Seizures – Treatment

The goal of seizure treatment is to reduce the frequency and severity of seizures as much as possible. Treatment should be considered when the benefits of treatment outweigh the risks and adverse effects of medication. Ultimately, successful treatment is a team effort, requiring “buy-in” from the owners and an understanding of seizure control vs. side effects, necessary monitoring, and the cost of treatment & monitoring. Realistically, many patients will continue to have breakthrough seizures while on anticonvulsants. Most owners find one short, isolated seizure every 2-3 months to be acceptable while on anticonvulsants. Approximately 20-25% of patients with epilepsy are refractory to standard anticonvulsants.

Important information to tell owners:

  1. Seizures are usually self-limiting and rarely life-threatening. They become life-threatening when any active seizure phase (ictus) lasts longer than 5 minutes (status epilepticus) or if the patient has 3 or more seizures in a single day (cluster seizures).*
  2. Pets do not suffer just from having seizures…we do. It’s very difficult to watch a pet having a seizure.
  3. The patient is unconscious during generalized seizures and does not know it is having a seizure.
  4. There are no pain nerve endings in the brain, so there is no pain. If the patient is vocalizing, it’s not due to pain.

* Author’s opinion: Many sources recommend that patients that have 3 or more seizures in a single day be admitted to the hospital and placed on a Valium CRI for 24 hours seizure-free, then slowly weaned off Valium and then monitored for another 24 hours before discharge. This is very costly to owners, especially if the patient has repeated cluster seizure episodes. Hospitalization can be very expensive and cost-prohibitive for some clients if this recommendation is followed. While we always recommend hospitalization, if the seizures are more spread out, we can try to adjust the medication(s) over the phone and/or start an at-home cluster seizure protocol (e.g., rectal valium, 3-day pulse protocol of gabapentin or clorazepate) in an attempt to avoid hospitalization.

One of the most common reasons for unsuccessful treatment is failure to fully optimize the dose of an anticonvulsant before starting or switching to another medication. There is no literature to support starting multiple anticonvulsants at the onset of seizures and there is very little, if any, synergism between anticonvulsants. There are also many disadvantages to polytherapy, including increased cost to the owner, decreased owner compliance, the need to monitor/adjust multiple medications, more complicated dosing, and drug interactions. As a result, monotherapy is preferred whenever possible.

Anticonvulsants

Anticonvulsants remain the cornerstone of therapy and should be started in the following circumstances:

  1. Immediately with any unprovoked status epilepticus or cluster seizures
  2. When an underlying, progressive disorder is identified that is causing the seizures (e.g., brain tumor, encephalitis, portosystemic shunt)
  3. If the patient has 2 or more seizures every 3-6 months. There is no definitive timeframe to decide when to start anticonvulsants.

Listed below are the common anticonvulsants. Click on the drug name to jump to the medication’s description. The monographs listed below are concise descriptions. Please consult a veterinary formulary for additional information. Other treatment options are discussed after anticonvulsants.

Common anticonvulsants

Phenobarbital

Along with potassium bromide, phenobarbital has long been one of two first-line anticonvulsants in dogs.  It remains the first-line anticonvulsant for cats. Phenobarbital is inexpensive, has a rapid onset and is very effective.  It controls seizures due to Idiopathic Epilepsy in 60-80% of dogs and 60% of cats.

Dose:

  • Starting dose: 2 mg/kg PO q12hr (dogs/cats)
  • Loading dose: 16-20 mg/kg total dose – typically divided so that level of sedation can be monitored

Therapeutic range: 10-40 µg/mL (ideally, should stay below 35 µg/mL – see below)

Mechanism of action: The exact mechanism of action is unknown, but it likely inhibits release of multiple neurotransmitters (acetylcholine, norepinephrine, glutamate) and well as being GABA-ergic.

Metabolism: Primarily liver.  Elimination half-life is about 2 days in both dogs and cats, so steady state serum levels are reached at about 10-14 days for both species. Phenobarbital causes autoinduction of liver enyzmes. As a result, increasing doses or frequency of administration may be required over time.

