Cerebellar Vermis Injury in Severe Neonatal Hypoxic-Ischemic Encephalopathy

Elvio Della Giustina^1*, Michele Sintini², Stefania Caramaschi³, Luca Reggiani Bonetti¹

¹Department of Medical and Surgical Sciences for Children and Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
²Casa di Cura “Sol et Salus”, Rimini, Italy
³Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy

*Corresponding author: Elvio Della Giustina, Department of Medical and Surgical Sciences for Children and Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy;
Email: elvio.dellagiustina@gmail.com; edellagi@unimore.it

Citation: Giustina ED, et al. Cerebellar Vermis Injury in Severe Neonatal Hypoxic-Ischemic Encephalopathy. J Pediatric Adv Res. 2025;4(3):1-6.

Copyright^© 2025 by Giustina ED, et al. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Table 1: Brain involvement in 13 newborns with HIE.

Results

Late brain MRI images revealed significant and symmetrical signal abnormalities in the basal ganglia and thalami, which were present in all cases. Of the basal ganglia regions, the globus pallidus was the most frequently affected, followed by the putamen. The thalami were always affected (Fig. 1). Only newborns with severe, long-standing HIE showed cerebral hemispheric white matter damage. In these cases, the corresponding cerebral cortex also showed ischemic injury.  Additionally, a peculiar injury consisting of a bilateral, hyperintense, transverse, horizontal signal was observed in the cerebellar hemispheres of a few newborns. The vermis itself showed more severe and extensive signal abnormalities.  Occasionally, there was initial vermis folia atrophy, which was only visible on late MRI images (Fig. 2). Abnormal tissue damage in the form of bilateral, symmetric signals was observed in the hippocampus of three out of thirteen newborns, generally progressing to late atrophy. The brainstem, particularly the dorsal pons and midbrain, was also affected in the most severe cases of HIE and exhibited pathological hyperlucency. Vermian involvement typically affected the antero-superior folia. It also extended into the mid and posterior compartments (Fig. 3).  

Figure 1: Example of brain MRI in newborns with moderate HIE. In newborns with less severe HIE, thalamic and basal ganglia involvement is constant. In general, the globus palliduus appears to be affected more often than the putamen (white arrows). The extent of the abnormal signal in the vermis generally parallels that of the basal ganglia, though it may be abnormally large in a few cases of less severe HIE (empty circle). Axial T2 SE MRI (Panel A and B; Patient No. 5).

Figure 2: Examples of brain MRI in newborns with more severe HIE. In patients with more severe HIE (Patient No. 12), the abnormal signal extension increases in the thalami and basal ganglia, particularly in the globus pallidus region (Panel A, axial FLAIR T1 MRI, white arrows). Additionally, anterior vermian damage extends further posteriorly (Panel C, axial T2 SE MRI, empty circle) and involvement of the dorsal midbrain and pons becomes evident (Panel B, sagittal T1 SE MRI, white arrow). Panel D (coronal FLAIR T1 MRI) shows involvement of the hemispheric and paracentral white matter. A new finding is the presence of thin stripes of symmetrical abnormal signals in both anterior cerebellar hemispheres, indicating white matter damage (small thin arrows).

Figure 3: Examples of brain MRI in newborns with the most severe HIE. In the case of very severe HIE (Patient No. 4), the thalami and basal ganglia are heavily affected, often symmetrically (Panel A, axial T1 SE MRI). Abnormal signals confirm the extent of the cerebral injury and indicate involvement of the cerebellar vermis and anterior cerebellar hemispheric white matter. They also indicate probable damage to the deep dentate nuclei (small thin arrows and empty circle) and bilateral injury to the hippocampi (white arrowheads) (Panel B, FLAIR MRI). Panel C shows the abnormal vermian signal (C, axial T2 SE MRI, empty circle) and initial atrophy of the superior-anterior third of the vermis (upper half of Panel C, sagittal T1 MRI, empty circle). Panel D clearly demonstrates bilateral involvement of the dorsal pons and midbrain (white arrows) (axial T2 SE MRI).

Discussion

Cerebellar abnormalities may accompany HIE in full-term newborns, with the vermis appearing to be the preferred target. Vermian lesions occur when the thalami and basal ganglia sustain severe, symmetrical damage. Occasionally, the deep cerebellar nuclei are maximally involved, often alongside an injury to the posterior pons and midbrain [12,14]. The antero-superior folia of the vermis are primarily affected and Purkinje cells are predominantly damaged [7,8,10,13-15]. 

