DeepDeep BrainBrain StimulationStimulation ff oror EpilepsyEpilepsy Kyung Jin Lee St. Mary’s Hospital The Catholic University of Kore a Introduction EpilepsyEpilepsy ! Common chronic neurological disorder that affects 0.5-1% of the population. ! Medically refractory epilepsy is associated with injury and death, psychosocial dysfunction, and significant cognitive impairment. ! Surgical resection, which is associated with long-term sei zure freedom in 60-80% of patients. ! After temporal lobectomy, the recurrence rate of seizures after a long period of seizure freedom is as high as 15% ! In spite of improvements in surgical technique, 4% of pat ients will suffer death or permanent neurological disabilit y. ! Up to 40% of patients refractory to antiepilepti c medications are not candidates for surgical re section. ! There are unsuitable cases for surgery because of the involvement of the eloquent areas or bila teral or multifocal nature of the ictal onset. ! So, Alternative therapeutic methods are introd uced, such as modulation of cortical excitability through chronic electrical neurostimulation DeepDeep brainbrain StimulationStimulation ! Deep brain stimulation for movement disorder s has meet with widespread success. ! Deep brain stimulation (DBS) has been succes sfully applied for the therapy of several neurol ogical disorders ! Due to the reversibility, programmability, and low risk of complication. ! Recently, stimulation of the nervous system h as been performed in an attempt to treat epile psy. DeepDeep BrainBrain StimulationStimulation (DBS)(DBS) Established for: ! Parkinson’s Disease (STN, GPi) ! Dystonia (GPi) ! Tremor (Vim Thalamus) Emerging treatment for: ! Chronic Pain (PAG/PVG, Thalamus) ! Obsessive compulsive disorder ! Depression (Area 25) ! Epilepsy (Anterior Thalamus) ! Tourette’s Syndrome (CM Thalamus) DeepDeep brainbrain stimulationstimulation ! The exact mechanism of action of DBS in r educion seizure activity is unknown. - DBS may interfere with synchronized oscillations by neurotransmitter release. - Stimulation-induced modulation of pathological neural networks. 1) Targeting of the CNS structures believed to have a “gating” role in the epileptogenic network, such as the STN or thalamus . 2) Targeting of the ictal onset zone with the theory that stimulation may lead to interference with seizure initiation. AnimalAnimal StudiesStudies ! Numerous animal models have been used to eluci date mechanism of DBS action and its potential us efulness in the treatment of epilepsy. ! Models of Pentylenetetrazol, kainic acid, bicuculli ne, picrotoxin, and kindling to induce seizures. ! To identify new targets, to achieve a better under standing of the mechanism of action in accepted t argets. StimulationStimulation forfor EpilepsyEpilepsy TargetsTargets ! Cerebellum (Cooper IS, 1973; Velasco F, 2005) ! Locus ceruleus (Farber J, 1983) ! Centromedian (CM) thalamic nucleus (Velasco F, 1987, 2006; Fisher RS, 1992) ! Anterior thalamus (Mirski MA, 1994 ; Lim et al, 2007) ! Subthalamic nucleus (Veliskova J, 1996; Vercueil L, 1998; Hand forth et al, 2006) ! Vagus nerve (approval by FDA in 1997) ! Amygdala (quenching, Weiss, 1995) ! Hippocampus (Velasco F, 2000 ; Vonek et, 2005) ! Trigeminal nerve, caudate nucleus, substantia nigra SubthalamicSubthalamic nucleusnucleus ! STN DBS for the treatment of Parkinson’s disease makes the STN an appealing target. ! The substantia nigra pars reticulata (SNr) plays a role in seizure propagation through its GABAergic nigrotectal progections to the superior colliculus. ! Inhibition of GABAergic SNr neurons results in su ppression of partial and generalized epileptic seiz ures in a rat model of epilepsy. (Iadarola MJ, 198 2) . STN stimulation for epilepsy treatment : Basis from some experimental evidence of the subcortical network that influences cortical excitability- nigral control of epilepsy system. AnteriorAnterior nucleusnucleus ofof thethe thalamusthalamus ! In 1937, James W. Papez26 described a circuit linking hippocam pal output via the fornix and mammillary nuclei to the ANT. ! The ANT is an appealing target because of its relatively small si ze and projection to limbic structures, ultimately affection wide regions of neocortex. AnimalAnimal studiesstudies ! Observations of enhanced glucose metabolism in the ANT after administration of both pentylenetetrazole and ethosuximide to guinea pigs supports the role of the ANT in propagating seizure activity. - basis from some experimental evidence by the finding of increased metabolic activity in ATN during seizure and high frequency stimulation of ATN. ! Bilateral ANT DBS may also prolong the latency of onset of status epilepticus after administration of pilocarpine (Mirski, MA, 1984). ATNATN stimulationstimulation inin RatRat ((MirskiMirski,, 1997)1997) ! HFS (50-100 Hz) raised clonic sz threshold in rats with PT Z-induced seizures ! LFS (8Hz) - proconvulsant ! HFS believed to be inhibitory (effects mimicked by injectio n of GABA agonist muscimol) ! Mirski and Fisher postulate disruption of corticothalamic tr ansmission with ATN stimulation, preventing normal recrui tment and synchronization into a generalized seizure RationaleRationale ofof DBSDBS ofof ATNATN ! The thalamus was chosen for these studies because stimulation of a relatively small anatomic region can influence physiologic activity in more widespread areas of cortex. ! The anterior nucleus of the thalamus projects largely to the cingulate gyrus, and via the cingulate gyrus, to limbic structure and wide regions of neocortex. ! Total 19 patients STN 3 patients ATN 16 patients ! Removal of electrode in 2 patients : Due to infection PatientPatient selectionselection ! Partial onset seizures with or without secondary ge neralization associated with frequent falls, injuries and impaired quality of life ! Seizures should be refractory to 12-18 months of at least two therapeutically dosed antiepileptic agents ! Failure to respond to surgical resection or vagal ner ve stimulation may also be indications for DBS ! Scalp video-EEG monitoring is necessary to characte ruze seizures and demonstrate bilateral or nonlocali zing findings consistent with preoperative imaging 1. Surgical precedure - MRI guided ATN or STN target with micro re cording - Intraoperative EEG recording with or witho ut stimulation 2. Postoperative management - Post op CT or MRI check - Follow up EEG DirectDirect VisualVisual TargetingTargeting inin MRIMRI Computer superimposition of the schaltenbrand Atlas on a stereotactic MRI with indication of the position in stereotact ic space of AN (ant thalamic nucleus) PostopPostop CTCT MicroMicro recordingrecording PreoperativePreoperative EEGEEG IntraoperativeIntraoperative EEGEEG (before(before insertion)insertion) FP1-F3 F3-C3 C3-P3 FP2-F4 F4-C4 C4-P4 T7-C3 C3-CZ CZ-C4 C4-T8 IntraoperativeIntraoperative EEGEEG (after(after insertion)insertion) FP1-F3 F3-C3 FP2-F4 F4-C4 C4-P4 T7-C3 C3-CZ CZ-C4 C4-T8 R STN1 R STN2 R STN3 Postop. 4 weeks Postop. 26 weeks Postop. 1 year PostoperativePostoperative MRIMRI ResultResult Seizure frequency ! Preoperative : 120.3 ± 304.1 / month ! Postoperative : 27.6 ± 61.2 / month ! Mean seizure reduction rate(%) : 70.4 ± 33.03 % Preoperative sei Postoperative seMean seizure Total F/U Seizure i Case Age Sex Seizure type zure frequency / izure frequency reduction (month) ntensity month /month (%) 1 28 F Both FTLE, cryptogenic 55 15 1 93 0 2 14 F Multifocal epilepsy 47 1200 230 80 0 Multifocal epilepsy (P-O dominant), 3 23 F 42 5 1 80 1 cryptogenic B FLE, symptomatic / prev meningi 4 49 M 22 100 2 98 2 oma resection (frontal) L hemispheric epilepsy, 5 54 F 21 35 1 97 0 R HS & hemispheric atrophy 6 37 F B C-PLE, cryptogenic 20 30 15 50 1 7 25 F B FLE, cryptogenic 19 16 2 93 0 8 41 M B C-PLE, cryptogenic 18 2 1 50 1 P-OLE, symptomatic 9 30 M 18 20 4 75 0 (B perisylvian PMG) Multifocal epilepsy, B schizencepha 10 42 M 16 5 2 60 0 ly 11 14 M Both FLE 12 95 95 0 1 B FLE, cryptogenic, previous cranie 12 23 M 51 12 0 100 2 ctomy (medulloblastoma) 13 35 M B TLE, symptomatic (B HS) 18 20 1 95 1 14 18 M B C-PLE, cryptogenic 16 30 30 0 0 15 25 M Rt. T-P LE, Cryptogenic 30 220 30 86 0 • Seizure intensity 0 : no interval change 1 : mild improved ( < 30% intensity compared with preoperative state) 2 : much improved ( > 30% intensity compared with preoperative state) [ Neurotherapeutics : The Journal of the American Society for Experimental NeuroTherapeutics ] Changes in regional cerebral blood flo w by deep brain stimulation on bilateral anterior thalamic nuclei in patients with intractable epilepsy ObjectivesObjectives ! There has been no information about the function ally and anatomically correlated metabolic or he modynamic changes after DBS on the ATN from r efractory epilepsy patients. ! To address this issue, functional neuro-imaging with SPECT and group ananalysis by statistical pa rametric mapping (SPM2) were used. ! 13 patients were serially performed 99m to measure rCBF changes with Tc- ECD SPECT scannings Dx of patients # of pts Improvement Without major anaotomic lesion or prev 8 64.3% ious surgery (NMA group) With major anaotomic lesion or previou 5 88.8% s surgery (WMA group) Average 73.7% • SPM analysis was performed in 8 patients (NMA) - Good Px group (sz reduction > 64.3%): 5 pts - Poor Px group (sz reduction < 64.3%): 3 pts ImagingImaging AcquisitionAcquisition ! SPECT image acquisition - IV injection of 99mTc-ECD (740-925 MBq ) was followed by s canning after 20-30min with multi-detector scanner (ECAM plu s; Siemens, Erlangen, Germany)