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Keywords:

  • Epilepsy;
  • Phenobarbital;
  • Outcome;
  • China

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Purpose:  To evaluate the long-term outcome of phenobarbital treatment for convulsive epilepsy in rural China, and to explore factors associated with overall seizure outcomes.

Methods:  We carried out follow-up assessments of people who took part in an epilepsy community management program conducted in rural counties of six provinces in China. People with convulsive epilepsy who were previously untreated (or on irregular treatment) were commenced on regular treatment with phenobarbital. Information was collected using a standardized questionnaire by face-to-face interviews of the individuals (and their families where necessary). Information collected included treatment status, medication change, seizure frequency, and mortality.

Key Findings:  Among the 2,455 people who participated in the original program, outcomes were successfully ascertained during the follow-up assessment in 1986. Among them, 206 had died. Information on treatment response was obtained in 1,780 (56% male; mean age 33.9 years, range 3–84; mean duration of follow-up 6.4 years). Among them, 939 (53%) were still taking phenobarbital. The most common reasons for stopping phenobarbital were seizure freedom or substantial seizure reduction, socioeconomic reasons, and personal preference. Four hundred fifty-three individuals (25%) became seizure-free for at least 1 year while taking phenobarbital, 88% of whom did so at daily doses of 120 mg or below. Four hundred six (23%) reported adverse events, which led to withdrawal of phenobarbital in <1%. The most common adverse effects were malaise/somnolence (7.4%), dizziness (3%), and lethargy (2.6%). At the follow-up assessment, 688 (39%) individuals had been seizure free for at least the previous year. People with persistent seizures had significantly longer duration of epilepsy and higher number of seizures in the 12 months before treatment. People who were taking AED treatment irregularly at recruitment were less likely to become seizure-free.

Significance:  We observed long-term benefits of regular treatment with phenobarbital for convulsive epilepsy in rural China. One hundred years after the discovery of its antiepileptic effect, phenobarbital is still playing an important role in the management of epilepsy.

The majority of people with epilepsy live in resource-poor countries, where up to 98% do not receive regular antiepileptic drug (AED) treatment (the “treatment gap”) (Mbuba et al., 2008). In the late 1990s, in an attempt to develop models of epilepsy care in resource-poor settings, a series of “demonstration projects” were initiated as part of the Global Campaign Against Epilepsy (Kale, 1997). As part of this, we carried out a community epilepsy management program in rural China. It was initiated with a door-to-door survey in 2000, estimating a treatment gap of >60% (Wang et al., 2003). In parallel with an educational program, we then conducted a pragmatic trial at the primary care level providing phenobarbital (PB) monotherapy to a total of 2,455 people (Wang et al., 2006). At the end of the trial in June 2004, 68% had significant benefit from treatment (34% were seizure-free and an additional 34% had at least 50% reduction in seizure frequency). We conducted a second survey 6 months after the end of the intervention and noted that the treatment gap had significantly decreased to 49.8% in the intervention area (Wang et al., 2008). It was concluded that the intervention measures used were effective and evidently feasible in rural China, contributing to reduction in the treatment gap of epilepsy. Based on the success of the intervention trial, the government has established nationwide epilepsy control programs across rural China (World Health Organization, 2009).

As epilepsy is a chronic condition it is important to determine the long-term impact of any intervention to assess its clinical effectiveness and to inform health care planning. We performed a follow-up assessment of the people enrolled in the original pragmatic trial to evaluate the long-term response to PB treatment in this setting, particularly in relation to its retention and effectiveness. We also explored factors associated with overall seizure outcomes.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Original pragmatic trial

