American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 142C:158–172 (2006) ARTICLE

Neurobehavioral Disorders in Children, Adolescents, and Young Adults With Down Syndrome

GEORGE CAPONE,* PARAG GOYAL, WILLIAM ARES, AND EMILY LANNIGAN

The term dual-diagnosis refers to a person with mental retardation and a psychiatric disorder. Most children with Down syndrome (DS) do not have a psychiatric or neurobehavioral disorder. Current prevalence estimates of neurobehavioral and psychiatric co-morbidity in children with DS range from 18% to 38%. We have found it useful to distinguish conditions with a pre-pubertal onset from those presenting in the post-pubertal period, as these are biologically distinct periods each with a unique vulnerability to specific psychiatric disorders. Due to the increased recognition that psychiatric symptoms may co-occur with mental retardation, and are not inextricably linked to cognitive impairment, these conditions are considered treatable, in part, under a medical model. Improvement in physiologic regulation, emotional stability, and neurocognitive processing is one of the most elusive but fundamental goals of pharmacologic intervention in these disorders. ß 2006 Wiley-Liss, Inc.

KEY WORDS: Down syndrome; dual-diagnosis; neurobehavioral disorder; psychiatric disorder; attention deficit hyperactivity disorder; oppositional defiant disorder; disruptive behavior disorder; autistic spectrum disorder; pervasive ; ; ; obsessive-compulsive disorder; ; aberrant behavior checklist; Reiss scales; Diagnostic & Statistical Manual IV How to cite this article: Capone G, Goyal P, Ares W, Lannigan E. 2006. Neurobehavioral disorders in children, adolescents, and young adults with Down syndrome. Am J Med Genet Part C Semin Med Genet 142C:158–172.

NEUROBEHAVIORAL could have co-existing mental illness was case-reports and case-series focus on the DISORDERS IN PERSONS not generally accepted on theoretical presentation, diagnosis, and treatment of WITH MENTAL grounds. It was widely held that all various psychiatric disorders in adults RETARDATION AND behavioral disturbances were inherently with DS. The existing literature however, DOWN SYNDROME linked to cognitive impairment in fails to capture the complex background persons with MR, and did not require upon which these disorders may present, The term dual-diagnosis refers to a further diagnostic consideration or so there is little information regarding person with mental retardation and a evaluation. In recent decades, there has associated medical conditions, develop- psychiatric disorder [Lovell and Reiss, been wider recognition that persons mental attributes, or treatment outcomes 1993]. In the past, the notion that with MR can also have a co-existing in children with DS and any psychiatric persons with mental retardation (MR) psychiatric disorder. Increasing interest disorder. This review, which focuses on from medical and practi- children, adolescents, and young adults tioners has resulted in practical guide- with DS, represents a distillation and George Capone, M.D. has been Director of the Down Syndrome Clinic (DSC) at lines on how to work with this synthesis of information from several Kennedy Krieger Institute since 1990. His population [Silka and Hauser, 1997; sources including: the available literature primary interests include characterization Aman et al., 2004; Summers et al., on DS, dual-diagnosis in persons with of neurobehavioral phenotypes, diagnosis and management of complex neurodevelop- 2004]. An important implication of MR, a growing body of literature in mental and behavioral conditions, and these efforts is the realization that pediatric and psychopharma- pharmacologic interventions. psychiatric disorders are not inextricably cology, as well as our own clinical Parag Goyal and William Ares worked as Research Associates with Dr. Capone in the linked to cognitive impairment, and are experience over the past 15 years. treatable, in part, using a medical model. DSC; they have recently graduated from PREVALENCE ESTIMATES Johns Hopkins University. The prevalence of various psychia- OF PSYCHIATRIC Emily Lannigan also worked as a Research tric and behavioral disorders in children Associate in the DSC and recently graduated AND BEHAVIORAL and adolescents with Down syndrome from Loyola College in Maryland. CO-MORBIDITY IN *Correspondence to: George Capone, (DS) is available from small community, M.D., Kennedy Krieger Institute, 707 N. DOWN SYNDROME Broadway, Baltimore MD 21205. school, or clinic samples; which use E-mail: [email protected] different terminology,diagnostic criteria, The majority of children with DS do DOI 10.1002/ajmg.c.30097 and design to derive their data. A few not have a coexisting psychiatric or

