Current medical thempy of epilepsy
R.J. Porter National Institute of Neurological Disorders and Stroke
Introduction The classical approach to the patient with epilepsy is to attempt medical control with standard antiepileptic drugs. This strategy remains viable, even though the imminent era of newly marketed drugs for seizure control is very nearly upon us; an astonishing new array of clinical decisions will be required for appropriate therapy for the seizure patient. This chapter is written from the classical perspective, i.e., with the assumption that the currently marketed drugs are still the fist line of therapy, and that newer drugs still need to prove their place in the armamenmiurn of the physician, especially as drugs of fxst choice. The physician should be alert, however, to the gradual displacement of classical medications by some - but certainly not all - of the newer drugs which will appear in the coming decade. Included in this chapter, however, will be vigabatrin, which is now available in the majority of countries throughout the world.
One must consider multiple levels of diagnosis in each patient with epilepsy. At a fundamental clinical level, the etiologic diagnosis requires identification of the cause of the epileptic seizures. At a more superficial yet therapeutically important level, the seizure diagnosis is based on the nature of the seizure type. These two diagnostic levels are often combined with other criteria (Figure 1) to provide the epilepsy syndrome diagnosis; an epileptic syndrome may be defied as a disorder characterized by a cluster of signs and symptoms customarily occurring together (1).
Cerebrospinal fluid exarninolion
Diagnosis Although this discussion is primarily designed to consider the therapy of epilepsy, no such discussion is complete without some consideration of the fundamentals of diagnosis. For it is the diagnosis which determines the correct therapy, and an incorrect diagnosis is the fEst error to be avoided in the therapeutic effort.
Address: R.J. Porter Dept. of Health and Human Services NIH, Building 31, room 8A52 7550 Wisconsin Av. Bethesda, Maryland 20892 USA.
fig I. Theepilepticsyndrornediagnosisisachioevedbyevaluatingallfactorsrelevantthe pknt
59
Porter The search for all three levels of diagnosis is necessary for the proper care of the patient with epilepsy. Failure to establish the etiologic diagnosis means that some patients will continue to have seizures because of undiagnosed brain lesions, e.g., a brain tumor. Failure to establish the seizure diagnosis means that some patients will continue to have seizures because the therapy is incorrect, e.g., absence seizures are mistaken for complex partial seizures and the incorrect medication is prescribed. Failure to establish the syndrome diagnosis will prevent the physician from understanding the prognosis and duration of therapy, e.g., mistaking the relatively benign juvenile myoclonic epilepsy for the comparatively malignant progressive myoclonus epilepsy (2).
A. Etiology Virtually any insult to the cerebrum is a potential substrate for epilepsy, which can be caused by congenital malformations, infections, tumors, vascular diseases, degenerative diseases, or injury. Many patients have the onset of their disease during childhood, an observation which is most likely related to the increased vulnerability of the young nervous system to seizure development, a fact which is documented both clinically and experimentally. In a substantial proportion of patients, the etiology of the seizures remains undetected. Future scientific advances are likely to identify two principal causes of epilepsy in this population. The first of these is inherited susceptibility. Although there is considerable evidence that absence seizures, for example, are an expression of an autosomal dominant gene (3), the role of genetic factors in epilepsy is just now being explored using the new techniques of molecular biology; genetics are a priority investigative area, especially for patients with generalized epilepsies (4). The second probable cause of epilepsy in patients with seizures of unknown origin is chronic or subclinical infection. With the eventual identification of various agents that can cause disease without overt evidence of inflammation, such as Creutzfeldt-Jacob disease, and with the observation that many viruses, such as herpes, are present in latent form in humans, persistent viral infection must be considered in any chronic central nervous system disease of unknown etiology (5). The concept of chronic encephalitis as a cause of epilepsy is not new, and derives from fundamental observations of Rasmussen et al. (6).
B. Seizure Type The vast majority of seizures can be divided into two fundamental groups--partial and generalized. Partial seizures have clinical or electroencephalographic evidence of a local onset, but the word partial does not imply a highly discrete focus; such a focus often does not exist. The abnormal discharge usually arises in a portion of one hemisphere and may spread to other parts of the brain 60
during a seizure. Generalized seizures, however, have no evidence of localized onset--the clinical manifestations and abnormal electrical discharge give no clue to the locus of onset of the abnormality, if indeed such a locus exists. Partial seizures are divided into three groups: (1) simple partial seizures, (2) complex partial seizures, and (3) partial seizures secondarily generalized. Simple partial seizures (SP) are associated with preservation of consciousness and usually with unilateral hemispheric involvement. Complex partial seizures (CP) are associated with alteration or loss of consciousness and usually with bilateral hemispheric involvement. A partial seizure can progress to secondary generalization, i.e., to a generalized tonic-clonic (GTC) seizure that proceeds directly from either a simple partial seizure or a complex partial seizure (2). Only six progression possibilities for partial seizures occur with any frequency; these are summarized in Table 1.
Tablel.
Possibleprogressionofpartialseizures
Selzureprogression SP SP‘ CP CP sp +GTC cp4
GTc
SP-
CP‘
GTC
Seizurename Simple partial seizures Complex partial seizures (with SP onset) Complex partial seizures Partialseizures secondarilygeneralized-generalized tonicclonic seizures Partialseizures secondarilygeneralized-generalized tonicclonic seizures Partialseizures secondarilygeneralizedgeneralized tonicclonic seizures
SP, simple partial seizure; CP, complex partial seizure; GTC, generalizedtonicclonic seizure. Adapted from Epilepsy: 1M) Elementaty Principles (2)
Seizures without evidence of a localized onset are termed generalized seizures, and form a very heterogenous group. The generalized seizures include (a.) generalized tonic-clonic seizures (grand mal), (b.) absence seizures (petit mal), (c.) myoclonic seizures, (d.) atonic seizures, (e.) clonic seizures, and (f.) tonic seizures. Further description of these seizure types is beyond the scope of this article.
