Childhood Epilepsy Uncontrolled by Phenytoin: Clinical and Electroencephalographic Study Kazuie Iinuma, MD, Norimitsu Takamatsu, MD, Akira Onuma, MD, and Keiya T ada, MD
Nine cases of childhood epilepsy manifesting motor convulsions uncontrolled despite high levels of phenytoin (PHT) were studied clinically and electroencephalographically. These cases consisted of fiv e cases of partial seizures without impairment of consciousness, two cases of partial seizures (occasionally generalized seizures beginning locally), one case of predominan tly unilateral seizures, and one case of generalized tonic-clonic seizures. The onset of seizures was at a rather early age, between 3 months and 9 years, and under 3 years of age in eight cases. All cases had single or multiple, cortical epileptic loci in EEG. The projection of spikes was localized to a rather limited area. Seizures of these patients were frequent. All cases, except one, did not respond to other medication. Convulsive seizures with cortical focal spike foci in EEG uncontrolled despite high levels of PHT were thought to have poor responsiveness to not only PHT itself, but also to other anticonvulsants. Iinuma K, Takamatsu N, Onuma A, Tada K: Childhood epilepsy uncontrolled by phenytoin: Clinical and electroencephalographic study. Brain Dev 1: 49-56, 1979
Since phenytoin (PHT) was introduced into antiepileptic treatment, II it has been used as the first choice of a drug for patients with epilepsy, and above all for seizures with convulsive movements such as grand mal and focal motor seizures. Recently, it has been possible to estimate the serum level of many antiepileptics as well as PHT. An optimum range for control of seizures can determined by the estimation of the serum level of antiepileptics. It has been reported by some authors that the optimum range of PHT
From the Department of Pediatrics, Tohoku University School of Medicine, Sendai. Accepted for pUblication; March 19, 1979.
Key words: Intractable convulsions, partial seizures, phenytoin, EEG. Correspondence address: Dr. Kazuie linuma, Department of Pediatrics, Tohoku University School of Medicine, Seiryo--4--_ JI--
R-shoulderJlo."-~'--'--·-
ECG ~-~~~----.y
• .-t,~Av A V'-.J~V .N..." A T4- T, '""'" .- .....,~A~ •• -.."r..r""v..'V
ECG
'r---
-Jr--
~ V-"
J ,~
!!O,.V~
Fig 1 EEG of case 1. Spikes appeared maximally at C3. The electrodes: C1 was placed on the intermediate position between Cz and C3 • and C s was placed between C3 and T3 according to Jasper's designation, 7
listed in Table 1. The characteristic types of clinical seizures were partial seizures with motor or sensory symptoms. There was no impairment of consciousness in five cases (cases 1,2, 3, 4 and 5). Partial seizures (occasionally generalized seizures beginning locally) was associated with or without impairment of consciousness in two, cases (cases 6 and 7). Case 8 showed predominantly unilateral seizures and case 9 generalized tonic-clonic seizures. The partial seizures were mostly restricted to certain limited portions of the body, for example, hand, arm, shoulder, eye-lid or oral angle. In three cases (cases 1, 4 and 5), the seizures later transformed into continuous partial seizures. But in two cases, the seizures later changed to be not continuous. In one case (case 5), the seizures later accompanied with tonic spasms of the l..ennox-Gastaut syndrome. In another case, the seizures transformed into minor abortive seizures (case 8). The onset of seizures was 52 Brain & Development, Vol 1, No 1,1979
between 3 months and 9 years of age, and was under 3 years of age in eight of the nine cases. The electroencephalographic findings of each patient are listed in Table 2. Examples of EEGs from the patients are shown in Figs. 1,2 and 3. The basic background activity of an awake EEG was obtained in seven out of the nine cases. The background activity was normal for the age in five Cases and showed a slow or disorganized pattern in two cases. A slow wave focus on the background which appeared in the same area as an epileptic focus was observed in two cases. Epileptic change in EEG was observed in all nine cases. In all cases the epileptic discharges appeared locally, and bilaterally synchronous spike-wave discharges representing secondary bilateral synchrony were observed in only one case. In all cases the spikes were steep and were thought to originate from the cortex, even if they propagated to a neighboring area. The maximal activity of spike discharges was
F,
P3-0,
F, - T4
5O/4VL-I sec
Fig 2 EEG of case 2. Sharp waves (underlined) appeared at F 7.
