A
Study
Eileen P. G.
of
Refractory Seizures
in
Valproate Sodium Efficacy
Vining, MD;
Elaine
Botsford, RN; John
\s=b\ Sodium valproate (N-dipropylacetic acid) is a newly released anticonvulsant drug with a broad spectrum of activity. Twenty-seven children with uncontrolled seizures, predominantly akinetic and myoclonic, were treated with this drug. Encouraging results were noted in those with head-nodding spells, body drops, and myoclonic jerks ("minor motor" seizures).
sodium (N-dipropylacetic a new anticonvulsant has been licensed in the United States for use in absence seizures. Its broad spectrum of activi¬ ty12 and reported lack of side effects has prompted its use for other seizure types.1-' This article reports the results of treatment in patients selected because of uncontrolled sei¬ zures.
SUBJECTS
Twenty-seven children with intractable and refractory seizures were selected for initiation of valproate sodium therapy. Most had frequent seizures of multiple types, predominantly akinetic and myo¬ clonic. The classification of the seizures, frequency, and age of patients are shown in the Table. Multiple medications had From the Departments of Pediatrics (Drs Vining and Freeman) and Neurology (Drs Vining and Freeman), Johns Hopkins University School of Medicine, Baltimore, and the Pediatric Seizure Clinic (Drs Vining and Freeman and Ms Botsford), John F. Kennedy Institute, Baltimore.
Reprint requests to Pediatric Seizure Clinic, John F. Kennedy Institute, 707 N Broadway, Baltimore, MD 21205 (Dr Vining).
Freeman, MD Description
of Patient
No. of Patients
Type of Seizure Generalized seizure
Population Frequency of Seizures Before Valproate Sodium
Regimen
Age, yr
Akinetic/atonic Head nods
Tonic-clonic Tonic Absences Partial seizures Partial seizures with
3/day-continuous 2/mo-50/day 6/day-contlnuous 1/mo-10/day 5/wk-6/day 35/day
7-13 3-19 5-9 3-18 2-12
15
Body drops Myoclonus
Side effects included occasional gastrointestinal disturbance. No important hepatotoxic complications were noted. Two persons displayed transient neurologic side effects. Of particular interest was the noticeable improvement in mental status noted in 17 of the 27 patients. Some variations in blood level of other anticonvulsant drugs were noted, emphasizing the importance of monitoring these drugs. Valproate sodium provides important improvement in our ability to manage minor motor seizures. (Am J Dis Child 133:274-276, 1979)
Valproate acid), recently drug,
M.
15
11 com¬
plex symptoms
Atypical absence Psychomotor
3-25 7-17
rare-15/day 3/wk-10/day
5-15 5-19
rare-4/wk
Partial seizures with elemen¬
tary symptoms Other, unclassified
2/yr-12/day
pmiiiiii
o rr
4L
SPIKE AND WAVE 3 Hz
Fig
ATYPICAL SPIKE AND WAVE
FOCAL SPIKE
MULTIPLE SPIKES
1—Distribution of EEG abnormalities in
previously been used in these children without obtaining seizure control even when increased to toxic levels. Most chil¬ dren were unable to function at a level commensurate with their given capabili¬ ties at home or in school. Seventeen had IQs less than 70. The retardation was accentuated by the sedative effects of medication and possibly by the myriad minor seizures. Eleven children had spikewave (Lennox-Gastaut) pattern on the EEG (Fig 1).
METHODS Patients were selected because of their uncontrolled seizures. Parents were in-
NON SPECIFIC
UNKNOWN
patient population.
formed of the known toxic effects and benefits of the drug and agreed to the use of valproate sodium in their children. This use of valproate sodium primarily for the benefit of the individual child rather than for the purpose of a formal study precluded
multiple laboratory procedures. Follow-up EEGs have not been possible in many cases for this reason. Laboratory studies, in¬ cluding blood chemical determinations, complete blood cell and platelet counts, and
blood levels of measurable anticonvulsant drugs were done at the initiation of valproate sodium therapy and these were repeated at approximately monthly inter¬ vals. Seventeen patients were receiving
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Arizona Health Sciences Library User on 05/31/2015
clonazepam or diazepam. The
serum levels measured. Seizure frequency was recorded and reported by parents. The patients have been followed for five to 12 months (mean, 7.6 months). Valproate sodium (LaBaz) was given at a dosage of 10 to 20 mg/kg per day in two or three divided doses while continuing the child's other anticonvulsant drugs. Efforts were made to maintain these drugs within
of these
were
not
accepted therapeutic ranges. Valproate sodium dosage was gradually increased
until either seizure control was obtained or the medication was judged unsuccessful. It was discontinued in two patients because of lack of effect at doses of 20 and 70 mg/kg per day, respectively. Seven chil¬ dren required a daily dosage of 50 to 60 mg/kg for seizure control. When lethargy or ataxia occurred, blood levels of other anticonvulsant drugs were measured and dosages altered as indicated.
