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Peripheral perfusion during septic shock increase blood pressure was unclear but, based on the ability of packed red blood cells to increase MAP and skin blood flow, it was suspected that relative hypovolemia prevented noradrenaline from increasing blood pressure. The apparent difference between the effects of volume expanders (i.e. 5% albumin and packed red blood cells) is explained by differences in the stability of these products within the blood vessels. Another possible explanation, however, is that vasoconstriction prior to the use of volume expander supported the effect of the volume expander by reducing the volume of the peripheral vascular bed and/or by decreasing capillary leakage. All of these observations must be confirmed by simultaneously measuring systemic blood flow, blood pressure and skin blood flow within larger studies. Although an accurate method of determining the effect of vasoactive drugs on the peripheral circulation in real time would be invaluable, no method or marker has previously been established to detect the changes in vasoregulation in neonates. Cardiac index and systemic vascular index (which are calculated from the MAP and cardiac output) have been previously used to evaluate abnormal vasoregulatory changes in children with septic shock.8 In neonates, however, shunt through the patent ductus arteriosus and foramen ovale makes it difficult to appropriately measure cardiac output and to calculate systemic vascular resistance. Capillary refill time also plays a role in the management of the septic shock,4 but this parameter is likely insufficient for detection of slight changes in peripheral blood flow. Recently developed orthogonal polarization spectral imaging techniques enable direct measurement of vessel diameter and functional capillary density,9,10 and can be used to assess vasoregulatory changes in neonates with septic shock. That method, however, is not suitable for prolonged and continuous monitoring. In contrast, continuous and real-time measurement of the skin blood flow using laser Doppler apparatus can detect the vasoregulatory changes induced by noradrenaline and facilitate determination of the optimal therapeutic dose of the drug. No previous study has shown direct evidence of the effects of vasoactive drugs, and we assume that studies using this technique in large subject groups

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would help to elucidate the mechanism of action of vasoactive drugs.

Acknowledgments This research was supported by a H25 Saitama Medical University Internal Grant. The authors have no conflicts of interest to disclose.

References 1 James LW, Hector R. Pathophysiology and treatment of septic shock in neonates. Clin. Perinatol. 2010; 37: 439–79. 2 Ishiguro A, Suzuki K, Sekine T et al. Effect of dopamine on peripheral perfusion in very-low-birth-weight infants during the transitional period. Pediatr. Res. 2012; 72: 86–9. 3 Ishiguro A, Suzuki K, Sekine T et al. Skin blood flow as a predictor of intraventricular hemorrhage in very-low-birth-weight infants. Pediatr. Res. 2014; 75: 322–7. 4 Brierley J, Carcillo JA, Choong K et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit. Care Med. 2009; 37: 666–88. 5 Silveira RC, Giacomini C, Procianoy RS. Neonatal sepsis and septic shock: Concepts update and review. Rev. Bras. Ter. Intensiv. 2010; 22: 280–90. 6 Barrington KJ. Hypotension and shock in the preterm infant. Semin. Fetal Neonatal Med. 2008; 13: 16–23. 7 Evans N, Seri I. Cardiovascular compromise in the newborn infant. In: Taeusch HW, Ballard RA, Gleason CA (eds). Avery’s Diseases of the Newborn, 8th edn. WB Saunders, Philadelphia, PA, 2004; 398–409. 8 Brierley J, Peters MJ. Distinct hemodynamic patterns of septic shock at presentation to pediatric intensive care. Pediatrics 2008; 122: 752–9. 9 Weidlich K, Kroth J, Nussbaum C et al. Changes in microcirculation as early markers for infection in preterm infants: An observational prospective study. Pediatr. Res. 2009; 66: 461–5. 10 Top AP, Ince C, de Meij N, van Dijk M, Tibboel D. Persistent low microcirculatory vessel density in nonsurvivors of sepsis in pediatric intensive care. Crit. Care Med. 2011; 39: 8–13.

