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Single-photonemission computed tomography analysis of cerebral blood flow in the evaluation of central nervous system involvement in patients with systemic lupus erythematosus.

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ARTHRITIS & RHEUMATISM Volume 36
Number 9, September 1993, pp 1253-1262
0 1993, American College of Rheumatology
1253
SINGLE-PHOTON-EMIS SION
COMPUTED TOMOGRAPHY ANALYSIS OF
CEREBRAL BLOOD FLOW IN THE
EVALUATION OF CENTRAL NERVOUS SYSTEM
INVOLVEMENT IN PATIENTS WITH
SYSTEMIC LUPUS ERYTHEMATOSUS
A. RUBBERT, J. MARIENHAGEN, K. PIRNER, B. MANGER, J. GREBMEIER,
A. ENGELHARDT, F. WOLF, and J. R. KALDEN
Objective. Single-photon-emission computed tomography (SPECT) scanning was used to detect potential central nervous system (CNS) involvement in patients with systemic lupus erythematosus (SLE), by
determining cerebral blood flow abnormalities.
Methods. SPECT scans were performed on 35
SLE patients, grouped into 3 categories: those without
neuropsychiatric symptoms (n = lo), those with definite
neurologic or psychiatric disorders (n = lo), and those
with mild symptoms such as headache or memory
disturbances (n = 15). SPECT scan features were
classified as normal or as focal or diffuse defects in
uptake.
Results. SPECT findings were normal in 9 of the
10 patients without CNS symptoms, and abnormal in 9
of the 10 patients with overt neuropsychiatric disease
(with motor or sensory deficits). Interestingly, only 4 of
the 15 patients (26.7%) with mild symptoms suggestive
of CNS disease had normal SPECT findings; the 11
From the Department of Medicine 111, Institute for Clinical
Immunology and Rheumatology, and the Departments of Nuclear
Medicine and Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.
A. Rubbert, MD: Department of Medicine 111, Institute for
Clinical Immunology and Rheumatology; J. Marienhagen, MD:
Department of Nuclear Medicine; K. Pirner, MD: Department of
Medicine 111, Institute for Clinical Immunology and Rheumatology;
B. Manger, MD: Assistant Professor, Department of Medicine 111,
Institute for Clinical Immunology and Rheumatology; J. Grebmeier,
MD: Department of Nuclear Medicine; A. Engelhardt, MD: Department of Neurology; F. Wolf, MD: Professor of Nuclear Medicine
and Head, Department of Nuclear Medicine; J. R. Kalden, MD:
Professor of Medicine and Head, Department of Medicine 111,
Institute for Clinical Immunology and Rheumatology.
Address reprint requests to A. Rubbert, MD, Department
of Medicine 111, Krankenhausstr. 12, 91054 Erlangen, Germany.
Submitted for publication April 1, 1992; accepted in revised
form October 17, 1992.
remaining patients showed focal (53.3%) or diffuse
(20%) uptake defects. An association between SPECT
findings and disease duration was also observed, but
there was no correlation of SPECT results with overall
disease activity, serologic findings, or medications used.
Conclusion. Our data suggest that in a substantial proportion of patients, SPECT analysis may provide
additional information on potential CNS involvement,
and may therefore be useful in therapeutic decisionmaking and disease monitoring in order to prevent CNS
damage.
One of the most important complications of
systemic lupus erythematosus (SLE) is involvement of
the central nervous system (CNS), with clinical signs
and symptoms occurring in approximately 40% of all
SLE patients (1) and minor neuropsychiatric symptoms at higher frequencies. Such symptoms as migraine have been reported in a substantial proportion
of patients (2). The frequency of psychiatric symptoms
is still a subject of much debate and largely depends on
the criteria applied.
Both immune-mediated and vascular mechanisms have been proposed as causes of CNS disease in
SLE. The concept of vascular disturbances has gained
substantial support by the demonstration of microinfarcts on magnetic resonance imaging (MRI) scans in
many patients and by reports of cerebral blood flow
abnormalities in patients with neuropsychiatric symptoms (3,4). Histologic studies have revealed a predominance of vasculopathic changes, usually consisting of
proliferation of the intima and vascular hyalinization.
However, several studies have found no evidence of
an association between vasculopathy and CNS symptoms, and rarely any true vasculitis (5,6).
