Brain correlates of apathy in Kleine Levin syndrome: a mean apparent propagator study

International audienceSynopsis Kleine-Levin syndrome (KLS) is a rare neurological disorder characterized by episodes of severe hypersomnia, apathy, cognitive impairment, derealization and behavioral disturbances. Between episodes, patients have normal sleep, mood and behavior. Apathy is a prominent clinical feature of KLS but its pathophysiology is not known. Here we used mean apparent propagator to investigate white matter changes in KLS and correlated diffusion changes with apathy scores. Results showed that the corpus callosum was involved in KLS during episodes and mean RTAP measures in the corpus callosum correlated with apathy scores. Results were in accordance with known motivation-based circuits involving the orbitomedial frontal cortex. Purpose Kleine-Levin syndrome (KLS) is a rare neurological disorder that mainly affects adolescents. KLS is characterized by relapsing-remitting episodes of severe hypersomnia, apathy, cognitive impairment, derealization and behavioral disturbances. Between episodes, patients have normal sleep, mood and behavior [1]. Each episode is of brief duration varying from a week to 1-2 months. No definite cause has been identified [1]. Anatomical MRI scan is normal, but brain scintigraphy can be abnormal during and between episodes [2]. Apathy is a prominent clinical feature of KLS [3] but its pathophysiology in the disease remains to be established. The mechanisms responsible for apathy may involve several circuits connecting the frontal lobes to the basal ganglia [4]. Here, we performed TBSS analyses on the return-to-the-axis probability (RTAP) measures that may be linked to apparent axonal diameter and inflammation [5] to analyze the integrity of white matter (WM) microstructure of healthy volunteers (HV) compared to symptomatic (KLS-S) and asymptomatic (KLS-AS) patients. Methods We prospectively included 20 KLS-AS (mean age: 22.2 ± 8.9 years, 9 males) and 20 HV age and sex-matched one by one. Twelve of these 20 patients were also scanned during episodes (KLS-S). Apathy was assessed using the Starkstein Apathy score [6]. Diffusion-weighted images were acquired using a Siemens Verio 3T with a 12-channel head coil (GRAPPA=2; TR/TE=7.7s/92ms; voxel size: 2.5mm isotropic; 64, 32 and 8 gradient directions for b-values of 1800, 700, and 300 s/mm² respectively) and 8 images without diffusion weighting were also acquired. We preprocessed the images using FSL (fsl.fmrib.ox.ac.uk/fsl/fslwiki/) and included correction for susceptibility (topup) and for eddy current distortions (eddycor) and creation of a binary mask of the brain (bet). Then, we generated RTAP maps of all subjects [7]. Voxelwise statistical analyses were carried out using TBSS, part of the FSL comparing RTAP maps of HV versus KLS-AS, HV versus KLS-S and KLS-AS versus KLS-S (paired t-test). Finally, in the TBSS-based ROI, we computed correlations between clinical scores (disease duration and apathy scores) and mean RTAP measures in this ROI and performed tractography on one healthy subject to determine its projection fibers. Results were considered significant at p<0.05, fully corrected for multiple comparisons across space. Results There were no significant differences in RTAP between HV and KLS-AS. In KLS-S compared to KLS-AS, RTAP increased in the corpus callosum (CC). There was a correlation between apathy scores and mean RTAP in the CC of KLS-S (p=0.03, r=0.61) (see Figure 2). There were no other correlations with clinical scores in KLS-AS as well as in KLS-S. Using the TBSS-ROI as a seed for tractography, fibers passing through the CC with abnormal RTAP measures projected to medial orbitofrontal cortex (see Figure 3). Discussion and conclusion The results highlight the presence of structural changes correlated to the apathy score in the anterior portion of the CC during episodes, a region where fibers project onto the medial orbitofrontal cortex. As, these prefrontal regions are involved in motivation processes [4], this suggests that apathy in KLS could result from difficulties to provide the affective/motivational value of a given behavioral context

Kleine-Levin Syndrome : long term impairment and mechanisms of cognitive disorders, apathy and derealization

