Dornase alfa for cystic fibrosis.

BACKGROUND: Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in the lungs, promoting improved clearance of secretions. This is an update of a previously published review. OBJECTIVES: To determine whether the use of dornase alfa in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other medications that improve airway clearance, and to identify any adverse events associated with its use. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstracts from conferences. Date of the most recent search of the Group's Cystic Fibrosis Register: 30 November 2015.Clinicaltrials.gov was also searched to identify unpublished or ongoing trials. Date of most recent search: 28 November 2015. SELECTION CRITERIA: All randomised and quasi-randomised controlled trials comparing dornase alfa to placebo, standard therapy or other medications that improve airway clearance. DATA COLLECTION AND ANALYSIS: Authors independently assessed trials against the inclusion criteria; two authors carried out analysis of methodological quality and data extraction. MAIN RESULTS: The searches identified 54 trials, of which 19 (including a total of 2565 participants) met our inclusion criteria. Three additional papers examined the healthcare cost from one of the clinical trials. Fifteen trials compared dornase alfa to placebo or no dornase alfa treatment (2447 participants); two compared daily dornase to hypertonic saline (32 participants); one compared daily dornase alfa with hypertonic saline and alternate day dornase alfa (48 participants); one compared dornase alfa to mannitol and the combination of both drugs (38 participants). Trial duration varied from six days to three years.Compared to placebo, forced expiratory volume at one second improved in the intervention groups, with significant differences at one, three, six months and two years. There was also a significant improvement in lung clearance index at one month. There was a decrease in pulmonary exacerbations compared to placebo in trials of longer duration. The quality of the evidence from placebo-controlled trials was moderate to high for outcomes of lung function and pulmonary exacerbations. Limited, low quality evidence was available for changes in quality of life from baseline. One trial that examined the cost of care, including the cost of dornase alfa, found that the cost savings from dornase alfa offset 18% to 38% of the medication costs.The results for trials comparing dornase alfa to other medications that improve airway clearance (hypertonic saline or mannitol) were mixed, with one trial showing a greater improvement in forced expiratory volume at one second for dornase alfa compared to hypertonic saline, and three trials finding no difference between medications. In the only trial to assess the combination of dornase alfa with another medication compared to dornase alone, there was no benefit seen with the combination of dornase alfa and mannitol. Evidence of dornase alfa compared to other medications was limited and the open-label design of the trials may have induced bias, therefore the quality of the evidence was judged to be low.Dornase alfa did not cause significantly more adverse effects, except voice alteration and rash. AUTHORS' CONCLUSIONS: There is evidence to show that, compared with placebo, therapy with dornase alfa improves lung function in people with cystic fibrosis in trials lasting one month to two years. There was a decrease in pulmonary exacerbations in trials of six months or longer. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials. There is not enough evidence to firmly conclude if dornase alfa is superior to hyperosmolar agents in improving lung function.

Transcranial magnetic stimulation for the treatment of epilepsy.

BACKGROUND: Epilepsy is a highly prevalent neurological condition characterized by repeated unprovoked seizures with various etiologies. Although antiepileptic medications produce clinical improvement in most individuals, nearly a third of individuals have drug-resistant epilepsy that carries significant morbidity and mortality. There remains a need for non-invasive and more effective therapies for this population. Transcranial magnetic stimulation (TMS) uses electromagnetic coils to excite or inhibit neurons, with repetitive pulses at low-frequency producing an inhibitory effect that could conceivably reduce cortical excitability associated with epilepsy. OBJECTIVES: To assess the evidence for the use of TMS in individuals with drug-resistant epilepsy compared with other available treatments in reducing seizure frequency, improving quality of life, reducing epileptiform discharges, antiepileptic medication use, and side-effects. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid 1946 to 10 March 2016), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP) up to March 2016. We also searched SCOPUS (1823 to June 2014) as a substitute for Embase (but it is no longer necessary to search SCOPUS, because randomized controlled trials (RCTs) and quasi-RCTs in EMBASE are now included in CENTRAL). SELECTION CRITERIA: Eligible studies were RCTs that were double-blinded, single-blinded or unblinded, and placebo, no treatment, or active controlled, which used repetitive transcranial magnetic stimulation (rTMS) without restriction of frequency, duration, intensity, or setup (focal or vertex treatment) on patients with drug-resistant epilepsy. The search revealed 274 records from the databases, that after selection provided seven full-text relevant studies for inclusion. Of the seven studies included, five were completed studies with published data and included randomized, blinded trials. The total number of participants in the seven trials was 230. DATA COLLECTION AND ANALYSIS: We extracted information from each trial including methodological data; participant demographics including baseline seizure frequency, type of epileptic drugs taken; intervention details and intervention groups for comparison; potential biases; and outcomes and time points, primarily change in seizure frequency or responder rates, as well as quality of life and epileptiform discharges, adverse effects, and changes in medication use. MAIN RESULTS: Two of the seven studies analyzed showed a statistically significant reduction in seizure rate from baseline (72% and 78.9% reduction of seizures per week from the baseline rate, respectively). The other five studies showed no statistically significant difference in seizure frequency following rTMS treatment compared with controls. We were not able to combine the results of the trials in analysis due to differences in the designs of the studies. Four studies evaluated our secondary endpoint of mean number of epileptic discharges, and three of the four showed a statistically significant reduction in discharges. Quality of life was not assessed in any of the studies. Adverse effects were uncommon among the studies and typically involved headache, dizziness, and tinnitus. No significant changes in medication use were found in the trials. AUTHORS' CONCLUSIONS: Overall, we judged the quality of evidence for the primary outcomes of this review to be low. There is evidence that rTMS is safe and not associated with any adverse events, but given the variability in technique and outcome reporting that prevented meta-analysis, the evidence for efficacy of rTMS for seizure reduction is still lacking despite reasonable evidence that it is effective at reducing epileptiform discharges.

Treatments for the prevention of Sudden Unexpected Death in Epilepsy (SUDEP).

