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Effect of levothyroxine on prolonged nocturnal sleep time and excessive daytime somnolence in patients with idiopathic hypersomnia
Sleep Medicine 12 (2011) 578–583
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Original Article
Effect of levothyroxine on prolonged nocturnal sleep time and excessive daytime somnolence in patients with idiopathic hypersomnia Hideto Shinno a,⇑, Ichiro Ishikawa a, Mami Yamanaka a, Ai Usui a, Sonoko Danjo a, Yasushi Inami b, Jun Horiguchi b, Yu Nakamura a a b
Department of Neuropsychiatry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793, Japan Department of Psychiatry, Shimane University Faculty of Medicine, 89-1 Enya, Izumo, Shimane 693-8501, Japan
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Article history: Received 20 December 2010 Received in revised form 18 February 2011 Accepted 22 February 2011 Available online 12 May 2011 Keywords: Excessive daytime somnolence Levothyroxine Idiopathic hypersomnia Idiopathic hypersomnia with long sleep time Epworth Sleepiness Scale International Classification of Sleep Disorders
a b s t r a c t Objective: This study aims to examine the effect of levothyroxine, a thyroid hormone, on a prolonged nocturnal sleep and excessive daytime somnolence (EDS) in patients with idiopathic hypersomnia. Methods: In a prospective, open-label study, nine patients were enrolled. All subjects met criteria for idiopathic hypersomnia with long sleep time defined by the International Classification of Sleep Disorders, 2nd edition (ICSD-2). Subjects with sleep apnea syndrome, obesity or hypothyroidism were excluded. Sleep architecture and subjective daytime somnolence were estimated by polysomnography (PSG) and Epworth Sleepiness Scale (ESS), respectively. After baseline examinations, levothyroxine (25 lg/day) was orally administered every day. Mean total sleep time, ESS score at baseline were compared with those after treatment (2, 4 and 8 weeks). Results: Mean age of participants was 23.8 ± 13.7 years old. At baseline, mean total sleep time (hours) and ESS score were 12.9 ± 0.3 and 17.8 ± 1.4, respectively. Mean total sleep times after treatment were 9.1 ± 0.7 and 8.5 ± 1.0 h at 4 and 8 treatment weeks, respectively. Mean ESS scores were 8.8 ± 2.3 and 7.4 ± 2.8 at 4 and 8 treatment weeks, respectively. One patient dropped out at the 2nd week due to poor effect. No adverse effects were noted. Conclusions: After treatment with levothyroxine for over 4 weeks, prolonged sleep time and EDS were improved. Levothyroxine was effective for hypersomnia and well tolerated. Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction Idiopathic hypersomnia was formerly characterized as prolonged sleep episodes, excessive sleepiness, or excessively deep sleep, which lasted for over 6 months. The International Classification of Sleep Disorders, 2nd edition (ICSD-2) has separated idiopathic hypersomnia into two entities [1]. The two conditions are referred to as idiopathic hypersomnia with long sleep time and that without long sleep time. The former is characterized by excessive daytime somnolence (EDS), prolonged nocturnal sleep and difficulty in awakening, and is considered to be polysymptomatic, primary, essential idiopathic hypersomnia. The latter is, on the other hand, remarkable only for EDS, and appears to be monosymptomatic. In both subtypes of idiopathic hypersomnia, Abbreviations: AHI, apnea-hypopnea index; ESS, Epworth Sleepiness Scale; ICSD-2, International Classification of Sleep Disorders, 2nd edition; MSLT, multiple sleep latency test; REM, rapid eye movement; SOREMP, sleep onset rapid eye movement sleep period; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone (thyrotropin). ⇑ Corresponding author. Tel.: +81 87 891 2165; fax: +81 87 891 2168. E-mail address: [email protected] (H. Shinno). 1389-9457/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2011.02.004
multiple sleep latency test (MSLT) reveals reduced mean sleep latency and less than two sleep onset rapid eye movement (REM) sleep periods (SOREMPs). In contrast to narcolepsy, idiopathic hypersomnia lacks specific clinical features such as cataplexy and characteristic polysomnographic features indicating alterations in rapid eye movement (REM) sleep. Previous reports involving cerebrospinal fluid (CSF) analyses in idiopathic hypersomnia patients have revealed that cell counts, cytology, and proteins were not altered [2]. A decrease in dopamine and indoleacetic acid in the CSF was identified in patients with hypersomnia including narcolepsy and idiopathic hypersomnia [3]. Another study demonstrated a dysregulation of the dopamine system in narcolepsy and of the norepinephrine system in hypersomnia [4]. While there have been reports on the pathologies of idiopathic hypersomnia, its pathogenesis has not been sufficiently discussed, and a strategy for its treatment has not been established. While narcolepsy is treated with psychostimulants for excessive daytime sleepiness and antidepressants for cataplexy and abnormal REM sleep [5], psychostimulants such as methylphenidate are not effective for excessive daytime sleepiness in most patients with idiopathic hypersomnia [2]. Naps are of no
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use because they are lengthy and not refreshing. A strategy treating EDS in patients with idiopathic hypersomnia has not yet been established, and investigation to identify an appropriate strategy for pharmacological intervention is necessary. This study aims to investigate the effect of a thyroid hormone on prolonged nocturnal sleep and excessive daytime somnolence in patients with idiopathic hypersomnia. It is well known that patients with hypothyroidism usually exhibit daytime sleepiness. Sleep apnea and its related arousal at night may cause reduction in quality of nocturnal sleep and daytime somnolence. Therefore, patients with hypothyroidism or sleep apnea syndrome were excluded. We previously reported two cases with latent hypothyroidism who presented prolonged daytime somnolence and EDS. They were successfully treated with levothyroxine [6]. In the present study, subjects with latent hypothyroidism were also excluded. 2. Methods 2.1. Study design This study was a prospective, open-label study design to assess the therapeutic effect of levothyroxine. Data were collected between April 2008 and September 2010. 2.2. Patients Nine patients with idiopathic hypersomnia with long sleep time were enrolled in this study. The diagnosis of idiopathic hypersomnia was made according to the criteria established by ICSD-2 [1]. Patients were eligible if (i) they were aged <60 years old; (ii) their body mass index was <25 kg/m2; (iii) they had not been treated for hypersomnia and had not been medicated with psychotropic agents such as psychostimulants, narcotics and antidepressants; (iv) no other drugs were prescribed during levothyroxine treatment; and (v) serum tri-iodothyronine (T3), thyroxine (T4) and thyrotropin (TSH) were within normal range. Patients were excluded for pregnancy or breast-feeding, for having contraindications to levothyroxine, for comorbidity with psychiatric disorders or medical illness. Psychiatrists diagnosed psychiatric comorbidity using the Structured Clinical Interview for Diagnostic and Statistical Manual for Mental Disorders, 4th edition (DSM-IV) [7]. To exclude medical disorders, clinical interview and laboratory examinations were carried out. Patients were also excluded from this study if the baseline polysomnography demonstrated the existence of other sleep disorders or a high apnea-hypopnea index (AHI) (>10). The local institutional research boards approved this study. All patients gave informed consent according to institutional guidelines and the tenets of the Declaration of Helsinki.
