Small Hypothalamic Hamartomas Research Articles

Gamma Knife Radiosurgery for Hypothalamic Hamartoma: A Multi-Institutional Retrospective Study on Safety, Efficacy, and Complication Profile.

Gamma knife radiosurgery (GKRS) is a safe and effective treatment option for hypothalamic hamartomas (HH), but there is no consensus opinion on its timing, dosage, and follow-up. The aim of this study was to define the safety, efficacy, outcome, and complication profile of GKRS in this patient population. This retrospective multicentric study involved 39 patients with the mean age of 16 ± 14.84 years. Early seizures resulted in an earlier age of diagnosis in 97% of patients. At baseline, no endocrine abnormalities were seen in 75% of patients while 18.9% showed precocious puberty (PP). The median target volume was 0.55 cc (0.1-10.00 cc), and a median margin dose of 16 Gy (8.1-20.0 Gy) was delivered in a single session. All patients were evaluated for clinical, endocrinological, and radiological outcomes. The median follow-up was 5 (0.1-15) years. The median target volume of the cohort was 0.55 (0.35-1.77) cc. The largest HH was of 10 cc. 24/39 (61.5%) were small HH (Regis I-III). At presentation, 94.8% patients suffered from seizures (87.18% with gelastic seizures). 7/39 patients (17.9%) were presented with both PP and epilepsy. Only one (2.6%) patient presented with PP alone. 29 patients had more than 3-year follow-up. All received ≥16 Gy targeting complete HH. 28% of patients showed regression in HH volume. Patients with Regis grade I-III and longer follow-up (>75 months) showed gradual improvement in seizures. 16/29 patients (55.2%) achieved good seizure control (Engel I/II) while 13 (44.8%) were in Engel III/IV status. Nine patients needed adjuvant treatment because of poor seizure control. Eight patients suffered from transient increase in seizures. One patient developed poikilothermia, and 2 patients developed new onset hormonal deficiency. GKRS is a safe and effective modality for treatment of HH with significant improvement in seizure control with minimal disruption of endocrine profile. It provides an excellent safety, efficacy, and complication profile, especially for small HH. Latency of results and its adjuvant nature remain the areas of research and breakthroughs among contemporary treatment options.

Stereotactic radiofrequency thermocoagulation and resective surgery for patients with hypothalamic hamartoma.

In this study, the authors compared the efficacy and safety of stereotactic radiofrequency thermocoagulation (SRT) and resective surgery (RS) for patients with hypothalamic hamartoma (HH). The authors included all patients with HHs who were treated by SRT or hamartoma resection. Seizure outcomes were assessed by blinded observers according to the International League Against Epilepsy (ILAE) classification. Favorable seizure outcomes were defined as ILAE classes 1 and 2, and unfavorable seizure outcomes were defined as ILAE classes 3-6. Twenty-nine patients who underwent SRT or RS met the inclusion criteria; 3 were excluded because they had completed less than 12 months of follow-up. Most of the patients (20 of 26; 76.9%) had small HHs (i.e., maximum HH diameter less than 20 mm). The patients' follow-up time ranged from 12 to 66 months (median 60 months). At the last follow-up, favorable outcomes were observed in 9 patients (69.2%) who had undergone SRT and 10 patients (76.9%) who had undergone HH resection. No significant difference was found in seizure outcomes between SRT and RS recipients. Patients with giant HHs were more likely than patients with smaller tumors to undergo multiple resections (p = 0.043, univariate logistic regression; significant). However, no significant difference was found between SRT and RS recipients in terms of the number of procedures per patient. SRT recipients had fewer and less-severe adverse events than RS recipients. For patients with small HHs, SRT provides similar seizure outcomes to RS with a less invasive procedure. Patients who underwent SRT experienced fewer and lighter adverse effects than patients who had RS. Patients with giant HHs were more likely to undergo multiple HH resections.

