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State of the Art &&&&&&&&&&&&&& and the Timing of Fetal and Neonatal Injury

Patrick D. Barnes, MD modalities provide spatial resolution based upon physiologic or metabolic data. Some modalities may actually be considered to provide both structural and functional information. Ultrasonography (US) Current and advanced structural and functional neuroimaging techniques is primarily a structural imaging modality with some functional 1±11 are presented along with guidelines for utilization and principles of imaging capabilities (e.g., Doppler ÐFigure 1). It is readily accessible, diagnosis in fetal and neonatal central abnormalities. portable, fast, real time and multiplanar. It less expensive than other Pattern of injury, timing issues, and differential diagnosis are addressed with cross-sectional modalities and relatively noninvasive (nonionizing emphasis on neurovascular . Ultrasonography and computed radiation). It requires no and infrequently needs provide relatively rapid and important screening information patient sedation. The resolving power of US is based on variations in regarding gross macrostructural abnormalities. However, current and acoustic reflectance of tissues. Its diagnostic effectiveness, however, is advanced MRI techniques often provide more definitive macrostructural, primarily dependent upon the skill and experience of the operator and microstructural, and functional imaging information. interpreter. Also, US requires a window or path unimpeded by bone or Journal of Perinatology 2001; 21:44±60. air for cranial and spinal imaging. Probably the most important uses of US are (1) fetal and neonatal screening, (2) screening of the who cannot be examined in the department (e.g., premature neonate with intracranial hemorrhage, ECMO, intrao- INTRODUCTION perative), (3) when important adjunctive information is quickly In this presentation, current and advanced neuroimaging needed (e.g., cystic versus solid, vascularity, vascular flow, e.g., technologies are discussed along with guidelines for utilization and Doppler Ðsee Figure 1, or increased intracranial pressure), and principles of imaging diagnosis in fetal, perinatal, and neonatal (3) for real-time guidance and monitoring of invasive diagnostic brain abnormalities. This includes pattern of injury and timing or therapeutic surgical and interventional procedures. issues with special emphasis on neurovascular and In the last few years, advances in US techniques have continued to differential diagnosis. In the causative differentiation of static improve at a dramatic pace.1±11 The development of high-resolution (e.g., ÐCP) from progressive transducers, improvements in color Doppler signal processing, and encephalopathies, specific disease categories and gestational timing new scanning techniques have significantly improved our ability to are addressed (Table 1). These include developmental abnormal- visualize structural and vascular abnormalities in the neonatal brain. ities, trauma, neurovascular disease, infections and inflammatory Examples are the mastoid view to better visualize the posterior fossa, processes, and metabolic disorders. Although a rare but important power Doppler and (TCD) to evaluate cause of progressive perinatal , neoplastic processes intracranial hemodynamics [e.g., resistive indices (RI) Ðsee are not considered in detail here. Figure 1], and the graded fontanelle compression Doppler technique to evaluate . Another recent advance in US technology is the development of vascular US contrast agents to amplify reflected NEUROIMAGING TECHNOLOGIES AND GENERAL sound waves. Potential applications include the detection of slow flow UTILIZATION and the assessment of organ perfusion. Increased sensitivity and

Imaging modalities may be classified as structural or functional.1±4 specificity also may soon be provided by advances in computerized Structural imaging modalities provide spatial resolution based analysis of textural features. primarily on anatomic or morphologic data. Functional imaging Computed tomography (CT) is also primarily a structural imaging modality that has some functional capabilities (e.g., CT ).1 ± 4,6 ± 8,12,13 Although using ionizing radiation, current- generation CT effectively collimates and restricts the X-ray exposure Lucile Salter Packard Children's Hospital, Stanford University Medical Center, 725 Welch Road, Palo Alto, CA 94304. to the immediate volume of interest. Direct imaging is usually restricted to the axial or coronal plane (Figures 2 and 3). Address correspondence and reprint requests to Patrick D. Barnes, MD, Lucile Salter Packard Children's Hospital, Stanford University Medical Center, 75 Welch Road, Palo Alto, CA 94304. Reformatting from thin axial sections to other planes (e.g., coronal

Journal of Perinatology 2001; 21:44 ± 60 # 2001 Nature Publishing Group All rights reserved. 0743-8346/01 $17 44 www.nature.com/jp Neuroimaging of Fetal and Neonatal Brain Injury Barnes

Table 1 Continued Table 1 Classification of CNS Abnormalities by Gestational Timing Modified from van der Knaap and Valk,34 and Wolpert and Barnes75 I. Disorders of dorsal development (3-4 wk) *Often require MRI for definitive diagnosis. Cephaloceles or sagittal) is the alternative. Projection scout images may provide Chiari malformations information similar to plain films but with less spatial resolution. CT Spinal dysraphism* of the pediatric CNS is usually done using either the conventional or Hydrosyringomyelia the helical/spiral technique. CT requires sedation in and II. Disorders of ventral neural tube development (5-10 wk) young children more often than does US but less often than MRI. The Holoprosencephalies neonate or very young infant, however, may be examined while Agenesis septum pellucidum asleep after a feeding or during a nap. CT occasionally needs Optic and olfactory hypoplasia/aplasia* intravenous iodinated contrast enhancement, and sometimes Pituitary-hypothalamic hypoplasia/aplasia* cerebrospinal (CSF) contrast opacification. High-resolution bone /aplasia and soft-tissue algorithms are important for demonstrating fine Dandy Walker spectrum anatomy (e.g., base). Advances in computer-display Craniosynostosis technology include image fusion, two-dimensional reformatting, three-dimensional volumetric and reconstruction methods, seg- III. Disorders of migration and cortical organization (2±5 mo) mentation, and surface-rendering techniques. These high-resolution * display techniques are used for CT angiography and , Neuronal heterotopia* craniofacial and spinal imaging for surgical planning, and for Agyria/* stereotactic image guidance of radiotherapy, interventional, and * neurosurgical procedures. Agenesis The role of CT has been redefined in the context of accessible and reliable US and MRI.2±4 US is the procedure of choice for IV. Disorders of neuronal, glial, and mesenchymal proliferation, primary imaging or screening of the brain and spinal neuraxis in differentiation, and histiogenesis (2±6 mo) the neonate and young infant. When US does not satisfy the clinical Micrencephaly inquiry, or an acoustic window is not available, then CT becomes the primary modality for brain imaging in children, especially in acute or emergent presentations. This is especially important for Aqueductal anomalies* acute neurologic presentations. In these situations, CT is primarily Cortical dysplasias* used to screen for acute or subacute hemorrhage (see Figure 2), Neurocutaneous * edema (see Figure 3), herniation, fractures, hypoxic±ischemic Vascular anomalies injury, focal infarction, hydrocephalus, tumor mass, or abnormal Malformative tumors collection (e.g., pneumocephalus, abscess, empyema). Other Arachnoid primary indications for CT include the evaluation of bony or air- space abnormalities of the skull base, cranial vault, orbit, paranasal V. Encephaloclastic processes ( >5±6 mo) sinuses, facial bones, and the temporal bone. Additionally, CT is the definitive procedure for detection and confirmation of calcification. It is also important in the bony evaluation of a localized spinal Multicystic encephalopathy column abnormality (e.g., trauma). Contraindications to CT in Encephalomalacia childhood are unusual, particularly with the proper application of Leukomalacia Hemiatrophy radiation protection, the appropriate use of nonionic contrast Hydrocephalus agents, the proper administration of sedation or anesthesia, and the Hemorrhage use of vital monitoring. Infarction When CT is used, intravenous enhancement for pool effect (e.g., CT angiography) or blood±brain barrier disruption is VI. Disorders of maturation (7 mo±2 yr) additionally recommended for the evaluation of suspected or known Hypomyelination* vascular malformation, infarction, neoplasm, abscess, or empye- Delayed myelination* ma.2±4 Enhanced CT may help evaluate a mass or hemorrhage of Dysmyelination* unknown etiology and identify the membrane of a chronic subdural Demyelination* collection (e.g., child abuse). By identifying the cortical , Cortical dysmaturity enhanced CT may distinguish prominent low-density subarachnoid

