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Keywords:

  • Epilepsy surgery;
  • Antiepileptic drug treatment;
  • Long-term follow-up;
  • Outcome

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Summary:  Purpose: To evaluate the long-term impact of surgical treatment on seizure outcome and antiepileptic drug (AED) use in patients with pharmacoresistant temporal lobe epilepsy (TLE).

Methods: Comparison of seizure outcome and AED us in operated-on TLE patients (n = 148) and nonsurgically treated TLE patients (n = 94) at a baseline visit and a follow-up visit after a mean period of 4.8 years.

Results: At follow-up, 44.6% of the surgical patients and 4.3% of the nonsurgical patients had been continuously seizure- free since the baseline visit (including the immediate postoperative period). A further 17.6% of the operated-on and 3.2% of the not operated-on patients had been seizure-free for at least the previous year; 37.8% of the surgical and 92.5% of the nonsurgical patients had had seizures during the previous 12 months (p < 0.001). Of the surgical patients, 8.8% versus none of the nonsurgical patients were AED free at follow-up; 55.4% versus 20.2% were receiving monotherapy, and 35.8% versus 79.8% were receiving polytherapy (p < 0.001). Mean number of AEDs and mean change in number of AEDs were significantly more favorable in operated-on than in non–operated-on patients. Further subgroup analysis revealed that not only the continuously seizure-free surgical patients, but also the operated-on patients with ongoing seizures took fewer AEDs than their respective non–operated-on counterparts.

Conclusions: This controlled study for the first time provides comprehensive information on long-term seizure outcome and AED use in surgical TLE patients. It shows a more favorable seizure outcome and AED use in the surgically treated patients. The latter holds true even for the not seizure-free patient subgroup.

Epilepsy surgery primarily aims at complete seizure control and, more generally, an improvement of health-related quality of life. Health-related quality of life in epilepsy patients depends, among other things, on the amount and the side effects of the daily antiepileptic drugs (AEDs) required for prolonged therapy (1). Only very few studies reported a seizure and AED outcome using a comparison between a group of surgically treated epilepsy patients and a control group of non–operated-on patients after a follow-up period of >1 year (2–6). The present study has therefore been designed to comprehensively address the question of the long-term impact of epilepsy surgery on seizure frequency and AED use in a large sample of patients with operated-on and non–operated-on pharmacoresistant temporal lobe epilepsy (TLE) under continuous specialized epileptologic care.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The study was conducted between May 1997 and May 2000 (“visit 2”) on patients who fulfilled the following criteria: (a) diagnosis of TLE by experienced epileptologists after a comprehensive investigation at this center (surgical candidacy selection or presurgical assessment, “visit 1”) between March 1987 and October 1997; (b) diagnosis of pharmacoresistant seizures at visit 1 in the sense that the adequate use of at least two standard AEDs in monotherapy had not led to acceptable seizure control (i.e., had not stopped seizures or had caused intolerable side effects) (7); (c) AED treatment between visit 1 and visit 2 at the discretion of the physicians of the outpatient clinic of this institution in agreement with the patients' wishes as far as possible; the physicians of the outpatient clinic treat the postsurgical patients and the conservative patients alike; this criterion excludes patients whose pharmacotherapy after visit 1 was modified by physicians outside this institution; (d) surgical treatment after visit 1 or mere anticonvulsive medical treatment at least at visit 1 or visit 2, thereby excluding patients with vagus nerve stimulation and patients who neither at visit 1 nor at visit 2 took AEDs; and (e) follow-up of ≥1 year.

For both visits, monthly seizure frequency was calculated as the number of seizures during the previous 12 months as reported in the patient's seizure diary divided by 12. At visit 2, outcome was rated as follows: class A, if the patient was continuously seizure-free since visit 1; class B, if the patient was seizure-free for ≥1 year but not permanently seizure-free since visit 1; and class C, if he or she had seizures during the previous 12 months. In surgical patients, all seizures (including auras) occurring after the surgical procedure were counted. In nonsurgical patients, all seizures after visit 1 were counted. AED use was evaluated as follows: the number of AEDs used for long-term treatment was recorded, the change in number of AEDs between visit 1 and visit 2 was calculated, and each patient was assigned to one of the following three groups: (a) no AEDs, (b) receiving monotherapy, or (c) receiving polytherapy (i.e., more than one AED). In patients with a monotherapy, patients with subtherapeutic blood levels were identified [carbamazepine (CBZ), <5 μg/ml; sodium valproate (VPA), <50 μg/ml; phenytoin (PHT), <10 μg/ml; phenobarbital (PB), <10 μg/ml; primidone (PRM), <6 μg/ml (8,9); for the new anticonvulsants, no subtherapeutic range was defined].

