Pediatric Annals

MEDICAL TREATMENT OF EPILEPSY

Samuel Livingston, MD; Lydia L Pauli, MD

Abstract

1 . Livingston, S. Etiologic factors in adult convulsions. An analysis of 689 patients whose attacks began after twenty years of age. New Eng. J. Med. 254 (1956), 1211-1216.

2. Livingston, S. Convulsive Disorders in Infants and Children. S. Z. Levine, ed. In /Advances in Pediatrics, Volume X. Chicago: Year Book Publishers, 1958.

3. Livingston, S. Comprehensive Management of Epilepsy in Infancy. Childhood and Adolescence. Springfield: Charles C Thomas, 1972, 167-377, 99, 101-102.

4. Livingston, S., Torres, I., Pauli, L. L., and Rider, R. V. Petit mal epilepsy: results of a prolonged follow-up study of 117 patients. J.A.M.A. 194 (1965), 227-232.

5. Woodbury, D. M., Penry, J. K., and Schmidt, R. P., eds. Antiepileptic Drugs. New York: Raven Press, 1972.

6. Diamond, W. D., and Buchanan. R. A. A clinical study of the effect of phénobarbital on diphenylhydantoin plasma levels. J. Clin. Pharmacol. 10 (1970), 306-311.

7. Schmid, F. Osteopathien bei antiepileptischer dauerbehandlung. Fortschr. Med. 85 (1967), 381-383.

8. Kruse, R. Osteopathien bein antiepileptischer langzeittherapie vorlaufige mitteilung). Mschr. Kinderheilk. 116 (1968). 378-381.

9. Dent, C. E., Richens. A., Rowe, D. J. F., and Stamp, T. C. B. Osteomalacia with long-term anticonvulsant therapy in epilepsy. Brit. Med. J. 4 (1970), 69-72.

10. Richens, A., and Rowe. D. J. F. Disturbance of calcium metabolism by anticonvulsant drugs. Brit. Med. J. 4 (1970). 73-76.

11. DeLuca, K., and Masotti, R. E. Hypocalcemia induced by anticonvulsant drugs. Canad. Paed. Soc, 48th annual meeting, Kingston, Ontario, Canada, June 12-16, 1971, 47.

12. Genel, M., Berman, P. H., Morrow G., and Bongiovanni, A. M. Vitamin D dependency with dibasic aminoaciduria associated with anticonvulsant therapy. Pediat. Res. 6 (1972), 395.

13. Matsuo, N., Herrera, C. Y., Tashjian, A., and Fellers, F. X. Diphenylhydantoin associated rickets. Pediat. Res. 6 (1972), 400.

14. Borgstedt, A. D., Bryson, M. F., Young. L. W., and Forbes, G. B. Long-term administration of antiepileptic drugs and the development of rickets. J. Pediat. 81 (1972). 9-15.

15. Buchthal. F.. and Lennox-Buchthal. M. A. Diphenylhydantoin: relation of anticonvulsant effect to concentration in serum. D. M. Woodbury. J. K. Penry, and R. P. Schmidt, eds. In Antiepileptic Drugs. New York: Raven Press, 1972, 204-205.

16. Livingston, S. The Diagnosis and Treatment of Convulsive Disorders in Children. Springfield: Charles C Thomas. 1954, 175-176.

17. Buchanan, R. A., Kinkel, A. W., Goulet. J. R.. and Smith, T. C. The metabolism of diphenylhydantoin (Dilantin) following once daily administration. Neurology 22 (1972), 126-130.

18. Svensmark, O. and Buchthal, F. Diphenylhydantoin and phénobarbital; serum levels in children. Amer. J. Dis. Child 108 (1964), 82-87.

19. Arnold, K. and Gerber, N. The rate of decline of diphenylhydantoin in human plasma. Clin. Pharmacol. Ther. 11 (1970), 121-134.

20. Gastaut, H. and Broughton, R. Epileptic Seizures: Clinical and Electrographic Features, Diagnosis and Treatment. Springfield: Charles C Thomas, 1972. 229.

21. Holowach, J., Thurston, D. L, and O'Leary, J. Prognosis in childhood epilepsy: follow-up study of 148 cases in which therapy had been suspended after prolonged anticonvulsant control. New Eng. J. Med. 286 (1972). 169-174.

22. Gastaut, H. and Vigouroux, M. Electroclinical correlations in 500 cases of psychomotor seizures. M. Baldwin and P. Bailey, eds. In Temporal Lobe Epilepsy. Springfield: Charles C Thomas. 1958, 128.

23. Lombroso, C. T. Treatment of status epilepticus with diazepam. Neurology 16 (1966). 629634.

24. Schwalb, E. Treatment of seizures with diazepam. Letter to the editor. New Eng. J. Med. 276 (1967), 1443.

25. Prensky, A. L. and Schwab, R. S. Treatment of seizures with diazepam. Letter to the editor. New Eng. J. Med. 276 (1967), 1443.

TABLE 1

DRUGS CURRENTLY USED FOR THE CONTROL OF EPILEPTIC SEIZURES*

TABLE 2…

We have found the following ten principles very valuable in the overall management of the epileptic patient, including the administration of antiepileptic drug therapy.

1. Patient and parental cooperation is very important and can be obtained best through understanding of the disorder.

Obviously, the ideal goal is to completely control seizures or at least reduce their frequency to the extent that they do not interfere with the patient's general well-being. The physician should tell the patient and parents that with understanding, cooperation, and proper treatment, this goal can be attained in the vast majority of epileptics. The physician should also emphasize the importance of taking medication regularly and precisely as prescribed.

In many instances the physician can lessen the likelihood of a patient becoming discouraged about seizure control by informing the patient that it may take a period of time before effective therapy can be determined. The physician should explain that antiepileptic medication must be prescribed in a systematic manner; that in some patients the appropriate therapy can be ascertained after a short trial on one drug, while in others it may take longer to determine the proper treatment since several drugs may have to be prescribed before the proper therapeutic regimen is established.

It is of the utmost importance that the physician inform the patient of possible untoward reactions from certain drugs, such as morbilliform rashes or diplopia from diphenylhydantoin sodium (Dilantin) and marked drowsiness from primidone (My soline). Of course, the physician definitely should not "frighten" the patient by calling attention to the rare occurrence of serious disturbances that have occurred in association with antiepileptic drugs.

