Reflection and Reaction

See Articles page 31 Carnaby and colleagues1 describe in this issue of TheLancet Neurology the results of their single centre, single-blind, randomised controlled trial of a standardbehavioural intervention for dysphagia after stroke as“encouraging”. I might even add the adjective exciting,because this trial has shown, for the first time, that anintervention can improve outcomes of patients withdysphagia. Dysphagia is more common in severe stroke,but is independently associated with poorer long-termoutcomes in mild-to-moderate stroke.2 This trialindicates that a behavioural intervention not onlyimproves recovery of swallowing, but also reduces thecomplications of dysphagia and improves long-termoutcomes. This finding lends support to the notion thatthe association between dysphagia and poor outcomesis, at least in part, causal. Because almost half of allpatients admitted to hospital with an acute strokeworldwide have dysphagia an effective treatment wouldbe applicable to millions of patients each year, andtherefore might have huge public-health benefits.However, before we get overly excited we must considerthe limitations of this study, some of which the authorsdescribe in their discussion.

There are several examples, even in the strokespecialty, of small, single-centre, randomised trialsreporting positive results that are then not confirmed bylarger multicentre trials. Two examples are theeffectiveness of percutaneous endoscopic gastrostomyfeeding after acute stroke3,4 and leisure therapy.5,6 Manysmall trials that yield overly optimistic results havemethodological failures that can introduce bias. Themost common problems are: failure to enrol enoughpatients to ensure that randomisation producestreatment groups with similar baseline characteristics;failure to use secure methods of randomisation thatprevent any foreknowledge of treatment allocation;failure to properly blind outcome assessments; failure tofollow up all patients and to include all patientsrandomised in the primary analyses; failure to stipulatein advance what the primary outcome is so that theanalysis becomes a data dredging operation, which islikely to produce false positive results; and failure toprespecify if any, or how many, interim analyses will beundertaken so that the trial is stopped simply when thechief investigator identifies a significant effect that they

think will make their trial acceptable to the editors ofjournals.

Carnaby and colleagues have avoided most, if not all,of these failures. They used a secure randomisationsystem to enrol a respectable number of patients whowere well described at baseline. They prespecified theirsample size, which they achieved, and prespecified theirprimary and secondary outcomes, which were assessedlargely blind to treatment allocation. They were rigorousin follow-up and accounted for all patients in theiranalysis. Moreover, they should be congratulated fordescribing their trial, their interventions, and theirresults in a way that would allow others to replicate theirwork.

We now need more precise estimates of theeffectiveness of the interventions and whether moreintensive, and thus presumably more expensive,behavioural interventions are more effective than lessintensive ones. We also need to determine whether thisbehavioural intervention, delivered by less specialist,skilful, or enthusiastic speech and language therapistsworking in many different environments, can achievesimilar improvements in clinically relevant outcomes.Determining whether videofluoroscopy is an essentialcomponent or whether it could be dispensed with orreplaced by other techniques, such as fibreopticendoscopic assessment of swallowing, would also beuseful.

To reliably answer these questions will need manyhundreds, or more likely thousands, of patients to berecruited into randomised trials. These patients mightbe enrolled in further single-centre trials, with similarmethods to those described by Carnaby and colleagues,which could then be summarised in an informativemeta-analysis. However, a family of large multicentretrials including a factorial design to address thequestions of videofluoroscopy or alternatives would bea better way forward. I am therefore frustrated andsomewhat disappointed that this trial has taken almost5 years to report its results. These are 5 wasted yearswhen further studies could have been planned, fundingidentified, and recruitment started. If we are to deliverbetter treatment to our patients we have to streamlineour research efforts, avoiding such delays in reportingencouraging results and establishing confirmatory

