ISVMA 2017 November 2017ISVMA 2017 November 2017 DR. MICHAEL PODELL 2 SEIZURE TYPES Focal (partial) Sensory (psychic) Motor Elementary Automatisms Orofacial pain syndromes Generalized

ISVMA 2017 November 2017

DR. MICHAEL PODELL 1

Michael Podell MSc, DVMDiplomate ACVIM (Neurology)

MedVet [email protected]

773‐281‐7110

PURPOSE To provide 10 guiding principles to the diagnosis and management of an epileptic cat to improve treatment outcome measures

Successful treatment is dependent upon the 3 “D”s: Diagnosis

Drug selection

Dose administration

Update on novel theories on etiology

Update on treatment strategies

Update on the International Veterinary Epilepsy Task Force (IVETF) Consensus Statement

International Veterinary Epilepsy Task Force

The International Veterinary Epilepsy TaskForce (IVETF) is formed by a mondial (among others Europe, United States of America, Australia) group of (veterinary) scientists interested and specialised in the field of epilepsy. Our group consists of clinical veterinary neurologists, neuropharmacologists, and veterinary neuropathologists

http://www.ivetf.org/

PRINCIPLE #1:THE BRAIN IS SIMILAR TO OTHER

ORGANS IN THE BODY Signs parallel severity of illness

Resiliency

Responsive to therapy

PRINCIPLE #2:

BE CERTAIN THAT AN EPILEPTIC SEIZURE HAS OCCURRED

Positive diagnosis is essential prior to therapy

Epileptic seizures: Paroxysmal onset, finite duration, +/‐ post‐ictal changes

Diagnosis of epilepsy = abnormal brain function



SEIZURE TYPES Focal (partial)

Sensory (psychic)

Motor Elementary

Automatisms

Orofacial pain syndromes

Generalized

Tonic‐clonic

Clonic

Myoclonic

Atonic

Cluster seizures

Status EpilepticusKitz et al. J Vet Intern Med. 2017 31(3): 633–640.

Feline Audiogenic Reflex SeizuresLowrie et al J Feline Med and Surg (2016) 18:328‐336

Seizures precipitated by sound High pitched (metal clinking, tin foil

Repetitive (computer keys, phone ring)

Myoclonic seizurespredominant type (94%)

Normal diagnostic testing

Treatment

Levetiracetam (93% success for myoclonic seizures)

Avoidance (dec by 75%)

PRINCIPLE #3:

IDENTIFY THE SEIZURE ETIOLOGYSEIZURE ETIOLOGY CLASSIFICATION

PRIMARY

SYMPTOMATIC

PROBABLE SYMPTOMATIC

EPILEPSY REACTIVE

RECURRENT

PRIMARY

SYMPTOMATIC

REACTIVE

NON-RECURRENT

EPILEPTIC SEIZURE NON-EPILPETIC SEIZURES

SEIZURE

PREVALENCE BY ETIOLOGYSTUDY TOTAL

NUMBERIDIOPATHIC SYMPTOMATIC METABOLIC

/ TOXIC

Barnes et alJAVMA 2004

17 7 7 3

Schriefl et alJAVMA 2008

91 23 45 20

Pakozdy et alJ Feline Med Surg 2010

125 47 70 8

TOTALS 233 77 (35%) 122 (52%) 31 (13%)

IDIOPATHIC (PRIMARY) EPILEPSY Normal brain structure with abnormal function

Less common than in dogs

Age of onset typically < 6 years

Not correlated with seizure type

Normal neurologic exam and interictal periods (except for status epilepticus)

SYMPTOMATIC EPILEPSY

Structural brain disease Any age of onset

(Raimondi et al Vet Rec 2017)

< = 1 year: 9.4% 1‐6 years: 5.4% >6 years: 23.1% Increase risk of 14% per year over 6

May OR may not be associated with abnormal exam or interictal period

Typically shorter initial interictal interval

Often associated with focal motor seizures

SILENT



SYMPTOMATIC CAUSES

Infectious FIP

Protozoal

Neoplasia Meningioma

Vascular

Head trauma < 6 % risk

Grohmannet al JAVMA 2012

T2W TRANSVERSE MRI SCANT2W TRANSVERSE MRI SCAN

RR

Developmental Anomaly

Hydrocephalus

Porencephaly

Cortical dysplasia

Functional disturbance (kindling)

