Epilepsiu, 33(2):343-345, 1992 Raven Press, Ltd., New York 0 International League Against Epilepsy
Calcium Antagon st Nimodipine in Intractab e Epilepsy “F. A. de Falco, U. Bartiromo, L. Majello, G. Di Geronimo, and P. Mundo *Department of Neurophysiology, 2nd School of Medicine, University of Naples, Naples; and Medical Rehabilitation Center “Villa Silvia,” Salerno, Italy
Summary: The influx of Ca2+ into the neuron seems to play an important role in the genesis of epileptic seizures, and current research suggests that calcium entry blockers may have anticonvulsant activity. We used nimodipine, a calcium antagonist with high central nervous system affinity at a fixed dosage of 30 mg, t.i.d., in 21 patients with intractable epilepsy caused by organic brain lesions in addition to basal antiepileptic drug (AED) therapy. After a 12-week treatment period 14 patients (67%) showed a
decrease in seizure frequency, four patients had no change, and three had an increase. In eight patients (38%) seizure frequency decreased by >40%. The p value with one-tailed t-test was 0.0491. No significant modifications in AED or electrolyte serum levels were found. One patient had a lowering of blood pressure at this dosage. Key
The calcium antagonists flunarizine (Overweg et al., 1984; Binnie et al., 1985; Starreveld et al., 1989) and nifedipine (Lowry et al., 1988) have been investigated as putative antiepileptic drugs (AEDs). Nimodipine (NMD), a Ca2+ antagonist with high central nervous system affinity reduces experimentally induced seizures in animals (Meyer et al., 1986a,b, 1988, 1990). We report the use of NMD in mentally retarded patients with epileptic seizures refractory to usual AED therapy.
were evaluated as mean number of discharges per minute. Serum AED levels, Ca, P, Na, K , and alkaline phosphatase were evaluated before and after NMD. Arterial pressure was evaluated twice a week. The paired samples t test was used for statistical analysis. The experimental and clinical evidence of an anticonvulsant effect of calcium antagonists suggested the use of a one-tailed test.
Words: Epilepsy-Anticonvulsants-Nimodipine-Drug-
induced abnormalities.
RESULTS PATIENTS AND METHODS
The overall seizure frequency with add-on NMD was significantly lower than during the previous 12week period (Fig. 1): 14 patients (67%) showed a decrease in seizure frequency. Three had no change (percentage variation 40% (Table 2). The statistical analysis of results by paired samples t test (one-tailed) showed a p value of 0.0491 (two-tailed p = 0.0983). Seizure type did not change for each patient. EEG findings were unchanged. No significant modification in serum AED levels or electrolytes was found, but valproate levels were slightly lowered in five of eight patients. One patient showed a decrease in blood pressure.
Twenty-one epileptic patients with mental retardation (13 male, 8 female; mean age 24.7, range 11-38 years) with seizures refractory to usual AEDs received NMD, 30 mg, t.i.d., for a 12-week period in addition to basal AEDs. All subjects were inpatients of a medical rehabilitation center (Table 1). Frequency and clinical seizure type were recorded by the paramedical staff, who were unaware of the administered medications. Patients were unable to distinguish AEDs because of their mental retardation. While this trial cannot be considered controlled, it can be considered blinded. Seizure frequency was compared to the previous 12-week period. Frequency of EEG focal and/or diffuse epileptic discharges before and after NMD
DISCUSSION Received July 1989; revision accepted June 1991. Address correspondence and reprint requests to Dr. F. A. de Falco at Via dei Mille, 59, 80121 Naples, Italy.
New AED research is based on knowledge of basic mechanisms of epileptogenesis. Influx of Ca2+ 343
F . A. DE FALCO ET AL.
