Frequency and Determinant Factors for Calcification in Neurocysticercosis

Abstract

Background

Neurocysticercosis is a major cause of acquired epilepsy. Larval cysts in the human brain eventually resolve and either disappear or leave a calcification that is associated with seizures. In this study, we assessed the proportion of calcification in parenchymal neurocysticercosis and risk factors associated with calcification.

Methods

Data for 220 patients with parenchymal NCC from 3 trials of antiparasitic treatment were assessed to determine what proportion of the cysts that resolved 6 months after treatment ended up in a residual calcification at 1 year. Also, we evaluated the risk factors associated with calcification.

Results

The overall proportion of calcification was 38% (188/497 cysts, from 147 patients). Predictors for calcification at the cyst level were cysts larger than 14 mm (risk ratio [RR], 1.34; 95% confidence interval [CI], 1.02–1.75) and cysts with edema at baseline (RR, 1.39; 95% CI, 1.05–1.85). At the patient level, having had more than 24 months with seizures (RR, 1.25; 95% CI, 1.08–1.46), mild antibody response (RR, 1.14; 95% CI, 1.002–1.27), increased dose albendazole regime (RR, 1.26; 95% CI, 1.14–1.39), lower doses of dexamethasone (RR, 1.36; 95% CI, 1.02–1.81), not receiving early antiparasitic retreatment (RR, 1.45; 95% CI, 1.08–1.93), or complete cure (RR, 1.48; 95% CI, 1.29–1.71) were associated with a increased risk of calcification.

Conclusions

Approximately 38% of parenchymal cysts calcify after antiparasitic treatment. Some factors associated with calcification are modifiable and may be considered to decrease or avoid calcification, potentially decreasing the risk for seizure relapses.

We demonstrated residual calcification in 38% of viable parenchymal brain neurocysticercosis cysts that resolved after antiparasitic treatment. Combined antiparasitic therapy, early retreatment, and enhanced corticosteroid doses appear to reduce the risk of calcification and potentially reduce future seizure recurrence.

(See the Editorial Commentary by Coyle on pages e2601–3 and White on pages e2604–6.)

Neurocysticercosis (NCC), the infection of the human central nervous system by larval cysts of the pork tapeworm Taenia solium, is an important cause of neurologic disease in most of the world. Brain cysts and the associated host inflammatory response lead to seizures, intracranial hypertension, and other neurological symptoms [1, 2].

The parasite initially establishes as a viable cyst that is in immunologic equilibrium with the host and induces minimal or no inflammation. Over time, the cyst degenerates into a granuloma as the infection is cleared by the host; it then disappears or results in a calcified lesion that persists in the brain [3–6]. Calcified lesions are associated with clinical manifestations contrary to previous suggestions [7, 8] and can be permanent foci of seizures and other neurological symptoms, although the pathogenic mechanisms are not well understood [9–13].

Not all cysts calcify, however. In individuals with a single degenerating cyst (a particular presentation of NCC that is highly frequent in the Indian subcontinent), the rate of residual calcification at 1 year ranges from 20% to 30% [14]. In individuals with multiple viable cysts, a common form of disease expression in most endemic regions, the proportion of calcifications that result after antiparasitic treatment has not been systematically assessed, although estimates range from 10% to 60%, and risk factors for subsequent calcification remain unknown [5, 6]. In this study, our aims were to estimate the incidence of calcification in patients with viable parenchymal brain cysticerci 1 year after antiparasitic treatment and to identify factors associated with a higher risk for calcification.

METHODS

Study Design

This was a retrospective cohort study that used data collected in 3 clinical trials on antiparasitic treatment for viable parenchymal NCC performed by our study group in Lima, Peru, between 2006 and 2014 [15–17].

Study Outcomes

The main study outcome was the proportion of cyst calcification at 1 year after antiparasitic treatment, which was evaluated at the level of the cyst rather than the participant. For each cyst that resolved after antiparasitic treatment, the presence or absence of a calcified lesion in the location of the original cyst 12 months after the start of antiparasitic treatment was defined by topographic identification of each lesion. Cyst characteristics were assessed using magnetic resonance imaging (MRI) at baseline and at month 6 after antiparasitic treatment, and calcifications were assessed by computed tomography (CT) scan at 12 months (Figure 1).

