Related Articles

Purpose

While the symptoms of narcolepsy are often amenable to treatment with sodium oxybate (SXB), the respiratory effects of long-term SXB treatment have not been systematically studied. Recent reports have implicated SXB with several cases of worsening sleep-related breathing disturbances and accidental death. In addition, these patients are at risk for obesity, which may aggravate co-morbid obstructive sleep apnea.

Methods

Based on a review of the literature and the clinical experience of the author, recommendations for the use of SXB in patients with sleep-disordered breathing have been developed.

Results

Among narcolepsy patients with evidence of sleep disordered breathing during baseline polysomnography, SXB should be prescribed only to those patients who fully comply with nasal continuous positive airway pressure therapy. The respiratory status of other SXB-treated patients should be periodically evaluated with nocturnal oximetry.

Conclusions

Based on the currently available data, physicians prescribing SXB should remain vigilant for the possible development of sleep-disordered breathing during long-term treatment with SXB.

Summary

Ten patients with narcolepsy were given five 20 min opportunities to remain awake throughout the day. Trials were offered at 2 h intervals beginning at 10:00, Polysomnographic variables were monitored during each trial. Sleep latency increased when patients were instructed to maintain wakefulness compared to when instructed to sleep; however, sleep latencies were still lower for narcoleptics than for control subjects. Unexpectedly, we were not always able to document patients’ reports of increased ability to stay awake. The findings suggested that clinical data on symptom control in narcolepsy do not predict ability to stay awake. Objective measures of the ability are potentially more useful in evaluating treatment.

Narcolepsy is a lifelong sleep disorder characterized by a classic tetrad of excessive daytime sleepiness with irresistible sleep attacks, cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucination, and sleep paralysis. There are two distinct groups of patients, ie, those having narcolepsy with cataplexy and those having narcolepsy without cataplexy. Narcolepsy affects 0.05% of the population. It has a negative effect on the quality of life of its sufferers and can restrict them from certain careers and activities. There have been advances in the understanding of the pathogenesis of narcolepsy. It is thought that narcolepsy with cataplexy is secondary to loss of hypothalamic hypocretin neurons in those genetically predisposed to the disorder by possession of human leukocyte antigen DQB1*0602. The diagnostic criteria for narcolepsy are based on symptoms, laboratory sleep tests, and serum levels of hypocretin. There is no cure for narcolepsy, and the present mainstay of treatment is pharmacological treatment along with lifestyle changes. Some novel treatments are also being developed and tried. This article critically appraises the evidence for diagnosis and treatment of narcolepsy.

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement (REM) sleep abnormalities. A genome-wide association study (GWAS) identified a novel narcolepsy-related single nucleotide polymorphism (SNP), which is located adjacent to the carnitine palmitoyltransferase 1B (CPT1B) gene encoding an enzyme involved in β-oxidation of long-chain fatty acids. The mRNA expression levels of CPT1B were associated with this SNP. In addition, we recently reported that acylcarnitine levels were abnormally low in narcolepsy patients. To assess the efficacy of oral l-carnitine for the treatment of narcolepsy, we performed a clinical trial administering l-carnitine (510 mg/day) to patients with the disease. The study design was a randomized, double-blind, cross-over and placebo-controlled trial. Thirty narcolepsy patients were enrolled in our study. Two patients were withdrawn and 28 patients were included in the statistical analysis (15 males and 13 females, all with HLA-DQB1*06:02). l-carnitine treatment significantly improved the total time for dozing off during the daytime, calculated from the sleep logs, compared with that of placebo-treated periods. l-carnitine efficiently increased serum acylcarnitine levels, and reduced serum triglycerides concentration. Differences in the Japanese version of the Epworth Sleepiness Scale (ESS) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) vitality and mental health subscales did not reach statistical significance between l-carnitine and placebo. This study suggests that oral l-carnitine can be effective in reducing excessive daytime sleepiness in narcolepsy patients.

Trial Registration

University hospital Medical Information Network (UMIN) UMIN000003760

Background

Narcolepsy is a neurologic disorder characterized by excessive daytime sleepiness, symptoms of abnormal rapid eye movement (REM) sleep, and a strong association with HLA-DRB1*1501, -DQA1*0102, and -DQB1*0602. Here, we investigated the clinico-physical characteristics of Korean patients with narcolepsy, their HLA types, and the clinical utility of high-resolution PCR with sequence-specific primers (PCR-SSP) as a simple typing method for identifying DRB1*15/16, DQA1, and DQB1 alleles.

