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MRI of Neonatal Encephalopathy
Clinical Radiology (2003) 58: 833–844 doi:10.1016/S0009-9260(03)00261-7, available online at www.sciencedirect.com
Pictorial Review MRI of Neonatal Encephalopathy P. L. KHONG * , B . C. C . L A M † , H . K . S . T U N G * , V . W O N G † , F. L. C H A N * , G . C . O O I * Departments of *Diagnostic Radiology, and †Paediatrics, Queen Mary Hospital, The University of Hong Kong, Hong Kong, People’s Republic of China Received: 25 March 2003
Revised: 16 May 2003
Accepted: 22 May 2003
We present the magnetic resonance imaging (MRI) findings in neonatal encephalopathy, including hypoxic – ischaemic encephalopathy, perinatal/neonatal stroke, metabolic encephalopathy from inborn errors of metabolism, congenital central nervous system infections and birth trauma. The applications of advanced MRI techniques, such as diffusion-weighted imaging and magnetic resonance spectroscopy are emphasized. Khong, P. L. et al. (2003). Clinical Radiology 58: 833–844. q 2003 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: neonate, MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, encephalopathy.
INTRODUCTION
Neonatal encephalopathy is a clinical syndrome characterized by disturbed neurological function in the infant at or near term, manifested by difficulty with initiating and maintaining respiration, abnormal tone, depression of reflexes, altered level of consciousness, feeding difficulties and often seizures [1]. The main causes of neonatal encephalopathy can be broadly divided into perinatal asphyxia [hypoxic–ischaemic encephalopathy (HIE)], perinatal stroke, metabolic encephalopathy from inborn errors of metabolism, congenital/neonatal central nervous system infections and severe birth trauma. Clinical evaluation alone often cannot provide adequate information regarding aetiology, diagnosis or prognosis. Depending on aetiology and severity, neonatal encephalopathy may or may not result in permanent neurological impairment. Neuroimaging, especially advanced magnetic resonance imaging (MRI) techniques, now plays an essential role in helping to determine aetiology, extent of injury and may also provide information regarding prognosis and temporal relationship of injury. Whilst ultrasonography is the first-line imaging technique for the evaluation of the newborn brain, especially the premature newborn, due to its portability and availability, MRI has an increasing role because of greater sensitivity and Guarantor and correspondent: P. L. Khong, Department of Diagnostic Radiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, People’s Republic of China. Tel: þ852-28553307; Fax: þ 85228551652; E-mail: [email protected] 0009-9260/03/$30.00/0
specificity, and its ability to perform functional imaging. Computed tomography (CT) remains an important imaging technique for emergent situations, especially in trauma, as it is quick to perform and is able to accurately detect acute haemorrhage, air and mass effect. We present a pictorial review of MRI in neonatal encephalopathy, with emphasis on advanced MRI techniques, such as diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy (MRS), and discuss the imaging findings and differential diagnosis.
HIE
HIE is a major cause of infant mortality and morbidity with long-term neurological sequelae, estimated to occur in approximately 1 to 2 per 1000 live births [2]. The clinical criteria for diagnosis of HIE related to an intrapartum event are listed in Table 1 [3]. The imaging patterns of HIE can be classified into three types [4 –6]; lesions predominantly located in the periventricular white matter, lesions predominantly located in the basal ganglia or thalamus, in particular the postero – lateral putamen and the ventro – lateral thalamus (Fig. 1), and multicystic encephalomalacia (Fig. 2). These lesions are bilateral and usually symmetrical in distribution. The pattern of injury is postulated to depend on the type of hypoxia–ischaemia, that is whether it was acute and profound or prolonged and partial, and the gestational age at the time of
q 2003 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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Table 1 – Diagnostic checklist for perinatal hypoxic ischaemic encephalopathy (HIE) related to intrapartum events [3] The diagnosis of HIE requires the presence of all three of the following criteria: 1. The presence of a clinically recognized encephalopathy within 72 h of birth (encephalopathy is defined as the presence of at least three of the following findings) Abnormal level of consciousness: hyper-alertness, lethargy, stupor or coma Abnormal muscle tone: hypertonia, hypotonia or flaccidity Abnormal deep tendon reflexes: increased, depressed or absent Seizures: subtle, multifocal or focal clonic Abnormal Moro reflex: exaggerated, incomplete or absent Abnormal suck: weak or absent Abnormal respiratory pattern: periodic, ataxic or apnoeic Oculomotor or pupillary abnormalities: skew deviation, absent or reduced, doll’s eyes or fixed unreactive pupils 2. Three or more supporting findings from the following list: Arterial cord blood pH ,7.00 Apgar score at 5 min of 5 or less Evidence of multiorgan system dysfunction involving one or more of the following systems within 72 h of birth: Renal: oliguria or acute renal failure Gastrointestinal: necrotizing entercolitis, hepatic dysfunction Haematological: thrombocytopaenia, disseminated intravascular coagulopathy Endocrine: hypoglycaemia, hyperglycaemia, hypocalcaemia, syndrome of inappropriate ADH secretion (SIADH) Pulmonary: persistent pulmonary hypertension Cardiac: myocardial dysfunction, tricuspid insufficiency Evidence of foetal distress on e.g. persistent late decelerations, reversals of end-diastolic flow on Doppler flow studies of the umbilical artery or a biophysical profile of 2 or less Evidence on CT, MRI, Technetium or ultrasound brain scan (preferably performed within 7 days of birth) of diffuse or multifocal ischaemia or of cerebral oedema Abnormal EEG: low amplitude and frequency, periodic, paroxysmal or isoelectric 3. The absence of an infectious cause, a congenital malformation of the brain or an inborn error of metabolism which could explain the encephalopathy These criteria may not apply to premature newborns #34 weeks gestation.
