Relationships of self-reported and objective measures of sleep, sleepiness, and sleep quality in Parkinson's disease.

INTRODUCTION: Disrupted sleep and excessive daytime sleepiness (EDS) are common and disabling symptoms of Parkinson's disease (PD). The relationships between subjective and objective assessments of sleep and sleepiness in PD are not well established. We aimed to examine the relationships between self-reported (subjective) and objective assessments of sleep and sleepiness in PD. METHODS: Epworth Sleepiness Scale (ESS), Pittsburg Sleep Quality Index (PSQI), Parkinson's Disease Sleep Scale (PDSS), sleep diaries, and overnight polysomnography (PSG) with next-morning multiple sleep latency testing (MSLT) were collected from 27 individuals with PD and EDS who participated in a clinical trial of light therapy for EDS in PD. RESULTS: No significant correlations were found between measures of EDS and night-time sleep quality and quantity. PDSS was correlated with PSQI. PDSS and PSQI had significant relationships with multiple metrics derived from sleep diaries, including sleep latency, quality, and ease of falling asleep. Several PSG-derived sleep metrics correlated well with sleep diary metrics. CONCLUSIONS: There is a poor correlation between metrics used to assess sleep and sleepiness in PD. A sleep diary may be a valuable tool for this purpose. Accurate clinical and research assessment and monitoring require refinement of existing and development of novel methods for measuring sleep and sleepiness in PD.

Pitolisant, a wake-promoting agent devoid of psychostimulant properties: Preclinical comparison with amphetamine, modafinil, and solriamfetol.

Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake-promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine-like properties within in vivo preclinical models.

Artery of Percheron Stroke as an Unusual Cause of Hypersomnia: A Case Series and a Short Literature Review.

The thalamus and the mesencephalon have a complex blood supply. The artery of Percheron (AOP) is a rare anatomical variant. Occlusion of this artery may lead to bithalamic stroke with or without midbrain involvement. Given its broad spectrum of clinical features, AOP stroke is often misdiagnosed. Usually, it manifests with the triad of vertical gaze palsy, memory impairment, and coma. In this article, we report three cases of bilateral thalamic strokes whose clinical presentations were dominated by a sudden onset of hypersomnia. We also reviewed last 5 years' publications related to the AOP strokes in males presenting sleepiness or equivalent terms as a delayed complication. The AOP stroke may present a diagnostic challenge for clinicians which should be considered in the differential diagnosis of hypersomnia.

Daily Morning Blue Light Therapy Improves Daytime Sleepiness, Sleep Quality, and Quality of Life Following a Mild Traumatic Brain Injury.

OBJECTIVE: Identify the treatment effects of 6 weeks of daily 30-minute sessions of morning blue light therapy compared with placebo amber light therapy in the treatment of sleep disruption following mild traumatic brain injury. DESIGN: Placebo-controlled randomized trial. PARTICIPANTS: Adults aged 18 to 45 years with a mild traumatic brain injury within the past 18 months (n = 35). MAIN OUTCOME MEASURES: Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Beck Depression Inventory II, Rivermead Post-concussion Symptom Questionnaire, Functional Outcomes of Sleep Questionnaire, and actigraphy-derived sleep measures. RESULTS: Following treatment, moderate to large improvements were observed with individuals in the blue light therapy group reporting lower Epworth Sleepiness Scale (Hedges' g = 0.882), Beck Depression Inventory II (g = 0.684), Rivermead Post-concussion Symptom Questionnaire chronic (g = 0.611), and somatic (g = 0.597) symptoms, and experiencing lower normalized wake after sleep onset (g = 0.667) than those in the amber light therapy group. In addition, individuals in the blue light therapy group experienced greater total sleep time (g = 0.529) and reported improved Functional Outcomes of Sleep Questionnaire scores (g = 0.929) than those in the amber light therapy group. CONCLUSION: Daytime sleepiness, fatigue, and sleep disruption are common following a mild traumatic brain injury. These findings further substantiate blue light therapy as a promising nonpharmacological approach to improve these sleep-related complaints with the added benefit of improved postconcussion symptoms and depression severity.

