Lynn Liu

The hypocretin neurotransmission system in myotonic dystrophy type 1

Background: Patients with myotonic dystrophy type 1 (DM1) frequently have symptoms of excessive daytime sleepiness (EDS). Some patients with DM1 show sleep-onset REM, similar to that observed in narcolepsy. Narcolepsy is characterized by impaired hypocretin (Hcrt) neurotransmission. Objective: To test for dysregulation of Hcrt neurotransmission in a prospective cohort of patients with DM1. Methods: Hcrt levels in CSF were measured by radioimmunoassay. Sleep physiology was assessed by overnight polysomnography (PSG) and a multiple sleep latency test (MSLT). Splicing of Hcrt receptor 1 and 2 (HcrtR1 and HcrtR2) mRNA was examined in postmortem samples of temporal cortex. Results: Seventeen of 38 patients with DM1 reported symptoms of EDS. Among patients with DM1 with EDS who underwent PSG/MSLT, 7 of 13 showed reduced sleep latency, sleep-onset REM, or both. However, CSF Hcrt levels in DM1 (mean 277 pg/mL, n = 38) were not different from controls (mean 277 pg/mL, n = 33). Also, splicing of HcrtR1 and HcrtR2 mRNA in patients with DM1 was similar to controls. Conclusions: Excessive daytime sleepiness and dysregulation of REM sleep occur frequently in patients with myotonic dystrophy type 1 (DM1). However, the pathophysiologic basis is distinct from narcolepsy, as patients with DM1 do not have a consistent defect of Hcrt release or receptor splicing.

Diagnosis of Sleep-Related Breathing Disorders by Visual Analysis of Transthoracic Impedance Signals in Pacemakers

Background—Minute ventilation sensors of cardiac pacemakers measure ventilation by means of transthoracic impedance changes between the pacemaker case and the electrode tip. We investigated whether this technique might detect sleep-related breathing disorders. Methods and Results—In 22 patients, analog waveforms of the transthoracic impedance signal measured by the pacemaker minute ventilation sensor over the course of a night were visualized, scored for apnea/hypopnea events, and compared with simultaneous polysomnography. Analysis of transthoracic impedance signals correctly identified the presence or absence of moderate to severe sleep apnea (apnea/hypopnea index, AHI >20 h−1) in all patients (receiver operating characteristics, ROC=1.0). The ROC for AHI scores of ≥5 h−1 and ≥10 h−1 showed an area under the curve of 0.95, P<0.005, and 0.97, P<0.0001, respectively. Accuracy over time assessed by comparing events per 5-minute epochs was high (Cronbach &agr; reliability coefficient, 0.85; intraclass correlation, 0.73). Event-by-event comparison within ±15 seconds revealed agreement in 81% (&kgr;, 0.77; P<0.001). Conclusions—Detection of apnea/hypopnea events by pacemaker minute ventilation sensors is feasible and accurate compared with laboratory polysomnography. This technique might be useful to screen and monitor sleep-related breathing disorders in pacemaker patients.

The practice of neurology, 2000–2010: Report of the AAN Member Research Subcommittee

Objective: To present an analysis of American Academy of Neurology (AAN) membership demographics and practice trends over the past decade. Methods: Data from the 2009 AAN Census and 2010 Practice Profile Form (PPF) surveys were compared to results from 2004 and 2000 surveys. The Census was sent to all AAN members, and the PPF was sent to a random sample of US practicing neurologists. Results: Since 2000, AAN membership increased by 31%, and the number of US neurologist-members increased by 14%. Mean age of US neurologists increased from 48.6 to 53.3 years, and 23.9% of neurologists are women. There was a 15% increase in the proportion of neurologists relative to the US population, from 3.41 neurologists per 100,000 population in 2000 to 3.92 neurologists in 2009. In 2009, 24.1% of US neurologists were in solo practice, 27.8% were in a neurology group, and 35.6% were in multispecialty/university settings, with little change in practice arrangements over time. The top 5 practice interest areas were unchanged since 2004 as were the number of hours devoted to patient care (42.3) or total work hours per week (57.1). Little change was observed in performed procedures, except increased use of botulinum toxin and nerve blocks and a decline in lumbar punctures. Neurologists rely more on physician assistants to see follow-up and new patients independently (p < 0.001). Conclusion: Despite advances in neurologic diagnosis and therapy, there has been little change in practice characteristics of US neurologists.

