Antihelminthic
Therapy for Neurocysticercosis
To the Editor.\p=m-\Soteloet al1,2 report clinical trials comparing albendazole with praziquantel as therapy for neurocysticercosis. In a trial of very similar design, Alarcon et al3 compared two dosing schedules of albendazole. These trials "randomly allocated" 251 or 232 subjects to one of three groups. The active drug treatment groups were of equal size in both trials, with 101 or nine2 subjects in each treatment group, and the control (no treatment) group had five subjects in each trial. The outcome variable evaluated was the change in cyst size as demonstrated by computed tomography. These reports are illustrative of the ills replicated in clinical trials touting various pharmacologic regimens in the treatment of neurocysticercosis. In these and other putatively seminal clinical trials in this disorder, several easily identified problems limit the utility of the data. The interpretation of these trials is particularly important, given the frequency with which neurocysticercosis is diagnosed and treated by physicians in the United States who are not inti¬ mately acquainted with the disease. These active control trials were unblinded and not placebo controlled; the control group had no treatment, not placebo. Thus the designs fail to pro¬ tect against potential bias in patient selection or evaluation of outcome. The treatment groups were small, almost certainly predisposing the treatment comparison to a no-difference outcome if statistical analysis had been per¬ formed. In addition, the outcome vari¬ able was the change in cyst size as demonstrated by computed tomogra¬ phy, but this was implied by the au¬ thors to correspond to a change in the clinical outcome of neurocysticercosis (clearly not the same thing). Com¬ pounding these problems, studies used as support for the efficacy of prazi¬ quantel are similarly flawed in that they were not blinded or randomized, had historical control groups or indi¬ viduals who served as their own con¬ trols, and regarded computed tomo-
graphie appearance as a change in clinical outcome.3 These untenable as¬ sumptions make the active control trial1 even more unreasonable as proof of efficacy. Recent data regarding the untreated (without antihelminthics) natural his¬ tory of neurocysticercosis indicate that all patients given enough time with acute neurocysticercosis, as indi¬ cated by cystic nonenhancing, nonedematous lesions, have an improve¬ ment in computed tomographic ap¬ pearance with either calcification or normalization of the computed tomo¬ graphic scan in time.4-5 Up to 55% of individual lesions may disappear.5 These same reports clearly indicate that in parenchymal lesions, clinical presentation usually
occurs
during
larval involution when the cyst be¬ comes edematous with ring enhance¬ ment on computed tomography and then proceeds toward normalization or calcification just as is noted with antihelminthic therapy. The authors1·2 have indicated that antihelminthics rapidly led to parasite death producing adverse experiences with clinical ex¬ acerbation during treatment and rapid increase in inflammatory reaction on computed tomographic scan. Taken in toto this may mean that an inevitable outcome without therapy, improve¬ ment in computed tomographic scan, is hastened at the expense of increased local scarring. Antihelminthic agents, although unproven in well-controlled, random¬ ized, double-blind clinical trials, may in fact hasten larval demise (I suspect they do). If so, then as the authors have suggested,13 an acute aggressive in¬ flammatory response following ther¬ apy may lead to a more profound cere¬ bral cicatrix than might occur if only palliative therapy was given. Patients with normalized computed tomo¬ graphic scans have been shown to be abnormal by magnetic resonance im¬ aging. Therefore, the outcome variable should be clinical outcome, not com¬ puted tomographic appearance. This requires a much larger population of properly randomized subjects, who are followed up for a long period of time. In
Downloaded From: http://archneur.jamanetwork.com/ by a University of Michigan User on 06/17/2015
addition, data5·6 indicate that the nat¬ ural history may be such that little if anything is gained by this therapy in the usual patient (one not in need of surgery). A clinical trial such as this should certainly be feasible and is nec¬ essary if these therapies are to be properly evaluated. Lynn D.
Kramer, MD
Wallace Laboratories Half Acre Road Cranbury, NJ 08512 1. Sotelo J, Escobedo F, Penagos P. Albendazole vs praziquantel for therapy for neurocysticercosis. Arch Neurol. 1988;45:532-534. 2. Sotelo J, Escobedo F, Rodriguez J, et al. Therapy of parenchymal brain cysticercosis with praziquantel. N Engl J Med. 1984;310:1001-1007. 3. Alarcon F, Escalante L, Duenas G, et al. Neurocysticercosis: short course of treatment with albendazole. Arch Neurol. 1989;46:1231-1236. 4. Kramer LD, Locke GE, Byrd SE, Darybagi J. Cerebral cysticercosis: documentation of natural history by CT. Radiology. 1989;171:459-462. 5. Mitchell WG, Crawford TO. Seizures in children with intraparenchymal cerebral cysticercosis. Epilepsia. 1987;28:627-628. 6. Locke GE, Kramer LD, Nelson L. The prognosis of epilepsy in patients with CT-documented
cysticercosis. Epilepsia. 1988;29:673.
