Anna Heidbreder

IgLON5 autoimmunity and abnormal behaviours during sleep

1590 www.thelancet.com Vol 385 April 18, 2015 In September, 2003, a 54-year-old female teacher was admitted to the department of neurology in Innsbruck with a 1·5-year history of insomnia aff ecting sleep onset and maintenance. She reported daytime sleepiness with unintentional sleep episodes at work. Colleagues reported that she had been found sleeping on the fl oor and they could only wake her by shaking her intensely. Her husband reported loud snoring, frequent talking, and hand and leg jerks during sleep. She complained of hoarseness, dysphagia, and mucous obstruction at night. Neurological examination showed slight dysarthria and hoarseness, mild bilateral ptosis, and a slightly broadbased gait. Video polysomnography showed long episodes of a sleep pattern incongruent with any physiological human sleep stages, accompanied by almost continuous apparently purposeful movements similar to picking up or sorting objects or knitting, and vocalisations such as greeting or calling someone and making comments (video). The patient was unaware of these behaviours. The polysomnography during these episodes consisted of low amplitude slow alpha activity, vertical more than horizontal rapid eye movements, and increased mental and submental muscle tone. She had obstructive apnoea with apnoea–hypopnoea index 14·6/h (normal ≤5/h) and loud high-pitched stridor. Her mean oxygen saturation was 90·6% with a nadir of 66% in the supine position. Videofl uoro-endoscopy of the upper airway during sleep showed obstruction at both the pharyngeal and laryngeal level and the vocal cords showed paradoxical adduction during expiration and no active opening during inspiration. We started nasal continuous positive airway pressure (CPAP) at 6 cmH2O and modafi nil that was increased to 200 mg daily. Video polysomnography while on modafi nil and nasal CPAP showed that both respiratory events and stridor and abnormal sleep patterns with nocturnal behaviours had greatly decreased. Further polysomnographic controls showed further improvement but her husband continued to note abnormal behaviours and sleep talking. In August, 2014, the patient was readmitted to hospital because of respiratory failure related to an increasing stridor. Sabater and colleagues reported eight patients with a novel parasomnia with sleep breathing dysfunction associated with IgG4 antibodies to IgLON5, a neuronal surface cell adhesion molecule, and extensive deposits of hyperphosphorylated tau in the tegmentum and hypothalamus, raising questions about the possible autoimmune or neurodegenerative mechanisms of the disorder. The association with HLA DRB1*1001 and DQB1*0501 alleles, an HLA with a very low prevalence in the population, and the presence of IgLON5 antibodies implied an autoimmune cause , whereas the chronic clinical course, poor response to immunotherapy, and pathological fi ndings suggested a neurodegenerative process. Our patient was tested for IgLON5 antibodies at the Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain, as previously described by Sabater. She had positive antibody isotype IgG4 in serum and CSF. The nocturnal behaviour was similar to that reported by Sabater and colleagues, and she also had the same HLA-type as the patients reported in that study (HLA-DRB1*1001 and HLA-DQB1*0501). These fi ndings support the possible autoimmune contribution of the disorder. In March, 2015, the patient was readmitted with severe respiratory insuffi ciency related to stridor and needed intubation. She refused tracheotomy but had successful laterofi xation of the left vocal cord (method of Lichtenberger) and was successfully extubated. She died 2 weeks later from aspiration pneumonia. The combination of sleep disordered breathing with abnormal sleep behaviours, especially if these are not clearly related to end-apnoeic arousals, should raise the suspicion of IgLON5 antibodies. A video polysomnography study showing abnormal sleep stages and apparently goaloriented behaviours will support the diagnosis, in combination with determination of the antibodies. The full spectrum and prevalence of the IgLON5 antibody associated sleep disorder awaits further study.

Not Only Sleepwalking But NREM Parasomnia Irrespective of the Type Is Associated with HLA DQB1*05:01.

