Faculty Bibliography

OBJECTIVE: Our goal was to evaluate the long-term safety and efficacy of recombinant human alpha-l-iduronidase (laronidase) in patients with mucopolysaccharidosis I. PATIENTS AND METHODS: All 45 patients who completed a 26-week, double-blind, placebo-controlled trial of laronidase were enrolled in a 3.5-year open-label extension study. Mean patient age at baseline was 16 (range: 6-43) years. All patients had attenuated disease (84% Hurler-Scheie, 16% Scheie phenotypes). Clinical, biochemical, and health outcomes measures were evaluated through the extension phase. Changes are presented as the mean +/- SEM. RESULTS: All 40 patients (89%) who completed the trial received at least 80% of scheduled infusions. As shown in earlier trials, urinary glycosaminoglycan levels decreased within the first 12 weeks and liver volume decreased within the first year. Percent predicted forced vital capacity remained stable, with a linear slope of -0.78 percentage points per year. The 6-minute walk distance increased 31.7 +/- 10.2 m in the first 2 years, with a final gain of 17.1 +/- 16.8 m. Improvements in the apnea/hypopnea index (decrease of 7.6 +/- 4.5 events per hour among the patients with significant baseline sleep apnea) and shoulder flexion (increase of 17.4 degrees +/- 3.6 degrees) were most rapid during the first 2 years. Improvements in the Child Health Assessment Questionnaire/Health Assessment Questionnaire disability index (decrease of 0.31 +/- 0.11, signifying a clinically meaningful improvement in activities of daily living) were gradual and sustained over the treatment period. Laronidase infusions were generally well tolerated except in 1 patient who experienced an anaphylactic reaction. Infusion-associated reactions, which occurred in 53% of the patients, were mostly mild, easily managed, and decreased markedly after 6 months. One patient died as a result of an upper respiratory infection unrelated to treatment. Antibodies to laronidase developed in 93% of the patients; 29% of the patients were seronegative at their last assessment. CONCLUSIONS: This trial demonstrates the long-term clinical benefit and safety of laronidase in attenuated patients with mucopolysaccharidosis I and highlights the magnitude and chronology of treatment effects. Prompt diagnosis and early treatment will maximize treatment outcomes

STUDY OBJECTIVES: Regularity of respiration is characteristic of stable sleep without sleep disordered breathing. Appearance of respiratory irregularity may indicate onset of wakefulness. The present study examines whether one can detect transitions from sleep to wakefulness using only the CPAP flow signal and automate this recognition. DESIGN: Prospective study with blinded analysis SETTING: Sleep disorder center, academic institution. PARTICIPANTS: 74 subjects with obstructive sleep apnealhypopnea syndrome (OSAHS) INTERVENTIONS: n/a. MEASUREMENTS AND RESULTS: 74 CPAP titration polysomnograms in patients with OSAHS were examined. First we visually identified characteristic patterns of ventilatory irregularity on the airflow signal and tested their relation to conventional detection of EEG defined wake or arousal. To automate recognition of sleep-wake transitions we then developed an artificial neural network (ANN) whose inputs were parameters derived exclusively from the airflow signal. This ANN was trained to identify the visually detected ventilatory irregularities. Finally, we prospectively determined the accuracy of the ANN detection of wake or arousal against EEG sleep/wake transitions. A visually identified irregular respiratory pattern (IrREG) was highly predictive of appearance of EEG wakefulness (Positive Predictive Value [PPV] = 0.89 to 0.98 across subjects). Furthermore, we were able to automate identification of this irregularity with an ANN which was highly predictive for wakefulness by EEG (PPV 0.66 to 0.86). CONCLUSIONS: Despite not detecting all wakefulness, the high positive predictive value suggests that analysis of the respiration signal alone may be a useful indicator of CNS state with potential utility in the control of CPAP in OSAHS. The present study demonstrates the feasibility of automating the detection of IrREG

