Narcolepsy Research Articles

Current diagnosis and treatment of common pediatric sleep disorders

Sleep disorders are common diseases in children, although in recent years, pediatric sleep medicine had sustained development, but sleep problems in children's daily life are still more common and serious, the visiting rate is becoming higher.Pediatric sleep disorder can result in damage to the cognitive growth and behavior of children.In order to capture the majority of pediatric medical workers and parents attention, this review focuses on current diagnosis and therapy for selected common pediatric sleep disorders including obstructive sleep apnea syndrome, restless legs syndrome and narcolepsy. Key words: Sleep disorder; Diagnosis; Treatment; Current; Child

Humor as a Reward Mechanism: Event-Related Potentials in the Healthy and Diseased Brain

Humor processing involves distinct processing stages including incongruity detection, emotional response, and engagement of mesolimbic reward regions. Dysfunctional reward processing and clinical symptoms in response to humor have been previously described in both hypocretin deficient narcolepsy-cataplexy (NC) and in idiopathic Parkinson disease (PD). For NC patients, humor is the strongest trigger for cataplexy, a transient loss of muscle tone, whereas dopamine-deficient PD-patients show blunted emotional responses to humor. To better understand the role of reward system and the various contributions of hypocretinergic and dopaminergic mechanisms to different stages of humor processing we examined the electrophysiological response to humorous and neutral pictures when given as reward feedback in PD, NC and healthy controls. Humor compared to neutral feedback demonstrated modulation of early ERP amplitudes likely corresponding to visual processing stages, with no group differences. At 270 ms post-feedback, conditions showed topographical and amplitudinal differences for frontal and left posterior electrodes, in that humor feedback was absent in PD patients but increased in NC patients. We suggest that this effect relates to a relatively early affective response, reminiscent of increased amygdala response reported in NC patients. Later ERP differences, corresponding to the late positive potential, revealed a lack of sustained activation in PD, likely due to altered dopamine regulation in reward structures in these patients. This research provides new insights into the temporal dynamics and underlying mechanisms of humor detection and appreciation in health and disease.

Orexinergic neuron susceptibility to neuroinflammatory and aging-related neurodegenerative diseases

Orexins (a.k.a. hypocretins) play a crucial role in several physiological functions, including energy balance and the maintenance of wakefulness. Deficient orexin signalling is the hallmark of the sleep disorder narcolepsy. Although immune mechanisms have been hypotesized, the pathogenesis of narcolepsy remains to be clarified. Less attention has been devoted to potential orexinergic system alterations in other conditions, and their potential relationships with inflammatory signalling. Neuroinflammation has raised increasing interest in recent years, not only in relation to typical neuroinflammatory diseases, but also with regard to aging-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. A role for neuroinflammatory signalling in normal, “healthy” aging is also currently debated, since several lines of evidence have pointed to aging as a chronic low-grade proinflammatory condition. We have examined neurons in the lateral hypothalamus expressing orexin A in different paradigms: i) normal aging in mice, ii) rodent models of a chronic infectious neuroinflammatory condition represented by a parasitic disease that causes sleep/wake alterations, iii) PDAAP mutant mice, a model of Alzheimer’s disease. In these paradigms, we have identified different degrees of neuronal loss in the orexinergic cell population and/or evidence of functional dysregulation of these neurons, together with glial activation in the lateral hypothalamus and sleep/wake changes. Altogether, the data point to a vulnerability of orexin to inflammatory signalling, and potentially place the neuropeptide at the center of neural-immune interactions, drawing attention on the relationships between neuroinflammation, sleep regulation, and orexin neuron damage.

