Murat Aksu

Periodic limb movements in sleep: State-dependent excitability of the spinal flexor reflex

Objective: To test the hypothesis that periodic limb movements (PLMs) are related to spinal flexor reflexes (FRs), the authors compared the state-dependent changes in FR excitability in 10 patients with restless legs syndrome (RLS) and PLMs with those from matched controls. Background: PLM is a disorder of motor control during sleep, frequently occurring in RLS. Clinically, PLMs resemble spinal FRs. Methods: FRs were obtained by electrically stimulating the medial plantar nerve and recording from antagonist leg and thigh muscles bilaterally. Results: Compared with controls, patients had significantly increased spinal cord excitability, as indicated by lower threshold and greater spatial spread of the FR, which was more prominent during sleep. Multiple late responses were seen during sleep in all patients and in some controls at higher threshold. The most prominent of these responses had a very long duration and a latency range of 250 to 800 msec, and because of its close temporal relationship to the FR stimulus, the authors considered it was a late, high-threshold component of the FR (FR3). The authors also found a similarity between the pattern of muscle recruitment and spatial spread of late components of the FR and those of spontaneous PLMs. Conclusions: The results support the hypothesis that PLMs in RLS and FRs share common spinal mechanisms and suggest that PLMs may result from enhanced spinal cord excitability in RLS patients. Because dopaminergic mechanisms are involved in spinal FR control, the results are consistent with the current view that RLS is a disorder of dopaminergic function.

Involvement of Insula and Cingulate Cortices in Control and Suppression of Natural Urges

The physiology of control and suppression of natural urges is not well understood. We used [(15)O]H(2)O positron-emission tomography imaging to identify neural circuits involved in suppression of spontaneous blinking as a model of normal urges. Suppression of blinking was associated with prominent activation of bilateral insular-claustrum regions, right more than left; activation was also found in bilateral anterior cingulate cortex (ACC), supplementary motor areas, and the face area of the primary motor cortex bilaterally. These results suggest a central role for the insula possibly together with ACC in suppression of blinking.

Ocular blood flow in patients with obstructive sleep apnea syndrome (OSAS).

BackgroundSleep-related disorders are among the important risk factors for neurovascular diseases. Obstructive sleep apnea syndrome (OSAS) is characterized by snoring, excessive daytime sleepiness, and insomnia. Our aim was to investigate the presence of glaucoma in patients with OSAS and to reveal vascular pathology related to the pathogenesis of glaucoma in those patients.Patients and methodsThe study included 31 patients with OSAS and 25 control subjects. Orbital Doppler ultrasonography was used to determine the resistivity index (RI) in the ophthalmic artery and central retinal artery. All patients and controls underwent perimetric examination.ResultsThe prevalence of glaucoma in the group of patients with OSAS was 12.9% (4/31); all of these 4 patients with glaucoma were in the “severe” OSAS group. No statistically significant difference was found between ophthalmic artery resistivity index (OARI), central retinal artery resistivity index (CRARI), and intraocular pressure (IOP) between patients and controls (p > 0.05). There was a positive correlation between OARI and mean defect (MD), CRARI and MD, and CRARI and loss variance (LV) values (p < 0.05). There was also a positive correlation between IOP and the apnea-hypopnea index (AHI) (p = 0.001).ConclusionsIn patients with OSAS, a high prevalence was found and it is interesting to note that all of the four glaucoma patients were in the severe OSAS group. The positive correlation observed between IOP and AHI suggests that increased IOP values may reflect the severity of OSAS. The positive correlation between OARI and MD and also between CRARI and MD as well as LV suggests that visual field defects may be due to optic nerve perfusion defects and these field defects also increase as the RI increases.

State dependent excitability changes of spinal flexor reflex in patients with restless legs syndrome secondary to chronic renal failure

OBJECTIVE Periodic limb movement in sleep (PLMS) is a common dysfunction of motor control during sleep, occurring either in isolation or associated with a variety of neurological disorders including restless legs syndrome (RLS). Although the PLMS generators have not been established, their occurrence in patients with spinal cord injury and their clinical resemblance to the spinal cord flexor withdrawal reflex (FR) suggest that PLMS may originate in the circuitry that mediates the FR. The significantly increased spinal cord excitability noted in primary RLS/PLMS patients may play an important role in the pathophysiology of primary RLS. The aim of this study is to establish whether the enhanced spinal cord excitability, which is represented by a lower threshold and/or greater spatial spread of the FR, is also true for the RLS/PLMS patients whose RLS is secondary to chronic renal failure (CRF). METHODS Twenty patients with RLS/PLMS secondary to CRF have been compared with matched controls according to the state dependent changes in FR excitability. All patients met the diagnostic criteria for RLS and PLMS. They had CRF for 5.2+/-3.5 years, and were under the hemodialysis treatment. Twenty healthy, age and sex matched subjects were tested as controls. The electrophysiological testing of the FR was performed during wakefulness (9:30-10:30 p.m.) and sleep (beginning of stage II, the first sleep cycle). RESULTS A significant increase in FR excitability was found in RLS/PLMS patients with CRF. This abnormality was prominent during sleep, which was also true for the primary RLS. CONCLUSIONS Our results suggest that similar neuronal pathways are involved in primary and secondary RLS/PLMS patients. Our results also support that RLS/PLMS and FR share a common spinal mechanism.

Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial

BACKGROUND Histaminergic neurons are crucial to maintain wakefulness, but their role in cataplexy is unknown. We assessed the safety and efficacy of pitolisant, a histamine H3 receptor inverse agonist, for treatment of cataplexy in patients with narcolepsy. METHODS For this randomised, double-blind, placebo-controlled trial we recruited patients with narcolepsy from 16 sleep centres in nine countries (Bulgaria, Czech Republic, Hungary, Macedonia, Poland, Russia, Serbia, Turkey, and Ukraine). Patients were eligible if they were aged 18 years or older, diagnosed with narcolepsy with cataplexy according to version two of the International Classification of Sleep Disorders criteria, experienced at least three cataplexies per week, and had excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score ≥12). We used a computer-generated sequence via an interactive web response system to randomly assign patients to receive either pitolisant or placebo once per day (1:1 ratio). Randomisation was done in blocks of four. Participants and investigators were masked to treatment allocation. Treatment lasted for 7 weeks: 3 weeks of flexible dosing decided by investigators according to efficacy and tolerance (5 mg, 10 mg, or 20 mg oral pitolisant), followed by 4 weeks of stable dosing (5 mg, 10 mg, 20 mg, or 40 mg). The primary endpoint was the change in the average number of cataplexy attacks per week as recorded in patient diaries (weekly cataplexy rate [WCR]) between the 2 weeks of baseline and the 4 weeks of stable dosing period. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01800045. FINDINGS The trial was done between April 19, 2013, and Jan 28, 2015. We screened 117 patients, 106 of whom were randomly assigned to treatment (54 to pitolisant and 52 to placebo) and, after dropout, 54 patients from the pitolisant group and 51 from the placebo group were included in the intention-to-treat analysis. The WCR during the stable dosing period compared with baseline was decreased by 75% (WCRfinal=2·27; WCRbaseline=9·15; WCRfinal/baseline=0·25) in patients who received pitolisant and 38% (WCRfinal=4·52; WCRbaseline=7·31; WCRfinal/baseline=0·62) in patients who received placebo (rate ratio 0·512; 95% CI 0·43-0·60, p<0·0001). Treatment-related adverse events were significantly more common in the pitolisant group than in the placebo group (15 [28%] of 54 vs 6 [12%] of 51; p=0·048). There were no serious adverse events, but one case of severe nausea in the pitolisant group. The most frequent adverse events in the pitolisant group (headache, irritability, anxiety, and nausea) were mild or moderate except one case of severe nausea. No withdrawal syndrome was detected following pitolisant treatment; one case was detected in the placebo group. INTERPRETATION Pitolisant was well tolerated and efficacious in reducing cataplexy. If confirmed in long-term studies, pitolisant might constitute a useful first-line therapy for cataplexy in patients with narcolepsy, for whom there are currently few therapeutic options. FUNDING Bioprojet, France.

Assessment of nitric oxide, advanced oxidation protein products, malondialdehyde, and thiol levels in patients with restless legs syndrome

OBJECTIVES We aimed to determine the importance of oxidative stress in the pathogenesis of restless legs syndrome (RLS) by quantification of advanced oxidation protein products and total thiol levels (as markers of oxidative protein damage), nitric oxide levels (as an antioxidant and endothelial function), and malondialdehyde levels (as a marker of lipid peroxidation) in patients with RLS. DESIGN AND METHODS A total of 22 patients with primary RLS were enrolled in the study and 20 age-and-gender-matched healthy subjects were enrolled as a control group. Serum nitric oxide, malondialdehyde, thiol levels, and plasma advanced oxidation protein products levels were determined by spectrophotometric methods. RESULTS Serum nitric oxide and thiol levels were lower in the patient group than in controls (p = 0.007 and p = 0.017, respectively). Plasma advanced oxidation protein products levels and serum malondialdehyde levels were found to be higher in patients with RLS than in controls (p = 0.017 and p = 0.008, respectively). Serum malondialdehyde level was found to be positively correlated with plasma advanced oxidation protein products levels (p = 0.039). Serum thiol level was found to be negatively correlated with plasma advanced oxidation protein products levels (p = 0.030). CONCLUSIONS Increased advanced oxidation protein products, malondialdehyde levels, and decreased thiol and nitric oxide levels, may suggest that patients with RLS are under oxidative stress. Although both lipid peroxidation and protein oxidation may have a role in atherosclerosis in RLS, those factors may be related to the pathogenesis of RLS.

