|Year : 2008 | Volume
| Issue : 1 | Page : 111-116
Neuromodulation for epilepsy
Pranshu Bhargava1, Paresh K Doshi2
1 Department of Stereotactic and Functional Neurosurgery, Jaslok Hospital and Research Centre, Mumbai, India
2 In charge-Stereotactic and Functional Neurosurgery Program, Jaslok Hospital and Research Centre, Mumbai, India
Paresh K Doshi
In charge - Stereotactic and Functional Neurosurgery Program, Jaslok Hospital and Research Centre, Mumbai
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Epilepsy is a common disease. WHO data suggests that 1 in 20 people may have an epileptic seizure in their lifetime and at least 1 in 200 go on to develop epilepsy. Anticonvulsant drug therapy using one or more drugs works as an effective tool to suppress seizures in only 70% of the patients, the remaining 30% are either not responsive or suffer major side effects. Surgical resection then forms the next line of management in selected patients. However in some cases surgical resection may not be possible, hence arises the need for alternative therapies. Neuromodulation of the Central Nervous system is a novel technique under evaluation for Medically Intractable epilepsy. CNS stimulation for epilepsy has been a matter of extensive research. We review the Neurophysiological basis of Neuromodulation in Epilepsy and various modalities viz Vagal nerve stimulation (VNS), Transcranial magnetic stimulation (TMS) and Direct cortical stimulation (DCS). Deep brain stimulation (Hippocampal, Anterior thalamic and STN) and RNS are newer modalities and are also reviewed.
Keywords: Epilepsy, neuromodulation
|How to cite this article:|
Bhargava P, Doshi PK. Neuromodulation for epilepsy. J Pediatr Neurosci 2008;3:111-6
| Introduction|| |
Epilepsy is a fairly common disease. WHO data suggests that 1 in 20 persons may have an epileptic seizure in his/ her lifetime and at least 1in 200 goes on to develop epilepsy.  Anticonvulsant drug therapy using one or more drugs works as an effective tool to suppress seizures in only 70% of the patients; the remaining 30% are either not responsive or suffer major side effects.  Surgical resection then forms the next line of management in selected patients. However, in some cases, surgical resection may not be possible; hence arises the need for alternative therapies.
Stimulation of the central nervous system (CNS) is a novel technique under evaluation for medically intractable epilepsy. CNS stimulation for epilepsy has been a matter of extensive research. Cerebellar stimulation  has been reported to reduce seizures. Vagal nerve stimulation (VNS)  has been approved by US FDA for use in epilepsy since 1997. Direct cortical stimulation,  which was previously used as a diagnostic tool, now finds a place in therapeutics. Another modality of electrical stimulation being studied in research settings is repetitive transcranial magnetic stimulation (rTMS),  which is the simplest and least invasive approach. Various institutions are also designing clinical trials to study the therapeutic effects of deep brain stimulation (DBS), either targeting the subthalamic or anterior thalamic nucleus, in the management of epilepsy. While preliminary studies regarding stimulation in the treatment of epilepsy have been suggestive, double-blind studies with larger number of patients will be needed before any definitive answers are found.  The role of subacute hippocampal electrical stimulation (SAHCS) is also being evaluated.
Focal cooling of small regions of the neocortical surface is another innovative approach currently being investigated in rats to determine if induced focal neocortical seizures could be terminated via cooling that region of the cortex. One such study showed that seizures with focal EEG findings were suppressed when cooling was applied directly over the seizure site. 
| Neurophysiological Basis|| |
The CNS is primarily a neural network. Neurostimulation is a means to modulate the information-processing activity of the CNS, so as to correct electrical dysfunction. This is typically carried out to compensate for the loss of normal function. It is important to localize specifically what part of the circuit has to be targeted and which is the part that is malfunctioning.
| Basic Principles of Neurostimulation|| |
The main components of neurostimulation are as follows: A neurostimulator consists of a power supply (i.e, a battery), a pair of electrodes in contact with the tissue, extension wires to connect the electrodes to the battery and a control that will enable the power to be intermittently connected to the electrodes. For current to flow, a cathode and an anode are required. With reference to neurostimulation, there are two types of electrode configurations, referred to as monopolar and bipolar stimulation. Monopolar stimulation refers to an electrode configuration in which the electrode of small surface area is located near or in the nervous tissue to be stimulated. This electrode is typically the negative electrode or cathode. The positive electrode has a larger surface area and is located remote to the stimulation target (commonly referred to as the case). When performing bipolar stimulation, both the positive and negative electrodes are in or near the nervous tissue targeted for stimulation and have the same or similar surface areas.
