Psychomotor retardation or developmental delay refers to the slow progress in the attainment of developmental milestones. This may be caused by either static ( Box 5-1 ) or progressive ( Box 5-2 ) encephalopathies. In contrast, psychomotor regression refers to the loss of developmental milestones previously attained. This is usually due to a progressive disease of the nervous system. In some cases, reports of regression may also result from parental misperception of attained milestones or by the development of new clinical features from an established static disorder as the brain matures ( Box 5-3 ).
Predominant Speech Delay
Bilateral hippocampal sclerosis
Congenital bilateral perisylvian syndrome (see Chapter 17 )
Hearing impairment ∗
∗ Denotes the most common conditions and the ones with disease modifying treatments
(see Chapter 17 )
Infantile autism
Predominant Motor Delay
Ataxia (see Chapter 10 )
Hemiplegia (see Chapter 11 )
Hypotonia (see Chapter 6 )
Neuromuscular disorders ∗ (see Chapter 7 )
Paraplegia (see Chapter 12 )
Global Developmental Delay
Cerebral malformations
Chromosomal disturbances
Intrauterine infection
Perinatal disorders
Progressive encephalopathies (see Box 5-2 )
A cquired I mmune D eficiency S yndrome E ncephalopathy ∗
D isorders of A mino A cid M etabolism
Guanidinoacetate methyltransferase deficiency ∗
∗ Denotes the most common conditions and the ones with disease modifying treatments
Homocystinuria (21q22) ∗
Maple syrup urine disease (intermediate and thiamine response forms) ∗
Phenylketonuria
Guanidinoacetate methyltransferase deficiency ∗
D isorders of L ysosomal E nzymes
Ganglioside storage disorders
GM 1 gangliosidosis
GM 2 gangliosidosis (Tay-Sachs disease, Sandhoff disease)
Gaucher disease type II (glucosylceramide lipidosis) ∗
Globoid cell leukodystrophy (Krabbe disease)
Glycoprotein degradation disorders
I-cell disease
Niemann-Pick disease type A (sphingomyelin lipidosis)
Sulfatase deficiency disorders
Metachromatic leukodystrophy (sulfatide lipidoses)
Multiple sulfatase deficiency
C arbohydrate -D eficient G lycoprotein S yndromes
H ypothyroidism ∗
M itochondrial D isorders
Alexander disease
Mitochondrial myopathy, encephalopathy, lactic acidosis, stroke (see Chapter 11 )
Progressive infantile poliodystrophy (Alpers disease)
Subacute necrotizing encephalomyelopathy (Leigh disease)
Trichopoliodystrophy (Menkes disease)
N eurocutaneous S yndromes
O ther D isorders of G ray M atter
Infantile ceroid lipofuscinosis (Santavuori-Haltia disease)
Infantile neuroaxonal dystrophy
Lesch-Nyhan disease ∗
Progressive neuronal degeneration with liver disease
Rett syndrome
O ther D isorders of W hite M atter
Aspartoacylase deficiency (Canavan disease)
Galactosemia: Transferase deficiency ∗
Neonatal adrenoleukodystrophy (see Chapter 6 ) ∗
Pelizaeus-Merzbacher disease
Progressive cavitating leukoencephalopathy
P rogressive H ydrocephalus ∗
Increasing spasticity (usually during the first year)
New onset movement disorders (usually during the second year)
New onset seizures
Parental misperception of attained milestones
Progressive hydrocephalus
Developmental Delay
Delayed achievement of developmental milestones is one of the more common problems evaluated by child neurologists. Two important questions require answers. Is developmental delay restricted to specific areas or is it global? Is development delayed or regressing?
In infants, the second question is often difficult to answer. Even in static encephalopathies, new symptoms such as involuntary movements and seizures may occur as the child gets older, and delayed acquisition of milestones without other neurological deficits is sometimes the initial feature of progressive disorders. However, once it is clear that milestones previously achieved are lost or that focal neurological deficits are evolving, a progressive disease of the nervous system is a consideration.
The Denver Developmental Screening Test (DDST) is an efficient and reliable method for assessing development in the physician’s office. It rapidly assesses four different components of development: personal–social, fine motor adaptive, language, and gross motor. Several psychometric tests amplify the results, but the DDST in combination with neurological assessment provides sufficient information to initiate further diagnostic studies.
Language Delay
Normal infants and children have a remarkable facility for acquiring language during the first decade. Those exposed to two languages concurrently learn both. Vocalization of vowels occurs in the first month, and, by 5 months, laughing and squealing are established. At 6 months, infants begin articulating consonants, usually M, D, and B. Parents translate these to mean “mama,” “dada,” and “bottle” or “baby,” although this is not the infant’s intention. These first attempts at vowels and consonants are automatic and sometimes occur even in deaf children. In the months that follow, the infant imitates many speech sounds, babbles and coos, and finally learns the specific use of “mama” and “dada” by 1 year of age. Receptive skills are always more highly developed than expressive skills, because language must be decoded before it is encoded. By 2 years of age, children have learned to combine at least two words, understand more than 250 words, and follow many simple verbal directions.
Developmental disturbances in the language cortex of the dominant hemisphere that occur before 5 years of age, and possibly later, displace language to the contralateral hemisphere. This does not occur in older children.
