Sex-specific patterns of discomfort in patients with restless legs syndrome.

STUDY OBJECTIVES: Sex differences in the prevalence of restless legs syndrome (RLS) have been reported, with a higher prevalence in women than in men. However, sex differences in clinical presentation remain unclear. We aimed to investigate the phenotypic differences in patients with RLS between sexes by comparing clinical presentations, iron status, polysomnographic parameters, and treatment. METHODS: We retrospectively evaluated 614 patients (225 men, 389 women) diagnosed with RLS. To enhance the robustness of the study, an age-matched control group of 179 men and 286 women without sleep disorders was also included. Information on demographics and sleep-related questionnaires were collected. Iron status was evaluated using blood samples, and polysomnography was performed to evaluate periodic leg movements and comorbid sleep disorders. RESULTS: Our analysis revealed no sex difference in the severity of RLS but a difference in the pattern of symptoms. Women had more frequent symptoms of pain and awakening during sleep, while men had more common motor symptoms (both self-reported symptoms and periodic leg movement on polysomnography). Women with RLS also had lower iron parameters and received more frequent iron supplementation therapy than men. In contrast to women with RLS, who presented higher sleep disturbances and depressive mood, men with RLS had a higher risk of comorbidities such as hypertension and cardiovascular disease. These sex differences were notably more pronounced than in the control group. CONCLUSIONS: This study suggests that sex differences exist in RLS phenotypes, and clinicians should consider these differences for treatment. CITATION: Kim J, Kim JR, Park HR, Joo EY. Sex-specific patterns of discomfort in patients with restless legs syndrome. J Clin Sleep Med. 2024;20(2):253-259.

Defining the optimal target for anterior thalamic deep brain stimulation in patients with drug-refractory epilepsy.

OBJECTIVE: The anterior thalamic nucleus (ATN) is a common target for deep brain stimulation (DBS) for the treatment of drug-refractory epilepsy. However, no atlas-based optimal DBS (active contacts) target within the ATN has been definitively identified. The object of this retrospective study was to analyze the relationship between the active contact location and seizure reduction to establish an atlas-based optimal target for ATN DBS. METHODS: From among 25 patients who had undergone ATN DBS surgery for drug-resistant epilepsy between 2016 and 2018, those who had follow-up evaluations for more than 1 year were eligible for study inclusion. After an initial stimulation period of 6 months, patients were classified as responsive (≥ 50% median decrease in seizure frequency) or nonresponsive (< 50% median decrease in seizure frequency) to treatment. Stimulation parameters and/or active contact positions were adjusted in nonresponsive patients, and their responsiveness was monitored for at least 1 year. Postoperative CT scans were coregistered nonlinearly with preoperative MR images to determine the center coordinate and atlas-based anatomical localizations of all active contacts in the Montreal Neurological Institute (MNI) 152 space. RESULTS: Nineteen patients with drug-resistant epilepsy were followed up for at least a year following bilateral DBS electrode implantation targeting the ATN. Active contacts located more adjacent to the center of gravity of the anterior half of the ATN volume, defined as the anterior center (AC), were associated with greater seizure reduction than those not in this location. Intriguingly, the initially nonresponsive patients could end up with much improved seizure reduction by adjusting the active contacts closer to the AC at the final postoperative follow-up. CONCLUSIONS: Patients with stimulation targeting the AC may have a favorable seizure reduction. Moreover, the authors were able to obtain additional good outcomes after electrode repositioning in the initially nonresponsive patients. Purposeful and strategic trajectory planning to target this optimal region may predict favorable outcomes of ATN DBS.

Development and evaluation of myofunctional therapy support program (MTSP) based on self-efficacy theory for patients with obstructive sleep apnea.