RUBBERT ET AL
1254
Because neuropsychiatric complications are
still a cause of death in 10-20% of SLE patients (1,7)
and organic alterations of the CNS can be refractory to
immunosuppressive treatment, techniques for detecting possible manifestations of CNS involvement early
in the course of disease are needed. Computed tomography (CT) or MRI can reveal morphologic alterations in a substantial proportion of patients who have
overt neurologic symptoms, but it would be desirable
to identify changes before structural damage occurs.
Functional neuroimaging by single-photon-emission
computed tomography (SPECT) should be able to
demonstrate brain perfusion abnormalities early.
In the present study, we used 99mTc-hexamethylpropylene amine oxime (99"Tc-HMPAO) SPECT
techniques to examine regional brain perfusion patterns in 35 patients with SLE. Ten patients had definite
neurologic or psychiatric disorders, 15 patients had
mild CNS symptoms (headache or cognitive disorders), and 10 patients had no neuropsychiatric symptoms. Additional CT andlor MRI scans were performed on 15 patients. The SPECT results were
compared with clinical, radiomorphologic, and serologic findings in the patients.
PATIENTS AND METHODS
Patient population. Between January 1990 and December 1991, 35 patients with SLE fulfilling at least 4 of the
American College of Rheumatology (formerly, the American
Rheumatism Association) criteria for SLE (8) were enrolled
in the study. Most of the patients were receiving medical
care in our outpatient clinic. Twenty-fivepatients had symptoms of neuropsychiatric disease (10 patients with definite
neuropsychiatric disease and 15 patients with only mild
symptoms); the other 10 patients did not report specific CNS
symptoms. After physical examination, routine hematology
and blood chemistry studies were performed. Immunologic
assays included the measurement of anti-double-stranded
DNA (anti-dsDNA) antibodies, C3 and C4 levels, antibodies
to Sm, Ro, RNP, La, and cardiolipin (by enzyme-linked
immunosorbent assay), levels of circulating immune complexes (by Clq binding assay and polyethyleneglycol [PEG]
precipitation, with laser nephelometry of the immunoglobulin component), and analysis for the lupus anticoagulant (by
tissue thromboplastin-inhibition test and kaolin clotting
time).
A neurologic consultant evaluated patients with neurologic symptoms. Neuropsychiatric symptoms due to SLE
were defined as those that could not be attributed to any
other cause (such as uremia, hypertension, or infection), and
were categorized as major or minor, according to the classification proposed by How et al (91, as follows. Major
neurologic manifestations: seizures, focal motor or sensory
deficits (hemiparesis, cranial nerve palsies, disorders of
movement or gait, transverse myelitis, or focal, peripheral,
or cranial neuropathy), or generalized disturbances (altered
consciousness, encephalomyelitis, organic brain syndrome).
Major psychiatric manifestations: psychosis (clinical [endogenous] depression, cyclic affective disorders, schizophreniform disorders) or organic brain syndrome. Minor neurologic manifestations: paresthesias without objective findings,
clumsiness without objective findings, headache (any type,
persistent), or pseudopapilledema or benign intracranial
hypertension. Minor psychiatric manifestations (not associated with other neurologic or psychiatric signs): reactive
depression, mood swings, cognitive disorders, severe anxiety or other psychoneuroses, or behavioral problems.
In 3 patients, SPECT scans were performed again
after a few months. In 15 patients, MRI and/or CT scans
were included in the diagnostic procedure.
SPECT scanning. 99"Tc-HMPA0 (Amersham,
Buchler, FRG) was prepared according to the manufacturer's recommendations. After their informed consent was
obtained, patients were placed in a supine position in a quiet
room with dimmed lights and were allowed to relax for 15
minutes prior to intravenous administration of 555-740 MBq
of 99"T~-HMPA0.The effective dose equivalent was 0.018
mSv/MBq; therefore, patients were exposed to 10-13.3
mSv during the procedure. SPECT data acquisition began 30
minutes after the injection. A rotating gamma camera (Siemens RotaMcroDelta System with high-resolution parallelhole collimator or Siemens Orbiter with neurofocal imaging
system; Siemens, Munich, FRG) with a 64 x 64 matrix and
a 360" step-and-shoot acquisition was used. Reconstruction
of transaxial slices was performed by filtered backprojection. Oblique (along the orbitomeatal line), sagittal,
and coronal slices were created from transaxial slices. Slice
thickness was 6.25 mm. Spatial resolution was 12 mm full
width at half maximum (FWHM) in the horizontal plane.
