Association between electroencephalogram-based sleep characteristics and physical health in the general adult population.

We examined the associations between electroencephalogram (EEG)-based sleep characteristics and physical health parameters in general adults via a cross-sectional study recruiting 100 volunteers aged 30-59 years. Sleep characteristics were measured at home using a portable multichannel electroencephalography recorder. Using the k-means + + clustering method, according to 10 EEG-based parameters, participants were grouped into better (n = 39), middle (n = 46), and worse (n = 15) sleep groups. Comparing 50 physical health parameters among the groups, we identified four signals of difference (P < 0.05), including systolic (sBP) and diastolic blood pressure (dBP), γ-glutamyl transpeptidase (γ-GTP), and serum creatinine, where sBP reached a Bonferroni-corrected threshold (P < 0.001). The sBP was higher by 7.9 (95% confidence interval 1.9-13.9) and 15.7 (7.3-24.0) mmHg before adjustment and 5.4 (- 0.1-10.9) and 8.7 (1.1-16.3) mmHg after adjustment for age, sex, body mass index, smoking, drinking habits, and 3% oxygen desaturation index in the middle and worse sleep groups, respectively, than in the better group. As another approach, among 500 combinations of EEG-based and physical health parameters, there were 45 signals of correlation, of which 4 (N1% and sBP, dBP, γ-GTP, and triglycerides) reached a Bonferroni-corrected threshold (P < 0.0001). Thus, EEG-based sleep characteristics are associated with several physical health parameters, particularly sBP.

Aripiprazole disrupts cellular synchrony in the suprachiasmatic nucleus and enhances entrainment to environmental light-dark cycles in mice.

Many patients with psychiatric conditions, such as bipolar disorder and major depressive disorder, frequently experience disruptions in their sleep-wake cycles. Several case studies and clinical trials have shown that the administration of aripiprazole, a commonly prescribed antipsychotic drug, alleviates the symptoms of circadian sleep disorders in these patients. This improvement may be attributed to the effects of aripiprazole on the circadian central clock, specifically the hypothalamic suprachiasmatic nucleus (SCN), which regulates various circadian physiological rhythms, including the sleep-wake cycle, in mammals. To examine whether aripiprazole facilitates adaptation to changes in the light-dark cycle, we orally administered aripiprazole to mice and subjected them to jet-lag experiments. Mice receiving aripiprazole were more rapidly entrained to 6 h advanced light-dark cycles. Moreover, we examined the effect of aripiprazole on the cellular rhythms of SCN slice cultures and found that aripiprazole disrupted cellular synchronization in the SCN, thereby accelerating the damping of the SCN rhythm at the population level. Adenosine 3'5' monophosphate (cAMP) assay using a bioluminescence indicator revealed that intracellular cAMP level in the SCN increased following aripiprazole treatment. However, this increase was blocked by pre-treatment with the serotonin 1A receptor (5-HT1AR) antagonist. Based on these findings, we propose that aripiprazole modulates intracellular signaling, including 5-HT1AR-mediated cAMP signaling, and desynchronizes SCN neurons, ultimately leading to enhanced entrainment to phase advanced light-dark cycles in mice. These findings indicate that the improvement in sleep symptoms reported in patients with psychiatric disorders receiving aripiprazole may be due to modulation of the circadian clock. Our study provides novel insights into the potential clinical applications of aripiprazole in patients with various circadian sleep disorders.

The validity of atypical psychosis diagnostic criteria to detect anti-NMDA receptor encephalitis with psychiatric symptoms.

