95.1 Clinical Features
and Laboratory Investigations Periventricular leukomalacia (PVL) is a post-hypox- ic–ischemic leukoencephalopathy resulting from pre- or perinatal hypoxic–ischemic insults. Little (1861) was the first to describe the clinical picture of the con- dition. It occurs in particular in preterm neonates with a gestational age of 32–36 weeks. Major risk fac- tors are prematurity and intrauterine infection. Be- fore that time, at a gestational age of 28–32 weeks, ger- minal layer, intraventricular, and intraparenchymal hemorrhages predominate. PVL is rarely seen in term neonates; if present, it is often in combination with cardiac disorders, intrauterine growth retardation, or any other sign of intrauterine incidents. There is a distinct relationship between PVL and the clinical concept of “cerebral palsy,” although it should be real- ized that the concept of cerebral palsy comprises all infants with a stable handicap which occurred before the age of one year. The increasing technology in neonatal medicine has made it possible to keep more premature infants alive. As a consequence, PVL as a cause of cerebral palsy has increased in relative fre- quency.
The typical location of PVL in the periventricular region, interfering with the corticospinal tracts of the legs more than of the arms, is responsible for the re- sulting spastic diplegia, tetraplegia (legs more severe- ly affected than arms), or hemiplegia (leg more se- verely affected than arm). Patients with motor dis- ability and PVL have a relatively high incidence of seizures. Epilepsy in patients with PVL is associated with multiple seizure types. Mental development is relatively better preserved than motor development, although there is increasing evidence that there are also cognitive deficits in PVL. Extension of the leuko- malacia into the optic radiation may lead to cortical blindness or, more often, delayed visual maturation.
The CNS manifestations of PVL take 1 or 2 years to show the full clinical impact.
In older preterm infants the white matter damage tends to have a more peripheral, subcortical location.
This condition is known as subcortical leukomalacia (SCL). In fact, PVL and SCL form a continuum, and SCL as a rule includes periventricular white matter damage. Clinically, so-called SCL leads to a more se- vere handicap than PVL. The children have spastic tetraplegia, are mentally more severely retarded, and
often have epilepsy. Delayed visual maturation and cerebral visual failure are usually present.
A third group of neonates develop a multicystic encephalopathy (MCE). Patients with MCE are more often born at term than preterm. In the majority of the children the clinical signs of a devastating en- cephalopathy are unexpected. The typical clinical course usually includes initially not very alarming signs of fetal distress, such as prolonged bradycardia or meconium-stained amniotic fluid, followed by moderate starting problems after delivery and rapid partial recovery. Several hours later a devastating encephalopathy develops, characterized by lowered consciousness, seizures and, on ultrasound, general- ized cerebral edema. These patients have a very poor outcome, with microcephaly, severe developmental retardation, spastic tetraplegia, visual handicap, and seizures.
A special clinical picture is seen as the result of acute profound hypoxia–ischemia in term or post- term babies. In the course of the first year of life an ex- trapyramidal movement disorder becomes apparent with choreoathetosis, dystonia, and orobuccolingual dyskinesia in combination with variable spasticity and variable mental retardation, although mental ca- pacities are often better preserved. The motor handi- cap is usually very severe, the combination of ex- trapyramidal and pyramidal abnormalities leading to serious impairment of intentional movements. This clinical picture is associated with lesions of the basal nuclei and the central, perirolandic cortical and sub- cortical area. A similar clinical condition may occur in preterm neonates, when they undergo a similar episode of acute profound hypoxia–ischemia, but the central cortical and subcortical areas are not similar- ly involved, probably due to the state of myelination in the preterm born infants.
It is estimated that post-hypoxic–ischemic en- cephalopathy is the cause of 90% of cases of cerebral palsy. For decisions on how to proceed with the treat- ment of a very sick patient in the neonatal intensive care unit, it is extremely useful to be able to predict the outcome of damage at an early stage. For the pre- diction of the outcome of pre- and perinatal injury one has to rely in the early phase on clinical sympto- matology and paraclinical test results available at the time. A classification of the severity of post- hypoxic–ischemic encephalopathy was proposed by Sarnat and Sarnat (1976) for neonates with a gesta-
Post-Hypoxic–Ischemic Encephalopathy of Neonates
J. Valk, R.J. Vermeulen, M.S. van der Knaap
Chapter 95
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tional age of over 36 weeks. This classification, based on clinical and EEG findings, has been shown to have prognostic significance and is the standard of clinical scoring in neonatal intensive care unit in infants with post-hypoxic–ischemic encephalopathy. Stage I usu- ally occurs during the first 24 h of life and is charac- terized by jitteriness, a state of irritability, hyperalert- ness, sympathetic nervous system preponderance, uninhibited reflexes, and a normal EEG. Stage II consists clinically of hypotonia, lethargy, or obtun- dation for at least 12 h after birth, strong distal flex- ion, parasympathetic predominance, and multifocal seizures. EEG displays periodicity, sometimes preced- ed by continuous delta wave activity. The period be- tween 48 and 72 h is critical, during which the en- cephalopathy either worsens or improves. Stage III is characterized by suppression of brain stem and auto- nomic functions, stupor or coma, and generalized flaccidity. Mechanical ventilation is necessary. The EEG is isoelectric or shows a burst–suppression pat- tern. Persistence of stage II for less than 5 days and absence of entry in stage III are associated with favor- able outcome. Entry into stage III, failure of the EEG to return to normal, or persistence of stage II for longer than 7 days predicts a poor neurological out- come.
