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Case report: 5 Years follow-up on posterior hypothalamus deep brain stimulation for intractable aggressive behaviour associated with drug-resistant epilepsy
Longitudinal changes after amygdala surgery for intractable Aggressive behavior: clinical, imaging genetics, and deformation-based morphometry study-A case series.
]. Highly prevalent among psychiatric patients and those with drug-resistant epilepsy, constitutes a leading cause for patient institutionalization and reduced quality of life [
Benedetti-Isaac JC, Torres-Zambrano M, Vargas-Toscano A, Perea-Castro E, a-Cerra GA, Furlanetti LL, et al. Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior, n.d. https://doi.org/10.1111/epi.13025.
]. For patients who do not improve with standard treatment, deep brain stimulation (DBS) may be performed to modulate the dysfunctional neurocircuitry underlying AB, resulting in widespread brain changes and symptom alleviation [
Benedetti-Isaac JC, Torres-Zambrano M, Vargas-Toscano A, Perea-Castro E, a-Cerra GA, Furlanetti LL, et al. Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior, n.d. https://doi.org/10.1111/epi.13025.
]. In particular, DBS targeting the posterior area of the hypothalamus (pHyp) – a key hub in the neurocircuitry of AB – has been shown to reduce both ABs and seizure frequency [
Benedetti-Isaac JC, Torres-Zambrano M, Vargas-Toscano A, Perea-Castro E, a-Cerra GA, Furlanetti LL, et al. Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior, n.d. https://doi.org/10.1111/epi.13025.
Here, we report on a patient (male, 31 years-old) with autism spectrum disorder, severe intellectual disability, drug-resistant epilepsy, and intractable AB towards self, objects, and others who was treated with pHyp-DBS for management of AB and epilepsy. This patient first presented ABs at age 9 and received a formal diagnosis of epilepsy at age 12, at which time he was experiencing 3–4 seizures/week. By age 25, the patient's epilepsy and AB were no longer effectively controlled by pharmacotherapy and he was suffering from ∼5 seizures/day and ∼2 outbursts/day of severe AB. An expert medical board was formed to discuss the case and decide on the best treatment strategy. Because the patient did not meet criteria for intracranial resective epilepsy surgery and based on previous reports of successful outcomes for both AB and seizures [
Benedetti-Isaac JC, Torres-Zambrano M, Vargas-Toscano A, Perea-Castro E, a-Cerra GA, Furlanetti LL, et al. Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior, n.d. https://doi.org/10.1111/epi.13025.
], pHyp-DBS was indicated, and approved by the Research Ethics Board (CAAE#27470619.8.0000.5461). The potential benefits and adverse effects of DBS were discussed with the patient's parents who signed an informed consent form. Preoperative assessments included clinical evaluations, whole-brain magnetic resonance imaging (MRI) and questionnaires quantifying AB (Overt Aggression Scale; OAS), agitation (Agitated Behaviour Scale; ABS) and quality of life (Short Form Health Survey; SF-36). Postoperative evaluation included whole-brain computed tomography (CT) and 5 years of clinical evaluations and questionnaires (OAS, ABS and SF-36). Retrospective imaging analysis was performed to elucidate the neurocircuitry underlying response to stimulation. This involved DBS electrode localization (https://www.lead-dbs.org/), volume of activated tissue (VAT) modelling, and mapping of areas functionally connected to the VATs using a normative connectome [
] (see supplementary materials for detailed description).
