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

  • Sergiu ScobioalaEmail author
  • Angela Brentrup
  • Khaled Elsayad
  • Hans Theodor Eich
Medicine
  • 190 Downloads
Part of the following topical collections:
  1. Topical Collection on Medicine

Abstract

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.

Keywords

Hamartoma Epilepsy Radiosurgery Gamma Knife Brachytherapy 

Introduction

Hypothalamic hamartomas (HH) are rare malformations that are associated with seizures, hormonal, and behavioral dysfunction. Most patients develop the condition in early childhood, experiencing typical gelastic seizures which are usually resistant to anticonvulsive drugs. The evolution of this disease during the following years may be characterized by a more generalized range of seizures, major cognitive disturbances, and psychiatric comorbidities [1, 2, 3, 4, 5].

A large spectrum of local treatment options that may potentially achieve complete ablation of HH has been proposed [6, 7]. The most widely practiced treatment includes different surgical techniques, as well as stereotactic radiosurgery (SRS). The advantage of SRS compared to microsurgery is in its noninvasive access. A series of SRS demonstrated low morbidity rates across various studies [8, 9, 10, 11, 12, 13]. This review analyzes both the efficacy and safety of different radiosurgery techniques, such as the Gamma Knife, linear accelerator (LINAC)-based RS, and interstitial brachytherapy in the treatment of HH-related epilepsy.

Material and Methods

This systematic review was structured according to the “PRISMA” reporting guidelines [14]. The “seven-step model” was used to perform the literature search, as described in detail, by Onwuegbuzie and Friels and Williams [15, 16]. The flow chart of reports from the selection process is presented in Fig. 1. Published trials, studies, and series (of any language) were identified using the Cochrane Library and PubMed® database. In addition, we searched the NIH clinical trials register ( https://clinicaltrials.gov/ ) to select the clinical trials. When searching for articles, we directly specified all terms used—namely, hypothalamic hamartoma, epilepsy, RS techniques, seizure outcome, and side effects. The following patients’ information was independently extracted from the databases: age, sex, tumor size, clinical signs (presence of seizures, hormonal, memory, and behavioral dysfunction), radiosurgery method, follow-up of the patients, seizure outcome, and side effects.
Fig. 1

Flow chart of report selection process. The database resources included: Cochrane Library, PubMed database, and the NIH clinical trials register (https://clinicaltrials.gov/). The following search terms were used: hypothalamic hamartoma, epilepsy, RS techniques, seizure outcome, side effects

Quality assessment of the selected studies was performed using the Cochrane Risk of Bias tool [17].

Biostatisticians determined these selected studies, and identified results were too inconvenient for aggregating any statistical comparative analysis due to significant heterogeneity within a variety of factors across the studies.

Results

From 82 screened reports, 43 were assessed for eligibility, and 34 reports with a total number of 123 patients were included in the review (Fig. 1). We also identified one randomized trial conducted for Gamma Knife RS [7]. The earliest article was published by Flickinger et al. in 1992 and the latest by Régis et al. in 2017 [7, 18]. The articles were reported from various clinical departments such as neurosurgery, radiotherapy, and pediatrics (Table 1).
Table 1

Safety and efficacy of different SRS modalities in the therapy of gelastic epilepsy associated with hypothalamic hamartoma (summary of reports limited with ≥ 3 patients)

Author

Year

Patients

Median age, years

Tumor size, (mean or range, cm3)

RS/dose (Gy)

Follow-up (mean or range, Mo)

Seizure free (Engel I + II)

Transient memory injury

Radiogenic edema

Schulze-Bonhage [19]

2008

24

21.9

1.2

Brachy/60 Gy (s.d.)

24

11/24 (45.8%)

2/24

5/24 (20.8%)

Wagner [20]

2014

26

26.7

1.4

Brachy/60 Gy (s.d.)

