1. So many seizures… so many drugs… What to choose and when
Courtenay Freeman, DVM, DACVIM (Neurology)
Southeast Veterinary Neurology

2. Objectives
Description
Lesion localization
Work up
Management

3. Definitions Seizure Epilepsy
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
Syncope secondary to arrhythmias or other cardiovascular abnormality

4. Definitions Prodrome Aura Ictus Post ictus
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)

5. Secondarily generalizes
Classification
seizure
generalized
focal
No impairment
of consciousness
Tonic-clonic
No impairment of consciousness: simple: primarily abnormal motor neuron d/c
Tremors, head turning, facial mm twitching, salivation, mydriaasis
Impairment of consciousness: complex
-staring into space, tail chasing, fly/light biting, abn aggression/rage
-brief episodes of loss of consciousness
Secondarily generalizes: most common, occurs in about 80-90% of dogs with IE (requires close observation to neote different staes)
Tonic/clonic: most common generalized sz
Tonic or clonic
Myoclonic: repetitve brief myoclonic jerking of head, neck thxic limbs
Atonic
Absence: very uncommon in animals, brief (sec), loss of consciousness, lacks motor activity
Absence
Impairment of
consciousness
Myoclonic
Secondarily generalizes
Tonic/clonic/atonic

6. Decrease d inhibitory neurotran smitters (e.g. GABA, Glycine)
Classification
Seizure
Intracranial
Extracranial
Vascular
Infect/infl
Trauma
Anomaly
Neoplasia
Cryptogenic
Structural
Altered membran e function leading to excessive depolariza tion(e.g. alteration of Na/K pump; permeabili ty changes in the cell membran e secondary to hypoxia, inflammati on, or trauma, Channelo pathies)
Decrease d inhibitory neurotran smitters (e.g. GABA, Glycine)
Increased excitatory neurotran smitters (e.g. glutamate, aspartate, acetylcholi ne)
Altered extracellul ar potassium and calcium concentrat ion
Toxic
Metabolic
Functional
Inherited/
Idiopathic

7. Differentials Syncope Narcolepsy/Cataplexy Vestibular episodes
Movement disorders

8. Narcolepsy

10. Idiopathic head bobbing

11. Lesion Localization Forebrain or Prosencephalon Includes
Rostral to tentorium cerebelli
Includes
Cerebrum (telencephalon)
Thalamus (diencephalon)
Cerebrum important for
Behavior
Vision
Hearing
Fine motor activity
Conscious perception of touch, pain (nociception), temperature, and body position (proprioception)
Diencephalon
Primary sensory integrating system in CNS

12. Forebrain dysfunction
Altered mental status and behavior changes
Depression/deliruim dementia/ stupor coma

13. Gait and Posture Normal gait Postural reactions Pleurothotonus
body turn toward lesion
Circling (toward)
Postural reactions
Deficits on
contralateral side

14. Menace response
Absent contralateral to lesion
Normal PLR

15. 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
Hemineglct:
indicates forebrain
lesion on contralateral
side to the side ignored

16. Other
Seizures!!

17. Idiopathic epilepsy Recurrent seizures with no identifiable cause
Genetic predisposition
Cryptogenic epilepsy
No identifiable cause
No genetic predisposition

18. IE: Signalment 6 months to 6 years of age
Normal neurologic examination
Normal inter-ictal examination
Purebred dog
Jaggy: as early as three months, as late as 10 years
AS: moderate to severe clinical course of sz activity; clusters and SE high frequency; poor control and a high initial frequency is associated with shorter survival
Poor sz control unrelated to ABCB1 mutations (MDR1)
Mutations in ABCB1 gene is associated with drug responsiveness in BC: mutation was significantly more freq in epileptic BC resistant to PB tx than in epileptic BC responsive to PB treatment

19. Diagnostics Minimum data base Advanced imaging?? CBC Chemistry Profile
Urinalysis
+/- Liver function tests
Advanced imaging??

20. Who should be imaged? Asymmetrical neurologic examination
Abnormal inter-ictal period
Patients > 6 years old
All dogs??

21. Treatment Goals? When to start? Maintain seizure control
Limit unacceptable side effects
Seizure control ≠ elimination
When to start?

22. Seizure therapy PRINCIPLES Life-long daily treatment
Frequent reevaluations are necessary
Potentials for emergency situations
Inherent risks of the drugs

23. Seizure therapy When to start? Intracranial disease Status epilepticus
Cluster seizures
2 or > isolated events in wk period

24. Phenobarbital “Broad spectrum” Increases seizure threshold
Decreases spread of seizures
Good first line drug
Controls ~ 80% of IE dogs
Binds to GABAA
prolongs the duration chloride channel is open
Inhibits AMPA receptor (glutamate)
Blocks voltage gated calcium channels
At high concentration: can slow sodium conductance

25. Phenobarbital Dose (a) Dog - 2 - 4 mg/kg every 12 hours
(b) Cat – mg/kg every 12 hours
Therapeutic serum concentration
(a) Dog µg / ml
(b) Cats µg / ml
Increases seizure threshold and decreases spread of seizures.“Broad spectrum”
Binds to GABAA
prolongs the duration chloride channel is open
Inhibits AMPA receptor (glutamate)
Blocks voltage gated calcium channels
At high concentration: can slow sodium conductance

26. How to use PB ? 45 15 2-4 mg/kg twice daily
Dosing interval << T1/2 (accumulation)
5.5 time T1/2 = 10 to 14 days

27. Phenobarbital T1/2; Steady State (SS) Dog – 32-90 hours; 10-18 days
Cat – hours; days
Horse – hours; 3-6 days
90-100% Bioavailable
Peak conc. 4-8hrs
Primarily Hepatic metabolism
Up to 25% excreted unchanged by kidneys
Microsomal enzyme action - oxidative hydroxylation to form hydroxyphenobarbital – metabolite has weak anticonvulsant activity (does not contribute). Up to 25% is excreted unchanged in the urine.