For all statistical analyses, operated-on patients were compared with non–operated-on patients. The t test for independent samples and the Mann–Whitney U test (two-tailed) were used. Differences were regarded as significant if p < 0.05. Differences between groups and 95% confidence intervals (CIs) were determined using tests for the cases of equal or unequal variance of the samples as appropriate.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

One hundred forty-eight surgically and 94 nonsurgically treated patients were included (group S and group NS, respectively). The following diagnostic procedures for localization of the epileptic focus were performed at visit 1 (in parentheses, the percentage of patients of the surgery/nonsurgery groups investigated by the procedure): history taking, especially with regard to seizure semiology (100%/100%), interictal surface EEG (100%/100%), ictal surface/sphenoidal EEG (40.5%/29.5%), ictal surface/sphenoidal plus depth EEG (51.4%/12.5%), neuropsychological testing (100%/100%), cranial magnetic resonance imaging (MRI; 98.6%/92.6%), cranial computed tomography (CT; 54.1%/52.1%), positron emission tomography (PET; 39.9%/23.4%), interictal single-photon emission CT (SPECT; 49.3%/28.7%), and ictal SPECT (8.1%/6.4%). Details on the epilepsy surgery program including the presurgical procedures at this center have been reported previously (10–12). At visit 1, the two groups were statistically equal with respect to gender, mean monthly seizure frequency, and mean number of AEDs. The patients of group S were younger and had an earlier onset of epilepsy. For details, see Table 1. In 58 (61.7%) of the nonsurgical patients, the reasons were clarified why they had not proceeded to epilepsy surgery: epileptogenic region not localized (15.5%), multiple foci (15.5%), neurologic or neuropsychological risk (8.6%), preference of further pharmacotherapy (5.2%), patient's decision (12.1%), or a combination of these reasons (43.1%).

Table 1. Patients' data at visit 1
 Operated-on patients (n = 148)Non–operated-on patients (n = 94)Difference (95% CI)
  • a

     All values are given as means with standard deviation and range.

  • b

     The formula for determining the two-sided 95% CI for the mean difference in the case of unequal variance was used.

  • c

     In six patients, an initial temporal lobe resection did not lead to seizure freedom and was extended during a second intervention. The first row indicates the data without these patients; the second includes them, giving the period between visit 1 and the second surgical procedure.

Gender (% female)54.7%53.2%1.5 (−11.5; 14.5)
Age (yr)a31.5 (±10.3; 8.8–63.8)35.5 (±11.3; 15.5–60.8)−4.0 (−6.8; −1.3)
Age at onset of epilepsy (yr)a11.4 (±9.0; 1–54)16.1 (±10.6; 1–53)−4.7 (−7.3; −2.3)b
Monthly seizure frequency (all types)a31.9 (±69.2; 0–612)25.4 (±57.3; 0–391)6.5 (−10.4; 23.4)
Monthly frequency of simple partial seizuresa14.1 (±55.1; 0–608)6.6 (±20.4; 0–145)7.5 (−2.3; 17.4)b
Monthly frequency of complex partial seizuresa17.1 (±39.1; 0–300)18.3 (±51.7; 0–392)−1.2 (−12.7; 10.4)
Monthly frequency of secondarily generalized seizuresa0.7 (±2.2; 0–16.7)0.5 (±1.1; 0–7)0.2 (−0.3; 0.7)
Surgical procedures   
 Temporal lobectomy69 (46.6%) 
 Amygdalohippocampectomy48 (32.4%) 
 Lesionectomy31 (21.0%) 
(Probable) morphologic substrate of epileptogenic regionHistopathologyMRI abnormalities 
 Hippocampal sclerosis 59 (39.9%) 20 (21.3%) 
 Low-grade tumor 44 (29.7%) 0 
 Neuronal migrational/developmental disorder 14 (9.5%) 3 (3.2%) 
 Vascular malformation 7 (4.7%) 2 (2.1%) 
 Other 8 (5.4%) 26 (27.7%) 
 Normal 13 (8.8%) 36 (38.3%) 
 Not investigated 3 (2.0%) 7 (7.4%) 
Duration visit 1, surgery (mo)a2.5  (±1.5; 0.3–9.9) 
 4.0  (±9.6; 0.3–82.9)c  
Number of antiepileptic drugsa2.11 (±0.87; 1–4)2.06 (+/−0.89; 0–4)0.05 (−0.18; 0.28)
No anticonvulsants03 (3.2%) ]  
Monotherapy38 (25.7%)22 (23.4%)Mann–Whitney U test:
 Subtherapeutic blood levels4 (2.7%)0p = 0.77
Polytherapy110 (74.3%)69 (73.4%) 

