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Magnetic Resonance Spectroscopy

Policy Number: MP-147

Effective for dates of service on or after March 1, 2019, refer to: PET, MRI, MRA, CT, CTA/CCTA (Advanced Imaging Guidelines)

Latest Review Date: September 2018

Category: Radiology                                                             

Policy Grade:  A

Description of Procedure or Service:

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. 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 in MRI, the emitted radiofrequency 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 MR 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 (VOI) is typically a cube or rectangular prism with a dimensional pixel with a volume of 1 to 8 cm cubed. 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, 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 brain reveals six principal spectra:

  • Arising from N-acetyl groups, especially n-acetylaspartate (NAA)

NAA is an amino acid that is generated by mitochondria and is present almost exclusively in neurons and axons in the adult central nervous system (CNS). NAA intensity is thought to be a marker of neuronal integrity and is the most important proton signal in studying central nervous system (CNS) pathology.  Decreases in the NAA signal are associated with neuronal loss, damage to neuronal structures, and/or reduced neural metabolism.

  • Arising from choline-containing compounds (Cho) such as membrane phospholipids (e.g., phosphocholine and glycerophosphocholine). An increase in Cho is considered a marker of pathologic proliferation/degradation of cell membranes and demyelination. Choline levels can increase in acute demyelinating disease, but an increase in Cho levels is most commonly associated with neoplasms. Cho levels can also be affected by diet and medication.
  • Arising from creatine and phosphocreatine: In the brain, creatine is a relatively constant element of cellular energetic metabolism and thus is sometimes used as an internal standard.
  • Arising from Myo-Inositol: Myo-Inositol is a polyalcohol that is present at high concentration in glial cells. An increase in the ratio of ml to NAA suggests gliosis and regional neuronal damage.
  • Arising from lipid 
  • Arising from lactate: Normally this spectrum is barely visible, but lactate may increase to detectable levels when anaerobic metabolism is present. Lactate may accumulate in necrotic areas, in inflammatory infiltrates, and in brain tumors.

Different patterns of these spectra and others, such as myoinositol and 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 choline (Cho) levels and reduced N-acetylaspartate (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 300 tumor spectra with histologically validated diagnoses to aid radiologists in MRS diagnosis.

One limitation of MRS is that it provides the metabolic composition of a given voxel, which may include more than one type of tissue. For some applications, the voxels are relatively large (e.g., more than 1 cm cubed), although they may be somewhat smaller using a 3T MRI machine versus a 1.5T magnet. High field strength increases the signal to noise ratio and spectral resolution. The 3T technique creates greater inhomogeneities, however, which require better shimming techniques.  There are two 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, e.g., 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 MR spectroscopy is often used with other MRI techniques, including diffusion-tensor imaging, susceptibility-weighted imaging, etc., and possibly 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-CNS oncologic evaluation have also been explored. New nomograms for prostate cancer are being developed that incorporate MRI and MRS results.

All the findings reported in this policy refer to proton MRS, unless otherwise indicated.

Policy:

Effective for dates of service on or after March 1, 2019:

Refer to PET, MRI, MRA, CT, CT/CCTA Advanced Imaging Guidelines

Effective for dates of service prior to March 1, 2019:

Magnetic Resonance Spectroscopy (MRS) is considered not medically necessary and investigational.

 

Key Points:

The most recent literature update was performed through July 9, 2018. This review was informed in part by a 2003 TEC Assessment.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Brain Tumors

Clinical Context and Test Purpose

The purpose of MRS in patients with brain tumors is to differentiate malignant from non-malignant tumors, evaluate the grade of tumors, and distinguish metastatic from primary brain tumors.

The question addressed in this evidence review is: Does MRS improve the net health outcome of patients with brain tumors?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is patients who are being evaluated for brain tumors.

Interventions

The intervention of interest is MRS.

Comparators

The comparator of interest is standard evaluation with magnetic resonance imaging (MRI).

Outcomes

The outcomes of interest are sensitivity and specificity and the impact of diagnosis on health outcomes.

Timing

The time of interest is at the time of biopsy or surgical resection or clinical follow-up.

