Pharmacological evaluation of E2730, a novel selective uncompetitive GAT1 inhibitor, on epileptiform activities in resected brain tissues from human focal cortical dysplasia ex vivo.

Focal cortical dysplasia (FCD) is an important etiology of focal epilepsy in children and adults. However, only a few preclinical models sufficiently reproduce the characteristic histopathologic features of FCD. To improve the success rate of clinical trials for antiseizure medications (ASMs) in patients with FCD, more human-relevant preclinical models are needed, and epileptic foci resected from patients are a powerful tool for this purpose. Here, we conducted ex vivo studies using epileptic foci resected from patients with FCD type II to evaluate the pharmacologic effects of the ASM candidate E2730, a selective uncompetitive inhibitor of γ-aminobutyric acid transporter 1. We used the same ex vivo assay system to assess carbamazepine (CBZ), an ASM often prescribed for focal epilepsy, as a reference. At the higher dose tested (200 µM), both E2730 and CBZ suppressed spontaneous epileptiform activities almost completely. At the lower dose (100 µM), CBZ reduced the area of brain tissue showing epileptiform activity, whereas E2730 significantly decreased the number of epileptiforms. These findings suggest that E2730-both as a single agent and in combination with CBZ-merits evaluation in clinical trials involving patients with FCD.

Comparison of visual outcomes between medical treatment alone and Ahmed glaucoma valve implantation in Shiba dogs with primary angle closure glaucoma.

OBJECTIVE: The objective of the study was to evaluate visual outcomes between medical treatment alone (MED) and Ahmed glaucoma valve implantation (AGVI) in Shiba dogs with primary angle closure glaucoma (PACG). PROCEDURES: Records of 65 Shiba dogs (104 eyes) with PACG were retrospectively reviewed. Vision was assessed qualitatively using both the menace response and maze testing. The significance of age, sex, intraocular pressure (IOP), and duration of clinical signs (≤72 h or >72 h) at first presentation (V1) was assessed. Eyes with vision at V1 were divided into groups according to subsequent treatment method (MED versus AGVI), and vision as a survival outcome was compared between group by the Kaplan-Meier method. RESULTS: At V1, 65 eyes (62.5%) of 54 dogs had vision. There was no statistically significant difference in age or sex on the presence of vision at V1. Median IOP was higher in blind (52 mmHg) compared to sighted eyes (28 mmHg) (p < .001). Eyes presenting in ≤72 h of the onset of clinical signs were more likely to have vision (86.7%) compared to those presenting after 72 h (44.1%) (p < .001). By the Kaplan-Meier analysis, the cumulative visual retention rate was significantly higher with AGVI than with MED (69.2% vs. 7.7%; p < .01) at 12 months. The median time to visual loss was 39.9 months with AGVI vs. 1.7 months with MED. CONCLUSIONS: AGVI resulted in better visual outcomes than MED and should be considered in Shiba dogs with PACG that are visual at the time of presentation and suitable for surgery.

TRPV4-mediated Ca2+ deregulation causes mitochondrial dysfunction via the AKT/α-synuclein pathway in dopaminergic neurons.

Mutations in the gene encoding the transient receptor potential vanilloid member 4 (TRPV4), a Ca2+ permeable nonselective cation channel, cause TRPV4-related disorders. TRPV4 is widely expressed in the brain; however, the pathogenesis underlying TRPV4-mediated Ca2+ deregulation in neurodevelopment remains unresolved and an effective therapeutic strategy remains to be established. These issues were addressed by isolating mutant dental pulp stem cells from a tooth donated by a child diagnosed with metatropic dysplasia with neurodevelopmental comorbidities caused by a gain-of-function TRPV4 mutation, c.1855C > T (p.L619F). The mutation was repaired using CRISPR/Cas9 to generate corrected isogenic stem cells. These stem cells were differentiated into dopaminergic neurons and the pharmacological effects of folic acid were examined. In mutant neurons, constitutively elevated cytosolic Ca2+ augmented AKT-mediated α-synuclein (α-syn) induction, resulting in mitochondrial Ca2+ accumulation and dysfunction. The TRPV4 antagonist, AKT inhibitor, or α-syn knockdown, normalizes the mitochondrial Ca2+ levels in mutant neurons, suggesting the importance of mutant TRPV4/Ca2+/AKT-induced α-syn in mitochondrial Ca2+ accumulation. Folic acid was effective in normalizing mitochondrial Ca2+ levels via the transcriptional repression of α-syn and improving mitochondrial reactive oxygen species levels, adenosine triphosphate synthesis, and neurite outgrowth of mutant neurons. This study provides new insights into the neuropathological mechanisms underlying TRPV4-related disorders and related therapeutic strategies.

