Narcolepsy with cataplexy and comorbid immunopathological

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1 J Sleep Res. (2014) 23, Narcolepsy and comorbidities Narcolepsy with cataplexy and comorbid immunopathological diseases FRANCISCO J. MARTÍNEZ-OROZCO 1, JOSÉ L. VICARIO 2, ISABEL VILLALIBRE-VALDERREY 1, CLARA DE ANDRÉS 3, MIGUEL FERNÁNDEZ-ARQUERO 4 and ROSA PERAITA-ADRADOS 5 1 Sleep Unit, Clinical Neurophysiology Service, San Carlos University Hospital, Madrid, Spain, 2 Histocompatibility, Blood Center of the Community of Madrid, Madrid, Spain, 3 Neurology Service, Gregorio Marañón University Hospital, Madrid, Spain, 4 Immunology Service, San Carlos University Hospital, Madrid, Spain and 5 Sleep and Epilepsy Unit Clinical Neurophysiology Service, Gregorio Marañón University Hospital, Madrid, Spain Keywords comorbidity, diagnostic delay, immunopathological diseases, narcolepsy, severity of cataplexy Correspondence Rosa Peraita-Adrados, MD, PhD, Sleep and Epilepsy Unit Clinical Neurophysiology Service, Gregorio Mara~non University Hospital, School of Medicine, UCM Madrid, C/ Dr. Esquerdo, 46, E Madrid, Spain. Tel.: ; fax: ; rosa-peraita@telefonica.net Accepted in revised form 18 January 2014; received 27 September 2013 DOI: /jsr SUMMARY Evidence suggests that autoimmune diseases tend to co-occur so that patients with an autoimmune disorder are at higher risk of a second autoimmune disease. The association between allergic and autoimmune diseases is also of considerable interest. There are no reports on the association between sporadic or familial narcolepsy with cataplexy and other non-neurological immune-mediated diseases. This study reported on the comorbid immunopathological diseases associated with narcolepsy. One-hundred and fifty six narcoleptic patients with a mean age at diagnosis of years (range, 6 70 years) were assessed using the clinical history, physical and neurological examinations, sleep questionnaires, neuroimaging and human leucocyte antigen typing. Diagnosis was confirmed by polysomnography followed by a multiple sleep latency test or by measuring hypocretin-1 levels. Patients with immunopathological diseases were matched for gender and age at the onset of narcoleptic symptoms with narcoleptic patients without immunopathological diseases. Twenty-six patients (16.6%; 50% women; one familial, 25 sporadic) had one or more immunopathological diseases associated: autoimmune diseases, such as idiopathic thrombocytopenic purpura, multiple sclerosis, systemic lupus erythematosus, psoriasis, Crohn s disease, ulcerative colitis, autoimmune thyroid disease, Peyronie s disease and idiopathic recurrent facial palsy; other immunopathological diseases, like atopic dermatitis, allergic asthma and allergic rhinitis. Although not significant, the age at diagnosis of narcolepsy was 9.3 years earlier in patients with narcolepsy + immunopathological diseases. The results demonstrate that the prevalence of comorbid immunopathological diseases is high in narcolepsy, and cataplexy is significantly more severe in patients with narcolepsy + immunopathological diseases. INTRODUCTION Narcolepsy is a chronic sleep disorder caused by a deficiency in hypothalamic hypocretin neurotransmission, through a selective loss of hypocretin-producing neurons (De Lecea et al., 1998; Nishino et al., 2000; Peyron et al., 1998). This very specific mechanism of neural destruction potentially indicates an autoimmune process. Based on its 414 tight association with the human leucocyte antigen (HLA) system, it has been postulated that narcolepsy may be autoimmune in nature, although no direct evidence is available. Most patients suffer from the non-familial (or sporadic) form of narcolepsy, but genetic factors still play an important role. In rare cases with a familial pattern the mode of inheritance is typically autosomal-dominant (Billiard et al., 1994). Genuine multiplex families (with several

