Seizure1992;
1: 281-289
Absence
epilepsy:
early prognostic
ATHANASIOS COVANIS, KONSTANTINOS VIRGINIA THEODOROU
signs
SKIADAS, NOMIKI LOLI, CHRISTINA
LADA &
The Department of Neurology, Children 3 Hospital ‘Aghia Sophia ‘, I 1527, Athens, Greece
We have studied 124 children with typical absence epilepsy. The onset of symptoms was in 12% under 4 years, in 51% between 4-8 years and in 37% above 8 years. The F:M ratio was 2:l in children under 4 years versus 1:l above 8 years. Absences alone occurred in 82% and absences followed or preceded by generalized tonic-clonic seizures (GTCS) in 6.5% and ll%, respectively. Simple absences were not seen in children under 4 years and were more frequent (14%) in the 4-8 years age group. Family history was positive for epilepsy in 20% and febrile convulsion in 7%. Sixteen percent had a positive past history of febrile convulsions. All patients showed bilateral, synchronous spike-wave discharges from 2.5 to 4 c/s. Lateralized spikes, spike-slow wave complexes were found in 27%. Photosensitivity was present in 18% and was marked in 12%. Monotherapy with sodium valproate or ethosuximide (91% SV) was successful in 85% of patients with absences alone and 68% of the absences with GTCS. Only 2% were not fully controlled either on monotherapy or polytherapy. Treatment was withdrawn in 41 patients and 13 relapsed. We have identified four factors associated with relapses: (a) poor initial response to treatment, (b) lateralized focal EEG abnormnality and/or marked photosensitivity, (cl the evolution to myoclonic epilepsy, and (d) early withdrawal of AED (~3 years). Key words: epilepsy; prognosis; monotherapy.
INTRODUCTION
Absence seizures were first described in 17701. The international classification of epileptic seizures2 distinguishes two types of absences, typical and atypical. Typical absences may be of simple or complex symptomatology. In simple absences, the impairment of consciousness is brief and may be associated with upward drifting of the eyes and slight rhythmic beating of the eyelids. In complex absences, the impairment of consciousness is usually of longer duration and is associated with other clinical phenomena, e.g. clonic, tonic, atonic, automatic and autonomic3-6. All absences observed clinically are associated with electroencephalographic discharges3 and, in addition, there is evidence that brief subclinical generalized spike and wave discharges do interfere with cognitive function7-Il. The prognosis of absence epilepsy is very variable6,12-15. It has been associated with the age of onset and the appearance of generalized tonic-clonic seizures12,‘“, the type of absences15, the response to treatment and the 1059-
1311/92/040281+09
$08.00/O
quality of antiepileptic drugs17,18, as well as the existence of an abnormal background EEG activity14y1’. Absence epilepsy, preceded by generalized tonic-clonic seizures has been considered as a separate entity, with poorer prognosis16”. In this study the patients with typical absences were classified according to the age of onset of their epilepsy in those, (a) under the age of 4 years, (b) between the ages of 4 to 8 years and (c) above the age of 8 years. Like other studies”, in each age group we distinguished, three subgroups of absence epilepsy: absences only (AE), absences followed by generalized tonic-clonic seizures (AE-GTCS) and absences preceded by GTCS (GTCS-AE). The purpose of this study was to discover early clinical and EEG characteristics that may help to forecast the outcome. MATERIAL
AND METHODS
One hundred and twenty-four children, with typical absences at the time of presentation @ 1992
Baillithe
Tindall
282 Table
A. Covanis ef a/. 1: AE: Clinical
findings
Type of seizures AE
Sex
FH+ve
n
n
F:M
CA
SA
E
FCs
h/o FCs
102
57F 45M 4F 4M 7F 7M 68F 56M
1.2:1
90
12
21
7
15
-
1
2
4
1
3
25
9
20
AE-GTCS
8
GTCS-AE
14
Total
Type of AE
124
1:l
8
-
1:l
14
-
1.2:1
112
12
AE = absence epilepsy with absences only, AE-GTCS = absences followed by generalized tonic-clonic seizures, GTCS-AE = GTCS followed by absences, CA = complex absences, SA = simple absences, E = epilepsy, FCS = febrile convulsions, h/o = history of, FH = family history.
attend our epilepsy clinic, established in 1987. All patients were diagnosed by clinical and EEG criteria based on the history of seizures, direct observation of the absences during overbreathing, the association of the clinical event with the spike and wave discharges in the EEG and, lately, by video-EEG analysis. The family history of seizure disorders was fully investigated. The EEG and the response to intermittent photic stimulation (IPS) was recorded using standard techniques2’, Patients were asked to hyperventilate for 3 min and occasionally up to 5min for those children who were not disturbed by the process. Both overbreathing and IPS were repeated during the recording. In the younger age group, hyperventilation was encouraged by blowing either a paper, a light out or a paper streamer. Counting during the deep breaths was also applied in order to assess lapses of consciousness. However, this process of counting was less successful in the young children since the pattern of breathing was disturbed and effective overbreathing was not achieved. If an absence was observed, the child’s response to a powerful stimulus such as calling his name or giving a simple command, was assessed and the clinical and EEG characteristics of the absence were recorded. The response during an absence was compared with that during a normal status and EEG activity. Video-EEG studies were made using Vidigraph, which allows simultaneous association of the clinical and EEG events. If an absence was not recorded, a sleep-waking record was taken after sleep deprivation. Treatment was initiated with one drug, usually sodium valproate (SV) once daily and the clinical response was assessed every 2 weeks until complete control (100%) was achieved. Once clinical control was achieved
the EEG was repeated after 2-3 months. If subclinical discharges were observed the daily dose of the anti-absence drug was adjusted. If SV was unsuccessful it was substituted by ethosuximide (ETH). If either drug was not successful, a combination of both was tried. If the combination of SV and ETH failed to achieve complete control, clonazepam (Clan) was also added. The withdrawal of the drugs in the cases of polytherapy was done in the reverse order of their introduction. The third drug was phased out after 2 years of successful treatment, the second after 3 years and the first after 4 years. If a relapse occurred, the drug which was last withdrawn was reintroduced.
RESULTS Clinical Of the 124 patients, 102 (82%) had absences only, eight (6.5%) had absences followed by GTCS and 14 (11%) had GTCS followed by absences (Table 1). The total female to male ratio was 1.2:1. Complex absences were observed in 112 (90%) cases and simple absences in 12 (10%). Epilepsy and febrile convulsions in the 1st and 2nd degree relatives was reported in 25 (20%) and 9 (7%) cases, respectively. Twenty children with absence epilepsy had a positive past history of febrile convulsions. In 15 of the 124 patients the age of onset of the absences was between 2.5 and 4 (mean 3.6 + 0.4) years. There were 10 girls and five boys giving a female to male ratio of 2:l. Simple absences were not observed in this group. In 63
Absence epilepsy:
early prognostic
signs
children the age of onset varied from 4 to 8 (mean 6.1 2 1.1) years. Complex absences occurred in 54 (86%) patients and simple absences in nine (14%). Of the 63 children, 36 were girls and 27 boys (F:M = 1.3:1). In 46 patients, their absences appeared between ages 8 to 13.5 (mean 10.3 ? 1.4) years. Simple absences occurred in three (6.5%) and complex absences in 43 (93.5%). The F:M ratio was 1:l.
School performance In 65 patients (52%) achievement at school was rated as low average. None of them had either positive lateralized neurological signs or positive brain CT scans. The duration of epilepsy prior to the start of an appropriate and effective treatment in this group, varied from 0.1 to 7 (1.5 + 1.6) years. In contrast, in the remaining 59 (48%) patients their performance at school was rated as good. In the latter group, the duration of epilepsy before introduction of treatment was 0.1 to 3 (mean 0.5 XL0.5) years.
Analysis of the clinical data Absences only (n = 102) Of the 102 patients who had only absence seizures, 12 (12%) had simple absences and 90 (88%) complex absences. The female to male ratio was 1.3:1. In 11% (6 females and 5 males), all with complex absences, the onset of the absences was under the age of 4 years; in 56% (34 females and 23 males), the absences had appeared from 4 to 8 years of age (9 simple absences, 48 complex absences) and in the remaining 33% (17 females and 17 males), absences had first occurred above the age of 8 years (3 simple absences, 31 complex absences). The family history was positive for epilepsy in 20% of cases and for febrile convulsions in 7%. Past history of febrile convulsions was positive in 15%. The frequency of the associated clinical features of the 90 patients with complex absences are as follows: automatisms occurred in 68% of the patients as de nouo and in 23% as perseverative. A clonic component was observed in 63%, tonic in 40% and atonic in 19%. Autonomic signs in the form of pallor and incontinence of urine occurred in 8%.
283
Onset with absences followed by generalized tonic-clonic seizures (n = 8) Eight patients (6.5%) had absence epilepsy followed by GTCS. In this group are included three cases that evolved to myoclonic epilepsy.
(i) Onset of absences under the age of 4 years. In two females, GTCS appeared 12 and 15 months after the start of treatment, respectively. The first case was taking sodium valproate (SV) and ethosuximide (ETH) was added for successful control. The second case was on ETH and changed to SV. The latter case evolved into myoclonic epilepsy. This became obvious when SV was discontinued after 5.5 years of successful (100%) control.
