Neurovascular, Muscle, and Skin Changes on [18f]FDG PET/MRI in Foot Complex Regional Pain Syndrome (CRPS)

Background: The goal of this study is to demonstrate the feasibility of [18F]uorodeoxyglucose (FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) for non-invasive visualization of muscular, neurovascular, and skin changes secondary to complex regional pain syndrome (CRPS). Methods: Seven adult patients with CRPS in the lower extremity and seven healthy adult controls participated in our [18F]FDG PET/MRI study. All participants received whole-body PET/MRI scans one hour after the injection of 10mCi [18F]FDG. Resulting PET/MRI images were reviewed by two radiologists. Metabolic and anatomic abnormalities identied, were grouped into muscular, neurovascular, and skin lesions. The [18F]FDG uptake of each lesion was compared with that of corresponding areas in controls using a Mann-Whitney U-test. Results: On PET images, muscular, neurovascular, and skin abnormalities were found in 5, 4 and 2 patients, respectively. However, on MRI images, no muscular abnormalities were detected. Neurovascular abnormalities and skin abnormalities in the affected limb were identied on MRI in 1 and 2 patients, respectively. The difference in [18F]FDG uptake between the patients and the controls was signicant in muscle (p = 0.018) and neurovascular bundle (p = 0.0005). Conclusions: The increased uptake of [18F]FDG in the symptomatic areas likely reects the increased metabolism due to the inammatory response causing pain. Therefore, our approach combining metabolic ([18F]FDG PET) and anatomic (MRI) imaging may offer non-invasive monitoring of the distribution and progression of inammatory changes associated with CRPS.


Introduction
Complex regional pain syndrome (CRPS) is a severe pain condition of extremities, presenting a variety of symptoms that signi cantly exceeds the expected clinical progression of the injury [1]. Depending on the type of the inciting injury, it is classi ed into two types: CRPS I if its onset has no association with a nerve injury, and CRPS II if it is caused by a con rmed nerve injury. Due to the complexity of symptoms and disease progression, it has been very challenging to identify the exact source of pain and design effective treatments for patients with CRPS [2].
A few diagnostic approaches have been adopted to aid the diagnosis of CRPS. Plain lm X-ray and three phase bone scan (TPBS) have been used for identifying bone loss or resorption by CRPS. However, these changes may appear temporarily and only at speci c stages of CRPS [3,4]. Magnetic resonance imaging (MRI) facilitated examining pathologic changes in musculoskeletal tissues [5], but its effectiveness has not been fully established yet [3]. Therefore, there is a pressing clinical need for improved localization of the CRPS-induced changes to better understand the disease mechanism and help monitor treatment effects.
In this communication, we introduce a novel imaging approach focusing on the detection of the in ammatory changes due to CRPS. In ammation without infection is one of the key features of CRPS recognized more than 100 years ago [6]. Positron emission tomography (PET) imaging with [18F] uorodeoxyglucose (FDG) has been frequently utilized for non-invasive localization of in amed tissues in many disease indications. The simultaneous acquisition of high-resolution MRI can facilitate the accurate speci cation of lesions presenting abnormally high tracer uptake on PET [7]. We performed a [18F]FDG PET/MRI comparison study on CRPS patients and healthy controls to evaluate its feasibility for non-invasive detection of CRPS-induced changes.

Patient population
Seven patients diagnosed with CRPS in the lower extremity by con rming their symptoms and signs to the Budapest criteria [8] were enrolled in our study, and their initial evaluation results are summarized in Table 1. All patients were female, and the mean ± standard deviation / range of their age was 38.7±12.4y / 20-54y. Seven healthy controls were recruited to compare the [18F]FDG uptake (4 males and 3 females; age mean ± standard deviation, 30.0±4.1y; age range, 22-37y).

Statistical analysis
Abnormalities detected on PET and MRI were classi ed into three tissue categories: muscle, neurovascular bundle, and skin/subcutaneous tissue. For each lesion on the PET images, an ROI was manually drawn to measure the maximum standardized uptake value (SUV max ). For each tissue type, the SUV max of the lesions was compared with the SUV max of healthy controls using the two-tailed Mann-Whitney U-test. The p-value of 0.05 was adopted as a signi cance level. The mean and the standard deviation of SUV max of the patients and the healthy controls was also calculated for individual tissue groups.

