Anticonvulsant Blood Levels Research Articles

Seizure control after chronic pharmacotherapy in epileptic disorders beginning after 40 years of age.

Few studies have been published on the pharmacologic response to treatment of patients whose seizures begin after 40 years of age. The purpose of this study was to assess the impact of chronic pharmacotherapy on the seizure control of such patients. We retrospectively studied the seizure frequency recorded during a 12-month period in a group of 94 outpatients whose seizure disorders began after 40 years of age (median age of seizure onset 56.5 years) and who had been treated with anticonvulsant medication for a median period of 6 years (range 18 months to 12 years). We assessed the relationship between the patients' seizure frequency during the last 12 months of treatment using (a) the present and previously prescribed pharmacologic regimens, (b) anticonvulsant blood levels of present regimen, (c) etiology and duration of seizure disorder, (d) age at onset of seizures, and (e) presence of electrographic (EEG) and neuroradiologic abnormalities. We only identified side effects occurring at blood levels within or below the drug's therapeutic range. Seventy-eight patients (83%) were seizure free during the last 12 months of treatment, 11 (11%) had rare seizures, and five (6%) had more than four seizures per year. Seizure frequency was not affected by duration and etiology of seizure disorder, age at onset of seizures, seizure type, neuroradiologic or electroencephalographic abnormalities, and present or previously prescribed pharmacologic regimens. Persistent side effects were reported in seven of 76 (9%) monotherapy regimens and in two of 12 (17%) polytherapy regimens. Our data suggest that seizures beginning after the age of 40 have a favorable prognosis after chronic pharmacotherapy.

Cognitive Side Effects of Antiepileptic Drugs

All of the established antiepileptic drugs (AEDs) can produce cognitive side effects, which are increased with polypharmacy and with increasing dosage and anticonvulsant blood levels. However, cognitive side effects are usually modest for AED monotherapy with anticonvulsant blood levels within the standard therapeutic ranges. Further, these effects are offset in part by reduced seizure activity. Controversy exists regarding possible differential cognitive effects of AEDs. A large portion of the literature examining the comparative cognitive effects of AEDs is limited by inadequate study designs. When these design flaws are considered, there is no convincing evidence of clinically significant differences in cognitive side effects of AEDs except possibly for bromide, phenobarbital and benzodiazepines. The role of cognitive side effects should be kept in proper perspective when choosing AED therapy. The cognitive side effects of anticonvulsant drugs may be overt but many times are rather subtle. It is important though to be able to recognize these effects and to put them into perspective as to how they affect our patients.

Review

Epilepsy has widespread direct and indirect effects on the patient's quality of life. These patients generally have neuropsychological impairments that lower their educational and occupational levels of achievement, and many have additional emotional and/or behavioral disorders. Multiple factors underlie the cognitive changes associated with epilepsy, including the effect of antiepileptic drug (AED) therapy itself. Although it is recognized that the beneficial results of reduced seizure frequency may compensate at least in part for detrimental cognitive AED side effects, polypharmacy and higher AED blood levels can shift this balance. Further, there is much debate concerning the existence and clinical importance of differential AED cognitive side effects. While all the major AEDs can produce cognitive side effects, more recent research indicates that the magnitude of these effects may not be clinically significant with monotherapy within standard therapeutic range. The impact of AED differential cognitive side effects on the patient's quality of life is only beginning to be appreciated as research focuses on this important aspect of patient management. The information gained from such investigations will influence not only current therapeutic decisions, but also the development of future anticonvulsants.

Clinical utility of unbound antiepileptic drug blood levels in the management of epilepsy.

We tabulated all unbound and total antiepileptic blood levels collected in 13 months. According to strict criteria, 24% of phenytoin and 15% of valproate unbound blood levels but none of the carbamazepine unbound levels had clinical significance in the management of seizures or side effects. These data support frequent use of unbound phenytoin or valproate blood levels in the management of epilepsy.

Comparative cognitive effects of carbamazepine and phenytoin in healthy adults

We investigated neuropsychological effects of carbamazepine and phenytoin in 21 healthy adults using a randomized, double-blind, double-crossover design and treating each subject with each drug for 1 month, separated by a 1-month washout. There were neuropsychological evaluations at baseline, the end of each treatment month, and 1 month after the last treatment phase. Cognitive measures included Symbol Digit Modalities Test, Selective Reminding Test, Complex Figures, Paced Auditory Serial Addition Test, Stroop, Finger Tapping, Grooved Pegboard, Choice Reaction Time, P3 Event-Related Potential, Hopkins Symptom Checklist, and Profile of Mood States (POMS). Compared with nondrug conditions, the anticonvulsants significantly impaired Stroop, Choice Reaction Time, Grooved Pegboard, Hopkins, and POMS. Employing anticonvulsant blood levels as covariates, there were only two significant differences between drugs, one in favor of carbamazepine (ie, Finger Tapping) and one in favor of phenytoin (ie, Stroop). The results suggest that differences in cognitive effects of carbamazepine and phenytoin are not clinically significant.

