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Objective: To determine if patterns of hypoxic-ischemic brain injury on magnetic resonance imaging (MRI) in term newborns predict subsequent childhood epilepsy. Methods: This retrospective cohort study includes term newborns with encephalopathy (n = 181) born between 2004-2012 and admitted to British Columbia Children’s Hospital. MRI was performed between 3 and 5 days of age. The predominant patterns of hypoxic-ischemic injury were classified as Normal, Watershed, Basal Nuclei, Total, and Focal-Multifocal. Lesions in hippocampus, motor and occipital cortex were noted. Results: Of 181 newborns, 166 (92%) survived the neonatal period, and 132 (80%) had follow-up with a median duration of 61 months (IQR: 28–95). Twenty-three children (17%) developed epilepsy. A higher proportion with Watershed, Basal Nuclei, or Total patterns developed epilepsy ( P < .001). Injury to motor cortex, hippocampus, and occipital lobe ( P < .01) were independent risk factors for epilepsy. In the adjusting logistic model, Watershed (odds ratio = 16.0, 95% CI [1.3, 197.2], P = .03) and Basal Nuclei injury (odds ratio = 19.4, 95% CI [1.9, 196.3], P = .01) remained independent risk factors. Therapeutic hypothermia did not alter these associations. Severity of brain injury and recurrent neonatal seizures are other clinical risk factors. Significance: In term newborns with hypoxic-ischemic encephalopathy, the predominant pattern of Watershed and Basal Nuclei injury are valuable predictors for development of epilepsy in later childhood.

Glutaminyl-tRNA synthetase (QARS) deficiency has been described to be a cause of a neurodegenerative disorder associated with severe developmental delay, microcephaly, delayed myelination, and intractable epilepsy. The epilepsy is thought to be more severe than other tRNA synthetase disorders. Only a few cases have been reported in the literature and there is little information about response to different treatment options. The ketogenic diet is a high-fat, low-carbohydrate diet that is used in treatment resistant epilepsy of various etiologies. There are reports that the diet can also improve neuro-cognitive parameters. The authors report a case of a patient with glutaminyl-tRNA synthetase deficiency and treatment resistant seizures where there was a marked and early favorable response in terms of seizures, alertness and behavior to the ketogenic diet.

Aim: To determine the association between lowest plasma magnesium concentration and brain metabolism, and whether magnetic resonance imaging brain injury patterns moderated the association in hypoxic-ischemic encephalopathy. Methods: In 131 early (day-of-life 3) and 65 late (day-of-life 10) scans of term encephalopathic infants born between 2004 and 2012, we examined the association of lowest plasma magnesium (until day-of-life 3) on basal ganglia and white matter peak metabolite ratios on magnetic resonance spectroscopy independent of covariates, stratified by the predominant patterns of injury (normal, basal nuclei/total, watershed, multifocal) using multiple linear regression. Results: Lowest plasma magnesium was associated with lower white matter N-acetyl-aspartate/choline in the multifocal pattern on early scan (regression-coefficient, β: 0.13; 95% CI: 0.04, 0.22) and in the basal nuclei/total pattern on late scan (β: 0.08; 95% CI: 0.02, 0.15), and was negatively associated with basal ganglia lactate/N-acetyl-aspartate (β: −0.16; 95% CI: −0.05, −0.28) and lactate/choline (β: −0.1; 95% CI: −0.03, −0.17) ratio in the basal nuclei/total pattern on late scan independent of hypomagnesaemia correction, cooling and postmenstrual age at scan. Lowest plasma magnesium was not associated with metabolite ratios in other brain injury patterns. Conclusion: In infants with hypoxic-ischaemic encephalopathy, predominant patterns of brain injury moderated the association between lowest plasma magnesium in the first three days of life and impaired brain metabolism.