Le syndrome de Kleine-Levin (KLS) est une pathologie neuropsychiatrique rare, intermittente, du sujet jeune, dont la cause est inconnue. Les épisodes durent plusieurs jours avec hypersomnie, apathie, déréalisation, troubles cognitifs et désinhibition comportementale. Entre les épisodes, les patients retrouveraient un sommeil et un fonctionnement normal. Existe-t-il des épisodes plus prolongés et des dysfonctionnements à long terme ? Pour répondre à ces questions, nous avons utilisé une approche clinique (entretiens, questionnaires), cognitive (évaluation neuropsychologique) et d'imagerie cérébrale fonctionnelle (scintigraphie) dans une étude contrôlée. Nos résultats montrent que près d'un tiers des patients ont des longues crises et sont plus anxieux, dépressifs et fatigués que les autres. Un quart à un tiers des patients ont des difficultés cognitives entre les crises. Des hypoperfusions persistent chez 41 patients, d'autant plus que la durée des épisodes est longue, que la dernière crise est récente et que la déréalisation en crise est sévère. L'émergence des symptômes est associée à l'hypoperfusion du cortex préfrontal dorso-médian et de la jonction temporo-pariétale, qui sont impliqués dans l'attention, l'intégration multi-sensorielle, les représentations mentales et la motivation. Bien que l'expression de la maladie soit intermittente, nos résultats suggèrent que les crises soient la partie émergée d'un " iceberg ", remettant en cause le caractère bénin de la maladie.Kleine-Levin syndrome (KLS) is a rare neuropsychiatric disease which occurs in young subjects and for wich the etiopathology is still unknown. It is characterized by recurrent episodes during several days with hypersomnia, apathy, derealization, cognitive disorders and behavioral disinhibition. Those episodes alternate with long periods of normal sleep, cognition, mood, and behavior. Are there more prolonged episodes and long-term impairment? What are the mechanisms of derealization and apathy in the KLS? To answer these questions, we used a clinical approach (interviews, questionnaires), cognitive (neuropsychological assessment) and functional brain imaging (scintigraphy) in a controlled study. Our results show that nearly one third of the patients have long episodes (over a month) and are more anxious, depressed, sleepy and tired than the others. A quarter to a third of the patients has cognitive impairment between the episodes. Cortical and subcortical hypoperfusion persists in 41 patients, especially if the duration of the episodes is long, the last episode is recent and the derealization is severe. The emergence of symptoms is associated with the hypoperfusion in the dorsal medial prefrontal cortex and in the temporoparietal junction. Those brain regions are involved in treating the information related to attention, multisensory integration, mental representations and motivation.Although the clinical expression of this disease obeys a relapsing- remitting pattern, our results suggest that those episodes could be only the tip of the "iceberg", challenging the concept of a benign disorder

Syndrome de Kleine-Levin : complications à long terme et mécanismes des troubles cognitifs, de l'apathie et de la déréalisation

Kleine-Levin syndrome (KLS) is a rare neuropsychiatric disease which occurs in young subjects and for wich the etiopathology is still unknown. It is characterized by recurrent episodes during several days with hypersomnia, apathy, derealization, cognitive disorders and behavioral disinhibition. Those episodes alternate with long periods of normal sleep, cognition, mood, and behavior. Are there more prolonged episodes and long-term impairment? What are the mechanisms of derealization and apathy in the KLS? To answer these questions, we used a clinical approach (interviews, questionnaires), cognitive (neuropsychological assessment) and functional brain imaging (scintigraphy) in a controlled study. Our results show that nearly one third of the patients have long episodes (over a month) and are more anxious, depressed, sleepy and tired than the others. A quarter to a third of the patients has cognitive impairment between the episodes. Cortical and subcortical hypoperfusion persists in 41 patients, especially if the duration of the episodes is long, the last episode is recent and the derealization is severe. The emergence of symptoms is associated with the hypoperfusion in the dorsal medial prefrontal cortex and in the temporoparietal junction. Those brain regions are involved in treating the information related to attention, multisensory integration, mental representations and motivation.Although the clinical expression of this disease obeys a relapsing- remitting pattern, our results suggest that those episodes could be only the tip of the "iceberg", challenging the concept of a benign disorder.Le syndrome de Kleine-Levin (KLS) est une pathologie neuropsychiatrique rare, intermittente, du sujet jeune, dont la cause est inconnue. Les épisodes durent plusieurs jours avec hypersomnie, apathie, déréalisation, troubles cognitifs et désinhibition comportementale. Entre les épisodes, les patients retrouveraient un sommeil et un fonctionnement normal. Existe-t-il des épisodes plus prolongés et des dysfonctionnements à long terme ? Pour répondre à ces questions, nous avons utilisé une approche clinique (entretiens, questionnaires), cognitive (évaluation neuropsychologique) et d'imagerie cérébrale fonctionnelle (scintigraphie) dans une étude contrôlée. Nos résultats montrent que près d'un tiers des patients ont des longues crises et sont plus anxieux, dépressifs et fatigués que les autres. Un quart à un tiers des patients ont des difficultés cognitives entre les crises. Des hypoperfusions persistent chez 41 patients, d'autant plus que la durée des épisodes est longue, que la dernière crise est récente et que la déréalisation en crise est sévère. L'émergence des symptômes est associée à l'hypoperfusion du cortex préfrontal dorso-médian et de la jonction temporo-pariétale, qui sont impliqués dans l'attention, l'intégration multi-sensorielle, les représentations mentales et la motivation. Bien que l'expression de la maladie soit intermittente, nos résultats suggèrent que les crises soient la partie émergée d'un " iceberg ", remettant en cause le caractère bénin de la maladie