Radiosurgery Techniques in the Treatment of Epilepsy Related to Hypothalamic Hamartomas (Systematic Review)

Various radiosurgery (RS) techniques are available for the therapy of epilepsy related to hypothalamic hamartomas (HH). As shown in previous reports, each RS method can reduce the frequency of seizures, as well as behavioral and cognitive alterations related to HH. This review summarizes the safety and efficacy of the most frequently used RS techniques for HH patients, with a particular focus on the Gamma Knife RS, interstitial brachytherapy, and linear accelerator (LINAC) RS. Literature compilation was achieved through use of a wide spectrum of information—namely, Cochrane Library, PubMed®, and the National Institute of Health (NIH) clinical trials register. All identified reports were peer-reviewed and less than 20 years old. Relevant patient information, including RS method, follow-up, seizure outcome, and side effects, were selected from the above databases. Thirty-four reports with a total number of 123 patients, including 48 patients from singular randomized trial, were included in the review. The most common clinical presentations were gelastic seizures and cognitive dysfunctions. All RS techniques demonstrate approximately the same seizure reduction outcomes achieving maximal values of 90%. The brachytherapy was reported to have a higher risk of brain edema or memory deterioration compared to the Gamma Knife or LINAC-based RS. Common limitations for the RS therapies included large sizes of hamartomas and their prolonged time latencies. RS is the least invasive curative therapy with a lower rate of complications compared to surgery. RS can be considered the therapy of choice especially for small or medium-sized HH.

Gap Junctions and Epileptogenesis: No Laughing Matter

Gap Junctions and Epileptogenesis: No Laughing Matter

Hope for hypothalamic hamartomas—Cofounders stories

Hope for hypothalamic hamartomas—Cofounders stories

A child with uncontrollable bursts of laughter

Hypothalamic hamartomas (HH) are rare (1:200,000), nonneoplastic heterotopic congenital malformations formed by neurons and glial cells located close to the posterior hypothalamus, tuber cinereum, or mammillary bodies [1]. The condition was first described in 1873 as a seizure presenting with laughter [2]. Later, Daly and Mulder named this condition ‘‘gelastic epilepsy’’ [3]. Gelastic seizures, central precocious puberty, and cognitive impairment are the predominant manifestations of HH in infancy [4]. The typical MRI features of HH are isoor hypo-intensity on T1weighted images and isoor slight hyper-intensity on T2-weighted images. A lack of contrast enhancement in the tuber cinereum region is valuable for radiological diagnosis to distinguish tumors from other lesions in this field, such as third-ventricular ependymomas, hypothalamic astrocytomas, germ cell tumors, Langerhans cell histiocytosis, and papillomas. Our patient was diagnosed with HH due to the similarity with previous case reports. The electroencephalogram showed interictal focal (mostly right frontal and temporal) paroxysmal activity (more frequently slow spike-andwave complexes) consistent with HH lateralization. Recent reports have demonstrated the intrinsic epileptogenicity of HH. The mechanism of gelastic epilepsy may be the spontaneous firing of gamma-aminobutyric acid (GABA)-ergic small HH neurons, which project synaptic connections onto the larger adjacent pyramidal-like HH neurons. The combination of these neurons acts as a pacemaker that synchronizes the numerous output neurons to mediate seizure activity in the brain, and this action results in the observed clinical symptoms. This groupof lesionshas been classifiedbyDelalandeas I through IV, based onmorphology onMRI [5]. Type I has a horizontal orientation and may be lateralized to one side. Type II has a vertical orientation and an intraventricular location. Type III is a combination of types I and IIwith a vertical plane of attachmentwithin the ventricle and a horizontal plane of attachment on the underside of the hypothalamus. Type IV is a giant hamartoma. In our patient, the lesion was located in its entirety in the third ventricle (Fig. 2 of Images in Neuroscience: Question) and was thus classified as type II. Due to the insufficient number of clinical reports, there is no consensus regarding the various therapeutic options. Despite the use of higher doses and several combinations of antiepileptic drugs, freedom from seizures or good seizure control is rarely achieved in HH patients [6]. At present, surgical resection, stereotactic endoscopic disconnection, Gamma Knife radiosurgery (Elekta AB, Stockholm, Sweden), and radiofrequency thermocoagulation appear to be useful and safe approaches, particularly for the treatment of small HH [7–9]. In our patient, numerous antiepileptic drugs were utilized in various combinations for approximately 4 years; however, none of these treatments exhibited any efficacy. Subsequently, the patient underwent Gamma Knife radiosurgery and long-term follow-up. Further studies are needed to assess the prognosis.