The pHyp was targeted bilaterally with permanent quadripolar DBS electrodes connected to an implantable pulse generator in the subpectoral region (Fig. 1A and B, Supplementary Material Fig. 1). The DBS device was first turned on 15 days after surgery, stimulation parameters were chosen to maximize clinical benefit (2.0v; 120μsec; 180Hz) and were adjusted as necessary during follow-up. Following stimulation onset, the patient experienced marked reduction in the number of seizures (<1 per month), frequency and severity of AB (90% reduction from pre-DBS), and degree of agitation (from moderate to normal, 61% reduction). Quality of life was also improved following stimulation onset (25% improvement from pre-DBS). These improvements were attenuated on the second follow-up (13 months after surgery), with the patient showing more frequent seizures (1 per week), increased agitation (94% increase from post-DBS, severe agitation) and AB (500% increase from post-DBS). An adjustment of the stimulation parameters (increasing voltage from 2V to 2.5V while maintaining frequency and pulse width) was necessary and sufficient to improve symptoms. At the fourth follow-up (4 years after surgery) the implantable pulse generator was found to be depleted and the patient presented with severe worsening of AB, agitation and renewed seizure frequency. Following battery replacement, agitation was reduced to normal levels (40% reduction from pre-battery replacement), AB were abolished, and seizure frequency was reduced to less than one per month (Fig. 1C and D, Supplementary Material Table 1 provides demographics at each timepoint).
Fig. 1Clinical outcome and imaging findings. A. Lateral x-ray showing the position of the leads and extension cables. B. 3D reconstruction of the DBS lead, localized in the posterior hypothalamic area (pHyp), and modelled volumes of activated tissue (VATs) on a 100 micron resolution, 7.0 T FLASH brain (https://openneuro.org/datasets/ds002179/versions/1.1.0) in MNI152 space (https://www.bic.mni.mcgill.ca/ServicesAtlases/ICBM152NLin2009). Electrode localization and VAT modelling were performed using Lead-DBS (https://www.lead-dbs.org/); the pHyp label was derived from a previously published high-resolution MRI atlas of the human hypothalamic region (https://zenodo.org/record/3903588#.YHiE7pNKiF0). C. Aggressive behaviour as measured by the Overt Aggression Scale (OAS), total score and subscales. D. Agitation measured by the Agitation Behaviour Scale (ABS) and quality of life measured by the 36-Item Short Form Survey (SF-36). Red lines in C and D indicate the timepoints when it was necessary to adjust the stimulation parameters (timepoint 2) or change the battery of the pulse generator (timepoint 4). E. Brain areas showing significant positive functional connectivity with the VATs (white dotted lines). Abbreviations: GPe: external globus pallidus; GPi: internal globus pallidus; pHyp n: posterior hypothalamic nucleus; VAT: volume of activated tissue. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Interestingly, the patient showed progressive reduction in body weight after pHyp-DBS surgery (38.75% reduction comparing last follow-up to preoperative measure), with his BMI status changing from obese to healthy (Supplementary Material Table 1). Blood tests showed that all markers in the lipid panel changed to ideal levels after surgery. The endocrine panel revealed a constant increase in total testosterone, free testosterone, and SHBG levels after surgery, although all preoperative and postoperative values were within the normal range for age and sex. All other blood tests were found to be within normal levels at all timepoints (Supplementary Material Table 2 provides blood tests at each timepoint). It is not possible, however, to determine the cause of this progressive reduction in body weight as many contributing factors are observed in this patient: I. The hormonal changes observed after surgery, with increase in total testosterone, free testosterone, and SHBG levels could contribute to the reduction of body fat; II. DBS of distinct hypothalamic areas have been reported to reduce body weight in patients with obesity [
]; III. The changes in medication after surgery, especially the removal of Olanzapine from the patient's drug regime, could play an important role in the reduction of body weight.
The functional connectivity mapping analysis showed that the pHyp-DBS VATs corresponding to therapeutic stimulation were significantly connected with the anterior limb of the internal capsule (ALIC), the bed nucleus of the stria terminalis (BNST), the habenula (Hb), and a large portion of the brainstem, including those areas responsible for monoamine synthesis (I. Serotonin: dorsal raphe nuclei; II. Dopamine: substantia nigra and ventral tegmental area; III. Norepinephrine: locus coeruleus; Fig. 1E). These areas have previously been identified as playing a role in agitation and AB. Maley et al. (2010) reported on the successful treatment of a 19-year-old woman with intractable intermittent explosive disorder with DBS targeting the orbitofrontal projections to the hypothalamus, an area that encompasses both the ALIC and BNST [
]. At 2 years follow-up this patient was no longer experiencing violent outbursts and had greater control over her emotions and agitation through verbal interaction [
]. Considering the reciprocal connections between BNST and the dorsal raphe, it is plausible that stimulation of this area strengthens inhibitory control mechanisms by inducing increased release of serotonin in the prefrontal cortex, an effect also observed in patients treated with selective serotonin reuptake inhibitors [
]. The Hb is a key area controlling the monoaminergic systems in the brainstem, with projections from the Hb's medial region reaching the serotonergic system, contributing to the regulation of mood [
Fully automated habenula segmentation provides robust and reliable volume estimation across large magnetic resonance imaging datasets, suggesting intriguing developmental trajectories in psychiatric disease.
