Literature search from ms 29/4/2010

Lugaresi, E., G. Coccagna, et al. (1968). "["Ondine's curse": the disorder of respiration and sleep in primary alveolar hypoventilation]." Sistema Nervoso 20(1): 27-37.

Lugaresi, E. and A. Vela-Bueno (1987). "Sleep-related respiratory disorders." SEMINARS IN NEUROLOGY 7(3): 259-68.

Sleep-induced narrowing of the upper airways underlies the widespread and supposedly trivial complaint of snoring, which may not only constitute a risk factor for the cardiocirculatory system, but in predisposed individuals may lead to the OSAS. The latter is a life-threatening condition characterized by repeated episodes of cessation of respiration at night with an associated drop in SaO2. Patients frequently present with hypersomnia, systemic and pulmonary hypertension, and even heart failure. HSD is the term we use to describe the evolutive stages from snoring to OSAS. ICAH, or Ondine's curse, is the clinical syndrome of sleep-related respiratory insufficiency in the absence of airway stenosis. We do not consider central sleep apnea to be an independent disorder. For the treatment of HSD, weight reduction should be attempted first. Also, if there are malformations in the upper airway, they should be surgically corrected. The use of various medications has been rather discouraging, and CPAP and other devices that are intended to overcome the obstruction are poorly tolerated by patients. The most effective surgical treatment for OSAS, even in progressed stages of the disease, is tracheostomy. [References: 102]
Maayan, C., D. W. Carley, et al. (1992). "Respiratory system stability and abnormal carbon dioxide homeostasis." JOURNAL OF APPLIED PHYSIOLOGY 72(3): 1186-93.

We have tested the hypothesis that interactions among eight parameters of the respiratory and cardiovascular systems that determine the loop gain (LG) of the respiratory CO2 feedback control system might account for the degree of stability or instability of breathing patterns in healthy sleeping volunteers as well as in familial dysautonomia (FD) and congenital central hypoventilation syndrome (CCHS) patients. The predictability of cycle duration was tested as well. We measured the values of CO2 sensitivity, CO2 delivery capacity in the circulation, circulation delay, mean lung volume for CO2, and mixed venous PCO2 in 8 FD patients, 2 CCHS patients, and 19 healthy controls. The values of these parameters were used in a mathematical model to compute the LG of the respiratory control system during sleep for each epoch of respiration analyzed. The strength of the ventilatory oscillations (R) was quantified using power density spectra of the ventilation time series. All subjects were studied at inspiratory O2 concentrations (FIO2) of 0.21 and 0.15; CCHS patients and controls were also studied at 0.12 FIO2 to examine the effect of steady-state hypoxia on respiratory system stability. In 2 FD patients, LG was elevated at both levels of FIO2 and periodic breathing was observed; the values of R were elevated. Elevated mixed venous PCO2 and reduced CO2 delivery capacity were chiefly responsible for the abnormally high LG observed. In three healthy volunteers, high LG and unstable patterns were associated with high chemosensitivity. The CCHS patients, however, remained stable even at 0.12 FIO2 because LG remained equivalent to zero due to a lack of chemosensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Macey, K. E., P. M. Macey, et al. (2004). "fMRI signal changes in response to forced expiratory loading in congenital central hypoventilation syndrome." JOURNAL OF APPLIED PHYSIOLOGY 97(5): 1897-907.

Congenital central hypoventilation syndrome (CCHS) patients show impaired ventilatory responses to CO2 and hypoxia and reduced drive to breathe during sleep but retain appropriate breathing patterns in response to volition or increased exercise. Breath-by-breath influences on heart rate are also deficient. Using functional magnetic resonance imaging techniques, we examined responses over the brain to voluntary forced expiratory loading, a task that CCHS patients can perform but that results in impaired rapid heart rate variation patterns normally associated with the loading challenge. Increased signals emerged in control (n = 14) over CCHS (n = 13; ventilator dependent during sleep but not waking) subjects in the cingulate and right parietal cortex, cerebellar cortex and fastigial nucleus, and basal ganglia, whereas anterior cerebellar cortical sites and deep nuclei, dorsal midbrain, and dorsal pons showed increased signals in the patient group. The dorsal and ventral medulla showed delayed responses in CCHS patients. Primary motor and sensory areas bordering the central sulcus showed comparable responses in both groups. The delayed responses in medullary sensory and output regions and the aberrant reactions in cerebellar and pontine sensorimotor coordination areas suggest that rapid cardiorespiratory integration deficits in CCHS may stem from defects in these sites. Additional autonomic and perceptual motor deficits may derive from cingulate and parietal cortex aberrations.

