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Narcolepsy in Slovakia – Epidemiology, clinical and polysomnographic features, comorbid diagnoses: a case-control study
Journal Pre-proof Narcolepsy in Slovakia – epidemiology, clinical and polysomnographic features, comorbid diagnoses: A case-control study Eva Feketeova, Maria Tormasiova, Katarina Klobučníková, Peter Durdik, Dominika Jarcuskova, Miroslav Benca, Marianna Vitkova PII:
S1389-9457(19)30361-2
DOI:
https://doi.org/10.1016/j.sleep.2019.10.012
Reference:
SLEEP 4214
To appear in:
Sleep Medicine
Received Date: 10 June 2019 Revised Date:
7 October 2019
Accepted Date: 25 October 2019
Please cite this article as: Feketeova E, Tormasiova M, Klobučníková K, Durdik P, Jarcuskova D, Benca M, Vitkova M, Narcolepsy in Slovakia – epidemiology, clinical and polysomnographic features, comorbid diagnoses: A case-control study, Sleep Medicine, https://doi.org/10.1016/j.sleep.2019.10.012. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
Narcolepsy in Slovakia – epidemiology, clinical and polysomnographic features, comorbid diagnoses: A case-control study. Eva Feketeova “Feketeová” 1, Maria Tormasiova “Tormašiová” 1 , Katarina “Klobučníková” 2
, Peter Durdik “Ďurdík” 3 , Dominika Jarcuskova “Jarčušková” 1, Miroslav Benca “Benča” 1,
Marianna Vitkova “Vítková” 1 1 Dept. of Neurology, Faculty of Medicine Pavol Jozef Safarik University and University Hospital of L. Pasteur, Tr. SNP 1, Kosice, Slovak Republic 2 1st Department of Neurology, Comenius University, Mickiewiczova 13, Bratislava, Slovak Republic 3 Pediatric Department, Comenius University in Bratislava, Jessenius Faculty of Medicine, Kollárova 2, Martin, Slovak Republic Marianna Vítková, corresponding author Dept. of Neurology, Faculty of Medicine Pavol Jozef Safarik University and University Hospital of L. Pasteur Tr. SNP 1, 04011 Kosice, Slovak Republic Email: [email protected] Tel.: +421 911 628 128
ABBREVIATIONS AHI- Apnoea-hypopnoea index CI- confidence interval ESS- Epworth Sleepiness Scale EDS- Excessive Daytime Sleepiness HLA- Human Leukocyte Antigen HCRT- hypocretin ICSD- International classification of sleep disorders NT1- narcolepsy type 1 NT2- narcolepsy type 2 OSA- Obstructive Sleep Apnoea PSG- Polysomnography SOREM- Sleep Onset REM
ABSTRACT
OBJECTIVE: An increase in the incidence of narcolepsy after the pandemic influenza with the H1N1 vaccination in 2009 resulted in an interest in narcolepsy epidemiology. The aim of the study was to examine the incidence and prevalence rates of narcolepsy and to describe the associated characteristics in Slovakia. METHODS: Epidemiology data were calculated for each year from 2000 to 2017 based on records found in specialized centres. Sixty-one narcoleptic patients were diagnosed, 51 (84%) with narcolepsy type 1 (NT1). Clinical data and results of polysomnography (PSG), Human Leukocyte Antigen (HLA)-typing, hypocretin (HCRT)-1 levels and body mass index (BMI) were summarised and evaluated for NT1 and narcolepsy type2 (NT2). Later, 244 sex and age matched controls were chosen to evaluate the comorbid diagnoses. RESULTS: The prevalence of narcolepsy in 2017 in Slovakia was 10.47 (CI 95% 8.26-14) cases/million inhabitants, and the mean incidence rate (2000-2017) was 0.57 (CI 95% 0.4- 0.74) cases/million inhabitants. Narcoleptic patients were comorbid with arterial hypertension (17%), ischemic heart disease (8%), dyslipidaemia (18%), diabetes mellitus type 2 (10%), cardiac arrhythmia/atrial fibrillation (5%), autoimmune disorders (20%), allergy (11%), malignancy (3%), headache (15%) and mental disorders (20%). Patients with narcolepsy showed double the excess prevalence in mental disorders (OR 2.15, p<0.05), and dyslipidaemia (OR 2.22, p<0.05). The presence of autoimmune disorders and allergy showed a mild increase in the narcolepsy group (OR 1.46, resp. 1.63). Hashimoto thyroiditis (HT) was the most frequent autoimmune disorder. CONCLUSIONS: Narcolepsy is a rare disorder in Slovakia. From the phenotype, genetic characteristics and comorbidities the disorder does not vary from other European countries.
KEY WORDS: Narcolepsy; incidence; prevalence; comorbidity; psychotic episode
1. INTRODUCTION Narcolepsy is a chronic neurological disease with hypersomnolence that belongs to the family of rare diseases. The estimated prevalence for narcolepsy ranges from 26 to 50/100,000 in Europe and North America [1]. Research on the epidemiology of narcolepsy prior to 2009 (pandemic influenza followed by vaccination) is very scarce, with the majority of prevalence estimates based on studies varying widely in methodology – questionnaire surveys and interviews. Scientific and clinical interest in the epidemiology of narcolepsy after vaccination has brought several studies with comparable case-defined methodologies. A retrospective study by the Vaccine Adverse Event Surveillance and
Communication group estimated the pool incidence rate between 2000-2010 in Denmark, Finland, Italy, Netherlands, Sweden and the United Kingdom to be 0.93/100,000 person-years (95% CI 0.90– 0.97) [2]. The overall incidence rate in Germany in the post-vaccination period was 0.64/100,000 person-years (95% CI 0.58–0.70) [3]. Both studies revealed the peak incidence in children and adolescents. The prevalence of narcolepsy in Catalunya (Spain) – a region with a very low level of H1N1 vaccination – was estimated to be 5.2 cases per 100,000 inhabitants [4]. Narcolepsy typically manifests with excessive daytime sleepiness (EDS) accompanied by hypnagogic/hypnopompic hallucinations, sleep paralysis and automatic behaviour, followed by cataplexy with latency. In recent years, the symptoms have been extended by fragmented sleep and weight gain [5]. Compared with the general population, narcoleptic patients are more likely to suffer from other sleep disorders, such as obstructive sleep apnoea (OSA), periodic limb movements [6], sleepwalking, or rapid eye movement (REM) sleep behaviour disorder [7]. Narcolepsy accompanied by the absence or a decreased level of hypocretin (HCRT)-1 with a typical phenotype constitutes a separate disease entity – narcolepsy type 1 (NT1). NT1 is caused by the extensive loss of hypothalamic HCRT-producing neurons. The strong association between NT1 and Human Leukocyte Antigen (HLA) Class II [8] and the overwhelming surveillance of the HLA Class I [9], immune-related polymorphisms (eg, variants in the T-cell receptor genes [TRA and TRB] and cathepsin H [10, 11]), suggests an autoimmune aetiology of NT1. While attempts to confirm the autoimmune responses demonstrated by the presence of specific autoantibodies and/or general inflammatory markers have been largely unsuccessful [12-14], some recent studies [15, 16] have proven the existence of autoreactive memory CD4+ and inconstant CD8+ T cells targeting selfantigens expressed by HCRT-producing neurons. This finding represents the missing connecting link for the autoimmune theory. Narcolepsy type 2 (NT2) includes most of the clinical and polysomnographic (PSG) symptoms of narcolepsy, but its cause seems to be heterogeneous, in general unknown, with some proportion of the patients progressing to full-blown NT1 with cataplexy and HCRT deficiency [17]. The onset of narcolepsy is usually in childhood or early adolescence. The mean diagnostic delay from the onset of symptoms is 15 years. This could be explained by unspecific initial spells, incomplete and atypical forms, which make diagnosis of narcolepsy particularly difficult at the onset [7]. Other biomarkers and PSG features are used to support the diagnosis, among these, HLA, HCRT-1 and Multiple Sleep Latency test (MSLT). A number of medical and psychiatric conditions have been consistently described in the narcolepsy cohort in excess (eg, mental illness, diseases of the digestive system, nervous system/sense organs,
endocrinopathies, and obesity) [18-20]. However, there are still conflicting findings on the comorbid immunopathological diseases associated with NT1 [21, 22]. The epidemiological situation and clinical and PSG data on narcolepsy have never been evaluated in Slovakia or any other Eastern European country. The aim of the study was to estimate the incidence and prevalence of the disorder and to describe clinical features and comorbidity.
2. SUBJECTS AND METHODS Narcolepsy can be diagnosed in three University hospitals in Slovakia: two sleep labs taking care of adult patients and one for children. All narcolepsy cases fulfilled International classification of sleep disorders (ICSD) 2 [23] or ICSD 3 [24] criteria. The diagnoses based on ICSD2 criteria were retrospectively re-evaluated by sleep specialists according to ICSD3 to confirm the accuracy of the diagnosis and categorization into type 1 and type 2. Patients with narcolepsy due to medical conditions were excluded. Cases diagnosed before 2000 in the Czech Republic, at the only sleep lab in the former Czechoslovakia, were also included in the analysis based on the aforementioned criteria. To be included in the incidence study, subjects had to reside within Slovakia at the time of narcolepsy onset. The clinical and PSG features of the disease were derived from the medical records, and if necessary (if the date of the last visit was longer than one year before), updated by telephone interview. The incidence rates for narcolepsy were calculated by dividing the number of annually diagnosed narcolepsy patients by the total number of inhabitants in Slovakia. The prevalence rates were calculated by dividing the number of already and newly diagnosed patients minus deceased cases by the total number of inhabitants in Slovakia in each year. The cases diagnosed before 2000 were not included in incident, just prevalence rates. The 95% confidence intervals (95% CI) are given for the mean incidence and prevalence rates for the years 2000–2017. Population data were obtained from the Statistical Office of the Slovak Republic (https://slovak.statistics.sk). All the statistics were compared each year to avoid the bias in the rates. The age at onset of EDS and/or cataplexy, Epworth Sleepiness Scale (ESS) score, presence of OSA, Restless Legs Syndrome (RLS), REM parasomnia, non-rapid eye movement (NREM) parasomnia, bruxism), results of night PSG studies, MSLT, HLA typing, HCRT-1 levels in cerebrospinal fluid (CSF) and body mass index (BMI) were summarised. Therapy data were collected for patients with NT1. For each narcolepsy case, four age- and sex-matched controls were identified from the hospital database. The controls were randomly chosen among the pool of unaffected residents. Comorbid diagnoses, obtained by medical records review or based on a telephone interview, were abstracted for all narcolepsy subjects at the medical visit in 2017 (or at the time of death).
The study was approved by the Ethics Committee, and all participants signed informed content. Demographic and clinical data were given in median, range (min-max), (for normally distributed samples mean, standard deviation), number and percentage. The mean incidence and prevalence rates of narcolepsy in Slovak population for years 2000-2017 were calculated using Student’s tdistribution. We used Exact Poisson test for calculating incidence and prevalence rate with 95% CI of narcolepsy in Slovak population for year 2017. Comparisons between groups were performed with Mann–Whitney U-tests. P-values < 0.05 were considered to be significant. Data were analysed using R language (version 3.6.1).
