The surgical treatment of epilepsy continues to advance in several new and exciting directions. Neural stimulation is a promising new technology for the treatment of medically-refractory seizures. In a significant number of patients with epilepsy, seizures remain poorly controlled despite maximal anti-epileptic medications and many of them are not eligible for traditional resective surgery. Novel therapeutic methods have been investigated to decrease the seizure burden in this population. "Neurostimulation" therapy for epilepsy has been receiving increased interest. By appropriate targeting of applied electrical activation at selected nervous system sites, anti-seizure effects may be achieved without the common sedative side effects of anti-epileptic medications.

Dr. Irving Cooper (1922-1985) was a neurosurgical pioneer in this field of "functional neurosurgery".1 After treating patients with tremor by1 creating deep lesions in the brain, he began to utilize methods of electrical brain stimulation as treatment for a variety of disorders. Chronic stimulation of the cerebellum (the hindbrain) was employed for patients with epilepsy, cerebral palsy, and dystonia. Later in his career, he placed deep brain electrodes in the internal capsule of the brain and thalamus to treat epilepsy. Since the pioneering studies of Cooper et al. to influence epilepsy by cerebellar stimulation, numerous attempts have been made to reduce seizure frequency by stimulation of deep brain structures.

High-frequency deep brain stimulation (DBS) of the thalamus or basal ganglia represents an effective clinical technique for the treatment of several medically refractory movement disorders (e.g., Parkinson's disease, essential tremor, and dystonia). Recently, new clinical applications of DBS for other neurologic and psychiatric disorders (e.g., epilepsy and obsessive-compulsive disorder) have been tested. Neurostimulation therapy for epilepsy is growing in popularity. By appropriate targeting of applied electrical activation at selected nervous system sites, antiseizure effects may be achieved without the common sedative side effects of antiepileptic medications. Deep brain stimulation, although experimental, has been applied to several regions of the brain, including the cerebellum, caudate nucleus, centromedian thalamus, anterior thalamus, subthalamus, hippocampus, and neocortical seizure foci. Preliminary results are encouraging, but not conclusive. Electrode implantation in the brain for indications other than seizures has been associated with a 5% risk for intracranial haemorrhage and 5% for infection."2 A controlled study of anterior thalamic stimulation in patients with intractable partial and secondarily generalized seizures is underway. Future investigations are likely to study extrathalamic sites of stimulation, and effects of stimulation contingent upon detection of or prediction of EEG patterns of epileptiform activity.

Several observations have indicated that the anterior thalamic region plays an important role in the maintenance and propagation of seizures. Groups have investigated neuromodulation of the anterior thalamus by using deep-brain stimulation in patients with intractable seizures. In one study, treatment showed a statistically significant decrease in seizure frequency, with a mean reduction of 54% (mean follow-up, 15 months)." 3 Two of the patients had a seizure reduction of > or =75%. No adverse effects were observed after DBS electrode insertion or stimulation. These authors concluded that DBS of the anterior thalamus is a safe procedure and possibly effective in patients with medically resistant seizures. Another group embarked on an open-label pilot study to determine initial safety and tolerability of bilateral stimulation of the anterior nucleus of the thalamus, to determine a range of appropriate stimulation parameters, and to begin to gather pilot efficacy data."4 They reported an open-label pilot study of intermittent electrical stimulation of the anterior nucleus of the thalamus in five patients (three men, two women; age range,24-47 years), with follow-up between 6 and 36 months. All patients had intractable partial epilepsy. Four of the five patients also had secondarily generalized seizures. Stimulation was delivered by bilateral implantable,programmable devices by using an intermittent, relatively high-frequency protocol. Stimulation parameters were 100 cycles per second with charge-balanced alternating current; pulse width, 90 ms; and voltages ranging between 1.0 and 10.0 V. Seizure counts were monitored and compared with preimplantation baseline. Four of the five patients 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. One patient showed a statistically significant reduction in total seizure frequency. No adverse events could clearly be attributed to stimulation. None of the patients could determine whether the stimulator was on or off at these parameters. The researchers concluded that electrical stimulation of the anterior nucleus of the thalamus appears to be well tolerated. Preliminary evidence suggests clinical improvement in seizure control in this small group of patients with medically-resistant seizures. Further controlled study of deep brain stimulation of the anterior nucleus is warranted.