RESULTS Seizure Control
Seizure control was analyzed by seizure type. Improvement was mea¬ sured on the basis of decrease in each seizure type reported by the patient. Improvement of 100% is equated with complete control of a particular type of seizure. Improvement of 75% to 99% indicates that percent decrease in seizures; if a child were having a hundred head nodding spells per day, this would indicate that while receiv¬ ing valproate sodium he was having less than 25 spells per day. On the other hand, if a child were having one seizure a day, 75% improvement could mean a seizure frequency of one seizure a year or perhaps one every four days. Most patients had multiple types of seizures, and one type might be controlled while others persisted. Minor Motor Seizures.—This term has been used to include myoclonic seizures, head nods, and body drops (akinetic-atonic). These seizures are the most resistant to conventional medication, responding on occasion to benzodiazepines (diazepam or clonaze¬ pam), to acetazolamide, or to the ketogenic diet, and are often asso¬ ciated with mental retardation. This lack of response to therapy and the sedative effect of many of the drugs cause these patients to be among the most refractory and challenging of
management problems.
Minor motor seizures
were
the
(grand mal) had additional seizure
predominant seizure type in 13 of the patients. Nine of these patients were mentally retarded; the mean IQ for eight of these patients was 48. Five had spike-wave (Lennox-Gas-
types that included minor
27
taut) EEG patterns. Seizures were occurring from two per month to
myriad per day, with most children in the latter category (Table). Medica¬
tions included ethosuximide, carbamazepine, phenytoin sodium, clonazepam, primidone, and diazepam, usual¬ ly in combination. The head-nodding spells of three patients were completely controlled with a mean valproate sodium dose of 47 mg/kg per day. Fifteen children had body drops (akinetic seizures) in addition to other seizure types. Al¬ though these spells occurred less
frequently, they were more incapaci¬ tating and required helmets or con¬
finement to a chair. Of the 15 children, the seizures of four were completely controlled, three had at least a 75% decrease in seizure frequency, four were 33% to 75% improved, and one showed less than 33% improvement. Three children with this seizure type showed no improvement (Fig 2). Five children had myoclonic sei¬ zures that consisted of brief, isolated jerking movements occurring from six times per day to continuously. The myoclonic seizures of two were com¬
pletely
controlled;
two
patients
showed 75% to 99% improvement; and one showed no improvement. Tonic-Clonic Seizures.—The 15 pa¬ tients with tonic-clonic seizures
] ^^
100% IMPROVED
motor and absence spells. In only one patient were the tonic-clonic seizures com¬ pletely controlled, whereas seven achieved 75% to 99% control. Thirtythree percent to 75% improvement was noted in three patients; 33% improvement was seen in two pa¬ tients; and two showed no improve¬ ment (Fig 2). Of those with greater than 75% improvement, only three required more than 30 mg/kg/day to achieve this degree of control. In several patients, control was main¬ tained only as long as another major anticonvulsant drug (usually pheny¬ toin oç phénobarbital) was continued. Other Seizures.—Two children with psychomotor seizures experienced 33% to 75% improvement in seizure con¬ trol. Of the three children with tonic
seizures,
two
improvement.
