Gray matter heterotopia: clinical and neuroimaging report on 22 children

Objective To investigate the clinical characteristics and neuroimaging features of childhood presenting with gray matter heterotopia observed in a single tertiary Pediatric Department in Catania and compare the data with those reported in the literature. Methods A retrospectively review of the history, clinical findings, electrophysiological features and magnetic resonance images of 22 children presenting with gray matter heterotopia observed from January 2010 to January 2020. Results Among the 22 children included in the study, 17 presented with periventricular heterotopia (PVNH), two with Subcortical Band Heterotopia (SBH), and three with other subcortical heterotopia (SUBH). In the affected children, the ages at first diagnosis ranged from 3 months to 16 years with a mean age of 8.2 years (± 5.4); twelve (54.5%) suffered by developmental delay and intellectual deficit; eleven children (50%) complained of epileptic seizures, mostly focal to bilateral tonic–clonic seizure. In addition, in the periventricular heterotopia group (PVNH), cerebral and systemic malformations were reported in twelve (70%) and in ten (58%) children, respectively, out of seventeen. In the SBH plus SUBH group, epileptic seizures were recorded in 3 (60%) out of 5 children, cerebral malformations in one child and systemic malformations in two children. Conclusions Heterotopic gray matter malformations include a group of disorders that manifest with a variety of neurological implications, such as cognitive impairment and epilepsy, and often related with epilepsy, other cerebral malformations and systemic anomalies.


Introduction
Heterotopic gray matter malformations (HET) are clusters of normal neurons in abnormal locations, mainly due to impaired migration from approximately the 6th to 16th weeks of gestation [1][2][3]. The increasing availability and resolution of MRI technology and molecular genetics has resulted in a classification published by Barkovich et al. in the 2012 describing different types of malformations of cortical development (MCD) [4]. In 2019, Oegema et al. reviewed this classification [5]. In particular, he distinguished five groups and subdivided them into specific entities. Subcortical Heterotopic gray matter heterotopy (SUBH) was included in Groups 1, 2, 4 and 5, differently periventricular nodular heterotopia (PVNH) and Subcortical Band Heterotopia (SBH) in group 3. In particular, Group 1 includes congenital microcephaly with premigrational reduced proliferation and variable additional MCD; group 2 includes multifocal or focal cortical and subcortical dysgenesis; group 3 includes malformations due to abnormal neuronal migration, PVNH and SBH [6][7][8][9][10]; group 4 includes malformations due to abnormal postmigrational development with subcortical or transmantle components; and group 5 includes heterotopic gray matter brain malformations with bilateral complex patterns.
The diagnosis of GMH requires highly specialized and multidisciplinary expertise. Clinically, it has been commonly related to developmental delay and other systemic 1 3 malformations. The purpose of this study was to evaluate the clinical and neuroimaging features of gray matter heterotopia observed over a 10-year period in a single tertiary pediatric department to improve the clinicians' and radiologists' understanding of the disease.

Methods
We reviewed retrospectively the clinical records of the 22 children presenting with epilepsy and/or development delay and diagnosed at Brain MRI with HET, admitted at single tertiary Pediatric Department at the "Policlinico G. Rodolico" University-Hospital, Catania, Italy from January 2010 to January 2020. In this study, children were grouped according to the main types of heterotopia: seventeen had PVNH (77%), three SBH (13%), and two SUBH (9%). The study was approved by the ethic Committee of the University Hospital of Catania University. We collected the data from the medical charts: sex, age at first diagnosis, seizure types, electroencephalograpic (EEG) results, neuropsychiatric evaluation, were reported together with other possible cerebral or systemic malformations presented by the children. Brain MRI studies included T1-weighted, T2-weighted, fluid-attenuated inversion recovery, diffusion-weighted and post-contrast T1 imaging. EEG was carried out for each child using the international 10-20 system.

Results
The age at first diagnosis ranged from 3 months to 16 years with a mean age of 8.2 years (± 5.4). Twelve children were males (54.6%) and ten (45.4%) were females. The results obtained are distinguished on the basis of the type of HET and beneath reported:

Periventricular nodular heterotopia (PVNH)
This group of children includes nine females (52.9%) and eight males (47.1%), with mean age of establishing a diagnosis of 8.1 years (± 6.1). This group of children includes nine females (52%) and eight males (47%), with mean age of the first diagnosis of 8 years (± 6). Table 1 shows the clinical features. Figure 1 shows the main characteristics and intensity of periventricular nodules on MRI.

Subcortical band heterotopia (SBH)
This group includes two children, one female and one male, with mean age of establishing a diagnosis of 7.5 years (± 5.5). Table 2 shows clinical features.

