CASE REPORTJ Neurosurg Pediatr 21:460–465, 2018

HypotHalamic hamartomas (HHs) are rare, benign malformations of cytologically normal neurons within the inferior hypothalamus. They arise dur-

ing fetal development and can be associated with preco-cious puberty, developmental delay, and medically refrac-tory epilepsy. A hallmark clinical symptom of HHs is gelastic seizures, which are characterized by mechanical bursts of laughter with retained consciousness. Nearly 75% of HH patients with gelastic seizures experience in-tractable epilepsy, which may lead to epileptic encepha-lopathy.2

Morphologically, HHs are classified as either pedun-culated or sessile. A large study assessing association between HH morphology and symptomatology found that intrahypothalamic position and mass effect upon the third ventricle, rather than hamartoma size and shape, are most strongly linked with preoperative seizure pre-sentation.10 The pathophysiology of seizures in HHs has been proposed to involve pathways between the HH and

the mamillo-thalamo-cingulate tract, by which ictal dis-charges propagate from the HH into surrounding and then distant brain structures.11 Seizure freedom rates following open resection of HHs are approximately 50%, although resection risks significant morbidity, such as visual im-pairment, endocrine dysfunction, and hemiparesis.1,7

MRI-guided laser ablation is a novel, minimally inva-sive treatment strategy that has yielded promising seizure outcomes in HH patients. Hypothalamic hamartoma laser ablative treatment was first demonstrated in a proof-of-concept clinical trial involving 2 pediatric patients.3 At follow-up periods of 2 and 5 months, both patients were seizure free. Since then, 2 additional studies have de-scribed the use of laser ablation for HH treatment; one demonstrated seizure freedom in 11 (79%) of 14 patients,22 while the second, smaller study involving 2 patients dem-onstrated seizure freedom in both.16 None of these stud-ies characterized lesion anatomy in detail. Thus, it is not known how HH morphology and size may influence the

ABBREVIATIONS HH = hypothalamic hamartoma; iMRI = interventional MRI; SRT = stereotactic radiofrequency thermocoagulation; UCSF = University of California, San Francisco.SUBMITTED May 27, 2017. ACCEPTED October 5, 2017.INCLUDE WHEN CITING Published online February 16, 2018; DOI: 10.3171/2017.10.PEDS17292.* L.P.S. and K.I.A. contributed equally to this work.

Laser ablative therapy of sessile hypothalamic hamartomas in children using interventional MRI: report of 5 cases*Derek G. Southwell, MD, PhD,1 Harjus S. Birk, MD,2 Paul S. Larson, MD,1 Philip A. Starr, MD,1 Leo P. Sugrue, MD, PhD,3,4 and Kurtis I. Auguste, MD1,4

Departments of 1Neurological Surgery and 3Radiology and Biomedical Imaging, University of California, San Francisco; 2Department of Neurosurgery, University of California, San Diego; and 4University of California, San Francisco Benioff Children’s Hospitals, Oakland and San Francisco, California

Hypothalamic hamartomas (HHs) are benign lesions that cause medically refractory seizures, behavioral disturbances, and endocrine dysfunction. Open resection of HHs does not guarantee seizure freedom and carries a relatively high risk of morbidity. Minimally invasive stereotactic laser ablation has recently been described as an effective and safe alterna-tive for HH treatment. Prior studies have not, however, assessed HH lesion size and morphology, 2 factors that may in-fluence treatment results and, ultimately, the generalizability of their findings. In this paper, the authors describe seizure outcomes for 5 pediatric patients who underwent laser ablation of sessile HHs. Lesions were treated using a frameless, interventional MRI-guided approach, which facilitated laser targeting to specific components of these complex lesions. The authors’ experiences in these cases substantiate prior work demonstrating the effectiveness of laser therapy for HHs, while elucidating HH complexity as a potentially important factor in laser treatment planning, and in the interpreta-tion of early studies describing this treatment method.https://thejns.org/doi/abs/10.3171/2017.10.PEDS17292KEY WORDS pediatric epilepsy; hypothalamic hamartoma; laser ablation; interventional MRI

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effectiveness of laser ablation. Given that laser probes cre-ate an ellipsoidal distribution of thermal energy,3 small and regularly shaped lesions may be more amenable to a destructive approach, whereby the entirety of the ham-artoma is ablated.21 In contrast, large and/or irregularly shaped lesions may be more difficult to destroy entirely, but may be amenable to disconnection, whereby pathways that conduct ictal activity from the HH to the rest of the brain are disrupted.4,21

