- Email: [email protected]
Characteristics of valproic acid resistant juvenile myoclonic epilepsy
Seizure 2000; 9: 385–388
doi: 10.1053/seiz.2000.0432, available online at http://www.idealibrary.com on
Characteristics of valproic acid resistant juvenile myoclonic epilepsy †
†
†
MARIA C. FERNANDO-DONGAS , RODNEY A. RADTKE , KEVAN E. VANLANDINGHAM & AATIF †‡ M. HUSAIN †
Department of Medicine (Neurology), Duke University; Medical Center, Durham, NC, USA
‡ Neurodiagnostic
Center, Veterans Affairs
Correspondence to: Aatif M. Husain, M.D., Box 3678, 202 Bell Building, Duke University Medical Center, Durham, NC 27710, USA. E-mail: [email protected]
Juvenile myoclonic epilepsy (JME) is often exquisitely responsive to treatment with valproic acid (VPA). However, a subset of patients does not respond to this medication and often has intractable seizures. We wanted to identify differences between these two subsets of JME patients. Charts of all JME patients followed at the Duke Epilepsy Center were reviewed. Clinical parameters, electroencephalogram (EEG) findings and magnetic resonance imaging (MRI) data were reviewed. These features were compared between patients with VPA sensitive and VPA resistant JME. Thirty-three patients with JME were identified: 23 (70%) were VPA sensitive (13 females, 10 males; mean age of onset 15.9 years) and 10 (30%) were VPA resistant (5 females, 5 males; mean age of onset 14.1 years). The VPA resistant group had a higher frequency of EEG asymmetries (40% vs. 10%); atypical seizure characteristics including auras and post-ictal confusion (30% vs. 4%); and intellectual deficiency (20% vs. 0%). Clinical characteristics combined with EEG data may help in predicting which JME patients will respond favorably to VPA. This study also raises the issue whether VPA resistant JME is in fact a localization-related epilepsy. c 2000 BEA Trading Ltd
Key words: juvenile myoclonic epilepsy; refractory; valproic acid; EEG.
INTRODUCTION
MATERIALS AND METHODS
Juvenile myoclonic epilepsy (JME) is a common type of epilepsy, representing 26% of idiopathic generalized epilepsies1 . It typically presents in adolescence with myoclonic seizures with or without absence and generalized tonic–clonic seizures (GTCS). Bilateral and synchronous 4–6/second polyspike and wave complexes characterize the electroencephalogram (EEG) in most patients. Most patients respond to valproic acid (VPA) monotherapy, with excellent seizure control achieved in as high as 82–97% of patients2–5 . There is a subset of patients, however, whose seizures do not respond to VPA. This study was undertaken to determine whether there were any differences between these two subgroups of JME patients.
Charts of all patients with JME followed at the Duke Epilepsy Center were reviewed. Demographic data including sex, age at seizure onset, time to diagnosis of JME, seizure types and characteristics, family history of seizures and assessment of mental functioning were reviewed. VPA responsive patients were defined as those who were seizure free on VPA monotherapy. Included in this group were patients with occasional myoclonus that did not interfere with functioning as well those with breakthrough seizures secondary to noncompliance. VPA resistance was defined as recurrent seizures despite therapeutic levels (50–100 mg dl−1 ) of VPA. Age at seizure onset was defined as the age at which the first seizure was noted, whether myoclonic, absence or generalized tonic–clonic. The time to diag-