ß 2006 Wiley-Liss, Inc. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c 159 behavioral disorder, and the available for significant behavior problems or activity level, physiologic estimates of psychiatric co-morbidity [Dykens et al., 2002]. Externalizing disturbance, atypical development, or range from 18% to 38% [Menolascino, behaviors (aggression, delinquency) neurocognitive function. Table I sum- 1965; Gath and Gumley, 1986; Gillberg tended to decrease after onset of puberty, marizes some of the attributes of young et al., 1986; Myers and Pueschel, 1991; while certain internalizing behaviors Coe et al., 1999; Dykens et al., 2002]. (social withdrawal, secretiveness) in- These estimates are greater compared to creased in adolescents and teenagers. Focus beyond overt behaviors children from the general population, Clark and Wilson sampled the parents but probably lower compared to other and teachers of 60 children with DS in search of diagnostic clues, children with similar levels of MR [Gath ascertained through an outpatient such as alterations in mood, and Gumley, 1986]. clinic and described an age-dependent arousal or activity level, Gath and Gumley sampled 193 increase in problems with attention children with DS from community deficit, anger/self-control, psychosis, physiologic disturbance, schools and used the Rutter Behavioral and withdrawal [Clark and Wilson, atypical development, or Scale and parent interviews to estimate 2003]. the prevalence of significant behavior neurocognitive function. problems at 38% (infantile 1%, LEARNED BEHAVIOR childhood psychosis 9%, conduct dis- AND PSYCHIATRIC children seen in our clinic with DS turbance 15%, emotional disturbance SYMPTOMATOLOGY diagnosed with psychiatric disorder. In 3%, and hyperactivity disorder 9%) adolescents and young adults with DS [Gath and Gumley, 1986]. Myers and It is too simplistic to dichotomize most who have achieved a previous stable level Pueschel sampled 261 children with DS, atypical or maladaptive behaviors in of function, the diagnostic process is ascertained from a large outpatient persons with MR as exclusively beha- only slightly less daunting. Guidelines to medical clinic, and used DSM-IIIR vioral or psychiatric, as neither ade- assist with diagnostic formulation in criteria to determine the prevalence of quately captures the complexity of most adults with MR have been proposed psychiatric disorders at 17.5% (infantile cases. Behavioral [Lowry and Sovner, [Sovner and Lowry, 1990; Schwartz and autism 1%, stereotypic-repetitive beha- 1991], psychiatric [Sovner, 1996], and Ruedrich, 1996], which caution against viors 4.5%, anxiety disorders 1.5%, integrated models [Gardner and Grif- over reliance upon DSM criteria as too conduct disturbance 12%, ADHD 6%) fiths, 2004] have been advanced to limiting, when used alone, to make a [Myers and Pueschel, 1991]. Kent et al. explain the nature of maladaptive beha- diagnosis [Sovner, 1986; Silka and used the Childhood Autism Rating viors. Maladaptive behaviors, which Hauser, 1997]. Scale, the Screening come to clinical attention are often Questionnaire, and ICD-9 criteria to related to unrecognized disturbance(s) BEHAVIORAL STYLE AND estimate the prevalence of autism spec- in social-psychological, developmental- COMMON CONCERNS IN trum disorders at 7% in a small commu- physiological, or medical-psychiatric YOUNG CHILDREN WITH nity-based sample of 33 children with factors [Silka and Hauser, 1997]. DOWN SYNDROME DS [Kent et al., 1999]. Problem behaviors in young pre- Pueschel characterized a pattern school and school-age children with DS Preschoolers with DS can exhibit the full of hyperactivity-impulsivity-inattention frequently occur within a setting of range of temperament styles; however, and stubbornness-disobedience in over atypical cognitive-language-social func- there may be qualitative differences half of the 40 school-age children with tion, inconsistent progress in achieving on such traits as ‘‘response intensity’’, DS ascertained from an outpatient clinic or demonstrating developmental skills, ‘‘threshold for stimulation,’’ and sample [Pueschel et al., 1991]. Coe et al. and considerable caregiver anxiety or ‘‘mood’’ when comparing toddlers with surveyed the parents and teachers of confusion. Distinguishing a component DS to mental-age-matched control chil- 44 children with DS ascertained from of psychiatric symptomatology within dren [Gunn and Berry, 1985]. There is a school and community sources and the setting of problem behavior is critical trend for infants with DS classified as determined the prevalence of behavior because it helps to prioritize and set ‘‘difficult’’ to become reclassified as problems at 32%; identifying attention, realistic expectations for pharmacologic, ‘‘easy’’ as they become older [Ganiban conduct, psychotic behavior, and social behavioral, and educational treatments. et al., 1990], which is consistent with withdrawal concerns as the most com- Because the distinction between psy- developmental theory which acknowl- mon [Coe et al., 1999]. Dykens et al. chiatric symptom and learned behavior edges the role of increasing biological reported on 211 children with DS is not always straightforward in young maturation, cognitive organization, and ascertained from community and clinical children or those with low-level skills we capacity for self-regulation [Robarth sources, and estimated the prevalence of have found it helpful to focus beyond and Derryberry, 1981]. The beha- maladaptive behavior at 20%; while an overt behaviors in search of diagnostic vioral-temperamental traits commonly additional 15% were rated as borderline clues, such as alterations in mood, observed in young children with DS 160 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c ARTICLE

TABLE I. Features Which may Suggest a Psychiatric Syndrome in Preschool Children With Down Syndrome Behavior New or sudden-onset Rapidly worsening in frequency, intensity or duration Associated with significant impairment in development, learning, or social function Physiologic or emotional symptoms Abnormal pattern, increased or decreased activity-level, mood instability, increased irritability, unusual responding to sensory stimuli, repetitive movements, or self-injury Neurocognitive symptoms Abnormal gaze-preference, regulation of attention, cognitive-organization, play-routines, reciprocal social-interaction, or loss of established skills (developmental regression) Family history Major psychiatric disorder in 1st degree relatives: , , OCD, autism

include a sociable-affectionate quality, include: (1) increased motor activity tings or situations, and are generally cognitive inflexibility, and resistance and impulsivity; (2) non-compliance or mild or self-limited. In contrast, beha- to change. Some children demonstrate tantruming; (3) agitation, anxiety, or viors which result in significant impair- a rather stubborn-persistence, need- disruptiveness; (4) repetitive move- ment in learning or socialization or any for-sameness, and repetitive or perse- ments; (5) peculiar sensory responding; dangerous behavior are a cause for verative qualities [Evans and Gray, (6) atypical neurocognitive processing; concern at any age. Table II emphasizes 2000]. and rarely (7) disinterest in social inter- some of the features helpful in distin- Common behavior concerns in action. Sometimes these behaviors will guishing between common conditions pre-school children with DS often occur infrequently only in certain set- of lesser significance, and serious

