- Email: [email protected]
Reduction of seizure frequency with clomipramine in patients with complex partial seizures
ELSEVIER
Brain & Development 1995; 17:291-3
Short communication
Reduction of seizure frequency with clomipramine in patients with complex partial seizures Yoichi Sakakihara a,*, Akira Oka a, Masaya Kubota a, Yuji Ohashi u a
Department of Pediatrics, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan b Enshu General Hospital, Hamarnatsu, Japan Received 19 December 1994; accepted 10 April 1995
Two patients with complex partial seizures who had been refractory to various antiepileptics were treated with clomipramine. The frequency of the seizures was reduced to 0-30% of the original levels. It has been reported that imipramine is effective in absence and minor motor seizures, and its antiepileptic effect is thought to be related to the inhibition of the presynaptic re-uptake of serotonin and norepinephrine. The basic effect of clomipramine is the same as that of imipramine except that the inhibitory action of clomipramine on serotonin re-uptake is 5- to 10-times more potent than that of imipramine. It is implied that clomipramine may be of use in the treatment of partial epilepsies. Keywords: C l o m i p r a m i n e ; I m i p r a m i n e ; C o m p l e x p a r t i a l s e i z u r e
1. I N T R O D U C T I O N Despite the advent of new antiepileptic drugs (AED), certain types of partial seizure have been refractory to drug treatment. Complex partial seizure (CPS) is one of the most refractory epileptic seizures, and many patients with CPS have not been free from seizures even with potent anticonvulsant medication. Imipramine has been reported to be effective in absence, myoclonic-astatic, and minor motor seizures [1-3]. Its antiepileptic action is thought to be related to the inhibition of presynaptic re-uptake of norepinephrine and 5-hydroxytryptamine (5-HT) [4,5]. However, the use of imipramine has not been accepted as the standard therapy because it is well known that imipramine possesses a proconvulsive effect [6,7]. Clomipramine is a derivative of imipramine, and its inhibitory action on 5-HT re-uptake has been shown to be 5- to 10-times more potent than that of imipramine [4]. Although both drugs have been widely used for the treatment of enuresis and behavioral disorders, there have been only two previous reports suggesting its possible usefulness in epilepsy
[8,9].
* Corresponding author. Fax: (81) (3) 3816 4108. 0387-7604/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSD! 0387-7604(95)00040-2
We used clomipramine in two patients with CPS who had been refractory to various AEDs. The seizures in these patients have been effectively reduced with small doses of clomipramine.
2. C A S E R E P O R T S The first patient is a 13-year-old girl with refractory falling attacks. She developed a prolonged tonic-clonic seizure after the heart surgery for endocardial cushion defect and pulmonary hypertension at the age of 2. The seizure stopped only after the initiation of artificial hibernation therapy with a large dose of phenobarbital. Although the cause of the seizure was presumed to be an air embolism, computed tomography (CT) was normal. Since the E E G revealed right occipital sharp waves, phenobarbital was started prophylactically to prevent further seizures. At age 5, it was discontinued, because no seizure had occurred until then. However, she experienced a falling attack preceded by a dazzling sensation 3 months after discontinuation of phenobarbital. E E G revealed a focus of spike and wave complex in the right occipital lead (Fig. 1). She remained free of falling seizures after resuming phenobarbital until the age of 10, when she had brief episodes of unconsciousness. The dose of phenobarbital was increased, but she continued to have falling
292
Y. Sakakihara et al. / Brain & Development 1995; 17:291-3
F p l -Al o
F7-A1
~ . . ~ ~ ,
~ ~ ,
~ ~ ~ .
l
Fe-nz
N
[,
T3-fll
=
T4-A2
clomipramine
t.
~
2
~ 87
C3-AI
~
.
~
~
88
89
98
91
92
93
~
94
year
Fig. 3. Changes of seizure frequency in Patient 2.
c4-R2 P3-fll P4-A2 Ol -Al
I Fig. 1. lnterictal EEG of Patient 1. Note a burst of spike and wave in the right occipital lead.
attacks. Since then several AEDs have been used to stop her falling attack without success (Fig. 2). In addition to the falling attacks, she started to show automatism which usually consisted of ictal speech and dystonic elevation of her left arm, followed by a confusional state. E E G showed diffuse bursts of irregular polyspike and waves. On magnetic resonance imaging (MRI), a well demarcated wedge-shaped high intensity area with T2-weighted imaging was apparent in the right occipital cortex. A small dose of clomipramine (20 m g / d a y ) was started at age 12, and since then she has been completely free of seizures until now (for 18 months). The second patient is a 34-year-old female suffering from intractable CPS. Her first epileptic episode was a brief attack of unconsciousness when she was 7. Since the E E G was normal, no treatment was started at that time. Two years later, she again experienced falling attacks, often preceded
I ,,
:Valp~ate
I-"7 Ethosuximide [ - ~ Zonisarnide! Carbamazepine [ Clornipramine[ - -
86
88
98
92
Fig. 2. ClinicalcourseofPatientl.
