Links between cancerous and noncancerous brain tumors and epilepsy have long been recognized. However, recent clinical and preclinical studies emphasize that not only do tumors impinge on surrounding brain tissue in ways that promote hyperexcitability and epileptogenesis, but that neural activity also influences tumor progression. In this review, inspired by the Merritt-Putnam Symposium of the 2025 meeting of the American Epilepsy Society, we present a cross-disciplinary dialog between cancer and epilepsy research, including discussion of tumors and epilepsies that are more prominent in pediatric versus adult populations. First, we discuss the neuropathology, genetics, and surgical outcomes of epileptogenic brain tumors, and associated mechanisms of epileptogenesis. Second, we evaluate tuberous sclerosis complex as a model disease for clinical and mechanistic investigation of tumor-epilepsy relationships. Third, we review recent evidence for somatic gene mutations as underlying factors in hypothalamic hamartomas. Lastly, we present evidence for bidirectional relationships between gliomas and neuronal activity.

Abstract Tuberous sclerosis complex, GATORopathies, and hypothalamic hamartomas represent some of the most important genetically determined brain lesions associated with early-onset epilepsy. Although they differ markedly in their histological appearance, all three conditions share converging disturbances in intracellular signaling pathways that regulate cell growth, differentiation, and tissue architecture. In particular, the mechanistic target of rapamycin (mTOR) and the Sonic Hedgehog (Shh) pathway emerge as central nodes of dysregulation. Evidence from developmental biology and tumor research further suggests cross-talk between these signaling systems, raising the possibility that similar mechanisms contribute to epileptogenesis in these otherwise distinct disorders. This review summarizes histopathological features, genetic underpinnings, and signaling interactions, with a focus on their clinical implications. We highlight how the two-hit model of genetic disease and the interplay of mTOR and Shh signaling provide unifying frameworks for understanding lesion formation and epilepsy, and how this knowledge may translate into therapeutic strategies.

Appetite and body weight changes after MR-guided laser interstitial thermal therapy of hypothalamic hamartomas in children with drug-resistant epilepsy.

Surgical Approaches to the Hypothalamus: A Systematic Review of Anatomical Corridors and Postoperative Outcomes.

There is discussion about the role of hypothalamic hamartoma (HH) in the epileptogenicity.

Dacrystic seizure is a rare phenomenon of crying during an epileptic episode. It has an established connection to hypothalamic hamartoma, but was also reported to be associated with frontal and temporal epileptic foci. We present two cases of dacrystic epilepsy. Patient 1 had suffered from magnetic resonance imaging-negative epilepsy that was characterized by both gelastic and dacrystic seizures; stereo-encephalography showed onset in the anterior cingulate/Brodmann area 8 with rapid prefrontal and orbitofrontal propagation, leading to crying onset. Patient 2 had dacrystic seizures arising from a temporal lobe lesion with spreading to the orbitofrontal cortex. Both patients became seizure-free following resection targeting these networks. These cases represent intracranial correlates of dacrystic seizures occurring outside the context of hypothalamic hamartoma and suggest a central contribution of the anterior cingulate and/or orbitofrontal cortices in their generation.

Objective: Patient self-report is known to be an inaccurate reflection of true seizure frequency in persons with epilepsy. The current study aimed to assess the safety and performance of the Minder system, a bilateral subscalp electroencephalographic (EEG) acquisition system for continuous long-term EEG recording. Methods: This prospective, multicenter first-in-human study enrolled adult patients with focal or generalized epilepsy and at least 2 seizures per month. The primary outcome was adverse events (AEs) in the first 6 months of implantation. Secondary analyses determined whether normal neurophysiological signals, interictal discharges, and seizures seen on scalp video EEG monitoring were identifiable on subscalp recordings, and signals were rated for clarity on subscalp and 2-channel scalp EEG recordings (1 = not recognizable, 5 = clear). Subscalp data were reviewed in relation to events reported in 6-month seizure diaries. Results: Twenty-six subjects were implanted between November 2019 and July 2023. No serious device- or implant procedure-related AEs were reported. The most common device-related AEs were mild or moderate postsurgical pain, headache, or scalp pain/paresthesia (9/26, 35%). All sleep spindles, chewing artifacts, interictal discharges, and electrographic seizures observed on scalp recordings (25 seizures from 8 patients) were identified on subscalp recordings and given higher clarity ratings compared to 2-channel scalp recordings (median seizure clarity rating was 3 for both scalp and subscalp EEG, range = 1-5, P = .0025). Subscalp recordings captured seizures from diverse seizure focus locations, including frontal and mesial temporal seizure foci and hypothalamic hamartoma. Bilateral recording revealed clinically relevant findings not possible with unilateral recordings (6/26 patients, 23%). Findings of potential clinical utility were identified on manual review of 6-month recordings in most patients (23/26, 88%). Significance: This study demonstrates the safety and performance of the Minder bilateral subscalp EEG acquisition system for long-term seizure monitoring in patients with epilepsy. Bilateral hemisphere coverage captured seizures in a diverse patient group and permitted lateralization of events.

