Hemispheric epilepsy surgery for hemimegalencephaly: The UCLA experience.

OBJECTIVES: Hemimegalencephaly (HME) is a rare congenital brain malformation presenting predominantly with drug-resistant epilepsy. Hemispheric disconnective surgery is the mainstay of treatment; however, little is known about how postoperative outcomes compare across techniques. Thus we present the largest single-center cohort of patients with HME who underwent epilepsy surgery and characterize outcomes. METHODS: This observational study included patients with HME at University of California Los Angeles (UCLA) from 1984 to 2021. Patients were stratified by surgical intervention: anatomic hemispherectomy (AH), functional hemispherectomy (FH), or less-than-hemispheric resection (LTH). Seizure freedom, functional outcomes, and operative complications were compared across surgical approaches. Regression analysis identified clinical and intraoperative variables that predict seizure outcomes. RESULTS: Of 56 patients, 43 (77%) underwent FH, 8 (14%) underwent AH, 2 (4%) underwent LTH, 1 (2%) underwent unknown hemispherectomy type, and 2 (4%) were managed non-operatively. At median last follow-up of 55 months (interquartile range [IQR] 20-92 months), 24 patients (49%) were seizure-free, 17 (30%) required cerebrospinal fluid (CSF) shunting for hydrocephalus, 9 of 43 (21%) had severe developmental delay, 8 of 38 (21%) were non-verbal, and 15 of 38 (39%) were non-ambulatory. There was one (2%) intraoperative mortality due to exsanguination earlier in this cohort. Of 12 patients (29%) requiring revision surgery, 6 (50%) were seizure-free postoperatively. AH, compared to FH, was not associated with statistically significant improved seizure freedom (hazard ratio [HR] = .48, p = .328), although initial AH trended toward greater odds of seizure freedom (75% vs 46%, p = .272). Younger age at seizure onset (HR = .29, p = .029), lack of epilepsia partialis continua (EPC) (HR = .30, p = .022), and no contralateral seizures on electroencephalography (EEG) (HR = .33, p = .039) independently predicted longer duration of seizure freedom. SIGNIFICANCE: This study helps inform physicians and parents of children who are undergoing surgery for HME by demonstrating that earlier age at seizure onset, absence of EPC, and no contralateral EEG seizures were associated with longer postoperative seizure freedom. At our center, initial AH for HME may provide greater odds of seizure freedom with complications and functional outcomes comparable to those of FH.

Technological and computational approaches to detect somatic mosaicism in epilepsy.

Lesional epilepsy is a common and severe disease commonly associated with malformations of cortical development, including focal cortical dysplasia and hemimegalencephaly. Recent advances in sequencing and variant calling technologies have identified several genetic causes, including both short/single nucleotide and structural somatic variation. In this review, we aim to provide a comprehensive overview of the methodological advancements in this field while highlighting the unresolved technological and computational challenges that persist, including ultra-low variant allele fractions in bulk tissue, low availability of paired control samples, spatial variability of mutational burden within the lesion, and the issue of false-positive calls and validation procedures. Information from genetic testing in focal epilepsy may be integrated into clinical care to inform histopathological diagnosis, postoperative prognosis, and candidate precision therapies.

Facial infiltrating lipomatosis with hemimegalencephaly and lymphatic malformations caused by nonhotspot phosphatidylinositol 3-kinase catalytic subunit alpha mutation.

We report an unusual case of facial infiltrating lipomatosis with hemimegalencephaly and lymphatic malformations. In addition to the clinical data and imaging findings, detection of a heterozygous PIK3CA nonhotspot known pathogenic variant C420R in a facial epidermal nevus provided novel insight into the pathogenic effect of somatic PIK3CA mutations.

Somatic mosaicism of the PI3K-AKT-MTOR pathway is associated with hemimegalencephaly in fetal brains.

