Herbert Saavedra

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.

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.

Diagnóstico y manejo de la neurocisticercosis en el Perú

Neurocysticercosis (NCC) is the most common parasitic disease of the central nervous system and is caused by larvae of the tapeworn Taenia solium. NCC is endemic in almost all developing countries. It presents as intraparenchymal forms associated with seizures or as extraparenchymal forms associated with intracranial hypertension. The clinical and epidemiological suspicion are important but the diagnosis is made primarily by images and confirmed by serology. Computed tomography (CT) and magnetic resonance imaging tests are used. Inmunodiagnosis by Western Blot, which is currently perform in the Instituto Nacional de Ciencias Neurologicas in serum and cerebrospinal fluid serves as confirmatory test. Treatment involves symptomatic measures (control of seizures or intracranial hypertension) and anticysticercal medications (albendazole and praziquantel). Anticysticercal treatment should be used under hospital conditions because of secondary effects.

Cysticidal Efficacy of Combined Treatment With Praziquantel and Albendazole for Parenchymal Brain Cysticercosis

BACKGROUND The efficacy of current antiparasitic treatment for cerebral Taenia solium cysticercosis with either albendazole (ABZ) or praziquantel (PZQ) is suboptimal. A recent study demonstrated that combining these 2 antiparasitic drugs improves antiparasitic efficacy. We present here the parasiticidal efficacy data obtained during a previous phase II pharmacokinetic study that compared combined ABZ plus PZQ with ABZ alone. METHODS The study was a randomized, double-blinded, placebo-controlled phase II evaluation of the pharmacokinetics of ABZ (15 mg/k/d, for 10 days) and PZQ (50 mg/k/d, for 10 days) in intraparenchymal brain cysticercosis. Patients received the usual concomitant medications, including an antiepileptic drug (phenytoin or carbamazepine), dexamethasone, and ranitidine. Randomization was stratified by antiepileptic drug. Patients underwent safety laboratory evaluations at days 4, 7, and 11, as well as magnetic resonance (MR) imaging at 6 months to assess parasiticidal efficacy. RESULTS Thirty-two patients were included, 16 in each arm. All of them completed antiparasitic treatment and underwent follow-up brain MR imaging. Cysticidal efficacy was strikingly higher in the combined ABZ-plus-PZQ group than in the ABZ-alone group (proportion of cysts resolved, 78 of 82 [95%] vs 23 of 77 [30%] [relative risk {RR}, 3.18; 95% confidence interval {CI}, 2.08-4.88; P < .001]; patients with complete cyst clearance, 12 of 16 [75%] vs 4 of 16 [25%] [RR, 3.00; 95% CI, 1.23-7.34; P = .005]). CONCLUSIONS The combination of ABZ plus PZQ is more effective in destroying viable brain cysticercosis cysts than ABZ alone. CLINICAL TRIALS REGISTRATION NCT00441285.

Low sensitivity and frequent cross-reactions in commercially available antibody detection ELISA assays for Taenia solium cysticercosis

To evaluate the diagnostic performance of two commercially available ELISA kits, Novalisa® and Ridascreen®, for the detection of antibodies to Taenia solium, compared to serological diagnosis of neurocysticercosis (NCC) by LLGP‐EITB (electro‐immunotransfer blot assay using lentil‐lectin purified glycoprotein antigens).

Occasional resolution of multiple parenchymal brain calcifications in patients with neurocysticercosis.

Neurocysticercosis is the infection of the CNS by cysts (larvae) of Taenia solium , a worldwide tropical disease. Cysticercosis lesions frequently locate in the gray-white matter border of the cerebral hemispheres but also occur in other neuroanatomical locations, e.g., spine, ventricles, subarachnoid space, etc.1,2 Parenchymal brain cysts usually undergo a degeneration process that ends in a calcified scar. Calcified cysticercosis cysts are easily demonstrated by CT scan3 and are assumed to persist unchanged throughout the years.4,5 We describe 2 patients in whom well-demonstrated calcified lesions were no longer seen on CT, one after 8 years and the other after 9 years. Although unusual, these cases provide proof that calcified brain cysticercosis lesions may occasionally resolve.

Antibody Banding Patterns of the Enzyme-Linked Immunoelectrotransfer Blot and Brain Imaging Findings in Patients With Neurocysticercosis

Background The enzyme-linked immunoelectrotransfer blot (EITB) assay is the reference serological test for neurocysticercosis (NCC). A positive result on EITB does not always correlate with the presence of active infections in the central nervous system (CNS), and patients with a single viable brain cyst may be EITB negative. Nonetheless, EITB antibody banding patterns appears to be related with the expression of 3 protein families of Taenia solium, and in turn with the characteristics of NCC in the CNS (type, stage, and burden of viable cysts). Methods We evaluated EITB antibody banding patterns and brain imaging findings of 548 NCC cases. Similar banding patterns were grouped into homogeneous classes using latent class analysis. The association between classes and brain imaging findings was assessed. Results Four classes were identified. Class 1 (patients negative or only positive to the GP50 band, related to the protein family of the same name) was associated with nonviable or single viable parenchymal cysticerci; class 2 (patients positive to bands GP42-39 and GP24, related to the T24-42 protein family, with or without anti-GP50 antibodies) was associated with intraparenchymal viable and nonviable infections; classes 3 and 4 (positive to GP50, GP42-39, and GP24 but also responding to low molecular weight bands GP21, GP18, GP14, and GP13, related to the 8 kDa protein family) were associated with extraparenchymal and intraparenchymal multiple viable cysticerci. Conclusions EITB antibody banding patterns correlate with brain imaging findings and complement imaging information for the diagnosis of NCC and for staging NCC patients.

Clinical topography relationship in patients with parenchymal neurocysticercosis and seizures

OBJECTIVE Discordances between imaging findings of parenchymal neurocysticercosis and seizure expression have been reported, and as such the possibility that neurocysticercosis and seizures may frequently coexist by chance has been raised. In this study, we evaluate the topographic relationship between seizure foci based on semiology and electroencephalography with the location of parenchymal neurocysticercotic lesions. METHODS Seizure information, neuroimaging (computed tomography and magnetic resonance imaging [MRI]) and electroencephalographic data from three randomized clinical trials of individuals with parenchymal neurocysticercosis and focal seizures were analyzed. Blinded epileptologists defined a potential seizure onset zone and a symptomatogenic zone for each individual based on semiology. The topographic relationship between semiology, either lesion location or areas of perilesional edema on baseline MRI, and electroencephalographic abnormalities were assessed. RESULTS Fifty-eight patients with one or two parenchymal neurocysticercotic lesions were included in this study. From them, 50 patients (86%; 95% CI, 75%-93%) showed a clinical-topography relationship with the potential seizure onset zone, and 44 (76%) also with the symptomatogenic zone. From the eight patients with no topographic relationship, five had focal seizures 30 days before or after the baseline MRI and showed perilesional edema. All of these five patients showed a clinical-topography relationship between such seizures and an area of perilesional edema, making a total of 55 patients (95%; 95% CI, 85%-99%) with clinical-topography relationship when perilesional edema is considered. Most patients with focal epileptiform discharges (7/8, 88%) had a topographic association between electroencephalographic focality, the potential seizure onset zone and a cysticercotic lesion. CONCLUSION Seizure semiology and focal epileptiform discharges are topographically related to neurocysticercotic lesions in most patients. These data strongly support seizure origin in the cortex surrounding these lesions.