(ii) Onset of absences between the ages of 4 and 8 years. In 2 males, the onset of absences occurred at 6.5 and 6.9 years of age, respectively. Both received ethosuximide. A tonicclonic seizure occurred 10 and 14 months, respectively after the start of the treatment and ethosuximide was substituted in both by sodium valproate. The former case evolved into myoclonic epilepsy, which only became obvious 5 years later during the intermittent photic stimulation (IPS) test. At that time the patient was not taking his treatment regularly.
(iii) Onset of absences above the age of 8 years. There were two males and two females whose first absence seizures had occurred above 8 years of age. The two male cases had a tonicclonic seizure about a year after the start of the treatment because of low daily dose of sodium valproate. One female, on ethosuximide for 2.5 years, relapsed with a GTCS seizure at 15 years old during IPS. She was changed to sodium valproate. The second female had a GTCS premenstrually with her menarche, 6 months after the onset of her absences. At the time she was not having any treatment.
Generalized tonic-clonic absences (n = 14)
seizures prior to
In 14 (11%) patients the onset of absences occurred 0.1 to 2 (mean 0.49 + 0.6) years after the onset of the GTCS. In seven patients the absences became obvious soon after the onset
A. Covanis et al.
284
of the GTCS prior to any treatment. In the other seven, the absences appeared after carbamazepine (5 cases) or phenobarbitone (2 cases) was introduced for the GTCS. The family history was positive for epilepsy in four patients and for febrile convulsions in one. Three patients had a positive past history of febrile convulsions.
(i) Onset of absences under the age of 4 years. Absences appeared before 4 years of age in two females of whom one had three GTCS from the ages of 3 to 4 years with absences appearing at the age of 4 years and the second patient had a GTCS at 3 years old and she was put on carbamazepine and her absences began 9 months later.
charges, especially induced by overbreathing, which varied from 2.5 to 4c/s. In all cases the generalized SW discharges disappeared during treatment. Lateralized single spikes or spike and slow wave complexes (Table 2) were seen in 34 (27%) patients, all with complex absences. In 32 of the 34 patients, the focal abnormality disappeared during the course of treatment, in two it continued and in one was only obvious in the follow-up EEGs. Intermittent photic stimulation induced abnormalities in 22 (18%) patients. In seven (5.6%), photosensitivity was mild and in 15 (12%) marked. Photosensitivity disappeared during the follow-up EEGs with an appropriate daily dose of sodium valproate (30-35 mg/kg).
Absences only (n = 102) (ii) Onset of absences between 4 and 8 years. This group consisted of two male and two female patients. The GTCS occurred in all of them between 2 weeks and 12 months prior to the onset of the absences. Two patients were on carbamazepine when their absences started. In two, the family history was positive for convulsive disorders.
(iii) Onset of absences above the age of 8 years. This group comprises five males and three females. The GTCS preceded the absences by between 6 days and 3 months. Two patients were taking carbamazepine and two phenobarbitone at the onset of their absences. Family history was positive for epilepsy in one case.
Of the 102 patients who suffered absence seizures only, spikes and/or spike and slow wave lateralized features were observed in the initial EEGs in 26 (25%) cases, all with complex absences (Table 2). In one case a focal abnormality appeared during the follow up EEGs. Of the 26 cases, in nine treatment was discontinued and two relapsed. Intermittent photic stimulation induced abnormality in 16 cases. Six had a mild (narrow range lo-3Of/s) response and 10 marked (wider range). In one case, with onset of her absences at the age of 3.5 years, myoclonic jerks and photosensitivity became apparent when SV was discontinued 5 years later.
AE-GTCS (n = 8) Electroencephalographic
data
All 124 patients showed in the initial EEGs bilateral and synchronous spike and wave dis-
Of the eight patients showed focal spikes or complexes (Table 2). In abnormality disappeared
with AE-GTCS, four spike and slow wave three cases the focal during the follow-up
Table 2: EEG focal S or SSWC and photosensitivity in absence epilepsy Type
of epilepsy
Lateralized rz
AE AE-GTCS GTCS-AE Total
102 8 14 124
Initial (+)
S or SSWC
EEG
26 4* 4 34
S = spikes, SSWC = spike and slow wave complexes, epilepsy with absences only, AE-GTCS = absences followed by AE. * One case is the same patient.
Photosensitivity
FU EEGs
Initial
(+)
(-)
mild
1 1* 1 3
26 3 3 32
6 1 7
FU = follow-up, (+) followed by generalized
= positive, tonic-clonic
EEG marked 10 3* 2 15
(-)
= negative, AE seizures, GTCS-AE
FU EEGs (+) = absence = GTCS
Absence epilepsy:
early prognostic
signs
EEGs. In one case the initial EEG showed focal abnormality and marked photosensitivity. In this patient the follow-up EEGs did show some focal spike and slow wave complexes, but the response to IPS was negative. Four years later she relapsed with myoclonic jerks during IPS. In the other two patients with initial marked photosensitivity, the follow-up EEGs became normal. Both relapsed with myoclonic jerks 5 years later when SV was discontinued.
GTCS-AE (n = 14) Of the 14 patients with GTCS-AE, four had in their initial EEGs focal single spikes or spike and slow wave complexes. In three the followup EEGs became normal. Of the 14, one had mild and two marked photosensitivity in their initial EEGs. The follow-up EEGs became normal.
Treatment Results according to the age of onset of AE and type of seizures (i) Onset of absences under the age of 4 years. Complex absences only (n = 11). Of the 11 patients, nine are completely (100%) controlled (6 on SV, 1 on ETH and 2 on SV + ETH) and two are controlled by 80%. Of the two patients who are partially controlled, one is on monotherapy with SV and has occasional absences because of non-compliance with treatment and the other, even on polytherapy (SV + ETH+ Clan), has occasional absences with a marked clonic component. In four of the nine cases with complete control, the treatment was discontinued. Two cases, both female, relapsed. The mean duration of treatment in the non-relapsers and the relapsers was no different (5.25 + 2.47 years vs 5.5 + 0.7 years). Of the relapsers, one case had a positive family history of FCs and positive past history of FCs. She responded fully to SV within 1 week of treatment. When she relapsed she showed marked eyelid jerking during the SW discharges and marked photosensitivity (range lo-50 f/s). In the second case complete control was achieved when ethosuximide was added to sodium valproate. She relapsed with eyelid jerking during spike and
285
wave or polyspike and wave discharges when the second drug (ETH) was reduced. AE and GTCS (n = 4). There were two patients with AE-GTCS and two with GTCSAE. In three of these patients (2 GTCS-AE, 1 AE-GTCS) complete control was achieved by monotherapy with SV and in the fourth patient by SV + ETH. In one case (AE-GTCS) of the monotherapy group the treatment was discontinued after 5.5 years. She relapsed during IPS with eyelid jerking and myoclonic jerks, after a month off treatment. Her initial absences had an associated marked clonic component and a photosensitivity range from 5-40 f/s.
(ii) Onset of absences between the ages 4-8 years. Absences only (n = 57). Of the 57 patients in this group, 47 are completely controlled by monotherapy (42 on SV and 5 on ETH) and 10 by polytherapy (7 on SV + ETH, 3 on SV + ETH + Clan). In 2106 CA, 5 SA) the treatment was discontinued. Fourteen have not relapsed. The non-relapsers had been receiving treatment for between 3.5 and 6 (mean 5 f 1) years and were followed since the treatment was discontinued for 2.4 + 0.9 years. Seven patients (6 CA, 1SA) relapsed. They were completely controlled for 4.4 f 2.2 years (3 of the 7, under 3 years). Three were on polytherapy (2 on SV + ETH + Clon, 1 on SV + ETH) and four on monotherapy (3 on SV, 1 on ETH). The three cases on monotherapy with SV were successfully treated for 3.5, 2.5 and 2.0 years and relapsed when the drug was discontinued. The one case on ETH monotherapy was treated for 8 years and relapsed when withdrawn from treatment. Of the relapsers, one case had complex absences with a marked clonic component and two females relapsed with their menarche. AE and GTCS (n = 61. Of the six patients, four are completely controlled by monotherapy with SV (3 GTCS-AE, 1 AE-GTCS) and two by SV + ETH (1 AE-GTCS, 1 GTCS-AE). One case relapsed during IPS with myoclonic jerks: he had been completely controlled on monotherapy for 5 years. At the time of his relapse he was not taking his treatment regularly.
