RESEARCH GRANTS RELATED TO THE SURGICAL MANAGEMENT OF EPILEPSY

NIH GUIDE, Volume 22, Number 5, February 5, 1993



PA NUMBER:  PA-93-50



P.T. 34



Keywords:

  Convulsive Disorders 

  Surgery 

  Clinical Medicine, General 



National Institute of Neurological Disorders and Stroke



PURPOSE



The Division of Convulsive, Developmental, and Neuromuscular

Disorders; National Institute of Neurological Disorders and Stroke

(NINDS) is revising and reissuing an existing NINDS program

announcement published January 8, 1988 to notify the scientific

community of continuing NINDS interest in research addressing the

surgical management of epilepsies.



Background



Intractable epilepsy remains a significant health problem despite the

availability of several efficacious antiepileptic medications and of

blood level monitoring to increase therapeutic effectiveness.

Partial epilepsy affects about 0.5 percent of the American population

(about 800,000 persons).  An estimated 350,000 patients in the United

States with partial seizures are intractable to medical therapy.

Over 100,000 of these patients in the United States are currently

considered candidates for management by surgical therapy.  Complex

partial seizures may arise from any portion of the brain (occipital,

frontal, or temporal lobes).  In reported series, 60 to 90 percent

excellent control of seizures have resulted from careful selection of

patients for resection of a temporal lobe epileptic focus.  Frontal

lobe resections have a lesser success rate.  Failures are attributed

to inadequate focus localization (focus beyond the extent of

resection or the presence of other unappreciated foci).  Surgery is

considered for patients if seizures persist after an adequate trial

of the correct antiepileptic drugs for the patients' seizure type

have been administered at an adequate dosage producing adequate blood

levels.



Extensive presurgical investigations are required to localize the

seizure focus.  Intensive monitoring of the EEG and videotaping of

many of the patient's typical seizures usually provides the first

evidence of a potential surgical candidate.  Other clinical and

experimental studies are employed to define underlying structural

abnormalities (angiography, computerized tomography, magnetic

resonance imaging), altered metabolism (positron emission

tomography), or impaired function (evoked potentials,

neuropsychological evaluation).



An international conference for epilepsy surgery was held in February

1986.  The conference highlighted the unique opportunity that exists

for collaboration between basic and clinical neuroscientists to

characterize the biochemistry, microanatomy, physiology and

pharmacology of specific human brain regions by studying tissue

samples resected at surgery.  The need for prospective surgical

therapy studies with well-defined entrance criteria and rigorously

standardized outcome measures was also emphasized.  This conference

resulted in two publications.



In March 1990, a National Institutes of Health Consensus Conference

addressed the issue of Surgery for Epilepsy. The Consensus Panel made

six recommendations for directions for future research.  (1) Surgery

is beneficial for selected patients, but the optimal timing of

surgery is not known.  Patients considered for temporal lobe

resection tend to have had uncontrolled (intractable) epilepsy for 10

to 20 years.  (2) Investigators differ in the selection of tests for

preoperative evaluation.  Studies are needed to assess the value of

ictal EEG surface recordings, invasive intracranial electrode

recording,  PET or SPECT.  This would require standardization of

definitions,  data collection, and central analysis of the data.  (3)

An outcome assessment method that combines validated measures already

used to assess general health  status and function in a population of

patients with other chronic conditions, with special items that are

sensitive to the unique characteristics of people with epilepsy and

those close to them is needed.  (4) Psychiatric and behavioral

functions should be systematically assessed before surgery and during

followup to determine whether there are specific contraindications to

any particular surgical procedure and whether these procedures

subsequently affect behavior.  (5) In temporal lobe surgery for

partial seizures, standard and "tailored" resections are used by

different groups but the results are apparently similar.  The

circumstances in which each technique is maximally effective should

be clarified by standardized data collection including documentation

of extent of surgical resection and multivariate analysis so that an

appropriate trial may ultimately be planned, if needed.  (6) Because

epilepsy surgery now may be used more often in children than in the

past, studies to determine the effects of uncontrolled seizures and

antiepileptic drug therapy on the  developing brain are needed.



In February of 1992 a second international conference on epilepsy

surgery was convened.  The conference highlighted new areas of

potential clinical research including identification of operable

syndromes, timing of surgical intervention, comparison of medical

versus surgical therapy, outcome evaluation and cost effectiveness.