Setting

MRS would be administered in an outpatient setting.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Systematic Reviews

In 2014, Wang et al reported a meta-analysis of 24 studies (615 cases, 408 controls) on the diagnostic performance of MRS for detecting or grading of brain tumors. Twenty-two studies assessed gliomas, and two studies assessed ependymomas and primitive neuroectodermal tumors. Seven studies evaluated recurrence, nine studies evaluated the grade of tumor, five studied evaluated the detection of tumors, one evaluated residual tumor, and two evaluated tumor metastases. The meta-analysis found the overall sensitivity and specificity of MRS were 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 than adult brain tumors and include tumor types such as embryonal tumors, germ cell tumors, polocytic astrocytoma, and ependymomas.

Manias et al (2018) reported on a multicenter U.K. study that retrospectively evaluated MRS for the noninvasive diagnosis of brain tumors.8 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 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.

Combined magnetic resonance imaging (MRI) and MRS to diagnose the type of pediatric brain tumor was reported in 2015 from multicenter children’s hospitals in the United States.  MRI/MRS imaging was performed in 120 pediatric patients as part of the usual presurgical workup, followed by biopsy or resection. For the first 60 patients (from 2001 to 2004), MRS was performed, but considered experimental and not used for diagnosis. For the next 60 patients (2005 to 2008), radiologists used information from both MRI and MRS. The percentage of correct diagnoses was reported for the first 60 patients using only MRI (63% correct). MRI scans were re-evaluated at the time of the study (71% correct), and the diagnosis at the second MRI reading was not significantly different from the first MRI reading. These results were compared with blinded diagnosis using MRI plus MRS (87% correct, p<0.05). For the second group of 60 patients who were diagnosed using MRI/MRS, tumor type was correctly identified in 87% of patients (p<0.005 vs initial diagnosis with MRI alone). Together, the results indicated an improvement (from 71% to 87% correct) in the diagnosis of tumor type when MRS was combined with MRI.

In 2013, Vicente et al reported on a multicenter study to evaluate the ability of MRS to differentiate 78 histologically confirmed pediatric brain tumors (29 medulloblastomas, 11 ependymomas, 38 pilocytic astrocytomas). 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 noninvasive diagnostic information.  MRS has also been evaluated as a prognostic tool.

A 2013 study by Wilson et al reported on single voxel, proton MRS to predict survival in 115 patients with pediatric brain tumors who were followed for a median of 35 months. Poor survival was associated with lipids and scyllo-inositol while glutamine and N-acetylaspartate (NAA) were associated with improved survival (p<0.05).

 

Differentiating Glioma Recurrence From Radiation Necrosis

A systematic review by Zhang et al (2014) assessed the use of MRS in the differential diagnosis of glioma recurrence from radiation necrosis; it included 18 studies (total N=455 patients).12 Only 3 studies were prospective. Fourteen of the studies used both pathology and clinical plus radiologic follow-up as the reference standard. Twelve studies examined the choline (Cho)/creatine (Cr) ratio, 9 studies calculated the Cho/NAA ratio, 5 studies calculated the NAA/Cr ratio, and 3 studies calculated the Cho/CR ratio. Meta-analysis showed moderate diagnostic performance for MRS using the Cho/Cr and Cho/NAA ratios.

The largest prospective study included in the review was a 2012 report by Amin et al. This study compared MRS with 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. MRS and SPECT results differed in nine 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.

Differentiating High-Grade From Low-Grade Glioma

Wang et al (2016) 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.14 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.

Gauging Treatment Response

The possibility of using MRS to track treatment response and failure has been explored. A small (N=16), preliminary study (2008) of tamoxifen treatment for recurrent gliomas found MRS patterns differed between responders and nonresponders. 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. Additionally, other types of imaging are being evaluated for the same use, including DCE MRI, diffusion-weighted MRI, and 18-fluorodeoxyglucose position emission tomography. Additional studies are needed, including studies comparing modalities or evaluating multimodalities.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

No RCTs were identified that support the clinical utility of MRS for this indication. The retrospective study by Manias et al (2018), discussed above, did report that patient management was influenced by MRS in 13 cases, including avoidance of biopsy in 10 cases, appropriate management in 1 case, and alerting to high-grade lesions in 2 cases.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of MRS has not been established for this indication, a chain of evidence cannot be constructed.

Section Summary: Brain Tumors

Several systematic reviews have evaluated the performance of MRS for diagnosis and evaluation of brain tumors. A number of small studies have assessed detection, characterization, grading, prognosis, and differentiation of tumor recurrence versus necrosis. Most 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.

Breast Cancer

Clinical Context and Test Purpose

The purpose of MRS in patients with breast cancer is to improve the specificity of MRI of the breast, which has a high false-positive rate.

