Download Implantable Devices: Treatment for Epilepsy

Implantable Devices:
Treatment for Epilepsy
By:Melanie Ostreicher
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
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
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
Implantable Devices
• The above can be achieved by:
-Electrical stimulation
-Focal cooling
-Localized drug infusion
Focal Cooling
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
Focal Cooling
• Cooling …
– reduces synaptic transmission in mammalian
brains
– reduces end plate potentials
– alters excitatory transmission of pre and postsynaptic mechanisms
– inhibits Sodium-Potassium ATPase
– reduces neurotransmitter release from presynaptic vesicles
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)
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
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
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)
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
Focal Cooling
• Neuronal Structures Involved:
– Neocortex (Rothman et al. 2005)
• needs direct cortical contact
• reduces seizure frequency, duration and severity
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
Electrical Stimulation
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
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
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
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
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
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
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
Limitations
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
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
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
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
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
Study: Electrical Stimulation of
the Anterior Nucleus of the
Thalamus
(Kerrigan et al., 2006)
Study: Electrical Stimulation of the
Anterior Nucleus of the Thalamus
• Subjects:
(Kerrigan et al., 2006)
– A total of 20 patients have received electrical
stimulation of ANT to treat seizures
– 5 patients with poorly controlled seizures used
in this study
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
Study: Electrical Stimulation of the
Anterior Nucleus of the Thalamus
• Methods:
(Kerrigan et al., 2006)
– 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
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
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
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
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
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
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