Folia Psychiatrica et Neurologica Japonica, Vol. 3 1, No. 2, 1977
A Clinical and Electroencephalographic Study on An ti-Epilepti c Activity of CIon azepam -Relationship Between Clinical Effects of Oral Administration and Electroencephalographic Effects of Intravenous AdministrationHideaki Kato, M.D. and Toshinori Mori, M.D. Department of Neuropsychiatry, School of Medicine, Gifu University, Gifu
INTRODUCTION Benzodiazepine derivatives are presently in wide use as anti-epileptic agents. Above all, nitrazepam has frequently been used for minor motor seizures, and diazepam for status epilepticus-as a first choice drug. Clonazepam is the first benzodiazepine derivative that was developed originally as an anti-epileptic agent and has been proved, through pharmacological studies in animal models, to have the most intensive anti-epileptic effects among all benzodiazepine derivatives.:< RO Its clinical efficacy also has begun to be recognized. The authors have reported-based on the results of a series of studies by the oral and intravenous administration-that this drug is an excellent anti-epileptic drug.” 29 It is difficult to evaluate objectively the effects of an anti-epileptic agent because it is impossible to treat patients with a new drug alone; moreover, interaction in combination with other drugs, various inducement for seizures in patients, and so on, militate against such evaluation. The EEG findings provide useful materials for objective evaluation, but improvement observed following the administration of a drug is not always considered to have been brought about by the drug. Received for publication Oct. 7, 1976.
Given this circumstance, this study was designed to evaluate objectively the effects of clonazepam and ascertain its characteristics by checking the results of oral administration with the EEG findings following intravenous administration. Since EEG changes produced by intravenous injection of clonazepam directly show the effects of the drug on the EEG, the comparison of the results of oral and intravenous administrations in the same case is considered to be useful in evaluating objectively the effects of clonazepam. ORAL ADMINISTRATION Subjects and Methods
Thirty patients of so-called refractory epilepsy with seizures that had not been controlled completely by conventional antiepileptic drugs were employed as subjects. As there were six patients in whom two different types of seizures were combined, the number of cases, in terms of seizures, was 36. Clonazepam was administered at a daily dose of one to eight mg (3.3 mg on the average) by either adding the drug to the anti-convulsants administered previously or replacing a part of them with clonazepam. The test period was four months to two years and eight months, and the average was 11.9 months.
H. Kato and T. Mori
184
Table 1: Clinical Effects of Oral Administration
Tonlc clonlc convulrion
@@
a0
15
000000 00000
Partial motor rlrun
Jaekwnhn Foorl motor Vrrsivr Complrx partial rlrura
00 0
80 0 8 0
Myoalonic r l r u n Tonlc rlrun Atonlo uirurr Typiorl abwncr
3
Total Notes:
.:
++: excellent, +:
0 . 0 0
13
2 5 1
0 . 0 0 0 0 00
7 2 2
.
1 1
20
0
36
+
good, : unchanged, -: aggravated, P: photosensitive epilepsy, case which fell by one step in the evaluation rating sat flnal evaluation.
-. Fig. 1A: EEG of a 17-year-old male with generalized convulsion. Prior to clonazepam medication, the basic activity was slow a with a small amount of slow wave ( 5 , 6 Hz) and a generalized spike-and-wave complex appeared. The electrode placement applied correspondingly to the ten-twenty electrode system. (This applies to the following cases.) (calibration: 1 sec, S o p )
Anti-Epileptic Activity of Clonazepam Efficacy was evaluated based on the criterion consisting of four ratings; “excellent” (free from seizures), “good” (over 60% decrease in seizure frequency), “unchanged” (below 50% decrease in seizure frequency) and “aggravated.” Results Table 1 shows the results of the evaluation. Clonazepam was effective in 44.4% of all cases: i.e., “excellent” in three cases, “good” in 13, and brought about no change in 55.6%, or 20 cases, there was no “aggravated” case. According to the type of seizures, clonazepam was “excellent” or “good” in four (26.7%) out of 15 cases with tonic clonic convulsion. For partial motor seizures, this drug was “good” in both of the two cases with Jacksonian seizure, while ineffective in all cases with focal motor and versive seizures. For complex partial seizures, clona-
185
zepam was most effective, being “excellent” or “good” in five (71.4%) out of seven cases. There were four patients who had photosensitivity on the EEG, consisting of five types of seizures. In Table 1, these cases are indicated by P. In two out of the five cases, clinical seizures were induced by photic stimulation. Clonazepam was “excellent” in two and “good” in three; the seizure either disappeared or decreased in frequency. In three cases, photosensitivity on the EEG disappeared after clonazepam medication. Among the cases which could be followed up for a long time, there were eight cases which responded well to clonazepam initially but turned less responsive and fell by one grade in the evaluation ratings. The black marks in Table 1 show the cases which fell by one step in ratings at the final evaluation. In the evaluation made at the initial
Fig. 1B: EEG of 90 seconds after intravenous injection of clonazepam in Fig. 1A. Following intravenous injection of clonazepam, a spike-and-wave complex disappeared, but big slow waves appeared continuously and the basic activity showed clear slowing. (reference electrode: each ear, calibration: 1 sec, 50 p v )
H. Kato and T. Mori
186
Table 2:
Electroencephalographic Effects of Intravenous Administration
++
Type of Seizure Discharge Generalized spike and wave polyspikees and wave slow spike and wave
+
f
-
Total
0 0 0
9
0
6
5
3
1
1 0
0 0
0 1
4 0 0 4
0 0 0 1
2 1 2 0
1 1
Localizd
temporal frontal
Hyparrhythmia Photosensitivity Total Not-:
++: mcdhti
1 +I
4
4
7
0
1
0 0 0
2 5
25
good; f: unchanged; -: aggravated,
stage of administration, clonazepam was “excellent” in seven cases, “good” in 13 and the rate of effectiveness amounted to 55.6%.
I n almost all patients who could be treated by clonazepam (per os), this injection test was performed before clonazepam was administered orally.