3. Gamma knife surgery in hypothalamic hamartoma: An effective treatment of refractory epilepsy with good outcome on quality of life and cognition

Hypothalamic hamartomas (HHs) are intrinsically epileptogenic congenital lesions typically presenting with drug resistant epilepsy. Patients affected also suffer from progressive cognitive deficits. Based upon previous studies, Gamma-knife surgery for HHs seems to be effective regarding epilepsy outcome with minimal side effects. Little data is available on the neurocognitive effect of this procedure. At the Centre Hospitalier Universitaire de Sherbrooke, we have undertaken a prospective observational study of patients who underwent radiosurgery for HHs, evaluating the response rate of seizures and the impact on cognition and quality of life. Patients were included in the study if they had an HH, refractory epilepsy, and no other suspected seizure focus. After radiosurgery, seizure status was assessed every three months and reported using the Engel Classification. Neuropsychological evaluation and quality of life evaluation using a standardized questionnaire (QOLIE-89) was performed at baseline and annually thereafter. Twelve patients with refractory epilepsy have been included so far in the study. Age ranged from 14 to 57 years. Margin doses ranged from 14 to 20 Gy. Nine patients had smaller hamartomas (Régis classification Grade I–III) and underwent treatment of the entire lesion. Three patients had larger lesions (Grade IV–VI) for which a radiosurgical disconnection was attempted. One of them had a second treatment with full lesion coverage. Among the seven patients treated with full lesion coverage with more than two years of follow-up, five (70%) are seizure free (Engel I). One patient has only rare seizure (Engel II), and one did not improve (Engel IV). Mean time to seizure freedom was twelve months (range 4–22). Disconnection led to no or little improvement in epilepsy (Engel IV in two patients and Engel IIIa in one). Nine patients had an abnormal cognitive profile at baseline. Four of them had a second evaluation after two years, and marked improvement in multiple domains of cognition occurred in three patients, and one remained stable. We observed a tendency toward improvement of quality of life evaluated with QOLIE-89, with a median result of 53% before treatment compared to 84% one or two years after treatment ( p = 0.068). Three patients had transient psychiatric disturbances after treatment (major depression with psychotic features requiring hospitalization in two, and impulsive behavior in one). In this prospective study of patients with refractory epilepsy associated with HHs, radiosurgery was effective in most patients when the entire lesion could be targeted. Some encouraging effects were also observed for cognition and quality of life, but this needs to be further evaluated in larger series of patients. Radiosurgical disconnection of large lesions was ineffective. Psychiatric disturbances as a possible side effect of this procedure need to be investigated further. For small HHs, radiosurgery with full lesion coverage should be a first line surgical therapy.

Ketogenic diet in the treatment of seizures associated with hypothalamic hamartomas

Seizures associated with hypothalamic hamartoma (HH) are notoriously intractable to medical therapy, and while surgical resection affords most affected patients with complete or near seizure-freedom, there remains a need to identify alternative treatments. In this retrospective study, we identified six patients from a large cohort of 220 patients with HH who were treated with the ketogenic diet (KD). Four patients had a 50-90% reduction in multiple seizure types (including gelastic, partial-onset and atonic seizures), and two individuals failed to respond. In order to study possible mechanisms, we then performed microelectrode recordings of small neurons in surgically resected HH tissue slices. Exposure to ketone bodies decreased spontaneous firing in 5 of 7 small HH neurons. These preliminary results suggest that seizures associated with HH may respond favorably to the KD, and that ketone bodies might directly modulate the intrinsic epileptogenicity of HH tissue.

