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Treatment of seizure disorders and myoclonus
FRITZ E. DREIFUSS, M.D.
Treatment of seizure disorders and myoclonus In this article we will review some of the features of the classification of the epilepsies so that we can talk about specific epileptic syndromes and briefly discuss clonazepam's use in epilepsy and where it now fits into the scheme of things. We will also discuss one of our studies of clonazepam, I which served as a paradigm of drug studies that have followed, in that it used a double-blind modified crossover design and objectively identified the endpoints of the study by means of a seizure count using intensive monitoring techniques. This approach enabled us to identify for the first time exactly how many seizures there were before treatment and how many seizures there were after treatment. Unlike the other benzodiazepines, clonazepam was introduced specifically as an anticonvulsant agent. 2 It was found to be extremely effective in reversing EEG abnormalities. It was also found to be quite effective clinically in open studies. 3•4 In the early literature on clonazepam, tltere are many uncontrolled studies and a relative paucity of well-controlled studies. 2 We do not really know how benzodiazepines or any other anticonvulsants act to produce seizure control. We guess at such things as increasing GABA-ergic function either by the benzodiazepine receptor sensitizing the brain to GABA or the GABA receptor to GABA, by facilitating presynaptic and postsynaptic GABA-mediated transmission. But these are explanations that remain largely speculative. It is known that benzodiazepines, particularly clonazepam, tend to elevate serotonin levels. 3 It has also been speculated that clonazepam may act by mimicking glycine's effects on glycine receptor sites in the brain. In terms of clonazepam's serotonin-elevating effects, it is interesting to speculate as to why
this drug is so effective in postanoxic myoclonus, which is the one condition that is particularly responsive to serotonin administration. Epilepsy seizure classification The international classification divides epileptic seizures into partial seizures, generalized seizures, and unclassified seizures (Table I). Partial seizures are those that begin locally. Under the new classification, which is under review,6 these partial seizures will be called localization-related seizures. There really is no such thing as a partial seizure, and the whole question of the distinction between partial and focal is going to be resolved by using the term localization-related seizures. Generalized seizures are bilaterally symmetrical and without local onset. Under the partial seizures, which are seizures that begin locally, there are simple partial seizures without impairment of consciousness. These may occur with motor symptoms, with special sensory or somatosensory symptoms, with autonomic symptoms, or with psychic symptoms. Thus, psychic symptoms may occur as partial seizures of the simple type and do not necessarily denote complex partial seizures ifconsciousness is not impaired. Complex partial seizures are those in which there is impairment of consciousness. They may begin as simple partial seizures and progress to complex partial seizures, or they may be complex partial seizures from the beginning with impairment of consciousness at the onset. These seizures mayor may not be accompanied by automatisms. And then these seizures are sometimes secondarily generalized, as may happen with all partial seizures.
PsYCHOSOMATICS
These are clearly important distinctions because of the relative specificity of certain of the anticonvulsant drugs. For example, clonazepam, like valproate, appears to be more effective in generalized seizures than in partial seizures,7 although generalized tonic-clonic seizures may not respond as well as other generalized seizures. 8 The generalized seizures include absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures. The epileptic syndromes, as distinct from seizure types, include neonatal seizures or infantile spasms, febrile seizure syndromes, absence or petit mal syndrome, and the benign juvenile epileptic syndromes, both those with focal seizures and the benign myoclonic syndromes (Table 2). These are some of the conditions in which drugs are used.
Most of the anti-epileptic drugs have been used to combat certain seizure syndromes, not individual seizure types. Schmidt9 analyzed a number of studies using clonazepam in different types of seizure syndromes, and found that grand mal seizures were studied in 16 instances, a total of 243 cases, of which 82, or34%, became seizure-free. Inabsence seizures, 86 of 156 patients, or 55%, were seizurefree on clonazepam. In myoclonic-atonic seizures, or Lennox syndrome, or Lennox-Gastaut syndrome, 118 of 327 patients, or 36%, were free of seizures. Twenty-seven of 125 patients (22%) with myoclonic seizures, or infantile spasms, were seizure-free on clonazepam, as were 13 of 67 ( 19%) with simple partial seizures and 45 of 164 (27%) with complex partial seizures (Table 3). I would submit, however, that these data are of minimal value because each of these syndromes comes in at least two varieties. For example, there are two varieties of Table 1-1nternational Classification the syndrome myoclonic-atonic seiof Epileptic Seizures zure, or Lennox syndrome, the one described by Dozier and then the true Lennox-Gastaut syndrome. Both are I. Partial seizures (seizures beginning locally) myoclonic-atonic seizures or astatic A. Simple partial seizures myoclonic seizures. The one is a pri(consciousness not impaired) mary generalized epilepsy that is fair1. With motor symptoms 2. With somatosensory or special sensory ly benign. It responds very well to sevsymptoms eral anticonvulsant drugs, including 3. With autonomic symptoms c10nazepam and valproate, with vir4. With psychic symptoms tual abolition of seizures in most B. Complex partial seizures cases. The true Lennox-Gastaut syn(with impairment of consciousness) drome, which is a secondary general1. Beginning as simple partial seizures; ized epilepsy from a focal lesion, is a progressing to impairment of consciousness rather malignant disease. It causes se2. With impairment of consciousness at onset vere mental retardation, and drop at(a) with impairment of consciousness only tacks that are intractable to all medica(b) with automatisms tions, including c10nazepam and valC. Partial seizures secondarily generalized proate. It is therefore misleading to II. Generalized seizures (bilaterally talk about myoclonic atonic seizures symmetrical and without local onset) without distinguishing that there are A. 1. Absence seizures two varieties. 2. Atypical absence Similarly, most work on infantile B. Myoclonic seizures spasm does not distinguish so-called C. Clonic seizures D. Tonic seizures primary infantile spasm from infantile E. Tonic-clonic seizures spasms that are symptomatic and F. Atonic seizures caused by a variety of disease entities such as perinatal anoxia, or perinatal III. Unclassified epileptic seizures periventricular hemorrhage. True pri(because of incomplete data) mary infantile spasms have quite a Abstracted from Epilepsia 22:489·501, 1981, published by Raven Press good prognosis for recovery with ACTH, and respond well to treat9
DECEMBER 1985· VOL 26· NO 12 (SUPPLEMENT)
31
Seizure disorders
Table 2-1nternational Classification of Epilepsies and Epileptic Syndromes 1.
