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## Complete Summary

#### GUIDELINE TITLE

Practice parameter: anticonvulsant prophylaxis in patients with newly
diagnosed brain tumors. Report of the Quality Standards Subcommittee of
the American Academy of Neurology.

#### BIBLIOGRAPHIC SOURCE(S)

Glantz MJ, Cole BF, Forsyth PA, Recht LD, Wen PY, Chamberlain MC,
Grossman SA, Cairncross JG. Practice parameter: anticonvulsant
prophylaxis in patients with newly diagnosed brain tumors. Report of the
Quality Standards Subcommittee of the American Academy of Neurology.
Neurology 2000 May 23;54(10):1886-93. \[85 references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

According to the guideline developer, this guideline has been reviewed
and is still considered to be current as of October 2003. This review
involved new literature searches of electronic databases followed by
expert committee review of new evidence that has emerged since the
original publication date.

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Seizures (convulsions) associated with primary or metastatic brain
tumors (brain neoplasms)

#### GUIDELINE CATEGORY

Assessment of Therapeutic Effectiveness\
Prevention\
Risk Assessment

#### CLINICAL SPECIALTY

Internal Medicine\
Neurological Surgery\
Neurology\
Oncology\
Radiation Oncology

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

To review the evidence on the administration of prophylactic
anticonvulsants to patients with brain tumors and to provide specific
recommendations based on the analysis of the evidence

#### TARGET POPULATION

Patients with newly diagnosed brain tumors (primary or metastatic)

#### INTERVENTIONS AND PRACTICES CONSIDERED

Prophylactic use of anticonvulsant medications (e.g., phenytoin
\[Dilantin\], carbamazepine, phenobarbital, and valproic acid
\[Depakote\]) in patients with primary or metastatic brain tumors.

#### MAJOR OUTCOMES CONSIDERED

-   Seizure-free survival (time to first seizure or death, whichever
    occurred first)

-   Overall survival

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Hand-searches of Published Literature (Secondary Sources)\
Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

Pertinent studies were identified through MEDLINE searches of the years
1966 to July 1999 using the search parameters SEIZURE (exp), BRAIN
NEOPLASMS (exp), ANTICONVULSANTS (exp), CRANIOTOMY (exp), and PRIMARY
PREVENTION (exp). All 829 articles identified in this way were reviewed,
and all studies, including randomized clinical trials, cohort studies,
and case series, that considered the prophylactic use of anticonvulsants
in patients with brain tumors were selected. The reference list of each
of the selected papers was reviewed for additional pertinent studies.
CANCERLIT and the Cochrane Database were also queried. Lastly, all
abstracts indexed under \"seizure,\" \"brain tumor,\" or
\"anticonvulsant,\" which appeared in the American Society of Clinical
Oncology, American Academy of Neurology, American Neurologic
Association, American Epilepsy Society, and American Association of
Neurologic Surgeons abstract books between the years 1982 and 1999, were
reviewed. When overlapping data were published more than once (for
example, as a preliminary communication and subsequently, with
additional patients, in final form) only the most updated version was
selected. Two studies addressed the issue of prophylactic anticonvulsant
use in patients with a variety of neurologic conditions, including
patients with brain tumors, but neither the published data nor queries
to the authors ultimately allowed separation of patients with brain
tumors from those with other diagnoses. In a third study, prophylactic
anticonvulsant medication was administered, and follow-up was carried
out for only 3 postoperative days. These studies were excluded.

#### NUMBER OF SOURCE DOCUMENTS

829 source documents

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**Ratings for the Quality of the Evidence**:

**Class I**. Must have all of a through d. (a) Prospective study of a
well-defined cohort which includes a description of the nature of the
population, the inclusion/exclusion criteria, demographic
characteristics such as age and sex, and seizure type. (b) The sample
size must be adequate with enough statistical power to justify a
conclusion or for identification of subgroups for whom testing does or
does not yield significant information. (c) The interpretation of
evaluations performed must be done blinded to outcome. (d) There must be
a satisfactory description of the technology used for evaluations (e.g.,
electroencephalogram, magnetic resonance imaging).