13.8

2/26 (7.7%)

20–50%

10/26 (38.5%)

Regis [7]

2013

48

16.5

0.398

GK/17 Gy (mean m.d.)

71

30/48 (65%)

0

0

Mathieu [21]

2010

9

29.8

0.8

GK/17 Gy (mean m.d.)

27.3

55.6%

0

0

Drees [18]

2012

4

27

0.20

GK/dose NA

58

2/3

0

0

Selch [12]

2005

3

34.7

0.15–1.12

LINAC/15-18 Gy (m.d.)

13–17

2/3

0

0

Golanov [22]

2010

6

8.5

0.3–3

LINAC/15.7 (mean m.d.)

3–50

NA*

NA

NA

SRS stereotactic radiosurgery, Brachy interstitial brachytherapy, GK Gamma Knife, LINAC linear accelerator, s.d. surface dose, m.d. marginal dose, NA not available, NA* seizure outcome according to the Engel’s grading is not available in the study of Golanov et al.

Among patients with HH treated with the SRS, 68% received Gamma Knife therapy; the interstitial brachytherapy was applied in 27% of patients, and the remaining 5% received LINAC-based RS. The average age for Gamma Knife, brachytherapy, and LINAC patients was 24.4 ± 8.4, 24.3 ± 11.3, and 21.6 ± 17.4 years. Age variability was cast over a wide spectrum across the studies. Patients included children, adolescents, young adults, and adults (Table 1). The mean follow-up was registered by 52.1 ± 14.7 months for Gamma Knife, and 18.9 ± 6.7 months for brachytherapy. For LINAC patients, the mean follow-up values were not available (Table 1). The patients treated with brachytherapy revealed significantly larger mean tumor size compared to Gamma Knife patients: 1.3 ± 0.2 cm3 versus 0.47 ± 0.3 cm3, correspondingly. For LINAC patients, the mean size of hamartomas was not available in selected reports (Table 1). For the Gamma Knife, the marginal dose averaged to 17 Gy, and for LINAC, the average marginal dose was found to be 15.7 Gy. Two reports which describe brachytherapy for HH, aver that only the surface dose (60 Gy) and not a marginal dose necessitate any inclusion in official findings (Table 1).

The evaluation of summarized results for the Gamma Knife RS was performed on the bases of studies provided by Regis et al. and by Mathieu et al. [7, 23]. Median dose of 17 Gy at the 50% isodose margin (range 13 to 26 Gy) was used. The seizure outcome, itself, was classified according to Engel et al. [21]. Complete seizure freedom was achieved in 39.6% of patients (Engel I), while 29.2% of patients with rare disabling seizures were almost seizure-free (Engel II). The latency time varied between 3 to 36 months. A temporary increase in seizure frequency was observed in 16.6% of patients with a median duration of 30 days. Significant seizure reduction was achieved in 28.6%. No permanent neurologic side effects, in particular no memory deficits, were reported. No radiologic changes in magnetic resonance imaging (MRI) were observed in the majority of patients (90.3%). Meanwhile, transient poikilothermia was observed in over 6.2% of patients [7].

