Transcript Evidence-based Guideline Update: NSAIDs, and other

Evidence-based Guideline: Treatment
of Parenchymal Neurocysticercosis
Report of the Guideline Development
Subcommittee of the American Academy of
Neurology
©2013 American Academy of Neurology
Guideline Endorsement
This guideline is endorsed by the American
Epilepsy Society.
©2013 American Academy of Neurology
Authors
 Ruth Ann Baird, MD
 Sam Wiebe, MD
 Joseph R. Zunt, MD, MPH
 John J. Halperin, MD, FAAN
 Gary Gronseth, MD, FAAN
 Karen L. Roos, MD, FAAN
©2013 American Academy of Neurology
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©2013 American Academy of Neurology
Presentation Objectives
 To present the review of the evidence base
for different treatment strategies in
intraparenchymal neurocysticercosis in
adults and children
 To present evidence-based
recommendations
©2013 American Academy of Neurology
Overview
 Background
 Gaps in care
 American Academy of Neurology (AAN) guideline


process
Analysis of evidence, conclusions,
recommendations
Recommendations for future research
©2013 American Academy of Neurology
Background
 Cysticercosis, infection with the larval form of
Taenia solium, is widely prevalent in developing
countries of Africa, Asia, and Latin America.
• Considered by the World Health Organization (WHO) to be the
most common preventable cause of epilepsy in the developing
world, with an estimated 2 million people having epilepsy caused
by T. solium infection.1
 Humans can acquire two different forms of
infection—by eating raw or undercooked pork
containing T. solium cysts or by eating food
contaminated with T. solium eggs.
• Cysts consumed in undercooked meat mature into adult
parasites in the human intestine, at which time they release eggs
and gravid proglottids in the stool. This form of intestinal
infection is called taeniasis.
©2013 American Academy of Neurology
Background, cont.
 When T. solium eggs are consumed, through

fecal–oral transmission from another human with
taeniasis or through autoinfection, they release
oncospheres into the host’s digestive tract and
can then migrate throughout the host’s body,
becoming encysted in end organs.
This systemic infection is called cysticercosis.
Seeding of larvae in the CNS results in
neurocysticercosis. Neurocysticercosis, in turn,
may affect the CNS parenchyma or the CSF space.
©2013 American Academy of Neurology
Background, cont.
 This guideline focuses solely on parenchymal

infections.
Optimal treatment of this infection has been the
subject of considerable debate, with controversy
regarding the appropriate role of both
corticosteroids and cysticidal drugs such as
praziquantel or albendazole for active infections.
©2013 American Academy of Neurology
AAN Guideline Process
 Clinical Question
 Evidence
 Conclusions
 Recommendations
©2013 American Academy of Neurology
Clinical Questions
 In patients with symptomatic intraparenchymal


neurocysticercosis, is cysticidal therapy more
effective than no therapy, and does it affect longterm seizure outcome?
In patients with symptomatic intraparenchymal
neurocysticercosis, is treatment with
corticosteroids more effective than no
treatment?
When during the course of antiparasitic
treatment should steroids be started?
©2013 American Academy of Neurology
Clinical Questions, cont.
 What is the efficacy of antiepileptic drugs (AEDs)
in treating or decreasing occurrence of
subsequent seizures secondary to
intraparenchymal neurocysticercosis, and what is
the optimal time course of AED treatment for
seizures secondary to intraparenchymal
neurocysticercosis?
©2013 American Academy of Neurology
Literature Search/Review
 Rigorous, Comprehensive, Transparent
Search
Search
Review abstracts
Review full text
Relevant
©2013 American Academy of Neurology
Select articles
AAN Classification of Evidence
 All studies meeting inclusion/exclusion
criteria defined a priori rated Class I, II, III,
or IV
 Five different classification systems
• Therapeutic
Randomization, control, blinding
• Diagnostic
Comparison with reference standard
• Prognostic
• Screening
• Causation
©2013 American Academy of Neurology
AAN Level of Recommendations
 A = Established as effective, ineffective or harmful (or
established as useful/predictive or not
useful/predictive) for the given condition in the
specified population
 B = Probably effective, ineffective or harmful (or
probably useful/predictive or not useful/predictive)
for the given condition in the specified population
 C = Possibly effective, ineffective or harmful (or
possibly useful/predictive or not useful/predictive) for
the given condition in the specified population
 U = Data inadequate or conflicting; given current
knowledge, treatment (test, predictor) is unproven
 Note that recommendations can be positive or negative
©2013 American Academy of Neurology
Translating Class to
Recommendations
 A = Requires at least two consistent Class I



