Bibliometric and visual study of narcolepsy from 2000 to 2023

Abstract

BACKGROUND

More studies explored the prevalence, causes, associated conditions, and therapeutic strategies of narcolepsy. With an increasing focus on understanding narcolepsy’s prevalence, associated conditions, and therapeutic strategies, there’s a notable absence of bibliometric analyses summarizing trends in research and identifying emerging areas of focus within this field.

AIM

To conduct a bibliometric analysis to investigate the current status and frontiers of narcolepsy.

METHODS

The documents related to narcolepsy are obtained from the Web of Science Core Collection database (WoSCC) from January 1, 2000, to December 31, 2023, and VOS viewer 1.6.16, and the WoSCC’s literature analysis wire were used to conduct the bibliometric analysis.

RESULTS

A total of 4672 publications related to narcolepsy were included, and 16182 authors across 4397 institutions and 96 countries/regions contributed to these documents in 1131 different journals. The most productive author, institution, country and journal were Yves Dauvilliers, Stanford University, United States, and Sleep Medicine, respectively. The first high-cited document was published in Nature in 2005 by Saper et al, and this research underscores the role of certain neurons in ensuring the stability of sleep-wake transitions, offering insights into narcolepsy’s pathophysiology.

CONCLUSION

In conclusion, the main research hotspots and frontiers in the field of narcolepsy are the diagnosis of narcolepsy, pathological mechanism of narcolepsy and the treatment of narcolepsy. More studies are needed to explore effective strategies for the diagnosis and treatment of narcolepsy.

Key Words: Narcolepsy; Diagnosis; Mechanisms; Treatment; Bibliometric analysis

Core Tip: This is the first bibliometric study to both quantitatively and qualitatively analyze publications in the field of narcolepsy. The main research hotspots and frontiers in the field of narcolepsy are the diagnosis of narcolepsy, pathological mechanism of narcolepsy and the treatment of narcolepsy. More studies are needed to explore effective strategies for the diagnosis and treatment of narcolepsy.

INTRODUCTION

Narcolepsy is a long-term sleep disorder which is characterized by overwhelming daytime drowsiness, and this condition may be accompanied by cataplexy, vivid dreams or hallucinations upon falling asleep or waking, sleep paralysis, and disturbed sleep at night[1-5]. Narcolepsy is categorized into two primary forms: Narcolepsy type (NT) 1, marked by cataplexy and the depletion of orexin-producing neurons in the lateral hypothalamus, and NT2[1]. Diagnosis of narcolepsy is supported by reduced or absent levels of orexin in the cerebrospinal fluid. While some patients diagnosed with narcolepsy have shown a partial decrease in orexin neurons, orexin levels in the cerebrospinal fluid generally remain within the normal range for NT2, whose exact pathophysiological mechanisms are still under investigation[2,6-8]. Previous studies demonstrated that orexin receptor 1 and orexin receptor 2 (OX2R) are associated with narcolepsy[9-11]. These receptors participate in various physiological functions, such as sleep-wake regulation, maintaining energy balance, endocrine activities, and rewarding behaviors, with OX2R significantly involved in sustaining alertness and initiating rapid eye movement (REM) sleep. The consequences of narcolepsy are significant in both magnitude and severity, impacting nearly every aspect of a person’s life. Frequent episodes of excessive daytime sleepiness (EDS) can severely impair daily functioning, affecting work performance, school activities, and social interactions. This can lead to issues like difficulty concentrating, memory lapses, and a decreased ability to complete tasks efficiently. Cataplexy, which is caused by narcolepsy, is a sudden loss of muscle tone triggered by strong emotions, adds further severity, potentially causing injuries from falls and contributing to social stigma and embarrassment. Narcolepsy also heightens the risk of accidents, such as car crashes, due to sudden sleep episodes. The cumulative impact on mental health is substantial, often resulting in anxiety, depression, and a diminished quality of life. Without effective management, these consequences can profoundly disrupt personal independence and overall well-being. Treatment options for narcolepsy currently include stimulants like modafinil, armodafinil, solriamfetol, methylphenidate, and amphetamines, along with medications such as pitolisant and hydroxybutyric acid[12-15]. The incidence of narcolepsy in estimated to range between 200 and 500 cases per million people[2].