PURPOSE: The aim of this study is to determine the impact of myofunctional therapy support program (MTSP) based on self-efficacy theory compared to no support during myofunctional therapy (MT) in patients with obstructive sleep apnea (OSA). METHODS: Thirty-one patients with OSA were randomized into two groups: 12 weeks of treatment with the MTSP developed in this study (experimental group) and one education session of MT (control group). Patients were evaluated at the beginning and the end of the study using questionnaires (self-efficacy scale, Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, snoring intensity and frequency, dry mouth) and polysomnography. RESULTS: The control (n = 15) and experimental (n = 16) groups had similar results for all variables at study entry. The control group showed no significant change in any variables during the study period. In contrast, the experimental group showed a significant increase in self-efficacy 61.38 ± 9.50 to 65.56 ± 10.89 (p = 0.020) and a significant decrease in apnea-hypopnea index (AHI) 19.51 ± 11.41 to 14.11 ± 9.13 (p = 0.039), daytime sleepiness 9.88 ± 3.84 to 7.56 ± 3.42 (p = 0.028), snoring intensity 5.57 ± 3.13 to 4.44 ± 2.68 (p = 0.008), and dry mouth 6.44 ± 3.14 to 3.63 ± 2.33 (p = 0.005), compared to the baseline. No significant change in lowest SaO2 (p = 0.969), sleep quality (p = 0.307), and snoring frequency (p = 0.321) during the study period. CONCLUSIONS: The intensive and interactive intervention of MTSP improved the self-efficacy of OSA patients, and consequently, resulted in sign and symptom relief, such as AHI, daytime sleepiness, snoring and dry mouth. The MTSP was dedicated to the nurse practitioner to improve the way to dispense the MT. This research has implications for the successful treatment of OSA.

The Role of Anterior Thalamic Deep Brain Stimulation as an Alternative Therapy in Patients with Previously Failed Vagus Nerve Stimulation for Refractory Epilepsy.

Deep brain stimulation (DBS) has provided new treatment options for refractory epilepsy; however, treatment outcomes of DBS in refractory epilepsy patients previously treated with vagus nerve stimulation (VNS) have not been clarified. Herein, treatment outcomes of DBS of the anterior nucleus of the thalamus (ANT-DBS) in patients who had previously experienced VNS failure are reported. Seven patients who had previously experienced VNS failure underwent ANT-DBS device implantation. VNS was turned off before DBS device implantation. Monthly seizure counts starting from baseline to 12-18 months after DBS were analyzed. Five (71.3%) of the 7 patients experienced a >50% reduction of seizure counts after DBS; 1 responder reached a seizure-free status after DBS therapy. Of the 2 nonresponders, 1 subject showed improvement in seizure strength and duration, which lessened the impact of the seizures on the patient's quality of life. This is the first study in which favorable outcomes of ANT-DBS surgery were observed in individual patients with refractory epilepsy who had not responded to prior VNS. Further studies with a larger number of subjects and longer follow-up period are needed to confirm the feasibility of ANT-DBS in patients who have previously experienced VNS failure.

White matter alterations in narcolepsy patients with cataplexy: tract-based spatial statistics.

Functional imaging studies and voxel-based morphometry analysis of brain magnetic resonance imaging showed abnormalities in the hypothalamus-thalamus-orbitofrontal pathway, demonstrating altered hypocretin pathway in narcolepsy. Those distinct morphometric changes account for problems in wake-sleep control, attention and memory. It also raised the necessity to evaluate white matter changes. To investigate brain white matter alterations in drug-naïve narcolepsy patients with cataplexy and to explore relationships between white matter changes and patient clinical characteristics, drug-naïve narcolepsy patients with cataplexy (n = 22) and healthy age- and gender-matched controls (n = 26) were studied. Fractional anisotropy and mean diffusivity images were obtained from whole-brain diffusion tensor imaging, and tract-based spatial statistics were used to localize white matter abnormalities. Compared with controls, patients showed significant decreases in fractional anisotropy of white matter of the bilateral anterior cingulate, fronto-orbital area, frontal lobe, anterior limb of the internal capsule and corpus callosum, as well as the left anterior and medial thalamus. Patients and controls showed no differences in mean diffusivity. Among patients, mean diffusivity values of white matter in the bilateral superior frontal gyri, bilateral fronto-orbital gyri and right superior parietal gyrus were positively correlated with depressive mood. This tract-based spatial statistics study demonstrated that drug-naïve patients with narcolepsy had reduced fractional anisotropy of white matter in multiple brain areas and significant relationship between increased mean diffusivity of white matter in frontal/cingulate and depression. It suggests the widespread disruption of white matter integrity and prevalent brain degeneration of frontal lobes according to a depressive symptom in narcolepsy.

Cerebral blood flow changes in man by wake-promoting drug, modafinil: a randomized double blind study.