In a large cohort, including 1807 preterm (32–36 weeks gestational age) and very preterm (25–32 weeks gestational age) infants it was shown that there was a significant inverse relationship between umbil- ical cord pH and base excess values and subsequent adverse outcome for infants delivered preterm (Vic- tory et al. 2003). Determination of CSF lactate levels in 150 nonasphyxiated and 46 asphyxiated neonates showed a significant relationship between elevated lactate levels, fetal distress, and APGAR scores and seems to be an objective way of assessing the severity of cerebral hypoxia (Mathew et al. 1980).
Abnormal VEP and SSEP results carry some nega- tive prognostic value.
Ultrasound (US), being versatile and a bedside ex- amination, is the imaging modality of first choice in the neonatal intensive care unit. It can help to identi- fy areas of hyperechogenicity located around the trigonum or the frontal horns with onset 3–7 days after the hypoxic–ischemic incident. This hypere- chogenicity is either transient or progresses to cysts in about 7–14 days. This time delay is also reported in histological studies. US can be helpful in demonstrat- ing SCL, depending on the type of equipment. US is also helpful in demonstrating germinal layer hemor- rhage, intraventricular hemorrhage, ventricular di- latation, intraparenchymal hemorrhage, focal infarc- tions, porencephalic cysts, and lesions in the basal ganglia. An important acquisition is the ability to measure flow velocity and pulsatility index in major cerebral vessels with the Doppler ultrasound tech-
nique. A lowered pulsatility index is associated with more severe post-hypoxic–ischemic encephalopathy, although the overlap with normal is rather large.
Near-infrared spectroscopy is a method with po- tential to measure changes in the oxy–deoxyhemo- globin ratio in the brain and to estimate cerebral blood flow. The method has the advantage of being bedside and providing continuous information.
There is, however, only a limited window available, because of interference with the skull. The method is in clinical use in some intensive care units and in re- search settings.
PET studies have occasionally been used to deter- mine the metabolic rate and the cerebral blood flow of the various brain regions. This is rather a research than a clinical tool for post-hypoxic–ischemic en- cephalopathy in neonates.
Clinical signs, EEG, US, and evoked potentials are of the highest importance as predictors of the out- come of perinatal asphyxia in the acute stage, espe- cially in those newborns that require intensive treat- ment to survive. In early stages of post-hypoxic–is- chemic damage special MR techniques, including dif- fusion-weighted imaging and MRS, have proved to be of great importance in the prediction of outcome. In a later phase the extent of lesions on MRI, in particular the presence of subcortical damage, glial retraction, and ulegyria, the presence of secondary phenomena, such as atrophy and hydrocephalus, and the distur- bance of myelination are helpful in predicting the de- gree of future disability.
95.2 Pathology
PVL was described histological for the first time in 1867 by Virchow and in 1868 and 1873 by Parrot. They described “pale” infarcts in the periventricular white matter as yellowish or chalky plaques, 1–6 mm in di- ameter, 1–15 mm from the ependymal surface of the lateral ventricles. Softening of the plaques forms cav- ities filled with a milky fluid. The most common lo- calizations are the area anterior to the frontal horn, the superolateral angles of the lateral ventricles, the peritrigonal area, and the area around the occipital horns.
Microscopically the lesions initially show coagula- tion necrosis, with nuclear pyknosis and sponginess of the tissue. Astrocytic proliferation at the borders sets in after a few days and varicose axon swellings develop. Microglia proliferate and lipid-laden macro- phages accumulate. The organizing lesions are delin- eated by active gliosis. Cavitation forms within a few weeks. The cavities are lined by fibrillary glial scar tis- sue. Swollen axons mineralize quickly and persist for many months. Most of the infarcts are ischemic and lack hemorrhage.Vascular-occlusive changes are usu-
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ally absent. Occasionally hemorrhages are found with a distribution similar to that of the leukomalacia.
They are due to secondary hemorrhages into periven- tricular infarcts. Under certain circumstances these hemorrhages can become massive.