2. Regular medical care (routine follow-up visits) is one of the most important aspects of treatment.

During the first year or so of treatment, the physician should see the patient at regular intervals to regulate the dosage of medication, to examine him or her for untoward drug reactions, and to discuss socioeconomic problems, when present.

The physician should also examine the patient for signs or symptoms of a specific cause for the seizure disorder which were not apparent at the initial visit.

It is our general policy that each patient return in two to three weeks after the initial administration of a drug, primarily to determine tolerance to the prescribed dosage. The frequency of subsequent return visits depends on the magnitude of the patient's problems and the type of antiepileptic medication used. We see every patient, including seizure-free patients, at least once every six months during the entire course of anticonvulsant therapy.

It is of particular importance to check all patients very closely for signs and symptoms of an intracranial neoplasm for at least two years following the initial attack. This is especially important for patients whose seizures commenced during late adolescence and early adulthood since seizures in this age group are more likely to be a manifestation of a brain tumor than in the younger child. The reader may be interested in a paper published from our clinic in 19561 that describes the etiologic factors in a large group of patients whose seizures began after 20 years of age.

3. Laboratory examinations should be carried out during the course of therapy with certain drugs.

Periodic blood, renal, and liver function tests should be performed on all patients receiving drugs known to have adversely affected the hematopoietic, renal, or hepatic system, such as mephenytoin (Mesantoin), primidone (Mysoline), paramethadione (Paradione), phenacemide (Phenurone), trimethadione (Tridione), and ethosuximide (Zarontin). These examinations should be done before such drugs are started and repeated during the entire course of therapy. In our clinic, we repeat these tests monthly during the first year of therapy and then at two- to three-month intervals.

The parents or the patient should be instructed to report promptly any sign or symptom not present before the drug was prescribed. They should be specifically directed to notify the physician immediately of signs or symptoms of possible damage to the hematopoietic system (e.g., easy bruising. petechiae, ecchymosis, epistaxis), to the renal system (e.g., hematuria, edema), or to the hepatic system (e.g. jaundice, dark urine, clay-colored stools).

4. Treatment should be instituted as soon as a diagnosis has been established.

Early treatment is important because, in our experience, the degree of successful control of seizures is in most cases related to the duration of the epilepsy: the longer the duration, the less likely it is that a satisfactory result will be obtained. It is also im- ' portant to institute measures to prevent a recurrence of seizures, not only because of the attacks, but because of injuries, emotional disorders, and hardships, such as loss of employment, sometimes associated with them.

The problem of whether or not the physician should assign a diagnosis of epilepsy to a person on the basis of one convulsion of undetermined etiology remains controversial. In 1958, we2 published the results of an investigation of 200 such children between the ages of three and six years who were seen at our clinic at the time of their first convulsion. They were divided at random into two equal groups. One group was given conventional daily dosages of phenobarbital and the other received no medication. They were followed either by regular visits to our epilepsy clinic, by followup visits to their homes, or by a follow-up questionnaire.

Of the 100 patients not given medication, 91 had a recurrence of at least one convulsion within the next four years, five had no recurrence, and four were lost to follow-up. In the group given phenobarbital daily, only 19 had a recurrence of seizures during the same interval; 79 remained free of seizures, and two were lost to follow-up.

We assign a diagnosis of epilepsy to children who suffer an unquestionable convulsion of undetermined etiology, and we continue with this diagnosis unless the passage of time proves the seizure was a manifestation of some other disorder. Our general policy is that daily antiepileptic medication be prescribed to these patients in essentially the same manner as to patients with recurrent epileptic convulsions, except in infants and young children whose first seizure was a simple febrile convulsion.

We do not make a positive diagnosis of grand mal epilepsy, for example, at the time of the first "attack" in children in whom this episode is not clearly described by the observer as a true convulsion, unless the electroencephalogram reveals typical grand mal abnormalities.

5. The selection of the drug of first choice should be based on the toxicity of the drug and the type of seizure (Table 1).

Space does not permit a presentation of the numerous untoward reactions reported in association with the use of antiepileptic drugs or measures for their prevention, detection, and management. The reader is referred to a recent publication for such detailed information.3

It is generally agreed that phenobarbital, primidone (Mysoline), and diphenylhydantoin sodium (Dilantin) possess significant anticonvulsant properties and are of considerable value in controlling major motor (grand mal) seizures. Our drug of first choice for the treatment of major motor epilepsy is phénobarbital because toxic reactions are singularly few. When properly given, the only major side effects are drowsiness (generally doserelated) and hyperactivity simulating the hyperkinetic behavioral syndrome (not dose-related and primarily in young children). These reactions are not serious and are reversible.

Diphenylhydantoin sodium (Dilantin) is our third choice (Table 1) because the number of adverse reactions observed with it is considerable. Some are very frequent and disturbing, such as gingival hyperplasia. Some are irreversible, such as hypertrichosis. Others may constitute an actual threat to the patient's life and have, on occasion, terminated fatally, such as Stevens-Johnson syndrome.

It is true that diphenylhydantoin is used by many physicians as the drug of first choice for grand mal epilepsy. However, in addition to its numerous toxic effects, there are no reports in the literature of controlled studies proving that it is superior to phenobarbital in the treatment of major motor epilepsy.

In our clinic, the use of diphenylhydantoin for the control of epileptic seizures is specifically contraindicated in three types of patients- infants, females (particularly adolescents), and children receiving orthodontic treatment.

Infants. The clinical recognition of diphenylhydantoin intoxication due to overdosage is frequently exceedingly difficult in infants. Ataxia and diplopia are common signs or symptoms. It is obvious that, for example, a 16-month-old child with grand mal epilepsy who is receiving the drug would be unable to describe diplopia to the physician. Also, if this child were just beginning to walk and presented unsteadiness of gait, one may have considerable difficulty in determining on clinical grounds whether the unsteadiness was a manifestation of overdosage or merely a result of the child's not yet having mastered the walking technique.

The blood of infants in whom the use of this drug is mandatory should be monitored at regular intervals with drug serum concentration determinations (q.v.).

Females, particularly adolescents. It is needless to state that gingival hyperplasia and hypertrichosis of any degree are cosmetically unattractive in any person.