28. Loading Dose Loading Total Phenobarbital loading dose:
10 to 14 days
Total Phenobarbital loading dose:
18 to 24 mg/kg intravenously over 24 hr

29. 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)

30. Phenobarbital: adverse effects
Dose-related / transient
(1) Sedation
(2) Polydipsia & polyuria
(3) Polyphagia
(less common in cats)
(4) Pelvic limb weakness

31. Phenobarbital: adverse effects
Laboratory changes
(1) Elevation of serum ALP
(2) Depression of serum albumin
(3) Serum T4 and fT4 significantly depressed in % dogs (minimal fluctuation in TT3)
(4) Serum TSH may even be elevated in <7% dogs (slow, compensatory)
(5) Cholesterol high normal
Phenobarb has no effect on adrenal function testing (acth, LDDS), it will start to influence thyroid function after 3 weeks of use, and this is manifested as a low T4, low free T4, and a normal to slightly increased TSH. Some dogs do become hypertriglyceridemic. Liver values will become elevated with mild to marked increases in ALKP, ALT should be normal/high end, AST, TBILI should not be elevated with phenobarb. Liver values will usually return to normal within 6-8weeks after lowering/discontinuing medications. Cytopenias are reported and usually resolve with discontinuation, it has been reported to cause myelofibrosis, does not appear to be autoimmune.

32. Potassium Bromide No biotransformation Competes with Cl-
Hyperpolarization
Synergistic effects
Controls 80% of refractory cases
Entirely excreted by kidneys
Hyperpolarization after traversing cl- ion channel

33. 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: µg/mL
Administration
Oral, rectal 30mg/kg Q24hr
IV (sodium bromide, reduce dose 15%)

34. Potassium Bromide Loading dose : Total dose = 600 mg/kg
Divided over 4 days = 150 mg/kg/day
Risks = vomiting / extreme sedation

35. Potassium Bromide PuPd, Polyphagia, Pruritus Hyperactivity/ behavioral
change
Pancreatitis (with PB)?
Asthma in cats
Allergic Pneumonitis 35-42%
Idiosyncratic
Resolves over 1-2 months

36. Bromism Dose-dependant Ataxia, Sedation
Pelvic limb stiffness and weakness

37. Benzodiazepines Mechanism of Action
Increase the frequency of the chloride channel opening
Hyperpolarizes cell

38. Diazepam Half-life: Develop tolerance to medication
Dogs ~ 3hrs
Cat ~ 8-10hrs
Develop tolerance to medication
Rapid withdrawal may induce seizures

39. Diazepam Emergency management of seizures Limited use in dogs
0.5-1 mg/kg divided bid - tid
Steady state in days
Monitor liver enzymes after 5 days due to risk of hepatic necrosis

40. 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

41. 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
Pregabalin – increased affinity for alpha2 subunit of voltage gated calcium channels and in some dogs can be used Q12hrs
liver (n-methylgabapentin)

42. Gabapentin (Neurontin)
Metabolized in liver
T1/2 3-4 hrs
10-20 mg/kg TID PO
50% improved control
Do not use liquid formulation!

43. Levetiracetam Binds to a synaptic vesicle (SVA2) Half-Life 2-4 hrs
Modulates of neurotransmitter release, reuptake, recycling
Half-Life 2-4 hrs
Excreted primarily through kidney
HONEYMOON EFFECT
Dogs develop recurrence of seizure frequency – tolerance?

44. Levetiracetam 20 mg/kg tid PO (Keppra XR?)
Use higher dose when with PB
50% improved control
IV use in emergencies
Ataxia & sedation

45. Zonisamide Synthetic sulfonamide “Broad spectrum”/multi-modal
Half-life 17 hrs (dog), ~35 hrs (cat)
Liver metabolism
Mechanism of action (multi-modal)
Blockade of voltage gated channels Sodium, T-Type calcium
Enhancement of GABA function
Modulation of serotonin, acetylcholine, serotonin
May have free radical properties

46. 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

47. 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
Mechanism of action
Inhibits NMDA and kainate receptor activation
Inhibits voltage dependent Na+ channels

48. 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

49. 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

50. Status epilepticus Treatment #1
Stop seizure activity
1. Diazepam
mg/kg IV, 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)

51. Status epilepticus Treatment #2
Valium/midazolam CRI
mg/kg/hour IV CRI in 0.9% saline
Respiratory depression possible
Reduce dose q3-6 hr to effect

52. Status epilepticus Treatment #3
Levetiracetam (Keppra) IV
Anticonvulsant and anti-epileptic
20 to 60 mg/kg IV over 2 minutes lasts 8 hours (dilute)

53. Status epilepticus Treatment #4
Barbituate coma
Pentobarbital 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 ( mg/kg/min)
Consider expense

54. 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

55. 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

56. Status epileptus Post seizure management
Thoracic and Abdominal imaging
Urinalysis / Indwelling urinary catheter
ECG
CT / MRI
CSF
+/-Gastric lavage

57. Courtenay Freeman, DVM, DACVIM (Neurology)
Questions?
Courtenay Freeman, DVM, DACVIM (Neurology)