injury, i.e. term or pre-term [5,6]. In pre-term babies, prolonged partial asphyxia is associated with periventricular leucomalacia, whilst the injury in term babies after prolonged partial asphyxia is in the watershed parasagittal areas (Fig. 3). Lesions in the deep grey nuclei are associated with acute profound asphyxia [4 –6]. Other sites susceptible to profound asphyxia are the hippocampus, the dorsal brainstem and the peri-rolandic cerebral cortex, the latter especially occurring in the term infant (Fig. 4). Multicystic encephalomalacia is found to mainly occur in term infants who develop a devastating encephalopathy after birth with generalized brain oedema [4]. As white matter is relatively unmyelinated in neonates, potential signal abnormalities on T2-weighted images can be obscured by the high T2 signal of white matter. In fact, T1shortening can be seen before obvious T2 signal changes during the first week of life, and is postulated to be due to lipid breakdown products of myelin or mineralization (Fig. 5) [6]. Multiple studies have shown that DWI and MRS are more sensitive in the detection of HIE lesions than conventional MRI [7–9]. Ischaemic lesions demonstrate restricted diffusion on DWI images due to cytotoxic oedema and are more
conspicuous on DWI images compared with conventional MR images (Figs 1, 2, 4). However, it has been shown that DWI may be negative or may underestimate the lesion size when performed very early (before 24 h of life) and that apparent diffusion coefficients are maximally decreased between days 1–3 of life [10]. Proton MRS demonstrates a lactate peak (Fig. 1d), which can be found within 24 h of life and subsequently, a reduction in N-acetyl aspartate (NAA) is evident due to neuronal loss [11,12]. Postulated mechanisms for production of cerebral lactate include anaerobic glycolysis, secondary energy failure associated with delayed mitochondrial dysfunction, and lactate generated by infiltrating macrophages during the repair phase [13]. Severe diffuse brain injury, lesions in the thalamus and basal ganglia [14], higher lactate:choline ratios, especially in the basal ganglia [13,15], are associated with poor neurological outcome. These new imaging techniques are therefore able not only to provide early diagnosis, essential for possible neuroprotective intervention within a narrow therapeutic window, but also prognostic information. It is now recommended that DWI and MRS be performed with conventional MRI between 2 days and 8 days of life [16].
PERINATAL OR NEONATAL STROKE
Perinatal strokes are increasingly recognized, although the exact incidence is unknown because of variations in presentation, evaluation and criteria for diagnosis. Based on estimates from population-based studies of infants with seizures, the incidence of perinatal/neonatal strokes is estimated to be about one per 4000 live births [17]. The majority of infarcts occur in full-term infants who present with neonatal encephalopathy and seizures in the first few days of life. The infarcts may be in the distribution of an arterial territory or in a border-zone distribution. Most frequently, the infarcts involve the middle cerebral artery territory and its branches, with the left hemisphere more frequently affected than the right [18,19] (Fig. 6). Although the reported causes of neonatal stroke include cardiac disorders, emboli, infection, coagulation abnormalities and/or perinatal events (birth asphyxia), the cause of a large number of cases remain undetermined. Similar to adult strokes, DWI, by demonstrating cytotoxic oedema, has been found to increase the sensitivity and conspicuity of detecting neonatal strokes compared with conventional MRI [10,20]. It has, however, been found that the normalization of restricted diffusion may occur earlier than in adult strokes (about 2 weeks) and DWI may be falsely negative after 1 week. T2-weighted sequences therefore should supplement DWI to reliably detect subacute ischaemic lesions [21].
METABOLIC ENCEPHALOPATHY AND INBORN ERRORS OF METABOLISM
Inborn errors of metabolism, though individually rare, are collectively of considerable clinical impact and pose a diagnostic challenge to the clinicians. Accurate diagnosis is important for prenatal counselling and for antenatal diagnosis
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Fig. 1 – Term baby born by difficult vacuum extraction. Born flaccid requiring intubation and ventilation after birth. Developed seizures. MRI was performed on day 2 of life. (a) Axial T1-weighted images are normal. (b) T2-weighted images show diffuse increase in signal in the white matter, in keeping with oedema, and also loss of normal hypointense signal in the posterior limbs of the internal capsule. Absence of the normal signal intensity in the posterior limb of the internal capsule is another finding in HIE at term and has been found to be associated with poor neurodevelopmental outcome. (c) DWI image at the same level shows restricted diffusion in the bilateral ventro–lateral thalami (arrows) and these lesions are better demonstrated than on T1-weighted and T2-weighted images. (d) Single voxel proton MRS using echo time ¼ 144 ms of the basal ganglia shows an inverted lactate peak at 1.33 ppm (arrowhead).
