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

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Presentation on theme: "So many seizures… so many drugs… What to choose and when Courtenay Freeman, DVM, DACVIM (Neurology) Southeast Veterinary Neurology."— Presentation transcript:

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

6 Classification Seizure IntracranialExtracranial Structural Functional Metabolic Toxic Vascular Infect/infl Trauma Anomaly Neoplasia Cryptogenic 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 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 mg/kg every 12 hours (b) Cat – mg/kg every 12 hours Therapeutic serum concentration (a) Dog µg / ml (b) Cats µg / ml

26 How to use PB ? 5.5 time T 1/2 = 10 to 14 days Dosing interval << T 1/2 (accumulation) mg/kg twice daily

27 Phenobarbital –T1/2; Steady State (SS) Dog – hours; 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

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 T 4 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

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 T 1/2 (dog): 25 to 46 days (cat 10 days) Steady state (dog): 3 to 6 months Serum concentration: 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 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

42 Gabapentin (Neurontin) Metabolized in liver T 1/2 3-4 hrs 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 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 Questions? Courtenay Freeman, DVM, DACVIM (Neurology)

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