INTRAVENOUS ADMINISTRATION
Results The basic EEG activity was improved by the intravenous injection of clonazepam in four (19%) out of 21 patients in whom the EEG could be examined during the waking and resting states. In one patient among the 2 I , a slower activity (slowing) was induced clearly (Figs. 1A and B). Table 2 summarizes the restraining effect of clonazepam on the paroxysmal activity. It proved “excellent” in six (54.570) out of 1 1 cases with generalized paroxysmal activity, and “good” in three, the effective rate amounting to 81.8%. For temporal spikes, this drug was “excellent” in four out of six cases. There were five patients with photosensitivity in whom epileptic discharges were induced on the EEG by photic stimulation. In four out of the five patients, such stimulation also induced clinical seizures. By intravenous injection of clonazepam, photosensitivity was suppressed for 10 minutes in four patients and four minutes in one patient. Clonazepam proved to be effective
Subjects and Methods
Twenty-three epileptic patients who showed abnormal paroxysmal activity on the EEG in the interictal period were picked as the subjects. As there were two patients in whom two different types of seizure discharge were combined, the number of cases, in terms of seizure discharge, was 25. Two ml of clonazepam solution (contained clonazepam 1 mg) was injected intravenously at the rate of 1 ml per minute. The EEG was taken for 10 minutes before and after administration. Depending on the changes of the paroxysmal activity, the effect of the drug was evaluated based on the criterion consisting of four ratings; “excellent” (almost complete disappearance of seizure discharge), “good” (over 50% decrease in frequency of seizure discharge), “unchanged” (below SOY; decrease in frequency of seizure discharge), “aggravated” (increase in frequency of seizure discharge).
Anti-Epileptic Activity of Clonazepam in all of the five cases.
187
zepam.
RELATIONSHIP BETWEEN THE RESULTS
1. A 17-year-old male with tonic clonic convulsion (Fig. 1 )
There were 13 patients who could undergo both oral and intravenous administration. Table 3 shows the relationship between the results of administration via both routes. In all cases-in which clonazepam proved "excellent" via the intravenous administration-it also proved "excellent" or "good" via the oral administration. The results of oral administration correlated roughly with those of intravenous administration. In the representative cases described below, anti-epileptic activity of clonazepam is clarified in relation to the EEG changes produced by intravenous injection of clona-
This is a clinically ineffective case in which clonazepam might exert unfavorable influence on clinical seizures, and EEG findings were aggravated by the intravenous injection of clonazepam. Prior to the administration of clonazepam, the basic activity was irregular slow a (8-9 Hz) with a small amount of slow wave (5--6 Hz) and a bilateral synchronous spikeand-wave complex (about 3 Hz) appeared for some 15 seconds. Twenty seconds after the intravenous injection of clonazepam, slow waves (3--4 Hz) appeared, which clearly showed a tendency toward EEG slowing. Slow bursts appeared after 50 seconds, and
v
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(A)
(B)
Fig. 2: EEG of a 16-year-old female with generalized convulsion. Prior to clonazepam medication, bilateral synchronous spike-and-wave complexes appeared frequently (A). Following intravenous injection of clonazepam, paroxysmal activity disappeared completely. The basic activity was also improved, owing to decrease of slow waves and appearance of low-voltage fast waves (B). (reference electrodes: each ear, calibration: 1 sec, 50 pv)
188
H. Kato and T. Mori
big slow waves continued after 90 seconds. This evident slowing of EEG predominated for some seven minutes, returning gradually to the original EEG pattern. High-voltage slow wave was partially accompanied by small spikes, and seemed to make spikeand-wave formation although not clearly.
2. A 16-year-old female with tonic clonic convulsion (Fig. 2 ) This is a case in which oral therapy with clonazepam was clinically effective. Prior to its administration, a bilateral synchronous spike-and-wave complex (3-3.5 Hz) appeared frequently. Following the intravenous injection of clonazepam, the paroxysmal activity disappeared completely. The basic activity was also improved, owing to a decrease in slow waves and appearance of low-voltage fast waves. This fact indi-
cated that clonazepam would be effective on the epileptic discharge in this case, and provided an objective proof of its clinical effectiveness by oral administration.
3. A 12-year-old girl with focal motor seizure and secondary generalized convulsion (Fig. 3 ) Prior to its administration, focal paroxysmal activity in the left frontal region and secondary bilateral synchronous spike-andwave complexes appeared. Following the intravenous injection of clonazepam, only bilateral sy~ichronousspike-and-wave complexes were suppressed, while the focal paroxysmal discharge in the left frontal region was more evident. This was a case which remained clinically unchanged after oral therapy with clonazepam. However, from the EEG changes
Anti-Epileptic Activity of Clonazepam produced by intravenous injection of clonazepam, it was considered that this drug might be effective in secondary generalized seizures in some cases, but ineffective for focal seizures.
