วารสารสมาคมจิตแพทย์แห่งประเทศไทย
Journal of the Psychiatrist Association of Thailand
ISSN: 0125-6985
บรรณาธิการ มาโนช หล่อตระกูล
Editor: Manote Lotrakul, M.D.

Seizure Threshold Changes During Acute and Maintenance ECT in Schizophrenic Patients*

Worrawat Chanpattana, M.D.**

Abstract

Objective This prospective study aims to determine changes in seizure threshold during acute and maintenance electroconvulsive therapy (ECT).

Method Seizure threshold was estimated by the empirical titration technique in 41 patients with schizophrenia from the beginning of acute ECT (Phase I) to the end of one-year maintenance ECT (Phase II). In Phase I, initial threshold was estimated at the first two treatment sessions, then the thresholds were quantified at the seventh, fourteenth, and twentieth ECT. During Phase II, seizure thresholds were estimated at the first treatment, then every 3 months for 1 year.

Results All patients had a rise in seizure threshold at the end of Phase I, which the magnitude of increase was 213 + 179%. Number of ECT treatments and onset of illness could predict the threshold-increase of Phase I. At the end of Phase II, fifteen patients had no change in thresholds compared to the first estimates of Phase II; eighteen others showed a further increase, and thresholds of the last eight patients decreased gradually. The magnitude of threshold-increase of Phase II was 17 + 43%. An overall increase of thresholds at the end of Phase II was 243 + 178%.

Conclusions Increases in seizure threshold seen during acute ECT are robust, but generally sustained during maintenance ECT in remitted patients with schizophrenia. Seizure threshold should be estimated regularly during the courses of acute and maintenance ECT.

J Psychiatr Assoc Thailand 2000; 45(2):129-144.

Key words : seizure threshold, acute and maintenance ECT, empirical titration technique, anticonvulsant effect, schizophrenia

* Present at the 2000 Annual Meeting of the Association for Convulsive Therapy, McCormick Place Convention Center, Chicago, IL, USA, May 14^th, 2000.

วัตถุประสงค์ เพื่อศึกษาการเปลี่ยนแปลงของปริมาณไฟฟ้าตำสุดที่ใช้ในการรักษา (seizure threshold) ตลอดช่วงการรักษาด้วยไฟฟ้าระยะแรกและระยะต่อเนื่อง

 Introduction

Since its inception in 1938, optimization of electroconvulsive therapy (ECT) has been a focus of interest^1-4. The most fundamental view of the mechanism of action of ECT probably came from the classic research conducted by Ottosson^5-7. This work led to the universally adopted conclusions that 1) eliciting an adequate generalized seizure is both necessary and sufficient for the ECT efficacy; and 2) increasing the stimulus intensity above that necessary to elicit an adequate seizure does not enhance either the response rate nor the speed of clinical response, but results in increased cognitive side effects. The consensus has had a great impact on clinical practice that optimization of ECT is likely to achieve when each patient has an adequate seizure at each treatment, using a minimum dosage of stimulus intensity⁸. Indeed, the National Institute of Health Consensus Conference of ECT (1985) also recommended that the lowest amount of electrical energy to induce an adequate seizure should be used⁹.

A substantial number of studies conducted over the last decade have demonstrated that each of these central principles is wrong. Electrically induced seizures are not ‘all-or-none’ phenomena, and are subject to a wide variety of influences that may affect both their therapeutic and adverse effects^10-13. In concept, seizure threshold is the smallest dose of electrical charge that can induce a seizure¹⁴. Several lines of evidence indicate that both the efficacy and the cognitive side effects of ECT may depend on the extent to which the stimulus intensity exceeds the patient’s seizure threshold^15-24. Some of these studies also demonstrate a progressive increase in seizure threshold over the treatment course^19-21,24. The results suggest that optimizing electrical stimulus intensity during ECT require a determination of seizure threshold.

