The possible effect of clinical recovery on regional cerebral blood flow deficits in fibromyalgia: a prospective study with semiquantitative SPECT.

Objectives: Regional deficits in cerebral blood flow have been reported in a few studies of fibromyalgia; however, there is no information on the effects of treatment and clinical recovery on these abnormalities. We evaluated the effects of amitriptyline treatment and consequent clinical recovery on cerebral blood flow changes in fibromyalgia.

Methods: We assessed cerebral blood flow with a semiquantitative functional brain mapping technique of single-photon emission computed tomography in 14 patients with primary fibromyalgia before and after 3 months of amitriptyline treatment. Patients were followed by visual analog scale, tender point count, and Beck Depression Inventory for clinical improvement.

Results: There was statistically significant improvement in visual analog scale and tender point count after treatment. Beck Depression Inventory did not change significantly. Statistically significant blood flow increase in bilateral hemithalami and basal ganglia and decrease in bilateral temporal, left temporo-occipital, and right occipital lobes were observed on single-photon emission computed tomography after treatment.

Conclusions: We speculate that these findings could indicate that deficits in cerebral blood flow in fibromyalgia improve parallel to clinical recovery.

Key Words: amitriptyline, cerebral blood flow, fibromyalgia, SPECT 

**********

Fibromyalgia is a common rheumatologic disease characterized by widespread pain, tenderness, unrefreshing sleep, fatigue, and emotional distress; however, the cause and pathogenic mechanisms of the disease are uncertain. Recently, there has been a tendency to localize the primary disorder underlying fibromyalgia in the central nervous system. (1)

Functional brain activity abnormalities are among the postulated central mechanisms. (2) Low levels of regional cerebral blood flow (rCBF) have been reported in thalamus and caudate nucleus, pontine tegmentum, and dorsolateral frontal cortical areas in patients with fibromyalgia, as detected by single-photon emission computed tomography (SPECT). (3-5) Unfortunately, there is no information regarding whether these abnormalities are resolved with the improvement of clinical symptoms and signs.

Various agents are used for the treatment of fibromyalgia, and amitriptyline has proved to be one of the most effective medications. (6) In this study, we sought to determine whether or not the rCBF abnormalities resolve as anticipated with amitriptyline treatment and consequent clinical response in patients with primary fibromyalgia.

Materials and Methods

A prospective clinical study was conducted from January 2002 to September 2002. Fourteen patients with primary fibromyalgia were recruited from the Rheumatology Clinic at Cumhuriyet University. Diagnosis of fibromyalgia was made according to the 1990 American College of Rheumatology criteria. (7) A systematic physical examination was conducted in all patients to rule out the presence of other possible medical problems and confirm the diagnosis. Patients were not receiving any medications at the time of diagnosis.

Complete blood count, erythrocyte sedimentation rate, blood glucose level, liver and kidney function tests, electrolytes, lipid profile, thyroid function tests, and urinalysis were performed for all of the patients. Patients with any abnormal results were not included in the study. Those patients with a history of the following parameters that would have an effect on the SPECT images were also not included: cerebrovascular accident, head trauma, alcohol or drug abuse, severe psychiatric disorders such as affective disorder, and drug usage for depression or psychosis. Pregnant patients were also not included. After diagnosis, tender point count on physical examination, pain evaluation by visual analog scale (VAS), and Beck Depression Inventory were obtained for each patient, and all patients underwent brain SPECT imaging.

VAS. A 10-cm line anchored at one end by the label "no pain" and at the other end by the label "the worst pain imaginable" was used for evaluation of pain. The patient was asked to mark the line to indicate the pain intensity.

Tender Point Count. All anatomic locations of the 18 tender point sites were examined by pressing the thumb against the tender point until the distal portion of the nail blanched. (7)

Beck Depression Inventory. A 21-item self-report measure yielding a numeric estimate of depression was used. Scores ranged between 0 and 63 and the cutoff score for likelihood of a major depression was accepted to be 21. (8)

SPECT Imaging Procedure. The subjects were asked not to drink coffee or tea, and not to smoke cigarettes before the study. Before the SPECT procedure, the physician explained details of the procedure to each patient individually. SPECT studies were performed between 9:00 and 11:00 AM for all patients.

