Keywords:
Narcolepsy - Hypocretin-1 - Quality of Life - Obesity
Palavras-chave:
Narcolepsia - Orexinas - Qualidade de Vida - Obesidade
INTRODUCTION
Narcolepsy is a central disorder of hypersomnolence with chronic daytime sleepiness
and abnormal rapid-eye-movement sleep. Cataplexy is a rapid-eye-movement sleep-like
state, triggered by positive and strong emotions, which arises in wakefulness. An
autoimmune attack of hypothalamic neurons determines deficiency of hypocretin-1 (Hcrt-1)
or orexin-A. It causes cataplexy episodes and characterizes patients with narcolepsy
type 1[1]. Hcrt-1 modulates many neurobiological systems[2]. Indeed, narcolepsy type 2 patients have Hcrt-1 normal levels.
Different tools have been used to investigate the quality of life (QoL) in patients
with narcolepsy (clinical aspects, socioeconomic status, and treatment intervention)[6]. Many studies, using the Medical outcomes study 36-Item Short-Form Health Survey
(SF-36), confirm that adult patients with untreated narcolepsy or on psychostimulant
medication have significantly decreased QoL. However, neither they evaluated the effect
of the type of narcolepsy nor the impact of the disease in Latin American patients.
This study describes health-related QoL in a sample of patients from a Sleep Center
in southeastern Brazil, regarding the type of narcolepsy (according to Hcrt-1 levels),
compared to healthy controls. Additionally, the impact of the nutritional status was
examined by categories of body mass index (BMI) in the scores of the survey.
METHODS
Sample and ethics
Adult patients with narcolepsy (33 type 1 and 33 type 2) and 33 controls, matched
by age and sex, participated in this study at Universidade Federal de São Paulo, São
Paulo, Brazil, from 2015 to 2016. All patients met the 2014 Narcolepsy criteria and
were on usual pharmacological treatment[7].
All controls, recruited among students and employees of the University, had normal
Epworth sleepiness scale and Stop-Bang questionnaire scores[8],[9]. Each participant had at least middle school level of education, in order to complete
the self-administered form. The University’s Institutional Ethics Committee approved
the protocol and consent forms. All participants provided written informed consent.
Study design
It was a cross-sectional study that assessed QoL through a self-report questionnaire,
during the regular follow-up of the patients in the outpatient clinic[10]. Participants were classified into narcolepsy type 1 (NT1), narcolepsy type 2 (NT2),
and control (Ctrl) groups, and according to nutritional status [normal range (BMI<25.0
kg/m2), overweight (25≤BMI<30.0 kg/m2), and obese (BMI≥30.0 kg/m2].
Hcrt-1 levels were measured by radioimmunoassay at the Center for Narcolepsy in the
Department of Psychiatric and Behavior Science at Stanford University, USA[11]. All participants answered the Epworth Sleepiness Scale (ESS) and the Beck Depression
Inventory (range 0–63)[12].
Outcomes - The 36-Item Short-Form Health Survey
The SF-36 is a multi-purpose tool that measures general health concepts in different
populations[13]. The 36 items, organized in an 8-scale profile, were selected from the 40 original
components of the Medical Outcomes Study[14]. The scores range from 0 to 100, with lower scores indicating a worse condition[10],[15].
Statistical analysis
Data were examined using SPSS software for Windows 8, version 21.0. Pearson’s chi-square,
parametric and non-parametric analyses were executed for descriptive statistics. The
results are presented as means ± standard deviation and percentages (%). Models of
the Generalized Linear Model (Poisson log-linear regression) analyzed the outcomes,
followed by a post-hoc with Bonferroni test. The significant level considered was p<0.05.
RESULTS
Each group had 27 (68.7%) women and the mean age in years was 36.2±10.2 in Ctrl, 36.3±9.7
in NT1 and 35.3±10.8 in NT2 (p=0.91). There were no significant differences among
the groups in terms of ethnicity, level of education, and occupation. As expected,
there was a higher frequency of cataplexy in NT1, compared to NT2 (93.9 vs. 0%; p<0.0001), but no significant differences in other narcolepsy-related symptoms.
NT2 had more history of depression, compared to both Ctrl and NT1 (24.2 vs. 3 vs. 3%; p=0.004), but did not see any other difference in anxiety, arterial hypertension,
diabetes or dyslipidemia.
