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- Material and Methods
Purpose: To determine the effect of administration of a short course of prednisolone on seizure and radiologic outcome in patients with solitary cysticercus granuloma (SCG).
Methods: One hundred forty-eight subjects presenting with new-onset seizures (<15 days duration) and with SCG demonstrated on imaging studies were randomly allocated to either treatment with prednisolone (40–60 mg/day for 2 weeks) or placebo in addition to standard antiepileptic drug therapy. The subjects were followed up for seizure recurrence for 9 months. Repeat computed tomography (CT, at 3 months) and magnetic resonance imaging (MRI, at 6 months) to evaluate resolution and calcification of the lesion.
Key Findings: There was no difference in the proportion of subjects with seizure recurrence during the follow-up period in the treatment (n = 16, 21.9%) and control (n = 19, 25.33%) groups (p = 0.7). However, generalized seizures occurred in a significantly lesser proportion of subjects in the treatment group (n = 3, 15.79%) in comparison to the control group (n = 12, 60.00%) (p = 0.015). There were no significant differences in the proportion of subjects with complete resolution of the SCG on repeat CT at 3 months [treatment group (27, 46.7%) and control group (23, 39.8%); p = 0.453] and repeat MRI at 6 months [treatment group (28, 46.7%) and control group (21, 38.9%); p = 0.402].
Significance: The administration of a short course of prednisolone does not offer significant improvement in seizure control, although a benefit in terms of reducing the likelihood of generalized seizures is possible. Furthermore, it does not improve the chances of resolution of the SCG on follow-up imaging studies.
Neurocysticercosis (NCC) is the most common parasitic infestation of human brain (Garcia & Del Brutto, 2005). The clinical presentation of NCC is varied and is determined by the number, location, and evolutionary stage of parasite(s) in the brain (Nash et al., 2006). A common and characteristic presentation of NCC is the solitary cysticercus granuloma (SCG), which essentially represents a single, degenerating cysticercus cyst in the cerebral parenchyma (Rajshekhar, 1991) (Mitchell & Crawford, 1988; Del Brutto, 1995; Singh et al., 2006). This entity manifests clinically with seizures that may be focal or focal with secondary generalization.
Despite several small clinical trials and recent guidelines, the treatment of the SCG remains controversial and comprises antiepileptic drugs (AEDs), antihelminthic drugs (including albendazole and praziquantel), and corticosteroids (Nash et al., 2006). Often, antihelminthic agents and corticosteroids are administered together, the former to obliterate the cyst and the latter to suppress host inflammatory response. The administration of corticosteroids alone (i.e., without specific antihelminthic agents) is a debatable option and has been advocated by some authors (Mall et al., 2003; Garg et al., 2006; Prakash et al., 2006; Kishore & Misra, 2007). Previously, four clinical trials reported clinical and radiologic improvement with administration of a short course of corticosteroids to individuals with SCG. These trials had small sample sizes and employed computed tomography (CT) to document resolution. We undertook a double-blind, randomized, placebo-controlled trial in order to evaluate the effect of administration of a short course (2 weeks) of prednisolone on seizure outcome and resolution as demonstrated on follow-up magnetic resonance imaging (MRI).
Material and Methods
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- Material and Methods
One hundred ninety-six patients (age range15–60 years) with new-onset seizures (<15 days duration) and imaging (either MRI or CT) fulfilling previously validated criteria for SCG, who presented to the Neurology Department at Post Graduate Institute of Medical Education & Research, Chandigarh between July 1, 2007 and December 31, 2008 were screened for the trial. Patients were excluded if they demonstrated calcific lesions on imaging; evidence of central nervous system, pulmonary or systemic tuberculosis or concomitant systemic disease; positive human immunodeficiency virus serology; were pregnant women; had received prior anticysticercal treatment or corticosteroids; or were unwilling to enter the trial or follow the trial protocols or were unable to provide informed consent. Hence, 148 subjects were finally included in the trial.
Following written, informed consent, thorough general physical and neurologic examinations were conducted on all patients. In addition, gadolinium-enhanced MRI (1.5 Tesla) with pre- and postcontrast T1 sequences [time to repetition (TR) 650, time to echo (TE) 12], proton-density (TR 4,800, TE 22), T2 (TR 4,800, TE 90), and fluid-attenuated inversion recovery (FLAIR) (TR 9,000, TE 119) sequences were undertaken upon study enrollment.
