Caveat that drugs may not be the answer to all problems: as we will hear today, new innovations may circumvent the need for drugs in at least some seizure disorders. However, I have been given the charge to address thss
Why new treaatments? We have the alphabet soup of meds: Partial epilepsy represents the most prevalent type of epilepsy accounitng for about 60% of cases Hauser WA et el, Prevalence of epilepsy in Rochester MN 1940-1980; Epilepsia;32;429 ~40-45% are intractable Williamson PD, Weiser, Delgado (Obrien 103 in Wiley) 1 million patients in US Most common seizure disorder 90% of the adult incident cases 40% medically refractory Seizure-free 1st monotherapy 47% 2nd monotherapy 13% 3rd monotherapy 1% Brodie et al. Neurology 2002;58:S2-8. Introduction: Olmstead County Lifetime risk of epielspy 3% 60-70% seizure control (30-40% Intractable) Despite 8 new drugs (GBT,TRIL,TPX,GBT,LGT,LEV,ZNG,FBM) 1997 VNS received FDA approval E03 and E05 Multicenter controlled trials -no placebo arm (patient can detect stimulaiton) -Low intensity stim v.s high The transfiguration Raphael (Raffaelo Santi, 1483-1520) Vatican Museums, Rome (Photograph Calvi) In the Renaissance , this disease was just as common as it is today, In the Christian Middle Ages, as in ancient Greek and Roman times, epilepsy was regarded as the ' unnatural, mysterious illness which is not of this world .' Raphael's last picture, the ' Transfiguration of Christ ', is divided into two parts: the upper part depicts the transfiguration of Christ, the lower part portrays the healing (or rather the scene immediately preceding it) of the boy with an evil spirit (epilepsy). This story comes immediately after the description of the transfiguration in the synoptic Gospels (Matthew, Mark, Luke). The lower part of this painting, which was never completely finished, is based on the following passage in the Bible: '...Teacher, I brought my son to you, because he has an evil spirit in him and cannot talk. Whenever the spirit attacks him, it throws him to the ground, and he foams at the mouth, grits his teeth and becomes stiff all over.' (Mark 9, 17-18) The scene shows the father (wearing a green robe to symbolize hope) bringing his son to the disciples. The painting shows the boy having a seizure: his father has to support him as he cannot stand upright. The boy's limbs are stiff (tonic) and twisted , his mouth is slightly open, his lips are blue , his eyes are fixed in a squint . It is clear to see that during such a convulsion the ' demon ' would throw the victim ' into the fire or into the water ' (Mt 17, 14) if he were not under the care of his family. Jesus heals the boy by driving out the evil spirit. This passage in the Bible led people in the Christian Middle Ages to believe that epilepsy was caused by demons, and this opinion was one of the main reasons why the falling sickness was called ' morbus daemonicus ' (the demonic disease) at that time. Art historians have repeatedly pointed to the symbolism of the themes portrayed in this masterpiece: they believe that Rafael intentionally included the simultaneous depiction of the transfiguration of Christ and the healing of the epileptic boy in one painting. In so doing he consciously created a link between the transfigured Christ and the epileptic boy - a symbolic incongruity between the later crucified and then risen Christ and the epileptic boy who falls to the ground in a seizure, lies there as if dead and then 'rises' up again. It is notable that in the painting, the only link between the two parts of the picture is made by the epileptic boy, who is the only person in the lower half of the picture whose face is turned to the transfigured Christ in the upper part of the painting.
Greg: These 3 slides are from the ANTs patients. The first 2 show that focal discharges on the EEG can be seen focally on biopolar recordings from the ANTs electrodes (they are shown at a different gain in referential and bipolar montages. The last slide shows a delay from the right frontal to left frontal regions (across the callosum) to the ANTs: I.e. frontal regions to thalamus in this patient with a right frontal focus with rapid spread. The ANTs stimulator stopped her falls. This slide supports a proposed functional disruption of conduction from the frontal to more central regions, which might be responsible for the therapeutic effect (the stim. Was off the entire time these recordings were obtained).
Animal Models of Epilepsy By Seizure Type In-vivo In-vitro Array Recordings Not limited by pt. Safety Map the network ? Analogous to Humans ?
