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REVIEW ARTICLE |
https://doi.org/10.5005/jp-journals-11002-0091 |
Utility of Point-of-care Ultrasound in Hypoxic-ischemic Brain Injury in Neonates
1Department of Neonatology, National Institute of Medical Sciences and Research, Jaipur, Rajasthan, India
2Global Newborn Society, Clarksville, Maryland, United States of America
3Department of Neonatology, Bharati Vidyapeeth University (BVU) Medical College Hospital, and Research Centre, Pune, Maharashtra, India
4Department of Neonatology, Motherhood Women and Children’s Hospital, Bengaluru, Karnataka, India
5Mbuya Nehanda Hospital, Mazowe Street, Harare Zimbabwe; African Neonatal Network, Zimbabwe
6Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
7Department of Pediatrics, Mercy Hospital, Nagaon, Assam, India
8Department of Pediatrics, Chhattisgarh Institute of Medical Sciences, Bilaspur, Chhattisgarh, India
9Department of Neonatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
10Department of Neonatology/Pediatrics, Louisville State University, Shreveport, Louisville
11Banaras Hindu University Institute of Excellence, Varanasi, Uttar Pradesh, India
12Department of Neonatology, BVU Medical College, Hospital and Research Center, Pune, Maharashtra, India
13Department of Neonatology/Pediatrics, Sahyadri Hospital, Pune, Maharashtra, India
Corresponding Author: Pradeep Suryawanshi, Global Newborn Society, Clarksville, Maryland, United States of America; Department of Neonatology, BVU Medical College, Hospital and Research Center; Department of Neonatology/Pediatrics, Sahyadri Hospital, Pune, Maharashtra, India, Phone: +91 9923540500, e-mail: drpradeepsuryawanshi@gmail.com
How to cite this article: Kumar G, Deshpande S, Sreekanth S, et al. Utility of Point-of-care Ultrasound in Hypoxic-ischemic Brain Injury in Neonates. Newborn 2024;3(2):124–138.
Source of support: Nil
Conflict of interest: Dr Akhil Maheshwari is associated as Editor-in-Chief of this journal and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of the Editor-in-Chief and his research group.
Received on: 17 April 2024; Accepted on: 20 May 2024; Published on: 21 June 2024
ABSTRACT
Background: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy (HIE) remain a significant cause of neonatal morbidity and mortality. This review focuses on the utilization of bedside cranial ultrasound in HIE to guide appropriate therapy, monitor disease progress, provide prognostic information, and help identify relevant research areas.
Methods: A comprehensive literature search was conducted to review recognized patterns of HIE seen on ultrasound. Further efforts were focused on understanding the clinical relevance of these changes in the management of such infants and the prediction of long-term neurodevelopmental outcomes.
Results: We reviewed cranial sonographic changes in asphyxiated neonates. Dynamic changes are observed across various time frames; hyperechogenicity of the thalamus, basal ganglia, and the altered appearance of the posterior limb of the internal capsule (PLIC) are frequently seen in acute and subacute insults. Also, a resistive index of 0.55 or less in cerebral Doppler studies within the first 72 hours of life is associated with adverse short- and long-term outcomes and increased mortality.
Conclusion: Bedside cranial ultrasound is a useful screening tool for the diagnosis and monitoring of neonates with HIE. However, further studies are needed to improve our understanding of sonographic findings as predictors of adverse neurodevelopmental outcomes and mortality in affected neonates.
Keywords: Basal ganglia, Birth asphyxia, Cerebral Doppler, Cranial ultrasound, Echogenicity, Four-column sign, Hypoxic-ischemic encephalopathy, Neonates, Periventricular leukomalacia, PLIC sign.
KEY POINTS
Cranial ultrasonography (USG) is a valuable screening tool in the diagnosis and management of asphyxiated neonates.
Serial USG can identify the evolution, pattern, timing, and severity of injury.
Near-total asphyxia with extensive grey and white matter involvement is associated with increased neurological morbidity and mortality.
Resistive index values on cerebral Doppler study before initiation of therapeutic hypothermia can serve as an important marker of long-term prognosis.
We need a better understanding of the progression of HIE in neonates, focusing on its diagnostic and prognostic implications, and identifying relevant research areas.
