Global Developmental Delay and Regression

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Chapter 7 Global Developmental Delay and Regression

Developmental delay occurs in approximately 1% to 3% of children. Since developmental delay is common, monitoring a child’s development is an essential component of well-child care. Ongoing assessment of the child’s development at each well-child visit creates a pattern of development that is more useful than measuring the discrete milestone achievements at a single visit; therefore, developmental screening should be completed at each well-child visit (Council on Children with Disabilities, 2006). Identification of a child with developmental delays should be accomplished as early as possible, because the earlier a child is identified, the sooner the child can receive a thorough evaluation and begin therapeutic interventions that can improve the child’s outcome. Developmental delay is common and one of the most frequent presenting complaints to a pediatric neurology clinic; neurologists should have a systematic approach to the child with developmental delay.

This chapter begins with a brief discussion of child development concepts related to typical and atypical development. Next, the clinical evaluation and management of developmental delay is reviewed. The chapter closes with a discussion of neurological regression.

Typical and Atypical Development

Child Development Concepts

Child development is a continuous process of acquiring new and advanced skills. This development depends on maturation of the nervous system. Although typical child development follows a relatively consistent sequence, it is not linear. Instead, there are spurts and lags. For example, motor development in the first year of life proceeds relatively rapidly. Babies typically mature from being completely immobile to walking in just over 12 months, but then motor development progresses less dramatically during the second year of life. Conversely, language development in the first year of life occurs slowly, but there is an explosion of language acquisition between a child’s first and second birthdays.

On average, most children achieve each developmental milestone within a defined and narrow age range (Table 7.1). Usually physicians learn the average age for acquiring specific skills. However, since each developmental skill can be acquired within an age range, it is much more useful clinically to know when a child’s development falls outside this range. These so-called red flags are important because they can be used to identify when a child has developmental delay for specific skills. For example, although the average age of walking is approximately 13 months, a child may walk as late as 17 months and still be within the typical developmental range. In this example, the red flag for independent walking is 18 months, and a child who is not walking by 18 months of age is delayed.

Global Developmental Delay

Developmental History

Child development is classically divided into five interdependent domains or streams: gross motor, fine motor and problem-solving, receptive language, expressive language, and socialization/adaptive. The approach to a child with possible developmental delays is based on a working knowledge of these domains and the typical age ranges for acquiring specific milestones within each domain. Therefore, the clinician should begin the evaluation of a child with developmental concerns by obtaining a developmental history, and emphasis should be placed on the pattern of milestone acquisition as well as the child’s current developmental skills. Clinicians working in a busy clinical setting may need to base this history primarily on the caregiver’s report of the child’s developmental abilities. Clinicians may also use standardized tools to aid in this portion of the history, including the Ireton Child Development Inventory (CDI), the Ages and Stages Questionnaire (ASQ), and the Parents’ Evaluation of Developmental Status (PEDS). However, if the clinician’s history confirms a developmental disability, standardized testing by a developmental specialist or clinical psychologist should be strongly considered; this formal evaluation will provide a much better assessment of the child’s developmental abilities.

When there is concern about developmental delay in a child, a developmental quotient should be calculated. The developmental quotient is the ratio of the child’s developmental age over the chronological age. The developmental quotient should be calculated for each developmental stream. Typical development is a developmental quotient greater than 70%, and atypical development it is a developmental quotient less than 70%. Toddlers and young children with atypical development are at risk for lifelong developmental problems. The term global development delay is used if a child younger than 5 to 6 years of age has a developmental quotient less than 70% in two or more domains. Children with global developmental delay should receive a thorough medical evaluation to try to determine the cause of the delay and begin management for their developmental disabilities.

Neurological and Other Medical History

For children with global developmental delay, the clinician should obtain a thorough medical history, including a detailed neurological history. Pertinent aspects of the history include the presence of any other neurological condition such as epilepsy, vision or hearing impairments, ataxia or a movement disorder, sleep impairment, and behavioral problems. The clinician should also inquire about prenatal, perinatal, and postnatal factors that can impact a child’s development (Tables 7.2 and 7.3). The social history should probe for environmental factors that can affect development, including physical or other forms of abuse, neglect, psychosocial deprivation, family illness, impaired personalities in family members, sociocultural stressors, and the economic status of the family.