Adverse effects:

  • Short term: 2-3 weeks of sedation, lethargy, weakness, ataxia
  • Long term: PU/PD, polyphagia, weight gain
  • Uncommon to rare hepatotoxicity, rare blood dyscrasias (anemia, neutropenia, thrombocytopenia) that are reversible if identified early, rare superficial necrolytic dermatitis

Monitoring:

  • A CBC and serum phenobarbital level should be obtained 2 weeks after starting phenobarbital for the first time to evaluate for blood dyscrasia and determine serum level.
  • A phenobarbital blood level should be obtained 2 weeks after any dosage change.
  • A CBC, liver panel, and serum phenobarbital blood level should be performed every 6 months or if the patient develops any clinical signs of possible hepatotoxicity. Phenobarbital induces hepatic microenzymes and leads to an elevation in ALP and ALT, but this does not necessarily indicate hepatotoxicity. Bile acids testing should be performed routinely every 6 months, if there is a rising phenobarbital serum level without increasing the phenobarbital dose, or if there are “typical” markers of liver dysfunction (ALT rising disproportionately to ALP, hypoglycemia, low BUN, low cholesterol, low albumin, etc.).

Monitoring tips:

  1. Serum phenobarbital levels can be taken at any time of day for most patients. A trough level used to be recommended, but this is often not practical in many clinical settings. A prospective study of 33 dogs receiving phenobarbital showed that the serum phenobarbital level was in the same therapeutic range at various times post-pill in 91% of the dogs, indicating that timing of blood collection does not alter treatment recommendations for most dogs.
  2. Blood should be collected into a non-serum separator tube as phenobarbital binds to the silicone gel, artificially lowering the measured value.
  3. Phenobarbital causes decreased T4 and T3 and increased TSH, but usually does not lead to clinical signs of hypothyroidism. Thyroid hormone analysis is recommended in patients older than 5 years of age to obtain a baseline prior to starting phenobarbital.

Phenobarbital safety: Many veterinarians and owners are justifiably concerned about the risk of hepatotoxicity with phenobarbital. While the exact incidence is uncertain, it likely occurs in less than 1% of patients. It is unclear whether hepatotoxicity is an idiosyncratic reaction or secondary to a dose-dependent toxicity, but it is more common in patients that have a chronic serum phenobarbital level greater than 35 µg/mL. This medication is generally safe if used and monitored appropriately and the serum phenobarbital is maintained below 35 µg/mL.

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Potassium bromide (KBr) & sodium bromide (NaBr)

Along with phenobarbital, KBr has long been one of two first-line anticonvulsants in dogs.  KBr is inexpensive and fairly effective, although one study (Boothe et al, JAVMA, 2012) found that only 52% of dogs with Idiopathic Epilepsy responded to KBr as a monotherapy.  It was also used for a long time in cats, but its use has fallen out of favor by many neurologists due to potential adverse effects (see below).

Dose: 

  • Maintenance dose: 20-50 mg/kg/day, often divided to BID to reduce GI side effects
  • Loading dose: 400-600 mg/kg total dose divided over 1-4 days

Therapeutic range: 1-3 mg/mL (1000-3000ppm)

Mechanism of action: The exact mechanism is uncertain, but it’s likely that Br competes with Cl at the neuronal cell membrane leading to hyperpolarization, thereby increasing the seizure threshold.

Metabolism: Eliminated unchanged by the kidneys. The elimination half-life is approximately 21 days in dogs and 10 days in cats, leading to steady state levels by 3-4 months in dogs and 2 months in cats.

