Approach
Children with cognitive impairment have an IQ that is below average, at <70. A specific learning difficulty, on the other hand, includes difficulties with learning but a normal IQ. Although the terms "learning difficulty" and "cognitive impairment" each have a specific definition, they are sometimes used interchangeably by clinicians.
There is a wide range of etiologies. Children with disordered and/or delayed speech may have an autism spectrum disorder or a specific language disorder. Those with a more generalized developmental delay and an unusual appearance are more likely to have a genetic disorder. However, inevitably, in some children, the disorder has no identifiable cause (idiopathic).
The neurodevelopmental history most importantly reveals diagnostic clues. A full developmental history should always be taken, even when the cause appears obvious, as there may be multiple coexisting pathologies. For example, a child with an autism spectrum disorder may have been born at 25 weeks' gestation, have cerebral palsy, and also have ADHD.
Further diagnostic clues are provided by the age at onset and progression of the disease, and by the physical exam. Many of the underlying syndromes have a characteristic phenotype. Investigations are guided by the history and clinical features.
Developmental milestones
The neurodevelopmental history is the most likely part of the assessment to reveal diagnostic clues. This consists of assessing developmental milestones (including the rate of progress), and establishing current functioning in terms of language and communication, social and motor development, hearing and vision, and the level of understanding. Children with cognitive delay frequently present with more general developmental delay (e.g., motor delay). Comprehensive lists of developmental milestones are given in all standard pediatric texts.[76] Relevant developmental milestones for the first 2 years of life include:
Using words besides “mama” and “dada” (usually 10-18 months)
Responding to simple instructions, exploring, and using trial and error approaches (12 months)
Walking unaided (12-18 months)
Pointing to objects that are of interest (12-18 months)
Naming parts of the body (18 months)
Speaking in two-word phrases (usually before 24-30 months).
However, children with developmental delay may not have cognitive impairment. For example, boys with motor and speech delay in the absence of general cognitive impairment may have Duchenne muscular dystrophy, and require appropriate investigations (e.g., serum creatine kinase).
The delay in developmental milestones may be associated with other specific features. For example, girls with an initial normal development followed by regression of skills at age 1 to 2 years may have Rett syndrome. Children with mild cognitive impairment who are initially small and poor feeders, but who subsequently become obese through hyperphagia at the age of 4 to 5 years, may have Prader-Willi syndrome. Parental concerns regarding hearing or vision in the child should be referred to the relevant specialist.
While detailed developmental assessments are best done by experienced pediatricians or members of the multidisciplinary team (MDT), nonexperts are encouraged to undertake "developmental screening" assessments, which may help clarify the decision of whether to refer on to an expert (e.g., the Ages and Stages Questionnaire, or the Schedule of Growing Skills). The Ages and Stages Questionnaire Opens in new window[77]
History
Prenatal history
A maternal history of prescription and recreational drug and alcohol use should be sought.
It is useful to inquire about the number of prenatal scans. Most mothers have 1 or 2 scans; more-frequent scanning may indicate concerns about fetal abnormalities such as delayed intrauterine growth.
Maternal and paternal age may also be of relevance. The risk of chromosomal disorders such as Down syndrome increases with maternal age, and some genetic changes leading to autism and other neuropsychiatric disorders may be associated with increasing paternal age.
Perinatal history
The gestational age at birth should be noted.
It is important to establish if there were any episodes of perinatal hypoxia, or if the child required resuscitation. It is often helpful to ask the parents if the child cried right away, or if he/she needed help breathing.
Hospital admissions
Establish if there have been any hospital admissions or periods of prolonged illness, either during the neonatal period or later in the course of the child's life.
The majority of neonates with prenatal and perinatal problems such as intrauterine infection, toxicity, or perinatal hypoxia require admission to neonatal units.
A history of later admissions due to serious conditions such as meningitis, encephalitis, or trauma should also be sought. Children with significant traumatic brain injury are usually hospitalized for many weeks during initial rehabilitation.
Family history
A history of developmental delay, specific learning difficulties, cognitive impairment, and seizures in parents, siblings, grandparents, and the extended family should be sought.
Inquire specifically about consanguineous marriage, as this increases the likelihood of rare or autosomal recessive metabolic disorders.
Due to Mendelian or complex genetics, conditions such as tuberous sclerosis, autism spectrum disorders, and dyslexia commonly run in families, as might less-severe phenotypes of social communication difficulties occurring with no autism spectrum disorder.
Social history
Children who have been adopted or fostered may have been exposed to drugs in utero, or may have been physically abused previously. Although foster parents may know some details about the child's previous circumstances, detailed information about the biological parents is rarely known unless the parent has a particular diagnosis.