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Fig. 2 – Term baby with a history of birth asphyxia. MRI was performed at 1 month of age. (a) Axial T2-weighted images at the level of the basal ganglia and (b) coronal fluid-attenuated inversion recovery (FLAIR) images show multicystic encephalomalacia. The basal ganglia and thalami are cystic and the thalami are markedly shrunken.
Fig. 3 – Term baby with a history of meconium aspiration and birth asphyxia. MRI was performed at day 6 of life. (a) Axial T1-weighted image shows punctate and linear areas of hyperintensity in the cortical and subcortical areas of the bilateral frontal and parietal lobes, in keeping with cortical laminar necrosis. Axial T2-weighted images were normal. (b) Axial DWI image shows increased signal in the white matter of the bilateral parieto-occipital lobes (arrows) and to a lesser degree in the frontal lobes (watershed areas). Proton MRS of the parietal lobe white matter showed prominent lactate peaks at 1.33 ppm.
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Fig. 4 – History of ruptured uterus and placental abruptio at term. MRI performed on day 7 of life. DWI images show hyperintense areas in keeping with restricted diffusion, at the (a) bilateral basal ganglia, (b) brainstem and hippocampus and (c) corona radiata. These lesions were not obvious on T1-weighted and T2-weighted images.
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Fig. 5 – Term-assisted breech delivery with birth asphyxia. APGAR scores at 1 min, 5 min and 10 min were 0, 0 and 1, respectively. MRI was performed at 5 weeks of age. Axial T1-weighted images show hyperintense signal in the ventro–lateral thalami and postero–lateral putamen (arrows). This is postulated to be due to lipid breakdown products of myelin or mineralization. Note also the right-sided subdural haematoma.
in subsequent pregnancies. Many of the inborn errors of metabolism, including urea cycle defects, organic acidaemias (Fig. 7), certain disorders of amino acid (Fig. 8) and fatty acid metabolism, can present with symptoms of acute metabolic encephalopathy in the neonatal period [22]. Bilirubin encephalopathy has dramatically reduced in incidence due to the development of effective therapeutic and preventive measures, such as neonatal glucose-6-phosphate dehydrogenase (G6PD) deficiency screening and the use of anti-Rhesus immune globulin. MRI is the most sensitive imaging technique for the evaluation of metabolic encephalopathy and inborn errors of metabolism. In addition, by using MRI, maturation of the developing brain can be estimated by signal intensity changes of myelination in the white matter [23]. There is, however, substantial overlap in the pattern of imaging appearances of metabolic diseases as a group. The MRI pattern may be classified by the site of predominant lesion involvement. The disorders primarily affecting white matter and presenting during the neonatal period include maple syrup urine disease, non-ketotic hyperglycinaemia, methylmalonic and propionic acidaemia. The disorders primarily affecting deep grey matter include kernicterus (postero–medial border of the globus pallidus). The disorders with a combination of lesions include
Fig. 6 – Term baby who was delivered by vacuum extraction because of foetal distress. Subsequently developed repeated seizures. MRI was performed on day 7 of life. Both (a) T2-weighted and (b) DWI images show an infarct in the left middle cerebral artery territory. There are hypointense foci of haemorrhage in the left basal ganglia (a).
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Neonatal meningitis is estimated to occur at a rate of approximately 0.3 per 1000 live births [31]. Bacterial meningitis is the most common and serious variety of neonatal intracranial infection with group B streptococci, Escherichia coli and Lysteria monocytogenes organisms accounting for approximately 70 – 80% of all cases [31]. The mode of transmission may be vertical during labour or delivery, or horizontal from human contacts, indwelling catheters, or contaminated equipment [31]. MRI may demonstrate oedema or infarcts, haemorrhage, and ependymal, leptomeningeal, or parenchymal contrast enhancement (subdural effusions). There may be progression to atrophy or encephalomalacia (Fig. 10).
BIRTH TRAUMA
Fig. 7 – Term baby with glutaric aciduria type I presented with limb dystonia and dyskinetic movements since birth. MRI was performed on day 21 of life. Axial T1-weighted image shows atrophy of both frontal and temporal lobes and basal ganglia. Both opercula are widened.
mitochondrial encephalopathies (Fig. 9). As in HIE, the lesions are bilateral and often symmetrical in distribution. The imaging appearance may therefore mimic HIE and clinical correlation is essential (Fig. 9). Inborn errors of metabolism should be suspected when there is no documented intrapartum event sufficient to explain the degree of encephalopathy, when there is persistent lactic acidosis, such as in disorders of pyruvate and mitochondrial energy metabolism [24,25], or when there is hypoglycaemia. Although most studies of DWI in neonatal imaging have been in HIE and neonatal strokes, there are some descriptions of DWI in metabolic diseases. DWI has been found to better demonstrate these lesions, and possibly at an earlier time [26]. This has been described in newborns with maple syrup urine disease [27] and non-ketotic hyperglycinaemia [28] (Fig. 8c, d). MRS may help to increase the specificity of diagnosis e.g. the presence of a lactate peak in mitochondrial encephalopathies and the glycine peak (3.55 ppm) in non-ketotic hyperglycinaemia [29].