STUDY OBJECTIVES Despite the high prevalence and clinical relevance of NREM parasomnias, data on supportive genetic markers are scarce, and mainly refer to sleepwalking only. METHODS We retrospectively analyzed clinical, polysomnographic, and HLA findings of 74 adults (37 men) with NREM parasomnia gathered from four neurological sleep centers. Parasomniac events were classified according to ICSD-2 criteria. HLA DQB1 genotyping was compared to regional-matched reference allele-frequencies. RESULTS Fifty-six patients had more than 2 different parasomnia type: 11 sleepwalking, 4 sleep terrors, 3 confusional arousals only. Parasomniac events were documented during video-polysomnography (V-PSG) in 70% (49/70) of subjects (71.4% confusional arousals, 8.2% sleep terrors, 4.1% sleepwalking, 16.3% ≥ 2 NREM parasomnia types). Violent behavior during V-PSG occurred in 8.5% (6/71). NREM parasomnia onset was reported after the age of 30 years in 6.8% (5/74). The HLA DQB1*05:01 allele was present in 41% (29/71) compared to 24.2% in the regional-matched reference allele group (p < 0.05). This haplotype prevalence did not differ within the NREM parasomnia type. Epworth Sleepiness Score was 10 or higher in 28.6%. CONCLUSIONS This is a large polysomnography-based case series of patients with NREM parasomnia. In patients with suspected sleepwalking or sleep terrors, polysomnography is highly useful in detecting arousals from NREM sleep as a marker of NREM parasomnia. We confirmed previous findings by demonstrating a high prevalence of the HLA DQB1*05:01 genotype for different types of NREM parasomnias. Our findings therefore support a common genetic background, and corroborate the importance of video-polysomnography in the work-up of parasomnia.

Augmentation and impulsive behaviors in restless legs syndrome Coexistence or association

Objectives: To assess the frequency of impulse control disorders (ICDs) in patients with restless legs syndrome (RLS) with and without augmentation under dopaminergic therapy in a case-control study. Augmentation and ICDs are both serious complications of dopaminergic treatment of RLS but little is known about possible associations between these drug-induced disorders. Methods: In total, 58 patients with idiopathic RLS diagnosed according to the International Restless Legs Syndrome Study Group criteria were recruited. Of these, 35 patients had augmentation. The frequency of ICD symptoms was assessed using semi-structural interviews. Results: Demographic variables did not differ between patients with RLS with and without augmentation but those with augmentation took higher dopaminergic medication than patients without augmentation. Twenty-three patients with RLS (39.7%) had ICD symptoms, with 12 patients (20.7%) having definitive ICDs. Patients with augmentation had an increased risk of expressing ICD symptoms (p = 0.007, odds ratio 5.64, 95% confidence interval 1.59–20.02). Conclusions: Patients with RLS with augmentation have an almost 6-fold increased risk of exhibiting ICD symptoms. This implies that augmentation and ICDs are related and may share a common pathophysiology. Moreover, our results have clinical implications, suggesting that patients with RLS with augmentation should be screened for ICD symptoms.

Natural course of restless legs syndrome/Willis–Ekbom disease: long-term observation of a large clinical cohort

OBJECTIVE Although restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is a common neurological disorder, data on the long-term course and management of the disease are scarce. The aim of the current study was to extend the knowledge on the long-term clinical course and treatment outcome of RLS/WED. METHODS In this retrospective analysis, we performed a chart review of consecutive visits of 160 patients with definite RLS/WED from the RLS/WED database of the Innsbruck Medical University. RESULTS A total of 160 patients (58.8% female, aged 58.9 years, range 21.5-86.8 years) met inclusion criteria of two or more visits during a follow-up of at least five years. The duration of the observational period was 8.1 ± 2.9 years. During the observational period, the percentage of treated patients increased (first vs last visit: 67.5% vs 77.5%). Of the patients, 59.4% had one or more switches of medication. Overall the RLS/WED severity, evaluated using a combined severity score (CSS) ranging from 1 to 5, decreased between the first and last visits (median [range], first visit: 3 [1-5] vs last visit 2.5 [1-5]; p <0.001). Symptoms improved in 55.0% of patients, worsened in 10.6%, and remained unchanged in 34.4% during the observational period. Augmentation of RLS/WED occurred in 42 patients (13/42 as the presenting cause; 29/42 occurring during treatment after 4.1 years). The annual rate of augmentation for subjects on dopaminergic medication was 8.1%. CONCLUSIONS Our data suggest that, with the possibility of regular treatment adjustments, RLS/WED remains treatable in the majority of patients over years. Nevertheless, in this study, despite the overall decreased severity, RLS symptoms remained unchanged or worsened in 45% of the patients during the observational period.

Altered Dynamics in the Circadian Oscillation of Clock Genes in Dermal Fibroblasts of Patients Suffering from Idiopathic Hypersomnia

