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Canine idiopathic epilepsy


Abstract and Figures

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.
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In Practice FOCUS September 2014
Canine idiopathic epilepsy
Clare Rusbridge
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
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 involuntar y 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
Vi deo 1).
Ictus – synonym for seizure.
Aura – a s ubjective s ensation that p recedes
and marks the onset of a neurological
Postictal phase – the recovery phase
after a seizure marked by altered state of
Interictal period – the time between
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
Clare Rusbridge
Fitzpatrick Referrals, Halfway Lane,
Eashing, Godalming, Surrey GU7 2QQ, UK
School of Veterinary Medicine, University of
Surrey, Guildford, Surrey GU2 7 XH, UK
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
caus e’.
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
Intracranial causes
Extracranial causes
(reactive causes)
Idiopathic epilepsy
Acquired epilepsy
Excess/ deficit
Static brain injury
eg, Following trauma,
cerebral vascular accident
Progressive brain disease
eg, brain tumour, inherited
disease, encephalitis
eg, metaldehyde, permethrin,
piperazine mycotoxins,
chocolate, metronidazole, blue-
green algae, caffeine, cannabis,
laburnum, lead, strychnine,
organophosphates, moxidectin
Internal – metabolic
disease or organ failure
eg, hepatic encephalopathy,
hypercalcemia hypertriglyceridaemi,
hypodipsia, hypoxia,
thiamine deficiency,
cobalamin deficiency
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 br ain disease. Static brain disease implie s 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
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18 In Practice FOCUS September 2014
ion chann els 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’.
The list of possible causes of seizures is long
(Fig 1) and when working up an epileptic patient,
a detailed histor y (Table 1) and a systematic
approach is necessar y to ‘narrow down’ the
likely possibilities. Idiopathic epilepsy is a
diagnosis of exclusion (Table 2). Encourage the
owner to o btain a video of the e vent (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 identif y 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 heav y sedation are required.
Epilepsy can be treated successfully in the
major ity of cas es and most an imals enjo y a good
qualit y of life. Treat ment is aime d at reducin g 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
Table 1: History taking for the epileptic animal
Question Explanatory notes
When was the fir st
Establish duration of the problem
What does the seizure
look like from start to
To establish whether the animal is hav ing a seizure and what type it is . A focal
seizure with secondary generalisation suggests that the seizure is generated
from a focus that may be suggestive of intr acranial disease
Can the owner obtain a
vide o?
Direct visualisation of the circumstances and char acter of the event is
Does the seizure affect all
of the bod y at once?
As above, asymmetr y may sugges t a focal lesion or a different par oxysmal
event, eg, a dys tonia
Do all the s eizures look
similar and if not how do
they differ?
Stereotypy is one of the most useful clue s that a series of events are indeed
Are there any autonomic
Autonomic signs (vomiting, salivation, urination, defecation) are strong
evidence that the event was a seizure
How long does the ictus
Most seizures last t wo to three minutes; longer episodes may be something
else, eg, a paroxysmal dyskinesia
How long does the animal
take to recover and what
signs does it have?
A seizure is a paroxysmal event characterised by tr ansient signs and a
recovery period that ty pically lasts five to 30 minutes. The animal is often
hungry and thirsty during the immediate postictal period. This supportive
histor y can be evidence that an event is a seizure.
In some instances, the postictal phase can be more distressing than the ictus,
for example, some dogs compulsively w alk, failing to avoid obstacles and/or
have repeated vocalisation
What time of day do
seizures occur?
Most dogs with idiopathic epilepsy have seizures when they are resting,
especially during the evening and early morning. Collapse or seizures during
exertion could suggest syncope
Does anything trigger
Important for management recommendations and if exercise or excitement
triggers then consider other paroxysmal events
Does the dog lose
consciousness/is the dog
aw ar e?
If the dog remains responsive to the owner during the seizure then this
suggests either a focal motor seizure or a different paroxysmal event. Note
that complex focal seizures may result in altered consciousness and this can
be difficult to assess objectively
Is the dog normal in
between the seizures?
