Neurostimulation as a Treatment Option for Epilepsy
seizure reduction of at least 50%, and 14 patients were seizure-free for at least six months. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events.
The medial temporal lobe region, more specifically the hippocampus, is a rational target for DBS. This region often shows specific initial electroencephalographic epileptiform discharges that can be recorded with invasive EEG electrodes and represent the seizure onset. Temporal lobectomy and, more specifically, selective amygdalohippocampectomy are effective in reducing seizures with a well-defined mesiobasal limbic seizure onset.97
records cortical EEG signals by means of subdural electrodes and delivers responsive stimulation. Chabolla et al. reported on 18 adults with uni- or bilateral temporal lobe epilepsy who were treated with the RNS and showed a 43 and 53% reduction in seizure frequency, respectively.108
Conclusion
Basic research involving evoked potential excitability studies in humans and anatomical studies with tracer injections and single-unit recordings with histological studies in animals have also confirmed the involvement of the amygdala and the hippocampus in the epileptogenic network.98–100
Some studies have applied electrical
fields to in vitro hippocampal slices with positive effects on epileptic activity.101
Bragin et al.
Also, in vivo studies in rats have shown that high-frequency stimulation affects seizures in the kindling model.102
described repeated stimulation of the hippocampal perforant path in rats showing spontaneous seizures four to eight months after intrahippocampal kainate injection.103
During perforant path stimulation,
spontaneous seizures were significantly reduced. In humans, preliminary short-term stimulation of hippocampal structures showed promising results on interictal epileptiform activity and seizure frequency.104
The lack of adequate treatments for all refractory epilepsy patients, the general search for less invasive treatments in medicine and progress in biotechnology have led to an renewed and increasing interest in neurostimulation as a therapeutic option. Apart from the invasive neurostimulation modalities VNS, DBS and cortical stimulation (CS), non-invasive neurostimulation modalities such as transcranial magnetic stimulation, transcutaneous VNS and transcranial direct current stimulation are under investigation. For all types of neurostimulation currently being used and investigated, major problems remain unresolved. The ideal targets and stimulation parameters for a specific type of patient, seizure or epilepsy syndrome are unknown. Long-term side effects need to be investigated further. The elucidation of the MOA of different neurostimulation techniques requires more basic research in order to demonstrate their potential to achieve long-term changes and true neuromodulation.
Not all patients with temporal lobe epilepsy who underwent resective epilepsy surgery remain seizure-free in the long term. Moreover, temporal lobe resection, especially left-sided, may be associated with memory decline, and temporal lobe resection is contraindicated in patients with bilateral ictal onset. In a pilot trial, 10 patients scheduled for invasive video-EEG monitoring of the medial temporal lobe were offered high-frequency medial temporal lobe DBS following ictal onset localisation.105
Long-term follow-up in 10 of these
patients showed that one out of 10 stimulated patients was seizure-free (>1 year), one out of 10 patients had a >90% reduction in seizure frequency, five out of 10 patients had a seizure frequency reduction of >50%, two out of 10 patients had a seizure frequency reduction of 30–49% and one out of 10 patients was a non-responder. None of the patients reported side effects. In one patient, MRI showed asymptomatic intracranial haemorrhages along the trajectory of the DBS electrodes. None of the patients showed changes in clinical neurological testing.
In four patients with complex partial seizures based on left-sided hippocampal sclerosis, high-frequency stimulation was performed by Tellez-Zenteno et al. in a randomised, double-blind protocol with periods of one month off or on. During the stimulation, on-period seizures decreased by 26% compared with baseline.106
During the off
periods, seizures increased by 49%. Neuropsychological testing revealed no difference between on or off periods, not even in one patient who was stimulated on the left-side following previous right- sided temporal lobectomy. Velasco et al. reported results in 11 patients after 18 months of hippocampal high-frequency stimulation (uni- or bilateral, with or without hippocampal sclerosis on MRI).107
VNS is a moderately efficacious treatment for patients with refractory epilepsy. It is a broad-spectrum treatment, but identification of specific responders on the basis of type of epilepsy or specific patient characteristics has proved difficult. Large patient groups have been examined, and the identification of predictive factors for response may demand more complex investigations. VNS is a safe treatment and lacks the typical cognitive side effects associated with many other antiepileptic treatments. Moreover, many patients enjoy a positive effect of VNS on mood, alertness and memory. In contrast to many pharmacological compounds, treatment tolerance does not develop in VNS. By contrast, efficacy tends to increase with longer treatment. To increase efficacy, research into the elucidation of the MOA and optimisation of stimulation parameters is crucial.
DBS is evolving from an experimental treatment towards a reasonable treatment option for patients with refractory epilepsy. In addition to several pilot trials in different targets, one randomised controlled trial of DBS in the AN of the thalamus showed that it is a feasible and safe treatment option and that the responder rate is slightly superior to the results of VNS. The precise role of DBS in the treatment of refractory epilepsy remains to be determined. n
Paul Boon is a Professor of Neurology and Chairman of the Department of Neurology at Ghent University Hospital. In 2009, he was appointed Chairman of the Head, Neck and Nervous System Division at Ghent University Hospital, which covers seven clinical departments: neurology, psychiatry, neurosurgery, ophthalmology, otorhinolaryngology, head and neck surgery and dentistry.
Patients with
normal MRIs showed optimal outcome, with four of them seizure-free after one to two months of stimulation. None of the patients showed neuropsychological decline, with a trend towards improvement.
An implanted responsive neurostimulator system (RNS) is being evaluated for safety and efficacy in a multicentre trial. The device
EUROPEAN NEUROLOGICAL REVIEW
Kristl Vonck is an Associate Professor of Neurology in the Department of Neurology at Ghent University Hospital. Her primary research interests include neurostimulation, stem cells and local drug delivery, and she has published over 90 articles in peer-reviewed journals. Dr Vonck has also published 140 abstracts and five book chapters and given 115 presentations. She obtained both her MD and PhD from Ghent University.
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