Figure 1.

Consecutive T2 MRI slides showing 2 viable cysts at baseline in T2 MRI (left), both lesions resolved by month 6 after antiparasitic treatment (middle), and only the larger cyst calcified at month 12 (right). Lesions are marked by arrows. Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging.

Study Population and Selection Criteria

We identified eligible individuals from a total population of 220 participants in 3 parent clinical trials. The first trial compared 2 regimes of dexamethasone (DXM; either 6 mg/d for 14 days [n = 32] or 8 mg/d for 28 days with a 2-week taper [n = 32]) in patients receiving standard doses of albendazole (ABZ; 15 mg/kg/d for 14 days) [15]. The other 2 parent trials assessed the pharmacokinetics, safety, and efficacy of combined ABZ plus praziquantel (PZQ). In the second trial, patients treated with ABZ at 15 mg/kg/d for 10 days were randomized to also receive either PZQ (n = 16) or placebo (n = 16) [17, 18]. In the third trial, patients were randomized to receive 10 days of standard ABZ treatment plus PZQ (n = 41), standard ABZ treatment without PZQ (n = 43), or increased (22.5 mg/kg/d) doses of ABZ without PZQ (n = 40) [16].

All participants were aged between 16 and 65 years, had epilepsy, and had NCC with 20 or fewer viable parenchymal brain cysts at baseline based on brain CT and MRI scans. Detailed eligibility criteria for each trial were described in the original publications [15–17]. Trial participants underwent an MRI scan 6 months after treatment to assess cyst resolution and a CT scan at 12 months to identify residual calcifications (typically seen as well-defined hyperdense rounded, nodular, or punctate solid lesions). Trial participants were eligible for this cohort study if they completed both the MRI and CT follow-up evaluations and if at least 1 of the baseline viable cysts had resolved after antiparasitic treatment (see Figure 2).

Figure 2.

Flow chart of selection of study participants. Abbreviations: ABZ, albendazole; CT, computed tomography; DXM, dexamethasone; MRI, magnetic resonance imaging; PK, pharmacokinetic; PZQ, praziquantel.

Data Sources

Anonymized demographic, clinical, and radiological information collected in the original trials was collated for this study. Data included participant age (years), sex, time period between first seizure and enrollment (months), number of reactive anti-T. solium antibody bands on enzyme-linked immunoelectrotransfer blot (EITB) using lentil-lectin–purified parasite glycoprotein antigens (Western blot, 1 to 7 bands), previous antiparasitic treatment, previous use of antiepileptic drugs, antiparasitic treatment regimen received in the trial (standard ABZ, increased ABZ, or combined ABZ plus PZQ), length of antiparasitic treatment (10 days vs 14 days), initial dose of DXM (mg/d), and length of DXM treatment (10–12 days vs 28 days). MRIs were performed before and after contrast agent injection on 1.5T or 3T MRI machines using T1, T2, and fluid-attenuated inversion recovery (FLAIR) protocols at baseline and 6 months after antiparasitic treatment. Unenhanced CT scans were performed at baseline and 12 months after treatment in a Siemens Somatom IV helical scanner.

Imaging data from MRI and CT scans included the number and topographic location of the cysts and calcified lesions as well as cyst size (using the greatest diameter in millimeters), cyst content (clear or turbid), and the presence of pericystic edema, defined as hyperintense signal on FLAIR or T2 MRI sequences. Cyst resolution at month 6 was defined as absence of discernible hyperintense content on T2 MRI sequences. In addition, study charts were revised to determine whether patients had received antiparasitic retreatment between their 6-month MRI scan follow-up and their 12-month CT scan assessment. Lesions that had not resolved at month 6 follow-up MRI were not considered for calcification assessments. For the current study, 2 NCC experts reevaluated all MRI and CT scans to verify the accuracy of recorded outcome data. Any potential discrepancies were resolved by consensus.

