Recommendations regarding imaging of the central nervous system in fetuses and neonates.

An abnormal presentation of the central nervous system in a fetus during a screening examination is an indication for extended diagnosis, the aim of which is to explain the character of such an anomaly (a congenital defect, destructive effect of intrauterine infection or abnormality with reasons that are difficult to explain). Knowledge of normal development sequence of the fetal brain, which is discussed in this paper, is the basis for correct interpretation of imaging findings. Together with the increase in survival of preterm neonates, a high risk of early brain damage is still a problem in this extremely immature population. Therefore, imaging examinations become necessary. The paper presents intrauterine and postnatal risk factors of early brain damage as well as classification of such lesions, of hemorrhagic and hypoxic-ischemic etiology. The diagnosis of the cerebellum damage, which is currently believed to be a significant cause of autism, is emphasized. The evolution of lesions over time is also presented. Moreover, the elements of diagnosis important for prognosis are stressed. The standards of imaging examinations of the central nervous system include the schedule of ultrasound examinations and provide indications for extended diagnosis with the use of magnetic resonance imaging.

Introduction

The overview of available literature indicates that the latest recommendations concerning medical imaging of the central nervous system (CNS) in fetuses and neonates were published in 2002 by the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society(. In Polish literature, such guidelines appeared one year later(. What has changed in the last 10 years?

The survival rate of the least mature neonates has not changed – it still is the 23rd – 2 4 th w eek o f p regnancy. However, survival rate of neonates born in and after the 25th week of pregnancy has i ncreased. The r isk of early brain damage (of hemorrhagic etiology or periventricular leukomalacia) is still inversely proportional to the duration of pregnancy. The available information indicates a decrease in the number of instances of post-infection brain damage, which is a consequence of a better organization of neonatal intensive care units, antibiotic strategy and faster diagnosis. The change of therapeutic possibilities is also observed in the group of newborns with the history of severe hypoxic-ischemic encephalopathy. The application of hypothermia not later than several hours after birth improves prognosis in terms of survival and development in a statistically significant way.

Hospital equipment is also changing. New-generation ultrasound (US) systems appear with increasingly better resolution. Thanks to the Great Orchestra of Christmas Charity, two magnetic resonance-compatible incubators were purchased. They allow safe examinations of young children to be performed and their vital functions to be monitored in the magnetic field.

Prenatal examinations

In most European countries, three ultrasound examinations are recommended to pregnant patients (after the 10th, in approximately 20th and after 30th weeks of gestation). If abnormalities are found, they need to be verified in a reference center. Apart from patients in whom a congenital defect is suspected based on a US image, the group of increased risk also involves fetuses whose mothers present with elevated serum α-fetoprotein (AFP), positive family history of CNS defects, insulin-dependent diabetes mellitus or epilepsy. A genetic consultation prior to pregnancy is needed in women with increased risk of having a child with a congenital defect.

The first examination in women at increased risk should be performed between the 11th a nd 14th weeks o f p regnancy with the use of an endovaginal probe in a reference center. If doubts occur, examinations should be repeated every 2 weeks until the 18 th week of gestation in order to rule out or confirm a defect. An experienced interdisciplinary team for prenatal diagnosis and therapy consisting of a geneticist, obstetrician, neonatologist, radiologist, surgeon and cardiologist should do everything they can to make the diagnosis precise. When abnormalities are observed in the structures of the CNS during an ultrasound examination, the severity of the pathology detected must be specified (e.g. ventricular dilatation or hydrocephalus) and the treatment options as well as prognosis must be established.

The indications for fetal magnetic resonance imaging (MRI) include:

unclear US image;

lateral ventricular dilatation;

difficulty to assess the structures of the midline and posterior cranial fossa;

assessment of fissures and gyration when the size of the brain is abnormal in search for neuronal migration.

search for hypoxic-ischemic lesions when the mother's history is positive: hypoxia in the mother or monochorionic (single placenta) twin pregnancy with intrauterine death of one of the twins;

search for brain damage in selected cases of intrauterine infection (CMV seroconversion – cytomegalovirus, toxoplasmosis);

suspicion of tuberous sclerosis;

suspicion of congenital brain tumor;

complex fetal defects;

brain defects in siblings(.

