1. health and fitness
2. disease
3. epilepsy

1
SEIZURES & EPILEPSY
Dr. Richard A. LeCouteur
Professor of Neurology & Neurosurgery
School of Veterinary Medicine
University of California
Davis CA 95616 USA
Seizure disorders occur frequently in dogs and cats. Estimates of seizure incidence during a lifetime
vary from 0.5% to 5.7% of all dogs, and from 0.5% to 1.0% of all cats. Discussion of seizure
disorders of all types must precede consideration of the clinical management of epilepsy. Such a
broad approach is necessary because dogs and cats with a seizure disorder frequently have similar
histories and physical signs despite a wide variety of underlying causes of cerebral dysfunction
(including epilepsy). Similarities in clinical histories of dogs or cats with a seizure disorder reflect the
similar pathophysiological mechanisms that underlie seizure disorders of all types.
Classification of Seizures
An epileptic seizure is a definable event that may be measured, recorded, and classified.
Classification of epileptic seizures is well established in people [Table 1]. Therapy for epilepsy of
people is best directed toward the seizure type. A description of seizures learned from a history (or
occasionally by means of videotape) is the single most important factor in providing a correct
therapeutic approach in people.
Table 1: Classification of Seizures.
I.
Partial Seizures (Local, Focal)
a.
b.
c.
II.
Simple Partial Seizures (consciousness not impaired)
i. With motor signs
ii. With somatosensory or special sensory signs
iii. With autonomic signs
iv. With behavioral signs
Complex Partial Seizures (consciousness impaired)
i. Beginning as a simple partial seizure & progressing to impairment of
consciousness
ii. With impairment of consciousness at onset
Partial seizures evolving to secondary generalised seizures
Primary Generalised Seizures (bilaterally symmetrical without local onset; consciousness
may be impaired or lost)
i.
ii.
iii.
iv.
v.
vi.
III.
Absence seizures
Myoclonic seizures
Clonic seizures
Tonic seizures
Tonic-clonic seizures
Atonic seizures
Unclassified Epileptic Seizures (inadequate or incomplete data)
A classification system specifically for cats and dogs does not exist. Many types of epileptic seizure
that occur in animals, however, are similar to those described for people, and attempts have been
made to classify epileptic seizures of cats and dogs by using a system of classification designed for
people. A classification system that is designed specifically for dogs and cats is needed to permit
understanding and comparison of prospective studies of anticonvulsant efficacy in animals. The
initial step in the classification of epileptic seizures of dogs and cats is to categorise the seizures as
either partial (focal) or generalised episodes.
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Causes of Seizures
The normal brain is capable of convulsing in response to a variety of stimuli within the central nervous
system and to many external influences. Consequently, the causes of seizures are numerous.
Disorders that induce seizures may arise either outside the nervous system (extracranial causes) or
within the nervous system (intracranial causes) [Table 2]. Each of these groups of causes may be
divided in turn into two categories:
1. “Symptomatic” Epilepsy
This incudes (i) extracranial causes that are divided into those that originate outside the body (eg,
toxic agents) and those that arise within the body but outside the nervous system (eg, hypoglycemia),
and (2) Progressive intracranial causes of seizure disorders including those diseases that, in time,
may affect an increasing volume of brain tissue (eg, neoplasia, encephalitis), and may produce
clinical signs other than seizures.
2. “True” Epilepsy
This includes non-progressive intracranial causes of seizures, including inherited, acquired, and
idiopathic epilepsy.
Table 2. Causes of Seizures.
Clinically, it is essential to distinguish between progressive and non-progressive brain diseases that
produce seizures. Therapy for progressive diseases requires not only control of seizures but also
specific therapy for the underlying disease. If therapy of the underlying disease is not possible, the
veterinarian should at least provide an accurate diagnosis and prognosis. On the other hand, it is
seldom possible to make a precise etiologic or anatomic diagnosis in non-progressive seizure
disorders of intracranial origin (ie, epilepsy). Once the non-progressive nature of the cause of a
seizure disorder is established, therapy with an anticonvulsant medication is indicated.
Extracranial Disorders. Extracranial disorders may alter brain metabolism and electrophysiology,
leading to paroxysmal discharges and seizures. Because the disorders affect both hemispheres,
primary generalised seizures usually occur, although other clinical signs may be superimposed on
them. Extracranial disorders frequently result from various metabolic conditions, such as
hypoglycemia, liver disease, hyperlipoproteinemia, renal disease, hypocalcemia, and hypothyroidism.
Toxicoses, including lead or organophosphate poisoning, caffeine or theobromine toxicosis (from
excessive chocolate consumption) may also result in seizures. Intestinal parasitism and
hyperthermia are other extracranial causes of seizures.
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Intracranial Disorders. Intracranial causes of seizures include malformations (eg, hydrocephalus),
inflammatory disorders (eg, canine distemper encephalitis), nutritional disorders (eg, thiamine
deficiency), neoplasia, cranial trauma, degenerative conditions (eg, storage diseases), and cerebral
infarction. Affected animals typically present with progressive neurological disease. In some
animals, such as animals with a previous history of cranial trauma, morphological brain lesions may
have occurred long before the first seizures occur, and may be inactive but leave the brain in a
seizure-prone state. In other animals, seizures may be an early sign of progressive brain disease,
such as cerebral neoplasia, and may be the sole clinical sign for a prolonged period.
With intracranial disease, secondary or primary generalised seizures occur in a wide variety of clinical
manifestations, depending on the location and extent of the underlying lesion(s). The frequency of
seizures may vary considerably, and the association with rest and sleep seems to be less
pronounced than in idiopathic epilepsy (see later). Most intracranial diseases lead to other
neurological or clinical signs during the interictal period, and these diseases may have a progressive
or non-progressive clinical course.
Epilepsy. The seizures seen in association with idiopathic epilepsy are caused by functional
disorders of the brain in which both hemispheres are affected by paroxysmal neuronal discharges.
Epileptic seizures are generalised and symmetrical from the onset. Morphological lesions are not
observed in the cerebrum of animals with epilepsy, with the exception of animals with
microdysgenesis (a condition where subtle alterations of embryo-foetal development, such as
increased neuron density, may result in a lowered seizure threshold). However, lesions such as
gliosis, atrophy, or laminar cortical necrosis, may occur secondary to severe seizures, clusters of
seizures, or status epilepticus. These lesions may evolve into a secondary epileptic focus.
Idiopathic epilepsy of dogs or cats usually begins with a single seizure. The seizures most often
occur during or following a period of sleep or rest, and rarely occur during periods of activity. Seizure
frequency is variable (days to months between seizures), however the time between seizures usually
decreases as the disorder becomes more chronic. Intervals between seizures may be uniform, or
highly variable. Clusters of seizures may occur over hours or days in some breeds of dog (eg,
German shepherd dogs, Saint Bernard dogs, Irish setters).
Diagnostic Approach
A comprehensive case history, complete physical and neurological examinations, and a minimum
data base consisting of results of hematological and serum chemistry analyses should be obtained
for all animals suspected of having a seizure disorder, even if only one seizure has been observed.
On the basis of this information a list of differential diagnoses should be made. Further clinical
laboratory, toxicological, or radiographical procedures may be indicated after the results of these
initial tests are known [Table 3] .
Differential Diagnosis
Information obtained from the history, physical, and neurological examinations and the results of a
minimum data base may be used to form a list of differential diagnoses. Idiopathic epilepsy may
occur at any age, but it occurs most frequently in dogs or cats between 6 months and 5 years of age.
Using idiopathic epilepsy as a reference point, a list of differential diagnoses for seizure disorders
may be formed for each of three age groups: <6 months of age, 6 months to 5 years of age, and >5
years of age. A list of the most common diseases other than epilepsy that may occur in association
with seizures in each of these age categories is included in Table 4.
Additional Diagnostic Tests
Selection of additional tests should be based on results of physical and neurological examinations
and on the results of tests that comprise a minimum data base [Table 3]. The dog's or cat's age
should also be considered because certain disorders that may result in seizures are more frequently
associated with younger dogs and cats [Table 4].
An extracranial cause of seizures is most likely associated with an abnormal minimum data base
[Table 3]. Additional tests may be selected to investigate such extracranial causes. For example, in
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animals with serum chemistry abnormalities that are consistent with liver disease (eg, low BUN,
elevated ALT and /or alkaline phosphatase, low glucose, low total protein, etc) further tests may be
needed to assess liver function. Quantification of serum bile acids after a 12-hour fast, and 2 hours
postprandially, provides a reliable indicator of liver function.
After confirmation of an extracranial cause for seizures, specific therapy may be indicated. In certain
instances, anticonvulsant medication may be instituted in addition to specific therapy of an
extracranial disorder to control seizure activity during such therapy. Depending on the nature of the
underlying extracranial disease, such anticonvulsant therapy may or may not be discontinued at
some later date.
It should be remembered that in rare instances both an extracranial and an intracranial disorder may
be present, and yet the extracranial disorder may not be related to the cause of the seizures. For
example, it is possible that a dog with seizures may have hepatic cirrhosis and a primary intracranial
neoplasm. For this reason, it is essential to monitor closely the response of an animal to therapy for
an extracranial cause of seizures. Should the seizures continue or worsen in the face of a response
to therapy of the extracranial disease, then further diagnostic tests may be indicated.
An intracranial cause of seizures is most likely associated with normal results of a minimum data
base [Table 3]. An intracranial cause should also be considered if the results of additional tests
completed to fully investigate abnormalities seen on a minimum data base prove to be normal.
Cerebrospinal fluid (CSF) analysis is essential for any dog or cat in which an intracranial cause for
seizures is suspected. In addition to submission of CSF for cytological examination and protein
quantification, aerobic and anaerobic bacterial and/or mycotic culture and sensitivity testing may be
done, and titers for infectious agents may be completed (eg, cryptococcosis, canine distemper, etc).
Radiographs of the skull may be useful for detecting calvarial tumors, mineralised intracranial
neoplasms, or fractures of the skull associated with head trauma.
Electroencephalography (EEG) is helpful in the diagnosis of congenital malformations such as
hydrocephalus or lissencephaly. The EEG can also be useful to evaluate electrical events associated
with a seizure that may occur during recording and in the identification of paroxysmal electrical events
that occasionally occur interictally in the recordings of some epileptic animals. Advanced imaging
modalities, such as x-ray computed tomography or magnetic resonance imaging, may provide
specific information regarding the location and extent of intracranial lesions such as neoplasms,
granulomas, infarcts, or hemorrhages.
Animals more than 6 months and less than 5 years of age that have a history of a seizure or of
recurrent seizures, that have normal physical and neurological examinations, and that have normal
results on a minimum data base most likely have a nonprogressive intracranial disorder. Ideally,
additional diagnostic procedures should be done in such animals, however, consideration of costs
inolved and potential for morbidity and mortality associated with anaesthesia may result in a decision
to delay further tests pending assessment of response to anticonvulsant medication. If a response to
therapy is not seen, if seizure frequency or severity increase, or if additional clinical signs develop,
then further diagnostic tests to investigate progressive intracranial causes of seizures should be
done.
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Table 3: Diagnostic Approach for a Dog or Cat with Seizures
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7
Table 4. Causes of Seizures
Anticonvulsant Therapy
Appropriate therapy for a seizure disorder depends on accurate determination of the cause of the
seizures. Treatment with anticonvulsants is indicated for animals with idiopathic epilepsy. Seizures
resulting from a structural brain disorder (progressive intracranial disease) require additional therapy,
depending on the cause of the disease (eg, neoplasia or inflammation). Anticonvulsants usually are
contraindicated in animals with extracranial causes of seizures, where therapy should be directed
towards the primary cause of the seizures (eg, hypoglycemia).
Objectives of Anticonvulsant Therapy. While the overall goal of anticonvulsant therapy is to eradicate
all seizure activity, this goal is rarely achieved. Most dogs and cats benefit from anticonvulsant
medication by reduction in frequency, severity, and duration of their seizures. A realistic goal is to
reduce seizure frequency to a point that is acceptable to an owner without intolerable or lifethreatening adverse affects to the animal.
General Principles of Anticonvulsant Therapy. Prevention of seizures in cats or dogs with epilepsy is
a pharmacological problem in clinical veterinary medicine. Surgical therapy for uncontrolled epilepsy
as applied in humans has not yet been reported for use in animals.
Prior to initiation of therapy for seizures induced by epilepsy, every reasonable effort must be made to
rule out either extracranial or progressive intracranial causes for the seizures.
