Epilepsia, 26(2):122- 126, 1985
Raven Press, New York
0 International League Against Epilepsy
Valproate and Clonazepam Comedication in Patients with
Intractable Epilepsy
Ruy Mireles and 110 E. Leppik
Comprehensive Epilepsy Program, University of Minnesota, Minneapolis, Minnesota, U . S . A .
Summary: The efficacy and the potential risk of inducing
convulsive o r nonconvulsive status epilepticus with the
combination of valproate (VPA) and clonazepam (CZP),
with or without other anticonvulsant drugs, in 55 patients
with intractable epilepsy was evaluated. The patients
were treated with VPA and CZP concomitantly for from
3 to 72 months (mean 21.7 months). Trough VPA serum
levels ranged from 26 t o 96 pgiml (mean 56.6 pgiml).
Trough C Z P s e r u m levels ranged from 5 t o 63 ng/ml
(mean 22.6 ng/ml). The treatment seizure frequency was
compared with baseline values before combination treat-
Although monotherapy is a commendable goal in
the treatment of epilepsy (Leppik, 1984), some pa-
tients with intractable epilepsy may need more than
one antiepileptic drug to improve seizure control.
Valproate (VPA) and clonazepam (CZP) comedi-
cation, with or without other antiepileptic drugs,
has been underutilized because reports in the med-
ical literature caution against such therapy. One re-
port described 1 1 patients with absence seizures
who were taking only VPA and CZP in combina-
tion. Five patients developed absence status. The
authors concluded that a combined use of these two
drugs is to be avoided (Jeavons et al., 1977). In a
textbook of clinical neuropharmacology, the state-
ment is made that the combination of VPA and CZP
has been reported to induce status epilepticus in a
number of cases, and concomitant use of these two
drugs is not recommended (Klawans et al., 1981).
Confusion has arisen, and some have misinter-
preted this information, concluding that these two
Received November 28. 1984.
Address correspondence and reprint requests to Dr. R.
Mireles at his present address: Matamoros 1010 Oriente, Mon-
terrey, Nuevo Leon, 64000 Mexico.
This study was presented at the American Epilepsy Society
meeting held in San Francisco, CA, U.S.A., in November 1984.
122
ment. Seizure improvement was obtained in 7 of 8 pa-
tients with absence seizures. 8 of 9 patients with myo-
clonic seizures, 19 of 39 patients with complex partial
seizures, 3 of 14 patients with primary generalized tonic-
clonic seizures, 8 of 23 patients with secondarily gener-
alized tonic-clonic seizures, and 3 of 14 patients with
atonic seizures. No single case of status epilepticus or
exacerbation of seizures of a n y type w a s seen. Key
Words: Clonazepam - Comedication - Epilepsy - In-
tractable seizures-Valproate.
drugs in combination may induce convulsive status
epilepticus.
VPA is an effective antiepileptic drug often used
in conjunction with other antiepileptic drugs for the
control of refractory seizures. It is a major drug for
the treatment of primary generalized seizure dis-
orders (Wilder and Karas, 1982) and is a most ef-
fective drug in the treatment of absence seizures
(Sato et al., 1982). It has also been shown to be as
effective as phenytoin for newly diagnosed gener-
alized tonic-clonic seizures in patients who had not
received prior therapy (Wilder et al., 1983).
CZP was approved by the U.S. Food and Drug
Administration in 1976 as a single or adjunctive an-
ticonvulsant for absence seizures, infantile spasms,
atypical absence seizures, minor motor seizures,
and Lennox-Gastaut syndrome (Browne, 1976). Re-
cent studies have demonstrated some efficacy for
generalized tonic-clonic and partial seizures
(Hussey, 1976; Nanda et al., 1977).
At the University of Minnesota Comprehensive
Epilepsy Program (UMCEP), we carefully with-
draw antiepileptic drugs during an inpatient period
for seizure observation, determine the antiepileptic
drug concentration-response and add
antiepileptic drugs one at a time to obtain maximum
 VALPROATE A N D CLONAZEPAM COMEDICATION
TABLE 1. Summary of seizure types
No. of
Seizure type patients
Absence
Simple 6 Phenytoin
Atypical 2 Carbamazepine
Primary generalized tonic-clonic 14
Myoclonic 9 Primidone
Atonic 15
Tonic 3 Mephenytoin
Simple partial 6
Complex partial 40
Secondarily generalized tonic-clonic 27
Total" I22
' More than 55 patients because many individuals had more
than one type of seizure.
control with minimal side effects. Initially, we were
reluctant to use the combination of CZP and VPA.