Intervention comprised prednisolone (Ind-Swift, Town Baddi, Himachal Pradesh, India) (three tablets of 20 mg each for subjects >40 kg and two tablets of 20 mg each for those ≤40 kg) for 2 weeks followed by tapering doses over 4 days. Placebo tablets prepared were identical in shape, size, strength, color, and packing. The active medicine (prednisolone) for each individual subject was packaged and labeled as group I and placebo labeled as group II. Patients were randomized to two groups (group I and group II) by a computer-generated simple randomization method administered by one study team member (BM), who had no other role in the conduct of the trial. Other study team members and patients were blinded to the randomization code and group-labeling. The code was opened upon completion of follow-up period of the trial. All subjects received AEDs [either carbamazepine (12 tablets 15 mg/kg/day, dose increased to 30 mg/kg/day in case of recurrent seizures) or phenytoin (3–6 mg/kg/day)]. Follow-up visits were scheduled at 1, 3, 6, and 9 months. During these visits, the patients submitted seizure diaries with records of seizures. Compliance to AEDs was assessed by inspection of residual medication packs. Any adverse effects reported by the subjects were recorded during these visits. A check-CT of the head was performed at the 3-month visit and MRI (on a same scanner using identical protocol to the baseline scan) was performed at 6 months.
The primary outcome measure was the number of patients who developed breakthrough seizures in either group over a follow-up period of 9 months. Secondary outcome measures included the numbers of patients with focal and generalized seizures in each group during the follow-up period. Other secondary outcome measures included the number of patients in whom complete radiologic resolution was demonstrated on CT at 3 months and on MRI at 6 months. Complete resolution was defined as complete disappearance of the lesion with no residual scar or calcification or perilesional edema.
A sample size of 140 was chosen so as to provide the trial with 80% power to detect a 10% difference in proportion of patients with breakthrough seizures over the follow-up period of 9 months, allowing for a 5% type 1 error and a 20% loss to follow-up. Analysis was done on an intention-to-treat basis. Baseline parameters for both the groups were recorded and continuous variables were compared using the Mann-Whitney test for equality of medians (Wilcoxon’s rank-sum test), whereas categorical variables were compared using the chi-square test for proportions. The Kaplan-Meier method was used to calculate the incidence rate of recurrent seizures in both the groups. The rates were then compared using the log rank test; hazard ratios (HRs) (with 95% confidence intervals, 95% CIs) for the incidence rates were then calculated. For other outcome measures, either the Student’s t-test (for continuous variables) or chi-square test (for categorical variables) was used. All statistical analysis was done using Stata Ver. 9.0 (Statacorp, College Station, TX, U.S.A.). Prior approval of the hospital ethics committee was obtained.
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Of the 148 patients, 73 were allocated to group I and 75 to group II. Twenty three patients (group I, 11; group II, 12) were lost to follow-up. Baseline characteristics of the two groups are shown in Table 1.
Table 1. Comparison of baseline characteristics of both groups
| ||Group I (n = 73)||Group II (n = 75)||p-value|
|Age|| || || |
| Median (IQR) (years)||20 (13–32)||18 (15–26)||0.14a|
|Sex (%)|| || || |
| Male||55 (75.3)||49 (65.3)||0.18a|
| Female||18 (24.66)||26 (34.67)|
|Median duration of seizures (days) (95% CI)||10 (7–13)||9 (7–11)||0.80a|
|Seizure type (%)|| || || |
| Focal||13 (17.8)||8 (10.7)||0.43a|
| Focal with secondary generalization/generalized||60 (73.2)||67 (91.3)|
|Type of lesion (%)|| || || |
| Ring enhancing||71 (97.3)||72 (96.0)|| |
| Without scolex||57 (78.1)||50 (66.7)|
| With scolex||14 (19.2)||22 (29.3)|
| Disk enhancing||2 (2.7)||3 (4)|
|Location of lesion (%)|| || || |
| Frontal||25 (34.24)||24 (32)||0.45a|
| Parietal||36 (49.31)||38 (50.67)|
| Temporal||8 (10.95)||8 (10.67)|
| Occipital||4 (5.5)||5 (6.66)|
|Size of lesion (%)|| || || |
| ≤10 mm||57 (78.08)||65 (86.67)||0.32a|
| >10 mm||16 (21.92)||10 (13.33)|
Follow-up amounted to 390 person-months in group I and 448 person-months in group II. The proportions of patients with seizure recurrence were similar in the group I (n = 16, 21.9%) and group II (n = 19, 25.33%) (p = 0.7) (Table 2). Likewise, the incidence rates of seizure recurrence in the two groups (group I, 1.41/1,000 person-days; group II, 1.37/1,000 person-days) were similar [HR (95% CI) 0.97 (0.47–1.99 )]. When seizures were categorized into those that were focal, focal with secondary generalization, or generalized, a statistically significant reduction in number of patients with generalized seizures in group I was noted (p = 0.015) (Table 2). None of the patients in either group reported significant adverse effects apart from the occurrence of a skin rash in three subjects in group I and two in group II. All five patients with skin rash were among those patients receiving treatment with carbamazepine.
