A diagnostic and therapeutic scheme for a solitary cysticercus granuloma

Abstract

Background:

Solitary cysticercus granuloma (SCG) is one of the most common forms of presentation of neurocysticercosis (NCC). The diagnostic workup and management approach to this condition remain uncertain and controversial.

Objective:

To review evidence and develop a consensus approach to the diagnosis and treatment of SCG.

Methods:

A multidisciplinary expert group meeting was convened in order to review and discuss various aspects of management of patients with SCG. Evidence reviewed was classified and a consensus was evolved according to standard protocols.

Results:

SCG is commonly recognized on CT as an enhancing lesion measuring <20 mm. Further evaluation with MRI does not add much information. The use of antihelminthic agents (specifically, albendazole in combination with corticosteroids) and corticosteroids alone have been shown to improve radiologic resolution and seizure outcome in patients with SCG. However, the sizes of the effects are modest. By convention, all patients with SCG presenting with seizures are initiated on antiepileptic drugs (AEDs). Available evidence suggests that withdrawal of AEDs after complete resolution of the SCG is safe. There is a high risk of seizure relapse after AED withdrawal in patients with calcific residue following resolution of the SCG. The duration of AED prophylaxis in these individuals is unclear.

Conclusions:

It is desirable to have large, multicenter trials with sufficiently long follow-up, comparing outcomes with the use of antihelminthics with or without corticosteroids and corticosteroids alone in order to dissect out the benefits accrued due to each of these classes of drugs.

GLOSSARY

AED

= antiepileptic drug;

CI

= confidence interval;

EITB

= enzyme-linked immunoelectrotransfer blot;

NCC

= neurocysticercosis;

OR

= odds ratio;

RCT

= randomized controlled trial;

SCG

= solitary cysticercus granuloma.

Neurocysticercosis (NCC) refers to infection of the human brain by the larval stage of the helminth Taenia solium. The disease is widely prevalent, especially in several low- and middle-income countries of the world, including India, China, sub-Saharan Africa, and Central and South America.^1,2 In addition, NCC is of emerging importance in many high-income countries (e.g., United States) with high volumes of immigration traffic from T solium–endemic regions of the world.^3,4

The clinical and radiologic manifestations of NCC are pleomorphic.^5,6 Several varieties of NCC have been recognized depending upon the number, location, and evolutionary stage of the cysticerci in the human brain.^7–12 At a previous consensus meeting, experts agreed that no single treatment approach could be advocated and that management options varied according to the type of clinical presentation.¹³ A common presenting form of NCC is the solitary cysticercus granuloma (SCG), which represents a single, degenerating parenchymal cysticercus cyst.^14,15 This form of presentation is more frequently reported from India and the United States.^4,16 It has also been reported in Latin American series, albeit with a somewhat lesser frequency.1,7,14,16,17 Treatment approach to SCG has not been optimally defined. While treatment with albendazole has been shown to improve outcome in live, cystic parenchymal cysticercosis, the benefits of antihelminthic treatment in patients with SCG remain uncertain despite several randomized trials.^18–25 Likewise, controversy exists regarding the use of corticosteroids, alone or in combination with antihelminthic drugs, and the optimal duration of antiepileptic drug (AED) therapy.^26–32 We report the outcome of an expert group meeting held in order to define the optimal management approach to SCG.

METHODS

Eighteen experts with published research experience in cysticercosis (mostly neurologists but also a neurosurgeon, pediatrician, general physician, parasitologist, infectious disease specialist, and neuroradiologist) were invited to the meeting. They reviewed and presented evidence regarding the following: 1) role of imaging and serology in the diagnosis of SCG; 2) benefit of (or lack thereof) antihelminthic treatment (albendazole, praziquantel, or combined albendazole and praziquantel) alone or in combination with corticosteroids and corticosteroids alone (without antihelminthic drugs) on seizure outcome and radiologic resolution in SCG; 3) the optimal choice of and duration of AED treatment; and 4) the appropriate timing and modality for follow-up imaging.