From the sound of breathing to the sound of distress: implications for dyspnoeic patients and their caregivers

No abstract availabl

Machine-learning based feature selection for a non-invasive breathing change detection

International audienceBackground: Chronic Obstructive Pulmonary Disease (COPD) is one of the top 10 causes of death worldwide, representing a major public health problem. Researchers have been looking for new technologies and methods for patient monitoring with the intention of an early identification of acute exacerbation events. Many of these works have been focusing in breathing rate variation, while achieving unsatisfactory sensitivity and/or specificity. This study aims to identify breathing features that better describe respiratory pattern changes in a short-term adjustment of the load-capacity-drive balance, using exercising data. Results: Under any tested circumstances, breathing rate alone leads to poor capability of classifying rest and effort periods. The best performances were achieved when using Fourier coefficients or when combining breathing rate with the signal amplitude and/or ARIMA coefficients. Conclusions: Breathing rate alone is a quite poor feature in terms of prediction of breathing change and the addition of any of the other proposed features improves the classification power. Thus, the combination of features may be considered for enhancing exacerbation prediction methods based in the breathing signal. Trial Registration : ClinicalTrials NCT03753386. Registered 27 November 2018, https:// clinicaltrials.gov/show/NCT0375338

Impact of earplugs and eye mask on sleep in critically ill patients: a prospective randomized study

International audienceBackgroundPoor sleep is common in intensive care unit (ICU) patients, where environmental factors contribute to reduce and fragment sleep. The objective of this study was to evaluate the impact of earplugs and eye mask on sleep architecture in ICU patients.MethodsA single-center randomized controlled trial of 64 ICU patients was conducted from July 2012 to December 2013. Patients were randomly assigned to sleep with or without earplugs and an eye mask from inclusion until ICU discharge. Polysomnography was performed on the first day and night following inclusion. The primary outcome was the proportion of stage N3 sleep over total sleep time. Secondary outcomes were other descriptors of sleep and major outcome variables.ResultsIn the intervention group, nine (30%) patients did not wear earplugs all night long. The proportion of N3 sleep was 21 [7–28]% in the intervention group and 11 [3–23]% in the control group (p = 0.09). The duration of N3 sleep was higher among the patients in the intervention group who wore earplugs all night long than in the control group (74 [32–106] vs. 31 [7–76] minutes, p = 0.039). The number of prolonged awakenings was smaller in the intervention group (21 [19–26] vs. 31 [21–47] in the control group, p = 0.02). No significant difference was observed between the two groups in terms of clinical outcome variables.ConclusionsEarplugs and eye mask reduce long awakenings and increase N3 duration when they are well tolerated

Impact of cytokine in type 1 narcolepsy: Role of pandemic H1N1 vaccination ?

