Decision analysis of intracranial monitoring in non-lesional epilepsy.

PURPOSE: Up to one third of epilepsy patients develop pharmacoresistant seizures and many benefit from resective surgery. However, patients with non-lesional focal epilepsy often require intracranial monitoring to localize the seizure focus. Intracranial monitoring carries operative morbidity risk and does not always succeed in localizing the seizures, making the benefit of this approach less certain. We performed a decision analysis comparing three strategies for patients with non-lesional focal epilepsy: (1) intracranial monitoring, (2) vagal nerve stimulator (VNS) implantation and (3) medical management to determine which strategy maximizes the expected quality-adjusted life years (QALYs) for our base cases. METHOD: We constructed two base cases using parameters reported in the medical literature: (1) a young, otherwise healthy patient and (2) an elderly, otherwise healthy patient. We constructed a decision tree comprising strategies for the treatment of non-lesional epilepsy and two clinical outcomes: seizure freedom and no seizure freedom. Sensitivity analyses of probabilities at each branch were guided by data from the medical literature to define decision thresholds across plausible parameter ranges. RESULTS: Intracranial monitoring maximizes the expected QALYs for both base cases. The sensitivity analyses provide estimates of the values of key variables, such as the surgical risk or the chance of localizing the focus, at which intracranial monitoring is no longer favored. CONCLUSION: Intracranial monitoring is favored over VNS and medical management in young and elderly patients over a wide, clinically-relevant range of pertinent model variables such as the chance of localizing the seizure focus and the surgical morbidity rate.

Understanding the Relationship Between Pruritus Severity and Work Productivity in Patients With Moderate-to-Severe Psoriasis: Sleep Problems Are a Mediating Factor.

BACKGROUND: Psoriasis is a debilitating skin disease associated with substantial pruritus, work impairment, and sleep disturbance. OBJECTIVE: This study evaluated associations between pruritus and work productivity, and the role of sleep problems as a possible mediator of the relationship between the two. METHODS AND MATERIALS: Data from a pruritus visual analog scale (Itch VAS), the Medical Outcomes Study Sleep Scale (MOS-SS), and the Work Productivity and Activity Impairment Questionnaire (WPAI) were collected in a phase 2 clinical trial in patients with psoriasis treated with ixekizumab or placebo. Mediating effects of sleep were tested in multiple regressions with pruritus severity (independent variable) and work productivity (dependent variable). Sobel tests evaluated the significance of sleep's effect. RESULTS: Several MOS-SS domains were significantly associated with the WPAI presenteeism, work productivity, and activity impairment scores, and decreased the effect of pruritus. Sobel tests indicated that the Sleep Problems Index I had a significant effect (P<.05) in mediating the relationship between pruritus and presenteeism, work productivity, and activity impairment. CONCLUSION: Sleep may mediate the role of pruritus on work productivity, but both factors appear to have independent negative effects on work.

Sleep apnea in patients reporting insomnia or restless legs symptoms.

OBJECTIVE: Insomnia and restless legs syndrome (RLS) are defined by self-reported symptoms, and polysomnography (PSG) is not routinely indicated. Occult obstructive sleep apnea (OSA), common even in asymptomatic adults, may complicate management of patients presenting with insomnia or restless legs. To this end, we investigated objective sleep apnea metrics in a large retrospective cohort according to self-reported symptom profiles. METHODS: We compared sleep apnea findings in patients referred to our center according to self-reported symptoms associated with insomnia, sleep apnea, and restless legs. The cohort included over 1900 adults who underwent diagnostic (n = 1418) or split-night (n = 504) PSGs and completed a symptom and medical history questionnaire. RESULTS: More than 30% of patients who did not endorse any OSA symptoms, but did endorse insomnia or restless legs symptoms, were found to have OSA based on apnea-hypopnea index (AHI) >5 during overnight laboratory testing. Regression models of the full cohort showed that the risk of OSA was related, as expected, to older age, male sex, elevated body mass index, and presence of OSA symptoms. The presence of insomnia symptoms did not alter the risk of OSA. The presence of restless legs symptoms showed a small odds ratio for lowered OSA risk. CONCLUSIONS: Objective evidence of OSA occurs similarly in those with insomnia or restless legs symptoms, even among those without self-reported OSA symptoms. Providers should be aware of the potential for occult OSA in populations with insomnia and restless legs, which may complicate their management in addition to presenting an independent medical risk itself.

Sleep-wake time perception varies by direct or indirect query.