Obstructive sleep apnoea prevalence in non-arteritic anterior ischaemic optic neuropathy

Aims The aim of this study was to show the prevalence of obstructive sleep apnoea (OSA) in non-arteritic anterior ischaemic optic neuropathy (NAION). Methods 20 patients diagnosed with NAION were included in the study. 20 age and sex matched subjects with similar risk factors for NAION, such as diabetes mellitus (DM) and hypertension (HT), constituted the control group. All cases underwent polysomnography for investigation of the presence of OSA. Cases with an Apnoea–Hypopnoea Index >5 were accepted as having OSA. Results Mean ages of the patients and controls were 60.90±8.14 and 61.15±7.23 years, respectively. There were no significant differences between the patient and control groups in terms of age, gender, body mass index, smoking/alcohol consumption or systemic diseases. In the patient group, 85% were diagnosed with OSA compared with 65% in the control group (p>0.05). Conclusions We found a high prevalence of OSA in patients with NAION but it was also high in the control group (p>0.05). This may be due to the fact that the two groups were matched for the same risk factors for NAION. The study indicates that OSA is not a risk factor for NAION in itself but is the contributing factor as it has effects on the vascular endothelium in DM, HT and atherosclerosis.

Prevalence of insomnia and its clinical correlates in a general population in Turkey.

The prevalence of insomnia is influenced by environmental factors. This study aimed to investigate the prevalence of insomnia and its sociodemographic and clinical correlates in a general population‐based survey in Turkey.

Sleep architecture in Sheehan’s syndrome before and 6 months after growth hormone replacement therapy

OBJECTIVE To characterize the sleep parameters in patients with growth hormone (GH) deficiency in Sheehans syndrome adults and to assess the effects of 6-month GH replacement therapy (GHRT). METHODS Twenty-two women with Sheehans syndrome, (mean age; 49.1+/-2.2 years), and 12 women with similar age (mean age; 51.3+/-3.8 years) and body mass index as control subjects were included in the study. Under baseline conditions, women received adequate hormone replacement therapy for all hormonal deficiencies other than GH. Twelve patients received recombinant GH (Genotropin; Pfizer Stockholm, Sweden) (treatment group) and eight patients received placebo (placebo group) for 6 months. Two patients had only baseline evaluation and were not followed up prospectively. Two polysomnography (PSG) recordings were performed on the patients group, one in the baseline period and the other at the sixth month of treatment (either GH or placebo). Control group had only baseline PSG. RESULTS GH deficient females with Sheehans syndrome have more NREM (95.9+/-1.5% and 88.6+/-0.9%, respectively; p<0.05), particularly in stage 4 sleep (11.4+/-1.9% and 4.9+/-1.6, respectively; p<0.05), less REM sleep (4.2+/-1.5% and 11.4+/-0.9, respectively; p<0.05) and also less sleep efficiency (69.7+/-3.4% and 81.1+/-2.8%, respectively; p<0.05) when compared to healthy controls. After 6 months of GHRT there was no significant difference in sleep parameters. CONCLUSION GH deficiency has sleep disturbing effects on Sheehans syndrome patients under baseline conditions.

Obstructive sleep apnoea syndrome is associated with relative hypocortisolemia and decreased hypothalamo–pituitary–adrenal axis response to 1 and 250 μg ACTH and glucagon stimulation tests

OBJECTIVE The investigations regarding the effect of obstructive sleep apnoea syndrome (OSAS) on hypothalamo-pituitary-adrenal (HPA) axis revealed conflicting results. We aimed to evaluate the effects of OSAS on HPA-axis with dynamic tests. METHODS This study was carried out on 26 patients with OSAS and 15 subjects without OSAS which, were defined according to the International Classification of Sleep Disorders. Patients were enrolled from either Endocrinology outpatient clinic or Neurology Sleep Center. Participants for the control group were included from the patients admitting to Endocrinology Department with the complaint of obesity or volunteers from hospital staff. All the participants were evaluated by polysomnography (PSG) and dynamic tests of HPA axis (dexamethasone suppression test, 1 and 250μg ACTH and glucagon stimulation tests). RESULTS Serum basal and peak cortisol levels were found to be lower in OSAS patients when compared to the control group during 1μg ACTH and glucagon stimulation tests. When the area under curve (AUC) of cortisol responses to dynamic stimulation tests were calculated according to trapezoid formula, patients with OSAS were found to have lower values compared to control group. AUC responses of all three dynamic stimulation tests were found to be negatively correlated with AHI. CONCLUSION OSAS is associated with relative hypocortisolemia in the morning with reduced responses to 1 and 250μg ACTH and glucagon stimulation tests.