Hypothalamic Hamartoma Research Articles

Introduction to the epilepsy syndrome papers.

The epilepsies comprise a broad group of disorders/diseases with diverse etiologies, diverse electroclinical presentations, and marked variability in clinical outcomes. The 2017 International League Against Epilepsy (ILAE) Classification of the Epilepsies defined three diagnostic levels including (1) seizure type, (2) epilepsy type, and (3) epilepsy syndrome, emphasizing that etiology and comorbidities must be considered at each level.1 Although epilepsy syndromes had been recognized as distinct electroclinical entities long before the first ILAE Classification of Epilepsies and Epilepsy Syndromes was proposed in 1985, and have been summarized in the Guide Bleu and Epileptic Syndromes in Infancy, Childhood, and Adolescence,2 there was no formally accepted ILAE classification of epilepsy syndromes. This series of ILAE position papers represents the work of the Nosology and Definitions Task Force, established by the ILAE in 2017 to provide definitions of epilepsy syndromes. We defined an epilepsy syndrome as “a characteristic cluster of clinical and EEG features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious).” The diagnosis of a syndrome in an individual with epilepsy frequently carries prognostic and treatment implications. Syndromes often have age-dependent presentations, meaning that they typically start at specific ages, and in some cases may also remit at certain ages. Many syndromes are strongly correlated with a range of specific intellectual, psychiatric, and other comorbidities, whereas in other syndromes, the absence of such comorbidities is a characteristic feature (Figure 1). Epilepsy syndromes have traditionally been grouped according to age at onset. Accordingly, the ILAE position papers describe separately syndromes with onset in neonates and infants (up to age 2 years), syndromes with onset in childhood, and syndromes that may begin at variable ages (meaning in both pediatric and adult patients). Additionally, a separate position paper on the idiopathic generalized epilepsies is included. The syndromes are further subdivided into generalized, focal, or generalized and focal, based on seizure type(s), with a separate category for syndromes with developmental and epileptic encephalopathy (DEE) or progressive neurological deterioration. The 2017 Classification of the Epilepsies proposed the term DEE to denote an epilepsy associated with developmental impairment that may be due to both the underlying etiology (developmental encephalopathy) and superimposed epileptic activity (epileptic encephalopathy).1 Most DEEs present very early in life; the term DEE is more challenging to apply when epilepsy begins later, following a prolonged period of normal development. Thus, the ILAE Nosology and Definitions Task Force identified syndromes with DEE and syndromes with progressive neurological deterioration. This approach clearly identifies the group of syndromes associated with cognitive impairment with or without other manifestations of neurological deterioration and recognizes that this impairment may be due to the underlying etiology, superimposed epileptic activity, or both. Furthermore, the ILAE Nosology and Definitions Task Force identified the concept of etiology-specific syndrome, to denote clearly defined entities with a distinct phenotype associated with a specific etiology, examples of which include certain monogenic epilepsies, such as CDKL5-DEE and PCDH19 clustering epilepsy, and structural entities such as mesial temporal lobe epilepsy with hippocampal sclerosis and gelastic seizures with hypothalamic hamartoma. In the current classification, a number of epilepsies with specific etiologies as well as some epilepsies that arise from or involve specific brain regions or networks have not been included as syndromes, although these often also have a characteristic cluster of clinical and electroencephalographic (EEG) features. Further work is needed to extend the range of epilepsies included in the ILAE syndrome classification and to determine whether some of those conditions meet criteria for classification as epilepsy syndromes. None. E.W. has served as a paid consultant for Encoded Therapeutics and Biomarin. She is the Editor-in-Chief of Epilepsy.com. P.T. has received speaker's or consultancy fees from Arvelle, Eisai, GW Pharma, LivaNova, UCB Pharma, Xenon Pharma, and Zogenix. E.P. has received speaker and/or consultancy fees from Angelini, Arvelle, Biogen, Biopas, Eisai, GW Pharma, Sanofi group of companies, SK Life Science, Takeda, UCB Pharma, Xenon Pharma, and Zogenix and royalties from Wiley, Elsevier, and Wolters Kluwer. S.L.M. is the Charles Frost Chair in Neurosurgery and Neurology and acknowledges grant support from the NIH (U54 NS100064, NS43209), the US Department of Defense (W81XWH-18–1–0612), the Heffer Family and Segal Family Foundations, and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/Dan Levitz families. S.L.M. is serving as Associate Editor of Neurobiology of Disease. He is on the editorial board of Brain and Development, Pediatric Neurology, Annals of Neurology, MedLink, and Physiological Research. He receives compensation from Elsevier for his work as Associate Editor of Neurobiology of Disease and from MedLink for his work as Associate Editor and royalties from two books he coedited. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

