Review ArticleDelayed diagnosis of narcolepsy: characterization and impact
Introduction
Narcolepsy is a chronic neurologic condition resulting from dysregulation of the sleep–wake cycle [1]. Evidence indicates an autoimmune component linked to specific genotypes including human leukocyte antigen (HLA DQB1∗06:02) and T-cell receptor alpha variants associated with loss of orexin (hypocretin)-producing neurons [2], [3], [4]. However, not all cases are associated with loss of hypocretin neurons. Narcolepsy can also be precipitated by seasonal Streptococcus infections, H1N1 influenza, and H1N1 vaccination in genetically predisposed individuals [5].
The estimated prevalence of narcolepsy is 0.05% in the United States [6] and 0.02–0.067% worldwide [7], and it is associated with a substantial socioeconomic burden. This burden results from increased health care resource utilization; reductions in patient function, quality of life, and productivity; and an adverse impact on the patient’s partner and family [8], [9], [10], [11], [12], [13]. Reduced employment and income can be present before diagnosis [11], and an early diagnosis leading to appropriate treatment may lessen the burden.
Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic or hypnopompic hallucinations, and sleep paralysis, although not all symptoms are present in all patients. Recognition of disturbed nocturnal sleep (DNS) as a patient-reported symptom and as a polysomnography (PSG)-characterized feature suggests that DNS can be added to the other symptoms to form a symptom pentad [14].
While narcolepsy onset can occur in children <10 years of age [15], [16], [17], symptom onset typically peaks during the second decade of life [15], with a main peak at approximately 15 years of age and possibly a lesser secondary peak at approximately 35 years [18]. However, evidence suggests that few patients are diagnosed within the first 10 years as indicated by the disproportionate number of patients who report onset prior to 20 years of age relative to those who have been diagnosed (Fig. 1) [19].
Numerous publications have reported the discordance between narcolepsy onset and its diagnosis. Because such a diagnostic gap results in delay of treatment and increases the disease burden, it is important to characterize this gap and identify factors that may potentially reduce it. Therefore, the purpose of this article is to provide an overview of the diagnostic delay between symptom onset and diagnosis, including discussion of the potential reasons and implications of this delay.
Section snippets
Methods
Articles reporting on the diagnostic delay were identified from several sources. Although the primary source was the authors’ knowledge of the narcolepsy literature, searches were also performed in PubMed. The PubMed searches, with no publication date limits and for English language articles, used the search term “narcolepsy” in combination with “delayed diagnosis,” “diagnostic delay,” and “diagnosis delay.” The PubMed searches returned 39 unique citations, of which 10 were relevant for
Delay duration
A delay between symptom onset and diagnosis was mentioned in the narcolepsy literature as early as 1976, with 5 years reported as the average time between symptom onset and a correct diagnosis [20]. Consistent with this duration, a 1995 study anecdotally reported survey results that stratified the delay between symptom onset and narcolepsy diagnosis at a single sleep disorders clinic in the UK by years of delay duration in 132 patients [21]. While the majority of patients (66%) were diagnosed
Conclusions
The long duration between symptom onset and diagnosis indicates that many narcolepsy patients remain undiagnosed or misdiagnosed, resulting in an increased burden of narcolepsy and a barrier to patient management.
Although the lack of an easy, accurate diagnostic test for narcolepsy may in part contribute to the diagnostic delay, this delay more likely results from the lack of diagnostic consideration, since these symptoms may be suggestive of other conditions for which there is greater
Conflict of interest
Dr. Thorpy is a consultant and on the speakers bureau for Jazz Pharmaceuticals, Inc., and Teva Pharmaceuticals. Dr. Krieger has nothing to disclose.
The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2014.01.015.
Acknowledgment
E. Jay Bienen, PhD, of The Curry Rockefeller Group, LLC (CRG), provided editorial assistance in developing this manuscript, which was funded by Jazz Pharmaceuticals, Inc.
References (59)
Clinical and neurobiological aspects of narcolepsy
Sleep Med
(2007)- et al.
Genetic association, seasonal infections and autoimmune basis of narcolepsy
J Autoimmun
(2013) - et al.
Therapeutics of narcolepsy
Sleep Med Clin
(2010) - et al.
Health-related quality of life in patients with narcolepsy
Sleep Med
(2007) - et al.
Health, social, and economic consequences of narcolepsy: a controlled national study evaluating the societal effect on patients and their partners
Sleep Med
(2012) - et al.
The burden of narcolepsy with cataplexy: how disease history and clinical features influence socio-economic outcomes
Sleep Med
(2012) - et al.
How age influences the expression of narcolepsy
J Psychosom Res
(2005) - et al.
Factors associated with a delay in the diagnosis of narcolepsy
Sleep Med
(2004) - et al.
A randomized trial of the long-term, continued efficacy and safety of modafinil in narcolepsy
Sleep Med
(2000) - et al.
Increased body-mass index in patients with narcolepsy
Lancet
(2000)
Cases of pediatric narcolepsy after misdiagnoses
Pediatr Neurol
Obstructive sleep apnea in narcolepsy
Sleep Med
Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population
Sleep Med
Narcolepsy is strongly associated with the T-cell receptor alpha locus
Nat Genet
Immunochip study implicates antigen presentation to T cells in narcolepsy
PLoS Genet
Low cerebrospinal fluid hypocretin (Orexin) and altered energy homeostasis in human narcolepsy
Ann Neurol
Epidemiology of narcolepsy
Health-related quality of life in narcolepsy
J Sleep Res
The socioeconomic impact of narcolepsy
Sleep
The economic consequences of narcolepsy
J Clin Sleep Med
Disrupted nighttime sleep in narcolepsy
J Clin Sleep Med
Clinical aspects of narcolepsy–cataplexy across ethnic groups
Sleep
Age at onset of narcolepsy in two large populations of patients in France and Quebec
Neurology
Age of onset and time to diagnosis of narcolepsy [abstract S20.002]
Neurology
The narcoleptic syndrome
J Neurol Neurosurg Psychiatry
Presentation of narcolepsy after 40
Neurology
Life effects of narcolepsy: measures of negative impact, social support and psychological well-being
Loss Grief Care
Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study
J Sleep Res
Cited by (183)
Clinical Evaluation and Management of Narcolepsy in Children and Adolescents
2023, Seminars in Pediatric NeurologyNarcolepsies, update in 2023
2023, Revue Neurologique