NEUROLOGICAL ASPECTS OF LYME DISEASE

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



PA NUMBER:  PA-93-49



P.T. 34



Keywords:

  Infectious Diseases/Agents 

  0715038 

  Epidemiology 

  Disease Model 

  Pathogenesis 

  Immunology 



National Institute of Neurological Disorders and Stroke

National Institute of Allergy and Infectious Diseases



PURPOSE



The National Institute of Neurological Disorders and Stroke (NINDS)

and the National Institute of Allergy and Infectious Diseases (NIAID)

invite research grant applications seeking support of a wide spectrum

of research directed at generating improved knowledge concerning Lyme

disease of the nervous system.



Lyme borreliosis is a multi-system disease caused by the spirochete

Borrelia burgdorferi.  It may affect skin, joints, heart, eye, and

the nervous system.  Reported neurological consequences of Lyme

borreliosis may range from minor to serious.  The infectious vector

is a tick commonly harbored by many sylvatic and domestic animals,

but the principal reservoirs of the adult infective tick are deer and

field mice.



Well described neurological disorders, meningoradiculitis and chronic

neuropathy in patients with acrodermatitis chronica atrophicans, and

an array of central and peripheral nervous system complications of

Lyme disease have all been found to result from borrelia infection.

Between 1982 and 1990 over 30,000 Lyme borreliosis cases were

reported in the U.S.



Reported neurological manifestations of the disease include one or

more of the following: meningitis, cranial neuritis,

radiculoneuritis, peripheral neuropathy, meningoencephalitis,

myelitis, ataxia, psychoses, encephalopathy, cognitive abnormalities,

pain, fatigue, and sleep disorder.  It has been reported that up to

half of patients with late Lyme neuroborreliosis (LNB) may exhibit

encephalopathy evidenced by impairment of memory and intellect.

Encephalopathy is probably caused by subacute infection of the

central nervous system.  Some patients may display small white matter

lesions visualized by magnetic resonance imaging.



Cerebrospinal fluid abnormalities may include lymphocytic

pleocytosis, intrathecal IgA, IgG, and IgM synthesis, anti-myelin

basic protein antibodies, oligoclonal bands, and increased total

protein.  CSF anti -B. burgdorferi specific antibody is helpful in

diagnosing the disease but may only be indicative of exposure, not

necessarily of active disease.  Peripheral blood may have B.

burgdorferi specific antibody and reactive T cells.  None of the

laboratory diagnostic tests is totally reliable because of false

negative and positive readings.



The cause of damage to the nervous system is unknown.  It may be due

to direct damage from spirochetes, tissue inflammation, or immune

response, separately or in combination.  Diagnosis of Lyme

neuroborreliosis is a major challenge because neurological signs and

symptoms may imitate those of multiple sclerosis, peripheral

neuropathy, Guillain-Barre syndrome, neurosyphilis, and many other

diseases of the nervous system.



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 priority areas.  This PA,

Neurological Aspects of Lyme Disease, is related to the priority area

of infectious diseases.  Potential applicants may obtain a copy of

"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0) or

"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)

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.

Applications from minority institutions, minority individuals, and

women are particularly encouraged.  Foreign institutions are not

eligible for FIRST Independent Research Support and Transition Awards

(R29) or Research Program Projects (P01).



MECHANISM OF SUPPORT



Research support may be requested through application for an

individual investigator-initiated research project grant (R01).

Applications from new investigators who have not received previous

PHS research grant support may apply for a First Independent Research

Support and Transition (FIRST) award (R29).  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.  To apply

for the support of a more broadly based multidisciplinary research

program, the Research Program Project (P01) mechanism is suggested.

NINDS also provides support for the career development of clinical

investigators (K08) and support for clinical investigators through

individual fellowships (F32) and institutional national research

service awards (T32).



RESEARCH OBJECTIVES



Neurological involvement is a frequent clinical manifestation of Lyme

disease.  In addition, it has been suggested that the CNS may serve

as a reservoir for persistent infection.  Central issues about

neurological aspects of Lyme disease are unresolved, including the

definition of the neurological disease in adults and children in the

U.S., the appropriate criteria to use for diagnosis, and the optimal

choice and duration of therapy.  The pathogenetic mechanisms which

produce central and peripheral nervous system syndromes are unknown;

in particular, the etiology of persistent post-infectious symptoms

and their optimal management is unclear.



