Abnormal [18F]FDG PET/MRI findings in paraspinal structures of patients with suspected cerebrospinal fluid leak

A combination of magnetic resonance imaging (MRI), computed tomography (CT), and radionuclide cisternography are typically used to locate a cerebrospinal fluid (CSF) leak. However, the site of leakage cannot be determined, making treatment more difficult. Therefore, more sensitive imaging tools are needed. A whole-body [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/MRI was conducted on six patients with suspected CSF leak and the resulting images were reviewed in comparison with those from six healthy controls. Paraspinal regions of focally increased uptake of [18F]FDG were quantified using maximum standardized uptake values (SUVmax) and compared to the SUVmax of corresponding regions in the healthy controls. All six patients with suspected CSF leak showed paraspinal regions of significantly greater [18F]FDG uptake compared to the corresponding areas in controls (P < 0.05). Two patients treated with local injections (epidural blood patches and/or epidural fibrin patches) on the site of abnormal PET/MRI findings reported temporary but significant improvement in symptoms. Our results suggest [18F]FDG PET/MRI is sensitive to abnormalities potentially due to suspected CSF leak, which are not necessarily visible on conventional MRI alone or by the standard-of-care imaging methods.


Scientific Reports
| (2021) 11:15926 | https://doi.org/10.1038/s41598-021-95056-w www.nature.com/scientificreports/ remains unknown. While these two imaging modalities often are consistent in retrospective comparison 17 , this may reflect the common clinical scenario of using invasive CT myelography much more frequently in patients with positive MRI than in patients with negative MRI-attempting to localize the source of leak suggested by findings seen on the subset of positive MRI. In contrast, prospective studies of patients with orthostatic headaches suggest a potentially much lower sensitivity. In one study of 100 patients with orthostatic headaches suspected of having CSF leaks from a consortium of 11 hospitals in Japan, 70 had axial T2 spine MRI, finding 14 leaks, while 86 had MR myelograms, where only 3 leaks were noted 18 . For CT myelography, cases with slow or intermittent CSF leakage are very difficult to identify due to the insufficient contrast and resolution between CSF and background 19 . Previous studies estimate that 46-55% of these cases present no detectable signs of CSF leak on CT myelogram 20,21 . Thus, better non-invasive imaging techniques for detecting and localizing spinal CSF leaks are needed.
In this report, we introduce the use of simultaneous [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/MRI to locate CSF leaks. We hypothesized that [18F]FDG PET, if coupled with the high spatial and contrast resolution of MRI, could accurately identify inflammation around the sites of CSF leak due to its pro-inflammatory nature 22 . We recently presented initial findings from our study 23 , and here we describe in detail our early experience of [18F]FDG PET/MRI of patients with chronic symptoms of suspected CSF leaks in comparison with healthy controls.

Abnormal [18F]FDG PET/MRI findings.
In all six patients, we observed sites of abnormally increased focal uptake of [18F]FDG in paraspinal structures at various levels of the spine (cervical, thoracic, and lumbar) as summarized in Table 1. However, only three patients showed MRI abnormalities (abnormal signal increase on T2-weighted contrast), which were in the same corresponding region of the PET abnormalities (Table 1). Abnormal [18F]FDG uptake was found on paraspinal muscles in 3 patients, interspinous ligament in 2 patients, osseous tissue in 3 patients, and fluid collection in one patient. Except one patient case, all other cases presented abnormalities at multiple spine levels.
The [18F]FDG SUV max in lesions from the patient group showed a higher mean value than the corresponding areas from the control group in all tissue types ( Table 2). The SUV max of the abnormal lesions in the patient group ranged from 1.148 to 6.565 while the SUV max of the corresponding tissues in the controls ranged from 0.416 to 2.893. P-values from the Mann-Whitney U-test comparing the SUV max between the patient and control groups were less than 0.05 in all tissue types, indicating a significant difference of the [18F]FDG uptake between the two groups. Figures 1, 2, 3, and 4 present different cases of abnormally increased [18F]FDG uptake in patients: in cervical paraspinal muscles (Fig. 1), at the level of the interspinous ligament in the lumbar spine (Figs. 2 and 3a), and in areas corresponding to fluid, neuroforamina, and osseous tissue (Fig. 4). The controls did not show areas of focally increased [18F]FDG uptake in these paraspinal regions as shown in an example case of Fig. 3b. Note that  Blood-patch treatment outcome. Epidural blood-patching was performed on multiple levels of the spine for three patients. Two patients underwent epidural blood-patching on the sites covering abnormalities identified by our PET/MRI study and reported temporary improvement in symptoms significantly greater than previous blood-patches (Table 3). However, the other patient whose blood-patch sites marginally included the PET/MRI abnormalities reported no symptomatic improvement.

