Stereo-EEG-based ictal functional connectivity in patients with periventricular nodular heterotopia-related epilepsy.

Nodular heterotopia (NH)-related drug-resistant epilepsy is challenging due to the deep location of the NH and the complexity of the underlying epileptogenic network. Using ictal stereo-electroencephalography (SEEG) and functional connectivity (FC) analyses in 14 patients with NH-related drug-resistant epilepsy, we aimed to determine the leading structure during seizures. For this purpose, we compared node IN and OUT strength between bipolar channels inside the heterotopia and inside gray matter, at the group level and at the individual level. At seizure onset, the channels within NH belonging to the epileptogenic and/or propagation network showed higher node OUT-strength than the channels within the gray matter (p = .03), with higher node OUT-strength than node IN-strength (p = .03). These results are in favor of a "leading" role of NH during seizure onset when involved in the epileptogenic- or propagation-zone network (50% of patients). However, when looking at the individual level, no significant difference between NH and gray matter was found, except for one patient (in two of three seizures). This result confirms the heterogeneity and the complexity of the epileptogenic network organization in NH and the need for SEEG exploration to characterize more precisely patient-specific epileptogenic network organization.

Periventricular nodular heterotopia associated with a "transmantle band sign" in patients with epilepsy.

OBJECTIVE: Previous studies using advanced magnetic resonance imaging (MRI) techniques have documented abnormal transmantle bands connecting ectopic nodules to overlying cortex in patients with periventricular nodular heterotopia (PNH). We describe a similar finding using conventional MRI techniques. METHODS: Patients were identified by means of a full-text search of radiological reports. All scanning was performed using conventional sequences at 3 Tesla (3T). Scans were reviewed by three neuroradiologists, and we characterized imaging features based on type of PNH and cortical irregularities associated with the transmantle band. RESULTS: A total 57 PNH patients were reviewed, of whom 41 demonstrated a "transmantle band" connecting the nodule to the overlying cortex. One or more periventricular heterotopic nodules was present in all 41 patients-this was bilateral in 29 of 41 (71%) and unilateral in the remaining 29%. In many cases there was more than one such band, and in some cases this band was nodular. In 19 of the cases, the cortex to which the band connected was abnormal, showing thinning in 4 cases, thickening in 5 cases, and polymicrogyria in another 10. SIGNIFICANCE: The transmantle band can be seen frequently in both unilateral and bilateral cases of PNH and can be visualized with conventional 3T MRI sequences. The band highlights the underlying neuronal migration issues at play in the pathogenesis of this disorder, but its underlying role in the complex, patient-specific epileptogenic networks in this cohort has yet to be determined and warrants further investigation.

The phenotypic spectrum of epilepsy associated with periventricular nodular heterotopia.

BACKGROUND: Periventricular nodular heterotopia (PVNH) is a congenital brain malformation often associated with seizures. We aimed to clarify the spectrum of epilepsy phenotypes in PVNH and the significance of specific brain malformation patterns. METHODS: In this retrospective cohort study, we recruited people with PVNH and a history of seizures, and collected data via medical record review and a standardized questionnaire. RESULTS: One hundred individuals were included, aged 1 month to 61 years. Mean seizure onset age was 7.9 years. Ten patients had a self-limited epilepsy course and 35 more were pharmacoresponsive. Fifty-five had ongoing seizures, of whom 23 met criteria for drug resistance. Patients were subdivided as follows: isolated PVNH ("PVNH-Only") single nodule (18) or multiple nodules (21) and PVNH with additional brain malformations ("PVNH-Plus") single nodule (8) or multiple nodules (53). Of PVNH-Only single nodule, none had drug-resistant seizures. Amongst PVNH-Plus, 55% with multiple unilateral nodules were pharmacoresponsive, compared to only 21% with bilateral nodules. PVNH-Plus with bilateral nodules demonstrated the highest proportion of drug resistance (39%). A review of genetic testing results revealed eight patients with pathogenic or likely pathogenic single-gene variants, two of which were FLNA. Five had copy number variants, two of which were pathogenic. CONCLUSIONS: The spectrum of epilepsy phenotypes in PVNH is broad, and seizure patterns are variable; however, epilepsy course may be predicted to an extent by the pattern of malformation. Overall, drug-resistant epilepsy occurs in approximately one quarter of affected individuals. When identified, genetic etiologies are very heterogeneous.