PET/MRI image review
Abnormalities were found at the reported site of pain in all seven patients on [18F]FDG PET, but in only three patients on MRI (Table 2). Increased uptake on foot muscles was the most frequent nding on PET ( ve patients), while, on MRI, skin thickening and nerve abnormalities were the most frequent observation (two patients, respectively).

Discussion
In this study, we evaluated the feasibility of [18F]FDG PET/MRI to detect metabolic and anatomic changes associated with CRPS. Radiologic evaluation and quantitative comparison con rmed that all seven patients with lower extremity CRPS exhibited signi cantly increased metabolism on [18F]FDG PET, possibly from in ammatory processes in CRPS. However, no single common abnormality was found in the affected limbs across all patients, re ecting the complicated heterogeneity of CRPS pathology.
Gross morphologic changes or signal abnormalities were identi ed at the site of elevated [18F]FDG uptake on MRI, but only from three patients (Patients 5,6, and 7). This suggests metabolic interrogation with [18F]FDG PET may identify CRPS-induced changes by earlier than MRI, and therefore potentially promote early and effective management of CRPS [9]. Note that the speci cation of lesions with high [18F]FDG uptake was only enabled by structural MRI data. For example, the subcutaneous tissue uptake in Figure 3 would probably have been misclassi ed into the muscle uptake if judged only by its location on PET images.
Our imaging ndings may facilitate speci c subtyping or staging of CRPS. All abnormal PET uptake was locally con ned except the case of the patient 3 presenting the global uptake on multiple neurovascular bundles ( Figure 2C). This likely supports the reported heterogeneity in the disease mechanism of CRPS [10], which could impart differing management approaches. High [18F]FDG uptake on the edematous skin and subcutaneous tissue (Figure 3) is another feature that could be unique to a speci c subtype or stage of CRPS. Edema is supposedly composed of body uid, lacking the cellular components for increased metabolism. However, our case of edema with elevated [18F]FDG uptake indicates the possibility to identify an in ammatory subtype of CRPS. It should be also noted that three cases of CRPS type I showed abnormal [18F]FDG uptake on peripheral nerves, while the only case of CRPS type II presented both PET and MRI abnormalities at the suspected nerve. This suggests that our method may provide the increased sensitivity to the causative nerve damage for the improved distinction between CRPS type I and II.
Our study has a few limitations, rstly, the relatively small number of enrolled patients and healthy controls. Our validation of the detected abnormalities regarding their potential contribution to pain is supported by their location, radiologic review and statistical comparison. However, a more direct evaluation of their association with pain, such as the outcome assessment of local anesthetic injection to detected abnormalities, would be desirable. There may be a chance that factors other than in ammation, such as increased muscle recruitment from limping, could result in increased muscular uptake of [18F]FDG in the favored limb. Therefore, additional diagnostic information, potentially through developments of novel MRI techniques in our case, might be necessary to improve the speci city.
In conclusion, we present a novel [18F]FDG PET/MRI approach that identi ed metabolic and structural abnormalities in muscles, neurovascular bundles, and skin likely due to the in ammatory process of CRPS. Our preliminary results demonstrate the diagnostic potential of this approach for the non-invasive monitoring of distribution and progression of CRPS-induced changes. This study was approved by the institutional review board of Stanford university. All research data such as participant information and images were acquired in compliance with the Health Insurance Portability and Accountability Act. Informed consent was obtained from all individual participants included in the study.

Consent for publication
All individual participants signed informed consent regarding publishing their data and acquired images.

Availability of data and material
The datasets generated during and/or analyzed during the current study are not publicly available due to the fact we are 1) describing the off-label use of [18F] uorodeoxyglucose and 2) the data is currently being utilized/analyzed for development of intellectual property, but are available from the corresponding author on reasonable request.

Competing interests
The authors, Daehyun Yoon, Peter Cipriano, and Sandip Biswal, received research support from General Electric Healthcare. No other potential con icts of interest relevant to this article exist.

Funding
This study was in funded by NIH P41 EB015891 and General Electric Healthcare.