]. The lateral region of the Hb projects to the substantia nigra, ventral tegmental area and locus coeruleus, modulating dopamine and norepinephrine transmission, considered key for mediating AB and social behaviours [
Benedetti-Isaac JC, Torres-Zambrano M, Vargas-Toscano A, Perea-Castro E, a-Cerra GA, Furlanetti LL, et al. Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior, n.d. https://doi.org/10.1111/epi.13025.
]. The Hb is thus considered to play a critical role in a wide range of psychiatric disorders and is currently being investigated as a new DBS target [
Fully automated habenula segmentation provides robust and reliable volume estimation across large magnetic resonance imaging datasets, suggesting intriguing developmental trajectories in psychiatric disease.
]. Considering the Hb's involvement in the monoaminergic system and its functional connectivity to the pHyp-DBS target described here, we suggest the Hb could be a possible new target for treating patients with intractable AB. Some limitations of this study should be highlighted. The results presented here are derived from a single subject and further studies in larger cohorts are necessary. Additionally, as no native resting state functional MRI data were available, the functional connectivity analysis was performed using high-resolution and high-fidelity normative data from healthy individuals. Although normative data may not fully represent patient or pathology-specific functional connectivity, it has been shown to yield similar results to patient-specific data in prior analyses [
This study reported on the long-term follow-up of a patient with refractory epilepsy and aggressive behaviour who was treated with pHyp-DBS. This therapy reduced seizure frequency, decreased aggressive behaviour and agitation, reduced body weight, improved lipid and diabetes blood markers, and improved quality of life up to four years after DBS implantation. Importantly, seizures and severe aggressive behaviour rebounded with battery depletion and were once again controlled with battery replacement.
Data availability statement
All data generated and analyzed during this study are available from the corresponding author upon reasonable request.
Author contributions
Flavia Venetucci Gouveia: Design of the study; Acquisition, analysis and interpretation of data; Drafting and revising the article. Jurgen Germann: Analysis and interpretation of data; Revising the article critically for important intellectual content. Gavin JB Elias: Analysis of data; Revising the article critically for important intellectual content. Clement Hamani: Revising the article critically for important intellectual content. Erich Talamoni Fonoff: Acquisition of data; Revising the article critically for important intellectual content. Raquel Chacon Ruiz Martinez: Design of the study; Acquisition of data; Revising the article critically for important intellectual content. All authors approved the final version of the manuscript to be submitted.
Declaration of competing interest
The authors declare no conflict of interest.
Acknowledgements
This work was supported by grants FAPESP #11/08575-7 (RCRM), #13/20602-5 (FVG) and #17/10466-8 (FVG) from the Brazilian government. The authors wish to thank the research assistants and staff of Hospital Sirio-Libanes, Brazil.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
Longitudinal changes after amygdala surgery for intractable Aggressive behavior: clinical, imaging genetics, and deformation-based morphometry study-A case series.
Benedetti-Isaac JC, Torres-Zambrano M, Vargas-Toscano A, Perea-Castro E, a-Cerra GA, Furlanetti LL, et al. Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior, n.d. https://doi.org/10.1111/epi.13025.
Fully automated habenula segmentation provides robust and reliable volume estimation across large magnetic resonance imaging datasets, suggesting intriguing developmental trajectories in psychiatric disease.
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