**4. Discussion**

Deranged circadian rhythms have been well recognized in jet lag. In this condition, one may have symptoms, and i.e. dysfunction of the autonomic nervous system, sleep awake rhythm, mental and physical activity. We presume that those patients with sleep disturbance suffered from an atypical but continuous jet lag condition in their daily life.

The international classification of sleep disorders (ICSD) was revised as a new sleep disorder nosology by the Association of Sleep Disorders Center in North America in 1990. Circadian rhythm sleep disorders, such as the delayed sleep phase syndrome (DSPS) and the non-24-hour sleep-wake syndrome, have been described as new types of sleep-wake disorders in the last decade. In this study, we presented children or adolescents who were evaluated as not having physical abnormalities, psychiatric disorders, or specific social problems, but they were suspected to have sleep disturbance because of their daily life pattern. They were healthy in terms of physical and psychiatric examinations, but unable to attend school because their overall conditions did not allow. Those patients who satisfied our inclusion criteria to this study accounted for 40% of the total school refusal cases whom we examined in a 2-year period. This portion is quite large, and indicates the difficulty to prescribe appropriate therapy for these patients.

In our study, all 22 patients were diagnosed as having sleep-wake rhythm disturbance based on their sleep log evaluation and CBT monitoring. Their body temperature rhythm was disturbed in the manner typically shown in adult sleep disorder patients. Among our 6 school refusal patients diagnosed as having non-24, 3 did not show clear rhythm of CBT. Because non-24 is considered most difficult to treat among the 4 categories of sleep disorder, this therapeutic difficulty could be attributable to the severely disturbed CBT rhythm.


Table 2. Type of sleep disturbance, and times of *hPer2* peak, cortisol peak, and lowest core body temperature (CBT) over 24 h, and results of component analysis of the cardiographic R–R interval and glucose tolerance test of each patient(Tomoda et al., 2009).

(both *P* < 0.05) (Tomoda, Kawatani, Joudoi, Hamada, & Miike, 2009). The mean plasma insulin concentration in the patient group was not significantly different from the controls at any time interval following oral glucose ingestion, except at 120 and 150 min (*P <*0.001 and *P <*0.05*,*  respectively). However, individual patient insulin levels varied widely compared with the corresponding BG levels. The insulin level did not correlate with the BG level in some patients. The mean sigma BG level in the patient group was significantly higher than that of controls (910.3 ± 189.9 vs. 865.1 ± 60.5 mg/dl, *P =* 0.027). However, the mean sigma IRI was not significantly different (patients vs. controls = 431.6 ± 194.8 vs. 892.8 ± 440.5 µU/ml, *P =* 0.103). The insulin/glucose ratio, the initial insulin response 30 min after glucose ingestion, was not significantly different (patients vs. controls = 0.95 ± 0.63 vs. 2.43 ± 1.03, *P =* 0.315). However, a significant difference was found in the insulinogenic index (patients vs. controls = 0.48 ± 0.20

18 of 22 unmedicated patients were examined. The mRNA level of *hPer2* was significantly higher at 6:00 in the control subjects. In contrast, the mRNA level of *hPer2* was higher at 6:00 in only 3 patients, at 2:00 in 3, at 10:00 in 4, at 14:00 in 3, and at 18:00 in 5. The timing of the *hPer2* peak expression level was significantly later in the patients than in the control subjects (*P <* 0.05, Mann–Whitney's *U*-test). The most phase-advanced cases (cases 1, 2, 11) showed the *hPer2* peak at 2:00, although the most phase-delayed cases (cases 9, 10, 15–17) showed

There were no significant differences in expression levels of *hPer1, hPer3, hBmal1, hClock.*

suffered from an atypical but continuous jet lag condition in their daily life.

