Brain Spect Imagining In Chronic Lyme Disease

[Guest guest]

NOTE: To view the article with Web enhancements, go to:

http://www.medscape.com/SLACK/JSTD/1999/v06.n02/std0604.06/std0604.06.plut-0

1.html

----------------------------------------------------------------------------

----

Tc-99m HMPAO Brain SPECT Imaging in Chronic Lyme Disease

Jeffery J. Plutchok, MD, Department of Radiology, New York-Presbyterian

Medical Center, New York, New York; S. Tikofsky, PhD, Department of

Radiology, New York-Presbyterian Medical Center, New York, New York;

Department of Radiology, Harlem Hospital Center, New York, New York;

B. Liegner, MD, Private Practice in Armonk, New York; Janice M. Kochevar,

FNP-C, Private Practice in Armonk, New York; A. Fallon, MD, Department

of Psychiatry, New York-Presbyterian Medical Center, New York, New York;

L. Van Heertum, MD, Department of Radiology, New York-Presbyterian

Medical Center, New York, New York.

[Journal of Spirochetal and Tick-Borne Diseases 6(4):117-122, 1999. © 1999

Lyme Disease Foundation, Inc.]

Abstract

Patients with Lyme disease may experience neuropsychiatric problems that

persist even after standard courses of antibiotic therapy. Objective

detection of neuroimaging brain abnormalities can be helpful to the

clinician by demonstrating either focal or diffuse deficits, thereby

supporting a CNS origin to the neuropsychiatric problems. To examine the

potential utility of SPECT brain imaging in the evaluation of chronic Lyme

disease (CLD), two questions were addressed: 1) Are SPECT brain scans

abnormal in CLD patients with neuropsychiatric findings? and 2) If abnormal,

are the perfusion abnormalities specific for CLD?

SPECT brain scans of 19 patients with CLD and 14 non-CLD patients with other

neurological diagnoses resulting in perfusion abnormalities were evaluated

in a blinded read without reference to clinical status. Scans were randomly

ordered for interpretation by three experienced SPECT readers. Final

interpretation was arrived at by consensus. Scans were interpreted as

normal, abnormal-focal hypoperfusion, or abnormal-diffuse hypoperfusion.

Hypoperfusion was described as homogenous or heterogenous. Results were

analyzed as percent normal or abnormal and pattern of abnormality.

CLD SPECT scans were interpreted as abnormal in 14 of 19 (74%) scans, each

characterized as heterogeneous with or without globally decreased perfusion.

One CNSLD scan showed a focal lesion. CLD patterns could be distinguished

from non-LD patients with a diagnosis of Alzheimer's or Moya-Moya disease

but not from non-LD patients with a diagnosis of Creutzfeldt- disease,

Lupus, cerebral vasculitis, or chronic fatigue syndrome. Of the 14 patients

who had brain MRI scans, only 2 (14.3%) were abnormal, revealing white

matter hyperintensities.

These findings suggest that brain SPECT may be a more sensitive tool than

MRI for identifying brain abnormalities in CLD, but that the heterogenenous

pattern is not specific to CLD.

Introduction

Patients with chronic Lyme disease (CLD) may have persistent

neuropsychiatric signs and symptoms.[1-3] The identification of objective

markers of brain involvement in this patient population is critical: a) to

support the hypothesis that the neuropsychiatric problems are related to a

diffuse brain disease; and to provide evidence of physiologic change that

may correlate with reduced symptoms following treatment. A variety of

imaging modalities including CT and MR have had limited value in the

evaluation of CLD patients. SPECT brain imaging is a potential tool for

establishing the presence of brain changes in these patients. In particular,

if SPECT brain scans reveal perfusion abnormalities, then such findings

would be helpful in establishing the physiological basis for the clinical

presentation. Preliminary reports suggest that brain SPECT studies of

patients with CLD who present with neurological and/or psychiatric

complaints[4-6] are often abnormal.