In this case series, we describe lesion morphologies and seizure outcomes in 5 cases involving pediatric pa-tients who underwent laser ablative therapy of HHs at the University of California, San Francisco (UCSF). In all cases, target selection and laser probe placement were performed using an interventional MRI (iMRI) sys-tem.13,20 Probes were implanted in a frameless fashion using a skull-mounted aiming device (SmartFrame; MRI Interventions) integrated with a targeting software pack-age (ClearPoint; MRI Interventions). This system offers several advantages over previously described stereotactic, frame-based approaches. Our frameless, iMRI strategy al-lows for the creation of multiple nonparallel probe trajec-tories through a single burr hole, real-time visualization of probe targeting, and measurement of thermal effect, all without requiring patient transport between the operating room and the radiology suite. These features make it par-ticularly well suited for safe and effective laser delivery to irregularly shaped HHs.

Surgical ProcedureThis study was performed with the approval of the

UCSF institutional review board. Procedures were per-formed by 3 senior surgeons (P.S.L., P.A.S., and K.I.A.). Hamartoma ablation was performed using the Visualase laser ablation system (Medtronic). All stages of the surgi-cal procedure, including laser applicator placement, were performed in an iMRI suite, using a software package (ClearPoint) integrated with a skull-mounted aiming de-vice (SmartFrame). We have previously described the use of this targeting method for deep brain stimulator place-ment.18,19

Briefly, contrast-enhanced volumetric MRI scans were obtained to identify the target site, brain entry point, and stylet trajectory. Target sites were selected with the aim of ablating the interface between the hamartoma and normal brain tissue, thereby disconnecting the lesion from normal brain. A burr hole was placed over the selected entry point, the SmartFrame was attached to the skull, and additional

MRI sequences (high-resolution T2-weighted sequences and gradient echo sequences) were obtained through the entire brain and SmartFrame device. These sequences were then used to register the SmartFrame position in the ClearPoint software. The SmartFrame was aligned in a stepwise fashion using oblique axial scans through the device’s targeting cannula. Once the ClearPoint software predicted a targeting error of less than 0.4 mm, a blunt ce-ramic stylet was advanced through the targeting cannula to the dorsal border of the target, with imaging obtained at intermediate points to confirm stylet trajectory. The ce-ramic stylet was then removed, and the guidance sheath for the Visualase laser fiber (which included a titanium inner stylet) was inserted into the hamartoma, beyond the endpoint of the ceramic stylet tract. The titanium inner sty-let was removed, and the Visualase laser fiber was passed through the guidance sheath so that 1 cm of the fiber was exposed. High-resolution T2-weighted imaging was used to confirm targeting of the laser fiber. Using the Visualase software, MR thermography was performed during laser application to ensure both ablation of the target tissue and avoidance of thermal injury to neighboring, critical brain tissue. Diffusion-weighted images were obtained immedi-ately following ablation to confirm treatment effect.

Case ReportsPatient demographics, preoperative seizure frequency,

and postoperative outcomes are listed in Table 1. Over-all, the patients’ ages ranged from 3 to 18 years (mean 9.8 years). Four (80%) of the 5 patients were male. Preopera-tive seizure frequencies ranged from 3 events per week to 30 per day. Postoperative outcomes after laser ablation, as characterized by the Engel Epilepsy Surgery Outcome Scale, ranged from class I to class III. Postoperatively, no patient experienced new neurological morbidity or new endocrine dysfunction. In all 5 patients both seizure fre-quency and duration were decreased by treatment, and 2 patients experienced complete resolution of seizures.

Case 1This 3-year-old boy with a 1.7 × 1.7 × 1.6–cm right-sided

HH presented with precocious puberty and epilepsy (Fig. 1A). He had developed precocious puberty by 6 months of age, at which time he began endocrinological treatment with leuprolide (Lupron Depot). Thereafter, his testoster-one levels remained elevated, and he exhibited rhythmic increases in seizure frequency prior to Lupron dosing. No

TABLE 1. Patient characteristics and seizure outcomes

Case No. Age at Tx (yrs), Sex Lesion Laterality Preop Sz Freq Preop Sz Duration (yrs) Sz Outcome (Engel class) Morbidity FU (mos)

1 3, M Rt 10–30/day 3 I None 122 5, M Rt 3/day 3 III Precocious puberty 453 9, M Lt 3/wk 3 I None 304 14, F Lt 2/wk 9 III None 215 18, M Lt 4/day 15 I None 7

Freq = frequency; FU = follow-up; Sz = seizure; Tx = treatment.