Consistent with previous reports, this small case series confirms that HIE involving the thalamus and basal ganglia can result in variable lesions. Therefore, vermian damage may also be variable, subtle and difficult to detect with conventional brain MRIs. However, more sophisticated neuroimaging techniques, such as Diffusion Tensor Imaging (DTI), can reveal vermian lesions in the days immediately following birth [10]. Therefore, DTI has the potential to become the gold standard for early, complete diagnosis of HIE in term newborns. Early neuroimaging that demonstrates the location and extent of brain injury is critical for subsequent therapeutic approaches and prognosis. Recent postmortem histopathological studies have confirmed the selective and early vulnerability of Purkinje cells in vermian lesions of term neonates with HIE. These studies revealed the early necrosis or apoptosis of these cells, as well as the subsequent defective growth of the cerebellar vermis. Consistent with previous reports, this small case series confirmed vermian injury in HIE newborns. The antero-superior vermian compartment was the most affected area. Bilateral thalamic involvement was always present. However, the extent of vermian injury did not systematically correspond to the extent of thalamic damage. This suggests that the extent of vermian injury depends on which thalamic nuclei are damaged despite their tight anatomical and metabolic connections. Indeed, the ventrolateral thalamic nuclei are not always affected, while the pulvinar often. We emphasize the rarely reported hippocampal signal abnormality. Notably, Connolly, et al., case series demonstrates bilateral hippocampal involvement in 10 out of 30 affected neonates [8]. All of these neonates showed vermis injury, as well as paracentral white matter, thalamic and putaminal involvement, cerebral and cerebellar white matter involvement and involvement of the dorsal pons and mesencephalon. Another difference between our cases and previous reports is the consistent and often obvious involvement of the globus pallidus, while the putamen was generally less affected. Our small series of HIE newborns confirms the presence of diffuse abnormal signals in the dorsal pons and midbrain, which occur almost exclusively in the most severely affected neonates with diffuse white matter involvement. 

The pathogenetic correlations between supratentorial brain injury and infratentorial lesions, primarily vermian, in term neonates with HIE have been approached inconsistently. The absence of visible vermis injury on conventional MRIs during the first few days of life and the late onset of progressive atrophy and growth failure in the injured vermis are pivotal factors in understanding pathogenesis. One possible explanation is that the pathogenesis of these vermian lesions, which evolve slowly into atrophy, depends on excessive apoptosis. This is plausible because, during this specific developmental stage, the vermis exhibits metabolic activity similar to that of the thalami and basal ganglia [6,7,9,13]. Le Strange, et al., considered impaired cerebellar growth, particularly vermian growth, to be a secondary consequence of perinatal injury to the supratentorial thalamus and basal ganglia [6]. This is significant because the ventrolateral thalamic nuclei have strong anatomical and functional connections with the cerebellum, especially the vermis. These nuclei act as primary relays to the cerebellum. Additionally, Sargent, et al., identified the vermis as one of the most metabolically active regions of the full-term neonate’s brain [7]. However, they emphasize the possibility of acute neuronal necrosis and late apoptosis, both of which contribute to vermian atrophy. Annink, et al., demonstrated histological necrosis and altered morphology of Purkinje neurons [13,15]. They also observed signs of neuroinflammation, as evidenced by activated microglia and macrophages. Indeed, cerebral tissue damage can still develop even after therapeutic hypothermia is introduced to protect against energy dysfunction and inflammation. Vermian injury is often overlooked in term HIE neonates. However, a histopathological study of the cerebellar vermis was performed on 14 HIE newborns who underwent autopsy and injury was found in 72% of them [9]. In addition to defects in oxidative phosphorylation and inflammation, Johnston’s study further supported neuronal excitotoxicity [17]. In extensive research on the causal role of excitotoxicity in perinatal brain injury, Johnston described the mechanisms by which NMDA and AMPA receptors become overstimulated in newborns with term HIE. Johnston also highlighted how this process intermingles with mitochondrial energy metabolism, secondary depolarization, energy depletion, cytochrome C deficiency and ultimately, caspase activation and apoptosis. Johnston’s study advanced our understanding of brainstem involvement by demonstrating that AMPA receptors fail to regulate calcium ion influx into neurons and mitochondria under hypoxic-ischemic conditions.

A similar mechanism may be at play in white matter injury because immature oligodendrocytes primarily express AMPA receptors. Uncontrolled Ca²⁺ influx in these cells can lead to cell death. Interestingly, topiramate and hypothermia can rescue normal AMPA receptor activity and prevent cell death. However, as mentioned above, altered Purkinje neuron morphology is evident through histopathological examination, even in HIE newborns protected by hypothermia.

Conclusion

In severe HIE in term neonates, damage to the antero-superior cerebellar vermis, as revealed by late MRIs, is much more prevalent than commonly recognized or demonstrated by conventional neuroimaging techniques. Conventional neuroimaging is crucial in demonstrating vermian involvement over time, usually after many weeks of life. Among the infratentorial structures, the dorsal pons and midbrain may often be affected. However, injury to the anterior cerebellar hemispheric white matter is rare, as demonstrated by some of our cases. Injury to the ventrolateral thalamus and putamen is recognized as a prerequisite for vermian damage. Interestingly, however, in our small series of thirteen HIE neonates, the globus pallidus exhibited more common, symmetrical alterations than the putamen. Furthermore, confirming hippocampal abnormalities in our cases not only increases the amount of affected cerebral tissue, but may also play a critical role in the future epilepsy of long-surviving newborns. More sophisticated neuroimaging procedures, particularly Diffusion Tensor Imaging (DTI), can detect vermian lesions in the early hours of life. These procedures may allow for a more precise therapeutic approach than hypothermia alone.

