Microcephaly

Microcephaly is broadly defined as a small head size, typically greater than two standard deviations below normal, as measured via occipital frontal circumference, a method by which a tape measure is used to assess the circumference encompassing the occiput and frontal bones (forehead). It is a clinical sign and not a disease.

Microcephaly has recently gained notoriety in the popular press because of its association with the Zika virus, one of many viruses that may lead to microcephaly by first damaging the brain.[4] However, causality has not definitely been proven.

The skull is comprised of six bones that are not fused at birth and which begin to fuse over the next few months. Head circumference typically grows because of the underlying brain growing, exerting physical force on the skull bones and causing them to expand as well. The rate of expansion is highest in the first few months and gradually plateaus over time. Various gender-specific growth charts have been published, but the Centers for Disease Control (CDC) currently recommends that children in the United States between the ages of 0 and 2 years old are tracked with the World Health Organization (WHO) growth charts, and with the CDC growth charts after children turn 2 years old. Minor differences do exist between the two charts. Clinicians can easily tell the difference because charts from WHO data tend to stop at 24 months of age, whereas the charts from CDC data extend to 36 months of age.[6, 7]

If the sutures fuse prematurely, the skull may take on an abnormal shape and the head circumference will grow at a much slower rate than age-matched controls. (For further information, please see the Medscape Reference article Pediatric Craniosynostosis.)

Alternatively, if an infant’s brain has a lower volume than normal (i.e., due to a decreased number of neurons and glial cells), it may not grow as much as other infants’ brains that have a higher number of neurons and glial cells. Decreased brain growth would then lead to decreased outward force exerted on the skull, and decreased expansion of the head circumference. This process may result in a normally shaped or symmetric head, as opposed to the abnormal shape that results from craniosynostosis. Various etiologies can lead to decreased brain volume. More commonly, prenatal or perinatal insults to the brain or genetic/metabolic conditions cause poor brain growth. Less commonly, genetic neurodegenerative diseases (e.g., Rett Syndrome) will cause progressive microcephaly in infants and toddlers.

The etiology of microcephaly can be broadly divided into two categories: premature fusion of cranial sutures (i.e., craniosynostosis) or poor brain growth.

Congenital microcephaly

Genetic conditions that can cause microcephaly include the following:

• Trisomy 21, 13, 18
• Cri du Chat syndrome - 5p deletion
• Wolf–Hirschhorn syndrome - 4p deletion
• Williams syndrome - 7q11.23 deletion
• Cornelia de Lange syndrome
• Smith-Lemli-Opitz syndrome
• Seckel syndrome
• Primary autosomal recessive microcephaly (microcephaly primary hereditary [MCPH]) - mutation in the abnormal spindle microtuble assembly (ASPM) gene, which impacts cell division of neural progenitor cells

Maternal deprivation problems can also lead to microcephaly (e.g., folate deficiency, malnutrition, and hypothyroidism).

Postnatal onset microcephaly

Postanatal onset microcephaly can result from inborn errors of metabolism including congenital disorders of glycosylation, mitochondrial disorders, peroxisomal disorders, and Menkes disease. Disruptive injuries such as traumatic brain injury, hemorrhagic and ischemic stroke, and hypoxic-ischemic encephalopathy can also lead to microcephaly.

Microcephaly is not a common condition. State birth defects tracking systems have estimated that microcephaly ranges from 2 babies per 10,000 live births to about 12 babies per 10,000 live births in the Unites States.[5] Two large population-based studies have found similar incidences of microcephaly in newborns: 0.56% and 0.54%, respectively.[1, 2]

Similar studies for postnatal onset microcephaly could not be found and are not mentioned in the American Academy of Neurology’s (AAN) Practice Parameter: Evaluation of the child with microcephaly (an evidence-based review).[3]

Microcephaly itself does not necessarily predict someone’s functional outcome but can be associated with many other clinical problems, depending  on the etiology of the microcephaly. For example, seizures, cerebral palsy, developmental delay, hyperactivity, and other neurodevelopmental problems occur more commonly in children with microcephaly.

The head circumference is measured at birth as well as at regular checks by primary care providers. Microcephaly can present at various ages and can be either static or progressive, depending on the etiology. Additionally, it may or may not be associated with syndromic features, depending on the etiology.