Abnormal behaviour in the interictal period, eg, lethargy, stereotypic pacing,
loss of training suggests intracranial pathology
How many seizures in an
Clusters seizures require more aggressive and earlier treatment
Any previous injury? To help rule out under lying causes, eg, a histor y of head trauma
Diet Determine if there is any history of intolerance. Establish if the dog is receiving
an appropriately balanced diet
Faecal consistency and
Anecdotally there can be improvement in seizure control if comorbidities such
as inflammatory bowel disease and food intolerance are managed
Other systemic signs,
medical or surgical
history, treatment
Anecdotally there can be improvement in seizure control if comorbidities are
treated. Important to establish if any contraindication to antiepilepsy treatment
Vaccination and worming
Establish r isk of infectious / parasitic disease
Table 2: Diagnostic work up for idiopathic epilepsy
Essential In ideal circumstances If indic ated by other tes t findings
Detailed history
Clinical examination
Neurological examination
Fasting serum biochemistry
(including resting bile acids,
triglycerides, electrolytes,
Advanced imaging (MRI or CT)
Thyroid function*
Dynamic bile acids
CSF analysis
Serum cobalamin, folate, trypsin-
like immunoreactivity
Faecal analysis
DNA tests
Organic acid urinalysis
* 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
CSF Cerebrospinal fluid
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In Practice FOCUS September 2014
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 th e brain mak ing fur ther seizu res 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 refractor y 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.
Monitoring the epileptic
Seizure diary
It is advisable for the owner to keep a diary,
which should be brought to veterinar y
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.
Serum antiepileptic drug
Monitoring the serum concentration
The lowest effective dose to be used
Dosing to be accurately adjusted
Possible toxicosis to be avoided
Better seizure control
Serum concentrations should be
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. (
Other laboratory tests
Monitor haematology and serum
biochemistry ever y six to 12 months (for
interpretation of liver parameters see
Table 5).
Periodic thy roid 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
(, 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
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
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 abnor mal
neurological examination or behaviour/ personality change. In the instance of progressive
disease, eg, slow growing neoplasm, motor and sensor y 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 avail able.
2. If there are neurologic al deficits, can these be related to disease of the forebrain?
Behavioural changes
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. A ny of the above deficits would suggest intracranial pathology. The side and
location of pathology can be established. Asymmetrical forebr ain disease is most likely to
have a neoplastic aetiology (see Neoplasia article of p 2 4 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 ner ve 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.
Box 2: Advantages and
disadvantages of advanced
diagnostic imaging (MRI)
If a dog is aged between six months and
six year s, 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.
Rules out many diseases with a poorer
prognosis, eg, brain tumour.
For intracranial disease, it can help with
decision making for treatment.
– Expensive.
Not a specific test for idiopathic
For dogs with idiopathic epilepsy, it does
not necessarily help with prognosis or
– Requires general anaesthetic.
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20 In Practice FOCUS September 2014
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).
Other considerations
Welfare impact of idiopathic
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
reaso ns are: failur e to achieve ad equate seizur e
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 s upervi sion may not be ad vised. If th e 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.
Table 3: DNA tests for inherited diseases associated with seizures
Disease Breed Other clinical signs Laboratory
Alaskan husky
Alaskan husky Ataxia, behavioural
blindness, facial
hypalgesia, difficulties in
prehension of food
UC Davis
Benign familial juvenile
Lagotto Romagnolo Ataxia and hypermetria Optigen
(methylmalonic aciduria)
Australian shepherd dog Failure to gain weight,
lethargy, vomiting
PennGen, Animal DNA
Giant schnauzer PennGen
Border collie
Fucosidosis English springer spaniel Behavioural
abnormalities, visual
impairment, progressive
motor and mental
Animal Health Trust
Pinmoore Animal
Laboratory Services
Staffordshire bull
Ataxia, hypermetria
dementia, tremors
Animal Health Trust
Pinmoore Animal
Laboratory Services
Lafora disease Miniature wire-haired
Bassett hound
Myoclonus, dementia The Hospital for Sick
Children, University of
encephalopathy with
Standard poodle Ataxia, whole-body
University of Missouri,
VetGen, Laboklin,
Pinmoore Animal
Laboratory Services
Neuronal ceroid
Tibetan terrier Behavioural
abnormalities, visual
impairment, progressive
motor and mental
Animal Health Trust,
University of Missouri
American Staffordshire
bull terrier, American pit
bull terrier
American bulldog University of Missouri
Border collie ,
dachshund, miniature
long-haired dachshund,
miniature smooth-
haired dachshund,
Australian shepherd
dog, English setter
DNA Diagnostics
Pinmoore Animal
Laboratory Services
meningoencephalitis in
pug dogs
Pug Visual deficits,
progressive motor and
mental dysfunction
(Susceptibility to)
UC Davis
Animal DNA Diagnostics:
Animal Health Trust:
Antagene: ww
Laboklin: ww
UC Davis:
University of Minnesota: vices-and-fees/canine-neuromuscular/
University of Missouri/Orthopaedic Foundation for Animals: ww
University of Toronto: www.veterinar
Pinmoore Animal Laboratory Services: /
Box 3: Resources that may be
useful for owners of epileptic
Canine Epilepsy
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
Telephone: 01296 715829
UK-based support group for owners of
epileptic dogs.