INTRODUCTION
Perinatal asphyxia and consequent hypoxic-ischemic encephalopathy (HIE) is a frequently seen pathology associated with considerable short- and long-term neurodevelopmental morbidities and mortality.1,2 Neuroimaging, including cranial ultrasonography (USG) and magnetic resonance imaging (MRI), are important tools for confirming the diagnosis, assessing the severity of the injury, guiding clinical decisions, and predicting the likelihood of adverse outcomes. Magnetic resonance imaging with diffusion-weighted imaging and proton-spectroscopy can help predict adverse outcomes in HIE, but it has limitations as an imaging modality including its cost, need for sedation, and limitations of portability of the equipment.3,4
Point-of-care ultrasound (POCUS) is increasingly being recognized as a useful tool in the management of HIE5 the equipment is widely available, is inexpensive and can be used for sequential evaluation of the progression of encephalopathy. If the care provider has a reasonable grasp of neuroanatomy seen through the acoustic window, cranial USG can help outline diverse pathologies including grey- and white-matter ischemic injury, intracranial bleeding, and any malformations. Additionally, Doppler studies can help in real-time assessment of perfusion and the evolution of the injury.6–8 These can also serve as pivotal screening tools prior to commencing therapeutic hypothermia (TH).9,10 In this article, we have reviewed the utility of cranial USG in the diagnosis, monitoring, management, and prognostication of HIE.
Technique and Normal Views
A brief summary of the technical needs in the sonographic assessment of HIE is provided below:
Transducer
A multi-frequency (5–10 MHz) convex or linear array transducer is useful. The lower-frequency transducer enables visualization of deeper structures including the deep grey matter, temporal lobes, and the posterior fossa, whereas the higher frequencies can improve the resolution for visualizing the more superficial cortex and underlying subcortical white matter.11,12 In addition to standard cranial USG views through the anterior fontanel, ancillary acoustic windows such as the mastoid fontanels for supratentorial structures and the temporal window for a transverse view of the brainstem area can improve diagnostic accuracy.11 Cine clips providing real-time evaluation are more useful than static images for appreciating subtle changes in echogenicity (Figs 1 to 4).13
Figs 1A and B: Anterior fontanel coronal and sagittal views. (A) Probe in coronal plane; (B) Mid-ventricle view showing various parts. The normal echogenicity of the brain parenchyma, including that of grey and white matter are notable
Figs 2A and B: Anterior fontanel sagittal view. (A) Probe in sagittal plane; (B) Midline sagittal view showing various parts. Parts of the corpus callosum shown in yellow font
Fig. 3: Anterior fontanel parasagittal view showing caudothalamic groove, thalamus, and the choroid plexus
Figs 4A and B: Axial view through the mastoid fontanel; please note the position of the probe in the mastoid area to visualize the cerebellar hemisphere
Normal Pattern of Echogenicity on Cranial USG
The white matter normally shows a loosely packed, low-level granular echogenicity. It becomes less echogenic as it merges with anechoic grey matter. This normal pattern of regional echogenicity progressively increases from grey matter, thalamus, and descending corticospinal tracts, to the choroid plexus (Figs 1 to 4).
Abnormalities on Grey-scale Cranial USG in Asphyxiated Neonates
Sequential assessment using cranial USG can provide a pictorial representation of the pattern, evolution, and severity of brain injury. In terms of pathophysiology, the acute phase of HIE is marked by anaerobic metabolism, depletion of high-energy metabolites, cytotoxic edema, and neuronal apoptotic cell death, followed by ongoing inflammation, and secondary energy failure. In contrast, the chronic phase includes reparative changes and reorganization that may continue for months.14–16 Cerebral edema, neuronal necrosis, gliosis, infarcts, hemorrhages, hypermyelination, and calcification may manifest as diffuse or patchy echogenicity on cranial USG, depending on neuropathological patterns of injury.17 Typical findings suggestive of near-total asphyxia become more apparent after the first 24–48 hours following the onset of HIE, but the variability of such findings depends on the severity of the injury, the presence of coexisting complications, and the onset of insult.17
Evolution and Pattern of Asphyxia-induced Brain Injury
Changes in Acute and Subacute Phase
Increased white matter echogenicity