Examples of research goals, many of which could be studied in humans

as well as animal models and tissue cultures and are appropriate for

pursuing an application in response to this PA, include, but are not

limited to:



o  The epidemiology of the neurological aspects of Lyme disease,

especially in endemic areas.  Identification of neurological

syndromes in children and adults that can be reliably attributed to

this disorder, including both primary and post-infectious syndromes.



o  Studies of diagnostic laboratory abnormalities which correlate

with the various syndromes, including cerebrospinal fluid, serum,

neurophysiological, and neuroimaging testing.



o  Studies of mechanisms of pathogenesis in development of

encephalopathy, encephalomyelitis, and neuropathies.



o  Characterization of the severity and frequency of cognitive

impairments in LNB, and studies of correlated laboratory parameters,

and their response to therapy.



o  Studies of immune-mediated and other pathogenic mechanisms role in

injury to the nervous system.  This may involve spirochete

interactions with the immune system, and definition of immune and

inflammatory abnormalities, including studies of auto-antibodies,

cytokines, cellular immune responses, and immune complexes.



o  Development of effective treatment regimen(s).  Optimization of

antibiotics, drug dosage, and treatment duration.  Development of

therapeutic approaches for patients who have persistent neurological

symptoms.  This could be accomplished by controlled clinical trials.



o  Studies of the molecular basis for B. burgdorferi neurotropism and

the role of strain differences in pathogenesis.



o  Development of reliable animal models for studies of the nervous

system infection and studies of viral latency neuropathogenicity.



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

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 which 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/ethnic group.  In addition, gender and

racial/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, NIH recognizes that it may not be feasible

or appropriate in all research projects to include representation of

the full array of United States racial/ethnic minority populations

(i.e., Native Americans (including American Indians or Alaska

Natives), Asian/Pacific Islanders, Blacks, 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 preventive 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/ethnic minorities when it is important to apply the results of

the study broadly, and this 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' populations, including

minorities.



If the required information is not contained within the application,

the review will be deferred until the information is provided.



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 NIH are required

to address these policies.  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) and will be accepted for any of the three application

receipt dates:  February 1, June 1, and October 1.  NINDS Application

Guidelines (rev. 4/92) for Program Project (P01) and Center (P50)

grants are available upon request from the Program Administrator

identified below.



Application kits are available at most business and grants and

contracts offices and may be obtained 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.



On the face page, item 2a, of the application, the word "yes" must be

checked and the title and number of the announcement typed in the

space provided: "Neurological Aspects of Lyme Disease" PA-93-49.



The original and five copies of the application must be sent or

delivered to:



Application Receipt Office

Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



The Division of Research Grants, NIH, serves as central point for

receipt of applications.



Applicants from institutions that have a General Clinical Research

Center (GCRC) funded by the NIH National Center for Research

Resources may wish to identify the GCRC as a resource for conducting

the proposed research.  If so, a letter of collaboration from the

GCRC Program Director or Principal Investigator should be included

with the application.



REVIEW CONSIDERATIONS



Applications received under this PA will be assigned to the Initial

Review Group (IRG) in accordance with established PHS referral

guidelines.  The IRGs, which are composed primarily of non-federal

scientific and technical experts, will review the applications for

scientific and technical merit.  Following IRG review, the

applications will receive a second-level review by one or more

appropriate Advisory Councils.



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 quality of the proposed projects as determined by peer

review; availability of funds; and program balance among research

areas.



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:



Dr. A. P. Kerza-Kwiatecki

Division of Demyelinating, Atrophic, and Dementing Disorders

National Institute of Neurological Disorders and Stroke

Federal Building, Room 804

Bethesda, MD  20892

Telephone:  (301) 496-1431

FAX:  (301) 402-2060



Dr. Robert L. Quackenbush

Division of Microbiology and Infectious Diseases

National Institute of Allergy and Infectious Diseases

Solar Building, Room 3A04

Bethesda, MD  20892

Telephone:  (301) 496-7728

FAX:  (301) 402-2508



Direct inquiries regarding fiscal matters to:



Ms. Laura Williams

Grants Management Branch, Division of Extramural Activities

National Institute of Neurological Disorders and Stroke

Federal Building, Room 1004

7550 Wisconsin Avenue

Bethesda, MD  20892

Telephone:  (301) 496-9231

FAX:  (301) 402-0219



Mr. Todd Ball

Grants Management Section

National Institute of Allergy and Infectious Diseases

Solar Building, Room 4B35

Bethesda, MD  20892

Telephone:  (301) 496-7075



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic

Assistance No. 93.853 and 93.854 and 93.856 - Microbiology and

Infectious Disease Research.  Awards are made under authorization of

the Public Health Service Act, Title IV, Part A (Public Law 78-410,

Public Law 97-219, as amended by Public Law 99-158, 42 USC 241 and

285), Public Law 99-500; and Report 99-711 to accompany HR 5233 and

administered under PHS grants policies and Federal Regulations 42 CFR

52 and 45 CFR Part 74.  This program is not subject to the

intergovernmental review requirements of Executive Order 12372 or

Health Systems Agency review.



.

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