The severity of the gliotic reaction and its extent depend on age. Before 24–28 weeks gestational age, the immature brain cannot fully respond to insults with astrogliosis. In premature neonates of 28–32 weeks gestational age, gliosis is usually limited to the periventricular area (PVL). In older premature neonates gliosis extends more often into the subcorti- cal area (SCL). This subcortical extension of the gliot- ic lesion is probably related to both gestational age and the severity of the hypoxic–ischemic insult. If subcortical cysts develop and the child dies during this stage, multicystic subcortical degeneration is found at autopsy. If the child survives, the cysts usual- ly disappear and gliotic scarring occurs with retrac- tion of white matter deforming ventricular system and cortex. The distribution of these lesions follows a pattern parallel to the periventricular area, closer to the cortical lining, extending from the frontal to the occipital region. The scars of PVL and SCL remain visible throughout life. The residual lesions of PVL are characterized by irregular borders of the ventri- cles, where periventricular cysts have made contact with the lumen of the ventricles, with glial retraction often at the level of the trigonum, focal loss of white matter, and deep sulci abutting the walls of the ventri- cles. In the case of SCL, glial retraction disfigures the centrum semiovale and causes crowding of gyri, eventually leading to parietal and occipital ulegyria (= sclerotic polymicrogyria).
In term neonates the pattern of damage is differ- ent. The post-hypoxic–ischemic lesions occur prefer- entially in a triangular area in the parasagittal, corti- cal, and subcortical region bordering the sulcus cen- tralis. The resulting gliotic scar has a typical triangu- lar shape with retraction of the parietal cortex, leading to local ulegyria. This is often combined with lesions in the dorsal part of the putamen and the ven- trolateral part of the thalamus. The hippocampus may also be involved. The nuclei of the brain stem and the dentate nucleus may also be affected in this con- dition, and pontosubicular necrosis, a histological en- tity, could also fit into this gamut of post-hypoxic–is- chemic damage of the term neonate.
Histopathology in MCE reveals multiple cystic cavities in the white matter, extending from the ven- tricular wall to the inner cortex, affecting frontal, parietal, and occipital lobes. Septa bridge the cyst walls. The medial and lateral parts of the temporal lobes are usually spared. Some convolutions are shrunken, and ulegyric regions are present. The later- al ventricles are dilated, but do not communicate with the cysts. The corpus callosum and fornix may be re-
markably thinned. Softening of the putamen, globus pallidus, and lateral thalamus may be present. There are foci of necrosis involving different levels of the brain stem down to the lower medulla. The spinal cord is not involved. Microscopically intensive gliosis and the presence of fat-laden macrophages are seen in the walls of the cysts. In the basal ganglia symmet- rical necrotic changes are apparent: the neuropil is destroyed and few neurons remain. Scattered calcifi- cations and encrusted neurons are seen in the cere- bral cortex and basal ganglia. In the cerebellum there is loss of Purkinje cells, many of which are swollen, with cactus-like dendrites in the molecular layer.
95.3 Pathogenetic Considerations
PVL and germinal-layer-related hemorrhages are considered to be due to hypoxic–ischemic insults of the preterm neonate, occurring in the pre-, peri-, or postnatal period. Age seems to be the pathoplastic factor. The incidence of germinal-layer-related hem- orrhage is highest before the 32nd week of gestation- al age; the highest incidence of PVL lies between the 32nd and 36th week of gestational age, but there cer- tainly is an overlap, and both conditions may be pre- sent at the same time. Both conditions are rare in neonates born at term. The high incidence of germi- nal-layer hemorrhage before the age of 32 weeks’ ges- tation can be explained by the presence of the germi- nal layer up until that time. After the 32nd week of gestation the germinal layer rapidly disappears. This germinal layer or matrix layer is considered to be the nurturing bed for the neuronal and glial cells of the developing brain. It is extremely well vascularized, whereas the vascular channels have thin endothelial walls without supportive tissue. The germinal layer therefore bleeds easily. A hemodynamic contribution comes from the pressure-passive cerebral blood flow in stressed premature children, causing a direct de- pendency of the cerebral blood flow on the systemic blood pressure and blood flow. The existence of a patent ductus arteriosus (ductus Botalli) and its drug-induced (indomethacin) closure can have a profound influence on the cerebral circulation, as it lacks the regulatory mechanism to buffer these changes. Another important factor is the immaturity of the lung, which requires mechanical ventilation with high pressures leading to indirect changes in the blood pressure. All these factors explain the relative high frequency of development of germinal-layer he- morrhage in early preterm babies. The hemorrhages potentially break through into the ventricles, which may or may not expand. Under certain conditions there is also a breakthrough of hemorrhage into the parenchyma. The intraparenchymal hemorrhages have a poor prognosis. There is growing evidence that
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intraparenchymal extension of the hemorrhage oc- curs in tissue that has already suffered from hypoxia.
In other words, the hemorrhage occurs in infarcted tissue, usually a venous infarction.
