Practical Neurology Seizure Disorders 1 The most common Neurologic Problem in Small Animal Medicine Wendy Blount, DVM Types of Seizures

Generalized Seizure • Used to be called “grand mal” • Usually tonic-clonic • Most common kind of seizure • Usual loss of consciousness – Sometimes partially conscious • First phase tonic – stiff, opisthotonus – May be cyanotic – Vocalize, salivate, urinate, defecate – A minute or so – fatal if longer • Second phase clonic – Paddling or jerking of the limbs – Chewing movements – May be several minutes Types of Seizures

Generalized Seizure • Sometimes just tonic • Sometimes just clonic • Less common types of generalized seizures: – Atonic seizures • Sudden loss of muscle tone – Myoclonic seizures • Generalized brief, shock-like contractions – Absence seizures – very rare • Formerly called “petit mal” Types of Seizures

Focal (Partial) Seizure (2 kinds)

• Simple focal seizure – Consciousness not impaired – motor seizure

• Complex focal seizure – Consciousness is altered – Unprovoked aggression • Canine rage syndrome • Aka Episodic dyscontrol – Irrational fear • Psychic seizure • Aka Psychomotor seizure Types of Seizures

Focal (Partial) Seizure • Any body part or behavior may be involved • Depends on the seizure focus location in the cerebrum – Facial spasms – head movements • “yes” or “no” – Fly biting – Repetitive limb movement – Licking or chewing a single area – Hypersalivation – Vomiting, diarrhea, abdominal pain • Limbic epilepsy Types of Seizures

Focal/Partial seizures can progress to Generalized Seizures

• This can be a clue in the history that distinguishes seizure from other episodes of collapse – Starts with a twitching limb or turning head – Progresses to generalized seizure Differential Diagnosis

Episodes resembling seizure • 4 kinds of syncope • Narcolepsy • Stereotypic Behavior, Hyperesthesia • 4 kinds of tremor • 3 kinds of ataxia • Rapidly progressive weakness – EIC, MG • Toxic Encephalopathy • Active sleep • Pain • Hyperviscosity Syndrome Differential Diagnosis

Seizure • Any brain activity can trigger, or can be spontaneous – Exercise triggers syncope & progressive weakness – Excitement triggers narcolepsy • Usually self limiting Differential Diagnosis

Seizure • Often composed of 3 stages – 1 - Pre-ictal – 2 parts • Prodrome – hours – normal EEG – Long term indication – Restless, vocalizing • Aura – minutes – abnormal EEG – Initial sensation of seizure before observable signs – Hiding, agitation, seek owner Differential Diagnosis

Seizure • Often composed of 3 stages – 2 – Ictal – the seizure (ictus) – 3 - Post-ictal – minutes to days • Transient abnormalities in brain function • Disorientation • Restlessness • Ataxia • Blindness • Deafness Differential Diagnosis

Syncope • Partial or complete loss of consciousness (confusion) • Short duration (< 1 minute) • Lack of clonus, but can have tonic like phase due to hypoxia • Lack of post ictal signs • Often associated with exercise • How do you tell the difference? • Confirmed by cardiopulmonary work- up, with bloodwork • Vagal syncope associated with very low heart rate Differential Diagnosis

Narcolepsy • Flaccid – no tonic phase • Loss of consciousness • Precipitated by excitement – Most common inciter? – Food/eating Differential Diagnosis

Stereotypic Behavior • Repetitive bizarre behavior – Tail chasing • Can usually be distracted • No pre-ictal or post-ictal phase Differential Diagnosis

Rapidly Progressive weakness • Myasthenia gravis • Exercise induced collapse • Gradually precipitated by vigorous activity • No loss of consciousness • Usually recovers fully with rest • May show postural tremors which might be confused with muscle contractions Differential Diagnosis

Encephalopathy • No distinct pre-ictal, ictal and post-ictal phases • Prolonged neurologic signs – Disorientation – Ataxia – Blindness – Abnormal behavior • Cerebral or hepatic • Encephalopathy leading to seizures can confuse the distinction Differential Diagnosis

