2017 Neuro Latin Veterinary Congress 10/1/2017

THE WORLD OF
EPILEPSY
TREATMENT IN
VETERINARY
MEDICINE IN
2017

Michael Podell MSc, DVM
Diplomate ACVIM (Neurology)
MedVet Chicago
Medical & Cancer Center for Pets
Michael.Podell@medvetforpets.com

REASONS FOR UNCONTROLLED SEIZURES:  REASONS FOR UNCONTROLLED SEIZURES: 
Clinical Variables Physiologic Variables
 Delay in onset of therapy  Idiopathic  etiology
 Non‐therapeutic AED   Genetic factors
concentration  Propagation of epileptic foci
 Multi‐drug resistant gene 
 Ineffective AED at  expression and altered blood 
therapeutic concentration brain barrier‐ drug 
 Seizure type dependent interaction
 Intron 1 mutation ABCB1 
 Adverse effects at  gene in Border Collies 
maximal concentration  (Alves et al, JVIM 2011)

 Owner and/or patient   Drug tolerance
 Symptomatic etiology *
noncompliance
 Developmental
 Cost limitations  Cortical dysplasia
* *
 Acquired

When Should a Second AED Be Started?
 Strict criteria for decision‐
What is Drug‐Resistant Epilepsy?
making strategy on starting a   ACVIM Panel Recommendations: International League Against Epilepsy Task Force
second AED is lacking in  Kwan et al, Epilepsia 52:1069-1077, 2010
veterinary medicine  Documentation of appropriate 
drug  and maximal level of  Drug Treatment Success Drug‐Resistant Epilepsy
 Risk factors associated with 
poorer seizure control include  first AED for a minimum of 3   Seizure free duration   Level 1
male dogs and prior cluster  months at least 3 times the   Undetermined outcome
seizure activity   longest seizure free   Inadequate time or drug dose
 (Packer et al. 2014)   > 50% increase in seizure 
period prior to onset   Monotherapy failure
 Factors to consider frequency over 3 months of treatment  Continued seizure recurrence 
 Selection of an AED with a 
different mechanism of action  New onset of status   Minimum duration of  despite appropriate drug 
 Minimizing drug‐drug  epilepticus 12 months selection, time of treatment 
interactions, avoiding additive  and serum concentration
toxicity  New onset of cluster seizures
 Level 2
 Determination of risk‐benefit of   Presence of drug‐toxicity
polypharmacy versus quality of   Failure of adequate trials of 2 
life tolerated and appropriately 
chosen AEDs

Dr. Michael Podell 1

2017 Neuro Latin Veterinary Congress 10/1/2017

What Causes  SELECTION 
Drug‐Resistance? CONSIDERATIONS
 Transporter hypothesis (1)
 Reduced AED CSF 
 Mechanisms of drug action
concentration
 Epileptic seizure type
 Target hypothesis (2)
 Decrease AED action at   Pharmacokinetic and 
receptor
pharmacodynamic profile
 Network hypothesis (3)
 Altered connectivity  Therapeutic index (safety)
 Gene variant hypothesis
 Genetic protein alteration
 Tolerability
 Intrinsic severity hypothesis  Clinical efficacy
 High seizure density and/or 
frequency correlated with   Cost
poorer prognosis
Kwan P et al. Drug-Resistant Epilepsy N Engl J Med 2011; 365:919-926

 First Generation
 Phenobarbital
AED BY  


Bromide
Benzodiazpines
GENERATION 
 Phenytoin
 Carbemazepine
 Valproate
 Second Generation
 Felbamate
 Levetiracetam
 Topiramate
 Lamotrigine
 Zonisamide
 Pregabalin

 Third Generation
 Lacosamide
 Rufinamide

Perucca et al Epil Beh, 2012

SUMMARY OF PHARMACOKINETIC PROPERTIES
SELECTION  PB BR FBM ZON TOP LEV PGL LAC RUF
CONSIDERATIONS
Bioavailablity High High High High High High High High High

 Mechanisms of drug action Parenteral form Yes Yes No No No Yes No Yes Yes

 Pharmacokinetic and pharmacodynamic
T1/2 (hrs) 24-40 15-20- 4-6 15-20 2-4 2-4 6-8 ? 5-14
profile days

 Therapeutic index (safety)
 Tolerability Linear kinetics Yes Yes No Yes Yes Yes Yes Yes Yes

 Clinical efficacy Autoinduction High Low High Med Med Low No Yes ?

