Symposium on Neurological Disorder–Advances in Management-II
Movement Disorders in Children: Recent Advances in Management Emilio Fernández-Alvarez Neuropediatric Department, Hospital Universitario Sant Joan de Déu, Avda Sant Joan de Déu 2, Barcelona, Spain
ABSTRACT In recent years there has been a growing interest towards pediatric movement disorders (PMD). The data derived from the synthesis of clinical observation, neuroimaging, biochemical and, molecular genetics studies have allowed for the identification of a significant number of pediatric diseases featuring movement disorders. The purpose of this review is to outline an approach to the advances in management of dystonia, neurotransmitter disorders, tics, and paroxysmal dyskinetic syndromes starting in children younger than 18 yr of age. [Indian J Pediatr 2009; 76 (5) : 531-536] E-mail:
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Key words : Pediatric movement disorders; Synthesis; Clinical observation; Advances; Management
Pediatric movement disorders (PMD) is a group of disorders that occurs in pediatric age. Their main symptoms are pathological movements that cannot be fully initiated, modulated or interrupted voluntarily. Involuntary movements caused by epileptic, cerebellar, pyramidal and neuromuscular disorders are excluded. This review will discuss on recent advances in PMD management Basic management of PMD The first step to an appropriate management of PMD is an accurate clinical history. The following aspects are especially important. 1. A positive family history suggestive of dominant genetic disorder, or the presence of consanguinity that may suggest a recessive condition, are to be carefully looked for, taking into account the marked variation of expressivity of many dominant conditions. 2. The presence of perinatal antecedents of neonatal encephalopathy or neonatal icterus is also of interest as it may explain such disorders as athetosis or dystonia. 3. Information about the age of onset of the disorder, its initial manifestations and course (acute onset, slow progression, spontaneous improvement) is essential even though the precise date of onset of certain symptoms Correspondence and Reprint requests : Dr Emilio FernándezAlvarez, Neuropediatric Department, Hospital universitario Sant Joan de Déu, Avda Sant Joan de Déu 2, 08950 Barcelona, Spain Phone: 0034 629719479; Fax: 0034 932033959 [Received March 17, 2009; Accepted March 17, 2009]
Indian Journal of Pediatrics, Volume 76—May, 2009
such as tremor may be difficult to document. 4. Attention should also be given to the possibility of precipitating factors (drugs, infections, muscular exercise) or of aggravating (e.g., effect of fatigue, diurnal fluctuation) or ameliorating factors (e.g., sleep). 5. Description of the abnormal movements by lay persons and even by physicians is often unreliable. Photographs and, especially, videotapes of patients are of extreme value and every effort should be made to look at these. The second step is the movement identification. Types of abnormal movement disorders include rigid/ hypokinetic syndrome, dystonia/athetosis, chorea/ ballismus, tremor, myoclonus, tics and stereotypies. 1 (Table 1 and 2). It is useful to distinguish whether the abnormal movement interferes with the voluntary movements. (Table 3). The next step is to see if the abnormal movement(s) are the sole symptoms (often a primary disorder) or is associated with other neurological and/or extraneurological symptoms (secondary disorder). In secondary disorders ancillary explorations (neuroimaging, biochemical studies etc) are specially useful diagnostic tools whereas in primary disorders usually only molecular studies may contribute to the diagnosis. Only a few pediatric diseases with abnormal movements have causal or substitutive treatment. In the majority the treatment is symptomatic or merely palliative. Fortunately, transient movement disorders 531
Emilio Fernandez-Alvarez TABLE 1. Types of Abnormal Movements 1. 2.
3.
4. 5. 6. 7.