In explaining the selective vulnerability of white matter in PVL and SCL, multiple risk factors probably play a role. There are three major factors in the selec- tive vulnerability of the periventricular white matter in premature infants: the incomplete state of develop- ment of the vascular supply to the cerebral white mat- ter; the maturation-dependent impairment in regula- tion of cerebral blood flow; and the maturation-de- pendent vulnerability of the oligodendroglial precur- sor cells. The first two factors are the underlying cause of susceptibility to ischemic factors. Arterial end zones and border zones around the ventricles are defined by branches of arteries penetrating the cere- bral wall from the pial surface and arteries from the choroid plexus penetrating the ventricular wall. Pres- sure-passive cerebral blood flow in stressed prema- ture children causes a direct dependency of the cere- bral blood flow on the systemic blood pressure and blood flow, hypotension leading to decreased cerebral perfusion. It has been shown that oligodendroglial precursor cells are highly vulnerable to attacks by free radicals, which are generated by the cascade of events in ischemia–reperfusion events. Mature oligoden- droglia are more resistant to this type of insult. The presence of intraventricular and intraparenchymal blood is a risk factor. In free radical attacks the pres- ence of oxygen and free iron is an important catalyst for the Haber–Weiss reaction and the formation of the perhydroxyl radicals, and the subsequent process of lipid peroxidation. Iron is present in hemorrhagic tissue. Fe
2+can be liberated from ferritin when the pH value is lower than 6. Iron is also actively acquired during the differentiation of oligodendroglia. In the ischemia–reperfusion cascade elevation of extra- cellular glutamate, contributing to excitotoxicity, is a factor contributing to tissue damage. Cytokines re- leased in the presence of maternal (antenatal) and fetal or neonatal infection contribute to the tissue damage. Hypocarbia leading to vasoconstriction has been shown to be a contributing factor to the white matter damage in premature neonates. This finding is of clinical importance, since premature children with respiratory distress supported by artificial ventilation are at risk of developing hypocarbia. Detailed knowl- edge of all the pathogenic factors active in this field is essential to pave the way for interventions and treat- ment regimes.
The pathophysiology of encephalopathy in prema- turely born neonates differs in many aspects from that of term-born neonates. In the postnatal period, the preterm neonate with a low birth weight and im- mature organs is going through an extremely stress- ful period, in which the baby depends on a special en-
vironment, monitoring, and life support measures.
These include artificial ventilation, administration of surfactant, gastric tube feeding, and drug-induced closure of the ductus arteriosus, to mention but a few.
Often there were already prenatal problems, which after preterm birth continue into postnatal problems.
It is often not possible to pinpoint one precise hypox- ic–ischemic incident as the cause of brain damage. In term-born neonates, on the other hand, most cases of hypoxia–ischemia are due to a single, severe, perina- tal incident. The cerebral damage resulting from an acute episode of severe asphyxia is completely differ- ent from the cerebral damage in premature neonates.
Selective vulnerability of the brain in this type of in- cident is apparently dictated by the biochemically most active parts of the brain, which demand the most glucose and oxygen: the zones of active myelina- tion. The resulting damage in the term-born neonate has the form of the so-called central cortico-subcor- tical pattern, with leukomalacia in the myelination zone, extending band-shaped from the basal ganglia into the pre- and postcentral gyri. There are also le- sions in the dorsal part of the putamen, the ventrolat- eral part of the thalamus, and the hippocampus, also actively myelinating at that time. In the premature neonate with a single episode of acute profound as- phyxia, there are as a rule only lesions in the basal ganglia and thalami. This can be explained by the fact that the central cortico-subcortical area is not yet myelinating in premature infants. As far as lesions in the basal ganglia and hippocampus are concerned, excitotoxicity and high local density of glutamate re- ceptors also play a role.
The pathophysiology of MCE is less clear. MCE is usually considered a rare condition in neonates, but still accounts for about 10% of the patients with post- hypoxic–ischemic injury (Sie et al. 2000a). The risk factors for this group show a striking difference as compared to patients developing PVL and those de- veloping the cortico-subcortical pattern. PVL is mainly found in preterm infants who suffer from pro- longed and repeated partial hypoxia–ischemia; the cortico-subcortical pattern mainly in term-born in- fants, following a single episode of acute profound hy- poxia–ischemia; MCE is mainly seen in term-born in- fants, initially with signs of mild hypoxia–ischemia, not requiring vigorous resuscitation at delivery, fol- lowed by a delayed-onset devastating encephalopathy with generalized brain edema. This sequence of de- layed-onset neuronal death resembles the sequence of ischemia–reperfusion damage and secondary energy failure as substantiated in animal experiments.
Without being linked directly to the concept of MCE, it has been noted that neonates, after an initial period of suboptimal responses, improve to a better functional level within the first day, only to present with a catastrophic reaction about 24 h after the first
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episode. The explanation for the first episode of sub- optimal function is sought in the acute reaction of neurons to energy depletion and cell membrane paralysis with edema, swelling, and impaired func- tion. When the cell survives, a second, calcium-de- pendent mechanism is triggered, leading via activa- tion of enzymes, formation of free radicals, lipid per-
oxidation, and accumulation of excitatory amino acids to delayed cell death. This sequence of events does not differ in essence from the general cascades triggered whenever energy failure occurs and can be seen as a final common path of secondary neuronal death.
