PICTORIAL REVIEW

 

Mimickers of hypoxic-ischaemic brain injury in term neonates: What the radiologist should know

 

 

Shalendra K. Misser^{I, II}; Moherndran Archary^III

^IFaculty of Radiology, Lake Smith and Partners Inc., Durban, South Africa
^IIDepartment of Radiology, Faculty of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
^IIIDepartment of Pediatrics, Faculty of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa

Correspondence

 

 

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ABSTRACT

Patterns of neonatal hypoxic-ischaemic brain injury (HIBI) are fairly well known. There are, however, other diagnoses with imaging patterns that may mimic HIBI. A review of MRI studies was conducted for children with suspected cerebral palsy, correlated with prior imaging, clinical details and laboratory tests where available. In the 63 identified cases, imaging features were, in many cases, very similar to the known patterns of HIBI. The alternative diagnoses can be classified as developmental, vascular, chromosomal, infections, metabolic disorders, and congenital syndromes. These findings are described in this pictorial essay. The potential mimickers of HIBI described in this essay can demonstrate similar imaging appearances to HIBI.
CONTRIBUTION: There are multiple possible causes of neonatal encephalopathy other than hypoxic-ischaemic encephalopathy. Many conditions may mimic HIBI, each of which can be associated with significant morbidity. It is prudent for the reporting radiologist to be aware of these alternate clinico-radiological diagnoses.

Keywords: hypoxic-ischaemic; cerebral palsy; term neonatal; magnetic resonance imaging; neurometabolic.

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Purpose

Cerebral palsy (CP) is the most common motor disorder of childhood globally.¹ In recent years, there has been a marked increase in medicolegal litigation pertaining to CP from perinatal hypoxic-ischaemic encephalopathy (HIE). Radiologists have become key figure in identifying patterns of brain injury on MRI that are indicative of hypoxic-ischaemic brain injury (HIBI). While these patterns² are fairly well known, it is also important for the reporting radiologist to be aware of other diagnoses with imaging patterns that may mimic HIBI. To highlight the variability of patterns of HIBI and the overlap of these patterns with other causes, we have hidden (in Figure 1) the diagnoses of each child imaged. Even the most experienced paediatric neuroradiologists have difficulty in correctly assigning the diagnosis to these cases, let alone separating them into those cases with HIBI and those with alternative causes. The correct diagnoses is revealed in the conclusion of this pictorial essay in Figure 34.

 

Background

There are typical features that the reporting radiologist seeks to identify while reviewing an MRI study performed for neonatal encephalopathy (NE) to suggest a diagnosis of perinatal term HIBI. The classic patterns of injury generally alluded to in daily reporting include the central, watershed or parasagittal, combined central and watershed (mixed pattern), and cystic encephalomalacia.² While HIE may be one of the commonest causes of perinatal encephalopathy, and accounting for 46% of cases of neonatal seizures,³ it must be observed that there are several other scenarios resulting in a similar constellation of clinical findings that may mimic the clinical diagnosis of HIE. Furthermore, it has been reported that only 14.5% of CP cases were associated with an intrapartum event⁴; yet, most medicolegal litigation cases are based on the premise of intrapartum negligence. An MRI serves a vital role in clarifying the imaging features that may indicate a condition mimicking HIE. This is critical in the evaluation of children with suspected medical negligence, who are imaged several months or years after birth. The radiologist is often the lead expert, providing supportive proof in describing the diagnostic MRI patterns. These patterns are still well-recognised in the chronic phase of evolution, long after delivery.⁵ An MRI should be undertaken whenever possible in CP cases, even in the absence of prior perinatal imaging. It was shown that out of a database of 1620 CP children, MRI could possibly avoid litigation in up to 31% of cases.⁵

 

Methods

A database of MRI studies of CP patients with clinically suspected term neonatal HIBI was accumulated. Some were imaged in the neonatal period. Other scans were acquired months to years later to assess for stigmata of HIBI. These MRI studies were all performed on 1.5T scanners at the imaging centres of Lake Smit and Partners Inc. Sequences obtained in all patients were previously enumerated.² All MRI studies of these full-term infants were retrospectively reviewed by the principal investigator. Of the composite database, we identified numerous cases where, although the pattern of cerebral injury identified on the MRI studies could be attributed to HIBI, we recorded the clinical and follow up investigations to arrive at a final clinical diagnosis. The data pertaining to these children were extracted from available clinical notes and in some instances, by confirmation from the clinicians involved in the management of the patients.