Radiopharmaceutical Preparation. Hexamethylpropylene amine oxime (HMPAO) labeled with technetium [Tc.sup.99m] was used as a brain perfusion agent. [.sup.99m]Tc-HMPAO was prepared from the commercially available Brain-SPECT Unit Dose kit (Frederic Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Budapest, Hungary) by reconstitution with sterile, nonpyrogenic, freshly eluted sodium pertechnetate ([.sup.99m]Tc) solution (1,110 MBq [30 mCi] in approximately 3 mL) and quality control measures were performed according to the manufacturer's instructions. After a 10-minute incubation period, 740 MBq (20 mCi) of [.sup.99m]Tc-HMPAO were drawn for injection under sterile conditions.

SPECT Imaging

Imaging of rCBF of patients was examined using the [.sup.99m]Tc-HMPAO SPECT method. Brain perfusion SPECT imaging was performed using a single-head gamma camera (Toshiba GCA-7100A, Toshiba, Tokyo, Japan) equipped with a low-energy, high-resolution, parallel-hole collimator and interfaced to a dedicated computer at the Department of Nuclear Medicine.

The brain perfusion SPECT imaging consisted of two steps: baseline and post-treatment. SPECT imaging was performed on all subjects with the same SPECT method and scanner. For baseline and post-therapy imaging, each subject received an injection of 740 MBq (20 mCi) of [.sup.99m]Tc-HMPAO through an intravenous catheter under sterile conditions in a quiet, semidark room free from visual or auditory distractions with the subject's eyes closed and ears unplugged. SPECT acquisitions were started after a 10-minute rest period for all patients.

A total of 60 images (30 seconds per projection) were obtained using a continuous-scan mode at 6-degree intervals over 360 degrees on a 128 X 128 matrix. One-pixel-thick (1 pixel = 4.3 mm) transaxial slices from the vertex of the brain to the level of the basal cerebellum were reconstructed (according to the canthomeatal line) using a Butterworth filter (order, 8; cutoff frequency, 0.23) after a ramp-back projection filter.

The procedures used for image reconstruction and other procedures were the same for baseline and posttreatment images. Five consecutive transaxial slices corresponding to the highest signal in the thalamus and basal ganglia were summed. In addition, five consecutive transaxial slices corresponding to the middle cerebellar region were summed. Regions of interest (ROIs) were drawn manually on these summed transaxial slices. ROIs corresponded to the following regions: 1) left hemisphere, 2) left frontal, 3) left temporal, 4) left temporo-occipital, 5) left occipital, 6) left basal ganglia, 7) left thalamus, 8) right frontal, 9) right temporal, 10) right temporo-occipital, 11) right occipital, 12) right thalamus, 13) right basal ganglia, 14) right hemisphere, and 15) total hemisphere. Another ROI was drawn manually on summed cerebellar slices (Figure).

All ROIs were applied by the same investigator to eliminate interobserver variations. For the regional activity ratio measurement, average counts per pixel of each ROI were taken into consideration. Average counts of each ROI were rated to the cerebellum. These ratios were compared statistically for baseline and posttreatment studies in all patients.

[ILLUSTRATION OMITTED]

Treatment Protocol

After the baseline evaluation, patients were started on amitriptyline (Laroxyl; Roche, Nutley, NJ) treatment for 3 months. The drug was given at 10 mg/d for the first 10 days at bedtime; then, the dose was increased to 25 mg/d. Patients were informed about the probable side effects of the drug. Patients were not allowed to receive any other medications within this period, including anti-inflammatory and analgesic drugs. Patient compliance was confirmed by regular phone calls every 10 days.

SPECT imaging, tender point count, VAS, and Beck Depression Inventory were performed again after the 3-month treatment period. All physical evaluations were performed by the same physician to rule out interobserver variations.