Intraventricular Endoscopic Surgery for Pediatric Hypothalamic Hamartomas: Surgical Series and Literature Meta-Analysis.

Challenges in hypothalamic hamartoma: focus on practical management

Central precocious puberty due to hypothalamic hamartoma in a 10-month-old infant girl

Hypothalamic hamartomas (HHs) are rare developmental lesions frequently associated with drug-resistant epilepsy. Multiple surgical techniques have been described, but the optimal strategy remains controversial. Endoscopic approaches have emerged as minimally invasive options, yet technical limitations persist, particularly in larger or firm lesions. This article aims to describe the technical nuances, safety, and clinical outcomes of endoscopic resection of pediatric HHs assisted by a neuroendoscopic ultrasonic aspirator (NUA). We retrospectively reviewed 21 pediatric patients who underwent purely endoscopic HH resection with NUA assistance between 2009 and 2025. Demographic, clinical, and radiological data were collected. Seizure outcomes were evaluated using the Engel classification at 12months, and resection extent was assessed with postoperative MRI. Fourteen patients (66.6%) were male, with a mean age at surgery of 6.1years (range, 0.4-17.5). According to the Delalande classification, lesions included 4 type I, 9 type II, 5 type III, and 3 type IV. The mean preoperative volume was 1.9cc. Gross-total resection was achieved in 19 patients (90%). At 12months, 14 of 18 evaluable patients (77.7%) achieved Engel class I seizure freedom, while 4 (22.2%) had Engel class IIB outcomes (> 90% reduction). There was no operative mortality. Complications included transient hyponatremia in 28% and obesity in 10%, all managed conservatively. Endoscopic resection of HHs using an ultrasonic aspirator is a safe and effective technique, providing high rates of seizure freedom with low morbidity. This approach expands the indications of purely endoscopic surgery for HHs, particularly in settings where laser ablation is not available.

Abstract Background Neurosurgeons are often faced with cases of intrinsic (intra-axial) neoplasms whether primary or secondary with nothing left to do for them after offering surgery and adjuvant therapy. Unfortunately, many of such cases carry a poor prognosis with estimate survival rate less than 2 years, even for those who were amenable for surgical resection prior to adjuvant chemotherapy and radiotherapy. Recurrent neoplasms even have a poorer prognosis, for example, the estimated overall survival for recurrent anaplastic astrocytoma is 39 weeks and for GBM is 30 weeks Objective To evaluate the efficacy and safety of treatment of surgically unresectable intra-axial brain neoplasms by Radiofrequency ablation or Laser Interstitial Thermal Therapy (LITT). Patients and Methods This single institution prospective pilot study involving adult participants that are assigned for stereotactic biopsy who received treatment by interstitial hyperthermia delivered by Radiofrequency (RF) simultaneously in the same setting as the brain biopsy. Study setting: This study was conducted in Ain Shams University Hospitals. Study population: Patients with intra-axial brain neoplasms that are undergoing stereotactic biopsy i.e., small, multiple, deep seated (non-accessible), near or on eloquent cortex, or recurrent cases that have exhausted response to other treatment modalities. Patients will be a minimum age of 5 years that can have a stereotaxy frame mounted. Results There is a potential trend that can be noticed in increasing indications of Laser in Neurosurgery and undoubtedly its use for treatment in brain tumors will expand as more and more institutions utilize it for cases that previously were managed with futile surgeries. One such example is the paradigm shift in the treatment of hypothalamic hamartomas that were previously offered craniotomy and is now Laser treatment is paving its way to becoming a first-line treatment over any craniotomy procedure with comparable if not more superior outcome. Conclusion This is the first prospective pilot case series from our region suggesting a potential safe role of ablation in deep-seated non-surgical lesions that were indicated for biopsy. We demonstrated in this study that although tumor regression in size may not be achieved, RF ablation can be used safely with minimal added cost and time safely during stereotactic brain biopsy. Tumor size is inversely proportion to progression-free interval after RF ablation, multi-target RF ablation can be considered for further tumor control. Ablation may pose a survival benefit over non- operative management of gliomas and metastasis that are not amenable for surgery however larger samples and longer follow-up studies are needed in the future. Even though RF ablation lacks real- time technology and may provide suboptimal delivery of heat to brain neoplasms, it can be used as a safe alternative modality to LITT in resource-limited settings.

