Nancy C. Brahm, Jerry R. McKee, and Douglas W. Stewart
KEY CONCEPTS
Persons diagnosed with Down syndrome (DS) can be at increased risk for medical and psychiatric comorbidities.
In persons with DS, a thorough evaluation is needed to differentiate between depression and Alzheimer’s disease.
Treatment plans for persons with autism focus on increasing social interactions, improving verbal and nonverbal communication, and minimizing the occurrence or impact of ritualistic, repetitive behaviors and other related mood and behavioral problems (e.g., overactivity, irritability, and self-injury).
Many purported pharmacologic and nonpharmacologic treatments for autism lack objective evidence-based support.
A structured teaching approach focusing on increasing social communication and integration with peers is needed when providing services to persons with autism.
Nonpharmacologic interventions for sleep disturbances in children with a diagnosis of autism spectrum disorder should be implemented prior to pharmacotherapy considerations.
Psychopharmacologic treatment planning should include monitoring of objective, measurable medication-responsive target behaviors, and assessment of potential adverse effects is of critical importance when treating behavioral symptoms of autism, as the response of individuals to medication therapy is highly variable.
The use of FDA-approved medication for off-label indications is an acceptable clinical practice if founded on evidence-based research and informed consent.
The four stages of Rett syndrome are associated with developmental regression.
INTRODUCTION
Intellectual disabilities (IDs) can be identified in childhood or adolescence. Current criteria for diagnosis are based on deficiencies in intellectual and adaptive functioning with an onset prior to 18 years of age.1 This diagnosis is made regardless of the presence or absence of concomitant medical or psychiatric disorders. In the case of mild ID, deficiencies may not be apparent in early life. Problems can be noted when the chronologic age of the child and the developmental milestones achieved by peers with similar backgrounds, cultures, socioeconomic status, and psychosocial settings differ significantly.1 These gaps between developmental advances widen as the individual ages. Adaptive functioning deficits pose a number of challenges in treating those with an ID.
Whereas it has been estimated that a psychiatric disorder may beset approximately one-fifth of the general population in the United States, the prevalence may be double for persons with an ID.2Underrecognition of the need for mental health services may be due to a lack of caregiver awareness regarding psychiatric disorders in persons with IDs and/or insufficient provider training and clinical experience with this population.2 Additional barriers to accurate diagnosis may arise from deficits in adaptive functioning, a mechanism by which individuals effectively manage commonly encountered life demands and independence compared with nondevelopmentally disabled peers.1Communication deficits are a barrier specific to this population. Furthermore, those with an ID often have few social interactions and limited integration into the community. Stimulation and interaction with peers typically shapes behaviors in the general population. A different set of coping skills can develop in their absence. Self-talk is an example of a coping mechanism that can be misinterpreted as a sign of psychosis. Inadequate coping skills may result in a higher risk for the development of adjustment problems.3 Another potential problem for the clinician assessing persons with an ID is a significant gap between receptive and expressive language skills. If not readily recognized, intellectual capabilities can be overestimated, resulting in incongruent expectations and/or abilities. In the general population, features of psychiatric illnesses are more readily identifiable, and the clinician is able to effectively interview and evaluate the patient. The term “diagnostic overshadowing” has been used to refer to clinician perceptions that behavioral problems are secondary to an ID and not the result of a psychiatric comorbidity.4
The term “mental retardation” (MR) is now generally used only with respect to the diagnostic criteria found in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR).1 The currently accepted designation is “ID.” The American Association on Intellectual and Developmental Disabilities (AAIDD) supports this designation and has a definition on their website.5 For this chapter, the designation “ID” will be applied to the population of individuals who scored 70 or less on standardized intelligence tests, indicative of some limitations in intellectual functioning and adaptive behavior(s) with onset before 18 years of age. The term MR will be applied sparingly. This chapter focuses on Down syndrome (DS), autistic disorder, and Rett syndrome (RTT).
CLINICAL PRESENTATION Mental Retardation
Diagnostic features
Essential feature: significantly subaverage general intellectual functioning and accompanied by:
Criterion A: significant limitations in adaptive functioning in at least two of the following skill areas:
• Communication
• Self-care
• Home living
• Social/interpersonal skills
• Use of community resources
• Self-direction
• Functional academic skills
• Work, leisure, health, and safety
Criterion B: onset must occur before age 18 years.
Criterion C: MR has many different etiologies and may be seen as a final common pathway of various pathologic processes that affect the functioning of the central nervous system.
Degrees of severity of MR
Mild MR: IQ level 50 to 55 to approximately 70
Moderate retardation: IQ level 35 to 40, to 50 to 55
Severe MR: IQ level 20 to 25, to 35 to 40
Profound MR: IQ level below 20 or 25
Data from reference 1, with permission.
DOWN SYNDROME
DS is associated with common dysmorphic features and a wide range of medical and psychiatric concerns, including a number of developmental abnormalities. Congenital heart defects, seizures, orthopedic abnormalities, sensory defects, and disorders of the eye (e.g., cataracts, glaucoma), GI tract, immune system, skin, and thyroid gland are all associated with DS. Persons diagnosed with DS also have a high probability of early onset Alzheimer’s disease (AD).6 This section will focus on DS and the comorbidities of AD and leukemia.
Epidemiology
DS is the most frequently occurring genetically based syndrome associated with an ID.7 In the United States, the incidence is estimated to be 1 in 732 births, although prevalence rates may be different for specific racial/ethnic populations.7
Etiology and Pathophysiology
Chromosomal analysis identified the etiology of DS as the presence of an extra chromosome 21. DS, also referred to as trisomy 21, represents one of the most studied abnormal chromosomal conditions. Nondisjunction of chromosome 21 accounts for the majority of the errors. Chromosomes divide and separate in a process known as disjunction during meiotic division. Failure to fully separate at this stage can result in both chromosomes remaining in the same cell, creating an abnormal number of chromosomes on each strand. The nondisjunction at chromosome 21 is strongly linked to increased maternal age.
For many years, advanced maternal age has been recognized to positively correlate with an increased risk for DS. Consideration has been given to paternal age as a potential risk factor for DS. The possibility of paternally mediated nondisjunction has not been eliminated, but evidence of a link has been inconclusive.8
Those with DS are more at risk for congenital heart defects. A retrospective, case–control study that included maternal questionnaire completion and medical records review sought to evaluate use of folic acid supplementation during the periconceptual period and any association between congenital heart defects and DS. Controlling for substance use during pregnancy and demographics, including maternal age at conception, supplementation use was compared between two groups. In the cohort with DS and congenital defects, specifically atrioventricular septal defects, supplement use was less compared with those with DS and no defects.9
Clinical Presentation and Diagnosis
The consequences of this chromosomal variance include characteristic facial features, some degree of ID, hypotonia, an increased risk for congenital heart disease, and early onset AD.6 The characteristic facial features make children with DS more readily identifiable at birth.10 IDs range from mild to severe.10
For the purpose of this chapter, the term dual diagnosis refers to an intellectually disabled person with a comorbid psychiatric disorder.2 The most prevalent psychiatric and/or behavioral disorders in persons with an ID involve attention, mood, personality, and cognitive processing.11 One population-based study of persons with ID (n = 1,023) sought to determine the prevalence of psychiatric disorders. Using regression analysis in conjunction with comprehensive individual evaluations, approximately 40% met criteria for needing mental health services.12 In persons with DS, depression prevalence rates ranged from zero to slightly over 11%.13 The risk for depression is increased by a number of factors, such as decreased total brain volume; reduced levels of the neurotransmitters, specifically serotonin, γ-aminobutyric acid (GABA), taurine, and dopamine, critical in mood regulation; and decreased cognitive function.13
The differential diagnosis for mood disorders in all patients should include an evaluation of thyroid function. The lifetime risk of thyroid disorder as a comorbidity in people with DS is estimated at 3% to 5%.10 Because clinical signs and symptoms of hypothyroidism can mimic some of the features of depression, thyroid function should be evaluated in patients with DS.