For statistical evaluation, SPSS version 9.05 (SPSS, Inc., Chicago, IL) was used. The difference between the pre- and post-treatment values of rCBF, tender point count, VAS, and Beck Depression Inventory was determined using the Wilcoxon test. Correlation between rCBF values (each region) and clinical parameters (tender point count and VAS values) was determined before and after the treatment using the Pearson correlation test.

All patients were informed about the study and gave consent. The research was approved by the Cumhuriyet University Faculty of Medicine Ethical Committee.

Results

All 14 patients were female and right-handed. The mean age of the patients was 33.42 [+ or -] 1.94 years, ranging between 18 and 42 years.

There was a significant difference in the VAS and tender point count after treatment (Table 1). Regarding the Beck Depression Inventory, two patients exceeded the limit for depression, and this did not change after treatment. Also, there was no significant difference in the Beck Depression Inventory of the patients before and after treatment (Table 1).

There was no significant correlation between the SPECT results and clinical parameters (VAS and tender point count) either before or after treatment (Table 2). There was a significant difference in pre- and post-treatment rCBF values in the left temporal lobe, left temporo-occipital lobe, left basal ganglion, left thalamus, right temporal lobe, right occipital lobe, right thalamus, and right basal ganglion. The rCBF was increased in bilateral hemithalami and bilateral basal ganglia, and was decreased in bilateral temporal, left temporo-occipital, and right occipital lobes (P < 0.05) (Table 3).

Discussion

The most prominent symptom of fibromyalgia is pain that is thought to be caused by a primary disturbance believed to originate within higher levels of the central nervous system. Regional cerebral blood flow, a very sensitive indicator of brain dysfunction, revealed a decrease in functional activity of the brain in specific regions in fibromyalgia, probably representing a response to high levels of nociceptive neural input. (2-5)

In our study, we measured rCBF before and after 3 months of amitriptyline treatment in 14 fibromyalgia patients. We observed a significant clinical improvement; however, there was no significant correlation between fibromyalgia symptoms and SPECT findings before or after treatment. There was also a lack of correlation between symptoms and rCBF in previous studies. (3,4) On post-treatment SPECT images, there was increased rCBF in bilateral hemithalami and basal ganglia. Previously, decreased rCBF in bilateral hemithalami and caudate nuclei was reported in fibromyalgia by Mountz et al (4) in 10 patients. The findings of Mountz et al (3) in the thalamus were later supported by another study (3) with improved SPECT and advanced complementary techniques that revealed a reduced pontine tegmental rCBF also. There is no information on rCBF changes after treatment for fibromyalgia in the literature. We evaluated the rCBF of the basal ganglia instead of separate caudate nuclei because of technical limitations. We think that the increased rCBF in basal ganglia after treatment is caused by the increased rCBF in caudate nuclei. The increased rCBF in bilateral hemithalami and basal ganglia is consistent with the changes anticipated in the previous studies in fibromyalgia. (1) Our results support the role of the functional abnormalities of these structures in fibromyalgia.

A decrease in rCBF in bilateral temporal regions was another significant change observed in SPECT after treatment. Activation of temporal lobes has been interpreted as part of the affective-emotional component of the pain response. (9) Thus, decreased activity of these structures after the resolution of pain in our study may suggest that there is also an emotional component of pain in fibromyalgia. Another reason for the decreased activity in temporal lobes could be the decreased activity of the cingulate cortices. The cingulate cortex lies partly within the temporal lobe, and its increased activity has been shown to be related to chronic pain. (10,11) It was also reported in a study with positron emission tomography that after hypnotically induced analgesia, a bilateral decrease of blood flow in the posterior cingulate cortex was observed in fibromyalgia. (12)

There was a decrease in rCBF of the left temporo-occipital and right occipital regions after treatment. It is difficult to relate these changes to chronic pain or fibromyalgia; however, pain perception is a complex procedure and can be affected by different factors, which can also induce activation of multiple areas of the brain. An increase in activation of the primary motor cortex, frontal, temporal, parietal, and parieto-occipital regions has been reported, related to painful conditions. (9,10,13)

Two of our patients exceeded the limit for the Beck Depression Inventory, and there was no significant difference in the scale after treatment. This may be because the dose of amitriptyline used in our patients was subtherapeutic and thus unable to achieve any antidepressive effect. We believe that the small number of patients with depression and the absence of changes on the Beck Depression Inventory after treatment encourage us to rule out the possible effects of depression on SPECT images.

