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Cases of Pediatric Narcolepsy After Misdiagnoses
Pediatric Neurology 47 (2012) 362e365
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Case Report
Cases of Pediatric Narcolepsy After Misdiagnoses Shilpa R. Kauta MD a, *, Carole L. Marcus MBBCh b a b
Sleep Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Sleep Center, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
article information
abstract
Article history: Received 8 June 2012 Accepted 1 August 2012
Narcolepsy is characterized by recurrent brief attacks of irresistible sleepiness. Signs can begin during childhood. However, diagnoses are frequently delayed by 10-15 years because of unfamiliarity with pediatric narcolepsy and variable presentations of its associated features (cataplexy, hypnagogic/hypnopompic hallucinations, and sleep paralysis). Therefore, patients may remain untreated during their formative years. Three children with narcolepsy who were initially misdiagnosed are described. Each child’s signs were initially related to depression, hypothyroidism, jaw dysfunction, or conversion disorder. However, after a multiple sleep latency test, the diagnosis of narcolepsy was established. All three patients were treated appropriately with stimulant medications, selective serotonin reuptake inhibitors, or sodium oxybate, and demonstrated positive responses. Although no definitive cure exists for narcolepsy, early recognition and appropriate symptomatic treatment with medications can allow affected children to improve quality of life and achieve normality, both academically and socially. Ó 2012 Elsevier Inc. All rights reserved.
Introduction
Coined by Gelineau in 1880, the term “narcolepsy” describes a pathologic condition characterized by recurrent brief attacks of irresistible sleepiness [1]. This disorder demonstrates a prevalence of approximately 1/2000, and causes significant impairment in those who are affected [2], including disabling daytime sleepiness, difficulty functioning at school or work, and depression. In addition to excessive daytime somnolence, narcolepsy can be associated with signs of cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations [3]. Narcolepsy has been linked to an extensive loss of hypothalamic neurons that produce hypocretin-1 and hypocretin-2 (also known as orexin-A and orexin-B). These hormones are sleep-wake and rapid eye movement sleepregulating neuropeptides [4]. They also exert control over appetite. When cerebrospinal fluid is tested in patients with narcolepsy, hypocretin 1 is low to undetectable. Many * Communications should be addressed to: Dr. Kauta; Hospital of the University of Pennsylvania Penn Sleep Center; 3624 Market Street, Suite 205; Philadelphia, PA 19104. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2012.08.005
patients with narcolepsy (more than 90%) also carry the human leukocyte antigen DQB1*0602 allele, but this allele does not need to be present for diagnostic purposes [3]. Initial signs of narcolepsy frequently present during childhood and adolescence. However, the tetrad of features (daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations) occurring together is extremely rare at a young age, thus impeding diagnosis. If these features (specifically cataplexy) are present, they may be atypical compared with adult presentations, and difficult to recognize. For instance, children may present with cataplexy that is unrelated to emotion [5]. As a result, the disorder can remain undiagnosed until patients are adults, up to 10-15 years after the onset of signs [6]. When a child presents with features of excessive daytime sleepiness, weight gain, episodic loss of muscle tone, and poor attention, pediatricians often think of depression, epilepsy, or endocrine problems. Narcolepsy is important to include in this differential diagnosis. Treatments are available to help these children improve their quality of life and allow them to achieve normality both academically and socially. To bring attention to this diagnosis, we present three patients with pediatric narcolepsy that was initially misdiagnosed.
S.R. Kauta, C.L. Marcus / Pediatric Neurology 47 (2012) 362e365
Case Reports Patient 1
The patient was a 9-year-old boy with signs of progressively worsening daytime sleepiness who was misdiagnosed with conversion disorder. Initially, he started taking naps and eventually could not function well in school. At the same time, he developed episodic muscle weakness with periods of ptosis and dysarthria, as well as a feeling of paralysis when he was playing video games. On a few occasions, he fell to the ground for a few seconds with no clear stimulus. None of these episodes were related to strong emotions. During some of these episodes, he progressed into sleep after the event. No history of hypnagogic hallucinations, sleep paralysis, or weight change was reported. Before being examined at the sleep clinic, he was hospitalized elsewhere for these signs. He underwent an extensive workup, including cerebrospinal fluid analysis and cranial magnetic resonance imaging. All results were unremarkable, and he was diagnosed with conversion disorder in the setting of his parents obtaining a divorce. His features continued to occur, and he was brought to a different hospital where he underwent repeated magnetic resonance imaging and cerebrospinal fluid analysis, which again produced unremarkable results. He was discharged with a plan for an outpatient overnight polysomnogram and a multiple sleep latency test. His overnight polysomnogram and multiple sleep latency test were consistent with severe narcolepsy (Table 1). His blood work tested positive for the human leukocyte antigen DQB1*0602 allele. Cerebrospinal fluid drawn during his previous hospitalization was subsequently checked for hypocretin levels, which proved to be reduced at 31.7 pg/mL (normal, 200 pg/mL). Based on these findings, he was diagnosed with narcolepsy with cataplexy, and began receiving modafinil for sleepiness and venlafaxine for cataplexy. On follow-up, he was much more awake and interactive. He was able to function normally in school, and observed a reduction in his cataplectic episodes and an improvement in nocturnal sleep quality. He did not report any side effects from the medications.
