Perfusion Scintigraphy for the Evaluation of Patients with Raynaud’s Phenomenon

Abstract

Raynaud’s phenomenon (RP) is a functional vascular disorder, which can be defined as transient vasospasm of the peripheral arteries and arterioles in the affected areas exposed to the cold or other stress. The diagnosis of RP is mainly based on symptoms. Perfusion scintigraphy, with or without cold stimulation, can be used to evaluate RP. Studies with perfusion scintigraphy for RP have shown that patients with RP showed lower finger-to-palm ratio than patients without RP. Responses after cold stimulation were also different in patients with RP. Not only decreased perfusion or blood pool after cold stimulation but also paradoxically increased perfusion can be shown in patients with RP. Some studies have shown that primary and secondary RP can be differentiated by perfusion scintigraphy. Correlation between duration of disease and findings on perfusion scintigraphy was reported. Perfusion scintigraphy can show differences before and after treatment as well. However, the protocols for perfusion scintigraphy for PR vary among studies. The standard protocol of perfusion scintigraphy for RP should be established.

Raynaud’s Phenomenon

Raynaud’s phenomenon (RP) is defined as a transient vasospasm of the peripheral arteries and arterioles that typically manifests as a biphasic or tri-phasic color change in the affected region [1, 2]. It is characterized by vasospasm due to ischemia (white discoloration), followed by dilation of the capillaries and venous stasis (cyanosis), and later by reperfusion (red flush) [1]. It is a painful condition and can last from minutes to hours. RP affects not only the fingers or toes but also other areas of the body such as the nose, earlobes, and tongue. RP is common, ranging between 4 and 15% of the general population [2]. Incidence is known to be higher in colder climates, and it predominantly affects young women [1, 3–5].

There are primary and secondary forms of RP. Primary RP is common, and it usually has a benign course [2]. However, RP can be secondary to scleroderma-related diseases which can cause irreversible digital ischemia resulting in ulcers and amputation [6]. In primary RP, attacks are usually symmetric and are of short duration without ulceration [7]. In secondary RP, attacks are usually asymmetric, extremely painful, and last longer than primary RP. Local complications such as digital ulcers, secondary infection, and tissue gangrene can be observed in secondary RP [7]. There are many potential causes of secondary RP, including autoimmune or connective tissue disease (such as systemic sclerosis), arterial disease, frostbite, neoplasms, coagulation disorders, infection, medications, and activities that cause repeated vibration or pressure in the extremities [7]. RP can be an early symptom of connective tissue disorders; these include scleroderma (> 90%), mixed connective tissue disease (85%), and systemic lupus erythematosus (40%) [3, 8, 9]. Therefore, early diagnosis of RP is important, and careful follow-up of the patient is needed [3, 10].

Diagnosis of Raynaud’s Phenomenon

Diagnosis of RP is mainly based on symptoms. However, the classic tri-phasic skin color change may not be evident in every patient. In the evaluation of RP, aside from the several laboratory tests (including autoimmune disease–related factors) that are usually performed, nailfold capillaroscopy (NC) is a widely used technique which can provide early identification of microvascular changes suggestive of connective tissue disease [7]. A scleroderma pattern can be shown in systemic sclerosis (giant capillaries, architectural modification, avascular areas, and microhemorrhages) [11]. However, in other connective tissue diseases, nonspecific changes or even normal findings are generally found. In addition, primary RP shows normal findings on NC [7]. Furthermore, there is no association between the degrees of alteration seen on NC versus that seen on clinical examination of the digits [12]. Other modalities such as video capillaroscopy, thermography, and Doppler ultrasonography can be used to evaluate the involved digital artery [13–16]. Although the involvement of the digital artery is seen in 63% of secondary RP cases and 6% of primary RP cases, evaluation using Doppler ultrasonography for digital artery is not easy [7, 17]. Conventional angiography or magnetic resonance angiography can be also be used to identify pathologic findings in large-to-medium arteries that can mimic RP [7]. However, these modalities are mainly to rule out secondary RP. For the measurement of disease activity, Raynaud’s Condition Score (RCS) is used. This is a daily self-assessment tool that uses a 0-to-10 ordinal scale [7]. However, this is a subjective evaluation and, as such, can elicit a placebo effect [18, 19].

Methods for Perfusion Scintigraphy for RP

RP can be evaluated using perfusion scintigraphy, and there have been several studies of perfusion scintigraphy [3, 20–25]. Various radiopharmaceuticals are used, including technetium-99m (Tc-99m), diethylenetriamine pentaacetate (DTPA) [26–28], Tc-99m red blood cell (RBC) [20, 23], Tc-99m pertechnetate [24, 29], Tc-99m methylene diphosphonate (MDP) [3], and Tc-99m hydroxymethylene diphosphonate (HDP) [22]. When the affected areas are the hands, intravenous injection of radiopharmaceuticals is done via the dorsal vein.