Methods

The study population consisted of 67 consecutively enrolled patients having unexplained daytime sleepiness and diagnosed narcolepsy based on clinical and neurological findings. Clinical data and the results of the multiple sleep latency test and polysomnography were reviewed, and HLA typing was performed using both high-resolution PCR-SSP and sequence-based typing (SBT).

Results

The 44 narcolepsy patients with cataplexy displayed significantly higher frequencies of DRB1*1501 (Pc= 0.003), DQA1*0102 (Pc=0.001), and DQB1*0602 (Pc=0.014) than the patients without cataplexy. Among patients carrying DRB1*1501-DQB1*0602 or DQA1*0102, the frequencies of a mean REM sleep latency of less than 20 min in nocturnal polysomnography and clinical findings, including sleep paralysis and hypnagogic hallucination were significantly higher. SBT and PCR-SSP showed 100% concordance for high-resolution typing of DRB1*15/16 alleles and DQA1 and DQB1 loci.

Conclusions

The clinical characteristics and somnographic findings of narcolepsy patients were associated with specific HLA alleles, including DRB1*1501, DQA1*0102, and DQB1*0602. Application of high-resolution PCR-SSP, a reliable and simple method, for both allele- and locus-specific HLA typing of DRB1*15/16, DQA1, and DQB1 would be useful for characterizing clinical status among subjects with narcolepsy.

Background

Narcolepsy is a rare neurological sleep disorder especially in children who are younger than 10 years. In the beginning of 2010, an exceptionally large number of Finnish children suffered from an abrupt onset of excessive daytime sleepiness (EDS) and cataplexy. Therefore, we carried out a systematic analysis of the incidence of narcolepsy in Finland between the years 2002–2010.

Methods

All Finnish hospitals and sleep clinics were contacted to find out the incidence of narcolepsy in 2010. The national hospital discharge register from 2002 to 2009 was used as a reference.

Findings

Altogether 335 cases (all ages) of narcolepsy were diagnosed in Finland during 2002–2009 giving an annual incidence of 0.79 per 100 000 inhabitants (95% confidence interval 0.62–0.96). The average annual incidence among subjects under 17 years of age was 0.31 (0.12–0.51) per 100 000 inhabitants. In 2010, 54 children under age 17 were diagnosed with narcolepsy (5.3/100 000; 17-fold increase). Among adults ≥20 years of age the incidence rate in 2010 was 0.87/100 000, which equals that in 2002–2009. Thirty-four of the 54 children were HLA-typed, and they were all positive for narcolepsy risk allele DQB1*0602/DRB1*15. 50/54 children had received Pandemrix vaccination 0 to 242 days (median 42) before onset. All 50 had EDS with abnormal multiple sleep latency test (sleep latency <8 min and ≥2 sleep onset REM periods). The symptoms started abruptly. Forty-seven (94%) had cataplexy, which started at the same time or soon after the onset of EDS. Psychiatric symptoms were common. Otherwise the clinical picture was similar to that described in childhood narcolepsy.

Interpretation

A sudden increase in the incidence of abrupt childhood narcolepsy was observed in Finland in 2010. We consider it likely that Pandemrix vaccination contributed, perhaps together with other environmental factors, to this increase in genetically susceptible children.

Background

Narcolepsy-cataplexy is characterized by excessive daytime sleepiness with recurrent episodes of irresistible sleep, cataplexy, hallucinations and sleep paralysis. Its aetiology is unknown, but it is positively associated with the human leukocyte antigens (HLA) in all studied populations. The purpose of the present study was to investigate the association of HLA class II DRB1/DQB1 alleles with narcolepsy-cataplexy in Mexican Mestizo patients.