Discussion
In this report, we introduce a novel [18F]FDG PET/MRI approach for detecting the sites of CSF leak. While other nuclear medicine approaches such as radioisotope cisternography have been used to identify CSF leaks 24 , to our knowledge neither [18F]FDG PET nor simultaneous PET/MRI has been used for this purpose until now. In this  On the other hand, abnormalities on MRI that might be related to CSF leak were identified in only half of the patients. In a limited number of patients followed for the treatment outcome, the patients whose blood-patch treatment sites covered the abnormalities identified by our method achieved better symptomatic relief than the patient whose treatment marginally included the identified abnormalities. The proposed approach for the improved detection of CSF leak is based on the observation that extradural CSF may irritate and inflame tissues outside of the nervous system 22 . This CSF-induced irritation is reflected clinically in studies of patients with chronic CSF leaks following accidental dural puncture, who report much higher rates of spinal pain at the site of CSF leak than controls without dural puncture 10,25 . Lesions with active inflammatory responses can have increased metabolism and energy requirements, becoming more glucose-avid than normal tissues 26 .
[18F]FDG PET is a highly sensitive imaging modality of glucose metabolism, and has demonstrated its effectiveness in detection of such hypermetabolic inflammation [27][28][29] . Our results show abnormally increased uptake of [18F]FDG in the paraspinal region of all patients, supporting the feasibility of our approach for the detection of CSF leak. More abnormalities were found with [18F]FDG PET than 3T MRI, which suggests [18F]FDG PET might be better suited than MRI for the detection of early inflammatory changes due to CSF leak. However, our approach may not be feasible for detecting other etiologies without extradural CSF inflammation, such as CSF-venous fistular where CSF escapes the thecal sac directly into adjacent epidural veins.
Unlike the conventional imaging methods for CSF leak diagnosis, our [18F]FDG PET approach is to find the paraspinal tissues potentially affected by CSF leak rather than the tear or puncture through which the CSF leaks. Therefore, using [18F]FDG PET in conjunction with an imaging modality that enables the investigation of the anatomic cause of the leak can create a synergistic effect in accurately specifying the site(s) of CSF leak. MRI is more advantageous than CT for accompanying [18F]FDG PET in that it can provide detailed anatomic examination with no further deposition of ionizing radiation to sensitive areas. The simultaneous acquisition of PET and MRI employed in this study also offers improved image co-registration compared to the conventional PET/CT that sequentially acquires PET and CT, rendering it susceptible to mis-registration due to patient motion between the two scans. Our PET/MRI approach has the additional benefit of potentially discriminating a benign   FDG is relatively non-specific and can be seen in other paraspinal inflammatory processes such as myositis and in musculoskeletal degenerative changes such as Baastrup's disease 31,32 . Therefore, careful consideration of other etiologies should be considered when abnormal uptake of [18F]FDG is observed in the paraspinal regions. Our early results suggest it could be effective as an additional tool for locating the sites of CSF leak and target sites for epidural patching. Optimizing MRI sequences that can better complement [18F]FDG PET is also necessary to pinpoint the site of CSF leaks. Additionally, post-treatment scans in these same patients will be useful in determining whether a decrease in symptoms correlates with a decrease in [18F]FDG tracer uptake.