studies*
B = Requires at least one Class I study or two
consistent Class II studies
C = Requires at least one Class II study or two
consistent Class III studies
U = Assigned in cases of only one Class III study,
only Class IV studies, or evidence that is
conflicting and cannot be reconciled
* In exceptional cases, one convincing Class I study may suffice for an “A” recommendation if 1)
all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and
the lower limit of the confidence interval is >2).
©2013 American Academy of Neurology
Applying the Process to the Issue
 We will now turn our attention to the
guideline.
©2013 American Academy of Neurology
Methods
 MEDLINE, EMBASE, LILACS and Cochrane
Database of Systematic Reviews and Controlled
Clinical trials were searched.
• 1980 to 2008, updated in 2012
 Authors reviewed each article for inclusion.
 Risk of bias was determined using the

classification of evidence scheme for therapeutic
articles.
Strength of recommendations was linked directly
to evidence levels.
 Resulted in 10 Class I or Class II trials of cysticidal drugs administered with
or without corticosteroids in the treatment of neurocysticercosis
 Conflicts of interest were disclosed.
©2013 American Academy of Neurology
Literature Search/Review
 Rigorous, Comprehensive, Transparent
610
abstracts
Inclusion criteria:
-
Randomized, controlled
trials; cohort studies; casecontrol studies; case series
(n ≥20); review articles;
meta-analyses
Exclusion criteria:
-
-
123
articles
©2013 American Academy of Neurology
-
Case reports, small case
series (n <20), review
articles without primary
data
Articles in languages other
than English or Spanish
Animal studies
AAN Classification of Evidence
for Therapeutic Intervention
 Class I: A randomized, controlled clinical trial of the
intervention of interest with masked or objective outcome
assessment, in a representative population. Relevant
baseline characteristics are presented and substantially
equivalent among treatment groups or there is
appropriate statistical adjustment for differences. The
following are also required:
•
•
•
•
Concealed allocation
Primary outcome(s) clearly defined
Exclusion/inclusion criteria clearly defined
Adequate accounting for dropouts (with at least 80% of enrolled
subjects completing the study) and crossovers with numbers
sufficiently low to have minimal potential for bias.
©2013 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Intervention, cont.
• For noninferiority or equivalence trials claiming to prove
efficacy for one or both drugs, the following are also
required*:
The authors explicitly state the clinically meaningful difference to
be excluded by defining the threshold for equivalence or
noninferiority.
The standard treatment used in the study is substantially similar to
that used in previous studies establishing efficacy of the standard
treatment (e.g., for a drug, the mode of administration, dose and
dosage adjustments are similar to those previously shown to be
effective).
The inclusion and exclusion criteria for patient selection and the
outcomes of patients on the standard treatment are comparable to
those of previous studies establishing efficacy of the standard
treatment.
The interpretation of the results of the study is based upon a per
protocol analysis that takes into account dropouts or crossovers.
©2013 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Intervention, cont.
 Class II: A randomized controlled clinical trial of the
intervention of interest in a representative population with
masked or objective outcome assessment that lacks one
criteria ae above or a prospective matched cohort study
with masked or objective outcome assessment in a
representative population that meets be above. Relevant
baseline characteristics are presented and substantially
equivalent among treatment groups or there is
appropriate statistical adjustment for differences.
 Class III: All other controlled trials (including well-defined
natural history controls or patients serving as own
controls) in a representative population, where outcome is
independently assessed, or independently derived by
objective outcome measurement.**
©2013 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Intervention, cont.
 Class IV: Studies not meeting Class I, II, or III criteria
including consensus or expert opinion.
*Note that numbers 13 in Class I, item 5 are required for Class II in equivalence
trials. If any one of the three is missing, the class is automatically downgraded
to Class III.
**Objective outcome measurement: an outcome measure that is unlikely to be
affected by an observer’s (patient, treating physician, investigator) expectation
or bias (e.g., blood tests, administrative outcome data).
©2013 American Academy of Neurology
Clinical Question 1
 In patients with symptomatic intraparenchymal
neurocysticercosis, is cysticidal therapy more
effective than no therapy, and does it affect longterm seizure outcome?
©2013 American Academy of Neurology
Cysticidal Therapy: Conclusion
 Based on imaging findings in 4 Class I studies (3
concordant, 1 underpowered study failing to
show an effect) and a meta-analysis of 2 Class I
and 4 Class II studies, albendazole (400 mg BID for
adults or weight-based dosing for either adults or
children) is probably safe and effective in
reducing both the number of cysts and long-term
seizure frequency in adults and children with
neurocysticercosis. In most studies,
corticosteroids were coadministered, in varying
dosages, and this combination appears effective.
Data are insufficient to indicate whether
corticosteroids are necessary in this setting.
©2013 American Academy of Neurology
Clinical Context
 The available studies have used different stratification