With an increasing focus on understanding narcolepsy’s prevalence, associated conditions, and therapeutic strategies, there’s a notable absence of bibliometric analyses summarizing trends in research and identifying emerging areas of focus within this field. Bibliometric studies offer an in-depth review by examining various factors like publications, authorship, citation counts, h-index, geographical distribution, affiliating institutions, and prevailing themes in a given area of study[16,17]. Therefore, this research aims to conduct a bibliometric analysis to pinpoint the leading edges and focal points in narcolepsy research.

MATERIALS AND METHODS

Search strategy

As the most reliable citation-based database commonly used for bibliometric analysis, Web of Science Core Collection (WoSCC) was utilized in our study to download literature, and the search term was TS = “narcolepsy”. The search was inclusive of all types of publications, imposing no restrictions on language, the documents published between January 1, 2000 and December 31, 2023 were included.

Data collection and bibliometric analysis

We downloaded the “Plain Text” versions of relevant records related to narcolepsy from WoSCC. For our analysis, we used the WoSCC literature analysis tool to identify the top 20 highly cited publications as well as the ten leading countries/regions, journals, authors, and institutions. Using VOS viewer, we created visual representations to illustrate the relationships among publications, including bibliometric networks of co-authorship for authors, institutions, countries, and journals, along with keyword co-occurrence.

RESULTS

Global publication trends

The bibliometric analysis revealed a total of 4672 publications related to “narcolepsy” after a thorough screening process, as illustrated in Figure 1. Among these, articles constituted the majority with 3766 entries (67.1%), followed by reviews numbering 906 (20%). In terms of subject categories, “Clinical Neurology” emerged as the predominant field with 1975 documents, making up 39.35% of the total, succeeded by “Neurosciences” with 1652 documents (17.42%), and “Pharmacology and Pharmacy” with 515 documents (16.67%). The temporal trend of publications from 2000 to 2023, as shown in Figure 2, indicates a steady growth in publication numbers, citations, and overall interest in narcolepsy research.

Figure 1  Flowchart of the inclusion and exclusion criteria.

Figure 2 The yearly quantity and literature type of publications on narcolepsy. A: Annual publications; B: Subject categories.

Global contributions to narcolepsy research

The narcolepsy research domain has seen contributions from 16182 authors across 4397 institutions and 96 countries/regions, publishing in 1131 different journals. The United States leads in terms of publications with 1836 papers, which have attracted a noteworthy 105886 citations and achieved an H-index of 151, showcasing the significant volume and impact of its research contributions. France and Japan also stand out with 506 and 83 publications, respectively. Stanford University is at the forefront among institutions with 415 publications, closely followed by the Institut National De La Santé Et with 325 publications, and the University of Bologna with 254 publications. In terms of individual contributors, Yves Dauvilliers leads with 223 publications and 4046 citations, with Giuseppe Plazzi and Emmanuel Mignot also being notable for their substantial contributions of 222 and 191 publications, respectively. The journals “Sleep Medicine”, “Sleep”, and “Journal of Clinical Sleep Medicine” are the most prolific in the field, with 323, 318, and 149 publications, respectively. This illustrates the significant focus narcolepsy research has received from top-tier journals, as well as the collaborative effort spanning across various countries and institutions. The key figures and entities in narcolepsy research are detailed in Table 1 and Table 2, while network visualization maps showcasing the citation relationships among countries/regions, institutions, authors and journals are presented in Figure 3A-D. This analysis highlights the global interest and collaborative nature of narcolepsy research, underscoring its importance and the contributions of leading researchers and institutions worldwide.

Figure 3 The visualization knowledge maps of co-authorship. A: Authors; B: Organizations; C: Countries; D: Journals; E: The citation relationships among publications in narcolepsy research; F: Keywords.

Table 1 The productive 10 authors, institutions and countries.

	Findings	Number	Ranking	Citation	H-index
Author	Carhart-Harris R	97	1	9188	45
	Griffiths RR	61	2	8713	39
	Roseman L	44	3	3289	26
	Nutt DJ	39	4	5257	26
	Ollenweider, FX	39	5	3925	29
	Erritzoe D	38	6	3920	20
	Liechti ME	32	7	1404	17
	Johnson M	31	8	6818	30
	Davis A	31	9	1831	20
	Hendricks PS	29	10	1067	13
Institution	Imperial College London	167	1	12490	59
	University of California System	155	2	5910	41
	Johns Hopkins University	145	3	11173	50
	University of London	95	4	5712	33
	Yale University	64	5	1721	22
	University of Zurich	63	6	3402	30
	University System of Ohio	63	7	1750	21
	Harvard University	56	8	2000	17
	King S College London	55	9	3774	23
	University of Toronto	53	10	1150	18
Country	United States	823	1	31979	86
	England	324	2	15473	64
	Canada	187	3	3392	32
	Germany	157	4	5873	43
	Switzerland	153	5	8685	54
	Australia	139	6	2861	29
	Netherlands	98	7	2555	28
	Brazil	83	8	3398	25
	Spain	79	9	3718	28
	Denmark	60	10	2273	23

Table 2 The productive 10 journals based on publications.