363
night, take a 1.5-hour nap during the day, and fall asleep during car rides. Despite her sleepiness, she was able to concentrate at school and maintain good grades. In addition to her sleepiness, she demonstrated periods of jaw dropping and tongue thrusting when she laughed. No hypnagogic hallucinations or episodes of sleep paralysis were reported. She was eventually referred to a sleep center at age 9 years, and a polysomnogram, multiple sleep latency test, and cranial magnetic resonance imaging were performed. These produced unremarkable results, with no evidence of narcolepsy or sleep-disordered breathing (Table 1). As a result, endocrine and orthodontic evaluations were pursued. She was diagnosed with hypothyroidism and treated appropriately, but with no resolution of her signs. By age 12 years, she exhibited a body mass index of 36.6 kg/m2 (95th percentile) and progressively became sleepier, with no clear diagnosis. She was evaluated by a speech pathologist for her tongue thrusting, and jaw surgery for her problems with jaw dropping was planned. Before her surgery, at age 13 years, she was referred to another sleep center, and a polysomnogram and multiple sleep latency test were performed. The results were consistent with severe narcolepsy (Table 1), and she was revealed to be human leukocyte antigen DQB1*0602-positive. She was diagnosed with narcolepsy with cataplexy (jaw dropping episodes), and began receiving modafinil. While receiving treatment, she was able to stay awake in school, but continued to experience problems with sleep fragmentation and jaw weakness. She also developed leg weakness when she was frightened. Therefore, she received sodium oxybate, in addition to modafinil, which reduced her daytime napping, improved her sleep quality at night, and decreased her episodes of cataplexy. In the setting of receiving sodium oxybate, she initially experienced enuresis once a month. Enuresis is a known side effect of the medication, and it resolved with fluid restriction. During the 2 years after the initiation of sodium oxybate, she was able to lose more than 25 kg and return to a normal body mass index for her age. Her weight loss was likely a result of the combination of her effort to lose weight, increased energy level, and a side effect of her medications. In conjunction with her medication regimen, the control of her daytime signs was dependent on receiving sufficient hours of sleep at night.
Patient 2 Patient 3
The second patient was a 7-year-old girl who developed daytime sleepiness and progressive weight gain. She was initially diagnosed with hypothyroidism and jaw dysfunction because of repetitive jaw-dropping episodes. At the onset of her features, she would sleep for 8 hours at
The third patient was a 9-year-old boy with restless sleep with multiple arousals and daytime drowsiness, originally diagnosed as attention deficit hyperactivity disorder and depression. He would not fall
Table 1. Patient characteristics, diagnostic findings, and treatments
Characteristics
Patient 1
Patient 2
Patient 3
Age at onset of signs Age at diagnosis Initial diagnosis
8 years 9 years Conversion disorder
Polysomnogram results
AHI, 0.5 events/hour EEG, normal
9 years 11 years ADHD Depression AHI, 0 events/hour EEG, normal
Multiple sleep latency test results
MSL, 4.3 minutes SOREMP, 3 of 4 naps
CSF hypocretin (normal, 200 pg/mL) Medications used
31.7 pg/mL Modafinil Venlafaxine None
7 years 12 years Hypothyroidism Jaw dysfunction 2004: AHI, 0 events/hour EEG, normal 2004: MSL, 17.6 minutes SOREMP, none N/A Modafinil Sodium oxybate Enuresis (resolved with
Side effects of medication
2008: AHI, 1 event/hour EEG, normal 2008: MSL, 1.4 minutes SOREMP, 4 of 4 naps
fluid restriction)
MSL, 2 minutes SOREMP, 4 of 4 naps 18 pg/mL Modafinil Methylphenidate None
Abbreviations: ADHD ¼ Attention deficit hyperactivity disorder AHI ¼ Apnea-hypopnea index (normal for children, <1.5 events/hour) CSF ¼ Cerebrospinal fluid EEG ¼ Electroencephalogram MSL ¼ Mean sleep latency (meets criteria for narcolepsy if 8 minutes) [3] N/A ¼ Not available SOREMP ¼ Sleep-onset rapid eye movement period (meets criteria for narcolepsy if two or more naps include sleep-onset rapid eye movement sleep after sufficient nocturnal sleep) [3]
364
