Clinical study of lamotrigine and valproic acid in patients with epilepsy: using a drug interaction to advantage?

Lamotrigine (LTG) is one of the newer antiepileptic drugs which has been shown to have a spectrum of drug interactions (including with other epilepsy drugs) that can have a pronounced effect on LTG kinetics. The present study examined the LTG metabolic inhibition dose-response relationship with valproic acid (VPA) in eight patients with epilepsy with a view to using this to benefit the patient. This could benefit the patient not only by attaining higher plasma LTG concentrations with "standard" dosages of LTG, but also possibly by achieving better seizure control through providing a less variable peak-to-trough fluctuation in LTG concentrations as a result of extending the half-life of LTG. The dosages of VPA trialed were 0, 200, 500, and 1,000 mg/d which resulted in a mean increase in LTG area under the curve of 83.7 +/- 14.7% at 200 mg VPA/d, to and 160 +/- 37.9% at 1,000 mg VPA/d. The presence of concomitant enzyme inducers in some patients did not influence the percentage increase from baseline in half-life observed, although clearly those on inducers started from a lower absolute half-life as a result of the induction. The effect was shown to be quite variable, particularly at the highest dosage of VPA tested (1,000 mg/d), suggesting that this effect could be best applied with the support of the therapeutic drug monitoring laboratory determining plasma LTG concentrations to allow individualization of the LTG dosage.

Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy.

PURPOSE: Lamotrigine (LTG) is recognised as effective add-on therapy for focal epilepsies, but this is the first double-blind, placebo-controlled, crossover study in treatment-resistant generalised epilepsy. METHODS: The study consisted of 2 x 8-week treatment periods followed by a 4-week washout period. Patients received doses of either 75 or 150 mg daily, depending on their concomitant antiepileptic drugs (AEDs). Long-term continuation was offered at the end of the study with open-label LTG. RESULTS: Five centres in Australia recruited 26 patients who were having absence, myoclonic, or generalized tonic-clonic seizures or a combination of these. Twenty-two patients completed the study. There was a significant reduction in frequency of both tonic-clonic and absence seizure types with LTG. A 350% decrease in seizures was observed for tonic-clonic seizures in 50% of cases and for absence seizures in 33% of evaluable cases. Rash was the only adverse effect causing discontinuation. Twenty-three of 26 opted for open-label LTG, with 20 still receiving LTG for a mean of 26 months. In these 20, 80% had > or =50% seizure reduction and five (25%) were seizure free. CONCLUSIONS: This study shows that LTG is effective add-on therapy in patients with refractory generalised epilepsies. Statistically significant reduction in seizures in both absence and tonic-clonic seizure types was seen even with low doses of LTG.

Lamotrigine and therapeutic drug monitoring: retrospective survey following the introduction of a routine service.

AIMS: To review (retrospectively) the relationships between lamotrigine (LTG) dosage and plasma concentrations based on data generated in a routine therapeutic drug monitoring laboratory from a heterogeneous sample of patients with epilepsy. To distinguish patients taking concomitant anti-epileptic therapy which induced or inhibited drug metabolising enzymes, or a combination of both, together with LTG. To survey medical staff who use a routine LTG assay service with a view to establishing the utility of higher plasma LTG concentrations than those used in early clinical trials. METHODS: All patient assays for LTG received over a 12 month period (339 requests from 149 patients) were reviewed and relationships between dosage and concentration calculated and grouped according to concomitant antiepileptic drug therapy. The doctors requesting the tests were surveyed by questionnaire (n=40 of 67 responded). They were asked for details about the patient's seizure control, rationale used for LTG dosage adjustment and their acceptance of the proposed 'therapeutic range' adopted by the laboratory of 3-14 mg(-1). RESULTS: Linear relationships were demonstrated between LTG dosage and concentration for the 3 treatment groups (LTG plus valproic acid (VPA), LTG plus enzyme inducing antiepileptic drugs, and LTG plus VPA and inducers), however, there were significant differences between groups (P<0.001) with a 4.4 fold difference in dosage: concentration ratios between the LTG plus VPA group and the LTG plus inducers group. The questionnaire showed that the therapeutic range was well accepted by 88% of responders, none of whom considered this higher range to be wrong. CONCLUSIONS: Metabolic inhibition by VPA was shown to have a marked effect on LTG kinetics, suggesting either a significant LTG dosage reduction is required if plasma LTG concentrations are elevated, or alternatively, higher plasma LTG concentrations could be attained from lower dosages. The higher therapeutic range adopted by the laboratory (3-14 mg(-1)) was widely accepted and increasingly applied in clinical practice in the management of patients with epilepsy.

