Novel LAMC3 pathogenic variant enriched in Finnish population causes malformations of cortical development and severe epilepsy.

OBJECTIVE: Recessive LAMC3 mutations are recognized to cause epilepsy with cortical malformations characterized by polymicrogyria and pachygyria. The objective of this study was to describe the clinical picture and epilepsy phenotype of four patients with a previously undescribed LAMC3 variant. METHODS: All epilepsy patients treated in Kuopio Epilepsy Center (located in Kuopio, Finland) are offered the possibility to participate in a scientific study investigating biomarkers in epilepsy (Epibiomarker study). We have collected a comprehensive database of the study population, and are currently re-evaluating our database regarding the patients with developmental and/or epileptic encephalopathy (DEE). If the etiology of epilepsy remains unknown in the clinical setting, we are performing whole exome sequencing to recognize the genetic causes. RESULTS: Among our study population of 323 DEE patients we recognized three patients with similar homozygous LAMC3 c.1866del (p.(Phe623Serfs*10)) frameshift variant and one patient with a compound heterozygous mutation where the same frameshift variant was combined with an intronic LAMC3 c.4231-12C>G variant on another allele. All these patients have severe epilepsy and either bilateral agyria-pachygyria or bilateral polymicrogyria in their clinical MRI scanning. Cortical malformations involve the occipital lobes in all our patients. Epilepsy phenotype is variable as two of our patients have DEE with epileptic spasms progressing to Lennox-Gastaut syndrome and intellectual disability. The other two patients have focal epilepsy without marked cognitive deficit. The four patients are unrelated. LAMC3 c.1866del p.(Phe623Serfs*10) frameshift variant is enriched in the Finnish population. SIGNIFICANCE: Only a few patients with epilepsy caused by LAMC3 homozygous or compound heterozygous mutations have been described in the literature. To our knowledge, the variants discovered in our patients have not previously been published. Clinical phenotype appears to be more varied than previously assumed and patients with a milder phenotype and normal cognition have probably remained unrecognized.

Navigated and individual α-peak-frequency-guided transcranial magnetic stimulation in male patients with treatment-refractory schizophrenia.

BACKGROUND: Previous electroencephalography (EEG) studies have indicated altered brain oscillatory α-band activity in schizophrenia, and treatment with repetitive transcranial magnetic stimulation (rTMS) using individualized α-frequency has shown therapeutic effects. Magnetic resonance imaging-based neuronavigation methods allow stimulation of a specific cortical region and improve targeting of rTMS; therefore, we sought to study the efficacy of navigated, individual α-peak-frequency-guided rTMS (αTMS) on treatment-refractory schizophrenia. METHODS: We recruited medication-refractory male patients with schizophrenia or schizoaffective disorder in this doubleblind, sham-controlled study. We randomized patients to a 3-week course of either active αTMS or sham stimulation applied to the left dorsolateral prefrontal cortex (DLPFC). We assessed participants with the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Scale (CGI) at baseline and after treatment. We conducted a follow-up assessment with the PANSS 3 months after intervention. RESULTS: We included 44 patients. After treatment, we observed a significantly higher PANSS total score (p = 0.029), PANSS general psychopathology score (p = 0.027) and PANSS 5-factor model cognitive-disorganized factor score (p = 0.011) in the αTMS group than the sham group. In addition, the CGI-Improvement score was significantly higher among those who received αTMS compared with sham stimulation (p = 0.048). LIMITATIONS: The limited number of study participants included only male patients. Depression was not formally evaluated. CONCLUSION: Navigated αTMS to the left DLPFC reduced total, general psychopathological, and cognitive-disorganized symptoms of schizophrenia. These results provide evidence for the therapeutic efficacy of individual α-peak-frequency-guided rTMS in treatment-refractory schizophrenia. CLINICAL TRIAL REGISTRATION: NCT01941251; ClinicalTrials.gov.

Detecting negative myoclonus during long-term home measurements using wearables.

