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Alternative Therapeutic Options for Medical Management ofEpilepsy in ApesAuthor(s): Trevor Gerlach, D.V.M., Victoria L. Clyde, D.V.M., George L. MorrisIII, M.D., Barbara Bell, B.S., and Roberta S. Wallace, D.V.M.Source: Journal of Zoo and Wildlife Medicine, 42(2):291-294. 2011.Published By: American Association of Zoo VeterinariansDOI: http://dx.doi.org/10.1638/2010-0184.1URL: http://www.bioone.org/doi/full/10.1638/2010-0184.1
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Journal of Zoo and Wildlife Medicine 42(2): 291–294, 2011
Copyright 2011 by American Association of Zoo Veterinarians
ALTERNATIVE THERAPEUTIC OPTIONS FOR MEDICAL
MANAGEMENT OF EPILEPSY IN APES
Trevor Gerlach, D.V.M., Victoria L. Clyde, D.V.M., George L. Morris III, M.D., Barbara Bell, B.S.,
and Roberta S. Wallace, D.V.M.
Abstract: Phenobarbital has been the primary antiepileptic drug used in primates, but the dosage required for
seizure control is frequently associated with significant side effects. Newer antiepileptic drugs and adjunctive
therapies currently being used in human medicine provide additional options for treatment of nonhuman
primates. This report describes different drug regimes used for control of epileptic seizures in apes at the
Milwaukee County Zoo (Milwaukee, Wisconsin, USA), including the addition of acetazolamide to phenobarbital,
levetiracetam, carbamazepine, and the use of extended cycle oral contraceptives to assist seizure control in female
apes with catamenial epilepsy.
Key words: Epilepsy, antiepileptic drug, bonobo, Pan paniscus, gorilla, Gorilla gorilla.
INTRODUCTION
In epilepsy, paroxysmal disturbances of normal
brain function lead to a loss of consciousness,
abnormal motor activity, or loss of sensory
capabilities.5 For primates with epilepsy, these
behavioral alterations are disturbing to the ani-
mals within its social group as well as to the
affected individual and to care staff. Epilepsy also
poses a significant risk of trauma, especially for
climbing animals. However, only limited informa-
tion has been published regarding options for the
treatment of epilepsy in nonhuman primates
(NHPs) or the effectiveness of various antiepi-
leptic drugs (AEDs) in NHPs. This report de-
scribes different approaches to seizure control
used for three apes at the Milwaukee County Zoo
(Milwaukee, Wisconsin, USA) with epilepsy or
seizure disorder.
CASE REPORTS
Case 1
A female bonobo (Pan paniscus), wild born
around 1950, had an observed seizure in 1986. A
diagnostic workup performed shortly thereafter
revealed several mineralized foci in the cerebrum
and cerebellum on a computed tomography (CT)
scan. Blood work, radiographs, and cerebral spinal
fluid (CSF) analysis were unremarkable. After
additional seizures, the animal was started on oral
phenobarbital in 1990 while residing at another
facility. By 1995, when the bonobo returned to the
Milwaukee County Zoo at an adult weight of 38 kg,
seizures were partially controlled with 100 mg of
phenobarbital given p.o. b.i.d.
Over the next 5 yr, the phenobarbital dosage
was adjusted depending on the frequency of
seizures, which occurred most often during the
week prior to menses. By 2000, the seizures were
becoming both more severe and more frequent,
and a dosage of 120 mg phenobarbital p.o. b.i.d.
was no longer controlling seizures adequately.
When the phenobarbital dosage was increased
much above 120 mg p.o. b.i.d., the animal would
become very somnolent. Abdominal bloating was
noted at 150 mg phenobarbital p.o. b.i.d. Because
of these side effects and the need for better
seizure control, acetazolamide was added to the
treatment regimen as an adjunctive drug. For
approximately 1 yr, the seizures were fully con-
trolled with a combination of 100 mg phenobar-
bital p.o. b.i.d. and 250 mg acetazolamide p.o.
b.i.d. When seizures recurred, the acetazolamide
dosage was increased to 312.5 mg p.o. b.i.d. For
several years, the daily phenobarbital dosage was
increased only for a few days during the week
prior to menses, which reduced the number of
days the animal was partially sedated by the
necessary elevation in dosage. However, as this
elderly bonobo entered perimenopause, its estrus
cycle became erratic and keepers were no longer
able to predict periods of higher seizure risk.
Rather than increasing the dosage of either AED,
the animal was started on extended-cycle oral
contraceptive, in which standard monotherapy
oral birth control pills (1 mg norethindrone
From the Milwaukee County Zoo, 10001 West Blue
Mound Road, Milwaukee, Wisconsin 53226, USA
(Gerlach, Clyde, Bell, Wallace); and Epilepsy and
Seizure Care Specialists S.C., 2801 W Kinnickinnic River
Parkway, Suite 570, Milwaukee, Wisconsin 53215, USA
(Morris). Present address (Gerlach): 4800 Walnut Street
#402, Philadelphia, Pennsylvania 19139, USA. Corre-
spondence should be directed to Dr. Clyde
291
acetate and 20 mcg ethinyl estradiol) were given
daily for 12 wk, followed by a shortened hormone-
free interval of 2 days before starting the next 12
wk of daily therapy. Since the addition of hor-
monal therapy, seizure occurrence has been
reduced. Breakthrough seizures occur infrequent-
ly and increased dosages of phenobarbital are
given only four times a year during the 2-day
hormone-free interval.