The question addressed in this evidence review is: Does MRS improve the net health outcome of patients with breast cancer?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is patients who are being evaluated for breast cancer.

Interventions

The intervention of interest is MRS.

Comparators

The comparator of interest is standard evaluation with MRI.

Outcomes

The outcomes of interest are sensitivity and specificity and the effect on health outcomes.

Timing

The time of interest is at biopsy, surgical resection, or clinical follow-up.

Setting

MRS would be administered in an outpatient setting.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

In 2013, Baltzer et al conducted a systematic review and meta-analysis of 19 studies on MRS for detecting benign versus malignant breast lesions. 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% (556/761; 95% confidence interval [CI], 64% to 82%) and specificity was 88% (386/439; 95% CI, 85% to 91%). The area under the receiver operating characteristic (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.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs were identified that support the clinical utility of MRS for this indication.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of MRS has not been established for this indication, a chain of evidence cannot be constructed.

Section Summary: Breast Cancer

The evidence on MRS to determine whether breast lesions are benign or malignant includes a systematic review. Pooled estimates of sensitivity and specificity were 73% and 88%, respectively. There was evidence of publication bias, limiting interpretation of findings.

Prostate Cancer

Clinical Context and Test Purpose

The purpose of MRS in patients with prostate cancer is to improve the evaluation of prostate cancer. There are several potential applications of MRS for prostate cancer, including diagnosis, recurrence assessment, and localization for biopsy and treatment planning.

The question addressed in this evidence review is: Does MRS improve the net health outcome of patients with prostate cancer?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is patients who are being evaluated for prostate cancer.

Interventions

The intervention of interest is MRS.

Comparators

The following practice is currently being used to make decisions about managing prostate cancer: standard evaluation with MRI.

Outcomes

The outcomes of interest are sensitivity and specificity and the effect on health outcomes.

Timing

The time of interest is the initial evaluation, prior to biopsy, and following treatment for prostate cancer.

Setting

MRS would be administered in an outpatient setting.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Systematic Reviews

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 (i.e., dynamic contrast-enhanced MRI and diffusion-weighted MRI) compared with T2-MRI and transrectal ultrasound. In these studies, the patients were individuals with suspicion of prostate cancer due to elevated prostate-specific antigen levels, despite a previous negative biopsy. 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%). The transrectal ultrasound-guided biopsy had the highest specificity (81%; 95% CI, 77% to 85%).

Randomized Controlled Trials

A single-institution randomized controlled trial published in 2010 compared conducting a second randomly selected biopsy (group A) with a biopsy selected partly based on MRS and dynamic contrast-enhanced (DCE) MRI results (group B). The participants were selected from 215 consecutive men with an elevated 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 two negative biopsy results agreed to undergo biopsy a third time using MRS and DCE MRI results; 26 more cancers were found. Overall, 61.6% of the cancers detected had Gleason scores of 7 (4+3) or more. The cancers detected after using MRS and DCE 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 DCE 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.

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. The addition of DCE-MRI to MRS yielded increased sensitivity and specificity over MRS alone (93.7% and 90.7% vs 82.8% and 91.8%, respectively).

Prospective Studies

Lahoti et al (2017), in a study from India, prospectively evaluated the diagnostic accuracy of ultrasonography, MRI, and a combination of MRI plus MRS in 66 patients with a strong clinical suspicion of prostate pathologies. All patients underwent ultrasonography, MRI, and MRS, followed by biopsy. Diagnostic accuracy of the 3 tests is shown in Table 1. Of 41 patients with malignant lesions, MRI identified 39 as malignant and MRI plus MRS identified 40 as malignant. Of 25 patients with benign lesions, MRI identified 21 as benign and MRI plus MRS identified 23 as benign.

Table 1. Clinical Validity of Technologies to Identify Malignant Prostate Lesions

Test

Sensitivity, %

Specificity, %

PPV, %

NPV, %

Ultrasonography

78.0

88.0

91.4

71.0

MRI

95.1

84.0

90.7

91.3

MRI plus MRS

97.6

92.0

95.2

95.8

Adapted from Lahoti et al (2017).

MRI: magnetic resonance imaging; MRS: magnetic resonance spectroscopy; NPV: negative predictive value; PPV: positive predictive value.

Pedrona et al (2013) also reported on the combined use of MRS and DCE-MRI for prostate cancer in 106 patients in a prospective cohort study. 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, because the negative predictive value was 91%; however, further study is needed.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs were identified that support the clinical utility of MRS for this indication.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of MRS has not been established for this indication, a chain of evidence cannot be constructed.

