Hypothalamic Hamartoma and Endocrinopathy: A Neurosurgeon's Perspective
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.287681
Source of Support: None, Conflict of Interest: None
Keywords: Central precocious puberty, drug-refractory epilepsy, gelastic seizures, gonadotrophins, radiofrequency ablation, robot
Hypothalamic hamartomas (HH) are rare developmental malformations often arising from the floor of the hypothalamus involving either tuber cinereum or mammillary bodies. These lesions occur most often sporadically and occasionally as a part of Pallister–Hall Syndrome (PHS) in approximately 10% of cases. The incidence of HH in the literature as per the Swedish study is 0.0005% with a slight male predominance. Another population-based study from Israel documented an incidence of one per 6, 25, 000 cases. HH express themselves, either featuring with central precocious puberty (CPP) in 1/3rd, drug refractory epilepsy (DRE) in up to 40%, or a mixture of both in the remaining 1/3rd patients. Historically, the management of HH irrespective of its presentation was solely limited to surgical excision. However, with the advent of gonadotrophin-releasing hormone (GnRH) analogs, medical management currently forms the most effective therapy with excellent results in HH patients presenting exclusively with CPP. Apart from CPP, these lesions also present with multiple seizure types with the gelastic semiology being characteristic. Nearly all the patients suffering from epilepsy are resistant to medication; hence, surgery offers the only chance of cure in this subset of patients. Therefore, approximately 2/3rd patients of HH suffering from CPP and DRE, either in combination or DRE alone, require neurosurgical care.,,,
A prospective observational study including 16 patients diagnosed with HH, managed at our institute in the neurosurgery department, over a period of 5 years (2014-2019). All these patients were evaluated with 3 Tesla magnetic resonance imaging (MRI) brain, a complete hormonal workup, and video electro-encephalography (VEEG) as a part of the evaluation for epilepsy. Most often, these investigations were sufficient for the diagnosis and management of HH. The hamartomas were classified as per Delalande's grading system, based on the MRI of the brain. Positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) were rarely performed, especially in cases with a diagnostic dilemma related to epilepsy. The hormonal workup was performed both in the pre and postoperative periods. The outcomes in terms of seizure freedom, requirement for hormone supplementation, and complications were recorded during the follow-up at regular intervals. All the data were retrieved from the case files, computerized patient record system (CPRS), and picture archiving and communication systems (PACS) and are shown in [Table 1].
The MRI images are transferred from the PACS into the ROSA platform and multiple trajectories and lesion points are planned a day prior to the surgery. The lesions are so planned that the hamartoma is effectively disconnected from the hypothalamic attachment and also to ablate the hamartomatous tissue to the maximal possible extent [Figure 1].
All the patients underwent robotic-guided radiofrequency ablation (RFA) of the hamartoma, a technique already described from our institution. The prerequisites for performing the procedure are [Figure 1]:
In brief, the lesioning is performed with the patient under general anesthesia. The patient is supine, head is fixed in slight flexion with Mayfield clamp. Following robotic registration, the lesioning is commenced by inserting the RFA probe, through multiple twist drill holes (2.5 mm drill bit) as per the number of planned trajectories. Once the probe is inserted to the precalculated distance by the ROSA software, an O-arm spin is performed prior performing the first lesion. The O-arm data acquired are then superimposed with the preplanned robotic trajectory to confirm the position of the probe. Once the probe position is deemed satisfactory, an “ablative disconnection” of the hamartoma is created using the radiofrequency pulse generator. We use the protocol of 74 °C temperature for 60 s to achieve the tissue ablation.
All patients were monitored in the intensive care unit (ICU) rigorously for any signs of dyselectrolytemia like diabetes insipidus (DI) and syndrome of inappropriate antidiuretic hormone (SIADH). The fluid and electrolyte balance was maintained in case of any derangement by appropriate therapy. Serum hormonal levels were repeated 72 h, two weeks and one month after surgery. Repeat MRI was performed in patients with recurrence or persistence of seizures at least three months following surgery, to look for a residual connection.
Among the 16 patients with HH managed at our center, there were 11 male and 5 female children. The age ranged between 7 months and 18 years, with a mean of 7.18 years. All the patients suffered from DRE and were on multiple antiepileptic drugs (AEDs). In addition, four patients suffered from CPP; one was a female and three male children. One of these male child harbored HH as a part of PHS with polysyndactyly in both the hands and feet, along with bifid epiglottis [Figure 2]. Majority of the hamartomas were: Delalande's grade-3 (n = 11), grade-4 (n = 2), and one each in grade-1 and grade-2 [Figure 3], [Figure 4], [Figure 5], [Figure 6]. Preoperative hormonal workup was abnormal in all the four patients presenting with CPP. One of the three male children was aged two years with Tanners stage-III on sexual maturity rating. This child had increased serum luteinizing hormone (LH) and FSH levels. The other two male and female children were in Tanners stage II and III, respectively, with elevated serum LH/FSH levels. The preoperative hormonal workup was within normal limits in the rest of the 12 patients [Table 1].