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antiepileptic medications were used prior to presentation; at that time he was experiencing 10–30 gelastic seizures per day, and approximately 5 absence seizures per day.

A single right frontal burr hole was made, and the laser was delivered at the termini of 2 stylet trajectories. Post-operatively, the patient experienced no seizures or neuro-logical deficits. One week after the operation, the patient reportedly gained 11 pounds, thought to be secondary to hypothalamic irritation or steroid therapy. Thereafter, he exhibited a normal pattern of weight gain. He remains sei-zure free at latest follow-up (12 months after treatment).

Case 2This 5-year-old boy with a right-sided HH presented

with gelastic seizures and behavioral disturbances (aggres-sion). He had previously undergone biopsy of a hypotha-lamic lesion at another institution, which was identified as a hamartoma. The patient was experiencing several clusters of gelastic seizures daily as well as weekly to bi-monthly tonic-clonic seizures lasting several minutes. MRI revealed a 2.0 × 1.3 × 1.4–cm hyperintense lesion involv-ing the right hypothalamic region, abutting the wall of the third ventricle (Fig. 1B).

Ablation was performed through a right frontal burr hole, using a single pass of the stylet. Postoperatively, he experienced no immediate complications. At his most recent follow-up (45 months after treatment), he had de-veloped precocious puberty, but his aggressive behaviors had resolved. His tonic-clonic seizures had reduced in fre-quency, to less than 1 seizure per month, and his gelastic seizures were slightly reduced in duration and frequency (occurring 4–5 times per day).

Case 3This 9-year-old boy with a 1.8 × 2 × 1.9–cm left-sid-

ed HH presented with gelastic and tonic-clonic seizures, which occurred approximately 3 times daily (Fig. 1C). He had also previously developed diabetes insipidus, for which he was receiving desmopressin (DDAVP).

Ablation was performed through a right frontal burr hole, using a single pass of the stylet. Following treatment, the patient’s seizures were briefly reduced, but over the next 8 months they returned to their preoperative frequen-cy (approximately 3 times per day). Postoperative imag-ing revealed a residual attachment of the hamartoma base along the ablation field. Given his refractory seizures, a second treatment of the hamartoma was recommended. Thermal ablations were performed at the termini of 2 separate stylet trajectories, which were made through the original burr hole.

Postoperatively, the patient experienced no new neuro-logical deficits. At latest follow-up (30 months after treat-ment), while continuing medical treatment of his epilepsy, he had experienced complete resolution of his tonic-clonic seizures, and his gelastic seizures had decreased in fre-quency to less than 2 per week.

Case 4This 14-year-old girl presented with medically refrac-

tory epilepsy and precocious puberty secondary to a 2.0

× 2.0 × 2.0–cm left-sided HH (Fig. 1D). Since 5 years of age, she had experienced nocturnal seizures involving her upper and lower extremities. The seizures were initially responsive to levetiracetam (Keppra) but eventually be-came resistant to medications, occurring approximately twice weekly.

A left frontal burr hole was made, and laser ablation was performed at the termini of 2 stylet trajectories. Post-

FIG. 1. Representative images from pre- and posttreatment scans obtained in cases 1 (A), 2 (B), 3 (C), 4 (D), and 5 (E). For each patient, pretreatment (left) and posttreatment (right) coronal images at the same level are shown with green arrows indicating the edge of the hamartoma and red arrows indicating the posttreatment lesion within the hamar-toma. Images are from T2-weighted (B) or FLAIR (fluid-attenuated inver-sion recovery) sequences (A and C–E). In C, the posttreatment image (right) shows a linear artifact (dark line) representing the probe still in place at the end of treatment. Figure is available in color online only.

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operatively, the patient experienced no complications. At latest follow-up (21 months after treatment), her seizure frequency had declined to less than 1 event per week.

Case 5This 18-year-old male with a 1.1 × 1.0 × 1.2–cm left-

sided HH presented with medically refractory epilepsy and chronic headaches (Fig. 1E). At 18 months of age, he began to experience generalized, tonic-clonic seizures, for which he underwent a partial endoscopic disconnection procedure at the age of 2 years. Afterward, he was sei-zure free until age 14 years, at which time he began to experience nocturnal tonic-clonic seizures (1 event every few months) and gelastic seizures (approximately 4 times daily). Given the refractory seizures, laser ablation was of-fered.