Children who grow up in conditions associated with severe deprivation may have either cognitive impairment or specific learning difficulties. Impairments may be amenable to intervention once the deprivation is removed (e.g., in the case of children in orphanages or areas associated with severe famine).
Schooling
Specific learning disabilities are more likely to become apparent once children are of school age and experience difficulties relating to progress in the classroom. Children may or may not have been assessed by an educational psychologist, or have had formal IQ testing.
Detailed discussion of the schooling difficulties is likely to provide diagnostic clues. For example, children with dyslexia may only have problems reading and spelling, and children with only mathematical difficulties may have dyscalculia.
Discussions with other caregivers or school staff members who know a child well are often valuable in assessing the pervasiveness of the child's difficulties, precipitating factors, and the effect on learning and behavior at school. This approach is particularly useful when assessing children suspected to have ADHD or an autism spectrum disorder.
Examination
Most children with specific learning disabilities have no clearly abnormal examination findings, although subtle neurologic signs (such as synkinesis) are common. In others, general examination may reveal dysmorphism or other deformities that are most likely to point toward a genetic disorder.
Oblique palpebral fissures, median epicanthic fold, low nasal bridge, low-set ears, central iris Brushfield spots, short curved fifth finger, and a single palmar crease are characteristic of Down syndrome.
Macrocephaly, long face, high arched palate, prominent jaw, epicanthic folds, macro-orchidism, and large ears are characteristic of fragile X syndrome. Strabismus may also be present.
Short stature, hypotonia, small hands and feet, and incomplete sexual development, often with cryptorchidism, are characteristic of Prader-Willi syndrome.
Widely spaced teeth, long philtrum, wide mouth, and full lips are seen in William syndrome.
Cleft palate, micrognathia, low-set ears, and facial dysmorphism are seen in DiGeorge syndrome.
Short stature, low-set ears, webbed neck, low hairline, and cubitus valgus are characteristic of Turner syndrome.
Skull deformity is seen in craniosynostosis.
The examination should also include the following elements.
Skin examination: signs of tuberous sclerosis, such as facial fibroangiomata or periungual lesions, may be seen.
Neurologic examination: common subtle findings in children with specific learning disabilities include synkinesis (involuntary movements of one body part when moving another, such as mirror movements of the left hand when moving the right), difficulty with voluntary saccades, dystonic posturing with stress gait, and mild hyperreflexia. Other neurologic signs are usually, but not always, in keeping with the developmental history. Spasticity, or variable tone, is likely to be due to cerebral palsy. Mild hypotonia is common; severe hypotonia is more likely to be associated with a genetic disorder (e.g., Down syndrome). Focal signs suggest intracerebral pathology.
Measurement of head circumference: microcephaly suggests a developmental disorder, which may be either genetic or acquired. Macrocephaly suggests a developmental disorder (such as fragile X syndrome or tuberous sclerosis), a metabolic disorder (such as glutaric aciduria), certain leukodystrophies (such as Alexander disease and Canavan disease), or possibly hydrocephalus, which is most commonly associated with structural brain abnormalities or a history of meningitis or intraventricular hemorrhage. It is important, when possible, to check parents’ head circumferences in cases of suspected macrocephaly, as macrocrania (enlarged head circumference without brain abnormalities) may be familial.
Ophthalmoscopy may aid in the diagnosis of congenital infections of the central nervous system (e.g., toxoplasma or cytomegalovirus [CMV]) and in some genetic disorders associated with cognitive delays (e.g., retinal or peripapillary astrocytic hamartomas in tuberous sclerosis).
Developmental assessment
Children with delayed developmental milestones should have a general developmental assessment. This provides an indication of the child's developmental age in different areas, which can then be compared with his/her chronologic age. Available tools include the Ages and Stages Questionnaire and the Schedule of Growing Skills. The Ages and Stages Questionnaire Opens in new window[77]
More detailed assessments of ability are also extremely valuable. Such examinations may include assessment of: cognitive ability by a clinical psychologist; expressive and receptive language by a speech therapist; or motor ability by an occupational therapist or physical therapist.
Developmental assessment may help the clinician make a specific diagnosis. For example, a child with isolated delayed walking but normal fine motor hand skills and no other difficulties might have diplegic cerebral palsy, and this finding may prompt the clinician to undertake an MRI brain scan, leading to diagnosis. Finding that a child has no motor difficulties but has delayed social communication skills might lead to a diagnosis of autism. Generalized developmental delay (gross motor, fine motor, social, and communication delay) is more suggestive of a genetic abnormality (such as Down syndrome) or a widespread brain abnormality leading to 4-limb cerebral palsy.