Autistic Spectrum Disorders
Infantile autism is not a single disorder, but rather many different disorders described by a broad behavioral phenotype that has a final common pathway of atypical development ( ). The terms autistic spectrum disorders (ASD) and pervasive developmental disorders are used to classify the spectrum of behavioral symptoms. Asperger disorder represents the high-functioning end of the autistic disorder spectrum. Many different gene loci are identifiable, some or all of which contribute to the phenotype ( ). The “broad autism phenotype” includes individuals with some symptoms of autism who do not meet the full criteria for autism or other disorders.
Autism has become an increasingly popular diagnosis. An apparent increasing incidence of diagnosis suggests to some an environmental factor. However, data does not confirm the notion of an autism epidemic nor causation by any environmental factor. The definition of ASD has become so wide that it is likely contributing to the apparent increase in prevalence. Most biological studies indicate genetic or other prenatal factors. Anxiety and obsessive-compulsive traits are highly represented in parents of children with ASD. It is possible that these children will have an overload of these genetic traits contributing to some of their symptoms.
Clinical Features
The major diagnostic criteria are impaired sociability, impaired verbal and nonverbal communication skills, and restricted activities and interests ( ). Failure of language development is the feature most likely to bring autistic infants to medical attention and correlates best with the outcome; children who fail to develop language before the age 5 years have the worst outcome. The IQ is less than 70 in most children with autism. However, IQ may be significantly underestimated due to their impaired interactive skills, which make testing difficult and less reliable. Some autistic children show no affection to their parents or other care providers, while others are affectionate on their own terms. Autistic children do not show normal play activity; some have a morbid preoccupation with spinning objects, stereotyped behaviors such as rocking and spinning, and relative insensitivity to pain. An increased incidence of epilepsy in autistic children is probable.
Diagnosis
Infantile autism is a clinical diagnosis and not confirmable by laboratory tests. Infants with profound hearing impairment may display autistic behavior, and tests of hearing are diagnostic. Electroencephalography (EEG) is indicated when seizures are suspected and to evaluate the less likely possibility of Landau-Kleffner syndrome. The study should be obtained with sedation in most cases, since sleep recording is needed and autistic children often become distressed by the procedure and do not cooperate with electrode placement.
Management
Autism is not curable, but several drugs may be useful to control specific behavioral disturbances. Behavior modification techniques improve some aspects of the severely aberrant behavior. However, despite the best program of treatment, these children function in a moderately to severely retarded range despite their level of intelligence. In our experience most children benefit from the use of selective serotonin reuptake inhibitors. csf Citalopram (10–20 mg/day) and escitalopram (5–10 mg/day) are commonly used. Children with ASD often suffer from anxiety and obsessive-compulsive behaviors that may interfere with their development and social skills. Obsessive-compulsive traits are often difficult to discern in patients with autism. Autistic children are typically unable to express themselves, and their obsessive thinking only becomes visible when associated with compulsions. Therefore a trial with the above medications should be offered in most cases. Many children also benefit from a management of hyperactive behaviors when present. Clonidine 0.05–0.1 mg bid or guanfacine 0.5–1 mg bid are good options.
Bilateral Hippocampal Sclerosis
Both bilateral hippocampal sclerosis and the congenital bilateral perisylvian syndrome cause a profound impairment of language development. The former also causes failure of cognitive capacity that mimics infantile autism, while the latter causes a pseudobulbar palsy (see Chapter 17 ). Infants with medial bilateral hippocampal sclerosis generally come to medical attention for refractory seizures. However, the syndrome emphasizes that the integrity of one medial hippocampal gyrus is imperative for language development.
Hearing Impairment
The major cause of isolated delay in speech development is a hearing impairment (see Chapter 17 ). Hearing loss may occur concomitantly with global developmental retardation, as in rubella embryopathy, cytomegalic inclusion disease, neonatal meningitis, kernicterus, and several genetic disorders. Hearing loss need not be profound; it can be insidious, yet delay speech development. The loss of high-frequency tones, inherent in telephone conversation, prevents the clear distinction of many consonants that we learn to fill in through experience; infants do not have experience in supplying missing sounds.
The hearing of any infant with isolated delay in speech development requires audiometric testing. Crude testing in the office by slamming objects and ringing bells is inadequate. Hearing loss is suspected in children with global retardation caused by disorders ordinarily associated with hearing loss or in retarded children who fail to imitate sounds. Other clues to hearing loss in children are excessive gesturing and staring at the lips of people who are talking. Brain auditory evoked potentials offer good screening for neonatal hearing deficits and are standard practice in many institutions.
Delayed Motor Development
Infants with delayed gross motor development but normal language and social skills are often hypotonic and may have a neuromuscular disease (see Chapter 6 ). Isolated delay in motor function is also caused by ataxia (see Chapter 10 ), mild hemiplegia (see Chapter 11 ), and mild paraplegia (see Chapter 12 ). Many such children have a mild form of cerebral palsy, sufficient to delay the achievement of motor milestones but not severe enough to cause a recognizable disturbance in cognitive function during infancy. The detection of mild disturbances in cognitive function more often occur when the child enters school. Children with benign macrocephaly may have isolated motor delay in the first 18 months, due to the difficulty achieving adequate head control with their larger head size.
