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  • 1. Implantable Devices:Implantable Devices: Treatment for EpilepsyTreatment for Epilepsy By:Melanie Ostreicher
  • 2. Implantable DevicesImplantable Devices • Electronic Devices are implanted into one’s brain • Patient usually is not responding to other treatments and therefore turns to surgery • Must undergo neurosurgery for implantation of the electrode • Many still take antiepileptic drugs • Patients are monitored closely to see effectiveness and any adverse reactions
  • 3. Implantable DevicesImplantable Devices • 2 major biological paradigms guide device interventions: 1) Excitation/Inhibition of central structures that exhibit abnormal cortical activity 2) Epileptic focal region interference
  • 4. Implantable DevicesImplantable Devices • Current Devices can be divided into 2 groups: 1) Closed-Loop- monitors physiological signals and triggers a therapeutic response based on changes 2) Open-Loop- chronically modulates brain activity to suppress seizures through a cycle of stimulation -switched on/off by an internal clock ie. Vagus Nerve Stimulation
  • 5. Implantable DevicesImplantable Devices • The above can be achieved by: -Electrical stimulation -Focal cooling -Localized drug infusion
  • 6. Focal CoolingFocal Cooling
  • 7. Focal CoolingFocal Cooling • The development of an implantable, electrically driven cooling device is a promising treatment for refractory epilepsy • Used to prevent focal seizures • Cooling has demonstrated seizure prevention, cessation and a decrease in frequency
  • 8. Focal CoolingFocal Cooling • Cooling … – reduces synaptic transmission in mammalian brains – reduces end plate potentials – alters excitatory transmission of pre and post- synaptic mechanisms – inhibits Sodium-Potassium ATPase – reduces neurotransmitter release from pre- synaptic vesicles
  • 9. Focal CoolingFocal Cooling • Thermoelectric devices or Peltier Devices: - small and light - semiconductors are connected electrically in series and thermally in parallel between 2 ceramic plates - when current is passed, one of the plates cools almost instantly and the other heats (various techniques to remove heat)
  • 10. Focal CoolingFocal Cooling • Thermoelectric devices or Peltier Devices: - allow thermoelectric device to come into direct contact with neocortex and activate local cooling - cooling localized to small region of neocortex - uses closed-loop feedback control: could cool at onset of seizure detection or seizure anticipation
  • 11. Focal CoolingFocal Cooling • Thermoelectric devices or Peltier Devices: – no implantable devices currently available for treatment – not yet approved but are in the process – can help identify the site of seizure origin then device could be implanted in this location
  • 12. Focal CoolingFocal Cooling • History: – Causal relationship between elevated temperature and seizures known since Hippocrates – German physiologist Trendelburg studied local hypothermia and investigated it’s effects on the brainstem and neocortex (1905)
  • 13. Focal CoolingFocal Cooling • History: – Local cooling used throughout 20th century to investigate cortical and subcortical localization of specific brain functions – In 1938 Fay suggested the use of brain cooling for the treatment of head trauma – In 1969 and 1970, clinical investigations documented the benefits of cooling in the therapy of epileptic patients
  • 14. Focal CoolingFocal Cooling • Neuronal Structures Involved: – Neocortex (Rothman et al. 2005) • needs direct cortical contact • reduces seizure frequency, duration and severity
  • 15. Focal CoolingFocal Cooling • Neuronal Structures Involved: – Hippocampus and Entorhinal cortex (Burton et al., 2005; Motamedi et al., 2006) • in implanted rats, cooled seizures did not fully generalize • induced seizures were terminated after focal cooling of rat hippocampal brain slices • terminated spontaneous epileptiform activity
  • 16. Electrical StimulationElectrical Stimulation
  • 17. Electrical StimulationElectrical Stimulation • Stimulation of nervous tissue in an attempt to interfere with mechanisms related to the physio-pathology of symptoms • Can affect deep brain structures • All patients must undergo EEG monitoring to characterize seizure types and localization
  • 18. Electrical StimulationElectrical Stimulation • Disruption of function at site of seizure onset (ictal onset zone) can prevent seizures or propagation • Target site determined (ie. Anterior Nucleus of the Thalamus, ANT) and electrode device is implanted • Electrode composition depends on specific study – ie. 4 platinum-iridium stimulation contacts each 1.5mm wide
  • 19. Electrical StimulationElectrical Stimulation • History: – Mineral sources of electric energy (ie. amber and magnetite) were used for therapeutic purposes as early as 9000 BC – Experiments with neurophysiology using electric currents began in 1786 with Galvani – In 1870 Fritsch and Hitzig produced seizures in a dog’s brain by applying electrical current therefore initiating the study of the CNS with electricity
  • 20. Electrical StimulationElectrical Stimulation • History: – Beginning of 20th century electric currents used to study spinal reflexes and motor and sensory responses – Stimulation of various brain regions to treat not only epilepsy but pain, movement disorders, spasticity and psychiatric disorders
  • 21. Electrical StimulationElectrical Stimulation • Neuronal Structures Involved: – Cerebellum (Cooke and Snider, 1955; Dow et al., 1962) • electrical stimulation to the cerebellar hemisphere • some efficacy but relatively mild – Centromedian Nucleus of the Thalamus (CM) (Velasco et al., 1987-2001) • suggested to suppress focal and generalized seizures • modest benefit in generalized tonic-clonic seizures but not in total number of seizures
  • 22. Electrical StimulationElectrical Stimulation • Neuronal Structures Involved: – Vagus Nerve (Uthman et al., 1990; Fisher et al., 1997) • stimulation increases metabolic activity in the thalamus • shown to be safe and effective and has been approved by FDA