Medline and Cochrane Central Register for Controlled Clinical Trials were searched using the terms “solitary cysticercus granuloma” or “single lesion” and “neurocysticercosis.” A similar search was later undertaken using the LILACs, from which no articles could be retrieved using the search strategy. The primary search was further refined using appropriate search terms by each of the reviewers according to their assigned topics (appendices e-1 and e-3 on the Neurology® Web site at www.neurology.org). Bibliographies of retrieved articles were hand-searched for additional primary studies. In addition, inquiries were made from all invited experts to identify unpublished treatment trials for SCG. The retrieved studies were appraised and assessed regarding method of treatment assignment (randomization), control of selection bias (intention-to-treat vs per-protocol analysis and reporting of loss to follow-up), blinding, and method of outcome assessment. Available evidence for and against various therapeutic interventions and investigations were classified according to criteria given in appendix e-2 (tables e-1 and e-2).^33,34 Where evidence regarding the study question was not available or was conflicting, attempt was made to generate consensus by discussion. Finally, the strength of recommendations made thereof were graded according to criteria outlined in appendix e-2 (table e-3).³⁵

RESULTS

Definition of SCG.

The working definition of SCG for the purpose of formulating the diagnostic and therapeutic scheme was based on previously validated clinical and CT criteria (figure 1).^15,36 These criteria were expanded and revised through consensus in order to include MRI features of SCG (figure 2, A–D, and table 1).

Figure 1 Contrast CT appearance of single enhancing lesion with an eccentric nodule representing the scolex in the left frontal region

Figure 2 MRI appearances of solitary cysticercus granuloma (SCG)

Coronal fluid-attenuated inversion recovery (A) and T1 unenhanced (B) both showing an eccentric scolex, and gadolinium-enhanced T1-weighted (C) and T2-weighted (D) images of an SCG in the right frontal location.

Table 1 Clinical and radiologic features consistent with a diagnosis of SCG

Natural history of SCG.

The natural history of SCG was studied under 2 aspects: 1) radiologic resolution and 2) seizure outcome.

Radiologic resolution.

To assess the natural resolution dynamics of SCG, only those studies that included patients soon after their first seizure were analyzed. Review of these observational studies suggested that the natural history of SCG could take one of the following paths: 1) the lesion could completely resolve or 2) the lesion could resolve by leaving a punctuate calcific residue.^37–39 In one prospective study of 210 patients with SCG followed up after their first seizure, the estimated resolution rates on follow-up CT were 19% at 3 months, 36% at 6 months, and 63% at 1 year.³⁷

Seizure outcome.

Seizure outcome in individuals with SCG was dichotomized into 1) those seizures that recurred while the granuloma was actively degenerating and 2) those that recurred following resolution of the granuloma. The natural history of seizure outcome was determined from data of control arms of the several controlled trials (no intervention other than AEDs) in SCG. These data refer to the incidence of seizure recurrence while the granuloma was actively degenerating and suggested that seizures could recur in 13%–48% of the individuals while on AEDs alone for 6–15 months (table 2).22,26,27,31,32 On the other hand, in a prospective, observational study evaluating the incidence of seizure recurrence following resolution of the granuloma and withdrawal of AEDs (mean follow-up period 66 months) in a referral hospital-based cohort of individuals, 15% of the individuals had seizures.³⁸

Table 2 Natural history (complete resolution on follow-up CT) and seizure outcome derived from control arms (no treatment apart from antiepileptic drugs) of various controlled trials in SCG

Statement.

The majority of SCGs resolve by 1 year. The natural history of SCG may take one of the following paths: 1) the lesion may completely resolve or 2) the lesion may resolve by leaving behind a punctuate calcific residue. The risk of seizure recurrence remains high as long as the granuloma is visible on imaging as an enhancing lesion (level of evidence: Class IV) (table 2).22,26,27,31,32 Seizure outcome improves following resolution of SCG (level of evidence: Class IV).

Investigative workup of SCG.

Imaging.

The initial imaging evaluation of SCG may be either contrast CT or MRI (figures 1 and 2, A–D). Two head-to-head comparison studies of CT and MRI in the characterization of SCG were available; however, these studies were performed on highly selected populations and the MRI techniques used were suboptimal.^21,40 In these studies, MRI was not found to be superior to CT in the diagnosis of SCG (level of evidence: Class II).

Recommendation.

Once CT demonstrates a single enhancing lesion consistent with a diagnosis of SCG (see table 1), further evaluation with MRI may not be required (strength of recommendation: C).

Immunologic tests.

