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Acute Dyskinetic Reaction in a Healthy Toddler Following Methylphenidate Ingestion
Pediatric Neurology 49 (2013) 58e60
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observation
Acute Dyskinetic Reaction in a Healthy Toddler Following Methylphenidate Ingestion Jeff L. Waugh MD, PhD * Resident in Child Neurology, Boston Children’s Hospital, Boston, MA 02115
article information
abstract
Article history: Received 16 December 2012 Accepted 26 January 2013
BACKGROUND: Acute dyskinetic or dystonic reactions are a long-recognized complication of
medications that alter dopamine signaling. Most reactions occur following exposure to agents that block dopamine receptors (e.g., neuroleptics). However, agents that increase dopaminergic transmission (such as methylphenidate) can also trigger acute dyskinesias. This has been previously reported only in patients also taking dopamine antagonists or, less commonly, in children with developmental abnormalities. CASE DESCRIPTION: The present report describes a previously healthy toddler who developed transient torticollis and orolingual dyskinesias following accidental exposure to methylphenidate. He had no preexisting movement disorder, central nervous system injury, or developmental abnormalitiesdin short, none of the previously reported risk factors for this side effect. HYPOTHESIS AND CONCLUSIONS: The unique features of this case led to the hypothesis that developmental shifts in dopamine signaling were the basis for his particular sensitivity to methylphenidate. If confirmed, this hypothesis has implications for the treatment of common childhood attentional and behavioral disorders. The article includes a literature review of dyskinetic/ dystonic reactions in children and the developmental regulation of dopamine metabolism. Ó 2013 Elsevier Inc. All rights reserved.
Introduction
Methylphenidate is an effective agent in the treatment of attention-deficit hyperactivity disorder (ADHD), presumably secondary to its effects as a dopamine/norepinephrine reuptake inhibitor. Because ADHD is the most common neuropsychiatric condition in childhood (diagnosed in 9% of children aged 6-17) [1], and treatment for ADHD typically continues for years, it is not surprising that methylphenidate use is so common: 5% of all US children (>2.7 million) take a stimulant medication [1]. Few case reports describe children or adolescents with abnormal movements attributable to methylphenidate. In each report, the child was either (1) on a chronic regimen of neuroleptics [2] or valproate [3] when methylphenidate was introduced or (2) was developmentally delayed and/or
* Communications should be addressed to: Dr. Waugh; Neurology; Massachusetts General Hospital; 55 Fruit Street; WAC 7; Boston, MA 02114. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2013.01.008
had ADHD [4]. Given the frequency of methylphenidate use, the paucity of such reports argues that movement disorders are a rare side effect. These previously reported casesdthose with iatrogenic D2 dopamine receptor hypersensitivity or presumed developmental abnormalities in dopamine signalingdoffer an intriguing insight into the etiology of dyskinetic reactions and perhaps of dystonia. However, in this case the child had none of these risk factors. Case Report The patient was a 23-month-old boy who presented to our emergency department after ingestion of methylphenidate. He was left unattended briefly and in that time consumed an unknown quantity of methylphenidate (10 mg, immediate release) from his nanny’s handbag. There were no other medications accessible. Two hours later, he developed agitation, slurred speech, and hyperactive behaviors that were unusual for him: running about without clear intent, picking at his skin and clothing, and hitting windows with sticks. His pupils were dilated. Four hours after ingestion, he developed repetitive tongue thrusting to the left, and less frequent
J.L. Waugh / Pediatric Neurology 49 (2013) 58e60
59
