Thesis
Reference
Hippocampal stimulation in epilepsy
BOEX, Colette
Abstract
Chez l'être humain la stimulation hippocampique, 130Hz, peut présenter des effets antiépileptiques, comme indiqué par le taux de décharges épileptiformes inter-crises, utilisé comme marqueur neurophysiologique de l'activité épileptogène; par la fréquence des crises de patients utilisateurs d'un stimulateur chronique. Au contraire une stimulation à basse fréquence, 5Hz, peut produire des crises et augmenter le taux de ces décharges. La forme des stimuli peut influencer les effets de la stimulation. Les stimuli biphasiques, qui permettent que chacun des contacts stimulés, soit alternativement une cathode et une anode, peuvent augmenter le potentiel antiépileptique de la stimulation en cas de sclérose hippocampique.
Nous illustrons comment l'enregistrement de microélectrodes chez l'humain peut participer à mieux comprendre les mécanismes d'action de la stimulation intracérébrale. La stimulation hippocampique peut être un traitement pour les épilepsies pharmacorésistantes temporales spécialement en l'absence de sclérose hippocampique. Son efficacité est dépendante de ses paramètres (fréquence, [...]
BOEX, Colette. Hippocampal stimulation in epilepsy . Thèse de privat-docent : Univ.
Genève, 2014
DOI : 10.13097/archive-ouverte/unige:34133
Available at:
http://archive-ouverte.unige.ch/unige:34133
Clinical Medicine Section Fundamental Medicine Section Dental Medicine Section
Department Neurosciences
Service Neurology
" HIPPOCAMPAL STIMULATION IN EPILEPSY "
Thesis submitted to the Medical School of the University of Geneva
for the degree of Privat-Docent by
Colette BOEX
Geneva
30th of September 2013
Section de Médicine clinique
Section de Médecine Fondamentale Section de Médecine dentaire Département des Neurosciences
Service de Neurologie
"STIMULATION HIPPOCAMPIQUE CONTRE L’EPILEPSIE"
Thèse soumise à l’Ecole de Médecine de l’Université de Genève
pour le titre de Privat-Docent par
Colette BOEX
Genève
30th of September 2013
To
Imane and Dan-juma
Acknowledgments
I would like to take the opportunity provided by this thesis to thank all the people that I have had the chance to meet thus far in my career and who have significantly enriched my career. First, when my research in Geneva was focused on cochlear implants, I had the privilege of working with Prof. P. Montandon, Prof. M. Pelizzone, Dr PD M.-I. Kòs, A. Sigrist, C. Mazaud-Muller, and C. Degive; in Boston with Prof. D.K. Eddington, Prof. N.Y. Kiang, and Dr J. Tierney. Later, while working in the field of deep brain stimulation, I had the chance to work with Prof. M. Seeck, Dr PD C. Pollo, R. Tyrand, Dr S. Vulliémoz and, more recently, with Prof. P. Pollak, Dr PD S. Momjian; finally, in the field of intraoperative monitoring, with Prof. K. Schaller and his team.
During these years, I had the chance to meet very nice people who deal with disease and who understood that participating in research may not help them but could help others with similar diseases in the future. I thank them.
I would like to thank my husband, Dan-juma, and my daughter, Imane.
Table of contents
Acknowledgments ... 4
Table of contents ... 5
List of abbreviations ... 6
Résumé ... 7
Abstract ... 8
1. Introduction ... 9
1.1 Temporal lobe epilepsy ... 10
1.1.1. Mesial temporal structures ... 11
1.1.2. Neuropsychological risks of temporal lobe resection ... 13
1.2. Cerebral stimulation for the treatment of epilepsy ... 15
1.2.1. Deep brain stimulation in animal models of epilepsy ... 15
1.2.2. Mechanisms of action of stimulation ... 18
1.2.3. Cerebral stimulation in patients with epilepsy ... 19
2. Own research on hippocampal DBS ... 26
2.1. Effects of the frequency of stimulation ... 27
2.2. Effects of the waveforms of the pulses of stimulation ... 28
2.3. Results of hippocampal stimulation in patients with temporal lobe epilepsy ... 44
3. Conclusion ... 46
3.1. How can we improve the efficiency of hippocampal stimulation? ... 46
3.1.1. New features of stimulation ... 46
3.1.2. Site of stimulation ... 46
3.1.3. Closed loop responsive system ... 48
3.2. Microstimulation to better understand the mechanisms of action of stimulation ... 50
3.3. Other applications of temporal lobe stimulation ... 52
4. Additional references ... 53
List of abbreviations
AED : Antiepileptic drug ATL : Anterior temporal lobe DBS : Deep brain stimulation EEG : Electroencephalogram
FMRI : Functional Magnetic Resonance Imaging GABA : Gamma-aminobutyric Acid
IED : Interictal epileptiform discharge IEDR : Interictal epileptiform discharge rate ILAE : International League against epilepsy SAH : Selective amygdalo-hippocampectomy TL : Temporal lobe
TLE : Temporal lobe epilepsy
Résumé
Cette thèse décrit l’état de la recherche sur le potentiel anti-épileptique de la stimulation hippocampique. En particulier les études réalisées sur ce sujet au Département des Neurosciences Cliniques des Hôpitaux Universitaires de Genève, sont ici présentées, discutées et mises en perspective.
Ce travail se découpe en quatre sous-chapitres précédés d’une introduction générale sur l’épilepsie et la stimulation intracérébrale appliquée à cette maladie. Ces quatre sous chapitres décrivent, une revue de la littérature du domaine, une étude comparative des effets de la fréquence de stimulation, une étude des effets de la forme des stimuli, ainsi qu’une présentation des résultats cliniques qui ont pu être obtenus avec ce traitement palliatif. Une conclusion présente les mécanismes d’action impliqués et des propositions de lignes de conduite pour poursuivre ces travaux.
Chez l’être humain la stimulation de l’hippocampe à une fréquence dite de haute fréquence, c’est-à- dire 130 Hz, peut présenter des effets anti-épileptiques. Ces effets ont pu être montrés : sur le taux de décharges épileptiques interictales utilisé comme un marqueur neurophysiologique de l’activité épileptogène ; sur la fréquence des crises chez quelques patients qui ont bénéficié d’un stimulateur chronique implanté. Au contraire une stimulation à basse fréquence, 5 Hz, peut produire des crises épileptiques, ainsi qu’augmenter le taux de ces décharges chez l’humain, et ce à priori contrairement à certaines études conduites avec des modèles animaux.
Nous avons également pu montrer que la forme des stimuli, pseudo-monophasiques versus biphasiques, pouvaient influencer les effets de la stimulation. En particulier, des stimuli biphasiques, qui permettent que chacun des contacts stimulés, soit alternativement une cathode et une anode, semblent augmenter le potentiel anti-épileptique de la stimulation hippocampique dite à haute fréquence.
Pour conclure nous illustrons comment l’enregistrement de microélectrodes chez l’humain peut participer à mieux comprendre les mécanismes d’action de la stimulation intracérébrale appliquée à l’épilepsie.
En conclusion la stimulation hippocampique peut être efficace chez les patients souffrant d’une épilepsie du lobe temporal, mais son efficacité sur la réduction de la fréquence des crises est variable et ses déterminants n'ont pas encore été identifiés. Ceux-ci pourraient être liés à des paramètres de stimulation et, évidemment au site de stimulation relativement au réseau épileptique.
Abstract
This thesis describes the state of research on the anti-epileptic potential of hippocampal stimulation.
Specifically, the studies conducted on this domain in the Department of Clinical Neurosciences at the University Hospital of Geneva are presented, discussed and put into perspective here.
This work is divided into four chapters that are preceded by a general introduction to epilepsy and the application of intracerebral stimulation for this disease. These four chapters include a review of the literature in the field, a comparative study of the effects of stimulation frequencies, a study of the effects of the waveforms of the stimuli, and a presentation of clinical results that have been obtained with this palliative treatment. The conclusion presents the different mechanisms of action that may be involved in this treatment and proposes guidelines for continuing this work.