CONGENITAL AND NEONATAL INFECTIONS
Of the TORCH [toxoplasmosis, others, i.e. syphilis, human immunodeficiency virus, rubella, cytomegalovirus and herpes simplex virus (HSV)] infections, HSV is the most common infection to present with overt neurological signs at birth [30]. The other infections more commonly present with microcephaly, chorioretinitis or other systemic manifestations, especially of the reticuloendothelial system, e.g. hepatosplenomegaly, petechial rash [30]. Neonatal HSV infection is typically multifocal, unlike the adult type whereby the temporal lobes are affected, and there may be associated haemorrhage. DWI has shown restricted diffusion during the acute phase and is presumably caused by necrosis [20].
Intracranial injuries related to birth trauma severe enough to cause encephalopathy often present with a large posterior fossa subdural haemorrhage on imaging. Subdural haemorrhages may be associated with tentorial laceration, occipital osteodiastasis, falx laceration and rupture of bridging superficial cerebral veins. In the posterior fossa, large subdural haemorrhages may cause brain-stem compression and result in death [32]. CT remains the imaging technique of choice for acute trauma, although MRI has the advantage of multiplanar imaging, especially useful in the posterior fossa (Fig. 11). The haematoma lies under the tentorium and extends laterally between the dura and the arachnoid overlying the cerebellar hemisphere. In the acute phase, the haematoma is isointense to brain on T1-weighted spin echo sequences and hypointense to brain on T2-weighted spin echo sequences. As the haematoma evolves, it develops a high signal on T1-weighted sequences and subsequently on T2-weighted sequences. Rarely, parenchymal injuries may be sustained from severe trauma to the brain leading to diffuse cerebral oedema, transtentorial herniation and posterior cerebral infarcts may result from compression of the posterior cerebral artery [32].
CONCLUSION
Neonatal neuroimaging has gained importance because of the advances in neonatal intensive care leading to improved survival statistics. Moreover, in view of the emergence of promising therapeutic interventions for HIE, there is an urgency to find early and effective means of diagnosis and evaluation. MRI can provide critical information on the presence and extent of brain injury and is sometimes specific in the diagnosis of aetiology in neonatal encephalopathy. However, imaging appearances can overlap and correlation with clinical history and presentation is important. Furthermore, a combination of conditions may co-exist in the same baby e.g. HIE and trauma or infection etc, making diagnosis difficult. The role of neuroimaging in the management of neonatal encephalopathy will undoubtedly expand, especially with developments in new imaging techniques and improvements in hardware and software.
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Fig. 8 – Term baby with non-ketotic hyperglycinaemia presented with shallow breathing and hypotonia requiring ventilator support. MRI was performed on day 15 of life. (a) Axial T2-weighted images show hyperintense signals in the posterior aspect of brainstem (arrows). (b) DWI images at the same level as (a) show restricted diffusion at the posterior brainstem. Artefact is noted in the left cerebellar hemisphere from an electrocardiogram lead. In non-ketotic hyperglycinaemia, a vacuolating myelinopathy, restricted diffusion may be due to accumulation of fluid between the layers of myelin lamellae. (c) DWI images show restricted diffusion at the posterior limbs of both internal capsules. (d) Axial T2-weighted images do not demonstrate signal abnormality in the posterior limbs of the internal capsules, which are better shown on DWI images (c).
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Fig. 9 – Newborn with uneventful birth history. Presented with excessive jitteriness and seizures at 24 h of life. MRI was performed on day 5 of life and subsequently, CT was performed at 3 months of life. Biochemical tests results were consistent with molybdenum co-factor deficiency. The imaging findings of this condition are known to mimic HIE. (a) Axial DWI images of the basal ganglia show increased signal in the cortex and subcortical white matter of the cerebral hemispheres in keeping with restricted diffusion. These abnormalities were not obvious on the T1-weighted and T2-weighted images. (b) Multivoxel proton MRS (echo time ¼ 288 ms) shows elevated lactate peaks (arrow) in the white matter. (c) Follow-up CT shows multicystic encephalomalacia.
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Fig. 10 – Premature twin baby with group B streptococcal meningitis. Presented with sepsis and seizure on day 1, generalized hypotonia, brisk jerks and absence of primitive reflexes. (a) Axial T2-weighted image on day 11 of life shows diffuse hyperintensity in the white matter consistent with encephalomalacia. (b) Axial FLAIR image performed 6 months later shows multiple cysts in the frontal and temporo–occpital lobes and marked ventriculomegaly. Only a very thin mantle of cortex is spared.
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Fig. 11 – History of forceps-assisted caesarian section for placenta previa at term. The baby presented with lethargy, hypotonia, hyporeflexia and seizures on day 1. CT was performed on day 1 of life. (a) CT shows a hyperdense posterior fossa subdural haematoma (arrow). (b) CT shows an extensive left-sided supratentorial subdural haematoma and a hypodense lesion in the left parieto– occipital lobe in keeping with an infarct (asterisk). There is diffuse cerebral oedema with loss of basal cisternal spaces. (c) MRI performed at 12 weeks of life shows a chronic infarct in the left parietal lobe with parenchymal loss.