BACKGROUND: Sudden Unexpected Death in Epilepsy (SUDEP) is defined as sudden, unexpected, witnessed or unwitnessed, non-traumatic or non-drowning death of people with epilepsy, with or without evidence of a seizure, excluding documented status epilepticus and in whom postmortem examination does not reveal a structural or toxicological cause for death. SUDEP has a reported incidence of 1 to 2 per 1000 patient years and represents the most common epilepsy-related cause of death. The presence and frequency of generalised tonic-clonic seizures (GTCS), male sex, early age of seizure onset, duration of epilepsy, and polytherapy are all predictors of risk of SUDEP. The exact pathophysiology of SUDEP is currently unknown, although GTCS-induced cardiac, respiratory, and brainstem dysfunction appears likely. Appropriately chosen antiepileptic drug treatment can render around 70% of patients free of all seizures. However, around one-third will remain drug refractory despite polytherapy. Continuing seizures place patients at risk of SUDEP, depression, and reduced quality of life. Preventative strategies for SUDEP include reducing the occurrence of GTCS by timely referral for presurgical evaluation in people with lesional epilepsy and advice on lifestyle measures; detecting cardiorespiratory distress through clinical observation and seizure, respiratory, and heart rate monitoring devices; preventing airway obstruction through nocturnal supervision and safety pillows; reducing central hypoventilation through physical stimulation and enhancing serotonergic mechanisms of respiratory regulation using selective serotonin reuptake inhibitors (SSRIs); reducing adenosine and endogenous opioid-induced brain and brainstem depression. OBJECTIVES: To assess the effectiveness of interventions in preventing SUDEP in people with epilepsy by synthesising evidence from randomised controlled trials of interventions and cohort and case-control non-randomised studies. SEARCH METHODS: We searched the following databases: Cochrane Epilepsy Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL, Issue 11, 2015) via the Cochrane Register of Studies Online (CRSO); MEDLINE (Ovid, 1946 onwards); SCOPUS (1823 onwards); PsycINFO (EBSCOhost, 1887 onwards); CINAHL Plus (EBSCOhost, 1937 onwards); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We used no language restrictions. The date of the last search was 12 November 2015. We checked the reference lists of retrieved studies for additional reports of relevant studies and contacted lead study authors for any relevant unpublished material. We identified duplicate studies by screening reports according to title, authors' names, location, and medical institute, omitting any duplicated studies. We identified any grey literature studies published in the last five years by searching: Zetoc database; ISI Proceedings; International Bureau for Epilepsy (IBE) congress proceedings database; International League Against Epilepsy (ILAE) congress proceedings database; abstract books of symposia and congresses, meeting abstracts, and research reports. SELECTION CRITERIA: We aimed to include randomised controlled trials (RCTs), quasi-RCTs, and cluster-RCTs; prospective non-randomised cohort controlled and uncontrolled studies; and case-control studies of adults and children with epilepsy receiving an intervention for the prevention of SUDEP. Types of interventions included: early versus delayed pre-surgical evaluation for lesional epilepsy; educational programmes; seizure-monitoring devices; safety pillows; nocturnal supervision; selective serotonin reuptake inhibitors (SSRIs); opiate antagonists; and adenosine antagonists. DATA COLLECTION AND ANALYSIS: We aimed to collect data on study design factors and participant demographics for included studies. The primary outcome of interest was the number of deaths from SUDEP. Secondary outcomes included: number of other deaths (unrelated to SUDEP); change in mean depression and anxiety scores (as defined within the study); clinically important change in quality of life, that is any change in quality of life score (average and endpoint) according to validated quality of life scales; and number of hospital attendances for seizures. MAIN RESULTS: We identified 582 records from the databases and search strategies. We found 10 further records by searching other resources (handsearching). We removed 211 duplicate records and screened 381 records (title and abstract) for inclusion in the review. We excluded 364 records based on the title and abstract and assessed 17 full-text articles. We excluded 15 studies: eight studies did not assess interventions to prevent SUDEP; five studies measured sensitivity of devices to detect GTCS but did not directly measure SUDEP; and two studies assessed risk factors for SUDEP but not interventions for preventing SUDEP. One listed study is awaiting classification.We included one case-control study at serious risk of bias within a qualitative analysis in this review. This study of 154 cases of SUDEP and 616 controls ascertained a protective effect for the presence of nocturnal supervision (unadjusted odds ratio (OR) 0.34, 95% confidence interval (CI) 0.22 to 0.53) and when a supervising person shared the same bedroom or when special precautions, for example a listening device, were used (unadjusted OR 0.41, 95% CI 0.20 to 0.82). This effect was independent of seizure control. Non-SUDEP deaths; changes to anxiety, depression, and quality of life; and number of hospital attendances were not reported. AUTHORS' CONCLUSIONS: We found very low-quality evidence of a preventative effect for nocturnal supervision against SUDEP. Further research is required to identify the effectiveness of other current interventions, for example seizure detection devices, safety pillows, SSRIs, early surgical evaluation, educational programmes, and opiate and adenosine antagonists in preventing SUDEP in people with epilepsy.

Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review.

BACKGROUND: This is an updated version of the original Cochrane Review, first published in Issue 1, 2003 and updated in 2015. This review is one in a series of Cochrane Reviews investigating pair-wise monotherapy comparisons.Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenobarbitone are commonly used broad-spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for partial onset seizures, and is used in the USA and Europe. Phenobarbitone is no longer considered a first-line treatment because of concerns over associated adverse events, particularly documented behavioural adverse events in children treated with the drug. However, phenobarbitone is still commonly used in low- and middle-income countries because of its low cost. No consistent differences in efficacy have been found between carbamazepine and phenobarbitone in individual trials; however, the confidence intervals generated by these studies are wide, and therefore, synthesising the data of the individual trials may show differences in efficacy. OBJECTIVES: To review the time to withdrawal, remission, and first seizure of carbamazepine compared with phenobarbitone when used as monotherapy in people with partial onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types). SEARCH METHODS: For the latest update, we searched the following databases on 18 August 2016: the Cochrane Epilepsy Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid, from 1946), the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov), and the World Health Organization International Clinical Trials Registry Platform (ICTRP). Previously we also searched SCOPUS (from 1823) as an alternative to Embase, but this is no longer necessary, because randomised controlled trials (RCTs) and quasi-RCTs in Embase are now included in CENTRAL. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. SELECTION CRITERIA: RCTs in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of carbamazepine monotherapy versus phenobarbitone monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'adverse events'. We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), with the generic inverse variance method used to obtain the overall pooled HR and 95% CI. MAIN RESULTS: IPD were available for 836 participants out of 1455 eligible individuals from six out of 13 trials; 57% of the potential data. For remission outcomes, HR > 1 indicated an advantage for phenobarbitone, and for first seizure and withdrawal outcomes, HR > 1 indicated an advantage for carbamazepine.The main overall results (pooled HR adjusted for seizure type, 95% CI) were HR 1.50 for time to withdrawal of allocated treatment (95% CI 1.15 to 1.95; P = 0.003); HR 0.93 for time to achieve 12-month remission (95% CI 0.72 to 1.20; P = 0.57); HR 0.99 for time to achieve six-month remission (95% CI 0.80 to 1.23; P = 0.95); and HR 0.87 for time to first seizure (95% CI 0.72 to 1.06; P = 0.18). Results suggest an advantage for carbamazepine over phenobarbitone in terms of time to treatment withdrawal and no statistically significant evidence between the drugs for the other outcomes. We found evidence of a statistically significant interaction between treatment effect and seizure type for time to first seizure recurrence (Chi² test for subgroup differences P = 0.03), where phenobarbitone was favoured for partial onset seizures (HR 0.76, 95% CI 0.60 to 0.96; P = 0.02) and carbamazepine was favoured for generalised onset seizures (HR 1.23, 95% CI 0.88 to 1.77; P = 0.27). We found no evidence of an interaction between treatment effect and seizure type for the other outcomes. However, methodological quality of the included studies was variable, with 10 out of the 13 included studies (4 out of 6 studies contributing IPD) judged at high risk of bias for at least one methodological aspect, leading to variable individual study results, and therefore, heterogeneity in the analyses of this review. We conducted sensitivity analyses to examine the impact of poor methodological aspects, where possible. AUTHORS' CONCLUSIONS: Overall, we found evidence suggestive of an advantage for carbamazepine in terms of drug effectiveness compared with phenobarbitone (retention of the drug in terms of seizure control and adverse events) and evidence suggestive of an association between treatment effect and seizure type for time to first seizure recurrence (phenobarbitone favoured for partial seizures and carbamazepine favoured for generalised seizures). However, this evidence was judged to be of low quality due to poor methodological quality and the potential impact on individual study results (and therefore variability (heterogeneity) present in the analysis within this review), we encourage caution when interpreting the results of this review and do not advocate that the results of this review alone should be used in choosing between carbamazepine and phenobarbitone. We recommend that future trials should be designed to the highest quality possible with considerations for allocation concealment and masking, choice of population, choice of outcomes and analysis, and presentation of results.

