Diagnostic pitfalls in children with sleep disorders - Wiley Online Library

Acta Pædiatrica ISSN 0803–5253

CLINICAL OBSERVATION

Diagnostic pitfalls in children with sleep disorders: two cases with hypersomnia Kutluhan Yilmaz ([email protected])1 , Meral Uyar2 , Hilal Adaletli3 , Ayse Kilincaslan4 1.Department of Pediatrics, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey 2.Department of Pulmonary Diseases, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey 3.Department of Child and Adolescent Psychiatry, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey 4.Child and Adolescent Psychiatry Clinic, Gaziantep Children’s Hospital, Gaziantep, Turkey

Keywords Hypersomnia, Kleine–Levin syndrome, Narcolepsy, Sleep disorders Correspondence ¨ Doç. Dr. Kutluhan YILMAZ, Gaziantep Universitesi, ¨ Tıp Fakultesi, Çocuk Sa˘glı˘gı ve Hast. ABD, Çocuk ¨ Norolojisi BD, Gaziantep, Turkey. Tel: +90 342 360 6060 | Fax: +90 342 360 3928 | Email: [email protected] Received 2 January 2008; Revised 22 May 2008; accepted 21 July 2008. DOI:10.1111/j.1651-2227.2008.00991.x

Abstract Sleep disorders are common in children, yet several clinical pitfalls give rise to the unrecognition or improper management of those children. Here, we present diagnostic difficulties in two adolescents with narcolepsy and Kleine–Levin syndrome. The first patient was a 12-year-old girl who had been given Na-valproate for nearly a year because hypersomnia was initially perceived as unconsciousness periods of epileptic spells, and later attributed to the antiepileptic drug. The other patient was a 14-year-old boy who had been managed as a specific psychiatric disorder for several months despite the characteristic symptoms of Kleine–Levin syndrome (hypersomnia, hyperphagia, hypersexuality, behavioural and cognitive dysfunction). Both cases emphasize that sleep disorders could be manifested with various clinics and that there are several diagnostic challenges in children. Conclusion: Sleep medicine needs to be given larger role in both training curriculum and post-graduate education for paediatricians.

INTRODUCTION Sleep problems are common in children, and have various clinical faces, one of which is hypersomnia or excessive daytime sleepiness (EDS)(1–3). However, many paediatricians have significant difficulties in the recognition of both EDS and the other sleep-related symptoms. Therefore, many children might have been undiagnosed or mislabelled. Here, we report two patients with narcolepsy and Kleine– Levin syndrome (KLS). These diseases are rare (incidences, 2–5/100 000 in narcolepsy; less frequent in KLS) but important illnesses because they are the main diseases of the primary sleep disorders with hypersomnia. While reporting these rare cases, we also summarize potentially diagnostic challenges in such diseases, and aim to take attention to paediatric sleep medicine. CASES Case 1, a 12-year-old girl, was referred to our paediatric electroencephalography (EEG) laboratory. The note written by the referring clinician took our attention, which stated that she had unconsciousness attacks lasting from several minutes to nearly an hour, and then we informed the clinician about our wish to evaluate the patient. On the admission, her major complaint was sleeping attacks in unsuitable conditions such as talking to someone or eating something. Her initial symptom was an unconsciousness attack, which she slumped down and remained unresponsive to tactile and verbal stimuli at school a year ago. This repeated several times, which resulted in frequent visits to the emergency ward, and that Na-valproate treatment was started. The dose