344
TABLE 1. Clinical data
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
16 17 18 19 20 21
F M F M F M F M M M M M M F F M M
M F F M
33 29 34 24 38 23 16 29 23 11 25 22 14
24 13 30 23 35 22 22 28
Diagnosis
Seizure types
Therapy
Perinatal brain damage Perinatal brain damage Encephalitis Encephalitis Bourneville disease Microcephaly Encephalitis Encephalitis Encephalitis Encephalitis Epileptic encephalopathy Perinatal brain damage Encephalitis Epileptic encephalopathy Encephalitis Perinatal brain damage Perinatal brain damage Perinatal brain damage Encephalitis Perinatal brain damage Encephalitis, traumatic hemorrhage
CPS, GTCS GTCS CPS, GTCS CPS, GTCS CPS, GTCS GTCS CPS, GTCS GTCS CPS CPS CPS, GTCS CPS, GTCS CPS, GTCS GTCS GTCS GTCS CPS, GTCS CPS, GTCS GTCS GTCS CPS
PB, CBZ PB, PHT CBZ PB PB PB, PHT PB, CBZ PB, PHT PB, PHT CBZ, VPA PB, VPA PB, CBZ VPA PB, VPA PB PB, VPA PB, CBZ, VPA PB, PHT PB, VPA PB PB, VPA
Patients are listed in descending order of percentage reduction in seizures. CPS, complex partial seizures; GTCS, generalized tonic-clonic seizures; PB, phenobarbital; CBZ, carbamazepine; PHT, phenytoin, VPA, valproate.
is associated with activation of Ca2+ conducting sites, and calcium currents trigger other changes in conductance, primarily to potassium (Adams and Galvan, 1986). Synaptic facilitation, i.e., increased transmitter release, is caused by Ca2+ accumulation in the nerve terminal (Kretz et al., 1982). The calcium entry blocker NMD has shown an-
ticonvulsant action in experimental models of epilepsy (Meyer et al., 1986u,b, 1988, 1990). Our clinical findings in intractable epilepsy support the hypothesis that NMD might have an anticonvulsant action in human epilepsy as well. The effect of NMD was not due to variations in serum levels of conventional AEDs. TABLE 2. Seizure frequency Case number 1 2 3 4 5 6 7 8 9 10 11
1 2 3 4 5 6 7 8 9 I D 11 17 1’3 14 15 1617’18 1 9 2 0 7 1
PA-[ IkNTS =Basal Nimodipine FIG. 1. Seizure frequency over a 12-week period. Asterisk indicates number of seizures x10.
Epilepsia, Vol. 33, No. 2, 1992
12 13 14 IS 16 17 18 19 20 21
Basal
Nimodipine
Percent variation
37 4 30 12 62 23 11 45 13 45 16 20 8 5 8 26 227 5 8 4 9
3 1 12 6 32 12 6 25 8 30 11 14 6 4 8 27 260 6 11 6 19
-91.89 - 75 - 60 - 50 -48.39 -47.82 - 45.45 44.44 - 38.46 -33.33 -31.25 - 30 25 - 20 0 + 3.85 + 14.53 + 20 +37.5 + 50 + 110.7 ~
~
Patients are listed in descending order of percentage of reduction of seizures. Paired sample t test: one-tailed, p = 0.0491; two-tailed, p = 0.0983
345
NIMODIPINE IN INTRACTABLE EPILEPS Y Further controlled double-blind trials are needed to determine the role of NMD in the therapy of epilepsy.
REFERENCES Adams PR, Galvan M. Voltage-dependent currents of vertebrate neurons and their role in membrane excitability. In: DelgadoEscueta AV, Ward AA Jr., Woodbury DM, Porter RJ, eds. Basic mechanisms of the epilepsies: molecular and cellular approaches. (Advances in Neurology, vol. 44.) New York: Raven Press. 1986:137-70. Binnie CD, de Beukelaar F, Meijer JWA, et al. Open doseranging trial of flunarizine as add-on therapy in epilepsy. Epilepsia 198S;26:424-8. Kretz R, Shapiro E, Kandel ER. Post-tetanic potentiation at an identified synapse in aplasia is correlated with a Ca+ + activated K + current in the presynaptic neuron: evidence for C a + + accumulation. Proc Nut1 Acad Sci (USA) 1982;79: 5430-4. Lowry SR, Shinton RA, Jamieson G . Nifedipine for epilepsy? A pilot study. BMJ 1988;296:.530. Meyer FB, Anderson RE, Sundt TM Jr. Anticonvulsant properties of dihydropyridine calcium antagonists. In: The calcium channel: structure, .function and implications. Berlin: Springer Verlag, 1988:503-19. Meyer FB, Anderson RE, Sundt TM Jr. Anticonvulsant effects of dihydropyridine Ca2+ antagonists in electrocortical shock seizures. Epilepsia 1990;31:68-74. Meyer FB, Anderson RE, Sundt TM Jr, Sharbrough FW. Selective central nervous system channel blockers-a new class of anticonvulsant agents. Mayo Clin Proc 1986a;61:239-47. Meyer FB, Tally PW, Anderson RE, Sundt TM Jr, Yaksh TL. Inhibition of electrically induced seizures by a dihydropyridine calcium channel blocker. Brain Res 19866;384:180-3. Overweg J, Binnie CD, Meijer JWA, et al. Double-blind placebocontrolled trial of flunarizine as add-on therapy in epilepsy. Epilepsia 1984;2S:2 17-22. Starreveld E, de Beukelaar F, Wilson AF, McLean DR, Findlay HP. Double-blind cross-over placebo controlled study of flunarizine in patients with therapy resistant epilepsy. Can J Neurol 1989;16:187-90.