Orexin (hypocretin; HCRT)-based immunoassays to diagnose narcolepsy

Orexin (hypocretin; HCRT)-based immunoassays to diagnose narcolepsy

Factors Associated with Duration Before Receiving Definitive Diagnosis of Narcolepsy among Japanese Patients Affected with the Disorder

Narcolepsy (NA) is a sleep disorder characterized by excessive daytime sleepiness and an increased propensity of rapid eye movement sleep. If left untreated, NA can lead to academic underachievement or job loss because of dozing off or mistakes caused by inattentiveness due to sleepiness. Although untreated narcolepsy patients may suffer from many social disadvantages due to excessive daytime sleepiness, mostly it takes a long time to receive a definitive diagnosis of the disorder. This retrospective study investigated factors related to the period until definitive diagnosis among patients with narcolepsy in Japan. We enrolled 181 consecutive patients (108 men, 73 women; mean age 37.6 ± 16.6 years old; narcolepsy with cataplexy/narcolepsy without cataplexy = 131:50). Multivariate logistic regression analysis was performed with period until definitive diagnosis as the dependent variable and descriptive clinical variables as the independent variables. The mean period until receiving the diagnosis among the participants was 9.9 ± 10.1 years. More than half of the patients first learned about the disorder from information provided by the media. Multivariate logistic analysis indicated that adult onset (p < 0.01), onset in 1995 or later (p < 0.001), and first learning about the disorder from a sleep disorder specialist physician or a general practitioner (p < 0.001) were associated with a time taken for receiving a definitive diagnosis less than or equal to the median value (7 years). Improving access to information about the concept of the disorder and the medical institutions specialized in sleep disorders, especially via the Internet, would be necessary to promote early diagnosis of the disorder.

MiRNA profiling in plasma from patients with sleep disorders reveals dysregulation of miRNAs in narcolepsy and other central hypersomnias

miRNAs have been implicated in the pathogenesis of human diseases including neurological disorders. The aim is to address the involvement of miRNAs in the pathophysiology of central hypersomnias including narcolepsy with cataplexy and hypocretin deficiency (NC), narcolepsy without cataplexy (NwC) and idiopathic hypersomnia (IH) in comparison with healthy controls (HC). We conducted high-throughput analysis of miRNA in plasma from patients with NC, NwC and IH in comparison with HC using quantitative real-time polymerase chain reaction (qRT-PCR) panels. Data were analyzed with the following softwares: GenEx qRT-PCR data analysis, miRNA expression atlas in normal tissues and DIANA-mirPath pathway analysis. Using analysis of miRNA in plasma with qRT-PCR we identified 50, 24 and 6 miRNAs that were changed in patients with NC, NwC, IH, respectively, compared to HC. Twenty miRNA candidates which fulfilled the criteria of twofold change and p -value < 0.05 were selected for validation of miRNA changes in an independent cohort of patients. Four miRNAs were significantly changed between NC patients and HC. Levels of miR-30c, let-7f and miR- 26a were increased, whereas the level of miR-130a was decreased in NC compared to HC. The miRNAs changes were not specific for NC, since the levels of the four miRNAs were also altered in patients with NwC and IH compared with HC. The levels of four miRNAs are changed in plasma from patients with NC, NwC and IH suggesting that alterations of miRNAs can be involved in the pathophysiology of central hypersomnias. Lundbeck Foundation is acknowledged for financial support. Birte Kofoed is thanked for technical assistance.