located at the frontal region in three cases, at the central region in five cases, and at the anterior temporal region in two cases. The spike foci were seen over both hemispheres in two cases. The projection of spike discharge was localized to a rather limited area (one or two electrodes of the 10-20 international system) in three cases, and spread to a slightly wide area (3 or 5 electrodes) in six cases. No Rolandic spike discharges characterized by diphasic, highvoltage, centro-temporal spikes 9 were observed in any of the cases. In general, seizures of these patients were rather frequent. Three cases gradually increased in the frequency, finally they had continuous attal:ks, so-called Koschewnikow's epilepsy; three cases had two or more attacks per day, and two cases had three or more attacks per month. Response to antiepileptic medication was exceedingly poor. In eight of nine cases, the seizure attacks were not completely controlled
inspite of all our efforts for medication. In the remaining one patient whose seizures propagated to generalized tonic-clonic convulsions, the attacks were completely controlled by the administration of carbamazepine. In all cases no complete control was obtained by the administration of PHT although the serum level of PHT was beyond 11.2 JIg/ml, usually 15 JIg/ml. Moderate mental retardation was observed in two and mild retardation in two cases. Hemiparesis was seen in four cases. One of them was thought to be due to subdural hematoma, one due to organic ' brain lesion associated with arachnoidal thickness, and the other two due to unknown etiology. Dilatation of the left lateral ventricle and left frontal atrophy were revealed by computed tomography in one case. Discussion Phenytoin (PHT) is one of the most widely
K Iinuma, et al: Convulsions unresponsive to PHT 53
F ' l F'-y-/'~'
C'\J~/\~~\'I~J\ c. '·")~~~i~\\r-0~Vyv.J'~~'f'-./w'fv-J{,I , P. P.
,._'i''''~~V'''/\.....~
~
·,~':~(~\~\f"'-v'l"v..lv-"~"'v{\v'\...>..~~
o. ~"VL--
1 lee
Fig 3 EEG of case 7. Spikes and spike-waves independently
appearedatC 3 - P 3 andC4 -P4 •
used antiepileptic drugs, and also is a primary drug for all types of epilepsy except those with the absence seizuresY But PHT is not always effective for every epileptic patient. Unsatisfactorily controlled patients can be divided into two groups6; (1) patients with no apparent anticonvulsant effect, low levels of PHT in the blood, and no evidence of intoxication, and (2) patients with poor control of seizures, evidence of intoxication, and high levels of PHT in the blood. Rowan 15 reported that seizure frequency showed a dramatic decrease in a case of partial seizures, when the serum concentration of PHT increased from 10.3 to 14.5 Ilg/mL The our present cases could not be controlled by a serum PHT concentration of more than 10 Ilg/ml, which was defined as the lower effective limit by several authors,6,19 and some cases could not be controlled even by a concentration of more than 20 Ilg/ml, which was considered to be a toxic leveL 6 Lund 10 mentioned that in patients with moderately severe epilepsy, the plasma level of PHT might have to be increased to about 20 Ilg/ml before satisfactory seizure control was obtained. Livingston and Berman 8 mentioned that in uncontrolled patients with DPH blood levels of 20 Ilg/ml, who were free of signs of 54 Brain & Development, Vall, No 1,1979
toxicity, they increased the drug dosage until the patient manifested clinical symptoms of overdosage or presented a satisfactory clinical seizure response. On the other hand, Borofsky et al,3 in replying to Livingston and Berman's opinion,S mentioned that 20llg/ml was an average level at which toxic manifestations began to be seen, and therefore they had relied on the blood level value of 20 Ilg/ml as a cut-off point. So it can be said that our present cases have seizures uncontrolled by a sufficient dose of PHT_ Travers et al 20 reported that in the treatment of epilepsy with PHT and phenobarbital, a higher dose and higher serum concentration of both drugs were found in the group with greater frequency and poorer control of seizures_ It seems likely that the concentration of PHT in the brain may be insufficient despite the high serum levels in these poorly controlled cases. However, Sherwin 16 de,scribed that the concentrations of PHT in cerebral grey matter as well as white matter were higher than in the plasma in cases of neurosurgical therapy for focal epilepsy _Therefore, it may not be acceptable that poor control of seizures is due to a low concentration of PHT in brain tissue_ The seizure types of our cases were charac-