To examine the potential utility of SPECT brain imaging in the evaluation of

the patient with CLD, we performed a retrospective study to address two

questions. First, do CLD patients with neurological and/or psychiatric

findings have abnormal SPECT brain scans? Second, if SPECT scans are

interpreted as abnormal, are the perfusion abnormalities specific for CLD?

Materials and Methods

Subjects

Lyme disease patients

SPECT brain scans of 19 patients (mean 35.6 years, SE 2.8, 9M/10F) with a

diagnosis of CLD who were referred to the Nuclear Medicine Division,

Department of Radiology, New York Presbyterian Medical Center prior to

11/19/96 were evaluated in a blind read. The clinical work-up and diagnosis

of CLD was made by the referring physicians.

Based on clinical records and examination the diagnosis of CLD was confirmed

by ensuring that all patients met the following criteria: a) a multisystem

illness affecting the neurologic, articular, cardiac, and/or dermatological

systems; a positive Western blot (IgG or IgM) for Lyme disease; and c)

exposure to a Lyme endemic area. Patients in this sample had Western blot

assays performed at one or both of the following two laboratories: BBI

Clinical Laboratories (New Britain, CT) and/or University Medical Center

Health Sciences Center, State University of New York at Stony Brook (Stony

Brook, New York). The standard for Westem blot interpretation varied

depending upon the individual laboratory.

Chart review showed that each patient had constitutional, musculoskeletal,

and neuropsychiatric symptoms. The most prominent complaints among the 19

patients were:

Constitutional -- fatigue (100%), insomnia (52.6%), night sweats (26.3%).

Musculoskeletal -- migrating large joint pains (84.2%), neck pain (52.6%),

arthritis (15.8%).

Neuropsychiatric -- cognitive complaints (eg, memory, attention) (94.7%),

headache (89.5%), paresthesias (57.9%), tinnitus (57.9%), depression

(52.6%), blurry vision (52.6%), photophobia (26.3%).

It was documented in the physician's chart that 31.6% of the patients had an

erythema migrans rash. Only 26.3% of the patients recalled a tick bite. All

CLD patients in this study had undergone prior antibiotic treatment for Lyme

disease. The majority of patients had been ill for more than a year before

Lyme disease was diagnosed and treated (median 88 weeks).

MRI, EEG, CSF, and neuropsychological test data were available on some of

the patients: 2 of 14 patients (14.3%) had abnormal brain MRIs (white matter

hyperintensities); 1 of 8 patients had an abnormal EEG; 6 of 11 patients

(54.5%) had abnormal spinal fluid (elevated protein, lymphocytosis, Borrelia

burgdorferi PCR, and/or elevated Lyme titer). None of these 6 patients met

criteria for intrathecal antibody production; 10 of the 19 patients had a

battery of neuropsychological tests with each of the 10 individuals

demonstrating clinically significant cognitive deficits.

Non-Lyme disease patients

SPECT brain images of 14 non-LD patients were selected from among the recent

scans performed in the Nuclear Medicine Laboratory of the Nuclear Medicine

Division of the Radiology Department at the New York-Presbyterian Hospital.

These scans were interspersed among the scans obtained on the CLD patients

as described below. Non-LD patients ranged in age from 29-47 years (mean 46

yrs). Clinical diagnoses in these patients were: presumed Alzheimer's

disease-2; cerebral vasculitis-4; chronic fatigue syndrome-3;

Creutzfeldt-s disease (pathologically confirmed)-l; Lupus-2; and

vascular insufficiency-2. The 3 patients with chronic fatigue syndrome were

seronegative for Lyme disease according to the referring physician. Because

this was a clinical series of scans, the medical work-up of these other 11

patients with other neurologic illnesses was unknown to us. In other words,

we do not know whether or not these patients had been tested for Lyme

disease.

SPECT Imaging Studies

Prior to their SPECT examination, LD patients were told not to use caffeine

and nicotine for at least 2 hours prior to the study. Patients were

administered an IV injection of Tc-99m-hexamethlypropyleneamine

(Tc-99m-HMPAO) in doses ranging from 555 to 814 megabecquerel (15-22

millicuries) while in a supine position with eyes open in a low-stimulation

environment. Imaging was begun 40 minutes post injection.