In additional to general information, this
Boehringer Ingelheim UK website has
specific information for owners about the
antiepilepsy drug imepitoin.
Epiphen Online
In addition to gener al information, this
Vetoquinol UK website has an online
monitor ing tool that allows owners to
record seizures, monitor trends and print
off reports for their veterinary surgeon.
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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
suppor t 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 eect
Epileptics can have a variation in number,
frequency and sever ity of seizure s despite their
medication. Some appear to have seasonal
variations, for example, more seizures during
late winter and early spring. Owner s 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).
It has be en advocated t hat epileptic do gs should
receive a low protein diet on the basis that
this affects the concentration of monoamine
neurotransmitters in the brain. However, there
has been n o scientific inv estigation of th is claim
and few do gs appear to re spond to a diet c hange.
It is worth considering a hypoallergenic or
hydrolysed diet in dogs with refr actory 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
dietar y consistency may help control seizures.
Diagnosis of idiopathic epilepsy
Consider treatment if two or more seizures in six months
Definitely start treatment if seizures are more frequent than every eight weeks or
trend towards a decreasing inter-ictal period or increasing seizure severity
Single seizure with two or more
week inter-ictal period
Cluster seizures and /or less
than two week inter-ictal period
Imepitoin 10 to 20 mg/kg BID
If seizure
control is
Phenobarbital 3 mg/kg BID
Unacceptable seizure control
Consider imepitoin
30 mg/kg BID
Combination phenobarbital 3 mg/kg BID,
imepitoin 10 to 20 mg/kg
Serum phenobarbital concentration
aim 100 to 140 µmol/l (20 to 28 µg/ml)
If seizure
control is
and with
Adjust dose – new dose = old dose x
(desired serum concentration ÷
actual serum concentration)
Avoid phenobarbital dose
more than 12 mg/kg/day
Potassium bromide dose more than
40 mg/kg may be associated with more
adverse effects eg, diarrhoea
Serum bromide
aim 15 to 25
mmol/l (1000 to
2000 mg/l)
If seizure control is acceptable,
If imepitoin is the first therapy,
consider withdrawing and
continuing phenobarbital
seizure control
Add potassium bromide
30 to 40 mg/kg per day
Withdraw imepitoin
If seizure control acceptable continue
and with laboratory monitoring
Unacceptable seizure control consider
adding unlicensed ‘human’ third generation
anti-epilepsy drugs, eg,
levetiracetum at 10 to 20 mg/kg BID-QID
1 to 2 weeks
8 to 16
Fig 2: Treatment algorithm for the management of idiopathic epilepsy that I have developed.
Note that the addition of multiple agent s 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 dr ugs should be done according to data
sheet guidelines. BID Twice a day, QID Four times a day
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 cohor t, 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 labr ador retriever
was the most popular breed and
is also treated most commonly for
epilepsy (
(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
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Table 4: Common antiepileptic drugs used in idiopathic epilepsy
Drug Mechanism action Advantage Potential adverse effects / disadvantage
Imepitoin Low-affinity par tial agonist
of benzodiazepine site GA BA
receptor and affects calcium
• Less severe adverse effects
• No tolerance
• No dependence
• Steady state in three days
No requirement to monitor
serum concentration
May not be as effective AED as phenobarbital
Liver metabolised
Phenobarbital Agonist GABA also af fects
glutamate receptor, calcium
channels and voltage-dependant
potassium currents
• Most effective AED
Controls epilepsy in ~50 per
cent patients and 33.5 per cent
Dose related /transient Idiosyncratic
Somnolence /sedation
Acute hepatotoxicity
Blood dyscrasia
Superficial necroly tic
dermatitis (hepatocutaneous
Liver metabolised
Bromide Negative ion thought to
hyperpolarise neurons by
passing through the neuronal
chloride channels
• No liver metabolism
• Once daily dosin g
Syner gistic with
Dose related Idiosyncratic
Somnolence /sedation
Gastrointestinal irritation
Neuromuscular signs,
including megaoesophagus
Not as effecti ve AED as phenobarbital
Steady state in three to four months
Excretion affected by dietary salt
Levetiracetum* Novel mechanism of action.