1059–1311/00/060385 + 04
$35.00/0
c 2000 BEA Trading Ltd
386
M. C. Fernando-Dongas et al.
nosis was defined as the number of years from seizure onset to time diagnosis and/or appropriate therapy, i.e. VPA was instituted, whichever came first. Unusual seizure characteristics and history were noted. These included previous history of febrile seizures, presence of auras and post-ictal confusion following absence and myoclonic seizures. Additionally, features of focal seizures, i.e. Todd’s paralysis, focal motor activity, aphasia, etc., were noted. Family history of seizures was determined. As most patients were unfamiliar with the type and etiology of seizures in the family members, all relatives with any type of seizure disorder were included. Mental functioning was assessed based on examiner’s mental status examination, school performance (whether patient required special education) and intelligence quotient (IQ) scores when available. Intellectual deficiency was defined as IQ scores less than 80, need for special education classes or mini-mental status scores less than 23. All EEGs in the VPA resistant group and 81% of the EEGs in the VPA sensitive group were performed at the Duke Epilepsy Center and examined for asymmetries by board-certified electroencephalographers. EEG asymmetry was defined as the presence of consistently unilateral epileptiform discharges independent of the generalized epileptiform activity, focal slowing, and persistent unilateral predominance of bilateral, synchronous polyspike and wave discharges. All magnetic resonance imaging (MRI) reports were reviewed for presence of lesions and other abnormalities.
5 (50%) males and 5 (50%) females in the VPA resistant subgroup.
RESULTS
The number of years prior to correct diagnosis and treatment of JME was delayed in most patients to an average of 9.73 years with greater than 2.5 years difference between the two subgroups of patients. The VPA sensitive group were diagnosed and treated earlier with a mean time to diagnosis of 8.91 years (range of 0–52 years, median 3 years) whereas the VPA resistant group were diagnosed and treated at a mean age of 11.60 years (range of 0–28 years, median 7 years).
Thirty-seven patients with JME were identified; two patients with well-controlled JME were excluded since neither had been tried on VPA. The first was unable to afford valproate hence was on lamotrigine through a drug assistance program. The second was a woman of childbearing age who planned to become pregnant and was well controlled on mysoline. Two patients with medically intractable JME were also excluded as both had only very brief trials of VPA and were unable to reach therapeutic levels due to intolerable gastrointestinal side-effects. Of the remaining 33 patients, 23 (70%) were VPA responsive and 10 (30%) were VPA resistant. The summary of results is shown in Table 1.
Table 1: Clinical characteristics of VPA sensitive vs. VPA resistant JME patients. VPA sensitive JME VPA resistant JME n = 23 (70%) n = 10 (30%) Sex: Male Female Mean age at seizure onset (years) Mean time to diagnosis of JME (years) Family history of seizures Atypical seizure characteristics Intellectual deficiency EEG asymmetries MRI abnormalities
10 (43) 13 (57) 15.9
5 (50) 5 (50) 14.1
8.9
11.6
7 (30) 1 (4)
3 (30) 3 (30)
0 (0) 2/21 (10) 1/5 (20)
2 (20) 4/10 (40) 2/9 (22)
VPA = valproic acid, JME = juvenile myoclonic epilepsy, EEE = electroencephalogram, MRI = magnetic resonance imaging.
Age at seizure onset Patients in the VPA sensitive group tend to have later onset of seizures, mean age of 15.91 years, median 16 years vs. the VPA resistant group who had mean seizure onset 2 years earlier at 14 years (median 14 years). Statistical analysis between the two groups could not be performed due to the small number of patients.
Time to diagnosis/treatment of JME
Family history of seizures Ten (30%) JME patients had family history of seizures. This was identified in 7 of the 25 (30%) VPA sensitive patients and in 3 of the 10 (30%) VPA resistant patients.
Sex Atypical seizure characteristics Eighteen females (55%) and 15 (45%) males with JME were identified. There were 10 (43%) males and 13 females (57%) in the VPA sensitive group and
One patient (4%) with VPA sensitive JME reported an aura of a strange cephalic sensation occurring sec-
VPA resistant JME
onds to minutes prior to a GTCS. Three (30%) patients in the VPA resistant group had atypical seizure history. One patient reported post-ictal confusion following a series of myoclonic jerks and a second patient described similar confusion following absence seizures. The third patient had history of one febrile and one afebrile seizure at 2.5 years of age.
Intellectual functioning
All patients with VPA sensitive JME had clinically normal intelligence as assessed by examination, school performance and daily functioning. Two patients (20%) in the VPA resistant group had intellectual deficiency with full-scale IQ scores of 64 and 78.