Rigid-hypokinetic: Rigidity,bradykinesia/hipokinesia, rest tremor Dystonia: dystonia is a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures” . Is caused by the simultaneous and sustained tonic contraction agonist and antagonist muscles and, diffusion of contraction to muscles that would not normally participate in the assumption/ maintenance of a given posture (overflow contraction). Athetosis: Dystal, continous, slow, irregular, dystonic movements Chorea/Ballismus: A state of excessive spontaneous movements, irregularly timed, non-repetitive, randomly distributed and abrupt in character occurring haphazardly with variable frequency and intensity.This may result in simple restlessness with mild intermittent exaggeration of gestures or expressions, walking motions like those of a dancer or produce a continuous flow of violent and incapacitating movements (Ballismus). Tremor: Rhythmical oscillation of a part of the body around a fixed point or plane Myoclonus: Sudden, brief, involuntary ,contractions of a muscle or group of muscles Tics: Stereotyped, involuntary, sudden, inopportune, non- propositional, absurd, irresistible movements or sounds or noises, of variable intensity Stereotypies: Motor behavior that is repetitive, patterned, often seemingly driven, and nonfunctional
TABLE 2. Some Peculiarities of the Main Types of Abnormal Movements Rigid-hypokinetic Rarely full syndrome before12 yr of age Athetosis Hand located Dystonia Task-specific (writing but not feeding; walking forward but not backward Sensory tricks ‘geste antagoniste’ Tremor Other abnormal movements may be rhythmic: myoclonus, stereotypies Myoclonus Chorea, tics, dystonia may appear as myoclonus Tics Are semi voluntary Do not interfere with voluntary movement Stereotypies Sometimes can be semi voluntary. Can be non rhythmic Do not interfere with voluntary movement Table 3. Abnormal Movements that Interfere Vs do not Interfere with Voluntary Movements Interfere • Rigid-hypokinetic síndrome • Dystonia • Tremor • Myoclonus • Chorea/Balismus Do not interfere: • Tics • Stereotypies
(as under) are quite common in the infantile period. Transient movement disorders Transient movement disorders are a clinically heterogeneous group of primary PMD (Table 4) with time limited expression, no or mild disability, and spontaneous fading.2,3 Except paroxysmal tonic upgaze deviation they disappear without, apparently, any after effects. Toxic, metabolic and, drug-induced conditions are excluded. Some have been recently identified such as fever induced dystonia.4 The investigations are always normal and there are no specific markers so the only diagnostic tool is clinical experience. The definite diagnosis can only be confirmed by the resolution of symptoms. Guided 532
TABLE 4. Transient Movement Disorders in Children Benign myoclonus of infancy Benign myoclonus of the newborn Benign opsoclonus Benign palatal myoclonus/tremor Benign paroxysmal tonic upgaze Benign paroxysmal torticollis of infancy Fever induced dystonia Jitteriness Head nodding Paroxysmal dyskinesia Paroxysmal tonic upgaze deviation Shuddering Spasmus nutans Tonic downgaze deviation Tonic reflex seizures of early infancy (Vigevano 1996,2001) Transient idiopathic dystonia of infancy Transient paroxysmal dystonia of infancy Transient tic
diagnostic clues are: age of onset mainly before 1 yr, monosymptomatic involvement (no developmental defect, pyramidal signs, or other defects), and a nonprogressive character. Familial cases have been reported in almost all these conditions, suggesting genetic factors. Management of transient MD is mainly through family information and close follow-up as long the symptoms are present. Exams are only indicated when sensible diagnostic doubt exists. Physical therapy or drug treatment has limited indications. Knowledge of these conditions prevents familial anxiety, unnecessary tests and unnecessary –sometimes adverse- treatment. Diagnostic mistakes are frequent, especially with epileptic or metabolic conditions. The dystonias The disorders that feature dystonia and athetosis as their main manifestation continue to raise difficult diagnostic and therapeutic problems more specifically in childhood5. Several mutant genes have been found to be linked to dystonic disorders (Table 5). Recently DYT16, a new recessively inherited form of Indian Journal of Pediatrics, Volume 76—May, 2009
Movement Disorders in Children: Recent Advances in Management TABLE 5. Molecular Classification of Dystonias with Pediatric Onset) Locus
Designation
DYT1 9q34 Idiopathic torsion dystonia (ITD). DYT3 Xq13.1 .X-linked dystonia /parkinsonism DYT5* 14q22.1 Deficit GTPCH DYT8 2q33-35 Paroxysmal non-kinesigenic choreoathetosis DYT9 1p21-23.3 Episodic choreothetosis with spasticity. DYT10 16p11.2-q12.1 Paroxysmal kinesigenic dyskinesia DYT11 7q21 Alcohol-responsive myoclonic dystonia DYT12 9q13 Rapid-onset dystonia parkinsonism DYT13 1p36.13-36.32 Early-onset dystonia with cranial cervical and upper limb involvement DYT16 2q31.2 Young onset dystnia-parkinsonism *DYT5 and DYT14 are the same forms
early onset generalized dystonia has been reported.6 It is caused by a homozygous mutation in PRKRA gene. Even if at present, the phenotype needs to be interpreted with caution because they are based on a small number of reported cases, DYT16 shows some peculiar characteristics: developmental delay and prominent bulbar involvement with dysphonia, dysarthria and even dysphagia. Moreover DYT16 has autosomal recessive inheritance and the other monogenic dystonias are autosomal dominant diseases. Concerning myoclonus-dystonia syndrome (DYT11) different studies confirm that SGDE gene plays a major role in their pathogenesis. 7 The autosomal dominant paternal inheritance, the very early onset (as young as before 1 yr of age) and, the presence of distal myoclonus in the upper limbs are important advances to the comprehension of this disorder.