A left frontal burr hole was made, and laser ablation was performed at the termini of 2 stylet trajectories. Post-operatively, the patient experienced no complications. At most recent follow-up (7 months after treatment), the pa-tient was free of seizures, with no neurological deficits.

Radiographic Analysis of HamartomasMeasurements of the preoperative hamartoma volumes

and the hamartoma-hypothalamus attachments were made using precontrast, 3D T1-weighted MRI sequences. Im-ages were processed using the FreeSurfer image analysis suite (http://surfer.nmr.mgh.harvard.edu/); this included surface-based cortical reconstruction, as well as segmen-tation of the subcortical white matter and deep gray mat-ter volumetric structures.5,6,14 Hamartomas were manually segmented by a neuroradiologist (L.P.S.) using both T1- and T2-weighted sequences. To estimate the “interface” between the hamartoma and normal brain, the volume of overlap between each hand-segmented lesion and the auto-segmented right and left ventral diencephalon (which includes the hypothalamus) was measured and expressed as a percentage of total hamartoma volume. To account for age-related variation in brain size, the volume of each le-sion was expressed as a percentage of the average volume of the patient’s auto-segmented putamen.

Table 2 and Fig. 2 describe and depict, respectively, the preoperative hamartoma volumes and their hypothalamic attachments. Lesion volumes ranged from 2.4 to 6.4 cm3 (mean 3.6 cm3), and their volumes were equivalent to 32% to 138% of the corresponding putamen volume (mean 66.2%). The total lesion volume that involved the ventral diencephalon (i.e., left and right diencephalon) ranged from 0.3 to 1.6 cm3 (mean 0.8 cm3). The percentage of the hamartoma volume that involved the ventral diencephalon ranged from 9% to 67% (mean 26%).

DiscussionHypothalamic hamartomas are an exceedingly hetere-

geneous group of lesions and therefore pose a significant treatment dilemma. Their deep location and fine morphol-ogy can render them difficult to access surgically, placing surrounding anatomy at considerable risk. Open resec-tion risks permanent neurological and endocrinological

deficits, and often does not achieve the primary goal of seizure control. Preliminary reports have described laser ablation as a minimally invasive and promising approach to treat these lesions. However, those studies did not assess the 3D heterogeneity of the treated lesions, nor did they consider how these features may relate to technical and clinical outcomes.

Here we have described 5 patients who underwent laser ablation of sessile hypothalamic hamartomas using iMRI and a skull-mounted aiming device (SmartFrame). Studies describing stereotactic radiofrequency thermocoagulation (SRT) of pediatric HHs have reported lower postopera-tive seizure freedom rates in cases involving “giant” HHs, suggesting that lesion size is an important determinant of seizure outcomes.12,17 To date, there is only one published series detailing laser ablation (Visualase) for HH treat-ment.22 This study, which described a seizure freedom rate of 79%, did not characterize the volumes or morphologies of the treated hamartomas. Two additional case reports, each involving 2 patients, have also described laser abla-tion of HHs. These studies reported seizure freedom rates of 100%,3,16 however one of them involved only adult pa-tients,16 and neither characterized lesion morphology. We hypothesize that differences in lesion morphology, espe-cially pertaining to the lesion’s attachment point, may ac-count for some of the differences in seizure control rates between the current study and prior studies (the latter of which may have involved smaller, regular lesions). How-ever, the relatively small size of our case series makes it difficult to definitively confirm relationships between HH size or morphology, and seizure outcomes. Larger future studies may address these factors.

Irregular HHs are challenging to ablate completely, as it is difficult to deliver the laser to all parts of the lesion (Fig. 1). This is a known challenge in SRT treatment, and it likely limits laser ablative methods as well.8 However, prior SRT studies indicate that HH “destruction” may not be necessary to achieve excellent seizure control.21 Rath-er, “disconnection” of the hamartoma from surrounding brain, by means of SRT, open surgery, or endoscopic sur-gery, can achieve excellent seizure control without HH de-struction.4,12,15,17 Electroencephalography, including depth electrode recordings of HHs, suggest that ictal activity spreads from the HH to the mamillo-thalamic-cingulate tract via the interface of the HH and normal brain.9,11,15 This tissue interface has been the target of SRT discon-nective approaches, which are effective for achieving HH

TABLE 2. Radiographic characterization of HHs

Case No.