People with epilepsy were recruited into the original pragmatic trial between December 2001 and June 2004. The methodology and results of the pragmatic trial have been reported previously (Wang et al., 2006). Briefly, it was a protocol-driven intervention program undertaken in rural counties of six provinces in China (Heilongjiang, Ningxia, Henan, Shanxi, Jiangsu, and the Shanghai Municipality). People >2 years old with at least two convulsive seizures in the previous 12 months and who were not receiving adequate medical treatment were recruited. Trained local primary care physicians made the initial diagnosis using a specially designed questionnaire to screen possible cases of convulsive epilepsy. A supervising neurologist then assessed screen-positive individuals to confirm or refute the diagnosis and to establish baseline seizure frequency in those in whom the diagnosis was confirmed. People entering the study were treated with PB monotherapy as the first option, starting with 60 mg for adults and 15 mg for children, taken once daily at night. Dosage was adjusted based on seizure control and tolerability. Patients who withdrew from the study because of adverse events or lack of efficacy were offered treatment with alternative AEDs according to clinical needs (Wang et al., 2006). Participants were followed up regularly until June 2004.

Follow-up assessment

In the present study, a follow-up assessment of people recruited in the pragmatic trial was conducted between June and December 2008 to evaluate their clinical outcomes. After receiving further training, local physicians who participated in the original study conducted face-to-face interviews of the patients (including their families, where necessary) to collect information using a standardized questionnaire. Information collected included treatment status, medication change, seizure frequency, and mortality. Duration of epilepsy was defined as the time between the diagnosis of epilepsy and the date of the follow-up assessment. Seizure freedom was defined as no convulsive seizure for at least 1 year. This study was approved by the Beijing Neurosurgical Institute Medical Ethics Committee and informed consent was obtained from the individuals or their guardians.

Statistical analysis

Data are expressed as mean ± standard deviation (SD), median, and interquartile range (IQR) if the variable is not normally distributed; categorical variables are given as frequencies (%). Continuous data were compared by Student’s t-test or Mann-Whitney U test, as appropriate, and categorical data by chi-square test. The retention rate of PB and seizure freedom rate were estimated by Kaplan-Meier analysis from recruitment into the original pragmatic trial. To explore predictive factors of seizure outcome at follow-up, sex, age of onset and duration of epilepsy, number of seizures in the 12 months preceding PB treatment, family history of epilepsy, and previous treatment pattern with AEDs were considered as potential factors in the univariate analysis. Factors with p < 0.05 were included as covariates in multivariate analysis using binary logistic regression. P-Values of <0.05 were considered significant. Data were analyzed using SPSS 13.0 (SPSS Inc., Chicago, IL, U.S.A.).

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Patient characteristics

Among the 2,455 people included in the original pragmatic trial, the outcomes of 1986 (81%) were successfully ascertained in the follow-up assessment. Of these, 206 had died. Their details are reported elsewhere (Ding et al., 2012b). Information on treatment response was obtained in 1,780. Of the remaining 469 people (19%), 340 could not be traced, 106 were known to be living out of the study sites at the time of the follow-up assessment and could not be contacted, and 23 refused to participate. Table 1 shows the clinical characteristics of the 1,780 people with treatment response available for analysis. The mean duration of follow-up from recruitment into the original pragmatic study to the follow-up assessment was 6.4 (SD 0.5) years.

Table 1.   Characteristics of patients who took part in the follow-up assessment (n = 1,780)
 Number (%)
  1. AED, antiepileptic drug; CT, computerized tomography; MRI, magnetic resonance imaging; PB, phenobarbital; SD, standard deviation;

Male1,002 (56.3)
Age at recruitment in years 
 Mean ± SD33.9 ± 15.5
 Range3–84
Age at onset of epilepsy in years 
 Median13
 Range1–70
Age groups (years) 
 <18343 (19.3)
 18 to <30461 (25.9)
 30 to <50728 (40.9)
 50 to <65202 (11.3)
 >6546 (2.6)
Duration of epilepsy in years 
 Mean ± SD21.9 ± 12.0
No. of seizures in 12 months before starting PB 
 Median10
 Mean ± SD43.7 ± 116.5
 Range2–1,200
Possible etiology 
 CNS infection310 (17.4)
 Head trauma306 (17.2)
 Birth injury/hypoxia263 (14.8)
 Stroke246 (13.8)
 Others190 (10.7)
 Unknown465 (26.1)
No. of individuals who had an EEG1,069 (60.1)
 Normal632 (35.5)
 Abnormal300 (16.9)
 Unknown137 (7.7)
No. of individuals who had CT/MRI of the brain609 (34.2)
 Normal412 (23.1)
 Abnormal114 (6.4)
 Unknown83 (4.7)
Previous AED treatment before starting PB 
 Never treated327 (18.4)
 Irregular treatment1,453 (81.6)