Human stimulation at high frequency (i.e., 130 Hz) may have anti-epileptic effects. This stimulation frequency has been shown to affect the rate of interictal epileptic discharges, which are used as a neurophysiological marker of seizure activity, and to affect the frequency of seizures in some patients who have received a chronic stimulator. In contrast, low frequency stimulation (e.g., 5 Hz) can produce seizures and increase the rate of these discharges in humans, which apparently contradicts some studies that have been conducted in animal models. We were also able to show that the waveform of the stimuli (i.e., pseudo-monophasic versus biphasic) can influence the effects of stimulation.
Specifically, biphasic stimuli, in which the cathode and anode contacts are stimulated alternatively, appear to increase the anti-epileptic efficiency of hippocampal high-frequency stimulation.
Finally, we illustrate how recordings from microelectrodes in humans can increase the understanding of the mechanisms of action by which intracerebral stimulation affects epilepsy.
In conclusion hippocampal stimulation can be efficient in patients with temporal lobe epilepsy, but its effectiveness in reducing seizures, although encouraging, is variable, and its determinants have not yet been identified. These determinants could be related to the parameters of stimulation and, obviously, to the site of stimulation within the epileptic network.
1. Introduction
As defined by the International League against Epilepsy (ILAE), the pathology of epilepsy is determined by the occurrence of at least one seizure, which is defined as “a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain” (Fischer et al., 2005).
The prevalence of epilepsy in developed countries is approximately 1% (Brodie et al., 1997) and is much higher in low-income countries (Newton et al., 2012). As described by the ILAE, many types of seizures and epilepsies exist (Berg et al., 2010). Seizures can be classified as generalized seizures, focal seizures or unknown seizures. Generalized seizures are characterized by paroxysmal activity that spreads almost immediately throughout both hemispheres with subcortical involvement (e.g., “grand mal” generalized tonic-clonic seizures and absence seizures). Focal seizures are confined to one region of one hemisphere but can propagate to other regions and result in a secondary generalized seizure. Focal seizures are described by the localization of the region involved. Hence, focal seizures can be seizures of the temporal, frontal or occipital lobes. Among unknown seizures, epileptic spasms are encountered. The etiologies of epilepsy are also used for classification, and these classes include genetic, structural/metabolic and unknown (previously cryptogenic). Other features, such as age at onset, cognitive performance, EEG characteristics, semiology, etc., are also integrated into the classification of these diseases (e.g., petit mal, juvenile myoclonic epilepsy, etc.).
The neurophysiological process of epilepsy mainly involves hyperexcitabilities due to combinations of excessive excitation and/or a lack of inhibition that result in an over-synchronization of cerebral activity.
The general goal of prophylactic anti-epileptic drugs (AEDs) is either to increase inhibition or to decrease excitation (Rogawski et al., 2002).
For 80% of patients with epilepsy, the use of one (50% of cases) or two or more (30% of cases) AEDs is able to completely prevent the occurrence of seizures, (Kwan et al., 2011). For 20% of patients with drug- resistant epilepsy (approximately 12,000 people in Switzerland), the occurrence of seizures cannot be controlled by any combination of two or more antiepileptic treatments. For approximately 4% of these patients, surgical treatment (i.e., surgical excision of the focus of epileptogenic activity) is an efficient option that is performed without or following intracranial electroencephalographic (EEG) exploration (Duncan et al., 2011). However, in 16% of patients with epilepsy, surgical treatment is not possible; these inoperable patients include those with severe Lenox Gastaut, Dravet, or West syndromes, those in which no specific focus can be identified, those in which multiple foci are suspected, and those in which surgical intervention would result in major postoperative neurological sequelae due to the location of the epileptic focus. Finally, for approximately 9,600 people in Switzerland who suffer from adverse effects of epilepsy drugs, alternative therapies have been sought to suppress seizure occurrence. Brain electrical stimulation is one such palliative treatment that has been explored for the treatment of drug-resistant epilepsy in patients who cannot undergo surgery.
1.1 Temporal lobe epilepsy
Approximately one-third of adult patients with pharmacoresistant epilepsy who receive surgery undergo temporal lobe (TL) resection (Neligan et al., 2013). These patients suffer from temporal lobe epilepsy (TLE), which is described by the ILAE as “a condition characterized by recurrent unprovoked seizures originating from the medial or lateral temporal lobe”. For pediatric epilepsy, this proportion is approximately 20%. The other types of surgeries are neocortical resections (with or without an identified lesion), hemispherectomy, corpus callosotomy or subpial transections (Spencer and Huh, 2008).
TL seizures are usually partial; i.e., a single hemisphere is involved, the seizure is complex, consciousness may or may not be lost, secondary generalization may occur, and the seizure may invade the other hemisphere after a few seconds. These partial TL seizures can be initiated either in the mesial structures of the TL (i.e., the hippocampus, the amygdala, and/or the parahippocampal gyrus) or in the neocortical temporal cortex. Mesial TLE seizures can be preceded by auras that include epigastric, olfactory or/and gustatory sensations or fear. The clinical manifestations of these seizures include ictal oroalimentary automatisms, vocalizations, contralateral upper limb movements, hyperventilation, searching head movements, and body shifting (for reviews, see Bercovici et al., 2012; Kennedy and Schuele, 2012).
Retrograde amnesia (i.e., the inability to recall past events) and coughing are encountered frequently in patients with mesial TLE immediately after seizure. Neocortical TLE often presents with auditory or psychic auras and ictal staring and unresponsiveness followed by ictal vocalizations and contralateral clonic movements (Kennedy and Schuele, 2012). Neocortical TL seizures are often secondarily generalized.
Anterior TL resection has proven to be efficient in suppressing seizures (Wiebe, 2001; Engel et al., 2003;
Spencer and Huh, 2008) but can be associated with important neuropsychological deficits. Additionally, the rate of seizure-free patients following anterior TL resection is of 70% initially (Wiebe et al., 2001), but this rate decreases to 49% after 10 years (McIntosh et al., 2004; de Tilsi et al., 2011).
1.1.1. Mesial temporal structures
The mesial structures have a propensity to synchronize and have been identified as key structures in TLE (Jefferys et al., 2012 for a review). This synchronization is generally attributed to a blockage of GABAergic inhibition and/or to an increase in glutamatergic excitation. The mesial structures are composed of the hippocampus, the parahippocampal gyrus including the entorhinal and perirhinal cortices, the subiculum and the amygdala. These structures are part of the circuit of Papez (Papez, 1937). Within the TL, the hippocampus has the ability to generate interictal discharges (IED, Huberfeld et al., 2011). The hippocampus, the entorhinal cortex, the perirhinal cortex and the amygdala can initiate seizures (Jefferys et al., 2012).
Figure A. Illustration of the organization of the hippocampus and parahippocampus.
The hippocampus, the Horn of Ammond (“Corne d’Ammond”, CA), is an archicortex composed of the three following cytoarchitectural layers: the plexiform layer contains axons and the pyramidal cell layer and the molecular layer contain dendrites. The hippocampus contains the following subregions: CA1, CA2, CA3 and the dentate gyrus (Figure A).
Approximately two-thirds of TLE cases are accompanied by hippocampal sclerosis. Post-mortem and surgical pathologic studies have shown that neuronal loss in the epileptic hippocampus is preferentially located in the dentate gyrus (e.g., the hilar regions in posttraumatic mesial TLE, Swartz et al. 2006) or in CA3 in classic hippocampal sclerosis (Houser et al., 1990; Sagar and Oxbury, 1987) and is associated with mossy fiber sprouting in the dentate gyrus that affects the subhippocampal network (Sutula et al., 1989).