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Pictorial Review MRI of Neonatal Encephalopathy P. L. KHONG * , B . C. C . L A M † , H . K . S . T U N G * , V . W O N G † , F. L. C H A N * , G . C . O O I * Departments of *Diagnostic Radiology, and †Paediatrics, Queen Mary Hospital, The University of Hong Kong, Hong Kong, People’s Republic of China Received: 25 March 2003
Revised: 16 May 2003
Accepted: 22 May 2003
We present the magnetic resonance imaging (MRI) findings in neonatal encephalopathy, including hypoxic – ischaemic encephalopathy, perinatal/neonatal stroke, metabolic encephalopathy from inborn errors of metabolism, congenital central nervous system infections and birth trauma. The applications of advanced MRI techniques, such as diffusion-weighted imaging and magnetic resonance spectroscopy are emphasized. Khong, P. L. et al. (2003). Clinical Radiology 58: 833–844. q 2003 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: neonate, MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, encephalopathy.
INTRODUCTION
Neonatal encephalopathy is a clinical syndrome characterized by disturbed neurological function in the infant at or near term, manifested by difficulty with initiating and maintaining respiration, abnormal tone, depression of reflexes, altered level of consciousness, feeding difficulties and often seizures [1]. The main causes of neonatal encephalopathy can be broadly divided into perinatal asphyxia [hypoxic–ischaemic encephalopathy (HIE)], perinatal stroke, metabolic encephalopathy from inborn errors of metabolism, congenital/neonatal central nervous system infections and severe birth trauma. Clinical evaluation alone often cannot provide adequate information regarding aetiology, diagnosis or prognosis. Depending on aetiology and severity, neonatal encephalopathy may or may not result in permanent neurological impairment. Neuroimaging, especially advanced magnetic resonance imaging (MRI) techniques, now plays an essential role in helping to determine aetiology, extent of injury and may also provide information regarding prognosis and temporal relationship of injury. Whilst ultrasonography is the first-line imaging technique for the evaluation of the newborn brain, especially the premature newborn, due to its portability and availability, MRI has an increasing role because of greater sensitivity and Guarantor and correspondent: P. L. Khong, Department of Diagnostic Radiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, People’s Republic of China. Tel: þ852-28553307; Fax: þ 85228551652; E-mail: [email protected] 0009-9260/03/$30.00/0
specificity, and its ability to perform functional imaging. Computed tomography (CT) remains an important imaging technique for emergent situations, especially in trauma, as it is quick to perform and is able to accurately detect acute haemorrhage, air and mass effect. We present a pictorial review of MRI in neonatal encephalopathy, with emphasis on advanced MRI techniques, such as diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy (MRS), and discuss the imaging findings and differential diagnosis.
HIE
HIE is a major cause of infant mortality and morbidity with long-term neurological sequelae, estimated to occur in approximately 1 to 2 per 1000 live births [2]. The clinical criteria for diagnosis of HIE related to an intrapartum event are listed in Table 1 [3]. The imaging patterns of HIE can be classified into three types [4 –6]; lesions predominantly located in the periventricular white matter, lesions predominantly located in the basal ganglia or thalamus, in particular the postero – lateral putamen and the ventro – lateral thalamus (Fig. 1), and multicystic encephalomalacia (Fig. 2). These lesions are bilateral and usually symmetrical in distribution. The pattern of injury is postulated to depend on the type of hypoxia–ischaemia, that is whether it was acute and profound or prolonged and partial, and the gestational age at the time of
q 2003 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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Table 1 – Diagnostic checklist for perinatal hypoxic ischaemic encephalopathy (HIE) related to intrapartum events [3] The diagnosis of HIE requires the presence of all three of the following criteria: 1. The presence of a clinically recognized encephalopathy within 72 h of birth (encephalopathy is defined as the presence of at least three of the following findings) Abnormal level of consciousness: hyper-alertness, lethargy, stupor or coma Abnormal muscle tone: hypertonia, hypotonia or flaccidity Abnormal deep tendon reflexes: increased, depressed or absent Seizures: subtle, multifocal or focal clonic Abnormal Moro reflex: exaggerated, incomplete or absent Abnormal suck: weak or absent Abnormal respiratory pattern: periodic, ataxic or apnoeic Oculomotor or pupillary abnormalities: skew deviation, absent or reduced, doll’s eyes or fixed unreactive pupils 2. Three or more supporting findings from the following list: Arterial cord blood pH ,7.00 Apgar score at 5 min of 5 or less Evidence of multiorgan system dysfunction involving one or more of the following systems within 72 h of birth: Renal: oliguria or acute renal failure Gastrointestinal: necrotizing entercolitis, hepatic dysfunction Haematological: thrombocytopaenia, disseminated intravascular coagulopathy Endocrine: hypoglycaemia, hyperglycaemia, hypocalcaemia, syndrome of inappropriate ADH secretion (SIADH) Pulmonary: persistent pulmonary hypertension Cardiac: myocardial dysfunction, tricuspid insufficiency Evidence of foetal distress on e.g. persistent late decelerations, reversals of end-diastolic flow on Doppler flow studies of the umbilical artery or a biophysical profile of 2 or less Evidence on CT, MRI, Technetium or ultrasound brain scan (preferably performed within 7 days of birth) of diffuse or multifocal ischaemia or of cerebral oedema Abnormal EEG: low amplitude and frequency, periodic, paroxysmal or isoelectric 3. The absence of an infectious cause, a congenital malformation of the brain or an inborn error of metabolism which could explain the encephalopathy These criteria may not apply to premature newborns #34 weeks gestation.
