Optimal Management of Canine Seizures Extracts from the 2015 ACVIM Consensus Statement on Seizure Management in Dogs By: Dr LL van der Merwe BVSc MMed Vet (Med)

Seizures are common in dogs and are characterised by a wide variety of clinical signs/presentations. Epilepsy is a syndrome and not a diagnosis as such, a specific diagnosis as to the cause of the seizure is not made in the majority of cases due to a variety of reason. In epilepsy, survivability depends more on the quality of life and financial constraints than the disease itself. The definition of successful treatment is a decrease in seizure episodes by at least 50%. The majority of patients are easily managed if a few basic guidelines are adhered to.

PHENOBARBITONE

Phenobarbitone (PB) is considered an effective mon­otherapy in 60 – 80% of dogs. When it fails it is more often due to inappropriate use of the drug than resist­ance to the medication. The control of seizures and minimisation of side effects using PB are correlated more closely with serum concentrations than with the dose administered.

Typically, consistent administration of a medication for a period of four to five half-lives is required to reach a steady state. The relatively long elimination half- life of PB (50 – 96 hrs) limits fluctuations in blood levels however, once on treatment, the elimination half-life becomes more variable, ranging from 20 – 140 hours.

Phenobarbitone induces drug metabolising pathways in the liver, including its own p450 cytochrome en­zyme and thus elimination becomes more rapid with long term administration. There is no predictability to this pattern, so we need to monitor serum drug levels to determine if the dosage of PB is sufficient to reach therapeutic drug levels.

The aim should be to reach mid therapeutic dos­es which could be classified as about 26 – 35ug/ml (range 15 – 45ug/ml) – this generally seems to require a higher starting dose than the traditional 2-5mg/kg/day.

I, however prefer to titrate upwards from about 5mg/ kg per day (2 -3 mg per kg BID)

Timing of sampling:

Trough levels are defined as sampling 2 – 0 hrs before the dose of medication.

Levitski showed using 33 animals that there was no real dif­ference in testing at 0, 3 or 6 hrs post treatment in 91% of dogs- which remained in the same serum concentration category. In the 9% which showed a significant difference in drug concentrations between samples – the mean dose of PB was 8.6mg/kg/day (6.3 – 10.9mg/kg/d) vs 5.6mg/kg/day in the “consistent” group.

So in the majority of cases on <8mg/kg/day –

sampling can occur at any time of the day.

However in some cases with higher/kg dosages – induction of hepatic metabolism may result in a significant decrease in serum levels and a shortening of elimination half-life. In these cases it may be preferable to collect a trough level.

Although the literature recommends trough samples for de­termining therapeutic ranges,the above studies show that it is only in a few cases, determined mainly by high daily dosage of PB, where trough sampling may be considered. However statistical significance is not always translated into clinical sig­nificance and the article concluded that consistency when collecting is in the end more important to allow proper comparison in the same patient with serial samples

Side effects:

  • Polyuria, polydipsia, polyphagia, sedation and ataxia

These signs are generally noted in the first month of ther­apy – but have generally decreased by 6 months. This is definitely true of the sedation and ataxia which general­ly resolves within the first week of therapy. Mean body­weights increased significantly over time many of the tri­als.

  • Induction of hepatic p450 cytochrome pathways:

– Cytochrome-p450, glucuronosyltransferases, glutathione-s-transferases.

  • Idiosyncratic liver disease – no morphological or histo­logical damage

– Infrequent side effects – resulting in clinical liver disease and increased liver enzymes.

  • Pancytopaenia

– Infrequent

  • Induction of liver enzyme ALP

A reversible increase in liver enzymes occurs. Increases above pre-treatment values are seen from week 5 and were above the reference range by 2-3 months. Increases were up to 10 x baseline values. ALP is found in bone, liver, intestine and kidney. The very short t 1/2 of intestinal and renal iso-enzymes makes them undetectable. In the dog there is practically only the bone, liver and the unique corticosteroid induced ALP present in the blood. No sin­gle iso-enzyme is responsible for the increase in ALP, thus iso-enzyme analysis cannot help differentiate PB induced elevations.

