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 »  Abstract
 »  DBS Mechanisms o...
 » Targets
 »  Anterior Nucleus...
 »  Centromedian Nuc...
 » Hippocampus
 »  Cerebellar Stimu...
 » Basal Ganglia
 » Adverse Effects
 »  DBS for Epilepsy...
 » Conclusion
 »  References
 »  Article Tables

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Table of Contents    
SYMPOSIUM
Year : 2020  |  Volume : 68  |  Issue : 8  |  Page : 268-277

Deep Brain Stimulation for Treatment of Refractory Epilepsy


1 Department of Neurosurgery, Epilepsy Surgery Program, Hospital Universitário Cajuru, Curitiba, Brazil
2 Department of Neurosurgery, Epilepsy Surgery Program, Clínica Cukiert, São Paulo, Brazil

Date of Web Publication5-Dec-2020

Correspondence Address:
Dr. Tatiana von Hertwig Fernandes de Oliveira
1040, Silveira Peixoto, Batel, Curitiba-PR -80240120
Brazil
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.302454

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 » Abstract 


Deep brain stimulation (DBS) has been used in the treatment of motor diseases with remarkable safety and efficacy, which abet the interest of its application in the management of other neurologic and psychiatric disorders such as epilepsy. Experimental data demonstrated that electric current could modulate distinct brain circuits and decrease the neuronal hypersynchronization seen in epileptic activity. The ability to carefully choose the most suitable anatomical target as well as to define the most reasonable stimulation parameters is highly dependable on the comprehension of the underlying mechanisms of action, which remain unclear. This review aimed to explore the relevant clinical data regarding the use of DBS in the treatment of refractory epilepsy.


Keywords: Deep brain stimulation, outcome, refractory epilepsy
Key Messages: DBS is a safe and efficacious treatment modality for patients with refractory epilepsy. The ANT, CM and hippocampus are the most investigated targets. Further research is needed to identify specific biomarkers, best patient profiles, and the most beneficial stimulation paradigm.


How to cite this article:
de Oliveira Tv, Cukiert A. Deep Brain Stimulation for Treatment of Refractory Epilepsy. Neurol India 2020;68, Suppl S2:268-77

How to cite this URL:
de Oliveira Tv, Cukiert A. Deep Brain Stimulation for Treatment of Refractory Epilepsy. Neurol India [serial online] 2020 [cited 2021 Feb 28];68, Suppl S2:268-77. Available from: https://www.neurologyindia.com/text.asp?2020/68/8/268/302454




Epilepsy is a chronic and debilitating neurologic disorder that affects more than 45 million people worldwide.[1] Despite advances in medical treatment with newer antiepileptic drugs (AEDs), approximately one third of these patients do not respond to therapy. Refractoriness is defined as failure to control seizures after at least two AEDs used in maximally tolerated doses.[2] Surgery is a suitable option in patients with refractory epilepsy in whom an epileptogenic focus is accurately localized and can render a high percentage of patients seizure-free, with improved quality of life and low morbidity.[3] Stimulation of central or peripheral nervous structures is an emerging procedure that shows promising results[4] in patients who are not candidates for or have failed resective surgery.

Deep brain stimulation (DBS) consists in the delivery of electrical current into brain structures with the purpose of modulating different pathological circuits. This can be achieved through two different stimulation modalities: open-loop or closed-loop systems. In the former, electrical current is continuously or intermittently delivered to brain tissue to modulate the activity of local neurons and passing axons involved in epileptogenesis. On the other hand, the latter consists in delivering bursts of electrical current directly to the compromised area in response to ongoing epileptiform activity, which is detected through an electrocorticogram (ECoG) recorded by the implantable device, with the intention of abolishing the epileptic activity. Although the concept of closed-loop stimulation is appealing, randomized trials that indicate superiority of one of the techniques are still lacking, and long-term efficacy of both systems are surprisingly similar.[5]