Journal of Perinatology 2001; 21:44 ± 60 45 Barnes Neuroimaging of Fetal and Neonatal Brain Injury

Figure 1. US with Doppler in a term newborn with acute±subacute profound HIE/HIRE. Sagittal US image at top of figure shows nonspecific echogenicity. Doppler sampling of the middle cerebral gives the cerebral arterial pulsatility profile at the bottom of the figure and an RI of 0.51 consistent with the postasphyxic hyperemic phase of HIE/HIRE. collections (benign extracerebral collections or benign external differentiate infarction from neoplasm or abscess, serve as an hydrocephalus of infancy) from low-density subdural collections indicator of disease activity, for example, in degenerative or (e.g., chronic subdural hematomas or hygromas). It also may help inflammatory disease and vasculitis, or provide a high-yield guide for stereotactic or open biopsy. Ventricular or subarachnoid CSF- contrast opacification may further assist in evaluating or confirming CSF compartment lesions or communication (e.g., arachnoid or ventricular encystment). As a rule, and except for suppurative infection, MRI is the preferred alternative to contrast-enhanced CT in the circumstances just enumerated. (NM) is primarily a functional imaging technology.2±4 NM involves imaging of the biologic distributions of administered radioactive pharmaceuticals. Whereas positron emis- sion tomography (PET) has the unique ability to provide specific metabolic tracers (e.g., utilization and ) the wider availability, relative simplicity, and rapid technical advancement of single photon emission computed tomography (SPECT) allows more practical functional assessment of the pediatric CNS. Clinical and investigative applications of these technologies at this time include the assessment of brain development and maturation, focus localization in refractory childhood (e.g., ictal perfusion SPECT, interictal PET), assessment of tumor progression versus treatment effects in childhood CNS neoplasia (perfusion and thallium SPECT, 18FDG-PET), the evaluation of occlusive cerebrovascular disease for surgical revascularization (e.g., perfusion SPECT), the diagnosis of (perfusion SPECT), the use of brain-activation techniques (e.g., perfusion SPECT, PET) Figure 2. CT in term newborn with parturitional trauma. Right frontal, in the elucidation of childhood cognitive disorders, the assessment of temporal, and peritentorial high-density subdural hemorrhage is shown CSF kinetics (e.g., in hydrocephalus, CSF leaks), and spinal column (arrows). screening (skeletal SPECT).2±4

46 Journal of Perinatology 2001; 21:44 ± 60 Neuroimaging of Fetal and Neonatal Brain Injury Barnes

and ``real-time'' MRI guided surgical and interventional procedures. Although, in general, MRI is more expensive than US or CT, it is less expensive than the more invasive modalities such as angiography, which more often requires anesthesia. The role of MRI

Figure 3. CT in a term newborn with acute±subacute profound HIE/ HIRE. There are bilaterally diffuse cerebral low densities with loss of gray± differentiation. Mixed high and low densities are present within the and thalami (arrows).

Magnetic resonance imaging (MR, MRI) is both a structural and functional imaging modality.2±4 MRI uses magnetic fields and radio waves. It is one of the less invasive or relatively noninvasive imaging technologies. Furthermore the MRI signal is exponentially derived from multiple parameters (e.g., T1, T2, proton density, T2*, proton flow, proton relaxation enhancement, chemical shift, magnetization transfer, and molecular diffusion) (Figures 4±14). MRI also employs many more basic imaging techniques than other modalities (e.g., spin echo, inversion recovery, gradient echo, and chemical shift imaging methods). Advancing MRI capabilities have further improved its sensitivity, specificity, and efficiency.2±4 These include the fluid attenuation inversion recovery technique (FLAIR), suppression short TI inversion recovery imaging (STIR), and magnetization transfer imaging (MTI) for increased structural resolution. Fast and ultrafast MRI techniques (fast spin echo, fast gradient echo, echo planar imaging) have also been developed to reduce imaging times, improve structural resolution, and provide functional resolution. Important applications include MR vascular Figure 4. MRI in preterm neonate with acute HIE/HIRE and PVL. (A) T2 imaging (MR angiography and venography ÐMRA) and image shows nonspecific cerebral white matter hyperintensities. (B) ADC perfusion MRI, diffusion imaging (DI), CSF flow and brain/cord map shows abnormally restricted diffusion as hypointensities throughout motion imaging, brain activation techniques, and MR spectroscopy the periventricular white matter (arrows) as contrasted against the normal (MRS). Fast and ultrafast imaging techniques are also being used hyperintensities of the lateral ventricular CSF (asterisk) and immature for fetal/obstetrical imaging, morphometrics, treatment planning, white matter.

Journal of Perinatology 2001; 21:44 ± 60 47 Barnes Neuroimaging of Fetal and Neonatal Brain Injury

STIR technique suppresses fat signal to provide improved conspicuity of water containing lesions in regions where fat dominates (e.g., orbit, head and neck, spine). The MTI method suppresses background tissues and increases conspicuity for vascular flow enhancement (e.g., MRA) and gadolinium enhancement. MRI is the imaging modality of choice in a number of clinical situations.2±4 These include developmental delay (e.g., static encephalopathy versus neurodegenerative disease); unexplained (especially focal), unexplained neuroendocrine disorder, or unexplained hydrocephalus; the pretreatment evaluation of neoplastic processes and the follow-up of tumor response and treatment effects; suspected infectious, postinfectious, and other inflammatory or noninflam- matory encephalitides (e.g., , postinfectious demyelina- tion, vasculitis); migrational and other submacroscopic dysgeneses (e.g., cortical dysplasia); neurocutaneous syndromes (e.g., 1, tuberous sclerosis); intractable or refractory epilepsy; vascular diseases, hemorrhage, and the sequelae of trauma. MRI frequently offers greater diagnostic specificity than does CT or US for delineating vascular and hemorrhagic processes. This includes the clear depiction of vascular structures and abnormalities based on proton flow parameters and software enhancements not requiring the