Statistical Analyses

The main covariates were described using summary statistics (mean ± standard deviation [SD] or median with ranges for numerical variables, and percentages for categorical variables) and compared initially between included and excluded participants to rule out selection biases. The overall percentage of residual calcification in cysts that resolved after antiparasitic treatment was calculated. Due to the 2-level nature of the data, we used a multilevel Poisson regression with random effects for individual intercepts to estimate risk ratios (RRs) of calcification with 95% confidence intervals (CIs) using covariates at the cyst and individual levels. Bivariate models were initially performed for each covariate of interest. Subsequently, we performed a multivariate model that included all covariates at the cyst level using a stepwise approach with backward selection algorithm retaining covariates with P < .05 derived from the Wald test. A second model was then performed with covariates selected in the first model and including all covariates at the patient level using a similar stepwise approach. All models were estimated using mean-variance adaptive Gauss-Hermite quadrature with 7 integration points for each level of random effects. Standard errors were estimated using cluster-robust variance estimates to account for correlation within each clinical trial from which the data came. All the analyses were performed using the statistical software Stata 15.1 (StataCorp, College Station, TX).

This study analyzed clinical and neuroimaging data obtained from previous trials. These clinical studies were reviewed and approved by their corresponding institutional review boards (IRBs). Additionally, this secondary analysis was also approved as a separate study by the main IRB of the Universidad Peruana Cayetano Heredia. Data were reviewed without personal identifiers to ensure patient confidentiality.

RESULTS

Seventy-three of 220 participants in the parent trials were excluded; in 47, no cysts resolved after antiparasitic treatment, 18 did not have a 12-month CT scan, 6 did not have 6-month MRI evaluations, and brain lesions were judged as not NCC on reassessment for 2 participants (see Figure 2). The study group was thus composed of 147 participants who had at least 1 cyst that resolved 6 months after antiparasitic treatment and had both MRI and CT at follow-up.

Baseline characteristics of the study population are shown in Table 1. Included participants had a mean age of 32 years (SD, 12.2), 95 (64.6%) were male, and the median time of preexisting seizures was 24 months (range, 0.9–294). Eighty patients (54.4%) had 3 or more viable cysts at baseline, and 95 (64.6%) had 4 or more EITB antibody bands. Previous antiparasitic treatment and previous use of antiepileptic drugs were reported by 14 (9.5%) and 71 (48.3%) patients, respectively. Seventy-six patients (51.7%) received standard-dose ABZ, 29 (19.7%) received increased-dose ABZ, and 42 (28.6%) received standard-dose ABZ plus PZQ. The median daily dose of DXM was 6.5 mg/d (range, 4.5–10). The duration of DXM therapy was 10–12 days in 123 participants (83.7%) and 28 days in 24 participants (16.3%), with all of the latter receiving >6.5 mg/d. Characteristics of included and nonincluded patients at baseline were not statistically different with the exception that more excluded participants had a history of prior antiparasitic therapy than those who were included (20.6% [15/73] vs 9.5% [14/147]; P = .023).

Table 1.

Demographic, Clinical, and Radiological Characteristics of Included and Excluded Participants at Baseline

Characteristic		Included (n = 147)	Excluded (n = 73)	P Value
Age,a y		32.0 ± 12.2	33.6 ± 12.8	.367
Sex
	Female	52 (35.4%)	28 (38.4%)	.665
	Male	95 (64.6%)	45 (61.6%)
Disease time,b mos		24 (0.9–294)	24 (0.1–181)	.329
Number of basal cysts
	1–2	67 (45.6%)	36 (50.7%)	.477
	≥3	80 (54.4%)	35 (49.3%)
Basal calcifications
	None	42 (28.6%)	17 (26.2%)	.717
	1 or more	105 (71.4%)	48 (73.8%)
Electroimmunotransfer blot bandsb
	≤3	52 (35.4%)	20 (27.4%)	.265
	>3	95 (64.6%)	53 (72.6%)
Previous APT
	No	133 (90.5%)	58 (79.5%)	.023
	Yes	14 (9.5%)	15 (20.5%)
Previous antiepileptic drug
	No	76 (51.7%)	33 (45.2%)	.364
	Yes	71 (48.3%)	40 (54.8%)
APT scheme
	ABZ +  Praziquantel	42 (28.6%)	15 (20.6%)	.202
	Standard ABZ	76 (51.7%)	47 (64.4%)
	Increased ABZ	29 (19.3%)	11 (15.1%)
Days with APT
	10	102 (69.4%)	54 (74.0%)	.481
	14	45 (30.6%)	19 (26.0%)
DEXA dose,b mg/d		6.5 (4.5–10)	6.5 (4–10)	.403
Days with DEXA
	10–12	123 (83.7%)	65 (89.0%)	.288
	28	24 (16.3%)	8 (11.0%)

Total sample were 220 participants.