Images were acquired on a triple-headed SPECT camera (Picker Prism 3000,

Cleveland, OH) following a previously validated rapid acquisition sequence

(RAS) imaging protocol.[6] The details of image acquisition and processing

are described in the Appendix. Axial, coronal, and sagittal Picker light box

images were reviewed using the Picker step-10 color scale. Studies were

normalized to mean cerebellar counts. Background counts were set to the

scalp activity (approximately 10% background subtraction). If cerebellar

disease was evident then the study scale was normalized to the deep grey

matter. The color scale was consistent across all patients.

Image Interpretation

The 33 SPECT brain scans (19 CLD and 14 non-LD patients) were randomly

ordered for a blinded interpretation by 3 experienced SPECT readers (RVH,

RST, JJP). Final interpretation was arrived at by consensus. No clinical

information was available to the readers when the images were subjected to

interpretation. Scans were interpreted as normal if there were no areas of

hypo/hyperfusion. An area of abnormal perfusion was defined as nonanatomic

cerebral hypoperfusion that was < 60% of the cerebellar or deep grey matter

perfusion. Perfusion abnormalities were defined as: a) focal if the

hypoperfusion was confined to one brain lobe, or diffuse if more than one

lobe showed hypoperfusion. Patterns of hypoperfusion are described as either

homogenous or heterogenous. A homogeneous pattern was defined as diffuse

hypoperfusion throughout the cerebrum. A heterogeneous pattern was defined

as multiple or diffuse areas of hypo perfusion interspersed with areas of

normal perfusion.

Data Analysis

Results of the consensus read of the SPECT scans were subsequently analyzed

to determine the percent of scans interpreted as normal or abnormal and

types of abnormal patterns observed.

Results

SPECT scans were interpreted as abnormal in 14 of the 19 (74%) patients with

CLD. In 13 of the 14 patients, a SPECT scan pattern was characterized by

diffuse cortical heterogeneity with or without globally decreased perfusion.

A focal lesion was seen in 1 abnormal scan. The patterns in the CLD scans

could not be accurately distinguished from the scan patterns observed in

patients with Creutzfeldt-s disease (1/1 incorrect), Lupus (1/2

incorrect), cerebral vasculitis (2/4 incorrect), and chronic fatigue

syndrome (3/3 incorrect). This heterogeneous pattern was not seen in the 2

Alzheimer's patients and the patient with Moya-Moya disease. Representative

SPECT scans for CLD and non-LD patients are shown in the Figure.

Figure. Representative examples of SPECT studies used in the blind read. (A)

Alzheimer's disease; ( cerebral vasculitis; (C-1) baseline -- Lyme disease

patient; (C-2) same patient after treatment showing improvement; (D-1)

baseline -- Lyme disease patient; and (D-2) same patient after treatment

whose condition worsened.

Of the 11 patients on whom CSF results were available, 6 had an abnormal CSF

of whom 4 also had an abnormal SPECT, and 5 had a normal CSF of whom 4 had

an abnormal SPECT. Of the 10 patients who had neuropsychological testing and

who demonstrated cognitive deficits, 6 of the 10 had abnormal brain SPECT

scans. Of the 14 patients on whom MRI results were available, 12 had normal

brain MRIs but 9 of these 12 had abnormal SPECT scans.

Discussion

Lyme disease is the most common vector-borne infectious disease in the

United States. It is caused by the bacterium, Borrelia burgdorferi, a

spirochete.[7] The disease may cause acute-subacute (days to weeks), and

chronic (months, years, and even decades) bouts of insidious, multisystem

signs and symptoms of infection. The most commonly reported symptoms are

musculoskeletal, dermatologic, neurologic, psychiatric, and cardiac.[8]

Neurologic/psychiatric signs and symptoms may occur in up to 40% of patients

shortly after infection. Neurologic findings may include Bell's palsy, acute

meningitis, acute encephalitis, or motor or sensory peripheral nervous

dysfunction. Memory loss, inattention, slow processing speed, anxiety,

depression, paranoia, and severe mood swings have been reported as

neuropsychiatric manifestations of central nervous system involvement.[3]