&SUME L’entrte de l’ion Ca2+ dans le neurone semble jouer un r6le important dans la gtnese des crises Cpileptiques, et les recherches actuelles suggtrent que les drogues qui bloquent I’entrte du calcium dans les cellules peuvent avoir un effet anticonvulsivant. Les auteurs ont utilists la Nimodipine (NMD), antagoniste calcique avec une forte affinitt pour le systtme nerveux central, a une dose fixe de 30 mg 3 fois parjour, chez 21 patients presentant
une epilepsie rebelle like & des lksions cerebrales organiques, en addition au traitement antiepileptique de base. Apres une periode de traitement de 12 sernaines, 14 patients (67%) ont prtsente une diminution de la frkquence des crises, 4 n’ont pas eu de changement et 3 une augmentation. Chez 8 patients (38%), la frequence des crises a diminue de plus de 40%. La valeur du p au t test simple etait de 0.0491. I1 n’y a pas eu de modifications significatives dans les taux seriques des mkdicarnents antitpileptiques ou des electrolytes. Un patient a presente une diminution de la tension arterielle a la dose utilisee. (P. Genton, Mar.seille)
RESUMEN La entrada de Ca2+ en las neuronas parece que juega un importante papel en la genesis de 10s ataques epilepticos y la investigacion reciente sugiere que 10s bloqueantes de la entrada del calcio pueden tener una actividad anticonvulsiva. Los autores han utilizado la Nimodipina (NMD), un antagonista del calcio con gran actividad por el Sistema Nervioso Central, en dosis fijas de 30 mg, 3 veces diarias, en 21 pacientes con epilepsia incontrolable causada por lesiones cerebrales organicas, anadiendo esta medication a la terapia basal antiepileptica. Desputs de 12 semanas de tratamiento, 14 enfermos (67%) mostraron una reduccion en la frecuencia de 10s ataques, 4 pacientes no mostraron ningun cambio y en 3 pacientes se observo un increment0 de las crisis. En 8 pacientes (38%) la frecuencia de ataques se redujo en mAs de un 40%. El valor p en un test t fue de 0.0491. No se encontraron modificaciones significativas en 10s niveles sericos de las medicaciones antiepilepticas o de 10s electrolitos. Un enfermo mostr6 una reducci6n de l ad e la presion arterial con las dosis utilizadas. (A. Portera-SAnchez, Madrid)
ZUSAMMENFASSUNG Der Kalzium-Einstrom in den Neuronen scheint eine wichtige Rolle in der Genese epileptischer Anfalle zu spielen. Die gegenwartige Forschung vermutet, daB Kalzium-Influx-Hemmer antiepileptische Aktivitat haben konnen. Wir verwendeten Nimodipine (NMD), ein Kalziurnantagonist mit hoher Affinitat zum ZNS, bei 21 Patienten mit therapieresistenter Epilepsie im Rahmen organische Hirnlasionen als comedikation. Nach 12 Wochen Behandlung zeigten 14 Patienten (67%) eine Verringerung der Anfallsfrequenz, 4 Patienten keine Veranderung, 3 Patienten eine Zunahme. Bei 8 Patienten (40%) sank die Anfallsfrequenz um 38% ab. Der P-Wert (one-tailed) des T-Test lag bei 0.0491. Eine signifikante Veranderung der AntiepileptikaBlutspiegel und Elektrolyte wurden nicht gefunden. Ein Patient bot einen verminderten Blutdruck. (C. G . Lipinski, Heidelberg Neckargemiind)
Epilepsia, Vol. 33, N o . 2,IY92
Calcium Antagon st Nimodipine in Intractab e Epilepsy “F. A. de Falco, U. Bartiromo, L. Majello, G. Di Geronimo, and P. Mundo *Department of Neurophysiology, 2nd School of Medicine, University of Naples, Naples; and Medical Rehabilitation Center “Villa Silvia,” Salerno, Italy