MRI can be performed as soon as in the 18th or 19th weeks of pregnancy. Before this moment, the size of the fetus and resolution of the method do not allow anomalies and pathologies to be visualized. MRI enables visualization of the fetus in any plane. At present, one series of images is obtained within a dozen or so seconds which makes it possible to visualize the fetus without the need for sedation despite the fact that this method is sensitive to movement.

A prenatal diagnosis should always be verified with an imaging examination in the postnatal period or, in the case of death, in a postmortem examination. If MRI verification is needed due to the type of pathology, one should consider performing it in the final period of pregnancy.

It was proven that conducting MRI prior to delivery is easier and safer than in an ill neonate soon after birth. This is particularly true if the neonate needs life-sustaining equipment since the mother's uterus is a natural and safe “incubator” for the child(. The MR-compatible incubators mentioned above eliminate the problem of postnatal diagnosis in such children.

Normal brain development

Knowledge of normal development of the brain is the basis for correct interpretation of imaging examinations(. Below, the most important stages of normal development of the brain in the prenatal period are listed.

The first convolutions of the brain appear in the occipital region after the 22nd or 23rd week of pregnancy. The wide Sylvian fissures close between the 25th and 36th week of gestation. In approximately 34th week, the occipital lobe has convolutions and the frontal lobe is still smooth.

The involution of the germinal matrix begins between the 24th and 30th week of gestation. After week 34, only a slight hyperechoic notch is visible in the region of the germinal matrix, i.e. in the region of the thalamocaudate groove.

Myelination begins in the second trimester and lasts long after birth until juvenile age. It proceeds towards the caudocranial direction. In the 37th week of pregnancy, it can be observed at the level of the thalamus and posterior limbs of the internal capsule. The posterior part of the medulla oblongata undergoes myelination earlier than its anterior part, internal capsule and cerebral hemispheres.

The width of the lateral ventricles measured in the third trimester in the axial plane at the level of the body of the ventricles should not exceed 10 mm.

The subdural (pericerebral) spaces are wide until the 24th or 25th week of pregnancy. Subsequently, they undergo narrowing, but the norm range for their width has not been established.

The corpus callosum develops in the 13th week of pregnancy and then grows to achieve its final shape in the 20th week of gestation.

The layers of the cerebellar cortex develop from the 25th week of pregnancy.

Fetal ventricular dilatation

Ventricular dilatation is the most frequent abnormality detected in neuroimaging examinations. It may be a primary defect (genetically-determined diseases, e.g. aqueductal stenosis), an element of brain defect, or it may have a secondary, post-infection character (e.g. in toxoplasmosis). Dilatation is classified as mild when it does not exceed 12 mm, moderate when it is not greater than 15 mm or severe when it exceeds 15 mm. The prognosis associated with development depends on the etiology of dilatation.

In the majority of cases, congenital defects of the CNS are caused by disorders in neural tube closure (dysrafism, Chiari malformation, Dandy-Walker syndrome or corpus callosum agenesis), disorders of cerebral division into two hemispheres (holoprosencephaly) or disorders in development of brain folds or neuronal migration (lissencephaly, schizencephaly or polymicrogyria)(. It should be remembered, however, that in fetuses and pre-term neonates, the lateral ventricles may not only be wider than in full-term newborns, but also asymmetrical – the left lateral ventricle is usually wider than the right one. In the case of a prenatal diagnosis of a severe CNS developmental defect that is resistant to treatment, parents must decide about continuation (or discontinuation) of pregnancy.

Etiology and diagnosis of early brain defects in neonates

There are a number of prenatal factors that can constitute a risk of CNS complications in a neonate. They include:

intrauterine factors resulting from abnormalities of the placenta or infection;

circulation pathologies resulting from cardiac developmental defects, patent ductus arteriosus (PDA) or autoregulation of cerebral blood flow;

diseases of the lungs and pulmonary vessels, such as respiratory distress syndrome (RDS), pulmonary hypertension or pneumothorax;

genetic diseases;

metabolic diseases;

infections resulting in meningitis or encephalitis and brain abscesses.

Preterm neonates are at a particular risk of early brain defects, and prenatal infections contribute to their development to a considerable degree. Chorioamnionitis increases the risk of a preterm delivery and makes the inflammatory factors damage the blood-cerebrospinal fluid barrier in the fetus and activate microglia and astrocytes. The shorter the gestation and the lower the birth weight of a neonate, the higher the risk of lesions in the form of intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL). Gestational age (duration of gestation) is a more accurate measure of maturity than the birth weight.