Anti-NMDAR encephalitis has a psychotic presentation that is difficult to distinguish from primary psychosis. An atypical psychosis that is similar to schizophrenia, mood disorder, and epilepsy is unique, and the original diagnostic criteria exist only in Japan. The clinical symptoms and courses of anti-NMDAR encephalitis and atypical psychosis are very similar. We investigated whether the diagnostic criteria of atypical psychosis are useful to increase the detection rate of anti-NMDAR encephalitis with psychiatric symptoms. The presence of anti-NR1/NR2B IgG antibodies in the cerebrospinal fluid of 218 newly admitted inpatients initially diagnosed with schizophrenia (n = 151), mood disorder (n = 47), or epilepsy with psychiatric symptoms (n = 20) was assessed by cell-based assay. Of 218 patients, 123 (36.3 years ± SD 17.2, 69.9 % females) fulfilled the diagnostic criteria of category B for atypical psychosis. All 12 patients (9.8 %, 12/123) with anti-NR1/NR2B IgG antibodies fulfilled category B of atypical psychosis statistically better than the patients without anti-NR1/NR2B IgG antibodies (P = 0.0009). Of the 12 patients with anti-NMDAR antibodies, two did not fulfill either criteria of catatonia (DSM-5) or Graus' diagnostic criteria of anti-NMDAR encephalitis during the time course, and 11 patients showed good prognosis with early immunotherapies. In ROC analysis, abnormal electroencephalogram findings showed the highest sensitivity (0.833) for detection of anti-NR1/NR2B IgG antibodies, and 31.3 % of patients with category B atypical psychosis and abnormal electroencephalogram findings had anti-NMDAR antibodies. Lumbar puncture and detection of anti-NMDAR antibodies should be considered for patients who fulfill atypical psychosis diagnosis criteria with an abnormal electroencephalogram.

Impairment of early neuronal maturation in anti-NMDA-receptor encephalitis.

RATIONALE: Adequate immunotherapies for anti-NMDAR encephalitis during pregnancy produce a relatively good clinical outcome for pregnant mothers and their infants, but there are no reports about the future growth of their babies. The damage of anti-NMDAR antibodies to early neuronal development is still unknown. OBJECTIVES: Serum or cerebrospinal fluid from one patient with anti-NMDAR encephalitis (the index patient) and one patient with schizophrenia (the control patient) was administered to primary cultures of dissociated rat cortical neurons, and dendritic outgrowth, centrosome elimination, and branching of dendrites were investigated. For rescue experiments, serum of the index patient was replaced with normal culture media after 3 days' administration of the index patient. RESULTS: Serum and cerebrospinal fluid of the index patient statistically significantly impaired dendritic outgrowth of cultured rat cortical primary neurons. Serum of the index patient also statistically significantly delayed centrosome elimination. Impaired dendritic outgrowth and delayed centrosome elimination were not perfectly rescued by changing to normal culture media. Serum of the index patient also statistically significantly reduced the branching of dendrites. CONCLUSIONS: This is the first demonstration of the damage by anti-NMDAR antibodies on early dendritic development in vitro. As a strategy to protect embryonic neurons, our findings may support the efficacy of early immunotherapy for anti-NMDAR encephalitis in pregnancy.

Rituximab Was Effective for Treatment of Anti-N-Methyl-d-Aspartate Receptor Encephalitis in Early Adolescence in Initially Suspected Dissociative Disorder.

OBJECTIVES: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an increasingly recognized etiology of psychiatric symptoms. Because patients with anti-NMDAR encephalitis frequently show aggression, mania, hallucination, depression, or delusion, they are initially diagnosed with schizophrenia or mood disorders. There is only 1 case report of an initially diagnosed dissociative disorder. METHODS: We obtained consent for the presentation and have not identified individuals for ethical reasons. RESULTS: We first report an adolescent female patient with anti-NMDAR encephalitis who was initially suspected of having dissociative disorder but was responsive to immunotherapies including rituximab. In this case, her symptoms and electroencephalogram findings were proportional to the antibody titer in the cerebrospinal fluid. CONCLUSIONS: It is important to consider the possibility of autoimmune encephalitis and immunotherapy including rituximab in cases of not only acute psychosis but also dissociation.

Risk of immunotherapy-related narcolepsy in genetically predisposed patients: a case report of narcolepsy after administration of pembrolizumab.