There were no significant differences between NT1 and NT2 according to the use of
psychostimulant or antidepressant drugs. However, NT1 and NT2 used more antidepressants
than Ctrl (48.5 vs. 54.5 vs. 12.1%; p=0.001). NT1 had BMI mean score higher than Ctrl and NT2 (30.7±5.8 vs. 25.5±4.6 vs. 24.6±4.2kg/m2; p<0.0001), such as higher numbers of obese people [19 (54.5%) in NT1, 5 (15.2%)
in Ctrl, and 2 (6.1%) in NT2; p<0.0001]. NT1 and NT2 had higher scores in ESS than
Ctrl (18.8±3.8 vs. 16.0±4.6 vs. 4.9±3.6; p<0.0001), as well as higher Beck Depression Inventory scores (14.6±0.7
vs. 15.9±0.7 vs. 4.5±0.4; p<0.0001).
NT1 and NT2 had lower SF-36 mean scores than Ctrl in the eight domains of physical
and mental health. Role-physical, Role-emotional, and Energy/Fatigue were the most
affected. The only domain in which the scores differed between narcolepsy groups was
the Role-physical one. NT1 had lower mean score than NT2 (37.8±1.0 vs. 50.0±1.2; p<0.0001) ([Table 1]).
Table 1
Medical outcomes study 36-Item short-form survey among control, narcolepsy type 1
and narcolepsy type 2 groups. Analysis performed by generalized linear model (Poisson
regression).
|
•Control
•(n=33)
|
•Narcolepsy type 1
•(n=33)
|
•Narcolepsy type 2
•(n=33)
|
p-value
|
|
Physical health scales (0–100)
|
|
Physical functioning
|
90.9±1.6
|
68.3±1.4*
|
64.2±1.3*
|
<0.0001
|
|
Role-physical
|
85.6±1.6
|
37.8±1.0*
|
50.0±1.2*#
|
<0.0001
|
|
Bodily pain
|
83.4±1.5
|
53.5±1.2*
|
53.5±1.2*
|
<0.0001
|
|
General health
|
78.4±1.6
|
50.0±1.2*
|
52.9±1.2*
|
<0.0001
|
|
Mental health scales (0–100)
|
|
Role-emotional
|
100±1.9
|
31.8±1.2*
|
28.0±1.0*
|
<0.0001
|
|
Social functioning
|
89.2±1.7
|
54.7±1.6*
|
57.1±1.6*
|
<0.0001
|
|
Mental health
|
81.4±1.5
|
53.5±1.2*
|
52.7±1.2*
|
<0.0001
|
|
Energy/Fatigue
|
72.7±1.4
|
38.6±1.0*
|
38.1±1.0*
|
<0.0001
|
*p<0.05 compared to the control group; #p<0.05 compared to narcolepsy type 1 group.
According to nutritional status, NT1 and NT2 had lower mean scores than Ctrl in all
physical and mental health scales ([Figures 1] and [2]). In obese and overweight individuals, NT2 showed lower mean scores than NT1 in
physical health scales and Physical functioning, respectively. In the normal range,
NT2 Role-physical mean score was higher than NT1 ([Figure 1]).
Figure 1 Health-related quality of life, assessed by 36-Item Short-Form Health Survey (SF-36)
physical health scales, according to the nutritional status and the diagnostic group.
A: Bodily pain (0–100); B: Physical functioning (0–100); C: Role limitations due to
physical health (0–100); D: General health (0–100). Analysis performed by generalized
linear model (Poisson regression).*p<0.05 compared to the control group; #p<0.05 compared
to the narcolepsy type 1 group.
Figure 2 Health-related quality of life, assessed by 36-Item Short-Form Health Survey (SF-36)
mental health scales, according to the nutritional status and the diagnostic group.
A: Energy/Fatigue (0-100); B: Social Functioning (0–100); C: Role limitations due
to emotional problems (0–100); D: Mental health (0–100). Analysis performed by generalized
linear model (Poisson regression).*p<0.05 compared to the control group; #p<0.05 compared
to the narcolepsy type 1 group.
In obese people, NT2 Energy/Fatigue and Role-emotional mean scores were lower than
NT1. Between overweight NT1 and NT2, the mean scores of SF-36 mental health varied
according to the domain. In overweight subjects, NT1 Energy/Fatigue, Social functioning,
and Mental health mean scores were higher than NT2. In contrast, in overweight individuals,
NT1 Role-emotional mean scores were lower than NT2. In normal range, NT2 showed higher
Energy/Fatigue mean score and lower Role-emotional mean score than NT1 ([Figure 2]).
