Clinical severity of seizures
Hot Topics Symposium
December 10, 2013
Frances E. Jensen M.D.
Professor and Chair
Neurology Department
Perelman School of Medicine
University of Pennsylvania
American Epilepsy Society | Annual Meeting
FE Jensen, MD 12/13 AES Hot Topcs
Disclosure
Name of Commercial Interest
• Eisai Pharmaceuticals
• Lundbeck
American Epilepsy Society | 2013 Annual Meeting
Type of Financial Relationship
• Investigator initiated preclinical trials
FE Jensen, MD 12/13 AES Hot Topcs
The utility of staging our disease
• While we have a wide array of epilepsy syndromes, there are many commonalities
• Timely as we are entering an era of disease modification – To accurately assess whether a disease has been
modified, staging offers a methodology • Movement from one stage to another
– As valuable in the preclinical animal models research as it is in human
– Provides a language for “translation” between animal to human trials
FE Jensen, MD 12/13 AES Hot Topcs
Initial insult
Temporal Profile of Epileptogenesis
Emergence of spontaneous seizures
“Time Zero” EPILEPSY:
Cascade of events?
Therapeutic targets?
Biomarkers?
FE Jensen, MD 12/13 AES Hot Topcs
Rakhade, S. N. and Jensen, F. E. (2009),Nat. Rev. Neurol.
Worsening cognitive deficit?
FE Jensen, MD 12/13 AES Hot Topcs
Staging is really just endophenotyping
• Endophenotyping
– Clinical trials fail when the patient study group is too inclusive
– Narrow our definitions to as pure a population as possible
– Useful for prognosis, diagnosis, treatment
• And research!
• Common data elements operationalize endophenotyping
FE Jensen, MD 12/13 AES Hot Topcs
Essentials for staging
• Common data elements – Syndromes and their severity defined by a unique set
of common data elements
• Biomarkers • May or may not be mechanistically relevant
• statistical association with certain common data elements
• Where possible, need to harmonize units of measure – Especially important in preclinical to clinical
translation
FE Jensen, MD 12/13 AES Hot Topcs
FE Jensen, MD 12/13 AES Hot Topcs
Common data elements
• Clinical and preclinical must align as best possible – Phenotypic equivalence – Laboratory measures
• EEG • Imaging • Tissue, fluid- standard, histopathologic, genomic,
metabolomic, proteomic measures
• Use of standards where possible, control values critical when methodology, instrumentation varies – Ie universal phantoms for different MRI machines,
standard curves, normal ranges
FE Jensen, MD 12/13 AES Hot Topcs
Alignment of CDE’s
• Must develop a strategy to use same common data elements in different epilepsy syndromes – Add unique modifiers specific to location, age etc
• Must develop a strategy to align major CDEs between species – Drosophila – Zebrafish – rodent - large mammal-non-
human primate – HUMAN • Be reasonable, the number of “common” CDEs will be
inversely related to distance on phylogenetic scale!
• Will be very rudimentary at invertebrate, with increasing ability to find analogies as we ascend thru species
FE Jensen, MD 12/13 AES Hot Topcs
Alignment of biomarkers
• Accessible with inaccessible – Ex: MRI with cellular histopathologic biomarker – Ex: EEG scalp with grid HFO
• Preclinical with clinical – Ex: Same MRI measure for T2 signal – Ex: same cytokine measure in serum (same units)
• Preclinical research filled with very promising, but inaccessible tissue markers – Must strive to develop noninvasive correlate
measures that can be used in widescale preclinical trials and human trials
FE Jensen, MD 12/13 AES Hot Topcs
Biomarkers
• Clinical – Seizure behavior – Nonseizure behavior – Non-neurologic signs/symptoms
• Physiologic measures of activity – EEG, MEG, PET/SPECT
• Imaging – MRI, CT, NIRS
• Cellular/molecular – Brain, CSF, urine, saliva measures
FE Jensen, MD 12/13 AES Hot Topcs
Cellular/molecular biomarker database issues
• Staging essential to create platform for ordering levels of disease, biomarker progression, and stage-specific biomarkers – Candidate or screening approaches
• Need non-invasive correlates – Databases ideal for validating correlations
• Much to learn from other scientific communities
• Expert advice re data quality, IP issues
FE Jensen, MD 12/13 AES Hot Topcs
Rakhade, S. N. and Jensen, F. E. (2009),Nat. Rev. Neurol.
Worsening cognitive deficit?
Many glutamate receptor mediated signaling cascades
pGluR sites pNR sites Kinases Phosphatases mTOR pCl transporters MeCP2 FMRP …..
FE Jensen, MD 12/13 AES Hot Topcs
MRI imaging of glutamate
Cai, et al, Nature Med 2012 FE Jensen, MD 12/13 AES Hot Topcs
Staging is really just endophenotyping
• Endophenotyping
– Clinical trials fail when the patient study group is too inclusive
– Narrow our definitions to as pure a population as possible
– Useful for prognosis, diagnosis, treatment
• And research!