Macey, P. M., J. R. Alger, et al. (2003). "Global BOLD MRI changes to ventilatory challenges in congenital central hypoventilation syndrome." Respiratory Physiology & Neurobiology 139(1): 41-50.

We evaluated global blood oxygen level dependent (BOLD) signal changes in gray and white matter in 14 congenital central hypoventilation syndrome (CCHS) and 14 control subjects. One baseline image series with room air and three series with 30 s room air followed by 120 s hypercapnia (5% CO2/95% O2), hypoxia (15% O2/85% N2) or hyperoxia (100% O2) were collected. Hypercapnia and hyperoxia raised, and hypoxia lowered gray and white matter global signal in both groups, with smaller changes in white matter. Signal changes in CCHS cases were lower than control subjects for hypercapnia in gray and white matter, slightly more-enhanced in hypoxia, and, except for initial transient responses, were nearly comparable during hyperoxia. Initial signal rate or pattern changes emerged in all three challenges in gray or white matter in control, but not CCHS cases. Neural or vascular mechanisms mediate perfusion differently in CCHS; the aberrant initial transient responses may reflect deficiencies in rapidly-varying physiologic interactions in the syndrome.

Macey, P. M., K. E. Macey, et al. (2005). "Aberrant neural responses to cold pressor challenges in congenital central hypoventilation syndrome." PEDIATRIC RESEARCH 57(4): 500-9.

Patients with congenital central hypoventilation syndrome (CCHS), a condition characterized by impaired ventilatory responses to chemoreceptor stimulation, do not show the normal increase in respiratory rate and respiratory-related heart rate variation to cold forehead stimulation, a challenge that bypasses central chemoreceptors. We hypothesized that a forehead cold pressor challenge would reveal abnormal neural response patterns, as assessed by functional magnetic resonance imaging, in brain regions that are responsible for the integration of cold afferent stimulation with respiratory and cardiovascular output in patients with CCHS. Primary sensory thalamic and cortical areas for the forehead showed diminished responses in 13 patients with CCHS (ventilator dependent during sleep but not waking, no Hirschsprung's disease) compared with 14 control subjects, despite initial signal changes in the cortex being similar in both groups. Cerebellar cortex and deep nuclei; basal ganglia; and middle to posterior cingulate, insular, frontal, and temporal cortices showed reduced signal rises in patients with CCHS. Areas within the frontal and anterior cingulate cortices exhibited marked signal declines in control subjects but little change in patients with CCHS. No response occurred in either group in the dorsal medulla, but medial and ventral medullary areas showed enhanced signals in patients with CCHS. The cold pressor stimulation did not recruit dorsal medullary sites that would be affected by PHOX2B (a mutation of which is associated with the syndrome) expression in either group but demonstrated deficient cerebellar and medial medullary influences that, by action on rostral sites, may underlie the loss of respiratory responses.

Macey, P. M., C. A. Richard, et al. (2009). "Hippocampal volume reduction in congenital central hypoventilation syndrome." PLoS ONE [Electronic Resource] 4(7): e6436.

Children with congenital central hypoventilation syndrome (CCHS), a genetic disorder characterized by diminished drive to breathe during sleep and impaired CO(2) sensitivity, show brain structural and functional changes on magnetic resonance imaging (MRI) scans, with impaired responses in specific hippocampal regions, suggesting localized injury.We assessed total volume and regional variation in hippocampal surface morphology to identify areas affected in the syndrome. We studied 18 CCHS (mean age+/-std: 15.1+/-2.2 years; 8 female) and 32 healthy control (age 15.2+/-2.4 years; 14 female) children, and traced hippocampi on 1 mm(3) resolution T1-weighted scans, collected with a 3.0 Tesla MRI scanner. Regional hippocampal volume variations, adjusted for cranial volume, were compared between groups based on t-tests of surface distances to the structure midline, with correction for multiple comparisons. Significant tissue losses emerged in CCHS patients on the left side, with a trend for loss on the right; however, most areas affected on the left also showed equivalent right-sided volume reductions. Reduced regional volumes appeared in the left rostral hippocampus, bilateral areas in mid and mid-to-caudal regions, and a dorsal-caudal region, adjacent to the fimbria.The volume losses may result from hypoxic exposure following hypoventilation during sleep-disordered breathing, or from developmental or vascular consequences of genetic mutations in the syndrome. The sites of change overlap regions of abnormal functional responses to respiratory and autonomic challenges. Affected hippocampal areas have roles associated with memory, mood, and indirectly, autonomic regulation; impairments in these behavioral and physiological functions appear in CCHS.