We have been called upon many times to change the antiepileptic regimen in persons who have been rendered seizure-free but in whom the drug produced marked gingival hyperplasia. Most of these patients, primarily adolescent females, stated that they would rather have seizures than suffer the embarrassment and emotional distress caused by the "swollen gums." In addition, pronounced hyperplasia frequently causes displacement of the teeth, which is also esthetically objectionable and may necessitate extensive orthodontic and periodontic procedures.

When hypertrichosis is marked and occurs on exposed surfaces, it presents a very serious cosmetic problem, particularly in females. The abnormal growth of hair persists to some degree in all patients after discontinuation of the drug.

Children receiving orthodontic treatment. Many patients receiving diphenylhydantoin while undergoing orthodontic therapy have been referred to our clinic for regulation of their antiepileptic regimens. In most, the gingival hyperplasia was so marked that it extended over the orthodontic appliances. These patients complained of a constant oral malodor and also of almost continually bleeding gums. Obviously, it was virtually impossible for them to keep their mouths free from residual food particles and other irritants that lodged between the hyperplastic tissues and the braces. The braces themselves probably acted as an additional local irritant.

It should be noted that some drugs are effective in controlling certain types of epileptic seizures while often increasing the frequency of other types. For example, diphenylhydantoin (Dilantin) is of value in the control of psychomotor seizures in some patients, but often increases the frequency of petit mal spells. Similarly, trimethadione (Tridione) is efficacious for controlling petit mal attacks, but sometimes precipitates major seizures or increases the frequency of preexisting major motor seizures.

Combined therapy for petit mal epilepsy. It is generally known that many patients with petit mal epilepsy subsequently develop other types of epileptic seizures, particularly grand mal attacks.

On the basis of prolonged followup study of 117 patients with petit mal epilepsy,4 we use the following regimen (combined therapy).

Treatment should be started with the conventional dosage of phenobarbital (Table 2). It should be noted that phenobarbital is prescribed as a prophylactic measure against development of grand mal seizures, not for controlling petit mal spells. Treatment should be continued with phenobarbital alone for approximately one month to determine tolerance to the prescribed dosage and to ascertain whether it adversely affects the frequency of petit mal spells.

After one month of phenobarbital therapy, we perform a blood level determination to ensure that the phenobarbital blood concentration falls within the range that we have found to be of therapeutic value in most patients (q.v.). If the blood level determination reveals subtherapeutic levels, we increase the daily dosage until the blood concentration reaches "clinically effective" levels.

If the patient does not tolerate this drug satisfactorily, another major motor anticonvulsant, such as primidone (Mysoline) or mephobarbital (Mebaral), should be prescribed, beginning with the conventional dosage (Table 2). We have not achieved sufficient experience with primidone or mephobarbital blood concentrations to define "average" therapeutic biood level ranges for either medication. Since diphenylhydantoin (Dilantin) often increases the frequency of petit mal spells, we give it as the major motor anticonvulsant only as a last choice.

It has been our experience that petit mal spells are occasionally controlled with phenobarbital, and, obviously, in such instances this drug should be continued as the sole therapeutic agent.

Table

TABLE 1DRUGS CURRENTLY USED FOR THE CONTROL OF EPILEPTIC SEIZURES*

TABLE 1

DRUGS CURRENTLY USED FOR THE CONTROL OF EPILEPTIC SEIZURES*

After the patient's tolerance to the major motor anticonvulsant has been determined, a specific antipetit mal agent should be added to the therapeutic regimen. Our antipetit mal drugs of choice are ethosuximide (Zarontin) and trimethadione (Tridione), respectively. If the petit mal spells do not respond satisfactorily to these drugs, the physician has no alternative but to prescribe less effective antipetit mal medications (Table 1).

The combined medications should be continued in full dosage until the patient has been free of clinical petit mal spells for at least four years and an eiectroencephalographic examination (performed after this period of freedom from spells) does not reveal the classic eiectroencephalographic discharge of petit mal epilepsy.

It is important to note that some patients who have been rendered free of petit mal spells continue to show eiectroencephalographic abnormalities of various types. It has been our experience, however, that there is a direct relation between the control of clinical spells and the disappearance of the typical diffuse, bilaterally synchronous spike and wave complex of petit mal epilepsy.

We withdraw the antipetit mal drug gradually over an interval of 6 to 12 months, depending upon the dosage. We continue the full daily dosage of prophylactic major motor anticonvulsant until the patient reaches 14 years of age because the peak incidence of development of major convulsions in our patients is from 10 through 13 years of age. We gradually withdraw the major motor anticonvulsant in one year in patients who have not developed major motor seizures by the time they reach 14 years of age.

6. The dosage of anticonvulsant medication varies from patient to patient.

The dosages of the various antiepileptic drugs used in our clinic are presented in Table 2.

The proper dosage of antiepileptic medication is that which controls seizures without producing untoward reactions that interfere with the patient's well-being. Obviously, the ideal goal is to attain complete control of seizures. However, the dosage necessary for complete control of seizures may, in some patients, produce unpleasant reactions, such as drowsiness, which are more of a handicap than the seizures themselves. Some patients may be better off leading a normal life between occasional seizures than living seizure-free in a perpetual state of drug-induced drowsiness and confusion. In many instances, reactions such as drowsiness can be alleviated or mitigated by the daily doses of stimulating drugs such as methamphetamine HCl (Desoxyn), dextroamphetamine sulfate (Dexedrine), or methylphenidate HCl (Ritalin).

Although clinical response is the most important criterion in titrating the dosage of anticonvulsant medication, we have found blood drug level determinations very helpful in managing most cases and of inestimable value in some patients, particularly those who do not respond to average or maximal doses or who present signs of toxicity while receiving small or conventional dosages of antiepileptic agents.

We have performed thousands of phenobarbital and diphenylhydantoin blood level determinations during the past 12 years. Our findings indicate that there is a good relationship between the blood concentration and signs of intoxication, but that the correlation of the blood level to the drug dosage and seizure control is inconsistent, particularly with diphenylhydantoin. Our investigations reveal that the usual therapeutic and tolerable blood levels of phenobarbital and diphenylhydantoin are, respectively, 10 to 30 mcg./ml. (1 to 3 mg.%), and 10 to 25 mcg./ml. (1 to 2.5 mg.%).

