| Coverage Policy Manual | |
| Policy #: | 2004005 |
| Category: | Radiology |
| Initiated: | February 2004 |
| Last Review: | November 2023 |
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| Magnetic Resonance Spectroscopy | |
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| Description: |
Magnetic resonance spectroscopy (MRS) is a noninvasive technique that can be used to measure the concentrations of different chemical components within tissues. The technique is based on the same physical principles as magnetic resonance imaging (MRI) and the detection of energy exchange between external magnetic fields and specific nuclei within atoms.
Magnetic resonance spectroscopy (MRS) is a noninvasive technique that can be used to measure the concentrations of chemical components within tissues. The technique is based on the same physical principles as magnetic resonance imaging (MRI) and the detection of energy exchange between external magnetic fields and specific nuclei within atoms. With MRI, this energy exchange, measured as a radiofrequency signal, is then translated into the familiar anatomic image by assigning different gray values according to the strength of the emitted signal. The principal difference between MRI and MRS is that the emitted radiofrequency in MRI is based on the spatial position of nuclei, while MRS detects the chemical composition of the scanned tissue. The information produced by MRS is displayed graphically as a spectrum with peaks consistent with the various chemicals detected. MRS may be performed as an adjunct to MRI. An MRI image is first generated, and then MRS spectra are developed at the site of interest, at the level of the voxel (3-dimensional volume X pixel). The voxel of interest is typically a cube or rectangular prism with a dimensional pixel with a volume of 1 to 8 cm3. While an MRI provides an anatomic image of the brain, MRS provides a functional image related to underlying dynamic physiology. MRS can be performed with existing MRI equipment, and modified with additional software and hardware, which are provided with all new MRI scanners. Imaging time in the scanner is increased by 15 to 30 minutes.
MRS has been studied most extensively in a variety of brain pathologies. In the brain, both 1-H (i.e., hydrogen proton) and 31-P are present in concentrations high enough to detect and thus have been used extensively to study brain chemistry. Proton MRS of the healthy brain reveals 6 principal spectra. They include those:
Different patterns of these spectra and others (eg, myo-inositol, glutamate/glutamine) in the healthy and diseased brain are the basis of clinical applications of MRS. The MRS findings characteristically associated with non-necrotic brain tumors include elevated Cho levels and reduced NAA levels. The International Network for Pattern Recognition using Magnetic Resonance has developed a user-friendly computer program for spectral classification and a database of over 300 tumor spectra with histologically validated diagnoses to aid radiologists in MRS diagnosis (Interpret Project, 2021; Sibtain, 2007; Julia-Sape, 2015).
One limitation of MRS is that it provides the metabolic composition of a given voxel, which may include more than 1 type of tissue. For some applications, the voxels are relatively large (eg, >1 cm3), although they may be somewhat smaller using a 3-tesla MRI machine versus a 1.5-tesla magnet. High-field strength increases the signal to noise ratio and spectral resolution. The 3-tesla technique creates greater inhomogeneities, however, which require better shimming techniques (Sood, 2010). There are 2 types of MRS data acquisition: single-voxel or simultaneous multivoxel also called chemical shift imaging. Reliable results are more difficult to obtain from some areas, eg, close to the brain surface or in children with smaller brains because of the lipid signal from the skull. Some techniques are used to deal with these issues; various MRS techniques continue to be explored as well. A combination of MRS is often used with other MRI techniques (eg, diffusion-tensor imaging, susceptibility-weighted imaging) and other types of imaging such as positron emission tomography.
Peripheral applications of MRS include the study of myocardial ischemia, peripheral vascular disease, and skeletal muscle. Applications in non-central nervous system oncologic evaluation have also been explored. Nomograms for prostate cancer are being developed that incorporate MRI and MRS results (Hricak, 2007).
Regulatory Status
Multiple software packages for performing proton MRS have received clearance by the U.S. Food and Drug Administration (FDA) through the 510(k) process since 1993. Single-voxel MRS is available on all modern MRI scanners. FDA product code: LNH.
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Policy/ Coverage: |
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Magnetic resonance spectroscopy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, magnetic resonance spectroscopy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
Validation of a new imaging technique involves the following steps:
The published data do not indicate that the second two criteria have been met for magnetic resonance spectroscopy (MRS). While MRS has been investigated in a wide variety of clinical situations, there are no studies specifically focusing on its sensitivity and specificity in specific clinical situations. There are no studies validating how the results of MRS may dictate patient management. For example, MRI is a sensitive tool for identifying space-occupying CNS lesions, but it is relatively nonspecific in distinguishing between benign and malignant lesions. MRS can provide a chemical profile of the lesions that may help in this determination. However, no clinical study detailing the positive and negative predictive value of MRS in distinguishing benign and malignant lesions is available. In known malignancies, MRS has been used to assess tumor histology before resection. However, there is no discussion of how this information will influence treatment decisions. For example, the standard approach to CNS tumors is initially complete surgical resection such that exact tumor histology is not relevant to initial treatment decisions. In this setting, the negative predictive value is probably the most critical statistic; i.e., there is a minimal chance of a missed diagnosis of malignancy. There are no such studies of MRS. After initial treatment, the distinction between tumor recurrence or radiation necrosis is frequently a difficult clinical issue. However, there are no data on whether MRS can be used to make this distinction.
There is much discussion in the literature regarding the role of MRS in diagnosing and monitoring patients with multiple sclerosis (MS). While MRS may provide some powerful insights into the pathogenesis of MS, there are no data about how MRS can be used to influence patient management compared to standard clinical assessment and serial MRIs. Similar considerations apply to the use of MRS in other neurodegenerative diseases, such as Parkinson’s disease, amyotrophic lateral sclerosis, or Alzheimer’s disease. MRS has also been widely investigated as a technique to identify epileptic foci, particularly in the temporal lobes. However, there are inadequate data to validate its performance compared to PET scanning or MRI imaging, or in those patients with equivocal or noncordant PET, MRI, or EEG studies.
