HLA associations in narcolepsy type 1 persist after the 2009 H1N1 pandemic.

We aimed to compare HLA-DQB1-associations in narcolepsy type 1 (NT1) patients with disease onset before and after the 2009 H1N1 pandemic in a large Dutch cohort. 525 NT1 patients and 1272 HLA-DQB1*06:02-positive healthy controls were included. Because of the discussion that has arisen on the existence of sporadic and post-H1N1 NT1, HLA-DQB1-associations in pre- and post-H1N1 NT1 patients were compared. The associations between HLA-DQB1 alleles and NT1 were not significantly different between pre- and post-H1N1 NT1 patients. Both HLA-DQB1-associations with pre- and -post H1N1 NT1 reported in recent smaller studies were replicated. Our findings combine the results of studies in pre- and post-H1N1 NT1 and argue against considering post-H1N1 NT1 as a different entity.

Rotavirus-Induced Neonatal Epileptic Encephalopathy-A Disease Spectrum Illustrated by Monochorionic Twins.

Rotavirus has been associated with neonatal seizures and specific white matter magnetic resonance imaging (MRI) abnormalities. We describe monochorionic twins who not only tested positive for rotavirus with these white matter MRI abnormalities but who also showed an electroencephalogram (EEG) pattern characteristic of early infantile epileptic encephalopathy (EIEE), which has so far solely been described in epileptic encephalopathies with a poor prognosis. This report suggests that rotavirus infection must be added to the list of causes of EIEE EEG, and that the outcome then is likely more favorable. As MRI and EEG signs of rotavirus encephalopathy were present in one twin with only subtle neurologic symptoms, rotavirus may well cause insidious central nervous system complications more often. We suggest considering rotavirus infection in neonates presenting with seizures, and to add rotavirus infection to the differential diagnosis of EIEE.

Core Body and Skin Temperature in Type 1 Narcolepsy in Daily Life; Effects of Sodium Oxybate and Prediction of Sleep Attacks.

STUDY OBJECTIVES: Previous laboratory studies in narcolepsy patients showed altered core body and skin temperatures, which are hypothesised to be related to a disturbed sleep wake regulation. In this ambulatory study we assessed temperature profiles in normal daily life, and whether sleep attacks are heralded by changes in skin temperature. Furthermore, the effects of three months of treatment with sodium oxybate (SXB) were investigated. METHODS: Twenty-five narcolepsy patients and 15 healthy controls were included. Core body, proximal and distal skin temperatures, and sleep-wake state were measured simultaneously for 24 hours in ambulatory patients. This procedure was repeated in 16 narcolepsy patients after at least 3 months of stable treatment with SXB. RESULTS: Increases in distal skin temperature and distal-to-proximal temperature gradient (DPG) strongly predicted daytime sleep attacks (P < 0.001). As compared to controls, patients had a higher proximal and distal skin temperature in the morning, and a lower distal skin temperature during the night (all P < 0.05). Furthermore, they had a higher core body temperature during the first part of the night (P < 0.05), which SXB decreased (F = 4.99, df = 1, P = 0.03) to a level similar to controls. SXB did not affect skin temperature. CONCLUSIONS: This ambulatory study demonstrates that daytime sleep attacks were preceded by clear changes in distal skin temperature and DPG. Furthermore, changes in core body and skin temperature in narcolepsy, previously only studied in laboratory settings, were partially confirmed. Treatment with SXB resulted in a normalisation of the core body temperature profile. Future studies should explore whether predictive temperature changes can be used to signal or even prevent sleep attacks.

Immunohistochemical screening for antibodies in recent onset type 1 narcolepsy and after H1N1 vaccination.

Narcolepsy type 1 patients typically have undetectable hypocretin-1 levels in the cerebrospinal fluid (CSF), as a result of a selective loss of the hypocretin containing neurons in the hypothalamus. An autoimmune attack targeting hypothalamic hypocretin (orexin) neurons is hypothesised. So far, no direct evidence for an autoimmune attack was found. One of the major limitations of previous studies was that none included patients close to disease onset. We screened serum of 21 narcolepsy type 1 patients close to disease onset (median 11 months), including 8 H1N1 vaccinated patients, for antibodies against hypocretin neurons using immunohistochemistry. No autoantibodies against hypocretin neurons could be detected.

