Prevalence, incidence, and health care utilization of patients with narcolepsy: a population-representative study

Ulf Kallweit; Georg Nilius; Daniel Trümper; Tobias Vogelmann; Tino Schubert

doi:10.5664/jcsm.9910

. 2022 Jun 1;18(6):1531–1537. doi: 10.5664/jcsm.9910

Prevalence, incidence, and health care utilization of patients with narcolepsy: a population-representative study

Ulf Kallweit ^1,^*,^✉, Georg Nilius ^1,^2,^*, Daniel Trümper ³, Tobias Vogelmann ⁴, Tino Schubert ⁴

PMCID: PMC9163623 PMID: 35088707

Abstract

Study Objectives:

Previous estimated prevalence of narcolepsy in Europe was 47 patients per 100,000 persons, with a yearly incidence of 0.64–1.37 per 100,000. However, analyses of representative datasets from large cohorts are limited. This study aimed to estimate the population-based diagnostic prevalence and incidence of narcolepsy in Germany and to describe these patients and their health care resource utilization.

Methods:

This study used the InGef research database, an anonymized representative dataset of 4 million persons covered by statutory health insurance in Germany. Patients with confirmed narcolepsy diagnoses in 2018 were included. Mid-p-exact tests were used to calculate 95% confidence intervals. Patients with narcolepsy diagnoses and narcolepsy-targeting therapy in 2014–2018 were included to describe health care resource utilization in the year prior to diagnosis.

Results:

In 2018, diagnostic prevalence was estimated as 17.88 (95% confidence interval 16.45–19.40) and 12-month incidence as 0.79 (0.52–1.15) per 100,000 persons. Forty-six percent of patients were in psycho-behavioral therapeutic treatment and 61% of employees had sick leave days. One in three patients was hospitalized for any cause; 28% received antibiotics.

Conclusions:

Diagnostic prevalence was lower, but incidence was consistent with previous reports, although previous estimates may diverge in terms of age/sex distributions. Patients showed a substantial utilization of health care resources, including sick leave and hospitalization. Almost half the patients underwent psycho-behavioral treatment in the year prior to diagnosis, which might indicate a high burden of psychiatric symptoms. The increased use of antibiotics could indicate more frequent infections than in the general population.

Citation:

Kallweit U, Nilius G, Trümper D, Vogelmann T, Schubert T. Prevalence, incidence, and health care utilization of patients with narcolepsy: a population-representative study. J Clin Sleep Med. 2022;18(6):1531–1537.

Keywords: narcolepsy, excessive daytime sleepiness, prevalence, incidence, claims data, Germany

BRIEF SUMMARY

Current Knowledge/Study Rationale: Limited data exist regarding population-representative estimates of current diagnostic prevalence of narcolepsy. This study aimed to address this unmet need by estimating the current prevalence and incidence of narcolepsy in Germany, covering all age groups and narcolepsy types and their resource used.

Study Impact: We provide an up-to-date prevalence and incidence estimate for narcolepsy and describe the characteristics of these patients with narcolepsy. This will help in clinical practice through a better understanding of narcolepsy symptoms and patient characteristics to delineate the symptom of excessive daytime sleepiness from depression and to overcome diagnostic barriers, enabling early therapy initiation.

INTRODUCTION

Narcolepsy is a chronic, immune-mediated brain disorder, characterized by excessive daytime sleepiness (EDS; a cardinal symptom),¹^–³ cataplexy, sleep-related hallucinations, sleep paralysis, and disturbed nocturnal sleep, often with concentration difficulties and depressed mood.⁴ In most of the cases EDS is the first symptom appearing in patients with narcolepsy⁵ and the main symptom of patients seeking medical consultation.⁶ EDS is associated with a poorer self-reported general health status,⁷ higher risk of work⁸ and traffic accidents,⁹ and difficulties in gaining and maintaining a job.¹⁰ Patients report reduced quality of life¹¹^,¹² and being stigmatized, which can be associated with, or result in, a depressed mood.¹¹

In addition to restrictions in private and professional life, patients experience a long diagnostic process. Several reports outlined a delay of 2–9 years between symptom onset and narcolepsy diagnosis and individual cases of even several decades.¹³ The absence of diagnostic standards for narcolepsy, controversies about the clinical spectrum,¹⁴ and a lack of awareness among nonspecialists¹⁵^,¹⁶ likely contribute to these delays and prior misdiagnoses, especially depression.¹⁷