A Special Approach for Stereotactic Radiofrequency Thermocoagulation of Hypothalamic Hamartomas With Bilateral Attachments to the Hypothalamus: The Transthird Ventricular Approach to the Contralateral Attachment.

Disconnection surgery for the treatment of epileptic hypothalamic hamartomas (HHs) is strategically difficult in cases with complex-shaped HHs, especially with bilateral hypothalamic attachments, despite its effectiveness. To evaluate the feasibility of a new approach for stereotactic radiofrequency thermocoagulation (SRT) using penetration of the third ventricle (SRT-TT) aiming to disconnect bilateral hypothalamic attachments in a single-staged, unilateral procedure. Ninety patients (median age at surgery, 5.0 years) who had HHs with bilateral hypothalamic attachments and were followed for at least 1 year after their last SRT were retrospectively reviewed. Thirty-three patients underwent SRT-TT as initial surgery. Of the 58 patients after mid-2013 when SRT-TT was introduced, 33 underwent SRT-TT and 12 (20.7%) required reoperation (ReSRT), whereas 20 of 57 patients (35.1%) without SRT-TT underwent reoperation. Reoperation was required in significantly fewer patients after mid-2013 (n = 12 of 58, 20.7%) than before mid-2013 (n = 15 of 32, 46.9%) ( P = .01). Final seizure freedoms were not different between before and after mid-2013 (gelastic seizure freedom, n = 30 [93.8%] vs n = 49 [84.5%] and other types of seizure freedom, n = 21 of 31 [67.7%] vs n = 32 of 38 [84.2%]). Persistent complications were less in SRT-TT than in ReSRT using the bilateral approach, but not significantly. However, hormonal replacement was required significantly more often in ReSRT using the bilateral approach (4 of 9, 44.4%) than in SRT-TT (3 of 32, 9.4%) ( P = .01). SRT-TT enabled disconnection of bilateral attachments of HHs in a single-staged procedure, which reduced the additional invasiveness of reoperation. Moreover, SRT-TT reduced damage to the contralateral hypothalamus, with fewer endocrinological complications than the bilateral approach.

Comparison of Surgical Outcomes in Individuals With Hypothalamic Hamartoma Alone or With Other Potentially Epileptogenic Focal Lesions

BackgroundHypothalamic hamartoma is a rare condition associated with refractory seizures. It can occur in isolation or with additional epileptogenic lesions. The aim of this study was to investigate the effects of additional potentially epileptogenic lesions on surgical outcomes in individuals with hypothalamic hamartoma. MethodsWe conducted a chart review of 112 patients with hypothalamic hamartoma who underwent magnetic resonance imaging (MRI)–guided laser interstitial thermal therapy targeted to the hypothalamic hamartoma. We compared surgical outcomes after at least six months of postoperative follow-up (N = 65) between patients with hypothalamic hamartoma alone and those with hypothalamic hamartoma plus additional potentially epileptogenic lesions. ResultsSixteen out of 112 (14%) patients had additional epileptogenic lesions, including focal cortical dysplasia, gray matter heterotopia, and polymicrogyria. Ten out of 16 patients with additional lesions and 55 out of 96 patients with hypothalamic hamartoma alone had more than six months of follow-up and are included in the outcome analysis. Mean follow-up in these patients is 21.5 ± 17.3 months (standard deviation, range: 7.3-76.8 months) for patients with hypothalamic hamartoma alone and 16.1 ± 15.0 months (standard deviation, range: 6.6-58.2 months) for those with hypothalamic hamartoma plus additional epileptogenic lesions. Fewer patients with hypothalamic hamartoma plus other lesions had Engel class I/II outcomes than patients with hypothalamic hamartoma alone (5/10 [50%] vs 46/55 [83.6%]; P = 0.031). ConclusionsMRI-guided laser interstitial thermal therapy remains an effective treatment option for patients with hypothalamic hamartoma. However, the outcome of surgical procedures targeted to the hypothalamic hamartoma may be less favorable in patients who have hypothalamic hamartoma coexisting with other potentially epileptogenic focal lesions. Thus, an additional surgical workup is warranted for these patients who have failed surgical treatment of hypothalamic hamartoma.