CA3 pyramidal cells are also thought to be the substrate of the propagation of synchronization due to their projections and their strong unitary potentials. Interictal discharges are definitely supported by the synchronized discharges of CA3 pyramidal cells (Jefferys, 2010). The dentate gyrus contains more neurons than the entorhinal or CA3 regions (Wilson et al., 2006). The dentate gyrus also supports adult
(ipsilateral and/or bilateral) also occurs and may be a seizure-induced phenomenon (Thom et al. 2009).
The oscillations in CA1 and the dentate gyrus are fast ripple oscillations that are a marker of epileptogenicity (250-600 Hz, Jiruska and Bragin, 2011).
The parahippocampus is a paleocortex with four to five cytoarchitectural layers. In its more anterior part, the parahippocampus contains the entorhinal and perirhinal cortices. Dendrites of hippocampal CA1 and dentate gyrus neurons are innervated by entorhinal cortical projections (i.e., the “input” of the hippocampus). The entorhinal cortex is cytoarchitecturally more similar to the neocortex than the hippocampus. The entorhinal cortex can generate interictal discharges and fast ripples that have not been well studied (Jiruska and Bragin, 2011). Stimulation of the entorhinal cortex can interrupt seizure generation, which suggests an antiepileptic role of interictal spikes (see Jefferys et al., 2012 for a review).
The entorhinal and perirhinal cortices both exhibit atrophy in patients with TLE (Bonilha et al., 2003).
The subiculum receives afferents from the hippocampus (i.e., the “output” of the hippocampus). In cases of hippocampal pathology, the activity of the subiculum can also become pathological (e.g., hyperexcitability, Huberfeld et al., 2011).
The amygdala has also been identified as a contributor to TLE due to its ability to produce interictal-like discharges. Specifically, the lateral nucleus of the amygdala can exhibit “abnormal patterns of receptor densities and synaptic function” (Graebenitz et al., 2011). The lateral nucleus is connected to the hippocampus.
1.1.2. Neuropsychological risks of temporal lobe resection
Declarative memory (i.e., autobiographical memory or that which we can consciously remember about facts and events), as opposed to procedural memory (i.e., implicit learning), involves the parahippocampal, perirhinal, and entorhinal regions and the subiculum. Memory function can be divided into episodic (i.e., memories of rare, specific events and contextual learning and memory (Tulving, E., 2002) and semantic memory (i.e., frequent and general events and factual knowledge (Squire, 2004).
The hippocampus is prominently involved in encoding declarative (also referred to as explicit) information that is subsequently stored neocortically (Eichenbaum, 2000; Squire et al., 2004). The core role of the hippocampus in the retrieval of memory contents has been disputed. It has been suggested that the retrieval of consolidated memory contents could be independent of the hippocampus.
Nevertheless, evidence suggests that the CA3 region of the hippocampus (along with the frontal cortex) is implicated in the retrieval of memory contents.
Additionally, hemispheric specificity has been described for the hippocampi; verbal memory functions are associated with the language-dominant (usually left) TL (Frisk and Milner, 1990), and visual memory functions are associated with the right mesial TL (Smith and Milner, 1989).
Accordingly, because TLE primarily targets the hippocampal complex, the predominant associated cognitive impairments are found in the domain of declarative memory. Patients with TLE suffer from verbal and/or visual episodic and semantic memory problems. Whether verbal (predominantly left hemispheric) or visual (predominantly right hemispheric) memory functions are impaired is diagnostically indicative of the localization of the epileptic focus. Nevertheless, because TLE does not necessarily only affect the TL per se but can be associated with other anatomical abnormalities, particularly in the neocortical TL or frontal neocortex, other cognitive domains such as language and executive functions can be affected (Bell et al., 2011).
Despite the curative gain in terms of freedom from epileptic seizures, anterior TL resection can produce new or additional neuropsychological impairments (Wiebe et al., 2001; Hamberger and Drake, 2006). Verbal episodic and semantic memory deterioration (e.g., anterograde amnesia and anomia, see Lambon Ralph et al., 2012 for a review; Bonelli et al., 2013) can be produced, particularly after left hemisphere resections, and visual memory deterioration can occur after right hemisphere resections.
The presence or absence of hippocampal sclerosis is indicative of resection-induced cognitive impairments. Neuropsychological deficits are more prominent in patients with minimal TLE lesion than in patients with hippocampal sclerosis, possibly due to the resection of healthy neuronal tissue.
Consequently, memory impairments are produced by anterior TL resections in cases without hippocampal sclerosis. The greater prevalence of post-surgical neuropsychological decline in late onset
Because of the cognitive impairments that are induced by resectioning of epileptic regions and functional neuronal tissue, it is of the utmost importance to most carefully monitor the surgical intervention to limit the resection and avoid any additional cognitive impairment.
For patients with TLE who do not exhibit any lesions, new therapeutic solutions are still being sought, and deep brain stimulation has been considered for these cases. Although no randomized, prospective, large-scale study of brain stimulation for the treatment for refractory epilepsy has yet been completed, the literature suggests promising results for this treatment modality. Particularly for patients with non- lesional TLE, hippocampal stimulation should be considered before surgery as a means to provide freedom from seizures that avoids the risk of neurophysiological deficits associated with surgery.
1.2. Cerebral stimulation for the treatment of epilepsy
1.2.1. Deep brain stimulation in animal models of epilepsy
Numerous stimulation sites, including neocortical and hypothalamic sites, have been evaluated in animal models of epilepsy (Graber et al., 2012 for a review). Here, we will focus on in vivo and in vitro hippocampal stimulation studies that have been performed with whole-animal models of epilepsy.
The effects of hippocampal stimulation have been studied in vivo in animal models produced by electrical kindling and/or with kainic acid injections (Table A). Initially, rodent models of mesial temporal epilepsy were generated with kindling. Kindling consists of 50 or 60 Hz stimulation at high amplitudes that are above the threshold for after-discharges (i.e., amplitudes with pro-epileptogenic effects; Weiss et al., 1998) and are applied for several days to the mesial temporal structures, particularly the amygdala. Studies of hippocampal stimulation that have been conducted in kindling- induced rat models were first analyzed in terms of the effects of kindling on after-discharges (Bragin et al., 2002a, 2002b). Next, low frequency stimulation was found to have antiepileptic effects (Mohammad-Zadeh et al., 2007; Zhang et al., 2009). Nevertheless, as will be described in this thesis, low frequency hippocampal stimulation failed to reduce epileptogenicity in humans. There are two major differences between studies conducted in humans and in vivo and in vitro animal studies: 1) chronic stimulation in humans can only be performed with charge balanced stimulation (Merril et al., 2005), which is not used in most in vitro studies (Table B); and 2) in humans, continuous stimulation is applied (as in our study, Boëx et al., 2007, included in the thesis). Non-charge balanced monophasic pulses are most frequently used in animal models, but these pulses can create damage to the tissue and likely produce inhibition that is actually due to lesions, which may have produced overestimations of the inhibitory effects that have been reported in animal studies using low frequency stimulation. In the studies listed in Tables A and B, low frequency stimulation was typically applied for a few seconds or minutes, which contrasts with the stimulation that is applied in humans (e.g., Boëx et al., 2007, included in the thesis). This difference may also have contributed to the differences observed between in vitro studies and in human studies using low frequency stimulation.
High frequency stimulation of the hippocampus has also been evaluated in kindled rats (Luna-Munguia et al. 2011; Table A) and in vitro (Lian et al., 2003; Table B). More recently, pseudo-random high frequency hippocampal stimulation was shown to be efficient in rat models of epilepsy (Wyckhuys et al., 2010).
In addition to the hippocampus per se, the hippocampal commissure has been studied in vivo with rat models, and low frequency stimulations that have also been evaluated in vitro (Tropani et al., 2013), have been shown to reduce seizures (Rashid et al., 2012, 1Hz, biphasic square pulses, 200 A, 0.1 ms phase width).