Lamotrigine versus carbamazepine monotherapy for epilepsy: an individual participant data review.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 1, 2006 of the Cochrane Database of Systematic Reviews.Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment up to 70% of individuals with active epilepsy have the potential to become seizure-free and to go into long-term remission shortly after starting drug therapy with a single antiepileptic drug (AED) in monotherapy.The correct choice of first-line antiepileptic therapy for individuals with newly diagnosed seizures is of great importance. It is important that the choice of AEDs for an individual is made using the highest quality evidence regarding the potential benefits and harms of the various treatments. It is also important that the effectiveness and tolerability of AEDs appropriate to given seizure types are compared to one another.Carbamazepine or lamotrigine are first-line recommended treatments for new onset partial seizures and as a first- or second-line treatment for generalised tonic-clonic seizures. Performing a synthesis of the evidence from existing trials will increase the precision of the results for outcomes relating to efficacy and tolerability and may assist in informing a choice between the two drugs. OBJECTIVES: To review the time to withdrawal, remission and first seizure with lamotrigine compared to carbamazepine when used as monotherapy in people with partial onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types). SEARCH METHODS: The first searches for this review were run in 1997. For the most recent update we searched the Cochrane Epilepsy Group Specialized Register (17 October 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 17 October 2016) and MEDLINE (Ovid, 1946 to 17 October 2016). We imposed no language restrictions. We also contacted pharmaceutical companies and trial investigators. SELECTION CRITERIA: Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures comparing monotherapy with either carbamazepine or lamotrigine. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was time to withdrawal of allocated treatment and our secondary outcomes were time to first seizure post-randomisation, time to six-month, 12-month and 24-month remission, and incidence of adverse events. We used Cox proportional hazards regression models to obtain trial-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), using the generic inverse variance method to obtain the overall pooled HR and 95% CI. MAIN RESULTS: We included 13 studies in this review. Individual participant data were available for 2572 participants out of 3394 eligible individuals from nine out of 13 trials: 78% of the potential data. For remission outcomes, a HR < 1 indicated an advantage for carbamazepine and for first seizure and withdrawal outcomes a HR < 1 indicated an advantage for lamotrigine.The main overall results (pooled HR adjusted for seizure type) were: time to withdrawal of allocated treatment (HR 0.72, 95% CI 0.63 to 0.82), time to first seizure (HR 1.22, 95% CI 1.09 to 1.37) and time to six-month remission (HR 0.84, 95% CI 0.74 to 0.94), showing a significant advantage for lamotrigine compared to carbamazepine for withdrawal but a significant advantage for carbamazepine compared to lamotrigine for first seizure and six-month remission. We found no difference between the drugs for time to 12-month remission (HR 0.91, 95% CI 0.77 to 1.07) or time to 24-month remission (HR 1.00, 95% CI 0.80 to 1.25), however only two trials followed up participants for more than one year so the evidence is limited.The results of this review are applicable mainly to individuals with partial onset seizures; 88% of included individuals experienced seizures of this type at baseline. Up to 50% of the limited number of individuals classified as experiencing generalised onset seizures at baseline may have had their seizure type misclassified, therefore we recommend caution when interpreting the results of this review for individuals with generalised onset seizures.The most commonly reported adverse events for both of the drugs across all of the included trials were dizziness, fatigue, gastrointestinal disturbances, headache and skin problems. The rate of adverse events was similar across the two drugs.The methodological quality of the included trials was generally good, however there is some evidence that the design choice of masked or open-label treatment may have influenced the withdrawal rates of the trials. Hence, we judged the quality of the evidence for the primary outcome of treatment withdrawal to be moderate for individuals with partial onset seizures and low for individuals with generalised onset seizures. For efficacy outcomes (first seizure, remission), we judged the quality of evidence to be high for individuals with partial onset seizures and moderate for individuals with generalised onset seizures. AUTHORS' CONCLUSIONS: Lamotrigine was significantly less likely to be withdrawn than carbamazepine but the results for time to first seizure suggested that carbamazepine may be superior in terms of seizure control. A choice between these first-line treatments must be made with careful consideration. We recommend that future trials should be designed to the highest quality possible with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.

Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic-clonic seizures: an individual participant data review.

BACKGROUND: Worldwide, phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset seizures, and that valproate is more effective for generalised onset tonic-clonic seizures (with or without other generalised seizure types). This review is one in a series of Cochrane reviews investigating pair-wise monotherapy comparisons. This is the latest updated version of the review first published in 2001 and updated in 2013. OBJECTIVES: To review the time to withdrawal, remission and first seizure of phenytoin compared to valproate when used as monotherapy in people with partial onset seizures or generalised tonic-clonic seizures (with or without other generalised seizure types). SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialised Register (19 May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2015, Issue 4), MEDLINE (1946 to 19 May 2015), SCOPUS (19 February 2013), ClinicalTrials.gov (19 May 2015), and WHO International Clinical Trials Registry Platform ICTRP (19 May 2015). We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of valproate monotherapy versus phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Outcomes were time to: (a) withdrawal of allocated treatment (retention time); (b) achieve 12-month remission (seizure-free period); (c) achieve six-month remission (seizure-free period); and (d) first seizure (post-randomisation). We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), and the generic inverse variance method to obtain the overall pooled HR and 95% CI. MAIN RESULTS: IPD were available for 669 individuals out of 1119 eligible individuals from five out of 11 trials, 60% of the potential data. Results apply to partial onset seizures (simple, complex and secondary generalised tonic-clonic seizures), and generalised tonic-clonic seizures, but not other generalised seizure types (absence or myoclonus seizure types). For remission outcomes: HR > 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes: HR > 1 indicates an advantage for valproate.The main overall results (pooled HR adjusted for seizure type) were time to: (a) withdrawal of allocated treatment 1.09 (95% CI 0.76 to 1.55); (b) achieve 12-month remission 0.98 (95% CI 0.78 to 1.23); (c) achieve six-month remission 0.95 (95% CI 0.78 to 1.15); and (d) first seizure 0.93 (95% CI 0.75 to 1.14). The results suggest no overall difference between the drugs for these outcomes. We did not find any statistical interaction between treatment and seizure type (partial versus generalised). AUTHORS' CONCLUSIONS: We have not found evidence that a significant difference exists between phenytoin and valproate for the outcomes examined in this review. However misclassification of seizure type may have confounded the results of this review. Results do not apply to absence or myoclonus seizure types. No outright evidence was found to support or refute current treatment policies.

Immediate antiepileptic drug treatment, versus placebo, deferred, or no treatment for first unprovoked seizure.

BACKGROUND: There is considerable disagreement about the risk of recurrence following a first unprovoked epileptic seizure. A decision about whether to start antiepileptic drug treatment following a first seizure should be informed by information on the size of any reduction in risk of future seizures, the impact on long-term seizure remission, and the risk of adverse effects. OBJECTIVES: To review the probability of seizure recurrence, seizure remission, mortality, and adverse effects of antiepileptic drug (AED) treatment given immediately after the first seizure compared to controls, in children and adults. SEARCH METHODS: We searched the following databases: Cochrane Epilepsy Group Specialized Register (accessed 13 October 2015), Cochrane Central Register of Controlled Trials (The Cochrane Library September 2015, issue 9, accessed 13 October 2015), PUBMED (accessed 22 April 2015), MEDLINE (Ovid, 1946 to 13 October 2015), EMBASE (accessed 22 April 2015), ClinicalTrials.gov (accessed 15 October 2015), and the WHO International Clinical Trials Registry Platform (ICTRP, accessed 13 October 2015). There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs that could be blinded or unblinded. People of any age with a first unprovoked seizure of any type. Included studies compared participants receiving immediate antiepileptic treatment versus those receiving deferred treatment, those assigned to placebo, and those untreated. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies identified by the search strategy for inclusion in the review and extracted data. The quality of the evidence was classified in four categories according to the GRADE approach. Dichotomous outcomes were expressed as Risk Ratios (RR) with 95% confidence intervals (CI). Time-to-event outcomes were expressed as Hazard Ratios (HR) with 95% CI. Only one trial used a double-blind design, and the two largest studies were unblinded. Most of the recurrences were generalized tonic-clonic seizures, a major type of seizures that is easily recognised, which should reduce the risk of outcome reporting bias. MAIN RESULTS: After exclusion of uninformative papers, only six studies (nine reports) were selected for inclusion. For the two largest studies data were available for individual participant meta-analysis. Compared to controls, participants randomised to immediate treatment had a lower probability of relapse at one year (RR 0.49, 95% CI 0.42 to 0.58, high quality evidence), at five years (RR 0.78; 95% CI 0.68 to 0.89; high quality evidence) and a higher probability of an immediate five-year remission (RR 1.25; 95% CI 1.02 to 1.54, high quality evidence). However there was no difference between immediate treatment and control in terms of five year remission at any time (RR 1.02, 95% CI 0.87 to 1.21, high quality evidence). Antiepileptic drugs did not affect overall mortality after a first seizure (RR 1.16; 95% CI 0.69 to 1.95, high quality evidence). Compared to deferred treatment (RR 1.49, 95% CI 1.23 to 1.79, moderate quality evidence), treatment of the first seizure was associated with a significantly higher risk of adverse events. Moderate to low quality imprecise evidence was available for the association of treatment of the first seizure compared to no treatment or placebo (RR 14.50, 95% CI 1.93 to 108.76) and(RR 4.91, 95% CI 1.10 to 21.93) respectively) AUTHORS' CONCLUSIONS: Treatment of the first unprovoked seizure reduces the risk of a subsequent seizure but does not affect the proportion of patients in remission in the long-term. Antiepileptic drugs are associated with adverse events, and there is no evidence that they reduce mortality. In light of this review, the decision to start antiepileptic drug treatment following a first unprovoked seizure should be individualized and based on patient preference, clinical, legal, and socio-cultural factors.