Binds synaptic vesicle protein
SV2A, which modulates
synaptic vesicle exocytosis and
neurotransmitter release
• Less severe adverse effects
• No liver metabolism
• Neuroprotective
Dose related Idiosyncratic
Somnolence /sedation None reported
Clearance enhanced by phenobarbital
Most dogs require TID therapy (some QID)
Used in combination, ie, ‘add on’ (in refr actory epilepsy)
Possible honeymoon effect
Zonisamide* Affects sodium and calcium ion
• Potential as monotherapy
• Neuroprotective
Dose related /transient Idiosyncratic
Acute hepatotoxicity
Clearance enhanced by phenobarbital
Better not in combination phenobarbital?
Possible honeymoon effect
* Not licensed for canine epilepsy
Tolerance: loss of anticonvulsant efficacy during prolonged treatment; Dependence: withdrawal signs observed on termination of long-term treatment; Honeymoon
effec t: initial positive re sponse lost within 12 months
AED Anti-epileptic dr ug, QID Dosing every six hours, TID Dosing every eight hours
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
star ted within t wo weeks. Non etheless, a sma ll
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.
Idiopathic epilepsy is one of the most common
chronic neurological diseases that a small
animal veterinar y surgeon will treat. The
severity ranges from a few isolated seizures to
a devas tating condi tion charac terised b y 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
Fig 3: Breeds with increased risk of epilepsy - a border terrier and German shepherd.
Pictures: Sue Thatcher
Rusbridge.indd 22 18/08/2014 16:51 on October 27, 2015 - Published by from
In Practice FOCUS September 2014
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.
LEEB, T. & DROGEMU LLER, M. (2 011) Polymo rphisms
in the AB CB1 gene in pheno barbital r esponsive a nd
resistant idiopathic epileptic border collies. Journal of
Veterinary Internal Medicine 25, 484-489
ALVING, J. (20 07) Premature death , risk factors,
and life patter ns in dogs with epilepsy. Jour nal of
Veterinary Internal Medicine 21, 754-759
Table 5: Laboratory monitoring: interpretation of canine serum biochemistry
when receiving phenobarbital
Biochemical parameter Changes suggestive of
hepatic enzyme induction by
Changes suggestive of
hepatocellular injury
Alanine aminotransferase (ALT) Less than 2 x the upper limit of
More than 2 x the upper limit of
Alkaline phosphatase (ALP) Up to 5 x upper limit of normal More than 5 x upper limit of
γ- glutamyltransferase (GGT) Normal/minimal changes Increased
Aspartate aminotransferase
Normal/minimal changes Increased
Changes suggestive of reduced
liver function
Bilirubin Normal Increased
Bile acids Normal Increased
Albumin Normal Decreased
Cholesterol Normal Decreased
Reproduced from Rusbridge (2013a), reference Webster and Cooper (2009)