Decisions Regarding the Need for Anticonvulsant Therapy. Many factors must be considered prior to
the initiation of anticonvulsant therapy. The most important considerations are seizure frequency,
seizure character, and owner factors.
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Seizure Frequency. The seizures observed in epileptic animals occur with varying frequency, and
two general approaches exist regarding the institution of anticonvulsant therapy. Some authors state
that therapy should not be started before the recurrent nature of the disease has been established.
This means that at least two seizures should have been observed. Otherwise animals may be
treated that would not have had additional seizures. However, there may be sound biological
reasons for beginning treatment after the first seizure. Experience in human epilepsy indicates that
when this is done, seizure control may be more effective.
Character of Seizures. In certain instances, early and aggressive control of seizures is required. For
example, in those animals where preictal and postictal phases are characterised by intolerable
changes in personality (eg, aggression) or in excretory behavior.
Owner Factors. In veterinary practice, the decision for or against anticonvulsant therapy ultimately
must be made by the owner of an epileptic dog or cat. This decision should be based on information
and advice provided by a veterinarian. An owner should be fully informed about the nature of the
disease and its treatment in terms that are easily understandable. The owner should have a realistic
knowledge of the objectives of anticonvulsant therapy because frequently an owner will expect
successful therapy to be curative with complete elimination of seizures. An owner must appreciate
the need for regular administration of an anticonvulsant drug and also understand that an animal may
require medication for the remainder of its life. Cost of medication and regular assessments by a
veterinarian should be discussed. Alterations in dosage without prior consultation must not occur.
Omission of a single dose may result in severe relapses and sometimes status epilepticus. Although
seizure frequency and severity will be reduced in the majority of cats or dogs that receive
anticonvulsant medications, a proportion of animals (perhaps as high as 20-30%) may not be
controlled adequately despite intensive medical management. With high dosages of anticonvulsant
medications, the risk of drug-induced complications increases and must be weighed against the
benefits of therapy. Once therapy has begun, a prescribed dosage schedule must be followed
exactly. An owner should have a detailed knowledge of expected undesirable effects of
anticonvulsant medications. Knowledge of these factors is essential for a high and intelligent degree
of cooperation between an owner and veterinarian. Euthanasia of an animal should be considered
when an owner cannot commit to supervision and lifetime treatment of a dog or cat with severe
epilepsy.
General Recommendations for Anticonvulsant Therapy
In general, owners should be encouraged to begin anticonvulsant medication in epileptic dogs or cats
that are known to have had one or more seizures within an eight week period. Treatment is not
routinely advised in animals with seizures that occur less frequently than once every eight weeks, as
owners of such animals often do not follow instructions diligently and may treat animals only
intermittently. Certain owners, however, are so distressed by seizures that occur in their pet that they
are willing to medicate an animal daily despite a history of infrequent seizures.
In animals that have had only one seizure, institution of therapy may be delayed. Such a delay may
permit the seizure interval to become apparent, thereby providing a basis for a decision regarding the
need for therapy and also for an assessment of the efficacy of therapy once it is initiated.
Exceptions to these recommendations are made for animals that have seizures in clusters or
episodes of status epilepticus even though the interval between clusters may be greater than eight
weeks. The seizure episodes have a tendency to become more frequent and severe in such animals
when control is not attempted.
When seizures have not occurred in a dog or cat for a period of 6-12 months, a cautious reduction of
dosage may be attempted. Such a reduction must be done slowly. In rare instances, a dog or cat
may remain free of seizures after withdrawal of drug therapy.
There are few alternatives to the use of pharmacological agents in the control of seizures.
Acupuncture, either as a sole therapy or in conjunction with conventional anticonvulsant therapy, has
9
been recommended by several authors. Results of these reports are encouraging, and it is likely that
acupuncture will be used with increasing frequency as an adjunctive therapy to conventional
anticonvulsant therapy in dogs in the future.
Selection of an Anticonvulsant Medication
The efficacy of an anticonvulsant depends on its serum concentration, because this determines its
concentration in the brain. Therapeutic success can be achieved only when serum concentrations of
a given anticonvulsant are consistently maintained within a therapeutic range. Therefore,
anticonvulsants that are eliminated slowly must be employed. The elimination half-lives of the
various anticonvulsants differ considerably between different species. Few of the anticonvulsant
drugs used for the treatment of epilepsy in people are suitable for use in dogs and cats. This is
largely because of differences in pharmacokinetics of antiepileptic drugs in animals and in humans.
Some drugs are metabolised so rapidly that it is not possible to reach consistently high serum
concentrations, even with very high doses. For many drugs, pharmacokinetic data and/or clinical
experience is lacking in cats, which usually metabolise anticonvulsants more slowly than dogs.
10
SEIZURES:
WHAT TO DO WHEN PHENOBARBITAL FAILS?
Dr. Richard A. LeCouteur
Professor of Neurology & Neurosurgery
School of Veterinary Medicine
University of California
Davis CA 95616 USA
PHENOBARBITAL
Phenobarbital is a safe, effective, and inexpensive drug, suitable for long-term therapy
of seizures in dogs and cats. Phenobarbital may be considered a broad spectrum
anticonvulsant, in that it may be effective in many types of epileptic seizures observed
in cats and dogs. It is particularly effective in delaying the progressive intensification
of seizure activity that may accompany epilepsy. Clinical reports indicate that
phenobarbital is effective in controlling seizures in 60% to 80% of epileptic dogs,
provided serum concentrations of the drug are maintained within the recommended
therapeutic range (20 to 45 ug/ml).
Mechanism of action
The exact anticonvulsant mechanism of action of barbiturates is not completely
understood, although it is known that phenobarbital both increases the seizure
threshold required for seizure discharge, and decreases the spread of discharge to
surrounding neurons. Unlike other barbiturates (e.g., pentobarbital), phenobarbital
suppresses seizure activity at subhypnotic doses.
Four potential mechanisms of action are: 1) Increasing the activity of the inhibitory
neurotransmitter gamma aminobutyric acid (GABA) in the central nervous system
(CNS) at the post-synaptic membrane, hence increasing neuronal inhibition (by means
of an allosteric effect, barbiturates increase the affinity of GABA for its own receptor,
and as a result the chloride ion channel is open for a longer time, resulting in greater
chloride flux and enhanced neuronal inhibition); 2) barbiturates may also interact with
glutamate receptors to reduce neuronal excitotoxicity; 3) inhibition of voltage gaited
calcium channels; and 4) competitive binding of the picrotoxin site of the chloride
channel.
For the chronic treatment of seizures, dosing should begin at 3-5 mg/kg/day per os
divided BID or TID. In severely affected dogs with frequent, severe, or prolonged
seizures, it may be necessary to commence therapy at a higher initial dosage. In
some dogs or cats the starting dose may result in adverse effects. Should these
adverse effects not resolve after two weeks of therapy, a reduction in dose may be
indicated. Steady state serum phenobarbital concentrations may be determined after
three weeks of therapy. If a patient’s seizures are adequately controlled, then serum
concentrations may be determined again after three to six months, or more frequently,
should seizure activity resume at an unacceptable frequency. If a patient’s seizures
are not adequately controlled after three weeks of therapy, the dose of phenobarbital
may be increased by 25%, and serum concentrations should be determined again
after two weeks of therapy at this higher dose. This process should be continued until
the patient’s seizures are controlled, or until a patient fails phenobarbital therapy (i.e.
becomes refractory). Dogs or cats may be considered refractory to phenobarbital
therapy should seizure activity or unacceptable effects persist after plasma
concentrations reach 35 ug/ml.
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Doses of phenobarbital as high as 18-20 mg/kg/day per os divided BID or TID rarely
may be necessary to achieve seizure control in some patients, due to variations in
individual drug metabolism. Adverse effects are commonly observed at doses above
20 mg/kg/day.
Reductions in dosage should be made gradually as physical dependence to
phenobarbital may develop, and withdrawal seizures may occur as serum levels
decline. Therapy should not be discontinued suddenly, except in animals that develop
fulminant liver dysfunction. Use of phenobarbital should be avoided in animals with
hepatic dysfunction.
Phenobarbital may be administered intravenously for the treatment of toxic seizures or
status epilepticus, however a lag time of 20-30 minutes may be observed prior to
control of seizures. Phenobarbital may be given as a loading dose of 12 to 24 mg/kg
IV to achieve therapeutic plasma concentrations immediately. Phenobarbital may also
be given as a bolus (2 - 4 mg/kg intravenously every 30 minutes) until a cumulative
dose of 20 mg/kg has been given. The dose should be decreased proportionately if
the patient is currently receiving phenobarbital.
Pharmacokinetics
Phenobarbital is fairly rapidly absorbed after oral administration, although variation
exists between animals probably as a result of differences in tablet or capsule
dissolution. Bioavailability is high (86-96%) and peak plasma levels are achieved at 46 hours after administration. Although phenobarbital is widely distributed into tissues,
its lower lipid solubility means that it does not penetrate the CNS as rapidly as other
barbiturates. After intravenous injection, therapeutic concentrations are reached in the
CNS in 15-20 minutes. Administration of the drug with food reduces absorption by
about 10%. Phenobarbital is primarily metabolised in the liver with only 25% excreted
unchanged by the kidneys. Alkalinization of the urine will enhance elimination of
phenobarbital and its metabolites. Plasma protein binding is approximately 45%.
Reported elimination half-life of phenobarbital ranges from 30 to 90 hours in dogs and
from 3 to 83 hours in cats. The wide range of values is a result of several variables,
including the use of multiple drug doses in different studies, and more importantly,
whether the drug was given as a single dose, a short course of several doses, or
administered for a length of time. In addition drugs capable of stimulating drug
metabolising enzyme systems were included in some studies. In studies in cats, the
use of different populations of cats appeared to be a contributing factor in the reported
variability in elimination half-life.
In dogs, phenobarbital elimination half-life significantly decreases when the drug is
administered chronically (47.3 10.7 hours when administered for 90 days vs 88.7 19.6
hours in a single dose study). The degree of autoinduction of hepatic metabolism of
the drug that occurs may be dose dependent. Phenobarbital increases its own rate of
metabolism, and therefore the drug concentration of phenobarbital may be expected to
decrease in patients receiving long-term therapy, and a dose increase should be
anticipated in patients after three to six months. In contrast, a study in cats comparing
pharmacokinetics after single and multiple doses suggested that repeated
phenobarbital administration did not alter serum steady state concentrations, but that
large differences in phenobarbital elimination rates may exist between different
populations of cats.
In dogs the elimination half-life of phenobarbital is similar after oral or intravenous
administration. Steady state concentrations are achieved within 18 days of initiation of
therapy and therefore dosage adjustments should not be made until three weeks after
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treatment has commenced, or been altered. The metabolism of phenobarbital is quite
variable in dogs and similar oral dosage regimes can result in up to a six fold
difference in peak serum concentrations. Beagles are reported to metabolise
phenobarbital more quickly (32 hour elimination half-life) than cross-bred dogs.
Clinical observations suggest that phenobarbital elimination half-life may be shorter in
puppies.
Since there may be extreme variations between the oral dosage of phenobarbital
administered and the serum concentration of drug achieved, it is recommended that
serum drug levels should be measured and used as a guide to alterations in drug
therapy. Therapeutic serum phenobarbital concentrations for dogs and cats are
estimated to be 15-45 &g/ml and 10-30 ug/ml respectively. Although monitoring of
serum drug levels may be used as a guide to alterations in drug therapy, such
monitoring is not a substitute for clinical judgement. Expected therapeutic serum drug
levels are average values, and each animal will have an individual optimal value. In
dogs this therapeutic range has been demonstrated to be achievable with a dose of
5.5 - 11 mg/kg/day. Due to the longer elimination half-life of phenobarbital in cats, a
once daily dose of 2.5 mg/kg may be appropriate.
Although pharmacokinetic studies in both cats and dogs suggest that once daily
dosing should be adequate to maintain appropriate serum concentrations, twice or
even three times a day dosing is usually recommended to decrease the fluctuations in
serum drug levels and minimise adverse effects. In measuring serum drug levels it
has been recommended that blood be collected at a similar time in the daily
administration cycle of phenobarbital. A blood sample should be collected within one
hour before the next scheduled drug administration time (so called trough levels). In a
recent study, epileptic dogs receiving chronic phenobarbital therapy were shown to
have minimal variations in serum phenobarbital concentrations throughout the day.
Should other studies confirm these results, it may be acceptable to measure
phenobarbital blood levels anytime during the day in chronically treated dogs.