Localized activity alternations in periventricular nodular heterotopia-related epilepsy.

OBJECTIVE: Periventricular nodular heterotopia (PNH) is a common type of heterotopia usually characterized by epilepsy. Previous studies have identified alterations in structural and functional connectivity related to this disorder, but its local functional neural basis has received less attention. The purpose of this study was to combine univariate analysis and a Gaussian process classifier (GPC) to assess local activity and further explore neuropathological mechanisms in PNH-related epilepsy. METHODS: We used a 3.0-T scanner to acquire resting-state data and measure local regional homogeneity (ReHo) alterations in 38 patients with PNH-related epilepsy and 38 healthy controls (HCs). We first assessed ReHo alterations by comparing the PNH group to the HC group using traditional univariate analysis. Next, we applied a GPC to explore whether ReHo could be used to differentiate PNH patients from healthy patients at an individual level. RESULTS: Compared to HCs, PNH-related epilepsy patients exhibited lower ReHo in the left insula extending to the putamen as well as in the subgenual anterior cingulate cortex (sgACC) extending to the orbitofrontal cortex (OFC) [p < 0.05, family-wise error corrected]. Both of these regions were also correlated with epilepsy duration. Furthermore, the ReHo GPC classification yielded a 76.32% accuracy (sensitivity = 71.05% and specificity = 81.58%) with p < 0.001 after permutation testing. INTERPRETATION: Using the resting-state approach, we identified localized activity alterations in the left insula extending to the putamen and the sgACC extending to the OFC, providing pathophysiological evidence of PNH. These local connectivity patterns may provide a means to differentiate PNH patients from HCs.

Magnetic resonance imaging features of isolated periventricular heterotopia in pediatric epilepsy: a comparative study

Objective: Periventricular nodular heterotopia is a neurodevelopmental disorder in which neurons fail to migrate to the cortical surface, forming discrete areas of grey matter adjacent to the lateral ventricles. Given that periventricular nodular heterotopia is seen as an incidental finding in patients without epilepsy, causality between periventricular nodular heterotopia and epilepsy cannot be assumed. Furthermore, the structural characteristics of periventricular nodular heterotopia in patients with epilepsy are poorly defined and can be misleading. In this article, we investigate whether structural radiological characteristics of heterotopia can predict epileptogenicity in pediatric patients. Methods: Pediatric patients with periventricular nodular heterotopia, but no other epilepsy-associated cortical abnormalities on magnetic resonance imaging, were identified and divided into two groups: with epilepsy and without epilepsy. Radiological characteristics of laterality, regionalization, largest dimension and number of nodules were compared between the two groups. Results: Only periventricular nodular heterotopia spreading across several regions was associated with a statistically higher chance of epilepsy. Other features including laterality, individual region, number and largest dimension did not reliably predict epileptogenicity. Significance: Most radiological characteristics of periventricular nodular heterotopia are similar in patients with and without epilepsy. The involvement of multiple periventricular regions with heterotopia was the only feature that inferred a higher risk of epilepsy. Periventricular nodular heterotopia requires a comprehensive work-up and should be interpreted in the context of each individual patient and not assumed to be directly causative of epilepsy, nor unrelated to it. Therefore, further studies using additional structural and functional imaging modalities are needed to determine the radiological features of epileptogenic periventricular nodular heterotopia.

Hypothalamic hamartoma associated with polymicrogyria and periventricular nodular heterotopia in children: report of three cases and discussion of the origin of the seizures.