C. Epilepsy Syndromes The concept of epileptic syndromes differs from that of epileptic seizures. A seizure is a f ~ t event; e it has a beginning and an end. Hughlings Jackson, in 1870, stated that a seizure is a symptomm occasional, an excessive and a disorderly discharge of nerve tissue...” (7). Epilepsy, on the other hand, is a chronic disorder. The World Health Organization (WHO) has stated that epilepsy is “a chronic brain disorder of various etiologies characterized by recurrent seizures due to excessive discharge of cerebral
Medical Therapy neurons...” (8). Epilepsy is more a group of syndromes than a disease; the “epilepsies” or “epileptic syndromes” have arisen to classify patients and to emphasize the heterogeneity of these symptom-complexes. Classification of the epilepsies depends on our ability to determine a framework of similarity in patient characteristics--includingseizures and many other factors. The earliest and most persistent subdivision is between epilepsy with a recognizable cause (symptomatic) and epilepsy without a recognizable cause (cryptogenic or idiopathic) (2) The current classification begins fust with the partial/generalized concept followed by the etiology concept:
1.
Partial (localization-related) epilepsies A. Idiopathic B. Symptomatic 11. Generalized epilepsies A. Idiopathic B. Idiopathic and/or symptomatic C. Symptomatic 111. Epilepsies undetermined whether partial generalized IV. Special syndromes
or
Therapy Although the appropriate care of patients with epilepsy requires consideration of all three of the above diagnostic concepts, the selection of medication is most dependent upon an accurate understanding of the seizure type. For that reason, consideration of the various medications will be divided by seizure type. Before considering the standard medications for the treatment of epilepsy, however, certain fundamental pharmacological principles need to be considered. A. Pharmacology of Antiepileptic Drugs One of the most important pharmacologic concepts with which the physician should be familiar is the half-Life of the drug. When one knows the half-life, one has a good handle on many of the factors that determine appropriate dosage. The half-life, for instance, determines the spacing of the drug intake intervals. From a pharmacokinetic standpoint, it makes no difference whether long half-life drugs are given frequently or infrequently. If maximum therapeutic effectiveness of the short half-life drugs is desired, however, they must be delivered frequently--often four times a day. The rule is simple: give short half-life drugs and (2)‘ Two antiepileptic drugs’ carbamazepine, have short half-lives, and unless a delayed release form of the drug is available, the dosage intervals should be spaced out during the day, especially in patients whose attacks are not completely controlled and who require maximum effectiveness from the limited antiepileptic armamentarium.
When one changes the dose of the drug, knowledge of the half-life again becomes important. As noted above, the disadvantage of drugs with short half-lives is the necessity of frequent administration. The advantage of drugs with short half-lives is the ability to change from one steadystate level to another in a relatively short time. The pharmacokinetic rule is simple: after every dose change it takes five half-lives to reach 97% of a new steady-state plasma drug level. Only after the new steady-state level is reached can drug efficacy be evaluated. For example, accurate evaluation of the efficacy of phenobarbital within a few days after a dose change is not possible. The half-life of phenobarbital may be 96 hr or more, and 3 weeks will often be required to reach a new steady-state level. With carbamazepine or valproate, however, a new steady state will be achieved within a few days, and the efficacy of the drug can be more rapidly determined. Of the antiepileptic drugs most commonly used, only carbamazepine and valproate, and to some extent primidone, have short halflives, which allow relatively rapid achievement of a steady-state level after a dose change (Table 2). Although dose-related toxicity can occur at any time in the course of drug administration, like efficacy, it cannot be fully evaluated until the new steady-state level is achieved. Occasionally, toxicity occurs before a steady-state level is reached, and a dosage decrease is indicated. Seizure control theoretically could also be evaluated before a steady-state level is attained, allowing for a lower dosage, but efficacy is best evaluated after a steady state is achieved. Seizure frequency will also affect the time required for efficacy evaluation. If a patient is having five seizures a day, for example, the efficacy can be determined quickly. If the patient is having only two seizures a year, a long time will be required to ascertain whether the regimen is satisfizctory (2).
Table II.
Plasmahaif-lteofsixantiepilepticdrugs
Half-lie‘ 12 hours 12 hours 12 hwrs 1d Y
2w
4 days
Timeto reach steadystate 3 days 3 dars
3daF 5 days”
’0 daF 3 w
Half-lifeis usually shorter when the drug is coadmmisteredwith enzyme-inducing drugs (including %me other antiepileptic drugs). Half-lie may be longer at onset of afministration (espedal,y\Mthm~amazepine), * Primidoneisconvertedr~~lytopheno~ital (Principle@). *- PhenytoinobeyssaturaSonkjnetics(Principle68). Mdfiedfrom PenlymdNmak(9).
61
Porter The time required to reach steady state is also determined by the half-life of the drug, and is not, for example determined by the size of the change is dosage. Whether the dose of an antiepileptic drug is increased by 15 mg or by 150 mg daily, the time necessary to achieve a new steady-state level is the same. Although this assumption is based on linear kinetics, only phenytoin (which has non-linear kinetics) deviates from this model. Explained in another way, the eventual height of the new steady-state plasma drug level is a function of the daily dose of the drug, whereas the time needed to reach this steady-state level is related not to the total dose nor to the amount of the dose change but to the half-life of the drug. The longer the half-life, the longer the time needed to reach a steady state, regardless of the dose or the amount of dose change. When changing the dose of a drug, especially at higher plasma levels, changes should be made infrequently and in small increments. Dose-related toxicity, when encountered, will thereby be relatively mild (2). Finally, the use of blood levels must be considered. The most important concept is to use the levels as a guide and to treat the patient, not the levels. One example of a table of so-called therapeutic levels is found in Table 3. The usual therapeutic level of phenytoin, for example, is 10 to 20 udml, which suggests that most patients will experience optimal seizure control with minimal toxicity if their plasma phenytoin level is within this range. Unfortunately, there are many exceptions to this guideline, and many patients are well controlled at higher or lower levels (2). Typical doses of antiepileptic drugs may also not be optimal. For example, the 300-mg daily dose of phenytoin-the “usual” neurologic dose--fully one-half the time gives a plasma phenytoin level of less than 10 udml (10).
Such levels, however, clearly provide total seizure control in certain patients, and vigorous attempts to raise the plasma level in these mildly affected patients add only the risk of dose-related toxicity (11). The major considerations in the use of plasma drug levels are as follows (12, 2):
1. Antiepileptic drug monitoring is useful only as a guide to changes in therapy; it is not a substitute for clinical judgment. 2. Expected therapeutic plasma drug levels are average values; each patient will have an individually optimal value. 3. The determinations help achieve maximal effects of each medication. The use of gradually increasing doses to establish the maximally tolerated dose is a valid concept in patients with refractory seizures.