Effort-based decision making in narcolepsy-cataplexy

Introduction Narcolepsy-cataplexy (NC) is caused by the loss of hypothalamic neurons that produce hypocretins. By interacting with the mesolimbic dopamine structures (i.e. amygdala, prefrontal cortex, nucleus accumbens), hypocretins are involved in modulation of the reward system. Nucleus accumbens dopamine activity is crucially involved in valuing effort and probability costs. Thereby, NC represents an interesting model to study the implication of the hypocretin system in reward-based effort expenditure in humans. Materials and methods Eighty-nine adult participants were included, 7 drug-free patients with NC, 32 patients medicated with psychostimulant (including 17 with antidepressant), and 40 matched healthy controls (HC). All completed the Effort Expenditure for Rewards Task (EEfRT). In this task running approximately 20 min, participants are given an opportunity to choose between two different task difficulty levels: (1) easy trials (less motoric effort) for a small, stable reward; (2) hard trials (more motoric effort) for a variable but consistently larger reward. Trials (n = 40) had three levels of probability of receiving a monetary reward (i.e. 12%, 50%, and 88%). Intrinsic Motivation Inventory was administered in order to assess participants subjective experience of this task. The Karolinska Sleepiness Scale (KSS) was fulfilled by participants before and after the EEfRT completion. Results There was no difference in the percentage of trials successfully completed by patients with NC (99.1%) or controls (99.5%, p = 0.92). There were no group differences in average responses times for choosing between the easy and hard task (respectively, p = 0.24 and p = 0.19). No group effect was observed for reward magnitude (p = 0.98). However, we found that patients with NC were less willing to expend effort for rewards than HC when probability of winning was low (12%, p = 0.016) compared to medium (50%) and high (80%) probabilities. Patients with NC had higher level of intrinsic motivation (p = 0.019) with no association with the EEfRT performances. Finally, groups did not differ on the KSSs (p = 0.73 and p = 0.82). Conclusion This is the first demonstration in humans that patients with NC showed decrease willingness to incur effort costs when probability of reward receipt was low. This study provides a starting point for exploring contributions of hypocretin system to motivation in humans.

Influence of cytochrome P450 and ABCB1 genetic polymorphisms on drug efficacy in narcolepsy with cataplexy

Treatments for narcolepsy-cataplexy (NC) are so far only symptomatic and aim to reconsolidate sleep and waking states as well as cataplexy attacks. The patients’ clinical response is influenced by a high interindividual variability. This leads, in clinical practice, to an empirical case-by- case management, mainly based on increasing drug dosages, but without a precise clue of the mechanisms of such variability. Genetic polymorphisms of cytochrome P450 (CYP450) are involved in drug metabolism and known to be responsible for the interindividual variability of drug response in different population groups. We genotyped CYP450 genes, CYP3A4 and CYP3A5, involved in the metabolism of two common NC drugs (i.e. modafinil (Mod), a wake promoting agent, and venlafaxine (Ven), a noradrenaline- serotonine reuptake inhibitor). Moreover, we genotyped the glycoprotein-P ABCB1(P-gp), also called multidrug resistance protein 1, a transmembrane efflux pump. Finally, genotypes were correlated with Mod and Ven efficacy and dosage, to provide a clue for the interindividual variability in clinical response of NC patients. 45 Caucasian NC patients (28 males, mean age 42 ± 20 y.o.), on chronic therapy with Mod alone or Mod plus Ven underwent blood withdrawal for genetic analysis. Mod and Ven efficacy was empirically scored by a sleep expert (1 = full, 2 = mild, 3 = low efficacy). Multiplex PCR was used for CYP3A4, CYP3A5 and P-gp loci amplification, followed by enzymatic purification, minisequencing reaction, and capillary electrophoresis typing. Out of 45 patients 17 were on Mod alone (38%), 28 on Mod plus Ven (62%). No significant correlation was found between CYP3A4/CYP3A5 genotypes and Mod or Ven efficacy or dosage. The CGC/TTT P- gp-haplotype (wild type/mutated allele), corresponding to a decreased activity, showed a significant correlation with an increased Mod efficacy ( p = 0.017). CGC/TTT haplotype was also the most represented in NC, according to general Caucasian population frequency distribution. This is the first attempt to correlate the interindividual variability of drug response to Mod and Ven in NC patients with the genotypes of proteins involved in their metabolism and transport. An increased Mod efficacy resulted to be related to a partially decreased activity of P-gp (partially mutated haplotype), suggesting that the Mod efficacy may be related to the intracellular permanence of Mod, consequent to damaged cell efflux. We thank the patients of the Italian Narcolepsy Association (AIN) for the precious collaboration.