TABLE II. Common Behavior Concerns in Preschool Children With Down Syndrome

Does not necessarily indicate a May indicate a neurobehavioral or neurobehavioral disorder psychiatric disorder General pattern Occurs only in specific settings or situations, Occurs across multiple environments, is is mild or self-limited, does not interfere intense or frequent, results in impairments with learning or socialization in learning or socialization Increased motor activity and impulsivity When excited or over-stimulated Associated with unsafe or high-risk behaviors Non-compliance or tantruming When limits are set or a sudden transition Associated with aggression, self-injury or occurs destructiveness Agitation, anxiousness, or disruptiveness When experiencing pain or physical Results in physical harm to self or others or discomfort property destruction Repetitive movements Usually easy to interrupt, of brief duration; Performed in a variety of situations, and motor ‘‘’’ may be seen when becomes a preferred activity which is tired or bored, perhaps to regulate levels of difficult to interrupt arousal; motor ‘‘overflow’’ phenomena may be seen when overexcited Peculiar sensory responding Tactile defensiveness, auditory hypersensi- Associated with agitation, anxiety, or tivity, or oral-motor sensitivity resulting in autonomic symptoms aversion or mild agitation in response to sensory stimulation Atypical neurocognitive processing With certain visual and hearing problems, or Inability to attend to fun tasks or organize acute medical illnesses purposeful activity; atypical attention or gaze abnormalities; inability to process or understand spoken words or gestures Disinterest in social interaction or play With medical illnesses Little peer interaction or interest imitating children at play; inability to engage in symbolic play or organized play activity ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c 161 neurobehavioral or psychiatric disorders Although speculative, it appears that explain-away every type of behavior. In in preschool children with DS. multiple etiologies are suspect, some TableIV we consider primary diagnostic common to all persons with develop- criteria, frequently associated behavioral mental cognitive impairment, and others, and developmental attributes, medical BEHAVIOR SCALES TO biological, physiological, or medical, considerations, treatment approaches CHARACTERIZE which are associated with trisomy 21. and long-term concerns for each of the NEUROBEHAVIORAL AND Table III organizes and summarizes some common categories of psychiatric dis- PSYCHIATRIC DISORDERS of the putative risk-factors which may order seen in pre-pubertal children with Little research exists whereby a cohort of predispose persons with DS to neurobe- DS. persons with DS diagnosed a priori with havioral and psychiatric disorders. When a psychiatric disorder are characterized considering specific categories of dis- Attention Deficit according to some well-validated beha- orders, we distinguish conditions with a Hyperactivity Disorder vioral rating scale. These behavioral pre-pubertal onset from those typically instruments could prove useful both in presenting in the post-pubertal period, as determining the symptom profile asso- theyare considered biologically distinct Definition, classification, and presentation. At- ciated with specific psychiatric disor- periods with unique vulnerability to tention deficit hyperactivity disorder ders, or as an outcome-measure of specific types of psychiatric disorder (ADHD) is diagnosed by the presence intervention. There are several easy to [Walker and Bollini, 2002]. of inattention, impulsivity, and hyper- administer, informant-based question- activity disproportionate to mental age, naires used to provide a snapshot of which results in significant academic or Disorders With Pre-Pubertal maladaptive behavior or psychiatric social impairment. Hyperactivity and Onset in DS symptomatology in children and adults impulsivity with or without inattention with mental retardation [Dykens, 2000; Most of the disorders of pre-pubertal may be seen in young children with DS Rush et al., 2004]. children present prior to age 7 years, before 36 months of age [Green et al., One of the most widely used often earlier. Clinicians evaluating chil- 1989]. Some degree of negativism and instruments for the assessment of persons dren with DS face the challenge of oppositional behavior in young DS with cognitive impairment and mala- children is not uncommon. daptive behavior is the Aberrant Beha- Associated behaviors and symptoms. Hyper- vior Checklist (ABC) [Aman et al., Young children with DS activity and impulsivity place DS children 1985]. The ABC was developed to frequently manifest atypical withcognitiveimpairmentatespecially measure a variety of maladaptive beha- high risk for accidental injury, , viors and their response to treatment in or an unusual combination running away, or becoming lost. In the persons with moderate to profound of neurobehavioral symptoms general population, ADHD may become mental retardation. It has been used in increasingly difficult to manage as a child children and adolescents with dual rather than classic gets older, especially if they have anxiety or diagnosis [Rojahn and Helsel, 1991] symptomatology. other co-morbidities [Biederman et al., and in children with DS [Capone et al., 1991; Aman et al., 1996]. 2005]. The Reiss Scales for Children’s Dual Diagnosis has been used for screen- interpreting the significance of behavior ing and diagnosis of maladaptive beha- within the context of an expanding Associated medical factors. Hyperthyr- viors and psychiatric symptoms in array of psychosocial influences (par- oidism, hearing loss, sleep disturbance children, adolescents, and young adults ent-family-school); and expectation for [Levanon et al., 1999] or sleep apnea with mental retardation [Reiss and increasingly sophisticated cognitive, [Marcus et al., 1991; Fallone et al., 2002; Valenti-Hein, 1994] and persons with behavioral, and adaptive skills, which is Blunden et al., 2005], and medication DS [Clark and Wilson, 2003]. occurring against a background of side effects (stimulants, SSRIs, antihista- delayed or atypical brain function and mines, adrenergic agonists, or caffeine) frequent medical illness. Upon observa- need to be considered as possible COMMON tion, young children with DS frequently etiologic factors when evaluating NEUROBEHAVIORAL AND manifest atypical or an unusual combi- children with DS þ ADHD. PSYCHIATRIC DISORDERS nation of neurobehavioral symptoms IN CHILDREN WITH rather than classic symptomatology. For Oppositional-Defiant and DOWN SYNDROME those unfamiliar with evaluating young Disruptive Behavior Disorders Persons with DS are at risk for exhibiting children with cognitive impairment, it is neurobehavioral and psychiatric disorders. important to avoid falling into the trap of The current status of DS research does not ‘‘diagnostic overshadowing’’ whereby Definition, classification, and presenta- allowustodeterminewhythisisso. the presence of MR is invoked to tion. We distinguish the related 162 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c ARTICLE

TABLE III. Factors Which may Predispose Persons With Down Syndrome to Neurobehavioral or Psychiatric Disorders

Social Psychological Developmental Neurophysiological Medical Pre-pubertal disorders All ages

Parenting style: overly Temperament style: Severe cognitive Developmental Recurrent rigid, anxious or difficult, anxious impairment neurobiological hospitalizations permissive Cognitive style: rigidity, Expressive speech: dysfunction: Pre-existing or active Family or need for sameness, non-verbal neuroplasticity, seizures dysfunction , Receptive synaptic function, Hearing or visual impulsiveness language: poor cell-signaling impairment comprehension GE reflux-esophagitis Extreme food refusal Pain (ENT, dental GI, skeletal, menstrual) Post-pubertal disorders Primary (without apnea) Awareness of being Cognitive style: executive Expressive speech: As above Obstructive sleep apnea different dysfunction (as above) non-verbal Ongoing CNS Hypo- or Unrealistically high impairment: amyloid, hyper-thyroidism expectations oxidative damage, Major life transitions mitochondrial Emotional loss, dysfunction, rejection, or trauma inflammation, neurotoxicity Neural response to physiologic stress