Table 7.2 Etiology of Developmental Delay by Time of Onset

Prenatal/Perinatal Examples
Congenital malformations of the CNS Lissencephaly, holoprosencephaly
Chromosomal abnormalities Down syndrome, Turner syndrome
Endogenous toxins Maternal hepatic or renal failure
Exogenous toxins from maternal use Anticonvulsants, anticoagulants, alcohol, drugs of abuse
Fetal infection Congenital infections
Prematurity and/or fetal malnutrition Periventricular leukomalacia
Perinatal trauma Intracranial hemorrhage, spinal cord injury
Perinatal asphyxia Hypoxic-ischemic encephalopathy
Postnatal Examples
Inborn errors of metabolism Aminoacidopathies, mitochondrial diseases
Abnormal storage of metabolites Lysosomal storage diseases, glycogen storage diseases
Abnormal postnatal nutrition Vitamin or calorie deficiency
Endogenous toxins Hepatic failure, kernicterus
Exogenous toxins Prescription drugs, illicit substances, heavy metals
Endocrine organ failure Hypothyroidism, Addison disease
CNS infection Meningitis, encephalitis
CNS trauma Diffuse axonal injury, intracranial hemorrhage
Neoplasia Tumor infiltration, radiation necrosis
Neurocutaneous syndromes Neurofibromatosis, tuberous sclerosis complex
Neuromuscular disorders Muscular dystrophy, myotonic dystrophy
Vascular conditions Vasculitis, ischemic stroke, sinovenous thrombosis
Other Epilepsy, mood disorders, schizophrenia

CNS, Central nervous system.

From Sherr, E.H., Shevell, M.I., 2006. Mental retardation and global developmental delay, in: Swaiman, K.F., Ashwal, S., Ferriero, D.I. (Eds.), Pediatric Neurology, Principles and Practice, fifth ed. Mosby, Philadelphia.

Table 7.3 Perinatal Risk Factors for Neurologic Injury

Maternal/Prenatal Natal Postnatal
Age <16 years or >40 years Intrauterine hypoxia: prolapsed umbilical cord, abruptio placenta, circumvallate placenta Abnormal feeding: poor sucking, weight gain, malnutrition, vomiting
Cervical or pelvic abnormalities Midforceps delivery or breech presentation Abnormal crying
Maternal illnesses: infection, shock, diabetes, nephritis, phlebitis, proteinuria, renal hypertension, thyroid disease, drug addiction, malnutrition Poor Apgar scores: cyanosis, poor respiratory effort, bradycardia, poor reflexes, hypotonia    Abnormal exam: asymmetrical face, asymmetrical extremities, dysmorphic features, hypotonia, birth injuries, seizures
Maternal features: unmarried, uneducated, nonwhite, low-income, thin, short Need for resuscitation: respiratory distress, bradycardia, hypotension Abnormal findings: hyperbilirubinemia, fever, hypothermia, hypoxia
Consanguinity Gestational age <30 weeks  
Prior abnormal pregnancy, miscarriages, stillbirths, abortions, neonatal deaths, infants less than 1500 g, abnormal placenta Vaginal bleeding in the second or third trimester  
  Hypoxic-ischemic encephalopathy  
  Polyhydramnios or oligohydramnios  

From Sherr, E.H., Shevell, M.I., 2006. Mental retardation and global developmental delay, in: Swaiman, K.F., Ashwal, S., Ferriero, D.I. (Eds.), Pediatric Neurology, Principles and Practice, fifth ed. Mosby, Philadelphia.

Though families now typically have fewer children, and the caregivers’ knowledge of family history is frequently quite limited, the clinician should still make an effort to obtain a three-generation pedigree. The pertinent aspects of the family history include developmental disabilities, special education services or failure to graduate from school, neurodegenerative disorders, multiple miscarriages or early postnatal death, ethnicity, and consanguinity. If a specific genetic syndrome is suspected, the clinician should inquire about the presence in other family members of medical problems associated with that syndrome. For example, if the child has the features of fragile X syndrome, the family history should include questions about maternal premature ovarian failure, parkinsonism or ataxia of unknown etiology in the maternal grandfather, and intellectual disability or learning problems in an X-linked pattern.