94
year
by a sensation of nausea. The E E G revealed small spikes in the right temporal lead. After that she began to show a variety of seizures, such as automatism and auditory hallucinations, as well as falling attacks. With the diagnosis of CPS, many AEDs were used with little effect. Her CT was normal. A small dose of clomipramine (20 m g / d a y ) was started at age 32. The frequency of the seizures decreased gradually, and in 8 months it had dropped to zero or once a month (Fig. 3). She has been free of seizures for as long as 3 months with clomipramine.
3. D I S C U S S I O N The major pharmacological effect of imipramine is inhibition of presynaptic re-uptake of norepinephrine and 5-HT. Although the exact role of these neurotransmitters in epileptogenesis is still controversial, it is known that imipramine has a biphasic effect on seizure [10]. Clinical and experimental evidence indicates that imipramine has an antiepileptic action at low doses, while it lowers seizure threshold at a high dose [4,6]. One of the possible mechanisms of seizure suppression with imipramine is elevation of the concentration of 5-HT. Fromm was the first to point out the similarity of the pharmacological action of imipramine to that of ethosuximide and trimethadione in an animal model of corticofugal inhibition [1,2]. He used imipramine in patients with refractory absence and myoclonic-astatic seizures [1]. Eleven of the 20 patients had a 90% to 100% reduction of seizures. He also demonstrated the similar effectiveness of imipramine in patients with absence and myoclonic-astatic seizures [2]. Recently, imipramine has been shown to be effective in children with minor motor seizures [3]. Clomipramine is a derivative of imipramine, and is known to be 5- to 10-times more potent in inhibiting 5-HT re-uptake [4]. It was demonstrated that a small dose of clomipramine (20 m g / d a y ) could effectively suppress or even stop seizures in two patients with CPS. Buge et al. reported that clomipramine (40-60 m g / d a y ) was effective in petit mal seizures [8]. We initially used clomipramine in Patient 2, whose seizure was refractory to virtually all available AEDs. It is of interest that our patients were suffering from CPS with hippocampal and occipital spike foci respectively. Although our cases are anecdotal, they suggest that clomipramine may be clinically useful for patients with par-
Y. Sakakihara et al. /Brain & Development 1995; 17." 291-3 tial epilepsies, a subject that has not been explored previously. A large-scale prospective open trial of clomipramine is necessary to draw a conclusion about its clinical effectiveness in the treatment of epilepsies.
5.
6. REFERENCES 1. Fromm GH, Amores CY, q~ies W. Imipramine in epilepsy. Arch Neurol 1972; 27: 198-204. 2. Fromm GH, Wessel HB, (;lass JD, et al. Imipramine in absence and myoclonic-astatic seizures. Neurology 1978; 28: 953-7. 3. Hurst DL. The use of imipramine in minor motor seizures. Pediatr Neurol 1985; 2: 13--7. 4. Trimble M, Anlezark G, Meldrum B. Seizure activity in photosensitive baboons following antidepressant drugs and the role of
7,
8. 9. 10.
293
serotoninergic mechanisms. Psychopharmacology 1977; 51: 159164. Fischer W. Muller M. Pharmacological modulation of central monoaminergic systems and influence on the anticonvulsant effectiveness of standard antiepileptics in maximal electroshock seizure. Biomed Biochim Acta 1988; 47: 631-45. Koella WP, Glatt A, Klebs K, et al. Epileptic phenomena induced in the cat by the antidepressants maprotiline, imipramine, clomipramine, and amitriptyline. Biol Psychiat 1979; 14: 485-97. Neuman RS, Thompson PM. Serotonin mediate suppression of focal epileptiform activity induced by noxious stimulation. Epilepsia 1989; 30: 307-13. Buge A, Poisson M, Rancurel G, et al. Un cas rebelle de petit mal: action de la clomipramine. Nouv Press Med 1974; 3: 373-5. Setiey A, Courjon J. Clomipramine et petit mal. Lyon Medical 1978; 239: 751-4. Lange SC, Julien RM, Fowler GW. Biphasic effects of imipramine in experimental models of epilepsy. Epilepsia 1976; 17: 183-96.