This report describes the UMCEP experience with
the combined use of VPA and CZP, with or without
other antiepileptic drugs, in individuals with refrac-
tory seizures.
PATIENTS AND METHODS
We reviewed -500 patients admitted to the Epi-
lepsy Treatment Unit of the UMCEP between June
1980 and April 1984. From this population, we iden-
tified 55 patients (24 women and 31 men), 15-44
years old (mean 26.7 years), with intractable sei-
zures who were treated with a combination of CZP
and VPA at some time. Medical intractability was
defined as daily or weekly seizures that occurred
despite documented therapeutic blood levels of ap-
propriate antiepileptic drugs under our supervision.
Seizure types are listed in Table 1. Etiology of the
epilepsy was undetermined in 26 patients, CNS in-
fections in 14, birth anoxia in 8, head injury in 3,
CNS neoplastic lesions in 3, and Lafora disease in
1. The duration of epilepsy ranged from 9 to 38
years (mean 19.7 years) at the time of study.
The patients were treated with VPA and CZP
concomitantly for from 3 to 72 months (mean 21.7
months). VPA trough serum levels ranged from 26
to 96 pgiml (mean 56.6 pgiml), and CZP trough
serum levels ranged from 5 to 63 ngiml (mean 22.6
ngiml). Five patients were taking only VPA and
CZP in combination. Fifty patients were taking one,
two, or three additional antiepileptic drugs (Table
2). Of these 50 patients, 20 were taking one drug,
28 were taking two drugs, and 2 were taking three
drugs in addition to the combination of VPA and
CZP. The drug dosages were adjusted if serum
levels changed significantly. The patients were fol-
lowed up after hospital discharge as outpatients and
123
TABLE 2 . Other antiepileptic drugs used during
treatment with valproate and cloncizepum
Drugs No. of patients
None 5
37
36
Ethosuximide 3
3
Phenobarbital 2
1
Total" 87
" More than 55 patients because some individuals were taking
additional antiepileptic drugs.
were readmitted for further evaluation if necessary.
The patients were taking either VPA or CZP prior
to the introduction of the other drug. CZP was
added only during hospitalization at 0.5 mg b.i.d.,
and the dosage was increased to 3-5 mgiday in -1
week to permit development of tolerance to seda-
tive side effects. VPA doses ranged from 13.3 to
67.4 mgikg (mean 29.8 mgikg); CZP doses ranged
from 0.02 to 0.23 mgikg (mean 0.09 mgikg). Anti-
epileptic drug levels were monitored often, and
drug dosage adjustments were made according to
clinical response and side effects.
Pretreatment evaluation consisted of a history,
general physical and neurological examination,
complete blood count, platelet count, urinalysis,
electrocardiogram, blood chemistries, chest radi-
ogram, and brain computed tomographic scan.
EEGs and ictal events were simultaneously docu-
mented in each patient by video electroencefalog-
raphy-telemetry recording (EEG-TR) to ensure an
accurate seizure type classification.
Parameters assessed were age, sex, seizure
types, duration of epilepsy, seizure etiology, mean
trough VPA and CZP serum levels, other antiepi-
leptic drugs given concomitantly, interval receiving
VPA and CZP treatment combination, and results
of seizure control. Seizure frequency was moni-
tored by observation in the hospital and patient re-
ports at clinic visits. Patients maintained records by
use of a calendar.
The results were classified as excellent (75- 100%
seizure reduction), good (50-74%), poor ( d o % ) ,
or increased seizure frequency. The treatment sei-
zure frequency was compared with the baseline sei-
zure frequency prior to combination treatment.
VPA and CZP levels were measured in blood
drawn prior to the first a.m. dose (trough), and drug
blood levels were determined at the University of
Minnesota Hospital Laboratory. CZP level was de-
termined by gas chromatography using an electron
capture detector (coefficient of variation 3 .5%).
Epilepsia, Vol. 26, N o . 2, 1985
 124 R. MIRELES A N D I. E. LEPPIK
VPA level was determined by gas chromatography
using a flame ionization detector (coefficient of
variation at 65 pg/ml 2%).
RESULTS
Absence seizures
Six patients had simple absences. One patient
was taking only the combination of VPA and CZP.