International audienceRecent advances in the identification of susceptibility genes and environmental exposures (pandemic influenza 2009 vaccination) provide strong support that narcolepsy type 1 is an immune-mediated disease. Considering the limited knowledge regarding the immune mechanisms involved in narcolepsy whether related to flu vaccination or not and the recent progresses in cytokine measurement technology, we assessed 30 cytokines, chemokines and growth factors using the Luminex technology in either peripheral (serum) or central (CSF) compartments in a large population of 90 children and adult patients with narcolepsy type 1 in comparison to 58 non-hypocretin deficient hypersomniacs and 41 healthy controls. Furthermore, we compared their levels in patients with narcolepsy whether exposed to pandemic flu vaccine or not, and analyzed the effect of age, duration of disease and symptom severity. Comparison for sera biomarkers between narcolepsy (n = 84, 54 males, median age: 15.5 years old) and healthy controls (n = 41, 13 males, median age: 20 years old) revealed an increased stimulation of the immune system with high release of several pro- and anti-inflammatory serum cytokines and growth factors with interferon-γ, CCL11, epidermal growth factor, and interleukin-2 receptor being independently associated with narcolepsy. Increased levels of interferon-γ, CCL11, and interleukin-12 were found when close to narcolepsy onset. After several adjustments, only one CSF biomarker differed between narcolepsy (n = 44, 26 males, median age: 15 years old) and non-hypocretin deficient hypersomnias (n = 57, 24 males, median age: 36 years old) with higher CCL 3 levels found in narcolepsy. Comparison for sera biomarkers between patients with narcolepsy who developed the disease post-pandemic flu vaccination (n = 36) to those without vaccination (n = 48) revealed an increased stimulation of the immune system with high release of three cytokines, regulated upon activation normal T-cell expressed and secreted, CXCL10, and CXCL9, being independently and significantly increased in the group exposed to the vaccine. No significant differences were found between narcoleptics whether exposed to flu vaccination or not for CSF biomarkers except for a lower CXCL10 level found in the exposed group. To conclude, we highlighted the role of sera cytokine with pro-inflammatory properties and especially interferon-γ being independently associated with narcolepsy close to disease onset. The activity of the interferon-γ network was also increased in the context of narcolepsy after the pandemic flu vaccination being a potential key player in the immune mechanism that triggers narcolepsy and that coordinates the immune response necessary for resolving vaccination assaults

Kleine-Levin syndrome in 120 patients: Differential diagnosis and long episodes

International audienceOBJECTIVE:Kleine-Levin syndrome is a rare disease characterized by recurrent episodes of hypersomnia with behavioral and cognitive disturbances. We aimed at describing the diagnosis procedure, risk factors, and severe forms.METHODS:In consecutive patients referred for suspected Kleine-Levin syndrome, we detailed differential diagnoses, and atypical and secondary cases, compared typical patients with healthy subjects, and examined the characteristics of patients with prolonged (>30 days) episodes.RESULTS:Among 166 referred patients, 120 had typical primary Kleine-Levin syndrome (syndrome secondary to brain diseases; n = 4, atypical syndrome, n = 7; differential diagnoses that were mostly psychiatric, n = 29; incomplete information, n = 6). The prevalence in France was 1.8 per million. The patients were often male (64%) and had more frequent birth and developmental abnormalities (45%) than controls (despite normal karyotypes), and most (80%) had teenage onset, with no difference between patients with prolonged (n = 34) and short (n = 85) episodes. In patients with prolonged episodes, the durations of the first episode (32 ± 33 vs 11 ± 6 days) and subsequent episodes were longer (mean episode duration = 23 ± 19 vs 10 ± 3 days) and the disease course tended to be longer (9 ± 6 vs 6 ± 4 years). During episodes, patients with prolonged episodes had shorter sleep time, higher levels of anxiety, increased agitation, and more feelings of disembodiment and amnesia. Between episodes, they were more tired, needed more naps, fell asleep more rapidly, and had higher anxiety/depression scores.INTERPRETATION:Mental disorders are frequent differential diagnoses of Kleine-Levin syndrome. One-third of patients have prolonged (>1 month) episodes with more frequent immediate and long-term consequences of the disease, prompting therapeutic trials

Brain correlates of apathy in Kleine Levin syndrome: a mean apparent propagator study