Methods

This is a case-control study of consecutive patients and ethnically matched controls. We included 32 patients diagnosed with typical narcolepsy-cataplexy, of the National Institute of Neurology, of the Institute of Psychiatry and at the Center of Narcolepsy at Stanford University. As healthy controls, 203 Mexican Mestizos were included. DRB1 alleles were identified using sequence based typing. A PCR-SSOP reverse dot blot was used for DQB1 typing. Allele frequency was calculated by direct counting and the significance of the differences was assessed using the Yates Chi square. Odds ratio and confidence intervals were evaluated.

Results

HLA-DRB1*1501 (OR = 8.2; pc < 0.0001) and DQB1*0602 (OR = 8.4; pc < 0.0001) were found positively associated with narcolepsy. When deleting DQB1*0602+ patients from the analysis, DQB1*0301 was also found increased (OR = 2.7; p = 0.035; pc = NS). DQB1*0602/DQB1*0301 genotype was present in 15.6% of the cases (OR = 11.5; p = 0.00035), conferring a high risk. DRB1*0407 (OR = 0.2; p = 0.016 pc = NS) and DQB1*0302(OR = 0.4; p = 0.017, pc = NS) were found decreased in the patients. The gender stratification analysis showed a higher risk in females carrying DRB1*1501 (OR = 15.8, pc < 0.0001) and DQB1*0602 (OR = 19.8, pc < 0.0001) than in males (OR = 5.0 for both alleles; p = 0.012, pc = NS for DRB1 & p = 0.0012, pc = 0.017 for DQB1). The susceptibility alleles found in Mexicans with narcolepsy are also present in Japanese and Caucasians; DRB1*04 linked protection has also been shown in Koreans. A stronger HLA association is suggested in females, in accordance with the sexual dimorphism claimed previously.

Conclusion

This knowledge may contribute to a better understanding of the disease pathogenesis in different populations. The evaluation of the risk to develop narcolepsy-cataplexy in carriers of the described alleles/genotypes may also be possible. A larger sample should be analysed in Mexican and in other Hispanic patients to confirm these results.

Narcolepsy is a common sleep disorder characterized by excessive daytime sleepiness and cataplexy - episodes of muscle weakness triggered by positive emotions. Over the last few years, researchers have discovered that narcolepsy results from a selective loss of neurons in the lateral hypothalamus that produce the orexin/hypocretin neuropeptides. While an autoimmune process is thought to underlie the loss of the orexin neurons this has not yet been conclusively demonstrated. Similarly, it is only partially understood how loss of the orexin neurons results in the various symptoms of narcolepsy. Studies in human patients and animal models of narcolepsy suggest that excessive sleepiness is due to behavioral state instability rather than disruption of sleep homeostasis or circadian rhythms. Cataplexy may result from the inappropriate activation during wakefulness of the pontine circuits that normally generate muscle atonia during REM sleep. This article reviews the clinical features and neurobiology of narcolepsy and outlines important areas in which progress might be achieved.

Successful management of patients with sleep disorders requires attention to the clinical history, particularly the sleep history, knowledge of the causes of insomnia and hypersomnia, and familiarity with a variety of therapeutic interventions. To illustrate these principles, the authors describe a 68-year-old woman who had a history of clinical depression but who, on further investigation, was found to suffer from three sleep disorders: narcolepsy, periodic leg movements during sleep, and rapid eye movement sleep behaviour disorder. Treatment of these sleep disorders caused a complete amelioration of the mood symptoms and a significant improvement in psychosocial functioning and well-being.

The wake-promoting agent modafinil is approved for the treatment of excessive sleepiness associated with obstructive sleep apnea (OSA), shift work disorder (SWD), and narcolepsy. In OSA, modafinil is recommended for use as an adjunct to standard therapies that treat the underlying airway obstruction. This article reviews the literature on modafinil (pharmacology, pharmacokinetics, efficacy, tolerability, and abuse potential), with emphasis on use of modafinil in the treatment of excessive sleepiness in patients with OSA, SWD, and narcolepsy. In large-scale, double-blind, placebo-controlled studies, modafinil improved objectively determined sleep latency, improved overall clinical condition related to severity of sleepiness, and reduced patient-reported sleepiness. Improvements in wakefulness were accompanied by improvements in behavioral alertness, functional status, and health-related quality of life. In patients with SWD, diary data showed modafinil reduced the maximum level of sleepiness during night shift work, level of sleepiness during the commute home, and incidence of accidents or near-accidents during the commute home when compared with placebo. Modafinil was well tolerated, without adversely affecting cardiovascular parameters or scheduled sleep. These findings and those of extension studies which reported improvements were maintained suggest modafinil has a beneficial effect on daily life and well-being in patients with excessive sleepiness associated with OSA, SWD, or narcolepsy.