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16:30. The patients entered their rooms at 18:00. Room lights were put off when patients required. Our staff checked and recorded the time. Nocturnal PSG was measured for 12 h (19:00 to 07:00). We performed overnight PSG by means of standard procedures that included recording a sleep electroencephalogram (C3-A2, C4-A1), bilateral eye movements, submental electromyography (EMG), an electrocardiogram, pulse oximetry, bilateral tibialis anterior EMG, nasal air flow by a pressure sensor, as well as rib cage and abdominal excursions. The sleep stage was scored according to standard criteria [8]. Sleep efficiency and the lengths of stages I, II, III, IV, and REM were obtained independently. Periodic limb movements during sleep (PLMs) and the apnea-hypopnea index (AHI) were also estimated. To evaluate the sleep latency and sleep onset REM periods (SOREMPs), the MSLT was performed following overnight PSG according to the standard guideline [9]. Sleep latency was calculated from the results obtained by five sleep latency tests that were repeated at 2 h intervals (08:00, 10:00, 12:00, 14:00, and 16:00). A SOREMP was defined as the appearance of an epoch of REM sleep during the first 15 min of naps on the MLST. 2.4.2. Evaluation of symptoms Mean daily sleep time, daytime somnolence and symptom severity were evaluated at baseline and treated for 2, 4, and 8 weeks. Mean daily sleep time indicates nocturnal plus daytime sleep, and was calculated with sleep logs and interview. Values were means of 7 days till each evaluation point. The subjective daytime somnolence was determined by the Epworth Sleepiness Scale (ESS) [10]. 2.4.3. Laboratory data Blood samples were collected before breakfast. Serum free T3, free T4, and TSH were evaluated. 2.4.4. Observation of adverse effect To examine whether adverse effects including symptoms due to an alteration in thyroid function were present, we examined the patients carefully at each visit, and laboratory data were also examined. 2.5. Data analysis To assess changes in scores on the mean daily sleep time and the ESS score, we used a Wilcoxon’s signed rank test. Calculation was carried out with software PASW Statistics 18.0™. When the p value is less than 0.05, we considered the difference statistically significant. 3. Results
2.3. Treatment After the baseline examination, 25 lg/day of levothyroxine was administered in the morning. To examine whether adverse effects including symptoms due to an alteration in thyroid function were present, we examined the patients carefully and laboratory data were also examined. 2.4. Measurements 2.4.1. Polysomnography and multiple sleep latency test Each patient received a standardized evaluation including a medical history, physical, and neurological examinations. At the baseline, polysomnography (PSG) was carried out following the adaptation night. Electrodes for polysomnogram were attached at
3.1. The demography and baseline characteristics of subjects (Table 1) Nine patients were enrolled in this study (four males and five females). All patients met criteria for idiopathic hypersomnia with long sleep time. The mean age of diagnosis was 23.8 ± 13.7 years old (14–59 years old). Prolonged nocturnal sleep and excessive daytime somnolence began in their teens, and the mean age of symptom onset was 15.1 ± 1.1. The mean duration of hypersomnia was 8.1 ± 13.3 years (1.0–44.0 years). The mean body mass index was 21.2 ± 2.5 kg/m2. The mean serum levels of fT3, fT4 and TSH were 3.00 ± 0.42 pg/mL (normal range, 2.2–4.1 pg/mL), 1.17 ± 0.15 ng/ mL (normal range, 0.88–1.81 ng/mL) and 1.71 ± 0.95 l-IU/mL (normal range, 0.35–3.73 l-IU/mL), respectively. No subjects exhibited an altered thyroid function at baseline.
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Table 1 The demography and baseline characteristics of the subjects. Case number
Mean ± SD
1
2
3
4
5
6
7
8
9
Gender Age of diagnosis (years) Age of symptom onset (years) Body mass index (kg/m2)
Male 22 16 18.8
Female 14 13 19.8
Female 59 15 24.6
Male 21 16 17.1
Female 17 15 24.2
Male 25 16 20.5
Male 17 15 20.9
Male 22 16 21.9
Female 17 14 23.3
23.8 ± 13.7 15.1 ± 1.1 21.1 ± 2.5
Baseline daily sleep time Time in bed (hours) Total sleep time (hours) Nocturnal sleep time (hours) Daytime sleep time (hours) Epworth Sleepiness Scale score
14.6 13.0 10.8 2.2 18
16.0 13.3 11.1 2.2 19
15.4 12.8 11.0 1.8 17
14.2 12.6 11.1 1.5 16
16.3 13.2 10.8 2.4 19
15.1 12.8 10.9 1.9 20
15.7 13.1 11.0 2.1 18
14.0 12.4 10.6 1.8 17
15.1 12.6 10.7 1.9 16
15.1 ± 0.8 12.9 ± 0.3 10.9 ± 0.2 2.0 ± 0.3 17.8 ± 1.4
Thyroid function Serum free T3 (pg/mL) Serum free T4 (ng/mL) Serum TSH (lIU/mL)
3.21 1.34 1.48
3.31 1.20 3.42
2.45 1.07 3.12
3.58 1.09 1.40
3.46 1.05 1.54
2.44 0.97 0.77
3.03 1.39 1.57
2.81 1.34 1.43
2.71 1.09 0.66
3.00 ± 0.42 1.71 ± 0.15 1.71 ± 0.95
Blood pressure Systolic/diastolic (mmHg) Pulse rate (bpm)
127/83 73
115/68 72
137/91 87
114/74 74
110/58 66
90/68 79
101/45 62
128/70 79
114/72 63
115 ± 14/70 ± 13 72.8 ± 8.2
Daily sleep time means the time of nocturnal and daytime sleep, and was calculated with sleep logs and interview. The normal ranges of serum free T3, T4 and TSH were 2.2– 4.1 pg/mL, 0.88–1.81 ng/mL and 0.35–3.73 lIU/mL), respectively.
Table 2 Polysomnography and multiple sleep latency test. Case number
Mean ± S.D.