Aitken showed that a high dose of PB and a long treatment period rather than a high serum concentration, were asso­ciated with increases in liver enzymes – a result consistent with enzyme induction rather than hepatotoxicity.

  • Hyperlipidaemia and pancreatitis

53% of epileptic dogs had serum fasting serum tri­glyceride levels above the reference range and a significant relationship was shown with BCS, but not with PB dose or serum concentration, increased canine specific lipase or seizure activity score. In­creased polyphagia and scavenging has been put forward as a risk factor for pancreatitis in dogs re­ceiving PB. Serum TG>11.3 can directly affect serum PB readings depending on test methodology

  • Thyroid Function

Short-term (3 weeks) administration of PB will not affect TT4, fT4 or TSH serum concentrations. The long-term use of PB can decrease TT4 and fT4 into the range seen with hypothyroid dogs, while cTSH generally remains unchanged. This decline starts at about 3 weeks and continues all the way through to 6 months after which it seems to stabilise.

( T0 )TT4 = 24.5nmol/L, (T3w) TT4 = 19nmol/L, (T6months) TT4 = 17.6nmol/L

TT3 concentrations are not affected by PB – which would explain the normal cTSH as T3 is the major regulator of TSH secretion.

Epilepsy per se is not a cause of euthyroid sick syn­drome however recent seizure activity (within 24hrs prior to blood collection) caused a significant de­crease in T4.

Clinical signs of hypothyroidism and some of the side effects of PB are similar: lethargy, weight gain, hypercholesterolaemia and lipidaemia. Interpret with great caution any low TT4 result you get when test­ing a patient on PB treatment.

The cTSH is likely to be normal with PB induced eu­thyroid sick syndrome – so requesting a cTSH may assist in making a diagnosis, as 60% of hypothyroid dogs have an elevated cTSH. However if you do de­cide to supplement thyroxine – it will induce drug metab­olising enzymes and may cause increased PB metabolism and reduced steady state concentrations requiring dosage increases.

Thyroid function will normalise at 4 weeks after ces­sation of PB treatment.

  • Adrenal function:

Phenobarbitone has no significant effect on ACTH stim test or LDDST test.

POTASSIUM BROMIDE

Potassium (PB) bromide is an attractive alternative to pheno-babritone as a sole therapy as it is freely availa­ble, is not expensive, has a very long elimination half-life and has less side effects than PB.

The t ½ of bromide is 15 – 46 days. The dose is 30mg/ kg/day with food (a liquid formulation causes less vom­iting).

Bromide is water soluble and absorbed along entire GI. Prandial state doesn’t affect absorption – if given with food you may get less gastric irritation.

Serum bromide levels should be between 1 – 3 mg/ml as a sole treatment.

Because of the long t 1/2 it will take months to attain therapeutic levels unless a loading dose is given. A load­ing protocol tested was 600mg/kg bromide together with the 30mg/kg/day maintenance dose given over 48 hrs. The full dose was divided into 10 smaller doses to avoid vomiting. Using this protocol 84.2% patients were in therapeutic range of 1 – 3mg/mL after 48 hrs, 13 % were not (0.74 – 0.95mg/L).

The drug is renally excreted. Bromide competes with chloride for reabsorption by the kidneys. Increase in di­etary salt from 0.2% to 1.3% decreased the elimination half-life from 69 days to 24 days – so diet changes may profoundly affect serum levels and increase the risk of seizures.

Common side effects are polyuria, polydipsia and poly­phagia, mild transient sedation as well as irritability and restlessness. Depression, ataxia, behavioural changes, mydriasis and stupor occur with more severe bromism. Adverse neurological effects are reversible and resolve within several days if bromide dose is reduced and within hours when patients are treated with IV saline due to increased renal excretion of the bromide.

Effective and toxic levels overlap and individual monitor­ing, using clinical signs, is probably the most practical.

Pancreatitis has been suggested as a side effect of KBr and has been associated with dogs with epilepsy. This association was made using amylase and lipse as in­dicators of pancreatitis – which are not really specific. When cPLi was used no risk was detected. Some re­ports indicate that dogs show increased pruritis. KBR doesn’t affect serum thyroxine levels(TT4), fT4or cTSH.

