- Email: [email protected]
A 15-Year-Old Girl With Sleep-Onset Insomnia and Poor Sleep Quality
[
Pulmonary, Critical Care, and Sleep Pearls
]
A 15-Year-Old Girl With Sleep-Onset Insomnia and Poor Sleep Quality Lourdes M. DelRosso, MD; Caroline V. Jackson, MD; and Raffaele Ferri, MD
A 15-year-old girl was referred to us for sleep difficulties and restless sleep. The parent stated that she was always a poor sleeper, having difficulty falling asleep and frequent nocturnal awakenings since she was a very young child, but in the past 6 months the symptoms had worsened. She slept in her own room and in her own bed. Her bedtime was 10:30 PM, staying in bed anywhere from 2 to 5 h before she could fall asleep. During this time, she felt discomfort in her legs with the urge to move her legs and relief after movement. This sensation was worse at night or when sitting for prolonged periods of time. Once she fell asleep, she woke up 2 to 3 times a night. She started her day at 7 AM but felt very sleepy and often would fall asleep again until 10 AM. During the day she was exhausted and often took a nap from 3 to 5 PM. There was soft snoring and no parasomnias. Her medical history was significant for beta-thalassemia trait. She was not on any medications. Social history included no dietary restrictions and no caffeine use. CHEST 2019; 156(1):e23-e26 CASE PRESENTATION:
Physical Examination Findings On physical examination, her vital signs were within the normal range and her BMI was 29 kg/m2. Physical examination showed a girl in no distress. There was no micrognathia or midface hypoplasia. Tonsil size was 1þ. The remainder of the examination was normal
Diagnostic Studies Iron studies showed ferritin level 33 ng/mL (30-300 ng/ mL), total iron level 63 ng/dL (37-145 ng/dL), transferrin saturation 18% (20%-50%), and iron binding capacity 278 mg/dL (200-360 mg/dL).
AFFILIATIONS: From the Department of Pediatrics (Drs DelRosso and Jackson), University of Washington, Seattle, WA; the Seattle Children’s Hospital (Drs DelRosso and Jackson), Seattle, WA; and Oasi Research Institute-IRCCS (Dr Ferri), Troina, Italy. CORRESPONDENCE TO: Lourdes M. DelRosso, MD, Seattle Children’s Hospital, 4800 Sand Point Way NE, Seattle, WA 98105; e-mail: [email protected]
chestjournal.org
A sleep study was performed to evaluate snoring, and OSA was ruled out. Sleep latency was 18.7 min. Sleep efficiency was 50% because of multiple awakenings. Sleep stage distribution showed stage 1 nonrapid eye movement (NREM) was 13.6%, stage 2 NREM was 64.7%, stage 3 NREM was 5.7%, and rapid eye movement sleep was 16%. The obstructive apneahypopnea index was 0.6. The periodic leg movement index was 1.6, and the isolated leg movement index was 17.9.
What is the next step in the care of this child?
Copyright Ó 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2019.02.015
e23
Answer: The diagnosis of restless leg syndrome was discussed with the family and treatment options were discussed. The family declined iron supplementation because of side effects and diagnosis of thalassemia but agreed on a therapeutic attempt with gabapentin. Gabapentin 100 mg was initiated while performing a sleep study. Discussion Restless legs syndrome (RLS) occurs in approximately 2% of children, affecting sleep, cognition, mood, and overall quality of life. The classic symptoms of RLS include the urge to move the legs, worsening of symptoms during rest and during the evening, and symptoms relieved by activity. RLS symptoms may be difficult to identify in children and RLS may be unrecognized, especially in infants and preschool children. The International Restless Legs Syndrome Study Group (IRLSSG) diagnostic guidelines include that symptoms must be able to be described in the child’s own words. Polysomnography (PSG) is not indicated when the clinical criteria of RLS are met. PSG however may be helpful when there is suspicion of RLS in children in whom the diagnosis is not clear. Contrary to RLS, periodic leg movements of sleep is defined polysomnographically. The identification of periodic leg movements of sleep in PSG has a high night-to-night variability and does not predict RLS in children. The IRLSSG has published updated scoring criteria based on recent research that includes other leg indices of importance, among them the total leg movement index and short interval leg movement index, which have shown to be more prominent in children than the classic periodic leg movements. RLS has been associated with genetic factors, dopaminergic dysfunction, and decreased iron storages. Iron is a cofactor for tyrosine hydroxylase in the dopamine synthesis pathway. Management of pediatric RLS includes nonpharmacologic and pharmacologic interventions. The former includes ensuring adequate sleep hygiene, avoiding caffeine, ensuring a healthy diet, and avoidance of medications that cause or exacerbate RLS (histaminergics, antidepressants, among others). The IRLSSG guidelines on iron supplementation for RLS in adults and children state that there is not enough