In dogs that have an unacceptable level of seizure control, serum phenobarbital
concentrations should be maintained between 30 to 40 ug/ml for 1-2 months before
the maximal effects of the drug may be fully assessed. After this time should
frequency and/or severity of the seizures remain unacceptable, additional or
alternative anticonvulsant medications should be considered. Serum separation tubes
have been shown to falsely reduce drug concentrations, and should be avoided for
therapeutic drug monitoring.
Methylphenobarbital is available in several countries. It requires hepatic demethylation
for activation. Dosage recommendations are usually similar to those recommended
for phenobarbital. However, it is possible that serum concentrations of the active
constituent, phenobarbital, may not be as high at equivalent milligram doses of
phenobarbital.
Adverse effects
Adverse effects that may be observed initially with phenobarbital therapy include
sedation, ataxia, polydipsia, polyuria, polyphagia and weight gain. Polyuria is due to
an inhibitory effect on the release of antidiuretic hormone. Polyphagia is believed to
be due to suppression of the satiety center in the hypothalamus. Most dogs develop a
tolerance to these effects after two to four weeks of therapy. Unless sedation is
extreme or persistent beyond four weeks, it should not be considered evidence of
toxicity and does not warrant an adjustment in the dose. Sedation at the initiation of
therapy has been reported to be more severe in cats. Occasionally, a dog may appear
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hyperactive during the initial phase of therapy, however this effect usually may be
overcome by increasing the dose.
Although there have been reports of hepatotoxicity in dogs associated with chronic
phenobarbital treatment, the reported incidence is extremely low. Hepatotoxicity has
not been reported in cats. The incidence of liver toxicity may be reduced significantly
in both species by avoiding combination therapy (i.e. use of more than one drug
metabolised by the liver), by using therapeutic monitoring to achieve adequate serum
concentrations at the lowest possible dosage, and by evaluating clinical pathology
alterations every six months while an animal is receiving phenobarbital. Induction of
liver enzymes will commonly occur in dogs, and elevations of ALT, ALP and GGT are
frequently present in association with phenobarbital therapy. In one study, serum
albumin concentrations were demonstrated to decrease initially, but then increased
back to pretreatment levels in most patients. The significance of hypoalbuminaemia
without other indications of hepatic dysfunction is unknown at this time. Enzyme
elevations do not imply hepatic damage or dysfunction, although if ALT is
disproportionately elevated in comparison to ALP, phenobarbital toxicity is possible.
Phenobarbital does not induce elevations in ALP in cats. If there is doubt about
whether hepatic dysfunction is present in an animal receiving anticonvulsant therapy,
measurement of serum bile acids is recommended, as these apparently are not
increased by anticonvulsant therapy.
Blood dyscrasias such as neutropaenia, thrombocytopaenia , anaemia and in some
cases, pancytopaenia have been reported in dogs receiving phenobarbital. These
adverse effects appear to be idiosyncratic or allergic, and resolve once the drug is
discontinued. Phenobarbital may increase the metabolism of thyroid hormones in liver
and peripheral tissues, and may also adversely impact thyroid stimulating hormone
concentrations.
Regular monitoring of animals receiving anticonvulsants by a veterinarian is important
to reduce the potential adverse effects of the drug. Animals receiving phenobarbital
should be examined at least once every six months. A complete blood count, serum
chemistry panel, urinalysis and serum phenobarbital concentration should be
completed at least annually, and ideally more frequently. It is recommended that
blood levels of phenobarbital be maintained at 35 ug/ml and below to reduce
hepatotoxicity.
Drug interactions
Hepatic microsomal P-450 enzyme activity is accelerated by phenobarbital. This
dose-related effect may enhance the biotransformation of other drugs such as digoxin,
glucocorticoids, phenylbutazone and certain anaesthetic drugs. As a result, the
therapeutic efficacy of these drugs may be reduced in patients also receiving
phenobarbital.
In contrast, drugs that inhibit hepatic microsomal enzymes may inhibit phenobarbital
metabolism and cause toxicity. Several cases of chloramphenicol-induced
phenobarbital toxicity in dogs have been documented. Although to the authors'
knowledge clinical toxicity has not been documented in dogs receiving phenobarbital
concurrently with cimetidine or valproic acid, the combination is best avoided.
Phenobarbital may impair the absorption of griseofulvin, and therefore reduce blood
levels and efficacy of this antifungal agent.
Chronic phenobarbital treatment has been reported to influence the results of ACTH
response tests, suggesting that this test should not be used to screen for
hyperadrenocorticism in dogs receiving phenobarbital. Although plasma ACTH levels
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are reported to be unchanged, not all studies have confirmed this observation.
Similarly, dexamethasone suppression tests may also be influenced in some, but not
all, dogs chronically treated with phenobarbital.
Total and free serum thyroxine concentrations have been reported to be significantly
reduced in dogs receiving phenobarbital.
BROMIDE
Bromide is a halide element, discovered in 1826 by Balard, and first reported for use
as an anticonvulsant in people by Sir Charles Locock in 1857. Until 1912 when
phenobarbital was introduced, bromide was the only effective anticonvulsant available.
There are reports of the use of bromide in dogs as early as 1907, but it was not until
1986 that interest in its use clinically to control seizures was reported. Until recently,
bromide was used only as an adjunct to phenobarbital therapy for the management of
dogs with refractory epilepsy. More recently, its use as a sole anticonvulsant therapy
in epileptic dogs has been recommended by some neurologists, particularly in dogs
with hepatic dysfunction. Although bromide is an effective anticonvulsant, it is not
approved for use for medical purposes in any species.
Dosage and formulations
Bromide is available as a potassium or a sodium salt. Bromide may be formulated as
a 200 mg/ml or 250 mg/ml solution of reagent grade potassium bromide in syrup or
distilled water. Potassium bromide is available in tablet form in some countries.
Alternatively, the powder may be placed in gelatin capsules. In solution in distilled
water, bromide has been found to be stable for more than one year at room
temperature or refrigerated, and in glass, plastic, clear or brown containers.
Information concerning stability of bromide in solution in syrup is not available,
however current recommendations include keeping the solution refrigerated, and
discarding it after three months.
Bromide may also be administered as the sodium salt to dogs that dislike the taste of
potassium or cannot tolerate it (e.g., due to hypoadrenocortism). Sodium bromide
should not be used in dogs with congestive heart failure, hypertension or liver disease.
The dose of sodium bromide should be reduced by 15% to account for the higher
bromide content per gram (KBr = 67% bromide, NaBr = 78% bromide).
The primary indication for bromide has been in combination with phenobarbital in
refractory epileptics or in patients that have developed liver disease. Bromide is also
the drug best suited for use by noncompliant owners because of its long half-life.
Bromide may also be used as the sole drug in patients whose seizure history is limited
to mild seizure activity.
Because reaching a steady state may require two to three months, a loading dose is
recommended to achieve therapeutic concentrations more rapidly. The maintenance
dose is designed to maintain concentrations achieved after loading. Alternatively the
maintenance dose may be given without a loading dose to allow more gradual
accommodation to effective serum concentrations.
The appropriate dose of bromide depends on concurrent anticonvulsants, diet, and
renal function. The maintenance dose of potassium bromide as a first line
anticonvulsant is 20-40 mg/kg/day PO once daily or in divided doses in both dogs and
cats. Steady state concentrations are not achieved for two to three months in dogs.
Steady state concentrations in dogs following administration of 30 mg/kg per day are
about 0.8 to 1.2 mg/ml. When used in conjunction with other anticonvulsants, the
15
recommended dose is 22-30 mg/kg PO once daily or divided. The author’s protocol
for a loading dose of potassium bromide is 400-600 mg/kg divided into four doses,
given over 24 hours.
Distribution of bromide is to the extracellular space. Bromide is eliminated slowly
(perhaps due to marked reabsorption) in the kidney. Its rate of elimination can change
with salt administration. Increased dietary salt will increase the rate of elimination of
bromide, and decreased dietary salt will result in the opposite effect.
The elimination of bromide in cats appears to be faster than that in dogs, with a mean
half-life of approximately six weeks. Following administration of 30 mg/kg orally for
eight weeks, mean bromide concentrations were 1.2 mg/ml at steady state. Cats
developed no adverse effects to bromide administration in one report.
Serum bromide concentrations may be determined one month after a maintenance
dose is instituted, regardless of whether a loading dose was given. This approach will
enable modification prior to steady state and prior to therapeutic failure or signs of
adverse reactions. Recommended target ranges are controversial and depend on
whether phenobarbital is being given concurrently. Most laboratories use 1-3 mg/ml
regardless of whether bromide is being given as a sole agent or in combination with
phenobarbital.
Mechanism of action
The exact mechanisms of anticonvulsant action of bromide are incompletely
understood. The action appears to involve chloride ion channels. These channels are
an important part of the inhibitory neuronal network of the CNS. Their function is
modulated by GABA, the most important inhibitory neurotransmitter in the mammalian
CNS. Increased chloride ion flow as a result of activation of GABA receptors by
barbiturates, or benzodiazepines results in increased neuronal inhibition and increases
the threshold for seizures. Bromide appears to cross neuronal chloride channels more
readily than chloride because it has a smaller hydrated diameter. It is therefore
believed that bromide, by competing with chloride ions, hyperpolarises post-synaptic
neuronal membranes and facilitates the action of inhibitory neurotransmitters.
Barbiturates may act synergistically with bromide to raise the seizure threshold by
enhancing chloride conductance via GABA-ergic activity.
Pharmacokinetics
The pharmacokinetics of bromide have not been well established. Bromide is
absorbed from the small intestine with peak absorption achieved 1.5 hours after oral
administration. It is not protein bound or metabolised and does not undergo hepatic
metabolism. Therefore bromide does not affect hepatic enzymes and is a useful
anticonvulsant for dogs with hepatic disease. Elimination of bromide from the body is
via the kidneys.
Although bromide replaces chloride throughout the body, the sum of these two halides
remains constant. Lower concentrations of bromide are found in the brain than would
be expected based on the chloride concentration, as it appears there is a barrier to the
free passage of bromide. However, the concentration of bromide in the brain of dogs
is higher than that found in humans. In humans after bromide treatment the CSF to
serum ratio is 31% whereas in dogs the ratio is 87%. As a result, seizure control may
be achieved in dogs at a lower serum bromide concentration than in humans, and the
potential for toxicity is much reduced.
The half-life of bromide is longer in dogs than in humans (24.9 vs 12 days). Two to
three weeks of therapy are required before serum bromide levels enter the therapeutic
16
range, and steady state levels are achieved in four months. Higher serum
concentrations are required if dogs are treated with bromide alone as compared to
dogs treated with bromide and phenobarbital. The therapeutic range for potassium
bromide when administered with phenobarbital is 0.8-2.4 mg/ml and 0.8 - 3.0 mg/ml
when it is used alone.
Adverse effects
Clinical signs of bromide toxicity appear to be dose dependent, and include
polyphagia, vomiting, anorexia, constipation, pruritis, muscle pain, sedation, and pelvic
limb weakness. Ataxia and sedation have been reported to be the major dose limiting
side effects in dogs. Other infrequently reported adverse effects include pancreatitis,
increased attention seeking, aggression, coprophagia and hyperactivity. High dose
bromide therapy has been associated with thyroid disfunction in people and rats.
Bromide toxicity has been reported in a dog with renal insufficiency, which resulted in
decreased clearance of bromide and therefore higher plasma levels. Reduced
efficacy of the drug has been reported in a dog fed a high chloride diet. Toxic
concentrations of bromide may be reached rapidly when chloride intake is decreased.
Bromide readily crosses the placenta is people, and there are a few reports of
neonatal bromism. Due the lack of information in dogs, bromide should be avoided in
breeding animals.
Drug interactions
Because bromide is not protein bound and not metabolized, it does not interact with
many drugs. However, chloride containing foods, food supplements, fluids, drugs, and
loop diuretics may enhance bromide elimination and lower serum bromide
concentrations. Bromide is a product of halothane metabolism in dogs, and therefore
small increases in serum bromide may be apparent after halothane anaesthesia. In
people, bromide administration has be reported to be associated with increased
visualisation of cerebral vessels with non-contrast computed tomography.
Pseudohyperchloraemia occurs with bromide administration as bromide ions interfere
with colourimetric and automated ion-specific electrolyte analysers used to measure
chloride. Treatment of bromide toxicity includes chloride loading (intravenous sodium
chloride) to increase bromide elimination.