Other drugs taken were phenytoin (two patients),
ethosuximide and phenytoin (one), primidone and
carbamazepine (one), and phenytoin and carbam-
azepine (one). Trough VPA serum levels ranged
from 51 to 68 p.g/ml (mean 57.1 pg/ml), and trough
CZP serum levels ranged from 6 to 50 ng/ml (mean
16.7 ng/ml). These patients received combination
treatment for from 3 t o 54 months (mean 29.6
months). One patient had excellent and four had
good results; in one patient absence seizure fre-
quency was unchanged.
Two patients with atypical absences (Penry et al.,
1975) were identified. One of them was taking only
the combination of VPA and CZP, and one was
taking carbamazepine in addition to the combina-
tion. Trough VPA serum levels ranged from 41 to
71 pg/ml (mean 56 pg/ml), and trough CZP serum
levels ranged from 12 to 33 ng/ml (mean 22.5 ng/
ml). These two patients received combination treat-
ment for from 2 to 24 months (mean 14 months).
One patient had an excellent and one had a poor
result. No patient had status or increased seizures.
Primary generalized tonic-clonic seizures
Of the 14 patients identified, two were taking only
the combination of VPA and CZP. Other drugs
taken were phenytoin (three patients), phenytoin
and carbamazepine (four), primidone and carbam-
azepine (two), carbamazepine (one), ethosuximide
and phenytoin (one), and phenytoin and primidone
(one). Trough VPA serum levels ranged from 38 to
72 pg/ml (mean 58.3 pg/ml), and trough CZP serum
levels ranged from 5 to 63 nglml (mean 22.4 ng/ml).
The patients received the combination for from 3 to
73 months (mean 25.3 months). One patient had ex-
cellent and two had good results while receiving
combination treatment; 11 had an unchanged sei-
zure frequency.
Atonic seizures
Of the 15 patients identified, all were taking other
drugs: phenytoin and carbamazepine (lo), carbam-
azepine and primidone (2), phenytoin (l), carbam-
azepine ( l ) , and phenytoin, carbamazepine, and
ethosuximide (1). They received the combination of
VPA and CZP for from 4 to 73 months (mean 28
months). Trough VPA serum levels ranged from 34
Epilepsia, Vol. 26, N o . 2,1985
to 96 yg/ml (mean 60.8 pg/ml), and trough CZP
serum levels ranged from 6 to 52 ng/ml (mean 26.6
ng/ml). One patient had good and two patients had
poor results; 12 patients had an unchanged seizure
frequency during the interval they received com-
bination treatment.
Tonic seizures
Of the three patients identified, two were taking
carbamazepine and phenytoin and one phenytoin
besides the VPA and CZP combination. They re-
ceived combination treatment for from 7 to 36
months (mean 18.3 months). Trough VPA serum
levels ranged from 52 to 70 pg/ml (mean 59.6 p.g/
ml), and trough CZP serum levels ranged from 6 to
30 ng/ml (mean 21.3 ngiml). No seizure frequency
changes were seen while the combination treatment
was being taken.
Myoclonic seizures
Nine patients were identified. One patient was
taking only VPA and CZP in combination. Other
drugs taken were phenytoin and carbamazepine
(two patients), phenytoin (one), carbamazepine
(one), ethosuximide (one), ethosuximide and phe-
nytoin (one), primidone and carbamazepine (one),
and phenytoin, carbamazepine, and ethosuximide
(one). The patients received VPA and CZP concom-
itantly for from 9 to 52 months (mean 27 months).
Trough VPA serum levels ranged from 38 to 96 p.g/
ml (mean 48 pgiml), and trough CZP serum levels
ranged from 12 to 63 ng/ml (mean 28.8 ng/ml). Three
patients had excellent, three had good, and two had
poor results; one patient had an unchanged seizure
frequency during the combination trial.
Simple partial seizures
Six patients were identified. Seizures were too
infrequent for valid analysis.
Complex partial seizures
Forty patients were identified. Two were taking
only VPA and CZP in combination. Other drugs
taken were mephenytoin (1 patient), phenobarbital
(I), phenytoin (6), carbamazepine (6), carbamaze-
pine and phenytoin (22), phenytoin, carbamaze-
pine, and ethosuximide (l), and carbamazepine and
primidone (I). The patients received VPA and CZP
for from 4 to 73 months (mean 21.6 months). Trough
VPA serum levels ranged from 33 to 96 pg/ml (mean
55.6 p.g/ml), and trough CZP serum levels ranged
from 6 to 45 ng/ml (mean 21.4 ng/ml). Two patients
had an excellent, eight had a good, and nine had a
poor response. Twenty had an unchanged seizure
frequency during the trial. In one patient, assess-
ment of results was not possible because of the in-
frequency of his epileptic episodes.