FIH"' -v~~ '.-/"~
Fs-C. ~i'--"'rJ"v""-~rvi\l"'~
terized by focal motor or sensory seizures, with elementary symptomatology,4 not with complex symptomatology, and in one case generalized seizures with focal somatosensory symptomatology. The symptoms of the patients were characterized by clonic movement or somatosensory symptoms of limited portions of the body such as unilateral eye-lid, finger, arm, shoulder, leg or foot. These symptoms did not spread to other portions of the body. The electrical activity of seizures is thought to originate from a limited area of the brain in our cases. The electroencephalograms of our cases also showed a localized epileptic change and its location was in the area corresponding to clinical symptoms. For instance, in a case whose clinical symptoms included clonic movement of the right eye-lid and oral angle, the epileptic focus was located in F 7, F 3 and F PI, maximal at F 7. According to Blume et al/ F 7 corresponds to the triangular portion of the inferior frontal gyrus near the motor area of eye-lid and face in infants. A feature of EEG in our cases was steep spike discharges spreading to limited neighboring areas, with phase reversal by bipolar derivation; suggesting that they were discharged from the cortical area. Reynolds 14 reported that only three out of 31 patients did not respond to the optimum
concentration of PHT and two of the three patients had minor focal attacks. Lund 10 mentioned that none of his 18 patients who had partial seizures became free from attacks. Kutt and McDowe1l 6 described that neurological evaluation demonstrated structural brain lesion such as progressive diffuse or focal cortical atrophy, in many of the epileptic patients who had frequent seizures despite high levels of PHI in the blood. Porter et al 13 also reported that seizure frequency of 23 patients reduced in 14 and was unimproved in nine by various treatments with monitoring of the serum levels of anticonvulsants, Therefore, epileptic patients who have partial seizures or focal cortical atrophy may have difficulty responding to PHT despite the high levels in the blood. It is suspected that most of our present cases had organic brain lesions judging from hemiparesis, brain atrophy or subdural hematoma. PHI is thought to be the drug which has the most active anticonvulsive effect. s Borofsky et al2 reported that two of their patients had remained uncontrolled despite a PHT dosage sufficient to produce clinical toxicity and had been refractory to all combinations of standard anticonvulsants. Our cases except for one did not respond despite all our efforts for medication. Our studies indicate that if a satisfactory dose of PHI does not show good result for convulsive seizures showing cortical focal epileptic changes in EEG, it may be difficult to control the seizures by other drugs. It has been reported that PHT does not elevate the threshold for seizures induced by injection of convulsant drugs such as strychnine, picrotoxin or pentylenetetrazol, and that it also has only limited ability to elevate threshold for electroshock seizures. 21 According to Morrell et al's 12 experiments, the effect of PHT is not suppression of the primary focus, but anti-spreading activity on seizure discharges. Ito et als also reported that PHT depresses the focal seizure as indicated by the shortening of seizure duration and the suppression of spreading. If PHI does not suppress the seizure activity of the primary focus, it may be ineffective on partial seizures which are caused directly by the primary focus without spreading to surrounding areas. Most clinical seizure patterns of our present cases were partial seizures with constant seizure activity in the cortical focal area in :BEG. It can be said that these cases had enougb. activity to cause clinical
K Iinuma, et al: Convulsions unresponsive to PHT 55
seizure attacks without spreading to other areas. We demonstrated in another literature 18 that epileptic children with generalized seizures that were electroencephalographically suspected to have developed from localized epileptic origin were well controlled by a PHT serum concentration of not more than 10 JIg/ml, but also below 9 JIg/ml. These nine cases may be representative cases to suggest that PHT does not have a suppressing activity on the primary focus but an anti-spreading activity.