From single cell organisms to the most complex life forms, the 24-hour circadian rhythm is important for numerous aspects of physiology and behavior such as daily periodic fluctuations in body temperature and sleep-wake cycles. Influenced by environmental cues – mainly by light input -, the central pacemaker in the thalamic suprachiasmatic nuclei (SCN) controls and regulates the internal clock mechanisms which are present in peripheral tissues. In order to correlate modifications in the molecular mechanisms of circadian rhythm with the pathophysiology of idiopathic hypersomnia, this study aimed to investigate the dynamics of the expression of circadian clock genes in dermal fibroblasts of idiopathic hypersomniacs (IH) in comparison to those of healthy controls (HC). Ten clinically and polysomnographically proven IH patients were recruited from the department of sleep medicine of the University Hospital of Muenster. Clinical diagnosis was done by two consecutive polysomnographies (PSG) and Multiple Sleep Latency Test (MSLT). Fourteen clinical healthy volunteers served as control group. Dermal fibroblasts were obtained via punch biopsy and grown in cell culture. The expression of circadian clock genes was investigated by semiquantitative Reverse Transcriptase-PCR qRT-PCR analysis, confirming periodical oscillation of expression of the core circadian clock genes BMAL1, PER1/2 and CRY1/2. The amplitude of the rhythmically expressed BMAL1, PER1 and PER2 was significantly dampened in dermal fibroblasts of IH compared to HC over two circadian periods whereas the overall expression of only the key transcriptional factor BMAL1 was significantly reduced in IH. Our study suggests for the first time an aberrant dynamics in the circadian clock in IH. These findings may serve to better understand some clinical features of the pathophysiology in sleep – wake rhythms in IH.

Peripheral nerve function in patients with excessive fragmentary myoclonus during sleep.

OBJECTIVES Excessive fragmentary myoclonus is a frequent incidental finding in patients undergoing polysomnography for other reasons. The aim of this study was to evaluate whether electrophysiological examination in patients with excessive fragmentary myoclonus during sleep according to American Academy of Sleep Medicine (AASM) criteria shows findings of peripheral nerve dysfunction. METHODS Ninety-eight of 100 patients with excessive fragmentary myoclonus detected as an incidental finding during routine polysomnography underwent electrophysiological workup. Motor nerve conduction studies of the right peroneal and tibial nerves, F-wave recordings of the tibial nerve, antidromic sensory nerve conduction studies of the left sural nerve and needle electromyography of the right tibialis anterior muscle were performed and classified as normal, peripheral neuropathy, lumbar 5 (L5) nerve root lesion, or benign fasciculations. RESULTS Fifty percent (49 out of 98) presented with electrophysiological abnormalities, most frequently polyneuropathy (32 out of 49, 65.3%), followed by L5 nerve root lesions (13 out of 49, 26.5%) and benign fasciculations (4 out of 49, 8.2%). Patients with electrophysiological abnormalities were older than those without. CONCLUSIONS The high prevalence of abnormal neurophysiological findings in patients with excessive fragmentary myoclonus during polysomnography suggests that excessive fragmentary myoclonus during sleep according to AASM criteria is not primarily a sleep-related phenomenon, but only persists during sleep and points to peripheral nerve pathology at least in part of the cases. Patients with incidental EFM during polysomnography should undergo electrophysiological workup for peripheral nerve pathology.

Haste makes waste: Decision making in patients with restless legs syndrome with and without augmentation

Objectives To investigate decision making in patients with primary restless legs syndrome (RLS) with and without augmentation treated with dopaminergic medication. Methods A total of 64 non-demented RLS patients treated with dopaminergic medication with and without augmentation were included in this study. We used an information sampling task to assess how much evidence participants gather before making a decision. Performance was compared to the results of 21 healthy controls. Results All patients with and without augmentation gathered less information than healthy controls before making a decision (p<0.001), but there was no difference between the two patient groups (p = 1.0). Furthermore, both patient groups made more irrational decisions (e.g. decisions against the evidence they had at the time) than healthy controls (p≤0.002). In addition, RLS patients with augmentation made significantly more irrational decisions than RLS patients without augmentation (p = 0.037) and controls (p<0.001). Conclusions Our results show that RLS patients treated with dopaminergic drugs, regardless of having augmentation or not, jumped to conclusions and decided significantly more often against the evidence they had at the time of their decision. However, those with augmentation performed worse than all other groups and made more often irrational decisions, a phenomenon which is also common in patients with substance abuse or behavioural addictions. Thus, jumping to conclusions and deciding with a higher degree of uncertainty as well as irrational decision making is more common in RLS patients treated with dopaminergic medication particularly in those with augmentation.