EEG asymmetries
Twenty-one (91%) patients with VPA sensitive JME and all patients with VPA resistant JME had EEGs, 87% of which were done at the Duke Epilepsy Center and were available for review. Among patients in the VPA sensitive group, 2 (10%) had EEGs with focal abnormalities. One patient had occasional right frontotemporal sharp waves. The second patient had left temporal slowing. The latter patient had a closed head injury at 20 years of age (6 years after the onset of JME) with residual mild right hemiparesis. If this patient was excluded, only 1 patient (5%) would have had focal EEG abnormalities in the VPA sensitive group. Among patients in the VPA resistant group, 4 (40%) had focal EEG abnormalities. The focal abnormalities seen in this group were left frontal amplitude predominance of generalized 1.5–6 Hz generalized polyspike and wave discharges; intermittent left temporal slowing; occasional right frontal epileptiform discharges; and left frontotemporal slowing with hyperventilation seen in one patient each.
MRI abnormalities
Five of the VPA sensitive patients had MRIs, 4 of which were normal and 1 (20%) had a smaller left temporal lobe. Nine patients in the VPA resistant group had MRIs, 7 (78%) of which were normal and 2 (22%) had smaller left hippocampus without accompanying signal abnormalities.
387
DISCUSSION VPA is the drug of choice for JME with excellent seizure control achieved in 82–97% of JME patients. In this study 30% of the patients were VPA resistant, probably reflecting the higher incidence of medically intractable seizures seen at epilepsy centers. There were no remarkable differences in sex, age of onset, family history of seizures and incidence of MRI abnormalities between the VPA sensitive and resistant JME subgroups. Studies have identified JME as one of the more common types of epilepsy, accounting for 5–10% of all epilepsies6–9 . Though common, JME is often missed and appropriate treatment frequently delayed. Grunewald et al.10 reported a mean delay in diagnosis of 14.5 years. Delay in diagnosis often occurs due to lack of familiarity with the syndrome, failure to elicit a history of myoclonic jerks and high prevalence of focal abnormalities on EEG. The shorter time to diagnosis seen in our patients probably represents improved awareness of the syndrome at referral centers. Diagnosis was delayed even more in patients with VPA resistant JME. This is likely due to a higher incidence of asymmetric EEG abnormalities, unusual seizure characteristics and intellectual deficiency as noted in the VPA resistant subgroup of this study. These findings may mislead physicians to diagnose a localizationrelated epilepsy in these patients. As JME is an idiopathic generalized epilepsy, focal features such as aura and post-ictal Todd’s paralysis are not expected. However a number of studies have noted focal seizure characteristics in JME patients11, 12 . Absence seizures in JME are usually of the simple type with rapid return to normal mental status. Panayiotopoulos et al.13 , however, have described atypical absence seizures in one patient with JME. A higher incidence of febrile seizure (4.4–10%) has been documented in JME as well1, 4 compared to the overall incidence of 2–5%14, 15 . This study had similar findings. One patient in the VPA sensitive group had a cephalic sensation prior to GTCS; this finding however can often be seen with GTCS. One patient in the VPA resistant group had post-ictal confusion following absence seizures and another had similar confusion following myoclonic seizures. Another patient in the VPA resistant group had febrile and afebrile seizures at age 2.5 years. In this study, atypical seizure characteristics were more frequently seen in the VPA resistant group (33% vs. 14%). This raises the issue of whether the VPA resistant JME group is in fact a refractory localizationrelated epilepsy. This may in part explain the resistance to VPA in these patients as VPA, despite being an anticonvulsant with broad spectrum activity, is more effective in primary generalized epilepsy16 .