MRS has also been investigated in patients with cerebrovascular injury. For example, infarcted areas may be associated with increased levels of lactate and decreased levels of NAA, both detectable by MRS. It has been suggested that changes in MRS may predate changes in MRI, and thus MRS could be used to evaluate stroke progression immediately after acute stroke. Persistence of these abnormalities suggests impaired neurologic functions. Thus MRS may be used to monitor response to thrombolytic therapy, although no specific clinical studies have been reported.
2003 Update
A 2003 Blue Cross Blue Shield Association Technology Evaluation Center Assessment concluded that MRS does not meet Blue Cross Blue Shield Association Technology Evaluation Center criteria for evaluation of suspected brain tumors. The Blue Cross Blue Shield Association Technology Evaluation Center Assessment does not change the above conclusion on MRS.
The assessment identified 7 studies including a total of up to 271 subjects. MRS would be judged to produce a beneficial effect on a health outcome when MRS correctly determines the presence or absence of a tumor and avoids the need for a brain biopsy, an invasive procedure with associated morbidity.
Sensitivity and specificity of MRS for differentiating neoplastic from non neoplastic lesions. One study of 12 children treated with radiation for a brain tumor had a MRI suggestive of either progressive/recurrent tumor or delayed cerebral necrosis. MRS identified 5 of 7 recurrent tumors for a sensitivity of 71%. MRS identified 4 of 5 cases (80%) of delayed necrosis and a 5th case was considered inconclusive.
Five studies evaluating a heterogeneous group of patients, some with known prior tumor, some with unknown new masses, showed variable diagnostic test characteristics for MRS with sensitivities ranging from 79% to 100% and specificity ranging from 74% to 100%. The positive predictive values ranged from 92% to 100%, while the negative predicative value ranged from 60% to 100%. The wide range reported for diagnostic performance in these studies may reflect heterogeneous groups of patients, differences in MRS protocols, or both.
One study evaluated 51 patients with intracranial cystic lesions. MRS properly assigned the correct diagnosis in 47/51 patients or 92%. However, MRS interpretation was based on investigator judgment but not formal criteria.
Effect of MRS to Avoid Brain Biopsy—Two studies reported findings relating to the effect of MRS on patient management, but these results were not derived using decision analytic modeling. In one study of 78 patients, MRS was considered to have a potentially positive influence on treatment decisions by correctly avoiding biopsy in 23 of 78 patients (29%). MRS was suggestive of neoplasm in about 1/3 of cases where biopsy was avoided and negative for tumor in the remaining 2/3 of cases. MRS did not influence treatment in 76% of cases in which MRS was suggestive of neoplasm. MRS had a potentially negative influence on patient management in 2 cases (3%) in which MRS suggested a neoplasm, and a non-neoplastic condition was found at biopsy or surgery. Another study of 15 patients reported that MRS results were used to avoid biopsy in 7 of 15 (46%) cases and may have been helpful in avoiding 2 additional biopsies if MRS results had been used in all patients.
Summary
The available studies all have some degree of shortcomings, and the overall body of evidence does not provide strong and consistent evidence regarding the diagnostic test characteristics of MRS. Studies of diagnostic performance usually mix together different populations of patients that had clinically important differences and do not clearly delineate how MRS information would be used to guide patient management. Thus, it is difficult to determine from the studies mixing patients with different clinical indications whether MRS provides sufficiently high sensitivity, specificity, positive or negative predictive values to safely avoid brain biopsy. Furthermore, there were differences in MRS technique and methods of analysis across studies that make it difficult to synthesize findings from different studies. Two studies report that MRS results may assist in avoiding biopsy in 29%–46% of patients, but 1 of these studies is quite small, and further replication of these findings in a prospectively defined population would be helpful.
2008 Update
Preliminary results from ACRIN Protocol 6659 (annual meeting of the Radiological Society of North American, abstract no. SSJ05-06, November 28, 2006, Chicago, IL) did not indicate any statistically significant improvement in prostate cancer localization due to the addition of MRS to MRI results (although other studies had different results [Futterer et al 2006]) . Peer-reviewed publication of the results of the ACRIN trial will provide further evidence on this issue.
Although a number of studies have examined the use of MRS to differentiate between brain tumor recurrence and radiation necrosis, the cumulative evidence is weak. The studies tend to have small sample sizes (Kimura et al, 2003; Schlemmer et al, 2002); they provide incomplete histopathological data to serve as the reference standard (Chernov et al, 2006); they find that combined imaging modalities, such as MRS and perfusion MRI or diffusion-weighted MRI outperform MRS by itself (Zeng et al, 2006; Truong et al, 2006); or they identify the patterns of interest and the cutoff values for making a diagnosis without providing validation studies (Weybright et al, 2005; Rock et al, 2002). In some cases, a mixed reference standard is used, with histopathological findings for lesions that are excised, biopsied, or reviewed at autopsy and longer follow-up for patients not undergoing surgery (Zeng et al, 2007; Weybright et al, 2005). Although having a mixed reference standard is not optimal, it may be the only feasible option in patients with brain tumors, some of which are located in parts of the brain not amenable to surgery. Some studies report mostly on primary brain tumors (Zeng et al, 2007; Zeng et al, 2007), while others focus mostly on metastases of cancers in other parts of the body (Kimura et al, 2003; Chernov et al, 2006). Studies on the use of MRS to categorize newly diagnosed brain tumors (Sibtain et al, 2007); to distinguish between tumors and abscesses or other infectious processes (Garg et al, 2004); or to diagnose mitochondrial diseases (Bianchi et al, 2003) identify the MRS patterns associated with each type of lesion but once again do not include the necessary validation study or report MRS findings that overlap across the categories of interest. Many are also retrospective (e.g., Weybright et al, 2005; Garg et al, 2004) Preliminary studies done in Asia with a 3T MRI machine for detecting tumor versus radiation injury reported diagnostic quality MRS studies in 26/28 (93%) cases, and the sensitivity and specificity for those 26 patients based on cutoffs identified in the study were 94.1% and 100%. (Zeng et al, 2007; see also Zeng et al, 2007). Validation studies using the same cutoffs in larger samples are needed. (Zeng et al, 2007)
No studies were found that provide sufficient evidence to warrant a change in the current policy.
