine patients were regular NIV users and 5 were non-users. NIV users had a significant reduction in serum leptin levels (p = 0.001), without a change in BMI. In these patients, there was a trend towards an improved daytime hypercapnia and hypoxemia, while in the 5 non-users, no changes in serum leptin, BMI or arterial blood gases occurred. Conclusion: Regular NIV use reduces serum leptin in OHS. Leptin may be a modulator of respiratory drive in patients with OHS.

Effectiveness of lifestyle interventions on obstructive sleep apnea (OSA): systematic review and meta-analysis.

BACKGROUND Obstructive sleep apnea (OSA) is a common sleep disorder associated with several adverse health outcomes. Given the close association between OSA and obesity, lifestyle and dietary interventions are commonly recommended to patients, but the evidence for their impact on OSA has not been systematically examined. OBJECTIVES To conduct a systematic review and meta-analysis to assess the impact of weight loss through diet and physical activity on measures of OSA: apnea-hypopnea index (AHI) and oxygen desaturation index of 4% (ODI4). METHODS A systematic search was performed to identify publications using Medline (1948-2011 week 40), EMBASE (from 1988-2011 week 40), and CINAHL (from 1982-2011 week 40). The inverse variance method was used to weight studies and the random effects model was used to analyze data. RESULTS Seven randomized controlled trials (519 participants) showed that weight reduction programs were associated with a decrease in AHI (-6.04 events/h [95% confidence interval -11.18, -0.90]) with substantial heterogeneity between studies (I(2) = 86%). Nine uncontrolled before-after studies (250 participants) showed a significant decrease in AHI (-12.26 events/h [95% confidence interval -18.51, -6.02]). Four uncontrolled before-after studies (97 participants) with ODI4 as outcome also showed a significant decrease in ODI4 (-18.91 episodes/h [95% confidence interval -23.40, -14.43]). CONCLUSIONS Published evidence suggests that weight loss through lifestyle and dietary interventions results in improvements in obstructive sleep apnea parameters, but is insufficient to normalize them. The changes in obstructive sleep apnea parameters could, however, be clinically relevant in some patients by reducing obstructive sleep apnea severity. These promising preliminary results need confirmation through larger randomized studies including more intensive weight loss approaches.

The effect of sibutramine-assisted weight loss in men with obstructive sleep apnoea

Objective:Obstructive sleep apnoea (OSA) occurs frequently in obese patients and may be reversible with weight loss. Obstructive sleep apnoea and obesity are both independent risk factors for hypertension and increased sympathetic activity. Sibutramine has been increasingly used in the management of obesity, but is relatively contraindicated in patients with hypertension. No studies have investigated the effect of sibutramine on OSA, blood pressure and heart rate. We aimed to assess the changes in OSA and cardiovascular parameters in obese men with OSA enrolled in a sibutramine-assisted weight loss programme (SIB-WL).Design:Open uncontrolled cohort study of obese male subjects with OSA in an SIB-WL.Subjects:Eighty-seven obese (body mass index =34.2±2.8 kg/m2) middle-aged (46.3±9.3 years) male subjects with symptomatic OSA (Epworth score 13.4±3.6; respiratory disturbance index (RDI) 46.0±23.1 events/h) completed the study.Results:At 6 months, there was significant weight loss (8.3±4.7 kg, P<0.0001), as well as a reduction in waist and neck circumference and sagittal height (all P<0.0001). These changes were accompanied by a reduction in OSA severity (RDI fell by 16.3±19.4 events/h and Epworth score by 4.5±4.6), both P<0.0001). There was no significant change to systolic (P=0.07) or diastolic blood pressure (P=0.87); however, there was a mild rise in resting heart rate (P<0.0001).Conclusion:Moderate (∼10%) weight loss with SIB-WL results in improvement in OSA severity without increase in blood pressure in closely monitored OSA subjects.

The Potential Association between Obstructive Sleep Apnea and Diabetic Retinopathy in Severe Obesity—The Role of Hypoxemia

Background Obstructive sleep apnea (OSA) is common in obese patients with type 2 diabetes mellitus (DM) and may contribute to diabetic microvascular complications. Methods To investigate the association between OSA, hypoxemia during sleep, and diabetic retinal complications in severe obesity. This was a prospective observational study of 93 obese patients mean (SD) age: 52(10) years; mean (SD) body mass index (BMI): 47.3(8.3) kg/m2) with DM undergoing retinal screening and respiratory monitoring during sleep. OSA was defined as apnea-hypopnea index (AHI) of ≥15 events/hour, resulting in two groups (OSA+ vs. OSA−). Results Forty-six patients were OSA+: median (95% CI) AHI = 37(23–74)/hour and 47 were OSA–ve (AHI = 7(4–11)/hour). Both groups were similar for ethnicity, BMI, cardiovascular co-morbidities, diabetes duration, HbA1c, and insulin treatment (p>0.05). The OSA+ group was significantly more hypoxemic. There was no significant difference between OSA+ and OSA− groups for the presence of retinopathy (39% vs. 38%). More OSA+ subjects had maculopathy (22% vs. 13%), but this did not reach statistical significance. Logistic regression analyses showed that AHI was not significantly associated with the presence of retinopathy or maculopathy (p>0.05). Whilst minimum oxygen saturation was not significantly associated with retinopathy, it was an independent predictor for the presence of maculopathy OR = 0.79 (95% CI: 0.65–0.95; p<0.05), after adjustment. Conclusions The presence of OSA, as determined by AHI, was not associated with diabetic retinal complications. In contrast, severity of hypoxemia during sleep (minimum oxygen saturations) may be an important factor. The importance of hypoxia in the development of retinal complications in patients with OSA remains unclear and further studies assessing the pathogenesis of hypoxemia in patients with OSA and diabetic retinal disease are warranted.