(iii) Onset of absences above the age of 8 years. Absences only (IZ = 34). Of the 34 patients in this group, 33 are completely (100%) controlled by monotherapy (30 SV, 3 ETH) and one by polytherapy (SV + ETH). Treatment was dis-
A. Covanis et al.
286 Table 3: AE: Resoonse to treatment and outcome Monotherapy
Type of epilepsy 100% AE AE & GTCS Total
a7* 15t 102
80%
Polytherapy 100%
80%
13$
1
61i 19
1
28 6 7 41
1t 1t 2
Relapsers
Off treatment
5 4 4
13
AE = absence epilepsy, absences only, AE & GTCS = absence epilepsy and generalized tonic-clonic seizures, 100% = complete control, 80% = occasional absences, * 78 sodium valproate (SW, 9 ethosuximide (ETH), t all SV, $ 10 SV + ETH, 3 SV + ETH + Clon, 0 all SV + ETH.
continued in nine cases (8 CA, 1 SA) of the monotherapy group (6 SV, 3 ETH) and have not relapsed. These non-relapsers were treated for between 3.5 and 6.5 (4.7 k 1) years and have been followed up after treatment was discontinued for from 1 to 2.5 (1.5 + 0.5) years. AE and GTCS (n = 12). Of the 12 patients in this group, 11 (5 AE-GTCS, 6 GTCS-AE) are completely controlled (7 SV, 1 ETH, 3 SV + ETH) and one (GTCS-AE) treated by monotherapy with SV has responded by 80%. Treatment was discontinued in five cases. Three have not relapsed and two have relapsed. The non-relapsers had been receiving treatment for between 3.5 and 4 (3.8 * 0.3) years and have so far followed up after the treatment was discontinued for 1 f 0.1 years. Of the two relapsers, one was treated for 2 years and the other for 4 years with ETH. The latter case relapsed during IPS with myoclonic jerks. In summary (Table 31, of the 102 children with absences only 88 (86%) received monotherapy (79 SV, 9 ETH) and 14 (14%) polytherapy (9 SV + ETH, 1 SV + Clon, 4 SV + ETH + Clon). On monotherapy 87 patients (78 SV, 9 ETH) were completely controlled and one was controlled by 80%. Monotherapy, therefore, was successful in 85% of cases. Of the 14 patients who received polytherapy, 13 are fully controlled (10 SV + ETH, 3 SV + ETH + Clon) and one (SV + ETH + Clon) has an occasional absence with a marked clonic component. Of those patients with absence epilepsy only, who were treated successfully, treatment was discontinued in 34 (33%) patients, nine of whom relapsed. Of the 22 patients with AE and GTCS, 15 (68%) responded completely to monotherapy with SV and six to the combination of SV and ETH. One patient on SV has occasional absences (non-compliance). The treatment was discontinued in seven (4 GTCS-AE, 3 AE-
GTCS) of the 22 patients and relapse occurred in four (3 AE-GTCS, 1 GTCS-AE). Only 2% of all the cases were not fully controlled either by monotherapy or polytherw. A total of 41 (33%) patients out of the 124 were withdrawn from treatment of whom thirteen relapsed between 1 week and 36 (2.6 f 2.3) months after the treatment was stopped. Table 4 shows the relationship between age of onset, age at which the treatment was discontinued and the present age of the 28 patients, who have so far not relapsed. Table 5 shows the mean age of onset in the three different age groups, of the 13 patients who relapsed, in relation to their relapse age. Table 4: Non-relapsers and present age Mean age at onset (years) 3.5 f 0.7 6 f 0.9 9.7 f 1.5*
(n = 28): Onset age vs age off Rx
No 1F 1M 8F 6M 3F 9M
Mean age treatment
Mean present age (years)
10 f 4
13 + 4.7
11.8 f 1.5
14.3 + 1.4
14.6 + 2
16 + 2.3
Vs = versus, off Rx = off treatment, male. * 3 patients GTCS-AE.
F = female, M =
Table 5: Relapsers (n = 13): OnSat aoe vs RelaDSe Mean age of onset (years)
n
3.6 f 0.2
3F
5.8 + 0.6
6F 2M 1F 1M
11.5 + 0.7
aoe
Mean relapse age (years) 10.9 f 2.8 (R 8.7-14)* 11.9 + 2.4 (R 8.5-15)t 16 + 4.0 (13.5519Q
Vs = versus, F = female, M = male, R = range. * 3 evolved to myoclonic, f 1 myoclonic, 1 marked clonic, 3 treatment less than 3 years, 3 other factors (see Table 6), $ 1 GTCS-AE, 1 AE-GTCS (myoclonic).
Absence epilepsy:
early prognostic
signs
DISCUSSION Typical absence epilepsy is well-defined and is classified as childhood absence epilepsy3T4F21 with an onset between the ages of 4 to 8 years and juvenile absence epilepsy22 with an onset age of above 8 years23. We evaluated our patients with absence epilepsy according to their clinical features as previously described18 and age of onset of their symptoms. As in the literature132 W24.25 absences occurred more frequently in girls than in boys and between the ages 4 to 8 years (51%). Females predominated in the younger age group (F:M = 2:l < 4 years vs 1:l > 8 years). In our study, as in others, a female preponderance was not found in juvenile absences. Wolf26 found a male to female ratio of 1.2:1. The difference in our results may be due to our paediatric group not including cases with an onset of absences above the age of 15 years. Simple absences are reported in less than 10% of typical absences16. We also found a 10% prevalence of simple absences. They occurred mainly between the ages of 4 to 8 years (14%), were less frequent above the age of 8 (6.5%) years and were not seen under the age of 4 years. The complex absences that evolve into myoclonic epilepsy did appear to have a marked clonic component from the beginning. This confirms observations made by others10>22,33
Positive family history for epilepsy in first degree relatives has been found to vary from 15% to 44%1g927-2g. We found, as others have2’ a 20% positive family history of epilepsy and 7% of febrile convulsions. Sixteen percent had a positive past history of febrile convulsions. Similar results were found in other studies”T3’. We found that absence epilepsy with absences only, occurred in 82% of the patients and absence epilepsy followed by GTCS in 7%. These findings differ from those of where the corresponding others 12,15,24,29 percentages were 60% and 40%. We believe that the use of sodium valproate as a first choice drug protects the patients from the development of subsequent GTCS. As we have shown before4’ sodium valproate is very effective in absence epilepsy, particularly when given as a single dose, usually at night41. Absences preceded by generalized tonicclonic seizures are regarded as a separate entity6,16,17 particularly if they present under the age of 5 years 17,18. In our study, as in
287
others’s, absence epilepsy with an initial GTCS occurred in 11% of patients. This group of patients behaved similarly to the other two groups, especially with respect to absences followed by GTCS. However, monotherapy was less successful in absences combined with GTCS than in absences only (68% vs 85%). In 50% of our patients carbamazepine or phenobarbitone were used for the GTCS and facilitated the appearance of absences. We have not seen GTCS evolving into absences when sodium valproate is used to control major seizures. A precise diagnosis is therefore missed in such cases. The characteristics of the SW discharge in typical absence epilepsy have already been reported13,31T32. We believe that the SW discharges in simple absences and in those with complex absences, which evolve into myoclonic epilepsy are of short duration (usually 1 to 8 s), with an abrupt onset and termination. The characteristic slow wave ending of the discharges and the movement artefact that supervenes in the interface of the burst during a clinical event are only seen in the complex absences. In comparison with other studies34, we found lateralized single spikes or spike and slow wave complexes in a higher percentage (27%). These results did not differ among the patients with absences only and those with absences associated with GTCS. The focal EEG abnormalities were found only in complex absences and, in combination with photosensitivity, predicted an unfavourable outcome. Photosensitivity in our patients was found in 18% and was marked in 12%. There is evidence that spike and wave discharges that are accentuated during overbreathing are inherited independently from spike and wave discharges evoked by intermittent photic stimulation 35-37. The coexistence of the two types of SW discharges in the same patient is indicative of a multifactorial model of inheritance38,3g. In contrast to some reports17, but consistent with others”, we did not find the duration of epilepsy to be a factor influencing response to treatment of relapse after drug withdrawal. Our results showed that (a) quick response to the treatment was a good prognostic sign and (b) the longer the duration of epilepsy prior to correct treatment and prompt resnonse, the more likely the children were to have ‘cognitive impairment’ and specific educational problems. Fifty-two percent of our children with educational difficulties in the secondary school
A. Covanls et al.
288
had a mean duration of epilepsy of 1.5 + 1.6 years as opposed to 0.5 f 0.5 years in the remaining 48% who had problems. These results indicate that SW discharges may interfere with cognitive function and if left untreated may cause permanent loss of abilities. Some authors advocate the withdrawal of AED after 2 years of successful treatment42Y43, others after 4 years44’45. Some studies did not find EEG of value in deciding to discontinue treatment44 others did43. We believe that individual predictors of favourable or unfavourable outcome should be found in each type of epilepsy. Follow-up EEGs in absence epilepsy are usually normal and therefore have no value in decision making. In 41 of the 124 patients with absence epilepsy treatment was discontinued and 13 relapsed (Table 3). The following factors were found to predict unfavourable outcome: (i) poor initial response to treatment-polytherapy, (ii) lateralized single spikes or spike and slow wave complexes and/or marked photosensitivity in the EEG, (iii) AE with marked clonic component, followed or not by GTCS-evolution into myoclonic epilepsy and (iv) early withdrawal of AED. The relationship between these factors and the cases that relapsed and those that did not is shown in Table 6. Table 6: AE: The coexistence of unfavourable factors in relapsers and non-relapsers No. of factors 0 1 2 3 Total
Relapsers 3 9 1 13
Non-relapsers
Total off treatment
21 6 1 28
21 9 10 1 41
CONCLUSIONS (1) In the three age groups studied, we found differences in distribution between the sexes of the different types of absence seizures. (2) Using sodium valproate as an initial drug, the response to treatment and the outcome of absence epilepsy is good, i.e. fewer cases develop GTCS. (3) A prolonged duration of epilepsy prior to treatment was associated with educational problems. (4) On withdrawal of treatment 32% relapsed.