2012 Update
The policy is being updated with a literature search using the MEDLINE database through July 2012. There was no new literature identified that would prompt a change in the coverage statement.
Brain Tumors
A 2009 review on MRS in radiation injury concludes the following:
MR spectroscopy is presently one of the noninvasive radiologic methods used to distinguish recurrent tumor and radiation injury in patients previously treated with radiation for neoplasm. Still, despite a considerable volume of research in the field, no consensus exists in the community regarding ratio calculations, the accuracy of MR spectroscopy to identify radiation necrosis, and the accuracy of MR spectroscopy in differentiating radiation necrosis from tumor recurrence or the true value of the method in clinical decision making (Sundgren, 2009); for another review, see (Martinez-Bisbal , 2009).
In a 2011 study, Amin and colleagues compared MRS to single photon emission computed tomography (SPECT) in the identification of residual or recurrent glioma versus radiation necrosis in 24 patients treated with surgery and radiotherapy (Amin, 2011). MRS and SPECT results differed in 9 cases of recurrence and were more accurate with SPECT. Specificity and positive predictive value were 100% in both MRS and SPECT; however, sensitivity was 61.1% versus 88.8% and negative predictive value was 46.2% versus 75%, respectively. The use of a single voxel rather than multiple voxels is noted as a limitation in interpreting the MRS results in this study.
Prostate Cancer
The results of the American College of Radiology Imaging Network (ACRIN) study 6659 were published in April 2009 (Weinreb, 2009). This prospective, multicenter study compared the use of MRI with and without MRS to identify the extent of prostate cancer by sextant prior to prostatectomy in 134 patients. The results from centralized histopathologic evaluation of prostate specimens served as the reference standard; MRI and MRS images were independently reviewed by 8 readers. With complete data on 110 patients, no difference was found in the area under the ROC curve for MRI alone versus MRI and MRS combined. That is, the use of MRS provided no incremental value in identifying the extent of prostate cancer.
In a meta-analysis of 7 studies (of 140 screened) on using MRS to diagnose prostate cancer, the pooled weighted sensitivity was 0.82 (95% confidence interval [CI]: 0.73–0.89); specificity, 0.68 (95% CI: 0.58–0.76); and the area under the curve, 83.40 (Wang, 2008). All of these results are based on a cutoff for identifying “definitive” tumor of 0.85 for the ratio of (choline plus creatine) to citrate.
A single-institution randomized, controlled trial (RCT) published in 2010 compared conducting a second randomly selected biopsy (group A) to a biopsy selected partly based on MRS and dynamic contrast-enhanced MRI results (group B) (Sciarra, 2010). The participants were selected from 215 consecutive men with an elevated prostate-specific-antigen (PSA) (between 4 and 10 ng/mL), an initial negative biopsy result, and a negative digital rectal examination; 180 patients participated in the study. Cancer was detected in 24.4% of group A patients and 45.5% of group B participants. Fifty patients from group A with 2 negative biopsy results agreed to undergo biopsy a third time using MRS and dynamic contrast-enhanced (DCE) MRI results; 26 more cancers were found. Overall, 61.6% of the cancers detected had Gleason scores 7 (4+3) or more. The cancers detected after using MRS and dynamic contrast-enhanced MRI imaging also lined up with the suspicious areas detected on imaging. The sensitivity and specificity of MRS were 92.3% and 88.2%, respectively; adding dynamic, contrast-enhanced MRI increased the sensitivity to 92.6%, and the specificity to 88.8%. Limitations of the study include that it was conducted at a single center, analysis was confined to the peripheral zone of the prostate gland, and more samples were drawn from group B patients than from group A patients (12.17 vs. 10 cores, respectively). Furthermore, given the concerns about potential overtreatment among patients with early stage prostate cancer, the benefits of detecting these additional cancers need to be evaluated by examining clinical outcomes for these patients. Similar issues arise in Policy 7.01.121 on saturation biopsy of the prostate.
In a similar report from this institution by these authors, 150 patients with a negative prostate biopsy, despite PSA elevations, were randomized to MRS or MRS plus DCE-MRI to locate prostate cancer foci for a second targeted biopsy (Panebianco, 2010). The addition of DCE-MRI to MRS yielded increased sensitivity and specificity over MRS alone (93.7% and 90.7% versus 82.8% and 91.8%, respectively). Pedrona and colleagues also reported on the combined use of MRS and DCE-MRI for prostate cancer in 106 patients in a prospective cohort study (Perdona, 2011). The authors reported combined MRS and DCE-MRI results yielded unacceptably low positive predictive value of 19%. Negative predictive value was 91%. Sensitivity was 71% and specificity was 48%. The authors indicated the combined MRS and DCE-MRI may be useful in avoiding biopsy since the negative predictive value was 91%; however, further study is needed.
