Laura Ehrmann

ImmunoChip Study Implicates Antigen Presentation to T Cells in Narcolepsy

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

Validation of the Innsbruck REM sleep behavior disorder inventory

A diagnosis of definite REM sleep behavior disorder requires both a positive history for REM sleep behavior disorder and polysomnographic demonstration of REM sleep without atonia. To improve and facilitate screening for REM sleep behavior disorder, there is a need for simple clinical tools with sufficient sensitivity and specificity for the identification of subjects with probable REM sleep behavior disorder. We developed a short REM sleep behavior disorder screening questionnaire with 7 REM sleep behavior disorder– and 2 non‐REM sleep behavior disorder–specific control items and performed a validation study in 70 REM sleep behavior disorder subjects and 140 sleep disorder controls. Response patterns to all 7 REM sleep behavior disorder–specific items differed between REM sleep behavior disorder and non‐REM sleep behavior disorder patients (all P < 0.05), whereas the 2 non‐REM sleep behavior disorder–specific control items did not differentiate between REM sleep behavior disorder and non‐REM sleep behavior disorder (all P > .05). In 5 of the 7 REM sleep behavior disorder–specific items, AUC was greater than 0.700. These 5 items were included in the Innsbruck REM sleep behavior disorder inventory. In this questionnaire, a cutoff of 0.25 (number of positive symptoms divided by number of answered questions) had a sensitivity of 0.914 and a specificity of 0.857 for both idiopathic and Parkinsons‐related REM sleep behavior disorder (AUC, 0.886). The Innsbruck REM sleep behavior disorder inventory is a promising, easy‐to‐use, short screening tool for REM sleep behavior disorder with excellent sensitivity and specificity for both idiopathic and Parkinsons‐related REM sleep behavior disorder.

Night-to-night variability of periodic leg movements during sleep in restless legs syndrome and periodic limb movement disorder: Comparison between the periodicity index and the PLMS index

BACKGROUND The number of periodic leg movements during sleep (PLMS index) shows high night-to-night variability, requiring multiple nights for its reliable estimation. It is currently not known if this is also the case for the degree of periodicity of leg movements, quantified by the Periodicity index. OBJECTIVE To compare night-to-night variability of PLMS and Periodicity indices in patients with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD). METHODS Eighteen idiopathic RLS patients and 9 PLMD patients were recruited. Subjects underwent two consecutive full night polysomnographic studies. Polysomnographic recordings were scored and leg movement activity analyzed during sleep for the computation of the PLMS and Periodicity indices. RESULTS In both patient groups, the Periodicity index showed a significantly lower degree of variability than that of PLMS index, being >6.5 times lower in RLS patients and 2 times lower in PLMD patients. CONCLUSIONS These data support the use of the Periodicity index in the evaluation of PLMS in RLS and PLMD and indicate that this parameter seems to be more stable than the widely used PLMS index which has higher night-to-night variability.

Investigation of autonomic function in idiopathic REM sleep behavior disorder

Idiopathic REM sleep behavior disorder (iRBD) has been suggested as an early “pre-motor” stage of Parkinson’s disease (PD) in a significant proportion of cases. We investigated autonomic function in 15 consecutive iRBD patients and compared these findings to PD patients and healthy controls. All participants underwent cardiovascular autonomic function testing, and were rated on the COMPASS scale. Symptomatic orthostatic hypotension was present in two iRBD patients, two PD patients and none of the healthy controls. In the tilt table examination, blood pressure changes were similar between iRBD patients and healthy controls. In the PD group, blood pressure drops were more pronounced. In the orthostatic standing test, iRBD patients had higher blood pressure changes than healthy controls. Highest drops were found in PD. Valsalva ratio was lower in iRBD and PD compared to healthy controls. Total COMPASS score was higher in iRBD compared to healthy controls. Highest scores were found in PD. These results support the presence of autonomic dysfunction in iRBD. On several measures, dysfunction was intermediate between healthy controls and PD consistent with the concept that iRBD can be manifestation of synuclein-associated neurodegenerative disorders. Follow-up studies are needed to determine whether iRBD patients with dysfunction on several autonomic domains are at particular risk for developing one of these diseases.

Delayed diagnosis, range of severity, and multiple sleep comorbidities: a clinical and polysomnographic analysis of 100 patients of the innsbruck narcolepsy cohort.

