Narcolepsy with cataplexy (NC) is a complex sleep-wake disorder, which was recently found to be associated with a reduction or loss of hypocretin (HCRT, also called orexin). HCRT is a hypothalamic peptide implicated in the regulation of sleep/wake, motor and feeding functions. Cataplexy refers to episodes of sudden and transient loss of muscle tone triggered by strong, mostly positive emotions, such as hearing or telling jokes. Cataplexy is thought to reflect the recruitment of ponto-medullary mechanisms that normally underlie muscle atonia during REM-sleep. In contrast, the suprapontine brain mechanisms associated with the cataplectic effects of emotions in human narcolepsy with cataplexy remain essentially unknown. Here, we used event-related functional MRI to assess brain activity in 12 NC patients and 12 controls while they watched sequences of humourous pictures. Patients and controls were similar in humour appreciation and activated regions known to contribute to humour processing, including limbic and striatal regions. A direct statistical comparison between patients and controls revealed that humourous pictures elicited reduced hypothalamic response together with enhanced amygdala response in the patients. These results suggest (i) that hypothalamic HCRT activity physiologically modulates the processing of emotional inputs within the amygdala, and (ii) that suprapontine mechanisms of cataplexy involve a dysfunction of hypothalamic-amygdala interactions triggered by positive emotions.

Background/Aims: Excessive daytime sleepiness (EDS) is frequent in patients with Parkinson’s disease (PD). Occasionally, EDS in PD exhibits narcolepsy-like features. We aimed to assess characteristics and determinants of EDS in consecutive patients with PD. Methods: Thirty consecutive patients with PD underwent a detailed clinical examination. EDS was assessed using the Epworth Sleepiness Scale (ESS) and Multiple Sleep Latency Test (MSLT). Sleep was assessed using video-polysomnography. Cerebrospinal fluid (CSF) hypocretin-1 levels were obtained in 3 patients. Results: ESS was >10 in 17 patients (57%). Mean sleep latency (MSL) on MSLT was <5 min in 11 patients (37%). There was a significant negative correlation between ESS and MSL. None of the 11 patients with MSL <5 min showed a sleep onset REM (SOREM) episode. Patients with EDS had higher dopamine agonists/levodopa equivalent doses, higher apnea/hypopnea index and exhibited wearing-off symptoms more often. Hypocretin-1 was normal in 3 patients tested. Conclusion: EDS, which can sometimes be severe, is common in PD patients even in the absence of SOREM and detectable CSF-hypocretin deficiency. In PD, EDS is a multifaceted phenomenon, the determinants of which include severity of PD, wearing-off symptoms, dosage of antiparkinsonian drugs and sleep-disordered breathing.

Our results reveal that activity in the dopaminergic ventral midbrain (ventral tegmental area) was not modulated in narcolepsy-cataplexy patients during high reward expectancy (unlike controls), and that ventral striatum activity was reduced during winning. By contrast, the patients showed abnormal activity increases in the amygdala and in dorsal striatum for positive outcomes. In addition, we found that activity in the nucleus accumbens and the ventral-medial prefrontal cortex correlated with disease duration, suggesting that an alternate neural circuit could be privileged over the years to control affective responses to emotional challenges and compensate for the lack of influence from ventral midbrain regions. Our study offers a detailed picture of the distributed brain network involved during distinct stages of reward processing and shows for the first time, to our knowledge, how this network is affected in hypocretin-deficient narcoleptic patients.

Summary After stroke, the injured brain undergoes extensive reorganization and reconnection. Sleep may play a role in synaptic plasticity underlying stroke recovery. To test this hypothesis, we investigated topographic sleep electroencephalographic characteristics, as a measure of brain reorganization, in the acute and chronic stages after hemispheric stroke. We studied eight patients with unilateral stroke in the supply territory of the middle cerebral artery and eight matched controls. All subjects underwent a detailed clinical examination including assessment of stroke severity, sleep habits and disturbances, anxiety and depression, and high‐density electroencephalogram examination with 128 electrodes during sleep. The recordings were performed within 10 days after stroke in all patients, and in six patients also 3 months later. During sleep, we found higher slow‐wave and theta activity over the affected hemisphere in the infarct area in the acute and chronic stage of stroke. Slow‐wave, theta activity and spindle frequency range power over the affected hemisphere were lower in comparison to the non‐affected side in a peri‐infarct area in the patients’ group, which persisted over time. Conversely, in wakefulness, only an increase of delta, theta activity and a slowing of alpha activity over the infarct area were found. Sleep slow‐wave activity correlated with stroke severity and outcome. Stroke might have differential effects on the generation of delta activity in wakefulness and sleep slow waves (1–8 Hz). Sleep electroencephalogram changes over both the affected and non‐affected hemispheres reflect the acute dysfunction caused by stroke and the plastic changes underlying its recovery. Moreover, these changes correlate with stroke severity and outcome.