We have also observed a more consistent relationship between the blood concentration and signs of intoxication in patients taking diphenylhydantoin than in those receiving phenobarbital. Our studies of diphenylhydantoin blood levels have demonstrated that most patients can tolerate concentrations below 25 mcg./ml. However, in some cases, levels of 25 mcg./ml. are associated with nystagmus, ataxia, and diplopia; as the level exceeds 30 meg. /ml., drowsiness and lethargy are encountered; extreme lethargy and sometimes comatose states are observed with levels above 50 meg. /ml.

We have determined that generally a phenobarbital blood level not exceeding 30 meg. /ml. is unassociated with toxic reactions; when the level approaches 50 meg. /ml., the patient frequently becomes drowsy; levels above 70 meg. /ml. are associated with marked drowsiness and in some instances with a comatose state.

The following enumeration includes only those indications for performance of blood drug level determinations that we have found to be both important and practical:

1. To establish whether or not a patient is taking medication as prescribed

2. To more rapidly establish the optimal dosage of drugs that do not consistently yield a predictable serum concentration in relation to a specific mg./kg. dosage

3. To make precise adjustments in the dosage schedule of patients who manifest evidence of intoxication while receiving small or conventional dosages of a drug

4. To determine the offending agent in a patient on a multiple drug program who presents evidence of intoxication and to determine if the failure of a multiple drug program is due to drug interaction

5. To ensure the maintenance of theoretically adequate blood concentrations in patients receiving medication for prophylactic purposes; e.g., combined therapy for petit mal epilepsy

6. To investigate the possibility of drug toxicity in a patient who displays symptoms which may also be manifestations of another disorder; e.g., a neurodegenerative disease in a patient receiving diphenylhydantoin

7. To investigate the feasibility of once daily administration of drugs with long plasma half-lives to patients in whom a daily divided dosage schedule is undesirable or unacceptable.

Comprehensive discussions of anticonvulsant drug blood level determinations are presented in a recent textbook/' to which the reader is referred for additional data.

7. Treatment should be started with one drug. Other drugs should be prescribed, if necessary, only after it has been determined that the maximal tolerated dosage of the initial drug failed to produce a satisfactory clinical response.

It was the practice in the past (and still is to a great extent today) to start treatment of an epileptic patient with small dosages of two or three antiepileptic drugs. Many patients with major motor epilepsy have been referred to our clinic whose therapy was started with therapeutically inappropriate dosages of phenobarbital and diphenylhydantoin. Others received, in addition to these two drugs, inappropriate dosages of primidone (Mysoline).

We do not believe that this is a scientific method of administration of antiepileptic drugs, and moreover, therapy prescribed in this manner presents many problems in patients who are not, by chance, controlled of their seizures.

We offer four objections to this method.

1. When two or more drugs are initially prescribed and the patient has some type of untoward reaction, it is obvious that the physician may have considerable difficulty in determining on clinical grounds which of the drugs is responsible.

2. In patients who continue to have seizures, the physician has no alternative but to increase the dosage of all the drugs initially prescribed or "to toss a coin" to decide which drug should be increased.

Table

TABLE 2AVERAGE DOSAGES OF ANTIEPILEPTIC DRUGS'

TABLE 2

AVERAGE DOSAGES OF ANTIEPILEPTIC DRUGS'

Table

TABLE 2AVERAGE DOSAGES OF ANTIEPILEPTIC DRUGS'

TABLE 2

AVERAGE DOSAGES OF ANTIEPILEPTIC DRUGS'

3. Since there are only a few "really good" drugs currently available for the control of seizures and since the effective therapeutic dosage of each drug varies from patient to patient, effective antiepileptic drugs may be run out of before any one drug has been given a satisfactory trial.

4. Another strong argument against simultaneous administration of two or three drugs to initiate treatment for medical disorders, including epilepsy, which only recently has become apparent, is the abnormal metabolism (acceleration or impairment) of certain medications caused by drug interactions.

We recommend the following method of administration of antiepileptic medication.

In patients with relatively infrequent seizures (monthly or less often), the conventional starting dosage of the appropriate drug should be prescribed initially (Table 2). Dosage should be increased gradually, if necessary, until a satisfactory control of seizures is attained or until the limit of tolerance for the drug has been reached. In some cases, it may be necessary to prescribe a second drug, but only after it has been determined that the maximal tolerated dosage of the first drug failed to produce a satisfactory clinical response.

If the maximal tolerated dosage of the first drug fails to satisfactorily control the seizures, but does reduce their frequency or severity to some extent, it should be continued at the same dosage and a second drug should be added. Dosage of the second drug should be increased as needed to tolerance.

If the maximal tolerated dosage of the first drug fails to help the patient in any manner, it should be gradually withdrawn simultaneously with the administration of a second drug. During withdrawal of the first drug and addition of the second, if a satisfactory combination of dosages of both drugs is found, the patient should continue with both drugs.

Occasionally, it may be necessary to prescribe the maximal tolerated dosage of more than two drugs in order to obtain good control of seizures.

For patients with relatively frequent (daily, weekly) seizures, the average maximum dosage of the appropriate drug should be prescribed initially (Table 2). This dosage should be decreased or increased, if necessary, depending upon the patient's tolerance and occurrence of seizures. Other drugs should be added to the therapeutic regimen, if necessary, as previously described.

Diphenylhydantoin sodium (Dilantin) is the antiepileptic agent most frequently involved in the reported cases of drug interaction in humans, most of which describe an impairment of metabolism presumably due to inhibition of hepatic microsomal enzyme systems. Conversely, evidence has been presented that phenobarbital, a potent inducer of liver microsomal activity, increases the rate of metabolism of diphenylhydantoin and diminishes its blood concentration and pharmacologie effects in both experimental animals and humans.

However, the concensus at present, including our own, is in agreement with Diamond and Buchanan,G whose investigation failed to demonstrate any stimulation of diphenylhydantoin metabolism by phenobarbital. We have not encountered acceleration of diphenylhydantoin metabolism with resultant pejoration of seizure control in any of the thousands of our patients who have taken the drugs simultaneously.

It should be noted, however, that some patients have presented an elevated diphenylhydantoin serum level in association with the use of phenobarbital. Carbamazepine (Tegretol) has been reported to cause a decline in diphenylhydantoin blood concentration, but our observations in a large number of patients receiving these drugs concomitantly do not reveal an adverse effect on seizure control.