Four unfavourable come.
factors
predicted
the out-
We believe that in absence epilepsy attempts to withdraw treatment should be made after 3 (preferably 4) years of successful monotherapy treatment. Early indicators of unfavourable outcome should not influence the decision to withdraw treatment under close clinico-EEG supervision. In this way correct diagnosis and prognosis can be made. Polytherapy helps some children to pass an acute stage of their problem. Therefore attempts to reduce polytherapy to monotherapy should be made after 2 years of successful treatment.
ACKNOWLEDGEMENTS We are grateful to our EEG technicians for their invaluable assistance with this study.
REFERENCES 1. Tissot, S.A. Traite de l’epilepsie, faisant le tome troisieme du triate des nerfs et de leurs maladies. Paris, 1770. 2. Commission on classification and terminology of the International League against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981; 22: 489501. 3. Penry, J.K., Porter, R.J. and Dreifuss, F.E. Simultaneous recording of absence seizures with video tape and electroencephalography. A study of 374 seizures in 48 patients. Brain 1975; 98: 427-440. 4. Sato, S. Generalized seizures: absence. In: Pediatric Epileptology (Ed. F.E. Dreifuss). Boston, John Wright, 1983; pp. 65-91. 5. Drury, I. and Dreifuss, F.E. Pyknoleptic petit mal. Acta Neurologica Scandinavica 1985; 72: 353-362. 6. Aicardi, J. Epilepsy in children. The International Review of Child Neurology. New York, Raven Press, 1986: pp. 79-99. I. Geller, M. and Geller, A. Brief amnestic effects of spike-wave discharges. Neurology 1970; 20: 10891095. 8. Goode, D.J., Peru-y, J.K. and Dreifuss, F.E. Effects of paroxysmal spike-wave on continuous visual-motor performance. Epilepsia 1970; 11: 241-254. 9. Browne, T.R., Penry, J.K., Porter, R.J. and Dreifuss, F.E. Responsiveness before, during and after spikewave paroxyms. Neurology 1974; 24: 659-665. 10. Panayiotopoulos, C.P., Obeid, T. and Waheed, G. Absences in juvenile myoclonic epilepsy. A clinical and video-electroencephalographic study. Annals of Neurology 1989; 25: 392-397. 11. Van Luijtelaar, E.I.J.M., De Bruijn, S.F.T.M., De-
Absence epilepsy:
12.
13.
14. 15.
early prognostic
signs
289
clerck, A.C., Renier, W.O., Vossen, J.M.H. and Coenen, A.M.L. Disturbances in time estimation during absence seizures in children, Epilepsy Research 1991; 9: 148-153. Livingston, S., Torres, I., Pauli, L.L. and Rider, R.V. Petit ma1 epilepsy. Results of a prolonged follow-up study of 117 patients. Journal of American Medical Association 1965; 194: 113-118. Dalby, M.A. Epilepsy and 3 per second spike-wave rhythms. A clinical, EEG and prognostic analysis of 346 patients. Acta Neurologica Scandinavica 1969; 40 (Suppl.1: l-183. Sato, S., Dreifuss, F.E. and Penry, J.K. Prognostic factors in absence seizures. Neurology 1976; 26: 788796. Loiseau, P., Pestre, M., Dartigues, J.F., Commenges, D., Barbeger-Gateau, C. and Cohadon, S. Long term prognosis in two forms of childhood epilepsy: Typical absence seizures and epilepsy with rolandic (centrotemporal) EEG foci. Annals of Neurology 1983; 13:
Syndromes
18. 19. 20.
in
Infancy,
Childhood
lepsy: A Review of the Literature Patients. London, Heinemann, Clinical nosis
22. 23. 24. 25. 26. 27.
28. 29.
32.
33. 34.
absence epilepsy. In: Epileptic and
Adolescence
(Eds J. Roger, C. Dravet, M. Bureau, F.E. Dreifuss and P. Wolf). London, John Libbey, 1985: pp. 106-120. Dieterich, E., Baier, W.K., Doose, H., Tuxhorn, I. and Fichsel, H. Long-term follow-up of childhood absence. Neuropediatrics 1985; 16: 149-154. Olsson, I. and Hagberg, G. Epidemiology of absence epilepsy: III. Clinical aspects. ActaPaediatrica Scandinuvica 1991; 80: 1066-1072. Gibberd, F.B. The prognosis of petit mal. Brain 1966; 89: 531-538. Jeavons, P.M. and Harding, G.F.A. Photosensitive epi-
21. Gastaut,
31.
35.
642-648.
16. Loiseau, P. Childhood
17.
30.
H. and Broughton, and
and
a Study
1975. R. Epileptic
Electroencephalographic Treatment. Springfield,
Features,
of 460 Seizures. Diag-
and 11, Charles C. Thomas, 1972: pp. 64-85. Janz, D. Die Epilepsien. Georg Thieme, Stuttgart, 1969. Aicardi, J. Epileptic syndromes in childhood. Recent advances in childhood epilepsy. Epilepsia 1988; 29 (Suppl. 3) SlS5. Charlton, M.H. and Yahr, M.D. Long-term follow-up of patients with petit mal. Archives of Neurology 1967; 16: 595-598. Roger, J. Prognostic features of petit ma1 absences. Epilepsia 1974; 15: 433. Wolf, P. and Inoue, Y. Therapeutic response of absence seizures in patients of an epilepsy clinic for adolescents and adults. Journal OfNeurology, 1984; 231: 225-229. Lugaresi, E., Pazzaglia, P., Frank, C. et al. Evolution and prognosis of primary generalized epilepsies of the petit ma1 absence type. In: Evolution and Prognosis of Epilepsy (Eds E. Lugaresi, P. Pazzaglia and CA. Tassinari). Bologna, 1973: pp. 3-22. Holowach, J., Thurston, D.L. and O’Learn, J.L. Petit ma1 epilepsy. Pediatrics 1962; 30: 893-901. Currier, R.D., Kooi, K.A. and Sandman, L.J. Prognosis
36. 37.
38. 39. 40. 41. 42. 43.
44.
45.
of pure petit mal. A follow-up study. Neurology (Minneap.) 1963; 13: 959-967. Doose, H., Gerken, H., Horstmann, T. and Volzke, E. Genetic factors in spike-wave absences. Epilepsia 1973; 14: 57-75. Browne, T.R. and Mirsky, A.E. Absence (petit mal) seizures. In: Epilepsy: Diagnosis and Management (Eds T.R. Browne and R.G. Feldman). Boston, Little Brown, 1983: pp. 61-74. Gastaut, H., Broughton, R., Roger, J. and Tassinari, C.A. Generalized nonconvulsive seizures without local onset. In: The Epilepsies: Handbook of Clinical Neurology (Eds P.J. Vinken and G.W. Bruyn). Amsterdam, 1974: Vol. 15, pp. 130-144. Janz, D. Epilepsy with impulsive petit ma1 (Juvenile myoclonic epilepsy). Actu Neurologicu Scandinavicu 1985; 72: 449-459. Ricci, G.F. and Vizzioli, R. Bilateral spike and wave complexes and cortical focus. Electroencephalography and Clinical Neurophysiology 1964; 6: 534. Quesney, L.E., Andermann, F., Lal, S. and Prelevic, S. Transient abolition of generalized photosensitive epileptic discharge in man by apomorphine, a dopaminereceptor agonist. Neurology 1980; 30: 1169-1174. Quesney, L.E., Andermann, F. and Gloor, P. Dopaminergic mechanism in generalized photosensitive epilepsy. Neurology 1981; 31: 1542-1544. Berkovic, S.F., Andermann, F., Andermann, E. and Gloor, P. Concepts of absence epilepsies: Discrete syndromes or biological continuum? Neurology 1987; 37: 993-1000. Gerken, H. and Doose, H. On the genetics of EEG anomalies in childhood. III. Spike and waves. Neuropadiatrie 1973; 4: 88-97. Doose, H. and Gerken, H. On the genetics of EEG anomalies in childhood. IV. Photoconvulsive reaction. Neuropadiatrie; 527: 1973; 4: 162-167. Covanis, A., Gupta, A.K. and Jeavons, P.M. Sodium valproate: monotherapy and polytherapy. Epilepsia 1982; 23: 693-720. Covanis, A. and Jeavons, P.M. Once daily sodium valproate in the treatment of epilepsy. Developmental Medicine and Child Neurology 1980; 22: 202-204. Juul-Jensen, P. Frequency of recurrence after discontinuance of anticonvulsant therapy in patients with epileptic seizures. Epilepsia 1964; 5: 352-363. Shinnar, S., Vining, E.P.G., Mellits, E.D. et al. Discontinuing antiepileptic medication in children with epilepsy after two years without seizures. A prospective study. Neti England Journal of Medicine 1985; 313: 976-980. Emerson, R., D’Souza, B.J., Vining, E.P., Holden, K.R., Mellits, E.D. and Freeman, J.M. Stopping medication in children with epilepsy. Predictors of outcome. New England Journal of Medicine 1981; 304: 1125-1129. Berg, B.O. Prognosis of childhood epilepsy-another look. New England Journal of Medicine 1982; 306: 861-862.