Global Developmental Delay
Most infants with global developmental delay have a static encephalopathy caused by an antenatal or perinatal disturbance. However, 1 % of infants with developmental delay and no evidence of regression have an inborn error of metabolism and 3.5–10 % have a chromosomal disorder ( ). An exhaustive search for an underlying cause in every infant whose development is slow but not regressing is not cost effective. Factors that increase the likelihood of finding a progressive disease are an affected family member, parental consanguinity, organomegaly, and absent tendon reflexes. Unenhanced cranial magnetic resonance imaging (MRI) and chromosome analysis/microarray is a reasonable screening test in all infants with global developmental delay. MRI often detects a malformation or other evidence of prenatal disease and provides a diagnosis that ends the uncertainty.
Chromosomal Disturbances
Abnormalities in chromosome structure or number are the single most common cause of severe mental retardation, but they still comprise only one-third of the total. Abnormalities of autosomal chromosomes are always associated with infantile hypotonia (see Chapter 6 ). In addition, multiple minor face and limb abnormalities are usually associated features. These abnormalities in themselves are common, but they assume diagnostic significance in combination. Box 5-4 summarizes the clinical features that suggest chromosomal aberrations and Table 5-1 lists some of the more common chromosome syndromes.
Genitourinary
Ambiguous genitalia
Polycystic kidney
Head and Neck
High nasal bridge
Hypertelorism or hypotelorism
Microphthalmia
Mongoloid slant (in non-Asians)
Occipital scalp defect
Small mandible
Small or fish mouth (hard to open)
Small or low-set ears
Upward slant of eyes
Webbed neck
Limbs
Abnormal dermatoglyphics
Low-set thumb
Overlapping fingers
Polydactyly
Radial hypoplasia
Rocker-bottom feet
| Defect | Features |
|---|---|
| 5p monosomy | Characteristic “cri du chat” cry |
| Moonlike face | |
| Hypertelorism | |
| Microcephaly | |
| 10p trisomy | Dolichocephaly |
| “Turtle’s beak” | |
| Osteoarticular anomalies | |
| Partial 12p monosomy | Microcephaly |
| Narrow forehead | |
| Pointed nose | |
| Micrognathia | |
| 18 trisomy | Pointed ears |
| Micrognathia | |
| Occipital protuberance | |
| Narrow pelvis | |
| Rocker-bottom feet | |
| 21 trisomy | Hypotonia |
| Round flat (mongoloid) facies | |
| Brushfield spots | |
| Flat nape of neck |
∗ Growth retardation and cognitive impairment are features of all autosomal chromosome disorders.
Fragile X Syndrome
The fragile X syndrome is the most common chromosomal cause of cognitive impairment. Its prevalence in males is approximately 20:100000. The name derives from a fragile site (constriction) detectable in folate-free culture medium at the Xq 27 location. The unstable fragment contains a trinucleotide repeat in the FMR1 gene that becomes larger in successive generations ( DNA amplification ), causing more severe phenotypic expression. A decrease in the repeat size to normal may also occur. Because FMR1 mutations are complex and may involve several gene-disrupting alterations, abnormal individuals may show atypical presentations with an IQ above 70 ( ).
Clinical Features
Males with a complete phenotype have a characteristic appearance (large head, long face, prominent forehead and chin, protruding ears), connective tissue findings (joint laxity), and large testes after puberty. Behavioral abnormalities, sometimes including ASD, are common. The phenotypic features of males with full mutations vary in relation to puberty. Prepubertal males grow normally but have an occipitofrontal head circumference larger than the 50th percentile. Achievement of motor and speech milestones is late and temperament is abnormal, sometimes suggesting autism. Other physical features that become more obvious after puberty include a long face, prominent forehead, large ears, prominent jaw, and large genitalia.
The phenotype of females depends on both the nature of the FMR1 mutation and random X-chromosome inactivation. About 50 % of females who inherit a full fragile X mutation are cognitively impaired; however, they are usually less severely affected than males with a full mutation. Approximately 20 % of males with a fragile X chromosome are normal, while 30 % of carrier females are mildly affected. An asymptomatic male can pass the abnormal chromosome to his daughters, who are usually asymptomatic as well. The daughters’ children, both male and female, may be symptomatic.
Diagnosis
DNA-based testing has replaced the use of chromosome analysis using modified culture techniques to induce fragile sites ( ). Molecular genetic testing is now the standard of diagnosis.
Management
Treatment consists of pharmacological management of behavior problems and educational intervention.
Cerebral Malformations
Approximately 3 % of all children have at least one major malformation, but the responsible etiological factors are identifiable in only 20 % of these cases. Many intrauterine diseases cause destructive changes that cause malformation of the developing brain. The exposure of an embryo to infectious or toxic agents during the first weeks after conception can disorganize the delicate sequencing of neural development at a time when the brain is incapable of generating a cellular response. Alcohol, lead, prescription drugs, and substances of abuse are factors in the production of cerebral malformations. Although a cause-and-effect relationship is difficult to establish in any individual, maternal cocaine use is probably responsible for vascular insufficiency and infarction of many organs, including the brain.
Suspect a cerebral malformation in any cognitively impaired child who is dysmorphic, has malformations of other organs, or has an abnormality of head size and shape (see Chapter 18 ). Noncontrast-enhanced computed tomography (CT) is satisfactory to show major malformations, but MRI is the better method to show migrational defects and is more cost-effective for diagnosis of malformations.
Intrauterine Infections
The most common intrauterine infections are human immunodeficiency virus (HIV) and cytomegalovirus (CMV). HIV infection can occur in utero, but acquisition of most infections occurs perinatally. Infected infants are asymptomatic in the newborn period and later develop progressive disease of the brain (see the section below: Progressive Encephalopathies with Onset Before Age 2). Rubella embryopathy has almost disappeared because of mass immunization but reappears when immunization rates decline.