Localization-related (focal, local, partial) epilepsies and syndromes
2.3.1 Non-specific etiology • Early myoclonic encephalopathy
1.1
Idiopathic (with age-related onset) At present, two syndromes are established but more may be identified in the future. • Benign childhood epilepsy with centrotemporal spike • Childhood epilepsy with occipital paroxysms
2.3.2 Specific syndromes Epileptic seizures may complicate many disease states. Under this heading are included those diseases in which seizures are a presenting or predominate feature.
1.2
Symptomatic This comprises syndromes of great individual variability, which will mainly be based on anatomic localization, clinical features, seizure types. and etiologic factors (if known),
2.
Generalized epilepsies and syndromes
2.1
Idiopathic (with age-related onset-listed in order of age) • Benign neonatal familial convulsions • Benign neonatal convulsions • Benign myoclonic epilepsy in infancy • Childhood absence epilepsy (pyknolepsy) • Juvenile absence epilepsy • Juvenile myoclonic epilepsy (impulsive petit mal) • Epilepsy with grand mal seizures (GTCS) on awakening Other generalized idiopathic epilepsies, if they do not belong to one of the above syndromes, can still be classified as generalized idiopathic epilepsies.
2.2
2.3
Idiopathic and/or symptomatic (in order of age) • West syndrome (infantile spasms, Blitz-Nick-Salaam Krampfel) • Lennox-Gastaut syndrome • Epilepsy with myoclonic-astatic seizures • Epilepsy with myoclonic absences
3.
Epilepsies and syndromes undetermined whether focal or generaliZed
3.1
With both generalized and focal seizures • Neonatal seizures • Severe myoclonic epilepsy in infancy • Epilepsy with continuous spike waves during slow-wave sleep • Acquired epileptic aphasia (Landau-Kleffner syndrome)
3.2
Without unequivocal generalized or focal features All cases with generalized tonic-clonic seizures where clinical and EEG findings do not permit classification as clearly generalized or localization-related, such as in many cases of sleep-grand mal.
4.
Special syndromes
4.1
Situation-related seizures (Gelegenheitsanfalle) • Febrile convulsions • Seizures related to other identifiable situations such as stress, hormones, drugs, alcohol, sleep deprivation, etc.
4.2
Isolated. apparently unprovoked epileptic events
4.3
Epilepsies characterized by specific modes of seizure precipitation
4.4
Chronic progressive epilepsia partialis continua of childhood
Symptomatic
From Epilepsia 26:268-278, 1985. published by Raven Press.
-32
PSYCHOSOMATICS
.....
. . . . . . 01
N
%
16
82/243
34
15
86/156
55
12
118/327
36
8
271125
22
10
13161
19
13
45/164
27
ment, whereas the secondary fonns are vinually intractable to all medications. The same is true, of course, when we look at febrile seizures and the same is true when we look at absence seizures. Among the absence seizures, the reason why some of the statistics are quite different from others is that one has to distinguish between the pyknoleptic petit mal, which is primary generalized absence, and absence that is phenotypically similar but that is probably due to a secondary fonn of epilepsy with a completely different ultimate outlook. Therefore, it is very difficult to say what Schmidt's numbers really mean. If one were to subdivide these groups, I suspect that one would find that all the patients with primary generalized epilepsy respond rather well to several anticonvulsant drugs, including c1onazepam, and that those who clearly have secondary epilepsy respond poorly. The fact remains that clonazepam is relatively effective in generalized epilepsy and is relatively ineffective in simple partial seizures and complex partial seizures. Even in the latter group, some patients may respond, and I suspect that if we studied a large enough series of simple partial seizures of the benign primary epileptic type, such as the benign juvenile focal seizures (Rolandic epilepsy), there may be a good response to this drug. Bilateral massive epileptic myoclonus responds reasonably well to clonazepam, responds extremely well to valproate, and responds somewhat to some of the other anti-
DECEMBER 1985' Y0L26'NO 12 (SUPPLEMENT)
convulsant drugs. This is a fairly unifonn syndrome, and about one third of patients are rendered seizure-free with clonazepam. In the akinetic atonic seizures-and I suspect that these are probably of the relatively benign variety-about half the patients receiving clonazepam are rendered seizure-free. These figures come from the study of Pinder and associates,2 which was probably the most exhaustive review of clonazepam when it was published, in 1976. Patients with grand mal seizures do not do as well with clonazepam. Those with psychomotor seizures (or what we now call complex partial seizures) and partial seizures (or focal motor seizures) also do not do as well.
1reatment of myoclonic seizures Clonazepam remains one of the drugs of choice in seizures with myoclonus. 7,10 Several syndromes fall under the rubric of myoclonus or myoclonic epilepsy (Table 4). Some are part of absence seizures. For example, there is absence with clonic components or myoclonic components, and there is a fonn of absence in small children in which myoclonus is the main feature and absence occurs, as it were, by the way. These two respond quite differently to medications. Adolescent myoclonus, or benign juvenile myoclonus, is a distinct entity. It is a relatively benign condition, but is extremely drugdependent in its benignity. When drugs are withdrawn, there tends to be a breakthrough of seizures. Unfortunately, clonazepam is less useful than valproate for this particular syndrome because of a tendency to develop tolerance to clonazepam. 7 Many patients with generalized tonic-clonic seizures also have interspersed myclonic seizures. Myoclonus also occurs as part of progressive neurologic disease that is not primarily epileptic. For example, there is progressive myoclonic epilepsy with Lafora bodies and without Lafora bodies, the one being the standard type of progressive myoclonic epilepsy that we all know about and the other being that particularly described in Scandinavia" but which is very much more widespread than used to be believed. Now that it has become so easy to look for Lafora bodies by doing skin biopsies and looking for the Lafora bodies in the sweat duct epithelium, we can distinguish quite easily between these two fonns of progressive myoclonic epilepsy.