A 17-year-old man presented with daytime sleepiness, episodic attacks of sleep and probable cataplexy. His EEG showed rapid eye movements and central sawtooth waves at sleep onset, and supported the clinical impression of narcolepsy. He improved with methylphenidate but died suddenly, and had cardiomegaly, right ventricular enlargement, and pulmonary hypertension at autopsy. These findings suggested concomitant features of sleep apnea which were not evident by history or examination.

Central apneas have been frequently described in the sleep of narcoleptic patients. Few patients have had indications of obstructive or mixed apneas. This patient's course suggests that ventilation during sleep should be included in the polygraphic assessment of patients with suspected narcolepsy, as the agents used for treatment of narcolepsy may aggravate the cardiac complications of sleep apnea.

Narcolepsy is usually an idiopathic disorder, often with a genetic predisposition. Symptomatic cases have been described repeatedly, often as a consequence of hypothalamic lesions. Conversely, REM (rapid eye movement) sleep behaviour disorder (RBD) is usually a secondary disorder, often due to degenerative brain stem disorders or narcolepsy. The case of a hitherto healthy man is presented, who simultaneously developed narcolepsy and RBD as the result of an acute focal inflammatory lesion in the dorsomedial pontine tegmentum in the presence of normal cerebrospinal fluid hypocretin‐1 levels and in the absence of human lymphocyte antigen haplotypes typically associated with narcolepsy and RBD (DQB1*0602, DQB1*05). This first observation of symptomatic narcolepsy with RBD underlines the importance of the mediotegmental pontine area in the pathophysiology of both disorders, even in the absence of a detectable hypocretin deficiency and a genetic predisposition.

Cataplexy is one of the most pathognomonic symptoms in narcolepsy. This study was designed to investigate the frequency of the HLA-DQB1 allele and cerebrospinal fluid (CSF) hypocretin levels in Korean narcoleptics with cataplexy as compared with those who do not have cataplexy. Seventy-two narcoleptics were selected based on polysomnography and multiple sleep latency test as well as their history and clinical symptoms at Sleep Disorders Clinic. The patients were divided into a narcolepsy with cataplexy group (n=56) and a narcolepsy without cataplexy group (n=16). All patients were subjected to HLA typing to determine the frequency of DQB1 allele and to spinal tapping to measure the level of CSF hypocretin. In cataplexy-positive patients, as compared with cataplexy-negative patients, the frequency of HLA-DQB1*0602 was found to be significantly high (89.3% vs. 50.0%) (p=0.003). On the other hand, the frequency of HLA-DQB1*0601 was found to be significantly low (0% vs. 43.8%) (p<0.001). In 48 of 56 cataplexy-positive patients (85.7%), hypocretin levels were decreased (≤110 pg/mL). However, only 6 of 16 cataplexy-negative patients (37.5%) exhibited a decreased hyopcretin level (p<0.001). The high frequency of HLA-DQB1*0602, low frequency of HLA-DQB1*0601 and low hypocretin levels in cataplexy-positive groups suggest that cataplexy-positive narcolepsy might be an etiologically different disease entity from the cataplexy-negative.

Background:

Narcolepsy is a severe sleep-wake cycle disorder resulting in most cases from a lack of orexin, the energy balance-regulating hormone. Narcoleptic patients have been reported to suffer from an excess morbidity of Type 2 diabetes, even after correction for their often elevated body mass index.

Methods:

To explore whether narcolepsy is specifically associated with a propensity to develop insulin resistance, we measured fasting glucose, insulin, and intact proinsulin levels in 43 narcoleptic patients and 47 controls matched for body mass index and age. The proinsulin-to-insulin ratio was calculated. Insulin resistance was determined using the homeostatic model assessment method.

Results:

Narcoleptic patients did not show elevated insulin resistance parameters.

Conclusion:

In contrast with earlier reports, we found no evidence that narcolepsy specifically elevates the risk of insulin resistance (and consequently of type 2 diabetes) independently of body mass index.

