The Neurotoxicity Scale: The validity of a patient-based scale, assessing neurotoxicity

EPILEPSY RESEARCH ELSEVIER

Epilepsy Research 20 (1995) 229-239

The Neurotoxicity Scale: The validity of a patient-based scale, assessing neurotoxicity A.P. Aldenkamp a,*, G. Baker b, M.S.M. Pieters c, H.C. Schoemaker c, A.F. Cohen c, S. Schwabe d a

Department ofNeuropsychology, 'Meer and Bosch' Epilepsy Centre, Heemstede, the Netherlands b Department of Neurosciences, University of Liverpool, Walton Hospital, Liverpool, UK c Centre for Human Drug Research, University Hospital Leiden, Leiden, the Netherlands d Ciba-Geigy, CNS Department, Basel, Switzerland

Received 16 Augustus 1994; revised 26 October 1994; accepted 31 October 1994

Abstract The validity of a patient-based scale, presumably measuring adverse effects of drugs on cognitive function, was examined in a normal volunteer study. Thirty subjects were randomly assigned to placebo or one of two doses of a benzodiazepine, temazepam (10 mg and 20 mg), in a double-blind placebo-controlled parallel group design. Plasma samples were taken before the scale was completed and up to 8 hours post-dose. After administration of the medication the subjects were asked to maintain their normal daily routine as much as possible (reading, studying, conversations). The inventory was administered twice, at 50 minutes and 2 hours post-dose (peak level). The overall score was different between the three groups, only for the second assessment, 2 h post-dose (ANOVA, P < 0.02). Multiple t-testing between the three groups revealed statistically significant differences between placebo and the 10 mg temazepam group ( P = 0.02) and between placebo and the 20 mg temazepam group ( P = 0.006). No significant difference was found between the two temazepam groups. Analysis of the ,~;eparate questions showed least sensitivity for questions related to the domain of 'hyperexcitability' and most sensitivity for 'fatigue' and 'slowing.' The overall score appeared to be sensitive already for the lower toxicity range suggesting an 'all or nothing effect'. The subjective reports, collected by using this scale, may therefore be used for the detection of gross overall changes in cognitive functioning. Keywords: Antiepilepticdnlgs; Neurotoxicity;Scale; Cognitivefunction

1. Introduction

* Correspondingauthor. Head Departmentof Neuropsychology, 'Meer and Bosch' Epilepsy Centre, Achterweg 5, 2103 SW Heemstede, or P.O. Box 21, 2100 AA, Heemstede, The Netherlands. Tel.: 31 (0)23-237555; Fax: 31 (0)23-289412.

The main focus of the study of cognitive impairment in epilepsy has gradually shifted from factors such as seizure activity to the adverse effects of antiepileptic drugs (AEDs, e.g. [1-7]). These studies suggest that AED treatment has a much greater

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impact on higher-order cortical 'cognitive' function than had hitherto been suspected [8]. In addition to the deteriorating effects of polypharmacy, as opposed to monotherapy [9], differential effects of specific drugs on higher cerebral functions were found, such as for phenytoin [10], for carbamazepine [11], and for valproic acid [12]. Recent studies used sensitive designs to control for the concomitant effects of epilepsy and AEDs on cognitive function, e.g. in new referrals [5,13] or in withdrawal designs [14,15]. These latter studies, that also control for serum concentrations and specific pharmacokinetic properties of the investigated drugs, reconfirmed cognitive side-effects of several AEDs such as the central ('mental') slowing in patients using phenytoin [15], disorders in memory function in patients using benzodiazepines or phenobarbital [5,13] and the motor slowing following high doses of valproate [16]. Accordingly, the emphasis in treatment has evolved from mere seizure control to a more comprehensive approach in which the prevention of adverse drug effects is given due attention [4,7]. Most studies have used neuropsychological testing procedures to assess the adverse drug effects on higher cerebral function. In clinical practice and in drug trials, however, the opportunities for such assessment are usually very limited [17]. Patient complaints suggestive of problems in cognitive behaviour often represent the only available evidence of possible cognitive dysfunction. Studies on the relationship between complaints about AED side-effects and results of cognitive tests show evidence that the latter have greater sensitivity for detecting effects on specific functions, whereas subjective complaints can only be used to detect global impairment, independent of the specific functions involved [21-23,25-27]. The primary theoretical assumption behind a project, aimed to devise a patient-based 'neurotoxicity scale', was that such an instrument should record the subjective perception of central adverse drug effects. The project is part of our attempts to reconsider the outcome measures in the treatment of epilepsy and in analysing side-effects of potential new AEDs [17]. Patient-based outcome measures, such as subjectively experienced adverse drug effects, have been shown to enhance the efficacy of new antiepileptic drugs [18].

