Page 22 - VETcpd - Vol 6 - Issue 3

VETcpd - Neurology Peer Reviewed

Nadia Shihab MA VetMB DipECVN MRCVS

RCVS and European Specialist in Veterinary Neurology Nadia graduated from the University of Cambridge in 2005 before completing a one-year internship at Dick White Referrals in Newmarket. She then moved to the Royal Veterinary College in London to complete a rotating internship before undertaking a residency in neurology. She became a diplomate of the European College of Veterinary Neurology in 2010. Since then, she has lectured in Neurology at the RVC, and joined Southern Counties Veterinary Specialist in September 2012.

E-mail: admin@scvetspecialists.co.uk

Refractory epilepsy continues to be a major concern in both human and veterinary medicine despite an increasing number of novel drugs being approved for use in human epilepsy. The use of add-on, off-licence anti-epileptic medications forms an important part of the management of refractory epilepsy, however this often results in relatively small improvements in seizure control. There should be additional focus on optimising first and second line medications, consideration of non-pharmacological treatments and management of significant comorbidities to achieve improved quality of life.

Key words: Refractory epilepsy, dog, comorbidity

Anti-epileptic drug therapy - what to do in cases of refractory canine epilepsy

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IntroductionIn human medicine, refractory or intractable epilepsy is defined as the failure to achieve sustained seizure freedom following treatment with two acceptably tolerated, and appropriately chosen, anti-epileptic drugs (Kwan et al. 2010; Sinha and Siddiqui 2011). There are inconsistencies in the definition of refractory canine epilepsy but it is generally considered to be unacceptable seizure frequency or severity despite appropriate therapy with conventional anti-epileptic drugs (typically phenobarbital and potassium bromide) or when side effects of these drugs are intolerable.

It is estimated that 20-30% of canine epilepsy cases are refractory (Schwartz-Porsche 1985; Trepanier et al. 1998). Equivalent statistics in people are also significant, potentially as high as 30% (Loscher 1997), and there is an ongoing drive to develop additional medical resources to combat this. Some of the drugs developed for humans are also being used to try to improve the management of canine patients with refractory epilepsy. Sadly, in spite of increasing numbers of novel drugs approved for use in

Video footage is useful in charactersing paroxysmal events but, aside from generalised tonic clonic seizures, it can still be difficult to differentiate epileptic from non-epileptic paroxysms.

human epilepsy, the refractory epilepsy rates in people have remained high. It is hypothesised that nonspecific mechanisms limit the efficacy of antiepileptic medications in general (Kwan et al. 2011) and this finding has stimulated research into non-pharmaceutical therapies for people which are starting to be explored in canine patients.

This article will describe a logical step-wise approach to assessing dogs with refractory epilepsy and will discuss some of the medical and non-pharmaceutical management options.

Verifying the diagnosis of refractory epilepsyIt is important to explore the alternative possibilities in patients who present with refractory epilepsy. Pseudoresistance is a term used in human medicine to describe perceived refractory epilepsy where the diagnosis is incorrect or anti-epileptic drug therapy is inappropriate or inadequately dosed. It can account for more than 25% of cases of apparent refractory epilepsy in human adults (Kwan et al. 2011).

The first step in confirming that the patient has refractory epilepsy is to re-evaluate the diagnosis of idiopathic epilepsy and the second is to ensure that the current conventional treatments have been optimised.

1. Re-evaluating the diagnosis of idiopathic epilepsy

The clinical examination of patients with idiopathic epilepsy will be unremarkable in the inter-ictal phase but this is also

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the typical finding in patients with non-epileptic paroxysms such as neuromuscular disorders resulting in intermittent collapse, syncope, metabolic causes of collapse, intermittent vestibular events and compulsive disorders. Movement disorders and paroxysmal dyskinesias are probably some of the most challenging non-epileptic events to differentiate from epileptic seizures. The typical characteristics and classification of paroxysmal dyskinesias have been the subject of several review articles (Lowrie and Garosi 2016; Lowrie and Garosi 2017).

A reliance on the owner’s description of the episodes has long been one of the challenges in characterising paroxysmal events in dogs. Even with the increased availability of mobile phone video footage, unless the patient is having generalised tonic-clonic seizures, there is still significant scope for error. A study investigating the classification of canine paroxysmal events presented as video footage, found that there was only a fair level of agreement between different vets in determining the presence of epileptic seizures (Packer et al. 2015). This relatively low level of agreement highlights how challenging it can be to differentiate epileptic from non-epileptic paroxysms, even when video footage is available. In patients that have had a poor response to anti-epileptic medications, it is especially important to re-evaluate the nature of the episodes and to remember that they may have changed in appearance over time.