Brain & Development 1995; 17:291-3
Short communication
Reduction of seizure frequency with clomipramine in patients with complex partial seizures Yoichi Sakakihara a,*, Akira Oka a, Masaya Kubota a, Yuji Ohashi u a
Department of Pediatrics, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan b Enshu General Hospital, Hamarnatsu, Japan Received 19 December 1994; accepted 10 April 1995
Two patients with complex partial seizures who had been refractory to various antiepileptics were treated with clomipramine. The frequency of the seizures was reduced to 0-30% of the original levels. It has been reported that imipramine is effective in absence and minor motor seizures, and its antiepileptic effect is thought to be related to the inhibition of the presynaptic re-uptake of serotonin and norepinephrine. The basic effect of clomipramine is the same as that of imipramine except that the inhibitory action of clomipramine on serotonin re-uptake is 5- to 10-times more potent than that of imipramine. It is implied that clomipramine may be of use in the treatment of partial epilepsies. Keywords: C l o m i p r a m i n e ; I m i p r a m i n e ; C o m p l e x p a r t i a l s e i z u r e
1. I N T R O D U C T I O N Despite the advent of new antiepileptic drugs (AED), certain types of partial seizure have been refractory to drug treatment. Complex partial seizure (CPS) is one of the most refractory epileptic seizures, and many patients with CPS have not been free from seizures even with potent anticonvulsant medication. Imipramine has been reported to be effective in absence, myoclonic-astatic, and minor motor seizures [1-3]. Its antiepileptic action is thought to be related to the inhibition of presynaptic re-uptake of norepinephrine and 5-hydroxytryptamine (5-HT) [4,5]. However, the use of imipramine has not been accepted as the standard therapy because it is well known that imipramine possesses a proconvulsive effect [6,7]. Clomipramine is a derivative of imipramine, and its inhibitory action on 5-HT re-uptake has been shown to be 5- to 10-times more potent than that of imipramine [4]. Although both drugs have been widely used for the treatment of enuresis and behavioral disorders, there have been only two previous reports suggesting its possible usefulness in epilepsy
[8,9].
* Corresponding author. Fax: (81) (3) 3816 4108. 0387-7604/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSD! 0387-7604(95)00040-2
We used clomipramine in two patients with CPS who had been refractory to various AEDs. The seizures in these patients have been effectively reduced with small doses of clomipramine.
2. C A S E R E P O R T S The first patient is a 13-year-old girl with refractory falling attacks. She developed a prolonged tonic-clonic seizure after the heart surgery for endocardial cushion defect and pulmonary hypertension at the age of 2. The seizure stopped only after the initiation of artificial hibernation therapy with a large dose of phenobarbital. Although the cause of the seizure was presumed to be an air embolism, computed tomography (CT) was normal. Since the E E G revealed right occipital sharp waves, phenobarbital was started prophylactically to prevent further seizures. At age 5, it was discontinued, because no seizure had occurred until then. However, she experienced a falling attack preceded by a dazzling sensation 3 months after discontinuation of phenobarbital. E E G revealed a focus of spike and wave complex in the right occipital lead (Fig. 1). She remained free of falling seizures after resuming phenobarbital until the age of 10, when she had brief episodes of unconsciousness. The dose of phenobarbital was increased, but she continued to have falling
292
Y. Sakakihara et al. / Brain & Development 1995; 17:291-3
F p l -Al o
F7-A1
~ . . ~ ~ ,
~ ~ ,
~ ~ ~ .
l
Fe-nz
N
[,
T3-fll
=
T4-A2
clomipramine
t.
~
2
~ 87
C3-AI
~
.
~
~
88
89
98
91
92
93
~
94
year
Fig. 3. Changes of seizure frequency in Patient 2.
c4-R2 P3-fll P4-A2 Ol -Al
I Fig. 1. lnterictal EEG of Patient 1. Note a burst of spike and wave in the right occipital lead.
attacks. Since then several AEDs have been used to stop her falling attack without success (Fig. 2). In addition to the falling attacks, she started to show automatism which usually consisted of ictal speech and dystonic elevation of her left arm, followed by a confusional state. E E G showed diffuse bursts of irregular polyspike and waves. On magnetic resonance imaging (MRI), a well demarcated wedge-shaped high intensity area with T2-weighted imaging was apparent in the right occipital cortex. A small dose of clomipramine (20 m g / d a y ) was started at age 12, and since then she has been completely free of seizures until now (for 18 months). The second patient is a 34-year-old female suffering from intractable CPS. Her first epileptic episode was a brief attack of unconsciousness when she was 7. Since the E E G was normal, no treatment was started at that time. Two years later, she again experienced falling attacks, often preceded
I ,,
:Valp~ate
I-"7 Ethosuximide [ - ~ Zonisarnide! Carbamazepine [ Clornipramine[ - -
86
88
98
92
Fig. 2. ClinicalcourseofPatientl.
