E. Javier Pretell

Perilesional brain oedema and seizure activity in patients with calcified neurocysticercosis: a prospective cohort and nested case–control study

BACKGROUND Cysticercosis due to Taenia solium is a cause of adult-acquired seizures and epilepsy even in patients with only calcified larval cysts. Transient perilesional brain oedema is seen around the calcified foci but its importance, association with seizures, incidence, and pathophysiology are unknown. METHODS 110 patients with only calcified lesions and a history of seizures or severe headaches were followed prospectively in a cohort design to assess the incidence of seizure relapse. In a nested case-control substudy, perilesional oedema was assessed by MRI at the time of seizure in symptomatic patients and in matched asymptomatic controls taken from the study population. FINDINGS Between November, 1999, and December, 2006, 29 patients had an incident seizure during a median follow up of 32.33 (SD 19.99) months, with an estimated 5-year seizure incidence of 36% (95% CI 25% to 49%). 24 of 29 (83%) patients with seizure relapse had an MRI evaluation within 5 days of the event; perilesional oedema was seen in 12 patients (50%) compared with two (9%) of 23 asymptomatic matched controls. INTERPRETATION Perilesional oedema is common and associated with episodic seizure activity in patients with calcified neurocysticercosis. Our findings are probably representative of symptomatic patients in regions where T solium neurocysticercosis is endemic and suggest a unique and possibly preventable cause of seizures in this population.

Detection of Taenia solium Antigens and Anti–T. solium Antibodies in Paired Serum and Cerebrospinal Fluid Samples from Patients with Intraparenchymal or Extraparenchymal Neurocysticercosis

BACKGROUND Neurocysticercosis (NCC) is a frequent cause of epilepsy worldwide. Compared with the more common parenchymal brain cysts, extraparenchymal infections are difficult to manage and have a poor prognosis. Serological assays are used to detect circulating Taenia solium antigens or anti-T. solium antibodies in serum or cerebrospinal fluid (CSF) samples. There are no guidelines on whether to use serum or CSF specimens for a particular assay. METHODS We obtained paired serum and CSF samples from 91 patients with NCC (48 had intraparenchymal NCC, and 43 had extraparenchymal NCC) for detection of antibodies, using an enzyme-linked immunotransfer blot (EITB) assay, and antigens, using a monoclonal antibody-based enzyme-linked immunosorbent assay (ELISA). RESULTS For the intraparenchymal NCC group, the EITB assay yielded more true-positive results for serum samples, and the ELISA yielded slightly more true-positive results for CSF samples than for serum samples, but none of these differences were statistically significant. Most patients with calcified NCC were antibody positive but antigen negative. For extraparenchymal disease, all samples were antibody positive, and all but 2 were antigen positive, with most samples containing high antigen levels. CONCLUSIONS The sensitivity of antibody-detecting EITB assays is not increased through the use of CSF samples rather than serum samples. The antigen-detecting ELISA performed better for CSF samples than for serum samples, but for both specimen types it was less sensitive than the EITB assay. Active and inactive NCC are better differentiated from each other by the antigen-detecting ELISA, for both serum and CSF samples. High antigen levels suggest the presence of subarachnoid NCC.

Efficacy of combined antiparasitic therapy with praziquantel and albendazole for neurocysticercosis: A double-blind, randomised controlled trial

BACKGROUND Neurocysticercosis causes a substantial burden of seizure disorders worldwide. Treatment with either praziquantel or albendazole has suboptimum efficacy. We aimed to establish whether combination of these drugs would increase cysticidal efficacy and whether complete cyst resolution results in fewer seizures. We added an increased dose albendazole group to establish a potential effect of increased albendazole concentrations. METHODS In this double-blind, placebo-controlled, phase 3 trial, patients with viable intraparenchymal neurocysticercosis were randomly assigned to receive 10 days of combined albendazole (15 mg/kg per day) plus praziquantel (50 mg/kg per day), standard albendazole (15 mg/kg per day), or increased dose albendazole (22·5 mg/kg per day). Randomisation was done with a computer generated schedule balanced within four strata based on number of cysts and concomitant antiepileptic drug. Patients and investigators were masked to group assignment. The primary outcome was complete cyst resolution on 6-month MRI. Enrolment was stopped after interim analysis because of parasiticidal superiority of one treatment group. Analysis excluded patients lost to follow-up before the 6-month MRI. This trial is registered with ClinicalTrials.gov, number NCT00441285. FINDINGS Between March 3, 2010 and Nov 14, 2011, 124 patients were randomly assigned to study groups (41 to receive combined albendazole plus praziquantel [39 analysed], 43 standard albendazole [41 analysed], and 40 increased albendazole [38 analysed]). 25 (64%) of 39 patients in the combined treatment group had complete resolution of brain cysts compared with 15 (37%) of 41 patients in the standard albendazole group (rate ratio [RR] 1·75, 95% CI 1·10-2·79, p=0·014). 20 (53%) of 38 patients in the increased albendazole group had complete cyst resolution at 6-month MRI compared with 15 (37%) of 41 patients in the standard albendazole group (RR 1·44, 95% CI 0·87-2·38, p=0·151). No significant differences in adverse events were reported between treatment groups (18 in combined treatment group, 11 in standard albendazole group, and 19 in increased albendazole group). INTERPRETATION Combination of albendazole plus praziquantel increases the parasiticidal effect in patients with multiple brain cysticercosis cysts without increased side-effects. A more efficacious parasiticidal regime without increased treatment-associated side-effects should improve the treatment and long term prognosis of patients with neurocysticercosis. FUNDING National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health.