PURPOSE: Hypothalamic hamartomas (HH) are malformations responsible for drug-resistant epilepsy. HH are usually isolated or part of a genetic syndrome, such as Pallister-Hall. Exceptionally they can be associated with other brain malformations such as polymicrogyria (PMG) and periventricular nodular heterotopia (PNH). We discuss the origin of the seizures associated with this combination of malformations, through electrophysiological studies, and review the literature on this rarely reported syndrome. METHODS: We retrospectively reviewed the patients with HH who had surgery between 1998 and 2020 and selected those with associated focal PMG and PNH, detected on MRIs. All patients had comprehensive clinical evaluation and surface video-EEG and one underwent stereoelectroencephalography (SEEG). RESULTS: Three male patients out of 182 were identified with a mean age at surgery of 7.5 years. MRI showed unilateral focal PMG (fronto-insulo-parietal, fronto-insulo-parieto-opercular, and fronto-insular, respectively) and multiple PNH homolateral to the main HH implantation side. In two patients, there were strong clinical and scalp EEG arguments for seizure onset within the HH. In the third, due to abnormalities on scalp video-EEG in the same area as PMG and the lack of gelastic seizures, SEEG was indicated and demonstrated seizure onset within the hamartoma. With a mean follow-up of 6 years, two patients were seizure-free. CONCLUSION: Our results show that HH is the trigger of epilepsy, which confirms the high epileptogenic potential of this malformation. In patients such as ours, as in those with isolated HH, we recommend to begin by operating the HH independently of seizure semiology or electrophysiological abnormalities.

Ophthalmic Findings Associated with NEDD4L-related Disorder.

Pathogenic variants in the NEDD4L gene are associated with a very rare neurodevelopmental disorder characterized by periventricular nodular heterotopia, developmental delay, 2-3 toe syndactyly, and cleft palate. Ophthalmic findings associated with this disorder have not been well described in literature. We have summarized the clinical findings that have been reported in this disorder previously and highlight a novel ophthalmic finding of foveal hypoplasia in a new case of NEDD4L-related disorder.

An Independent Seizure-Onset Zone in Medial Temporal Lobe Found by 18 F-FDG PET Imaging Besides Epileptogenic Periventricular Nodular Heterotopia.

ABSTRACT: A 23-year-old man with drug-resistant epilepsy was admitted for presurgical evaluation. The epileptogenic zone could not be derived from seizure semiology and scalp electroencephalographic monitoring definitely. MRI showed periventricular nodular heterotopia in occipital horn of left lateral ventricle with high FDG uptake on interictal 18 F-FDG PET scan, whereas the hypometabolic zone in the left medial temporal lobe was also found on PET with no abnormality on MRI. Stereoelectroencephalographic implantation was performed to identify the seizure-onset zone. Two independent epileptogenic foci located in periventricular nodular heterotopia and left hippocampus were validated by stereoelectroencephalographic monitoring and the outcome of subsequent thermocoagulation.

Phenotypic manifestations in FLNA-related periventricular nodular heterotopia: a case report and review of the literature.

Periventricular nodular heterotopia (PVNH) is an X-linked disease caused by loss-of-function variants in the filamin A (FLNA) gene. FLNA-PVNH is a heterogeneous disorder, and the phenotype is associated with neurological and non-neurological features including cardiovascular, gastrointestinal, pulmonary, haematological, cutaneous and skeletal manifestations. No clear definition of the FLNA-PVNH phenotype has been established, but the patients are predominantly females with seizures, cardiovascular manifestations, and normal intelligence or mild intellectual disability. Herein, we describe a PVNH patient diagnosed with a novel heterozygous missense variant in FLNA after an atypical presentation of deep vein thrombosis and thrombocytopenia. Clinical evaluation found hypermobility, cardiovascular and skin manifestations. Moreover, we conducted a literature review of 186 FLNA-PVNH patients to describe the phenotypic spectrum. In conclusion, our patient highlights the importance of thorough clinical evaluation to identify manifestations in this very heterogeneous disorder. The phenotypic review may guide clinicians in the assessment and follow-up of FLNA-PVNH patients.