Effect of sodium oxybate on sleep stage shifts and sleep quality in patients with narcolepsy

Disrupted nighttime sleep (DNS) is a well-recognized symptom affecting 50–80% of narcolepsy patients. Recent expert consensus on the definition and measurement of DNS identified that frequent shifts to lighter stages of sleep and awakenings and patient-reported poor sleep quality are defining clinically important measures of DNS. Xyrem®, sodium oxybate (SXB) is approved for the treatment of cataplexy and excessive daytime sleepiness in narcolepsy. The effects of SXB on DNS in narcolepsy have not been reported. In the present study, polysomnograms (PSGs) from a randomized clinical trial were analyzed retrospectively to evaluate the effects of SXB on DNS in patients with narcolepsy. Subjects were randomized to 4.5, 6, or 9 g SXB or placebo nightly for 8 weeks; those receiving 6 and 9 g/night doses were titrated in weekly 1.5 g increments. PSGs and sleep quality diaries were obtained at baseline and after 4 and 8 weeks. Sleepiness, cataplexy measures and safety have been previously reported. Post-hoc analysis of shifts from S2, 3, 4 or REM to 1/W was performed for 159 patients with evaluable sleep stage data and for 211 patients with evaluable sleep quality rated from 1 = Excellent to 4 = Poor. SXB significantly decreased the number of shifts from Stage 2, 3, 4 or REM to Stage 1/Wake. The median (range) change from baseline was −0.5 (−38 to 24), −7∗ (−37 to 33), −10∗ (−35 to 21), and −13∗ (−59 to 33) shifts in the placebo, SXB 4.5 g, 6 g, and 9 g groups, respectively; ∗ P < 0.01. Patient reported sleep quality was improved with LS Mean change (SE) 0.11 (0.081), −0.42∗ (0.077), −0.31 (0.081), and −0.48∗ (0.093), respectively. For the population treated with SXB (all doses combined), the most commonly reported adverse events (⩾5%) were headache, nausea, dizziness, enuresis, nasopharyngitis, diarrhea, and vomiting. This retrospective analysis suggested that sodium oxybate may help improve PSG and patient-reported measures of sleep that define DNS in narcolepsy. This study was sponsored by Jazz Pharmaceuticals, Inc.

Predictive power of HLA-DQB1∗ to identify narcoleptic patients

Introduction The determination of HLA class II genotype is widely used to confirm the diagnosis of Narcolepsy without (N) or with Cataplexy (NC). The use of HLA genotyping in clinical diagnosis is reliable and is a contributing factor to the reinforcement of the wide acceptance of the hypothesis of autoimmune origin for Narcolepsy. We evaluate the contribution of genetic markers (HLA) in the differential diagnosis between narcolepsy with and without Cataplexy and their relevance in the context of our population (Northern Portugal). Materials and methods A cohort of 53 patients with Narcolepsy with Cataplexy (NC) or without (N) was studied. Patients followed up to the Outpatient Sleep Clinic of Hospital Santo Antonio/CH Porto were assessed by clinical, night sleep polygraphic recording, MSLT on the following day. Blood sampling for HLA-DQB1 ∗ analysis was performed after informed consent. The genotyping was achieved by using a PCR-Sequence Specific Primer (SSP) methodology. Control Population (CP) comprised 206 reportedly healthy individuals from the same geographic origin. Data from laboratory parameters was confronted with the clinical diagnostic hypothesis. Patients’ clinical reevaluation was considered if phenotype-genotype did not match. Results Of the 53 patients, 14 were classified as N and 39 as NC. The frequency of HLA-DQB1 ∗ 06:02 allele was overrepresented in N and NC patients (43% and 69%, respectively) when compared with the control population (16%) – p value = 1.38 × 10–12 for NC. Interestingly the frequency of the HLA- DQB1 ∗ 03 allele was decreased in NC patients (36% NC vs. 56% CP, p = 0.01917). No differences were found in other DQB1 ∗ 06 frequencies between the cohort of patients and the control population. Conclusion The HLA-DQB1 ∗ 06:02 allele, a susceptibility factor for other autoimmune disorders, was confirmed as the most important susceptibility allele to NC in our population. The frequency of this allele in our NC patients (69%) is within the range of other studies. Such values pointed out to 11.8 OR for NC comparing with 3.9 OR for N patients. These findings point out to the relevance of the allele DQB1 ∗ 0602 in this sleep entity and on the autoimmune involvement in the picture of Narcolepsy–Cataplexy.

