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.
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.
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.
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 Centre, Phoenix, Arizona, found that in four of their five patients, 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 respective 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.