Article Text

PDF

Canine idiopathic epilepsy
  1. Clare Rusbridge
  1. Fitzpatrick Referrals, Halfway Lane, Eashing, Godalming, Surrey GU7 2QQ, UK
  2. School of Veterinary Medicine, University of Surrey, Guildford, Surrey GU2 7XH, UK
  1. e-mail: clarer{at}fitzpatrickreferrals.co.uk

Abstract

Canine idiopathic epilepsy has an estimated prevalence of 0.62 per cent in primary veterinary practice (Kearsley-Fleet and others 2013) and as such is one of the most common chronic neurological diseases. Descriptions of ‘epilepsy of unknown origin . . . where no symptom characteristic of any other condition has as yet presented’ can be found in early veterinary textbooks (Kirk 1922) and although our knowledge is now considerably greater, and we are no longer treating it with arsenic, we are still a long way from preventing or curing this enigmatic disease. This article describes the diagnosis, management and considerations to take when dealing with this condition.

Statistics from Altmetric.com

Definitions

▪ A seizure is caused by abnormal electrical activity in the brain and is characterised by a sudden episode of transient neurological clinical signs, such as involuntary muscle movements, sensory disturbances and/ or altered consciousness. Seizures in idiopathic epilepsy can be generalised, ie, affecting both cerebral hemispheres or focal (partial) where the electrical disturbance is limited to a specific area(s) of the brain. The most common seizure type in the dog is a generalised tonic-clonic characterised by stiffening of the limbs (the tonic phase), followed by jerking of the limbs and jaw (the clonic phase) (see Video 1).

▪ Ictus – synonym for seizure.

▪ Aura – a subjective sensation that precedes and marks the onset of a neurological condition.

▪ Postictal phase – the recovery phase after a seizure marked by altered state of consciousness

▪ Interictal period – the time between seizures.

▪ Epilepsy is defined as a brain disorder characterised by predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures more than 24 hours apart. However, the International League Against Epilepsy (ILAE) has recently modified this definition to:

  • At least two unprovoked seizures occurring more than 24 hours apart;

  • One unprovoked seizure and a high probability of further seizures; and

  • At least two seizures in a setting of reflex epilepsy, eg, provoked by flashing light (Fisher and others 2014).

▪ This refined definition is important for treatment decisions, for example, a decision to start treatment in a patient that is at high risk of further seizures, eg, following a cerebral vascular accident.

▪ Idiopathic epilepsy is defined as epilepsy of unknown cause other than possible hereditary predisposition; not in consequence of some other disease or injury. In humans, idiopathic epilepsy is defined as epilepsy of predominately genetic or presumed genetic origin and in which there is no gross neuroanatomic or neuropathologic abnormality (Shorvon 2011). The acknowledgement that idiopathic epilepsy has a genetic aetiology is important. In the veterinary world, the term idiopathic is often used inappropriately as ‘unknown cause’.

Pathophysiology

Canine idiopathic epilepsy is suspected to have a hereditary basis; however, finding the predisposing genes has proved more difficult than expected. In rodent models and humans, the majority of known epilepsy genes encode ion channels or associated proteins that modify membrane currents controlling neuronal excitability and bursting and/or affect other cellular signalling pathways. It is hypothesised that many canine idiopathic epilepsies will also ultimately prove to be ‘channelopathies’.