Bromide in cats causes coughing and dyspnoea and an influx of eosinophils into the bronchi – allergic bronchi­al disease – causing a severe bronchial lung pattern on radiographs.

Primidone

Is rapidly metabolised to PB – which is responsible for more than 85% of its antiepileptic activity. It is however less effective or as effective then PB alone and is less well tolerated in dogs. Not recommended

Imepitoin

Imepitoin was originally developed for the treatment of anxiety and epilepsy in people. Development of the drug for humans was terminated due to an effect smok­ing had on the drug, thus development continued only in the canine field. Imepitoin potentiates GABA-nergic inhibition. The drug is administered BID in incremental doses of 10, 20 or 30mg/kg.

Bromide is water soluble and absorbed along entire GI. Prandial state doesn’t affect absorption – if given with food you may get less gastric irritation.

Serum bromide levels should be between 1 – 3 mg/ml as a sole treatment.

Because of the long t 1/2 it will take months to attain therapeutic levels unless a loading dose is given. A load­ing protocol tested was 600mg/kg bromide together with the 30mg/kg/day maintenance dose given over 48 hrs. The full dose was divided into 10 smaller doses to avoid vomiting. Using this protocol 84.2% patients were in therapeutic range of 1 – 3mg/mL after 48 hrs, 13 % were not (0.74 – 0.95mg/L).

The drug is renally excreted. Bromide competes with chloride for reabsorption by the kidneys. Increase in di­etary salt from 0.2% to 1.3% decreased the elimination half-life from 69 days to 24 days – so diet changes may profoundly affect serum levels and increase the risk of seizures.

Common side effects are polyuria, polydipsia and poly­phagia, mild transient sedation as well as irritability and restlessness. Depression, ataxia, behavioural changes, mydriasis and stupor occur with more severe bromism. Adverse neurological effects are reversible and resolve within several days if bromide dose is reduced and within hours when patients are treated with IV saline due to increased renal excretion of the bromide.

Effective and toxic levels overlap and individual monitor­ing, using clinical signs, is probably the most practical.

Pancreatitis has been suggested as a side effect of KBr and has been associated with dogs with epilepsy. This association was made using amylase and lipse as in­dicators of pancreatitis – which are not really specific. When cPLi was used no risk was detected. Some re­ports indicate that dogs show increased pruritis. KBR doesn’t affect serum thyroxine levels(TT4), fT4or cTSH.

Bromide in cats causes coughing and dyspnoea and an influx of eosinophils into the bronchi – allergic bronchi­al disease – causing a severe bronchial lung pattern on radiographs.

Primidone

Is rapidly metabolised to PB – which is responsible for more than 85% of its antiepileptic activity. It is however less effective or as effective then PB alone and is less well tolerated in dogs. Not recommended Levetiracetam

Levetiracetam (LEV) has been used in pharmaco-resist­ant dogs and resulted in a decreased seizure frequency in 54% of patients. The drug has limited hepatic metab­olism and the plasma t ½ in dogs is 3.6 ± 0.8 hrs, which will require TID administration. The drug is well toler­ated in dogs and has no side effects apart from mild sedation.

A recent study sought to evaluate the long-term effects of this drug and it was administered at 10mg/kg tid for 2 months and in patients which showed a poor response (<50% decrease in seizure activity) the dose was in­creased to 20mg/kg TID. Eight of 14 dogs responded to the initial dose and a further 6 patients to the higher dose. However most of the dogs experienced an in­crease in seizure frequency again (relapse) about 4-8 months after treatment was initiated.

