- Email: [email protected]
Combined drug therapy in petit mal epilepsy
C O M B I N E D DRUG T H E R A P Y IN P E T I T MAL E P I L E P S Y DOrA CHAO, M.D., AND WILLIAM S.
FIELDS,M.D.
I-IousToN, TEXAS
N R E C E N T years a considerable n u m b e r of new anticonvulsant drugs have become available both in the pharmacopeia and for investigation. Most of these have been advocated for use in the control of m a j o r seizures (i.e., grand real, psychomotor) and have proved inadequate in the control of petit real epilepsy. In 1945 Lennox first reported on the use of a new drug, Tridione (3,5,5-trimethyloxazolidinc-2,4-dione), in the petit real epilepsies. Since then it has been considered that this drug is the most effective thus f a r available in the treatment of this condition. However, it has the disadvantage of being toxic to the hematopoietic system upon prolonged use, as well as having other less severe side effects. In 1951 another compound, Milontin (N-mcthyl-q-phenylsuecinimide), ~ was introduced for clinical investigation. In 1951 Zimmerman ~ reported the use of Milontin on fifty patients with petit mal epilepsy. He concluded that Milontin equaled or surpassed Tridione in therapeutic efficacy and had the advantage of being relatively nontoxic. Millichap 2 in London reported on the use of Milontin among twenty cases in 1952. His studies also produced similar results although he en-
I
F r o m ti~e Deioartments of Pedi~trics, }'syc h i a t r y and Neurology, ]~aytor University College of Medicine. *We a r e indebted to l)r. I-I. E. (2a.rnes of Farke, D~vis & Comp~tny for our supply of Milontin. 293
countered more toxic effects than reported by Zimmerman. Doyle and associates 4 ill August, 1953, reported the use of Milontin i~ twenty-one patients, with simple absence seizures associated with 3 per second spike and wave p a t t e r n in electroencephalogram. They reported that not one of these patients responded to this medication in the dosages employed. The following is a report of our experience in the use of this new drug alone and more particularly in combination with Tridione. CLASSIFICATION OF CLINICAL MATERIAL
In our series there were fifteen patients with petit real seizures. These were classified as follows: 1. I d i o p a t h i c p e t i t real t r i a d . (a) Absence (pyknolepsy)--manifested b y t r a n s i e n t loss of consciousness with no m o t o r component. ( b ) A k i n e t i c - - t r a n s i e n t loss of consciousness a c c o m p a n i e d b y loss of p o s t u r a l tone. (e) M y o c l o n i e - - m i n o r t r a n s i e n t m o t o r p h e n o m e n a i n v o l v i n g one or more muscle groups. 2. S y m p t o m a t i c seizures m a n i f e s t e d by one or m o r e of t h e p e t i t real t r i a d p a t t e r n . 3. M i x e d p e t i t r e a l - - p e t i t m a l combined with g r a n d real seizures. CASE !~IATERIAL
We recognize that fifteen patients constitute a small series, but it is believed that some of our observations warrant reporting at this time. Tile cases were selected from a large group
294
THE
JOURNAL
of children between the ages of 2 and 15 years in the Blue B i r d Children's Clinic for Neurological Disorders and the consultation practice of one of us (W. S . F . ) . Eleven were clinic a n d four were private patients. All clinical diagnoses were correlated with electroencephalographic data. Eleven of these patients had been previously tried on other medication as follows: Nv/mber of Cases Phenobarbital Tridione Mebaral Dilantin Dexedrine Gemonil Paradione Glutamie acid
6 5 4 4 3 2 2 1
W e have selected cases in which the control of seizures was f a r f r o m adequate. Other patients with petit real seizures in our clinic group who were already adequately controlled on other medication were not included in this study. There were nine eases of idiopathic petit real, four cases of symptomatic seizures with petit real pattern
and two of mixed petit real. Of the nine eases of idiopathic petit real, seven had absence seizures alone, one had akinetie and myoelonie seizures, and one had the entire t r i a d of seizures. All of these patients were having more t h a n t w e n t y seizures daily and two were in petit real status epilepticus when first seen. E a c h was started on Milontin 0.5 Gin. three times daily and the dosage increased a f t e r one week to 1.0 Gin. three times daily. Once this dosage was reached, all of these patients showed reduction in the frequency of their attacks and three were seizure-free for f r o m f o u r to five weeks. I n each instance, however, a f t e r periods v a r y i n g f r o m four
OF
PEDIATRICS