 » DBS Mechanisms of Action Top


The mechanism by which DBS exerts its effects is still unclear. It might include local activity inhibition, as it mimics the effects caused by a lesion in some structures. This functional network disruption is possibly achieved by activation of GABAergic connections or inactivation of excitatory voltage-gated channels with ensuing depolarization suppression. Furthermore, it is not clear what structure or part of the cell is being modulated. Myelinated fibres have the lowest threshold for stimulation, followed by unmyelinated fibres, dendrites and cell bodies. Changes in different variables may yield distinct effects on the network, which further hinders the identification of the responsible element.[6]

DBS seems to modify the pathological network by disrupting afferent and efferent information through orthodromic activation of efferent fibres as well as antidromic and orthodromic activation of afferent fibers.[7] This rationale should be taken into consideration when deciding for the most appropriate target. The Circuit of Papez connects the hippocampus via the fornix, mammillary bodies (MB) and mammillothalamic tract (MMT) to the anterior nucleus of the thalamus, followed by the cingulate gyrus, parahippocampal gyrus and enthorinal cortex, and back to the hippocampus through the perforant pathway. It is involved in the generation of limbic seizures and allows for multiple potential targets to modulate the circuitry, as the ANT, the MB, the fornix and the hippocampus itself. Cortico-subcortical loops, as the cortico-thalamic, cortico-cerebellar and the basal ganglia, are apparently involved in the spread of generalized and motor seizures and include other targets amenable for stimulation, such as the centromedian nucleus (CM) of the thalamus, the cerebellum, the caudate nucleus (CN), the subthalamic nucleus (STN) and the substantia nigra (SN).[8]

Other mechanisms that are likely involved in seizure control are neurotransmitter release, protein and gene expression and cell proliferation. High frequency stimulation of ferret thalamic slices increased astrocytic release of glutamate, with cessation of abnormal oscillatory activity.[9] Immunohistochemical analysis of brain tissue of patients with Parkinson's disease treated with DBS showed an increased number of proliferating and neural precursor cells close to the lead, which could suggest a state of increased plasticity.[10] This could explain the progressive improvement seen in seizure frequency reduction during brain stimulation, although it has not been clearly related to clinical benefits.


 » Targets Top


Distinct areas of the brain have been explored as potential targets for stimulation to reduce the burden of epilepsy since the 1950s. However, most of the evidence comes from case series and only a few randomized trials have been published, which makes it difficult to draw any conclusions based on statistical analysis. The most employed targets in clinical practice are discussed below:


 » Anterior Nucleus of the Thalamus Top


The ANT is a thalamic nucleus located in its most rostral and dorsal area. It is separated from the other thalamic nuclei by the anterior Y-shaped internal medullary lamina. It is composed of 3 subnuclei: the anteroventral (AV), anteromedial (AM) and anterodorsal (AD) nucleus, each one connected with specific regions of the subiculum, cingulum and retrosplenial cortex. The inputs from the hippocampus arrive through the postcommissural fornix, directly or through the mamilothalamic tract (MMT). The ANT is considered a key component of the Circuit of Papez and plays an essential role on episodic memory, with each subnucleus being part of distinct networks connected to the hippocampus, the MB and the cortex.[11],[12]

The exact position of the ANT in the stereotactic space is highly variable, although its theoretical coordinates are 12 mm superior, 5-6 mm lateral and 0-2 mm anterior to the midcomissural point. The most reliable way to target the ATN, though, is by direct visualization on the MMT, which is located slightly inferior to the centre of the nucleus, as seen on short tau inversion recovery (STIR) or magnetization prepared gradient echo (MPRAGE) MRI sequences.[13]