Other seizures,
some
of which could
not be
clearly classified, were not as one patient showed well, 100% improvement, one had 75% to controlled:
$*$$
33 75% IMPROVED
75-99% IMPROVED
experienced complete
control. The third showed 33% to 75% improvement but was still on a regi¬ men of less than 40 mg/kg/day. The pure absence seizures of one child were completely controlled. Atypical absence seizures were varia¬ bly controlled. The seizures of one child were completely controlled, two patients showed 75% to 99% improve¬ ment, two showed 33% to 75% improvement, one showed less than 33% improvement, and two showed no
NOT IMPROVED
33% IMPROVED
15
10
m
m
D 2
mr~¡ HEAD
BODY
NODS
DROPS
Fig 2.—Percentage valproate sodium.
of
MYO CLONUS
TONIC CLONIC
improvement
TONIC
PURE
ATYPICAL PSYCHO
ABSENCE
for various seizure
ABSENCE
types
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Arizona Health Sciences Library User on 05/31/2015
E
OTHER
MOTOR
in controls
receiving
improvement, and improvement.
four had
99%
no
Side Effects
According to the literature,1-2 the commonly reported side effects of valproate sodium include gastroin¬ testinal disturbances (16%), sedation usually associated with combination drug therapy (5%), platelet dysfunc¬ tion possibly reflected in prolonged bleeding times, and occasional behav¬ more
ioral deterioration. Transient hair loss has also been noted. Transient eleva¬ tion of liver enzyme levels is reported and isolated cases of severe hepatoxic effects have been observed. In 18 of the 27 patients in this study, liver enzyme levels were found to be mildly elevated. In no case were these altera¬ tions considered sufficient to require discontinuation of valproate sodium, and in many cases the liver enzyme values returned to normal while medi¬ cation was continued. Four individu¬ als had transient gastrointestinal dis¬ turbances, including nausea and vom¬ iting. These symptoms responded to administration of medications with meals. Two individuals displayed neu¬ rologic side effects: one became very
drowsy secondary to high phénobar¬ a
bital level and one demonstrated temporary ataxia that resolved with¬ out any alteration of medication. Mentation
Improved
mental status
by parents, teachers,
or
was
noted of
physicians
was
patients. In most cases, it impossible to determine if this
was
due to
17 of the 27
a
decrease in seizure
frequency (particularly in those with frequent minor motor seizures), to
decreased toxic effects associated with withdrawl of other anticonvul¬ sant
drugs (clonazepam, phénobarbi¬
tal, etc), or to the valproate sodium itself. However, in those with minor motor seizures, this improvement in alertness was frequently as important the decrease in seizure and was even noted in frequency those whose seizures had not been completely controlled. a
feature
as
Other Medications
Twenty youngsters have had one or of their medications decreased;
more
nine of these have had one or more medications discontinued. At this time only one patient is receiving valproate sodium alone. Blood levels of other anticonvulsant drugs were monitored, and consider¬ able fluctuation was noted, though dosages remained constant. Trends indicated a decrease in ethosuximide and phenytoin levels after institution of valproate sodium. Phénobarbital and carbamazepine levels seemed to increase slightly. After the first month, phenytoin levels often re¬ turned to pre-valproate sodium levels without alterations of phenytoin dos¬ ages.
COMMENT
Valproate sodium has been a major addition to our selection of anticonvul¬ sant medications. A double-blind con¬ trolled study has documented its effi¬ cacy in absence seizures'3; uncontrolled studies such as ours have documented its effectiveness in the minor motor seizure group as well as in other seizure types. It is worth noting that 60% of those children with less than 75% improvement have not yet reach¬ ed a dosage level of 50 to 60 mg/ kg/day. However, four of the seven with greater than 75% improvement in the minor motor seizure group are receiving 30 mg/kg/day or less. It may be that there is a relationship between the severity of seizures and the amounts of valproate sodium required for control. It is our overall impression, and that of the parents, that valproate sodium has been of major benefit in most of these chil¬ dren. Review of Fig 2 indicates that some seizures have been only mini¬ mally effected by valproate sodium. However, the child with frequent head nods and occasional akinetic spells would be noticeably improved if the head nods were controlled despite continuation of the occasional akinetic spell.
Controlled and carefully docu¬ mented studies by seizure type are still needed. In the minor motor group, these studies will be compli¬ cated by the severity of the disorder, the combination of these with other seizure types, and the fact that most patients will already have been dem-
onstrated to be refractory to manage¬ ment by other anticonvulsant drugs. For these patients, the use of placebo may be unethical, and the comparison between valproate sodium and other anticonvulsant drugs may have to be made by using the patient as his own control. If valproate sodium is effec¬ tive in controlling many patients with this refractory seizure type, as has been demonstrated by this study and others in the literature,14T and is as safe as already demonstrated by multiple studies,1 it will make a major difference in the lives of these chil¬ dren. At the present time, we believe that valproate sodium is the treat¬ ment of choice for children with minor motor seizures.
