Clinical Trials to Date, Next Steps Kimford Meador, MD Department - - PowerPoint PPT Presentation

Cognition in Epilepsy: Issues, Challenges, Clinical Trials to Date, Next Steps

Kimford Meador, MD Department of Neurology & Neurosciences Stanford University Palo Alto, California kmeador@stanford.edu

Financial Disclosures

Grants:

• NIH/NINDS 2U01-NS038455-11A1. Meador (Multi-PI). “Maternal Outcomes

and Neurodevelopmental Effects of Antiepileptic Drugs.”*

• NIH/NINDS R01NS088748-01. Drane (PI). “Dissecting the Cognitive Roles of

Hippocampus & Other Temporal Lobe Structures.” Role: Co-I.

• Medtronics. Halpern (PI). “Stereotactic Laser Ablation for Temporal Lobe

Epilepsy (SLATE).” Role: Co-I.

• Eisai Inc. Razavi (PI). “Multicenter, Open-Label Study to Evaluate the Efficacy

and Safety of Perampanel as Monotherapy or First Adjunctive Therapy in Subjects With Partial Onset Seizures With or Without Secondarily Generalized Seizures or With Primary Generalized Tonic-Clonic Seizures.” Role: Co-I.

• Sunovion Pharma. Meador (PI). “Cognitive and Behavioral Effects of

Eslicarbazepine Acetate and Carbamazepine in Healthy Adults.” Consultant (Note direct no personal income):

• Epilepsy Consortium (funds paid to my university)* for Eisai, GW

Pharmaceuticals, Medtronics, NeuroPace, Novartis, Supernus, Upsher Smith Labs, UCB Pharma, and Vivus Pharm. Other: Clinical income: EEG procedures and patient care* *Items with asterisk involve income > $10,000 for recent years.

International Bureau for Epilepsy: 2004 Cognitive Function Survey

• 44% Difficulty learning
• 45% Felt that they were slow thinkers
• 59% Felt sleepy or tired
• 63% ASM effects prevented them from

achieving activities or goals N = 425 Europeans with epilepsy

http://www.ibe- epilepsy.org/downloads/IBE%20Epilepsy%20and%20CognitiveFunctionResults.pdf

ASMs= anti-seizure medications

Factors Affecting Cognition and Behavior in Epilepsy

Seizure- Related Variables Treatment- Related Variables Non–Seizure- Related Variables

Gilliam, et al. Neurology 2004;62:23-27

Relationship of Subtle ASM Toxicity to Quality of Life

Adverse Events Profile Summary Score QOLIE-89 Total Score N = 200 r = -0.76, P<0.0001

75 60 45 30 15 100 80 60 40 20

Average Monthly Seizure Rate QOLIE-89 Total Score

ASMs= anti-seizure medications

Perception of Cognitive Function is More Related to Mood than Function

Subjective Mood Best All Perception Objective Objective Test Tests Memory 17.2% 4.3% 7.9% Language 14.6% 4.9% 12.7% Attention 28.7% 3.6% 9.3% QOLIE-89 total 46.7% 5.2% 13.3%

Perrine et al, Arch Neurol 1995;52:997-1003

% Variance explained by each factor

N = 257 epilepsy patients

Cognitive Effects

Wine ASMs

• Higher Dose/ABL
• Polytherapy
• Rapid Titration
• Habituation
• AED differences
• Individual

differences

ASMs= anti-seizure medications

Challenges to Interpreting Studies

Methodological

• Measures: choice &

administration

– Appropriate measures administered

by properly trained personnel

• Dosing regimen

– Consistent current guidelines – Are comparators being dosed

equivalently?

– Length of exposure

• Subject selection bias

– Why did these patients receive the

different drugs in the first place?

• Confounding factors

– seizures, etiology, depression

• Generalization

To what extent will results with this sample generalize to my patients?

Statistical

• Failure to correct for

multiple comparisons (Type I error)

• Over correction

(Type II error)

• Low power due to

small sample sizes

• Statistical vs. Clinical

Significance

Trial Design Issues

• Randomized double-blind crossover or parallel group

with matched control group & repeated measures design.

• Placebo vs. Head-to-head drug comparisons
• Anti-seizure vs Disease Modifying Treatments

(eg, truly antiepileptic, everolimus for tuberous sclerosis, immune therapies for autoimmune epilepsy)

• Future Goal: Cognitive enhancing treatments

Trial Design Issues

• Need to consider test-retest effects (practice effects) and

variability across repeat testing.