Animal models demonstrated that stimulation of the ANT have anticonvulsant properties.[14],[15],[16] Several case series and small open label studies have been published since the 1980s demonstrating the effects of bilateral ANT high frequency stimulation in the management of refractory epilepsy.[17] Rates of seizure frequency reduction varied from 24% to 90%, and microlesional and carryover effects[18],[19],[20],[21],[22],[23] were noted. Promising results from these early series led to a randomized, double-blinded, multicentre trial known as the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy trial (SANTE). In this study, 110 patients with focal seizures (including the ones secondarily generalized) underwent cycling bilateral ANT stimulation. There was a 22% reduction in seizure frequency compared to baseline during the pre-stimulation phase, likely reflecting a lesional effect. Additionally, by the end of the third month of the blinded phase, the active group experienced a 40% reduction in seizure frequency, compared to 15% in the sham group. Open label long-term follow-up demonstrated 56% of median seizure reduction with 54% of the patients being considered responders (at least 50% seizure frequency reduction) after 2 years,[24] and 69% mean seizure reduction with a 68% responder rate after 5 years.[25] Objective testing of cognition and mood did not show differences between groups, although some stimulated patients reported depression and memory impairment. Patients with temporal lobe seizures appeared to have a better outcome than others, which is likely linked to the circuit to which the ANT is related.[24] The same promising results were not obtained in a more recent double-blind, randomized trial of 18 patients, which found no statistical difference between sham and stimulation after a 6 month blinded period, in addition to no improvement overtime in rates of seizure reduction.[26] Several factors could have influenced these results, such as seizure severity, target planning and cohort size. Clinical studies are summarized in [Table 1].
Table 1: Clinical studies of ANT DBS for the treatment of refractory epilepsy

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Adequate location of the electrode's contacts is mandatory to achieve satisfactory results, and the two most superior contacts should be located inside the nucleus.[13] Direct targeting by visualization of the MMT is currently favoured,[27] as there is substantial anatomical variability among subjects. Although some centres advocate placement of the lead in the anterosuperior aspect of the nucleus,[28] others have demonstrated better outcomes when the active contact is near the anterior centre of the ANT,[29] 5 mm lateral to the wall of the third ventricle,[30] or at the junction of the ANT and the MTT.[31] The trajectory of the lead may also correlate with results and, due to the shape and position of the ANT, the transventricular approach proved to be more efficacious than the extraventricular one.[13]


 » Centromedian Nucleus of the Thalamus Top


The centromedian (CM)/parafascicular (PF) complex (CM/PF) is part of the intralaminar thalamic nuclei and displays widespread connections with the cerebral cortex, limbic circuit and basal ganglia. The CM appears to behave as a gateway to modulate cortical excitability through various projections, such as the reticulothalamocortical system. It is also directly related to the striatum and influences attention-related processes, wakefulness and sensorimotor coordination.[32] Likewise, the PF, located medially to CM, regulates cortical excitability as part of the cerebellar-basal ganglia-thalamic-cortical circuitry, as evidenced by the excitatory substantia nigra (SN)-PF connections.[33] CM targeting is carried out using indirect coordinates (at the level of the posterior comissure, 10 mm lateral from midline), as it is not visualized on CT or standard MRI sequences.[13] However, contemporary techniques to improve delineation of the nucleus are under investigation and demonstrate promising results, as the use of quantitative susceptibility mapping reconstructed from a 3-D multi-echo gradient recalled echo (GRE) sequence.[34]

Animal models demonstrated the relation between PF and mesial temporal lobe seizures,[35] including the suppression of hippocampal paroxysmal discharges with high frequency PF stimulation in mice.[36] CM stimulation, however, is indicated essentially for treatment of patients with generalized epilepsy, such as those with Lennox-Gastaut syndrome, as demonstrated by Velasco et al. in different uncontrolled and unblinded studies. There was a significant reduction of tonic, atonic, atypical absence and generalized tonic-clonic seizures, but not myoclonic seizures, in an open-label study of 20 patients with Lennox-Gastaut or Lennox-Gastaut like syndrome, after a mean follow-up time of 2.5 years. One patient became seizure-free and 90% were responders. Interestingly, all demonstrated improvement in attention scores, which was significantly related to seizure reduction.[37] Similar results of decreased epileptiform activity on EEG and significant overall seizure reduction in generalized tonic-clonic and atypical absence seizures were described by others,[38],[39],[40],[41],[42] although it was not able to reduce focal seizures.[43] This was supported by a randomized double-blind cross-over trial in which patients with mesial temporal epilepsy did not show a substantial response[44] and by a single-blind controlled trial in which only one in five patients with frontal epilepsy had more than 50% improvement.[45] A possible explanation for this finding could be the spatiotemporal activation pattern seen after CM stimulation. There is involvement of the anterior cingulate, followed by the frontotemporal area, as demonstrated by scalp EEG and diffusion tensor imaging (DTI).[46] Apart from seizure type, final electrode position also appears to be a predictive factor for better outcomes, as seen when contacts are positioned at the anterosuperior[47] aspect of the ventrolateral CM (parvocellular subnucleus).[43],[45] Moreover, in patients with multilobar epilepsy, the active contacts were more dorsally located than in patients with generalized epilepsies.[47] Clinical studies are summarized on [Table 2].
Table 2: Clinical studies of CM DBS for the treatment of refractory epilepsy