& ALBAN, L. (20 08) Prevalence and characteristics
of epilepsy in the Belgian shepherd variants
Groenendael and Tervueren born in Denmark 1995-
200 4. Acta Veterinaria Scandinavica 50, 51
(2014) IL AE official report: a practical cl inical
definition of epilepsy. Epilepsia 55, 475-482
SAUTER-LOUIS, C. & F ISCHER, A. (2010) Ep ilepsy in
border collies: clinical manifestation, outcome, and
mode of inheritance. Journa l of Veterinary Internal
Medicine 24, 171-178
CHURCH , D. B. & BRODBELT, D. C. (2013) P revalence
and ris k factors for canine epileps y of unknown
origin in the UK . Veterinary Record
do i: 10 .1136/v r.10113 3
KIRK , H. (1922) Symptoms. In C anine Distemp er - Its
Complications, Sequelae, and Treatment. Balliere,
Tindall and Cox. p 109
S. R. (2012) Canine idiopathic epilepsy: prevalence,
risk factor s and outcome as sociated wit h cluster
seizures and status epilepticus. Journ al of Small
Animal Practice 53, 526-530
E. (2010) Placebo effect in canine epilepsy trials.
Journal of Veterinary Internal Medicine 24, 166-17 0
RUSBRIDGE, C. (2013a) Choosin g the right drug
1. Anticonvul sants used for first-line the rapy. In
Practice 35, 106 -113
RUSBRIDGE, C. (2013b) Ch oosing the right drug
2. Anti convulsa nts used for second-line therapy,
other anticonvulsants and alternative therapies. In
Practice 35, 183-189
A. (2013) Relationship of angiogenesis and microglial
activation to seizure-induced neuronal death in the
cerebral cortex of Shetland sheepdogs with familial
epilepsy. American Journal of Veterinary Research 74,
763 -770
SHIHA B, N., BOWEN, J. & VOLK, H. A. (2011)
Behav ioral changes in dogs associated w ith the
development of idiopathic epilepsy. Epilepsy and
Behavior 21, 160-167
CARTER, S. D., TIMO FTE, D. & OLLIER, W. E . (2011)
Characteristics of epileptic episodes in UK dog
breeds: an epidemiological approach. Veterinary
Record doi: 10.1136/ vr.d1901
SHORVON, S. D. (2011) The etiologic cl assification of
epilepsy. Epilepsia 52, 1052-1057
SMITH, P. M., TALBOT, C. E. & JEFFERY, N. D. (2008)
Findings on low-field crani al MR images in epileptic
dogs that lack interictal neurological deficits.
Veterinary Journal 176, 320-325
K. & VAN H AM, L. M. (2014) The infl uence of sex
hormones on seizures in dogs and humans.
Veterinary Journal 201, 15-20
WEBS TER, C. R. L . & COOPER, J. C. (2 009) Diagn ostic
appro ach to hepatobi liary disease. In K irk’s Curr ent
Veterin ary Ther apy XIV. 14th edn . Eds J. D. Bonagur a,
D. C. Twedt, Saunders. pp 543 -549
doi: 10.1136/inp.g5126
Clinical signs
Video recordings of dogs suffering from different forms of epilepsy.
These videos can be viewed at
Video 1: Generalised tonic-clonic seizure in a
one-year-old German shepherd dog
Video 2: Eight-year-old miniature wirehaired
dachshund with L afora disease and reflex (to
sound) myoclonic jerks
Video 3: Paroxysmal dyskinesia in a
two-year-old female Belgian shepherd dog
Rusbridge.indd 23 18/08/2014 16:51 on October 27, 2015 - Published by from
Canine idiopathic epilepsy
Clare Rusbridge
doi: 10.1136/inp.g5126
2014 36: 17-23 In Practice
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Patients with acute blindness typically present with mydriasis and a history of disorientation that may involve bumping into familiar objects. Acute blindness may be transient or permanent. For simplicity, lesions typically occur in one of three zones along this complex pathway: the retina, the optic nerve, or the visual cortex. Retinal lesions include dysplasia and degeneration syndromes, drug‐induced and taurine‐deficient retinopathies, and retinal detachment. Optic nerve lesions include optic neuritis and traumatic injury. Visual cortex lesions include hypotensive and ischemic encephalopathies and neoplasia. Disease localization is important for determining diagnosis and prognosis. Important disease localization and diagnostic tools involve the pupillary light reflex (PLR) and fundoscopy.
Full-text available
Background One of the most common chronic neurological disorders in dogs is idiopathic epilepsy (IE) diagnosed as epilepsy without structural changes in the brain. In the current study the hypothesis should be proven that subtle grey matter changes occur in epileptic dogs. Therefore, magnetic resonance (MR) images of one dog breed (Beagles) were used to obtain an approximately uniform brain shape. Local differences in grey matter volume (GMV) were compared between 5 healthy Beagles and 10 Beagles with spontaneously recurrent seizures (5 dogs with IE and 5 dogs with structural epilepsy (SE)), using voxel-based morphometry (VBM). T1W images of all dogs were prepared using Amira 6.3.0 for brain extraction, FSL 4.1.8 for registration and SPM12 for realignment. After creation of tissue probability maps of cerebrospinal fluid, grey and white matter from control images to segment all extracted brains, GM templates for each group were constructed to normalize brain images for parametric statistical analysis, which was achieved using SPM12. ResultsEpileptic Beagles (IE and SE Beagles) displayed statistically significant reduced GMV in olfactory bulb, cingulate gyrus, hippocampus and cortex, especially in temporal and occipital lobes. Beagles with IE showed statistically significant decreased GMV in olfactory bulb, cortex of parietal and temporal lobe, hippocampus and cingulate gyrus, Beagles with SE mild statistically significant GMV reduction in temporal lobe (p < 0.05; family- wise error correction). Conclusion These results suggest that, as reported in epileptic humans, focal reduction in GMV also occurs in epileptic dogs. Furthermore, the current study shows that VBM analysis represents an excellent method to detect GMV differences of the brain between a healthy dog group and dogs with epileptic syndrome, when MR images of one breed are used.