The Prevalence and Severity of Obstructive Sleep Apnea in Severe Obesity: The Impact of Ethnicity

STUDY OBJECTIVES The South Asian population is at increased risk of cardiovascular disease. We compared the prevalence and severity of obstructive sleep apnea (OSA) in South Asians and white Europeans with severe obesity. METHODS Data from consecutive patients attending a specialist weight management service were analyzed. Self-reported age, gender, and ethnicity were recorded. Objective measurements of blood pressure, body mass index (BMI), and apneahypopnea index (AHI) were also acquired. RESULTS A total of 308 patients (72.7% women; 13% South Asian) were included, with mean age and BMI of 46 ± 12 y and 49 ± 8 kg/m2, respectively. South Asians had significantly increased prevalence of OSA compared to white Europeans (85% vs. 66% [p = 0.017]) and were more likely to have severe OSA (42.5% vs. 21.6% [p = 0.015]). South Asians had significantly higher median AHI (24 events/h: interquartile range [IQR] 9.3-57.6 vs. 9 events/h: IQR 3.4-26.6; p < 0.01), significantly lower minimum oxygen saturation (76%: IQR 64% to 84% vs. 83%: IQR 77% to 87%; p < 0.01), and spent a significantly greater amount of time < 90% oxygen saturation (8.4%: IQR 1.0% to 24.3% vs. 2.4%: IQR 0.2% to 16.0%; p = 0.03). South Asian ethnicity, independent of demographics, BMI, and comorbidities, was associated with β = 1.84 (95% CI: 1.27-2.65) increase in AHI+1 compared to white Europeans. Furthermore, we confirmed other independent OSA risk factors including increasing age, BMI, and male gender (all p < 0.001). CONCLUSIONS Severely obese South Asians had significantly greater prevalence and severity of OSA than white Europeans. OSA may contribute to increased cardiovascular risk in South Asians compared to white Europeans with severe obesity. Mechanisms mediating the observed associations between these ethnicities require further investigation.

The impact of hypoxemia on nephropathy in extremely obese patients with type 2 diabetes mellitus.

STUDY OBJECTIVES Diabetes mellitus (DM) is associated with obstructive sleep apnea (OSA) and nephropathy. The hypoxemia associated with OSA may exacerbate renal deterioration in DM nephropathy. We examined the role of hypoxemia in the development of DM nephropathy in severely obese patients. METHODS This cross-sectional study examined anonymized data from 90 DM patients with extreme obesity attending a weight management service. All patients underwent a routine overnight sleep study. Respiratory parameters measured included apnea-hypopnea index (AHI), mean and minimum oxygen (O2) saturations, and time spent under 90% O2 saturation (%TST < 90%). Chronic kidney disease (CKD+) was defined as estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m(2). RESULTS Twenty (22%) patients were CKD+. These patients were 7 years older (mean age ± SD 57 ± 11 years, p = 0.003) and had greater adiposity (mean body mass index [BMI] ± SD 50.6 ± 8.7 kg/m(2), p = 0.012). No significant differences were found for median AHI and minimum O2 saturation. %TST < 90% was 4 times greater in CKD+ group (p = 0.046). Multivariate regression analysis showed that AHI (β = -0.17, 95% CI: -0.316 to -0.024) and %TST < 90% (β = -0.215, 95% CI: -0.406 to -0.023) were negatively correlated with eGFR after adjustment for age, gender, BMI, comorbidities, insulin treatment, and drugs affecting the renin-angiotensin system. No associations were found between mean and minimum O2 saturations, and eGFR. CONCLUSION Apnea and hypopnea events as well as duration of nocturnal hypoxemia were inversely associated with renal function after adjusting for potential confounders. Given the significant burden of renal disease in diabetes, greater vigilance is required in identifying OSA in DM patients with extreme obesity.

Spectral EEG analysis and sleepwalking defense: unreliable scientific evidence.