Click here to view



 » Hippocampus Top


The position of the hippocampus within the Papez circuit makes it an appealing target for the treatment of mesial temporal lobe epilepsy (MTLE). Animal studies showed the efficacy of hippocampal stimulation in decreasing epileptic activity,[48],[49],[50],[51] but the optimal parameters were not clearly defined; both high and low frequency stimulation were found to have antiepileptic properties. However, it has been inferred that high frequency stimulation might be more efficient than low frequency stimulation.[52] The exact mechanism of action is still under debate but may be related to hyperpolarization and a concurrent decrease of hippocampal after-discharges.[53] Increased GABA levels and up-regulation of GABA receptors seem to be involved. It might also display neuroprotective properties as a decrease in apoptosis-related proteins and neuronal loss[38] were noted.

The first randomized trial, including 4 patients, reported a non-significant 15% seizure frequency reduction.[54] A modest result was achieved in another trial including 2 patients, who achieved a 33% reduction in seizure frequency after stimulation for 3 months; a carry-over effect of 25% was noted.[55] Diversely, in a prospective cohort of 9 patients with temporal lobe epilepsy with or without mesial sclerosis, there were only 2 non-responders an the median reduction in seizure frequency in the responder group was 80% after 30 months of follow-up.[56] In a randomized trial of 9 patients, all stimulated patients showed seizure frequency reduction against none in the sham group; an at least 50% reduction of seizure frequency was noted in all patients during the 18-month open-label phase.[57],[58]

Responsive neurostimulation (RNS) is a closed-loop paradigm in which stimulation is delivered on demand according to real-time ECoG activity. There was a 37,9% seizure frequency reduction in the active group against 17.3% in the sham group during the blinded phase of a randomized trial; results progressively improved to 53% in the open-label phase after 2 years. The response of patients with MTLE (n = 90) was similar to others (n = 93) after 2 years of stimulation (55% versus 58%, respectively).[59] Positive results were reported during hippocampal DBS by another double-blind randomized trial including 16 patients, with an 87.5% responder rate and a 50% seizure-free rate in the stimulation group during the 6 months of the blinded phase.[60] Hippocampal stimulation appears to be a valuable tool for the treatment of patients with refractory MTLE in whom resection is not indicated, with minimal cognitive or psychiatric morbidity.[61] Clinical results are summarized in [Table 3].
Table 3: Clinical studies of Hippocampus DBS for the treatment of refractory epilepsy

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To identify biomarkers for positive clinical response, Velasco and colleagues investigated the association between non-lesional MRI and outcome. Patients with normal MRI had more than 95% of seizure frequency reduction, while 50-70% of the patients with hippocampal sclerosis did so.[57] This suggested that patients with hippocampal sclerosis might need higher stimulation intensity to achieve satisfactory results due to the cicatricial tissue.[62] The location of the active contacts may correlate with clinical response as well and a precise targeting is essential for a satisfactory outcome. T1 MRI coronal slices perpendicular to the hippocampus axis are used to localize the most anterior part of the hippocampus head, followed by the identification of another point in the middle of the hippocampal body in the sagittal view. The resulting line is used to determine the entry point at the occipital bone.[13] Apparently, proximity of the lead to the ictal onset zone did not correlate with reduction of epileptiform activity in 8 patients implanted with hippocampal DBS. On the other hand, all 6 patients that had the active contacts located at least 3 mm from the subiculum had more than 50% seizure reduction.[63]


