Acta Neurol Scand 2015: 131: 347–354 DOI: 10.1111/ane.12372
`
`© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
`ACTA NEUROLOGICA
`SCANDINAVICA
`
`Cognitive effects of lacosamide as
`adjunctive therapy in refractory epilepsy
`
`IJff DM, van Veenendaal TM, Majoie HJM, de Louw AJA, Jansen
`JFA, Aldenkamp AP. Cognitive effects of lacosamide as adjunctive
`therapy in refractory epilepsy.
`Acta Neurol Scand 2015: 131: 347–354.
`© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
`
`Background – Lacosamide (LCM) is a novel antiepileptic drug (AED)
`with potential benefit as adjunctive treatment in patients with partial-
`onset seizures. As yet, limited information on cognitive effects of
`LCM is available, especially in real-life settings. Aims – In this open
`clinical prospective study, the cognitive effects of LCM were evaluated
`when used as adjunctive antiepileptic therapy in patients with
`refractory epilepsy. Methods – We included 33 patients aged between
`16 and 74 years (mean: 37 years). All patients had a localization-
`related epilepsy. Patients were assessed at baseline before starting
`LCM treatment and during follow-up when the optimal clinical dose
`was achieved. Materials – Subjective complaints were evaluated using
`the SIDAED; effects on cognition were evaluated using the
`computerized visual searching task (CVST). Results – The CVST
`showed significant faster information processing reaction times at the
`second evaluation (P = 0.013), which was not correlated with seizure
`control, type of epilepsy, age, gender, drug load, number of
`concomitant drugs, dose or duration of LCM treatment. On the
`SIDAED, patients complained more about their cognitive function at
`the second evaluation (P = 0.005). For the SIDAED, a positive
`correlation at follow-up was found between the total severity score
`and higher age (r = 0.375, P = 0.031), but not with epilepsy factors or
`treatment characteristics. Discussion/Conlusion – Screening of the
`cognitive effects of LCM showed that LCM does not have negative
`effects on information processing speed. As this is the most sensitive
`function for cognitive side effects of AEDs, LCM does not seem to
`induce the common negative cognitive effects. Remarkably, patients
`complained more, especially about their cognitive function, which is
`possible the ‘doing better, feeling worse phenomenon’.
`
`D. M. IJff1,2, T. M. van
`Veenendaal2,3, H. J. M. Majoie1,2,
`A. J. A. de Louw1, J. F. A.
`Jansen2,3, A. P. Aldenkamp1,2,4,5,6
`1Departments of Neurology and Neuropsychology
`Epilepsy Centre Kempenhaeghe, Heeze, The
`Netherlands; 2School for Mental Health and
`Neuroscience, Maastricht University, Maastricht, The
`Netherlands; 3Department of Radiology, Maastricht
`University Medical Centre, Maastricht, The
`Netherlands; 4Department of Neurology, Maastricht
`University Medical Centre, Maastricht, The
`Netherlands; 5Department of Neurology, Gent
`University Hospital, Gent, Belgium; 6Faculty of
`Electrical Engineering, University of Technology,
`Eindhoven, The Netherlands
`
`Key words: adverse effects; anti-epileptic drug;
`cognition; epilepsy
`
`D. M. IJff, Department of neuropsychology, Epilepsy
`centre Kempenhaeghe, P.O. Box 61, NL-5590 A.B.
`Heeze, The Netherlands.
`Tel.: +31 40 2279233
`Fax: +31 40 2260426
`e-mail: IJffD@kempenhaeghe.nl
`
`Accepted for publication February 12, 2014
`
`Introduction
`
`Lacosamide (LCM) is a relatively recent intro-
`duced antiepileptic drug (AED). It was approved
`in Europe and USA in 2008 as adjunctive therapy
`for the treatment of partial-onset seizures in
`patients with epilepsy aged 16 and older in Eur-
`ope and in patients 17 and older in the United
`States (1). LCM is unique among existing AEDs
`in that it has been shown to exert its anticonvul-
`sant effects predominantly by enhancement of the
`slow inactivation of voltage-gated sodium chan-
`nels without effecting fast inactivation (2, 3).The
`
`post hoc analysis of pooled clinical data by Sake
`et al. (4) suggests that there may be an improved
`tolerability for LCM in patients not on other
`sodium channel blockers (SCB’s).