Case of early childhood-onset narcolepsy with cataplexy: Comparison with a monozygotic co-twin Hiromichi Ito, Kenji Mori, Tatsuo Mori, Aya Goji and Shoji Kagami Department of Pediatrics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan Abstract

We describe here a rare case of early childhood-onset (5 years of age) narcolepsy. This case was interesting because of the ability to compare the patient’s symptoms to the condition of her healthy monozygotic co-twin sister. The only environmental difference between the co-twins was head injury, which may be associated with the presence of

Correspondence: Hiromichi Ito, MD PhD, Tokushima University Hospital, 3-18-15, Kuramoto, Tokushima 770-8503, Japan. Email: michiito@ tokushima-u.ac.jp Received 5 March 2013; revised 4 November 2013; accepted 20 March 2014. doi: 10.1111/ped.12377

© 2014 Japan Pediatric Society

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H Ito et al. narcolepsy. The co-twin was extroverted, sociable, reliable, and dexterous. In contrast, the patient could be described as introverted, gentle, honest and persevering, but was weak at conversation, assessment of a situation, memory, planning, activity (she was inactive), a sense of time, understanding of an analog clock, operating efficiency, and physical education (due to obesity). The sisters showed the same degree of appetite and dexterity with their fingers. Narcolepsy is often under-recognized or underdiagnosed, especially when the onset occurs in childhood. When we observe preschoolers with excessive daytime sleepiness, we should consider the possibility of narcolepsy with cataplexy.

Key words dyssomnia, excessive daytime sleepiness, narcolepsy with cataplexy, orexin, twin.

Narcolepsy with cataplexy is dyssomnia characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Disrupted nocturnal sleep, automatic behavior, and obesity are adjunct symptoms. Dysfunction of the orexin system is considered to be the main cause of narcolepsy with cataplexy. The onset of narcolepsy with cataplexy usually occurs during the teenage years and young adulthood and it persists throughout the patient’s lifetime. Narcolepsy with cataplexy is often under-recognized or underdiagnosed, especially when its onset is in childhood. We describe here a rare case of early childhood-onset (5 years of age) narcolepsy with cataplexy. The patient was not diagnosed accurately for 2 years. This case highlights the fact that one should consider narcolepsy with cataplexy in preschoolers who show excessive daytime sleepiness.

Case report A 7-year-old girl was referred to our hospital because of daily excessive daytime sleepiness. She fell from her bed and bruised her head twice at 10 months of age, and showed no sequelae at that time. Her monozygotic co-twin sister was healthy. Monozygosity was confirmed by fetal ultrasonography findings (one chorion, two amnion twins). They had also resembled each other very closely. There were no signs of fetal asphyxia, and the gestation was normal. The patient often napped and showed excessive weight at 5 years of age. At 6 years of age, her excessive daytime sleepiness worsened. She even slept in class, and while playing and eating meals. She also had somniloquence. At night, she showed light sleep and frequent arousal. She was apt to forget and fall behind in her schoolwork. She also showed cataplexy when she laughed. On her first visit to our hospital at 7 years of age, her body height was 126.1 cm (reference value 121.2 cm) and her bodyweight was 33.2 kg (reference value 23.6 kg), which suggested that she was obese. Her co-twin sister (co-twin) was 127.0 cm and 26.0 kg. The patient did not show any other neurological findings, such as developmental delay, regression, hypotonia, abnormal deep tendon reflex, abnormal personality, sleep paralysis, or hypnagogic hallucinations. Blood examination (complete blood count and various other biochemical profiles) was within normal limits and human leukocyte antigen DR2 was positive. The results of brain magnetic resonance imaging were normal. The level of orexin in the cerebrospinal fluid was less than 40 pg/mL (reference value: 250–300 pg/mL). A polysomnogram at 7 years of age showed a © 2014 Japan Pediatric Society