to twelve weeks, the n u m b e r of seizures began to increase or toxic effects became manifest. I n six of the patients, Tridione 0.3 Gin. t.i.d, was added to the Milontin while the dose of the latter was decreased to 0.5 Gin. t.i.d. Two were changed to Tridione alone because of m a r k e d u r i n a r y frequency and u r g e n c y which was felt to be attributable to Milontin. Another was changed to Tridione alone because of severe drowsiness and poor control of seizures on Milontin alone. One patient with absence seizures developed gross h e m a t u r i a when the total dose of Milontin reached 3.0 Gin. This was followed b y microscopic h e m a t u r i a until the dose was reduced to 1.5 Gin. daily. A f t e r reducing the medication, more seizures were noted. W h e n Tridione 0.9 Gm. daily was added, complete control was achieved except when the child was exposed to bright, flickering sunlight. This was surprising in view of the complete failure of Tridione previously, without Milontin. There were, in addition, three others in this group who are now seizure-h'ee on the combined d r u g t h e r a p y who had failed previously to respond to Tridione alone. Of the f o u r with symptomatic seizures, all had more t h a n one manifestation of the petit real t r i a d as well as other types of seizures. The electroencephalogram in each showed diffuse slow spike wave dysrhytbmia, which was considered suggestive of the existence of a symptomatic convulsive state. Milontin in a dose of 3.0 Gm. daily completely controlled only one of these patients. Two others still have one to three seizures daily on Milontin 1.5 Gm. together with other medication. One of these developed h e m a t u r i a on a dose of 3.0 Gm. daily. The fourtt~
CHAO AND FIELDS:
COMBINED DRUG THERAPY I N PETIT MAL EPILEPSY
patient, who has a postencephalitic convulsive disorder, developed severe anorexia on Milontin 1.5 Gm. daily and the medication had to be discontinued and replaced by Tridione and phenobarbital. Two patients had idiopathic petit real combined with grand real seizures. Both are well controlled on Milontin 3.0 Gin. with Mebaral 0.2 Gin. daily. One has been seizure-free for seven months and the other, a 12-year-old girl, has had only one or two attacks during menstruation over a period of seventeen months. The length of treatment of these fifteen patients varied from seven to twenty-one months. DISCUSSION
The results in this series of patients suggest that Milontin is effective in the treatment of idiopathic petit real seizures. The best results in this group were achieved when Milontin 0.5 Gin. was combined with Tridione 0.3 Gin. three times daily. With the seven patients on this regime, 100 per cent control of seizures was achieved. This was remarkable in several instances where the patients had not been adequately controlled previously by either one of these drugs independently. Milontin in combination with Mebaral was very useful in controlling idiopathic seizures when both minor and major attacks were present. Major attacks were not exacerbated by the introduction of Milontin. The results in the patients in whom the petit real type of seizures were of symptomatic origin have been the least satisfactory. Toxic
Manifestations.--The
t ox i c
manifestations of Tridione are well documented but those of Milontin are still under investigation. Miller and
295
Long 3 reported that Milontin was well tolerated in laboratory animals and was effective in the control of MetrazoMndueed seizures. In Zimmerman's series of fifty patients, toxic reactions occurred in 22 per cent and the symptoms were: nausea, dizziness, drowsiness, vomiting, and headache. In Millichap's twenty patients, 62 per cent exhibited toxic effects which included: abnormal urinary findings (10), drowsiness (5), nausea (4), dreamlike state (3), dizziness (2), erythema multiforme (1), vomiting (1). Doyle and associates 4 found no toxic reaction in the twenty-one cases they studied. Eight of these patients had monthly urinalyses but no hematuria was encountered. All of our patients have had complete blood studies at least once a month and no abnormality has been encountered. In addition, urinalysis has been made at the same time as each blood examinatioh. Two patients developed hematuria and one of these also had urinary frequency. Two other patients had frequency and urgency of urination without hematuria. Two patients developed enuresis. In all of these patients urinary symptoms disappeared when the dosage of the drug was reduced. One patient dev e l o p e d anorexia sufficiently severe to necessitate discontinuing Milontin therapy. Another patient developed a dreamlike state for a few hours e ve r y day. In this instance, Milontin was also discontinued. Our observation agrees with that of Millichap, that uri nary symptoms are the most frequent toxic manifestations when larger doses of Mi]ontin (3.0 Gin. or over, daily) are employed. However, five of Millichap's patients
296
THE JOURNAL OF PEDIATRICS
had microscopic hematuria on a dosage as low as 0.9 Gin. daily. None of our patients developed toxic symptoms oil this small a dose. Nothing is known about the pathological basis of the hematuria. The presence of bladder symptoms and the absence of other abnormal urinary findings would seem to indicate that it is an irritative phenomenon. Parents of three patients observed that the medication must be given promptly, according to the prescribed schedule, or seizures would occur. This suggests that there is no cumulative effect of this drug. The effective blood level can be maintained for only about four to five hours following an oral dose of Milontin. SUMMARY
1. The therapeutic efficacy and toxic manifestations of Milontin were investigated in a series of fifteen patients with petit real epilepsy. 2. Milontin alone, when employed in sufficiently large doses, controlled only three of the patients without toxic effects.
