2005 Report submitted by Benchmark Steward(s):
Brian Litt, M.D. (University of Pennsylvania)
Background of the benchmark goal:
Multifocal epilepsies and conditions in which seizures spread rapidly throughout the brain (symptomatic generalized epilepsies)
are among the most difficult epileptic disorders to treat. This is because they are often refractory to medical therapy and
not treatable by resective epilepsy surgery. For these reasons, there is great interest in understanding pathways regulating
seizure generation and spread that may be dysfunctional in these disorders, and in modulating their activity to suppress seizures
that arise from multiple foci or networks regulating seizure spread.
Current status of the field:
Current research in the field is focused on several pathways, including those centered on the striato-nigral, anterior, central
and subthalamic regions for seizure spread. Other investigation is focused on connected regions, including periaqueductal
gray. Currently, these areas are being investigated in animal models of epilepsy with array recordings from these regions
during acute and less commonly spontaneous seizures. Equally important as these ongoing studies is the great interest in
devices to treat medically refractory epilepsy, and the need for research to support this task. This includes renewed interest
in mapping epileptic networks, understanding seizure generation and spread, developing quantitative tools to predict seizures
and guide intervention strategies, and methods to translate animal work in this area rapidly into human therapy. While multifocal
and symptomatic generalized epilepsies present specific challenges, specifically that seizures spread so rapidly that focal
onset may vary or not be indentifiable by current methods, they have much in common with simpler cases which are the subject
of clinical trials of implantable devices. Functional imaging, electrophysiological and modeling studies in patients with
multifocal and symptomatic generalized epilepsies are getting underway. These include individuals with cortical dysplasia,
tuberous sclerosis and genetic causes of multifocal and symptomatic generalized epilepsies (band and multinodular periiventricular
heterotopias, lissencephaly, schizencephaly, hypothalamic hamartoma, and similar disorders). This is also interest in new
imaging tools to study non-invasive, real-time imaging correlates of seizure generation and spread. It is hoped that these
types of studies may help identify central regions that are and can be activated to suppress poorly localized, multifocal
or refractory seizures. It is clear from ongoing clinical research that even surgical therapy can be very effective in this
patient population, with proper electrophysiologic evidence of discrete seizure onset.
- Significant progress is being made in understanding seizure generation, brain stimulation, and seizure localization. These
activities are noted in Benchmark IIIE.
- Continued evidence is being accumulated that focal surgery in properly selected patients with tuberous sclerosis, with proper
seizure localization by electrophysiology (often intracranial), can have excellent results (1-5).
- There is considerable ongoing work regarding the genetics of multifocal and symptomatic generalized epilepsy syndromes. Identification
of underlying channelopathies and other mutations, in a subset of these patients, may open new therapeutic options in the
future, and perhaps guide selection of appropriate antiepileptic drugs (6-11).
- See Benchmark IIIE
Top priorities for next 5-10 years:
- To localize the epileptic network, understand seizure generation and spread, and to develop methods to predict, intervene
and prevent seizures in multifocal and symptomatic generalized epilepsies (see Benchmark IIIE for details).
- To understand genetic and other processes that lead to the development of multifocal and symptomatic generalized epilepsies,
and methods to affect this process.
- To develop specific tools, such as less invasive, high resolution electrophysiology and function imaging to identify regions
important to seizure generation in individuals with multifocal abnormalities.
Roadblocks to progress:
- The relative inaccessibility of brainstem and other functional brain structures to interventions such as functional Neurosurgery
and diagnostic electrphysiologic recording.
- The lack of imaging methods to noninvasively distinguish regions of functional/ dysfunctional importance from those that are
structurally abnormal but functionally quiet, with respect to seizure generation.
- Lack of good animal models of multifocal and symptomatic generalized epilepsy on which to perfect and validate new methods
to localize and treat dysfunctional areas to prevent seizures.
- Thiele EA. Managing epilepsy in tuberous sclerosis complex. J Child Neurol 2004;19(9):680-6.
- Romanelli P, Verdecchia M, Rodas R, Seri S, Curatolo P. Epilepsy surgery for tuberous sclerosis. Pediatr Neurol 2004;31(4):239-47.
- Shields WD. Surgical Treatment of Refractory Epilepsy. Curr Treat Options Neurol 2004;6(5):349-356.
- Crino PB. Malformations of cortical development: molecular pathogenesis and experimental strategies. Adv Exp Med Biol 2004;548:175-91.
- Jarrar RG, Buchhalter JR, Raffel C. Long-term outcome of epilepsy surgery in patients with tuberous sclerosis. Neurology 2004;62(3):479-81.