Summary Sleep–wake disturbances are frequent in patients with Parkinson’s disease, but prospective controlled electrophysiological studies of sleep in those patients are surprisingly sparse, and the pathophysiology of sleep–wake disturbances in Parkinson’s disease remains largely elusive. In particular, the impact of impaired dopaminergic and hypocretin (orexin) signalling on sleep and wakefulness in Parkinson’s disease is still unknown. We performed a prospective, controlled electrophysiological study in patients with early and advanced Parkinson’s disease, e.g. in subjects with presumably different levels of dopamine and hypocretin cell loss. We compared sleep laboratory tests and cerebrospinal fluid levels with hypocretin‐deficient patients with narcolepsy with cataplexy, and with matched controls. Nocturnal sleep efficiency was most decreased in advanced Parkinson patients, and still lower in early Parkinson patients than in narcolepsy subjects. Excessive daytime sleepiness was most severe in narcolepsy patients. In Parkinson patients, objective sleepiness correlated with decrease of cerebrospinal fluid hypocretin levels, and repeated hypocretin measurements in two Parkinson patients revealed a decrease of levels over years. This suggests that dopamine and hypocretin deficiency differentially affect sleep and wakefulness in Parkinson’s disease. Poorer sleep quality is linked to dopamine deficiency and other disease‐related factors. Despite hypocretin cell loss in Parkinson’s disease being only partial, disturbed hypocretin signalling is likely to contribute to excessive daytime sleepiness in Parkinson patients.

Background Current guidelines do not recommend primary prophylactic anti-epileptic drug (AED) therapy for patients with brain metastases (BM). Yet, subgroups of patients at high seizure risk might still benefit from prophylaxis. Methods We identified 799 patients diagnosed with BM by retrospective screening of our electronic chart system. Candidate risk factors for the development of epilepsy were tested by univariate and multivariate Cox regression models. Results Epilepsy was diagnosed in 226 of 799 patients (28%). Risk factors for epilepsy in non-operated patients were single BM (P = 0.002, hazard ratio [HR] 3.2, 95% CI: 1.5–6.6) and detection of tumoral hemorrhage (P = 0.008, HR 2.5, 95% CI: 1.3–4.9). Preoperative seizures occurred predominantly in patients with supratentorial BM (P = 0.003, HR 20.78, 95% CI: 2.8–153.4) and lung cancer (P = 0.022; HR 2.0, 95% CI: 1.1–3.6). Postoperative seizures were associated with supratentorial localization (P = 0.017, HR 5.8, 95% CI: 1.4–24.3), incomplete resection (P = 0.005, HR 4.6, 95% CI: 1.6–13.1), and by trend for multiple brain surgeries (P = 0.095, HR 1.9, 95% CI: 0.9–4.0). These risk factors were integrated into a predictive score model for postoperative epilepsy (score sum 0–8). A gradual increase of seizure rates along with higher sum score was confirmed post hoc (score 0 = no seizures; score 8 = 48% seizures). Receiver operating characteristic analysis supported diagnostic accuracy (P = 0.00001, area under the curve = 0.75). Conclusions Here we have defined risk profiles for the development of BM-related epilepsy and derived a score which might help to estimate the risk of postoperative seizures and identify individuals at risk who might benefit from primary prophylactic AED therapy.

Narcolepsy with cataplexy is a sleep-wake disorder caused by a loss of hypothalamic hypocretins. Here we assessed the time course of amygdala activation during aversive conditioning in unmedicated patients with narcolepsy. Unlike healthy matched control subjects, narcolepsy patients had no enhancement of amygdala response to conditioned stimuli and no increase in functional coupling between the amygdala and medial prefrontal cortex. These findings suggest that human narcolepsy is accompanied by abnormal emotional learning, and that, in line with animal data, the hypocretin system and the amygdala are involved in this process.

bRIEF SUMMaRYCurrent Knowledge/Study Rationale: RBD is very common in PD and there have been multiple attempts to fi nd a questionnaire based diagnostic tool for RBD. For the fi rst time we use a previously validated questionnaire tool assessment of RBD in a large, unselected sample of PD patients. Study Impact: RBD in PD could be detected by a validated questionnaire tool in 42.6% of the patients, which is comparable to the frequency found in PSG-based studies. It was associated with more advanced disease, sleep fragmentation and hallucinations.