Journal	Number	Ranking	Citation	H-index
Sleep Medicine	323	1	9586	55
Sleep	318	2	16150	69
Journal of Clinical Sleep Medicine	149	3	3634	33
Journal of Sleep Research	126	4	4058	34
Journal of Neuroscience	80	5	10902	56
Sleep Medicine Reviews	71	6	5295	43
Plos One	69	7	2572	27
Neurology	61	8	4893	40
Neuroscience Letters	40	9	1329	22
Brain Research	38	10	1654	21

Visualization of citation networks and top-cited publications analysis

Figure 3E presents a network visualization map highlighting the citation relationships among publications in narcolepsy research. Table 3 summarizes the attributes of the top 20 most-cited publications, providing insights into pivotal findings in the field[18-37]. The foremost publication, appearing in Nature in 2005 by Saper et al[32], explores the intricate brain mechanisms governing sleep and wakefulness. The authors describe a network of cellular clusters activating the thalamus and cerebral cortex, vital for maintaining alertness, and a key hypothalamic mechanism that suppresses the arousal system during sleep. This research underscores the role of certain neurons in ensuring the stability of sleep-wake transitions, offering insights into narcolepsy’s pathophysiology, the effects of medications on sleep patterns, and the influence of environmental factors on the sleep-wake cycle. The second notable publication by Peyron et al[29], published in Nature Medicine in 2000, investigates the role of hypocretins in narcolepsy through histopathological examination of brains from affected individuals and genetic screening. The study reveals a common deficiency in the hypocretin system among narcolepsy patients, highlighted by a critical mutation affecting peptide trafficking in a case of early-onset narcolepsy, underscoring a universal hypocretin loss as a central aspect of the condition. The third highly-cited study, conducted by Thannickal et al[34] and published in Neuron in 2000, contrasts narcolepsy’s genetic background in humans with that in animal models. The authors report a significant reduction in hypocretin neuron numbers in humans with narcolepsy, pointing to a selective degeneration of these neurons, as evidenced by surrounding gliosis, which implicates a degenerative process in the pathology of narcolepsy. Nishino et al[27], in a publication featured in Lancet, provide evidence of absent hypocretin levels in a majority of examined narcolepsy cases, suggesting a crucial impairment in hypocretin signaling as a feature of the disorder. Lastly, a study by Marcus et al[25], also in Lancet, discusses the varied roles of orexin receptors in body regulation and hints at the specific function of the OX2R receptor in maintaining stable sleep states, highlighting orexin’s comprehensive role in sleep-wake regulation. These pivotal publications collectively enhance our understanding of narcolepsy, from its neurobiological underpinnings to genetic predispositions and pathophysiological mechanisms, illustrating the collaborative effort to unravel the complexities of this sleep disorder.

Table 3 The top 20 highest cited references.