International audienceSynopsis Kleine-Levin syndrome (KLS) is a rare neurological disorder characterized by episodes of severe hypersomnia, apathy, cognitive impairment, derealization and behavioral disturbances. Between episodes, patients have normal sleep, mood and behavior. Apathy is a prominent clinical feature of KLS but its pathophysiology is not known. Here we used mean apparent propagator to investigate white matter changes in KLS and correlated diffusion changes with apathy scores. Results showed that the corpus callosum was involved in KLS during episodes and mean RTAP measures in the corpus callosum correlated with apathy scores. Results were in accordance with known motivation-based circuits involving the orbitomedial frontal cortex. Purpose Kleine-Levin syndrome (KLS) is a rare neurological disorder that mainly affects adolescents. KLS is characterized by relapsing-remitting episodes of severe hypersomnia, apathy, cognitive impairment, derealization and behavioral disturbances. Between episodes, patients have normal sleep, mood and behavior [1]. Each episode is of brief duration varying from a week to 1-2 months. No definite cause has been identified [1]. Anatomical MRI scan is normal, but brain scintigraphy can be abnormal during and between episodes [2]. Apathy is a prominent clinical feature of KLS [3] but its pathophysiology in the disease remains to be established. The mechanisms responsible for apathy may involve several circuits connecting the frontal lobes to the basal ganglia [4]. Here, we performed TBSS analyses on the return-to-the-axis probability (RTAP) measures that may be linked to apparent axonal diameter and inflammation [5] to analyze the integrity of white matter (WM) microstructure of healthy volunteers (HV) compared to symptomatic (KLS-S) and asymptomatic (KLS-AS) patients. Methods We prospectively included 20 KLS-AS (mean age: 22.2 ± 8.9 years, 9 males) and 20 HV age and sex-matched one by one. Twelve of these 20 patients were also scanned during episodes (KLS-S). Apathy was assessed using the Starkstein Apathy score [6]. Diffusion-weighted images were acquired using a Siemens Verio 3T with a 12-channel head coil (GRAPPA=2; TR/TE=7.7s/92ms; voxel size: 2.5mm isotropic; 64, 32 and 8 gradient directions for b-values of 1800, 700, and 300 s/mm² respectively) and 8 images without diffusion weighting were also acquired. We preprocessed the images using FSL (fsl.fmrib.ox.ac.uk/fsl/fslwiki/) and included correction for susceptibility (topup) and for eddy current distortions (eddycor) and creation of a binary mask of the brain (bet). Then, we generated RTAP maps of all subjects [7]. Voxelwise statistical analyses were carried out using TBSS, part of the FSL comparing RTAP maps of HV versus KLS-AS, HV versus KLS-S and KLS-AS versus KLS-S (paired t-test). Finally, in the TBSS-based ROI, we computed correlations between clinical scores (disease duration and apathy scores) and mean RTAP measures in this ROI and performed tractography on one healthy subject to determine its projection fibers. Results were considered significant at p<0.05, fully corrected for multiple comparisons across space. Results There were no significant differences in RTAP between HV and KLS-AS. In KLS-S compared to KLS-AS, RTAP increased in the corpus callosum (CC). There was a correlation between apathy scores and mean RTAP in the CC of KLS-S (p=0.03, r=0.61) (see Figure 2). There were no other correlations with clinical scores in KLS-AS as well as in KLS-S. Using the TBSS-ROI as a seed for tractography, fibers passing through the CC with abnormal RTAP measures projected to medial orbitofrontal cortex (see Figure 3). Discussion and conclusion The results highlight the presence of structural changes correlated to the apathy score in the anterior portion of the CC during episodes, a region where fibers project onto the medial orbitofrontal cortex. As, these prefrontal regions are involved in motivation processes [4], this suggests that apathy in KLS could result from difficulties to provide the affective/motivational value of a given behavioral context

Attention-deficit/hyperactivity disorder (ADHD) symptoms in pediatric narcolepsy: a cross-sectional study

Pediatric patients with narcolepsy have high levels of treatment-resistant ADHD symptoms. The optimal treatment for ADHD symptoms in these patients warrants further evaluation in longitudinal intervention studies