Gauging Treatment Response
The possibility of using MRS to track treatment response and failure has been explored. A small (n=16), preliminary study of tamoxifen treatment for recurrent gliomas found MRS patterns differed between responders and nonresponders (Sankar, 2008). Serial MRS demonstrated that metabolic spectra stabilized after initiation of therapy among responders and then changed in advance of clinical or radiologic treatment failure. In other words, MRS might help predict imminent treatment failure. However, there are relatively few studies with small sample sizes assessing this possible use of MRS. In addition, a number of other types of imaging are being evaluated for the same use, including dynamic, contrast-enhanced MRI, diffusion-weighted MRI, and 18-fluorodeoxyglucose position emission tomography (FDG-PET). Additional studies are needed, including studies comparing modalities or evaluating multimodalities (Dhermain, 2010; Harry 2010).
Liver Disease
MRS has been evaluated as a noninvasive alternative to liver biopsy in the diagnosis of hepatic steatosis. It has been compared to other noninvasive imaging procedures such as computed tomography (CT), dual-gradient echo magnetic resonance imaging (DGE-MRI), and ultrasonography (US); liver biopsy was the reference standard and a 3T MRI machine was used. In a prospective study of 161 consecutive potential living liver donors, DGE-MRI was reported to be the most accurate test for diagnosing hepatic steatosis. While DGE-MRI and MRS were similar for hepatic steatosis 5% or greater, DGE-MRI outperformed MRS for hepatic steatosis 30% or greater (especially regarding specificity) and on quantitative estimates (Lee, 2010); see also (Taouli, 2009).
Other Indications
MRS has also been evaluated for other uses, such as tracking disease changes among patients with multiple sclerosis (MS), (Bellmann-Strobl, 2009) assessing carotid plaque morphology, (Hermus, 2010) as biomarkers of traumatic brain injury (Kou, 2010) predicting long-term neurodevelopmental outcome after neonatal encephalopathy, (Thayyil, 2010); but see also (Wilkinson, 2010) and other applications in children (Rossi, 2010) (Yuh, 2009). Additional evidence on these applications is needed.
Summary
The available studies do not provide strong and consistent evidence regarding the diagnostic test characteristics of MRS. Studies do not clearly delineate how MRS information would be used to guide patient management. Thus, it is not possible to determine whether MRS provides relevant clinical information that will safely influence diagnostic thinking and therapeutic choice. The scientific evidence at this time does not permit conclusions concerning the net effect of this technology on health outcomes.
2013 Update
A search of the MEDLINE database was conducted through July 2013. There was no new information identified that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
Brain Tumors
In 2012, Vicente and colleagues reported on a multi-center study to evaluate the ability of single voxel, proton MRS to differentiate 78 histologically confirmed pediatric brain tumors (29 medulloblastomas, 11 ependymomas, and 38 pilocytic astrocytomas) (Vicente, 2012). Significant metabolic differences in tumor types were identified by MRS when results from short and long echo times were combined, suggesting that MRS may provide non-invasive diagnostic information.
In 2012, Wilson et al. evaluated MRS as a prognostic tool. This study reported on single voxel, proton MRS using short echo times to predict survival of patients with pediatric brain tumors in 115 patients followed for a median of 35 months (Wilson, 2012). Metabolic changes were identified that predicted survival. Poor survival was associated with lipids and scyllo-inositol while glutamine and N-acetyl aspartate were associated with improved survival (p<0.05).
Dementia
In a 2012 study, Shiino and colleagues compared proton MRS in 99 patients with Alzheimer's disease (AD), 31 patients with subcortical ischemic vascular dementia (SIVD) and 45 elderly controls (Shiino, 2012). Differences in metabolic patterns were seen in both AD and SVID patients. Especially notable were increases in myoinositol concentration in the hippocampus identified in AD but not in SIVD (0.95 area under the receiver operating characteristic (ROC) curve).
Clinical Trials
A search of online site ClinicalTrials.gov in July 2013 identified many studies using MRS as a research tool. Two active studies on the utility of MRS include the use of MRS to detect cervical cancer (NCT01060033) and for guidance on glioma treatment choice (NCT01263821).
Practice Guidelines and Position Statements
The National Comprehensive Cancer Network’s clinical practice guidelines on central nervous system tumors identifies MRS, along with MR perfusion or brain PET, as a modality that can be considered to rule out radiation necrosis, as compared to recurrence of brain tumors (NCCN, V.2.2013). The authors also state that MRS may be helpful in grading tumors or assessing response and that the most abnormal area on MRS would be the best target for biopsy. The limitations include tumors near vessels, air spaces, or bone; the extra time required in an MRI machine; and the limitations occurring with any MRI, such as the exclusion of patients with implantable devices. The guidelines on prostate cancer mention MRS as a possible element of “more aggressive workup for local recurrence (e.g., repeat biopsy, MR spectroscopy, endorectal MRI),” which is one possible element of salvage therapy for patients after radical prostatectomy with rising PSA or positive digital rectal examination after radical prostatectomy with a negative biopsy and studies negative for metastases (NCCN, V2.2013). The guideline on breast cancer does not mention MRS.
In conclusion, there is a lack of scientific evidence to draw conclusions regarding the effect net effects of magnetic resonance spectroscopy on health outcomes.
2014 Update
A literature search conducted through July 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Dementia
Research continues on using MRS to identify dementia, especially in its early stages. Tumati et al conducted a systematic review and meta-analysis of 29 studies on MRS for mild cognitive impairment (MCI) (Tumati, 2013). Included in the analysis were a total of 607 MCI patients and 862 healthy controls. Patterns in metabolite concentration, including NAA, creatine (Cr), choline (Cho), and myoinositolin, in various regions of the brain were identified and associated with MCI. For example, levels of creatine were found to be significantly lower in the hippocampus and paratrigonal white matter. NAA was found to be most associated with MCI, but other markers including myoinositolin, Cho, and Cr may also contribute to MCI.