S.R. Kauta, C.L. Marcus / Pediatric Neurology 47 (2012) 362e365
asleep in school, but would fall asleep immediately upon entering the car after school. He would also fall asleep while reading, watching television, and playing video games. He manifested no cataplexy, hypnagogic hallucinations, or sleep paralysis. He was diagnosed with attention deficit hyperactivity disorder and depression, and received methylphenidate and paroxetine. By age 11 years, he was significantly overweight, with a body mass index of 22.9 (95th percentile). When he was examined at the sleep clinic, he reported some improvement in his concentration during school while on treatment, but otherwise remained excessively sleepy during the day. An overnight polysomnogram and multiple sleep latency test were performed. The multiple sleep latency test results met the criteria for narcolepsy. However, he had slept for less than 6 hours during his polysomnogram preceding the multiple sleep latency test, and he was receiving psychotropic medications at the time of the study. Both of these factors affected the interpretation of the results (Table 1). As a result, cerebrospinal fluid hypocretin levels were tested to confirm the diagnosis, and were demonstrated to be reduced, at 18 pg/mL. With the diagnosis of narcolepsy, he discontinued methylphenidate and paroxetine, and received modafinil. His sleepiness was insufficiently controlled on this regimen, and as a result, methylphenidate was reinitiated, in addition to the modafinil. On these medications, significant improvement in his alertness and concentration occurred, with no reported side effects. During the next 6 years, control of his difficulties depended on his daily use of medications and proper sleep hygiene. Subsequent polysomnograms and the maintenance of wakefulness testing confirmed improved daytime wakefulness. However, his nocturnal sleep remained fragmented. He did not lose weight while on treatment, and he never developed signs of cataplexy, sleep paralysis, or hypnagogic hallucinations. Although he was intermittently monitored by a psychiatrist, he never required treatment for depression.
Discussion
Diagnosing narcolepsy in pediatric patients can be challenging. Key reasons include the unfamiliarity of the diagnosis among pediatricians, variable presentations compared with those of adults, and negative test results in early stages [7]. In addition, the sleepy child may take longer to receive the attention of teachers and parents than the hyperactive child. Rendering the diagnosis even more difficult, as demonstrated in patients 2 and 3, these children are occasionally able to maintain their function in school and become sleepy after they return home, where their parents may not be consider sleepiness a problem. Each of these three cases portrays examples of some of these issues, and also underscores the remarkable response to and benefit of treatment. Cataplexy, sleep paralysis, and hypnagogic hallucinations, i.e., the associated features of narcolepsy, are not always present in children manifesting narcolepsy, and when they are present, they can be difficult to identify. Cataplexy is a transient loss of muscle tone, usually in response to emotions such as surprise, fright, or laughter. This appearance of rapid eye movement atonia can range in severity from falling to the ground to buckling of the knees, or even just an internal sensation of weakness [8]. Sixty percent to 90% of patients with narcolepsy experience cataplexy, but the presentation of this feature can follow the onset of sleepiness by months to years [9]. Thus, children often do not present with cataplexy, and should be regularly asked about symptoms during follow-up, because treatment is different than with excessive daytime sleepiness alone. In addition, children frequently exhibit atypical cataplexy. For instance, patient 1 manifested cataplexy with no emotional triggers, and was misdiagnosed with