Figure 5. MRI in a young infant with chronic PVL. FLAIR image shows abnormal periventicular hyperintensities (arrows) contrasted against the normally suppressed, hypointense CSF intensities of the and subarachnoid spaces. in imaging of the developing CNS is defined by its superior sensitivity and specificity in a number of areas compared to US and CT.1±4,6 MRI has also redefined the roles of invasive procedures like myelography, ventriculography, cisternography, and angiography. MRI provides multiplanar imaging with equivalent resolution in all planes without repositioning the patient. Bone does not interfere with soft-tissue resolution, although metallic objects often produce signal void or field-distortion artifacts. Some ferromagnetic or electronic devices (e.g., ferrous aneurysm clips and pacemakers) pose a hazard, and MRI is usually contraindicated in these cases. MRI is not as fast as US or CT, and patient sedation or anesthesia is often required in most infants and younger children, because image quality is easily compromised by motion. MRI may not be as readily accessible to the pediatric patient as is US or CT and may not be feasible in emergencies or for intensive care cases unless magnet-compatible vital monitoring and support is available. This is particularly important for the neonate. MRI demonstrates superior sensitivity and specificity in a number of circumstances, particularly with the addition of new structural and functional techniques such as FLAIR, STIR, MTC, DI, PMRI, and MRS.2±4 The FLAIR sequence attenuates the signal from flowing Figure 6. MRI in a term newborn with acute±subacute partial prolonged water (i.e., CSF) and increases the conspicuity of nonfluid water HIE/HIRE and borderzone cerebral hemispheric injury. T2 image shows containing lesions lying in close approximation to the CSF filled abnormal bilateral frontal and temporoparietal cortical and subcortical subarachnoid and ventricular spaces (see Figures 5 and 7). The hyperintensities (arrows).

48 Journal of Perinatology 2001; 21:44 ± 60 Neuroimaging of Fetal and Neonatal Brain Injury Barnes

Figure 7. MRI in term profound HIE/HIRE. (A) In the hyperacute±acute phase, ADC map shows abnormal bilateral hypointensities (restricted diffusion) involving the basal ganglia and thalami (arrows).(B) In the acute±hyperacute phase, T1 image shows abnormal bilateral hyperintensities of the putamina and thalami (arrows). (C) In the chronic phase, FLAIR image shows abnormal hyperintensities of the putamina and ventrolateral thalami (arrows). injection of contrast agents (e.g., MRA). MRA techniques may tion and staging of hemorrhage and clot formation according to the additionally be used to differentiate arterial from venous occlusive evolution of hemoglobin breakdown. MRI is often reserved for more disease.1±4 Using gradient recalled echo (GRE, GE) magnetic definitive evaluation of hemorrhage and as an indicator or guide for susceptibility sequences, MRI also provides more specific identifica- angiography in a number of special situations. MRI may be used to

Journal of Perinatology 2001; 21:44 ± 60 49 Barnes Neuroimaging of Fetal and Neonatal Brain Injury

evaluate an atypical or unexplained intracranial hemorrhage by distinguishing hemorrhagic infarction from hematoma and by distinguishing among the types of vascular malformations (e.g., cavernous malformation versus AVM). MRA may obviate the need in some cases of vascular malformation for conventional angiography in the follow-up of surgery, interventional treatment, or radio- surgery. In the evaluation of intracranial vascular anomalies (e.g., vascular malformation, aneurysm), MRI may identify otherwise unsuspected prior hemorrhage (i.e., hemosiderin).2±4 When CT demonstrates a nonspecific focal high density (calcification versus hemorrhage), MRI may provide further specificity, for example, by distinguishing an occult vascular malformation (e.g., cavernous malformation) from a neoplasm (e.g., glioma).It may further assist US or CT in differentiating benign infantile collections (i.e., external hydrocephalus) from subdural hematomas (e.g., in child abuse). MRI often also provides definitive evaluation of muscular and cutaneous vascular anomalies (i.e., hemangiomas, vascular malformations) that arise in parameningeal locations (e.g., head and neck, paraspinal) and extend to involve the CNS directly or are associated with other CNS vascular or nonvascular abnormalities. MRS offers a noninvasive in vivo approach to biochemical Figure 8. MRI in term combined partial prolonged and profound HIE/ analysis.2 ± 4,14 ± 19 Furthermore, MRS provides additional quantitative HIRE with chronic cystic encephalomalacia. T2 image shows bilateral information regarding cellular metabolites because signal intensity is extensive septated hyperintense , or cavities, of the cerebral hemispheres linearly related to steady-state metabolite concentration. MRS can (small arrows) along with abnormal basal ganglia and thalamic detect cellular biochemical changes before the detection of hypointensities (large arrows). morphologic changes by MRI or other imaging modalities. MRS may

Figure 9. MRS in a term newborn with acute±subacute HIE/HIRE. The spectrum shows an abnormally elevated and inverted lactate doublet peak (L), a diminished NAA peak (N), elevated glutamate/glutamine peak (G), and normal creatine (Cr), choline (Ch), and myoinositol (I) peaks.

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relatively short acquisitions to detect low-concentration metabolites in healthy and diseased tissues. Phosphorus-31 spectroscopy has also been developed for pediatric use. Currently, MRS has been primarily used in the assessment of brain development and maturation, perinatal brain injury (see Figure 9), childhood CNS neoplasia versus treatment effects, and metabolic and neurodegenerative disorders. PMRI is currently being used to evaluate cerebral perfusion dynamics through the application of a dynamic contrast-enhanced T2*-weighted MR imaging technique.2 ± 4,20 This new technique is undergoing further development to qualitate and quantitate normal and abnormal cerebrovascular dynamics of the developing brain by analyzing hemodynamic parameters including relative cerebral blood volume, relative cerebral blood flow, and mean transit time, all as complementary to conventional MR imaging. It is of limited utilization in the neonatal period because of venous access and safety issues. Current and advanced applications of this and other PMRI techniques not requiring contrast administration (e.g., flow- activated inversion recovery ÐFAIR, blood oxygen level determination ÐBOLD) include the evaluation of ischemic cerebrovascular disease (e.g., ±ischemia, moyamoya, sickle disease), the differentiation of tumor progression from treatment effects, and brain activation imaging,.2±4 One of the most active areas of research is the localization of brain activity, an area previously dominated by NM including single photon emission computed

Figure 10. Advanced MRI techniques. (A) Coronal fMRI image (BOLD technique) shows hyperintensity (arrow) associated with localized increase in cerebral blood flow associated with voluntary activation (contralateral finger tapping) of the primary motor cortex. (B) Coronal white matter map derived from diffusion tensor MRI techniques shows the fiber tracts of the genu of the corpus callosum and the internal capsule (arrows). therefore provide further insight into both follow-up assessment and prognosis. With recent advances in instrumentation and methodol- ogy, and utilizing the high inherent sensitivity of hydrogen-1, Figure 11. Ultrafast MRI of early preterm fetus. Coronal image shows single-voxel and multivoxel proton MRS is now carried out with bilateral asymmetric hypointense germinal matrix hemorrhages (arrows).