Comparative cognitive effects of anticonvulsants

We investigated the neuropsychological effects of carbamazepine, phenobarbital, and phenytoin in 15 partial complex epilepsy patients treated with each drug for 3 months, using a randomized double-blind, triple crossover design. Neuropsychological evaluation at the end of each treatment period included Digit Span, Selective Reminding Test, Digit Symbol, Finger Tapping, Grooved Pegboard, Choice Reaction Time, P3 evoked potential, and Profile of Mood States. Employing anticonvulsant blood levels and seizure frequencies as covariates, the only significant difference was for Digit Symbol. Performance with phenobarbital was significantly worse than with the other 2 anticonvulsants despite phenobarbital's having had the lowest overall blood levels. Our data show that patients receiving carbamazepine, phenobarbital, and phenytoin have comparable neuropsychological performance on most measures. The results suggest that the differential cognitive effects of anticonvulsants may be subtle.

Sepulveda Epilepsy Education: The Efficacy of a Psychoeducational Treatment Program in Treating Medical and Psychosocial Aspects of Epilepsy

The present study evaluated the efficacy of the Sepulveda Epilepsy Education program (SEE), using a controlled outcome design. SEE is a 2-day psychoeducational treatment program designed to provide medical education and psychosocial therapy. Thirty-eight outpatients, matched according to seizure type and frequency, were randomly assigned to treatment (n = 20) or waiting-list control (n = 18) groups. The major outcome measures used were a 50-item true-false test specifically designed to evaluate the SEE program, the Washington Psychosocial Seizure Inventory, the Beck Depression Inventory, Lubin's Depression Adjective Checklist, the State-Trait Anxiety Inventory, the Acceptance of Disability Scale, and Sherer's Self-Efficacy Scale. Significant differences between the two groups were found on the three major subscales of the 50-item true-false test. The treatment group demonstrated a significant increase in overall understanding of epilepsy, a significant decrease in fear of seizures, and a significant decrease in hazardous medical self-management practices. In addition, an objective measure of blood levels of antiepileptic drugs (AEDs) showed the treatment group to have a significant increase in medication compliance.

The rational use of antiepileptic drugs in children.

The general rules of antiepileptic drug therapy in children with epilepsy have been reviewed. The first step should always consist of making every effort to document the diagnosis of epilepsy and to determine the exact type of seizure. The choice of the appropriate antiepileptic drug is dictated entirely by the seizure type. Once the drug of choice has been selected, it should be given alone. If the first drug remains ineffective against the seizures at the highest tolerated dose, a second drug should be tried alone. Drug combinations may be justified in patients with resistant disease or in patients with multiple seizure types. Because of their relatively high metabolic rate, children require high dosages of antiepileptic drugs in relation to their body weight. Determining blood levels of antiepileptic drugs is particularly important in children, but it should be kept in mind that the therapeutic range is a relative concept and that it should not be applied blindly.

Cognitive and behavioral effects of antiepileptic drugs.

In managing epilepsy, drugs that offer the best seizure control to the patient should be used, but their influence on quality of life must also be considered. This must include any effects on mood and mental state, which should be minimal in order that these patients may achieve their full potential. Subtle behavioral and cognitive disadvantages may occur with anticonvulsant drug use. Behavioral changes with phenobarbital are both idiosyncratic and dose related. Carbamazepine and valproic acid can have adverse effects on mood and cognition, but do so less frequently than the other medications or combinations (Table 1). Cognitive dysfunction may relate to antiepileptic drug blood levels, but impairment of skills can occur in the nonintoxicated patient. Thus, office neurologic examinations are insufficient to detect these subtle mental impairments. Practical methods need to be developed to identify and monitor these problems so that in the future cognitive and behavioral dysfunction in epileptic patients can be minimized.

Postoperative prophylactic anticonvulsant therapy in cerebral gliomas.