The effects of sodium oxybate on core body and skin temperature regulation in narcolepsy.

Patients suffering from narcolepsy type 1 show altered skin temperatures, resembling the profile that is related to sleep onset in healthy controls. The aim of the present study is to investigate the effects of sodium oxybate, a widely used drug to treat narcolepsy, on the 24-h profiles of temperature and sleep-wakefulness in patients with narcolepsy and controls. Eight hypocretin-deficient male narcolepsy type 1 patients and eight healthy matched controls underwent temperature measurement of core body and proximal and distal skin twice, and the sleep-wake state for 24 h. After the baseline assessment, 2 × 3 g of sodium oxybate was administered for 5 nights, immediately followed by the second assessment. At baseline, daytime core body temperature and proximal skin temperature were significantly lower in patients with narcolepsy (core: 36.8 ± 0.05 °C versus 37.0 ± 0.05 °C, F = 8.31, P = 0.01; proximal: 33.4 ± 0.26 °C versus 34.3 ± 0.26 °C, F = 5.66, P = 0.03). In patients, sodium oxybate administration increased proximal skin temperature during the day (F = 6.46, P = 0.04) to a level similar as in controls, but did not affect core body temperature, distal temperature or distal-proximal temperature gradient. Sodium oxybate administration normalised the predictive value of distal skin temperature and distal-proximal temperature gradient for the onset of daytime naps (P < 0.01). In conclusion, sodium oxybate administration resulted in a partial normalisation of the skin temperature profile, by increasing daytime proximal skin temperature, and by strengthening the known relationship between skin temperature and daytime sleep propensity. These changes seem to be related to the clinical improvement induced by sodium oxybate treatment. A causal relationship is not proven.

Comparing Treatment Effect Measurements in Narcolepsy: The Sustained Attention to Response Task, Epworth Sleepiness Scale and Maintenance of Wakefulness Test.

STUDY OBJECTIVES: To validate the Sustained Attention to Response Task (SART) as a treatment effect measure in narcolepsy, and to compare the SART with the Maintenance of Wakefulness Test (MWT) and the Epworth Sleepiness Scale (ESS). DESIGN: Validation of treatment effect measurements within a randomized controlled trial (RCT). PATIENTS: Ninety-five patients with narcolepsy with or without cataplexy. INTERVENTIONS: The RCT comprised a double-blind, parallel-group, multicenter trial comparing the effects of 8-w treatments with pitolisant (BF2.649), modafinil, or placebo (NCT01067222). MWT, ESS, and SART were administered at baseline and after an 8-w treatment period. The severity of excessive daytime sleepiness and cataplexy was also assessed using the Clinical Global Impression scale (CGI-C). MEASUREMENTS AND RESULTS: The SART, MWT, and ESS all had good reliability, obtained for the SART and MWT using two to three sessions in 1 day. The ability to distinguish responders from nonresponders, classified using the CGI-C score, was high for all measures, with a high performance for the SART (r = 0.61) and the ESS (r = 0.54). CONCLUSIONS: The Sustained Attention to Response Task is a valid and easy-to-administer measure to assess treatment effects in narcolepsy, enhanced by combining it with the Epworth Sleepiness Scale.

HLA dosage effect in narcolepsy with cataplexy.