Abbreviations: ABZ, albendazole; APT, antiparasitic treatment; DEXA, dexamethasone.

^aMean ± standard deviation.

^bMedian (minimum–maximum).

Of the 147 participants, 92 (62%) had complete cyst cure. For the 55 patients in whom some but not all cysts resolved, 17 had received a new course of antiparasitic treatment before the 12-month CT exam, and 38 were not retreated.

A total of 497 cysts resolved after antiparasitic treatment. Of these, 188 calcified lesions were detected by CT in the topographic area that corresponded to the original viable cyst 12 months after treatment, representing a proportion of cyst calcification of 38% (95% CI, 33.68–42.17). The proportions of cysts that resulted in calcification according to study covariates are shown in Table 2. At the cyst level, variables significantly associated with risk of calcification included cyst size greater than 14 mm, location of cyst in the parietal lobe, and the presence of surrounding edema. At the patient level, a higher risk of calcification was associated with having had seizures for more than 24 months, having 3 or fewer reactive antibody bands on EITB, having received an increased dose of ABZ compared with combined treatment (ABZ plus PZQ), having received a lower daily dose of DXM (less than 6.5 mg), and not having received retreatment in the presence of incomplete cyst resolution at month 6 (Table 2).

Table 2.

Risk Ratios for the Development of Residual Calcifications After Antiparasitic Treatment in Patients With Viable Brain Parenchymal Neurocysticercosis

Study Variable	Calcified/Cysts Resolved (%)	Univariate Models		Multivariate Model 1b		Multivariate Model 2c
		RR (95% CI)	P Value	RR (95% CI)	P Value	RR (95% CI)	P Value
Cyst level
Cyst size, mm
≤14	166/453 (36.6)	Ref.		Ref.		Ref.
>14	22/44 (50.0)	1.35 (1.14–1.60)	<.001	1.30 (1.07–1.57)	.007	1.34 (1.02–1.75)	.035
Cyst content
Clear	158/435 (36.3)	Ref.
Turbid	30/62 (48.4)	1.30 (.18–2.15)	.313
Cyst location
Frontal lobe	67/172 (39.0)	1.02 (.78–1.35)	.866
Parietal lobe	60/182 (33.0)	.82 (.67–1.00)	.047
Occipital lobe	27/63 (42.9)	1.13 (.85–1.52)	.402
Temporal lobe	36/98 (36.7)	.98 (.70–1.38)	.902
Cyst edema
No	125/365 (34.3)	Ref.		Ref.		Ref.
Yes	63/132 (47.7)	1.37 (1.17–1.62)	<.001	1.36 (1.16–1.59)	<.001	1.39 (1.05–1.85)	.023
Patient level
Age (tertiles), y
16–25	67/177 (37.9)	Ref.
26–35	56/156 (35.9)	.98 (.69–1.38)	.899
>35	65/164 (39.6)	1.03 (.81–1.32)	.796
Sex
Female	63/172 (36.6)	Ref.
Male	125/325 (38.5)	1.04 (.83–1.30)	.733
Disease time, mos
≤24	79/229 (34.5)	Ref.				Ref.
>24	109/268 (40.7)	1.17 (1.13–1.21)	<.001			1.25 (1.08–1.46)	.003
Number of cysts
1–2	38/78 (48.7)	Ref.	Ref.
3 or more	150/419 (35.8)	.74 (.44–1.25)	.261
Number of calcifications at baseline
None	39/98 (39.8)	Ref.
1 or more	149/399 (37.3)	.95 (.55–1.69)	.891
Electroimmunotransfer blot bands
≥4	140/388 (36.1)	Ref.	Ref.			Ref.
≤3	48/109 (44.0)	1.21 (1.14–1.28)	<.001			1.14 (1.02–1.27)	.020
Previous APT
No	173/440 (39.3)	Ref.
Yes	15/57 (26.3)	.69 (.36–1.30)	.249
Previous antiepileptic drugs
No	92/254 (36.2)	Ref.
Yes	96/243 (39.5)	1.11 (.99–1.23)	.064
APT scheme
ABZ +  Praziquantel	78/224 (34.8)	Ref.				Ref.
Standard ABZ	73/190 (38.4)	1.09 (.84–1.41)	.525			1.04 (.71–1.51)	.861
Increased ABZ	37/83 (44.6)	1.27 (1.18–1.36)	<.001			1.26 (1.14–1.39)	<.001
Days with APT
10	136/361 (37.7)	Ref.	Ref.
14	52/136 (38.2)	.99 (.88–1.13)	.958
Dose of DXM, mg/d
>6.5	71/217 (32.7)	Ref.	Ref.			Ref.	Ref.
≤6.5	117/280 (41.8)	1.26 (1.04–1.52)	.018			1.36 (1.02–1.81)	.037
Days with DXM
10–12	163/429 (38.0)	Ref.	Ref.
28	25/68 (36.8)	.95 (.86–1.06)	.366
Cyst cure and retreatment
Incomplete cure and retreated	19/66 (28.8)	Ref.	Ref.			Ref.	Ref.
Complete cure and not retreated	111/280 (39.6)	1.41 (1.21–1.63)	<.001			1.48 (1.29–1.71)	<.001
Incomplete cure and not retreated	58/151 (38.4)	1.33 (1.16–1.53)	<.001			1.45 (1.08–1.93)	.012