Summary: The influx of Ca2+ into the neuron seems to play an important role in the genesis of epileptic seizures, and current research suggests that calcium entry blockers may have anticonvulsant activity. We used nimodipine, a calcium antagonist with high central nervous system affinity at a fixed dosage of 30 mg, t.i.d., in 21 patients with intractable epilepsy caused by organic brain lesions in addition to basal antiepileptic drug (AED) therapy. After a 12-week treatment period 14 patients (67%) showed a
decrease in seizure frequency, four patients had no change, and three had an increase. In eight patients (38%) seizure frequency decreased by >40%. The p value with one-tailed t-test was 0.0491. No significant modifications in AED or electrolyte serum levels were found. One patient had a lowering of blood pressure at this dosage. Key
The calcium antagonists flunarizine (Overweg et al., 1984; Binnie et al., 1985; Starreveld et al., 1989) and nifedipine (Lowry et al., 1988) have been investigated as putative antiepileptic drugs (AEDs). Nimodipine (NMD), a Ca2+ antagonist with high central nervous system affinity reduces experimentally induced seizures in animals (Meyer et al., 1986a,b, 1988, 1990). We report the use of NMD in mentally retarded patients with epileptic seizures refractory to usual AED therapy.
were evaluated as mean number of discharges per minute. Serum AED levels, Ca, P, Na, K , and alkaline phosphatase were evaluated before and after NMD. Arterial pressure was evaluated twice a week. The paired samples t test was used for statistical analysis. The experimental and clinical evidence of an anticonvulsant effect of calcium antagonists suggested the use of a one-tailed test.
Words: Epilepsy-Anticonvulsants-Nimodipine-Drug-
induced abnormalities.
RESULTS PATIENTS AND METHODS
The overall seizure frequency with add-on NMD was significantly lower than during the previous 12week period (Fig. 1): 14 patients (67%) showed a decrease in seizure frequency. Three had no change (percentage variation 40% (Table 2). The statistical analysis of results by paired samples t test (one-tailed) showed a p value of 0.0491 (two-tailed p = 0.0983). Seizure type did not change for each patient. EEG findings were unchanged. No significant modification in serum AED levels or electrolytes was found, but valproate levels were slightly lowered in five of eight patients. One patient showed a decrease in blood pressure.
Twenty-one epileptic patients with mental retardation (13 male, 8 female; mean age 24.7, range 11-38 years) with seizures refractory to usual AEDs received NMD, 30 mg, t.i.d., for a 12-week period in addition to basal AEDs. All subjects were inpatients of a medical rehabilitation center (Table 1). Frequency and clinical seizure type were recorded by the paramedical staff, who were unaware of the administered medications. Patients were unable to distinguish AEDs because of their mental retardation. While this trial cannot be considered controlled, it can be considered blinded. Seizure frequency was compared to the previous 12-week period. Frequency of EEG focal and/or diffuse epileptic discharges before and after NMD
DISCUSSION Received July 1989; revision accepted June 1991. Address correspondence and reprint requests to Dr. F. A. de Falco at Via dei Mille, 59, 80121 Naples, Italy.
New AED research is based on knowledge of basic mechanisms of epileptogenesis. Influx of Ca2+ 343
F . A. DE FALCO ET AL.