We therefore aimed at constructing a scale that is patient based, i.e. uses self reports, and is valid, i.e. sensitive for the adverse effects of drugs on higher cortical (cognitive) functions. Before the present study was conducted, the scale was devised, using the following steps: a. Targets Based on the literature about potential adverse effects of AEDs on higher cortical function [2-5,1315] and on the results of our own previous studies [15,17], seven critical domains of cognitive dysfunction were selected: Tiredness/fatigue Hyperexcitability Slowing (motor and mental) Memory impairment Attentional disorders Impairment of motor coordination - Language disorders -

-

-

-

-

-

-

-

b. Questions - The actual selection of questions was based on our previous research on approximately 300 patients with the 'adverse events list' [17]; on approximately 200 patients with the 'quality of life scale' in the Holmfrid Study [15,19]; and on approximately 200 patients with the 'GKLEMemory Questionnaire for Epilepsy' [20]. The first draft of the scale was therefore based on questions with proven reliability and validity in a sample of 700 patients in total. Before constructing a final draft, 20 patients were interviewed in the neuropsychological departments of Walton Hospital Liverpool and 'Meer and Bosch' Epilepsy Centre, to compare unstructured reports with the selected questions. Discrepancies led to additional questions. In addition, three more practical arguments helped us in designing the questions: Several studies showed that direct prompting of cognitive complaints (i.e. 'do you have memory problems') could lead to overestimation of impairment [21-24]. This is probably one of the factors that cause the low correlation between subjective patient complaints and results of cognitive tests that is generally reported in literature (see for a discussion [25-27]). Therefore the questions in

A.P. Aldenkamp et al. / Epilepsy Research 20 (1995) 229-239

the scale are based on an indirect approach and avoid suggestive prompting. - The questions were formulated in daily life language and used examples that people recognize. Previous research has reconfirmed the importance of this approach [17]. - The scale was primarily devised to be used in drug trials. Consequently the questions in the scale were focused on 'state' factors, i.e. assessed the reports for the last 4 - 6 weeks, a period that generally covers the period in which a steady-state phase of a drug can be reached. c. The scoring sysi!em

It follows from our theoretical assumptions that the primary outcome measure of the Neurotoxicity Scale is the overall score, demonstrating 'neuro-impairment' (defined as the subjectively perceived adverse effect of drugs on cognitive function). We do not expect sensitivity of the scale in terms of impairment in specific cognitive functions. The scale was given a Likert-format for recording patient responses, with 'severity-ranking' from the score 0 (no problem) to 3 (a serious problem). The score for each question accordingly varies from 0 to 3. A total of 33 questions were included in the scale, covering the selected domains of cognitive function (three to six questions per domain). The questions are shown in Appendix 1, ordered by cognitive domain. The scale was named the 'Neurotoxicity Scale'. Primary score is the overall score that is obtained by summing the scores (0-3) per question (33) and thus can vary between 0 and 99. After a pilot study had shown sufficient facevalidity, the present study was designed to test the validity of the scale in relation to a CNS drug. As we aimed at a well controlled study, the scale was tested in healthy volunteers who were given a drug with known adverse effects on higher cortical functions. This drug would then serve as a 'gold standard' to assess the clinical sensitivity of the scale for drug-induced neuro-impairment. For this purpose we selected temazepam, a benzodiazepine that is commonly prescribed as a tranquillizer with relatively mild effects and that is well investigated in the Centre for Human Drug Research, Leiden, the Netherlands. Temazepam has a half-life of 5-8½

231

hours. The usual clinical doses are 10-40 mg/day. Common side-effects are drowsiness, concentration disorders and slowed reaction times; however, most of the reactions to this drug are relatively mild. The study is therefore also valid for impairment in the lower toxicity ranges.