Clinical effect of venlafaxine combined with methylphenidate hydrochloride on narcolepsy

This study aims to explore the clinical effect of venlafaxine sustained-release capsules combined with methylphenidate hydrochloride tablets on narcolepsy. Thirty-eight cases of narcoleptic patients were randomly divided into venlafaxine combined with methylphenidate hydrochloride treatment group (observation group, N = 19) and methylphenidate hydrochloride and clomipramine treatment group (control group, N = 19). After a total of 12-week treatment, clinical curative effect and adverse drug reactions were observed in 2 groups of patients. The results showed that effective rate of the treatment for excessive daytime sleepiness (EDS) in observation group was higher than that of the control group (15/19 vs 8/19, P = 0.044), and effective rate of the treatment for cataplexy in observation group was higher than that of the control group (13/19 vs 6/19, P = 0.048). The rate of adverse drug reactions in observation group was lower than that in the control group (χ2 = 8.889, P = 0.003). It was indicated that venlafaxine combined with methylphenidate had good curative effect on narcolepsy with EDS and cataplexy symptoms. doi：10.3969/j.issn.1672-6731.2013.11.010

Effectiveness of Pitolisant in the Treatment of Narcolepsy

Narcolepsy is a clinical syndrome of daytime sleepiness along with cataplexy, hypnagogic hallucinations, and sleep paralysis. Narcolepsy results from

Narcolepsy–cataplexy and schizophrenia in adolescents

BackgroundDespite advances in the understanding of narcolepsy, little information the on association between narcolepsy and psychosis is available, except for amphetamine-related psychotic reactions. Our case-control study aimed to compare clinical differences and analyze risk factors in children who developed narcolepsy with cataplexy (N–C), schizophrenia, and N–C followed by schizophrenia. MethodsThree age- and gender-matched groups of children with N–C schizophrenia (study group), N–C (control group 1), and schizophrenia only (control group 2) were investigated. Subjects filled out sleep questionnaires, sleep diaries, and quality of life scales, followed by polysomnography (PSG), multiple sleep latency tests (MSLT), routine blood tests, HLA typing, genetic analysis of genes of interest, and psychiatric evaluation. The risk factors for schizophrenia also were analyzed. ResultsThe study group was significantly overweight when measuring body mass index (BMI) (P=.016), at narcolepsy onset compared to control group 1, and the study group developed schizophrenia after a mean of 2.55±1.8years. Compared to control group 2, psychotic symptoms were significantly more severe in the study group, with a higher frequency of depressive symptoms and acute ward hospitalization in 8 out of 10 of the subjects. They also had poorer long-term response to treatment, despite multiple treatment trials targeting their florid psychotic symptoms. All subjects with narcolepsy were HLA DQ B1∗0602 positive. The study group had a significantly higher frequency of DQ B1∗-03:01/06:02 (70%) than the two other groups, without any significant difference in HLA-DR typing, tumor necrosis factor α (TNF-α) levels, hypocretin (orexin) receptor 1 gene, HCRTR1, and the hypocretin (orexin) receptor 2 gene, HCRTR2, or blood infectious titers. ConclusionBMI and weight at onset of narcolepsy as well as a higher frequency of DQ B1∗-03:01/06:02 antigens were the only significant differences in the N–C children with secondary schizophrenia; such an association is a therapeutic challenge with long-term persistence of severe psychotic symptoms.

