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Epilepsy, anti-seizure medicines and me

Written by Professor Martin J Brodie, Clinical Research Director

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Introduction

While at the Royal Postgraduate Medical School based at Hammersmith Hospital in West London between 1977 and 1981, I carried out volunteer studies examining the effects of enzyme induction with rifampicin on the metabolism of vitamin D and sex hormones in healthy volunteers.1,2

On returning to Scotland, I continued by investigating the inducing properties of carbamazepine on a range of endogenous targets, including androgens and thyroid hormones.3,4

In 1982, I set up the first epilepsy service in Scotland in anticipation of the imminent arrival, for pharmacological and clinical investigation, of antiseizure medications (ASMs) developed as potential treatments for newly diagnosed and refractory epilepsy in adolescents and adults.

Epilepsy unit

Early in 1982, I established the Epilepsy Unit as a basic science and clinical research facility at the University of Glasgow. From the outset, all patients with newly diagnosed and treated epilepsy were systematically reviewed and their clinical data collected prospectively for inclusion in a database. We particularly focused on untreated patients, who we started to treat with their first ASM once a diagnosis of epilepsy was confirmed. We also wrote to all general practitioners in the west of Scotland offering to review their patients following a first seizure or with possible untreated epilepsy, within a week or two of referral to the Epilepsy Unit.

Finally, we began an audit of patients presenting at our local Accident and Emergency department with a first seizure or suspected untreated epilepsy, establishing a direct referral route to our service.5 Ever since, we have registered all new patients in our database, each with a “pink folder” (including a data collection form and investigative protocol) stored in the Epilepsy Unit.6 There are currently more than 8,500 patients registered in the system. We have produced several analyses of this population, exploring long-term outcomes at different timepoints after starting treatment.

Outcome studies

The first analysis looked at outcomes in 470 newly diagnosed patient referrals and follow-ups from 1984 to 1997. Overall, 64% of them remained seizure-free for more than a year (61% with monotherapy) – 47% of which were controlled on their first ASM, 13% were responding to a second schedule and a further 4% were on subsequent regimens.7

The second set of analyses, in 2003, involved 780 newly diagnosed patients.8 Overall, 64.6% of this population remained seizure-free for at least 12 months with 5.4% being controlled by treatment with two or more ASMs. At that time, the prognosis appeared better for patients aged 65 years and above (85% in remission, p<0.001) and in adolescents (65% in remission, p<0.01) than in the remainder of the population (53% in remission).8 Predictors of refractoriness were: a family history of epilepsy, febrile convulsions, traumatic brain injury, psychiatric comorbidities, recreational drug use and patients who reported 10 or more seizures before starting treatment.9

A separate analysis explored mortality data by comparing newly diagnosed patients (n=890) and patients with chronic epilepsy (n=2689) with age- and sex-matched comparison groups. Newly diagnosed patients had a 42% increase in mortality compared with the comparison group (standard mortality ratio [SMR]: 1.42, 95% confidence interval [CI]: 1.16-1.72). Patients who had not responded to treatment had increased mortality, with no increase in risk in those attaining seizure freedom. In the chronic epilepsy cohort, there was more than double the expected number of deaths (SMR 2.05, 95% CI: 1.83–2.26). The incidence of sudden unexpected death in epilepsy was 1.08 and 2.46 per 1000 patient-years in the newly diagnosed and chronic epilepsy cohorts, respectively. Interestingly, the greatest excess in mortality was in patients younger than 30 years.10

The third major set of analyses explored outcomes from 1098 adolescent and adult patients (median age 32 years) starting treatment with their first ASM between 1982 and 2006 and followed up for at least 2 years (median 7.5 years follow-up). Seizure freedom/Seizure free represents a patient with no seizure for at least the previous 12 months. There were four patterns of response: A, seizure freedom immediately/within 6 months of starting treatment with no subsequent recurrence (n=408, 37%); B, delayed response of seizure freedom after 6 months of treatment (n=246, 22%); C, fluctuating control with periods of seizure freedom lasting at least a year followed by relapses (n=172, 16%); D, never attaining seizure freedom for any single 12-month period (n=272, 25%). A total of 188 patients (17%) remained seizure-free for at least 10 years. Most patients who attained seizure freedom did so on their first (49.5%), second (13.3%) or third (3.7%) ASM schedules, although a few became fully controlled on their fourth, fifth, sixth or even seventh regimens, with some of these being treated on late monotherapy.11

