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

Objectives Description Lesion localization Work up Management

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

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)

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

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

Differentials Syncope Narcolepsy/Cataplexy Vestibular episodes Movement disorders

Narcolepsy

Idiopathic head bobbing

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

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

Gait and Posture Normal gait Postural reactions 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 Hemineglct: indicates forebrain lesion on contralateral side to the side ignored

Other Seizures!!

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

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

Diagnostics Minimum data base Advanced imaging?? 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? When to start? 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 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

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 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

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

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 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.

Loading Dose Loading Total Phenobarbital loading dose: 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)

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 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.

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

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 Administration Oral, rectal 30mg/kg Q24hr IV (sodium bromide, reduce dose 15%)

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: Develop tolerance to medication 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 Pregabalin – increased affinity for alpha2 subunit of voltage gated calcium channels and in some dogs can be used Q12hrs liver (n-methylgabapentin)

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) 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?

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 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

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

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 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 Thoracic and Abdominal imaging Urinalysis / Indwelling urinary catheter ECG CT / MRI CSF +/-Gastric lavage

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