Conflict of Interests

The authors declare that they have no conflicts of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or non-profit sectors.

Author Contributions

The authors contributed equally to the work.

Institutional Review Board Statement

This study was conducted in accordance with the ethical standards of the Helsinki Declaration of the World Medical Association. Furthermore, the manuscript did not need the approval of the Ethical Committee of our University Administration as this is not a requirement for the publication of a single case provided that it is of definite interest to the scientific community (Regulations of the Ethical Committee of “Area Vasta Emilia Nord”, Italy, approved on September 22, 2020). 

Informed Consent Statement

Informed consent was verbally obtained from the parents of all subjects involved in the study.

Data Availability Statement

Data and Materials are available from the authors upon reasonable request.

References

1. Valk J, Vermeulen RJ, van der Knaap MS. Post-hypoxic-ischemic encephalopathy of neonates. In: Valk J, van der Knaap MS, editors. Magnetic resonance of myelination and myelin disorders. Berlin, Heidelberg: Springer. 2005:823-42.
2. Martin E, Barkovich AJ. Magnetic resonance imaging in perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed. 1995;72(1):F62-70.
3. Volpe JJ. Hypoxic-ischemic encephalopathy: Clinical aspects. In: Neurology of the newborn. 4^th Philadelphia: WB Saunders; 2001:331-94.
4. Barkovich AJ. MR and CT evaluation of profound neonatal and infantile asphyxia. AJNR Am J Neuroradiol. 1992;13(3):959-72.
5. Sie LT, van der Knaap MS, Oosting J, de Vries LS, Lafeber HN, Valk J. MR patterns of hypoxic-ischemic brain damage after prenatal, perinatal or postnatal asphyxia. Neuropediatrics. 2000;31(3):128-36.
6. Le Strange E, Saeed N, Cowan FM, Edwards AD, Rutherford MA. MR imaging quantification of cerebellar growth following hypoxic-ischemic injury to the neonatal brain. AJNR Am J Neuroradiol. 2004;25(3):463-8.
7. Sargent MA, Poskitt KJ, Roland EH, Hill A, Hendson G. Cerebellar vermian atrophy after neonatal hypoxic-ischemic encephalopathy. AJNR Am J Neuroradiol. 2004;25(6):1008-15.
8. Connolly DJA, Widjaja E, Griffiths PD. Involvement of the anterior lobe of the cerebellar vermis in perinatal profound hypoxia. AJNR Am J Neuroradiol. 2007;28(1):16-9.
9. Kwan S, Bi W, Brown A, Millman T, Traubici J, Whyte H, et al. Injury to the cerebellum in term asphyxiated newborns treated with hypothermia. AJNR Am J Neuroradiol. 2015;36(8):1542-9.
10. Lemmon ME, Wagner MW, Bosemani T, Carson KA, Northington FJ, Huisman TA, et al. Diffusion tensor imaging detects occult cerebellar injury in severe neonatal hypoxic-ischemic encephalopathy. Dev Neurosci. 2017;39(1-4):207-14.
11. Koehler RC, Yang ZJ, Lee JK, Martin LJ. Perinatal hypoxic-ischemic brain injury in large animal models: Relevance to human neonatal encephalopathy. J Cereb Blood Flow Metab. 2018;38(12):2092-111.
12. Hayakawa K, Tanda K, Koshino S, Nishimura A, Kizaki Z, Ohno K. Pontine and cerebellar injury in neonatal hypoxic-ischemic encephalopathy: MR features and clinical outcomes. Acta Radiol. 2020;61(10):1398-405.
13. Annink KV, Meerts L, van der Aa NE, Alderliesten T, Nikkels PGJ, Nijboer CHA, et al. Cerebellar injury in term neonates with hypoxic-ischemic encephalopathy is underestimated. Pediatr Res. 2021;89(5):1171-8.
14. Hayakawa K, Tanda K, Nishimura A, Kinoshita D, Nishimoto M, Kizaki Z, et al. Morphological changes in the pons and cerebellum during the first two weeks in term infants with pontine and cerebellar injury and profound neonatal asphyxia. Acta Radiol. 2022;63(8):1110-7.
15. Annink KV, van Leeuwen ICE, Smeets NA, Peeters LAJ, van der Aa NE, Alderliesten T, et al. Uneven distribution of Purkinje cell injury in the cerebellar vermis of term neonates with hypoxic-ischemic encephalopathy. Cerebellum. 2024;24(1):17.
16. Myers RE. Two patterns of brain damage and their conditions of occurrence. Am J Obstet Gynecol. 1972;112(2):245-76.
17. Johnston MV. Excitotoxicity in perinatal brain injury. Brain Pathol. 2005;15(3):234-40.