Response to phenobarbital

Of the 1,780 people with information on treatment response ascertained at the follow-up assessment, 939 (53%) were still taking PB (including 18 who had restarted PB after temporarily stopping treatment). The median daily dose was 120 mg (IQR 90–150 mg; Table S1). The median duration of PB treatment was 4.6 years (IQR 2.6–5.7). Among them, 116 (12.4% of 939) were seizure-free during the entire treatment period, 375 (39.9%) had >75–99% reduction in seizure frequency, 212 (22.6%) had >50–75% reduction, and 236 (25.1%) had <50% reduction, compared with pretreatment baseline. Among the 841 people who had stopped PB, 244 were seizure-free.

Figure 1 shows the Kaplan-Meier estimates of the probability of retention of PB treatment from recruitment into the original pragmatic trial to the follow-up assessment. The estimated probability of retention at 2, 4, and 6 years were 0.74, 0.62, and 0.53, respectively. Table 2 shows the reasons for stopping PB, the most common of which was seizure freedom or substantial seizure reduction. Approximately one fifth stopped because of lack of access to PB or to medical care, or because they could not afford PB. Of those who changed to other AEDs, most changed to carbamazepine (n = 112) or phenytoin (n = 87). At the follow-up assessment, 78 people were taking two other AEDs; 12 were taking three others.

image

Figure 1.   Kaplan-Meier plot of probability of retention of phenobarbital treatment (n = 1,780).

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Table 2.   Reasons for withdrawal of phenobarbital (n = 841)
ReasonN%
Good seizure control28734.1
 Seizure-free24429.0
 Substantial seizure reduction435.1
Changed to other antiepileptic drugs for personal preference27732.9
Could not afford treatment9311.1
Lack of efficacy9210.9
Phenobarbital not available locally546.4
No access to medical care232.8
Adverse effects101.2
Others50.6
Total841100

During PB treatment, 453 (25.4% of 1,780) people became seizure-free for at least 1 year. They included 236 of 1,452 people who had at least four convulsive seizures in the year prior to commencing PB. The majority (88%) of people who became seizure-free while taking PB did so at daily doses of 120 mg or below (Fig. 2). Of the 1,780 people reviewed at the follow-up assessment, 406 (22.8%) reported adverse effects, which led to withdrawal of PB treatment in 10 (0.6%) only. Adverse effects reported by at least 1% of individuals were malaise/somnolence (7.4%), dizziness (3.1%), lethargy (2.6%), memory decline (1.4%), gastrointestinal upset (1.2%), and mental slowing (1.2%).

image

Figure 2.   Cumulative percentage of patients who were seizure-free while taking different dose levels of phenobarbital (n = 453).

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Outcome over time and prognostic factors

At the follow-up assessment, 688 (39%) people had been seizure-free for at least the previous year, and 797 (45%) had been seizure-free for at least 1 year at any one time during follow-up. Figure 3 shows the Kaplan-Meier estimates of probability of seizure freedom from recruitment into the original invention trial to the follow-up assessment. Univariate analysis found no significant difference between patients who were seizure-free and not seizure-free in terms of age at onset or family history of epilepsy, or past history of any treatment with western medicine (Table S2). Patients with persistent seizures were more likely to be male (p = 0.04), had significantly longer duration of epilepsy (p = 0.001), and had higher number of seizures in the 12 months before treatment (p = 0.0001). People who were taking AED treatment (whether PB or other AEDs) irregularly at recruitment were less likely to be seizure-free compared to those who were not taking any AED treatment (p = 0.001). These factors remained significantly predictive of not being seizure-free at multivariate analysis (Table 3).

image

Figure 3.   Kaplan-Meier plot of probability of seizure freedom from recruitment into the original pragmatic trial (n = 1,780).