STUDY OBJECTIVES: The diagnosis of insomnia rests on self-report of difficulty initiating or maintaining sleep. However, subjective reports may be unreliable, and possibly may vary by the method of inquiry. We investigated this possibility by comparing within-individual response to direct versus indirect time queries after overnight polysomnography. METHODS: We obtained self-reported sleep-wake times via morning questionnaires in 879 consecutive adult diagnostic polysomnograms. Responses were compared within subjects (direct versus indirect query) and across groups defined by apnea-hypopnea index and by self-reported insomnia symptoms in pre-sleep questionnaires. Direct queries required a time duration response, while indirect queries required clock times from which we calculated time durations. RESULTS: Direct and indirect queries of sleep latency were the same in only 41% of cases, and total sleep time queries matched in only 5.4%. For both latency and total sleep, the most common discrepancy involved the indirect value being larger than the direct response. The discrepancy between direct and indirect queries was not related to objective sleep metrics. The degree of discrepancy was not related to the presence of insomnia symptoms, although patients reporting insomnia symptoms showed underestimation of total sleep duration by direct response. CONCLUSIONS: Self-reported sleep latency and total sleep time are often internally inconsistent when comparing direct and indirect survey queries of each measure. These discrepancies represent substantive challenges to effective clinical practice, particularly when diagnosis and management depends on self-reported sleep patterns, as with insomnia. Although self-reported sleep-wake times remains fundamental to clinical practice, objective measures provide clinically relevant adjunctive information.

Automated sleep apnea quantification based on respiratory movement.

Obstructive sleep apnea (OSA) is a prevalent and treatable disorder of neurological and medical importance that is traditionally diagnosed through multi-channel laboratory polysomnography(PSG). However, OSA testing is increasingly performed with portable home devices using limited physiological channels. We tested the hypothesis that single channel respiratory effort alone could support automated quantification of apnea and hypopnea events. We developed a respiratory event detection algorithm applied to thoracic strain-belt data from patients with variable degrees of sleep apnea. We optimized parameters on a training set (n=57) and then tested performance on a validation set (n=59). The optimized algorithm correlated significantly with manual scoring in the validation set (R2=0.73 for training set, R2=0.55 for validation set; p<0.05). For dichotomous classification, the AUC was >0.92 and >0.85 using apnea-hypopnea index cutoff values of 5 and 15, respectively. Our findings demonstrate that manually scored AHI values can be approximated from thoracic movements alone. This finding has potential applications for automating laboratory PSG analysis as well as improving the performance of limited channel home monitors.

Alpha1 and alpha6 subunits specify distinct desensitization, deactivation and neurosteroid modulation of GABA(A) receptors containing the delta subunit.

GABA(A) receptor alpha subunit subtypes have distinct CNS distributions and confer different pharmacological and biophysical properties to alphabetagamma receptor isoforms. However, the alpha subtype-dependent properties of alphabetadelta receptor isoforms that may be targeted to extrasynaptic sites remain poorly understood. We investigated the properties of alpha1beta3delta and alpha6beta3delta receptor currents evoked by concentration jumps using a saturating GABA concentration (1 mM). alpha1beta3delta receptor currents desensitized slowly, deactivated rapidly and displayed voltage-dependence only of peak amplitude. In contrast, alpha6beta3delta receptor currents had voltage-dependent increased desensitization and slower deactivation, but did not show rectification. The neurosteroid THDOC (1 microM) enhanced alpha1beta3delta more than alpha6beta3delta currents, but increased the extent of desensitization and prolonged deactivation for both receptor isoforms. alpha1-alpha6 and alpha6-alpha1 chimeras (spliced in transmembrane domain 1) suggested that differences in deactivation rate and its voltage-dependence correlated with N-terminal domains, while the extent of desensitization and its voltage-dependence correlated with C-terminal domains. Both chimeras showed outward rectification. alpha1 subunit-like THDOC enhancement was observed with the alpha1-alpha6 chimera, but the alpha6-alpha1 chimera did not confer alpha6 subunit-like enhancement, suggesting that multiple alpha1 subunit domains contributed to neurosteroid efficacy. Thus, alpha subunit subtypes may regulate the kinetic and pharmacological properties of tonic neuronal inhibition.

Agonist Trapping by GABAA Receptor Channels.