Publication Animal/
Models Site of stimulation Stimulation parameters Site of
recordings Effects Mechanisms of action
suggested
In vivo
Bragin et al.
2002a
Rats Kainic acid
Perforant path Rostrum of the hippocampus (commissural pathway)
Long term: square pulses, 2 h, 50 Hz or 1 Hz
Dentate gyrus Entorhinal cortex
Reduce IEDs
No change in seizure frequency
Bragin et al.
2002b Perforant path
Kindling:
5 Hz, square pulses, 10 s, 0.2 ms, 50 – 200 A, once per 24 h, for 15 days
Dentate gyrus CA1
Increased thresholds of after discharges
Reduced seizure frequency with kindling
“Restoration of inhibitory dentate gyrus gate function within entorhinal-
hippocampal circuitry”
Wyckhuys et al.
2010
Hippocampus
High frequency, charge balanced pulses, Poisson distributed stimulation or 130 Hz, 100 s pulse width
Seizure frequency reduction e.g., “disruption of synchrony”
Mohammad- Zadeh et al.
2007
Kindled Rats
Perforant path
Low frequency: 1 Hz, 0.1 ms phase width, monophasic square pulses 12 periods per day of 200 pulses, 50-150 A
Dentate gyrus Retarded kindling acquisition
“Inhibition of synaptic transmission in dentate gyrus”
Zhang et al.,
2009 CA3
Low frequency:
1 Hz, monophasic square pulses, 0.1 ms phase width, 15 minutes, 100 A
Retardation of progression from focal to generalized seizures (also shorter duration of generalized seizures)
Long term depression of CA3
Luna- Munguia et al. 2011
Hippocampus High frequency, 130 Hz,
60 s Hippocampus Reduced seizure susceptibility Increased interictal GABA release
Rashid et al., 2012
Ventral hippocampal commissure
Low frequency: 1 Hz, biphasic square pulses, 0.1 ms phase width, duration 60‘ ON, 15’ OFF, over 2 weeks, 200 A
Reduced seizure frequency Reduced interictal discharges
Table A. In vivo studies of hippocampal stimulation conducted with animal models of epilepsy.
Publication Animal/
Models
Site of stimulation
Stimulation parameters
Site of
recordings Effects Mechanisms of action
suggested
In vitro
Durand et al.
1986 Rats
CA1 Stratum radiation
Square pulse, 10 to 1000 s e.g., 300
CA1 Decreased of synchronized activity
Warren and Durand
1998 Rats
Low calcium
CA1
Anodal or cathodal monophasic square pulses 1 A, 1 s
CA1 Suppression of epileptiform activity Cellular swelling
Ghai et al.
2000 CA1 DC anodal or
cathodal currents CA1 Suppression of epileptiform activity Somatic polarization
Lian et al.
2003
Rats Low calcium, high potassium
CA1, CA3
Sinusoidal, 50 Hz, 140 Hz;
DC anodal square pulses, 120 s, 140 Hz, 3-5 s
CA1, CA3 Inhibition of epileptiform activity
Sinusoidal stimulation:
Depolarization block through increase in extracellular potassium Square pulses: blocked activity by membrane hyperpolarization
Albensi et al.
2004
Rats Bicuculine
methiodide Schaffer collateral
1 to 100 Hz;
square pulses, 100 s, 10
minutes CA1
Inhibition of epileptiform activity Long-term depression
Albensi et al.
2008
Rats Low magnesium
0.03 Hz to 25 Hz;
50 Hz, square pulses, 100 s
Reduced epileptiform activity
Table B. In vitro studies of hippocampal stimulation (this list is not exhaustive; other similar studies were conducted between 1986 and 1998).
1.2.2. Mechanisms of action of stimulation
Currently, the understanding of the phenomena involved in electrical brain stimulation at the neuronal and biochemical levels is incomplete. The phenomena involved in vagal nerve stimulation are localized to the locus coeruleus and the dorsal raphe nucleus, which mediate noradrenergic and serotonergic modulation, respectively (Krahl and Clarck, 2012), and are also related to muscarinic and acetylcholinergic modulation (Nichols et al., 2011). Changes in inhibition and excitation could certainly induce antiepileptic effects, but these effects have not yet been clearly identified in the domain of epilepsy. The imposed rate of axonal stimulation may also be a possible mechanism of the effects of DBS in epilepsy. These mechanisms certainly differ according to stimulation sites, which, for epilepsy, can be in the anterior nucleus, the hippocampus or the neocortex. The mechanisms of action can be studied with multiple modalities that range from functional magnetic resonance imaging (fMRI) to in vitro animal models of epilepsy. Thus far, no fMRI or positron emission tomography (PET) studies have examined the effects of DBS on epilepsy. These latter two methods have provided support for mechanisms of excitation with subthalamic nucleus DBS for the treatment of movement disorders (Shah et al., 2010).
1.2.3. Cerebral stimulation in patients with epilepsy
The first paper included in this work is a review of transcranial magnetic stimulation, vagal nerve stimulation and deep brain stimulation in humans (“Possible new avenues in epilepsy treatment: the stimulation techniques: Deep brain stimulation, vagal nerve stimulation, transcranial magnetic stimulation”; by Boëx C, Brodbeck V, Vulliémoz S, Spinelli L, Rossetti AO, Foletti GF, Pollo C, Seeck M;
published in Schweizer Archiv für Neurologie und Psychiatrie 2011 (162(2):51–6). As described in this paper, recommendations for single sites of stimulation for each type of non-operable pharmacoresistant epilepsy have not yet been established, and several sites of stimulation for the different types of epilepsy have been examined, but not preferable sites have emerged.
The multicenter SANTE study conducted in the United States (Medtronic, Minneapolis, MN, USA;
Clinicaltrials.gov NCT00101933) on a group of 110 patients showed that bilateral stimulation of the anterior nucleus of the thalamus can reduce the frequency of seizures in patients with secondarily generalized partial seizures (median reduction -56%, 6 patients were free of seizures; Fisher et al., 2010).
The anterior nucleus of the thalamus is now a validated target for stimulation for the treatment of epilepsy in Europe. As of 2012, a few patients have benefited from this treatment in Switzerland.
The NeuroPace system (RNS, Mountain View, CA, USA) has been evaluated in a group of 191 adults taking with epilepsy drugs (Clinicaltrials.gov NCT00264810; Morrell et al., 2011). This system is a so-called closed- loop stimulator; the electrical stimulation is triggered in response to the detection of an impeding seizure through the signals recorded by intracranial electrodes placed at the epileptogenic focus. The current necessary to stop the seizure is delivered by the same electrodes. The mean reduction in seizure frequency calculated across 97 patients was 38%. This system is not currently available in Switzerland. At the time of this thesis, no new reports describing the performance of this system have been published.
More recently, stimulation of the trigeminal nerve has been reported (DeGiorgio et al., 2013). This stimulation target requires further study to determine whether stimulation at this site is relevant to decreasing seizure frequencies.
Controlled randomized studies of hippocampal stimulation for patients with hippocampal sclerosis (CoRaStir, Prospective Randomized Controlled Study of Neurostimulation in the Medial Temporal Lobe for Patient with Medial Temporal Lobe Epilepsy; Clinicaltrials.gov, NCT00431457) and without hippocampal sclerosis (METTLE, Randomized Controlled Trial of Hippocampal Stimulation for Temporal Lobe Epilepsy;
Clinicaltrials.gov, NCT00717431) are under way.
Because the most common pharmacoresistant epilepsies are TLEs, the hippocampus is a key structure within the temporal lobe that has the ability to promote the synchronization of neuronal activity, and most TLEs are accompanied by hippocampal sclerosis in adults, we focused on hippocampal stimulation.