Macey, P. M., C. Valderama, et al. (2004). "Temporal trends of cardiac and respiratory responses to ventilatory challenges in congenital central hypoventilation syndrome." PEDIATRIC RESEARCH 55(6): 953-9.

Congenital central hypoventilation syndrome (CCHS) patients exhibit respiratory deficits to ventilatory challenges, diminished breathing drive during sleep, and reduction of respiratory-related heart rate variation, but at least partially preserved peripheral chemoreception. We hypothesized that integration of afferent activity with respiratory motor output is deficient in CCHS, rather than chemoreceptor failure, and that examination of trends in heart and breathing rates and variabilities following ventilatory challenges may clarify the deficient mechanisms. Twelve children with CCHS and 12 age- and gender-matched control cases were subjected to hyperoxic hypercapnic, poikylocapnic hypoxic, and hyperoxic challenges while supine. Heart and respiratory rates and variabilities during 60-s baseline and 120-s challenge periods were assessed. Hypoxia and hypercapnia enhanced breathing rate in control subjects; in CCHS cases, the rise differed during hypercapnia and did not occur to hypoxia. Hyperoxia showed initial transient patterns in breathing rate that differed between groups. A heart rate increase to hypoxia and late decline to hyperoxia were muted in CCHS patients. In hypercapnia, heart rate followed similar rising patterns in both groups. Overall CCHS heart rate variability was lower in baseline and challenge periods, principally due to diminished respiratory-related variation, especially during hypercapnia. No heart rate variability group differences emerged in hypoxia, and only a late increase for CCHS cases developed in hyperoxia. The findings indicate retention of aspects of chemoreceptor sensitivity in CCHS cases. The heart rate alterations to ventilatory challenges suggest specific compensatory responses of a slower nature remain intact in CCHS, whereas other rapidly changing components are deficient.

Macey, P. M., M. A. Woo, et al. (2005). "Hypoxia reveals posterior thalamic, cerebellar, midbrain, and limbic deficits in congenital central hypoventilation syndrome." JOURNAL OF APPLIED PHYSIOLOGY 98(3): 958-69.

Congenital central hypoventilation syndrome (CCHS) patients show deficient respiratory and cardiac responses to hypoxia and hypercapnia, despite apparently intact arousal responses to hypercapnia and adequate respiratory motor mechanisms, thus providing a model to evaluate functioning of particular brain mechanisms underlying breathing. We used functional magnetic resonance imaging to assess blood oxygen level-dependent signals, corrected for global signal changes, and evaluated them with cluster and volume-of-interest procedures, during a baseline and 2-min hypoxic (15% O(2), 85% N(2)) challenge in 14 CCHS and 14 age- and gender-matched control subjects. Hypoxia elicited significant (P < 0.05) differences in magnitude and timing of responses between groups in cerebellar cortex and deep nuclei, posterior thalamic structures, limbic areas (including the insula, amygdala, ventral anterior thalamus, and right hippocampus), dorsal and ventral midbrain, caudate, claustrum, and putamen. Deficient responses to hypoxia included no, or late, changes in CCHS patients with declining signals in control subjects, a falling signal in CCHS patients with no change in controls, or absent early transient responses in CCHS. Hypoxia resulted in signal declines but no group differences in hypothalamic and dorsal medullary areas, the latter being a target for PHOX2B, mutations of which occur in the syndrome. The findings extend previously identified posterior thalamic, midbrain, and cerebellar roles for normal mediation of hypoxia found in animal fetal and adult preparations and suggest significant participation of limbic structures in responding to hypoxic challenges, which likely include cardiovascular and air-hunger components. Failing structures in CCHS include areas additional to those associated with PHOX2B expression and chemoreceptor sites.

Maddigan, S. L., D. H. Feeny, et al. (2006). "Health Utilities Index mark 3 demonstrated construct validity in a population-based sample with type 2 diabetes." JOURNAL OF CLINICAL EPIDEMIOLOGY 59(5): 472-7.