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Table 3.   Multivariate logistic regression analysis to explore the predictive factors of not being seizure-free at the follow-up assessment
 β CoefficientSEWaldp-ValueOR (95% CI)
  1. AED, antiepileptic drug; CI, confidence interval; OR, odds ratio; PB, phenobarbital; SE, standard error.

Female−0.260.106.70.0090.77 (0.63–0.94)
No. of seizures 12 months before PB0.010.00245.20.0071.21 (1.1–1.26)
Duration of epilepsy0.020.00417.70.0031.52 (1.21–1.58)
Taking AED irregularly2.112.710.80.0011.75 (1.65–1.80)
Taking PB irregularly2.322.870.40.0011.73 (1.64–1.80)
Taking other AEDs irregularly2.042.630.80.0011.79 (1.72–1.87)

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Despite the subsequent availability of >20 compounds for the treatment of epilepsy, PB, introduced in 1912, remains the most widely prescribed AED worldwide. Its propensity for cognitive and behavioral adverse effects are of concern, but it has many potential advantages including reliability of supply, affordable cost, broad spectrum of action, and ease of use (Kwan & Brodie, 2004). PB is included in WHO’s Model List of Essential Medicines and, given the low acquisition costs, is recommended as a first option for children and adults with convulsive epilepsy (World Health Organization, 2012). In line with this recommendation, PB was selected as the standard monotherapy in the original pragmatic trial of this community management project in rural China. In this setting, PB showed good efficacy and tolerability when evaluated at up to 2 years of treatment (Wang et al., 2006), and helped to reduce the treatment gap (Wang et al., 2008). In the present study, we assessed the long-term outcomes of PB treatment by extending the follow-up period to 6 years. To our knowledge, this represents the largest study of long-term response to PB, and the largest outcome study of patients followed-up prospectively in a resource-poor setting.

Our findings suggest that PB had maintained its benefits in the long-term, with an estimated probability of 0.53 for people remaining on treatment at 6 years. This long-term retention rate compares favorably with newer AEDs used in similar settings. For instance, a recent study of topiramate as initial monotherapy for newly diagnosed epilepsy in southwest China estimated a probability of retention of 0.47 at 6 years (Hu et al., 2010). Retention of an AED is often regarded as a reflection of its effectiveness, which is a composite measure of efficacy and tolerability (Glauser et al., 2006). One fourth of people became seizure-free for at least 1 year while taking PB, despite the long duration of epilepsy in many of them (mean 21.9 years), and 244 (13.7% of the total cohort) stopped treatment after a period of seizure freedom. The reason for discontinuation could not be accurately ascertained in 33% of the withdrawals, other than “personal preference.” The third most common reason people stopped taking PB, accounting for 20% of all withdrawals, related to socioeconomic factors, such as unavailability of PB or medical care, or unaffordability of treatment, once the original pragmatic trial completed. We have previously estimated that the total 1-year treatment expenses (including medication, health care contact, and other related medical expenses) per treated patient outside the trial setting ranged from 213 to 1,494 yuan (US$26 to 179) (Ding et al., 2008). Evidently this amount was prohibitive to some people, emphasizing the need to improve the economic situation and health care system in rural China if the treatment gap of epilepsy is to be further reduced.

The majority (nearly 90%) of those who became seizure-free did so on modest doses (up to 120 mg/day). This is consistent with the findings on responses to other AEDs in both observational and double-blind randomized controlled studies in which 80–90% of individuals who became seizure-free on their first AED did so on only 600 mg/day of carbamazepine, 1,000 mg/day of valproate, 200 mg/day of lamotrigine (Kwan & Brodie, 2001), or 1,000 mg/day of levetiracetam (Brodie et al., 2007).