Adverse effects:

  • Short term: 2-3 weeks of sedation, lethargy, weakness, ataxia
  • Long term: PU/PD, polyphagia, weight gain
  • GI side effects may be noted, including nausea, inappetence and vomiting. This is reduced by dividing the daily dose into BID dosing and giving with food.
  • Pancreatitis has been reported in dogs, especially those that are concurrently receiving phenobarbital or primidone. It is unclear if the medications directly cause pancreatitis or if it’s a side effect of polyphagia and dietary indiscretion.
  • Coughing and dyspnea have been reported in approximately 40% of cats given KBr. Thoracic radiographs may show peribronchial infiltrates and appear very similar to cats with feline asthma. Pneumonitis is usually reversible, but coughing was so severe that it lead to euthanasia in a small number of cats. Its use is no longer recommended in cats unless there are no other options.
  • Rare pruritic dermatitis – often seen as small, red miliary lesions on the skin
  • Anecdotal reports of megaesophagus

Monitoring:

  • Serum bromide blood levels can be measured immediately after loading or at 3-4 months after starting maintenance therapy in dogs and 2 months in cats.
  • A CBC, renal profile, and urinalysis are recommended annually until the senior years when it should be monitored every 6 months as kidney function declines with age.

Bromide toxicity: Clinical signs of bromide toxicity are exactly the same as those of the short term side effects: sedation, lethargy, weakness, and ataxia. If mild toxicity signs are observed, reduce the dose by 25-33%. If the signs are moderate in nature, the KBr can be discontinued for 2-4 days and then restarted at a lower dose. Stopping the KBr entirely will lead to minimal reduction in the level and rarely will lead to seizures, but is enough to take the edge of the signs. If toxicity signs are moderate to severe, a serum bromide level should be obtained and the patient started on intravenous 0.9% NaCl. Bromide and chloride compete for excretion by the kidneys.  Chloride is preferentially reabsorbed and bromide is eliminated into the urine.

Tips & tricks:

  • Time of day for collection is unimportant for therapeutic monitoring
  • Author’s note: To be honest, I rarely obtain bromide levels for several reasons:
    1. The signs of toxicity are readily visible and, if they occur, this author simply follows the toxicity guidelines above.
    2. The test can be expensive.
    3. The level rarely changes the treatment plan. Assuming no kidney dysfunction, if seizures are frequent and there are few side effects, then I increase the dose. If side effects are excessive, I lower the dose and/or alter the dose of other medications
  • KBr and NaBr are both salts that need to be compounded either into a liquid or capsules. There are also commercials-available products (e.g, KBroVet). Personally, I much prefer the liquid formulation because the dose can be titrated easily, unlike capsule. The KBroVet chewable tablets are somewhat easier to titrate, but, unlike a liquid formulation, small adjustments cannot be made.
  • Many neurologists split the daily dose into BID dosing to decrease GI side effects. The liquid formulation should NEVER be given directly by mouth via syringe. This is a highly-concentrated salt solution that tastes like sea water x 10 (trust me, I know!). I recommend mixing the medication into the food – it makes the food taste saltier, which many dogs prefer.
  • Salty treats should be avoided. As stated above, chloride competes with bromide for excretion. Excessively high salt diets will lead to increased bromide elimination and a lower-than-expected bromide level, while low salt diets lead to higher-than-expected bromide levels. Owners should be instructed not to feed their pet a lot of treats (e.g., basted rawhides, pigs ears, milk bones). Carrots, green beans, or other safe treats are recommended instead.

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Zonisamide

Zonisamide is one of the “newer” anticonvulsants in veterinary medication, traditionally used as an “add on” medication for patients refractory to phenobarbital and bromide. It is being used more often as a first-line anticonvulsant because it appears to have fewer adverse effects and the price has come down with a generic version.

Dose:

  • Dogs: 5-10 mg/kg PO q12hr
  • Cats: 5-10 PO q24hr may be sufficient given longer elimination half-life

Therapeutic range: There is no proven therapeutic range in dogs. Many advocate using the human therapeutic range of 10-40 µg/mL.

Mechanism of action: The exact mechanism is uncertain, but it may reduce sodium transmission across the cell membrane reducing neuronal hypersynchronicity.

Metabolism: Eliminated primarily by the kidneys, but approximately 20% is metabolized by the liver. The elimination half-life is 15 hours in dogs leading to steady state levels in approximately 4-5 days.