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focal ischemic injury. The ADC of water is reduced within minutes of an ischemic insult and is progressive within the first hour. Abnormal signal is demonstrated on DI at a time when conventional imaging is negative and likely reflects cellular injury (e.g., necrosis). Further investigation is underway regarding the roles of DI, PMRI, and MRS in the early diagnosis and treatment of potentially reversible ischemic injury. Motion sensitive MRI techniques are not only used to evaluate vascular flow (e.g., MRA) and perfusion, but may also be used to demonstrate the effect of pulsatile cardiovascular flow on other fluid tissues (e.g., CSF) and on nonfluid tissues such as the brain and . Using cardiac or pulse gating, these MRI techniques may be used to evaluate, preoperatively and postoperatively, abnormalities of CSF dynamics (e.g., hydrocephalus, hydrosyringomyelia), as well as abnormalities of brain motion (e.g., ), and spinal cord motion (e.g., tethered cord ).2±4

GUIDELINES AND PRINCIPLES OF IMAGING DIAGNOSIS Developmental Abnormalities Congenital abnormalities of the CNS may be developmental or acquired in origin and result from defective formation, postforma- tional destruction, or disordered maturation.2 ± 4,28 ± 34 These are probably best classified according to gestational timing (Table 1)

Figure 12. MRI of a young infant with diffuse cortical dysgenesis associated with early gestational cytomegaloviral infection. T2 image shows a bilaterally serrated, hypointense cortical ribbon consistent with polymicrogyria (arrows) along with ventriculomegaly. tomography (SPECT) and positron emission tomography (PET). Functional MRI (fMRI) is the terminology often applied to brain activation imaging in which local or regional changes in cerebral blood flow are displayed that accompany stimulation or activation of sensory (e.g., visual, auditory, somatosensory), motor, or cognitive centers.2±4 fMRI is providing important information regarding the spatial distribution of motor and cognitive function and functional impairment (Figure 10). Also, it may serve as a guide for safer and more effective interventions including microneurosurgery or conformal radiotherapy, for example, the ablation of tumors, vascular malformations, and foci. Using echo planar or line-scan spin echo techniques, diffusion imaging (DI) provides information based upon differences in the rate of diffusion of water and is especially sensitive to intracellular changes.2 ± 4,21 ± 27 The rate of diffusion, or apparent diffusion coefficient (ADC), is higher for free or pure water than for macromolecular bound water. The ADC varies according to the microstructural or physiologic state of a tissue. Current clinical applications include the assessment of brain maturation, the evaluation of acute ischemic injury (see Figures 4 and 7), and the analysis of the sequelae of injury (see Figure 10). A particularly Figure 13. MRI of kernicterus in a young infant. T2 image shows important application of DI is in the early detection of diffuse and bilateral hyperintensities (arrows).

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complex macrostructural CNS anomalies for diagnosis, treatment, prognosis, and .2 ± 4,34 In fact, ultrafast MRI techniques are being increasingly used prenatally to evaluate for fetal CNS abnormalities in at-risk or as detected by obstetrical US (Figure 11).2 ± 4,35 ± 38 Furthermore, MRI is often indicated if more specific treatment is planned beyond simple shunting of hydrocephalus. Intraoperative guidance may be provided by real time and Doppler US. Patients with craniosynostosis are initially evaluated with plain films. Those with multiple suture involvement, especially when associated with craniofacial syndromes, often require more extensive evaluation including three-dimensional CT, CT venogra- phy, MRI, and MR venography (jugular venous stenoocclusive disease with collateralization). MRI is often required to structurally delineate the more subtle macrostructural anomalies arising as disorders of migration and cortical organization (category III Ð Figure 12) or as disorders of proliferation, differentiation, and histiogenesis (category IV).2 ± 4,34 The perfusional and metabolic characteristics of these anomalies (e.g., focal cortical dysgenesis, hemimegalencephaly) may be investigated with SPECT and PET, respectively, in children with medically refractory partial epilepsy who Figure 14. Diffusion MRI of a term newborn with congenital disease are candidates for surgical ablation. For added precision, the SPECT and multifocal embolic cerebral infarction. ADC map shows multiple or PET data may be fused with the MRI data to provide a higher abnormal hypointense foci (restricted diffusion) within arterial distribu- resolution spatial display of the functional information. MRS, DI, tions (arrows). and PMRI with fMRI are also contributing to the evaluation and treatment of these patients. MRI is now the preferred modality for the and include disorders of dorsal and ventral neural tube formation; screening and definitive evaluation of the dysgenetic, neoplastic, and disorders of neural, glial, and mesenchymal formation; neuroclastic vascular manifestations of the neurocutaneous syndromes. After processes (i.e., encephaloclastic, myeloclastic); and disorders of initial screening with US or CT, MRI is also considered the primary maturation (i.e., myelination and cortical maturation). technology for treatment planning and follow-up of vascular Developmental anomalies readily identified by US (prenatal or malformations and developmental tumors.2±4 Although arachnoid postnatal) or CT are the gross formational macrostructural defects of cysts are often readily delineated by US or CT, MRI may be necessary categories I±IV and the gross neuroclastic macrostructural lesions of for confirmation (i.e., to exclude solid tumor) and for surgical category V (Table 1).2 ± 4,34 This is especially true for those planning. FLAIR or DI may readily distinguish an arachnoid cyst abnormalities involving the or containing CSF. from other lesions (e.g., dermoid±epidermoid, fibrillary astro- These include hydrocephalus, hydranencephaly, , cytoma). Maturation (i.e., myelination and cortical maturation) absent septum pellucidum, agenesis of the corpus callosum, and disorders of maturation (category VI) may be precisely assessed porencephaly, open schizencephaly, the Dandy±Walker±Blake only by MRI.2 ± 4,39 ± 41 The MRI findings, however, are often nonspecific spectrum, arachnoid cysts, and cephaloceles. US may not clearly regarding causation particularly in the first year of life because of the distinguish between hydranencephaly (absent cerebral mantle) and watery character of the immature brain. MRS may add specificity to severe hydrocephalus (attenuated cerebral mantle). Other gross the diagnostic evaluation of these infants. macrostructural anomalies often delineated by US or CT include Chiari II malformation, lissencephaly, and vascular malformations Neurovascular Disease such as the Galenic malformation. In fact, any lesion detected by US, Neurovascular disease characteristically presents as an acute particularly a cystic one, should be examined with Doppler to neurologic event. However, a recently discovered but fixed deficit determine if it is vascular in nature. Neuroclastic processes are those (e.g., hemiplegia, spastic diplegia, ) may be the first destructive lesions of the already formed CNS and may result from a indication of a remote prenatal or perinatal neurovascular injury. variety of prenatal or perinatal insults including hypoxia±ischemia Imaging assists in the clinical evaluation and differentiation of and infection (Table 1).2 ± 4,34 MRI may occasionally demonstrate hypoxia±ischemia, hemorrhage, and occlusive vascular disease subtle macrostructural abnormalities not revealed by US or CT (e.g., (Tables 2±4).1±4,6 periventricular leukomalacia). MRI is important when the US or CT fails to satisfy the clinical Hypoxic±ischemic injury and sequelae. In general, the pattern of investigation. MRI often provides a more complete delineation of injury associated with hypoxic±ischemic±reperfusion encephalo-

Journal of Perinatology 2001; 21:44 ± 60 53 Barnes Neuroimaging of Fetal and Neonatal Brain Injury