4. The determinations are invaluable in the presence of toxic side effects, especially in patients taking multiple drugs and when using phenytoin, which has non-linear kinetics.
5. Noncompliance, malabsorption, and altered (idiosyncratic) metabolism can be identified, but only noncompliance is a common problem. 6. A reliable laboratory is critical to proper interpretation of the results. 7. If the blood samples for determination of plasma drug levels are drawn at various times during the day, such levels may be misleading.
B. Medication choices: Partial Seizures Table 111.
Only after all of the above considerations have been taken into account can the physician logically and appropriately choose and prescribe the correct medication for the patient. Because of space limitations, only three seizure types will be considered: partial, generalized tonic-clonic, and absence.
Effective plasmalevelsof six antiepilep’dcdrugs
Catmazepine PrimidDne Phenytcin Pherdwbltal Ethosmimide Valproate
4510 10 -
12 15
20 40
5 0 - 1M) 5 0 - 1m
7 10 18 35 80 80
>8 >12
>a >40 >lo3 >loo
Levelthatshouldbeachieved,Ipossible,inpatientswithrefractoryseuures, assuming that bloodsamples are drawn before administrationof the morning medimtion (Pnnaple 58). Higher levels are often possible -withouttoxidty -when the drugs are used alone, i.e. as monotherapy(Principle47).
For partial seizures, a variety of medications, including carbamazepine, hydantoins, barbiturates and perhaps valproate are efficacious. The drugs of choice, according to two large multicentre mals (13, 14), are the frst two. In choosing between them, the physician should weigh factors other than efficacy, i.e., phenytoin and carbamazepine are approximately equally efficacious, but differ in their potential toxicity. The choice of phenytoin as the primary drug has certain advantages. It is an old, safe compound, and most physicians are familiar with its use.
Medical Therapy m a g per day. The most frequent adverse events reported were drowsiness, ataxia, headache, dizziness, confusion, irritability, and abdominal discomfort (22).
Serious side effects are rare and almost always reversible. The parenteral formulation is very useful, although intramuscular administration is not recommended. Plasma phenytoin level determinations are commonly available. Disadvantages of phenytoin use include hirsutism, gingival hyperplasia, coarsening of the features, and a teratogenic potential, including the fetal hydantoin syndrome. Dose-related toxicity is occasionally a problem because of the drug’s non-linear kinetics. Phenytoin was discovered in the late 1930’s, and was marketed before controlled clinical trials were required. Its effectiveness against partial seizures and generalized tonic-clonic seizures is documented, if only anecdotally. The choice of carbamazepine also has several advantages. It is easily tolerated by most patients and does not cause hirsutism or gingival hyperplasia. Disadvantages of carbamazepine use include the rare occurrence of blood dyscrasias (an overrated fear), and its short half-life, which may require a dosing schedule of several times a day. Carbamazepine was first used as an antiepileptic drug in the early 1960’s (15), at which time it was reported in Europe to be an effective agent. Later, several trials were reported in the United States. In general, carbamazepine was shown to be as effective as the other drugs in preventing partial and generalized tonic-clonic seizures. The study by Mattson et al. (13) documents the equal efficacy of carbamazepine and phenytoin and quite clearly shows that these two drugs - for most patients - are superior to phenobarbital or primidone. Similarly, the followup study by Mattson et al., (14) documents the superiority of carbamazepine when compared directly with valproate for these types of seizures. One additional hydantoin is worthy of mention even though it is rarely utilized. Mephenytoin is limited by frequent toxic reactions (16), and its use is rarely warranted. Finally, phenacemide is a ring-opened analog of phenytoin, but also has frequent idiosyncratic toxicity, including organ toxicity and personality changes (17).
D. Medication Choices: Absence Seizures For absence seizures that occur alone, ethosuximide is the drug of choice, whereas valproate is preferred if the patient has generalized tonic-clonic seizures in addition to absence attacks. The effect of ethosuximide occurs rapidly. In 18 patients with long-term telemetered EEG recordings, the most impressive decline in spike-and-wave bursts was seen in the frrst 48 hr of therapy (25). Ethosuximide has a long half-life, but spacing of the doses during the day may be necessary to avoid gastrointestinal side effects. The common dose-related side effects of ethosuximide are nausea, vomiting, headache, and anorexia. Ethosuximide should be chosen only if the patient has typical absence seizures; valproate is the drug of choice for most other patients (2).
One new drug for complex partial seizures and generalized tonic clonic seizures deserves mention. Vigabatrin is a potent GABA- transaminase inhibitor and an effective anti-epileptic drug. Early clinical development of this drug was slowed because microvacuolization of white matter was noticed in the brains of animals, especially rodents and dogs. Fears about this complication in humans have not been realized. A number of double blind placebo controlled trials have been published (18-21). From these studies, conducted with patients resistant to marketed anti-epileptic drugs and suffering at least from two to four seizures per month, vigabatrin emerges as an effective drug in a quarter of the patients; more than a 75 percent reduction of seizures was observed in the study period. Most patients suffered from complex partial seizures, with or without secondary generalization. Typical dosages averaged 3 grams or 50
Valproate is the drug of choice for absence seizures complicated by concomitant generalized tonic-clonic seizures. Valproate is highly effective against absence seizures (26) and decreases the generalized spike-andwave paroxysms that accompany such attacks (27). With the use of 12-hr telemetered EEGs to measure the frequency of generalized spike-and-wave discharges, valproate was compared with ethosuximide in a doubleblind, response-conditional crossover study of absence seizures in 45 patients (28). Valproate was as effective as ethosuximide. Patients who meet the diagnostic criteria for absence seizures and who do not respond to ethosuximide, should be considered for treatment with valproate. The drug should be started in relatively low doses, with gradual build-up to a therapeutic level. Valproate shares with ethosuximide a tendency to irritate the gastrointestinal tract. This tendency can usually be overcome with slowly
C. Medication choices: Generalized Tonic-Clonic Seizures The treatment of generalized tonic-clonic seizures thai occur secondary to partial seizures is similar to that of partial seizures themselves. Carbamazepine and/or phenytoin are the current drugs of choice. These drugs are especially effective when used together. Conclusive data are now available to document the effectiveness of valproate against primary generalized tonic-clonic seizures, whether these seizures occur in isolation or in combination with other generalized seizure types such as absence or myoclonia (23; 24). The use of barbiturates for the control of generalized tonic-clonic seizures is rarely necessary, considering the effectiveness and nonsedative characteristics of phenytoin, carbamazepine, and valproate. Likewise, benzodiazepines are usually ineffective in the long-term treatment of generalized tonicclonic attacks, and are rarely indicated (2).