Although several serologic assays for cysticercosis are available, currently the enzyme-linked immunoelectrotransfer blot (EITB) assay is the standard of serologic diagnostic evaluation.⁴¹ It is highly sensitive and specific as a screening test for cysticercosis and detects exposure to the parasite. In multiple NCC, the EITB was found to be 100% sensitive and 99% specific when performed on serum. In hospital-based series of SCG, however, the yield of the EITB was considerably lower, i.e., 20%–80%^42–44 (level of evidence: III). No published studies of the performance of the EITB in the CSF in cases of SCG are available. A practical limitation is that the EITB is not widely available in many parts of the world where cysticercosis is endemic.

Recommendation.

Where available, the EITB may be performed on serum in order to establish exposure to T solium parasite in individuals with SCG (strength of recommendation: C).

Antihelminthic treatment of SCG.

Overview of randomized controlled trials and meta-analysis.

Several randomized trials attempted to clarify the effect of antihelminthic treatment in SCG. However, data from these trials were conflicting (table 3).^22–25 Subsequently, a meta-analysis of randomized trials of albendazole in individuals with 1–2 parenchymal granuloma was undertaken.⁴⁵ Following this meta-analysis, more randomized controlled and pseudo-randomized trials comparing albendazole alone or with corticosteroids with corticosteroids alone or with a combination of albendazole, praziquantel, and corticosteroids were performed.20,28,46,47 A summary of these trials with the 2 main outcome measures, i.e., radiologic resolution and seizure outcome, is presented in tables 3 and 4.

Table 3 Randomized controlled trials of treatment in SCG

Table 4 Active comparator trials of antihelminthic drugs (albendazole and praziquantel) and corticosteroids in solitary cysticercus granuloma

The meta-analysis revealed a trend toward early resolution of 1–2 brain cysticercus granulomas with the administration of albendazole (odds ratio [OR] 1.18; 95% confidence interval [95% CI] 0.82–1.71).⁴⁵ However, a recalculation done after excluding one trial with an outlier OR showed that albendazole significantly improved resolution of the granuloma (OR 1.93; 95% CI 1.21–3.08). The meta-analysis also demonstrated a significant benefit of intervention in preventing seizure recurrence (OR 0.36; 95% CI 0.21–0.62).22,23,25,45

Dose, duration, and side effects.

All available trials used albendazole in a universally accepted dose of 15 mg/kg/day in 2–3 divided doses. However, the duration of treatment was quite variable (1–4 weeks).^22–25 An uncontrolled study of subjects with SCG treated with albendazole reported adverse effects in 35%.⁴⁸ In one study, treatment was associated with a trend toward increased risk of seizures for the period during which albendazole was administered.²⁵

Statement and recommendation.

The meta-analysis and other studies suggest a possible beneficial effect of albendazole in subjects with SCG in the form of improved resolution rates of the granuloma and better seizure control (level of evidence: Class II). However, the size of these effects appears to be modest. Moreover, the component trials of the meta-analysis appear to have several limitations. Hence, in order to make definite conclusions regarding the effect of albendazole in SCG, larger multicentric trials with sound methodology are required. Until such evidence is available, a short course (1–2 weeks) of albendazole (with or without corticosteroids, depending upon the judgment of the treating physician) may be prescribed soon after presentation, i.e., the first seizure (strength of recommendation: A).

Role of corticosteroids.

The routine use of corticosteroids alone (without specific antihelminthic treatment) in the management of SCG was advocated by some authors. Four small published trials and one unpublished trial were available (table 3).26,27,31,32,49 Three of the published trials were from one center, thus essentially constituting a single-center experience.^26,27,31 The study designs in some of these trials had limitations. All except the recent unpublished trial demonstrated both significantly better rates of radiologic resolution on follow-up CT scans and significantly lesser incidence of seizure recurrence with corticosteroid treatment.26,27,31,32,49

Statement and recommendation.

While treating individuals with SCG, one can either prescribe a short course of corticosteroids alone (without specific antihelminthic treatment) or antihelminthic drugs (alone or with corticosteroids). The concept of prescribing a short course of corticosteroids alone is in conflict with the practice of administering antihelminthic drugs (alone or with corticosteroids) to individuals with SCG. Ideally, a large randomized, double-placebo-controlled trial comparing corticosteroids alone, albendazole alone, and albendazole with corticosteroids is required in order to dissect out the benefits accrued due to either agent. Until such evidence is available, definite recommendations regarding the use of corticosteroids alone in the management of SCG cannot be made (strength of recommendation: C).