Depending on the severity of the injury, diffuse or patchy echogenicity in periventricular and subcortical regions is associated with similar or slightly less prominent echogenicity in the choroid plexus.13,18 Severe subcortical white matter hyper-echogenicity appears as ‘tramlines’ due to hypoechoic signals of cortex in between, best seen in sagittal views (Fig. 5).18 Primary white matter injury manifests within a context of both partial and sustained hypoxia.17
Fig. 5: Tramline appearance in parasagittal view. Hyperechoic subcortical white matter superimposed over the hypoechoic signals of the cortex viewed as forming ‘tramlines’. Differentiation of the grey and white matter can be noted throughout the entire brain both in anterior and posterior distributions
Loss of grey-white matter differentiation
In less severe cases, grey-white matter differentiation may be accentuated due to enhanced white matter echogenicity compared with the cortical grey matter.19 However, parenchymal edema in more severe injury shows a loss of the anatomical landmarks of the brain such as sulci and interhemispheric and sylvian fissures (Fig. 6).13,18
Fig. 6: Cerebral edema with poorly distinguished grey-white matter. Both lateral ventricles show a slit-like appearance due to parenchymal edema and consequent compression. There is effacement of cerebral sulci and narrowing of intrahemispheric fissures
Compression of brain structures due to parenchymal edema
Cerebral edema may be seen within 24–48 hours following injury due to ongoing intrapartum sentinel events. The resultant parenchymal compressive changes appear as slit-like ventricles, effacement of cerebral sulci, narrowing of intrahemispheric fissures, and basal cisterns (Fig. 6).17 However, one must bear in mind that ventricles may appear small in size in some normal infants in the first 36 hours of life. Consequently, caution is advised in the interpretation of these observations.20
Hyperechogenicity of deep grey matter
A central, unilateral or bilateral, pattern of injury could be seen as focal or diffuse hyperechogenicity of the thalamus and putamen (Figs 7 and 8). This is usually described as the ‘four-column sign’ in the coronal view, with echogenic thalamus and basal ganglia on each side, giving an appearance of four pillars parallel to each other, thereby enhancing the visibility of the hypoechoic crescentic posterior limb of internal capsule (often referred to as PLIC sign; Fig. 8).18 This pattern often implies severe HIE following near-total asphyxia, due to sentinel events such as placental abruption or cord prolapse.17,21
Fig. 7: Parasagittal view from a 7-day-old asphyxiated neonate showing a hyperechoic thalamus representing grey matter injury
Fig. 8: Coronal view from a severely asphyxiated acute neonate showing the ‘four-column sign with involvement of the posterior limb of the internal capsule (PLIC sign). Due to the acute insult, the thalami and basal ganglia on both sides appear hyperechogenic and are visualized as four pillars separated by a hypoechoic internal capsule
Cerebellar involvement
A hyperechogenic cerebellum is best seen in axial view. This is one of the least recognized patterns of injury in neonates and represents severe insult. Cerebellar USG is a niche area of research that requires more rigorous evaluation; these results could help understand the extent of disease injury.17,22
Hemorrhages
Term infants may develop intraventricular hemorrhages originating in the choroid plexus. In contrast, preterm infants typically show germinal matrix and/or parenchymal hemorrhages.21
Distinct Patterns of Hypoxic-ischemic Injury
Myers described four distinct patterns, which are likely related to variations in the cause, timing, site, and severity of insults across diverse clinical situations (Table 1).23
| Pattern of injury | Severity of injury | Specific USG findings |
|---|---|---|
| 1. Near-total asphyxia | – Severe compromise in fetal blood flow | – Areas involved basal ganglia, thalamus sparing the internal capsule, the brainstem, and the cerebellum.27,28 |
| – High mortality or survival with disability.24,25 | – Extensive grey and white matter regions of hyperechogenicity on CUS (Fig. 9). | |
| – Can be unilateral/bilateral/focal. | ||
| – More pronounced after 24–48 hours. | ||
| – Brainstem involvement is an independent risk factor for death in the neonatal period.26 | ||
| 2. Watershed injury | – Seen in cases of partial prolonged asphyxia.29 | – Wedge-shaped region of hyperechogenicity at border zones. |
| – Cortical hypoperfusion manifests at the outer edges of major arterial perfusion territories.30,31 | – Watershed zones include area of frontal lobe, near the posterior horn, in the parafalcine region in the subcortical white matter, and in parieto-occipital region. | |
| – Milder clinical signs than near-total asphyxia and less severe outcome.32 | – Cortical injury may appear as parenchymal edema (Fig. 10). | |