4. A 68-year-old female with complex partial seizure (Fig. 4) This is a case in which clonazepam resulted in significant clinical effects by oral administration. Prior to its administration, spikes or sharp waves had frequently appeared in the right temporal region. Three months after the oral administration at a daily dose of 2 mg, the incidence of spikes was decreased and the amplitude was also lowered. By intravenous injection of clonazepam, the temporal spikes that had appeared before clonazepam therapy were suppressed completely. This fact was considered as providing an objective verification for the remarkable clinical effectiveness of this drug when administered orally. DISCUSSION
According to the reports published so far, considerably favorable results have been obtained with clonazepam in generalized convuIsion.10 21 23 ZR In the present study, 26.7% of the effective rate was attained with this drug in tonic clonic convulsion. However, three out of four cases responding well were specific cases with photosensitivity on the EEG. In the experimental studies, it has been shown that clonazepam is not an effective drug for a grand ma1 seizure.O Therefore, the effectiveness of this drug on this type of epilepsy cannot be emphasized from the results of our study. It is generally said that benzodiazepine derivatives might aggravate generalized convulsion,O and the same caution has also been made for ~lonazepam.~25 In this connection, it is necessary to take note of the fact that slow waves in the background
189
EEG became dominant with high-voltage slow bursts after intravenous administration of clonazepam in a case with tonic clonic convulsion in our study (Fig. 1 ) . This might suggest that only the spike component in the spike-and-wave complex, which had appeared before the clonazepam therapy, was suppressped. However, in view of the frequency of the slow waves, the matter cannot be considered to be explained sufficiently by this interpretation. The possibility that the patient might have fallen asleep during the examination cannot be denied. There is also the possibility that the EEG slowing was induced by some other mechanisms following the intravenous injection of clonazepam. As to tonic seizures of Lennox-Gastaut syndrome, the intravenous injection of diazepam and nitrazepam has been reported to have precipitated tonic status epileptiC U S . ~31~ Browne7 has mentioned that the possible explanation of the worsening by clonazepam might be: 1) the natural variability of seizure frequency, 2 ) actual aggravation of grand ma1 seizure disorder by clonazepam or a clonazepam metabolite; or 3) enzyme induction by clonazepam, reducing the plasma concentration of other anti-convulsants. But, these possibilities still remain to be examined. In the already published reports on the intravenous administration of clonazePam," l3 28 *' there are only a limited number of cases in which the EEG finding was aggravated by the intravenous injection of clonazepam (a case in our study and one reported by Rosenmyer et al.).zo Aggravation in the EEG findings after intravenous injection may not be linked to precipitation of seizures by oral administration. However, the case in the present study is a clinically ineffective one in which clonazepam is considered to cxert an unfavorable influence on seizurcs. Considering the paradoxical influence of clonazepam on the generalized convulsion, the authors consider that the case in the present study in which the EEG
H. Kato and T. Mori
190
F3-P3 P3-T3 T3-F3 FB-cz F4-P4 1'4-T4 'r4-F4 F4--CZ CZ-P3 CZ-P4 F3-F7 F7-T3 F4-F8
F8-T4 P3-01 P4-02
Fig. 4: EEG of a 68-year-old female with complex partial seizure. Prior to clonazepam medication, spikes appeared frequently in the right temporal region (A). Following intravenous injection of clonazepam, temporal spikes were suppressed completely (B) After oral clonazepam therapy, the incidence of spikes was decreased and their amplitude was also lowered ( C ) . (calibration: 1 sec, 50 pv)
.
Anti-Epileptic Activity of Clonazepam findings were aggravated by the intravenous injection of clonazepam provides a precious example. Initially, clonazepam drew attention because of its possible effectiveness for focalmotor seizures.? '" However, the evaluation of this drug on this type of epilepsy has not been definite at present in the light of the negative reports so far published. Recently, Sccolo-Lavizzari et aZ.20have stressed, based on the favorable results in 16 out of 24 cases of focal epilepsy (single administration in eight cases), that focalmotor seizures among all seizures respond best to clonazepam. In the present study, the rate of effectiveness of this drug on focal-motor seizures was low. However, it is noticeable that clonazepam was effective in the Jacksonian seizure in our study, and it is also interesting to note that clonazepam restrained the development of focal-motor seizures into the secondary generalized convulsion (Jacksonian march), although focal-motor seizures appeared occasionally. In studies of focal-motor seizures in animal models,' benzodiazepine has becn shown to be ineffective in abolishing abnormal discharges at the site of the cortical lesion, but capable of preventing motor manifestation of focal seizures and also in suppressing the spread of abnormal electrical activity from the site of the lesion. Similarly, in humans, clonazepam given intravenously does not abolish the EEG focus, but suppresses the spread of the electrical discharge from the focus.6 22 27 Since clonazepam administered intravenously does not suppress the focal seizure discharge but does suppress the secondary generalized one, Rossi et al.'? have considered that orally administered clonazepam would also be clinically effective for secondary generalized convulsion. In the present study, the authors confirmed this finding by oral and intravenous administration in the same case (Fig. 3). Classifying generalized convulsion into the primary and
191
Table 3: Relationship between Clinical Effects of Oral Administration and Electroencephalographic Effects of Intravenous Administration Clinical Effects (oral)
++ +
EEG Effects (intravenous)
++ +
f
-
Total 2
2
0
0
0
f
1 0
3 1
3 2
0 1
-
0
0
0
0
4 0
Total
3
4
5
1
13
I
secondary ones, AarW has reported that clonazepam is more effective in secondary generalized convulsion. In addition, the present findings are considered to be identical to those in some previous reports,272o indicating that the clinical seizure can be suppressed by clonazepam even when the focal seizure discharge is not suppressed on the EEG, and in another report2 stating that clonazepam is more effective in generalized convulsion with focal EEG abnormality. So far, little attention has been paid to the beneficial effect of clonazepam vis-d-vis complex partial seizures. Birket-Smith et aL4 and Lehtovaara et d Z o pointed to the beneficial effects of clonazepam on complex partial seizures (over 60% effective fate in 20 and 25 cases, respectively). Recently, the efficacy of clonazepam in this field has been claimed by Higano et aZ.14 in Japan. Observing the beneficial effects in 12 out of 14 cases with refractory seizures, they have considered clonazepam as an antiepileptic drug to be used for this kind of refractory epilepsy. In the laboratory screening test, clonazepam appeared to be less potent against complex partial seizures than phenobarbital, diphenylhydantoin or carbamazepine,6 but its effectiveness for complex partial seizures seems due to the mechanism by which it
192
H.Kato and T. Mori
has an inhibitory influence on the hippocampus, amygdala and septum (the limbic system)6 l2 which have a close anatomical and functional relation to the temporal lobe. In the present study, clonazepam was most effective in complex partial seizures, and the effective rate reached 71.4%. Our cases were refractory to other anticonvulsant and all of the cases responding well to clonazepam were those which did not respond sufficiently to diphenylhydantoin or carbamazepine, thus far the first choice drugs for complex partial seizures.s2In addition, clonazepam administered intravenously suppressed remarkably temporal spikes in four out of six cases. In two cases among the four, clonazepam proved remarkably effective not only by intravenous, but also by long-term oral administration (Fig. 4).1° 22 As mentioned above, the peculiar effect of clonazepam on complex partial seizures is worth noting. What is most striking in this study is that favorable effects were observed on the clinical seizures and on the EEG in the photosensitive epilepsy. It has been proved by experimental studies that clonazepam can, like other benzodiazepine derivatives, rapidly abolish the paroxysmal activity induced by photic stimulation.is It had been foreseen from the pharmacological action of clonazepam that it would be effective for photosensitive epilepsy. There are reports showing the clinical efficacy of this drug on photomyoclonic responses in various diseases,26 self-induced photogenic epilepsyi5 and myoclonus epilepsy.l0 However, little investigation has been made on the longterm oral administration of benzodiazepine derivatives, including clonazepam, in photosensitive epi1epsy.O Since photosensitive epilepsy is generally said to become resistant to any treatment,"? it is noteworthy that four of the present cases responded well to clonazepam over a considerable long term (four months to two years).
