Vitamin B12 deficiency is associated with narcolepsy.

BACKGROUND: Narcolepsy can be defined as a sleep disorder. However, whether changes in the serum vitamin B12 levels are involved in the pathophysiological mechanism of narcolepsy remains unclear. Our study aimed to assess whether vitamin B12 levels are independently related to the occurrence of narcolepsy. METHODS: The serum folate, vitamin B12, and homocysteine levels of 40 patients with narcolepsy and 40 age- and gender-matched healthy controls (HC) were retrospectively analyzed. According to the results of the univariate logistic analysis, a multiple logistic regression model was constructed to predict the independent influencing indicators. RESULTS: Serum folic acid and vitamin B12 levels in the narcolepsy group were significantly reduced. Moreover, through the sex subgroup, males in the narcolepsy group had lower serum vitamin B12 levels. Multivariate logistic regression revealed serum vitamin B12 to be independently associated with narcolepsy (p < 0.05; odds ratio=0.97; 95% confidence interval: 0.95-0.98). CONCLUSION: Decreased serum vitamin B12 levels are independently associated with the development of narcolepsy, which illustrates the complex relationship between vitamin B12 and narcolepsy. Future studies should explore whether vitamin B12 supplementation can improve the symptoms of patients.

Reassessment of the risk of narcolepsy in children in England 8 years after receipt of the AS03-adjuvanted H1N1 pandemic vaccine: A case-coverage study.

BACKGROUND: Early studies of narcolepsy after AS03-adjuvanted pandemic A/H1N12009 vaccine (Pandemrix) could not define the duration of elevated risk post-vaccination nor the risk in children aged under 5 years who may not present until much older. METHODS/FINDINGS: Clinical information and sleep test results, extracted from hospital notes at 3 large pediatric sleep centers in England between September 2017 and June 2018 for narcolepsy cases aged 4-19 years with symptom onset since January 2009, were reviewed by an expert panel to confirm the diagnosis. Vaccination histories were independently obtained from general practitioners (GPs). The odds of vaccination in narcolepsy cases compared with the age-matched English population was calculated after adjustment for clinical conditions that were indications for vaccination. GP questionnaires were returned for 242 of the 244 children with confirmed narcolepsy. Of these 5 were under 5 years, 118 were 5-11 years, and 119 were 12-19 years old at diagnosis; 39 were vaccinated with Pandemrix before onset. The odds ratio (OR) for onset at any time after vaccination was 1.94 (95% confidence interval [CI] 1.30-2.89), The elevated risk period was restricted to onsets within 12 months of vaccination (OR 6.65 [3.44-12.85]) and was highest within the first 6 months. After one year, ORs were not significantly different from 1 up to 8 years after vaccination. The ORs were similar in under five-year-olds and older ages. The estimated attributable risk was 1 in 34,500 doses. Our study is limited by including cases from only 3 sleep centers, who may differ from cases diagnosed in nonparticipating centers, and by imprecision in defining the centers' catchment population. The potential for biased recall of onset shortly after vaccination in cases aware of the association cannot be excluded. CONCLUSIONS: In this study, we found that vaccine-attributable cases have onset of narcolepsy within 12 months of Pandemrix vaccination. The attributable risk is higher than previously estimated in England because of identification of vaccine-attributable cases with late diagnoses. Absence of a compensatory drop in risk 1-8 years after vaccination suggests that Pandemrix does not trigger onsets in those in whom narcolepsy would have occurred later.

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.

Risk of narcolepsy associated with inactivated adjuvanted (AS03) A/H1N1 (2009) pandemic influenza vaccine in Quebec.

CONTEXT: An association between an adjuvanted (AS03) A/H1N1 pandemic vaccine and narcolepsy has been reported in Europe. OBJECTIVE: To assess narcolepsy risk following administration of a similar vaccine in Quebec. DESIGN: Retrospective population-based study. SETTING: Neurologists and lung specialists in the province were invited to report narcolepsy cases to a single reference centre. POPULATION: Patients were interviewed by two sleep experts and standard diagnostic tests were performed. Immunization status was verified in the provincial pandemic influenza vaccination registry. MAIN OUTCOME MEASURES: Confirmed narcolepsy with or without cataplexy with onset of excessive daytime sleepiness between January 1st, 2009, and December 31st, 2010. Relative risks (RRs) were calculated using a Poisson model in a cohort analysis, by a self-controlled case series (SCCS) and a case-control method. RESULTS: A total of 24 cases were included and overall incidence rate was 1.5 per million person-years. A cluster of 7 cases was observed among vaccinated persons in the winter 2009-2010. In the primary cohort analysis, 16-week post-vaccination RR was 4.32 (95% CI: 1.50-11.12). RR was 2.07 (0.70-6.17) in the SCCS, and 1.48 (0.37-7.03) using the case-control method. Estimates were lower when observation was restricted to the period of pandemic influenza circulation, and tended to be higher in persons <20 years old and for cataplexy cases. CONCLUSIONS: Results are compatible with an excess risk of approximately one case per million vaccine doses, mainly in persons less than 20 years of age. However, a confounding effect of the influenza infection cannot be ruled out.

Narcolepsy and H1N1 vaccination: a link?

