Elsevier

Brain and Development

Volume 41, Issue 6, June 2019, Pages 507-515
Brain and Development

Original article
Disrupted cortico-ponto-cerebellar pathway in patients with hemimegalencephaly

https://doi.org/10.1016/j.braindev.2019.01.002Get rights and content

Abstract

Objective

Cerebellar dysmaturation and injury is associated with a wide range of neuromotor, neurocognitive and behavioral disorders as well as with preterm birth. We used diffusion tensor MR imaging to investigate a disruption in structural cortico-ponto-cerebellar (CPC) connectivity in children with infantile-onset severe epilepsy.

Methods

We performed CPC tract reconstructions in 24 hemimegalencephaly (HME) patients, 28 West syndrome (WS) of unknown etiology patients, and 25 pediatric disease control subjects without a history of epilepsy nor brain abnormality on MRI. To identify the CPC tract, we placed a seeding ROI separately in each right and left cerebral peduncle. We evaluated the distribution patterns of the CPC tracts to the cerebellum and their correlation with clinical findings.

Results

In control and WS of unknown etiology groups, both sides’ CPC tracts descended to bilateral hemispheres in 20 (80.0%) and 21 (75.0%); mixed (bilateral on one side and unilateral on the other side) in five (20.0%) and five (17.9%); and unilateral in zero (0.0%) and two (7.1%), respectively. However, in the HME, both sides’ CPC tracts descended to bilateral hemispheres in four (16.7%); mixed in 13 (54.1%); and unilateral in seven (29.2%). These CPC patterns differed significantly between the HME and other groups (p < 0.001). Among HME patients, those with a unilateral cerebellar distribution on both sides had significantly earlier seizure onset (p = 0.049) and more frequent seizures (p = 0.052) at a trend level compared to those with bilateral and mixed distributions.

Conclusion

Disrupted CPC tracts were observed more frequently in HME patients than in WS of unknown etiology patients and controls, and they may be correlated with earlier seizure onset and more frequent seizures in HME patients. DTI is a useful and non-invasive method for speculating the pathology in the developing brain.

Introduction

Cerebellar dysmaturation and injury is associated with a wide range of neuromotor, neurocognitive and behavioral disorders, including dystonia, ataxia, hemiplegia, stroke, autism, and preterm brain injury [1], [2], [3], [4], [5], [6]. The cerebellum exerts its functions in close communication with the cerebral cortex by exploiting two main pathways: the efferent cerebello-thalamo-cortical (CTC) pathway and the afferent cortico-ponto-cerebellar (CPC) pathway [7]. The association of cerebellar underdevelopment with supratentorial abnormalities may involve remote trophic transneuronal interactions via the CPC pathway [4]. The CPC fibers consist of two neuron chains: the cortico-pontine fibers and the ponto-cerebellar fibers. Successive studies performed with neuronal tracer procedures revealed that the pontine fibers entering the cerebellum innervated both sides of the cerebellum [8], [9].

Several authors mentioned disrupted cerebellar development in epilepsy. Michelucci reported CPC axonal loss was demonstrated by specific diffusion tensor imaging in a patient with Rasmussen encephalitis [10]. Messerschmidt reported epilepsy were significantly related to disrupted cerebellar development in preterm infants [5]. However, structural cerebro-cerebellar connectivity in children with infantile-onset severe epilepsy have not been evaluated.

Hemimegalencephaly (HME) is a rare malformation characterized by partial or whole enlargement of one cerebral hemisphere [11], sometimes with many types of abnormal fibers detected by MR diffusion tractography [12], [13], [14]. West syndrome (WS) is a one of the epilepsy syndromes composed of the triad of infantile spasms, an interictal electroencephalogram (EEG) pattern termed hypsarrhythmia, and mental retardation. WS includes two etiological groups: symptomatic (including HME) and unknown etiology. Both HME and WS patients often show early-onset severe epilepsy and developmental delays, while cognitive impairment in WS may vary, according to the etiology of the syndrome, ranging from normal to greater cognitive impairment.

We have experienced “ipsilateral (uncrossed) cerebellar diaschisis (ICD)” in some patients with HME. In Hamano et al. study [15], ICD was observed in some patients whose brain injuries occurred before the age of 3 years. They speculated that ICD is related to maturation of the CPC fibers. We hypothesized that the CPC pathway might not cross the midline to enter the cerebellum in some pediatric patients with infantile-onset severe epileptic syndrome (that causes cortical damage in early childhood). We aimed to investigate the CPC pathway in HME comparing with WS of unknown etiology by using diffusion tensor MR imaging and their correlation with clinical findings.

Section snippets

Subjects

Twenty-four patients with HME (8 males, 16 females, age range, 1.6 months to 50 years; median age, 3.9 months) and 28 patients with MRI-negative WS of unknown etiology (16 males, 12 females, age range, 3.7 months to 23 years; median age, 34.9 months) who underwent MR imaging including diffusion tensor imaging (DTI) were identified at our institution between October 2010 and September 2017. All patients were hospitalized for intractable epilepsy, and detailed examinations were performed to

Demographics

Table 1 summarizes the clinical demographics of the HME and WS of unknown etiology patients and controls.

MR imaging findings and fiber tractography

The MR imaging findings and distribution patterns of the CPC tracts in the two disease groups and controls are illustrated in Fig. 1, Fig. 2, Fig. 3 and summarized in Table 2, Table 3, Table 4. The number of subjects whose DTI using 12 directions was 26 and 15 directions was 51. For the ROI based tractography analyses, the interobserver agreement was excellent; the κ value was 0.88.

Among the

Discussion

We detected a higher incidence of unilateral and mixed CPC fiber distributions in patients with HME than in patients with WS of unknown etiology and disease controls, and they may be correlated with earlier seizure onset and more frequent seizures. These results raise the speculation that the severe damage of epilepsy in the developing brain during childhood may affect the maturation of the CPC tracts. To the best of our knowledge, no previous studies have focused on abnormalities of the CPC

Conflict of interest

The authors have no conflicts of interest to declare.

Acknowledgments

This work was supported by Intramural Grant (30-6) for Neurological and Psychiatric Disorders of NCNP.

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