Epilepsy and driving in South Australia--an assessment of compulsory notification.

We examined the licensing of drivers with conditions likely to endanger the public in a State in which doctors are obliged to notify the licensing authority. During 1991, 1460 medically endorsed licenses were cancelled. A sample of 245, including all 49 with epilepsy were mostly voluntary, the twenty exceptions with retained files being drivers with epilepsy. In the same period, 115 traffic accidents were attributed to illness, with the only four (4) investigated by the licensing authority being those with licenses endorsed "epilepsy" where a seizure was responsible. Compulsory notification appeared to result in the identification of epilepsy as the important medical reason for controlling licenses, but failed to recognise sleep disorders or alcoholism, both more significant causes of traffic accidents. In those accidents attributed to illness, almost no action was taken to review the medical fitness of drivers, suggesting a reliance on doctors rather than police or road safety authorities.

Localization of temporal lobe epileptic foci with iodine-123 iododexetimide cholinergic neuroreceptor single-photon emission computed tomography.

There is evidence suggesting that muscarinic cholinergic neuroreceptors (mChR) are reduced at seizure foci. Iodine-123 (I-123) iododexetimide (IDEX) single-photon emission computed tomography (SPECT) permits in vivo imaging of mChR. We assessed 23 patients with temporal lobe epilepsy (TLE) undergoing preoperative assessment. Regions of interest were placed over the amygdala, hippocampus, and lateral temporal cortex on IDEX SPECT images. Eighteen patients had unilateral TLE. In these, IDEX binding in the ipsilateral hippocampal region was reduced by 19.1 +/- 12%. This was significantly greater than blood flow asymmetry (p < 0.02 by Wilcoxon's signed-rank test). Changes were less marked in the amygdala (11.3 +/- 6.4%) and lateral cortex (7.6 +/- 12.1%). Blinded visual analysis gave correct localization in 14 (78%) patients, and hexamethylpropylenamine oxide (HMPAO) SPECT gave correct localization in 50%. MRI revealed hippocampal sclerosis in 13 (72%) patients and was normal in 5 patients. Of the latter group, four were correctly localized by IDEX. This study confirms that mChR receptors are altered in medial temporal lobe structures in TLE. IDEX SPECT appears to be superior to interictal HMPAO SPECT and complimentary to MRI for seizure focus localization.

Combination vigabatrin and lamotrigine therapy for intractable epilepsy.

Vigabatrin (GVG) and lamotrigine (LTG) are new antiepileptic drugs (AEDs) individually effective as add-on therapy for refractory seizures. The efficacy of GVG and LTG in combination was evaluated in a prospective audit of 42 patients with intractable epilepsy. There was a statistically significant median reduction of 62% (P < 0.025) from a median baseline monthly seizure frequency (MSF) of 29 (mean 59, 95% CI 22, 96) to a median MSF of 11 (mean 23, 95% CI 8, 38) during a median treatment period of eight months, with a greater than 50% reduction in MSF in 29 patients (69%) treated with the add-on combination of GVG and LTG. The additional MSF reduction achieved by the combination amounted to 21% (18% when GVG was added to LTG and 24% when LTG was added to GVG). The median trough plasma lamotrigine concentration was 9.9 mg/l (range 3.4-19.6 mg/l). The average daily dose of LTG was 517 mg (range, 175-800 mg) and GVG 2400 mg (range, 1500-3500 mg). Adverse events requiring alteration of therapy occurred in 24 patients (57%) with a drop-out rate of 12%. The combination of GVG and LTG should be considered as a therapeutic option in patients with intractable epilepsy. The results of the present study support the need to confirm additive efficacy of GVG and LTG by conducting controlled trials of this combination therapy.

Quality assurance in a neurophysiology laboratory.