This work was supported in part by grant 03-H-000,143-09 from the Department of Health
Education and Welfare. Eldo Bergman, Kenton Holden, and Harvey Singer allowed us to present the case reports of their patients. The staff of the Pediatrie Seizure Clinic aided in this study. Kathy Schmidt provided secretarial assistance.
Names and Trademarks of Drugs
Nonproprietary
Carbamazepine- Tegretol. Clonazepam—Clonopin. Ethosuximide—Zarontin.
Valproate sodium—Depakene. References 1. Simon D, Penry JK: Sodium di-n-propylacetate (DPA) in the treatment of epilepsy: A review. Epilepsia 16:549-573, 1975. 2. Pinder RM, Brogden RN, Speight TM, et al: Sodium valproate: A review of its pharmacological properties and therapeutic efficacy in epilepsy. Drugs 13:81-123, 1977. 3. Sillanpaa M, Donner M: Experiences on the use of dipropylacetate in the treatment of childhood epilepsy. Acta Pediatr Scand 65:209-215, 1976. 4. Lance JW, Anthony M: Sodium valproate and clonazepam in the treatment of intractable epilepsy. Arch Neurol 34:14-17, 1977. 5. Schobben F, van der Kleijn E, Gabreels FJM: Pharmacokinetics of di-n-propylacetate in epileptic patients. Europ J Clin Pharmacol 8:97\x=req-\ 105, 1975. 6. Suzuki M, Maruyama M, Ishibashi Y, et al: A double blind comparative trial of sodium dipropylacetate and ethosuximide in epilepsy in children\p=m-\withspecial emphasis in pure petit mal seizure. Med Prog 82:470-488, 1972. 7. Jeavons PM, Clark JE, Maheshwasi MC: The treatment of generalized epilepsies of childhood and adolescence with sodium valproate (Epilim). Develop Med Child Neurol 19:9-25, 1977.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Arizona Health Sciences Library User on 05/31/2015
Study
Eileen P. G.
of
Refractory Seizures
in
Valproate Sodium Efficacy
Vining, MD;
Elaine
Botsford, RN; John
\s=b\ Sodium valproate (N-dipropylacetic acid) is a newly released anticonvulsant drug with a broad spectrum of activity. Twenty-seven children with uncontrolled seizures, predominantly akinetic and myoclonic, were treated with this drug. Encouraging results were noted in those with head-nodding spells, body drops, and myoclonic jerks ("minor motor" seizures).
sodium (N-dipropylacetic a new anticonvulsant has been licensed in the United States for use in absence seizures. Its broad spectrum of activi¬ ty12 and reported lack of side effects has prompted its use for other seizure types.1-' This article reports the results of treatment in patients selected because of uncontrolled sei¬ zures.
SUBJECTS
Twenty-seven children with intractable and refractory seizures were selected for initiation of valproate sodium therapy. Most had frequent seizures of multiple types, predominantly akinetic and myo¬ clonic. The classification of the seizures, frequency, and age of patients are shown in the Table. Multiple medications had From the Departments of Pediatrics (Drs Vining and Freeman) and Neurology (Drs Vining and Freeman), Johns Hopkins University School of Medicine, Baltimore, and the Pediatric Seizure Clinic (Drs Vining and Freeman and Ms Botsford), John F. Kennedy Institute, Baltimore.
Reprint requests to Pediatric Seizure Clinic, John F. Kennedy Institute, 707 N Broadway, Baltimore, MD 21205 (Dr Vining).
Freeman, MD Description
of Patient
No. of Patients
Type of Seizure Generalized seizure
Population Frequency of Seizures Before Valproate Sodium
Regimen
Age, yr
Akinetic/atonic Head nods
Tonic-clonic Tonic Absences Partial seizures Partial seizures with
3/day-continuous 2/mo-50/day 6/day-contlnuous 1/mo-10/day 5/wk-6/day 35/day
7-13 3-19 5-9 3-18 2-12
15
Body drops Myoclonus
Side effects included occasional gastrointestinal disturbance. No important hepatotoxic complications were noted. Two persons displayed transient neurologic side effects. Of particular interest was the noticeable improvement in mental status noted in 17 of the 27 patients. Some variations in blood level of other anticonvulsant drugs were noted, emphasizing the importance of monitoring these drugs. Valproate sodium provides important improvement in our ability to manage minor motor seizures. (Am J Dis Child 133:274-276, 1979)
Valproate acid), recently drug,
M.