e24 Pulmonary, Critical Care, and Sleep Pearls
evidence to recommend iron for RLS in children. However, iron supplementation still remains the firstline therapy of RLS in children. Patients with thalassemia pose a particular challenge to iron supplementation. Thalassemia is a group of hereditary blood disorders characterized by anomalies in the synthesis of hemoglobin that can have variable presentation, from severe anemia to clinically asymptomatic anemia. The presence of anemia stimulates gastrointestinal iron absorption and production of erythropoietin with intensive but ineffective expansion of the bone marrow, hepatosplenomegaly, and extramedullary erythropoiesis. Therefore, iron supplementation is often contraindicated in these patients. There are limited data on the use of dopaminergic medications in children. Concern exists for similar side effect seen in adults, among them augmentation, withdrawal symptoms, sleepiness, insomnia, obsessive compulsive behavior, and hallucinations. For these reasons, gabapentin is often used as second-line agent in the treatment of pediatric RLS. Gabapentin is an TABLE 1
] Polysomnographic Parameter Comparison Between the Baseline Study and the Gabapentin Study
Variable
Baseline
Gabapentin
Total sleep time, min
128
417.6
Sleep efficiency, %
50.6
86.7
Sleep latency, min
18.7
18.9
Arousal index, No./h
7.4
3.2
Stage N1, %
13.6
8.3
Stage N2, %
64.7
55.8
Stage N3, %
5.7
25.3
Stage REM, %
16
10.7
Apnea-hypopnea index, No./h
0.3
0.6
Saturation nadir, %
90
92
1.6
0
PLMS index, No./h REM, No./h
12.4
0
NREM, No./h
1
0
Periodicity index
0.059
N/A
PLMS duration, s
1.4
N/A
Short LM index, No./h
6.8
2.3
Short LM duration, s
1.6
2.2
17.9
6.8
1.5
1.8
Isolated LM index, No./h Isolated LM duration, s
LM ¼ leg movement; N/A ¼ not applicable; N1 ¼ stage 1 nonrapid eye movement; N2 ¼ stage 2 nonrapid eye movement; N3 ¼ stage 3 nonrapid eye movement; NREM ¼ nonrapid eye movement; PLMS ¼ periodic leg movements of sleep; REM ¼ rapid eye movement.
[
156#1 CHEST JULY 2019
]
alpha-2-delta voltage-gated calcium channel ligand that appears to bind tightly to presynaptic neurons that modulate the release of excitatory neurotransmitters, functioning very similarly to gamma aminobutyric acid. With this in mind, one can hypothesize how gabapentin’s inhibitory properties might be effective in relieving symptoms associated with the activation of sensory neurons in RLS. In adults, alpha-2-delta antagonists such as gabapentin, along with dopamine agonists, are approved for the treatment of RLS. Unfortunately, they are not approved in children. Gabapentin enacarbil is a prodrug of gabapentin, designed to increase its oral bioavailability. Studies in adults have shown both subjective and objective improvement in sleep efficiency in patients with RLS taking various doses of gabapentin.
The IRLSSG did not find enough evidence to recommend in favor or against gabapentin for the treatment of RLS. Compared with gabapentin, the most recent research has focused on gabapentin enacarbil, which is one of the four Food and Drug Administration-approved drugs for the treatment of RLS (the other three are dopaminergic). Also, the studies using gabapentin enacarbil have been done in adults with doses ranging from 600 to 1,800 mg, for < 1 year, and assessing effectiveness by the use of validated questionnaires. In the past decade, concern has been raised about abuse potential of gabapentin, and studies have suggested that higher daily doses can be associated with diversion and abuse. In the current case report, we demonstrate a significant Baseline
W R N1 N2 N3 0
1
2
3
4 time, h
40
50 interval, s
5
6
7
No. of LMs
15 10 5 0
0
10
20
30
60
70
80
90
100
After gapapentin W R N1 N2 N3 0
1
2
3
4 time, h
5
6
7
8
No. of LMs
15 10 5 0
0
10
20
30
40
50 interval, s
60
70
80
90
100
Figure 1 – Hypnogram (small vertical lines indicate LMs) and leg intermovement interval diagram obtained at baseline and after gabapentin. LM ¼ leg movement; N1 ¼ stage 1 nonrapid eye movement; N2 ¼ stage 2 nonrapid eye movement; N3 ¼ stage 3 nonrapid eye movement; R ¼ rapid eye movement; W ¼ wake.