TREATMENT
Desired Outcomes
Treatment goals in DS are to identify medical and psychiatric comorbidities, set realistic goals, and provide effective nonpharmacologic and pharmacologic interventions to improve the quality and length of life.
CLINICAL PRESENTATION Down Syndrome
General
• Individual may have the characteristic physical features described below.
Diagnostic features
• Facial features can suggest DS, but an additional diagnostic evaluation is necessary.
• Degree of ID ranges from mild to profound.
• Growth delays are common.
Common physical characteristics
• Hypotonia can be evident at birth.
• Facial features include flattened, broad facies with upslanted eye folds, and a large, protruding tongue.
• The palate can be narrow and the neck thick and broad.
• Hands are characteristically short and broad.
Other clinical concerns
• An increased risk for congenital heart problems, and a cardiac evaluation is generally done shortly after birth with periodic followup.
• Congenital cataracts and hypothyroidism are common.
• Leukemia is often diagnosed in early childhood.
• Features of AD can present by the third or fourth decade.
Data from references 10 and 14.
General Approach to Treatment
Medical screenings should assess for hypothyroidism, cardiac problems, sensory impairments (including hearing loss secondary to chronic otitis media with effusion or vision defects due to congenital cataracts or glaucoma), and GI problems (including constipation and celiac disease).10 Guidelines for health supervision and anticipatory guidance in infants, children, and adolescents with DS are available through the American Academy of Pediatrics (AAP).10Routine screenings are also recommended throughout the course of life to address psychosocial changes, potential residential or vocational stressors, and the consequences of aging.10
Nonpharmacologic Treatments
The use of social supports for both individuals with DS and their family is known to help develop functional adaptive skills and therefore the fulfillment of the potential of the person with DS.10 Family education and support network development assist caregivers by providing tools and resources necessary to more effectively manage persons with DS, allowing these persons to achieve their full potential. In the treatment of psychiatric disorders, treatment modalities available to the general population also apply to those with DS. Nonpharmacologic options for depression include psychotherapy and electroconvulsive therapy (ECT).13 Information on the effectiveness of ECT in the DS population is limited to case reports. If communication skills are adequate, psychotherapy may also be an option. Treatment strategies include psychodynamic and cognitive behavior therapy (CBT). A review of the literature found that psychotherapy applicability results can vary with the level of ID. For persons with mild intellectual impairment and depression, this treatment modality may be beneficial. The current behavioral therapy models are more effective in addressing specific problematic behaviors rather than the underlying emotional problems of persons with ID. The extent to which these strategies translate to persons with DS and moderate to severe ID is not known.13
Pharmacologic Treatments
Pharmacotherapy for the treatment of depression in patients with DS follows guidelines used in the general population. For more information on the treatment of depression, see Chapter 51.
Features of depression commonly seen in persons with DS, in order of frequency, include apathy, disordered sleep, and changes in weight. Difficulty identifying depression in this population is impacted by the level of cognitive impairment, the ability to express abstract concepts (such as helplessness or hopelessness), and the level of adaptive functioning.13 Clinical trials focused specifically on this population are few, and most information has been based on small studies or case reports. Efficacy of selective serotonin reuptake inhibitors (SSRIs) and amitriptyline is reported. If psychotic features (e.g., delusions, hallucinations) are present, low-dose antipsychotic augmentation is recommended. In the studies reviewed, treatment duration was 2 to 3 years.13
As with treatment of depression in the general population, it is essential to ensure that the medication trial is of appropriate dose and duration of antidepressant or combination antidepressant/antipsychotic. Ruling out comorbid medical conditions that could contribute to depression is essential.
Personalized Pharmacotherapy
In addition to the chromosomal aberration and dysmorphic features associated with DS, certain hematologic malignancies are more common in children with DS, with acute lymphoblastic leukemia (ALL) and the megakaryoblastic form of acute myelogenous leukemia (AML) seen much more frequently than other cancers. Children with DS have anecdotally been observed to have higher rates of methotrexate toxicity during treatment for cancers compared with other children. Speculation concerning causality has focused on alterations in methotrexate metabolism controlled by genes on chromosome 21. Even though mouth ulcers and bone marrow suppression are seen more frequently in children with DS receiving methotrexate, differences in pharmacokinetics do not appear to explain the higher rate of toxicity in patients with DS.15
Down Syndrome with Alzheimer’s Disease
Persons with IDs, including DS, are at greater risk for AD. In adults with DS, more than 25% experience neuropsychiatric symptoms,16 including aggression, inattention, impulsivity, and stereotypies. In adults with DS evaluated for AD, it was reported that depressed adults with no discernible reason for sadness were more likely to be positive for dementia.16
Assessing changes in functionality and cognition are problematic in this population, particularly in those with greater intellectual impairments. Early studies in this population did not specify the diagnostic criteria used for identification of dementia of Alzheimer’s type. A well-delineated diagnosis of AD or dementia, Alzheimer’s type, requires a documented decline from baseline cognitive functioning. To meet the diagnostic criteria, the following are needed: baseline functioning data, functionality changes not explained by general aging, and progressive decline.1 Identification of appropriate assessment scales for use in those with DS has also been problematic. The Dementia Scale for Mentally Retarded Persons (DMR) was used as the primary outcome measure in a medication efficacy trial. It also provided secondary outcome measurement and assessment of cognition, neuropsychiatric features, adaptive behavior, and a global impression.17
In persons older than 40 with DS, behavior changes are the primary features of the early stages of dementia. For this older cohort, higher frequencies of irritability, fear, sadness, and suspicion are seen than in a younger population. Violent outbursts have not been identified as a reliable indicator of dementia, but methodologic shortcomings preclude firm conclusions.16 Furthermore, there is a fivefold greater prevalence of comorbid DS and dementia compared with other IDs and dementia. Gender also is important, as the male-to-female ratio is 3:1 for DS and AD.18 Selected task skills were found to decline 2 years prior to a diagnosis of AD.19 In the absence of documentation of change, specific criteria needed for a diagnosis of AD may not be met. Diagnostic criteria for AD include changes in memory, language skills, and activities of daily living (ADLs).1 Information on the natural progression of cognitive changes in those with DS and AD is limited.
Pathophysiology
Neuritic plaques and neurofibrillary tangles are the hallmarks of AD. A gene for amyloid-β precursor protein is located on chromosome 21.20 Neuropathic changes associated with AD are typically found in those with DS by middle age.16 The severity of ID has been theorized to significantly impact the incidence of AD, but study results are inconclusive, and the level of ID may limit evaluation. A study of DS (n= 405) with and without dementia identified specific amyloid-β precursor proteins that might be predictors of dementia in DS regardless of age, gender, and level of ID.20 A more extensive discussion of the pathophysiology of AD is beyond the scope of this chapter. For more information about AD, see Chapter 38.