Porter
increasing doses and considerable patience. Valproate is also effective against certain myoclonias and, as noted above, primary generalized tonic-clonic seizures. It should be recognized that the drug has a short half-life and, in the absence of a delayed-release formulation, the drug should be given frequently during the day (2).
Summary The treatment of epilepsy firstly depends upon the correct diagnosis, with emphasis on considerations of etiology, seizure type, and epilepsy syndrome. Following an appropriate diagnostic conclusion, the patient may be started on the medication matched to the seizure type. A full understanding of the pharmacology of antiepileptic drugs will enable the physician to obtain maximum benefit from the available pharmaceutical armamentarium.
References I.
2. 3.
4.
5.
6. 7.
8. 9. 10.
64
Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for classification of epilepsies and epileptic syndromes. Epilepsia 1985: 26: 268-78. Porter RJ. Epilepsy - 100 Elementary Principles Second Edition. London: WB Saunders Company, 1989. Metrakos K, Metrakos JD. Genetics of convulsive disorders: II. Genetic and electroencephalographic studies in centrencephalic epilepsy. Neurology 1961 : I 1: 474-83. Delgado-Escueta AV, Ward AA, Woodbury DM. Porter RJ. New wave of research in the epilepsies. In Basic Mechanisms of the Epilepsies. In: Delgado-Escueta AV et al, eds. New York: Raven Press, 1986: 3-55. Porter, R.J. Etiology and classification of epileptic seizures. In: Robb P eds. Epilepsy Updated: Causes and Treatment. Chicago: Year Book Medical Publishers, 1980 1-10. Rasmussen T, Olszewski J, Lloyd-Smith D. Focal seizures due to chronic localized encephalitis. Neurology 1958: 8: 435-45. Taylor J. editor (1931) Selected Writings of John Hughlings Jackson, Vol 1: On Epilepsy and Epileptiform Convulsions. London: Hodder and Stoughton. Reprint 1958. New York: Basic Books. Gastaut H. Dictionary of Epilepsy. Geneva: World Health Organization. 1973: 75 pp. Penny JK. Newark, ME. The use of antiepileptic drugs Annals of Internal Medicum 1979: 90:207-218. Porter RJ, Layzer RB. Plasma albumin concentration and diphenylhydantoin binding in man. Arch Neurol 1975: 32: 298-303.
1 1. Woo E, Chan YM, Yu YL, Chan YW. Huang CY. If a well-stabilized epileptic patient has a subtherapeutic antiepileptic drug level, should the dose be increased? A randomized prospective study. Epilepsia 1988: 29: 129-39. 12. Porter RJ. Efficacy of antiepileptic drugs. In: Ward AA et al, eds. Epilepsy. New York: Raven Press, 1983: 225-37. 13. Mattson RH, Cramer JA, Collins JF et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985: 313: 145-51. 14. Mattson RH, Cramer JA, Collins JF and the VA Epilepsy Cooperative Study #264 Group. Comparison between carbamazepine and valproate for complex partial and secondarily generalized tonic-clonic seizures. Epilepsia 1991 : 42: 18. 15. Penry JK, Porter RJ. Epilepsy: Mechanisms and therapy. Med Clin North America 1979: 63: 801-12. 16. Robins MM. Aplastic anemia secondary to anticonvulsants. Am J Dis Child 1962: 104: 614-24. 17. Troupin AS, Ojemann LM, Dodrill CB. Mephenytoin: A reappraisal. Epilepsia 1976: 17: 403-14. 18. R i m e r EM, Richens A. Double-blind study of gamma-vinyl GABA in patients with refractory epilepsy. Lancet 1984: 1: 189-90 19. Gram L, Klosterkov P, Dam M. Gamma-vinyl: A double blind placebo-controlled trial in partial epilepsy. Ann Neurol 1985: 17: 262-6. 20. Tartara AR, Manni CA, Galimbert et al. Vigabatrin in the treatment of epilepsy: A double-blind, placebo-controlled study. Epilepsia 1986: 27: 717-23. 2 1. Tassinari CA, Michelucci R, Ambrosetto G et al. Double-blind study of vigabatrin in the treatment of drug-resistant epilepsy. Arch Neurol 1987: 44: 907-10. 22. Meinardi H, Porter RJ. New Anti-Epileptic Drugs. In: Froscher et al, eds. Epilepsie: Grundlagen, Klinik, Behandlung. Germany 1991. 23. Collaborative Study Group: Bourgeois B, Beaumanoir A, Blajev B et al. Monotherapy with valproate in primary generalized epilepsies. Epilepsia 1987: 28 (Suppl. 2): S8-I I . 24. Chadwick DW. Valproate monotherapy in the management of generalized and partial seizures. Epilepsia 1987: 28 (Suppl. 2): S 12-7. 25. Penry JK, Porter RJ, Dreifuss FE. Ethosuximide: Relation of plasma levels to clinical control. In: Woodbury et al, eds. Antiepileptic Drugs. New York Raven Press, 1972: 431-41. 26. Simon D, Penry JK. Sodium di-N-propylacetate (DPA) in the treatment of epilepsy: A review. Epilepsia 1975: 16: 549-73. 27. Penry JK. Porter RJ, Sato S, Reddenbough J, Dreifuss FE.Effect of sodium valproate on generalized spike-wave paroxysms in the electroencephalogram. In: Legg NJ. et al, eds. Clinical and Pharmacological Aspects of Sodium Valproate (Epilim) in the Treatment of Epilepsy. MCS Consultants: Tunbridge Wells. 1976: 158-64. 28. Sat0 S, White BG, Penry JK, Dreifuss FE, Sackellares JC, Kupferberg HJ. Valproic acid versus ethosuximide in the treatment of absence seizures. Neurology 1982: 32: 157-63.