Diagnosis

The list of possible causes of seizures is long (Fig 1) and when working up an epileptic patient, a detailed history (Table 1) and a systematic approach is necessary to ‘narrow down’ the likely possibilities. Idiopathic epilepsy is a diagnosis of exclusion (Table 2). Encourage the owner to obtain a video of the event (see Videos 1 to 3). The animal's signalment (ie, breed, age and history) is important, for example, brain tumours are uncommon in animals less than six years old. If a dog is aged between six months and six years, has recurrent seizures and is normal interictally then there is a more than 97 per cent confidence in a diagnosis of idiopathic epilepsy (Smith and others 2008). The dog should have a neurological examination for which the main objective is to identify other signs of brain disease (Box 1). A general clinical examination should be performed to look for another indications of disease that could be associated with or confused with seizures, eg, heart disease. A haematology, routine serum biochemistry and urinalysis should rule out the majority of reactive causes of seizures. DNA testing may be appropriate to rule out inherited diseases associated with recurrent seizures, for example, in the Lagotto Romagnola (juvenile epilepsy), miniature wire-haired dachshund (Lafora's disease) and Staffordshire bull terrier (L2-hydroxyglutaric aciduria) (Table 3). Depending on the signalment and other results it may be appropriate to eliminate other metabolic disease, eg, hypothyroidism or (rarely) organic acid urinalysis for some inherited metabolic diseases. Further investigation of intracranial disease will depend on the clinical history, neurological finding, and facilities available, and whether they are affordable. After neurological examination, MRI or CT are the most helpful tests to evaluate the epileptic patient (Box 2). Cerebrospinal fluid analysis is used to rule out inflammatory disease. Electroencephalogy plays an important role in diagnosis and management of epilepsy in humans. It is less useful in animals because needle electrodes and heavy sedation are required.

Fig 1:

Causes of seizures. Seizures are traditionally divided into intracranial and extracranial (reactive) causes. Intracranial causes of epilepsy can be separated into idiopathic (also known as primary/genetic/hereditary) and acquired (also known as structural/metabolic, secondary, symptomatic, cryptogenic). For prognostic purposes, it is useful to divide secondary epilepsy into static brain disease and progressive brain disease. Static brain disease implies that there is non-progressive damage to the brain resulting in a seizure focus, whereas progressive brain disease implies an on-going disorder that causes seizures among other neurological dysfunction

Table 1:

History taking for the epileptic animal

Table 2:

Diagnostic work up for idiopathic epilepsy

Box 1:

Objectives when performing a neurological examination in a dog with epilepsy

Dogs with primary idiopathic epilepsy will have a normal neurological examination. Repeat examinations several weeks apart is recommended for animals where further diagnostic tests are not available.

There are three objectives when performing neurological examination in a dog with epilepsy:

1. Is the animal normal?

Dogs with primary idiopathic epilepsy will have a normal neurological examination (except in the postictal period). Dogs with progressive brain disease generally have an abnormal neurological examination or behaviour/ personality change. In the instance of progressive disease, eg, slow growing neoplasm, motor and sensory deficits may develop with time so it is therefore important to repeat the neurological examination after a few weeks especially if other diagnostic tests such as MRI and CT are not available.

2. If there are neurological deficits, can these be related to disease of the forebrain?

▪ Behavioural changes

▪ Depression/stupor/coma

▪ Circling (towards side of lesion)

▪ Postural deficits (contralateral to lesion)

▪ Visual deficits (contralateral to lesion, normal pupillary light responses)

In the absence of metabolic disease or poisons, seizures indicate disease of the cerebrum or diencephalon. Any of the above deficits would suggest intracranial pathology. The side and location of pathology can be established. Asymmetrical forebrain disease is most likely to have a neoplastic aetiology (see Neoplasia article of p 24 of this supplement).

3. Is there multifocal disease?

Are there deficits relating to pathology of more than one area of the nervous system? This would either suggest an inflammatory process, metabolic disease or a multifocal tumour such as lymphoma. For example, head tilt, balance problems with cranial nerve deficits suggests brainstem disease. Hyperaesthesia, hypermetria or an intention tremor suggests cerebellar disease. Central nervous system inflammatory disease (and occasionally lymphoma) is often associated with spinal pain.

Table 3:

DNA tests for inherited diseases associated with seizures

Box 2:

Advantages and disadvantages of advanced diagnostic imaging (MRI)

If a dog is aged between six months and six years, has recurrent seizures and is normal interictally then there is a more than 97 per cent confidence in a diagnosis of idiopathic epilepsy and the advantages and disadvantages for this expensive diagnostic test should be considered for each case.

▪ Advantage

– Rules out many diseases with a poorer prognosis, eg, brain tumour.

– For intracranial disease, it can help with decision making for treatment.

▪ Disadvantage

– Expensive.

– Not a specific test for idiopathic epilepsy.

– For dogs with idiopathic epilepsy, it does not necessarily help with prognosis or treatment.

– Requires general anaesthetic.