OBJECTIVE: The aim of this study was to develop a feasible method for the detection of negative myoclonus (NM) through long-term home measurements in patients with progressive myoclonus epilepsy type 1. METHODS: The number and duration of silent periods (SP) associated with NM were detected during a 48 h home recording using wearable surface electromyography (EMG) sensors. RESULTS: A newly developed algorithm was able to find short (50-69 ms), intermediate (70-100 ms), and long (101- 500 ms) SPs from EMG data. Negative myoclonus assessed by the algorithm correlated significantly with the video-recorded and physician-evaluated unified myoclonus rating scale (UMRS) scores of NM and action myoclonus. Silent period duration, number, and their combination, correlated strongly and significantly also with the Singer score, which assesses functional status and ambulation. CONCLUSIONS: Negative myoclonus can be determined objectively using long-term EMG measurements in home environment. With long-term measurements, we can acquire more reliable quantified information about NM as a symptom, compared to short evaluation at the clinic. SIGNIFICANCE: As measured using SPs, NM may be a clinically useful measure for monitoring disease progression or assessing antimyoclonic drug effects objectively.

Progressive myoclonic epilepsy type 1 (EPM1) patients present with abnormal 1H MRS brain metabolic profiles associated with cognitive function.

PURPOSE: Progressive myoclonic epilepsy, type 1A (EPM1, Unverricht-Lundborg disease), is a rare neurodegenerative autosomal recessive disorder characterized by stimulus-sensitive and action myoclonus and tonic-clonic epileptic seizures. Patients develop neurological symptoms, including ataxia, intention tremor, and dysarthria, over time, with relatively limited and nonspecific MRI atrophy findings. The effects of the disease on brain metabolism are largely unknown. METHOD: Eighteen EPM1 patients (9 M, 9F) underwent clinical evaluation and neuropsychological testing, which included the assessment of intellectual ability, verbal memory, and psychomotor and executive functions. Magnetic resonance spectroscopy (MRS) and imaging (MRI) were performed on a 1.5 T MRI system. 2D MRS chemical shift imaging (CSI) maps (TE = 270) were obtained from the following regions of the brain: basal ganglia, thalamus, insula, splenium, and occipital white and gray matter, and N-acetyl-aspartate (NAA)-, choline (Cho)-, and lactate (Lac)-to-creatine (Cr) ratios were analyzed. Ten healthy age-and sex-matched subjects (5M, 5F) were used as controls for MRS. RESULTS: We found significant brain metabolic changes involving lactate, NAA, and choline, which are widespread in the basal ganglia, thalamic nuclei, insula, and occipital areas of EPM1 patients. Changes, especially in the right insula, basal ganglia, and thalamus, were associated with intellectual abilities and impairment of the psychomotor and executive functions of EPM1 patients. CONCLUSION: Multiple brain metabolic alterations suggest the presence of neurodegeneration associated with EPM1 progression. The changes in metabolite ratios are associated with the neurocognitive dysfunction caused by the disease. However, the role of MRS findings in understanding pathophysiology of EPM1 warrants further studies.

Short- and long-interval intracortical inhibition in EPM1 is related to genotype.

OBJECTIVE: Progressive myoclonic epilepsy type 1 (EPM1) is caused by biallelic alterations in the CSTB gene, most commonly dodecamer repeat expansions. Although transcranial magnetic stimulation (TMS)-induced long-interval intracortical inhibition (LICI) was previously reported to be normal in EPM1, short-interval intracortical inhibition (SICI) was reduced. We explored the association between these measures and the clinical and genetic features in a separate group of patients with EPM1. METHODS: TMS combined with electromyography was performed under neuronavigation. LICI was induced with an inter-stimulus interval (ISI) of 100 ms, and SICI with ISIs of 2 and 3 ms, and their means (mSICIs) were expressed as the ratio of conditioned to unconditioned stimuli. LICI and mSICI were compared between patients and controls. Nonparametric correlation was used to study the association between inhibition and parameters of clinical severity, including the Unified Myoclonus Rating Scale (UMRS); among patients with EPM1 due to biallelic expansion repeats, also the association with the number of repeats was assessed. RESULTS: The study protocol was completed in 19 patients (15 with biallelic expansion repeats and 4 compound heterozygotes), and 7 healthy, age- and sex-matched control participants. Compared to controls, patients demonstrated significantly less SICI (median mSICI ratio 1.18 vs 0.38; p < .001). Neither LICI nor SICI was associated with parameters of clinical severity. In participants with biallelic repeat expansions, the number of repeats in the more affected allele (greater repeat number [GRN]) correlated with LICI (rho = 0.872; p < .001) and SICI (rho = 0.689; p = .006). SIGNIFICANCE: Our results strengthen the finding of deranged γ-aminobutyric acid (GABA)ergic inhibition in EPM1. LICI and SICI may have use as markers of GABAergic impairment in future trials of disease-modifying treatment in this condition. Whether a higher number of expansion repeats leads to greater GABAergic impairment warrants further study.