injury, i.e. term or pre-term [5,6]. In pre-term babies, prolonged partial asphyxia is associated with periventricular leucomalacia, whilst the injury in term babies after prolonged partial asphyxia is in the watershed parasagittal areas (Fig. 3). Lesions in the deep grey nuclei are associated with acute profound asphyxia [4 –6]. Other sites susceptible to profound asphyxia are the hippocampus, the dorsal brainstem and the peri-rolandic cerebral cortex, the latter especially occurring in the term infant (Fig. 4). Multicystic encephalomalacia is found to mainly occur in term infants who develop a devastating encephalopathy after birth with generalized brain oedema [4]. As white matter is relatively unmyelinated in neonates, potential signal abnormalities on T2-weighted images can be obscured by the high T2 signal of white matter. In fact, T1shortening can be seen before obvious T2 signal changes during the first week of life, and is postulated to be due to lipid breakdown products of myelin or mineralization (Fig. 5) [6]. Multiple studies have shown that DWI and MRS are more sensitive in the detection of HIE lesions than conventional MRI [7–9]. Ischaemic lesions demonstrate restricted diffusion on DWI images due to cytotoxic oedema and are more
conspicuous on DWI images compared with conventional MR images (Figs 1, 2, 4). However, it has been shown that DWI may be negative or may underestimate the lesion size when performed very early (before 24 h of life) and that apparent diffusion coefficients are maximally decreased between days 1–3 of life [10]. Proton MRS demonstrates a lactate peak (Fig. 1d), which can be found within 24 h of life and subsequently, a reduction in N-acetyl aspartate (NAA) is evident due to neuronal loss [11,12]. Postulated mechanisms for production of cerebral lactate include anaerobic glycolysis, secondary energy failure associated with delayed mitochondrial dysfunction, and lactate generated by infiltrating macrophages during the repair phase [13]. Severe diffuse brain injury, lesions in the thalamus and basal ganglia [14], higher lactate:choline ratios, especially in the basal ganglia [13,15], are associated with poor neurological outcome. These new imaging techniques are therefore able not only to provide early diagnosis, essential for possible neuroprotective intervention within a narrow therapeutic window, but also prognostic information. It is now recommended that DWI and MRS be performed with conventional MRI between 2 days and 8 days of life [16].
PERINATAL OR NEONATAL STROKE
Perinatal strokes are increasingly recognized, although the exact incidence is unknown because of variations in presentation, evaluation and criteria for diagnosis. Based on estimates from population-based studies of infants with seizures, the incidence of perinatal/neonatal strokes is estimated to be about one per 4000 live births [17]. The majority of infarcts occur in full-term infants who present with neonatal encephalopathy and seizures in the first few days of life. The infarcts may be in the distribution of an arterial territory or in a border-zone distribution. Most frequently, the infarcts involve the middle cerebral artery territory and its branches, with the left hemisphere more frequently affected than the right [18,19] (Fig. 6). Although the reported causes of neonatal stroke include cardiac disorders, emboli, infection, coagulation abnormalities and/or perinatal events (birth asphyxia), the cause of a large number of cases remain undetermined. Similar to adult strokes, DWI, by demonstrating cytotoxic oedema, has been found to increase the sensitivity and conspicuity of detecting neonatal strokes compared with conventional MRI [10,20]. It has, however, been found that the normalization of restricted diffusion may occur earlier than in adult strokes (about 2 weeks) and DWI may be falsely negative after 1 week. T2-weighted sequences therefore should supplement DWI to reliably detect subacute ischaemic lesions [21].
METABOLIC ENCEPHALOPATHY AND INBORN ERRORS OF METABOLISM
Inborn errors of metabolism, though individually rare, are collectively of considerable clinical impact and pose a diagnostic challenge to the clinicians. Accurate diagnosis is important for prenatal counselling and for antenatal diagnosis
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Fig. 1 – Term baby born by difficult vacuum extraction. Born flaccid requiring intubation and ventilation after birth. Developed seizures. MRI was performed on day 2 of life. (a) Axial T1-weighted images are normal. (b) T2-weighted images show diffuse increase in signal in the white matter, in keeping with oedema, and also loss of normal hypointense signal in the posterior limbs of the internal capsule. Absence of the normal signal intensity in the posterior limb of the internal capsule is another finding in HIE at term and has been found to be associated with poor neurodevelopmental outcome. (c) DWI image at the same level shows restricted diffusion in the bilateral ventro–lateral thalami (arrows) and these lesions are better demonstrated than on T1-weighted and T2-weighted images. (d) Single voxel proton MRS using echo time ¼ 144 ms of the basal ganglia shows an inverted lactate peak at 1.33 ppm (arrowhead).