`The efficacy and safety of adjunctive LCM
`for partial-onset
`seizures was
`established in
`three multicenter,
`randomized,
`double-blind,
`(5–7). Drug-induced
`placebo-controlled trials
`adverse events with an incidence of at
`least
`10% during the treatment period were general
`CNS and gastrointestinal effects (dizziness, nau-
`sea, diplopia, vision blurred, headache, vomit-
`ing,
`ataxia,
`fatigue,
`somnolence,
`vertigo,
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`IJff et al.
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`coordination,
`abnormal
`nasopharyngitis,
`nystagmus, and tremor). All of these with the
`exception of headache appeared to be dose
`related, and four of these adverse effects were
`greater for LCM than for placebo; dizziness
`[31% vs 8%], headache [13% vs 9%], nausea
`[11% vs 4%], and diplopia [11% vs 2%] (7,8).
`A recent published meta-analysis of all available
`randomized controlled trials with LCM which
`included these three trials and seven trials with
`other disorders (neuropathic pain, migraine, fi-
`bromyalgia, knee osteoarthritis)
`found that
`these
`adverse
`events were more
`frequent
`reported in patients with drug-resistant epilepsy
`compared to other disorders (9). LCM was not
`associated with any adverse event unambigu-
`ously related to cognition in this analysis. How-
`ever, Doty et al. (10) criticized that no formal
`cognitive testing was performed in these ran-
`domized controlled trials.
`In none of
`the trials, cognitive side effects
`were recorded as a dominant complaint, which
`is
`remarkable given the high incidence of
`reported cognitive side effects in antiepileptic
`treatment (11, 12). The only item indicative of
`cognitive dysfunction reported was memory
`impairment, but its association with LCM was
`limited and not significant. However, no formal
`cognitive testing was performed in any of these
`trials, and cognitive effects notoriously evade
`subjective detection, especially in cases where
`patient use the drug as a ‘last resort’ (9, 10).
`In a long-term study rates of adverse events
`commonly attributed to other AEDS such as
`changes in cognition were low (13). Recently,
`the cognitive effects of LCM were compared
`with lamotrigine and topiramate suggesting a
`cognitive profile
`similar
`to lamotrigine and
`superior to that of topiramate (14).
`For our specific patient group (i.e., patients
`with refractory epilepsies in a tertiary epilepsy
`referral and care center), data about the cogni-
`tive effects of LCM are important for clinical
`decision making. Cognitive complaints of
`the
`epilepsy, the seizures and the drugs may be con-
`fusingly entangled,
`limiting evaluation of
`the
`effectiveness of a drug in an individual patient.
`Preferably, cognitive effects of LCM would be
`studied in a randomized clinical trial. However,
`rarely cognition is an outcome (primary or sec-
`ondary) of the industry driven RCT’s. The alter-
`native reports of clinical experience (often case
`reports) have led, however, to a substantial delay
`in detecting and understanding some behavioral
`effects of AEDs (15). Our study must therefore
`be seen as a systematic clinical audit, collecting
`
`348
`
`information on the cognitive effects in the natu-
`ralistic clinical setting.
`
`Methods
`
`Subject selection
`
`Patients who were scheduled to start with LCM
`between March 2009 and September 2011 were
`included. They were investigated before this
`drug was added to their current treatment and
`when they were using LCM. The study was
`approved by the local medical ethical commit-
`tee.
`
`Assessment procedures
`
`Cognitive effects of LCM were assessed at two
`different times: at baseline before starting with
`this drug
`and at
`follow-up. The
`intervals
`between baseline and follow-up are variable
`because data were collected as part of normal
`clinical practice. The patient characteristics (age
`and sex), type of epilepsy, comedication, drug
`load, average dose of LCM, length of treatment
`with LCM at follow-up, efficacy, and reasons
`for discontinuation of LCM were included in
`the database. Efficacy was evaluated by change
`in seizure frequency from baseline to follow-up
`using a 3-point scale; reduction in seizure fre-
`quency, seizure remission, or increase in seizure
`frequency.