It is known that somatic activation of PI3K-AKT-MTOR signaling causes malformations of cortical development varying from hemimegalencephaly to focal cortical dysplasia. However, there have been few reports of fetal cases. Here we report two fetal cases of hemimegalencephaly, one associated with mosaic mutations in PIK3CA and another in AKT1. Both brains showed polymicrogyria, multiple subarachnoidal, subcortical, and subventricular heterotopia resulting from abnormal proliferation of neural stem/progenitor cells, cell differentiation, and migration of neuroblasts. Scattered cell nests immunoreactive for phosphorylated-S6 ribosomal protein (P-RPS6) (Ser240/244) were observed in the polymicrogyria-like cortical plate, intermediate zone, and arachnoid space, suggesting that the PI3K-AKT-MTOR pathway was actually activated in these cells. Pathological analyses could shed light on the mechanisms involved in disrupted brain development in the somatic mosaicism of the PI3K-AKT-MTOR pathway.

A rare case of hemimegalencephaly diagnosed prenatally.

Hemimegalencephaly (HME), or unilateral megalencephaly, is a rare congenital brain malformation defined as overgrowth of one cerebral hemisphere or part of it resulting from abnormal cortical development and neuronal migration. However, cortical developmental abnormalities are rarely diagnosed prenatally. This is the reason for our study, in which we describe and compare ultrasound and MRI findings in a fetus with HME.

Somatic variants in diverse genes leads to a spectrum of focal cortical malformations.

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.

Profiling PI3K-AKT-MTOR variants in focal brain malformations reveals new insights for diagnostic care.

Focal malformations of cortical development including focal cortical dysplasia, hemimegalencephaly and megalencephaly, are a spectrum of neurodevelopmental disorders associated with brain overgrowth, cellular and architectural dysplasia, intractable epilepsy, autism and intellectual disability. Importantly, focal cortical dysplasia is the most common cause of focal intractable paediatric epilepsy. Gain and loss of function variants in the PI3K-AKT-MTOR pathway have been identified in this spectrum, with variable levels of mosaicism and tissue distribution. In this study, we performed deep molecular profiling of common PI3K-AKT-MTOR pathway variants in surgically resected tissues using droplet digital polymerase chain reaction (ddPCR), combined with analysis of key phenotype data. A total of 159 samples, including 124 brain tissue samples, were collected from 58 children with focal malformations of cortical development. We designed an ultra-sensitive and highly targeted molecular diagnostic panel using ddPCR for six mutational hotspots in three PI3K-AKT-MTOR pathway genes, namely PIK3CA (p.E542K, p.E545K, p.H1047R), AKT3 (p.E17K) and MTOR (p.S2215F, p.S2215Y). We quantified the level of mosaicism across all samples and correlated genotypes with key clinical, neuroimaging and histopathological data. Pathogenic variants were identified in 17 individuals, with an overall molecular solve rate of 29.31%. Variant allele fractions ranged from 0.14 to 22.67% across all mutation-positive samples. Our data show that pathogenic MTOR variants are mostly associated with focal cortical dysplasia, whereas pathogenic PIK3CA variants are more frequent in hemimegalencephaly. Further, the presence of one of these hotspot mutations correlated with earlier onset of epilepsy. However, levels of mosaicism did not correlate with the severity of the cortical malformation by neuroimaging or histopathology. Importantly, we could not identify these mutational hotspots in other types of surgically resected epileptic lesions (e.g. polymicrogyria or mesial temporal sclerosis) suggesting that PI3K-AKT-MTOR mutations are specifically causal in the focal cortical dysplasia-hemimegalencephaly spectrum. Finally, our data suggest that ultra-sensitive molecular profiling of the most common PI3K-AKT-MTOR mutations by targeted sequencing droplet digital polymerase chain reaction is an effective molecular approach for these disorders with a good diagnostic yield when paired with neuroimaging and histopathology.

Prenatal MR Imaging Phenotype of Fetuses with Tuberous Sclerosis: An Institutional Case Series and Literature Review.