33
Seizure disorders
It is in these diseases that clonazepam finds its major use at this time. It Table 4-Forms of Myoclonic Epilepsy is an extremely effective drug in myoclonic epilepsy, particularly the relatiI. As part of other forms of corticoreticular epilepsy vely nonprogressive myoclonic epiA. Absence with clonic components lepsies, those without Lafora bodies. II B. Adolescent myoclonus Dyssynergia cerebellaris progressiva, C. As a component of generalized tonic-clonic seizures or the Ramsay Hunt syndrome, an inII. As part of progressive neurologic disease, not primarily epileptic teresting nonepileptic fonn of myoA. Progressive myoclonic epilepsy clonus, is a progressive familial dis1. With Lafora bodies ease that responds quite well to clona2. Without Lafora bodies zepam in a large percentage of cases. 12 B. Dyssynergic cerebellaris myoclonica Myoclonus may also appear as part III. As part of generalized disease of the cerebral gray matter of generalized disease of the cerebral A. Lipid storage diseases gray matter, including the lipid storB. Infections, eg, SSPE, age diseases, various infectious disJakob-Creutzfeldt eases such as subacute sclerosing panC. Progressive poliodystrophy (Alpers) encephalitis and Creutzfeldt-Jakob IV. Massive infantile spasms disease and the progressive polio-dystrophy described by Alpers in small children. And then, finally, we have respond quite well to clonazepam. In fact, clonazepam has massive infantile spasm, which, as previously described, been the drug of choice in the treatment of paroxysmal chormay occur without demonstrable organic etiology or may be eoathetosis, particularly of the kinesiogenic type." secondary; the two conditions have a different outlook. Other reflex seizure types such as photically sensitive epilepsy also respond well to clonazepam.'6 Essential tremTreatment of absence seizures or, which is not an epileptic condition, is also quite effecIn absence seizures, clonazepam has been found to be an extively treated with clonazepam. tremely effective drug. It is probably as effective or more effective than is ethosuxamide. It is as effective as valproate in controlling absence seizures over the short haul. I think in Pharmacokinetics In one of our early studies," we looked at the pharmacomost of the series the good results in this particular synkinetics of this drug in five patients, and we found that there drome have been somewhat vitiated by the development of was a very close relationship between clonazepam dose and tolerance and by the relatively high incidence of adverse the serum concentration of clonazepam, with a standard side effects. 7 correlation coefficient. This held up at all levels of dosage (Figure). The half-life of the drug ranged between 22 and 31 Less responsive seizures hours. There is a much faster turnover in children than in In generalized clonic-tonic seizures, the response is less faadults." vorable and the side effects are just as bad. Indeed, some cases of generalized clonic-tonic seizures are exacerbated Side effects by the administration of clonazepam.•. 13 Simple partial seiFinally, I want to mention the side effects that we saw in our zures also respond less favorably except for epilepsia parlarger studies of 49 patients.' Drowsiness, ataxia, and nytialis continua. In epilepsia partialis continua, clonazepam stagmus were seen quite often. Hyperactivity in children sometimes is quite effective. '0 was precipitated by this drug. There was a certain amount of Other paroxysmal conditions personality change, particularly in older children and teenagers, in which there was a relative lack of inhibition of imClonazepam has been used in some other paroxysmal conpulsive behavior, leading to antisocial activity during the ditions, including paroxysmal choreoathetosis. Paroxysmal period of time that the drug was administered (which did not choreoathetosis is again a potpourri of conditions. Some of occur prior to or after withdrawal from the medication). An the paroxysmal choreoathetoses are kinesiogenic; they are increased number of seizures was seen in some patients, set off by movement, by proprioceptive stimulation. These 34
PSYCHOSOMATICS
dropout rate from side effects in various studies in the literature ranges from 20% to 35% or 40%.'
80
•
:::J
Conclusion
Clonazepam is thus a very effective .ECl 60 anticonvulsant. On the other hand, in S c our experience and in the literature, o the development of tolerance inter~ 40 feres to some extent with its desirabilC Q) o ity in long-term administration. The c oo incidence of side effects is sufficiently E high to make this other than the drug :J 20 Correlation coefficient .93 of frrst choice in a large number ofsei~ zure types in which the drug is clinically effective. Because of these limitations, it would appear that with the 0.12 development of newer anticonvulsant drugs, particularly valproate-with which there seems to be a significant overlap in terms of protectiveness for FIGURE-Relationship between clonazepam dosage and serum concentration. various seizure types"---clonazepam has really a relatively small place in the treatment of these types of epilepsies. mainly the precipitation of generalized clonic-tonic seizures Whenever the clinician administers an anticonvulsant in patients with absence seizures. Some had a change in seidrug he or she makes a compromise between seizure control zure type, with the development of more severe seizures. and adverse side effects. All anticonvulsant drugs have adAbout 10% of the patients had a significant weight gain, and verse side effects of one form or another, and it is the physithere were very few patients with leukopenia. cian's responsibility to weigh the risk!benefit ratio very Side effects led to the discontinuation of medication in carefully in every case in which anticonvulsant drugs are ad30% of the patients who were started on it, despite an atministered. 0 tempt at titration of dosage to minimize the side effects. The
•
REFERENCES I. Sato S, Penry JK, Oreifuss, FE, et al: Clonazepam in the treatment of absence seizures. Neurology 27:371, 1977. 2. Pinder RM, Brogden, EN, Speight TM, et al: Clonazepam: A review of its pharmacological properties and therapeutic efficacy. Drugs 12:321-361, 1976. 3. Mikkelsen B, Birket-Smith E, Brandt S, et al: Clonazepam in the treatment of epilepsy. A controlled clinical trial in simple absences, bilateral epileptic myoclonus, and tonic seizures. Arch Neuro/33:322-325, 1976. 4. Lund M, Trolle E: Clonazepam in the treatment of epilepsy. Acta Neurol Scand49:82-90, 1973. 5. WeinerWJ, Goetz C, Nansieda PA, et al: Clonazepam and 5-hydroxylryptophan-induced myoclonic stereotypy. Eur J Pharmaco/46:21-24, 1977. 6. Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for classification of epilepsies and epileptic syndromes. Epilepsia 26:268-278, 1985. 7. Oreifuss FE, Sato S: Clonazepam, in Woodbury OM, Penry JK, Pippenger CE: Antiepileptic Drugs. New York, Raven Press, 1982. 8. Kruse R, Blankenhom V: Zusammenfassender Erfahrungsbericht uber die Klinische Anwendung und Wirksamkeit von R05-4023 (Clonazepam) auf verschiedene Formen epileptischer Anfalle. Acta Neurol Scand 49:60-71,1973. 9. SChmidl 0: Behandlung der Epilepsien,ed 2. Stullgart, G. Thieme, 1984.