Journal	Finding	Year	Ranking	Citation	Ref.
Nature	Hypothalamic regulation of sleep and circadian rhythms	2005	1	1752	Saper et al[32]
Nature Medicine	A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains	2000	2	1566	Peyron et al[29]
Neuron	Reduced number of hypocretin neurons in human narcolepsy	2000	3	1530	Thannickal et al[34]
Lancet	Hypocretin (orexin) deficiency in human narcolepsy	2000	4	1315	Nishino et al[27]
Journal of Comparative Neurology	Differential expression of orexin receptors 1 and 2 in the rat brain	2001	5	1246	Marcus et al[25]
Sleep	Practice parameters for the indications for polysomnography and related procedures: An update for 2005	2005	6	1118	Kushida et al[53]
Neuron	Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity	2001	7	1085	Hara et al[19]
Trends in Neurosciences	The sleep switch: Hypothalamic control of sleep and wakefulness	2001	8	1081	Saper et al[30]
Nature	Neural substrates of awakening probed with optogenetic control of hypocretin neurons	2007	9	913	Adamantidis et al[18]
Neuron	Sleep state switching	2010	10	851	Saper et al[31]
Nature	A putative flip-flop switch for control of REM sleep	2006	11	810	Lu et al[24]
Archives of Neurology	The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias	2002	12	784	Mignot et al[26]
Sleep	Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. An American academy of sleep medicine report standards of practice committee of the American academy of sleep medicine	2005	13	724	Littner et al[23]
Neuron	Hypothalamic orexin neurons regulate arousal according to energy balance in mice	2003	14	694	Yamanaka et al[37]
Journal of Neuroscience	Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle	2005	15	642	Lee et al[22]
Movement Disorders	The REM sleep behavior disorder screening questionnaire: A new diagnostic instrument	2007	16	634	Stiasny-Kolster et al[33]
Annual Review of Neuroscience	To eat or to sleep? Orexin in the regulation of feeding and wakefulness	2001	17	564	Willie et al[35]
Brain	Rapid eye movement sleep behaviour disorder: Demographic, clinical and laboratory findings in 93 cases	2000	18	558	Olson et al[28]
Journal of Sleep Research	Sensitivity and specificity of the MSLT, the maintenance of wakefulness test and the Epworth sleepiness scale: Failure of the MSLT as a gold standard	2000	19	556	Johns[20]
Journal of Neuroscience	Dopaminergic role in stimulant-induced wakefulness	2001	20	548	Wisor et al[36]

MSLT: Multiple sleep latency test; REM: Rapid eye movement.

Analysis of keywords

Figure 3F displayed the visualization maps of keyword analysis. There were four distinct color-coded clusters, which likely represent thematic groups of keywords within the field. The central node labeled “narcolepsy” suggests it’s the primary subject of the dataset from which this visualization is generated. It is closely associated with a cluster that likely represents the first thematic group, possibly focused on symptoms and related disorders, as suggested by terms such as “sleep”, “cataplexy”, and “excessive daytime sleepiness”. The connections between “narcolepsy” and “orexin” or “hypocretin” indicate a second cluster, which may explore the biochemical or neurological aspects of the disorder, including research on neurons, neurotransmitters, and brain structures involved in sleep-wake regulation. Another cluster, identifiable by its distinct color and the proximity of certain keywords, may examine diagnostic tools, treatment methods, and the impact of narcolepsy on quality of life. This is evident from terms like “sleep latency test”, “polysomnography”, and “Epworth sleepiness scale”, along with references to medications such as “modafinil” and “methylphenidate”. A fourth cluster might cover the broader impacts and associations of narcolepsy, potentially addressing comorbidities, genetic factors, and epidemiological studies, as suggested by terms like “population”, “genomics”, and “prevalence”.

DISCUSSION

General information

In general, 4672 publications related to “narcolepsy” were included. From 2000 to 2023, the number of publications increased steady, and this upward trajectory not only underscores the expanding research focus within the narcolepsy field but also mirrors the broader evolution of scientific inquiry. The most productive author, institution, country and journal were Dauvilliers Y, Stanford University, United States and Sleep Medicine, respectively. A landmark study by Saper et al[32], published in the Nature in 2005, stands out as a highly-cited publication, demonstrating the narcolepsy’s pathophysiology. The keyword analysis further enriches this bibliometric perspective, revealing interconnected clusters around multifaceted research domain, from clinical symptoms to genetic predispositions of narcolepsy. The keyword analysis offers a comprehensive overview of the interconnected research topics within narcolepsy, showcasing the diversity of research areas from clinical to molecular studies, and providing insights into the most studied concepts and potential gaps in the literature.