1: 281-289
Absence
epilepsy:
early prognostic
ATHANASIOS COVANIS, KONSTANTINOS VIRGINIA THEODOROU
signs
SKIADAS, NOMIKI LOLI, CHRISTINA
LADA &
The Department of Neurology, Children 3 Hospital ‘Aghia Sophia ‘, I 1527, Athens, Greece
We have studied 124 children with typical absence epilepsy. The onset of symptoms was in 12% under 4 years, in 51% between 4-8 years and in 37% above 8 years. The F:M ratio was 2:l in children under 4 years versus 1:l above 8 years. Absences alone occurred in 82% and absences followed or preceded by generalized tonic-clonic seizures (GTCS) in 6.5% and ll%, respectively. Simple absences were not seen in children under 4 years and were more frequent (14%) in the 4-8 years age group. Family history was positive for epilepsy in 20% and febrile convulsion in 7%. Sixteen percent had a positive past history of febrile convulsions. All patients showed bilateral, synchronous spike-wave discharges from 2.5 to 4 c/s. Lateralized spikes, spike-slow wave complexes were found in 27%. Photosensitivity was present in 18% and was marked in 12%. Monotherapy with sodium valproate or ethosuximide (91% SV) was successful in 85% of patients with absences alone and 68% of the absences with GTCS. Only 2% were not fully controlled either on monotherapy or polytherapy. Treatment was withdrawn in 41 patients and 13 relapsed. We have identified four factors associated with relapses: (a) poor initial response to treatment, (b) lateralized focal EEG abnormnality and/or marked photosensitivity, (cl the evolution to myoclonic epilepsy, and (d) early withdrawal of AED (~3 years). Key words: epilepsy; prognosis; monotherapy.
INTRODUCTION
Absence seizures were first described in 17701. The international classification of epileptic seizures2 distinguishes two types of absences, typical and atypical. Typical absences may be of simple or complex symptomatology. In simple absences, the impairment of consciousness is brief and may be associated with upward drifting of the eyes and slight rhythmic beating of the eyelids. In complex absences, the impairment of consciousness is usually of longer duration and is associated with other clinical phenomena, e.g. clonic, tonic, atonic, automatic and autonomic3-6. All absences observed clinically are associated with electroencephalographic discharges3 and, in addition, there is evidence that brief subclinical generalized spike and wave discharges do interfere with cognitive function7-Il. The prognosis of absence epilepsy is very variable6,12-15. It has been associated with the age of onset and the appearance of generalized tonic-clonic seizures12,‘“, the type of absences15, the response to treatment and the 1059-
1311/92/040281+09
$08.00/O
quality of antiepileptic drugs17,18, as well as the existence of an abnormal background EEG activity14y1’. Absence epilepsy, preceded by generalized tonic-clonic seizures has been considered as a separate entity, with poorer prognosis16”. In this study the patients with typical absences were classified according to the age of onset of their epilepsy in those, (a) under the age of 4 years, (b) between the ages of 4 to 8 years and (c) above the age of 8 years. Like other studies”, in each age group we distinguished, three subgroups of absence epilepsy: absences only (AE), absences followed by generalized tonic-clonic seizures (AE-GTCS) and absences preceded by GTCS (GTCS-AE). The purpose of this study was to discover early clinical and EEG characteristics that may help to forecast the outcome. MATERIAL
AND METHODS
One hundred and twenty-four children, with typical absences at the time of presentation @ 1992
Baillithe
Tindall
282 Table
A. Covanis ef a/. 1: AE: Clinical
findings
Type of seizures AE
Sex
FH+ve
n
n
F:M
CA
SA
E
FCs
h/o FCs
102
57F 45M 4F 4M 7F 7M 68F 56M
1.2:1
90
12
21
7
15
-
1
2
4
1
3
25
9
20
AE-GTCS
8
GTCS-AE
14
Total
Type of AE
124
1:l
8
-
1:l
14
-
1.2:1
112
12
AE = absence epilepsy with absences only, AE-GTCS = absences followed by generalized tonic-clonic seizures, GTCS-AE = GTCS followed by absences, CA = complex absences, SA = simple absences, E = epilepsy, FCS = febrile convulsions, h/o = history of, FH = family history.
attend our epilepsy clinic, established in 1987. All patients were diagnosed by clinical and EEG criteria based on the history of seizures, direct observation of the absences during overbreathing, the association of the clinical event with the spike and wave discharges in the EEG and, lately, by video-EEG analysis. The family history of seizure disorders was fully investigated. The EEG and the response to intermittent photic stimulation (IPS) was recorded using standard techniques2’, Patients were asked to hyperventilate for 3 min and occasionally up to 5min for those children who were not disturbed by the process. Both overbreathing and IPS were repeated during the recording. In the younger age group, hyperventilation was encouraged by blowing either a paper, a light out or a paper streamer. Counting during the deep breaths was also applied in order to assess lapses of consciousness. However, this process of counting was less successful in the young children since the pattern of breathing was disturbed and effective overbreathing was not achieved. If an absence was observed, the child’s response to a powerful stimulus such as calling his name or giving a simple command, was assessed and the clinical and EEG characteristics of the absence were recorded. The response during an absence was compared with that during a normal status and EEG activity. Video-EEG studies were made using Vidigraph, which allows simultaneous association of the clinical and EEG events. If an absence was not recorded, a sleep-waking record was taken after sleep deprivation. Treatment was initiated with one drug, usually sodium valproate (SV) once daily and the clinical response was assessed every 2 weeks until complete control (100%) was achieved. Once clinical control was achieved
the EEG was repeated after 2-3 months. If subclinical discharges were observed the daily dose of the anti-absence drug was adjusted. If SV was unsuccessful it was substituted by ethosuximide (ETH). If either drug was not successful, a combination of both was tried. If the combination of SV and ETH failed to achieve complete control, clonazepam (Clan) was also added. The withdrawal of the drugs in the cases of polytherapy was done in the reverse order of their introduction. The third drug was phased out after 2 years of successful treatment, the second after 3 years and the first after 4 years. If a relapse occurred, the drug which was last withdrawn was reintroduced.
RESULTS Clinical Of the 124 patients, 102 (82%) had absences only, eight (6.5%) had absences followed by GTCS and 14 (11%) had GTCS followed by absences (Table 1). The total female to male ratio was 1.2:1. Complex absences were observed in 112 (90%) cases and simple absences in 12 (10%). Epilepsy and febrile convulsions in the 1st and 2nd degree relatives was reported in 25 (20%) and 9 (7%) cases, respectively. Twenty children with absence epilepsy had a positive past history of febrile convulsions. In 15 of the 124 patients the age of onset of the absences was between 2.5 and 4 (mean 3.6 + 0.4) years. There were 10 girls and five boys giving a female to male ratio of 2:l. Simple absences were not observed in this group. In 63
Absence epilepsy:
early prognostic
signs
children the age of onset varied from 4 to 8 (mean 6.1 2 1.1) years. Complex absences occurred in 54 (86%) patients and simple absences in nine (14%). Of the 63 children, 36 were girls and 27 boys (F:M = 1.3:1). In 46 patients, their absences appeared between ages 8 to 13.5 (mean 10.3 ? 1.4) years. Simple absences occurred in three (6.5%) and complex absences in 43 (93.5%). The F:M ratio was 1:l.
School performance In 65 patients (52%) achievement at school was rated as low average. None of them had either positive lateralized neurological signs or positive brain CT scans. The duration of epilepsy prior to the start of an appropriate and effective treatment in this group, varied from 0.1 to 7 (1.5 + 1.6) years. In contrast, in the remaining 59 (48%) patients their performance at school was rated as good. In the latter group, the duration of epilepsy before introduction of treatment was 0.1 to 3 (mean 0.5 XL0.5) years.
Analysis of the clinical data Absences only (n = 102) Of the 102 patients who had only absence seizures, 12 (12%) had simple absences and 90 (88%) complex absences. The female to male ratio was 1.3:1. In 11% (6 females and 5 males), all with complex absences, the onset of the absences was under the age of 4 years; in 56% (34 females and 23 males), the absences had appeared from 4 to 8 years of age (9 simple absences, 48 complex absences) and in the remaining 33% (17 females and 17 males), absences had first occurred above the age of 8 years (3 simple absences, 31 complex absences). The family history was positive for epilepsy in 20% of cases and for febrile convulsions in 7%. Past history of febrile convulsions was positive in 15%. The frequency of the associated clinical features of the 90 patients with complex absences are as follows: automatisms occurred in 68% of the patients as de nouo and in 23% as perseverative. A clonic component was observed in 63%, tonic in 40% and atonic in 19%. Autonomic signs in the form of pallor and incontinence of urine occurred in 8%.
283
Onset with absences followed by generalized tonic-clonic seizures (n = 8) Eight patients (6.5%) had absence epilepsy followed by GTCS. In this group are included three cases that evolved to myoclonic epilepsy.
(i) Onset of absences under the age of 4 years. In two females, GTCS appeared 12 and 15 months after the start of treatment, respectively. The first case was taking sodium valproate (SV) and ethosuximide (ETH) was added for successful control. The second case was on ETH and changed to SV. The latter case evolved into myoclonic epilepsy. This became obvious when SV was discontinued after 5.5 years of successful (100%) control.