2. Methods 2.1. Subjects and study centre

Thirty male and female healthy volunteers, with a mean age of 23.4 years (s.d. 2.8 y) were included in the study. Body weight had to be within 20% of the ideal body weight according to Geigy scientific tables (average weight is 70.1 kg; s.d. 10.0 kg). The volunteers were recruited by advertisement in a local university newspaper. Subjects could perform normal daily routines (reading, studying, discussions, conversations, TV) during the study day. Exclusion criteria were: a. Evidence of significant clinical abnormalities detected by full medical history, physical examination, ECG and routine blood and urine analysis. b. Female volunteers not using reliable anticonception. c. Pregnancy. d. Use of drugs known to affect CNS performance. e. Drug abuse or evident abuse of alcohol. f. Participation in a clinical trial within 6 months prior to this study. g. Blood donation within the preceding 3 months of this study. h. Use of benzodiazepines for longer than 3 weeks within the last 4 years. i. Inability to give informed consent. 2.2. Design

The study used a randomized double-blind, parallel group design. The volunteers were randomly assigned to one of the following treatments: temazepam 10 mg, temazepam 20 mg, or placebo. The doses 10 and 20 mg temazepam are usual clinical doses. Treatment was given as a single oral dose in the morning of the study day. Normison ® soft gelatine capsules were used. The placebo cap-

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sules had identical appearance as the Normison ® capsules. Medication was taken with a glass of tap water (200 ml).

mittent injections of physiological saline. After the samples were taken, the plasma was separated by centrifugation and stored - 4 0 ° C until the analysis.

2.3. Consent

Study day

The study was approved by the Ethical Committee of Leiden University Hospital. Subjects were given oral and written explanations about the study and any (side) effects that could be expected. After they had given written acknowledgement of informed consent to participate, a medical screening was carried out. After approval by the subjects, their general practitioners were notified.

2.4. Measurements and procedure Screening Screening took place within the two weeks prior to the study. Each subject was clinically assessed, including medical history, physical examination, ECG, blood chemistry and dipstick urine analysis. Demographical data including age, sex, level of education, medical diagnoses, use of drugs, smoking habits and use of alcohol were recorded. Finally all subjects were assessed with a personality inventory: the Dutch revision of the Spielberger State-Trait Anxiety Inventory. This inventory includes two selfrating scales, each consisting of 20 statements. The scales allow assessment of state and trait anxiety [28]. For premenopausal women, a urine pregnancy test (CARD-O.S., Pacific Biotech, San Diego, CA 92191, US) was performed on the study day, prior to drug administration.

Blood sampling During the study day 12 blood samples of 10 ml were taken via a cannula (Venflon 18G) inserted in a fore-arm vein. The cannula was kept patent by inter-

Subjects were instructed not to use any alcoholic beverages from the evening preceding the study day until 36 hours after intake of medications. In addition, use of coffee, tea, or chocolate, as well as smoking was not allowed during the study day. On each study day five subjects participated. Subjects arrived at 8:00 a.m. and received standard breakfast. At 8:30 intravenous catheters were inserted and baseline measurements were made at 8:40 until 9:20. Oral administration of the trial medication took place at 9:30. 50 minutes and two hours later the Dutch version of the Neurotoxicity Scale was completed (we will refer to these measures as 1 h and 2 h post-dose). Plasma samples were taken before the scale was completed and up to 8 hours post-dose. After administration of the medication the subjects were asked to maintain their normal daily routine as much as possible. After dinner the volunteers were returned home by taxi at 19:00, unless the investigating physician regarded this as unsafe.

