Initial experience with magnetic resonance–guided focused ultrasound stereotactic surgery for central brain lesions in young adults

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  • 1 Department of Brain Sciences, Imperial College London, London, United Kingdom;
  • | 2 Department of Radiology,
  • | 3 Division of Neurosurgery, Brain Institute, and
  • | 4 Division of Neurology, Brain Institute, Nicklaus Children’s Hospital;
  • | 5 Departments of Radiology,
  • | 6 Neurosurgery, and
  • | 7 Neurology, University of Miami Miller School of Medicine; and
  • | 8 Departments of Radiology,
  • | 9 Neurology,
  • | 10 Pediatrics, and
  • | 11 Neurosciences and Biomedical Engineering, Florida International University, Miami, Florida
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OBJECTIVE

Magnetic resonance–guided focused ultrasound (MRgFUS) is an incisionless procedure capable of thermoablation through the focus of multiple acoustic beams. Although MRgFUS is currently approved for the treatment of tremor in adults, its safety and feasibility profile for intracranial lesions in the pediatric and young adult population remains unknown.

METHODS

The long-term outcomes of a prospective single-center, single-arm trial of MRgFUS at Nicklaus Children’s Hospital in Miami, Florida, are presented. Patients 15–22 years of age with centrally located lesions were recruited, clinically consistent with WHO grade I tumors that require surgical intervention. This cohort consisted of 4 patients with hypothalamic hamartoma (HH), and 1 patient with tuberous sclerosis complex harboring a subependymal giant cell astrocytoma (SEGA).

RESULTS

In each case, high-intensity FUS was used to target the intracranial lesion. Real-time MRI was used to monitor the thermoablations. Primary outcomes of interest were tolerability, feasibility, and safety of FUS. The radiographic ablation volume on intra- and postoperative MRI was also assessed. All 5 patients tolerated the procedure without any complications. Successful thermoablation was achieved in 4 of the 5 cases; the calcified SEGA was undertreated due to intratumor calcification, which prevented attainment of the target ablation temperature. The HHs underwent target tissue thermoablations that led to MR signal changes at the treatment site. For the patients harboring HHs, FUS thermoablations occurred without procedure-related complications and led to improvement in seizure control or hypothalamic hyperphagia. All 5 patients were discharged home on postoperative day 1 or 2, without any readmissions. There were no cases of hemorrhage, electrolyte derangement, endocrinopathy, or new neurological deficit in this cohort.

CONCLUSIONS

This experience demonstrates that FUS thermoablation of centrally located brain lesions in adolescents and young adults can be performed safely and that it provides therapeutic benefit for associated symptoms.

ABBREVIATIONS

ASM = antiseizure medication; FUS = focused ultrasound; HH = hypothalamic hamartoma; ICU = intensive care unit; LITT = laser interstitial thermal therapy; MRgFUS = magnetic resonance–guided FUS; POD = postoperative day; SEGA = subependymal giant cell astrocytoma; TSC = tuberous sclerosis complex.

OBJECTIVE

Magnetic resonance–guided focused ultrasound (MRgFUS) is an incisionless procedure capable of thermoablation through the focus of multiple acoustic beams. Although MRgFUS is currently approved for the treatment of tremor in adults, its safety and feasibility profile for intracranial lesions in the pediatric and young adult population remains unknown.

METHODS

The long-term outcomes of a prospective single-center, single-arm trial of MRgFUS at Nicklaus Children’s Hospital in Miami, Florida, are presented. Patients 15–22 years of age with centrally located lesions were recruited, clinically consistent with WHO grade I tumors that require surgical intervention. This cohort consisted of 4 patients with hypothalamic hamartoma (HH), and 1 patient with tuberous sclerosis complex harboring a subependymal giant cell astrocytoma (SEGA).

RESULTS

In each case, high-intensity FUS was used to target the intracranial lesion. Real-time MRI was used to monitor the thermoablations. Primary outcomes of interest were tolerability, feasibility, and safety of FUS. The radiographic ablation volume on intra- and postoperative MRI was also assessed. All 5 patients tolerated the procedure without any complications. Successful thermoablation was achieved in 4 of the 5 cases; the calcified SEGA was undertreated due to intratumor calcification, which prevented attainment of the target ablation temperature. The HHs underwent target tissue thermoablations that led to MR signal changes at the treatment site. For the patients harboring HHs, FUS thermoablations occurred without procedure-related complications and led to improvement in seizure control or hypothalamic hyperphagia. All 5 patients were discharged home on postoperative day 1 or 2, without any readmissions. There were no cases of hemorrhage, electrolyte derangement, endocrinopathy, or new neurological deficit in this cohort.

CONCLUSIONS

This experience demonstrates that FUS thermoablation of centrally located brain lesions in adolescents and young adults can be performed safely and that it provides therapeutic benefit for associated symptoms.