388
Patients with JME have a normal neurologic examination17 . In this study, one VPA sensitive patient exhibited mild right hemiparesis and left temporal slowing on EEG following a closed head injury. The head injury, which was presumably the cause of the focal slowing, was sustained 6 years after onset of seizures. The rest of the VPA sensitive patients had normal neurologic examinations. Two (20%) patients in the VPA resistant group had IQ scores less than 80, indicating diffuse neuronal dysfunction, raising the suspicion that these patients may have a different form of epilepsy, i.e. a localization-related or symptomatic generalized epilepsy. Bilateral and synchronous 4–6/second polyspike and wave discharges characterize the EEGs of patients with JME. EEG asymmetries, however, are not uncommon in JME17–19 . Aliberti et al.18 found amplitude asymmetries in the generalized discharges in 72.7% and focal abnormalities in 54.5% of JME patients. Lancman et al.19 noted EEG asymmetries in 16% of their JME patients. These studies included shifting EEG asymmetries. In this study, focal abnormalities were seen in 40% of the VPA resistant group and only in 10% of the VPA sensitive group. These findings suggest that patients with VPA resistant JME have higher incidence of focal EEG abnormalities, suggestive of a partial epilepsy. Neuroimaging abnormalities have not been demonstrated in JME patients20 . In this study one (20%) of the 5 patients with VPA resistant JME who had MRIs had a smaller left temporal lobe though the hippocampi looked symmetric. The significance of this finding was questionable. However 2 (22%) VPA resistant patients had asymmetric hippocampal sizes without signal abnormalities. These focal MRI findings also suggest the possibility of localization-related epilepsy in these patients. The findings of this study are consistent with Dasheiff and Ritaccio’s21 report of 12 patients with medically intractable JME who had higher incidence of asymmetric EEG abnormalities as well as longer duration of seizures with delay in diagnosis and treatment. In addition to these factors, neurologic abnormalities as well as atypical seizure characteristics and history also appear to be more common in patients with VPA resistant JME. This study suggests that there are two relatively distinct JME subgroups. The clinical characteristics of the VPA sensitive group resemble the typical JME syndrome described by Janz22 . The VPA resistant group, however, has a higher incidence of atypical characteristics including asymmetric EEG abnormalities, atypical seizure characteristics and history, and neurological and neuroimaging abnormalities. The presence of these characteristics may help predict which patients will respond to VPA and which
M. C. Fernando-Dongas et al.
ones would require different or additional medications. Whether the VPA resistant subgroup represents atypical JME or a different type of epilepsy (i.e. localization related) remains to be determined.
REFERENCES 1. Genton, P., Salas Puig, X., Tunon, A., Lahoz, C. and Del Socorro Gonzales Sanchez, M. JME and related syndromes: Clinical and neurophysiologic aspects. In: Idiopathic Generalized Epilepsies (Eds A. Malafosse, P. Genton, E. Hirsch, C. Marescaux, Broglin and R. Bemasconi). London, R. John Libbey, 1994: pp. 253–265. 2. Asconape, J. and Penry, J. K. Some clinical and EEG aspects of benign JME. Epilepsia 1984; 25: 108–114. 3. Delgado-Escueta, A. V. and Enrile-Bacsal, F. Juvenile myoclonic epilepsy of Janz. Neurology 1984; 34: 285–294. 4. Janz, D. and Durner, M. Juvenile myoclonic epilepsy. In: Epilepsy, A Comprehensive Textbook (Eds J. Engel and T. A. Pedley). Philadelphia, Lippincott-Raven, 1998: pp. 2389– 2404. 5. Penry, J. K., Dean, J. C. and Riela, A. R. JME: long term response to therapy. Epilepsia 1989; 30 (Suppl. 4): S19–S23. 6. Tsuboi, R. and Christian, W. On the genetics of the primary generalized epilepsy with sporadic myoclonics of impulsive petit mal type. Human Genetik 1973; 19: 155–182. 