Using magnetic resonance fingerprinting to characterize periventricular nodular heterotopias in pharmacoresistant epilepsy.

OBJECTIVE: We aimed to use a novel magnetic resonance fingerprinting (MRF) technique to examine in vivo tissue property characteristics of periventricular nodular heterotopia (PVNH). These characteristics were further correlated with stereotactic-electroencephalographic (SEEG) ictal onset findings. METHODS: We included five patients with PVNH who had SEEG-guided surgery and at least 1 year of seizure freedom or substantial seizure reduction. High-resolution MRF scans were acquired at 3 T, generating three-dimensional quantitative T1 and T2  maps. We assessed the differences between T1 and T2  values from the voxels in the nodules located in the SEEG-defined seizure onset zone (SOZ) and non-SOZ, on -individual and group levels. Receiver operating characteristic analyses were performed to obtain the optimal classification performance. Quantification of SEEG ictal onset signals from the nodules was performed by calculating power spectrum density (PSD). The association between PSD and T1 /T2  values was further assessed at different frequency bands. RESULTS: Individual-level analysis showed T1 was significantly higher in SOZ voxels than non-SOZ voxels (p < .05), with an average 73% classification accuracy. Group-level analysis also showed higher T1 was significantly associated with SOZ voxels (p < .001). At the optimal cutoff (normalized T1 of 1.1), a 76% accuracy for classifying SOZ nodules from non-SOZ nodules was achieved. T1  values were significantly associated with ictal onset PSD at the ultraslow, θ, ß, γ, and ripple bands (p < .05). T2  values were significantly associated with PSD only at the ultraslow band (p < .05). SIGNIFICANCE: Quantitative MRF measures, especially T1 , can provide additional noninvasive information to separate nodules in SOZ and non-SOZ. The T1 and T2 tissue property changes carry electrophysiological underpinnings relevant to the epilepsy, as shown by their significant positive associations with power changes during the SEEG seizure onset. The use of MRF as a supplementary noninvasive tool may improve presurgical evaluation for patients with PVNH and pharmacoresistant epilepsy.

Cardiovascular and connective tissue disorder features in FLNA-related PVNH patients: progress towards a refined delineation of this syndrome.

BACKGROUND: FLNA Loss-of-Function (LoF) causes periventricular nodular heterotopia type 1 (PVNH1), an acknowledged cause of seizures of various types. Neurological symptoms are inconstant, and cardiovascular (CV) defects or connective tissue disorders (CTD) have regularly been associated. We aimed at refining the description of CV and CTD features in patients with FLNA LoF and depicting the multisystemic nature of this condition. METHODS: We retrospectively evaluated FLNA variants and clinical presentations in FLNA LoF patient with at least one CV or CTD feature, from three cohorts: ten patients from the French Reference Center for Rare Vascular Diseases, 23 patients from the national reference diagnostic lab for filaminopathies-A, and 59 patients from literature review. RESULTS: Half of patients did not present neurological symptoms. Most patients presented a syndromic association combining CV and CTD features. CV anomalies, mostly aortic aneurysm and/or dilation were present in 75% of patients. CTD features were present in 75%. Variants analysis demonstrated an enrichment of coding variants in the CH1 domain of FLNA protein. CONCLUSION: In FLNA LoF patients, the absence of seizures should not be overlooked. When considering a diagnosis of PVNH1, the assessment for CV and CTD anomalies is of major interest as they represent interlinked features. We recommend systematic study of FLNA within CTD genes panels, regardless of the presence of neurological symptoms.

Three Different FDG Patterns in Periventricular Nodular Heterotopia Correlated to Video Stereoelectroencephalography.