Section Summary: Prostate Cancer

Although a number of studies have examined the use of MRS for diagnosing prostate lesions, localizing prostate cancer for biopsy and for monitoring of patients with prostate cancer, the cumulative evidence remains uncertain. Data comparing the diagnostic accuracy of MRS with alternative imaging strategies is limited. Additionally, the impact of MRS imaging compared with other imaging strategies on clinical management and health outcomes is unknown.

Noncancer Indications

Clinical Context and Test Purpose

The purpose of MRS in patients with noncancer indications is to improve the diagnosis and management of a variety of conditions.

The question addressed in this evidence review is: Does MRS improve the net health outcome of patients with noncancer indications?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is patients who are being evaluated for dementia, liver disease, multiple sclerosis, or other noncancer indications.

Interventions

The intervention of interest is MRS.

Comparators

The comparator of interest is observation for patients with dementia or multiple sclerosis or liver biopsy for patients with liver disease.

Outcomes

The outcomes of interest are sensitivity and specificity and the effect on health outcomes.

Timing

The time of interest is in the initial evaluation.

Setting

MRS would be administered in an outpatient setting.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Dementia

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Research continues on the use of MRS to identify dementia, especially in its early stages. 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. 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.

In 2013, Tumati et al conducted a systematic review and meta-analysis of 29 studies on MRS for mild cognitive impairment (MCI). 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 myo-inositolin, 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 myo-inositolin, Cho, and Cr may also contribute to MCI.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs were identified that support the clinical utility of MRS for this indication.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of MRS has not been established for this indication, a chain of evidence cannot be constructed.

Section Summary: Dementia

Although a number of studies have examined the use of MRS for identifying and monitoring cognitive impairment and dementia, the cumulative evidence is insufficient to determine any role for MRS outside of the research setting. There are no clear criteria for diagnosing cognitive impairment or dementia with MRS and there are insufficient data on diagnostic comparators. Additionally, the impact of MRS imaging on clinical management and health outcomes is unknown.

Liver Disease

MRS has been evaluated as a noninvasive alternative to liver biopsy in the diagnosis of hepatic steatosis. It has been compared with other noninvasive imaging procedures such as computed tomography (CT), dual-gradient echo magnetic resonance imaging (DGE-MRI), and ultrasonography; liver biopsy was the reference standard and a 3T MRI machine was used.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

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 (see also Taouli et al, 2009). In a systematic review of imaging liver fat in children, Awai et al (2014) reviewed five MRI studies and found varying methodologies for measuring liver fat by MRI or MRS.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs were identified that support the clinical utility of MRS for this indication.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of MRS has not been established for this indication, a chain of evidence cannot be constructed.

Section Summary: Liver Disease

The available evidence does not support the utility of MRI or MRS for assessment of hepatic steatosis in children.

Multiple Sclerosis

Multiple sclerosis (MS) is a chronic disease with a variable prognosis and clinical course. Predictors of future disease course may help in selecting patient who will benefit most from disease-modify treatments.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

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. The change in brain volume and measures of disability were obtained annually. The mI:NAA ratio in normal-appearing white matter was found to be a predictor of brain-volume change over four years (p=0.02) and of clinical disability (e.g., 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.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs were identified that support the clinical utility of MRS for this indication.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of MRS has not been established for this indication, a chain of evidence cannot be constructed.

Section Summary: Multiple Sclerosis

Future studies are needed that include larger cohorts with progressive MS, serial measurements of outcomes, and complementary measures of disease activity.

Other Indications

MRS has also been evaluated for other uses, such as tracking disease changes among patients with systemic lupus erythematosus, assessing carotid plaque morphology and identifying biomarkers of traumatic brain injury, predicting long-term neurodevelopmental outcome after neonatal encephalopathy (see also Wilkinson (2010), van Laerhoven et al (2013)). MRS has also been used in the evaluation of pediatric patients with seizures, and other applications in children. Additional evidence on these applications is needed. MRS has also 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.