BACKGROUND AND PURPOSE: Most patients with tuberous sclerosis complex (TSC) do not receive prenatal diagnosis. Our aim was to describe MR imaging findings to determine the following: 1. Whether normal fetal MR imaging is more common in fetuses imaged at ≤24 weeks' gestation compared with >24 weeks 2. The frequency of cardiac rhabdomyoma 3. The range of MR imaging phenotypes in fetal tuberous sclerosis complex. MATERIALS AND METHODS: Our institutional fetal MR imaging data base was searched between January 1, 2011 and June 30, 2021, for cases of TSC confirmed either by genetic testing, postnatal imaging, postmortem examination, or composite prenatal imaging findings and family history. A MEDLINE search was performed on June 8, 2021. RESULTS: Forty-seven published cases and 4 of our own cases were identified. Normal findings on fetal MR imaging were seen at a lower gestational age (mean, 24.7 [SD, 4.5 ] weeks) than abnormal findings on MR imaging (mean, 30.0 [SD, 5.3] weeks) (P = .008). Nine of 42 patients with abnormal MR imaging findings were ≤24 weeks' gestation. Subependymal nodules were present in 26/45 cases (57.8%), and cortical/subcortical lesions, in 17/46 (37.0%). A foramen of Monro nodule was present in 15 cases; in 2/7 cases in which this was unilateral, it was the only abnormal cerebral finding. Cardiac rhabdomyoma was absent in 3/48 cases at the time of fetal MR imaging but was discovered later. Megalencephaly or hemimegalencephaly was observed in 3 cases. CONCLUSIONS: Fetuses with abnormal cranial MR imaging findings were older than those with negative findings. Fetal hemimegalencephaly and megalencephaly should prompt fetal echocardiography. Cardiac rhabdomyoma was not always present at the time of fetal MR imaging.

Hemispherectomy for hemimegalencephaly in a 6.5-week-old infant with tuberous sclerosis complex.

The aim of this report is to present a unique case of hemimegalencephaly and concomitant tuberous sclerosis complex (TSC1 mutation) with severe neonatal-onset epilepsy, which successfully underwent an anatomical hemispherectomy at 6.5 weeks of age for refractory seizures. Genetic testing confirmed a rare pathogenic, sporadic, heterozygous c.2041 + 1G > A gene mutation in intron 16 of the TSC1 gene, diagnostic for tuberous sclerosis. Post-operatively, the infant remained seizure free for at least 1 year. Following recurrence of her seizures, she has continued on multiple anti-seizure medications and everolimus therapy. We review the pathological and molecular features of this condition and highlight the ethics of intervention and steps taken toward safe neurosurgical intervention in this very young infant.

Functional cognitive and language outcomes after cerebral hemispherectomy for hemimegalencephaly.

OBJECTIVE: Hemispheric surgeries are an effective treatment option to control seizures for children with hemimegalencephaly (HME); however, not enough is known about their cognitive outcomes. This study aimed to delineate the cognitive and language outcomes after hemispherectomy for HME and identify the clinical characteristics associated with cognition and language. METHODS: Data came from the Global Pediatric Epilepsy Surgery Registry, a patient-driven web-based registry for epilepsy surgery. We focused on children's functional status, assessed through parent-reports of cognitive and language skills. Parents also reported on their satisfaction with surgery, their child's quality of life, and various demographic, clinical, and surgery characteristics. RESULTS: Parents of 45 children (40% female) participated. Children were aged 2.6 (SD 6.5) months at seizure onset, 10.8 (SD 12.7) months at hemispherectomy, and 8.7 (SD 4.8) years at follow-up, at which point 68% were seizure-free. We found that at follow-up, 43% had average or mildly impaired cognition, 26% could speak age appropriately, and 21% had satisfactory reading skills. A total of 55%, 43%, and 17% of children first babbled, spoke their first words, and started speaking in sentences at an age-appropriate period, respectively. Children who had undergone a right hemisphere resection and those who were older at epilepsy onset were more likely to have better cognitive and language outcomes. SIGNIFICANCE: Children with HME have delayed language milestones and continue to require significant language and literacy support long-term after cerebral hemispherectomy.