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10. Mikkelsen B, Birket-Smith E: A clinical study of the benzodiazepine R054023 (clonazepam) in the treatment of epilepsy. Acta Neural Scand 49:91-96,1973. 11. Laitinen L, Toivakka E: Clonazepam (R05-4023) in the treatment of myoclonus epilepsy. Acta Nauro Scand 49: 72-76, 1973. 12. Bergamiui L, Mutani R, Liboui W: Elektroenzephalographische und Klinische Bewertung des neuen Benzodiazepin R05-4023. Electroencephalogr E/ectromyogr I: 182-188, 1970. 13. Bladin PO: The use of clonazepam as an anticonvulsant: Clinical evaluation. MedJ Austl:683-688, 1973. 14. Drug and Therapeutics Bulletin: Drugs for status epilepticus. Drug Ther BuI/14:89-91,1976. 15. Peiris JV, Boralessa H, Lionel NOW: Clonazepam in the treatment of choreiform activity. Med J Aust 1:225-227, 1976. 16. Ames FF, Enderstain 0: Clinical and EEG response to Clonazepam in four patients with self-induced photosensitive epilepsy. S Air J Med 50:14321434,1976. 17. Oreifuss FE, Penry JK, Rose SW, et al: Serum clonazepam concentrations in children with absence seizures. Neurology 23:255-258, 1975. 18. Jeavons RM, Clark, JE, Maheshwari MC: Treatment of generalized epilepsies of childhood and adolescence with sodium valproate ('Epilim'). Dev Med Child Neuro/19:9-25, 1977.
35
Panel discussion Dr. Chouinard: You mentioned a linear correlation between the dosage and serum concentration, but Browne' in his article in the New England Journal ofMedicine said that you cannot accurately predict serum concentration from dosage.
Dr. Penry: Dr. Browne found a correlation for individuals, but there are some differences between individuals. By comparison, you would find more variability in serum concentrations with phenytoin or carbamazepine than with clonazeparn.
thiS-{)nly case reports. I have treated five patients with paroxysmal choreoathetosis very successfully. It is useful particularly in the kinesiogenic type. It has also been used successfully in the photic sensitive epilepsies. From a psychiatric point of view it might be of interest that the self-stimulating absence type of photic sensitive epilepsy in children can be treated quite effectively with this drug; it even removes the desire to look at light and move the hand in front of the eyes while gazing into the light, which seems to drive these children. I also have one adult patient who gets an orgasm when she does this and she therefore is driven to the window, but clonazepam takes away that desire.
Dr. Chouinard: Do you have patients who respond to nitrazeparn and not to clonazepam?
Dr. DreiJuss: Yes, particularly infantile spasm patients. We're in the middle of a study now with nitrazepam in infantile spasm, and it looks to be extremely effective here. It appears to hold up fairly well without the same development of tolerance as we see in cionazepam. And it appears to do quite well in the secondary or severe forms of infantile spasms in which clonazepam has a less than 30% success rate.
Dr. Chouinard: Are there many studies of clonazepam for paroxysmal choreoathetosis? This would be of interest, since some investigators say that clonazepam is rather effective in suppressing dyskinesia, which is a choreoathetotic movement.
Dr. Chouinard: Regarding behavioral changes with adolescents, it would seem that if you have a very disturbed adolescent, clonazepam can help to prevent a lot of agitation. But if he is not psychiatrically disturbed, clonazepam can produce changes similar to those induced by any other benzodiazepine.
Dr. DreiJuss: Our adolescent patients were not overtly psychiatrically disturbed, although we did not screen all of them. But the behavioral problems were never previously overt until they had been taking the drug.
Dr. Chouinard: This is similar to the ability of lithium or antidepressants to produce dysphoria when given to normal subjects.
Dr. DreiJuss: The other point that has to be brought up is the Dr. DreiJuss: There are no good studies in the literature on 36
difficulty that we have experienced in discontinuing clonaz-
PSYCHOSOMATICS
other every two or three weeks and preventing breakthrough seizures from qccurring in this way.
epam, even when the drug is no longer as effective by virtue of tolerance having developed. We have had to discontinue c10nazepam extremely slowly, reducing the dosage by 0.25 mg per week, in order to avoid breakthrough convulsions.
Dr. Green: Did you once suggest that the combination of
Dr. Chouinard: For us, comparison drugs were loraze-
c10nazepam llQd valproate was useful in some intractable patients?
pam, triazolam, and alprazolam, and all of these are many times more difficult than c10nazepam to discontinue. With c1onazepam, discontinuation is not any more difficult than with diazepam or fturazepam in our population. Even rebound anxiety does not come up as much as with alprazolam, for example, or triazolam used for insomnia.
Dr. Dreifuss: One thing to do for inpatients who develop tolerance is to use a different benzodiazepine. For example, if somebody breaks through after developing tolerance to c1onazepam, I may use c10razepate or one of the other benzodiazepines and it appears then that the new benzodiazepine is again effective for a period of time, I have one child whom I am switching back and forth from one drug to the
DECEMBER 1985·VOL26·NO 12 (SUPPLEMENT)
Dr. Dreifuss: There are areas in which these two drugs are useful, including, on occasion, intractable absence or some of the myoclonic absences. While it has of course been reported that absence status may be precipitated by the use of these two drugs together, 2 this is a very much exaggerated fear, It is actually a very rare occurrence. In fact, when the two drugs are used together in intractible seizure forms they are very often quite beneficial. 0
REFERENCES 1. Browne TR: Clonazepam. N EnglJ Med299:812-816, 1978. 2. Jeavons RM, Clark, JE, Maheshwari MC: Treatment 01 generalized epilepsies 01 childhood and adolescence with sodium valproate ('Epilim'). Dev Med Child Neurol 19:9·25, 1977.