Table 1: Recommended Anticonvulsant Drug Dosages
DRUG
RECOMMENDED DOSES
Phenobarbital
Dogs: 2 - 5 mg/kg divided BID (up to 18 - 20 mg/kg BID if
necessary)
Cats: 0.5 - 1.5 mg/kg divided BID
Potassium bromide
Dogs and Cats: 20 - 40 mg/kg PO SID or divided BID
Dogs: Loading dose 400-600 mg/kg divided into four doses, given
over 24 hours.
Sodium Bromide
Dogs: 20-40 mg/kg PO SID, reduce by 15%
Dogs: 1200-1500 mg/kg over 24 hours as a continuous rate
infusion of 3% NaBR in D5W.
17
Phenobarbital Resistant Epilepsy
Using multiple anti-convulsant drugs has several potential disadvantages, including the
increased cost, the need to monitor and to interpret serum concentrations of multiple drugs,
potential drug interactions, and more complicated dosing schedules. Indications for such
'polytherapy' include failure of diligent monotherapy and the treatment of cluster seizures.
Before polytherapy is started, all reasonable options for monotherapy should be tried. If the
initial drug is ineffective, a second drug should be added. If the dog responds, the veterinarian
should attempt to withdraw the first drug gradually and continue with polytherapy if this is
unsuccessful.
Factors to consider when choosing an add-on medication include 1) mechanism of action,
with preference given to drugs with a differing mechanism, 2) side effects, 3) the potential for
drug interactions among antiepileptic drugs, 4) the required frequency of administration, which
in turn may influence compliance, and 5) the cost.
Potassium Bromide (KBr)
Potassium bromide has no known hepatic toxicity and all the adverse effects of KBr are
completely reversible once the drug is discontinued. Potassium bromide is excreted
unchanged in the urine and is not metabolised by the liver. There have been no liver enzyme
alterations or thyroid axis effects after administration of this drug. KBr controls approximately
70-80% of the epileptic dogs it is used to treat and is often effective in dogs that fail
phenobarbital therapy. When high dose KBr and low dose PB are used together,
approximately 95% of epileptic dogs can be controlled.
Where do you turn when an epileptic dog responds poorly to PB and/or KBr?
Management of refractory epilepsy presents a considerable challenge to veterinary
practitioners and pet owners. Appropriate therapy and monitoring should be used to optimise
treatment results. Ongoing patient follow-up is critical. With the approval of several new
antiepileptic drugs for the management of human epilepsy over the last two decades, the
treatment options available for dogs and cats have increased. Although information on the use
of these novel antiepileptic drugs in animals is lacking, studies and clinical experience
available to date suggest that they have the potential to improve seizure control and minimise
adverse effects. Continued evaluation of these drugs in veterinary patients should provide
additional details on their use in managing canine epilepsy. Aspects of these new
antiepileptic drugs have been summarised by Munana.1
Newer anticonvulsant drugs to consider include:
Felbamate
Gabapentin
Pregabalin
Zonisamide
Levetiracetam
Efficacy of new anticonvulsant drugs
When recommending a novel treatment, it is helpful if you can provide information on the
expected effectiveness of the treatment, especially when the treatment involves a
considerable investment of time or money on the pet owner's part. Unfortunately, extensive
data of this nature are not available for the use of the new antiepileptic drugs in canine or
feline epilepsy. Rather, information on drug use has been obtained by administering the new
antiepileptic drug in an open-label fashion: Dogs with poorly controlled seizures were given a
new antiepileptic drug, and seizure frequency during administration of the new drug was
compared with seizure frequency before the new drug was initiated. Because the studies were
not placebo-controlled, the information obtained regarding drug efficacy may be inaccurate.
This has been called the placebo effect.
18
From the information available to date, a veterinarian can recommend a trial with a new
antiepileptic drug, but, no representation should be made with respect to efficacy. As
experience with these drugs grows in veterinary medicine and more research is performed on
their applicability to dogs and cats, additional information will become available to further
guide recommendations on their use.
Factors to consider when choosing an add-on medication include:
1. Mechanism of action, with preference given to drugs with a differing
mechanism,
2. Adverse effects,
3. Potential for drug interactions among antiepileptic drugs,
4. Required frequency of administration, which in turn may influence compliance,
and,
5. Cost.
New antiepileptic drugs approved for use in people that may be considered for extralabel use in dogs are summarised in Table 1.1
Levetiracetam
Levetiracetam is one of the more recently approved human antiepileptic drugs. Points
of interest regarding levetiracetam are as follows:
1. levetiracetam has a unique mechanism of action, which is a potential
advantage when the drug is used in combination with other antiepileptic drugs,
2. Levetiracetam has minimal hepatic metabolism in dogs, with more than 80% of
the drug excreted in the urine,
3. The half-life in dogs is three to four hours, which necessitates frequent
administration,
4. The recommended oral dose is 20 mg/kg every eight hours.
A recent study2 evaluated levetiracetam as an add-on medication in dogs with
idiopathic epilepsy that was refractory to phenobarbital and potassium bromide. Nine
of 14 dogs responded, and the only adverse effect was sedation (observed in one
dog).
The main factor limiting the use of levetiracetam in dogs has been its expense,
although a generic form of this drug recently has become available.
Levetiracetam also is available in a parenteral formulation. Levetiracetam may prove
useful in treating cluster seizures and status epilepticus in dogs, with the option of
administering the drug intramuscularly if venous access cannot be obtained. The
disposition of levetiracetam has been evaluated in six dogs after intravenous and
intramuscular administration.3 A dose of 20 mg/kg IV resulted in desirable serum
concentrations in a short period; with intramuscular administration, peak
concentrations were reached in 40 minutes.
Felbamate
Felbamate was the first of the newer antiepileptic drugs to be approved in the United
States for epilepsy in people. Side effects of aplastic anemia and hepatotoxicosis
have since been reported in people, so its use has declined.
Points of interest regarding felbamate are as follows:
1. The half-life of felbamate in dogs is five to eight hours,
19
2. The recommended oral dosage is 15 to 60 mg/kg every eight hours.
3. Treatment should be initiated at the low end of the dosage range, and the
dosage should be increased as needed to control seizures.
4. Felbamate serum concentrations are not routinely monitored, as is the case for
many of the newer antiepileptic drugs. Rather, the drug is used to effect, and
dosage adjustments are based on seizure frequency and side effects,
5. Felbamate is mostly excreted in the urine in dogs, although some hepatic
metabolism occurs, increasing the potential for drug interactions when
phenobarbital and felbamate are administered concurrently.
Felbamate is used infrequently in veterinary patients because of the potential for
adverse effects and drug interactions, and because of the expense. It is
recommended that complete blood counts and liver enzyme activities be measured
every two or three months during treatment to assess for adverse effects.
Felbamate was evaluated as a sole antiepileptic drug in six dogs with partial onset
seizures.4 Dosages ranged from 60 to 220 mg/kg/day, and all dogs showed reduced
seizure frequency. Two dogs developed blood dyscrasias, characterised by
thrombocytopenia, lymphopenia, and leukopenia, which resolved after the drug was
discontinued. One dog developed keratoconjunctivitis sicca, although it was not
determined that this problem was drug-related.
The use of felbamate as an add-on therapy has been reported in 16 dogs refractory to
phenobarbital and potassium bromide.5 Twelve dogs had improved seizure control, but
four of these dogs developed signs of liver dysfunction. Other side effects anecdotally
reported in dogs receiving felbamate in combination with phenobarbital include
sedation, nausea, and vomiting.6
Gabapentin
Gabapentin was approved in the United States for use in people as an antiepileptic
drug shortly after felbamate. Since its introduction, gabapentin has also been
approved to treat neuropathic pain. In people, gabapentin is eliminated entirely by the
kidneys.
1. In dogs gabapentin undergoes partial hepatic metabolism,
2. The elimination half-life in dogs is two to four hours, requiring frequent drug
administration to achieve steady-state concentrations,
3. The recommended oral dosage is 10 to 20 mg/kg every six to eight hours.
Two studies have examined the use of gabapentin in refractory canine epilepsy. The
first study involved 11 dogs administered gabapentin (10 mg/kg t.i.d.) in addition to
phenobarbital and potassium bromide.7 A positive response to gabapentin, defined as
≥ 50% reduction in seizure frequency, was reported in six of the 11 dogs. The second
study evaluated 17 dogs with refractory seizures that were administered gabapentin at
a dose of 35 to 50 mg/kg/day divided twice or three times daily, also in conjunction
with phenobarbital and potassium bromide (16 dogs) or phenobarbital alone (1 dog).8
This study found no significant decrease in the number of seizures over the study
period for the entire population of dogs. However, seizures resolved in three dogs
while they were receiving the medication. The adverse effects reported in both studies
were sedation and ataxia.
The availability of a generic form of gabapentin has made it affordable relative to other
antiepileptic drugs used in veterinary medicine.
20
A liquid formulation (50 mg/ml) of gabapentin exists, which facilitates the
administration of lower doses to smaller patients. However, the liquid product contains
300 mg xylitol/ml, so it has the potential of causing adverse effects associated with the
ingestion of this sugar alcohol.9
Pregabalin
Pregabalin is a newer-generation drug in the same class as gabapentin. Limited
information exists on its use in dogs for the treatment for epilepsy. Based on
pharmacokinetic data in normal dogs, a dose of 2 to 4 mg/kg orally every eight hours
has been recommended and was administered to six dogs with idiopathic epilepsy
refractory to treatment with phenobarbital, potassium bromide, or both drugs.10 One
dog was considered a drug failure, and four of the five remaining dogs had a mean
seizure reduction of 59.3%. Five dogs exhibited side effects (sedation and ataxia)
attributed to pregabalin.
Zonisamide
Zonisamide is a sulfonamide-derived antiepileptic drug introduced in the United States
in 2000.
Points of interest are as follows:
1. The half-life of zonisamide in dogs is 15 to 20 hours, which is relatively long
when compared with the other new antiepileptic drugs,
2. Zonisamide requires only twice-daily administration
3. Most of the drug is excreted unchanged by the kidneys, although some hepatic
metabolism occurs,
4. The dosage in dogs is 5 to 10 mg/kg given orally every 12 hours. The high end
of the dose range is recommended when the drug is used in combination with
phenobarbital since phenobarbital appears to facilitate zonisamide clearance.11
For this reason, it may also be helpful to measure serum zonisamide
concentrations in dogs being treated concurrently with Phenobarbital,
5. A therapeutic range of 10 to 40 μg/ml has been suggested,12 which is similar to
the therapeutic range in people,
6. Zonisamide is a known teratogen in dogs, so its use should be avoided in
pregnant animals.
A generic form of zonisamide is available, which has reduced the cost considerably
since its introduction.
Two recent reports on zonisamide as add-on therapy in dogs with refractory epilepsy
demonstrated a favorable response in seven of 12, and nine of 11 dogs,
respectively.13,14 Reported side effects included sedation, ataxia, and loss of appetite.
Efficacy of new antiepileptic drugs – The placebo effect15
Extensive data are not available regarding the effectiveness of treatment of the new
antiepileptic drugs in canine epilepsy. Rather, the information on drug use described
above was obtained by administering the new antiepileptic drug in an open-label
fashion: Dogs with poorly controlled seizures were given a new antiepileptic drug, and
seizure frequency during administration of the new drug was compared with seizure
frequency before the new drug was initiated. Because the studies were not placebocontrolled, the information obtained regarding drug efficacy may be inaccurate.
A reduction in seizure frequency during placebo administration has been documented
in people with epilepsy,15 and, a similar phenomenon may occur in dogs. One likely
cause for this placebo effect is regression to the mean, which is a statistical term used
21
to describe the fluctuations that occur in biological variables over time and take the
form of a sine wave around the mean. Epilepsy is a waxing and waning disorder, and
fluctuations in seizure frequency are common over the course of the disease. Clients
are most likely to seek a change in therapy for their pets when seizures are poorly
controlled. Over time, improvement in the seizure frequency is probable, regardless of
the treatment administered. However, this improvement may be erroneously attributed
to a recently instituted change in therapy. Open-label studies cannot account for this
bias, and, consequently, the efficacy reported in such studies may be falsely elevated.
Thus, from the information available to date, a veterinarian may recommend a trial with
a new antiepileptic drug, but should not make any representation with respect to
efficacy. As experience with these drugs grows in veterinary medicine and more
research is performed on their applicability to dogs, additional information will become
available to further guide recommendations on their use.
Conclusion
The management of refractory seizures can pose a considerable challenge to
practitioners and pet owners. Ongoing patient follow-up is critical, and directed,
appropriate therapy and monitoring should be used to optimize treatment results. With
the approval of several new antiepileptic drugs for the management of human epilepsy
over the last two decades, the treatment options available for our canine patients have
also increased. Although our knowledge is still somewhat limited on these novel
antiepileptic drugs, studies and clinical experience available to date suggest that they
have the potential to improve seizure control and minimize adverse effects in affected
dogs. Continued evaluation of these drugs in veterinary patients should provide
additional details on how to use these therapies most effectively in managing canine
epilepsy.