IntroductionEpilepsy due to hypothalamic hamartoma (HH) is associated with epileptic encephalopathy and often requires surgical intervention, as medications are ineffective at reducing the seizures. However, the first step of disentangling the impact of the surgery on the broader whole-brain networks, a biomarker of encephalopathy compared to controls, is not quantified. Subtle pre- and post-operative networks can elude conventional rs-fMRI analysis.MethodsWe retrospectively analyzed rs-fMRI from 56 HH patients scanned before and 6 months after surgery. We developed a two-stage contrastive learning-based algorithm to classify the motor, vision, language, frontal, and temporal networks as pre- vs post-operative. In stage one, a multimodal contrastive encoder jointly ingests 3D spatial Independent Component Analysis (ICA) maps and their corresponding 1D temporal ICA time series to learn embeddings that distinguish pre-operative from post-operative states for each network while separating embeddings of different networks. In stage two, a lightweight classifier refines these embeddings, augmented by original ICA inputs, to classify each network as pre-operative or post-operative.ResultsVisualization of the learned feature space with t-SNE revealed clear separation by pre- vs post-surgical condition across all five networks. Across networks, mean accuracy ranged from 0.85 to 0.90, sensitivity from 0.79 to 0.90, specificity from 0.87 to 0.93, F1‐score from 0.83 to 0.90 and AUC from 0.90 to 0.94 in stratified cross validation.ConclusionsContrastive learning can sensitively detect functional shifts in critical cortical networks that previous traditional analyses may overlook. These findings inform broader shifts in whole-brain network functioning following effective HH surgery and establish a featurewise distinction between preoperative and postoperative states, motivating future studies that compare HH patients to healthy controls to quantify network recovery.

Central precocious puberty (CPP) is defined as the early onset of secondary sexual characteristics due to premature activation of the hypothalamic pituitary gonadal (HPG) axis. Hypothalamic hamartomas are rare but classical causes of CPP. We report a case of a 2 years 7 months old girl with progressive breast enlargement and pubic hair development, found to have a hypothalamic hamartoma on MRI.