TREATMENT
The therapeutic goal is to maintain functioning and quality of life as close to baseline as possible for as long as possible. Approaches to therapy for persons with DS combined with AD include nonpharmacologic and pharmacologic interventions. As with the general population with AD, treatment of AD for those with DS is multimodal and includes currently available treatments and supports in order to maintain functionality as long as possible.21
Nonpharmacologic Treatments
Traditionally, this population receives some level of residential living supports in either the family home or a residential facility. Depending on the level of ID, a family member, other caregiver, or residential facility staff may provide information to the clinician regarding functional status.
Pharmacologic Treatments
Pharmacologic treatments neither cure nor stop the pathologic changes associated with AD. The goals of pharmacotherapy in persons with DS and AD, as in the general population of AD patients, are to slow the decline in cognitive function and help preserve ADLs to the greatest extent possible. The use of cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA) receptor antagonist in the DS population is being studied.
There is evidence to support the use of cholinesterase inhibitors to enhance learning and memory in persons with DS. The majority of the research in this area has been with donepezil. In a review of the literature, a 24-week, double-blind, placebo-controlled, parallel-group trial (n = 30, 27 completed) used the DMR as the primary outcome measure and the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), and Adaptive Behavior Scale (ABS) as secondary measures. Findings with the DMR, SIB, and ABS indicated less deterioration for the treatment group versus the control group. The results for the NPI were reversed: the placebo group demonstrated more improvement compared with the treatment group. Dosing was 5 mg daily for the first 4 weeks, and 10 mg daily thereafter. Side effects included diarrhea, insomnia, fatigue, and nausea.22
Use of rivastigmine, galantamine, or memantine in those with an ID has not been studied as extensively as donepezil. An assessment of the efficacy of rivastigmine for dementia in AD in the DS population was not statistically significant compared with that in a placebo group from a previous study. Rating scales used were the DMR, NPI, and ABS.23 Rivastigmine-associated adverse effects included GI upset (e.g., diarrhea, nausea, vomiting), fatigue, and insomnia.23 For more information about pharmacotherapy treatment guidelines in AD, see Chapter 38.
Preexisting medical comorbidities, such as congenital heart defects, or concomitant pharmacotherapy may limit use of cholinesterase inhibitors in persons with DS. Clinicians are encouraged to monitor patients receiving cholinesterase inhibitors for bradycardia24 and the potential for drug interactions.
A potential neurologic comorbidity of concern in this population is seizures. Overall, approximately 8% of the DS population has a seizure disorder, and seizure activity increases with age.25 Distribution of seizure onset is bimodal, with the first peak incidence appearing before 1 year of age. This first peak is predominantly composed of infantile spasms. Seizure patterns in the DS population, in order of prevalence, are partial (47%), infantile spasms (32%), and generalized tonic–clonic (21%).25 Advanced AD is an independent risk factor for new-onset seizures.25 Monitoring for new-onset seizure activity and medicating with anticonvulsants as appropriate are essential. For more information about epilepsy and seizure disorders, see Chapter 40.
Evaluation of Therapeutic Outcomes
Baseline functioning must be established early in adult life prior to the onset of AD, which generally occurs during the third or fourth decade of life. This can be particularly crucial in individuals without expressive language skills. Followup evaluations should be performed annually. If cholinesterase inhibitors are used, evaluations every 2 to 4 months (after achieving a maintenance dose) are recommended to monitor for effectiveness if the anticipated gains have not been observed. Monitoring for potential medication-related side effects, including diarrhea, nausea, vomiting, insomnia, and headache, is also essential.21
Clinical Controversy…
The role of pharmacotherapy for persons 40 years or older with DS and AD is unclear.22,26 A 52-week prospective, randomized double-blind trial of memantine in persons with DS with and without dementia showed no improvement in cognition or function. In a 24-week, double-blind, placebo-controlled trial of donepezil, three rating scales showed less deterioration in the group taking donepezil than in the placebo group, but differences were not statistically significant.
Down Syndrome and the Immune System
Leukemia is frequently diagnosed in DS children. The relative risk for leukemia is 10 to 20 times greater in persons with DS than in the general population.27 The two forms more commonly encountered in DS children are ALL and AML. While ALL is the most common form of leukemia in all children, the rate of DS-AML is about equal to DS-ALL in children who are younger than 5 years of age (this ratio is about 1:4 in children without DS). The most commonly identified form of DS-AML is acute megakaryoblastic leukemia (AMKL). The incidence of this disorder in DS has been identified as high as 500 times greater than in the non-DS pediatric population.28 Another myelodysplastic disorder almost unique to children with DS is transient myeloproliferative disorder (TMD). For TMD, the period prevalence in infants with DS has been estimated to be 10% to 20%.27 It can spontaneously remit and cannot be clinically differentiated from AML. However, within 4 years following spontaneous remission of TMD, 20% of this population will develop AMKL.28
In the DS population, ALL survival rates are lower than in the non-ID pediatric population.27 Children with DS also experience more chemotherapy-related toxicities (specifically mucositis and infection) compared with non-DS children with ALL.27
Chemotherapy-induced cardiotoxicity is of particular concern in children with DS, as 50% may have a congenital heart defect.10 High rates of cardiomyopathy (17.5%) are reported with treatment with anthracyclines.27 Children with DS and newly diagnosed with AML (n = 54) were enrolled into a standard protocol with daunorubicin and mitoxantrone to evaluate treatment efficacy and toxicities. Researchers reported the treatment protocol effective for remission and survival for the children in the DS-AML arm, but 17.5% of this group developed cardiomyopathy during or shortly after treatment completion, supporting the current practice of dosage reductions.29 In addition, higher levels of the methotrexate metabolite were found, supporting the link between DS and drug metabolism alterations secondary to alterations on chromosome 21.27
Evaluation of Therapeutic Outcomes
Assessment of therapeutic outcomes for those with DS starts with a thorough multidisciplinary evaluation to establish a baseline problem list, identification of clear therapeutic goals, and using valid pharmacotherapeutic rationale to guide medication dosing and adverse drug effect monitoring.
An in-depth list of treatment targets, both subjective and objective, is important in persons with DS to assist in evaluation of medication response. Careful monitoring for emergence of potential side effects should be regularly conducted and documented as part of ongoing assessment of medication effectiveness and to ensure that side effects are not a contributing factor to behavioral changes.