Congenital Syphilis
Reported cases of congenital syphilis have increased since 1988, partly because of an actual increase in case number but also because the case definition has broadened. By the current definition, all stillborn infants and live infants born to a woman with a history of untreated or inadequately treated syphilis have congenital syphilis.
Clinical Features
Infection of the fetus is transplacental. Two-thirds of infected newborns are asymptomatic and are identified only on screening tests. The more common features in symptomatic newborns and infants are hepatosplenomegaly, periostitis or osteochondritis, pneumonia (pneumonia alba), persistent rhinorrhea (snuffles), and a maculopapular rash that can involve the palms and soles. If left untreated, the classic stigmata of Hutchinson’s teeth, saddle nose, interstitial keratitis, saber shins, cognitive impairment, hearing loss, and hydrocephalus develop.
The onset of neurological disturbances is usually after age 2 years and includes eighth nerve deafness and cognitive impairment. The combination of nerve deafness, interstitial keratitis, and peg-shaped upper incisors is the Hutchinson triad.
Diagnosis
Every newborn infant’s mother should have serologic testing to exclude syphilis infection prior to discharge from the nursery. Nontreponemal antibody tests (Venereal Disease Research Laboratory [VDRL] and rapid plasma reagin card tests) are screening tests and the fluorescent treponemal antibody test absorbed with nonpallidum treponemas is confirmatory. Suspect concomitant HIV infection in every child with congenital syphilis.
Management
Consultation with an infectious disease specialist is beneficial in all children suspected of having congenital syphilis. Treatment typically consists of intravenous aqueous penicillin G at a dose of 50000 units/kg/dose q12 hours for the first 7 days of life, then q8h thereafter, for a total of 10 days. Alternatively, administer procaine penicillin G intramuscularly at a dose of 50000 units/kg/day for 10 days.
Cytomegalic Inclusion Disease
Cytomegalovirus (CMV) is a member of the herpes virus group and produces a chronic infection characterized by long periods of latency punctuated by intervals of reactivation. CMV is the most common congenital viral infection (1–2 % of all live births) and results either from primary maternal infection or from reactivation of the virus in the mother. Pregnancy may cause reactivation of maternal infection. Risks to the fetus are greatest during the first half of gestation. Fortunately, less than 0.05 % of newborns with viruria have symptoms of cytomegalic inclusion disease.
Clinical Features
Less than 10 % of infected newborns are symptomatic. Clinical manifestations include intrauterine growth retardation, jaundice, petechiae/purpura, hepatosplenomegaly, microcephaly, hydrocephaly, intracerebral calcifications, glaucoma, and chorioretinitis. Except for the brain, most organ involvement is self-limited.
Migrational defects (lissencephaly, polymicrogyria, and cerebellar agenesis) are the main consequence of fetal infection during the first trimester. Some infants have microcephaly secondary to intrauterine infection without evidence of systemic infection at birth.
Diagnosis
Virus must be isolated within the first 2 to 3 weeks of life to confirm congenital infection. Afterwards, virus shedding no longer differentiates congenital from postnatal infection. While CMV can be isolated from many sites, urine and saliva are preferred samples for congenital CMV infection, because of their viral content. For these samples, a shell vial technique using monoclonal antibodies to detect CMV early antigens in inoculated fibroblasts grown on cover slips after centrifugation is diagnostic. Detection of CMV DNA by polymerase chain reaction (PCR) or in situ hybridization of tissues and fluids is available in specialized laboratories. Infected newborns should be isolated from women of childbearing age.
In infants with developmental delay and microcephaly, establishing the diagnosis of cytomegalic inclusion disease is by serological demonstration of prior infection and a consistent pattern of intracranial calcification.
Management
Much of the brain damage from congenital CMV occurs in utero and is not influenced by postnatal treatment. The antiviral agents currently approved for CMV treatment are ganciclovir (and its prodrug, valganciclovir), foscarnet, and cidofovir. The risk–benefit ratio of these agents in treating congenital CMV infection is uncertain.
Congenital Lymphocytic Choriomeningitis
Clinical Features
The lymphocytic choriomeningitis virus (LCMV) causes minor respiratory symptoms when inhaled postnatally, but prenatal infection causes severe brain malformation ( ). Because the virus targets the developing brain all infected children have retinal injury and brain malformations.
The most commonly described congenital anomalies are chorioretinopathy, macrocephaly, and microcephaly. LCMV is a common cause of hydrocephalus. Up to one-third of newborns with hydrocephalus have positive serology to LCMV, and conversely almost 90 % of children with serologically confirmed perinatal infection with LCMV have hydrocephalus. Almost 40 % have hydrocephalus at birth; the remainder develop it over the first 3 months of age. Blindness and psychomotor retardation are potential long-term complications. Outcome severity depends on the timing of infection; early infection produces the worse outcomes.
Diagnosis
Imaging of the brain reveals major malformations. Viral culture of blood, cerebrospinal fluid (CSF), and urine are diagnostic. Immunofluorescent antibody tests or enzyme-linked immunosorbent assays are currently available for serum and CSF. PCR for detection of LCMV RNA may be available in the near future.
Management
Much of the brain damage from congenital LCMV occurs in utero and is not influenced by postnatal treatment.