Figure 1. Screen shots from the supplementary video demonstrate the patient’s leftward torticollis and orolingual dyskinesias (left and center panels), with prominent tongue thrusting into the left cheek. These dyskinesias were repetitive and persistent over hours, but were interrupted by periods of normal behavior lasting seconds (right panel). (The supplementary video accompanying this article can be found in the online version at http:10.1016/j. pediatrneurol.2013.01.008.) left laterocollis and grimace of the left face (Fig 1 and Video; supplementary material associated with this article can be found in the online version at doi:10.1016/j.pediatrneurol.2013.01.008). Throughout this period, he was responsive and distractible, with no loss of consciousness or epileptiform movements. He was taken to a local emergency department where his vital signs and general and neurological exams were normaldwith the exception of his dilated pupils and dyskinesias. He was given diphenhydramine (1.1 mg/kg), which slowed the frequency of the dyskinesias. Two hours later, the movements returned to their pretreatment intensity and continued at lower amplitude during sleep. The family presented to our emergency department for a second opinion. Diphenhydramine was repeated 15 hours after ingestion, with complete resolution of the movements. Normal diagnostic studies included a urine toxicology screen and an electrocardiogram. He was admitted for observation. The neurology senior resident examined the boy at 19 hours after ingestion. At that time, the patient had a normal general and neurological exams with no abnormal movements. Detailed assessment showed him to be within the normal range for gross motor, fine motor, social, and language development. No family members had movement or psychiatric disorders or any other recognized disorders affecting the dopamine system. At 14 months after this ingestion, he has had no return of the described symptoms. His development has continued on a normal trajectory, with nothing to suggest a derangement of dopaminergic signaling. This case is therefore the solitary report of a healthy, normally developing child with an acute dyskinetic reaction in response to methylphenidate. Similarly, at 23 months, this child is the youngest ever reported to develop an acute dyskinetic reaction, though it is notable that an acute, fixed dystonic reaction was reported in two younger children [5].
Discussion
Given the ubiquity of stimulant medications, it is likely that accidental ingestions by toddlers have taken place previously. The absence of any cases linked to morbidity or mortality underscores the safety of these medications. Because the risk of harm to children appears to be quite low, what is the utility in reporting such a case? This unusual clinical observation suggests that dopamine signaling in
toddlers differs from that in school-age children and adults, a hypothesis with implications for the treatment of ADHD and other behavioral disorders in young children. One possible explanation for this child’s reaction is that he ingested a supratherapeutic dosedthe number of pills missing was believed to be only one or two, but was not known for certain. Therefore, it is impossible to refute the conjecture that an older child taking a proportionate excess of methylphenidate would develop a similar reaction. It is also possible that this child’s exposure unmasked a latent movement disorder, as has been documented for tics, paroxysmal kinesigenic dyskinesia [6], and Huntington disease [7]. However, unlike these prior reports, this child had no further symptoms following the acute event and has a negative family history. Transient movement disorders following methylphenidate ingestion (chorea and stereotypies) are rare and do not fit this child’s clinical semiology: the movements were repetitive and invariant over hours (nonchoreiform) and continued during sleep (unlike stereotypies). Because this child had none of the predisposing features reported in cases of methylphenidateinduced movement disorders, we must seek an alternative explanation. The rates of synthesis, transport, and reuptake of dopamine strongly influence neurotransmitter availability at the synapse. Likewise, the regional specificity and relative ratios of dopamine receptor subtypes (DRs 1-5) affect whether movement is facilitated or inhibited. Each of these steps in dopamine signal transduction is developmentally regulated. Autopsy samples of prefrontal cortex [8,9] (spanning from neonate to older adult) demonstrated marked shifts in dopamine-related proteins: tyrosine hydroxylase is highest in the neonate and falls throughout life; DR2 expression predominates during the neonatal through preschool period and reverses to a DR1-dominant pattern in adolescence and adulthood. These are not subtle differences: protein levels differ by three- to 10-fold between toddlers
60
J.L. Waugh / Pediatric Neurology 49 (2013) 58e60