Expanding the phenotype of males with OFD1 pathogenic variants-a case report and literature review

Pathogenic variants in the OFD1 gene have been classically associated with the Orofaciodigital syndrome type 1 in females, a condition previously considered to be X-linked dominant with male embryonic lethality. However, an increasing number of males with pathogenic OFD1 variants who survived beyond the neonatal period have now been reported in the literature. Although each new report has added to the ever-broadening spectrum of clinical findings seen in males, many questions about genotype-phenotype correlations and disease mechanism remain. Herein, we describe a 9-year-old male child with a novel hemizygous pathogenic OFD1 variant identified by exome sequencing and a unique combination of findings, not previously reported, including presence of both a hypothalamic hamartoma and the molar tooth sign. His clinical features overlap multiple ciliopathy phenotypes, blurring the boundaries of distinct ciliopathy gene-disease relationships. This case provides further evidence for the consideration of a broad OFD1-relateddisorder spectrum in affected males rather than multiple distinct phenotypes. Additionally, a review of previously published cases of the disorder in males support the inclusion of the OFD1 gene in the differential diagnosis and work up for all individuals who present with primary ciliopathy-type features, regardless of their gender. We also highlight current information about OFD1 variant types and pathogenesis and explore how these could mechanistically drive some of the observed phenotypic differences.

Neuroimaging appearance of hypothalamic hamartomas in monozygotic twins with Pallister-Hall syndrome: case report and review of the literature

BackgroundPallister-Hall syndrome (OMIM #146510) is a rare autosomal dominant condition caused by a mutation in the GLI3 gene. The cardinal feature of Pallister-Hall syndrome is the presence of hypothalamic hamartomas, which may manifest with seizures, panhypopituitarism and visual impairment. In Pallister-Hall syndrome, dysplastic histogenetic processes responsible for hypothalamic hamartomas are thought to disrupt early craniofacial development. The clinical presentation of Pallister-Hall syndrome may include: characteristic facies (low-set and posteriorly angulated ears, short nose with flat nasal bridge), cleft palate and uvula, bifid epiglottis and laryngotracheal cleft, limb anomalies (e.g., polysyndactyly, short limbs and nail dysplasia), anal atresia, genitourinary abnormalities and congenital heart defects.Case presentationWe report the case of two monochorionic diamniotic twins diagnosed with Pallister-Hall syndrome during the neonatal period, after the identification of a hypothalamic hamartoma on day 1 by cerebral ultrasound scan, later confirmed by brain magnetic resonance imaging. Cerebral ultrasound and magnetic resonance imaging presentations were identical in both twins.Discussion and conclusionsWe review previously published cases (four reports) of hypothalamic hamartomas identified via cerebral ultrasound and compare reported ultrasonographic features. Main differential diagnoses based on cerebral ultrasound findings are discussed. Full description of typical magnetic resonance imaging appearance is also provided. This is the first case reported in the literature of monochorionic diamniotic twins affected by genetically confirmed Pallister-Hall syndrome with identical hypothalamic hamartomas at cerebral ultrasound and magnetic resonance imaging. Moreover, this paper adds to the existing literature on the sonographic appearance of hypothalamic hamartomas. Considering the consistency in hypothalamic hamartomas’ sonographic appearance, we support the use of cerebral ultrasound as a first-line neuroimaging modality in case of clinical suspicion of Pallister-Hall syndrome.Graphical

Antenatelly detected hypothalamic hamartoma-A case report

Hypothalamic hamartoma (HH) is a non-neoplastic malformationthat appears in the hypothalamus. It is congenital, and it grows as the child’s brain grows, but HH doesn’t spread to other parts of the brain or body. In 95% of cases, it is sporadic in origin. HH present with diverse neurologic, endocrinologic, cognitive, behavioraland psychiatric comorbidities. Irrespective of their large size of this intracranial tumor, some of them may be asymptomatic also. Very rarely they may be detected during routine antenatal checkup.