7. Janz, D. Epilepsy with impulsive petit mal (JME). Acta Neurologica Scandinavica 1985; 72: 449–459. 8. Wolf, P. and Goosses, R. Relation of photosensitivity to epileptic syndromes. Journal of Neurology, Neurosurgery and Psychiatry 1986; 49: 1368–1391. 9. Obeid, T. and Panayiotopoulos, C. P. JME: a study in Saudi Arabia. Epilepsia 1988; 29: 280–282. 10. Grunewald, R. A., Chroni, E. and Panayiotopoulos, C. P. Delayed diagnosis of JME. Journal of Neurology, Neurosurgery and Psychiatry 1992; 55: 497–499. 11. Lancman, M. E., Asconape, J. J. and Golimstok, A. Circling seizures in a case of JME. Epilepsia 1994; 35: 317–318. 12. Oguni, H., Mukahira, K., Oguni, M., Uehara, T., Su, Y. H., Izumi, T. and Fukuyama, Y. Video-polygraphic analysis of myoclonic seizures in JME. Epilepsia 1994; 35: 307–316. 13. Panayiotopoulos, C. P., Obeid, T. and Waheed, G. Absences in JME: a clinical and video-EEG study. Annals of Neurology 1989; 25: 391–397. 14. Hauser, W. A. and Kurkland, L. T. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 1975; 16: 1–66. 15. Nelson, K. B. and Ellenberg, J. H. Prognosis in children with febrile seizures. Pediatrics 1978; 61: 720–727. 16. Rowan, A. J. Valproate. In: Epilepsy, A Comprehensive Textbook (Eds J. Engel and T. A. Pedley). Philadelphia, Lippincott-Raven, 1998: pp. 1599–1607. 17. Panayiotopoulos, C. P., Obeid, T. and Tahan, A. R. JME: a 5year prospective study. Epilepsia 1994; 35: 285–296. 18. Aliberti, V., Grunewald, R. A., Panayiotopoulos, C. P. and Chroni, E. Focal EEG abnormalities in JME. Epilepsia 1994; 35: 297–301. 19. Lancman, M. E., Asconape, J. J. and Penry, J. K. Clinical and EEG asymmetries in JME. Epilepsia 1994; 35: 302–306. 20. Janz, D. JME: epilepsy with impulsive petit mal. Cleveland Clinic Journal of Medicine 1989; 56 (Suppl. 1): S23–S33. 21. Dasheiff, R. M. and Ritaccio, A. L. Characterization of intractable JME: new perspectives on primary generalized seizures. Seizure 1993; 2: 11–19. 22. Janz, D. The natural history of primary generalized epilepsies with sporadic myoclonias of the ‘impulsiv petit mal’ type. In: Evolution and Prognosis of Epilepsies (Eds E. Lugaresi et al.). Bologna, Italy, Aulo Gaggi, 1973: pp. 55–61.
doi: 10.1053/seiz.2000.0432, available online at http://www.idealibrary.com on
Characteristics of valproic acid resistant juvenile myoclonic epilepsy †
†
†
MARIA C. FERNANDO-DONGAS , RODNEY A. RADTKE , KEVAN E. VANLANDINGHAM & AATIF †‡ M. HUSAIN †
Department of Medicine (Neurology), Duke University; Medical Center, Durham, NC, USA
‡ Neurodiagnostic
Center, Veterans Affairs
Correspondence to: Aatif M. Husain, M.D., Box 3678, 202 Bell Building, Duke University Medical Center, Durham, NC 27710, USA. E-mail: [email protected]
Juvenile myoclonic epilepsy (JME) is often exquisitely responsive to treatment with valproic acid (VPA). However, a subset of patients does not respond to this medication and often has intractable seizures. We wanted to identify differences between these two subsets of JME patients. Charts of all JME patients followed at the Duke Epilepsy Center were reviewed. Clinical parameters, electroencephalogram (EEG) findings and magnetic resonance imaging (MRI) data were reviewed. These features were compared between patients with VPA sensitive and VPA resistant JME. Thirty-three patients with JME were identified: 23 (70%) were VPA sensitive (13 females, 10 males; mean age of onset 15.9 years) and 10 (30%) were VPA resistant (5 females, 5 males; mean age of onset 14.1 years). The VPA resistant group had a higher frequency of EEG asymmetries (40% vs. 10%); atypical seizure characteristics including auras and post-ictal confusion (30% vs. 4%); and intellectual deficiency (20% vs. 0%). Clinical characteristics combined with EEG data may help in predicting which JME patients will respond favorably to VPA. This study also raises the issue whether VPA resistant JME is in fact a localization-related epilepsy. c 2000 BEA Trading Ltd
Key words: juvenile myoclonic epilepsy; refractory; valproic acid; EEG.