The following drugs have been reported to inhibit diphenylhydantoin metabolism with resultant intoxication or elevation of plasma levels; their usage should be avoided, if possible, or scrupulously supervised in patients receiving diphenylhydantoin: disulfiram (Antabuse), chloramphenicol (Chloromycetin), bishydroxycoumarin (Dicumarol), and isoniazid, alone or in combination with paraaminosalicylic acid. In addition, phenylbutazone (Butazolidin), prochlorperazine (Compazine), propoxyphene HCl (Darvon), (Fluothane), chlordiazepoxide HCl (Librium), methylphenidate HCI (Ritalin), (Sulfabid), chlorpromazine (Thorazine), diazepam (Valium),andethosuximide(Zarontin) have also been reported to impair diphenylhydantoin metabolism, but the evidence for drug interaction resulting in an adverse clinical effect is generally lacking or so meager as to preclude the formation of definite conclusions. We have administered Compazine, Librium, Ritalin, Thorazine, Valium, and Zarontin to hundreds of patients in conjunction with diphenylhydantoin therapy and have not encountered any clinical proof of altered diphenylhydantoin metabolism.

Nevertheless, the physician should bear in mind that diphenylhydantoin intoxication may result from the concurrent use of any of the previously cited drugs.

It has also been reported that diphenylhydantoin can stimulate the metabolism of endogenously produced steroids; e.g., cortisol, and those administered exogenously; e.g., dexamethasone, vitamin D, in humans. The development of osteomalacia, rickets, and hypocalcemia in epileptic patients has been attributed to the acceleration of vitamin D metabolism by anticonvulsant drugs, notably diphenylhydantoin, and is currently a topic of great interest and controversy. While it is an attractive hypothesis, we do not believe that liver enzyme induction by anticonvulsant drugs, with a resultant relative lack of vitamin D activity, has been unequivocally proved in any of the published reports.7"14 Many other factors may have played a role in the development of the rachitic skeletal and chemical changes in the reported cases.

We have not encountered chemical or clinical evidence of rickets or osteomalacia in any of the 22,000 patients seen and followed in our clinic since 1936, most of whom were continued on an antiepileptic regimen consisting of diphenylhydantoin, phenobarbital, or primidone, taken singly or in combination in high doses for prolonged periods, except for several cases of vitamin D-deficiency rickets. Initial evaluation at our clinic has always included a skull roentgenogram series, a fasting glucose determination, S.U.N., calcium and phosphorus levels, and liver function tests. In view of our observations and findings over a period of many years, we are reluctant to accept at this time the evidence so far presented in the literature that anticonvulsant drug therapy plays a significant role in the causation of the chemical or skeletal changes associated with rickets.

Since hundreds of thousands, and probably millions, of epileptic patients have been treated throughout the world for prolonged periods with an antiepileptic regimen consisting of diphenylhydantoin, phenobarbital, and primidone in various combinations, it is incredulous that no case of rachitic bone and chemical changes, to our knowledge, had been described to that by Schmid7 in 1967. We believe that all one can opine is that rickets occurred coincidentally in patients receiving anticonvulsant drug therapy.

The use of a multiple anticonvulsant drug program rather than a single antiepileptic agent on the basis of synergism has been recently challenged by the Buchthals,15 who state: "There is a venerable clinical belief that a combination of anticonvulsant drugs is more apt to control seizures than one, and there is even a school which advocates giving a number of drugs in small doses, in the belief that toxic effects will be avoided and that the drugs potentiate each other in anticonvulsant effect. There is no decisive proof that this is so, documented by the serum concentration." We are in complete agreement with the Buchthals' opinion, and have for many, many years advocated the use of a single drug rather than a combination of anticonvulsant agents to initiate treatment of epileptic seizures.1"

8. Medication should be taken daily in divided dosages that do not interfere with the patient's routine activities - with meals, upon returning home from school, or at bed' time.

Generally, we recommend that medication be given in two to four equal parts throughout the day. However, in treating certain types of epileptic seizures, such as those occurring in association with sleep or the menses, it is frequently of value to give medication differently. Our methods of prescribing antiepileptic drugs in such instances are described in a previous publication.3

Several investigators, notably Buchanan et al.,17 have advocated giving the total daily dosage in a single dose, preferably at bedtime. We are not convinced that this is superior to or even as effective as divided doses, particularly in children. Moreover, Svensmark and Buchthal18 have demonstrated that the maintenance of constant serum concentrations of phénobarbital and diphenylhydantoin in children requires divided daily doses. In addition, there is considerable variation in the rate of diphenylhydantoin metabolism, as evidenced by the wide halflife range (7 to 42 hours) reported by Arnold and Gerber.19

Some of our patients who received their total daily dosage at bedtime were so drowsy and sleepy that they were unable to perform their routine activities for the greater part of the following morning. Others either forgot or neglected to take their medication at bedtime and experienced a recurrence of seizures the following afternoon or evening. These patients had received no antiepileptic medication for almost 48 hours.

9. Medication should be taken for a prolonged period of time.

By and large, it has been our experience that the longer anticonvulsant medication is continued in epileptic patients, the less likely it is that they will experience a recurrence of seizures after therapy has been terminated.

It is our general policy to continue effective and well-tolerated antiepileptic medication in all patients in full dosage for at least four years after the last seizure plus one or two years during which medication is gradually withdrawn (see principle 10).

We do make exceptions, however, some of which are as follows:

Shorter periods of therapy. It is needless to state that a drug should be discontinued immediately in patients in whom there is even suggestive evidence that it is causing serious untoward reactions. The physician also should consider withdrawal of medication sooner than the four-year period in patients in whom there is an indication that the medication is causing a reaction, regardless of its severity, such as drowsiness, which interferes with the performance of the patient's general duties (scholastic, occupational, etc.) and in patients in whom there is evidence that the taking of the medication per se is causing emotional difficulties. Many patients, particularly teenagers, have told us that they "just don't want to be bothered taking medicine every day, that the taking of medication makes them feel different from their friends," and so forth,

Longer than four years. The onset of puberty, particularly in females, is a time when epilepsy frequently makes its initial appearance and when many controlled epileptics experience a recurrence of seizures. If the four-year period of freedom from seizures should coincide with the usual age of onset of puberty, the medication should be continued in full dosage throughout the adolescent period.