and adults. Similar age-related changes in mRNA transcription [10,11] and dopamine receptor availability [12] have been demonstrated. These data suggest that the clinical response to dopamine-modulating medications shifts throughout development and may be quite different in preschool children relative to adolescents and adults. How might recognition of the developmental regulation of dopamine change clinical management? In the United States, stimulants are approved for children aged 6 years and older, but ADHD is frequently diagnosed at younger ages. Indeed, current ADHD practice parameters state that pharmacotherapy is permissible at 4 years if the child has failed behavioral therapy [13]. Of children diagnosed with ADHD before 5 years of age, three quarters have comorbid oppositional behavior and half have developmental delay [14]. These children are thus more likely than older ADHD sufferers to receive psychotropic medications, further increasing the likelihood of dyskinetic reactions. In light of these clinical realities and the previously reviewed developmental shifts in dopamine pharmacology, differentiating those children at greatest risk for side effects from those likely to show clinical benefit is difficult. This leads to a question unanswered by the medical literature: is there a minimum age below which dopaminergic stimulants should not be used? The boy described herein developed an acute, secondary movement disorder despite his lack of any previously reported risk factors. I hypothesize that his age is the likely predisposing feature. The relative excess of D2-mediated signaling at this stage of development may make infants and toddlers susceptible to secondary dyskinetic or dystonic reactions. Such shifts in dopamine pharmacology may also underlie the patterns in age and symptom progression in other childhood-onset movement disorders (e.g., tics, Sydenham chorea, benign hereditary chorea, myoclonusdystonia, Oppenheim dystonia, paroxysmal dyskinesias). A thorough characterization of dopamine neurotransmission throughout development has the potential, therefore, to both illuminate dyskinetic/dystonic disorders and to allow for safer treatment of our youngest patients. I am grateful for the assistance of Dr. Sandra Schumacher, who made and graciously shared the video associated with this case, and Drs. Nutan Sharma, Michael Dowling, and April Levin, who offered thoughtful suggestions to improve the manuscript. J.W. has been employed as a resident in clinical training for the past 5 years: for 2 years by the Children’s Medical Center of Dallas and for 3 years by Boston Children’s Hospital.
Supplementary Material
Supplementary material accompanying this article can be found in the online version at http:10.1016/j. pediatrneurol.2013.01.008.
References [1] Centers for Disease Control and Prevention. Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among childrendUnited States, 2003 and 2007. MMWR Morb Mortal Wkly Rep 2010;59:1439e43. [2] Husain A, Chapel J, Malek-Ahmadi P. Methylphenidate, neuroleptics and dyskinesia-dystonia. Can J Psychiatry 1980;25: 254e8. [3] Gara L, Roberts W. Adverse response to methylphenidate in combination with valproic acid. J Child Adolesc Psychopharmacol 2000;10:39e43. [4] Senecky Y, Lobel D, Diamond GW, Weitz R, Inbar D. Isolated orofacial dyskinesia: A methylphenidate-induced movement disorder. Pediatr Neurol 2002;27:224e6. [5] Carey MJ, Aitken ME. Diverse effects of antiemetics in children. N Z Med J 1994;107:452e3. [6] Gay CT, Ryan SG. Paroxysmal kinesigenic dystonia after methylphenidate administration. J Child Neurol 1994;9:45e6. [7] Waugh JL, Miller VS, Chudnow RS, Dowling MM. Juvenile Huntington disease exacerbated by methylphenidate: case report. J Child Neurol 2008;23:807e9. [8] Weickert CS, Webster MJ, Gondipalli P, et al. Postnatal alterations in dopaminergic markers in the human prefrontal cortex. Neuroscience 2007;144:1109e19. [9] Rothmond DA, Weickert CS, Webster MJ. Developmental changes in human dopamine neurotransmission: Cortical receptors and terminators. BMC Neurosci 2012;13:18. [10] Tarazi FI, Baldessarini RJ. Comparative postnatal development of dopamine D(1), D(2) and D(4) receptors in rat forebrain. Intl J Dev Neurosci 2000;18:29e37. [11] Araki KY, Sims JR, Bhide PG. Dopamine receptor mRNA and protein expression in the mouse corpus striatum and cerebral cortex during pre- and postnatal development. Brain Res 2007;1156: 31e45. [12] Jucaite A, Forssberg H, Karlsson P, Halldin C, Farde L. Age-related reduction in dopamine D1 receptors in the human brain: From late childhood to adulthood, a positron emission tomography study. Neuroscience 2010;167:104e10. [13] Subcommittee on ADHD, Steering Committee on Quality Improvement and Management. ADHD: Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/ hyperactivity disorder in children and adolescents. Pediatrics 2011;128:1007e22. [14] Eysbouts Y, Poulton A, Salmelainen P. Stimulant medication in preschool children in New South Wales. J Paediatr Child Health 2011; 47:870e4.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observation