INTRODUCTION
MATERIALS AND METHODS
Juvenile myoclonic epilepsy (JME) is a common type of epilepsy, representing 26% of idiopathic generalized epilepsies1 . It typically presents in adolescence with myoclonic seizures with or without absence and generalized tonic–clonic seizures (GTCS). Bilateral and synchronous 4–6/second polyspike and wave complexes characterize the electroencephalogram (EEG) in most patients. Most patients respond to valproic acid (VPA) monotherapy, with excellent seizure control achieved in as high as 82–97% of patients2–5 . There is a subset of patients, however, whose seizures do not respond to VPA. This study was undertaken to determine whether there were any differences between these two subgroups of JME patients.
Charts of all patients with JME followed at the Duke Epilepsy Center were reviewed. Demographic data including sex, age at seizure onset, time to diagnosis of JME, seizure types and characteristics, family history of seizures and assessment of mental functioning were reviewed. VPA responsive patients were defined as those who were seizure free on VPA monotherapy. Included in this group were patients with occasional myoclonus that did not interfere with functioning as well those with breakthrough seizures secondary to noncompliance. VPA resistance was defined as recurrent seizures despite therapeutic levels (50–100 mg dl−1 ) of VPA. Age at seizure onset was defined as the age at which the first seizure was noted, whether myoclonic, absence or generalized tonic–clonic. The time to diag-
1059–1311/00/060385 + 04
$35.00/0
c 2000 BEA Trading Ltd
386
M. C. Fernando-Dongas et al.
nosis was defined as the number of years from seizure onset to time diagnosis and/or appropriate therapy, i.e. VPA was instituted, whichever came first. Unusual seizure characteristics and history were noted. These included previous history of febrile seizures, presence of auras and post-ictal confusion following absence and myoclonic seizures. Additionally, features of focal seizures, i.e. Todd’s paralysis, focal motor activity, aphasia, etc., were noted. Family history of seizures was determined. As most patients were unfamiliar with the type and etiology of seizures in the family members, all relatives with any type of seizure disorder were included. Mental functioning was assessed based on examiner’s mental status examination, school performance (whether patient required special education) and intelligence quotient (IQ) scores when available. Intellectual deficiency was defined as IQ scores less than 80, need for special education classes or mini-mental status scores less than 23. All EEGs in the VPA resistant group and 81% of the EEGs in the VPA sensitive group were performed at the Duke Epilepsy Center and examined for asymmetries by board-certified electroencephalographers. EEG asymmetry was defined as the presence of consistently unilateral epileptiform discharges independent of the generalized epileptiform activity, focal slowing, and persistent unilateral predominance of bilateral, synchronous polyspike and wave discharges. All magnetic resonance imaging (MRI) reports were reviewed for presence of lesions and other abnormalities.
5 (50%) males and 5 (50%) females in the VPA resistant subgroup.
RESULTS
The number of years prior to correct diagnosis and treatment of JME was delayed in most patients to an average of 9.73 years with greater than 2.5 years difference between the two subgroups of patients. The VPA sensitive group were diagnosed and treated earlier with a mean time to diagnosis of 8.91 years (range of 0–52 years, median 3 years) whereas the VPA resistant group were diagnosed and treated at a mean age of 11.60 years (range of 0–28 years, median 7 years).
Thirty-seven patients with JME were identified; two patients with well-controlled JME were excluded since neither had been tried on VPA. The first was unable to afford valproate hence was on lamotrigine through a drug assistance program. The second was a woman of childbearing age who planned to become pregnant and was well controlled on mysoline. Two patients with medically intractable JME were also excluded as both had only very brief trials of VPA and were unable to reach therapeutic levels due to intolerable gastrointestinal side-effects. Of the remaining 33 patients, 23 (70%) were VPA responsive and 10 (30%) were VPA resistant. The summary of results is shown in Table 1.