Active Sleep • Twitching • Paddling • Vocalizing • No post-ictal signs upon waking • Many think the pet is dreaming Differential Diagnosis

Pain • Especially neck pain • Muscle rigidity • stiffness • Crying or screaming • Consciousness not impaired Differential Diagnosis

Hyperviscosity • Polycythemia • High triglycerides, cholesterol • High Proteins • Results in sludging in the brain tissue capillaries – poor microcirculation Epilepsy

• Recurrent seizures over time • A syndrome, not a disease Different from Provoked seizures • Aka reactive seizures • Secondary to metabolic or brain disease, at the time of insult • Can resolve with underlying cause – Hypoglycemia – Hypocalcemia – Toxicity – Trauma Epilepsy

• Idiopathic epilepsy – Aka primary epilepsy – No identifiable cause – Onset young adult – Normal between seizures • “well dog with seizures” – Normal bloodwork and neurologic exam – Neuro exam can be abnormal during post-ictal stage – Anticonvulsant therapy can also affect neurologic exam Epilepsy

• Symptomatic epilepsy – Aka secondary epilepsy – Identifiable cause of seizures over time • Intracranial – Senile atrophy of the brain – lysosomal storage diseases – Hydrocephalus – Neoplasia – Infectious – Inflammatory – Trauma – Vascular/ischemia • Extracranial – Hepatic encephalopathy – Insulinoma Epilepsy

• Symptomatic epilepsy – Suspect if onset < 1 yrs or >5 years – Suspect if focal seizures – Sudden onset of cluster seizures – Interictal abnormalities on bloodwork or neuro exam • “sick dog with seizures” Breed Predispositions

Fly snapping seizures • Cavalier King Charles Spaniel

Canine Rage Syndrome • Springer Spaniel

Head Movement partial seizure • Boxers and Bulldogs – “no” • Doberman Pinschers – “yes”

Exercise induced collapse • Labrador Retriever Breed Predispositions

Idiopathic epilepsy • Beagle, Belgian tervuren, Keeshond, Dachshund, GSD, Labrador retriever, Golden retriever, Collie Status epilepticus • Labrador retriever • Large dogs Narcolepsy • Rottweiler, Labrador, Dachshund Tail Chasing • Bull terrier Bismarck

7 year CM GSD – 98 lbs CC: had a seizure tonight HPI: has never had a seizure before • Started with stretching the lower jaw open, progressed to tonic-clonic seizure x 30 seconds • Urinated, vocalized, paddled Hx: • perianal fistulas – on cyclosporine and doing OK • Has had excessive swallowing movements for several months & chronic colitis – wants GI scope • Works his jaw, stretches it open, same time period • History of being excessively sensitive to sedation Exam: NSAF, except more quiet than usual Bismarck

Dx Plan: • MDB: CBC, GHP, UA, HWTest • Neuro Exam: • All Tests & Neuro Exam normal Tx Plan: • levetiracetam XR 500mg – 2 PO BID

The next day: Bismarck was totally fine last night, and also when I left this morning. Gave the Keppra® just before I left for work. I got home for lunch, and he is drunk as a skunk. Exam: lethargic, disoriented, obtunded Bismarck

Neuro Exam: • sensory ataxia • CP deficits all 4 legs (worse rear) • cranial & spinal reflexes normal, except cannot elicit a gag reflex DDx Cerebral Deficits: • Keppra overdose or sensitivity • Liver Disease • Cerebral Disease or post-ictal behavior DDx excessive swallowing and working jaw: • Brain stem disease (multifocal CNS disease) • Megaesophagus, dysphagia • Partial seizure Bismarck

Dx Plan: • Chest x-rays (3 views) • abdominal ultrasound • Oropharyngeal & rectal exams under sedation • Barium esophagram • Levetiracetam drug level** • Bile Acids – fasting and post prandial** • Keep Bismarck for observation • All in house tests normal Tx Plan: • Doxycycline 300 mg PO BID x 3 weeks • End of day - no change, not eating or drinking • Start IV fluids Bismarck