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Fig. 2 – Term baby with a history of birth asphyxia. MRI was performed at 1 month of age. (a) Axial T2-weighted images at the level of the basal ganglia and (b) coronal fluid-attenuated inversion recovery (FLAIR) images show multicystic encephalomalacia. The basal ganglia and thalami are cystic and the thalami are markedly shrunken.
Fig. 3 – Term baby with a history of meconium aspiration and birth asphyxia. MRI was performed at day 6 of life. (a) Axial T1-weighted image shows punctate and linear areas of hyperintensity in the cortical and subcortical areas of the bilateral frontal and parietal lobes, in keeping with cortical laminar necrosis. Axial T2-weighted images were normal. (b) Axial DWI image shows increased signal in the white matter of the bilateral parieto-occipital lobes (arrows) and to a lesser degree in the frontal lobes (watershed areas). Proton MRS of the parietal lobe white matter showed prominent lactate peaks at 1.33 ppm.
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Fig. 4 – History of ruptured uterus and placental abruptio at term. MRI performed on day 7 of life. DWI images show hyperintense areas in keeping with restricted diffusion, at the (a) bilateral basal ganglia, (b) brainstem and hippocampus and (c) corona radiata. These lesions were not obvious on T1-weighted and T2-weighted images.
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Fig. 5 – Term-assisted breech delivery with birth asphyxia. APGAR scores at 1 min, 5 min and 10 min were 0, 0 and 1, respectively. MRI was performed at 5 weeks of age. Axial T1-weighted images show hyperintense signal in the ventro–lateral thalami and postero–lateral putamen (arrows). This is postulated to be due to lipid breakdown products of myelin or mineralization. Note also the right-sided subdural haematoma.
in subsequent pregnancies. Many of the inborn errors of metabolism, including urea cycle defects, organic acidaemias (Fig. 7), certain disorders of amino acid (Fig. 8) and fatty acid metabolism, can present with symptoms of acute metabolic encephalopathy in the neonatal period [22]. Bilirubin encephalopathy has dramatically reduced in incidence due to the development of effective therapeutic and preventive measures, such as neonatal glucose-6-phosphate dehydrogenase (G6PD) deficiency screening and the use of anti-Rhesus immune globulin. MRI is the most sensitive imaging technique for the evaluation of metabolic encephalopathy and inborn errors of metabolism. In addition, by using MRI, maturation of the developing brain can be estimated by signal intensity changes of myelination in the white matter [23]. There is, however, substantial overlap in the pattern of imaging appearances of metabolic diseases as a group. The MRI pattern may be classified by the site of predominant lesion involvement. The disorders primarily affecting white matter and presenting during the neonatal period include maple syrup urine disease, non-ketotic hyperglycinaemia, methylmalonic and propionic acidaemia. The disorders primarily affecting deep grey matter include kernicterus (postero–medial border of the globus pallidus). The disorders with a combination of lesions include
Fig. 6 – Term baby who was delivered by vacuum extraction because of foetal distress. Subsequently developed repeated seizures. MRI was performed on day 7 of life. Both (a) T2-weighted and (b) DWI images show an infarct in the left middle cerebral artery territory. There are hypointense foci of haemorrhage in the left basal ganglia (a).
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Neonatal meningitis is estimated to occur at a rate of approximately 0.3 per 1000 live births [31]. Bacterial meningitis is the most common and serious variety of neonatal intracranial infection with group B streptococci, Escherichia coli and Lysteria monocytogenes organisms accounting for approximately 70 – 80% of all cases [31]. The mode of transmission may be vertical during labour or delivery, or horizontal from human contacts, indwelling catheters, or contaminated equipment [31]. MRI may demonstrate oedema or infarcts, haemorrhage, and ependymal, leptomeningeal, or parenchymal contrast enhancement (subdural effusions). There may be progression to atrophy or encephalomalacia (Fig. 10).
BIRTH TRAUMA
Fig. 7 – Term baby with glutaric aciduria type I presented with limb dystonia and dyskinetic movements since birth. MRI was performed on day 21 of life. Axial T1-weighted image shows atrophy of both frontal and temporal lobes and basal ganglia. Both opercula are widened.
mitochondrial encephalopathies (Fig. 9). As in HIE, the lesions are bilateral and often symmetrical in distribution. The imaging appearance may therefore mimic HIE and clinical correlation is essential (Fig. 9). Inborn errors of metabolism should be suspected when there is no documented intrapartum event sufficient to explain the degree of encephalopathy, when there is persistent lactic acidosis, such as in disorders of pyruvate and mitochondrial energy metabolism [24,25], or when there is hypoglycaemia. Although most studies of DWI in neonatal imaging have been in HIE and neonatal strokes, there are some descriptions of DWI in metabolic diseases. DWI has been found to better demonstrate these lesions, and possibly at an earlier time [26]. This has been described in newborns with maple syrup urine disease [27] and non-ketotic hyperglycinaemia [28] (Fig. 8c, d). MRS may help to increase the specificity of diagnosis e.g. the presence of a lactate peak in mitochondrial encephalopathies and the glycine peak (3.55 ppm) in non-ketotic hyperglycinaemia [29].