ABSTRACT: A 40-year-old woman with a drug-resistant focal epilepsy underwent cerebral FDG PET in phase 1 presurgical epilepsy study. MRI essentially showed multiple periventricular nodular heterotopias. The stereoelectroencephalography coupled to MRI and FDG PET helped to define the anatomofunctional correlation of the epileptogenic zone network. This procedure brought to light 3 distinct patterns of FDG consumption, corresponding to different anatomoelectroclinical features. This pattern was already found in a previous FDG PET reflecting a "stable" permanent intralesional intercritical stereoelectroencephalography activity, an electrical "signature" of the lesion. Finally, functional imaging improved thermocoagulation in this patient and emphasized the use of FDG in drug-resistant epilepsy.

Neural functional connectivity in patients with periventricular nodular heterotopia-mediated epilepsy.

Periventricular nodular heterotopia (PNH) is characterized by disabled neural migration and is usually associated with epilepsy. Despite awareness of PNH-related epilepsy, little is known about the brain-level underlying functional neural bases. Thus, we used functional magnetic resonance imaging (MRI) to examine the neurobiology of 42 subjects with PNH-related epilepsy and 42 sex- and age-matched healthy controls. Measurements of functional connectivity (FC) and whole-brain graph theory analysis of data in the resting state were performed to assess neurological organization and topology. PNH patients exhibited significantly higher FC in the parietal lobe, cingulum and thalamus, as well as significantly lower FC in frontoparietal, hippocampal, and precentral regions. Graph theory analysis identified no significant differences between patients and controls, while patients showed lower network global efficiency in the limbic and cerebellum network and occipital cortex. Seed-based FC analysis confirmed disruption of activities and interregional connectivity in remote epileptic networks of patients, which may point to underlying pathological mechanisms. The cerebellum and limbic system of patients showed altered topology, suggesting that these regions or hubs may contribute to whole-brain circuits in PNH and epilepsy.

Hippocampal deep brain stimulation: a therapeutic option in patients with extensive bilateral periventricular nodular heterotopia: a case report.

A female adult patient with extensive bilateral periventricular nodular heterotopia (PNH), who was referred for bilateral hippocampal deep brain stimulation (Hip-DBS), was investigated. She presented with daily focal aware and impaired-awareness seizures with automatism and weekly generalized tonic-clonic seizures. Her EEG showed bilateral independent ictal and interictal neocortical temporal lobe discharges and her MRI showed extensive, symmetric PNH. She was treated with bilateral Hip-DBS which led to a major decrease in her seizure frequency (one seizure per trimester). The outcome was stable over three years, and there was no additional neuropsychological deficits or device-related adverse effects. This is the first reported patient to be undergo long-term continuous Hip-DBS to treat bilateral PNH. DBS, a non-lesional, reversible, neuromodulatory technique, may prove to be a good therapeutic option in patients with extensive bilateral epileptogenic networks who present with temporal lobe epilepsy and who are usually considered poor candidates for resective surgery.

Treatment of Epilepsy Associated with Periventricular Nodular Heterotopia.

PURPOSE OF REVIEW: Epilepsy associated with periventricular nodular heterotopia (PNH), a developmental malformation, is frequently drug-resistant and requires focal therapeutic intervention. Invasive EEG study is usually necessary to delineate the epileptogenic zone, but constructing an accurate hypothesis to define an appropriate electrode implantation scheme and the treatment is challenging. This article reviews recent studies that help understanding the epileptogenicity and potential therapeutic options in PNH. RECENT FINDINGS: New noninvasive diagnostic and intracerebral EEG analytic tools demonstrated that cortical hyperexcitability and aberrant connectivity (between nodules and cortices and among nodules) are likely mechanisms causing epilepsy in most patients. The deeply seated PNH, if epileptogenic, are ideal target for stereotactic ablative techniques, which offer concomitant ablation of multiple regions with relatively satisfactory seizure outcome. Advance in diagnostic and analytic tools have enhanced our understanding of the complex epileptogenicity in PNH. Development in stereotactic ablative techniques now offers promising therapeutic options for these patients.

Laser Interstitial Thermal Therapy for Epileptogenic Periventricular Nodular Heterotopia.