**Class II**. Must have a or b. (a) Retrospective study of a
well-defined cohort which otherwise meets criteria for class 1a, b and
1d. (b) Prospective or retrospective study which lacks any of the
following: adequate sample size, adequate methodology, a description of
inclusion/exclusion criteria, and information such as age, sex and
characteristics of the seizure.

**Class III**. Must have a or b. (a) A small cohort or case report. (b)
Relevant expert opinion, consensus, or survey. A cost-benefit analysis
or a meta-analysis may be class I, II, or III, depending on the strength
of the data upon which the analysis is based.

#### METHODS USED TO ANALYZE THE EVIDENCE

Meta-Analysis of Observational Trials\
Meta-Analysis of Randomized Controlled Trials

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

A meta-analysis was conducted on seizure incidence using all identified
prospective, randomized clinical trials. Seizure-free survival (time to
first seizure or death, whichever occurred first) and overall survival
(time to death) were also calculated for the two studies from which
patient-level data were available.

For each end point in each trial, an odds ratio, comparing the odds of
the event in the anticonvulsant prophylaxis group relative to the
control group, was computed. The trial-specific odds ratios were then
averaged to provide a meta-analysis summary. The meta-analysis odds
ratio was used subsequently to test whether anticonvulsant prophylaxis
affected the odds of an event. All statistical tests were performed
using a Z test. Two-sided *p* values were used to compare the treatment
groups with respect to the odds of an event. A *p* value less than 0.05
was considered significant.

For each clinical trial used in the seizure incidence analysis, the odds
ratio describing the odds of seizure in the anticonvulsant group
relative to the control group was computed along with the variance (V)
of log(odds ratio), and a 95% confidence interval for the odds ratio
estimate. These computations were performed using standard techniques.
The meta-analysis odds ratio was then obtained by computing the weighted
average of the log(odds ratio) estimates, for which the weightings were
defined by the inverse variance (1/V) of log(odds ratio) for each trial.
In this way, each trial was weighted inversely according to the amount
of variation associated with the log(odds ratio) estimate. The standard
error of the weighted average was obtained by dividing the sum of the
â€œexponentiatedâ€ to obtain the overall summary odds ratio. Statistical
inference was carried out on the log(odds ratio) scale using normal (Z)
distribution theory.

The meta-analysis of seizure-free survival was performed using
previously established techniques. For each clinical trial the
Kaplan--Meier method was used to estimate seizure-free survival
according to treatment group. The treatment comparison was then made
using the logrank test, which evaluates the observed number of events
(seizure or death) on each study arm compared with the number of events
that would be expected to occur if each treatment group had the same
risk. The logrank analyses were then averaged to obtain a meta-analysis
comparison of the treatment groups in terms of an odds ratio. The
meta-analysis of overall survival was conducted in a similar fashion.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**Definitions for the Strength of the Recommendations**:

**Standard**. A principle for patient management that reflects a high
degree of clinical certainty (usually requires one or more Class I
studies that directly address the clinical question, or overwhelming
Class II evidence when circumstances preclude randomized clinical
trials).

**Guideline**. A recommendation for patient management that reflects
moderate clinical certainty (usually requires one or more Class II
studies or a strong consensus of Class III evidence).

**Practice Option**. Strategy for patient management for which clinical
utility is uncertain (inconclusive or conflicting evidence or opinion).

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Not stated

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

*Excerpted by the National Guideline Clearinghouse (NGC)*

Each clinical recommendation is rated based on the strength of the
evidence. Definitions of the strength of the recommendations (standard,
guideline, practice option) and quality of the evidence (Class I-Class
III) are presented at the end of the Major Recommendations field.

**Summary**

Twelve studies have examined, either in randomized controlled trials or
cohort studies, the ability of prophylactic anticonvulsants to prevent
first seizures in patients with brain tumors, and none have demonstrated
efficacy. Four of these studies provide level I evidence. A
meta-analysis of these four studies also revealed no evidence of an
effect on the frequency of first seizures in patients receiving
anticonvulsant prophylaxis. In contrast, deleterious interactions with
cytotoxic drugs and corticosteroids are a major concern, and the
incidence and severity of anticonvulsant side effects appear to be
appreciably higher (20 to 40%) in brain tumor patients than in the
general population of patients receiving anticonvulsants. This increased
incidence is due at least in part to the additive or synergistic effects
of concurrently administered drugs (especially chemotherapeutic agents)
and to the underlying brain tumor.