Breast Cancer
MRS is being investigated to improve the specificity of MRI of the breast, which has a high false-positive rate. In 2013, Baltzer et al conducted a systematic review and meta-analysis of 19 studies on MRS for detecting benign versus malignant breast lesions (Baltzer, 2013). The combined total number of patients in the studies reviewed was 1183 and included 452 benign and 773 malignant lesions. In the pooled estimates, sensitivity of MRS was 73% (556 of 761; 95% confidence interval [CI], 64% to 82%) and specificity was 88% (386 of 439; 95% CI, 85% to 91%). The area under the ROC curve for MRS detecting breast cancers versus benign lesions was 0.88. There was significant heterogeneity between studies and evidence of publication bias, limiting interpretation of findings.
Liver Disease
In a systematic review of imaging liver fat in children, Awai et al reviewed 5 MRI studies and found varying methodologies for measuring liver fat by MRI or MRS. Therefore, the available evidence was not sufficient to evaluate the utility of MRI or MRS for assessment of hepatic steatosis in children (Taouli, 2009).
Prostate Cancer
The utility of MRS has also been investigated for identifying whether prostate cancer is confined to the organ, which has implications for prognosis and treatment. In a 2013 Health Technology Assessment, Mowatt et al systematically reviewed 51 studies to evaluate image-guided prostate biopsy with MRS and other enhanced MRI techniques (ie, dynamic contrast-enhanced MRI and diffusion-weighted MRI) compared to T2-MRI and transrectal ultrasound (TRUS) in patients with suspicion of prostate cancer due to elevated prostate-specific antigen (PSA) levels, despite a previous negative biopsy (Mowatt, 2013). MRS had the highest sensitivity in the meta-analysis of individual tests (92%; 95% CI, 86% to 95%), with an estimated specificity of 76% (95% CI, 61% to 87%). TRUS-guided biopsy had the highest specificity (81%; 95% CI, 77% to 85%).
Other Indications
MRS has been evaluated for other uses, such as patients with systemic lupus erythematosus (Zimny, 2013). Additional evidence on these applications is needed. Additionally MRS has been studied in a variety of psychiatric disorders in the research setting, but no studies on the clinical use of MRS for the treatment of psychiatric disorders were found (Fervaha, 2013; Chitty. 2013).
2015 Update
A literature search was conducted through July 2015. The results of two studies identified and summarized below do not prompt a change in the coverage statement.
In 2014, Llufriu et al published a study of MRS in a preliminary data set of 59 patients with MS and 43 healthy controls, and a confirmatory independent data set of 220 patients (Llufriu, 2014).The change in brain volume and measures of disability were obtained annually. The ml:NAA ratio in normal-appearing white matter was found to be a predictor of brain-volume change over 4 years (p=0.02) and of clinical disability (eg, a decrease in the Multiple Sclerosis Functional Composite evolution scale of -0.23 points annually, p=0.01). Effect sizes in this study were low, indicating that the measure is not sufficiently reliable to predict the future disease course in individual patients. Future studies are needed that include larger cohorts with progressive MS, serial measurements of outcomes, and complementary measures of
disease activity (Miller, 2014).
In a 2014 review, Zhang et al identified 30 studies since 2007 on low-field (<1.5T) MRS and 27 studies on high-field (>3.0T) MRS that compared results from patients with Alzheimer disease, MCI, and healthy controls (Zhang, 2014). While metabolite changes are heterogeneous across brain regions, most of these studies focused on detecting changes in individual metabolites or their ratios. The review concluded that to effectively characterize Alzheimer disease-associated neurochemical changes, future approaches should interactively analyze multiple quantifiable metabolites from different brain regions.
2016 Update
A literature search conducted through June 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Wang and colleagues reported a meta-analysis of 24 studies (615 cases and 408 controls) on the diagnostic performance of MRS for detection or grading of brain tumors (Wang, 2014). Twenty-two studies assessed gliomas, and 2 studies assessed ependymomas and primitive neuroectodermal tumors. Seven studies evaluated recurrence, 9 studies evaluated the grade of tumor, 5 studied evaluated the detection of tumors, 1 evaluated residual tumor, and 2 evaluated tumor metastases. Meta-analysis found the overall sensitivity and specificity of MRS to be 80.1% and 78.5%, respectively. The area under the receiver operating characteristics (ROC) curve was 0.78.
Diagnosis of Pediatric Brain Tumor Type
Pediatric brain tumors are histologically more diverse that adult brain tumors and include tumor types such as embryonal tumors, germ cell tumors, polocytic astrocytoma, and ependymomas (Shiroishi, 2015). Combined MRI and MRS to diagnose the type of pediatric brain tumor was reported in 2015 from multicenter Children’s Hospitals in the U.S.14 MRI/MRS imaging was performed in 120 pediatric patients as part of the usual pre-surgical workup, followed by biopsy or resection. For the first 60 patients (from 2001 to 2004), MRS was performed but was considered experimental and was not used for diagnosis. For the next 60 patients (2005 to 2008), radiologists utilized information from both MRI and MRS. The percentage of correct diagnoses was reported for the first 60 patients using only MRI (63% correct), when re-diagnosed with blinded MRI at the time of the study (71% correct, not significantly different from the first MRI reading) and compared with blinded diagnosis using both MRI/MRS (87% correct, p<0.05). For the second group of 60 patients who were diagnosed using MRI/MRS, the type of tumor was correctly identified in 87% of patients (p < 0.005 compared to initial diagnosis with MRI alone). Together, the results indicate an increase (from 71% to 87% correct) in the diagnosis of tumor type when MRS is combined with MRI.