(ii) Onset of absences between the ages of 4 and 8 years. In 2 males, the onset of absences occurred at 6.5 and 6.9 years of age, respectively. Both received ethosuximide. A tonicclonic seizure occurred 10 and 14 months, respectively after the start of the treatment and ethosuximide was substituted in both by sodium valproate. The former case evolved into myoclonic epilepsy, which only became obvious 5 years later during the intermittent photic stimulation (IPS) test. At that time the patient was not taking his treatment regularly.
(iii) Onset of absences above the age of 8 years. There were two males and two females whose first absence seizures had occurred above 8 years of age. The two male cases had a tonicclonic seizure about a year after the start of the treatment because of low daily dose of sodium valproate. One female, on ethosuximide for 2.5 years, relapsed with a GTCS seizure at 15 years old during IPS. She was changed to sodium valproate. The second female had a GTCS premenstrually with her menarche, 6 months after the onset of her absences. At the time she was not having any treatment.
Generalized tonic-clonic absences (n = 14)
seizures prior to
In 14 (11%) patients the onset of absences occurred 0.1 to 2 (mean 0.49 + 0.6) years after the onset of the GTCS. In seven patients the absences became obvious soon after the onset
A. Covanis et al.
284
of the GTCS prior to any treatment. In the other seven, the absences appeared after carbamazepine (5 cases) or phenobarbitone (2 cases) was introduced for the GTCS. The family history was positive for epilepsy in four patients and for febrile convulsions in one. Three patients had a positive past history of febrile convulsions.
(i) Onset of absences under the age of 4 years. Absences appeared before 4 years of age in two females of whom one had three GTCS from the ages of 3 to 4 years with absences appearing at the age of 4 years and the second patient had a GTCS at 3 years old and she was put on carbamazepine and her absences began 9 months later.
charges, especially induced by overbreathing, which varied from 2.5 to 4c/s. In all cases the generalized SW discharges disappeared during treatment. Lateralized single spikes or spike and slow wave complexes (Table 2) were seen in 34 (27%) patients, all with complex absences. In 32 of the 34 patients, the focal abnormality disappeared during the course of treatment, in two it continued and in one was only obvious in the follow-up EEGs. Intermittent photic stimulation induced abnormalities in 22 (18%) patients. In seven (5.6%), photosensitivity was mild and in 15 (12%) marked. Photosensitivity disappeared during the follow-up EEGs with an appropriate daily dose of sodium valproate (30-35 mg/kg).
Absences only (n = 102) (ii) Onset of absences between 4 and 8 years. This group consisted of two male and two female patients. The GTCS occurred in all of them between 2 weeks and 12 months prior to the onset of the absences. Two patients were on carbamazepine when their absences started. In two, the family history was positive for convulsive disorders.
(iii) Onset of absences above the age of 8 years. This group comprises five males and three females. The GTCS preceded the absences by between 6 days and 3 months. Two patients were taking carbamazepine and two phenobarbitone at the onset of their absences. Family history was positive for epilepsy in one case.
Of the 102 patients who suffered absence seizures only, spikes and/or spike and slow wave lateralized features were observed in the initial EEGs in 26 (25%) cases, all with complex absences (Table 2). In one case a focal abnormality appeared during the follow up EEGs. Of the 26 cases, in nine treatment was discontinued and two relapsed. Intermittent photic stimulation induced abnormality in 16 cases. Six had a mild (narrow range lo-3Of/s) response and 10 marked (wider range). In one case, with onset of her absences at the age of 3.5 years, myoclonic jerks and photosensitivity became apparent when SV was discontinued 5 years later.
AE-GTCS (n = 8) Electroencephalographic
data
All 124 patients showed in the initial EEGs bilateral and synchronous spike and wave dis-
Of the eight patients showed focal spikes or complexes (Table 2). In abnormality disappeared
with AE-GTCS, four spike and slow wave three cases the focal during the follow-up
Table 2: EEG focal S or SSWC and photosensitivity in absence epilepsy Type
of epilepsy
Lateralized rz
AE AE-GTCS GTCS-AE Total
102 8 14 124
Initial (+)
S or SSWC
EEG
26 4* 4 34
S = spikes, SSWC = spike and slow wave complexes, epilepsy with absences only, AE-GTCS = absences followed by AE. * One case is the same patient.
Photosensitivity
FU EEGs
Initial
(+)
(-)
mild
1 1* 1 3
26 3 3 32
6 1 7
FU = follow-up, (+) followed by generalized
= positive, tonic-clonic
EEG marked 10 3* 2 15
(-)
= negative, AE seizures, GTCS-AE
FU EEGs (+) = absence = GTCS
Absence epilepsy:
early prognostic
signs
EEGs. In one case the initial EEG showed focal abnormality and marked photosensitivity. In this patient the follow-up EEGs did show some focal spike and slow wave complexes, but the response to IPS was negative. Four years later she relapsed with myoclonic jerks during IPS. In the other two patients with initial marked photosensitivity, the follow-up EEGs became normal. Both relapsed with myoclonic jerks 5 years later when SV was discontinued.
GTCS-AE (n = 14) Of the 14 patients with GTCS-AE, four had in their initial EEGs focal single spikes or spike and slow wave complexes. In three the followup EEGs became normal. Of the 14, one had mild and two marked photosensitivity in their initial EEGs. The follow-up EEGs became normal.
Treatment Results according to the age of onset of AE and type of seizures (i) Onset of absences under the age of 4 years. Complex absences only (n = 11). Of the 11 patients, nine are completely (100%) controlled (6 on SV, 1 on ETH and 2 on SV + ETH) and two are controlled by 80%. Of the two patients who are partially controlled, one is on monotherapy with SV and has occasional absences because of non-compliance with treatment and the other, even on polytherapy (SV + ETH+ Clan), has occasional absences with a marked clonic component. In four of the nine cases with complete control, the treatment was discontinued. Two cases, both female, relapsed. The mean duration of treatment in the non-relapsers and the relapsers was no different (5.25 + 2.47 years vs 5.5 + 0.7 years). Of the relapsers, one case had a positive family history of FCs and positive past history of FCs. She responded fully to SV within 1 week of treatment. When she relapsed she showed marked eyelid jerking during the SW discharges and marked photosensitivity (range lo-50 f/s). In the second case complete control was achieved when ethosuximide was added to sodium valproate. She relapsed with eyelid jerking during spike and
285
wave or polyspike and wave discharges when the second drug (ETH) was reduced. AE and GTCS (n = 4). There were two patients with AE-GTCS and two with GTCSAE. In three of these patients (2 GTCS-AE, 1 AE-GTCS) complete control was achieved by monotherapy with SV and in the fourth patient by SV + ETH. In one case (AE-GTCS) of the monotherapy group the treatment was discontinued after 5.5 years. She relapsed during IPS with eyelid jerking and myoclonic jerks, after a month off treatment. Her initial absences had an associated marked clonic component and a photosensitivity range from 5-40 f/s.
(ii) Onset of absences between the ages 4-8 years. Absences only (n = 57). Of the 57 patients in this group, 47 are completely controlled by monotherapy (42 on SV and 5 on ETH) and 10 by polytherapy (7 on SV + ETH, 3 on SV + ETH + Clan). In 2106 CA, 5 SA) the treatment was discontinued. Fourteen have not relapsed. The non-relapsers had been receiving treatment for between 3.5 and 6 (mean 5 f 1) years and were followed since the treatment was discontinued for 2.4 + 0.9 years. Seven patients (6 CA, 1SA) relapsed. They were completely controlled for 4.4 f 2.2 years (3 of the 7, under 3 years). Three were on polytherapy (2 on SV + ETH + Clon, 1 on SV + ETH) and four on monotherapy (3 on SV, 1 on ETH). The three cases on monotherapy with SV were successfully treated for 3.5, 2.5 and 2.0 years and relapsed when the drug was discontinued. The one case on ETH monotherapy was treated for 8 years and relapsed when withdrawn from treatment. Of the relapsers, one case had complex absences with a marked clonic component and two females relapsed with their menarche. AE and GTCS (n = 61. Of the six patients, four are completely controlled by monotherapy with SV (3 GTCS-AE, 1 AE-GTCS) and two by SV + ETH (1 AE-GTCS, 1 GTCS-AE). One case relapsed during IPS with myoclonic jerks: he had been completely controlled on monotherapy for 5 years. At the time of his relapse he was not taking his treatment regularly.
