So many seizures…
so many drugs…
What to choose and when
Courtenay Freeman, DVM, DACVIM
(Neurology)
Southeast Veterinary Neurology
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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
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seizure
focal
No impairment
of consciousness
Impairment of
consciousness
generalized
Tonic-clonic
Absence
Myoclonic
Secondarily
generalizes
Tonic/clonic/atonic
Classification
Seizure
Intracranial
Structural
Functional
•Vascular
•Infect/infl
•Trauma
•Anomaly
•Neoplasia
•Cryptogenic
•Inherited/
Idiopathic
Extracranial
Metabolic
Toxic
Differentials
• Syncope
• Narcolepsy/Cataplexy
• Vestibular episodes
• Movement disorders
Narcolepsy
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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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Other
Seizures!!
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Idiopathic epilepsy
• Recurrent seizures with no
identifiable cause
• Genetic predisposition
• Cryptogenic epilepsy
– No identifiable cause
– No genetic predisposition
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IE: Signalment
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6 months to 6 years of age
Normal neurologic examination
Normal inter-ictal examination
Purebred dog
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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?
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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 ?
2-4 mg/kg twice daily
45
15
Dosing interval << T1/2 (accumulation)
5.5 time T1/2 = 10 to 14 days
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
Loading
10 to 14 days
Total Phenobarbital loading dose:
18 to 24 mg/kg intravenously over 24 hr
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)
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Phenobarbital: adverse effects
Dose-related / transient
(1) Sedation
(2) Polydipsia & polyuria
(3) Polyphagia
(less common in cats)
(4) Pelvic limb weakness
Phenobarbital: adverse effects
Laboratory changes
(1) Elevation of serum ALP
(2) Depression of serum albumin
(3) Serum T4 and fT4 significantly depressed in 6070% dogs (minimal fluctuation in TT3)
(4) Serum TSH may even be elevated in <7% dogs
(slow, compensatory)
(5) Cholesterol high normal
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Potassium Bromide
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No biotransformation
Competes with ClHyperpolarization
Synergistic effects
Controls 80% of refractory
cases
• Entirely excreted by kidneys
Potassium Bromide
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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/kg
Divided 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 Medication
Clorazepate
• 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 epilepticus
ADMISSION 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 epilepticus
Treatment #1
• Stop seizure activity
1. 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)
Status epilepticus
Treatment #2
• 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
Status epilepticus
Treatment #3
• Levetiracetam (Keppra) IV
• Anticonvulsant and anti-epileptic
• 20 to 60 mg/kg IV over 2 minutes lasts 8
hours (dilute)
Status epilepticus
Treatment #4
• Barbituate coma
– Pentobarbital 3 - 24 mg/kg IV
to effect
– Profound respiratory and
cardiac depression
– Especially if toxin induced
seizures
• Propofol coma
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–
–
–
Anticonvulsant properties
Bolus 1-4 mg/kg IV to effect
CRI (0.1-0.6 mg/kg/min)
Consider expense
Status epilepticus
Treatment #5
Last Ditch!!
• Inhalational Anesthesia vs.
thiopental
• Ketamine – 5mg/kg IV then 5
mg/kg/hr
• Potassium bromide rectally – 100
mg/kg q4hrs 6 doses
Status epilepticus
Treatment #6
• Cerebral edema?
– Oxygen and Fluids
– Methylprednisolone sodium
succinate?
– Furosemide 1.0 mg/kg IM, IV
– Mannitol 20% 0.5 g/kg IV
Status epileptus
Post seizure management
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Thoracic and Abdominal imaging
Urinalysis / Indwelling urinary catheter
ECG
CT / MRI
CSF
+/-Gastric lavage
Questions?
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Courtenay Freeman, DVM, DACVIM (Neurology)