3. RESULTS Sixty-one narcolepsy patients diagnosed and/or treated in Slovakia were identified (Table 1). All the patients were Caucasians, although one female patient was a member of the Roma minority (2%). Two patients died within the observation period. There was a mild male dominance (57%) in the cohort. The mean narcolepsy prevalence in Slovakia (2000-2017) was 5.74/million inhabitants (95% CI 4.297.2), with an increasing trend over time, which reached its peak in 2017 with the rate of 10.84 cases/million inhabitants. The mean incidence rate (2000-2017) was 0.57 (95% CI 0.4- 0.74) cases/million inhabitants, with the maximum occurring during 2010-2011 (Fig. 1). However, the analysis of EDS onset in narcolepsy cases did not confirm such an increase (Fig. 2). Narcolepsy was manifested by EDS accompanied by cataplexy from disease onset in 51% of patients; cataplexy onset was slightly delayed. The age at the onset of narcolepsy indicated bimodal distribution, with the highest peak in the age range of 16-20 years, and the second one in the 36-40 years range (Fig. 3). The diagnostic delay was 6.5 (median) years in NT1 and 3 (median) years in NT2. Five (8%) were diagnosed with narcolepsy in puberty or adolescence; however no patients were diagnosed before the age of 11. The onset of EDS was dated to the childhood or adolescence in 21 (34%) patients. The only duplex family (mother and daughter) was identified in the NT1 group (4% of familial cases). The proportion of NT1 was 84% (n=51). NT1 and NT2 patients did not vary in age of onset of symptoms, and diagnostic delay (Table 1). Hypnagogic/hypnopompic hallucinations, sleep paralysis and fragmented night sleep were more frequent in NT1 patients, as were sleep comorbidities (parasomnias, RLS, bruxism), apart from OSA, which was more frequent in NT2 patients. Night PSG showed a sleep latency of 8 min or less in NT1, Sleep Onset REM (SOREM) in 44% NT1 and 29% in NT2, worse sleep efficiency, higher Periodic Leg Movements index in NT1, and higher Apnoeahypopnoea index (AHI) in NT2. Sleep latency in the MSLT was less than 5 min with more than two
SOREMs in night PSG and/or MSLT, fulfilling the PSG diagnostic criteria in all cases (according to ICSD3). In all 96% of NT1 patients were HLA-DQB1*0602 allele carriers in comparison with 50% of NT2 patients. HCRT-1 was examined in three NT1 patients, supporting the diagnosis in the uncertain/absent cataplexy presence. Narcoleptic patients were comorbid with arterial hypertension (16%), ischemic heart disease (8%), dyslipidaemia (18%), diabetes mellitus type 2 (10%), cardiac arrhythmia/atrial fibrillation (5%), autoimmune disorders (20%), allergy (11%), malignancy (3%), headache (15%) and mental disorders (20%). The presence of narcolepsy doubled the risk for mental disorders, and dyslipidaemia, which was of statistical significance (p<0.05) (Tab 2). The presence of autoimmune disorders and allergy showed a very mild increase in the narcolepsy group in comparison with the general population (OR 1.46, resp. 1.63). Hashimoto thyroiditis (HT) was the most frequent autoimmune disorder in both the patient and control groups (15%, 9%). Being a narcolepsy patient increases the chances for the presence of mental disorders (OR 2.15). Narcoleptic patients were diagnosed with neurotic, stress-related and somatoform disorders (29%), affective disorders (21%) and mental retardation (14%). Two patients (5%) suffered from mental and behavioural disorders due to psychoactive substance. In the first case, alcohol abuse was already present at the diagnosing of narcolepsy, manifested by status cataplecticus in the withdrawal period. The other case developed alcohol addiction and probably combined with gamma-hydroxybutyrate abuse in the course of narcolepsy. Two of three diagnosed adolescent patients developed psychotic episodes within couple of months after the onset of EDS and cataplexy. The first case was later diagnosed with schizophrenia comorbid with narcolepsy; the other had experienced a single psychotic episode at the onset of narcolepsy, afterwards she was successfully treated with psychostimulants. The frequencies of comorbid diagnoses were calculated separately for NT1 and NT2 subgroup (Tab. 2). Comparison between NT1 and NT2 was not of statistical significance.
4. DISCUSSION To our knowledge, this is the first epidemiological study on narcolepsy in an Eastern European country. We used narcolepsy-diagnosed cases according to ICSD 3 [24] to express the prevalence and incidence rates, clinical picture, PSG and other laboratory characteristics, as well as comorbidity.
4.1 Epidemiology
This study shows a narcolepsy prevalence in 2017 10.47 (CI 95% 8.26-14)/million inhabitants and an incidence rate of 0.57 (CI 95%: 0.4-0.74) cases/million inhabitants/year in Slovakia. Finland, the country of about similar number of inhabitants (5,523,231 in 2017), reported the prevalence of narcolepsy in 1994 to be 26/100 000 inhabitants (95% CI 0-60) [25]. Annual incidence (2002-2009) was 0.79 per 100 000 inhabitants (95% CI 0.62–0.96) [26]. Slovak prevalence rates were 45 times lower and the incidence rates 10 times lower. A recent study from Catalunya, Spain [4], found the prevalence of narcolepsy to be 5.2 cases/100,000 inhabitants, which is 10 times higher during 2000-2017 (5-times higher in 2017) compared to Slovakia, the incidence rates were not calculated in the Spanish sample. Israel had an estimated lower prevalence than Slovakia (2/ million inhabitants), however, the estimates were reported in 1987 [27]. The only epidemiological estimates of narcolepsy in the area of Slovakia came from Roth – 1957 [25], the only sleep laboratory in Czechoslovakia (Prague). The eventual split of the republic resulted in developing sleep medicine and the establishing of the first Slovakian sleep lab in 1994. Currently, there are three sleep labs with the capacity to diagnose narcolepsy (two adult, one paediatric), the largest one takes care for 85% of narcolepsy patients. As the treatment is centralized to the adult centers, all patients should be referred to the center to confirm a diagnosis as well as be treated. The diagnosing in the center provides the only legal possibility to apply for social advantages, which is another reason why all the patients with working or school performing disability are referred to specialized centers. In comparison with existing studies, both incidence and prevalence rates in Slovakia are low. However, the incidence rates are more comparable with literature reported data (eg, 10 times lower than in Finland [25]) than the prevalence rates, which have greater contrast (eg, 45 times lower than in Finland [25]). Such a disproportion may reflect that despite the increasing diagnosing of narcolepsy each year, there are still some undiagnosed patients. Otherwise, the prevalence rates in Slovakia should be higher. The other reasons for lower epidemiological rates in Slovakia could be the genetic factors as there is a lower frequency of HLA DQB1*O602 in Slovakia- 10% [29] versus 18.9 % in the UK, 4.1 in Italy, and 37.5 % in Finland [30]. The incidence trend (Fig 2) has shown the peak incidence rates in 2009-2010 in Slovakia, the years of pandemic influenza A. An increase in the incidence of narcolepsy especially in children and adolescents was reported in Finland, France, Ireland, the Netherlands, Norway, Sweden and the UK, the countries where Pandemrix vaccine was widely used in 2009–2010 [31]. Slovakia, is the country with fewer than 5% of inhabitants vaccinated (2009-2015), and no cases of narcolepsy related to the H1N1 vaccination were detected in our sample. Even more, detailed history data mining showed,
that EDS as an onset symptom (followed by cataplexy or being accompanied by cataplexy) does not have the same trend and cannot be hypothesized, that the seasonal upper airway infections in 20092010 would play a role in the narcolepsy incidence in Slovakia similar to China [32]. Currently, data about the epidemiology of NT2 are scarce. In Slovakia, the incidence per 1 million inhabitants/ year was estimated to be 0.49 (CI 95% 0.33-0.85) for NT1 and 0.1 (95%CI 0.05-0.15) for NT2. The prevalence of NT1 was 5.07 (CI 95% 3.77-6.37) and 0.48 (95% CI 0.2-0.76) /1 million inhabitants/ year for NT2. The study by Tió et al. [4], expressing the prevalence data separately for NT1 and NT2 in Spain, has shown 7 fold increased prevalence for NT1 and 15 fold increase for NT2 in comparison with our estimated rates. According to professional demographic estimates, roughly 430,000 Roma live in Slovakia, which represents about 8% of the total population of the country. From diagnosed narcolepsy cases, this would mean having five Roma patients in the sample. The only affected Roma in our sample, a woman, suggests an even higher number of undiagnosed cases in this minority group. Moreover, we may assume that there are still some cases with a milder form of the disease in the general population who have not been referred for consultation or who do not seek medical advice because of “simple sleepiness”. This point is even more pronounced in a minority with so many socioeconomic barriers. The cohort is not big enough to evaluate the potential presence of protective genetic factors in the Roma group.
4.2 Clinical features, polysomnography, HLA typing, hypocretin measurement Chronic EDS on an everyday basis is the key symptom of narcolepsy: no Slovakian cases with narcolepsy scoring normally in ESS were included in the database (even if it was not exclusion criteria), contrary to the European narcolepsy database [7], where 10% of narcoleptics scored 10 points or fewer on the ESS. The Slovakian sample registers clinically clear-cut definitive cases with a diagnosis of specific PSG findings (night SOREM in 44% of NT1 and 29% of NT2, overall mean sleep latency less than 5 min, MSLT: mean 3 SOREMs in NT1, 2 SOREMs in NT2 patients). The borderline cases are usually not diagnosed or are diagnosed later with narcolepsy, because patients with narcolepsy are not allowed to drive in Slovakia, even if being treated. The proportion of Slovakian NT1 and NT2 cases (84:16%) did not vary from the Spanish sample (85:15%) [4]. Patients with narcolepsy without cataplexy comprised 36% in the study by Silber et al., in 2002 [27], probably due to the different methodology used 15 years ago and discussed diagnostic issues nowadays. According to ICSD-3, NT1 is well-defined condition. NT2 is less well-defined disorder with variability in the EDS phenotype, and few reliable biomarkers. Furthermore, EDS must explain symptoms rather than another cause (eg, sleep deprivation, OSA, circadian rhythm disorders,
or the effect of a medication or substance abuse). Confirming the diagnosis of NT2 in the presence of
OSA is a challenge and could be the source of misdiagnosis [33]. High number of comorbid OSA in the both NT1 and NT2 groups compared with the studies by Frauscher et al. [34], (24%, AHI cut off 5/h) and Sansa et al. [35], (24.8%, AHI cut off 10/h), points at necessity to increase the usage of other biomarkers in diagnostic process, especially HCRT-1 examination in Slovakia. Increased number of comorbid OSA in the presented cohort could be connected with different cut off values for OSA across the studies. The other technical issue could be the date of PSG, it is usually not identified: if it was an entrance diagnostic PSG or retesting because of various clinical reasons. Retesting would turn after 15-20 years observation period many borderline cases to comorbid OSA, as it could be in Slovak sample. However, we believe that two level diagnostic process of NT2 comorbid with OSA (PSG retesting in the presence of persisted EDS while being successfully treated for OSA at least three months before retesting), guarantees the accuracy of NT2 diagnosis, as far as some of the cases would be reclassified to NT1 group if they would have been tested for HCRT-1 (none of NT2 patients was tested for HCRT-1). The sex ratio in the presented paper showed male predominance in accordance with the previous findings [4, 7, 36, 37]. The explanation for this gender effect is unknown. The suggested explanation that men seek more medical attention due to their alleged predominance at work cannot be accepted, as two-thirds of patients referred for daytime sleepiness to sleep specialists (after exclusion of moderate to severe OSA) are women. The mean age of onset with a bimodal peak and mean diagnostic delay in the presented cohort are within the range of the previous study by Luca et al., [7]. A clinical-based study of narcoleptics in Quebec and in France also suggested a bimodal pattern of age of onset, with a larger peak in the second decade and a smaller peak in the fourth decade, despite the different ethnic populations studied [38]. A total of 4% (two women) of familial cases were identified, similar to the reported proportion in the Czech Republic (2.28%, 1.20% if only clinically confirmed cases were counted) [39] and slightly higher than in Spain (1–3%) [4]. In the period 2000-2017 5 (8%) patients were diagnosed 18-year old or younger, none of them before 11 year of age, however the onset symptoms (EDS) was dated to the childhood or adolescence in 21 (34%) patients. Our results are in line with those reported in Finland, where narcolepsy was extremely rare in children aged less than 11 years (the only diagnosed nine-year-old child up to 2008) [26]. HLA typing is not routinely used at all Slovakian sleep labs; thus, the results of HLA typing are available in 50% of NT1 cases, and 97% of them were positive for the DQB1*0602 allele. High
proportion of positive NT1 cases for DQB1*0602 was in agreement with previous findings [4, 8], 100% positivity is typically shown in post-Pandemrix narcolepsy cases [40]. HCRT-1 measurement in cerebrospinal fluid was used in 3% of NT1 patients, to confirm the NT1 diagnosis.