Treatment strategies are dependent on the type of narcolepsy. The third edition of the International Classification of Sleep Disorders distinguishes narcolepsy in 2 types. Type 1 is, in contrast to type 2, marked by the presence of cataplexy.² Different wake-promoting agents, such as modafinil, pitolisant, or solriamfetol are effective to treat EDS symptoms in narcolepsy. Tricyclic antidepressants, selective serotonin reuptake inhibitors, and pitolisant may be an effective strategy to treat cataplexy, and sodium-oxybate is effective for EDS and cataplexy and disturbed nocturnal sleep.¹^,¹⁸

The frequently cited prevalence estimate for narcolepsy with cataplexy is 25–50 per 100,000 persons.¹⁹ Generally, existing data are representative to specific age groups or regions only, partly based on nonclinical evaluations and variable survey methods, or were collected several years ago. Incidence rates per year range from 0.64 to 1.37 per 100,000 person¹^,²⁰^–²² and also is based on more recent analyses compared to prevalence data. Currently, up-to-date representative analyses from large patient cohorts to assess narcolepsy incidence and prevalence on a population level are missing. Also, the specific health care resource use of patients with narcolepsy is poorly understood.

First, this study aimed to estimate the current diagnostic prevalence and incidence of narcolepsy, representative to the whole population in Germany, covering all age groups and narcolepsy types. Second, epidemiological patient characteristics, including health care utilization, should be described.

METHODS

Study design and data source

This retrospective observational study was based on the InGef research database, which consisted of an anonymized 5% sample of the German population covered by statutory health insurances. The dataset covered more than 4 million insured persons from 69 health insurance providers, allowing analysis of rare conditions. Data were age-adjusted and sex-adjusted to the German population and also is considered representative to the German population in terms of morbidity, mortality, and drug use.²³ The dataset was previously used to assess a large sample of the German statutory health insurances for representative prevalence estimates.²⁴ In accordance with the recommendations of the German society for epidemiology, a detailed predefined analysis protocol was created²⁵ and results were reported oriented on German Reporting Standard for Secondary Data Analyses.²⁶

Epidemiological estimates and resource utilization can be assessed due to the nature of German claims data, because they comprise a comprehensive picture of all reimbursed health-related services at the patient level.²⁷ With approximately 90% of the German population enrolled in the statutory health insurance system and no opt-out possibility for this anonymized analysis, Germany offers a near-ideal setting to analyze population-based epidemiological estimates.

Cohort definition

This study comprised 2 study cohorts to address different research questions. The objective of the first cohort was to estimate the 12-month prevalence and incidence of narcolepsy. The second cohort investigates patient characteristics and health care utilization. Cohorts differed by inclusion criteria and observational period (see Table 1). In both cohorts, patients with at least 2 claims in the database that included diagnoses of narcolepsy in 2 different quarters were included. Two claims were required to exclude misdiagnosis by primary care physicians and nonspecialists. For incidence estimates in the first cohort and for the second cohort, inclusion further required at least 1 prescription of pharmaceutical drugs to treat EDS. This narrower inclusion criterion was applied to enable statements about patients with narcolepsy in need of EDS treatment and to enhance diagnostic security.

Table 1.

Overview of prevalence/incidence and pharmacological treated cohort.

	Cohort 1	Cohort 2
Research question	Prevalence and incidence in 2018	Patient characteristics and health care utilization
Observational period	2017–2018; 2017 was considered as the pre-index period to identify incident patients without narcolepsy diagnosis the year before 2018.	2014–2018
Inclusion criteria	Prevalence: At least 2 claims of narcolepsy diagnoses, operationalized by ICD-10-GM Code G47.4. Incidence: At least 2 diagnoses of narcolepsy, operationalized by ICD-10-GM Code G47.4. AND At least 1 prescription of indication-specific drugs* prescribed in the same quarter as narcolepsy diagnosis.	At least 2 claims of narcolepsy diagnoses, operationalized by ICD-10-GM Code G47.4. AND At least 1 prescription of indication specific drugs* prescribed in the same quarter as narcolepsy diagnosis.
Exclusion criteria	Patients < 18 years with ADHD (ICD-10-GM Codes F90x, F98.80)	Patients < 18 years with ADHD (ICD-10-GM Codes F90x, F98.80)

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*Modafinil, pitolisant, methylphenidate, ephedrine, amphetamine, selegiline, sodium-oxybate activating antidepressants, operationalized by Anatomical Therapeutic Chemical (ATC) code (see Table S1^{(21.5KB, pdf)} in the supplemental material). % comprises all subcategories under the mentioned ATC-Code. Cohort 1 was used to estimate incidence and prevalence of narcolepsy in Germany in 2018. Cohort 2 was used to describe the epidemiological characteristics and health care utilization of patients with narcolepsy. ADHD = attention-deficit/hyperactivity disorder, ICD-10-GM = German modification of the International Classification of Diseases, 10th Revision.