STUDY OBJECTIVES Narcolepsy is reported to affect 26-56/100,000 in the general population. We aimed to describe clinical and polysomnographic features of a large narcolepsy cohort in order to comprehensively characterize the narcoleptic spectrum. METHODS We performed a chart- and polysomnographybased review of all narcolepsy patients of the Innsbruck narcolepsy cohort. RESULTS A total of 100 consecutive narcolepsy patients (87 with cataplexy [NC], 13 without cataplexy [N]) were included in the analysis. All subjects had either excessive daytime sleepiness or cataplexy as their initial presenting clinical feature. Age at symptom onset was 20 (6-69) years. Diagnostic delay was 6.5 (0-39) years. The complete narcolepsy tetrad was present in 36/100 patients; 28/100 patients had three cardinal symptoms; 29/100 had two; and 7/100 had only excessive daytime sleepiness. Severity varied broadly with respect to excessive daytime sleepiness (median Epworth Sleepiness Scale score: 18, range 10-24), cataplexy (8-point Likert scale: median 4.5, range 1-8), hypnagogic hallucinations (median 4.5, range 1-7), and sleep paralysis (median 3, range 1-7). Sleep comorbidity was highly prevalent and ranged from sleeprelated movement disorders (n = 55/100), parasomnias (n = 34/100), and sleeprelated breathing disorders (n = 24/100), to insomnia (n = 28/100). REM sleep without atonia or a periodic limb movement in sleep index > 5/h were present in most patients (90/100 and 75/100). A high percentage of narcoleptic patients in the present study had high frequency leg movements (35%) and excessive fragmentary myoclonus (22%). Of the narcolepsy patients with clinical features of REM sleep behavior disorder (RBD), 76.5% had EMG evidence for RBD on the multiple sleep latency test (MSLT), based on a standard cutoff of a minimum of 18% of 3-sec miniepochs. CONCLUSION This study is one of the largest monocentric polysomnographic studies to date of patients with narcolepsy and confirms the frequent comorbidity of narcolepsy with many other sleep disorders. Our study is the first to evaluate the percentage of patients with high frequency leg movements and excessive fragmentary myoclonus in narcolepsy and is the first to demonstrate EMG evidence of RBD in the MSLT. These findings add to the growing body of literature suggesting that motor instability is a key feature of narcolepsy.

Motor events during healthy sleep: a quantitative polysomnographic study.

STUDY OBJECTIVES Many sleep disorders are characterized by increased motor activity during sleep. In contrast, studies on motor activity during physiological sleep are largely lacking. We quantitatively investigated a large range of motor phenomena during polysomnography in physiological sleep. DESIGN Prospective polysomnographic investigation. SETTING Academic referral sleep laboratory. PARTICIPANTS One hundred healthy sleepers age 19-77 y were strictly selected from a representative population sample by a two-step screening procedure. INTERVENTIONS N/A. MEASUREMENTS AND RESULTS Polysomnography according to American Academy of Sleep Medicine (AASM) standards was performed, and quantitative normative values were established for periodic limb movements in sleep (PLMS), high frequency leg movements (HFLM), fragmentary myoclonus (FM), neck myoclonus (NM), and rapid eye movement (REM)-related electromyographic (EMG) activity. Thirty-six subjects had a PLMS index > 5/h, 18 had a PLMS index > 15/h (90th percentile: 24.8/h). Thirty-three subjects had HFLM (90th percentile: four sequences/night). All subjects had FM (90th percentile 143.7/h sleep). Nine subjects fulfilled AASM criteria for excessive FM. Thirty-five subjects had NM (90th percentile: 8.8/h REM sleep). For REM sleep, different EMG activity measures for the mentalis and flexor digitorum superficialis muscles were calculated: the 90th percentile for phasic mentalis EMG activity for 30-sec epochs according to AASM recommendation was 15.6%, and for tonic mentalis EMG activity 2.6%. Twenty-five subjects exceeded the recently proposed phasic mentalis cutoff of 11%. None of the subjects exceeded the tonic mentalis cutoff of 9.6%. CONCLUSION Quantification of motor phenomena is a basic prerequisite to develop normative values, and is a first step toward a more precise description of the various motor phenomena present during sleep. Because rates of motor events were unexpectedly high even in physiological sleep, the future use of normative values for both research and clinical routine is essential.

Can observers link dream content to behaviours in rapid eye movement sleep behaviour disorder? A cross‐sectional experimental pilot study

Motor activity in rapid eye movement (REM) sleep behaviour disorder (RBD) has been linked to dream content. Systematic and controlled sleep laboratory studies directly assessing the relation between RBD behaviours and experienced dream content are, however, largely lacking. We aimed to investigate whether a link can be established between RBD behaviours and dream content when both are systematically sampled in a controlled setting. We investigated six patients with Parkinson syndrome and RBD who underwent 2–3 nights of video–polysomnographic recording during which they were awakened from REM sleep (10 min after the onset of the second and successive REM periods). Spontaneous free‐worded dream reports and a structured dream questionnaire were obtained. Video recordings of motor manifestations were each combined with four dream reports, and seven judges had to match the video clip with the correctly reported dream content from a choice of four possibilities. Of the 35 REM sleep awakenings performed, a total of 17 (48.6%) motor‐behavioural episodes with recalled dream content were obtained. The mean of correctly identified video‐dream pairs was 39.5% (range 0–100%). Our data showed that reported dream content can be linked to motor behaviours above chance level. Matching accuracy was affected mainly by the clarity of dream reports and the specific nature of movements manifest in video recordings.