Computer models of neuronal stimulation
Computational models aid to study the effects of extracellular excitation of central nervous system neurons. The volume of tissue stimulus parameters, both for fibers and cells and how this changes with electrode geometry, stimulus parameters; and the volume of the neuronal elements are quite challenging to determine experimentally. Using a computer model enables these parameters to be examined under controlled conditions and enables determination of the effects of stimulation on all the different neural elements around the electrode simultaneously. Further, well-designed modeling studies enable generation of experimentally testable hypotheses on the effects of stimulation conditions on the pattern and selectivity of neuronal stimulation within the nervous system. However, the models need to be supported further, by experimental work.
Peripheral nervous system (PNS) stimulation
Electrical stimulation of the vagus nerve with a surgically implanted circumneural-cuff bipolar cuff electrode is used for the treatment of intractable epilepsy.  The vagus nerve is composed of a comparatively homogeneous population of myelinated nerve fibers with diameters between 2 mm and 12 mm, with a large majority of fibers having a diameter of 2-6 mm. Electrical stimulation of sufficient magnitude will lead to generation and bidirectional propagation of action potentials from the electrode site.
Central nervous system stimulation
As compared to PNS, the CNS contains a heterogeneous population of neuronal elements including local cell projecting locally around the electrode, as well as those projecting away from the region of stimulation, axons passing by the electrode and presynaptic terminals projecting onto neurons in the region of the electrode. Effects of stimulation can be mediated by activation of any or all of these elements and include both direct effects mediated by electrical stimulation of presynaptic terminals that mediate the effects of stimulation via synaptic transmission, as well as indirect effects mediated by electrical stimulation of presynaptic terminals that modulate synaptic transmission It is thus difficult to find out what neuronal elements are activated by extracellular stimulation and how targeted elements can be stimulated selectively. This forms the main issue for therapeutic neurostimulation. 
| Effect of Electrical Fields on Membrane Polarization|| |
Direct Cortical (DC) stimulation
Direct cortical stimulation is high-frequency electrical stimulation (50 Hz). The efficacy of the DC suppression method has been demonstrated.  This method was applied clinically in the hippocampus with an anode located along the hippocampus in order to inhibit the basal dendrites and the somatic region of the CA1 neurons. However, it may be possible that this would produce excitation in other regions, such as the CA3 layer. Thus, low-amplitude DC stimulation protocols have some potential for clinical implementation, provided the stimulation can be applied in a targeted fashion and without significant electrochemical damage.
It has been seen that high-frequency stimulation of deep brain structures, like the subthalamic nucleus (STN), mimics the effect of lesioning that same structure. This may suggest that electrical stimulation is suppressing neuronal activity.  It has been shown that thalamic neurons were depolarized and stopped firing during high-frequency stimulation.  After termination of high-frequency stimulation, STN neurons recovered slowly from depolarization, during which time their excitability was reduced for several minutes; the reduction in excitability was mediated through nonsynaptic mechanisms.  Studies have also revealed that during high-frequency stimulation, extracellular potassium increases, leading neuronal suppression by depolarization block, independent of synaptic function. , After stimulation was turned off, epileptiform activity was suppressed for several additional minutes (until potassium returned to baseline). Whether depolarization block (mediated in part by extracellular potassium increases) plays a role in clinical deep brain stimulation (DBS) remains to be tested. Currently, used DBS protocols are most likely causing a large extracellular potassium rise, which in turn will dramatically affect function. In addition, other effects of high-frequency extracellular stimulation observed experimentally could also promote depolarization block, such as extracellular Ca 2+ concentration reduction, depolarizing GABA-induced synaptic potentials and swelling. 
