[Modified posterior quadrant disconnection in surgical treatment of drug-resistant epilepsy in a patient with left temporal and occipital lobe malformation]. / Modifitsirovannaya zadnekvadrantnaya diskonnektsiya v khirurgicheskom lechenii farmakorezistentnoi epilepsii u patsienta s porokom razvitiya levykh visochnoi i zatylochnoi dolei.

Adults with large multilobar lesions of temporal, parietal and occipital lobes of the dominant hemisphere suffering from drug-resistant epilepsy were considered inoperable for a long time. OBJECTIVE: To demonstrate favorable postoperative outcome in a patient with massive periventricular heterotopia of the left temporal and occipital lobes complicated by drug-resistant epilepsy. MATERIAL AND METHODS: We analyzed localization of the brain malformation (massive periventricular heterotopia) and its relationship with surrounding structures in a 38-year-old patient considering preoperative MRI, functional MRI and MR tractography data. Quality of modified posterior quadrant disconnection was assessed within a day and 6 months after surgery in accordance with MRI data. Transcranial stimulation, direct cortical and subcortical monopolar stimulation were used for intraoperative monitoring of corticospinal tract. We also assessed neurological status and linguistic testing data before surgery, 4 days and 6 months after surgery. RESULTS: Modified posterior disconnection of temporal, parietal and occipital lobes was performed. Intraoperative neurophysiological cortical mapping (asleep-awake-sedation protocol) verified localization of Wernicke's area. There was an expected right-sided homonymous hemianopsia in postoperative period without speech disorders. Postoperative outcome Engel grade 1A under anticonvulsant therapy was obtained. CONCLUSION: The authors report successful surgical treatment of massive malformation of the left temporal, parietal and occipital lobes and literature review devoted to this issue.

Asymmetrical aortic root aneurism in patient with Filamin A mutation.

We report the case of a 28 years old woman with periventricular nodular heterotopia, due to Filamin A mutation. She had an asymmetrical aneurysm of the aortic root, involving, above all, noncoronary Valsalva sinus. She was asymptomatic and she had moderate aortic regurgitation. Reimplantation of the aortic valve with replacement of the aortic root was successfully accomplished. Filamin A is a protein that is encoded by the FLNA gene, which shows X-linked dominant inheritance. This protein is involved in neuronal migration, angiogenesis, cytoskeleton regulation, and cell signaling. Therefore, mutations of FLNA gene might result in brain, blood vessels, heart, and connective tissue disorders. A miscellany of cardiovascular abnormalities could be present in this subset of patients; cardiac symptoms may precede neurological manifestations. Aorta seems to be frequently affected. Consequently, in presence of FLNA gene mutations, cardiovascular evaluation should include vascular magnetic resonance imaging or computed tomography scan.

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.

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.

Surgical techniques: Stereoelectroencephalography-guided radiofrequency-thermocoagulation (SEEG-guided RF-TC).

Stereoelectroencephalography-guided radiofrequency-thermocoagulation (SEEG-guided RF-TC) consists of coupling SEEG investigation with RF-TC stereotactic lesioning directly through the recording electrodes. In this systematic review the surgical technique, indications, and outcomes are described. Maximum accuracy is reached when a frame-based procedure with a robotic assistance and a per-operative vascular X-ray imaging are performed. Monitoring of the lesioning procedure based on the impedance, a sharp modification of which indicates that the thermocoagulation has reached its maximum volume, allows the optimization of the lesion size. The first indication concerns patients in whom a SEEG is required to determine whether surgery is feasible and in whom resection is indeed possible. Even if surgery is performed owing to insufficient efficacy of SEEG-guided RF-TC, the procedure remains interesting owing to its high positive predictive value for good outcome after surgery. The second indication concerns patients in whom phase I non-invasive investigations have concluded to surgical contraindication and who may still undergo SEEG in a purely therapeutic perspective (small deep zones inaccessible to surgery and network nodes of large epileptic networks). Lastly, SEEG-guided RF-TC can be considered as a first-line treatment for periventricular nodular heterotopia (PNH). Independently of indication, the overall seizure-free rate is 23% and the responder rate is 58%. The best results are obtained for PNH (38% seizure-free and 81% responders), while the worst results have been reported for temporal lobe-epilepsy in a dedicated study. The overall complication rate is 2.5%. More evidence is needed to help determine the exact place of SEEG-guided RF-TC in the surgical management algorithm.

Experience on the use of Vagus Nerve Stimulation during pregnancy.