Physical Examination

The growth parameters of the child should be measured, and the growth charts should be reviewed to determine the child’s rate of growth. This is pertinent because many chromosomal anomalies and other genetic disorders that cause global developmental delay and intellectual disability are associated with failure to thrive or short stature, large stature, microcephaly, and macrocephaly.

In the mental status portion of the examination, the clinician should note the interactions the child has with his or her caregivers and the clinician. Abnormal behaviors such as impaired eye contact, limited or absent social reciprocity, restricted or repetitive behaviors, and communication impairment may indicate that the child has an autism spectrum disorder, and the child should be referred to a psychologist for assessment or confirmation of this condition. Other abnormal behaviors such as hyperactivity, impulsivity, and inattention, as well as suboptimal parenting skills, may also be noted during these observations. However, the clinician should use caution when raising concerns about a behavior problem based solely on the child’s behavior in clinic, since this stressful situation may lead the child to manifest uncharacteristic behaviors.

A complete general physical and neurological examination should be performed to the extent the child will allow. The general examination should include but not be limited to an evaluation for dysmorphic features; abnormalities of the eyes (Table 7.4), skin, and hair; and organomegaly (Table 7.5). The neurological examination should include signs of impairment in extraocular movements; hypertonia or hypotonia; focal or generalized weakness; abnormal posture or movements; abnormal or asymmetrical tendon reflexes; ataxia, incoordination or other signs of cerebellar dysfunction; and gait abnormalities (see Table 7.5).

Table 7.4 Ocular Findings Associated with Selected Syndromic Developmental Disorders

Finding Examples
Cataracts Cerebrotendinous xanthomatosis, galactosemia, Lowe syndrome, LSD, Wilson disease
Chorioretinitis Congenital infections
Corneal opacity Cockayne syndrome, Lowe syndrome, LSD, xeroderma pigmentosa, Zellweger syndrome
Glaucoma Lowe syndrome, mucopolysaccharidoses, Sturge-Weber syndrome, Zellweger syndrome
Lens dislocation Homocystinuria, sulfite oxidase deficiency
Macular cherry-red spot LSD, multiple sulfatase deficiency
Nystagmus Aminoacidopathies, AT, CDG, Chédiak-Higashi syndrome, Friedreich ataxia, Leigh syndrome, Marinesco-Sjögren syndrome, metachromatic leukodystrophy, neuroaxonal dystrophy, Pelizaeus-Merzbacher disease, SCD
Ophthalmoplegia AT, Bassen-Kornzweig syndrome, LSDs, mitochondrial diseases   
Optic atrophy Alpers disease, Leber optic atrophy, leukodystrophies, LSDs, neuroaxonal dystrophy, SCD  
Photophobia Cockayne syndrome, Hartnup disease, homocystinuria
Retinitis pigmentosa or macular degeneration AT, Bassen-Kornzweig syndrome, Cockayne syndrome, CDG, Hallervorden-Spatz syndrome, Laurence-Moon-Biedl syndrome, LSD, mitochondrial diseases, Refsum disease, Sjögren-Larsson syndrome, SCD

AT, Ataxia-telangiectasia; CDG, congenital disorders of glycosylation; LSD, lysosomal storage diseases; SCD, spinocerebellar degeneration.

From Sherr, E.H., Shevell, M.I., 2006. Mental retardation and global developmental delay, in: Swaiman, K.F., Ashwal, S., Ferriero, D.I. (Eds.), Pediatric Neurology, Principles and Practice, fifth ed. Mosby, Philadelphia.