TREATMENT Although a large number of pharmaceuticals and other therapeutic methods have been used in the treatment of dystonia, both idiopathic and symptomatic, only a few controlled studies are available. The beneficial effects on chronic dystonia of pharmacological agents are often limited and transient. Unfortunately, it may be wiser to accept the persistence of some dystonia rather than to use massive doses as the effect of drugs on higher cognitive functions are poorly known. The response to therapy is unpredictable and the mechanisms of action unknown. The agents commonly used include dopaminergic, anticholinergic and antidopaminergic drugs, benzodiazepines and baclofen. Deep brain stimulation is the most important advance in the treatment of generalized dystonia mainly in DYT1. In focal or segmental dystonias botulinum toxin may be useful. Continuous infusion of intrathecal baclofen can be useful in cases of severe secondary dystonia. Indian Journal of Pediatrics, Volume 76—May, 2009
A trial of L-DOPA is indicated in all cases of chronic dystonia. Small doses are used (62.5-100 mg 2-3 times daily) in association with a carboxylase inhibitor (carbidopa, benzerazide) to assess the efficacy and may be secondarily adjusted. Benzhexol (trihexyphenidyl) may be partially effective, start with a initial dose of 1.5 mg/day; the dose is then increased slowly (0.5 mg/d every other week) to reach doses as high as 20 mg/day in children. Side-effects (dryness of mouth, constipation, blurred vision, urinary hesitancy, anorexia, chorea, confusion and psychosis) can be avoided in many cases if the doses progression is slow enough. When benzhexol fails tetrabenazine, pimozide (ORAP) benzodiazepines, baclofen, carbamazepine have to be tried In case of generalised primary dystonia, chronic high frequency stimulation of the thalamic ventrolateral nucleus or of the globus pallidus internus may results in dromatic improvement. Botulinum toxin (BT) is now mainly used for the treatment of focal dystonias. Physiotherapy is useful for preventing or treating muscle retractions. Psychotherapeutic support is obviously necessary in a chronic disabling disease with preservation of intellectual functions. In summary treatment of generalized dystonia in children requires consistence and common sense on the part of the family, patient and physician. The physician must keep in mind that benefit of treatment is seldom complete and stable and advise the patient and family accordingly. Dopamine defects Pediatric dopamine defects show peculiar clinical characteristics (Table 6). Extraneurologic symptoms, neuroimaging abnormalities and metabolic studies in serum and urine are usually lacking or normal. Only CSF studies show a specific diagnostic metabolic profile. Phenotypes Broadly, two main phenotypes may be distinguished: TABLE 6. Symptoms That May Occur in Pediatric Dopamine Defects Dystonia Daily fluctuation of symptoms Tremor Brisk reflexes Oculogyric crises Palpebral ptosis Axial hypotonia Swallowing/alimentation difficulties Hypersalivation Excessive sweating Psychomotor/mental delay Unstable temperature
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Emilio Fernandez-Alvarez (1) Congenital or early infantile onset forms. Usually these patients show a complex syndrome mixed rigidhypokinetic-like syndrome and a variety of symptoms such as dyskinesias, severe hypotonia with brisk reflex, abnormal ocular movements, ptosis, hypersalivation and, thermoregulation and sweating disturbances. Episodes of coarse upper extremity tremor is an almost constant symptom. Diurnal fluctuation is difficult to assess at so young age. Stress may aggravate the symptoms, mainly tremor and ocular dyskinesia. EEG abnormalities, both associated and not with epilepsy (mainly myoclonic), may occur. As the child grows up, developmental delay is often obvious. By reason of severe hypotonia, hypomimia and ptosis, congenital neuromuscular disorders or hypoxic ischemic encephalopathy are frequent misdiagnosis. Tyrosine hydroxylase (TH), aromatic L-aminoacid decarboxylase (AADC), sepiapterin reductase (SR) and recessive GTP cyclohydrolase I deficiences are known causes. 