SPECT slices were evaluated by an investigator (JM) who
had no knowledge of the clinical data.
Visual qualitative grading was performed, and features were diagnosed according to the criteria established by
Podreka et a1 (10) and Stefan et a1 (11). Normal findings
consisted of homogenous brain perfusion without focal uptake defects or visible asymmetry. SPECT focal uptake
defects in at least 2 consecutive slices in 2 reconstructions
were evaluated as follows. A predefined table of 256 rainbow
colors on the computer screen was utilized, which condensed (with a constant upper and lower threshold) into 16
discrete color steps on hard copy (from dark blue to white),
each representing a 6.25% difference in the percentage of
maximum pixel counts. A visible contrast of at least 2 color
steps compared with the contralateral hemisphere was considered a perfusion deficit on the side with the lower color
intensity. If there were more than 2 focal uptake defects in at
least 2 consecutive slices, SPECT scans were classified as
showing diffuse uptake defects.
CT and MRI scanning. CT scans were obtained with
a Siemens DR3 computer tomograph, using standard techniques (transverse slices, 8 mm thick, with orbitomeatal
orientation). Contrast-enhanced studies (single-dose technique) were performed in all 7 patients studied.
MRI studies were performed with a Siemens Magne-
-
SPECT SCANNING IN CNS LUPUS
1255
Table 1. Summary of clinical data about the 35 patients with systemic lupus erythematosus*
Patientlsexlage
Disease
duration
(years)
Clinical
manifestations
Major neuropsychiatric
symptoms
1lFl24
2lFl33
5
1
3IFl50
4lMl22
10
1.5
5IMl59
5
6lFl63
1
7lMl48
8lFl19
9lFl3 1
1OlFl25
4
0.5
3
0.5
S, A, N, stroke 4 years ago
S, L, T, N, serositis, cerebral hemorrhage 6 months ago,
seizures, organic brain syndrome, hemiparesis, cranial
nerve palsy (VII), polyneuropathy
S, A, seizures, organic brain syndrome
S, A, N, L, phlebothrombosis I year ago, organic brain
syndrome
A, ataxia, organic brain syndrome, polyneuropathy,
spastic paraparesis
S, A, stroke 3 months ago, reactive depression, ataxia,
residual hemiparesis
A, T, N, ataxia, hemiparesis, reactive depression
S, A, polyneuropathy
A, N, polyneuropathy
A, L, incomplete Brown-Stquard syndrome
Minor neuropsychiatric
symptoms
11lFl21
12lFl48
13lFl 19
14lFl30
15lFl24
0.7
2
1
9
0.7
16lFl33
17lF147
18lFl29
19lFl24
20lMl43
2 1IFl71
22lFl46
23lFl56
24lFl44
25lFl48
7
2
10
4
5
9
1
13
4
0.7
S, A, N, headache, cognitive disorders
S, A, migraine, reactive depression
S, A, fever, headache, cognitive disorders
S, A, N, headache, mood swings
S, A, repeated abortions, phlebothrombosis 6 months
ago, migraine, cognitive disorders
S, A, L, migraine, cognitive disorders
S, A, headache, reactive depression
S, A, N, mood swings, headache, cognitive disorders
A, T, lung fibrosis, headache
S, A, alopecia totalis, migraine
S, A, transient paresthesia, dizziness
A, reactive depression, anxiety
S, A, cognitive disorders
S, A, lung fibrosis, reactive depression
S, A, reactive depression
No neuropsychiatric
symptoms
26lFl35
27lFl3 1
28lFl44
11
1.5
3
29lFl25
30lFl3 1
3 1lF151
32lFl25
33lFl32
34/M/23
35lMl29
0.2
0.7
12
1
9
7
0.5
S, A, N
A, N, serositis, hemolytic anemia
A, N, hemolytic anemia, transient ischemic attack
1 month ago
S, A, L, myositis, anemia
S, A, L, 12-year history of seizures
A, L, lung fibrosis
S, A, L
S, A, N
A, N
S, A
* Ages, disease durations, and clinical manifestations were those at the time of single-photon-emission
computed tomography, unless otherwise noted. See Patients and Methods for descriptions of
neuropsychiatric categories. S = skin involvement; A = arthralgias; N = nephropathy; L =
leukopenia; T = thrombocytopenia.
tom, 1.5 Tesla, using standard spin-echo techniques (transverse slices, 5 m m thick, with axial orientation). For routine
evaluation, proton-density (time to recoveryhime to echo
[TR/TE] = 3,000/25) and T2-weighted images (TR/TE =
3,000/90) were obtained in all 12 patients. Both CT and MRI
studies were evaluated by one investigator (JG) who had no
knowledge of the clinical data.