According to the American Academy of Neurology, routine screening US examinations of the brain through the fontanelle should be conducted in all neonates born prior to the 30th week of gestation. These examinations are relatively easy, inexpensive and possible to perform at the site where the neonate stays without the need for his or her transportation. They may be repeated multiple times if this is required by the clinical condition of the patient. An MRI examination is superior in visualizing the cerebral parenchyma and subtle lesions in the developing white matter. Its more advanced options facilitate obtaining additional information. Nevertheless, it is a much more expensive modality, requires transporting neonates and in certain cases also their sedation/anesthesia, which is associated with a greater risk for patients.

Epidemiology and classification of lesions

The predominant early brain injuries involve IVH and PVL. According to the information from the European Union published in the EuroNeoNet(, the prevalence of bleeding (calculated as the sum of IVH III and periventricular hemorrhagic infarction, PVHI, that used to be called grade IV hemorrhage) ranges from 2–25% with the mean value of approximately 10%. In Poland, there have been no population studies that would determine the prevalence of IVH. The only data we have come from individual centers. Based on this information, it may be concluded that the prevalence of extensive hemorrhage amounts to approximately 20% thus placing itself in the aforementioned broad range, but on average, this serious complication occurs twice as often(. The prevalence of cystic PVL is estimated at 5% whereas the diffuse form is much more frequent – it is diagnosed in 50% of patients born with birth weight below 1,500 g(.

The prevalence of hemorrhagic and hypoxic-ischemic injuries is reversely proportional to gestational age and is the highest in very immature neonates. No differences in prevalence were observed between boys and girls. The greatest number of instances of bleeding occur in the first days of life (between the first and third day). In 20–40% of cases, the primary scope of bleeding becomes more extensive towards the end of the first week of life(. Leukomalacia is most often identified from the third week of life – the topography of such lesions is presented in fig. 1. Both hemorrhagic lesions and leukomalacia are discussed according to the classification that indicates the extensiveness of damage (tab. 1 and 2). Noncystic lesions (grade I PVL) occur in the white matter in a diffuse form. In a US examination, they are observed as hyperechoic areas. Their presence should be suspected if they persist in the same localizations for more than 7 days after birth. Prognosis concerning development of a child is established on the basis of the range of damage and type of its evolution.

Fig. 1

Topography of leukomalacia

Tab. 1

Classification of intraventricular hemorrhage

Grade I	Bleeding in the germinal matrix
Grade II	Intraventricular bleeding occupies up to 50% of ventricular lumen volume
Grade III	Intraventricular bleeding occupies >50% of the lumen of the lateral ventricular volume. It frequently enlarges the ventricle
Grade IV	Hemorrhagic periventricular infarction (bleeding to the periventricular parenchyma)

Tab. 2

Classification of periventricular leukomalacia

Grade I	Noncystic leukomalacia, diffuse lesions in the middle area of the white matter which disturb its development
Grade II	Small localized cystic lesions
Grade III	Diffuse cystic lesions
Grade IV	Extensive damage in the subcortical region

Bleeding to the cerebellum may be a diagnostic challenge. In this pathology, MRI scanning is of key importance. This damage may involve cerebellar vermis or cerebellar hemispheres and have both uni- and bilateral character (fig. 2). The best “acoustic window” for visualizing the cerebellum in a US examination is the mastoid process (asterion – a craniometric point palpable just behind the concha where the lambdoid, parieto-mastoid and occipito-mastoid sutures meet). It enables access to the posterior cranial fossa in the frontal (coronal) and axial planes. It is currently believed to be the second standard acoustic window (after the anterior fontanelle) which should be used to visualize the cerebellum and other structures of the posterior cranial fossa in a neonate at the end of the first week of life. The prevalence of cerebellar damage is estimated at 7–14% in the population of neonates with extremely low birth weight. The etiology of these lesions is not entirely clear, but, similarly to ventricular bleeding, it may be a consequence of blood flow disorders in the immature brain(. They are usually observed in ill neonates, with multiple complications of prematurity, including ventricular bleeding, with considerable mortality risk. They are sometimes observed in patients in a better condition in whom such lesions are not suspected and are detected incidentally. More and more frequent MRI examinations in neonates indicate that the prevalence of hemorrhage in the infratentorial region is higher than it was previously believed. Detecting lesions in the cerebellum is a significant prognostic factor – they are associated with development disorders, including autism(.