AUTISM
Autistic disorder is one of five behaviorally defined pervasive developmental disorders (PDDs). Others include RTT, Asperger’s disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS).1 These disorders are grouped together and referred to as autism, or autism spectrum disorders (ASDs), by the DSM-IV-TR. RTT and childhood disintegrative disorder are rarer, typically more severe in manifestations, and are generally considered separately. This section will focus specifically on autism, which is characterized by severe and sustained impairments in three behavioral domains: (a) reciprocal social interaction (withdrawal or lack of interest in peers), (b) language and communication skills (limitations in the use of speech and nonverbal skills), and (c) range of interests and activities (repetitive, restricted behaviors, stereotyped mannerisms).1,30 Autism is not a disease but a neurodevelopmental disorder with multiple possible etiologies.31 The onset is typically younger than 3 years of age and is usually, but not always, associated with some degree of ID.1Autism was first described by Leo Kanner in 1943 and has been historically described as early infantile autism, childhood autism, and Kanner’s autism.1
Epidemiology
There has been a recent sharp increase in the reported prevalence of autism. Newer surveys estimate the prevalence to be 1:88.32 It is suggested that the reported increased prevalence is primarily related to changing and broadening diagnostic criteria, along with an increased index of suspicion, rather than by an actual increased incidence, as autism is behaviorally identified, and the diagnostic boundaries are not always clear.33,34 In addition, inclusion of individuals with diagnoses of Asperger’s disorder and PDD-NOS in newer studies may contribute to the increase.34 Some behaviors (e.g., stereotypies) seen in persons with autism can also be seen in nonautistic individuals. One study found children with a history of early institutionalization demonstrated more stereotypical behaviors that markedly decreased following increased interactions postplacement.35 There is a significant impact of intellectual ability on the expression of symptoms of autism,36 resulting in a lack of homogeneity in clinical expression of the condition. Autism is between four and five times more prevalent in males.31 When present, ID ranges from mild to severe. The heterogeneity and early onset represent two methodologic problems for large-scale research studies.31
Etiology and Pathophysiology
The etiology of autism is attributed to multiple causal factors, including gene mutations, abnormalities in brain development, and genetic–environment interactions.30 Autism frequently occurs concomitantly with other developmental disorders that have a known genetic basis such as RTT and fragile X syndrome.34 Current research primarily focuses on genetics and neuropathology. Although a single genetic mutation or variant leading to autism has yet to be identified, research findings indicate that structural alterations in the genome DNA, known as copy number variations (CNVs), may be involved in ASD. Research identified a number of CNVs associated with ASDs, as this appears to be a highly heritable disorder.37
These findings provide support for the heterogeneity of neurodevelopmental disorders, whereby disruption represents a critical period in the development of excitatory and inhibitory neuron development. A combination of genetic and/or environmental factors, in the absence of any compensatory mechanism, may interfere with brain plasticity.36 A meta-analysis provided some support for the theory that ASD may arise from interference in the excitatory and inhibitory balance expression and/or timing during critical periods.38 A review of the literature found persons with autism demonstrated what was termed “unusual sensory processing.” Additional findings included (a) a diagnosis of autism was associated with greater sensory symptoms than in other developmental disorders, (b) increased age was associated with decreased symptoms, and (c) for children there was a positive correlation between social impairment and sensory symptoms.39
Siblings of affected children have a significantly greater risk of having autism (3% to 18.7%) than those in the general population.40 Results from a national volunteer registry (n = 2,920 children, 1,235 families, a minimum of 1 child meeting ASD diagnostic criteria, and a minimum of 1 full sibling) found that the sibling concordance rate was 10.9%. Overall an additional 8.9% of the siblings demonstrated language delay with autistic-like speech quality.41
Further support for the high heritability of the disorder was shown by additional research in this area. Sibling risk varies based on the gender of the index child: 4% versus 7% for female compared with male. If a second child is diagnosed, the risk for concordance in subsequent siblings increases to between 25% and 30%, higher than previously reported. The risk for a monozygotic twin with autism ranges from 60% to 95% that both twins will be diagnosed with autism.42
Parental age has been investigated as a potential risk factor for autism. While results are thus far inconclusive, a number of intriguing results have been found. A case–control study design of a cohort of age- and sex-matched pairs (n = 68) found a significant effect linking the age of both parents and a child with a diagnosis of autism. Unadjusted parental ages were higher for both parents (paternal 4 years higher, maternal 4.8 years higher) compared with controls. After adjusting for variables such as educational level and gestational age, the differences widened to 5.9 and 6.5 years, respectively.43 Shelton et al. found parental age was a risk factor if the mother was less than 30 years old.44
Environmental exposures including toxic chemical exposure, teratogens, perinatal insults, prenatal infections,34 and copper and zinc levels45 are under investigation. Immunization with measles/mumps/rubella vaccine has been investigated, and no causal association identified.46
Autism frequently occurs concomitantly with epilepsy47 and may be associated with microdeletion gene defects that are also risk factors for schizophrenia and attention-deficit/hyperactivity disorder (ADHD). Examples include the association between autism, ID, schizophrenia, and seizures with microdeletions on the 15q13.3 and 1q21.1 regions.48 Other sites also may be implicated. The two most common single gene abnormalities associated with autism are fragile X syndrome and tuberous sclerosis.42
The neurodevelopmental foundation of autism has sparked significant interest in early morphologic changes in brain development, particularly findings of early brain overgrowth. Head circumference at birth ranges from slightly below normal to within normal limits. This finding changes by 2 to 3 months of age when accelerated head growth occurs. The rate of growth may exceed 2 standard deviations above the average. Approximately 60% of infants diagnosed with autism compared with 6% of normal infants have this rate of accelerated head growth. The increase positively correlates to the increase in ID severity. Following this period of accelerated head growth, during which time the infant brain may achieve the size of the adult brain, deceleration or a complete cessation of head growth is noted.31
Accelerated brain growth may predispose the developing brain to increased vulnerability. This is consistent with the concept of plasticity, whereby development of cortical circuitry is established during critical postnatal periods. During this period of development, a balance of excitatory and inhibitory neurofunctionality occurs. It has been theorized that during this critical period if an imbalance occurs, this results in neurodevelopmental disorders, such as autism.36 This theory is consistent with the diagnostic criteria of onset within the first 3 years, abnormalities in three major areas (socialization, communication, and repetitive behaviors1), and disruption in neurocircuitry development.
Dysfunction of virtually all neural systems in the brain has been proposed at some point as a potential basis of autism.49 The neuropathologic changes noted in persons with autism are suggested to be of prenatal origin, primarily in the first 6 months of gestation.31 Evidence has been published that suggests that autism affects a functionally diverse and widely distributed set of neural systems, making the disorder far broader in scope than a simple social interaction disorder.49 Despite these findings, the pattern of brain abnormality appears somewhat discrete. Autism spares many perceptual and cognitive systems. A localized neural deficit can have more widespread neurofunctional implications through its influence on brain development.49
There is research to support abnormalities in cholinergic receptors and decreases in the nicotinic receptor binding in the cholinergic system as well as dysfunction in the GABAergic system47 in persons with autism. Nicotinic receptors enhance cognitive processing (i.e., memory and attention) and open the possibility of therapeutic intervention via cholinergic receptor modulation.50 Approximately 25% to 60% of children with autism have elevated peripheral platelet concentrations of the neurotransmitter serotonin.51 Studies of dopamine and catecholamine metabolites have failed to consistently show abnormalities.
Clinical Controversy…
In the absence of clearly effective drug therapies for the behavioral symptoms of autism, scientifically unsupported complementary and alternative treatments are sometimes used.52 A study using a naturalistic, case–control design compared the use of micronutrients (vitamins and minerals) with standard medication (e.g., antipsychotics, SSRIs, mood stabilizers, stimulants, clonidine, and bupropion) on rates of self-injurious behavior, aggression, and temper tantrums. Both groups improved on formal assessment measures. The micronutrient group demonstrated significant advantages with less anger, weight gain, and social withdrawal. Frequency remained the same, but the intensity of self-injury was significantly lower in the micronutrient group as well. Despite a desire to assist sometimes desperate families, the clinician should examine the evidence-based support of complementary and alternative medicines prior to recommending or prescribing such treatments. Clearly, more study is needed.
