Implantable Devices: Treatment for Epilepsy

1. Implantable Devices:Treatment for Epilepsy By:Melanie Ostreicher

2. Implantable 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 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 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 Devices • The above can be achieved by: -Electrical stimulation -Focal cooling -Localized drug infusion

6. Focal Cooling

7. Focal 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 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 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 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 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 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 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 Cooling • Neuronal Structures Involved: • Neocortex (Rothman et al. 2005) • needs direct cortical contact • reduces seizure frequency, duration and severity

15. Focal 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 Stimulation

17. Electrical 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 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 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 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 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 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 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. Limitations

25. Limitations • 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. Limitations • 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. Limitations • 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. Limitations • 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. Limitations • 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. Study: Electrical Stimulation of the Anterior Nucleus of the Thalamus (Kerrigan et al., 2006)

31. Study: Electrical Stimulation of the Anterior 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. Study: Electrical Stimulation of the Anterior 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. Study: Electrical Stimulation of the Anterior 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. Study: Electrical Stimulation of the Anterior 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. Study: Electrical Stimulation of the Anterior 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. Study: Electrical Stimulation of the Anterior 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. Evaluation

38. 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: • 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: • 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