Idiopathic Epilepsy is a condition that affects more than 0.6% of dogs in the UK1 and it can have a significant detrimental effect on the quality of life of the dog and the family.
Many owners suffer feelings of fear, stress and uncertainty, resulting in lifestyle changes far greater than previously estimated2.
Here we will address scenarios for:
- Uncontrolled dogs under treatment with Phenobarbital
- Uncontrolled dogs under treatment with Imepitoin
- Dogs already on two AEDs (Refractory Epilepsy)
- Dogs already on three AEDs
Diagnosis of genetic epilepsy is based on the following:
1
Description and/or video evidence of the episodes:
– Partial or complete loss of awareness
– Autonomic signs (salivation, urination)
– Short-lived (unless status epilepticus)
– Post-ictal period and/or pre-ictal period
– Full recovery in between episodes,
– Autonomic signs (salivation, urination)
– Short-lived (unless status epilepticus)
– Post-ictal period and/or pre-ictal period
– Full recovery in between episodes,
2
Two or more episodes, at least 24 hours apart.
3
Onset between 6 months and 6 years of age.
4
Normal physical and neurological examination.
5
Normal haematology, biochemistry, electrolytes, urinalysis, and bile acid stimulation test.
6
If possible, MRI of the brain, cerebrospinal fluid analysis and infectious disease testing.
7
If possible, electroencephalographic evidence of epileptic waves.
If the first 5 criteria are met, the chances of intracranial disease is very low (2.2%) MRI is especially recommended for dogs that do not meet these criteria3,4.
With the many anti-epileptic drugs (AEDs) on the market and the addition of new treatment modalities, it is understandable that confusion may arise when dealing with an epileptic dog that is not well-controlled by their current medication5.
The first-line AEDs are Imepitoin and Phenobarbital. Following initiation of treatment with one of these medications, you should expect that the frequency and severity of seizures will reduce by at least 50%. But what happens when the seizure frequency does not decrease by 50%, or if it increases again after some time?
Uncontrolled dogs under treatment with phenobarbital
1
Always check phenobarbital serum levels as the first step. These should be monitored regularly even in well-controlled dogs (every 3 to 6 months). For most dogs, careful timing of blood sampling for phenobarbital concentrations is not critical for clinical decision-making.
Phenobarbital is metabolised in the liver by the cytochrome P450 system: some dogs will need a much higher dose than others to maintain therapeutic levels.
Serum level units and therapeutic level ranges vary between laboratories.
As a rule, levels should be in the top end of the therapeutic range (if tolerable).
‘Desirable’ phenobarbital serum levels:
30-35 µg/ml (or mg/L)5
30-35 µg/ml (or mg/L)5
2
Make sure it is safe to continue phenobarbital treatment by also checking CBC and liver parameters.
ALKP increases are expected and should not be a reason for concern.
ALT increases above 3 times the upper limit of normal and above concomitant ALKP levels, reduced urea or albumin and clinical signs of liver failure are markers for phenobarbital liver toxicity.
Rarely, marked anaemia or pancytopenia can occur with phenobarbital, which should be addressed.
3
If phenobarbital levels are lower than desired, we advise you to increase the dose based on the following formula:
New total dose of phenobarbital in mg = (desired serum concentration/actual serum concentration) x actual dose in mg.
- If levels are now closer to the suggested range: monitor seizure frequency for a period of time depending on seizure frequency (usually 3 times the longest interictal period for the dog).
- If levels are still low, increase the dose and retest as above.
4
If or when levels are at the ‘desirable’ range and the seizures are still not controlled: initiate a second-line drug alongside phenobarbital. Potassium bromide or levetiracetam can be suitable options depending on the dog, the owner and the safety profile and side effects from these drugs:
- Potassium bromide may be more effective but will take 2 to 3 months to reach adequate levels. Serum levels should be checked after 3 months. Side effects can include sedation, polyphagia and polydipsia, gastrointestinal problems, occasionally pancreatitis, skin problems or paresis. A loading dose is possible (600mg/kg divided in more than 8 doses, over 48 hours) but will cause excessive sedation. Levels can be checked 1 month after loading dose.