`
`Instruments
`
`Patients were tested with two measurements: a
`standardized inventory to evaluate subjectively
`perceived cognitive side effects and a neuropsy-
`chological test to assess possible effects indepen-
`dent of subjective complaints. Complaints were
`assessed using a list of 46 items with possible
`AED-related complaints, the SIDAED (16, 17).
`A complete overview of the SIDAED is provided
`in the Appendix A. The included items form 10
`categories: general CNS, behavior (increased irri-
`tability), depressive symptoms, cognitive function,
`motor problems and coordination, visual com-
`plaints, headache, cosmetic and dermatological
`complaints, gastrointestinal complaints, and sexu-
`ality and menses. For each item, the patient rates
`the severity of the complaint on a four-point Lik-
`ert scale (no problem, mild, moderate, or serious
`problem). In addition, the duration of the com-
`plaints is scored (since a few weeks, since months
`or half a year or longer). A total subjective com-
`plaints score was calculated for each patient from
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`the SIDAED complaints questionnaire, consisting
`of the number of mentioned complaints, weighing
`a mild score as 1, moderate as 2, and severe as 3
`points. Thus, the range of the total severity com-
`plaints score could vary from 0 to 138. This
`questionnaire can be analyzed in different ways:
`regarding the total reported complaints, the dif-
`ferent categories and the different items. The SI-
`DAED is
`chosen because
`the psychometric
`properties have been established (16–18) and cog-
`nitive complaints can be measured relative to
`other domains.
`task
`searching
`visual
`The
`computerized
`(CVST), an adaptation of Goldstein’s visual
`searching task gives an indication of the visual
`(complex) information processing speed (19). A
`target grid pattern in the centre of the computer
`screen has to be compared with 24 surrounding
`patterns. Only one of them is identical to the tar-
`get pattern. An example of this test is provided in
`the Appendix B. The patient is asked to react as
`fast as possible; reaction times are recorded. After
`each correct response, the central target pattern
`changes. The test consists of 24 different patterns,
`and after 12 presentations, the surrounding grids
`change. This task was included as slowing of cen-
`tral information processing is observed to be the
`0
`dominant cognitive effect of most AED
`s and
`also the first sign of cognitive adverse effects (11,
`12).
`
`Dosing and titration
`
`The initial dose of 50 mg was increased at weekly
`intervals by 50 mg up to the recommended main-
`tenance dose of 200–400 mg/day. However, the
`titration schedule was individualized in response
`to patient complaints and seizure frequency.
`
`Statistical analysis
`
`Data were analyzed with SPSS version 21.0,
`Chicago, IL, USA. For analyzing the neuropsy-
`chological data, paired sample t-tests were used.
`Pearson correlations were used to exclude for
`influential
`effects on the neuropsychological
`results. Patients characteristics (gender and age),
`epilepsy factors (seizure control and type of epi-
`lepsy), and treatment characteristics (number of
`concomitant drugs, drug load, dose and dura-
`tion of LCM treatment) were
`taken into
`account. Because the SIDAED consisted of 10
`a P-value ≤0.005 was
`different
`categories,
`considered significant
`for the subscales of
`the
`SIDAED. This more stringent criterion of sig-
`nificance was based on the Bonferroni adjust-
`
`Cognitive effects of lacosamide
`
`ment for multiple tests. For the items of the
`corrected P-value
`SIDAED,
`a Bonferroni
`≤ 0.001 was considered significant.
`
`Results
`
`Patient characteristics
`
`A total of 33 patients were included in this
`study. Most patients (73%, n = 24) were female.
`Mean age at baseline was 37 years (SD: 14.5).
`Most patients (58%, n = 19) had a symptom-
`atic
`localization-related
`epilepsy,
`and
`42%
`(n = 14) had a cryptogenic localization-related
`epilepsy.
`Five patients (15%) discontinued their LCM
`treatment before the second evaluation and were
`excluded for further analysis. Reasons for discon-
`tinuation were unsatisfactory therapeutic effect in
`two patients and side effects in three patients.