Disclosure: Z.A. Erbowor-Becksen: None. D. Mak: None. V.C. Benavides: None.Background: Central precocious puberty (CPP) is a common clinical scenario treated amongst pediatric endocrinologists. CPP typically responds well to gonadotropin-releasing hormone agonists (GnRHa), with resistance rarely reported. The paucity of GnRHa-resistant cases presents a therapeutic challenge, as alternative treatment protocols remain poorly defined.Clinical Cases: We conducted a two-center case series following male patients with GnRHa-resistant CPP associated with hypothalamic hamartoma. Patient follow-up ranged from 2 to 10 years. Treatment efficacy was evaluated through serial bone age/chronological age (BA/CA) ratios, anthropometric measurements, and hormonal parameters. The initial presentation occurred at ages 1 and 3 years. Both children had evidence of bilateral testicular enlargement, with baseline testosterone levels averaging 501 ng/dL (<7-20 ng/dL) and markedly advanced BA/CA ratios (2.25 and 2.0). Work-up for other causes of pubertal onset was unremarkable. In both cases, therapy included one GnRHa and an aromatase inhibitor; one case included an antiandrogen agent (bicalutamide) as a third agent. Overall, treatments were well tolerated, with no reports of hepatotoxicity. Testosterone was not entirely suppressed, with a mean post-treatment testosterone level of 61 ng/dL at the last follow-up. The patient receiving triple therapy demonstrated progressive improvement in BA/CA ratio (2.25 to 1.07), height velocity (12.7 to 4.8 cm/year), and height SDS (2.05 to 0.94) over 10 years. The patient receiving dual therapy showed testosterone suppression (457 to 85.6 ng/dL) but maintained accelerated growth (height velocity 16.9 cm/year) and advancing BA/CA ratio, suggesting incomplete pubertal suppression.Conclusion: In males with hypothalamic hamartoma-associated GnRHa-resistant CPP, triple therapy combining GnRHa, aromatase inhibitors, and antiandrogens demonstrated superior efficacy over dual treatment. It achieved near-normalization of growth parameters, bone maturation, and endocrine profiles without compromising safety. Treatment was well-tolerated during long-term follow-up. These findings suggest a potential therapeutic strategy for GnRHa-resistant CPP, though more extensive studies are needed to confirm optimal treatment protocols.Presentation: Sunday, July 13, 2025

Hypothalamic hamartomas (HHs) lead to refractory epilepsy, and minimally invasive surgical approaches are standard of care for affected patients. Stereotactic radiofrequency thermocoagulation (SRT) is one of the treatment methods recognized to achieve seizure freedom. This study reports surgical outcome from a single center reporting an ablation technique using fewer trajectories than previously reported and assesses the effect of coagulated volume on long-term seizure freedom. Retrospective analysis was made of all patients who underwent SRT at the University of Freiburg between 2016 and 2024 with a follow-up of ≥12 months. Statistical analysis was made of outcome dependent on type of hamartoma, seizure type, coagulation volume (based on magnetic resonance imaging evaluation), and epilepsy duration. Forty-three patients received SRT; 35 (22 children) had >12 months of follow-up, with a median of 38 months. Nine patients had two SRTs, and two patients had three SRTs. Twelve months after their last SRT, 60% of patients were seizure-free, 88.6% were free of bilateral tonic-clonic seizures, and 77.1% were free of gelastic seizures (last follow-up: 54.3% seizure-free, 88.6% free of bilateral tonic-clonic seizures, 74.3% free of gelastic seizures). There was a significant reduction of antiseizure medication (ASM) postsurgically, with an average number of ASMs of two prior to surgery and one after surgery. After 12 months, 14.3% of patients experienced ongoing but mostly mild surgical complications, with hypothalamic dysfunction being the most common. Coagulation volumes were higher in larger HHs, but no correlation was observed between coagulated volume and seizure freedom or complication rates. SRT is a minimally invasive method to successfully treat refractory seizures in patients with HH. Disconnection seems to be more important for successful treatment than volume reduction. Even large HHs can be successfully treated with small coagulation volumes.

ABSTRACTBackgroundPallister‐Hall syndrome (PHS) is an extremely rare genetic disorder. It presents as a polymalformative syndrome affecting craniofacial structures, the central nervous system, limbs, various internal organs, and the endocrine system. It is considered a ciliopathy, as it is associated with loss‐of‐function variants in the GLI3 gene, a transcription factor essential for primary cilium signaling. The syndrome shows marked clinical heterogeneity depending on the type of genetic variant, which makes diagnosis challenging. It is usually suspected at an early age when a hypothalamic hamartoma is associated with polydactyly. Endocrine manifestations are often linked to the hamartoma, further complicating diagnosis.Case PresentationA 23‐year‐old Colombian patient presented with a history of hypothalamic hamartoma, gelastic seizures, postaxial polydactyly of hands and feet, and craniofacial dysmorphisms. Physical examination revealed dolichocephaly, bilateral epicanthus, broad nasal bridge, short and broad neck, mild cervical kyphosis, mild scoliosis, micrognathia, bilateral ulnar deviation of the fourth and fifth fingers, and overlapping toes on both feet. No genital anomalies were found. Neuropsychological evaluation reported a borderline intellectual quotient of 78. Whole‐exome sequencing identified a de novo heterozygous pathogenic variant in GLI3 (c.2151del; p.(Gln71HisfsTer16)), confirmed by Sanger sequencing.ConclusionsWe report the first case described in Colombia of a previously unreported truncating genetic variant. We performed a clinical–molecular correlation in a 23‐year‐old adult whose diagnosis of PHS was delayed until adulthood, years after the initial identification of a hypothalamic hamartoma, refractory gelastic seizures, polydactyly, and mild cognitive impairment. This case broadens the clinical spectrum regarding the viability of patients with PHS into adulthood, showing that it is not restricted to the severe neonatal or infantile presentations classically described.