37
Treatment of seizure disorders and myoclonus In this article we will review some of the features of the classification of the epilepsies so that we can talk about specific epileptic syndromes and briefly discuss clonazepam's use in epilepsy and where it now fits into the scheme of things. We will also discuss one of our studies of clonazepam, I which served as a paradigm of drug studies that have followed, in that it used a double-blind modified crossover design and objectively identified the endpoints of the study by means of a seizure count using intensive monitoring techniques. This approach enabled us to identify for the first time exactly how many seizures there were before treatment and how many seizures there were after treatment. Unlike the other benzodiazepines, clonazepam was introduced specifically as an anticonvulsant agent. 2 It was found to be extremely effective in reversing EEG abnormalities. It was also found to be quite effective clinically in open studies. 3•4 In the early literature on clonazepam, tltere are many uncontrolled studies and a relative paucity of well-controlled studies. 2 We do not really know how benzodiazepines or any other anticonvulsants act to produce seizure control. We guess at such things as increasing GABA-ergic function either by the benzodiazepine receptor sensitizing the brain to GABA or the GABA receptor to GABA, by facilitating presynaptic and postsynaptic GABA-mediated transmission. But these are explanations that remain largely speculative. It is known that benzodiazepines, particularly clonazepam, tend to elevate serotonin levels. 3 It has also been speculated that clonazepam may act by mimicking glycine's effects on glycine receptor sites in the brain. In terms of clonazepam's serotonin-elevating effects, it is interesting to speculate as to why
this drug is so effective in postanoxic myoclonus, which is the one condition that is particularly responsive to serotonin administration. Epilepsy seizure classification The international classification divides epileptic seizures into partial seizures, generalized seizures, and unclassified seizures (Table I). Partial seizures are those that begin locally. Under the new classification, which is under review,6 these partial seizures will be called localization-related seizures. There really is no such thing as a partial seizure, and the whole question of the distinction between partial and focal is going to be resolved by using the term localization-related seizures. Generalized seizures are bilaterally symmetrical and without local onset. Under the partial seizures, which are seizures that begin locally, there are simple partial seizures without impairment of consciousness. These may occur with motor symptoms, with special sensory or somatosensory symptoms, with autonomic symptoms, or with psychic symptoms. Thus, psychic symptoms may occur as partial seizures of the simple type and do not necessarily denote complex partial seizures ifconsciousness is not impaired. Complex partial seizures are those in which there is impairment of consciousness. They may begin as simple partial seizures and progress to complex partial seizures, or they may be complex partial seizures from the beginning with impairment of consciousness at the onset. These seizures mayor may not be accompanied by automatisms. And then these seizures are sometimes secondarily generalized, as may happen with all partial seizures.
PsYCHOSOMATICS
These are clearly important distinctions because of the relative specificity of certain of the anticonvulsant drugs. For example, clonazepam, like valproate, appears to be more effective in generalized seizures than in partial seizures,7 although generalized tonic-clonic seizures may not respond as well as other generalized seizures. 8 The generalized seizures include absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures. The epileptic syndromes, as distinct from seizure types, include neonatal seizures or infantile spasms, febrile seizure syndromes, absence or petit mal syndrome, and the benign juvenile epileptic syndromes, both those with focal seizures and the benign myoclonic syndromes (Table 2). These are some of the conditions in which drugs are used.
Most of the anti-epileptic drugs have been used to combat certain seizure syndromes, not individual seizure types. Schmidt9 analyzed a number of studies using clonazepam in different types of seizure syndromes, and found that grand mal seizures were studied in 16 instances, a total of 243 cases, of which 82, or34%, became seizure-free. Inabsence seizures, 86 of 156 patients, or 55%, were seizurefree on clonazepam. In myoclonic-atonic seizures, or Lennox syndrome, or Lennox-Gastaut syndrome, 118 of 327 patients, or 36%, were free of seizures. Twenty-seven of 125 patients (22%) with myoclonic seizures, or infantile spasms, were seizure-free on clonazepam, as were 13 of 67 ( 19%) with simple partial seizures and 45 of 164 (27%) with complex partial seizures (Table 3). I would submit, however, that these data are of minimal value because each of these syndromes comes in at least two varieties. For example, there are two varieties of Table 1-1nternational Classification the syndrome myoclonic-atonic seiof Epileptic Seizures zure, or Lennox syndrome, the one described by Dozier and then the true Lennox-Gastaut syndrome. Both are I. Partial seizures (seizures beginning locally) myoclonic-atonic seizures or astatic A. Simple partial seizures myoclonic seizures. The one is a pri(consciousness not impaired) mary generalized epilepsy that is fair1. With motor symptoms 2. With somatosensory or special sensory ly benign. It responds very well to sevsymptoms eral anticonvulsant drugs, including 3. With autonomic symptoms c10nazepam and valproate, with vir4. With psychic symptoms tual abolition of seizures in most B. Complex partial seizures cases. The true Lennox-Gastaut syn(with impairment of consciousness) drome, which is a secondary general1. Beginning as simple partial seizures; ized epilepsy from a focal lesion, is a progressing to impairment of consciousness rather malignant disease. It causes se2. With impairment of consciousness at onset vere mental retardation, and drop at(a) with impairment of consciousness only tacks that are intractable to all medica(b) with automatisms tions, including c10nazepam and valC. Partial seizures secondarily generalized proate. It is therefore misleading to II. Generalized seizures (bilaterally talk about myoclonic atonic seizures symmetrical and without local onset) without distinguishing that there are A. 1. Absence seizures two varieties. 2. Atypical absence Similarly, most work on infantile B. Myoclonic seizures spasm does not distinguish so-called C. Clonic seizures D. Tonic seizures primary infantile spasm from infantile E. Tonic-clonic seizures spasms that are symptomatic and F. Atonic seizures caused by a variety of disease entities such as perinatal anoxia, or perinatal III. Unclassified epileptic seizures periventricular hemorrhage. True pri(because of incomplete data) mary infantile spasms have quite a Abstracted from Epilepsia 22:489·501, 1981, published by Raven Press good prognosis for recovery with ACTH, and respond well to treat9
DECEMBER 1985· VOL 26· NO 12 (SUPPLEMENT)
31
Seizure disorders
Table 2-1nternational Classification of Epilepsies and Epileptic Syndromes 1.