predominance of sleep stage I and rapid eye movement period, frequent arousal, six episodes of the sleep-onset rapid eye movement period, and disrupted nocturnal sleep at night (Fig. 1). Epileptiform discharges were not present. She satisfied all of the criteria from A to D in the diagnostic criteria of narcolepsy in the International Classification of Sleep Disorders – 2nd edition,2 which suggested that she had narcolepsy with cataplexy. The tendency toward obesity compared to her co-twin was an adjunct finding to support the diagnosis. As she did not show abnormal neurological symptoms (except for excessive daytime sleepiness and cataplexy) or laboratory results, we gave a diagnosis of idiopathic narcolepsy. She was given methylphenidate hydrochloride and achieved good control of excessive daytime sleepiness. However, 3 years later, she still exhibited poor school performance, forgetfulness, and obesity. She showed marked increases in both bodyweight and body height after the onset of narcolepsy (Fig. 2). The Wechsler Intelligence Scale for Children – 3rd edition (WISC-III)3,4 at 8 years of age revealed a verbal intelligence quotient (VIQ) of 109, a performance intelligence quotient (PIQ) of 129, and a full-scale intelligence quotient (FIQ) of 121, which suggested a normal FIQ and a significant difference between VIQ and PIQ. There were also significant differences among the subtest scores (the scores for the information, similarities, arithmetic, vocabulary, comprehension, digit span, picture completion, coding, picture arrangement, block design, object assembly, symbol search, and maze subtests were 6, 11, 9, 6, 15, 10, 12, 10, 6, 11, 13, 6, and 13, respectively). The Kaufman Assessment Battery for Children (K-ABC)5,6 showed a successive processing score of 86, a simultaneous processing score of 113, an overall cognitive processing score of 101, and acquirement score of 77; the score for acquirement was significantly lower than that for overall cognitive processing, and there was a significant difference between the scores for successive and simultaneous processing. She showed a very slow processing speed on WISC-III and K-ABC. Her co-twin was extroverted, sociable, reliable, and dexterous. In contrast, the patient could be described as introverted, gentle, honest and persevering, but was weak at conversation, assessment of a situation, memory, planning, activity (she was inactive), a sense of time, understanding of an analog clock, operating efficiency, and physical education (due to obesity). The sisters showed the same degree of appetite and dexterity with their fingers.

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Awake REM Stage I Stage II Stage III Stage IV

(hours) Awake REM Stage I Stage II Stage III Stage IV

(hours) Fig. 1 Polysomnogram at 7 years of age. This polysomnogram could be interpreted as a predominance of sleep stage I and rapid eye movement (REM) period, frequent arousal, six episodes of the sleep-onset rapid eye movement period, and disrupted nocturnal sleep at night. The X-axis represents hours.

Discussion Orexin neurons widely project from the hypothalamus to various brain regions, such as the cerebral cortex and brainstem, and play a role in the sleep–wake pattern, feeding, metabolism, and higher brain function. Dysfunction of the orexin system, especially a loss of orexin neurons in the lateral hypothalamus, is considered to be the main cause of narcolepsy with cataplexy. Lin et al. determined that canine narcolepsy is caused by disruption of the orexin receptor 2 gene.7 It has been reported that orexin-knockout mice exhibit a phenotype that is strikingly similar to that in human narcolepsy patients.8 Orexin is undetectable in seven of nine patients with narcolepsy, which indicates abnormal orexin transmission.9 In an autopsy study, a reduced number of orexin neurons was found in human narcolepsy.10 However, mutations in orexin-related genes are rare in humans. Peyron et al. performed a mutation screening for orexin, orexin receptor 1 and orexin receptor 2 in 74 patients, and found only one case of prepro orexin mutation.11 Neural loss could have an autoimmune origin, as most patients have human leukocyte antigen DR2 or DQ1, which predisposes individuals to the disorder. This case was very interesting because of the ability to compare the patient’s symptoms to the condition of her co-twin.

Various higher brain dysfunctions in this patient, such as the fact that she was very weak with regard to school performance, conversation, assessment of a situation, memory, planning, activity, a sense of time, understanding an analog clock, operating efficiency, etc., and obesity may have been due to impairment of the orexin system because these symptoms were not seen in the co-twin. Although the co-twin was not evaluated by the WISC-III or K-ABC, the significant difference between the patient’s VIQ and PIQ may also have been due to impairment of the orexin system. There have been a few reports on higher brain function in narcolepsy. Dorris et al. reported that while narcolepsy is associated with a normal intelligence quotient, there is a significant difference between VIQ and PIQ.12 They also reported that narcolepsy patients have both VIQ > PIQ and VIQ < PIQ patterns, which suggests that there is no specific pattern of higher brain function. Ha et al. reported that narcolepsy patients have deficits in the efficiency of attention allocation and execution.13 Indeed, our patient satisfied these conditions. She showed poor knowledge and vocabulary, and a very slow processing speed on WISCIII. On the other hand, she showed a good PIQ, comprehension, object assembly, and maze scores on WISC-III. K-ABC showed poor acquirement and successive processing scores. Her very slow processing speed may be related to her poor performance in © 2014 Japan Pediatric Society

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H Ito et al.

