The Context of the IOM Study on the Epilepsies

Transcription

1 The Context of the IOM Study on the Epilepsies January 10, 2011 Frances E. Jensen, MD Professor of Neurology, Harvard Medical School Co Chair, Vision Vice President and President elect, American Epilepsy Society

2 Epilepsy ἐπιληψία (epilēpsía) "to seize") Episodic, unpredictable alteration in neurologic status Ranging from mild motor to severe prolonged generalized convulsion Profound effects on patient and family s medical, social, academic, and financial status Can be lethal Highly stigmatized

3 EPILEPSY IS COMMON but often hidden Existing statistics reveal up to 3 million people in the US suffer from epilepsy 50 million worldwide Highest incidence of new cases at the 2 ends of life Population segments that have been least surveyed in prior studies Prevalence changing as population ages Increase in elderly, returning veterans 1 in 10 people will have a seizure in their lifetime Lifetime risk of epilepsy (recurrent seizures) is 3.3%

4 Incidence of Epilepsy by Age Composite of 12 Studies in Developed Countries, Courtesy David Thurman

5 Epilepsy Spectrum Disorder SEIZURES Attention Cognitive Psychiatric Dementia Mental SUDEP deficit deficits disorders retardation Spectrum of seizure syndromes Spectrum of etiologies Spectrum of severity Spectrum of non ictal symptoms NINDS Epilepsy Benchmarks Area III: Prevent, limit, and reverse the co morbidities associated with epilepsy and its treatment.

6 Seizures are the tip of the iceberg Neurobiology of epileptogenesis is shared with the pathophysiology of non ictal symptoms (comorbidities) Developmental disorders Cognitive impairment, attention deficits Psychiatric disorders SUDEP Implications for diagnosis and treatment beyond the seizures

7 Epilepsy in 2011 Ideal time for an IOM study: Our field is poised for advancement Explosion of new information from basic and clinical neurosciences redefining this disease Inadequate assessment of populations at risk, incidence, prevalence, with wider definition of the disease Complex therapeutic landscape emerging Pharmacologic, nutritional, surgical and device driven Pipeline is a problem from T1 to T4 No cure yet, only symptom suppression at best Problematic delivery of care to heterogeneous population from demographic and symptomatic standpoint

8 Areas of advancement Genetics Molecular/cellular signaling involved in epileptogenesis Age specific mechanisms Shared neurobiology of ictal and nonictal components Imaging Cellular Clinical Quantitative neurophysiology Spectral analysis, LTM, MEG AED development

9 >100 Genes Linked to Monogenic Epilepsy Ion channels are the largest subset SCN1A SCN2A SCN1B KCNA1 KCNC2 KCNQ1 KCNQ2 KCNQ3 KCNMA KCNMB4 CACNA1A CACNB4 CACNG4 CACNA2D2 ClCN2 HCN2 GABRA1 GABRB3 GABRG2 CHRNA4 CHRNB2 HTR2C GRIA2 Courtesy, Jeff Noebels, MD, PhD SLC9A1 SLC1A2 SLC2A1 KCC2 ATP1A2 NPY GAD2 ITPR1 CAMK2A PLCB1 SYN1+2 SV2A BSN AP3D1 DCX DLX1 OTX EMX2 SOX1 FCN2 UPAR ARX NEUROD1 GABBR1 KCNJ6 MECP2 EPM2A FLN1 CASPR2 ALPL TRK1 LAMR1P11 RORA PTEN CBP B AMT UBE3a CIT CYSTB MYO5A TSC1, 2 NHLRC1 LGi1 APP related Human Mouse Both