R.J. Porter National Institute of Neurological Disorders and Stroke
Introduction The classical approach to the patient with epilepsy is to attempt medical control with standard antiepileptic drugs. This strategy remains viable, even though the imminent era of newly marketed drugs for seizure control is very nearly upon us; an astonishing new array of clinical decisions will be required for appropriate therapy for the seizure patient. This chapter is written from the classical perspective, i.e., with the assumption that the currently marketed drugs are still the fist line of therapy, and that newer drugs still need to prove their place in the armamenmiurn of the physician, especially as drugs of fxst choice. The physician should be alert, however, to the gradual displacement of classical medications by some - but certainly not all - of the newer drugs which will appear in the coming decade. Included in this chapter, however, will be vigabatrin, which is now available in the majority of countries throughout the world.
One must consider multiple levels of diagnosis in each patient with epilepsy. At a fundamental clinical level, the etiologic diagnosis requires identification of the cause of the epileptic seizures. At a more superficial yet therapeutically important level, the seizure diagnosis is based on the nature of the seizure type. These two diagnostic levels are often combined with other criteria (Figure 1) to provide the epilepsy syndrome diagnosis; an epileptic syndrome may be defied as a disorder characterized by a cluster of signs and symptoms customarily occurring together (1).
Cerebrospinal fluid exarninolion
Diagnosis Although this discussion is primarily designed to consider the therapy of epilepsy, no such discussion is complete without some consideration of the fundamentals of diagnosis. For it is the diagnosis which determines the correct therapy, and an incorrect diagnosis is the fEst error to be avoided in the therapeutic effort.
Address: R.J. Porter Dept. of Health and Human Services NIH, Building 31, room 8A52 7550 Wisconsin Av. Bethesda, Maryland 20892 USA.
fig I. Theepilepticsyndrornediagnosisisachioevedbyevaluatingallfactorsrelevantthe pknt
59
Porter The search for all three levels of diagnosis is necessary for the proper care of the patient with epilepsy. Failure to establish the etiologic diagnosis means that some patients will continue to have seizures because of undiagnosed brain lesions, e.g., a brain tumor. Failure to establish the seizure diagnosis means that some patients will continue to have seizures because the therapy is incorrect, e.g., absence seizures are mistaken for complex partial seizures and the incorrect medication is prescribed. Failure to establish the syndrome diagnosis will prevent the physician from understanding the prognosis and duration of therapy, e.g., mistaking the relatively benign juvenile myoclonic epilepsy for the comparatively malignant progressive myoclonus epilepsy (2).
A. Etiology Virtually any insult to the cerebrum is a potential substrate for epilepsy, which can be caused by congenital malformations, infections, tumors, vascular diseases, degenerative diseases, or injury. Many patients have the onset of their disease during childhood, an observation which is most likely related to the increased vulnerability of the young nervous system to seizure development, a fact which is documented both clinically and experimentally. In a substantial proportion of patients, the etiology of the seizures remains undetected. Future scientific advances are likely to identify two principal causes of epilepsy in this population. The first of these is inherited susceptibility. Although there is considerable evidence that absence seizures, for example, are an expression of an autosomal dominant gene (3), the role of genetic factors in epilepsy is just now being explored using the new techniques of molecular biology; genetics are a priority investigative area, especially for patients with generalized epilepsies (4). The second probable cause of epilepsy in patients with seizures of unknown origin is chronic or subclinical infection. With the eventual identification of various agents that can cause disease without overt evidence of inflammation, such as Creutzfeldt-Jacob disease, and with the observation that many viruses, such as herpes, are present in latent form in humans, persistent viral infection must be considered in any chronic central nervous system disease of unknown etiology (5). The concept of chronic encephalitis as a cause of epilepsy is not new, and derives from fundamental observations of Rasmussen et al. (6).
B. Seizure Type The vast majority of seizures can be divided into two fundamental groups--partial and generalized. Partial seizures have clinical or electroencephalographic evidence of a local onset, but the word partial does not imply a highly discrete focus; such a focus often does not exist. The abnormal discharge usually arises in a portion of one hemisphere and may spread to other parts of the brain 60
during a seizure. Generalized seizures, however, have no evidence of localized onset--the clinical manifestations and abnormal electrical discharge give no clue to the locus of onset of the abnormality, if indeed such a locus exists. Partial seizures are divided into three groups: (1) simple partial seizures, (2) complex partial seizures, and (3) partial seizures secondarily generalized. Simple partial seizures (SP) are associated with preservation of consciousness and usually with unilateral hemispheric involvement. Complex partial seizures (CP) are associated with alteration or loss of consciousness and usually with bilateral hemispheric involvement. A partial seizure can progress to secondary generalization, i.e., to a generalized tonic-clonic (GTC) seizure that proceeds directly from either a simple partial seizure or a complex partial seizure (2). Only six progression possibilities for partial seizures occur with any frequency; these are summarized in Table 1.
Tablel.
Possibleprogressionofpartialseizures
Selzureprogression SP SP‘ CP CP sp +GTC cp4
GTc
SP-
CP‘
GTC
Seizurename Simple partial seizures Complex partial seizures (with SP onset) Complex partial seizures Partialseizures secondarilygeneralized-generalized tonicclonic seizures Partialseizures secondarilygeneralized-generalized tonicclonic seizures Partialseizures secondarilygeneralizedgeneralized tonicclonic seizures
SP, simple partial seizure; CP, complex partial seizure; GTC, generalizedtonicclonic seizure. Adapted from Epilepsy: 1M) Elementaty Principles (2)
Seizures without evidence of a localized onset are termed generalized seizures, and form a very heterogenous group. The generalized seizures include (a.) generalized tonic-clonic seizures (grand mal), (b.) absence seizures (petit mal), (c.) myoclonic seizures, (d.) atonic seizures, (e.) clonic seizures, and (f.) tonic seizures. Further description of these seizure types is beyond the scope of this article.