The fundamental difference between DC and other stimulation is that effective DC fields (<15 mV/mm field, <20 mA local) are subthreshold. (They do not trigger action potentials.) In contrast, single-pulse, low-frequency and high-frequency techniques all use high intensity (>50 mV/mm field, >50 mA local) suprathreshold stimulation. (They are also, as a result, not as highly orientation-, polarity- and location-dependent.) By taking advantage of the nonlinear dynamic properties of tissue, epileptic activity can be controlled with these approaches.
Vagal nerve stimulation (VNS)
As of today, VNS is an approved therapy for the management of medically intractable partial-onset epilepsy.  VNS therapy is indicated for use as an adjunctive therapy in reducing the frequency of seizures in patients whose epileptic disorder is dominated by partial seizures (with or without secondary generalization); or generalized seizures, which are refractory to antiepileptic medications.
Till mid-2006, about 40,000 people had been treated with VNS. About 80% of all implanted patients have some seizure improvement while on VNS therapy and more than 40% of all implanted patients have a greater than or equal to 50% reduction in the number of seizures over time. It has also been found that the antiepileptic effects of VNS improve over time.  Zabara ,, first reported vagal stimulation as a modality of treatment for epilepsy, Woodbury confirmed his results in the rat model.  A randomized control trial of 125 patients showed a reduction in seizure frequency by 24.5%, using high-stimulation parameters. The first VNS implantation in a human patient was done in November 1998. ,
VNS is indicated for use as an adjunctive therapy in reducing the frequency of seizures in patients whose epileptic disorder is dominated by partial seizures (with or without secondary generalization); or generalized seizures, which are refractory to antiepileptic medications. It can also be used in patients who have medical contraindications for surgery.
A preoperative evaluation includes video-EEG, magnetic resonance imaging (MRI), positron emission tomography (PET) and evaluation by a multidisciplinary team.
Technical aspects 
Left vagus nerve is selected for stimulation. It is approached through a carotid or transverse neck incision at the mid-neck level. The main vagal trunk is identified and exposed for 3-4 cm in the carotid sheath. Electrode coils are passed around the nerve without putting undue tension on the nerve or the coil. The electrodes are tunneled subcutaneously and connected to a pacemaker (after trial stimulation) implanted in the infraclavicular region.
Labar et al.  have found a decline in seizure rate by 37% at one year and 43% at two and three years. Menachem et al. also report an average seizure rate reduction of 43%.  VNS has been shown to benefit primary generalized seizures as well.  Adverse effects include coughing, hoarseness (most common), dyspnea, vocal cord paralysis, infection, Horner's facial palsy, hardware-related complications and death. Contraindications include patients with a history of prior left neck surgery or vagal surgery.
Direct cortical electrical stimulation (DCS)
DCS is used as routine evaluation and localization of the eloquent cortex, as a part of the presurgical workup in a subset of patients with intractable epilepsies who require electrode implantation for further localization. Cortical stimulation helps map the brain functionally. A standard stimulation protocol consists of current pulses delivered in trains lasting 3-8 seconds at 50 Hz. It has been found that 'after discharges' (AD) elicited by DC stimulation were significantly decreased in duration when the application of another brief burst of pulse was given. 
This led Nair and colleagues to explore this form of stimulation to control epilepsy. An 18-year-old right-handed female was diagnosed with right frontal lobe epilepsy. The seizures were characterized as beginning with a sensory aura involving her right foot, hand and face. The seizures often evolved into a tonic contraction of the right side of her body, followed by a right versive head movement. The seizures were medically intractable, hence the patient underwent l evaluation in the form of placement of subdural electrodes over the left cerebral hemisphere. The epileptogenic zone mapped in this patient involved the left lateral frontal region; also, there was involvement of the left mesial frontal region. The four pairs of electrodes used to stimulate spontaneous seizures were located also in the lateral and mesial frontal region. The seizure appeared to abort at the time of stimulation. The study concluded that the institution of a closed-loop direct cortical (DC) stimulation is a feasible protocol, which did not interface with the patient's routine medical care as a part of the pre-surgical evaluation for epilepsy surgery. The closed-loop stimulation protocol did not cause any significant adverse effects when care was taken regarding the adjustments of stimulation parameters to minimize the changes of including seizures with the stimulus. 