‘Desirable’ KBr serum levels:
2000 mg/L5 - Levetiracetam has a high safety profile and low risk of side effects. It is effective in a shorter period of time and it is not necessary to monitor serum levels 7.
5
If phenobarbital levels are above the therapeutic range, there is risk for liver toxicity:
Reduce the dose by 20% – 30% and initiate a second-line drug.
Recheck phenobarbital levels, CBC and liver parameters 3 weeks later.
Uncontrolled dogs under treatment with phenobarbital
Option
one
one
Swap to phenobarbital treatment
Dogs that do not respond to imepitoin may have a very good response to phenobarbital. When using both imepitoin and phenobarbital together, the side effects are more significant, and some owners find them unacceptable.
1
Start phenobarbital at 2.5 to 3mg/kg BID and reduce imepitoin dose gradually over 3 weeks, halving the dose every 7 days, before stopping completely.
2
After 3 weeks, check phenobarbital levels. Refer to the above for monitoring on phenobarbital.
3
Note that dogs can have sedation as a common side effect during the transition period, but this should improve shortly after the imepitoin is stopped.
Option
two
two
Add a second-drug line
Imepitoin can work very well when combined with a second-line drug. We advise using imepitoin at the maximum dose of 30mg/kg BID before deciding to add a second-line drug
1
Potassium bromide may be more effective than levetiracetam, and therefore may be a preferred combination with imepitoin. Potassium bromide can take 2 to 3 months to be effective, so take this into account if the dog has a high seizure frequency and a more rapid solution is needed. In that case, consider a loading KBr course as previously mentioned or use levetiracetam instead
Dogs already on two AEDs (Refractory Epilepsy)
Around 20% of epileptic dogs will have ‘refractory’ epilepsy. This means that 2 (or more) appropriate AEDs have failed to give adequate seizure control, despite serum concentrations in the standard therapeutic range. Make sure both drugs are used at the appropriate doses and serum levels are at the desired levels. If not, increase the doses and repeat levels at appropriate times6.
1
Introduce a third drug from the second-line treatment:
- If already on levetiracetam, add potassium bromide.
- If on potassium bromide, add levetiracetam.
2
Consider phenobarbital treatment three times a day: In one study, 90% of dogs whose phenobarbital elimination half-life was less than 20 hours improved seizure frequency when phenobarbital was administered every eight hours1:
- Measure phenobarbital serum levels at peak (4 hours after phenobarbital oral dose) and trough (0 hours, before phenobarbital dose).
- If there is too much disparity between these values (less than 20h half-life)*, consider phenobarbital dosing every 8 hours instead of every 12 hours, maintaining the same total daily dose (or slightly increased if safe to do so).
*Phenobarbital elimination half-life (T1/2) = 0.693/Kelim, where Kelim=[Ln (PB peak)–Ln (PB trough)]/time interval1
3
Never reduce or stop the other anti-epileptic drugs unless there are undesirable side effects or the levels exceed the therapeutic range6.
Dogs already on three AEDs
It is considered that dogs with refractory Epilepsy may also fail to respond to a fourth drug, however it is worth trying alternative therapies:
1
Zonisamide
5-10mg/kg BID. Side effects are rare (vomiting and ataxia, hepatic necrosis, renal tubular acidosis, and erythema). The dose ranges from 5mg/kg PO q12h in dogs not receiving phenobarbital to 10mg/kg PO q12h in dogs receiving phenobarbital.
Therapeutic monitoring levels have not yet been established in dogs8.
2
Diet Purina Neuro Care©
This contains a specific proportion of medium-chain triglycerides that can reduce seizure frequency. This combination of medium-chain triglycerides is difficult to achieve by supplementation of a normal diet9.