Seizure outcome

At visit 1, 146 (98.6%) of the patients to be operated on and 93 (98.9%) of the control patients had had seizures during the previous 12 months. At visit 2, significantly more operated-on patients were seizure-free than in the nonsurgical group (outcome class A: 44.6% in group S vs. 4.3% in group NS; class B: 17.6% vs. 3.2%). The mean monthly number of seizures (all seizures, complex partial seizures, secondarily generalized tonic–clonic seizures) was lower in the operated-on group. Only the number of simple partial seizures was not significantly smaller, see Table 2.

Table 2. Outcome: Patients at visit 2
 Operated-on patients (n = 148)Non–operated-on patients (n = 94)Difference (95% CI)
  • a

     All values are given as means with standard deviation and range.

  • b

     The formula for determining the two-sided 95% CI for the mean difference in the case of unequal variance was used.

Mean follow-up period visit 1 to visit 2 (yr)4.8 (±2.4; 2.0–10.4)4.7 (±2.1; 1.2–11.5)0.1 (−0.5; 0.7)a
Seizure outcome   
 Monthly seizure frequency (all types)a4.3 (±20.0; 0–167)15.7 (±46.2; 0–333)−11.4 (−21.3; −1.3)b
 Monthly frequency of simple partial seizuresa2.7 (±15.6; 0–146)5.8 (±21.2; 0–448)−3.1 (−7.8; 1.6)b
 Monthly frequency of complex partial seizuresa1.6 (±8.1; 0–83)9.1 (±30.7; 0–250)−7.5 (−14.0; −1.1)b
 Monthly frequency of secondarily generalized seizuresa0.1 (±0.3; 0–3)0.8 (±3.1; 0–21)−0.7 (−1.3; −0.1)b
 Outcome class A66 (44.6%)4 (4.3%)] Mann–Whitney U test: p < 0.001
 Outcome class B26 (17.6%)3 (3.2%) 
 Outcome class C56 (37.8%)87 (92.5%) 
AED outcome   
 Number of antiepileptic drugsa1.34 (±0.75; 1–4)2.33 (±0.94; 0–4)−0.99 (−1.22; −0.76)
 Change in number of AEDs (visit 2–visit 1)a−0.78 (±1.1; −4–2)0.27 (±1.0; −3–2)−1.05 (−1.32; −0.77)
 No anticonvulsants13 (8.8%)0]  
 Monotherapy82 (55.4%)19 (20.2%)Mann–Whitney U
  Subtherapeutic blood levels8 (5.4%)0p < 0.001
 Polytherapy53 (35.8%)75 (79.8%) 

AED use

The three groups of patients without AEDs, with monotherapy, and with polytherapy were equally filled at visit 1 in the surgical and the nonsurgical groups (approximately one fourth with monotherapy and three fourths with polytherapy).

The mean number of AEDs in both groups (group S, 2.11; group NS, 2.06) was statistically not different, see Table 1. At visit 2, significantly more patients of group S were off medication (8.8% vs. none in group NS) or receiving monotherapy (55.4 vs. 20.2% in group NS). The mean number of AEDs in group S (1.34) was significantly lower than in group NS (2.33), see Table 2.

We performed further subgroup analyses with regard to the different outcome classes, see Tables 3 and 4. The subgroups of control patients with outcome classes A and B were too small to perform t tests. Nonparametric testing revealed that significantly more operated-on class A patients were off medication (16.7%) or receiving monotherapy (74.2%) than their non–operated-on counterparts (none and 25%). Eight operated-on patients (12.1%), but none of the control patients was receiving monotherapy with subtherapeutic blood levels. The operated-on class B patients had no statistical advantage compared with the controls (in parentheses): 3.8% (none) off medication, 53.8% (66.7%) receiving monotherapy (no patient with subtherapeutic blood levels). The numbers of patients with a class C outcome (not seizure-free) permitted meaningful statistical analyses, see Table 4. Significantly more operated-on patients than control patients were off medication (1.8% vs. none) or receiving monotherapy (33.9 vs. 18.4%; no patient with subtherapeutic blood levels). The mean number of AEDs was smaller in the operated-on than in the non–operated-on patients (1.79 vs. 2.38), as was the mean change in number of AEDs (−0.27 vs. +0.24). The mean follow-up duration was significantly larger in the operated-on group (5.6 vs. 4.6 years). In the operated-on group, the mean total seizure frequency (11.5 vs. 16.9/month) as well as the mean frequencies of simple and complex partial seizures were lower in the operated-on group, but this difference was not significant. The mean grand mal frequency in the operated-on group, however, was significantly smaller than in the controls (0.2 vs. 0.8 per month). In these patients, the same calculations for visit 1 revealed no significant differences between group S and group NS (data not shown).