In
Reply.\p=m-\Kramerdetects some ills replicated in trials for drug treatment of neurocysticercosis conducted by us1 and by others; each of these "ills" has been previously discussed by us,2,3 actually, we believe that some points that for Kramer are ills, for us are the strength of our trials: A different protocol of drug therapy has to be planned for every disease considering its peculiarities, there is not a universal recipe for all drug trials; in our trials we have chosen imaging studies for evaluation of therapeutic response precisely to avoid the subjective clinical evaluation so highly recommended by Kramer that is quite misleading in the case of neurocysticercosis due to its complex clinical picture that depends on several factors related to number, location, stage of lesions, and individual immunological factors4; double-blind, placebo-controlled trials are useful in studies where subjective evaluation of symptoms is to be made, evaluation of imaging studies that has been the rule in our studies is objective, fairly pre-
Therapy for Neurocysticercosis
To the Editor.\p=m-\Soteloet al1,2 report clinical trials comparing albendazole with praziquantel as therapy for neurocysticercosis. In a trial of very similar design, Alarcon et al3 compared two dosing schedules of albendazole. These trials "randomly allocated" 251 or 232 subjects to one of three groups. The active drug treatment groups were of equal size in both trials, with 101 or nine2 subjects in each treatment group, and the control (no treatment) group had five subjects in each trial. The outcome variable evaluated was the change in cyst size as demonstrated by computed tomography. These reports are illustrative of the ills replicated in clinical trials touting various pharmacologic regimens in the treatment of neurocysticercosis. In these and other putatively seminal clinical trials in this disorder, several easily identified problems limit the utility of the data. The interpretation of these trials is particularly important, given the frequency with which neurocysticercosis is diagnosed and treated by physicians in the United States who are not inti¬ mately acquainted with the disease. These active control trials were unblinded and not placebo controlled; the control group had no treatment, not placebo. Thus the designs fail to pro¬ tect against potential bias in patient selection or evaluation of outcome. The treatment groups were small, almost certainly predisposing the treatment comparison to a no-difference outcome if statistical analysis had been per¬ formed. In addition, the outcome vari¬ able was the change in cyst size as demonstrated by computed tomogra¬ phy, but this was implied by the au¬ thors to correspond to a change in the clinical outcome of neurocysticercosis (clearly not the same thing). Com¬ pounding these problems, studies used as support for the efficacy of prazi¬ quantel are similarly flawed in that they were not blinded or randomized, had historical control groups or indi¬ viduals who served as their own con¬ trols, and regarded computed tomo-
graphie appearance as a change in clinical outcome.3 These untenable as¬ sumptions make the active control trial1 even more unreasonable as proof of efficacy. Recent data regarding the untreated (without antihelminthics) natural his¬ tory of neurocysticercosis indicate that all patients given enough time with acute neurocysticercosis, as indi¬ cated by cystic nonenhancing, nonedematous lesions, have an improve¬ ment in computed tomographic ap¬ pearance with either calcification or normalization of the computed tomo¬ graphic scan in time.4-5 Up to 55% of individual lesions may disappear.5 These same reports clearly indicate that in parenchymal lesions, clinical presentation usually
occurs
during
larval involution when the cyst be¬ comes edematous with ring enhance¬ ment on computed tomography and then proceeds toward normalization or calcification just as is noted with antihelminthic therapy. The authors1·2 have indicated that antihelminthics rapidly led to parasite death producing adverse experiences with clinical ex¬ acerbation during treatment and rapid increase in inflammatory reaction on computed tomographic scan. Taken in toto this may mean that an inevitable outcome without therapy, improve¬ ment in computed tomographic scan, is hastened at the expense of increased local scarring. Antihelminthic agents, although unproven in well-controlled, random¬ ized, double-blind clinical trials, may in fact hasten larval demise (I suspect they do). If so, then as the authors have suggested,13 an acute aggressive in¬ flammatory response following ther¬ apy may lead to a more profound cere¬ bral cicatrix than might occur if only palliative therapy was given. Patients with normalized computed tomo¬ graphic scans have been shown to be abnormal by magnetic resonance im¬ aging. Therefore, the outcome variable should be clinical outcome, not com¬ puted tomographic appearance. This requires a much larger population of properly randomized subjects, who are followed up for a long period of time. In
Downloaded From: http://archneur.jamanetwork.com/ by a University of Michigan User on 06/17/2015
addition, data5·6 indicate that the nat¬ ural history may be such that little if anything is gained by this therapy in the usual patient (one not in need of surgery). A clinical trial such as this should certainly be feasible and is nec¬ essary if these therapies are to be properly evaluated. Lynn D.
Kramer, MD
Wallace Laboratories Half Acre Road Cranbury, NJ 08512 1. Sotelo J, Escobedo F, Penagos P. Albendazole vs praziquantel for therapy for neurocysticercosis. Arch Neurol. 1988;45:532-534. 2. Sotelo J, Escobedo F, Rodriguez J, et al. Therapy of parenchymal brain cysticercosis with praziquantel. N Engl J Med. 1984;310:1001-1007. 3. Alarcon F, Escalante L, Duenas G, et al. Neurocysticercosis: short course of treatment with albendazole. Arch Neurol. 1989;46:1231-1236. 4. Kramer LD, Locke GE, Byrd SE, Darybagi J. Cerebral cysticercosis: documentation of natural history by CT. Radiology. 1989;171:459-462. 5. Mitchell WG, Crawford TO. Seizures in children with intraparenchymal cerebral cysticercosis. Epilepsia. 1987;28:627-628. 6. Locke GE, Kramer LD, Nelson L. The prognosis of epilepsy in patients with CT-documented
cysticercosis. Epilepsia. 1988;29:673.
In
Reply.\p=m-\Kramerdetects some ills replicated in trials for drug treatment of neurocysticercosis conducted by us1 and by others; each of these "ills" has been previously discussed by us,2,3 actually, we believe that some points that for Kramer are ills, for us are the strength of our trials: A different protocol of drug therapy has to be planned for every disease considering its peculiarities, there is not a universal recipe for all drug trials; in our trials we have chosen imaging studies for evaluation of therapeutic response precisely to avoid the subjective clinical evaluation so highly recommended by Kramer that is quite misleading in the case of neurocysticercosis due to its complex clinical picture that depends on several factors related to number, location, stage of lesions, and individual immunological factors4; double-blind, placebo-controlled trials are useful in studies where subjective evaluation of symptoms is to be made, evaluation of imaging studies that has been the rule in our studies is objective, fairly pre-