2 Comorbidity in narcolepsy with cataplexy 415 generations affected) are very rare (Hor et al., 2011). Some neurological diseases, such as multiple sclerosis (MS) and acute disseminated encephalomyelitis can cause focal lesions in the hypothalamus and, thus, symptomatic narcolepsy demonstrating that an autoimmune mechanism can damage the hypocretin system (Kanbayashi et al., 2001; Nishino and Kambayashi, 2005). Early 1980s studies on the genetics of narcolepsy found an association with two HLA class II antigens, DR2 and DQ1. HLA-DQB1*06 : 02 is the most strongly associated (in up to 98% of cases) and the best HLA marker for the disease. A genome-wide association study (GWAS) in Caucasian individuals (Hallmayer et al., 2009), all of them HLA- DQB1*06 : 02-positive, identified an association with the T-cell receptor-a (TCA) locus on chromosome 14, supporting the autoimmune hypothesis. The TCA is expressed on the surface of T-cells and plays an important role in the recognition of antigens bound to HLA molecules. Later, another GWAS found an association with a protective effect of the DRB1*13 : 01-HLA-DQB1*06 : 03 haplotype (Hor et al., 2010). Several diseases with a proven autoimmune etiology have been described. The genetic background in these disorders is a predisposing factor for autoimmunity, but their association with HLA is not as strong as in narcolepsy with cataplexy (NC). Multiple markers are often detected in patients with autoimmune diseases, but investigators have unsuccessfully searched in patients with narcolepsy for the presence of autoantibodies to many antigens (Black et al., 2005). The findings that hypocretin-containing neurons are enriched in Trib2 protein, and that patients with narcolepsy diagnosed early after first symptoms have auto-antibodies against Trib2, together with the HLA association, are interpreted as suggestive of an autoimmune disease (Cvetkovic-Lopes et al., 2010). Recent studies suggest again the involvement of the immune system in the aetiology of the disease (Faraco et al., 2013; Kornum et al., 2011). The role of environmental factors as a trigger in genetically predisposed subjects is strongly suspected in patients with narcolepsy. Recent studies have reported associations with Streptococcus pyogenes (Aran et al., 2009); upper airway infections (Koepsell et al., 2010); seasonal and annual pattern of upper airway infections, including H1N1 influenza (Han et al., 2011); and H1N1 vaccinations (Partinen et al., 2012). Thus, hypocretin neurons might become damaged in subjects with predisposal genetic factors triggered by environmental factors. These neurons would express specific peptides recognized as auto-antigens by a mechanism such as molecular mimicry. The autoimmune response could be acute and the symptoms of narcolepsy would appear when most neurons are damaged, and this explains the absence of inflammatory signs or auto-antibodies once the condition is finally diagnosed. The association between autoimmune diseases and allergies is actually provoking considerable interest. Autoimmune diseases have been mapped to many shared loci with variable specificities to different diseases. Furthermore, recent studies have identified loci with overlapping effects on autoimmune diseases and allergies. For the purpose of this study, all autoimmune and other immune-mediated disorders will be named immunopathological diseases (IDs). The aim of this retrospective study is to evaluate the comorbidity of NC with IDs in a series of patients with NC, and to find out: (i) the frequency of the association; and (ii) the influence of that association on the outcome of the disease and on the severity of symptoms. PATIENTS AND METHODS The study was conducted at the Sleep Disorders Units of the San Carlos University Hospital and Gregorio Marañón University Hospital in Madrid (Spain). We included 156 Caucasian patients with NC diagnosed in our Sleep Units during the last 20 years, all of them taken from our respective databases. The study was approved by the local ethic committees, and a written patient s inform consent was obtained in all cases. Narcolepsy assessment Patient assessment consisted of a complete clinical history, complete physical [including anthropometric measurements (weight, height and body mass index, BMI)] and neurological examinations, Epworth Sleepiness Scale (ESS), an overnight polysomnographic (PSG) recording followed by an multiple sleep latency test (MSLT), neuroimaging studies and HLA class II molecular typing. The diagnosis of narcolepsy was made according to the International Classification of Sleep Disorders (ICSD-2; American Academy of Sleep Medicine, 2005). The diagnostic criteria included the presence of excessive daytime sleepiness (EDS 3 months) and typical cataplexy not explained by other medical or psychiatric disorders. Diagnosis was confirmed by an overnight PSG recording (electroencephalogram, electrooculogram, electrocardiogram, submental and tibialis anterior electromyograms, nasal-oral air flow, thoracic and abdominal effort, and SaO 2 ) followed by a MSLT [sleep latency 8 min; 2 sleep-onset REM periods (SOREMPs)] and/or by detection of low Hcrt-1 levels in the cerebrospinal fluid (CSF; 110 pg ml 1 ), whenever possible. Brain magnetic resonance imaging (MRI) was performed only in selected cases (see cases 6 and 7 in Table 1). ID assessment For the assessment of IDs, patients were questioned retrospectively using a comprehensive list of these diseases and symptoms. We also reviewed the past medical history and the medical reports from other specialists. The regular follow-up visits of the patients with NC varied from 3 to 6 months. Once the presence of other/s IDs was confirmed, we systematically asked about the age at onset of the ID: previous to the onset of the first symptom of NC (EDS in our

3 416 F. J. Martınez-Orozco et al. Table 1 Demographic, clinical and PSG characteristics of NC with associated IDs EDS onset ESS cataplexy onset Frequency of cataplexy* diagnosis of NC PSG sleep efficiency index (%) MSLT mean sleep latency (min) MSLT number of SOREMP IDs diagnosis of IDs Case Idiopathic recurrent facial 12 palsy Case Allergic rhinitis, food allergy 7 Case Allergic rhinitis 20 Case Peyronie s disease 30 Case ITP 17 Case MS 26 Case SLE 39 Case Psoriasis 34 Case ,5 4 Allergic asthma, food 16 allergy Case ,5 4 Cow milk allergy, allergic 1 asthma Case Atopic dermatitis, allergic 10 rhinitis Case Allergic asthma Case Multinodular goiter 53 autoimmune Case Allergic rhinitis 18 Case Psoriasis 10 Case ,5 2 Crohn s disease, allergic 9 rhinitis Case ,5 2 Allergic rhinitis 9 Case ,5 2 Allergic rhinitis 10 Case ,5 0 Allergic rhinitis, heavy 14 metals allergy Case Allergic asthma 15 Case ,5 0 Allergic rhinitis, atopic 14 dermatitis Case Allergic asthma 21 Case Atopic dermatitis 16 Case Allergic rhinitis 17 Case Ulcerative colitis, 36 autoimmune thryroid disease Case Allergic asthma, allergic rhinitis 10 EDS, excessive daytime sleepiness; ESS, Epworth Sleepiness Scale; ID, immunopathological disease; ITP, idiopathic thrombocytopenic purpura; MS, multiple sclerosis; MSLT, multiple sleep latency test; NC, narcolepsy with cataplexy; PSG, polysomnograpy; SLE, systemic lupus erythematosus; SOREMP, sleep-onset REM period. *European Narcolepsy-Network database: 0 = no; 1 = <1 per year; 2 = <1 per month; 3 = <1 per week; 4 = <1 per day; 5 = >1 per day series), simultaneously with EDS, or subsequent to the onset of EDS. Comparison group Twenty-six patients with NC without IDs from the same series of 156 patients included in our databases, matched for gender and age at onset of the first symptom (EDS), were used for comparisons with patients with NC with comorbid IDs. All patients in this comparison group were interviewed to discard the presence of autoimmune diseases or allergies at the time of this study. Clinical parameters diagnosis of NC and IDs; BMI; severity of EDS (measured by ESS); age at onset and severity of cataplexy; and presence of other narcolepsy symptoms (hallucinations, sleep paralysis) were evaluated. To establish the severity of cataplexy, we took as a reference the parameters of the European Narcolepsy- Network Retrospective Database (Luca et al., 2013). The frequency of cataplexy was assessed using a scale from 1 to 5, reporting rare to very frequent cataplexy attacks: 1 = one or less cataplexy attack per year; 2 = more than one