Perfusion scintigraphy for RP can be done with or without cold stimulation. The one-hand chilling method is widely used for cold stimulation [3, 20, 21, 23, 25–28]. It is done by immersion of one hand (the non-dominant hand or the hand with more severe symptoms) in cold water (4 °C) [22]. During recovery time, the subjects are instructed not to wipe or shake their hands. After recovery time, an intravenous injection is administered. Dynamic blood flow images and blood pool images are obtained. However, there have been various protocols for the one-hand chilling method regarding the length of time allotted for immersion and recovery: (1) 30 s of immersion and 10 min of recovery [30], (2) 30 s of immersion and 15 min of recovery [21, 22], (3) 60 s of immersion and 20 min of recovery [23], (4) 2 min of immersion with at least 10 min of recovery time [3], and (5) 5 min of immersion with 15 min of recovery [25]. Porter et al. reported that the average time to recovery of normal temperature after chilling (20 s of immersion) was 10 min for the control group vs 35 min in patients with RP [31]. In addition, Sarikaya et al. reported that about 7.85% of patients in the control group still showed decreased perfusion after 10 min of recovery time had passed [30]. Based on these findings, Kwon et al. decided to allow for 15 min of recovery time after chilling [22]. Kunnen et al. used two-hand chilling methods [29]. At first, perfusion scintigraphy of normal skin temperature condition was done (after immersion of two hands in water at 29 °C for 10 min). Later, scintigraphy of two-hand chilling method (after immersion of two hands in melting ice-containing water until pain and/or skin color change) was done. Each scan was with interval at least about 1 week [29].

For quantitative analysis, the region-of-interest (ROI) was manually drawn. However, among the various studies available in the literature, there are differences in the way in which the ROI is drawn. Previous studies used two ROIs that were manually drawn on all the fingers except the thumb (similar to a hexagonal shape; not regular) and on the whole palm area [3, 23, 24, 28]. Sarikaya et al. used a regular elliptic ROI for the fingers (images were not shown in their article) [30]. Kwon et al. used a manually drawn ROI along the margin of the second to the fifth fingers except the palm area, which looked like a four-fingered glove [30]. They also used a lead shield over the palms [22]. Lee et al. also used a similar four-fingered glove tracing for the ROI, and they incorporated another ROI in the wrist, not in the palm region [25]. Examples of ROI are shown in Fig. 1.

Fig. 1.

Examples of region-of-interest (ROI) of hands. a Two ROIs which are manually drawn from the second to the fifth fingers and palmar area with straight lines [3, 24, 28]. b ROI which is manually drawn around all fingers except thumb proximal to digital crease which is demarcated by a lead shield ring [22]. c Two ROIs which are manually drawn around all fingers except thumb and wrist area [25]

For analysis, various ratios were used including blood pool images, finger-to-palm ratio (FPR) [3, 23, 24, 28], and blood pool uptake ratios of the hand and wrist [25]. To compare the chilled vs ambient hand, a perfusion graph, initial slope ratio, first peak height ratio, and 30-s area-under-curve (AUC) ratio were employed [3, 20, 22, 25]. The percent decrease of perfusion (%DP) was calculated from the ROIs of the chilled and ambient hands [32]. Some researchers used both a summed image of the blood pool from the perfusion image and a static blood pool image and reported that they were not significantly different [3, 28]. However, Lee et al. commented that they used summed flow images for FPR because FPRs from the summed blood flow image showed better performance in their later analysis [3]. Aside from the ratio, other features such as a slow progression pattern on perfusion graph, the inhomogeneous/homogeneous radioactivity uptake on blood pool image, or the paradoxical increased uptake pattern have been used [23, 25]. Table 1 shows variables of perfusion scintigraphy for RP.

Table 1.

Examples of variables for quantitative analysis of perfusion scintigraphy for evaluation of patients with Raynaud’s phenomenon

Variables	References
Variables from dynamic images
Initial slope ratio	[3, 22, 25]
First peak height ratio	[3, 22, 25]
30-s AUC ratio	[22]
Uptake pattern of initial curve (slow progression)	[25]
Finger-to-palm ratio (FPR)	[28, 30]
Time to reach peak level	[29]
Peak level and plateau level of radioactivity	[29]
Perfusion index (count at peak level/plateau count at 100 s)	[29]
Variables from static images
Percentage decrease of perfusion (%DP)	[30]
Finger-to-palm ratio (FPR)	[3, 27, 28]
Blood pool uptake ratio	[3]
Uptake pattern (paradoxical, inhomogenous)	[25]

Results of Perfusion Scintigraphy of RP

Raynaud scintigraphy scanning showed the following results: even without cold stimulation, patients with RP had lower FPR (0.40 ± 0.14) than individuals without FP (0.94 ± 0.18; p < 0.05) [28].