The outcome of the interstitial brachytherapy was based on the analysis of two large trials performed by Schulze-Bonhage et al. (24 patients) and by Wagner et al. (26 patients) (Table 1) [24, 25]. I125 seeds (sized 4.5 × 0.5 mm) were stereotactically implanted into the target volume. Treatment plans were calculated to a dose of 60Gy for the surface of hamartoma with a mean energy dose rate of 10 cGy/h. Over 46% of patients were seizure-free or achieved a seizure reduction of at least 90% (Engel classes I and II). Treatment effects appeared in the mean time-period of 8 weeks after seeds implantation, and remained stable in the majority of patients. Due to unsatisfactory initial outcomes, treatment was repeated in 54% of patients. In 29% of patients, tests revealed a radiological reduction in HH volume. The interstitial brachytherapy was tolerated well in most patients. Neither perioperative mortality nor neurological deficits, as well as visual-filed impairments or endocrinologic dysfunction, were revealed. Weight gain of more than 5 kg was registered with four patients (17%). Transient radiation-related edema appeared in five patients (20.8%), and was not associated with further cognitive dysfunction. Considering the rarity of the LINAC-based RS in the therapy of epilepsy related to the HH, the information about efficacy and safety of this technique is very scare (Table 1). Patients received 11 Gy to 18 Gy (mean dose of 15.7Gy) in a single fraction prescribed at the 90 to 95% isodose by using of 6-MV linear accelerator (Novalis, BrainLAB, Germany). In the study of Golanov et al. (six patients), decreased frequency of seizures was observed in 100% of cases, albeit without further clinical specification of seizure reduction [26]. Selch et al. (three patients) received two seizure-free patients (Engel class IA). The third patient experienced a significant reduction in the seizure rate (Engel class II) without any improvement in cognitive function [12]. The latency time varied between 7 to 9 months. No changes in the tumor size or signal features were observed in the follow-up MRI. None of patients in both evidences developed neurologic or endocrinologic dysfunction.

Discussion

This systematic review is the first to assess the efficacy and safety of different RS techniques in the therapy of HH-associated seizures. However, the heterogeneity of identified studies or case series did not allow for a statistical analysis of the RS outcome. Even though the literature search was not restricted with specific criteria for variables, identified reports overwhelmingly consisted of case series or case reports. For these reasons, our systematic review had some limitations: first, a great heterogeneity across studies/case series in such variables as age, estimation of seizure outcome, side effects, and follow-up; second, a high ratio of incompletely reported outcome (Table 1); third, lack of prospectively randomized trials, directly comparing different RS methods or RS with surgical modalities for HH. To reiterate, it is due to these reasons that we did not validate the efficacy of outcomes, as they would ultimately suggest a significant risk for bias in any observable results. From this point of view, any interpretations for efficacy/safety ratios for RS methods are not altogether expressive enough.