Table 2 Imaging Patterns of Diffuse or Global Hypoxic±Ischemic associated with periventricular borderzone/watershed injury to the Encephalopathy (HIE)* preterm fetus or neonate (e.g., 27±35 weeks GA Ðsee Figures 4 Hemorrhage and 5), or cortical and subcortical border zone/watershed cerebral Germinal matrix Ðintraventricular hemorrhage injury during term gestation (e.g., 37±42 weeks GA Ðsee Figure Ðintraventricular hemorrhage 6). A combined partial prolonged HIE/HIRE pattern (cortical/ Subarachnoid hemorrhage subcortical/periventricular) may be seen in the late preterm to the early midterm GA (e.g., 36±39 weeks). Fetal or neonatal brain Partial HIE injury may also occur with more profound HIE/HIRE insults (e.g., Preterm: periventricular leukomalacia anoxia or circulatory arrest) and involve the thalami, basal ganglia Term/postterm: cortical/subcortical injury (borderzone, watershed, para- (especially putamina), brain stem (especially midbrain), hippo- sagittal) campi, paraventricular white matter, and perirolandic cortex (see Intermediate: combined or transitional pattern Ulegyria Figure 7). This type of injury may also vary with GA (thalamic greater than putaminal involvement in the preterm GA; putaminal, Profound HIE hippocampal, and paracentral injury more common in the term Thalamic and basal ganglia injury GA). Combined patterns (i.e., partial prolonged plus profound HIE/ Brain stem injury HIRE) are also common (see Figure 8).1 ± 4,6,12,27,42 ± 52 Hippocampal injury US, CT, or MRI (e.g., DI) may demonstrate evolving edema, Cerebral white matter injury necrosis, or hemorrhage in the hyperacute, acute, and subacute Paracentral injury phases.1 ± 4,6,12,27,42 ± 52 There may be subarachnoid hemorrhage, germinal Global injury (prolonged profound) matrix and intraventricular hemorrhage (e.g., premature fetus or neonate), choroid plexus/intraventricular hemorrhage (e.g., term Combined partial and prolonged HIE fetus or neonate), or (e.g., hemorrhagic *Depends on gestational age, chronological age, duration and severity of the insult. infarction). The hemorrhage usually appears hyperechoic on US and high density on CT in the acute to subacute phases (range 3 hours to 7 days) unless there is associated coagulopathy (see Figure 2). With pathy (HIE/HIRE), or other insults, varies with severity and evolution and resolution, the hemorrhage becomes isoechoic to duration of the insult as well as with the gestational age (GA) of the hypoechoic and isodense to low density. MRI may offer more fetus or infant at the time of the insult (Table 2).1 ± 4,6,12,42 ± 52 Different specific characterization of the hemorrhagic component with regard brain structures are more vulnerable than others to the different types to timing (Table 3). The edema (range 1±5 days) of of HIE/HIRE insults (e.g., partial prolonged, profound, combined) nonhemorhagic HIE/HIRE often peaks between 2 and 4 days after the at different stages of brain development (e.g., formational versus insult(s).1 ± 4,6,12,27,42 ± 52 US may show hyperechogenicity (see Figure 1), postformational GA, preterm versus term versus full term versus CT may show hypodensities with decreased gray±white matter postterm GA). Brain tissues in the arterial borderzones or watersheds, differentiation (see Figure 3). In the early phases of the injury, the brain tissues with high metabolic demands, mature or actively neuroimaging findings are often nonspecific as to specific causation maturing tissues, and tissues with higher concentrations of (e.g., HIE/HIRE versus infection versus metabolic disorder).1 ± 4,6,52 neuroexcitatory amino acids, are particularly vulnerable to HIE/ MRI or US may provide greater sensitivity and specificity depending HIRE and to other insults (e.g., , trauma, infection, upon the techniques used and the timing of the imaging (see seizures).1 ± 4,6,27,52 Prenatal or perinatal partial prolonged HIE/HIRE Figures 1±9). Conventional MRI may show characteristic T1- (e.g., one or more insults of hypoxia/hypoperfusion) may be hypointensities/T2-hyperintensities (12±48 hours), followed by

Table 3 MRI of Intracranial Hemorrhage and Thrombosis*

Stage Biochemical form Site T1-MRI T2-MRI Hyperacutey ( +edema) [ <12 hr] Fe II oxyHb Intact RBCs Iso-Low I High I Acute ( +edema) [1±3 d] Fe II deoxy Hb Intact RBCs Iso-Low I Low I Early subacute ( +edema) [3±7 d] Fe III metHb Intact RBCs High I Low I Late subacute ( Àedema) [1±2 wk] Fe III metHb Lysed RBCs (extracellular) High I High I Early Chronic ( Àedema) [ >2 wk] Fe III transferrin Extracellular High I High I Chronic (cavity) Fe III ferritin and hemosiderin Phagocytosis Iso-low I Low I

*Modified from Wolpert and Barnes;75 Kleinman and Barnes;60 does not include influence of fetal Hb. yCT more sensitive and more specific than MRI or US for hyperacute/acute hemorrhage in all compartments. RBCs, red blood cells; I, signal intensity; +, present; À, absent; Hb, hemoglobin; Fe II, ferrous; Fe III, ferric; Iso, isointense.