1
2
3
4
5
6
7
8
9
Nocturnal polysomnography Time in bed (min) Total sleep time(TST) (min) Sleep efficiency (%) Sleep latency (min) REM sleep latency (min) Stage I (%TST) Stage II (%TST) Stage III + IV (%TST) Stage REM (%TST) Apnea/hypopnea index(n/h) Periodic limb movement during sleep (n/h)
705 669.0 94.9 8.7 71 7.9 50.5 24.8 16.8 2.2 1.9
699 662.7 94.8 8.3 73 9.2 52.1 19.6 19.1 3.5 2.2
700 656.7 93.8 9.7 89 11.1 51.3 19.4 18.2 8.2 9.1
671 628.3 93.6 8.3 68 9.7 48.4 24.3 17.6 1.9 2.3
667 620.3 93.0 8.7 92 10.8 48.9 20.5 19.8 3.2 1.8
702 657.0 93.6 9.3 94 9.0 47.8 21.0 22.3 4.1 3.9
688 643.0 93.5 9.7 86 9.3 46.1 24.7 19.9 2.7 2.5
707 656.7 92.9 11.3 68 12.3 44.7 25.4 16.6 2.8 3.0
679 636.0 93.7 10.7 71 7.4 50.5 23.1 19.0 2.3 1.9
Multiple sleep latency test Mean sleep latency(min) 1st test 2nd test 3rd test 4th test 5th test
6.3 5.0 6.0 5.3 7.3 7.7
6.3 5.3 6.3 6.0 6.7 7.3
6.7 6.0 5.7 7.0 7.3 7.3
7.3 6.3 7.3 7.0 8.0 7.7
6.0 4.7 6.0 5.7 7.0 7.3
5.7 5.0 6.0 5.7 5.0 7.0
6.7 5.3 6.7 7.0 7.0 7.7
7.3 6.3 7.7 6.7 7.7 8.0
7.0 6.3 7.0 6.3 7.7 7.7
691 ± 15 648 ± 17 93.8 ± 0.7 9.4 ± 1.1 79 ± 11 9.6 ± 1.6 48.9 ± 2.5 22.5 ± 2.4 18.8 ± 1.8 3.4 ± 1.9 3.1 ± 2.3 6.6 ± 0.5
At baseline, polysomnography [8] and multiple sleep latency test [9] were carried out with standard guidelines.
Polysomnography was carried out at baseline. Their total sleep time and percentage of time spent in stages I, II, III + IV and REM are shown in Table 2. Mean REM sleep latency was 79 ± 11 min. Mean AHI was 3.4 ± 1.9. There were no subjects with AHI over 10. MLST revealed that mean sleep latency was 6.6 ± 0.5 min, and that all subjects had fewer than two sleep onset REM sleep periods (SOREMPs; Table 2). 3.2. Outcome after levothyroxine treatment Levothyroxine (25 lg/day) was administered orally once a day in the morning. Of nine subjects eight patients completed the 8 week study. One patient (case 4) dropped out, because treatment with levothyroxine for 16 days failed to improve prolonged nocturnal sleep and EDS. We analyzed daily sleep time and EDS of nine cases including one dropped-out case. 3.2.1. The daily sleep time Time in bed, total sleep time, nocturnal sleep time and daytime sleep time at baseline were shown in Table 1. The mean daily sleep
time at baseline was 12.9 ± 0.3 h. As defined by ICSD-2 criteria, all patients had nocturnal sleep time more than 10 h. After treatment, the mean daily sleep time was 11.0 ± 1.4, 9.1 ± 0.7 and 8.5 ± 1.0 at 2nd, 4th and 8th week, respectively (Fig. 1). When compared with baseline, reductions in nocturnal sleep after treatment were statistically significant (p = 0.012 at 2nd week, p = 0.008 at 4th week and p = 0.008 at 8th week). Proportion of patients whose nocturnal sleep exceeded 10 h/day was 67%, 11% and 11% at 2nd, 4th and 8th week, respectively. The values include one droppedout patient. 3.2.2. The daytime somnolence The mean ESS score was 17.8 ± 1.4 at baseline. After treatment, the mean ESS score was 12.8 ± 3.7, 8.8 ± 2.3 and 7.4 ± 2.8 at 2nd, 4th and 8th week, respectively (Fig. 2). The values include one dropped-out patient. When compared with baseline, reductions in ESS score after treatment were statistically significant (p = 0.017 at 2nd week, p = 0.008 at 4th week and p = 0.008 at 8th week).
H. Shinno et al. / Sleep Medicine 12 (2011) 578–583 mean daily sleep time (min)
0
2
4
8 treatment days (week)
Fig. 1. Effect of levothyroxine on prolonged daily sleep time. Daily sleep time was calculated with each patient’s sleep log and interview, which include nocturnal and daytime sleep. Mean daily sleep time at baseline was compared with that after treatment for 2, 4, and 8 weeks. Mean daily sleep time shortened significantly after treatment (p = 0.012 at 2nd week, p = 0.008 at 4th week and p = 0.08 at 8th week). While sleep time began to reduce at 2nd week, 6 of 9 patients still slept over 10 h/ day. Values obtained from one dropped-out patient were indicated with dotted line. Data were analyzed by Wilcoxon’s signed-rank test.
ESS score
0
2
4
8 treatment days (week)
Fig. 2. Effect of levothyroxine on excessive daytime somnolence. Daytime somnolence was evaluated using Epworth Sleepiness Scale (ESS) [10]. The ESS scores at baseline were compared with that after treatment for 2, 4, and 8 weeks. There were significant reductions in the ESS scores after treatment (p = 0.017 at 2nd week, p = 0.008 at 4th week and p = 0.08 at 8th week). Values obtained from one droppedout patient were indicated with dotted line. Data were analyzed by Wilcoxon’s signed-rank test.