Teaching Video Neuro Images : Hypothalamic hamartoma

A 21-year-old man presented with brief spells of inappropriate laughter since 6 years of age. Three gelastic seizures were recorded during video-EEG monitoring (video on the Neurology ® Web site at www.neurology.org). MRI revealed a small hypothalamic hamartoma (figure 1). Gelastic seizures …

Gamma Knife surgery for hypothalamic hamartomas and epilepsy: patient selection and outcomes

The authors present outcomes obtained in patients who underwent Gamma Knife surgery (GKS) at 1 institution as part of a multimodal treatment of refractory epilepsy caused by hypothalamic hamartomas (HHs). Between 2003 and 2010, 19 patients with HH underwent GKS. Eight patients had follow-up for less than 1 year, and 1 patient was lost to follow-up. The 10 remaining patients (mean age 15.1 years, range 5.7-29.3 years) had a mean follow-up of 43 months (range 18-81 months) and are the focus of this report. Five patients had undergone a total of 6 prior surgeries: 1 transcallosal resection of the HH, 2 endoscopic transventricular resections of the HH, 2 temporal lobectomies, and 1 arachnoid cyst evacuation. In an institutional review board-approved study, postoperative complications and long-term outcome measures were monitored prospectively with the use of a proprietary database. Seven patients harbored Delalande Type II lesions; the remainder harbored Type III or IV lesions. Seizure frequency ranged from 1-2 monthly to as many as 100 gelastic seizures daily. The mean lesion volume was 695 mm(3) (range 169-3000 mm(3), median 265 mm(3)). The mean/median dose directed to the 50% isodose line was 18 Gy (range 16-20 Gy). The mean maximum point dose to the optic chiasm was 7.5 Gy (range 5-10 Gy). Three patients underwent additional resection 14.5, 21, and 32 months after GKS. Of the 10 patients included in this study, 6 are seizure free (2 after they underwent additional surgery), 1 has a 50%-90% reduction in seizure frequency, 2 have a 50% reduction in seizure frequency, and 1 has observed no change in seizure frequency. Overall quality of life, based on data obtained from follow-up telephone conversations and/or surveys, improved in 9 patients and was due to improvements in seizure control (9 patients), short-term memory loss (3 patients), and behavioral symptoms (5 patients); in 1 patient, quality of life remains minimally affected. Incidences of morbidity were all temporary and included poikilothermia (1 patient), increased depression (1 patient), weight gain/increased appetite (2 patients), and anxiety (1 patient) after GKS. Of the approximately 150 patients at Barrow Neurological Institute who have undergone treatment for HH, the authors have reserved GKS for treatment of small HHs located distal from radiosensitive structures in patients with high cognitive function and a stable clinical picture, which allows time for the effects of radiosurgery to occur without further deterioration. The lack of significant morbidity and the clinical outcomes achieved in this study demonstrated a low risk of GKS for HH with results comparable to those of previous series.

Hypothalamic hamartoma causing gelastic seizures treated with stereotactic radiofrequency thermocoagulation

To present a case of small hypothalamic hamartoma (HH) causing gelastic seizures and treated with stereotactic radiofrequency thermocoagulation. A 22-year-old man presented with intractable gelastic seizures and focal seizures refractory to medical treatment. Magnetic resonance imaging showed a 6 mm x 6 mm x 7 mm sessile intraventricular HH. Under local anesthesia, four intra-hamartoma lesions were made via stereotactic radiofrequency thermocoagulation using a depth electrode for recording and stimulation. Transient central hyperthermia, hypertension, and tachycardia were observed during the coagulation procedure. Intra-hamartoma spikes and slow waves were identified on depth electrode recordings. No gelastic seizure was induced by deep stimulation. The patient was seizure-free during the 12-month follow up and no permanent surgical complications occurred. Stereotactic radiofrequency thermocoagulation may be an effective and safe treatment option in selected cases of hypothalamic hamartoma with gelastic seizures.

The syndrome gelastic seizures–hypothalamic hamartoma: Severe, potentially reversible encephalopathy

Hypothalamic hamartoma (HH) is the pathologic hallmark of a spectrum of epileptic conditions, ranging from a mild form of epilepsy, whose seizures are an urge to laugh without cognitive defects, to the fully developed syndrome of early onset gelastic seizures (GS) associated with precocious puberty and the evolution to a catastrophic epilepsy syndrome. However, a refractory focal or generalized epilepsy develops during the clinical course in nearly all cases. Neurophysiologic and neuroimaging studies have assessed the role of HH in the generation of the GS as well as in the process of secondary epileptogenesis. Electrophysiologic properties of small gamma-aminobutyric acid (GABA)ergic, spontaneously firing neurons might explain the intrinsic epileptogenicity of HH. Surgical ablation of the HH can reverse both epilepsy and encephalopathy. Gamma-knife radiosurgery and image-guided robotic radiosurgery can be useful and safe approaches for treatment, in particular of small HH.