Clinical Presentation and Diagnosis
The differential diagnostic features of autism and nonautistic PDDs are listed in Table 56-1. A multiple-step process has been suggested as a structured approach to differential diagnosis of suspected ASD. As a spectrum disorder, the severity or level of impairment may be highly variable. This structured approach includes a determination of intellectual function and level of language development, followed by assessment of the child’s behavior as it relates to chronologic age, mental age, and language age. It is important to identify relevant comorbid medical conditions and the presence of any related contributing psychosocial factors.53
Persons with autism are typically normal in physical appearance. Seizure rates are reported for between 5% and 40% of those with an ASD diagnosis.47 Patients with comorbid seizure disorders often have greater impairment in intellectual function.1 Other medical comorbidities commonly reported in this population include sleep disturbances, food intolerances, and GI dysfunction.54
TABLE 56-1 Differential Diagnostic Features of Autism and Nonautistic Pervasive Developmental Disorders
The cardinal features of autism are gross and sustained impairment of reciprocal social interaction, sustained abnormalities in verbal and nonverbal communication skills, and restricted, repetitive, and stereotypical patterns of behavior, interests, and activities.1,53 These are primarily manifested as gaze aversion, little/no interest in making friends, preference for solitary activities, repetition of words/phrases, monotone voice, insistence on sameness, and a lack of awareness of other’s feelings.1,55 In most cases (~75%), there is an associated diagnosis of ID, ranging from mild to profound: approximately 30% of function in the mild to moderate range of ID, whereas 45% to 50% have severe to profound impairment.53 Epidemiologic data suggest that the risk for development of autism increases as the IQ decreases.53 A few individuals with autism have unusual abilities called splinter functions or islets of precocity. The most significant of these are evidenced in the autistic savant, in which the individuals can have precocity in mathematic calculations, art, music, or rote memory.1,53
In many instances, parents note that they were concerned about the child’s lack of interest in social interactions since birth, but were sure at least by 3 years of age.1 In a controlled setting, use of an integrated model for screening was effective in diagnosing children before 36 months of age.56 Original findings of behaviors suggesting the need for an intellectual evaluation included lack of babbling, pointing, or other gestures by 12 months, no single-word language development by 16 months, no two-word language development by 24 months of age, and loss of previously held language or social skills at any age.57Earlier intervention is recommended when the early signs and symptoms of autism are recognized. It is difficult to determine if autism is present in persons with severe to profound ID. A diagnosis is made in such cases when there are qualitative deficits in social and communicative skills and the specific behaviors characteristic of ASD are present.1 A central difference is that persons with ID alone typically relate to adults in a manner consistent with their mental age, use their language to communicate with others, and present with a relatively even profile of impairments without splinter functions.53
Although there are no definitive biologic markers for identifying individuals with autism, a number of medical evaluations should occur at baseline, to assist in distinguishing the diagnosis as autism and to rule out other disorders. Table 56-2 delineates the parameters to be considered in a medical evaluation for persons suspected of having autism and the rationale for the assessment.
TABLE 56-2 Medical Screening for Individuals with Autism
Those individuals with autism and IQs above 70 who use communicative language by ages 5 to 7 have the best prognoses.53 Conversely, low IQ scores and failure to develop communicative language by age 5 years correlate with a poorer long-term prognosis.58 Outcome studies in persons with autism correlate IQ, particularly verbal IQ, with the ability to be employed and live independently.49,59 Learning disabilities are an independent risk factor for development of behavioral problems, and 41% of children with mild, moderate, or severe learning difficulties have a significant emotional behavioral disturbance.59 Studies indicate that high-IQ children with autism can make positive changes in communication and social domains more effectively over time. The areas less likely to improve are those related to ritualistic and repetitive behaviors.54 Up to 80% of children diagnosed with ASD continued to experience marked impairment in social interactions as adults. Mild to moderate ID was reported for approximately 30%.60
In addition to the core symptoms of autism, many persons with this disorder exhibit other significant maladaptive behaviors, such as aggression to self and others. These behavioral issues can interfere with day-to-day activities and are challenging for the individual, families, and caregivers.61
Clinical Controversy…
It has been postulated that thimerosal, an organomercury compound and a preservative previously used in many vaccines, could be causally linked to neurodevelopmental disorders such as autism.62 Well-conducted case–control, cross-sectional ecologic and cohort studies found no causal association between thimerosal-containing vaccines and the development of autism or deficits in neuropsychological function. Further concerns were posed specific to a postulated link between mercury exposures secondary to dental amalgam restoration (while pregnant) or environmental mercury exposure and autism. A review of the evidence was unclear regarding a causal link between maternal dental exposure and autism. More research is needed to evaluate risk from other environmental exposures. Despite the lack of evidence, the neurotoxic effect of mercury and exposure continue to be a hotly debated issue among many advocates for persons with autism.
CLINICAL PRESENTATION Autism
General
• Individuals typically present with delays or abnormalities in six or more of the symptoms below with at least two impairments in social interactions and one each in communication and restricted interests or repetitive behaviors.
Diagnostic features
• Significant impairment in nonverbal communications
• Unable to develop peer relationships
• Lack of spontaneous interactions with people or the environment
• Developmental delays in communication
• Inability to use expressive language appropriate to developmental level
• Lack of developmentally appropriate play
• Stereotypical or nonfunctional ritualistic behavior
• Inability to tolerate change
• Stereotypic or repetitive, nonfunctional motor movements
• Limited scope of play or interest
Data from references 1, 57, 61, and 63.
TREATMENT
Desired Outcomes
Treatment goals in persons with a diagnosis of ASD are to address deficits in communication and social interaction using a structured approach and minimize the impact of restricted behaviors (e.g., stereotypies or repetition) appropriate to the level of intellectual ability, language development, and chronologic age.
General Approach to Treatment
The multimodal treatment plan should address (a) establishing realistic goals for educational efforts, (b) identifying the presence of behavioral target symptoms for intervention, (c) prioritizing target symptoms and comorbid conditions for intervention, (d) using specific methods of outcome monitoring of functional domains (behavioral, adaptive skills, academic skills, social interaction skills, communication skills), and (e) monitoring for efficacy and potential adverse effects of medication (if used). The National Institutes of Health (NIH) suggests that evidence-based treatment strategies include the use of both psychoeducational therapies and medications.64 An effective, well-designed, multimodal treatment plan that is consistently executed has the most potential to positively shape the autistic individual’s interaction with the environment and improve the quality of life of patients and their families.
After a thorough diagnostic evaluation, treatment planning for the individual with autism is critical to assure consistency and efficacy of interventions. With the often severe nature of the behavioral and adaptive problems, it is not surprising that many potential treatment modalities lacking an evidence basis have been proposed for persons with autism. 
The two treatment approaches for autism with evidence-based support and clinical consensus are behavioral/psychoeducational therapies34,65 and psychoactive medication intervention30 as appropriate. All stakeholders (family, educators, and clinical professionals) should be involved in the treatment planning process. Treatment decisions should be evidence-based and individualized to the specific identified needs of the individual. The potential for communication deficits often limit self-reporting of psychopathology. A multifaceted approach to information gathering should include direct observation; interviews with patient, parents, family, caregivers, and teachers; and review of the medical record, including any behavioral rating scale information.
Available evidence suggests that appropriately designed, consistently implemented educational services positively impact the acquisition of social, communicative, self-care, and cognitive skills, each of which facilitates the person’s long-term success. Services, such as occupational therapy, physical therapy, and speech pathology, are often integral aspects of an overall educational plan. 