2.5. Statistical analysis Our design used two factors: Treatment (placebo, temazepam 10 mg, temazepam 20 mg) and Time (the assessment was completed twice, 1 h and 2 h postdose). Consequently, the scale results were analyzed using Repeated Measures ANOVA with Treatment as between-subject factors, Time and Treatment by Time as within-subject factors. In case of significant results (Treatment or Treatment by Time) only (in order to compensate for multiple testing) these analyses were followed by ordinary one-way ANOVAper time point to test the three possible contrasts: placebo vs 10 mg, placebo vs 20 mg, 10 mg vs 20 mg, using

Table 1 Description of the sample Gender (m/f) Age (y) Weight (kg)

Placebo

Temazepam 10 mg

Temazepam 20 mg

Total group

5/5 23.1 (2.9) 73.1 (7.3)

4/5 24.5 (2.7) 69.0 (9.7)

5/5 22.6 (2.8) 68.2 (12.5)

14/15 23.4 (2.8) 70.1 (10.0)

Standard deviations between parentheses.

A.P. Aldenkampet al. / EpilepsyResearch20 (1995) 229-239 pooled variance estimates. The significance level was set at 5%. The overall score was used as the primary outcome variable. In addition, the treatment differences for each of the separate 33 questions were analyzed to investigate differential sensitivity. All calculations were carried out using S P S S / P C + V4.01.

233

Table 3 Serum levels (ng/ml) of temazepam at baseline and 1 h or 2 h post-dose Baseline 1 h post-dose 2 h post-dose

Temazepaml0mg

Temazepam20mg

0.00 224.9(138.7) 229.0(74.7)

0.00 286.5 (244.0) 414.4 (127.6)

Standard deviations between parentheses.

3. Results 3.1. Demographical characteristics of the study group The study consists of 30 subjects, 10 subjects per group. One of the subjects withdrew consent. Table 1 gives a general description of the sample. The three groups have an equal m a l e / f e m a l e ratio. The age distribution shows that all subjects are young adults with a mean age that is not different between the three groups (ANOVA, P = 0.32). Weight shows comparable data for all three groups ( P = 0.51). Educational level is similar for all three groups: all subjects are university students or students in other forms of higher education. Clinical assessment, physical examination and medical history did not show any signs that were set as exclusion criteria prior to the study. The results of the Spielberger State-Trait Anxiety Inventory revealed that none of the subjects showed elevated scores for anxiety, when compared to the norm group (see Table 2). The scores for trait and state anxiety are at the lower average range for all groups. Statistical analysis (ANOVA) confirms that the differences between ~Lhe groups are not significant ( P = 0.12 for trait anxiety; P = 0.35 for state anxiety). Therefore we may conclude that none of the subjects had a high disposition for anxiety. Also, the experimental situation appeared not to be particularly

anxiety arousing for any of the selected individuals. W e may thus conclude that no medical or personality factors were found that could have had a confounding effect on our investigations.

3.2. Serum levels of temazepam Baseline samples, and samples of temazepam at the moment of assessment with the Neurotoxicity Scale (1 h and 2 h post-dose) are given in Table 3. Differences between the groups are only apparent at the 2 h post-dose measurement. The pharmacokinetic profile, based on 12 measurements during the day, shows that the assessment at 2 h post-dose is at or near peak level for both temazepam groups: at 90 minutes for temazepam 10 mg and at 70 minutes for temazepam 20 mg.

3.3. Overall score Repeated Measures ANOVA showed a F - v a l u e of 3.28 (d.f. = 2) for the overall treatment effect (the difference between the treatment groups over both measurements, 1 h and 2 h post-dose) ( P = 0.054). The interaction effect (Treatment with Time) shows a F-value of 2.29 (d.f. = 2; P = 0.12). This latter effect implies that the direction of difference between the groups does not change from the measurement 1 h post-dose to the second measurement 2 h

Table 2 Results on the Spielberger State-Trait anxiety inventory Placebo Temazepam 10 mg

Temazepam 20 mg

Total group

Trait anxiety State anxiety

35.0 (5.2) 29.4 (4.0)

35.9 (6.4) 31.1 (5.3)

39.4 (8.0) 32.9 (6.9)

33.2 (4.4)" 31.1 (4.1)

Scores range from 20 (extremely low anxiety; a score of 1 on all 20 items) to 80 (extremely high anxiety score; a score of 4 on all 20 items). Compared to a norm group, the score of > 55 is considered as 'high'. Standard deviations between parentheses.