Lee et al. reported an FPR cutoff value of 0.51 for diagnosing RP (sensitivity 63% and specificity 83%) in scans without cold stimulation [3]. In a study of Pavlov-Dolijanovic et al., they reported that the blood pool was able to discriminate patients with secondary RP from those with primary RP or healthy control [24]. The patients with RP secondary to systemic sclerosis (0.36 ± 0.07) showed a significantly lower blood pool than patients with primary RP (0.42 ± 0.06; p < 0.05) [24]. Sarikaya et al. reported that there was a strong correlation between %DP and the duration of the disease [30]. Csiki et al. also reported that longer disease duration was negatively correlated with FPR. They also reported in patients with early-onset RP that the FPR was significantly lower [26].

Figure 2 shows representative images of hand perfusion scintigraphy after cold stimulation. After cold stimulation, the chilled hand of the RP patient (Fig. 2a) shows a remarkable decrease of blood pool compared to the hand of a normal individual (Fig. 2b). After analyzing the results of the one-hand chilling method, Sarikaya et al. reported that patients with primary RP had more severe hypoperfusion than subjects without RP (%DP ± SD, 46.86 ± 19.04 vs 7.85 ± 4.53; p = 0) [30]. Kwon et al. reported that the chilled-to-ambient hand ratio of the initial slope, first peak height, 30-s AUC, and blood pool uptake were lower in patients with RP than in patients without RP [22]. They also mentioned that the patterns of the perfusion graph (low height of the initial spike or slow progression of curve) or the inhomogeneous uptake patterns of blood pool images are a characteristic finding of patients with RP [22]. Lee et al. reported that patients with hand-arm vibration syndrome (HAVS)-related RP showed lower perfusion and blood pool ratios than patients with primary RP [25].

Fig. 2.

Two cases of hand perfusion scintigraphy with one-hand chilling method. After 2 min of immersion to cold water (4 °C) of the non-dominant hand, 10 min of recovery was done. ^99mTc-pertechnetate (740 MBq) was injected intravenously to the foot. Blood pool images of palmar view after 5 min were obtained. Region-of-interest (ROI) was manually drawn from the second to the fifth fingers with straight lines (like Fig. 1a). a A blood pool image of a 75-year-old male with Raynaud’s phenomenon. The ratio of chilled hand to ambient hand finger blood pool count was 0.34. b A blood pool image of a 64-year-old male without Raynaud’s phenomenon. The ratio of the chilled hand to the ambient hand finger blood pool count was 1.05

Methods using cold stimulation can reflect the pathophysiology of RP because the results are related to an abnormal vascular response to temperature changes [3]. Lee et al. compared hand perfusion scintigraphy with and without the one-hand chilling protocol and they concluded that, although both protocols showed high specificity, the protocol using one-hand chilling showed better diagnostic ability [3]. However, reduced blood pool uptake after cold stimulation is not the only finding of RP. There can be a paradoxical increase in blood pool uptake after cold stimulation in the area of RP [3, 20, 23, 25]. Lee et al. reported there were groups with both low and high ratios after cold stimulation in patients with RP [3]. They reported that there was a tendency for low blood flow in the ambient hand of the patients who had a paradoxical response in their chilled hand [3]. Lim et al. also reported that the patients with this paradoxical response showed reduced digital blood flow at room temperature [20]. Lee et al. also reported that the incidence of this paradoxical pattern after cold stimulation is lower in HAVS-related RP than in primary RP [25]. This paradoxical response makes it difficult to use simple cutoff values of blood pool uptake after cold stimulation for diagnosis of RP.

Perfusion scintigraphy can show different results after treatment in patients of RP. Sarikaya et al. reported that %DP values were significantly decreased after treatment [30]. Kunnen et al. showed the treatment effect of selective antagonist of serotonin S2-receptor (ketanserin) in patients with RP using Tc-99m pertechnetate scintigraphy [29]. They used double-blind and cross-over design [29]. In their study, ketanserin improved perfusion index significantly compared to placebo treatment [29]. Also, Chong et al. reported that in a patient whose RP symptoms recurred after treatment, her post-treatment Raynaud scan showed paradoxically increased blood pool uptake in the chilled hand. This was not shown in her pretreatment scan [23]. These findings suggest that Raynaud scintigraphy can evaluate changes in the vascular response after treatment of RP.

Conclusion

Perfusion scintigraphy for RP, with or without cold stimulation, can be used to evaluate RP. It can discriminate patients with RP from normal individuals. It also can discriminate patients with secondary RP from those with primary RP or healthy control. In addition, it can be used for treatment monitoring. However, as mentioned previously, there has been a large variation in the protocols used. Several of the studies reported in the literature differ in relation to radiopharmaceuticals, cold stimulation protocol, and the shape and location of the ROI. Standard protocols for scintigraphy for RP should be established. In addition, future studies are needed to evaluate and compare other modalities of RP testing, including a comparison of their protocols and correlation with disease severity.

Compliance and Ethical Standards

Conflict of Interest

Ari Chong declares that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

Ethical Approval

This work does not contain any studies with human participants or animals performed by the author.

Informed Consent

Not applicable.