Idiopathic narcolepsy is associated with deficient hypocretin transmission. Narcoleptic symptoms have recently been described in paraneoplastic encephalitis with anti-Ma2 antibodies. The authors measured CSF hypocretin-1 levels in six patients with anti-Ma2 encephalitis, and screened for anti-Ma antibodies in patients with ideopathic narcolepsy. Anti-Ma autoantibodies were not detected in patients with idiopathic narcolepsy. Four patients with anti-Ma2 encephalitis had excessive daytime sleepiness; hypocretin-1 was not detectable in their cerebrospinal fluid, suggesting an immune-mediated hypocretin dysfunction.

Narcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis. Both sporadic (95%) and familial (5%) forms of narcolepsy exist in humans. The major pathophysiology of human narcolepsy has been recently discovered based on the discovery of narcolepsy genes in animals; the genes involved in the pathology of the hypocretin/orexin ligand and its receptor. Mutations in hypocretin-related genes are rare in humans, but hypocretin-ligand deficiency is found in a large majority of narcolepsy with cataplexy.

Hypocretin ligand deficiency in human narcolepsy is likely due to the postnatal cell death of hypocretin neurons. Although tight association between human leukocyte antigen (HLA) association and human narcolepsy with cataplexy suggests an involvement of autoimmune mechanisms, this has not yet been proven. Hypocretin deficiency is also found in symptomatic cases of narcolepsy and EDS with various neurological conditions, including immune-mediated neurological disorders, such as Guillain-Barre syndrome, MA2-positive paraneoplastic syndrome and neuromyelitis optica (NMO) related disorder. These findings likely have significant clinical relevance and for understanding the mechanisms of hypocretin cell death and choice of treatment option.

These series of discoveries in humans lead to the establishment of the new diagnostic test of narcolepsy (i.e. low cerebrospinal fluid [CSF] hypocretin-1 levels for narcolepsy with cataplexy and narcolepsy due to medical condition). Since a large majority of human narcolepsy patients are ligand deficient, hypocretin replacement therapy may be a promising new therapeutic option, and animal experiments using gene therapy and cell transplantations are in progress.

Summary

Narcolepsy and other syndromes associated with excessive daytime sleepiness can be challenging to treat. New classifications now distinguish narcolepsy/hypocretin deficiency (also called type 1 narcolepsy), a lifelong disorder with well-established diagnostic procedures and etiology, from other syndromes with hypersomnolence of unknown causes. Klein-Levin Syndrome, a periodic hypersomnia associated with cognitive and behavioral abnormalities, is also considered a separate entity with separate therapeutic protocols. Non hypocretin-related hypersomnia syndromes are diagnoses of exclusion. These diagnoses are only made after eliminating sleep deprivation, sleep apnea, disturbed nocturnal sleep, and psychiatric comorbidities as the primary cause of daytime sleepiness. The treatment of narcolepsy/hypocretin deficiency is well-codified, and involves pharmacotherapies using sodium oxybate, stimulants, and/or antidepressants, plus behavioral modifications. These therapies are almost always needed, and the risk-to-benefit ratio is clear, notably in children. Detailed knowledge of the pharmacological profile of each compound is needed to optimize use. Treatment for other syndromes with hypersomnolence is more challenging and less codified. Preferably, therapy should be conservative (such as modafinil, atomoxetine, behavioral modifications), but it may have to be more aggressive (high-dose stimulants, sodium oxybate, etc.) on a case-by-case, empirical trial basis. As cause and evolution are unknown in these conditions, it is important to challenge diagnosis and therapy over time, keeping in mind the possibility of tolerance and the development of stimulant addiction. Kleine-Levin Syndrome is usually best left untreated, although lithium can be considered in severe cases with frequent episodes. Guidelines are provided based on the literature and personal experience of the author.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-012-0150-9) contains supplementary material, which is available to authorized users.

Background

Relatively few epidemiologic studies have focused on narcolepsy, a disabling sleep disorder with strong association with HLA-DQB1*0602.

