Cerebellar Contribution to Absence Epilepsy

Epilepsia, 2005

Summary: Purpose: The efficacy and safety of cerebellar stimulation (CS) was reevaluated in a double-blind, randomized controlled pilot study on five patients with medically refractory motor seizures, and especially generalized tonic–clonic seizures.Methods: Bilateral modified four-contact plate electrodes were placed on the cerebellar superomedial surface through two suboccipital burr holes. The implanted programmable, battery-operated stimulator was adjusted to 2.0 μC/cm2/phase with the stimulator case as the anode; at this level, no patient experienced the stimulation. Patients served as their own controls, comparing their seizure frequency in preimplant basal phase (BL) of 3 months with the postimplant phases from 10 months to 4 years (average, eight epochs of 3 months each). During the month after implantation, the stimulators were not activated. The patient and the evaluator were blinded as to the next 3-month epoch, as to whether stimulation was used. The patients were randomized into two groups: three with the stimulator ON and two with the stimulator OFF. After a 4-month postimplantation period, all patients had their stimulator ON until the end of the study and beyond. Medication was maintained unchanged throughout the study. EEG paroxysmal discharges also were measured.Results: Generalized tonic–clonic seizures: in the initial 3-month double-blind phase, two patients were monitored with the stimulation OFF; no change was found in the mean seizure rate (patient 1, 100%, and patient 5, 85%; mean, 93%), whereas the three patients with the stimulation initially ON had a reduction of seizures to 33% (patient 2, 21%; patient 3, 46%; patient 4, 32%) with a statistically significant difference between OFF and ON phase of p = 0.023. All five patients then were stimulated and monitored. At the end of the next 6 months of stimulation, the five patients had a mean seizure rate of 41% (14–75%) of the BL. The second patient developed an infection in the implanted system, which had to be removed after 11 months of stimulation; the seizures were being reduced with stimulation to a mean of one per month from a mean of 4.7 per month (BL level) before stimulation. At the end of 24 months, three patients were monitored with stimulation, resulting in a further reduction of seizures to 24% (11–38%). Tonic seizures: four patients had these seizures, which at 24 months were reduced to 43% (10–76%). Follow-up surgery was necessary in four patients because of infection in one patient and lead/electrode displacement needing repositioning in three patients. The statistical analysis showed a significant reduction in tonic–clonic seizures (p < 0.001) and tonic seizures (p < 0.05).Conclusions: The superomedial cerebellar cortex appears to be a significantly effective and safe target for electrical stimulation for decreasing motor seizures over the long term. The effect shows generalized tonic–clonic seizure reduction after 1–2 months and continues to decrease over the first 6 months and then maintains this effectiveness over the study period of 2 years and beyond.

Brain Research Bulletin, 1977

firing patterns during generalized penicillin epilepsy in the awake cat. BRAIN RES. BULL. 2(5) 317-321, 1977.-Single unit activity was recorded in the neocortex of awake cats during spontaneous spike wave discharges. Ongoing activity was interrupted during paroxysmal events and was replaced by (1) bursts of action potentials coincident with the EEG spike and cessation of firing during the wave, or (2) cessation of firing for the duration of the paroxysm. Other units which displayed little or no background activity were recruited to tire during the EEG spike. Surface cerebellar stimulation at high frequencies led to decreased neuronal activity while single pulse shocks resulted in short latency activation. These results were compared to studies of spike wave activity elicited by electrical stimulation.

Frontiers in Neurology

Cerebellar stimulation reduces seizures in animals and in humans with drug-resistant epilepsy. In a pilot safety and feasibility study, we applied continuous cutaneous vibratory stimulation (limb proprioceptive cerebellar stimulation) to foot limb proprioceptive receptors to activate cerebellar, pontine, and thalamic structures in drug-resistant epilepsy patients for 8-h nocturnally up to 6-months after a 4-week pre-treatment control baseline. Seizure frequency was evaluated during the baseline control period, and at 6, 12, and 24 weeks after the control recordings. Five-subjects completed at least the first 6-week treatment. At 12-weeks, the median reduction in seizure frequency was −27.8% (mean reduction = −22.3%). Two subjects continued for 24 weeks, with a decline of −44.1 and −45.4%. This pilot study provides support for further clinical studies into the safety and efficacy of limb proprioceptive cerebellar stimulation for epilepsy.