Hippocampal stimulation should be considered for patients with TLEs, particularly for patients with non- lesional mesial structures; i.e., patients for whom imaging does not identify any pathological tissue.
Review article
Summary
Stimulation techniques have been extensively explored as new treatments for epilepsy, and their efficacy is still being investigated, albeit several approaches appear to be very promising. Vagal nerve stimulation (VNS) has been a well established palliative therapy for almost 20 years, however, complete seizure control is rarely obtained. Its favourable effect on mood has been noted in several studies, and VNS was FDA-approved for the treatment of major depression in 2005. Intracerebral electrical stimulation is currently being evaluated as a potential treatment for patients with drug-resistant focal epilepsy in whom surgery cannot be offered. We summarise the results of various studies applying deep brain stimulation (DBS) to different brain struc- tures, particularly to the mesial temporal lobe. From these studies, it appears that the efficiency of DBS to reduce epileptic seizures is demonstrated in a sufficiently large patient population but the exact determinants (physical parameters, syndromes) of its success (or its absence) remain unknown.
Repetitive Transcranial Magnetic Stimulation (rTMS) has been investigated as an antiepileptic treatment in patients with focal seizure onset by several groups, however, the clinical success is variable and in most studies rather low.
Keywords: epilepsy; deep brain stimulation; vagus nerve stimulation; transcranial magnetic stimulation; pharmacoresistance
Introduction
A total of 20–30% of all patients with epilepsy become drug- resistant, which means that the seizures cannot be con- trolled by medication. In some of these patients, surgical treatment is an important therapeutic option. However, in approximately 30% of all pharmaco-resistant patients, the resection of the epileptogenic zone is not feasible a) because a dominant epileptogenic zone cannot be unequivocally identified and/or b) due to a major risk of postoperative neurological or cognitive impairment.
Possible new avenues in epilepsy treatment:
the stimulation techniques
Deep brain stimulation, vagal nerve stimulation, transcranial magnetic stimulation
Colette Boëxa, Verena Brodbecka, Serge Vulliémoza, Laurent Spinellia, Andrea O. Rossettib, Giovanni F. Folettib, Claudio Polloc, Margitta Seecka
aUnité d’Evaluation Préchirurgicale de l’Epilepsie & Unité EEG et Epileptologie, Clinique de Neurologie, Hôpitaux Universitaires de Genève (HUG), Genève
bService de Neurologie, CHUV, Lausanne, Switzerland
cService de Neurochirurgie, CHUV, Lausanne, Switzerland No funding; no conflict of interest.
Correspondence:
Dr sc. Colette Boëx
Unité d’Evaluation Préchirurgicale de l’Epilepsie et Unité EEG et Epileptologie
Clinique de Neurologie
Hôpitaux Universitaires de Genève Rue Gabrielle-Perret-Gentil 4 CH-1211 Genève 14
For patients with drug-resistant epilepsy in whom surgical therapy has been excluded, alternative therapies are critically needed. If a prevalence of epilepsy of 0.7%
is assumed, the lack of efficient drug and surgical therapy affects 4000–5000 patients in Switzerland. In order to fill the treatment gap, stimulation techniques have been developed and/or adapted from strategies applied in other neurological diseases. Alternative therapies based on intra- cranial electrical or transcranial magnetic stimulation have been developed mainly in the last 5–10 years, complement- ing vagal nerve stimulation (VNS). VNS has the longest history as an epilepsy treatment since its introduction onto the market in the 1990s, and is currently also approved in some countries for antidepressant therapy. Deep brain stimulation (DBS) is a well established treatment for patients with Parkinson’s disease (or other movement disorders) or for pharmaco-resistant pain. The first reports on repetitive transcranial magnetic stimulation (rTMS) as an antiepilep- tic stimulation method were published in the late 1990s as well. Common to all three techniques is that 1) they are minimally (DBS, VNS) or noninvasive (rTMS), 2) they are reversible treatments, 3) there is still ongoing research concerning the optimal stimulation parameters (frequency, pulse width, amplitude etc.) and 4) they can be adapted individually to each patient and the stimulation parameters can be altered during treatment.
In the following brief review, we will discuss the follow- ing stimulation devices:
– Vagal Nerve Stimulation (VNS)
– Intracranial or Deep Brain Stimulation (DBS) – Repetitive Transcranial Magnetic Stimulation (rTMS)
Vagal nerve stimulation
Vagal nerve stimulation is the most widely used stimu- lation tool in the field of epilepsy (approximately 40000 cases implanted so far). An electrode is wrapped around a branch of the vagus nerve during a brief surgical inter- vention and connected to a control box, which is then implanted underneath the collarbone. The most com- monly-used protocol consists of intermittent stimulation (30 sec. ON, 5 min. OFF), but other cycles have been
Review article
spond to the initially recommended cycle, faster cycles have been evaluated and were well tolerated (e.g. 30 sec.
ON, <1 min. OFF). Acute adjustment of the VNS is possi- ble. By means of an external magnet held over the pace- maker, the stimulation can be changed to continuous mode;
stimulation which is particularly interesting when the patient feels an aura and is still able to abort the seizure by this manipulation. VNS is approved by the Food and Drug Administration (FDA) in the U.S. (patients over 12 years and with partial epilepsy syndromes) and received the European CE mark (with no age restrictions and all epilepsy syndromes).
The first double-blind, multicenter studies have shown that stimulation of the vagus nerve can produce a signifi- cant reduction in seizure frequency [1, 2]. In the long term, 40–50% of patients using this system observed a reduction of at least 50% in seizure frequency [3, 4]. Interestingly, a lack of response during the first 3 months is not necessar- ily related to absence of response during later stimulation periods. Even up to 12 months after the onset of VNS, there are still responders.
Despite the large number of patients stimulated with VNS so far, no particular profile of the “perfect” VNS-candi- date has emerged. Moreover, no particular antiepileptic drug pairs optimally with VNS, leading to enhanced synergis- tic efficiency than either VNS or the drug alone [4]. Among patients who appear to benefit most from VNS are patients with Lennox-Gastaut syndrome (LGS). Tonic seizures were reduced by 88% and atypical absences by 81% in a study of 46 LGS-patients [5]. In addition, VNS was correlated to improved behaviour. Patients with frequent ictal falls who are candidates for corpus callosotomy (CC) benefitted from VNS as much as from CC, with lower complication rates for VNS [6]. Thus, it is now recommended to firstly try VNS, and reserve CC for the more refractory cases.
Adverse events are mainly seen as hoarseness and coughing caused by stimulation of the recurrent laryngeal nerve, a branch of the vagus nerve, and tend to disappear in the first two years after implantation of the VNS. Over- all, adverse events occur at an acceptable rate and can be grouped into stimulation-related (coughing, dyspnea, hoarseness etc.) or surgery-related side effects (haematoma, lead breakage, device migration etc.). The mechanisms of action of VNS have been recently reviewed, but still remain unclear [7]. Autopsies of patients with VNS did not reveal any histopathological changes at the vagus nerve itself or in the brainstem [8]. While only a minority of patients become seizure-free (<10%), it is a safe procedure providing seizure reduction in many patients as well as positive behavioural changes. This might be due to its antidepressant effect, and it is of note that VNS received the FDA approval for treat- ment-resistant major depression in July 2005.
Deep brain stimulation
The first human brain electrical stimulation was performed
in 1941, can be found in the review by Bancaud and his colleagues published in 1966 [10].
The rapid increase in the number of publications on DBS since the 1970s is evidence for the resurging interest in DBS. The most frequent stimulated sites are the subthalamic nucleus (STN) [11], the cerebellum [12–17] and various sites in the basal ganglia or thalamus.