3. Milontin in smaller doses, combined with Tridione, was more effective in the control of seizures in seven patients than either drug independently. 4. Because of toxic manifestations, Milontin was reduced in dosage in six patients and completely discontinued in three patients. 5. Milontin does not appear to have greater benefit in the control of petit real seizures when used alone than drugs previously available. However, it is more effective when used in combination with Tridione. 6. The toxic manifestations of this combined drug therapy are no greater than those of either drug used independently. REFERENCES 1. Zimmerman~ F . T . : Use of Methylphenylsuccinimide in Treatment of P e t i t Mal Epilepsy, Arch. Neurol. & Psyehiat. 66: 156, 1951. 2. 2~[illichap, J. G. : ~V[ilontin, a N e w Drug in the T r e a t m e n t of P e t i t Mal~ L a n c e t 2: 907, 1952. 3. Miller, C. A., and Long, L. ~ . : Anticonvu]sants. I. An I n v e s t i g a t i o n of N-R-~-RI-~-Phe~ ylsuceinimide~ J. Am. Chem. Soc. 73: 4895, 1951. 4. DoyIe~ P. J , Livingstone, Samuel~ and Pearson, P a u l H.: Use of 1Yfilontin in the T r e a t m e n t of P e t i t lVfal Epilepsy (Three P e r Second Spike a n d W a v e Dysr h y t h m i a ) , 3-. PEDIAT. 43: 164, 1953.
FIELDS,M.D.
I-IousToN, TEXAS
N R E C E N T years a considerable n u m b e r of new anticonvulsant drugs have become available both in the pharmacopeia and for investigation. Most of these have been advocated for use in the control of m a j o r seizures (i.e., grand real, psychomotor) and have proved inadequate in the control of petit real epilepsy. In 1945 Lennox first reported on the use of a new drug, Tridione (3,5,5-trimethyloxazolidinc-2,4-dione), in the petit real epilepsies. Since then it has been considered that this drug is the most effective thus f a r available in the treatment of this condition. However, it has the disadvantage of being toxic to the hematopoietic system upon prolonged use, as well as having other less severe side effects. In 1951 another compound, Milontin (N-mcthyl-q-phenylsuecinimide), ~ was introduced for clinical investigation. In 1951 Zimmerman ~ reported the use of Milontin on fifty patients with petit mal epilepsy. He concluded that Milontin equaled or surpassed Tridione in therapeutic efficacy and had the advantage of being relatively nontoxic. Millichap 2 in London reported on the use of Milontin among twenty cases in 1952. His studies also produced similar results although he en-
I
F r o m ti~e Deioartments of Pedi~trics, }'syc h i a t r y and Neurology, ]~aytor University College of Medicine. *We a r e indebted to l)r. I-I. E. (2a.rnes of Farke, D~vis & Comp~tny for our supply of Milontin. 293
countered more toxic effects than reported by Zimmerman. Doyle and associates 4 ill August, 1953, reported the use of Milontin i~ twenty-one patients, with simple absence seizures associated with 3 per second spike and wave p a t t e r n in electroencephalogram. They reported that not one of these patients responded to this medication in the dosages employed. The following is a report of our experience in the use of this new drug alone and more particularly in combination with Tridione. CLASSIFICATION OF CLINICAL MATERIAL
In our series there were fifteen patients with petit real seizures. These were classified as follows: 1. I d i o p a t h i c p e t i t real t r i a d . (a) Absence (pyknolepsy)--manifested b y t r a n s i e n t loss of consciousness with no m o t o r component. ( b ) A k i n e t i c - - t r a n s i e n t loss of consciousness a c c o m p a n i e d b y loss of p o s t u r a l tone. (e) M y o c l o n i e - - m i n o r t r a n s i e n t m o t o r p h e n o m e n a i n v o l v i n g one or more muscle groups. 2. S y m p t o m a t i c seizures m a n i f e s t e d by one or m o r e of t h e p e t i t real t r i a d p a t t e r n . 3. M i x e d p e t i t r e a l - - p e t i t m a l combined with g r a n d real seizures. CASE !~IATERIAL
We recognize that fifteen patients constitute a small series, but it is believed that some of our observations warrant reporting at this time. Tile cases were selected from a large group
294
THE
JOURNAL