SUMMARY
The anti-epileptic activity of clonazepam was evaluated, based on the relationship between clinical effects of the long-term oral administration and electroencephalographic effects of the intravenous administration. 1 . There were 13 patients who could undergo both oral and intravenous administration. Both results correlated roughly. 2. In a clinically ineffective case with tonic clonic convulsion, EEG findings were aggravated after the intravenous injection of clonazepam. The possibility of inducing the clinical seizures by clonazepam was discussed. 3. Since clonazepam was clinically effective in the Jacksonian type by oral administration and suppressed secondary generalized discharge on the EEG by intravenous administration, it was considered that this drug will be clinically effective for secondary generalization. 4. Clonazepam was most clinically effective on complex partial seizures by oral administration and suppressed remarkably temporal spikes by intravenous injection. It can be suggested that clonazepam has specific effects on complex partial seizures. 5. Clonazepam suppressed remarkably the photosensitivity on the EEG by intravenous injection and was effective over a long time on the photosensitive epilepsy by oral administration. Clonazepam was considered to be a beneficial drug for the photosensitive epilepsy. ACKNOWLEDGMENT
We wish to express our thanks to all members of our clinics for their kind cooperation. Thanks are also due to Mr. Kohichi Kumagaya of Nippon Roche for his cooperation.
Anti-Epileptic Activity of Clonazepam REFERENCES 1 Aarli, J. A.: Effect of clonazepam (Ro
4023) on epileptic seizures, Acta Neurol Scandinav, 49: 11-17, 1973. 2 Balassa, M. und Deisenbammer, E.: Erste Untersuchungergebnisse mit einem neuen Antikonvulsion der Benzodiazepine-Reiche (clonazepam), Wien M'ed Wshr, 122: 2731, 1972. 3 Banziger, R. and Hane, D.: Evaluation of a new convulsant screening, Arch int Pharmacodyn, 167: 245-249, 1967. 4 Birket-Smith, E., Lund, M., Mikkelsen, B., Vestermark, S., Zander, P. 0. and Holm, P.: A controlled trial on Ro 5-4023 (clonazepam) in the treatment of psychomotor epilepsy, Acta Neurol Scandinav, 49: 1825, 1973. 5 Blum, J.E.W., Haefely, W., Jalfre, M., Polc, P. und Scharer, K.: Pharmakologie und Toxikologie des Antiepileptikums Clonazepam, Aezneimittel Forschung, 23: 377-389, 1973. 6 Browne, T. R. and Penry, J. K.: Benzodiazepine in the treatment epilepsy, Epilepsia, 14: 277-310, 1973. 7 Browne, T. R.: Clonazepam-A review of a new anticonvulsant drug, Arch Neurol, 33: 326-332, 1976. 8 Duijn, H. V.: Superiority of clonazepam over diazepam in experimental epilepsy, Epilepsia, 14: 195-202, 1973. 9 Eidelberg, E., Neer, H. M. and Miller, M. K.: Anticonvulsant properties of some benzodiazepine derivatives, possible use against psychomotor seizures, Neurology, 15: 223-230, 1965. 10 Groh, Ch. und Rosenmayr, F. W.: Orale Dauertherapie mit Clonazepam (Ro 54023) bei Epilepsien des Kindes-und Jungendalers, Acta Neurol Scandinav, 49: 3643, 1973. 11 Groh, Ch. and Rosenmayr, F. W.: Immediate EEG changes produced by i.v. clonazepam medication-A new criterion for specific antiepileptic therapy?, Wien klin Wochenschr, 86: 480-484, 1974. 12 Guerrero-Figueroa, R., Rye, M. M. and Heath, R. G.: Effects of two benzodiazepine derivates on cortical and subcortical epileptogenic tissues in the cat and monkey, I, Limbic system structures, Current Therap Res, 11: 27-39, 1968. 13 Hakkinen, V.: Effect of clonazepam (Ro 5-4023) on interictal EEG abnormalities, Acta Neurol Scandinav, 49: 44-46, 1973.