| – MRI is superior to USG for the extent of injury.24 | ||
| 3. Primary white matter injury | – Denotes partial asphyxia with sustained hypoxia. | – Subcortical and periventricular white matter hyperechogenicity. |
| – Internal capsule involvement, commonly precedes global developmental delay, visual impairment, and seizures. | – Increased corticomedullary differentiation on CUS (Fig. 11). | |
| 4. Concurrent partial and near-total asphyxia | – Worst prognosis as compared with other pattern of injury. | – Most affected area – Basal ganglia. |
| – Bilateral involvement and higher echogenicity predict high risk of mortality and poor long-term neurodevelopmental outcomes.33,34 | – Other concurrent injury – Watershed cortical involvement, focal infarctions, or global injury. |
Figs 9A to D: Central pattern of injury. Full-term neonate with history of cord prolapse with images obtained through anterior fontanel obtained after 4 hours of insult coronal (A–C) and parasagittal view (D), note the bilateral symmetrical increased echogenicity in the thalamus and basal ganglia representing ischemic injury along with a hypoechoic internal capsule
Figs 10A and B: Partial prolonged insult: (A) Cranial ultrasound images through anterior fontanel on coronal; (B) Parasagittal view, obtained within 24 hours of birth showing gross cerebral edema with slit-like ventricles
Figs 11A to D: (A and B) Subcortical and periventricular echogenicity in a full-term neonate. The cranial ultrasound performed at 36 hours of life with severe hypoxic-ischemic injury, coronal view; (C) Midline sagittal view; (D) Parasagittal view
Figs 12A and B: Chronic changes on ultrasound: (A) Cranial ultrasound through anterior fontanel of a 24-day-old term neonate with a severe asphyxiated insult at birth both coronal; and (B) Parasagittal view. Note the exvacuo hydrocephalous due to cortical atrophy and the visual cyst along the cortical area
Changes during the Chronic Phase of Injury
In a few weeks after the initial hypoxic insult, generalized atrophy of affected regions is seen. These changes result in volume loss of central grey matter and white matter with sonographic findings of exvacuo ventriculomegaly and widening of subarachnoid space.17 As the brain injury progresses, cortical necrosis and cystic changes in the injured brain regions might be seen.3 Cysts may be seen after ≥10 days following hypoxic insult to the brain (Fig. 12).35,36
Absence of Abnormal Findings in HIE Infants on Cranial USG
A normal cranial USG does not exclude brain injury. Advanced imaging modalities such as contrast-enhanced ultrasound or diffusion-weighted MRI can help detect subtle abnormalities that may not be apparent on conventional imaging.
Time Frame of Hypoxic Changes on Cranial USG
Hypoxic-ischemic encephalopathy is a dynamic brain injury, and therefore, relying on imaging at a solitary time point may fail to fully capture the extent of cerebral damage. In the initial phases, cerebral edema might exhibit minimal severity, and cranial USG may be unremarkable for 24–48 hours post-insult. Hyperechogenicity of the thalamus and basal ganglia and the appearance of PLIC sign may take 48–72 hours to develop. In cases with a near total pattern of injury, loss of grey-white matter differentiation and appearance of slit-like ventricles may take 48–72 hours to appear on cranial USG. If the insult is remote from the time of delivery, edema may have already developed and resolved by the time of birth.17,22
Pattern of Cranial USG in Preterm Hypoxic Insult
The anatomical area and pattern of acute ischemic insult differ between preterm and term infants, secondary to differences in the maturity of cerebral vessels. The periventricular white matter in the preterm brain is particularly susceptible to injury from ischemia, owing to the coexistence of immature premyelinating oligodendrocytes and watershed zones.37
Periventricular leukomalacia (PVL) is seen most frequently in preterm infants born at ≤33 weeks’ gestation with a birth weight of <1500 g.38 Cranial USG typically reveals the most pronounced bilateral diffuse and uneven sonographic enhancement in the periventricular white matter, which is almost equal to the intensity of choroid plexus.39 Three to four weeks after the initial insult, cranial USG may show cysts of varying sizes within the previously hyperechoic regions with atrophic changes in the surrounding parenchyma.39 It is important to emphasize that unlike in term neonates, diffuse echogenicity of the basal ganglia and thalami is a common normal finding observed in over 90% of preterm infants, particularly those born before 32 weeks’ gestation.40 This demands caution in the interpretation of the findings (Fig. 13).