Gamma Knife RS

Outcomes of Gamma Knife RS in the therapy of gelastic epilepsy caused by HH were evaluated though use of a prospective methodology performed by Regis et al. [7]. However, this single-arm study did not provide comparative assessment of the therapy outcome with surgical techniques or other RS methods. Fifty-seven patients treated with Gammy Knife RS were included for evaluation of the therapy outcome; 48 of whom exceeded 3 years of follow-up. Significant seizure reduction was achieved in more than 50% of patients treated for HH. Beyond seizure reduction, a greater improvement of psychiatric, as well as cognitive comorbidities, was acknowledged. For comparison, the use of endoscopic surgical approaches achieved a significant alleviation of seizures in 43–68% of HH patients. This finding, notably, came accompanied by a major reduction in rates of surgery-related morbidity and mortality [27, 28]. For example, there were no recorded instances of severe long-lasting neurophysiological or endocrinologic side effects (i.e. malignant obesity, diabetes insipidus, etc.) related to resective surgery after Gamma Knife treatment [6, 29]. A series of retrospective evidences that evaluated the efficacy of Gamma Knife RS demonstrated a seizure remission rate from 27 to 66% across studies [8, 9, 10, 11, 12, 13]. Drees et al. observed a similar efficacy between surgical or Gamma Knife procedures in adults with small HH occurrences, for instance, achieving complete seizure freedom in over one-third of patients [30]. This, by comparison, is a worsened outcome for seizure control compared to that of younger patients, in which the seizure freedom rate after Gamma Knife treatment varies between 37 and 66% [11, 23, 31]. Interestingly, only the absence of mental retardation was significantly associated with the seizure-free outcome [30]. There are no prospective studies directly comparing the outcome and safety of minimally invasive techniques, such as Gamma Knife with open surgery/microsurgery in the therapy of HH. However, the realization of such prospective trials could be complicated due to the relative rarity of this disease. Regis et al. offered treatment strategies for the HH according to its topological type [29]. Types I and II and small type III HH are good candidates for the Gamma Knife RS. Types IV, V, and VI are frequently operable or undergo the combined therapy including surgery following by Gamma Knife RS. An example of a large HH is showed in Fig. 2. Some single-center reports showed low rates of the primary morbidities after surgical treatment although they remain significantly higher compared to the Gamma Knife treatment [19, 32, 33]. According to Thom et al., the risk of death in surgery averaged to 0.24%; a chance of serious permanent complications averaged to 2%, and transient complications averaged to 6% [33]. In the study of Drees et al., only the patients who underwent resection suffered a stroke (15%) and mortality rate averaged to 10% [30]. One adult patient treated with Gamma Knife RS experienced weight gain (25%), although no weight gain was typically found in younger populations [20, 23, 30]. The impairments in neurocognition related to open surgery remain significant, with patients experiencing occurrence rates upwards of 10–60% [20, 22, 27, 30]. Analysis of several evidences, including a large prospective trial performed by Regis et al., revealed the correlation between margin radiation dose of HH in the Gamma Knife RS and seizure remission rate. Patients who received a dose of at least 17 Gy to the margin of HH demonstrated a higher outcome of seizure remission than those treated with less than 13 Gy [7]. However, the efficacy of Gamma Knife RS was found to be diminished in therapies for large hamartomas, as defined by stages V and VI, according to the classification of Delalande et al. [7, 29, 34]. The combined therapy with resection of the part of hamartomas, as a first step, and by using of Gamma Knife RS of the residue in a second treatment step, was found to be more effective for larger lesions [7, 29]. In the retrospective data reported by Drees et al., 70% of patients with a HH volume < 0.2 cm3 underwent either endoscopic resection or Gamma Knife RS with similar efficacy concerning seizure control [30]. The second limitation factor of Gamma Knife treatment is its delayed outcome. According to analyzed reports, the latency time varied between 3 to 36 months. Delayed efficacy of the Gamma Knife RS may be problematic in patients with severe epilepsy that affects the psychiatric and cognitive functions. For these patients, primarily standard surgical treatments may be preferred over Gamma Knife treatment. To summarize, the Gamma Knife RS may have a superior seizure outcome in patients if they are children rather than adults. Smaller occurrences of HH, which are localized a sufficient distance from the optic chiasm, optic tracts, or fornices, may be favored for their therapy with Gamma Knife RS as compared to standard surgical treatment.
Fig. 2

Pattern of a large hypothalamic hamartoma in an 11 years old female patient who developed pronounced hydrocephaly. Partial resection with a subsequent Gamma Knife RS was performed for reducing of a seizure frequency and hydrocephaly-related occlusion symptoms. MRI-images are provided by the Department of Neurosurgery, University Hospital of Muenster