The use of modest doses of PB in the majority of people might have accounted for its good tolerability in the present study, with <1% of individuals withdrawing PB due to side effects, and less than one fourth reporting adverse events at the follow-up assessment. A decline in the incidence of adverse events was noted in the original pragmatic trial (Wang et al., 2006), probably reflecting tolerance to the neurotoxic effects of PB. We may have underestimated the cognitive effects of PB, as formal psychometric testing was not carried out in this pragmatic study. The evidence on the propensity of PB to cause neurobehavioral effects is conflicting. A recent systematic review of 11 randomized controlled trials comparing PB and other older AEDs (carbamazepine, phenytoin, and valproate) concluded no evidence of association between PB and a higher risk of central nervous system–related adverse effects, and no consistent effect on cognition and behavior, although PB was associated with higher rates of withdrawal due to adverse effects in studies performed in developed but not in developing countries (Zhang et al., 2011). This discrepancy has been postulated to be related to the differences in PB dosage employed and in the medicosocial context, potential bias in open label design in some studies, and the possibility of genetic influence (Kwan & Brodie, 2004). In a recent prospective controlled study in rural China, PB monotherapy was not found to have a major negative impact on cognitive function in people with epilepsy (Ding et al., 2012a).

Overall, approximately 40% of participants had been seizure-free for at least a year at the follow-up assessment. Consistent with other prospective cohort studies performed in developed countries (MacDonald et al., 2000; Mohanraj & Brodie, 2006), higher pretreatment seizure frequency was a poor prognostic factor. A longer duration of epilepsy before regular treatment with PB also predicted poorer response. These findings suggest that in resource-poor settings with a large treatment gap, a substantial proportion of patients may derive long-term benefits from AED therapy despite a long duration of recurrent seizures. Although a history of previous AED treatment per se did not seem to predict outcome, irregular AED treatment at baseline was found to be a poor prognostic factor (compared with no treatment at all). This observation is intriguing, and although it might simply reflect disease severity perceived by the patients, it might also have implication of possible neurobiologic changes resulting from irregular AED treatment. This type of analysis is not possible in developed countries where most patients receive regular treatment. The results may suggest that regular treatment should be initiated as early as possible to maximize the benefits.

Like all observational studies, this study is limited in its ability to determine causation. Therefore, the changes in seizure control in some people might have reflected the “remitting-relapsing” treatment outcome pattern that is increasingly recognized (Brodie et al., 2012). Limited by the local expertise at the primary care level, only convulsive seizures were considered in the present study. Outcomes were assessed at a single follow-up visit; therefore, it was not possible to accurately ascertain their various temporal patterns in this study. Less than one fourth of patients reported adverse effects, although very long-term complications could not be ascertained.

In conclusion, we observed long-term benefits of regular treatment with PB for convulsive epilepsy in rural China. These findings have relevance for the implementation of similar intervention programs in other resource-poor settings where the great majority of people with epilepsy live. One hundred years after the discovery of its antiepileptic effect, PB is still playing an important role in the management of epilepsy.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

We thank all the local primary care physicians, patients, and their families for participating in this study. We thank Dr. Gail Bell for critical review of an earlier version of this article. The study was funded by the Chinese Ministry of Health and Stichting Epilepsie Instellingen Nederland. The sponsors were not directly involved in the study design, collection, analysis, interpretation of data, writing of the report, or decision to submit the report for publication.

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

PK serves on the scientific advisory board of GSK, Pfizer, and UCB Pharma; speaker’s bureau of GSK, Sanofi, and UCB Pharma; provides consultancy to Eisai and GSK; and receives research grants from Eisai, Johnson & Johnson, Pfizer, and UCB Pharma. ZH serves on the editorial advisory boards of Chinese Journal of Neurology; has received research support from the Chinese Ministry of Health and the China Association Against Epilepsy; and has been a commissioner of the neurology branch of the Chinese Medical Association. JWS served on scientific advisory boards for GSK, UCB, and Viropharma; has received funding for travel from UCB and Janssen; serves on the editorial boards of Lancet Neurology and Epileptic Disorders; serves on the speaker’s bureaus of UCB and GSK; and has received research support from UCB, GSK, the NIH, the European Union Seventh Framework Programme, the Wellcome Trust, WHO, the National Epilepsy Funds of the Netherlands, and the Epilepsy Society. The other authors have no competing interests. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
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