of Na-valproate had been increased because of the worsening of her symptoms, and hypersomnia had become the major complaint since then. The referring clinician thought that hypersomnia was secondary to the antiepileptic drug. The patient also told us that she felt a sensation of weakness in her body as if falling down when being teased by her friends. Physical examination and awake EEG recording revealed no abnormality. Her score at the Epworth sleepiness scale was 21, which suggested EDS. Polysomnography (PSG) revealed shortened sleep-onset latency (2 min), early onset of rapid eye movement (REM) sleep (5 min) and fragmentation of the nocturnal sleep. Multiple sleep latency test (MSLT) demonstrated shortened mean sleep latency (3 min) and two sleep-onset REM periods (SOREMPs). Blood tests including thyroid hormones and cranial magnetic resonance imaging (MRI) showed no abnormality. Finally, the findings suggested the diagnosis of narcolepsy with cataplexy, rather than epilepsy or drug side effect. Case 2, a 14-year-old boy, was referred due to behavioural abnormalities, cognitive difficulties and hypersomnia. He had an operation for an enlarged inguinal lymph node emerging 1 week after a few days of fever. Two days after the uneventful operation, improper smiling, mimics and gestures, unreactivity/misreactivity to conversations, restlessness and masturbation with no social inhibition emerged. His physician gave olanzapine (5 mg/day). A week later, excessive sleeping and eating were noted additionally. He was sleeping all day long excluding the time for feeding, and gained nearly 10 kg in a month. Because the symptoms did not improve, olanzapine treatment (10 mg/day) was changed to carbamazepine (600 mg/day) first, and later

C 2008 The Author(s)/Journal Compilation C 2008 Foundation Acta Pædiatrica/Acta Pædiatrica 2008 97, pp. 1749–1757

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the patient was referred to our hospital. We diagnosed the patient as KLS due to the symptoms of hypersomnia, hyperphagia, hypersexuality, behavioural and cognitive dysfunction and normal results in the physical examination, blood chemistry tests, awake EEG and cranial MRI. After blood level of carbamazepin reached to 10.17 (8–12 μg/mL), the symptoms improved. That symptomatic period lasted for 2 months. Despite our plan to perform PSG during the symptomatic period, the patient improved just before the PSG, and PSG revealed no abnormality. Another episode of mildly increased daytime sleepiness, dullness and cognitive difficulties occurred 3 months later. After lithium was added to carbamazepine, the symptoms improved gradually in a week. Three more episodes lasting for 2–7 days were observed in the following 12 months. The patient expressed a few days of itching with no apparent skin problem before these episodes.

DISCUSSION Narcolepsy is a disorder characterized by EDS that is associated with cataplexy and other REM sleep phenomena such as sleep paralysis and hallucinations (4). EDS is the most invariant symptom of narcolepsy, however, the most reliable marker is cataplexy. Cataplexy is a sudden loss of bilateral muscle tone, leading to falling down, face weakness or jaw/head drops, which is often provoked by emotional stimuli such as laughter, anger, elation or surprise. Consciousnesses, respiration and ocular motility are not affected. Hallucinations or paralysis occur either at the onset of sleep or during awakening from sleep. Clinical diagnosis of narcolepsy should be confirmed with nocturnal PSG followed by daytime MSLT (4,5). MSLT measures sleep onset time and REM sleep onset time, and so reveals both the tendency of falling asleep and early-onset REM sleep (i.e. SOREMP) in narcolepsy. In addition, decreased cerebrospinal fluid hypocretin-1 concentration is a highly specific but moderately sensitive finding. Approximately 85– 100% of the patients with narcolepsy and cataplexy are positive for HLA DQB1∗ 0602. Nevertheless, it is not diagnostic because it is positive in nearly one-fourth of the general population (4,5). Kleine–Levin syndrome is another primary sleep disease associated with EDS, which occurs mainly in adolescent males. Hypersomnia emerges episodically, lasting from 1–2 days to several weeks, and is characteristically combined with mental disturbances (such as concentration, attention and memory defects, abnormal speech and confusion) and abnormal behaviours (such as compulsive hyperphagia and hypersexuality) (6). Nearly one-third of the patients have been associated with a history of infection. Symptomatic periods seem to be associated with reversible thalamic hypoperfusion (7). Both KLS and narcolepsy might be associated with congenital or acquired organic cerebral disorder as well (6,8). Because sleep problems are common in children, and mostly occur temporarily, several clinicians underestimate sleep-related complaints and do not evaluate sleep. This tendency would result in overlooking primary seep disorders