• Need to control for habituation & titration effects.

– (CNS side effects most marked early)

• Cognitive studies in patients need to control for effects
• f seizures.
• Difficult to combine efficacy and cognition studies.
• Early cognitive assessment in treatment has potential to

compensate for dropouts, thus allowing imputations for missing later assessments. But only to a degree.

Cognitive Domains Most Likely to Be Affected by Anti-seizure Meds

• Processing Speed (e.g., reaction time)
• Complex or Sustained Attention
• Dual Processing
• Memory: Verbal learning

– Paragraphs more sensitive than word lists

• Verbal fluency
• Executive function
• Mood (FDA requires only a measure of Suicidality)

Assessment Tools

• NIH Toolbox

http://www.healthmeasures.net/explore-measurement- systems/nih-toolbox

• Epitrack

Lutz MT, Helmstaedter C. Epilepsy Behav. 2005;7(4):708-14

• Computerized Tests

e.g., CNS-Vitals, Cogstate, Cognitive Drug Research (CDR) System

• Standard Paper & Pencil Neuropsych Tests

e.g., SDMT, Stroop, COWA

• Subjective Measures

e.g., POMS, AEP, BDI

Newer ASMs vs Placebo

Kalviainen et al, Epi Res 1996;25:291-7. Dodrill et al, Neurology 1997;48:1025-31. Leach et al, JNNP 1997;62:372-6. Meador et al., Epilepsia 1999;40(9):1279-1285. Meador et al., Neurology 2001;56:1177-82. Salinsky et al., Epilepsy & Behavior 2004;5:894-

• 902. Aldenkamp et al., Epilepsia 2000;41:1167-7. Meador et al., Neurology 2003;13;60:1483-8. Salinsky et al., Neurology

2005;64:792-8. Meador et al., Neurology 2005;64(12):2108-2115. Blum et al., Neurology 2006;67:400-406. Meador et al. Epilepsia 2016;57(2):243-51.

ASM % placebo > ASM gabapentin 0 – 19% lamotrigine 1 – 17% levetiracetam 11% perampanel* 30%

• xcarbazepine

46% topiramate 29 – 88% tiagabine 0%

ASMs= anti-seizure medications

*all healthy volunteer studies except perampanel patient study

Healthy Adult Volunteer Studies: Newer ASMs vs Older ASMs

Meador et al., Epilepsia 1999;40(9):1279-1285. Meador et al., Neurology 2001;56:1177-82. Salinsky et al., Epilepsy & Behavior 2004;5:894-902. Meador et al., Neurology 2003;13;60:1483-8. Salinsky et al., Neurology 2005;64:792-8. Meador et al., Neurology 2005;64(12):2108-2115. Meador et al. Epi & Beh 2019;94:151-157.

LESS impact on cognition MORE impact on cognition % tests Gabapentin Carbamazepine 26% Gabapentin Topiramate 50% Eslicarbazepine Carbamazepine 43% Lacosamide Carbamazepine 75% Lamotrigine Carbamazepine 48% Lamotrigine Topiramate 80% Levetiracetam Carbamazepine 42% Oxcarbazepine Phenytoin 0%

ASMs= anti-seizure medications

Cognitive Effects

• f ASMs

at Age Extremes are Less Studied

CBZ LTG PHT VPA Mean IQ 105 * 108 * 108 * 97 Verbal IQ 104 * 105 * 106 * 97 Non-Verbal IQ 104 T 108 * 106 T 101 Memory Index 104 * 106 * 101 * 92 Exec Index 105 107 * 103 101

* Significantly better than VPA. T = trend.

Fetal Exposure to Valproate Associated with Cognitive Deficits at Age 6 Years Old

(VPA 7-10 IQ points lower)

CBZ=carbamazepine, LTG=lamotrigine, PHT=phenytoin, VPA=valproate

Meador et al. Lancet Neurology 2013: 12(3):244-52.

