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.

This book marks the first step in a new review of health policy - a review that focuses specifically on sub - Saharan Africa. Several factors make this exercise particularly timely: 1) the concern that the economic downturn of the early 1980s may have adversely affected the health sector in Africa; 2) the need to evaluate the impact of primary health care strategies, especially the key elements of immunization and oral rehydration; 3) the completion of a substantial body of epidemiological and demographic analyses, which provides a much improved empirical basis for assessing health conditions and recent health trends; 4) the concern that the global emergence of Acquired Immune Deficiency Syndrome (AIDS) and its sharp impact in selected African foci have undermined development prospects in some countries; and 5) the potential value of explicitly seeking lessons from the Bank's experience with health sector operations in Africa. The chapters in this book were commissioned to address the third point - to assemble in one place lessons from the analyses of the epidemiological and demographic conditions that define the problems facing Africa's health systems. This book sets an important part of the agenda of work for African health officials over the next decade.

Disease and Mortality in Sub-Saharan Africa

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

The consequences of refractory epilepsy and its treatment

Background: In developing countries, most people with mental, neurological and substance-abuse (MNS) disorders do not receive adequate care mainly because of a lack of mental health professionals. Non-specialist health workers, but also other professionals with health roles, such as teachers, may therefore have an important role to play in delivering MNS health care. Researchers in The Cochrane Collaboration carried out a review of the effects of using non-specialist health workers or other professionals with health roles to help people with MNS disorders in developing countries. After searching for all relevant studies in scientific databases, they found 38 studies published before October 2012. Their findings are summarised below. What is a non-specialist health worker? Any type of health worker (like a doctor, nurse or lay health worker) who is not a specialist in mental health or neurology but who may have had some training in these fields. We also looked at teachers, as they can be particularly important in the care of children and youths. What the research says: The studies in this review were from 22 developing countries. In most studies, lay health workers delivered the mental health care, and addressed depression or anxiety (or both), or post-traumatic stress disorder. The review shows that the use of non-specialist health workers, compared with usual healthcare services: Â· may increase the number of adults who recover from depression or anxiety (or both) two to six months after treatment; Â· may slightly reduce symptoms formothers with depression; Â· may slightly reduce the symptoms of adults with post-traumatic stress disorder (non-specialists and teachers were used in one study); Â· probably slightly improves the symptoms of people with dementia; Â· probably improves/slightly improves the mental well-being, burden and distress of carers of people with dementia; Â· may decrease the quantity of alcohol consumed by problem drinkers. It is uncertain whether lay health workers or teachers reducepost-traumatic stress disorder symptoms among children. There were too few studies to draw any conclusions about the cost-effectiveness of using non-specialist health workers or teachers, or about their impact on people with other MNS conditions such as epilepsy, schizophrenia, and alcohol and drug abuse problems. In addition, very few studies measured unintended consequences of non-specialist health worker-led care - such effects could impact on the appropriateness and quality of care. Quality of the evidence: Overall, non-specialist health workers and teachers have some promising benefits in improving people's outcomes for general and perinatal depression, post-traumatic stress disorder and alcohol-use disorders, and patient and carer outcomes for dementia. However, this evidence is of low or very low quality in some areas, and for some issues no evidence is available. Therefore, we cannot make conclusions about which specific interventions using non-specialist health workers to help people with MNS disorders are more effective.

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S. Gatiti

Papers

Comprehensive primary health care antiepileptic drug treatment programme in rural and semi-urban Kenya

A comprehensive community epilepsy programme: the Nakuru project.