BACKGROUND: Immune-related adverse events associated with immune checkpoint therapy cause autoimmune disease-like symptoms. People who carry specific genotypes or haplotypes of human leucocyte antigen (HLA) are known to be predisposed to develop autoimmune diseases including narcolepsy. Immunotherapy could be a trigger to develop narcolepsy in predisposing HLA positive patients. CASE PRESENTATION: A 66-year-old woman with stage IVB endometrial carcinosarcoma experienced daytime sleepiness and temporary muscle weakness 14 days after the administration of an immune checkpoint inhibitor, pembrolizumab. These were consistent with the main symptoms of narcolepsy with cataplexy. This patient carried a highly predisposing HLA haplotype for narcolepsy; HLA-DQB1*06:02, DRB1*15:01, DQA1*01:02 and DRB5*01:01:01. A hypocretin-1/orexin-A concentration in the patient's cerebrospinal fluid was low at 9.6 pg/mL in ELISA, and 155.5 pg/mL in radioimmunoassay that was below the normal level of 200 pg/mL. Therefore, she was diagnosed with narcolepsy tentatively according to the International Classification of Sleep Disorders, third edition diagnostic criteria for narcolepsy. The onset of narcolepsy in the 60s is very rare, and narcoleptic symptoms in our patient were likely to be caused by pembrolizumab. CONCLUSIONS: This case suggests that treatment with immune checkpoint inhibitors potentially causes narcolepsy in genetically predisposed patients.

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.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis in Psychiatry.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently-discovered autoimmune disorder in which antibodies target NMDAR in the brain. The number of reported cases of anti-NMDAR encephalitis has increased rapidly. Anti-NMDAR encephalitis can be mistakenly diagnosed as psychiatric disorders because many patients present with prominent psychiatric symptoms and visit psychiatric institutions first. Thus, psychiatrists should cultivate a better understanding of anti-NMDAR encephalitis. In this review, we present the mechanisms, epidemiology, symptoms and clinical course, diagnostic tests, treatment and outcomes of patients with anti-NMDAR encephalitis. Furthermore, we discuss the diversity of clinical spectra of anti-NMDAR encephalitis, and demonstrate a differential diagnosis of psychiatric disease from the perspective of psychiatry.

Orexin secretion abnormality involved in excessive somnolence in CNS lymphoma without hypothalamic lesions.

A 72-year-old woman developed excessive somnolence as one of the symptoms of diffuse large B-cell lymphoma in the central nervous system (CNS). Although somnolence might be caused by reduced orexin secretion associated with hypothalamic lesions, neither brain MRI nor 18F-fluorodeoxyglucose positron emission tomography identified hypothalamic lesions. However, the decreased cerebrospinal fluid (CSF) orexin levels recovered to near normal values with improvement of somnolence after chemotherapy. The alteration of CSF orexin levels suggested the involvement of potential hypothalamic lesions. Therefore, measurements of CSF orexin levels may be useful for understanding the pathological background of somnolence in CNS lymphoma without hypothalamic lesions.

Anorexia nervosa-associated pancytopenia mimicking idiopathic aplastic anemia: a case report.