I a recent publication in JCSM,1 Drs. Cartwright and Guilleminault suggest that spectral analysis of the sleep EEG can be used to support a defense of sleepwalking in criminal cases. In particular the authors point to 3 publications that concluded that the sleep of sleepwalkers is defi ned by frequent arousals during SWS (slow wave sleep) as well as—or as a result of—lower % of SWA (slow wave activity).2-4 However, the authors of the study most often referred to have themselves concluded that spectral analysis of the sleep EEG in sleepwalkers is not suitable for forensic use. Gadreau and colleagues2 write: “ Given the likelihood that results of our study could be used in medico-legal settings, it is worth noting that the presence or absence of a decrease of SWA early in the night and of awakenings from SWS in a given individual does not conclusively establish or refute a tendency toward sleepwalking” (pages 4-5). The issue of frequent arousals and changes in SWS% in sleepwalkers as forensic evidence has also been previously reviewed in detail5 and was the subject of a series of letters to the editor of Sleep Medicine Reviews between Drs. Cartwright and Pressman in 2007-8 that readers might fi nd of interest.6-9 As noted by Drs. Cartwright and Guilleminault, establishing a current diagnosis of sleepwalking for a defendant is not the same as establishing that the defendant was sleepwalking during the commission of a crime. Nevertheless, this article suggests that spectral analysis of sleep recorded months or years after the incident offense can be used to support such a sleepwalking defense. There are 3 scientifi c publications currently available that conclude that arousals from SWS sleep and hypersynchronous delta waves are not diagnostic for sleepwalking.10-12 These published scientifi c studies analyzed arousals and SWS using standard visual methods and have reported a lack of statistical sensitivity and especially specifi city as diagnostic markers. Further, there are now more than 7 published studies that report arousals indexes for patients with sleepwalking (see Table 1 in ref. 10). While they are often elevated compared to normal controls there is signifi cant interstudy variability and there is no specifi c cutoff statistically or otherwise to assist in making the diagnosis. Additionally, the Spectral EEG Analysis and Sleepwalking Defense: Unreliable Scientifi c Evidence Mark R. Pressman, Ph.D., F.A.A.S.M.1; Mark Mahowald, M.D., F.A.A.S.M.2; Carlos Schenck, M.D.2; Michel Cramer Bornemann, M.D., F.A.A.S.M.3; Dev Banerjee, M.D.4; Michael Howell, M.D.2; Peter Buchanan, M.D.4; Alon Avidan, M.D., M.P.H., F.A.A.S.M.5 1Lankenau Medical Center and Lankenau Institute for Medical Research, Jefferson Medical School, Villanova School of Law, Villanova, PA; 2University of Minnesota, Minneapolis, MN; 3Sleep Medicine Services, HealthEast Care Systems of Minnesota, Minneapolis, MN; 4NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, Sydney, Australia; 5UCLA Sleep Disorders Center, Department of Neurology David Geffen School of Medicine at UCLA, UCLA, Los Angeles, CA

Alcohol, sleepwalking and violence: lack of reliable scientific evidence.

Sir, The recent Letter to the Editor by Drs Ebrahim and Fenwick (2012) challenges one sentence in a 2010 article published in Brain (Siclari et al. , 2010) stating that, because of the lack of reliable evidence, alcohol-induced sleepwalking should not be allowed as a defence to criminal acts. This, in turn, refers to an article published 22 years ago (Mahowald et al. , 1990). Drs Ebrahim and Fenwick express concern that defendants who have allegedly committed criminal acts while severely intoxicated with alcohol are potentially being denied a valid defence. In our opinion, claims of alcohol-induced sleepwalking violence or sleep sex …

Obstructive sleep apnoea as a cause of headache presenting to the emergency department

A 48-year-old South Asian lady presented to the emergency department complaining of predominantly right-sided temporal headache, associated with lacrimation and swelling around the right eye. She had type 2 diabetes mellitus and chronic kidney disease. She was obese with a body mass index of 58.1 kg/m2. Clinical examination revealed no signs of meningism. Computerized tomogram (CT) of her head was normal. Erythrocyte sedimentation rate (ESR) was raised at 97 mm/h. She was started on oral corticosteroids for a presumptive diagnosis of temporal arteritis based on the ESR and discharged. Three weeks later, while on corticosteroids, she was readmitted with a relapse of the acute headache. Temporal artery biopsy from her previous admission showed no evidence of temporal arteritis. A rheumatology review concluded that her relatively young age, long duration of headaches (6–9 months of headaches prior to presentation) and normal temporal arteries on palpation, made temporal arteritis …

IgLON5-mediated neurodegeneration is a differential diagnosis of CNS Whipple disease

A 49-year-old man developed cold intolerance as an isolated symptom 2 years prior to presentation. At age 48, he developed jerks in the trunk and lower limbs during the day and tapping movements in the arms during sleep. After 6 months, sleep disturbance worsened with talking and gesticulations, culminating in sleeping 1–3 hours per night with associated daytime somnolence. He developed mild slurred speech, hypersalivation, and dysphagia. He reported poor memory but was able to continue driving and working. He had been diagnosed with obstructive sleep apnea 4 years prior.