Statistical analysis. Contingency analyses, including
chi-square tests of independence with Yates’ correction, and
nonparametric statistical methods (Spearman rank cor-
RUBBERT ET AL
1256
Table 2. SPECT and CTiMRI scan results in the 35 patients with systemic lupus erythematosus, according to neuropsychiatric
manifestations*
SPECT scan
findings
CT/MRI scan
findings
MRI, large defect R parietal cortex
MRI/CT, large intracerebral hemorrhage R frontoparietal region
5
Focal, R parietal region
Focal, R frontal, parietal, thalamic
regions
Focal, L parietal, occipital regions
Diffuse uptake defects
Focal, L temporal, parietal regions
6
7
8
9
10
Focal, R parietal, occipital regions
Focal, L parietal, occipital regions
Normal
Diffuse uptake defects
Diffuse uptake defects
ND
ND
MRI, multiple lesions in the white matter of R and L
frontoparietal cortex, temporal regions
MRI, ischemic lesion R parietal cortex
CT, lesions in cerebellum, periventricular white matter
MRI, 1 lesion (3 mm) in the white matter of parietal cortex
MRIICT, normal
ND
Normal
Focal, L frontal, parietal regions
Normal
Diffuse uptake defects
Focal, L parietal region
Diffuse uptake defects
Normal
Focal, R parietal region
Diffuse uptake defects
Focal, L temporal region
Focal, L temporal region
Focal, L temporal, parietal regions
Focal, L temporal, parietal regions
Normal
Focal, L temporal region
ND
ND
ND
ND
ND
CT, normal
ND
MRIICT, normal
MRI, multiple lesions periventricular and parietal white matter
ND
MRI, normal
MRI, lesions L putamen
ND
ND
M R K T , normal
Normal
Normal
Normal
Normal
Normal
Diffuse uptake defects
Normal
Normal
Normal
Normal
ND
ND
CT, ischemic lesion L capsula interna
MRI, normal
ND
ND
ND
ND
ND
ND
Patient
Major neuropsychiatric symptoms
1
2
3
4
Minor neurops ychiatric symptoms
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
No neuropsychiatric symptoms
26
27
28
29
30
31
32
33
34
35
* The findings of single-photon-emission computed tomography (SPECT) and the neuropsychiatric symptoms were classified as described in
Patients and Methods. Focal defects were in the left (L) or right (R) hemisphere. CT = computed tomography; MRI = magnetic resonance
imaging; ND = not done.
relation), were performed. P values less than or equal to 0.05
were considered significant. A commercially available software package was used (Statgraphics 4.0).
RESULTS
Patient characteristics. Over the 2-year period
of January 1990 through December 1991, 35 SLE
patients (6 men and 29 women) underwent SPECT
analysis. The median age of the patients was 31.5
years (range 19-71 years), and the median disease
duration was 2.5 years (range 2 months to 13 years).
The neuropsychiatric symptoms as well as the
non-CNS manifestations in these patients are shown in
Table 1. Among the non-CNS symptoms, involvement
of the skin (25 of 35 patients, 71.4%) and arthralgias
(34 of 35 patients or 97.1%) were the most frequent.
Thirteen patients (37.1%) had renal manifestations.
Thrombocytopenia and pulmonary fibrosis were
present in 3 patients, deep vein thrombosis had occurred in 2 patients (6-12 months previously), and
serositis and hemolytic anemia were seen in 2 patients.
Data in Table 1 are at the time of, or relative to,
SPECT scanning.