conditions, oppositional-deficit disorder pattern of undesirable behavior may cus et al., 1991; Chervin, 2003], and (ODD) and disruptive behavior disorder become established which is difficult to medication side effects need to be (DBD), according to the severity, inten- change. considered as possible etiologic factors- sity, and pattern of negativistic, opposi- when evaluating children with tional, disruptive, or aggressive behavior. DS þ ODD or DBD. Associated behaviors and symptoms. Children with DS þ ODD or DBD Individuals in the general population frequently have comorbid ADHD. who become increasingly disruptive or Autistic Spectrum and Similarly, children with DS þ ADHD aggressive over time may have other Stereotypy Movement Disorders and comorbid anxiety or associated conditions which contribute are frequently oppositional, disruptive, to their worsening problem, such as or aggressive. Taken together, DS þ Definitions and classification. The autis- inadequate structure and discipline, ADHD-ODD-DBD align themselves spectrum disorders (ASD) and stereo- unstable environmental factors, poor along a continuum of disruptive beha- typy movement disorder (SMD) are speech skills, learned behavioral vior or conduct disturbance. Opposi- considered together because they may responses, rigid-inflexible cognitive tional behavior with ADHD may be present similarly and are frequently style, anxiety, rapid-cycling, or atypical seen in young DS children prior to age of confused with one another. Persons mood disorder [Biederman et al., 36 months, or oppositional behavior diagnosed with autism manifest qualita- 1991; Dilsaver et al., 2003; Vance may develop in temperamentally vul- tive impairment in reciprocal social and et al., 2005]. The degree of cognitive- nerable toddlers without obvious hy- communication skills, along with language impairment is also an peractivity or impulse dyscontrol. restricted interests, and repetitive play- important prognostic factor to Aggression in young DS children is very routines or movements. When this consider. often impulsive or attention-seeking social-communication-stereotypy triad rather than malicious. Children with manifests prior to 36 months, a diagnosis moderate-severe cognitive impairment Associated medical factors. Physical pain of autism is made. Pervasive develop- are quite capable of manipulating their (GI, ENT, headache, dental, musculos- (PDD)—not otherwise caretakers through the use of disrup- keletal, menstrual), hyperthyroidism, specified is a term used when a child fails tive behavior. Thus, a long-standing sleep disturbance, or sleep apnea [Mar- to meet clinical threshold of all three ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c 163 core-criteria for autism, yet all the Associated behaviors and symptoms. Some havioral phenotype of children with essential elements (must include social degree of increased sensory seeking or DS þ ASD, and DS þ SMD [Capone impairment) are present. In some chil- unusual sensory responding, anxiety,and et al., 2005]. Subjects with DS þ ASD dren with DS, developmental regression sleep disturbance are often associated score significantly higher (>7 points occurs after 36 months, without a prior with DS þ ASD [Ghaziuddin et al., average, P < 0.0001) on Hyperactivity, indication of atypical development. 1992; Howlin et al., 1995]. Some Irritability, Lethargy, and Stereotypy When significant impairments in children with DS þ ASD also manifest subscales compared with DS controls, social-language reciprocity result, such significant impulsivity, cognitive disor- while subjects with DS þ SMD score cases are thought to represent late-onset ganization, disruptive behavior or significantly higher (>7 points average, autism or childhood disintegrative dis- self-injury, while others may appear P < 0.0001) on the Hyperactivity and order (CDD). In about 1/3 of our markedly inactive, withdrawn and self- Stereotypy subscales [Capone et al., subjects with DS þ ASD, there is a absorbed. Agitation or disruptive 2005]. In another comparison, subjects history given of lost cognitive-lan- behavior can result when children are diagnosed with DS þ ADHD score guage-social skills without co-occurring transitioned away from preferred activ- moderately higher (3–7 points average, clinical seizures. ities too abruptly. The severity of P < 0.001) on the Hyperactivity sub- Dyskinesia and stereotypic move- cognitive-language impairment and the scale, while those with DS þ ODD and ments are common in persons with DS presence of other co-morbidities are DS þ DBD score significantly higher [Haw et al., 1996]. Children diagnosed important prognostic factors to consider. (>7 points average, P < 0.0001) on both with DS þ SMD may at first glance be the Hyperactivity and Irritability sub- regarded as ‘‘autistic-like’’ because of scales compared with DS controls Associated medical factors. Children with their frequently intense repetitive beha- (Capone, unpublished). DS and a history of difficult to control viors or stereotypic movements, how- infantile spasms or myoclonic seizures ever they retain functional social- are at risk for developing ASD [Gold- PHARMACOLOGIC communication and reciprocity, thus berg-Stern et al., 2001; Eisermann et al., STRATEGIES IN PRE- excluding them from a label of ASD. 2003], and should be monitored closely. PUBERTAL CHILDREN When considered together however, DS þ Autism-PDD-SMD appear to The use of psychotropic medications for align along a continuum of cognitive- young children and adolescents with PRE-PUBERTAL CHILDREN: language-social impairment [Capone psychiatric disorders has grown drama- ABERRANT BEHAVIOR et al., 2005]. tically during the past decade [DeBar CHECKLIST et al., 2003; Zito et al., 2003]. Presentation. Children may display The outpatient DS Clinic at Kennedy Fewer research studies address children unusual or atypical behaviors during Krieger Institute has evaluated over and adolescents with dual-diagnosis infancy or the toddler years [Capone, 200 children (<13 years) with DS and specifically, thus we know little about 2002]. Social disinterest, lack of a neurobehavioral or psychiatric disor- tolerability, safety, and long-term con- sustained joint attention, and little der since 1990. The Aberrant Behavior sequences of medication use in this interest in signing or gestures may be Checklist (ABC) is utilized to character- population [Stavrakaki, 2004]. In 2004, noted. Behaviors often seen prior to 36 ize behavioral profiles for clinical and an Expert Consensus Panel published its months include: repetitive motor beha- research purposes. After obtaining update on the ‘‘Treatment of Psychiatric vior, head banging or self hitting, informed consent from parents, a 58- and Behavioral Problems in Individuals fascination and staring at lights or ceiling item ABC is typically completed at the with Mental Retardation’’ which is an fans, episodic deviation of eye gaze, time of the child’s initial evaluation. A excellent resource addressing diagnosis, extreme food refusal, and unusual play comprehensive medical, developmental, assessment and psychosocial treatments with toys or other objects. Auditory behavioral and psychiatric history, and and provides detailed guidance on med- processing impairments may cause the assessment is performed by a neurode- ication selection and management in child to act as if deaf or produce little velopmental pediatrician (gc) after this population [Aman et al., 2004]. A speech. In some children symptoms which a diagnosis is made. Our findings summary of medications used to treat suggesting PDD have a slow and insi- based on 190 children with DS, between specific target symptoms in children dious onset, progressing over many 3 and 13 years, suggests that common with DS and dual diagnosis is provided months or years; or sometimes there is psychiatric disorders have a character- in Table V. a distinct developmental regression in istic profile on the ABC which permits speech, language, and social skills them to be distinguished from each DISORDERS WITH POST- between 3 and 6 years. Repetitive other, and ‘‘control’’ DS subjects with- PUBERTAL ONSET IN DS motor behaviors, anxiety, and sensory out behavioral co-morbidity. We aversions may appear or intensify at that recently reported our findings using Disorders of post-pubertal children time. the ABC to characterize the neurobe- typically present after 13 years of age. 6 MRCNJUNLO EIA EEISPR SMNR NMDCLGNTC) O 010/jgcARTICLE 10.1002/ajmg.c DOI GENETICS): MEDICAL IN (SEMINARS C PART GENETICS MEDICAL OF JOURNAL AMERICAN 164