3.3. The adverse events We observed the physical condition and examined adverse events at every visit. No subjects exhibited subjective and objective adverse events. The baseline systolic/diastolic blood pressures and pulse rates are indicated in Table 1. There were no differences in systolic (p = 0.285) and diastolic blood pressure (p = 0.188) as well as pulse rate (p = 0.439). 4. Discussion All patients had complained of excessive daytime sleepiness and prolonged nocturnal sleep (over 10 h). They had not felt refreshed after naps. It had been difficult for them to wake up in the morning. Excessive daytime sleepiness and prolonged
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nocturnal sleep started when they were 13–16 years old and continued for more than one year (1–44 years). Their PSG and MLST revealed a short sleep latency, a prolonged sleep time, a normal apnea/hypopnea index, and a normal REM sleep latency. Their laboratory examinations revealed the normal serum levels of free T3 and free T4, and TSH. They met the ICSD-2 diagnostic criteria for idiopathic hypersomnia with long sleep time [1]. However, we adopted the sleep log and interview to calculate daily sleep time, and concluded that their daily and nocturnal sleep times were prolonged. Subjectively reported total sleep time may not necessarily be accurate to distinguish total sleep time from wake time in bed. We consider that actigraphy may be helpful to give a different account of total sleep time than a subjective report [11]. The pathophysiology of idiopathic hypersomnia has not been sufficiently understood, and the strategy for its treatment has not been established. In this study, the effect of levothyroxine (a thyroid hormone) on prolonged nocturnal sleep and EDS was investigated. While mean sleep time and EDS began to reduce in the 2nd treatment week, nocturnal sleep times still exceeded 10 h for most of the patients. After treated for over 4 weeks, mean nocturnal sleep time was less than 10 h and EDS was also reduced in all subjects, which did not meet criteria for idiopathic hypersomnia. We demonstrated that treatment with 25 lg of levothyroxine for over 4 weeks improved prolonged nocturnal sleep and EDS, and levothyroxine was well tolerated. There have been several studies that investigated the association between hypothalamo–pituitary–thyroid (HPT) axis and alertness. Thyrotropin releasing hormone (TRH) has shown to be distributed widely in the CNS, and its receptors are reported to exist in structures such as pituitary, cortex, brainstem, thalamus, hippocampus, amygdala, and spinal cord [12]. Besides its role in stimulating the release of thyroid stimulating hormone (TSH) and prolactin, TRH has been shown to exhibit various neuromodulating effects that are separate from its hormonal effects [13]. These effects include CNS stimulant and antidepressant effects and neurotrophic effects. The clinical application of exogenous TRH, however, appears to be greatly limited because of a short biological half-life and limited access to the CNS. Therefore, biologically-stable TRH analogs have been developed for possible clinical application. Several reports have demonstrated the association between TRH and alertness in narcolepsy [14], while the association remains to be unclear in other diseases such as idiopathic hypersomnia and sleep apnea syndrome. There have been reports that investigated the effect of TRH analogs in narcoleptic dogs. Acute and chronic oral administration of CG-3703 (a TRH analog) was demonstrated to significantly reduce daytime sleep as well as cataplexy [14]. The effect of CG-3703 was also demonstrated to appear rapidly, while the effect of levothyroxine required about a month in our study. TRH and TRH analogs are also known to enhance dopaminergic transmission in the nucleus accumbens, which is important for locomotor activation and arousals [15]. It is possible that the effect of TRH on sleep and wakefulness may be mediated by enhancement of dopamine turnover, which is a common mechanism for most CNS stimulants [16]. TRH analogs could be beneficial for excessive daytime sleepiness, but evidence has not accumulated in other types of hypersomnia such as idiopathic hypersomnia. In addition, previous studies demonstrated that oral administration of TRH analog did not cause significant changes in serum T3, T4 and TSH, and concluded that the effect may be independent of its effect on the thyroid system [14,17]. On the other hand, it may be argued whether administration of levothyroxine induces suppression of TRH or TSH in subjects in the present study. Although data on thyroid function after treatment are available only in three subjects (data not shown) and are not sufficient for comparing with that at baseline, TSH as well as T3 and T4 after treatment were within
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normal ranges in three patients. We consider two possible reasons. Dose of levothyroxine was so low that it induced suppression of TSH. Another is that patients with idiopathic hypersomnia may exhibit the alteration in HPT axis. Precise mechanism remains to be elucidated, and further investigations are necessary. Studies have also indicated the interaction between HPT axis and neuronal transmission systems that influence alertness. Cerebrospinal fluid (CSF) homovanillic acid, a major metabolite of dopamine, was negatively correlated with plasma TSH and T3 in healthy humans [18], which indicated the physiological significance of the interaction between dopamine and thyroid in central nervous system at the normal, euthyroid human. As clinical and experimental data have suggested, thyroid hormone influences the central neurochemical systems, and may also affect the wake-promoting systems. The pathogenesis of idiopathic hypersomnia is unknown. In idiopathic hypersomnia the involvement of alterations in HPT axis remains to be elucidated, while neuroendocrinological investigations have been performed in narcolepsy [14]. The histaminergic tuberomammillary nucleus of the hypothalamus [19] and the noradrenergic locus coeruleus of the pons [20] are major wakefulness-promoting nuclei, and also play a role in autonomic regulation. On the other hand, thyroid hormones have been reported to serve as co-transmitters with some neurotransmitters such as histamine and noradrenalin [21]. Levothyroxine administration has been indicated to raise the histamine level of the hypothalamus and cerebral cortex [22]. Previous reports have suggested that T3 is localized in brain nuclei receiving strong noradrenergic innervation [23] and concentrated in both noradrenergic centers and noradrenergic projection sites [21]. It is possible that the altered thyroid function or the serum TSH level may affect the arousal-promoting system. To discriminate the influences by sleep-disordered breathing, we excluded the subjects with hypothyroidism, sleep apnea syndrome and obesity. The subjects with high BMI (over 25 kg/m2) or high AHI (over 10) were excluded in this study. Myxoedema is associated with sleep apnea. Several mechanisms have been proposed to explain the association between sleep apnea and hypothyroidism. Patients with hypothyroidism commonly present with disordered breathing. Due to obstructive sleep apnea (OSA), it is often difficult to maintain sleep continuity. Patients usually complain of excessive daytime sleepiness, fatigue, snoring, decreased libido, and impaired concentration. Several studies have demonstrated that OSA is more prevalent in patients with hypothyroidism than control subjects [24–26]. Further examinations have focused on how strong hypothyroidism correlates to OSA. Lin et al. also compared hypothyroidism patients with OSA and without OSA, and suggested that age and body weight were related to the development of OSA [24]. To our knowledge, there have not been any studies that investigated the effect of thyroid hormone on symptoms presented in patients with idiopathic hypersomnia. The present study demonstrates the important and practical findings that had not been investigated in patients with idiopathic hypersomnia. Although a lower dose of levothyroxine was prescribed and did not cause cardiological or physiological alterations, it is necessary to determine carefully in every patient whether treatment with levothyroxine is appropriate. We fixed inclusion and exclusion criteria with careful deliberations. Our study, however, has some limitations since it was an open-label trial. Further studies using a double-blind design or a crossover design with a larger sample size are recommended. Second, we have not investigated what proportions of the total patient with idiopathic hypersomnia respond to levothyroxine administration because only nine subjects were enrolled in the present study. To realize the effect of levothyroxine in idiopathic hypersomnia, it may be helpful to elucidate the difference
in somnological or hormonal properties between responders and non-responders. Conflict of Interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2011.02.004.