10 >100 Genes Linked to Monogenic Epilepsy Ion channels are the largest subset SCN1A SCN2A SCN1B KCNA1 KCNC2 KCNQ1 KCNQ2 KCNQ3 KCNMA KCNMB4 CACNA1A CACNB4 CACNG4 CACNA2D2 ClCN2 HCN2 GABRA1 GABRB3 GABRG2 CHRNA4 CHRNB2 HTR2C GRIA2 Courtesy, Jeff Noebels, MD, PhD SLC9A1 SLC1A2 SLC2A1 KCC2 ATP1A2 NPY GAD2 ITPR1 CAMK2A PLCB1 SYN1+2 SV2A BSN AP3D1 DCX DLX1 OTX EMX2 SOX1 FCN2 UPAR ARX NEUROD1 GABBR1 KCNJ6 MECP2 EPM2A FLN1 CASPR2 ALPL TRK1 LAMR1P11 RORA PTEN CBP B AMT UBE3a CIT CYSTB MYO5A TSC1, 2 NHLRC1 LGi1 APP related Human Mouse Both

11 Temporal Profile of Epileptogenesis Time Zero Cascade of events? EPILEPSY: Emergence of spontaneous seizures Biomarkers? Therapeutic targets? Initial insult

12 Rakhade, S. N. and Jensen, F. E. (2009),Nat. Rev. Neurol. Worsening cognitive deficit?

13 Timing Target Therapeutic strategy Candidate agents Immediate early changes Subacute changes Post translational phosphorylation Kinase, phosphatase inhibitors, mtor KN 62, FK506, rapamycin Acetylation HDACs Valproate, SHA AMPA receptors AMPAR antagonists Talampanel, topiramate, levetiracetam NMDA receptors NMDAR antagonists Memantine, xenon, ifenprodil, Mg 2+ GABA receptor GABAR agonists BZs, barbiturates NKCC1 NKCC1 inhibitors Bumetanide Inflammation Neuronal death Anti inflammatory compounds, microglial inactivators Block excitotoxicity, oxidative stress HCN1 channels i h blocker ZD7288 ACTH, minocycline, doxycycline, Memantine, Epo Cannabinoid receptors CB1 R antagonists SR14176A, SR Chronic changes Sprouting Block protein synthesis Rapamycin, cyclohexamide Gliosis Anti inflammatory agents Cox2 inhibitor, minocycline Rakhade, S. N. and Jensen, F. E. (2009),Nat. Rev. Neurol.

14 Maturational changes in Glutamate and GABA receptor function in the developing brain Rakhade, S. N. and Jensen, F. E. (2009),Nat. Rev. Neurol. Talos et al J. Comp Neurol, 2006; Dzhala V et.al. Nature Medicine, 2005

15 Maturational changes in Glutamate and GABA receptor function in the developing brain Neonatal Seizures Infantile Spasms Landau Kleffner Benign Rolandic Rakhade, S. N. and Jensen, F. E. (2009),Nat. Rev. Neurol. Talos et al J. Comp Neurol, 2006; Dzhala V et.al. Nature Medicine, 2005

16 Maturational changes in Glutamate and GABA receptor function in the developing brain AUTISM Rakhade, S. N. and Jensen, F. E. (2009),Nat. Rev. Neurol. Talos et al J. Comp Neurol, 2006; Dzhala V et.al. Nature Medicine, 2005

17 Risk of epilepsy in children with autism Large cohort of children with autism Degree of MR N N (%) Epilepsy Severe (39%) Moderate/Mild (6%) Nl intelligence 68 9 (13%) Total (16%) Modified from Table 1 Tuchman et al. Pediatrics, 1991

18 Interaction and convergence between brain development, epilepsy and autism? cognitive deficits autism Enhanced excitability in the developing brain Synaptic plasticity Synaptic receptors Signaling molecules neurotrophins epilepsy epileptogenesis ALL SEIZURE INDUCED Rett s TSC Lissencephaly West s Fragile X Angelmans autism NT receptors p AMPA p NMDA p GABA Signaling kinases phosphatases mecp 2 mtor, Rheb reelin ERK AKT CDKL5 FMRP Ube3A Neurotrophins BDNF