One of the first stimulation sites investigated for the treatment of epilepsy was the thalamus. Stimulation of the anterior nucleus of the thalamus has so far been tested in about 31 patients worldwide with multifocal epilepsy and symptomatic generalised seizures or partial complex [18–23]. These studies report that stimulation at a frequency between 90 and 200 Hz, produces a significant reduction of the seizure frequency (≥60%) in 16/31 of the patients. There is currently an ongoing multicenter study in the US, called the SANTE trial (Medtronic, Minneapolis, MN, USA; Clini- caltrials.gov NCT00101933). The stimulation of the centro- median nucleus of the thalamus, at a stimulation frequency ranging from 4 to 185 Hz, has been tested in 78 patients so far [20, 24–26, 32] where it leads to a significant reduc- tion in seizure frequency of generalised tonic-clonic seizures and of absences, but not of partial complex seizures [23].
Other studies have indicated no reduction in seizure fre- quency [20, 32]. Stimulation of the centromedian nucleus of the thalamus has also been investigated as a treatment of Lennox-Gastaut syndrome [27]. Overall, a seizure reduc- tion of about 80% was achieved and 2 out of 13 patients became seizure-free. This is a promising result in this dif- ficult-to-treat patient group, but needs to be verified in further studies.
Similar to DBS in Parkinson’s Disease, the subthalamic nucleus (STN) has been also explored as a target region for epilepsy patients, but so far with less success than the studies of thalamic DBS. Two research groups have studied STN-DBS in a total of 14 patients with frontal or tempo- ral lobe epilepsy with a stimulation frequency between 100 and 130 Hz [28–32]. A total of 9 patients showed no or only a slight (≤50%) decrease in their seizure frequency.
In 5 patients, a more significant reduction in seizure fre- quency (≥50%) was obtained. DBS of the caudate nucleus was investigated by the group of Chkhenkeli [33]. At low stimulation frequencies (i.e. 4 to 8 Hz), a decrease of interictal epileptic activity was found in 41 out of 57 pa- tients with temporal lobe epilepsy, leading to the implanta- tion of a permanent pacemaker in 38 patients. The authors reported good efficacy regarding generalised tonic-clonic, complex partial and tonic seizures with reduction frequen- cies ranging from 70 to 90%, however, this study has not yet been replicated.
Regarding the stimulation of the cerebellum, the encour- aging results that have been reported in animals and uncon- trolled studies [34] could not be confirmed by controlled clinical studies [35, 36]. Only 2 patients out of 17 benefited from this procedure [37]. However, a recent study reported that stimulation of the superior-mesial cerebellar cortex in 5 patients with generalised tonicoclonic seizures (4 patients
Review article Review article
Amygdalo-hippocampal stimulation (fig. 1) has so far been applied in 22 patients with temporal lobe epilepsy [39–41], with overall positive clinical results. Out of these 22 patients, 5 became seizure-free, 10 patients showed a reduction of seizure frequency of at least 50%, 6 patients had a reduction of less than 50% and one patient experi- enced an increase of seizure frequency. In this group, high frequency stimulations of 130 or 190 Hz, with a pulse width of 90 or 450ms, were applied continuously or in intermittent cycles [39].
With regard to the epilepsy surgery program of Geneva-Vaud, 8 patients suffering from temporal lobe epilepsy were subject to DBS and had a follow-up of >1 year [42]. All patients were initially subject to an extensive examination to test whether they could be surgical candi- dates. In all patients, surgery could not be recommended, due to a high risk of postoperative memory function impairment (evaluated by neuropsychological testing and
Wada tests), and unilateral, continuous DBS of amygdalo- hippocampal complex was initiated. The optimal electrical stimulation parameters appear to be different for lesional and nonlesional mesial temporal lobe epilepsy. A total of 2 patients became seizure-free, one patient before the stimulation was switched on (fig. 1), suggesting a micro- lesional effect, and 4 had a >60% seizure reduction; a result which is in line with the current literature. AH-DBS appears to be an interesting alternative for temporal lobe epilepsy patients in whom surgery is not an option. The microlesional effects should be systematically evaluated by including periods with stimulation OFF in the appropriate protocols.
Other sites of stimulation have been evaluated in very small cohorts of patients. Elisevich et al. [43] obtained a decrease of seizure frequency of 90% in one patient with postencephalitic epilepsy by the stimulation of the primary motor cortex. More recently, Franzini et al. [44] obtained significant reduction in seizure frequency with the stimu- lation of the posterior hypothalamus in two patients with multifocal epilepsy (reductions of 75 and 85%), and with stimulation of the caudal zona incerta in the subthalamus in another two patients with focal sensorimotor epilepsy (reduction of 80% in one patient, the other patient became seizure-free).
Histopathological analyses of the brain tissue of DBS patients did not reveal any parenchymal alterations due to the electrical stimulation [45, 46]. While in some cases of AH-DBS, impairments of memory have been reported [47], we observed transient impairments of memory functions only when stimulating large zones or with high intensity.
When stimulation parameters were readjusted, the patients regained their habitual memory performance. Up to now, no psychiatric side effects have been reported.
Optimisation of DBS parameters
The previously mentioned studies demonstrate the capacity of DBS to reduce the frequency of epileptic seizures in a sufficiently large patient population. Still, the exact Figure 1 Amygdalo-hippocampal DBS: 3D electrode reconstruction after
coregistration of the CT with the 3D preoperative MRI, in one seizure free patient.
Table 1 Summary of reported effects on seizure frequencies. VNS: vagal nerve stimulation, DBS: deep brain stimulation, rTMS: repetitive trans- cranial magnetic stimulation. GTCS: generalized tonic-clonic seizures, TLE: temporal lobe epilepsy. LGS: Lennox-Gastaut Syndrome.
Stimulation device Site Effect Remarks
VNS Vagal nerve LGS: Seizure reduction of tonic seizures or other seizures with falls (80%), atypical absences (90%
in 50% of patients)
Alternative to corpus callosotomy
All other types of epilepsy: in 40–50%, decrease of >50%, very rarely complete seizure control DBS Amygdala-hippocampus Reduction (>50%) or absence of seizure in 70%
of all patients Works better in nonlesional TLE
Centromedian nucleus
of the thalamus Major reduction (>87%) or absence of seizure GTCS, atypical absences in LGS Anterior nucleus of the
thalamus Major reduction (mean 60% in most recent studies) Under investigation in a multicenter study in the US
Subthalamic nucleus Very variable results, none seizure-free In patients with epilepsy with focal seizure onset
Caudate nucleus Reduction of 70–90% Examined mainly for TLE
Cerebellum (vermis) No effect or decrease Probably works best for GTCS
rTMS Applied over vertex Very variable results Only one study with good effects on
Review article
determinants of the therapeutic success (or its absence) remain unknown. The physical parameters of the applied stimuli vary considerably between studies and/or are not controlled. Moreover, the high variability regarding the individual epilepsy syndrome/epileptogenic site of the included patients imposes an additional difficulty for the delineation of optimal stimulation parameters. Preliminary results in amygdalo-hippocampal DBS suggest that stimula- tion of epileptogenic zones at a frequency of 130 Hz is able to reduce or limit the interictal epileptogenic activity, whereas stimulation at low frequencies (5 Hz) seems to increase the epileptic activity. Although the relationship between inter- ictal activity and the frequency of seizures is controversial, a positive correlation seems to be present at least in mesial temporal lobe epilepsy [48–51].
Patients with focal seizure onset seem to be the best candidates for stimulation. The potential beneficial effect of electrical stimulation in various encephalopathies with re- fractory seizures (e.g. Lennox-Gastaut, Dravet, progressive myoclonic epilepsy) is not yet known, despite encouraging results [26, 52, 53].
DBS closed-loop systems
A study is currently underway in the United States to assess the effectiveness of an intracranial “pacemaker” which triggers electrical stimulation in response to the detection of an ongoing seizure through intracerebral electrodes [54, 55].
This system, the NeuroPace RNS system (Mountain View, CA, USA), is being evaluated for medically refractory par- tial-onset epilepsy (Clinicaltrials.gov NCT00264810) [56].