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Original Article
Effect of levothyroxine on prolonged nocturnal sleep time and excessive daytime somnolence in patients with idiopathic hypersomnia Hideto Shinno a,⇑, Ichiro Ishikawa a, Mami Yamanaka a, Ai Usui a, Sonoko Danjo a, Yasushi Inami b, Jun Horiguchi b, Yu Nakamura a a b
Department of Neuropsychiatry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793, Japan Department of Psychiatry, Shimane University Faculty of Medicine, 89-1 Enya, Izumo, Shimane 693-8501, Japan
a r t i c l e
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Article history: Received 20 December 2010 Received in revised form 18 February 2011 Accepted 22 February 2011 Available online 12 May 2011 Keywords: Excessive daytime somnolence Levothyroxine Idiopathic hypersomnia Idiopathic hypersomnia with long sleep time Epworth Sleepiness Scale International Classification of Sleep Disorders
a b s t r a c t Objective: This study aims to examine the effect of levothyroxine, a thyroid hormone, on a prolonged nocturnal sleep and excessive daytime somnolence (EDS) in patients with idiopathic hypersomnia. Methods: In a prospective, open-label study, nine patients were enrolled. All subjects met criteria for idiopathic hypersomnia with long sleep time defined by the International Classification of Sleep Disorders, 2nd edition (ICSD-2). Subjects with sleep apnea syndrome, obesity or hypothyroidism were excluded. Sleep architecture and subjective daytime somnolence were estimated by polysomnography (PSG) and Epworth Sleepiness Scale (ESS), respectively. After baseline examinations, levothyroxine (25 lg/day) was orally administered every day. Mean total sleep time, ESS score at baseline were compared with those after treatment (2, 4 and 8 weeks). Results: Mean age of participants was 23.8 ± 13.7 years old. At baseline, mean total sleep time (hours) and ESS score were 12.9 ± 0.3 and 17.8 ± 1.4, respectively. Mean total sleep times after treatment were 9.1 ± 0.7 and 8.5 ± 1.0 h at 4 and 8 treatment weeks, respectively. Mean ESS scores were 8.8 ± 2.3 and 7.4 ± 2.8 at 4 and 8 treatment weeks, respectively. One patient dropped out at the 2nd week due to poor effect. No adverse effects were noted. Conclusions: After treatment with levothyroxine for over 4 weeks, prolonged sleep time and EDS were improved. Levothyroxine was effective for hypersomnia and well tolerated. Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction Idiopathic hypersomnia was formerly characterized as prolonged sleep episodes, excessive sleepiness, or excessively deep sleep, which lasted for over 6 months. The International Classification of Sleep Disorders, 2nd edition (ICSD-2) has separated idiopathic hypersomnia into two entities [1]. The two conditions are referred to as idiopathic hypersomnia with long sleep time and that without long sleep time. The former is characterized by excessive daytime somnolence (EDS), prolonged nocturnal sleep and difficulty in awakening, and is considered to be polysymptomatic, primary, essential idiopathic hypersomnia. The latter is, on the other hand, remarkable only for EDS, and appears to be monosymptomatic. In both subtypes of idiopathic hypersomnia, Abbreviations: AHI, apnea-hypopnea index; ESS, Epworth Sleepiness Scale; ICSD-2, International Classification of Sleep Disorders, 2nd edition; MSLT, multiple sleep latency test; REM, rapid eye movement; SOREMP, sleep onset rapid eye movement sleep period; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone (thyrotropin). ⇑ Corresponding author. Tel.: +81 87 891 2165; fax: +81 87 891 2168. E-mail address: [email protected] (H. Shinno). 1389-9457/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2011.02.004
multiple sleep latency test (MSLT) reveals reduced mean sleep latency and less than two sleep onset rapid eye movement (REM) sleep periods (SOREMPs). In contrast to narcolepsy, idiopathic hypersomnia lacks specific clinical features such as cataplexy and characteristic polysomnographic features indicating alterations in rapid eye movement (REM) sleep. Previous reports involving cerebrospinal fluid (CSF) analyses in idiopathic hypersomnia patients have revealed that cell counts, cytology, and proteins were not altered [2]. A decrease in dopamine and indoleacetic acid in the CSF was identified in patients with hypersomnia including narcolepsy and idiopathic hypersomnia [3]. Another study demonstrated a dysregulation of the dopamine system in narcolepsy and of the norepinephrine system in hypersomnia [4]. While there have been reports on the pathologies of idiopathic hypersomnia, its pathogenesis has not been sufficiently discussed, and a strategy for its treatment has not been established. While narcolepsy is treated with psychostimulants for excessive daytime sleepiness and antidepressants for cataplexy and abnormal REM sleep [5], psychostimulants such as methylphenidate are not effective for excessive daytime sleepiness in most patients with idiopathic hypersomnia [2]. Naps are of no
H. Shinno et al. / Sleep Medicine 12 (2011) 578–583
use because they are lengthy and not refreshing. A strategy treating EDS in patients with idiopathic hypersomnia has not yet been established, and investigation to identify an appropriate strategy for pharmacological intervention is necessary. This study aims to investigate the effect of a thyroid hormone on prolonged nocturnal sleep and excessive daytime somnolence in patients with idiopathic hypersomnia. It is well known that patients with hypothyroidism usually exhibit daytime sleepiness. Sleep apnea and its related arousal at night may cause reduction in quality of nocturnal sleep and daytime somnolence. Therefore, patients with hypothyroidism or sleep apnea syndrome were excluded. We previously reported two cases with latent hypothyroidism who presented prolonged daytime somnolence and EDS. They were successfully treated with levothyroxine [6]. In the present study, subjects with latent hypothyroidism were also excluded. 2. Methods 2.1. Study design This study was a prospective, open-label study design to assess the therapeutic effect of levothyroxine. Data were collected between April 2008 and September 2010. 2.2. Patients Nine patients with idiopathic hypersomnia with long sleep time were enrolled in this study. The diagnosis of idiopathic hypersomnia was made according to the criteria established by ICSD-2 [1]. Patients were eligible if (i) they were aged <60 years old; (ii) their body mass index was <25 kg/m2; (iii) they had not been treated for hypersomnia and had not been medicated with psychotropic agents such as psychostimulants, narcotics and antidepressants; (iv) no other drugs were prescribed during levothyroxine treatment; and (v) serum tri-iodothyronine (T3), thyroxine (T4) and thyrotropin (TSH) were within normal range. Patients were excluded for pregnancy or breast-feeding, for having contraindications to levothyroxine, for comorbidity with psychiatric disorders or medical illness. Psychiatrists diagnosed psychiatric comorbidity using the Structured Clinical Interview for Diagnostic and Statistical Manual for Mental Disorders, 4th edition (DSM-IV) [7]. To exclude medical disorders, clinical interview and laboratory examinations were carried out. Patients were also excluded from this study if the baseline polysomnography demonstrated the existence of other sleep disorders or a high apnea-hypopnea index (AHI) (>10). The local institutional research boards approved this study. All patients gave informed consent according to institutional guidelines and the tenets of the Declaration of Helsinki.