NEAD STUDY

Fetal Levetiracetam & Topiramate: Cognition at 5-9 years old

No ASM TPM LEV VPA N 55 27 42 47 FSIQ* 100 100 99 96 (SD) (14) (13) (14) (14) VIQ 102 99 101 94 (SD) (13) (11) (11) (15)

Bromley et al, Neurology 2016;87:1-11 *Man Full Scale IQ (standard deviation)

ASMs= anti-seizure medications

ASMs with Reasonable* Data on Neuropsychological Neurodevelopment

• Acetazolamide
• Breviracetam
• Carbamazepine
• Clobazam
• Clonazepam
• Eslicarbazepine
• Ethosuximide
• Felbamate
• Gabapentin
• Lacosamide
• Lamotrigine
• Levetiracetam
• Lorazepam
• Nitrazepam
• Oxcarbazepine
• Perampanel
• Piracetam
• Phenobarbital
• Phenytoin
• Pregabalin
• Primidone
• Retigabine
• Rufinamide
• Stiripentol
• Tiagabine
• Topiramate
• Valproate
• Vigabatrin
• Zonisamide

* Note that “reasonable” does not imply “adequate.”

ASMs= anti-seizure medications

ASMs and Apoptosis in Developing Brain

• Widespread neural apoptosis in rats aged 3-30 days.

Apoptosis associated with impaired synaptogenesis for surviving neurons

– Apoptosis present for clonazepam, diazepam,

phenobarb, phenytoin, valproate, & vigabatrin1,2

• Apoptosis absent for carbamazepine, lamotrigine,

levetiracetam, & topiramate monotherapy3-8

• 1. Bittigau et al. Proc Natl Acad Sci U S A. 2002. 2. Bittigau et al. Ann N Y Acad Sci.
• 2003. Glier et al. Exp Neurology. 2004. 4. Manthey et al. Exp Neurol 2005. 5. Kim et
• al. JPET 2007. 6. Katz et al, JPEG 2007. 7. Forcelli et al, JPEG 2012. 8. Forcelli et al,

Ann Neurol 2012.

ASMs= anti-seizure medications

Methylphenidate, Cognition, & Epilepsy

• Seizures are not increased in those treated with

sympathometics for ADHD

• Double-blind, placebo-controlled, single-dose

study (n=35 adults)

– Significantly improved cognitive performance at both

10mg (p = 0.030) & 20mg (p = 0.034) doses for summary score (CPT, SDMT, & MCG memory) test.

• 1-month open-label trial (n=28)

– Improvements in CPT, SDMT, MCG memory, BDI,

QOLIE cog scales at 20-40mg/day

– No Increase in Seizures

Wiggs et al, Neurology 2018;90(13):e1104-10; Brikell et al, Epilepsia 2019;60:284-93; Adams et al, Neurology. 2017 Jan 31;88(5):470-476; Adams et al, Epilepsia. 2017 Dec;58(12):2124-2132.

Vinpocetine for Seizures, Memory and Fetal Alcohol Deficits

• Vinpocetine is an anticonvulsant and a

phosphodiesterase inhibitor that improves memory.

• Vinpocetine can reverse fetal alcohol deficits in animal

models.

– Medina et al. Restoration of neuronal plasticity by a

phosphodiesterase type 1 inhibitor in a model of fetal alcohol

• exposure. J Neurosci. 2006;26(3):1057-60.

– Medina AE. Therapeutic utility of phosphodiesterase type I inhibitors

in neurological conditions. Front Neurosci. 2011 Feb 18;5:21. doi: 10.3389/fnins.2011.00021

– Lantz et al. Early alcohol exposure disrupts visual cortex plasticity in

• mice. Int J Dev Neurosci. 2012;30(5):351-7.

Needed Research on Cognition in Epilepsy:

• Delineate effects of seizures & interictal discharges
• n cognition
• Delineate cognitive/behavioral effects of different

ASMs for:

– Short & Long term effects, esp. in childhood – Fetal & Neonatal exposure

• Determine underlying mechanisms & reasons for

individual variability

• Develop disease modifying & cognitive enhancing

treatments

Cognitive Impairment in Multiple Sclerosis

• Cognitive impairment is a common in MS affecting

43-70% of patients.

• Involved cognitive domains include:

– Speed of Information Processing – Memory – Attention – Executive Functions – Visuospatial Functions

Grzegorski T, Losy J. Rev Neurosci. 2017;27;28(8):845-860.

Effects of Symptomatic Medication on Cognition in Multiple Sclerosis

• Symptomatic medications for cognition:

– no consistent positive effect demonstrated for Cholinesterase

Inhibitors, Memantine, & Amphetamines (some mixed results)

• Symptomatic medications for other symptoms:

– Some positive cognition effects:

• Fampridine & Dalfampridine, and Vitamin D

– No effect demonstrated on cognition:

• Cannabinoids and Anticholinergics