DISCUSSION
Brazilian normative data for SF-36 selected individuals from urban and rural areas
of the five regions of the country, which reflects a possible inequality of the population[16]. The mean scores of almost all the domains in Brazil were lower than the compared
countries. This study attempted to diminish the heterogeneity among the groups[17].
In our sample, narcolepsy groups were not different in daytime sleepiness, medications,
and depression indicators. Many comorbidities contributed to the poor QoL in narcolepsy,
and narcolepsy patients had lower overall scores on all domains when compared to controls.
Role-physical, Role-emotional, and Energy/Fatigue were the most affected domains.
Our results confirm the negative impact of narcolepsy in QoL, mainly on type 1.
Indeed, psychostimulants improve QoL in narcolepsy patients[18],[19]. Only one Japanese study showed disabling QoL in narcolepsy type 2 patients, without
significant difference in the domains between the types of narcolepsy in drug-naïve
patients[20].
Perception of QoL in Brazilian adult patients with narcolepsy showed diminishing in
psychological, social, and all aspects of physical domains comparing to controls without
difference in the social-economic profile[21].
Overall, the domains affected in narcolepsy groups were similar to those of previous
publications, with a higher impact in the physical domain. Patients with narcolepsy
in Germany and the United Kingdom had the greatest deficiency in the Role-physical,
Energy/Fatigue, and Vitality domains[22],[23]. Norwegian patients with narcolepsy type 1 had lower scores than those of the general
population, particularly in Bodily pain, Social functioning, and General Health[24].
The scores of NT1 in QoL, in all domains, were lower than Ctrl, according to SF-36
Brazilian Portuguese version. In contrast to Portuguese patients with narcolepsy,
Italian patients with narcolepsy had neither lower scores in Physical functioning
nor in Bodily pain than those in national surveys[25],[26]. A five-year prospective cohort identified a stable impairment in Italian patients
with narcolepsy[27].
Role-physical NT1 had lower score than NT2, aware of what can be associated to physical
aspects, such as obesity. Obese NT2 revealed the lowest scores of physical health,
mostly Role-physical. Narcolepsy healthcare programs are suggested to closely target
weight control in all patients.
As narcolepsy is a rare disease, the superimposition with the insufficient recognition
of the disease in our country restricted patient recruitment[28]. Due to the smaller number of obese in NT2, and the low prevalence of obesity in
the literature in this group, the differences in the physical health domain in the
narcolepsy groups may represent a statistical influence bias on the type of data distribution[29]. Thus, additional studies are necessary to investigate how obesity influences the
scores.
Factors influencing the QoL in our narcolepsy groups may comprise the difficulties
to accurately diagnose (delayed suspicion, onset symptoms, mistaken identification)
and treat (prompt availability and costs of medicines) narcolepsy. This occurs in
various degrees in all populations, largely in our country, which has few centers
with electrodiagnostic investigation.
Especially in this sample, narcolepsy groups were not different in sleepiness, medication,
depression indicators or detailed functional capacity (Stanford Health Assessment
Questionnaire). The elevated prevalence of comorbidity and associated medical conditions
in these patients are possible causes to understand our outcomes.
Although there is no specific study on the contribution of physical activity and healthy
habits of life to improve the health status of these patients, it is intuitive that
these procedures could help them to control obesity, its complications, and comorbidities.
However, a future analysis must be carried out on the most radical intervention to
treat obesity in narcolepsy, regardless of a healthy lifestyle routine.
A narcolepsy-specific instrument of QoL for young patients was developed[30]. However, multilingual generic surveys are the main tools to achieve health status.
A questionnaire is still crucial to elucidate intrinsic aspects of the types of narcolepsy
that reflect the impact of the illness in order to verify the effect of the interventions
and the progression of the disease. The correlation between the scales elements with
biological markers of disease should be explored.
The QoL of narcolepsy patients seen in a Sleep Center from São Paulo-Brazil was studied.
This study confirmed the impairment of QoL according to SF-36 in NT1 and NT2, especially
in the domains Role-physical, Role-emotional, and Energy/Fatigue. It is also the first
report of the poor health status in narcolepsy patients in Brazil regarding the two
different disease forms (NT1 and NT2) and nutritional status.