Adverse effects: Side effects are usually mild. The most commonly reported adverse effects are decreased appetite, mild sedation, mild ataxia, and occasional vomiting/diarrhea. KCS and polyarthropathy were observed in one study, but the significance is uncertain. Zonisamide is a sulfonamide drug so it should be avoided in dogs that are sensitive to other sulfa drugs.

Monitoring: Zonisamide levels can be obtained. However, this author rarely performs them at this time since the test is expensive and the “true” therapeutic levels are currently unknown.

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Levetiracetam (Keppra)

Levetiracetam is one of the “newer” anticonvulsants in veterinary medication, traditionally used as an “add on” medication for patients refractory to phenobarbital and bromide. It is being used more often as a first-line anticonvulsant because it appears to have fewer adverse effects and the price has come down with a generic version. For many, it has become the preferred anticonvulsant in patients with liver dysfunction and hepatic encephalopathy.

Dose:

  • Standard release form: 20-30 mg/kg PO q8hr
  • Extended release form: 30 mg/kg PO q12hr (DO NOT crush or cut tablets; cannot be used in smaller patients because smallest table size is 500mg)
  • NOTE: Phenobarbital has been shown to increase levetiracetam clearance and reduce the elimination half-life in dogs so the dose may need to be adjusted.

Therapeutic range: There is no proven therapeutic range in dogs, but may be similar to human therapeutic levels.

Mechanism of action: The exact mechanism is uncertain, but it may selectively reduce hypersynchronization of epileptiform burst-firing, thus reducing the risk of seizures

Metabolism: Levetiracetam appears to be hydroylyzed in the serum and metabolized by organs other than the liver. The elimination half-life is only 4 hours in dogs and cats, but its anticonvulsant properties may last longer.

Adverse effects: Side effects are usually mild, including transient sedation, paresis, and ataxia.

Monitoring: Long-term safety studies are lacking, but a CBC & biochemical profile are recommended every 6-12 months. Serum levels can be obtained, but are not highly recommended since the therapeutic range is uncertain and there may be a poor correlation between serum and brain levels.

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Gabapentin (Neurontin)

Gabapentin is one of the “newer” anticonvulsants in veterinary medication, traditionally used as an “add on” medication for patients refractory to phenobarbital and bromide. It can also be used in a pulse protocol for patients with recurrent episodes of cluster seizures, but its efficacy is variable.

Dose: 

  • Maintenance dose: 10 – 20 mg/kg PO q8hr for both dogs and cats. Start at the low end and titrate up.
  • Cluster seizure protocol for patients not on maintenance gabapentin: Give 20 mg/kg PO TID x 3 days starting as soon as the patient is awake/alert enough to take oral medications after the first seizure.

Therapeutic range: There is no proven therapeutic range in dogs & cats.

Mechanism of action: The exact mechanism is not entirely known, but it appears to decrease calcium influx in the neuron by binding to CaVa2-d voltage-gated calcium channels, which, in turn, reduces release of excitatory neurotransmitters (glutamate, substance P, and norepinephrine). Although it is structurally similar to GABA, but does not have have GABA agonist properties.

Metabolism: The majority of the drug is excreted unchanged by the kidneys, but, approximately 30-40% is metabolized by the liver in dogs. A decreased dose may be needed for patients with moderate kidney disease.

Adverse effects: Side effects are usually mild with sedation and ataxia most common.

Monitoring: The medication is generally very safe and only monitored for efficacy and side effects. Patients with kidney disease should be monitored more closely.

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Diazepam (Valium)

Diazepam is a short-acting benzodiazepine that is used most often intravenously or rectally for emergency treatment of seizures. Oral diazepam is used most commonly in cats (very cautiously given reports of fatal hepatic necrosis), but it’s half-life is so short in dogs that oral administration is not practical. Dogs also develop tolerance to oral diazepam.