**Conclusions**

Seizures are a common and sometimes devastating complication of brain
tumors, and meticulous attention to their diagnosis and treatment is
critical. The available evidence suggests, however, that prophylactic
administration of anticonvulsant medications does not provide
substantial benefit (i.e., a risk reduction of 26% or more for
seizure-free survival), whereas anticonvulsant-associated side effects
are especially common and occasionally life-threatening.

Many patients who experienced seizures while receiving anticonvulsant
prophylaxis had subtherapeutic anticonvulsant blood levels. Although
this may provide one explanation for the ineffectiveness of
anticonvulsant prophylaxis in some patients, it did not change the
conclusions of the one randomized controlled trial that addressed that
issue specifically. In that study, 23% of patients receiving
anticonvulsant prophylaxis who experienced a seizure had subtherapeutic
levels. Reanalysis excluding patients with subtherapeutic levels still
showed no benefit for anticonvulsant prophylaxis. Moreover, even in the
setting of scrupulously monitored prospective studies in epileptic
patients, subtherapeutic levels are extremely common, partly because of
drug interactions. Rather than change the implications of these studies,
this high rate of subtherapeutic levels simply reflects a clinical
reality.

**Clinical Recommendations**

1.  In patients with newly diagnosed brain tumors, anticonvulsant
    medications are not effective in preventing first seizures. Because
    of their lack of efficacy and their potential side effects,
    prophylactic anticonvulsants should not be used routinely in
    patients with newly diagnosed brain tumors **(Standard)**.

2.  In patients with brain tumors who have not had a seizure, tapering
    and discontinuing anticonvulsants after the first postoperative week
    is appropriate, particularly in those patients who are medically
    stable and who are experiencing anticonvulsant-related side effects
    **(Guideline)**.

**Definitions**:

**Strength of the Recommendations**:

**Standard**. A principle for patient management that reflects a high
degree of clinical certainty (usually requires one or more Class I
studies that directly address the clinical question, or overwhelming
Class II evidence when circumstances preclude randomized clinical
trials).

**Guideline**. A recommendation for patient management that reflects
moderate clinical certainty (usually requires one or more Class II
studies or a strong consensus of Class III evidence).

**Practice Option**. Strategy for patient management for which clinical
utility is uncertain (inconclusive or conflicting evidence or opinion).

**Quality of the Evidence**:

**Class I**. Must have all of a through d. (a) Prospective study of a
well-defined cohort which includes a description of the nature of the
population, the inclusion/exclusion criteria, demographic
characteristics such as age and sex, and seizure type. (b) The sample
size must be adequate with enough statistical power to justify a
conclusion or for identification of subgroups for whom testing does or
does not yield significant information. (c) The interpretation of
evaluations performed must be done blinded to outcome. (d) There must be
a satisfactory description of the technology used for evaluations (e.g.,
electroencephalogram, magnetic resonance imaging).

**Class II**. Must have a or b. (a) Retrospective study of a
well-defined cohort which otherwise meets criteria for class 1a, b and
1d. (b) Prospective or retrospective study which lacks any of the
following: adequate sample size, adequate methodology, a description of
inclusion/exclusion criteria, and information such as age, sex and
characteristics of the seizure.

**Class III**. Must have a or b. (a) A small cohort or case report. (b)
Relevant expert opinion, consensus, or survey. A cost-benefit analysis
or a meta-analysis may be class I, II, or III, depending on the strength
of the data upon which the analysis is based.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

Twelve studies were identified that provided data on the frequency of
first seizures in patients with brain tumors relative to the treatment
of interest (prophylactic anticonvulsant use versus no prophylactic
anticonvulsants). Of these, four were randomized clinical trials that
provided level I evidence, and eight were cohort studies that provided
level II evidence (see the \"Major Recommendations\" section for a
description of the levels of evidence).