(iii) Onset of absences above the age of 8 years. Absences only (IZ = 34). Of the 34 patients in this group, 33 are completely (100%) controlled by monotherapy (30 SV, 3 ETH) and one by polytherapy (SV + ETH). Treatment was dis-
A. Covanis et al.
286 Table 3: AE: Resoonse to treatment and outcome Monotherapy
Type of epilepsy 100% AE AE & GTCS Total
a7* 15t 102
80%
Polytherapy 100%
80%
13$
1
61i 19
1
28 6 7 41
1t 1t 2
Relapsers
Off treatment
5 4 4
13
AE = absence epilepsy, absences only, AE & GTCS = absence epilepsy and generalized tonic-clonic seizures, 100% = complete control, 80% = occasional absences, * 78 sodium valproate (SW, 9 ethosuximide (ETH), t all SV, $ 10 SV + ETH, 3 SV + ETH + Clon, 0 all SV + ETH.
continued in nine cases (8 CA, 1 SA) of the monotherapy group (6 SV, 3 ETH) and have not relapsed. These non-relapsers were treated for between 3.5 and 6.5 (4.7 k 1) years and have been followed up after treatment was discontinued for from 1 to 2.5 (1.5 + 0.5) years. AE and GTCS (n = 12). Of the 12 patients in this group, 11 (5 AE-GTCS, 6 GTCS-AE) are completely controlled (7 SV, 1 ETH, 3 SV + ETH) and one (GTCS-AE) treated by monotherapy with SV has responded by 80%. Treatment was discontinued in five cases. Three have not relapsed and two have relapsed. The non-relapsers had been receiving treatment for between 3.5 and 4 (3.8 * 0.3) years and have so far followed up after the treatment was discontinued for 1 f 0.1 years. Of the two relapsers, one was treated for 2 years and the other for 4 years with ETH. The latter case relapsed during IPS with myoclonic jerks. In summary (Table 31, of the 102 children with absences only 88 (86%) received monotherapy (79 SV, 9 ETH) and 14 (14%) polytherapy (9 SV + ETH, 1 SV + Clon, 4 SV + ETH + Clon). On monotherapy 87 patients (78 SV, 9 ETH) were completely controlled and one was controlled by 80%. Monotherapy, therefore, was successful in 85% of cases. Of the 14 patients who received polytherapy, 13 are fully controlled (10 SV + ETH, 3 SV + ETH + Clon) and one (SV + ETH + Clon) has an occasional absence with a marked clonic component. Of those patients with absence epilepsy only, who were treated successfully, treatment was discontinued in 34 (33%) patients, nine of whom relapsed. Of the 22 patients with AE and GTCS, 15 (68%) responded completely to monotherapy with SV and six to the combination of SV and ETH. One patient on SV has occasional absences (non-compliance). The treatment was discontinued in seven (4 GTCS-AE, 3 AE-
GTCS) of the 22 patients and relapse occurred in four (3 AE-GTCS, 1 GTCS-AE). Only 2% of all the cases were not fully controlled either by monotherapy or polytherw. A total of 41 (33%) patients out of the 124 were withdrawn from treatment of whom thirteen relapsed between 1 week and 36 (2.6 f 2.3) months after the treatment was stopped. Table 4 shows the relationship between age of onset, age at which the treatment was discontinued and the present age of the 28 patients, who have so far not relapsed. Table 5 shows the mean age of onset in the three different age groups, of the 13 patients who relapsed, in relation to their relapse age. Table 4: Non-relapsers and present age Mean age at onset (years) 3.5 f 0.7 6 f 0.9 9.7 f 1.5*
(n = 28): Onset age vs age off Rx
No 1F 1M 8F 6M 3F 9M
Mean age treatment
Mean present age (years)
10 f 4
13 + 4.7
11.8 f 1.5
14.3 + 1.4
14.6 + 2
16 + 2.3
Vs = versus, off Rx = off treatment, male. * 3 patients GTCS-AE.
F = female, M =
Table 5: Relapsers (n = 13): OnSat aoe vs RelaDSe Mean age of onset (years)
n
3.6 f 0.2
3F
5.8 + 0.6
6F 2M 1F 1M
11.5 + 0.7
aoe
Mean relapse age (years) 10.9 f 2.8 (R 8.7-14)* 11.9 + 2.4 (R 8.5-15)t 16 + 4.0 (13.5519Q
Vs = versus, F = female, M = male, R = range. * 3 evolved to myoclonic, f 1 myoclonic, 1 marked clonic, 3 treatment less than 3 years, 3 other factors (see Table 6), $ 1 GTCS-AE, 1 AE-GTCS (myoclonic).
Absence epilepsy:
early prognostic
signs
DISCUSSION Typical absence epilepsy is well-defined and is classified as childhood absence epilepsy3T4F21 with an onset between the ages of 4 to 8 years and juvenile absence epilepsy22 with an onset age of above 8 years23. We evaluated our patients with absence epilepsy according to their clinical features as previously described18 and age of onset of their symptoms. As in the literature132 W24.25 absences occurred more frequently in girls than in boys and between the ages 4 to 8 years (51%). Females predominated in the younger age group (F:M = 2:l < 4 years vs 1:l > 8 years). In our study, as in others, a female preponderance was not found in juvenile absences. Wolf26 found a male to female ratio of 1.2:1. The difference in our results may be due to our paediatric group not including cases with an onset of absences above the age of 15 years. Simple absences are reported in less than 10% of typical absences16. We also found a 10% prevalence of simple absences. They occurred mainly between the ages of 4 to 8 years (14%), were less frequent above the age of 8 (6.5%) years and were not seen under the age of 4 years. The complex absences that evolve into myoclonic epilepsy did appear to have a marked clonic component from the beginning. This confirms observations made by others10>22,33
Positive family history for epilepsy in first degree relatives has been found to vary from 15% to 44%1g927-2g. We found, as others have2’ a 20% positive family history of epilepsy and 7% of febrile convulsions. Sixteen percent had a positive past history of febrile convulsions. Similar results were found in other studies”T3’. We found that absence epilepsy with absences only, occurred in 82% of the patients and absence epilepsy followed by GTCS in 7%. These findings differ from those of where the corresponding others 12,15,24,29 percentages were 60% and 40%. We believe that the use of sodium valproate as a first choice drug protects the patients from the development of subsequent GTCS. As we have shown before4’ sodium valproate is very effective in absence epilepsy, particularly when given as a single dose, usually at night41. Absences preceded by generalized tonicclonic seizures are regarded as a separate entity6,16,17 particularly if they present under the age of 5 years 17,18. In our study, as in
287
others’s, absence epilepsy with an initial GTCS occurred in 11% of patients. This group of patients behaved similarly to the other two groups, especially with respect to absences followed by GTCS. However, monotherapy was less successful in absences combined with GTCS than in absences only (68% vs 85%). In 50% of our patients carbamazepine or phenobarbitone were used for the GTCS and facilitated the appearance of absences. We have not seen GTCS evolving into absences when sodium valproate is used to control major seizures. A precise diagnosis is therefore missed in such cases. The characteristics of the SW discharge in typical absence epilepsy have already been reported13,31T32. We believe that the SW discharges in simple absences and in those with complex absences, which evolve into myoclonic epilepsy are of short duration (usually 1 to 8 s), with an abrupt onset and termination. The characteristic slow wave ending of the discharges and the movement artefact that supervenes in the interface of the burst during a clinical event are only seen in the complex absences. In comparison with other studies34, we found lateralized single spikes or spike and slow wave complexes in a higher percentage (27%). These results did not differ among the patients with absences only and those with absences associated with GTCS. The focal EEG abnormalities were found only in complex absences and, in combination with photosensitivity, predicted an unfavourable outcome. Photosensitivity in our patients was found in 18% and was marked in 12%. There is evidence that spike and wave discharges that are accentuated during overbreathing are inherited independently from spike and wave discharges evoked by intermittent photic stimulation 35-37. The coexistence of the two types of SW discharges in the same patient is indicative of a multifactorial model of inheritance38,3g. In contrast to some reports17, but consistent with others”, we did not find the duration of epilepsy to be a factor influencing response to treatment of relapse after drug withdrawal. Our results showed that (a) quick response to the treatment was a good prognostic sign and (b) the longer the duration of epilepsy prior to correct treatment and prompt resnonse, the more likely the children were to have ‘cognitive impairment’ and specific educational problems. Fifty-two percent of our children with educational difficulties in the secondary school
A. Covanls et al.
288
had a mean duration of epilepsy of 1.5 + 1.6 years as opposed to 0.5 f 0.5 years in the remaining 48% who had problems. These results indicate that SW discharges may interfere with cognitive function and if left untreated may cause permanent loss of abilities. Some authors advocate the withdrawal of AED after 2 years of successful treatment42Y43, others after 4 years44’45. Some studies did not find EEG of value in deciding to discontinue treatment44 others did43. We believe that individual predictors of favourable or unfavourable outcome should be found in each type of epilepsy. Follow-up EEGs in absence epilepsy are usually normal and therefore have no value in decision making. In 41 of the 124 patients with absence epilepsy treatment was discontinued and 13 relapsed (Table 3). The following factors were found to predict unfavourable outcome: (i) poor initial response to treatment-polytherapy, (ii) lateralized single spikes or spike and slow wave complexes and/or marked photosensitivity in the EEG, (iii) AE with marked clonic component, followed or not by GTCS-evolution into myoclonic epilepsy and (iv) early withdrawal of AED. The relationship between these factors and the cases that relapsed and those that did not is shown in Table 6. Table 6: AE: The coexistence of unfavourable factors in relapsers and non-relapsers No. of factors 0 1 2 3 Total
Relapsers 3 9 1 13
Non-relapsers
Total off treatment
21 6 1 28
21 9 10 1 41
CONCLUSIONS (1) In the three age groups studied, we found differences in distribution between the sexes of the different types of absence seizures. (2) Using sodium valproate as an initial drug, the response to treatment and the outcome of absence epilepsy is good, i.e. fewer cases develop GTCS. (3) A prolonged duration of epilepsy prior to treatment was associated with educational problems. (4) On withdrawal of treatment 32% relapsed.