54 Journal of Perinatology 2001; 21:44 ± 60 Neuroimaging of Fetal and Neonatal Brain Injury Barnes

T1-hyperintensities (about 3 days), and then T2 hypointensities developmental venous anomalies, and ).1 ± 4,54,57 (about 6 days).45 DI may be abnormal before conventional MRI and Aneurysms are exceedingly rare in children but may be show restricted diffusion with decreased ADC as increased intensity on developmental, associated with a syndrome (e.g., ), diffusion images and decreased intensity on ADC maps (see Figures 4 or related to trauma (e.g., dissection) or infection (i.e., mycotic and 7).2 ± 4,21 ± 27 Doppler with resistive indices (e.g., RI <60) or MRS aneurysm). The vein of Galen malformations are subclassified as (e.g., elevated lactate, elevated glutamate, elevated lipids, decreased choroidal, mural, and AVM types. They rarely hemorrhage and more N-acetylaspartate ÐNAA) may provide additional early indicators commonly present in infancy with congestive heart failure, cerebral of timing and outcome (see Figures 1 and 9).1 ± 11,14 ± 19,53 The more ischemia, or hydrocephalus.57 subtle ischemic PVL lesions (e.g., cystic phase) are occasionally US or CT remains the primary imaging choice in acute better delineated by US [2±6 weeks after insult(s)] than by CT or situations 1 ± 4,6 ± 8,52,56 and the imaging findings are described in the MRI, in which the density and intensity character of immature white previous section (see Figure 2). Acute intracranial hemorrhage, matter often obscures the injury. However, CT and MRI often show particularly subarachnoid, is most specifically diagnosed by CT and gray matter injury better than US.1 ± 4,6 ± 8 Further developments of for CSF analysis. Although FLAIR may identify PMRI, DI, and MRS may further improve diagnostic sensitivity and subarachnoid hemorrhage as hyperintensity and GRE/GE may specificity. In fact, DI has demonstrated restricted diffusion in the identify acute hemorrhage in any location as hypointensity, MRI acute phase of PVL when US, CT, and conventional MRI were often provides better specificity beyond the acute phases (Table 3). negative or nonspecific (see Figure 4).47 Such advances may Hemorrhagic manifestations and sequelae of HIE/HIRE in the facilitate the early institution of neuroprotective measures to treat premature infant readily detected by US include germinal matrix potentially reversible primary injury (necrosis, ) and hemorrhage, intraventricular hemorrhage, periventricular hemor- secondary injury (transneural degeneration) in HIE/HIRE.27 These rhagic infarction, and posthemorrhagic hydrocephalus.56 Choroid advanced MRI techniques may also assist in distinguishing HIE/ plexus hemorrhage and hemorrhagic infarction in the term infant HIRE from other causes of encephalopathy including other common are also easily demonstrated. Portable US may effectively delineate metabolic disorders (e.g., hypoglycemia, hyperbilirubinemia Ð the potential hemorrhagic or ischemic sequelae of ECMO. Although Figure 13), nonmetabolic conditions (e.g., infection), and other CT has been more reliable, high resolution US using transfontanelle rarer disorders (e.g., inborn metabolic errors). and transcranial approaches, including the mastoid view, may now The long-term result of HIE/HIRE is a static encephalopathy accurately detect extracerebral hemorrhage (subdural and sub- (i.e., CP) and imaging may demonstrate injury in the chronic arachnoid) and posterior fossa collections (cerebellar or subdural). phases [ >14±21 days after the insult(s) ] including porencephaly, Color Doppler US, MRA, and CTA are all able to identify and hydranencephaly, , chronic periventricular leukomalacia, distinguish the types of Galenic malformations, and provide follow- cystic encephalomalacia, , or mineralization in a characteristic up. Angiography is more specifically directed to the definitive distribution as described above (see Figures 5±8).1 ± 4,6,12,27,42 ± 52 The interventional or surgical management of these and other vascular chronic changes are best demonstrated by CT or MRI. In general, for anomalies.57 Real-time, Doppler US provides intraprocedural pattern of injury and timing purposes, two pieces of imaging guidance and monitoring. The long-term sequelae of intracranial evidence are optimally desired: (1) late imaging, and preferably hemorrhage are best demonstrated by CT and MRI (e.g., MRI, beyond 2±3 years of age when the brain is greater than 90% hydrocephalus, atrophy, encephalomalacia, porencephaly, calcifica- mature (no more water of immaturity) to get a final, permanent tion, hemosiderin). injury pattern for causative etiology and GA timing, and (2) early postnatal (and/or prenatal) serial imaging to evaluate evolution in Occlusive neurovascular disease and sequelae. Occlusive the acute, subacute, and chronic phases so that timing as to ``day neurovascular disease in the child may be arterial or venous in origin range'' relative to the perinatal and peripartum periods may be and typically results in focal or multifocal lesions within the assessed.1 ± 4,6,12,27,42 ± 52 distribution of the occluded vessel or vessels (Table 4).1 ± 4,6,52 ± 55 Arterial occlusive disease may be partial or complete and due to Intracranial hemorrhage and sequelae. Intracranial hemorrhage stenosis, thrombosis, or embolization. The result may be ischemic may result from parturitional trauma (see Figure 2), HIE/HIRE, a infarction or hemorrhagic infarction followed by atrophy. Arterial coagulopathy (e.g., thrombocytopenia, disseminated intravascular occlusive disease may occur as a prenatal or perinatal event (emboli coagulopathy ÐDIC, extracorporal membrane oxygenation Ð of placental origin, fetal heart, or involuting fetal vessels), as a ECMO), vasoocclusive disease (e.g., venous thrombosis), or may be complication of infection (e.g., ), with congenital heart idiopathic.1 ± 4,6 ± 8,52,54 ± 57 Hemorrhage may occasionally be associated disease (Figure 14), or from a hypercoagulopathy. Other causes with infection (e.g., herpes simplex virus 2). Vascular malforma- include trauma (e.g., dissection), arteriopathies (e.g., moyamoya), tions producing intracranial hemorrhage are rare in the neonate and and metabolic disorders (e.g., mitochondrial cytopathies). Condi- young infant and usually not encountered until later childhood (i.e., tions commonly associated with cortical or dural venous sinus arteriovenous malformationsÐAVM, cavernous malformations, occlusive disease include infection, dehydration, perinatal encepha-

Journal of Perinatology 2001; 21:44 ± 60 55 Barnes Neuroimaging of Fetal and Neonatal Brain Injury

Table 4 Occlusive Neurovascular Disease in the Fetus, Neonate, and Acute myelopathy due to HIE/HIRE, vascular occlusion, Infant hemorrhage, or vascular malformation is extremely rare in the Idiopathic vascular maldevelopment perinatal period. Spinal MRI is the definitive procedure to evaluate Atresia spinal cord infarction or hemorrhage (see section on Trauma). Hypoplasia Spinal angiography is necessary to evaluate for vascular malformation in anticipation of interventional or surgical therapy.2±4 Vasculopathy Familial proliferative Trauma Isoimmune thrombocytopenia With improvements in resolution and the use of additional views (e.g., mastoid view), US may be used as the primary modality for Vasospasm evaluating the newborn with parturitional trauma. CT, however, is Maternal use usually relied upon for delineating scalp and skull injury, Vascular distortion extracerebral hemorrhage (e.g., subarachnoid or subdural Extreme head and neck motion hemorrhage Ðsee Figure 2), posterior fossa hemorrhage, and direct (e.g., contusion) versus indirect (e.g., HIE/HIRE) brain ECMO injury.1 ± 4,6,52,58 ± 62 CT is sufficiently sensitive and specific for acute Emboli hemorrhage and the complications or sequelae of fractures (e.g., Involuting fetal vessels growing fracture, leptomeningeal cyst). Occasionally, skull films Congenital heart disease will demonstrate a skull fracture not shown by CT. MRI is often Catheterized vessels reserved for circumstances in which neurologic deficits persist and the CT is negative or nonspecific. In this situation MRI may reveal Thrombosis lesions such as brain stem infarction, diffuse axonal (shear) Meningitis injury, and cortical contusion, or sequelae such as gliosis, HIE/DIC microcystic encephalomalacia, and hemosiderin deposition. MRI is Dehydration/hypernatremia /DIC often more specific than CT for hemorrhage beyond the hyperacute/ Polycythemia/hyperviscosity acute stage (Table 3). Color Doppler US, contrast-enhanced CT, or S or C deficiency MRI may distinguish external hydrocephalus (dilated subarachnoid Antithrombin III deficiency spaces) from chronic subdural hematomas (e.g., in child abuse) Antiphospholipid antibodies when nonenhanced CT demonstrates nonspecific extracerebral Factor V deficiency collections.2 ± 4,10,11 Furthermore, hemosiderin as demonstrated by MRI is confirmation of a previous hemorrhage. In children with atypical Thromboembolic intracranial hemorrhage (hemorrhage out of proportion to the history Placental vascular anastomoses of trauma), MRI may detect an existing vascular malformation, show Cotwin fetal death a hemorrhagic neoplasm, or suggest child abuse (e.g., interhemis- Fetofetal transfusion pheric , hemorrhages of different age). Initial evaluation of spine trauma (e.g., fracture/dislocation) HIE/thromboembolism may include plain films, US, CT (including reformatting), or rarely Modified from Volpe JJ76 SPECT. Radiologic abnormality, changing clinical signs, or signs not explained by brain imaging may provide the indication for spinal lopathy, cyanotic congenital heart disease, polycythemia, other MRI.2±4 An existing spinal anomaly or mass should be ruled out. MRI hypercoagulable states, DIC, and trauma. Color Doppler US may be is the procedure of choice to demonstrate acute spinal injury (e.g., used as a noninvasive tool for initial identification and monitoring of intraspinal hemorrhage, cord contusion, cord edema, transection, these infants. MRI may be more sensitive and specific than US or CT brachial plexus injury, ligamentous injury, etc.) and the sequelae of for ischemic infarction, hemorrhagic infarction, and venous spinal injury (e.g., hydrosyringomyelia, cystic myelopathy, myelo- thrombosis.7,8 MRA or CTA may also contribute to the diagnosis of malacia, etc.). arterial or venous occlusion and clarify the need for , particularly when anticoagulation or thrombolysis is Infections and Inflammatory Processes being considered. As mentioned above, PMRI, DI, and MRS are US or CT is often used to delineate CNS infection and the sequelae or contributing to the early diagnosis and timely treatment of ischemic complications that may accompany TORCH (i.e., toxoplasmosis, insults. The long-term sequelae of infarction include atrophy, other [e.g., syphilis], rubella, cytomegalovirus ÐCMV, herpes encephalomalacia, gliosis, mineralization, and porencephaly. These simplex virus ÐHSV2, immunodeficiency virus ÐHIV) are readily shown by follow-up CT or MRI. causes of meningoencephalitis, and neonatal meningitis (e.g., group