Epilepsia, 2006

Epilepsia, 2006

Background In recent years, the cerebellum and its nuclei have become important targets for understanding and suppressing the mechanisms of seizures. The aim of this study was to investigate the effects of electrical stimulation (ES) applied to the lateral cerebellar nucleus (LCN) in rats with early and fully developed pentylenetetrazol (PTZ)-kindled seizures. MethodsThe experimental groups were represented by rats kindled with PTZ (35.0 mg/kg, i.p.) to myoclonus (9-11 PTZ injections) and generalized tonic-clonic seizures (21 PTZ injections). Unilateral ES (100 Hz, 0.25 ms, 4.5-5.0 duration) was delivered daily for five days after the last kindled PTZ administration with PTZ seizure testing after the last ES. Results ES of LCN performed at the early stage of kindling facilitated the appearance of myoclonus and increased seizure severity by 30.2% - up to 2.25+0.46 scored points compared to the control group (P&lt;0.05). In fully developed kindling, ES prevented generalized seizure an...

Neuroscience Letters, 2006

Electrical stimulation of the cerebellar cortex by implanted electrodes has been shown to ameliorate refractory epilepsy. We investigated the potential therapeutic role of high-frequency cerebellar rTMS in patients affected by refractory epilepsy due to single or multiple foci. Six patients, three with single and three with multiple epileptic foci, underwent 20 rTMS sessions. Each session was given daily, excluding weekends, and consisted of two trains of 50 stimuli (5 Hz frequency and 90% motor threshold intensity), separated by 50 s interval. rTMS was delivered through a focal coil (2 cm below and lateral to the inion) bilaterally in patients with multiple foci (two trains for hemisphere: 100 stimuli each side) and contralaterally to the epileptic focus in the others. Seizure frequency was monitored four weeks before stimulation (pre-rTMS), during the four-week treatment (rTMS) and four weeks after the treatment (post-rTMS). The rTMS over the cerebellar cortex was associated with a significant decrease of rTMS versus pre-rTMS seizure frequency both in patients with single and multiple epileptic foci. However, during the post-rTMS period seizure frequency was back to the pre-rTMS frequency. Although the results are still preliminary, they encourage further studies on larger series of patients. In particular, this rTMS approach, as compared with others, might be more useful in patients with multiple epileptic foci.

Epilepsy Research, 2010

The aim of this study was to determine the current intensities necessary to elicit three levels of varying EEG and behavioural phenomena with electrical stimulation, and also to determine the consistency of the EEG and behavioural components of the triggered seizures over time. Electrical stimulation of the primary motor/somatosensory cortex was performed in 16 adult rats with multichannel microwire electrode arrays. Stimulation was delivered at a frequency of 60 Hz (1 ms pulse width), for 2 s duration, as biphasic rectangular pulses over four of the eight available electrode pairs. Current intensity thresholds for interruption of normal behaviour, epileptiform afterdischarge (EAD) longer than 5 s and motor seizures with Racine severity greater than 3 were not correlated to time post-surgery. The Racine threshold was shown to be negatively correlated to the EAD duration and Racine severity of seizures elicited in the following sessions. Seizures were reliably generated in rats through cortical stimulation with microwire electrode arrays and these seizures were not shown to be subject to any kindling type effects up to 53 days post-implantation. Both the electrographic duration and behavioural severity of stimulated seizures remained, on average, constant during this experimental period. Approximately one-third of stimulations did not cause observable motor seizures and of those that did result in seizures, forelimb clonus was the most common manifestation and the mean EAD duration was 18.5 s. No damage beyond that caused by surgical implantation of electrodes was observed in the histological analyses of stimulated and non-stimulated tissue. The consistency, duration and severity of seizures within this timeframe make this cortical stimulation model suitable for investigations into novel therapeutic interventions for epilepsy that require a known seizure focus.

Experimental Neurology, 2010

The cerebral cortex is tightly and reciprocally linked to the cerebellum and the ascending dentatothalalmo-cortical pathway influences widespread cortical regions. Using a rodent model of middle cerebral artery stroke, we showed previously that chronic, 20 Hz stimulation of the contralateral lateral cerebellar nucleus (LCN) improved motor recovery, while 50 Hz stimulation did not. Using motor evoked potentials (MEP) elicited by intracortical microstimulation, we now show the effect of LCN stimulation on motor cortex excitability as a function of pulse frequency in propofolanesthetized rats. MEPs were recorded serially, at 15-second intervals, with cerebellar stimulation delivered in 10-minute blocks at rates of 20, 30, 40, 50 or 100 Hz. Stimulation at 20, 30, 40 or 50 Hz enhanced the average MEP response across the block, with the maximal overall increase observed during 30 Hz stimulation. However, the effect varied as a function of both repeated trials within the block and LCN stimulation frequency, such that 40 Hz and 50 Hz stimulation showed a reduced effect over time. Stimulation at 100 Hz produced a transient increase in MEP amplitude in some animals; however the overall effect across the block was a trend towards reduced cortical excitability. These results suggest that direct stimulation of the LCN can yield frequency-dependent changes in cortical excitability and may provide a therapeutic approach to modulating cortical activity for the treatment of strokes or other focal cortical lesions, movement disorders and epilepsy.