REACTIVE EPILEPTIC SEIZURES

Normal brain structure Age of onset: younger Portosystemic shunt

Pre‐ligation: > 80% Post‐ligation: >35%

Lipscomb et al Vet Rec 2007

Toxicity Permethrin

Nutritional Thiamine depletion

Cardiogenic A‐V block May not be syncopal

Feline Hippocampal Necrosis Syndrome

Adult cats with high frequency seizure activity

Histopathologic evidence of selective hippocampal necrosis

Difficult to treat cases

Temporal Lobe Epilepsy in People Anatomy

Neocortex (6 layer)

Hippocampus (3 layer)

Subcortical nuclei

Complex partial seizures Ambulatory automatisms

Hallucinatory phenomenon

Hippocampal sclerosis

Highest degree of medically intractable epilepsy

Scharfman and Pedley, 2007



Limbic Encephalitis Autoimmune disease in adult people

CSF autoantibody Onconeuronal Voltage‐gated potassium channels

MRI scan of hyperintense hippocampal lesions on T2W and FLAIR images

Normal CSF analysis Progression to temporal lobe epilepsy and hippocampal sclerosis

Treatment of primary disease may prevent need for chronic antiepileptic drug therapy

23 yo woman

Bien et al Neurol 2007;69:1236-1244

Feline Limbic Encephalitis

35 yo man with hippocampalsclerosis and LE

6 yo MC DSH cat with refractory epilepsy

Bien et al Neurol 2007;69:1236-1244Podell and Oglesbee 2008 2/10 cats with serum & CSF VGKC AB

Pakozdy et al JVIM 20135/14 cats with serum VGKC AB

PRINCIPLE #4:ALWAYS TREAT THE UNDERLYING DISEASE Antiepileptic drug therapy manages the signs ONLY

Reversal of metabolic abnormalities often prevents the need for chronic AED therapy

Symptomatic epilepsy may still need to be treated with AEDs despite removal of the inciting cause

PRINCIPLE #5:“SEIZURES BEGET SEIZURES”

William Gowers

Accurate history and documentation is essential

The earlier AED therapy is started, the better the potential outcome for seizures control

Earlier therapy may reduce the need for multiple drug therapy

Kindling Progression of clinical and EEG seizures induced by repeated activation in neural pathways

Critical period exists (< 6 months) for onset of sustained temporal lobe epilepsy

Early treatment results in more favorable prognosis Shouse et al. Brain Res 1027:126, 2004

Realistic Goals of Therapy Balance between seizure control and quality of life

Seizure control, not necessarily seizure elimination

Decrease in frequency and severity of seizures

Prevention of cluster seizure events

Decrease post‐ictal severity



Realistic Expectations by Owners

Life‐long commitment

Daily medication commitment

Potential for emergency treatment

Inherent risks of therapy

Time for another pill?!!

Reasons to Start Antiepileptic Drug Therapy Identifiable structural lesion present (symptomatic epileptic seizures)

Status epilepticus has occurred

More than 3 generalized seizures occurred within a 24 hour period

Reasons to Start Antiepileptic Drug Therapy

Two or more cluster seizure events (2 or more seizures) occur within a 12 month period

Two or more isolated seizure events occur within a 6 month period

The first seizure is within 6 months of head trauma

Prolonged, severe, or unusual post‐ictal periods occur

PRINCIPLE #6:Start with the Appropriate AED

First Generation

Phenobarbital

Benzodiazepines

Bromide

Second Generation

Levetiracetam

Zonisamide

Topiramate

Gabapentin

IVETF Recommendations

High • Phenobarbital

• Levetiracetam

Moderate

• Zonisamide

• Diazepam

• Gabapentin

• Pregabalin

Low

• Clonazepam

• Topiramate

• Propentofylline

• Taurine

PHENOBARBITAL Efficacious

Well‐tolerated

Consistent in its effect

Can be monitored

Can be given as an injectable or oral formulation

Relatively rapid acting

Can serve as a cerebral protectant

Inexpensive

Phenobarbital Is the Drug of Choice for the

Majority of Cases



PHENOBARIBITAL TREATMENT PEARLS

2.5 mg/kg PO daily at night to start Elimination half‐life 34‐43 hours

No hepatic enzymeautoinduction

IV loading dose: Total mg IV = (Body weight [kg] X (0.8 L/kg) X 10 ug/ml)

= 8 mg/kg over 3 minutes

Therapeutic range: 10‐50 mg/dl

Hepatot0xicity is very rare

POTASSIUM BROMIDE PEARLS

Not recommended for use in cats due to potential for allergic bronchitis syndromewhich can be fatal

PRINCIPLE # 7:MONITOR AED CONCENTRATIONS(Be Proactive Rather Than Reactive) Determine if therapeutic level present at lowest daily time point (trough)

Document steady‐state concentration

Prevent toxic effects

Individualize therapy

PHENOBARBITAL MONOTHERAPY Range:

