REVIEW ARTICLE

https://doi.org/10.5005/jp-journals-11002-0065
Newborn
Volume 2 | Issue 2 | Year 2023

Importance of Neuroimaging in Infants with Microcephaly

Sabrina Rangwani¹, Gunes Orman¹, Maroun Mhanna², Akhil Maheshwari²^,³, Thierry AGM Huisman¹

¹Department of Radiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, Texas, United States of America

²Department of Pediatrics, Louisiana State University – Shreveport, Shreveport, Louisiana, United States of America

³Global Newborn Society (https://www.globalnewbornsociety.org/)

Corresponding Author: Sabrina Rangwani, Department of Radiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, Texas, United States of America, Phone: +832 824 7237, e-mail: sabrina.rangwani@gmail.com

How to cite this article: Rangwani S, Orman G, Mhanna M. Importance of Neuroimaging in Infants with Microcephaly. Newborn 2023;2(2):148–157.

Source of support: Nil

Conflict of interest: Dr Akhil Maheshwari is associated as Editor-in-Chief of this journal and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of the Editor-in-Chief and his research group.

Dr Thierry AGM Huisman is associated as the Editorial Board member of this journal and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of this editorial board member and his research group.

Received on: 07 June 2023; Accepted on: 30 June 2023; Published on: 30 June 2023

ABSTRACT

Microcephaly is diagnosed in infants and children with a head circumference (HC) 2 standard deviations less than average, accounting for age and gender. There is not a standard method of diagnosis, as growth charts vary by country and methodology used. The most popular method of diagnosis is the use of a tape to measure a child’s head. There are various conundrums that affect diagnoses: volume of the brain, deformities in skull shape that affect size measurements, and the etiology of microcephaly. The size of the skull is not the most important factor in diagnosing microcephaly, but rather the volume of the brain. Finally, a distinction between primary and secondary microcephaly must be made; primary microcephaly develops prenatally, and secondary microcephaly develops postnatally. The effects of primary microcephaly are generally more severe, but through imaging, it can be detected before birth. This article analyzes various conditions in which neuroimaging can add considerable information to current methods of clinical evaluation. There is a clear need for a multifaceted approach.

Keywords: Aminoacylase-2, Apert, Brain volume, Brain volume loss, Canavan’s disease, Cavum septum pellucidum, child abuse, Crouzon, cytomegalovirus, Ex vacuo enlargement of ventricles, Head circumference, Meckel-Gruber syndrome, Melting brain, near-drowning, Neuroimaging, Skull deformities, Thalami, TORCH, Toxoplasma gondii, Trisomy 13, Trisomy 18, Trisomy 21, Twin-to-twin transfusion syndrome, Vein of Galen aneurysmal malformation, Zika virus, Zika.

KEY POINTS

Microcephaly is diagnosed in infants and children with a head circumference (HC) 2 standard deviations less than average, accounting for age and gender.
There are various conundrums that affect diagnoses: volume of the brain, deformities in skull shape that affect size measurements, and the etiology of microcephaly.
A distinction between primary and secondary microcephaly must be made; primary microcephaly develops prenatally, and secondary microcephaly develops postnatally.
This article analyzes various conditions in which neuroimaging can add considerable information to current methods of clinical evaluation. There is a need for a multifaceted approach.

INTRODUCTION

Microcephaly in infants and children is defined as a head circumference (HC) 2 standard deviations (SD) below the mean compared with age and gender-matched healthy population.^1–5 Severe microcephaly refers to a HC more than 3 SD below the mean, whereas proportional microcephaly is characterized by HC, height, and weight scalars that are simultaneously 2–3 SD below the mean.^6–10 It is generally acknowledged that HC is correlated to overall brain volume; however, there are many confounding factors that may offer alternatives to this claim.^6,11–14 The HC measures the size of the skull which may be normal, while the brain volume is too small for age.^12,15,16 For example, global brain volume loss with co-existing ex vacuo ventriculomegaly may be accompanied by a normal skull size.^9,17–20 An additional limiting factor using the HC as an indicator of microcephaly is that currently no global standards or guidelines exist on using HC growth charts.^21–23 Depending on the included normal population, various growth charts exist.^24–28 As such, determining microcephaly requires a careful selection of the correct growth charts.^25,29,30

Microcephaly can be primary, related to a genetic or unknown cause, or secondary, which is obviously related to another illness.^2,3,31–34 Furthermore, the evolution of the HC over time should also be considered.^14,35 Neuroimaging plays a vital role in the diagnostic workup of suspected microcephaly.^36–38 CT and MRI allow qualitative and quantitative evaluation of the brain.^39–41 Combining the data of the HC and neuroimaging findings is essential for adequate diagnosis.^42–43 Neuroimaging should assist to differentiate between microcephaly secondary to a brain malformation, disruption or destruction.^43–45 The goal of this paper is to outline the basic aspects of diagnosing microcephaly as well as various anatomical imaging findings that may result in a normal HC measurement while the brain is overall too small in volume. Every (neuro-) radiologist should be familiar with these pitfalls.