Localization-related (focal, local, partial) epilepsies and syndromes
2.3.1 Non-specific etiology • Early myoclonic encephalopathy
1.1
Idiopathic (with age-related onset) At present, two syndromes are established but more may be identified in the future. • Benign childhood epilepsy with centrotemporal spike • Childhood epilepsy with occipital paroxysms
2.3.2 Specific syndromes Epileptic seizures may complicate many disease states. Under this heading are included those diseases in which seizures are a presenting or predominate feature.
1.2
Symptomatic This comprises syndromes of great individual variability, which will mainly be based on anatomic localization, clinical features, seizure types. and etiologic factors (if known),
2.
Generalized epilepsies and syndromes
2.1
Idiopathic (with age-related onset-listed in order of age) • Benign neonatal familial convulsions • Benign neonatal convulsions • Benign myoclonic epilepsy in infancy • Childhood absence epilepsy (pyknolepsy) • Juvenile absence epilepsy • Juvenile myoclonic epilepsy (impulsive petit mal) • Epilepsy with grand mal seizures (GTCS) on awakening Other generalized idiopathic epilepsies, if they do not belong to one of the above syndromes, can still be classified as generalized idiopathic epilepsies.
2.2
2.3
Idiopathic and/or symptomatic (in order of age) • West syndrome (infantile spasms, Blitz-Nick-Salaam Krampfel) • Lennox-Gastaut syndrome • Epilepsy with myoclonic-astatic seizures • Epilepsy with myoclonic absences
3.
Epilepsies and syndromes undetermined whether focal or generaliZed
3.1
With both generalized and focal seizures • Neonatal seizures • Severe myoclonic epilepsy in infancy • Epilepsy with continuous spike waves during slow-wave sleep • Acquired epileptic aphasia (Landau-Kleffner syndrome)
3.2
Without unequivocal generalized or focal features All cases with generalized tonic-clonic seizures where clinical and EEG findings do not permit classification as clearly generalized or localization-related, such as in many cases of sleep-grand mal.
4.
Special syndromes
4.1
Situation-related seizures (Gelegenheitsanfalle) • Febrile convulsions • Seizures related to other identifiable situations such as stress, hormones, drugs, alcohol, sleep deprivation, etc.
4.2
Isolated. apparently unprovoked epileptic events
4.3
Epilepsies characterized by specific modes of seizure precipitation
4.4
Chronic progressive epilepsia partialis continua of childhood
Symptomatic
From Epilepsia 26:268-278, 1985. published by Raven Press.
-32
PSYCHOSOMATICS
.....
. . . . . . 01
N
%
16
82/243
34
15
86/156
55
12
118/327
36
8
271125
22
10
13161
19
13
45/164
27
ment, whereas the secondary fonns are vinually intractable to all medications. The same is true, of course, when we look at febrile seizures and the same is true when we look at absence seizures. Among the absence seizures, the reason why some of the statistics are quite different from others is that one has to distinguish between the pyknoleptic petit mal, which is primary generalized absence, and absence that is phenotypically similar but that is probably due to a secondary fonn of epilepsy with a completely different ultimate outlook. Therefore, it is very difficult to say what Schmidt's numbers really mean. If one were to subdivide these groups, I suspect that one would find that all the patients with primary generalized epilepsy respond rather well to several anticonvulsant drugs, including c1onazepam, and that those who clearly have secondary epilepsy respond poorly. The fact remains that clonazepam is relatively effective in generalized epilepsy and is relatively ineffective in simple partial seizures and complex partial seizures. Even in the latter group, some patients may respond, and I suspect that if we studied a large enough series of simple partial seizures of the benign primary epileptic type, such as the benign juvenile focal seizures (Rolandic epilepsy), there may be a good response to this drug. Bilateral massive epileptic myoclonus responds reasonably well to clonazepam, responds extremely well to valproate, and responds somewhat to some of the other anti-
DECEMBER 1985' Y0L26'NO 12 (SUPPLEMENT)
convulsant drugs. This is a fairly unifonn syndrome, and about one third of patients are rendered seizure-free with clonazepam. In the akinetic atonic seizures-and I suspect that these are probably of the relatively benign variety-about half the patients receiving clonazepam are rendered seizure-free. These figures come from the study of Pinder and associates,2 which was probably the most exhaustive review of clonazepam when it was published, in 1976. Patients with grand mal seizures do not do as well with clonazepam. Those with psychomotor seizures (or what we now call complex partial seizures) and partial seizures (or focal motor seizures) also do not do as well.
1reatment of myoclonic seizures Clonazepam remains one of the drugs of choice in seizures with myoclonus. 7,10 Several syndromes fall under the rubric of myoclonus or myoclonic epilepsy (Table 4). Some are part of absence seizures. For example, there is absence with clonic components or myoclonic components, and there is a fonn of absence in small children in which myoclonus is the main feature and absence occurs, as it were, by the way. These two respond quite differently to medications. Adolescent myoclonus, or benign juvenile myoclonus, is a distinct entity. It is a relatively benign condition, but is extremely drugdependent in its benignity. When drugs are withdrawn, there tends to be a breakthrough of seizures. Unfortunately, clonazepam is less useful than valproate for this particular syndrome because of a tendency to develop tolerance to clonazepam. 7 Many patients with generalized tonic-clonic seizures also have interspersed myclonic seizures. Myoclonus also occurs as part of progressive neurologic disease that is not primarily epileptic. For example, there is progressive myoclonic epilepsy with Lafora bodies and without Lafora bodies, the one being the standard type of progressive myoclonic epilepsy that we all know about and the other being that particularly described in Scandinavia" but which is very much more widespread than used to be believed. Now that it has become so easy to look for Lafora bodies by doing skin biopsies and looking for the Lafora bodies in the sweat duct epithelium, we can distinguish quite easily between these two fonns of progressive myoclonic epilepsy.