Hypothalamic Hamartomas Associated With Epilepsy

Hypothalamic hamartomas (HHs) are associated with a catastrophic form of childhood epilepsy and are intrinsically epileptogenic for the gelastic seizures that are peculiar to this disorder. The cellular mechanisms of seizure generation within HH tissue are unknown. Hypothalamic hamartoma tissue consists of well-differentiated neurons interspersed with glial cells. Based on intrinsic electrophysiologic properties, we hypothesized that small and large HH neurons would have different ultrastructural features. Surgically resected HH tissue samples from 7 patients with refractory epilepsy were studied using electron microscopy. Models of neurons were made from reconstruction of serial sections. Nissl body density, polyribosome density, glycogen density, and the ratio of nuclear area to cytoplasmic area differed significantly between small and large neurons. Abundant small neurons were found in clusters and elaborated terminals that made symmetric, putatively inhibitory, synapses. Symmetric synapses were found predominantly on the soma and proximal dendrites of large projection-like neurons, whereas asymmetric, putatively excitatory, synapses were found primarily on distal dendrites. All samples showed unusual dendritic varicosities. The presence of these morphologically and functionally distinct neurons, the large number of nerve fibers in the neuropil, and the presence of inhibitory and excitatory synapses suggest that HH tissue has the necessary substrate to generate seizures.

Electrophysiological Properties and Subunit Composition of GABAA Receptors in Patients With Gelastic Seizures and Hypothalamic Hamartoma

Abnormalities in GABA(A) receptor structure and/or function have been associated with various forms of epilepsy in both humans and animals. Whether this is true for patients with gelastic seizures and hypothalamic hamartoma (HH) is unknown. In this study, we characterized the pharmacological properties and native subunit composition of GABA(A) receptors on acutely dissociated single neurons from surgically resected HH tissues using patch-clamp, immunocytochemical, and RT-PCR techniques. We found that 1) GABA induced an inward current (I(GABA)) at a holding potential of -60 mV; 2) I(GABA) was mimicked by the GABA(A) receptor agonist muscimol and blocked by the GABA(A) receptor antagonist bicuculline, suggesting that I(GABA) was mediated principally through the GABA(A) receptor; 3) the EC(50) and Hill coefficient derived from the I(GABA) concentration-response curve were 6.8 muM and 1.9, respectively; 4) the current-voltage curve was linear at a reversal potential close to zero; and 5) I(GABA) exhibited low sensitivity to zinc and diazepam but higher sensitivity to pentobarbital and pregnanolone. Additionally, using Xenopus oocytes microtransplanted with normal human hypothalamic tissue, we confirmed that the functional properties of GABA(A) receptors were similar to those seen in small isolated HH neurons. Finally, the expression profile of GABA(A) receptor subunits obtained from normal control human hypothalamic tissue was identical to that from surgically resected human HH tissue. Taken together, our data indicate that GABA(A) receptors on small HH neurons exhibit normal pharmacosensitivity and subunit composition. These findings bear relevance to a broader understanding of inhibitory neurotransmission in human HH tissue.

Endoscopic Resection of Hypothalamic Hamartoma Using a Novel Variable Aspiration Tissue Resector

We present a novel variable aspiration tissue resector for use with neuroendoscopy. Two patients, 4 and 14 years old, respectively, presented with intractable gelastic seizures refractory to maximal medical therapies. Magnetic resonance imaging showed mass lesions of the third ventricle consistent with hypothalamic hamartoma. The patients underwent magnetic resonance imaging wand-guided endoscopic resection of the tumor with the Suros novel variable aspiration tissue resector. There were no device-associated complications or adverse events. The hamartoma was disconnected in one patient, and gross total resection was achieved in the other. Endoscopy for tumor resection is still frustrated by the lack of surgical tools, such as ultrasonic aspirators, comparable with those available for use during open procedures. The variable-aspiration tissue resector reported here can be used to resect tumor tissue safely. These two cases demonstrate that gross total resection of small hypothalamic hamartomas is feasible with minimal morbidity through an endoscopic approach.

