Neurocysticercosis — Is the Elimination of Parasites Beneficial?
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《新英格兰医药杂志》
Taenia solium causes two different diseases. When the adult cestode infests the human intestine, taeniasis develops; it is generally asymptomatic, but the host becomes a continuous source of taenia eggs, which are expelled every day in the feces, which may then contaminate vegetables and food in areas with poor sanitary conditions. Cysticercosis develops when humans or pigs ingest food contaminated with taenia eggs, which cross the digestive tract, enter the circulation, and lodge in the tissues (usually the brain or muscles). Humans are the only hosts for the cestode, whereas both humans and pigs are hosts for the embryo. The life cycle proceeds as humans ingest undercooked pork containing cysticerci, the metacestode emerges and anchors in the intestinal wall, and (within two months) the worm grows to a length of 2 to 4 m and becomes a new and continuous source of contamination.
Two drugs, praziquantel and albendazole, have proved effective for the successful destruction of brain cysticerci.1 Both of these drugs have been in use since the 1980s. They have minimal toxicity and can be given according to the brief drug schedules that have been developed in recent years. Adequate cysticidal efficacy can be achieved with a one-week course of albendazole or a one-day treatment with praziquantel,2 but albendazole seems to have better and more effective penetration into the brain tissue.1,3 These two medications are inexpensive — a fact that is of paramount importance because most infected patients belong to lower economic strata. Given these advantages, why is it that there has been so much discussion, from the very beginning, about the appropriateness of cysticidal drug therapy? It is important to remember that before the introduction of these two medications, brain surgery was the only therapeutic approach to neurocysticercosis. Moreover, in most cases, neurosurgery was an unsatisfactory method of treating a disorder in which lesions are often scattered throughout the brain and difficult to reach by surgery. Thus, the advent of effective drug therapy for the most common parasitic disease of the brain was long overdue.
Neurocysticercosis is not a simple infection. It is the result of a complex encounter between a highly sophisticated parasite and an elaborate immune response in its potential host.4 The consequence in some cases is rapid elimination of the parasite, whereas in others the parasite remains unharmed for several years, generating giant cysts.1,4 In still other cases, the immune response is active but insufficient to eliminate the parasite, and as a result, there is chronic damage to the surrounding brain tissue.2 In the latter instance, even if the parasite is finally eliminated, cicatricial tissue will remain as a permanent sequela.5 Among the various peculiarities of this disease is the fact that even within a single patient, some lesions are due to live parasites, whereas others are due to remnant granulomas or to degenerating cysts that are already dead. In the best of cases, a cysticidal substance would be effective only against viable cysticerci. In patients whose symptoms (mostly epilepsy) are due to granulomas, gliosis, or fibrosis, the condition is not expected to improve with treatment aimed at the destruction of cysticerci. The core question is whether cysticidal treatment really does make a difference in the clinical outcome.
Initial reports on the successful treatment of neurocysticercosis were followed by controversy. Skeptics pointed out four main arguments. First, the sudden destruction of parasites may trigger an inflammatory reaction that precipitates seizures and transient neurologic effects, mostly headache and vomiting. Second, in a considerable number of patients, neurocysticercosis is clinically silent, producing only occasional seizures that are easy to manage with anticonvulsive therapy; thus, exposing these patients to the risk of adverse reactions to cysticidal therapy may be unnecessary. Third, in some cases, the cysticerci will be adequately eliminated either by the host's immune response or by spontaneous regression. Finally, the physical elimination of a parasite, objectively confirmed by neuroimaging studies, does not in itself mean that the patient's neurologic dysfunction will improve.
On the other side, defendants of cysticidal therapy have argued that if antiparasitic treatment is deliberately withheld, neurocysticercosis will be unique among infectious diseases, in that a convenient and effective treatment against the infectious agent is available but is being withheld because of the contention that improvement in secondary symptoms has not been clearly demonstrated. A parallel example would be the omission of treatment for cerebral malaria because the destruction of parasites may be accompanied by clinical worsening, also as a result of the host's immune response to the sudden destruction of parasites; another example would be the withholding of therapy for tuberculosis because of the contention that the dyspnea associated with the infection might not improve after elimination of the active disease.
As Garcia et al.6 point out in their report in this issue of the Journal, we must also consider patients' perception of the disease and their natural expectation that they will be healed. In areas where the infection is endemic, the term "cysticercosis" is widely recognized to mean "parasites in the brain," and quite understandably this is a fearful diagnosis. Most patients are acquainted with the disease because they have known relatives or neighbors with neurocysticercosis. As Garcia et al. mention, patients may feel "highly uncomfortable" when we suggest leaving the live parasites within their brain.