Management

Epilepsy can be treated successfully in the majority of cases and most animals enjoy a good quality of life. Treatment is aimed at reducing the frequency, duration or severity of the seizures. It is unusual for the seizures to stop altogether. The mainstay of therapy is antiepileptic drugs (AEDs or anticonvulsants). This name tag is somewhat inappropriate as the mode of action of most AEDs is to suppress seizures but, unfortunately, not epileptogenesis. In other words, unlike the majority of other drugs prescribed in veterinary medicine, they do not ‘cure’ but merely suppress signs of disease. A suggested management approach used by the author is detailed in Fig 2. Table 4 details the most common drugs used; the reader is referred to recent In Practice articles for more details regarding individual drugs (Rusbridge 2013a, b). There is no precise answer when to start treatment, but a prescription of AED should be considered if there are two seizures within six months and treatment is strongly recommended if seizures are more frequent than every two months. Treatment should also be started if there is a trend towards more frequent or severe seizures. Epilepsy is a progressive disorder and repeated seizures damage the brain making further seizures more likely (Sakurai and others 2013). The number and frequency of seizures before commencing treatment is negatively correlated with prognosis. It is estimated that one-third of all individuals with epilepsy are refractory to AED therapy. One study of 49 epileptic border collies found that drug resistance was apparent in 71 per cent of 24 dogs treated with more than two AEDs and that prognosis was worse for dogs that were less than two years old when the first seizure occurred (Hülsmeyer and others 2010). Many individuals with drug-resistant epilepsy are unresponsive to multiple drugs with a wide range of mechanistic actions.

Fig 2:

Treatment algorithm for the management of idiopathic epilepsy that I have developed. Note that the addition of multiple agents to control seizures may result in increasing adverse effects in particular sedation. In this instance, it is recommended to attempt to reduce the dose of the pre-existing drugs. Withdrawal of any antiepileptic drugs should be done according to data sheet guidelines. BID Twice a day, QID Four times a day

Table 4:

Common antiepileptic drugs used in idiopathic epilepsy

Monitoring the epileptic animal

Seizure diary

It is advisable for the owner to keep a diary, which should be brought to veterinary consultations. A simple chart indicating the frequency of seizures is the most useful as this allows quick visualisation of progress (there are many resources for owners to use, as shown in (Box 3). Other notes, such as time of day, length of seizure, severity, pre- and postictal period can also be useful.

Box 3:

Resources that may be useful for owners of epileptic dogs

Canine Epilepsy

www.canineepilepsy.co.uk

In additional to general information, this website has downloadable information sheets (including owner fact sheets, seizure diaries and owner questionnaire) and links to other canine epilepsy sites.

Phyllis Croft Foundation for Canine Epilepsy

http://pcfce.org/forum/index.php

Telephone: 01296 715829

UK-based support group for owners of epileptic dogs.

Pexion

www.pexion.co.uk

In additional to general information, this Boehringer Ingelheim UK website has specific information for owners about the antiepilepsy drug imepitoin.

Epiphen Online

www.epiphenonline.co.uk

In addition to general information, this Vetoquinol UK website has an online monitoring tool that allows owners to record seizures, monitor trends and print off reports for their veterinary surgeon.

Serum antiepileptic drug concentrations

Monitoring the serum concentration enables

  • The lowest effective dose to be used

  • Dosing to be accurately adjusted

  • Possible toxicosis to be avoided

  • Better seizure control

Serum concentrations should be determined

  • After initiating a new drug

  • After changing the dosage

  • If there is a breakdown in seizure control

  • Every six to 12 months

Other notes

  • Measuring trough and peak phenobarbital concentrations are not necessary if the daily dose is less than 12 mg/kg/day (I would not recommend phenobarbital doses greater than 12 mg/kg/day).

  • Imepitoin does not require serum concentration monitoring.

  • Serum concentration of unlicensed third generation ‘human’ AED may be determined through the NHS Therapeutic Drug Monitoring Unit. (www.epilepsysociety.org.uk/WhatWeDo/Treatmentandfacilities/Therapeuticdrugmonitoring).

Other laboratory tests

  • Monitor haematology and serum biochemistry every six to 12 months (for interpretation of liver parameters see Table 5).

