Hypothalamic hamartoma: open surgery versus endoscopic surgery versus stereotactic radiosurgery versus stereotactic ablation (MR-guided laser ablation/Radiofrequency ablation) versus MRFUS

Introduction

Hypothalamic hamartomas (HH) are rare intrinsically epileptogenic lesions that affect 0.5 in 100,000 children . They are composed of heterotopic neuronal and glial cells attached to the hypothalamus, typically provoking gelastic seizures through connections to limbic pathways . Additional seizure types can arise from secondary epileptogenesis involving extra-hypothalamic regions . Epilepsy is refractory to antiseizure medications (ASMs) in most patients with HH and over half develop a progressive neurodevelopmental decline characterized by major cognitive and behavioral disturbances . Mutations in the Sonic hedgehog pathway have been described in nonsyndromic patients and GLI3 pathway mutations occur in Pallister-Hall syndrome, which is characterized by HH along with additional features, such as polydactyly or syndactyly, bifid epiglottis, imperforate anus and renal malformations .

Since ASMs are generally ineffective in controlling HH-related epilepsy, surgery is the mainstay of treatment. Resection or complete disconnection of the hamartoma from the pathways of seizure propagation (e.g., mammillothalamic tracts, fornices, hypothalamus) has shown, despite significant associated risks, to provide long-lasting control of the epileptic syndrome as well as improvement in behavior and cessation of cognitive decline . Several surgical procedures have been proposed as treatment options to achieve seizure control, each with inherent advantages, disadvantages and risk-benefit profiles.

Classification

The symptoms and severity of the seizure disorder and encephalopathy associated with HH depend, in part, on their dimensions (e.g., size, localization, type of attachment, and degree of hypothalamic displacement). Typically, precocious puberty is observed in cases with the more ventrally located pedunculated type, while the epileptic syndrome and behavioral issues originate from the dorsal sessile type, which is connected to the dorsal hypothalamus and mammillary bodies . Consequently, several classifications of HHs have been described based on the size, extension, and type of attachment to the hypothalamus .

Valdueza et al. developed a classification system based on topographic and clinical data and correlated the surgical risk with the subtype, that is, pedunculated (Types 1a and 1b) or sessile (Types 2a and 2b). Arita et al. later described a dichotomous classification of these lesions into a parahypothalamic type and an intrahypothalamic type . In the parahypothalamic type, the HH is attached to the floor of the third ventricle or on a peduncle (the latter is often associated with precocious puberty). In the intrahypothalamic type, the HH is surrounded by the hypothalamus, distorting the third ventricle (more commonly associated with gelastic seizures, with or without precocious puberty, developmental delay, and behavioral problems). Recently, Choi et al. introduced their own system based on HH size and location, suggesting different approaches for these types. An HH smaller than 20 mm is considered small, while one that is larger than 20 mm is considered giant (Type IV). Additional classifications include midline (Type I), lateral (Type II), or intraventricular (Type III), based on HH’s location relative to the hypothalamus and third ventricle. While more complex classifications have been proposed , Delalande’s classification into four subtypes remains the most used worldwide and is summarized in Table 10.1 . These classification systems are crucial for understanding the topography of a given HH and determining the appropriate surgical approach. The feasibility of complete removal is correlated with the degree of attachment to various hypothalamic structures, including the mammillary bodies and the tuber cinereum . Recently, resting-state functional magnetic resonance imaging has been used to map and localize the seizure onset zone within the HH for targeted ablation, resulting in an improvement of seizure freedom rates from 45% to 92% .

Table 10.1

Delalande classification for hypothalamic hamartomas based on its plane of insertion in the hypothalamus .

Delalande type	Description
I	Small HH with a horizontal implantation plane and may be lateralized to one side
II	Small HH with a vertical insertion plane and intraventricular location
III	Combination of types I and II
IV	Giant HH that doesn’t fit the criteria of other subtypes

Disease course and secondary epileptogenesis

A clear understanding of the natural history of the underlying epileptic networks in patients with HH are crucial for surgical decision-making. While it is widely acknowledged that HH is inherently epileptogenic and should be the primary therapeutic target in most cases, there is compelling evidence suggesting that the epileptic network undergoes progressive remodeling and expansion over time. Seizure semiology evolves to encompass nongelastic seizures as extra-hypothalamic neocortical regions, which are anatomically and functionally connected to the HH, become incorporated into the epileptic network. Drug-resistant epilepsy (DRE) associated with HH represents a prototypical mode of secondary epileptogenesis. In this process, neocortical regions and normal neuronal networks, persistently exposed to synchronous ictal and interictal epileptic activity, become epileptic through kindling mechanisms . All three stages of secondary epileptogenesis as described by Morell, have been observed in HH patients undergoing stereoelectroencephalography (SEEG). In the initial/dependent stage of secondary epileptogenesis, the epileptic discharges identified in extra-hypothalamic nodes are driven by the hypothalamic focus. These patients are likely to achieve immediate seizure freedom following complete removal/disconnection of the HH . This stage was recently elucidated using computational methodology in a case involving a 9-year-old undergoing SEEG-guided radiofrequency ablation thermocoagulation (RFTC) . As the disease progresses to the second/intermediate stage of secondary epileptogenesis, independent interictal, and eventually ictal epileptic activities develop in extra-hypothalamic neocortical network nodes (e.g., amygdalo-hippocampal complex, cingulate, etc.) . A recent study involving 15 cases of HH-related DRE undergoing SEEG found that 33% ( n =3/9) of patients exhibited independent ictal discharges involving the amygdalo-hippocampal complex . Thus, while secondary epileptogenesis beyond the HH is likely an unfavorable prognostic indicator, some patients with this “intermediate-stage” of secondary epileptogenesis may achieve seizure freedom. In this phase, although seizures may persist following ablation/disconnection of the HH, they will eventually subside and vanish. In contrast, seizures will endure in patients undergoing HH ablation if they have reached the third (independent) stage of secondary epileptogenesis, aligning with prior reports that have shown improved seizure outcomes following temporal lobectomy in cases where targeting the HH has failed .