Chapter 95 Post-Hypoxic–Ischemic Encephalopathy of Neonates 722
Fig. 95.1. A CT scan of a girl with PVL at the age of 2 years (first row) shows asymmetrical ventriculomegaly and calcifications around the ventricles. The T
2-weighted MR images obtained at the age of 3 years (second and third rows) show severe PVL
with dilatation of the lateral ventricles, deformation of the ventricular walls (due to scarring), white matter volume loss, and periventricular gliosis. In addition, pulvinar lesions are pre- sent
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95.4 Therapy
Because of the serious consequences of post-hypox- ic–ischemic damage, many attempts have been di- rected at preventing PVL and other forms of post-hy- poxic–ischemic damage from happening. Intensive check-ups during pregnancy, early in utero diagnosis of congenital abnormalities, electronic fetal monitor- ing during delivery, and technically advanced neona- tal intensive care units have not, however, led to a reduction in the incidence of cerebral palsy, which stands at 1–2 per 10,000 newborns. This is at least partially due to a population shift. Neonates of very low birth weight can now be kept alive and carry high risk factors for the development of post-hypoxic–is- chemic damage. Preventive measures applied in the past to reduce brain metabolism and thus to increase the resistance against hypoxia, such as the use of phe- nobarbital and low body temperature, have failed to improve the outcome. Better understanding of the pathophysiological mechanisms underlying post-hy- poxic–ischemic encephalopathy has triggered new efforts to develop cerebroprotective drugs. It has become clear that disrupted calcium homeostasis within ischemic cells is an essential factor in delayed cell death. Energy depletion leads to high calcium concentration within the cytosol, triggering many other cascades that can damage the cell. Calcium en- try blockers would seem to be a logical answer to this problem. Results of trials, however, have not been satisfactory. One of the cascades triggered by high cytosol calcium is the transformation of xanthine de- hydroxygenase into xanthine oxidase, both of them enzymes of the adenosine-nucleotide biochemical pathway. The formation of xanthine oxidase leads to formation of free radicals and to cell damage by lipid peroxidation after reperfusion. It was hoped that blocking of this cascade would improve the outcome.
Free radical scavengers have also been tested for their ability to prevent reperfusion damage. Substantial
beneficial results have not yet been reported. Energy depletion leads to the accumulation of excitatory amino acids, glutamate in particular. Glutamate ex- erts its stimulating action via at least three different receptors, which have unequal topographical distrib- ution. Of the glutamate receptors, the pharmacologi- cal properties of the NMDA receptor are best under- stood. An attempt has been made to counteract exci- totoxicity by the administration of antagonists for specific sites of the NMDA receptor. Although neuro- protective effects have been obtained in vitro, clinical trials in preterm neonates have been disappointing.
This is probably because glutamate is extremely im- portant for many reactions, and nonselective inhibi- tion may lead to tampering with the other functions of this neurotransmitter. For instance, maturing neu- roreceptors in developing neurosynapses also play a role in the maturation of brain parts and brain func- tions; in the fetal period they are intermediates of cell plasticity and essential in processes of memory and learning.
Once a static encephalopathy has developed, the child should be given physical therapy, special ed- ucation if necessary, and neurological treatment to limit secondary consequences such as spasticity and epilepsy.
95.5 Magnetic Resonance Imaging
Because of its versatility and ability to be used at the bedside, neurosonography (ultrasound, US) will re- main the first-line imaging modality in intensive care units for neonates. Detection and staging of germi- nal-layer-related hemorrhage can be done satisfacto- rily with US. This is also true for the evolution of PVL, which can be followed day by day. Many other brain conditions can be correctly diagnosed by US: for example, cerebral infarctions, hydrocephalus, poren- cephaly, hydranencephaly, and congenital anomalies,
95.5 Magnetic Resonance Imaging 723
Table 95.1. MRI sequences for the evaluation of neonates
Sequence Purpose/contribution
Sagittal T
1-weighted spin echo Small hemorrhages, cysts, congenital anomalies
Proton density and T
2-weighted spin echo Signal changes of white matter and cortical rim, ventricular size
FLAIR Differential diagnosis: asphyxia versus infection
Gradient echo Macro- and microhemorrhages, calcifications
IR Progress of myelination, gray/white matter differentiation
T
1-weighted + contrast Cortical laminar necrosis, infections
DWI–anisotropy–Trace Infarcted and preinfarcted tissue, pattern of abnormalities DTI-FA; fiber tracking Quantitative estimation of brain maturation
MRS Biochemical developmental age; presence of lactate
MRA Vascular anomalies, abnormal vein of Galen
FLAIR, fluid-attenuated inversion recovery; IR, inversion recovery; DWI, diffusion-weighted imaging; DTI-FA, diffusion tensor imaging–fractional anisotropy; MRS, MR spectroscopy; MRA, MR angiography
095_Valk_Post_Hypoxic 08.04.2005 16:53 Uhr Seite 723
such as schizencephaly, corpus callosum agenesis, vein of Galen malformations, and Dandy–Walker malformations.