Subcortical heterotopia (SUBH)
This group includes three children, all males, with mean age of establishing a diagnosis of 9 years (± 1.8). Table 3 shows the clinical features. Figure 2 shows the main characteristics and intensity of periventricular nodules on MRI.

Discussion
In this retrospective review, we selected 22 children affected by HET: 17 presenting with PVNH 2 with SBH, and 3 with SUBH. HET manifests with variable clinical expression, mainly presenting with DD/ID, epilepsy and other brain and systemic malformations [3,[9][10][11][12]. In this series, 12 out of 22 (54%) subjects showed delayed cognitive function, and 11 out of 22 subjects (50%) showed epilepsy with a lower frequency than the results from other studies that reported cognitive disability and epilepsy in a greater number of cases [11,12].
In literature HET is associated with epilepsy [13][14][15]; about this, in our experience 11/22 patients (50%) developed epilepsy. Several studies reported that periventricular heterotopia is the type of GMH more associated with the epilepsy (80-90%) [12,16], which was more common focal seizure than general [12,13], and more detected in females than males [4,15]. Differently, in our periventricular group we detected epilepsy in 8/17 patients (47%), with a female predominance (female to male ratio 5:3). About the type of epilepsy, we found generalized seizures in 4/8 patients, followed by two patients with infantile spasms and two with focal seizure. In the report of Srour et al., all patients with infantile spasms showed bilateral lesions [16]: in our case series, only 1/2 with infantile spasms showed bilateral lesions in accordance with the study of Hung et al. [11]. Consistent with the literature, the most common EEG abnormality was focal epileptiform.
About the subcortical group, we collected three patients affected by epilepsy, two focal type and one generalized seizures, and no other anomalies. Only one patient had strabismus. Raza et al. report a study with ten patients affected by subcortical heterotopia [17]: they describe an association with subcortical heterotopia, central nervous system (CNS) anomalies and neurological dysfunction. Probably due to the low number of patients, we did not detect these findings.
About the band group, we collected two patients with psychomotor delay, without seizures. One of the two patients had hemispheric cystic. Hung et al. describe 10 patients with band heterotopia [11], associating it with 1 3 brain anomalies and congenital malformations. As the precedent group, due to the low number of patients, it is difficult compare our results.

in accordance with
In accordance with the data of Hung et al., we report the case of a patient with Dandy-Walker cyst and the case of a patient with Ehlers-Danlos syndrome. Advances in genetic show a correlation between connective tissue disorder and periventricular heterotopia [18]: our experience confirms this date.    Interestingly, we report the case of a patient with periventricular heterotopia and Aicardi syndrome, showing seizures and agenesis of corpus callosum, typical features described in the syndrome [19].
About the other systemic malformations, our experience shows a correlation between heterotopia and cardiac diseases, previously described by other studies [11,16]. Also, we found ocular abnormalities, especially strabismus, in 6/22 patients. Interestingly, we found two patients with growth hormone deficiency (GH) and heterotopia. We attribute this incidence in our case series, never described before, because our center is a reference department of endocrinology and neurology pediatric. In these patients MRI did not show pituitary lesions, so they received diagnosis of GH deficiency idiopathic. In literature, growth hormone deficiency and heterotopia are rarely correlated, such as Vilboux et al. in a Joubert patient [20]. Mitchell et al. reported a study with a possible correlation between periventricular heterotopia, ectopic posterior pituitary lobe and GH deficiency [21]. In our case series, one patient had ectopic posterior pituitary lobe and periventricular heterotopia (Fig. 6); differently, in two patients with GH deficiency MRI did not show anomalies to the posterior pituitary. c Unenhanced T2-weighted MR coronal image show bilateral perive-ntricular nodular heterotopia (PVNH) (arrows), enlarged lateral ventricles and cerebellar vermis atrophy. d Unenhanced T1-weighted MR midsagittal image show dysmorphic ventricular system and periventricular nodular heterotopia (arrows). e T2 -weighted MR coronal image shows the "Viking helmet appearance" refers to the morphology of the lateral ventricles in the coronal plane in patients with dysgenesis of the corpus callosum. The cingulate gyrus is everted into narrowed and elongated frontal horns Our study had some limitations. The study population was small, especially for the subcortical and band group. All the data were obtained retrospectively. Our patients were only from a single tertiary hospital in Catania. In addition, genetic testing was not performed in our cohort.
Our report confirms that heterotopia may be a clue of different and various cerebral and systemic anomalies; for this reason, in case of GMHs for the clinicians it's important value the cardiac function, ocular abnormalities and eventually skeletal or renal anomalies.