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    PPT PPT Presentation Transcript

    • 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 post-synaptic mechanisms
        • inhibits Sodium-Potassium ATPase
        • reduces neurotransmitter release from pre-synaptic 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 20 th 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 20 th 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 (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
    • 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 (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
    • 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