 Cost
Drug interaction High Low High Med Low Med Low Low Low

Dr. Michael Podell 2

2017 Neuro Latin Veterinary Congress 10/1/2017

CNS THERAPEUTIC INDEX OF AED
SELECTION 
CONSIDERATIONS EFFICACY TI TI

 Mechanisms of drug action
TOXICITY
 Pharmacokinetic and pharmacodynamic 
profile
 Therapeutic index (safety)  Low TI  High TI
 Phenobarbital  Levetiracetam
 Tolerability
 Primidone  Zonisamide
 Clinical efficacy  Benzodiazepines  Topiramate

 Cost  Bromide  Felbamate

 Lacosamide
 Rufinamide

Additional AED Information for Use
• 1 clinical study (N= 6) (III)
ACVIM Panel Grade of Recommendations  Felbamate • 6/6 with > 50% reduction for 6 months (CP 
seizures)
(Level of Evidence) for Add‐On AED Therapy  • 2 clinical studies N=25 (III)
Gabapentin • 11/25 with > 50% reduction for 3 or 4 months

A (HIGH) B (MODERATE) C (LOW) D (NO) • 1 clinical study (n =9) (III)

Pregabalin • 7/9 with > 50% reduction for 3 months
• Levetiracetam  • Imepitoin (III) • Primidone (II)
(IB)
• 1 clinical study (n =10) (III)
• Bromide (II)
Topiramate • 5/10 dogs with > 50% reduction for 6‐15 months
• Zonisamide 
(III)
• Phenobarbital  • No clinical studies 
(IV) Lacosamide

Rufinamide • No clinical studies

Lacosamide
TOPIRAMATE  Mechanism
 Enhances slow inactivation 
 Sulphamate‐substituted  T1/2 Tss Vd Protein of sodium channels only 
(hr) (d) (L/g) Binding
monosaccharide (%) (unique)
 Block voltage‐gated Na  Topiramate 2-4 1-3 0.65 15
 Interacts with CRMP‐2
channels  Neuroprotective and 
 Enhance Cl‐ conductance  neuropathic effect
with GABA receptor   Pharmocology (Human)
activation T1/2=elimination half-life;  Low protein bound (15%)
Tss= time to steady-state;
 Increase brain GABA  Vd= volume of distribution.
 Primary renal excretion
concentration  12‐16 hour half‐life
 Inhibit kainic/AMPA   Low drug‐drug interaction
subtype of glutamate   Safety: Dose‐related
receptors  Dizziness, headache, diplopia
 Nausea and vomiting

Dr. Michael Podell 3

2017 Neuro Latin Veterinary Congress 10/1/2017

Lacosamide Efficacy and Dosing Next Generation:
Levetiracetam Analogs
 Efficacy  and dosing study
 Brivaracetam  Seletracetam
 Significant partial onset seizure 
improvement above 200   >10 fold SV2A protein affinity  >10 fold SV2A protein
mg/day that is dose dependant  Animal studies affinity
 Dosage  Higher potency  Highly effective against 
 Adult: 50 mg BID with gradual  myoclonic seizures
 Effective against  greater range 
titration to 200 to 400 mg/day
of seizure types  Very well‐tolerated in 
 Formulation
 50, 100, 150, 200 mg tablets  Variable margin safety for  people 
 10 mg/ml IV hepatotoxicity  No canine studies found
 Monitoring  Dogs: 1.2 fold

 Serum levels not well correlated   Monkey: 81 fold 
with response  Phase III: Partial onset seizure 
control with 50 mg/day

The Next Generation:
 Mechanism
Rufinamide  Retigabine
 Enhances slow and fast   Direct activation of voltage‐gated 
sodium channels  potassium channels (Kv7 subunit) 
inactivation that conducts M‐current
 Inhibit glutamate receptor 
 Prevents escalation of single 
activity (mguR5)
spike to burst discharge
 Pharmocology (Human)  Highly effective in 
 Low protein bound (30%)  Enterohepatic circulation of 
treatment of Lennox‐ retigabine result of reversible 
 Delay gastric absorption  Gastaut syndrome
 8‐12 hour half‐life
glucuronidation‐
 Proven to delay kindling in  deglucuronidation reactions in 
 85% renal metabolized
feline epilepsy model (Arroyo,   human and dogs
 Enzyme induction lowers drug  2007)
level  No interaction with hepatic 
 Dosing metabolized drugs
 Adverse effects: Sedation, 
 5 mg/kg bid with titration
dizziness  Phase III clinical studies in 
 200 and 400 mg tablets
progress

The Next Generation:
Carisbamate Generic Substitutions
 Benefits  Risks
 Blocks voltage –gated brain calcium 
 Less expensive
channels but other mechanisms   Breakthrough seizures with 
possible  More accessible variable  serum drug level 
 FDA standard of therapeutic  due to narrow therapeutic 
 Highly effective in numerous rat 
equivalent range
epilepsy models (genetic, 
 90% CI for area under the curve be   Quality assurance variability 
electrical, and chemical) within 80‐125% of reference  outside of US
 In people: compound
 24‐36 healthy volunteers  Increased cost with need for 
 Predominant renal excretion hospitalization to control 
 Approximate 10‐12 hour T1/2 breakthrough seizures
 Approximately 50% protein   Potential for toxicity
bound
 Wide‐range of seizure type 
response
 Minimal (<5%) adverse effects