The role of CT is limited to the diagnosis of hem- orrhages and of calcifications, an important feature of some disorders, for example bilateral thalamic necro- sis. In later cases of PVL, CT may be helpful to show
calcifications in the damaged periventricular region (Fig. 95.1).
When uncertainty remains after US, or discrepan- cy exists between US findings and clinical condition, MRI is indicated. The role of MRI in the diagnosis of post-hypoxic–ischemic conditions in neonates has become increasingly prominent. This is the result of
Chapter 95 Post-Hypoxic–Ischemic Encephalopathy of Neonates 724
Fig. 95.2. a Boy born at 38 weeks of gestation.The pregnancy was complicated by hypertension and perinatal asphyxia oc- curred. MRI at the age of 1 week showed mildly dilated lateral ventricles.T
2-weighted (first and second rows) and T
1-weighted
(third row) images show an intraparenchymal hemorrhage on the left. This type of hemorrhage usually has its origin in a venous infarction and suggests a previous condition of venous congestion
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improvement of MR techniques and, not least, to bet- ter adaptation of the MR procedure to the needs of preterm or term neonates. These improvements con- sist of improvement of monitoring vital signs with MR-compatible equipment, the development of MR- compatible incubators containing the usual life sup- port systems, adapted head coil for neonates, and the
development of faster and new MR sequences. When the requirements for MRI of neonates are fulfilled, a protocol for MRI of neonates could include quite a gamut of sequences (Table 95.1). With the sequences listed in Table 95.1 it is possible to survey the condi- tion of the neonatal brain tissue and in many cases to predict outcome, which is often of major importance
95.5 Magnetic Resonance Imaging 725
Fig. 95.2. b Follow-up studies after 3 months (first row, T
2- weighted; second row T
1-weighted) and 18 months (T
2-weight- ed, third row) show that the left lateral ventricle is enlarged and
there is loss of white matter in the left hemisphere. Myelina- tion is delayed in the left hemisphere
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in patient management. In daily routine not all these sequences will be applied; the first six, however, can considerably help in the initial diagnosis. Fast (turbo) spin echo sequences decrease acquisition time but have the disadvantage of canceling inhomogeneities in the local magnetic field and thus masking the pres-
ence of hemorrhages or calcifications. MRS may con- tribute to the prediction of outcome of post-hypox- ic–ischemic damage in the neonatal period. An ele- vated level of lactate, particularly when present in the basal nuclei of a term neonate, predicts a poor out- come.
Chapter 95 Post-Hypoxic–Ischemic Encephalopathy of Neonates 726
Fig. 95.3. a A boy born at 34 weeks’ gestation with respirato- ry insufficiency.The T
2-weighted images (first and second rows) show a row of dark dots along the lateral upper borders of the ventricles (arrow) and narrow ventricles. Sagittal T
1-weighted
images (third row) show the row as bright dots along the ven- tricular borders, representing small hemorrhagic lesions (ar- row)
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MR patterns in post-hypoxic–ischemic encephalo- pathy can be subdivided into early and late, residual, patterns.
Post-hypoxic–ischemic encephalopathy in preterm neonates encompasses several conditions.
Venous infarctions, often in the wake of germinal- layer- (or matrix-)related hemorrhage, are often still referred to as grade 4 hemorrhages. Venous infarc- tions, frequently located along the border of the later- al ventricles, may occur isolated or together with more extensive PVL (Fig. 95.2).
The most important post-hypoxic–ischemic en- cephalopathy in preterm neonates is PVL. In the first postnatal week the diagnosis may be difficult. Small bright foci around the ventricles on T
1-weighted sagittal or hypointense foci on T
2*-weighted trans- verse images (Figs. 95.3a and 95.4a) are not always followed by cystic changes. More extensive lesions usually do (Figs. 95.3b and 95.4b). It is difficult in the first week to differentiate periventricular white mat- ter changes, with high signal on proton density and T
2-weighted images, from normal white matter, which
also has high signal intensity due to the high water content of the premature brain. In this early phase dif- fusion-weighted images (Trace images, ADC maps) are helpful. In acute PVL, the affected area has lower signal intensity on ADC maps and decreased ADC values. However, it should be noted that the hemor- rhagic components also influence the ADC due to susceptibility effects. Diffusion tensor imaging and quantification of fractional anisotropy values may assist in the diagnosis. In the second week of life the changes become more obvious, also on conventional images. ADC values become higher; subependymal cystic changes appear around the ventricles and will often make contact with the ventricles. The most common late pattern of PVL consists of slightly widened lateral ventricles with irregular borders; loss of white matter volume, with cortical sulci nearly touching the ventricular walls; gliosis in the periven- tricular area; and focal or diffuse thinning of the cor- pus callosum (Figs. 95.1, 95.3b, 95.4b, 95.5, and 95.6).