Methods

We sought to estimate prevalence of narcolepsy using multiple overlapping techniques to identify residents of King County, Washington who were 18 years or older with physician-diagnosed narcolepsy. Patients were entered into a registry and recruited into an epidemiologic study entailing interview and buccal scrapings to determine HLA-DQB1*0602 status. Missing values were imputed to allow prevalence to be estimated based on all 425 patients entered into the registry between 2001 and 2005, whether they were recruited into the epidemiologic study (n=279) or not (n=146).

Results

As of 2001 July 01, estimated prevalence per 100,000 of physician-diagnosed narcolepsy with cataplexy was 21.8 (95% confidence interval (CI): 18.8 to 24.8), similar to prior studies. The median age of onset was 14 (interquartile range: 10 to 18). For narcolepsy with HLA-DQB1*0602, prevalence was 15.3 (95% CI: 12.8 to 17.9). Estimated prevalence was higher in women than men and in African-Americans than other racial groups.

Conclusions

These differences could reflect problems in identification and recruitment or may provide etiologic clues about narcolepsy. This study illustrates the challenges in performing population-based studies of narcolepsy.

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2–3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataplexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder.

Summary

An ongoing study of the genetics of narcolepsy ascertains families through a case series of narcoleptic probands using diagnostic criteria consisting of 1) clinical history of excessive somnolence, 2) a mean sleep latency on the multiple sleep latency test (MSLT) of less than 7.9 minutes, 3) the rapid eye movement (REM) sleep-related symptom of cataplexy, 4) nocturnal polysomnography ruling out sleep apnea syndrome, and 5) two or more transitions to REM sleep on the MSLT. All probands and first-degree relatives received clinical and laboratory evaluations as well as human leukocyte antigen (HLA) typing. Demographic characteristics of the 32 probands are as follows: 17 males and 15 females; mean age was 42.1 years (range 13–70 years). The polysomnographic data confirmed daytime sleepiness and increased tendency for REM sleep for the 32 probands. Nocturnal polysomnographic results are as follows: sleep latency, 3.2 minutes; total sleep time, 442 minutes. MSLT results are as follows: sleep latency, 3.1 minutes; REM latency, 6.9 minutes; number of REM periods, 3.2. HLA typing revealed the presence of the HLA haplotypes, DRB1*15 and DQB1*0602, in 21 narcoleptic probands, with two African-Americans having the DQB1*0602 but not the DRB1*15 allele. Among the 57 relatives of the 32 probands, 1/31 females and 7/26 males were found to be affected with narcolepsy (p < 0.02), which suggests a higher diagnostic rate in male relatives. The 21 probands who were positive for the DRB1*15 and DQB1*0602 haplotypes did not differ from the 10 probands who were negative for these alleles in terms of their nocturnal sleep parameters, MSLT findings, or clinical presentation. Three families with multiple individuals affected with narcolepsy are presented. Two families have more than one affected individual who does not have the high-risk HLA haplotype. In one of these families, the disease is segregating independently of any HLA haplotype. In the third family, there is cosegregation with HLA DRB1*15 and DQB1*0602. One family contains a pair of DNA-confirmed, monozygotic twins with narcolepsy who are discordant for cataplexy and have the HLA DR14(Dw9)/DQB1*0503 and DR4(Dw4)/DQB1*0302 haplotypes.

Cerebrospinal fluid (CSF) hypocretin‐1 deficiency is associated with definite (“clear cut”) cataplexy in patients with narcolepsy. The relationship between CSF hypocretin‐1 levels and other narcoleptic symptoms (including excessive daytime sleepiness, EDS) is not properly understood.

In a consecutive series of 18 subjects with narcolepsy and definite cataplexy, patients with undetectable CSF hypocretin‐1 (n = 12) were found to have significantly lower mean sleep latencies (p = 0.045) and a higher frequency of sleep onset REM periods (SOREMPs, p = 0.025) on multiple sleep latency test than patients (n = 6) with detectable levels. Conversely, Epworth sleepiness scale scores, the frequency of hallucinations/sleep paralysis, and the frequency and severity of cataplexy were similar in both groups.

These results suggest that hypocretin deficiency identifies a homogenous group of patients with narcolepsy characterised by the presence of definite cataplexy, severe EDS, and frequent SOREMPs.

