Comment

www.thelancet.com/infection Published online July 4, 2014 http://dx.doi.org/10.1016/S1473-3099(14)70829-1 1

Determining better treatments for neurocysticercosisNeurocysticercosis, caused by Taenia solium, is emerging as a major cause of neurological disease worldwide.1 Despite the availability of antiparasitic drugs for this infection for more than 35 years, the role of antiparasitic drugs in management remains controversial.2–4 In these 35 years, several controlled and uncontrolled trials have attempted to clarify the role of antiparasitic drugs in the management of neurocysticercosis; data from these trials were mostly confl icting. Most controversies were due to poorly collected and uncontrolled data. Strangely, the controversies revolved around to treat or not to rather than how to optimally treat? In 2004, Garcia and colleagues5 reported the results of a randomised placebo-controlled trial of albendazole (800 mg per day for 7 days) in viable parenchymal cysticercosis. At 6 months, nearly 35% of participants given albendazole were free of viable cysts compared with 13% of those given placebo. The results of the trial clearly showed the benefi ts of albendazole treatment in terms of cyst resolution. Even so, viable cysts persisted in nearly 65% of those given antiparasitic treatment with albendazole. When the total number of viable cysts persisting at 6 months were analysed, 41% of the cysts remained viable despite albendazole treatment, prompting the search for better treatment regimens with the available antiparasitic drugs.

Several options were considered to improve parasiticidal activity. lncreased duration of treatment with albendazole was considered, but was shown to not off er any advantage over the standard 7-day course, specifi cally in viable parenchymal cysticercosis.6 Other options were a repeat course of albendazole and use of increased doses of albendazole, which was reported to be associated with increased parasiticidal activity in one study.7 Finally, another option considered was combination anthelmintic treatment with albendazole and praziquantel given simultaneously. The theoretical premise for combination treatment was provided by the diff erent mechanisms of action of the two drugs. The combination had been tried previously in cystic echinococcosis and also parenchymal cysticercosis in small trials.8,9

ln this issue of The Lancet lnfectious Diseases, Garcia and colleagues10 report the results of a rigorously conducted randomised, active-comparator trial of combination

antiparasitic treatment. The three arms of the trial were standard albendazole dose (maximum 800 mg per day), increased albendazole dose (maximum 1200 mg per day), and combination albendazole and praziquantel (in standard doses). Combination antiparasitic treatment was associated with a signifi cantly increased proportion of participants with complete resolution (64% compared with 37% in standard albendazole group), showing a signifi cantly improved rate of parasite clearance. A previous study by the investigators11

assessed the pharmacokinetics of the combination regimen and reported increased serum albendazole concentrations raising the question of whether the improved resolution associated with combination treatment was due to the eff ects of combination or only increased albendazole effi cacy.

The report10 combined two diff erent study designs addressing two somewhat disparate issues: (1) a randomised controlled trial comparing the three diff erent regimens, and (2) a cohort design, which addressed the association between cyst resolution and seizure incidence. ln the randomised study, combination therapy was associated with more rapid resolution of lesions. ln the cohort study, resolution of infestation was signifi cantly associated with reduced seizure recurrence even after adjustment for treatment regimens.

These results resolve some questions but raise others. For example, does the choice of treatment (combined or enhanced albendazole treatment versus

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Comment

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standard albendazole treatment) have any eff ect on seizure recurrence? This study was not designed to assess the eff ect of treatment regimen on seizure incidence. From the theoretical standpoint, all stages of neurocysticercosis, whether viable, degenerating, or resolved calcifi ed might be associated with seizures.12

Hence, the improved rates of resolution reported in the Garcia and colleagues10 trial might not translate to improved seizure outcome because seizures might still occur in the resolved (calcifi ed) stage. Another question, what is the eff ect of the choice of regimen on the incidence of calcifi cation? Further analysis of the trial data with CT fi ndings at later timepoints should provide the answer to this question. Finally, will the improved parasite clearance rate be benefi cial in other severe forms of disease—eg, subarachnoid cysticercosis? This issue was not addressed in the study.

The ultimate goal of any intervention is to improve the clinical outcome by providing complete seizure freedom. Hence, although the study by Garcia and colleagues is a major advance towards the treatment of parenchymal cysticercosis, we still need to devise optimal strategies to improve the control of seizures in individuals with neurocysticercosis.

*Gagandeep Singh, Arthur Clinton White JrDepartment of Neurology, Dayanand Medical College, Ludhiana, 141001, Punjab, India (GS); and Infectious Diseases Division, Department of Medicine, University of Texas, Galveston, TX, USA (ACW Jr)gagandeep_si@yahoo.co.uk

We declare no competing interests.

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10 Garcia HH, Gonzales I, Lescano AG, and The Cysticercosis Working Group in Peru. Effi cacy of combined antiparasitic therapy with praziquantel and albendazole for neurocysticercosis: a double-blind, randomised controlled trial. Lancet Infect Dis 2014; published online July 4. http://dx.doi.org/10.1016/S1473-3099(14)70829-1

11 Garcia HH, Lescano AG, Lanchote VL, et al. Pharmacokinetics of combined treatment with praziquantel and albendazole in neurocysticercosis. Br J Clin Pharmacol 2011; 72: 77–84.

12 Singh G, Burneo JG, Sander JW. From seizures to epilepsy and its substrates: neurocysticercosis. Epilepsia 2013; 54: 783–92.