OBJECTIVE: Epilepsy with periventricular nodular heterotopia (PVNH) lacks a conclusive surgical treatment strategy as eloquent cortex and important white matter tracts frequently overlay the deep periventricular nodules. Our goal was to evaluate the safety and efficacy of laser interstitial thermal therapy (LITT) for the treatment of epilepsy in PVNH. METHODS: Data on demographic characteristics, complications, visual outcomes, Engel classification at last follow-up, antiepileptic drug use, morbidity, and mortality among patients who underwent this procedure were retrospectively reviewed. RESULTS: Between May 2015 and January 2019, 5 patients underwent 6 LITT procedures for epilepsy with PVNH. One patient had residual nodules after their first procedure and underwent a second ablation. The average follow-up time was 12 months. Three patients were Engel class Ia, 1 patient was Engel class II, and 1 patient was Engel class III at last follow-up. Two patients were able to reduce their antiepileptic drugs postoperatively. Three patients had no changes in vision, 1 patient experienced a quadrantanopsia, and 1 patient had subjective blurry vision after their procedures. No patients experienced motor deficits, dysphasia, infection, or mortality. CONCLUSIONS: LITT appears to be a safe and promising option to provide seizure relief for patients with refractory epilepsy and PVNH that otherwise may not be surgical candidates. Some appropriately determined patients with refractory epilepsy may benefit from LITT before proceeding with an invasive intracranial evaluation. A larger sample size and long-term follow-up is necessary to further elucidate safety and efficacy.

[Clinical and genetic analysis of a patient with periventricular nodular heterotopia 7 caused by NEDD4L gene variant].

OBJECTIVE: To explore the genetic basis of a patient featuring global developmental delay, intellectual disability, cleft palate, seizures and hypotonia. METHODS: Clinical examination and laboratory tests were carried out. Peripheral blood samples were obtained from the patient and his parents. Whole genomic DNA was extracted and subjected to next generation sequencing. Candidate variation was analyzed by using bioinformatic software and validated by Sanger sequencing. RESULTS: The proband was found to carry a heterozygous c.2117T>C (p.Leu706Pro) variant of the NEDD4L gene, which was a de novo variant validated by Sanger sequencing and predicted to be likely pathogenic according to the American College of Medical Genetics Guidelines. CONCLUSION: The heterozygous variant of c.2117T>C (p.Leu706Pro) of the NEDD4L gene probably underlies the disorders in the patient.

Resting-state functional connectivity alterations in periventricular nodular heterotopia related epilepsy.

Periventricular nodular heterotopia (PNH) is a neural migration disorder which often presents clinically with seizures. However, the underlying functional neural basis of PNH is still unclear. We aimed to explore the underlying pathological mechanism of PNH by combining both whole brain functional connectivity (FC) and seed-based FC analyses. We utilized resting-state fMRI to measure functional connectivity strength (FCS) in 38 patients with PNH-related epilepsy and 38 control subjects. The regions with FCS alterations were selected as seeds in the following FC analyses. Pearson correlation analyses were performed to explore associations between these functional neural correlates and clinical features. In comparison with controls, PNH patients showed lower FCS in bilateral insula (P < 0.05, family wise error (FWE) correction), higher FC in the default mode network and lower FC in the fronto-limbic-cerebellar circuits (P < 0.05, FWE correction). Pearson correlation analyses revealed that FCS in bilateral insula was negatively correlated with the epilepsy duration (P < 0.05); medial prefronto-insular connectivity was negatively correlated with Hamilton Anxiety Scale (P < 0.05) and cerebellar-insular connectivity was also negatively correlated with Hamilton Depression Scale (P < 0.05). Using the resting-state FCS analytical approach, we identified significant insular hypoactivation in PNH patients, which suggests that the insula might represent the cortical hub of the whole-brain networks in this condition. Additionally, disruption of resting state FC in large-scale neural networks pointed to a connectivity-based neuropathological process in PNH.