Figs 13A to D: Periventricular echogenicity (A: Coronal view, B: Parasagittal view) observed in 28-week neonate. Subsequently, the neonate developed a cystic lesion demarcating the ongoing changes as a result of hypoxic injury in the frontotemporal area (C and D: Sagittal view)
Therapeutic Hypothermia and Imaging
Therapeutic hypothermia is a widely accepted modality for improving neurodevelopmental outcomes and reducing the severity of injury on imaging in neonates with asphyxiated insult.41,42 Crucially, ultrasound performed before initiation of therapeutic hypothermia can help assess alternative brain pathologies mimicking HIE. Additionally, it may identify relative contraindications to therapeutic hypothermia; including focal hemorrhage, arterial stroke, metabolic disorders, infections, or brain malformations. Therapeutic hypothermia reduces the secondary energy failure and hence represents the delay in the MRI changes such as pseudonormalization of diffusion restriction, which is deferred for several days following therapeutic hypothermia.43 Specific changes in cranial USG in neonates undergoing therapeutic hypothermia remain a potential area of research.
Cerebral Doppler Changes in Hypoxic Insults
Hypoxic-ischemic insults to the fetal and neonatal brain can alter cerebral blood flow (CBF).44–46 This phenomenon could serve as a protective mechanism aimed at preventing additional injury, or it may signify the repercussions of existing brain damage.45 Vascular hemodynamics are affected by many factors including alteration in intracranial pressure, partial pressure of carbon dioxide (pCO2), prostaglandins, nitric oxide, free radicals, and temperature, in addition to alterations in cardiac output.47–49
After a hypoxic insult, the autoregulatory mechanism causes CBF to decrease, which is reflected by an increasing resistive index (RI) of cerebral vessels. If not treated with therapeutic hypothermia, the brain often shows hyperemia for hours to days with an accompanying drop in RI.50,51 Therapeutic hypothermia can interrupt this cycle and limit this hyperemic period.52,53
Changes in the RI have been associated with prognostic implications. Although many of the hitherto-reported studies show differences in results, RI ≤ 0.55 within the initial 72 hours following birth has a strong predictive value for adverse outcomes, including death or severe disability (Fig. 14).54–58 Even though abnormal RI prior to the initiation of cooling is associated with poor outcomes, its accuracy decreases during therapeutic hypothermia.53 This might be attributed to relative vasoconstriction in the cerebral circulation or altered metabolic demand during the period of cooling.59–61 Elstad et al. demonstrated that therapeutic hypothermia significantly reduced the positive predictive value of a low RI value and an unfavorable outcome from around 84% to only 60%.59 However, this predictive value returned to the same range following rewarming.60 Interestingly, an RI of >1 may be associated with brain death.62
Fig. 14: Cerebral Doppler: Term infant with a history of severe perinatal asphyxia. Ultrasound examination performed on day 1 showed a sagittal view PWD in ACA showing increased EDV and decreased RI (0.37) in early asphyxia
A normal RI in the early stages of injury, within the first 6–12 hours, can be misleading as these patients may still show substantial disability or even mortality. This discrepancy may stem from the confounding influence of factors such as elevated intracranial pressure, patent ductus arteriosus, cardiac dysfunction, or the natural transition of the injured brain from a reduced cerebral blood flow soon after insult to subsequent hyperemia.54,55
Rath et al. systematically reviewed 26 studies and evaluated the importance of Doppler parameters separately in precooling and cooling eras in predicting long-term outcomes following perinatal asphyxia.63 They concluded that cerebral Doppler may be useful in predicting death or disability in infants with HIE who are not cooled, or if performed prior to cooling. Although no individual clinical sign or investigation is good at predicting neurological outcomes and the sensitivity of abnormal RI is relatively poor, its specificity resembles that of MRI, EEG, and aEEG.63,64
HIE Scores Based on Cranial USG
Composite cranial USG scores seem to be valuable as predictors of outcomes in sick asphyxiated neonates especially where transportation, affordability, and availability of MRI is challenging.65–67 Four cranial USG scoring systems were compared. The first classified CUS findings into 8 grades based on pattern and severity of grey/white matter involvement. A second by Swarte et al. defined 6 patterns using a combination of a deep grey matter and a subcortical white matter injury score.26,68 Another scoring system tried to identify early brain injury including a basal ganglia and thalami score and a white matter score.65 However, none of the above-mentioned scores has been validated.