Specialist developmental and cognitive assessments used vary according to the ability of the child, personal preferences, and geographic location. For example, the Bayley Developmental Scales, Griffiths Mental Development Scales, and Kaufman Scales are widely used to assess the development of young children. Regarding specific cognitive assessments, clinical psychologists might use the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) or the Wechsler Intelligence Scale for Children (WISC) during assessment of IQ. Reading, language, and mathematical ability can be assessed using the Wechsler Individual Achievement Test (WIAT); when children have normal IQ and are found to have a specific difficulty (e.g., reading and spelling), this points toward a specific diagnosis (e.g., dyslexia).
Investigations
Children with specific learning difficulties generally do not require laboratory investigations, and are diagnosed by clinical history, including observations and assessments of their abilities.
Further laboratory tests are used in children with cognitive impairment, to help identify the underlying cause. In general, these children should have targeted investigations depending on clinical features. Tests most likely to lead to a relevant finding on the basis of clinical history and examination should be performed first. Stepwise investigation is usually preferred, due to potential harm from testing (e.g., due to repeated testing prompted by borderline results).[76] Children with developmental delay should have chromosome and fragile X testing, thyroid function tests, and, in severe delay, an MRI brain scan; boys should also have a serum creatine kinase.
Congenital hypothyroidism is routinely screened for ideally after 24 hours of life (preferably between 48 to 72 hours) and before hospital discharge or 1 week of life; consult local protocols.[70][71] A low thyroxine with elevated thyroid-stimulating hormone is seen. Some cases may be missed at birth, and re-screening is therefore warranted if there is clinical suspicion.[72]
Guthrie bacterial inhibition assay detects elevated levels of phenylalanine in suspected phenylketonuria. The test is rarely required, as screening is performed for phenylketonuria.
Testing for toxoplasma or rubella antibodies is required if intrauterine infection is suspected.
Cerebral spinal fluid (CSF) cytology is required if bacterial meningitis or encephalitis is suspected. Elevated protein, with a pleocytosis and WBC count >1000 cells/microliter and predominance of polymorphonuclear leukocytes, suggests bacterial meningitis.[80] A CSF Gram stain identifies the causative organism in 85% to 90% of cases.[81][82] Findings in encephalitis vary according to the cause, and include an elevated WBC count, normal or elevated protein, normal or low glucose, and normal red blood cell count. CSF serology for arboviruses, HSV-1 and HSV-2, VZV, CMV, EBV, lymphocytic choriomeningitis virus, rabies, West Nile, mumps, or measles identifies the underlying cause.
A peripheral blood smear for Plasmodium falciparum or Ehrlichia should be considered in patients with encephalitis if these infections are suspected.
Genetic testing
Genetic tests should be carried out by an attending pediatric physician or clinical geneticist following referral.
Historically, chromosome and fragile X testing have been performed initially. In recent years, however, chromosomal microarray (CMA) testing has become a first-line investigation in people with learning disabilities, and can provide a firm diagnosis in up to 7% of patients with so-called "syndromic cognitive impairment."[83] Interpretation of data regarding potentially pathogenic copy number variants usually requires input from clinical geneticists or other clinicians with appropriate expertise.[84]
Testing for rarer syndromes depends on the associated clinical features. For example, a girl with normal initial development, loss of skills, and epilepsy should be tested for the MECP2 gene deletion associated with Rett syndrome. Children who have eaten poorly and been of low weight in early life, but who subsequently eat excessively and gain large amounts of weight, should be tested for Prader-Willi syndrome (15q11-q13 mutation).
When clinical features point to no specific genetic diagnosis, whole exome sequencing (WES) may be useful. As many as 40% to 50% of families experience a change in management and clinical impression with the use of WES, which may reduce the overall cost of testing by eliminating unnecessary tests and arriving at a diagnosis more quickly.[85] Like CMA testing, it requires input from clinicians with expertise in genetics.
Imaging
Children with abnormalities, on neurologic examination, that are either not explicable from the clinical features or suggest serious intracranial pathology require neuroimaging. MRI is preferred. CT should be used when the imaging is urgent, or when recent hemorrhage or intracranial calcification are suspected.
Intracerebral bleeding, cerebral contusion, contre-coup injury, or skull fracture may be seen in traumatic brain injury. Initial edema or loss of gray-white matter differentiation, with subsequent brain atrophy and cavitation, are seen with hypoxia. Intracranial tumors are clearly visualized. Other useful signs include indications of tuberous sclerosis and decreased brain size in Rett syndrome. MRI is also used to assess organic brain damage in patients with fetal alcohol syndrome or teratogen-induced changes. MRI or CT of the brain may require the child to be sedated or have a general anesthetic; if so, blood or CSF investigations, if required, should be performed at the same time.
Skull x-ray may be performed if craniosynostosis is suspected; diagnosis of the condition is based on the finding of prematurely fused cranial sutures.
Electroencephalography (EEG)
An EEG may be indicated in children with developmental regression (to evaluate for epileptic encephalopathy) or symptoms that are variable or episodic in nature.
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