Pharmacokinetics of combined treatment with praziquantel and albendazole in neurocysticercosis

AIMS Neurocysticercosis is the most common cause of acquired epilepsy in the world. Antiparasitic treatment of viable brain cysts is of clinical benefit, but current antiparasitic regimes provide incomplete parasiticidal efficacy. Combined use of two antiparasitic drugs may improve clearance of brain parasites. Albendazole (ABZ) has been used together with praziquantel (PZQ) before for geohelminths, echinococcosis and cysticercosis, but their combined use is not yet formally recommended and only scarce, discrepant data exist on their pharmacokinetics when given together. We assessed the pharmacokinetics of their combined use for the treatment of neurocysticercosis. METHODS A randomized, double-blind, placebo-controlled phase II evaluation of the pharmacokinetics of ABZ and PZQ in 32 patients with neurocysticercosis was carried out. Patients received their usual concomitant medications including an antiepileptic drug, dexamethasone, and ranitidine. Randomization was stratified by antiepileptic drug (phenytoin or carbamazepine). Subjects had sequential blood samples taken after the first dose of antiparasitic drugs and again after 9 days of treatment, and were followed for 3 months after dosing. RESULTS Twenty-one men and 11 women, aged 16 to 55 (mean age 28) years were included. Albendazole sulfoxide concentrations were increased in the combination group compared with the ABZ alone group, both in patients taking phenytoin and patients taking carbamazepine. PZQ concentrations were also increased by the end of therapy. There were no significant side effects in this study group. CONCLUSIONS Combined ABZ + PZQ is associated with increased albendazole sulfoxide plasma concentrations. These increased concentrations could independently contribute to increased cysticidal efficacy by themselves or in addition to a possible synergistic effect.

Neurocysticercosis: A natural human model of epileptogenesis

To develop a better understanding of mechanisms of seizures and long‐term epileptogenesis using neurocysticercosis.

Short regimen of praziquantel in the treatment of single brain enhancing lesions

Twenty-six patients with single enhancing brain lesion (SEL) were openly assigned to receive single-day praziquantel therapy (n=14), or not (n=12). From 14 treated patients, complete resolution was found in 11, partial resolution in two, and the remaining case was later diagnosed as an arteriovenous malformation. Side effects presented in only one patient and remitted in the same day with symptomatic treatment. Conversely, the lesions persisted unchanged in six of 12 patients in the non-treatment group. Untreated patients with persisting lesions were prescribed praziquantel treatment. After this, SELs disappeared in three cases, other diagnoses (brain tuberculoma and arteriovenous malformation) were made in two, and one was not evaluated. When analyzed in regard to the baseline serology, resolution of lesions on computed tomography was found in 13 (complete=12, partial=1) of 14 seropositive patients, whereas it only happened in six (complete=5, partial=1) of 12 seronegative patients. Serological screening defines a subset of SEL patients with good prognosis. If antiparasitic therapy is to be used in patients with SEL, and we cannot find a strong argument against it, single-day praziquantel is the regimen of choice based on duration, costs, and minimal side effects.

Failure of one-day praziquantel treatment in patients with multiple neurocysticercosis lesions

A recently described one-day regimen of praziquantel (PZQ) therapy for neurocysticercosis (NCC), three doses of 25 mg/k given at 2 h intervals, was applied in eight patients with viable NCC cysts without any evidence of inflammation. Resolution of lesions in computed tomography (CT) was observed in all five patients with a single cyst, whereas all cysts survived in three patients with multiple brain parasites. One-day praziquantel is a good regimen for patients with a single viable brain cysticercus but is poorly effective for multiple cysts.

Enhanced steroid dosing reduces seizures during antiparasitic treatment for cysticercosis and early after.

Neurocysticercosis (NCC) is a major cause of seizures and epilepsy in endemic countries. Antiparasitic treatment of brain cysts leads to seizures due to the hosts inflammatory reaction, requiring concomitant steroids. We hypothesized that increased steroid dosing will reduce treatment‐associated seizures.