Acute Dyskinetic Reaction in a Healthy Toddler Following Methylphenidate Ingestion Jeff L. Waugh MD, PhD * Resident in Child Neurology, Boston Children’s Hospital, Boston, MA 02115
article information
abstract
Article history: Received 16 December 2012 Accepted 26 January 2013
BACKGROUND: Acute dyskinetic or dystonic reactions are a long-recognized complication of
medications that alter dopamine signaling. Most reactions occur following exposure to agents that block dopamine receptors (e.g., neuroleptics). However, agents that increase dopaminergic transmission (such as methylphenidate) can also trigger acute dyskinesias. This has been previously reported only in patients also taking dopamine antagonists or, less commonly, in children with developmental abnormalities. CASE DESCRIPTION: The present report describes a previously healthy toddler who developed transient torticollis and orolingual dyskinesias following accidental exposure to methylphenidate. He had no preexisting movement disorder, central nervous system injury, or developmental abnormalitiesdin short, none of the previously reported risk factors for this side effect. HYPOTHESIS AND CONCLUSIONS: The unique features of this case led to the hypothesis that developmental shifts in dopamine signaling were the basis for his particular sensitivity to methylphenidate. If confirmed, this hypothesis has implications for the treatment of common childhood attentional and behavioral disorders. The article includes a literature review of dyskinetic/ dystonic reactions in children and the developmental regulation of dopamine metabolism. Ó 2013 Elsevier Inc. All rights reserved.
Introduction
Methylphenidate is an effective agent in the treatment of attention-deficit hyperactivity disorder (ADHD), presumably secondary to its effects as a dopamine/norepinephrine reuptake inhibitor. Because ADHD is the most common neuropsychiatric condition in childhood (diagnosed in 9% of children aged 6-17) [1], and treatment for ADHD typically continues for years, it is not surprising that methylphenidate use is so common: 5% of all US children (>2.7 million) take a stimulant medication [1]. Few case reports describe children or adolescents with abnormal movements attributable to methylphenidate. In each report, the child was either (1) on a chronic regimen of neuroleptics [2] or valproate [3] when methylphenidate was introduced or (2) was developmentally delayed and/or
* Communications should be addressed to: Dr. Waugh; Neurology; Massachusetts General Hospital; 55 Fruit Street; WAC 7; Boston, MA 02114. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2013.01.008
had ADHD [4]. Given the frequency of methylphenidate use, the paucity of such reports argues that movement disorders are a rare side effect. These previously reported casesdthose with iatrogenic D2 dopamine receptor hypersensitivity or presumed developmental abnormalities in dopamine signalingdoffer an intriguing insight into the etiology of dyskinetic reactions and perhaps of dystonia. However, in this case the child had none of these risk factors. Case Report The patient was a 23-month-old boy who presented to our emergency department after ingestion of methylphenidate. He was left unattended briefly and in that time consumed an unknown quantity of methylphenidate (10 mg, immediate release) from his nanny’s handbag. There were no other medications accessible. Two hours later, he developed agitation, slurred speech, and hyperactive behaviors that were unusual for him: running about without clear intent, picking at his skin and clothing, and hitting windows with sticks. His pupils were dilated. Four hours after ingestion, he developed repetitive tongue thrusting to the left, and less frequent
J.L. Waugh / Pediatric Neurology 49 (2013) 58e60
59
Figure 1. Screen shots from the supplementary video demonstrate the patient’s leftward torticollis and orolingual dyskinesias (left and center panels), with prominent tongue thrusting into the left cheek. These dyskinesias were repetitive and persistent over hours, but were interrupted by periods of normal behavior lasting seconds (right panel). (The supplementary video accompanying this article can be found in the online version at http:10.1016/j. pediatrneurol.2013.01.008.) left laterocollis and grimace of the left face (Fig 1 and Video; supplementary material associated with this article can be found in the online version at doi:10.1016/j.pediatrneurol.2013.01.008). Throughout this period, he was