Differentiating Glioma Recurrence from Radiation Necrosis
A 2014 meta-analysis of the use of MRS for the differential diagnosis of glioma recurrence from radiation necrosis included 18 studies (Zhang, 2014). The total sample size was 455 patients; only 3 of the studies were prospective. Fourteen of the studies used both pathology and clinical/radiological follow-up as the reference standard. Twelve studies examined the Cho/Cr ratio, 9 studies calculated the ratio of Cho/NAA, 5 studies calculated the NAA/Cr ratio, and 3 studies calculated the ratio of Cho/nCR. Meta-analysis showed moderate diagnostic performance for MRS using the Cho/Cr and Cho/NAA ratio.
Section Summary: Brain Tumors
There are several systematic reviews evaluating the performance of MRS for diagnosis and evaluation of brain tumors. A number of small studies have evaluated detection, characterization, grading, prognosis, and differentiation of tumor recurrence versus necrosis. Most of the studies included in the meta-analyses were small, retrospective, and used various ratios of MRS spectra. The largest prospective study found that combining MRS with MRI resulted in a greater percentage of correct diagnoses of pediatric brain tumor type. This report had limited information on the specific MRS spectra associated with the different tumor types. Additional study is needed to better define the spectra associated with tumor characteristics, to evaluate the diagnostic accuracy, and to determine the effect on health outcomes.
Practice Guidelines and Position Statements National Comprehensive Cancer Network
The National Comprehensive Cancer Network’s (NCCN) clinical practice guidelines on central nervous system (CNS) cancers identifies MRS, along with magnetic resonance (MR) perfusion or brain amino acid positron emission tomography, as a modality that can be considered to rule out radiation necrosis, as compared with recurrence of brain tumors. The guidelines also state that MRS may be helpful in grading tumors or assessing response and that the most abnormal area on MRS would be the best target for biopsy. The limitations include tumors near vessels, air spaces, or bone; the extra time required in a magnetic resonance imaging (MRI) machine; and the limitations occurring with any MRI, such as the exclusion of patients with implantable devices.
NCCN guidelines on prostate cancer mention MRS may be a part of a “more aggressive workup for local recurrence (eg, repeat biopsy, MR spectroscopy, endorectal MRI),” which is 1 possible element of salvage therapy for patients after radical prostatectomy with rising PSA or positive digital rectal examination after radical prostatectomy with a negative prostate biopsy and negative studies for metastases. “The panel believes that multiparametric MRI may help identify regions of cancer missed on prior biopsies and should be considered in selected cases of men with at least 1 negative biopsy.” The NCCN guideline on breast cancer does not mention MRS.
American College of Radiology
The American College of Radiology (ACR) updated its practice guideline on MRS of the central nervous system in 2014. Most of the guideline is devoted to the actual performance of MRS, but it also lists 22 possible indications for MRS when MRI or computed tomography is inadequate for answering specific clinical questions.
ACR appropriateness criteria for prostate cancer, last reviewed in 2012, states that MRS cannot yet be considered to provide significant advantages in local staging prior to treatment (ACR, 2012)
ACR appropriateness criteria for imaging for cerebrovascular disease, dementia and movement disorders considers MRS to be usually not appropriate (De La Paz, 2014; Dormont, 2014).
2017 Update
A literature search conducted using the MEDLINE database did not reveal any new literature that would prompt a change in the coverage statement.
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Differentiating High-Grade From Low-Grade Glioma
In 2016, Wang et al reported a systematic review of 30 studies (total N=228 patients) on the diagnostic performance of MRS to differentiate high- from low-grade gliomas (Wang, 2016). Articles were included that used pathology or clinical follow-up as the reference standard for the identification of high-grade gliomas. Only 5 studies were prospective, sample sizes ranged from 7 to 160 patients, and there was considerable variability in the thresholds used to identify high-grade gliomas. There was evidence of publication bias. The pooled sensitivity and specificity in the meta-analysis were 75% and 60% for the Cho/Cr ratio, 80% and 76% for Cho/NAA ratio, and 71% and 70% for NAA/Cr ratio. The area under the receiver operating characteristic curve were 0.83, 0.87, and 0.78, respectively. Thus, MRS had moderate diagnostic accuracy in distinguishing high-grade from low-grade gliomas in the published studies.
PRACTICE GUIDELINES AND POSITION STATEMENTS
American Association of Neurological Surgeons et al
In 2015, the American Association of Neurological Surgeons and Congress of Neurological Surgeons gave a level III recommendation (level C) for the addition of MRS to anatomic imaging for the management of diffuse low-grade glioma, because the diagnostic accuracy is not well-defined and the role in clinical practice is still being defined (Fouke, 2015).
Congress of Neurological Surgeons
In 2016, the Congress published an evidence-based guideline on preoperative imaging assessment of patients with suspected nonfunctioning pituitary adenomas (Chen, 2016). The Congress found that although the results were promising, there was insufficient evidence to recommend the use of MRS formally.
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Hellstrom et al evaluated whether MRS adds to the diagnostic value of MRI in differentiating low-grade tumors, high-grade tumors, and non-neoplastic lesions through the retrospective analysis of data on 208 lesions from 186 patients (Hellstrom, 2018). No statistically significant difference was found between MRI and MRI + MRS (p = 0.055). Furthermore, additional data from MRS was found to be very beneficial, beneficial, inconsequential, or misleading in 3%, 12%, 68%, and 17% of cases, respectively. Therefore, in most cases, complementary MRS was not shown to add to the diagnostic value of MRI.