 

Results

There were 25 male patients and 38 female patients in this study. The youngest child imaged was 2 days old and the oldest 15 years of age. There were numerous diagnoses reported, verified clinically, explaining the NE and accounting for the presentation other than due to HIE. Metabolic causes or inborn errors of metabolism were identified in 12 cases, congenital malformations in 10 cases, cerebrovascular causes in 8 cases, infection related changes in 20 cases, chromosomal and other causes accounting for the remaining cases. Following from the categorisation of final diagnoses, we established the differential diagnosis of NE, to include congenital malformations, inborn errors of metabolism, central nervous system (CNS) infections, severe trauma and cerebrovascular syndromes, as shown in Figure 2.³

 

 

Congenital malformations

A myriad of congenital malformations are known with the potential to develop a clinical syndrome depicting CP and these are sometimes attributed, often erroneously, to perinatal HIE. These malformations develop in utero and many of them manifest with neonatal or infantile seizures. Although some neonates can appear encephalopathic, there is generally a lack of supportive features of HIE such as metabolic acidosis. Cord blood gas analyses have been recommended to confirm neonatal acidosis.⁶ Despite this lack of supportive clinical context, several cases are referred for medicolegal evaluation to exclude features of HIBI. The MRI studies are often quite instructive in excluding HIBI because of the clear depiction of specific malformations. Some of these are listed in Figure 3.

 

 

Corpus callosum agenesis is one of the commonest malformations identified in clinical radiology and may be categorised as a partial or total dysgenesis.⁷ These may be associated with other brain malformations (hindbrain, heterotopia or cortical dysplasia) as in the patient presented in Figure 4. Malformations of cortical development, gyration abnormalities (Figure 5), neuronal migration abnormalities and posterior fossa cysts, are among several other malformations that may be clinically similar with encephalopathic neonates; yet, the key would be the lack of recorded perinatal metabolic acidosis in these instances. Pontocerebellar hypoplasia, for instance, may mimic dyskinetic or ataxic CP. Dedicated early genetic testing has been recommended⁸ in identifying potential mimickers of CP in around one-third of cases.

 

 

 

 

Neurometabolic disorders

The approach to neurometabolic disorders envisages two broad presentations: one with a relatively normal neonatal period, and the second with NE.⁹ Metabolic disorders that manifest in the neonatal period are often devastating.^10,11 Many metabolic disorders may present with neonatal seizures, as enumerated in Figure 6, making these important differential considerations for NE.¹² These are distinguishable from those inborn errors of metabolism that have a relatively normal neonatal period or the disorder may be masked by the support provided by the mother and placenta in the late gestational period before delivery.¹¹

 

 

The thalamus L-sign¹³ described in 2022 is a useful MRI finding distinguishing pure perinatal hypoglycaemia from HIBI or combined HIBI/hypoglycaemia. In the series of 297 cases, the thalamus L-sign was shown as a potential biomarker for the parasagittal/partial prolonged subtype of HIBI, noticed in 86% of such patients. None of the patients with pure hypoglycaemia demonstrated this sign (Figure 7).

 

 

Of the metabolic aetiologies, lactic acidosis can be one of the commonest features (e.g. because of mitochondrial disorders - Figure 8 - Figure 10) identified on imaging using magnetic resonance spectroscopy (MRS). Urea cycle disorders, amino acidurias (including maple syrup urine disease [Figure 11]) and molybdenum co-factor deficiency/sulfite oxidase deficiency (Figure 12) are others to consider. Genomic assessment in CP children is crucial in identifying neurogenetic conditions masquerading as HIBI. This is achieved using chromosomal microarray and whole exome/genome sequencing, with identification of specific genetic mutations. Although each genetic and metabolic cause may be individually rare, collectively, these are clinically important masqueraders of CP.¹⁴ Leach et al.¹⁵ described, through a systematic literature review, 54 treatable inborn errors of metabolism that can mimic CP.

Disorders of myelination result in abnormal white matter signals, which can mimic periventricular leukomalacia, which can also be a feature of HIBI in some neonates, although more commonly reported in premature children. These may include hypomyelinating disorders (Figure 13). Some leukodystrophies also have deep nuclear changes^16,17 involving the corpus striatum, thalami as well as grey and white matter changes, as listed in Figure 14. When there is putaminal and thalamic involvement, it is difficult for the radiologist to differentiate these inborn errors of metabolism from the basal ganglia-thalamus pattern of HIBI. In the latter case, it is often associated with perirolandic cortex injury (the combination of which has previously been called the RBGT pattern¹⁸), especially when precipitated by a sentinel event or severe asphyxiation of the neonate. Such cases of HIBI are often associated with an acute profound pathophysiology where these high metabolic areas of the brain are subjected to a severe reduction in perfusion and oxygenation. The perirolandic sensorimotor cortex may also be abnormal in polymerase gamma-related disorders (POLG-RD) (Figure 16).¹⁹ The brainstem may also be injured along with these substrates (deep nuclear-brainstem pattern as per Volpe²⁰). This is often life-threatening to both mother and child (e.g. uterine rupture or abruptio placentae). Therefore, in most cases, there is generally a correlative recording of such an event or stormy perinatal period in the patient's notes. Furthermore, these cases of HIBI will have severe metabolic acidosis and the attendant cascade of inflammatory or other pathways activated, which is typically not seen in the first day of life in the case of most metabolic causes. Figures 15 to 20 highlight the typical imaging features of several metabolic disorders, which can be referred for diagnostic or medicolegal evaluation. These are examples of cases that we encountered with very similar imaging phenotypes to the broad subtypes of HIBI.