The American Psychiatric Association (APA) Task Force on ECT (2000)

concludes that the empirical titration technique provides the most precise method for quantifying seizure threshold. They recommend the use of moderately suprathreshold stimulation (50-150% above seizure threshold, or 1.5-2.5 times threshold) in patients treated with bilateral ECT, and moderately-to-markedly suprathreshold stimulation (150-450% above threshold, or 2.5-5.5 times threshold) in patients treated with right unilateral ECT¹⁵. Both the APA Task Force on ECT and the Royal College of Psychiatrists’ Special Committee on ECT have reached the same conclusions that 1) seizure threshold should be estimated regularly during the treatment course; and 2) administering proper stimulus intensity is necessary to insure the therapeutic efficacy of ECT^15,17.

Unfortunately, there has been a dearth of studies in assessing seizure threshold during maintenance ECT as well as in patients with schizophrenia. At the present time, a number of studies of depressed patients report the threshold estimates over 6-8 sessions^19-21,25-27, and only one study of schizophrenic patients examines up to 20 sessions²⁸. We lack this information in maintenance ECT. There has never been a long-term study using the structured dose-titration method in assessing the threshold-change during an ECT course. I report here seizure threshold changes assessed by the empirical titration technique in patients with schizophrenia during the courses of acute and maintenance ECT.

Forty-one patients with acute psychotic exacerbations and with a history of prior responsiveness to ECT, who met the DSM-IV criteria for schizophrenia²⁹ were referred for ECT because of failure to respond to neuroleptic treatment. Psychiatric diagnosis was based on the consensus of three psychiatrists and also had to concur with the patients’ medical records. Diagnosis in the medical records had to be consistent throughout the episodes of illness. Other inclusion criteria were a minimum pretreatment score of 37 on the Brief Psychiatric Rating Scale³⁰ (BPRS, 18 items, rated 0-6), and age 16-50 years. Patients were excluded if they received treatment with depot neuroleptics or ECT during the past 6 months, psychotic disorders due to a general medical condition, alcohol or other substance abuse, serious medical illness, or were receiving medicines with known effects on seizure threshold (e.g., antiepileptics, benzodiazepines, b -blocker, theophylline). Consent was obtained from the patients and/or their guardians after complete description of the study.

The study consisted of two phases: Phase I- acute treatment, and Phase II-

maintenance treatment (M-ECT) for one year.

Psychotropic medicines prescribed prior to the study were discontinued at least 5 days before the first ECT treatment. Flupenthixol 12 mg/day was prescribed to each patient during the first week and increased up to 24 mg/day depending on tolerability, and was continued throughout the study. Benzhexol (4-15 mg/day) was used to control extrapyramidal symptoms, with dosage titrated on a clinical basis. The dosages of both medicines were kept constant after the eighth week. No other medicines were used.

ECT was administered three times per week. After atropine 0.4 mg intravenously, anesthesia was given with a minimal dosage of thiopental (2-4 mg/kg) and 0.5-1 mg/kg of succinylcholine. Patients received positive pressure ventilation from the administration of anesthetic agent until resumption of spontaneous respiration. The ECT instruments were a MECTA SR1 and Thymatron DGx; each patient was treated with the same instrument throughout the treatment course. Bitemporal bilateral electrode placement was used exclusively. The tourniquet method and two channels of prefrontal electroencephalogram (EEG) were used to assess seizure duration.

Operationally for study purposes seizure threshold was defined as the lowest stimulus charge that produced an adequate seizure, i.e., bilateral tonic-clonic motor activity that lasted at least 30 seconds together with EEG evidence of seizure. Initial seizure threshold was estimated by Srinakharinwirot University dose-titration schedule (Table 1) at the first two treatments. The first stimulus at the first session was 10% of total charge. If this failed to elicit an adequate seizure the stimulus charge was increased in increments of 10% step. A maximum of four stimulations per session was allowed, with an interval of at least 40 seconds between each without giving additional thiopental. At the second treatment session for each patient, stimulus dose lower by 5% than at the first session was given, as listed in Table 1. If an adequate seizure occurred, that dose was taken as initial threshold; if not, the first session’s stimulus dose was so taken. The stimulus charge 10% above threshold was given at the subsequent treatment; thereafter, the stimulus dose was increased by 10% step for a short seizure.