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16:30. The patients entered their rooms at 18:00. Room lights were put off when patients required. Our staff checked and recorded the time. Nocturnal PSG was measured for 12 h (19:00 to 07:00). We performed overnight PSG by means of standard procedures that included recording a sleep electroencephalogram (C3-A2, C4-A1), bilateral eye movements, submental electromyography (EMG), an electrocardiogram, pulse oximetry, bilateral tibialis anterior EMG, nasal air flow by a pressure sensor, as well as rib cage and abdominal excursions. The sleep stage was scored according to standard criteria [8]. Sleep efficiency and the lengths of stages I, II, III, IV, and REM were obtained independently. Periodic limb movements during sleep (PLMs) and the apnea-hypopnea index (AHI) were also estimated. To evaluate the sleep latency and sleep onset REM periods (SOREMPs), the MSLT was performed following overnight PSG according to the standard guideline [9]. Sleep latency was calculated from the results obtained by five sleep latency tests that were repeated at 2 h intervals (08:00, 10:00, 12:00, 14:00, and 16:00). A SOREMP was defined as the appearance of an epoch of REM sleep during the first 15 min of naps on the MLST. 2.4.2. Evaluation of symptoms Mean daily sleep time, daytime somnolence and symptom severity were evaluated at baseline and treated for 2, 4, and 8 weeks. Mean daily sleep time indicates nocturnal plus daytime sleep, and was calculated with sleep logs and interview. Values were means of 7 days till each evaluation point. The subjective daytime somnolence was determined by the Epworth Sleepiness Scale (ESS) [10]. 2.4.3. Laboratory data Blood samples were collected before breakfast. Serum free T3, free T4, and TSH were evaluated. 2.4.4. Observation of adverse effect To examine whether adverse effects including symptoms due to an alteration in thyroid function were present, we examined the patients carefully at each visit, and laboratory data were also examined. 2.5. Data analysis To assess changes in scores on the mean daily sleep time and the ESS score, we used a Wilcoxon’s signed rank test. Calculation was carried out with software PASW Statistics 18.0™. When the p value is less than 0.05, we considered the difference statistically significant. 3. Results
2.3. Treatment After the baseline examination, 25 lg/day of levothyroxine was administered in the morning. To examine whether adverse effects including symptoms due to an alteration in thyroid function were present, we examined the patients carefully and laboratory data were also examined. 2.4. Measurements 2.4.1. Polysomnography and multiple sleep latency test Each patient received a standardized evaluation including a medical history, physical, and neurological examinations. At the baseline, polysomnography (PSG) was carried out following the adaptation night. Electrodes for polysomnogram were attached at
3.1. The demography and baseline characteristics of subjects (Table 1) Nine patients were enrolled in this study (four males and five females). All patients met criteria for idiopathic hypersomnia with long sleep time. The mean age of diagnosis was 23.8 ± 13.7 years old (14–59 years old). Prolonged nocturnal sleep and excessive daytime somnolence began in their teens, and the mean age of symptom onset was 15.1 ± 1.1. The mean duration of hypersomnia was 8.1 ± 13.3 years (1.0–44.0 years). The mean body mass index was 21.2 ± 2.5 kg/m2. The mean serum levels of fT3, fT4 and TSH were 3.00 ± 0.42 pg/mL (normal range, 2.2–4.1 pg/mL), 1.17 ± 0.15 ng/ mL (normal range, 0.88–1.81 ng/mL) and 1.71 ± 0.95 l-IU/mL (normal range, 0.35–3.73 l-IU/mL), respectively. No subjects exhibited an altered thyroid function at baseline.
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Table 1 The demography and baseline characteristics of the subjects. Case number
Mean ± SD
1
2
3
4
5
6
7
8
9
Gender Age of diagnosis (years) Age of symptom onset (years) Body mass index (kg/m2)
Male 22 16 18.8
Female 14 13 19.8
Female 59 15 24.6
Male 21 16 17.1
Female 17 15 24.2
Male 25 16 20.5
Male 17 15 20.9
Male 22 16 21.9
Female 17 14 23.3
23.8 ± 13.7 15.1 ± 1.1 21.1 ± 2.5
Baseline daily sleep time Time in bed (hours) Total sleep time (hours) Nocturnal sleep time (hours) Daytime sleep time (hours) Epworth Sleepiness Scale score
14.6 13.0 10.8 2.2 18
16.0 13.3 11.1 2.2 19
15.4 12.8 11.0 1.8 17
14.2 12.6 11.1 1.5 16
16.3 13.2 10.8 2.4 19
15.1 12.8 10.9 1.9 20
15.7 13.1 11.0 2.1 18
14.0 12.4 10.6 1.8 17
15.1 12.6 10.7 1.9 16
15.1 ± 0.8 12.9 ± 0.3 10.9 ± 0.2 2.0 ± 0.3 17.8 ± 1.4
Thyroid function Serum free T3 (pg/mL) Serum free T4 (ng/mL) Serum TSH (lIU/mL)
3.21 1.34 1.48
3.31 1.20 3.42
2.45 1.07 3.12
3.58 1.09 1.40
3.46 1.05 1.54
2.44 0.97 0.77
3.03 1.39 1.57
2.81 1.34 1.43
2.71 1.09 0.66
3.00 ± 0.42 1.71 ± 0.15 1.71 ± 0.95
Blood pressure Systolic/diastolic (mmHg) Pulse rate (bpm)
127/83 73
115/68 72
137/91 87
114/74 74
110/58 66
90/68 79
101/45 62
128/70 79
114/72 63
115 ± 14/70 ± 13 72.8 ± 8.2
Daily sleep time means the time of nocturnal and daytime sleep, and was calculated with sleep logs and interview. The normal ranges of serum free T3, T4 and TSH were 2.2– 4.1 pg/mL, 0.88–1.81 ng/mL and 0.35–3.73 lIU/mL), respectively.
Table 2 Polysomnography and multiple sleep latency test. Case number
Mean ± S.D.