PURPOSE OF REVIEW: A number of European countries have reported a dramatic increase in the rates of childhood narcolepsy with cataplexy in children immunized with a split-virion adjuvanted swine flu vaccine. Here, we review the strengths and weaknesses of these epidemiological studies and possible neuroimmunological mechanisms. RECENT FINDINGS: Initial concerns of a 13-fold increased relative risk of narcolepsy were raised by the Scandinavian health protection agencies in 2010. Subsequent retrospective studies support these findings in Canada, France, Ireland, England and Denmark. The cases are predominantly young children who present with severe and rapid onset of cataplexy as well as narcolepsy often within a few weeks of vaccination. The proposed mechanism for postvaccination narcolepsy is one in which an environmental trigger causes or enhances an antibody-mediated autoimmune response in patients with a preexisting genetic susceptibility. However, there have not yet been any reports of specific autoimmunity, either antibody or T-cell-mediated. SUMMARY: There is a strong association between narcolepsy and H1N1 vaccination. However, whether this reflects a true increase in affected individuals or a hastening of disease onset in individuals who would otherwise have developed narcolepsy later will become clear in the coming years. The pathological explanation of this association and narcolepsy is likely to be autoimmune, although supportive evidence is lacking.Video abstract available: See the Video Supplementary Digital Content 1 (http://links.lww.com/COPM/A9).

[Diagnostic and therapeutic update in narcolepsy]. / Actualizacion diagnostica y terapeutica en narcolepsia.

Narcolepsy is an emblematic, unique disease within sleep disorders that is characterised by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep. In the last 14 years truly spectacular progress has been made in our knowledge of this disease, since the discovery of its cause, i.e. a loss of the hypothalamic neurons that synthesise hypocretin, a previously unknown neurotransmitter, and its probable aetiopathogenic mechanisms, i.e. an autoimmune process in a patient with very precise immunological characteristics - a specific type of HLA and a specific type of T-cell receptor. The cause of this autoimmune process remains unknown. The definitive treatment - the administration of hypocretin, which is the substance missing in the organism - is still unavailable, but there are powerful drugs for treating its main symptoms, the sleepiness and the cataplexy. Some of these are classic compounds (methylphenidate, clomipramine), while others are more recent (modafinil, venlafaxine, sodium oxybate), but together they allow many patients to experience significant improvements. Lack of knowledge about the disease, both on the part of patients and their relatives as well as physicians, is the reason for the great delay in its diagnosis, with even more dramatic consequences when the disease begins in infancy.

Narcolepsy in the pediatric population.

Narcolepsy is characterized by excessive daytime sleepiness, with or without cataplexy. Associated features include sleep paralysis, hypnagogic or hypnopompic hallucinations, and disturbed nocturnal sleep. Narcolepsy is strongly associated with the HLA DQB1*0602 allele, and its symptoms stem from destruction of hypocretin-secreting neurons in the hypothalamus. Recently identified autoantibodies to Tribbles homologue 2 in some patients, as well as cases associated with H1N1 vaccination, support an autoimmune mechanism. There are many challenges in diagnosing and treating pediatric narcolepsy. Caution must also be used in interpreting polysomnography and multiple sleep latency test results in children. HLA testing is nonspecific, and no commercial test exists to measure cerebrospinal fluid hypocretin levels. Neuroimaging has not yet proven useful in primary narcolepsy. Treatment of sleepiness and cataplexy in children requires extrapolating from adult studies. Hopefully, further insights into the pathophysiology of narcolepsy will allow for new therapeutics to manage the symptoms and modify the course of the disease.

Recent advances in the treatment and management of excessive daytime sleepiness.

Excessive daytime sleepiness (EDS) is a prevalent complaint among patients in psychiatric care. Patients with conditions of EDS have often been misdiagnosed with depression due to their complaints of lack of energy, poor concentration, memory disturbance, and a reduced interest in life. Impaired alertness associated with EDS can be detrimental to a person's quality of life by causing decreased work performance, self-consciousness, low self esteem, and social isolation. Excessive sleepiness is also associated with various health problems, comorbid medical and psychiatric conditions, and fatal accidents occurring after the driver has fallen asleep at the wheel. Contributing factors leading to EDS range from insufficient sleep hours to central nervous system-mediated debilitating hypersomnolence. Circadian rhythm disorders, sleep disorders such as obstructive sleep apnea and narcolepsy, and medications that cause sleepiness may also contribute to symptoms of EDS. Recognition of the symptoms of sleep deprivation is essential, as many such patients do not have a clear awareness of their own sleepiness. Treatment options, depending upon the condition, include light therapy or appropriate airway management techniques such as nasal continuous positive airway pressure (CPAP). Occasionally, wakefulness-promoting medications are necessary, particularly in patients with narcolepsy. In this expert roundtable supplement, Stephen P. Duntley, MD, reviews the definition and prevalence of EDS and discusses the contributing factors and consequences of daytime sleepiness. Next, Richard K. Bogan, MD, FCCP, gives an overview of the differential diagnosis of EDS and the assessment tools available for identifying sleepiness in symptomatic patients. Finally, Mary B. O'Malley, MD, PhD, reviews treatment of EDS, including counseling on sleep hygiene and duration of sleep, mechanical treatments, bright-light therapy, and wake-promoting medications.