Context Narcolepsy, a neurological disorder affecting 1 in 2000 individuals, is associated with HLA-DQB1*0602 and low cerebrospinal fluid (CSF) hypocretin (orexin) levels. Objectives To delineate the spectrum of the hypocretin deficiency syndrome and to establish CSF hypocretin-1 measurements as a diagnostic tool for narcolepsy. Design Diagnosis, HLA-DQ, clinical data, the multiple sleep latency test (MSLT), and CSF hypocretin-1 were studied in a case series of patients with sleep disorders from 1999 to 2002. Signal detection analysis was used to determine the CSF hypocretin-1 levels best predictive for International Classification of Sleep Disorders (ICSD)–defined narcolepsy (blinded criterion standard). Clinical and demographic features were compared in narcoleptic subjects with and without low CSF hypocretin-1 levels. Setting Sleep disorder and neurology clinics in the United States and Europe, with biological testing performed at Stanford University, Stanford, Calif. Participants There were 274 patients with narcolepsy; hypersomnia; obstructive sleep apnea; restless legs syndrome; insomnia; and atypical hypersomnia cases such as familial cases, narcolepsy without cataplexy or without HLA-DQB1*0602, recurrent hypersomnias, and symptomatic cases (eg, Parkinson disease, depression, Prader-Willi syndrome, Niemann-Pick disease type C). The subject group also included 296 controls (healthy and with neurological disorders). Intervention Venopuncture for HLA typing, lumbar puncture for CSF analysis, primary diagnosis using the International Classification of Sleep Disorders, Stanford Sleep Inventory for evaluation of narcolepsy, and sleep recording studies. Main Outcome Measures Diagnostic threshold for CSF hypocretin-1, HLA-DQB1*0602 positivity, and clinical and polysomnographic features. Results HLA-DQB1*0602 frequency was increased in narcolepsy with typical cataplexy (93% vs 17% in controls), narcolepsy without cataplexy (56%), and in essential hypersomnia (52%). Hypocretin-1 levels below 110 pg/mL were diagnostic for narcolepsy. Values above 200 pg/mL were considered normal. Most subjects with low levels were HLA-DQB1*0602–positive narcolepsy-cataplexy patients. These patients did not always have abnormal MSLT. Rare subjects without cataplexy, DQB1*0602, and/or with secondary narcolepsy had low levels. Ten subjects with hypersomnia had intermediate levels, 7 with narcolepsy (often HLA negative, of secondary nature, and/or with atypical cataplexy or no cataplexy), and 1 with periodic hypersomnia. Healthy controls and subjects with other sleep disorders all had normal levels. Neurological subjects had generally normal levels (n = 194). Intermediate (n = 30) and low (n = 3) levels were observed in various acute neuropathologic conditions. Conclusions Narcolepsy-cataplexy with hypocretin deficiency is a genuine disease entity. Measuring CSF hypocretin-1 is a definitive diagnostic test, provided that it is interpreted within the clinical context. It may be most useful in cases with cataplexy and when the MSLT is difficult to interpret (ie, in subjects already treated with psychoactive drugs or with other concurrent sleep disorders).

https://jamanetwork.com/journals/jamaneurology/articlepdf/782942/NOC20071.pdf

The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias.

https://gwern.net/docs/modafinil/2008-minzenberg.pdf

Modafinil: A Review of Neurochemical Actions and Effects on Cognition

Narcolepsy with cataplexy

Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles—DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)—were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of λ statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy.

/pdf/complex-hla-dr-and-dq-interactions-confer-risk-of-narcolepsy-39snagpr22.pdf

Complex HLA-DR and -DQ Interactions Confer Risk of Narcolepsy-Cataplexy in Three Ethnic Groups

It is a common belief that we are more susceptible to infections when deprived of sleep. Consistent with this, there is increasing evidence that sleep deprivation has detrimental effects on the immune response, indicating that sleep should be considered a vital part of the immune system and that there is a reciprocal relationship between sleep and immunity. This relationship is important because, over recent decades, there has been a documented decrease in the mean duration and quality of sleep in the population. The concept that lack of sleep might be compromising immunity in the population has far-reaching public-health implications for both individuals and society.

Sick and tired: does sleep have a vital role in the immune system?

Study Objectives: The objectives of this study were to compare severity and clinical presentation for narcolepsy-cataplexy across various ethnic groups. A large sample of narcoleptic patients was also used to further describe symptomatology and natural history for this sleep disorder. Design: Retrospective review of clinical data ascertained from the Stanford Sleep Inventory, polysomnography and MSLT data, as well as clinical notes. Ethnicity was narrowly defined as African (Black) Americans, Caucasians, Asians, and Latinos when both parents and the subject identified with a given ethnic group. Setting: N/A Participants: We compared the severity and clinical presentation of narcolepsy in 64 African Americans, 353 Caucasians, 32 Asians, 26 Latinos, and 9 subjects of mixed ethnicity. Subjects were recruited through the Stanford center for narcolepsy research. Interventions: N/A Measurements and Results: A striking similarity in symptomatology, age of onset, and disease severity was found across ethnic groups. Mean age of onset for sleepiness, hypnagogic hallucinations, sleep paralysis and cataplexy were 19.20, 19.50, 20.11 and 23.02 years old. We also found that narcoleptic patients have slightly but significantly elevated body mass index relative to normative data (106.6% of matched controls, p<0.005) and are born slightly more frequently during the month of March. A tight correlation between our previously validated cataplexy scale and DQB1 * 0602 positivity was observed. Two thirds of patients reported having cataplexy with laughing, 92% of those being DQB1 * 0602 positive independent of ethnicity. Conclusions: These results confirm the similarities in clinical presentation and natural history of narcolepsy-cataplexy in a large number of patients of various ethnic groups and cultural backgrounds.