Topiramate versus carbamazepine monotherapy for epilepsy: an individual participant data review.

BACKGROUND: Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy, the majority of which may be able to achieve remission with a single antiepileptic drug (AED).The correct choice of first-line antiepileptic therapy for individuals with newly diagnosed seizures is of great importance. It is important that the choice of AED for an individual is based on the highest-quality evidence available regarding the potential benefits and harms of various treatments. It is also important to compare the efficacy and tolerability of AEDs appropriate to given seizure types.Topiramate and carbamazepine are commonly used AEDs. Performing a synthesis of the evidence from existing trials will increase the precision of results of outcomes relating to efficacy and tolerability, and may help inform a choice between the two drugs. OBJECTIVES: To assess the effects of topiramate monotherapy versus carbamazepine monotherapy for epilepsy in people with partial-onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types). SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (14 April 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (14 April 2016) and MEDLINE (Ovid, 1946 to 14 April 2016). We imposed no language restrictions. We also contacted pharmaceutical companies and trial investigators. SELECTION CRITERIA: Randomised controlled trials in children or adults with partial-onset seizures or generalised-onset tonic-clonic seizures with or without other generalised seizure types with a comparison of monotherapy with either topiramate or carbamazepine. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to first seizure post randomisation', 'time to 6-month remission, 'time to 12-month remission' and incidence of adverse events. We used Cox proportional hazards regression models to obtain trial-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), and used the generic inverse variance method to obtain the overall pooled HRs and 95% CIs. MAIN RESULTS: IPD were available for 1151 of 1239 eligible individuals from two of three eligible studies (93% of the potential data). A small proportion of individuals recruited into these trials had 'unclassified seizures;' for analysis purposes, these individuals are grouped with those with generalised onset seizures. For remission outcomes, a HR < 1 indicated an advantage for carbamazepine, and for first seizure and withdrawal outcomes, a HR < 1 indicated an advantage for topiramate.The main overall results, given as pooled HR adjusted for seizure type (95% CI) were: for time to withdrawal of allocated treatment 1.16 (0.98 to 1.38); time to first seizure 1.11 (0.96 to 1.29); and time to 6-month remission 0.88 (0.76 to 1.01). There were no statistically significant differences between the drugs. A statistically significant advantage for carbamazepine was shown for time to 12-month remission: 0.84 (0.71 to 1.00).The results of this review are applicable mainly to individuals with partial-onset seizures; 85% of included individuals experienced seizures of this type at baseline. For individuals with partial-onset seizures, a statistically significant advantage for carbamazepine was shown for time to withdrawal of allocated treatment (HR 1.20, 95% CI 1.00 to 1.45) and time to 12-month remission (HR 0.84, 95% CI 0.71 to 1.00). No statistically significant differences were apparent between the drugs for other outcomes and for the limited number of individuals with generalised-onset tonic-clonic seizures with or without other generalised seizure types or unclassified seizures.The most commonly reported adverse events with both drugs were drowsiness or fatigue, 'pins and needles' (tingling sensation), headache, gastrointestinal disturbance and anxiety or depression The rate of adverse events was similar across the two drugs.We judged the methodological quality of the included trials generally to be good; however, there was some evidence that the open-label design of the larger of the two trials may have influenced the withdrawal rate from the trial. Hence, we judged the evidence for the primary outcome of treatment withdrawal to be moderate for individuals with partial-onset seizures and low for individuals with generalised-onset seizures. For efficacy outcomes (first seizure, remission), we judged the evidence from this review to be high for individuals with partial-onset seizures and moderate for individuals with generalised-onset or unclassified seizures. AUTHORS' CONCLUSIONS: For individuals with partial-onset seizures, there is evidence that carbamazepine is less likely to be withdrawn and that 12-month remission will be achieved earlier than with topiramate. No differences were found between the drugs in terms of the outcomes measured in the review for individuals with generalised tonic-clonic seizures with or without other seizure types or unclassified epilepsy; however, we encourage caution in the interpretation of these results due to the small numbers of participants with these seizure types.We recommend that future trials should be designed to the highest quality possible and take into consideration masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.

Individual participant data meta-analyses compared with meta-analyses based on aggregate data.

BACKGROUND: Meta-analyses based on individual participant data (IPD-MAs) allow more powerful and uniformly consistent analyses as well as better characterisation of subgroups and outcomes, compared to those which are based on aggregate data (AD-MAs) extracted from published trial reports. However, IPD-MAs are a larger undertaking requiring greater resources than AD-MAs. Researchers have compared results from IPD-MA against results obtained from AD-MA and reported conflicting findings. We present a methodology review to summarise this empirical evidence . OBJECTIVES: To review systematically empirical comparisons of meta-analyses of randomised trials based on IPD with those based on AD extracted from published reports, to evaluate the level of agreement between IPD-MA and AD-MA and whether agreement is affected by differences in type of effect measure, trials and participants included within the IPD-MA and AD-MA, and whether analyses were undertaken to explore the main effect of treatment or a treatment effect modifier. SEARCH METHODS: An electronic search of the Cochrane Library (includes Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, CENTRAL, Cochrane Methodology Register, HTA database, NHS Economic Evaluations Database), MEDLINE, and Embase was undertaken up to 7 January 2016. Potentially relevant articles that were known to any of the review authors and reference lists of retrieved articles were also checked. SELECTION CRITERIA: Studies reporting an empirical comparison of the results of meta-analyses of randomised trials using IPD with those using AD. Studies were included if sufficient numerical data, comparing IPD-MA and AD-MA, were available in their reports. DATA COLLECTION AND ANALYSIS: Two review authors screened the title and abstract of identified studies with full-text publications retrieved for those identified as eligible or potentially eligible. A 'quality' assessment was done and data were extracted independently by two review authors with disagreements resolved by involving a third author. Data were summarised descriptively for comparisons where an estimate of effect measure and corresponding precision have been provided both for IPD-MA and for AD-MA in the study report. Comparisons have been classified according to whether identical effect measures, identical trials and patients had been used in the IPD-MA and the AD-MA, and whether the analyses were undertaken to explore the main effect of treatment, or to explore a potential treatment effect modifier.Effect measures were transformed to a standardised scale (z scores) and scatter plots generated to allow visual comparisons. For each comparison, we compared the statistical significance (at the 5% two-sided level) of an IPD-MA compared to the corresponding AD-MA and calculated the number of discrepancies. We examined discrepancies by type of analysis (main effect or modifier) and according to whether identical trials, patients and effect measures had been used by the IPD-MA and AD-MA. We calculated the average of differences between IPD-MA and AD-MA (z scores, ratio effect estimates and standard errors (of ratio effects)) and 95% limits of agreement. MAIN RESULTS: From the 9330 reports found by our searches, 39 studies were eligible for this review with effect estimate and measure of precision extracted for 190 comparisons of IPD-MA and AD-MA. We classified the quality of studies as 'no important flaws' (29 (74%) studies) or 'possibly important flaws' (10 (26%) studies).A median of 4 (interquartile range (IQR): 2 to 6) comparisons were made per study, with 6 (IQR 4 to 11) trials and 1225 (542 to 2641) participants in IPD-MAs and 7 (4 to 11) and 1225 (705 to 2541) for the AD-MAs. One hundred and forty-four (76%) comparisons were made on the main treatment effect meta-analysis and 46 (24%) made using results from analyses to explore treatment effect modifiers.There is agreement in statistical significance between the IPD-MA and AD-MA for 152 (80%) comparisons, 23 of which disagreed in direction of effect. There is disagreement in statistical significance for 38 (20%) comparisons with an excess proportion of IPD-MA detecting a statistically significant result that was not confirmed with AD-MA (28 (15%)), compared with 10 (5%) comparisons with a statistically significant AD-MA that was not confirmed by IPD-MA. This pattern of disagreement is consistent for the 144 main effect analyses but not for the 46 comparisons of treatment effect modifier analyses. Conclusions from some IPD-MA and AD-MA differed even when based on identical trials, participants (but not necessarily identical follow-up) and treatment effect measures. The average difference between IPD-MA and AD-MA in z scores, ratio effect estimates and standard errors is small but limits of agreement are wide and include important differences in both directions. Discrepancies between IPD-MA and AD-MA do not appear to increase as the differences between trials and participants increase. AUTHORS' CONCLUSIONS: IPD offers the potential to explore additional, more thorough, and potentially more appropriate analyses compared to those possible with AD. But in many cases, similar results and conclusions can be drawn from IPD-MA and AD-MA. Therefore, before embarking on a resource-intensive IPD-MA, an AD-MA should initially be explored and researchers should carefully consider the potential added benefits of IPD.