Rubella Embryopathy
The rubella virus is a small, enveloped RNA virus with worldwide distribution and is responsible for an endemic mild exanthematous disease of childhood (German measles). Major epidemics, in which significant numbers of adults are exposed and infected, occurred every 9 to 10 years in both the United States and the United Kingdom. However, the incidence of rubella embryopathy in the United States has steadily declined with introduction of the rubella vaccine.
Clinical Features
Rubella embryopathy is a multisystem disease characterized by intrauterine growth retardation, cataracts, chorioretinitis, congenital heart disease, sensorineural deafness, hepatosplenomegaly, jaundice, anemia, thrombocytopenia, and rash. Eighty percent of children with a congenital rubella syndrome have nervous system involvement. The neurological features are bulging fontanelle, lethargy, hypotonia, and seizures. Seizure onset is from birth to 3 months of age.
Diagnosis
In order to provide accurate counseling, make every effort to confirm rubella infection in the exposed pregnant woman. Virus isolation is complicated and the diagnosis is established best by documenting rubella-specific IgM antibody in addition to a 4-fold or greater rise in rubella-specific IgG.
Management
Prevention is by immunization and avoiding possible exposure during pregnancy. No treatment is available for active infection in the newborn.
Toxoplasmosis
Toxoplasma gondii is a protozoan estimated to infect 1 per 1000 live births in the United States each year. The symptoms of toxoplasmosis infection in the mother usually go unnoticed. Transplacental transmission of toxoplasmosis is possible in situations of primary maternal infection during pregnancy or in immunocompromised mothers who have chronic or recurrent infection. The rate of placental transmission is highest during the last trimester, but fetuses infected at that time are least likely to have symptoms later on. The transmission rate is lowest during the first trimester, but fetuses infected at that time have the most serious sequelae.
Clinical Features
One-quarter of infected newborns have multisystem involvement (fever, rash, hepatosplenomegaly, jaundice, and thrombocytopenia) at birth. Neurological dysfunction is manifest as seizures, altered states of consciousness, and increased intracranial pressure. The triad of hydrocephalus, chorioretinitis, and intracranial calcification is the hallmark of congenital toxoplasmosis in older children. About 8 % of infected newborns, who are asymptomatic at birth, later show neurological sequelae, especially psychomotor retardation.
Diagnosis
Detection of the organism is diagnostic, as are commercially available serological techniques. Presume any patient with positive IgG and IgM titers to be recently infected. In the United States the Toxoplasma Serology Laboratory of the Palo Alto Medical Foundation Research Institute offers confirmatory serological and PCR testing and methods for isolation of the organism. In addition, medical consultants are available for interpretation of test results and advice on management
The presence of positive or rising IgM and IgG titers confirms acute T. gondii infection in a pregnant woman. Detection of T. gondii DNA in amniotic fluid by PCR is less invasive and more sensitive than isolating parasites from fetal blood or amniotic fluid. Serial fetal ultrasonographic examinations monitor for ventricular enlargement and other signs of fetal infection.
In older children, the diagnosis requires not only serological evidence of prior infection but also compatible clinical features.
Management
A combined prenatal and postnatal treatment program for congenital toxoplasmosis can reduce the neurological morbidity. When seroconversion indicates acute maternal infection, fetal blood and amniotic fluid are cultured and fetal blood tested for Toxoplasma -specific IgM. The mother requires only spiramycin treatment unless proven fetal infection exists, when pyrimethamine and sulfadoxine are required. In newborns with clinical evidence of toxoplasmosis, administer pyrimethamine (Daraprim ® ) and sulfadiazine for 1 year. Because pyrimethamine is a folic acid antagonist, administer folinic acid (leucovorin) during therapy and for 1 week after termination of treatment. Routine monitoring of the peripheral platelet count is required. Newborns with a high protein concentration in the CSF or chorioretinitis also require prednisone, 1–2 mg/kg/day. The optimal duration of therapy for congenital toxoplasmosis is unknown but 1 year is the rule. Because of the high likelihood of fetal damage, termination of pregnancy is frequently recommended if T. gondii infection is confirmed and infection is thought to have occurred at less than 16 weeks of gestation or if the fetus shows evidence of hydrocephalus.
Perinatal Disorders
Perinatal infection, asphyxia, maternal drug use, and trauma are the main perinatal events that cause psychomotor retardation (see Chapter 1 ). The important infectious diseases are bacterial meningitis (see Chapter 4 ) and herpes encephalitis (see Chapter 1 ). Although the overall mortality rate for bacterial meningitis is now less than 50 %, half of survivors show significant neurological disturbances almost immediately. Mental and motor disabilities, hydrocephalus, epilepsy, deafness, and visual loss are the most common sequelae. Psychomotor retardation may be the only or the most prominent sequelae. Progressive mental deterioration can occur if meningitis causes a secondary hydrocephalus.
Telling Parents Bad News
It is not possible to make bad news sound good or even half-bad. The goal of telling parents that their child will have neurologic or cognitive impairment is that they hear and understand what you are saying. The mind must be prepared to hear bad news. It is a mistake to tell people more than they are ready to accept. Too often, parents bring their child for a second opinion because previous doctors “didn’t tell us anything.” In fact, they may have said too much too fast and the parents tuned out.