CONGENITAL AND NEONATAL INFECTIONS
Of the TORCH [toxoplasmosis, others, i.e. syphilis, human immunodeficiency virus, rubella, cytomegalovirus and herpes simplex virus (HSV)] infections, HSV is the most common infection to present with overt neurological signs at birth [30]. The other infections more commonly present with microcephaly, chorioretinitis or other systemic manifestations, especially of the reticuloendothelial system, e.g. hepatosplenomegaly, petechial rash [30]. Neonatal HSV infection is typically multifocal, unlike the adult type whereby the temporal lobes are affected, and there may be associated haemorrhage. DWI has shown restricted diffusion during the acute phase and is presumably caused by necrosis [20].
Intracranial injuries related to birth trauma severe enough to cause encephalopathy often present with a large posterior fossa subdural haemorrhage on imaging. Subdural haemorrhages may be associated with tentorial laceration, occipital osteodiastasis, falx laceration and rupture of bridging superficial cerebral veins. In the posterior fossa, large subdural haemorrhages may cause brain-stem compression and result in death [32]. CT remains the imaging technique of choice for acute trauma, although MRI has the advantage of multiplanar imaging, especially useful in the posterior fossa (Fig. 11). The haematoma lies under the tentorium and extends laterally between the dura and the arachnoid overlying the cerebellar hemisphere. In the acute phase, the haematoma is isointense to brain on T1-weighted spin echo sequences and hypointense to brain on T2-weighted spin echo sequences. As the haematoma evolves, it develops a high signal on T1-weighted sequences and subsequently on T2-weighted sequences. Rarely, parenchymal injuries may be sustained from severe trauma to the brain leading to diffuse cerebral oedema, transtentorial herniation and posterior cerebral infarcts may result from compression of the posterior cerebral artery [32].
CONCLUSION
Neonatal neuroimaging has gained importance because of the advances in neonatal intensive care leading to improved survival statistics. Moreover, in view of the emergence of promising therapeutic interventions for HIE, there is an urgency to find early and effective means of diagnosis and evaluation. MRI can provide critical information on the presence and extent of brain injury and is sometimes specific in the diagnosis of aetiology in neonatal encephalopathy. However, imaging appearances can overlap and correlation with clinical history and presentation is important. Furthermore, a combination of conditions may co-exist in the same baby e.g. HIE and trauma or infection etc, making diagnosis difficult. The role of neuroimaging in the management of neonatal encephalopathy will undoubtedly expand, especially with developments in new imaging techniques and improvements in hardware and software.
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Fig. 8 – Term baby with non-ketotic hyperglycinaemia presented with shallow breathing and hypotonia requiring ventilator support. MRI was performed on day 15 of life. (a) Axial T2-weighted images show hyperintense signals in the posterior aspect of brainstem (arrows). (b) DWI images at the same level as (a) show restricted diffusion at the posterior brainstem. Artefact is noted in the left cerebellar hemisphere from an electrocardiogram lead. In non-ketotic hyperglycinaemia, a vacuolating myelinopathy, restricted diffusion may be due to accumulation of fluid between the layers of myelin lamellae. (c) DWI images show restricted diffusion at the posterior limbs of both internal capsules. (d) Axial T2-weighted images do not demonstrate signal abnormality in the posterior limbs of the internal capsules, which are better shown on DWI images (c).
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Fig. 9 – Newborn with uneventful birth history. Presented with excessive jitteriness and seizures at 24 h of life. MRI was performed on day 5 of life and subsequently, CT was performed at 3 months of life. Biochemical tests results were consistent with molybdenum co-factor deficiency. The imaging findings of this condition are known to mimic HIE. (a) Axial DWI images of the basal ganglia show increased signal in the cortex and subcortical white matter of the cerebral hemispheres in keeping with restricted diffusion. These abnormalities were not obvious on the T1-weighted and T2-weighted images. (b) Multivoxel proton MRS (echo time ¼ 288 ms) shows elevated lactate peaks (arrow) in the white matter. (c) Follow-up CT shows multicystic encephalomalacia.
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Fig. 10 – Premature twin baby with group B streptococcal meningitis. Presented with sepsis and seizure on day 1, generalized hypotonia, brisk jerks and absence of primitive reflexes. (a) Axial T2-weighted image on day 11 of life shows diffuse hyperintensity in the white matter consistent with encephalomalacia. (b) Axial FLAIR image performed 6 months later shows multiple cysts in the frontal and temporo–occpital lobes and marked ventriculomegaly. Only a very thin mantle of cortex is spared.
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Fig. 11 – History of forceps-assisted caesarian section for placenta previa at term. The baby presented with lethargy, hypotonia, hyporeflexia and seizures on day 1. CT was performed on day 1 of life. (a) CT shows a hyperdense posterior fossa subdural haematoma (arrow). (b) CT shows an extensive left-sided supratentorial subdural haematoma and a hypodense lesion in the left parieto– occipital lobe in keeping with an infarct (asterisk). There is diffuse cerebral oedema with loss of basal cisternal spaces. (c) MRI performed at 12 weeks of life shows a chronic infarct in the left parietal lobe with parenchymal loss.
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