Brain Stimulation for The Treatment Of Epilepsy Associate Professor of Neurology and Bioengineering University of Pennsylvania Brian Litt, MD Disclosure
Why devices to treat epilepsy ? <ul><li>60 million people </li></ul><ul><li>No Effective Rx in 25% </li></ul><ul><li>Entree: intelligent BCI </li></ul><ul><li> treat disease </li></ul>
Other Applications <ul><li>Movement Disorders </li></ul><ul><li>Schizophrenia </li></ul><ul><li>Depression </li></ul><ul><li>Stroke, TBI </li></ul>
Seizure -5 -4 -3 -2 0 -1 -6 Hours 0 hrs: Seizure - 2 hrs: “Chirps” start & build Accumulated Energy 50 min epochs Raw EEG: 6 sec burst Energy Accumulates - 1 hour EEG: 10 sec shown - 8 hrs: bursts increase Raw EEG: 15 min epoch Energy over time to Seizure Onset (A) (B) (C) (D)
Gamma Precursors in Neocortical Epilepsy ~85 Hz Sz onset (in red) Worrell, et al., Brain , in press
Interictal HFEO: Seizure Precusors? Worrell et al., 2004 50 V 100 ms ~70-100 Hz oscillation
Ictal Recording/ Mapping Defining the Network Dysplasia (stealth) Ictal onset zone Rapid Sz spread Epileptogenic Zone Brocca’s area HFEOs
Hippocampal Interneurons Diversity & characteristic anatomy Images reproduced from Freund TF, Buzsaki G: Interneurons of the Hippocampus . Hippocampus 1996, 6(4):345-470.
Hippocampal Neuromodulation Intrinsic and subcortical sources Neuromodulator Receptor Source Glutamate mGluR Intrinsic GABA GABA B Intrinsic Acetylcholine m1 Medial septal nucleus m2 Diagonal band of Broca m3 m4 Serotonin 5HT-3 Median raphé nucleus 5HT-2 Dorsal raphé nucleus 5HT-1A Norepinephrine 1 Locus coeruleus 2 1 Dopamine D1 Ventral tegmental area D2 Histamine H2 Tuberomamillary nucleus Adenosine Intrinsic Somatostatin Intrinsic NPY Intrinsic CRF Hypothalamus
Where we’re going….. <ul><li>Sensor : Arrays, harmless, network, units, fields, single cell to function system </li></ul><ul><li> MHz throughput </li></ul><ul><li> Gigabytes storage </li></ul><ul><li> Wireless, on net </li></ul><ul><li> In the head </li></ul><ul><li> “ MRI-able” small </li></ul><ul><li> UpgradableLogic: Learns “on the fly” </li></ul><ul><ul><ul><ul><li>Long battery life </li></ul></ul></ul></ul>
Where we’re going….. <ul><li>Logic: Learns “on the fly” </li></ul><ul><ul><ul><li> Anticipates activity (AI) </li></ul></ul></ul><ul><ul><ul><li> Rapid processing and response </li></ul></ul></ul><ul><li>Stimulation: Multiplexed, microsecond resolution </li></ul><ul><li>Neuroscience: neuro-encoding, decoding </li></ul>
Bio <ul><li>Brian Litt received the A.B. degree in engineering and applied science from Harvard University in 1982 and the M.D. degree from Johns Hopkins University in 1986. Residency in Neurology, Johns Hopkins University, 1988–1991. Neurology Faculty, Johns Hopkins Hospital, 1991–1996. Neurology/Biomedical Engineering Faculty, Emory University/Georgia Institute of Technology 1997–1999. Dr. Litt is an Associate Professor of Neurology; Associate Professor of Bioengineering, and Director, EEG Laboratory at the Hospital of the University of Pennsylvania. His scientific research is focused on his clinical work as a Neurologist specializing in the care and treatment of individuals with epilepsy. It encompasses a number of related projects: 1) automated implantable devices for the treatment of epilepsy, 2) seizure prediction: developing an engineering model of how seizures are generated and spread in human epilepsy, 3) localization of seizures in extratemporal epilepsy, 5) Translation of computational neuroscience into clinical application, and 4) minimally invasive tools for acquisition and display of high fidelity electrophysiologic recording. </li></ul>