J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.46.3.227 on 1 March 1983. Downloaded from Journal of Neurology, Neurosurgery, and Psychiatry 1983;46: 227-233 Anticonvulsant serum levels: relationship to impairments of cognitive functioning PJ THOMPSON, MR TRIMBLE* From the Department ofNeuropsychiatry, The National Hospital for Nervous Diseases, Queen Square, London UK SUMMARY Twenty-eight patients with epilepsy were seen on two occasions at an interval of three months. On one session anticonvulsant serum levels were high and on the other session the serum levels were lower. On each of the two sessions patients performed a series of psychological tests and had a blood sample taken for the analysis of anticonvulsant serum concentrations. Seizure frequency in the previous three months was documented and several patients had an EEG recording made. Deficits in psychological test performance were found at high serum concentra- tions. Furthermore, lower serum level concentrations did not appear to be accompanied by worsened seizure control. Protected by copyright. Anticonvulsant serum levels are thought to provide influencing the cognitive state of patients with a better indicator of clinical response and the inci- epilepsy.'0 Patients with high anticonvulsant serum dence of neurotoxic side effects in patients with levels may well differ with respect to a number of epilepsy than doses of drugs.' Therapeutic ranges such important parameters from patients with lower have been established for several anticonvulsants serum concentrations. within which maximum seizure control may be Investigations involving non-epileptic volunteers expected with minimum occurrence of side effects, offers a partial solution to investigating drug effects such as nystagmus, ataxia, diplopia and mental con- as the contaminating influence of other epileptic var- fusion.2 However, it is unclear whether serum level iables is avoided. Authors have reported deficits in monitoring may also prove useful for avoiding psychological test performance of normal volunteers detrimental drug-induced changes in cognitive at therapeutic and sub-therapeutic levels of functioning which have been reported.3 In the phenobarbitonell 12 and phenytoin.13 In our own assessment of the effects of these drugs on cognition research we have also found adverse effects of only a few investigators have included measure- phenytoin at sub-therapeutic concentrations and for ments of anticonvulsant serum concentrations and sodium valproate and carbamazepine less marked several have reported impairments in association impairments at values within their respective http://jnnp.bmj.com/ with high but not always toxic levels.4-9 therapeutic ranges." ls Extrapolation from these The majority of studies have either compared the acute drug studies involving non-epileptic individu- psychological test performance of two groups of als to patients with epilepsy, administered anticon- patients, divided about some arbitrary cut-off value vulsants chronically, must be made with caution. into high and low serum groups,56 or have correlated Detrimental effects recorded may reflect only trans- psychological test scores of a sample of patients with ient impairments of functioning which may not be their individual serum concentrations.8 9 Interpreta- observed following more prolonged use. tion of the findings from such studies unfortunately To explore further the relationship between anti- on September 28, 2021 by guest. is complicated since many interrelated factors such convulsant serum levels and cognitive functioning, as seizure severity and frequency, head traumas and in particular whether adverse effects do occur at psychosocial problems have been implicated as therapeutic concentrations, we have undertaken a study involving patients with epilepsy. To avoid the Address for reprint requests: Dr MR Trimble, The National Hospi- problems of interpretation of earlier investigations, tal for Nervous Diseases, Queen Square, London, WC1 3BG, UK. a longitudinal design was adopted in which patiente Received 15 July 1982 and in revised form 3 November 1982. performance on a series of specially designed Accepted 20 November 1982. psychological tests was measured at high and low 227 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.46.3.227 on 1 March 1983. Downloaded from 228 Thompson, Trimble anticonvulsant serum concentrations. The findings 2 Concentration (i) Stroop Test. The version used con- of this study are reported in this paper. sisted of three cards. The task was to read the colour words (red, blue, green) on the first card (I) and to name the Method coloured rectangles (red, blue, green) on the second card (II) as quickly as possible. On the third card the colour Patients words (red, blue, green) were printed in various colours Sixteen male and twelve female patients with a diagnosis of (red, blue, green) never congruent with the word, and sub- epilepsy participated in the study. No patient had under- jects were required to name the colour the words