Seizure threshold was quantified at the seventh, fourteenth, and twentieth treatment sessions. Starting with the patient’s prior threshold dose, if resulted in a short seizure, a 50% increment from prior threshold to the present stimulus dose was used. If an adequate seizure was not obtained, a 75% increase in stimulus dose was administered. Should this increase still not produce an adequate seizure, the last stimulus dose was used and adapted as patient’s threshold. Increments of stimulus charge were adjusted close to this protocol in patients whom their threshold-increases were modest.

A 3-week stabilization period was used as a response criterion^31-36; the patients who passed this criterion were eligible to enter Phase II. Briefly, patients who showed clinical improvement (BPRS scores < 25), went on to pass a 3-week stabilization period in which these effects had to be sustained. The stabilization period had the following treatment schedule: 3 regular ECT (3 treatments/week) in the first week, then once a week for the second and third weeks, during which BPRS scores must always be < 25. The total number of ECT was limited to 20 treatments. All patients in the study could pass this response criterion, and acute ECT treatments were terminated.

All patients received a combination treatment with M-ECT and the same dosage of flupenthixol. The ECT treatment procedures were the same as in Phase I. The ECT schedule was fixed during the first six months, starting with 4 weekly followed by 10 biweekly treatments. Then M-ECT was given every 2-4 weeks depending on the patient’s clinical status for the last 6 months. No additional ECT treatment was given outside of this schedule. Relapse was defined as a BPRS score of > 37 that persisted for 2 consecutive ratings, 3 days apart.

Seizure threshold was estimated at the first weekly treatment, then at the third, sixth, ninth months, and one year. The stimulus dose lower by 10% than a prior threshold was given. If resulted in a short seizure, a prior threshold dose was administered. If a short seizure was elicited, a 50% increase from prior threshold to the present stimulus

dose was used. Then, the last stimulus dose was taken if an adequate seizure was not

obtained. The stimulus charge 10% above threshold was given at the subsequent treatment; thereafter, the stimulus dose was increased by 10% step for a short seizure.

Seizure thresholds were analyzed after logarithmic transformation to improve the normality of the data distribution. For discontinuous data, c 2 tests were used to test for significant differences among groups. When sample size was small, the Fisher’s exact test was used. Differences between groups on single, continuous variables were evaluated with t tests. Paired t tests were used to assess the differences of thresholds between two estimations. Relations between continuous variables were examined with the Pearson’s product-moment correlation. The degree to which variables could predict seizure threshold was examined by a stepwise multiple regression analysis.

Table 2 shows clinical characteristics of 41 patients who participated in this study. Twenty-seven patients received ECT with MECTA SR1 and 14 with Thymatron DGx. Figure 1 summarizes seizure threshold at each estimation. Table 3 presents seizure

thresholds as a function of gender and ECT instruments, of both Phases I and II.

Initial seizure threshold was 82.7 + 36.6 millicoulomb (mC). There was a substantial

variability in thresholds, ranging from 25.2 to 180 mC (7-fold). There was no difference

between gender, t (39) = 1.02, p = 0.3 (Table 3). Initial threshold estimated with the MECTA was higher than the Thymatron, t (39) = 3.02, p = 0.004. All patients seized at the first session with averaging 1.7 + 0.7 stimulations (range: 1-3). Initial threshold was positively related with ECT instrument (Spearman’s r = 0.43, p = 0.005; Thymatron = 1, MECTA = 2) and thiopental dosage (r = 0.43, p = 0.005). Stepwise multiple regression analysis revealed that both the instrument (t = 3.39, p = 0.002) and thiopental [t = 3.34, p = 0.002; F (2,40) = 11.31, p < 0.0001] accounted for 37.3% of the variance, 62.7% remaining unexplained.