Narcolepsy with cataplexy is a sleep disorder caused by the loss of hypocretin-producing neurons in the hypothalamus. It is tightly associated with a specific human leukocyte antigen (HLA)-allele: HLA-DQB1*06:02. Based on this, an autoimmune process has been hypothesized. A functional HLA-DQ molecule consists of a DQα and a DQß chain. HLA-DQB1*06:02 (DQß) has a strong preference for binding to HLA-DQA1*01:02 (DQα), and together they form the functional DQ0602 dimer. A dosage effect would be expected if the HLA-DQ0602 dimer itself is directly involved in the aetiology. An increased expression of the HLA-DQ0602 dimer is expected in individuals homozygous for HLA-DQB1*06:02-DQA1*01:02, but is also hypothesized in individuals heterozygous for HLA-DQB1*06:02 and homozygous for HLA-DQA1*01:02. To study the impact of the expression of the HLA-DQ0602 dimer on narcolepsy susceptibility, 248 Dutch narcolepsy patients and 1272 Dutch control subjects, all of them positive for DQB1*06:02 (heterozygous and homozygous), were HLA-genotyped with attention not only to DQB1 but also to DQA1*01:02. DQB1*06:02-DQA1*01:02 homozygosity was significantly more often seen in patients compared to controls (O.R. 2.29) confirming previous observations. More importantly, a significantly higher prevalence of homozygosity for DQA1*01:02 was found in HLA-DQB1*06:02 heterozygous patients compared to controls (O.R. 2.37, p < 0.001). The latter finding clearly supports a direct role of the HLA-DQ molecule in the development of disease.

DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe.

STUDY OBJECTIVE: Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects. DESIGN: Retrospective case-control study. SETTING: A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication. PATIENTS AND PARTICIPANTS: For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included. MEASUREMENTS AND RESULTS: None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified. CONCLUSION: An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.

Narcolepsy and pregnancy: a retrospective European evaluation of 249 pregnancies.

In a retrospective cohort study undertaken in 12 European countries, 249 female narcoleptic patients with cataplexy (n = 216) and without cataplexy (n = 33) completed a self-administrated questionnaire regarding pregnancy and childbirth. The cohort was divided further into patients whose symptoms of narcolepsy started before or during pregnancy (308 pregnancies) and those in whom the first symptoms of narcolepsy appeared after delivery (106 pregnancies). Patients with narcolepsy during pregnancy were older during their first pregnancy (P < 0.001) and had a higher body mass index (BMI) prior to pregnancy (P < 0.01). Weight gain during pregnancy was higher in narcoleptic patients with cataplexy (P < 0.01). More patients with narcolepsy-cataplexy during pregnancy had impaired glucose metabolism and anaemia. Three patients experienced cataplexy during delivery. The rate of caesarean sections was higher in the narcolepsy-cataplexy group compared to the narcolepsy group (P < 0.05). The mean birth weight and gestational age of neonates were within the normal range and did not differ across groups. Neonatal care was affected adversely by symptoms of narcolepsy in 60.1% of those with narcolepsy during pregnancy. This study reports more obstetric complications in patients with narcolepsy-cataplexy during pregnancy; however, these were not severe. This group also had a higher BMI and higher incidence of impaired glucose metabolism during pregnancy. Caesarian section was conducted more frequently in narcolepsy-cataplexy patients, despite cataplexy being a rare event during delivery. Furthermore, symptoms of narcolepsy may render care of the infant more difficult.

Identification of the epileptogenic zone in patients with tuberous sclerosis: concordance of interictal and ictal epileptiform activity.

OBJECTIVE: In the majority of patients with tuberous sclerosis complex (TSC) multifocal epileptiform activity is present interictally. Therefore, its value in identifying epilepsy surgery candidates has been doubted. We hypothesize that dominant interictal epileptiform foci are concordant with the ictal onset zone in TSC patients. METHODS: Consistency and dominance of focal interictal epileptiform activity was assessed in 19 patients with a clinical definite diagnosis of TSC. The ictal onset zone was identified. Concordance between interictal en ictal findings was analyzed. If concordance was found epilepsy surgery was proposed. RESULTS: We found dominant, consistently present, focal interictal epileptiform activity in 14 of the 19 patients. Concordance between the dominant interictal focus and the ictal onset zone was found in 11 of the 14 patients (79%). In one patient the ictal onset zone could not be identified and discordance was present in two patients. Epilepsy surgery was performed in six patients rendering three of them seizure free, and one had a seizure reduction >90%. In these patients local concordance was found whereas regional concordance was found in the two patients who did not benefit from epilepsy surgery. CONCLUSIONS: A dominant as well as a consistent interictal focus is concordant with the ictal onset zone in the majority of TSC patients. SIGNIFICANCE: Future studies of TSC patients addressing the value of interictal foci in the consideration of epilepsy surgery, in absence of clear ictal onset zone, are necessary.