Table 1: Clinical characteristics of VPA sensitive vs. VPA resistant JME patients. VPA sensitive JME VPA resistant JME n = 23 (70%) n = 10 (30%) Sex: Male Female Mean age at seizure onset (years) Mean time to diagnosis of JME (years) Family history of seizures Atypical seizure characteristics Intellectual deficiency EEG asymmetries MRI abnormalities
10 (43) 13 (57) 15.9
5 (50) 5 (50) 14.1
8.9
11.6
7 (30) 1 (4)
3 (30) 3 (30)
0 (0) 2/21 (10) 1/5 (20)
2 (20) 4/10 (40) 2/9 (22)
VPA = valproic acid, JME = juvenile myoclonic epilepsy, EEE = electroencephalogram, MRI = magnetic resonance imaging.
Age at seizure onset Patients in the VPA sensitive group tend to have later onset of seizures, mean age of 15.91 years, median 16 years vs. the VPA resistant group who had mean seizure onset 2 years earlier at 14 years (median 14 years). Statistical analysis between the two groups could not be performed due to the small number of patients.
Time to diagnosis/treatment of JME
Family history of seizures Ten (30%) JME patients had family history of seizures. This was identified in 7 of the 25 (30%) VPA sensitive patients and in 3 of the 10 (30%) VPA resistant patients.
Sex Atypical seizure characteristics Eighteen females (55%) and 15 (45%) males with JME were identified. There were 10 (43%) males and 13 females (57%) in the VPA sensitive group and
One patient (4%) with VPA sensitive JME reported an aura of a strange cephalic sensation occurring sec-
VPA resistant JME
onds to minutes prior to a GTCS. Three (30%) patients in the VPA resistant group had atypical seizure history. One patient reported post-ictal confusion following a series of myoclonic jerks and a second patient described similar confusion following absence seizures. The third patient had history of one febrile and one afebrile seizure at 2.5 years of age.
Intellectual functioning
All patients with VPA sensitive JME had clinically normal intelligence as assessed by examination, school performance and daily functioning. Two patients (20%) in the VPA resistant group had intellectual deficiency with full-scale IQ scores of 64 and 78.
EEG asymmetries
Twenty-one (91%) patients with VPA sensitive JME and all patients with VPA resistant JME had EEGs, 87% of which were done at the Duke Epilepsy Center and were available for review. Among patients in the VPA sensitive group, 2 (10%) had EEGs with focal abnormalities. One patient had occasional right frontotemporal sharp waves. The second patient had left temporal slowing. The latter patient had a closed head injury at 20 years of age (6 years after the onset of JME) with residual mild right hemiparesis. If this patient was excluded, only 1 patient (5%) would have had focal EEG abnormalities in the VPA sensitive group. Among patients in the VPA resistant group, 4 (40%) had focal EEG abnormalities. The focal abnormalities seen in this group were left frontal amplitude predominance of generalized 1.5–6 Hz generalized polyspike and wave discharges; intermittent left temporal slowing; occasional right frontal epileptiform discharges; and left frontotemporal slowing with hyperventilation seen in one patient each.
MRI abnormalities
Five of the VPA sensitive patients had MRIs, 4 of which were normal and 1 (20%) had a smaller left temporal lobe. Nine patients in the VPA resistant group had MRIs, 7 (78%) of which were normal and 2 (22%) had smaller left hippocampus without accompanying signal abnormalities.