 

 

 

 

Cerebrovascular causes

A few perinatal vascular causes must be considered as HIBI mimics. These may manifest as haemorrhagic or ischaemic phenomena. Perinatal arterial ischaemic stroke (PAIS) syndrome, which can present with NE, is defined as infarction in an arterial distribution between 28 weeks gestation and 28 days after birth.²⁰ Focal clonic seizures are the typical initial presentation. Perinatal arterial ischaemic stroke may be difficult to differentiate clinically from HIE without acute and follow-up imaging, especially by MRI. The sustained injury is usually unilateral and limited to a single vascular territory, most commonly the middle cerebral artery territory. There can be marked variability (Figure 21) in the severity of PAIS, and there is also a propensity for haemorrhagic transformation.

 

 

The differential diagnosis for PAIS would include COL4A-1 and A-2 mutations (Figure 22). These children commonly may not have a history of perinatal encephalopathy, and there may be other clinical features such as cataracts.²¹ These collagen type IV genes encode for nearly all vascular basement membranes and have been shown to be associated with foetal intracranial haemorrhages, schizencephaly, porencephaly, and hydrocephalus.²²

 

 

Non-accidental injury

One of the most difficult diagnoses a radiologist may be required to make is that of non-accidental injury (NAI), shown in Figure 23. In a neonate, the distinction of NAI from traumatic brain injury during delivery may sometimes be difficult. The combination of subdural haemorrhages, juxtacallosal shearing-type injuries and areas of ischemia are all highly suspicious for NAI. Furthermore, the location of subdural haemorrhages has been shown to be useful in distinguishing benign subdural haemorrhages (usually in the posterior fossa, around the tentorium cerebelli or around the occipital lobes) versus NAI (interhemispheric or over the cerebral convexities).²³ Incontinentia pigmenti would be an important differential consideration, as shown in the companion case (Figure 24).

 

 

 

 

 

Figure 27

 

 

Figure 28

 

 

Figure 29

 

 

Figure 30

 

 

Figure 31

 

 

Figure 32

 

Limitation

A major limitation lies in the accurate diagnosis of metabolic, chromosomal and genetic disorders because of the lack of available testing in resource-constrained settings. This is, however, improving as such laboratory and high-level gene sequencing facilities are becoming more accessible in South Africa.²⁶ Some patients without clinical and laboratory results (no objective proof in the form of relevant serum or urine testing, genetics, etc.) have been excluded from the study. Including such cases, if clinical information was available, would add significantly to the findings of this study. Larger studies with available clinical data are therefore strongly encouraged.

 

Conclusion

There are several potential radiological mimickers of neonatal HIE that can have a similar imaging appearance to HIBI (see Figure 34). It is prudent for the reporting radiologists to be aware of these alternate diagnoses, which may be associated with significant morbidity and have implications for medicolegal evaluations. To describe the clinical syndrome affecting these neonates, it has been proposed²⁷ that a more descriptive terminology, such as NE, is preferable to a specific aetiology, such as HIE, which conveys a definitive known aetiology. By classifying the neonatal syndrome as NE, other causes (genetic conditions, infection, vascular, or multifactorial aetiology), will be considered and greater clarity is afforded to all parties involved. This, in effect, ensures that the parents are well-informed early on, and there is an opportunity for better patient outcomes with directed therapy where applicable.

 

 

Acknowledgements

The authors would like to acknowledge Professor Anthony James Barkovich, School of Medicine, University of California, San Francisco, California, United States, as the promoter and co-supervisor of this research study.

Competing interests

The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article.

Authors' contributions

S.K.M. was the guarantor of integrity of the entire manuscript. M.A. was the principal supervisor and reviewer of the manuscript. S.K.M. was responsible for key concepts, design, and literature research. S.K.M. also compiled the draft, collated the data following analysis and finalised the manuscript of the article for publication. Both the authors read and agreed on the final article.

Ethical considerations

Ethical clearance to conduct this study was obtained from the University of KwaZulu-Natal, Biomedical Research Ethics Committee (No. BREC/00001036/2020).

Funding information

No funding was received to assist with the preparation of this manuscript.

Data availability

All imaging studies utilised in the compilation of this pictorial essay are available from the Picture Archive and Communication System (PACS) of Lake Smit and Partners Inc (https://imageviewer.lakesmit.co.za). For access to specific imaging studies, contact helpdesk@lakesmit.co.za. The studies will need to be anonymised prior to being released for viewing, and time must be allowed for this process.

Disclaimer

The views and opinions expressed in this article are those of the authors and are the product of professional research. It does not necessarily reflect the official policy or position of any affiliated institution, funder, agency, or that of the publisher. The authors are responsible for this article's results, findings, and content.

 

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Correspondence:
Shalendra Misser
shalendra.misser@lakesmit.co.za

Received: 03 Nov. 2023
Accepted: 12 Dec. 2023
Published: 29 Feb. 2024