Endoscopic Hemispherotomy for Nonatrophic Rasmussen's Encephalopathy.

BACKGROUND: Hemispheric disconnection represents a challenging and major epilepsy surgical procedure. This procedure in experienced hands offers excellent results in terms of seizure outcomes, especially for hemispheric pathologies such as Rasmussen's encephalitis, hemispheric dysplasias, hemimegalencephaly. The technique of hemispherotomy has witnessed various modifications over the years, beginning from anatomical hemispherectomy to the current era of minimally invasive functional hemispheric disconnections. OBJECTIVE: This study aimed to describe the technique of performing endoscopic vertical hemispherotomy using interhemispheric corridor developed by the senior author. MATERIALS AND METHODS: A 12-year-old girl with seizure onset at the age of 10 years presented with an aura of fear and nausea followed by tonic deviation of eyes to the right and blinking with speech arrest. There were tonic-clonic movements of the right-sided limbs along with ictal spitting and occasional deviation of the angle of mouth to the right. The patient had loss of awareness for the event along with postictal confusion lasting few minutes. RESULTS: Video electroencephalography (VEEG) revealed left parietocentral and left temporal localization. Serial magnetic resonance imaging (MRI) brain over 3 years revealed progressive left hemispheric changes suggestive of Rasmussen's encephalitis. The patient underwent left-sided endoscopic hemispherotomy. At 2 years follow-up, the patient is seizure-free (ILAE [International League Against Epilepsy] Class 1). CONCLUSION: Endoscopic hemispherotomy using the interhemispheric approach is an elegant, minimally invasive, reproducible, safe, and efficacious technique.

Postoperative seizure and developmental outcomes of children with hemimegalencephaly and drug-resistant epilepsy.

OBJECTIVE: To evaluate seizure and developmental outcomes in the short and long term in children with hemimegalencephaly (HMEG) after surgery. METHODS: This is a cohort study of 36 children who underwent surgery for HMEG were followed up for at least 1 year postoperatively. The Griffiths Mental Development Scales, Ages and Stages Questionnaire version 3, and Peabody Developmental Motor Scales were used to assess development. RESULTS: The median postoperative follow-up duration was 2.7 (1.0-5.0) years, and median age at surgery was 1.9 years (5.8 months-5.9 years). At the last follow-up, 83% of children were seizure-free. the predicted probability of being seizure-free three years after surgery was 79%. The proportion of patients who were moderate to severe delay declined from 97% preoperatively to 76% at least 1 year after surgery. Catch-up, stabilization, and regression of developmental quotient (DQ) was observed in 41%, 35%, and 24% of children 3 months after surgery, respectively. The corresponding proportions during long-term follow-up were 40%, 33%, and 27%, respectively. Change of DQ shortly after surgery was negatively correlated with age at seizure onset and age at surgery. The long-term DQ was positively correlated with the preoperative DQ. Long-term change of DQ was positively correlated with change of DQ shortly after surgery. CONCLUSIONS: Most of patients with HMEG could achieve seizure free after surgery. After surgery, the proportion of catch-up, stabilization, and regression in both short- and long-term DQ was approximately 40%, 35%, and 25%, respectively. The change of DQ shortly after surgery may be a predictor for long-term developmental change.

PTEN somatic mutations contribute to spectrum of cerebral overgrowth.