BACKGROUND: Patients with anorexia nervosa (AN) often present with pancytopenia. In most cases described in the literature, AN with pancytopenia demonstrates gelatinous marrow transformation (GMT), which is a typical bone marrow feature of malnutrition. Differentiation of AN-associated pancytopenia from other types of pancytopenia, especially idiopathic aplastic anemia (IAA), has not been studied. We encountered a case of pancytopenia in a patient with AN and relatively poor nutritional status, whose hematological findings mimicked those of IAA, specifically fatty bone marrow and absence of GMT. CASE PRESENTATION: The patient was a 32-year-old woman with poorly controlled AN. At 31 years of age, her body mass index (BMI) had fallen from 17.0 kg/m2 to below 13.8 kg/m2. The patient presented with ongoing fatigue and thus was examined by a hematologist. Hematological findings were consistent with IAA: peripheral blood tests revealed pancytopenia, whereas the bone marrow displayed fatty replacement without GMT. Despite the absence of bone marrow features typically seen in malnutrition, the patient's hematological abnormalities had manifested after a decrease in body weight. Thus, although the bone marrow findings indicated IAA, we considered that the nutritional etiology of pancytopenia could not be thoroughly ruled out. Using nutritional therapy alone, the hematological abnormalities improved as BMI increased to 16.5 kg/m2. The final diagnosis was pancytopenia secondary to malnutrition because pancytopenia and fatty bone marrow improved after implementation of nutritional therapy alone. CONCLUSIONS: The present case is the first documented case of AN with pancytopenia for which bone marrow examination confirmed fatty marrow without any evidence of GMT. IAA and pancytopenia secondary to malnutrition can present the same clinical findings. This case is significant because it suggests a need to differentiate between malnutrition and IAA.

Insulinoma Masquerading as Rapid Eye Movement Sleep Behavior Disorder: Case Series and Literature Review.

Insulinoma is a rare endocrine tumor that can cause a wide variety of symptoms, including abnormal nocturnal behavior. We report on 3 patients with insulinoma who presented with abnormal nocturnal behavior and injury during sleep, which simulated rapid eye movement (REM) sleep behavior disorder (RBD). In case 1, the fasting glucose level was 15  mg/dL, and insulin levels were elevated (15  µU/mL). In case 3, when the patient was transferred to the hospital because of a disturbance of consciousness, hypoglycemia (29  mg/dL) was detected. In contrast, in case 2, fasting glucose sampling did not indicate hypoglycemia, but continuous glucose monitoring revealed nocturnal hypoglycemia. The time from initial symptoms to a diagnosis of insulinoma ranged from 7 months to 2 years. All 3 patients had previously received anticonvulsant drugs for suspected epilepsy, but the medications were ineffective. Polysomnography showed no evidence of REM sleep without atonia in any of the 3 patients. No patient remembered any events that occurred during sleep. When a patient manifests abnormal behavior during the night and early morning, glucose monitoring should be performed, especially during the night and early morning. Clinicians should be aware that although insulinomas are rare, they can mimic parasomnias, such as RBD.

[A 39 years old woman responding to modafinil with bilateral hypothalamic lesion associated with hyperthermia and hypersomnia: a case report].

A 39 years old woman was admitted to our hospital with a status epilepticus, with high fever of 41°C. Magnetic resonance Imaging (MRI) revealed high signal intensities of both sides of thalami and hypothalami in T2 weighted and fluid attenuated inversion recovery (FLAIR) images. A needle biopsy of the thalamic lesion was consistent with neuromyelitis optica spectrum disorder although her serum antibody to aquaporin-4 was negative. The level of orexin in celebrospinal fluid (CSF) was reduced. She presented hypersomnia, which didn't improve even after intravenous methylprednisolone 1 g daily for 3 days. Administration of oral modafinil extended her waking time. There is a number of reports about neuromyelitis optica (NMO) with hypothalamic lesions. We report this case as important suggestion of treatment of these cases.

[Anti-NMDA encephalitis in psychiatry; malignant catatonia, atypical psychosis and ECT].