Average number of stimulations at the seventh, fourteenth, and twentieth sessions were 2.4 + 0.7 (1-4), 2.4 + 1.2 (1-4), and 1.4 + 1.1 (1-4), respectively. Seizure threshold quantified, at each patient’s last estimation, with MECTA was higher than Thymatron (t = 3.43, df = 39, p = 0.001). All patients had a rise in seizure threshold at the end of Phase I, the magnitude of increase was 213 + 179% [range: 40-860%; t (1,40) = 13.4, p < 0.0001] (Fig. 1). There were no differences in the threshold-increase either between gender [t (39) = 1.05, p = 0.3] or instrument [t (39) = 1.7, p = 0.1]. Seizure-threshold increase was positively related to number of ECT treatments (r = 0.46, p = 0.003) and onset of illness (r = 0.43, p = 0.005), and negatively related to succinylcholine dosage (r = 0.35, p = 0.027). Stepwise multiple regression analysis revealed that number of treatments (t = 2.43, p = 0.02) and onset of illness [t = 2.12, p = 0.04; F (2,40) = 7.95, p = 0.001] explained 29.5% of the variance. There was a substantial reduction in seizure duration over an ECT course [motor: t (1,40) = 4.23, p < 0.0001; EEG: t (1,40) = 4.26, p < 0.0001].

All patients received ECT combined with flupenthixol, using a fixed treatment schedule during the first 6 months. Thereafter, 30 patients continued to receive biweekly treatment, 7 had ECT every 3 weeks, and monthly ECT was scheduled to 4 patients over the last 6 months. No patients suffered relapse at the end of Phase II.

Seizure thresholds of patients receiving MECTA were consistently higher than Thymatron, in all estimations (Table 3). The average number of stimulations were 1.9 + 0.4 (1-3), 2.2 + 0.6 (1-3), 2.2 + 0.5 (1-3), 1.9 + 0.5 (1-3), and 1.8 + 0.5 (1-3), respectively. There was a trend for the difference in the threshold-increase between instruments, t (39) = 1.86, p = 0.08. Women had larger increments in threshold than men, t (39) = 2.07, p = 0.045. Fifteen patients had no change in thresholds, 4 of which had their thresholds at the maximum charge of the instruments; 18 had a modest threshold-increase, and 8 patients had a gradual decrease in seizure thresholds. The magnitude of threshold-increase of Phase II was 17 + 43% [range: 60% decrease-150% increase, t (1,40) = 1.52, p = 0.14], which only had an inverse correlation with thiopental dosage (r = 0.46, p = 0.004). Threshold-increase during the first six months (21 + 41%, range: 50% decrease-150% increase) was larger than that of the last six months [-0.7 + 31%, range: 67% decrease-100% increase; t (1,40) = 2.43, p = 0.02]. There was a further reduction in seizure duration over Phase II [motor: t (1,40) = 3.85, p < 0.0001; EEG: t (1,40) = 4.3, p < 0.0001].

In the total sample, one-way analyses of variance (ANOVAs) were conducted on the demographic, clinical, and treatment variables, with threshold-change group (i.e., threshold-increased, threshold-stable, and threshold-decreased groups) as a between-subject factor. Significant main effects of threshold-change group were followed by Scheffe post hoc comparisons of the three groups based on least-square adjusted means to identify pair-wise differences. Values are given as mean + SD. All significances are two-tailed. SPSS 9.05 (1996 SPSS Inc.) was used for all analyses.