TABLE IV. Diagnostic Considerations, Evaluation and Management of Childhood Psychiatric Disorders in Pre-Pubertal Children With Down Syndrome

Psychiatric disorder DSMIV diagnosis Associated features Medical conditions Treatment approaches Long-term concerns Primary criteria and other Variable Variable Prioritize individually considerations Attention deficit Inattention (Developmental) Sleep apnea (Child) (Child) hyperactivity disorder Impulsivity Mild-moderate Sleep disturbance Discipline Academic failure Hyperactivity cognitive/adaptive Hyperthyroidism Mental-age appropriate Accidental injury Consider anxiety impairment Hearing loss rules/expectations Monitor for co-morbid disorders (Behavioral) Medication effects Behavior management Negativistic Medications Defiant Anxious (Caregivers) (Caregivers) Education, support Frustration, anxiety

Oppositional-defiant Negativistic (Developmental) Sleep apnea (Child) (Child) disorder Resistant Mild-moderate Sleep disturbance Discipline Academic failure Defiant cognitive/adaptive Mental-age appropriate Anxiety or mood-disorder in Consider ADHD or anxiety impairment rules/expectations evolution? disorder (Behavioral) Behavior management Tantrums, argumentive, non-compliant, angry, runs away, stops- drops-plops Hyperactivity, impulsivity Anxiety (Caregivers) (Caregivers) As above As above

Disruptive disorder-NOS Agitation, Aggression (Developmental) Sensory impairment (Child) (Child) Disruptiveness Moderate-severe Sleep apnea Medications Academic failure Property destruction cognitive/adaptive Occult pain Discipline Safety Consider ADHD, anxiety, impairment Hyperthyroidism Mental-age appropriate Social rejection OCD or mood disorder (Behavioral) Medication effects rules/expectations Difficulty with medical/dental Physical-injury to self or Behavior management procedures others Medication non-responder Hyperactivity, impulsivity (common) Mood-instability, anxiety (Caregivers) (Caregivers) Rigid-inflexible style As above As above Training, respite Depression Marital-family problems disorders Qualitative impairment in (Developmental) Infantile spasms or (Child) (Child) 165 10.1002/ajmg.c DOI GENETICS): MEDICAL IN (SEMINARS C PART GENETICS MEDICAL OF JOURNAL AMERICAN ARTICLE social-communication Regression myoclonic seizures Medications Safety reciprocity skills Inconsistent Visual or hearing Functional communication Constant supervision Narrowly restricted interests developmental progress impairment Behavior management Low cognitive/adaptive function and repetitive motor acts Non-communicative Occult pain, ENT, dental, ABA-type curriculum Difficulty with medical/dental or ritualized play Severe cognitive/adaptive GI, menstrual (If SIB or Monitor sensory procedures Consider CDD if onset after impairment aggression is present) environment Medication non-responder 36 mo Dysphagia (common) (Behavioral- Medication side-effects (limiting) Physiological) (Requires supportive Residential placement Self-injury evidence) Disruptiveness CNS effects of Anxiety, irritability chemotherapy? Unusual vocalizations Autoimmune disorders? Food refusal Unusual sensory seeking/responding Cognitive disorganization Sleep disturbance (Caregivers) (Caregivers) Education, support, Frustration-anxiety, training, respite, waivers depression-guilt, isolation-despair Marital-family problems

Stereotypy movement Repetitive motor acts which (Developmental) Occult pain, ENT, dental, (Child) (Child) disorder impair function Speech dyspraxia GI, menstrual (If SIB or Medications (SIB or ASD in evolution? Consider PDD if socially Moderate-severe aggression is present) anxiety) Poor cognitive/adaptive impaired cognitive/adaptive Monitor sensory function impairment environment, Poor developmental/academic Dysphagia communication, skills (Behavioral-Physiological) educational progress Self-injury Unusual or atypical attention Disruptiveness Anxiety Unusual vocalizations Food refusal Unusual sensory seeking/responding Inconsistent social and communication skills (Caregivers) (Caregivers) Sleep disturbance Education, Support? As above 166 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c ARTICLE

TABLE V. Medication Guidelines for Children with Down Syndrome

Psychiatric syndrome Common target behaviors Initial considerations Other considerations Attention deficit hyperactivity Inattention Stimulant/atomoxetine Bupropion disorder Hyperactivity-impulsivity Guanfacine/clonidine Stimulant/atomoxetine Guanfacine/clonidine Melatonin

Oppositional-defiant disorder ADHD As above Bupropion and disruptive disorder-NOS Defiance Bupropion Physical aggression or Atypical neuroleptic Mood stabilizer or destructiveness beta-adrenergic antagonist Agitation-anxiety-irritability Mood stabilizer or SSRI Atypical neuroleptic OCD-like perseveration SSRI Atypical neuroleptic

Autism spectrum disorders or Social withdrawal and cognitive Atypical neuroleptic Second-atypical neuroleptic stereotypy movement disorder disorganization Atomoxetine with complex features (SIB, Stereotypy (with SIB) Atypical neuroleptic Second-Atypical neuroleptic, ADHD, anxiety) Physical aggression or As above mood stabilizer, SSRI destructiveness As above Perseveration Atypical neuroleptic SSRI Anxiety Buspirone SSRI Distractibility Stimulant/atomoxetine Bupropion Hyperactivity Guanfacine/clonidine Stimulant/atomoxetine Insomnia Atypical neuroleptic (HS) Melatonin, guanfacine/clonidine Minor medical procedures Benzodiazapine (Short-acting) Atypical neuroleptic (sedation) (X-rays, phlebotomy, dental)