We did not perform anatomic imaging to localize the perfusion deficits strictly, because our aim was not to show the rCBF deficit in fibromyalgia. Instead, we wanted to demonstrate the consequent changes with treatment and clinical recovery. Therefore, we did not need a control group, and intrapatient evaluation also ruled out many factors such as the effects of anxiety and psychological disorders.

Conclusion

Our results revealed that rCBF increases in the thalamus and basal ganglia and decreases in temporal regions after clinical improvement. We speculate that the clinical improvement in FM is possibly related to the reversal of functional changes in these regions, which might have affected pain perception.

Table 1. VAS, Beck Depression Inventory, and tender point counts before
and after treatment (a)

                        Pretreatment       Posttreatment          P
                     (mean [+ or -] SD)  (mean [+ or -] SD)     value

VAS                  7.42 [+ or -] 1.50   5.21 [+ or -] 1.71  0.002 (b)
Beck Depression     13.71 [+ or -] 7.05  12.21 [+ or -] 7.60  0.60
  Inventory
Tender point count  12.57 [+ or -] 1.28   7.85 [+ or -] 2.71  0.001 (b)

(a) VAS, visual analog scale.
(b) P < 0.05.

Table 2. Correlation between rCBF values and clinical parameters (tender
point counts and VAS values) before and after treatment (a)

                                                   Pretreatment
                                           Tender point    VAS values
Cortical ROI/cerebellar ratio             count (r value)  (r value)

Left hemisphere/cerebellar ratio                0.35         -0.21
Left frontal/cerebellar ratio                   0.18         -0.47
Left temporal/cerebellar ratio                  0.11         -0.37
Left temporo-occipital/cerebellar ratio         0.19         -0.28
Left occipital/cerebellar ratio                -0.02          0.35
Left basal ganglion/cerebellar ratio           -0.27          0.02
Left thalamus/cerebellar ratio                 -0.23         -0.02
Right frontal/cerebellar ratio                 -0.33         -0.13
Right temporal/cerebellar ratio                -0.005        -0.36
Right temporo-occipital/cerebellar ratio        0.31         -0.32
Right occipital/cerebellar ratio                0.01         -0.22
Right thalamus/cerebellar ratio                -0.34         -0.04
Right basal ganglion/cerebellar ratio          -0.39         -0.21
Right hemisphere/cerebellar ratio               0.41         -0.05
Total hemisphere/cerebellar ratio               0.14         -0.3

                                                  Posttreatment
                                           Tender point    VAS values
Cortical ROI/cerebellar ratio             count (r value)  (r value)

Left hemisphere/cerebellar ratio               -0.45         -0.46
Left frontal/cerebellar ratio                  -0.56         -0.41
Left temporal/cerebellar ratio                 -0.47         -0.47
Left temporo-occipital/cerebellar ratio        -0.45         -0.46
Left occipital/cerebellar ratio                -0.45         -0.48
Left basal ganglion/cerebellar ratio           -0.47         -0.44
Left thalamus/cerebellar ratio                 -0.49         -0.51
Right frontal/cerebellar ratio                 -0.47         -0.47
Right temporal/cerebellar ratio                -0.46         -0.45
Right temporo-occipital/cerebellar ratio       -0.42         -0.45
Right occipital/cerebellar ratio               -0.42         -0.49
Right thalamus/cerebellar ratio                -0.50         -0.48
Right basal ganglion/cerebellar ratio          -0.50         -0.42
Right hemisphere/cerebellar ratio              -0.44         -0.46
Total hemisphere/cerebellar ratio              -0.45         -0.46

(a) rCBF, regional cerebral blood flow; VAS, visual analog scale: ROI,
region of interest.