OBJECTIVE: Vagus Nerve Stimulation (VNS) is a neuromodulation device approved for the treatment of medically refractory epilepsy. Worldwide, only 35 cases of pregnancies that has been described. This study aims to continue to increase the limited knowledge of the use of VNS during pregnancy. METHODS: We interrogated the database of the Epilepsy program at Western University (1998-2018), and identified those patients who were implanted with VNS and became pregnant. RESULTS: From 114 patients implanted with VNS in our centre, four patients had a total of seven pregnancies. This is the first report with one woman implanted with VNS having three pregnancies. Three patients had genetic generalized epilepsy and one focal epilepsy due to periventricular nodular heterotopia. The median duration since implantation was 3.17 years (IQR: 1.33-4.33) and the output was 2.75 mA (IQR: 1.5-3.5). No modifications in stimulation settings were made in any patient during pregnancy. Three patients had obstetric complications, requiring c-sections. All babies were healthy, except one with intellectual disabilities of unclear severity. CONCLUSION: Our small sample suggests VNS could increase the obstetrical complications, but is likely safe for the fetus. However, a larger sample size should be collected to determine safety and potential teratogenicity of VNS.

High-frequency oscillations and spikes running down after SEEG-guided thermocoagulations in the epileptogenic network of periventricular nodular heterotopia.

OBJECTIVE: Epilepsy associated with periventricular nodular heterotopia (PNH) is characterized by complex relationships between the heterotopic and the normotopic cortex during the interictal state and at seizure onset. High-frequency oscillations (HFO) have been proposed as a marker of epileptogenicity that might reflect disease activity. The effects of thermocoagulations on epileptogenicity in this context remain unknown. We aimed to investigate the interictal HFO- and spike profiles of different cortical structures before and after two consecutive SEEG-guided thermocoagulations, in correlation with seizure outcome, in a patient with PNH-related drug-resistant epilepsy. METHODS: The epileptogenic zone (EZ) was defined by SEEG analysis based on the Epileptogenicity Index. Interictal spikes, ripples (80-250 Hz) and fast ripples (FR, 250-330 Hz) were analyzed within the heterotopia, the temporal neocortex and the hippocampus. RESULTS: The SEEG recordings revealed a distributed EZ involving the heterotopia and the posterior temporal neocortex. Both structures were targeted by thermocoagulations. Background spikes, ripples and FR-rates were significantly higher in PNH compared to the normotopic cortex. A drastic reduction of spikes (by over 80%) and absence of FR were demonstrated both in the PNH and in the neocortex during the second SEEG exploration 6 months after the first thermocoagulation, whereas no significant difference was observed in the posterior hippocampus. Ripples were significantly reduced by the first and suppressed by the second thermocoagulation within the three structures. Seizures relapsed after two months but decreased in frequency after the first thermocoagulation. Sustained seizure-freedom was achieved only after the second procedure. CONCLUSIONS: Our data demonstrate the running down of interictal HFO and spikes within the epileptogenic network following thermocoagulations of heterotopic and normotopic sites involved at seizure onset. This dynamics was in good correlation with significantly improved seizure control. SIGNIFICANCE: Combination of ictal and different interictal markers of epileptogenicity, including HFO and spike analysis, is important to get the full picture of the epileptogenic zone and could help to evaluate the disease activity.

RF-ablation in periventricular heterotopia-related epilepsy.

Drug-resistant focal epilepsy is a common occurrence in patients with gray matter nodular heterotopia (NH), and surgical treatment is often considered in these cases. NH-related epileptogenicity is sustained by complex networks, which may involve the nodules and extralesional cortex in various combinations. Therefore, invasive EEG is usually required to identify the structures involved in seizure generation. It has been reported that surgery may be effective in cases with unilateral lesions, whereas bilateral cases are not optimal candidates for surgical success. Furthermore, violation of cortical and subcortical structures for approaching deep-seated nodules may result in neurological deficits. For these reasons, selective stereotactic ablation with radiofrequency thermocoagulation (RFTC) has been proposed as an alternative option in these patients. In particular, RFTC may be performed by using the same recording intracerebral electrodes implanted for stereo-electro-encephalo-graphy (SEEG) monitoring, with the advantage of a reliable electro-clinical guide. Excellent results on seizures have been initially reported following coagulation of single, unilateral NH. Subsequent experience has indicated that, basing on the evidence of SEEG recording, promising results may be obtained also in more extended unilateral and bilateral cases. In more complex cases, coagulation of both the nodules and of the involved extralesional cortical structures is often required. In a recently reported series, 67% of patients experienced sustained seizure freedom after the procedure. However, post RFTC seizure outcome in complex cases (NH plus other malformations of cortical development) is not as good as in other patterns of NH. RFTC, especially if guided by SEEG evaluation, should be considered as a first-line treatment option in NH-related epilepsy. Satisfactory results may be obtained also in cases not amenable to traditional surgery. The procedure is safe and does not prevent eventual resective surgery in case of failure in seizure control. For these reasons, in patients undergoing SEEG evaluation, electrode arrangement should be planned with the aim to cover as extensively as possible the heterotopic and extralesional areas, which will presumably be the targets of RFTC.

Stereo-EEG: Diagnostic and therapeutic tool for periventricular nodular heterotopia epilepsies.