94
year
by a sensation of nausea. The E E G revealed small spikes in the right temporal lead. After that she began to show a variety of seizures, such as automatism and auditory hallucinations, as well as falling attacks. With the diagnosis of CPS, many AEDs were used with little effect. Her CT was normal. A small dose of clomipramine (20 m g / d a y ) was started at age 32. The frequency of the seizures decreased gradually, and in 8 months it had dropped to zero or once a month (Fig. 3). She has been free of seizures for as long as 3 months with clomipramine.
3. D I S C U S S I O N The major pharmacological effect of imipramine is inhibition of presynaptic re-uptake of norepinephrine and 5-HT. Although the exact role of these neurotransmitters in epileptogenesis is still controversial, it is known that imipramine has a biphasic effect on seizure [10]. Clinical and experimental evidence indicates that imipramine has an antiepileptic action at low doses, while it lowers seizure threshold at a high dose [4,6]. One of the possible mechanisms of seizure suppression with imipramine is elevation of the concentration of 5-HT. Fromm was the first to point out the similarity of the pharmacological action of imipramine to that of ethosuximide and trimethadione in an animal model of corticofugal inhibition [1,2]. He used imipramine in patients with refractory absence and myoclonic-astatic seizures [1]. Eleven of the 20 patients had a 90% to 100% reduction of seizures. He also demonstrated the similar effectiveness of imipramine in patients with absence and myoclonic-astatic seizures [2]. Recently, imipramine has been shown to be effective in children with minor motor seizures [3]. Clomipramine is a derivative of imipramine, and is known to be 5- to 10-times more potent in inhibiting 5-HT re-uptake [4]. It was demonstrated that a small dose of clomipramine (20 m g / d a y ) could effectively suppress or even stop seizures in two patients with CPS. Buge et al. reported that clomipramine (40-60 m g / d a y ) was effective in petit mal seizures [8]. We initially used clomipramine in Patient 2, whose seizure was refractory to virtually all available AEDs. It is of interest that our patients were suffering from CPS with hippocampal and occipital spike foci respectively. Although our cases are anecdotal, they suggest that clomipramine may be clinically useful for patients with par-
Y. Sakakihara et al. /Brain & Development 1995; 17." 291-3 tial epilepsies, a subject that has not been explored previously. A large-scale prospective open trial of clomipramine is necessary to draw a conclusion about its clinical effectiveness in the treatment of epilepsies.
5.
6. REFERENCES 1. Fromm GH, Amores CY, q~ies W. Imipramine in epilepsy. Arch Neurol 1972; 27: 198-204. 2. Fromm GH, Wessel HB, (;lass JD, et al. Imipramine in absence and myoclonic-astatic seizures. Neurology 1978; 28: 953-7. 3. Hurst DL. The use of imipramine in minor motor seizures. Pediatr Neurol 1985; 2: 13--7. 4. Trimble M, Anlezark G, Meldrum B. Seizure activity in photosensitive baboons following antidepressant drugs and the role of
7,
8. 9. 10.
293
serotoninergic mechanisms. Psychopharmacology 1977; 51: 159164. Fischer W. Muller M. Pharmacological modulation of central monoaminergic systems and influence on the anticonvulsant effectiveness of standard antiepileptics in maximal electroshock seizure. Biomed Biochim Acta 1988; 47: 631-45. Koella WP, Glatt A, Klebs K, et al. Epileptic phenomena induced in the cat by the antidepressants maprotiline, imipramine, clomipramine, and amitriptyline. Biol Psychiat 1979; 14: 485-97. Neuman RS, Thompson PM. Serotonin mediate suppression of focal epileptiform activity induced by noxious stimulation. Epilepsia 1989; 30: 307-13. Buge A, Poisson M, Rancurel G, et al. Un cas rebelle de petit mal: action de la clomipramine. Nouv Press Med 1974; 3: 373-5. Setiey A, Courjon J. Clomipramine et petit mal. Lyon Medical 1978; 239: 751-4. Lange SC, Julien RM, Fowler GW. Biphasic effects of imipramine in experimental models of epilepsy. Epilepsia 1976; 17: 183-96.