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14 Higano, H., Miyasaka, M. Otaka, T. and Yamamoto, K.: Clinical evaluation of clonazepam on epileptic seizures, especially on psychomotor seizures, Clin Psychiat, 17: 145-153, 1975 (in Japanese). 15 Huang, C. Y., McLeod, J. G., Sampson, D. and Hensley, W.J.: Clonazepam in the treatment of epilepsy, Med J. Aust, 2: 58, 1974. 16 Kato, H., Mori, T. et al.: A case of startle epilepsy with laughing seizures, Clin Psychiat, 17: 699-707, 1975 (in Japanese). 17 Kato, H., Mori, T. et al.: Antiepileptic activity of clonazepam, a benzodiazepine antiepileptic, I, Effects of oral administration, Brain and Nerve, 28: 565-577, 1976 (in Japanese), 18 Killan, E. K., Matsuzaki, M. and Killan, K. F.: Effects of chronic administration of benzodiazepine of epileptic seizures and hrain electrical activity in PAP10 PAPIO. In: Benzodiazepines, ed, Garattini, S., Mussini, E. and Randall, L. O., Raven Press, New York, 1973, pp. 443-460. 19 Laitinen, L. and Toivakka, E.: Clonazepam ( R o 5-4023) in the treatment of myoclonus epilepsy, Acta Neurol Scandinav, 49: 72-76, 1973. 20 Lehtovaara, R.: A clinical trial with clonazepam (Ro 5-40231, Acta Neurol Scandinav, 49: 77-81, 1973. 21 Mikkelsen, B. and Birket-Smith, E.: A clinical study of the benzodiazepine Ro 5-4023 (clonazepam) in the treatment of epilepsy, Acta Neurol Scandinav, 49: 9196, 1973. 22 Mori, T., Kato, H. et al.: Antiepileptic activity of clonazepam, a benzodiazepine antiepileptic, 11, Electroencephalographic effects of intravenous administration, Brain and Nerve, 29: 171-180, 1977 (in Japanese 1. 23 Munthe-Kaas, A. W. and Strandjord, R. E.: Clonazepam in the treatment of epileptic seizures, Acta Neurol Scandinav, 49: 97-102, 1973. 24 Prior, P. F., Maclaine, G. N. Scott, D. F. and Laurance, B. M.: Tonic status epilepticus precipitated by intravenous diazepam in a child with petit ma1 status, Epilepsia, 13: 467-472, 1972. 25 Pruvot, P. et Pruvot, L.: Etude de 1 action du Ro 5-4023 sur les photomyoclonies, Therapeutique, 49: 47-48, 1973. 26 Rosenmayr, F. W. und Groh, C. H.: Wirkung von Clonazepam auf das EEG von Kindern und Jungendlichen, Acta Neurol
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Scandinav, 49: 117-123, 1973. 27 Rossi, G. F., Di ROCCO, C., Maira, G. and Meglio, M. : Experimental and clinical studies of the anticonvulsant properties of a benzodiazepine derivative, clonazepam (Ro 5-4023), In: Benzodiazepine, ed, Garattin, S., Mussini, E. and Randall, L. O., Raven Press, New York, 1973, pp. 46 1-488. 28 Schlack, H. G.: Erfahrungen mit Clonazepam (Ro 5-4023) in der Therapie kindlicher Epilepsien, Fortschr Med, 92: 11761179, 1974. 29 Scollo-Lavizzari, G. W. and De La Cruz, N.: Clinical experience with clonazepam
(Rivotrill) in the treatment of epilepsy in adults, Europe Neurol, 11: 340-344, 1974. 30 Swinyard, E. A. and Castellion, A. W.: Anticonvulsant properties of some benzo-
diazepine, J Pharmacol Exp Ther, 151: 369-375, 1966. 31 Tassinari, C. A. Dravet, C., Roger, J.,
Cano, J. P. and Gastaut, H.: Tonic status epilepticus precipitated by intravenous benzodiazepine in five patients with Lennox-Gastaut syndrome, Epilepsia, 13: 421435, 1972. 32 Tassinari, C.A. and Roger, J.: Prognosis and therapy of complex partial seizures
with barbiturates, hydantoin, and other drugs, In: Advance Neurology, vol 11, Complex Partial Seizure and Their Treatment, ed, Penry, J. K. and Daly, D. D., Raven Press, New York, 1976, pp. 201219. 33 Terao, A.: Photosensitive epilepsy, A review, Med J Kawasaki Hosp, 3: 195-211, 1971 (in Japanese).
A Clinical and Electroencephalographic Study on An ti-Epilepti c Activity of CIon azepam -Relationship Between Clinical Effects of Oral Administration and Electroencephalographic Effects of Intravenous AdministrationHideaki Kato, M.D. and Toshinori Mori, M.D. Department of Neuropsychiatry, School of Medicine, Gifu University, Gifu
INTRODUCTION Benzodiazepine derivatives are presently in wide use as anti-epileptic agents. Above all, nitrazepam has frequently been used for minor motor seizures, and diazepam for status epilepticus-as a first choice drug. Clonazepam is the first benzodiazepine derivative that was developed originally as an anti-epileptic agent and has been proved, through pharmacological studies in animal models, to have the most intensive anti-epileptic effects among all benzodiazepine derivatives.:< RO Its clinical efficacy also has begun to be recognized. The authors have reported-based on the results of a series of studies by the oral and intravenous administration-that this drug is an excellent anti-epileptic drug.” 29 It is difficult to evaluate objectively the effects of an anti-epileptic agent because it is impossible to treat patients with a new drug alone; moreover, interaction in combination with other drugs, various inducement for seizures in patients, and so on, militate against such evaluation. The EEG findings provide useful materials for objective evaluation, but improvement observed following the administration of a drug is not always considered to have been brought about by the drug. Received for publication Oct. 7, 1976.
Given this circumstance, this study was designed to evaluate objectively the effects of clonazepam and ascertain its characteristics by checking the results of oral administration with the EEG findings following intravenous administration. Since EEG changes produced by intravenous injection of clonazepam directly show the effects of the drug on the EEG, the comparison of the results of oral and intravenous administrations in the same case is considered to be useful in evaluating objectively the effects of clonazepam. ORAL ADMINISTRATION Subjects and Methods
Thirty patients of so-called refractory epilepsy with seizures that had not been controlled completely by conventional antiepileptic drugs were employed as subjects. As there were six patients in whom two different types of seizures were combined, the number of cases, in terms of seizures, was 36. Clonazepam was administered at a daily dose of one to eight mg (3.3 mg on the average) by either adding the drug to the anti-convulsants administered previously or replacing a part of them with clonazepam. The test period was four months to two years and eight months, and the average was 11.9 months.
H. Kato and T. Mori
184
Table 1: Clinical Effects of Oral Administration
Tonlc clonlc convulrion
@@
a0
15
000000 00000
Partial motor rlrun
Jaekwnhn Foorl motor Vrrsivr Complrx partial rlrura
00 0
80 0 8 0
Myoalonic r l r u n Tonlc rlrun Atonlo uirurr Typiorl abwncr
3
Total Notes:
.:
++: excellent, +:
0 . 0 0
13
2 5 1
0 . 0 0 0 0 00
7 2 2
.
1 1
20
0
36
+
good, : unchanged, -: aggravated, P: photosensitive epilepsy, case which fell by one step in the evaluation rating sat flnal evaluation.