2 Days Later: • Bismarck gradually improving • Bile Acids normal • Keppra® level below TDR Dx: Cerebral disease and likely multifocal CNS disease DDx: • Epilepsy is possible, if lower brain stem stuff was partial seizures • If metastatic neoplasia is there, we have not found it • Infectious – rickettsial, fungal, protozoal > bacterial • Inflammatory – (GME > IM meningitis) Bismarck

Plan: • If Bismarck fails to improve, either do CSF here or refer for MRI and CSF, depending on severity 1 week after initial seizure: Bismarck back to normal. Owner wants to schedule GI scope. 2 weeks after initial seizure: • Bismarck has another seizure, owner wants MRI • MRI shows multifocal infiltrative CNS disease in brain and brainstem • CSF tap yields non-staining fungal hyphae resembling Aspergillus spp. • Owner elects euthanasia Working Up the Seizure Patient

• Physical Exam

• Neurologic Exam – Avoid post-ictal period – Impossible to evaluate if groggy due to anticonvulsants Working Up the Seizure Patient

• Laboratory Evaluation – CBC, profile (TG, Ca), electrolytes – Thyroid panel • TSH, T4, freeT4 • hypoT4 associated with seizures • Phenobarbital can suppress thyroid function – Bile Acids if indicated • Young animals • High liver enzymes, low albumin, low BUN, abnormal cholesterol, low glucose • Yorkies, Maltese – Blood lead if indicated Working Up the Seizure Patient

• Advanced Diagnostics – CSF tap • Prior to antibiotic, antifungal or anti- inflammatory therapy • Easy in any practice with gas anesthesia and a spinal needle – Referral for CT or MRI • Interictal neurologic deficits • Focal/partial seizures • < 1 year and normal bile acids • > 5 years • Any cat – Referral for EEG Seizure Treatment When to Treat?? • Single seizure not treated unless status epilepticus (>5 minutes) • Provoked seizures not usually treated unless prolonged or severe • Cluster seizures should be treated aggressively (>3 in one day) • Epileptic dogs are better controlled long term when treated early – Recurrent seizures can lead to more seizures in the future, and to AED resistance – And of they can increase cost of care Seizure Treatment When to Treat?? • Seizures that last longer than a minute or two should be treated • More than one seizure every 6 months should be treated • Seizures associated with unusual or dangerous post-ictal activity should be treated Seizure Treatment

Client Education • Medications must be given daily, for life • Explain side effects & drug interactions (handouts) • Missed dose should be given as soon as remembered, then back on schedule with next dose • Owner seizure log – date, time, description, duration • Dose determined over time by blood tests • Dose may increase or decrease over time • Drugs will not reach full effect for days, to weeks, to months • Initial side effects often subside with time Seizure Treatment Therapeutic Drug Monitoring • When steady state achieved after initial treatment • When steady state achieved after changing dose • When seizure control is suboptimal • To prevent toxicity • Periodic monitoring, for pre-emptive dose changes (q6-12 months) – Induction of liver enzyme can increase PB metabolism rate – Prevent poor episodes of control – Minimize side effects Seizure Treatment