• Common data elements operationalize endophenotyping
FE Jensen, MD 12/13 AES Hot Topcs
Staging epilepsy and its comorbities
• Cancer as an example
– Temporal information captured
– Extent of disease captured
– Specific type captured
• Alzheimers/PD a examples
– Similar in that primary organ clinically inaccessible for direct measurement
– Progressive symptoms, but presymptomatic stages
– Comorbidities
FE Jensen, MD 12/13 AES Hot Topcs
Lessons from AD, PD, cancer
• Define stages to increase precision of biomarker identification – endophenotypes
• Two major approaches – Candidate marker – Non-hypothesis driven screens
• Start “backwards”- look at incident cases – Then move forward again
• Early efforts to create non-invasive correlates – Plasma/serum, neuroimaging
FE Jensen, MD 12/13 AES Hot Topcs
FE Jensen, MD 12/13 AES Hot Topcs
Biomarker development in Alzheimers
Trojanowski, et al. Alzheimers and Dementia, 2010 FE Jensen, MD 12/13 AES Hot Topcs
CSF CSF PET
MRI MMS
exam
Forlenza et al. BMC Medicine 2010 8:89 doi:10.1186/1741-7015-8-89 FE Jensen, MD 12/13 AES Hot Topcs
Candidate biomarker approach
Forlenza et al. BMC Medicine 2010 8:89 doi:10.1186/1741-7015-8-89 FE Jensen, MD 12/13 AES Hot Topcs
Parkinson’s biomarker core
FE Jensen, MD 12/13 AES Hot Topcs
Staging epilepsy and its comorbities
• Cancer as an example
– Temporal information captured
– Extent of disease captured
– Specific type captured
• Alzheimers/PD a examples
– Similar in that primary organ clinically inaccessible for direct measurement
– Progressive symptoms, but presymptomatic stages
– Comorbidities
FE Jensen, MD 12/13 AES Hot Topcs
Staging
Cancer
• Type- organ system
• Stage- pre cancerous to end-stage malignant
• Secondary involvement – Organ failure due to invasion
Epilepsy
• Syndrome- brain region
• Stage- pre-epilepsy to drug resistant
• Secondary involvement – Comorbidities
FE Jensen, MD 12/13 AES Hot Topcs
Can we stage epileptogenesis?
• Stage 0- risk factor • Stage 1 – one seizure and one biomarker • Stage 2 – one seizure and progressive biomarker(s) change
– 2b- with behavioral change
• Stage 3 – recurrent seizures but responsive to AEDs, (possible effect on stabilizing changes in biomarkers) – 3b – with worsening behavior
• Stage 4- treatment resistant epilepsy, with multiple biomarker changes – 4b- with progressive behavioral deterioration
• Biomarkers can be in 4-5 axes – need to define these element Cellular Molecular Behavioral Imaging Neurophys
FE Jensen, MD 12/13 AES Hot Topcs
Can we stage epileptogenesis?
• Stage 0- risk factor (“pre-epilepsy”) genetics • Stage 1 – one seizure and one biomarker • Stage 2 – one seizure and progressive biomarker(s) change
– 2b- with behavioral change • Stage 3 – recurrent seizures but responsive to AEDs, (possible effect on stabilizing
changes in biomarkers) – 3b – with worsening behavior
• Stage 4- treatment resistant epilepsy, with multiple biomarker changes – 4b- with progressive behavioral deterioration
• Keep in mind % of life with epilepsy – absolute # number of years probably not a good measure
• Biomarkers can be in 4-5 axes – need to define these element – Cellular – Molecular/genetic/inflammatory – Behavioral – Imaging – Neurophys
FE Jensen, MD 12/13 AES Hot Topcs
Ideal world - example
• Have a new disease modifying “Rx –A”
• Target “A” identified to transiently activate on relevant networks at 12 hours after SE in a rat – The 12 hr point has been defined as “stage 1a” by using a
combination of behavioral, EEG, serum biomarkers ALSO seen in patients following TBI at 1 week, defining them as “stage 1a” patients
• Rx “A” prevents later epilepsy and long term effect is correlated with decreased serum levels of downstream metabolite of Target “A” in animal models. Metabolite is validated as present and measurable in human
FE Jensen, MD 12/13 AES Hot Topcs
Ideal world example
• Have a new disease modifying “Rx –B” • Target “B” identified to occur after onset of spontaneous
seizures (SRS) in animals (Stage 3a) that will go on to develop refractory status after TBI (Stage 4) – The early onset of treatable SRS has been defined as “stage 2a”
by using a combination of behavioral, EEG, serum and MRI biomarkers ALSO seen in patients following TBI ranging from weeks to years, defining them as “stage 2a” patients
• Rx “B” prevents progression to “Stage 3” refractory epilepsy (defined as drug resistant epilepsy),and maintains animals in a drug sensitive status. This stage is correlated lack of progressive MRI changes that are associated with progression to stage 4. MRI changes are also seen in post TBI patients with refractory seizures
FE Jensen, MD 12/13 AES Hot Topcs
Jump in and try
• Demonstration project- compare 2 epilepsies…are there common stages with a proposed scheme.
– Cancer: Breast vs prostate
– Epilepsy: JME vs TLE vs PTE?
FE Jensen, MD 12/13 AES Hot Topcs