EVALUATION

Primary microcephaly is usually noticeable at birth, indicating an onset in utero. In contrast, secondary microcephaly is acquired postnatally.^7,36 There are many etiologies for both causes of microcephaly, which are addressed in the Etiology section of this review.

Prenatally, HC is typically measured with ultrasound studies.^46–52 Using the axial image of the brain at the level of thalami and cavum septum pellucidum, a circular or ovoid curser is placed around the skull to mimic postnatal HC measurement techniques.^53–55 Bi-parietal diameter, as well as other biomarkers, such as the femur length and abdominal circumference, should also be measured to differentiate between an isolated microcephaly versus a proportional microcephaly due to intrauterine growth retardation.^56–61

Postnatally, HC is first evaluated clinically through cross-sectional and longitudinal measurements.^6,62 The measuring tape is wrapped around the widest possible circumference of the child’s head in an axial plane above the eyebrow and above the ears including the most prominent part of the back of the head.⁶² Typically, the measurement is done three times and the largest measurement is selected.⁶³ Temporal evolution of HC is critical and serial HC measurements can be useful if there are concerns such as progressing neurologic deficits.^35,64,65 Infants with microcephaly often present with developmental and intellectual disability, epilepsy, cerebral palsy, language delay, strabismus.^66–68 However, microcephaly may be just one manifestation of a multisystem disorder; cardiac anomalies, renal, urinary tract, and skeletal anomalies may accompany microcephaly.^6,69–74 Consequently, microcephaly requires a full diagnostic workup to exclude additional organ involvement, or multisystem syndromes.

IMAGING-RELATED CONUNDRUMS

Correct and relevant evaluation of microcephaly can be more challenging than initial impressions. Several misleading conundrums or pitfalls exist of which the (neuro-) radiologist should be aware. The very first conundrum is that there are variations between country-specific growth charts, possibly due to different cultural, socioeconomic or health standards impacting growth or the average height and weight of various age groups in a certain country.^21,75–78 The large ranges of “normal” growth parameters (Figs 1 and 2) may result in an infant being diagnosed to have microcephaly in one, but not in a neighboring country.⁸

Fig. 1: CDC head circumference chart for boys from age 0 to 36 months

Fig. 2: Brazilian growth chart for boys aged 0–24 months⁷⁹

A second conundrum is that the size/volume of the brain is much more important than the size of the skull, but external measurements only measure the size/circumference of the skull.^80,81 Imaging in important because even though the HC usually correlates well with the brain volume, there are situations in which slower brain growth leaves “extra space” within the skull.⁸⁰ Acquired pediatric brain volume loss following accidents such as near-drowning may present with a normal HC with ex vacuo enlargement of the ventricles, subarachnoid spaces, and brain sulci.⁸² These infants may show widened diploic spaces of the skull on follow-up. Some may also show progressive enlargement of the paranasal sinuses including that of the mastoid air-cell complex, reactive to the brain volume loss.⁸³ The severity of these manifestations might vary based on age, gender, and ethnicity (Fig. 3). Neuroimaging is essential to identify these pitfalls of a normal HC measurement despite global brain volume loss.⁸⁴ Serial imaging and HC measurements beyond the time of an apparent acute injury will increase diagnostic accuracy.⁸⁵ Correlation with the clinical history is equally important. An infant with a high-grade hydrocephalus secondary to aqueductal stenosis may initially present with an enlarged HC.⁸⁶ After ventriculo-peritoneal shunting, the ventricles may decompress, typically resulting in a decreasing or normalizing HC.⁸⁷ The measured HC may however underestimate possible brain volume loss. Long-standing hydrocephalus may impair normal brain development and/or result in irreversible brain injury.⁸⁸ The HC may pseudonormalize, or in some cases, the HC remains unchanged/increased due to reactive skull thickening.^89,90

Fig. 3: Axial T2-weighted magnetic resonance imaging showing follow-up changes in an infant who suffered a hypoxic injury. Visible reduction of brain volume, despite the widened sulci, thickened skull, large mastoids, and normal head circumference

An additional conundrum seen in many syndromes/systemic diseases is in deformities that alter the shape of the skull, resulting in skewed HC measurements and overdiagnosis of microcephaly.⁷ Various syndromic cranio-synostoses, such as Apert or Crouzon syndrome present with a significant skull deformity due to premature closure of skull sutures.^91,92 In these infants, clinical assessment may need to be supported by appropriate neuroimaging.^93,94

