So many seizures… so many drugs… What to choose and when

So many seizures…so many drugs…

What to choose and when

Courtenay Freeman, DVM, DACVIM (Neurology)

Southeast Veterinary NeurologyQuickTime™ and a decompressor

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Objectives

• Description

• Lesion localization

• Work up

• Management

Definitions

• Seizure– The clinical manifestation of an abnormal

and excessive synchronization of a population of cortical neurons

• Epilepsy– Tendency toward recurrent seizures

• Unprovoked by systemic or acute neurologic insults

Definitions• Prodrome

– Longterm indication of seizure– hours to days before seizures

• Aura– Initial sensation of seizure before observable

signs– seconds-minutes prior to seizure

• Ictus– Seizure itself, usually 1-3minutes

• Post ictus– Transient abnormalities in brain function– Several hours to 1-2 days, 3-4 days (horses)

Classification

focal generalized

Impairment of consciousness

No impairment of consciousness

seizure

Secondarily generalizes

Absence

Tonic-clonic

Myoclonic

Tonic/clonic/atonic

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Classification

Seizure

Intracranial Extracranial

Structural

Functional

Metabolic Toxic

•Vascular•Infect/infl•Trauma•Anomaly•Neoplasia•Cryptogenic

•Inherited/Idiopathic

Differentials

• Syncope

• Narcolepsy/Cataplexy

• Vestibular episodes

• Movement disorders

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Narcolepsy



Idiopathic head bobbing

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Lesion Localization

• Forebrain or Prosencephalon– Rostral to tentorium

cerebelli

• Includes• Cerebrum (telencephalon)• Thalamus (diencephalon)

Forebrain dysfunction

• Altered mental status and behavior changes

Gait and Posture

• Normal gait– Pleurothotonus • body turn toward lesion

– Circling (toward)

• Postural reactions– Deficits on contralateral side

Menace response

• Absent contralateral to lesion• Normal PLR

Sensory

• Facial hypoalgesia• Hypoaesthesia on

contralateral side of body

• Hemineglect– Ignore sensory

input from one half of their body• Eat out of one half

of bowl

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OtherSeizures!!



Idiopathic epilepsy

• Recurrent seizures with no identifiable cause

• Genetic predisposition• Cryptogenic epilepsy– No identifiable cause– No genetic predisposition



IE: Signalment

• 6 months to 6 years of age• Normal neurologic examination• Normal inter-ictal examination• Purebred dog





Diagnostics

• Minimum data base– CBC– Chemistry Profile– Urinalysis–+/- Liver function tests

• Advanced imaging??

Who should be imaged?

• Asymmetrical neurologic examination• Abnormal inter-ictal period• Patients > 6 years old

• All dogs??

Treatment

• Goals?– Maintain seizure control– Limit unacceptable side

effects– Seizure control ≠ elimination

• When to start?

Seizure therapy

PRINCIPLES

• Life-long daily treatment

• Frequent reevaluations are necessary

• Potentials for emergency situations

• Inherent risks of the drugs

Seizure therapy

When to start?

• Intracranial disease • Status epilepticus• Cluster seizures• 2 or > isolated

events in 4 - 6 wk period

Phenobarbital

– “Broad spectrum”

– Increases seizure threshold

– Decreases spread of seizures

– Good first line drug• Controls ~ 80% of IE dogs

Phenobarbital

Dose (a) Dog - 2 - 4 mg/kg every 12 hours

(b) Cat – 1.5 - 2.5 mg/kg every 12 hours

Therapeutic serum concentration (a) Dog - 15 - 40 µg / ml

(b) Cats - 23.2 - 30.2 µg / ml

How to use PB ?

5.5 time T1/2 = 10 to 14 days

Dosing interval << T1/2 (accumulation)

15

45

2-4 mg/kg twice daily

Phenobarbital

– T1/2; Steady State (SS)• Dog – 32-90 hours; 10-18 days• Cat – 34-43 hours; 10-14 days• Horse – 14-25 hours; 3-6 days

– 90-100% Bioavailable

– Peak conc. 4-8hrs

– Primarily Hepatic metabolism• Up to 25% excreted unchanged by

kidneys

Loading Dose

Total Phenobarbital loading dose: 18 to 24 mg/kg intravenously over 24 hr

Loading 10 to 14 days

Phenobarbital: adverse effects

Idiosyncratic

(1) Hyperexcitability

(2) Acute toxic hepatopathy in dogs

(3) Immune-mediated bone marrow suppression

(4) Lymphadenopathy in cats (pseudolymphoma)

(5) Superficial necrotizing dermatitis

(6) Facial pruritus and limb edema (cat)




Dose-related / transient

(1) Sedation (2) Polydipsia & polyuria (3) Polyphagia

(less common in cats) (4) Pelvic limb weakness


Laboratory changes

(1) Elevation of serum ALP (2) Depression of serum albumin

(3) Serum T4 and fT4 significantly depressed in 60-70% dogs (minimal fluctuation in TT3)(4) Serum TSH may even be elevated in <7% dogs (slow, compensatory)

(5) Cholesterol high normal



Potassium Bromide

• No biotransformation• Competes with Cl-

• Hyperpolarization• Synergistic effects• Controls 80% of refractory

cases• Entirely excreted by kidneys

Potassium Bromide

• 30 mg/kg/day orally • T1/2 (dog): 25 to 46 days (cat 10 days)• Steady state (dog): 3 to 6 months• Serum concentration: 800-1500 µg/mL