A recent cranial USG scoring study by Annink et al. (Table 2) performed between day 3 and 7 after birth included composite scores of white matter and deep grey matter involvement, each consisting of multiple separate items.18 This scoring system was validated with a cut-off of ≥3 to consider the need for additional future neuroprotective strategies and/or redirection of care (Fig. 15). However, the inter-rater variability was still moderate. The subjectivity could be improvised with structured training.
| Item | Normal-mildly abnormal (0) | Moderately abnormal (1) | Severely abnormal (2) |
|---|---|---|---|
| White matter involvement (0–6 points) | |||
| Impaired grey/white matter differentiation and/or slit-like ventricles | Normal differentiation between grey and white matter and open ventricles | Reduced differentiation between grey and white matter and/or slit-like ventricles | No differentiation between grey and white matter and slit-like ventricles |
| Periventricular WM hyperechogenicity | Normal echogenicity or minor hyperechogenicity | Moderate or focal hyperechogenicity, not as white as choroid plexus | Severe and diffuse hyperechogenicity, as white as choroid plexus |
| Subcortical WM hyperechogenicity | Normal echogenicity or minor hyperechogenicity | Focal hyperechogenicity of the subcortical WM Moderate differentiation of white and (subcortical) grey matter | Clear “tramlines” sign; hyperechogenicity of subcortical WM almost similar to sulci with the reduced signal intensity of cortex in between |
| Grey matter involvement (0–6 points) | |||
| Thalamus hyperechogenicity | Normal echogenicity or minor hyperechogenicity | Moderate or focal hyperechogenicity of thalamus | Hyperechogenicity is severe and diffuse |
| Putamen hyperechogenicity | Normal echogenicity or minor hyperechogenicity | Moderate or focal hyperechogenicity of putamen | Hyperechogenicity is severe and diffuse |
| Absent (0) | Present (1) | ||
| Four-column sign | Normal echogenicity to minor hyperechogenicity | On the coronal plane, there is a four-column sign caused by moderate or severe bilateral hyperechogenicity of the thalamus and putamen. | |
| PLIC visibility | PLIC is not visible as a hypoechogenic line between the putamen and thalamus | PLIC is clearly visible as a hypoechogenic line between the hyperechogenic putamen and thalamus | |
Figs 15A to L: Scoring HIE images on ultrasound (A) Moderate cerebral edema (1 point); (B) Severe cerebral edema (2 points); (C) Moderate periventricular white matter hyperechogenicity (1 point); (D) Severe periventricular white matter hyperechogenicity (2 points); (E) Moderate subcortical white matter hyperechogenicity (1 point); (F) Severe subcortical white matter hyperechogenicity (2 points); (G) Moderately hyperechogenic thalamus (1 point); (H) Severely hyperechogenic thalamus (2 points); (I) Moderately hyperechogenic putamen (1 point); (J) Severely hyperechogenic putamen (2 points); (K) Four-column sign (1 point); (L) Visibility of the PLIC (1 point)
Mimickers of HIE
Neonatal encephalopathy (NE) has varied etiology. Hence, it is important to consider conditions that may mimic HIE. It is equally important to consider that HIE can co-exist with other causes of NE. Often there can be similarities in various presentations, and targeted investigation guided by clinical suspicion can differentiate various states. Table 3 delineates several conditions that could mimic HIE with the differentiating clinical-radiological factors.