OBJECTIVE: To assess the cross-sectional construct validity of the Health Utilities Index mark 3 (HUI3) in type 2 diabetes using population health survey data. STUDY DESIGN AND SETTING: Data used were from 5,134 adult respondents of Cycle 1.1 (2000-2001) of the Canadian Community Health Survey (CCHS) with type 2 diabetes. Analyses of covariance models were used to assess differences in overall and single-attribute HUI3 scores between groups hypothesized a priori to differ in HRQL. The association between health-care resource use (i.e., hospitalizations and physician and emergency room visits) and overall HUI3 scores was assessed using logistic regression models. RESULTS: For overall HUI3 scores, clinically important and statistically significant differences were observed between all groups expected to differ in HRQL. Depression was the comorbidity associated with the largest deficit (-0.17; 95% confidence interval CI=-0.22, -0.12), followed by stroke (-0.15; 95% CI=-0.21, -0.10) and heart disease (-0.08; 95% CI=-0.11, -0.05). Insulin use and comorbidities were associated with clinically important deficits in pain. Overall HUI3 scores were significantly predictive of all three categories of health-care resource use. CONCLUSION: Observed differences between groups contribute further evidence of the construct validity of the HUI3 in type 2 diabetes.

Maher, C. G. and R. D. Adams (1996). "Stiffness judgments are affected by visual occlusion." JOURNAL OF MANIPULATIVE AND PHYSIOLOGICAL THERAPEUTICS(4): 250-6.

OBJECTIVE: The current protocol for judging posteroanterior (PA) spinal stiffness has been shown to provide unreliable estimates of PA stiffness. It is possible that a failure to standardize therapists' use of vision in the test protocol partly contributes to the disagreement between raters. This study sought to establish whether vision affects stiffness judgments and so needs to be standardized when judging PA stiffness. DESIGN: Perceptual study using a mechanical device to provide stiffness stimuli with physiotherapists and lay people as judges. SETTING: University psychophysics laboratory. INTERVENTIONS: Occlusion of vision via opaque goggles. MAIN OUTCOME MEASURES: Measures of interstimulus discriminability and bias. RESULTS: Occluding vision had no effect on judges' ability to discriminate between stiffness stimuli; however, the same stimuli were judged as significantly stiffer under the visual occlusion condition. CONCLUSION: The data from this study suggest that vision needs to be controlled when using manual tests to judge PA spinal stiffness.

Maitra, A., J. Shine, et al. (2004). "The investigation and care of children with congenital central hypoventilation syndrome." Current Paediatrics 14(4): 354-360.

Congenital central hypoventilation syndrome (CCHS) - previously commonly known as 'Ondine's curse' - is a rare congenital condition in which there is an abnormality of control of respiration in the absence of any identifiable primary central nervous system, neuromuscular, lung or cardiac disease. Affected children show hypoventilation during sleep, especially non-rapid-eye-movement (non-REM) sleep, but some severely affected patients may hypoventilate while awake. Approximately 300 cases of CCHS have been identified worldwide. In many families CCHS is inherited as a single-gene autosomal-dominant condition with incomplete penetrance. With well-co-ordinated multiprofessional care, most affected children survive with a good quality of life, though most remain permanently dependent upon assisted ventilation during sleep. In this article we outline current knowledge of the genetics and pathophysiology of CCHS and provide an outline of optimal care and investigation of affected children. copyright 2004 Elsevier Ltd. All rights reserved.

Majumdar, S. and P. Wood (2009). "Congenital central hypoventilation syndrome (CCHS) with Hirschsprung disease (Haddad syndrome): an unusual cause of reduced baseline variability of the fetal heart rate." Journal of Obstetrics & Gynaecology 29(2): 152-3.

Makhija, M. C., H. J. Bronfman, et al. (1978). "Ventilation patterns mimicking COPD in patients with diaphragmatic pacing for Ondine's curse." RADIOLOGY 129(1): 111-6.

Ventilation was studied with 133Xe in 18 patients with central hypoventilation (Ondine's Curse) in whom diaphragmatic pacers were implanted. Three distinct patterns emerged: Type I, improvement in ventilation on the paced side (11 of 18 patients); Type II, improvement on both the paced and unpaced side (4 of 18); and Type III, no improvement (3 of 18). With the pacer off, many of these patients have patterns that mimic chronic obstructive pulmonary disease and that revert to normal with pacing. This retention, clearly reversible, cannot reflect permanent airways or airspace disease.
Manconi, M., S. Mondini, et al. (2003). "Anterior spinal artery syndrome complicated by the ondine curse.[Erratum appears in Arch Neurol. 2004 Mar;61(3):350]." ARCHIVES OF NEUROLOGY 60(12): 1787-90.