4.3 Comorbidities Compared with controls, patients with narcolepsy showed double the excess prevalence in mental disorders, and dyslipidaemia. The increased frequency of metabolic and cardiovascular disorders in the study, we believe, is due to the excessive weight gain at the time of narcolepsy diagnosis and its persistence over time in the majority of patients [41], 72% of patients in our cohort were obese or overweight. This is due to several reasons: hypocretin deficiency, changed lifestyle due to sleepiness, frequent mood disorders and this could be fixed by adverse reactions to medication. Our findings are in an agreement with the results of previous epidemiological studies [18, 19]. In comparison with previous studies demonstrating equal frequency of comorbid autoimmune disorders in adult NT1 patients and controls [22] or the opposite reporting a higher frequency of immunopathological diseases and allergic comorbidities in NT1 patients [21], our results are in between, with a moderate, but nonsignificant increase in OR (1.6) for autoimmune and allergic diseases in the narcoleptic group. There was also no significant difference in the occurrence of autoimmune conditions between NT1 and NT2 cases. HT was the most frequent autoimmune disease in narcolepsy patients in our cohort (15%). The high frequency of HT also among the controls (9%), does not allow for the hypothesis of a connection between narcolepsy and HT. Headache was not more prevalent in patients with narcolepsy than in controls, which is in disagreement with the increased rate of migraine previously found in narcolepsy patients [19, 42, 43]. The excess prevalence in our narcolepsy cohort was seen for mental illness (OR 2.15). The high rate of a mental comorbidity, especially depression and anxiety, is a constant finding in narcolepsy [18, 19, 44]. There are several possible explanations for the high prevalence of psychiatric symptoms among patients with narcolepsy: symptoms of narcolepsy and those of mental disorders overlap; psychiatric symptoms may arise as a consequence of the disease burden of narcolepsy and its treatment; HCRT dysfunction plays a role in the pathogenesis of narcolepsy as well as mental disorders.
There is an increasing awareness of psychotic symptoms in narcolepsy, apart from hypnagogic/hypnopompic hallucinations as a core narcolepsy feature [45]. Two of the 61 narcolepsy patients (3%) in the presented cohort experienced their first ever psychotic episode in life along with narcolepsy onset/the onset of fully blown symptoms (before treatment initiation). While the first patient developed clinically expressed schizophrenia, the second one experienced symptoms for three months and then later started treatment with stimulants (without relapsed symptoms for more than a five-year observational period). Our experience points to two clinical possibilities: narcolepsy comorbid with schizophrenia and narcolepsy onset accompanied by psychotic episode due to neurotransmitter imbalance. Both conditions task further observations, especially due to their rarity.
4.4 Study strengths and limits Our study is unique in that it is the first ever multicentre case-based study of narcolepsy in Slovakia, an Eastern Europe country of more than five million inhabitants. This case-oriented study with manual review data and added information by interview represents the highest quality standard for epidemiological study, in our opinion (eg, mood disorder diagnosed in a mistake due to onset narcolepsy symptoms [46]) would not be counted. On the other hand, this approach could be limited by voluntarily reported diagnoses and attributable to health-seeking behaviour in chronically sick patients. Getting information from community-based health registries could be the source of discrepancies due to the split of clinical information and health system statistics: eg, to examine hypersomnolent patients for HLA typing or PSG, we would use the code G47.4, even if it were to be later not confirmed (in Slovakia). The limited number of patients did not allow the children and adult populations to be analysed separately. The results of comparison in NT1 and NT2 subgroups are influenced by the statistical error raising from small numbers. Our results cannot be fully generalized to the population level as our controls were from hospitals. However, we tried to minimize a potential bias by selecting the controls from neurological patients being referred for the treatment of acute pain syndrome (radiculopathy caused by spondylosis or intervertebral disc herniation), or facial nerve palsy, first ever in their lives. To avoid the influence of chronic disease consequences, we strictly insisted on first ever onset of pain syndrome, or cranial nerve palsy, which was not a case of comorbidity calculation.
5. Conclusion
The present study reveals a low incidence and prevalence of narcolepsy in Slovakia, an Eastern European country. In terms of phenotype, genetic characteristics and comorbidities, the disorder does not vary from other European countries. Further epidemiological studies should respond if its rarity in Slovakia is due to underdiagnosing of narcolepsy connected with low awareness of the disorder, especially in minority groups, an effort to avoid social disability in mild narcolepsy forms, environmental exposure, or a pattern of geographical variety similar to other autoimmune disorders (eg, multiple sclerosis).
REFERENCES [1]
Ohayon MM, Priest RG, Caulet M, Guilleminault C. Hypnagogic and hypnopompic hallucinations: pathological phenomena? Br J Psychiatry 1996;169:459–67.
[2]
Wijnans L, Lecomte C, de Vries C, Weibel D, Sammon C, Hviid A, et al. The incidence of narcolepsy in Europe: Before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns. Vaccine 2013;31:1246–54. doi:10.1016/J.VACCINE.2012.12.015.
[3]
Oberle D, Drechsel-Bäuerle U, Schmidtmann I, Mayer G, Keller-Stanislawski B. Incidence of Narcolepsy in Germany. Sleep 2015;38:1619–28. doi:10.5665/sleep.5060.
[4]
Tió E, Gaig C, Giner-Soriano M, Romero O, Jurado M-J, Sansa G, et al. The prevalence of narcolepsy in Catalunya (Spain). J Sleep Res 2018;27:e12640. doi:10.1111/jsr.12640.
[5]
Partinen M, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol 2014;13:600–13. doi:10.1016/S1474-4422(14)70075-4.
[6]
Pizza F, Tartarotti S, Poryazova R, Baumann CR, Bassetti CL. Sleep-disordered breathing and periodic limb movements in narcolepsy with cataplexy: a systematic analysis of 35 consecutive patients. Eur Neurol 2013;70:22–6. doi:10.1159/000348719.
[7]
Luca G, Haba-Rubio J, Dauvilliers Y, Lammers G-J, Overeem S, Donjacour CE, et al. Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. J Sleep Res 2013;22:482–95. doi:10.1111/jsr.12044.
[8]
Mignot E, Lin L, Rogers W, Honda Y, Qiu X, Lin X, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet 2001;68:686–99. doi:10.1086/318799.
[9]
Tafti M, Hor H, Dauvilliers Y, Lammers GJ, Overeem S, Mayer G, et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep 2014;37:19–25. doi:10.5665/sleep.3300.
[10]
Kornum BR, Kawashima M, Faraco J, Lin L, Rico TJ, Hesselson S, et al. Common variants in P2RY11 are associated with narcolepsy. Nat Genet 2011;43:66–71. doi:10.1038/ng.734.
[11]
Faraco J, Lin L, Kornum BR, Kenny EE, Trynka G, Einen M, et al. ImmunoChip study implicates antigen presentation to T cells in narcolepsy. PLoS Genet 2013;9:e1003270. doi:10.1371/journal.pgen.1003270.
[12]
Dauvilliers Y, Jaussent I, Lecendreux M, Scholz S, Bayard S, Cristol JP, et al. Cerebrospinal fluid and serum cytokine profiles in narcolepsy with cataplexy: A case-control study. Brain Behav Immun 2014;37:260–6. doi:10.1016/J.BBI.2013.12.019.
[13]
Kornum BR, Pizza F, Knudsen S, Plazzi G, Jennum P, Mignot E. Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset. Brain Behav Immun 2015;49:54–8. doi:10.1016/J.BBI.2015.03.004.
[14]
Kornum BR, Burgdorf KS, Holm A, Ullum H, Jennum P, Knudsen S. Absence of autoreactive CD4+ T-cells targeting HLA-DQA1*01:02/DQB1*06:02 restricted hypocretin/orexin epitopes in narcolepsy type 1 when detected by EliSpot. J Neuroimmunol 2017;309:7–11. doi:10.1016/j.jneuroim.2017.05.001.
[15]
Latorre D, Kallweit U, Armentani E, Foglierini M, Mele F, Cassotta A, et al. T cells in patients with narcolepsy target self-antigens of hypocretin neurons. Nature 2018;562:63–8. doi:10.1038/s41586-018-0540-1.
[16]
Pedersen NW, Holm A, Kristensen NP, Bjerregaard A-M, Bentzen AK, Marquard AM, et al. CD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuronspecific antigens. Nat Commun 2019;10:837. doi:10.1038/s41467-019-08774-1.
[17]
Baumann CR, Mignot E, Lammers GJ, Overeem S, Arnulf I, Rye D, et al. Challenges in diagnosing narcolepsy without cataplexy: a consensus statement. Sleep 2014;37:1035–42. doi:10.5665/sleep.3756.
[18]
Ohayon MM. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med 2013;14:488–92. doi:10.1016/j.sleep.2013.03.002.
[19]
Black J, Reaven NL, Funk SE, McGaughey K, Ohayon MM, Guilleminault C, et al. Medical comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study. Sleep Med 2017;33:13–8. doi:10.1016/J.SLEEP.2016.04.004.
[20]
Cohen A, Mandrekar J, St Louis EK, Silber MH, Kotagal S. Comorbidities in a community sample of narcolepsy. Sleep Med 2018;43:14–8. doi:10.1016/j.sleep.2017.11.1125.
[21]
Martinez-Orozco FJ, Vicario JL, De Andres C, Fernandez-Arquero M, Peraita-Adrados R. Comorbidity of Narcolepsy Type 1 With Autoimmune Diseases and Other Immunopathological Disorders: A Case-Control Study. J Clin Med Res 2016;8:495–505. doi:10.14740/jocmr2569w.
[22]
Barateau L, Lopez R, Arnulf I, Lecendreux M, Franco P, Drouot X, et al. Comorbidity between central disorders of hypersomnolence and immune-based disorders. Neurology 2017;88:93– 100. doi:10.1212/WNL.0000000000003432.
[23]
American Academy of Sleep Medicine. International classification of sleep disorders (2nd ed) Westchester, IL: American Academy of Sleep Medicine; 2005.
[24]
American Academy of Sleep Medicine. International classification of sleep disorders (3rd ed). Darien, IL: American Academy of Sleep Medicine; 2014.
[25]
Hublin C, Kaprio J, Partinen M, et al. The prevalence of narcolepsy: An epidemiological study of the Finnish Twin Cohort. Ann Neurol. 1994;35(6):709-716. doi:10.1002/ana.410350612
[26]
Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, et al. Increased Incidence and Clinical Picture of Childhood Narcolepsy following the 2009 H1N1 Pandemic Vaccination Campaign in Finland. Cowling BJ, ed. PLoS One. 2012;7(3):e33723. doi:10.1371/journal.pone.0033723
[27]
Lavie P, Peled R. Narcolepsy is a Rare Disease in Israel. Sleep. 1987;10(6):608-609.
[28]
Roth B. Narkolepsie a Hypersomnie z hlediska fyziologie spánku. [Narcolepsy and hypersomnia from the aspect of physiology of sleep]. Praha: Státni Zdravotnické Nakladatelství; 1957.
[29]
Cechová E, Fazekasová H, Ferencík S, Shawkatová I, Buc M. HLA-DRB1, -DQB1 and -DPB1 polymorphism in the Slovak population. Tissue Antigens. 1998;51(5):574-576. http://www.ncbi.nlm.nih.gov/pubmed/9672160. Accessed July 30, 2019.