With respect to the neuropsychiatric manifesta-
SPECT SCANNING IN CNS LUPUS
1257
Table 3. SPECT findings and neuropsychiatric manifestations in
the 35 patients with systemic lupus erythematosus*
Neuropsychiatric symptoms
SPECT results
Major
Minor
None
Normal
Focal uptake defects
Diffuse uptake defects
1
6
3
4
8
3
9
10
15
10
Total
0
1
* The findings of single-photon-emission computed tomography
(SPECT) and the neuropsychiatric symptoms were classified as
described in Patients and Methods.
tions, 2 patients had experienced a stroke 4 years and
3 months previously, respectively, and 1 patient had
an intracerebral hemorrhage 6 months before SPECT
scanning. Residual hemiparesis was present clinically
in these 3 patients. Other neuropsychiatric symptoms
were organic brain syndrome (4 patients), peripheral
neuropathy (4 patients), spastic paraparesis (1 patient), incomplete Brown-SCquard syndrome (1 patient), and seizures (2 patients; another patient had
documented epilepsy for 11 years before the diagnosis
of SLE).
According to the classification proposed by
How et a1 (9), 10 of the 35 patients could be classified
as having “major” neurologic and/or psychiatric
symptoms. Of the remaining 25 patients, 10 had headaches or migraines, 6 patients described cognitive
A
disorders (attenuation of concentration and weakness
of memory), and reactive depression was evident in 7
patients. According to the criteria, 15 patients were
considered to have “minor” neuropsychiatric symptoms. Ten of the SLE patients included in this study
had no signs of CNS disease.
The results of the SPECT, CT, and/or MRI
scans are shown in Table 2. MRI scans were performed in 12 patients, 4 of whom also had CT scans.
Three patients underwent CT scanning only.
SPECT scan findings. Of the 38 SPECT scans
performed on the 35 patients, 15 (39.5%) showed
normal results, 7 scans (18.4%) showed diffuse uptake
defects, and 16 (42.1%) showed focal uptake defects.
Interestingly, 12 of these 16 scans showed focal uptake
defects confined to the left hemisphere.
Association of SPECT findings with MRYCT
results and neuropsychiatric manifestations. Nine of the
10 patients with major neuropsychiatric symptoms had
abnormal SPECT findings, with diffuse (n = 3) and
focal (n = 6) uptake defects (Table 3). Only 1 patient
(patient 8) had normal findings. This woman had no
signs of CNS disease, but she did have peripheral
neuropathy . Another patient with peripheral neuropathy (patient 9) showed diffuse uptake defects on the
SPECT scan.
MRI and/or CT scanning was performed in 7 of
these 10 patients (see Table 2). Findings were abnormal in 6 of them. Even patient 8, who had normal
B
Figure 1. A, Single-photon-emission computed tomography (SPECT) and B, magnetic resonance imaging (MRI) studies of patient 2, who had
an intracerebral hemorrhage 6 months previously. Both the MRI and the SPECT (focal uptake defect) images show a corresponding lesion of
the right frontoparietal hemisphere. MRI (T2-weighted image; time to echo [TE] 90 ms; time to repetition [TR] 3,000 ms) and SPECT were
performed as described in Patients and Methods.
1258
SPECT findings, showed a small lesion within the
white matter of the parietal cortex on the MRI scans.
The MRI changes appeared as areas of increased
signal intensity, mostly in the white matter of the
parietal and frontal cortex. In patients with cerebral
bleeding or infarction, MRI and SPECT findings were
consistent (Figure 1). The sensitivity of SPECT for
detecting cerebral blood flow abnormalities in patients
with major CNS symptoms was calculated as 90%.
Among the 15 patients who had minor neuropsychiatric symptoms, only 4 had normal findings on
SPECT (26.7%). Eight patients (53.3%) showed focal
uptake defects, and 3 (20%) had diffuse uptake defects.
MRI (n = 5 ) and/or CT scanning (n = 3) was performed in 6 of these patients, and revealed small
lesions in the white matter in 2 patients.
SPECT scans were also performed on 10 SLE
patients without neuropsychiatric symptoms. Results
of 9 of the 10 SPECT scans were classified as normal;
1 patient (patient 31) had diffuse uptake defects. None
of the patients had focal abnormalities.
MRI or CT scans of patients 28 and 29 from the
group with no neuropsychiatric symptoms revealed
small lesions in the left internal capsule in patient 28.
Thus, the SPECT scanning technique had a specificity
of 90%.
SPECT analysis was repeated in 3 patients
(patients 19, 13, and 5 ) . Patient 19 had migrainous
headaches for 2 months. SPECT analysis revealed
diffuse uptake defects and on MRI scan, areas of
increased signal intensity were noted predominantly in
the periventricular white matter (Figures 2A and B).