Neuromyelitis optica spectrum disorder with severe orthostatic hypotension due to hypothalamic lesions.

BACKGROUND: Rare cases of neuromyelitis optica spectrum disorder (NMOSD) occur with only hypothalamic lesions as the initial lesion, and such cases can present with hypersomnia, endocrinopathy, and autonomic failure. However, orthostatic hypotension (OH) caused by hypothalamic lesions due to NMOSD has not been reported. CASE REPORT: We report the case of a patient with NMOSD who presented with severe OH due to hypothalamic lesions. CONCLUSION: We suggest that clinicians should be aware that NMOSD with hypothalamic lesions can present with OH.

Secondary hypersomnia as an initial manifestation of neuromyelitis optica spectrum disorders.

The identification of AQP4-IgG, a specific and pathogenic antibody of NMO/SD has led to a broadening of the clinical spectrum of manifestations of NMO/SD including the presence of encephalic symptoms. Lesions are often distributed on peri­ependymal area and sometimes affected the diencephalon leading to sleep disorders. We report a case of hypersomnia with polysomnographic documentation during the first attack of NMO/SD. Brain MRI revealed bilateral hypothalamic lesions around the third ventricle, whereas optic nerves and spinal cord were intact. The record of the nocturnal video-polysomnography followed by multiple sleep latency tests (MSLT) revealed an abnormal shortened sleep period with a single sleep onset in REM allowing secondary central hypersomnia diagnosis. The recovery of hypersomnia was complete within few months without psychostimulant treatment and the diencephalic lesion disappeared. Thus, diencephalic form of NMO/SD seems to cause narcolepsy or non-narcoleptic central hypersomnia and have a good recovery.

Sudden onset of sleep caused by hypothalamic infarction: a case report.

BACKGROUND: Hypothalamic lesions, such as tumors and demyelinating diseases, reportedly cause abnormal sleepiness. However, stroke involving the hypothalamus has rarely been described. Here, we report a patient with infarction restricted to the hypothalamus who presented with sudden onset of sleep. CASE PRESENTATION: A 42-year-old woman with a history of migraine without aura presented with irresistible sleepiness and developed several episodes of sudden onset of sleep. Neurological examinations were unremarkable except for partial left Horner syndrome. Brain magnetic resonance imaging (MRI) revealed a high-intensity lesion restricted to the left hypothalamus on diffusion-weighted and fluid-attenuated inversion recovery MRI images. Cerebrospinal fluid (CSF) orexin-A levels obtained on hospital day 3 after her sleepiness had resolved were normal (337 pg/mL; normal > 200 pg/mL). Serum anti-nuclear and anti-aquaporin 4 (AQP4) antibodies and CSF myelin basic protein and oligoclonal band were negative. A small hypothalamic infarction was suspected, and the patient was treated with intravenous edaravone and argatroban, as well as oral clopidogrel. Three months later, there had been no clinical relapse, and the hypothalamic lesion had almost disappeared on follow-up MRI. No new lesion suggestive of demyelinating disease or tumor was observed. CONCLUSION: Hypothalamic stroke should be considered a cause of sudden onset of sleep.

[Encephalitis lethargica. The epidemic at the dawn of neurology]. / Encefalitis letargica. La epidemia en los albores de la neurologia.

Lethargic encephalitis is a neurological illness that shows a wide range of symptoms and signs, including neurological and psychiatric spectrum. It presented in an epidemic way, following influaenza relapses. The last relapse started at the beginning of 20th century and it was deeply described by Constantin von Economo. The illness described first in Europe and North America, was described in many others countries including Chile. There were beautiful descriptions by Chilean physicians like Lea-Plaza, Tello, Iturra and Cienfuegos. Their works showed the complexity of the illness like European physicians did too. The etiology is still unknown; however growing evidence about autoinmune aetiology is gaining force with the use of actual medical technology. In this work, we show encephalitis lethargica, focusing in clinical picture, the beauty of medical descriptions that physicians did at this date.