[30]
Fennessy M, Hitman GA, Moore RH, et al. HLA-DQ Gene Polymorphism in Primary IgA Nephropathy in Three European Populations. Vol 49.; 1996. doi:10.1038/ki.1996.67 [31] Sarkanen TO, Alakuijala APE, Dauvilliers YA, Partinen MM. Incidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis. Sleep Med Rev 2018;38:177–86. doi:10.1016/J.SMRV.2017.06.006.
[32]
Han F, Lin L, Warby SC, et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol. 2011;70(3):410-417. doi:10.1002/ana.22587.
[33]
Rosenberg R, Hirshkowitz M, Rapoport DM, Kryger M. The role of home sleep testing for evaluation of patients with excessive daytime sleepiness: focus on obstructive sleep apnea and narcolepsy. Sleep Med. 2019;56:80-89. doi:10.1016/j.sleep.2019.01.014
[34]
Frauscher B, Ehrmann L, Mitterling T, et al. Delayed Diagnosis, Range of Severity, and Multiple Sleep Comorbidities: A Clinical and Polysomnographic Analysis of 100 Patients of the Innsbruck Narcolepsy Cohort. J Clin Sleep Med. 2013;9(8):805-812. doi:10.5664/jcsm.2926
[35]
Sansa G, Iranzo A, Santamaria J. Obstructive sleep apnea in narcolepsy. Sleep Med. 2010;11(1):93-95. doi:10.1016/j.sleep.2009.02.009
[36]
Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep 2002;25:197–202.
[37]
Alakuijala A, Sarkanen T, Partinen M. Polysomnographic and actigraphic characteristics of patients with H1N1-vaccine-related and sporadic narcolepsy. Sleep Med. 2015;16(1):39-44. doi:10.1016/j.sleep.2014.07.024
[38]
Dauvilliers Y, Montplaisir J, Molinari N, Carlander B, Ondze B, Besset A, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 2001;57:2029–33. doi:10.1212/wnl.57.11.2029.
[39]
Nevšímalová S, Mignot E, Šonka K, Arrigoni †J. L. Familial Aspects of Narcolepsy-Cataplexy in the Czech Republic. Sleep 1997;20:1021–6. doi:10.1093/sleep/20.11.1021.
[40]
Sarkanen T, Alakuijala A, Partinen M. Clinical course of H1N1-vaccine-related narcolepsy. Sleep Med. 2016;19:17-22. doi:10.1016/j.sleep.2015.11.005
[41]
Kovalská P, Kemlink D, Topinková E, Nevšímalová S, Maurovich Horvat E, Šonka K. Higher body mass index in narcolepsy with cataplexy: lifelong experience. Sleep Med 2017;32:277. doi:10.1016/j.sleep.2016.11.010.
[421] Dahmen N, Kasten M, Wieczorek S, Gencik M, Epplen J, Ullrich B. Increased Frequency of Migraine in Narcoleptic Patients: A Confirmatory Study. Cephalalgia 2003;23:14–9. doi:10.1046/j.1468-2982.2003.00343.x. [43]
Suzuki K, Miyamoto M, Miyamoto T, Inoue Y, Matsui K, Nishida S, et al. The Prevalence and Characteristics of Primary Headache and Dream-Enacting Behaviour in Japanese Patients with Narcolepsy or Idiopathic Hypersomnia: A Multi-Centre Cross-Sectional Study. PLoS One 2015;10:e0139229. doi:10.1371/journal.pone.0139229.
[44]
Fortuyn HAD, Lappenschaar MA, Furer JW, Hodiamont PP, Rijnders CAT, Renier WO, et al. Anxiety and mood disorders in narcolepsy: a case–control study. Gen Hosp Psychiatry 2010;32:49–56. doi:10.1016/J.GENHOSPPSYCH.2009.08.007.
[45]
Canellas F, Lin L, Julià MR, Clemente A, Vives-Bauza C, Ollila HM, et al. Dual cases of type 1 narcolepsy with schizophrenia and other psychotic disorders. J Clin Sleep Med 2014;10:1011– 8. doi:10.5664/jcsm.4040.
[46]
Kryger MH, Walid R, Manfreda J. Diagnoses received by narcolepsy patients in the year prior to diagnosis by a sleep specialist. Sleep. 2002;25(1):36-41. doi:10.1093/sleep/25.1.36
NARCOLEPSY Incidence 2000-2017/1 million inhabitants/ year
n=61 0.57 (CI 95% 0.4- 0.74)
Prevalence in 2017 /1 million inhabitants
10.47 (CI 95% 8.26-14)
Gender: Males (n, %)
35 (57%)
Narcolepsy type (n, %)
NT1 (51, 84%)
NT2 (10, 16%)
Incidence 2000- 2017 /1 million inhabitants/ year
0.49 (CI 95% 0.31-0.67) 9.01 (CI 95% 6.6211.51) 51 (28)
0.1 (CI 95% 0.05-0.16)
Prevalence in2017 /1 million inhabitants/ year N (Males)
1.84(CI 95% 0.9-2.32) 10 (7)
Age of EDS onset: median (IQR) yy
21.5 (19)
22 (13)
Age of cataplexy onset: median, range, yy
26.5 (23.25)
NA
Diagnostic delay: median, range, yy
6.5 (10.25) 1 affected family (2 females)
3 (11)
H/H hallucinations: n, %
26 (51%)
4 (37.5%)
Sleep paralysis: n, %
27 (53%)
19 (37.5%)
Fragmented night sleep: n, %
35 (69%)
6 (12.5%)
Familial form Clinical features, BMI, sleep comorbidities
BMI: median (IQR), kg.m
-2
27.1 (7)
30.2 (5.45)
REM parasomnia: n, %
19 (37%)
0 (0%)
NREM parasomnia: n, %
6 (13%)
0 (0%)
Restless Leg syndrome: n, %
6 (13%)
0 (0%)
Bruxism: n, %
1 (2%)
0 (0%)
OSA (AHI above 5/h of sleep): n, %
20 (40%)
5 (50%)
ESS: median (IQR)
17 (6)
17 (5.5) 525 (146.7)*
Polysomnography TST: median (IQR) min
438.5 (135)
Sleep latency: median (IQR) min
5.5 (8.63)
8 (8)
REM latency: median (IQR) min
8.5 (46.25)
53 (64.75)
SOREM in night sleep (n, %)
18 (44%)
2 (29%)
Sleep efficiency: median (IQR) %
84.24 (16.6)
87.3 (9.1)
N1: median (IQR) %
6.95 (12.25)
5.6 (8.75)
N2: median (IQR) %
48.75 (19)
48 (15.1)
N3: median (IQR) %
15.8 (13.85)
16 (7.05)
REM: median (IQR) %
22.95 (11.9)
26.9 (11.7)
AHI: median (IQR) /h
2.85 (9.83)
5 (17.83)
PLMS index: median (IQR) /h
5 (12.48)
5 (16.25)
Mean sleep latency in MSLT: median (IQR) min
2.55 (1.85)
5 (4.49)*
Number of SOREMS in MSLT: median (IQR)
3 (2)
2 (2)*
HLA typing (n)
21
4
presence of DQB1*06:02
20 (95%)
2 (50%)
Hcrt-1 in CSF (available samples, positive findings, %)
3, 3, 100%
0, 0, 0%
Table 1 Epidemiological, clinical, polysomnographic features, and comorbid diagnoses of Narcolepsy cases in Slovakia. NT1- Narcolepsy type 1, NT2- Narcolepsy type 2, BMI- Body Mass Index, H/H hallucinations- Hypnagogic/Hypnopompic hallucinations, OSA- Obstructive Sleep Apnea, AHI- Apnea-Hypopnea Index, ESS- Epworth Sleepiness Scale, PLMS- Periodic Leg movements, MSLT- Multiple Sleep Latency test, SOREM- Sleep Onset REM, HLA- Human Leukocyte Antigen Complex, Hcrt-1 Hypocretin-1 IQR- Inter Quartile Range, *Significant difference at level 0,05
NT1
Controls to NT1
NT2
Controls to NT2
N=51
N=204
N=10
N=40
Arterial hypertension
9, 19%
42, 20%
1, 10%
Ischemic heart disease
4, 8%
8, 4%
Dyslipidaemia
11, 23%
Diabetes mellitus type 2
Narcolepsy N=61
Controls N=244
OR (CI 95% Lower- Pearson ChiUpper) Square
5, 14%
10, 16%
47, 19%
0.95 (0.46-1.96)
0.883
1, 10%
2, 6%
5, 8%
10, 4%
2.09 (0.69-6.37)
0.186
19, 9%
0, 0%
3, 9%
11, 18%
23, 9%
2.22 (1.01-4.88)
0.043
5, 10%
11, 5%
1, 10%
3, 9%
6, 10%
14, 6%
1.79 (0.66-4.88)
0.247
Cardiac arrhytmia/ atrial fibrillation
3, 6%
11, 5%
0, 0%
1, 3%
3, 5%
12, 5%
1.25 (0.39-3.97)
0.708
Autoimmune disorders
11, 23%
31, 15%
1, 10%
4, 11%
12, 20%
35, 14%
1.46 (0.71-3.02)
0.303
Allergy
6, 12%
14, 7%
1, 10%
4, 10%
7, 11%
18, 7%
1.63 (0.65-4.1)
0.297
Malignancy
2, 5%
17, 8%
0, 0%
2, 6%
2, 3%
19, 8%
0.4 (0.09-1.77)
0.214
Headache
9, 23%
32, 16%
0, 0%
2, 6%
9, 15%
34, 14%
1.21 (0.56-2.61)
0.625
Mental disorders
10, 20%
20, 10%
2, 20%
4, 10%
12, 20%
24, 10%
2.15 (1.01-4.57)
0.044
Table 2 Frequency of somatic and mental comorbidities of narcolepsy cases and sex and age matched controls (N), separately for NT1 (narcolepsy type 1) and NT2 (narcolepsy type 2), and narcolepsy at all (NT1+ NT2). Odds Ratio (OR) with Confidence Interval (CI) 95% (Lower-Upper limit) and Pearson Chi-Square for comorbid diagnoses in the presence of narcolepsy, statistical significance of the difference in the frequency of comorbid diagnoses in narcolepsy cases and controls are in bold if <0,05.
Figure 1 Incidence and Prevalence rates (number of cases per million of inhabitants per year) Incidence Prevalence 2000 0.185563 0.927816 2001 0 0.927816 2002 0.742253 1.670069 2003 0.742253 2.412321 No of narcolepsy cases 2004 0.371126 2.783448 /1million inhabitants 2005 0.55669 3.340137 12 2006 0.55669 3.896827 10 2007 0.55669 4.453516 2008 0.370302 4.813923 8 2009 0.184366 4.977876 6 2010 0.737327 5.714286 4 2011 1.665433 7.216876 2012 0.924214 8.133087 2 2013 0.369344 8.494922 0 2014 0.553403 8.854455 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2015 0.922339 9.592326 2016 0 9.592326 Incidence Prevalence 2017 0.918611 10.47217
Figure 2 Narcolepsy incidence by year of diagnosis and year of excessive daytime sleepiness onset based on patient's medical history. No of narcolepsy cases EDS onset Narcolepsy diagnosis /1million inhabitants 2000 2 1 2001 6 0 2002 1 4 2003 3 4 2004 0 2 No of narcolepsy cases /1million inhabitants 2005 1 3 2006 5 3 9 2007 3 3 8 2008 2 2 7 2009 0 1 6 2010 2 4 5 2011 1 8 4 2012 2 5 3 2013 4 2 2 2014 2 3 1 2015 0 5 0 2016 1 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2017 0 5 EDS onset Narcolepsy diagnosis
Figure 3 Histogram- Age at Narcolepsy onset (EDS) Age groupNo of patients 6-10 1 11-15 11 16-20 9 21-25 7 No of patients 26-30 6 12 31-35 5 10 36-40 6 41-45 3 8 6 4 2 0 6-10
11-15
16-20
21-25
26-30
31-35
36-40
41-45 Age group
Narcolepsy is a rare disorder in Slovakia. Its phenotype, genetic features and comorbidity do not vary from other European countries. The comorbidity with the greatest excess prevalence in the narcolepsy cohort is a mental disorder. Two of three adolescent patients experienced psychotic episode at the onset of narcolepsy.