Table 4 presents all variables among the three threshold-change groups that had

statistically significant differences. There were significant main effects of the three groups for illness duration [F (2,40) = 3.48, p = 0.041], episode duration [F (2,40) = 3.69, p = 0.034], number of ECT in Phase I [F (2,40) = 5.85, p = 0.006], and threshold-increase of Phase I [F (2,40) = 4.93, p = 0.013]. Post hoc comparisons indicated that the threshold-increased group received fewer numbers of ECT than two others (p’s = 0.02 and 0.035), and had less increment of thresholds in Phase I than the threshold-decreased group (p = 0.014).

An overall threshold-increase from the beginning of Phase I to the end of Phase II was 243 + 178% [range: 33.3% decrease-700% increase; t (1,40) = 13.75, p < 0.0001]. Interestingly, there was one patient who had a threshold estimate at the end of Phase II (50.4 mC) lowered than her initial threshold at Phase I entry (75.6 mC). There was no difference in threshold-increase between instruments, t (39) = 0.07, p = 0.95. Women had more threshold-increase compared to men (t = 3.59, df = 39, p = 0.001). An overall threshold-increase was negatively related to gender (Spearman’s r = 0.39, p = 0.013; women = 0, men = 1) and initial threshold (r = 0.35, p = 0.027). Stepwise multiple regression analysis revealed only gender [t = 2.4, F (1,39) = 5.78, p = 0.021] represented 12.9% of the variance. There was a marked reduction in seizure duration over the ECT course [motor: t (1,40) = 7.02, p < 0.0001; EEG: t (1,40) = 7.46, p < 0.0001].

In Phase I, all patients had a rise in seizure threshold; the magnitude of increase

was 213 + 179%. During Phase II, 15 patients had no change in thresholds compared to the first estimates of Phase II; 18 showed a further increase, and the thresholds of the last 8 patients decreased gradually. The magnitude of threshold-increase of Phase II was 17 + 43%. An overall increase of thresholds at the end of Phase II was 243 + 178%. The present study demonstrates a substantive increase in threshold over acute ECT, which appears to reach a plateau during maintenance ECT. Therefore, regular estimation of seizure threshold of each patient during ECT is necessary to justify using the proper stimulus dose. This is the first study examining seizure-threshold changes during both acute and maintenance ECT treatments in remitted patients with schizophrenia.

Overestimation of seizure threshold is of critical concern. In order to avoid using too weak stimulus intensity in treating patients with treatment-refractory schizophrenia, a criterion for seizure adequacy was set longer than the usual recommendations (20-25s¹⁵; 15s of motor, and/or 25s of EEG¹⁷). This criterion might affect the results of both Phases. Nonetheless, initial threshold was quantified at the first two treatments instead of once at the first session as used in other studies; in order to have a more accurate estimate. And, a conservative dose-titration schedule was used in all subsequent threshold estimations. Therefore, these particular dose-titration strategies might be a methodological strength of this study. Restriction on concomitant pharmacotherapy also provides an additional strength of this study. Nonetheless, the question remains on whether flupenthixol might have any effects on seizure threshold. Unfortunately, there has been only one study in literature pertaining to this issue. Chanpattana et al²⁸ estimated initial seizure threshold and its changes by means of the empirical titration technique in 93 patients with schizophrenia receiving ECT combined with flupenthixol; they could not find such effects, since there were no correlations between thresholds and flupenthixol dosages in all 4 assessments. Seizure thresholds of patients quantified with MECTA were always higher than with Thymatron. There are three likely reasons for this. First, there was a different gender ratio of patients receiving ECT with each instrument. There were more men with MECTA (9 men, 18 women) than Thymatron (2 men, 12 women), F = 0.013. Seizure threshold is known to be higher in men than women ^{1,26,27,37,38}. Second, this dose-titration schedule provided a uniform increment of stimulus dose (10% step, Table 1), which referred to the maximum charges of each instrument (576 mC of MECTA and 504 mC of Thymatron), to contribute to the systematic and impartial measurement of seizure threshold. Thus, the stimulus charge of MECTA was always higher than Thymatron in all levels. And, third, Chanpattana et al ³⁹ conducted a prospective, randomized controlled trial study in 88 patients with schizophrenia and schizoaffective disorders comparing initial seizure threshold estimated by the empirical titration technique with MECTA SR1 and Thymatron DGx instruments. The measured seizure thresholds were found to be higher with the MECTA than the Thymatron instrument, 61% on average. Underlying the differences between the two instruments are systematic differences in stimulus characteristics, and the greater efficiency associated with stimuli of lower charge rate⁴⁰, lower pulsewidth⁴¹, lower pulse frequency⁴², and longer train duration^42,43.