Because of the pervasive need for sameness in routine, ongoing and consistent year-round educational programming is more effective than intermittent, episodic interventions. Effective language and communication training can lead to generalized improvements in social skills and repetitive behaviors, and thus positively impact other nonspecific maladaptive behavioral problems such as noncompliance, self-injury, and aggression.66
Nonpharmacologic Treatment
Intervention strategies, such as discrete trial training, have demonstrated improvement in challenging behaviors. Educational techniques include structuring the environment, family training, peer role modeling, and sensory integration to optimize environmental interactions.65
Pharmacologic Treatment
Many of the studies of psychopharmacologic interventions in persons with ASD have methodologic shortcomings including problems in experimental design and sample size, loose or poorly defined diagnostic criteria, and many clinical outcomes that were limited in duration or of dubious clinical significance.
Among a number of scientifically unsupported treatments for autism is secretin, a polypeptide hormone promoted in the late 1990s as an efficacious therapy. Controlled trials found no reliable evidence of such efficacy.67Elimination diets in which casein (from dairy products) and/or gluten (from wheat products) are excluded from the diet also have no scientific basis for efficacy. Other such purported therapies include omega-3 fatty acids and St. John’s wort. Only one randomized controlled trial was found regarding use of omega-3 fatty acids for hyperactivity and stereotypic behavior. At this time, safety and efficacy are not established.68 Modest benefits were reported with St. John’s wort for eye contact and expressive language deficits.69
Current research on the neurobiologic basis of autism is centered on the serotonergic, peptidergic, dopaminergic, and noradrenergic systems. This research has particular applications for insomnia in children with ASD, as the prevalence of sleep disorders has been reported to range from 44% to 83%.70 Parents commonly rate sleep disturbance as a significant clinical issue. As with nonautistic individuals, it is important to determine the underlying etiology of the sleep problem. Behavioral interventions (e.g., improved sleep hygiene, eliminating maladaptive sleep habits, and parental education) should be undertaken prior to implementing pharmacotherapy. No medication has been FDA-approved for pediatric insomnia. While controlled trial data are limited, there is support for the use, safety, and effectiveness of melatonin.70,71 In a review of the literature for use of melatonin in ASD, doses ranged from 0.75 up to 6 mg of the immediate-release formulation and from 2 up to 15 mg of the controlled-release formulations. Additional studies are needed for safety and effectiveness.70 In an analysis of 12 studies of potential melatonin-mediated adverse effects, serious side effects were not reported.71
Aggression to self and others and severe tantrums are a concern, particularly with adults with ASD. In addition to inclusion of nonpharmacologic interventions, pharmacotherapy is frequently utilized. Despite limited evidence-based support, psychoactive medications have been widely used to minimize the frequency and intensity of these behaviors. 
It is important that clinicians identify and carefully monitor specific behavioral target symptom response to avoid the practice of overprescribing psychoactive medications.
An association between dopamine dysregulation and increased aggression, including self-injury, consistent with animal models, has been proposed.61 Such findings have led to the use of antipsychotic agents that act as dopaminergic antagonists to address aggression and self-injurious behavior. The first-generation antipsychotic agent with the most evidence for short- and long-term safety and efficacy is haloperidol. Target behaviors included impaired learning, anger, mood lability, hyperactivity, and social withdrawal. Although results for improvement in the target behaviors were greater in the antipsychotic treatment compared with the placebo group, the risk for the development of dyskinesias and the introduction of new antipsychotic medications have severely limited haloperidol’s use.30
As few psychopharmacologic agents have been well studied in this population, and even fewer have received FDA approval, current research is directed primarily toward the second-generation antipsychotics (SGAs). 
Off-label use of FDA-approved medications (i.e., use of an approved drug for an unapproved use) is an acceptable clinical practice when there is evidence-based support for the use of the medication and informed consent is obtained; however, there is a relative lack of robust research in this area at the present time.
Aripiprazole and risperidone are currently FDA-approved to treat the behavioral symptoms associated with autism. A review of the literature found both short- and long-term use of orally administered aripiprazole was effective for irritability in pediatric patients with ASD, aged 6 to 17 years. The dosage range was 2 to 15 mg/day. In this range, aripiprazole was well tolerated with moderate side effects that resolved with continued use.72–75 Weight gain was reported during the first 3 to 6 months, and then it plateaued.72 Risperidone has the most evidence-based support for treating behavioral problems associated with autism. It is FDA-approved for treatment of the following behaviors in children and adolescents with autism: aggression, self-injury, temper tantrums, and irritability.30
The use of olanzapine is supported by limited trial data in children and adolescents with autism. Trial durations were generally short (6 to 8 weeks) with small numbers of participants. Positive results are generally reported in global improvement scale assessment; however, the significant weight gain and sedation noted in olanzapine trials are important considerations in weighing risk versus potential benefit.30
At this time there is no FDA-approved medication for the core symptoms of autism. Prior to the inclusion of pharmacotherapy for behavior as a component of the plan, utilization of a multifaceted approach is recommended.76
The SGAs are less likely to elicit extrapyramidal side effects than first-generation agents due to more potency at serotonin2A (5-HT2A) receptors versus dopamine receptors. However, the SGAs have been implicated in weight gain in some persons with autism.30 The potential serum prolactin elevation related to risperidone use is of concern. Elevated serum prolactin may lead to amenorrhea, galactorrhea, and osteoporosis in females and gynecomastia and sexual dysfunction in males. The minimum degree of prolactin elevation that is clinically relevant is uncertain as are the implications for long-term use in a pediatric population. If detected, strategies include evaluating the risk–benefit with continued use, reducing doses, or changing to another agent with less impact on prolactin. It is recommended that clinicians monitor for the evidence of potential risperidone-mediated prolactin elevations regardless of whether a prolactin level is obtained.77 Additional monitoring recommendations for antipsychotic use can be found in Chapter 50.
Serotonin synthesis differs between children diagnosed with ASD and children without this diagnosis. Compared with adults, 5-hydroxytryptamine (5-HT) synthesis may peak at twice the adult level in developmentally normal children by age 5 years, whereas children with ASD have a more gradual developmental arc with a lower peak.78 The use of SSRIs is often associated with a decrease in some of the core behavioral symptoms such as stereotypies, social withdrawal, and rigid adherence to routine. A review of the literature for citalopram,79 escitalopram, fluoxetine, and fluvoxamine78 found limited support for use of SSRIs to address behaviors of ASD.