S1389-9457(19)30361-2
DOI:
https://doi.org/10.1016/j.sleep.2019.10.012
Reference:
SLEEP 4214
To appear in:
Sleep Medicine
Received Date: 10 June 2019 Revised Date:
7 October 2019
Accepted Date: 25 October 2019
Please cite this article as: Feketeova E, Tormasiova M, Klobučníková K, Durdik P, Jarcuskova D, Benca M, Vitkova M, Narcolepsy in Slovakia – epidemiology, clinical and polysomnographic features, comorbid diagnoses: A case-control study, Sleep Medicine, https://doi.org/10.1016/j.sleep.2019.10.012. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
Narcolepsy in Slovakia – epidemiology, clinical and polysomnographic features, comorbid diagnoses: A case-control study. Eva Feketeova “Feketeová” 1, Maria Tormasiova “Tormašiová” 1 , Katarina “Klobučníková” 2
, Peter Durdik “Ďurdík” 3 , Dominika Jarcuskova “Jarčušková” 1, Miroslav Benca “Benča” 1,
Marianna Vitkova “Vítková” 1 1 Dept. of Neurology, Faculty of Medicine Pavol Jozef Safarik University and University Hospital of L. Pasteur, Tr. SNP 1, Kosice, Slovak Republic 2 1st Department of Neurology, Comenius University, Mickiewiczova 13, Bratislava, Slovak Republic 3 Pediatric Department, Comenius University in Bratislava, Jessenius Faculty of Medicine, Kollárova 2, Martin, Slovak Republic Marianna Vítková, corresponding author Dept. of Neurology, Faculty of Medicine Pavol Jozef Safarik University and University Hospital of L. Pasteur Tr. SNP 1, 04011 Kosice, Slovak Republic Email: [email protected] Tel.: +421 911 628 128
ABBREVIATIONS AHI- Apnoea-hypopnoea index CI- confidence interval ESS- Epworth Sleepiness Scale EDS- Excessive Daytime Sleepiness HLA- Human Leukocyte Antigen HCRT- hypocretin ICSD- International classification of sleep disorders NT1- narcolepsy type 1 NT2- narcolepsy type 2 OSA- Obstructive Sleep Apnoea PSG- Polysomnography SOREM- Sleep Onset REM
ABSTRACT
OBJECTIVE: An increase in the incidence of narcolepsy after the pandemic influenza with the H1N1 vaccination in 2009 resulted in an interest in narcolepsy epidemiology. The aim of the study was to examine the incidence and prevalence rates of narcolepsy and to describe the associated characteristics in Slovakia. METHODS: Epidemiology data were calculated for each year from 2000 to 2017 based on records found in specialized centres. Sixty-one narcoleptic patients were diagnosed, 51 (84%) with narcolepsy type 1 (NT1). Clinical data and results of polysomnography (PSG), Human Leukocyte Antigen (HLA)-typing, hypocretin (HCRT)-1 levels and body mass index (BMI) were summarised and evaluated for NT1 and narcolepsy type2 (NT2). Later, 244 sex and age matched controls were chosen to evaluate the comorbid diagnoses. RESULTS: The prevalence of narcolepsy in 2017 in Slovakia was 10.47 (CI 95% 8.26-14) cases/million inhabitants, and the mean incidence rate (2000-2017) was 0.57 (CI 95% 0.4- 0.74) cases/million inhabitants. Narcoleptic patients were comorbid with arterial hypertension (17%), ischemic heart disease (8%), dyslipidaemia (18%), diabetes mellitus type 2 (10%), cardiac arrhythmia/atrial fibrillation (5%), autoimmune disorders (20%), allergy (11%), malignancy (3%), headache (15%) and mental disorders (20%). Patients with narcolepsy showed double the excess prevalence in mental disorders (OR 2.15, p<0.05), and dyslipidaemia (OR 2.22, p<0.05). The presence of autoimmune disorders and allergy showed a mild increase in the narcolepsy group (OR 1.46, resp. 1.63). Hashimoto thyroiditis (HT) was the most frequent autoimmune disorder. CONCLUSIONS: Narcolepsy is a rare disorder in Slovakia. From the phenotype, genetic characteristics and comorbidities the disorder does not vary from other European countries.
KEY WORDS: Narcolepsy; incidence; prevalence; comorbidity; psychotic episode
1. INTRODUCTION Narcolepsy is a chronic neurological disease with hypersomnolence that belongs to the family of rare diseases. The estimated prevalence for narcolepsy ranges from 26 to 50/100,000 in Europe and North America [1]. Research on the epidemiology of narcolepsy prior to 2009 (pandemic influenza followed by vaccination) is very scarce, with the majority of prevalence estimates based on studies varying widely in methodology – questionnaire surveys and interviews. Scientific and clinical interest in the epidemiology of narcolepsy after vaccination has brought several studies with comparable case-defined methodologies. A retrospective study by the Vaccine Adverse Event Surveillance and
Communication group estimated the pool incidence rate between 2000-2010 in Denmark, Finland, Italy, Netherlands, Sweden and the United Kingdom to be 0.93/100,000 person-years (95% CI 0.90– 0.97) [2]. The overall incidence rate in Germany in the post-vaccination period was 0.64/100,000 person-years (95% CI 0.58–0.70) [3]. Both studies revealed the peak incidence in children and adolescents. The prevalence of narcolepsy in Catalunya (Spain) – a region with a very low level of H1N1 vaccination – was estimated to be 5.2 cases per 100,000 inhabitants [4]. Narcolepsy typically manifests with excessive daytime sleepiness (EDS) accompanied by hypnagogic/hypnopompic hallucinations, sleep paralysis and automatic behaviour, followed by cataplexy with latency. In recent years, the symptoms have been extended by fragmented sleep and weight gain [5]. Compared with the general population, narcoleptic patients are more likely to suffer from other sleep disorders, such as obstructive sleep apnoea (OSA), periodic limb movements [6], sleepwalking, or rapid eye movement (REM) sleep behaviour disorder [7]. Narcolepsy accompanied by the absence or a decreased level of hypocretin (HCRT)-1 with a typical phenotype constitutes a separate disease entity – narcolepsy type 1 (NT1). NT1 is caused by the extensive loss of hypothalamic HCRT-producing neurons. The strong association between NT1 and Human Leukocyte Antigen (HLA) Class II [8] and the overwhelming surveillance of the HLA Class I [9], immune-related polymorphisms (eg, variants in the T-cell receptor genes [TRA and TRB] and cathepsin H [10, 11]), suggests an autoimmune aetiology of NT1. While attempts to confirm the autoimmune responses demonstrated by the presence of specific autoantibodies and/or general inflammatory markers have been largely unsuccessful [12-14], some recent studies [15, 16] have proven the existence of autoreactive memory CD4+ and inconstant CD8+ T cells targeting selfantigens expressed by HCRT-producing neurons. This finding represents the missing connecting link for the autoimmune theory. Narcolepsy type 2 (NT2) includes most of the clinical and polysomnographic (PSG) symptoms of narcolepsy, but its cause seems to be heterogeneous, in general unknown, with some proportion of the patients progressing to full-blown NT1 with cataplexy and HCRT deficiency [17]. The onset of narcolepsy is usually in childhood or early adolescence. The mean diagnostic delay from the onset of symptoms is 15 years. This could be explained by unspecific initial spells, incomplete and atypical forms, which make diagnosis of narcolepsy particularly difficult at the onset [7]. Other biomarkers and PSG features are used to support the diagnosis, among these, HLA, HCRT-1 and Multiple Sleep Latency test (MSLT). A number of medical and psychiatric conditions have been consistently described in the narcolepsy cohort in excess (eg, mental illness, diseases of the digestive system, nervous system/sense organs,
endocrinopathies, and obesity) [18-20]. However, there are still conflicting findings on the comorbid immunopathological diseases associated with NT1 [21, 22]. The epidemiological situation and clinical and PSG data on narcolepsy have never been evaluated in Slovakia or any other Eastern European country. The aim of the study was to estimate the incidence and prevalence of the disorder and to describe clinical features and comorbidity.
2. SUBJECTS AND METHODS Narcolepsy can be diagnosed in three University hospitals in Slovakia: two sleep labs taking care of adult patients and one for children. All narcolepsy cases fulfilled International classification of sleep disorders (ICSD) 2 [23] or ICSD 3 [24] criteria. The diagnoses based on ICSD2 criteria were retrospectively re-evaluated by sleep specialists according to ICSD3 to confirm the accuracy of the diagnosis and categorization into type 1 and type 2. Patients with narcolepsy due to medical conditions were excluded. Cases diagnosed before 2000 in the Czech Republic, at the only sleep lab in the former Czechoslovakia, were also included in the analysis based on the aforementioned criteria. To be included in the incidence study, subjects had to reside within Slovakia at the time of narcolepsy onset. The clinical and PSG features of the disease were derived from the medical records, and if necessary (if the date of the last visit was longer than one year before), updated by telephone interview. The incidence rates for narcolepsy were calculated by dividing the number of annually diagnosed narcolepsy patients by the total number of inhabitants in Slovakia. The prevalence rates were calculated by dividing the number of already and newly diagnosed patients minus deceased cases by the total number of inhabitants in Slovakia in each year. The cases diagnosed before 2000 were not included in incident, just prevalence rates. The 95% confidence intervals (95% CI) are given for the mean incidence and prevalence rates for the years 2000–2017. Population data were obtained from the Statistical Office of the Slovak Republic (https://slovak.statistics.sk). All the statistics were compared each year to avoid the bias in the rates. The age at onset of EDS and/or cataplexy, Epworth Sleepiness Scale (ESS) score, presence of OSA, Restless Legs Syndrome (RLS), REM parasomnia, non-rapid eye movement (NREM) parasomnia, bruxism), results of night PSG studies, MSLT, HLA typing, HCRT-1 levels in cerebrospinal fluid (CSF) and body mass index (BMI) were summarised. Therapy data were collected for patients with NT1. For each narcolepsy case, four age- and sex-matched controls were identified from the hospital database. The controls were randomly chosen among the pool of unaffected residents. Comorbid diagnoses, obtained by medical records review or based on a telephone interview, were abstracted for all narcolepsy subjects at the medical visit in 2017 (or at the time of death).
The study was approved by the Ethics Committee, and all participants signed informed content. Demographic and clinical data were given in median, range (min-max), (for normally distributed samples mean, standard deviation), number and percentage. The mean incidence and prevalence rates of narcolepsy in Slovak population for years 2000-2017 were calculated using Student’s tdistribution. We used Exact Poisson test for calculating incidence and prevalence rate with 95% CI of narcolepsy in Slovak population for year 2017. Comparisons between groups were performed with Mann–Whitney U-tests. P-values < 0.05 were considered to be significant. Data were analysed using R language (version 3.6.1).