4 Comorbidity in narcolepsy with cataplexy 417 cataplexy attack per year but <1 per month; 3 = more than one attack per month but <1 per week; 4 = more than one per week but <1 per day; 5 = at least one cataplexy attack per day. We classified the patients into two groups: mild to moderate cataplexy (scores 0, 1 and 2); and severe cataplexy (scores 4 and 5). Statistical analysis Data are reported as mean SD. The Mann Witney and v 2 - tests were used for the parametric comparison, and the Fisher s exact test to evaluate the severity of cataplexy. Differences were considered as statistically significant if P < RESULTS The mean age at diagnosis was years (range: 6 70 years). Twenty-six patients (16.6% out of 156, 13 males and 13 females) had one or more IDs associated: nine had an autoimmune disease; 16 an allergic disorder; and one patient had both. Among these 26 patients with NC and IDs, 25 were sporadic and one familial. The prevalence of NC in Spain is considered to be similar to other European countries, as well as in North American populations, ranging between 0.025% and 0.40% (Ohayon et al., 2002), but there are no epidemiological studies in Spain confirming these figures. Eighteen patients (69.2%) had one ID associated, and eight (30.8%) had two IDs in addition to NC. In those cases with more than one ID, we considered the age at onset of the first ID. The IDs found were: idiopathic thrombocytopenic purpura (ITP; n = 1, familial case, prevalence unknown in adults); MS (n = 1, prevalence in Spain 41/ ); systemic lupus erythematosus (SLE; n = 1, prevalence in Spain 40 50/ ); autoimmune thyroid disease (n = 2, prevalence increases with age, up to 33% at 70 years); psoriasis (n =2, prevalence 1 3%); Crohn s disease (n = 1, prevalence in Spain 1.9/ ); ulcerative colitis (n = 1, prevalence in Spain 8/ ); Peyronie s disease (n = 1, prevalence unknown); idiopathic recurrent facial palsy (n = 1, prevalence unknown); atopic dermatitis (n = 3, prevalence 2 14% in childhood); allergic asthma and/or allergic rhinitis (n = 16, prevalence unknown). The demographic, clinical and PSG data are summarized in Table 1. One patient with NC and hypocretin-1 deficiency developed MS 14 years later, evolving into secondary-progressive MS. The MRI performed when MS was diagnosed showed lesions in the periventricular white matter regions, but no lesions at other hypothalamic sites were documented. The course of both diseases in this patient seemed to be independent (Peraita-Adrados et al., 2013; see case 6 in Table 1). The case with SLE was a woman in whom NC appeared 10 years after the SLE, and the cranial MRI was normal (Pablos et al., 1993; see case 7 in Table 1). Hcrt-1 level was determined in patients 6 and 10, and was undetectable in both cases. In case 10, the level of Hcrt-1 in CSF remained undetectable after 6 months of treatment with intravenous immunoglobulins. In the NC comparison group, Hcrt-1 was determined in two cases, and was undetectable. The results of the statistical analysis are reported in Table 2. The analysis of the temporal relationship between the first symptom of narcolepsy (the EDS in our series) and the presentation of the IDs showed that in 13 cases the diagnosis of the ID preceded the EDS, and in four cases both EDS and ID appeared simultaneously (e.g. immediately after the first allergic event in three cases). This indicates that immune-mediated responses could have acted as a trigger for narcolepsy in some patients. The rate of IDs was not increased over time in our series. None of these 17 patients was treated with antidepressants or stimulants at the time of diagnosis of ID. The remaining nine patients were treated with stimulants, and in four cases with antidepressants. The age at diagnosis of NC was 9.3 years earlier in the group with IDs, although not statistically significant. No significant differences were found between NC with and without ID regarding the age at onset of