Efficacy and tolerability in patients with chronic facial pain of two consecutive treatment periods of rTMS applied over the facial motor cortex, using protocols differing in stimulation frequency, duration, and train pattern.

OBJECTIVE: We conducted an open-label cross-over study assessing the global effect of two high-frequency protocols of electric-field navigated repetitive transcranial magnetic stimulation (rTMS) targeted to functional facial motor cortex and comparing their efficacy and tolerability in patients with chronic facial pain. Outcome predictors were also assessed. METHODS: We randomized twenty consecutive patients with chronic facial pain (post-traumatic trigeminal neuropathic pain, n=14; persistent idiopathic facial pain, n=4; secondary trigeminal neuralgia, n=2) to receive two distinct 5-day rTMS interventions (10Hz, 2400 pulses and 20Hz, 3600 pulses) separated by six weeks. The target area was assessed by mapping of lower face representation. The primary endpoint was the change in weekly mean of pain intensity (numeric rating scale, NRS) between the baseline and therapy week (1st week), and follow-up weeks (2nd and 3rd weeks) for each rTMS intervention. Response was defined using a combination scale including the patient's global impression of change and continuance with maintenance treatment. RESULTS: Overall, pain intensity NRS decreased from 7.4 at baseline to 5.9 ten weeks later, after the second rTMS intervention (p=0.009). The repetition of the treatment had a significant effect (F=4.983, p=0.043) indicating that the NRS scores are lower during the second four weeks period. Eight (40%) patients were responders, 4 (20%) exhibited a modest effect, 4 (20%) displayed no effect, and 4 (20%) experienced worsening of pain. High disability and high pain intensity (>7) predicted a better outcome (p=0.043 and p=0.045). Female gender, shorter duration of pain and low Beck Anxiety Inventory scores showed a trend towards a better outcome (p=0.052, 0.060 and 0.055, respectively). CONCLUSIONS: High-frequency rTMS targeted to face M1 alleviates treatment resistant chronic facial pain. Repeated treatment improves the analgesic effect. A protocol with higher frequency (above 10Hz), longer session duration (more than 20 minutes) and higher number of pulses (above 2400 pulses/session) did not improve the outcome. The results support early consideration of rTMS.

Wearable monitoring of positive and negative myoclonus in progressive myoclonic epilepsy type 1.

OBJECTIVE: To develop and test wearable monitoring of surface electromyography and motion for detection and quantification of positive and negative myoclonus in patients with progressive myoclonic epilepsy type 1 (EPM1). METHODS: Surface electromyography and three-dimensional acceleration were measured from 23 EPM1 patients from the biceps brachii (BB) of the dominant and the extensor digitorum communis (EDC) of the non-dominant arm for 48 hours. The patients self-reported the degree of myoclonus in a diary once an hour. Severity of myoclonus with action was evaluated by using video-recorded Unified Myoclonus Rating Scale (UMRS). Correlations of monitored parameters were quantified with the UMRS scores and the self-reported degrees of myoclonus. RESULTS: The monitoring-based myoclonus index correlated significantly (p < 0.001) with the UMRS scores (ρ = 0.883 for BB and ρ = 0.823 for EDC) and with the self-reported myoclonus degrees (ρ = 0.483 for BB and ρ = 0.443 for EDC). Ten patients were assessed as probably having negative myoclonus in UMRS, while our algorithm detected that in twelve patients. CONCLUSIONS: Wearable monitoring was able to detect both positive and negative myoclonus in EPM1 patients. SIGNIFICANCE: Our method is suitable for quantifying objective, real-life treatment effects at home and progression of myoclonus.

Cognitive functioning in progressive myoclonus epilepsy type 1 (Unverricht-Lundborg Disease, EPM1).