The pharmacokinetics of LEV are significantly altered by the concurrent administration of PB, this despite hepat­ic metabolism playing such a small role: in dogs 89% is excreted by the kidneys and of this approximately 50% is unchanged. There is no canine recommended range for levetiracetum – the human reference range for plas­ma concentrations of LEV is 5 – 40μg/ml. If using this drug as an add-on – monitoring of serum drug levels is recommended. The mean plasma concentrations of LEV (at a mean dose of 24mg/kg tid) in the PB treat­ed group was 5.52μg/ml, in the PB – KBR group was 3.06μg/ml and in the KBR group was 33.5μg/ml. How­ever there was no difference in the reported seizure fre­quency between the 3 groups – although comparisons pre and post treatment in individual animals were not made in this study.

Zonisamide

Has shown efficacy (60% showed >50% decrease in seizures) as a monotherapy in a single trial of 10 dogs followed for 12 – 36 months using it BID at 5-15mg/kg to attain serum levels of 10 – 40ug/ml

Zonisamide has a t ½ of about 15 hrs in dogs. Dosage is 10mg/kg po BID as an add-on therapy. The dosages of the previous anti-epileptics were gradually reduced in individual patients (n=7) if the patients usual seizure interval was exceeded. There was a significant decrease in seizure episodes in the 11 dogs evaluated. Eight of 10 dogs responded with a reduction of 82% (58 –100%), Side effects reported were ataxia and sedation. These resolved in some patients when the PB was removed.

 

CONSENSUS RECOMMENDATIONS

When should treatment be started?

This decision to start treatment is based on aetiology, sei­zure type, risk of recurrence and tolerability and adverse effects of medication. In people, current or previously di­agnosed cerebral lesions or trauma predisposes to recur­rence. In people there is also overwhelming evidence that treatment should not be instituted after one (unprovoked) seizure event. There is also evidence that the earlier treat­ment is started, the better the potential of seizure control. So a balance must be created.

ACVIM panel recommendations to initiate treatment are:

  1. Identifiable structural brain lesion or prior history of brain disease or trauma
  2. Acute repetitive seizures (≥3 generalised seizures within 24hrs) or status epilepticus (≥5 min of seizuring)

iii. ≥ 2 seizure events in a 6 month period

  1. Prolonged, severe or unusual post-ictal periods

Which treatment should be used first?

As Monotherapy:

  1. Phenobarbitone – Highly recommended, based on lev­el 1 data (designed and controlled trials). In 5 studies evaluating a total of 289 dogs for 5 – 32 months, the cumulative success (> 50% reduction in seizure events) was 82% with a cumulative seizure free rate of 31% and a failure rate of 15%.
  2. Imepitoin (Pexion®) – Highly recommended-based on level 1 data (designed and controlled trials). In a multi­centre study imepitoin was shown to be as effective as phenobarbitone in 226 epileptic dogs in a randomised blinded parallel group design with a lower frequency of side effects (ataxia, sleepiness, increased appetite and polydipsia) compared to the phenobarbitone group.
  3. Potassium Bromide – Moderately recommended and likely to be effective – based on level 2 data (case con­trolled series). A single study evaluating monotherapy showed an efficacy of 73.9% patients showing > 50% seizure reduction and 53% seizure free in a 6 month period.
  4.  Levetiracetum and zonisamide were graded as low recommendation and may not be effective. This was based on level 3 and 4 data (case series type studies) only as not much is published.
  5.  Primidone was contraindicated

Monitoring

Optimal comparison of successive drug concentrations is best achieved by evaluating samples collected at the same time after dosing.

Trough concentrations are indicated when the patient has shown a predilection to seizure just before the next dose is due. It is important to determine if treatment failure is due to pharmacological (short half-life), met­abolic (tolerance) or poor client compliance before re­moving a drug from a regimen

Consensus recommendations regarding monitoring:

Phenobarbitone:

  • 2 and 6 weeks after initiating the drug and thereafter every 6 months or 2 weeks after a dose change
  • Range 15 – 35 ug/ml (65 – 150 umol/l)

Bromide:

  • Measure 1 and 3 months after initiation of treatment and thereafter yearly or if > 3 seizures occur or if toxicity is suspected.
  • Bromide concentrations between 810 – 2500 ug/ml with PB combination treatment are effective.
  • Efficacy with monotherapy is seen in higher concentra­tions, up to 3000 ug/ml.