Abstract 145: Etiological profile of precocious puberty: A JIPMER experience

Background: Precocious puberty (PP) is defined as the appearance of secondary sexual characteristics before 8 years in girls and 9 years in boys. The data on the etiological spectrum of precocious puberty from India is limited. Here, we present the analysis of retrospective data of children who presented with PP to the Department of Endocrinology, JIPMER from 2015 to 2021.Aims and Objectives: To describe the etiological profile of children presenting with PP.Results: A total of 26 children (16 girls) presented during this period with PP. 17 children presented with central PP (CPP). The median age of presentation was 6 years (range 2.5-8 years). The most common etiology for CPP was idiopathic CPP [n=7 (females-6)]) followed by congenital adrenal hyperplasia (CAH) with CPP (n=5) and hypothalamic hamartoma (n=3). One child developed CPP after surgery and radiotherapy for astrocytoma and another child developed CPP after surgery for Leydig cell tumour. 13 children had peripheral PP (PPP). The median age of presentation was 5 years (range 0.8-8 years). 2 cases each were due to adrenal neoplasms and gonadal neoplasms. 2 girls were diagnosed with Mccune Albright syndrome. 6 children (2 girls) had poorly controlled CAH with peripheral PP. 4 of them had progressed to central PP after optimising the GC medication. A girl was diagnosed with Van Wyk-Grumbach syndrome.Conclusion: We present here the retrospective data showing the etiological spectrum of precocious puberty from a tertiary medicare centre. The most common cause of CPP was idiopathic CPP whereas the most common cause of peripheral PP was CAH.

Focused Ultrasound for Pediatric Diseases.

Focused ultrasound (FUS) is a noninvasive therapeutic technology with multiple pediatric clinical applications. The ability of focused ultrasound to target tissues deep in the body without exposing children to the morbidities associated with conventional surgery, interventional procedures, or radiation offers significant advantages. In 2021, there are 10 clinical pediatric focused ultrasound studies evaluating various musculoskeletal, oncologic, neurologic, and vascular diseases of which 8 are actively recruiting and 2 are completed. Pediatric musculoskeletal applications of FUS include treatment of osteoid osteoma and bone metastases using thermal ablation and high-intensity FUS. Pediatric oncologic applications of FUS include treatment of soft tissue tumors including desmoid tumors, malignant sarcomas, and neuroblastoma with high-intensity FUS ablation alone, or in combination with targeted chemotherapy delivery. Pediatric neurologic applications include treatment of benign tumors such as hypothalamic hamartomas with thermal ablation and malignant diffuse intrinsic pontine glioma with low-intensity FUS for blood brain barrier opening and targeted drug delivery. Additionally, low-intensity FUS can be used to treat seizures. Pediatric vascular applications of FUS include treatment of arteriovenous malformations and twin-twin transfusion syndrome using ablation and vascular occlusion. FUS treatment appears safe and efficacious in pediatric populations across many subspecialties. Although there are 7 Food and Drug Administration-approved indications for adult applications of FUS, the first Food and Drug Administration approval for pediatric patients with osteoid osteoma was obtained in 2020. This review summarizes the preclinical and clinical research on focused ultrasound of potential benefit to pediatric populations.

Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions.