Overall 12 (75%) among 16 patients achieved ILAE Class-1 seizure outcomes, following first lesioning. Out of the four patients with persistent seizures, three were in Class-III and one patient continued to be in Class-IV, after a brief seizure-free interval. All the four patients underwent repeat RFA with one patient achieving seizure freedom and the remaining three continued to have recurrent seizures requiring a third RFA. Only two patients underwent 3rd RFA and attained Class-1 seizure freedom at the last follow-up 12 and 14 months. The remaining one patient is awaiting a 3rd RFA. The seizure outcomes achieved at the end of 3 RFAs were ILAE Class-1 in 93.75% cases with a mean follow-up of 15 months (Range: 9–36 months) [Table 2] and [Figure 7], [Figure 8].
The basal serum LH reduced significantly to the prepubertal level (<0.3 mIU/mL) in three patients and marginal decrease was noted in one patient with CPP [Table 3]. Four patients developed DI in the immediate postoperative period; two of these recovered spontaneously without any additional therapy. The remaining two patients developed permanent DI requiring regular desmopressin nasal spray. Two patients needed cortisol supplementation owing to persistent low serum cortisol in the postoperative period. One patient developed thyroid hormone deficiency following repeat surgery and hence was started on thyroxin replacement. Two patients developed postoperative weight gain of more than 5 kg within a year after surgery. No new deficits were encountered in the remaining patients [Table 2].
Nonhormonal complications included transient visual deterioration in one patient, persistent fever of central origin without any evidence of sepsis and prolonged drowsiness was encountered in the same patient, which resolved spontaneously over a period of 1 month [Table 2].
Hypothalamic hamartomas are benign developmental lesions comprising of dysplastic neurons, interspersed with glial tissue. The only and most common endocrine abnormality detected in these lesions is the GnRH hypersecretion at an inappropriate age. Rest of the other hormonal secretion often remains unaffected, with unusually rare exceptions where growth hormone hypersecretion is noted. Molecular studies have revealed the cell groups within these lesions are comprised of GnRH granules. It is also noted that certain cells also stain positively for some proteins like TGF-Alfa (Transforming Growth Factor) and Kiss-peptin, both responsible for pubertal growth. It is seen in normal individuals that the pulsatile secretion of GnRH ensues at the time of onset of puberty., This pulsatile release is the most important prerequisite for the pubertal growth in humans., Electrophysiological studies have shown that the hamartoma cells are intrinsically highly epileptogenic, thereby rendering these patients susceptible to DRE. These lesions, therefore, usually present either with CPP, DRE or a combination of both.,,
Imaging (MRI brain) usually is sufficient for the diagnosis of HH, as these are nonprogressive lesions (on serial imaging) arising from the hypothalamus, showing up as T1 isointense to the normal gray matter without contrast enhancement. Nebulae of classification schemes for HH exist in the literature published by multiple authors. Beginning from the era of CT scans to high-resolution MRI, all these classification schemes were devised so as to address the surgical approach and also to predict the clinical presentation. The following significant observations are noted and well documented in the literature, based on the imaging findings:
The above findings are frequently witnessed but not absolute and may vary with the individual patient [Figure 9].,,
Management of hypothalamic hamartomas
The management of the HH should be individualized depending upon their presentations. Hence, for the purpose of simplicity, they can be divided into 3 groups:
In our series, we had 75% (n = 12) patients belonging to group-2, 25% (n = 4) patients in the group-3, and none in the group-1 (as these patients are primarily referred to the endocrinology department).