Psychostimulants have been studied in persons with autism to address hyperactivity, impulsivity, and inattention. Psychostimulants block the reuptake of dopamine and norepinephrine. It is hypothesized that ADHD represents a dysfunction in regulation of these catecholamines.80 Study design of methylphenidate trials in persons with autism or PDD complicates interpretation of results. Some trials were uncontrolled, and some included children with various diagnoses. The largest and most rigorously controlled trial involved 72 participants, with 74% having a primary diagnosis of autism. In this placebo-controlled trial, methylphenidate was given in divided doses of 0.125, 0.25, and 0.5 mg/kg (morning and noon doses). In an analysis of the 66 youths completing the trial, 16 could not tolerate the 0.5 mg/kg dose phase. All three doses performed better than placebo on improving the core symptoms of ADHD according to parent and teacher ratings. Parent ratings for ADHD were better with the medium dose compared with the low dose. Teacher ratings for inattention were better with the medium dose compared with the low dose.81Overall, findings suggest that treatment response to psychostimulants varies and, in general, stimulants do not work as well in this population of children compared with normally developing peers.82
The α2-agonists, clonidine and guanfacine, have been used to treat hyperactivity and agitation in persons with autism because of their effects on inhibition of noradrenergic release and transmission. Both agents have FDA approval for treating symptoms associated with ADHD. However, as with many psychoactive medications used in the population with autism, there is a lack of methodologically sound studies supporting use of these agents. Two trials with guanfacine targeted symptoms that included inattentiveness and hyperactivity. Both reported positive outcomes. In the first (n = 80, average age of 7.7 years), guanfacine use was associated with statistically significant improvement in global functioning. In the second trial (n = 25, 20 completed), all subjects had not tolerated previous methylphenidate use. Improvement was noted on measures; some reached statistical significance.82
Limited data are available on the use of cholinesterase inhibitors for disruptive behaviors, such as hyperactivity and irritability. Use of donepezil for these or the core autism symptoms cannot be supported.82No benefit for ADHD or core symptoms was found for galantamine, and results for rivastigmine were unclear. Use of the NMDA receptor antagonist memantine was associated with hyperactivity as both a side effect and a target behavior. Additional study is needed for this agent. Limited support for anticonvulsants for ADHD symptoms in children with ASD was found despite the high comorbidity of seizures in this population.82
The current dearth of evidence-based psychopharmacologic and behavioral research in persons with autism is being addressed by a network of NIH-funded research centers, including the Research Units of Pediatric Psychopharmacology, Centers for Programs of Excellence in Autism, and Studies to Advance Autism Research and Treatment. The mission of these units is to foster well-controlled, multicenter, behavioral, and psychopharmacologic intervention studies targeting behavioral symptoms in persons with autism. Additional information can be found at http://psychmed.osu.edu/.
Personalized Pharmacotherapy
Aggression to self and others and severe tantrums are a concern, particularly in adults with ASD. In addition to nonpharmacologic interventions, pharmacotherapy is frequently utilized. Despite limited evidence-based support, psychoactive medications have been widely used to minimize the frequency and intensity of these behaviors. Although pharmacogenomics to guide rational and targeted pharmacotherapy would be helpful, at present this information is not available.83 This may be in part because of the heterogeneity of the ASD population.
Pharmacogenetic research has been limited by lack of sensitive outcome assessment tools to measure the effectiveness of treatments and the presence of multiple confounding factors in studies such as age, sex, medication dosage, and treatment duration, and whether or not the study subjects were drug naive.84 Studies that have been conducted (primarily with risperidone) are of limited clinical utility due to small sample size, and they need to be replicated in larger populations with more diverse makeup.84,85 Until more well-conducted, reproducible study results are available to confirm the early work that has been done, using the patient’s genotype to algorithmically predict a medication and dose likely to be effective and safe for a given patient with autism remains elusive.
Clinical Controversy…
The reported prevalence of autism has increased dramatically in the last 30 years, and evidence suggests that much of the increase is related to improved identification of children with these disorders.32,33,86,87Clear diagnostic boundaries are not always apparent, and there is a lack of homogeneity in clinical expression of the condition. The next edition of the DSM-IV-TR proposes a different categorization structure for the diagnosis of autism, causing much debate in the psychiatric community. Many families, clinicians, and advocates are concerned that this new diagnostic categorization will have the unintended consequence of eliminating some persons with previously diagnosed high-functioning autism or Asperger’s disorder from eligibility for services. The most significant change in criteria is the proposal to combine Asperger’s disorder, PDD-NOS, and autistic disorder into a new category of ASD to recognize the essential shared features of the autism spectrum, while attempting to individualize diagnosis through dimensional descriptors.
Evaluation of Therapeutic Outcomes
Monitoring the safety, efficacy, and tolerability of psychopharmacologic interventions in persons with autism is imperative to minimize adverse medication-related sequelae and optimize desired therapeutic outcomes. Clinical investigators have used a variety of psychometric assessment instruments in attempts to measure changes in core symptoms.
There are a variety of instruments that have been developed and used in clinical trials to measure symptoms, such as communication impairment, restricted interests, and repetitive behavior. A comprehensive review of many of these instruments is beyond the scope of this chapter. Pharmacotherapy in autism is usually directed toward minimizing maladaptive behaviors, such as irritability, hyperactivity, compulsive, ritualistic, and perseverative behavior, and variants of self-injurious behavior. The Aberrant Behavior Checklist was designed for assessment of behavioral changes in institutionalized individuals enrolled in pharmacotherapy trials; however, a community-based version is also available.88,89 The Aberrant Behavior Checklist consists of 54 items divided into 5 domains: irritability, hyperactivity, stereotypic behavior, lethargy, and inappropriate speech. The lower the score in each domain, the greater the behavioral improvement. The Children’s Yale-Brown Obsessive Compulsive Scale modified for pervasive developmental disorders is a validated scale sensitive to changes in repetitive behavior severity pretreatment and posttreatment.90
Intensive medication-related side effects monitoring and assessment is important in this population, as self-reporting can be unreliable. An instrument that is caregiver-rated such as the Monitoring of Side Effects Scale can be useful for this purpose. The Monitoring of Side Effects Scale is a multisystem, quantitative, and qualitative caregiver assessment that rates the presence or absence and severity of a variety of potential medication-related adverse effects for clinician review.91 Signs and symptoms are written in layperson language and are listed by body area or system. As such, it is a broad-based screening tool that can be enhanced by side effect–specific scales such as those for akathisia (Barnes Akathisia Scale [BAS]), extrapyramidal effects (Simpson-Angus Scale), or tardive dyskinesia (Dyskinesia Identification System: Condensed User Scale [DISCUS]).92–94
Use of SGAs has been associated with increased risk of developing metabolic syndrome. Children receiving these agents should be monitored for hyperglycemia, dyslipidemia, and weight gain in a manner consistent with the consensus guidelines suggested by the American Diabetes Association and the American Psychiatric Association.95 For monitoring guidelines, see Chapter 59.
RETT SYNDROME
Andreas Rett, an Austrian physician, published the first paper describing this disorder in a German language journal in 1966. He documented a sequence of developmental changes affecting young girls who initially achieved normal developmental milestones and then experienced regression. The significance of these findings and the rate of worldwide occurrence were not fully apparent until more formal evaluative and diagnostic criteria were developed.96Seizures, scoliosis, and cardiac dysfunction are frequent comorbidities in persons with RTT that can significantly impact the quality of life. The primary goals of treatment are to optimize seizure control and mobility.