Hypothalamic hamartoma with gelastic seizures is a well-established cause of drug-resistant epilepsy in early life. The development of novel surgical techniques has permitted the genomic interrogation of hypothalamic hamartoma tissue. This has revealed causative mosaic variants within GLI3, OFD1 and other key regulators of the sonic-hedgehog pathway in a minority of cases. Sonic-hedgehog signalling proteins localize to the cellular organelle primary cilia. We therefore explored the hypothesis that cilia gene variants may underlie hitherto unsolved cases of sporadic hypothalamic hamartoma. We performed high-depth exome sequencing and chromosomal microarray on surgically resected hypothalamic hamartoma tissue and paired leukocyte-derived DNA from 27 patients. We searched for both germline and somatic variants under both dominant and bi-allelic genetic models. In hamartoma-derived DNA of seven patients we identified bi-allelic (one germline, one somatic) variants within one of four cilia genes-DYNC2I1, DYNC2H1, IFT140 or SMO. In eight patients, we identified single somatic variants in the previously established hypothalamic hamartoma disease genes GLI3 or OFD1. Overall, we established a plausible molecular cause for 15/27 (56%) patients. Here, we expand the genetic architecture beyond single variants within dominant disease genes that cause sporadic hypothalamic hamartoma to bi-allelic (one germline/one somatic) variants, implicate three novel cilia genes and reconceptualize the disorder as a ciliopathy.

Giant cystic hypothalamic hamartoma in an infant associated with persistent syndrome of inappropriate antidiuretic hormone secretion

A giant hypothalamic hamartoma (GHH) is a rare congenital malformation only reported in a few cases in the literature and is often associated with precocious puberty, gelastic seizures, or less commonly, Pallister-Hall syndrome. Persistent syndrome of inappropriate antidiuretic hormone secretion (SIADH) is very rare in infancy, and most patients with GHH do not develop persistent SIADH, usually only transient electrolyte disturbances postoperatively. Previous cases of GHH have not been associated with persistent derangements in antidiuretic hormone levels. A 7-month-old male infant presented to our hospital with a history of an intracranial cystic lesion diagnosed at 23weeks gestational age (GA), later impressed as a solid-cystic mass at 37weeks GA by ultrasound prenatally. Postnatal MRI after birth showed a large mass with a dorsal cyst occupying the hypothalamus, causing hydrocephalus and brainstem compression. The patient started to have subtle seizures on the seventh day after birth and eventually developed dacrystic seizures. Hyponatremia with persistent SIADH was observed at 3months of age before surgery. He received long-term oral sodium supplementation, polytherapy of anti-epileptic medications, ventriculocystostomy for progressive enlargement of the cystic cavity, and later surgical treatment for disconnection and partial resection which confirmed a histological diagnosis of hypothalamic hamartoma. In this case study, we present a novel association of GHH with persistent SIADH and a rare presentation of a cystic component at the dorsal part of the tumor. Clinicians should be aware of this potential endocrine derangement and provide emergent treatment.

Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder

SummaryFree oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent identification of NGLY1 deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss of function of an enzyme involved in fOS metabolism, has elicited increased interest in fOS processing. The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1, which cleaves α1,2-, α1,3-, and α1,6-mannose residues. In this study, we report the clinical, biochemical, and molecular features of six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1; the individuals are from four different families. These individuals exhibit dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants. We further demonstrate that MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells. These results emphasize the involvement of MAN2C1 in human neurodevelopmental disease and the importance of fOS catabolism.

Bi-allelic SMO variants in hypothalamic hamartoma: a recessive cause of Pallister-Hall syndrome.

Pallister-Hall syndrome, typically caused by germline or de novo variants within the GLI3 gene, has key features of hypothalamic hamartoma and polydactyly. Recently, a few similar cases have been described with bi-allelic SMO variants. We describe two siblings born to non-consanguineous unaffected parents presenting with hypothalamic hamartoma, post-axial polydactyly, microcephaly amongst other developmental anomalies. Previous clinical diagnostic exome analysis had excluded a pathogenic variant in GLI3. We performed exome sequencing re-analysis and identified bi-allelic SMO variants including a missense and synonymous variant in both affected siblings. We functionally characterised this synonymous variant showing it induces exon 8 skipping within the SMO transcript. Our results confirm bi-allelic SMO variants as an uncommon cause of Pallister-Hall syndrome and describe a novel exon-skipping mechanism, expanding the molecular architecture of this new clinico-molecular disorder.