In Brief

MRI-guided high-frequency focused ultrasound can pass through the scalp and skull to precisely heat and destroy tissue in the brain. Currently, this treatment is approved only for use in adults with movement disorders. This study showed that deep brain lesions can be treated safely in subjects aged 15–22 years old. The trial is ongoing and hopes to enroll children as young as 8 years old and lead to an expanded trial to show efficacy.

Transcranial magnetic resonance–guided focused ultrasound (MRgFUS) is capable of conformal target thermoablation without a skin or scalp incision or passing instruments through the brain.1,2 FUS was approved in 2016 by the US FDA for focal thalamotomy to treat refractory essential tremor in adults.3–6 Under an Investigational Device Exemption (no. G160189), our group conducted a pilot study aimed at treating pediatric and young adult brain lesions using the InSightec Exablate 4000 MRgFUS device.

For appropriate candidates, an FUS ablation procedure has many possible advantages over open surgery or MR-guided laser interstitial thermal therapy (LITT). FUS may be a favorable alternative to stereotactic radiosurgery because it does not use ionizing radiation, which conveys advantages, especially in the pediatric population. Additionally, FUS is performed using real-time MR thermography monitoring of the thermoablation process that leads to immediate radiographic changes and clinical results. The current intracranial application of FUS is limited to deep, central brain lesions located within the treatment envelope, where acoustic beams can be optimally focused.7–9

In this pilot study, we aim to demonstrate the safety and feasibility of FUS in children as young as 8 years of age. Patients were recruited in incrementally decreasing age groups to demonstrate safety in young adults and adolescents prior to treating younger children, as agreed upon by the protocol with the US FDA. This case series of 5 patients, the first of whom was treated in 2017, represents our first efforts in the treatment of centrally located benign brain lesions in adolescents and young adults between 15 and 22 years of age. Abstracts of the first 3 cases have been previously presented in conferences.10,11

Methods

Study Population

This study was approved by the WCG IRB. Eligible patients were 8–22 years of age, with a minimum head circumference of 52 cm, who required intervention for a benign brain tumor consistent with WHO grade I pathology. Patients with known or radiographic features of malignant tumors, or lesions that required histopathology confirmation, were excluded. Patients with contraindications to MRI, or who were unable to undergo general anesthesia, were excluded. Participants were recruited in tiers of descending age groups to ensure that the safety profile of the procedure was appraised in a gradual and progressive fashion. Previous craniotomy or surgical intervention was not an exclusion criterion. Adult patients provided informed consent to participate. A full description of inclusion and exclusion criteria can be found online (https://clinicaltrials.gov/ct2/show/NCT03028246).

Outcome Variables

The primary outcomes of the study were FUS treatment safety and feasibility, in addition to radiographic changes in tumor volume in the postoperative period up to 12 months following the procedure. The incidence of treatment-related adverse events was noted, including medical, neurological, endocrinological, and radiographic outcomes. Secondary outcomes focused on the patient’s general physical profile, changes in neurological examination, and visual field testing, in addition to physician and patient impression of global change following FUS.

Surgical Procedure

We followed a modified surgical method, described in detail elsewhere.1,5 Briefly, after induction of general anesthesia, the patient was intubated and intravenous dexamethasone was administered. For patients with epilepsy, the preoperative antiseizure regimen was continued. A Foley catheter and leads for pulse oximetry, core body temperature, and cardiac monitoring were placed. The scalp was razor-shaved, prepped with povidone-iodine, and infused with local anesthetic at the pin sites for placement of a customized CRW frame (Integra LifeSciences). The patient was transported to the MRI machine (General Electric Discovery MR750w 3.0 T) and the head frame was secured to the phased-array device (InSightec Exablate 4000). Cooled, degassed water acoustically coupled the transducer array to the patient’s scalp. A series of high-resolution FLAIR and T2-weighted sequences were obtained and fused to previously acquired CT bone window images. These images were then used for phase correction of each individual operating piezoelectric driver within the 30-cm-diameter, 1024-element hemispherical phased-array ultrasound transducer attached to a four-axis positioner mounted on a modified GE Healthcare patient table. Elements for which the acoustic path crossed a density interface (i.e., frontal air sinuses, intracranial calcifications, or previous burr holes) were turned off to reduce off-target heating. The primary carrier frequency of the system was 650 kHz. Acoustic microphones housed in the transducer array and MR phase thermography were used to detect cavitation events and monitor the thermoablations, respectively. Tracking coils embedded within the transducer housing detected device array movement within the MR space. Image coregistration software detected any movement of the head relative to the device immediately before each sonication event. These safety features reduced the chance of off-target tissue damage.

A series of low-energy sonications using less than 200 W to raise tissue to 40°–45°C were used to detect and, if necessary, correct the alignment of the sonication centroid in 3 cardinal imaging planes (axial, coronal, and sagittal). Once the target and low-energy coalignment were completed, high-energy sonications with acoustic power up to 1500 W were undertaken to create a series of overlapping thermoablations to cover the region of interest. Goal peak temperature at target was 56°–60°C, a range known to create nearly instantaneous tissue coagulation and necrosis12 but reduce the occurrence of inertial cavitation.13

Following FUS ablation, the patient was monitored in the intensive care unit (ICU) for neurological assessment and routine biochemical bloodwork. MRI was performed at the time of FUS and at 3-, 6-, and 12-month intervals postoperatively. As indicated, endocrine laboratory work was performed preoperatively and at 6- and 12-month intervals following FUS ablation.