methods for seizure analysis and different criteria for
judging improvement in imaging. On the basis of the 3
Class I studies it appears albendazole plus corticosteroids
decreases the number of active brain lesions relative to
placebo and, on the basis of a meta-analysis of available
data, decreases the number of patients with seizures, at
modest cost. These findings appear to be consistent in
adults and children.
Side effects of treatment appear minimal. Of greatest
concern has been the potential — emphasized in a single
large study2 — for increased seizures and encephalopathy
as a result of treatment-induced parasite death.
©2013 American Academy of Neurology
Clinical Context, cont.
 Recommendations often emphasize the danger of

antihelminthic treatment in patients with a very large
lesion burden. The cited studies all excluded patients with
massive cerebral edema or innumerable lesions but were
otherwise inconsistent.
Three studies3–5 were limited to patients with single
lesions. In one study, patients had 1 or 2 cysts.6 In another
study, 84% of patients had 1 or 2; the remainder had
fewer than 100. In the remaining 3 studies, the number of
cysts was described as “multiple,”7 “less than 20,”8 and
“less than 36.”9
©2013 American Academy of Neurology
Cysticidal Therapy: Recommendation
 Albendazole plus either dexamethasone or
prednisolone should be considered for adults and
children with neurocysticercosis, both to
decrease the number of active lesions on brainimaging studies (Level B) and to reduce long-term
seizure frequency (Level B).
©2013 American Academy of Neurology
Clinical Question 2
 In patients with symptomatic intraparenchymal
neurocysticercosis, is treatment with
corticosteroids more effective than no
treatment?
©2013 American Academy of Neurology
Corticosteroids: Conclusion
 On the basis of one Class I study showing no
benefit radiologically and ambiguous benefit
clinically and one Class II/IV study showing
benefit, there is insufficient evidence to
recommend steroid treatment alone for patients
with solitary intraparenchymal neurocysticercosis.
©2013 American Academy of Neurology
Clinical Context
 The effect of corticosteroid treatment alone in
neurocysticercosis has not been widely studied.
Most trials include a combination of cysticidal
therapy and steroid treatment.
©2013 American Academy of Neurology
Corticosteroids: Recommendation
 The evidence is insufficient to support or refute
the use of steroid treatment alone in patients
with intraparenchymal neurocysticercosis (Level
U).
©2013 American Academy of Neurology
Clinical Question 3
 When during the course of antiparasitic
treatment should steroids be started?
We found no studies to answer this question.
©2013 American Academy of Neurology
Clinical Question 4
 What is the efficacy of AEDs in treating or
decreasing occurrence of subsequent seizures
secondary to intraparenchymal
neurocysticercosis, and what is the optimal time
course of AED treatment for seizures secondary
to intraparenchymal neurocysticercosis?
We found no studies to answer this question.
©2013 American Academy of Neurology
Clinical Context
 Given the well-established efficacy and safety of a
broad range of AEDs and the frequency with
which neurocysticercosis causes seizures, it is
reasonable to treat these patients with AEDs at
least until the active lesions have subsided.
©2013 American Academy of Neurology
Future Research
Recommendations
Several aspects of treatment require further study:
 Cysticercal cysts evolve through four stages: the living
larva, the degenerating larva, a reactive thickening of