Cognitive Changes and Quality of Life in Neurocysticercosis: A Longitudinal Study

Background Few studies have focused on the cognitive morbidity of neurocysticercosis (NCC), one of the most common parasitic infections of the central nervous system. We longitudinally assessed the cognitive status and quality of life (QoL) of patients with incident symptomatic NCC cases and matched controls. Methodology/Principal Findings The setting of the study was the Sabogal Hospital and Cysticercosis Unit, Department of Transmissible Diseases, National Institute of Neurological Sciences, Lima, Peru. The design was a longitudinal study of new onset NCC cases and controls. Participants included a total of 14 patients with recently diagnosed NCC along with 14 healthy neighborhood controls and 7 recently diagnosed epilepsy controls. A standardized neuropsychological battery was performed at baseline and at 6 months on NCC cases and controls. A brain MRI was performed in patients with NCC at baseline and 6 months. Neuropsychological results were compared between NCC cases and controls at both time points. At baseline, patients with NCC had lower scores on attention tasks (p<0.04) compared with epilepsy controls but no significant differences compared to healthy controls. Six months after receiving anti-parasitic treatment, the NCC group significantly improved on tasks involving psychomotor speed (p<0.02). QoL at baseline suggested impaired mental function and social function in both the NCC and epilepsy group compared with healthy controls. QoL gains in social function (p = 0.006) were noted at 6 months in patients with NCC. Conclusions/Significance Newly diagnosed patients with NCC in this sample had mild cognitive deficits and more marked decreases in quality of life at baseline compared with controls. Improvements were found in both cognitive status and quality of life in patients with NCC after treatment.

Efficacy of a 3-day course of albendazole treatment in patients with a single neurocysticercosis cyst.

0 d Neurocysticercosis (NCC) is the most important parasitic isease of the central nervous system (CNS), and a major ause of acquired epilepsy worldwide [1]. NCC is a pleomorhic disease in which a single therapeutic approach can hardly e of value in every patient. Besides symptomatic medicaion, the treatment of NCC includes the use of anti-parasitic gents, albendazole (ABZ) or praziquantel (PZQ). It has been onsistently shown that anti-parasitic agents are effective in illing the parasitic cysts and also provide clinical benefits n the evolution of seizures secondary to NCC [2]. However, he optimal length of cysticidal drug therapy remains undened. We report a study carried out to evaluate the efficacy f the shorter reported regimen of ABZ in patients with few ntracranial lesions. After written informed consent was obtained, patients beween 15 and 65 years old attending the Instituto de Ciencias eurologicas in Lima, Peru, with a definitive diagnosis of CC based on neuroimaging and serology [3], and who had ess than five viable parenchymal brain cysticerci were aditted to the hospital and were given ABZ at 15 mg/kg/day in two divided doses, for 3 days. Seventeen patients completed the study between August 1999 and April 2002 (10 men and 7 women, mean age 30.9 years, S.D. 10.17). Eight of them had a single brain cyst, and the other nine had from two to four cysts, for a total of 31 cysts. Control CTs were obtained after a mean of 105.8 days after treatment (range 69–180 days). Overall, 19 out of 31 cysts (55%) disappeared and 12 out of 17 patients (70%) were completely free of viable cysts on control CTs (Table 1). Response to therapy differed between patients with one cyst and those with more than one cyst. There were no persisting viable cysts in any of the eight patients who had a single cyst at baseline (six of these cysts disappeared and the other two were seen as residual inflammatory nodules). In the nine patients with 2–4 lesions, 11 out of 23 cysts (48%) became non-viable (10 cysts disappeared and one became an inflammatory nodule), and four patients (44%) were free of viable cysts. When comparing the efficacy of ABZ between these subgroups of patients, the drug was significantly more effective in patients with a single cyst in terms of both cyst death (8/8, 100% versus 11/23, 48%, p= 0.003, Fisher’s exact test) and number of patients free of viable ∗ Corresponding author. Tel.: +51 13287360. E-mail address: hgarcia@jhsph.edu (H.H. Garcia). 1 Other members of the CWGP who collaborated in this work include S. odriguez (Instituto de Ciencias Neurologicas, Lima, Peru), A.E. Gonzaez (Universidad de San Marcos, Lima, Peru), M. Verastegui (Universidad cysts (8/8, 100% versus 4/9, 44%, p= 0.049, Fisher’s exact test). Spontaneous degeneration of a single viable brain cysticercus is unlikely, occurring in 20% of cases or less [4–6]. A ayetano Heredia, Lima, Peru), and V.C.W. Tsang (Centers for Disease ontrol, Atlanta, GA).