In cooled newborns with encephalopathy, although late magnetic resonance imaging (MRI) scan (10-14 days of age) is reliable in predicting long-term outcome, it is unknown whether early scan (3-6 days of life) is. We compared the predominant pattern and extent of lesion between early and late MRI in 89 term neonates with neonatal encephalopathy. Forty-three neonates (48%) were cooled. The predominant pattern of lesions and the extent of lesion in the watershed region agreed near perfectly in noncooled (kappa = 0.94; k = 0.88) and cooled (k = 0.89; k = 0.87) infants respectively. There was perfect agreement in the extent of lesion in the basal nuclei in noncooled infants (k = 0.83) and excellent agreement in cooled infants (k = 0.67). Changes in extent of lesions on late MRI occurred in 19 of 89 infants, with higher risk in infants with hypoglycemia and moderate-severe lesions in basal nuclei. In most term neonates with neonatal encephalopathy, early MRI (relative to late scan) robustly predicts the predominant pattern and extent of injury.

Brain injury in term neonatal hypoxic-ischemic encephalopathy (HIE) emerges on magnetic resonance imaging (MRI) by day 3. This study aimed to address the relationship of MRI, diffusion tensor imaging (DTI), and MR spectroscopic imaging (MRSI) findings on days 1 and 3 in a prospective cohort of term newborns with HIE.A total of 24 term newborns with HIE were prospectively studied with MRI on days 1 and 3; 19 were imaged with DTI and MRSI on days 1 and 3. MRI was assessed using validated scores. The relationship between MRI, DTI, and MRSI values on days 1 and 3 was determined using linear regression for repeated measures.Conventional MRI showed a complex variation of findings from day 1 to 3. In gray matter, mean diffusivity (Dav) and metabolite ratios measured on day 1 were predictive of values on day 3 (all P ≤ 0.04). In white matter, Dav, fractional anisotropy (FA), and N-acetylaspartate (NAA)/choline on days 1 and 3 were strongly related (all P ≤ 0.003). Hypothermia appeared to attenuate the severity and progression of brain injury in the six treated newborns.In term newborns with HIE, quantitative MR values on days 1 and 3 are strongly associated, providing an objective measure of injury before qualitative images.

The role of generalized hypoxia-ischemia in the genesis of perinatal focal arterial stroke remains puzzling. Animal studies have demonstrated that hypoxia-ischemia may alter blood flow through the ductus venosus, thereby increasing the risk for placental emboli entering the cerebral circulation. A retrospective review was performed of clinical records of all term newborns admitted to a tertiary perinatal center between January 1995 and May 2007 with acute arterial stroke on neuroimaging during the first week of life. Newborns were classified into 2 groups on the basis of neuroimaging abnormalities: stroke alone, or stroke and nonfocal hypoxic-ischemic brain injury. A total of 62 newborns had focal or multifocal stroke, 36 with stroke alone and 26 with stroke with nonfocal hypoxia-ischemia. Multiple risk factors for hypoxia-ischemia occurred in most newborns in both groups. These data indicate that hypoxia-ischemia may play a role in the genesis of stroke in the term newborn with or without evidence of nonfocal hypoxic-ischemic brain injury on neuroimaging.

We describe a family with QARS deficiency due to compound heterozygous QARS mutations, including c.1387G > A (p.R463*) in the catalytic core domain and c.2226C > G (p.Q742H) in the anticodon domain, both previously unreported and predicted damaging. The phenotype of the male index further confirms this specific aminoacyl-transfer RNA (tRNA) synthetase disorder as a novel genetic cause of progressive microcephaly with diffuse cerebral atrophy, severely deficient myelination, intractable seizures, and developmental arrest. However, in contrast to the two hitherto published families, the cerebellum and its myelination are not affected. An awareness that QARS mutations may cause isolated supratentorial changes is crucial for properly directing genetic analysis.

Enhanced survival of very premature infants may be regarded as the most striking demonstration of the major improvements in perinatal medicine during the last two decades. This article discusses recent perinatal interventions in the context of the pathogenesis and known risk factors for intraventricular hemorrhage (IVH). In addition, controversies related to the evolution and management of posthemorragic hyrdocephalus (PHH) are examined, and current concepts concerning potential brain injury to PHH are reviewed.

