Narcolepsy and comorbidities
J Sleep Res. (2014) 23, 414–419
Narcolepsy with cataplexy and comorbid immunopathological diseases FRANCISCO J. MARTÍNEZ-OROZCO1, JOSÉ L. VICARIO2, ISABEL VILLALIBRE-VALDERREY1, CLARA DE ANDRÉS3, MIGUEL F E R N Á N D E Z - A R Q U E R O 4 and R O S A P E R A I T A - A D R A D O S 5 1
Sleep Unit, Clinical Neurophysiology Service, San Carlos University Hospital, Madrid, Spain, 2Histocompatibility, Blood Center of the Community of Madrid, Madrid, Spain, 3Neurology Service, Gregorio Marañón University Hospital, Madrid, Spain, 4Immunology Service, San Carlos University Hospital, Madrid, Spain and 5Sleep 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 ~o n University Hospital, Service, Gregorio Maran School of Medicine, UCM Madrid, C/ Dr. Esquerdo, 46, E-28007 Madrid, Spain. Tel.: +34-914265187; fax: +34-915868901; e-mail: [email protected] Accepted in revised form 18 January 2014; received 27 September 2013 DOI: 10.1111/jsr.12143
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 39.1 17.8 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 ª 2014 European Sleep Research Society
Comorbidity in narcolepsy with cataplexy 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 HLADQB1*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, ª 2014 European Sleep Research Society
415
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 SaO2) 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
F. J. Martınez-Orozco et al.
416
Table 1 Demographic, clinical and PSG characteristics of NC with associated IDs
Age at EDS onset (years)
ESS
Age at cataplexy onset (years)
Case 1
22
23
Case Case Case Case Case Case Case Case
7 16 15 17 12 29 19 21
Case 10
MSLT mean sleep latency (min)
Frequency of cataplexy*
Age at diagnosis of NC (years)
PSG sleep efficiency index (%)
22
4
32
85
5
4
16 16 14 15 24 15 16
8 53 15 18 12 29 21 21
4 5 3 5 4 5 4 4
8 56 30 21 28 30 22 22
88 85 68 75 76 81 94
1 2 4 5 1 4 4,5
3 3 4 5 1 2 4
6
15
5
5
7
85
7,5
4
Case 11
16
19
16
4
20
Case 12 Case 13
39 45
17 15
39 45
5 1
42 48
87 84
3 1
2 2
Case 14 Case 15 Case 16
45 12 9
14 19 17
47 25 9
3 4 5
49 19 28
73 61
2 1,5
2 2
Case 17 Case 18 Case 19
20 10 23
19 21
22 10 26
4 5 5
26 20
91 71
2,5 7,5 7,5
2 2 0
Case 20 Case 21
25 23
22 12
23 23
4 4
34 25
72 80
3 5,5
1 0
Case Case Case Case
22 23 24 25
10 27 19 18
11 24 16 17
17 29 20 20
5 4 3 5
37 21 51
76 92 80
4 3 11 2
2 2 1 2
Case 26
17
21
17
5
22
89
1
3
2 3 4 5 6 7 8 9
MSLT number of SOREMP
2
IDs Idiopathic recurrent facial palsy Allergic rhinitis, food allergy Allergic rhinitis Peyronie’s disease ITP MS SLE Psoriasis Allergic asthma, food allergy Cow milk allergy, allergic asthma Atopic dermatitis, allergic rhinitis Allergic asthma Multinodular goiter autoimmune Allergic rhinitis Psoriasis Crohn’s disease, allergic rhinitis Allergic rhinitis Allergic rhinitis Allergic rhinitis, heavy metals allergy Allergic asthma Allergic rhinitis, atopic dermatitis Allergic asthma Atopic dermatitis Allergic rhinitis Ulcerative colitis, autoimmune thryroid disease Allergic asthma, allergic rhinitis
Age at diagnosis of IDs (years) 12 7 20 30 17 26 39 34 16 1 10
53 18 10 9 9 10 14 15 14 21 16 17 36
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 =