chestjournal.org
e25
improvement in sleep efficiency (Table 1) with a very low dose of gabapentin. It also suggests that low-dose gabapentin might be sufficient to consolidate sleep and decrease leg movements in children; however, a component of first night effect cannot be excluded. In this patient, symptoms of RLS, sleep quality, and daytime sleepiness improved on gabapentin. A second PSG was performed while on treatment. Sleep was consolidated from a sleep efficiency of 50.6% to 86.7%, without a change in sleep latency (Fig 1, Table 1).
Clinical Pearls 1. Iron status should be evaluated in children with RLS. 2. Children who cannot tolerate iron supplementation can be offered gabapentin. 3. Low doses of gabapentin may be effective in children.
Acknowledgments Financial/nonfinancial disclosures: None declared. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
e26 Pulmonary, Critical Care, and Sleep Pearls
Suggested Readings Garcia-Borreguero D, Larrosa O, de la Llave Y, Verger K, Masramon X, Hernandez G. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology. 2002;59(10):1573-1579. Simakajornboon N, Kheirandish-Gozal L, Gozal D. Diagnosis and management of restless legs syndrome in children. Sleep Med Rev. 2009;13(2):149-156. Galanello R, Origa R. Beta-thallasemia. Orphanet J Rare Dis. 2010;5:11. Winkelman JW, Bogan RK, Schmidt MH, Hudson JD, DeRossett SE, Hill-Zabala CE. Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome. Mov Disord. 2011;26(11):2065-2072. Garcia-Borreguero D, Kohnen R, Silber MH, et al. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidencebased guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Med. 2013;14(7):675-684. Picchietti DL, Bruni O, de Weerd A, et al. Pediatric restless legs syndrome diagnostic criteria: an update by the International Restless Legs Syndrome Study Group. Sleep Med. 2013;14(12):1253-1259. Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria–history, rationale, description, and significance. Sleep Med. 2014;15(8):860-873. Allen RP, Picchietti DL, Auerbach M, et al. Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report. Sleep Med. 2018;41:27-44.
[
156#1 CHEST JULY 2019
]
Pulmonary, Critical Care, and Sleep Pearls
]
A 15-Year-Old Girl With Sleep-Onset Insomnia and Poor Sleep Quality Lourdes M. DelRosso, MD; Caroline V. Jackson, MD; and Raffaele Ferri, MD
A 15-year-old girl was referred to us for sleep difficulties and restless sleep. The parent stated that she was always a poor sleeper, having difficulty falling asleep and frequent nocturnal awakenings since she was a very young child, but in the past 6 months the symptoms had worsened. She slept in her own room and in her own bed. Her bedtime was 10:30 PM, staying in bed anywhere from 2 to 5 h before she could fall asleep. During this time, she felt discomfort in her legs with the urge to move her legs and relief after movement. This sensation was worse at night or when sitting for prolonged periods of time. Once she fell asleep, she woke up 2 to 3 times a night. She started her day at 7 AM but felt very sleepy and often would fall asleep again until 10 AM. During the day she was exhausted and often took a nap from 3 to 5 PM. There was soft snoring and no parasomnias. Her medical history was significant for beta-thalassemia trait. She was not on any medications. Social history included no dietary restrictions and no caffeine use. CHEST 2019; 156(1):e23-e26 CASE PRESENTATION:
Physical Examination Findings On physical examination, her vital signs were within the normal range and her BMI was 29 kg/m2. Physical examination showed a girl in no distress. There was no micrognathia or midface hypoplasia. Tonsil size was 1þ. The remainder of the examination was normal
Diagnostic Studies Iron studies showed ferritin level 33 ng/mL (30-300 ng/ mL), total iron level 63 ng/dL (37-145 ng/dL), transferrin saturation 18% (20%-50%), and iron binding capacity 278 mg/dL (200-360 mg/dL).