Therapeutic Drug Monitoring • Other drugs added (Phenobarbital) – Organophosphate pesticides – Ketoconazole – Other narcotics – Phenothiazines – Antihistamines – Chloramphenicol – Corticosteroids – Doxycycline – Beta blockers – Theophylline – Metronidazole Seizure Treatment Anticonvulsants aka AED (anti-epileptic drugs) ACVIM Grading System (2015) • Grade A - High recommendation and likely be effective treatment • Grade B - Moderate recommendation and most likely to be effective treatment • Grade C - Low recommendation and may not be effective treatment • Grade D - Not recommended for treatment and may be ineffective and/or dangerous to the patient Seizure Treatment Anticonvulsants aka AED (anti-epileptic drugs) ACVIM Risk Assessment System (2015) • Type I - Predictable and directly related to pharmacologic effects in a dose • Type II - Unpredictable (idiosyncratic) and potentially life-threatening • Type III - Cumulative with long-term treatment and potentially life- threatening • Type IV - Delayed (carcinogenic or teratogenic) and life-threatening Seizure Treatment Anticonvulsants aka AED (anti-epileptic drugs) • Dogs – Monotherapy • Phenobarbital (ACVIM A) • Imepitoin (ACVIM A) • Bromide (ACVIM B) • Levetiracetam SR (ACVIM C) • Zonisamide (ACVIM C) • Primidone (ACVIM D) Seizure Treatment Anticonvulsants aka AED (anti-epileptic drugs) • Dogs – Add On Drugs • Phenobarbital (ACVIM B) • Bromide (ACVIM B) • Levetiracetam (ACVIM B) • Zonisamide (ACVIM B) • Imepitoin (ACVIM C) • Primidone (ACVIM D) – Not addressed by ACVIM – gabapentin, clorazepate, felbamate Seizure Treatment Anticonvulsants aka AED (anti-epileptic drugs) • Cats – Monotherapy • Levetiracetam • Phenobarbital – Ancillary drugs • Zonisamide • Diazepam • Bromide • Not much information on other ancillary drugs Seizure Treatment

Phenobarbital • The most well studied AED for dogs and cats • Absorbed within 2 hours • Peak serum concentration 4-8 hours post pill • Half life 40-90 hrs • 5 half lives to steady state • Steady state in 10-15 days Seizure Treatment

Phenobarbital • Initial dose – 2.5 mg/kg PO BID in dogs • >80% success as monotherapy • Lower dose if liver disease – 1 mg/lb PO BID in cats • Check levels in 2-3 weeks – Don’t use SST – Goal is 20-40 ug/ml – If control suboptimal, push >30 – But >30 increases likelihood of toxicity – Timing with respect to dose doesn’t matter 91% 0f the time – Dose may need to be increased due to hepatic enzyme induction Seizure Treatment

Phenobarbital Side effects

• Type I: resolve within a few weeks – hyperexcitability, restlessness, panting – sedation

• Type II: 1. idiosyncratic IMHA, neutropenia, ITP – Happens within 6 months – Usually responds to stopping drug and appropriate treatment 2. Liver toxicity 3. Dermal necrosis Seizure Treatment

Phenobarbital Side effects

• Type III: – PU-PD, polyphagia, weight gain, – increased ALKP – falsely low TT4 and fT4, falsely high TSH – Potentially life threatening liver toxicity

• Type IV: not reported Seizure Treatment

Bromide • Na or K bromide – KBr preferred for heart disease – NaBr preferred for Addison’s Dz • Added to phenobarbital when TDL 20- 30 ug/ml does not achieve control • Half life 15 days in dogs • Steady State 10-16 weeks in dogs – Steady state levels fluctuate • Liquid 250 mg/ml • Chewable tablets also available (250mg, 500mg) Seizure Treatment

Bromide • Initial Dose – KBr 40 mg/kg PO SID or divided BID – NaBr 17-30 mg/kg PO SID or dBID – Higher if on diuretics or high chloride diets – Half dose for patients with renal failure • >70% success rate as monotherapy Seizure Treatment

Bromide • Loading dose for cluster seizures – 400-600 mg/kg – Divided into 4-10 doses over 1-5 days (divide BID-QID) – Hospitalize the patient – If obtunded or anisocoria, skip & resume when alert – Start initial dose next day • Not often used any longer, now that we have levetiracetam & zonisamide which reach SS in less than a week Seizure Treatment

Bromide • Therapeutic drug monitoring – One week after loading – 3 & 6 months after maintenance dose – Timing of sample unimportant – Ideal range 1-3 mg/ml – 0.8-2.5 OK if also on phenobarbital – Can push to 4 when control suboptimal and phenobarbital >30 • If adequate control, phenobarbital can be reduced and eliminated over 4 months when Br > 1.5 mg/ml Seizure Treatment