responsive and distractible, with no loss of consciousness or epileptiform movements. He was taken to a local emergency department where his vital signs and general and neurological exams were normaldwith the exception of his dilated pupils and dyskinesias. He was given diphenhydramine (1.1 mg/kg), which slowed the frequency of the dyskinesias. Two hours later, the movements returned to their pretreatment intensity and continued at lower amplitude during sleep. The family presented to our emergency department for a second opinion. Diphenhydramine was repeated 15 hours after ingestion, with complete resolution of the movements. Normal diagnostic studies included a urine toxicology screen and an electrocardiogram. He was admitted for observation. The neurology senior resident examined the boy at 19 hours after ingestion. At that time, the patient had a normal general and neurological exams with no abnormal movements. Detailed assessment showed him to be within the normal range for gross motor, fine motor, social, and language development. No family members had movement or psychiatric disorders or any other recognized disorders affecting the dopamine system. At 14 months after this ingestion, he has had no return of the described symptoms. His development has continued on a normal trajectory, with nothing to suggest a derangement of dopaminergic signaling. This case is therefore the solitary report of a healthy, normally developing child with an acute dyskinetic reaction in response to methylphenidate. Similarly, at 23 months, this child is the youngest ever reported to develop an acute dyskinetic reaction, though it is notable that an acute, fixed dystonic reaction was reported in two younger children [5].
Discussion
Given the ubiquity of stimulant medications, it is likely that accidental ingestions by toddlers have taken place previously. The absence of any cases linked to morbidity or mortality underscores the safety of these medications. Because the risk of harm to children appears to be quite low, what is the utility in reporting such a case? This unusual clinical observation suggests that dopamine signaling in
toddlers differs from that in school-age children and adults, a hypothesis with implications for the treatment of ADHD and other behavioral disorders in young children. One possible explanation for this child’s reaction is that he ingested a supratherapeutic dosedthe number of pills missing was believed to be only one or two, but was not known for certain. Therefore, it is impossible to refute the conjecture that an older child taking a proportionate excess of methylphenidate would develop a similar reaction. It is also possible that this child’s exposure unmasked a latent movement disorder, as has been documented for tics, paroxysmal kinesigenic dyskinesia [6], and Huntington disease [7]. However, unlike these prior reports, this child had no further symptoms following the acute event and has a negative family history. Transient movement disorders following methylphenidate ingestion (chorea and stereotypies) are rare and do not fit this child’s clinical semiology: the movements were repetitive and invariant over hours (nonchoreiform) and continued during sleep (unlike stereotypies). Because this child had none of the predisposing features reported in cases of methylphenidateinduced movement disorders, we must seek an alternative explanation. The rates of synthesis, transport, and reuptake of dopamine strongly influence neurotransmitter availability at the synapse. Likewise, the regional specificity and relative ratios of dopamine receptor subtypes (DRs 1-5) affect whether movement is facilitated or inhibited. Each of these steps in dopamine signal transduction is developmentally regulated. Autopsy samples of prefrontal cortex [8,9] (spanning from neonate to older adult) demonstrated marked shifts in dopamine-related proteins: tyrosine hydroxylase is highest in the neonate and falls throughout life; DR2 expression predominates during the neonatal through preschool period and reverses to a DR1-dominant pattern in adolescence and adulthood. These are not subtle differences: protein levels differ by three- to 10-fold between toddlers
60
J.L. Waugh / Pediatric Neurology 49 (2013) 58e60