`These side effects were tiredness, dizziness, coor-
`dination, and balance problems.
`The 28 remaining patients were using LCM
`treatment with a mean daily dose at follow-up of
`298.2 mg/day (SD: 120.6). LCM was added to
`the anticonvulsant regimen. Twenty-one of 28
`patients (75%) were taking LCM in addition to a
`SCB. Concurrent AED’s ranged from 1 to 4
`(mean: 1.9, SD: 0.8). The majority of the patients
`were
`taking carbamazepine
`(43%),
`clobazam
`(32%),
`lamotrigine
`(25%), and levetiracetam
`(21%).
`Mean follow-up time was 7 months (SD: 6,
`range 1–24). In nine patients (28%), comedication
`was changed at follow-up; in five patients, only
`the dose of comedication was optimized, and in
`four patients, there was a medication switch in
`which LCM was added in exchange for one other
`anticonvulsant.
`Seizure frequency was reduced in 50% (n = 14)
`of the patients. In 12 patients (43%), LCM did
`not have an effect on seizure frequency. Two
`patients (7%) had more seizures than before
`treatment with LCM was started.
`Patients characteristics and their clinical date
`are provided in Table 1.
`
`Neuropsychological findings
`
`The CVST showed significant faster information
`processing
`speed at
`the
`second evaluation
`(t = 2.644, P = 0.013). At
`follow-up, patients
`showed an average increase of speed of more
`than 3-s (18%) on this task at follow-up (mean at
`baseline: 18.67 s; SD: 8.9; mean at follow-up:
`15.40 s; SD: 7.5).
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`Table 1 Clinical characteristics of patients
`
`Patient
`
`Sex
`
`Age
`
`Type of
`localization-related
`epilepsy
`
`Dosage LCM (mg)
`at second evaluation
`
`Concurrent AED
`
`Effect on seizure
`frequency
`
`Treatment duration (LCM)
`at second evaluation (months)
`
`Reason for
`discontinuation
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`
`F
`F
`F
`F
`F
`F
`F
`F
`F
`M
`M
`F
`M
`F
`F
`M
`F
`F
`F
`M
`M
`M
`F
`F
`M
`F
`F
`F
`F
`F
`F
`M
`F
`
`74
`44
`28
`62
`59
`16
`62
`45
`25
`34
`35
`19
`18
`37
`50
`24
`23
`45
`19
`47
`25
`51
`42
`44
`29
`29
`41
`22
`44
`24
`36
`35
`24
`
`Cryptogenic
`Symptomatic
`Symptomatic
`Symptomatic
`Cryptogenic
`Symptomatic
`Cryptogenic
`Cryptogenic
`Cryptogenic
`Symptomatic
`Symptomatic
`Symptomatic
`Cryptogenic
`Symptomatic
`Cryptogenic
`Symptomatic
`Symptomatic
`Symptomatic
`Cryptogenic
`Symptomatic
`Symptomatic
`Symptomatic
`Cryptogenic
`Symptomatic
`Cryptogenic
`Symptomatic
`Cryptogenic
`Cryptogenic
`Symptomatic
`Cryptogenic
`Symptomatic
`Symptomatic
`Cryptogenic
`
`200
`300
`200
`250
`400
`Discontinued
`200
`100
`200
`300
`Discontinued
`300
`400
`300
`200
`600
`400
`250
`300
`Discontinued
`500
`Discontinued
`550
`400
`150
`Discontinued
`300
`200
`400
`300
`250
`200
`200
`
`PB 25 CLB 30
`CBZ 600 CZP 1
`PHT 350 OXC 1800 CLB 20
`VPA 300 CLB 10
`CBZ 1000
`
`LEV 200 LTG 300 CLB 40
`LEV 500
`VPA 2250
`LEV 3000 OXC 1200 LTG 500
`
`
`LTG 150
`OXC 2700 PGB 225
`CBZ 1600 LTG 200
`GBP 1200 CBZ 600
`LTG 550 TPM 200
`AZM 500 CZP 3
`CBZ 800 LTG 600
`VPA 1200 CBZ 1100
`
`LEV 3000 CBZ 800 CLB 30
`
`LEV 2000 PB 150
`
`CBZ 100 TPM 200
`
`
`CBZ 1000
`LTG 175 CLB 20
`CLB 20
`CBZ 800 CLB 10
`PHT 187.5
`CBZ 1400
`LEV 1000 CBZ 800 CLB 20
`
`=
`
`+
`=
`=
`
`=
`
`
`=
`
`
`=
`
`=
`=
`=
`
`
`
`