psychogenic behavior. Patient 2 also exhibited signs of cataplexy with jaw dropping that were atypical and led to an unnecessary plan for jaw surgery. In children, to obtain an accurate history for sleep paralysis and hypnagogic hallucinations can be difficult. Sleep paralysis is similar in etiology to cataplexy, with the inappropriate appearance of rapid eye movement atonia while the patient is awake. Patients are usually frightened by the inability to move when they awaken [9]. Hypnagogic hallucinations are realistic dreams or experiences of sound, image, or feeling that occur at sleep onset or while waking up (i.e., hypnopompic) [9]. In children, these hallucinations can assume simple forms (colored circles, images of animals, or people) and frequently occur with sleep paralysis [10]. As already mentioned, although the presence of these signs can be helpful in diagnosis, obtaining an accurate history of these abnormalities from a young child can be difficult. None of the patients in our case series reported these signs. Although the multiple sleep latency test is an adequate tool for diagnosis, it can be inconclusive in prepubertal children or when performed close to disease onset [7,11]. Early in the course of the disorder, patients may not demonstrate sleep-onset rapid eye movement periods. In addition, mean sleep latencies differ in children vs adults. On the multiple sleep latency test, the mean sleep latency for preadolescent children averages 19 1.6 minutes, in contrast to the 10-20 minute range considered normal for healthy adults [12,13]. This discrepancy may inappropriately cause a child with brief sleep latency, e.g., 11 minutes, to fall into the apparently normal range. Furthermore, at present, the same criteria for diagnosing narcolepsy during multiple sleep latency testing (sleep latency, 8 minutes) are used for both adults and children, despite the observed differences in their normative data. As revealed in patient 2 (Table 1), repeated testing and regular monitoring are essential to evaluating sleepy children with normal polysomnograms and multiple sleep latency tests, because significant daytime sleepiness is not normal in preadolescent children. Human leukocyte antigen typing, cranial magnetic resonance imaging, drug screening, and cerebrospinal fluid hypocretin levels (not yet commercially available) comprise additional tools to support or exclude a diagnosis of narcolepsy. In a retrospective evaluation of 51 children with narcolepsy, Aran et al. reported a striking weight gain (8-12 kg) within 6 months of the onset of signs in children [11]. The weight gain usually occurred after puberty, but when it occurred before puberty, an association with an earlier onset of puberty was frequently evident. This association may reflect greater hypothalamic dysfunction in narcolepsy patients with drastic weight gain and an early onset of puberty [11]. As observed in patient 2, this significant weight gain can cloud the signs of sleepiness in the process of diagnosis, and direct the patient to more of an endocrine evaluation rather than a sleep evaluation. After diagnosis, recognizing the relationship between narcolepsy and weight gain is important in counseling patients. They should be aware that weight gain is a manifestation of the disorder, and they should be encouraged to maintain healthy diets and regular exercise. They may benefit from weight management programs. In conclusion, we report on three cases of narcolepsy that were initially misdiagnosed. Narcolepsy can occur alone or
S.R. Kauta, C.L. Marcus / Pediatric Neurology 47 (2012) 362e365
with other common childhood disorders, with overlapping features such as obstructive sleep apnea, hypothyroidism, or depression. The evaluation and treatment of one disorder should not preclude the presence of the other. The key to the diagnosis and treatment of children manifesting narcolepsy involves regular evaluation, to allow for identification, testing, counseling, and adjustments to medication. The early recognition of the features in this disorder is essential for allowing children to grow, develop, and function in social environments. As evidenced by the three patients in this case series, although narcolepsy is a lifelong condition, treatment can restore a sense of normality and opportunity to the childhoods of these patients. References [1] Gelineau J. De la narcolepsie. Gaz Hosp (Paris) 1880;53:626e8. [2] Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998;50:16e22. [3] American Academy of Sleep Medicine. International classification of sleep disorders: Diagnostic and coding manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005. p. 81e94.