Table 7.5 Other Findings Associated with Selected Syndromic Developmental Disorders

Finding Examples
Cerebellar dysfunction Aminoacidopathies, AT, Bassen-Kornzweig syndrome, CDG, cerebrotendinous xanthomatosis, Chédiak-Higashi syndrome, Cockayne syndrome, Friedreich ataxia, Lafora disease, LSD, Marinesco-Sjögren syndrome, mitochondrial disease, neuroaxonal dystrophy, Pelizaeus-Merzbacher disease, Ramsay Hunt syndrome, SCD, Wilson disease
Hair abnormalities:  
Synophrys Cornelia de Lange syndrome
Fine hair Homocystinuria, hypothyroidism
Kinky hair Argininosuccinic aciduria, Menkes disease
Hirsutism LSD
Balding Leigh syndrome, progeria
Gray hair AT, Chédiak-Higashi syndrome, Cockayne syndrome, progeria
Hearing abnormalities:  
Hyperacusis LSD, SSPE, sulfite oxidase deficiency
Conductive loss Mucopolysaccharidoses
Sensorineural loss Adrenoleukodystrophy, CHARGE, Cockayne syndrome, mitochondrial diseases, SCD, Refsum disease
Infantile hypotonia Canavan disease, myopathies, LSD, Leigh syndrome, Menkes disease, neuroaxonal dystrophy, spinal muscular atrophy, Zellweger disease
Limb abnormalities:  
Micromelia Cornelia de Lange syndrome
Broad thumbs Rubinstein-Taybi syndrome
Macrocephaly Alexander disease, Canavan histiocytosis X, LSD
Microcephaly Alpers disease, CDG, Cockayne syndrome, incontinentia, pigmenti, neuronal ceroid lipofuscinoses, Crabbe disease, neuroaxonal dystrophy, Rett syndrome
Movement disorders AT, LSD, dystonia musculorum deformans, Hallervorden-Spatz, juvenile Huntington disease, juvenile Parkinson disease, Lesch-Nyhan disease, phenylketonuria, Wilson disease, xeroderma pigmentosa
Odors:  
Cat urine β-Methyl-crotonyl-CoA carboxylase deficiency  
Maple Maple syrup urine disease
Musty Phenylketonuria
Rancid butter Methionine malabsorption syndrome
Sweaty feet Isovaleric acidemia
Organomegaly Aminoacidopathies, CDG, galactosemia, glycogen storage diseases, LSD, Zellweger syndrome
Peripheral neuropathy AT, Bassen-Kornzweig syndrome, cerebrotendinous xanthomatosis, Cockayne syndrome, LSD, Refsum disease
Short stature Cockayne syndrome, Cornelia de Lange syndrome, hypothyroidism, leprechaunism, LSD, Prader-Willi syndrome, Rubinstein-Taybi syndrome, Seckel bird-headed dwarfism
Seizures Aminoacidopathies, CDG, glycogen synthetase deficiency, HIE, LSD, Menkes disease, mitochondrial diseases, neuroaxonal dystrophy
Skin abnormalities:  
Hyperpigmentation
Hypopigmentation
Adrenoleukodystrophy, AT, Farber disease, neurofibromatosis, Niemann-Pick disease, tuberous sclerosis complex, xeroderma pigmentosa
Nodules Chédiak-Higashi syndrome, incontinentia pigmenti, Menkes disease, tuberous sclerosis complex
Thick skin Cerebrotendinous xanthomatosis, Farber disease, neurofibromatosis, LSD, Refsum disease,
Thin skin Sjögren-Larsson syndrome, AT, Cockayne syndrome, progeria, xeroderma pigmentosa

AT, Ataxia-telangiectasia; CDG, congenital disorders of glycosylation; CHARGE, coloboma, heart disease, choanal atresia, retardation, genital anomalies, ear anomalies; HIE, hypoxic-ischemic encephalopathy; LSD, lysosomal storage diseases; SCD, spinocerebellar degeneration; SSPE, subacute sclerosing panencephalitis.

From Sherr, E.H., Shevell, M.I., 2006. Mental retardation and global developmental delay, in: Swaiman, K.F., Ashwal, S., Ferriero, D.I. (Eds.), Pediatric Neurology, Principles and Practice, fifth ed. Mosby, Philadelphia.