The empty cells correspond to variables that were not not selected for multivarate models 1 and 2.

Abbreviations: ABZ, albendazole; APT, antiparasitic treatment; CI, confidence interval; DXM, dexamethasone; RR, risk ratio.

^aRisk ratios from univariate and multivariate models were estimated using multilevel Poisson regression with random effects for individual intercepts.

^bMultivariate multilevel Poisson regression model 1 initially included all covariates at the cyst level using a stepwise approach with backward selection algorithm to retain covariates with P value < .05 for the Wald Test.

^cMultivariate multilevel Poisson regression model 2 included covariates retained in model 1 and all covariates at the patient level using a similar stepwise approach for selection of covariates.

An initial multivariate analyses that included cyst-level covariates only demonstrated a significantly higher risk of residual calcification for cysts with a diameter greater than 14 mm (RR, 1.30; 95% CI, 1.07–1.57; P = .007) and for cysts with surrounding edema (RR, 1.36; 95% CI, 1.16–1.59; P < .001). In a second model that included these significant variables plus patient-level covariates, the risk of calcification remained higher for cysts larger than 14 mm (RR, 1.34; 95% CI, 1.02–1.75; P = .035) and for cysts with surrounding edema (RR, 1.39; 95% CI, 1.05–1.85; P = .023). Additional patient-level covariates associated with a significantly increased risk of calcification included having had seizures for more than 24 months (RR, 1.25; 95% CI, 1.08–1.46; P = .003), having 3 or fewer reactive antibody bands on EITB (RR, 1.14; 95% CI, 1.02–1.27; P = .020), having received an increased-dose ABZ regime compared with combined treatment with ABZ plus PZQ (RR, 1.26; 95% CI, 1.14–1.39; P < .001), and having received a lower daily dose of DXM (RR, 1.36; 95% CI, 1.02–1.81; P = .037). Receipt of standard-dose ABZ was not associated with a different risk of calcification compared with combined treatment.

Interestingly, the proportion of calcification in cysts that resolved after antiparasitic treatment was lower in individuals who had incomplete cyst cure and received retreatment before the 12-month CT exam compared with participants with incomplete cure who did not receive retreatment (RR, 1.45; 95% CI, 1.08–1.93; P = .012) and to participants with complete cure at month 6 (RR, 1.48; 95% CI, 1.29–1.71; P < .001; Table 2)

DISCUSSION

The majority of patients with symptomatic parenchymal brain NCC either present with brain lesions that have calcified or that have evolved from viable/degenerating cysts into calcified lesions [13]. Despite the important role of brain calcification in the pathogenesis of seizures and resulting morbidity in NCC, little is known about its frequency and characteristics and, more importantly, how residual calcifications can be avoided. This study shows that approximately 2 of 5 (37.8%) viable parenchymal brain cysts result in residual calcification 12 months after antiparasitic treatment. In addition, the design of our study took advantage of 3 independent trials with homogeneous methodology for systematic assessment factors associated with residual calcification. Large cysts and cysts with perilesional edema prior to treatment were more likely to result in residual calcification. Other factors associated with an increased risk of calcification included a longer duration of disease (epilepsy), a mild antibody response, increased doses of ABZ vs combined antiparasitic treatment (ABZ–PZQ), lower doses of corticosteroids, and lack of antiparasitic retreatment among those with incomplete cyst cure.