TITLE: Encefalitis letargica. La epidemia en los albores de la neurologia.La encefalitis letargica es un cuadro neurologico con una variada gama de manifestaciones clinicas en el ambito neurologico y tambien en el psiquiatrico. El cuadro se ha presentado de manera epidemica en brotes que han seguido a los de la gripe. El ultimo brote acaecido a comienzos del siglo XX lo describio en profundidad Constantin von Economo. La epidemia notificada inicialmente en Europa y luego en Norteamerica se presento tambien en otras latitudes, incluyendo Chile. Asi, las descripciones de Lea-Plaza, Tello, Iturra, Cienfuegos y otros medicos chilenos dieron cuenta del cuadro en Chile con toda la complejidad que tambien tuvo en Europa. El origen sigue siendo un misterio, aunque la evidencia creciente de que fuera autoinmune gana fuerza con los hallazgos de la tecnologia medica actual. En este trabajo presentamos el cuadro, privilegiando la riqueza clinica y la belleza de las descripciones realizada por los medicos de la epoca en que esta enfermedad se presento.

Reduced resting-state thalamostriatal functional connectivity is associated with excessive daytime sleepiness in persons with and without depressive disorders.

BACKGROUND: Excessive daytime sleepiness (EDS) is a common and significant problem encountered in affective illness, however, the biological underpinnings of EDS in persons with psychiatric disorders are not clear. This study evaluated the associations between thalamic connectivity with cortical and subcortical brain regions with EDS in persons with and without depressive disorders (DD). METHODS: Resting-state functional connectivity magnetic resonance imaging scans from 67 unmedicated young to middle-aged women with current DD (n = 30), remitted DD (n = 13), and healthy controls (n = 24) were utilized to examine the associations between thalamic connectivity with cortical/subcortical structures and EDS. RESULTS: After correction for multiple comparisons and adjustment for age, habitual sleep duration, and depressive symptomatology, reduced resting-state connectivity between the bilateral thalamus and left rostral striatum (caudate/putamen) was significantly associated with EDS. LIMITATIONS: Causal inferences between thalamostriatal connectivity and EDS could not be determined. CONCLUSIONS: These results further implicate the role of the striatum and thalamus as central components of the experience of EDS. Further research is indicated to clarify the specific role these structures play in EDS in psychiatric disorders.

Timed Light Therapy for Sleep and Daytime Sleepiness Associated With Parkinson Disease: A Randomized Clinical Trial.