Diagnostic Testing

Diagnostic testing in an individual with global developmental delay should be offered to the family, because the testing may provide an etiology for the developmental delays, could alert the physician and family to comorbid conditions the child is at risk for developing, can help provide recurrence information to the family, and may rarely lead to specific medical treatments or therapeutic interventions.

Genetic Testing

Based on the developmental history obtained, a diagnosis of global developmental delay can be made. In addition, the clinician should attempt to identify an underlying etiology for the delay. Occasionally, the history and examination suggest a specific recognizable genetic condition or other cause. In these situations, confirmatory testing should be performed if possible. For example, a girl with a history of global developmental delay who has acquired microcephaly, epilepsy, and midline hand wringing should be tested for Rett syndrome.

Frequently, however, the underlying cause is unknown despite the acquisition of a comprehensive history and physical examination. In these situations, a chromosomal microarray analysis (CMA) should be offered to the family, since it has the highest diagnostic yield of any single assay for children with global developmental delay: approximately 8% to 12%. A clinical CMA tests for submicroscopic deletions or duplications that can be associated with a variety of neurodevelopmental delays, including global developmental delay. This is also the first-line test for individuals with nonspecific intellectual disability, an autism spectrum disorder, and multiple congenital anomalies (Miller et al., 2010). Though this test has a relatively high diagnostic yield, it will typically not detect inversions and other balanced rearrangements. Consequently, if the microarray is within normal limits, a follow-up high-resolution karyotype should be considered.

The CMA is also unable to detect trinucleotide repeat expansions, point mutations, and imprinting abnormalities. Therefore, every child with nonspecific global developmental delay regardless of gender should also have fragile-X testing performed. Based on the phenotype, the clinician should also consider performing methylation testing for Angelman and Prader-Willi syndrome, since the microarray analysis will miss the uniparental disomy or imprinting center abnormalities associated with these syndromes. Based on the patient’s constellation of clinical features, molecular testing for UBE3A (Angelman syndrome), MeCP2 (Rett syndrome), and other genetic disorders may be considered if the microarray analysis is within normal limits.

In children with global developmental delay, it is important to confirm that the universal newborn screening test was normal at birth. Nonetheless, the diagnostic yield of biochemical testing in a child with nonspecific global developmental delay is quite low (<1%) (Moeschler and Shevell, 2006). The yield may be slightly higher if there is a history of: (1) metabolic decompensation, hyperammonemia, hypoglycemia, protein aversion, acidosis or other evidence of an inborn metabolic disease; (2) neonatal seizures, stroke, movement disorder, or other neurological diagnosis; (3) a family history of unexplained death or neurological disease in a first-degree relative; (4) parental consanguinity; or (5) prenatal history of acute fatty liver of pregnancy (AFLP) or toxemia with hemolysis, elevated liver enzymes, and low platelets (HELLP). Physical examination findings that should increase the suspicion of a metabolic disease include microcephaly, macrocephaly, growth failure, unusual odor, coarse facial features, unusual birthmarks, abnormal hair, hypotonia, dystonia, and focal weakness.

Biochemical tests from the blood to consider in the evaluation of a child with global developmental delay include complete blood count, comprehensive metabolic panel, serum lactate (and possibly serum pyruvate if the result is reliable at the clinician’s institution), plasma amino acids, serum creatinine kinase level, uric acid level, and creatine metabolites (in girls). Urine studies to consider include organic acid analysis, purine and pyrimidine metabolites, and creatine metabolites (in boys). Selective metabolic testing may be warranted in specific clinical cases, such as serum 7-dehydrocholesterol level for Smith-Lemli-Opitz syndrome, screening for congenital disorders of glycosylation, biotinidase activity in the blood, cerebrospinal fluid (CSF) neurotransmitter metabolites for neurotransmitter deficiencies, and white blood cell enzyme analysis and urine glycosaminoglycans and oligosaccharides for lysosomal storage diseases.