of children between the ages of 2 and 15 years in the Blue B i r d Children's Clinic for Neurological Disorders and the consultation practice of one of us (W. S . F . ) . Eleven were clinic a n d four were private patients. All clinical diagnoses were correlated with electroencephalographic data. Eleven of these patients had been previously tried on other medication as follows: Nv/mber of Cases Phenobarbital Tridione Mebaral Dilantin Dexedrine Gemonil Paradione Glutamie acid
6 5 4 4 3 2 2 1
W e have selected cases in which the control of seizures was f a r f r o m adequate. Other patients with petit real seizures in our clinic group who were already adequately controlled on other medication were not included in this study. There were nine eases of idiopathic petit real, four cases of symptomatic seizures with petit real pattern
and two of mixed petit real. Of the nine eases of idiopathic petit real, seven had absence seizures alone, one had akinetie and myoelonie seizures, and one had the entire t r i a d of seizures. All of these patients were having more t h a n t w e n t y seizures daily and two were in petit real status epilepticus when first seen. E a c h was started on Milontin 0.5 Gin. three times daily and the dosage increased a f t e r one week to 1.0 Gin. three times daily. Once this dosage was reached, all of these patients showed reduction in the frequency of their attacks and three were seizure-free for f r o m f o u r to five weeks. I n each instance, however, a f t e r periods v a r y i n g f r o m four
OF
PEDIATRICS
to twelve weeks, the n u m b e r of seizures began to increase or toxic effects became manifest. I n six of the patients, Tridione 0.3 Gin. t.i.d, was added to the Milontin while the dose of the latter was decreased to 0.5 Gin. t.i.d. Two were changed to Tridione alone because of m a r k e d u r i n a r y frequency and u r g e n c y which was felt to be attributable to Milontin. Another was changed to Tridione alone because of severe drowsiness and poor control of seizures on Milontin alone. One patient with absence seizures developed gross h e m a t u r i a when the total dose of Milontin reached 3.0 Gin. This was followed b y microscopic h e m a t u r i a until the dose was reduced to 1.5 Gin. daily. A f t e r reducing the medication, more seizures were noted. W h e n Tridione 0.9 Gm. daily was added, complete control was achieved except when the child was exposed to bright, flickering sunlight. This was surprising in view of the complete failure of Tridione previously, without Milontin. There were, in addition, three others in this group who are now seizure-h'ee on the combined d r u g t h e r a p y who had failed previously to respond to Tridione alone. Of the f o u r with symptomatic seizures, all had more t h a n one manifestation of the petit real t r i a d as well as other types of seizures. The electroencephalogram in each showed diffuse slow spike wave dysrhytbmia, which was considered suggestive of the existence of a symptomatic convulsive state. Milontin in a dose of 3.0 Gm. daily completely controlled only one of these patients. Two others still have one to three seizures daily on Milontin 1.5 Gm. together with other medication. One of these developed h e m a t u r i a on a dose of 3.0 Gm. daily. The fourtt~
CHAO AND FIELDS:
COMBINED DRUG THERAPY I N PETIT MAL EPILEPSY
patient, who has a postencephalitic convulsive disorder, developed severe anorexia on Milontin 1.5 Gm. daily and the medication had to be discontinued and replaced by Tridione and phenobarbital. Two patients had idiopathic petit real combined with grand real seizures. Both are well controlled on Milontin 3.0 Gin. with Mebaral 0.2 Gin. daily. One has been seizure-free for seven months and the other, a 12-year-old girl, has had only one or two attacks during menstruation over a period of seventeen months. The length of treatment of these fifteen patients varied from seven to twenty-one months. DISCUSSION
The results in this series of patients suggest that Milontin is effective in the treatment of idiopathic petit real seizures. The best results in this group were achieved when Milontin 0.5 Gin. was combined with Tridione 0.3 Gin. three times daily. With the seven patients on this regime, 100 per cent control of seizures was achieved. This was remarkable in several instances where the patients had not been adequately controlled previously by either one of these drugs independently. Milontin in combination with Mebaral was very useful in controlling idiopathic seizures when both minor and major attacks were present. Major attacks were not exacerbated by the introduction of Milontin. The results in the patients in whom the petit real type of seizures were of symptomatic origin have been the least satisfactory. Toxic