A final conundrum to be recognized is that the overall volume of the brain may not always correlate with neurocognitive and senso-motor functionality.^95,96 For instance, in Canavan’s disease, a rare and fatal autosomal recessive degenerative CNS disorder caused by deficiency of aminoacylase-2, infants and young children typically present with an enlarged HC due to a significant increased overall brain volume.⁹⁷ However, a few cases might present with microcephaly.⁹⁶ Most patients present with intellectual disability, loss of previously acquired motor skills, feeding difficulties, hypotonia, spasticity, paralysis, blindness, and seizures.⁹⁷

Etiology-related Conundrum: Microcephaly due to Malformation, Disruption/Deformation, or Destruction

Primary microcephaly can be seen in the setting of a prenatal brain malformation, brain disruption/deformation, or brain destruction. Familiarity with these three different etiologies is important for correct diagnosis, determining treatment options, predicting outcome, and counseling of the parents and families including recurrence risk for future pregnancies.

Primary, congenital brain malformation refers to an anomalous or abnormal brain development which may be an isolated occurrence such as agenesis of the corpus callosum or secondary to a chromosomal disorder as in Joubert syndrome. Such findings could also be one of the manifestations in a multisystem condition such as Aicardi syndrome. Brain disruption/deformation sequence refers to a process where exposure to toxin(s) as in intrauterine alcohol exposure or in inborn error(s) of metabolism, infections, such as ToRCH (toxoplasmosis, others, rubella, cytomegalovirus (CMV), and herpes simplex, and now including Zika virus infections), or an ischemic/hemorrhagic (thrombo-embolic) event, interferes with the normal brain development. The timing of the event is often more impactful than the intrinsic nature of the injury; the earlier the event occurs during gestation, the more severe might be the resultant brain disruption/deformation sequence at delivery (Fig. 4). In contrast to the “programmed” brain malformation, in the setting of a brain disruption/deformation sequence the brain had the potential to be normally developed. However, many developmental abnormalities may arise in altered neuronal migration, cortical organization, sulcation/gyration, and myelination. In these infants, brain malformations are usually evident at birth. Brain destruction refers to a process where initially normally developed brain is injured/destructed due to an acute event like a focal hemorrhage or ischemia. Congenital microcephaly may be seen in all the settings of brain malformation, brain disruption/deformation sequences, as well as in brain destruction. It is essential for physicians to be familiar with these different qualities and etiologies of microcephaly.

Fig. 4: Primary microcephaly patient shows a simplified gyral pattern

The (neuro-)radiologist should recognize and describe the additional findings that may be seen in children with microcephaly. Focal or diffuse migrational abnormalities, ventriculomegaly, cerebellar dysplasia/hypoplasia, abnormal or delayed myelination, white and gray matter calcifications and white matter gliosis may exist. The combination of findings assists narrowing down the differential diagnosis.

There are many causes of microcephaly. Primary (genetic) microcephaly is believed to result from early exhaustion of the neuronal precursors or accelerated apoptosis.¹ Imaging of the brains of those with primary microcephaly typically show a simplified gyral pattern, shallow sulci, and/or delayed, or impaired myelination. The cortical ribbon is typically of normal thickness with a normal internal laminar organization, the corpus callosum may be thin, and the brain may be hypoplastic but is typically completely formed. Genetic syndromes, including chromosomal abnormalities, are a common etiology of microcephaly. This category includes trisomy 13, 18, and 21. There is often a more severe prognosis in those who develop microcephaly due to a chromosomal abnormality.³⁶

Etiologies of Congenital Microcephaly

Congenital infectious microcephaly is often viral (cytomegalovirus, CMV), whereas postnatal microcephaly is more frequently due to a bacterial infection (Fig. 5). Cytomegalovirus infections occurring during early gestation result in white matter loss, ventriculomegaly, cortical anomalies, and microcephaly. Cytomegalovirus infections seen during later pregnancy cause microcephaly less frequently but may still cause many of the aforementioned anomalies. Microcephaly is infrequent in infants who acquire CMV infections during later pregnancy, but many infants may still develop ventriculomegaly. Cytomegalovirus has an affinity for the germinal matrix; intrauterine infections are associated with cortical abnormalities and periventricular calcification. Many patients also show acute and chronic vasculitis, which may cause brain injury due to ischemia.