33
Seizure disorders
It is in these diseases that clonazepam finds its major use at this time. It Table 4-Forms of Myoclonic Epilepsy is an extremely effective drug in myoclonic epilepsy, particularly the relatiI. As part of other forms of corticoreticular epilepsy vely nonprogressive myoclonic epiA. Absence with clonic components lepsies, those without Lafora bodies. II B. Adolescent myoclonus Dyssynergia cerebellaris progressiva, C. As a component of generalized tonic-clonic seizures or the Ramsay Hunt syndrome, an inII. As part of progressive neurologic disease, not primarily epileptic teresting nonepileptic fonn of myoA. Progressive myoclonic epilepsy clonus, is a progressive familial dis1. With Lafora bodies ease that responds quite well to clona2. Without Lafora bodies zepam in a large percentage of cases. 12 B. Dyssynergic cerebellaris myoclonica Myoclonus may also appear as part III. As part of generalized disease of the cerebral gray matter of generalized disease of the cerebral A. Lipid storage diseases gray matter, including the lipid storB. Infections, eg, SSPE, age diseases, various infectious disJakob-Creutzfeldt eases such as subacute sclerosing panC. Progressive poliodystrophy (Alpers) encephalitis and Creutzfeldt-Jakob IV. Massive infantile spasms disease and the progressive polio-dystrophy described by Alpers in small children. And then, finally, we have respond quite well to clonazepam. In fact, clonazepam has massive infantile spasm, which, as previously described, been the drug of choice in the treatment of paroxysmal chormay occur without demonstrable organic etiology or may be eoathetosis, particularly of the kinesiogenic type." secondary; the two conditions have a different outlook. Other reflex seizure types such as photically sensitive epilepsy also respond well to clonazepam.'6 Essential tremTreatment of absence seizures or, which is not an epileptic condition, is also quite effecIn absence seizures, clonazepam has been found to be an extively treated with clonazepam. tremely effective drug. It is probably as effective or more effective than is ethosuxamide. It is as effective as valproate in controlling absence seizures over the short haul. I think in Pharmacokinetics In one of our early studies," we looked at the pharmacomost of the series the good results in this particular synkinetics of this drug in five patients, and we found that there drome have been somewhat vitiated by the development of was a very close relationship between clonazepam dose and tolerance and by the relatively high incidence of adverse the serum concentration of clonazepam, with a standard side effects. 7 correlation coefficient. This held up at all levels of dosage (Figure). The half-life of the drug ranged between 22 and 31 Less responsive seizures hours. There is a much faster turnover in children than in In generalized clonic-tonic seizures, the response is less faadults." vorable and the side effects are just as bad. Indeed, some cases of generalized clonic-tonic seizures are exacerbated Side effects by the administration of clonazepam.•. 13 Simple partial seiFinally, I want to mention the side effects that we saw in our zures also respond less favorably except for epilepsia parlarger studies of 49 patients.' Drowsiness, ataxia, and nytialis continua. In epilepsia partialis continua, clonazepam stagmus were seen quite often. Hyperactivity in children sometimes is quite effective. '0 was precipitated by this drug. There was a certain amount of Other paroxysmal conditions personality change, particularly in older children and teenagers, in which there was a relative lack of inhibition of imClonazepam has been used in some other paroxysmal conpulsive behavior, leading to antisocial activity during the ditions, including paroxysmal choreoathetosis. Paroxysmal period of time that the drug was administered (which did not choreoathetosis is again a potpourri of conditions. Some of occur prior to or after withdrawal from the medication). An the paroxysmal choreoathetoses are kinesiogenic; they are increased number of seizures was seen in some patients, set off by movement, by proprioceptive stimulation. These 34
PSYCHOSOMATICS
dropout rate from side effects in various studies in the literature ranges from 20% to 35% or 40%.'
80
•
:::J
Conclusion
Clonazepam is thus a very effective .ECl 60 anticonvulsant. On the other hand, in S c our experience and in the literature, o the development of tolerance inter~ 40 feres to some extent with its desirabilC Q) o ity in long-term administration. The c oo incidence of side effects is sufficiently E high to make this other than the drug :J 20 Correlation coefficient .93 of frrst choice in a large number ofsei~ zure types in which the drug is clinically effective. Because of these limitations, it would appear that with the 0.12 development of newer anticonvulsant drugs, particularly valproate-with which there seems to be a significant overlap in terms of protectiveness for FIGURE-Relationship between clonazepam dosage and serum concentration. various seizure types"---clonazepam has really a relatively small place in the treatment of these types of epilepsies. mainly the precipitation of generalized clonic-tonic seizures Whenever the clinician administers an anticonvulsant in patients with absence seizures. Some had a change in seidrug he or she makes a compromise between seizure control zure type, with the development of more severe seizures. and adverse side effects. All anticonvulsant drugs have adAbout 10% of the patients had a significant weight gain, and verse side effects of one form or another, and it is the physithere were very few patients with leukopenia. cian's responsibility to weigh the risk!benefit ratio very Side effects led to the discontinuation of medication in carefully in every case in which anticonvulsant drugs are ad30% of the patients who were started on it, despite an atministered. 0 tempt at titration of dosage to minimize the side effects. The
•
REFERENCES I. Sato S, Penry JK, Oreifuss, FE, et al: Clonazepam in the treatment of absence seizures. Neurology 27:371, 1977. 2. Pinder RM, Brogden, EN, Speight TM, et al: Clonazepam: A review of its pharmacological properties and therapeutic efficacy. Drugs 12:321-361, 1976. 3. Mikkelsen B, Birket-Smith E, Brandt S, et al: Clonazepam in the treatment of epilepsy. A controlled clinical trial in simple absences, bilateral epileptic myoclonus, and tonic seizures. Arch Neuro/33:322-325, 1976. 4. Lund M, Trolle E: Clonazepam in the treatment of epilepsy. Acta Neurol Scand49:82-90, 1973. 5. WeinerWJ, Goetz C, Nansieda PA, et al: Clonazepam and 5-hydroxylryptophan-induced myoclonic stereotypy. Eur J Pharmaco/46:21-24, 1977. 6. Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for classification of epilepsies and epileptic syndromes. Epilepsia 26:268-278, 1985. 7. Oreifuss FE, Sato S: Clonazepam, in Woodbury OM, Penry JK, Pippenger CE: Antiepileptic Drugs. New York, Raven Press, 1982. 8. Kruse R, Blankenhom V: Zusammenfassender Erfahrungsbericht uber die Klinische Anwendung und Wirksamkeit von R05-4023 (Clonazepam) auf verschiedene Formen epileptischer Anfalle. Acta Neurol Scand 49:60-71,1973. 9. SChmidl 0: Behandlung der Epilepsien,ed 2. Stullgart, G. Thieme, 1984.