References 1. Blume WT, Buza RC, Okazaki H: Anatomic correlates of the ten-twenty electrode placement system in infants. Electroencephalogr Clin Neurophysiol 36: 303-307, 1974. 2. Borofsky LG, Louis S, Kutt H, et al: Diphenylhydantoin: Efficacy, toxiciy, and dose-serum level relationships in children. J Pediatr 81: 995-1002,1972. 3. Borofsky LG, Louis S, Kutt H, et al: Reply to "Control rate in diphenylhydantoin therapy". J Pediatr 83: 349-350, 1973. 4. Gastaut H: Clinical and electroencephalographical classification of epileptic seizures. Epilepsia 11: 102-113,1970. 5. Ito T, Hori M, Yoshida K, et al: Effect of anticonvulsan ts on cortical focal seizure in cats. Epilepsia 18: 63-71, 1977. 6. Kutt H, McDowell F: Management of epilepsy with diphenylhydantoin sodium. JAJlL4 203: 969-972, 1968. 7. Jasper HH: Report of the committee on methods of clinical examination in electroencephalography. Electroencephalogr Clin N europhysiol 10: 370-375, 1958. 8. Livingston S, Berman W: Control rate in diphenylhydantoin therapy. J Pediatr 83: 348-349,1973. 9. Lombroso CT: Sylvian seizures and mid temporal spike foci in children. Arch Neurol 17: 52-59,
56Brain & Development, Vol 1, No 1,1979
1967. 10. Lund L: Anticonvulsant effect of diphenylhydantoin relative to plasma levels: A prospective three-year study in ambulant patients with generalized epileptic seizures. Arch Neural 31: 289-294,1974. 11. Merritt HH, Putnam TJ: Sodium diphenylhydantoinate in treatment of convulsive disorders. JAJlL4 111: 1068-1073, 1938. 12. Morrell F, Bradley W, Ptashne M: Effect of drugs on discharge characteristics of chronic epileptogenic lesions. Neurology (Minneap) 9: 492498, 1959. 13. Porter RJ, Penry JK, Lacy JR: Diagnostic and therapeutic reevaluation of patients with intractable epilepsy. Neurology (Minneap) 27: 10061011,1977. 14. Reynolds EH, Chadwick D, Galbraith AW: One drug (phenytoin) in the treatment of epilepsy. Lancet 1: 923-926, 1976. 15. Rowan AJ, Pippenger CE, McGregor PA, et al: Seizure activity and anticonvulsant drug concentration: 24-hour sleep-waking studies. Arch Neurol32: 281-288, 1975. 16. Sherwin AL, Eisen AA, Sokolowski CD: Anticonvulsant drugs in human epileptogenic brain. Arch Neurol29: 73-77, 1973. 17. Solow EB, Green JB: The simultaneous determination of multiple anticonvulsant drug levels by gas liquid chromatography. Neurology (Minneap) 22: 540-550,1972. 18. Takamatsu N, Iinuma K: Anticonvulsive effects of diphenylhydantoin on partial seizures. Brain Dev (Tokyo) 11: 17-24, 1979. 19. Tanabu M: Relation among serum diphenylhydantoin concentrations, clinical response and toxic signs in epileptic children. Brain Dev (Tokyo) 7: 348-353, 1975. 20. Travers RD, Reynolds EH, Gallagher BB: Variation in response to anticonvulsants in a group of epileptic patients. Arch Neural 27: 29-33, 1972. 21. Woodbury DM, Fingl E: Drugs effective in the therapy of the epilepsies. In Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics. 5th ed. Macmillan, New York, 1975, pp 201-226.