Dr. Michael Podell 4

2017 Neuro Latin Veterinary Congress 10/1/2017

Alternative and  Diet
Complimentary Treatment
Ketogenic  Fatty acid 
Hypoallergenic
(MCT) supplementation
 Herbal
Level of 
Level of evidence: 
 Nutrition evidence: IB  Level of evidence: IB 
Insufficient Data to  IV
Insufficient Data to 
 Alternative  Recommend Recommend Insufficient Data to 
Recommend
Pharmacologic Therapy Randomized placebo cross‐over  Single blinded randomized, 
for 6 months (N=11) placebo cross over for 3 
One retrospective non‐
 Physical treatment • Patterson et al, 2005 months (N=15)
controlled study (abstract 
• No difference in seizure control • Matthews et al 2012 N =8) with report of 
 Neurobehavioral • 3 cases pancreatitis • No difference in seizure 
control
improvement (Luján et al, 
2004)

 Stress and sleep  Randomized, blinded placebo 
control for 3 months (N=21) 
 Environmental factors (Law et al. 2015)
• 7 with > 50% improvement

What Are The Guidelines for Success And 
Quality of Life Parameters? At Home Rescue Therapy
Etiology
Treatment 
• Symptomatic  Tolerance  Considerations:
• Breed risks
 Seizure type
Seizure severity Owner Considerations  Propensity to have cluster seizures vs isolated 
• Cluster • Restrictive lifestyle  Owner lifestyle and work schedule
• Prolonged post‐ • Cost
ictal • Emotional stress
• Family stress

Efficacy Quality  Client Education 

• Frequency and Support
• Nocturna of Life
l

Which drug to use
Non‐Intravenous Rescue Therapy Strategies Pharmacology of Rescue Therapy

Pulse dose of existing  Pulse dose of new 
oral AED oral AED
IN or PR

Ease vs  
Efficacy

Non‐IV rapid AED  Complimentary or 
absorption alternative therapy

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2017 Neuro Latin Veterinary Congress 10/1/2017

Non‐Intravenous Access 
Benzodiazepine Therapy
Non‐IV Rapid Therapy DRUG DELIVERY DOSE PHARMACOLOGY RISKS
METHOD
Advantages Disadvantages
Diazepam Rectal 1 mg/kg PB naïve Peak concentration  Irritation
 Rapid increase serum   Shorter duration of action 2 mg/kg PB  8 min  Owner risk
concentration = rapid rise CNS   Less predictable therapeutic  treated Sedation
concentration level  Midazolam Intranasal 0.5 to 1 mg/kg  Peak concentration Irritation
 Proven to stop cluster seizures   Difficulty in administration 15 min Owner risk
and SE Stable 30 days in  Sedation
 Cost syringe  Excitability
 Avoid ER visit
Midazolam  Rectal Not  > 30 min peak  and 
recommended non‐therapeutic

Lorazepam Rectal  Not  Non‐therapeutic 

recommended
Diazepam Oral Not  Non‐therapeutic
recommended Drug‐resistance 
Enzyme induction

Pulse Dose of Existing Oral AED Protocol for Pulse Dose of Existing Oral AED

Advantages Disadvantages Phenobarbital

• Greater of 5 
 Ease of use  Requires ability to swallow/interact mg/kg or 
twice current 
 Minimal adverse effects  Slow onset (15 to 30 minutes) dose
Levetiracetam
 Inexpensive  Minimal relative increase in AED 
 Potential for prolonged effect level (3‐5%)
• Greater of  Zonisamide
 May cause increased clearance and  40 mg/kg or 
twice 
rebound decreased drug level due  current dose • Greater 10 
to enzyme auto‐induction mg/kg or 
twice 
Bromide
current dose
• Not 
recommended

Protocol for Pulse Dose of Novel Oral AED
Pulse Dose of Novel Oral AED
Levetiracetam
Advantages Disadvangates
• 50 mg/kg and 
 Novel mechanism of action  Drug‐drug interaction repeat in 6 
hours
 Short duration therapy  Enzyme induction to lower 
 Ease of administration primary AED level
 Inexpensive  Hepatic toxicity Clorazepate

 Sedation • 1‐2 mg/kg every 8 
hours for 24 hours
 Potentiate drug‐resistance
Zonisamide
 IV Benzodiazepines 
• 10 mg/kg oral once
 Future add‐on therapy
Phenobarbital
• Not 
recommended

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2017 Neuro Latin Veterinary Congress 10/1/2017

When to seek ER care 

 Seizure duration of > 5 minutes
 4th generalized seizure in 24 hours
 Persistent change in behavior, arousability or orientation
 Altered breathing patterns

Dr. Michael Podell 7