C. Epilepsy Syndromes The concept of epileptic syndromes differs from that of epileptic seizures. A seizure is a f ~ t event; e it has a beginning and an end. Hughlings Jackson, in 1870, stated that a seizure is a symptomm occasional, an excessive and a disorderly discharge of nerve tissue...” (7). Epilepsy, on the other hand, is a chronic disorder. The World Health Organization (WHO) has stated that epilepsy is “a chronic brain disorder of various etiologies characterized by recurrent seizures due to excessive discharge of cerebral
Medical Therapy neurons...” (8). Epilepsy is more a group of syndromes than a disease; the “epilepsies” or “epileptic syndromes” have arisen to classify patients and to emphasize the heterogeneity of these symptom-complexes. Classification of the epilepsies depends on our ability to determine a framework of similarity in patient characteristics--includingseizures and many other factors. The earliest and most persistent subdivision is between epilepsy with a recognizable cause (symptomatic) and epilepsy without a recognizable cause (cryptogenic or idiopathic) (2) The current classification begins fust with the partial/generalized concept followed by the etiology concept:
1.
Partial (localization-related) epilepsies A. Idiopathic B. Symptomatic 11. Generalized epilepsies A. Idiopathic B. Idiopathic and/or symptomatic C. Symptomatic 111. Epilepsies undetermined whether partial generalized IV. Special syndromes
or
Therapy Although the appropriate care of patients with epilepsy requires consideration of all three of the above diagnostic concepts, the selection of medication is most dependent upon an accurate understanding of the seizure type. For that reason, consideration of the various medications will be divided by seizure type. Before considering the standard medications for the treatment of epilepsy, however, certain fundamental pharmacological principles need to be considered. A. Pharmacology of Antiepileptic Drugs One of the most important pharmacologic concepts with which the physician should be familiar is the half-Life of the drug. When one knows the half-life, one has a good handle on many of the factors that determine appropriate dosage. The half-life, for instance, determines the spacing of the drug intake intervals. From a pharmacokinetic standpoint, it makes no difference whether long half-life drugs are given frequently or infrequently. If maximum therapeutic effectiveness of the short half-life drugs is desired, however, they must be delivered frequently--often four times a day. The rule is simple: give short half-life drugs and (2)‘ Two antiepileptic drugs’ carbamazepine, have short half-lives, and unless a delayed release form of the drug is available, the dosage intervals should be spaced out during the day, especially in patients whose attacks are not completely controlled and who require maximum effectiveness from the limited antiepileptic armamentarium.
When one changes the dose of the drug, knowledge of the half-life again becomes important. As noted above, the disadvantage of drugs with short half-lives is the necessity of frequent administration. The advantage of drugs with short half-lives is the ability to change from one steadystate level to another in a relatively short time. The pharmacokinetic rule is simple: after every dose change it takes five half-lives to reach 97% of a new steady-state plasma drug level. Only after the new steady-state level is reached can drug efficacy be evaluated. For example, accurate evaluation of the efficacy of phenobarbital within a few days after a dose change is not possible. The half-life of phenobarbital may be 96 hr or more, and 3 weeks will often be required to reach a new steady-state level. With carbamazepine or valproate, however, a new steady state will be achieved within a few days, and the efficacy of the drug can be more rapidly determined. Of the antiepileptic drugs most commonly used, only carbamazepine and valproate, and to some extent primidone, have short halflives, which allow relatively rapid achievement of a steady-state level after a dose change (Table 2). Although dose-related toxicity can occur at any time in the course of drug administration, like efficacy, it cannot be fully evaluated until the new steady-state level is achieved. Occasionally, toxicity occurs before a steady-state level is reached, and a dosage decrease is indicated. Seizure control theoretically could also be evaluated before a steady-state level is attained, allowing for a lower dosage, but efficacy is best evaluated after a steady state is achieved. Seizure frequency will also affect the time required for efficacy evaluation. If a patient is having five seizures a day, for example, the efficacy can be determined quickly. If the patient is having only two seizures a year, a long time will be required to ascertain whether the regimen is satisfizctory (2).
Table II.
Plasmahaif-lteofsixantiepilepticdrugs
Half-lie‘ 12 hours 12 hours 12 hwrs 1d Y
2w
4 days
Timeto reach steadystate 3 days 3 dars
3daF 5 days”
’0 daF 3 w
Half-lifeis usually shorter when the drug is coadmmisteredwith enzyme-inducing drugs (including %me other antiepileptic drugs). Half-lie may be longer at onset of afministration (espedal,y\Mthm~amazepine), * Primidoneisconvertedr~~lytopheno~ital (Principle@). *- PhenytoinobeyssaturaSonkjnetics(Principle68). Mdfiedfrom PenlymdNmak(9).
61
Porter The time required to reach steady state is also determined by the half-life of the drug, and is not, for example determined by the size of the change is dosage. Whether the dose of an antiepileptic drug is increased by 15 mg or by 150 mg daily, the time necessary to achieve a new steady-state level is the same. Although this assumption is based on linear kinetics, only phenytoin (which has non-linear kinetics) deviates from this model. Explained in another way, the eventual height of the new steady-state plasma drug level is a function of the daily dose of the drug, whereas the time needed to reach this steady-state level is related not to the total dose nor to the amount of the dose change but to the half-life of the drug. The longer the half-life, the longer the time needed to reach a steady state, regardless of the dose or the amount of dose change. When changing the dose of a drug, especially at higher plasma levels, changes should be made infrequently and in small increments. Dose-related toxicity, when encountered, will thereby be relatively mild (2). Finally, the use of blood levels must be considered. The most important concept is to use the levels as a guide and to treat the patient, not the levels. One example of a table of so-called therapeutic levels is found in Table 3. The usual therapeutic level of phenytoin, for example, is 10 to 20 udml, which suggests that most patients will experience optimal seizure control with minimal toxicity if their plasma phenytoin level is within this range. Unfortunately, there are many exceptions to this guideline, and many patients are well controlled at higher or lower levels (2). Typical doses of antiepileptic drugs may also not be optimal. For example, the 300-mg daily dose of phenytoin-the “usual” neurologic dose--fully one-half the time gives a plasma phenytoin level of less than 10 udml (10).
Such levels, however, clearly provide total seizure control in certain patients, and vigorous attempts to raise the plasma level in these mildly affected patients add only the risk of dose-related toxicity (11). The major considerations in the use of plasma drug levels are as follows (12, 2):
1. Antiepileptic drug monitoring is useful only as a guide to changes in therapy; it is not a substitute for clinical judgment. 2. Expected therapeutic plasma drug levels are average values; each patient will have an individually optimal value. 3. The determinations help achieve maximal effects of each medication. The use of gradually increasing doses to establish the maximally tolerated dose is a valid concept in patients with refractory seizures.