-. Fig. 1A: EEG of a 17-year-old male with generalized convulsion. Prior to clonazepam medication, the basic activity was slow a with a small amount of slow wave ( 5 , 6 Hz) and a generalized spike-and-wave complex appeared. The electrode placement applied correspondingly to the ten-twenty electrode system. (This applies to the following cases.) (calibration: 1 sec, S o p )
Anti-Epileptic Activity of Clonazepam Efficacy was evaluated based on the criterion consisting of four ratings; “excellent” (free from seizures), “good” (over 60% decrease in seizure frequency), “unchanged” (below 50% decrease in seizure frequency) and “aggravated.” Results Table 1 shows the results of the evaluation. Clonazepam was effective in 44.4% of all cases: i.e., “excellent” in three cases, “good” in 13, and brought about no change in 55.6%, or 20 cases, there was no “aggravated” case. According to the type of seizures, clonazepam was “excellent” or “good” in four (26.7%) out of 15 cases with tonic clonic convulsion. For partial motor seizures, this drug was “good” in both of the two cases with Jacksonian seizure, while ineffective in all cases with focal motor and versive seizures. For complex partial seizures, clona-
185
zepam was most effective, being “excellent” or “good” in five (71.4%) out of seven cases. There were four patients who had photosensitivity on the EEG, consisting of five types of seizures. In Table 1, these cases are indicated by P. In two out of the five cases, clinical seizures were induced by photic stimulation. Clonazepam was “excellent” in two and “good” in three; the seizure either disappeared or decreased in frequency. In three cases, photosensitivity on the EEG disappeared after clonazepam medication. Among the cases which could be followed up for a long time, there were eight cases which responded well to clonazepam initially but turned less responsive and fell by one grade in the evaluation ratings. The black marks in Table 1 show the cases which fell by one step in ratings at the final evaluation. In the evaluation made at the initial
Fig. 1B: EEG of 90 seconds after intravenous injection of clonazepam in Fig. 1A. Following intravenous injection of clonazepam, a spike-and-wave complex disappeared, but big slow waves appeared continuously and the basic activity showed clear slowing. (reference electrode: each ear, calibration: 1 sec, 50 p v )
H. Kato and T. Mori
186
Table 2:
Electroencephalographic Effects of Intravenous Administration
++
Type of Seizure Discharge Generalized spike and wave polyspikees and wave slow spike and wave
+
f
-
Total
0 0 0
9
0
6
5
3
1
1 0
0 0
0 1
4 0 0 4
0 0 0 1
2 1 2 0
1 1
Localizd
temporal frontal
Hyparrhythmia Photosensitivity Total Not-:
++: mcdhti
1 +I
4
4
7
0
1
0 0 0
2 5
25
good; f: unchanged; -: aggravated,
stage of administration, clonazepam was “excellent” in seven cases, “good” in 13 and the rate of effectiveness amounted to 55.6%.
I n almost all patients who could be treated by clonazepam (per os), this injection test was performed before clonazepam was administered orally.
INTRAVENOUS ADMINISTRATION
Results The basic EEG activity was improved by the intravenous injection of clonazepam in four (19%) out of 21 patients in whom the EEG could be examined during the waking and resting states. In one patient among the 2 I , a slower activity (slowing) was induced clearly (Figs. 1A and B). Table 2 summarizes the restraining effect of clonazepam on the paroxysmal activity. It proved “excellent” in six (54.570) out of 1 1 cases with generalized paroxysmal activity, and “good” in three, the effective rate amounting to 81.8%. For temporal spikes, this drug was “excellent” in four out of six cases. There were five patients with photosensitivity in whom epileptic discharges were induced on the EEG by photic stimulation. In four out of the five patients, such stimulation also induced clinical seizures. By intravenous injection of clonazepam, photosensitivity was suppressed for 10 minutes in four patients and four minutes in one patient. Clonazepam proved to be effective
Subjects and Methods
Twenty-three epileptic patients who showed abnormal paroxysmal activity on the EEG in the interictal period were picked as the subjects. As there were two patients in whom two different types of seizure discharge were combined, the number of cases, in terms of seizure discharge, was 25. Two ml of clonazepam solution (contained clonazepam 1 mg) was injected intravenously at the rate of 1 ml per minute. The EEG was taken for 10 minutes before and after administration. Depending on the changes of the paroxysmal activity, the effect of the drug was evaluated based on the criterion consisting of four ratings; “excellent” (almost complete disappearance of seizure discharge), “good” (over 50% decrease in frequency of seizure discharge), “unchanged” (below SOY; decrease in frequency of seizure discharge), “aggravated” (increase in frequency of seizure discharge).
Anti-Epileptic Activity of Clonazepam in all of the five cases.
187
zepam.
RELATIONSHIP BETWEEN THE RESULTS
1. A 17-year-old male with tonic clonic convulsion (Fig. 1 )
There were 13 patients who could undergo both oral and intravenous administration. Table 3 shows the relationship between the results of administration via both routes. In all cases-in which clonazepam proved "excellent" via the intravenous administration-it also proved "excellent" or "good" via the oral administration. The results of oral administration correlated roughly with those of intravenous administration. In the representative cases described below, anti-epileptic activity of clonazepam is clarified in relation to the EEG changes produced by intravenous injection of clona-
This is a clinically ineffective case in which clonazepam might exert unfavorable influence on clinical seizures, and EEG findings were aggravated by the intravenous injection of clonazepam. Prior to the administration of clonazepam, the basic activity was irregular slow a (8-9 Hz) with a small amount of slow wave (5--6 Hz) and a bilateral synchronous spikeand-wave complex (about 3 Hz) appeared for some 15 seconds. Twenty seconds after the intravenous injection of clonazepam, slow waves (3--4 Hz) appeared, which clearly showed a tendency toward EEG slowing. Slow bursts appeared after 50 seconds, and
v
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(A)
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Fig. 2: EEG of a 16-year-old female with generalized convulsion. Prior to clonazepam medication, bilateral synchronous spike-and-wave complexes appeared frequently (A). Following intravenous injection of clonazepam, paroxysmal activity disappeared completely. The basic activity was also improved, owing to decrease of slow waves and appearance of low-voltage fast waves (B). (reference electrodes: each ear, calibration: 1 sec, 50 pv)
188
H. Kato and T. Mori
big slow waves continued after 90 seconds. This evident slowing of EEG predominated for some seven minutes, returning gradually to the original EEG pattern. High-voltage slow wave was partially accompanied by small spikes, and seemed to make spikeand-wave formation although not clearly.