Dose: 

  • Oral dose: 0.5 – 2.0 mg/kg PO q8-12hr
  • Intravenous dose: 0.5 – 1.0 mg/kg IV
  • Rectal dose: 1 – 2 mg/kg per rectum; can give up to 3 doses as close together as every 5 minutes at home if seizure persists, although IV route should be used whenever possible in hospital

Mechanism of action: Benzodiazepines appear to enhance GABA effects in the brain. GABA is an inhibitory neurotransmitter.

Metabolism: Diazepam is metabolized by the liver into several pharmacologically-active metabolites, including desmethyldiazepam (nordiazepam), oxazepam, and temazepam. The metabolites are conjugated with glucoronide and then eliminated by the kidneys.

Adverse effects: As with other anticonvulsants, side effects are usually mild, including transient sedation, paresis, and ataxia. Fatal hepatic necrosis has been reported with oral administration of diazepam in cats so use this medication with extreme caution.

Monitoring: Liver enzymes should be checked in cats at 1 week and 1 month, and then every 6 months.

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Clorazepate

Clorazepate is a long-acting benzodiazepine that can be used in conjunction with other oral medications to reduce seizure frequency. It can also be used in a pulse protocol for 2-3 days to help control cluster seizures. While hepatic necrosis has not been reported in cats as of this writing, extreme caution should be used if given to cats.

Dose: 1-2 mg/kg PO q8-12hr (dogs)

Mechanism of action: Benzodiazepines appear to enhance GABA effects in the brain. GABA is an inhibitory neurotransmitter.

Metabolism: Clorazepate is metabolized by the liver. Serum levels tend to decline over time necessitating increasing doses. As with oral diazepam, dogs may develop tolerance to its anticonvulsant effects so it is not routinely used for daily maintenance treatment.

Adverse effects: As with other anticonvulsants, side effects are usually mild, including transient sedation and ataxia. Dogs can develop physical dependence on the medication so it should not be discontinued abruptly.

Monitoring: Liver enzymes should be monitored closely.

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Imepitoin (Pexion®)

Imepitoin is a new anticonvulsant for dogs that is currently available in the U.K. and E.U. As of this writing, it is not available in the USA. It is a long-acting anticonvulsant that appears to be a low-affinity, partial agonist at the benzodiazepine binding site of GABAA receptors. It’s partial agonist properties are thought to cause fewer side effects and less risk for development of tolerance or dependence compared to benzodiazepines.

Dose: 10 mg/kg PO q12hr (dogs)

Mechanism of action: Imepitoin is a low-affinity partial agonist of the benzodiazepine binding site on GABAA receptors, which have inhibitory effects on neurons. Imepitoin also appears to have weak inhibitory effects on neuronal calcium channels.

Metabolism:  Imepitoin is well-absorbed (92% bioavailability), albeit slowly, after oral administration. Peak levels occur 2 hours after administration. It is primarily metabolized by oxidative metabolism into 4 major inactive components. The elimination half-life is about 1.5-2 hour, primarily in the feces.

Adverse effects:  In general, adverse effects are usually mild and transient. Reported adverse effects have included polyphagia (primarily at onset of treatment), hyperactivity, PU/PD, somnolence, hypersalivation, vomiting, ataxia, apathy, diarrhea, prolapsed third eyelid, visual deficits, and sensitivity to sound. This medication is contraindicated in patients with hypersensitivity to the medication or severe liver, kidney, or cardiovascular dysfunction. Imepitoin has been “used in combination with phenobarbital in a small number of cases and no harmful clinical interactions were observed” according to the U.K. product label.

Monitoring: Baseline liver and kidney function tests, as well as annual (at minimum) monitoring.

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Topiramate (Topomax)

Topiramate is a newer anticonvulsant used in dogs, particularly for partial seizure activity.

Dose: 2-10 mg/kg PO q8-12hr (dogs)

Mechanism of action: The exact mechanism of action is unknown, but topiramate possibly has 3 actions: (1) blocking repetitive action potentials in neurons with sustained depolarization, (2) increasing the frequency that GABA activates its receptors, and (3) antagonizing kainite/AMPD receptors.