344
TABLE 1. Clinical data
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
16 17 18 19 20 21
F M F M F M F M M M M M M F F M M
M F F M
33 29 34 24 38 23 16 29 23 11 25 22 14
24 13 30 23 35 22 22 28
Diagnosis
Seizure types
Therapy
Perinatal brain damage Perinatal brain damage Encephalitis Encephalitis Bourneville disease Microcephaly Encephalitis Encephalitis Encephalitis Encephalitis Epileptic encephalopathy Perinatal brain damage Encephalitis Epileptic encephalopathy Encephalitis Perinatal brain damage Perinatal brain damage Perinatal brain damage Encephalitis Perinatal brain damage Encephalitis, traumatic hemorrhage
CPS, GTCS GTCS CPS, GTCS CPS, GTCS CPS, GTCS GTCS CPS, GTCS GTCS CPS CPS CPS, GTCS CPS, GTCS CPS, GTCS GTCS GTCS GTCS CPS, GTCS CPS, GTCS GTCS GTCS CPS
PB, CBZ PB, PHT CBZ PB PB PB, PHT PB, CBZ PB, PHT PB, PHT CBZ, VPA PB, VPA PB, CBZ VPA PB, VPA PB PB, VPA PB, CBZ, VPA PB, PHT PB, VPA PB PB, VPA
Patients are listed in descending order of percentage reduction in seizures. CPS, complex partial seizures; GTCS, generalized tonic-clonic seizures; PB, phenobarbital; CBZ, carbamazepine; PHT, phenytoin, VPA, valproate.
is associated with activation of Ca2+ conducting sites, and calcium currents trigger other changes in conductance, primarily to potassium (Adams and Galvan, 1986). Synaptic facilitation, i.e., increased transmitter release, is caused by Ca2+ accumulation in the nerve terminal (Kretz et al., 1982). The calcium entry blocker NMD has shown an-
ticonvulsant action in experimental models of epilepsy (Meyer et al., 1986u,b, 1988, 1990). Our clinical findings in intractable epilepsy support the hypothesis that NMD might have an anticonvulsant action in human epilepsy as well. The effect of NMD was not due to variations in serum levels of conventional AEDs. TABLE 2. Seizure frequency Case number 1 2 3 4 5 6 7 8 9 10 11
1 2 3 4 5 6 7 8 9 I D 11 17 1’3 14 15 1617’18 1 9 2 0 7 1
PA-[ IkNTS =Basal Nimodipine FIG. 1. Seizure frequency over a 12-week period. Asterisk indicates number of seizures x10.
Epilepsia, Vol. 33, No. 2, 1992
12 13 14 IS 16 17 18 19 20 21
Basal
Nimodipine
Percent variation
37 4 30 12 62 23 11 45 13 45 16 20 8 5 8 26 227 5 8 4 9
3 1 12 6 32 12 6 25 8 30 11 14 6 4 8 27 260 6 11 6 19
-91.89 - 75 - 60 - 50 -48.39 -47.82 - 45.45 44.44 - 38.46 -33.33 -31.25 - 30 25 - 20 0 + 3.85 + 14.53 + 20 +37.5 + 50 + 110.7 ~
~
Patients are listed in descending order of percentage of reduction of seizures. Paired sample t test: one-tailed, p = 0.0491; two-tailed, p = 0.0983
345
NIMODIPINE IN INTRACTABLE EPILEPS Y Further controlled double-blind trials are needed to determine the role of NMD in the therapy of epilepsy.
REFERENCES Adams PR, Galvan M. Voltage-dependent currents of vertebrate neurons and their role in membrane excitability. In: DelgadoEscueta AV, Ward AA Jr., Woodbury DM, Porter RJ, eds. Basic mechanisms of the epilepsies: molecular and cellular approaches. (Advances in Neurology, vol. 44.) New York: Raven Press. 1986:137-70. Binnie CD, de Beukelaar F, Meijer JWA, et al. Open doseranging trial of flunarizine as add-on therapy in epilepsy. Epilepsia 198S;26:424-8. Kretz R, Shapiro E, Kandel ER. Post-tetanic potentiation at an identified synapse in aplasia is correlated with a Ca+ + activated K + current in the presynaptic neuron: evidence for C a + + accumulation. Proc Nut1 Acad Sci (USA) 1982;79: 5430-4. Lowry SR, Shinton RA, Jamieson G . Nifedipine for epilepsy? A pilot study. BMJ 1988;296:.530. Meyer FB, Anderson RE, Sundt TM Jr. Anticonvulsant properties of dihydropyridine calcium antagonists. In: The calcium channel: structure, .function and implications. Berlin: Springer Verlag, 1988:503-19. Meyer FB, Anderson RE, Sundt TM Jr. Anticonvulsant effects of dihydropyridine Ca2+ antagonists in electrocortical shock seizures. Epilepsia 1990;31:68-74. Meyer FB, Anderson RE, Sundt TM Jr, Sharbrough FW. Selective central nervous system channel blockers-a new class of anticonvulsant agents. Mayo Clin Proc 1986a;61:239-47. Meyer FB, Tally PW, Anderson RE, Sundt TM Jr, Yaksh TL. Inhibition of electrically induced seizures by a dihydropyridine calcium channel blocker. Brain Res 19866;384:180-3. Overweg J, Binnie CD, Meijer JWA, et al. Double-blind placebocontrolled trial of flunarizine as add-on therapy in epilepsy. Epilepsia 1984;2S:2 17-22. Starreveld E, de Beukelaar F, Wilson AF, McLean DR, Findlay HP. Double-blind cross-over placebo controlled study of flunarizine in patients with therapy resistant epilepsy. Can J Neurol 1989;16:187-90.