15
11 com¬
plex symptoms
Atypical absence Psychomotor
3-25 7-17
rare-15/day 3/wk-10/day
5-15 5-19
rare-4/wk
Partial seizures with elemen¬
tary symptoms Other, unclassified
2/yr-12/day
pmiiiiii
o rr
4L
SPIKE AND WAVE 3 Hz
Fig
ATYPICAL SPIKE AND WAVE
FOCAL SPIKE
MULTIPLE SPIKES
1—Distribution of EEG abnormalities in
previously been used in these children without obtaining seizure control even when increased to toxic levels. Most chil¬ dren were unable to function at a level commensurate with their given capabili¬ ties at home or in school. Seventeen had IQs less than 70. The retardation was accentuated by the sedative effects of medication and possibly by the myriad minor seizures. Eleven children had spikewave (Lennox-Gastaut) pattern on the EEG (Fig 1).
METHODS Patients were selected because of their uncontrolled seizures. Parents were in-
NON SPECIFIC
UNKNOWN
patient population.
formed of the known toxic effects and benefits of the drug and agreed to the use of valproate sodium in their children. This use of valproate sodium primarily for the benefit of the individual child rather than for the purpose of a formal study precluded
multiple laboratory procedures. Follow-up EEGs have not been possible in many cases for this reason. Laboratory studies, in¬ cluding blood chemical determinations, complete blood cell and platelet counts, and
blood levels of measurable anticonvulsant drugs were done at the initiation of valproate sodium therapy and these were repeated at approximately monthly inter¬ vals. Seventeen patients were receiving
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Arizona Health Sciences Library User on 05/31/2015
clonazepam or diazepam. The
serum levels measured. Seizure frequency was recorded and reported by parents. The patients have been followed for five to 12 months (mean, 7.6 months). Valproate sodium (LaBaz) was given at a dosage of 10 to 20 mg/kg per day in two or three divided doses while continuing the child's other anticonvulsant drugs. Efforts were made to maintain these drugs within
of these
were
not
accepted therapeutic ranges. Valproate sodium dosage was gradually increased
until either seizure control was obtained or the medication was judged unsuccessful. It was discontinued in two patients because of lack of effect at doses of 20 and 70 mg/kg per day, respectively. Seven chil¬ dren required a daily dosage of 50 to 60 mg/kg for seizure control. When lethargy or ataxia occurred, blood levels of other anticonvulsant drugs were measured and dosages altered as indicated.
RESULTS Seizure Control
Seizure control was analyzed by seizure type. Improvement was mea¬ sured on the basis of decrease in each seizure type reported by the patient. Improvement of 100% is equated with complete control of a particular type of seizure. Improvement of 75% to 99% indicates that percent decrease in seizures; if a child were having a hundred head nodding spells per day, this would indicate that while receiv¬ ing valproate sodium he was having less than 25 spells per day. On the other hand, if a child were having one seizure a day, 75% improvement could mean a seizure frequency of one seizure a year or perhaps one every four days. Most patients had multiple types of seizures, and one type might be controlled while others persisted. Minor Motor Seizures.—This term has been used to include myoclonic seizures, head nods, and body drops (akinetic-atonic). These seizures are the most resistant to conventional medication, responding on occasion to benzodiazepines (diazepam or clonaze¬ pam), to acetazolamide, or to the ketogenic diet, and are often asso¬ ciated with mental retardation. This lack of response to therapy and the sedative effect of many of the drugs cause these patients to be among the most refractory and challenging of
management problems.