The Role of Continuous Positive Airway Pressure in the Treatment of Hypertension in Patients with Obstructive Sleep Apnea-Hypoapnea Syndrome: A Review of Randomized Trials

Obstructive sleep apnea-hypoapnea syndrome (OSA) is a disorder that results in repetitive occlusion of the airway and hypoxemia during sleep. Epidemiologic studies have associated this disorder with increased cardiovascular morbidity and mortality. Systemic hypertension is prevalent among patients with OSA and has been recognized as a common identifiable cause of hypertension. Nasal continuous positive airway pressure (nCPAP) ventilation is an effective therapy for OSA and it may additionally reduce blood pressure. The use of nCPAP ventilation to treat hypertension in patients with OSA has been studied extensively. However, whether it is effective in treating hypertension in this population remains unclear. This review evaluates the recent literature that investigates the effects of nCPAP ventilation on hypertension in patients with OSA.

The Baroreflex in Hypertension

Hypertension is a complex syndrome that increases the risk of developing other medical comorbidities and interacts with other medical conditions to increase the risk of target end-organ damage such as cardiovascular disease, stroke, and renal disease. Hypertension remains under-recognized and poorly controlled in the USA and worldwide. In some patients, hypertension is resistant to optimal medical therapy. Over the last few decades, there has been an increasing understanding of the role of the sympathetic nervous system in the development and maintenance of hypertension. This update reviews the physiology and role of the sympathetic nervous system in hypertension and pharmacological and interventional treatments directed at nervous system involvement in secondary hypertension.

Evaluation of phenytoin serum levels following a loading dose in the acute hospital setting

PURPOSE Due to the complex pharmacokinetic profiles of phenytoin (PHT) and fosphenytoin (FOS), achieving sustained, targeted serum PHT levels in the first day of use is challenging. METHODS A population based approach was used to analyze total serum PHT (tPHT) level within 2-24h of PHT/FOS loading with or without supplementary maintenance or additional loading doses among PHT-naïve patients in the acute hospital setting. Adequate tPHT serum level was defined as ≥20μg/mL. RESULTS Among 494 patients with 545 tPHT serum levels obtained in the first 2-24h after the loading dose (LD), tPHT serum levels of either <or≥20μg/mL were observed along wide and overlapping cumulative dose ranges. Among those receiving 15-20mg/kg and 20-55mg/kg weight-based loading dose, 63% and 51% respectively did not attain tPHT serum level of ≥20μg/mL even within the first 6h of treatment. For the 393 available concomitant free and total serum PHT levels, correlation was weak, r=0.36. CONCLUSION Close laboratory surveillance and PHT/FOS dose adjustments are recommended to ensure adequate and sustained tPHT serum levels early in treatment. Free serum PHT level is the preferred method of drug monitoring.

A Randomized, Prospective, Double-Blinded Study of Physostigmine to Prevent Sedation-Induced Ventilatory Arrhythmias.

BACKGROUND:Physostigmine, a centrally acting acetylcholinesterase inhibitor, is most commonly used by anesthesiologists in the postanesthetic setting to reverse confusion caused by central anticholinergic medication effects. It has also been proposed as a treatment for sleep-disordered breathing. We investigated whether physostigmine was effective in decreasing the frequency of ventilatory arrhythmias produced during moderate sedation with midazolam and remifentanil during the conditions of breathing room air or 2 L/min nasal O2. METHODS:Ten healthy male volunteers participated in this randomized, double-blind control trial of physostigmine (0.24 µg·kg−1·min−1) versus placebo. Moderate sedation was achieved with infusions of midazolam and remifentanil and monitored with full and processed electroencephalogram. Analgesia was quantified with subjective pain score to thermal stimulation. Ventilatory arrhythmias, as measured by the sedation apnea–hypopnea index (S-AHI), were scored as the number of apneas and hypopneas during two 1-hour periods on room air or 2 L/min nasal O2. RESULTS:All subjects tolerated the sedation and physostigmine without significant adverse effects. Sedation during placebo infusion resulted in clinically significant (S-AHI > 15) ventilatory arrhythmias in 5 conditions in 3 subjects (2 on room air and then O2, and 1 on O2 only). Physostigmine did not significantly (P > 0.46) reduce the total number of ventilatory arrhythmias on either room air or O2 (13.4 ± 18.8 events/h [mean ± SEM], 95% confidence interval [CI] = −9.9 to 62.7; and 6.2 ± 8.0, 95% CI = −3.1 to 28.7, respectively). Physostigmine did reduce the S-AHI in all 5 instances of clinically significant ventilatory arrhythmias (S-AHI decreased by 67.0 ± 22.2; CI = 29.2–111.7; P = 0.04). CONCLUSIONS:Physostigmine does not appear to be useful as a pretreatment to prevent ventilatory arrhythmias during moderate sedation. However, it may be useful as a treatment for clinically significant ventilatory arrhythmias during moderate sedation.