Mechanisms of DBS
Different hypotheses have been considered to explain the observed effects [57]: 1) depolarisation blockade [58] which is an alteration in the activation of voltage-gated currents that block neural output near the electrode; 2) synaptic inhibition [59] which is an indirect inhibition of neuronal output by means of activation of axon terminals that make synaptic connections with neurons near the electrode; and 3) synaptic depression [60] which is a synaptic transmis- sion failure of the efferent output of stimulated neurons as a result of transmitter depletion. Another hypothesis would be that DBS force the neuronal activity to be synchronised to a high frequency (i.e. 130 Hz) [61], preventing any other rate of synchronisation.
Transcranial Magnetic Stimulation
Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive method for cortical stimulation, based on principles of electromagnetic induction. Small intracra- nial electrical currents are generated by a strong fluctuating extracranial magnetic field [62–64]. rTMS has been applied with therapeutic attempts in several pathologies such as
itself [65]. Inhibition of epileptic activity with rTMS is based on the notion that rTMS can achieve a reorganisation of the cortical circuitry in humans leading to potentially ther- apeutic effects [66]. The inhibitory effects of low frequency rTMS have been attributed to the transsynaptic activation of GABAergic inhibitory interneurons to the recurrent in- hibition of the targeted cortical neurons through axonal collaterals [67]. As a lack of GABAergic surround inhibition is assumed to be involved in the spreading of local epilep- tic activity, the concept of inhibitory rTMS in epilepsy with focal seizure onset is convincing. In epilepsy, rTMS has been applied either in single sessions to study acute effects on the number of epileptic discharges, or multiple sessions applied on five to ten consecutive days. Using this method of appli- cation, an antiepileptic effect is thought to accumulate over days and therefore a decrease of seizure frequency is more likely to be obtained.
First studies using low frequency rTMS in epilepsy patients reported promising results with beneficial effects on seizure frequency and/or number of epileptic spikes after stimulation [68, 69]. Several case reports and open-label studies have reported beneficial, some even long-lasting, reductions of seizures and/or epileptic seizures [70–72] or complete arrest of seizure signs in a patient with epilepsia partialis continua [73]. Other studies failed to demonstrate significant effects on seizure frequencies [74].
A total of 4 placebo-controlled human studies have been published so far. Fregni et al. [75] found a significant reduc- tion of epileptic spikes and long-lasting (>2 months) signifi- cant seizure reduction after five days of 1Hz rTMS in the real rTMS group only. Theodore et al. [57] used 1Hz rTMS and found a nonsignificant reduction of seizures after real stim- ulation. Tergau et al. [76] did not find significant differences after 1Hz stimulation. Using 0.3 Hz stimulation, they found a significant decrease of seizure frequencies during the stimulation period only, and when compared to baseline but not to placebo. Cantello et al. used 0.3 Hz stimulation on five consecutive days showing a nonsignificant reduction of seizures and epileptic spikes in the active stimulation group [77]. Despite promising results regarding seizure reduction at least in some studies, rTMS as a therapeutic option has not yet become a routine application. The rather mild and variable success rate together with the relatively time consuming application on several consecutive days has prevented its clinical utilisation until now [78, 79]. A relatively new stimulation protocol is theta burst stimula- tion with which longer-lasting excitability changes can be obtained even after few seconds of stimulation [80].
Conclusion
VNS is an established palliative epilepsy treatment, leading to significant seizure reduction in approximately half of all implanted patients. Its good effect on mood and behaviour has now been described in several studies, leading to its FDA approval also for major depression. In some patients with
Review article
seizure frequency, and in rare cases, even complete seizure control. Larger clinical studies are necessary to determine the role of DBS, and are currently underway for the thalamic and neocortical DBS. Repetitive TMS, on the other hand, still has a controversial effect and has not gained clinical acceptance so far.
References
1 Ben-Menachen E, Mañon-Espaillat R, Ristanovic R, Wilder B, Stefan H, Mirza W, et al. Vagus Nerve stimulation for treatment of partial seizure: 1.
A controlled study of effect on seizures. Epilepsia. 1994;35:616–26.
2 Handforth A, DeGiorgio CM, Schachter SC, Uthman BM, Naritoku DK, Tecoma ES, et al. Vagus Nerve Stimulation therapy for partial-onset seizures: a randomized active control trial. Neurology. 1998;51(1):48–55.
3 Ben-Menachem E. Vagus-nerve stimulation for the treatment of epilepsy.
The Lancet Neurology. 2002;1:477–82.
4 Tecoma ES, Iragui VJ. Vagus nerve stimulation use and effect in epilepsy:
what have we learned? Epileps. and Behav. 2006;8:127–36.
5 Frost M, Gates J, Helmers SL, Wheless JW, Levisohn P, Tardo C, et al.
Vagus nerve stimulation in children with refractory seizures associated with Lennox-Gastaut syndrome. Epilepsia. 2001;42(9):1148–52.
6 Nei M, O’Connor M, Liporace J, Sperling MR. Refractory generalized seizures: response to corpus callosotomy and vagal nerve stimulation.
Epilepsia. 2006;47(1):115–22.
7 Vonck K, De Herdt V, Boon P. Vagal nerve stimulation—1 15 year survey of an established treatment modality in epilepsy surgery. Adv Tech Stand Neurosurg. 2009;34:111–46.
8 Tecoma ES, Iragui VJ, Vagus nerve stimulation use and effect in epilepsy:
what have we learned? Epilepsy & Behavior. 2006;8:127–36.
9 Krause F. Surgery of the brain and spinal cord based on personal experi- ence. Vol III. 1912.
10 Bancaud J, Talairach J, Morel P, Bresson M. La corne d’Ammon et le noyau amygdalien: Effets cliniques et électriques de leur stimulation chez l’homme. Revue Neurologique. 1966;115(3):329–52.
11 Tress KH, Herberg LJ. Permanent reduction in seizure threshold resulting from repeated electrical stimulation. Exp Neurol. 1972;37(2):347–59.
12 Cooper IS, Amin I, Gilman S. The effect of chronic cerebellar stimulation upon epilepsy in man. Trans Am Neurol Assoc. 1973;98:192–6.
13 Cooper IS, Amin I, Riklan M, Waltz JM, Poon TP. Chronic cerebellar stimu- lation in epilepsy. Clinical and anatomical studies. Arch Neurol. 1976;
33(8):559–70.
14 Cooper IS, Upton AR. Effects of cerebellar stimulation on epilepsy, the EEG and cerebral palsy in man. Electroencephalogr Clin Neurophysiol Suppl. 1978;(34):349–54.
15 Gilman S. Cerebellar stimulation: safety factors. Surg Neurol. 1978;9(3):
194.
16 Fenton GW, et al. Chronic cerebellar stimulation in the treatment of epilepsy. In Epilepsy: the eight international symposium. 1978.
17 Levy LF, Auchterlonie WC. Chronic cerebellar stimulation in the treatment of epilepsy. Epilepsia. 1979;20(3):235–45.
18 Hodaie M, Wennberg RA, Dostrovsky JO, Lozano AM. Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia. 2002;43(6):
603–8.
19 Kerrigan JF Litt B, Fisher RS, Cranstoun S, French JA, et al. Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy. Epilepsia. 2004;45(4):346–54.
20 Osorio I, Frei MG, Sunderam S, et al. Automated seizure abatement in humans using electrical stimulation. Ann Neurol. 2005;57(2):258–68.
21 Andrade DM, Zumsteg D, Hamani C, et al. Long-term follow-up of patients with thalamic deep brain stimulation for epilepsy. Neurology. 2006;66:
1571:3
22 Lim SN, Lee ST, Tsai YT, et al. Electrical stimulation of the anterior nucleus of the thalamus for intractable epilepsy; a long-term follow-up study. Epilepsia. 2007;48(2):342–7.