 V ALPR O A TE A N D CLONAZEPAM COMEDICAT I 0N 125

TABLE 3. Summary o j results according t o seizure type

Results Mean Mean
valproate clonazepam Length of
No. of Excellent Good Poor level level treatment
Seizure type patients (75- 100%) (50-74%) (0-49%;) Unchanged Increased (pgiml) (ngind) (mo)
Simple absence 6 1 4 - I 0 57.1 16.7 29.6
Atypical absence 2 I - 1 - 0 56.0 22.5 14.0
Atonic 15 - 1 2 12 0 60.8 26.6 28.0
Tonic 3 - - - 3 0 59.6 21.3 18.3
Myoclonic 9 3 3 2 1 0 48.0 28.8 27.0
Complex partial 40" 2 8 9 20 0 55.6 21.4 21.6
Primary generalized
tonic-clonic 14 I 2 - 11 0 58.3 22.4 3.3
Secondarily generalized
tonic-clonic 27" 1 6 I 15 0 S2.4 22 20.0

" The effects of therapy were not assessed for one patient with complex partial and four patients with secondarily generalized tonic-clonic aeizures
because of insufficient ictal events for valid analysis

Secondarily generalized tonic-clonic seizures
Twenty-seven patients were identified. Two were
taking only VPA and CZP in combination. Other
drugs taken were phenytoin (6 patients), carbam-
azepine (4), carbamazepine and phenytoin (13), me-
phenytoin (l), and phenytoin and phenobarbital (1).
The patients received the combination of VPA and
CZP for from 5 to 51 months (mean 20 months).
Trough VPA serum levels ranged from 26 to 75 pg/
ml (mean 52.4 pg/ml), and trough CZP serum levels
ranged from 6 to 45 ng/ml (mean 22 ng/ml). In 15
patients seizure frequency was unchanged. One pa-
tient had excellent, six had good, and one had poor
results. Assessment in four patients was not made
because of infrequent epileptic episodes.
DISCUSSION
None of the six patients in our population with
simple absence had an exacerbation of seizures or
developed absence status, contrary to a previous
report (Jeavons et al., 1977).
Two of our five patients who were taking only
VPA and CZP in Combination had absence seizures.
They achieved excellent results in the combination
treatment. Our reports support the comments that
absence status is a rare event and that with careful
clinical and pharmacological monitoring, the con-
comitant use of these two drugs is not absolutely
contraindicated (Dreifuss, 1983; Sherwin, 1983).
Our study indicates that some patients with in-
tractable epilepsy achieved a good to excellent re-
sponse to a combination of VPA and CZP, with or
without other antiepileptic drugs. Overall, no single
case of exacerbation of seizures of any type or in-
duction of convulsive or nonconvulsive status epi-
lepticus was seen during the time that the combi-
nation treatment of VPA and CZP was adminis-
tered.
The degree of improvement in seizure frequency
was not directly related to known therapeutic serum
levels of VPA and CZP by itself. Rather, it seemed
to be an individual response to the medication by
each particular patient.
Previous studies have shown an increase in sei-
zure frequency in a minority of patients receiving
CZP for tonic-clonic seizures (Browne, 1976), ab-
sence seizures (D'onghia et al., 1973), tonic and
atonic seizures (Alvarez et al., 1981>, myoclonic
seizures (Roussounis and de Rudolph, 1977), com-
plex partial seizures (Bang et al., 1976; Shakir et
al., 1977), and elementary partial seizures (Browne,
1976). Most of our patients were also taking addi-
tional anticonvulsant drugs, which might have pro-
tected them from seizure exacerbation. Our results
indicated no seizure exacerbation of any type as
compared with baseline values. In individuals with
severe refractory seizure disorders with multiple
seizure types including absence, myoclonic, pri-
mary or secondary generalized tonic-clonic, or par-
tial complex seizures, a combination of VPA and
CZP may be used to attempt better seizure control
when all other avenues of monotherapy and poly-
therapy have failed.
Acknowledgment: This study was supported in part by
grant NPSO-NS 16308 from the National Institute of Neu-
rological and Communicative Disorders and Stroke. Dr.
Mireles is the recipient of a Hughlings Jackson Fellow-
ship from the Epilepsy Foundation of America.
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Bang F , Birket-Smith E, Mikkelsen B. Clonazepam in the treat-
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Browne TR. Clonazepam: a review of a new anticonvulsant
drug. Arch Neurol 1976;33:326-32.
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Sato S, et al. Valproic acid versus ethosuximide in the treatment
of absence seizures. Neitrology 1982;32:157-63.