Clinicians evaluating adolescents and DEPRESSIVE ILLNESS disorder [Pary et al., 1996, 1999]. young adults with DS face the challenge Psychosocial stressors may precede the of interpreting behavioral change within Definition, Classification, onset of mood disorder in adolescents the context of personal transition in the and Presentation and young adults with DS. Increasing family-school-workplace setting, and awareness of being different, lack of expectation for increasingly sophisti- Major depression and minor mood acceptance by school peers and sudden cated socially appropriate function. disturbance () are included change or loss in personal relationships While symptoms of mood, anxiety, or here together. Depressed mood, crying, are commonly cited occurrences. thought disorder can be seen across all decreased interest, psychomotor slow- Bereavement, which often goes unrec- levels of cognitive function, psychiatric ing, fatigue, /weight change, ognized, and hence untreated, may symptoms are more noticeable in those and sleep disturbance are the most exacerbate symptoms of depression or with higher pre-morbid cognitive and common DSMIV criteria observed in anxiety in persons with DS who experi- adaptive function. In the MR popula- persons with DS and major depression. ence emotional loss [Dodd et al., 2005]. tion, individuals with severe cognitive Poor concentration, reduced speech, impairment may present with ‘‘difficult- feelings of worthlessness or guilt and Associated Behaviors to-diagnose’’ behavior disorders [Mik- agitation may also be present [Cooper and Symptoms kelsen and McKenna, 1999]. In Table VI and Collacott, 1994; Myers and we consider primary diagnostic criteria, Pueschel, 1995]. Self-care routines may Obsessions, compulsions, anxiety, and frequently associated behavioral and deteriorate, requiring assistance, or fre- extreme social withdrawal are com- developmental attributes, medical con- quent prompting. In minor mood dis- monly associated with major depression siderations, treatment approaches and turbances typically fewer than five of the in persons with DS [Myers and Pueschel, long-term concerns for each of the above symptoms are present, and are less 1995; McGuire and Chicoine, 1996]. common categories of psychiatric dis- severe. Rarely individuals will present Premenstrual syndrome may occur in order seen in adolescents and young with hypomanic or mixed-mood state conjunction with menstrual cycles in adults with DS. suggestive of a bipolar or atypical mood females. Psychotic or catatonic-like RIL MRCNJUNLO EIA EEISPR SMNR NMDCLGNTC) O 010/jgc167 10.1002/ajmg.c DOI GENETICS): MEDICAL IN (SEMINARS C PART GENETICS MEDICAL OF JOURNAL AMERICAN ARTICLE

TABLE VI. Diagnostic Considerations, Evaluation and Management of Psychiatric Disorders in Adolescents and Adults With Down Syndrome

Psychiatric disorder DSMIV diagnostic criteria Associated features Medical conditions Treatment approaches Long-term concerns Primary criteria and other Variable Variable Prioritize individually considerations Depressive illness Depressed mood Anxiety Sleep apnea (Adolescent/adult) Medication non-responder Decreased interest Obsessions, compulsions Sleep disturbance Treat medical concerns Medication side-effects Psychomotor slowing Mood fluctuation, PMS Hypothyroidism Medications Risk for weight gain, Fatigue (females) Chronic pain Reduce stressors metabolic syndrome, Sleep disturbance Reduced speech Visual or hearing Counseling OSA Appetite, weight loss Catatonic-like impairment (Caregivers) Employability, quality of life Psychosocial stressors, Education, Support Ageing parents bereavement

Obsessive-compulsive Compulsions Agitation, disruptiveness PANDAS (especially if pre- (Adolescent/adult) Medication non-responder disorder Obsessions Mood disturbance pubertal onset) Treat medical concerns Medication side-effects Anxiety Verbal perseveration Medications Risk for weight gain, Consider PTSD , stammering Maintain routines metabolic syndrome, , mannerisms Reduce stressors OSA EPS, cogwheel rigidity Behavior management Employability, quality of life Obsessional slowness Counseling Ageing parents Physical-emotional trauma (Caregivers) Education, training, support