Table 2. Breakthrough seizures in the two groups after randomization
| ||Group I (n = 73), %||Group II (n = 75), %||p-value|
|Number of patients with breakthrough seizures||16 (21.9)||19 (25.3)||0.7a|
|Number of patients with focal seizures during follow-up||12 (63.2)||5 (25.0)||0.015b|
|Number of patients with focal seizures with secondary generalization||4 (21.1)||3 (15.0)|
|Number of patients with generalized seizures||3 (15.8)||12 (60.0)|
CT was performed in 116 (78.4%) patients [group I (58, 79.5%); group II (58, 77.3%)] at 3 months of follow-up. Complete resolution was observed in 27 patients (46.6%) in group I and 23 (39.7%) in group II (p = 0.45). Residual calcification was noted in eight patients (13.8%) in group I and six patients (10.3%) in group II (p = 0.81). At 6 months follow-up, MRI was performed in 114 patients (77.0%) (group I (60, 82.2%); group II (54, 72.0%)]. Complete resolution was noted in 28 patients (46.7%) in group I and 21 patients (38.9%) in group II (p = 0.40).
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We were unable to demonstrate significant benefit of corticosteroid administration in terms of most outcome measures in this trial and, therefore, were unable to replicate the improved outcome reported in the previous trials (Mall et al., 2003; Garg et al., 2006; Prakash et al., 2006). The only outcome measure for which significant clinical benefit was noted was in the proportion of subjects with generalized seizures, which was significantly less in group I (Table 2). This might be of consequence as generalized seizures have a greater impact on the quality of life of patients. In addition, although the number of seizures in group II was more than twice the number of seizures in group I, this was largely due to one patient in group II who had 20 seizures (Table 2). If this subject was excluded from group II, the total number of seizures in both the groups was nearly similar (25 in group I and 31 in group II).
The rationale for the routine administration of corticosteroids alone (without any specific antihelminthic treatment and in addition to AEDs) is based on anecdotal observations of the clinical improvement in several symptoms related to the host inflammatory response in NCC. Seizures in individuals with SCG are believed to be the result of the host inflammatory response to the degenerating parasite. Possibly the antiinflammatory properties of corticosteroids may underlie the observed symptomatic benefit. However, it is possible that corticosteroids might modify the natural history of SCG by increasing the chances of resolution of the granuloma.
The differences in the results of our trial and previous ones might be due to differences in the subject population or the methods used. Moreover, the rates of complete resolution of the SCG on follow-up imaging in the absence of any specific treatment (e.g., antihelminthic treatment or corticosteroids) apart from AEDs is variable, that is, from 23–53% (Gogia et al., 2003; Mall et al., 2003; Garg et al., 2006; Kishore & Misra, 2007). The rates of complete resolution in our study of 39% in the placebo group and 47% in the treatment group are well within the range of rates of complete resolution of SCG in previously reported studies. Similarly, the proportion of patients who develop seizure recurrence in the absence of any specific intervention other than AEDs has varied from 19–46% in previous studies (Gogia et al., 2003; Mall et al., 2003; Garg et al., 2006; Prakash et al., 2006; Kishore & Misra, 2007). In our trial, 22% subjects in the treatment group and 25% in the control group reported seizure recurrence during the follow-up period. These rates are also within the previously reported range of the proportion of subjects with seizure recurrence in SCG.
Two limitations of this study are noteworthy. One is that the wide confidence intervals of the hazard ratio of the incidence rates of seizures in the two groups do not exclude a beneficial effect of corticosteroids. Secondly, although both the physician and the subjects were blinded to the nature of the intervention, the blinding is never ideal due to the clinically obvious effects and side effects of corticosteroids.
The problem with administration of corticosteroids alone (without specific antihelminthic treatment) is that this approach precludes the administration of specific antihelminthic agents, which at present are the only agents shown to modify the course of SCG, albeit to a modest degree (Padma et al., 1994; Baranwal et al., 1998; Gogia et al., 2003; Kalra et al., 2003; Del Brutto et al., 2006). Therefore, the options for specific treatment of SCG include corticosteroids alone, antihelminthic agents, and antihelminthic agents combined with corticosteroids. Which of these options is best remains an unsettled issue. The only way to settle this issue is by conducting a sufficiently randomized, double placebo-controlled, double-blind, large trial comparing several different treatment approaches including corticosteroids alone, corticosteroids with antihelminthic agents, and antihelminthic agents alone.