A.P. Aldenkamp et al. / Epilepsy Research 20 (1995) 229-239

234

Table 4 M e a n overall scores of the Neurotoxicity Scale

Group

1 h post-dose

2 h post-dose

Placebo Temazepam 10 mg Temazepam 20 mg

6.6 (6.0) 12.8 (10.2) 12.7 (12.9)

4.2 (5.7) 15.1 (11.5) 17.6 (11.4)

Standard deviation between parentheses.

Table 5 Statistical analysis of the differences between the treatment groups, 2 h post-dose (t-tests) Comparison

Value

t-Value

P

Placebo vs 1 0 m g Placebo vs 2 0 m g 1 0 m g vs 2 0 m g

10.9 13.4 2.4

2.39 3.02 0.54

0.024 * 0.006 * * 0.589

Effects: * P < 0.05; * * P < 0.01.

post-dose. Table 4 shows the mean overall scores for the first (1 h post-dose) and second (2 h post-dose) measurement. Fig. 1 gives an illustration of the differences between placebo on the one hand and the temazepam treatment groups on the other hand. Although the direction of differences between the groups does not change over time, the magnitude of these differences tends to increase from first to second assessment. Differences between the 10 mg and 20 mg temazepam groups can only be seen at the second measurement, 2 h post-dose and are limited in magnitude. This pattern is statistically confirmed: the ANOVA for the first assessment does not show differences between the groups on a statistically significant level. This is probably due to the large standard deviation in the temazepam groups, causing great overlap between the groups. At the second measurement (2 h postdose), however, the differences between the treatment groups are significant ( F = 5.144; P < 0.02). Table 5 shows the results of multiple t-test comparisons between the groups during the second assessment, 2 h post-dose. The analyses show significant differences for the comparisons between placebo and the both temazepam groups. Although the absoEndscore

15

o

5

0 1 h postdose

~placebo

2 h ~Tem.

lO mg

~Tem.

poatdose 20 mg

Fig. 1. Results of the overall score for the Neurotoxicity Scale, 1 h and 2 h post-dose.

lute difference between placebo and temazepam 20 mg is greater than between placebo and temazepam 10 mg, the comparison between the two temazepam groups do not show differences that are significant.

3.4. Separate questions Analysis of the differences between the treatment groups for the separate questions of the scale showed that most of the significant placebo-temazepam differences concerned questions that belong to the cognitive domains of fatigue or slowing (questions 1, 9, 16, 22 and 23: P < 0.01; questions 2, 8, 15: P < 0.05). Domains that only showed weak differences between the groups were language and memory. Concentration and motor coordination consisted of more questions that differentiated between the groups on a statistically significant level (questions 12, 19 and 20: P < 0.01; question 6: P < 0.05). Questions that were classified in the domain of 'hyperexcitability' showed no statistically significant differences between the groups. The questions, ordered per domain, are given in Appendix 1. In an attempt to explore a shortened version of the scale, the questions about hyperexcitability and other questions that did not show differences between the groups were removed. In total nine questions were removed: 3, 10, 17, 21, 24, 28, 30, 31 and 33. For this shortened, 24-questions version of the scale, the overall treatment effect is significant at the level of P = 0.03. The pattern of differences is, however, similar to the differences obtained with the original 33-questions version of the scale: no significant differences at 1 h post-dose and significant differences between placebo and the 10 mg temazepam group ( P = 0 . 0 2 ) and--more clearly--between placebo and the 20 mg temazepam group ( P = 0.004) at the second measurement, 2 h post-dose. The scale in Appendix 1 shows the original 33-questions version.

A.P. Aldenkamp et al. / Epilepsy Research 20 (1995) 229-239

The removed items for the shortened version are indicated with an asterisk. The shortened 24-questions version is shown as Appendix 2.