Interstitial Brachytherapy

The first major evidence for interstitial brachytherapy of gelastic epilepsy related to HH was published by Schulze-Bonhage et al. in 2008 [24]. Over 46% of patients were seizure-free or achieved a seizure reduction of at least 90% (Engel classes I and II). The duration and severity of epilepsy before therapy negatively affected the treatment outcome. Patients who achieved a significant seizure reduction often demonstrated positive behavioral effects and improvement in cognitive function. In 29% of patients, tests revealed a radiological reduction in HH volume, suggesting seizure reduction without complete tumor destruction in most patients. The treatment outcome following seeds implantation ranged from 2 up to 8 months, which is faster than after Gamma Knife RS, but ranks similar to results following microsurgical resection [6, 7, 28, 29]. Unlike external radiation by use of LINAC or Gamma Knife, the smaller effective dose rate corresponding to hyperfractionated radiotherapy is applied with interstitial brachytherapy. Moreover, the advantage in the dose distribution of radiation to the surrounding organ at risk can be expected for the interstitial RS compared to the external radiation modalities. The authors judged the risk for bleeding during seed implantation in about 0.6% of patients. Such side effects as hyperphagia, and treatment-related brain edema, appeared in a small number of patients (20.8%). This phenomenon was accompanied by the transient appearance of headaches, fatigue, and lethargy. The majority of patients, however, showed a marked improvement in overall cognitive functionality. Similar to the Gamma Knife RS, a longer duration of epilepsy and large hamartoma size were negatively associated with seizure control and cognitive function. On the contrary, there was a 1 to2% risk of haemorrhage associated with insertion of stereotactic probes into the brain during interstitial brachytherapy. Wagner et al. took cognizance of memory outcome by use of a median follow-up at around 13.8 months [25]. Impairments appeared more often in declarative memory function in 20 to 50% of the patients, while attentional functions were stable or revealed an improved performance in a more than 80% of patients. To summarize, in about half of all patients treated with interstitial brachytherapy featured a significant reduction in seizures. A longer duration of epilepsy prior to interstitial brachytherapy is negatively correlated with seizure control. A larger hamartoma size, along with eccentric seeds positioning, were correlated with radiogenic edema.

LINAC-Based RS

The indication of LINAC RS for patients with medically refractory gelastic seizures related to HH was rather exceptional. In the literature, we find that only 13 patients with HH received the LINAC RS. For this reason, the meta-analysis of therapy efficacy and safety for LINAC-based RS is actually not factful. The largest studies were performed by Selch et al. and by Golanov et al. [12, 26]. The authors showed significant reduction in the seizure rate; however, the therapy efficacy was delayed from 7 to 9 months in these experiences. Similarly, the median latency time reported in the large series with Gamma Knife RS was 9 months [7]. Due to the limited number of patients, the authors could not elucidate upon any prognostic factors for therapy outcome. Additionally, any adequate radiation doses for seizure control could not be determined due to the small number of patients treated with LINAC RS. Munari et al. observed no effect after 18Gy delivered by LINAC [35]. Some relevant additional predictive factors as number of gelastic seizures prior to treatment or tumor size may affect the SRS outcome. Nonetheless, the study of Selch et al. revealed that seizure-free patients experienced two to six gelastic seizures per day [12]. Thus, the independent effects of radiation dose and seizure frequencies remain uncertain and should be evaluated in a multivariate analysis. The patients treated with LINAC-based RS did not develop any neurological or endocrinological injury; however, a longer follow-up is needed to establish long-term RS side effects [36, 37]. Thus, the LINAC RS may represent an alternative therapy approach for epilepsy related to HH. Extensive trials recruiting a large number of patients with a longer follow-up are needed to evaluate the efficacy and tolerability of the LINAC-based RS.

Conclusion

This systematic review emphasizes both the safety and efficacy of different radiosurgery techniques in the therapy of gelastic epilepsy related to the HH. The literature demonstrates that all modern surgical and RS techniques achieve approximately the same probability of seizure freedom and lower rate of therapy-related side effects, particularly, neuropsychological deterioration or endocrinologic toxicity. There are several common limitations for the RS therapies, such as the large size of hamartomas and its delayed efficacy. For these reason, the treatment option must be individually selected given the severity of epilepsy and the feasibility of the therapy method per each individual case. Considering the safety/efficacy profile, the RS can be considered as a first-line treatment option in patients with both small- or middle-sized HH and low seizure frequency prior to applied therapy.

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants performed by any of the authors.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Sergiu Scobioala
    • 1
    Email author
  • Angela Brentrup
    • 2
  • Khaled Elsayad
    • 1
  • Hans Theodor Eich
    • 1
  1. 1.Department of Radiotherapy and RadiooncologyUniversity Hospital of MuensterMuensterGermany
  2. 2.Department of NeurosurgeryUniversity Hospital of MuensterMuensterGermany

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