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., )
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 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