OBJECTIVE: The aim of this neuropsychological study of a large cohort of patients with progressive myoclonus epilepsy type 1 (Unverricht-Lundborg disease, EPM1) was to characterize the cognitive function of EPM1 patients and to explore the association between the disability caused by the disease and cognitive performance. METHOD: Sixty-eight genetically verified EPM1 patients homozygous for the expansion mutation in the CSTB gene (37 males and 31 females aged 35 ±â€¯11) participated in a neuropsychological assessment of intellectual ability, verbal memory, and executive and psychomotor function. The clinical evaluation comprised administering (and video-recording) the unified myoclonus rating scale (UMRS) to assess the severity of each patient's myoclonus. Forty-six healthy volunteers (19 males and 27 females aged 32 ±â€¯11) served as the control group for the neuropsychological tests. RESULTS: The cognitive performance of the EPM1 patient group was impaired. Verbal Intelligence Quotient (VIQ) was below the average range (VIQ < 85) in 49% of the patients; further, Performance Intelligence Quotient (PIQ) was below average in 75% of the patients. The patients performed worse than the controls in both immediate and delayed story recall (p = 0.001); however, in the word list learning task, the patients performed only slightly worse than the controls. The one-hour delayed recall of the learned words was similar in both groups, and the percentage of retained words and story contents did not differ between the patients and controls. The patients were impaired in all of the executive function tests as well as in the psychomotor speed tests (p < 0.001 for all). Also, the patients' simple psychomotor speed in the tapping task was significantly slowed in comparison to controls (p < 0.001). CONCLUSION: The patients had impaired performance in the majority of the cognitive measures; they showed the highest level of impairment in all the executive function tests and in the psychomotor speed tests. The measures of these cognitive domains are timed-therefore, it is clear that severe myoclonus limits patients' performance. In contrast, verbal memory, especially delayed recall, was the least affected cognitive domain.

Neural network analysis of nocturnal SpO2 signal enables easy screening of sleep apnea in patients with acute cerebrovascular disease.

Current diagnostics of sleep apnea relies on the time-consuming manual analysis of complex sleep registrations, which is impractical for routine screening in hospitalized patients with a high probability for sleep apnea, e.g. those experiencing acute stroke or transient ischemic attacks (TIA). To overcome this shortcoming, we aimed to develop a convolutional neural network (CNN) capable of estimating the severity of sleep apnea in acute stroke and TIA patients based solely on the nocturnal oxygen saturation (SpO2) signal. The CNN was trained with SpO2 signals derived from 1379 home sleep apnea tests (HSAT) of suspected sleep apnea patients and tested with SpO2 signals of 77 acute ischemic stroke or TIA patients. The CNN's performance was tested by comparing the estimated respiratory event index (REI) and oxygen desaturation index (ODI) with manually obtained values. Median estimation errors for REI and ODI in patients with stroke or TIA were 1.45 events/hour and 0.61 events/hour, respectively. Furthermore, based on estimated REI and ODI, 77.9% and 88.3% of these patients were classified into the correct sleep apnea severity categories. The sensitivity and specificity to identify sleep apnea (REI > 5 events/hour) were 91.8% and 78.6%, respectively. Moderate-to-severe sleep apnea was detected (REI > 15 events/hour) with sensitivity of 92.3% and specificity of 96.1%. The CNN analysis of the SpO2 signal has great potential as a simple screening tool for sleep apnea. This novel automatic method accurately detects sleep apnea in acute cerebrovascular disease patients and facilitates their referral for a differential diagnostic HSAT or polysomnography evaluation.

Severe Obstructive Sleep Apnea and Increased Cortical Amyloid-ß Deposition.