Unilateral chorea linked to cavernous haemangioma involving the putamen improved by surgery.

Unilateral chorea movements caused by cavernous haemangioma in the putamen are extremely rare. We report a case with chorea movements linked to cavernous haemangioma, localised to an area including the putamen in which pharmacotherapy was found to be ineffective. Symptoms were, however, improved by resection of the cavernous haemangioma. In cases where chorea movements linked to cavernous haemangioma, involving the putamen, prove intractable with watchful waiting or pharmacotherapy, improvement can be expected with surgical removal of the cavernous haemangioma. It is also possible to reduce the risk of complications through the use of intraoperative navigation and monitoring.

Evaluation of temperature-dependent fluctuations in skin microcirculation flow using a light-emitting diode based photoacoustic imaging device.

PURPOSE: Skin microvessels maintain temperature homeostasis by contracting and dilating upon exposure to changes in temperature. Under general anesthesia, surgical invasiveness, including incisions and coagulation, and the effects of anesthetics may cause variations in the threshold temperature, leading to the constriction and dilation of cutaneous blood vessels. Therefore, studies on skin microvascular circulation are necessary to develop appropriate interventions for complications during surgery. METHODS: We visualized and quantified skin microcirculatory fluctuations associated with temperature variations using a light-emitting diode photoacoustic imaging (LED-PAI) device. The hands of ten healthy volunteers were stressed with four different water temperatures [25℃ (Control), 15℃ (Cold1), 40℃ (Warm), and 15℃ (Cold2)]. The photoacoustic images of the fingers were taken under each condition, and the microvascular flow owing to temperature stress was quantified as the area of photoacoustic signal (S) in each image. The S values were compared with the variations in blood flow (Q) measured by laser Doppler flowmetry (LDF). RESULTS: The correlation between Q and S according to the 40 measurements was r = 0.45 (p＜0.01). In addition, the values of S under each stress condition were as follows: Scontrol = 10,826 ± 3364 pixels, Scold1 = 8825 ± 2484 pixels, Swarm = 13,369 ± 3001 pixels, and Scold2 = 8838 ± 1892 pixels; the differences were significant. The LDF blood flow (Q) showed similar changes among conditions. CONCLUSION: These findings suggest that the LED-PAI device could be an option for evaluating microcirculation in association with changes in temperature.

An integrated genetic analysis of epileptogenic brain malformed lesions.

Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway.

Nascent peptide-induced translation discontinuation in eukaryotes impacts biased amino acid usage in proteomes.

Robust translation elongation of any given amino acid sequence is required to shape proteomes. Nevertheless, nascent peptides occasionally destabilize ribosomes, since consecutive negatively charged residues in bacterial nascent chains can stochastically induce discontinuation of translation, in a phenomenon termed intrinsic ribosome destabilization (IRD). Here, using budding yeast and a human factor-based reconstituted translation system, we show that IRD also occurs in eukaryotic translation. Nascent chains enriched in aspartic acid (D) or glutamic acid (E) in their N-terminal regions alter canonical ribosome dynamics, stochastically aborting translation. Although eukaryotic ribosomes are more robust to ensure uninterrupted translation, we find many endogenous D/E-rich peptidyl-tRNAs in the N-terminal regions in cells lacking a peptidyl-tRNA hydrolase, indicating that the translation of the N-terminal D/E-rich sequences poses an inherent risk of failure. Indeed, a bioinformatics analysis reveals that the N-terminal regions of ORFs lack D/E enrichment, implying that the translation defect partly restricts the overall amino acid usage in proteomes.

The effects of hydroxyethyl starch 130/0.4 on perioperative renal function in patients undergoing cardiac surgery: A randomised controlled trial.