were gone surgery in the past five years, had any signs of a written in as quickly as possible. The difference in the time progressive brain lesion or was prescribed any regular taken to complete cards II and III and the number of errors medication other than anticonvulsants. The mean age of made on card III were used as the measures of perfor- the sample was 23-3 years (range 12-51) and their mean mance. IQ was 99 (range 64-130). Three patients were still attefid- (ii) Visual scanning. The time taken to cancel a target digit ing school or college and the remaining 27 had completed a from a page of random numbers was recorded in two con- mean of 1 1-4 years' education (range 9-16). The mean age ditions: (a) alone, and (b) in the presence of an auditory of onset of epilepsy was 8-4 years (range 1-21) with a distracting task. mean duration of 14-8 years (range 4-45). Seizure type 3 Mental speed (i) Perceptual speed. The minimum was primary generalised in six cases, secondary generalised exposure duration at which subjects could recognise pic- in nineteen, partial in two and mixed in one. Sixteen tures of objects and words in a masking paradigm was used patients were seen while attending a short-stay unit at a to assess the speed of perceptual registration. special centre for epilepsy and the remaining twelve were (ii) Decision-making. Subjects' response latencies to sim- seen as outpatients at a neurological hospital. Patients ple questions either about the colour of an object (Is it were prescribed the same medication throughout the inves- red?) or more difficult ones about category membership (Is tigation; eight were taking phenytoin, five carbamazepine, it a living thing?) were measured. The median reaction five sodium volproate, three phenytoin and car- time for each question type was recorded. bamazepine, two sodium valproate and carbamazepine, (iii) A measure was also made of the visuo-motor compo- two primidone and carbamazepine, one primidone and nent of the above task, that is the time taken to respond to Protected by copyright. phenytoin, one phenytoin and phenobarbitone and one light onset when no further decision was required. primidone. 4 Motor speed Tapping rate between two metal plates Design with a metal stylus was used to measure the speed of simple All patients formed part of a larger investigation manual movements. Three conditions were investigated, (Thompson-in preparation) and were seen on at least two tapping with the non-dominant hand, dominant hand and occasions at three-monthly intervals. Following the first both hands simultaneously. session patients had their drug(s) dosages raised or low- ered for treatment reasons. The main investigator (PJT) 5 Subjective ratings On each session patients completed was unaware of the direction of the change. On each ses- a Mood Adjective Check List which is a self-rating scale to sion patients performed a series of psychological tests (see assess their mood at the time of the psychological testing. below) on completion of which a blood sample was taken for the analysis of anticonvulsant serum levels. In addition, Seizures their seizure frequency for the previous three months was Seizures were classified into three categories: first, tonic- documented and seventeen patients also had a twenty clonic attacks, both primary and secondary generalised; minute standard EEG recording made. The test perfor- secondly, partial seizures, excluding any which were sec- mance of all patients was compared on a session in which and ondary generalised; thirdly, other generalised attacks. http://jnnp.bmj.com/ the anticonvulsant serum concentrations of all the drugs For the patients at the Centre for Epilepsy, seizure fre- they were receiving was high, to a session in which the quencies were documented by trained personnel. The serum level of the same drugs was lower. A second analysis out-patient sample kept a record of their own seizures dur- was also undertaken excluding any patients with serum ing the study and for the majority of these the completion levels that exceeded the upper limit of the anticonvulsant of fit charts was already standard practice. No patient was therapeutic ranges. seen within 48 hours of a tonic-clonic attack. Psychological measures The psychological tests employed are outlined briefly hav- EEG Recordings ing been described in detail elsewhere.'4 's EEG recordings were performed on 17 patients and these on September 28, 2021 by guest. were rated independently on a three-point scale as normal, 1 Memory Twenty pictures and twenty words were dis- moderately abnormal or severely abnormal. played as slides at the beginning of each session. One Paired one-tailed t tests were calculated for each of the minute and again one hour following the presentation of measures of psychological test performance. Data from the the last stimuli in each set, recall was tested. A yes/no MACL and seizure frequencies were analysed non- recognition test was then administered in which the twenty parametrically using Wilcoxon t tests.