Bromide Side effects - warn owners of Type I

• Type I: resolve within 30 days – PU-PD, polyphagia, weight gain – Lethargy, mild ataxia, rear limb stiffness – Falsely increased serum Cl assays

• Type II: – Surface irritation: esophagitis, vomiting, diarrhea, constipation (capsules help) – Follow with water and give with food, or try NaBr – Pancreatitis – use with caution in dogs/cats with history of pancreatitis Seizure Treatment

Bromide Side effects

• Type III: 1. Intoxication to the point of stupor if TDL >3 – dogs with renal disease are predisposed – Treat with IV 0.9%NaCl diuresis 2. Reversible pneumonitis in the cat 3. Rebound seizures if stopped abruptly

• Type IV: not reported Buddy 12 yr MC DLH CC: having a seizure, 10 min HPI: never had a seizure before Tx: • IN midazolam – 1/2 cc • Seizure subsides, place IV cath, draw blood • Can’t get urine – bladder empty • Talk to owner to get history and permission to treat Dx Plan: • Complete exam including rectal exam, neuro exam • CBC, GHP, UA Buddy Later that day: • Recovered from seizure & Tx • Bloodwork shows increased globulins Neuro Exam: Buddy Later that day: • Recovered from seizure & Tx • Bloodwork shows increased globulins Neuro Exam: • When put on the floor, Buddy makes big circles around the treatment area, to the left • Buddy is apparently blind in the right eye, though there is a dazzle reflex and a slow PLR, there is anisocoria • Gait otherwise normal • Front limbs normal • CP deficits rear limbs, worse on right • Lesion localization: left cerebrum Buddy DDx seizures, hemi-inattention: • Brain Tumor • Senile Atrophy of brain • (Other things) Plan: • Owner declines referral to neurologist • We can do CSF here, but it is a low yield test for brain tumor, and any cerebral edema might make it dangerous today • We table this discussion for another day • Prednisone 0.5 mg/lb/day, tapering off over 30 days • Phenobarbital 1 mg/lb PO BID – long term Buddy 6 months later: • Buddy having seizures again • Cluster seizures this time • Response to dexamethasone, IN midazolam, IV diazepam is more gradual

• Buddy goes home, but has seizures 1-2x a week • Levetiracetam is added • Buddy does well until another cluster seizure episode that requires CRI anticonvulsants to control • Owner elects euthanasia, rather than referral surgery • L cerebral meniingioma confirmed on necropsy Seizure Treatment

Imepitoin (Pexoin®) • AED approved for idiopathic epilepsy in Europe In 2013 – Approved in Australia in 2015 – Approved in the US Dec 2018 • MOA - potentiates GABAergic inhibition by acting as a low-affinity, low-efficacy partial agonist at the benzodiazepine site of the GABAA receptor, although it differs in chemical structure from benzodiazepines Seizure Treatment

Imepitoin (Pexoin®) • imepitoin was as effective as phenobarbital in controlling generalized seizures in dogs • Starting dose 15 mg/kg PO BID • Half life 2 hours • No steady state is achieved – no TDLs • adverse events was significantly higher in the phenobarbital group – Sleepiness – Ataxia – PU-PD – Polyphagia Seizure Treatment

Imepitoin (Pexoin®) Side effects – no adverse reactions at 90 mg/kg PO BID

• Type I: less frequent than with phenobarbital – hyperactivity – Somnolescence, sedation – PU-PD, polyphagia

• Type II: not reported • Type III: no evidence of tolerance or rebound seizures with abrupt discontinuation • Type IV: not reported Seizure Treatment

Levetiracetam (Keppra®) • approved in 1999 for treatment of refractory focal onset seizures in adult people • Advantages in dogs: – rapid, complete PO absorption – minimal protein-binding – lack of hepatic metabolism with the drug primarily excreted unchanged in the urine (like bromide) – wide safety margin • Generics have made this drug affordable Seizure Treatment