Background: Acute kidney injury (AKI) after cardiac surgery increases the risk of morbidity and mortality. Hydroxyethyl starch (HES) is often used during surgery due to its plasma-volume expanding effect, but the impact of HES 130/0.4 on renal function in patients undergoing cardiac surgery remains unclear. The aim of our study is to investigate the impact of HES 130/0.4 on postoperative renal function in patients undergoing cardiac surgery using cardiopulmonary bypass. Methods: Our study was a randomised, single-center, single-blind study conducted on 60 adult patients who underwent cardiac surgery using cardiopulmonary bypass: 30 patients were intraoperatively administered with HES 130/0.4; the other 30 with Ringer's bicarbonate. The primary endpoints were occurrence of AKI within 30 days of surgery and the disease stages. Results: The mean dose of 6% HES 130/0.4 was 28 ml/kg. AKI occurred within 30 days of the operation in 8 cases (28.6%) in the HES group and 6 cases (21.4%) in the crystalloid group (no significance: p = 0.5371). Disease stages were as follows: "no AKI", "stage 1", "stage 2″ and "stage 3″, accounting for 20 cases (71.5%), 6 cases (21,4%), 2 cases (7.1%), and 0 cases, respectively, in the HES group, and 22 cases (78.6%), 6 cases (21.4%), 0 cases, and 0 cases, respectively, in the crystalloid group (no significance: p = 0.3508). Conclusion: There was no significant difference in the occurrences or stages of AKI during the 30 days following cardiac surgery with cardiopulmonary bypass between patients administered with HES 130/0.4 or Ringer's bicarbonate.

Nascent polypeptide within the exit tunnel stabilizes the ribosome to counteract risky translation.

Continuous translation elongation, irrespective of amino acid sequences, is a prerequisite for living organisms to produce their proteomes. However, nascent polypeptide products bear an inherent risk of elongation abortion. For example, negatively charged sequences with occasional intermittent prolines, termed intrinsic ribosome destabilization (IRD) sequences, weaken the translating ribosomal complex, causing certain nascent chain sequences to prematurely terminate translation. Here, we show that most potential IRD sequences in the middle of open reading frames remain cryptic and do not interrupt translation, due to two features of the nascent polypeptide. Firstly, the nascent polypeptide itself spans the exit tunnel, and secondly, its bulky amino acid residues occupy the tunnel entrance region, thereby serving as a bridge and protecting the large and small ribosomal subunits from dissociation. Thus, nascent polypeptide products have an inbuilt ability to ensure elongation continuity.

Nanopore sequencing reveals TACC2 locus complexity and diversity of isoforms transcribed from an intronic promoter.

Gene expression is controlled at the transcriptional and post-transcriptional levels. The TACC2 gene was known to be associated with tumors but the control of its expression is unclear. We have reported that activity of the intronic promoter p10 of TACC2 in primary lesion of endometrial cancer is indicative of lymph node metastasis among a low-risk patient group. Here, we analyze the intronic promoter derived isoforms in JHUEM-1 endometrial cancer cells, and primary tissues of endometrial cancers and normal endometrium. Full-length cDNA amplicons are produced by long-range PCR and subjected to nanopore sequencing followed by computational error correction. We identify 16 stable, 4 variable, and 9 rare exons including 3 novel exons validated independently. All variable and rare exons reside N-terminally of the TACC domain and contribute to isoform variety. We found 240 isoforms as high-confidence, supported by more than 20 reads. The large number of isoforms produced from one minor promoter indicates the post-transcriptional complexity coupled with transcription at the TACC2 locus in cancer and normal cells.

Dependence of stimulus-induced rotary saturation on the direction of target oscillating magnetic fields: A phantom and simulation study.

Several noninvasive techniques for the direct measurement of the neuronal activity using magnetic resonance imaging (MRI) have recently been reported. As a promising candidate, we focus on a spin-lock MRI sequence (i.e., stimulus-induced rotary saturation (SIRS)) directly measuring a tiny oscillating magnetic field. Previous phantom studies on SIRS have applied the target oscillating magnetic field parallel to the direction of the static magnetic field B0. However, in practice, the neuromagnetic fields are not always aligned in the same direction as in such a condition. This study investigates the MR signal changes during SIRS when the target magnetic field direction is not the same as that of the B0 field through both phantom experiments and Bloch simulations. The experimental results indicate that only the target magnetic field component along the B0 field affects the signal change, indicating that SIRS has partial sensitivity, even if the target magnetic fields are tilted from the B0 field. Furthermore, the simulation results show good agreements with the experimental results. These results clarify the sensitivity direction of SIRS-based fMRI and lead to the possibility that the direction of the generated neuromagnetic fields can be estimated, such that we can separate directional information from the other information contained in neuromagnetic fields (e.g., phase information).