New insights to hypothalamic hamartoma syndrome.

Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to open resection for pediatric drug-resistant epilepsy (DRE). This systematic review and individual participant data meta-analysis aimed to identify independent predictors of seizure outcomes and operative and neurological complications following MRgLITT. Uni- and multivariable mixed-effects Cox proportional-hazards regressions models were used to identify independent predictors of time to seizure recurrence following MRgLITT. Among patients with at least 12 months of follow-up, uni- and multivariable mixed-effects logistic regression analyses were conducted to ascertain the independent risk factors associated with seizure recurrence at last follow-up, operative complications, and postoperative neurological complications. A literature review identified 354 pediatric patients with a mean epilepsy duration of 7.5 (SD 5.3) years prior to MRgLITT. The mean age at seizure onset was 4.52 (SD 4.69) years, and focal seizures were more common (85.5%) than generalized seizures (14.5%). Lesions were detected on MRI in 82.1% of cases. The most common epilepsy etiologies were hypothalamic hamartoma (HH; 23.7%) and malformations of cortical development (23.7%). The mean follow-up duration after MRgLITT was 16.02 (SD 11.63) months. Engel class I outcomes were achieved in 57% of patients. In 205 cases where information was available regarding postoperative neurological complications, 35 patients (17.1%) experienced postoperative neurological complications, with hemiparesis as the most frequent complication (n = 16 patients). Of the 354 total patients who underwent MRgLITT, 8.2% underwent revision epilepsy surgery. No operative or clinical characteristics were associated with seizure recurrence. Seizure freedom probability was significantly higher among patients with HH compared to those with nonlesional MRI (p = 0.012). Patients with mesial temporal sclerosis experienced earlier seizure recurrence (p = 0.023), and an extratemporal surgical location was associated with longer seizure freedom probability (p = 0.034). Lesional MRI was associated with reduced odds of postoperative neurological complications (p = 0.031). MRgLITT may be a safe and effective alternative option for pediatric DRE. Further prospective studies are warranted to elucidate MRgLITT strategies in pediatric DRE.

Hypothalamic hamartoma (HH) is a rare congenital malformation that can significantly disrupt patient quality of life and typically presents with either central precocious puberty or gelastic seizures. We seek to add to the current literature through a retrospective review of all cases of HH seen at our paediatric tertiary centre over the previous two decades. We also sought to test the novel hypothesis that lesions located closer to or contacting the infundibulum were more likely to present with central precocious puberty (CPP). Retrospective review of the public PACS system was performed, yielding a total of sixteen patients with HH identified on MRI between January 2000 and February 2022. Imaging and patient records were retrospectively evaluated. Six patients presented with central precocious puberty (CPP), six with gelastic or other seizure disorders, and four had alternate presenting issues. Our study demonstrates a statistically significant relationship between pedunculated lesions and CPP and between sessile/intrahypothalamic lesions and gelastic seizure/neuropsychiatric symptoms. We did not demonstrate a relationship between tumour location relative to the infundibulum or mammillary bodies and clinical manifestations. Hypothalamic hamartomas are rare congenital malformations which typically present with one of two classical phenotypes: CPP or gelastic seizure. The study demonstrates a statistically significant relationship between pedunculated lesions and CPP and between lesions with third ventricular involvement and gelastic seizure/neuropsychiatric symptoms. We did not demonstrate a clear relationship between specific tumour location within the hypothalamus and phenotype; larger cohort studies are recommended to further investigate this hypothesis.