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| Ahead of print
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A study on neurosonography in neonates with hypoxic–ischemic encephalopathy and its correlation with neurodevelopmental outcome
Nachiketa Mangaraj1, Pradosh Kumar Sarangi2, Vinita Malhotra3, Arij Javed4
1 Department of Neuroimaging & Interventional Neuroradiology, AIIMS, New Delhi, India
2 Department of Radiodiagnosis, SCB Medical College, Cuttack, Odisha, India
3 Department of Radiodiagnosis, GSVM Medical College, Kanpur, Uttar Pradesh, India
4 Department of Paediatrics, GSVM Medical College, Kanpur, Uttar Pradesh, India
| Date of Submission | 25-Nov-2020 |
| Date of Acceptance | 22-Feb-2021 |
| Date of Web Publication | 11-Oct-2021 |
Correspondence Address:
Nachiketa Mangaraj,
Department of Neuroimaging & Interventional Neuroradiology, AIIMS, New Delhi.
India
 Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpn.JPN_310_20
 Abstract | | |
Background: Hypoxic–ischemic encephalopathy (HIE) is a devastating condition causing severe neurologic deficits and deaths in children, occurring in about 1.5 out of 1000 live births. The pattern of brain injury depends on the severity and duration of hypoxia as well as the degree of brain maturation at the time of insult. The prognosis can depend largely on diagnosing the early screening of suspected cases, assessment of severity of the injury, and timely intervention. Aims and Objectives: This study is aimed at signifying the importance of neurosonography in neonates with HIE as a diagnostic tool and screening modality in the neonatal intensive care unit (NICU) and at establishing the role of neurosonography and Doppler sonography as an investigatory modality for predicting the neurological damage and influencing their neurodevelopmental outcome. Design: This is a prospective longitudinal-type study. Materials and Methods: A total of 50 neonates admitted in the NICU were included in the study from January 2017 to August 2018 with FUJIFILM SONOSITE (Bothell, Washington, USA) machine using a high-frequency linear probe (6–12 MHz) and convex probe (2–5 MHz). A total of 50 neonates admitted to the NICU were selected and enrolled in the study after fulfilling the selection criteria. The first scans were obtained within 72h of birth, and subsequent follow-up scans were done between the 8th and 10th day and on the 30th day. The infants were then followed up after 6 to 12 months for a detailed neurological assessment. Statistical Analysis Used: All the statistical analyses were carried out using Fisher’s exact test. Results: Out of the eight neurosonographic (NSG) findings analyzed in our study that were found to be associated with hypoxemic brain changes, four of them showed a statistically significant correlation with high positive predictive value (PPV) with poor clinical outcome at 6 to 12 months of age. The PPV of neonates with ventriculomegaly, multicystic leukomalacia, abnormal Doppler indices, and intraventricular hemorrhage (IVH) was found to be 78%, 80%, 82%, and 87%, respectively. Conclusions: Neurosonography was found to be highly significant to predict the clinical outcome in neonates with HIE, and it should be used as the initial screening modality.