Promoter-level transcriptome in primary lesions of endometrial cancer identified biomarkers associated with lymph node metastasis.

For endometrial cancer patients, lymphadenectomy is recommended to exclude rarely metastasized cancer cells. This procedure is performed even in patients with low risk of recurrence despite the risk of complications such as lymphedema. A method to accurately identify cases with no lymph node metastases (LN-) before lymphadenectomy is therefore highly required. We approached this clinical problem by examining primary lesions of endometrial cancers with CAGE (Cap Analysis Gene Expression), which quantifies promoter-level expression across the genome. Fourteen profiles delineated distinct transcriptional networks between LN + and LN- cases, within those classified as having the low or intermediate risk of recurrence. Subsequent quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses of 115 primary tumors showed SEMA3D mRNA and TACC2 isoforms expressed through a novel promoter as promising biomarkers with high accuracy (area under the receiver operating characteristic curve, 0.929) when used in combination. Our high-resolution transcriptome provided evidence of distinct molecular profiles underlying LN + /LN- status in endometrial cancers, raising the possibility of preoperative diagnosis to reduce unnecessary operations in patients with minimum recurrence risk.

Additional resective surgery after the failure of initial surgery in patients with intractable epilepsy.

Objectives There are three conceivable reasons for the failure of resective surgery for intractable epilepsy: incomplete resection of the epileptogenic zone including or overlapping with eloquent area (group A); incorrect determination of the epileptogenic zone prior to the first surgery (group B); and the development of a new epileptic focus after the first surgery (group C). We examined the relationship between the reason for failure of initial surgery and patient outcomes after repeated surgical resection. Methods The study included 18 patients (5.1%) underwent additional surgery after failure of the initial operation. Post-operative outcomes, complications and other clinical data were collected by retrospective chart review. Results Four patients (22.2%) were assigned to group A, 13 (72.2%) were assigned to group B, and 1 patient was assigned to group C (5.6%). Six patients (40.0%) were seizure-free for 2 or more years after additional surgery. In group B, 11 patients underwent additional resection of the cortex adjacent to the previously resected area and 2 underwent re-operation involving a site distant from the previously resected area; notably, the latter 2 patients did not achieve seizure-free status post-surgery. After the first operation, only one patient (group A) experienced transient paresis; after additional surgery, 10 of 18 patients (56%; 3 group A, 6 group B, and 1 group C) experienced various complications. Discussion Although additional resective surgery provided freedom from seizures in about 40% of the patients, it is important to weigh a high risk of complications against possible benefits when considering additional surgery.

Predictors of cognitive function in patients with hypothalamic hamartoma following stereotactic radiofrequency thermocoagulation surgery.

OBJECTIVE: To determine the predictors of cognitive function in patients with drug-resistant gelastic seizures (GS) related to hypothalamic hamartoma (HH) before and after stereotactic radiofrequency thermocoagulation surgery (SRT). METHODS: We studied 88 patients with HH who underwent SRT between October 1997 and December 2014. Patients received neuropsychological tests preoperatively and postoperatively. Based on the preoperative measures, patients were categorized as "high-functioning" (full-scale intelligence quotient [FSIQ] ≥70; n = 48) and "low-functioning" group (FSIQ <70; n = 40). Univariate and multivariate linear regression analyses determined the clinical, electroencephalography (EEG), and imaging factors associated with preoperative cognitive function as well as postoperative cognitive change. RESULTS: Eighty-seven patients (98.8%) were followed postoperatively for an average of 3.3 years, and 75 (85.2%) of them achieved GS remission at the last hospital visit. Neuropsychological performance was significantly improved after surgery in both groups. Multivariate linear regression analysis showed that a smaller HH size (p = 0.002) and a smaller number of antiepileptic drugs (p < 0.001) were preoperatively associated with better neuropsychological performance. Multivariate linear regression analysis showed that better postoperative improvement in cognition was associated with a shorter duration of epilepsy (p = 0.03). SIGNIFICANCE: Cognitive impairment related to epileptic encephalopathy may improve following SRT in substantial proportions of HH patients. Reduced improvement in postoperative cognitive function in patients with longer duration of epilepsy warrants further studies to determine if earlier SRT provides a greater chance of postoperative cognitive improvement in patients with HH.