GABAergic IPSCs have a relatively slow decay (deactivation) that appears to result from GABA(A) receptor channel openings that occur well beyond the predicted duration of free GABA at central synapses. Open and desensitized states have been suggested to prevent dissociation of agonist from the receptor, thus prolonging deactivation. However, simultaneous assessment of GABA binding and channel gating has not been possible. We developed a functional assay for occupancy of the GABA binding site or sites to test the GABA "trapping" hypothesis. Deactivation currents were compared in the absence and presence of bicuculline, a competitive antagonist that also allosterically inhibits GABA(A) receptors. This provided a model-independent, functional test of the hypothesis that GABA is trapped on the receptor during gating: bicuculline could only inhibit the channel if it was open but unbound by GABA. Although bicuculline inhibited spontaneous and neurosteroid-activated GABA(A) receptor currents, it failed to alter the deactivation time course of GABA-activated GABA(A) receptor currents. Protection of deactivation current from bicuculline block indicated that GABA remained bound to the receptors while the channel was open, thus suggesting that all open states, as well as all closed and desensitized states from which channel opening can occur, must be GABA liganded states. Trapping may be specific to agonists, because the positive allosteric modulator diazepam unbound from GABA(A) receptors independent of GABA binding and channel activity.

Mutation of the 9' leucine in the GABA(A) receptor gamma2L subunit produces an apparent decrease in desensitization by stabilizing open states without altering desensitized states.

A conserved leucine near the middle (9' position) of the second transmembrane domain of ligand-gated ion channels has been implicated in both gating and desensitization. Specifically, L9'S and L9'T mutations decreased agonist EC50, decreased apparent desensitization and prolonged deactivation in members of the LGIC superfamily, suggesting that this residue may regulate channel properties including desensitization. GABA(A) receptors desensitize in three phases, but in previous 9' leucine studies, only slow phases of desensitization were resolved. We used excised patches containing alpha1beta3gamma2L or alpha1beta3gamma2L(L9'S) GABA(A) receptors and combined single channel recording and concentration jump techniques to reevaluate the effects of this mutation on desensitization. Although desensitization extent was decreased in mutated channels, desensitization still occurred in three phases, suggesting that desensitized states may be intact. Interestingly, deactivation rate was slowed by the mutation, opposite to that expected if desensitization was attenuated. alpha1beta3gamma2L(L9'S) receptor single channels had increased open durations. Simulations revealed that stabilizing the open state (by decreasing the channel closing rate) could account for multiple macroscopic findings: left-shifted GABA EC50, smaller extent of desensitization, slower desensitization rate, and longer deactivation. We concluded that changes in efficacy can alter macroscopic desensitization without affecting desensitized states per se.

Structural determinants of fast desensitization and desensitization-deactivation coupling in GABAa receptors.

Fast IPSCs in the brain are predominantly caused by presynaptic release of GABA that activates GABA(A) receptor (GABA(A)R) channels. The IPSCs are shaped by the gating and desensitization properties of postsynaptic GABA(A)Rs. Specifically, fast desensitization has been suggested to decrease IPSC amplitude and to increase IPSC duration by slowing deactivation; however, the mechanisms underlying desensitization, deactivation, and their coupling are poorly understood. Consistent with this suggestion, alpha1beta3gamma2L GABA(A)Rs desensitize with a prominent fast phase and deactivate slowly, whereas alpha1beta3delta GABA(A)Rs desensitize without a fast phase and deactivate rapidly. Using the concentration-jump technique applied to excised patches, we studied GABA(A)Rs containing chimeras or exchange mutants between delta and gamma2L subunits to gain insight into the structural bases for fast desensitization and its coupling to deactivation. We demonstrated that the N terminus and two adjacent residues (V233, Y234) in the first transmembrane domain (TM1) of the delta subunit were both required to abolish fast desensitization. Additionally, these residues in TM1 of the gamma2L subunit (Y235, F236) were critical for desensitized states to prolong deactivation after removal of GABA, because mutations resulted in accelerated deactivation despite unaltered desensitization time course. Interestingly, control of desensitization and deactivation was independent of the identity (gamma2L or delta subunit sequence) of TM2, indicating that structures related to the putative channel gate may play a less direct role in desensitization than previously suggested.

Psychosocial factors in women who undergo cholecystectomy. A case-control study.

Thirty women admitted to hospital for cholecystectomy were compared with a healthy community control group. Univariate comparisons showed that patients had significantly more social problems, manifested greater psychological distress and reported poorer social support. Logistic multiple regression analysis indicated that patient status was best predicted by manual occupational class and the interaction between employment and presence/absence of young children. The findings are discussed within the framework of illness behaviour.