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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

(vclyde@milwcnty.com).

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