Short-term deep brain stimulation (DBS) recently has been shown to be efficacious in refractory temporal lobe epilepsy. One group 5 evaluated long-term DBS in medial temporal lobe structures in patients with normal magnetic resonance imaging (MRI) findings and investigated the use of chronic DBS electrodes for the localization of the ictal onset zone before DBS. In three patients with complex partial seizures (CPSs), DBS electrodes were implanted in the amygdalohippocampal region to identify and subsequently stimulate the ictal onset zone. CPSs were compared before and after chronic DBS. Side effects were carefully monitored. DBS electrodes yielded high-quality electroencephalogram recordings showing unilateral seizure onset in medial temporal lobe structures. For all patients, unilateral amygdalohippocampal stimulation was performed. After a mean follow-up of 5 months (range, 3-6 months), all patients had a greater than 50% reduction in seizure frequency. In two patients, antiepileptic drugs could be tapered. None of the patients reported side effects. This study demonstrated the feasibility of consecutive electroencephalographic recordings and DBS in medial temporal lobe structures using DBS electrodes.These results prompt further studies in a larger patient population to establish the efficacy and safety of chronic DBS as an alternative treatment for refractory temporal lobe epilepsy.

Evidence from experimental animal studies suggests the existence of a "nigral" control of the epilepsy system. It is hypothesized that the dorsal midbrain anticonvulsant zone in the superior colliculi of the brainstem is under inhibitory control of efferents from the substantia nigra pars reticulata. Inhibition of the subthalamic nucleus (STN) could release the inhibitory effect of the substantia nigra pars reticulata on the dorsal midbrain anticonvulsant zone and thus activate the latter, raising the seizure threshold. Modulation of the seizure threshold by stimulation of deep brain structures-in particular, of the STN is considered a promising treatment option forpatients with pharmacologically intractable epilepsy. Experimental studies supporting the existence of the nigral control of epilepsy system and preliminary results of STN stimulation in animals and humans are being investigated."6 7

1. Stereotact Funct Neurosurg.2003;78(2):95-112.Irving S. Cooper and his role in intracranial stimulation for movement disorders and epilepsy.Rosenow J, Das K, Rovit RL, Couldwell WT.

2. Lancet Neurol.2004 Feb;(3):111-8.Brain stimulation for epilepsy.Theodore WH, Fisher RS.

3. Epilepsia.2002 Jun;43(6):603-8.Chronic anterior thalamus stimulation for intractable epilepsy.

4. Epilepsia.2004 Apr;45(4):346-54.Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy.Kerrigan JF, Litt B, Fisher RS, Cranstoun S, French JA, Blum DE, Dichter M, Shetter A, Baltuch G, Jaggi J, Krone S, Brodie M, Rise M, Graves N.

5. Ann Neurol.2002 Nov;52(5):556-65.Long-term amygdalohippocampal stimulation for refractory temporal lobe epilepsy.Vonck K,Boon P, Achten E, De Reuck J, Caemaert J.

6. Epileptic Disord.2002Dec;4 Suppl 3:S83-93.Deep brain stimulation in epilepsy with particular reference to the subthalamic nucleus.Chabardes S, Kahane P, Minotti L, Koudsie A, Hirsch E, Benabis AL.

7. Sterotact Func Neurosurg.2003;80(1-4):32-6. Effect of high-frequency stimulation of the subthalamic nucleus on the subthalamic neurons: an intracellular study. Lee KH, Roberts DW, Kim U.

Authored By: 
Howard L. Weiner MD
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Authored Date: 
11/2004