Results

A total of 5 patients (3 female, 2 male) between 15 and 22 years of age were recruited as of November 2019 and comprise this proof-of-concept trial (Table 1). All patients required treatment of central lesions that had either failed prior resection (3/5) or for which patients declined resection (2/5). Four patients had hypothalamic hamartoma (HH), and 1 patient had a subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC). All patients underwent uncomplicated FUS procedures without new endocrine, electrolyte, metabolic, or neurological sequelae. All 5 patients were discharged home on postoperative day (POD) 1–2 on a 5-day taper of oral dexamethasone with ranitidine. There were no significant adverse events or readmissions to the hospital. One patient experienced a minor drug reaction, manifested as rash and itching, which responded to antihistamine treatment. The length of postoperative clinical follow-up ranged between 13 and 43 months (mean [± SD] 24.8 ± 12.4 months, median 24 months). Radiographically, the patients underwent immediate postoperative MRI, followed by routine imaging at 3, 6, and 12 months postoperatively (Fig. 1).

TABLE 1.

Description of patient demographics, pathologic substrates, clinical variables, and treatment details

VariablePatient No.Mean ± SD (range)
12345
Age (yrs), sex21, F22, F18, M15, F19, M19.2 ± 2.7 (15–22)
Pathologic substrateHHHHHHHHSEGA
Primary concernSeizures, precocious puberty, neurodevelopmental delay, psychiatric disorder NOS (aggression, suicide attempts, self-mutilation)Seizures, neurodevelopmental delay, hypothalamic obesity w/ BMI 44 kg/m2Seizures, precocious puberty, severe autism, neurodevelopmental delayHypothalamic obesity w/ BMI 31 kg/m2, hyperphagiaGrowth of SEGA despite mTOR inhibitor (everolimus) therapy; no seizures or cognitive issues
Prior interventionsEndoscopic rt-frontal transventricular resection of lt-sided HHLITTGamma Knife radiosurgery, LITTNoneNone
Target dimensions/description4.2 × 2.1 × 3.3 mm; lt-sided HH remnant11.8 × 11.5 × 12.2 mm; lt-sided isthmus of HH18.0 × 18.0 × 17.0 mm; rt-sided isthmus of HH10.6 × 10.3 × 7.3 mm; lt-sided stalk of pedunculated HH18.5 × 10.5 × 13.5 mm; rt frontal SEGA
Treated volume6.7 × 5.2 × 6.7 mm; 0.12 cm36.0 × 2.5 × 2.3 mm; 0.04 cm310.0 × 4.0 × 6.0 mm; 0.24 cm35.9 × 3.9 × 4.3 mm; 0.05 cm3NA*0.11 ± 0.09 (0.035–0.24)
Treatment duration, sec133531413931.8 ± 11.2 (13–41)
Max temp, °C545954505654.6 ± 3.3 (50–59)
Max energy, kJ144224505036 ± 16.2 (14–50)
Length of FU, mos433024141324.8 ± 12.4 (13–43)
Changes to primary concernSeizure-free (while on ASMs)95% seizure reduction, from 30 per wk to 1 every 2 mos90% seizure reduction, from 4–5 per wk to 1 every 3 mos13 kg weight loss, sustained & complete resolution of hyperphagiaEnlargement of SEGA on follow-up MRI 13 mos after FUS
Physiological functionHypothalamic dysfunction, hyperprolactinemia w/ galactorrhea, no post-FUS changesHypothalamic dysfunction & obesity, no post-FUS changes Hypothalamic dysfunction, no post-FUS changesNo pre- or post-FUS endocrine or electrolyte abnormalitiesNo pre- or post-FUS endocrine or electrolyte abnormalities
Changes to general behaviorGraduated from school & off risperidone, no subjective behavioral improvementImproved: better mood & quality of lifeImproved: increased focus, concentration, responding more to his primary caregiverImproved: less antagonistic, better mood & quality of lifeUnchanged

FU = follow-up; mTOR = mammalian target of rapamycin; NOS = not otherwise specified.

No appreciable post-FUS treatment MRI changes seen.

FIG. 1.
FIG. 1.

MR images of patients 1–4 with HHs. A–C: Patient 1. Preoperative T2-weighted coronal images of a small left-sided HH remnant (A), intraoperative T2-weighted image demonstrating the area of thermoablation (B), and decreased T2 signal change at 13 months following FUS (C). D–F: Patient 2. Preoperative T2-weighted coronal images of a large left-sided HH remnant (D); intraoperative T2-weighted image demonstrating the thermoablation (E), which was sustained at 12 months following FUS (F). G–I: Patient 3. Preoperative T2-weighted sagittal images showing preexisting cavitation from LITT and large residual HH (G); intraoperative T2-weighted image demonstrating thermoablative cavitation (H), which was sustained at 13 months following FUS (I). J–L: Patient 4. Preoperative T2-weighted coronal images of a large pedunculated HH with narrow left-side neck (J); intraoperative T2-weighted image demonstrating thermoablation and disconnection (K), and decreased T2 signal change at 3 months following FUS (L).