Nine cases of childhood epilepsy manifesting motor convulsions uncontrolled despite high levels of phenytoin (PHT) were studied clinically and electroencephalographically. These cases consisted of fiv e cases of partial seizures without impairment of consciousness, two cases of partial seizures (occasionally generalized seizures beginning locally), one case of predominan tly unilateral seizures, and one case of generalized tonic-clonic seizures. The onset of seizures was at a rather early age, between 3 months and 9 years, and under 3 years of age in eight cases. All cases had single or multiple, cortical epileptic loci in EEG. The projection of spikes was localized to a rather limited area. Seizures of these patients were frequent. All cases, except one, did not respond to other medication. Convulsive seizures with cortical focal spike foci in EEG uncontrolled despite high levels of PHT were thought to have poor responsiveness to not only PHT itself, but also to other anticonvulsants. Iinuma K, Takamatsu N, Onuma A, Tada K: Childhood epilepsy uncontrolled by phenytoin: Clinical and electroencephalographic study. Brain Dev 1: 49-56, 1979
Since phenytoin (PHT) was introduced into antiepileptic treatment, II it has been used as the first choice of a drug for patients with epilepsy, and above all for seizures with convulsive movements such as grand mal and focal motor seizures. Recently, it has been possible to estimate the serum level of many antiepileptics as well as PHT. An optimum range for control of seizures can determined by the estimation of the serum level of antiepileptics. It has been reported by some authors that the optimum range of PHT
From the Department of Pediatrics, Tohoku University School of Medicine, Sendai. Accepted for pUblication; March 19, 1979.
Key words: Intractable convulsions, partial seizures, phenytoin, EEG. Correspondence address: Dr. Kazuie linuma, Department of Pediatrics, Tohoku University School of Medicine, Seiryo--4--_ JI--
R-shoulderJlo."-~'--'--·-
ECG ~-~~~----.y
• .-t,~Av A V'-.J~V .N..." A T4- T, '""'" .- .....,~A~ •• -.."r..r""v..'V
ECG
'r---
-Jr--
~ V-"
J ,~
!!O,.V~
Fig 1 EEG of case 1. Spikes appeared maximally at C3. The electrodes: C1 was placed on the intermediate position between Cz and C3 • and C s was placed between C3 and T3 according to Jasper's designation, 7
listed in Table 1. The characteristic types of clinical seizures were partial seizures with motor or sensory symptoms. There was no impairment of consciousness in five cases (cases 1,2, 3, 4 and 5). Partial seizures (occasionally generalized seizures beginning locally) was associated with or without impairment of consciousness in two, cases (cases 6 and 7). Case 8 showed predominantly unilateral seizures and case 9 generalized tonic-clonic seizures. The partial seizures were mostly restricted to certain limited portions of the body, for example, hand, arm, shoulder, eye-lid or oral angle. In three cases (cases 1, 4 and 5), the seizures later transformed into continuous partial seizures. But in two cases, the seizures later changed to be not continuous. In one case (case 5), the seizures later accompanied with tonic spasms of the l..ennox-Gastaut syndrome. In another case, the seizures transformed into minor abortive seizures (case 8). The onset of seizures was 52 Brain & Development, Vol 1, No 1,1979
between 3 months and 9 years of age, and was under 3 years of age in eight of the nine cases. The electroencephalographic findings of each patient are listed in Table 2. Examples of EEGs from the patients are shown in Figs. 1,2 and 3. The basic background activity of an awake EEG was obtained in seven out of the nine cases. The background activity was normal for the age in five Cases and showed a slow or disorganized pattern in two cases. A slow wave focus on the background which appeared in the same area as an epileptic focus was observed in two cases. Epileptic change in EEG was observed in all nine cases. In all cases the epileptic discharges appeared locally, and bilaterally synchronous spike-wave discharges representing secondary bilateral synchrony were observed in only one case. In all cases the spikes were steep and were thought to originate from the cortex, even if they propagated to a neighboring area. The maximal activity of spike discharges was
F,
P3-0,
F, - T4
5O/4VL-I sec
Fig 2 EEG of case 2. Sharp waves (underlined) appeared at F 7.