387
DISCUSSION VPA is the drug of choice for JME with excellent seizure control achieved in 82–97% of JME patients. In this study 30% of the patients were VPA resistant, probably reflecting the higher incidence of medically intractable seizures seen at epilepsy centers. There were no remarkable differences in sex, age of onset, family history of seizures and incidence of MRI abnormalities between the VPA sensitive and resistant JME subgroups. Studies have identified JME as one of the more common types of epilepsy, accounting for 5–10% of all epilepsies6–9 . Though common, JME is often missed and appropriate treatment frequently delayed. Grunewald et al.10 reported a mean delay in diagnosis of 14.5 years. Delay in diagnosis often occurs due to lack of familiarity with the syndrome, failure to elicit a history of myoclonic jerks and high prevalence of focal abnormalities on EEG. The shorter time to diagnosis seen in our patients probably represents improved awareness of the syndrome at referral centers. Diagnosis was delayed even more in patients with VPA resistant JME. This is likely due to a higher incidence of asymmetric EEG abnormalities, unusual seizure characteristics and intellectual deficiency as noted in the VPA resistant subgroup of this study. These findings may mislead physicians to diagnose a localizationrelated epilepsy in these patients. As JME is an idiopathic generalized epilepsy, focal features such as aura and post-ictal Todd’s paralysis are not expected. However a number of studies have noted focal seizure characteristics in JME patients11, 12 . Absence seizures in JME are usually of the simple type with rapid return to normal mental status. Panayiotopoulos et al.13 , however, have described atypical absence seizures in one patient with JME. A higher incidence of febrile seizure (4.4–10%) has been documented in JME as well1, 4 compared to the overall incidence of 2–5%14, 15 . This study had similar findings. One patient in the VPA sensitive group had a cephalic sensation prior to GTCS; this finding however can often be seen with GTCS. One patient in the VPA resistant group had post-ictal confusion following absence seizures and another had similar confusion following myoclonic seizures. Another patient in the VPA resistant group had febrile and afebrile seizures at age 2.5 years. In this study, atypical seizure characteristics were more frequently seen in the VPA resistant group (33% vs. 14%). This raises the issue of whether the VPA resistant JME group is in fact a refractory localizationrelated epilepsy. This may in part explain the resistance to VPA in these patients as VPA, despite being an anticonvulsant with broad spectrum activity, is more effective in primary generalized epilepsy16 .
388
Patients with JME have a normal neurologic examination17 . In this study, one VPA sensitive patient exhibited mild right hemiparesis and left temporal slowing on EEG following a closed head injury. The head injury, which was presumably the cause of the focal slowing, was sustained 6 years after onset of seizures. The rest of the VPA sensitive patients had normal neurologic examinations. Two (20%) patients in the VPA resistant group had IQ scores less than 80, indicating diffuse neuronal dysfunction, raising the suspicion that these patients may have a different form of epilepsy, i.e. a localization-related or symptomatic generalized epilepsy. Bilateral and synchronous 4–6/second polyspike and wave discharges characterize the EEGs of patients with JME. EEG asymmetries, however, are not uncommon in JME17–19 . Aliberti et al.18 found amplitude asymmetries in the generalized discharges in 72.7% and focal abnormalities in 54.5% of JME patients. Lancman et al.19 noted EEG asymmetries in 16% of their JME patients. These studies included shifting EEG asymmetries. In this study, focal abnormalities were seen in 40% of the VPA resistant group and only in 10% of the VPA sensitive group. These findings suggest that patients with VPA resistant JME have higher incidence of focal EEG abnormalities, suggestive of a partial epilepsy. Neuroimaging abnormalities have not been demonstrated in JME patients20 . In this study one (20%) of the 5 patients with VPA resistant JME who had MRIs had a smaller left temporal lobe though the hippocampi looked symmetric. The significance of this finding was questionable. However 2 (22%) VPA resistant patients had asymmetric hippocampal sizes without signal abnormalities. These focal MRI findings also suggest the possibility of localization-related epilepsy in these patients. The findings of this study are consistent with Dasheiff and Ritaccio’s21 report of 12 patients with medically intractable JME who had higher incidence of asymmetric EEG abnormalities as well as longer duration of seizures with delay in diagnosis and treatment. In addition to these factors, neurologic abnormalities as well as atypical seizure characteristics and history also appear to be more common in patients with VPA resistant JME. This study suggests that there are two relatively distinct JME subgroups. The clinical characteristics of the VPA sensitive group resemble the typical JME syndrome described by Janz22 . The VPA resistant group, however, has a higher incidence of atypical characteristics including asymmetric EEG abnormalities, atypical seizure characteristics and history, and neurological and neuroimaging abnormalities. The presence of these characteristics may help predict which patients will respond to VPA and which
M. C. Fernando-Dongas et al.
ones would require different or additional medications. Whether the VPA resistant subgroup represents atypical JME or a different type of epilepsy (i.e. localization related) remains to be determined.
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