EDS and cataplexy, the presence of hypnagogic hallucinations and/or sleep paralysis, the sleep Table 2 Clinical variables NC Mean SD NC + IDs Mean SD P Mean age at diagnosis of NC (range 10 78) (range 7 56) ESS (range 13 24) (range 11 24) Mean age at EDS onset (range 6 50) (range 6 45) Mean age at diagnosis of ID (median = 16, range 1 53) Mean age at onset of cataplexy (range 6 70) (range 5 53) Severity of cataplexy (% of patients)* Mild to moderate (1, 2, 3) Severe (4, 5) Hypnagogic hallucinations (% of patients) Sleep paralysis (% of patients) EDS, excessive daytime sleepiness; ESS, Epworth Sleepiness Scale; IDs, immunopathological diseases; NC, narcolepsy with cataplexy. *European Narcolepsy-Network database: 0 = no; 1 = <1 per year; 2 = <1 per month; 3 = <1 per week; 4 = <1 per day; 5 = >1 per day. Bold value denotes severity of cataplexy is statistically significant in the group of severe cataplexy (4, 5).

5 418 F. J. Martınez-Orozco et al. efficiency index, and the mean sleep latency and number of SOREMPs on MSLT. The ESS score showed more severe EDS in the NC group without IDs ( years) than in the group with IDs ( years), but this result was not statistically significant. On the contrary, cataplexy was significantly more severe in the group with IDs. DISCUSSION Evidence suggests that autoimmune diseases tend to coexist within individuals and within families (Somers et al., 2006), and the concept of an autoimmune diathesis is now widely accepted. Although many autoimmune diseases are individually rare, as a whole they are estimated to affect one in 31 Americans (Jacobson et al., 1997). They have been traditionally considered as separate entities, and their aetiologies are poorly understood in many cases because they are conventionally treated by separate medical specialties according to the type of organ involvement. The concept of shared autoimmunity, often referred to as the kaleidoscope of autoimmunity, is gaining acceptance, although it remains unclear whether there are predisposing factors in general or to specific combinations of autoimmune diseases. A recent population-based study demonstrated positive associations between autoimmune thyroiditis, rheumatoid arthritis (RA) and insulin-dependent diabetes mellitus, and found a reduced comorbidity between RA and MS (Somers et al., 2009). In our series, all but one case (familial case) were HLA- DQB1*06 : 02-positive. The familial case, suffering from extreme obesity, belongs to the largest ever-reported NC family with 12 affected members. The index case was diagnosed with ITP at the age of 18 years, and his EDS and cataplectic attacks started at the same age. The ITP was initially successfully treated with corticoids. He was heterozygous HLA-DQB1*06 : 03/02 : 01. A myelin oligodendrocyte glycoprotein mutation was identified in this family (Hor et al., 2011; see case 5 in Table 1). It has been suggested that NC is induced in susceptible individuals by molecular mimicry, a bystander activation mechanism, a specific immune response, or generalized stimulation of the immune system (Salemi and D Amelio, 2010). We have reported a case of paediatric NC in a child associated with desensitization to cow milk allergy, which represents a good example to illustrate that mechanism (Peraita-Adrados et al., 2011; see case 10 in Table 1). Recently, another study has described atopy as a risk factor for thyroid autoimmunity in children (Pedulla et al., 2012). More recently, a GWA study of atopic dermatitis has identified 10 loci with overlapping effects on asthma and psoriasis (Weidinger et al., 2013), which underlines the importance of genetic aspects in the aetiology of IDs. The newly described T-cell immunoglobulin and mucin domain (Tim) gene family (Li et al., 2013), a group of molecules expressed on many types of immune cells and involved in asthma, allergic rhinitis, food allergy and autoimmunity, supports this role. Autoimmune disorders affecting neurons in the central nervous system (CNS) have also been described, most of them mediated by an antibody response. It