Association analysis of the major histocompatibility complex, class II, DQ β1 gene, HLA-DQB1, with narcolepsy in Han Chinese patients from Taiwan

BackgroundNarcolepsy is a rare, chronic, disabling neuropsychiatric disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis, and abnormal rapid eye movement sleep. It is strongly associated with the HLA-DQB1∗06:02 allele in various ethnic groups. Our study aimed to investigate the allelic spectrum of HLA-DQB1 in a sample of Han Chinese patients with narcolepsy and control subjects from Taiwan. MethodsWe determined the genotype of the major histocompatibility complex, class II, DQ β1 gene, HLA-DQB1, in 72 narcolepsy subjects (44 men, 28 women), including 52 narcolepsy subjects with cataplexy (narcolepsy+cataplexy), 20 narcolepsy subjects without cataplexy (narcolepsy–cataplexy), and 194 control subjects (94 men, 100 women) using a sequence-specific oligonucleotide-probe hybridization technique. ResultsWe found a strong HLA-DQB1∗06:02 association in narcolepsy+cataplexy subjects (odds ratio [OR], 321.4 [95% confidence interval {CI}, 70.7–1461.4]). The association was less prominent in narcolepsy–cataplexy subjects (OR, 6.9 [95% CI, 2.4–20.1]). In addition to the DQB1∗06:02, we found that ∗03:01 also was a predisposing allele (OR, 2.0 [95% CI, 1.1–3.7]) in narcolepsy+cataplexy subjects, though the ∗06:01 was a predisposing allele (OR, 2.8 [95% CI, 1.2–6.7]) in narcolepsy–cataplexy subjects. Furthermore, we found a significant overrepresentation of DQB1∗06:02 homozygotes in narcolepsy+cataplexy subjects. ConclusionsOur data add further support to the strong association of the HLA-DQB1∗06:02 allele with narcolepsy, especially in narcolepsy+cataplexy patients. Our study also indicates additional HLA-DQB1 alleles may modify the presentation of narcolepsy+cataplexy patients, such as DQB1∗03:01 and DQB1∗06:01 in our study. Our results are limited by the small sample size and can only be considered as preliminary findings.

Pandemrix-induced narcolepsy claims reconsidered

Pandemrix-induced narcolepsy claims reconsidered

No Serological Evidence of Influenza A H1N1pdm09 Virus Infection as a Contributing Factor in Childhood Narcolepsy after Pandemrix Vaccination Campaign in Finland

BackgroundNarcolepsy cataplexy syndrome, characterised by excessive daytime sleepiness and cataplexy, is strongly associated with a genetic marker, human leukocyte antigen (HLA) DQB1*06:02. A sudden increase in the incidence of childhood narcolepsy was observed after vaccination with AS03-adjuvanted Pandemrix influenza vaccine in Finland at the beginning of 2010. Here, we analysed whether the coinciding influenza A H1N1pdm pandemic contributed, together with the Pandemrix vaccination, to the increased incidence of childhood narcolepsy in 2010. The analysis was based on the presence or absence of antibody response against non-structural protein 1 (NS1) from H1N1pdm09 virus, which was not a component of Pandemrix vaccine.MethodsNon-structural (NS) 1 proteins from recombinant influenza A/Udorn/72 (H3N2) and influenza A/Finland/554/09 (H1N1pdm09) viruses were purified and used in Western blot analysis to determine specific antibody responses in human sera. The sera were obtained from 45 patients who fell ill with narcolepsy after vaccination with AS03-adjuvanted Pandemrix at the end of 2009, and from controls.FindingsBased on quantitative Western blot analysis, only two of the 45 (4.4%) Pandemrix-vaccinated narcoleptic patients showed specific antibody response against the NS1 protein from the H1N1pdm09 virus, indicating past infection with the H1N1pdm09 virus. Instead, paired serum samples from patients, who suffered from a laboratory confirmed H1N1pdm09 infection, showed high levels or diagnostic rises (96%) in H1N1pdm virus NS1-specific antibodies and very high cross-reactivity to H3N2 subtype influenza A virus NS1 protein.ConclusionBased on our findings, it is unlikely that H1N1pdm09 virus infection contributed to a sudden increase in the incidence of childhood narcolepsy observed in Finland in 2010 after AS03-adjuvanted Pandemrix vaccination.