Currently, Neuropace is conducting a trial in USA at the Mayo Clinic, Johns Hopkins University and many other institutions using the responsive neurostimulation (RNS).
RNS system has been designed to detect abnormal electrical activity in the brain and to deliver small amounts of electrical stimulation to suppress seizures before there are any seizure symptoms.
Transcranial magnetic stimulation (TMS)
TMS offers a noninvasive access to the intact human brain. TMS has a potential of seizure reduction, at low frequencies. In animal models, low-frequency stimulation, electrical or magnetic, has been known to induce long-term anticonvulsant effects, as well as to reduce the threshold of epilepsy. In contrast, high frequency seems to facilitate pentylenetetrazole-induced seizures. TMS can be used as a single-pulse or repetitive TMS (rTMS).
Repetitive transcranial magnetic stimulation (rTMS) can be used to induce both elevation and reduction of cortical excitability respectively. Whether the excitability of the stimulated cortical network is up- or down-regulated and therefore is facilitated or inhibited seems mainly to depend on the stimulation frequency.  From studies on rTMS of the primary motor cortex in normal humans, evidence exists that rTMS frequencies of 5 Hz and above lead to an increase of excitability,  while frequencies of 1 Hz or less result in reduced motor cortical excitability, , This seems to be confirmed by a PET study, showing that high frequency leads to an increase of regional cerebral blood flow (rCBF) in the stimulated brain areas; whereas under low frequency, the rCBF decreased.  This can also be demonstrated for brain regions remote from the stimulated areas. , So far, the mechanisms behind this phenomenon are not well understood. It is hence fairly unknown whether the separation between those two obviously contradictory modifications of cortical excitability, facilitation and inhibition, is fixed at a certain frequency. Indeed, a possibly large inter-individual variability in the susceptibility to inhibitory and inhibitory and excitatory rTMS was demonstrated.  Moreover, it is not clear whether the results on the motor cortex or on the visual cortex can be seen as generally valid for all brain regions. 
Subacute hippocampal electrical stimulation (SAHCS)
Anterior temporal lobectomy (ATL) is the standard procedure of choice for the majority of patients suffering from intractable temporal lobe seizures. ATL cannot be performed when there is evidence of bilateral independent temporal lobe foci or temporal lobe atrophy in the contralateral side. SAHCS may be an alternative to ATL in such cases. SAHCS at the epileptic foci has shown significant decrease in the number of clinical seizures and interictal spikes.  Seizure control lasted throughout the period of SAHCS, even when antiepileptic drugs (AEDs) were discontinued. Simultaneously, the threshold and amplitude of evoked potentials induced through paired stimuli in the amygdala and recorded at the hippocampus were modified, indicating local inhibitory effects on the stimulated tissue. Also, preliminary results using bilateral chronic electrical stimulation of the hippocampus (CSHC) through implantable devices in cases of bilateral independent temporal lobe were accompanied by a substantial decrease in clinical seizures and interictal EEG spikes without concomitant memory deficits.
Velasco et al. of the Hospital General De Mexico conducted a study including ten patients. It included patients with intractable, incapacitating complex-partial seizures and frequently secondary generalized tonic-clonic convulsions (GTC).
All patients underwent a period of subacute hippocampal electrical stimulation (SAHCS) (16-21 days). The contacts were chosen on the basis of the maximal amplitude and frequency of interictal spike and the occurrence of fast or spike activity during spontaneous epileptic seizures. Bipolar stimulation was performed. Forty-eight hours after the onset of SAHCS, a temporary increment in the number of seizures was observed, probably related to discontinuation of AEDs. Thereafter, the patients had a significant decrease in the number of seizures per day, which lasted throughout the SAHCS period. A concomitant decrease in the number of interictal spikes was also observed that became significant five days after the onset of SAHCS. The EEG and clinical seizures that accompanied AD before SAHCS, disappeared after SAHCS. 