Patient 1: Small Residual Hamartoma

The first patient of the series underwent FUS thermoablation of an HH in early March of 2017. This patient was a 21-year-old, right-handed woman with a history of gelastic seizures and precocious puberty. She had previously undergone a right frontal transventricular endoscopic resection of a Delalande and Fohlen14 type IIIA HH at age 16 years. She was initially seizure-free for 2 years, but then relapsed and experienced almost daily seizures despite an augmented antiseizure regimen consisting of clobazam, topiramate, and lamotrigine. She was also maintained on risperidone for oppositional defiant disorder. The gelastic events did not generalize. MRI revealed a small remnant of the lesion along the left hypothalamic wall. The HH and its vertical gliotic attachment plane immediately adjacent to the hypothalamus were targeted. After the low-energy sonication alignment steps, we initiated a series of high-energy sonications starting approximately 4–5 mm from the wall of the third ventricle and moved the target progressively more medially toward the ependymal surface. At 1.5 mm from the ventricular wall during the penultimate sonication, cavitation was acoustically detected and transducer power shutdown was automatically tripped. We then obtained T2- and susceptibility-weighted imaging sequences to evaluate our progress and exclude an obvious intraparenchymal or intraventricular hemorrhage. Diffusion restriction did not extend completely through the hamartoma-hypothalamic interface, but it was visualized within the more lateral gliotic tissue within the left hypothalamus, suggesting that lethal peak temperatures had been achieved. After waiting for the pre-prescribed cooling period, we completed one final sonication and achieved a peak temperature of 54°C. Postoperative imaging revealed complete coverage of the hamartoma remnant and its gliotic attachment plane with no evidence of off-target restriction or hemorrhage (Fig. 1AC).

The patient awoke uneventfully from anesthesia. As per the protocol, she spent 1 night in the ICU and was then transferred to the floor the next day and discharged on POD 2. Biochemistry panels revealed no postoperative abnormalities. She remained neurologically intact and seizure-free for 9 months following FUS. Endocrine investigations remained normal for 12 months following FUS. Despite counseling, the patient became pregnant shortly after her FUS procedure and self-discontinued her antiseizure medications (ASMs). While off medication, she did experience generalized seizures but gave birth to her child and resumed her ASMs without further seizures.

Patient 2: Large Residual Hamartoma

Patient 2 was a 22-year-old, right-handed woman with seizures since the age of 8 years. She underwent subtotal LITT of a 1.2-cm left-sided HH at age 19 years. After this procedure, her seizure frequency was greatly reduced, but she remained on several ASMs (clobazam, topiramate, lacosamide, and levetiracetam) and was not rendered seizure-free. Repeat LITT and radiosurgery were both considered; due to the significant weight gain associated with her previous LITT procedure, she was not enthusiastic about a repeat invasive procedure. The relative risks and benefits of radiosurgery and FUS were discussed, and FUS was chosen to disconnect the HH via thermal lesioning.

After low-energy sonication alignment steps, a series of overlapping high-energy sonications were performed, beginning posteriorly and superomedially from the laser cavity and progressing anteriorly and inferiorly along the lateral border of the hamartoma. Acoustic cavitation was detected, and the ablations were stopped. Anatomical re-imaging at the end of the ablation demonstrated T2 hyperintensity surrounded by T2 hypointensity with FLAIR signal abnormalities, suggesting tissue lethality near the cystic LITT ablation cavity. There was no evidence of hemorrhage on intraoperative interval imaging (Fig. 1DF).

This patient awoke uneventfully from anesthesia, was neurologically intact, and developed no electrolyte abnormalities. She was discharged home on POD 2 with the same steroid taper. Her endocrine laboratory results remained normal at 12 months following FUS. At 30 months post-procedure, she experienced a 95% seizure reduction in generalized tonic-clonic seizures, and no further gelastic or absence seizures. She also reported subjective improvements in her mood and cognition without weight gain.

Patient 3: Large Residual Hamartoma

Patient 3 was an 18-year-old man with developmental delay, severe autism, seizures, and precocious puberty attributed to HH (Fig. 1GI). He had comorbid left perisylvian polymicrogyria and focal cortical dysplasia. He underwent Gamma Knife radiosurgery at 4 years of age, later followed by LITT, with initial improvement. Unfortunately, his seizures worsened at the onset of puberty, and he experienced 4–5 seizures weekly. He was believed to be a good candidate for FUS thermoablation. The targeted area of interest was a narrow isthmus of tissue connecting the large right-sided pedunculated hamartoma, measuring approximately 4 mm in diameter and 10 mm in length. The initial sonication series aligned the heating centroid at the center of the isthmus. Once the center of heating was identified, incremental sonications were performed, raising the temperature to an average maximum of 54°C. This required a series of 14 progressive sonications with increasing total energy and time. Intraoperative imaging revealed no evidence of hemorrhage or off-target heating. The cooling periods between sonications grew increasingly longer and the last 3 sonications were separated by nearly 30 minutes to allow for scalp/skull cooling. The patient recovered well postoperatively and was discharged home on POD 1 with a steroid taper.