BACKGROUND: The suggested association between severe obstructive sleep apnea (OSA) and risk of Alzheimer's disease (AD) needs further study. Only few recent reports exist on associations between brain amyloid-ß (Aß) burden and severe OSA in middle-aged patients. OBJECTIVE: Examine the possible presence of cortical Aß accumulation in middle-aged patients with severe OSA. METHODS: We performed detailed multimodal neuroimaging in 19 cognitive intact patients (mean 44.2 years) with severe OSA (Apnea-Hypopnea Index >30 h-1). Known etiological factors for possible Aß accumulation were used as exclusion criteria. Aß uptake was studied with [11C]-PiB-PET, glucose metabolism with [18F]-FDG-PET, and structural imaging with 3.0T MRI. RESULTS: When analyzed individually, in [11C]-PiB-PET a substantial number (∼32%) of the patients exhibited statistically significant evidence of increased cortical Aß uptake based on elevated regional Z-score values, mostly seen bilaterally in the precuneus and posterior cingulum regions. Cortical glucose hypometabolism in [18F]-FDG-PET was seen in two patients. MRI did not show structural changes suggestive of AD-related pathology. CONCLUSION: Increased [11C]-PiB uptake was seen in middle-aged cognitively intact patients with severe OSA. These findings are similar to those described in cognitive unimpaired older OSA patients. The changes in cortical Aß uptake suggest that severe OSA itself may predispose to alterations related to AD already in middle-age. Aß clearance may be compromised without simultaneous evidence of metabolic or structural alterations. The results emphasize the importance of early diagnostics and proper treatment of severe OSA in cognitively intact middle-aged subjects, possibly diminishing the individual risk for later cognitive dysfunction.

Automatic assessment of the myoclonus severity from videos recorded according to standardized Unified Myoclonus Rating Scale protocol and using human pose and body movement analysis.

PURPOSE: Myoclonus in progressive myoclonus epilepsy type 1 (EPM1) patients shows marked variability, which presents a substantial challenge in devising treatment and conducting clinical trials. Consequently, fast and objective myoclonus quantification methods are needed. METHODS: Ten video-recorded unified myoclonus rating scale (UMRS) myoclonus with action tests were performed on EPM1 patients who were selected for the development and testing of the automatic myoclonus quantification method. Human pose and body movement analyses of the videos were used to identify body keypoints and further analyze movement smoothness and speed. The automatic myoclonus rating scale (ARMS) was developed. It included the jerk count during movement score and the log dimensionless jerk (LDLJ) score to evaluate changes in the smoothness of movement. RESULTS: The scores obtained with the automatic analyses showed moderate to strong significant correlation with the UMRS myoclonus with action scores. The jerk count of the primary keypoints and the LDLJ scores were effective in the evaluation of the myoclonic jerks during hand movements. They also correlated moderately to strongly with the total UMRS test panel scores (r2 = 0,77, P = 0,009 for the jerk count score and r2 = 0,88, P = 0,001 for the LDLJ score). The automatic analyses was weaker in quantification of the neck, trunk, and leg myoclonus. CONCLUSION: Automatic quantification of myoclonic jerks using human pose and body movement analysis of patients' videos is feasible and was found to be quite consistent with the accepted clinical gold standard quantification method. Based on the results of this study, the automatic analytical method should be further developed and validated to improve myoclonus severity follow-up for EPM1 patients.

Acute stroke and TIA patients have specific polygraphic features of obstructive sleep apnea.

PURPOSE: Obstructive sleep apnea (OSA) is associated with increased risk for stroke, which is known to further impair respiratory functions. However, it is unknown whether the type and severity of respiratory events are linked to stroke or transient ischemic attack (TIA). Thus, we investigate whether the characteristics of individual respiratory events differ between patients experiencing TIA or acute ischemic stroke and matched patients with clinically suspected sleep-disordered breathing. METHODS: Polygraphic data of 77 in-patients with acute ischemic stroke (n = 49) or TIA (n = 28) were compared to age, gender, and BMI-matched patients with suspected sleep-disordered breathing and no cerebrovascular disease. Along with conventional diagnostic parameters (e.g., apnea-hypopnea index), durations and severities of individual apneas, hypopneas and desaturations were compared between the groups separately for ischemic stroke and TIA patients. RESULTS: Stroke and TIA patients had significantly shorter apneas and hypopneas (p < 0.001) compared to matched reference patients. Furthermore, stroke patients had more central apnea events (p = 0.007) and a trend for higher apnea/hypopnea number ratios (p = 0.091). The prevalence of OSA (apnea-hypopnea index ≥ 5) was 90% in acute stroke patients and 79% in transient ischemic attack patients. CONCLUSION: Stroke patients had different characteristics of respiratory events, i.e., their polygraphic phenotype of OSA differs compared to matched reference patients. The observed differences in polygraphic features might indicate that stroke and TIA patients suffer from OSA phenotype recently associated with increased cardiovascular mortality. Therefore, optimal diagnostics and treatment require routine OSA screening in patients with acute cerebrovascular disease, even without previous suspicion of OSA.