23 Osorio I, Overman J, Giftakis J, Wilkinson SB. High frequency thalamic stimulation for inoperable mesial temporal lobe epilepsy. Epilepsia.
2007;48(8):1561–71.
24 Velasco M, Velasco f, Velasco AL. Centromedian-thalamic and hippocam- pal electrical stimulation for the control of intractable epileptic seizures.
J Clin Neurophys. 2001;18(6):495–513.
25 Velasco F, Velasco M, Ogarrio C, Fanghanel G. Electrical stimulation of the centromedian thalamic nucleus in the treatment of convulsive seizures:
a preliminary report. Epilepsia. 1987;28(4):421–30.
26 Fisher RS, Uematsu S, Krauss GL, Cysyk J, McPherson R, Lesser RP, et al. Placebo-controlled pilot study of centromedian thalamic stimulation in treatment of intractable seizures. Epilepsia. 1992;33(5):841–51.
27 Velasco AL, Velasco F, Jiménez F, Velasco M, Castro G, Carrillo-Ruiz JD, et al. Neuromodulation of the centromedian thalamic nuclei in the treatment of generalized seizures and the improvement of the quality of life in patients with Lennox-Gastaut syndrome. Epilepsia. 2006;47(7):
28 Neme S, Montgomery EB Jr, Rezai A, Wilson K, Lüders HO. Subthalamic nucleus stimulation in patients with intractable epilepsy: the Cleveland experience. In Deep brain stimulation and epilepsy. Lüders HO Eds; 2004.
p. 349–55.
29 Habardès S, Kahane P, Minotti L, Koudsie A, Hirsh E, Benabid AL. Deep brain stimulation in epilepsy with particular reference to the subthalamic nucleus. Epileptic Disord. 2002;4(Suppl 3):S83–93.
30 Shon YM, Lee KJ, Kim HJ, Chung YA, Ahn KJ, Yang DW, Kim BS. Effect of chronic deep brain stimulation of the subthalamic nucleus for frontal lobe epilepsy: substraction SPECT analysis. Stereotact Funct Neurosurg.
2005;83:84–90.
31 Handforth A, DeSalles AAF, Krahl SE. Deep brain stimulation of the sub- thalamic nucleus as adjunct treatment for refractory epilepsy. Epilepsia.
2006;47(7):1239–41.
32 Vesper J, Steinhoff B, Rona S, Wille C, Bilic S, Nikkhag G, Osterag C.
Chronic high-frequency deep brain stimulation of the STN/SNr for progres- sive myoclonic epilepsy. Epilepsia. 2007;48(10):1984–9.
33 Chkhenkeli SA, Sramka M, Lortkipanidze GS, Rakviashvili TN, Bregvadze ES, Magalashvili GE, et al. Electrophysiological effects and clinical results of direct brain stimulation for intractable epilepsy. Clin Neurol Neurosurg.
2004;106(4):318–29.
34 Davis R, Gray E, Engel H, Dusnak A. Reduction of intractable seizures using cerebellar stimulation. Appl Neurophysiol. 1983;46(1-4):57–61.
35 Wright GDS, McLellan DL, Brice JG. A double-blind trial of chronic cerebel- lar stimulation in twelve patients with severe epilepsy. J Neurol Neurosurg Psychiatry. 1984;47:769–74.
36 Van Buren JM, Wood JH, Oakley J, Hambrecht F. Preliminary evaluation of cerebellar stimulation by double-blind stimulation and biological criteria in the treatment of epilepsy. J Neurosurg. 1978;48:107–16.
37 Krauss GL, Fisher RS. Cerebellar and thalamic stimulation for epilepsy.
Adv Neurol. 1993;63:231–45.
38 Velasco F, Carrillo-Ruiz JD, Brito F, Velasco M, Velasco AL, Marquez I, Davis R. Double-blind, randomized controlled pilot study of bilateral cerebellar stimulation for treatment of intractable motor seizures.
Epilepsia. 2005;46(7):1071–81.
39 Tellez-Zenteno JF, McLachlan RS, Parrent A, et al. Hippocampal electrical stimulation in mesial temporal lobe epilepsy. 2006;66(10):1490–4.
40 Velasco AL, Velasco F, Velasco M, Trejo D, Castro G, Carillo-Ruiz JD.
Electrical stimulation of the hippocampal epileptic foci for seizure control:
a double-blind, long-term follow-up study. Epilepsia. 2007;48(10):1895–
903.
41 Boon P, Vonck K, De Herdt V, Van Dycke A, Goethals M, Grossens L, et al. Epilepsia. 2007;48(8):1551–60.
42 Boëx C, Seeck M, Vullièmoz S, Rossetti AO, Staedler C, Spinelli L, et al.
Chronic deep brain stimulation in temporal lobe epilepsy. Epilepsia, in revision.
43 Elisevich K, Jenrow K, Shuh L, Smith B. Lon-term electrical stimulation- induced inhibition of partial epilepsy. J Neurosurg. 2006;105:894–7.
44 Franzini A, Messina G, Marras C, Villani F, Cordella R, Broggi G.
Deep brain stimulation on two unconventional targets in refractory non- resectable epilepsy. Stereotact Funct Neurosurg. 2008;86:373–81.
45 Haberler C, Alesh F, Mazal PR, et al. No tissue damage by chronic deep brain stimulation in Parkinson’s disease. Ann Neurol. 2000;48:372–6.
46 Moss J, Ryder T, Aziz TZ, Graeber MB, Bain PG. Electron microscopy of tissue adherent to explanted electrodes in dystonia and Parkinson’s disease. Brain. 2004;127:2755–63.
47 Van Roost D, Miatton M, Thiery E., Vonck K, Boon P, Vingerhoets G.
Cognitive effects of hippocampal DBS for refractory temporal lobe epilepsy. Acta Neurochirg (Wien). 2008;150:933–1012.
48 Lebowitz RM. Autorhythmicity of spontaneous interictal spike discharge at hippocampal penicillin foci. Brain Res. 1979;172:35–55.
49 Lange HH, Lieb JP, Engel J Jr, Crandall PH. Temporo-spatial patterns of pre-ictal spike activity in human temporal lobe epilepsy. Electro- encephalogr Clin Neurophysiol. 1983;56(6):543–55.
50 Litt B, Esteller R, Echauz J, D’Alessandro M, Shor R, Henry T, et al.
Epileptic seizures may begin hours in advance of clinical onset: a report of five patients. Neuron. 2001;30(1):51–64.
51 Avoli M, Biagini G, de Curtis M. Do interictal spikes sustain seizures and epileptogenesis ? Epilepsy Curr. 2006;6(6):203–7.
52 Andrade DM, Hamani C, Lozano AM, Wennberg RA. Dravet syndrome and deep brain stimulation: seizure control afte 10 years of treatment.
Epilepsia. In press.
53 Vesper J, Steinhoff B, Rona S, Wille C, Bilic S, Nikkhah G, Ostertag C.
Chronic high-frequency deep brain stimulation of the STN/SNr for progres- sive myoclonic epilepsy. Epilepsia. 2007;48(10):1984–9.
54 Fountas KN, Smith JR, Murro AM, Politsky J, Park YD, Jenkins PD.
Imlantation of a closed-loop stimulation in the management of medically refractory focal epilepsy. Stereotact Funct Neurosurg. 2005;83:153–8.
55 Skarpaas TL, Morrell MJ. Intracranial stimulation therapy for epilepsy.
Neurotherapeutics. 2009;6(2):238–43.
56 Sun FT, Morrell MJ, Wharen RE. Responsive cortical stimulation for the treatment of epilepsy. Neurotherapeutics. 2008;5(1):68–74.
57 McIntyre CC, Savasta M, Walter BL, Vitek JL. How does deep brain stimulation work? Present understanding and future questions. J Clin