Recent epidemiologic data demonstrate that prenatal factors play a major role in the genesis of brain injury in childhood, e.g., cerebral palsy and mental retardation. Nevertheless, there is extensive experimental, clinical, and neuroimaging data that show that acute, intrapartum hypoxic-ischemic insult is an important factor in the genesis of irreversible brain injury, especially in term newborns. The precise timing of onset of hypoxic-ischemic cerebral injury in premature newborns may be more difficult to establish, and postnatal complications (e.g., intraventricular hemorrhage, posthemorrhagic hydrocephalus) undoubtedly play a major role. When the potential deleterious consequences of severe, intrapartum asphyxia are minimized, there is a risk that important opportunities for prevention of newborn cerebral injury may be missed. In this context, new techniques may permit rapid, in vivo delineation of the critical processes involved in newborn hypoxic-ischemic brain injury that are key factors for the development of effective preventive and interventional strategies. MRDD Research Reviews 3:22–27, 1997. © 1997 Wiley-Liss, Inc.

BACKGROUND AND PURPOSE: Low glucose values are often seen in term infants with NE, including HIE, yet the contribution of hypoglycemia to the pattern of neurologic injury remains unclear. We hypothesized that MR features of neonatal hypoglycemia could be detected, superimposed on the predominant HIE injury pattern. MATERIALS AND METHODS: Term neonates (n = 179) with NE were prospectively imaged with day-3 MR studies and had glucose data available for review. The predominant imaging pattern of HIE was recorded as watershed, basal ganglia, total, focal-multifocal, or no injury. Radiologic hypoglycemia was diagnosed on the basis of selective edema in the posterior white matter, pulvinar, and anterior medial thalamic nuclei. Clinical charts were reviewed for evidence of NE, HIE, and hypoglycemia (

OBJECTIVE. Our goal was to compare the patterns of brain injury detected by computed tomography, conventional MRI (T1- and T2-weighted sequences), and diffusion-weighted MRI in a cohort of term newborns with neonatal encephalopathy studied uniformly with all 3 modalities on the third day of life.METHODS. Term newborns (≥36 weeks' gestation) admitted to our center with neonatal encephalopathy were scanned with computed tomography, MRI, and diffusion-weighted MRI at 72 (±12) hours of life (n = 48). Each modality was scored independently of the other with previously validated scoring systems. The predominant pattern of brain injury was classified as: normal, watershed, basal nuclei, total (maximal basal nuclei and watershed), and focal-multifocal (presence of strokes and/or white matter injury alone).RESULTS. The agreement for the predominant pattern of injury was excellent between MRI and diffusion-weighted MRI (77% agreement). The agreement for the pattern of injury was also good for computed tomography and diffusion-weighted MRI (67% agreement). The extent of cortical injury and focal-multifocal lesions, such as strokes and white matter injury, were less apparent on computed tomography than diffusion-weighted MRI. In 19 newborns with a repeat MRI in the second week of life, the predominant pattern seen on the day 3 diffusion-weighted MRI was confirmed.CONCLUSIONS. Diffusion-weighted MRI is the most sensitive technique with which to assess brain injury on day 3 of life in term newborns with neonatal encephalopathy, particularly for cortical injury and focal-multifocal lesions such as stroke and white matter injury. All 3 modalities identify the most serious patterns of brain injury similarly.

A common pattern of hypoxic-ischemic cerebral injury in the term newborn involves predominantly cerebral cortex and subcortical white matter. We describe 20 term newborns with moderate or severe acute hypoxic-ischemic encephalopathy who exhibit a different pattern of abnormalities on computed tomography, with evidence of decreased tissue attenuation predominantly in thalami and basal ganglia and relative preservation of cerebral cortex and white matter. Profound, acute hypoxic-ischemic insult (eg, umbilical cord prolapse, uterine rupture, or massive placental abruption) was documented in 16 of 20 infants (80%). Characteristic clinical features during the newborn period included irritability, tonic posturing of limbs, and persistent lower cranial nerve dysfunction, often with prominent tongue fasciculations. This pattern of central injury appears to be highly predictive of poor outcome; 7 newborns (35%) died, and all survivors who had follow-up to 18 months of age (11) had major neurological sequelae (eg, spastic quadriplegia, choreoathetosis, and persistent feeding problems). This pattern of hypoxic-ischemic cerebral injury corresponds closely to experimental animal models of "acute total" perinatal asphyxia.