Minor motor seizures
were
the
(grand mal) had additional seizure
predominant seizure type in 13 of the patients. Nine of these patients were mentally retarded; the mean IQ for eight of these patients was 48. Five had spike-wave (Lennox-Gas-
types that included minor
27
taut) EEG patterns. Seizures were occurring from two per month to
myriad per day, with most children in the latter category (Table). Medica¬
tions included ethosuximide, carbamazepine, phenytoin sodium, clonazepam, primidone, and diazepam, usual¬ ly in combination. The head-nodding spells of three patients were completely controlled with a mean valproate sodium dose of 47 mg/kg per day. Fifteen children had body drops (akinetic seizures) in addition to other seizure types. Al¬ though these spells occurred less
frequently, they were more incapaci¬ tating and required helmets or con¬
finement to a chair. Of the 15 children, the seizures of four were completely controlled, three had at least a 75% decrease in seizure frequency, four were 33% to 75% improved, and one showed less than 33% improvement. Three children with this seizure type showed no improvement (Fig 2). Five children had myoclonic sei¬ zures that consisted of brief, isolated jerking movements occurring from six times per day to continuously. The myoclonic seizures of two were com¬
pletely
controlled;
two
patients
showed 75% to 99% improvement; and one showed no improvement. Tonic-Clonic Seizures.—The 15 pa¬ tients with tonic-clonic seizures
] ^^
100% IMPROVED
motor and absence spells. In only one patient were the tonic-clonic seizures com¬ pletely controlled, whereas seven achieved 75% to 99% control. Thirtythree percent to 75% improvement was noted in three patients; 33% improvement was seen in two pa¬ tients; and two showed no improve¬ ment (Fig 2). Of those with greater than 75% improvement, only three required more than 30 mg/kg/day to achieve this degree of control. In several patients, control was main¬ tained only as long as another major anticonvulsant drug (usually pheny¬ toin oç phénobarbital) was continued. Other Seizures.—Two children with psychomotor seizures experienced 33% to 75% improvement in seizure con¬ trol. Of the three children with tonic
seizures,
two
improvement.
Other seizures,
some
of which could
not be
clearly classified, were not as one patient showed well, 100% improvement, one had 75% to controlled:
$*$$
33 75% IMPROVED
75-99% IMPROVED
experienced complete
control. The third showed 33% to 75% improvement but was still on a regi¬ men of less than 40 mg/kg/day. The pure absence seizures of one child were completely controlled. Atypical absence seizures were varia¬ bly controlled. The seizures of one child were completely controlled, two patients showed 75% to 99% improve¬ ment, two showed 33% to 75% improvement, one showed less than 33% improvement, and two showed no
NOT IMPROVED
33% IMPROVED
15
10
m
m
D 2
mr~¡ HEAD
BODY
NODS
DROPS
Fig 2.—Percentage valproate sodium.
of
MYO CLONUS
TONIC CLONIC
improvement
TONIC
PURE
ATYPICAL PSYCHO
ABSENCE
for various seizure
ABSENCE
types
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Arizona Health Sciences Library User on 05/31/2015
E
OTHER
MOTOR
in controls
receiving
improvement, and improvement.
four had
99%
no
Side Effects
According to the literature,1-2 the commonly reported side effects of valproate sodium include gastroin¬ testinal disturbances (16%), sedation usually associated with combination drug therapy (5%), platelet dysfunc¬ tion possibly reflected in prolonged bleeding times, and occasional behav¬ more
ioral deterioration. Transient hair loss has also been noted. Transient eleva¬ tion of liver enzyme levels is reported and isolated cases of severe hepatoxic effects have been observed. In 18 of the 27 patients in this study, liver enzyme levels were found to be mildly elevated. In no case were these altera¬ tions considered sufficient to require discontinuation of valproate sodium, and in many cases the liver enzyme values returned to normal while medi¬ cation was continued. Four individu¬ als had transient gastrointestinal dis¬ turbances, including nausea and vom¬ iting. These symptoms responded to administration of medications with meals. Two individuals displayed neu¬ rologic side effects: one became very
drowsy secondary to high phénobar¬ a
bital level and one demonstrated temporary ataxia that resolved with¬ out any alteration of medication. Mentation
Improved
mental status
by parents, teachers,
or
was
noted of
physicians
was
patients. In most cases, it impossible to determine if this
was
due to
17 of the 27
a
decrease in seizure
frequency (particularly in those with frequent minor motor seizures), to
decreased toxic effects associated with withdrawl of other anticonvul¬ sant
drugs (clonazepam, phénobarbi¬
tal, etc), or to the valproate sodium itself. However, in those with minor motor seizures, this improvement in alertness was frequently as important the decrease in seizure and was even noted in frequency those whose seizures had not been completely controlled. a
feature
as
Other Medications
Twenty youngsters have had one or of their medications decreased;
more
nine of these have had one or more medications discontinued. At this time only one patient is receiving valproate sodium alone. Blood levels of other anticonvulsant drugs were monitored, and consider¬ able fluctuation was noted, though dosages remained constant. Trends indicated a decrease in ethosuximide and phenytoin levels after institution of valproate sodium. Phénobarbital and carbamazepine levels seemed to increase slightly. After the first month, phenytoin levels often re¬ turned to pre-valproate sodium levels without alterations of phenytoin dos¬ ages.