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[4] 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;6:991e7. [5] Marcus C, Trescher W, Halbower A, Lutz J. Secondary narcolepsy in children with brain tumors. Sleep 2002;25:435e9. [6] Morrish E, King M, Smith I, Shneerson J. Factors associated with a delay in the diagnosis of narcolepsy. Sleep Med 2004;5:37e41. [7] Kotagal S. Narcolepsy in children. In: Marcus C, Carroll J, Donnelly D, Loughlin G, editors. Sleep in children: Developmental changes in sleep patterns. 2nd ed. New York: Informa Healthcare USA, Inc.; 2008. p. 243e57. [8] Peterson P, Husain A. Pediatric narcolepsy. Brain Dev 2008;30: 609e23. [9] Overeem S, Mignot E, van Dijk J, Lammers G. Narcolepsy: Clinical features, new pathophysiologic insights, and future perspectives. J Clin Neurophysiol 2001;18:78e105. [10] Macleod S, Ferrie C, Zuberi S. Symptoms of narcolepsy in children misinterpreted as epilepsy. Epileptic Disor 2005;25:27e35. [11] Aran A, Einen M, Lin L, Plazzi G, Nishino S, Mignot E. Clinical and therapeutic aspects of childhood narcolepsy-cataplexy: A retrospective study of 51 children. Sleep 2010;33:1457e63. [12] Hoban TF, Chervin RD. Assessment of sleepiness in children. Semin Pediatr Neurol 2001;8:216e28. [13] Carskadon MA, Dement WC, Mitler MM, Roth T, Westbrook PR, Keenan S. Guidelines for the Multiple Sleep Latency Test (MSLT): A standard measure of sleepiness. Sleep 1986;9:519e24.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Case Report
Cases of Pediatric Narcolepsy After Misdiagnoses Shilpa R. Kauta MD a, *, Carole L. Marcus MBBCh b a b
Sleep Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Sleep Center, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
article information
abstract
Article history: Received 8 June 2012 Accepted 1 August 2012
Narcolepsy is characterized by recurrent brief attacks of irresistible sleepiness. Signs can begin during childhood. However, diagnoses are frequently delayed by 10-15 years because of unfamiliarity with pediatric narcolepsy and variable presentations of its associated features (cataplexy, hypnagogic/hypnopompic hallucinations, and sleep paralysis). Therefore, patients may remain untreated during their formative years. Three children with narcolepsy who were initially misdiagnosed are described. Each child’s signs were initially related to depression, hypothyroidism, jaw dysfunction, or conversion disorder. However, after a multiple sleep latency test, the diagnosis of narcolepsy was established. All three patients were treated appropriately with stimulant medications, selective serotonin reuptake inhibitors, or sodium oxybate, and demonstrated positive responses. Although no definitive cure exists for narcolepsy, early recognition and appropriate symptomatic treatment with medications can allow affected children to improve quality of life and achieve normality, both academically and socially. Ó 2012 Elsevier Inc. All rights reserved.
Introduction
Coined by Gelineau in 1880, the term “narcolepsy” describes a pathologic condition characterized by recurrent brief attacks of irresistible sleepiness [1]. This disorder demonstrates a prevalence of approximately 1/2000, and causes significant impairment in those who are affected [2], including disabling daytime sleepiness, difficulty functioning at school or work, and depression. In addition to excessive daytime somnolence, narcolepsy can be associated with signs of cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations [3]. Narcolepsy has been linked to an extensive loss of hypothalamic neurons that produce hypocretin-1 and hypocretin-2 (also known as orexin-A and orexin-B). These hormones are sleep-wake and rapid eye movement sleepregulating neuropeptides [4]. They also exert control over appetite. When cerebrospinal fluid is tested in patients with narcolepsy, hypocretin 1 is low to undetectable. Many * Communications should be addressed to: Dr. Kauta; Hospital of the University of Pennsylvania Penn Sleep Center; 3624 Market Street, Suite 205; Philadelphia, PA 19104. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2012.08.005
patients with narcolepsy (more than 90%) also carry the human leukocyte antigen DQB1*0602 allele, but this allele does not need to be present for diagnostic purposes [3]. Initial signs of narcolepsy frequently present during childhood and adolescence. However, the tetrad of features (daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations) occurring together is extremely rare at a young age, thus impeding diagnosis. If these features (specifically cataplexy) are present, they may be atypical compared with adult presentations, and difficult to recognize. For instance, children may present with cataplexy that is unrelated to emotion [5]. As a result, the disorder can remain undiagnosed until patients are adults, up to 10-15 years after the onset of signs [6]. When a child presents with features of excessive daytime sleepiness, weight gain, episodic loss of muscle tone, and poor attention, pediatricians often think of depression, epilepsy, or endocrine problems. Narcolepsy is important to include in this differential diagnosis. Treatments are available to help these children improve their quality of life and allow them to achieve normality both academically and socially. To bring attention to this diagnosis, we present three patients with pediatric narcolepsy that was initially misdiagnosed.