References
1. Munana KR. Newer options for medically managing refractory canine epilepsy.
http://veterinarymedicine.dvm360.com/vetmed/ArticleStandard/Article/detail/608398
2. Volk HA, Matiasek LA, Reliu-Pascual AL, et al. The efficacy and tolerability of
levetiracetam in pharmacoresistant epileptic dogs. Vet J 2008;176(3):310-319.
3. Patterson EE, Goel V, Cloyd JC, et al. Intramuscular, intravenous and oral
levetiracetam in dogs: safety and pharmacokinetics. J Vet Pharmacol Ther
2008;31(3):253-258.
4. Ruehlmann D, Podell M, March P. Treatment of partial seizures and seizure-like
activity with felbamate in six dogs. J Small Anim Pract 2001;42(8):403-408.
5. Boothe DM. Anticonvulsant therapy in small animals. Vet Clin North Am Small Anim
Pract 1998;28(2):411-448.
6. Dayrell Hart B, Tiches D, Vite C, et al. Efficacy and safety of felbamate as an
anticonvulsant in dogs with refractory seizures (abst). J Vet Intern Med 1996;10:174
7. Platt SR, Adams V, Garosi LS, et al. Treatment with gabapentin of 11 dogs with
refractory idiopathic epilepsy. Vet Rec 2006;159(26):881-884.
8. Govendir M, Perkins M, Malik R. Improving seizure control in dogs with refractory
epilepsy using gabapentin as an adjunctive agent. Aust Vet J 2005;83(10):602-608.
9. Dunayer EK, Gwaltney-Brant SM. Acute hepatic failure and coagulopathy
associated with xylitol ingestion in eight dogs. J Am Vet Med Assoc 2006;229(7):11131117.
10. Dewey CW, Cerda-Gonzalez S, Levine JM, et al. Pregabalin therapy for refractory
idiopathic epilepsy in dogs (abst). J Vet Intern Med 2008;22:765.
11. Orito K, Saito M, Fukunaga K, et al. Pharmacokinetics of zonisamide and drug
interaction with phenobarbital in dogs. J Vet Pharmacol Ther 2008;31(3):259-264.
22
12. Dewey CW, Guiliano R, Boothe DM, et al. Zonisamide therapy for refractory
idiopathic epilepsy in dogs. J Am Anim Hosp Assoc 2004;40(4):285-291.
13. von Klopmann T, Rambeck B, Tipold A. Prospective study of zonisamide therapy
for refractory idiopathic epilepsy in dogs. J Small Anim Pract 2007;48(3):134-138.
14. Burneo JG, Montori VM, Faught E. Magnitude of the placebo effect in randomised
trials of antiepileptic agents. Epilepsy Behav 2002;3(6):532-534.
15. Munana KR, Zhang D, Patterson EE. Placebo effect in canine epilepsy trials. J Vet
Intern Med 2010; 24:166-170.
Table 1 . Characteristics of new anticonvulsant drugs used to treat canine
epilepsy1
Drug
Dosage
Mechanism of
Action
Time to reach
Hepatic
steady state
Metabolism
concentrations
Adverse
Effects
Levetiracetam
20
mg/kg
PO t.i.d.
Binds to
synaptic vesicle
protein,
modulating
release of
neurotransmitter
15-20 hours
No
Sedation,
ataxia
Felbamate
15-60
mg/kg
PO t.i.d.
Inhibits
glutamine by
blocking
calcium
channels;
Potentiates
GABA
25-40 hours
Yes
Sedation,
ataxia,
blood
dyscrasias,
vomiting,
hepatic
disease
Gabapentin
10-20
mg/kg
PO t.i.d.
to q.i.d.
Inhibits voltagegated calcium
channels
10-20 hours
Partial
Sedation,
ataxia
Pregabalin
2-4
mg/kg
PO t.i.d.
Inhibits voltagegated calcium
channels
30-40 hours
Partial
Sedation.
ataxia
Zonisamide
5-10
mg/kg
PO
b.i.d.
Inhibits voltagegated calcium &
sodium
channels
15-20 hours
Yes
Sedataion,
ataxia,
vomiting,
appetite
loss
23
INFLAMMATORY BRAIN DISEASES
“YOU, ME, AND GME”
Dr. Richard A. LeCouteur
Professor of Neurology & Neurosurgery
School of Veterinary Medicine
University of California
Davis CA 95616 USA
Definition
• Inflammatory central nervous system (CNS) diseases are a group of sporadic
inflammatory diseases that affect the brain and/or spinal cord of dogs in the
absence of an infectious cause (ie, pathogen-free).
• Based on histopathological findings, 3 distinct forms of inflammatory CNS disease
have been identified in dogs:
1. Granulomatous meningoencephalomyelitis (GME): Canine GME is the current
term for an idiopathic CNS disease (most likely first described in 1936). GME
still attracts a confusing and lengthy number of synonyms reflecting changes
only in immunologic terminology (eg, inflammatory reticulosis, lymphoreticulosis, neoplastic reticulosis).
2. Necrotizing meningoencephalitis (NME): Canine NME was originally
recognized in dogs in the U.S. in the 1970’s as a breed-specific disease of pug
dogs (colloquially known as “pug dog encephalitis”). Since 1989, based on
morphologically defined lesion patterns and histology, NME has been
recognized in other small-breed dogs, including Maltese, Chihuahua, Pekinese,
Boston terrier, Shih Tzu, Coton de Tulear, and Papillon.
3. Necrotizing encephalitis (NE): Canine NE was first described in 1993 in
Yorkshire terriers and has been reported in other breeds, including French
bulldogs.
Signalment
• GME affects dogs older than 6 months of age, and is most prevalent in dogs
between 4 and 8 years of age.
• Onset of NME is 6 months to 7 years of age, with a mean age of 29 months.
• NE typically manifests between 4 months and 10 years of age, with 4.5 years as a
mean onset age.
Breed & Gender Predilection
• GME affects all sizes and breeds of dog (with toy and terrier breeds overrepresented), whereas NME and NE affect predominantly small-breed dogs.
• Both males and females are affected, although females may be at higher risk of
developing the disease.
Causes
• Obscure, although an autoimmune or immune-mediated/immune-dysregulatory
cause is suspected.
• PCR-based screening for viral DNA (eg, herpes, adeno- or parvoviruses ) has
been negative.
Pathophysiology
Suggested possible mechanisms include autoimmune encephalitis induced by anti-GFAP (glial
fibrillary acidic protein) antibodies in CSF and T-cell-mediated delayed hypersensitivity
mechanisms.
24
Clinical Signs
• Signs of neurologic dysfunction reflect the location of the lesion(s) within the CNS.
• Multifocal involvement of the cerebrum, brainstem, cerebellum, and spinal cord
(GME only) is common.
• Clinical signs of GME may include visual disturbances (ie, the ophthalmic form of
GME affects the optic nerve), cranial nerve deficits (particularly central vestibular
signs), seizures, apparent cervical pain, ataxia, and paresis.
• NME and NE frequently affect the forebrain, resulting in abnormal mentation,
seizures, blindness, circling, and behavior changes, or brainstem, resulting in
cranial nerve deficits, changes in mentation, and difficulty walking.
Diagnosis
A tentative antemortem diagnosis may be based on analysis of a combination of
the patient’s signalment, history, clinical signs, neurological examination findings,
results of bloodwork, infectious disease titers, CSF analysis (including culture and
PCR analysis), and advanced imaging (CT and MRI). Neurological signs, results of
CSF analysis, and neuro-imaging findings will vary with intensity and location of
the pathological lesions.
• Definitive antemortem diagnosis is based on characteristic findings on
histopathology of brain and/or spinal cord tissue obtained by surgical biopsy.
• Definitive postmortem diagnosis is based on characteristic findings on
histopathology of brain and spinal cord.
Differential Diagnosis
• Other causes of focal and multifocal CNS dysfunction of dogs (see Table 1).
Laboratory findings
• CSF from dogs with inflammatory CNS disease usually is abnormal, although
normal CSF may be present (particularly should corticosteroids have been
administered up to 6 weeks prior to CSF collection).
• Typical findings consist of an elevated total nucleated cell count and an elevated
CSF protein. The predominant cell type is lymphocytes, with smaller numbers of
neutrophils and macrophages present (Figure 1).
• Infectious causes of the CSF abnormalities should be considered, and culture,
serological testing, electrophoresis or PCR analysis (of CSF and/or serum) for the
presence of infectious agents may be appropriate, although results of these tests
are unlikely to contribute to a diagnosis.
Imaging
• Characteristic findings on MRI include asymmetric, bilateral (often multifocal)
lesions in the forebrain, brainstem, and/or spinal cord (Figure 2). These lesions
variably enhance with intravenous contrast administration. Cystic areas may be
seen in areas of the brain that are necrotic.
• The classical lesions in GME, NME, and NE may be distinctly different based on
both distribution pattern and microscopic lesions. While this information may be
helpful in differentiating between the 3 forms of inflammatory CNS disease, it may
not be possible to differentiate GME, NME, and NE based on imaging
characteristics alone (except that spinal cord involvement is only present with
GME).
Postmortem findings
• A unique histopathological appearance is present in each of the inflammatory CNS
disorders.
25
•
•
•
GME is characterized by a unique angiocentric granulomatous encephalitis
consisting of a perivascular accumulation of macrophages often intermixed with
lymphocytes and plasma cells. Three major patterns of histologic lesion distribution
in brain and spinal cord have been described for GME:
1. The disseminated form, in which the most intense lesions occur in the upper
cervical spinal cord, brainstem, and midbrain, often with less severe extension
involving white matter of the rostral cerebrum (Figure 3A).
2. A disseminated form with angiocentric expansion forming multiple coalescing
mass lesions of similar distribution.
3. A focal form, in which single discrete mass lesions occur in either the spinal
cord, brainstem, midbrain, thalamus, optic nerves, or cerebral hemispheres,
without dissemination. It remains contentious whether this form is a neoplastic
rather than an immunoproliferative process.
NME has both a characteristic anatomic distribution pattern and unique histological
lesions. Gross lesions occur as asymmetrical, multifocal bilateral areas of either
acute encephalitis or chronic foci of malacia, necrosis, and collapse of hemispheric
gray and white matter decreasing in intensity rostrocaudally. Histologically, there is
a unique combination of focal meningitis and polio- and leukoencephalitis of
adjacent white matter. The lesions are intensely inflammatory with meningitis and
parenchymal histiocytic, microglial infiltrates accompanied by perivascular cuffing
of lymphocytes and plasma cells. Coexisting with chronic lesions can be acute
nonsuppurative encephalitis in the hippocampus, septal nuclei, and thalamus.
Usually, few inflammatory lesions are present in cerebellum, brainstem, and spinal
cord (Figure 3B).
In canine NE, grossly the large focal asymmetric bilateral malacic necrotizing
lesions are confined mostly to the white matter of the cerebral hemispheres. There
is an intense histiocytic, microglial and macrophage cellular infiltrate with loss of
white matter and thick perivascular lymphocytic cuffing. Other areas have acute
exudation, severe edema, necrosis, and eventual cyst formation, with a dramatic
gemistocytic astrogliosis, histiocytes, and gitter cells intermixed with thick
perivascular lymphocytic cuffing. Characteristically, the overlying cortex and
meninges are not involved. Multifocal intense inflammatory cell infiltrates of
macrophages with dramatically thick perivascular lymphocytic cuffing are seen in
the midbrain, brainstem, and cerebellum (Figure 3C).
Treatment
• Therapy is based on the use of immunomodulatory drugs at immunosuppressive
doses.
• The most common therapy utilized is corticosteroids. Dogs often have a favorable
response to corticosteroid monotherapy. Response to corticosteroids may be
temporary.
• Other immunomodulatory drugs may be used if the dog does not tolerate
corticosteroids, to reduce the dose of corticosteroids, or if there is inadequate
clinical response to corticosteroids. Many drugs have been recommended,
including cyclosporine, procarbazine, lomustine (CCNU), leflunomide,
mycophenolate mofetil (MMF), azathioprine, and cytosine arabinoside. All have
been used by different authors in relatively small numbers of patients. There is no
published evidence of the risks and benefits of these treatments when compared to
the use of immunosuppressive regimens of corticosteroids alone for the same
diseases. <Reviewer comment: Regarding the use of drugs such as cytosine
arabinoside, it seems that many feel that it may be very effective in acute
encephalititis in improving clinical signs when corticosteroids alone are
ineffective.>
26
•
The author recommends starting treatment with immunosuppressive doses of
prednisone, giving the patient 1.5 mg/kg BID for 3 weeks; then 1.0 mg/kg BID for 6
weeks; then 0.5 mg/kg BID for 3 weeks; then 0.5 mg/kg once daily for 3 weeks.