Effects of Secreted Mast Cell Mediators on Retinal Pigment Epithelial Cells: Focus on Mast Cell Tryptase.

Numerous mast cells are present in the choroid, but the effects of mast cell mediators on retinal pigment epithelial (RPE) cells are not well understood. We investigated the influence of mast cell mediators on RPE cells in vitro, focusing on tryptase. Expression of receptors was examined by the reverse transcription polymerase chain reaction. We also assessed production of interleukin 8 and vascular endothelial growth factor (VEGF) after RPE cells were stimulated with mast cell mediators by using an antibody array and enzyme-linked immunosorbent assay. Furthermore, we investigated the influence of tryptase on RPE cell migration and integrity by the scratch assay and the transepithelial resistance. RPE cells expressed protease-activated receptor 2 (PAR2), histamine receptor 1, tumor necrosis factor-α (TNF-α) receptor 1, and CCR 1, 3, 4, 8, and 11. Tryptase, PAR2 agonists, histamine, and TNF-α all enhanced interleukin 8 production by RPE cells, while only tryptase enhanced VEGF production. Tryptase also enhanced expression of phosphorylated extracellular signal-regulated kinases 1/2, resulting in increased migration of RPE cells. However, tryptase did not alter epithelial integrity or the expression of zonula occludens-1 and junctional adhesion molecule-A by RPE cells. Mast cell mediators, especially tryptase, may influence RPE cell inflammation.

Ca2+ -permeable AMPA receptors associated with epileptogenesis of hypothalamic hamartoma.

Hypothalamic hamartoma (HH), composed of neurons and glia without apparent cytologic abnormalities, is a rare developmental malformation in humans. Patients with HH often have characteristic medically refractory gelastic seizures, and intrinsic epileptogenesis within the lesions has been speculated. Herein we provide evidence to suggest that in HH neurons, Ca2+ permeability through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors is aberrantly elevated. In needle biopsy specimens of HH tissue, field potential recordings demonstrated spontaneous epileptiform activities similar to those observed in other etiologically distinct epileptogenic tissues. In HH, however, these activities were clearly abolished by application of Joro Spider Toxin (JSTX), a specific inhibitor of the Ca2+ -permeable AMPA receptor. Consistent with these physiologic findings, the neuronal nuclei showed disappearance of adenosine deaminase acting on RNA 2 (ADAR2) immunoreactivity. Furthermore, examination of glutamate receptor 2 (GluA2) messenger RNA (mRNA) revealed that editing efficiency at the glutamine/arginine site was significantly low. These results suggest that neurons in HH may bear Ca2+ -permeable AMPA receptors due to dislocation of ADAR2.

[A Case of a Stuck Bioprosthetic Mitral Valve Leaflet Diagnosed by Intraoperative Transesophageal Echocardiography: Suture Loop Jamming].

We present a case of a very rare complication of valvular surgery-suture loop jamming. A 77-year-old woman was admitted for surgical treatment of moderate aortic regurgitation, severe mitral regurgitation (MR) and severe tricuspid regur- gitation. She underwent mitral valve replacement (MVR) with porcine bioprosthetic valve and tricuspid annuloplasty by DeVega procedure. Before termination of cardiopulmonary bypass, transesophageal echocardiography (TEE) showed se- vere MR at the center of the bioprosthetic valve along the posterior left atrial wall In addition, echogenic fili- form structure which disturbed the movement of the leaflets was detected. The patient was placed on car- dioplegic arrest again and the heart was reopened, suture loop jamming around the stents of the biopros- thetic valve resulting in significant mitral regurgitation was diagnosed. The implanted bioprosthetic valve was removed and a new bioprosthetic valve was subse- quently re-implanted. Intraoperative TEE provided a visible assessment of mitral prosthetic valve dysfunction and we were immediately able to reach diagnosis of this rare and serious complication-suture loop jamming. Our case makes us recognize suture loop jamming as one of the complications of MVR.

[Anesthetic Management of a 69-year-old Patient with Eisenmenger Syndrome for Abdominoperineal Resection].