Overall, factors associated with increased risk of calcification suggest a significant role of inflammation in the pathogenesis of the calcification process, including baseline perilesional edema (reflecting significant ongoing inflammation), the use of lower corticosteroid doses (poorer modulation of inflammation), larger cysts (greater host exposure to parasite antigen), use of a higher dose of ABZ (causing important cyst damage but not lethal effects such as is seen with ABZ–PZQ and thus enhancing and extending inflammation), and lack of antihelmintic retreatment (failing to eliminate cyst remnants).

A single degenerating cysticercus is the most common presentation of NCC in India, where it comprises 50% to 80% of all NCC cases [19–21]. This is a milder presentation of NCC [22–25]. Multiple reports on the frequency of residual calcification in Indian patients with a single degenerating brain cysticercus, commonly ranging from 15% to 26%, can be found in the literature [14, 26–28]. Studies of this type of NCC report increased risk for calcification in cases with moderate to severe edema at baseline (odds ratio, 3.3; 95% CI, 1.50–7.36) [10] and no changes in frequency of residual calcification in response to antiparasitic treatment [3, 24, 29–32] or steroids [25, 33–36]. In some of these studies, however, follow-up CT scans were done less than 6 months after the intervention, likely underestimating the rates of calcification and missing later differential effects. In this series of patients with viable cysts, we found similarly increased risk for cysts with edema. We could not directly compare the effects of antiparasitic treatment and steroids with no intervention because of the nature of the parent trials.

Unlike the situation in single-lesion NCC, very few studies have reported the proportion of viable parenchymal brain cysts that result in calcification after antiparasitic treatment when compared with placebo. In a prior study by our group, the proportions of residual calcifications were higher than what we report here, at 62% and 38.4% for the ABZ and placebo groups, respectively [5]. In that study, however, the occurrence of calcifications was measured at 2 years (vs 12 months here), a difference that might explain the higher proportions of observed calcification.

In individuals for whom all cysts were not cured at month 6 after treatment, a new course of treatment was indicated. Some, but not all, of these individuals received early courses of retreatment (6 to 10 months after the first course of treatment, before the 12-month CT scan assessment of calcification). Interestingly, early retreatment was strongly associated with lower proportions of subsequent calcification for the subgroup of patients whose cysts had resolved by 6 months. In this subset of individuals, cysts that had resolved and that were not exposed to a second course of antiparasitic treatment were 1.5 times more likely to result in calcification than those that were exposed to a second treatment. There is no clear mechanistic explanation for why antiparasitic treatment in an already dying parasite can help to decrease the proportion of calcified lesions. One possible explanation is that antiparasitic treatment helps eliminate active or living parasite remnants that continue causing an inflammatory reaction. New clinical trials are needed to confirm that additional courses of antiparasitic treatment with or without resolution are beneficial to avoid the calcification process.

This study has some limitations. While MRI is the best neuroimaging modality to assess the viability of cysts and CT scan allows more prominent visualization of calcifications, the sensitivity and specificity of these neuroimaging techniques are not perfect. Participants in the original trials may have been evaluated using different neuroimaging machines, and this could have introduced measurement biases. However, these biases were likely nondifferential and it is unlikely that they could have significantly altered the results observed in this study. Although there was some loss to follow-up in the original trials, this was also likely nondifferential in nature. Also, while it is not entirely impossible, the close follow-up of our cohort makes it highly unlikely that patients could have received antiparasitic drug courses not registered in our records.