Four unfavourable come.
factors
predicted
the out-
We believe that in absence epilepsy attempts to withdraw treatment should be made after 3 (preferably 4) years of successful monotherapy treatment. Early indicators of unfavourable outcome should not influence the decision to withdraw treatment under close clinico-EEG supervision. In this way correct diagnosis and prognosis can be made. Polytherapy helps some children to pass an acute stage of their problem. Therefore attempts to reduce polytherapy to monotherapy should be made after 2 years of successful treatment.
ACKNOWLEDGEMENTS We are grateful to our EEG technicians for their invaluable assistance with this study.
REFERENCES 1. Tissot, S.A. Traite de l’epilepsie, faisant le tome troisieme du triate des nerfs et de leurs maladies. Paris, 1770. 2. Commission on classification and terminology of the International League against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981; 22: 489501. 3. Penry, J.K., Porter, R.J. and Dreifuss, F.E. Simultaneous recording of absence seizures with video tape and electroencephalography. A study of 374 seizures in 48 patients. Brain 1975; 98: 427-440. 4. Sato, S. Generalized seizures: absence. In: Pediatric Epileptology (Ed. F.E. Dreifuss). Boston, John Wright, 1983; pp. 65-91. 5. Drury, I. and Dreifuss, F.E. Pyknoleptic petit mal. Acta Neurologica Scandinavica 1985; 72: 353-362. 6. Aicardi, J. Epilepsy in children. The International Review of Child Neurology. New York, Raven Press, 1986: pp. 79-99. I. Geller, M. and Geller, A. Brief amnestic effects of spike-wave discharges. Neurology 1970; 20: 10891095. 8. Goode, D.J., Peru-y, J.K. and Dreifuss, F.E. Effects of paroxysmal spike-wave on continuous visual-motor performance. Epilepsia 1970; 11: 241-254. 9. Browne, T.R., Penry, J.K., Porter, R.J. and Dreifuss, F.E. Responsiveness before, during and after spikewave paroxyms. Neurology 1974; 24: 659-665. 10. Panayiotopoulos, C.P., Obeid, T. and Waheed, G. Absences in juvenile myoclonic epilepsy. A clinical and video-electroencephalographic study. Annals of Neurology 1989; 25: 392-397. 11. Van Luijtelaar, E.I.J.M., De Bruijn, S.F.T.M., De-
Absence epilepsy:
12.
13.
14. 15.
early prognostic
signs
289
clerck, A.C., Renier, W.O., Vossen, J.M.H. and Coenen, A.M.L. Disturbances in time estimation during absence seizures in children, Epilepsy Research 1991; 9: 148-153. Livingston, S., Torres, I., Pauli, L.L. and Rider, R.V. Petit ma1 epilepsy. Results of a prolonged follow-up study of 117 patients. Journal of American Medical Association 1965; 194: 113-118. Dalby, M.A. Epilepsy and 3 per second spike-wave rhythms. A clinical, EEG and prognostic analysis of 346 patients. Acta Neurologica Scandinavica 1969; 40 (Suppl.1: l-183. Sato, S., Dreifuss, F.E. and Penry, J.K. Prognostic factors in absence seizures. Neurology 1976; 26: 788796. Loiseau, P., Pestre, M., Dartigues, J.F., Commenges, D., Barbeger-Gateau, C. and Cohadon, S. Long term prognosis in two forms of childhood epilepsy: Typical absence seizures and epilepsy with rolandic (centrotemporal) EEG foci. Annals of Neurology 1983; 13:
Syndromes
18. 19. 20.
in
Infancy,
Childhood
lepsy: A Review of the Literature Patients. London, Heinemann, Clinical nosis
22. 23. 24. 25. 26. 27.
28. 29.
32.
33. 34.
absence epilepsy. In: Epileptic and
Adolescence
(Eds J. Roger, C. Dravet, M. Bureau, F.E. Dreifuss and P. Wolf). London, John Libbey, 1985: pp. 106-120. Dieterich, E., Baier, W.K., Doose, H., Tuxhorn, I. and Fichsel, H. Long-term follow-up of childhood absence. Neuropediatrics 1985; 16: 149-154. Olsson, I. and Hagberg, G. Epidemiology of absence epilepsy: III. Clinical aspects. ActaPaediatrica Scandinuvica 1991; 80: 1066-1072. Gibberd, F.B. The prognosis of petit mal. Brain 1966; 89: 531-538. Jeavons, P.M. and Harding, G.F.A. Photosensitive epi-
21. Gastaut,
31.
35.
642-648.
16. Loiseau, P. Childhood
17.
30.
H. and Broughton, and
and
a Study
1975. R. Epileptic
Electroencephalographic Treatment. Springfield,
Features,
of 460 Seizures. Diag-
and 11, Charles C. Thomas, 1972: pp. 64-85. Janz, D. Die Epilepsien. Georg Thieme, Stuttgart, 1969. Aicardi, J. Epileptic syndromes in childhood. Recent advances in childhood epilepsy. Epilepsia 1988; 29 (Suppl. 3) SlS5. Charlton, M.H. and Yahr, M.D. Long-term follow-up of patients with petit mal. Archives of Neurology 1967; 16: 595-598. Roger, J. Prognostic features of petit ma1 absences. Epilepsia 1974; 15: 433. Wolf, P. and Inoue, Y. Therapeutic response of absence seizures in patients of an epilepsy clinic for adolescents and adults. Journal OfNeurology, 1984; 231: 225-229. Lugaresi, E., Pazzaglia, P., Frank, C. et al. Evolution and prognosis of primary generalized epilepsies of the petit ma1 absence type. In: Evolution and Prognosis of Epilepsy (Eds E. Lugaresi, P. Pazzaglia and CA. Tassinari). Bologna, 1973: pp. 3-22. Holowach, J., Thurston, D.L. and O’Learn, J.L. Petit ma1 epilepsy. Pediatrics 1962; 30: 893-901. Currier, R.D., Kooi, K.A. and Sandman, L.J. Prognosis
36. 37.
38. 39. 40. 41. 42. 43.
44.
45.
of pure petit mal. A follow-up study. Neurology (Minneap.) 1963; 13: 959-967. Doose, H., Gerken, H., Horstmann, T. and Volzke, E. Genetic factors in spike-wave absences. Epilepsia 1973; 14: 57-75. Browne, T.R. and Mirsky, A.E. Absence (petit mal) seizures. In: Epilepsy: Diagnosis and Management (Eds T.R. Browne and R.G. Feldman). Boston, Little Brown, 1983: pp. 61-74. Gastaut, H., Broughton, R., Roger, J. and Tassinari, C.A. Generalized nonconvulsive seizures without local onset. In: The Epilepsies: Handbook of Clinical Neurology (Eds P.J. Vinken and G.W. Bruyn). Amsterdam, 1974: Vol. 15, pp. 130-144. Janz, D. Epilepsy with impulsive petit ma1 (Juvenile myoclonic epilepsy). Actu Neurologicu Scandinavicu 1985; 72: 449-459. Ricci, G.F. and Vizzioli, R. Bilateral spike and wave complexes and cortical focus. Electroencephalography and Clinical Neurophysiology 1964; 6: 534. Quesney, L.E., Andermann, F., Lal, S. and Prelevic, S. Transient abolition of generalized photosensitive epileptic discharge in man by apomorphine, a dopaminereceptor agonist. Neurology 1980; 30: 1169-1174. Quesney, L.E., Andermann, F. and Gloor, P. Dopaminergic mechanism in generalized photosensitive epilepsy. Neurology 1981; 31: 1542-1544. Berkovic, S.F., Andermann, F., Andermann, E. and Gloor, P. Concepts of absence epilepsies: Discrete syndromes or biological continuum? Neurology 1987; 37: 993-1000. Gerken, H. and Doose, H. On the genetics of EEG anomalies in childhood. III. Spike and waves. Neuropadiatrie 1973; 4: 88-97. Doose, H. and Gerken, H. On the genetics of EEG anomalies in childhood. IV. Photoconvulsive reaction. Neuropadiatrie; 527: 1973; 4: 162-167. Covanis, A., Gupta, A.K. and Jeavons, P.M. Sodium valproate: monotherapy and polytherapy. Epilepsia 1982; 23: 693-720. Covanis, A. and Jeavons, P.M. Once daily sodium valproate in the treatment of epilepsy. Developmental Medicine and Child Neurology 1980; 22: 202-204. Juul-Jensen, P. Frequency of recurrence after discontinuance of anticonvulsant therapy in patients with epileptic seizures. Epilepsia 1964; 5: 352-363. Shinnar, S., Vining, E.P.G., Mellits, E.D. et al. Discontinuing antiepileptic medication in children with epilepsy after two years without seizures. A prospective study. Neti England Journal of Medicine 1985; 313: 976-980. Emerson, R., D’Souza, B.J., Vining, E.P., Holden, K.R., Mellits, E.D. and Freeman, J.M. Stopping medication in children with epilepsy. Predictors of outcome. New England Journal of Medicine 1981; 304: 1125-1129. Berg, B.O. Prognosis of childhood epilepsy-another look. New England Journal of Medicine 1982; 306: 861-862.