Reports suggest that not all patients with Lyme infection become

seropositive.[9,10] There is a need for " objective " tools to aid in

diagnosis, and to gauge the efficacy of antibiotic therapy in patients with

neuroborreliosis. Such tools include neuropsychological testing and

noninvasive imaging procedures. MR imaging in CLD reveals a wide variety of

noncortical abnormalities. Reports show that the percent MR abnormalities

vary between 10% and 40% in LD patients with neurologic signs and

symptoms.[3,11,16] In our sample, 14.3% had abnormal MR scans, each

demonstrating white matter hyperintensities. Although not a sensitive test

in detecting abnormalities among patients with CLD, MRI is a very useful

technique for excluding other diseases such as neoplasms, vascular or

congenital malformations, and chronic extra-axial bleeds that could result

in clinical presentations like those of CLD.

SPECT brain imaging is another noninvasive imaging modality that may have

utility for assessing CNS involvement associated with Lyme disease. Das et

al reported that 51.4% of 35 suspected CNS Lyme disease patients showed

SPECT abnormalities.[4] The pattern described was that of heterogenous

decreased cortical perfusion in 83% of cases with abnormal scans. We report

a similar finding, with 14/19 scans (74%) being abnormal. The most prominent

pattern was that of a diffuse heterogenous reduction of cortical perfusion.

At the present time there is no satisfactory explanation for the pattern

observed in LD. The cortical abnormalities seen on SPECT scans may represent

a secondary response to involvement of subcortical white matter. These

abnormalities may also be caused by vasculitis.[16] Logigian et al,[5] using

quantitative brain SPECT analysis, reported multifocal white matter

perfusion abnormalities in patients with LD.

The pattern of diffuse cortical heterogeneous hypoperfusion reported in the

present study is similar to that seen in patients with Creutzfeldt-

disease, primary cortical vasculitis, Lupus, and chronic fatigue syndrome.

This pattern has also been reported for patients with AIDS infection and

polysubstance abuse.[17,21] However, the pattern is distinct from that of

Alzheimer's disease or the watershed hypoperfusion in Moya-Moya disease. In

Alzheimer's disease, for example, we would typically see decreased perfusion

in the temporo-parietal regions of the brain in both hemispheres with

sparing of the sensory-motor strip.

Our findings suggest that brain SPECT scans may be an objective and useful

tool for visualizing the cortical changes that may be correlated with the

central nervous system manifestations of Lyme disease. It must, however, be

emphasized that the finding of a " normal " brain SPECT scan is not sufficient

to " rule out " the presence of CNS Lyme disease. Likewise, an abnormal SPECT

scan by itself does not suffice to establish a diagnosis of Lyme disease,

but with other clinical and laboratory data may point to CNS involvement

when the diagnosis of Lyme disease cannot be established by other means.

Abnormalities revealed in the SPECT scans are not typically seen with

standard anatomic imaging procedures such as MRI or CT.

Although a significant number of scans of the CLD patients revealed

abnormalities, these abnormalities could not be distinguished from other

disease entities that show diffuse heterogenous hypoperfusion. Our findings,

therefore, demonstrate that SPECT brain imaging can be helpful in

identifying the presence of a disease process that affects the brain

diffusely, but the lack of specificity in the heterogeneous pattern limits

its usefulness in distinguishing one diffuse brain disorder from another.

Our study does not answer the question of whether brain SPECT scans can be

used to differentiate patients with primary psychiatric disorders from

patients with Lyme disease accompanied by secondary psychiatric disorders

because none of our control patients had a primary psychiatric disorder as

the main diagnosis.

This study by nature of its retrospective design has limitations that

preclude definitive conclusions. For example, although we presumed that the

non-Lyme disease patients did not have Lyme disease based on the referring

physician's clinical information, this is not certain given that we did not

conduct Lyme tests on these patients. This issue is particularly problematic

regarding patients with chronic fatigue syndrome whose symptom constellation

is quite like that of patients with CLD. Although the referring physician

assured us that patients with chronic fatigue syndrome had negative Lyme

serologies, we still could not be certain that they did not have Lyme

disease as the trigger to their chronic fatigue given the problems with

serologic sensitivity in Lyme disease.