56 Journal of Perinatology 2001; 21:44 ± 60 Neuroimaging of Fetal and Neonatal Brain Injury Barnes

B streptococcal, listeria, Gram-negative).1 ± 4,63 ± 65 The imaging pattern imaging findings (e.g., kernicturus Ðsee Figure 13, Zellweger is often asymmetric and progressive. Such findings include disease). MRS contributes to the specific metabolic characterization subarachnoid exudate, ventriculitis, edema, cerebritis, infarction, of these disorders.14 ± 19,53 Stereotactic CT or MRI may serve as a guide hydrocephalus, effusion, empyema, abscess, cystic encephalomalacia, for biopsy. atrophy, gliosis, and calcification. In the absence or nonspecificity of The classification of metabolic diseases may be biochemical, findings on US or CT, MRI may provide more definitive evaluation molecular, genetic, pathologic, or clinical.2 ± 4,66 ± 74 These disorders are (e.g., CMV ÐFigure 12). CT or MRI with intravenous contrast often categorized according to the metabolic defect. Such a enhancement may also be preferred for the diagnosis and follow-up classification includes the lysosomal disorders (e.g., Krabbe), of suppurative collections. Less common but increasingly prevalent peroxisomal defects (e.g., Zellweger), the mitochondrial disorders causes of subacute and chronic CNS inflammation are the (e.g., Leigh, Menkes), organic and amino acidopathies (e.g., granulomatous meningoencephalitic infections (e.g., tuberculosis, nonketotic hyperglycinemia), disorders of carbohydrate metabolism spirochete, fungal, parasitic), particularly in immunocompromised (e.g., glycogen storage disease), liver metabolic disorders, and hosts. miscellaneous. Certain clinical features that assist in directing the Recurrent infectious or noninfectious CNS infection (e.g., initial evaluation of these patients may also provide a basis for meningitis) may require investigation for a ``parameningeal focus'' classification (e.g., in maple syrup urine disease). The (e.g., sinus or mastoid infection, dermal sinus, primitive neurenteric ideal radiologic classification would categorize the diseases by the connection, CSF leak after trauma, dermoid±epidermoid).63 Brain anatomic distribution of the pathologic process using CT and MRI. abscess or empyema may be associated with Gram-negative Unfortunately, most of these conditions affect multiple sites and meningitis (e.g., citrobacter) in the neonate. Suppurative collections considerable overlap in appearance is found. However, a practical related to sinus infection, trauma, surgery, sepsis, the immuno- imaging classification may be based on the predominant areas of compromised state, or uncorrected cyanotic congenital heart disease involvement including the white matter (subcortical, periventricu- primarily occur in older children. Contrast-enhanced CT usually lar), gray matter (cortical, deep), basal ganglia, brain stem, suffices for diagnosis and follow-up. Occasionally, multiplanar T2- , spinal cord, and peripheral nervous system.2 ± 4,66 ± 74 MRI or gadolinium-enhanced T1-MRI is needed to delineate subtle collections for drainage. Contrast-enhanced stereotactic CT or Disorders primarily affecting cortical gray matter. Endogenous intraoperative US may provide direct guidance. metabolic disorders that primarily, or predominately, affect the Plain films or SPECT are recommended for screening of suspected cortical gray matter include the storage diseases that result from spinal column infection (discitis, osteomyelitis).2±4 CT and MRI are lysosomal defects.2 ± 4,66 ± 74 However, these findings are often often needed, however, for definitive diagnosis, treatment planning, nonspecific and the differential diagnosis may include diffuse cortical and follow-up. MR is the procedure of choice for evaluating spinal atrophy due to any number of causes. Other considerations include neuraxis infection and gadolinium enhancement is particularly the end-stage of a static encephalopathy (e.g., post-HIE/HIRE or important for demonstrating suppurative collections (e.g., epidural postinfection), or ``atrophy'' related to chronic systemic disease, abscess). malnutrition, or certain types of therapy (e.g., steroids, chemother- apy, radiation, ). Metabolic Disorders Particularly in the evaluation of developmental delay (e.g., static Disorder primarily affecting deep gray matter. Metabolic disorders encephalopathy versus progressive encephalopathy), MRI is the only may primarily involve the deep gray matter (including modality that can provide an accurate assessment of brain mineralization).2 ± 4,66 ± 74 Those disorders primarily involving the maturation based on myelination and cortical development.2 ± 4,66 ± 74 corpus striatum (i.e., caudate and ) include the The clinical hallmark of a metabolic, toxic, or neurodegenerative mitochondrial disorders, organic and amino acidopathies, juvenile disorder is progressive neurologic impairment in the absence of a Huntington's disease, Wilson disease, and Cockayne's syndrome. CNS tumor or another readily identifiable process (e.g., infection). Those disorders primarily involving the globus pallidus include These disorders may be exogenous and internal (e.g., hypoglycemia, Hallervorden±Spatz disease, the aminoacidopathies, hyperbilirubi- hyperbilirubinemia Ðsee Figure 13) or external (e.g., fetal nemia (see Figure 13), and toxic exposure (e.g., carbon dioxide). alcohol syndrome). The endogenous disorders (e.g., inborn errors of It is unusual to see isolated involvement of the thalami in any of metabolism) are rare and often untreatable. Many are genetic and the metabolic disorders. However, thalamic involvement may be an heredofamilial disorders such that genetic counseling and prenatal early or dominant feature of or GM2 . screening are important when possible. Diagnosis is primarily a It may also be seen in the infantile form of Leigh disease along clinical one and may involve metabolic testing (e.g., enzymatic with extensive brain stem, basal ganglia, and cerebral white matter assays), genetic evaluation, or biopsy of CNS or extra-CNS tissues. involvement. In general, the differential diagnosis, depending on MRI is superior to CT in evaluating disease extent and anatomic the clinical picture and timing of the imaging, may also include distribution. Occasionally MRI may demonstrate characteristic profound HIE/HIRE, hypoglycemia, toxic exposure (e.g., methane,