Recently, Velasco et al. have published the results of chronic electrical stimulation of the hippocampus (ESH) in nine patients with complex partial seizures and at least 18 months' follow-up. The MRI scan was normal in five; while in four patients, it showed hippocampal sclerosis. The seizure frequency ranged from 10 to 50 seizures per month. Following DBS, all patients improved. With respect to outcome, patients were divided into two groups, one seizure-free (five patients) and the other with residual seizures (four patients). Both groups shared similar clinical features. However, the patients who were seizure free had normal MRI scan, while those who had residual seizures were being stimulated on a sclerotic hippocampus. They concluded that electrical stimulation of the epileptic hippocampal formation can control mesial temporal seizures. Best results are obtained if with stimulation, a hippocampus does not show sclerosis in the MRI. In these cases, seizures are stopped and the recent memory tests improve even in patients with bilateral foci. 
Anterior thalamic nucleus stimulation
Recently, deep brain stimulation (DBS) of the anterior thalamic nucleus (AN) has come up again as treatment for medically intractable seizures.  The therapy has its basis in studies done in the 1940s and 1950s.  It was introduced in human subjects by Cooper in the 1970s.  Rationale : Although its mechanism is not well understood, DBS produces a functional lesion in the brain likely through depolarization blockade. It has been found that a specific subcortical pathway that synaptically links the anterior thalamic nuclear complex (AN) to the hypothalamus and midbrain is important in the expression of pentylenetetrazole (PTZ) seizures. Disturbance of neuronal activity along this path via focal disruption or chemical inhibition significantly raises seizure threshold. It was also seen that high-frequency (100 Hz) stimulation of AN did not alter the expression of low-dose PTZ-induced cortical bursting but did raise the clonic seizure threshold compared to naive animals or those stimulated at sites near, but not in, AN. The basic procedure is the same as for DBS for Parkinson's disease. A superior frontal approach is used to approach the AN. Stereotactic targeting and MRI visualization are used as a guide to the target, i.e, the dorsal anterior portion of the thalami. 
A study done at St. Joseph's Hospital and Medical Center, Phoenix, Arizona, found that in four of their five patients, AN stimulation showed clinically and statistically significant improvement with respect to the severity of their seizures, specifically with respect to the frequency of secondarily generalized tonic-clonic seizures and complex partial seizures associated with falls. No adverse events could clearly be attributed to stimulation.  A further study by Hodaie et al. at the University of Toronto used AN stimulation in five patients suffering from medically intractable epilepsy. They found a statistically significant decrease in seizure frequency, with a mean reduction of 54% (mean follow-up, 15 months). Two of the patients had a seizure reduction of more than or equal to 75%. No adverse effects were observed after DBS electrode insertion or stimulation. The observed benefits did not differ between stimulation-on and stimulation-off periods. 
Subthalamic nucleus (STN) stimulation
In carefully selected patients, STN stimulation is an accepted modality of management of Parkinson's disease. It was the Grenoble group  that initially described chronic electrical stimulation of this region. The first patient was reported in 1994; later they described the first DBS for Parkinson's disease.  Recently, chronic STN stimulation has been sought as a potential treatment for medically intractable epilepsy. Rationale : The subthalamic nucleus exerts an excitatory control on the nigral system. It has been seen that pharmacological or electrical inhibition of the STN leads to suppression of attacks in animal models of epilepsy.  Benabid et al.  performed STN high-frequency stimulation (HFS) in five patients suffering from medically intractable seizures and considered unsuitable for resective surgery. A 67% to 80% reduction in seizure frequency was observed in three patients, with partial symptomatic epilepsy of the central region. An additional patient suffering from severe myoclonic epilepsy also responded to STN HFS, with a weaker reduction of seizure frequency. The Cleveland study in patients with medically intractable nonsurgical focus epilepsy found that high-frequency stimulation of the subthalamic nucleus (STN) was effective in two of its four patients, with a marked decrease in seizure frequency - ranging from 42% to 75%. Constant and intermittent stimulation modes were similarly effective. These two patients also reported that STN stimulation elicited a significant decrease in seizure severity and duration. 
| Conclusion|| |
Intractable epilepsy forms 30% of all treated patients. Surgery cannot be offered to all such patients. Thus arises the need for alternative modalities of treatment. VNS has shown very good results and has been approved by US FDA. TMS and TCS have also shown promising results. Deep brain stimulation (hippocampal, anterior thalamic and STN) and RNS are newer modalities under evaluation.
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