Studies of neurocysticercosis and animal cestode infections

National Institute Of Allergy And Infectious Diseases

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Abstract

Seizures are the most common clinical manifestation of cerebral cysticercosis and occur in the presence of viable, dying, and calcified or non-calcified dead cysts. How calcified cysts provoke seizures is not known but recent observations demonstrated edema around some calcified lesions at the time of seizure activity and disappearance during periods when seizures were not occurring. Edema associated with foci in idiopathic epilepsy is highly unusual so that this observation suggests that the mechanism(s) associated with calcified cysts is unique. Documenting and understanding this phenomenon is important for a number of reasons. First, although by definition these lesions are inactive, e.g., not living larvae and do not require anti-parasitic treatment, they are frequently mistaken for active lesions and patients undergo unnecessary treatment. Second, a likely reason for perilesional edema is intermittent antigen release and subsequent host immune response resulting in inflammation and edema. If proven, then the treatment for this would not only involve suppression of seizure activity with anti- seizure medication, but also the use of anti-inflammatory medications such as corticosteroids. A study was initiated in Peru to determine 1) the frequency of perilesional edema around calcifications 2) the nature and presence of associated symptoms 3) what lesions and patients have a propensity to undergo this phenomenon and 4) the natural history of perilesional edema. A prospective study of 110 patients with only calcified granulomas and a history of seizures or severe headache was recently published. Seizures were common with a predicted 36% experiencing an incident seizure after 5 years. Of the 29 who experienced seizures, 24 had an MRI within 5 days and 12 or 50% showed perilesional edema compared to 8.7% ( 2 of 23) of asymptomatic matched controls. Recurrent seizures are common in patients with calcified neurocysticercosis and a prior history of seizures. Perilesional edema was found in 50%. Since calcified neurocysticercosis is the most common form of cysticercosis in endemic populations, the results suggest it is a common in endemic population. The unusual and distinct nature of perilesional edema indicates a specific pathophysiology that may be amendable to unique interventions and treatments. A new treatment protocol for neurocysticercosis is ongoing in Lima, Peru. The purpose of the protocol is to determine if enhanced dosing of corticosteroids for one month with a two week taper decreases seizure frequency compared to 10 days of corticosteroids in albendazole treated patients with intraparenchymal cysticercosis without an unacceptable increase in side effects or a decrease in treatment efficacy. Much of the pathology and subsequently symptoms caused by cysticercosis are due to the host's immune response to the parasite that causes inflammation, seizures or focal neurological deficits. This leads to cyst degeneration, granuloma formation and/or calcification. The cysticidal agents, albendazole and praziquantel, initiate a similar process and until recently it was unclear if clinical benefit occurred with treatment. A recent double blinded randomized treatment sudy showed a clear benefit of treatment compared to no treatment . Although an overall decrease in generalized seizures was found after treatment with a standard regimen of albendazole and 6 mg dexamethasone/day for 10 days, a relative increase in seizures in the first month compared to later time periods suggested that inflammation was inadequately suppressed. Exactly what is the best way to suppress treatment-induced inflammation has not been studied and therefore is not known. The current protocol is an open label controlled study comparing the previous dexamethasone dosing of 10 days of 6 mg/day of dexamethasone with an enhanced dosing of 4 weeks of 8 mg/day with a 2 week taper. Albendazole dosing of both grouups is identical. The primary end point is the number of seizures at specific time periods over the subsequent year, the number and severity of side effects and cure rates at 1 year. This protocol has enrolled over half of the projected subjects. Thus far there is a substantial decrease in focal and generalized seizures in the enhanced corticosteroid treatment arm. Observations at NIH suggested that patients with basal subarachnoid neurocysticercosis have an increased incidence of spinal neurocysticerocsis compared to paraenchymal neurocysticercosis. A study was initiated in Peru to compared the incidence of spinal disease in patients with subarachnoid basal disease compared to those with only parenchymal involvement. Results thus far show a substantial increase in spinal disease in those with basal subarachnoid disease. Collaborative studies with Dr. Mahanty have been started to study the immune responses to cestodes that occur during the natural course of disease and also after treatment with the cysticidal agents albendazole and praziquantel. In cysticercosis the treatment of viable cysts many times initiates a vigorous immune response that appears similar if not identical to the type of inflammation found during the course of the natural infection. Seizures and other symptoms are common during treatment. Consequently, the problem in treatment is how to minimize symptoms and long-term damage due to treatment without preventing or inhibiting evolution to a relatively less destructive and less symptomatic granuloma. This question cannot be readily studied in humans. Therefore, studies using the cestode T. crassiceps infection in rats and mice have been initiated to answer this and other questions. A rat intracerebral model of T. crassciceps has been developed and is currently being used to understand the host parasite interaction in the brain, to determine the inflammatory response to the parasite, to determine how best to treat the infection and suppress potentially harmful inflammatory responses. Treatment of neurocysticercosis consists of anthelmintic drugs albendazole (ABZ)or praziquantel (PZQ) as well as corticosteroids. There are no standard methods to assess drug activity to Taenia solium cysts in vitro. Morphological, functional and biochemical changes that might reflect damaging drug effects were analyzed after exposure of cysts to albendazole sulfoxide, the major active metabolite of ABZ, PZQ or a combination of both. PZQ exposure led to a decrease in cyst size and inhibition of evagination while ABZ exposure resulted in minimal changes. Alkaline phosphatase (AP) is normally secreted by cysts and both drugs inhibited AP secretions at concentrations of 5 ng/ml and 50 ng/ ml, respectively. Some combination of both drugs resulted in additive and/or synergistic activities. Parasite-specific antigen, detected in the CSF and blood of infected patients is normally secreted by cysts. Antigen secretion was similarly inhibited by ABZ and PZQ and a combination of both drugs suggesting that inhibition of secretion is a common downstream consequence of both drugs. These studies establish quantitative method to measure in vitro anthelmintics activity and suggest combination therapy with ABZ and PZQ may have clinical benefit.