The headache improved with steroids and low-dose
aspirin treatment. After 4 months, when the patient
was asymptomatic, MRI and SPECT were again performed. The MRI findings appeared unchanged, but
the SPECT scan revealed a normal pattern of cerebral
blood flow (Figures 2C and D).
Patient 13, who had headaches, had no abnormalities on the initial SPECT scans. During the following months, she experienced several SLE flares, with
fever, exanthema, and arthralgias. At the time the
SPECT scan was repeated, she had been having
headaches, cognitive disorders, and memory disturbances for 4 weeks. Focal uptake defects in the
temporal and occipital white matter of the left hemisphere were evident on these images.
Patient 5 , whose SLE had been diagnosed 5
years previously, presented with ataxia, spastic paraparesis, and organic brain syndrome. Initial SPECT
analysis revealed focal uptake defects in the temporal
RUBBERT ET AL
and parietal white matter. Despite intensification of
immunosuppressive therapy, both the uptake defects
noted on SPECT scans and the neuropsychiatric
symptoms noted clinically were unchanged 12 months
later.
Association of SPECT findings with other clinical
manifestations. There was no correlation between clinical manifestations other than CNS involvement, especially, renal or cutaneous involvement, and SPECT
findings or neuropsychiatric symptoms. However,
with regard to the patients' age at the time of SPECT,
some interesting observations were made. In the 21
patients under age 40, 11 patients (52.4%) had normal
SPECT scans; diffuse and focal uptake defects were
seen in 6 and 4 patients, respectively. In patients older
than 40, normal SPECT findings were rare (3 of 14,
21.4%). Most had focal uptake defects (10 of 14,
71.4%). Thus, 78.6% of all normal SPECT scans (11 of
14) and 85.7% of all SPECT scans with diffuse abnormalities (6 of 7) occurred in the group of patients
younger than age 40. For this association, a contingency coefficient of 0.4 was calculated.
Twenty-two of the patients studied had disease
duration of less than 5 years. Eleven (50%) of them
had normal and 11 patients had pathologic SPECT
findings (focal in 7 patients, diffuse in 4). With a longer
disease duration (5 years or more), the frequency of
normal SPECT findings was reduced to 23%, and in
most of the patients (7 of 13, 53.8%) focal uptake
defects were apparent. Thus, a duration of SLE of 5
years and more was associated with a reduced frequency of normal findings but an increased frequency
of focal defects.
Correlation of SPECT findings with immunologic
parameters. Antibodies to cardiolipin were present in
10 patients; the lupus anticoagulant was detected in 1
patient. A decrease in C3 levels was noted in 18
patients and a decrease in C4 in 14 patients. Elevated
titers of anti-dsDNA antibodies (>20 unitdml) were
present in 19 patients. Circulating immune complexes
were detected in 8 patients by the Clq binding assay,
and in 10 patients by the PEG precipitation assay. Six
patients had both IgG-containing and IgM-containing
immune complexes; 3 patients had exclusively IgMcontaining immune complexes. An elevated erythrocyte sedimentation rate (230 mm/hour) was present in
14 patients. Antibodies against the Ro antigen were
present in 17 patients, anti-La antibodies in 12 patients, anti-Sm in 13, and anti-RNP antibodies in
20 patients. There was no significant correlation of
1259
SPECT SCANNING IN CNS LUPUS
C
D
Figure 2. A, SPECT and B, MRI studies of patient 19, who had been experiencing a migrainous headache for 2 months. The SPECT scan
revealed diffuse uptake defects, and the MRI scan (proton-density horizontal; TE 22 ms; TR 3,000 ms) showed areas of increased signal
intensity, predominantly in the periventricular white matter of the right hemisphere. After 4 months of treatment with immunosuppressants,
the symptoms resolved. C, SPECT scan performed at this time was interpreted as normal. D, MRI scan (proton-density horizontal; TE 25 ms;
TR 3,000 ms) also performed at this time appeared unchanged from initial studies. See Patients and Methods for details of SPECT and MRI
techniques. See Figure 1 for explanations of abbreviations.
the SPECT findings with any of the immunologic
parameters.
Correlation of SPECT findings with therapeutic
regimen. At the time of SPECT scanning, 12 patients
were not taking steroids, 16 patients were taking
low-dose steroids (524 mg of prednylidene per day),
and 7 patients were taking as much as 60 mg of
prednylidene per day. Low-dose aspirin (100 mg/day)
was taken by 7 patients. There was no correlation
between the SPECT scan results and either the steroid
or the aspirin therapy. Five of the patients were not
taking medications, and 9 patients were taking only
steroids. Chloroquine was given to 10 of the 35 patients and azathioprine to 6. Only a few patients (4 of
35) received cyclophosphamide (oral or pulse) therapy. No correlation between SPECT findings and the
different therapeutic regimens was noted.