The last set of analyses included 1795 newly diagnosed patients who started treatment between 1982 and 2014 (median follow-up 11 years).12 Clear changes in ASM prescribing choices were documented over the 30 years, yet no significant differences in efficacy among the drugs prescribed could be demonstrated. I expect this could arguably be a consequence of the clear split between the fully controlled and refractory epilepsy populations that did not depend on the choice of ASMs.

Overall 1-year seizure-free rates for the first seven successive schedules in the complete population were 45.7%, 11.6%, 4.4%, 1.2%, 0.6%, 0.3% and 0.1% respectively, but this did not entirely reflect the rates of seizure freedom in patients actually treated with further ASMs, which were 45.7%, 28.0%, 23.6%, 15.0%, 14.1%, 14.0% and 6.7% respectively (Table 1).12 Indeed, some of these patients became controlled on ASM monotherapy even though they may have previously failed five, six or seven other schedules, most of which were drug combinations. Recently developed ASMs appear not to have improved long-term outcomes for those with newly diagnosed epilepsy, while there is evidence here that current ASMs are seizure suppressing.12

Table 1. Rates of 1-year seizure freedom with successive drug schedules. Adapted from Chen et al, 2018.12*

*Publication includes data for up to 11 successive anti-epilepsy drug regimens. In this study, 0 patients achieved seizure freedom on their 8th to 11th drug regimen tried.12

Comparing outcomes in the first 470 patients and the complete cohort of 1795 showed no overall improvement in seizure-free rates over 30 years, with both being 64% (Figure 1).

Some may, however, have had fewer and less severe events over the course of their follow-up.

Nevertheless, seizure freedom without adverse effects is the primary prerequisite to improving quality of life, and this should be the goal of treatment for every person with epilepsy.1,2

Conclusions

Has the probability of achieving prolonged seizure freedom increased significantly in the last three decades, with the advent of several more ASMs, with apparently different mechanisms of action? Regrettably, the answer appears to be “no”, but it is evident that ASMs suppress seizures.12 Although second-generation ASMs have not substantially reduced the proportion of patients with pharmacoresistant epilepsy, their availability has given clinicians more opportunities to tailor drug choices to the characteristics of the individual patient and their epilepsy.14 Understanding the natural history of, and pathophysiological factors associated with, the development of pharmacoresistant epilepsy may provide the foundation for formulating a mechanistic hypothesis that could be evaluated scientifically to drive the identification and production of novel pharmacotherapies.15

Written by Martin J Brodie

Clinical and Research Director
Epilepsy Unit, University of Glasgow, University Avenue, Glasgow, G12 8QQ, Scotland, United Kingdom

  1. Brodie MJ et al. Clin Pharmacol Ther. 1980;27:810–4.
  2. Brodie MJ et al. Br J Clin Pharmacol. 1981;12:431–3.
  3. Connell JM et al. Eur J Clin Pharmacol. 1984;26:453–6.
  4. Connell JM et al. Br J Clin Pharmacol. 1984;17:347–51.
  5. McKee PJW et al. BMJ. 1990;300:978–9.
  6. Brodie MJ. Seizure. 2017;44:206–10.
  7. Kwan P, Brodie MJ. N Engl J Med. 2000;342:314–9.
  8. Mohanraj R, Brodie MJ. Eur Neurol. 2006;13:277–82.
  9. Hitiris N et al. Epilepsy Res. 2007;75:192–6.
  10. Mohanraj R et al. Lancet Neurol. 2006;5:481–7.
  11. Brodie MJ et al. Neurology. 2012;78:1548–54.
  12. Chen Z et al. JAMA Neurol. 2018;75:279–86.
  13. Luoni C et al. Epilepsia. 2011;52:2181–91.
  14. Perucca E et al. Lancet Neurol. 2020;19:544–56.
  15. Janmohamed M et al. Neuropharmacology. 2020;168:107790.

 

UK14623P | November 2022

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