Summary of Evidence

For individuals who have brain tumors who receive MRS, the evidence includes a number of small studies and systematic reviews. Relevant outcomes are test accuracy, change in disease status, morbid events, and functional outcomes. Small studies have evaluated detection, characterization, grading, prognosis, and differentiation of tumor recurrence vs necrosis. Most 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 magnetic resonance imaging 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 define better the spectra associated with tumor characteristics, to evaluate the diagnostic accuracy, and to determine the effect on health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have breast cancer, prostate cancer, dementia, liver disease, or multiple sclerosis who receive MRS, the evidence includes prospective studies on diagnostic accuracy and systematic reviews. Relevant outcomes are test accuracy, change in disease status, and morbid events. A number of studies have examined the use of MRS for localizing prostate cancer for biopsy and for monitoring of patients with prostate cancer. However, the cumulative evidence remains uncertain. Data comparing the diagnostic accuracy of MRS with alternative imaging strategies is limited. A systematic review of MRS to identify dementia concluded that to characterize Alzheimer disease‒associated neurochemical changes effectively, future approaches need to analyze interactively multiple quantifiable metabolites from different brain regions. A study of MRS as a noninvasive alternative to liver biopsy indicates that dual-gradient echo magnetic resonance imaging outperforms MRS. Data on use of MRS in multiple sclerosis has indicated that the measure is not sufficiently reliable to predict the future disease course. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

The National Comprehensive Cancer Network’s (NCCN) clinical guidelines on central nervous system cancers (v.1.2018) identifies magnetic resonance spectroscopy (MRS), as a modality that can be considered to rule out radiation necrosis, as compared with a recurrence of brain tumors.43 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, and the extra time required in a magnetic resonance imaging machine.

NCCN clinical guidelines on prostate cancer (v.4.2018) list MRS as an advanced imaging technique, but make no recommendations for its use.

NCCN clinical guidelines on breast cancer (v.1.2018) do not mention MRS.

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.

Congress of Neurological Surgeons

In 2016, the Congress published an evidence-based guideline on preoperative imaging assessment of patients with suspected nonfunctioning pituitary adenomas. The Congress found  that although the results were promising, there was insufficient evidence to recommend the use of MRS formally.

American College of Radiology et al

The American College of Radiology, American Society of Neuroradiology, and Society for Pediatric Radiology updated their joint practice parameters on MRS of the central nervous system in 2013.  Most of the update addressed the actual performance of MRS, but it also listed 22 possible indications for MRS when MRI or CT is inadequate for answering specific clinical questions.

American College of Radiology appropriateness criteria for prostate cancer, last reviewed in 2016, stated that MRS cannot yet be considered to provide significant advantages in local staging before treatment.

American College of Radiology appropriateness criteria for imaging for dementia and movement disorders (updated in 2015) considers MRS to be usually inappropriate.

U.S. Preventive Services Task Force Recommendations

Not applicable

 

Key Words

Magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), brain tumors, voxel, N-acetylaspartate (NAA), choline (cho), magnetic resonance spectroscopy imaging

Approved by Governing Bodies:

Multiple software packages for performing proton MRS have been cleared for marketing by the U.S. Food and Drug Administration through the 510(k) process since 1993. Single voxel MRS is available on all modern magnetic resonance scanners.

Benefit Application:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

Current Coding: 

CPT:              

76390              Magnetic resonance spectroscopy

 

References:

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Policy History:

Medical Policy Group, December 2003

Medical Policy Administration Committee, December 2003

Available for comment February 7-March 22, 2004

Medical Policy Group, December 2005 (1)

Medical Policy Group, February 2007 (2)

Medical Policy Group, March 2008 (2)

Medical Policy Administration Committee, April 2008

Medical Policy Group, March 2010 (1) Updated Key Points, no policy change

Medical Policy Group, November 2010 (1) No policy change

Medical Policy Group, January 2012 (2): Updated Key Points & References

Medical Policy Group, January 2013 (2): 2013 Update to Key Points and References; no change in policy statement

Medical Policy Panel, December 2014

Medical Policy Group, January 2015 (3):  2014 Updates to Description, Key Points, and References, no change to policy statement.

Medical Policy Panel, December 2015

Medical Policy Group, January 2016 (3):  2015 Updates to Description, Key Points & References; no change in policy statement

Medical Policy Panel, September 2017

Medical Policy Group, October 2017 (3): 2017 Updates to Description, Key Points, Approved by Governing Bodies & References; no change in policy statement

Medical Policy Group, December 2017: Annual Coding Update 2018.  Added new CPT code 0024U to the Current Coding section.

Medical Policy Panel, September 2018

Medical Policy Group, September 2018 (9): 2018 Updates to Description, Key Points & References; no change in policy statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.