19 Synaptic plasticity and synaptic strengthening reelin mtor CDKL5 MeCP2 Ube3a FMRP New faster synapses Modified from Lamprecht and LeDoux, Nature Neurosci Rev, 2004

20 Epilepsy and autism converge at the synapse Lissencephaly West s syndrome reelin mtor CDKL5 Ube3a FMRP Tuberous Sclerosis Rett s syndrome Mecp2 Angelman s syndrome Fragile X syndrome Shared molecular targets? Modified from Lamprecht and LeDoux, Nature Neurosci Rev, 2004

21 Bidirectional Relationship Between Epilepsy and Depression Authors Forsgren and Nystrom Hersdorffer et al Hersdorffer et al Type of Study Population-based Population-based (Onset of epilepsy >age 55) Population-based (Iceland all ages) Psychiatric History Preceding the Onset of Epilepsy/Controls 7 times the history of depression 17 times in case of TLE 4 times the history of depression 5 times the history of suicidality Twice the history of major depression Courtesy Andres Kanner, MD

22 Neurotransmitters Involved in the Pathogenesis of Depression and Epilepsy Epilepsy Serotonin Norepinephrine Dopamine GABA Glutamate CRF Mood disorders Serotonin Norepinephrine Dopamine GABA Glutamate CRF Courtesy Anders Kanner, MD

23 Serotonin, Epilepsy & Depression Increased risk of suicide in epilepsy patients Bi directional effects Increased incidence of seizures in depression Increased incidence of depression in seizures Underlying 5 HT defects in both? Many antidepressants (SSRIs & SNRIs) inhibit seizures Many anticonvulsants are used in affective disorders Vagal Nerve Stimulation (VNS) has effects on depression Ecstasy toxicity May cause depression & seizures Courtesy Gary Richerson, MD

24 Death rates in epilepsy patients Patients with epilepsy are 24 times more likely to die of sudden death than the general population SUDEP is the leading cause of death in patients with uncontrolled epilepsy 12% risk of SUDEP in refractory epilepsy not on medication Mechanism(s) unknown: Cardiac vs respiratory vs electrocerebral shutdown Serotonin depleted by seizures, involved in central control of respiratory drive Channelopathies are common to heart and brain Tomson et al, Lancet Neurology, 2008 Silanpaa and Shinnar, NEJM 2010

25 Death rates in epilepsy patients Patients with epilepsy are 24 times more likely to die of sudden death than the general population SUDEP is the leading cause of death in patients with uncontrolled epilepsy 12% risk of SUDEP in refractory epilepsy not on medication Mechanism(s) unknown: Cardiac vs respiratory vs electrocerebral shutdown Serotonin depleted by seizures, involved in central control of respiratory drive Channelopathies are common to heart and brain Tomson et al, Lancet Neurology, 2008 Silanpaa and Shinnar, NEJM 2010

26 Death rates in epilepsy patients

27 Clinical diagnostic advances Epilepsy centers can access the cutting edge of clinical diagnostics on an every day basis Advanced neurophysiology Digitial EEG, Long term monitoring, Intracranial grids and strips (electrocorticography/ecog) Quantitative computational analysis, high frequency oscillations Magnetoencephalography Advanced anatomical imaging MRI, DTI Advanced functional imaging PET, SPECT, fmri, connectomics Genetic screening Genome, SNPs. Pharmacogenomics

28 Technological advances and epilepsy Worrel, et al 2004; Suedo, et al Epil Res 2010; Van der Heide,et al, Clin Neurophys, 2010; 2010; Hagmann, et al PloS Biol. 2010

29 Treatment Advances 25 new drugs developed for clinical trials in the last 25 years, 11 now FDA approved Despite this, up to 40% of patients with epilepsy are not adequately controlled on medication And that is just the seizures Increased rate of surgical resection for focal lesional/nonlesional epilepsy no survey covering adult and pediatrics since 1993 (Engel et al) No change in number of years to referral Pediatric cases 5 years Adult cases 20+ years Success rate from surgery approximately 30 50% depending on age New devices VNS DBS TMS No medical treatment in 2011 represents a CURE Surgical treatment may cure but only applicable to a small % of the refractory population Comorbidities largely overlooked as a unique treatment target