Manias et al reported on a multicenter U.K. study that retrospectively evaluated MRS for the noninvasive diagnosis of brain tumors (Manias, 2018). This study analyzed 64 consecutive children who had MRI, MRS, and histopathology. The clinical information was reviewed by a tumor board, which included pediatric oncologists, pediatric radiologists specializing in neuroradiology, clinical oncologists, neurosurgeons, and histopathologists, who arrived at consensus diagnosis and treatment planning. The reference standard was the diagnosis by the tumor board, verified through the clinical course. MRI alone was correct in 38 (59%) of 64 patients. The addition of MRS increased diagnostic accuracy to 47 (73%) out of 64, with 17 cases incorrectly diagnosed by MRI plus MRS. A subsequent study by Manias et al assessed the diagnostic accuracy of MRS alone in diagnosing children (n=26) with pilocytic astrocytoma, ependydoma, and medulloblastoma, reporting modest correct classification rates of 60%, 50%, and 80%, respectively (Manias, 2018).
A systematic review and meta-analysis of 460 patients with stage II-IV glioma by Suh et al was conducted to assess 2-hydroxyglutarate (2HG) MRS as a noninvasive and accurate diagnostic alternative to confirmation via biopsy with immunohistochemistry and/or genomic sequencing analysis (Suh, 2018). According to the World Health Organization, isocitrate dehydrogenase (IDH) mutation status (IDH1/IDH2) is one of the most valuable prognostic biomarkers for appropriate clinical management of gliomas. The pooled sensitivity and specificity was 95% (95% confidence interval [CI], 85-98%) and 91% (95% CI, 83-96%), respectively.
Andronesi et al reported on an open-label phase I clinical trial investigating the utility of 2HG MRS to assess the pharmacodynamics of an investigational mutant IDH1 inhibitor drug (IDH305, Novartis Pharmaceuticals) (Andronesi, 2018). Eight patients were enrolled, and data from five patients were available for tumor 2HG level analysis at baseline and following one week of treatment with IDH305. Tumor 2HG levels were found to decrease during mutant IDH1 inhibition, with statistically significant decreases in the ratios of 2HG to healthy creatinine (2HG/hCr), tumor creatinine (2HG/tCr), and glutamine plus glutamate (2HG/Glx). However, further study is required to validate whether these results can identify treatment response as patient clinical outcomes were not reported in the present study. Furthermore, the authors acknowledge that recent preclinical data has failed to show an effect on tumor growth with mutant IDH1 inhibitors. Importantly, mutant IDH1 patients have significantly longer survival compared to patients with wild-type IDH1, therefore the value of mutant IDH1 treatment and response monitoring is currently unclear.
Wang et al reported on a systematic review of 30 studies (total n=228 patients) evaluating the diagnostic performance of MRS in differentiating high- from low-grade gliomas (Wang, 2016). The articles included used pathology or clinical follow-up as the reference standard for the identification of high-grade gliomas. Only 5 studies were prospective, sample sizes ranged from 7 to 160 patients, and there was considerable variability in the thresholds used to identify high-grade gliomas. There was also evidence of publication bias. The pooled sensitivity and specificity in the meta-analysis were 75% and 60% for the Cho/Cr ratio, 80% and 76% for Cho/NAA ratio, and 71% and 70% for NAA/Cr ratio. The areas under the receiver operating characteristic curve were 0.83, 0.87, and 0.78, respectively. Thus, MRS had moderate diagnostic accuracy in distinguishing high-grade from low-grade gliomas in the published studies. A recent study by Lin et al only noted a significant difference for the Cho/NAA ratio, with a sensitivity and specificity of 61.54% and 86.36%, respectively (Lin, 2018).
A meta-analysis by Cai et al reviewed 19 studies utilizing MRS imaging for the diagnosis of prostate cancer (Cai, 2019). In a health technology assessment, Mowatt et al (2013) systematically reviewed 51 studies to evaluate image-guided prostate biopsy with MRS and other enhanced MRI techniques (ie, dynamic contrast-enhanced MRI, diffusion-weighted MRI) compared with T2-MRI and transrectal ultrasound (Mowatt, 2013). In these studies, the patients had a suspicion of prostate cancer due to elevated prostate-specific antigen levels, despite a previous negative biopsy.
Godlewska et al published a study assessing the use of MRS to track and predict treatment response to lamotrigine in 21 patients with bipolar depression. Before starting lamotrigine and after 10-12 weeks of treatment, patients underwent MRS scanning to determine levels of glutamate (Glx) in the anterior cingulate cortex (Godlewska, 2019). Baseline levels of Glx did not predict response to lamotrigine (p = 0.49). Responders to lamotrigine showed a significant increase in Glx levels from baseline (p = 0.012), however, the size of this increase was small (14.8 ± 1.3 to 14.3 ± 0.98 µmol/g). The significance between final Glx levels in responders and nonresponders was not reported.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Manias et al prospectively evaluated children with brain lesions aged 16 and under (N=51) between December 2015 and 2017 via MRI and single-voxel MRS, blinded to histopathology (Manias, 2019). MRS spectra were obtained in 47/51 eligible patients, however, only 72% of tumors were considered analyzable via MRS. Proportions of correct diagnoses and interrater agreement at each stage were assessed. The diagnostic accuracy of the principal MRI diagnosis in was 69%, improving to 77% with MRS. Together, MRI and MRS resulted in a significant increase in additionally correct diagnoses compared to MRI alone (P = 0.035) and a significant increase in interrater agreement (P = 0.046). Patients were managed without conclusive histopathology in 25% of cases. This study by Manias et al reported that 25% of patients were managed without a conclusive histopathological diagnosis (Manias, 2019).