8,9 (2) Late infantile or juvenile onset forms. First reported by Segawa as ‘hereditary progressive dystonia with marked diurnal fluctuation’, and later designated as Dopa-responsive dystonia, this condition is now-adays considered a clinical syndrome. Dystonia and/or parkinsonism and a marked and sustained response to low doses of L-Dopa are necessary criteria. Several enzymatic disorders cause this syndrome: defect of GTP cyclohydrolase I, and defect of tyrosine hydroxylase. The median age of onset is around 5 yr. A very few cases may have onset in the first year of life. The ratio of females to males is 2.5:1. The prevalence is estimated at 0.5 per million. An insidious onset, with fatigability, clumsiness of gait, and dystonic postures of the feet are the first symptoms. Often a progressive increase in severity of symptoms during the day and a marked decreasesometimes complete disappearance-following sleep are highly characteristic. The clinical picture of GTP cyclohydrolase I deficiency is quite variable so that a therapeutic test with L-Dopa is indicated in all primary dystonic syndromes. The dystonia is not ‘fluctuating’ in upto 23% of cases, Congenital correctable pes equinovarus and at 5 yr segmental dystonia, focal dystonia as writer’s cramp or guitarist’s fingers, cases with subtle signs sometimes induced only by writing, cases without progression, cases with spontaneous reduction/remission of dystonia and relapses, and cases that require higher doses of L-dopa for control have been reported. Usually the disease is progressive and eventually 534
involves all four extremities but generally does not affect the trunk. Abnormalities consistently predominate in the lower limbs even in the rare cases of onset in the upper extremities. Mild parkinsonian features such as rigidity of the limbs and trunk and hypomimia are commonly present. The disease may lead to severe disability if left to its natural course. In 25 % of longlasting untreated cases, fixed dystonia and muscular contractions in equinovarus develop and the benefit of sleep becomes less obvious. Brisk deep tendon reflexes and, in some cases, clonus may erroneously suggest a diagnosis of diplegia or spastic paraplegia. TREATMENT In late infantile and juvenile forms, administration of small doses (3-5 mg/kg/d) of L-Dopa combined with an inhibitor of peripheral decarboxylation usually produces a rapid response which is independent of the delay in initiating treatment. The tolerance of treatment is good. When the dose is excessive, choreic movements can occur but disappear with reduction of the dose. As treatment is lifelong, the lowest effective dose should be used. When the dose is too low there may be mild stiffness of the limbs or a tremor at the end of the day. In congenital or early infantile onset the response to L-Dopa treatment is variable. In some cases low-dose of L-Dopa (0,3-1 mg/kg/d) therapy may produce a rapid, spectacular improvement of symptoms. However, in others even with low L-Dopa doses marked choreic and dystonic movements may occur and a very slow dose increase is necessary. But even with this strategy effective therapeutic levels of L-Dopa cannot be achieved. This phenomenon is unclear. Compensatory receptor upregulation due to chronic partial catecholamine deficiency has been suggested. 10 Clumsiness and mild mental retardation have been reported in the follow-up of severe cases. Choreas One of the most interesting advances in chorea is the identification of the autosomal dominant benign hereditary chorea associated with extraneurological features, mainly primary hypothyroidism and lung disease. This syndrome is caused by mutations in the TITF1 gene on chromosome 14.11 Interesting benefit with L-Dopa treatment has been reported. 12 New paroxysmal disorders Paroxysmal movement disorders are a group of heterogeneous conditions that have been grouped according their most salient features as kinesigenic, Indian Journal of Pediatrics, Volume 76—May, 2009
