Original articleDisrupted cortico-ponto-cerebellar pathway in patients with hemimegalencephaly
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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