Several studies have been performed with the aim of resolving the questions that surround the treatment of neurocysticercosis. However, the polemic has continued because none of the studies have been double-blind, controlled trials. The need for such trials is debatable, given the argument that the main contribution of double-blind studies is to the therapy of disorders that can be evaluated subjectively, and that in the case of neurocysticercosis, the presence and subsequent disappearance of the parasites can be evaluated objectively, through imaging studies. In this sense, well-controlled, open-label studies abound.7,8,9,10 The controlled study by Garcia et al., who evaluated albendazole in comparison with placebo, has been long awaited because it was designed to fill this gap and to complete the spectrum of clinical information available regarding the treatment of neurocysticercosis. In addition to its contributions to knowledge about treatment, this well-planned study provides valuable information about the natural course of untreated cysticercosis and shows that, contrary to some arguments, in most instances the natural course of untreated cysticercosis does not lead to spontaneous resolution and its clinical prognosis is not so benign. Neurocysticercosis is a frequent cause of seizures, which in many cases do not easily remit with anticonvulsants. The latter problem is not trivial. Neurocysticercosis is the single most important reason why the incidence of epilepsy in the developing world is significantly higher than that in industrialized countries.4,11,12
An interesting finding in the study by Garcia et al. is the more frequent appearance of granulomas in place of cysticerci in the patients treated with albendazole than in the patients who received placebo. Other studies have indicated the contrary — that granulomas replace cysticerci that have resolved spontaneously more often than they replace cysticerci that have been destroyed by medications. Potential reasons for this disparity could be the relatively short follow-up in the study by Garcia et al. and the fact that routine magnetic resonance imaging (MRI) fails to detect some granulomas.13 The development of granulomas or calcifications has been documented years after the disappearance of cysts. Special MRI techniques, such as T1-weighted magnetization-transfer spin-echo imaging,5 may help to resolve this important issue.
After two decades of experience with cysticidal drugs, many studies have described the clinical spectrum that follows treatment. As a result of the sudden destruction of cysts, some patients are, for a brief period, at increased risk for seizures because of the acute inflammatory process that accompanies the removal of parasite debris, a phenomenon that can be inhibited with a short course of corticosteroids. In contrast to the initial period, the long-term course with respect to seizures is better in patients who are treated with cysticidal agents than it is in patients who do not receive these drugs.
Data from studies with longer follow-up periods are necessary. So far, however, it seems that the answer to the initial question is yes: the expeditious elimination of parasites is beneficial, and cysticidal treatment should be administered to all patients with active parenchymal neurocysticercosis.
Source Information
From the National Institute of Neurology and Neurosurgery, Mexico City, Mexico.
References
Riley T, White AC Jr. Management of neurocysticercosis. CNS Drugs 2003;17:577-591.
Sotelo J. Neurocysticercosis. In: Aminoff MJ, Daroff RB, eds. Encyclopedia of the neurological sciences. San Diego, Calif.: Academic Press, 2003:474-5.
Proa?o JV, Madrazo I, Avelar F, López-Felix B, Díaz G, Grijalva I. Medical treatment for neurocysticercosis characterized by giant subarachnoid cysts. N Engl J Med 2001;345:879-885.
Sotelo J. Neurocysticercosis: eradication of cysticercosis is an attainable goal. BMJ 2003;326:511-512.
Pradhan S, Kathuria MK, Gupta RK. Perilesional gliosis and seizure outcome: a study based on magnetization transfer magnetic resonance imaging in patients with neurocysticercosis. Ann Neurol 2000;48:181-187.
Garcia HH, Pretell EJ, Gilman RH, et al. A trial of antiparasitic treatment to reduce the rate of seizures due to cerebral cysticercosis. N Engl J Med 2004;350:249-258.
Kim SK, Wang KC, Paek SH, Hong KS, Cho BK. Outcomes of medical treatment of neurocysticercosis: a study of 65 cases in Cheju Island, Korea. Surg Neurol 1999;52:563-569.
Kalra V, Dua T, Kumar V. Efficacy of albendazole and short-course dexamethasone treatment in children with 1 or 2 ring-enhancing lesions of neurocysticercosis: a randomized controlled trial. J Pediatr 2003;143:111-114.
Pérez López C, Isla Guerrero A, álvarez F, et al. Actualización en el tratamiento de la neurocisticercosis. Rev Neurol 2003;36:805-811.
Singhi P, Dayal D, Khandelwal N. One week versus four weeks of albendazole therapy for neurocysticercosis in children: a randomized, placebo-controlled double blind trial. Pediatr Infect Dis J 2003;22:268-272.