Facial nerve function and hearing after microsurgical removal of sporadic vestibular schwannomas in a population-based cohort.

BACKGROUND: Vestibular schwannoma (VS) is a benign tumor originating from the vestibulocochlear nerve. The optimal treatment strategy is debated, since surgery may result in iatrogenic facial nerve injury. We report the results of VS surgery in a population-based unselected cohort in a center with access to Cyber Knife (CK) radiosurgery. METHODS: We reviewed 117 consecutive operations and found 95 patients who had their primary operation due to vestibular schwannoma between 2001 and 2017. Facial nerve function was evaluated with the House-Brackmann (HB) scale and hearing with the EU classification. RESULTS: The population consisted of 37 males and 58 females with a median age of 54 years (range 19-79). One year after surgery 67% of patients had a good outcome (HB 1-2). The rate of good outcome was 90% if no facial nerve damage was observed during intraoperative monitoring, the size of the tumor was under 30 mm and no hydrocephalus was present. During the study period, the treatment strategy changed from total to near-total resection after the introduction of CK radiosurgery, which could be used as a second-line treatment in case of residual tumor regrowth. This resulted in an improvement of outcomes (0% HB 5-6) despite the larger tumor sizes (25 ± 14 mm vs. 31 ± 9 mm, p < 0.05). Hearing preservation rates did not increase. CONCLUSIONS: Near-total resection and subsequent CK radiosurgery in case of residual tumor regrowth during follow-up seems to provide a good outcome of facial nerve function even in large VSs.

Intra-night variation in apnea-hypopnea index affects diagnostics and prognostics of obstructive sleep apnea.

BACKGROUND: Diagnostics of obstructive sleep apnea (OSA) is based on apnea-hypopnea index (AHI) determined as full-night average of occurred events. We investigate our hypothesis that intra-night variation in the frequency of obstructive events affects diagnostics and prognostics of OSA and should therefore be considered in clinical practice. METHODS: Polygraphic recordings of 1989 patients (mean follow-up 18.3 years) with suspected OSA were analyzed. Number and severity of individual obstructive events were calculated hourly for the first 6 h of sleep. OSA severity was determined based on the full-night AHI and AHI for the 2 h when the obstructive event frequency was highest (AHI2h). Hazard ratios for all-cause, cardiovascular, and non-cardiovascular mortalities were calculated for different OSA severity categories based on the full-night AHI and AHI2h. RESULTS: Frequency and duration of obstructive events varied hour-by-hour increasing towards morning. Using AHI2h led to a statistically significant rearrangement of patients between the OSA severity categories. The use of AHI2h for severity classification showed clearer relationship between the OSA severity and mortality than the full-night AHI. CONCLUSIONS: Currently, the intra-night variation in frequency and severity of obstructive events is completely ignored by conventional, full-night AHI and considering this information could improve the diagnostics of OSA.

Polysomnographic scoring of sleep bruxism events is accurate even in the absence of video recording but unreliable with EMG-only setups.

PURPOSE: To determine the accuracy of scoring masticatory muscle activity (MMA) events in seven different polysomnography (PSG) setups. METHODS: Nineteen volunteers (13 females, 6 males, age 31.1 ± 12.9 years, 12 self-proclaimed bruxers) attended one-night PSG recording, supplemented with audio, video, and a separate frontal electroencephalography electrode set (FES). The same examiner scored the MMA events with seven different setups, with varying number of channels available: (1) one, (2) two, and (3) four EMG channels, (4) PSG without audio or video (PSG-N), (5) home PSG with FES and audio (FES-A), (6) PSG with audio (PSG-A), and (7) PSG with audio and video (PSG-AV). A subset (n = 10) of recordings was scored twice to determine intra-scorer reliability. MMA indices and accuracy of scoring the events in different setups were compared against PSG-AV. RESULTS: The intra-class correlation coefficient (ICC) between PSG-AV and PSG-A was high (0.940, p < 0.001) as well as for FES-A (0.927, p < 0.001), whereas for PSG-N, it was lower (0.835, p < 0.001); for setups with only EMG channels, coefficients were very low (ICC < 0.100 for all). Intra-examiner reliability was high (ICC > 0.939 for all setups), with the exception of PSG-N (ICC = 0.764, p = 0.002). When comparing against the MMA events scored in PSG-AV, the sensitivity of MMA event recognition for PSG-A was 78.5% and specificity 95.5%, which were substantially higher than sensitivity (52.0%) and specificity (87.2%) of PSG-N. CONCLUSIONS: MMA event scoring accuracy with PSG-A or FES-A is almost comparable to PSG-AV. Since precise event recognition is essential for accurate MMA scoring, it is evident that one cannot rely exclusively on EMG.