The observational period for the first cohort (prevalence/incidence) comprised 2018 to estimate the 12-month prevalence and incidence. The second cohort was composed by pooling the years 2014–2018 to enlarge the cohort to cover a broader spectrum of patients and so allow more sensitivity in identifying patient characteristics, for example, rarely prescribed pharmaceutical drugs.

Outcome variables

Cohort 1 was used to estimate yearly prevalence and incidence in 2018. Patients fulfilling the inclusion criteria in 2018 were designated as prevalent. Patients fulfilling inclusion criteria in 2018 and had no narcolepsy diagnosis in 2017 were considered as incident. Prevalent and incident patients, identified in the dataset, were counted and further extrapolated to the German population by the following calculation method, using the example of incidence: We divided the number of incident patients in the dataset by the total number of participants in the dataset and multiplied them by the number of the German population in 2018 following the official census data.

Outcomes of the cohort 2 were patient characteristics at baseline: age, comorbidities (see Table S2 for defined comorbidites), working status, and comedication, stratified by sex and in total. Health care utilization (in the broadest sense), such as therapeutic measures, specialist consultations, hospitalizations, and sick leave days, were analyzed 1 year before narcolepsy was diagnosed and pharmaceutical drug therapy was initiated to get insights into the diagnostic process.

Statistical analysis

Categorical outcome variables were analyzed descriptively using frequencies and percentages. Continuous variables were described with means and standard deviations. The software packages MS Excel 2016 (Microsoft Corporation, Redmond, WA) and SAS 9.4 (SAS Institute, Cary, NC) were used for statistical analyses. We used Mid-P exact test of OpenEpi version 3 (Andrew G. Dean and Kevin M. Sullivan, Atlanta, GA) to calculate 95% confidence intervals (CIs) of prevalence and incidence.²⁸

RESULTS

Prevalence and incidence

In 2018, 565 patients with narcolepsy claims were identified, leading to 17.88 (95% CI 16.45–19.40) patients with narcolepsy per 100,000 persons. Extrapolated to the German population, this yielded in 14,846 (95% CI 13,657–16,106) prevalent patients with narcolepsy in Germany in 2018.

Incident (25) patients were identified in the dataset in 2018, leading to a yearly calculated incidence rate of 0.79 (95% CI 0.52–1.15) per 100,000 persons, which corresponds to 657 (95% CI 432–955) patients in the German population in 2018.

Patient characteristics

From 2014 to 2018, 824 patients with at least 1 narcolepsy claim were identified in the database, 413 patients (50.1%) had at least 2 claims with a narcolepsy diagnosis and prescriptions of pharmaceutical drugs to treat narcolepsy. More than half the patients (54.8%) were male. The mean age was 50 years (see Figure 1).

The most frequent comorbidities were depression (57%), back pain (47%), hypertension (41%), and obstructive sleep apnea (OSA) (41%) (see Figure 2).

*Multiple diagnoses and treatments were possible. Since prescriptions were not linked to diagnoses, prescriptions might be for conditions other than narcolepsy. **No patient received a prescription of ephedrine, amphetamine, selegiline, sodium-oxybate, and selective monoaminoxidase inhibitors.

Due to the inclusion criteria, every included patient received at least 1 pharmaceutical treatment for EDS. The most frequently prescribed compound was modafinil (43%). Roughly every fourth patient was prescribed more than 1 pharmaceutical treatment; 28% of patients received antibiotics.