BACKGROUND: Anterior spinal artery (ASA) syndrome results in motor palsy and dissociated sensory loss below the level of the lesion, accompanied by bladder dysfunction. When the cervical spine is involved, breathing disorders may be observed. OBJECTIVE: To describe the polysomnographic findings in a patient with cervical ASA syndrome complicated by a sleep breathing disorder. SETTING: Unit of neurology at a sleep center. Patient A 30-year-old man had an ischemic lesion that affected the anterior cervical spinal cord (C2-C6) bilaterally because of an ASA thrombosis. He developed ASA syndrome associated with respiratory impairment during sleep. RESULTS: The polysomnographic study during sleep showed a severe sleep disruption caused by continuous central apneas that appeared immediately after falling asleep. Treatment by intermittent positive pressure ventilation normalized the respiratory pattern and sleep architecture. CONCLUSIONS: The sleep breathing pattern was compatible with central alveolar hypoventilation due to automatic breathing control failure caused by a lesion of the reticulospinal pathway, which normally activates ventilatory muscles during sleep. This autonomic sleep breathing impairment resembles that found as a complication in patients who undergo spinothalamic tract cervical cordotomy for intractable pain. This surgical complication is known as the Ondine curse.

Manning, H. L. and J. C. Leiter (2000). "Respiratory control and respiratory sensation in a patient with a ganglioglioma within the dorsocaudal brain stem." AMERICAN JOURNAL OF RESPIRATORY & CRITICAL CARE MEDICINE 161(6): 2100-6.

We encountered a young woman with severe central sleep apnea caused by a medullary glioma located slightly dorsal to and to the right of the midline, a region not generally associated with CO(2) chemosensitivity. The patient had normal spirometric readings, lung volumes, diffusing capacity, maximal inspiratory pressure, and alveolar-arterial oxygen difference. While awake, she displayed marked irregularity in her breathing pattern; her end-tidal CO(2) (FET(CO(2))) ranged from 5.3 to 10.9%. During voluntary hyperpnea, she could quickly reduce her FET(CO(2)) to 4.2%, but her PCO(2) did not change after administration of acetazolamide or progesterone. Like patients with congenital central hypoventilation syndrome (CCHS), our patient had a relatively intact ventilatory response to exercise; her PCO(2) was high at the start of exercise and increased slightly thereafter. In contrast to CCHS patients, however, our patient had an intact hypoxic ventilatory response (DeltaVE/ DeltaSa(O(2)) = -0.37 L/min/Sa(O(2))). In further contrast to CCHS patients, our patient had a very short breathholding time and described a sensation of air hunger as the factor limiting her breathholding ability. Her heart rate and blood pressure responses to the Valsalva maneuver were normal.

Manuel, D. G., M. Leung, et al. (2003). "Burden of cardiovascular disease in Canada." CANADIAN JOURNAL OF CARDIOLOGY 19(9): 997-1004.

BACKGROUND: This report updates the death estimates for cardiovascular disease (CVD) in Canada and introduces a population-based perspective on disease prevalence and health-related quality of life (HRQOL) burden. METHODS: The Canadian Mortality Database was used to estimate the mortality of men and women in different age groups for the 139 Canadian health regions from 1950 to 1999. Heart disease prevalence and its impact on HRQOL were estimated using the 2000-2001 Canadian Community Health Survey (CCHS). Life table techniques were used to estimate the impact of heart disease on life and health expectancy. RESULTS: Although CVD remains the leading cause of death in Canada, between 1950 and 1999 the death rates from CVD dropped from 702 per 100,000 to 288 per 100,000 men, and from 562 per 100,000 to 175 per 100,000 women. Results from the CCHS indicated that 5.4% of men and 4.6% of women reported having heart disease as diagnosed by a medical professional. Of these individuals, 14% of men and 21% of women reported difficulty ambulating - about six times more than people without heart disease. In total, 4.5 years of life expectancy and 2.8 years of health expectancy were lost due to CVD. The study also found large differences in the burden of CVD among men and women and across the 139 Canadian health regions. CONCLUSIONS: CVD is a major disease burden in terms of both mortality and HRQOL and is an important source of health inequalities between populations in Canada. Any attempt to improve the health of Canadians or to reduce health inequalities should include interventions to reduce CVD mortality and morbidity. Given the present impact of CVD on HRQOL, reducing or eliminating heart disease may potentially result in an increase in life expectancy that will be larger than the gains in health expectancy.