OBJECTIVE: Periventricular nodular heterotopias (PNHs) are malformations of cortical development related to neuronal migration disorders, frequently associated with drug-resistant epilepsy (DRE). Stereo-electroencephalography (SEEG) is considered a very effective step of the presurgical evaluation, providing the recognition of the epileptogenic zone (EZ). At the same time, via the intracerebral electrodes it is possible to perform radiofrequency thermocoagulation (SEEG-guided RF-TC) with the aim of ablating and/or disrupting the EZ. The purpose of this study was to evaluate both the relationships between PNH and the EZ, and the efficacy of SEEG-guided RF-TC. METHODS: Twenty patients with DRE related to PNHs were studied. Inclusion criteria were the following: (1) patients with epilepsy and PNHs (unilateral or bilateral, single or multiple nodules) diagnosed on brain magnetic resonance imaging (MRI); (2) SEEG recordings available as part of the presurgical investigations, with at least one intracerebral electrode inside the heterotopia; (3) complete surgical workup with SEEG-guided RF-TC and/or with traditional neurosurgery, with a follow-up of at least 12 months. RESULTS: Complex and heterogenic epileptic networks were found in these patients. SEEG-guided RF-TC both into the nodules and/or the cortex was efficacious in the 76% of patients. Single or multiple, unilateral or bilateral PNHs are the most suitable for this procedure, whereas patients with PNHs associated with complex cortical malformations obtained excellent outcome only with traditional resective surgery. SIGNIFICANCE: Each patient had a specific epileptogenic network, independent from the number, size, or location of nodules and from the cortical malformation associated with. SEEG-guided RF-TC appears as a new and very effective diagnostic and therapeutic approach for DRE related to PNHs.

Intracranial evaluation and laser ablation for epilepsy with periventricular nodular heterotopia.

Surgical treatment of focal epilepsy in the presence of periventricular nodular heterotopia (PVNH) poses a challenge, as the relative roles of the nodular tissue and the overlying cortex in the generation of seizures can be complex and variable. Here, we review the literature on chronic invasive EEG recordings in humans with this substrate and present two illustrative cases from our practice. We found that while inter-ictal spiking from nodules is common, clinical seizures rarely arise solely from nodular tissue. More typically, ictal onset is simultaneous with overlying neocortex or mesial temporal structures. Surgical outcome is more favorable in cases with unilateral (as opposed to bilateral) PVNH, and when a substantial or complete ablation of PVNH is performed. In rare cases, nodular ablation alone may be sufficient, as may be completed by MRI-guided laser interstitial thermal therapy. The mechanism(s) by which PNVH interacts with overlying cortex are not fully understood, but we suggest that PVNH either orchestrates or amplifies local network epileptogenicity. At present, invasive recordings with penetrating depth electrodes are required prior to surgical therapy, as illustrated in our cases.

Successful treatment of epilepsy by resection of periventricular nodular heterotopia.

We report on a case of successful surgical treatment of drug-resistant epilepsy associated with a solitary lesion of periventricular nodular heterotopia (PNH). In the reported patient, intracranial ictal electroencephalography disclosed that seizures did not originate from the heterotopic nodules. However, the seizures were completely suppressed by lesionectomy of PNH alone. Epileptogenesis associated with PNH likely involves a very complex network between PNH and the surrounding cortex, and the disruption of this network may be an effective means of curing intractable, PNH-associated epilepsy.

Periventricular nodular heterotopia functionally couples with the overlying hippocampus.

Patients with periventricular nodular heterotopia (PVNH) often have severe epilepsy. However, it is unclear how the heterotopia contributes to epileptogenesis. Recently, electrophysiologic studies using intraoperative depth electrodes have indicated that interaction between the heterotopia and overlying cortex is crucial for seizure onset. We performed an in vitro physiologic study using slices of resected brain from a 22-year-old man with PVNH, who manifested medically refractory mesial temporal lobe epilepsy. Preoperative evaluation indicated that the right mesial temporal structure and PVNH were the epileptogenic focus. The resected tissue was immediately immersed in cold artificial cerebrospinal fluid, and then slices of the brain tissue including the heterotopic nodules and overlying hippocampus were prepared. We electrically stimulated the incubated slices, and the elicited neural activities were analyzed as changes in the flavoprotein fluorescence signals. When we stimulated either the heterotopic nodule or the overlying hippocampus, clear functional coupling of neural activities between these structures was observed. The coupling response evoked by stimulation of the subiculum and developing within the heterotopic nodule was enhanced by application of bicuculline. Therefore, activities of the hippocampus and the nodule are closely correlated.

Radiofrequency lesioning for epileptogenic periventricular nodular heterotopia: a rational approach.

Periventricular nodular heterotopias (PNHs) are frequently associated with pharmacoresistant epilepsy. They are considered part of a dysfunctional network, connected to the overlying cortex. Therefore, removal of the PNHs and additional cortectomy or lobectomy seem to be essential for significant and long-lasting seizure reduction. These procedures, however, can have considerable limitations, especially in patients with functional eloquent cortex adjacent to the PNH. Alternatively, stereotactic neurosurgery can reduce the surgical trauma. Presented is a 56-year-old man who became seizure-free after stereotactically guided radiofrequency lesioning of a solitary PNH.