Precocious puberty (PP) is defined as the development of secondary sexual characteristics prior to eight years in females and before nine years in male. PP occurring due to any intracranial lesion in the sellar/parasellar or hypothalamic involvement, which is GnRH dependent, is termed as central. Clinical evaluation of the breast development in females and testicular volume in males forms an important aspect of diagnosing PP. This is based upon the Tanners classification or sexual maturity rating. Biochemical evaluation includes complete hormonal workup including basal levels of serum leutinizing hormonal (LH)/follicle stimulating hormone (FSH). GnRH stimulation testing is also used for the diagnosis of CPP, whenever the elevation in basal level of LH is ambiguous. In the presence of HH with PP clinically, either random basal serum LH >0.3 IU/mL or a peak stimulated LH of >8 mIU/mL or 5 IU/L after GnRH or GnRH analog stimulation, respectively, are considered indicative of CPP.,
The management of CPP is mainly medical and focuses on two most important aspects of development, namely, the attainment of final adult height and dealing with the psychosocial aspects. As the premature secretion of the sex steroids leads to premature fusion of the epiphysis, the final adult height attained becomes restricted. Therefore, it is prudent to start the therapy with GnRH analogs the earliest. The best results are obtained when the therapy is begun before six years of age. Modest results are noted between 6–8 years and no benefit if started at eight years and beyond. The other most important aspect is the psychological and the social issues the child has to deal with. These patients' outlook is that of the adults but with a lesser mental age equivalent to their peer group. Often, they are stigmatized by the peer group at school and might end up being the victims of abuse. The inability to handle menstrual hygiene and aggressive behavior in the male children are other major concerns needing attention. Hence, GnRH therapies are offered so as to slow-down and regularize the development, till the age of puberty and then withdraw once appropriate age and proper understanding is attained. This is done after detailed discussion with the parents.,
There has been a paradigm shift in the management of patients belonging to group-1. Surgical excision of the HH was the only treatment option available in the past. The development of effective GnRH analogs over the past 50 years, following the discovery of the gonadotropins structure in 1971, has revolutionized the treatment of CPP. Nevertheless, there have been few reports in the literature offering surgical excision both in pre and post GnRH era. Although good clinical and biochemical outcomes have been demonstrated, the data are limited to a few case reports and short series.,,,,, Currently, the availability of long-acting GnRH analogs like leuprolide (7.5 / 11.25 mg) and triptorelin (7.5 / 11.25 mg), which can be administered as 1 or 3 monthly depot intramuscular injections, respectively, offer a convenient mode of therapy., Similarly, GnRH nasal sprays (Busarelin/Nefarelin) have made the therapy more acceptable, avoiding the need for repeated injections.
In this era of best available medical therapy, subjecting a patient to invasive surgery and its complications seems inappropriate for isolated CPP. As CPP represents a normal physiological phenomenon, beginning at an inappropriately early developmental stage, postponing the process till appropriate age with GnRh analogs offers a more logical solution.
The group-2 patients present with the characteristic gelastic (laughing episodes) seizures, which is the predominant seizure type witnessed in patients with HH. Dacrystic (crying episodes) and rarely focal or generalized seizures types are other forms of epilepsy associated with HH. These patients are to be managed in a specialized neurosurgical setup with experience in managing DRE, as surgery offers the only chance of cure. The surgical approach for HH has evolved with time from open surgical resection to endoscopic transcallosal-transventricular disconnection. Stereotactic “ablative disconnection” using laser and RFA of the HH are the latest modalities with excellent seizure-free outcomes with minimal morbidity.,,,,,,,,,, Kameyama et al. have reported the largest single center experience (n = 150) of ablative disconnection using RFT. They reported overall 71.3% International League Against Epilepsy (ILAE) Class-1 seizure outcomes, without any mortality or permanent morbidity, following first RFA.
In our experience, overall 12 (75%) among 16 patients achieved ILAE Class-1 seizure outcomes, following first lesioning. Repeat surgeries were performed in four patients with persistent seizures with evidence of residual connection on the MRI. Class-1 ILAE outcome was attained in 93.75% patient at the end of two repeat surgery in one and three times in two patients. One patient still awaits a repeat surgery following two failed attempts [Figure 8].
The group-3 patients require a well-coordinated, multispecialty team management involving the neurosurgeon, neurologist, and endocrinologist. Early seizure control takes the precedence, as these patients continue to worsen progressively in the psychosocial intelligence and irreversible brain damage, leading to severe epileptic encephalopathy if left untreated. This along with the appropriate endocrinological management, as already outlined for the group-1 and 2 patients leads to a successful outcome.,,
We encountered four patients with DRE and CPP accounting for 25% of the total cases. Two of these patients had giant HH (Delalande's type-IV). All the 4 lesions had a broad attachment to the 3rd ventricular floor, as noted in the midsagittal section of MRI brain. Following stereotactic RFA, three patients had the serum LH returned to the prepubertal level and one patient had marginal reduction in the serum LH. Only one patient required repeat RFA for persistent seizures.
Hypothalamic hamartomas are rare congenital lesions presenting with endocrinopathy, drug-refractory epilepsy, or a combination of both. The location of the HH in relation to the 3rd ventricular floor determines their presentation. A multidisciplinary approach involving neurophysicians, neurosurgeons, and endocrinologist yields best results. Isolated CPP is best managed medically under the care of an endocrinologist. Early seizure control should be the goal in all cases with drug-refractory epilepsy and promptly referred to specialized epilepsy center.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This study has been partly supported by Center of Excellence For Epilepsy (COE-E), funded by Dept of Biotechnology, Ministry of Science and Technology, India.
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
[Table 1], [Table 2], [Table 3]