Women had higher thresholds than men did over both two phases (Table 3). This might be an artifact from a small number of patients in the study, since there was no significant difference of age between women and men [32 + 7 vs. 32.9 + 5.8 years, respectively; t (39) = 0.4, p = 0.69]. The relationship between onset of illness and threshold-increase presumably follows the correlation between onset of illness and age (r = 0.48, p = 0.001).

Number of ECT treatments was the most significant predictor of threshold-increase of Phase I. This finding is similar to our prior study²⁸. The result may be explained on the basis of a decrease in neural metabolic activity that reflects potentiation of the endogenous inhibitory processes following ECT-induced seizure^44-47. The findings from these studies might explain as well the results of a progressive decrease in seizure duration over both acute and maintenance treatments.

There was one patient whom a threshold estimate at the end of Phase II (50.4 mC) lowered than her initial seizure threshold (75.6 mC). This patient received prior treatment with psychotropic agents possessing anticonvulsant properties⁴⁸ (i.e., diazepam 10 mg hs and propanolol 30 mg/day for agitation), that might explain this finding.

Interestingly, the threshold-increased group received fewer numbers of ECT than two others despite having longer durations of illness and current episode. The longer durations of illness and current episode are known to indicate poor responsiveness to both ECT and pharmacotherapy^34,35,49,50. The results may be explained by the quality of their responsiveness to prior ECT of the threshold-increased patients. Twelve of 18 patients in the threshold-increased group had good responses to prior M-ECT, compared to 6 of 15 and 3 of 8 patients in the threshold-stable and threshold-decreased groups (F’s = 0.04), respectively.

Because an ethical concern precluded the rigorous threshold estimations at all subsequent ECT sessions; this dose-titration strategy might cause a substantial elevation of thresholds, and thus becoming a limitation of the study.

This study provides some of the first information on seizure threshold and its change with ECT among patients with schizophrenia over both acute and maintenance treatments. The magnitude of threshold-increase was large during an index course, then appeared to reach a plateau over maintenance treatment. Our findings emphasize the recommendation that seizure threshold should be estimated regularly in each patient during the treatment course, to justify the proper stimulus intensity and optimize the ECT efficacy. In addition, this study also sheds light on future research investigating another important question ‘how long seizure threshold will return to its baseline?’

This study was supported by the Thailand Research Fund, grant BRG 3980009. The author thanks M.L. Somchai Chakrabhand, M.D., Wiwat Yatapootanon, M.D., Yaowalak Prasertsuk, B.Sc, M.S., for their technical supports.

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Level* Pulse Frequency Duration Current Charge % Charge

width (mC) (mC)

1 1.0 40 1.25 0.6 60 10 50.4

2 1.0 40 2.0 0.75 120 20 100.8

3 1.0 60 2.0 0.75 180 30 151.2

4 1.2 60 2.0 0.8 230.4 40 201.6

5 1.0 90 2.0 0.8 288 50 252

6 1.4 90 2.0 0.8 403.2 70 352.8

7 2.0 90 2.0 0.8 576 100 504

1 1.0 40 0.5 0.8 32 5 25.2

2 1.0 40 1.5 0.7 84 15 75.6

3 1.0 90 1.0 0.8 144 25 126

4 1.0 60 2.0 0.8 192 35 176.4

5 1.2 70 2.0 0.75 252 45 226.8

6 1.2 90 2.0 0.8 345.6 60 302.4

7 1.6 90 2.0 0.8 460.8 80 403.2

8 1.8 90 2.0 0.8 518.4 90 453.6

* Increase by one level (10% step) is recommended for using in dose titration at the first or subsequent treatments.