Hotspots and frontiers

Based on the publications of narcolepsy, highly-cited documents, and important keywords with high frequency related to narcolepsy, the research hotspots in the field of narcolepsy were summarized as follows: (1) The diagnosis of narcolepsy. Narcolepsy often goes unrecognized or is incorrectly identified, with a significant delay in diagnosis[1-3,38-40]. Research conducted in Europe indicates the average time from when symptoms first appear to when narcolepsy is diagnosed can be up to 14 years. According to the global sleep disorder classification, NT1 diagnosis is considered when there is EDS persisting for over three months, paired with either low cerebrospinal fluid (CSF) orexin levels (less than 110 pg/mL) or cataplexy, plus a mean sleep latency under 8 minutes on the multiple sleep latency test (MSLT)[1]. Additionally, the presence of at least two sleep-onset REM periods (SOREMPs) either in MSLT or overnight sleep study is required. EDS typically emerges first, but only cataplexy is uniquely indicative of narcolepsy, making its accurate detection essential[2]. Cataplexy is not often seen and must be identified based on the patient’s medical history, as there are no established diagnostic tools, though a standardized trigger test may be beneficial. There’s limited evidence to support the effectiveness of video and neurophysiological recording to confirm cataplexy. NT2 is characterized by EDS persisting for over three months without cataplexy, a mean sleep latency of less than 8 minutes on the MSLT, and two or fewer SOREMPs on the MSLT or nocturnal polysomnography, with CSF orexin levels above 110 pg/mL. Compared to NT1 patients, those with NT2 experience milder EDS and fewer REM sleep-related symptoms; (2) Pathological mechanisms of narcolepsy. Narcolepsy has been associated with the human leukocyte antigen (HLA) system, indicating a significant role of the immune system in the disease’s development[41-44]. The observation that patients with narcolepsy often have reduced levels of orexin A in their CSF suggests that the disorder may involve an immune-mediated attack on the cells responsible for producing this neuropeptide. Orexin A and B are peptides that activate neurons through types 1 and 2 orexin receptors. The loss of orexin-producing neurons impacts several brain networks, leading to the various symptoms seen in narcolepsy. Type 1 narcolepsy, recognized by cataplexy and a lack of the neurotransmitter hypocretin, is believed to result from an interaction of genetic factors, environmental triggers, and a predisposition to immune system dysfunction that destroys the cells that produce hypocretin in the hypothalamus. The link between certain HLA alleles, notably HLA-DQB106:02, and narcolepsy underscores the immune system’s involvement. Factors such as infections, vaccinations, and stress are thought to act as catalysts in those genetically at risk, triggering an autoimmune response that targets hypocretin neurons. This leads to the characteristic symptoms of narcolepsy. The progression of narcolepsy, therefore, stems from a complex interaction of genetic susceptibility and environmental influences, rather than a single causative agent; and (3) The treatment of narcolepsy. Management of narcolepsy utilizes a combination of lifestyle measures and medication to alleviate symptoms and enhance the well-being of individuals. Lifestyle modifications are essential for managing narcolepsy and include establishing a consistent sleep routine, practicing good sleep hygiene, incorporating brief, planned naps to combat daytime drowsiness, and adjusting daily habits to avoid triggering symptoms[45]. Psychological support and group therapy can be invaluable in addressing the social and mental challenges associated with narcolepsy[46]. Medically, wakefulness-promoting agents such as ritalin, modafinil and armodafinil are commonly prescribed[12,13,47-51], while sodium oxybate has been effective in reducing cataplexy episodes and improving sleep quality. Stimulants like methylphenidate and amphetamines are options for managing daytime sleepiness[15,52-54]. For symptoms like cataplexy, sleep paralysis, and hallucinations, selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors may be beneficial[55,56]. Personalizing treatment is crucial, as different approaches work for different individuals, requiring tailored adjustments and close supervision by healthcare professionals.

Strengths and limitations

This is the first bibliometric study to both quantitatively and qualitatively analyze publications in the field of narcolepsy. The findings from this analysis provide valuable insights into the evolving landscape of scientific research on this complex sleep disorder. By thoroughly examining scholarly publications, the study has highlighted key advancements, major research centers, and influential authors who have significantly contributed to the understanding and management of narcolepsy. The data reveal a multidisciplinary approach, with the fields of neurology, psychiatry, genetics, and pharmacology converging to address the various challenges posed by narcolepsy. Despite progress in understanding the pathophysiology and developing therapeutic interventions, the analysis also identifies research gaps, particularly in long-term patient outcomes and personalized medicine. The global distribution of research efforts underscores the growing recognition of narcolepsy’s impact on diverse populations, while also pointing to the need for increased international collaboration and resource allocation to improve the quality of life for those affected by the disorder. Further research is essential to better understand the clinical spectrum of narcolepsy, the precise mechanisms behind orexin neuronal loss, and the potential of emerging treatments, including orexin agonists and immunomodulation. However, several limitations should be noted. First, the publications analyzed were exclusively retrieved from the WoSCC database, which may limit the generalizability of the findings. Additionally, the study focused on literature related to narcolepsy published between 2000 and 2023, excluding earlier publications before 2000, in order to capture the latest research trends and developments in the field of narcolepsy.

CONCLUSION

In conclusion, the main research hotspots and frontiers in the field of narcolepsy are the diagnosis of narcolepsy, pathological mechanism of narcolepsy and the treatment of narcolepsy. More studies are needed to explore effective strategies for the diagnosis and treatment of narcolepsy.