Psychotic-like disorder Positive symptoms: Major depression Sleep apnea (Adolescent/adult) Medication non-responder -hallucinations Anxiety, Sleep disturbance Treat medical concerns Medication side-effects Negative symptoms: Sleep disturbance Hypothyroidism Medications Risk for weight gain, Cognitive and behavioral Fatigue calcifications Reduce stressors metabolic syndrome, disorganization Appetite, weight loss Maintain stable OSA Social withdrawal EPS, cogwheel rigidity environment Employability, quality of life Reduced speech Catatonic-like (Caregivers) Ageing parents Affective blunting Education, support Apathy Psychosocial stressors Psychomotor slowing 168 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c ARTICLE features may further complicate the and Antochi, 2004]. Sudden, unplanned as the primary syndrome without neu- interpretation of symptoms and their changes at school or workplace, the loss rovegetative signs of depression. Though treatment in some individuals. A history of a friend or family member, and uncommon in persons with DS, delu- of daytime somnolence, frequent yawn- physical or emotional trauma are com- sions or psychosis may represent the ing, and excessive fatigue should raise monly cited occurrences. manic-phase of bipolar disorder [Pary the suspicion of obstructive sleep apnea et al., 1999]. Positive symptoms such as (OSA) or sleep disturbance. Associated Behaviors paranoia, delusions, and hallucinations and Symptoms often exist in the setting of low mood, apathy, motor slowing, and sleep dis- Associated Medical Factors Hording of seemingly worthless objects turbance [Myers and Pueschel, 1994, Occult OSA or primary sleep disorders (clips, pens, or papers), and repetitive 1995; Khan et al., 2002]. It is important are common in adolescents and adults list-making may be seen. Perseveration not to mistake increased self-talk, or talk with DS [Marcus et al., 1991; Resta on past relationships or events, and the to imaginary friends, which may occur et al., 2003]. Disturbance of sleep need to frequently ask about scheduled during times of stress or isolation, as architecture related to frequent micro- activities may be annoying to caretakers. prima facia evidence of psychosis [Hurley, can have a significant impact on If some degree of physical or emotional 1996]. Occasionally, the presentation mood, attention, cognition, and motiva- trauma can be substantiated a diagnosis is characterized predominantly by tion level [Andreou et al., 2002; Means of post-traumatic stress disorder (PTSD) ‘‘negative symptoms’’ in the absence of et al., 2003]. Individuals with both should be considered. Mood distur- delusions or hallucinations. Negative depression and OSA are not uncom- bance is often present, which may be symptoms such as cognitive and beha- mon. A full response to anti-depressant mild without neurovegetative signs, or vioral disorganization, social with- medication may not be achieved until severe enough that a diagnosis of major drawal, apathy, psychomotor slowing, the sleep abnormality is recognized depression is warranted. Self-care rou- reduced speech, and affective blunting and treated successfully. Chronic pain, tines typically take progressively more may be striking. Except in cases where sudden loss of hearing or vision and time to complete and require excessive neurovegetative signs are absent, pure hypothyroidism can occasionally trigger prompting or supervision by caretakers. negative symptoms can be difficult to symptoms of mood disturbance. Resting tremor, cogwheel rigidity and distinguish from depression. As in motor slowing suggesting a Parkinso- depression, self-care skills may be lost nian-like condition is sometimes noted or greatly impaired in persons with OBSESSIVE-COMPULSIVE on examination. Occasionally, extreme DISORDER DS þ Psychotic-like disorder. A history motor slowing may take the form of of daytime somnolence, frequent yawn- ‘‘obsessional slowness’’ [Charlot, 2002]. Definition, Classification, ing, and fatigability especially in con- junction with negative symptoms alone, and Presentation Associated Medical Factors should raise a suspicion of sleep apnea. Obsessive thoughts may be difficult to In the general population, motor or ascertain in persons with cognitive vocal tics, adventitial movements, com- Associated Behaviors impairment and limited speech. Repe- plex-mannerisms, or bizarre motor and Symptoms titive, compulsive acts, by their very behaviors may be seen in OCD [Yar- nature, are easier to appreciate in persons yura-Tobias et al., 2003]. These symp- Anxiety, motor slowing, and persevera- with DS [O’Dwyer, 1992; Prasher and toms, when present in pre-pubertal tion may be prominent. In our experi- Day, 1995]. In persons with DS þ OCD, children with an abrupt symptom onset, ence, many subjects have subtle ordering and tidiness compulsions should raise suspicion of pediatric auto- extrapyramidal symptoms, tremor, cog- are common, especially rearranging immune neuropsychiatric disorders wheel rigidity, or adventitial movements. personal belongings or opening/closing associated with streptococcal infection doors, cabinets, blinds, and light or (PANDAS), [Snider and Swedo, Associated Medical Factors switches. If the compulsion to perform 2004; Van Toorn et al., 2004]. a certain action is so strong that anxiety In the general population disturbance of or agitation ensues when the person is sleep architecture related to frequent PSYCHOTIC-LIKE interrupted or prohibited from carrying microarousals, or severe sleep apnea with DISORDER it out, then criteria for obsessive-com- hypoxemia or hypercarbia, has a signifi- pulsive disorder (OCD) may be met. cant impact on frontal executive Definition, Classification, Caretakers sometimes report the sudden function, attention, and cognition orga- and Presentation appearance or intensification of pre- nization [Jones and Harrison, 2001; existing OCD symptomatology, accom- Psychotic disorder usually occurs within Beebe and Gozal, 2002]. In persons with panied by notable changes in affect and the setting of major depression in DS, it may be necessary to manage sociability [O’Dwyer, 1992; Stavrakaki persons with DS, but sometimes occurs positive symptoms with medication in ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c 169 order to obtain the level of cooperation have a profile on the Reiss, which adolescents and young adults with DS needed for an overnight sleep study.Basal permits them to be distinguished from and dual diagnosis is provided in ganglia calcifications are common in control DS subjects without behavioral Table VII. persons with DS [Wisniewski et al., co-morbidity. Subjects diagnosed with 1982], and have been associated with major depression scored significantly CONSIDERATIONS FOR mood disturbance and psychotic symp- higher (>3 points average, P < 0.0001) STARTING PSYCHOTROPIC toms [Jakab, 1978; Thase, 1984]. on the Withdrawal, Depression, Atten- MEDICATIONS tion, Anxiety subscales compared to typical subjects with DS and no beha- Many parents prefer to utilize low-risk, ADOLESCENTS AND vioral concerns. Those with major developmentally based interventions or ADULTS WITH MOOD depression also demonstrated moderate DISORDERS: REISS SCALE but significantly increased (1–3 points The DS Clinic at Kennedy Krieger average, P < 0.001) scores on the Psy- Prompt management of Institute has evaluated over 100 adoles- chosis, Conduct and Anger subscales. In physiologic, emotional, and cents and young adults (13–30 years) comparison, subjects diagnosed with a with DS and co-morbid psychiatric minor mood disorder had moderately neurocognitive symptoms disorders since 1999. The Reiss Scale is increased scores on Withdrawal, De- would permit educational used to characterize their behavioral pression, Attention, Anxiety, Conduct, profile for clinical and research purposes. and Psychosis subscales which were and behavioral strategies to Parents provide informed consent and also significant (1–3 points average, be more successful early on. typically complete the 60-item Reiss at P < 0.001) when compared to DS con- the time of initial evaluation. A com- trols (Capone, unpublished). prehensive medical, developmental, other techniques in young children behavioral, and psychiatric history and before considering medications. Some assessment is performed by a neurode- of these interventions may be unfamiliar PHARMACOLOGIC velopmental pediatrician (gc) after to physicians [Lilienfeld, 2005]. If devel- STRATEGIES which a diagnosis is made. Our findings opmental progress becomes stifled and from 68 adolescents and young adults A summary of medications often used chronic behavioral problems ensue, with DS suggest that mood disorders to treat specific target symptoms in parents may avail themselves to try

TABLE VII. Medication Guidelines for Adolescents and Adults With Down Syndrome

Psychiatric syndrome Common target behavior Initial consideration Other considerations Depressive illness Depressed mood SSRI Second SSRI, dual re-uptake Anxiety, OCD SSRI inhibitor, Bupropion Insomnia Trazadone (HS) Second SSRI, Alprazolam Melatonin Atypical mood or cycling Mood stabilizer Atypical neuroleptic, low-dose Pre-menstrual dysphoria and SSRI SSRI (cautiously) anxiety (females) Oral contraceptives Fatigue, somnolence Dual re-uptake inhibitor Bupropion, Modafinil Benzodiazepine ECT Poor responder Dual re-uptake inhibitor, SSRI Augmentation, ECT þ Bupropion CPAP?