Neuroimaging

Magnetic resonance imaging (MRI) of the brain has a yield of 65% in children with developmental delay (Shevell et al., 2003). The abnormalities most frequently identified include cerebral malformations, cerebral atrophy, delayed myelination, other white matter changes, postischemic changes, widened Virchow-Robin spaces, and phakomatoses. However, many of these changes are nonspecific and do not lead to the diagnosis of a specific etiology for the developmental delay. The yield of a brain MRI is higher if the child has neurological abnormalities on physical examination such as microcephaly, macrocephaly, focal neurological deficits, epilepsy, strokes, or a movement disorder. Given the nonnegligible risk of sedation in a child with global developmental delay, neuroimaging with an MRI should be recommended as a first-line study in children with focal neurological findings and may be offered as a second-line study if genetic testing is nondiagnostic.

Because the diagnostic yield of head computed tomography (CT) is much lower than brain MRI, head CT is primarily indicated in children with global developmental delay who are suspected of having calcifications.

Management

Medical management of global developmental delay begins with a disclosure to the family of the clinician’s concern for the diagnosis. As with any situation in which the physician discloses difficult news, this must be done gently but clearly. The clinician should be prepared to respond to a full range of emotions including doubt, denial, sorrow, and anger. Furthermore, the family will usually need time to process the information that their child has or is at risk for having lifelong developmental problems. Therefore, a follow up appointment should be scheduled to review the diagnosis and address additional questions or concerns the family may have.

In addition, any comorbid conditions should be treated, or the clinician should refer the patient to the appropriate subspecialist who can provide treatment for the comorbid condition. The clinician can also help facilitate social, community, or educational supports for the family. These may include family support groups, national parent organizations, and other resources in the community for families of children with developmental disabilities.

One of the most important aspects of the management of a child with global developmental delay is ensuring that the child receives early and appropriate therapeutic and educational interventions. Children younger than 3 years of age with developmental delays can be enrolled in early intervention programs. Each state’s program includes a multidisciplinary team of therapists who complete a comprehensive assessment and provide appropriate interventions. Their assessment is summarized in a report called the Individualized Family Service Plan; this plan serves as the basis for provision of therapeutic services.

Children who are older than 3 years of age receive services through the special education program within the local school district. These services are usually provided by a multidisciplinary team of therapists as well as a psychologist. They also complete an assessment and summarize their findings in a report called the Individualized Education Plan (IEP). The IEP serves as the basis for the services that will be provided to the child within the school system. Federal law mandates that children receive the special services they need in the least restrictive environment possible. Therefore, many children with developmental disabilities are now educated in the regular (“mainstream”) classroom with an aide instead of being placed in a separate classroom. However, some children with more significant intellectual or behavioral problems may require placement in a special education classroom for part or all of the day.

Prognosis

Once a child is diagnosed with global developmental delay, the family will inquire about the child’s ultimate developmental outcome, including cognitive and motor abilities, future level of independence, and life expectancy. In young children with mild developmental delay, it is not prudent to predict a developmental outcome with certainty. Instead, the potential range of outcomes should be discussed. Depending on the severity of the delays and associated medical problems, this range may include typical development once the child is school-aged. In an otherwise healthy individual with developmental delay, the life expectancy is normal. Children with significantly impaired mobility or other neurological impairments may have a shortened life expectancy.

Though some toddlers and young children with developmental delay may “catch up” and ultimately have typical development, global developmental delay is associated with an increased risk for having a developmental disability—a lifelong and chronic condition due to impairments in mental and/or physical impairments that impacts major life activities such as language function, learning, mobility, self-help, and independent living. Several types of developmental disabilities exist, including cerebral palsy, learning disabilities like dyslexia, intellectual disability, autism spectrum disorders, attention deficit-hyperactivity disorder, hearing impairment, and vision impairment.

These developmental disabilities are predominantly impairments in a specific subset of the developmental domains. For example, cerebral palsy is primarily an impairment of gross and fine motor skills; intellectual disability is primarily an impairment of language, problem-solving, and social-adaptive abilities; and autism spectrum disorders are primarily disorders of social-adaptive behaviors with or without language and communication impairments.