Metabolism: Topiramate’s metabolism is not completely known. The elimination half-life ranges from 2-4 hours in dogs. In humans, approximately 70% is excreted unchanged by the kidneys.

Adverse effects: As with other anticonvulsants, side effects are usually mild, including transient sedation, paresis, and ataxia. Fatal hepatic necrosis has been reported with oral administration of diazepam in cats.

Monitoring: Liver enzymes should be checked at 1 week and 1 month, and then every 6 months.

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Felbamate

Felbamate is an anticonvulsant that has been used primarily as a 2nd or 3rd-line anticonvulsant. It appears to be effective in helping reduce seizure frequency in patients on phenobarbital and/or KBr.

Dose: 15 mg/kg PO q8-12hr (dogs)

Mechanism of action: The exact mechanism of action is unknown, but possibly has 3 actions: (1)  interfering with volated-gated sodium channels, (2) blocking NMDA-glutamate receptors, and (3) blocking glycine binding.

Metabolism: Felbamate and its metabolites are excreted by the kidneys. It can induce liver enzymes leading to reduced serum levels over time.  Felbamate causes increased serum phenobarbital. Liver toxicity may be more common in patients being given phenobarbital.

Adverse effects: Side effects tend to be very mild at recommended doses, but higher doses can cause KCS, tremors, limb rigidity, excessive salivation, agitation, and restlessness.

Monitoring: Felbamate appears to be safe and well-tolerated, but it should be monitored every 6 months with a CBC & biochemical profile. Serum levels are not performed.

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Anticonvulsants that SHOULD NOT BE USED

Primidone – This medication is metabolized into phenobarbital and PEMA. The parent drug and both metabolites have anticonvulsant properties, but its efficacy is no better than phenobarbital alone. More importantly, it may be more hepatotoxic than phenobarbital and may be toxic to cats.

Lamotrigine (Lamictal) – This medication has a very short half-life making it impractical to use, but also has a potentially cardiotoxic byproduct.

Many other medications are not good candidates in dogs due to a short elimination half-life that would require administration more frequent than is practical for owners. These include phenytoin (Dilantin), carbamazepine, valproic acid, ethosuximide and many of the newer anticonvulsants, such as vigabatrin, tiagabine, and oxcarbazepine.

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Other treatment options

Acupuncture

Several studies have suggested that acupuncture may be helpful in the treatment of seizures in dogs and cats, but controlled studies are lacking. However, it is a safe form of treatment that would not be harmful to the patient and could potentially help. Anecdotally, acupuncture improves seizure control in approximately 10% of patients.

Holistic treatments

Numerous holistic therapies have been described, such as implantation of gold beads, herbs, magnets, and Rescue Remedy. However, as with many holistic treatments, placebo-controlled double-blind studies are lacking.

Ketogenic diets

Ketogenic diets have a proven place in the treatment of specific types of seizures in children. However, veterinary studies have shown that it is difficult to obtain a ketotic state in animals and the ketogenic diet did not improve seizure control.

Novel protein diets

There is anecdotal evidence that novel protein diets may help reduce seizure frequency in animals, but there are no controlled studies that support this notion. That being said, it is an inexpensive form of “treatment” and is not harmful.

Surgery

Refractory seizures in people are occasionally treated surgically, including focal cerebral cortical resection, corpus callosotomy, and, in severe cases, complete cerebral hemispherectomy. Surgical treatment of seizures has been described, but results were mixed. As a result, surgical treatment of seizures is rarely performed in veterinary medicine.

Vagal nerve stimulator

Electrical stimulation of the vagus nerve has been shown to be an effective adjunctive therapy in human patients with medically refractory seizures. A double-blind, placebo-controlled study showed that vagus nerve stimulation using a programmable pacemaker-like device was well-tolerated by patients and reduced seizure frequency in approximately 1/3 of dogs refractory to anticonvulsants. However, the device is extremely expensive and not commercially available.

Last updated by NeuroPetVet on December 17, 2017.