Executive Functions, Information Sampling, and Decision Making in Narcolepsy With Cataplexy

OBJECTIVE Narcolepsy with cataplexy (NC) affects neurotransmitter systems regulating emotions and cognitive functions. This study aimed to assess executive functions, information sampling, reward processing, and decision making in NC. METHOD Twenty-one NC patients and 58 healthy participants performed an extensive neuropsychological test battery. RESULTS NC patients scored as controls in executive function tasks assessing set shifting, reversal learning, working memory, and planning. Group differences appeared in a task measuring information sampling and reward sensitivity. NC patients gathered less information, tolerated a higher level of uncertainty, and were less influenced by reward contingencies than controls. NC patients also showed reduced learning in decision making and had significantly lower scores than controls in the fifth block of the IOWA gambling task. No correlations were found with measures of sleepiness. CONCLUSIONS NC patients may achieve high performance in several neuropsychological domains, including executive functions. Specific differences between NC patients and controls highlight the importance of the hypocretin system in reward processing and decision making and are in line with previous neuroimaging and neurophysiological studies.

Narcolepsy and pregnancy: a retrospective European evaluation of 249 pregnancies.

In a retrospective cohort study undertaken in 12 European countries, 249 female narcoleptic patients with cataplexy (n = 216) and without cataplexy (n = 33) completed a self‐administrated questionnaire regarding pregnancy and childbirth. The cohort was divided further into patients whose symptoms of narcolepsy started before or during pregnancy (308 pregnancies) and those in whom the first symptoms of narcolepsy appeared after delivery (106 pregnancies). Patients with narcolepsy during pregnancy were older during their first pregnancy (P < 0.001) and had a higher body mass index (BMI) prior to pregnancy (P < 0.01). Weight gain during pregnancy was higher in narcoleptic patients with cataplexy (P < 0.01). More patients with narcolepsy–cataplexy during pregnancy had impaired glucose metabolism and anaemia. Three patients experienced cataplexy during delivery. The rate of caesarean sections was higher in the narcolepsy–cataplexy group compared to the narcolepsy group (P < 0.05). The mean birth weight and gestational age of neonates were within the normal range and did not differ across groups. Neonatal care was affected adversely by symptoms of narcolepsy in 60.1% of those with narcolepsy during pregnancy. This study reports more obstetric complications in patients with narcolepsy–cataplexy during pregnancy; however, these were not severe. This group also had a higher BMI and higher incidence of impaired glucose metabolism during pregnancy. Caesarian section was conducted more frequently in narcolepsy–cataplexy patients, despite cataplexy being a rare event during delivery. Furthermore, symptoms of narcolepsy may render care of the infant more difficult.

White and gray matter abnormalities in narcolepsy with cataplexy.

STUDY OBJECTIVES The authors applied diffusion-tensor imaging including measurements of mean diffusivity (MD), which is a parameter of brain tissue integrity, fractional anisotropy (FA), which is a parameter of neuronal fiber integrity, and voxel-based morphometry, which is a measure of gray and white matter volume, to detect brain tissue changes in patients with narcolepsy-cataplexy. DESIGN N/A. PATIENTS Patients with narcolepsy-cataplexy (n = 16) and age-matched healthy control subjects (n = 12) were studied. INTERVENTIONS Whole cerebral MD, FA measures, and the volumes of the gray and white matter compartments were analyzed using statistical parametric mapping. MEASUREMENT AND RESULTS Significant MD increases and concomitant FA decreases were localized in the fronto-orbital cortex (P < 0.001) and the anterior cingulate (FA, P < 0.001; MD, P = 0.03) in narcolepsy-cataplexy. Additional MD increases without FA changes were detected in the ventral tegmental area, the dorsal raphe nuclei (P < 0.001), and the hypothalamus (P < 0.01). FA signal decreases were observed in the white matter tracts of the inferior frontal and inferior temporal cortices of narcolepsy-cataplexy patients (P < 0.001). Brain volume loss was evident in focal areas of the inferior and superior temporal cortices (P < 0.001) and the cingulate (P = 0.038). CONCLUSIONS Areas of increased diffusivity in the hypothalamus appear consistent with hypocretinergic cell loss reported in narcolepsy-cataplexy. Signal abnormalities in the ventral tegmental area and the dorsal raphe nuclei correspond to major synaptic targets of hypocretin neurons that were associated with the regulation of the sleep-wake cycle. Brain tissue alterations identified in the frontal cortex and cingulate are crucial in the maintenance of attention and reward-dependent decision making, both known to be impaired in narcolepsy-cataplexy.