the cyst membrane, and calcification. Only cysts in
the first two stages contain live cysts.10 A study that
evaluates the response to therapy on the basis of the
stage of the cyst would be useful.
 The successful treatment trials cited all used cysticidal
therapy administered with or without corticosteroids.
Studies are needed to determine the appropriate use
and timing of administration of adjuvant
corticosteroids and the potential benefit of
combination cysticidal therapy.
©2013 American Academy of Neurology
Future Research
Recommendations, cont.
 Neurocysticercosis can be intraventricular or intraocular
or can involve the subarachnoid space. Studies have not
addressed these forms of the infection. Assessment of
different treatment strategies, medical or surgical, for
such patients would be helpful.
 HIV coinfection may alter efficacy of antihelminthic
treatment or produce important drug–drug interactions;
determination of best treatment for neurocysticercosis in
such patients is needed.
 Additional studies should focus on clinical outcomes
rather than surrogate CT outcomes, as the two do not
always correlate. Patients may experience seizure
recurrence despite resolution of lesions on CT.
©2013 American Academy of Neurology
References
1. Coyle CM, Mahanty S, Zunt JR, et al. Neurocysticercosis: Neglected but not
2.
3.
4.
5.
6.
forgotten. PLoS neglected tropical diseases 2012;5:e1500.
Das K, Mondal GP, Banerjee M, Mukherjee BB, Singh OP. Role of antiparasitic
therapy for seizures and resolution of lesions in neurocysticercosis patients: An
8 year randomised study. J Clin Neurosci 2007;14:1172–1177.
Chaurasia RN, Garg RK, Agarwal A, et al. Three day albendazole therapy in
patients with a solitary cysticercus granuloma: a randomized double blind
placebo controlled study. Southeast Asian J Trop Med Public Health
2010;41:517–525.
Baranwal AK, Singhi PD, Khandelwal N, Singhi SC. Albendazole therapy in
children with focal seizures and single small enhancing computerized
tomographic lesions: a randomized, placebo-controlled, double blind
trial. Pediatr Infect Dis J 1998;17:696–700.
Singhi P, Jain V, Khandelwal N. Corticosteroids versus albendazole for treatment
of single small enhancing computed tomographic lesions in children with
neurocysticercosis. J Child Neurol 2004;19:323–327.
Kalra VK, Dua T, Kumar V. Efficacy of albendazole and short-course
dexamethasone treatment in children with 1 or 2 ring-enhancing lesions of
neurocysticercosis: a randomized controlled trial. J Pediatr 2003;143:111–114.
©2013 American Academy of Neurology
References, cont.
7. Padma MV, Behari M, Misra NK, Ahuja GK. Albendazole in
neurocysticercosis. Natl Med J India 1995;8:255–258.
8. Garcia HH, Pretell EJ, Gilman RH, et al. A trial of antiparasitic treatment to
reduce the rate of seizures due to cerebral cysticercosis. N Engl J Med
2004;350:249–258.
9. Carpio A, Kelvin EA, Bagiella E, et al. Effects of albendazole treatment on
neurocysticercosis: a randomised controlled trial. J Neurol Neurosurg Psychiatry
2008;79:1050–1055.
10.Murthy JMK, Reddy YVS. Prognosis of epilepsy associated with single CT
enhancing lesion: a long term followup study. J Neurol Sci 1998;159:151–155.
For a complete list of references, please
access the full guideline at
www.aan.com/guidelines.
©2013 American Academy of Neurology
Question-and-Answer Period
 Questions/comments?
©2013 American Academy of Neurology
Closing
 To access the complete guideline and
related guideline summary tools, visit
www.aan.com/guidelines.
 Thank you for your participation!
©2013 American Academy of Neurology