Table 3. AED use in patients with outcome classes A, B (i.e., continuously seizure-free since visit 1 or seizure-free for ≥1 year)
 Class AClass B
Operated-on patients (n = 66)Non–operated-on patients (n = 4)Operated-on patients (n = 26)Non–operated-on patients (n = 3)
  • Subtherap, subtherapeutic blood levels; AED, antiepileptic drug.

  • a

     Due to the small groups of non-operated patients, all values are given as medians with minimum and maximum in brackets. No t tests were performed.

Follow-up period visit 1–visit 2 (yr)3.2 (2.0–10.2)6.3 (3.5–8.7)5.4 (2.2–9.9)4.9 (4.3–5.3)
Number of antiepileptic drugsa1 (0–2)2 (1–3)1 (0–3)1 (1–2)
Change in number of AEDs (visit 2–visit 1)a−1 (−4–0)0.5 (−1–2)−1 (−2–2)1 (0–1)
     
No anticonvulsants11 (16.7%)01 (3.8%)0
Monotherapy49 (74.2%)1 (25.0%)14 (53.8%)2 (66.7%)
 Subtherap.8 (12.1%)000
Polytherapy6 (9.1%)3 (75.0%)6 (9.1%)1 (33.3%)
Mann–Whitney}}
 U testp = 0.003p = 0.84
Table 4. AED use in patients with outcome class C (i.e., not seizure free)
 Operated-on patients (n = 56)Non–operated-on patients (n = 87)Difference (95% CI)
  • a

     All values are given as means with standard deviation and range.

  • b

     The formula for determining the two-sided 95% CI for the mean difference in the case of unequal variance was used.

Follow-up period visit 1–visit 2 (yr)5.6 (±2.5; 2.3–10.4)4.6 (±2.1; 1.2–11.5)1.0 (0.2; 1.8)b
Seizure outcome   
 All seizure/mo11.5 (±31.4; 0.1–167)16.9 (±47.8; 0.1–333)−5.4 (−19.7; 8.9)
 SPS/mo7.0 (±24.9; 0–150)6.2 (±21.9; 0–167)0.8 (−7.0; 8.6)
 CPS/mo4.2 (±12.9; 0–83)9.9 (±31.9; 0–250)−5.7 (−14.5; 3.2)
 SGTCS/mo0.2 (±0.5; 0–3)0.8 (±3.2; 0–21)−0.6 (−1.3; 0.1)b
AED outcome   
 Number of antiepileptic drugsa1.79 (±0.8; 0–3)2.38 (±0.9; 0–4)−0.59 (−0.89;−0.29)
 Change in number of AEDs (visit 2–visit 1)a−0.27 (±1.0; −2–1)0.24 (±1.0;−3–2)−0.51 (−0.85; −0.17)
    
No anticonvulsants1 (1.8%)0]  
Monotherapy19 (33.9%)16 (18.4%)Mann–Whitney U test:
 Subtherapeutic blood levels00 p = 0.018
Polytherapy36 (64.3%)71 (81.6%) 

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

This controlled long-term follow-up study provides for the first time statistically comprehensive information on seizure outcome and pharmacotherapy in a large sample of surgically and nonsurgically treated population of TLE patients. It shows that surgically treated pharmacoresistant TLE patients compared with non–operated-on TLE patients have a significantly better seizure outcome and need significantly fewer AEDs.