Increase in Body Mass Index Decreases Duration of Apneas and Hypopneas in Obstructive Sleep Apnea.

BACKGROUND: Obesity is one of the most prominent risk factors for obstructive sleep apnea (OSA). Weight loss decreases the number of shorter respiratory events (<40 s), whereas the number of longer events remains almost unchanged. However, it is unknown how body mass index (BMI) affects individual obstruction event severity within OSA severity categories when age, sex, smoking, daytime sleepiness, snoring, hypertension, heart failure, and sleeping posture are considered. Therefore, we investigated whether individual obstruction event severity varies with BMI within the OSA severity categories when considering the most important confounding factors. METHODS: Polygraphic recordings of 723 subjects without CPAP treatment and with an apnea-hypopnea index (AHI) of ≥5 events/hour were reanalyzed retrospectively. The effect of BMI on the severities of OSA and individual obstruction events was evaluated in general, within OSA severity categories, and between different BMI groups (ie, BMI < 25; 25 ≤ BMI < 30; 30 ≤ BMI < 35; 35 ≤ BMI < 40; and BMI ≥ 40 kg/m2). RESULTS: AHI increased in mild and severe (ß ≥ 0.10, P < .001) OSA categories, with increasing BMI. However, the proportion of apneas from all respiratory events decreased (ß = -0.55, P = .068) with increasing BMI in all the OSA categories. An increase in BMI led to a decrease in the median duration of individual apneas, hypopneas, and desaturations in all OSA categories, whereas desaturation depth increased statistically significantly in the severe category (ß = 0.20, P < .001). CONCLUSIONS: Because BMI is related to the duration of individual obstruction events, its effect on OSA severity is more complex than its effect on AHI would implicate. Therefore, overall severity of OSA may not be the same for non-obese patient and obese patient who have similar AHI. Thus, these patient-specific characteristics of individual breathing cessations should be considered when estimating the severity of disease and risk of related adverse health effects.

Required CPAP usage time to normalize AHI in obstructive sleep apnea patients: a simulation study.

OBJECTIVE: Adherence to continuous positive airway pressure (CPAP) is often limited. The aim of the current work was to create a simulation tool to enable determination of the individual CPAP therapy time required to normalize apnea-hypopnea index (AHI) (<5 events h-1) in a cohort of OSA patients. APPROACH: Polygraphic studies of 1989 consecutive patients were analyzed. CPAP therapy was simulated in 5 min intervals starting from the beginning of the night and continuing until the end. In simulation, events inside the simulated CPAP therapy periods were considered to be prevented. The cutoff points where AHI reached a normal level of < 5 events h-1 were determined for mild, moderate and severe OSA categories. MAIN RESULTS: The median values of the required simulated CPAP usage times to normalize the AHI values were 3.3 h, 5.6 h and 6.5 h in the mild, moderate and severe OSA categories, respectively. However, there were great differences between individuals in the CPAP usage times required to normalize AHI. SIGNIFICANCE: An arbitrary threshold for CPAP adherence (e.g. 4 h) leaves many OSA patients with a significant residual AHI, which could explain why some clinical trials fail to show significant benefits. Thresholds for adherence should be adjusted based on the patient-specific distribution of obstruction events during the night.

Bayesian Network Model to Evaluate the Effectiveness of Continuous Positive Airway Pressure Treatment of Sleep Apnea.