Screening for idiopathic REM sleep behavior disorder: usefulness of actigraphy

Abstract Study Objectives To evaluate the utility of multimodal low-cost approaches including actigraphy, a wrist-worn device monitoring rest/activity cycles, in identifying patients with idiopathic REM sleep behavior disorder (iRBD). Methods Seventy patients diagnosed with sleep disorders causing different motor manifestations during sleep (iRBD, sleep apnea, restless legs syndrome) and 20 subjects without any relevant motor manifestation during sleep, underwent video-polysomnography (vPSG) and 2 week actigraphy, completed six validated RBD screening questionnaires, and sleep apps use was assessed. Actigraphy was analyzed automatically, and visually by seven blinded sleep medicine experts who rated as “no,” “possible,” and “probable” RBD. Results Quantitative actigraphy analysis distinguished patients from controls, but not between patients with different types of motor activity during sleep. Visual actigraphy rating by blinded experts in sleep medicine using pattern recognition identified vPSG confirmed iRBD with 85%–95% sensitivity, 79%–91% specificity, 81%–91% accuracy, 57.7% ± 11.3% positive predictive value, 95.1% ± 3.3% negative predictive value, 6.8 ± 2.2 positive likelihood ratio, 0.14 ± 0.05 negative likelihood ratio and 0.874–0.933 area under the ROC curve (AUC). AUC of the best performing questionnaire was 0.868. Few patients used sleep apps; therefore, their potential utility in the evaluated patients’ groups is limited. Conclusions Visual analysis of actigraphy using pattern recognition can identify subjects with iRBD, and is able to distinguish iRBD from other motor activities during sleep, even when patients are not aware of the disease in contrast to questionnaires. Therefore, actigraphy can be a reliable screening instrument for RBD potentially useful in the general population.

Determination of GHB and GHB-β-O-glucuronide in hair of three narcoleptic patients—Comparison between single and chronic GHB exposure

Gamma-hydroxybutyric acid (GHB) can be used as a knock-out drug in drug facilitated crime (DFC). Due to its rapid metabolism and resulting narrow detection window, uncovering GHB use in DFC still constitutes a problem. In this experiment we determined the GHB and GHB-β-O-glucuronide (GHB-Gluc) concentrations in hair samples after single and chronic GHB exposures. Hair samples of three narcoleptic patients therapeutically taking sodium oxybate (GHB-sodium-salt) were collected. Patients 1 (P1) and 2 (P2) took the medication for nine and six years, respectively. P1 took daily the pharmaceutical Xyrem® in a total dose of 5.78g GHB at bed time (2.89g) and four hours (2.89g) later. P2 took a dose of 3.10g GHB at bed time and an additional dose of 2.68g GHB four hours later. Patient 3 (P3) was newly diagnosed with narcolepsy and started his therapy with oral dose of 6g (divided in three portions of 2g GHB) within 24h. The hair samples were extracted both with and without forerunning washing steps. GHB and GHB-Gluc were determined by a published ultra-high performance liquid chromatography-tandem mass spectrometry method using GHB-d6 and GHB-Gluc-d4 as internal standards. GHB and GHB-Gluc concentrations in unwashed hair samples of P1 and P2 were determined in a range of 0.56-1.30ng/mg and <0.48-0.85ng/mg, respectively. In washed hair samples of P1 and P2 the concentrations were in a range of <0.32-0.68ng/mg and <0.48-1.20ng/mg for GHB and GHB-Gluc, respectively. The determined concentrations were within the published endogenous range. The confirmed results showed that the washing procedure before extraction causes a minor decrease of GHB concentrations in hair (difference: <1ng/mg). The investigations showed that a single GHB exposure might not be determined by hair analysis of GHB and GHB-Gluc. The chronical intake of therapeutic sodium oxybate with doses up to 7g per night was also not confirmed by hair analysis maybe due to hair treatments. Therefore, GHB hair analysis should be assessed critically and determined negative results could not exclude GHB exposures.

Validation of a leg movements count and periodic leg movements analysis in a custom polysomnography system

BackgroundPeriodic leg movements (PLM) during sleep (PLMS) are considered strongly related to restless legs syndrome (RLS), and are associated with polymorphisms in RLS risk genes. Various software for automatic analysis of PLMS are available, but only few of them have been validated. Aim of this study was to validate a leg movements count and analysis integrated in a commercially available polysomnography (PSG) system against manual scoring.MethodsTwenty RLS patients with a PLMS index > 20/h and 20 controls with a PLMS index < 5/h were included. Manual and computerized scoring of leg movements (LM) and PLM was performed according to the standard American Academy of Sleep Medicine (AASM) criteria. LM and PLM indices during sleep and wakefulness, the rate of PLMS associated with respiratory events, intermovement interval and periodicity indices were manually and automatically scored.ResultsThe correlation between manual and computerized scoring was high for all investigated parameters (Spearman correlation coefficients 0.751–0.996, p < 0.001; intraclass correlation coefficients 0.775–0.999, p < 0.001). Bland-Altman plots showed high agreement between manual and automatic analysis.ConclusionsThis study validated an automatic LM count and PLM analysis against the gold standard manual scoring according to AASM criteria. The data demonstrate that the software used in this study has an outstanding performance for computerized LM and PLM scoring, and LM and PLM indices generated with this software can be reliably integrated in the routine PSG report. This automatic analysis is also an excellent tool for research purposes.