Dysphagia in acute stroke: a long-awaited trial

16 http://neurology.thelancet.com Vol 5 January 2006

Reflection and Reaction

See UK Clinical ResearchCollaboration home page:http://www.ukcrc.org/

See Articles page 46

http://neurology.thelancet.com Vol 5 January 2006 17

studies. Hopefully, initiatives such as the StrokeResearch Networks, funded through the UK ClinicalResearch Collaboration and Chief Scientist Office inScotland, which aim to provide infrastructure tofacilitate multicentre stroke trials, will help us to assesssuch promising interventions more quickly. Delays inintroducing thrombolytic therapy as a standardtreatment for myocardial infarction worldwide, whicharose from failures to summarise existing dataindicating its effectiveness and to carry out reallydefinitive trials earlier, have been estimated to havekilled thousands of patients.7 I hope that our delay inconfirming the effectiveness of a standard behaviouralintervention for stroke patients with dysphagia does notprove to be as costly.

Martin Dennis

Division of Clinical Neurosciences, University of Edinburgh,Western General Hospital, Edinburgh EH4 2XU, UKmartin.dennis@ed.ac.uk

I have no conflicts of interest.

1 Carnaby G, Hankey GJ, Pizzi J. Behavioural intervention for dysphagia inacute stroke: a randomised controlled trial. Lancet Neurol 2005; 5: 31–37.

2 Smithard DG, O’Neill PA, Park C, et al. Complications and outcome afteracute stroke: does dysphagia matter? Stroke 1996; 27: 1200–04.

3 Norton B, Homer-Ward M, Donnelly MT, Long RG, Holmes GKT.A randomised prospective comparison of percutaneous endoscopicgastrostomy and nasogastric tube feeding after acute dysphagic stroke.BMJ 1996; 312: 13–16.

4 FOOD Trial Collaboration. Effect of timing and method of enteral tubefeeding for dysphagic stroke patients (FOOD): a multicentre randomisedcontrolled trial. Lancet 2005; 365: 764–72.

5 Drummond A, Walker MF. A randomised controlled trial of leisure therapyafter stroke. Clin Rehab 1994; 9: 283–90.

6 Parker CJ, Gladman JR, Drummond AE, et al. A multicentre randomizedcontrolled trial of leisure therapy and conventional occupational therapyafter stroke: Trial of Occupational Therapy and Leisure. Clin Rehab 2001;15: 42–52.

7 Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mosteller F, Chalmers TC.Cumulative meta-analysis of therapeutic trials for myocardial infarction.New Engl J Med1992; 327: 248–54.

For at least 25 years, the use of phenobarbital hasdeclined substantially in developed nations because ofpersistent reports of adverse cognitive side-effects,especially hyperkinetic disorder and attention deficitdisorder in children. Nevertheless, driven by economicrealities that include costs per tablet up to ten times lessthan the cost of the next most affordableanticonvulsant, physicians in developing countries havecontinued to prescribe phenobarbital.1 The drug is alsorecommended as the first choice treatment for epilepsyin many national treatment guidelines from thesecountries—eg, in the essential drugs list of Zimbabwe,2000—and in the formulary of the World HealthOrganization.

Reliable evidence for the efficacy of phenobarbital inthe developing world setting has been notably lacking,and it is here that Wang and co-workers,2 in reportingthis issue on 1324 patients who completed (of 2455who began) 2 years of treatment with the drug, achieveimpressive results. The partnership of the BeijingNeurosurgical Institute and the Global Campaignagainst Epilepsy3 ensured rigorous assessment of thedata with careful inclusion criteria. Wang and colleaguesmade two separate points in their report. First, goodefficacy (26% of patients were seizure free and 72% hadmore than a 50% reduction in seizure frequency after24 months) and few adverse effects (27% of patients

had one of all adverse effectss between 19 and 24months, including minor gastrointestinal complaintsand headache) can be expected. Second, diagnosis andtreatment by primary-care physicians withoutadditional resources are sustainable.

This good news is clearly important for public-healthplanners in China. Coming hard on the heels of thefinding of a 63% treatment gap,4 and thus the probableexistence of more than five million untreated people

Phenobarbital for convulsive epilepsy at primary care level

Epilepsy imposes a large economic burden on health-care systems in rural China

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