DISCUSSION
One of the most important and disabling complications of SLE is involvement of the central ner-
1260
vous system. A range of symptoms-global cerebral
dysfunction, seizures, psychosis, nerve palsies, migraines, mood swings-have been attributed to CNS
lupus (2,12,13). The true frequency of neuropsychiatric abnormalities in SLE is difficult to estimate because of marked variations in presentation and severity, the often transient nature, and the lack of sensitive
and specific diagnostic tools. Several large clinical
series suggest that CNS involvement occurs in up to
50% of SLE patients (7,14,15); however, few patients
with mild symptoms were included in those studies.
Due to this lack of diagnostic accuracy, it is not
surprising that the pathogenic mechanisms that lead to
CNS involvement are still debated. Immune complexes and autoantibodies to cellular molecules, including brain-specific autoantibodies, are considered
to be of importance. The lack of correlation between
the presence of mental disorders and CNS lesions at
autopsy (5,6,12), together with the transient nature of
the neuropsychiatric symptoms, or their occasionally
prompt response to immunosuppressive therapy, support this notion. Previous studies have shown little
evidence of a cerebral vasculitis with inflammatory
cell invasion of the vessel walls (5,6); however, a
diffuse vasculopathy , with thickening of the vascular
wall, intimal proliferation, and microinfarction, was
reported (5,6). Although the mechanisms of damage to
the small cerebral vessels are undefined, the pathologic features are similar to those found in the diseased
coronary arteries of mice with experimental autoimmune disease, in which immune complexes induce
vascular damage without an associated inflammatory
response (12).
The diagnosis of CNS disease is also hampered
by the relative insensitivity of conventional imaging
techniques applied in the past. Although MRI changes
of focal ischemia or edema may be reversible (16-18),
findings of both MRI and CT mainly correspond to
structural, not functional, abnormalities, In psychiatric disease, no MRI or CT defect was consistently
demonstrated (17). Thus, the imaging techniques available provide evidence of morphologic alterations that
correspond to clinically established CNS manifestations.
Few studies of positron emission tomography
(PET) scans in CNS lupus patients have been conducted (19-21). Abnormal glucose metabolism measured by PET scan in 10 SLE patients with CNS
involvement has been described (21), with normal
findings in 3 SLE patients without CNS disease. Those
authors concluded that PET showed predominantly
RUBBERT ET AL
functional abnormalities (in contrast to MRI); however, a detailed comparison of PET and MRI scans has
not been done. Because PET scanning is expensive
and is not widely available, this may limit the widespread use of this diagnostic technique.
Oxygen-15 scanning of the brain in SLE patients has demonstrated abnormalities in regional
distribution not only in most patients with definite
CNS disease, but also in most patients in whom CNS
disease was not clinically apparent (22). Tan et a1
(23) have reported abnormal findings on brain scanning with sodium-99 pertechnetate in all SLE patients
presenting with psychosis, seizures, hemiparesis, organic brain syndrome, or intractable headache. All
brain scans performed on the control SLE patients
(without clinical evidence of CNS involvement) were
normal (23).
Because of mounting evidence that vasculitic
processes are the mechanisms of cerebral symptoms in
SLE, determinations of cerebral blood flow as indicators of early CNS involvement seems promising.
HMPAO SPECT scanning provides information on
regional brain perfusion, which is closely linked to
cerebral metabolism. SPECT scans have been used to
detect regional cerebral blood flow abnormalities in
patients with acute stroke, transient ischemic attack,
brain metastasis, epilepsy (1l), and more recently, in
human immunodeficiency virus-associated CNS disease (24).
Nossent et a1 (3) performed HMPAO SPECT
scans in 20 SLE patients with clinical evidence of
cerebral involvement, which revealed abnormalities
not only in patients with active CNS lupus, but also in
patients with neuropsychiatric symptoms not attributed to CNS involvement (as judged by neurologic and
psychiatric examination). However, that study did not
include a group of SLE patients without CNS symptoms, nor did it include information about the patients’
therapeutic regimens.