Levetiracetam (Keppra®) • Half life 4-8 hours in the dog – Despite the short half life, antiseizure effects persist after serum levels fall off • Initial dose 20 mg/kg PO TID or BID for the LEV-XR formulation – Reduce dose if renal disease – Dose may to be increased if also on phenobarbital • Steady state in 1-4 days • Side effects uncommon • TDLs are generally not done unless phenobarbital co-therapy, but ideal range is 12-26 mcg/ml Seizure Treatment

Levetiracetam (Keppra®) • At the time of ACVIM Guidelines, there were no published studies • Several studies in dogs/cats since then • Smith et al – AJVIM – Mar 2019 – 400 mg/ml PLO gel TID for cats – 60 mg/kg on ear TID – Maintained acceptable blood values in normal cats • Kelly et al – Vet Rec – Oct 2017 – 37% excellent control – 47% poor response – Cluster seizures reduced – Recommended as an add-on therapy Seizure Treatment Levetiracetam (Keppra®) • Munana et al – AJVIM – Sep 2018 – variation exists in the pharmacokinetics of LEV-XR in dogs with epilepsy – Concurrent administration of phenobarbital contributed significantly to the variation. – co-administration of zonisamide was not shown to contribute to the variability – Drug monitoring may be beneficial • Lowrie et al – J Fel Med Sx – Feb 2017 – levetiracetam 20-25 mg/kg q8h compared to phenobarbital 3-5 mg/kg q12h in cats with Feline Audiogenic Reflex Seizures – levetiracetam more effective than phenobarbital for myoclonic seizures in cats and well tolerated Seizure Treatment Levetiracetam (Keppra®) • Packer et al – BMC Vet Res – Feb 2015 – LEV treatment resulted in 69% of dogs having a 50% or greater reduction of seizure frequency – 15% of all the dogs were completely free from seizures • Peters et al – ACVIM – Mar 2014 – Levetiracetam is effective when administered rectally – Recommend for add on for cluster seizures • Mullins et al - Vet Surg – Feb 2019 – LEV does not afford protection against development of PAS (post attenuation seizures) in dogs undergoing surgery for PSS Seizure Treatment Levetiracetam (Keppra®) Side effects

• Type I: only with very high doses – Ataxia, sedation – restlessness – Salivation, vomiting, decreased appetite

• Type II: not reported • Type III: note reported • Type IV: not reported Seizure Treatment

Zonisamide • Initial dose 10-15 mg/kg PO BID – Reduce dose if renal disease – Dose may need to be increased if also taking phenobarbital • Half life 15 hours in the dog • Steady state in 3-4 days • Therapeutic range 10-40 mg/L • Small number of studies in dogs & cats – 60% good control as monotherapy in dogs – 40% unsatisfactory response in dogs • Generics have made this drug affordable Seizure Treatment Zonisamide Side effects

• Type I: – Ataxia, sedation – vomiting, decreased appetite

• Type II: – Allergies to sulfonamide drugs – Acute hepatotoxicity in 2 dogs – Dermal necrosis in 1 dog – Renal tubular acidosis in 1 dog Seizure Treatment Zonisamide Side effects

• Type III: – Decreased TT4 – Increased ALKP, mildly decreased albumin – Increased calcium – Renal tubular acidosis in 1 dog

• Type IV: teratogen – handle as a hazardous chemical Seizure Treatment Gabapentin • NOT EVEN MENTIONED BY ACVIM • Half life 3-4 hours in the dog • Initial dose 100-300 mg TID – Increase every 1-2 weeks until control – Up to 1200 mg TID – Reduce dose if renal disease • Or 25-60 mg/kg divided TID-QID • Do not give within 2 hours of antacids • Side effects uncommon – Little sedation – Opiates increase effectiveness and side effects – False positive proteinuria on dipstick Seizure Treatment Felbamate • Half life 5-14 hours in the dog • Initial dose 15 mg/kg BID-TID – Increase every 2 weeks until control – Up to 70 mg/kg TID – May need to increase with time due to hepatic enzyme induction • Steady state in 4-6 days • TDL 15-100 mcg/ml • Side effects uncommon – Little sedation – Nervousness at high doses – Hepatotoxicity esp. with phenobarbital • $$$$$ Seizure Treatment