White matter injury (WMI) is the characteristic pattern of brain injury detected on magnetic resonance imaging in the premature newborn. Focal noncystic WMI is increasingly recognized in populations of term newborns. The aim of this study was to describe the occurrence of focal noncystic WMI in a cohort of 48 term newborns with encephalopathy studied with magnetic resonance imaging at 72 +/- 12 h of life, and to identify clinical risk factors for this pattern of injury. Eleven newborns (23%; 95% CI 11-35) were found to have WMI (four minimal, three moderate, and four severe). In 10 of the 11 newborns, the WMI was associated with restricted diffusion on apparent diffusion coefficient maps. An increasing severity of WMI was associated with lower gestational age at birth (p = 0.05), but not lower birth weight. Newborns with WMI had milder encephalopathy and fewer clinical seizures relative to other newborns in the cohort. Other brain injuries were seen in three of the 11 newborns: basal nuclei predominant pattern of injury in one and cortical strokes in two. These findings suggest that WMI in the term newborn is acquired near birth and that the state of brain maturation is an important determinant of this pattern of brain injury.

Intraventricular hemorrhage is an uncommon problem in the full-term newborn. In a review of 19 full-term infants with intraventricular hemorrhage diagnosed on computed tomography prior to 1 month of age, thalamic hemorrhage associated with the intraventricular hemorrhage was documented in 12 infants. Thus, thalamic hemorrhage appears to be the most common source of intraventricular hemorrhage in this age group, particularly in infants who had uneventful birth histories and in whom clinical abnormalities (signs of increased intracranial pressure, seizures, altered level of consciousness) developed after the first week of life. The majority of these infants had predisposing factors for cerebral venous infarction such as sepsis, cyanotic congenital heart disease, and coagulopathy. The clinical appearance and outcome for infants with thalamic hemorrhage/intraventricular ular hemorrhage were similar to those in infants with intraventricular hemorrhage originating from other sites, except for an increased incidence of cerebral palsy in infants with thalamic hemorrhage/intraventricular hemorrhage. Definitive diagnosis was made on the basis of characteristic radiologic abnormalities.

Germinal matrix-intraventricular hemorrhage (GMH-IVH) in the premature newborn results from rupture of fragile capillaries in the germinal matrix. Its pathogenesis is multifactorial and relates principally to a pressure-passive cerebral circulation, fluctuations in cerebral blood flow, and derangements of coagulation and fragility of the germinal matrix microvasculature. Several interventions have beneficial effects for prevention of GMH-IVH. Outcome after GMH-IVH relates largely to the severity of hemorrhage, the extent of hemorrhagic and ischemic parenchymal involvement, and complications (e.g., posthemorrhagic hydrocephalus). Even in the absence of neuroimaging abnormalities, VLBW infants have a high incidence of academic and behavioral problems which persist into adolescence and early adulthood.

Four newborns presented with isolated radial nerve palsy during the first 2 days of life. In three, there was a history of failure of progression of labor, which may have resulted in prolonged radial nerve compression. Furthermore, three infants had fat necrosis of the upper arm above the elbow, suggestive of compression of the radial nerve in the region of the spiral groove. Significant recovery of function was evident within 1 month in all four infants. The authors review published reports about the rare condition of isolated radial nerve palsy in the newborn.

Perinatal hypoxic-ischemic cerebral injury is a significant cause of neurological morbidity and mortality in childhood. It is often difficult to determine the precise timing of such injury. Data from epidemiological and neuropathological studies have identified several maternal and fetal risk factors that seem to be associated with suspected prenatal brain injury. Hypoxic-ischemic cerebral injury that originates earlier in gestation may result in few, if any, clinical abnormalities during the newborn perlod. Clinical abnormalities may also be difficult to recognize in the premature newborn, and greater reliance must be placed on other adjunctive investigations, eg, neuroimaging. In contrast, term infants who sustain acute, intrapartum hypoxic-ischemic insult of sufficient magnitude to result in long-term sequelae invariably show recognizable encephalopathy during the newborn period. A combination of clinical data and adjunctive investigations during the neonatal period is a powerful predictive tool for long-term outcome.

The understanding of the molecular genetics of inherited neuromuscular disorders has unfolded rapidly in recent years. Identification of the genetic defects involved has enhanced diagnosis, prognosis, carrier detection, and prenatal diagnosis and has provided a basis for rational treatment strategies. This review provides an update on the most common neuromuscular disorders that present in childhood, eg, spinal muscular atrophy, muscular dystrophies, and myotonic disorders, and includes information on molecular genetics, pathogenesis, natural history, and experimental therapeutic strategies.