My goal for the first visit is to establish that the child’s development is not normal (not a normal variation), that something is wrong with the brain, and that I share the parents’ concern. I order imaging of the brain, usually MRI, in every developmentally delayed child. When abnormal, review the MRI with the parents to help their understanding of the problem. Unfortunately, many mothers come alone for this critical visit and must later restate your comments to doubting fathers and grandparents. Most parents cannot handle more information than “the child is not normal” at the first consultation and further discussion awaits a later visit. However, always answer probing questions fully. Parents must never lose confidence in your willingness to be forthright. The timing of the next visit depends on the age of the child and the severity of the cognitive impairment. The more the child falls behind in reaching developmental milestones, the more ready parents will be to accept the diagnosis of cognitive impairment.
When the time comes to tell a mother that her child has cognitive impairment, it is not helpful to describe the deficit as mild, moderate, or severe. Parents want to know what the child will do. Will he walk, need special schools, and live alone? The next question is “What can I do to help my child?” Direct them to programs that provide developmental specialists and other parents who can help them learn how to live with a chronic handicapping disorder and gain access to community resources.
Providing a prognosis after a brain insult in a neonate or young infant is often difficult. Fortunately, the plasticity of the young brain may offer improved outcomes in some cases, making it difficult to provide a definite prognosis. Prognosis is often better in cases that affect only one hemisphere. In fact, complete encephalomalacia of one hemisphere may be associated with better development than having a very injured but still “functional” hemisphere. In all cases we have to make families aware of the spectrum of possibilities and high probability of deficits.
Progressive Encephalopathies with onset before Age 2
The differential diagnosis of progressive diseases of the nervous system that start before age 2 years is somewhat different from those that begin during childhood (see Box 5-5 ). The history and physical examination must answer three questions before initiating laboratory diagnosis:
- 1.
Is this multi-organ or only central nervous system (CNS) disease? Other organ involvement suggests lysosomal, peroxisomal, and mitochondrial disorders.
- 2.
Is this a (CNS) or both central and peripheral nervous systems process? Nerve or muscle involvement suggests mainly lysosomal and mitochondrial disorders.
- 3.
Does the disease affect primarily the gray matter or the white matter? Early features of gray matter disease are personality change, seizures, and dementia. Characteristic of white matter disease is focal neurological deficits, spasticity, and blindness. Whether the process begins in the gray matter or the white matter, eventually clinical features of dysfunction develop in both. The EEG is usually abnormal early in the course of gray matter disease and late in the course of white matter disease. MRI shows cortical atrophy in gray matter disease and cerebral demyelination in white mater disease ( Figure 5-1 ). Visual evoked responses and motor conduction velocities are useful in documenting demyelination, even subclinical, in the optic and peripheral nerves, respectively.
FIGURE 5-1
Krabbe’s disease. T 2 axial MRI shows an early stage of symmetric demyelination (arrows).
Disorders of Lysosomal Enzymes
Gaucher disease type III (glucosylceramide lipidosis)
Globoid cell leukodystrophy (late-onset Krabbe disease)
Glycoprotein degradation disorders
Aspartylglycosaminuria
Mannosidosis type II
GM 2 gangliosidosis (juvenile Tay-Sachs disease)
Metachromatic leukodystrophy (late-onset sulfatide lipidoses)
Mucopolysaccharidoses types II and VII
Niemann-Pick type C (sphingomyelin lipidosis)
Infectious Disease
Acquired immune deficiency syndrome encephalopathy ∗
∗ Denotes the most common conditions and the ones with disease modifying treatments
Congenital syphilis ∗
Subacute sclerosing panencephalitis
Other Disorders of Gray Matter
Ceroid lipofuscinosis
Juvenile
Late infantile (Bielschowsky-Jansky disease)
Huntington disease
Mitochondrial disorders
Late-onset poliodystrophy
Myoclonic epilepsy and ragged-red fibers
Progressive neuronal degeneration with liver disease
Xeroderma pigmentosum
Other Disorders of White Matter
Adrenoleukodystrophy
Alexander disease
Cerebrotendinous xanthomatosis
Progressive cavitating leukoencephalopathy
Acquired Immune Deficiency Syndrome Encephalopathy
Acquired immune deficiency syndrome (AIDS) is a human retroviral disease caused by the lentivirus subfamily now designated as human immunodeficiency virus (HIV). Adults spread HIV by sexual contact, intravenous drug abuse, and blood transfusion. Pediatric AIDS cases result from transplacental or perinatal transmission. Transmission may occur by breastfeeding. The mother may be asymptomatic when the child becomes infected.
Clinical Features
Evidence of infection is apparent during the first year in 30 % of children born to AIDS-infected mothers. As a rule, the outcome is worse when the onset of symptoms is early, and the rate of progression in the child relates directly to the severity of disease in the mother.
Twenty percent of children with HIV present with severe symptoms or die in infancy ( ). The cause of their poor prognosis is unknown. The spectrum of neurological and non-neurological manifestations in HIV-infected children is somewhat different from adults. Hepatosplenomegaly and bone marrow failure, lymphocytic interstitial pneumonia, chronic diarrhea and failure to thrive, acquired microcephaly, cerebral vasculopathy, and basal ganglia calcification occur more frequently in children. Opportunistic infections that represent recrudescence of previously acquired infections in adults, e.g., cerebral toxoplasmosis, progressive multifocal leukoencephalopathy, are rare in infants.
AIDS encephalopathy may be subacute or indolent and is not necessarily associated with failure to thrive or opportunistic infections. The onset of encephalopathy may occur from 2 months to 5 years after exposure to the virus. Ninety percent of affected infants show symptoms by 18 months of age. Progressive loss of developmental milestones, microcephaly, dementia, and spasticity characterize the encephalopathy. Other features in less than 50 % of children are ataxia, pseudobulbar palsy, involuntary movement disorders, myoclonus, and seizures. Death usually occurs a few months after the onset of AIDS encephalopathy.