Table 3. Cortical ROI/cerebellar ratios before and after treatment (a)

Cortical                  Pretreatment        Posttreatment
ROI/cerebellar               values              values          P
ratio                  (mean [+ or -] SD)  (mean [+ or -] SD)  value

Left hemisphere/       0.81 [+ or -] 0.08  0.78 [+ or -] 0.04  0.16
  cerebellar ratio
Left frontal/          0.82 [+ or -] 0.09  0.77 [+ or -] 0.05  0.056
  cerebellar ratio
Left temporal/         0.88 [+ or -] 0.14  0.79 [+ or -] 0.06  0.04 (b)
  cerebellar ratio
Left temporo-          0.87 [+ or -] 0.14  0.77 [+ or -] 0.05  0.03 (b)
  occipital/
  cerebellar ratio
Left occipital/        0.88 [+ or -] 0.11  0.82 [+ or -] 0.04  0.19
  cerebellar ratio
Left basal ganglion/   0.72 [+ or -] 0.09  0.82 [+ or -] 0.05  0.005 (b)
  cerebellar ratio
Left thalamus/         0.75 [+ or -] 0.10  0.81 [+ or -] 0.05  0.04 (b)
  cerebellar ratio
Right frontal/         0.83 [+ or -] 0.09  0.77 [+ or -] 0.04  0.07
  cerebellar ratio
Right temporal/        0.88 [+ or -] 0.15  0.78 [+ or -] 0.05  0.03 (b)
  cerebellar ratio
Right temporo-         0.86 [+ or -] 0.13  0.76 [+ or -] 0.06  0.07
  occipital/
  cerebellar ratio
Right occipital/       0.90 [+ or -] 0.11  0.81 [+ or -] 0.04  0.03 (b)
  cerebellar ratio
Right thalamus/        0.74 [+ or -] 0.10  0.80 [+ or -] 0.06  0.03 (b)
  cerebellar ratio
Right basal ganglion/  0.73 [+ or -] 0.10  0.84 [+ or -] 0.06  0.004 (b)
  cerebellar ratio
Right hemisphere/      0.83 [+ or -] 0.11  0.78 [+ or -] 0.04  0.12
  cerebellar ratio
Total hemisphere/      0.85 [+ or -] 0.12  0.79 [+ or -] 0.04  0.15
  cerebellar ratio

(a) ROI, region of interest.
(b) P < 0.05.

Accepted April 3, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9707-0651

References

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3. Kwiatek R, Barnden L, Tedman R, et al. Regional cerebral blood flow in fibromyalgia: Single-photon-emission computed tomography evidence of reduction in the pontine tegmentum and thalami. Arthritis Rheum 2000; 43:2823-2833.

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RELATED ARTICLE: Key Points

* Regional cerebral blood flow, a very sensitive indicator of brain dysfunction, revealed a decrease in functional activity of the brain in specific regions in fibromyalgia, probably representing a response to high levels of nociceptive neural input. Unfortunately, there is no information regarding whether these abnormalities are resolved with the improvement of clinical symptoms and signs.

* Fibromyalgia is a common rheumatologic disease characterized by widespread pain, tenderness, unrefreshing sleep, fatigue, and emotional distress; however, the cause and pathogenic mechanisms of the disease are uncertain. Recently, there has been a tendency to localize the primary disorder underlying fibromyalgia in the central nervous system.

* Our results revealed that rCBF increases in the thalamus and basal ganglia and decreases in temporal regions after clinical improvement. We speculate that the clinical improvement in FM is possibly related to the reversal of functional changes in these regions, which might have affected pain perception.

O. Adiguzel, MD, E. Kaptanoglu, MD, B. Turgut, MD, and V. Nacitarhan, MD

From the Departments of Rheumatology and Nuclear Medicine, Cumhuriyet University, Sivas, Turkey.

This study is the authors' own work. They did not receive any financial support or provision of supplies used in the study. They also do not have any commercial or proprietary interest in any drug, device, or equipment.

Reprint requests to Ece Kaptanoglu, MD, P.K. 702, Sivas 58141, Turkey. Email: [e-mail]