Further research, combining systematic neurologic/neuropsychologic testing

with serial SPECT scanning is needed to further elucidate the role of SPECT

scanning in Lyme disease and to assess the effects of various therapeutic

interventions for CLD.

References

Shadick NA, CB, Logigian EL, Steere AC, Kaplan RF, Berardi VP,

Duray PH, Larson MG, EA, Ginsburg KS, et al. The long-term clinical

outcomes of Lyme disease. A population-based retrospective cohort study. Ann

Intern Med 1994;121:560-567.

Asch ES, Bujak DI, Weiss M, MG, Weinstein A. Lyme disease: an

infectious and post infectious syndrome. J Rheumatol 1994;21:454-461.

Halperin JJ, Pass HL, Anand AK, Luft BJ, Volkman DJ, Dattwyler RJ. Nervous

system abnormalities in Lyme disease. Ann NY Acad Sci 1988;539:24-34.

Das S, Plutchok JJ, Liegner KB, et al. Tc-99m-HMPAO brain SPECT detection of

perfusion abnormalities in Lyme disease patients with clinical

encepholopathy [abstract]. J Nucl Med 1996;37:270P.

Logigian EL, KA, Kijewski MF, Kaplan RF, Becker JA, KJ, Garada

BM, Holman BJ, Steere AC. Reversible cerebral hypoperfusion in Lyme

encephalopathy. Neurology 1997;49:1661-1670.

Bloom M, s S, Pile-Spellman J, Pozniakoff A, Mabutas MI, Fawwaz RA, Van

Heertum RL. Cerebral SPECT imaging: effects on clinical management. J Nucl

Med 1996;37:1070-1074.

Burgdorfer W. Discovery of the Lyme disease spirochete and its relation to

tick vectors. Yale J Biol Med 1984;57:515-520.

Steere AC. Lyme disease. N Engl J Med 1989;321:586-596.

Oksi J, Uksila J, Marjamaki M, Nikoskelainen J, Viljanen MK. Antibodies

against whole sonicated Borrelia burgdorferi spirochetes, 41-kilodalton

flagellum and P39 protein in patients with PCR- or culture-proven late Lyme

borreliosis. J Clin Microbiol 1995;33:2260-2264.

Coyle PK, Schutzer SE, Deng Z, Krupp LB, Belman AL, Benach JL, Luft BJ.

Detection of Borrelia burgdorferi-specific antigen in antibody-negative

cerebrospinal fluid in neurologic Lyme disease. Neurology 1995;45:2010-2015.

Fernandez RE, Rothberg M, Ferencz G, Wujack D. Lyme disease of the CNS: MRI

findings in 14 cases. Am J Neuroradiol 1990;11:479-481.

JA, Wolf MD, Yuh WT, Peeples ME. Cranial nerve involvement with Lyme

borreliosis demonstrated by magnetic resonance imaging. Neurology

1992;42:671-673.

Belman AL, Coyle PK, Roque C, Cantos E. MRI findings in children infected by

Borrelia burdorferi. Pediatr Neurol 1992;8:428-431.

Demaerel P, Wilms G, Van Lierde S, Delanote J, Baert AL. Lyme disease in

childhood presenting as primary leptomeningeal enhancement without

parenchymal findings on MR. Am J Neuroradiol 1994;15:302-304.

Rafto SE, Milton WJ, Galetta SL, Grossman RI. Biopsy confirmed CNS Lyme

disease: MR appearance at 1.5T. Am J Neuroradiol 1990;11:482-484.

Oksi J, Kalimo H, Marttila RJ, Marjamaki M, Sonninen P, Nikoskelainen J,

Viljanen MK. Inflammatory brain changes in Lyme borreliosis. A report on

three patients and review of the literature. Brain 1996;119:2143-2154.