We also generally advise that effective antiepileptic medication be continued longer than four years in adolescents and young adults who drive an automobile or are in the process of applying for a driver's license.

10. Medication should be discontinued very gradually.

A sudden withdrawal of anticonvulsant medication, particularly phénobarbital and diphenylhydantoin, is a frequent cause of recurrence of seizures or grand mal status. Thus, dosages of anticonvulsant medication should be reduced very gradually in a patient rendered seizure-free.

The period necessary for complete withdrawal is governed by the severity of the patient's previous seizure state and by dosage. In patients who had a "mild form of epilepsy" controlled by an average dosage, we generally withdraw the medication by gradual reduction of dosage over one to two years. In patients who had severe epilepsy and were taking large amounts of medication, we extend the period of withdrawal to three or four years. It should be noted that we generally withdraw antipetit mal drugs over a period of 6 to 12 months, depending upon the amount of medication the patient had been taking.

If seizures recur during or after the period of withdrawal, the patient should be restarted immediately on the same dosage that previously controlled the seizures and the physician should consider continuing this medication in full dosage for the rest of the patient's life.

It has been our experience, by and large, that the EEG has but little to offer relative to prognostic implications. In our clinic we rarely, if ever, use information from an EEG examination as a complete indicator of a patient's progress, except in petit mal epilepsy, in which there is almost invariably a direct relationship between the disappearance of the classic electrical discharge and the control of clinical spells, and in myoclonic epilepsy of infancy, in which we have noted absence of the typical hypsarrhythmic pattern concurrent with cessation of attacks in many patients.

Over the past 30 years, we have performed serial EEG examinations on thousands of epileptic patients, and exclusive of those with petit mal spells and some with infantile myoclonic attacks, we have not observed a direct relation between normalization of the EEG and clinical improvement in a significantly large number of our patients. In many, the EEG became more abnormal even though the patient experienced fewer or no seizures. In others, the EEG continued to reveal abnormalities despite the fact that the patient had remained free of seizures for a period of years. It should be noted that in many children the EEG tends to revert to normal during adolescence, regardless of their clinical progress.

We have found that the results of EEG examinations are not predictive of prognosis subsequent to termination of drug therapy and recommend that the presence of specific EEG abnormalities usually need not interdict discontinuance of a drug withdrawal program. Corroborative expressions have recently been published by Gastaut and Broughton-" and Holowach and associates.-1

TREATMENT OF ACUTE PROLONGED SEIZURE ACTIVITY OFEP(LEPTICORIGIN

A universally accepted definition of status epilepticus in the medical literature is lacking, and the interpretation of this term varies from physician to physician and from clinic to clinic. Many physicians use this designation to refer to a series of recurrent major seizures. Others, however, include all types of prolonged seizure activity. Obviously, such nosologie inconsistency has led to pronounced differences of opinion regarding the etiologic, therapeutic, and prognostic aspects of this epileptic disorder.

Definitions. In our clinic, we use the term "prolonged seizure activity" to designate epileptic manifestations of long duration as follows:

1. Status

a. Major motor (grand mal) status

b. Petit mal status

c. Myoclonic status (myoclonus)

2. Prolonged major motor (grand mal) seizure

3. Prolonged psycHomotor (temporal lobe) seizure.

Major motor (grand mal) status. This term refers to a state of recurrent major motor seizures between which the patient does not completely regain consciousness. It may continue for three or four days or even longer.

Petit mal status. This term refers to a state of recurring, almost continuous petit mal spells, during which the patient frequently appears disoriented and confused, but is usually able to function to the extent that he or she can walk about and be given medication and nourishment by mouth.

Myoclonic status (myoclonus). This term refers to a state of recurring, almost continuous, episodes of myoclonic attacks. It is commonly observed in patients with cerebral degenerative diseases; e.g., amaurotic familial idiocy of Tay-Sachs (Hpidoses), encephalitis periaxialis diffusa of Schilder, subacute inclusion body encephalitis of Dawson (subacute sclerosing panencephalitis), and Unverricht-Lundborg progressive familial myoclonus epilepsy.

Patients with myoclonic epilepsy frequently have numerous seizures daily, some as many as 100 or so a day. In some instances, these myoclonic attacks recur in clusters (series) lasting for one or two minutes. However, we have only rarely encountered true myoclonus in patients with myoclonic epilepsy.

Prolonged major motor (grand mal) seizure. This occurs in association with diseases of the brain, such as meningitis and encephalitis, and also in epilepsy. A prolonged major motor convulsion refers to a seizure in which the active stages, generally the clonic aspects, are of long duration. The active phases of a prolonged seizure are almost always followed by a postconvulsive state of much longer duration than in patients with major seizures of average duration (several minutes or so).

Prolonged grand mal convulsions are usually generalized; however, local prolonged seizures are occasionally seen. This latter is referred to in the older medical literature as epilepsia partialis continua.

Our criterion in distinguishing between a prolonged major seizure, which may last three to four hours or even longer, and major motor status epilepticus, is that in the former condition the patient does not experience a recurrence of the tonic or clonic aspects after the termination of the seizure.

Prolonged psychomotor (temporal lobe) seizure. Generally, psychomotor seizures are of relatively short duration. However, we have encountered some patients with psychomotor epilepsy whose attacks persisted for hours. There are also reports of patients who suffered with attacks of amnesia, thought to be manifestations of psychomotor epilepsy, that lasted from several to as long as 30 days.22

ANTICONVULSANT THERAPY FOR PROLONGED MAJOR SEIZURE AND STATUS

When the physician is confronted with a patient suffering with a prolonged major seizure or major motor status of epileptic origin, he or she should direct treatment toward two goals: the administration of anticonvulsant therapy to terminate the seizure and the general care of the patient. If the patient has been treated earlier, the physician should consider the nature and dosage of the previous therapy so that unduly large dosages of the same medication or of drugs of similar chemical structure are not prescribed.

When a physician is called upon to give stat. therapy to a child in an active convulsion, the past history may supply pertinent information about the type of therapy needed. Where there is a history of convulsive episodes, it is reasonable for the physician to assume that the current seizure will follow the same pattern as previous ones. On the other hand, in patients in whom there is no history of seizures, it is obvious that it is impossible to tell whether the seizure is more likely one of a prolonged convulsion or the beginning of major motor status. In such instances, the seizure state should be treated as a prolonged convulsion.