Case 2
A female bonobo, wild born around 1972, had
an observed seizure in 2008 on the same day as
ovulation, as verified by a urine ovulation test.
The next observed seizures occurred approxi-
mately 3 and 4 mo later, with all incidences
occurring on days of ovulation. Staff began to
question whether this animal’s previous falls on
exhibit may have been due to unobserved sei-
zures. A review of historic records indicated that a
series of injuries over the past 15 yr all occurred
on days of ovulation as verified by urine ovulation
tests. Repeated veterinary examinations over the
years were essentially normal, including a CT scan
and magnetic resonance imaging. The 42-kg
animal was started on 121.5 mg phenobarbital
p.o. b.i.d., but extreme lethargy was noted after
each treatment, followed in a few days by
pronounced and painful abdominal bloating.
Due the severity of these side effects, phenobar-
bital treatment was discontinued. Levetiracetam,
a newer AED, was started at 250 mg p.o. b.i.d.,
with fatigue and asthenia noted initially. After
lowering of the dosage to 125 mg p.o. b.i.d., the
animal’s behavior and activity level returned to
normal. At this dosage, a 6.5-hr postingestion
blood level of levetiracetam was determined to be
3.7 mcg/ml, considered subtherapeutic in human
epilepsy patients. After an additional seizure was
observed 6 mo later, the levetiracetam dosage was
increased to 250 mg p.o. b.i.d. No fatigue or
asthenia was noted after the dosage elevation.
Repeat blood levels taken 4 mo later were 7.2
mcg/ml at 5.5 hr postingestion. Because of the
association between seizure occurrence and ovu-
lation, this bonobo was also started on an
extended-cycle oral contraceptive regimen given
continuously. No additional seizures were noted
prior to death due to cardiovascular disease and
stroke.
Case 3
An infant male western lowland gorilla (Gorilla
gorilla), captive born in 1983, developed seizures
at 1 mo of age, which initially self-resolved but
then recurred 5 mo later. Initial treatments with
phenobarbital 15–30 mg p.o. s.i.d. to t.i.d. and
dilantin 15–30 mg p.o. s.i.d to b.i.d. were not
successful in suppressing seizures, which contin-
ued at 1–4-hr intervals. At day 4, the serum
phenobarbital level was 19 mcg/ml, a level
considered therapeutic in human epilepsy pa-
tients at the time. The only blood work abnor-
mality was an elevation of alkaline phosphatase,
attributed to age and drug administration. A CT
scan revealed enlarged ventricles suggestive of
hydrocephalus. Dilantin was discontinued on day
6 of treatment because of excessive drowsiness. At
day 19, carbamazepine 50 mg p.o. b.i.d. was
initiated, and phenobarbital was gradually dis-
continued over the next week. After 14 days of
treatment, the serum carbamazepine level was 8.8
mg/L. The frequency of carbamazepine adminis-
tration was increased to t.i.d. at 1 yr of age.
Seizures remained well controlled until the gorilla
was transferred to another institution a year later.
No further seizures were observed and the animal
was gradually weaned from antiepileptic therapy
several years later. The gorilla died of unrelated
causes in 2006 at the age of 23 yr, and hydroceph-
alus was confirmed on postmortem examination
(Murray, pers. comm.).
DISCUSSION
Epileptic syndromes are well described in the
human literature.9 With little information pub-
lished on epilepsy and its treatment in NHPs,
veterinarians often extrapolate from human med-
icine when developing treatment options for
animals. Historically, phenobarbital has been
used for treatment of epilepsy in primates.
However, the side effects of phenobarbital in-
clude profound lethargy and sedation, as well as
clotting and connective tissue disorders and
osteoporosis.1,3 In humans, children appear par-
ticularly prone to adverse cognitive or behavioral
effects.1,3 Breakthrough seizures are common
when phenobarbital is used as a monotherapy.
These concerns make phenobarbital nonideal for
the treatment of primates with epilepsy, making
the use of adjunctive or alternative therapies
warranted in these cases.