Epidemiology
The classical form of RTT96 affects females almost exclusively. The prevalence of RTT depends on the population surveyed and the diagnostic criteria used. Studies from Sweden and Scotland reported the prevalence to be 1:10,000 to 15,000,97 whereas more recent estimates varied in the methodology used. Rates from several countries were reported with age ranges for the females. Prevalence for these groups ranged from 0.57 to 0.88:10,000.98
Etiology and Pathophysiology
RTT is a neurodevelopmental disorder originating from an X-linked dominant mutation at the Xq28 site involving the methyl-CpG-binding protein 2 (MECP2). This represents the most commonly identified mutation in the majority (95%) of classic cases identified in females.99 In-depth molecular studies found a variety of mutations on the MECP2 gene that impact the presentation of the clinical phenotype. These mutations may provide an explanation for differences in severity, presentation, and onset.100
The etiology of RTT has not been fully identified. Theoretical explanations have extrapolated data from animal models and involve neuronal changes. These include the loss of the MECP2 protein in the dopaminergic pathways in the substantia nigra and the potential impact on alterations in the nigrostriatal pathways. An age-dependent study involving MECP2-altered mice found that mice with dopamine2(D2) neurons in the substantia nigra region of the brain demonstrated less conductivity as early as 4 weeks of age. Changes preceded symptoms and were lifelong. The authors postulated that D2 dysfunctions in dopamine release could account for motor deficits in symptomatic females.101
Clinical Presentation and Diagnosis
Genetic variations have been identified that are thought to moderate the symptoms and progression of RTT, the extent of which is not fully understood. What is known is that females are predominately affected by RTT, and no causal event has been identified. An uneventful pregnancy and birth are followed by seemingly normal development with acquisition of developmentally appropriate milestones. Growth, including head circumference, is within normal limits at birth. Developmental regression appears between 6 and 18 months with the loss of previously acquired skills. Additional developmentally regressive changes have been grouped into a series of stages associated with a range of ages during which these changes occur.1
The order of symptom appearance and regressive changes associated with RTT distinguish it from other developmental disorders. The developmental changes for the classical presentation of RTT can be grouped into four stages (Table 56-3). Important features for each stage include the onset of stage I (stagnation) that typically begins at approximately 6 months of age, after initially meeting developmental milestones.99 The key indicators for the onset of stage 2 (rapid destructive or developmental regression) include lack of head growth and features with autistic-like qualities (e.g., stereotypic hand movements and loss of social interactions). The onset of stage 3 (pseudostationary or stationary) varies and previously lost skills may partially reappear. Seizure activity may appear. In one study, the age at which the last seizure occurred ranged from 6 to 15.5 years.102 Scoliosis may develop and limit ambulation.103 Stage 4 (late motor deterioration) may last for decades.99
TABLE 56-3 Rett Syndrome Stages
Not all RTT presentations fit this classical stage model. Presentations vary in terms of onset and severity. Genetic mutations may be one partial explanation for atypicality.99 At this time, only the following X-linked gene mutations are recognized as potential moderating influences: cyclin-dependent kinase-like 5 (CDKL5) on early seizure onset, MECP2 for speech preservation, and forkhead box protein G1 (FOXG1) considered responsible for one of the key indicators of the syndrome, small head circumference.104
CLINICAL PRESENTATION Rett Syndrome
General features
• RTT is diagnosed primarily in females.
• Previously acquired skills are lost following apparently normal prenatal and early development.
• There is an increased risk for seizure disorders in the RTT population compared with the general population.
Additional features
• Head growth slows.
• Periods of hyperventilation and apnea may occur.
• Motor skills may vary.
• Stereotypies may occur.
• Unprovoked laughing and/or screaming.
• Intense eye gaze communication.
• Bruxism.
Data from references 1, 96, and 97.
The presence of stereotypic hand movements, social and environmental withdrawal, and irritability (including the inability to be soothed when crying) have given rise to investigating commonalities between RTT and autism.105Impairments in communication and environmental interactions, eye contact, and stereotypies are temporary, whereas with autism, these persist.105
TREATMENT
Desired Outcomes
Treatment goals in RTT are to identify the characteristic developmental changes of each stage and provide effective nonpharmacologic and pharmacotherapy interventions, as appropriate, to improve quality of life.
General Approach to Treatment
Treatment plans should address the physiologic changes of each stage, optimizing pharmacotherapy, as appropriate. Effective strategies require a systematic approach to (a) address the specific medical needs identified, (b) monitor the medications used as appropriate, and (c) reassess the need for continued pharmacotherapy.
Nonpharmacologic Therapy
Behavioral problems are not commonly encountered with RTT. Other considerations include evaluating for respiratory complications such as obstructive sleep apnea with polysomnography and therapeutic interventions if indicated.106 Surgical intervention may be indicated to lessen the severity of scoliosis-associated pain, maintain mobility, and decrease respiratory problems. Caregivers provided input on ADL questionnaires related to function and behavior for RTT females who either had surgery (n = 16) or did not have surgery (n = 86). In the wheelchair-bound surgical intervention group, ADL skills improved. No differences were reported for social interactions, communication skills, or daytime napping presurgical or postsurgical intervention.107
Pharmacologic Therapy
Information on pharmacotherapy for comorbidities associated with the RTT population comes from case reports, case series, and small trials. One of the more thoroughly investigated aspects is the treatment of seizures that may appear in stage 2 or 3. Krajnc et al. retrospectively analyzed seizure data on 19 RTT females and found seizure activity present in 84% (16 of 19).102
Specific gene mutations may also influence seizure activity, with seizure activity reported in up to 90% of the RTT population. Medication usage was reviewed in two populations with confirmed MECP2 mutations. In the first (n= 162), authors found seizure activity was age-dependent, influenced by the gene mutation, and positively associated with an earlier and more severe regression. The most commonly used medications, either as monotherapy or in combination, were carbamazepine, valproate, and lamotrigine.108 In a second population (n = 110), carbamazepine (n = 15), sulthiame (n = 15), and valproate (n= 16) were the only medications administered as monotherapy that could be evaluated for analysis. Seizure-free periods were reported with use of all three. Reductions were greatest with carbamazepine, and then sulthiame. Valproate was least effective.109
Comorbidities, including seizures and cardiac problems, can impact drug selection. Cardiac mortality is significantly elevated in RTT. There is a 300-fold increase in sudden death from arrhythmias compared with the general population.110 Causality has not been determined. Electrocardiogram (ECG) findings of QT prolongation and dyssynchronous innervations cannot account for the marked increase in mortality. Concurrent administration of medications that prolong the QT interval should be undertaken with caution and ECG monitoring. Any pharmacotherapy should take into consideration cardiac implications and other potential adverse drug effects.
Personalized Pharmacotherapy
RTT is an X-linked dominant mutation at the Xq28 site. Four mutations on this gene have been identified, CDKL5, FOXG1, R168X, and R294X, that may provide an explanation for differences in severity, onset, and developmental regression. To date, neither pharmacokinetic nor pharmacogenetic considerations have been identified in those with RTT. Continued advances in pharmacogenomics may be identified with CDKL5 and early seizure onset. Monotherapy with carbamazepine has been used,102 but the extent to which biomarker HLA-B*1502 is involved has not been identified.
Clinical Controversy…
Although poorly understood, fracture risk in RTT appears to be approximately four times greater than in the general population.111,112 While the primary genetic mutation site is the X-linked MECP2 gene, phenotype and fracture risk may be mutation-specific. In a 7-year longitudinal study (n = 233) adjusted for antiepileptic drug used, mobility, seizure diagnosis, and genotype, use of valproate was associated with a threefold increase in the fracture rate after 1 year.
Evaluation of Therapeutic Outcomes
The most medication-responsive feature of RTT is seizure activity. Seizure frequency changes with age.108 For more information about epilepsy and seizure disorders, see Chapter 40. Depending on the anticonvulsant used, laboratory monitoring may be needed. Seizure frequency and adverse effects should be monitored when medications are added or doses changed and at regular intervals thereafter. During the late teens and 20s, reassessing the need for continued anticonvulsant treatment is recommended, since seizures have been known to spontaneously abate with age.
ABBREVIATIONS
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