and adults. Similar age-related changes in mRNA transcription [10,11] and dopamine receptor availability [12] have been demonstrated. These data suggest that the clinical response to dopamine-modulating medications shifts throughout development and may be quite different in preschool children relative to adolescents and adults. How might recognition of the developmental regulation of dopamine change clinical management? In the United States, stimulants are approved for children aged 6 years and older, but ADHD is frequently diagnosed at younger ages. Indeed, current ADHD practice parameters state that pharmacotherapy is permissible at 4 years if the child has failed behavioral therapy [13]. Of children diagnosed with ADHD before 5 years of age, three quarters have comorbid oppositional behavior and half have developmental delay [14]. These children are thus more likely than older ADHD sufferers to receive psychotropic medications, further increasing the likelihood of dyskinetic reactions. In light of these clinical realities and the previously reviewed developmental shifts in dopamine pharmacology, differentiating those children at greatest risk for side effects from those likely to show clinical benefit is difficult. This leads to a question unanswered by the medical literature: is there a minimum age below which dopaminergic stimulants should not be used? The boy described herein developed an acute, secondary movement disorder despite his lack of any previously reported risk factors. I hypothesize that his age is the likely predisposing feature. The relative excess of D2-mediated signaling at this stage of development may make infants and toddlers susceptible to secondary dyskinetic or dystonic reactions. Such shifts in dopamine pharmacology may also underlie the patterns in age and symptom progression in other childhood-onset movement disorders (e.g., tics, Sydenham chorea, benign hereditary chorea, myoclonusdystonia, Oppenheim dystonia, paroxysmal dyskinesias). A thorough characterization of dopamine neurotransmission throughout development has the potential, therefore, to both illuminate dyskinetic/dystonic disorders and to allow for safer treatment of our youngest patients. I am grateful for the assistance of Dr. Sandra Schumacher, who made and graciously shared the video associated with this case, and Drs. Nutan Sharma, Michael Dowling, and April Levin, who offered thoughtful suggestions to improve the manuscript. J.W. has been employed as a resident in clinical training for the past 5 years: for 2 years by the Children’s Medical Center of Dallas and for 3 years by Boston Children’s Hospital.
Supplementary Material
Supplementary material accompanying this article can be found in the online version at http:10.1016/j. pediatrneurol.2013.01.008.
References [1] Centers for Disease Control and Prevention. Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among childrendUnited States, 2003 and 2007. MMWR Morb Mortal Wkly Rep 2010;59:1439e43. [2] Husain A, Chapel J, Malek-Ahmadi P. Methylphenidate, neuroleptics and dyskinesia-dystonia. Can J Psychiatry 1980;25: 254e8. [3] Gara L, Roberts W. Adverse response to methylphenidate in combination with valproic acid. J Child Adolesc Psychopharmacol 2000;10:39e43. [4] Senecky Y, Lobel D, Diamond GW, Weitz R, Inbar D. Isolated orofacial dyskinesia: A methylphenidate-induced movement disorder. Pediatr Neurol 2002;27:224e6. [5] Carey MJ, Aitken ME. Diverse effects of antiemetics in children. N Z Med J 1994;107:452e3. [6] Gay CT, Ryan SG. Paroxysmal kinesigenic dystonia after methylphenidate administration. J Child Neurol 1994;9:45e6. [7] Waugh JL, Miller VS, Chudnow RS, Dowling MM. Juvenile Huntington disease exacerbated by methylphenidate: case report. J Child Neurol 2008;23:807e9. [8] Weickert CS, Webster MJ, Gondipalli P, et al. Postnatal alterations in dopaminergic markers in the human prefrontal cortex. Neuroscience 2007;144:1109e19. [9] Rothmond DA, Weickert CS, Webster MJ. Developmental changes in human dopamine neurotransmission: Cortical receptors and terminators. BMC Neurosci 2012;13:18. [10] Tarazi FI, Baldessarini RJ. Comparative postnatal development of dopamine D(1), D(2) and D(4) receptors in rat forebrain. Intl J Dev Neurosci 2000;18:29e37. [11] Araki KY, Sims JR, Bhide PG. Dopamine receptor mRNA and protein expression in the mouse corpus striatum and cerebral cortex during pre- and postnatal development. Brain Res 2007;1156: 31e45. [12] Jucaite A, Forssberg H, Karlsson P, Halldin C, Farde L. Age-related reduction in dopamine D1 receptors in the human brain: From late childhood to adulthood, a positron emission tomography study. Neuroscience 2010;167:104e10. [13] Subcommittee on ADHD, Steering Committee on Quality Improvement and Management. ADHD: Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/ hyperactivity disorder in children and adolescents. Pediatrics 2011;128:1007e22. [14] Eysbouts Y, Poulton A, Salmelainen P. Stimulant medication in preschool children in New South Wales. J Paediatr Child Health 2011; 47:870e4.