Value of cerebral spinal fluid measurement of hypocretin-1 in the diagnosis of Chinese patients with narcolepsy

To evaluate the diagnostic value of cerebral spinal fluid (CSF) measurement of hypocretin-1 (hcrt-1) in Chinese patients with narcolepsy. A total of 139 narcoleptic patients, including 111 narcolepsy with typical cataplexy (NC) and 28 narcolepsy without cataplexy (NWC), were diagnosed at the sleep centre of Peking University People's Hospital from April 2003 to March 2012. And 64 non-narcoleptic controls were recruited. CSF hcrt-1 levels were measured in all subjects.Receiver operating characteristic curve (ROC) was applied to determine the cutoff value of hcrt-1 for Chinese narcoleptic patients. The diagnostic utility of hcrt-1 ≤ 110.0 ng/L and hcrt-1 ≤ 30% of mean normal level defined by International Classification of Sleep Disorders-II and the new Chinese cutoff value were evaluated respectively. The level of hcrt-1 in narcolepsy patients was significantly lower than that of normal controls and the NC group was even lower than NWC group (20 (13, 36) vs 319 (244, 379) and 36 (15, 114) ng/L) (all P < 0.01).Using the international criteria of CSF hcrt-1 ≤ 110.0 ng/L or a level of 1/3 of mean normal control values, a specificity of 100% and sensitivity of 90.6% were generated.ROC curve indicated that CSF hcrt-1 level of 138.0 ng/L was the best cutoff value for the diagnosis of narcolepsy in Chinese narcoleptic patients. There were a specificity of 100%, a sensitivity of 92.8% and the area under the ROC curve of 0.98. CSF hcrt-1 measurement with high specificity and sensitivity is a useful diagnostic tool for Chinese narcoleptics. And the level of 138.0 ng/L may be the optimal cutoff for the diagnosis of narcolepsy in this group of patients.