COMMENT
Valproate sodium has been a major addition to our selection of anticonvul¬ sant medications. A double-blind con¬ trolled study has documented its effi¬ cacy in absence seizures'3; uncontrolled studies such as ours have documented its effectiveness in the minor motor seizure group as well as in other seizure types. It is worth noting that 60% of those children with less than 75% improvement have not yet reach¬ ed a dosage level of 50 to 60 mg/ kg/day. However, four of the seven with greater than 75% improvement in the minor motor seizure group are receiving 30 mg/kg/day or less. It may be that there is a relationship between the severity of seizures and the amounts of valproate sodium required for control. It is our overall impression, and that of the parents, that valproate sodium has been of major benefit in most of these chil¬ dren. Review of Fig 2 indicates that some seizures have been only mini¬ mally effected by valproate sodium. However, the child with frequent head nods and occasional akinetic spells would be noticeably improved if the head nods were controlled despite continuation of the occasional akinetic spell.
Controlled and carefully docu¬ mented studies by seizure type are still needed. In the minor motor group, these studies will be compli¬ cated by the severity of the disorder, the combination of these with other seizure types, and the fact that most patients will already have been dem-
onstrated to be refractory to manage¬ ment by other anticonvulsant drugs. For these patients, the use of placebo may be unethical, and the comparison between valproate sodium and other anticonvulsant drugs may have to be made by using the patient as his own control. If valproate sodium is effec¬ tive in controlling many patients with this refractory seizure type, as has been demonstrated by this study and others in the literature,14T and is as safe as already demonstrated by multiple studies,1 it will make a major difference in the lives of these chil¬ dren. At the present time, we believe that valproate sodium is the treat¬ ment of choice for children with minor motor seizures.
This work was supported in part by grant 03-H-000,143-09 from the Department of Health
Education and Welfare. Eldo Bergman, Kenton Holden, and Harvey Singer allowed us to present the case reports of their patients. The staff of the Pediatrie Seizure Clinic aided in this study. Kathy Schmidt provided secretarial assistance.
Names and Trademarks of Drugs
Nonproprietary
Carbamazepine- Tegretol. Clonazepam—Clonopin. Ethosuximide—Zarontin.
Valproate sodium—Depakene. References 1. Simon D, Penry JK: Sodium di-n-propylacetate (DPA) in the treatment of epilepsy: A review. Epilepsia 16:549-573, 1975. 2. Pinder RM, Brogden RN, Speight TM, et al: Sodium valproate: A review of its pharmacological properties and therapeutic efficacy in epilepsy. Drugs 13:81-123, 1977. 3. Sillanpaa M, Donner M: Experiences on the use of dipropylacetate in the treatment of childhood epilepsy. Acta Pediatr Scand 65:209-215, 1976. 4. Lance JW, Anthony M: Sodium valproate and clonazepam in the treatment of intractable epilepsy. Arch Neurol 34:14-17, 1977. 5. Schobben F, van der Kleijn E, Gabreels FJM: Pharmacokinetics of di-n-propylacetate in epileptic patients. Europ J Clin Pharmacol 8:97\x=req-\ 105, 1975. 6. Suzuki M, Maruyama M, Ishibashi Y, et al: A double blind comparative trial of sodium dipropylacetate and ethosuximide in epilepsy in children\p=m-\withspecial emphasis in pure petit mal seizure. Med Prog 82:470-488, 1972. 7. Jeavons PM, Clark JE, Maheshwasi MC: The treatment of generalized epilepsies of childhood and adolescence with sodium valproate (Epilim). Develop Med Child Neurol 19:9-25, 1977.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Arizona Health Sciences Library User on 05/31/2015