| Disease state | Relevant clinical history | Differentiating radiological features |
|---|---|---|
| Perinatal asphyxia | – Perinatal risk factors. | – Bilateral watershed area, white matter, deep grey matter injury, basal ganglia, thalamus, brainstem injury. |
| – Encephalopathy soon after birth. | – Abnormal PLIC – a good predictor of motor outcome. | |
| – Associated hemodynamic instability. | ||
| – Seizures mostly within 24 hour of birth. | ||
| Vascular injury69–73 | – Perinatal risk factor – Uncommon. | – Focal ischemia in an arterial distribution. |
| a. Arterial ischemic stroke | – Encephalopathy not after birth. | – May show IVH and/or intraparenchymal hemorrhage, hydrocephalous, thrombosis on venogram. |
| b. CSVT | – Usually not associated with hemodynamic instability. | |
| – Seizures can be present, not usually soon after birth. | ||
| Cerebral vascular malformation74–77 | – Perinatal risk – Uncommon. | – Cranial Doppler represents flow turbulence across the malformation. |
| – Hemodynamic instability, associated with vein of Galen malformation or hemorrhage. | ||
| – Seizures may be present if the lesion is close to cortex or complicated with hemorrhage. | ||
| Subgaleal hemorrhage78,79 | – Perinatal risk factors associated. | – Difficult to differentiate on USG. |
| – Encephalopathy – unusual in the early phase. | ||
| – Can present with hypovolemic shock. | ||
| Infections-Meningitis/Meningoencephalitis/Encephalitis80–84 | – Clinical features of sepsis. | – Hydrocephalous, cerebral abscess, subdural effusion. |
| – History suggestive of chorioamnionitis. | – White matter injury, frontal and temporal lobe involved in HSV infection. | |
| – Blood and CSF culture PCR. | – Diffuse echogenicity periventricular and deep white matter in parechovirus/enterovirus. | |
| – Infarction secondary to bacterial infections. | ||
| Metabolic derangements – Hypoglycemia | – Propensity of risk factor to develop hypoglycemia. – Can be associated with seizures. |
– Hyperechogenicity of posterior subcortical white matter and overlying cortex with sparing of the central grey matter. |
| Syndromes85 • Prader–Willi Syndrome • Aicardi–Goutieres syndrome • Congenital central hypoventilation syndrome |
–Dysmorphism, organomegaly, hematological abnormality, variable presentation from birth till early infancy. | – Polymicrogyria – Prader Willi. |
| – Multiple white matter abnormalities, hypothalamus, posterior thalamus, midbrain, caudal raphe, locus coeruleus, lateral medulla, parabrachial pons, cerebellum, insular, and cingulate cortex changes in Congenital central hypoventilation syndrome. | ||
| – Frontotemporal white matter changes, basal ganglia calcification in Aicardi syndrome. | ||
| Neuromuscular disorder86–90 | – Presents with hypotonia immediately or soon after birth. | – Absence of acute brain injury on imaging. |
| – Facial or bulbar weakness related to dysfunction of the lower cranial nerves out of proportion to appendicular weakness is more suggestive of neuromuscular etiology. | – EMG/NCS can help localize symptoms to the nerve, muscle or neuromuscular junction. | |
| Brain malformation91–98 • Joubert syndrome. • Dandy–Walker malformation. |
– Antenatal USG suggestive. | Specific features: |
| – Can be symptomatic at birth or thereafter. | – Molar Tooth appearance – Joubert syndrome. | |
| – Hypoplasia of the cerebellar vermis and dilatation of the fourth ventricle, with variable degree of posterior fossa enlargement and hydrocephalus. | ||
| Metabolic diseases | ||
| Overlapping features of HIE | Differentiating factors | |
| • Sulphite oxidase deficiency.99–101 | Basal ganglia involvement Loss of grey-white matter differentiation |
Cystic encephalomalacia, corpus callosum hypoplasia, ventriculomegaly |
| • Molybdenum cofactor deficiency.102 | Diffuse parenchymal hyperechogenicity | Calcifications in the basal ganglia, white matter cysts, and later cerebral atrophy |
| • Zellweger syndrome.103,104 | Clinical picture overlaps HIE | Subependymal cysts, ventricular enlargement, lenticulostriate vasculopathy, and gyral malformations |
| • Nonketotic hyperglycinemia (NKH).105,106 | –Involvement of brainstem | Hypoplasia of corpus callosum |
| • Maple syrup urine disease.107 | Diffuse cerebral edema Presentation after 4–7 days of life |
White matter and central grey matter hyperechogenicity with corresponding white matter tract disease |
| *Metabolic diseases require detail evaluation based on MRI and MRS | ||
Correlation between Cranial USG and MRI
Cranial USG lacks the sensitivity for defining the full extent of cerebral lesions, even in severe encephalopathy, and particularly in the first 24 hours after birth.108,109 Because of the delay in the evolution of cranial USG abnormalities by a minimum of 48 hours, detection of pronounced abnormalities on postnatal day 1 may assist in identifying established severe HIE originating before the onset of labour.110 Mahantesh et al. elaborated on the limited accuracy of duplex ultrasound in mild HIE, with increasing precision of 77% in moderate and 100% in severely asphyxiated neonates with distinguishingly raised RI.111
Aun et al. reported the diagnostic accuracy of USG as 78.9% in comparison to MRI, with 92.3 and 40% of positive- and negative-predictive values, respectively.112 The advent of recent advances in MRI sequences, such as diffusion-weighted, susceptibility-weighted imaging, and metabolic sequencing, allow for better tissue characterization. These sequences can reveal subtle abnormalities and provide insights into brain injuries especially in mild to moderate cases with white matter injury that may not be as apparent on cranial USG.