Inhaled mannitol for cystic fibrosis.

BACKGROUND: Several agents are used to clear secretions from the airways of people with cystic fibrosis. Inhaled dry powder mannitol is now available in Australia and some countries in Europe. The exact mechanism of action of mannitol is unknown, but it increases mucociliary clearance. Phase III trials of inhaled dry powder mannitol for the treatment of cystic fibrosis have been completed. The dry powder formulation of mannitol may be more convenient and easier to use compared with established agents which require delivery via a nebuliser. OBJECTIVES: To assess whether inhaled dry powder mannitol is well tolerated, whether it improves the quality of life and respiratory function in people with cystic fibrosis and which adverse events are associated with the treatment. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic databases, handsearching relevant journals and abstracts from conferences.Date of last search: 16 April 2015. SELECTION CRITERIA: All randomised controlled studies comparing mannitol with placebo, active inhaled comparators (for example, hypertonic saline or dornase alfa) or with no treatment. DATA COLLECTION AND ANALYSIS: Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias in included studies. MAIN RESULTS: The searches identified nine separate studies (45 publications), of which four studies (36 publications) were included with a total of 667 participants, one study (only available as an abstract) is awaiting assessment and two studies are ongoing. Duration of treatment in the included studies ranged from two weeks to six months with open-label treatment for an additional six months in two of the studies. Three studies compared mannitol with control (a very low dose of mannitol or non-respirable mannitol); two of these were parallel studies with a similar design and data could be pooled, where data for a particular outcome and time point were available; also, one short-term cross-over study supplied additional results. The fourth study compared mannitol to dornase alfa alone and to mannitol plus dornase alfa. There was generally a low risk of bias in relation to randomisation and blinding; evidence from the parallel studies was judged to be of low to moderate quality and from the cross-over studies was judged to be of low to very low quality. While the published papers did not provide all the data required for our analysis, additional unpublished data were provided by the drug's manufacturer and the author of one of the studies. There was an initial test to see if participants tolerated mannitol, with only those who could tolerate the drug being randomised to the studies; therefore the study results are not applicable to the cystic fibrosis population as a whole.For the comparison of mannitol and control, we found no consistent differences in health-related quality of life in any of the domains, except for burden of treatment, which was less for mannitol up to four months in the two pooled studies of a similar design; this difference was not maintained at six months. Up to and including six months, lung function in terms of forced expiratory volume at one second (millilitres) and per cent predicted were significantly improved in all three studies comparing mannitol to control. Beneficial results were observed in these studies in adults and in both concomitant dornase alfa users and non users. A significant reduction was shown in the incidence of pulmonary exacerbations in favour of mannitol at six months; however, the estimate of this effect was imprecise so it is unclear whether the effect is clinically meaningful. Cough, haemoptysis, bronchospasm, pharyngolaryngeal pain and post-tussive vomiting were the most commonly reported side effects on both treatments. Mannitol was not associated with any increase in isolation of bacteria over a six-month period.In the 12-week cross-over study (28 participants), no significant differences were found in the recorded domains of health-related quality of life or measures of lung function between mannitol versus dornase alfa alone and versus mannitol plus dornase alfa. There seemed to be a higher rate of pulmonary exacerbations in the mannitol plus dornase alfa arm compared with dornase alfa alone; although not statistically significant, this was the most common reason for stopping treatment in this arm. Cough was the most common side effect in the mannitol alone arm but there was no occurrence of cough in the dornase alfa alone arm and the most commonly reported reason of withdrawal from the mannitol plus dornase alfa arm was pulmonary exacerbations. Mannitol (with or without dornase alfa) was not associated with any increase in isolation of bacteria over the 12-week period. AUTHORS' CONCLUSIONS: There is evidence to show that treatment with mannitol over a six-month period is associated with an improvement in some measures of lung function in people with cystic fibrosis compared to control. There is no evidence that quality of life is improved for participants taking mannitol compared to control; a decrease in burden of treatment was observed up to four months on mannitol compared to control but this difference was not maintained to six months. Randomised information regarding the burden of adding mannitol to an existing treatment is limited. There is no randomised evidence of improvement in lung function or quality of life comparing mannitol to dornase alfa alone and to mannitol plus dornase alfa.Mannitol as a single or concomitant treatment to dornase alfa may be of benefit to people with cystic fibrosis, but further research is required in order to establish who may benefit most and whether this benefit is sustained in the longer term.The clinical implications from this review suggest that mannitol could be considered as a treatment in cystic fibrosis; however, studies comparing its efficacy against other (established) mucolytic therapies need to be undertaken before it can be considered for mainstream practice.

Physical exercise training for cystic fibrosis.

BACKGROUND: Physical exercise training may form an important part of regular care for people with cystic fibrosis. This is an update of previously published reviews. OBJECTIVES: To determine the effects of physical exercise training compared to no training on aerobic exercise capacity, forced expiratory volume in one second, health-related quality of life and other patient-relevant (secondary) outcomes in cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search: 10 March 2015. SELECTION CRITERIA: All randomised and quasi-randomised controlled clinical trials comparing exercise training of any type and duration with conventional care in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion, assessed methodological quality and extracted data. MAIN RESULTS: Of the 48 studies identified, 13 studies which included 402 participants, met the inclusion criteria. The numbers in each study ranged from nine up to 72 participants; one study was in adults, six were in children and adolescents and six studies included all age ranges. Four studies of hospitalised participants lasted less than one month and nine studies were outpatient-based, lasting between two months and three years. The studies included participants with a wide range of disease severity and employed differing levels of supervision with a mixture of types of training. There was also wide variation in the quality of the included studies.This systematic review shows limited evidence from both short- and long-term studies that in people with cystic fibrosis aerobic or anaerobic physical exercise training or a combination of both has a positive effect on aerobic exercise capacity, pulmonary function and health-related quality of life. Although improvements are not consistent between studies and ranged from no effects to clearly positive effects, the most consistent effects of the heterogeneous exercise training modalities and durations were found for maximal aerobic exercise capacity (in four out of six studies) with unclear effects on FEV1 (in two out of 10 studies) and health-related quality of life (in two out of five studies). AUTHORS' CONCLUSIONS: Evidence about the efficacy of physical exercise training in cystic fibrosis from 13 small studies with low to moderate methodological quality is limited. Exercise training is already part of regular outpatient care offered to most people with cystic fibrosis, and since there is some evidence for beneficial effects on aerobic fitness and no negative side effects exist, there is no reason to actively discourage this. The benefits from including physical exercise training in an individual's regular care may be influenced by the type and duration of the training programme. High quality randomised controlled trials are needed to comprehensively assess the benefits of exercise programmes in people with cystic fibrosis and the relative benefits of the addition of aerobic versus anaerobic versus a combination of both types of physical exercise training to the care of people with cystic fibrosis.

Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 2, 2002 and its subsequent update in 2010.Epilepsy is a common neurological condition in which recurrent, unprovoked seizures are caused by abnormal electrical discharges from the brain. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenytoin are commonly used broad spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first line treatment for partial onset seizures in the USA and Europe. Phenytoin is no longer considered a first line treatment due to concerns over adverse events associated with its use, however the drug is still commonly used in low- to middle-income countries due to it's low cost. No consistent differences in efficacy have been found between carbamazepine and phenytoin in individual trials, however the confidence intervals generated by these studies are wide. Therefore, differences in efficacy may be shown by synthesising the data of the individual trials. OBJECTIVES: To review the time to withdrawal, six- and 12-month remission, and first seizure of carbamazepine compared to phenytoin when used as monotherapy in people with partial onset seizures (simple partial, complex partial, or secondarily generalised tonic-clonic seizures) or generalised tonic-clonic seizures, with or without other generalised seizure types. SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialised Register (16 September 2014), the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 8), MEDLINE (1946 to 16 September 2014), SCOPUS (1823 to 16 September 2014), ClinicalTrials.gov (16 September 2014), and the World Health Organization (WHO) International Clinical Trials Registry Platform ICTRP (18 September 2014). We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of carbamazepine monotherapy versus phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was time to withdrawal of allocated treatment, and our secondary outcomes were time to 12-month remission, time to six-month remission and time to first seizure post-randomisation. We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) and the generic inverse variance method to obtain the overall pooled HR and 95% CI. MAIN RESULTS: IPD were available for 595 participants out of 1192 eligible individuals, from four out of 12 trials (i.e. 50% of the potential data). For remission outcomes, HR > 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes, HR > 1 indicates an advantage for carbamazepine. Methodological quality of the four studies providing IPD was generally good and we rated it at low risk of bias overall in the analyses.The main overall results (pooled HR adjusted for seizure type) were time to withdrawal of allocated treatment: 1.04 (95% CI 0.78 to 1.39); time to 12-month remission: 1.01 (95% CI 0.78 to 1.31); time to six-month remission: 1.11 (95% CI 0.81 to 1.37); and time to first seizure: 0.85 (95% CI 0.70 to 1.04). The results suggest no overall statistically significant difference between the drugs for these outcomes. There is some evidence of an advantage for phenytoin for individuals with generalised onset seizures for our primary outcome (time to withdrawal of allocated treatment): pooled HR 0.42 (95% CI 0.18 to 0.96); and a statistical interaction between treatment effect and epilepsy type (partial versus generalised) for this outcome (P = 0.02), however misclassification of seizure type for up to 48 individuals (32% of those with generalised epilepsy) may have confounded the results of this review. Despite concerns over side effects leading to the withdrawal of phenytoin as first line treatment in the USA and Europe, we found no evidence that phenytoin is more likely to be associated with serious side effects than carbamazepine; 26 individuals withdrew from 290 randomised (9%) to carbamazepine due to adverse effects compared to 12 out of 299 (4%) randomised to phenytoin from four studies conducted in the USA and Europe (risk ratio (RR) 1.42, 95% CI 1.13 to 1.80, P = 0.014). We rated the quality of the evidence as low - moderate according to GRADE criteria, due to imprecision and potential misclassification of seizure type. AUTHORS' CONCLUSIONS: We have not found evidence that a statistically significant difference exists between carbamazepine and phenytoin for the efficacy outcomes examined in this review, however, CIs are wide and the possibility of important differences existing has not been excluded. There is no evidence in this review that phenytoin is more strongly associated with serious adverse events than carbamazepine. There is some evidence that participants with generalised seizures may be less likely to withdraw early from phenytoin than carbamazepine, but misclassification of seizure type may have impacted upon the results of this review. We recommend caution when interpreting the results of this review, and do not recommend that the results of this review alone should be used in choosing between carbamazepine and phenytoin. We recommend that future trials should be designed to the highest quality possible with considerations on allocation concealment and masking, choice of population, choice of outcomes and analysis, and presentation of results.

Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 1, 2003, of the Cochrane Database of Systematic Reviews.Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug (AED) in monotherapy.Worldwide, carbamazepine (CBZ) and phenobarbitone (PB) are commonly used broad-spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for partial onset seizures in the USA and Europe. Phenobarbitone is no longer considered a first-line treatment because of concerns over associated adverse events, particularly documented behavioural adverse events in children treated with the drug. However, PB is still commonly used in low- and middle-income countries because of its low cost. No consistent differences in efficacy have been found between CBZ and PB in individual trials; however, the confidence intervals generated by these studies are wide, and therefore, synthesising the data of the individual trials may show differences in efficacy. OBJECTIVES: To review the time to withdrawal, remission, and first seizure of CBZ compared with PB when used as monotherapy in people with partial onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types). SEARCH METHODS: We searched the following databases up to September 2014: the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2014, Issue 8), MEDLINE (from 1946), Scopus (from 1823), the US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov), and the World Health Organization International Clinical Trials Registry platform (WHO ICTRP). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. SELECTION CRITERIA: Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of CBZ monotherapy versus PB monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was 'Time to withdrawal of allocated treatment', and our secondary outcomes were 'Time to 12-month remission', 'Time to 6-month remission', and 'Time to first seizure postrandomisation'. We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), with the generic inverse variance method used to obtain the overall pooled HR and 95% CI. MAIN RESULTS: Individual participant data were available for 836 participants out of 1455 eligible individuals from 6 out of 13 trials, 57% of the potential data. For remission outcomes, HR > 1 indicated an advantage for PB, and for first seizure and withdrawal outcomes, HR > 1 indicated an advantage for CBZ.The main overall results (pooled HR adjusted for seizure type, 95% CI) were HR 1.50 for time to withdrawal of allocated treatment (95% CI 1.15 to 1.95, P = 0.003); HR 0.93 for time to 12-month remission (95% CI 0.72 to 1.20, P = 0.57); HR 0.99 for time to 6-month remission (95% CI 0.80 to 1.23, P = 0.95); and HR 0.87 for time to first seizure (95% CI 0.72 to 1.06, P = 0.18). Results suggest an advantage for CBZ over PB in terms of time to treatment withdrawal and no statistically significant evidence between the drugs for the other outcomes. We found evidence of a statistically significant interaction between treatment effect and seizure type for time to first seizure recurrence (Chi² test for subgroup differences P = 0.03), where PB was favoured for partial onset seizures (HR 0.76, 95% CI 0.60 to 0.96, P = 0.02) and CBZ was favoured for generalised onset seizures (HR 1.23, 95% CI 0.88 to 1.77, P = 0.27). However, methodological quality of the included studies was variable, with 10 out of the 13 included studies (4 out of 6 studies contributing IPD) judged as high risk of bias for at least 1 methodological aspect, leading to variable individual study results and therefore heterogeneity in the analyses of this review. We conducted sensitivity analyses to examine the impact of poor methodological aspects where possible. AUTHORS' CONCLUSIONS: Overall, we found evidence suggestive of an advantage for CBZ in terms of drug effectiveness compared with PB (retention of the drug in terms of seizure control and adverse events) and evidence of an association between treatment effect and seizure type for time to first seizure recurrence (PB favoured for partial seizures and CBZ favoured for generalised seizures). Given the varying quality of studies included in this review and the impact of poor methodological quality on individual study results (and therefore variability (heterogeneity) present in the analysis within this review), we recommend caution when interpreting the results of this review and do not recommend that the results of this review alone should be used in choosing between CBZ and PB. We recommend that future trials should be designed to the highest quality possible with considerations for allocation concealment and masking, choice of population, choice of outcomes and analysis, and presentation of results.

Early versus late antiepileptic drug withdrawal for people with epilepsy in remission.