Antiepileptic drug therapy.

Duration of AED therapy.

Three open-labeled trials compared administration of AEDs for short duration (6 months) vs longer duration (12–24 months) in individuals with SCG and seizures.^29,30,50 The studies concluded that there was no additional benefit of the longer-duration AED administration in individuals in whom the SCG had resolved. However, pooled data from the 3 studies also suggested that the risk of seizure recurrence was greater (OR 1.29; 95% CI 0.70–2.35; p = 0.42) with short-duration AED treatment. This increased risk with early withdrawal of AEDs was largely due to an increased incidence of seizure recurrence in those individuals in whom the granuloma resolved leaving behind a calcific residue. The presence of a calcific residue increased the risk of seizure/second in the postresolution period (pooled OR 11.47; 95% CI 4.96–26.51; p = 0.0001).

Statement and recommendations.

The risk of seizure recurrence in an individual with SCG is related to the persistence of the enhancing lesion (level of evidence: Class IV). The currently used AEDs effectively prevent seizure recurrence. It is appropriate to continue AEDs until such time that the lesion (granuloma) is actively degenerating (i.e., appears as an enhancing lesion on imaging studies). The AED may be withdrawn once complete resolution of the granuloma is demonstrated on follow-up imaging studies (strength of recommendation: C).

The long-term seizure outcome in patients with SCG is generally good (level of evidence: Class III). However, the risk of seizure recurrence remains high if the granuloma resolves leaving behind a calcific residue (level of evidence: Class II). In the case of resolution with calcification, longer duration of AED should be considered (strength of recommendation: B). It is unclear how long AEDs should be administered to individuals with SCG that resolve with calcification.

Choice of AEDs.

Apart from a single, small, open-labeled trial (clobazam vs phenytoin), there were no comparison studies of various AEDs in the management of seizures associated with SCG.⁵¹ Both phenytoin and carbamazepine were shown to increase the metabolism of praziquantel and albendazole, though the clinical significance of these interactions remained uncertain.^52,53 Thus, these AEDs should ideally be avoided at least for the period of treatment with antihelminthic drugs in individuals with SCG. There is no reported experience with the newer AEDs in the treatment of seizures associated with SCG.

Recommendation.

Any AED might be used for much of the period of treatment in individuals with SCG. A newer, non-enzyme-inducing AED might be considered for the period of time that antihelminthic treatment is administered (strength of recommendation: C).

Appropriate timing and modality of follow-up imaging.

In an observational study of subjects with SCG and seizures followed up within 1 month of the first seizure, resolution of the granuloma on follow-up CT was demonstrated in 19% of cases at 3 months, 36% at 6 months, and 63% at 12 months.³⁷ The choice of follow-up imaging is between CT and MRI. Head-to-head comparison studies that might determine which of the 2 imaging modalities is superior for follow-up purposes have not been undertaken. An observational follow-up study based on magnetization transfer MRI demonstrated resolution with perilesional gliosis in a proportion of patients with SCG.⁵⁴ The authors of this study suggested that the occurrence of perilesional gliosis correlated with seizure recurrence in the follow-up period.

Recommendation.

Follow-up imaging (either contrast-enhanced CT or MRI) should be undertaken at 6 months following initial symptomatic presentation in all individuals with SCG (strength of recommendation: C). However, earlier CT (e.g., at 3 months) might be useful in order to identify those lesions that enlarge or change morphology, hence suggesting an alternative etiology (e.g., neoplasm, tuberculoma, or fungal granuloma) (strength of recommendation: C).

DISCUSSION

A logical first step in formulating the diagnostic and therapeutic scheme is to accurately define SCG. The SCG may be identified on either CT or MRI. The appearance on CT is commonly referred to as the single enhancing lesion (figure 1). The notion that these lesions represent solitary infestation of the cerebral parenchyma by cysticercus is based on a single, small, highly selected series of stereotactic-guided biopsies from a referral hospital, which suggested a histologic diagnosis of cysticercosis in the majority (level of evidence: Class IV).⁵⁵ From a pathologic standpoint, the lesions might represent either the colloidal or granular-nodular stage in the evolutionary cycle of cysticerci as a clearcut differentiation between the 2 stages might not be possible upon imaging. In essence, the SCG represents a degenerating single cerebral cysticercus cyst. A scolex might or might not be identified upon imaging studies. In controlled follow-up studies of SCG, lesions with evidence of calcification upon imaging at presentation have mostly been excluded. Hence, the observation of a single, ring- or disc-enhancing lesion on CT is highly suggestive of a cysticercus granuloma, provided the size criterion of less than 20 mm is strictly met (level of evidence: Class IV) (table 1).⁵⁶ Lesions larger than 20 mm or conglomerate ring lesions might not denote SCG (level of evidence: Class IV).⁵⁷

Investigative workup of SCG.