Full-text available
Epidemiological evaluation of canine epilepsy is an under-researched area. The objectives of this study were to estimate prevalence and investigate risk factors for epilepsy of unknown origin (EUO) among dogs attending primary veterinary practices in the UK. The clinical data analysed spanned a two-year period and included all dogs attending 92 primary veterinary clinics participating in the VetCompass project. Five hundred and thirty-nine EUO cases were identified giving a prevalence of 0.62% (95% CI 0.57% to 0.67%). Males were over 1.5 times as likely to have EUO compared with females (95% CI 1.44 to 2.06; P < 0.001). Of purebred dogs, the border terrier had 2.70 (95% CI 1.57 to 4.62; P < 0.001) and the German shepherd dog had 1.90 (95% CI 1.28 to 2.80; P=0.001) times increased odds of EUO compared with crossbred dogs. In addition, the West Highland white terrier had reduced odds (OR 0.23; 95% CI 0.08 to 0.62; P=0.004) of EUO compared with crossbred dogs (likelihood ratio test P < 0.0001). No association was found with neuter status, colour or weight. The current study highlights the clinical importance of epilepsy as a canine disorder in the UK. Increased awareness of sex and breed predispositions may assist clinicians with diagnosis. Further research is merited to evaluate the specific breed associations identified.
Many epileptic patients will have satisfactory seizure control using the first-line anticonvulsants phenobarbital and/or bromide, as discussed in the first article of this series (In Practice, March 2013, vol 35, pp 106-113). However, some patients will continue to have an unacceptable number or severity of seizures despite adequate drug serum concentrations. Some patients have a compromised quality of life because of the adverse effects of their medication. In this article, the anticonvulsant drugs used for second-line therapy are discussed, together with other anticonvulsants and alternative therapies.
This article aims to give the general practitioner a step by step approach to first-line medical management of epilepsy in both cats and dogs. The licensed drugs, bromide and phenobarbital, are discussed in detail with particular reference to the common problems that might be observed. A second article in this two-part series, to be published in a subsequent issue of In Practice, will discuss second-line medical management of epilepsy.
Epilepsy is the most common chronic neurological disorder in both humans and dogs. The effect of sex hormones on seizures is well documented in human medicine. Catamenial epilepsy is defined as an increase in frequency and severity of seizures during certain periods of the menstrual cycle. Oestradiol increases seizure activity and progesterone is believed to exhibit a protective effect. The role of androgens is controversial and there is a lack of research focusing on androgens and epilepsy. Indeed, little is known about the influence of sex hormones on epilepsy in dogs. Sterilisation is believed to improve seizure control, but no systematic research has been conducted in this field. This review provides an overview of the current literature on the influence of sex hormones on seizures in humans. The literature on idiopathic epilepsy in dogs was assessed to identify potential risk factors related to sex and sterilisation status. In general, there appears to be an over-representation of male dogs with idiopathic epilepsy but no explanation for this difference in prevalence between sexes has been reported. In addition, no reliable conclusions can be drawn on the effect of sterilisation due to the lack of focused research and robust scientific evidence.
Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy (ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years. “Resolved” is not necessarily identical to the conventional view of “remission or “cure.” Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Objective: To determine whether angiogenesis and microglial activation were related to seizure-induced neuronal death in the cerebral cortex of Shetland Sheepdogs with familial epilepsy. Animals: Cadavers of 10 Shetland Sheepdogs from the same family (6 dogs with seizures and 4 dogs without seizures) and 4 age-matched unrelated Shetland Sheepdogs. Procedures: Samples of brain tissues were collected after euthanasia and then fixed in neutral phosphate-buffered 10% formalin and routinely embedded in paraffin. The fixed samples were sectioned for H&E staining and immunohistochemical analysis. Results: Evidence of seizure-induced neuronal death was detected exclusively in samples of cerebral cortical tissue from the dogs with familial epilepsy in which seizures had been observed. The seizure-induced neuronal death was restricted to tissues from the cingulate cortex and sulci surrounding the cerebral cortex. In almost the same locations as where seizure-induced neuronal death was identified, microvessels appeared longer and more tortuous and the number of microvessels was greater than in the dogs without seizures and control dogs. Occasionally, the microvessels were surrounded by oval to flat cells, which had positive immunohistochemical results for von Willebrand factor. Immunohistochemical results for neurons and glial cells (astrocytes and microglia) were positive for vascular endothelial growth factor, and microglia positive for ionized calcium-binding adapter molecule 1 were activated (ie, had swollen cell bodies and long processes) in almost all the same locations as where seizure-induced neuronal death was detected. Double-label immunofluorescence techniques revealed that the activated microglia had positive results for tumor necrosis factor-α, interleukin-6, and vascular endothelial growth factor receptor 1. These findings were not observed in the cerebrum of dogs without seizures, whether the dogs were from the same family as those with epilepsy or were unrelated to them. Conclusions and clinical relevance: Signs of angiogenesis and microglial activation corresponded with seizure-induced neuronal death in the cerebral cortex of Shetland Sheepdogs with familial epilepsy. Microglial activation induced by vascular endothelial growth factor and associated proinflammatory cytokine production may accelerate seizure-induced neuronal death in dogs with epilepsy.
To evaluate the prevalence of cluster seizures and status epilepticus in dogs with idiopathic epilepsy and determine risk factors for cluster seizure frequency, severity and patient outcome. Retrospective review of medical records of 407 dogs with idiopathic epilepsy was made. Follow-up questionnaires were evaluated in cases with cluster seizures. Mean age at diagnosis of idiopathic epilepsy was 4 years. Cluster seizures were documented in 169 (41%) dogs. German shepherds and boxers were significantly (P=0·04 and 0·01, respectively) more likely to suffer from cluster seizures compared to Labrador retrievers. There was no association between the occurrence of status epilepticus and cluster seizures and frequency and severity of cluster seizures and status epilepticus episodes with age or breed. Intact males were twice as likely (P=0·003) than neutered dogs to suffer from cluster seizures. Intact females had significantly (P=0·007) more frequent cluster seizures than neutered dogs. The median survival time for all dogs with cluster seizures was 95 months. Significantly (P=0·03) more dogs with frequent cluster seizures were euthanased because of the cluster seizures. There was a high prevalence of cluster seizures in dogs with idiopathic epilepsy. Neutering status appears to influence cluster seizure occurrence with intact females more likely to experience more frequent episodes. Euthanasia is associated with frequency of cluster seizure episodes.
In this study, previously unreported cohort characteristics and seizure patterns for canine epilepsy were identified from a series of UK-based epileptic dogs containing 1260 cases from 79 known pedigree breeds and a group of crossbreed dogs.
Variation in the ABCB1 gene is believed to play a role in drug resistance in epilepsy. Variation in the ABCB1 gene encoding the permeability-glycoprotein could have an influence on phenobarbital (PB) resistance, which occurs with high frequency in idiopathic epileptic Border Collies (BCs). Animals: Two hundred and thirty-six client-owned BCs from Switzerland and Germany including 25 with idiopathic epilepsy, of which 13 were resistant to PB treatment. Prospective and retrospective case-control study. Data were collected retrospectively regarding disease status, antiepileptic drug (AED) therapy, and drug responsiveness. The frequency of a known mutation in the ABCB1 gene (4 base-pair deletion in the ABCB1 gene [c.296_299del]) was determined in all BCs. Additionally, the ABCB1 coding exons and flanking sequences were completely sequenced to search for additional variation in 41 BCs. Association analyses were performed in 2 case-control studies: idiopathic epileptic and control BCs and PB-responsive and resistant idiopathic epileptic BCs. One of 236 BCs (0.4%) was heterozygous for the mutation in the ABCB1 gene (c.296_299del). A total of 23 variations were identified in the ABCB1 gene: 4 in exons and 19 in introns. The G-allele of the c.-6-180T > G variation in intron 1 was significantly more frequent in epileptic BCs resistant to PB treatment than in epileptic BCs responsive to PB treatment (P(raw) = .0025). A variation in intron 1 of the ABCB1 gene is associated with drug responsiveness in BCs. This might indicate that regulatory mutations affecting the expression level of ABCB1 could exist, which may influence the reaction of a dog to AEDs.