located at the frontal region in three cases, at the central region in five cases, and at the anterior temporal region in two cases. The spike foci were seen over both hemispheres in two cases. The projection of spike discharge was localized to a rather limited area (one or two electrodes of the 10-20 international system) in three cases, and spread to a slightly wide area (3 or 5 electrodes) in six cases. No Rolandic spike discharges characterized by diphasic, highvoltage, centro-temporal spikes 9 were observed in any of the cases. In general, seizures of these patients were rather frequent. Three cases gradually increased in the frequency, finally they had continuous attal:ks, so-called Koschewnikow's epilepsy; three cases had two or more attacks per day, and two cases had three or more attacks per month. Response to antiepileptic medication was exceedingly poor. In eight of nine cases, the seizure attacks were not completely controlled
inspite of all our efforts for medication. In the remaining one patient whose seizures propagated to generalized tonic-clonic convulsions, the attacks were completely controlled by the administration of carbamazepine. In all cases no complete control was obtained by the administration of PHT although the serum level of PHT was beyond 11.2 JIg/ml, usually 15 JIg/ml. Moderate mental retardation was observed in two and mild retardation in two cases. Hemiparesis was seen in four cases. One of them was thought to be due to subdural hematoma, one due to organic ' brain lesion associated with arachnoidal thickness, and the other two due to unknown etiology. Dilatation of the left lateral ventricle and left frontal atrophy were revealed by computed tomography in one case. Discussion Phenytoin (PHT) is one of the most widely
K Iinuma, et al: Convulsions unresponsive to PHT 53
F ' l F'-y-/'~'
C'\J~/\~~\'I~J\ c. '·")~~~i~\\r-0~Vyv.J'~~'f'-./w'fv-J{,I , P. P.
,._'i''''~~V'''/\.....~
~
·,~':~(~\~\f"'-v'l"v..lv-"~"'v{\v'\...>..~~
o. ~"VL--
1 lee
Fig 3 EEG of case 7. Spikes and spike-waves independently
appearedatC 3 - P 3 andC4 -P4 •
used antiepileptic drugs, and also is a primary drug for all types of epilepsy except those with the absence seizuresY But PHT is not always effective for every epileptic patient. Unsatisfactorily controlled patients can be divided into two groups6; (1) patients with no apparent anticonvulsant effect, low levels of PHT in the blood, and no evidence of intoxication, and (2) patients with poor control of seizures, evidence of intoxication, and high levels of PHT in the blood. Rowan 15 reported that seizure frequency showed a dramatic decrease in a case of partial seizures, when the serum concentration of PHT increased from 10.3 to 14.5 Ilg/mL The our present cases could not be controlled by a serum PHT concentration of more than 10 Ilg/ml, which was defined as the lower effective limit by several authors,6,19 and some cases could not be controlled even by a concentration of more than 20 Ilg/ml, which was considered to be a toxic leveL 6 Lund 10 mentioned that in patients with moderately severe epilepsy, the plasma level of PHT might have to be increased to about 20 Ilg/ml before satisfactory seizure control was obtained. Livingston and Berman 8 mentioned that in uncontrolled patients with DPH blood levels of 20 Ilg/ml, who were free of signs of 54 Brain & Development, Vall, No 1,1979
toxicity, they increased the drug dosage until the patient manifested clinical symptoms of overdosage or presented a satisfactory clinical seizure response. On the other hand, Borofsky et al,3 in replying to Livingston and Berman's opinion,S mentioned that 20llg/ml was an average level at which toxic manifestations began to be seen, and therefore they had relied on the blood level value of 20 Ilg/ml as a cut-off point. So it can be said that our present cases have seizures uncontrolled by a sufficient dose of PHT_ Travers et al 20 reported that in the treatment of epilepsy with PHT and phenobarbital, a higher dose and higher serum concentration of both drugs were found in the group with greater frequency and poorer control of seizures_ It seems likely that the concentration of PHT in the brain may be insufficient despite the high serum levels in these poorly controlled cases. However, Sherwin 16 de,scribed that the concentrations of PHT in cerebral grey matter as well as white matter were higher than in the plasma in cases of neurosurgical therapy for focal epilepsy _Therefore, it may not be acceptable that poor control of seizures is due to a low concentration of PHT in brain tissue_ The seizure types of our cases were charac-
