Seizures are the most common manifestation of neurocysticercosis (NCC) and understanding the pathophysiology is necessary to prevent and effectively treat them. The pig naturally infected model was employed to study treatment-induced inflammation that is a common cause of seizures in treated infected persons. The vital dye Evans Blue (EB) was injected to 11 pigs naturally infected with Taenia solium cysts to visualize disruption of the blood brain barrier (BBB). A total of 369 cysts were recovered from the 11 brains and classified according to the blue staining or lack of it of their capsules. The proportion of cysts with blue capsules was significantly higher in brains from pigs that had received anthelmintic treatment 48 and 120 h before the EB infusion, indicating a higher compromise of the blood brain barrier due to treatment. Measures to decrease BBB disruption and subsequent inflammation would be expected to prevent or control treatment induced seizures. Perilesional edema around calcifications is a recently described cause of seizures. Studies performed by us earlier indicated that about 50% of seizures experienced by persons with NCC and only calcifications will show perilesional edema at the time of seizure activity. Whether edema is consequence of the seizure, or a result of host inflammation directed against parasite antigens or other processes is unknown. We imaged a marker of neuroinflammation, translocater protein (TSPO), using positron emission tomography (PET) and the selective ligand 11C-PBR28. In nine patients with perilesional edema, degenerating cyst or both, PET findings were compared to the corresponding magnetic resonance images. Degenerating cysts were also studied because unlike perilesional edema, degenerating cysts are known to have inflammation. In three of the nine patients, changes in 11C-PBR28 binding were also studied over time. 11C-PBR28 binding was compared to the contralateral un-affected region. Results 11C-PBR28 binding increased by a mean of 13% in perilesional edema or degenerating cysts (P =0*0005, n = 13 in nine patients). Among these 13 lesions, perilesional edema (n=10) showed a slightly smaller increase of 10% compared to the contralateral side (P = 0*005) than the three degenerating cysts. In five lesions with perilesional edema in which repeated measurements of 11C-PBR28 binding were done, increased binding lasted for 2 - 9 months. These studies strongly support an inflammatory etiology of perilesional edema. . The long duration of increased TSPO binding after resolution of the original perilesional edema and the pattern of periodic episodes is consistent with intermittent exacerbation from a continued baseline presence of low level inflammation. Novel anti-inflammatory measures may be useful in the prevention or treatment of seizures in this population. Another study suggested that one mechanism of activation of perilesional edema is acute corticosteroid withdrawal. We report 6 cases where acute withdrawal of corticosteroids precipitated perilesional edema around calcifications. Some of the calcifications showed neither edema nor enhancement before corticosteroids indicating that there is potential for inactive calcifications to show edema. Furthermore this suggests that perilesional edema is an immune mediated phenomenon. Whether perilesional edema results from new release or recognition of sequestered parasite antigen or inhibition of suppression is unclear. Discovery of new anthelmintics with activity against T. solium has been limited by the lack of suitable sensitive assays that allow high throughput screening. Using an in vitro culture system with T. crassiceps metacestodes we demonstrate that changes in secretion of parasite-associated alkaline phosphatase (AP) and phophoglucose isomerase (PGI) can be used to detect and quantify anthelmintic effects of praziquantel (PZQ), a drug with activity against T. solium. We applied two enzyme release assays to screen for anti-T. crassiceps activity in non-conventional anti-parasitic drugs and demonstrate that nitazoxanide and artesunate induced release of both AP and PGI in a differing time and dose related patterns. Furthermore, imatinib, a tyrosine kinase inhibitor previously reported to have cidal activity against Schistosoma mansoni, also induced release of both AP and PGI in a dose dependent manner, similar in pattern to that observed with the other anthelmintics. We also evaluated release of adenine triphosphate (ATP) into cyst supernatants as an indicator of drug effects, but did not see any differences between treated and untreated cysts. These data provide the basis for rapid and quantitative screening assays for testing for anthelmintic activity in candidate anti-cestode agents

Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2013
Total Cost
$345,789
Indirect Cost
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Nash, Theodore E; Bartelt, Luther A; Korpe, Poonum S et al. (2014) Calcified neurocysticercus, perilesional edema, and histologic inflammation. Am J Trop Med Hyg 90:318-21
Marzal, Miguel; Guerra-Giraldez, Cristina; Paredes, Adriana et al. (2014) Evans blue staining reveals vascular leakage associated with focal areas of host-parasite interaction in brains of pigs infected with Taenia solium. PLoS One 9:e97321
Cantey, Paul T; Coyle, Christina M; Sorvillo, Frank J et al. (2014) Neglected parasitic infections in the United States: cysticercosis. Am J Trop Med Hyg 90:805-9
Garcia, Hector H; Gonzales, Isidro; Lescano, Andres G et al. (2014) Enhanced steroid dosing reduces seizures during antiparasitic treatment for cysticercosis and early after. Epilepsia 55:1452-9
Nash, Theodore E (2014) Parasitic Diseases that Cause Seizures. Epilepsy Curr 14:29-34
Nash, Theodore E; Mahanty, Siddhartha; Garcia, Hector H (2013) Neurocysticercosis-more than a neglected disease. PLoS Negl Trop Dis 7:e1964
Guerra-Giraldez, Cristina; Marzal, Miguel; Cangalaya, Carla et al. (2013) Disruption of the blood-brain barrier in pigs naturally infected with Taenia solium, untreated and after anthelmintic treatment. Exp Parasitol 134:443-6
Mahanty, Siddhartha; Madrid, Elise M; Nash, Theodore E (2013) Quantitative screening for anticestode drugs based on changes in baseline enzyme secretion by Taenia crassiceps. Antimicrob Agents Chemother 57:990-5
Burneo, Jorge G; Del Brutto, Oscar; Delgado-Escueta, Antonio V et al. (2009) Workshop report: Developing an international collaborative research network in neurocysticercosis and epilepsy. Epilepsia 50:1289-90
Nash, Theodore E; Pretell, E Javier; Lescano, Andres G et al. (2008) Perilesional brain oedema and seizure activity in patients with calcified neurocysticercosis: a prospective cohort and nested case-control study. Lancet Neurol 7:1099-105