Review of 17 newborns with muscle disease demonstrated that clinical features associated with survival beyond 1 year of age included gestational age of at least 35 weeks and requirement of mechanical ventilation for less than 21 days. In contrast, poor outcome was associated with Apgar scores below 5 at 5 min, pulmonary complications, arthrogryposis, or other congenital anomalies. The incidence of decreased fetal movements, polyhydramnios, hypotonia, and assisted delivery was not statistically different between infants who died early and those who survived beyond 1 year of age. Clinical features of newborns with muscle disease may be useful for prediction of outcome, especially when muscle biopsy abnormalities are nonspecific.

Sixty-five cases of periventricular leukomalacia (PVL) documented by CT were assessed in terms of the location and severity in reduction of periventricular white matter. CT studies of these and 75 age-matched controls were assessed for thalamic volume. The thalamic volume estimates were correlated with the location and severity of PVL on CT, and with clinical features. Asymmetric loss of thalamic volume was a frequent observation in PVL (38%) and correlated well with both clinical findings and asymmetry of periventricular white matter loss. Symmetric absolute loss of thalamic volume was common and was directly proportional to the severity of PVL. These observations support the hypothesis that neuronal injury and Wallerian degeneration following the hypoxic-ischemic insult cause secondary thalamic atrophy proportional to the severity of periventricular atrophy.

• Recent data suggest that early loss of brain tissue water content, ie, decreased extravascular cerebral tissue pressure, may play a role in the pathogenesis of germinal matrix/intraventricular hemorrhage in the premature newborn. This study examines the relationship between the concentration of serum sodium and germinal matrix/intraventricular hemorrhage in 299 premature infants with birth weights of less than 1500 g during the first 4 days of life. Intraventricular hemorrhage developed in 34 (32%) of the 106 infants with maximum serum sodium levels of 145 mmol/L or less and in 54 (28%) of 193 infants whose highest serum sodium levels were greater than 145 mmol/L (χ 2 =0.37). These data suggest that concentrations of serum sodium greater than 145 mmol/L are not associated with an increased risk of germinal matrix/intraventricular hemorrhage in the premature newborn. Consequently, more liberal administration of fluids to maintain extravascular cerebral tissue pressure is unlikely to reduce the incidence of germinal matrix hemorrhage/intraventricular hemorrhage. ( AJDC . 1990;144:1019-1021)

Hypoxic-Ischemic Encephalopathy in the Term Newborn in British Columbia throughout a Three Year Period: Regional Incidence and Sociodemographic Factors 1061

Periventricular leukomalacia (PVL) occurs commonly in premature infants. The white matter injury is considered to be principally a consequence of ischemic insult to vascular watershed zones with high intrinsic vulnerability. However, other factors, eg., bacterial endotoxins, have also been implicated. In premature newborns with PVL, we observed a high incidence (50%) of presumed antenatal infection compared with controls, based on clinical data. In this study, we describe placental abnormalities associated with cystic PVL and assess their clinical relevance in its pathogenesis.

139 COMPARISON OF FOREARM OXYGENATION DURING ISCHAEMIA BY NEAR INFRARED SPECTROSCOPY AND PO 2 HISTOGRAPHY

Visual defects are often poorly recognized in children with multiple neurologic problems due to perinatal hypoxic-ischemic encephalopathy. We report the clinical, radiologic, and electrodiagnostic characteristics of 20 children with cortical visual impairment secondary to birth asphyxia. Clinical diagnosis often was delayed. Ten patients recovered vision during the first two years of life. Four infants had coexisting damage to the pregeniculate visual pathway. Useful investigations included cranial computed tomography and visual evoked potential mapping. Electroencephalographic abnormalities were nonspecific. The classical definition of cortical blindness must be modified for children.