The 1992 conference again highlighted the unique opportunity for

collaboration between basic and clinical neuroscientists.  Particular

opportunities would seem to exist in the basic science disciplines of

electrophysiology, anatomy, immunohistochemistry,biochemistry,

pharmacology and molecular biology.



HEALTHY PEOPLE 2000



The Public Health Service (PHS) is committed to achieving the health

promotion and disease prevention objectives of "Healthy People 2000,"

a PHS-led national activity for setting priorities.  This program

announcement, Research Grants Related to the Surgical Management of

Epilepsy, is related to the priority areas of the epilepsies.

Potential applicants may obtain a copy of "Healthy People 2000" (Full

Report:  No. 017-001-00474-0, or Summary Report:  Stock No.

017-001-00473-0) through the Superintendent of Documents, Government

Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).



ELIGIBILITY REQUIREMENTS



Applications may be submitted by foreign and domestic institutions,

for-profit and non-profit organizations, public and private, such as

universities, colleges, hospitals, laboratories, units of state and

local governments, and eligible agencies of the Federal government.

Foreign institutions are eligible to apply for research project

grants (R01) only.  Foreign institutions are not eligible for First

Independent Research Support and Transition Awards (R29).

Applications from minority institutions, minority individuals, and

women are encouraged.



MECHANISM OF SUPPORT



The support mechanisms for grants in this area will be the

traditional investigator-initiated research project grant (R01), the

First Independent Research Support and Transition (FIRST) award

(R29), the program project grant (P01), and the center grant (P50).

As consistent with the aforementioned mechanisms, the Principal

Investigator or program director, as well as any participating

investigators, will plan, direct, and perform the research.

Applicants for program project and center grants should contact the

NINDS representative listed below as early as possible in the

planning stages.



RESEARCH GOALS AND SCOPE



The goal of this research activity is to explore the use of various

modalities of surgery for the treatment of different seizure types.

The research scope of this program encompasses both animal and human

studies, utilizing a variety of experimental approaches and methods.



Clinical investigators are encouraged to (a) define specific criteria

or clinical syndromes for selecting the use of the various surgical

procedures, (b) determine the optimal means of evaluating surgical

candidates to localize the seizure focus, (c) define the long-term

improvement and/or adverse effects by appropriately designed,

standardized, and validated follow-up measures, and (d) establish

age-related indications for surgery in the pediatric age group to

assure appropriate neuro-developmental timing of the procedure for

different types of epilepsy, and also establish age-appropriate pre-

surgical evaluation, surgical procedures, and post-surgical

follow-up.  Collaborative clinical investigations to achieve an

adequate and appropriate study population are encouraged.



Basic science investigators are encouraged to utilize the human model

to explore all aspects of epilepsy particularly in the areas of

developmental neurobiology, neural science, cellular pathology and

neuropharmacology.  Examples of potential research areas include, but

are not limited to pathogenesis of mesial temporal sclerosis;

relative roles of decreased inhibition versus increased excitation in

seizure generation, likely mechanisms of hypersynchrony and;

localization of normal human cerebral function.



STUDY POPULATIONS



POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



NIH policy is that applicants for NIH clinical research grants and

cooperative agreements will be required to include minorities and

women in study populations so that research findings can be of

benefit to all persons at risk of the disease, disorder, or condition

under study; special emphasis should be placed on the need for

inclusion of minorities and women in studies of diseases, disorders,

and conditions that disproportionately affect them.  This policy is

intended to apply to males and females of all ages.  If women or

minorities are excluded or inadequately represented in clinical

research, particularly in proposed population-based studies, a clear

compelling rationale should be provided.



The composition of the proposed study population must be described in

terms of gender and racial or ethnic group. In addition, gender and

racial or ethnic issues should be addressed in developing a research

design and sample size appropriate for the scientific objectives of

the study.  This information should be included in the form PHS 398

in Sections 1-4 of the Research Plan AND summarized in Section 5,

Human Subjects.  Applicants are urged to assess carefully the

feasibility of including the broadest possible representation of

minority groups; however, the NIH recognizes that it may not be

feasible or appropriate in all research projects to include

representation of the full array of Unites States racial or ethnic

minority populations:  Native Americans (including American Indians

or Alaska Natives), Asian or Pacific Islanders, Blacks, and

Hispanics).  The rationale for studies on single minority population

groups should be provided.