Phosphatase and tensin homologue (PTEN) regulates cell growth and survival through inhibition of the mammalian target of rapamycin (MTOR) signalling pathway. Germline genetic variation of PTEN is associated with autism, macrocephaly and PTEN hamartoma tumour syndromes. The effect of developmental PTEN somatic mutations on nervous system phenotypes is not well understood, although brain somatic mosaicism of MTOR pathway genes is an emerging cause of cortical dysplasia and epilepsy in the paediatric population. Here we report two somatic variants of PTEN affecting a single patient presenting with intractable epilepsy and hemimegalencephaly that varied in clinical severity throughout the left cerebral hemisphere. High-throughput sequencing analysis of affected brain tissue identified two somatic variants in PTEN. The first variant was present in multiple cell lineages throughout the entire hemisphere and associated with mild cerebral overgrowth. The second variant was restricted to posterior brain regions and affected the opposite PTEN allele, resulting in a segmental region of more severe malformation, and the only neurons in which it was found by single-nuclei RNA-sequencing had a unique disease-related expression profile. This study reveals brain mosaicism of PTEN as a disease mechanism of hemimegalencephaly and furthermore demonstrates the varying effects of single- or bi-allelic disruption of PTEN on cortical phenotypes.

Hemimegalencephaly and intractable seizures associated with the NPRL3 gene variant in a newborn: A case report.

Hemimegalencephaly (HME) is a rare hamartomatous congenital malformation of the brain characterized by dysplastic overgrowth of either one of the cerebral hemispheres. HME is associated with early onset seizures, abnormal neurological findings, and with subsequent cognitive and behavioral disabilities. Seizures associated with HME are often refractory to antiepileptic medications. Hemispherectomy is usually necessary to provide effective seizure control. The exact etiology of HME is not fully understood, but involves a disturbance in early brain development and likely involves genes responsible for patterning and symmetry of the brain. We present a female newborn who had refractory seizures due to HME. Whole genome sequencing revealed a novel, likely pathogenic, maternally inherited, 3Kb deletion encompassing exon 5 of the NPRL3 gene (chr16:161898-164745x1). The NPRL3 gene encodes for a nitrogen permease regulator 3-like protein, a subunit of the GATOR complex, which regulates the mTOR signaling pathway. A trial of mTOR inhibitor drug, Sirolimus, did not improve her seizure control. Functional hemispherectomy at 3 months of age resulted in total abatement of clinical seizures.

Neuroimaging and genetic characteristics of malformation of cortical development due to mTOR pathway dysregulation: clues for the epileptogenic lesions and indications for epilepsy surgery.

Introduction: Malformation of cortical development (MCD) is strongly associated with drug-resistant epilepsies for which surgery to remove epileptogenic lesions is common. Two notable technological advances in this field are identification of the underlying genetic cause and techniques in neuroimaging. These now question how presurgical evaluation ought to be approached for 'mTORpathies.'Area covered: From review of published primary and secondary articles, the authors summarize evidence to consider focal cortical dysplasia (FCD), tuber sclerosis complex (TSC), and hemimegalencephaly (HME) collectively as MCD mTORpathies. The authors also consider the unique features of these related conditions with particular focus on the practicalities of using neuroimaging techniques currently available to define surgical targets and predict post-surgical outcome. Ultimately, the authors consider the surgical dilemmas faced for each condition.Expert opinion: Considering FCD, TSC, and HME collectively as mTORpathies has some merit; however, a unified approach to presurgical evaluation would seem unachievable. Nevertheless, the authors believe combining genetic-centered classification and morphologic findings using advanced imaging techniques will eventually form the basis of a paradigm when considering candidacy for early surgery.

Hemimegalencephaly and tuberous sclerosis complex: A rare yet challenging association.

Hemimegalencephaly is a rare malformation of cortical development characterised by enlargement of one cerebral hemisphere. The association between hemimegalencephaly and tuberous sclerosis complex, an autosomal dominant genetic disorder, is uncommon and has so far been reported only in a few cases. Intractable epilepsy and severe developmental delay are typical clinical manifestations. Aberrant activation of the mTOR signalling pathway is considered to be the hallmark of the pathogenesis of these two disorders. Thus, mTOR inhibitors such as everolimus represent a promising therapeutic approach to mTOR-associated manifestations. We present a thorough literature review of the association between hemimegaloencephaly and tuberous sclerosis complex.