The role of brain swelling following acute hypoxic-ischemic insult in the genesis of brain injury in the term newborn is controversial. Recent experimental animal studies suggest that it may result from prior irreversible cerebral necrosis and therefore represents a consequence as opposed to a cause of major brain injury. In this study, 32 asphyxiated term newborns were studied during the first week of life with serial intracranial pressure measurements. A total of 26 infants had scans during the first five days of life. Seven patients had two CT scans within this period. These investigations were correlated with outcome at 18 months of age. Seven infants had increased intracranial pressure (> 10 mm Hg) that reached a maximum between 36 and 72 hours of age. Cerebral perfusion pressures remained normal, which makes ongoing ischemic injury unlikely as a cause. The seven patients with increased intracranial pressure had decreased attenuation on CT that was generalized in six infants and patchy in one infant. Of the infants with increased intracranial pressure and severe CT abnormalities, three died and four had severe neurologic sequelae. In seven infants, a second CT scan at three to four days of life demonstrated progression of the decrease in tissue attenuation. Most of the infants with normal intracranial pressure (23/25) had no or had only minor neurologic abnormalities at follow-up. These data suggest that brain swelling is relatively uncommon in the asphyxiated term newborn. The temporal profile of increased intracranial pressure and CT abnormalities, with maximum abnormalities at 36 to 72 hours of age, is most consistent with cerebral necrosis as a cause that, in turn, implies a poor prognosis.

Eight children with clinical and radiologic abnormalities consistent with periventricular leukomalacia were investigated with MR imaging of the brain that employed both inversion-recovery and T2-weighted spin-echo imaging sequences. The more precise delineation of white and gray matter on inversion-recovery images as compared with CT allows a detailed demonstration of the anatomic features of periventricular leukomalacia; specifically, a reduced quantity of white matter in the periventricular region and centrum semiovale and, in more severe cases, cavitated infarcts that replace the immediate periventricular white matter. The T2-weighted spin-echo and short inversion time inversion-recovery images demonstrated abnormally increased signal in white matter that appeared normal on CT scans and only minimally abnormal on conventional inversion-recovery images. These abnormalities most probably represent white matter gliosis that extends beyond the immediate periventricular regions. MR recognition of cerebral white matter abnormalities associated with periventricular leukomalacia may confirm the clinical suspicion of this diagnosis in children with spastic diplegia or quadriplegia.

This article outlines the approach to clinical evaluation of the hypotonic newborn with suspected neuromuscular disease. Specific conditions that affect primarily the anterior horn cell, peripheral nerve, neuromuscular junction, and skeletal muscle are reviewed in the context of current understanding of the development of the motor system. Thus, it may be speculated that the distinction between myopathies and neuronal disorders is somewhat artificial. The difficult ethical decision regarding long-term mechanical ventilation for severe neonatal neuromuscular disease is discussed briefly.

Aicardi's syndrome occurs in females and is associated with profound mental retardation, agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms. We report a distinctive combination of abnormalities which was observed on real-time cranial ultrasound scans of two infants with Aicardi's syndrome. These abnormalities include bilateral prominent cysts in the choroid plexus in conjunction with agenesis of the corpus callosum. Recognition of these radiologic findings may suggest the diagnosis of Aicardi's syndrome in early infancy even prior to the onset of seizures or visualization of chorioretinal lacunae. (J Child Neurol 1989;4:307-310).

The recent epidemic of cocaine abuse, especially among young individuals, has caused increasing concern about the potential hazards of prenatal cocaine exposure on the developing fetus and newborn. Although large-scale epidemiologic studies and long-term data are lacking, a review of the literature suggests strongly that the popular belief about the relative safety of cocaine is unfounded and that maternal cocaine abuse during pregnancy may be associated with increased perinatal morbidity and mortality.

• The role of thrombocytopenia as a risk factor for intraventricular hemorrhage in infants of very low birth weight is unclear. This study investigates the relationship between the lowest platelet count and the occurrence of intraventricular hemorrhage in 302 consecutively admitted infants with birth weights under 1500 g. Intraventricular hemorrhage, which occurred in 90 infants (29.8%), was correlated with the lowest platelet count obtained during the first 4 days of life. In 27 infants with intraventricular hemorrhage, the lowest platelet count was less than 100×10 9 /L. Statistical analysis of the data demonstrated that reduced platelet count was not associated significantly with intraventricular hemorrhage. Similarly, the severity of intraventricular hemorrhage did not correlate with the lowest platelet count. These data suggest that a reduced platelet count does not play a major role in the pathogenesis of intraventricular hemorrhage in infants of very low birth weight. ( AJDC 1988;142:1222-1224)