3
Cannabidiol (CBD)
May help reduce seizures (around 33% according to one study) in dogs with epilepsy. ALKP levels were significantly increased in the CBD group 10.
4
Vagal Nerve Stimulation
There is little research in dogs assessing efficacy, and a full referral evaluation would be necessary to consider a surgical approach for epileptic dogs
Key Points
- Conclusion: Idiopathic epilepsy can be difficult to manage but applying a stepwise approach enables you to achieve the best possible control with the fewest treatments and side effects
- Suspect idiopathic epilepsy if dog aged 6m-6y at onset of seizures and normal neurological examination and bloods
- Always remember to run a bile-acid stimulation test alongside initial bloods to rule out extra-cranial causes of seizures
- Always maximise serum levels of one drug before considering addition of another
- Imepitoin is not licensed for focal or cluster seizures. phenobarbital should be used in these cases
- If phenobarbital is at adequate serum levels and seizure control is not adequate consider adding levetiracetam or potassium bromide
References
- Stabile et al. Phenobarbital administration every eight hours: improvement of seizure management in idiopathic epileptic dogs with decreased phenobarbital elimination half-life. Vet Rec. 2017;180(7):178.
- Pergande et al., ‘We have a ticking time bomb’: a qualitative exploration of the impact of canine epilepsy on dog owners living in England. BMC Vet Res. 2020;16(1):443
- Smith et al. Findings on low-field cranial MR images in epileptic dogs that lack interictal neurological deficits. Vet J. 2008; 176(3):320-5
- De Risio L, Bhatti S, Munana K, et al. International Veterinary Epilepsy Task Force consensus proposal: diagnostic approach to epilepsy in dogs. BMC Vet Res 2015;11:148
- Bhatti S, De Risio L, Muñana KR, et al. International Veterinary Epilepsy Task Force consensus proposal: medical treatment of canine epilepsy in Europe. BMC Vet Res 2015;11:176
- Muñana KR. Management of refractory epilepsy. Top Compan Anim Med 2013;28(2):67-71
- Muñana KR, Thomas WB, Inzana KD, et al. Evaluation of levetiracetam as adjunctive treatment for refractory canine epilepsy: a randomized, placebo-controlled, crossover trial. J Vet Intern Med 2012;26(2):341-348
- Dewey CW, Guiliano R, Boothe DM, et al. Zonisamide therapy for refractory idiopathic epilepsy in dogs. JAAHA 2004;40(4):285-291
- Law TH, Davies ES, Pan Y, et al. A randomised trial of a medium-chain TAG diet as treatment for dogs with idiopathic epilepsy. Br J Nutr 2015;114(9):1438-1447
- McGrath S, Bartner LR, Rao S, et al. Randomized blinded controlled clinical trial to assess the effect of oral cannabidiol administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with intractable idiopathic epilepsy. JAVMA 2019;254(11):1301
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Tags:
ALKP, Anaemia, Anti-Epileptic Drugs (AEDs), Canine Epilepsy, Cannabidiol (CBD), Cerebrospinal Fluid Analysis, Complete Blood Count (CBC), Cytochrome P450 System, Diet Purina Neuro Care©, Electroencephalographic Evidence, Epilepsy, Epileptic Dog, Epileptic Waves, Extra-Cranial Causes of Seizures, Focal or Cluster Seizures, Genetic Epilepsy, Idiopathic Epilepsy, Imepitoin, Infectious Disease Testing, Intercranial Disease, KBr, Levetiracetam, Liver Parameters, Management of Refractory Epilepsy, Medium-Chain Triglycerides, Neurological Examination, Pancytopenia, Pheno, Phenobarbital, Phenobarbital Liver Toxicity, Phenobarbital Serum Levels, Phenobarbitone, Potassium Bromide (KBr), Refractory Epilepsy, Seizure Frequency, Seizures, Vagal Nerve Stimulation, Zonisamide