Imaging.

Imaging and serologic studies are widely used in the diagnosis of NCC. Either CT or MRI may be used in the imaging evaluation of SCG (figures 1 and 2, A–D). Although MRI better characterizes the pathologic stage of the lesion (colloidal vs granular-nodular stage), identifies an eccentric nodule (or scolex), and may rarely reveal granulomas at sites that are obscured by bone artifacts (e.g., temporal location),¹⁴ it rarely provides additional information that might impact the management of SCG.^21,40 In addition, there are limitations to performing MRI in resource-poor countries including the lack of widespread availability and the additional cost imposed. Hence, the expert group accepts by consensus that contrast-enhanced CT sufficiently establishes the radiologic diagnosis of SCG provided all criteria listed (table 1) are met (strength of recommendation: C). However, it may be cautioned here that in many resource-poor countries, the available CT scanners might be of the older generation and characterization of SCG on these scanners might be suboptimal.

Antihelminthic treatment of SCG.

There are several problems with the published randomized trials of antihelminthic treatment in SCG. In most trials, sample size calculations have not been performed and many have not explicitly described the randomization procedures. Apparently, only some of the studies blinded the evaluators to outcome measures. Outcome measures and study designs relating to the assessment of seizure recurrence following therapeutic intervention with antihelminthic agents have varied quite considerably between the various trials. For instance, some studies excluded seizures that occurred during the first month.²⁵ The period of follow-up in the trials also varied from 6 months to 15 months. Finally, all the randomized studies involved small numbers of subjects. Based on the results of the meta-analysis, it seems that albendazole provides modest benefit in the form of improved rates of radiologic resolution and a reduction in the incidence of seizure recurrence.⁴⁵ However, these effects have been evaluated only in the short term since the follow-up in the available trials is mostly less than 1 year.^22–25

Subgroup effects and covariates.

It is possible that the effect of antihelminthic treatment on resolution of the lesion may vary among different subgroups of SCG. Examples of subgroups include colloidal vs granular-nodular morphology, the presence or absence of a demonstrable scolex on MRI, and disc vs ring pattern of enhancement on CT. None of the studies have analyzed subgroup effects on the outcome parameters, though it would be ideal to determine whether such effects exist in future trials. Likewise, the effect of timing of therapeutic intervention in relation to duration of symptoms on outcome has not been adequately studied. It is a matter of debate whether antihelminthic treatment should be instituted upon initial presentation following the first seizure or only if follow-up imaging shows persistence of granuloma.⁵⁸

Role of corticosteroids.

Several trials regarding the use of a short course of corticosteroids alone (without specific antihelminthic treatment) are now available.26,27,31,32,49 One problem with the available trials is that they do not provide information on the timing of recurrent seizures in relation to the administration of corticosteroids. Thus, it is not clear if the benefits in seizure outcome due to corticosteroids are a result of the reduced likelihood of seizures during and immediately after corticosteroid administration owing to their anti-inflammatory action or due to a more sustained effect by altering the natural history of the granuloma.

Antiepileptic drug therapy.

Carbamazepine and phenytoin are the most frequently used AEDs for prevention of seizure recurrence in individuals with SCG. The drugs are relatively cheap and easily available in most low- and middle-income countries. There is virtually no experience with the use of the newer AEDs in SCG. In addition, the newer AEDs may not be widely available and are more expensive.

Appropriate timing and modality of follow-up imaging.

Based on limited data available, it is conventional practice to perform follow-up imaging 6 months after initial presentation of the SCG.³⁷ Either CT or MRI might be used for follow-up imaging. An argument in favor of CT is that it is thought to be superior to MRI in detecting calcific residues. However, modern MRI techniques (e.g., T2* imaging) are sufficiently sensitive for detecting minor calcifications.⁵⁹ Access to MRI may be restricted due to limited availability of MRI machines and also the cost involved. Hence, the choice of follow-up imaging between MRI and CT (or both) may be based on availability and cost considerations.