Microsurgical Management of Complex Hypothalamic Hamartomas in the Era of Minimally Invasive Therapy: A Case Series and Narrative Review

There has been a paradigm shift in the management of hypothalamic hamartoma (HH) from traditional microsurgical techniques to less invasive alternatives. However, large and extensive HH may fail to respond to these therapies, necessitating craniotomies. All patients who underwent microsurgical resection of a complex HH by the 2 senior authors from 2011 to 2021 were included. Charts were retrospectively reviewed and demographic, clinical, imaging, and outcome data were recorded. Eight patients (mean age, 7 years) were included. Two had failed previous treatments. All 7 presented with gelastic seizures and cognitive dysfunction, 6 showed central precocious puberty, and 3 had behavioral problems. The mean lesion size was 21.6 mm and all had interpeduncular extension, 5 had intraventricular extension (Delalande type I, 3; type III, 4; type IV, 1). A frontotemporal orbitozygomatic approach with optic nerve decompression was used in all patients, supplemented by another approach in 3 (endoscopic transventricular, 3; transcallosal, 1). Gross total resection was achieved in 6 patients and subtotal resection in 2. Transient complications occurred in 3 patients (37.5%): self-limited sodium imbalance (n= 3), subdural hygroma (n= 2). Permanent complications occurred in 2 patients (25%): perforator infarct (n= 1) and short-term memory loss (n= 1). All patients experienced seizure resolution with preserved hypothalamic-pituitary axis function. After a mean follow-up of 41 months (range, 2-66 months), 7 patients remained seizure free, and 1 had rare seizures. Cognitive and behavioral symptoms improved in all patients. For large HH with interpeduncular extension, microsurgery via the frontotemporal orbitozygomatic approach is a safe and highly effective treatment modality.

Exploring immunoreactivity of TTF-1 and AVP in hypothalamic hamartoma.

Hypothalamic hamartoma (HH) is a rare developmental disorder presenting with gelastic seizures or precocious puberty attributed to gonadotrophin-releasing hormone expression by the hamartoma. The histogenesis of HH is uncertain, and diagnosis of HH is difficult in small biopsies due to its close resemblance to normal hypothalamic nuclei. TTF-1 and arginine vasopressin (AVP) are associated with gonadotropin-releasing hormone release. In this study, we explored the expression pattern of TTF-1 and AVP in HH and its utility, if any, in diagnosis. We reviewed the clinical, radiologic, and histopathological features of 23 HH diagnosed over the past decade at our Institute. The age at presentation ranged from 11 months to 34 years with gelastic seizures (82.6%), precocious puberty (17.4%), and developmental delay (8.7%) as presenting symptoms. On imaging, all the lesions (n = 9) involved the posterior and tuberal group of hypothalamic nuclei, while 5 cases involved the anterior hypothalamus. Anatomically, the lesions involved mammillary body, arcuate and periventricular nuclei. On histopathology, 52% cases revealed nodular arrangement of small neurocytic cells separated by glial stroma. TTF-1 and AVP immunoreactivity was absent in all the cases, whereas in normal hypothalamus, AVP was expressed in periventricular nuclei. Our results suggest that immunoexpression of TTF-1 is absent in HH, particularly in those arising from the posterior hypothalamus, and this can be used in small biopsies to distinguish from a normal hypothalamus as well as from posterior pituitary tumors.

Stereotactic radiosurgery for epilepsy related to hypothalamic hamartoma

To define the indications for SRS in patients with HH and to clarify the irradiation parameters. Twenty-two patients with HH and epilepsy underwent SRS at the Moscow Gamma-knife Center. A retrospective analysis included 19 patients with sufficient follow-up data. Median age of patients was 11.5 years (range 1.3-25.8). The diameter of irradiated HHs ranged between 5.5 and 40.9 mm. In 8 (36%) cases, the volume of hamartoma exceeded 3 cm3. Mean prescribed dose was 18±2.0 Gy, mean prescribed isodose - 48±4.2%. Median follow-up period was 14.8 months (range 3.4 - 96.1). Three (15.8%) patients were free of seizures. One patient (5.3%) improved dramatically after treatment with compete resolution of generalized seizures and experienced only rare emotional seizures (Engel IB). Eleven (57.8%) patients reported lower incidence of seizures. Severity and incidence of seizures were the same in 4 patients (21.1%). The best results were achieved in mean target dose over 20-22 Gy, minimal target dose over 7-10 Gy, covering by the prescribed dose of at least 70-80% of hamartoma volume, as well as in patients with the prescribed dose of 12 Gy delivered to almost entire volume of tumor. None patient had any complications after SRS. SRS is safe regarding neurological, endocrine or visual disturbances. Careful patient selection for SRS makes it an effective option for HH-related epilepsy. The best candidates for SRS are children with seizures aged over 1 year, hamartoma <3 cm3 and area of fusion with hypothalamus <150 mm2.