STUDY OBJECTIVES: To evaluate the validity of the Apnea Risk Evaluation System (ARES) Unicorder, a self-applied, limited-channel portable monitoring device for the evaluation of sleep disordered breathing (SDB). DESIGN: Prospective study with blinded analysis. SETTING: Sleep disorder center, academic institution. PARTICIPANTS: Eighty patients with suspected obstructive sleep apnea hypopnea syndrome (OSAHS) and 22 volunteers. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Subjects used the ARES Unicorder at home for 2 nights using only written instructions. Within 2 weeks, they returned to the laboratory for full nocturnal polysomnography (NPSG) with simultaneous monitoring with the Unicorder. NPSGs were scored manually to obtain an apnea-hypopnea index based on Medicare guidelines (AHI4%) and a respiratory disturbance index (RDI). ARES studies were autoscored and reviewed to obtain indices based on equivalent definitions i.e., AHI4%(ARES) and apnea hypopnea (events with 1% desaturation) index (AHI1%(ARES)). Indices from the NPSG were compared to the in-lab ARES and in-home ARES indices using mean differences and the intraclass correlations (ICC). For the in-lab comparison, there was high concordance between AHI4%(NPSG) and AHI4%(ARES) (ICC = 0. 96, mean difference = 0.5/hour) and RDI(NPSG ) and AHI1%(ARES) (ICC =0.93, mean difference = 3.2/hour). For NPSG versus In-Home ARES comparison, there was good concordance between AHI4%(NPSG) and AHI4%(ARES) (ICC = 0.8, mean difference = 4.1/ hour) and RDI(NPSG) and AHI1%(ARES) (ICC = 0.8 mean difference = 8.6/hour). The diagnostic sensitivity of in-lab ARES for diagnosing SDB using an RDI cut-off of 15 per hour was 95% and specificity was 94%, with a positive likelihood ratio (LR+) =17.04, and negative likelihood ratio (LR-) = 0.06. For in-home ARES data the sensitivity was 85% and specificity 91% (LR+ = 9.34, LR- = 0.17). There was good agreement between the manually scored NPSG SDB indices and the autoscoring ARES algorithm. CONCLUSIONS: ARES Unicorder provides acceptably accurate estimates of SDB indices compared to conventional laboratory NPSG for both the simultaneous and in-home ARES data. The high sensitivity, specificity, and positive and negative likelihood ratios obtained in the group we studied supports the utility of an ambulatory limited-monitoring approach not only for diagnosing sleep disordered breathing but also to rule out SDB in suitably selected groups.

This paper presents a series of experiments, both in patients and computer models, investigating the transition from acute to chronic hypercapnia in OSA. The data demonstrate that acute hypercapnia during periodic breathing occurs due to either reduction in magnitude of inter-event ventilation and/or reduction in inter-event ventilatory duration relative to duration of the preceding event. The transition between acute hypercapnia during sleep and chronic sustained hypercapnia during wakefulness may be determined by an interaction between respiratory control and renal handling of HCO3-.

INTRODUCTION: We evaluated polysomnograms of chronic fatigue syndrome (CFS) patients with and without fibromyalgia to determine whether patients in either group had elevated rates of sleep-disturbed breathing (obstructive sleep apnea or upper airway resistance syndrome) or periodic leg movement disorder. We also determined whether feelings of unrefreshing sleep were associated with differences in sleep architecture from normal. METHODS: We compared sleep structures and subjective scores on visual analog scales for sleepiness and fatigue in CFS patients with or without coexisting fibromyalgia (n = 12 and 14, respectively) with 26 healthy subjects. None had current major depressive disorder, and all were studied at the same menstrual phase. RESULTS: CFS patients had significant differences in polysomnograpic findings from healthy controls and felt sleepier and more fatigued than controls after a night's sleep. CFS patients as a group had less total sleep time, lower sleep efficiency, and less rapid eye movement sleep than controls. A possible explanation for the unrefreshing quality of sleep in CFS patients was revealed by stratification of patients into those who reported more or less sleepiness after a night's sleep (a.m. sleepier or a.m. less sleepy, respectively). Those in the sleepier group reported that sleep did not improve their symptoms and had poorer sleep efficiencies and shorter runs of sleep than both controls and patients in the less sleepy group; patients in the less sleepy group reported reduced fatigue and pain after sleep and had relatively normal sleep structures. This difference in sleep effects was due primarily to a decrease in the length of periods of uninterrupted sleep in the a.m. sleepier group. CONCLUSION: CFS patients had significant differences in polysomnographic findings from healthy controls and felt sleepier and more fatigued than controls after a night's sleep. This difference was due neither to diagnosable sleep disorders nor to coexisting fibromyalgia but primarily to a decrease in the length of periods of uninterrupted sleep in the patients with more sleepiness in the morning than on the night before. This sleep disruption may explain the overwhelming fatigue, report of unrefreshing sleep, and pain in this subgroup of patients

During sleep, the development of a plateau on the inspiratory airflow/time contour provides a non-invasive indicator of airway collapsibility. Humans recognize this abnormal contour easily, and this study replicates this with an artificial neural network (ANN) using a normalized shape. Five 10 min segments were selected from each of 18 sleep records (respiratory airflow measured with a nasal cannula) with varying degrees of sleep disordered breathing. Each breath was visually scored for shape, and breaths split randomly into a training and test set. Equally spaced, peak amplitude normalized flow values (representing breath shape) formed the only input to a back propagation ANN. Following training, breath-by-breath agreement of the ANN with the manual classification was tabulated for the training and test sets separately. Agreement of the ANN was 89% in the training set and 70.6% in the test set. When the categories of 'probably normal' and 'normal', and 'probably flow limited' and 'flow limited' were combined, the agreement increased to 92.7% and 89.4% respectively, similar to the intra- and inter-rater agreements obtained by a visual classification of these breaths. On a naive dataset, the agreement of the ANN to visual classification was 57.7% overall and 82.4% when the categories were collapsed. A neural network based only on the shape of inspiratory airflow succeeded in classifying breaths as to the presence/absence of flow limitation. This approach could be used to provide a standardized, reproducible and automated means of detecting elevated upper airway resistance.