Keywords: Doppler, hypoxic ischemic encephalopathy, neonates, neurodevelopmental outcome, neurosonography
How to cite this URL:
Mangaraj N, Sarangi PK, Malhotra V, Javed A. A study on neurosonography in neonates with hypoxic–ischemic encephalopathy and its correlation with neurodevelopmental outcome. J Pediatr Neurosci [Epub ahead of print] [cited 2023 May 30]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=327907 |
| Introduction | |  |
Neonatal encephalopathy, when caused by diffuse hypoxic–ischemic brain injury, is called HIE. HIE is one of the most common causes of severe neurologic deficits in children, apart from being the third most common cause of neonatal deaths worldwide and occurring in about 1.5 out of 1000 live births.[1],[2] Perinatal asphyxia is the most important cause of HIE that can occur either in utero or postnatally. Intrauterine asphyxia is a result of inadequate placental perfusion and impaired gaseous exchange that may be caused by fetal factors (fetal bradycardia, fetal thrombosis, and fetal hemorrhage), maternal factors (preeclampsia, abruption-placentae, maternal hypotension, severe anemia, asthma, and chronic vascular disease), or tight nuchal cord and cord prolapse. Postnatal asphyxia results from conditions causing neonatal pulmonary failure, such as severe hyaline membrane disease, meconium aspiration syndrome, pneumonia, or congenital cardiac disease. Basic pathophysiology involves a lack of sufficient blood flow (ischemia) with decreased oxygen content in the blood (hypoxia), leading to a loss of normal cerebral autoregulation and diffuse brain injury. Apart from oxidative damage from reactive oxygen intermediates (ROIs) due to reperfusion,[3] molecular research has indicated a role of enhanced release of excitatory neurotransmitters (glutamate) as well as abnormal calcium accumulation in the asphyxiated neurons, thereby triggering cellular necrosis.[4] This has opened the doors to emerging targets of intervention and neuroprotection targeting the molecular pathways, including excitotoxicity, inflammation, oxidative stress, and cell death apart from therapeutic hypothermia.[5]
Neurosonography has become an essential diagnostic tool in modern neonatology for depicting normal anatomy and pathological changes in the neonatal brain. It detects most of the hemorrhagic, ischemic, and cystic brain lesions as well as calcifications, cerebral infections, and major structural abnormalities in high-risk infants. It is also very helpful in the early diagnosis of neonatal encephalopathy, assessing its severity and the subsequent monitoring of progress of hypoxic–ischemic brain injury.
The prognosis of HIE depends not only on the severity of injury and gestational age of the infant but also on the time of starting of the intervention, that is, the earlier it is, the better is the prognosis. For maximum benefits, the intervention must be initiated within six hours of hypoxic injury.[6]
The quality of imaging and its diagnostic accuracy depends on the ultrasound machine and also the expertise of the examiner. Sonography can be initiated even immediately after birth and is, hence, suitable for screening and can be repeated as often as possible.
| Materials and Methods | | |
A total of 80 neonates admitted to the NICU of G.S.V.M. Medical College and L.L.R. Hospital, Kanpur were initially enrolled in the study after obtaining informed consent from their parents/guardians. All newborns with perinatal asphyxia were included if at least one of these were present: A. Intrapartum signs of fetal distress, as indicated by a nonreassuring non-stress test on continuous electronic fetal monitoring and by meconium staining of the amniotic fluid. B. Apgar score of <3 at 1min or <7 at 5min of life. C. The requirement of positive pressure ventilation. D. Profound metabolic or mixed acidemia (pH <7.10) in an umbilical artery blood sample (if obtained). E. Clinically staged by Sarnat and Sarnat staging. The exclusion criteria of the study included neonates born with major congenital malformations, chromosomal abnormalities, or any metabolic disorders; neonates born with birth trauma; or neonates born to mothers who have received magnesium sulfate or opioids within four hours before delivery.
About 20 of them either did not fulfil the inclusion and exclusion criteria or were found to be completely normal neurosonographically. Another 10 were lost to follow-up. The remaining 50 neonates were included into the study after obtaining consent from their respective parents/guardians. The NSG studies were performed with FUJIFILM SONOSITE (Bothell, Washington, USA) machine using a multi-frequency high-frequency linear probe (6–12 MHz) and convex probe (2–5 MHz), in accordance with the ethical standards. The first scans were obtained within 72h of birth, and subsequent follow-up scans were done between the 8th and 10th day and on the 30th day so as not to miss the relatively late developing intracranial changes. The infants were then followed up after 6 to 12 months for a detailed neurological assessment for correlation of clinical outcome with NSG findings using statistical analysis.
Brief description of the NSG parameters assessed in the study
Increased cerebral echogenicity
Increased subcortical (in terms) and periventricular (in preterms) echogenicity persisting for >1 week as compared with choroid plexus is termed as Grade 1 periventricular leukomalacia and is found to be more common in preterms [Figure 1].[7],[8] It is usually caused by edema from infarction and coagulative necrosis, and it may also result from hemorrhage.