At the 3-month follow-up, the patient experienced a total of 3 hypnopompic seizures, which involved shoulder lifting and head drops. At 24 months following surgery, he continues to experience an overall 90% reduction in seizure frequency, having only 1 seizure every 3 months for the previous 18 months. No endocrinopathy was detected at 12 months following FUS. Subjectively, his primary caregiver reports a sustained improvement in his focus, concentration, and social interactions.

Patient 4: Hypothalamic Hamartoma

Patient 4 was a 15-year-old, right-handed girl with precocious puberty since 6 months of age, and hypothalamic obesity since adolescence. The child did not suffer from seizures; however, she experienced constant hyperphagia and rapid weight gain to a BMI of 31 kg/m2 by her teenage years. She received extensive medical, nutritional, and behavioral therapies at a tertiary institution in London, United Kingdom. Her brain MRI revealed a thin, left-sided isthmus connecting to a large bulbous hamartoma (Fig. 1JL).

Following the pretreatment test dose, the patient underwent lesioning therapy that created an average maximum temperature of 50°C over the 6 × 4 × 4-mm treatment area. There was appreciable hyperintensity on T2-weighted MRI sequences, corresponding with the region of targeted interest. After the procedure, she experienced minor flushing and a transient rash, believed to be a drug reaction that resolved with diphenhydramine. She was discharged home on POD 2 with a steroid taper.

Immediately following FUS, the patient experienced controlled appetite without effort or further behavioral modifications. She lost 13 kg within the first 6 months after FUS and has maintained her weight loss with a lower BMI of 26 kg/m2 over the ensuing year. No endocrinopathy was detected at 12 months after FUS thermoablation. Furthermore, she has been able to enjoy improved self-esteem and social engagements, without any postprocedural complications.

Patient 5: Subependymal Giant Cell Astrocytoma

Patient 5 was a 19-year-old male university student with TSC diagnosed in childhood, and a slowly enlarging midline SEGA (Fig. 2). Although he experienced no seizures, he began receiving everolimus for increasing SEGA size. The patient disliked the medication’s side-effects and wished to discontinue medical treatment.

FIG. 2.
FIG. 2.

Patient 5. Preoperative CT (A) and MR (B) axial images demonstrating a SEGA with calcification. There was known undertreatment that produced no FLAIR signal changes during the FUS procedure (C). At 13 months following FUS, there was interval SEGA growth, demonstrating treatment failure (D).

As per protocol, under general anesthesia, the patient’s head was affixed in a CRW frame, and multiple images were taken to align the sonication centroid. To avoid the largest calcification in the SEGA, the treatment centroid was positioned at the superior border of the tumor and an effort was made to increase both wattage and time to achieve 25,000 kJ. A series of sonications were performed, each interrupted by cavitation events, which resulted in maximal heating to an average temperature of 56°C for only a few seconds. Attempts to move the target treatment area to other regions of the SEGA were unsuccessful in preventing cavitation events and the procedure was stopped. Target ablation temperatures were not reached, resulting in undertreatment. There were no hemorrhage, diffusion restriction, or significant MRI signal changes in the SEGA. The patient recovered uneventfully and was discharged home on POD 2. Follow-up MRI at 13 months post-FUS treatment showed that the SEGA had grown slightly and the everolimus therapy was restarted. This case represents a treatment failure due to cavitation, presumably due to the microscopic calcification within the SEGA.

Discussion

Using the Insightec ExAblate 4000 FUS system, we treated centrally located benign intracranial lesions in 5 adolescent and young adult patients between 15 and 22 years of age (Fig. 3). Consistent with the study design, patients were recruited in tiers of descending age groups, and these 5 patients serve as the trial’s experience with the oldest cohort. The participants included 4 patients with HH and either seizures or hypothalamic hyperphagia, and 1 patient with a SEGA associated with TSC. The FUS procedure was well-tolerated by every patient. No significant adverse events related to the general anesthesia, CRW frame application, or FUS treatment were observed. There were no unexpected radiographic findings of abnormal diffusion restriction, hemorrhage, or off-target heating during the procedure. The patients were all monitored in the ICU for 24 hours and discharged home on POD 1–2. There were no transient or delayed electrolyte abnormalities. The patients with HH were monitored for postoperative endocrinological function for 6–12 months, and no new abnormalities were detected in any patient. Lastly, there were no new postoperative neurological deficits in this cohort.

FIG. 3.
FIG. 3.