In order to assess patient satisfaction with the Neurophysiology Services within our department, we undertook a pilot study using a simple questionnaire designed by staff members (MAHB and ABB). Patients were approached after their tests (nerve conduction tests (NCTs), electromyography (EMG) and electroencephalography (EEG)) were completed, by staff not involved in the testing. 31 patients were approached and all completed the questionnaire. None reported being inconvenienced by an undue waiting time. All felt that adequate information about the test had been provided, that their personal comfort and feelings were considered, and that they were adequately informed of the time and place at which the test results would be available. 61% considered their overall treatment excellent, the remainder good. To date, increased departmental awareness has resulted in staff participation in program evaluation, design of an outcomes hierarchy for the department, redesigning the patients' waiting area and, overall, a more active participation in quality assurance. We see this pilot study as a baseline for future more in-depth client and staff evaluations thereby promoting quality performance improvement.

Video-audio/EEG monitoring in epilepsy--the Queen Elizabeth Hospital experience.

Our experience of using video-audio/EEG monitoring in the diagnosis and management of epilepsy at The Queen Elizabeth Hospital Comprehensive Epilepsy Service from March 1987 to December 1990 is described. We performed 75 long term monitoring studies on a total of 66 patients. Following monitoring, a change in seizure diagnosis was made in 21 of 66 patients (32%). Pseudoseizures were diagnosed in 17 patients. A change in management as a consequence of monitoring occurred in 53 of the 66 patients (80%). The referring neurologists considered that 56 of the 75 studies (75%) were successful. The investigational technique is effective and is particularly useful for the diagnosis of pseudoseizures.

Evaluation of evoked potentials and cerebrospinal fluid analysis in the differential diagnosis of multiple sclerosis.

During the 6 years to December 1988, 191 patients underwent evoked potential (EP) studies and cerebrospinal fluid (CSF) analysis for oligoclonal bands at the Queen Elizabeth Hospital, for the differential diagnosis of multiple sclerosis (MS). Clinical data at the time of study separated patients into 3 groups, as follows: (i) multiple sclerosis (n = 90) - McDonald and Halliday Classification, 1977, (ii) other neurological disease (n = 82) and (iii) no neurological disease (n = 19). In cases of clinically definite MS, visual evoked potentials (VEPs) were abnormal and oligoclonal bands were detected in 64% and 59% of cases, respectively. However, only 15% of patients with suspected MS had abnormal VEPs, and only 23% had oligoclonal bands. Other studies have shown figures differing from these, though not necessarily significantly. We found a substantial number of EP (20%) but few CSF (4%) abnormalities in disorders other than MS, and no abnormalities in cases without neurological disease. The various figures for abnormal results in cases assessed for the differential diagnosis of MS are influenced not only by laboratory methods, but by the degree of clinical suspicion in relation to the cases selected, as well as by differences in populations from which cases are derived. Long-term prospective studies of diagnostically indeterminate cases are still required to determine the diagnostic weighting that can be applied on the basis of abnormal investigational results. Magnetic resonance imaging will not resolve these questions since it has limitations of its own, particularly with regard to specificity.

The flight of colours test. Its value as an indicator of dysfunction of the visual pathways.

The flight of colours (FOC) test was compared with visual evoked potentials (VEPs) in 135 patients in a 2 year prospective study, to determine whether the FOC test is a sensitive and reliable alternative. We obtained an 80% overall agreement between the tests, confirming the levels of agreement reported by Rolak (87%) and Swart and Millac (92%). Abnormal VEPs, however, were more closely associated with cases of clinically definite multiple sclerosis (MS) while abnormal FOCs were more frequent in cases of non-demyelinating disease and cases without clinically evident optic nerve or other ocular disorder. We cannot explain this result by any demonstrated superiority of the FOC test over VEPs in non-demyelinating visual disturbances, whether clinically evident or not. Thus the study does not confirm the earlier expectation that the FOC test would be a reliable alternative to the study of VEPs in the differential diagnosis of MS.

McArdle's disease presenting with rhabdomyolysis.

A patient with McArdle's disease is described who presented with rhabdomyolysis following severe exertion. An episode of acute renal failure four years earlier was probably secondary to a combination of myoglobinuria and an intravenous contrast agent.