- Dixon-Salazar TJ, Keeler LC, Trauner DA, Gleeson JG. Autism in several members of a family with generalized epilepsy with
febrile seizures plus. J Child Neurol 2004;19(8):597-603.
- Crino PB. Molecular pathogenesis of tuber formation in tuberous sclerosis complex. J Child Neurol 2004;19(9):716-25.
- Jentsch TJ, Hubner CA, Fuhrmann JC. Ion channels: function unravelled by dysfunction. Nat Cell Biol 2004;6(11):1039-47.
- Simpson MA, Cross H, Proukakis C, Priestman DA, Neville DC, Reinkensmeier G, et al. Infantile-onset symptomatic epilepsy syndrome
caused by a homozygous loss-of-function mutation of GM3 synthase. Nat Genet 2004;36(11):1225-9.
- Tan NC, Mulley JC, Berkovic SF. Genetic association studies in epilepsy: "the truth is out there". Epilepsia 2004;45(11):1429-42.
- Richards MC, Heron SE, Spendlove HE, Scheffer IE, Grinton B, Berkovic SF, et al. Novel mutations in the KCNQ2 gene link epilepsy
to a dysfunction of the KCNQ2-calmodulin interaction. J Med Genet 2004;41(3):e35.
- Kerrigan JF, Litt B, Fisher RS, Cranstoun S, French JA, Blum DE, et al. Electrical stimulation of the anterior nucleus of
the thalamus for the treatment of intractable epilepsy. Epilepsia 2004;45(4):346-54.
- Kossoff EH, Ritzl EK, Politsky JM, Murro AM, Smith JR, Duckrow RB, et al. Effect of an external responsive neurostimulator
on seizures and electrographic discharges during subdural electrode monitoring. Epilepsia 2004;45(12):1560-7.
- Bragin A, Wilson CL, Almajano J, Mody I, Engel J, Jr. High-frequency oscillations after status epilepticus: epileptogenesis
and seizure genesis. Epilepsia 2004;45(9):1017-23.
- Worrell GA, Parish L, Cranstoun SD, Jonas R, Baltuch G, Litt B. High-frequency oscillations and seizure generation in neocortical
epilepsy. Brain 2004;127(Pt 7):1496-506.
- Staba RJ, Wilson CL, Bragin A, Jhung D, Fried I, Engel J, Jr. High-frequency oscillations recorded in human medial temporal
lobe during sleep. Ann Neurol 2004;56(1):108-15.
- Parish LM, Worrell GA, Cranstoun SD, Stead SM, Pennell P, Litt B. Long-range temporal correlations in epileptogenic and non-epileptogenic
human hippocampus. Neuroscience 2004;125(4):1069-76.
- McIntyre CC, Savasta M, Kerkerian-Le Goff L, Vitek JL. Uncovering the mechanism(s) of action of deep brain stimulation: activation,
inhibition, or both. Clin Neurophysiol 2004;115(6):1239-48.
- McIntyre CC, Mori S, Sherman DL, Thakor NV, Vitek JL. Electric field and stimulating influence generated by deep brain stimulation
of the subthalamic nucleus. Clin Neurophysiol 2004;115(3):589-95.
- McIntyre CC, Savasta M, Walter BL, Vitek JL. How does deep brain stimulation work? Present understanding and future questions.
Journal of Clinical Neurophysiology 2004;21(1):40-50.
- Yang KH, Franaszczuk PJ, Bergey GK. Inhibition modifies the effects of slow calcium-activated potassium channels on epileptiform
activity in a neuronal network model. Biol Cybern 2004.
- Frohlich F, Jezernik S. Annihilation of single cell neural oscillations by feedforward and feedback control. J Comput Neurosci
- Chiu AW, Bardakjian BL. Control of state transitions in an in silico model of epilepsy using small perturbations. IEEE Trans
Biomed Eng 2004;51(10):1856-9.
- Lee KH, Roberts DW, Kim U. Effect of high-frequency stimulation of the subthalamic nucleus on subthalamic neurons: an intracellular
study. Stereotact Funct Neurosurg 2003;80(1-4):32-6.
- Guenot M, Isnard J, Ryvlin P, Fischer C, Mauguiere F, Sindou M. SEEG-guided RF thermocoagulation of epileptic foci: feasibility,
safety, and preliminary results. Epilepsia 2004;45(11):1368-74.
- Rothman S, Yang XF. Local Cooling: A Therapy for Intractable Neocortical Epilepsy. Epilepsy Curr 2003;3(5):153-156.
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- Iasemidis LD, Litt B, Witte H. Special IEEE Issue on Seizure Prediction. IEEE Trans Biomed Eng 2003;50(5):537-39.