 » Cerebellar Stimulation Top


Electrical stimulation of the cerebellum has been shown to influence motor control,[64] with promising results in the treatment of epilepsy in animal studies,[65],[66] since the 1940s. Initial uncontrolled human studies of stimulation of the superior cerebellar cortex had favourable outcomes,[67],[68] but the same was not achieved in controlled trials.[69],[70],[71] There was a 67% seizure frequency reduction in the stimulation group compared to 7% in the sham group during the blinded phase in a randomized double-blind trial including 5 patients, followed by a mean seizure reduction of 59% after 6 months of open-label follow-up.[72] Distinct factors could contribute to the inconsistency of results during cortical cerebellar stimulation: the complexity of Purkinje cells and deep nuclei connections, and the considerable variability of the localization of the target in relation to seizure type.[73] Optogenetic closed-loop stimulation of the medial nuclei may supposedly improve temporal lobe seizures,[74],[75] while stimulation of the lateral nuclei may be related to modulation of generalized spike and wave discharges (GSWD).[76] Clinical results are summarized on [Table 4].
Table 4: Clinical studies of Cerebellar DBS for the treatment of refractory epilepsy

Click here to view



 » Basal Ganglia Top


There is substantial evidence that the basal ganglia are implicated in epileptic circuits.[77],[78],[79],[80],[81],[82],[83],[84],[85],[86],[87],[88],[89],[90],[91],[92],[93],[94] Clinical results are summarized on [Table 5].
Table 5: Clinical studies of Basal Ganglia DBS for the treatment of refractory epilepsy

Click here to view



 » Adverse Effects Top


Adverse effects may be surgical-related, hardware-related, or stimulation-related, and most of the published data come from movement disorders procedures. Infection was the most common complication (5.12%), followed by lead migration (1.6%), fracture of the lead (1.46%) or other component of the device (0.73%), internal pulse generator (IPG) malfunction (1.06%) and skin erosion without infection (0.48%). In epileptic patients, the rate of pain at the implantation site was higher than in movement disorders (16.55%).[95] According to the SANTE trial, the rate of subclinical haemorrhage was 4.5%; infection, 12.7%; pain at the implantation site, 10.9% and inadequate lead positioning requiring revision, 8.2%. Stimulation-related side effects were highly variable depending on the chosen target. In the SANTE trial, paraesthesia was the most common complaint (18.2%) and was followed by new onset or worsening of seizures (15%); depression and memory impairment were reported by patients, but not confirmed by objective testing.[24]

There is no apparent decline in cognition and mood during DBS, although a major limitation to this assertion is that the strongest evidence comes from few studies as the SANTE trial.[96],[97] Psychiatric comorbidities may occur, but are mostly transient and reversed with settings adjustments.[97]


 » DBS for Epilepsy in Children Top


Yan and colleagues analysed, in a systematic review, 40 children who underwent DBS implantation for treatment of refractory epilepsy. Only one of the 21 included articles was a randomized trial[60] and 5 were blinded.[20],[44],[43],[45],[57] Most of the children were implanted at the CM (45%) or at the ANT (20%), although other targets such as the hippocampus, STN, posterior hypothalamus, MTT and caudal zona incerta, were described as well. Approximately 12.5% of the patients was classified as Engel class I and 15% did not show any improvement. Complication rates were low, and no deaths were reported. However, infection rate was 7.5% and lead breakage, 2.5%,[99] which are apparently higher than in adults. The outcome of 3 children submitted to DBS was reviewed in a retrospective analysis of a pilot study. One child with CM DBS had 60% improvement and another one was rated as Engel IV. The child with ANT DBS showed 60% improvement as well, but reported behavioural worsening.[100]


 » Conclusion Top


The considerable heterogenicity among studies regarding selection criteria, type of epileptic syndrome, methodology, short blinded phases, different stimulation settings and outcome reports makes data interpretation complex and confusing. Additionally, further understanding of the intricated cerebral circuits involved in epilepsy and the mechanisms that underlie stimulation of this pathological network is necessary to enhance identification of predictive factors and specific selection criteria to optimize results.

DBS is a safe and efficacious therapy in well selected patients who are not candidates for resective surgery. The ANT, hippocampus and CM are the most investigated targets to date. Additional randomized, double-blind trials are needed to further delineate indication and stimulation parameters, and for direct comparison of different neuromodulation modalities.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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