2. A 16-year-old female with tonic clonic convulsion (Fig. 2 ) This is a case in which oral therapy with clonazepam was clinically effective. Prior to its administration, a bilateral synchronous spike-and-wave complex (3-3.5 Hz) appeared frequently. Following the intravenous injection of clonazepam, the paroxysmal activity disappeared completely. The basic activity was also improved, owing to a decrease in slow waves and appearance of low-voltage fast waves. This fact indi-
cated that clonazepam would be effective on the epileptic discharge in this case, and provided an objective proof of its clinical effectiveness by oral administration.
3. A 12-year-old girl with focal motor seizure and secondary generalized convulsion (Fig. 3 ) Prior to its administration, focal paroxysmal activity in the left frontal region and secondary bilateral synchronous spike-andwave complexes appeared. Following the intravenous injection of clonazepam, only bilateral sy~ichronousspike-and-wave complexes were suppressed, while the focal paroxysmal discharge in the left frontal region was more evident. This was a case which remained clinically unchanged after oral therapy with clonazepam. However, from the EEG changes
Anti-Epileptic Activity of Clonazepam produced by intravenous injection of clonazepam, it was considered that this drug might be effective in secondary generalized seizures in some cases, but ineffective for focal seizures.
4. A 68-year-old female with complex partial seizure (Fig. 4) This is a case in which clonazepam resulted in significant clinical effects by oral administration. Prior to its administration, spikes or sharp waves had frequently appeared in the right temporal region. Three months after the oral administration at a daily dose of 2 mg, the incidence of spikes was decreased and the amplitude was also lowered. By intravenous injection of clonazepam, the temporal spikes that had appeared before clonazepam therapy were suppressed completely. This fact was considered as providing an objective verification for the remarkable clinical effectiveness of this drug when administered orally. DISCUSSION
According to the reports published so far, considerably favorable results have been obtained with clonazepam in generalized convuIsion.10 21 23 ZR In the present study, 26.7% of the effective rate was attained with this drug in tonic clonic convulsion. However, three out of four cases responding well were specific cases with photosensitivity on the EEG. In the experimental studies, it has been shown that clonazepam is not an effective drug for a grand ma1 seizure.O Therefore, the effectiveness of this drug on this type of epilepsy cannot be emphasized from the results of our study. It is generally said that benzodiazepine derivatives might aggravate generalized convulsion,O and the same caution has also been made for ~lonazepam.~25 In this connection, it is necessary to take note of the fact that slow waves in the background
189
EEG became dominant with high-voltage slow bursts after intravenous administration of clonazepam in a case with tonic clonic convulsion in our study (Fig. 1 ) . This might suggest that only the spike component in the spike-and-wave complex, which had appeared before the clonazepam therapy, was suppressped. However, in view of the frequency of the slow waves, the matter cannot be considered to be explained sufficiently by this interpretation. The possibility that the patient might have fallen asleep during the examination cannot be denied. There is also the possibility that the EEG slowing was induced by some other mechanisms following the intravenous injection of clonazepam. As to tonic seizures of Lennox-Gastaut syndrome, the intravenous injection of diazepam and nitrazepam has been reported to have precipitated tonic status epileptiC U S . ~31~ Browne7 has mentioned that the possible explanation of the worsening by clonazepam might be: 1) the natural variability of seizure frequency, 2 ) actual aggravation of grand ma1 seizure disorder by clonazepam or a clonazepam metabolite; or 3) enzyme induction by clonazepam, reducing the plasma concentration of other anti-convulsants. But, these possibilities still remain to be examined. In the already published reports on the intravenous administration of clonazePam," l3 28 *' there are only a limited number of cases in which the EEG finding was aggravated by the intravenous injection of clonazepam (a case in our study and one reported by Rosenmyer et al.).zo Aggravation in the EEG findings after intravenous injection may not be linked to precipitation of seizures by oral administration. However, the case in the present study is a clinically ineffective one in which clonazepam is considered to cxert an unfavorable influence on seizurcs. Considering the paradoxical influence of clonazepam on the generalized convulsion, the authors consider that the case in the present study in which the EEG
H. Kato and T. Mori
190
F3-P3 P3-T3 T3-F3 FB-cz F4-P4 1'4-T4 'r4-F4 F4--CZ CZ-P3 CZ-P4 F3-F7 F7-T3 F4-F8
F8-T4 P3-01 P4-02
Fig. 4: EEG of a 68-year-old female with complex partial seizure. Prior to clonazepam medication, spikes appeared frequently in the right temporal region (A). Following intravenous injection of clonazepam, temporal spikes were suppressed completely (B) After oral clonazepam therapy, the incidence of spikes was decreased and their amplitude was also lowered ( C ) . (calibration: 1 sec, 50 pv)
.