OBJECTIVES: The association between obstructive sleep apnea (OSA) and mortality or serious cardiovascular events over a long period of time is not clearly understood. The aim of this observational study was to estimate the clinical effectiveness of continuous positive airway pressure (CPAP) treatment on an outcome variable combining mortality, acute myocardial infarction (AMI), and cerebrovascular insult (CVI) during a follow-up period of 15.5 years (186 ± 58 months). METHODS: The data set consisted of 978 patients with an apnea-hypopnea index (AHI) ≥5.0. One-third had used CPAP treatment. For the first time, a data-driven causal Bayesian network (DDBN) and a hypothesis-driven causal Bayesian network (HDBN) were used to investigate the effectiveness of CPAP. RESULTS: In the DDBN, coronary heart disease (CHD), congestive heart failure (CHF), and diuretic use were directly associated with the outcome variable. Sleep apnea parameters and CPAP treatment had no direct association with the outcome variable. In the HDBN, CPAP treatment showed an average improvement of 5.3 percentage points in the outcome. The greatest improvement was seen in patients aged ≤55 years. The effect of CPAP treatment was weaker in older patients (>55 years) and in patients with CHD. In CHF patients, CPAP treatment was associated with an increased risk of mortality, AMI, or CVI. CONCLUSIONS: The effectiveness of CPAP is modest in younger patients. Long-term effectiveness is limited in older patients and in patients with heart disease (CHD or CHF).

Bifrontal active and sham rTMS in treatment-resistant unipolar major depression.

BACKGROUND AND AIM: Prevention of the recurrence of major depression and its residual symptoms requires effective treatment. Our aim was to study the effects of bifrontal active rTMS controlled by sham rTMS in treatment-resistant unipolar major depressive disorder (MDD). METHODS: Thirty-seven patients with treatment-resistant MDD were randomized into two groups. One group received a total of 30 sessions of active bifrontal rTMS (10 Hz rTMS on left dorsolateral prefrontal cortex (DLPFC) and 1 Hz rTMS on right DLPFC) and the other group received bilateral sham rTMS on five days a week for six weeks. RESULTS: Depressive symptoms significantly improved in both the groups, but without a significant group difference. Furthermore, patients with psychotic depression improved similarly to those with moderate or severe depression. CONCLUSIONS: The results of present study indicate a large sham effect of stimulation treatment. The intensive structured treatment protocol may explain the positive outcome in both the groups. It is important to recognize, appreciate, and utilize placebo effects as a significant means of rehabilitation in psychiatric care.

Differences in arousal probability and duration after apnea and hypopnea events in adult obstructive sleep apnea patients.

OBJECTIVE: In obstructive sleep apnea (OSA), breathing cessations are often followed by arousals, leading to sleep fragmentation and thus impaired sleep quality. Arousals and fragmented sleep are also related to detrimental cardiovascular events. The key index for OSA diagnosis (i.e. the apnea-hypopnea index) attributes equal diagnostic value to apneas and hypopneas, despite the fact that the associated arousals and desaturations may be very different. Thus, considering the severity of the consequences of apneas and hypopneas could enhance the estimation of OSA severity. In this study, we investigate whether the probability and duration of apnea- and hypopnea-related arousals differ and whether the differences in desaturation severity following apneas and hypopneas are dependent on sleep stage. APPROACH: Polysomnographic recordings of 348 consecutive OSA patients were included for analysis. The severity of arousals and desaturations associated with hypopneas within different sleep stages was compared to that of arousals and desaturations associated with apneas. In addition, the probability of arousals related to apneas and hypopneas was evaluated within OSA severity categories. MAIN RESULTS: Apneas caused arousals less frequently than hypopneas in N1, N2, and N3 sleep in all OSA severity categories. However, the arousals caused by apneas were longer (p < 0.001) and the desaturations related to apneas were more severe (p < 0.001) than those related to hypopneas in N1, N2, and rapid eye movement sleep even after adjustment for respiratory event durations. SIGNIFICANCE: Desaturations and arousals related to apneas are more severe than those related to hypopneas. Therefore, apneas followed by arousal or desaturation should have a different diagnostic value than hypopneas when assessing OSA severity and related risk for cardiovascular consequences.