Deranged circadian rhythms have been well recognized in jet lag. In this condition, one may have symptoms, and i.e. dysfunction of the autonomic nervous system, sleep awake rhythm, mental and physical activity. We presume that those patients with sleep disturbance

The international classification of sleep disorders (ICSD) was revised as a new sleep disorder nosology by the Association of Sleep Disorders Center in North America in 1990. Circadian rhythm sleep disorders, such as the delayed sleep phase syndrome (DSPS) and the non-24-hour sleep-wake syndrome, have been described as new types of sleep-wake disorders in the last decade. In this study, we presented children or adolescents who were evaluated as not having physical abnormalities, psychiatric disorders, or specific social problems, but they were suspected to have sleep disturbance because of their daily life pattern. They were healthy in terms of physical and psychiatric examinations, but unable to attend school because their overall conditions did not allow. Those patients who satisfied our inclusion criteria to this study accounted for 40% of the total school refusal cases whom we examined in a 2-year period. This portion is quite large, and indicates the difficulty to

In our study, all 22 patients were diagnosed as having sleep-wake rhythm disturbance based on their sleep log evaluation and CBT monitoring. Their body temperature rhythm was disturbed in the manner typically shown in adult sleep disorder patients. Among our 6 school refusal patients diagnosed as having non-24, 3 did not show clear rhythm of CBT. Because non-24 is considered most difficult to treat among the 4 categories of sleep disorder, this therapeutic difficulty could be attributable to the severely disturbed CBT rhythm.

vs. 1.04 ± 0.50, *P =* 0.044). The results are summarized in Table 2.

**3.5 Abnormal mammalian circadian clock** 

prescribe appropriate therapy for these patients.

the *hPer2* peak at 18:00.

**4. Discussion** 

Adolescents with Sleep Disturbance: Causes and Diagnosis 29

dominant factor in the pathogenesis of such conditions. Immunological, autonomic, and neuroendocrine abnormalities might be mutually dependent and reinforcing factors. More studies must be done to elucidate this mechanism and to reveal the relation between clock gene expression in the suprachiasmatic nucleus and the peripheral blood cells. Furthermore, additional study of a larger series of cases will elucidate the usefulness of this technique.

[1] Tomoda A, Kawatani J, Joudoi T, Hamada A, Miike T. Metabolic dysfunction and

[2] Tomoda A, Miike T, Uezono K, Kawasaki T. A school refusal case with biological rhythm disturbance and melatonin therapy. *Brain Dev* 1994;16(1):71-6. [3] Boergers J, Hart C, Owens JA, Streisand R, Spirito A. Child sleep disorders: associations

[4] Giannotti F, Cortesi F, Sebastiani T, Ottaviano S. Circadian preference, sleep and

[5] Stein MA, Mendelsohn J, Obermeyer WH, Amromin J, Benca R. Sleep and behavior

[6] Archer SN, Robilliard DL, Skene DJ, Smits M, Williams A, Arendt J, et al. A length

[7] Ebisawa T, Uchiyama M, Kajimura N, Mishima K, Kamei Y, Katoh M, et al. Association

[8] Iwase T, Kajimura N, Uchiyama M, Ebisawa T, Yoshimura K, Kamei Y, et al. Mutation

[9] Pirovano A, Lorenzi C, Serretti A, Ploia C, Landoni S, Catalano M, et al. Two new rare

[10] Takimoto M, Hamada A, Tomoda A, Ohdo S, Ohmura T, Sakato H, et al. Daily

[11] Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, et al. An hPer2

[12] Wijnen H, Boothroyd C, Young MW, Claridge-Chang A. Molecular genetics of timing in intrinsic circadian rhythm sleep disorders. *Ann Med* 2002;34(5):386-93. [13] Iwatani N, Miike T, Kai Y, Kodama M, Mabe H, Tomoda A, et al. Glucoregulatory disorders in school refusal students. *Clin Endocrinol (Oxf)* 1997;47(3):273-8. [14] Reppert SM, Weaver DR. Coordination of circadian timing in mammals. *Nature*

[15] Miike T, Tomoda A, Jhodoi T, Iwatani N, Mabe H. Learning and memorization

impairment in childhood chronic fatigue syndrome manifesting as school phobia in

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**5. References** 

2009;47 Suppl 2:T21-6.