/pdf/clinical-aspects-of-narcolepsy-cataplexy-across-ethnic-1u2zmrlnk3.pdf

Clinical aspects of narcolepsy-cataplexy across ethnic groups.

Narcolepsy is a neurological disorder known to be tightly associated with HLA-DQA1*0102 and DQB1*0602. In this study, we have examined if homozygosity for DQB1*0602 increases disease susceptibility and/ or severity. Patients diagnosed at Stanford University (n=160) or enrolled in a multicenter clinical trial (n=509) were included in this analysis. In both African-Americans and Caucasian-Americans with or without cataplexy, a significantly higher than expected number of subjects were DQB1*0602 homozygotes. Relative risks were 2–4 times higher in DQB1*0602 homozy-gotes vs heterozygotes across all patient groups. In contrast, symptom severity did not differ between DQB1*0602 homozygous and heterozygous subjects. These results indicate that HLA-DQB1*0602 homozygosity increases susceptibility to narcolepsy but does not appear to influence disease severity.

HLA‐DQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups

It is a common belief that sleep deprivation increases the susceptibility to diseases. In order to evaluate the effects of sleep deprivation on immune profile in humans, peripheral venous blood was obtained from sixteen healthy young male volunteers. Ten of the volunteers underwent 48 hours of sleep deprivation and the other six maintained their regular sleep schedule and acted as controls. The first blood samples were taken at the end of the first polysomnographic recording at 8:00 a.m. After this sampling, ten subjects were sleep deprived for 48 hours in sedentary conditions. The second and third blood samples were taken at the 24th and 48th hours. The subjects were recorded again to verify rebound effects of sleep deprivation after the third blood sampling. In this second polysomnographic recording, all sleep-deprived subjects showed slow wave and REM sleep rebound. The last blood samples were taken at the 72nd hour of study at 8:00 a.m. CD4, CD8, CD5, CD16, CD19 surface antigen positive lymphocyte subsets, serum IgG, IgM, and cortisol levels were assessed in all samples. Our results showed that the proportion of NK cells were decreased during sleep deprivation and returned to normal values after recovery sleep. In the control group, we did not observe any changes in the same direction as the sleep-deprived group.

Effects of 48 hours sleep deprivation on human immune profile.

Introduction: Electrocardiographic (ECG) changes are observed in patients with acute stroke and are related with the prognosis. Aims: To determine the frequency and significance of ECG changes in patients with acute ischemic stroke. 
Material and Methods: In a prospective hospital-based study 87 patients with cerebral infarction were observed for ECG changes during their stay in the hospital. All the patients had ischemic stroke for the first time. The ECG changes observed were compared with those of the control group consisting of 87 patients. Results: Of the 87 patients of the study group, 47.1% were females and 52.9% males. The mean age was 65.5 ± 11.9 (range 31–91 yrs). The control group consisted of 50.6% females and 49.4% males. The mean age was 64.5 ± 11.9 (range 31–87 yrs). The frequency of the ECG changes observed in patients with cerebral infarct was 62.1% while it was 29.9% in the control group (P<0.0001). ECG changes observed were mostly related to myocardial ischemia. The six-month mortality 
rate in the patients with ECG changes was 38.9% whereas it was 15.2% in those with normal ECG (P<0.05). 
Conclusions: The observations of this study suggest that cardiac evaluation in patients with acute ischemic stroke is of prognostic importance.

Electrocardiographic findings and prognosis in ischemic stroke.

A number of recent studies have suggested that apnea and/or hypopnea episodes may be in a causal relationship with nocturnal gastroesophageal reflux (GER) episodes in obstructive sleep apnea (OSA) patients. In this study, we addressed the possible factors that may affect the occurrence of reflux events in OSA patients. For this reason, we investigated respiratory and sleep parameters in OSA patients with or without nocturnal GER episodes. Nineteen patients who were referred to the sleep laboratory for suspected sleep apnea were included in the study. All subjects underwent polysomnographic evaluation simultaneously with distal and proximal esophageal pH monitoring. During the recording period, a total of 134 reflux events, 134 from distal probes and none from proximal probes, were recorded. We divided patients into two groups: (1) nocturnal GER-positive patients (n=8; age: 41.9±11.9) and (2) nocturnal GER-negative patients (n=11; age: 45.4±3.3). We compared demographic, respiratory and sleep parameters between the two groups. Then we analysed the time relation between GER episodes and obstructive respiratory events. The two groups were matched by age and body mass index. Sleep and respiratory parameters were not different between the two groups. In conclusion, we suggested that age, body mass index and the severity of disease in obstructive sleep apnea patients are not effective determinants of gastroesophageal reflux. There is no sufficient evidence to accept arousals and obstructive apneas as primary causes of gastroesophageal reflux and vice versa. And finally, sleep macroorganisation has no impact on the occurrence of GER in OSAS.

Zerrin Pelin

Papers

Clinical aspects of narcolepsy-cataplexy across ethnic groups.

HLA‐DQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups

Effects of 48 hours sleep deprivation on human immune profile.

Electrocardiographic findings and prognosis in ischemic stroke.

Variables affecting the occurrence of gastroesophageal reflux in obstructive sleep apnea patients