The patient then receives 0.5 mg/kg every other day indefinitely. After the first 4–6
weeks of prednisone therapy, cytosine arabinoside may be added at 3–6 week
intervals (administered as a subcutaneous injection at a dose of 50 mg/m2 Q 12 H
for 2 consecutive days).
Precautions
• Adverse effects of long-term high dose corticosteroid therapy include polyuria/polydipsia,
polyphagia, weight gain, hepatotoxicity, gastrointestinal ulceration, pancreatitis, and
iatrogenic hyperadrenocorticism.
• Adverse effects of cytosine arabinoside are dose dependent, and include
myelosuppression, vomiting, diarrhea, and hair loss.
Nutritional aspects
• Avoid weight gain associated with prolonged corticosteroid administration.
Activity
• Exercise restrictions are not recommended.
Client Education
• Clients should be informed that there is no definitive treatment for inflammatory
CNS diseases of dogs. Therapy is aimed at suppressing the dog’s immune system
for as long as possible.
• Prognosis is extremely guarded to poor.
Patient Monitoring
• Regular rechecks (suggested at monthly intervals or as needed) to assess
progress of disease and to assess adverse effects of medications.
• Repeat blood counts, chemistry panels, urinalysis, CSF analysis and advanced
imaging procedures may be necessary.
Complications
• Complications usually are related to adverse effects of immunomodulatory drugs.
Relative Cost
• Diagnosis and long-term management are costly due to need for specialized
diagnostic procedures, immunomodulatory drug maintenance, and repeated
assessments.
Prognosis
• Prognosis for dogs with inflammatory CNS disease is poor, and most affected dogs
eventually die from the disease, or are euthanized. Some survive only a short time, while
others have a more prolonged clinical course, from 6 months to, rarely, years.
Future considerations
• Research to date on canine inflammatory CNS diseases, and the nature of the
histopathologic lesions, suggests the likelihood of an autoimmune or immunemediated/immune-dysregulatory disease. In people, many autoimmune diseases
have strong associations with certain MHC genotypes and this information may be
used to assist in diagnosis or patient counseling. It is now possible to determine
the MHC haplotype of dogs, and some disease associations with MHC haplotype
27
in dogs already have been demonstrated. Assessment of MHC haplotype in dogs
with GME may help to determine if there is a genetic component to disease
susceptibility and development.
References
1. Clinical findings and treatment of non-infectious meningoencephalomyelitis in
dogs: A systematic review of 457 published cases from 1962 to 2008. Granger N,
Smith PM, Jeffery ND. Vet J 184(3):290-7, 2010.
2. Idiopathic granulomatous and necrotizing inflammatory disorders of the canine
central nervous system: A review and future perspectives. Talarico LR, Schatzberg
SJ. J Small Anim Pract 51(3):138-49, 2010.
3. Dog leukocyte antigen class II association in Chihuahuas with necritotizing
meningoencephalitis. Vernau KM, Liu H, Higgins RJ, et al. J Vet Intern Med
24(3):736, 2010.
Figure 1. Cytofuge smear of CSF from a 5-year-old spayed female Maltese. Total
nucleated cell count was 1,057/mcL (reference range: <3/mcL) with 1% neutrophils,
93% small mononuclear cells, and 6% large mononuclear cells. Protein content was
576 mg/dL (reference range: <25 mg/dL). These findings are consistent with a
diagnosis of GME. (Wright’s stain x100).
Figure 2. Transverse, FLAIR MRI at the level of the midbrain and cerebral
hemispheres of a 4-year-old, castrated male Maltese with acute onset of mild
obtundation and generalized ataxia caused by GME. Note the localized hyperintensity
28
of the white matter throughout the cerebral cortex, with bilateral periventricular edema.
Ill-defined multifocal hyperintensity is also identified in the brainstem. These findings
are consistent with a diagnosis of GME.
A.
B.
C.
Figure 3. A: GME. Perivascular accumulation of macrophages, lymphocytes, and
plasma cells (H&E X 130); B: NME. Focal meningitis with polio- and leukoencephalitis
of adjacent white matter. The lesions are intensely inflammatory with parenchymal
histiocytic, microglial infiltrates accompanied by perivascular cuffing of lymphocytes
and plasma cells (H&E X 110); C: NE. Acute exudation, edema, and necrosis, with
gemistocytic astrogliosis. Histiocytes and gitter cells are intermixed with perivascular
lymphocytic cuffing (H&E X 265).
29
Table 1: Possible causes of brain dysfunction in dogs
Degenerative
 Lysosomal storage diseases
 Leukodystrophy/spongy degeneration
 Cognitive dysfunction syndrome
Anomalous/Developmental
 Congenital hydrocephalus
 Caudal occipital malformation
 Intracranial arachnoid cyst
Metabolic
 Hepatic encephalopathy
 Renal-associated encephalopathy
 Hypoglycemic encephalopathy
 Electrolyte-associated encephalopathy
 Endocrine-related encephalopathies
 Encephalopathy associated with acid-base disturbances
 Mitochondrial encephalopathy
Neoplastic
 Primary brain tumors
 Secondary brain tumors
Nutritional
 Thiamine deficiency
Inflammatory/Infectious/Immune-mediated
 Bacterial meningoencephalitis
 Fungal encephalitis
 Viral meningoencephalitis
 Protozoal meningoencephalitis
 Rickettsial meingoencephalitis
 Verminous meningoencephalitis
 Granulomatous meningoencephalomyelitis
 Necrotizing meningoencephalitis
 Necrotizing encephalitis
 Eosinophilic meningoencephalitis
Toxic
Vascular
 Ischemic encephalopathy
 Hemorrhagic encephalopathy
30
UPDATE ON BRAIN DISEASES IN DOGS & CATS
Dr. Richard A. LeCouteur
Professor of Neurology & Neurosurgery
School of Veterinary Medicine
University of California
Davis CA 95616 USA
The term encephalopathy refers to any disorder or disease affecting the brain. In its
broadest interpretation, this includes disorders affecting the cerebrum (cerebral cortex
and basal nuclei), brainstem (thalamus, hypothalamus, midbrain, pons and medulla),
and cerebellum. This lecture will concentrate on disorders affecting the cerebrum.
Clinical Signs
The principal clinical signs associated with cerebral dysfunction are as follows;

Altered mental status (obtundation, stupor (semi-coma) or coma)

Change in behavior (loss of trained habits, failure to recognize owner,
aggression, or hyperexcitability)

Abnormal movements/postures such as pacing, wandering, circling, head
pressing, twisted head and trunk (pleurothotonus)

Postural reaction deficits in contralateral limbs

Visual impairment (e.g. bumping into objects, menace deficit contralateral
to side of lesion) with normal pupillary light reflexes

Seizures
On the basis of signalment, history, and the results of a physical and neurologic
examination, it may be possible to localize a lesion to the brain and occasionally to
determine an approximate location. A similar neurologic syndrome will result from any
one of a number of different diseases occurring at a given location. Many
degenerative, metabolic, infectious, inflammatory, toxic, and vascular diseases may
result in clinical signs of cerebral dysfunction. The cerebral cortex coordinates
voluntary movements and reactions.
Clinical signs of cerebral cortex dysfunction include changes in behavior (lethargy, loss
of trained habits, irritable, aggressive) or mental status (obtundation, semicoma,
coma), and visual and postural reaction deficits. Behavioral changes usually result
from a lesion of the limbic system or frontal lobe of the cerebral cortex. Since the
frontal lobe has an inhibitory effect on some motor functions, a lesion here removes
this inhibition and as a result the animal may continually pace. When as animal
reaches a barrier pacing may be replaced with head pressing. Some animals circle,
usually to the side of the lesion. Seizures may be partial or generalized.
Conscious visual perception requires intact visual pathways to the occipital lobes of
the cerebral cortex. Unilateral lesions of the occipital cortex result in visual deficits in
31
the contralateral temporal visual field, with intact pupillary light reflexes. Bilateral
lesions produce blindness.
Although the motor cortex is important for voluntary motor activity, it is not necessary
for relatively normal gait and posture. Animals with lesions here may be able to stand,
walk and run with minimal deficits, but control of finer movements is lost and they may
have difficulty avoiding obstacles and contralateral postural reactions are usually
deficient.
Although it is possible to localize a problem to the brain and sometimes to the
approximate location within the brain, it must be remembered that clinical signs may
be the same regardless of the underlying cause. Brain tumors, infections, congenital
disorders, trauma, vascular disorders, degeneration, immunologic and metabolic
disorders, toxicities, and idiopathic disorders may result in similar clinical signs. For
this reason it is essential to follow a logical diagnostic plan for a cat or dog with signs
of brain dysfunction.
Some Common Disorders Affecting the Cerebrum of Dogs and Cats
1.
2.
3.
4.
5.
Degenerative a.
Lysosomal storage diseases:
Fucosidosis - Springer spaniel
Gangliosidosis - cats, dogs
Ceroid lipofuscinosis - dogs
Anomalous/ Developmental a.
Hydrocephalus
b.
Lissencephaly - small smooth brain with absent gyri and abnormal
arrangement of cells in cerebral cortex
c.
Hydranencephaly - virtual absence of cerebral hemispheres and basal
nuclei, with remnants of mesencephalic structures
d.
Porencephaly - a circumscribed cerebral defect that communicates with
the ventricular system
e.
Meningoencephalocele - herniation of part of the brain and meninges
through a defect in the skull
Metabolic
a.
Hepatic encephalopathy
b.
Miscellaneous
Hypoglycemia
Neoplastic
a.
Primary brain tumor
b.
Secondary brain tumor
Local extensions from skull, middle ear, pituitary, nasal
cavity
Metastasis
Inflammatory/Infectious
a.
Viral
Canine distemper
Old dog encephalitis
Feline infectious peritonitis
Parvovirus encephalitis
b.
Unknown cause
Granulomatous meningoencephalomyelitis
Eosinophilic meningoencephalitis
c.
Protozoal
Toxoplasmosis
32
Neosporosis
Mycotic
Cryptococcus neoformans
Others - Blastomyces dermititidis, Histoplasma capsulatum,
Coccidioides immitis, Cladosporium trichoides, paecilomyces,
Aspergillus spp., etc
e.
Bacterial
Abcessation
Sub-dural empyema
f.
Miscellaneous
Verminous encephalitis
Foreign body migration
Traumatic
Vascular
a.
Hemorrhage
b.
Infarction
Feline ischemic encephalopathy
d.
6.
7.
Diagnostic Plan
Patient signalment, history and physical and neurological examination findings will
help to localize a lesion to the brain and possibly a particular area of the brain. Further
diagnostic tests are required to localize the affected area within the brain, and to
obtain an accurate diagnosis. These tests include CSF analysis, CT or MR imaging,
and brain biopsy.
Following a complete history and physical and neurologic examination, a minimum
data base for an animal with signs of brain dysfunction should be obtained. This
should include a hemogram, serum chemistry panel, and urinalysis. Survey thoracic
radiographs and abdominal ultrasound help to rule out problems elsewhere. The
major objective in doing these tests is to exclude disease outside the brain as a cause
of the signs of cerebral dysfunction.
Plain skull radiographs are useful for detecting problems of the skull or nasal cavity
that may have extended to the brain. Occasionally, lysis or hyperostosis of the skull
may accompany a primary brain tumor (e.g., meningioma of cats) or there may be
mineralization of a neoplasm. Skull radiographs are of little value in detecting
dysfunction within the brain.
Cerebrospinal Fluid
Analysis of cerebrospinal fluid (CSF) is recommended as an aid in the diagnosis of a
brain disorders. The results of CSF analysis may help to identify inflammatory causes
of cerebral dysfunction, and in some cases may support diagnosis of a brain tumor.
CSF bathes the entire CNS, both internally (the ventricles and central canal) and
externally (the subarachnoid space). CSF composition may be affected by many
nervous system diseases and the ease with which this fluid may be collected has
made it a useful diagnostic tool in the diagnosis of CNS disease. Unfortunately, for
cells to be shed into the CSF a disease must involve the ventricular system or the
subarachnoid space. Disorders involving deeper brain structures (e.g. neoplasms)
may not shed cells into the CSF. Frequently these diseases disrupt the blood-brain
barrier allowing protein to leak into the CSF and resulting in an increased protein level.