Adjunctive therapies work in synergy with
primary AEDs to decrease the frequency of
epileptiform seizures. Adjunctive drugs used in
human medicine include acetazolamide and ga-
bapentin. Acetazolamide is a weak carbonic
anhydrase inhibitor with mild diuretic actions
often used in the treatment of glaucoma and
292 JOURNAL OF ZOO AND WILDLIFE MEDICINE
metabolic acidosis. Acetazolamide is believed to
exert antiepileptic effects by causing a slight
acidosis in the central nervous system (CNS),
thus decreasing neuronal excitation.12 Acetazol-
amide is not metabolized by the liver and is safe to
give in combination with phenobarbital. It has a
rapid onset of anticonvulsant action and has been
shown to decrease the frequency of menstruation-
associated seizures.12 Its use as an adjunctive
therapy in case 1 allowed for a decrease in the
dosage of phenobarbital with a concomitant
reduction in associated side effects while still
preserving effective seizure suppression. The
twice-daily dose of 312.5 mg of acetazolamide
given to this bonobo falls within the recommend-
ed dosage of the drug for humans of 8–30 mg/kg
in 1–4 divided doses, not to exceed 1 g/day.8
Another possible adjunctive therapy for treat-
ment of epilepsy in NHPs is gabapentin, which
increases synthesis and release of c-aminobutyric
acid, the major inhibitory neurotransmitter in the
CNS.2,4 Gabapentin is not metabolized by the liver
and does not interact with most other AEDs or
oral contraceptives. In human patients, side
effects are rare, and it is well tolerated and very
affordable in its current generic form.
Hormonal manipulations may also be used as a
form of adjunctive therapy for seizure control.
Catamenial epilepsy has long been recognized in
humans and refers to seizure exacerbation in
relation to the menstrual cycle. In women with
regular ovulatory cycles, seizures may be more
frequent at the time of ovulation because of the
proconvulsant effects of estrogen or during the
perimenstrual period because of the drop in
progesterone, which is protective against sei-
zures.7,11 For the bonobo in case 2, seizures were
noted only on the day of ovulation, which would
correlate to the seizure-generating effects of
estrogen. In case 1, seizures were most commonly
noted the week prior to menstruation, which
correlates to the loss of the protective effect of
progesterone. Case 1 also demonstrated an exac-
erbation of seizures during perimenopause, which
is seen in women as cycles become irregular. After
complete menopause, seizure control in women
may improve.
To ameliorate the natural hormonal cycles in
these bonobos, both were started on extended
cycle administration of standard oral birth control
pills. For the bonobo in case 1, a short 2-day
contraceptive holiday every 3 mo was allowed,
which was managed by a short-term increase in
the phenobarbital dosage. Because phenobarbital
induces hepatic cytochrome P450 enzymes, in-
creased metabolism of estrogens should occur,
which could render oral contraceptives less effec-
tive.11 Fortunately, contraception is not needed for
the bonobo in case 1. For the bonobo in case 2,
extended cycle oral contraceptives were given
continuously without a drug holiday, with the
goal of preventing the large spike in endogenous
estrogens at the time of ovulation. Even though
oral administration of hormones has not been
found effective in women with catamenial epilep-
sy, decreased seizure frequency has been noted in
both bonobos after starting extended cycle oral
contraceptives.
Phenobarbital was not tolerated by the bonobo
in case 2 because of the adverse effects of marked
sedation and painful abdominal bloating. In this
case, an alternative primary AED was utilized.
After dosage adjustments, levetiracetam at 250
mg p.o. b.i.d. effectively controlled seizures with
no observed side effects. Levetiracetam is chem-
ically unrelated to other AEDs and is believed to
prevent hyperactivity of neuronal tissue and the
spread of depolarization.10 It is not extensively
metabolized and a majority of the drug is excreted
unchanged by the kidneys.13 In general, levetir-
acetam has a wide margin of safety with few drug
interactions. The main side effects of fatigue,
incoordination, and behavioral problems usually
occur only during the initial few weeks of
treatment and respond to dosage reductions.13
Levetiracetam is effective as a monotherapy to
prevent epileptic seizures, reaches therapeutic
levels rapidly, and is available as a generic
crushable tablet in multiple concentrations.10,13
Carbamazepine, the AED used in case 3, is a
tricyclic anticonvulsant agent believed to stabilize
hyperexcited neuronal membranes by blocking
voltage-dependant ionic membrane channels.6 It
comes in multiple oral formulations and its
absorption is not affected by food. However,
because carbamazepine induces its own metabo-
lism, dosages may need to be increased frequently
during the first few weeks of therapy. Oxcarbaze-
pine is a new drug of the same group, with less
induction of cytochrome P450 and no autoinduc-
tion period. It also has good oral absorption and
comes in multiple formulations, including chew-
able tablets. Although rare, oxcarbazepine-asso-
ciated hyponatremia has been reported, and the
drug is not recommended in older or moribund
patients.2
CONCLUSION
Although phenobarbital has been a mainstay in
the treatment of NHPs with epilepsy in the past,
GERLACH ET AL.—ANTIEPILEPTIC DRUGS IN APES 293
its side effects and limitations often make it
inappropriate as the sole AED. Adjunctive drugs
can assist with seizure control, and allow for a
reduction in phenobarbital dosage. Newer AEDs
may allow for the control of epileptiform seizures
with fewer observed side effects, and their use
should be considered for treatment of NHPs with
epilepsy. When evidence of catamenial epilepsy is
present, oral contraceptives may help control
hormonal changes that trigger seizure occurrence.
Additional pharmacologic studies of the newer
AEDs in NHPs and additional clinical experience
are needed to provide more effective options in
the treatment of NHPs with epilepsy.
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Received for publication 13 October 2010
294 JOURNAL OF ZOO AND WILDLIFE MEDICINE
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