Obsessive-compulsive disorder Obsessions-compulsions SSRI, TCA Second SSRI, atypical perseveration neuroleptic Anxiety, agitation, disruptiveness Alprazolam, atypical neuroleptic SSRI, mood stabilizer Tics, mannerisms Typical/atypical neuroleptic Guanfacine/clonidine

Psychotic-like disorder Delusions-Hallucinations Atypical neuroleptic Second atypical neuroleptic Negative symptoms Atomoxetine, Bupropion Atypical neuroleptic? EPS, tremor, cogwheel rigidity Lower dose of neuroleptic Benzotropine, Amantadine Catatonia Benzodiazepine Lower neuroleptic dosage, ECT 170 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c ARTICLE

TABLE VIII. Considerations for Use of Psychotropic Medications in Persons With Down Syndrome

Medications are unlikely to be helpful Medications may be helpful Only mild or occasional behavior problems exist Behaviors are rapidly becoming worse in an otherwise stable The child is young <3–4 years environment, in the absence of acute medical illness Behaviors are limited to a specific environment (aggressive at home, A major psychiatric disorder is present: autism-spectrum disorder, but not at school); or only in the presence of a specific person, (hits bipolar disorder, obsessive-compulsive disorder, depression or mother but not father) or situation, (becomes agitated-disruptive mood disorder, psychosis when exposed to loud noise or chaos) A psychiatric disorder or syndrome is present: ADHD, anxiety, A medical condition exists which is triggering or maintaining the oppositional-defiant disorder, disruptive behavior disorder, with behavior, such as: pain or physical discomfort (ENT, dental, GI, complex co-morbidity and/or significant impairment musculoskeletal, menstrual) Physiologic, emotional or neurocognitive changes are VERY Physiologic, emotional or neurocognitive changes are NOT present prominent There has NOT been an adequate trial of behavior management Person did well on medications previously, but they were stopped and/or functional communication There has been an adequate trial of behavioral management and/or functional communication

‘‘anything that works’’ including medi- childhood and adolescent psychiatric Aman MG, Crismon ML, Frances A, King BH, Rojahn J. 2004. Treatment of psychiatric cations. It is unfortunate that so many disorders. Recommended reading for and behavioral problems in individuals with families choose this entry into medica- childhood disorders include: general mental retardation: An update of the expert tions, as a last resort, for it is likely that overview and guidelines [Reiss and concensus guidelines. www.psychguideli- nes.com. Englewood CO. Postgraduate prompt management of physiologic, Aman, 1998]; ADHD [Hunt et al., Institute of Medicine:1–20. emotional, and neurocognitive symp- 2001]; ODD-DBD [Althoff et al., Andreou G, Galanopoulou C, Gourgoulianis K. toms would permit educational and 2003; Ruths and Steiner, 2004]; anxiety 2002. Cognitive status in Down syndrome individuals with sleep disordered breath- behavioral strategies to be more success- disorders [Rosenberg et al., 2003]; ing deficits (SDB). Brain Cogn 50:145– ful early on. In Table VIII we have ASD-SMD [King et al., 2004; Findling, 149. specified circumstances which can 2005]; treatment of sleep apnea [Gold- Antochi R, Stavrakaki C. 2004. Determining pharmacotherapy options for behavioral inform clinicians about when to con- stein et al., 2000; Pakyurek et al., 2002]. disturbances in patients with developmental sider use of medication as part of their Recommended reading for adolescent disabilities. Psychiatr Annals 34:205–212. treatment plan. and adult disorders include: general Beebe DW, Gozal D. 2002. Obstructive sleep apnea and the prefrontal cortex: Towards a Improvement in physiologic regu- overview and guidelines [Reiss and comprehensive model linking nocturnal lation, emotional stability, and neuro- Aman, 1998; Mikkelsen and McKenna, upper airway obstruction to daytime cogni- cognitive processing is one of the most 1999; Antochi and Stavrakaki, 2004]; tive and behavioral deficits. Eur Sleep Res Soc 11:1–16. elusive but fundamental goals of phar- depression [Shoaf et al., 2001; Cheung Biederman J, Newcorn J, Sprich S. 1991. macotherapy. Enhanced behavioral self- et al., 2005; Ryan, 2005; Thase, 2005; Comorbidity of attention deficit hyperac- regulation with concomitant reduction Zajecka and Goldstein, 2005]; psychotic tivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry in the intensity, severity, or duration of disorders [Birmaher, 2003]; obsessive- 148:564–577. maladaptive behaviors often occurs once compulsive disorder [Grados and Rid- Birmaher B. 2003. Treatment of psychosis in impulse control, activity level, sleep dle, 2001; Rosenberg et al., 2003]; children and adolescents. Psychiatr Annals 33:257–264. quality, anxiety-mood state, and atten- treatment of sleep apnea [Means et al., Blunden S, Lushington K, Lorenzen B, Martin J, tion-cognitive dysorganization have 2003]. Kennedy D. 2005. Neuropsychological and improved. In many individuals, success- psychosocial function in children with a history of snoring or behavioral sleep ful management of these impairing REFERENCES problems. J Pediatr 146:780–786. physiologic and behavioral symptoms Capone G. 2002. Down syndrome and autistic will allow play-leisure activities, Althoff RR, Rettew DC, Hudziak JJ. 2003. spectrum disorders. In: Cohen W, Madnick Attention-deficit/hyperactivity disorder, M, editors. Down syndrome: Visions of the learning-academics, and social function oppositional defiant disorder, and conduct 21st century. New York: John Wiley & to progress. disorder. Psychiatr Annals 33:245–251. Sons, Inc. Aman M, Singh N, Stewart A, Field C. 1985. The Capone G, Grados M, Kaufmann W, Bernad- Aberrant Behavior Checklist: A behavior Ripoll S, Jewell A. 2005. Down Syndrome RECOMMENDED READING rating scale for the assessment of treatment and co-morbid Autism-spectrum disorder: effects. Am J Ment Defic 89:485–491. Characterization using the Aberrant Beha- There are many timely reviews in the Aman MG, Pejeau C, Osbourne P, Rojahn J. vior Checklist. Am J Med Genet Part A 1996. Four-Yearfollow- up of children with 134A:373–380. pediatric and psychiatric literature low intelligence and ADHD. Res Dev Charlot L. 2002. Obsessional slowness in addressing medication management for Disabil 17:417–432. Down syndrome: Severe variant of OCD ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c 171

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