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Reduction in the incidence of anticonvulsant-associated side
    effects, which are occasionally life-threatening, in patients with
    brain tumors who are not experiencing seizures

-   Reduction in the incidence of anticonvulsant drug interactions with
    chemotherapeutic agents and steroids in patients with brain tumors

#### POTENTIAL HARMS

Not stated

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   This statement is provided as an educational service of the American
    Academy of Neurology. It is based on an assessment of current
    scientific and clinical information. It is not intended to include
    all possible proper methods of care for a particular neurologic
    problem or all legitimate criteria for choosing to use a specific
    procedure. Neither is it intended to exclude any reasonable
    alternative methodologies. The American Academy of Neurology
    recognizes that specific patient care decisions are the prerogative
    of the patient and the physician caring for the patient, based on
    all of the circumstances involved.

-   The meta-analysis technique itself is not infallible. Its value
    depends on the quality of its component studies. A meta-analysis
    cannot evaluate or correct for bias in its component studies, and
    can provide misleading results if the component studies are very
    heterogeneous with respect to patient characteristics, the disease
    studied, or the intervention. The studies included in the current
    meta-analysis were all prospective, randomized, and controlled; the
    most effective strategy for minimizing the risk of bias and
    confounding. As described in the sections titled \"Description of
    Process\" and \"Results\" in the original guideline document, and as
    summarized in Table 2 titled \"Anticonvulsant Prophylaxis Studies in
    Patients with Brain Tumors\" (see the original guideline document),
    the studies were evaluated specifically to ensure good patient
    homogeneity. For these reasons, this meta-analysis does provide a
    reliable estimate of the overall lack of effect of anticonvulsant
    prophylaxis in patients with brain tumors.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Living with Illness\
Staying Healthy

#### IOM DOMAIN

Effectiveness\
Safety

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Glantz MJ, Cole BF, Forsyth PA, Recht LD, Wen PY, Chamberlain MC,
Grossman SA, Cairncross JG. Practice parameter: anticonvulsant
prophylaxis in patients with newly diagnosed brain tumors. Report of the
Quality Standards Subcommittee of the American Academy of Neurology.
Neurology 2000 May 23;54(10):1886-93. \[85 references\]

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2000 May (reviewed 2003)

#### GUIDELINE DEVELOPER(S)

American Academy of Neurology - Medical Specialty Society

#### SOURCE(S) OF FUNDING

American Academy of Neurology (AAN)

#### GUIDELINE COMMITTEE

Quality Standards Subcommittee

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Subcommittee Members*: Gary Franklin, MD, MPH (Co-Chair); Catherine
Zahn, MD (Co-Chair); Milton Alter, MD, PhD; Stephen Ashwal, MD; John
Calverley, MD; Richard Dubinsky, MD; Jacqueline French, MD
(facilitator); Michael Greenberg, MD; Gary Gronseth, MD; Deborah Hirtz,
MD; Robert Miller, MD; and James Stevens, MD

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Not stated

#### GUIDELINE STATUS

This is the current release of the guideline.

According to the guideline developer, this guideline has been reviewed
and is still considered to be current as of October 2003. This review
involved new literature searches of electronic databases followed by
expert committee review of new evidence that has emerged since the
original publication date.

#### GUIDELINE AVAILABILITY

Electronic copies: A list of American Academy of Neurology (AAN)
guidelines, along with a link to a Portable Document Format (PDF) file
for this guideline, is available at the [AAN Web
site](http://aan.com/go/practice/guidelines).

Print copies: Available from the AAN Member Services Center, (800)
879-1960, or from AAN, 1080 Montreal Avenue, St. Paul, MN 55116.

#### AVAILABILITY OF COMPANION DOCUMENTS

-   Practice statement definitions. St. Paul (MN): American Academy of
    Neurology.

-   Practice statement development. St. Paul (MN): American Academy of
    Neurology.

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on November 4, 2001. The
information was verified by the guideline developer as of December 20,
2001.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is
copyrighted by the American Academy of Neurology.

### DISCLAIMER

#### NGC DISCLAIMER

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approve, or endorse the guidelines represented on this site.

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Inclusion Criteria which may be found at
<http://www.guideline.gov/about/inclusion.aspx> .

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© 1998-2008 National Guideline Clearinghouse

Date Modified: 11/3/2008