** The extra level is used at the second treatment session only.

Table 2. Subject Characteristics

Variable mean + SD range

Age (yr) 32.2 + 6.7 22-45

Sex 30 women, 11 men

Subtype 32 paranoid, 5 disorganized, 2 catatonic, 2 undifferentiated

Onset (yr) 21 + 4.8 13-32

Duration of illness (yr) 11.3 + 6 3-25

Duration of current episode (yr) 1.2 + 1.4 1mo-5yrs

Prior failure of adequate neuroleptic trials 3.8 + 1.2 2-7

Mean CPZ equivalent dose (mg) 1,162 + 311 800-2,080

Prior failure of flupenthixol treatment 24

No. of psychiatric admissions 5.5 + 4.3 1-15

No. of ECT treatments 12.5 + 5 7-23

Dosage of flupenthixol (mg) 23 + 2.3 18-24

BPRS scores at entry 50.3 + 9.1 37-67

GAF scores at entry 32.2 + 5.1 25-45

MMSE scores at entry 27 + 3.2 20-30

Thiopental (mg) 136.7 + 25.8 100-250

Succinylcholine (mg) 23.7 + 5.5 12.5-37.5

Abbrev. BPRS-Brief Psychiatric Rating Scale, GAF-Global Assessment of Functioning, MMSE-Mini-Mental State Exam, CPZ-chlorpromazine.

Table 3. Seizure Threshold as a Function of Gender and ECT Devices.*

Women Men MECTA SR1 Thymatron DGx

(n = 30) (n = 11) (n = 27) (n = 14)

Initial threshold 80.7 + 40 88.1 + 25.6 92 + 34.3 64.8 + 35.2 ^a

Last estimates 254.5 + 165.5 227.1 + 104.3 291.3 + 150.2 162 + 113.9 ^b

% Threshold-increase 263.5 + 170.3 168.9 + 119.8 275.2 + 181.4 185.4 + 114.6

First treatment 231.2 + 193.9 165 + 127.2 241.4 + 204 159.5 + 104.9 ^c

Third month 291 + 171.4 216.7 + 88.4 314.5 + 160 187.2 + 110.8 ^d

Sixth month 305.2 + 166.3 216.7 + 88.4 322.8 + 156.9 201.6 + 113.6 ^e

Ninth month 300.4 + 158.5 216.7 + 88.4 315.6 + 150.1 205.2 + 112.6 ^f

One year 284.6 + 163.2 212.1 + 90.1 303.6 + 153.8 190.8 + 112.1 ^g

% Threshold-increase 22.9 + 48.1 1.3 + 18.7 ^h 6.8 + 30.4 37 + 56.8

% Overall increases 281.4 + 191.9 138.6 + 62.7 ⁱ 244.5 + 175.5 240.5 + 190.1

* Values are given in mean + SD, in millicoulombs.

^a t = 3.02, df = 39, p = 0.004; ^b t = 3.43, df = 39, p = 0.001; ^c t = 3.74, df = 39, p = 0.001

^d t = 2.79, df = 39, p = 0.008; ^e t = 2.63, df = 39, p = 0.012; ^f t = 2.59, df = 39, p = 0.013 ^g t = 2.71, df = 39, p = 0.01; ^h t = 2.07, df = 39, p = 0.045; ⁱ t = 3.59, df = 39, p = 0.001

Table 4. Clinical characteristics of patients as a function of the threshold-change group*.

Threshold-change Groups

* Values are expressed in mean + SD.

Only clinical variables having statistical significances are presented.

Figure Caption

Figure 1. Seizure thresholds at each estimation, both Phases (millicoulombs).