Shakir RA, et al. Comparison of sodium valproate (Epilim) and
clonazepam (Rivotril) in intractable epilepsy. In: Penry JK,
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&SUME
Lefficacite de I’association vatproate (VPA) et clonazepam
(CZP), avec ou sans autre anticonvulsivant, et son risque poten-
tiel d’induire des etats de mal, convulsifs ou non convulsifs, ont
ete evalues chez 55 patients ayant une Cpilepsie rebelle. Les
patients ont ete traites par VPA et CZP associks pendant des
periodes allant de 3 a 72 rnois (moyenne 21,7). Les taux plas-
matiques de VPA allaient de 26 a 96 p,g/ml (moyenne: 56,6). Les
taux plasmatiques de CZP allaient de 5 a 63 ng/ml (moyenne:
22,6). La frequence des crises pendant le traitement a ete com-
parke a leur frequence de base avant ce traitement. Une am&
lioration a ete obtenue chez 7 des 8 patients ayant des absences,
chez 8 des 9 patients ayant des acces myocloniques, chez 19 des
39 patients ayant des crises partielles complexes, chez 3 des 14
Epilepsia, Vol. 26, N o . 2 , 1985
patients ayant des crises tonico-cloniques generalisees d’emblee,
chez 8 des 23 patients ayant des crises tonico-cloniques secon-
dairement genCralisCes, et chez 3 des 14 patients ayant des crises
atoniques. Aucun cas d’etat de ma1 ni d’exacerbation des crises
n’a Cte observe, quel que soit le type des crises.
(C. Dravet, Marseille)
RESUMEN
Se ha evaluado la eficacia y el riesgo potencial de inducir un
status epileptico convulsivo o no-convulsivo con la combinacion
de valproato (VPA) y clonazepan (CZP) con o sin otros drogas
anticonvulsivas en 55 pacientes con epilepsia incontrolable. Los
enfermos fueron tratados con VPA y CZP durante 3 a 72 meses
(promedio: 21.7). Los niveles sericos de VPA oscilaron entre 26
y 96 pgirnl (prornedio: 56.6). Los niveles sericos de CZP variaron
entre 5 y 63 ngiml (prornedio: 22.6). El tratamiento de la fre-
cuencia de 10s ataques se cornpar6 con la situacion basal antes
del tratamiento combinado. Se consiguio una mejoria de 10s
ataques en 7 de 10s 8 pacientes con ataques de ausencia, 8 de 9
pacientes con ataques mioclonicos, 19 de 10s 39 pacientes con
ataques parciales complejos, 3 de 10s 14 pacientes con GTC pri-
maria, 8 de 10s 23 pacientes con GTC secundaria y 3 de 10s 14
pacientes con ataques atonicos. No se observo ningun caso de
status epileptico o de exacerbacion de 10s ataques.
(A. Portera Sanchez, Mudrid)
ZUSAMMENFASSUNG
Die Wirkung und das potentielle Risiko einen konvulsiven
oder nicht-konvulsiven Status epilepticus durch Kombination
von Valproat (VPA) und Clonazepam (CZP) mit oder ohne wei-
tere Antikonvulsiva hervorzurufen, wurde bei 55 Patienten mit
therapieresistenter Epilepsie untersucht. Die Patienten wurden
mit VPA und CZP 3 bis 72 Monate lang (Mittel: 21,7) behandelt.
Die minimalen Serum VPA Spiegel variierten von 26 bis 96 pg/
mi (Mittel: 56,6). Die niedrigsten Serum CZP Spiegel betrugen
5 his 63 ng/ml (Mittel: 22,6). Die Anfallsfrequenz unter Behan-
dlung wurde verglichen mit der Haufigkeit vor der Kombina-
tionsbehandlung. Eine Verbesserung der Anfallssituation ereig
nete sich bei 7 von 8 Patienten mit Absencen, 8 von 9 Patienten
mit myoklonischen Anfdlen und 19 von 39 Patienten mit kom-
plexen Partialanfallen. 3 von 14 Patienten mit prirnar generali-
sierten, tonisch-klonischen Anfallen, 8 von 23 Patienten mit sek-
undaren generalisierten, tonisch-klonischen Anfallen sowie 3
von 14 Patienten mit atonischen Anfallen wurden positiv beein-
flusst. Kein einziger Fall von Status epilepticus oder einer Ex-
azerbation von Anfallen irgendeines Typs wurde beobachtet.
(D. Scheffner, Heidelberg)