3. RESULTS Sixty-one narcolepsy patients diagnosed and/or treated in Slovakia were identified (Table 1). All the patients were Caucasians, although one female patient was a member of the Roma minority (2%). Two patients died within the observation period. There was a mild male dominance (57%) in the cohort. The mean narcolepsy prevalence in Slovakia (2000-2017) was 5.74/million inhabitants (95% CI 4.297.2), with an increasing trend over time, which reached its peak in 2017 with the rate of 10.84 cases/million inhabitants. The mean incidence rate (2000-2017) was 0.57 (95% CI 0.4- 0.74) cases/million inhabitants, with the maximum occurring during 2010-2011 (Fig. 1). However, the analysis of EDS onset in narcolepsy cases did not confirm such an increase (Fig. 2). Narcolepsy was manifested by EDS accompanied by cataplexy from disease onset in 51% of patients; cataplexy onset was slightly delayed. The age at the onset of narcolepsy indicated bimodal distribution, with the highest peak in the age range of 16-20 years, and the second one in the 36-40 years range (Fig. 3). The diagnostic delay was 6.5 (median) years in NT1 and 3 (median) years in NT2. Five (8%) were diagnosed with narcolepsy in puberty or adolescence; however no patients were diagnosed before the age of 11. The onset of EDS was dated to the childhood or adolescence in 21 (34%) patients. The only duplex family (mother and daughter) was identified in the NT1 group (4% of familial cases). The proportion of NT1 was 84% (n=51). NT1 and NT2 patients did not vary in age of onset of symptoms, and diagnostic delay (Table 1). Hypnagogic/hypnopompic hallucinations, sleep paralysis and fragmented night sleep were more frequent in NT1 patients, as were sleep comorbidities (parasomnias, RLS, bruxism), apart from OSA, which was more frequent in NT2 patients. Night PSG showed a sleep latency of 8 min or less in NT1, Sleep Onset REM (SOREM) in 44% NT1 and 29% in NT2, worse sleep efficiency, higher Periodic Leg Movements index in NT1, and higher Apnoeahypopnoea index (AHI) in NT2. Sleep latency in the MSLT was less than 5 min with more than two
SOREMs in night PSG and/or MSLT, fulfilling the PSG diagnostic criteria in all cases (according to ICSD3). In all 96% of NT1 patients were HLA-DQB1*0602 allele carriers in comparison with 50% of NT2 patients. HCRT-1 was examined in three NT1 patients, supporting the diagnosis in the uncertain/absent cataplexy presence. Narcoleptic patients were comorbid with arterial hypertension (16%), ischemic heart disease (8%), dyslipidaemia (18%), diabetes mellitus type 2 (10%), cardiac arrhythmia/atrial fibrillation (5%), autoimmune disorders (20%), allergy (11%), malignancy (3%), headache (15%) and mental disorders (20%). The presence of narcolepsy doubled the risk for mental disorders, and dyslipidaemia, which was of statistical significance (p<0.05) (Tab 2). The presence of autoimmune disorders and allergy showed a very mild increase in the narcolepsy group in comparison with the general population (OR 1.46, resp. 1.63). Hashimoto thyroiditis (HT) was the most frequent autoimmune disorder in both the patient and control groups (15%, 9%). Being a narcolepsy patient increases the chances for the presence of mental disorders (OR 2.15). Narcoleptic patients were diagnosed with neurotic, stress-related and somatoform disorders (29%), affective disorders (21%) and mental retardation (14%). Two patients (5%) suffered from mental and behavioural disorders due to psychoactive substance. In the first case, alcohol abuse was already present at the diagnosing of narcolepsy, manifested by status cataplecticus in the withdrawal period. The other case developed alcohol addiction and probably combined with gamma-hydroxybutyrate abuse in the course of narcolepsy. Two of three diagnosed adolescent patients developed psychotic episodes within couple of months after the onset of EDS and cataplexy. The first case was later diagnosed with schizophrenia comorbid with narcolepsy; the other had experienced a single psychotic episode at the onset of narcolepsy, afterwards she was successfully treated with psychostimulants. The frequencies of comorbid diagnoses were calculated separately for NT1 and NT2 subgroup (Tab. 2). Comparison between NT1 and NT2 was not of statistical significance.
4. DISCUSSION To our knowledge, this is the first epidemiological study on narcolepsy in an Eastern European country. We used narcolepsy-diagnosed cases according to ICSD 3 [24] to express the prevalence and incidence rates, clinical picture, PSG and other laboratory characteristics, as well as comorbidity.
4.1 Epidemiology
This study shows a narcolepsy prevalence in 2017 10.47 (CI 95% 8.26-14)/million inhabitants and an incidence rate of 0.57 (CI 95%: 0.4-0.74) cases/million inhabitants/year in Slovakia. Finland, the country of about similar number of inhabitants (5,523,231 in 2017), reported the prevalence of narcolepsy in 1994 to be 26/100 000 inhabitants (95% CI 0-60) [25]. Annual incidence (2002-2009) was 0.79 per 100 000 inhabitants (95% CI 0.62–0.96) [26]. Slovak prevalence rates were 45 times lower and the incidence rates 10 times lower. A recent study from Catalunya, Spain [4], found the prevalence of narcolepsy to be 5.2 cases/100,000 inhabitants, which is 10 times higher during 2000-2017 (5-times higher in 2017) compared to Slovakia, the incidence rates were not calculated in the Spanish sample. Israel had an estimated lower prevalence than Slovakia (2/ million inhabitants), however, the estimates were reported in 1987 [27]. The only epidemiological estimates of narcolepsy in the area of Slovakia came from Roth – 1957 [25], the only sleep laboratory in Czechoslovakia (Prague). The eventual split of the republic resulted in developing sleep medicine and the establishing of the first Slovakian sleep lab in 1994. Currently, there are three sleep labs with the capacity to diagnose narcolepsy (two adult, one paediatric), the largest one takes care for 85% of narcolepsy patients. As the treatment is centralized to the adult centers, all patients should be referred to the center to confirm a diagnosis as well as be treated. The diagnosing in the center provides the only legal possibility to apply for social advantages, which is another reason why all the patients with working or school performing disability are referred to specialized centers. In comparison with existing studies, both incidence and prevalence rates in Slovakia are low. However, the incidence rates are more comparable with literature reported data (eg, 10 times lower than in Finland [25]) than the prevalence rates, which have greater contrast (eg, 45 times lower than in Finland [25]). Such a disproportion may reflect that despite the increasing diagnosing of narcolepsy each year, there are still some undiagnosed patients. Otherwise, the prevalence rates in Slovakia should be higher. The other reasons for lower epidemiological rates in Slovakia could be the genetic factors as there is a lower frequency of HLA DQB1*O602 in Slovakia- 10% [29] versus 18.9 % in the UK, 4.1 in Italy, and 37.5 % in Finland [30]. The incidence trend (Fig 2) has shown the peak incidence rates in 2009-2010 in Slovakia, the years of pandemic influenza A. An increase in the incidence of narcolepsy especially in children and adolescents was reported in Finland, France, Ireland, the Netherlands, Norway, Sweden and the UK, the countries where Pandemrix vaccine was widely used in 2009–2010 [31]. Slovakia, is the country with fewer than 5% of inhabitants vaccinated (2009-2015), and no cases of narcolepsy related to the H1N1 vaccination were detected in our sample. Even more, detailed history data mining showed,
that EDS as an onset symptom (followed by cataplexy or being accompanied by cataplexy) does not have the same trend and cannot be hypothesized, that the seasonal upper airway infections in 20092010 would play a role in the narcolepsy incidence in Slovakia similar to China [32]. Currently, data about the epidemiology of NT2 are scarce. In Slovakia, the incidence per 1 million inhabitants/ year was estimated to be 0.49 (CI 95% 0.33-0.85) for NT1 and 0.1 (95%CI 0.05-0.15) for NT2. The prevalence of NT1 was 5.07 (CI 95% 3.77-6.37) and 0.48 (95% CI 0.2-0.76) /1 million inhabitants/ year for NT2. The study by Tió et al. [4], expressing the prevalence data separately for NT1 and NT2 in Spain, has shown 7 fold increased prevalence for NT1 and 15 fold increase for NT2 in comparison with our estimated rates. According to professional demographic estimates, roughly 430,000 Roma live in Slovakia, which represents about 8% of the total population of the country. From diagnosed narcolepsy cases, this would mean having five Roma patients in the sample. The only affected Roma in our sample, a woman, suggests an even higher number of undiagnosed cases in this minority group. Moreover, we may assume that there are still some cases with a milder form of the disease in the general population who have not been referred for consultation or who do not seek medical advice because of “simple sleepiness”. This point is even more pronounced in a minority with so many socioeconomic barriers. The cohort is not big enough to evaluate the potential presence of protective genetic factors in the Roma group.
4.2 Clinical features, polysomnography, HLA typing, hypocretin measurement Chronic EDS on an everyday basis is the key symptom of narcolepsy: no Slovakian cases with narcolepsy scoring normally in ESS were included in the database (even if it was not exclusion criteria), contrary to the European narcolepsy database [7], where 10% of narcoleptics scored 10 points or fewer on the ESS. The Slovakian sample registers clinically clear-cut definitive cases with a diagnosis of specific PSG findings (night SOREM in 44% of NT1 and 29% of NT2, overall mean sleep latency less than 5 min, MSLT: mean 3 SOREMs in NT1, 2 SOREMs in NT2 patients). The borderline cases are usually not diagnosed or are diagnosed later with narcolepsy, because patients with narcolepsy are not allowed to drive in Slovakia, even if being treated. The proportion of Slovakian NT1 and NT2 cases (84:16%) did not vary from the Spanish sample (85:15%) [4]. Patients with narcolepsy without cataplexy comprised 36% in the study by Silber et al., in 2002 [27], probably due to the different methodology used 15 years ago and discussed diagnostic issues nowadays. According to ICSD-3, NT1 is well-defined condition. NT2 is less well-defined disorder with variability in the EDS phenotype, and few reliable biomarkers. Furthermore, EDS must explain symptoms rather than another cause (eg, sleep deprivation, OSA, circadian rhythm disorders,
or the effect of a medication or substance abuse). Confirming the diagnosis of NT2 in the presence of
OSA is a challenge and could be the source of misdiagnosis [33]. High number of comorbid OSA in the both NT1 and NT2 groups compared with the studies by Frauscher et al. [34], (24%, AHI cut off 5/h) and Sansa et al. [35], (24.8%, AHI cut off 10/h), points at necessity to increase the usage of other biomarkers in diagnostic process, especially HCRT-1 examination in Slovakia. Increased number of comorbid OSA in the presented cohort could be connected with different cut off values for OSA across the studies. The other technical issue could be the date of PSG, it is usually not identified: if it was an entrance diagnostic PSG or retesting because of various clinical reasons. Retesting would turn after 15-20 years observation period many borderline cases to comorbid OSA, as it could be in Slovak sample. However, we believe that two level diagnostic process of NT2 comorbid with OSA (PSG retesting in the presence of persisted EDS while being successfully treated for OSA at least three months before retesting), guarantees the accuracy of NT2 diagnosis, as far as some of the cases would be reclassified to NT1 group if they would have been tested for HCRT-1 (none of NT2 patients was tested for HCRT-1). The sex ratio in the presented paper showed male predominance in accordance with the previous findings [4, 7, 36, 37]. The explanation for this gender effect is unknown. The suggested explanation that men seek more medical attention due to their alleged predominance at work cannot be accepted, as two-thirds of patients referred for daytime sleepiness to sleep specialists (after exclusion of moderate to severe OSA) are women. The mean age of onset with a bimodal peak and mean diagnostic delay in the presented cohort are within the range of the previous study by Luca et al., [7]. A clinical-based study of narcoleptics in Quebec and in France also suggested a bimodal pattern of age of onset, with a larger peak in the second decade and a smaller peak in the fourth decade, despite the different ethnic populations studied [38]. A total of 4% (two women) of familial cases were identified, similar to the reported proportion in the Czech Republic (2.28%, 1.20% if only clinically confirmed cases were counted) [39] and slightly higher than in Spain (1–3%) [4]. In the period 2000-2017 5 (8%) patients were diagnosed 18-year old or younger, none of them before 11 year of age, however the onset symptoms (EDS) was dated to the childhood or adolescence in 21 (34%) patients. Our results are in line with those reported in Finland, where narcolepsy was extremely rare in children aged less than 11 years (the only diagnosed nine-year-old child up to 2008) [26]. HLA typing is not routinely used at all Slovakian sleep labs; thus, the results of HLA typing are available in 50% of NT1 cases, and 97% of them were positive for the DQB1*0602 allele. High
proportion of positive NT1 cases for DQB1*0602 was in agreement with previous findings [4, 8], 100% positivity is typically shown in post-Pandemrix narcolepsy cases [40]. HCRT-1 measurement in cerebrospinal fluid was used in 3% of NT1 patients, to confirm the NT1 diagnosis.