4. Discussion The Neurotoxicity Scale showed clear differences between placebo and two dose groups of temazepam. This suggests that patient-based reports may be used to detect the adverse effects of drugs on cognitive function. Nonetheless, several additional comments have to be made. Our data represent the subjective reported CNS effects of a benzodiazepine. It is yet to be investigated whether these data can be extrapolated to other classes of CNS drugs, in particular to AEDs. Moreover, the results show that the differences between placebo and temazepam are relatively small at the first assessment, 1 h post-dose and only yield statistical significance at the second assessment, 2 h post-dose. This is foand for both dose-groups. An important factor, that may have contributed to this effect is that the subjects needed some time to be confronted with problems in daily routines that were assessed with the scale. The time schedule of the study day allowed the subjects to maintain their daily routines, but they may not have had the opportunity to experience difficulties in several functions until the second assessment. A longer time interval may

235

therefore increase the sensitivity of some of the questions. We are presently exploring the value of the shortened 24-questions version of the scale in patients with epilepsy on chronic AED therapy. Although it is clear that the specific questions that were classified in the domains of 'fatigue' and 'slowing' have a greater impact on the overall score, the results on the scale can not be used to draw conclusions about impairment in specific cognitive domains. In fact the construction of the scale does not permit such differential interpretation. Rather, the scale gives an overall (global) evaluation of subjectively experienced drug-induced functional impairment. The overall score appears to be sensitive already in the lower toxicity range, i.e. for the comparison placebo-10 mg. Although the differences increase for the higher dose-range, none of the 10 mg-20 mg comparisons yield statistical significance. This suggests an 'all or nothing effect' that follows our theoretical assumptions: subjects are capable of detecting and reporting gross overall changes in their functioning. They are not able to express their complaints in terms of magnitude or specificity of their impairments. This implies that the scale has optimal applicability as a screening instrument, e.g. in outpatient treatment, where it may identify patients who are at risk for developing drug-induced cognitive impairment and may need further neuropsychological assessment.

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A.P. Aldenkamp et al. // Epilepsy Research 20 (1995) 229-239

Appendix 1 Questions o f the Neurotoxieity Scale

The numbers refer to the order in which the questions were presented in the study. The scale in the study did not have the 'heads' ('Fatigue' etc.) Numbers with an asterisk are removed in the shortened version of the scale

Fatigue 1. 8. 15. 22. * 28. 32. Slowing 2. 9. 16. 23. 29. Hyperexcitability *3. ~10. "17. * 24. * 30. * 33. Memory 4. 11. 18. 25. Concentration 5. 12. 19. 26. "31. Motor coordination 6. 13. 20. Language 7. 14. "21. 27.

I I I I I I

am less enthusiastic about day to day activities am less capable of undertaking initiatives tire easily and have little energy feel worn out feel depressed and worry cannot keep an activity going for long

My mind does not work as fast as it should My thinking has slowed down It takes me longer to do day to day things It costs more time for me to get started I feel I react too slow to things that are said to me I I I I I I

get easily irritated with my family and friends have aggressive feelings towards other people feel irritable, angry am unable to sit still feel as if driven by a motor feel excited

I I I I

have difficulties remembering names of people forget things, for example an appointment or were I put an object forget things what people have said to me get confused and forget what I was doing

I I I I I

have difficulties in following a book or a film have difficulties concentrating on the things I am doing can't concentrate for more than a short period of time get distracted more easily daydream too much

I feel clumsy I cannot use a pen or pencil accurately I constantly bump against things I I I I

have problems finding the correct word have problems understanding what I read sometimes use the wrong words sometimes stutter or are unable to find the correct words

A.P. Aldenkamp et aL / Epilepsy Research 20 (1995) 229-239

237

Appendix 2

Revised 24-questions version of the Neurotoxicity Scale TheA -B neurmavocilyscale Version: U.K (11/11/93) patient n u m b e r : ....... a s s e s s m e n t n u m b e r ....... A-B e n d s c o r e : .......

THE NEUROTOXICI'IY SCALF~

I

BELOW IS A LIST OF PROBLEMS PEOPLE SOMETIMES HAVE WITH THE MEDICINE THEY TAKE FOR THEIR EPILEPSK HAVE YOU HAD A N Y PROBLEMS LISTED WHICH YOU THINK MAY HAVE BEEN CAUSED B Y THE DRUGS YOU TAKE? FOR F_~CH ITEM, IF 1T IS NO PROBLEM RING 0; IF IT IS A MILD PROBLEM RING 1; IF IT IS A MODERATE PROBLEM RING 2 AND IF IT IS A SERIOUS PROBLF~M RING 3. IF A QUESTION IS N O T RELEVANT FOR YOU, NO ANSWER SHOULD BE GIVEN.