Imepitoin

  • Imepitoin has a short half-life in dogs so no drug accumulation occurs during prolonged treatment. Inter-individual differences are also low and the therapeutic index is high – meaning toxicity is min­imal and rapid dose adjustments are unlikely to cause side effects. Therapeutic monitoring is thus not needed.

 

Risk of Treatment

Adverse effects can be divided into transient, persistent and life-threatening. Most transient effects are avoida­ble with dose titration and resolve within weeks. Persis­tent effects are generally CNS related (sedation, ataxia, imbalance, cognitive impairment). Life-threatening side effects are mainly associated with idiosyncratic bone marrow toxicity or predictable organ damage over time (hepatotoxicity).

Imepitoin scores the best in this category with only transient adverse effects listed. Safety studies showed a dose up to 3X the maximum dose for 26 weeks showed no observed adverse events/changes. In clinical stud­ies mild adverse effects such as sleepiness, ataxia and transient polyphagia, polyuria, polydipsia, vomiting and diarrhoea were observed – all were less frequent than in the PB group. The hyperactivity scores were higher in the PB group. Phenobarbitone shows dose related transient effects such as sedation and these resolve within a few weeks. Chronic adverse effects are polyphagia and polydipsia. The most common serum change is increased ALP which can occur from 2 weeks after treatment initita­tion. A less common life-threatening complication is drug induced hepatotoxicity (rapid increase ALT and bile acids), which is correlated with the higher serum levels (>35ug/ml). Important idiosyncratic reaction is immune mediated bone marrow disorders and possible toxic epidermal necrolysis (TEN).

Bromide is generally well tolerated by the dog – com­mon transient side effects being sedation, ataxia poly­dipsia and polyphagia. Bromide can cause contact irri­tation to the stomach mucousa causing vomiting. This is minimised by splitting the doses. Bromism may occur at levels >3000mg/L and is more likely in animals with renal impairment.

Levetiracetum side effects are predictable and dose dependent. They include sedation, ataxia, restlessness and vomiting

Zonisamide causes sedation ataxia, inappetance and vomiting – in some dogs these were transient and in other dogs dosage reductions were required. Suspect­ed life-threatening idiosyncratic events include acute toxic hepatopathy. Zonisamide may affect thyroid testing.

When should a second AED be started?

Risk factors associated with poorer seizure control in­clude male dogs and prior clustering seizure activity. Strict criteria for add-on therapy are lacking in veterinary science.

Phenobarbitone has important drug-drug interactions with other drugs metabolised by the liver due to its mi­crosomal enzyme induction effect and this can influ­ence the concentrations of other drugs used.

Concomitant bromide and PB therapy has been re­ported to decrease the number of seizure events. This allows for a decrease in the dose of PB, which also re­duces the long term risk of hepatotoxicity .

Imepitoin, when added to PB therapy in a prospective trial of 17 dogs showed a decrease in seizure frequency in most dogs.

Levetiracetum is classically used as a third add-on drug to phenobarbitone and bromide. TID treatment is re­quired. In most reports approximately 50% of animals responded (>50% decrease seizure frequency) however in one trial a relapse was seen after 4-8 month of con­tinuing treatment.

Zonisamide as an add-on is effective in about 80% of cases in the initial 4 months but is did appear that there may also be a delayed relapse during long term follow up in some cases.

 

SELECTED REFERENCES (REMAINDER ONLINE – WWW.VET360.VETLINK.CO.ZA)

  1. Levitski RE et al . 2000 Effect of timing of blood collection on serum phenobarbital concentrations in dogs with epilepsy. Journal of the American Veterinary Medical Association. (217) p: 200 – 204
  2. Podell M, Volk HA et al. 2016. 2015 ACVIM Small Animal Consensus Statement on Seizure Management in Dogs. Journal of Veterinary In­ternal Medicine (30) p: 477 -490
  3. Tipold A, Keefe TJ et al 2014 Clinical Efficacy and safety of Imepitoin in comparison with Phenobarbital for the control of Idiopathic Epilep­sy in Dogs .Veterinary Pharmacology and Therapeutics (38) p:160 – 168

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