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10. Mikkelsen B, Birket-Smith E: A clinical study of the benzodiazepine R054023 (clonazepam) in the treatment of epilepsy. Acta Neural Scand 49:91-96,1973. 11. Laitinen L, Toivakka E: Clonazepam (R05-4023) in the treatment of myoclonus epilepsy. Acta Nauro Scand 49: 72-76, 1973. 12. Bergamiui L, Mutani R, Liboui W: Elektroenzephalographische und Klinische Bewertung des neuen Benzodiazepin R05-4023. Electroencephalogr E/ectromyogr I: 182-188, 1970. 13. Bladin PO: The use of clonazepam as an anticonvulsant: Clinical evaluation. MedJ Austl:683-688, 1973. 14. Drug and Therapeutics Bulletin: Drugs for status epilepticus. Drug Ther BuI/14:89-91,1976. 15. Peiris JV, Boralessa H, Lionel NOW: Clonazepam in the treatment of choreiform activity. Med J Aust 1:225-227, 1976. 16. Ames FF, Enderstain 0: Clinical and EEG response to Clonazepam in four patients with self-induced photosensitive epilepsy. S Air J Med 50:14321434,1976. 17. Oreifuss FE, Penry JK, Rose SW, et al: Serum clonazepam concentrations in children with absence seizures. Neurology 23:255-258, 1975. 18. Jeavons RM, Clark, JE, Maheshwari MC: Treatment of generalized epilepsies of childhood and adolescence with sodium valproate ('Epilim'). Dev Med Child Neuro/19:9-25, 1977.
35
Panel discussion Dr. Chouinard: You mentioned a linear correlation between the dosage and serum concentration, but Browne' in his article in the New England Journal ofMedicine said that you cannot accurately predict serum concentration from dosage.
Dr. Penry: Dr. Browne found a correlation for individuals, but there are some differences between individuals. By comparison, you would find more variability in serum concentrations with phenytoin or carbamazepine than with clonazeparn.
thiS-{)nly case reports. I have treated five patients with paroxysmal choreoathetosis very successfully. It is useful particularly in the kinesiogenic type. It has also been used successfully in the photic sensitive epilepsies. From a psychiatric point of view it might be of interest that the self-stimulating absence type of photic sensitive epilepsy in children can be treated quite effectively with this drug; it even removes the desire to look at light and move the hand in front of the eyes while gazing into the light, which seems to drive these children. I also have one adult patient who gets an orgasm when she does this and she therefore is driven to the window, but clonazepam takes away that desire.
Dr. Chouinard: Do you have patients who respond to nitrazeparn and not to clonazepam?
Dr. DreiJuss: Yes, particularly infantile spasm patients. We're in the middle of a study now with nitrazepam in infantile spasm, and it looks to be extremely effective here. It appears to hold up fairly well without the same development of tolerance as we see in cionazepam. And it appears to do quite well in the secondary or severe forms of infantile spasms in which clonazepam has a less than 30% success rate.
Dr. Chouinard: Are there many studies of clonazepam for paroxysmal choreoathetosis? This would be of interest, since some investigators say that clonazepam is rather effective in suppressing dyskinesia, which is a choreoathetotic movement.
Dr. Chouinard: Regarding behavioral changes with adolescents, it would seem that if you have a very disturbed adolescent, clonazepam can help to prevent a lot of agitation. But if he is not psychiatrically disturbed, clonazepam can produce changes similar to those induced by any other benzodiazepine.
Dr. DreiJuss: Our adolescent patients were not overtly psychiatrically disturbed, although we did not screen all of them. But the behavioral problems were never previously overt until they had been taking the drug.
Dr. Chouinard: This is similar to the ability of lithium or antidepressants to produce dysphoria when given to normal subjects.
Dr. DreiJuss: The other point that has to be brought up is the Dr. DreiJuss: There are no good studies in the literature on 36
difficulty that we have experienced in discontinuing clonaz-
PSYCHOSOMATICS
other every two or three weeks and preventing breakthrough seizures from qccurring in this way.
epam, even when the drug is no longer as effective by virtue of tolerance having developed. We have had to discontinue c10nazepam extremely slowly, reducing the dosage by 0.25 mg per week, in order to avoid breakthrough convulsions.
Dr. Green: Did you once suggest that the combination of
Dr. Chouinard: For us, comparison drugs were loraze-
c10nazepam llQd valproate was useful in some intractable patients?
pam, triazolam, and alprazolam, and all of these are many times more difficult than c10nazepam to discontinue. With c1onazepam, discontinuation is not any more difficult than with diazepam or fturazepam in our population. Even rebound anxiety does not come up as much as with alprazolam, for example, or triazolam used for insomnia.
Dr. Dreifuss: One thing to do for inpatients who develop tolerance is to use a different benzodiazepine. For example, if somebody breaks through after developing tolerance to c1onazepam, I may use c10razepate or one of the other benzodiazepines and it appears then that the new benzodiazepine is again effective for a period of time, I have one child whom I am switching back and forth from one drug to the
DECEMBER 1985·VOL26·NO 12 (SUPPLEMENT)
Dr. Dreifuss: There are areas in which these two drugs are useful, including, on occasion, intractable absence or some of the myoclonic absences. While it has of course been reported that absence status may be precipitated by the use of these two drugs together, 2 this is a very much exaggerated fear, It is actually a very rare occurrence. In fact, when the two drugs are used together in intractible seizure forms they are very often quite beneficial. 0
REFERENCES 1. Browne TR: Clonazepam. N EnglJ Med299:812-816, 1978. 2. Jeavons RM, Clark, JE, Maheshwari MC: Treatment 01 generalized epilepsies 01 childhood and adolescence with sodium valproate ('Epilim'). Dev Med Child Neurol 19:9·25, 1977.
37