For the purpose of this policy, clinical research includes human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and prevention strategies), diagnosis, or treatment of

diseases, disorders, or conditions, including, but not limited to,

clinical trials.



The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded; however,

every effort should be made to include human tissues from women and

racial or ethnic minorities when it is important to apply the results

of the study broadly.  This directive should be addressed by

applicants.



For foreign awards, the policy on inclusion of women applies fully.

Since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' population, including

minorities.



Peer reviewers will address specifically whether the research plan in

the application conforms  to these policies.  If the representation

of women or minorities in a study design is inadequate to answer the

scientific question(s) addressed and the justification for the

selected study population is inadequate, it will be considered a

scientific weakness or deficiency in the study design and will be

reflected in assigning the priority score to the application.



All applications for clinical research submitted to the NIH are

required to address these policies.  If the required information is

not contained within the application, the review will be deferred

until the information is provided. NIH funding components will not

award grants or cooperative agreements that do not comply with these

policies.



APPLICATION PROCEDURES



Applications are to be submitted on the grant application form PHS

398 (rev. 9/91) according to the instructions included in the

application package.  These application packages are available at the

business offices of most institutions eligible to receive Federal

grants and from the Office of Grants Inquiries, Division of Research

Grants, National Institutes of Health, Westwood Building, Room 449,

Bethesda, MD 20892, telephone 301-496-7441.



Applicants for program project grants should request, from the

program contact listed under INQUIRIES, a copy of the NINDS

Guidelines:  Program Project and Research Center Grants (rev. 6/92).

Receipt dates for new research project grant (R01) applications and

FIRST awards (R29) and for program project (P01) and center grant

(P50) applications are February 1, June 1, and October 1.



FIRST award applications must include at least three sealed letters

of reference attached to the face page of the original application.

FIRST award applications submitted without the required number of

reference letters will be considered incomplete and will be returned

without review.



On page 1 of form PHS 398, check "yes" in Item 2a, enter the number

of this Program Announcement in the space provided, and provide the

name of this Program Announcement (Surgical Management of the

Epilepsy) in the blank space labeled "Title."



Use the mailing label provided in the application package to mail the

signed original and five exact copies of it to the Division of

Research Grants.  If the application is for a program project or

center grant, please send the original and three copies to the

Division of Research Grants.  An additional two copies of the program

project or center grant application sent to the address below would

be useful for expediting the processing of these applications for

multidisciplinary efforts.



REVIEW CONSIDERATIONS



Research project grant (R01) applications and FIRST award (R29)

applications will be reviewed for scientific and technical merit by

an appropriate study section in the Division of Research Grants.

Program project grant (P01) and center grant (P50) applications will

be reviewed according to the practice of the Institute to which the

application is assigned.  The second level of review will be by the

appropriate national advisory council.



AWARD CRITERIA



The standard review criteria will be used to assess the scientific

merit of applications.  Applications will compete for available funds

with all other applications.  The following will be considered when

making funding decisions:



o  quality of the proposed projects as determined by peer review,

o  availability of funds, and

o  program balance among research areas.



INQUIRIES



Questions concerning scientific aspects may be addressed to:



Charlotte B. McCutchen,  M.D.

Division of Convulsive, Developmental, and Neuromuscular Disorders

National Institute of Neurological Disorders and Stroke

Federal Building, Room 114

Bethesda, MD  20892

Telephone:  (301) 496-1917

FAX:  (301) 496-9916



Questions concerning fiscal aspects may be addressed to:



Patricia Driscoll

Grants Management Branch

National Institute of Neurological Disorders and Stroke

Federal Building, Room 1004

Bethesda, MD  20892

Telephone:  (301) 496-9231



AUTHORITY AND REGULATIONS



This program is described in the Catalogue of Federal Domestic

Assistance, Number 93.853, Clinical Research Related to Neurological

Disorders, and 93.854, Biological Basis Research in the

Neurosciences.  Grants will be awarded under the authority of the

Public Health Service Act, Title IV, Section 301 (Public Law 78-410,

as amended: 42 USC 241) and administered under PHS grants policies

and Federal Regulations 42 CFR Part 52 and 45 CFR 74.  This program

is not subject to Health Services Agency Review of the

intergovernmental review requirements of Executive Order 12372.



.

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