CSF must be evaluated keeping in mind history and clinical signs. Neoplasms and
some other non-inflammatory diseases may result in inflammatory changes in CSF
composition. CSF composition may also change as a disease becomes more chronic.
Also, following various therapies CSF may no longer accurately reflect an etiology
Care should be used in the collection of CSF, because frequently an increased
intracranial pressure (ICP) may be present in association with a brain tumor, and
33
pressure alterations associated with CSF removal may cause brain herniation.
Because CSF pressure measurements are of limited usefulness, it is often desirable to
utilize techniques such as hyperventilation to decrease intracranial pressure prior to
CSF collection.
CSF may be collected at either the cerebellomedullary cistern or by lumbar puncture.
In general the cerebellomedullary cistern is easier to perform, allows collection of a
larger volume and generally collection from this area results in less blood
contamination. All patients undergoing CSF collection should be anesthetized
appropriately. If it is suspected that intracranial pressure is elevated the patient should
be hyperventilated for several minutes prior to collection as well as during and after
collection in order to decrease arterial CO2 and intracranial pressure. Complications
of CSF collection include needle injury to the brain and herniation of the brain, usually
due to high intracranial pressure. Both these complication may be fatal if appropriate
steps to reduce intracranial pressure (hyperventilation and mannitol administration) are
not instituted immediately.
CT and MRI
CT and MRI allow imaging of brain tissue rather than just the surrounding bony skull.
Both can distinguish lesions which have only slightly different densities than the
surrounding tissues and this can be further enhanced by contrast agents allowing the
identification of masses and other abnormal tissues within the brain. Images obtained
by means of MRI may be superior to those of CT especially in certain areas such as
the brain stem, although CT is usually better for bony lesions (e.g. middle ear studies).
While the major tumor types are reported to have characteristic CT or MRI
appearances , non neoplastic lesions may mimic the CT or MRI appearance of a
neoplasm, and occasionally a metastasis may resemble a primary brain tumor on CT
or MRI images. Patients for either CT or MRI must be anesthetized, intubated, and
hyperventilated whenever an increase in ICP is even suspected. Proper patient
positioning is extremely important. The animals should be placed in sternal
recumbency with the head extended. The entire calvaria should be examined in the
non contrast series of images. This should be followed by a post contrast series of
images.
Cerebrovascular Disease of Dogs & Cats
Cerebrovascular disease is defined as any abnormality of the brain resulting from a
pathologic process affecting its blood supply.
Stroke or cerebrovascular accident (CVA) is the most common clinical manifestation of
cerebrovascular disease, and may be broadly divided into (1) ischemic stroke and (2)
hemorrhagic stroke. Ischemic stroke results from occlusion of a cerebral blood vessel
by a thrombus or embolism, depriving the brain of oxygen and glucose, whereas
hemorrhagic stroke results from rupture of a blood vessel wall within the brain
parenchyma or subarachnoid space. Ischemic strokes are more common, and an
underlying cause is found in about 50% of cases. The most common concurrent
medical conditions found in dogs are hyperadrenocorticism, chronic kidney disease,
hypothyroidism and hypertension. Hemorrhagic strokes are rare and have been
reported secondary to rupture of congenital vascular abnormalities, brain tumors,
intravascular lymphoma, cerebral amyloid angiopathy and impaired coagulation.
Signs are typically peracute in onset, and then they plateau. Worsening edema can
sometimes lead to progression of neurologic signs
MRI is the imaging modality of choice. CT can detect hemorrhage and is useful for
ruling out mimics of stroke, but it is not very sensitive in detecting ischemic changes.
Ancillary diagnostic tests for ischemic strokes include CBC, chemistry, UA, serial blood
pressure measurements, urine protein/creatinine ratio, d-dimers, endocrine testing,
thoracic radiographs, abdominal ultrasound and echocardiography.
34
Ancillary diagnostic tests for hemorrhagic stroke include serial blood pressure
measurement, CBC, chemistry, BMBT, PT/PTT, thoracic radiographs and abdominal
ultrasound.
Treatment, regardless of type, includes supportive care and management of
neurologic and non-neurologic complications, as well as treating any underlying
causes.
Most cases of ischemic stroke recover within a few weeks with just supportive care.
Hemorrhagic stroke is far less common, but associated with higher mortality. The risk
of neurologic deterioration is highest in the first 24 hours. Dogs with concurrent
medical conditions have significantly shorter survival times and are more likely to
suffer from subsequent infarcts.
Previously considered uncommon, CVA is being recognized with greater frequency in
veterinary medicine since magnetic resonance imaging (MRI) has become more
readily available. Once the diagnosis of ischemic or hemorrhagic stroke is confirmed,
potential underlying causes should be investigated and treated accordingly.
Hippocampal Necrosis of Cats
A profound encephalopathy of cats, caused by necrosis of the hippocampus, has been
described. The syndrome is characterized by progressive, partial or generalized
seizures, behavior changes (particularly aggression), and pathological features
confined to the limbic system (including hippocampus and piriform lobe of the
cerebrum).
In one study, the clinical records of 38 cats (1985-1995) with a neuropathologically
confirmed diagnosis of necrosis of the hippocampus and occasionally the piriform lobe
of the cerebrum were evaluated retrospectively. There was no sex or breed
predisposition. Most cats were between 1 and 6 years of age (mean age 35 months)
and had either generalized or complex-partial seizures of acute onset and rapid
progression. The seizures had a tendency to become recurrent and to present as
clusters or even status epilepticus later in the course of the disease. Fourteen cats
died spontaneously, and 24 were euthanized. Histopathologic examination revealed
bilateral lesions restricted to the hippocampus and occasionally the piriform lobe of the
cerebrum. The lesions seemed to reflect different stages of the disease and consisted
of acute neuronal degeneration to complete malacia, affecting mainly the layer of the
large pyramidal cells but sometimes also the neurons of the dentate gyrus and the
piriform lobe. The clinical, neuropathologic, and epidemiologic findings suggest that
the seizures in these cats were triggered by primary structural brain damage, perhaps
resulting from excito-toxicity. The cause remains unknown, but epidemiologic analysis
suggests an environmental factor, probably a toxin.
Brain Tumors of Dogs & Cats
The Past: Surgery, Irradiation and Chemotherapy
The major goals of therapy for a brain tumor have been to control secondary effects,
such as increased intracranial pressure or cerebral edema, and to eradicate the tumor
or reduce its size. Beyond general efforts to maintain homeostasis, palliative therapy
for dogs or cats with a brain tumor has consisted of glucocorticoids for edema
reduction, and in some cases (e.g., lymphoma), for retardation of tumor growth. Some
animals with a brain tumor will demonstrate dramatic improvement in clinical signs for
weeks or months with sustained glucocorticoid therapy. Should anti-seizure
medications be needed, phenobarbital or bromide are the drugs best suited for the
control of generalized seizures.
Three major methods of therapy for a brain tumor have been available for use in dogs
and cats: surgery, irradiation, and chemotherapy.
35
Surgery
In association with the availability of CT and MRI, and the development of advanced
neurosurgical, anesthetic, and critical care techniques, complete or partial surgical
removal of intracranial neoplasms is being practiced with increasing frequency.
Neurosurgical intervention is an essential consideration in the management of
intracranial neoplasms of cats or dogs, whether for complete excision, partial removal,
or biopsy.
Radiation Therapy
The use of radiation therapy for the treatment of primary brain tumors of dogs and cats
is well established. Irradiation may be used either alone or in combination with other
treatments. Radiation therapy also is recommended for the treatment of secondary
brain tumors. Metastases, pituitary macroadenomas or macrocarcinomas, and skull
tumors have been successfully managed by means of either radiation therapy alone or
as an adjunct to surgery. Lymphoma may also be sensitive to radiation therapy.
Chemotherapy
Traditionally, cytotoxic drugs have had a limited role in the treatment of dogs or cats
with brain tumors, and progress in the development of truly effective chemotherapeutic
protocols for humans or companion animals has been slow. Several factors affect the
use of chemotherapeutic agents for the treatment of brain tumors in dogs or cats. The
first, unique to the brain, is that the blood-brain barrier (BBB) may prevent exposure of
all or some of the tumor to a chemotherapeutic agent injected parenterally. Second,
tumor cell heterogeneity may be such that only certain cells within a tumor are
sensitive to a given agent. Third, a tumor may be sensitive only at dosages that are
toxic to the normal brain or other organs (kidney or liver).
The Present: Therapeutic Delivery Strategies for Canine Brain Tumors
The use of Surgery, irradiation and chemotherapy remains the mainstay of brain tumor
therapy today.
Development of novel therapeutic strategies to combat primary brain tumors has
followed closely behind elucidation of the basic molecular and genetic mechanisms
underlying both tumorigenesis and subsequent progression. Despite the wealth of data
documenting successful treatment of experimental tumors, translation into the clinical
setting has been slow. Many existing therapeutics are rendered ineffective in the
treatment of brain tumors due to the inability to effectively deliver and sustain them
within the brain. The major obstacle to therapeutic delivery via the vascular route
(following either orally administration or direct vascular administration) is the BBB.
Transport across the brain vascular endothelium is essentially trans-cellular, therefore
the ideal substance to be transported should be:
 Small (< 400Da)
 Lipophilic (lipid soluble)
 Non-polar at physiological pH
 Non-protein bound
Unfortunately, a majority of chemotherapeutic agents are large positively charged,
hydrophilic molecules. Many therapeutic molecules such as cyclosporine, doxorubicin
and vincristine have poor BBB penetration despite being lipophilic (cyclosporine A is
more lipophilic than diazepam). This is the result of additional “barriers” such as high
levels of degrading enzymes within the endothelial cells, and high concentrations of
efflux transporter proteins such as P-glycoprotein, multiple organic anion transporter
proteins (MOAT) and multi-drug-resistance proteins (MRP).
In addition to barriers preventing movement of therapeutic agents from the blood into
the brain parenchyma, mechanisms are also present to limit movement into the
36
cerebrospinal fluid (CSF). Passage of substances through the arachnoid membrane is
prevented by tight junctions and is generally impermeable to hydrophilic molecules.
While the capillaries of the choroids plexus are fenestrated, non-continuous and allow
free movement of small molecules, the adjacent choroidal epithelial cells form tight
junctions preventing the passage of most macromolecules. An active organic acid
transporter system in the choroid plexus also is capable of driving therapeutic organic
acids such as penicillin or methotrexate back into the blood from the CSF. Entry of
drugs into the CSF does not necessarily guarantee that they will reach the interstitial
fluid in the brain, suggesting the presence of the so-called CSF-brain barrier, mainly
attributed to insurmountable diffusion distances required to equilibrate CSF with brain
interstitial fluid.
Although the BBB may be inconsistently compromised in tumor vasculature, a variety
of obstacles still restrict delivery of therapeutic agents. Tumor microvascular supply
often is heterogeneous and chaotic, with significant areas of inefficient or poor blood
flow, vascular shunting, blind-ending vessels, etc., resulting in erratic distribution of
drugs that are able to penetrate the BBB.
Improving delivery of therapeutic agents to brain tumors in the face of these obstacles
has focused on the following areas of research:
 Improve entry through the BBB by modification of therapeutic drugs.
a.
Increase influx.
b.
Decrease efflux.
c.
Utilization of carriers/receptors.
 Disruption of the BBB.
a.
A variety of approaches have been used to disrupt BBB integrity
including:
i. Chemical (often toxic), DMSO, ethanol, aluminium, irradiation,
hypertension, hypercapnia, hypoxia.
ii. Osmotic agents such as mannitol and arabinose.
iii. Biochemical agents such as leukotriene C4, bradykinin,
histamine etc.
 Circumventing the BBB.
a.
Using non-vascular delivery of therapeutic agents directly into
the CNS is appealing in many ways. Apart from removing the
BBB as a restriction to delivery of many potent anticancer
therapies, targeting the drugs directly potentially reduces
systemic toxicity, degradation and immunological stimulation
(particularly with protein and virally based therapies). However
strategies are generally more invasive requiring craniotomy or
insertion of catheters.
i. Intraventricular/intrathecal infusion.
ii. Wafers/microspheres/microchips.
iii. Delivery from biological tissues
b.
Delivery of therapies directly from living cells within the brain or
tumor itself can provide sustained levels of drugs in specific
targeted regions. The two main strategies examined to date are:
i. Implantation of transfected cell lines.
ii. Transduction of resident CNS cells or brain tumor cells with
gene therapy constructs.