J Sleep Res. (2014) 23, 414–419
Narcolepsy with cataplexy and comorbid immunopathological diseases FRANCISCO J. MARTÍNEZ-OROZCO1, JOSÉ L. VICARIO2, ISABEL VILLALIBRE-VALDERREY1, CLARA DE ANDRÉS3, MIGUEL F E R N Á N D E Z - A R Q U E R O 4 and R O S A P E R A I T A - A D R A D O S 5 1
Sleep Unit, Clinical Neurophysiology Service, San Carlos University Hospital, Madrid, Spain, 2Histocompatibility, Blood Center of the Community of Madrid, Madrid, Spain, 3Neurology Service, Gregorio Marañón University Hospital, Madrid, Spain, 4Immunology Service, San Carlos University Hospital, Madrid, Spain and 5Sleep 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 ~o n University Hospital, Service, Gregorio Maran School of Medicine, UCM Madrid, C/ Dr. Esquerdo, 46, E-28007 Madrid, Spain. Tel.: +34-914265187; fax: +34-915868901; e-mail: [email protected] Accepted in revised form 18 January 2014; received 27 September 2013 DOI: 10.1111/jsr.12143
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 39.1 17.8 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 ª 2014 European Sleep Research Society
Comorbidity in narcolepsy with cataplexy 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 HLADQB1*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, ª 2014 European Sleep Research Society
415
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 SaO2) 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
F. J. Martınez-Orozco et al.
416
Table 1 Demographic, clinical and PSG characteristics of NC with associated IDs
Age at EDS onset (years)
ESS
Age at cataplexy onset (years)
Case 1
22
23
Case Case Case Case Case Case Case Case
7 16 15 17 12 29 19 21
Case 10
MSLT mean sleep latency (min)
Frequency of cataplexy*
Age at diagnosis of NC (years)
PSG sleep efficiency index (%)
22
4
32
85
5
4
16 16 14 15 24 15 16
8 53 15 18 12 29 21 21
4 5 3 5 4 5 4 4
8 56 30 21 28 30 22 22
88 85 68 75 76 81 94
1 2 4 5 1 4 4,5
3 3 4 5 1 2 4
6
15
5
5
7
85
7,5
4
Case 11
16
19
16
4
20
Case 12 Case 13
39 45
17 15
39 45
5 1
42 48
87 84
3 1
2 2
Case 14 Case 15 Case 16
45 12 9
14 19 17
47 25 9
3 4 5
49 19 28
73 61
2 1,5
2 2
Case 17 Case 18 Case 19
20 10 23
19 21
22 10 26
4 5 5
26 20
91 71
2,5 7,5 7,5
2 2 0
Case 20 Case 21
25 23
22 12
23 23
4 4
34 25
72 80
3 5,5
1 0
Case Case Case Case
22 23 24 25
10 27 19 18
11 24 16 17
17 29 20 20
5 4 3 5
37 21 51
76 92 80
4 3 11 2
2 2 1 2
Case 26
17
21
17
5
22
89
1
3
2 3 4 5 6 7 8 9
MSLT number of SOREMP
2
IDs Idiopathic recurrent facial palsy Allergic rhinitis, food allergy Allergic rhinitis Peyronie’s disease ITP MS SLE Psoriasis Allergic asthma, food allergy Cow milk allergy, allergic asthma Atopic dermatitis, allergic rhinitis Allergic asthma Multinodular goiter autoimmune Allergic rhinitis Psoriasis Crohn’s disease, allergic rhinitis Allergic rhinitis Allergic rhinitis Allergic rhinitis, heavy metals allergy Allergic asthma Allergic rhinitis, atopic dermatitis Allergic asthma Atopic dermatitis Allergic rhinitis Ulcerative colitis, autoimmune thryroid disease Allergic asthma, allergic rhinitis
Age at diagnosis of IDs (years) 12 7 20 30 17 26 39 34 16 1 10
53 18 10 9 9 10 14 15 14 21 16 17 36
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 =