4.3 Comorbidities Compared with controls, patients with narcolepsy showed double the excess prevalence in mental disorders, and dyslipidaemia. The increased frequency of metabolic and cardiovascular disorders in the study, we believe, is due to the excessive weight gain at the time of narcolepsy diagnosis and its persistence over time in the majority of patients [41], 72% of patients in our cohort were obese or overweight. This is due to several reasons: hypocretin deficiency, changed lifestyle due to sleepiness, frequent mood disorders and this could be fixed by adverse reactions to medication. Our findings are in an agreement with the results of previous epidemiological studies [18, 19]. In comparison with previous studies demonstrating equal frequency of comorbid autoimmune disorders in adult NT1 patients and controls [22] or the opposite reporting a higher frequency of immunopathological diseases and allergic comorbidities in NT1 patients [21], our results are in between, with a moderate, but nonsignificant increase in OR (1.6) for autoimmune and allergic diseases in the narcoleptic group. There was also no significant difference in the occurrence of autoimmune conditions between NT1 and NT2 cases. HT was the most frequent autoimmune disease in narcolepsy patients in our cohort (15%). The high frequency of HT also among the controls (9%), does not allow for the hypothesis of a connection between narcolepsy and HT. Headache was not more prevalent in patients with narcolepsy than in controls, which is in disagreement with the increased rate of migraine previously found in narcolepsy patients [19, 42, 43]. The excess prevalence in our narcolepsy cohort was seen for mental illness (OR 2.15). The high rate of a mental comorbidity, especially depression and anxiety, is a constant finding in narcolepsy [18, 19, 44]. There are several possible explanations for the high prevalence of psychiatric symptoms among patients with narcolepsy: symptoms of narcolepsy and those of mental disorders overlap; psychiatric symptoms may arise as a consequence of the disease burden of narcolepsy and its treatment; HCRT dysfunction plays a role in the pathogenesis of narcolepsy as well as mental disorders.
There is an increasing awareness of psychotic symptoms in narcolepsy, apart from hypnagogic/hypnopompic hallucinations as a core narcolepsy feature [45]. Two of the 61 narcolepsy patients (3%) in the presented cohort experienced their first ever psychotic episode in life along with narcolepsy onset/the onset of fully blown symptoms (before treatment initiation). While the first patient developed clinically expressed schizophrenia, the second one experienced symptoms for three months and then later started treatment with stimulants (without relapsed symptoms for more than a five-year observational period). Our experience points to two clinical possibilities: narcolepsy comorbid with schizophrenia and narcolepsy onset accompanied by psychotic episode due to neurotransmitter imbalance. Both conditions task further observations, especially due to their rarity.
4.4 Study strengths and limits Our study is unique in that it is the first ever multicentre case-based study of narcolepsy in Slovakia, an Eastern Europe country of more than five million inhabitants. This case-oriented study with manual review data and added information by interview represents the highest quality standard for epidemiological study, in our opinion (eg, mood disorder diagnosed in a mistake due to onset narcolepsy symptoms [46]) would not be counted. On the other hand, this approach could be limited by voluntarily reported diagnoses and attributable to health-seeking behaviour in chronically sick patients. Getting information from community-based health registries could be the source of discrepancies due to the split of clinical information and health system statistics: eg, to examine hypersomnolent patients for HLA typing or PSG, we would use the code G47.4, even if it were to be later not confirmed (in Slovakia). The limited number of patients did not allow the children and adult populations to be analysed separately. The results of comparison in NT1 and NT2 subgroups are influenced by the statistical error raising from small numbers. Our results cannot be fully generalized to the population level as our controls were from hospitals. However, we tried to minimize a potential bias by selecting the controls from neurological patients being referred for the treatment of acute pain syndrome (radiculopathy caused by spondylosis or intervertebral disc herniation), or facial nerve palsy, first ever in their lives. To avoid the influence of chronic disease consequences, we strictly insisted on first ever onset of pain syndrome, or cranial nerve palsy, which was not a case of comorbidity calculation.
5. Conclusion
The present study reveals a low incidence and prevalence of narcolepsy in Slovakia, an Eastern European country. In terms of phenotype, genetic characteristics and comorbidities, the disorder does not vary from other European countries. Further epidemiological studies should respond if its rarity in Slovakia is due to underdiagnosing of narcolepsy connected with low awareness of the disorder, especially in minority groups, an effort to avoid social disability in mild narcolepsy forms, environmental exposure, or a pattern of geographical variety similar to other autoimmune disorders (eg, multiple sclerosis).
REFERENCES [1]
Ohayon MM, Priest RG, Caulet M, Guilleminault C. Hypnagogic and hypnopompic hallucinations: pathological phenomena? Br J Psychiatry 1996;169:459–67.
[2]
Wijnans L, Lecomte C, de Vries C, Weibel D, Sammon C, Hviid A, et al. The incidence of narcolepsy in Europe: Before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns. Vaccine 2013;31:1246–54. doi:10.1016/J.VACCINE.2012.12.015.
[3]
Oberle D, Drechsel-Bäuerle U, Schmidtmann I, Mayer G, Keller-Stanislawski B. Incidence of Narcolepsy in Germany. Sleep 2015;38:1619–28. doi:10.5665/sleep.5060.
[4]
Tió E, Gaig C, Giner-Soriano M, Romero O, Jurado M-J, Sansa G, et al. The prevalence of narcolepsy in Catalunya (Spain). J Sleep Res 2018;27:e12640. doi:10.1111/jsr.12640.
[5]
Partinen M, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol 2014;13:600–13. doi:10.1016/S1474-4422(14)70075-4.
[6]
Pizza F, Tartarotti S, Poryazova R, Baumann CR, Bassetti CL. Sleep-disordered breathing and periodic limb movements in narcolepsy with cataplexy: a systematic analysis of 35 consecutive patients. Eur Neurol 2013;70:22–6. doi:10.1159/000348719.
[7]
Luca G, Haba-Rubio J, Dauvilliers Y, Lammers G-J, Overeem S, Donjacour CE, et al. Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. J Sleep Res 2013;22:482–95. doi:10.1111/jsr.12044.
[8]
Mignot E, Lin L, Rogers W, Honda Y, Qiu X, Lin X, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet 2001;68:686–99. doi:10.1086/318799.
[9]
Tafti M, Hor H, Dauvilliers Y, Lammers GJ, Overeem S, Mayer G, et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep 2014;37:19–25. doi:10.5665/sleep.3300.
[10]
Kornum BR, Kawashima M, Faraco J, Lin L, Rico TJ, Hesselson S, et al. Common variants in P2RY11 are associated with narcolepsy. Nat Genet 2011;43:66–71. doi:10.1038/ng.734.
[11]
Faraco J, Lin L, Kornum BR, Kenny EE, Trynka G, Einen M, et al. ImmunoChip study implicates antigen presentation to T cells in narcolepsy. PLoS Genet 2013;9:e1003270. doi:10.1371/journal.pgen.1003270.
[12]
Dauvilliers Y, Jaussent I, Lecendreux M, Scholz S, Bayard S, Cristol JP, et al. Cerebrospinal fluid and serum cytokine profiles in narcolepsy with cataplexy: A case-control study. Brain Behav Immun 2014;37:260–6. doi:10.1016/J.BBI.2013.12.019.
[13]
Kornum BR, Pizza F, Knudsen S, Plazzi G, Jennum P, Mignot E. Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset. Brain Behav Immun 2015;49:54–8. doi:10.1016/J.BBI.2015.03.004.
[14]
Kornum BR, Burgdorf KS, Holm A, Ullum H, Jennum P, Knudsen S. Absence of autoreactive CD4+ T-cells targeting HLA-DQA1*01:02/DQB1*06:02 restricted hypocretin/orexin epitopes in narcolepsy type 1 when detected by EliSpot. J Neuroimmunol 2017;309:7–11. doi:10.1016/j.jneuroim.2017.05.001.
[15]
Latorre D, Kallweit U, Armentani E, Foglierini M, Mele F, Cassotta A, et al. T cells in patients with narcolepsy target self-antigens of hypocretin neurons. Nature 2018;562:63–8. doi:10.1038/s41586-018-0540-1.
[16]
Pedersen NW, Holm A, Kristensen NP, Bjerregaard A-M, Bentzen AK, Marquard AM, et al. CD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuronspecific antigens. Nat Commun 2019;10:837. doi:10.1038/s41467-019-08774-1.
[17]
Baumann CR, Mignot E, Lammers GJ, Overeem S, Arnulf I, Rye D, et al. Challenges in diagnosing narcolepsy without cataplexy: a consensus statement. Sleep 2014;37:1035–42. doi:10.5665/sleep.3756.
[18]
Ohayon MM. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med 2013;14:488–92. doi:10.1016/j.sleep.2013.03.002.
[19]
Black J, Reaven NL, Funk SE, McGaughey K, Ohayon MM, Guilleminault C, et al. Medical comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study. Sleep Med 2017;33:13–8. doi:10.1016/J.SLEEP.2016.04.004.
[20]
Cohen A, Mandrekar J, St Louis EK, Silber MH, Kotagal S. Comorbidities in a community sample of narcolepsy. Sleep Med 2018;43:14–8. doi:10.1016/j.sleep.2017.11.1125.
[21]
Martinez-Orozco FJ, Vicario JL, De Andres C, Fernandez-Arquero M, Peraita-Adrados R. Comorbidity of Narcolepsy Type 1 With Autoimmune Diseases and Other Immunopathological Disorders: A Case-Control Study. J Clin Med Res 2016;8:495–505. doi:10.14740/jocmr2569w.
[22]
Barateau L, Lopez R, Arnulf I, Lecendreux M, Franco P, Drouot X, et al. Comorbidity between central disorders of hypersomnolence and immune-based disorders. Neurology 2017;88:93– 100. doi:10.1212/WNL.0000000000003432.
[23]
American Academy of Sleep Medicine. International classification of sleep disorders (2nd ed) Westchester, IL: American Academy of Sleep Medicine; 2005.
[24]
American Academy of Sleep Medicine. International classification of sleep disorders (3rd ed). Darien, IL: American Academy of Sleep Medicine; 2014.
[25]
Hublin C, Kaprio J, Partinen M, et al. The prevalence of narcolepsy: An epidemiological study of the Finnish Twin Cohort. Ann Neurol. 1994;35(6):709-716. doi:10.1002/ana.410350612
[26]
Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, et al. Increased Incidence and Clinical Picture of Childhood Narcolepsy following the 2009 H1N1 Pandemic Vaccination Campaign in Finland. Cowling BJ, ed. PLoS One. 2012;7(3):e33723. doi:10.1371/journal.pone.0033723
[27]
Lavie P, Peled R. Narcolepsy is a Rare Disease in Israel. Sleep. 1987;10(6):608-609.
[28]
Roth B. Narkolepsie a Hypersomnie z hlediska fyziologie spánku. [Narcolepsy and hypersomnia from the aspect of physiology of sleep]. Praha: Státni Zdravotnické Nakladatelství; 1957.
[29]
Cechová E, Fazekasová H, Ferencík S, Shawkatová I, Buc M. HLA-DRB1, -DQB1 and -DPB1 polymorphism in the Slovak population. Tissue Antigens. 1998;51(5):574-576. http://www.ncbi.nlm.nih.gov/pubmed/9672160. Accessed July 30, 2019.
[30]
Fennessy M, Hitman GA, Moore RH, et al. HLA-DQ Gene Polymorphism in Primary IgA Nephropathy in Three European Populations. Vol 49.; 1996. doi:10.1038/ki.1996.67 [31] Sarkanen TO, Alakuijala APE, Dauvilliers YA, Partinen MM. Incidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis. Sleep Med Rev 2018;38:177–86. doi:10.1016/J.SMRV.2017.06.006.