Evaluation of small hypothalamic hamartomas with 3D constructive interference in steady state (CISS) sequence

Hypothalamic hamartomas are relatively rare, non-neoplastic congenital malformations. With conventional MR images alone, small hypothalamic hamartomas may be difficult to diagnose because of artifacts from cerebrospinal fluid. We present the usefulness of three-dimensional constructive interference in steady state sequence for evaluating small hypothalamic hamartomas in three pediatric patients.

Small hypothalamic hamartomas and gelastic seizures

ABSTRACT Purpose To describe the clinical history of patients with gelastic seizures (GSs) related to small‐size hypothalamic hamartomas (HHs), and to show some of these unusual seizures. Material and methods Patients with GSs and the MRI finding of HH < 1 cm diameter. Ictal EEG or video EEG are required. Results Three patients, among 6 with GSs and HH, had a small sessile HH. None of them had a history of precocious puberty, nor any relevant cognitive defects. All patients suffered from other seizure types, in addition to GSs. GSs were drug‐resistant in all cases. Conclusion since small, not easily recognizable HHs may be present in patients with GSs, a careful MRI study of the hypothalamic, infundibular and mammillary bodys areas is mandatory in these cases [published with videosequences].

Hypothalamic Hamartoma: Comparison of Clinical Presentation and Magnetic Resonance Images

Background/Aims: Hypothalamic hamartoma (HH) is one of the most frequent causes of organic central precocious puberty (CPP). We compared the clinical presentation and the magnetic resonance images (MRI) of 19 patients with HH aged 5.7 ± 4.1 (SD) years at the first endocrine evaluation. They had isolated CPP (group 1, n = 9), CPP plus gelastic seizures (group 2, n = 5), isolated seizures (group 3, n = 4), and 1 patient was asymptomatic. Methods/Results: All patients without neurological symptoms (group 1 and the asymptomatic patient) had pedunculated lesion (diameter 6.4 ± 3.6 (3–15) mm), suspended from the floor of the third ventricle. All patients with neurological symptoms (groups 2 and 3) had sessile lesion (diameter 18.3 ± 9.6 (10–38) mm, p = 0.0005 compared to the others), located in the interpeduncular cistern with extension to the hypothalamus. Seven patients were overweight. The growth hormone peak, free thyroxine, cortisol and prolactin concentrations, and the concomitant plasma and urinary osmolalities were normal in all the cases evaluated. The mean predicted or adult heights of 10 patients treated 5.2 ± 3.3 years for CPP with gonadotropin hormone releasing hormone (GnRH) analog were –0.3 ± 1.7 SD, similar to their target height –0.1 ± 0.9 SD. Conclusion: The clinical presentation of HH depends on its anatomy: small and pedunculated HH are associated with CPP, while large and sessile HH are associated with seizures. The hypothalamic-pituitary function in these cases is normal, which suggests that the absence of CPP is not due to gonadotropin deficiency. GnRH analog treatment preserves the growth potential in those with CPP.

Gelastic Epilepsy and Hypothalamic Hamartoma

Three patients with small hypothalamic hamartomas and a recurrent “pressure to laugh,” often without actual laughter, are reported from the University of Melbourne, Australia, and McGill University, Canada.

Stereotaxy for hypothalamic hamartoma with intractable gelastic seizures: technical case report

OBJECTIVE AND CLINICAL IMPORTANCE: We report a patient with a hypothalamic hamartoma treated by stereotactic radiofrequency thermocoagulation. CLINICAL PRESENTATION: A 15-year-old girl presented with a hypothalamic hamartoma associated with intractable gelastic and tonic seizures. There were no clinical signs of precocious puberty. Magnetic resonance imaging revealed an isointense suprasellar mass, about 1 cm in diameter. TECHNIQUE: A depth electrode was placed into the hamartoma using a computed tomography-compatible stereotactic frame. Depth electroencephalographic studies allowed us to record the seizure onset from the lesion, and stereotactic radiofrequency thermocoagulation produced seizure remission. CONCLUSION: These findings suggest that hypothalamic hamartoma itself has intrinsic epileptogenicity. We believe that this surgical treatment is effective for the relatively small hypothalamic hamartoma associated with intractable gelastic seizures.