has been suggested that some autoimmune disorders, including MS, share susceptibility genes (Becker et al., 1998), and familial cases of MS and NC were first described by Ekbom in four families (Ekbom, 1966). It has also been reported that patients with MS have a greater risk for other autoimmune diseases compared with the general population (Baranzini, 2009; Barcellos et al., 2006; Henderson et al., 2000). Using MS and NC as an example, it is clear that the susceptibility to these diseases results from interaction of genes, environment and gene/ environment. Our patient with NC and hypocretin-1 deficiency, who developed MS 14 years later, is a good example to illustrate this hypothesis (Peraita-Adrados et al., 2013). Except for the previously mentioned CNS autoimmune diseases (MS, autoimmune encephalomyelitis), no studies so far have reported an association between NC and other nonneurological IDs. In this series of HLA-DQB1*06 : 02-positive patients with idiopathic NC, and one familial casehla- DQB1*06 : 03, the prevalence of IDs was high (16.6%), suggesting that the disease might arise on a background of generalized susceptibility to immunopathology. Besides, in 50% of cases the ID preceded the first NC symptom (EDS in our series). In our series the group with IDs had an earlier age at diagnosis of NC (9.3 years), probably because the patients visit their physician more frequently, thereby increasing the possibility to be diagnosed. The significantly more severe cataplexy in the group with IDs supports the hypothesis that a higher genetic load in these patients could modulate the symptom expression. Autoimmune reactions could provoke vulnerability in these genetically predisposed patients. Whether this vulnerability could cause a more extensive destruction of hypocretinergic neurons should be investigated in the future. None of the NC + ID patients was treated with antidepressants (for cataplexy) at the time of ID diagnosis, which eliminates the possibility of a biased immunomodulatory effect of the medication. There are several limitations to our study. The study is retrospective, and the questions on IDs in the work-up of patients with NC had been more carefully worded over the last decade due to consistent evidence of the autoimmune nature of NC. Besides, the prevalence of asthma and allergic rhinitis (present in 16 of our cases) is unknown in Spain, but is high in other countries (asthma has been detected in 8.4% of USA population). The next step of our research will be to study the prevalence of IDs in a normal HLA-DQB1*06 : 02- positive population. There are no epidemiological studies in the Spanish population concerning the prevalence of NC, but there are studies on the prevalence of HLA-DQB1*06 : 02 in controls that demonstrate the presence of this allele in 15% of the population in our area (Vicario, unpublished results), far less than the figures of northern European populations. Further studies, including epidemiological studies, will be necessary to identify clinical and genetic associations between

6 Comorbidity in narcolepsy with cataplexy 419 NC and IDs, and might aid in better understanding the implication of immune-related processes in the pathophysiology of these diseases and, perhaps, it would allow the detection of more severe cases in the early stages of the disease, providing the opportunity for immune-modulating therapies. AUTHORS CONTRIBUTIONS F-JM-O, RP-A, IV-V and CDA saw the patients at their outpatient clinics, conducted all the clinical work-up and revised the manuscript for intellectual content. JLV and MF-A performed the HLA analysis and revised the manuscript for intellectual content. F-JM-O and RP-A drafted the original manuscript. CONFLICT OF INTEREST No conflicts of interest declared. REFERENCES American Academy of Sleep Medicine. The International Classification of Sleep Disorders, Second Edition: Diagnostic and Coding Manual. American Academy of Sleep Medicine, Westchester, Illinois, Aran, A., Lin, L., Nevsimalova, S. et al. 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