  • Periodic thyroid function testing is advised in older breeds predisposed to hypothyroidism. A diagnosis of hypothyroidism should not be made on the basis of thyroid hormone concentrations alone as epilepsy and phenobarbital therapy can result in a euthyroid sick syndrome.

Genetics of idiopathic epilepsy

Many dog breeds are predisposed to epilepsy. The ‘Inherited Diseases in Dogs’ website (www.vet.cam.ac.uk/idid/), for example, lists 48 breeds. Assuming that epilepsy (all causes) has one to two per cent prevalence in the dog population then a higher breed prevalence suggests an inherited tendency (Box 4). One study found that the border terriers and German shepherd dogs (Fig 3) are at most risk of idiopathic epilepsy (2.70 and 1.9 times the odds compared with a crossbreed dogs, respectively) and West Highland white terrier were at reduced risk (Kearsley-Fleet and others 2013). The inheritance of idiopathic epilepsy is likely to be complex and the result of polygenic susceptibility alleles along with environmental influences; research is ongoing in many institutions. The lack of a definitive diagnostic test and the variable age of onset makes it very difficult for breeders to select against the disorder. For example the mean ‘age at first seizure’ for Belgian shepherd dogs is 3.3 years and the range is 0.5 to eight years meaning that many dogs will have been bred before it is known that they have the disease (Berendt and others 2008). Genetics not only confers risk of epilepsy but also may affect the success of treatment and may explain why some breeds are more predisposed to refractory epilepsy (Alves and others 2011). This may be because of an alteration in AED target, ie, decreased sensitivity to treatment, or overexpression of blood-brain barrier drug transport proteins limiting penetration of AEDs into the brain. Resistance to phenobarbital therapy in border collies has been associated to a single nucleotide substitution in the canine MDR1/ABCB1 gene (Alves and others 2011).

Box 4:

Most common breeds seen with epilepsy in the UK

The ‘top’ 14 breeds with epilepsy (ranked in order) based on samples submitted for antiepileptic drugs serum concentration (Short and others 2011).

These breeds accounted for more than 75 per cent of the epileptic cohort, with the top five breeds accounting for more than 50 per cent of the epileptic cohort. This may be, in part, due to the popularity of the breed.

The ranking for position within the top 20 dogs registered with the Kennel Club UK for 2011 to 2012 is indicated in brackets, ie, the labrador retriever was the most popular breed and is also treated most commonly for epilepsy (www.thekennelclub.org.uk/media/350279/2011_-2012_top_20.pdf).

(1) Labrador retriever (1)

(2) Border collie

(3) German shepherd dog (4)

(4) Staffordshire bull terrier (8)

(5) Crossbreeds

(6) Cavalier King Charles spaniel (6)

(7) Cocker spaniel (2)

(8) Springer spaniel (3)

(9) Boxer (11)

(10) Jack Russell terrier

(11) Golden retriever (5)

(12) Border terrier (7)

(13) Yorkshire terrier (18)

(14) Dalmatian

Table 5:

Laboratory monitoring: interpretation of canine serum biochemistry when receiving phenobarbital

Fig 3:

Breeds with increased risk of epilepsy - a border terrier and German shepherd. Pictures: Sue Thatcher

Other considerations

Welfare impact of idiopathic epilepsy

Although many dogs can be successfully treated, a diagnosis of epilepsy has serious implications for both pet and owner. Dogs with epilepsy have an increased risk of premature death as compared to the general population of dogs (Berendt and others 2007). The main reasons are: failure to achieve adequate seizure control and/or perceived poor quality of life, on-going expense of treatment and increased susceptibility to other life-threatening diseases, eg, pancreatitis. Rarely, sudden unexpected death in epilepsy (SUDEP) may occur. Owning an epileptic dog can be problematic. Medication usually must be given at set times, which may impact on work schedules and social life. The ability to take holidays may be influenced as leaving the dog in a boarding kennel without 24 hours supervision may not be advised. If the dog is prone to clusters of seizures then during the cluster the owner may feel unable to leave the dog unattended and/or have disrupted sleep. Finally, taking antiepilepsy drugs can have a daily impact on the dog, for example, increased drowsiness and may predispose to other diseases, such as obesity. Support resources available for owners are detailed in Box 3.