30 Therapy development pipeline past 25 years SOURCE CLINICAL TRIALS FDA approval ASP/NINDS Pharma/Industry Academia+ NIH/VA/DOD/FDA NGOs 26 new drugs/4+ devices Felbamate Gabapentin Vigabatrin Lamotrigine Topiramate Tiagabine Oxcarbazepine Levetiracetam Zonisamide Pregabalin Rufinamide Lacosamide Brivaracetam DP VPA Ganaxolone Carisbamate Seletracetam Stiripentol Talampanel Valrocemide Eslicarbazepine Retigabine Perampanel Losigamone Bumetanide VNS DBS SANTE trial RNS trial TMS 13 new drugs, 1 device Felbamate Gabapentin Vigabatrin Lamotrigine Topiramate Tiagabine Oxcarbazepine Levetiracetam Zonisamide Pregabalin Rufinamide Lacosamide ACTH VNS

31 Advances that are making a difference Molecular mechanisms or epileptogenesis Plasticity cascades Ion channels and transporters, etc new targets Immunology Molecular mechanisms of comorbidities Depression Autism Alzheimer s Dementia SUDEP Clinical and genetic correlations (GWAS, sequencing) Example SCN1A gene New technologies Imaging in daily use PET, MEG, SPECT, DTI Connectome Quantitative analysis of digital EEG Algorithms for seizure prediction High frequency oscillations a potential biomarker New treatments 26 new drugs, dietary regimens, improved surgical techniques, devices

32 Public Health Surveillance In 2011, how do we use existing clinical networks, ongoing studies to evaluate the burden of epilepsy lists over 600 epilepsy related trials is this a source of selected data? How to utilize new tools provided by reformed health care system, comparative effectiveness, in the age of electronic medical records Cover previously understudied specific populations including pediatrics, elderly, women Definition of what constitutes active epilepsy (to include comorbidities) or epilepsy in remission definition of cure (to ascertain more than simply seizure control) will be an issue

33 Population and Public Health Research What are risk factors for refractory epilepsy? Accelerate path to care, diagnostics and pharmacogenomics Enriched populations for research study What are risk factors for comorbidities, including SUDEP? Accelerate path to referral, new diagnostics Enriched populations for research study If seizures are treated, there is still a need for surveillance of burden of residual comorbidity Recognition that epilepsy is often hidden inside another primary diagnosis (eg. depression, dementia, autism) What is long term outcome after epilepsy surgery? How do we define cure? Newly emerging populations with epilepsy Survivors of prematurity, infant injury New therapeutic choices during pregnancy Growing population of elderly patients afflicted with epilepsy

34 Health Policy Access to care Define guidelines as to what level of epilepsy meets criteria for immediate referral to an epilepsy center Define what constitutes treatment failure Examine social, educational, and workplace support services for patients with epilepsy Early intervention not only of seizures, but of comorbid symptoms Payment of care What path to referral to an epilepsy care center will be approved How will nutritional treatments be covered (ketogenic diet) What will policy be with respect to generic/brand name pharmaceuticals High level of diagnostic testing must be covered due to changing nature of disease, and changing response to treatment within an individual

35 Education Patient and public Broader definition of the spectrum of epilepsy to improve self identification Awareness of wide range of treatment options Address and eliminate stigma Health care professionals Improve education at all levels Improve accuracy of diagnosis in primary care Develop and then educate with guidelines for referrals to different levels of specialized care

36 January 10, 2011 The IOM report is necessary to enable patients and the professional community involved in care, education, and research to meet the challenges of this disease in the 21 st century and work towards the eventual eradication of this common, disabling, and stigmatized condition