No problem

A mild problem

A moderate problem

A serious problem

l

I

I

I

1. I a m less e n t h u s i a s t i c ab~mt d a y to d a y activities

0 ......................

1 ......................

2 ...................... 3

2. M y m i n d d o e s n o t w o r k as fast as it should

0 ......................

1 ......................

2 ...................... 3

3. I h a v e difficulties r e m e m l h e r i n g n a m e s o f p e o p l e

0 ......................

1 ......................

2 ...................... 3

4. I h a v e difficulties in foilo~cing a b o o k o r a film

0 ......................

1 ......................

2 ...................... 3

5. I feel c l u m s y

0 ......................

1 ......................

2 ...................... 3

6. I h a v e p r o b l e m s finding t h e correct w o r d

0 ......................

1 ......................

2 ...................... 3

7. I a m less c a p a b l e o f u n d e r t a k i n g initiatives

0 ......................

1 ......................

2 ...................... 3

8. M y t h i n k i n g h a s slowed d o w n

0 ......................

1 ......................

2 ...................... 3

9. I f o r g e t things, for e x a m p l e a n a p p o i n t m e n t o r w e r e I put a n object

0 ......................

1 ......................

2 ...................... 3

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20 (1995) 229-239

10. I have difficulties c o n c e n t r a t i n g on the things I a m doing

0 ......................

1 ......................

2 ......................

3

11. I cannot use a p e n o r pencil accurately

0 ......................

1 ......................

2 ......................

3

12. I have p r o b l e m s u n d e r s t a n d i n g w h a t I r e a d

0 ......................

1 ......................

2 ......................

3

13. I tire easily a n d h a v e little e n e r g y

0 ......................

1 ......................

2 ......................

3

14. It takes m e longer to do day to day things

0 ......................

1 ......................

2 ......................

3

15. I forget things w h a t p e o p l e h a v e said to m e

0 ......................

1 ......................

2 ......................

3

16. I can't c o n c e n t r a t e for m o r e t h a n a short p e r i o d of t i m e

0 ......................

1 ......................

2 ......................

3

17. I constantly b u m p against tables, d o o r I x ~ t s etc,

0 ......................

1 ......................

2 ......................

3

18. ! feel w o r n out

0 ......................

1 ......................

2 ......................

3

19. It costs m o r e t i m e for m e to get started

0 ......................

1 ......................

2 ......................

3

20. I get confused a n d forget w h a t I was doing

0 ......................

1 ......................

2 ......................

3

21. I get distracted m o r e easily

0 ......................

1 ......................

2 ......................

3

22. I s o m e t i m e s stutter or a r e u n a b l e to find t h e correct w o r d s

0 ......................

1 ......................

2 ...................... 3

23. I feel I react too slow to t h i n ~ that are said to m e

0 ......................

1 ......................

2 ...................... 3

24. 1 cannot k e e p a n activity going for long

0 ......................

1 ......................

2 ...................... 3

A R E T H E R E ANY O T H E R C O M P L A I N T S T H A T A R E N O T M E N T I O N E D I N T H E Q U E S T I O N S ? P L E A S E w R r r E

THEM DOWN AND RING 0, I, 2 OR 3:

0 ......................

1 ......................

2 ...................... 3

0 ......................

1 ......................

2 ...................... 3

3 ................................................

0 ......................

1 ......................

2 ...................... 3

4 ................................................

0 ......................

1 ......................

2 ...................... 3

0 ......................

1 ......................

2 ...................... 3

6 ................................................

0 ......................

1 ......................

2 ...................... 3

7 ................................................

0 ......................

1 ......................

2 ...................... 3

8 ................................................

0 ......................

1 ......................

2 ...................... 3

9 ................................................

0 ......................

1 ......................

2 ...................... 3

10 ...............................................

0 ......................

1 ......................

2 ...................... 3

I ................................................

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