Illustration of the FUS procedure for patient 5, involving application of the custom CRW frame and silastic cap (A), planning and target of the pedunculated left-sided HH stalk for disconnection of the lesion (B), and intraoperative thermoablation of the target (C). The blue outline in panel B on the left corresponds to the red areas on the right, which represent the areas of actual heating. Copyright Shannon Zhang (panels A and C). Published with permission.

The only treatment failure in this cohort occurred in the patient with SEGA and TSC. We encountered cavitation events due to internal SEGA calcification during the procedure. Although we avoided the macroscopic calcifications, cavitation events occurred likely due to the microscopic calcium evident in many SEGAs. We decided not to proceed with further thermoablation attempts despite known undertreatment at the time. There was no evidence of thermoablative MRI signal changes on T2-weighted or FLAIR sequences. Follow-up MRI 13 months after FUS demonstrated interval SEGA enlargement. This case, although unsuccessful in preventing SEGA growth, contributed to our understanding of intracranial pathologic substrates that are appropriate for FUS treatment.

In this small series, patients with HH benefited from FUS and were able to enjoy not only improved seizure frequency or weight loss, but also attenuation of neurocognitive and behavioral issues often associated with this pathology. This differs substantially from cognitive and endocrinological complications that can accompany endoscopic and open resections for this type of tumor. In 3 of the 4 patients with HH and previous surgical management, our own resection and LITT procedures resulted in transient or permanent weight gain and behavioral impairment in this cohort. The complications associated with their surgical and LITT procedures partially led to the patients’ decisions to pursue an alternative approach to repeat surgery.

Our group, as well as many others, have used radiosurgery to control gelastic seizures associated with HH.15–20 We offered our second patient the option of Gamma Knife radiosurgery. One potential advantage of transcranial FUS over radiosurgery is the immediacy of the clinical effect. Rapid seizure control is obviously important clinically, especially if encephalopathy is associated with frequent gelastic events. Using FUS, unlike with radiosurgery, there is no latent period of several weeks to months for behavioral or electrographic verification that the focus has been ablated. In the case of poor seizure control following radiosurgery, it is often uncertain when treatment failure has occurred and when to pursue repeat surgery with another modality. Theoretically, in the case of failed FUS, a repeat procedure may be undertaken immediately. A final advantage of FUS over conventional radiosurgery in childhood may be the avoidance of ionizing radiation to the developing brain.

During the procedure, MRI signal changes from the thermoablative sonications were well-visualized using gradient echo thermal mapping techniques and T2-weighted sequences. Diffusion-weighted imaging and FLAIR sequences also demonstrated signal changes. Unlike permanent cavitations created by LITT, thermoablative changes associated with FUS sonications were often only transiently visualized on the immediate postoperative MRI. The signal changes on follow-up MRI performed months after FUS were less perceptible compared to the intraoperative imaging. Of note, 2 of our cases showed consistent T2 hyperintensity on follow-up MRI, while 2 other cases demonstrated resolution of the T2-weighted and FLAIR signal changes over time. In this limited sample, MR signal evolution does not appear to correlate with the clinical outcome of FUS. The seizure and hyperphagia benefits of FUS have persisted for all 4 successfully treated HH patients, despite regression in the MRI changes over the ensuing months after thermoablation.

Conclusions

The 5 cases illustrated in this paper demonstrate that FUS appears feasible and safe for the treatment of benign central intracranial lesions and contributes to the current literature on the role of FUS ablation for movement disorders, psychiatric conditions, and epilepsy.7 Further work is necessary to refine optimal patient selection criteria, determine the long-term therapeutic durability of this approach, and demonstrate safety in younger children. As part of the tiered age-group recruitment process, this pilot trial will continue to enroll progressively younger patients to definitively demonstrate the safety of FUS in children.

Dedication

To the memory of our friend and colleague Dr. Sanjiv Bhatia (1958–2018). As Professor of Neurosurgery and Chief of Surgery at Nicklaus Children’s Hospital, Sanjiv had the inaugural honor to launch the initial sonication alignment sequences for our first patient on March 7, 2017. We miss him dearly.

Acknowledgments

The Focused Ultrasound Foundation (grant no. FUS 530 to T.S.T.) funded this trial (clinicaltrials.gov identifier no. NCT03028246). The device manufacturer, InSightec Ltd., is our FDA regulatory sponsor but we have not requested any commercial financial support for this study. We thank Mor Dayan, BSc, and Jacob Chen, BSc (InSightec Ltd.), for the technical support of these cases; Shannon Zhang, MD, who provided the medical illustrations in Figure 3; and Patricia Dean, ARNP, MSN, and Aileen Rodriguez, ARNP, BSc, clinical coordinators for the comprehensive epilepsy center at Nicklaus Children’s Hospital, who kept our focus on the care of the whole child.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Ragheb, Tierney, Alavian, Altman, Bhatia, Jayakar, Miller. Acquisition of data: all authors. Analysis and interpretation of data: all authors. Drafting the article: all authors. Critically revising the article: Ragheb, Tierney, Alavian, Altman, Duchowny, Jayakar, Resnick, Wang, Miller. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Ragheb. Statistical analysis: Tierney, Alavian, Altman, Bhatia. Administrative/technical/material support: all authors. Study supervision: Ragheb, Tierney, Alavian, Altman, Bhatia, Miller.