If, following re-evaluation, the events are still considered to be epileptic seizures it must then be determined if the epilepsy is idiopathic. The International Veterinary Epilepsy Task Force presented a consensus proposal for the diagnostic approach to epilepsy in dogs, describing a three-tier system of criteria for the diagnosis of idiopathic epilepsy (Box 1). Tier III confidence level includes the identification of ictal or inter-ictal EEG (electroencephalogram) abnormalities compatible with a seizure disorder.

Box 1:

Tier I confidence level• Two or more unprovoked epilepsy

seizures at least 24 hours apart.• Age at seizure onset between six

months and six years.• Unremarkable inter-ictal physical

and neurological examination .• No significant abnormalities on

minimum data base blood tests and urinalysis.

Tier II confidence level• All factors listed in tier I.• Unremarkable fasting and

post-prandial bile acids.• Magnetic resonance imaging

of the brain.• Cerebrospinal fluid analysis.

Tier III confidence level• All factors listed in tier I and II.• Electroencephalographic abnormalities

characteristic for seizure disorders.

Consensus proposal for the diagnosis of epilepsy in dogs by the International Veterinary Epilepsy Task Force. Criteria for the diagnosis of idiopathic epilepsy are described in a three-tier system.

Since the optimal protocols for EEG use in clinical veterinary practice are not yet characterised, tier III criteria for the diagnosis of idiopathic epilepsy is currently not commonly fulfilled (De Risio et al. 2015).

When investigating a poor response to anti-epileptic medications, it is important that both the vet and owner are comfortable with the diagnostic confidence level reached. Tier I diagnostic tests (inter-ictal physical and neurological examination, routine bloods and urinalysis) should always be repeated in these cases to ensure that neurological deficits have not developed and that no evidence of causal or aggravating metabolic/systemic disease has emerged.

Transverse T2w MR images at the level of the thalamus. Blue arrows point to the region of the piriform lobe.A) Idiopathic epileptic dog with brain MRI within normal limits.B) Idiopathic epileptic dog with seizure-related changes in the piriform lobe as a result of severe cluster seizures.

The arrow identifies an area of increased hyperintensity relative to the surrounding normal grey matter.C) Dog with seizures secondary to a piriform lobe glioma. The arrow identifies a region of increased hyperintensity

relative to normal grey matter with enlargement of the piriform lobe and associated mass effect.

2. Optimising conventional anti-epileptic drug treatment

Although a myriad of new anti-epileptic drugs are available for human epilepsy and several of these are used in canine patients, the advantage of these therapies is often limited to a reduction in side effects. In terms of seizure control, it is unlikely that any of them will significantly surpass phenobarbitone or potassium bromide as monotherapy in dogs. As such, it is important to try to optimise these treatments before adding further medications.

Repeat drug serum concentrations are required to determine if it is possible to increase the dose (dependant on the current drug side effects) and also to ensure there has not been a recent and unexpected reduction in serum concentrations. The latter may arise due to problems with administering the medications (owner/patient compliance), malabsorption or drug interactions. Examples of drug interactions include furosemide which increases renal loss of bromide, and chlorpromazine where concurrent use with phenobarbital can reduce the serum concentrations of either drug. Dietary changes can also affect dogs treated with potassium bromide. Togawa et al. (2018) demonstrated a strong negative correlation between dietary chloride intake and serum bromide concentration. A sudden increase in the chloride intake (for example due to a change in diet, new treats or drinking seawater) can therefore cause a sudden decline in seizure control via a reduction in serum bromide concentration. There can also be individual variation in drug metabolism which should be considered when attempting to improve seizure control. This is most commonly recognised with phenobarbital, which can have a reduced elimination half-life. In some dogs the half life is reduced by more than 50% to less than 20 hours. In a study of 10 such dogs in which the trough serum drug concentration was still within the reported therapeutic range but seizure control was poor, dividing the total dose into three rather than two doses (eight versus 12 hour intervals) resulted in improved seizure control in eight of the 10 patients (Stabile et al. 2017).

A final option to maximise the benefits of conventional anti-epileptic drugs exists for patients in which imepitoin has been given as the first line treatment. In one study approximately 25% of dogs treated with imepitoin monotherapy did

VETcpd - Neurology