Bharucha NE. Epidemiology of epilepsy in India. Epilepsia 2003;44:Suppl 1:9-11.
Rosenfeld EA, Byrd SE, Shulman ST. Neurocysticercosis among children in Chicago. Clin Infect Dis 1996;23:262-268.
Salgado P, Rojas R, Sotelo J. Cysticercosis: clinical classification based on imaging studies. Arch Intern Med 1997;157:1991-1997.(Julio Sotelo, M.D.)
Two drugs, praziquantel and albendazole, have proved effective for the successful destruction of brain cysticerci.1 Both of these drugs have been in use since the 1980s. They have minimal toxicity and can be given according to the brief drug schedules that have been developed in recent years. Adequate cysticidal efficacy can be achieved with a one-week course of albendazole or a one-day treatment with praziquantel,2 but albendazole seems to have better and more effective penetration into the brain tissue.1,3 These two medications are inexpensive — a fact that is of paramount importance because most infected patients belong to lower economic strata. Given these advantages, why is it that there has been so much discussion, from the very beginning, about the appropriateness of cysticidal drug therapy? It is important to remember that before the introduction of these two medications, brain surgery was the only therapeutic approach to neurocysticercosis. Moreover, in most cases, neurosurgery was an unsatisfactory method of treating a disorder in which lesions are often scattered throughout the brain and difficult to reach by surgery. Thus, the advent of effective drug therapy for the most common parasitic disease of the brain was long overdue.
Neurocysticercosis is not a simple infection. It is the result of a complex encounter between a highly sophisticated parasite and an elaborate immune response in its potential host.4 The consequence in some cases is rapid elimination of the parasite, whereas in others the parasite remains unharmed for several years, generating giant cysts.1,4 In still other cases, the immune response is active but insufficient to eliminate the parasite, and as a result, there is chronic damage to the surrounding brain tissue.2 In the latter instance, even if the parasite is finally eliminated, cicatricial tissue will remain as a permanent sequela.5 Among the various peculiarities of this disease is the fact that even within a single patient, some lesions are due to live parasites, whereas others are due to remnant granulomas or to degenerating cysts that are already dead. In the best of cases, a cysticidal substance would be effective only against viable cysticerci. In patients whose symptoms (mostly epilepsy) are due to granulomas, gliosis, or fibrosis, the condition is not expected to improve with treatment aimed at the destruction of cysticerci. The core question is whether cysticidal treatment really does make a difference in the clinical outcome.
Initial reports on the successful treatment of neurocysticercosis were followed by controversy. Skeptics pointed out four main arguments. First, the sudden destruction of parasites may trigger an inflammatory reaction that precipitates seizures and transient neurologic effects, mostly headache and vomiting. Second, in a considerable number of patients, neurocysticercosis is clinically silent, producing only occasional seizures that are easy to manage with anticonvulsive therapy; thus, exposing these patients to the risk of adverse reactions to cysticidal therapy may be unnecessary. Third, in some cases, the cysticerci will be adequately eliminated either by the host's immune response or by spontaneous regression. Finally, the physical elimination of a parasite, objectively confirmed by neuroimaging studies, does not in itself mean that the patient's neurologic dysfunction will improve.
On the other side, defendants of cysticidal therapy have argued that if antiparasitic treatment is deliberately withheld, neurocysticercosis will be unique among infectious diseases, in that a convenient and effective treatment against the infectious agent is available but is being withheld because of the contention that improvement in secondary symptoms has not been clearly demonstrated. A parallel example would be the omission of treatment for cerebral malaria because the destruction of parasites may be accompanied by clinical worsening, also as a result of the host's immune response to the sudden destruction of parasites; another example would be the withholding of therapy for tuberculosis because of the contention that the dyspnea associated with the infection might not improve after elimination of the active disease.
As Garcia et al.6 point out in their report in this issue of the Journal, we must also consider patients' perception of the disease and their natural expectation that they will be healed. In areas where the infection is endemic, the term "cysticercosis" is widely recognized to mean "parasites in the brain," and quite understandably this is a fearful diagnosis. Most patients are acquainted with the disease because they have known relatives or neighbors with neurocysticercosis. As Garcia et al. mention, patients may feel "highly uncomfortable" when we suggest leaving the live parasites within their brain.