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    Tierney T, Miller I, Dean P, Altman N, Jayakar P, Bhatia S. Focused ultrasound surgery for hypothalamic hamartoma: case report from a tumor trial. In: Annual Meeting of the American Epilepsy Society; December 1–5, 2017; Washington, DC.Accessed October 22, 2021. https://cms.aesnet.org/abstractslisting/focused-ultrasound-surgery-for-hypothalamic-hamartoma--case-report-from-a-tumor-trial

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  • 12

    Sapareto SA, Dewey WC. Thermal dose determination in cancer therapy. Int J Radiat Oncol Biol Phys. 1984;10(6):787800.

  • 13

    Arvanitis CD, McDannold N. Integrated ultrasound and magnetic resonance imaging for simultaneous temperature and cavitation monitoring during focused ultrasound therapies. Med Phys. 2013;40(11):112901.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Delalande O, Fohlen M. Disconnecting surgical treatment of hypothalamic hamartoma in children and adults with refractory epilepsy and proposal of a new classification. Neurol Med Chir (Tokyo). 2003;43(2):6168.

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    • Search Google Scholar
    • Export Citation
  • 15

    Butragueño Laiseca L, Oikonomopoulou N, Miranda Herrero MC, Barredo Valderrama E, Vázquez López M, Jiménez de Domingo A, et al. Neurological complications after gamma-knife radiosurgery for hypothalamic hamartoma. Eur J Paediatr Neurol. 2016;20(5):745749.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Abla AA, Shetter AG, Chang SW, Wait SD, Brachman DG, Ng YT, et al. Gamma Knife surgery for hypothalamic hamartomas and epilepsy: patient selection and outcomes. J Neurosurg. 2010;113(suppl):207214.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Mathieu D, Kondziolka D, Niranjan A, Flickinger J, Lunsford LD. Gamma knife radiosurgery for refractory epilepsy caused by hypothalamic hamartomas. Stereotact Funct Neurosurg. 2006;84(2-3):8287.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Régis J, Lagmari M, Carron R, Hayashi M, McGonigal A, Daquin G, et al. Safety and efficacy of Gamma Knife radiosurgery in hypothalamic hamartomas with severe epilepsies: a prospective trial in 48 patients and review of the literature. Epilepsia. 2017;58(suppl 2):6071.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Selch MT, Gorgulho A, Mattozo C, Solberg TD, Cabatan-Awang C, DeSalles AA. Linear accelerator stereotactic radiosurgery for the treatment of gelastic seizures due to hypothalamic hamartoma. Minim Invasive Neurosurg. 2005;48(5):310314.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Dunoyer C, Ragheb J, Resnick T, Alvarez L, Jayakar P, Altman N, et al. The use of stereotactic radiosurgery to treat intractable childhood partial epilepsy. Epilepsia. 2002;43(3):292300.

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Schematics of transseptal interforniceal resection of a superiorly recessed colloid cyst. ©Mark Souweidane, published with permission. See the article by Tosi et al. (pp 813–819).

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    MR images of patients 1–4 with HHs. A–C: Patient 1. Preoperative T2-weighted coronal images of a small left-sided HH remnant (A), intraoperative T2-weighted image demonstrating the area of thermoablation (B), and decreased T2 signal change at 13 months following FUS (C). D–F: Patient 2. Preoperative T2-weighted coronal images of a large left-sided HH remnant (D); intraoperative T2-weighted image demonstrating the thermoablation (E), which was sustained at 12 months following FUS (F). G–I: Patient 3. Preoperative T2-weighted sagittal images showing preexisting cavitation from LITT and large residual HH (G); intraoperative T2-weighted image demonstrating thermoablative cavitation (H), which was sustained at 13 months following FUS (I). J–L: Patient 4. Preoperative T2-weighted coronal images of a large pedunculated HH with narrow left-side neck (J); intraoperative T2-weighted image demonstrating thermoablation and disconnection (K), and decreased T2 signal change at 3 months following FUS (L).

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    Patient 5. Preoperative CT (A) and MR (B) axial images demonstrating a SEGA with calcification. There was known undertreatment that produced no FLAIR signal changes during the FUS procedure (C). At 13 months following FUS, there was interval SEGA growth, demonstrating treatment failure (D).

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    Illustration of the FUS procedure for patient 5, involving application of the custom CRW frame and silastic cap (A), planning and target of the pedunculated left-sided HH stalk for disconnection of the lesion (B), and intraoperative thermoablation of the target (C). The blue outline in panel B on the left corresponds to the red areas on the right, which represent the areas of actual heating. Copyright Shannon Zhang (panels A and C). Published with permission.

  • 1

    Field WM, Selvakumar T, Hayes MT, Tierney TS. Treating patients with movement disorders using MRI-guided focused ultrasound: recent developments and challenges. Res Rep Focus Ultrasound. 2015;3:59.