&SUME L’entrte de l’ion Ca2+ dans le neurone semble jouer un r6le important dans la gtnese des crises Cpileptiques, et les recherches actuelles suggtrent que les drogues qui bloquent I’entrte du calcium dans les cellules peuvent avoir un effet anticonvulsivant. Les auteurs ont utilists la Nimodipine (NMD), antagoniste calcique avec une forte affinitt pour le systtme nerveux central, a une dose fixe de 30 mg 3 fois parjour, chez 21 patients presentant
une epilepsie rebelle like & des lksions cerebrales organiques, en addition au traitement antiepileptique de base. Apres une periode de traitement de 12 sernaines, 14 patients (67%) ont prtsente une diminution de la frkquence des crises, 4 n’ont pas eu de changement et 3 une augmentation. Chez 8 patients (38%), la frequence des crises a diminue de plus de 40%. La valeur du p au t test simple etait de 0.0491. I1 n’y a pas eu de modifications significatives dans les taux seriques des mkdicarnents antitpileptiques ou des electrolytes. Un patient a presente une diminution de la tension arterielle a la dose utilisee. (P. Genton, Mar.seille)
RESUMEN La entrada de Ca2+ en las neuronas parece que juega un importante papel en la genesis de 10s ataques epilepticos y la investigacion reciente sugiere que 10s bloqueantes de la entrada del calcio pueden tener una actividad anticonvulsiva. Los autores han utilizado la Nimodipina (NMD), un antagonista del calcio con gran actividad por el Sistema Nervioso Central, en dosis fijas de 30 mg, 3 veces diarias, en 21 pacientes con epilepsia incontrolable causada por lesiones cerebrales organicas, anadiendo esta medication a la terapia basal antiepileptica. Desputs de 12 semanas de tratamiento, 14 enfermos (67%) mostraron una reduccion en la frecuencia de 10s ataques, 4 pacientes no mostraron ningun cambio y en 3 pacientes se observo un increment0 de las crisis. En 8 pacientes (38%) la frecuencia de ataques se redujo en mAs de un 40%. El valor p en un test t fue de 0.0491. No se encontraron modificaciones significativas en 10s niveles sericos de las medicaciones antiepilepticas o de 10s electrolitos. Un enfermo mostr6 una reducci6n de l ad e la presion arterial con las dosis utilizadas. (A. Portera-SAnchez, Madrid)
ZUSAMMENFASSUNG Der Kalzium-Einstrom in den Neuronen scheint eine wichtige Rolle in der Genese epileptischer Anfalle zu spielen. Die gegenwartige Forschung vermutet, daB Kalzium-Influx-Hemmer antiepileptische Aktivitat haben konnen. Wir verwendeten Nimodipine (NMD), ein Kalziurnantagonist mit hoher Affinitat zum ZNS, bei 21 Patienten mit therapieresistenter Epilepsie im Rahmen organische Hirnlasionen als comedikation. Nach 12 Wochen Behandlung zeigten 14 Patienten (67%) eine Verringerung der Anfallsfrequenz, 4 Patienten keine Veranderung, 3 Patienten eine Zunahme. Bei 8 Patienten (40%) sank die Anfallsfrequenz um 38% ab. Der P-Wert (one-tailed) des T-Test lag bei 0.0491. Eine signifikante Veranderung der AntiepileptikaBlutspiegel und Elektrolyte wurden nicht gefunden. Ein Patient bot einen verminderten Blutdruck. (C. G . Lipinski, Heidelberg Neckargemiind)
Epilepsia, Vol. 33, N o . 2,IY92