S.R. Kauta, C.L. Marcus / Pediatric Neurology 47 (2012) 362e365
Case Reports Patient 1
The patient was a 9-year-old boy with signs of progressively worsening daytime sleepiness who was misdiagnosed with conversion disorder. Initially, he started taking naps and eventually could not function well in school. At the same time, he developed episodic muscle weakness with periods of ptosis and dysarthria, as well as a feeling of paralysis when he was playing video games. On a few occasions, he fell to the ground for a few seconds with no clear stimulus. None of these episodes were related to strong emotions. During some of these episodes, he progressed into sleep after the event. No history of hypnagogic hallucinations, sleep paralysis, or weight change was reported. Before being examined at the sleep clinic, he was hospitalized elsewhere for these signs. He underwent an extensive workup, including cerebrospinal fluid analysis and cranial magnetic resonance imaging. All results were unremarkable, and he was diagnosed with conversion disorder in the setting of his parents obtaining a divorce. His features continued to occur, and he was brought to a different hospital where he underwent repeated magnetic resonance imaging and cerebrospinal fluid analysis, which again produced unremarkable results. He was discharged with a plan for an outpatient overnight polysomnogram and a multiple sleep latency test. His overnight polysomnogram and multiple sleep latency test were consistent with severe narcolepsy (Table 1). His blood work tested positive for the human leukocyte antigen DQB1*0602 allele. Cerebrospinal fluid drawn during his previous hospitalization was subsequently checked for hypocretin levels, which proved to be reduced at 31.7 pg/mL (normal, 200 pg/mL). Based on these findings, he was diagnosed with narcolepsy with cataplexy, and began receiving modafinil for sleepiness and venlafaxine for cataplexy. On follow-up, he was much more awake and interactive. He was able to function normally in school, and observed a reduction in his cataplectic episodes and an improvement in nocturnal sleep quality. He did not report any side effects from the medications.
363
night, take a 1.5-hour nap during the day, and fall asleep during car rides. Despite her sleepiness, she was able to concentrate at school and maintain good grades. In addition to her sleepiness, she demonstrated periods of jaw dropping and tongue thrusting when she laughed. No hypnagogic hallucinations or episodes of sleep paralysis were reported. She was eventually referred to a sleep center at age 9 years, and a polysomnogram, multiple sleep latency test, and cranial magnetic resonance imaging were performed. These produced unremarkable results, with no evidence of narcolepsy or sleep-disordered breathing (Table 1). As a result, endocrine and orthodontic evaluations were pursued. She was diagnosed with hypothyroidism and treated appropriately, but with no resolution of her signs. By age 12 years, she exhibited a body mass index of 36.6 kg/m2 (95th percentile) and progressively became sleepier, with no clear diagnosis. She was evaluated by a speech pathologist for her tongue thrusting, and jaw surgery for her problems with jaw dropping was planned. Before her surgery, at age 13 years, she was referred to another sleep center, and a polysomnogram and multiple sleep latency test were performed. The results were consistent with severe narcolepsy (Table 1), and she was revealed to be human leukocyte antigen DQB1*0602-positive. She was diagnosed with narcolepsy with cataplexy (jaw dropping episodes), and began receiving modafinil. While receiving treatment, she was able to stay awake in school, but continued to experience problems with sleep fragmentation and jaw weakness. She also developed leg weakness when she was frightened. Therefore, she received sodium oxybate, in addition to modafinil, which reduced her daytime napping, improved her sleep quality at night, and decreased her episodes of cataplexy. In the setting of receiving sodium oxybate, she initially experienced enuresis once a month. Enuresis is a known side effect of the medication, and it resolved with fluid restriction. During the 2 years after the initiation of sodium oxybate, she was able to lose more than 25 kg and return to a normal body mass index for her age. Her weight loss was likely a result of the combination of her effort to lose weight, increased energy level, and a side effect of her medications. In conjunction with her medication regimen, the control of her daytime signs was dependent on receiving sufficient hours of sleep at night.