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as well as temporary sleep problems. Besides this tendency, sleep problems frequently present with indirect symptoms in children, and therefore, many children with sleep problems experience incorrect or late diagnoses. The present cases exemplify such difficulties and their undesirable consequences. For instance, many clinicians assume that narcolepsy is an adult illness. However, the first symptom in 1/3–1/2 of the cases emerges in childhood (9). The clinical diagnosis of narcolepsy presenting with the classical tetrad of symptoms is straightforward. But, all four symptoms do not always coexist, as seen in Case 1. Moreover, recognizing hypersomnia might not be straightforward in children. EDS might be considered as normal daytime naps in children younger than 4– 5 years of age. Children express their subjective experience or symptoms with words pertaining more to their cognitive or emotional state such as ‘bored’, ‘cranky’ or ‘sad’. EDS occurs in only boring monotonous situations requiring no active participation in milder cases, or it might be combined with automatic behaviours and semiconscious continuation of activity in more severe cases, all of which might lead to unrecognizing EDS. Another clinical pitfall is that increased sleep need is likely to be manifested with indirect symptoms in children. During the sleepiness episodes, children might demonstrate motor restlessness or paradoxical overactivity in an attempt to self-stimulate, emotional liability, irritability and aggression, rather than EDS. These symptoms might be misinterpreted as laziness, attention deficit/hyperactivity disorder or behavioural disorder. Hypersomnia might also be mistaken with some other symptoms such as fatigue, unconsciousness or encephalopathy (10,11). Similarly, Case 1 had been given epilepsy treatment for nearly a year because hypersomnia was initially perceived as unconsciousness of epileptic fits and later attributed to antiepileptic treatment. Regarding the other narcolepsy symptoms, cataplexy might be the initial symptom and present with repetitive bruises or parental label of clumsiness (12). It should also be considered in the differential diagnosis of drop attacks. Hallucinations in children with narcolepsy might be attributed to dreams or normal nighttime fears and illusions, or to a psychiatric disorder. As for KLS, its characteristic clinical picture is recurrent spells of hypersomnia, hyperphagia, and hypersexuality, as seen in Case 2. Despite this characteristic triad, misinterpretation of these interesting symptoms would not be surprising if KLS is not a known disease by clinician. Due to behavioural abnormalities, hypersomnia might be considered as a part of a specific psychiatric disorder, rather than a primary sleep disorder. Similarly, Case 2 had been managed without taking the primary sleep disorders into consideration for several weeks. Some other interesting symptoms such as sweating and acrocyanosis have also been noted in KLS. Itching was the predictive symptom in our case. They are presumably related to autonomic dysfunction. In summary, there are several clinical pitfalls in the recognition of children with sleep disorders. In order to prevent undesirable consequences, clinicians need to obtain a basic sleep history from every child, regardless of his/her presenting symptom. They need to be cautious for indirect or


Aviner et al.

Langerhans cell histiocytosis in a premature baby

confusing symptoms as well. Otherwise wrong or late diagnoses would be inevitable.

References 1. Lamberg L. Pediatric sleep medicine comes of age. JAMA 2005; 293: 2327–9. 2. Spruyt K, O’Brien LM, Cluydts R, Verleye GB, Ferri R. Odds, prevalence and predictors of sleep problems in school-age normal children. J Sleep Res 2005; 14: 163–76. 3. Millman RP, Working Group on Sleepiness in Adolescents/ Young Adults; AAP Committee on Adolescence. Excessive sleepiness in adolescents and young adults: causes, consequences, and treatment strategies. Pediatrics 2005; 115: 1774–86. 4. Wise MS, Lynch J. Narcolepsy in children. Semin Pediatr Neurol 2001; 8: 198–206. 5. Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet 2007; 369: 499–511.