`
`
`=
`
`+
`
`=
`=
`
`4
`5
`3
`3
`3
`Discontinued
`2
`24
`1
`3
`Discontinued
`3
`4
`3
`4
`10
`12
`3
`10
`Discontinued
`6
`Discontinued
`7
`22
`2
`Discontinued
`4
`17
`8
`2
`3
`10
`14
`
`Ineffectiveness
`
`Adverse events
`
`Ineffectiveness
`
`Adverse events
`
`Adverse events
`
`PB, phenobarbital; CLB, clobazam (Frisium); CBZ: carbamazepine (Tegretol); CZP, clonazepam (Rivotril); PHT, phenytoin (Diphantoine); OXC, oxcarbazepine (Trileptal); VPA, val-
`proate (Depakine); LEV, levetiracetam (Keppra); LTG, lamotrigine (Lamictal); PGB, pregabalin (Lyrica); GBP, gabapentin (Neurontin); AZM, acetazolamide (Diamox), seizure fre-
`quency; , reduction; +, increase; =, seizure remission, no effect; AED, antiepileptic drug; LCM, lacosamide.
`
`On the SIDAED, none of the patients men-
`tioned zero complaints at baseline or follow-up.
`At baseline, before the start of treatment with
`LCM, the distribution of subjective complaints as
`measured by the SIDAED ranged from 3 to 36
`(maximal range on the scale is 0–46), with a
`mean number complaints of 15.8 (SD: 7.0). At
`second evaluation, the average rate of subjective
`complaints
`did
`not
`differ
`from baseline
`(P = 0.431) with a mean number of complaints of
`16.8 (SD: 8.5; range: 1–35).
`A statistically significant effect was only found
`for the subscale cognitive complaints. For the
`other subscales, results did not yield statistical
`significance (see Fig. 1). Both the severity of the
`cognitive complaints (t = 3.367, P = 0.002) as
`the
`number
`of
`the
`cognitive
`complaints
`(t = 2.992, P = 0.005) increased in the treatment
`phase. The mean severity score on the subscale
`
`350
`
`cognitive function per item increased from 0.78
`to 1.11 (see Table 2). At baseline, patients
`reported to experience on average 4.2 (SD: 1.9)
`of the nine possible cognitive complaints. In the
`treatment phase, this was increased to an average
`of 5.3 (SD: 2.4).
`When analyzing the 46 items, a significant
`higher severity score was found at the second
`evaluation for the following items from the cogni-
`tive function category; ‘I have difficulty remem-
`bering names’ (t = 4.917, P < 0.000), ‘I notice I
`sometimes have difficulty
`expressing myself’
`(t = 3.783, P < 0.000), and ‘I have difficulty
`finding the right words’ (t = 3.475, P = 0.001).
`
`Correlational analysis
`
`A significant positive correlation was found at
`follow-up between processing speed and the
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`Cognitive effects of lacosamide
`
`*
`
`Baseline
`
`Follow-up
`
`1.2
`
`1
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`Mean severity score per item
`
`0
`
`GENERAL CNS
`BEHAVIOR
`DEPRESSION
`M OTOR/CO-ORDINATION
`COGNITION
`
`VISUAL
`HEADACHE
`
`LOOKS
`
`SEXUALITY & MENSES
`W EIGHT/STO MACH
`
`Figure 1. Differences in the subscales of the SIDAED between baseline and follow-up. *P ≤ 0.05.
`
`Table 2 The mean reported severity score per item per subscale
`
`Subscale
`
`Baseline
`
`Follow-up
`
`General CNS
`Behavior (increased irritability)
`Depressive symptoms
`Cognitive function
`Motor problems and coordination
`Visual complaints
`Headache
`Cosmetic and dermatological complaints
`Gastrointestinal complaints
`Sexuality and menses
`
`*P ≤ 0.05.