Effect of clomipramine in a dog with cataplexy

Abstract : A 5-year-old, castrated male, Maltese was presented with history of acute flaccid paralysis. The dog waspresented with sudden loss of muscle tone and involuntary movements of hind limbs. Neurologic examination revealedreduced postural reaction in the bilateral hind limbs. MRI of brain showed moderate hydrocephalus, but otherexamination results were normal. Based on the characteristic episodes and examination results, canine cataplexy wassuspected. Treatment was initiated with clomipramine as cataplexy control. Clinical signs resolved with 3-monthmedication. This case demonstrates therapeutic diagnosis of cataplexy. To the author’s knowledge, this is the first reportof cataplexy treating with clomipramine.Keywords : cataplexy, clomipramine, narcolepsy Cataplexy in dogs is relatively rare disease and manifestsitself as sudden weakness of muscle tone, often triggered bypositive emotional stimuli [5]. In genetically narcolepticDoberman puppies, the mean age of onset of cataplexy isabout 9 weeks, and female has more severe cataplexy thanmales [9]. Most of narcolepsy, which is sleep disorder, dogs experi-ence clinical signs of cataplexy [2]. Two different pathophys-iology mechanisms are involved in cataplexy and narcolepsy.Mutation in the hypocretin-receptor-2 gene causes the famil-ial type [7, 8, 10]. This type is inherited autosomal recessivetransmission and onset is young age (≤ 6 months) [10]. Theother is sporadic type caused by loss of the hypocretinligand, which is an excitatory peptide neurotransmitter madein the hypothalamus [4]. Onset of age is wide range as com-pared with familial type [10]. In human medicine, generalized cataplexy causes com-plete collapse of patients, whereas partial cataplexy affectsonly the face, voice or arms. In severe cases, respiratory andextraocular muscles could be attacked [6]. In veterinary med-icine, cataplexy attack may be affect all muscles or restrictedto head, trunk or certain limbs [4]. According to the previousreports [4], most cataplexy attacks initiated in the hind legsand affected bilateral.This report describes therapeutic diagnosis and successfuluse of clomipramine in the treatment of dog with cataplexy.A 5-year-old, castrated male, Maltese dog was presented tohistory of flaccid paralysis 1 to 2 times a week. The dog fellto the ground completely atonic, and bilateral hind limbsmoved involuntary. There was no loss of consciousness. Thisneurological signs observed 2 months prior to the presenta-tion, and episode lasted a few seconds to 2 min. A severeepisode also occurred with loss of consciousness, elicited byexcitement. Previous administration of nonsteroidal antin-flammatory drug (Firocoxib, Previcox; Merial, France) bythe referring veterinarian for pain control didn’t improve theclinical signs. Physical examination revealed intermittenthind limbs weakness when physical manipulation of bothpatellar (grade I/IV medial patellar luxation), but no otherabnormalities were found. The hemogram showed stress leu-kogram (21,030/µL, reference range, 6,000~17,000/µL), andserum chemistry profiles were within normal limits. Therewere no remarkable abnormalities in the thoracic, abdominaland accurately positioned hind limb radiographs. Electrocar-diography was also examined for exclusion of possibility ofcardiogenic episode, and result had no remarkable findings.To rule out myasthenia gravis and neurologic sign inducedby canine distemper virus infection, laboratory examinationswere performed, and acetylcholine receptor antibody concen-tration was within reference range (0.02 nmol/L, referencerange 0.0~0.6 nmol/L), and canine distemper polymerase chainreaction (PCR) of cerebrospinal fluid (CSF) sample result wasnegative. Result of food-elicited cataplexy test (FECT) foridentifying cataplexy was not revealed unusual outcome. Onneurologic examination, the dog presented reduced posturalreaction in the bilateral hind limbs, and this result could besuspected lesion of 4th lumbar vertebra to 3rd sacral verte-bra. However, lumbosacral region was normal at magnetic

Increased incidence of narcolepsy following the 2009 H1N1 pandemic

Narcolepsy is an autoimmune sleep disease characterized by excessive daytime sleepiness, cataplexy, and intrusive rapid eye movement sleep. Deficit in endogenous orexin is a major pathogenic component of the disease. This disorder is also associated with the gene marker HLADQB1*0602. After the 2009, H1N1 pandemic, a remarkable increased incidence of narcolepsy, especially in children, was noticed in different countries. In Finland and Sweden, this was attributed to the H1N1 vaccine, especially the adjuvanted pandemic vaccines. In China, there was a 3-fold increase in narcolepsy onset but was due to H1N1 virus infection per se. This review will first summarize the epidemiological data of post H1N1 narcolepsy, then possible mechanisms of the H1N1-related immune process to link the HLA (human leukocyte antigen) genetic background and hypocretin deficiency in narcolepsy–cataplexy will be discussed.

Etiology of narcolepsy:a review of the literature

Narcolepsy is a disabling sleep disorder characterized mainly by irresistible excessive daytime sleepiness.It seriously influences patient's academic,family,and social function.The etiology of narcolepsy is still elusive,but the hereditary and environmental factors have been suggested to contribute the most.It is a multi-gene regulation disease,the researches of Human Leucocyte Antigen(HLA) gene type HLA-DQB1 * 0602 and HLA-DRB1 * 1501 are most popular in recent years.Especially the HLA-DQB1 * 0602 is regard as the major HLA susceptibility allele for narcolepsy almost in all ethnic groups.And the hypocretin excreting neurons and the hypocretin's deficits would directly lead to somnolence.Some environmental factors which are newly found these years are still playing important roles,such as the contact with certain antigens,infection of beta hemolytic streptococcus,passive smoking and so on. Key words: Narcolepsy; Etiology; Genetic factor ; Environmental factor