6. Arnulf I, Zeitzer JM, File J, Farber N, Mignot E. Kleine-Levin syndrome: a systematic review of 186 cases in the literature. Brain 2005; 128: 2763–76. 7. Huang YS, Guilleminault C, Kao PF, Liu FY. SPECT findings in the Kleine-Levin syndrome. Sleep 2005; 28: 955–60. 8. Yoshikawa S, Suzuki S, Kanbayashi T, Nishino S, Tamai H. Hypersomnia and low cerebrospinal fluid hypocretin levels in acute disseminated encephalomyelitis. Pediatr Neurol 2004; 31: 367–70. 9. Ohayon MM, Ferini-Strambi L, Plazzi G, Smirne S, Castronovo V. How age influences the expression of narcolepsy. J Psychosom Res 2005; 59: 399–405. 10. Hood BM, Harbord MG. Paediatric narcolepsy: complexities of diagnosis. J Paediatr Child Health 2002; 38: 618–21. 11. Macleod S, Ferrie C, Zuberi SM. Symptoms of narcolepsy in children misinterpreted as epilepsy. Epileptic Disord 2005; 7: 13–7. 12. Guilleminault C, Pelayo R. Narcolepsy in prepubertal children. Ann Neurol 1998; 43: 135–42.

Langerhans cell histiocytosis in a premature baby presenting with skin-isolated disease: case report and literature review Shraga Aviner ([email protected])1,2 , Meir Ronen2,3 , Daniel London2,4 , Ana Tobar5,6 , Shmuel Zangen2,7 1.Department of Pediatrics, The Barzilai Medical Center, Ashkelon, Israel 2.Faculty of Health Sciences, The Ben-Gurion University of the Negev, Beer-Sheva, Israel 3.Department of Dermatology, The Barzilai Medical Center, Ashkelon, Israel 4.Radiology Department, The Barzilai Medical Center, Ashkelon, Israel 5.Pathology Department, Rabin Medical Campus, Petach Tikva, Israel 6.Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel 7.Neonatal Intensive Care Unit, The Barzilai Medical Center, Ashkelon, Israel

Keywords Gastrointestinal tract, Langerhans cell histiocytosis, Premature baby Correspondence Shraga Aviner, M.D., Ph.D., Pediatric Day Care Center, The Barzilai Medical Center, 2 Hahistadrut Street, Ashkelon 78278, Israel. Tel: +972-8-674-6118 | Fax: +972-8-674-5165 | Email: [email protected] Received 29 April 2008; revised 21 July 2008; accepted 24 July 2008.

Abstract Langerhans cell histiocytosis (LCH) in premature babies is extremely rare as is a vesicular skin rash, while gastrointestinal involvement is associated with a poor outcome. We report a case of LCH in a premature baby presented with isolated vesiculo-papulo-macular skin lesions and insidiously developed gastrointestinal symptoms, haematological and severe pulmonary involvement. We also reviewed a few cases of LCH in premature babies in the English language medical literature. LCH in preterm babies appears to be a severe systemic disease, usually lethal in-utero or post delivery. Conclusion: Careful observation should be applied to newborns with skin-only Langerhans cell histiocytosis in order to identify in time progression to potentially fatal systemic disease.

DOI:10.1111/j.1651-2227.2008.00999.x

INTRODUCTION LCH is regarded as clonal accumulation and proliferation of abnormal bone marrow-derived dendritic cells. The infiltrates typical for the disease may be found in many organs to different extents, thus implicating a wide range of clinical presentations. It may affect any age group with a peak incidence in children aged 1–4 years. The course of the disease is unpredictable, ranging from spontaneous regression and resolution to rapid deterioration and progression to death, or recurrences and convalescent periods. Patients with localized disease need minimum or even no treatment, whereas

patients with multiorgan disease, more frequent in young children, might benefit from cytotoxic drugs and steroids. A special form termed congenital self-healing reticulohistiocytosis describes neonates with isolated skin lesions with excellent outcome; they do not need treatment. A careful search of the medical literature revealed only three cases of documented LCH onset in premature babies. We reported a case of LCH in a preterm baby, presented with isolated skin lesions and developed severe systemic disease. We also reviewed a few cases of LCH in premature babies in the English language medical literature.


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