Bayoumi et al conducted a prospective study evaluating the additive role of MRS and MRI in the confirmation of pathological complete response after neoadjuvant chemotherapy of breast cancer in 47 patients (Bayoumi, 2019). Patients were evaluated via MRI and MRS at baseline and following treatment with 4 cycles of anthracycline-based chemotherapy administered at 3-week intervals. Pathological response to neoadjuvant chemotherapy was confirmed via histopathological evaluation following surgical excision. A choline (Cho) peak at 3.2 ppm was considered positive. The mean tumor size before and after treatment was 4.21 ± 0.99 cm and 0.9 ± 0.44 cm, respectively, with corresponding mean Cho signal-to-noise ratios of 9.53 ± 1.7 ppm and 2.53 ± 1.3 ppm. MRI detected a complete response in 22/47 patients, corresponding to a sensitivity of 83.3%, specificity of 65.7%, positive predictive value (PPV) of 45.5%, negative predictive value (NPV) of 92%, and a diagnostic accuracy of 70.2%. In contrast, combined MRI and MRS demonstrated a sensitivity of 75%, specificity of 97.1%, PPV of 75%, NPV of 91.9%, and an improved diagnostic accuracy of 91.5%. The cut-off for differentiating between complete response and residual disease was 1.95 ppm with a corresponding diagnostic accuracy of 85.11%. Patient characteristics and eligibility criteria were not specified.
Piersson et al conducted a systematic review of 24 studies to clarify the relationship between neurochemical changes and MRS metabolite levels against validated Alzheimer's disease (AD) biomarkers (Piersson, 2020). Decreased levels of N-aspartylacetate (NAA), NAA/creatine (NAA/Cr), and NAA/myo-inositol (NAA/mI), and increased mI, mI/Cr, choline/Cr (Cho/Cr), and mI/NAA were detected in the posterior cingulate cortex and precuneus. Increased mI and decreased NAA/Cr was associated with increased tau levels. NAA and glutathione levels are reduced in APOE ε4 carriers. The authors conclude that large, longitudinal studies are necessary to elucidate the effect of APOE ε4 on brain metabolites.
Henigsberg et al evaluated 48 patients with unipolar depression from recovery onset until recurrence of depression or until discontinuation of antidepressant maintenance therapy (Henigsberg, 2019). Depressive symptom remission was confirmed with a Montgomery-Asberg rating Scale (MARDS) score ≤10. 1H MRS scans were performed at the onset of recovery and after 6 months. N-acetylaspartate (NAA), choline (Cho), and glutamine/glutamate and GABA (Glx) metabolic spectra were obtained from the left amygdala region. Patients were evaluated with psychiatric interviews and MARDS assessments during the study period at regular intervals of 6 months or less, for up to 7 years. Twenty patients experienced recurrence, 23 patients achieved antidepressant discontinuation, and follow-up data was missing for 5 patients. Cho levels at the beginning of recovery and subsequent changes conveyed the highest risk for earlier recurrence. Patients with higher amygdala Cho after recovery were found to be at significantly lower risk for depression recurrence (HR 0.32; 95% CI, 0.13 to 0.77). Patients were managed on various antidepressant medications, and criteria for antidepressant discontinuation were unclear.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Solanky et al published a cross-sectional analysis of 119 patients with secondary-progressive MS recruited from the MS-Secondary Progressive Multi-Arm Randomization Trial (MS-SMART) (Solanky, 2020). The relationship between neurometabolites and various clinical disability measures was examined via Spearman rank correlations. Significant associations were further analyzed via multiple regression models adjusted for age, sex, disease duration, T2 lesion load, normalized brain volume and history of recent relapse occurrence. Significant associations in normal-appearing white matter were found for tNAA and Nine-Hole Peg Test (9HPT) (r = 0.23; 95% CI, 0.06 to 0.40), tNAA and Paced Auditory Serial Addition Test (PASAT) (r = 0.21; 95% CI, 0.03 to 0.38), tNAA/tCr and PASAT (r = 0.19; 95% CI, 0.01 to 0.36), and mIns/tCr and PASAT (r = -0.23; 95% CI, -0.39 to -0.05). No significant associations were found for any neurometabolite levels and the Expanded Disability Status Scale (EDSS) or Timed 25-Foot Walk (T25FW) tests following multiple regression analysis.
Research use of MRS continues to evolve and test correlations between brain biomarker levels and various psychiatric disorders (eg, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder, psychosis risk, and others) to inform diagnosis or patient management (Fervaha, 2013; Chitty, 2013; Fisher, 2020; Moriguchi, 2019; Quadrelli, 2018; Pruett, 2020; Truong, 2021; Sydnor, 2020; Wang, 2020).
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A systematic review conducted by Bhandari et al evaluated the diagnostic accuracy of 2HG MRS for determination of IDH status in differentiating low-grade glioma (WHO grade II or III) from glioblastoma (WHO grade IV) (Bhandari, 2021). The Bhandari review included 9 studies of individuals with low-grade glioma (n=181) or glioblastoma (n=77) undergoing preoperative 2HG MRS using histopathological diagnosis as a reference standard. Pooled sensitivity and specificity was 93% (95% CI 58% to 99%; I2=82%) and 84% (95% CI 51% to 96%; I2=60%) for low-grade glioma; for glioblastoma, sensitivity was 84% (95% CI 25% to 99%; I2=0%) and specificity was 97% (95% CI 43% to 100%; I2=23%). There was no statistical difference between tumor type senstivities (p=.58) or specificities (p=.06). Positive and negative predictive values were 87% and 73% for low-grade glioma and 50% and 97% for glioblastoma. Study quality was assessed using the QUADAS-2 tool and studies were generally judged to be of low risk of bias and applicability concerns, although 2 studies were found to have high risk of patient selection bias. The included studies also used different MRS techniques and cut-off values, potentially affecting pooled measures of diagnostic accuracy.
As previously stated, research for use of MRS continues to evolve and test correlations between brain biomarker levels and various psychiatric disorders (e.g., major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder, psychosis risk, and others) to inform diagnosis or patient management. Two additional sources were identified (Smucny, 2021; Nakagara, 2022).
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2023. No new literature was identified that would prompt a change in the coverage statement.
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