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  • 2

    Lele PP. A simple method for production of trackless focal lesions with focused ultrasound: physical factors. J Physiol. 1962;160(3):494512.

  • 3

    Ahmed H, Field W, Hayes MT, Lopez WO, McDannold N, Mukundan S Jr, Tierney TS. Evolution of movement disorders surgery leading to contemporary focused ultrasound therapy for tremor. Magn Reson Imaging Clin N Am. 2015;23(4):515522.

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  • 4

    Elias WJ, Huss D, Voss T, Loomba J, Khaled M, Zadicario E, et al. A pilot study of focused ultrasound thalamotomy for essential tremor. N Engl J Med. 2013;369(7):640648.

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    • Search Google Scholar
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  • 5

    Elias WJ, Lipsman N, Ondo WG, Ghanouni P, Kim YG, Lee W, et al. A randomized trial of focused ultrasound thalamotomy for essential tremor. N Engl J Med. 2016;375(8):730739.

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    • Export Citation
  • 6

    Hynynen K, Jolesz FA. Demonstration of potential noninvasive ultrasound brain therapy through an intact skull. Ultrasound Med Biol. 1998;24(2):275283.

  • 7

    Franzini A, Moosa S, Prada F, Elias WJ. Ultrasound ablation in neurosurgery: current clinical applications and future perspectives. Neurosurgery. 2020;87(1):110.

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  • 8

    Meng Y, Hynynen K, Lipsman N. Applications of focused ultrasound in the brain: from thermoablation to drug delivery. Nat Rev Neurol. 2021;17(1):722.

  • 9

    The University of Virginia Darden School of Business. Focused Ultrasound Foundation. Brain mini workshop: treatment envelope expansion; June 17–18, 2013;. Charlottesville, VA.Accessed October 22, 2021.https://www.fusfoundation.org/images/pdf/2013-Brain-Workshop-WP.pdf

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  • 10

    Tierney T, Alavian K, Altman N, Miller I, Ragheb J. Focused ultrasound surgery for subcortical epilepsy. In: 18th Biennial Meeting of the World Society for Stereotactic and Functional Neurosurgery.Stereotact Funct Neurosurg. 2019;97(suppl 1):58.

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    • Export Citation
  • 11

    Tierney T, Miller I, Dean P, Altman N, Jayakar P, Bhatia S. Focused ultrasound surgery for hypothalamic hamartoma: case report from a tumor trial. In: Annual Meeting of the American Epilepsy Society; December 1–5, 2017; Washington, DC.Accessed October 22, 2021. https://cms.aesnet.org/abstractslisting/focused-ultrasound-surgery-for-hypothalamic-hamartoma--case-report-from-a-tumor-trial

    • Search Google Scholar
    • Export Citation
  • 12

    Sapareto SA, Dewey WC. Thermal dose determination in cancer therapy. Int J Radiat Oncol Biol Phys. 1984;10(6):787800.

  • 13

    Arvanitis CD, McDannold N. Integrated ultrasound and magnetic resonance imaging for simultaneous temperature and cavitation monitoring during focused ultrasound therapies. Med Phys. 2013;40(11):112901.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Delalande O, Fohlen M. Disconnecting surgical treatment of hypothalamic hamartoma in children and adults with refractory epilepsy and proposal of a new classification. Neurol Med Chir (Tokyo). 2003;43(2):6168.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Butragueño Laiseca L, Oikonomopoulou N, Miranda Herrero MC, Barredo Valderrama E, Vázquez López M, Jiménez de Domingo A, et al. Neurological complications after gamma-knife radiosurgery for hypothalamic hamartoma. Eur J Paediatr Neurol. 2016;20(5):745749.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Abla AA, Shetter AG, Chang SW, Wait SD, Brachman DG, Ng YT, et al. Gamma Knife surgery for hypothalamic hamartomas and epilepsy: patient selection and outcomes. J Neurosurg. 2010;113(suppl):207214.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Mathieu D, Kondziolka D, Niranjan A, Flickinger J, Lunsford LD. Gamma knife radiosurgery for refractory epilepsy caused by hypothalamic hamartomas. Stereotact Funct Neurosurg. 2006;84(2-3):8287.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Régis J, Lagmari M, Carron R, Hayashi M, McGonigal A, Daquin G, et al. Safety and efficacy of Gamma Knife radiosurgery in hypothalamic hamartomas with severe epilepsies: a prospective trial in 48 patients and review of the literature. Epilepsia. 2017;58(suppl 2):6071.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Selch MT, Gorgulho A, Mattozo C, Solberg TD, Cabatan-Awang C, DeSalles AA. Linear accelerator stereotactic radiosurgery for the treatment of gelastic seizures due to hypothalamic hamartoma. Minim Invasive Neurosurg. 2005;48(5):310314.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Dunoyer C, Ragheb J, Resnick T, Alvarez L, Jayakar P, Altman N, et al. The use of stereotactic radiosurgery to treat intractable childhood partial epilepsy. Epilepsia. 2002;43(3):292300.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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