1
2
3
4
5
6
7
8
9
Nocturnal polysomnography Time in bed (min) Total sleep time(TST) (min) Sleep efficiency (%) Sleep latency (min) REM sleep latency (min) Stage I (%TST) Stage II (%TST) Stage III + IV (%TST) Stage REM (%TST) Apnea/hypopnea index(n/h) Periodic limb movement during sleep (n/h)
705 669.0 94.9 8.7 71 7.9 50.5 24.8 16.8 2.2 1.9
699 662.7 94.8 8.3 73 9.2 52.1 19.6 19.1 3.5 2.2
700 656.7 93.8 9.7 89 11.1 51.3 19.4 18.2 8.2 9.1
671 628.3 93.6 8.3 68 9.7 48.4 24.3 17.6 1.9 2.3
667 620.3 93.0 8.7 92 10.8 48.9 20.5 19.8 3.2 1.8
702 657.0 93.6 9.3 94 9.0 47.8 21.0 22.3 4.1 3.9
688 643.0 93.5 9.7 86 9.3 46.1 24.7 19.9 2.7 2.5
707 656.7 92.9 11.3 68 12.3 44.7 25.4 16.6 2.8 3.0
679 636.0 93.7 10.7 71 7.4 50.5 23.1 19.0 2.3 1.9
Multiple sleep latency test Mean sleep latency(min) 1st test 2nd test 3rd test 4th test 5th test
6.3 5.0 6.0 5.3 7.3 7.7
6.3 5.3 6.3 6.0 6.7 7.3
6.7 6.0 5.7 7.0 7.3 7.3
7.3 6.3 7.3 7.0 8.0 7.7
6.0 4.7 6.0 5.7 7.0 7.3
5.7 5.0 6.0 5.7 5.0 7.0
6.7 5.3 6.7 7.0 7.0 7.7
7.3 6.3 7.7 6.7 7.7 8.0
7.0 6.3 7.0 6.3 7.7 7.7
691 ± 15 648 ± 17 93.8 ± 0.7 9.4 ± 1.1 79 ± 11 9.6 ± 1.6 48.9 ± 2.5 22.5 ± 2.4 18.8 ± 1.8 3.4 ± 1.9 3.1 ± 2.3 6.6 ± 0.5
At baseline, polysomnography [8] and multiple sleep latency test [9] were carried out with standard guidelines.
Polysomnography was carried out at baseline. Their total sleep time and percentage of time spent in stages I, II, III + IV and REM are shown in Table 2. Mean REM sleep latency was 79 ± 11 min. Mean AHI was 3.4 ± 1.9. There were no subjects with AHI over 10. MLST revealed that mean sleep latency was 6.6 ± 0.5 min, and that all subjects had fewer than two sleep onset REM sleep periods (SOREMPs; Table 2). 3.2. Outcome after levothyroxine treatment Levothyroxine (25 lg/day) was administered orally once a day in the morning. Of nine subjects eight patients completed the 8 week study. One patient (case 4) dropped out, because treatment with levothyroxine for 16 days failed to improve prolonged nocturnal sleep and EDS. We analyzed daily sleep time and EDS of nine cases including one dropped-out case. 3.2.1. The daily sleep time Time in bed, total sleep time, nocturnal sleep time and daytime sleep time at baseline were shown in Table 1. The mean daily sleep
time at baseline was 12.9 ± 0.3 h. As defined by ICSD-2 criteria, all patients had nocturnal sleep time more than 10 h. After treatment, the mean daily sleep time was 11.0 ± 1.4, 9.1 ± 0.7 and 8.5 ± 1.0 at 2nd, 4th and 8th week, respectively (Fig. 1). When compared with baseline, reductions in nocturnal sleep after treatment were statistically significant (p = 0.012 at 2nd week, p = 0.008 at 4th week and p = 0.008 at 8th week). Proportion of patients whose nocturnal sleep exceeded 10 h/day was 67%, 11% and 11% at 2nd, 4th and 8th week, respectively. The values include one droppedout patient. 3.2.2. The daytime somnolence The mean ESS score was 17.8 ± 1.4 at baseline. After treatment, the mean ESS score was 12.8 ± 3.7, 8.8 ± 2.3 and 7.4 ± 2.8 at 2nd, 4th and 8th week, respectively (Fig. 2). The values include one dropped-out patient. When compared with baseline, reductions in ESS score after treatment were statistically significant (p = 0.017 at 2nd week, p = 0.008 at 4th week and p = 0.008 at 8th week).
H. Shinno et al. / Sleep Medicine 12 (2011) 578–583 mean daily sleep time (min)
0
2
4
8 treatment days (week)
Fig. 1. Effect of levothyroxine on prolonged daily sleep time. Daily sleep time was calculated with each patient’s sleep log and interview, which include nocturnal and daytime sleep. Mean daily sleep time at baseline was compared with that after treatment for 2, 4, and 8 weeks. Mean daily sleep time shortened significantly after treatment (p = 0.012 at 2nd week, p = 0.008 at 4th week and p = 0.08 at 8th week). While sleep time began to reduce at 2nd week, 6 of 9 patients still slept over 10 h/ day. Values obtained from one dropped-out patient were indicated with dotted line. Data were analyzed by Wilcoxon’s signed-rank test.
ESS score
0
2
4
8 treatment days (week)
Fig. 2. Effect of levothyroxine on excessive daytime somnolence. Daytime somnolence was evaluated using Epworth Sleepiness Scale (ESS) [10]. The ESS scores at baseline were compared with that after treatment for 2, 4, and 8 weeks. There were significant reductions in the ESS scores after treatment (p = 0.017 at 2nd week, p = 0.008 at 4th week and p = 0.08 at 8th week). Values obtained from one droppedout patient were indicated with dotted line. Data were analyzed by Wilcoxon’s signed-rank test.