BACKGROUND: Epilepsy is a chronic neurological disorder which affects millions of people around the world. Antiepileptic drugs (AED) are the main interventions used to prevent seizures and control epilepsy. Although effective in most cases, AEDs are related to long-term adverse effects, such as cognitive and behavioural alterations. Thus when epilepsy is in remission, it may be in the individual's best interest to discontinue medication. However, the optimal timing of AED discontinuation is still unknown.This is an updated version of the original Cochrane review published in Issue 3, 2001. OBJECTIVES: (1) To quantify and compare risk of seizure recurrence, status epilepticus and mortality after early and late AED discontinuation in adult and pediatric epilepsy patients.(2) To assess which variables modify the risk of seizure recurrence.(3) To define a subpopulation in which early AED discontinuation is safe. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (June 2014); CENTRAL (Issue 5, The Cochrane Library, May 2014); MEDLINE (1946 to June 2014); CINAHL (23 June 2014); Scopus (1823 to June 2014); ClinicalTrials.gov (23 June 2014); and WHO International Clinical Trials Registry Platform (23 June 2014). We also checked the reference lists of studies found through the electronic searches. SELECTION CRITERIA: Randomised controlled trials that evaluate withdrawal of AEDs after varying periods of seizure remission in adults and children with epilepsy. Included studies compared an early AED discontinuation time (defined as a period of remission of seizures of less than two years) versus a late AED discontinuation time (defined as a period of remission of seizures of more than two years). DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed trial quality. Risk ratio (RR) with 95% confidence interval (CI) was calculated for each trial. Summary RRs and 95% CIs for dichotomous data were calculated using a fixed-effect model. A test of statistical heterogeneity was conducted for each pooled risk ratio calculation. Each included study underwent a 'Risk of bias' assessment, based on the Cochrane Handbook recommendations, and we examined the overall quality of information through the GRADE system, presented in two 'Summary of Findings' tables. MAIN RESULTS: Five trials were included in this review, representing 924 randomised children with epilepsy, all under 16 years of age at randomisation, with a median follow-up of 5.6 years. No eligible trial evaluated adults or assessed mortality or status epilepticus as outcomes. The pooled risk ratio for seizure relapse after AED withdrawal was 1.34 (95% CI 1.13 to 1.59, P = 0.0007). Conforming to this estimate, the number needed to harm, that is expose an individual to a higher risk of seizure relapse because of early withdrawal of AED, is 8 (95% CI 5 to 20). Early discontinuation was associated with greater relapse rates in people with partial seizures with a pooled risk ratio of 1.51 (95% CI 0.97 to 2.35, P = 0.07). Absence type epilepsy showed a lower risk of relapse. Variables associated with higher risk of seizure relapse were abnormal EEG findings (pooled RR 1.44, 95% CI 1.13 to 1.83, P = 0.003), especially epileptiform activity (RR 2.58, 95% CI 2.03 to 3.28, P < 0.0001); epilepsy onset before 2 years or after 10 years of age; history of status epilepticus; intellectual disability (IQ < 70); and high seizure frequency before and during treatment. Gender and family history did not show any significant influence over seizure relapse. Overall, the included trials were classified as low or unclear risk of bias where methodological information was not reported and could not be provided by original study authors. AUTHORS' CONCLUSIONS: There is evidence to support waiting for at least two seizure-free years before discontinuing AEDs in children, particularly if individuals have an abnormal EEG or partial seizures, or both. There is insufficient evidence to establish when to withdraw AEDs in children with generalised seizures. There is no evidence to guide the timing of withdrawal of AEDs in seizure-free adults. Further high-quality randomised controlled trials are needed, particularly recruiting adults and recruiting those with generalised seizure types, to identify the optimal timing of AED withdrawal and risk factors predictive of relapse.

Surgery for epilepsy.

BACKGROUND: Focal epilepsies are caused by a malfunction of nerve cells localised in one part of one cerebral hemisphere. In studies, estimates of the number of individuals with focal epilepsy who do not become seizure-free despite optimal drug therapy vary according to the age of the participants and which focal epilepsies are included, but have been reported as at least 20% and in some studies up to 70%. If the epileptogenic zone can be located surgical resection offers the chance of a cure with a corresponding increase in quality of life. OBJECTIVES: The primary objective is to assess the overall outcome of epilepsy surgery according to evidence from randomised controlled trials.The secondary objectives are to assess the overall outcome of epilepsy surgery according to non-randomised evidence and to identify the factors that correlate to remission of seizures postoperatively. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (June 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 6), MEDLINE (Ovid) (2001 to 4 July 2013), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for relevant trials up to 4 July 2013. SELECTION CRITERIA: Eligible studies were randomised controlled trials (RCTs), cohort studies or case series, with either a prospective and/or retrospective design, including at least 30 participants, a well-defined population (age, sex, seizure type/frequency, duration of epilepsy, aetiology, magnetic resonance imaging (MRI) diagnosis, surgical findings), an MRI performed in at least 90% of cases and an expected duration of follow-up of at least one year, and reporting an outcome relating to postoperative seizure control. DATA COLLECTION AND ANALYSIS: Three groups of two review authors independently screened all references for eligibility, assessed study quality and risk of bias, and extracted data. Outcomes were proportion of participants achieving a good outcome according to the presence or absence of each prognostic factor of interest. We intended to combine data with risk ratios (RR) and 95% confidence intervals. MAIN RESULTS: We identified 177 studies (16,253 participants) investigating the outcome of surgery for epilepsy. Four studies were RCTs (including one that randomised participants to surgery or medical treatment). The risk of bias in the RCTs was unclear or high, limiting our confidence in the evidence that addressed the primary review objective. Most of the remaining 173 non-randomised studies had a retrospective design; they were of variable size, were conducted in a range of countries, recruited a wide demographic range of participants, used a wide range of surgical techniques and used different scales used to measure outcomes. We performed quality assessment using the Effective Public Health Practice Project (EPHPP) tool and determined that most studies provided moderate or weak evidence. For 29 studies reporting multivariate analyses we used the Quality in Prognostic Studies (QUIPS) tool and determined that very few studies were at low risk of bias across the domains.In terms of freedom from seizures, one RCT found surgery to be superior to medical treatment, two RCTs found no statistically significant difference between anterior temporal lobectomy (ATL) with or without corpus callosotomy or between 2.5 cm or 3.5 cm ATL resection, and one RCT found total hippocampectomy to be superior to partial hippocampectomy. We judged the evidence from the four RCTs to be of moderate to very low quality due to the lack of information reported about the randomised trial design and the restricted study populations.Of the 16,253 participants included in this review, 10,518 (65%) achieved a good outcome from surgery; this ranged across studies from 13.5% to 92.5%. Overall, we found the quality of data in relation to the recording of adverse events to be very poor.In total, 118 studies examined between one and eight prognostic factors in univariate analysis. We found the following prognostic factors to be associated with a better post-surgical seizure outcome: an abnormal pre-operative MRI, no use of intracranial monitoring, complete surgical resection, presence of mesial temporal sclerosis, concordance of pre-operative MRI and electroencephalography (EEG), history of febrile seizures, absence of focal cortical dysplasia/malformation of cortical development, presence of tumour, right-sided resection and presence of unilateral interictal spikes. We found no evidence that history of head injury, presence of encephalomalacia, presence of vascular malformation or presence of postoperative discharges were prognostic factors of outcome. We observed variability between studies for many of our analyses, likely due to the small study sizes with unbalanced group sizes, variation in the definition of seizure outcome, definition of the prognostic factor and the influence of the site of surgery, all of which we observed to be related to postoperative seizure outcome. Twenty-nine studies reported multivariable models of prognostic factors and the direction of association of factors with outcome was generally the same as found in the univariate analyses. However, due to the different multivariable analysis approaches and selective reporting of results, meaningful comparison of multivariate analysis with univariate meta-analysis is difficult. AUTHORS' CONCLUSIONS: The study design issues and limited information presented in the included studies mean that our results provide limited evidence to aid patient selection for surgery and prediction of likely surgical outcome. Future research should be of high quality, have a prospective design, be appropriately powered and focus on specific issues related to diagnostic tools, the site-specific surgical approach and other issues such as the extent of resection. Prognostic factors related to the outcome of surgery should be investigated via multivariable statistical regression modelling, where variables are selected for modelling according to clinical relevance and all numerical results of the prognostic models are fully reported. Protocols should include pre- and postoperative measures of speech and language function, cognition and social functioning along with a mental state assessment. Journal editors should not accept papers where adverse events from a medical intervention are not recorded. Improvements in the development of cancer care over the past three to four decades have been achieved by answering well-defined questions through the conduct of focused RCTs in a step-wise fashion. The same approach to surgery for epilepsy is required.

The role of high-frequency oscillations in epilepsy surgery planning.