Surgical treatment

Surgical treatment of HHs is extremely challenging due to its deep localization surrounded by critical brain structures (hypothalamus, pituitary stalk, mammillary bodies and mamillo-thalamic tract, fornices, cerebral peduncle, optic tracts, oculomotor nerve) and major vessels . Multiple surgical approaches have been described for the resection or disconnection of HHs. Surgical options currently available include open surgery through a transcallosal or pterional approach, transventricular endoscopic approach, stereotactic radiosurgery (SRS), interstitial radiosurgery, and minimally invasive stereotactic ablative techniques, such as RFTC, and MR-guided laser interstitial thermal therapy (MRgLITT). More recently, MR-focused ultrasound (MRgFUS) has emerged as a noninvasive ablative option. Each of these surgical techniques carries inherent risk profiles, including the potential for debilitating complications resulting from injury to structures encountered either during the approach or adjacent to the HH. The intricate anatomy in the area poses significant risks, such as lacunar stroke of the thalamic or internal capsule, cognitive impairment due to damage to the mammillary bodies or fornixes, neurological injuries such as third nerve palsies, hypothalamic injury leading to hyperphagia, and neuro-endocrine deficits (e.g., hypopituitarism) resulting from infundibulum/stalk injury . There are currently no guidelines for this procedure and controversy exists regarding the relative selection of a given surgical approach for a particular patient.

Open surgery

In 1967, Northfield and Russell carried out the first successful removal of an HH-causing central precocious puberty (CPP). In 1969, Paillas et al. described the clinical, radiographic, and histological findings in a patient who underwent microsurgical excision of an HH. Since these pioneering reports, a wide variety of open surgical approaches for HHs have emerged and been reported in the literature . Broadly speaking, microsurgical approaches can be divided into those that reach the diencephalic mass from below and those from above .

Initial surgical approaches used an inferior trajectory to reach the HH. These approaches include the midline transbasal or subfrontal approaches or the standard antero-lateral pterional approach and its orbito-zygomatic or supraorbital variations . While the antero-lateral approaches provide direct access, they have limitations, including a blindspot of the ipsilateral third ventricle and hypothalamus. In contrast, midline approaches provide superior bilateral exposure of the third ventricle. The subtemporal approach is particularly well suited to HHs with a significant prepontine component. However, while these approaches are appropriate for Delalande Type I HHs, these inferior approaches have difficulties reaching lesions higher up inside the third ventricle (e.g., Delalande Types II and IV) . Over time, superior approaches have been described trying to expand the exposure of intraventricular hamartomas .

Pterional approach

The pterional approach was used in the initial clinical series reporting microsurgical resection of HHs . This approach offers the most direct and short path to the suprasellar cistern while providing early identification and preservation of critical structures, such as the arteries of the anterior circulation, the ipsilateral optic apparatus, and excellent exposure of the HH within the extra-ventricular suprasellar region. However, the working corridor between the third cranial nerve, optic nerve and carotid artery is narrow, and access the third ventricle and intraventricular HH through the lamina terminalis is challenging. ( Fig. 10.1 ). Identifying the margins of the hamartoma is also challenging, particularly if it is broadly attached to the hypothalamus or mammillary bodies. Although the reported seizure control is higher than 90% in some series , the morbidity is important and includes risk to the surrounding neurological structures, transient third nerve palsy, lenticulostriate injury and thalamo-capsular infarcts, neurohypophysis injury with postoperative central diabetes insipidus, and hyperphagia from hypothalamic injury . On the contrary, a pterional approach seems best for targeting pedunculated HHs that cause CPP. Even a partial resection has been shown to relieve the related endocrinological disturbances . Hamlat et al. recently described a transamygdala extension of a transtemporal, transchoroidal approach for radical resection of suprasellar, retrochiasmatic, diencephalomesencephalic lesions, including in HH. This approach may be valuable for large HHs occupying the interpeduncular cistern .