Several studies have been performed with the aim of resolving the questions that surround the treatment of neurocysticercosis. However, the polemic has continued because none of the studies have been double-blind, controlled trials. The need for such trials is debatable, given the argument that the main contribution of double-blind studies is to the therapy of disorders that can be evaluated subjectively, and that in the case of neurocysticercosis, the presence and subsequent disappearance of the parasites can be evaluated objectively, through imaging studies. In this sense, well-controlled, open-label studies abound.7,8,9,10 The controlled study by Garcia et al., who evaluated albendazole in comparison with placebo, has been long awaited because it was designed to fill this gap and to complete the spectrum of clinical information available regarding the treatment of neurocysticercosis. In addition to its contributions to knowledge about treatment, this well-planned study provides valuable information about the natural course of untreated cysticercosis and shows that, contrary to some arguments, in most instances the natural course of untreated cysticercosis does not lead to spontaneous resolution and its clinical prognosis is not so benign. Neurocysticercosis is a frequent cause of seizures, which in many cases do not easily remit with anticonvulsants. The latter problem is not trivial. Neurocysticercosis is the single most important reason why the incidence of epilepsy in the developing world is significantly higher than that in industrialized countries.4,11,12
An interesting finding in the study by Garcia et al. is the more frequent appearance of granulomas in place of cysticerci in the patients treated with albendazole than in the patients who received placebo. Other studies have indicated the contrary — that granulomas replace cysticerci that have resolved spontaneously more often than they replace cysticerci that have been destroyed by medications. Potential reasons for this disparity could be the relatively short follow-up in the study by Garcia et al. and the fact that routine magnetic resonance imaging (MRI) fails to detect some granulomas.13 The development of granulomas or calcifications has been documented years after the disappearance of cysts. Special MRI techniques, such as T1-weighted magnetization-transfer spin-echo imaging,5 may help to resolve this important issue.
After two decades of experience with cysticidal drugs, many studies have described the clinical spectrum that follows treatment. As a result of the sudden destruction of cysts, some patients are, for a brief period, at increased risk for seizures because of the acute inflammatory process that accompanies the removal of parasite debris, a phenomenon that can be inhibited with a short course of corticosteroids. In contrast to the initial period, the long-term course with respect to seizures is better in patients who are treated with cysticidal agents than it is in patients who do not receive these drugs.
Data from studies with longer follow-up periods are necessary. So far, however, it seems that the answer to the initial question is yes: the expeditious elimination of parasites is beneficial, and cysticidal treatment should be administered to all patients with active parenchymal neurocysticercosis.
Source Information
From the National Institute of Neurology and Neurosurgery, Mexico City, Mexico.
References
Riley T, White AC Jr. Management of neurocysticercosis. CNS Drugs 2003;17:577-591.
Sotelo J. Neurocysticercosis. In: Aminoff MJ, Daroff RB, eds. Encyclopedia of the neurological sciences. San Diego, Calif.: Academic Press, 2003:474-5.
Proa?o JV, Madrazo I, Avelar F, López-Felix B, Díaz G, Grijalva I. Medical treatment for neurocysticercosis characterized by giant subarachnoid cysts. N Engl J Med 2001;345:879-885.
Sotelo J. Neurocysticercosis: eradication of cysticercosis is an attainable goal. BMJ 2003;326:511-512.
Pradhan S, Kathuria MK, Gupta RK. Perilesional gliosis and seizure outcome: a study based on magnetization transfer magnetic resonance imaging in patients with neurocysticercosis. Ann Neurol 2000;48:181-187.
Garcia HH, Pretell EJ, Gilman RH, et al. A trial of antiparasitic treatment to reduce the rate of seizures due to cerebral cysticercosis. N Engl J Med 2004;350:249-258.
Kim SK, Wang KC, Paek SH, Hong KS, Cho BK. Outcomes of medical treatment of neurocysticercosis: a study of 65 cases in Cheju Island, Korea. Surg Neurol 1999;52:563-569.
Kalra V, Dua T, Kumar V. Efficacy of albendazole and short-course dexamethasone treatment in children with 1 or 2 ring-enhancing lesions of neurocysticercosis: a randomized controlled trial. J Pediatr 2003;143:111-114.
Pérez López C, Isla Guerrero A, álvarez F, et al. Actualización en el tratamiento de la neurocisticercosis. Rev Neurol 2003;36:805-811.
Singhi P, Dayal D, Khandelwal N. One week versus four weeks of albendazole therapy for neurocysticercosis in children: a randomized, placebo-controlled double blind trial. Pediatr Infect Dis J 2003;22:268-272.
Bharucha NE. Epidemiology of epilepsy in India. Epilepsia 2003;44:Suppl 1:9-11.
Rosenfeld EA, Byrd SE, Shulman ST. Neurocysticercosis among children in Chicago. Clin Infect Dis 1996;23:262-268.
Salgado P, Rojas R, Sotelo J. Cysticercosis: clinical classification based on imaging studies. Arch Intern Med 1997;157:1991-1997.(Julio Sotelo, M.D.)