In conjunction with the middle cerebral artery Doppler, cranial USG shows higher predictive accuracy and differentiation between the severity grades of HIE. However, predictive accuracy is relatively low for abnormal neurologic outcomes at 18 months.113 There is also some disagreement over the value of early USG compared with more definitive MRI after rewarming.10 Moreover, USG can help predict the neurodevelopmental outcomes at early school age in full-term neonates with asphyxia. Moderate hypoxic-ischemic brain changes detected in cranial USG were associated with hearing disorders, cerebellar dysfunction, epilepsy, and a lower Working Memory Index in children at an early school age.7
Long-term Implications of the Cranial USG
The prognosis of a neonate with hypoxic insult depends on multiple factors including the severity, extent and timing of the insult, gestational age, other associated comorbidities and metabolic derangements, congenital malformation, infection, hyperbilirubinemia, developmentally supportive and family participatory care, along with quality of follow-up.
Studies based on the topographic pattern of brain injury have indicated that term infants experiencing predominant damage to the basal ganglia and thalamus tend to have unfavorable neurological outcomes.114,108 Involvement of the cortex and basal ganglia within the first 24 hours of life, along with severe EEG abnormalities, can predict a poor outcome. This may indicate either a particularly severe insult or that the injury occurred before the onset of labour.68,115 Guan et al. concluded in their study of 158 neonates with hypoxic insult (54-mild HIE, 60-moderate, and 44-severe HIE) that abnormal ultrasound findings of brain parenchyma were found in 46.3% of neonates with mild HIE, 96.7% with moderate and 100% of neonates with severe HIE.116 Almost all neonates with severe HIE also had decreased cerebral artery blood flow velocity and increased RI of cerebral arteries. Of the 104 neonates with moderate or severe HIE, follow-up cranial USG revealed cystic parenchymal lesions in 11.5%, progressive ventricular dilatation and brain atrophy in 11.5%, mild ventricular dilatation in 14.4%, and leukoencephalomalacia in 1.9% neonates. On the other hand, cranial USG findings in neonates with mild HIE returned to normal during the follow-up, consistent with the clinical course, and most of the lesions in those with moderate HIE also returned to normal. Neonates with severe HIE followed up to 12 months had sequelae such as ventricular expansion, brain atrophy, and nervous system symptoms.116
In another study, Robertson et al. found the onset of CNS abnormalities to be closely associated with the severity of HIE and neurological dysfunction at 3.5 years of age.117 In conclusion, cranial USG features such as the size of lateral ventricles, altered brain parenchymal echogenicity and cerebral blood flow parameters are useful for the early diagnosis of HIE and help predict outcome.
Limitations
Being a nonhazardous, low-cost, and noninvasive intervention, cranial USG has evoked interest for clinical use. However, there are limitations as it is an operator-dependent tool with a learning curve. Furthermore, its sensitivity for subtle-mild changes is operator-dependent. There is a need for predictive tools with combination of USG and clinical parameters that could help assess severity of changes and prognosticate long-term neurological outcomes.
CONCLUSION
Cranial USG is potentially a valuable screening tool in both the diagnosis and management of neonatal encephalopathy. Serial high-resolution cranial USG with Doppler evaluations can help in real-time assessment of clinically important changes in HIE. This may also help predict disability in infants with hypoxic brain damage before cooling. Further research is needed to assess its value in predicting long-term neurological outcomes.
ORCID
Gunjana Kumar https://orcid.org/0000-0003-2449-9128
Sujata Deshpande https://orcid.org/0000-0003-1721-0250
Sreevidya Sreekantha https://orcid.org/0009-0008-7445-3594
Alex Stevenson https://orcid.org/0000-0002-7077-8518
Anu Sharma https://orcid.org/0000-0002-3014-9602
Jayanta Hazarika https://orcid.org/0009-0006-4285-5113
Poonam Agrawal https://orcid.org/0009-0009-4890-6489
Kirti Naranje https://orcid.org/0000-0002-8659-7658
Akhil Maheshwari https://orcid.org/0000-0003-3613-4054
Pradeep Suryawanshi https://orcid.org/0000-0002-4364-2041
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