For a patient with major motor (grand mal) status, but who is in an unconscious interseizure state, we emphasize that although the patient has experienced seizures just previously, the physician should administer general care and not antiepileptic drugs at this time.

Many antiepileptic drugs and other drugs, chemicals, and therapeutic regimens have been and are still being used to control prolonged seizure activity. Diphenylhydantoin, for example, is still widely used in treating major motor status epilepticus. We have given it parenterally to many of our patients with acute seizure disturbances and found it to be essentially ineffective. The following presentation is limited to our current methods and drugs used for the various types of prolonged seizure activity.

Prolonged major motor (grand mal) seizure. We give diazepam (Valium) intravenously slowly over a period of two minutes in a dosage not exceeding 10 mg. If the convulsion does not stop within five minutes, we give paraldehyde by intramuscular injection in a dosage of 1 ml. per year of age, but not exceeding 5 ml., regardless of age.

If the convulsion continues, the intravenous diazepam injection should be repeated 20 to 30 minutes after the administration of paraldehyde, and if the convulsion is not terminated within five minutes, the intramuscular injection of paraldehyde should be repeated.

If the convulsion persists despite the administration of diazepam and paraldehyde, intravenous barbiturates, such as sodium amobarbital (Amytal Sodium), may be given 30 minutes after the second injection of paraldehyde. If the convulsion still continues, the administration of sodium thiopental (Pentothal Sodium) or ether by an anesthesiologist should be considered.

Most seizures can be terminated almost immediately by intravenous injection of the quicker-acting barbiturates. We prefer, however, to initiate treatment with diazepam and paraldehyde, since the barbiturates, particularly the quicker-acting ones, when given intravenously, sometimes cause acute respiratory depression. The quicker-acting barbiturates should be given intravenously only under hospital conditions where oxygen therapy and other means of resuscitation are readily available.

Major motor (grand mal) status. This is generally referred to in the literature as status epilepticus. It has been our experience that major motor status usually persists for a prolonged period of time, seldom less than 24 hours and many times for three or four days or even longer. We have used essentially all the therapeutic agents which have been and still are recommended for the control of grand mal status and, by and large, have found most of them not to be spectacularly effective.

The principal aspect of treatment is the general care of the patient, since if this condition persists, the patient frequently sinks deeper and deeper into a coma and becomes dehydrated and exhausted. Death may ensue.

Most patients recover; however, there is no doubt that death is due, in some instances, to a depression of the central nervous system caused by the cumulative effect of overtreatment (frequent injections of large dosages of depressant drugs, particularly the long-acting barbiturates). Lombroso23 has expressed the opinion that many deaths from status epilepticus are due to overtreatment.

Initial treatment depends upon the state of the patient. If in a comatose state, the patient should be treated symptomatically, but definitely should not be given anticonvulsant therapy.

If the patient had been treated previously with large dosages of barbiturates or hydantoinates, stat blood level determinations of these drugs should be obtained for two reasons: to ascertain whether the patient's comatose state is possibly related to overtreatment with these medications and because it is important to know the drug blood level in case either is used to control recurrence of seizures.

If the patient is seen during the convulsive phase of grand mal status, we give diazepam intravenously slowly over a period of two minutes in a dose not exceeding 10 mg., immediately followed by the subcutaneous injection of phénobarbital in a dose of 65 mg. per year of age, but not exceeding a total dose of 325 mg,, regardless of age. Phénobarbital is not given to control the convulsive reaction in progress, but as a prophylaxis against the occurrence of subsequent active seizure phases of the grand mal status episode.

Intravenous diazepam may be repeated in 20 to 30 minutes, if necessary. If the convulsions do not stop within five minutes after the second injection of diazepam, we then administer paraldehyde intramuscularly in a dose of 1 ml. per year of age, but not exceeding a total dose of 5 ml., regardless of age. If the seizures are not controlled, the same dose of paraldehyde may be repeated, but not sooner than one hour.

Beginning six hours after the initial subcutaneous injection of phénobarbital, we prescribe the daily maintenance doses of phénobarbital recommended in Table 2. The medication should be given by mouth, if possible; otherwise, it should be given by the subcutaneous route. We perform daily blood barbiturate levels until the patient has completely recovered from the attack of status to make sure that toxic levels are not achieved.

Mention has been made in the literature of a possible synergistic action of diazepam and barbiturates. ~4' 25 We have given diazepam and phénobarbital concomitantly to many children and have not encountered evidence of a synergistic relationship.

Petit mal status and prolonged psychomotor seizure. These forms of prolonged seizure activity are, in our experience, generally refractory to antiepileptic medication. Both are usually self-limited. It is important that these patients be kept under close surveillance to prevent them from performing harmful acts or injuring themselves during the attacks.

Myoclonic status (myoclonus). Myoclonic status, as stated previously, occurs primarily in cerebral degenerative diseases. It is generally refractory to anticonvulsant therapy.

We have found diazepam given intravenously slowly over a period of two minutes in a dose not exceeding 10 mg. to be of some value in some patients with myoclonus. This dose may be repeated in 20 to 30 minutes, if necessary. The underlying cerebral pathology in patients with myoclonus, however, is such that in most patients the myoclonic attacks become progressively more severe and of longer duration as the basic disease worsens.

GENERAL CARE DURING PROLONGED SEIZURE ACTIVITY

This aspect of treatment is exceedingly important and is frequently neglected. The patient should be allowed to remain where the seizure occurred, if possible, until the active phase has subsided. The patient should be placed in a position in which he or she cannot hurt himself or herself by knocking the body against hard objects. Tight clothing, especially around the neck, should be loosened or removed.

It is exceedingly important that the patency of the air passages be maintained. This may be accomplished by suction or endotracheal intubation. If anoxia becomes apparent, as often happens in greatly prolonged or frequently repeated convulsions, oxygen should be given.

If the seizure occurs while the patient is in bed, he or she should be observed to prevent falls. Such falls can also be prevented by placing protective guardrails or boards on the sides of the bed. All pillows should be removed from the bed. There are reports of patients who presumably died of suffocation caused by the head being buried in a soft pillow or mattress.