Health care resource usage

One year before narcolepsy was diagnosed for the first time and pharmaceutical therapy was initiated, patients utilized, among other health care resources, the following: 43% received antidepressants and 46% were in psycho-/behavioral therapy. Eight specialists’ visits (65% visited neurologists, 38% radiologists, 28% ear, nose and throat specialist, 22% psychiatrists or psychotherapists, and 18% pneumologists) per year were observed, 31% were hospitalized for any cause with an average length of stay of 14 days. Most common hospitalization reasons were polysomnography/cardiorespiratory polygraphy, invasive cardiology diagnostics, and diseases of the nervous system without complex diagnosis. Sixty-one percent of employees were unable to work with an average of 51 sick leave days (see Figure 3).

Sick leave days are related to employees in the sense of social security (n = 229). Number of specialist consultations is related to all patients and patients treated as non-inpatients. SD = standard deviation.

DISCUSSION

The present study was the first population-representative study estimating prevalence and incidence as well as associated health care usage of narcolepsy in Germany. Prevalence of narcolepsy was estimated to be 17.88 (95% CI 16.45–19.40) per 100,000 persons, which corresponds to 14,846 (95% CI 13,657–16,106) patients when extrapolated to German population in 2018. The 12-month incidence rate of narcolepsy was 0.79 (95% CI 0.52–1.15) per 100,000 persons, which corresponds to 657 (95% CI 432–955) patients in the German population in 2018.

The commonly used and broadly accepted prevalence range of 25–50 patients with narcolepsy type 1 per 100,000 persons was based on a review, including studies from all over the world. Our findings were based on a conservative approach, because patients had to have at least 2 claims with narcolepsy diagnoses, guaranteeing a high-level diagnostic reliability. If we had included all patients with only 1 narcolepsy claim in 2018, the prevalence would have been 25 per 100,000 patients. Our conservative findings were slightly below the Norwegian estimates and the lower range of Longstreth et al. ¹⁹ Deviations to previous estimates, eg, by Ohayon et al²⁹ could occur due to different datasets and strictness of inclusion criteria. Ohayon et al used self-reported information. Inclusion criteria were broader and diagnostic tests were not necessary for inclusion, what could enhance the prevalence.³⁰ Deviations to Silber et al²² could occur due to the fact that data were from 1984 and potentially outdated. In the last 30 years, diagnostics and definitions have changed.

The 12-month incidence reported here was in line with other studies: Silber et al estimated an incidence rate of 1.37 per 100,000 person-years²²; Wijnans et al²⁰ a rate of 0.93, Partinen et al²¹ a rate of 0.79 per 100,000 in Norway, and Oberle et al⁴¹ a rate of 0.64 per 100,000 in Germany. Partinen et al and Oberle et al⁴¹ analyzed incidence rates post-H1N1 pandemic. The estimate of Oberle et al underlay the limitation of lacking completeness, as data of only 68% of sleep centers were used.

Before patients were treated or diagnosed at all, a huge diagnostic delay was determined in several studies: Available data from 738 patients revealed that the mean delay between the onset of the first clinical symptom (EDS or cataplexy) and diagnosis was 14.6 ± 14.3 years (median 10.5 years).¹³ A further diagnostic barrier was misdiagnosis, such as iron deficiency, burnout, psychosomatic disorders, insufficient sleep hygiene, sleep apnea, puberty related, and depression.⁶

To overcome the barriers of diagnostic delays, the Italian Association of Patients with Narcolepsy and Hypersomnia developed a list of red flags, which should support physicians to system recognition and further early referral of the patients. Red flags represent clinical characteristics of narcolepsy, separated for pediatric and adult patients.¹⁶ Such campaigns should be also discussed for other countries to enhance awareness, reduce diagnostic delays, and initiate therapy as early as possible. Since the present study focused on patients who were already diagnosed with narcolepsy, our approach does not cover patients who were not (yet) diagnosed with narcolepsy. Further research is needed to analyze the diagnostic barriers in Germany to develop strategies to accelerate this process.

One year before narcolepsy was diagnosed, health care utilization was increased compared to the general German population: 8 specialists were consulted (mean number of specialist consultations in Germany per year: 4³¹), 31% of patients were hospitalized (compared to 20% in the general population³¹; patients with other chronic conditions like diabetes type II: 30%, depression 29%, chronic obstructive pulmonary disease: 26%³²^,³³). Also, the average length of stay was 14 days and thus noticeably longer than the average length of stay of 7.2 days.

This could be a hint of uncoordinated utilization of health care services and indicate the complexity of the diagnostic process. Black et al³⁵ found significantly higher health care utilization and doubled costs in patients with narcolepsy compared to general population in the United States.