4. The determinations are invaluable in the presence of toxic side effects, especially in patients taking multiple drugs and when using phenytoin, which has non-linear kinetics.
5. Noncompliance, malabsorption, and altered (idiosyncratic) metabolism can be identified, but only noncompliance is a common problem. 6. A reliable laboratory is critical to proper interpretation of the results. 7. If the blood samples for determination of plasma drug levels are drawn at various times during the day, such levels may be misleading.
B. Medication choices: Partial Seizures Table 111.
Only after all of the above considerations have been taken into account can the physician logically and appropriately choose and prescribe the correct medication for the patient. Because of space limitations, only three seizure types will be considered: partial, generalized tonic-clonic, and absence.
Effective plasmalevelsof six antiepilep’dcdrugs
Catmazepine PrimidDne Phenytcin Pherdwbltal Ethosmimide Valproate
4510 10 -
12 15
20 40
5 0 - 1M) 5 0 - 1m
7 10 18 35 80 80
>8 >12
>a >40 >lo3 >loo
Levelthatshouldbeachieved,Ipossible,inpatientswithrefractoryseuures, assuming that bloodsamples are drawn before administrationof the morning medimtion (Pnnaple 58). Higher levels are often possible -withouttoxidty -when the drugs are used alone, i.e. as monotherapy(Principle47).
For partial seizures, a variety of medications, including carbamazepine, hydantoins, barbiturates and perhaps valproate are efficacious. The drugs of choice, according to two large multicentre mals (13, 14), are the frst two. In choosing between them, the physician should weigh factors other than efficacy, i.e., phenytoin and carbamazepine are approximately equally efficacious, but differ in their potential toxicity. The choice of phenytoin as the primary drug has certain advantages. It is an old, safe compound, and most physicians are familiar with its use.
Medical Therapy m a g per day. The most frequent adverse events reported were drowsiness, ataxia, headache, dizziness, confusion, irritability, and abdominal discomfort (22).
Serious side effects are rare and almost always reversible. The parenteral formulation is very useful, although intramuscular administration is not recommended. Plasma phenytoin level determinations are commonly available. Disadvantages of phenytoin use include hirsutism, gingival hyperplasia, coarsening of the features, and a teratogenic potential, including the fetal hydantoin syndrome. Dose-related toxicity is occasionally a problem because of the drug’s non-linear kinetics. Phenytoin was discovered in the late 1930’s, and was marketed before controlled clinical trials were required. Its effectiveness against partial seizures and generalized tonic-clonic seizures is documented, if only anecdotally. The choice of carbamazepine also has several advantages. It is easily tolerated by most patients and does not cause hirsutism or gingival hyperplasia. Disadvantages of carbamazepine use include the rare occurrence of blood dyscrasias (an overrated fear), and its short half-life, which may require a dosing schedule of several times a day. Carbamazepine was first used as an antiepileptic drug in the early 1960’s (15), at which time it was reported in Europe to be an effective agent. Later, several trials were reported in the United States. In general, carbamazepine was shown to be as effective as the other drugs in preventing partial and generalized tonic-clonic seizures. The study by Mattson et al. (13) documents the equal efficacy of carbamazepine and phenytoin and quite clearly shows that these two drugs - for most patients - are superior to phenobarbital or primidone. Similarly, the followup study by Mattson et al., (14) documents the superiority of carbamazepine when compared directly with valproate for these types of seizures. One additional hydantoin is worthy of mention even though it is rarely utilized. Mephenytoin is limited by frequent toxic reactions (16), and its use is rarely warranted. Finally, phenacemide is a ring-opened analog of phenytoin, but also has frequent idiosyncratic toxicity, including organ toxicity and personality changes (17).
D. Medication Choices: Absence Seizures For absence seizures that occur alone, ethosuximide is the drug of choice, whereas valproate is preferred if the patient has generalized tonic-clonic seizures in addition to absence attacks. The effect of ethosuximide occurs rapidly. In 18 patients with long-term telemetered EEG recordings, the most impressive decline in spike-and-wave bursts was seen in the frrst 48 hr of therapy (25). Ethosuximide has a long half-life, but spacing of the doses during the day may be necessary to avoid gastrointestinal side effects. The common dose-related side effects of ethosuximide are nausea, vomiting, headache, and anorexia. Ethosuximide should be chosen only if the patient has typical absence seizures; valproate is the drug of choice for most other patients (2).
One new drug for complex partial seizures and generalized tonic clonic seizures deserves mention. Vigabatrin is a potent GABA- transaminase inhibitor and an effective anti-epileptic drug. Early clinical development of this drug was slowed because microvacuolization of white matter was noticed in the brains of animals, especially rodents and dogs. Fears about this complication in humans have not been realized. A number of double blind placebo controlled trials have been published (18-21). From these studies, conducted with patients resistant to marketed anti-epileptic drugs and suffering at least from two to four seizures per month, vigabatrin emerges as an effective drug in a quarter of the patients; more than a 75 percent reduction of seizures was observed in the study period. Most patients suffered from complex partial seizures, with or without secondary generalization. Typical dosages averaged 3 grams or 50
Valproate is the drug of choice for absence seizures complicated by concomitant generalized tonic-clonic seizures. Valproate is highly effective against absence seizures (26) and decreases the generalized spike-andwave paroxysms that accompany such attacks (27). With the use of 12-hr telemetered EEGs to measure the frequency of generalized spike-and-wave discharges, valproate was compared with ethosuximide in a doubleblind, response-conditional crossover study of absence seizures in 45 patients (28). Valproate was as effective as ethosuximide. Patients who meet the diagnostic criteria for absence seizures and who do not respond to ethosuximide, should be considered for treatment with valproate. The drug should be started in relatively low doses, with gradual build-up to a therapeutic level. Valproate shares with ethosuximide a tendency to irritate the gastrointestinal tract. This tendency can usually be overcome with slowly
C. Medication choices: Generalized Tonic-Clonic Seizures The treatment of generalized tonic-clonic seizures thai occur secondary to partial seizures is similar to that of partial seizures themselves. Carbamazepine and/or phenytoin are the current drugs of choice. These drugs are especially effective when used together. Conclusive data are now available to document the effectiveness of valproate against primary generalized tonic-clonic seizures, whether these seizures occur in isolation or in combination with other generalized seizure types such as absence or myoclonia (23; 24). The use of barbiturates for the control of generalized tonic-clonic seizures is rarely necessary, considering the effectiveness and nonsedative characteristics of phenytoin, carbamazepine, and valproate. Likewise, benzodiazepines are usually ineffective in the long-term treatment of generalized tonicclonic attacks, and are rarely indicated (2).