The symptoms of malignant (lethal) catatonia has been reported similar to initial symptoms of anti-NMDAR encephalitis. Subsequently, this autoimmune limbic encephalitis has been noticed in many psychiatrists. We have experienced several cases with malignant catatonia having anti-NMDAR antibody without clinical signs of encephalitis. Thereafter, we have also found anti-NMDAR antibody positive patients of young females with acute florid psychiatric symptoms without clinical signs of encephalitis. The features of these patients mirror-those of "Atypical psychosis" proposed by Mitsuda in Japan, a notion derived from "Cycloid psychosis" conceptualized by German psychiatrist, Leonhard. Both cycloid and atypical psychosis have coinciding features of acute onset, emotional disturbances, psychomotor disturbances, alternations of consciousness, high prevalence in women and oriented premorbid personality. Both malignant catatonia and atypical psychosis have been known to be effectively treated with modified electro convulsion therapy (m-ECT). Our 5 cases with anti-NMDAR antibody, m-ECT treatments were effective. Infectious encephalitis is contra indication of m-ECT, but this autoimmune encephalitis would be careful indication. Schizophrenia is a common, heterogeneous, and complex disorder with unknown etiology. There is established evidence of NMDAR hypofunction as a central component of the functional disconnectivity; this is one of the most accepted models for schizophrenia. Moreover, autoimmune mechanisms have been proposed to be involved, at least in subgroups of schizophrenia patients. Further research of anti-NMDAR antibody and encephalitis would be important clues for the investigation of schizophrenia, catatonia and atypical psychosis.

Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features.

BACKGROUND: Causative role of encephalitis in major psychotic features, dyskinesias (particularly orofacial), seizures, and autonomic and respiratory changes has been recently emphasized. These symptoms often occur in young females with ovarian teratomas and are frequently associated with serum and CSF autoantibodies to the NMDA receptor (NMDAR). METHODS: The study included a total of 61 patients from age 15 to 61 and was carried out between January 1, 2005, and Dec 31, 2010. The patients were divided into the following three clinical groups for comparison. Group A; Patients with typical clinical characteristics of anti-NMDAR encephalitis. Group B; Patients with narcolepsy with severe psychosis. Group C; Patients with schizophrenia or schizo-affective disorders. RESULTS: Ten out of 61 cases were anti-NMDAR antibody positive in typical encephalitis cases (group A: 3 of 5 cases) and cases in a broader range of psychiatric disorders including narcolepsy (group B: 3 of 5 cases) and schizophrenia (group C: 4 of 51 cases). CONCLUSION: In addition to 3 typical cases, we found 7 cases with anti-NMDAR antibody associated with various psychotic and sleep symptoms, which lack any noticeable clinical signs of encephalitis (seizures and autonomic symptoms) throughout the course of the disease episodes; this result suggest that further discussion on the nosology and pathophysiology of autoimmune-mediated atypical psychosis and sleep disorders is required.

Possible mechanism of secondary narcolepsy with a long sleep time following surgery for craniopharyngioma.

A 19-year-old woman suffered from severe excessive daytime sleepiness accompanied with long sleep episodes both in the daytime and nighttime and frequent episodes of cataplexy shortly after the removal of craniopharyngioma in the intrasellar space. Multiple sleep latency test showed a typical finding of narcolepsy, and cerebrospinal fluid orexin concentration was below the narcolepsy cut-off value. MRI-tractography showed a clear lack of neuronal fiber connections from the hypothalamus to the frontal lobe. SPECT using (123)I-IMP showed frontal hypoperfusion. These connection damages could have been responsible for the occurrence of narcolepsy-like symptoms and long daytime sleep episodes in this case.

The pathophysiologic basis of secondary narcolepsy and hypersomnia.

The symptoms of narcolepsy can occur during the course of other neurologic conditions (ie, symptomatic narcolepsy). Inherited disorders, tumors, and head trauma were the three most frequent causes for symptomatic narcolepsy. Other causes include multiple sclerosis (MS), vascular disorders, and encephalitis. Cerebrospinal fluid hypocretin-1 measures were carried out in some recent cases with symptomatic narcolepsy, and moderate decreases in hypocretin levels were seen in a large majority of these cases. Excessive daytime sleepiness (EDS) in these symptomatic cases was sometimes reversible with an improvement of the causative neurologic disorder and with an improvement of the hypocretin (orexin) status. Recently, we found that several symptomatic narcoleptic cases with MS show unique bilateral symmetric hypothalamic lesions associated with significant hypocretin ligand deficiency. In addition, these patients often share the clinical characteristics of neuromyelitis optica (NMO) and the detection of NMO-IgG (or anti-aquaporin-4 [AQP4] antibodies), suggesting a new clinical entity. Further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiologic mechanisms for occurrence of EDS and cataplexy.