Behavioural changes

Dogs with idiopathic epilepsy may have behavioural problems especially if the seizures are poorly controlled, for example, excessive fear/anxiety, abnormal perception (eg, barking without apparent cause), abnormal reactivity, attachment disorder, demented behaviour, apathetic behaviour and aggression. This might suggest a more widespread brain disorder and neurochemical imbalance and/or effect of medication (Shihab and others 2011).

Sex hormones and neutering

There is an over-representation of male dogs with idiopathic epilepsy (Van Meervenne and others 2014). Although others have reported that entire dogs (male and female) are more likely to have clusters of seizures (Monteiro and others 2012), Van Meervenne and others (2014) found no compelling evidence to support this. However, studies have suggested that oestrogen has a pro-convulsant effect. Therefore, if a relationship between seizure cluster and oestrus can be demonstrated then ovariohysterectomy is advised. However, there may be other reasons for recommending neutering especially as dogs with idiopathic epilepsy should not be bred from as there is a high likelihood of passing on the genetic tendency to their offspring.

Triggers for seizures

Understandably owners often analyse the possible relationship of environment factors and seizures. However, evidence for repeatable triggers is typically individual and anecdotal. Occasionally, an individual dog will have an obvious repeatable trigger factor, for example, exercise or visiting the vet. When a seizure is imminent, there may be stress triggers, for example, a sudden noise, waking the animal from sleep. However, in the interictal period the same trigger has no effect.

Epilepsy and the placebo effect

Epileptics can have a variation in number, frequency and severity of seizures despite their medication. Some appear to have seasonal variations, for example, more seizures during late winter and early spring. Owners of epileptic animals are more likely to seek a second opinion following a severe bout of seizures. All of these reasons can mean that an apparent improvement in seizures following medication change may be erroneously interpreted (Muñana and others 2010).

Diet

It has been advocated that epileptic dogs should receive a low protein diet on the basis that this affects the concentration of monoamine neurotransmitters in the brain. However, there has been no scientific investigation of this claim and few dogs appear to respond to a diet change. It is worth considering a hypoallergenic or hydrolysed diet in dogs with refractory epilepsy and other possible signs of food intolerance, for example, skin or gastrointestinal disease, as there have been a few anecdotal case reports of such dogs whose clinical signs resolved or improved when fed a restricted diet. A trial of a ketogenic diet (high fat, low carbohydrate) did not find that there was a significant reduction in seizures compared to a control diet, although interestingly the number of seizures did decrease in both groups suggesting that dietary consistency may help control seizures.

Vaccination

In an unpublished study of 92 epileptic dogs, presented consecutively to me in referral practice, I was not able to prove a statistically significant association between vaccination and the onset of epilepsy. A total of 26 per cent of the population started their seizures within three months of vaccination and 4 per cent started within two weeks. Nonetheless, a small number of dogs do appear to have seizures associated with vaccination/veterinary visits. I would consider this more likely due to the stress of a veterinary visit than because of the immunological effects of the vaccination.

Conclusion

Idiopathic epilepsy is one of the most common chronic neurological diseases that a small animal veterinary surgeon will treat. The severity ranges from a few isolated seizures to a devastating condition characterised by severe clusters of seizures that are unresponsive to treatment and have great emotional and financial cost. Fortunately, the condition is manageable in approximately 80 per cent of patients and although lifelong medication is likely in most animals, the majority enjoy a good quality of life. The increased prevalence in many breeds suggests an inherited predisposition and identification of the genetic factors associated with epilepsy is pivotal to being able to develop a DNA screening test. To achieve this, cooperation between breeders, breed clubs, primary veterinary surgeons and researchers is paramount.

Clinical signs

Video recordings of dogs suffering from different forms of epilepsy. These videos can be viewed at inpractice.bmj.com/content/supplemental

Video 1:

Generalised tonic-clonic seizure in a one-year-old German shepherd dog

Video 2:

Eight-year-old miniature wirehaired dachshund with Lafora disease and reflex (to sound) myoclonic jerks

Video 3:

Paroxysmal dyskinesia in a two-year-old female Belgian shepherd dog

References

View Abstract

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.