3.3. The adverse events We observed the physical condition and examined adverse events at every visit. No subjects exhibited subjective and objective adverse events. The baseline systolic/diastolic blood pressures and pulse rates are indicated in Table 1. There were no differences in systolic (p = 0.285) and diastolic blood pressure (p = 0.188) as well as pulse rate (p = 0.439). 4. Discussion All patients had complained of excessive daytime sleepiness and prolonged nocturnal sleep (over 10 h). They had not felt refreshed after naps. It had been difficult for them to wake up in the morning. Excessive daytime sleepiness and prolonged
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nocturnal sleep started when they were 13–16 years old and continued for more than one year (1–44 years). Their PSG and MLST revealed a short sleep latency, a prolonged sleep time, a normal apnea/hypopnea index, and a normal REM sleep latency. Their laboratory examinations revealed the normal serum levels of free T3 and free T4, and TSH. They met the ICSD-2 diagnostic criteria for idiopathic hypersomnia with long sleep time [1]. However, we adopted the sleep log and interview to calculate daily sleep time, and concluded that their daily and nocturnal sleep times were prolonged. Subjectively reported total sleep time may not necessarily be accurate to distinguish total sleep time from wake time in bed. We consider that actigraphy may be helpful to give a different account of total sleep time than a subjective report [11]. The pathophysiology of idiopathic hypersomnia has not been sufficiently understood, and the strategy for its treatment has not been established. In this study, the effect of levothyroxine (a thyroid hormone) on prolonged nocturnal sleep and EDS was investigated. While mean sleep time and EDS began to reduce in the 2nd treatment week, nocturnal sleep times still exceeded 10 h for most of the patients. After treated for over 4 weeks, mean nocturnal sleep time was less than 10 h and EDS was also reduced in all subjects, which did not meet criteria for idiopathic hypersomnia. We demonstrated that treatment with 25 lg of levothyroxine for over 4 weeks improved prolonged nocturnal sleep and EDS, and levothyroxine was well tolerated. There have been several studies that investigated the association between hypothalamo–pituitary–thyroid (HPT) axis and alertness. Thyrotropin releasing hormone (TRH) has shown to be distributed widely in the CNS, and its receptors are reported to exist in structures such as pituitary, cortex, brainstem, thalamus, hippocampus, amygdala, and spinal cord [12]. Besides its role in stimulating the release of thyroid stimulating hormone (TSH) and prolactin, TRH has been shown to exhibit various neuromodulating effects that are separate from its hormonal effects [13]. These effects include CNS stimulant and antidepressant effects and neurotrophic effects. The clinical application of exogenous TRH, however, appears to be greatly limited because of a short biological half-life and limited access to the CNS. Therefore, biologically-stable TRH analogs have been developed for possible clinical application. Several reports have demonstrated the association between TRH and alertness in narcolepsy [14], while the association remains to be unclear in other diseases such as idiopathic hypersomnia and sleep apnea syndrome. There have been reports that investigated the effect of TRH analogs in narcoleptic dogs. Acute and chronic oral administration of CG-3703 (a TRH analog) was demonstrated to significantly reduce daytime sleep as well as cataplexy [14]. The effect of CG-3703 was also demonstrated to appear rapidly, while the effect of levothyroxine required about a month in our study. TRH and TRH analogs are also known to enhance dopaminergic transmission in the nucleus accumbens, which is important for locomotor activation and arousals [15]. It is possible that the effect of TRH on sleep and wakefulness may be mediated by enhancement of dopamine turnover, which is a common mechanism for most CNS stimulants [16]. TRH analogs could be beneficial for excessive daytime sleepiness, but evidence has not accumulated in other types of hypersomnia such as idiopathic hypersomnia. In addition, previous studies demonstrated that oral administration of TRH analog did not cause significant changes in serum T3, T4 and TSH, and concluded that the effect may be independent of its effect on the thyroid system [14,17]. On the other hand, it may be argued whether administration of levothyroxine induces suppression of TRH or TSH in subjects in the present study. Although data on thyroid function after treatment are available only in three subjects (data not shown) and are not sufficient for comparing with that at baseline, TSH as well as T3 and T4 after treatment were within
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normal ranges in three patients. We consider two possible reasons. Dose of levothyroxine was so low that it induced suppression of TSH. Another is that patients with idiopathic hypersomnia may exhibit the alteration in HPT axis. Precise mechanism remains to be elucidated, and further investigations are necessary. Studies have also indicated the interaction between HPT axis and neuronal transmission systems that influence alertness. Cerebrospinal fluid (CSF) homovanillic acid, a major metabolite of dopamine, was negatively correlated with plasma TSH and T3 in healthy humans [18], which indicated the physiological significance of the interaction between dopamine and thyroid in central nervous system at the normal, euthyroid human. As clinical and experimental data have suggested, thyroid hormone influences the central neurochemical systems, and may also affect the wake-promoting systems. The pathogenesis of idiopathic hypersomnia is unknown. In idiopathic hypersomnia the involvement of alterations in HPT axis remains to be elucidated, while neuroendocrinological investigations have been performed in narcolepsy [14]. The histaminergic tuberomammillary nucleus of the hypothalamus [19] and the noradrenergic locus coeruleus of the pons [20] are major wakefulness-promoting nuclei, and also play a role in autonomic regulation. On the other hand, thyroid hormones have been reported to serve as co-transmitters with some neurotransmitters such as histamine and noradrenalin [21]. Levothyroxine administration has been indicated to raise the histamine level of the hypothalamus and cerebral cortex [22]. Previous reports have suggested that T3 is localized in brain nuclei receiving strong noradrenergic innervation [23] and concentrated in both noradrenergic centers and noradrenergic projection sites [21]. It is possible that the altered thyroid function or the serum TSH level may affect the arousal-promoting system. To discriminate the influences by sleep-disordered breathing, we excluded the subjects with hypothyroidism, sleep apnea syndrome and obesity. The subjects with high BMI (over 25 kg/m2) or high AHI (over 10) were excluded in this study. Myxoedema is associated with sleep apnea. Several mechanisms have been proposed to explain the association between sleep apnea and hypothyroidism. Patients with hypothyroidism commonly present with disordered breathing. Due to obstructive sleep apnea (OSA), it is often difficult to maintain sleep continuity. Patients usually complain of excessive daytime sleepiness, fatigue, snoring, decreased libido, and impaired concentration. Several studies have demonstrated that OSA is more prevalent in patients with hypothyroidism than control subjects [24–26]. Further examinations have focused on how strong hypothyroidism correlates to OSA. Lin et al. also compared hypothyroidism patients with OSA and without OSA, and suggested that age and body weight were related to the development of OSA [24]. To our knowledge, there have not been any studies that investigated the effect of thyroid hormone on symptoms presented in patients with idiopathic hypersomnia. The present study demonstrates the important and practical findings that had not been investigated in patients with idiopathic hypersomnia. Although a lower dose of levothyroxine was prescribed and did not cause cardiological or physiological alterations, it is necessary to determine carefully in every patient whether treatment with levothyroxine is appropriate. We fixed inclusion and exclusion criteria with careful deliberations. Our study, however, has some limitations since it was an open-label trial. Further studies using a double-blind design or a crossover design with a larger sample size are recommended. Second, we have not investigated what proportions of the total patient with idiopathic hypersomnia respond to levothyroxine administration because only nine subjects were enrolled in the present study. To realize the effect of levothyroxine in idiopathic hypersomnia, it may be helpful to elucidate the difference
in somnological or hormonal properties between responders and non-responders. Conflict of Interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2011.02.004.
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