The connection between depression and narcolepsy has been widely discussed and can be found in our sample as well: 57% were diagnosed with depression, 46% were in psycho-/behavioral therapy. Psychotherapy and behavioral therapy are used and reimbursed in Germany exclusively for mental and behavioral disorders, so these data do most probably not include counseling for coping with narcolepsy. Forty-three percent of patients were on antidepressant therapy, although for some patients this may be used for treatment of cataplexy.¹⁸ Black et al³⁵ analyzed medical claims of more than 9,000 patients with narcolepsy in the United States and found mental illnesses in two-thirds of patients. The meta-analysis of Li et al³⁶ estimated a pooled prevalence of depression in narcolepsy of 32% and identified an increased risk of depression and depressive symptoms in patients with narcolepsy (odds ratio of 3.48 [95% CI 2.73–4.45]). Lopez et al³⁷ mentioned that depression in patients with central hypersomnia could be over diagnosed due to overlapping symptoms between sleep disorder and depression.

Besides depressive conditions, we found that patients also more often have other sleep-related diseases, such as OSA (41%); this confirmed results from other studies.³⁵^,³⁸ The fact that many patients with OSA also have EDS may have increased the number of narcolepsy diagnoses in patients with OSA in our sample. As there was no in-label pharmaceutical drug therapy available for EDS in patients with OSA at the time of analysis, prescribers could not risk an off-label use and problems with health insurance companies and diagnose patients with OSA with narcolepsy to guarantee in-label use of modafinil, for example. In interpreting the high number of patients with OSA, one should also keep in mind the high prevalence of sleep-disordered breathing in the general population: In a population-based sample in Switzerland, the prevalence of moderate-to-severe sleep-disordered breathing (≥ 15 events/h) was 23.4% in women and 49.7% in men.³⁹

Findings of this study also indicated an enhanced number of patients with acute infections, measured on the proportion of patients with antibiotic prescriptions in the sample (28%) compared to the general German population (15%),⁴⁰ which might indicate more frequent infections than in the general population.

Several limitations restricted the validity and significance of this study: First, the observational period did not reflect the entire diagnostic process. Second, uncertainty exists regarding patient adherence to the prescribed pharmaceutical therapies. Also, clinical parameters, for example, the results of Multiple Sleep Latency Test, polygraphy, or polysomnography were not obtainable in the present claims database. Third, inclusion criteria for estimating prevalence and incidence were conservative. To exclude misdiagnosis, we included patients with 2 narcolepsy diagnoses only, this allowed us to report epidemiological information of high diagnostic reliability, but may have missed some patients. Fourth, the dataset comprised statutory health insurance-insured persons only, which represent roughly 90% of the German population, the remaining 10% are privately insured and could systematically differ regarding socioeconomic variables. Fifth, we examine all patients with narcolepsy (type 1 and type 2), as, with International Statistical Classification of Diseases and Related Health Problems-10 codes, it is not possible to distinguish between the 2 types of narcolepsy.

CONCLUSIONS

Using a population-representative sample of a large cohort, we demonstrated that diagnostic prevalence of narcolepsy in Germany (17.88 per 100,000 persons) is lower than previously reported. Incidence was consistent with previous reports. Almost half of these patients were in psycho-/behavioral therapy, indicating a high psychological burden. The increased use of antibiotics could indicate more frequent infections than in the general population. In clinical practice, a better understanding of narcolepsy symptoms is required to delineate the symptom EDS from depression to overcome diagnostic barriers and enable early therapy initiation.

DISCLOSURE STATEMENT

All authors have seen and approved this manuscript. This study was funded by Jazz Pharmaceuticals. G. Nilius has received honoraria from Jazz. U. Kallweit has received honoraria from AOP Orphan Pharmaceuticals, Bioprojet, Harmony Biosciences, Jazz, Takeda, and UCB Pharma. D. Trümper is employed at Jazz. T. Vogelmann and T. Schubert are consultants to Jazz.

ABBREVIATIONS

CI: confidence interval
EDS: excessive daytime sleepiness
OSA: obstructive sleep apnea

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PERMALINK

Prevalence, incidence, and health care utilization of patients with narcolepsy: a population-representative study

Ulf Kallweit, MD

Georg Nilius, MD

Daniel Trümper, MS

Tobias Vogelmann, MS

Tino Schubert, PhD