AFFILIATIONS: From the Department of Pediatrics (Drs DelRosso and Jackson), University of Washington, Seattle, WA; the Seattle Children’s Hospital (Drs DelRosso and Jackson), Seattle, WA; and Oasi Research Institute-IRCCS (Dr Ferri), Troina, Italy. CORRESPONDENCE TO: Lourdes M. DelRosso, MD, Seattle Children’s Hospital, 4800 Sand Point Way NE, Seattle, WA 98105; e-mail: [email protected]
chestjournal.org
A sleep study was performed to evaluate snoring, and OSA was ruled out. Sleep latency was 18.7 min. Sleep efficiency was 50% because of multiple awakenings. Sleep stage distribution showed stage 1 nonrapid eye movement (NREM) was 13.6%, stage 2 NREM was 64.7%, stage 3 NREM was 5.7%, and rapid eye movement sleep was 16%. The obstructive apneahypopnea index was 0.6. The periodic leg movement index was 1.6, and the isolated leg movement index was 17.9.
What is the next step in the care of this child?
Copyright Ó 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2019.02.015
e23
Answer: The diagnosis of restless leg syndrome was discussed with the family and treatment options were discussed. The family declined iron supplementation because of side effects and diagnosis of thalassemia but agreed on a therapeutic attempt with gabapentin. Gabapentin 100 mg was initiated while performing a sleep study. Discussion Restless legs syndrome (RLS) occurs in approximately 2% of children, affecting sleep, cognition, mood, and overall quality of life. The classic symptoms of RLS include the urge to move the legs, worsening of symptoms during rest and during the evening, and symptoms relieved by activity. RLS symptoms may be difficult to identify in children and RLS may be unrecognized, especially in infants and preschool children. The International Restless Legs Syndrome Study Group (IRLSSG) diagnostic guidelines include that symptoms must be able to be described in the child’s own words. Polysomnography (PSG) is not indicated when the clinical criteria of RLS are met. PSG however may be helpful when there is suspicion of RLS in children in whom the diagnosis is not clear. Contrary to RLS, periodic leg movements of sleep is defined polysomnographically. The identification of periodic leg movements of sleep in PSG has a high night-to-night variability and does not predict RLS in children. The IRLSSG has published updated scoring criteria based on recent research that includes other leg indices of importance, among them the total leg movement index and short interval leg movement index, which have shown to be more prominent in children than the classic periodic leg movements. RLS has been associated with genetic factors, dopaminergic dysfunction, and decreased iron storages. Iron is a cofactor for tyrosine hydroxylase in the dopamine synthesis pathway. Management of pediatric RLS includes nonpharmacologic and pharmacologic interventions. The former includes ensuring adequate sleep hygiene, avoiding caffeine, ensuring a healthy diet, and avoidance of medications that cause or exacerbate RLS (histaminergics, antidepressants, among others). The IRLSSG guidelines on iron supplementation for RLS in adults and children state that there is not enough
e24 Pulmonary, Critical Care, and Sleep Pearls
evidence to recommend iron for RLS in children. However, iron supplementation still remains the firstline therapy of RLS in children. Patients with thalassemia pose a particular challenge to iron supplementation. Thalassemia is a group of hereditary blood disorders characterized by anomalies in the synthesis of hemoglobin that can have variable presentation, from severe anemia to clinically asymptomatic anemia. The presence of anemia stimulates gastrointestinal iron absorption and production of erythropoietin with intensive but ineffective expansion of the bone marrow, hepatosplenomegaly, and extramedullary erythropoiesis. Therefore, iron supplementation is often contraindicated in these patients. There are limited data on the use of dopaminergic medications in children. Concern exists for similar side effect seen in adults, among them augmentation, withdrawal symptoms, sleepiness, insomnia, obsessive compulsive behavior, and hallucinations. For these reasons, gabapentin is often used as second-line agent in the treatment of pediatric RLS. Gabapentin is an TABLE 1
] Polysomnographic Parameter Comparison Between the Baseline Study and the Gabapentin Study
Variable
Baseline
Gabapentin
Total sleep time, min
128
417.6
Sleep efficiency, %
50.6
86.7
Sleep latency, min
18.7
18.9
Arousal index, No./h
7.4
3.2
Stage N1, %
13.6
8.3
Stage N2, %
64.7
55.8
Stage N3, %
5.7
25.3
Stage REM, %
16
10.7
Apnea-hypopnea index, No./h
0.3
0.6
Saturation nadir, %
90
92
1.6
0
PLMS index, No./h REM, No./h
12.4
0
NREM, No./h
1
0
Periodicity index
0.059
N/A
PLMS duration, s
1.4
N/A
Short LM index, No./h
6.8
2.3
Short LM duration, s
1.6
2.2
17.9
6.8
1.5
1.8
Isolated LM index, No./h Isolated LM duration, s
LM ¼ leg movement; N/A ¼ not applicable; N1 ¼ stage 1 nonrapid eye movement; N2 ¼ stage 2 nonrapid eye movement; N3 ¼ stage 3 nonrapid eye movement; NREM ¼ nonrapid eye movement; PLMS ¼ periodic leg movements of sleep; REM ¼ rapid eye movement.