Clorazepate • Can be used as an add-on drug, when refractory to add-on levetiracetam and/or zonisamide • Initial dose 0.5-1 mg/kg PO TID – SR available but still given TID • Dose may need to be increased if also taking phenobarbital • Serum levels often decrease over time – Dose increases often necessary – Ineffectiveness due to tolerance can occur • Do not give within 2 hours of antacids Seizure Treatment

Clorazepate • Side effects – Sedation and ataxia – Can increase phenobarbital levels • Monitor levels closely • Monitor for side effects – Enhances effects of narcotics – Exacerbates open angle glaucoma – Liver toxicity if possible – exacerbates fear induced aggression • $$$$$ Seizure Treatment

Primidone • Until Pexoin®, it was the only AED approved for dogs in the US • Phenobarbital, imepitoin, and bromide as an add-on are approved in Europe • Primidone converted to phenobarbital, which is responsible for 85% of anticonvulsant activity • Success rate half of phenobarbital • There is no advantage of primidone over phenobarbital to the patient • Liver toxicity more common (esp. cats) • RECOMMENDED AGAINST BY ACVIM Seizure Treatment

Primidone Side effects

• Type I: resolve within a few weeks – hyperexcitability, restlessness, panting – sedation

• Type II: 1. idiosyncratic IMHA, neutropenia, ITP – Happens within 6 months – Usually responds to stopping drug and appropriate treatment 2. Liver toxicity 3. Dermal necrosis Seizure Treatment

Primidone Side effects

• Type III: – PU-PD, polyphagia, weight gain, – increased ALKP – falsely low TT4 and fT4, falsely high TSH – Potentially life threatening liver toxicity – more frequent and more severe than with phenobarbital

• Type IV: not reported Summary PowerPoints • .pptx • .pdf – 1 slide per page • .pdf – 6 slides per page

Scientific Articles • ACVIM – Guidelines for Siezure Control

Client Drug Handouts • Imepetoin • Bromide • Levetiracetam • Clorazepate • Phenobarbital • Felbamate • Primidone • Gabapentin • Zonisamide Acknowledgements

Smith et al. Serum levetiracetam concentrations after transdermal levetiracetam administration, 3 times daily, to healthy cats. J Vet Intern Med. March 2019;33(2):827-830.

Curtis Dewey, ACVIM (Neurology) Ronaldo C de Costa • Practical Guide to Canine and Feline Neurology, 3rd ed. 2016.

2015 ACVIM Small Animal Consensus Statement on Seizure Management in Dogs. J Vet Intern Med 2016;30:477–490. Acknowledgements

Kelly et al. Levetiracetam monotherapy for treatment of structural epilepsy in dogs: 19 cases (2010-2015). Vet Rec. October 2017;181(15):401.

Munana et al. Population pharmacokinetics of extended-release levetiracetam in epileptic dogs when administered alone, with phenobarbital or zonisamide. J Vet Intern Med. September 2018;32(5):1677-1683. Acknowledgements

Lowrie et al. Levetiracetam in the management of feline audiogenic reflex seizures: a randomised, controlled, open- label study. J Feline Med Surg. February 2017;19(2):200-206.

Packer et al. Assessment into the usage of levetiracetam in a canine epilepsy clinic. BMC Vet Res. February 2015;11(0):25.

Peters et al. Levetiracetam rectal administration in healthy dogs. J Vet Intern Med. 2014 Mar-Apr;28(2):504-9. Acknowledgements

Mullins et al. Effect of prophylactic treatment with levetiracetam on the incidence of postattenuation seizures in dogs undergoing surgical management of single congenital extrahepatic portosystemic shunts. Vet Surg. February 2019;48(2):164-172.