Patient 2 Patient 3
The second patient was a 7-year-old girl who developed daytime sleepiness and progressive weight gain. She was initially diagnosed with hypothyroidism and jaw dysfunction because of repetitive jaw-dropping episodes. At the onset of her features, she would sleep for 8 hours at
The third patient was a 9-year-old boy with restless sleep with multiple arousals and daytime drowsiness, originally diagnosed as attention deficit hyperactivity disorder and depression. He would not fall
Table 1. Patient characteristics, diagnostic findings, and treatments
Characteristics
Patient 1
Patient 2
Patient 3
Age at onset of signs Age at diagnosis Initial diagnosis
8 years 9 years Conversion disorder
Polysomnogram results
AHI, 0.5 events/hour EEG, normal
9 years 11 years ADHD Depression AHI, 0 events/hour EEG, normal
Multiple sleep latency test results
MSL, 4.3 minutes SOREMP, 3 of 4 naps
CSF hypocretin (normal, 200 pg/mL) Medications used
31.7 pg/mL Modafinil Venlafaxine None
7 years 12 years Hypothyroidism Jaw dysfunction 2004: AHI, 0 events/hour EEG, normal 2004: MSL, 17.6 minutes SOREMP, none N/A Modafinil Sodium oxybate Enuresis (resolved with
Side effects of medication
2008: AHI, 1 event/hour EEG, normal 2008: MSL, 1.4 minutes SOREMP, 4 of 4 naps
fluid restriction)
MSL, 2 minutes SOREMP, 4 of 4 naps 18 pg/mL Modafinil Methylphenidate None
Abbreviations: ADHD ¼ Attention deficit hyperactivity disorder AHI ¼ Apnea-hypopnea index (normal for children, <1.5 events/hour) CSF ¼ Cerebrospinal fluid EEG ¼ Electroencephalogram MSL ¼ Mean sleep latency (meets criteria for narcolepsy if 8 minutes) [3] N/A ¼ Not available SOREMP ¼ Sleep-onset rapid eye movement period (meets criteria for narcolepsy if two or more naps include sleep-onset rapid eye movement sleep after sufficient nocturnal sleep) [3]
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S.R. Kauta, C.L. Marcus / Pediatric Neurology 47 (2012) 362e365
asleep in school, but would fall asleep immediately upon entering the car after school. He would also fall asleep while reading, watching television, and playing video games. He manifested no cataplexy, hypnagogic hallucinations, or sleep paralysis. He was diagnosed with attention deficit hyperactivity disorder and depression, and received methylphenidate and paroxetine. By age 11 years, he was significantly overweight, with a body mass index of 22.9 (95th percentile). When he was examined at the sleep clinic, he reported some improvement in his concentration during school while on treatment, but otherwise remained excessively sleepy during the day. An overnight polysomnogram and multiple sleep latency test were performed. The multiple sleep latency test results met the criteria for narcolepsy. However, he had slept for less than 6 hours during his polysomnogram preceding the multiple sleep latency test, and he was receiving psychotropic medications at the time of the study. Both of these factors affected the interpretation of the results (Table 1). As a result, cerebrospinal fluid hypocretin levels were tested to confirm the diagnosis, and were demonstrated to be reduced, at 18 pg/mL. With the diagnosis of narcolepsy, he discontinued methylphenidate and paroxetine, and received modafinil. His sleepiness was insufficiently controlled on this regimen, and as a result, methylphenidate was reinitiated, in addition to the modafinil. On these medications, significant improvement in his alertness and concentration occurred, with no reported side effects. During the next 6 years, control of his difficulties depended on his daily use of medications and proper sleep hygiene. Subsequent polysomnograms and the maintenance of wakefulness testing confirmed improved daytime wakefulness. However, his nocturnal sleep remained fragmented. He did not lose weight while on treatment, and he never developed signs of cataplexy, sleep paralysis, or hypnagogic hallucinations. Although he was intermittently monitored by a psychiatrist, he never required treatment for depression.