Multicystic leukomalacia
Cavitations develop in about 10% of cases with periventricular increased echogenicity after two to four weeks of initial insult. Pathologically, this signifies areas of astrocytic proliferation and glial septations [Figure 2]A and B. These cysts typically do not show a connection with the ventricles. The size, number, and position of the cysts affect the prognosis.[9],[10] Based on their location, they are categorized by De Vries[11] as Grade 2 (frontoparietal cortex), 3 (occipital cortex), and 4 (subcortical), which indicates the progression pattern in increasing severity. | Figure 2: (A) Multicystic leukomalacia involving frontoparietal subcortical region. (B) Sagittal and coronal scans showing periventricular frontoparietal cysts
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Multicystic encephalopathy is associated with quadriplegia, bulbar and choreoathetoid symptoms, microcephaly, and mental retardation. Abnormal electroencephalographic (EEG) findings may predict adverse clinical outcome, such as long-term neurologic sequelae or impending death.[2]
Diffuse parenchymal echoes and slit-like ventricles
Salt-and-pepper pattern of cerebral hemispheric echogenicity and/or effacement and obliteration of cerebrospinal fluid-containing spaces are early findings in hypoxic injury that are suggestive of diffuse cerebral edema and these can be observed on day 1 itself [Figure 3] and [Figure 4].[12]  | Figure 4: Coronal scan showing slit-like ventricles with diffuse parenchymal echoes
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Echodense deep gray nuclei and cerebellum
Actively myelinating areas exhibit the highest concentration of NMDA receptors. Increased echogenicity in these areas is usually more apparent after seven days of initial insult and indicates profound hypoxia–ischemia [Figure 5]A and B.[13] | Figure 5: (A) Sagittal sonograms comparing echogenic cerebellum of neonate with severe hypoxic injury with that of a normal neonate. (B) Close-up axial view showing prominent and echogenic bilateral thalami
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Ventriculomegaly
Ventricular enlargement usually results by a passive mechanism due to progressive necrosis, leading to a loss of periventricular white matter [Figure 6]. However, it can also be post-obstructive due to IVH. Ventricular size is usually measured in the coronal section slightly posterior to the foramen of Monroe, with optimum time being at two weeks and at the third month.[14] | Figure 6: Ventriculomegaly in a 10-day-old neonate with slight asymmetry
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Levene was the first to publish reference values for the size of the neonatal lateral ventricles on cranial US images, and his curve is still widely used to decide whether an infant with progressive posthemorrhagic ventricular dilation needs treatment.[15]
In an Indian study on ventricular dimensions in 600 healthy newborns and infants by Soni et al.,[16] observations of the normal range of ventricular measurements and indices were obtained in various age groups till 18 months postnatal, including premature born.
Lateral Ventricular Width (LVW) index was used in our study to label ventriculomegaly.
Intraventricular hemorrhage
Papile et al.[17] graded IVH according to increasing severity as follows [Figure 7]A–C:
- Grade I (germinal matrix hemorrhage)
- Grade II (blood within ventricles but without ventricular dilatation)
- Grade III (blood filling and dilating ventricles)
- Grade IV (intraparenchymal extension of hemorrhage/periventricular hemorrhagic infarction)
Grades I and II resolve spontaneously; grades III and IV are associated with progressive hydrocephalus and are associated with bad prognosis, especially in preterms.[18]
Abnormal Doppler indices
Usually, most of the major intracranial arteries have a resistive index (RI) of 0.6–0.8 with a peak systolic velocity of <50cm/s [Figure 8]A and B.[9] Anterior cerebral arterial (ACA) Doppler values were obtained at the point of ACA just anterior to the third ventricle. Studies have reported that the values of cerebral blood flow velocity (CBFV) and the values of RI correlated with the severity of HIE (P < 0.0001) and subsequent neurodevelopmental outcome (P < 0.001),[19] with a prediction outcome of upto 100% sensitivity and 86% accuracy when performed within 62h of birth.[20] | Figure 8: (A) Site of Doppler evaluation of ACA just anterior to third ventricle. (B) Doppler study showing reduced RI and increased PSV of ACA in a two-day-old neonate with hypoxic injury
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Statistical analysis
The number of cases related to each NSG parameter was obtained and plotted against the clinical outcome of either healthy or severe sequelae/expired in 2 × 2 contingency tables. Sensitivity, specificity, PPV, negative predictive value (NPV), and their individual statistical significance in the form of P-value were obtained using Fisher’s exact test. A combined parametric analysis using the statistically significant parameters associated with high PPV was also done.
| Results | | |
The prevalence and distribution of HIE according to sex, gestational age, birth weight, mode and place of delivery, APGAR score, SARNAT staging, and additional risk factors are shown in [Table 1].