Diagnosis
HIV DNA PCR is the preferred method for the diagnosis of HIV infection in infants and children younger than 18 months of age. It is performed on peripheral blood mononuclear cells and is highly sensitive and specific by 2 weeks of age. Approximately 30 % of infants with HIV infection will have a positive DNA PCR assay result by 48 hours, 93 % by 2 weeks, and almost all infants by 1 month of age.
Management
The introduction of routine maternal treatment with highly active antiretroviral therapy (HAART) in 1996 has greatly decreased the incidence of pediatric AIDS. Combined treatment with zidovudine (azidothymidine, AZT), didanosine, and nevirapine is well tolerated and may have sustained efficacy against HIV-1. Bone marrow suppression is the only important evidence of toxicity.
Disorders of Amino Acid Metabolism
Disorders of amino acid metabolism impair neuronal function by causing excessive production of toxic intermediary metabolites and reducing the production of neurotransmitters. The clinical syndromes are either an acute neonatal encephalopathy with seizures and cerebral edema (see Chapter 1 ) or cognitive impairment and dementia. Some disorders of amino acid metabolism cause cerebral malformations, such as agenesis of the corpus callosum. Although the main clinical features of aminoaciduria are referable to gray matter dysfunction (cognitive impairment and seizures), myelination is often profoundly delayed or defective.
Guanidinoacetate Methyl transferase (GAMT) Deficiency
Amidinotransferase converts glycine to guanidoacetate and GAMT converts guanidoacetate to creatine. GAMT deficiency causes cognitive impairment, hypotonia, and a movement disorder ( ). Transmission is by autosomal recessive inheritance. Gene map locus is 19p13.3. This disorder is rare but treatable.
Clinical Features
Affected children appear normal at birth and may develop normally during infancy. By the end of the first year, development fails to progress and hypotonia is noted. Regression of development follows and is associated with dyskinesias, dystonia, and myoclonic jerks.
Diagnosis
MRI reveals marked demyelination and magnetic resonance spectroscopy shows creatine depletion and guanidinoacetate phosphate accumulation.
Management
Early oral administration of creatine monohydrate significantly prevents and reverses all symptoms and late treatment provides some reduction in abnormal movements.
Homocystinuria
The main defect responsible for the syndrome is almost complete deficiency of the enzyme cystathionine-β-synthase ( ). Two variants are recognized: B6-responsive homocystinuria and B6-nonresponsive homocystinuria . B6-responsive homocystinuria is usually milder than the nonresponsive variant. Transmission of all forms is by autosomal recessive inheritance. Heterozygotes have partial deficiencies. Cystathionine synthase catalyzes the condensation of serine and homocysteine to form cystathionine ( Figure 5-2 ). When the enzyme is deficient, the blood and urine concentrations of homocysteine, homocystine, and methionine are increased. Newborn screening programs detect hypermethioninemia.
Clinical Features
Affected individuals appear normal at birth. Neurological features include mild to moderate cognitive impairment, ectopia lentis, and cerebral thromboembolism. Developmental delay occurs in half of cases, and intelligence declines progressively with age in untreated children. Most will eventually function in the mildly cognitive impaired range. Intelligence is generally higher in B6-responsive than B6-nonresponsive homocystinuria.
High plasma homocysteine concentrations adversely affect collagen metabolism and are responsible for intimal thickening of blood vessel walls, leading to arterial and venous thromboembolic disease. Cerebral thromboembolism is a life-threatening complication. Emboli may occur in infancy, but is usually in adult life. Young adult heterozygotes are also at risk. Occlusion of the coronary or carotid arteries can lead to sudden death or severe neurological handicap. Thromboembolism is the first clue to the diagnosis in 15 % of cases.
Dislocation of the lens, an almost constant feature of homocystinuria, typically occurs between 2 and 10 years of age. Almost all patients have lens dislocation by age 40 years. Older children have osteoporosis, often first affecting the spine resulting in scoliosis. Many children are tall and thin, with blond, sparse, brittle hair and a Marfan syndrome habitus. This habitus does not develop until middle or late childhood and serves as a clue to the diagnosis in fewer than 40 % of cases.
The diagnosis is suspect in any infant with isolated and unexplained developmental delay, since disease-specific features may not appear until later childhood. The presence of either thromboembolism or lens dislocation strongly suggests homocystinuria.
Diagnosis
The biochemical features of homocystinuria are increased concentrations of plasma homocystine, total homocysteine, and methionine; increased concentration of urine homocystine; and reduced cystathionine β-synthase enzyme activity. Molecular genetic diagnosis is available.
Prenatal diagnosis is available for fetuses at risk by measurement of cystathionine β-synthase enzyme activity assayed in cultured amniocytes but not in chorionic villi, since this tissue has very low activity of the enzyme
Management
Challenge all patients with pyridoxine (vitamin B6) before starting treatment. Treat those who are responsive with pyridoxine, approximately 200 mg/day. Those that are not responsive still receive doses of 100–200 mg daily. All patients also require a protein-restricted diet, but B6-nonresponsive neonates also require frequent metabolic monitoring. Continue the diet indefinitely. Identification of disease in newborn screening yields the best results. Treatment with betaine, 5–10 g/day in two divided doses, provides an alternate remethylation pathway to convert excess homocysteine to methionine and may help prevent thrombosis. Folate and vitamin B12 optimize the conversion of homocysteine to methionine and help to decrease homocysteine levels.