Methodic considerations

The outcome evaluation of surgical treatment for chronic epilepsy is restricted by the fact that “gold standard” prospective randomized controlled trials have never been completed and are probably impossible. This is mainly because epilepsy surgery candidates are unwilling to be randomized to surgical or nonsurgical treatment (13). Results of uncontrolled epilepsy surgery series, however, may be biased. As has been suggested, patients treated at specialized centers may give incorrect (e.g., too positive) accounts of their seizure frequency. Another source of systematic errors may be that physicians may overestimate the effect of the treatment they provide (14). Thus a control group enhances the meaning of epilepsy surgery results. The control group of the present study consisted of demographically comparable pharmacoresistant TLE patients who underwent candidacy selection or presurgical assessment, but did not proceed to surgery for different reasons. All patients were under continuous care of one institution that treated them according to the same principles of pharmacotherapy. It must be noted, however, that the patients of the two groups are not totally comparable. A fraction of >30% of the medically treated patients were considered inoperable because of a nonlocalized epileptogenic focus or because of multiple foci. Finally, the outcome of surgical as well as medical epilepsy treatment should be determined after a follow-up period of ≥1 year, because up to that time, considerable changes in outcome figures may occur (5,15).

For interpretation of data on long-term outcome with respect to AED use, we combined the approaches of previous studies that reported either the number of patients with and without AEDs (3) or the number of patients without AEDs/on monotherapy/on polytherapy (5) or the mean number and mean change in number of AEDs (4). We furthermore analyzed AED use in subgroups of patients defined by their seizure outcome, because it has been assumed that this parameter might strongly influence the number of long-term administered AEDs (16).

Seizure outcome

The superior seizure outcome of operated-on patients confirms the results of previous controlled studies (2,4,5). The figures of 44.6% of patients who were continuously and completely free of all seizure types (i.e., including auras) after the surgical procedure, and another 17.6% of patients who had been completely seizure-free for ≥1 year at follow-up, are comparable to the results of other series on the long-term outcome of surgically treated epilepsy patients. They range from 31.3% of patients seizure-free for ≥1 year at a follow-up visit after a mean of 5.8 years after temporal and extratemporal operations in Vickrey's series to 67% of Gilliam's pediatric TLE patients who had been seizure-free for >6 months at a mean follow-up of 2.7 years (4–6,17–20).

AED use

The reduced number of AEDs in surgically treated TLE patients, as shown by parametric and nonparametric tests, is congruent with the findings of the existing controlled studies. Each of them, however, used another statistical approach (3–5). The most often reported figure on AED use after surgery is the percentage of AED-free patients. The following results have been reported by controlled and noncontrolled studies (results of nonsurgical patients in parentheses, if reported): 21% of 52 patients >1 year after selective amygdalohippocampectomy (17), 25.4% of 147 surgically treated patients with temporal and extratemporal foci (and 8.5% of the 94 non–operated-on control patients) with a mean follow-up of 16 years (3), 35% of 51 operated-on TLE patients (and 8% of 21 non–operated-on patients) after 24 months (5), 30% in 33 surgically treated children after a mean follow-up of 2.7 years (19), 44% in 93 TLE patients after 24 months (20), and 30, 35, and 60% of drug-free patients after 2, 5, and 10 years, respectively, in a pediatric TLE series (6). Our result of 8.8% operated-on AED-free patients (and none of the control patients) in the present study is considerably lower (one might, however, add the figure of 5.4% of the operated-on patients who were receiving a subtherapeutically dosed monotherapy). These figures might reflect a more conservative attitude of the physicians and the patients at this institution to complete AED reduction after surgery. This may in part be due to German peculiarities regarding prolonged driving restrictions or problems in getting back into a regular job if seizures recur after surgery. Recent data support this conservative attitude demonstrating a higher frequency of seizure recurrence in postoperatively seizure-free patients, in whom AEDs had been discontinued, as compared with operated-on seizure-free patients who had been kept on AEDs (21).

It is surprising that even the not seizure-free operated-on patients take fewer AEDs, have a greater reduction in the number of AEDs, and take more often no AEDs or a monotherapy than the conservatively treated patients with ongoing seizures. This might be explained by the fact that the seizure frequency is lower in the operated-on patients (even if that is significant only for secondarily generalized tonic–clonic seizures). Another explanation might be that patients who undergo epilepsy surgery do so because they wish to reduce the number of AEDs requested for daily therapy and that this hope is realized although seizures still occur. On the other hand, it might be worthwhile to reduce the number of AEDs in medically treated, chronically pharmacoresistant patients. This can lead to lessening of side effects in patients in whom seizure freedom cannot be achieved (1,22).

Acknowledgement: This study was supported by BONFOR (research support program of the University of Bonn, No. 111/28) and Deutsche Forschungsgemeinschaft (EL 122/6-1).

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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    Schiller Y, Cascino GD, So EL, et al. Discontinuation of antiepileptic drugs after successful epilepsy surgery. Neurology 2000;54:3469.
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    Schmidt D. Reduction of two-drug therapy in intractable epilepsy. Epilepsia 1983;24:36876.