Several issues in the management of SCG need to be resolved in the future. The role of initial and follow-up investigations including CT and MRI needs to be determined in a larger controlled study. In addition, a carefully planned, double-blind, (double-) placebo-controlled randomized trial is desirable in order to define the role of various classes of therapeutic agents alone or in combination in individuals with SCG. The trial should incorporate quality of life measures and cost-benefit analyses especially in the economic conditions of the geographic regions in which SCG are commonly found.

AUTHOR CONTRIBUTIONS

The meeting was conceptualized and organized by G.S., S.P., and M.M.; V.R., J.M.K., and G.S. wrote the paper, which was reviewed by H.H.G. and S.P. All invited speakers reviewed the literature. Imaging illustrations were selected and provided by N.K.

COINVESTIGATORS

The following were the participants in the Expert Group Committee: J.S. Chopra, FRCP, PhD (Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India; Advisor, Expert Group Committee), R.S. Wadia, MD (Department of Neurology, BJ Medical College, Pune, India; Advisor, Expert Group Committee), Meena Gupta, MD, DM (Department of Neurology, GB Pant Hospital, New Delhi, India; Member, Expert Group Committee), M. Gourie Devi, MD, DM, DSc (Department of Neurology, Ganga Ram Hospital, New Delhi; Advisor, Expert Group Committee), M.V. Padma, MD, DM (Department of Neurology, All India Institute of Medical Science, New Delhi, India; Reviewer and Speaker, Expert Group Committee), Manjari Tripathi, MD, DM (Department of Neurology, All India Institute of Medical Science, New Delhi, India; Reviewer and Speaker, Expert Group Committee), Rakesh Shukla, MD, DM (Department of Neurology, Chatrapati Shahuji Medical University, Lucknow, India; Reviewer and Speaker, Expert Group Committee), Gursaran Kour, MD (Sidhu Hospital Doraha, India; Resource General Practitioner, Expert Group), U.K. Misra, MD, DM (Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India; Reviewer and Speaker, Expert Group Committee), Kurupath Radhakrishnan, MD, DM (Department of Neurology, Shri Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala, India; Reviewer and Speaker, Expert Group Committee), Pratibha Singhi, MD (Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India; Reviewer and Speaker, Expert Group Committee), Pratap Sanchetee, MD, DM (Consultant Neurologist, Jodhpur, India; Member, Expert Group).

DISCLOSURE

Prof. Singh serves as an Associate Editor for Neurology India; has funding for travel from Janssen and Sanofi-Aventis; and has received research support from the Indian Council of Medical Research. Dr. Rajshekhar serves on the editorial boards of Neurology India, the British Journal of Neurosurgery, and Stereotactic and Functional Neurosurgery; and receives research support from the Indian Council of Medical Research and the Flemish InterUniversity Council. Dr. Murthy serves as Editor for Neurology India and on the editorial board of Neurocritical Care. Dr. Prabhakar has received research support from the Indian Council of Medical Research and Department of Biotechnology, India. Dr. Modi and Prof. Khandelwal report no disclosures. Dr. García serves as an Associate Editor of PLoS Neglected Tropical Diseases, as an editorial consultant for The Lancet, and on the editorial boards of the American Journal of Tropical Medicine and Hygiene, Experimental Parasitology, the World Journal of Gastroenterology, Annals of Neurosciences (India), and the Journal of Neuroparasitology; and receives research support from the NIH (NINDS R01 NS054805 [PI] and TW001140 [PI]), the Gates Foundation, and The Wellcome Trust.

Address correspondence and reprint requests to Dr. Gagandeep Singh, Department of Neurology, Dayanand Medical College, Ludhiana, 141001, Punjab, India gagandeep_si@yahoo.co.uk

Supplemental data at www.neurology.org

Study funding: The meeting was partially supported by a grant from Zydus-Cadilla, India Ltd., which had no role in the organization and proceedings of the meeting and in the formulation of the recommendations and the decision to publish.

Disclosure: Author disclosures are provided at the end of the article.

Received March 14, 2010. Accepted in final form August 23, 2010.