Fig. 2

Hemorrhage in the right cerebellar hemisphere

Early brain damage in term neonates

The prevalence of perinatal hypoxic-ischemic encephalopathy (HIE) in full-term neonates is estimated at 1:1,000 births. This encephalopathy results from insufficient oxygen supply to the brain in the perinatal period and is one of the most severe forms of early brain injury sustained in the perinatal period. In some of these children the brain remains permanently damaged.

Hypoxic-ischemic lesions in term children, if they result from acute and deep hypoxia, mainly involve the gray matter: basal ganglia and thalamus. In severe forms, such injuries, called selective neuronal necrosis, also involve the cerebral cortex and the white matter. In the most severe form, called multicystic necrosis, such lesions lead to the development of cavities in the white matter with concomitant involvement of the basal nuclei, thalamus and/or cerebral cortex. Mild or moderate subacute hypoxia may lead to parasagittal brain injury. It is located in the watershed locations (those border-zone regions in the brain supplied by the major cerebral arteries where blood supply is decreased) – parasagittaly and bilaterally, and involves the cerebral cortex and subcortical white matter. Moderate, prolonged hypoxia causes periventricular leukomalacia in preterm neonates(.

No connection was detected between anomalies detected in the US image in the first day following birth with development following the first year of life. A low resistance index (0.6 or lower) in the middle cerebral artery is of significant prognostic relevance and is associated with development disorders in the second year of life. A rare consequence of hypoxia is brain edema (it occurs in merely 20% of hypoxic neonates) which does not have a fully pathognomonic sonographic presentation. In 2D sonography, the following can be observed: a generalized increase in parenchymal echogenicity (so-called “white brain”), blurring of normally visible structures and narrow (“tightened”) lateral ventricles. “Focal brain edema,” imaged as a restricted area of enhanced echogenicity, is observed even more rarely. The basis for brain edema diagnosis is Doppler examination of cerebral vessels. During the examination, one should visualize a decrease or inversion of diastolic Doppler wave and increase in the RI index (resistance index) above 0.85. The type of brain injury is determined based on the following imaging examinations: US (remains irrelevant if only a single examination is performed, but is more relevant when examinations are repeated) as well as MRI and MR spectroscopy.

Assessing evolution of lesions

Transfontanelle US examinations must be repeated with the frequency that depends on the extensiveness of lesions detected in the first examinations. Evolution of lesions in the injured brain cannot be predicted. In I and II grade hemorrhage, the persistent ventricular dilatation does not usually occur (figs. 2 and 3). In grade III hemorrhage and in periventricular hemorrhagic infarction (PVHI), unfavorable evolution of lesions in the form of posthemorrhagic hydrocephalus occurs more frequently (figs. 4–7). The risk that ventricular dilatation will progress until hydrocephalus develops and that intracranial hypertension occurs requiring subcutaneous implantation of Rickham reservoir that temporarily decompresses the ventricular system or, finally, ventriculoperitoneal shunt placement, concerns 15% of all patients with extensive hemorrhages (fig. 8)(.

Fig. 3

Sonographic evolution of grade I hemorrhage (IVH I°)

Fig. 4

Sonographic evolution of grade II intraventricular hemorrhage (IVH II°)

Fig. 7

Periventricular infarction (hemorrhage IV°) in a neonate born in the 24th week of gestation. Anterior frontal plane (A), posterior frontal plane (B) and right parasagittal plane (C)

Fig. 8

Prevalence of posthemorrhagic ventricular dilatation

Sonographic evolution of grade III intraventricular hemorrhage (IVH III°)

Sonographic evolution of grade IV intraventricular hemorrhage (IVH IV°)

The aim of treating posthemorrhagic hydrocephalus (PHH) is to prevent damage caused by increase in intracranial pressure. The selection of an optimal method for measuring extending ventricular system allows a proper therapy to be implemented in the right moment. Various scales are used to evaluate progression of ventricular dilatation in the US image: according to Levene, Davies and Monset-Couchard(. Levene's ventricular index is commonly used. It is defined as a distance between the midline (falx cerebri) and the most external point of the left and right lateral ventricles (figs. 9 and 10)(. Intervention (ventricular system decompression) is indicated when the lateral ventricle exceeds the 97th centile plus 4 mm. At present, it is known that earlier intervention contributes to better development of children with posthemorrhagic ventricular dilatation (PHVD). Prior to the decision to place a valve to decompress hydrocephalus, an MRI scan is performed which provides a better image of concomitant injuries.