Although the exact mechanisms of how NCC calcifications produce seizures and epilepsy have not been determined, there are several potential pathways. Perilesional gliosis and neuronal damage have been shown in human and animal NCC, becoming enduring epileptogenic foci [27, 37–40]. In 1994, Del Brutto described perilesional edema around a calcified NCC lesion [41]. In 1998, Sheth et al reported contrast enhancement around already calcified cysticerci [42] and reported enhancement and edema in 1 symptomatic case as “disease reactivation” [43]. Soon after, Nash and Patronas reported a small series that focused on the presence of perilesional edema and its temporal relation to symptomatic episodes [44]. Subsequently, they and others [27, 44–48] suggested that calcified lesions intermittently expose parasitic antigenic material to the immune system (from morphological changes similar to bone remodeling), triggering a focal inflammatory response. It has also been proposed that direct contact of calcium with cerebral tissues can have a toxic effect, resulting in seizure activity [49].

We were able to identify a small subgroup of 18 participants in whom all cysts had resolved by month 6 and who had additional follow-up CT scans after the 12-month study period. In these cases, 21 of 79 cysts (26.6%) had calcified by month 12, and only 3 newly calcified lesions (in 3 different participants) were detected in later CT scans (mean time, 3.6 years; range, 1.0–6.6). We thus found an increment of only 3.4% in the proportion of lesion calcification after a span of 2 to 6 years postantiparasitic treatment in this subgroup of patients.

Since residual calcifications are strongly associated with an increased frequency of seizure relapses, clinical interventions to reduce calcification may reduce the risk of subsequent seizures and associated morbidity. The differential risk seen with varying regimens of both antiparasitic drugs and corticosteroids suggests that the combination of selected regimes of antiparasitic treatment and optimized control of the resulting inflammatory reaction can result in decreased calcification, likely reducing future seizure recurrences. The application of combined ABZ–PZQ treatment, higher doses of corticosteroids or perhaps newer antiinflammatory agents [50–52], and early retreatment in patients with partial or even complete cure could reduce the likelihood of calcification.

Notes

Members of the Cysticercosis Working Group in Peru include the following: Hector H. Garcia, MD, PhD; Robert H. Gilman, MD, DTMH; Armando E. Gonzalez, DVM, PhD; Seth E. O’Neal, MD, MPH; Manuela Verastegui, PhD; Mirko Zimic, PhD; Javier A. Bustos, MD, MSc, MPH, PhD (coordination board); Sofia Sanchez, MD; Manuel Martinez, MD (Instituto Nacional de Ciencias Neurológicas, Lima, Perú); Saul Santivanez, MD, PhD; Holger Mayta, PhD; Yesenia Castillo, MSc; Monica Pajuelo, PhD (Universidad Peruana Cayetano Heredia, Lima, Perú); Maria T. Lopez, DVM, PhD; Luis Gomez, DVM; Eloy Gonzalez, DVM, PhD; Ana Vargas, DVM; Cesar M. Gavidia, DVM, PhD (School of Veterinary Medicine, Universidad Nacional Mayor de San Marcos, Lima, Perú); Luz M. Moyano, MD, PhD; Ricardo Gamboa, MSc; Claudio Muro; Percy Vichez, MSc (Cysticercosis Elimination Program, Tumbes, Perú); Sukwan Handali, MD; John Noh (Centers for Disease Control, Atlanta, Georgia); Theodore E. Nash MD, MD (National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland); and Jon Friedland (Imperial College, London, United Kingdom).

Acknowledgments. The authors are particularly grateful for the enormous effort given by our clinical coordination team (M. Vera, K. Fernandez, J. Del Carpio, C. Castillo, C. Arias) and our clinical laboratory team (S. Rodriguez,^† Y. Castillo, E. Perez, P. Berrios, K. Arteaga) during the development of these 3 clinical trials.

Disclaimer. The funders had no role in study design, sample collection, analysis, interpretation, writing the manuscript, and the decision to submit the article for publication.

Financial support. The parent clinical trials were supported by intramural funding from the National Institute of Allergy and Infectious Diseases - National Institutes of Health of United States (grant 05-I-N124) and from the National Institute of Neurological Disorders and Stroke - National Institutes of Health of United States (grant RO1-NS054805). Addition partial support provided by the Fogarty International Center National Institutes Health of United States - Training Grant D43 TW001140), Tropical Medicine Research Center Program - National Institute of Allergy and Infectious Diseases - National Institutes of Health of United States (grants U19AI129909) and National Institute of Allergy and Infectious Diseases - National Institutes of Health of United States (grants 1R01AI116456) is acknowledged.

Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.