FIH"' -v~~ '.-/"~
Fs-C. ~i'--"'rJ"v""-~rvi\l"'~
terized by focal motor or sensory seizures, with elementary symptomatology,4 not with complex symptomatology, and in one case generalized seizures with focal somatosensory symptomatology. The symptoms of the patients were characterized by clonic movement or somatosensory symptoms of limited portions of the body such as unilateral eye-lid, finger, arm, shoulder, leg or foot. These symptoms did not spread to other portions of the body. The electrical activity of seizures is thought to originate from a limited area of the brain in our cases. The electroencephalograms of our cases also showed a localized epileptic change and its location was in the area corresponding to clinical symptoms. For instance, in a case whose clinical symptoms included clonic movement of the right eye-lid and oral angle, the epileptic focus was located in F 7, F 3 and F PI, maximal at F 7. According to Blume et al/ F 7 corresponds to the triangular portion of the inferior frontal gyrus near the motor area of eye-lid and face in infants. A feature of EEG in our cases was steep spike discharges spreading to limited neighboring areas, with phase reversal by bipolar derivation; suggesting that they were discharged from the cortical area. Reynolds 14 reported that only three out of 31 patients did not respond to the optimum
concentration of PHT and two of the three patients had minor focal attacks. Lund 10 mentioned that none of his 18 patients who had partial seizures became free from attacks. Kutt and McDowe1l 6 described that neurological evaluation demonstrated structural brain lesion such as progressive diffuse or focal cortical atrophy, in many of the epileptic patients who had frequent seizures despite high levels of PHI in the blood. Porter et al 13 also reported that seizure frequency of 23 patients reduced in 14 and was unimproved in nine by various treatments with monitoring of the serum levels of anticonvulsants, Therefore, epileptic patients who have partial seizures or focal cortical atrophy may have difficulty responding to PHT despite the high levels in the blood. It is suspected that most of our present cases had organic brain lesions judging from hemiparesis, brain atrophy or subdural hematoma. PHI is thought to be the drug which has the most active anticonvulsive effect. s Borofsky et al2 reported that two of their patients had remained uncontrolled despite a PHT dosage sufficient to produce clinical toxicity and had been refractory to all combinations of standard anticonvulsants. Our cases except for one did not respond despite all our efforts for medication. Our studies indicate that if a satisfactory dose of PHI does not show good result for convulsive seizures showing cortical focal epileptic changes in EEG, it may be difficult to control the seizures by other drugs. It has been reported that PHT does not elevate the threshold for seizures induced by injection of convulsant drugs such as strychnine, picrotoxin or pentylenetetrazol, and that it also has only limited ability to elevate threshold for electroshock seizures. 21 According to Morrell et al's 12 experiments, the effect of PHT is not suppression of the primary focus, but anti-spreading activity on seizure discharges. Ito et als also reported that PHT depresses the focal seizure as indicated by the shortening of seizure duration and the suppression of spreading. If PHI does not suppress the seizure activity of the primary focus, it may be ineffective on partial seizures which are caused directly by the primary focus without spreading to surrounding areas. Most clinical seizure patterns of our present cases were partial seizures with constant seizure activity in the cortical focal area in :BEG. It can be said that these cases had enougb. activity to cause clinical
K Iinuma, et al: Convulsions unresponsive to PHT 55
seizure attacks without spreading to other areas. We demonstrated in another literature 18 that epileptic children with generalized seizures that were electroencephalographically suspected to have developed from localized epileptic origin were well controlled by a PHT serum concentration of not more than 10 JIg/ml, but also below 9 JIg/ml. These nine cases may be representative cases to suggest that PHT does not have a suppressing activity on the primary focus but an anti-spreading activity.