A patient with anti-aquaporin 4 antibody who presented with recurrent hypersomnia, reduced orexin (hypocretin) level, and symmetrical hypothalamic lesions.

Recent studies have demonstrated that hypothalamic lesions associated with brain tumor, head trauma, and encephalopathy can cause symptomatic hypersomnia with a reduced orexin (hypocretin) level in the cerebrospinal fluid (CSF). Aquaporin 4 (AQP4), a member of the AQP superfamily, is strongly expressed in the hypothalamus in which orexin (hypocretin)-containing neurons are primarily concentrated. We report the case of a patient with a serum anti-AQP4 antibody who presented with recurrent hypersomnia, symmetrical hypothalamic lesions with long spinal cord lesions on MRI, and a reduced CSF orexin (hypocretin) level, all of which were improved simultaneously by steroid therapy. Further studies should be performed to determine the roles of anti-AQP4 antibody positivity in patients with hypersomnia associated with orexin (hypocretin) deficiency and hypothalamic lesions.

[Symptomatic hypersomnia due to orexin deficiency in hypothalamic lesions].

Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy and other abnormal manifestations of REM sleep. Recently, it was discovered that the pathophysiology of idiopathic narcolepsy-cataplexy is linked to orexin ligand deficiency in the brain and cerebrospinal fluid. Orexin neurons localize in the posterior hypothalamic area, which was previously described as "waking center" by von Economo in 1920s. Hypersomnia due to orexin ligand deficiency can also occur during the course of other neurological conditions, such as hypothalamic tumor, encephalopathy and demyelinating disorder (i.e. symptomatic hypersomnia). We experienced 8 pediatric cases with symptomatic hypersomnia. These cases were diagnosed as brain tumor (n = 2), head trauma (n = 1), encephalopathy (n = 1), demyelinating disorder (n = 3) and infarction (n = 1). Six pediatric cases with orexin measurements from the literatures were additionally included and total 14 cases were studied. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, a review of the case histories reveals numerous unquestionable cases of symptomatic hypersomnia. In these cases, the occurrences of the hypersomnia run parallel with the rise and fall of the causative diseases. Most of symptomatic hypersomnia cases show both extended nocturnal sleep time and EDS consisting of prolonged sleep episodes of NREM sleep. The features of nocturnal sleep and EDS in symptomatic hypersomnia are more similar to idiopathic hypersomnia than to narcolepsy.

Expression pattern of FOS in orexin neurons during sleep induced by an adenosine A2A receptor agonist.

The present study examined the expression pattern of FOS in the hypothalamic peptide neurons during the sleep-dominant state induced by an adenosine A2A receptor agonist. The control rats, those that received the microdialysis-perfusion of their ventral striatum with artificial cerebrospinal fluid in the dark-active phase, spent 24% of the 90-min period prior to sacrifice in non-rapid eye movement (non-REM) sleep and 2.3% of that in REM sleep. These rats exhibited FOS, a transcription factor, in 21% of their orexin neurons and in 1.0% of their melanin-concentrating hormone (MCH) neurons in the perifornical/lateral hypothalamic areas. However, the rats perfused with 50 microM CGS21680, an adenosine A2A receptor agonist, spent 60% of the 90-min period prior to sacrifice in non-REM sleep and 11% of that in REM sleep. These rats exhibited FOS in 1.7% of their orexin neurons and FOS in 0.5% of their MCH neurons. When the sleep-dominant state was disturbed by mild stimulation and the rats were kept in the sleepy state by treatment with a sleep-inducing dose of CGS21680, the rats exhibited FOS in 13.3% of their orexin neurons, which percentage was about half of that for the control rats. These results suggest that the sleep-promoting process induced by this adenosine A2A receptor agonist was associated with a decline in the activity of orexin neurons. MCH neurons are not likely to change their activities during this sleep-promoting process.