IMPORTANCE: Impaired sleep and alertness are some of the most common nonmotor manifestations of Parkinson disease (PD) and currently have only limited treatment options. Light therapy (LT), a widely available treatment modality in sleep medicine, has not been systematically studied in the PD population. OBJECTIVE: To determine the safety and efficacy of LT on excessive daytime sleepiness (EDS) associated with PD. DESIGN, SETTINGS, AND PARTICIPANTS: This randomized, placebo-controlled, clinical intervention study was set in PD centers at Northwestern University and Rush University. Participants were 31 patients with PD receiving stable dopaminergic therapy with coexistent EDS, as assessed by an Epworth Sleepiness Scale score of 12 or greater, and without cognitive impairment or primary sleep disorder. Participants were randomized 1:1 to receive bright LT or dim-red LT (controlled condition) twice daily in 1-hour intervals for 14 days. This trial was conducted between March 1, 2007, and October 31, 2012. Data analysis of the intention-to-treat population was conducted from November 1, 2012, through April 30, 2016. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the change in the Epworth Sleepiness Scale score comparing the bright LT with the dim-red LT. Secondary outcome measures included the Pittsburgh Sleep Quality Index score, the Parkinson's Disease Sleep Scale score, the visual analog scale score for daytime sleepiness, and sleep log-derived and actigraphy-derived metrics. RESULTS: Among the 31 patients (13 males and 18 females; mean [SD] disease duration, 5.9 [3.6] years), bright LT resulted in significant improvements in EDS, as assessed by the Epworth Sleepiness Scale score (mean [SD], 15.81 [3.10] at baseline vs 11.19 [3.31] after the intervention). Both bright LT and dim-red LT were associated with improvements in sleep quality as captured by mean (SD) scores on the Pittsburg Sleep Quality Index (7.88 [4.11] at baseline vs 6.25 [4.27] after bright LT, and 8.87 [2.83] at baseline vs 7.33 [3.52] after dim-red LT) and the Parkinson's Disease Sleep Scale (97.24 [22.49] at baseline vs 106.98 [19.37] after bright LT, and 95.11 [19.86] at baseline vs 99.28 [16.94] after dim-red LT). Bright LT improved several self-reported mean (SD) sleep metrics, including sleep fragmentation (number of overnight awakenings, 1.51 [1.03] at baseline vs 0.92 [0.97] after the intervention), sleep quality (sleep diary score, 3.03 [1.01] at baseline vs 3.53 [0.91] after the intervention), and ease of falling asleep (sleep diary score, 2.32 [0.89] at baseline vs 1.83 [0.88] after the intervention). Light therapy was associated with increased daily physical activity as assessed by actigraphy (average activity [SD] counts, 165.01 [66.87] at baseline vs 194.59 [87.81] after the intervention). CONCLUSIONS AND RELEVANCE: Light therapy was well tolerated and may be a feasible intervention for improving the sleep-wake cycles in patients with PD. Further studies are required to determine optimal parameters of LT for PD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01338649.

Obstructive Sleep Apnea: Update and Future.

Obstructive sleep apnea (OSA) is a worldwide disease whose prevalence is increasing as obesity rates increase. The link between obesity and OSA is likely to be the deposition of fat in the tongue, compromising upper airway size. The role of obesity varies in different ethnic groups, with Chinese being particularly sensitive to increases in weight. OSA lends itself to a personalized approach to diagnosis and therapy. For example, different clinical OSA subtypes likely benefit from therapy in different ways. Hypoglossal nerve stimulation is a useful second-line therapy in patients who cannot tolerate continous positive airway pressure (CPAP) machines or intraoral devices. Technological advances allow patients to participate in their own care, and doing so improves CPAP compliance. We are entering a future where we can focus efforts to predict and prevent OSA on an individual level.

Investigating the Role of Hypothalamic Tumor Involvement in Sleep and Cognitive Outcomes Among Children Treated for Craniopharyngioma.

OBJECTIVE: Despite excellent survival prognosis, children treated for craniopharyngioma experience significant morbidity. We examined the role of hypothalamic involvement (HI) in excessive daytime sleepiness (EDS) and attention regulation in children enrolled on a Phase II trial of limited surgery and proton therapy. METHODS: Participants completed a sleep evaluation (N = 62) and a continuous performance test (CPT) during functional magnetic resonance imaging (fMRI; n = 29) prior to proton therapy. RESULTS: EDS was identified in 76% of the patients and was significantly related to increased HI extent (p = .04). There was no relationship between CPT performance during fMRI and HI or EDS. Visual examination of group composite fMRI images revealed greater spatial extent of activation in frontal cortical regions in patients with EDS, consistent with a compensatory activation hypothesis. CONCLUSION: Routine screening for sleep problems during therapy is indicated for children with craniopharyngioma, to optimize the timing of interventions and reduce long-term morbidity.

[Posterior reversible encephalopathy syndrome of the midbrain and hypothalamus - a case report of uremic encephalopathy presenting with hypersomnia].