[
156#1 CHEST JULY 2019
]
alpha-2-delta voltage-gated calcium channel ligand that appears to bind tightly to presynaptic neurons that modulate the release of excitatory neurotransmitters, functioning very similarly to gamma aminobutyric acid. With this in mind, one can hypothesize how gabapentin’s inhibitory properties might be effective in relieving symptoms associated with the activation of sensory neurons in RLS. In adults, alpha-2-delta antagonists such as gabapentin, along with dopamine agonists, are approved for the treatment of RLS. Unfortunately, they are not approved in children. Gabapentin enacarbil is a prodrug of gabapentin, designed to increase its oral bioavailability. Studies in adults have shown both subjective and objective improvement in sleep efficiency in patients with RLS taking various doses of gabapentin.
The IRLSSG did not find enough evidence to recommend in favor or against gabapentin for the treatment of RLS. Compared with gabapentin, the most recent research has focused on gabapentin enacarbil, which is one of the four Food and Drug Administration-approved drugs for the treatment of RLS (the other three are dopaminergic). Also, the studies using gabapentin enacarbil have been done in adults with doses ranging from 600 to 1,800 mg, for < 1 year, and assessing effectiveness by the use of validated questionnaires. In the past decade, concern has been raised about abuse potential of gabapentin, and studies have suggested that higher daily doses can be associated with diversion and abuse. In the current case report, we demonstrate a significant Baseline
W R N1 N2 N3 0
1
2
3
4 time, h
40
50 interval, s
5
6
7
No. of LMs
15 10 5 0
0
10
20
30
60
70
80
90
100
After gapapentin W R N1 N2 N3 0
1
2
3
4 time, h
5
6
7
8
No. of LMs
15 10 5 0
0
10
20
30
40
50 interval, s
60
70
80
90
100
Figure 1 – Hypnogram (small vertical lines indicate LMs) and leg intermovement interval diagram obtained at baseline and after gabapentin. LM ¼ leg movement; N1 ¼ stage 1 nonrapid eye movement; N2 ¼ stage 2 nonrapid eye movement; N3 ¼ stage 3 nonrapid eye movement; R ¼ rapid eye movement; W ¼ wake.
chestjournal.org
e25
improvement in sleep efficiency (Table 1) with a very low dose of gabapentin. It also suggests that low-dose gabapentin might be sufficient to consolidate sleep and decrease leg movements in children; however, a component of first night effect cannot be excluded. In this patient, symptoms of RLS, sleep quality, and daytime sleepiness improved on gabapentin. A second PSG was performed while on treatment. Sleep was consolidated from a sleep efficiency of 50.6% to 86.7%, without a change in sleep latency (Fig 1, Table 1).
Clinical Pearls 1. Iron status should be evaluated in children with RLS. 2. Children who cannot tolerate iron supplementation can be offered gabapentin. 3. Low doses of gabapentin may be effective in children.
Acknowledgments Financial/nonfinancial disclosures: None declared. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
e26 Pulmonary, Critical Care, and Sleep Pearls
Suggested Readings Garcia-Borreguero D, Larrosa O, de la Llave Y, Verger K, Masramon X, Hernandez G. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology. 2002;59(10):1573-1579. Simakajornboon N, Kheirandish-Gozal L, Gozal D. Diagnosis and management of restless legs syndrome in children. Sleep Med Rev. 2009;13(2):149-156. Galanello R, Origa R. Beta-thallasemia. Orphanet J Rare Dis. 2010;5:11. Winkelman JW, Bogan RK, Schmidt MH, Hudson JD, DeRossett SE, Hill-Zabala CE. Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome. Mov Disord. 2011;26(11):2065-2072. Garcia-Borreguero D, Kohnen R, Silber MH, et al. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidencebased guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Med. 2013;14(7):675-684. Picchietti DL, Bruni O, de Weerd A, et al. Pediatric restless legs syndrome diagnostic criteria: an update by the International Restless Legs Syndrome Study Group. Sleep Med. 2013;14(12):1253-1259. Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria–history, rationale, description, and significance. Sleep Med. 2014;15(8):860-873. Allen RP, Picchietti DL, Auerbach M, et al. Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report. Sleep Med. 2018;41:27-44.
[
156#1 CHEST JULY 2019
]