 Interstitial delivery.
a.
Both gene therapies and direct acting drugs, such as
chemotherapeutics, can be delivered directly into tumor or brain
parenchyma. AAV vectors carrying thymidine kinase suicide
constructs and antiangiogenic agents have been shown to be
efficacious in both in vitro and in vivo models, and direct
37
injection into canine primary brain tumors has been done.
Results in clinical tumors however have been disappointing
mainly due to limited distribution of the therapy beyond the local
region of the injection site.
The Future: Biopsy and Convection Enhanced Delivery
Brain Biopsy
Biopsy remains the sole method available for the ante mortem definitive diagnosis of
brain tumor type in cats or dogs, and is an essential step prior to consideration of any
type of therapy. However, biopsy is not always attempted because of practical
considerations, such as cost and morbidity. The most recent advance in the biopsy of
brain tumors of dogs and cats has been the development of CT-guided stereotactic
brain biopsy systems for use in cats and dogs. These CT-guided stereotactic biopsy
systems provide a relatively rapid and extremely accurate means of tumor biopsy, with
a low rate of complications. Cytological evaluation of brain tumor smear preparations,
rapidly fixed in 95% alcohol and stained with hematoxylin and eosin, may be done
within minutes of biopsy collection. Diagnostically accurate information from this rapid
technique is generally available from both primary and metastatic nervous system
tumors.
Convection enhanced delivery (CED
CED is a local delivery technique that utilizes a bulk-flow mechanism to deliver and
distribute macromolecules over clinically relevant volumes of targeted tissue. Unlike
local injection techniques, CED uses a pressure gradient established at the tip of an
infusion catheter that pushes the infusate through the interstitial space. Volumes of
distribution of infused molecules are significantly increased compared to local injection
or surgical implantation methods that rely primarily on diffusion and are limited by
concentration gradients and molecular weight of the delivered substance. Distribution
of infusates over centimeters, rather than millimeters, has been reported in a variety of
experimental model systems using CED. Real time in vivo imaging of CED is an
essential consideration if adequate drug distribution is to be confirmed ante mortem.
Additionally, the ability to detect and minimize distribution or leakage of drugs to
normal tissues during delivery has the potential to significantly decrease toxicity and
increase therapeutic effectiveness. Several surrogate marker systems have been
described, facilitating image-guided CED, including magnetic resonance imaging
(MRI) systems utilizing T2 imaging correlated with 123I-labelled serum albumin, single
photon emission computed tomography (SPECT), and liposomes co-labeled with
gadolinium. Liposomes are phospholipid nanoparticles composed of a bi-layered
membrane capable of encapsulating a variety of therapeutic molecules. Liposomal
encapsulation of a variety of drugs, including chemotherapeutics, has been shown to
result in prolonged half-life, sustained release, and decreased toxicity. CED of
liposomes, containing therapeutic drugs, directly into targeted brain tissue offers
several advantages over systemic delivery of un-encapsulated drug, including
bypassing of the BBB, increased volume of distribution within the target tissue, and
increased therapeutic index as a result of both liposomal encapsulation and minimal
systemic exposure. Irinotecan/CPT-11 is a camptothecin derivative and topoisomerase
I inhibitor with activity against a variety of cancer types, including brain tumors. The
efficacy and safety of direct delivery of liposomally encapsulated camptothecin
analogs in rodent models of glioma has been reported. Translation of this promising
therapeutic approach into clinical trials will require demonstration of the safety and
efficacy of combined real time gadolinium based imaging and liposomally
encapsulated CPT-11 treatment in a large animal model system. The advantages of a
canine model system over established rodent and primate models are several and
include the ability to investigate aspects of feasibility and toxicity on a scale relevant to
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human clinical patients, and the unique potential to investigate CED efficacy, and
adverse effects in large, spontaneously occurring tumors.
Thiamine Deficiency of Cats
Cats are susceptible to thiamine deficiency because of their high-dietary requirement
for thiamine, and because fish-based diets that contain thiaminases before processing
are often fed to cats. In people, thiamine requirement is directly related to both total
caloric intake and the proportion of calories provided as carbohydrates.
All of the published reports to date of thiamine deficiency in cats eating commercially
available diets have involved canned foods. Canned foods are more susceptible to
thiamine loss because of the high temperature involved in the processing of these
diets, in particular when the pH is above 5.
The primary sources of thiamine supplementation in commercially available pet foods
are synthetic (thiamine mononitrate and thiamine hydrochloride), and these sources
are more susceptible to destruction than the thiamine present in plant and animal
tissues. Thiamine can be destroyed by sulfate trace minerals and sulfite preserved
meats which cleave the thiamine at the methylene bridge. In addition, thiamine is
oxidized by ultraviolet and gamma irradiation and degraded by thiaminase enzyme
activity found predominantly in shellfish, fish viscera, and some bacteria. Thiaminase
is destroyed by heat processing; however, if raw ingredients are not promptly or
properly cooked, destruction could result in lower than expected concentrations of
thiamine. Given there are no real safety concerns regarding increased dosages of
thiamine in either the cat or dog, and processing losses can exceed 90%, fortification
in diet premixes warrants careful consideration to ensure appropriate thiamine
concentrations in the final product.
Thiamine deficiency is a readily reversible neurological disorder that warrants
consideration in any cat manifesting compatible clinical and neurological signs. The
differential diagnoses for the multifocal intracranial disease suspected in all cats based
on their neurological examinations included toxic and metabolic disease. Foods should
also be evaluated for their adequacy as the sole or primary diet, as many unbalanced
canned products are widely available and are marketed and labeled similarly to
complete diets. Further studies assessing thiamine content of canned feline diets are
warranted.
Abscessation of the Central Nervous System in Cats
Infection of the CNS may result in an abscess formation (a circumscribed collection of
purulent material within the CNS, its surrounding membranes, or in the epidural space)
and/or much less frequently, empyema (collection of pus in subdural or epidural
locations). The term "pyocephalus" refers to a purulent effusion within the cranium and
is synonymous with "pyencephalus". In animals, the empyema tends to be in cranial
subdural sites and in spinal epidural locations.
Abscesses within the CNS are uncommon in cats but may arise as a result of either
metastasis from distant foci of infection (e.g., lung abscesses and bacterial
endocarditis), by direct extension from sinuses, ears, and eyes, as a result of trauma
(e.g., bite wound), or from contaminated surgical instruments (e.g., spinal needle).
Brain abscess may also result from penetration of the cranial cavity and brain
substances by an exopharyngeal foreign body (e.g., sewing needle). Several
instances of spinal epidural infection in the cat have followed tail fracture or a purulent
granulomatous dermatitis involving the tail. The common sites for direct extension are
the cribriform plate and the inner ear, resulting in abscess formation in the frontal lobe
and the cerebellopontine angle, respectively. Spinal epidural infections also may
result from vertebral osteomyelitis or paraspinal abscess. Abscesses of hematogenous
origin, such as those that spread from pulmonary infection, bacterial endocarditis, or
congenital heart disease with right to left shunting, appear to have a predilection for
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the CNS parenchyma, especially in the hypothalamus and cerebral cortex, and
particularly in less vascularized areas such as white matter and junctions of gray and
white matter. It is thought that neuraxial abscessation occurs preferentially in areas of
focal ischemia or necrosis. Typically, CNS abscesses are associated with bacteria, but
are occasionally caused by fungi.
Aerobic bacteria such as Streptococcus, Staphylococcus, Pasteurella, and Nocardia
may be more common than anaerobic bacteria as causes of CNS infection in dogs
and cats. Nevertheless, anaerobic bacteria such as Bacteroides, Fusobacterium,
Peptostreptococcus, Actinomyces, and Eubacterium are reported to be important
pathogens in cats, casuing either brain abscesses or subdural empyema. Actinomyces
typically spreads by direct extension, although brain and possibly vertebral abscesses
may result from hematogenous dissemination.
Otogenic Intracranial Infection
Extension of otitis media/interna into the central nervous system is a serious
complication that may occur in cats of any age, breed or gender. Most intracranial
complications originate from sub-acute to chronic ear infections, resulting in abscess
formation in the brain.
Cerebral Phaeohyphomycosis
Phaeohyphomycosis refers to invasive disease caused by several species of
dematiaceous fungi.
Cognitive Dysfunction Syndrome
Cognitive dysfunction syndrome (CDS) is an age-related neurodegenerative disease that
impairs memory and learning. CDS may manifest itself in multiple nonspecific clinical signs
that increase in frequency and severity over time in affected cats.
 Cognitive dysfunction is an age-related neurodegenerative disease that impairs
memory and learning.
 Cognitive dysfunction can cause various behavioral changes. Make sure to rule
out diseases that can mimic these signs.
 There are many forms of cognitive dysfunction and often they involve the
depletion of neurotransmitters or disruption of neural pathways.
 The common denominator in all cases of neurodegeneration and cognitive
decline is oxidative stress and mitochondrial dysfunction.
Alterations in cell function and neurotransmission in the brain of the CDS patients lead
to malfunctions of short-term memory, loss of learned behavior, impairment of the
processing of sensory information, reduction in cognitive capacity, and alterations of
mood. The progression of CDS is related to the general rate of aging of cats and
dogs. Quite significant changes may occur in the space of weeks or months.
Worsening of the condition may be precipitated by stressful events such as
hospitalization, kenneling, surgery or a house move. Ideally, cats should be
behaviorally assessed before these events.
 Emotional changes: mild emotional changes may be the first signs of the
onset of dementia. Signs include depression (reduction in activity, play and
interest in activities the cat formerly enjoyed).
Increases in anxiety and fear leading to irritability and aggressiveness.
 Defects of short-term memory: the animal repeatedly performs certain
actions such as asking for attention, food and other rewards.
Malfunction of short-term memory is at the root of many of the problems seen
in CDS.
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Disorientation: the animal has trouble recognizing people, locations, or
objects. This may lead to secondary problems, such as house soiling and
difficulty finding locations in the home (e.g., door to outside, cat flap, water and
food dish).
Changes in sleep-wake cycle: the animal tends to sleep mostly during the
day and appears restless at night, often waking up and crying out loudly. Pain
and illness are also significant factors in night-time restlessness (e.g., chronic
arthritic pain may make rest uncomfortable, and deafness can result in the cry
becoming loader than previously).
Loss of learned behaviors: failure to respond to commands and social signals
that inhibit unwanted behavior. This contributes to loss of social inhibition and
alterations in relationships with people and other animals in the home.
Loss of house training (example of a learned behavior): a previously house
trained animal will suddenly urinate and/or defecate inside the house and/or
outside its littler box. This clinical sign can be caused by numerous medical
and behavioral problems that have to be ruled out, especially osteoarthritis,
hyperthyroidism and hypertension.
Changes in interaction with the environment: reduced greeting of the
owner, familiar persons or pets, decreased response to commands. A
depressed mood and lack of interaction tends to isolate animal from their
owners, who may not instigate play or give attention. Through a loss of
stimulation and reward of normal activity the degradation of the human-animal
bond leads to social isolation that contributes to worsening signs of CDS.
Neurological : in the latter stages of CDS, neurological impairment may be
seen. These include ataxia, apparent sensory loss (loss of vision/hearing) and
changes in locomotion. Any neurological signs must be investigated thoroughly
as there are numerous other potential medical causes.
Treatment
The drug Anipryl (selegiline), used by humans to treat Parkinson’s disease, has been
reported to dramatically improve clinical signs and the quality of life for many dogs with
cognitive dysfunction syndrome.
An additional benefit may come from feeding the therapeutic diet Hill’s b/d. This diet is
specifically formulated with extra antioxidants for older dogs.
Older dogs may also benefit from treatment with acupuncture and Chinese herbs.
References
Dickinson PJ, LeCouteur RA, Higgins RJ et al. 2008. Canine model of convectionenhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic
resonance imaging: laboratory investigation. J Neurosurg 108, 989-98.
Dickinson PJ, LeCouteur RA, Higgins RJ et al. 2010.
Canine spontaneous glioma: a translational model system for convection-enhanced
delivery. Neuro Oncol 12, 928-40.
Thomas R, Duke SE, Wang HJ, et al. 2009. 'Putting our heads together': insights into
genomic conservation between human and canine intracranial tumors. J Neurooncol
94, 333-49.
Wisner ER, Dickinson PJ, Higgins RJ. 2011. Magnetic resonance imaging features of
canine intracranial neoplasia. Vet Radiol Ultrasound.52(1 Suppl 1):S52-61.
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