Porter
increasing doses and considerable patience. Valproate is also effective against certain myoclonias and, as noted above, primary generalized tonic-clonic seizures. It should be recognized that the drug has a short half-life and, in the absence of a delayed-release formulation, the drug should be given frequently during the day (2).
Summary The treatment of epilepsy firstly depends upon the correct diagnosis, with emphasis on considerations of etiology, seizure type, and epilepsy syndrome. Following an appropriate diagnostic conclusion, the patient may be started on the medication matched to the seizure type. A full understanding of the pharmacology of antiepileptic drugs will enable the physician to obtain maximum benefit from the available pharmaceutical armamentarium.
References I.
2. 3.
4.
5.
6. 7.
8. 9. 10.
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Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for classification of epilepsies and epileptic syndromes. Epilepsia 1985: 26: 268-78. Porter RJ. Epilepsy - 100 Elementary Principles Second Edition. London: WB Saunders Company, 1989. Metrakos K, Metrakos JD. Genetics of convulsive disorders: II. Genetic and electroencephalographic studies in centrencephalic epilepsy. Neurology 1961 : I 1: 474-83. Delgado-Escueta AV, Ward AA, Woodbury DM. Porter RJ. New wave of research in the epilepsies. In Basic Mechanisms of the Epilepsies. In: Delgado-Escueta AV et al, eds. New York: Raven Press, 1986: 3-55. Porter, R.J. Etiology and classification of epileptic seizures. In: Robb P eds. Epilepsy Updated: Causes and Treatment. Chicago: Year Book Medical Publishers, 1980 1-10. Rasmussen T, Olszewski J, Lloyd-Smith D. Focal seizures due to chronic localized encephalitis. Neurology 1958: 8: 435-45. Taylor J. editor (1931) Selected Writings of John Hughlings Jackson, Vol 1: On Epilepsy and Epileptiform Convulsions. London: Hodder and Stoughton. Reprint 1958. New York: Basic Books. Gastaut H. Dictionary of Epilepsy. Geneva: World Health Organization. 1973: 75 pp. Penny JK. Newark, ME. The use of antiepileptic drugs Annals of Internal Medicum 1979: 90:207-218. Porter RJ, Layzer RB. Plasma albumin concentration and diphenylhydantoin binding in man. Arch Neurol 1975: 32: 298-303.
1 1. Woo E, Chan YM, Yu YL, Chan YW. Huang CY. If a well-stabilized epileptic patient has a subtherapeutic antiepileptic drug level, should the dose be increased? A randomized prospective study. Epilepsia 1988: 29: 129-39. 12. Porter RJ. Efficacy of antiepileptic drugs. In: Ward AA et al, eds. Epilepsy. New York: Raven Press, 1983: 225-37. 13. Mattson RH, Cramer JA, Collins JF et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985: 313: 145-51. 14. Mattson RH, Cramer JA, Collins JF and the VA Epilepsy Cooperative Study #264 Group. Comparison between carbamazepine and valproate for complex partial and secondarily generalized tonic-clonic seizures. Epilepsia 1991 : 42: 18. 15. Penry JK, Porter RJ. Epilepsy: Mechanisms and therapy. Med Clin North America 1979: 63: 801-12. 16. Robins MM. Aplastic anemia secondary to anticonvulsants. Am J Dis Child 1962: 104: 614-24. 17. Troupin AS, Ojemann LM, Dodrill CB. Mephenytoin: A reappraisal. Epilepsia 1976: 17: 403-14. 18. R i m e r EM, Richens A. Double-blind study of gamma-vinyl GABA in patients with refractory epilepsy. Lancet 1984: 1: 189-90 19. Gram L, Klosterkov P, Dam M. Gamma-vinyl: A double blind placebo-controlled trial in partial epilepsy. Ann Neurol 1985: 17: 262-6. 20. Tartara AR, Manni CA, Galimbert et al. Vigabatrin in the treatment of epilepsy: A double-blind, placebo-controlled study. Epilepsia 1986: 27: 717-23. 2 1. Tassinari CA, Michelucci R, Ambrosetto G et al. Double-blind study of vigabatrin in the treatment of drug-resistant epilepsy. Arch Neurol 1987: 44: 907-10. 22. Meinardi H, Porter RJ. New Anti-Epileptic Drugs. In: Froscher et al, eds. Epilepsie: Grundlagen, Klinik, Behandlung. Germany 1991. 23. Collaborative Study Group: Bourgeois B, Beaumanoir A, Blajev B et al. Monotherapy with valproate in primary generalized epilepsies. Epilepsia 1987: 28 (Suppl. 2): S8-I I . 24. Chadwick DW. Valproate monotherapy in the management of generalized and partial seizures. Epilepsia 1987: 28 (Suppl. 2): S 12-7. 25. Penry JK, Porter RJ, Dreifuss FE. Ethosuximide: Relation of plasma levels to clinical control. In: Woodbury et al, eds. Antiepileptic Drugs. New York Raven Press, 1972: 431-41. 26. Simon D, Penry JK. Sodium di-N-propylacetate (DPA) in the treatment of epilepsy: A review. Epilepsia 1975: 16: 549-73. 27. Penry JK. Porter RJ, Sato S, Reddenbough J, Dreifuss FE.Effect of sodium valproate on generalized spike-wave paroxysms in the electroencephalogram. In: Legg NJ. et al, eds. Clinical and Pharmacological Aspects of Sodium Valproate (Epilim) in the Treatment of Epilepsy. MCS Consultants: Tunbridge Wells. 1976: 158-64. 28. Sat0 S, White BG, Penry JK, Dreifuss FE, Sackellares JC, Kupferberg HJ. Valproic acid versus ethosuximide in the treatment of absence seizures. Neurology 1982: 32: 157-63.