Maple Syrup Urine Disease (Intermediate)
The three major branched-chain amino acids (BCAA) are leucine, isoleucine, and valine. In the course of their metabolism, they are first transaminated to α-ketoacids and then further catabolized by oxidative decarboxylation (see Figure 1-1 ). Branched-chain ketoacid (BCKA) dehydrogenase is the enzyme responsible for oxidative decarboxylation. Mutations in three different genes cause maple syrup urine disease (MSUD). These genes encode the catalytic components of the branched-chain alpha-keto acid dehydrogenase complex (BCKD), which catalyzes the catabolism of the branched-chain amino acids, leucine, isoleucine, and valine.
Clinical Features
Deficiency is associated with several different phenotypes ( ). Three recognized clinical phenotypes are classic , intermittent , and intermediate . An acute encephalopathy with ketoacidosis characterizes the classic and intermittent forms (see Chapter 1 , Chapter 10 ). The levels of dehydrogenase enzyme activity in the intermediate and intermittent forms are approximately the same (5–40 %), whereas activity in the classic form is 0–2 % of normal.
The onset of the intermediate form is late in infancy, often in association with a febrile illness or a large protein intake. In the absence of vigorous early therapeutic intervention, moderate cognitive impairment results. Ataxia and failure to thrive are common. Infants with intermediate MSUD are slow in achieving milestones and hyperactive. As children, they generally function in the moderately cognitively impaired range of intelligence. Physical development is normal except for coarse, brittle hair. The urine may have the odor of maple syrup. Acute mental changes, seizures, and focal neurological deficits do not occur.
Some infants with the intermediate form are thiamine responsive. In such children, cognitive impairment is moderate.
Diagnosis
BCAA and BCKA concentrations are elevated, though not as high as in the classic disease. A presumptive diagnosis requires the demonstration of BCAA in the urine by a ferric chloride test or the 2,4-dinitrophenylhydrazine test. Quantitative measurement of blood and urine BCAA and BCKA is diagnostic.
Treatment
Treatment of MSUD includes dietary leucine restriction, high-calorie BCAA-free formulas, and frequent monitoring. Correct metabolic decompensation by treating the precipitating stress and delivering sufficient calories, insulin, free amino acids, isoleucine, and valine, and, in some centers, hemodialysis/hemofiltration, to establish net positive protein accretion.
A protein-restricted diet is the main treatment of infants with intermediate MSUD. In addition, a trial of thiamine, 100 mg/day, tests if the biochemical error is thiamine responsive. If 100 mg is not effective, try daily dosages up to l g of thiamine before designating the condition as thiamine refractory. Brain edema, a common potential complication of metabolic decompensation, requires immediate therapy in an intensive care setting.
Orthotopic liver transplantation is an effective therapy for classic MSUD. Frequent monitoring of plasma amino acid concentrations and fetal growth is necessary to avoid essential amino acid deficiencies during pregnancy.
Phenylketonuria
Phenylketonuria is a disorder of phenylalanine metabolism caused by partial or total deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH) ( ). Genetic transmission is autosomal recessive and occurrence is approximately 1 per 16000 live births. Failure to hydroxylate phenylalanine to tyrosine leads to further metabolism by transamination to phenylpyruvic acid ( Figure 5-3 ). Oxidation of phenylpyruvic acid to phenylacetic acid causes a musty odor in the urine.
The completeness of deficiency produces three categories of PAH deficiency; these are classic phenylketonuria (PKU), non-PKU hyperphenylalaninemia (HPA), and variant PKU. In classic PKU , PAH deficiency is complete or near complete. Affected children tolerate less than 250–350 mg of dietary phenylalanine per day to keep plasma phenylalanine concentration below a safe level of 300 µmol/L (5 mg/dL). If untreated, plasma phenylalanine concentrations are greater than 1000 µmol/L and dietary phenylalanine tolerance is less than 500 mg/day. Classic PKU has a high risk of severely impaired cognitive development.
Children with non-PKU hyperphenylalaninemia have plasma phenylalanine concentrations between 120 µmol/L and 1000 µmol/L on a normal diet and a lower risk of impaired cognitive development without treatment. Variant PKU includes individuals who do not fit the description for either PKU or non-PKU HPA.
HPA may also result from the impaired synthesis or recycling of tetrahydrobiopterin (BH4). BH4 is the cofactor in the phenylalanine, tyrosine, and tryptophan hydroxylation reactions. Inheritance of HPA caused by BH4 deficiency is as an autosomal recessive trait and accounts for 2 % of patients with HPA.
Clinical Features
Because affected children are normal at birth, early diagnosis requires compulsory mass screening. The screening test detects HPA, which is not synonymous with PKU ( Box 5-6 ). Blood phenylalanine and tyrosine concentrations must be precisely determined in every newborn detected by the screening test in order to differentiate classic PKU from other conditions. In newborns with classic PKU, HPA develops 48 to 72 hours after initiation of milk feeding. Blood phenylalanine concentrations are 20 mg/dL or greater, and serum tyrosine levels are less than 5 mg/dL. When blood phenylalanine concentrations reach 15 mg/dL, phenylalanine spills over into the urine and the addition of ferric chloride solution (5–10 drops of FeCl to l mL of urine) produces a green color.
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