Anti-Epileptic Activity of Clonazepam findings were aggravated by the intravenous injection of clonazepam provides a precious example. Initially, clonazepam drew attention because of its possible effectiveness for focalmotor seizures.? '" However, the evaluation of this drug on this type of epilepsy has not been definite at present in the light of the negative reports so far published. Recently, Sccolo-Lavizzari et aZ.20have stressed, based on the favorable results in 16 out of 24 cases of focal epilepsy (single administration in eight cases), that focalmotor seizures among all seizures respond best to clonazepam. In the present study, the rate of effectiveness of this drug on focal-motor seizures was low. However, it is noticeable that clonazepam was effective in the Jacksonian seizure in our study, and it is also interesting to note that clonazepam restrained the development of focal-motor seizures into the secondary generalized convulsion (Jacksonian march), although focal-motor seizures appeared occasionally. In studies of focal-motor seizures in animal models,' benzodiazepine has becn shown to be ineffective in abolishing abnormal discharges at the site of the cortical lesion, but capable of preventing motor manifestation of focal seizures and also in suppressing the spread of abnormal electrical activity from the site of the lesion. Similarly, in humans, clonazepam given intravenously does not abolish the EEG focus, but suppresses the spread of the electrical discharge from the focus.6 22 27 Since clonazepam administered intravenously does not suppress the focal seizure discharge but does suppress the secondary generalized one, Rossi et al.'? have considered that orally administered clonazepam would also be clinically effective for secondary generalized convulsion. In the present study, the authors confirmed this finding by oral and intravenous administration in the same case (Fig. 3). Classifying generalized convulsion into the primary and
191
Table 3: Relationship between Clinical Effects of Oral Administration and Electroencephalographic Effects of Intravenous Administration Clinical Effects (oral)
++ +
EEG Effects (intravenous)
++ +
f
-
Total 2
2
0
0
0
f
1 0
3 1
3 2
0 1
-
0
0
0
0
4 0
Total
3
4
5
1
13
I
secondary ones, AarW has reported that clonazepam is more effective in secondary generalized convulsion. In addition, the present findings are considered to be identical to those in some previous reports,272o indicating that the clinical seizure can be suppressed by clonazepam even when the focal seizure discharge is not suppressed on the EEG, and in another report2 stating that clonazepam is more effective in generalized convulsion with focal EEG abnormality. So far, little attention has been paid to the beneficial effect of clonazepam vis-d-vis complex partial seizures. Birket-Smith et aL4 and Lehtovaara et d Z o pointed to the beneficial effects of clonazepam on complex partial seizures (over 60% effective fate in 20 and 25 cases, respectively). Recently, the efficacy of clonazepam in this field has been claimed by Higano et aZ.14 in Japan. Observing the beneficial effects in 12 out of 14 cases with refractory seizures, they have considered clonazepam as an antiepileptic drug to be used for this kind of refractory epilepsy. In the laboratory screening test, clonazepam appeared to be less potent against complex partial seizures than phenobarbital, diphenylhydantoin or carbamazepine,6 but its effectiveness for complex partial seizures seems due to the mechanism by which it
192
H.Kato and T. Mori
has an inhibitory influence on the hippocampus, amygdala and septum (the limbic system)6 l2 which have a close anatomical and functional relation to the temporal lobe. In the present study, clonazepam was most effective in complex partial seizures, and the effective rate reached 71.4%. Our cases were refractory to other anticonvulsant and all of the cases responding well to clonazepam were those which did not respond sufficiently to diphenylhydantoin or carbamazepine, thus far the first choice drugs for complex partial seizures.s2In addition, clonazepam administered intravenously suppressed remarkably temporal spikes in four out of six cases. In two cases among the four, clonazepam proved remarkably effective not only by intravenous, but also by long-term oral administration (Fig. 4).1° 22 As mentioned above, the peculiar effect of clonazepam on complex partial seizures is worth noting. What is most striking in this study is that favorable effects were observed on the clinical seizures and on the EEG in the photosensitive epilepsy. It has been proved by experimental studies that clonazepam can, like other benzodiazepine derivatives, rapidly abolish the paroxysmal activity induced by photic stimulation.is It had been foreseen from the pharmacological action of clonazepam that it would be effective for photosensitive epilepsy. There are reports showing the clinical efficacy of this drug on photomyoclonic responses in various diseases,26 self-induced photogenic epilepsyi5 and myoclonus epilepsy.l0 However, little investigation has been made on the longterm oral administration of benzodiazepine derivatives, including clonazepam, in photosensitive epi1epsy.O Since photosensitive epilepsy is generally said to become resistant to any treatment,"? it is noteworthy that four of the present cases responded well to clonazepam over a considerable long term (four months to two years).
SUMMARY
The anti-epileptic activity of clonazepam was evaluated, based on the relationship between clinical effects of the long-term oral administration and electroencephalographic effects of the intravenous administration. 1 . There were 13 patients who could undergo both oral and intravenous administration. Both results correlated roughly. 2. In a clinically ineffective case with tonic clonic convulsion, EEG findings were aggravated after the intravenous injection of clonazepam. The possibility of inducing the clinical seizures by clonazepam was discussed. 3. Since clonazepam was clinically effective in the Jacksonian type by oral administration and suppressed secondary generalized discharge on the EEG by intravenous administration, it was considered that this drug will be clinically effective for secondary generalization. 4. Clonazepam was most clinically effective on complex partial seizures by oral administration and suppressed remarkably temporal spikes by intravenous injection. It can be suggested that clonazepam has specific effects on complex partial seizures. 5. Clonazepam suppressed remarkably the photosensitivity on the EEG by intravenous injection and was effective over a long time on the photosensitive epilepsy by oral administration. Clonazepam was considered to be a beneficial drug for the photosensitive epilepsy. ACKNOWLEDGMENT
We wish to express our thanks to all members of our clinics for their kind cooperation. Thanks are also due to Mr. Kohichi Kumagaya of Nippon Roche for his cooperation.
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Scandinav, 49: 117-123, 1973. 27 Rossi, G. F., Di ROCCO, C., Maira, G. and Meglio, M. : Experimental and clinical studies of the anticonvulsant properties of a benzodiazepine derivative, clonazepam (Ro 5-4023), In: Benzodiazepine, ed, Garattin, S., Mussini, E. and Randall, L. O., Raven Press, New York, 1973, pp. 46 1-488. 28 Schlack, H. G.: Erfahrungen mit Clonazepam (Ro 5-4023) in der Therapie kindlicher Epilepsien, Fortschr Med, 92: 11761179, 1974. 29 Scollo-Lavizzari, G. W. and De La Cruz, N.: Clinical experience with clonazepam
(Rivotrill) in the treatment of epilepsy in adults, Europe Neurol, 11: 340-344, 1974. 30 Swinyard, E. A. and Castellion, A. W.: Anticonvulsant properties of some benzo-
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