Developmental disabilities are common. Approximately 16% to 18% of children have a developmental disability that includes behavior problems, and 1% to 3% of the population has an intellectual disability. Approximately 1 in 150 children have an autism spectrum disorder.

Toddlers or preschool children who are diagnosed with global developmental delay are at highest risk for being diagnosed with intellectual disability at an older age, especially as the developmental quotient worsens. Intellectual disability is defined as significantly subaverage general intellectual functioning (IQ less than 70) with limitations in adaptive functioning in at least two of the following skill areas: communication, self-help, social skills, academic skills, work, leisure, and health and/or safety. The incidence of intellectual disability is 1% to 3% in the general population. Males are more likely to be affected than females; occurrence rates are 1 : 4000 males and only 1 : 6000 females.

In general, the diagnosis of intellectual disability is not made in a toddler or preschool child unless they have been diagnosed with a specific genetic condition associated with intellectual disability. In the absence of a specific genetic diagnosis, the diagnosis of intellectual disability in most children is made once they are able to complete formal psychology testing at approximately 5 years of age.

In our practice, when the developmental delays of a child younger than 4 are very severe, we will occasionally tell the family that the child will likely have intellectual disability. In these situations, we may share this concern even if the child does not have a formal diagnosis of a genetic syndrome or before the child is old enough to complete formal psychology testing. Children with severe developmental delays may in fact be too impaired to perform formal psychology testing.

Regression

A regressive or neurodegenerative disease should be suspected when a child has ongoing and relentless loss of developmental skills. In addition, a regressive disease may begin to manifest itself as the development of a new neurological problem, such as a new-onset seizure disorder or movement disorder, development of a different type of seizure in a child with epilepsy, vision impairment, behavior problems, and dementia or cognitive decline.

In a child with neurological regression, a thorough neurological history and examination is warranted. The history should focus on any modifiable factors that could contribute to neurological decline, including worsening of another medical problem, recent modification to an existing medication regimen or initiation of a new medication, recovery from a prolonged acute illness or surgery, or a psychosocial stressor. All children with neurological decline should receive an extensive physical examination, with attention to those aspects of the examination that could provide clues to an underlying neurodegenerative disease (see Table 7.5). A pediatric ophthalmologist should also examine the patient for ocular stigmata of a neurodegenerative disease (see Table 7.4). A brain MRI should be performed to assess for changes that can be seen in many regressive diseases—atrophy, ventriculomegaly, white matter changes, and infarcts. Additional studies should be considered based on the patient’s clinical presentation: comprehensive metabolic panel, lipid panel, creatine kinase, EEG, EMG and nerve conduction studies, echocardiogram, and hearing test.

The need for genetic testing is based on the patient’s presentation and results of the recommended studies. Categories of genetic diseases that should be considered include aminoacidopathies, organic acidurias, fatty acid oxidation defects, glycogen storage diseases, mitochondrial cytopathies, lysosomal storage diseases, neuronal ceroid lipofuscinoses, peroxisomal disorders, neurotransmitter synthesis disorders, spinal muscular atrophy syndromes, creatine synthesis disorders, congenital disorders of glycosylation, metal metabolism disorders (Menkes, Wilson, pantothenate kinase-associated neurodegeneration), and purine and pyrimidines disorders. Testing for most conditions can now be done on blood, urine, and/or CSF samples. Rarely, more invasive procedures may be warranted, including biopsies of the skin, muscle, liver, nerve, bone marrow, or conjunctiva.

Many reasons exist to aggressively pursue a diagnosis of an underlying neurodegenerative disease. Most regressive disorders are irreversible, and the treatment is symptomatic. However, early diagnosis can reverse the neurological impairment or prevent future morbidity is some conditions such as Wilson disease, homocystinuria, and glutaric aciduria type I. Occasionally, pharmaceutical trials may be available to patients. Furthermore, a correct diagnosis can help the clinician provide better information about prognosis and life expectancy. Recurrence risk information and prenatal diagnosis may also be offered to families. For those conditions that are progressive and life limiting, the clinician should collaborate with a pediatric palliative care team to discuss end-of-life goals of care with the family.