Potassium Bromide

Loading dose :Total dose = 600 mg/kgDivided over 4 days = 150 mg/kg/day

Risks = vomiting / extreme sedation

Potassium Bromide

• PuPd, Polyphagia, • Pruritus• Hyperactivity/ behavioral

change• Pancreatitis (with PB)?• Asthma in cats– Allergic Pneumonitis 35-42%– Idiosyncratic– Resolves over 1-2 months

Bromism

• Dose-dependant• Ataxia, Sedation • Pelvic limb stiffness and weakness

Benzodiazepines

• Mechanism of Action– Increase the

frequency of the chloride channel opening

– Hyperpolarizes cell

Diazepam

• Half-life: – Dogs ~ 3hrs – Cat ~ 8-10hrs

• Develop tolerance to medication• Rapid withdrawal may induce

seizures

Diazepam

• Emergency management of seizures

• Limited use in dogs

• 0.5-1 mg/kg divided bid - tid

• Steady state in 3.5 - 4.5 days

• Monitor liver enzymes after 5 days due to risk of hepatic necrosis

Adjunctive MedicationClorazepate

• Metabolized to nordiazepam

• Tolerance develops but slower than to diazepam

• 0.5 mg/kg q8-12 hrs

• Useful for ‘breakthroughs’ as only effective for 2 months

Gabapentin / PREGABALIN

• Structural analogue of GABA

• Binds to the a2-d sub-unit of high voltage pre-synaptic calcium channels– Decreases NT release

• Half-life 3-4 hrs

• 30% metabolized in liver – rest unchanged in urine

Gabapentin (Neurontin)

• Metabolized in liver

• T1/2 3-4 hrs

• 10-20 mg/kg TID PO

• 50% improved control

• Do not use liquid formulation!

Levetiracetam

• Binds to a synaptic vesicle (SVA2)– Modulates of neurotransmitter release,

reuptake, recycling

• Half-Life 2-4 hrs

• Excreted primarily through kidney

• HONEYMOON EFFECT– Dogs develop recurrence of seizure

frequency – tolerance?

Levetiracetam

• 20 mg/kg tid PO (Keppra XR?)

• Use higher dose when with PB

• 50% improved control

• IV use in emergencies

• Ataxia & sedation

Zonisamide

• Synthetic sulfonamide

• “Broad spectrum”/multi-modal

• Half-life 17 hrs (dog), ~35 hrs (cat)

• Liver metabolism

Zonisamide (Zonegran)

• 50% refractory epileptics respond

• 5-10 mg/kg bid PO

• Need increased dose with PB

• Side Effects– Transient sedation, ataxia– Acute hepatoxicity (idiosyncratic)– KCS

Felbamate• Mechanism of action– Inhibits NMDA and kainate receptor

activation– Inhibits voltage dependent Na+ channels

• High bioavailability• T ½ of 4-6 hours• 70% excreted in urine unchanged, 30% liver

• Side Effects– blood dyscrasias, hepatotoxicity

Status epilepticus

• Definition: seizure activity > 5 min• Cluster seizures: 2 or > seizures in a 12

to 24 hour period

• Anticonvulsants: drug to stop seizure activity

• Antiepileptic: drug to prevent seizure activity

Status epilepticusADMISSION MANAGEMENT

• History• Rectal temperature – cool if >104˚F/40˚C• Blood work – Electrolytes/ Ca++ / Glucose / bile acids /

Toxicity screen / PCV / TP• +/- Dextrose 10% solution; 100 mg/kg IV• Oxygen administration• +/- IV catheter

Status epilepticusTreatment #1

• Stop seizure activity1. Diazepam– 0.5 - 1.0 mg/kg IV, 0.5 - 2.0 mg/kg rectally or IN– Midazolam 0.2 mg/kg IV/IM/nasally

2. Phenobarbital 2-4 mg/kg IV/IM– Onset of action ~20 min– q 30 min intervals if needed (20-24 mg/kg/24 hr)


• Valium/midazolam CRI– 0.5 - 2.0 mg/kg/hour IV CRI in 0.9%

saline– Respiratory depression possible– Reduce dose q3-6 hr to effect


• Levetiracetam (Keppra) IV

• Anticonvulsant and anti-epileptic

• 20 to 60 mg/kg IV over 2 minutes lasts 8 hours (dilute)


• Barbituate coma– Pentobarbital 3 - 24 mg/kg

IV to effect– Profound respiratory and

cardiac depression– Especially if toxin induced

seizures

• Propofol coma– Anticonvulsant properties– Bolus 1-4 mg/kg IV to

effect – CRI (0.1-0.6 mg/kg/min)– Consider expense


Last Ditch!!• Inhalational Anesthesia vs.

thiopental

• Ketamine – 5mg/kg IV then 5 mg/kg/hr

• Potassium bromide rectally – 100 mg/kg q4hrs 6 doses


• Cerebral edema?– Oxygen and Fluids– Methylprednisolone sodium

succinate?– Furosemide 1.0 mg/kg IM, IV– Mannitol 20% 0.5 g/kg IV

Status epileptusPost seizure management

• Thoracic and Abdominal imaging• Urinalysis / Indwelling urinary catheter• ECG• CT / MRI• CSF• +/-Gastric lavage

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Courtenay Freeman, DVM, DACVIM (Neurology)

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So many seizures… so many drugs… What to choose and when