Discussion
Diagnosing narcolepsy in pediatric patients can be challenging. Key reasons include the unfamiliarity of the diagnosis among pediatricians, variable presentations compared with those of adults, and negative test results in early stages [7]. In addition, the sleepy child may take longer to receive the attention of teachers and parents than the hyperactive child. Rendering the diagnosis even more difficult, as demonstrated in patients 2 and 3, these children are occasionally able to maintain their function in school and become sleepy after they return home, where their parents may not be consider sleepiness a problem. Each of these three cases portrays examples of some of these issues, and also underscores the remarkable response to and benefit of treatment. Cataplexy, sleep paralysis, and hypnagogic hallucinations, i.e., the associated features of narcolepsy, are not always present in children manifesting narcolepsy, and when they are present, they can be difficult to identify. Cataplexy is a transient loss of muscle tone, usually in response to emotions such as surprise, fright, or laughter. This appearance of rapid eye movement atonia can range in severity from falling to the ground to buckling of the knees, or even just an internal sensation of weakness [8]. Sixty percent to 90% of patients with narcolepsy experience cataplexy, but the presentation of this feature can follow the onset of sleepiness by months to years [9]. Thus, children often do not present with cataplexy, and should be regularly asked about symptoms during follow-up, because treatment is different than with excessive daytime sleepiness alone. In addition, children frequently exhibit atypical cataplexy. For instance, patient 1 manifested cataplexy with no emotional triggers, and was misdiagnosed with
psychogenic behavior. Patient 2 also exhibited signs of cataplexy with jaw dropping that were atypical and led to an unnecessary plan for jaw surgery. In children, to obtain an accurate history for sleep paralysis and hypnagogic hallucinations can be difficult. Sleep paralysis is similar in etiology to cataplexy, with the inappropriate appearance of rapid eye movement atonia while the patient is awake. Patients are usually frightened by the inability to move when they awaken [9]. Hypnagogic hallucinations are realistic dreams or experiences of sound, image, or feeling that occur at sleep onset or while waking up (i.e., hypnopompic) [9]. In children, these hallucinations can assume simple forms (colored circles, images of animals, or people) and frequently occur with sleep paralysis [10]. As already mentioned, although the presence of these signs can be helpful in diagnosis, obtaining an accurate history of these abnormalities from a young child can be difficult. None of the patients in our case series reported these signs. Although the multiple sleep latency test is an adequate tool for diagnosis, it can be inconclusive in prepubertal children or when performed close to disease onset [7,11]. Early in the course of the disorder, patients may not demonstrate sleep-onset rapid eye movement periods. In addition, mean sleep latencies differ in children vs adults. On the multiple sleep latency test, the mean sleep latency for preadolescent children averages 19 1.6 minutes, in contrast to the 10-20 minute range considered normal for healthy adults [12,13]. This discrepancy may inappropriately cause a child with brief sleep latency, e.g., 11 minutes, to fall into the apparently normal range. Furthermore, at present, the same criteria for diagnosing narcolepsy during multiple sleep latency testing (sleep latency, 8 minutes) are used for both adults and children, despite the observed differences in their normative data. As revealed in patient 2 (Table 1), repeated testing and regular monitoring are essential to evaluating sleepy children with normal polysomnograms and multiple sleep latency tests, because significant daytime sleepiness is not normal in preadolescent children. Human leukocyte antigen typing, cranial magnetic resonance imaging, drug screening, and cerebrospinal fluid hypocretin levels (not yet commercially available) comprise additional tools to support or exclude a diagnosis of narcolepsy. In a retrospective evaluation of 51 children with narcolepsy, Aran et al. reported a striking weight gain (8-12 kg) within 6 months of the onset of signs in children [11]. The weight gain usually occurred after puberty, but when it occurred before puberty, an association with an earlier onset of puberty was frequently evident. This association may reflect greater hypothalamic dysfunction in narcolepsy patients with drastic weight gain and an early onset of puberty [11]. As observed in patient 2, this significant weight gain can cloud the signs of sleepiness in the process of diagnosis, and direct the patient to more of an endocrine evaluation rather than a sleep evaluation. After diagnosis, recognizing the relationship between narcolepsy and weight gain is important in counseling patients. They should be aware that weight gain is a manifestation of the disorder, and they should be encouraged to maintain healthy diets and regular exercise. They may benefit from weight management programs. In conclusion, we report on three cases of narcolepsy that were initially misdiagnosed. Narcolepsy can occur alone or
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with other common childhood disorders, with overlapping features such as obstructive sleep apnea, hypothyroidism, or depression. The evaluation and treatment of one disorder should not preclude the presence of the other. The key to the diagnosis and treatment of children manifesting narcolepsy involves regular evaluation, to allow for identification, testing, counseling, and adjustments to medication. The early recognition of the features in this disorder is essential for allowing children to grow, develop, and function in social environments. As evidenced by the three patients in this case series, although narcolepsy is a lifelong condition, treatment can restore a sense of normality and opportunity to the childhoods of these patients. References [1] Gelineau J. De la narcolepsie. Gaz Hosp (Paris) 1880;53:626e8. [2] Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998;50:16e22. [3] American Academy of Sleep Medicine. International classification of sleep disorders: Diagnostic and coding manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005. p. 81e94.
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