The number of cases of each NSG parameter were obtained and plotted in a bar chart, which shows periventricular leukomalacia to be the most common and echogenic basal ganglia/thalami to be the least common among all [Figure 9]. Each parameter was studied individually with 2 × 2 contingency tables based on the impact that each had on the clinical outcome [Table 2][Table 3][Table 4][Table 5][Table 6][Table 7][Table 8][Table 9]. Also, a statistical analysis of the combined parameters with significantly high PPV and NPV (i.e., IVH, ventriculomegaly, multicystic leukomalacia, and abnormal Doppler indices of ACA) was done [Table 10]. The individual sensitivity, specificity, NPV, PPV, and their statistical significance in the context of prognosis in HIE is calculated and summarized [Table 11]. | Figure 9: A schematic diagram showing the number of cases of each NSG parameter
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 | Table 11: NSG parameters used in our study along with their statistical significance and positive correlation with poor neurodevelopmental outcome
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| Discussion | | |
Despite tumultuous advancements, perinatal asphyxia is still a major cause of neuromotor sequelae in infants. A complete analysis on all aspects of perinatal asphyxia, including the details of the newborn population, obstetrical background of the mother with application of modern imaging and lab techniques, is required to make an impact in the diagnosis and prediction of the prognosis of neonates affected with HIE.
Sarnat and Sarnat[21] combined neurological and EEG features to study the effects of birth asphyxia and labeled it as “neonatal encephalopathy following foetal distress” before dividing them into three stages. This classification has been utilized to define the clinical stages of HIE. In our study, 14% of neonates documented features of stage 1 whereas 52% of neonates were in stage 2 and 34% were in stage 3 of HIE.
The use of multiple acoustic windows and variable frequency transducers has greatly improved the diagnostic sensitivity and specificity of NSG in detecting a wide spectrum of intracranial abnormalities associated with HIE.[9],[12],[22] According to various studies conducted, the sensitivity and specificity of the abnormal sonograms can be as high as 86% and 100%, respectively.[23]
Neurosonogram findings as predictors of outcome
In our study, the first ultrasonographic scanning was carried out within the first three days of life. Follow-up scans at 8 to 10days and on the 30th day of postnatal life were done. We studied the neurodevelopmental outcome during the first year of life (6–12 months) in these infants with perinatal asphyxia. The neurological features that were assessed at the time of clinical examination were the presence of microcephaly, cerebral palsy, presence of postneonatal seizures, failure to thrive, medical illness during infancy, presence of neurodevelopmental impairment, and delayed milestones as per Denver developmental scales[24] which were associated with adverse neurologic sequalae. Our study showed that 50 out of 60 cases of asphyxia had an abnormal sonogram (83%), which closely correlates with that of Boo et al.’s[25] findings (80%).