Movement Disorders in Children: Recent Advances in Management nonkinesigenic, and exercise-induced. Clinical entities associating epilepsy and paroxysmal dyskinesia have recently been described. Infantile convulsions and paroxysmal choreoathetosis (ICCA) is an autosomal dominant disorder in which afebrile, brief, infantile convulsions and later (childhood or adolescence) paroxysmal choreoathetosis are associated. 13-17 The paroxysmal dyskinesias have been reported as spontaneous, exertion-induced or kinesigenic. Autosomal recessive rolandic epilepsy and paroxysmal exercise-induced dystonia and writer’s cramp have been reported in 3 patients of a consanguineous family. 14 The main symptoms are partial motor seizures of the Rolandic type, dystonic writer’s cramp and, from age 2-3 yr to 8-11 yr dystonic attacks involving the trunk or a hemibody appearing after exercise. Interestingly, in spite of the different type of inheritance both disorders have been linked to a close region of chromosome 16 suggesting that they might be caused by a defect in the same gene.13,15,16 Paroxysmal choreoathetosis with clinical characteristics reminiscent of those of non-kinesigenic paroxysmal dyskinesia but associated in some cases with spasticity has been described under the term of autosomal dominant paroxysmal choreoathetosis/ spasticity syndrome (CSE). Linkage to chromosome 1p has been demonstrated.18 Cases associating paroxysmal exertion-induced dyskinesia and epilepsy due to mutations in SLC2AI gene encoding the glucose transporte GLUT-1 have been reported.19 The high prevalence of metabolic diseases A large number of inborn errors of metabolism (IEM) are expressed in childhood age. PMD may be the first or the predominant symptom. When tics are excluded, more than 10% of PMD cases are due to metabolic diseases.20 A full description of these diseases is beyond the scope of this review. Unlike primary PMD, PMD caused by IEM have, sometimes, a rapid, sometimes abrupt, generalised onset associated with other signs of neurological dysfunction (spasticity, ataxia, cognitive impairment, seizures). They can appear in catabolic situations such as infections or fasting. The presence of systemic involvement, consanguinity or familial antecedents reinforces the suspicion. The most common metabolic PMD in terms of the onset age are shown in table 7. Tics Tics are the most prevalent PMD11 . Excellent reviews and books have been published on this subject. 21 Here we will only emphasise that because of their tremendous poly- and proteomorphism, tics must be Indian Journal of Pediatrics, Volume 76—May, 2009
TABLE 7. Common Inborn Metabolic Diseases Associated with PMD 1-New-born (a) branched-chain organic acidurias (b) Non ketotic hyperglycinemia 2-Infant (a) Glutaric aciduria type I (b) Leigh syndrome (subacute necrotizing encephalomyelopahy) 3 Children and adolescents Niemann-Pick disease type C Homocystinuria, Pantothenate-kinase-associated neurodegeneration (Hallervorden-Spatz disease), GM1 GM2 gangliosidosis
suspected in any child showing abnormal localised movement(s) starts without recognised cause. If there is a familial history of tics, attention deficit and/or obsessive traits, the possibility of tics is increased. Perhaps it could be useful to keep in mind a poorly reported feature: tics can start at very early age. The average age of onset of tics is between 5 and 10 yr but cases of onset earlier than 2 yr have been reported. 22 Interestingly, very early onset does not appear to have a predictive value of severity or impairment. CONCLUSION In summary, PMD are not only an increasingly interesting group of conditions within the large pediatric brain dysfunction disorders, but also an expanding area of neuroscientific knowledge. Many unsolved significant questions are arising from accurate clinical observations. Given the long life expectancy of children, appropriate treatment given at the correct moment in time will have an important, lasting effect on the personal, social and healthcare domains. REFERENCES 1. Fernández-Alvarez E, Aicardi J. Movement disorders in children. London; MacKeith Press, 2001. 2. Fernández-Alvarez E Transient movements disorders in children. J Neurol 1998; 245: 1-5 3. Moharir MD, Ouvrier RA, Grattan-Smith P Transient movement disorders of infancy and childhood In Fernández-Alvarez E, Arzimanogolou A, Tolosa E, eds. Paediatric movement disorders. Paris; John Libbey Eurotext, 2005. 4. Dooley JM, Furey S, Gordon KE, Wood EP. Fever-induced dystonia. Pediatric Neurol 2003; 58: 149-150. 5. Sanger TD. Toward a definition of childhood dystonia. Curr Opin Pediatr 2004; 16: 623-627. 6. Camargos S, Scholtz S, Simón-Sanchez J, Paisán-Ruiz C, Lewis P et al DYT16, a novel young-onset dystoniaparkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA. Lancet Neurol 2008; 7: 215-222.
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Indian Journal of Pediatrics, Volume 76—May, 2009