Conclusion
Increased [18F]FDG uptake can be observed on PET in the paraspinal tissues of patients with suspected CSF leak. Our results suggest [18F]FDG PET/MRI is sensitive to abnormalities potentially due to suspected CSF leak, which are not necessarily visible on the standard-of-care diagnostic imaging modalities. Study participants. For the patient group, 4 male and 2 female patients suspected of suffering from CSF leaks were recruited (mean age ± standard deviation: 36.2 ± 8.9 y; age range: 25-54 y). All patients presented with orthostatic headache and previously received standard-of-care imaging methods (including CT myelogram), which did not identify sources of CSF leak. The events identified by the patients as a precipitating event were epidural steroid injection (Patient 1 and 3), traumatic injury (Patient 4 and 5), lumbar puncture (Patient 6), and none (Patient 2). Six healthy controls (mean age ± standard deviation: 28.5 ± 3.3; age range: 22-31 y) were also imaged with the same [18F]FDG PET/MRI protocol used for patients to compare the [18F]FDG uptake between the patient and control groups. Prior to imaging, all participants signed an informed consent form regarding study participation and publishing acquired data and images. All data were acquired in compliance with the Health Insurance Portability and Accountability Act. The clinical trial registration number of our study is NCT03195270 (registration date: 07/22/2017), and the name of the associated clinical trial registry is Clini-calTrials.gov. Image acquisition. All subjects were requested to fast for 4 hours before our imaging study to avoid nonspecific elevation of the blood glucose level. One hour after a single 10-mCi injection of [18F]FDG, subjects were admitted to a SIGNA PET/MRI scanner (GE Healthcare, Waukesha, WI, U.S.) for imaging. We performed a whole-body PET/MRI scan of subjects, which consisted of 8 to 10 consecutive imaging stations. In each station, 4-8-min simultaneous PET/MRI scan was performed, making the total scan time to be 1 to 1.5 h depending on the patient's height. Acquired PET and MRI raw data were reconstructed using the algorithms equipped in the scanner 33,34 .

Methods
In each station, we conducted following two MRI sequences: 3D axial T1-weighted spoiled gradient-recalled echo sequence with two-point Dixon fat-water separation (TR: 4.6 ms, TE: 1.8 ms, resolution: 1.3 × 1.3 × 3.4 mm, flip angle: 15°) and 2D axial T2-weighted fast-spin-echo sequence with two-point Dixon fat-water separation (TR: 7.6 s TE: 93.3 ms, resolution: 1.5 × 1.5 × 4 mm, echo train length: 15). For one or two imaging stations where we suspected CSF leaks might occur based on the patient's history, we additionally ran the following two sequences for high-resolution imaging: 3D axial double-echo-in-steady-state (DESS) with water-only excitation (TR: 18.7 ms, TE: 8.1 ms, resolution: 0.8 × 0.8 × 2 mm, flip angle: 30°) and 3D coronal motion-sensitized-drivenequilibrium (MSDE) fast-spin-echo sequence (CUBE) with triple-echo Dixon fat-water separation (TR: 2.5 s, TE: 71.8 ms, resolution: 1.4 × 1.4 × 1.4 mm echo train length: 80). For MRI signal acquisition, a 16-channel head-neck coil, an integrated spine coil, and two 32-channel anterior body array coils were employed. Data analysis. Two radiologists reviewed patient PET and MRI images concurrently to find abnormalities that are likely to be related with patients' symptoms. Abnormal [18F]FDG hotspots were identified as potential lesions and the maximum standardized uptake value (SUV max ) of [18F]FDG was measured. We used image analysis software (Horos v.3.3.5, 64 bit) for measuring SUV max . The lesions on the PET images were categorized into 5 types: paraspinal muscle, interspinous ligament, osseous tissue, neuroforamina, and fluid collection. The SUV max measurements in each lesion type were compared with the SUV max of corresponding areas in the healthy controls using a two-sided Mann-Whitney U-test. We employed this nonparametric test because we could not assume the normality in the measurements from patients and the sample size was small. P-value of 0.05 was adopted as a significance level. www.nature.com/scientificreports/ Patient follow-up. After our imaging study, three patients received epidural blood-patch treatments based on the information from the standard-of-care diagnostic methods, without using our imaging findings. Patient 2 had targeted fibrin epidural patches while Patients 4 and 6 had targeted epidural blood patches. When a leak site has been identified, fibrin patches may resolve the symptoms of some patients with CSF leak refractory to epidural patching with blood 35 . The intervals between the imaging and the treatment of these patients were about 2.5 months, 2 months, and 3 months, respectively. We recorded the patient's qualitative evaluation on the symptomatic improvements (Yes/No) following the treatments in comparison with previous treatments, if possible. We compared the sites of the blood patches with the sites of PET/MRI abnormalities from our study to assess the relevance of detected abnormalities to the symptom based on the patient's post-treatment evaluation.

Data availability
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]fluorodeoxyglucose and (2) the data is currently being utilized/ analyzed for development of intellectual property, but are available from the corresponding author on reasonable request.