The presence of gliosis depends on the gestational age at the time of the insult; immaturity of astrocytes be-
95.5 Magnetic Resonance Imaging 727
Fig. 95.3. b Follow-up at the age of 18 months.The T
2-weight- ed images show the typical triad of PVL: irregular borders of the lateral ventricles, especially the trigonum; white matter
volume loss, also predominantly in the peritrigonal area with
cortical sulci abutting the ventricles; and periventricular gliosis
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fore 28 weeks’ gestation may lead to less prominent or absent gliosis. DTI fiber tracking may show the de- fects in the ascending and descending cortical tracts.
Severe cases of PVL are often associated with lesions in the thalamus, especially in the pulvinar (Fig. 95.1).
PVL is not the only manifestation of post-hypox- ic–ischemic encephalopathy in preterm neonates.
Findings at autopsy are enlightening. In 97 autopsies of preterm neonates (Skullerud and Westre 1986), 48 had germinal-layer-related hemorrhage, 23 had PVL,
Chapter 95 Post-Hypoxic–Ischemic Encephalopathy of Neonates 728
Fig. 95.4. a Boy born at 36 weeks’ gestation. In the last trimester there were diminished fetal movements. During de- livery worsening of the condition occurred with cardiac decel- erations, necessitating emergency cesarean section. He had low APGAR scores. The T
2-weighted images (first and second
rows) show small hemorrhages in the germinal matrix along the ventricular border. The sagittal T
1-weighted images (third row) show a number of bright spots along the border of the lateral ventricles, consistent with hemorrhages
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and 57 had pontosubicular necrosis. Of course these findings are not representative of the surviving group.
The diagnosis pontosubicular necrosis is rarely con- sidered in MR reports of preterm neonates and may demand more attention. Sagittal proton density and T
2-weighted images may help to demonstrate abnor- malities in the subiculum.
PVL may occur in term-born neonates, but less frequently than in preterm neonates. Acute profound hypoxia–ischemia occurs more frequently in term neonates. Conventional MR images, including con- trast-enhanced images, may show diffuse cerebral edema. Because the cerebellum is less susceptible to hypoxia, it often is not involved. This results in what may be called a “white cerebrum” on ADC maps or
“black cerebellum” sign on Trace diffusion-weighted images, the reverse of what was already known on CT as the “white cerebellum” sign (Figs. 95.7 and 95.8).
This appearance is even more obvious on coronal dif- fusion-weighted Trace images. When the insult is less severe, another typical pattern develops with lesions in the basal ganglia and the central cortico-subcorti- cal area (Figs. 95.9 and 95.10). On conventional im- ages this pattern of damage may be difficult to ap-
praise in the acute phase; the images suggest most often diffuse edema. Diffusion-weighted Trace images bring out the pattern with high signal intensity, with low ADC values in the affected areas. This pattern typically involves the perirolandic cortex, the corti- cospinal tracts, the dorsal part of the putamen, the ventrolateral part of the thalamus, the hippocampus, and, in the most severe cases, dentate nucleus and brain stem nuclei. The typical late manifestation of severe post-hypoxic–ischemic damage in the term- born neonate consists of gliosis and or atrophy in the above-mentioned brain areas (Figs. 95.9 and 95.10).
In MCE the initial pattern seen on MR is general- ized brain edema of the hemispheres, with sparing of the cerebellum. This is followed by the development of large subcortical cysts that may be spread through all cerebral lobes or confined to the frontal and pari- eto-occipital lobes. The cerebellum is least affected (Figs. 95.11 and 95.12).
Aside from the described patterns, other presenta- tions of post-hypoxic–ischemic encephalopathy are possible. Cortical laminar necrosis (Fig. 95.13) usual- ly shows on T
1-weighted and FLAIR images as a thin rim of higher signal intensity within the cortical
95.5 Magnetic Resonance Imaging 729
Fig. 95.4. b T
2-weighted images at 18 months show the triad of PVL. Myelination is delayed
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layer. On proton density and T
2-weighted images the cortical ribbon in the affected areas is usually less clearly seen. After contrast injection there may be enhancement of this rim. On follow-up this will result in gliosis and atrophy of the affected areas.
In neonates territorial infarctions are relatively rare, but will be seen occasionally. Often they involve the territory of the middle cerebral artery (Fig. 95.14).
The infarction most often involves the entire middle cerebral territory.A polycystic degeneration of the af- fected area follows.
In our experience border zone infarctions are rela- tively rare, but do occur (Fig. 95.15).