Neurobiology of Disease, 2007

Pharmacological inhibition and high-frequency stimulation (HFS) of the substantia nigra pars reticulata (SNr) suppress seizures in different animal models of epilepsy. The aim of the present study was to determine the optimal parameters of HFS to control spontaneous seizures in a genetic model of absence epilepsy in the rat. Single SNr stimulation that was bilateral, bipolar and monophasic at 60 Hz frequency and with 60-micros pulse width was optimal. However, when used for repeated stimulations, long-term suppression did not occur and even the number of seizures increased. A delay of at least 60 s between stimulations was necessary to be fully effective. Although single HFS of the SNr can be used to suppress ongoing seizures, repeated HFS is ineffective and could even aggravate seizures in our model. Thus investigations of accurate stimulation procedures are still needed.

Neurological Research, 2011

Objective: Cerebellar Purkinje cells (PCs) fire burst of Na z spikes riding on a Ca 2z spike which basically involves the same ionic channels and currents establishing the paroxysmal depolarization shift (PDS) discharges. Methods: Intracellular recordings were taken from somata of PCs to explore effects of the epileptogenic drugs of pentylenetetrazol (PTZ), bicuculline methiodide (BCC) and 4-aminopyridine (4-AP) on the firing behavior of these cells. Results: PCs showed spontaneous PDS-like events in presence of these drugs. Generally, PTZ and BCCinduced PDSs were similar in shape and properties but were remarkably different from 4-AP-induced PDSs. Blockade of glutamate transmission inhibited generation of PDSs by PTZ and BCC but it did not affect discharge of PDSs induced by 4-AP. Careful analysis of PDS discharges revealed that they have remarkable differences with normal and 4-AP-induced spontaneous activity. Discussion: Data presented here indicate that PDS discharges in PCs are induced either by the imbalance between excitatory and inhibitory synaptic transmission or by the suppression of 4-AP-sensitive currents.

The Canadian Journal of Neurological Sciences, 2012

Neurosurgery, 2011

BACKGROUND: Cortical stimulation is under investigation in clinical trials of drugresistant epilepsy. Results are heterogeneous; therefore, more evidence from animal studies is required. OBJECTIVE: To investigate the therapeutic effects of parameters of direct stimulation of the cortical focus in a Macaca fascicularis presenting focal motor epilepsy. METHODS: We developed a model of motor seizures after intracortical injection of penicillin G in the primary motor cortex of a Macaca fascicularis. We performed electric epidural cortical stimulation at low, medium, and high frequency using continuous or short-term stimulation. Short-term stimulation was triggered on seizure onset, either visually or automatically with a seizure detection algorithm connected to a programmable stimulator. RESULTS: Automated detection could detect 100% of the seizures, but ensuing cortical electric stimulation failed to abort seizures. CONCLUSION: This study demonstrates the inefficacy of the stimulation of the cortical focus to prevent seizures induced by local injection of penicillin G. Because this model may be too severe to allow comparison to human epilepsies, further work is required in other monkey models of focal epilepsy.

Epilepsy Research, 2004

We evaluated the efficacy of vagus nerve stimulation (VNS) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a validated model for absence epilepsy. In the first experiment, we investigated whether VNS applied at seizure onset can interrupt spike and wave discharges (SWD). In the second experiment, we investigated whether SWD are suppressed or shortened in duration when VNS is applied several hours per day. Both control and VNS groups underwent EEG and VNS electrode implantation. For the first experiment, a randomized crossover design was used. Stimuli (amplitude: 3 V; frequency: 30 Hz; pulse duration: 500 s) were given when an SWD occurred on the EEG. The experiment was repeated the next day. In the second experiment, treated animals were stimulated (amplitude: 1.5 mA; frequency: 30 Hz; pulse duration: 500 s; on/off time cycle: 30 s/5 min) for 3 h per day, during five consecutive days. In the first experiment, the duration of the SWD was increased on day 1, (P < 0.05). There was no difference in SWD duration on Day 2. In the second experiment, no significant differences could be found in number, duration and EEG frequency of SWD. VNS applied at the onset of an SWD can prolong the duration of SWD in GAERS. As a 5-day stimulation protocol had no effect, long-term VNS might be necessary to affect SWD.

Journal of Neurosurgery: Pediatrics, 2013

Epilepsy, especially with refractory seizures, is thought to arise only from cortical lesions or substrate. The authors report on 2 patients with refractory epilepsy and cerebellar lesions. Depth electrodes were placed within the cerebellar lesions in both patients, and intracranial electroencephalographic recordings showed seizure origin from the cerebellar lesions. One patient eventually attained seizure control with antiepileptic drugs. The other case involved a child with generalized myoclonic epilepsy associated with a pilocytic astrocytoma of the cerebellum. This patient obtained seizure control following gross-total resection of the tumor.