Initial goal is 15‐20 mg/dl

Maximum: 50 mg/dl

Measure at: Trough times

14, 45, 90, 180, and 360 days after the initiation of treatment

At 6 months intervals thereafter

If pet has more than two seizure events between these times

14 days after the last dosage adjustment

Benzodiazepine Therapy Diazepam

Oral: 2.5 to 5 mg q 12 hours

IV: 0.5 mg/kg bolus CRI IV: 0.25 mg/kg/hrin saline

Per rectal: Not recommended

Clonazepam Oral: 0.25 to 0.5 mg q 12‐24 hours

Evaluate liver panel 2 weeks post‐chronic treatment for idiosyncratic hepatic necrosis

PRINCIPLE # 8:KNOW HOW AND WHEN TO ADJUST AED DOSAGE

Weight based dosing used on initial therapy only

Follow established therapeutic serum concentration ranges

Adjust after steady‐state concentrations achieved

Adjust for metabolic tolerance

Gradual increments are most effective

TOLERANCE= LOSS OF EFFECTIVENESSTOLERANCE= LOSS OF EFFECTIVENESSACQUIREDACQUIRED

POSITIVEPOSITIVE NEGATIVENEGATIVE

METABOLICMETABOLIC FUNCTIONALFUNCTIONAL

UP REGULATION

OF RECEPTORS

UP REGULATION

OF RECEPTORS

ENZYME INDUCTION

ENZYME INDUCTION

CROSS- TOLERANCE

CROSS- TOLERANCE

DOWN REGULATION

OF RECEPTORS

DOWN REGULATION

OF RECEPTORS

DECREASED BBB

DELIVERY

DECREASED BBB

DELIVERY

PROGRESSION OF DISEASE

PROGRESSION OF DISEASE

TIMETIME

DOSE

[SERUM]



Phenobarbital Dose Adjustments

Monitor trough serum concentrations Consistent time point for comparison

Time period of highest risk for relapse

Comparison to peak levels for toxicity

New total mg phenobarbital per day= (desired concentration / actual concentration) X total mg per day

Differential dosing for animals with more frequent night/early AM seizures

PRINCIPLE # 9:CHECK ON OWNER COMPLIANCE

Seizure records

Review of dosing schedule and method

20% drop of trough steady‐state concentration can be an indicator of poor compliance

MONTH 1 MONTH 2 MONTH 3

DAY 1 SEIZURE #

DAY 2

DAY 3

SINGLESHEETRECORDFOR 1YEARTOTAL

PRINCIPLE # 10:KNOW WHEN TO ADD, CHANGE, OR

STOP MEDICATIONS Reasons for adjustments

Refractory epilepsy: Recurrent seizure activity at a rate of > 1 per 8 weeks

Toxicities Expense

Discontinuation is always a gamble Higher probability of success with longer history of control

Gradual reductions are important to avoid withdrawal seizures

IVETF BMC Vet Res. 2015; 11: 177.

LEVETIRACETAM

PHARMACOKINETICS Low protein binding results in minimal drug interactions

Renal excreted (70%)

Minimal hepatic metabolism

Elimination half‐life of 2.9 hr (1.9‐19.6 range) Bailey et al JAVMA 2008:232: 867‐872

Pharmacodynamic effect > pharmacokinetic effect



LEVETIRACETAM TREATMENT

Primary drug Liver disease or older cats Dose: 20 mg/kg po TID with gradual up‐titration

Best add‐on drug Best tolerated of all new AED in cats Excellent add‐on option for all seizure types Dose: Dose: 20 mg/kg po TID with gradual up‐titration

Best used with orofacial complex partial seizures/pain syndrome

Monitoring drug levels not recommended due to high therapeutic index

Maximal dose: 50 mg/kg PO TID or adverse effects

ZONISAMIDE

ZONISAMIDE Blocks Na+ and Ca+2 channels to reduce depolarization

Long elimination half‐life of 30 + hours

Dose 5 mg/kg/day

25, 50, 100 mg capsules

Therapeutic range 10‐40 mcg/ml

Metabolic acidosis prevalent

Wahle AM et al JVIM 2014 28(1): 182-188

PROGNOSIS

EPILEPSY OF UNDETERMINED CAUSE

SYMPTOMATIC EPILEPSY

4 mo

“SAPERE VADERE”

Documents

ISVMA 2017 November 2017ISVMA 2017 November 2017 DR. MICHAEL PODELL 2 SEIZURE TYPES Focal (partial) Sensory (psychic) Motor Elementary Automatisms Orofacial pain syndromes Generalized