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

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 • 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

4. 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)

5. Classification seizure generalized focal No impairment of consciousness Tonic-clonic Absence Impairment of consciousness Myoclonic Secondarily generalizes Tonic/clonic/atonic

6. Classification Seizure Intracranial Extracranial • Vascular • Infect/infl • Trauma • Anomaly • Neoplasia • Cryptogenic Structural 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 • Rostral to tentorium cerebelli • Includes • Cerebrum (telencephalon) • Thalamus (diencephalon)

12. Forebrain dysfunction • Altered mental status and behavior changes

13. Gait and Posture • Normal gait • 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

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

19. Diagnostics • Minimum data base • 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? • 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 4 - 6 wk period

24. Phenobarbital • “Broad spectrum” • Increases seizure threshold • Decreases spread of seizures • Good first line drug • Controls ~ 80% of IE dogs

25. 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

26. 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

27. 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

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

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 60-70% dogs (minimal fluctuation in TT3) (4) Serum TSH may even be elevated in <7% dogs (slow, compensatory) (5) Cholesterol high normal

32. Potassium Bromide • No biotransformation • Competes with Cl- • Hyperpolarization • Synergistic effects • Controls 80% of refractory cases • Entirely excreted by kidneys

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: 800-1500 µg/mL

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: • 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 3.5 - 4.5 days • Monitor liver enzymes after 5 days due to risk of hepatic necrosis

40. 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

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

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) • 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

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

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 epilepticusTreatment #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)