References 1. Blume WT, Buza RC, Okazaki H: Anatomic correlates of the ten-twenty electrode placement system in infants. Electroencephalogr Clin Neurophysiol 36: 303-307, 1974. 2. Borofsky LG, Louis S, Kutt H, et al: Diphenylhydantoin: Efficacy, toxiciy, and dose-serum level relationships in children. J Pediatr 81: 995-1002,1972. 3. Borofsky LG, Louis S, Kutt H, et al: Reply to "Control rate in diphenylhydantoin therapy". J Pediatr 83: 349-350, 1973. 4. Gastaut H: Clinical and electroencephalographical classification of epileptic seizures. Epilepsia 11: 102-113,1970. 5. Ito T, Hori M, Yoshida K, et al: Effect of anticonvulsan ts on cortical focal seizure in cats. Epilepsia 18: 63-71, 1977. 6. Kutt H, McDowell F: Management of epilepsy with diphenylhydantoin sodium. JAJlL4 203: 969-972, 1968. 7. Jasper HH: Report of the committee on methods of clinical examination in electroencephalography. Electroencephalogr Clin N europhysiol 10: 370-375, 1958. 8. Livingston S, Berman W: Control rate in diphenylhydantoin therapy. J Pediatr 83: 348-349,1973. 9. Lombroso CT: Sylvian seizures and mid temporal spike foci in children. Arch Neurol 17: 52-59,
56Brain & Development, Vol 1, No 1,1979
1967. 10. Lund L: Anticonvulsant effect of diphenylhydantoin relative to plasma levels: A prospective three-year study in ambulant patients with generalized epileptic seizures. Arch Neural 31: 289-294,1974. 11. Merritt HH, Putnam TJ: Sodium diphenylhydantoinate in treatment of convulsive disorders. JAJlL4 111: 1068-1073, 1938. 12. Morrell F, Bradley W, Ptashne M: Effect of drugs on discharge characteristics of chronic epileptogenic lesions. Neurology (Minneap) 9: 492498, 1959. 13. Porter RJ, Penry JK, Lacy JR: Diagnostic and therapeutic reevaluation of patients with intractable epilepsy. Neurology (Minneap) 27: 10061011,1977. 14. Reynolds EH, Chadwick D, Galbraith AW: One drug (phenytoin) in the treatment of epilepsy. Lancet 1: 923-926, 1976. 15. Rowan AJ, Pippenger CE, McGregor PA, et al: Seizure activity and anticonvulsant drug concentration: 24-hour sleep-waking studies. Arch Neurol32: 281-288, 1975. 16. Sherwin AL, Eisen AA, Sokolowski CD: Anticonvulsant drugs in human epileptogenic brain. Arch Neurol29: 73-77, 1973. 17. Solow EB, Green JB: The simultaneous determination of multiple anticonvulsant drug levels by gas liquid chromatography. Neurology (Minneap) 22: 540-550,1972. 18. Takamatsu N, Iinuma K: Anticonvulsive effects of diphenylhydantoin on partial seizures. Brain Dev (Tokyo) 11: 17-24, 1979. 19. Tanabu M: Relation among serum diphenylhydantoin concentrations, clinical response and toxic signs in epileptic children. Brain Dev (Tokyo) 7: 348-353, 1975. 20. Travers RD, Reynolds EH, Gallagher BB: Variation in response to anticonvulsants in a group of epileptic patients. Arch Neural 27: 29-33, 1972. 21. Woodbury DM, Fingl E: Drugs effective in the therapy of the epilepsies. In Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics. 5th ed. Macmillan, New York, 1975, pp 201-226.