Transcallosal approach

In 2001, Rosenfeld et al. first reported an anterior transcallosal, transseptal, interforniceal approach to remove HHs through the third ventricle . Their approach consisted of a small (15–20 mm in length) postgenual callosotomy followed by mid-line transseptal dissection and separation of the fornices, which allowed entry through the roof of the third ventricle with subsequent removal and/or disconnection of the HH ( Fig. 10.2 ) . This technique allows adequate debulking or disconnection of the HH from an intraventricular view reducing the risk of injury to the mammillary bodies, pituitary stalk, and optic chiasm . The incidence of cerebral infarction and oculomotor nerve palsy seems to be reduced by avoiding manipulation of the neurovascular structures in the suprasellar cistern and interpeduncular fossa. This approach can be advantageous in HHs Delalande Types II and III.

However, there is an inherent risk of septal, forniceal, or mammillary body injury resulting in short-term memory problems which are transient in 58% and permanent in 8% of patients . A modified subchoroidal approach has been described to avoid splitting the fornices and to decrease the risk of postsurgical memory deficits .

Endoscopic surgery

Endoscopic techniques with resection and/or disconnection of the hamartoma have been employed in an attempt to minimize complications while maintaining favorable efficacy . The endoscopic transventricular approach was first reported by Akai et al. in 2002 using an endoscope for transventricular biopsy of an HH in a 5-year-old girl with gelastic seizures. The hamartoma was then treated with SRS using a linear accelerator (LINAC). Later, in 2006, the Barrow group published their results using endoscopy for HHs . In their series, 44 patients underwent an endoscopic transventricular approach with frameless stereotaxy for resection of the HHs. Of the 14 patients (31.8%) who had complete resection, 13 became seizure-free following surgery. The remaining 30 patients underwent an endoscopic disconnection rather than resection of the HH.

Not all patients with HHs are ideal candidates for endoscopic resection . It is imperative that a space between the bottom of the hamartoma and the pial surface of the interpeduncular cistern exists. The mass must not be under the optic tract. There must also be minimal working space within the third ventricle for forceps and coagulator maneuvering, as well as a definite interface to achieve a successful endoscopic disconnection. A working distance of at least 6 mm should be present between the top of the HH and the roof of the third ventricle. This approach should be considered for small HHs with a unilateral attachment to the hypothalamic wall .

Most epileptiform discharges in HHs arise from the broad attachment side . Delalande and Fohlen hypothesized that disconnection (without excision) of the HH could be sufficient to isolate the intrinsically epileptogenic lesion and thereby result in good seizure outcomes . In their recently published series of 112 patients under the age of 19, 57.1% obtained seizure freedom with low morbidity (8.3%) . Moreover, most patients showed a marked improvement in social and behavioral outcomes. Surgical complications were less in comparison to microsurgical resection, although it included short memory deficit in five patients, oculomotor palsy in 12 (nine transient and three with the ongoing neurological deficit at last follow-up), hemiplegia in four patients due to focal thalamic or mesencephalic infarct and/or hemorrhage, postoperative infection in four (two meningitis, one chest infection, and one lymphangitis), hormonal disturbances in three (mainly diabetes insipidus), and status epilepticus in one patient . These results have been reproduced by other groups using variations of the transventricular endoscopic disconnection technique .

Stereotactic radiosurgery

SRS, first introduced by Lars Leksell in 1951, is a noninvasive incisionless radiosurgical technique that employs highly precise radiation beams, stereotactically focused in a specific area of the brain to induce a desired biological effect . The largest published experience on SRS for HH-causing epilepsy comes from the Marseille group employing Gamma Knife radiosurgery (GKS) . GKS utilizes 192 cobalt-90 sources focused on a single point. Prior to treatment, the lesion is meticulously delineated on preoperative brain MRI conducted under stereotaxic conditions with a frame secured on the patient’s head. An example of an SRS preoperative plan is shown in Fig. 10.3 .

The efficacy of SRS closely mirrors that of open and endoscopic surgery. Overall, 68.8% of cases with Regis classes I–IV HH treated by GKS attained Engel class I (39.6%) or II (29.2%) with a median follow-up of 6 years . Of these, 60% required two treatments to obtain seizure freedom . Furthermore, global psychiatric comorbidity was considered cured in 28% of the cases and improved in 56%. Cognitive comorbidities also showed improvement . It’s important to note that giant HH (grades V–VI per Régis classification) did not exhibit worthwhile improvement with GKS and should not be considered an indication for this procedure . A summary of the Régis classification is provided in Table 10.2 .

Table 10.2

Topological classification of hypothalamic hamartomas by Régis .

Régis type	Description
I	Small HH located inside the hypothalamus extending more or less into the third ventricle
II	Small HH manly within the third ventricle
III	Small HH located in the floor of the third ventricle
IV	Sessile lesion within the interpeduncular cistern
V	Pedunculated HH within the interpeduncular cistern, connected to the inferior aspect of the hypothalamus by a clear stalk
VI	Giant HH
Mixed	HH that can involve the hypothalamus, the third ventricle, the floor of the third ventricle and/or the interpeduncular cistern without being giant