[32]
Han F, Lin L, Warby SC, et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol. 2011;70(3):410-417. doi:10.1002/ana.22587.
[33]
Rosenberg R, Hirshkowitz M, Rapoport DM, Kryger M. The role of home sleep testing for evaluation of patients with excessive daytime sleepiness: focus on obstructive sleep apnea and narcolepsy. Sleep Med. 2019;56:80-89. doi:10.1016/j.sleep.2019.01.014
[34]
Frauscher B, Ehrmann L, Mitterling T, et al. Delayed Diagnosis, Range of Severity, and Multiple Sleep Comorbidities: A Clinical and Polysomnographic Analysis of 100 Patients of the Innsbruck Narcolepsy Cohort. J Clin Sleep Med. 2013;9(8):805-812. doi:10.5664/jcsm.2926
[35]
Sansa G, Iranzo A, Santamaria J. Obstructive sleep apnea in narcolepsy. Sleep Med. 2010;11(1):93-95. doi:10.1016/j.sleep.2009.02.009
[36]
Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep 2002;25:197–202.
[37]
Alakuijala A, Sarkanen T, Partinen M. Polysomnographic and actigraphic characteristics of patients with H1N1-vaccine-related and sporadic narcolepsy. Sleep Med. 2015;16(1):39-44. doi:10.1016/j.sleep.2014.07.024
[38]
Dauvilliers Y, Montplaisir J, Molinari N, Carlander B, Ondze B, Besset A, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 2001;57:2029–33. doi:10.1212/wnl.57.11.2029.
[39]
Nevšímalová S, Mignot E, Šonka K, Arrigoni †J. L. Familial Aspects of Narcolepsy-Cataplexy in the Czech Republic. Sleep 1997;20:1021–6. doi:10.1093/sleep/20.11.1021.
[40]
Sarkanen T, Alakuijala A, Partinen M. Clinical course of H1N1-vaccine-related narcolepsy. Sleep Med. 2016;19:17-22. doi:10.1016/j.sleep.2015.11.005
[41]
Kovalská P, Kemlink D, Topinková E, Nevšímalová S, Maurovich Horvat E, Šonka K. Higher body mass index in narcolepsy with cataplexy: lifelong experience. Sleep Med 2017;32:277. doi:10.1016/j.sleep.2016.11.010.
[421] Dahmen N, Kasten M, Wieczorek S, Gencik M, Epplen J, Ullrich B. Increased Frequency of Migraine in Narcoleptic Patients: A Confirmatory Study. Cephalalgia 2003;23:14–9. doi:10.1046/j.1468-2982.2003.00343.x. [43]
Suzuki K, Miyamoto M, Miyamoto T, Inoue Y, Matsui K, Nishida S, et al. The Prevalence and Characteristics of Primary Headache and Dream-Enacting Behaviour in Japanese Patients with Narcolepsy or Idiopathic Hypersomnia: A Multi-Centre Cross-Sectional Study. PLoS One 2015;10:e0139229. doi:10.1371/journal.pone.0139229.
[44]
Fortuyn HAD, Lappenschaar MA, Furer JW, Hodiamont PP, Rijnders CAT, Renier WO, et al. Anxiety and mood disorders in narcolepsy: a case–control study. Gen Hosp Psychiatry 2010;32:49–56. doi:10.1016/J.GENHOSPPSYCH.2009.08.007.
[45]
Canellas F, Lin L, Julià MR, Clemente A, Vives-Bauza C, Ollila HM, et al. Dual cases of type 1 narcolepsy with schizophrenia and other psychotic disorders. J Clin Sleep Med 2014;10:1011– 8. doi:10.5664/jcsm.4040.
[46]
Kryger MH, Walid R, Manfreda J. Diagnoses received by narcolepsy patients in the year prior to diagnosis by a sleep specialist. Sleep. 2002;25(1):36-41. doi:10.1093/sleep/25.1.36
NARCOLEPSY Incidence 2000-2017/1 million inhabitants/ year
n=61 0.57 (CI 95% 0.4- 0.74)
Prevalence in 2017 /1 million inhabitants
10.47 (CI 95% 8.26-14)
Gender: Males (n, %)
35 (57%)
Narcolepsy type (n, %)
NT1 (51, 84%)
NT2 (10, 16%)
Incidence 2000- 2017 /1 million inhabitants/ year
0.49 (CI 95% 0.31-0.67) 9.01 (CI 95% 6.6211.51) 51 (28)
0.1 (CI 95% 0.05-0.16)
Prevalence in2017 /1 million inhabitants/ year N (Males)
1.84(CI 95% 0.9-2.32) 10 (7)
Age of EDS onset: median (IQR) yy
21.5 (19)
22 (13)
Age of cataplexy onset: median, range, yy
26.5 (23.25)
NA
Diagnostic delay: median, range, yy
6.5 (10.25) 1 affected family (2 females)
3 (11)
H/H hallucinations: n, %
26 (51%)
4 (37.5%)
Sleep paralysis: n, %
27 (53%)
19 (37.5%)
Fragmented night sleep: n, %
35 (69%)
6 (12.5%)
Familial form Clinical features, BMI, sleep comorbidities
BMI: median (IQR), kg.m
-2
27.1 (7)
30.2 (5.45)
REM parasomnia: n, %
19 (37%)
0 (0%)
NREM parasomnia: n, %
6 (13%)
0 (0%)
Restless Leg syndrome: n, %
6 (13%)
0 (0%)
Bruxism: n, %
1 (2%)
0 (0%)
OSA (AHI above 5/h of sleep): n, %
20 (40%)
5 (50%)
ESS: median (IQR)
17 (6)
17 (5.5) 525 (146.7)*
Polysomnography TST: median (IQR) min
438.5 (135)
Sleep latency: median (IQR) min
5.5 (8.63)
8 (8)
REM latency: median (IQR) min
8.5 (46.25)
53 (64.75)
SOREM in night sleep (n, %)
18 (44%)
2 (29%)
Sleep efficiency: median (IQR) %
84.24 (16.6)
87.3 (9.1)
N1: median (IQR) %
6.95 (12.25)
5.6 (8.75)
N2: median (IQR) %
48.75 (19)
48 (15.1)
N3: median (IQR) %
15.8 (13.85)
16 (7.05)
REM: median (IQR) %
22.95 (11.9)
26.9 (11.7)
AHI: median (IQR) /h
2.85 (9.83)
5 (17.83)
PLMS index: median (IQR) /h
5 (12.48)
5 (16.25)
Mean sleep latency in MSLT: median (IQR) min
2.55 (1.85)
5 (4.49)*
Number of SOREMS in MSLT: median (IQR)
3 (2)
2 (2)*
HLA typing (n)
21
4
presence of DQB1*06:02
20 (95%)
2 (50%)
Hcrt-1 in CSF (available samples, positive findings, %)
3, 3, 100%
0, 0, 0%
Table 1 Epidemiological, clinical, polysomnographic features, and comorbid diagnoses of Narcolepsy cases in Slovakia. NT1- Narcolepsy type 1, NT2- Narcolepsy type 2, BMI- Body Mass Index, H/H hallucinations- Hypnagogic/Hypnopompic hallucinations, OSA- Obstructive Sleep Apnea, AHI- Apnea-Hypopnea Index, ESS- Epworth Sleepiness Scale, PLMS- Periodic Leg movements, MSLT- Multiple Sleep Latency test, SOREM- Sleep Onset REM, HLA- Human Leukocyte Antigen Complex, Hcrt-1 Hypocretin-1 IQR- Inter Quartile Range, *Significant difference at level 0,05
NT1
Controls to NT1
NT2
Controls to NT2
N=51
N=204
N=10
N=40
Arterial hypertension
9, 19%
42, 20%
1, 10%
Ischemic heart disease
4, 8%
8, 4%
Dyslipidaemia
11, 23%
Diabetes mellitus type 2
Narcolepsy N=61
Controls N=244
OR (CI 95% Lower- Pearson ChiUpper) Square
5, 14%
10, 16%
47, 19%
0.95 (0.46-1.96)
0.883
1, 10%
2, 6%
5, 8%
10, 4%
2.09 (0.69-6.37)
0.186
19, 9%
0, 0%
3, 9%
11, 18%
23, 9%
2.22 (1.01-4.88)
0.043
5, 10%
11, 5%
1, 10%
3, 9%
6, 10%
14, 6%
1.79 (0.66-4.88)
0.247
Cardiac arrhytmia/ atrial fibrillation
3, 6%
11, 5%
0, 0%
1, 3%
3, 5%
12, 5%
1.25 (0.39-3.97)
0.708
Autoimmune disorders
11, 23%
31, 15%
1, 10%
4, 11%
12, 20%
35, 14%
1.46 (0.71-3.02)
0.303
Allergy
6, 12%
14, 7%
1, 10%
4, 10%
7, 11%
18, 7%
1.63 (0.65-4.1)
0.297
Malignancy
2, 5%
17, 8%
0, 0%
2, 6%
2, 3%
19, 8%
0.4 (0.09-1.77)
0.214
Headache
9, 23%
32, 16%
0, 0%
2, 6%
9, 15%
34, 14%
1.21 (0.56-2.61)
0.625
Mental disorders
10, 20%
20, 10%
2, 20%
4, 10%
12, 20%
24, 10%
2.15 (1.01-4.57)
0.044
Table 2 Frequency of somatic and mental comorbidities of narcolepsy cases and sex and age matched controls (N), separately for NT1 (narcolepsy type 1) and NT2 (narcolepsy type 2), and narcolepsy at all (NT1+ NT2). Odds Ratio (OR) with Confidence Interval (CI) 95% (Lower-Upper limit) and Pearson Chi-Square for comorbid diagnoses in the presence of narcolepsy, statistical significance of the difference in the frequency of comorbid diagnoses in narcolepsy cases and controls are in bold if <0,05.
Figure 1 Incidence and Prevalence rates (number of cases per million of inhabitants per year) Incidence Prevalence 2000 0.185563 0.927816 2001 0 0.927816 2002 0.742253 1.670069 2003 0.742253 2.412321 No of narcolepsy cases 2004 0.371126 2.783448 /1million inhabitants 2005 0.55669 3.340137 12 2006 0.55669 3.896827 10 2007 0.55669 4.453516 2008 0.370302 4.813923 8 2009 0.184366 4.977876 6 2010 0.737327 5.714286 4 2011 1.665433 7.216876 2012 0.924214 8.133087 2 2013 0.369344 8.494922 0 2014 0.553403 8.854455 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2015 0.922339 9.592326 2016 0 9.592326 Incidence Prevalence 2017 0.918611 10.47217
Figure 2 Narcolepsy incidence by year of diagnosis and year of excessive daytime sleepiness onset based on patient's medical history. No of narcolepsy cases EDS onset Narcolepsy diagnosis /1million inhabitants 2000 2 1 2001 6 0 2002 1 4 2003 3 4 2004 0 2 No of narcolepsy cases /1million inhabitants 2005 1 3 2006 5 3 9 2007 3 3 8 2008 2 2 7 2009 0 1 6 2010 2 4 5 2011 1 8 4 2012 2 5 3 2013 4 2 2 2014 2 3 1 2015 0 5 0 2016 1 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2017 0 5 EDS onset Narcolepsy diagnosis
Figure 3 Histogram- Age at Narcolepsy onset (EDS) Age groupNo of patients 6-10 1 11-15 11 16-20 9 21-25 7 No of patients 26-30 6 12 31-35 5 10 36-40 6 41-45 3 8 6 4 2 0 6-10
11-15
16-20
21-25
26-30
31-35
36-40
41-45 Age group
Narcolepsy is a rare disorder in Slovakia. Its phenotype, genetic features and comorbidity do not vary from other European countries. The comorbidity with the greatest excess prevalence in the narcolepsy cohort is a mental disorder. Two of three adolescent patients experienced psychotic episode at the onset of narcolepsy.