Manifestations.--The
t ox i c
manifestations of Tridione are well documented but those of Milontin are still under investigation. Miller and
295
Long 3 reported that Milontin was well tolerated in laboratory animals and was effective in the control of MetrazoMndueed seizures. In Zimmerman's series of fifty patients, toxic reactions occurred in 22 per cent and the symptoms were: nausea, dizziness, drowsiness, vomiting, and headache. In Millichap's twenty patients, 62 per cent exhibited toxic effects which included: abnormal urinary findings (10), drowsiness (5), nausea (4), dreamlike state (3), dizziness (2), erythema multiforme (1), vomiting (1). Doyle and associates 4 found no toxic reaction in the twenty-one cases they studied. Eight of these patients had monthly urinalyses but no hematuria was encountered. All of our patients have had complete blood studies at least once a month and no abnormality has been encountered. In addition, urinalysis has been made at the same time as each blood examinatioh. Two patients developed hematuria and one of these also had urinary frequency. Two other patients had frequency and urgency of urination without hematuria. Two patients developed enuresis. In all of these patients urinary symptoms disappeared when the dosage of the drug was reduced. One patient dev e l o p e d anorexia sufficiently severe to necessitate discontinuing Milontin therapy. Another patient developed a dreamlike state for a few hours e ve r y day. In this instance, Milontin was also discontinued. Our observation agrees with that of Millichap, that uri nary symptoms are the most frequent toxic manifestations when larger doses of Mi]ontin (3.0 Gin. or over, daily) are employed. However, five of Millichap's patients
296
THE JOURNAL OF PEDIATRICS
had microscopic hematuria on a dosage as low as 0.9 Gin. daily. None of our patients developed toxic symptoms oil this small a dose. Nothing is known about the pathological basis of the hematuria. The presence of bladder symptoms and the absence of other abnormal urinary findings would seem to indicate that it is an irritative phenomenon. Parents of three patients observed that the medication must be given promptly, according to the prescribed schedule, or seizures would occur. This suggests that there is no cumulative effect of this drug. The effective blood level can be maintained for only about four to five hours following an oral dose of Milontin. SUMMARY
1. The therapeutic efficacy and toxic manifestations of Milontin were investigated in a series of fifteen patients with petit real epilepsy. 2. Milontin alone, when employed in sufficiently large doses, controlled only three of the patients without toxic effects.
3. Milontin in smaller doses, combined with Tridione, was more effective in the control of seizures in seven patients than either drug independently. 4. Because of toxic manifestations, Milontin was reduced in dosage in six patients and completely discontinued in three patients. 5. Milontin does not appear to have greater benefit in the control of petit real seizures when used alone than drugs previously available. However, it is more effective when used in combination with Tridione. 6. The toxic manifestations of this combined drug therapy are no greater than those of either drug used independently. REFERENCES 1. Zimmerman~ F . T . : Use of Methylphenylsuccinimide in Treatment of P e t i t Mal Epilepsy, Arch. Neurol. & Psyehiat. 66: 156, 1951. 2. 2~[illichap, J. G. : ~V[ilontin, a N e w Drug in the T r e a t m e n t of P e t i t Mal~ L a n c e t 2: 907, 1952. 3. Miller, C. A., and Long, L. ~ . : Anticonvu]sants. I. An I n v e s t i g a t i o n of N-R-~-RI-~-Phe~ ylsuceinimide~ J. Am. Chem. Soc. 73: 4895, 1951. 4. DoyIe~ P. J , Livingstone, Samuel~ and Pearson, P a u l H.: Use of 1Yfilontin in the T r e a t m e n t of P e t i t lVfal Epilepsy (Three P e r Second Spike a n d W a v e Dysr h y t h m i a ) , 3-. PEDIAT. 43: 164, 1953.