For a concern of abnormal head size, the exam should comment on both head shape and head size (in comparison to age and gender matched controls). The head should be measured formally in the standard method. According to the AAN Practice Parameter, “Accurate head circumference (HC) measurement is obtained with a flexible non-stretchable measuring tape pulled tightly across the most prominent part on the back (occiput) and front (supraorbital ridges) of the head.”[3]

The clinician should also note the percentile of head circumference at birth, and if the current head circumference has remained consistent or has changed over time. (For details on the types of head shape changes, please see the Medscape Reference article Pediatric Craniosynostosis.) A head circumference of more than 2 standard deviations below the mean is considered microcephaly; a circumference of more than 3 standard deviations below the mean is classified as severe microcephaly, which should prompt consideration of neuroimaging.[4]  (See image below.)

Illustration of typical head size, Microcephaly, and Severe Microcephaly

Furthermore, comment about syndromic features, developmental level, and presence (or lack of) neurologic deficits should also be made since those features can help dictate which further workup, if any, should be performed.

Microcephaly can be diagnosed prenatally via ultrasound conducted late in the 2nd trimester or early in the third.

Postnatally, microcephaly is determined via physical examination. Measure the infant's head circumference and compare it against population standards. If the child's head circumference is less than 2 standard deviations (SD) below the average, microcephaly is indicated. 

Congenital microcephaly

Congenital microcephaly is present either prenatally or at the time of birth or delivery. It can develop as a result of abnormal brain development or disruption in the normal development of the brain.

If the infant has clinical features suggesting a specific disease or syndrome, conduct specific testing for that condition. An MRI should be obtained, particularly if the child's development is delayed. Results may show a specific malformation or pattern of injury. If the MRI is normal or non-specific, consider testing for infectious (e.g., toxoplasmosis, cytomegalovirus, HIV), toxic, genetic, or metabolic disorders.[3]

Postnatal-onset microcephaly

Acquired microcephaly can develop after birth due to hypoxic-ischemic injury or a post-natal insult such as trauma or infection. In this instance, the head circumference is normal at birth but becomes comparatively smaller as the baby grows in length. An MRI may be helpful in these cases to rule in or out specific conditions, particularly if the microcephaly is severe (< -3SD) or if there are neurological signs or symptoms present. Consider testing girls for Rett syndrome if other typical findings are present such as loss of purposeful hand movements and loss of language, appearance of compulsive movements such as hand wringing, and appearance of breathholding or apnea.[3]

Outside of surgery for craniosynostosis, there is no treatment to normalize the head size. However, some metabolic diseases (such as phenylketonuria) lead to progressive problems over time, and early diagnosis and treatment then would prevent further degeneration.

Craniosynostosis warrants consultation with a neurosurgeon and/or craniofacial surgeon, to consider surgery to treat increased intracranial pressure or for cosmetic reasons. Concerns about seizures suggest the need for consultation with a child neurologist. According to the AAN Practice Parameter, there is no evidence to support or refute the use of a routine EEG as a screening test in children with microcephaly. Concerns about poor vision may suggest the need for consultation with a pediatric ophthalmologist. The AAN Practice Parameter suggests that routine ophthalmologic screening may be of benefit.[3]

The head size should be tracked over time to make sure it is growing proportionally. Changes in the head circumference percentile should make the clinician consider further diagnostic workup as appropriate. Because children with microcephaly may have various comorbidities, they may require more thorough investigation than is typical at well-child checks.

The American Academy of Neurology's Practice Parameter for Evaluation of the Child with Microcephaly recommends the following:[3]

Diagnostic testing

• Neuroimaging may be considered useful in identifying structural causes in the evaluation of the child with microcephaly ( Level C).
• Specific targeted genetic testing may be considered in the evaluation of the child with microcephaly in order to determine a specific etiology ( Level C).
• There is insufficient evidence to support or refute obtaining metabolic testing on a routine basis for the evaluation of the newborn or infant with microcephaly ( Level U).

Associated neurological disorders

• Because children with microcephaly are at risk for epilepsy, physicians may consider educating caregivers of children with microcephaly on how to recognize clinical seizures ( Level C).
• There are insufficient data to support or refute obtaining a routine EEG in a child with microcephaly ( Level U).
• Because children with microcephaly are at risk for cerebral palsy (CP), physicians and other care providers may consider monitoring them for early signs so that supportive treatments can be initiated ( Level C).
• Because children with CP are at risk for developing acquired microcephaly, serial HC measurements should be followed ( Level A).
• Because children with microcephaly are at risk for developmental disability, physicians should periodically assess development and academic achievement to determine whether further testing and rehabilitative efforts are warranted ( Level A).

No medications exist for the condition in general, though medications may be used to treat some of the specific clinical issues that commonly occur with microcephaly, e.g. seizures, hyperactivity, behavioral changes, etc.