A retrospective study was performed to evaluate the efficacy of prophylactic anticonvulsants in preventing seizures in 68 patients with supratentorial astrocytomas who had been treated with operation and irradiation and who had no previous history of convulsions. Thirty-three patients received prophylactic anticonvulsants and 38 patients did not. The incidence of all types of seizures (generalized convulsions or partial) was lower in patients receiving anticonvulsants. No seizures with an impairment of consciousness occurred in the patients with documented therapeutic anticonvulsant blood levels. The overall incidence of seizures was 39% in untreated patients and 21% in treated patients. The incidence of major seizures including tonic/clonic or partial complex seizures with impairment of consciousness was zero in patients with therapeutic anticonvulsant levels and 18% in untreated patients. Regarding the overall incidence of seizures in both groups, there tend to be fewer seizures in older patients, females, patients with a higher grade of malignancy, and patients who had a more radical resection of the tumor. This study suggests that seizures are a frequent occurrence after operation and irradiation for supratentorial glioma and that anticonvulsants may be effective in reducing the incidence of those seizures.

An overview of therapeutic drug monitoring principles.

Recent technological advances allow determination of anticonvulsant blood levels. Consequently, the principles of pharmacokinetics can be applied in managing patients with seizures. We review these principles as well as those of therapeutic drug monitoring for the control of antiepileptic drug levels.

Correlation between EEG and auditory perceptual measures in auditory agnosia

We describe a child who acquired a gradual sustained speech deficit for which no specific etiology was found, and who had an associated epileptogenic abnormality on EEG. Assessment of auditory perceptual skills and receptive language confirmed that gradual parallel improvement occurred with the EEG after therapeutic anticonvulsant blood levels were obtained. Prospective trials of anticonvulsant drugs in conjunction with serial measures of central auditory abilities are necessary to establish their value in the management of the linguistic deficit in children with auditory agnosia.

Epileptic patients who are refractory to anticonvulsant medications.

To evaluate criteria that predict success or failure of currently available anticonvulsant medications, we studied 194 epileptic patients who were admitted to an intensive treatment unit. Seizures were present in the hospital in 78.3% and could not be controlled in 33.7%. Combinations of at least two of the following criteria were associated with limited treatment responses: multiple handicap (intellectual limitations or abnormal neurologic signs), different seizure types, cluster seizures, slowing of EEG background rhythms, and seizures discharges in the EEG despite adequate anticonvulsant blood levels. Presumed etiology was not associated with predictive ability. Patients who were neurologically and intellectually intact and had frequent clinical attacks, normal EEG background rhythms, and no seizure discharges usually had pseudoseizures.

Correlation of antiepileptic drug blood levels with EEG findings and somatosensory evoked potentials : L. Ilievska, R. Naumovski and Lj. Novotni (Skopje, Yugoslavia)

Correlation of antiepileptic drug blood levels with EEG findings and somatosensory evoked potentials : L. Ilievska, R. Naumovski and Lj. Novotni (Skopje, Yugoslavia)

Quantitative analysis of training, sleep EEG and clinical response to EEG operant conditioning in epileptics

This report is a follow-up to a previous paper which described seizure rate changes with central cortical EEG feedback training in 8 poorly controlled epileptic subjects. Data examined here include associated training compliance and performance, sleep EEG spectra, clinical EEG and anticonvulsant blood levels. The study employed a double-crossover, single-blind ABA design applied to two subgroups of epileptic patients. Both groups had in common two training periods (A 1, A 2) in which either 12–15 c/sec (subgroup I, n = 4) or 18–23 c/sec (subgroup II, n = 4) was reinforced in the absence of 6–9 c/sec, movement or epileptiform discharge, and one training period (B) in which 6–9 c/sec was reinforced in the absence of 12–15 or 18–23 c/sec as well as movement and epileptiform discharge. Training periods occurred primarily in the home and lasted 3 months. Compliance with training instructions and response acquisition were demonstrated. Overall anticonvulsant blood levels were low and unrelated to EEG or seizure changes. Clinical EEG findings corresponded to sleep EEG and seizure rate outcomes. Power spectral analysis of sampled non-REM sleep from all-night EEG recordings obtained after each training phase indicated contingency specific changes which were limited to sensorimotor recordings in subgroup I and corresponded to the pattern of seizure rate changes in this group. EEG changes were also limited to sensorimotor cortex in subgroup II, but were linear and paralleled a progressive decrease in seizure rate. Both groups, however, showed the same pattern of EEG changes with seizure reductions; low and high frequencies were reduced and intermediate, rhythmic frequencies increased. Correlational analysis confirmed this relationship. The pattern, duration and topographic specificity of these changes suggested a normalization of sensorimotor EEG substrates related to the EEG feedback training.