Aharon-Peretz J, Peretz A, Hemli JA, Honigman S, Israel O. SPECT diagnosis

of Creutzfeld- disease. J Nucl Med 1995;36:616-617.

Meusser S, Rubbert A, Manger B, Bock E, Platsch G, Feistel H, Engelhardt A,

Wolf F, Kalden JR. 99m-Tc-HMPAO SPECT in the diagnosis of early cerebral

vasculitis. Rheumatol Int 1996;16:37-42.

Emmi L, Bramati M, De Cristofaro M, Mascalchi M, Dal Pozzo G, Marconi GP,

Massai G, Passalera A. MRI and SPECT investigations of the CNS in SLE

patients. Clin Exp Rheumatol 1993;11;13-20.

Schwartz RB, Komaroff AL, Garada BM, Gleit M, Doolittle TH, Bates DW, Vasile

RG, Holman BJ. SPECT imaging of the brain: comparison of findings in

patients with chronic fatigue syndrome, AIDS dementia complex, and major

unipolar depression. Am J Roentgenol 1994;162:943-951.

Holman BL, Carvalho PA, Mendelson J, Teoh SK, Nardin R, Hallgring E, Hebben

N, KA. Brain perfusion is abnormal in cocaine-dependent polydrug

users: a study using technetium-99m-HMPAO and SPECT. J Nucl Med

1995;32:1206-1210.

Perani D, Di Piero V, Valla G, Cappa S, Messa C, Bottini G, Berti A,

Passafiorne D, Scarlato G, Gerundini P, et al. Technetium-99m-HM-PAO-SPECT

study of regional cerebral perfusion in early Alzheimer's disease. J Nucl

Med 1988;29:1507-1514.

Testa HJ, Snowden JS, Neary D, Shields RA, Burjan AW, Prescott MC, Northen

B, Goulding P. The use of [Tc-99m]-HM-PAO in the diagnosis of primary

degenerative dementia. J Cereb Blood Flow Metab 1988;8:S123-S126.

Bonte FJ, Horn J, Tinter R, et al. Single photon emission tomography in

Alzheimer's disease and the dementias. Sem Nucl Med 1990;20:342-352.

Holman BL, KA, Gerada B, Carvalho PA, Satlin A. The scintigraphic

appearance of Alzheimer's disease: a prospective study using technetium-99m

HMPAO SPECT. J Nucl Med 1992;33:181-185.

JH, Khonsary A, Raffel C. The scintigraphic appearance of childhood

Moya-Moya disease on cerebral perfusion imaging. Pediatr Radiol

1996;26:833-838.

Appendix

SPECT images were obtained by acquisition of four RAS data sets with a

Leuhr-Fan beam collimators (Picker). Each data set was a 360° continuous

mode. Acquisition was comprised of 120 total projection images (40

projection images per detector). The radius of rotation was equal to or less

than 14 cm, with a hardware zoom-magnification factor of 1.0. Each

projection image was 7.5 seconds with a total acquisition time of

approximately 20 minutes. Axial images were aligned parallel with the

canthomeatal line and the corona/sagittal planes were aligned perpendicular

to the axial rotation of the camera. Images were acquired into a 128 3 128

digital computer matrix. The four rapid acquisitions sequences were

subsequently summed together and reconstructed with filtered backprojection

and attenuation correction of 0.11 (Picker). A low-pass (Butterworth,

Picker) filter was used with a fifth order slope and the cut-off frequency

of .35-.45 cycles per pixel. Single pixel width transaxial images were used

to reconstruct the coronal and sagittal planes. All image planes were

displayed as 3 pixel width (6.6 mm) thick slices. The SPECT system spatial

resolution was 0.78 cm (FWHM).

----------------------------------------------------------------------------

----

All material on this website is protected by copyright. Copyright ©

1994-2000 by Medscape Inc. All rights reserved. This website also contains

material copyrighted by 3rd parties. CME means Continuing Medical Education

credit is available. Medscape requires 3.x browsers or better from Netscape

or Microsoft.