The 2 biological rhythms (sleep and CBT) are sometimes desynchronized with each other, e.g., when the person was completely isolated from time cues. Once the desynchronization occurred, psychosomatic symptoms, such as headache, gastrointestinal discomfort, or general fatigue. These symptoms could make the affected person unable to perform ordinary daily activities.

Furthermore, our findings obtained in this study suggest that physiological homeostasis might be seriously impaired by sleep deprivation and emotional distress, as reflected clearly by depressive symptoms in these patients. Easy fatigability and disturbed learning and memorization are among the primary characteristics of sleep disturbance and chronic fatigue in adolescents (Miike et al., 2004). Fatigue and gastrointestinal discomfort were quite severe in our patients. Another feature of this illness is the individuality of symptom patterns and the unpredictability of symptom severity.

It is particularly interesting that diurnal hypersecretion of glucocorticoids and altered regulation of the hypothalamo–pituitary–adrenocortical axis are known in patients with poorly controlled or uncontrolled diabetes (Archer et al., 2003; Chiodini et al., 2006; Roy, Roy, & Brown, 1998). We found no cortisol hypersecretion in the present patients, suggesting the absence of diabetic status. However, those patients with sleep disturbance had glucoregulatory dysfunction. Results of a previous study show that emotionally stressful events result in hyperglycemia in diabetic patients (Lustman, Carney, & Amado, 1981). On the other hand, sleep deficit has a harmful impact on carbohydrate metabolism and endocrine function, even in healthy subjects (Spiegel, Leproult, & Van Cauter, 1999). Abnormalities of the biological stress response (hypothalamic–pituitary–adrenal axis and autonomic nervous system) were also identified in a previous animal study, the results of which suggested that cortisol can act directly on the central nervous system (Sandoval, Ping, Neill, Morrey, & Davis, 2003). Multiple factors including autonomic nervous system dysfunction, derangement of neuropeptides in the hypothalamus, and hormonal imbalance might also affect the glucoregulatory metabolism.

The biological clock (circadian clock) in human beings is formed and regulated through interrelationships of various clock genes such as *Per1, Per2, Per3*, *Bmal1*, *Clock, Cry1, Cry2, Bmal, Rev-ervA, CK1 d/e,* and *glycogen synthase kinase 3-b (GSK3ß*) (Ebisawa et al., 2001; Gietzen & Virshup, 1999; Jones et al., 1999; Takano et al., 2004; Toh et al., 2001; Vanselow et al., 2006). Currently, the markers of circadian rhythms are considered to be the profiles of plasma melatonin, cortisol, and core body temperature (Tomoda, Miike, Yonamine, Adachi, & Shiraishi, 1997). However, even if these markers show normal rhythmic patterns, certain patients suffer from circadian rhythm sleep disorders and indeterminate symptoms, suggesting that these markers may not be reliable for the diagnosis of circadian rhythm sleep disorders.

Presumably, autonomic and metabolic dysfunction causing sleep disturbance may be related to the *hPer2* phase shift because of chronobiological abnormality. Results of a previous study indicate that such disturbances might be related closely to the desynchronization of biorhythms, particularly the circadian rhythm of body temperature and the sleep–wake rhythm (Tomoda, Jhodoi, & Miike, 2001; Tomoda et al., 2000). Previous and present results suggest that sleep deprivation may originate from a dysfunctional network of brain areas related to the circadian rhythm and peripheral nervous system involved in the autonomic nervous system including cardiac function and gastrointestinal digestion. However, dysregulation of the circadian rhythm is neither the only nor the dominant factor in the pathogenesis of such conditions. Immunological, autonomic, and neuroendocrine abnormalities might be mutually dependent and reinforcing factors. More studies must be done to elucidate this mechanism and to reveal the relation between clock gene expression in the suprachiasmatic nucleus and the peripheral blood cells. Furthermore, additional study of a larger series of cases will elucidate the usefulness of this technique.