A Comparison of Plasma Phenytoin Level Determinations by EMIT and Gas-Liquid Chromatography in Patients with Renal Insufficiency

Monitoring the blood levels of antiepileptic drugs (AED) has proven to be of value in the clinical management of epileptic patients. We have compared the plasma concentrations of AED determined by enzyme multiplied immunoassays (EMIT) and gas-liquid chromatography (GLC) assays and identified a group of patients (n = 22) in whom the EMIT values for phenytoin were up to three times higher than those obtained by GLC. All these patients were oliguric with various degrees of azotemia, most of them undergoing weekly hemodialysis. The ratio of EMIT over GLC was 2.0 in 14 patients, 2.5 in 5 patients, and near 3.0 in 3 patients. These ratios remained relatively constant during repeated determinations over several months. The magnitude of difference between EMIT and GLC values (microgram/ml) was not related to the degree of azotemia. The discrepancy remained unchanged when various modifications of EMIT and GLC techniques were used. When phenytoin was added in vitro to plasma from nonepileptic oliguric azotemic patients, the measured phenytoin values were close to and not higher than the target values by either methodology. We feel that, when monitoring phenytoin blood levels in epileptic patients with renal insufficiency, one should be aware of a discrepancy between phenytoin values assayed by GLC and EMIT.

Quantitative analysis of EEG's in epileptic patients.

The objective of computer assisted analysis of EEG's of epileptic patients lies not only in the interest of providing the EEGer with quantitative data but also in the need for data reduction. This is particularly felt whenever the aim is to evaluate EEG characteristics in long-term (24 hour) records. Computer analysis of the long-term EEG is essential whenever one wishes to determine the effectiveness of medication and the influence of behavioral parameters. In this communication we deal with the problems which arise in the analysis of long EEG records: data acquisition, selection of relevant epochs, detection of significant EEG features, analysis of spatial relationships, graphical and alpha-numeric displays of relevant data. Data acquisition and selection are faciliated by using a telemetric amplifier and multiplexing system to allow recording from freely mobile subjects. In our practice this recording system is coupled to a special purpose digital buffer system, the so called “ICTUS system”. The “ICTUS system” can digitize up to 16 channels at a maximum rate of 1024/sec. The detection of significant EEG features comprises the use of the “Automatic Spike Detection1” program combined with a recently written classification algorithm which performs a pattern recognition and classification of EEG nonstationarities. Analysis of spatial relationships includes a measure of coincidence between spikes and other paroxysmal events recorded from different derivations. In our system special attention is given to the graphical displays of relevant data which should be directly interpretable for the clinician. A few applications of this system for (a) the localization of an epileptogenic area and for (b) the analysis of the relationship between EEG paroxysmal events and blood levels of antiepileptic drugs (sodium valproate) are discussed.

Uncontrollable Seizures in an Epileptic

A case of possible phenytoin-induced systemic lupus erythematosus is presented in a patient with a twenty-year history of epilepsy. The failure of seizure control in the presence of adequate anticonvulsant blood levels pointed to an underlying disease state. Drug-induced and idiopathic systemic lupus erythematosus are quite similar in clinical and laboratory manifestations. However, antibodies to native (double-stranded)-DNA seem to be consistent with the idiopathic form. A review of drug-induced systemic lupus erythematosus is presented.

Chronic Cerebellar Stimulation-Reply

In Reply.— Dr Van Woert is correct concerning the advisability of a trial of L-5-hydroxytryptophan with carbidopa and clonazepam in cases of myoclonic epilepsy. However, the three patients reported in our series were all treated before the five references cited by Dr Van Woert appeared in the literature. Second, the measurement of blood levels of antiepileptic drugs is a routine procedure on any patient being treated for epilepsy on our service.

Reporting of Anticonvulsant Blood Levels

To the Editor.— The article by McDanal and Bolman (231:1063, 1975) presents a psychotic reaction to phenytoin (formerly diphenylhydantoin) that they conclude was an idiosyncratic reaction because blood levels of phenytoin were low. Unfortunately, there is as yet no generally agreed standard way of reporting anticonvulsant blood levels. Most laboratories report the levels as indicated by McDanal and Bolman in μg/mg, but others, including our own, continue to report the levels in mg/100 ml. This can lead to obvious confusion both on the part of the reporter as well as on the part of the reader. For example, the therapeutic range of phenytoin is indicated by the authors to be 10μg to 15μg/ml, which is the same as 1 to 1.5 mg/100 ml. Confusion in making this transposition led to erroneous statements, for example, in the 1969 Physician's Desk Reference , concerning therapeutic and toxic levels of phenytoin, in which a