Background

Frequent reporting of cases of hysterical conversion reaction (HCR) among hospitalized female medical patients in Bangladesh’s public hospital system led us to explore the prevalence of “HCR” diagnoses within hospitals and the manner in which physicians identify, manage, and perceive patients whom they diagnose with HCR.

Methods

We reviewed admission records from women’s general medicine wards in two public hospitals to determine how often and at what point during hospitalization patients received diagnoses of HCR. We also interviewed 13 physicians about their practices and perceptions related to HCR.

Results

Of 2520 women admitted to the selected wards in 2008, 6% received diagnoses of HCR. HCR patients had wide-ranging symptoms including respiratory distress, headaches, chest pain, convulsions, and abdominal complaints. Most doctors diagnosed HCR in patients who had any medically-unexplained physical symptom. According to physician reports, women admitted to medical wards for HCR received brief diagnostic evaluations and initial treatment with short-acting tranquilizers or placebo agents. Some were referred to outpatient psychiatric treatment. Physicians reported that repeated admissions for HCR were common. Physicians noted various social factors associated with HCR, and they described failures of the current system to meet psychosocial needs of HCR patients.

Conclusions

In these hospital settings, physicians assign HCR diagnoses frequently and based on vague criteria. We recommend providing education to increase general physicians’ awareness, skill, and comfort level when encountering somatization and other common psychiatric issues. Given limited diagnostic capacity for all patients, we raise concern that when HCR is used as a "wastebasket" diagnosis for unexplained symptoms, patients with treatable medical conditions may go unrecognized. We also advocate introducing non-physician hospital personnel to address psychosocial needs of HCR patients, assist with triage in a system where both medical inpatient beds and psychiatric services are scarce commodities, and help ensure appropriate follow up.

Narcolepsy is a human sleep disorder resulting from the loss of neurons containing the neuropeptide orexin, also known as hypocretin. Cataplexy, which is a sudden loss of muscle tone during waking, is an important diagnostic symptom of narcolepsy. In humans and canines with narcolepsy, cataplexy is considered to be a separate and distinct behavioral state. However, in the mouse model of the disease this issue is not resolved. The present study monitored the activity of forty four neurons in the rostral pons in hypocretin knock-out mice. Majority of the neurons were active during wake and REM sleep, while four neurons were selectively active during REM sleep. All of these neurons were less active during cataplexy compared with REM sleep. Thus, although cataplexy and REM sleep share many common features, including the muscle atonia, cataplexy is a distinct state in mice.

We describe a patient who presented with a clinical syndrome of limbic encephalitis, narcolepsy, and cataplexy. The anti-Ma2 antibody was positive. Although there was no mass on imaging, orchiectomy was performed in this patient, and testicular carcinoma was found. This is the first known case of limbic encephalitis and anti-Ma2 antibody to be associated with cataplexy and possible narcolepsy. Neurological symptoms precede the diagnosis of cancer in 50% of patients with paraneoplastic syndromes, and clinicians are therefore strongly advised to evaluate patients with neurological symptoms for this condition.

The management of narcolepsy is presently at a turning point. Three main avenues are considered in this review: 1) Two tendencies characterize the conventional treatment of narcolepsy. Modafinil has replaced methylphenidate and amphetamine as the first-line treatment of excessive daytime sleepiness (EDS) and sleep attacks, based on randomized, double blind, placebo-controlled clinical trials of modafinil, but on no direct comparison of modafinil versus traditional stimulants. For cataplexy, sleep paralysis, and hypnagogic hallucinations, new antidepressants tend to replace tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) in spite of a lack of randomized, double blind, placebo-controlled clinical trials of these compounds; 2) The conventional treatment of narcolepsy is now challenged by sodium oxybate, the sodium salt of gammahydroxybutyrate, based on a series of randomized, double-blind, placebo-controlled clinical trials and a long-term open label study. This treatment has a fairly good efficacy and is active on all symptoms of narcolepsy. Careful titration up to an adequate level is essential both to obtain positive results and avoid adverse effects; 3) A series of new treatments are currently being tested, either in animal models or in humans, They include novel stimulant and anticataplectic drugs, endocrine therapy, and, more attractively, totally new approaches based on the present state of knowledge of the pathophysiology of narcolepsy with cataplexy, hypocretine-based therapies, and immunotherapy.