Fig. 2 The patient showed marked increases in both bodyweight and body height after the onset of narcolepsy.

successive processing. Her poor school performance may also be due to her very slow processing speed. Some unknown higher brain dysfunction may play a role, as her acquirement score was lower than her successive processing score. Obesity is a frequent complication in narcolepsy, but its cause is not fully clarified. A decrease in basal metabolism has been considered to be a possible cause.14 The fact that she was obese compared to her co-twin, despite their same degree of appetite, supports this opinion. With regard to the relation between sleep and obesity, there is a significant dose–response relation between a late bedtime or short duration of sleeping and childhood obesity.15 A short duration of sleeping could cause obesity through increased sympathetic activity, elevated cortisol secretion and decreased glucose tolerance.15 Narcolepsy is classified as hypersomnia; however, its essential pathophysiology is dysfunction of the maintenance of arousal due to dysfunction of the orexin system. It manifests as a frequent sleep–arousal rhythm in neonates, resulting in disrupted nocturnal sleep and excessive daytime sleepiness. Although a genetic predisposition is likely to be involved in the development of narcolepsy, the relatively low rate of concord© 2014 Japan Pediatric Society

ance in narcoleptic monozygotic twins (5/16) indicates that environmental factors also play a role in the development of this disease.16 Orellana et al. found that the proportion of narcoleptic subjects who reported life events in the year preceding the onset of narcolepsy was significantly greater than the proportion in control subjects.17 However, the nature of these possible environmental factors is not yet fully understood. Frequently cited factors include head trauma,18 sudden change in sleep/wake habits,17 major family events, major psychological stress, various infections, and immunization.19 The month of birth has also been proposed as a risk factor for narcolepsy; however, this proposal is controversial. A few studies have shown an excess number of March births, and a decreased number September births.20,21 In another study, there was a higher percentage of births in the first half of the year, and a lower percentage in the second half of the year.22 These results may provide clues to help identify specific environmental factors, such as infectious agents and temperature. However, Donjacour et al. showed that the birth month did not affect the occurrence of narcolepsy with cataplexy in a study of 307 cases.23 In the present case, the only environmental difference between the co-twins was head injury (twice), which may be associated with the presence of narcolepsy. The onset of narcolepsy with cataplexy usually occurs during the teenage years and young adulthood, and this patient is a rare case of early childhood-onset (5 years of age) narcolepsy with cataplexy. Differential diagnoses include secondary hypersomnia due to dysfunction of the orexin system (for example, triggered by a brain tumor), epilepsy, attention deficit (hyperactivity) disorder, depression and obstructive sleep apnea, etc. Unfortunately, narcolepsy patients are often considered to be simply lazy. Excessive daytime sleepiness might be mistaken for epileptic absences, and cataplexy might be confused with a variety of seizure types (astatic seizure, etc.). A misdiagnosis can have a negative influence on patients, and early diagnosis and treatment can greatly improve their quality of life. When we observe preschoolers with excessive daytime sleepiness, we should consider the possibility of narcolepsy with cataplexy.

Acknowledgments We thank Takashi Kanbayashi (Department of Psychiatry, Akita University, Itabashi, Akita, Japan) for examining the orexin concentration in spinal fluid.

References 1 Ito H, Mori K, Mori T, Kagami S. A case of early childhood-onset narcolepsy. J. Jpn. Pediatr. Soc. 2012; 116: 1728–32. 2 American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic & Coding Manual, 2nd edn. American Academy of Sleep Medicine, Darien, 2005. 3 Wechsler D. Wechsler Intelligence Scale for Children-Third Edition (WISC-III). Psychological Corporation, San Antonio, TX, 1991. 4 Wechsler D. Wechsler Intelligence Scale for Children-Third Edition (WISC-III). (Japanese version) (translated by WISC-III (Japanese version) Publishing Committee). Nihon Bunka Kagakusha Co., Ltd., Tokyo, 1998. 5 Kaufman AS, Kaufman NL. K-ABC Interpretive Manual. American Guidance Service, Circle Pines, MN, 1983.

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Early childhood-onset narcolepsy 6 Matsubara T, Fujita K, Maekawa H, Ishikuma T. Japanese Kaufman Assessment Battery for Children. Maruzen Publishing Co., Ltd., Tokyo, 1993. 7 Lin L, Faraco J, Li R et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98: 365–76. 8 Chemelli RM, Willie JT, Sinton CM et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999; 98: 437–51. 9 Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355: 39–40. 10 Thannickal TC, Moore RY, Nienhuis R et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000; 27: 469– 74. 11 Peyron C, Faraco J, Rogers W et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat. Med. 2000; 6: 991–7. 12 Dorris L, Zuberi SM, Scott N, Moffat C, McArthur I. Psychosocial and intellectual functioning in childhood narcolepsy. Dev. Neurorehabil. 2008; 11: 187–94. 13 Ha KS, Yoo HK, Lyoo IK, Jeong DU. Computerized assessment of cognitive impairment in narcoleptic patients. Acta Neurol. Scand. 2007; 116: 312–16. 14 Chabas D, Foulon C, Gonzalez J et al. Eating disorder and metabolism in narcoleptic patients. Sleep 2007; 30: 1267–73.