To investigate the effects of a wake-promoting drug, modafinil on regional cerebral blood flow (rCBF) in healthy volunteers, we performed (99m)Tc-ethylcysteinate dimer single photon emission computed tomography (SPECT) before and after modafinil or placebo administration. Twenty-one healthy subjects received single doses of 400 mg modafinil or placebo in a double blind randomized crossover study design. Administrations of modafinil or placebo in a subject were separated by a 2-week washout. Brain SPECT was performed twice before and 3 h after modafinil or placebo administration. For statistical parametric mapping analysis, all SPECT images were spatially normalized to the standard SPECT template and then smoothed using a 12-mm full width at half-maximum Gaussian kernel. The paired t-test was used to compare pre- versus post-modafinil and pre- versus post-placebo SPECT images. Differences in rCBF between post-modafinil and post-placebo conditions were also tested. Modafinil decreased Epworth and Stanford sleepiness scales whereas placebo did not. The post-modafinil condition was associated with increased rCBF in bilateral thalami and dorsal pons, whereas the post-placebo condition showed increased rCBF in a smaller area of the dorsal pons when compared with the drug naïve baseline condition. Compared with the post-placebo condition, the post-modafinil condition showed higher rCBF in bilateral frontopolar, orbitofrontal, superior frontal, middle frontal gyri, short insular gyri, left cingulate gyrus, left middle/inferior temporal gyri, left parahippocampal gyrus, and left pons. In healthy volunteers, modafinil increased wakefulness and rCBF in the arousal-related systems and in brain areas related to emotion and executive function.

Episodic diencephalic hypoperfusion in Kleine-Levin syndrome.

A 22 year-old woman suffered from recurrent episodes of hypersomnia, apathy, and hyperphagia. The symptoms occurred 3 to 4 times per year, and each attack lasted 2 to 3 weeks. 99mTc-ethylcysteinate dimer brain single photon emission computed tomography (SPECT) was performed during symptomatic and asymptomatic periods. To localize brain regions with perfusion changes during symptomatic period, asymptomatic SPECT was subtracted from symptomatic SPECT. The subtracted SPECT showed significant hypoperfusion in the left hypothalamus, bilateral thalami, basal ganglia, bilateral medial and dorsolateral frontal regions, and left temporal lobe during the symptomatic period. These cerebral hypoperfusion areas support the diencephalic hypothesis and clinical symptoms of Kleine-Levin syndrome.

Cerebral perfusion abnormality in narcolepsy with cataplexy.

To investigate abnormal cerebral perfusion in narcoleptics with cataplexy, 25 narcoleptics with cataplexy and 25 normal controls were enrolled in this study. Cerebral perfusion was measured by brain single photon emission computed tomography (SPECT) using 99mTc-ethylcysteinate dimer. Patients and normal controls had not received any medication prior to the SPECT scan. Differences in cerebral perfusion between narcoleptics and normal controls were subjected to statistical parametric mapping (SPM) analysis. Overnight polysomnography and multiple sleep latency test (MSLT) were performed in all patients. Brain SPECT was carried out on all patients and normal controls during the waking state. Clinical symptoms and MSLT results of all patients are in accord with the International Classification of Sleep Disorders criteria for narcolepsy. MSLT showed a short mean sleep latency (1.69 +/- 1.0 min) and 2-5 sleep onset REM periods in individual patient. SPM analysis of brain SPECT showed hypoperfusion of the bilateral anterior hypothalami, caudate nuclei, and pulvinar nuclei of thalami, parts of the dorsolateral/ventromedial prefrontal cortices, parahippocampal gyri, and cingulate gyri in narcoleptics [P < 0.05 by Student's t test with false discovery rate (FDR) correction]. Significant hypoperfusion in the white matter of frontal and parietal lobes was also noted in narcoleptics. This study shows reduced cerebral perfusion in subcortical structures and cortical areas in narcoleptics. The distribution of abnormal cerebral perfusion is concordant with the pathway of the cerebral hypocretin system and may explain the characteristic features of narcolepsy, i.e., cataplexy, emotional lability, and attention deficit.

Cerebral perfusion changes in mesial temporal lobe epilepsy: SPM analysis of ictal and interictal SPECT.