Journal of Perinatology 2001; 21:44 ± 60 57 Barnes Neuroimaging of Fetal and Neonatal Brain Injury

cyanide), osmolar myelinolysis, striatal necrosis, and meningoen- carbon dioxide, methane, cyanide, radiation, chemotherapy), and cephalitis (e.g., mycoplasma). infectious, or postinfectious, processes (e.g., TORCH, HIV, ADEM). Hydrogen-1 MRS is being increasingly used in patients with Disorders primarily affecting white matter. Those disorders that metabolic disorders.2 ± 4,14 ± 19 Although many of the metabolic and primarily, or predominately, affect the white matter are known as the neurodegenerative disorders have specific biochemical markers, leukoencephalopathies.2 ± 4,66 ± 74 Traditionally, leukoencephalopathies most of the disorders have no differentiating features. Nonspecific have been divided into dysmyelinating and myelinoclastic disorders. MRS abnormalities are those that reflect brain destruction and In dysmyelinating disorders an intrinsic (inherited) enzyme reactive changes including delayed maturation, neuronal loss, deficiency results in the disturbed formation, destruction, or turnover axonal degeneration, demyelination, and gliosis. Alterations in of the essential components of . They are also referred to as the metabolites are often displayed as a ratio relative to the reference . The pattern of damage is symmetrical in both metabolite, creatine (Cr), an energy marker. In disorders in which hemispheres, has diffuse margins, often spares the arcuate fibers, and there is predominant neuronal degeneration (i.e., loss of cell consistently involves the cerebellar white matter. The leukodystro- bodies, ) and atrophy, the major MRS finding is a decrease in phies are primarily associated with the lysosomal and peroxisomal NAA (see Figure 9), a neuronal ( including axons) and disorders (e.g., metachromatic , Krabbe leukodystro- immature oligodendroglial marker. In disorders in which there is phy, and the complex), and with diseases of predominant loss of myelin sheaths with secondary axonal white matter (e.g., Pelizaeus±Merzbacher, Canavan, Alexander, and degeneration and gliosis (e.g., demyelination), the characteristic Cockayne). Included in the differential diagnosis is infantile-onset spectral abnormalities are characterized by elevated lipids, a marker leukoencephalopathy with swelling (macrocephaly) and mild for myelin destruction; elevated choline (Cho), a marker of clinical course. The lack of myelination (hypomyelination) may membrane turnover (e.g., myelin, glial); variable increases in suggest Pelizaeus±Merzbacher disease or Menkes' disease. lactate (L), a marker of anaerobic glycolysis; elevated glutamate/ In myelinoclastic disorders, the myelin sheath is intrinsically glutamine (G), neuroexcitatory amino acid markers; and, elevated normal until it yields to exogenous or endogenous myelinotoxic myoinositols (M), also an osmolyte and glial marker. Associated factors. The pattern of damage is asymmetric, is sharply demarcated, neuronal (e.g., axonal) or immature oligodendroglial damage is irregularly involves the subcortical arcuate fibers, and may spare the indicated by a decrease in NAA. More specific MRS abnormalities cerebellum. Examples are the infectious demyelinating diseases (e.g., may be seen in a number of disorders, for example, disorders of TORCH, HIV, SSPE), postinfectious encephalitides (ADEM), and the energy metabolism (predominant lactate elevation, e.g., hypoxia± vasculitidies. ischemia ÐFigure 9, mitochondrial disorder), (increased phenylalanine peak at 7.37 ppm), maple syrup urine Disorders affecting both white matter and cortical gray matter. disease (abnormal peak at 0.9 ppm), nonketotic hyperglycinemia A number of metabolic disorders involve both gray and white (elevated glycine peak at 3.55 ppm), Niemann±Pick disease matter.2 ± 4,66 ± 74 Those disorders associated with cortical atrophy along (abnormal lipid peak at 1.2 ppm), and Canavan disease with white matter involvement include lysosomal disorders such as (increased NAA). the lipidoses and mucopolysaccharidoses (also, associated skeletal dysplasia), and mitochondrial disorders such as Alper disease and SUMMARY Menkes' disease. If there is a diffuse cortical dysgenesis (e.g., lissencephaly, polymicrogyria) associated with white matter US and CT may provide important screening information, abnormalities, then peroxisomal disorders such as Zellweger particularly with regard to hemorrhage, trauma, hydrocephalus, syndrome should be considered along with congenital infections infection, and gross macrostructural anomalies. However, current (e.g., cytomegaloviral), and the congenital muscular dystrophies and advanced MRI techniques often provide more definitive (e.g., Fukuyama, Walker±Warburg, Santavuori). macrostructural, microstructural, and functional imaging informa- tion in both the early and late assessment of fetal and neonatal CNS Disorders affecting both white matter and deep gray matter. injuries. Disorders associated with deep gray matter involvement, in addition to white matter abnormalities, include those with primarily corpus References striatum involvement (Leigh, MELAS, Wilson's, Cockayne's), those 1. Ball WS Jr, Franz DN. Neonatal brain injury. In: Ball WS Jr, editor. Pediatric with predominant thalamic abnormalities (Krabbe, GM2 gang- Neuroradiology. Philadelphia: Lippincott-Raven; 1997. p. 239. liosidoses), and those with primarily globus pallidus involvement 2. Barnes PD, Taylor GA. Imaging of the neonatal . (Canavan, maple syrup urine disease, methylmalonic/propionic Neurosurg Clin North Am 1998;1:17±48. acidopathy, Kearns±Sayre).2 ± 4,66 ± 74 Also, included in the differential 3. Barnes PD, Robertson RL. Neuroradiologic evaluation of the cerebral palsies. diagnoses, depending on the clinical context, are profound In: Miller G, Clark G, editors. The Cerebral Palsies: Causes, Consequences, hypoxia±ischemia, osmolar myelinolysis, toxic exposure (e.g., and Management. Boston: Butterworth-Heinemann; 1998. p. 109±50.

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4. Huppi PS, Barnes PD. Magnetic resonance techniques in the evaluation of the 25. Neil JJ, Shiran SI, McKinstry RC. Normal brain in human newborns: newborn brain. Clin Perinatol 1997;24:693±723. apparent diffusion coefficient and diffusion anisotropy measured by using 5. Allison JW, Seibert JJ. Transcranial Doppler in the newborn with asphyxia. diffusion tensor MR imaging. Radiology 1998;209:57±66. Neuroimaging Clin N Am 1999;9:11±6. 26. Phillips MD, Zimmerman RA. Diffusion imaging in pediatric hypoxic± 6. Barkovich A, Hallam D. Neuroimaging in perinatal hypoxic±ischemic ischemic injury. Neuroimaging Clin N Am 1999;9:41±52. injury. Ment Retard Dev Disabil Res Rev 1977;3:28±41. 27. Robertson RL, Ben-Sira L, Barnes PD, et al. MR line scan diffusion imaging 7. Blankenberg FG, Norbash AM, Lane B, et al. Neonatal intracranial ischemia of term neonates with perinatal . AJNR 1999;20:1658±70. and hemorrhage: diagnosis with US, CT, and MR imaging. Radiology 28. 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