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15 Sekine M, Yamagami T, Handa K et al. A dose-response relationship between short sleeping hours and childhood obesity: results of the Toyama Birth Cohort Study. Child Care Health Dev. 2002; 28: 163–70. 16 Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998; 50: S16–22. 17 Orellana C, Villemin E, Tafti M, Carlander B, Beset A, Billiard M. Life events in the year preceding the onset of narcolepsy. Sleep 1994; 17: S50–3. 18 Lankford DA, Wellman JJ, O’Hara C. Posttraumatic narcolepsy in mild to moderate closed head injury. Sleep 1994; 17: S25– 8. 19 Poli F, Overeem S, Lammers GJ et al. Narcolepsy as an adverse event following immunization: case definition and guidelines for data collection, analysis and presentation. Vaccine 2013; 31: 994– 1007. 20 Okun ML, Lin L, Pelin Z, Hong S, Mignot E. Clinical aspects of narcolepsy-cataplexy across ethnic groups. Sleep 2002; 25: 27– 35. 21 Dauvilliers Y, Carlander B, Molinari N et al. Month of birth as a risk factor for narcolepsy. Sleep 2003; 26: 663–5. 22 Dahmen N, Tonn P. Season of birth effect in narcolepsy. Neurology 2003; 61: 1016–17. 23 Donjacour CE, Fronczek R, LE Cessie S, Lammers GJ, Van Dijk JG. Month of birth is not a risk factor for narcolepsy with cataplexy. J. Sleep Res. 2011; 20: 522–5.

Spontaneous pneumomediastinum as a complication in human bocavirus infection Sevgi Pekcan,1 Bahar Gokturk,1 Hasibe Uygun Kucukapan,1 Ugur Arslan2 and Duygu Fındık2 Department of Pediatrics, Konya University Meram Faculty of Medicine, Konya and 2Department of Clinical Microbiology, Selcuk University Selcuklu Faculty of Medicine, Selcuk, Turkey

1

Abstract

The most common causes of spontaneous pneumomediastinum (SPM) in children are asthma attack and respiratory tract infection. Here, we describe a case of SPM in a human bocavirus-infected 2-year-old boy with bronchiolitis.

Key words child, human bocavirus infection, spontaneous pneumomediastinum.

Human bocavirus (HBoV) was first described by Allander et al. in September 2005. It belongs to the family Parvoviridae and, after parvovirus B19, it is the second virus in this family to be associated with human disease.1 HBoV infection has been detected frequently in young children around the age of 2 years with acute diseases of the respiratory tract and gastroenteritis. Pneumomediastinum, which is also known as mediastinal emphysema, is usually secondary to alveolar rupture in the Correspondence: Bahar Gokturk, MD, Division of Immunology and Allergy, Department of Pediatrics, Necmettin Erbakan University Meram Faculty of Medicine, Beysehir yolu, 42080 Konya, Turkey. Email: [email protected] Received 22 January 2012; revised 1 May 2012; accepted 7 August 2014. doi: 10.1111/ped.12475

pulmonary interstitium, followed by dissection of gas towards the hilum and mediastinum. The events, which end with increase in alveolar and intrabronchial pressure, can cause pneumomediastinum and subcutaneous emphysema.2 Spontaneous pneumomediastinum (SPM) is uncommon in children and generally a benign condition. The most common causes of SPM in children are asthma attack and infection, and the sudden increase in intra-alveolar pressure during severe cough attacks causes peribronchial alveolar rupture.3 On radiology, vertical lucent streak along the left side of the heart and aortic arch, continuous diaphragm sign, lucent streak along the retrosternal, pericardiac and peritracheal areas, subcutaneous emphysema of the shoulder and neck can be detected. Spontaneous pneumomediastinum is generally benign and can be treated conservatively.3 Its clinical importance and © 2014 Japan Pediatric Society

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Case of early childhood-onset narcolepsy with cataplexy: comparison with a monozygotic co-twin.

We describe here a rare case of early childhood-onset (5 years of age) narcolepsy. This case was interesting because of the ability to compare the pat...
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