We examined cerebral perfusion changes in mesial temporal lobe epilepsy (mTLE) by the statistical parametric mapping of brain single photon emission computed tomography (SPECT) images of 38 mTLE patients and 19 normal controls. Ictal and interictal SPECTs were compared with control SPECTs by independent t test, and ictal and interictal SPECTs by paired t test. We evaluated the number of heterotopic neurons in temporal lobe white matter, white matter changes of the anterior temporal lobe (WCAT) and ictal hyperperfusion of the temporal stem (IHTS). Left mTLE showed interictal hypoperfusion in the ipsilateral hippocampus, bilateral thalami, and paracentral lobules. Right mTLE showed hypoperfusion in bilateral hippocampi, contralateral insula, bilateral thalami, and paracentral lobules. Both mTLEs showed ictal hyperperfusion in bilateral temporal lobes with ipsilateral predominance, and in the anterior frontal white matter bilaterally. By paired t test, ictal hyperperfusion was found in the ipsilateral temporal lobe, temporal stem, hippocampus, thalamus, putamen, insula, and bilateral precentral gyri, whereas ictal hypoperfusion was found in bilateral frontal poles and middle frontal gyri. Fifteen patients showed WCAT and 19 showed IHTS, a weak correlation was observed between WCAT and IHTS (r = 0.377, P = 0.02). WCAT was found to correlate with an early seizure onset age. In 35 patients, heterotopic neurons were found in the white matter of the resected temporal lobe, but the number of heterotopic neurons did not correlate with WCAT or IHTS. In summary, the cerebral perfusion patterns of mTLE suggest interictal hypofunction and ictal activation of the cortico-thalamo-hippocampal-insular network and ictal hypoperfusion of the anterior frontal cortex.

Glucose hypometabolism of hypothalamus and thalamus in narcolepsy.

It has been hypothesized that hypothalamus is involved in narcolepsy. The relative difference between cerebral glucose metabolism of 24 narcoleptic patients and 24 normal controls was studied using 18F-fluorodeoxy glucose positron emission tomography. Patients with narcolepsy showed significantly reduced cerebral glucose metabolism in bilateral rectal and subcallosal gyri, the medial convexity of right superior frontal gyrus, bilateral precuneus, right inferior parietal lobule, and in left supramarginal gyrus (uncorrected p < 0.001). Bilateral posterior hypothalami and mediodorsal thalamic nuclei showed hypometabolism with significance at the level of corrected p < 0.05, with small volume correction. This study showed cerebral glucose hypometabolism of the hypothalamus-thalamus-orbitofrontal pathways in the narcoleptic brain.

Regional cerebral hyperperfusion with ictal dystonic posturing: ictal-interictal SPECT subtraction.

PURPOSE: Ictal-interictal single-photon emission computed tomography (SPECT) subtraction was performed to find brain structures related to ictal dystonic posturing (DP) in patients with temporal lobe epilepsy (TLE). METHODS: Thirty-two patients with mesial TLE who had ictal and interictal SPECTs were included. They were divided into two groups; DP group with ictal dystonia during ictal SPECT (n = 15) and Non-DP group without ictal DP (n = 17). Ictal-interictal SPECT subtraction was performed, and then subtracted SPECT was coregistered with brain spoiled gradient recalled (SPGR) magnetic resonance imaging (MRI). The ictal hyperperfusion on subtracted SPECT was analyzed in basal ganglia, frontal cortex, thalamus, temporal lobe, and insular cortex. RESULTS: The incidences of ictal hyperperfusion on brain regions in DP versus Non-DP groups were 80.0% (12 of 15 patients) versus none (0 of 17), p = 0.001, chi2, in caudate nucleus; 93.3% (14 of 15) versus 47.0% (eight of 17), p = 0.005, in putamen; and 80.0% (12 of 15) versus 41.2% (seven of 17), p = 0.026, in thalamus. No significant difference of ictal hyperperfusion was found in globus pallidus, temporal lobes, insular and frontal cortices between DP and Non-DP groups. DP patients showed an earlier age at seizure onset [8.6 years (DP) vs. 15.7 years (Non-DP) (p = 0.015)] and a longer duration of seizure history [19.0 years (DP) vs. 11.9 years (Non-DP) (p = 0.015)]. CONCLUSIONS: Caudate nucleus, putamen, and thalamus were significantly related to the ictal DP during TLE seizures. Our study showed first an active involvement of the caudate nucleus in the generation of ictal DP.