We report the case of a 73-year-old woman presenting with hypersomnia and loss of appetite. She suffered from diabetic nephropathy without receiving dialysis, in addition to hypertension, which was well controlled without marked fluctuation. There were no objective neurological findings. Her laboratory findings showed renal failure with 3.7 mg/dl of serum creatinine and decreased serum sodium and potassium. Brain magnetic resonance imaging (MRI) showed posterior reversible encephalopathy syndrome (PRES) with vasogenic edema, which was distributed in the dorsal midbrain, medial thalamus, and hypothalamus. After we addressed the electrolyte imbalance and dehydration, her symptoms and MRI findings gradually improved, but faint high signals on MRI were still present 3 months later. Orexin in the cerebrospinal fluid was decreased on admission, but improved 6 months later. We diagnosed uremic encephalopathy with atypical form PRES showing functional disturbance of the hypothalamus.

Neuromyelitis optica spectrum disorder presenting with repeated hypersomnia due to involvement of the hypothalamus and hypothalamus-amygdala linkage.

We report the case of a 46-year-old Japanese woman with neuromyelitis optica spectrum disorder presenting with repeated hypersomnia accompanied by decreased CSF orexin level. First episode associated with hypothalamic-pituitary dysfunction showed bilateral hypothalamic lesions that can cause secondary damage to the orexin neurons. The second episode associated with impaired memory showed a left temporal lesion involving the amygdala. The mechanism remains unknown, but the reduced blood flow in the hypothalamus ipsilateral to the amygdala lesion suggested trans-synaptic hypothalamic dysfunction secondary to the impaired amygdala. A temporal lesion involving the amygdala and hypothalamus could be responsible for hypersomnia due to neuromyelitis optica spectrum disorder.

Sudden onset of sleep due to hypothalamic lesions in neuromyelitis optica spectrum disorder positive for anti-aquaporin-4 antibody.

We report a patient with neuromyelitis optica spectrum disorders who presented with sudden onset of sleep as the sole manifestation. Magnetic resonance imaging investigation revealed lesions in the hypothalamus bilaterally, which vanished completely after methylprednisolone pulse therapy.

Cognitive decline and hypersomnolence: thalamic manifestations of a tentorial dural arteriovenous fistula (dAVF).

BACKGROUND: Intracranial dural arteriovenous fistulas (dAVFs) often present with pulsatile tinnitus, orbital congestion, and headache. Occasionally, they present with focal neurologic deficits, a dementia-like syndrome, hemorrhage, or ischemic infarction. METHODS: This study is based on the case of a 71-year-old gentleman who presented with 6 months of progressive forgetfulness, inattention, and hypersomnolence. Four weeks prior to presentation, he developed symptoms of left-sided pain, numbness, and worsening weakness. Neurologic examination demonstrated hypersomnolence, a score of 30/38 on the Kokmen Short Test of Mental Status, and left hemiparesis. MRI brain revealed bilateral thalamic T2 hyperintensities with associated enhancement. MR venogram (MRV) showed a vascular malformation in the posterior fossa and occlusion of the straight sinus. Conventional cerebral angiogram confirmed a tentorial dAVF. The dAVF was definitively treated with transarterial embolization, followed by clip ligation of the arterialized draining vein. Twelve weeks later, there was clinical resolution of left hemiparesis and improvement in cognitive status. MRI revealed complete resolution of the thalamic hyperintensities. MRV demonstrated recanalization of the straight sinus. RESULTS: Intracranial dAVFs are uncommon but potentially life-threatening acquired vascular malformations. The initiating factor is venous hypertension, causing retrograde flow, venous congestion, ischemia, and sometimes infarction. The spectrum of clinical manifestations in dAVFs reflects the degree of venous congestion present. If retrograde venous flow is surgically obliterated, then venous hypertension may be reversible. Bilateral thalamic venous congestion can present as a thalamic dementia. CONCLUSION: We conclude that intracranial dAVFs with thalamic venous congestion should be considered in the diagnostic differential for patients who present with subacute cognitive decline and T2 hyperintense thalamic signal change.