PPT

Implantable Devices:Implantable Devices:Treatment for EpilepsyTreatment for Epilepsy

By:Melanie Ostreicher

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


• 2 major biological paradigms guide device interventions:

1) Excitation/Inhibition of central structures that exhibit abnormal cortical activity

2) Epileptic focal region interference


• Current Devices can be divided into 2 groups:1) Closed-Loop- monitors physiological signals and triggers a therapeutic response based on changes2) Open-Loop- chronically modulates brain activity to suppress seizures through a cycle of stimulation

-switched on/off by an internal clockie. Vagus Nerve Stimulation


• The above can be achieved by:

-Electrical stimulation

-Focal cooling

-Localized drug infusion

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


• 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


• 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)


• 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


• 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


• 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)


• 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


• Neuronal Structures Involved:– Neocortex (Rothman et al. 2005)

• needs direct cortical contact

• reduces seizure frequency, duration and severity


• 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

Electrical Stimulation Electrical Stimulation

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


• 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


• 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


• 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


• 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


• 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


• 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

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


• 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


• 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


• 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


• 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

StudyStudy: Electrical Stimulation of : Electrical Stimulation of the Anterior Nucleus of the the Anterior Nucleus of the

ThalamusThalamus (Kerrigan et al., 2006)

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


(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



– 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



– 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


(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


(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

EvaluationEvaluation

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


• 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


• 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

PPT

Documents

local cooling cooling

focal seizures cooling

benefits of cooling

use of brain cooling

peltier devices

driven cooling device

cycle of stimulation

brain activity