HH Vol

(cm3)

% Putamen

Vol

Overlap w/ Lt VDC Overlap w/ Rt VDCVol

(cm3)% HH

VolVol

(cm3)% HH

Vol

1 3.6 67% 0.1 4% 0.3 8%2 2.4 32% 0.1 4% 1.5 63%3 3.2 59% 0.2 6% 0.1 3%4 6.4 138% 0.9 14% 0.2 3%5 2.4 35% 0.6 25% 0 0%

VDC = ventral diencephalon.

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seizure control.12,15,17 Similarly, our experiences with iMRI-guided laser ablation indicate that ablation of the HH-brain interface, rather than complete ablation of the lesion, can provide good seizure outcomes.

Previous studies have used stereotactic, frame-based approaches for delivering laser probes to HHs. These methods are limited in that they require patient transport between the operating room (for probe placement) and the MRI suite (for laser application/thermometry). This in-creases operative time and entails a risk of probe disrup-tion during patient transport. Also, using a frame-based system, changing probe trajectory between sequential ab-lations may require exiting the MR suite.

Here we used a combination of iMRI, a skull-mount-ed aiming device (SmartFrame), and guidance software (ClearPoint) to target the Visualase laser probe. This com-bined system allowed flexibility and efficiency, particular-ly for targeting multiple components of the hamartomas (cases 1, 4, and 5). SmartFrame fixation relies on 5-mm percutaneous screws, which are low profile and provide tactile feedback regarding bony purchase. This feature re-duces the risk of pin-site infections and skull fractures, the latter of which can occur relatively easily due to varia-tions in pediatric skull thickness. The associated incision is likewise small, as the cannula can be placed through a burr hole approximately 1 cm in diameter. Addition-ally, the SmartFrame is integrated with the ClearPoint software, allowing “on the fly” adjustments to be quickly made based on near real-time iMRI. In this manner, the

probe trajectory is adjusted to minimize error to submil-limeter levels. Many such adjustments are often avoided altogether during preoperative planning. The software not only enables surgeons to propose and illustrate optimal trajectories based on lesion size, morphology, and interac-tion with neighboring anatomy, but it also constructs vir-tual trajectory views down the path of the proposed plan. The overall result is that multiple safe passes with mini-mal error are achievable in one setting, without the need for transporting the patient between the operating room and radiology suite.

Our experience in this small patient series suggests that iMRI-guided laser ablation allows precise targeting of multiple sites in complex lesions and is effective for treatment of hypothalamic hamartomas. Our experience further suggests that a disconnection strategy, focused on ablation of the HH-brain interface, rather than destruc-tion of the entire lesion, is an effective method for treat-ing these often broad-based lesions. Future studies should continue to systematically characterize lesion features such as size, morphology, and hypothalamic contact, as careful description of these factors will allow clinicians to better compare findings across studies and develop lesion-specific ablative approaches.

ConclusionsTreatment of sessile hypothalamic hamartomas is

feasible using iMRI and a skull-mounted aiming device

FIG. 2. T1-weighted cross-sectional renderings of hypothalamic hamartomas from cases 1 (A), 2 (B), 3 (C), 4 (D), and 5 (E). Images are rendered such that the viewer’s perspective is from the side of the lesion, looking down toward the third ventricle and at the contralateral hemisphere. Images are colored to depict the lesion and related anatomy (red, lesion; green, auto-segmented ipsilateral ventral diencephalon; yellow, volume of contact between the lesion and the ipsilateral ventral diencephalon). While many lesions showed bilateral contact with the ventral diencephalon (see Table 2), for clarity, only the diencephalon ipsilateral to the lesion (and thus with greater lesion contact) is shown.

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(SmartFrame). This strategy allows for multiple passes with minimal error in one setting, without the need for transporting the patient between the operating room and radiology suite. Patients experience significant reduction in seizure frequencies and can achieve seizure freedom without residual postoperative complications.

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Disclosures Dr. Larson reports receipt of a private contract from MRI Inter-ventions to assess and provide feedback on technical improve-ments to the ClearPoint surgical implantation system. Dr. Birk reports being supported by a medical research fellowship from the Howard Hughes Medical Institute.

Author ContributionsConception and design: Auguste, Southwell. Acquisition of data: all authors. Analysis and interpretation of data: Auguste, South-well, Sugrue. Drafting the article: Auguste, Southwell, Birk, Sugrue. Critically revising the article: Auguste, Southwell, Lar-son, Starr, Sugrue. Reviewed submitted version of manuscript: Auguste, Southwell, Larson, Starr. Study supervision: Auguste.

CorrespondenceKurtis I. Auguste: University of California, San Francisco, CA. augustek@neurosurg.ucsf.edu.

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