`
`0.80
`0.55
`0.65
`0.78
`0.54
`0.69
`0.52
`0.40
`0.35
`0.59
`
`0.94
`0.56
`0.70
`1.11*
`0.60
`0.61
`0.30
`0.41
`0.38
`0.70
`
`SIDAED cognitive items ‘I notice my reaction to
`(r = 0.465, P = 0.013) and ‘I
`others
`is
`slow’
`notice my speech is slow’ (r = 0.467, P = 0.012).
`Improvement of processing speed was associated
`with a decrease of complaints. No other cognitive
`complaints were correlated with the information
`processing task.
`The improved information processing speed
`could not be explained by patient characteristics
`such as gender (P = 0.712) or age (P = 0.771), or
`by epilepsy factors
`such as
`seizure
`control
`(P = 0.332) or type of epilepsy (P = 0.494), or by
`treatment characteristics such as number of con-
`(P = 0.359),
`comitant
`drugs
`drug
`load
`(P = 0.927), or dose (P = 0.830) and duration of
`LCM treatment (P = 0.659).
`For the SIDAED, a positive correlation at fol-
`low-up was found between the total severity score
`
`and age (r = 0.375, P = 0.031). The older the
`patients,
`the more complaints were reported.
`Gender, epilepsy factors or other treatment char-
`acteristics did not affect the results.
`
`Discussion
`
`Lacosamide is a relatively recent introduced AED
`with potential benefit as adjunctive treatment in
`patients with partial-onset seizures (20). In this
`open clinical prospective study,
`the cognitive
`effects of LCM when used as adjunctive antiepi-
`leptic therapy in adolescent and adult patients
`with refractory epilepsy were evaluated in the
`real-life setting.
`During LCM treatment, we found a statisti-
`cally significant improvement of information pro-
`cessing speed (increase of 18%). This function is
`generally impaired in individuals taking other
`AEDs (9, 11, 12). Speed of information process-
`ing is the most sensitive function affected by
`AED treatment; therefore, this result is remark-
`able. However, activating effects have also been
`reported for lamotrigine (11, 12, 21, 22). Ketter
`et al. (23) divided AEDs in activating and sedat-
`ing drugs, and our results suggest that LCM may
`be classified as a cognitive activating drug. The
`results were not biased by interfering factors. The
`significant
`improvement of central
`information
`processing speed was not correlated with change
`in seizure frequency, type of epilepsy, age, gender,
`drug load, number of concomitant drugs or dose
`and duration of LCM treatment. Therefore, our
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`study suggests that LCM does not have a nega-
`tive impact on this sensitive measurement.
`There is a difference between the results of the
`objective cognitive assessment and the subjective
`patient report. Patients reported no increase in
`overall complaints from baseline to treatment
`phase. However, there is an increase in number
`and severity of cognitive complaints. More specif-
`ically, patients had more complaints about mem-
`ory
`(‘remembering
`names’)
`and
`language
`(‘expressing themselves’ and ‘finding the right
`words’). On the other hand, correlational analysis
`showed a significant positive
`correlation at
`follow-up between processing speed and the
`SIDAED items ‘I notice my reaction to others is
`slow’ and ‘I notice my speech is slow’. Improve-
`ment of processing speed was associated with a
`decrease of complaints. This concurs with the
`findings on the information processing task and
`these
`results
`in
`combination
`suggest
`that
`improvement of the processing speeds increases
`awareness in patients of other difficulties such as
`memory and language, which are generally not
`related to drug treatment but to the epilepsy.
`This improvement of adverse drug effect followed
`by an increased awareness of other cognitive diffi-
`culties can be described as the ‘doing better, feel-
`ing worse phenomenon’.
`None of the patients in our study discontinued
`LCM treatment because of the complaints about
`cognitive difficulties, which collaborates the result
`of the cognitive assessment. The reason for with-
`drawal was adverse events in three patients and
`unsatisfactory seizure control
`in two patients.
`The most common drug-related adverse events
`were tiredness, dizziness, coordination, and bal-
`ance problems. This is in line with the study of
`Garcıa-Morales et al.