If possible, the patient should be kept on his or her side so that mucus and saliva will flow more freely from the mouth. Since patients are unable to swallow during convulsive episodes, mucus or saliva may flow down into the lungs and cause respiratory distress. Therefore, the patient should not be placed or be permitted to lie flat on his or her back for any length of time. Also, vomiting sometimes occurs during a seizure and if the patient is on his or her side, the vomitus is more likely to be expelled from the mouth than flow back into the lungs. Occasionally food or vomitus may so choke the air passages that suction becomes necessary.

We emphasize that, in most instances, placing an object between the teeth of a person having a seizure is unnecessary and can sometimes do more harm than good. Nevertheless, this procedure should be carried out in patients who bite their tongue or cheeks. Any firm, blunt, nondamaging object of the right size and not too hard, such as a padded tongue depressor, a folded leather belt, a leather glove, or a Resusitube Airway can be inserted between the patient's teeth. Extreme care should be exercised when any object is inserted into the mouth of a patient with carious teeth because such teeth are easily broken and can cause respiratory difficulties if aspirated.

As with any other unconscious patient, it is necessary to maintain fluid intake. Catheterization may be necessary if the patient does not void spontaneously. Hyperthermia, if present, should be dealt with appropriately.

BIBLIOGRAPHY

1 . Livingston, S. Etiologic factors in adult convulsions. An analysis of 689 patients whose attacks began after twenty years of age. New Eng. J. Med. 254 (1956), 1211-1216.

2. Livingston, S. Convulsive Disorders in Infants and Children. S. Z. Levine, ed. In /Advances in Pediatrics, Volume X. Chicago: Year Book Publishers, 1958.

3. Livingston, S. Comprehensive Management of Epilepsy in Infancy. Childhood and Adolescence. Springfield: Charles C Thomas, 1972, 167-377, 99, 101-102.

4. Livingston, S., Torres, I., Pauli, L. L., and Rider, R. V. Petit mal epilepsy: results of a prolonged follow-up study of 117 patients. J.A.M.A. 194 (1965), 227-232.

5. Woodbury, D. M., Penry, J. K., and Schmidt, R. P., eds. Antiepileptic Drugs. New York: Raven Press, 1972.

6. Diamond, W. D., and Buchanan. R. A. A clinical study of the effect of phénobarbital on diphenylhydantoin plasma levels. J. Clin. Pharmacol. 10 (1970), 306-311.

7. Schmid, F. Osteopathien bei antiepileptischer dauerbehandlung. Fortschr. Med. 85 (1967), 381-383.

8. Kruse, R. Osteopathien bein antiepileptischer langzeittherapie vorlaufige mitteilung). Mschr. Kinderheilk. 116 (1968). 378-381.

9. Dent, C. E., Richens. A., Rowe, D. J. F., and Stamp, T. C. B. Osteomalacia with long-term anticonvulsant therapy in epilepsy. Brit. Med. J. 4 (1970), 69-72.

10. Richens, A., and Rowe. D. J. F. Disturbance of calcium metabolism by anticonvulsant drugs. Brit. Med. J. 4 (1970). 73-76.

11. DeLuca, K., and Masotti, R. E. Hypocalcemia induced by anticonvulsant drugs. Canad. Paed. Soc, 48th annual meeting, Kingston, Ontario, Canada, June 12-16, 1971, 47.

12. Genel, M., Berman, P. H., Morrow G., and Bongiovanni, A. M. Vitamin D dependency with dibasic aminoaciduria associated with anticonvulsant therapy. Pediat. Res. 6 (1972), 395.

13. Matsuo, N., Herrera, C. Y., Tashjian, A., and Fellers, F. X. Diphenylhydantoin associated rickets. Pediat. Res. 6 (1972), 400.

14. Borgstedt, A. D., Bryson, M. F., Young. L. W., and Forbes, G. B. Long-term administration of antiepileptic drugs and the development of rickets. J. Pediat. 81 (1972). 9-15.

15. Buchthal. F.. and Lennox-Buchthal. M. A. Diphenylhydantoin: relation of anticonvulsant effect to concentration in serum. D. M. Woodbury. J. K. Penry, and R. P. Schmidt, eds. In Antiepileptic Drugs. New York: Raven Press, 1972, 204-205.

16. Livingston, S. The Diagnosis and Treatment of Convulsive Disorders in Children. Springfield: Charles C Thomas. 1954, 175-176.

17. Buchanan, R. A., Kinkel, A. W., Goulet. J. R.. and Smith, T. C. The metabolism of diphenylhydantoin (Dilantin) following once daily administration. Neurology 22 (1972), 126-130.

18. Svensmark, O. and Buchthal, F. Diphenylhydantoin and phénobarbital; serum levels in children. Amer. J. Dis. Child 108 (1964), 82-87.

19. Arnold, K. and Gerber, N. The rate of decline of diphenylhydantoin in human plasma. Clin. Pharmacol. Ther. 11 (1970), 121-134.

20. Gastaut, H. and Broughton, R. Epileptic Seizures: Clinical and Electrographic Features, Diagnosis and Treatment. Springfield: Charles C Thomas, 1972. 229.

21. Holowach, J., Thurston, D. L, and O'Leary, J. Prognosis in childhood epilepsy: follow-up study of 148 cases in which therapy had been suspended after prolonged anticonvulsant control. New Eng. J. Med. 286 (1972). 169-174.

22. Gastaut, H. and Vigouroux, M. Electroclinical correlations in 500 cases of psychomotor seizures. M. Baldwin and P. Bailey, eds. In Temporal Lobe Epilepsy. Springfield: Charles C Thomas. 1958, 128.

23. Lombroso, C. T. Treatment of status epilepticus with diazepam. Neurology 16 (1966). 629634.

24. Schwalb, E. Treatment of seizures with diazepam. Letter to the editor. New Eng. J. Med. 276 (1967), 1443.

25. Prensky, A. L. and Schwab, R. S. Treatment of seizures with diazepam. Letter to the editor. New Eng. J. Med. 276 (1967), 1443.

TABLE 1

DRUGS CURRENTLY USED FOR THE CONTROL OF EPILEPTIC SEIZURES*

TABLE 2

AVERAGE DOSAGES OF ANTIEPILEPTIC DRUGS'

TABLE 2

AVERAGE DOSAGES OF ANTIEPILEPTIC DRUGS'

10.3928/0090-4481-19730901-04

Sign up to receive

Journal E-contents