In the present study, we evaluated patients with
overt neuropsychiatric disease (focal motor or sensory
deficits, or psychiatric disease), patients with subtle
symptoms (headache, reactive depression, or cognitive disorders), and patients without any complaints
suggestive of CNS disease. We did not include healthy
subjects in our study because of the radiation exposure
and because of the well-established utility of SPECT in
detecting functional abnormalities in patients with other
conditions of impaired CNS perfusion (11,2426).
As expected, patients with clear neuropsychiatric disturbances, or “major” symptoms (9), showed
1261
SPECT SCANNING IN CNS LUPUS
abnormal SPECT scans (9 of 10 patients), with predominantly focal uptake defects, corresponding to
lesions visible on MRI and/or CT scans. In contrast,
SPECT findings in the majority of patients without
neuropsychiatric symptoms were normal (90% of the
patients). We were especially interested in the SPECT
scan results in patients with mild, or “minor,” symptoms suggestive of CNS disease. These patients had
frequent symptoms of headache, depressed mood or
anxiety, and cognitive disturbances. Interestingly,
only a minority of these patients had normal SPECT
scan results (26.7%). Most of these patients had abnormalities of cerebral blood flow, with focal uptake
defects in 53.3% and diffuse uptake defects in 20%.
Thus, cerebral blood flow abnormalities are present in
a substantial proportion of SLE patients with only
mild CNS symptoms.
Correlations between the anatomic location of
perfusion defects or the pattern of uptake defects and
clinical symptoms were not evident, although this may
be due to the limited number of study subjects. Visible
focal perfusion defects in one part of the brain might
also be indicative of other smaller, but symptomatic,
perfusion abnormalities in areas of the brain that lie
beyond the detection limit of the scan. Since SPECT
predominantly shows perfusion abnormalities of the
cortex, abnormal SPECT findings may not correlate
with visible changes of the white matter shown on
MRI. Because SPECT findings may normalize after
immunosuppressive therapy, SPECT scanning may
represent a sensitive monitoring technique, especially
in SLE patients with CNS involvement.
Interestingly, most patients with longstanding
disease ( 2 5 years) showed cerebral blood flow abnormalities, with a predominance of focal uptake defects.
Most of the normal SPECT findings and most of the
diffuse uptake defects were seen in patients with
shorter disease duration. These findings support the
notion that cerebral vasculopathy arises during the
course of disease, and although it is often subclinical,
leads to focal cerebral blood flow disturbances in a
substantial proportion of patients. This finding is consistent with data from autopsy studies suggesting that
subclinical CNS disease may occur in a considerable
proportion of SLE patients. Moreover, cerebral lesions have been detected in the absence of previous
neuropsychiatric symptoms (25).
Major neuropsychiatric symptoms can be diagnosed by means of clinical assessment and conventional radioimaging techniques such as MRI. The
domain of SPECT as a diagnostic tool may lie in the
early detection of brain perfusion defects in patients
with clinical symptoms such as headache, cognitive
disorders, or depressed mood. SPECT scanning could
therefore be helpful in substantiating the clinician’s
suspicion of an incipient CNS involvement. Since the
number of patients included in this study is limited, it
may be too early to judge whether therapeutic decisions should be based on our findings. Additional
studies to determine the significance of SPECT alterations over the long-term course of disease need to be
performed.
Although advancing age is not an expected
influence on SPECT scan results (26), we observed
differences in the SPECT results, depending on the
patient’s age. Most patients older than 40 showed focal
uptake defects; most of the patients with normal
SPECT results and most of the patients with diffuse
uptake defects were younger than 40. Similar findings
were reported by McCune et a1 (16), whose patients
with focal lesions on MRI scans were significantly
older than those without such lesions. Whether this
association simply reflects an increased frequency of
vascular changes with increasing age or represents an
increase in SLE-specific CNS vasculopathy in older
lupus patients remains unresolved. Consistent with the
findings by Nossent et a1 (3), we identified no correlation of SPECT findings and non-neuropsychiatric lupus manifestations or serologic findings.
In conclusion, CNS disease does not seem to be
predictable by any other clinical or serologic disease
parameter. As shown by our study findings, SPECT
analysis appears to be a sensitive and feasible diagnostic technique for detecting cerebral blood flow abnormalities in SLE patients and may be of considerable
diagnostic value, especially early in the course of
disease and in patients with mild neuropsychiatric
symptoms.
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