`(24) who reported that
`about half of the patients who reported dizziness
`were taking other sodium channel blockers. In
`our study, all patients who discontinued their
`LCM treatment were using a sodium channel
`modulator in combination. It has been suggested
`that neurotoxicity with LCM may be more likely
`with concomitant use of
`the more traditional
`voltage-gated sodium channel blockers such as
`carbamazepine,
`phenytoin,
`lamotrigine,
`and
`oxcarbazepine due to a pharmacodynamic inter-
`action (4, 25–27). However, Wehner et al. and
`Stephen et al. concluded that LCM is as well tol-
`erated in patients on traditional SCBs than on
`non-SCB’s (28, 29).
`There are some methodological issues that limit
`the interpretation of our study. With respect to
`the neuropsychological outcome, this study has
`assessed the most commonly reported effect on
`
`352
`
`cognition, but no tests using other cognitive func-
`tions has been used. Furthermore, preferably the
`rules of a randomized controlled trial
`(RCT)
`would have been applied. However, generally,
`cognitive outcomes are not investigated in the
`industry driven RCT’s when a new drug is in
`development. The alternative is then to study the
`effects in a naturalistic setting with limited pro-
`tection against bias. Nonetheless, LCM is used in
`clinical practice and cognition is important for
`medical decision making. Our recommendation is
`that in new drug development of AEDs cognition
`is always used as outcome measure in the RCT’s.
`In conclusion, screening of the cognitive effects
`of LCM showed that LCM does not have nega-
`tive effects on information processing speed. Fur-
`ther research is needed to investigate the other
`cognitive domains. However, as this is the most
`sensitive function for cognitive side effects of
`anti-epileptic drugs, LCM does not
`seem to
`induce the common negative cognitive effects.
`Possibly,
`it has a potential cognitive enhancing
`effect similar to that reported for lamotrigine.
`
`Acknowledgments
`
`None.
`
`Conflict of interest and sources of funding statement
`
`None of the authors have any conflict of interest to disclose.
`
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`Appendix A
`SIDAED list of subjective complaints
`
`1. I have problems with my gums
`2. I have lost weight
`3. I have difficulty remembering names
`4. I often feel drowsy and sleepy
`5. I sometimes have to hold on to something to
`stop myself from falling
`6. I forget all sorts of things, such as appoint-
`ments
`7. I find it hard to concentrate
`8. I tire easily and have little energy
`9. I am easily aggressive
`10.I can only concentrate on something for short
`periods
`11.I constantly walk into tables, doorposts etc.
`12.I feel agitated and restless
`13.I notice my reaction to others is slow
`14.I cannot concentrate on the same thing for
`long periods of time
`15.I notice my speech is slow
`16.I constantly feel pressurized and excitable
`17.I often suffer from dizzy spells
`18.I have little appetite
`19.My periods are irregular
`20.I notice I sometimes have difficulty expressing
`myself
`21.I often feel nauseous
`22.I worry all day
`23.I often suffer from diarrhea
`24.My hands shake all the time
`25.I have surplus saliva
`26.I often suffer from double vision
`27.I suffer from skin rash or other skin problems
`28.I have gained weight
`29.I think more slowly than I used to
`30.I am easily irritated
`31.I feel depressed and miserable
`32.My bowel movement is often difficult
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`IJff et al.
`
`33.I have difficulty finding the right words
`34.I am becoming less and less active
`35.I cannot get to sleep and often lie awake
`36.I am less often in the mood for sex
`37.Sometimes I cannot do anything because of
`headaches
`38.I suffer from hair loss
`39.My vision is blurred
`40.My hair growth has increased
`41.When I want to pick up something, my hands
`start shaking
`42.I do not feel capable of performing normal
`my daily activities
`43.I often suffer from headaches
`44.Making love has become less pleasant
`45.I often suffer from stomach trouble
`46.I often feel light-headed
`
`Severity was stated as no problem/mild/moder-
`ate/serious problem.
`
`Duration was stated as since a few weeks/
`months/half a year or longer.
`Appendix B
`
`Example of an item of the CVST from FePsy
`
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