Surgical treatment of epilepsy in patients with hypothalamic hamartomas

When choosing the optimal treatment option, it is necessary to take into account patient age and course of disease, anatomical and topographic features of hamartoma location, previous attempts of treatment, opinion of the patient and his guardians, as well as surgical experience.

Discerning Seizure-Onset v. Propagation Zone: Pre-and-Post-Operative Resting-State fMRI Directionality and Boerwinkle Neuroplasticity Index

The goal of this study was to determine resting state fMRI (rs-fMRI) effective connectivity (RSEC) capacity, agnostic of epileptogenic events, in distinguishing seizure onset zones (SOZ) from propagation zones (pZ). Consecutive patients (2.1–18.2 years old), with epilepsy and hypothalamic hamartoma, pre-operative rs-fMRI-directed surgery, post-operative imaging, and Engel class I outcomes were collected. Cross-spectral dynamic causal modelling (DCM) was used to estimate RSEC between the ablated rs-fMRI-SOZ to its region of highest connectivity outside the HH, defined as the propagation zone (pZ). Pre-operatively, RSEC from the SOZ and PZ was expected to be positive (excitatory), and pZ to SOZ negative (inhibitory), and post-operatively to be either diminished or non-existent. Sensitivity, accuracy, positive predictive value were determined for node-to-node connections. A Parametric Empirical Bayes (PEB) group analysis on pre-operative data was performed to identify group effects and effects of Engel class outcome and age. Pre-operative RSEC strength was also evaluated for correlation with percent seizure frequency improvement, sex, and region of interest size. Of the SOZ’s RSEC, only 3.6% had no connection of significance to the pZ when patient models were individually reduced. Among remaining, 96% were in expected (excitatory signal found from SOZ → pZ and inhibitory signal found from pZ → SOZ) versus 3.6% reversed polarities. Both pre-operative polarity signals were equivalently as expected, with one false signal direction out of 26 each (3.7% total). Sensitivity of 95%, specificity 73%, accuracy of 88%, negative predictive value 88%, and positive predictive value of 88% in identifying and differentiating the SOZ and pZ. Groupwise PEB analysis confirmed SOZ → pZ EC was excitatory, and pZ → SOZ EC was inhibitory. Patients with better outcomes (Engel Ia vs. Ib) showed stronger inhibitory signal (pZ → SOZ). Age was negatively associated with absolute RSEC bidirectionally but had no relationship with Directionality SOZ identification performance. In an additional hierarchical PEB analysis identifying changes from pre-to-post surgery, SOZ → pZ modulation became less excitatory and pZ → SOZ modulation became less inhibitory. This study demonstrates the accuracy of Directionality to identify the origin of excitatory and inhibitory signal between the surgically confirmed SOZ and the region of hypothesized propagation zone in children with DRE due to a HH. Thus, this method validation study in a homogenous DRE population may have potential in narrowing the SOZ-candidates for epileptogenicity in other DRE populations and utility in other neurological disorders.

Epilepsy.

GKNS has been introduced as an alternative to microsurgery for the treatment of certain types of focal epilepsy. It was first noted that epilepsy associated with AVMs often improved before the obliteration of the vascular lesion. It was subsequently shown that the treatment could be effective in mesial temporal lobe epilepsy (MTLE) producing remission in around 60% of patients, provided the treatment was carried out as originally designed. GKNS has also been useful in the treatment of gelastic epilepsy associated with hypothalamic hamartomas.

Three pediatric cases of hypothalamic hamartoma presenting different clinical courses

Three pediatric cases of hypothalamic hamartoma presenting different clinical courses

Surgical outcomes of patients with hypothalamic hamartoma treated at preschool age

Surgical outcomes of patients with hypothalamic hamartoma treated at preschool age