Although life expectancy of the patients with Eisenmenger syndrome (ES) is currently reported to be lower than 40 years, life span of the patients with ES may be extended because of development of medical care. According to recently reported middle-aged patients with ES undergoing non-cardiac surgeries, per-operative mortality and morbidity of the patients with ES undergoing non-cardiac surgeries may be lower than previously thought, and even elderly patients may be able to undergo major surgeries such as laparotomies for cancers. We described the anesthetic management of a 69-year-old patient with ES who had undergone abdominoperineal resection. In the anesthetic management it is important to maintain adequate blood volumne and systemic vascular resistance and this avoids increases of right-to-left shunt. Perioperative monitoring of pulmonary arterial pressure was useful for hemodynamic management. Good pain control and management of body temperature were also needed for a perioperative course with no adverse events. The appropriate anesthetic management of the 69-year-old patient with ES for abdominoperineal resection resulted in the successful perioperative course.

Ephaptic transmission is the origin of the abnormal muscle response seen in hemifacial spasm.

OBJECTIVE: In patients with hemifacial spasm, stimulation of a branch of the affected facial nerve elicits an abnormal response in the muscles innervated by another branch. We tested the hypothesis that this anomaly results from lateral spread of impulses from one motor axon to another at the site of the nerve compression by the offending artery. METHODS: In a preoperative study of 21 patients, we delivered a series of stimuli, in short increments, successively distally along the temporal branch of the facial nerve to record abnormal muscle responses from the orbicularis oculi and mentalis muscles. In intraoperative monitoring of 10 patients during microvascular decompression, we monitored propagating nerve action potentials with a handheld electrode placed on the facial nerve 3mm distal to the vascular compression site. RESULTS: With incremental shifts of stimulating points distally, the latency of abnormal muscle responses increased by 0.3±0.1ms/cm. This finding implicates the antidromic motor impulse as the trigger for lateral spread. The nerve action potentials recorded during surgery comprised the initial antidromic signal followed by one or more additional peaks. The latter immediately abated, together with abnormal muscle responses, after microvascular decompression. Thus, the secondary peaks must represent the orthodromic impulses generated by ephaptic transmission. An average inter-peak interval of 1.1ms between the first and secondary peaks is consistent with the estimated conduction time from the stimulation point to the site of vascular compression but not to the facial nucleus and return. CONCLUSION: An abnormal muscle response results from lateral spread of impulses between motor axons at the site of vascular compression rather than at the facial nucleus. SIGNIFICANCE: This study establishes the mechanism of lateral spread responsible for abnormal muscle responses and contributes to the understanding of pathophysiology underlying hemifacial spasm.

Stereotactic radiofrequency thermocoagulation for giant hypothalamic hamartoma.

OBJECTIVE The authors undertook this study to validate the feasibility and safety of stereotactic radiofrequency thermocoagulation (SRT) for the surgical treatment of giant hypothalamic hamartoma (HH). METHODS Of the 109 patients who underwent SRT for hypothalamic hamartoma (HH) at the authors' institution between 1997 and 2013, 16 patients (9 female, 7 male) had giant HHs (maximum diameter ≥ 30 mm). The clinical records of these 16 patients were retrospectively reviewed. RESULTS The patients' age at first SRT ranged from 1 to 22 years (median 5 years). The maximum diameter of their HHs was 30-80 mm (mean 38.5 mm). Eleven HHs had bilateral attachments to the hypothalamus. All patients had gelastic seizures (GS), and 12 had types of seizures other than GS. Some of these patients also had mental retardation (n = 10, 62.5%), behavioral disorders (n = 8, 50.0%), and precocious puberty (n = 11, 68.8%). A total of 22 SRT procedures were performed; 5 patients underwent repeat SRT procedures. There was no mortality or permanent morbidity. After 17 of the 22 procedures, the patients experienced transient complications, including high fever (n = 7), hyperphagia (n = 3), hyponatremia (n = 6), disturbance of consciousness (n = 1), cyst enlargement (n = 1), and epidural hematoma (n = 1). Thirteen patients (81.3%) achieved freedom from GS after the final SRT procedure during a follow-up period ranging from 6 to 60 months (mean 23 months). Twelve patients had nongelastic seizures in addition to GS, and 7 (58.3%) of these 12 patients experienced freedom from their nongelastic seizures. CONCLUSIONS SRT provided minimal invasiveness and excellent seizure outcomes even in patients with giant HHs. Repeat SRT is safe for residual GS. SRT is a feasible single surgical strategy for HH regardless of the tumor's size or shape.