Our study showed that 25 neonates (50%) showed good prognosis whereas the remaining 50% of neonates showed poor prognosis, and this 50% either had severe neurodevelopmental sequelae or had expired. Among them, eight had severe sequelae and 17 expired; of these, four expired in the first week whereas 11 expired in the first month. This highlights the necessity of early detection and intervention for a better prognosis. The maximum number of cases showed increased cerebral parenchymal echogenecities (40 out of 50) and, hence, had maximum sensitivity for detection among all parameters. However, this is a less specific feature with low PPV and NPV for the prediction of outcome and is, hence, statistically insignificant. The early markers of diffuse cerebral edema, that is, slit-like ventricles and diffuse parenchymal echoes, were also detected in a significant number of cases (21 and 29, respectively, out of 50); however, they were found to be statistically insignificant with a poor correlation with clinical outcome (PPV of 43% and 63%, respectively). Echodense deep gray nuclei/cerebellum was only detected in three cases in those neonates with severe hypoxic injury in the form of additional materno–fetal risk factors such as meconium aspiration, maternal anemia/hypothyroidism, eclampsia, etc. All the three cases expired early in the course of follow-up, thereby reflecting the high specificity and positive correlation (100%) of this finding for poor neurodevelopmental outcome. However, the low number of cases detected made the study insignificant along with a low sensitivity and NPV. Out of 50 neonates, eight showed evidence of IVH. Among the eight, two were of grade 1, two were of grade 2, three were of grade 3, and one showed grade 4 IVH. Seven out of the eight either expired or showed severe neurodevelopmental sequelae, whereas only one turned out to be healthy; five of them were preterms, whereas only three were term neonates. The study was found to be significant (P = 0.04) with a good positive correlation of 87% with poor prognosis, especially if detected in preterms. Ventriculomegaly was detected in 14 cases, mostly between the 8th and 10th day of examination. A significant (P = 0.02) positive correlation of 78% with poor prognosis was found to be associated with it. Multicystic leukomalacia in the form of small (2–3mm) peiventricular frontoparietal as well as large cysts almost completely replacing the cerebral parenchyma were seen in five cases on scans at/beyond one month of postnatal life, thus representing a late sonographic finding in HIE. A significant (P = 0.04) positive correlation with poor neurodevelopmental outcome was seen in 80% of cases (4 out of 5 cases). Abnormal Doppler indices of ACA (RI of <0.6 and PSV > 50cm/s) was found to have maximum correlation with poor prognostic outcome when taken within the first 72 hours of birth. A positive predictive outcome of about 82% was seen with a high statistical significance (P = 0.0001). In an effort to make sonography less cumbersome and more specific, a combined analysis of all the statistically significant parameters with a high positive correlation with clinical outcome was made. The results proved to be extremely statistically significant (P < 0.0001), which shows that there is 82% chance of poor neurological outcome in the presence of at least one of the four significant parameters (PPV = 82%). Also, it is possible to confidently rule out poor neurodevelopmental outcome in about 87% of cases where none of the significant parameters are detected (NPV = 87%). The relative risk of the neonates with HIE showing positive significant parameters compared with those with no significant NSG findings is as high as 6.3. This finding was a bit higher in correlation as compared with that of a study by Khaled et al,[26] where the PPV and NPV of cranial sonographic findings were 78.1% and 58.3%, respectively, with a sensitivity and specificity of 73.3% and 64.1%, respectively, thus proving improved efficiency due to ignoring other less specific and insignificant parameters. Our results disagree with Ezgu et al.,[27] who found that ultrasonographic findings did not seem to predict the grade of encephalopathy or the outcome.
According to Jose et al.,[28] CT and MRI have greater sensitivity and specificity (100% and 82%, respectively) with a slight increase in PPV (94% and 90%, respectively) as well as NPV (100% and 88%, respectively) for the detection of cortical injury and the prediction of abnormal outcome at one year as compared with that of NSG findings, as found in our study by using the four statistically significant parameters. Also, interobserver variability with operator dependency remains a limitation in neurosonography. However, this is comparatively much cheaper, easier, faster, and a portable modality with no risks of radiation or any need of sedation as compared with other imaging modalities, The NSG should be used as the initial baseline investigatory modality of choice for HIE.
| Conclusion | | |
There is a significant role of the neurosonogram in neonates with perinatal asphyxia, as quite a higher proportion of neonates with perinatal asphyxia revealed abnormal neurosonogram findings.
The NSG findings can be used reliably as a screening investigatory modality in the NICU setup for suspected neonatal HIE for early detection and management, as prognosis depends on the time of intervention. Despite the proven fact of having a relatively lower sensitivity in detecting cortical lesions, but being comparatively safer, easier, faster, affordable, and portable modality with no risks of sedation or radiation as compared with CT or MRI, neurosonography must be used as the initial baseline investigatory modality of choice in any NICU for screening as well as diagnosing neonates with HIE.
Consent
Written informed consent was obtained from the study subjects for publication of study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11]
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