BACKGROUND: Epilepsy is a serious brain disorder characterized by recurrent unprovoked seizures. Approximately two-thirds of seizures can be controlled with antiepileptic medications (Kwan 2000). For some of the others, surgery can completely eliminate or significantly reduce the occurrence of disabling seizures. Localization of epileptogenic areas for resective surgery is far from perfect, and new tools are being investigated to more accurately localize the epileptogenic zone (the zone of the brain where the seizures begin) and improve the likelihood of freedom from postsurgical seizures. Recordings of pathological high-frequency oscillations (HFOs) may be one such tool. OBJECTIVES: To assess the ability of HFOs to improve the outcomes of epilepsy surgery by helping to identify more accurately the epileptogenic areas of the brain. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (15 April 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 3), MEDLINE (Ovid) (1946 to 15 April 2013), CINAHL (EBSCOhost) (15 April 2013), Web of Knowledge (Thomson Reuters) (15 April 2013), www.clinicaltrials.gov (15 April 2013), and the World Health Organization International Clinical Trials Registry Platform (15 April 2013). SELECTION CRITERIA: We included studies that provided information on the outcomes of epilepsy surgery at at least six months and which used high-frequency oscillations in making decisions about epilepsy surgery. DATA COLLECTION AND ANALYSIS: The primary outcome of the review was the Engel Class Outcome System. Secondary outcomes were responder rate, International League Against Epilepsy (ILAE) epilepsy surgery outcome, frequency of adverse events from any source and quality of life outcomes. We intended to analyse outcomes via an aggregated data fixed-effect model meta-analysis. MAIN RESULTS: Two studies met the inclusion criteria. Both studies were small non-randomised trials, with no control group and no blinding. The quality of evidence for all outcomes was very low. The combination of these two studies resulted in 11 participants who prospectively used ictal HFOs for epilepsy surgery decision making. Results of the postsurgical seizure freedom Engel class I to IV outcome were determined over a period of 12 to 38 months (average 23.4 months) and indicated that six participants had an Engel class I outcome (seizure freedom), two had class II (rare disabling seizures), three had class III (worthwhile improvement). No adverse effects were reported. Neither study compared surgical results guided by HFOs versus surgical results guided without HFOs. AUTHORS' CONCLUSIONS: No reliable conclusions can be drawn regarding the efficacy of using HFOs in epilepsy surgery decision making at present.

Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalised onset tonic-clonic seizures.

BACKGROUND: This is an updated version of the original Cochrane review published in The Cochrane Library 2001, Issue 4.Worldwide, particularly in the developing world, phenytoin and phenobarbitone are commonly used antiepileptic drugs, primarily because they are inexpensive. The aim of this review is to summarise data from existing trials comparing phenytoin and phenobarbitone. OBJECTIVES: To review the best evidence comparing phenobarbitone and phenytoin when used as monotherapy in participants with partial onset seizures or generalised tonic-clonic seizures with or without other generalised seizure types. SEARCH METHODS: We searched the Cochrane Epilepsy Group trials register (31 May 2012), the Cochrane Central Register of Controlled Trials (CENTRAL Issue 5 of 12, The Cochrane Library 2012) and MEDLINE (1946 to May week 4, 2012). We hand-searched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field.   SELECTION CRITERIA: Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of phenobarbitone monotherapy with phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Outcomes were time to (a) treatment withdrawal (b) 12-month remission (c) six-month remission and (d) first seizure post randomisation. Cox proportional hazards regression models were used to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) with the generic inverse variance method used to obtain the overall pooled estimate of HRs and 95% CIs. MAIN RESULTS: Data have been obtained for four of eight studies meeting the inclusion criteria, amounting to 599 individuals, or approximately 63% of the potential data.The main overall results (pooled HR, 95% CI) were (a) time to treatment withdrawal 1.62 (1.23 to 2.14); (b) time to 12-month remission 0.90 (0.69 to 1.18) (c) time to six-month remission 0.92 (0.73 to 1.16) and (d) time to first seizure 0.85 (0.68 to 1.05). These results indicate a statistically significant clinical advantage for phenytoin in terms of treatment withdrawal. However, this result may have been confounded by several factors including substantial statistical heterogeneity between studies and lack of blinding in two studies. AUTHORS' CONCLUSIONS: The results of this review show that phenobarbitone was significantly more likely to be withdrawn than phenytoin. Given that no significant differences for seizure outcomes were found, the higher withdrawal rate with phenobarbitone may be due to adverse effects. Several factors may have confounded the results of this review.  

Oxcarbazepine versus phenytoin monotherapy for epilepsy.

BACKGROUND: This is an updated version of the original Cochrane review published in The Cochrane Library 2006, Issue 2.Worldwide, phenytoin is a commonly used antiepileptic drug. For the newer drugs such as oxcarbazepine, it is important to know how they compare with standard treatments. OBJECTIVES: To review the best evidence comparing oxcarbazepine and phenytoin when used as monotherapy in participants with partial onset seizures or generalised tonic-clonic seizures with or without other generalised seizure types. SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialised Register (22 January 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 12) and MEDLINE (1946 to 22 January 2013). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators and experts in the field. SELECTION CRITERIA: Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of oxcarbazepine monotherapy with phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual participant data review. Outcomes were time to (a) treatment withdrawal (b) 12-month remission (c) six-month remission and (d) first seizure post randomisation. We used Cox proportional hazards models to obtain study-specific estimates of hazard ratios (HR) with 95% confidence intervals (CI) with the generic inverse variance method used to obtain the overall pooled HR and 95% CI. MAIN RESULTS: Individual participant data were available for 480 out of 517 participants (93%) from three included trials. For remission outcomes, a HR > 1 indicates an advantage to phenytoin and for first seizure and withdrawal outcomes a HR > 1 indicates an advantage to oxcarbazepine.The main overall results (pooled HR, 95% CI) were: (i) time to withdrawal of allocated treatment 1.65 (1.08 to 2.52), (ii) time to 12-month remission 0.92 (0.68 to 1.24), (iii) time to six-month remission 0.90 (0.70 to 1.15), (iv) time to first seizure 1.07 (0.83 to 1.39). Results indicate a statistically significant advantage for oxcarbazepine over phenytoin for time to treatment withdrawal, but insufficient evidence to suggest a difference between the drugs for other outcomes. By epilepsy type, there is no significant advantage for either drug for generalised epilepsy, however there is a significant advantage for partial epilepsy with oxcarbazepine for time to treatment withdrawal (HR 1.95; 95% CI 1.15 to 3.33). AUTHORS' CONCLUSIONS: For participants with partial onset seizures oxcarbazepine is significantly less likely to be withdrawn, but current data do not allow a statement as to whether oxcarbazepine is equivalent, superior or inferior to phenytoin in terms of seizure control. However, the design of the studies may have biased seizure outcomes and misclassification of epilepsy type may have biased withdrawal rates.

Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic-clonic seizures.

BACKGROUND: This is an updated version of the previously published Cochrane review (Issue 4, 2009)Worldwide, phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset seizures, and that valproate is more effective for generalised onset tonic-clonic seizures with or without other generalised seizure types. OBJECTIVES: To review the best evidence comparing phenytoin and valproate when used as monotherapy in individuals with partial onset seizures or generalised onset tonic-clonic seizures with or without other generalised seizure types. SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialised Register (19 February 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, The Cochrane Library, January 2013), MEDLINE (1946 to 18 February 2013), SCOPUS (19 February 2013), ClinicalTrials.gov (19 February 2013), and WHO International Clinical Trials Registry Platform ICTRP (19 February 2013). We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field. SELECTION CRITERIA: Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of valproate monotherapy versus phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Outcomes were time to (a) treatment withdrawal (b) 12-month remission (c) six-month remission and (d) first seizure post randomisation. Cox proportional hazards regression models were used to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) with the generic inverse variance method used to obtain the overall pooled HR and 95% CI. MAIN RESULTS: Individual patient data were available for 669 individuals out of 1119 eligible individuals from five out of 11 trials, 60% of the potential data. Results apply to generalised tonic-clonic seizures, but not absence or myoclonus seizure types. For remission outcomes, HR > 1 indicates an advantage for phenytoin and for first seizure and withdrawal outcomes HR > 1 indicates an advantage for valproateThe main overall results (pooled HR adjusted for seizure type, 95% CI) were time to (a) withdrawal of allocated treatment 1.09 (0.76 to 1.55); (b) 12-month remission 0.98 (0.78 to 1.23); (c) six-month remission 0.95 (0.78 to 1.15) and (d) first seizure 0.93 (0.75 to 1.14). The results suggest no overall difference between the drugs for these outcomes. No statistical interaction between treatment and seizure type (partial versus generalised) was found, but misclassification of seizure type may have confounded the results of this review. AUTHORS' CONCLUSIONS: We have not found evidence that a significant difference exists between phenytoin and valproate for the outcomes examined in this review. However misclassification of seizure type may have confounded the results of this review. Results do not apply to absence or myoclonus seizure types. No outright evidence was found to support or refute current treatment policies.