Fig. 9

Levene's scale

Fig. 10

Assessment of posthemorrhagic hydrocephalus advancement

An examination that is particularly important for prognosis is US performed at the time of expected term birth or near that date. This is usually the time when the neonate is discharged from the neonatal intensive care unit or neonatal pathology ward where the patient stayed from his or her birth.

Indications for MRI

Despite a continuously growing number of MRI scanners, access to this examination is still restricted particularly for neonates since only few centers in Poland perform such examinations. Moreover, the knowledge of normal brain image that changes over time and pathologies typical of this age is essential for establishing a correct diagnosis.

MRI-compatible incubators are available only in two centers in Poland. High costs of such examinations must also be taken into account. Thus, it is not currently possible to perform MRI examinations in all preterm neonates and they are conducted only in the high-risk group:

in extremely premature neonates (born earlier than in the 28th week of gestation);

in neonates born earlier than in the 33rd week of gestation who manifest the following risk factors: chorioamnionitis with confirmed inflammation syndrome, congenital infection or monochorionic (single placenta) twin pregnancy;

in twins if their brother/sister is diagnosed with brain lesions or died;

in individual indications in cases when defects are diagnosed in a US examination or when such an examination raises suspicions of anomalies(.

Attempts should be made to perform MRI examinations in preterm children on the date of the expected term delivery, i.e. at or near the time of discharge from hospital. Such an examination is relevant for prognosis and has been recommended since 2004(. A prognostic value of information provided by MRI examinations performed at the time of normal delivery was demonstrated again a few years later by (partially) the same authors in their latest publication devoted to preterm children at the corrected age of 4 and 6. The children in whom MRI performed on the expected delivery date did not reveal lesions in the white matter did not manifest neurocongnitive deficits with respect to intelligence, speaking and social functions compared to their healthy peers. On the other hand, the children in whom MRI detected lesions in the white matter (from mild to severe) manifested impairment in multiple areas with cognitive deficits being the most prominent(.

Since thanks to the possibilities offered by MRI, it has become a method of choice in evaluating a genuine degree of the CNS involvement in neonates, this examination is indicated in term children when:

the transfontanelle US examination shows anomalies;

the neurological status does not correspond to normal ultrasound presentation of the brain;

neurological symptoms are present, e.g. seizures;

cerebral venous thrombosis is suspected.

Standards of CNS MRI in neonates

1. Equipment

MRI examinations should be performed with use of scanners with magnetic field strength of 1.5 T. Low-field scanners (0.2–0.5 T) must not be used for examining neonates.

Neonates should be examined in specialized centers that possess adequate knowledge and experience in examining neonates.

2. Examination technique

Neonates are most frequently examined in their sleep (anesthesia is needed in only some cases). The examination protocol should include essential sequences set in appropriate order so as to obtain diagnostic images without motion artefacts associated with the child awakening:

coronal T2-weighted images;

axial T1-weighted images;

SWI (preferred) or GRE/T2-weighted images in the transverse plane;

DWI;

sagittal T2-weighted images;

axial T2-weighted images;

axial FLAIR images.

The usage of thin layer 3D sequences that enable reconstruction in any plane as well as venous and/or arterial option in MR angiography depends on clinical indications or findings in a standard examination. A radiologist present during the examination makes the decisions regarding the aforementioned examinations and administration of a contrast agent(. Neonatal examinations must never be performed without a physician present and a teleradiologic approach is inadmissible.

Prognosis concerning development based on US and MRI examinations in preterm neonates

A normal ultrasound image obtained in repeated transfontanelle examinations indicates high (94%) probability of normal motor development in children born with low and very low birth weight.

a risk of impaired motor development in neonates with grade I and II IVH is estimated at 9%(;

a risk of impaired motor development in neonates with grade III IVH is estimated at 26% (13–45%)(;

a risk of impaired motor development in neonates with grade IV IVH (PVHI) is estimated at 53% (29–76%)(;

a risk of impaired motor development in neonates with PVL is estimated at 74% (42–92%)(.