Fig. 5: Microcephaly caused by an infection during early development

Intrauterine infections or exposure to teratogens are frequently associated with adverse prognosis. Many maternal diseases have been identified as important causes of microcephaly. Neurotropic infectious agents, such as Zika and TORCH viruses, CMV, rubella, and Toxoplasma gondii, have all been linked with congenital microcephaly. In mothers with phenylketonuria who have high serum levels of phenylalanine, the amino acid may be transmitted to the fetus and at high levels, may act as a teratogen. In other cases, maternal infections may be vertically transmitted to the fetus and cause neural tissue destruction that progresses to calcification.⁹⁸ Vertical transmission of the Zika virus can result in global white matter volume loss, a matching small-sized skull, and cortical or central gray matter calcifications. In these fetuses who are infected in utero, there may be evidence of overlapping/simultaneous disruptive and destructive processes. These neurotropic infections result in extensive damage in the fetal central nervous system (CNS), particularly if the infection occurs during the first or second trimester. There may also be disruption of subsequent brain development.

Microcephaly may also be seen in other conditions. For instance, infants who developed twin-to-twin transfusion syndrome (TTTS) in utero can show severe microcephaly (Fig. 6).⁹⁹ In TTTS, identical twins who shared a placenta (monochorionic-diamniotic pregnancy) may develop injuries due to multiple placental arterio-arterial, arteriovenous, and veno-venous connections.^100,101 These connections disrupt the normal balance of fetal perfusion and blood volumes. In symptomatic TTTS, a “donor” twin shunts/pumps blood to the other “recipient” twin.¹⁰² Due to the excessive blood volume, the recipient twin may develop progressive heart failure while the donor twin remains small for gestational age.¹⁰³ Progressive brain injury may result in severe destructive microcephaly.¹⁰⁴ In other infants, microcephaly may also result from progressive heart failure in fetuses with a Vein of Galen aneurysmal malformation (VGAM).¹⁰⁵ The combination of fetal heart failure, systemic and cerebral venous congestion, steal phenomena, and hydrocephalus results in progressive white and gray matter injury which explains the microcephaly. This process is also known as “melting brain.”¹⁰⁶ Placental insufficiency, either due to a too small placenta, chorioamnionitis, placental infarctions, or placenta dehiscence with subsequent fetal hypoperfusion or thromboembolic processes are also linked to fetal and neonatal microcephaly.^107–110

Fig. 6: TTTS twins. The smaller twin on the right has limited white matter and an altered gyral pattern

Infants who develop perinatal hypoxic-ischemic injury usually do not have microcephaly in the perinatal period, but they may show progressive brain volume loss during follow-up.^111,112 Similarly, infants who have had to suffer from diffuse brain injury related to child abuse (Fig. 7), near-drowning, trauma, or inborn errors of metabolism with accumulating neurotoxins may develop microcephaly due to arrested brain growth within the first few years.^68,113–116

Figs 7A and B: (A) Axial CT including a 3D reconstruction of the skull of a neonate that was a victim of severe child abuse. A global hypodensity of both cerebral hemispheres due to severe brain edema is noted as well as mildly hyperdense blood along the tentorium cerebelli in the subarachnoid space along both occipital lobes as well as within the lateral ventricles. The sutures are widened secondary to global edema; (B) Sagittal T1-weighted and axial T2-weighted MRI of the same child 7 months later shows high-grade, chronic, secondary/destructive diffuse brain volume loss with resultant microcephaly, and partially overriding sutures

Finally, congenital meningoencephaloceles can also be associated with microcephaly.¹¹⁷ These are embryonic development abnormalities, characterized by a sac-like protrusion of the brain, meninges, and other intracranial structures through the skull. Nearly 75% of encephaloceles are occipital¹¹⁸ (Fig. 8). These malformations can be seen as isolated or be seen as a part of multisystem conditions, such as the Meckel-Gruber syndrome.^119–121

Figs 8A and B: (A) Sagittal and axial T2-weighted fetal MRI of a fetus with severe microcephaly secondary to a large malformative occipital meningoencephalocele; (B) Matching sagittal T1-weighted and axial T2-weighted postnatal MRI of the same fetus confirms the extensive occipital meningoencephalocele and microcephaly

CONCLUSION

Microcephaly refers to a HC measuring less than 2 SD below average and may be secondary to multiple etiologies, including malformation, disruption/deformation sequence, destruction, and idiopathic forms of microcephaly. Microcephaly may become apparent during a physical exam and the first step is to get a good/reliable HC measurement and then follow-up measurements for temporal evolution. HC has typically been recognized as an indirect marker of brain size. However, a normal HC does not exclude microcephaly. Neuroimaging is essential for correct diagnosis and may reveal anatomical findings that are causative of normal HC measurements. Measuring the HC is not sufficient and may underestimate the degree of microcephaly due to the various conundrums discussed in this paper. The size of the brain is much more important than the size of the skull. There are multiple factors that must be considered in the diagnosis of microcephaly, including but not limited to, primary vs secondary, congenital vs acquired, malformation vs disruption vs destruction. The differential diagnosis list is broad and there are multiple etiologies. Lastly, a multidisciplinary approach is the key to timely diagnosis and appropriate management.

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