So many seizures… so many drugs… What to choose and when
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Transcript of 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
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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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OtherSeizures!!
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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
• 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?
• 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)
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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 60-70% 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
• 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)
Status epilepticusTreatment #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 epilepticusTreatment #3
• Levetiracetam (Keppra) IV
• Anticonvulsant and anti-epileptic
• 20 to 60 mg/kg IV over 2 minutes lasts 8 hours (dilute)
Status epilepticusTreatment #4
• 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
Status epilepticusTreatment #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 epilepticusTreatment #6
• 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)