https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(11)60555-2.pdf

Inequality in early childhood: risk and protective factors for early child development

Summary: Purpose: To assess which antiepileptic medications (AEDs) have the best evidence for long-term efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy.

Methods: A 10-member subcommission of the Commission on Therapeutic Strategies of The International League Against Epilepsy (ILAE), including adult and pediatric epileptologists, clinical pharmacologists, clinical trialists, and a statistician evaluated available evidence found through a structured literature review including MEDLINE, Current Contents and the Cochrane Library for all applicable articles from 1940 until July 2005. Articles dealing with different seizure types (for different age groups) and two epilepsy syndromes were assessed for quality of evidence (four classes) based on predefined criteria. Criteria for class I classification were a double-blind randomized controlled trial (RCT) design, ≥48-week treatment duration without forced exit criteria, information on ≥24-week seizure freedom data (efficacy) or ≥48-week retention data (effectiveness), demonstration of superiority or 80% power to detect a ≤20% relative difference in efficacy/effectiveness versus an adequate comparator, and appropriate statistical analysis. Class II studies met all class I criteria except for having either treatment duration of 24 to 47 weeks or, for noninferiority analysis, a power to only exclude a 21–30% relative difference. Class III studies included other randomized double-blind and open-label trials, and class IV included other forms of evidence (e.g., expert opinion, case reports). Quality of clinical trial evidence was used to determine the strength of the level of recommendation.

Results: A total of 50 RCTs and seven meta-analyses contributed to the analysis. Only four RCTs had class I evidence, whereas two had class II evidence; the remainder were evaluated as class III evidence. Three seizure types had AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy: adults with partial-onset seizures (level A, carbamazepine and phenytoin; level B, valproic acid), children with partial-onset seizures (level A, oxcarbazepine; level B, None), and elderly adults with partial-onset seizures (level A, gabapentin and lamotrigine; level B, None). One adult seizure type [adults with generalized-onset tonic–clonic (GTC) seizures], two pediatric seizure types (GTC seizures and absence seizures), and two epilepsy syndromes (benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) had no AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy.

Conclusions: This evidence-based guideline focused on AED efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. The absence of rigorous comprehensive adverse effects data makes it impossible to develop an evidence-based guideline aimed at identifying the overall optimal recommended initial-monotherapy AED. There is an especially alarming lack of well-designed, properly conducted RCTs for patients with generalized seizures/epilepsies and for children in general. The majority of relevant existing RCTs have significant methodologic problems that limit their applicability to this guideline's clinically relevant main question. Multicenter, multinational efforts are needed to design, conduct and analyze future clinically relevant RCTs that can answer the many outstanding questions identified in this guideline. The ultimate choice of an AED for any individual patient with newly diagnosed or untreated epilepsy should include consideration of the strength of the efficacy and effectiveness evidence for each AED along with other variables such as the AED safety and tolerability profile, pharmacokinetic properties, formulations, and expense. When selecting a patient's AED, physicians and patients should consider all relevant variables and not just efficacy and effectiveness.

/pdf/ilae-treatment-guidelines-evidence-based-analysis-of-52n1wiaqh8.pdf

ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes.

The purpose of this report was to update the 2006 International League Against Epilepsy (ILAE) report and identify the level of evidence for long-term efficacy or effectiveness for antiepileptic drugs (AEDs) as initial monotherapy for patients with newly diagnosed or untreated epilepsy. All applicable articles from July 2005 until March 2012 were identified, evaluated, and combined with the previous analysis (Glauser et al., 2006) to provide a comprehensive update. The prior analysis methodology was utilized with three modifications: (1) the detectable noninferiority boundary approach was dropped and both failed superiority studies and prespecified noninferiority studies were analyzed using a noninferiority approach, (2) the definition of an adequate comparator was clarified and now includes an absolute minimum point estimate for efficacy/effectiveness, and (3) the relationship table between clinical trial ratings, level of evidence, and conclusions no longer includes a recommendation column to reinforce that this review of efficacy/evidence for specific seizure types does not imply treatment recommendations. This evidence review contains one clarification: The commission has determined that class I superiority studies can be designed to detect up to a 20% absolute (rather than relative) difference in the point estimate of efficacy/effectiveness between study treatment and comparator using an intent-to-treat analysis. Since July, 2005, three class I randomized controlled trials (RCT) and 11 class III RCTs have been published. The combined analysis (1940-2012) now includes a total of 64 RCTs (7 with class I evidence, 2 with class II evidence) and 11 meta-analyses. New efficacy/effectiveness findings include the following: levetiracetam and zonisamide have level A evidence in adults with partial onset seizures and both ethosuximide and valproic acid have level A evidence in children with childhood absence epilepsy. There are no major changes in the level of evidence for any other subgroup. Levetiracetam and zonisamide join carbamazepine and phenytoin with level A efficacy/effectiveness evidence as initial monotherapy for adults with partial onset seizures. Although ethosuximide and valproic acid now have level A efficacy/effectiveness evidence as initial monotherapy for children with absence seizures, there continues to be an alarming lack of well designed, properly conducted epilepsy RCTs for patients with generalized seizures/epilepsies and in children in general. These findings reinforce the need for multicenter, multinational efforts to design, conduct, and analyze future clinically relevant adequately designed RCTs. When selecting a patient's AED, all relevant variables and not just efficacy and effectiveness should be considered.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/epi.12074

Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes

https://www.who.int/social_determinants/resources/articles/lancet_stephens.pdf

Disappearing, displaced, and undervalued: a call to action for Indigenous health worldwide

Epilepsy is the most common serious neurological disorder and is one of the world's most prevalent noncommunicable diseases. As the understanding of its physical and social burden has increased it has moved higher up the world health agenda. Over four-fifths of the 50 million people with epilepsy are thought to be in developing countries; much of this condition results from preventable causes. Around 90% of people with epilepsy in developing countries are not receiving appropriate treatment. Consequently, people with epilepsy continue to be stigmatized and have a lower quality of life than people with other chronic illnesses. However, bridging the treatment gap and reducing the burden of epilepsy is not straightforward and faces many constraints. Cultural attitudes, a lack of prioritization, poor health system infrastructure, and inadequate supplies of antiepileptic drugs all conspire to hinder appropriate treatment. Nevertheless, there have been successful attempts to provide treatment, which have shown the importance of community-based approaches and also indicate that provision for sustained intervention over the long term is necessary in any treatment programme. Approaches being adopted in the demonstration projects of the Global Campaign Against Epilepsy--implemented by the International League Against Epilepsy, the International Bureau for Epilepsy, and the World Health Organization--may provide further advances. Much remains to be done but it is hoped that current efforts will lead to better treatment of people with epilepsy in developing countries.

/pdf/the-treatment-of-epilepsy-in-developing-countries-where-do-4lpdrgp3bd.pdf

The treatment of epilepsy in developing countries: where do we go from here?

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140673697062508.pdf

Randomised controlled trial to assess acceptability of phenobarbital for childhood epilepsy in rural India.

Social integration of children with epilepsy in rural India.

Summary:  Purpose: Most people in the world with epilepsy are untreated with antiepileptic drugs (AEDs). In some developing countries, this is because treatment facilities are unavailable or difficult to access. It has even been suggested that indigenous health systems threaten the prospect of the global control of epilepsy with AEDs. We have investigated patterns and costs of help seeking for children with epilepsy in a region of rural India where only 12% of children with epilepsy were in treatment. Our objective was to find out (a) whom families had consulted; (b) if nonconsulting families differed in demographic or child medical factors; (c) if indigenous treatment was taken, exclusive of allopathic treatment; and (d) the direct and indirect cost of various providers.



Methods: We conducted a cross-sectional interview study in a community-based program for childhood epilepsy in rural West Bengal, India. We interviewed parents of 85 children aged 2 to 18 years with untreated epilepsy who had entered a clinical trial of AEDs during 1995 through 1996.



Results: Eighty percent of families had sought some help in the past: 62% with an allopathic practitioner, 44% with traditional practitioners. Primary health centres (PHCs) and quacks were not popular. Twenty-four percent of families never sought help of any kind, and this was unassociated with sex, income, maternal literacy, or medical variables. There was evidence of both exclusivity and pluralism: 42% of families first consulting allopathic practitioners also visited traditional practitioners, whereas 30% of families first consulting traditional practitioners also went to allopathic practitioners. One visit to a physician cost a median of 9–13% of monthly income and 5–12 person-hours; the cost of visiting indigenous providers was negligible.



Conclusions: Most families sought some form of help and were motivated to spend large amounts of money and time for allopathic treatments from qualified practitioners. The typical cost of allopathic treatment was unsustainable in the long term. Medical pluralism is common and does not adversely influence use of allopathic treatment. The phenomenon of nonconsulting merits further study. Traditional practitioners play a complementary role and might become involved in community treatment programs. Low-cost, local treatment is essential to the public health control of epilepsy.

Help-seeking patterns for children with epilepsy in rural India: implications for service delivery.

Background The Conners' Parent Rating Scales (CPRS) have been used to measure behavioural problems in drug trials in children for many years. This study in rural India aimed to validate a translated version of the CPRS-48 for use in a study of anti-epileptic drug side-effects. Method The Scale was translated into local dialect, back-translated, and piloted among healthy families. The revised version was then administered to mothers of 60 healthy children and 63 children with epilepsy. Tests of internal reliability, test-retest reliability and factor analysis were performed. Results Cronbach's alpha ranged from 0.60 to 0.75 for the subscales, and correlation coefficients after retesting from 0.84 to 0.99. The overall factor structure was very similar to that reported in the original USA sample. Conclusion The Bengali version of the CPRS-48 and its Hyperactivity Index have validity for rural Bengali children, and the process demonstrates that such instruments can be usefully adapted for local purposes.

Gautam Chaudhury

Papers

Randomised controlled trial to assess acceptability of phenobarbital for childhood epilepsy in rural India.

Social integration of children with epilepsy in rural India.

Help-seeking patterns for children with epilepsy in rural India: implications for service delivery.

Validation of a Bengali adaptation of the Conners' Parent Rating Scale (CPRS-48).