Other lesions caused by intrauterine hypoxic con- ditions of the neonate include hydranencephaly, porencephaly, and acquired schizencephaly.
Chapter 95 Post-Hypoxic–Ischemic Encephalopathy of Neonates 730
Fig. 95.5. A girl was born at a gestational age of 31 weeks with perinatal asphyxia and respiratory distress at birth demanding prolonged artificial ventilation. At 2 years T
2-weighted images
show white matter loss and gliosis restricted to the frontal lobes. Frontal localization of PVL is unusual
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95.5 Magnetic Resonance Imaging 731
Fig. 95.6. Images of a 32-year-old mentally retarded and visu- ally handicapped man with a history of perinatal asphyxia. It is unclear whether he also suffered from hypoglycemia. The T
2-
weighted (first and second rows) and FLAIR (third row) images
show severe white matter loss and gliosis in the parieto-occip-
ital area and crowding of the occipital gyri (ulegyria)
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Chapter 95 Post-Hypoxic–Ischemic Encephalopathy of Neonates 732
Fig. 95.7. a Images of a female neonate, born at a gestational age of 41.5 weeks, who suffered from extremely severe perina- tal asphyxia. The MRI was obtained at obtained at 4 days. The proton density images (first row) show an almost complete loss of white–gray matter demarcation. The basal ganglia stand out as white. The T
2-weighted images (second row) con- firm the loss of the cortical ribbon with decreased demarca-
tion between white and gray matter.There is generalized ede- ma.The brain stem and cerebellum are the only structures that seem to have preserved their normal gray–white differentia- tion. The contrast-enhanced T
1-weighted images (third row) show diffuse faint enhancement of the basal ganglia and per- haps the cortex
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95.5 Magnetic Resonance Imaging 733
Fig. 95.7. b Transverse diffusion-weighted Trace images (first row, b = 1000) and ADC maps (second row) show diffuse abnor- malities in the supratentorial regions, which makes them diffi- cult to read: because all structures are abnormal, they do not stand out as abnormal as compared to normal structures. The lower slices show the normal brain stem and cerebellum. The
coronal images (third row,Trace diffusion-weighted image left, and ADC map in the middle) are much easier to interpret. Only the cerebellum has a normal aspect. This “dark” cerebellum on Trace images is the counterpart of the “white” cerebellum as seen on CT in severe hypoxia (third row, right)
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Chapter 95 Post-Hypoxic–Ischemic Encephalopathy of Neonates 734
Fig. 95.8. a
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95.5 Magnetic Resonance Imaging 735
Fig. 95.8. (continued). a Images of a term-born male neonate, victim of a very difficult delivery and repeated attempts at vacuum extraction.The MRI was obtained at the age of 4 days.
The T
2-weighted images (first and second rows) show loss of the cortical ribbon with decreased demarcation between white and gray matter over the large parts of the brain and
generalized edema. The FLAIR images (third and fourth row) show fuzziness of brain structures. The contrast-enhanced T
1-weighted images (fifth and sixth rows) show a remarkable pattern of enhancement in the rolandic area. It remains diffi- cult to assess the condition of the neonate’s brain
Fig. 95.8. b Diffusion-weighted Trace images (first and second rows, b = 1000) and ADC maps (third and fourth rows) show involvement of the cortical and subcortical structures of both hemispheres. Only the cerebellum has a normal aspect.
(Fig. 95.8. b see next page)
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Chapter 95 Post-Hypoxic–Ischemic Encephalopathy of Neonates 736
Fig. 95.8. b
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95.5 Magnetic Resonance Imaging 737
Fig. 95.9. a
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Chapter 95 Post-Hypoxic–Ischemic Encephalopathy of Neonates 738
Fig. 95.9. b
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95.5 Magnetic Resonance Imaging 739
Fig. 95.9. c
Fig. 95.9. a A boy was born at 42 weeks gestational age by emergency cesarean section. There was a severe hypoxic–is- chemic insult. The T
2-weighted images (first and second rows) show perhaps a less clear cortical ribbon in the parietal region and ill-defined basal ganglia, but the abnormalities are not prominent and the images are difficult to interpret. The con- trast-enhanced T
1-weighted images (third and fourth rows) confirm the fuzziness together with some enhancement of the basal ganglia. b Diffusion-weighted Trace images (first and second rows, b = 1000) reveal the cortico-subcortical pattern
and help to establish the prognosis of the child.The ADC maps (third and fourth rows) confirm the low ADC values in the bright areas of the Trace images. c Follow-up MRI at 2 years shows the pattern also on conventional images. The T
2- weighted images (first and second rows) show a gliotic lesion involving the cortex and subcortical white matter in the perirolandic area, and lesions in the dorsal part of the puta- men, the ventrolateral part of the thalamus, the substantia nigra, and the hippocampus on both sides.The pattern is even more conspicuous on FLAIR images (third row)
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