  • 23. Electrical StimulationElectrical Stimulation • Neuronal Structures Involved: – Anterior Thalamic Nuclei (Sussman et al. 1988; Hodaie et al., 2002) • hypothesized to modulate epileptiform activity in the frontocentral cortex and the anterior temporal brain regions that are functionally connected to them • electrical stimulation effective in modulation of partial seizures arising from these regions • stimulation interferes with seizure propagation with lesser efficacy on seizure onset
  • 24. LimitationsLimitations
  • 25. LimitationsLimitations • Focal Cooling: – No studies done with implantable devices on human brains, just animals – Difficulty in inserting any device beyond sulcal margin (can still cool portions of substantial area of exposed cortex) – Unknown how extensive an area of cortex will need to be cooled to effectively prevent or terminate seizures
  • 26. LimitationsLimitations • Focal Cooling: – Exact temperature required is unknown – If patients have seizure foci colocalizing with eloquent cortex they would not be good surgical candidates because surgical resection carries significant morbidity
  • 27. LimitationsLimitations • Electrical Stimulation: – Long periods of time may be required to observe therapeutic effects – Effects may not occur by decreasing number of seizures – Lack of ability to discern if intended amount of stimulation was actually delivered to target tissue
  • 28. LimitationsLimitations • Both: – Control and trial design issues: blinded, randomized designs are not practical – Placebo controls usually not possible given the need for surgery therefore no control group (use active controls) – Morbidity and risk of implantation – Universities and medical device companies are reluctant to provide coverage for implantable epilepsy device trials due to risk of severe disability and death
  • 29. LimitationsLimitations • Both: – Equipment failures can occur – Approval of devices involves lengthy processes (3-4 years) – Studies usually done on refractory patients therefore results are biased – Very small number of participants involved – Unknown if animal results can be generalized to the human brain – Results must be sufficiently better than other methods
  • 30. StudyStudy: Electrical Stimulation of: Electrical Stimulation of the Anterior Nucleus of thethe Anterior Nucleus of the ThalamusThalamus (Kerrigan et al., 2006)
  • 31. StudyStudy: Electrical Stimulation of the: Electrical Stimulation of the Anterior Nucleus of the ThalamusAnterior Nucleus of the Thalamus (Kerrigan et al., 2006) • Subjects: – A total of 20 patients have received electrical stimulation of ANT to treat seizures – 5 patients with poorly controlled seizures used in this study
  • 32. StudyStudy: Electrical Stimulation of the: Electrical Stimulation of the Anterior Nucleus of the ThalamusAnterior Nucleus of the Thalamus (Kerrigan et al., 2006) • Methods: – Target site of ANT determined by MRI – Subjects underwent surgery and electrode was inserted to desired target – Programmable pulse generators were surgically placed into a subcutaneous pocket in the subclavicular region and connected to the electrode by means of a lead extension
  • 33. StudyStudy: Electrical Stimulation of the: Electrical Stimulation of the Anterior Nucleus of the ThalamusAnterior Nucleus of the Thalamus (Kerrigan et al., 2006) • Methods: – Electrodes were electrically stimulated to determine if a driving response could be elicited – Stimulation system set to deliver 1 minute of stimulation every 10 minutes – Stimulation voltage was incrementally increased over 12-30 weeks – Voltage setting determined specifically for each patient
  • 34. StudyStudy: Electrical Stimulation of the: Electrical Stimulation of the Anterior Nucleus of the ThalamusAnterior Nucleus of the Thalamus (Kerrigan et al., 2006) • Methods: – Used EEG recordings to monitor for adverse changes after reprogramming of stimulation parameters – Seizure counts recorded in a daily diary by each patient and their family – Each patient acted as own control
  • 35. StudyStudy: Electrical Stimulation of the: Electrical Stimulation of the Anterior Nucleus of the ThalamusAnterior Nucleus of the Thalamus (Kerrigan et al., 2006) • Results and Discussion: • Surgical implantation and electrical stimulation was well tolerated by all 5 patients • Only 1 subject demonstrated a statistically significant decrease in total seizure frequency • After 3 months, 4 of the patient’s potentially injurious seizures had decreased to less than half of their baseline value
  • 36. StudyStudy: Electrical Stimulation of the: Electrical Stimulation of the Anterior Nucleus of the ThalamusAnterior Nucleus of the Thalamus (Kerrigan et al., 2006) • Results and Discussion: – Significant decrease in seizures potentially resulting in falls for 4 of the subjects – Examining each patient individually demonstrates greater efficacy
  • 37. EvaluationEvaluation
  • 38. Evaluation:Evaluation: • Advantages: – Offers alternative treatment for those who have not responded to medicine and are not candidates for surgical resection – Sound research proves the methods of cooling and stimulation are efficacious – Studies done have shown significant results
  • 39. Evaluation:Evaluation: • Advantages: – Associated with low incidence of surgical complications – Schmidt et al. (2001) suggest that these methods carry a lower incidence of the adverse cognitive, neurological and systemic effects that occur with anticonvulsant drugs
  • 40. Evaluation:Evaluation: • Disadvantages: – Treatment is very novel and rare – Treatment cost may be very expensive – Risk of surgical implantation – Cooling can only effectively be applied to areas of the cortex – Process of therapy relatively unknown – Many limitations exist in the available literature

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