Medical Policy

Policy Num:     06.001.007
Policy Name:   Magnetic Resonance Spectroscopy
Policy ID:         [6.001.007]  [Ac / B / M- / P-]  [6.01.24]

Last Review:     November 12, 2024
Next Review:     November 20, 2025
 

Related Policies:

06.001.053 - Selected Positron Emission Tomography Technologies for Evaluation of Alzheimer Disease

Magnetic Resonance Spectroscopy

summary

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 and the detection of energy exchange between external magnetic fields and specific nuclei within atoms.

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 versus necrosis. Most studies included in the meta-analyses were small, retrospective, and used various ratios of MRS spectra. The largest prospective studies found that combining MRS with MRI resulted in a greater percentage of correct diagnoses of pediatric brain tumor type. These reports had limited information on the specific MRS spectra associated with 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have breast cancer, prostate cancer, dementia, liver disease, multiple sclerosis (MS), or psychiatric disorders who receive MRS, the evidence includes prospective studies on diagnostic accuracy and systematic reviews. Relevant outcomes are test accuracy, change in disease status, morbid events, and functional outcomes. A number of studies have examined the use of MRS for localized prostate cancer for biopsy, for diagnosis, and for the monitoring of patients with prostate cancer. However, the cumulative evidence remains uncertain. Data comparing the diagnostic accuracy of MRS with alternative imaging strategies are 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 indicated that dual-gradient echo MRI outperforms MRS. Data on the use of MRS in MS has indicated that the measure is not sufficiently reliable to predict the future disease course. Research assessing MRS for the management of bipolar disorder has thus far failed to demonstrate its ability to predict treatment response. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

OBJECTIVE

The objective of this evidence review is to evaluate whether magnetic resonance spectroscopy improves health outcomes in patients with brain tumors, breast cancer, prostate cancer, and various non-cancer indications.

POLICY

Magnetic resonance spectroscopy is considered investigational.

POLICY GUIDELINES

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Coding

Please see the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

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 brain reveals 6 principal spectra. They include those:

• 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. NAA intensity is thought to be a marker of neuronal integrity and is the most important proton signal in studying central nervous system 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 (eg, phosphocholine, glycerophosphocholine): An increase in Cho is considered a marker of pathologic proliferation/degradation of cell membranes and demyelination. Cho 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 present at high concentration in glial cells. An increase in the ratio of myo-Inositol 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 (eg, myo-inositol, glutamate/glutamine) in the healthy and diseased brain are the basis of clinical applications of MRS. 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.^1,2,

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.^3, 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.

All findings reported in this evidence review refer to proton MRS unless otherwise indicated.

Use of positron emission tomography (PET) in Alzheimer disease is addressed separately in evidence review 6.01.55.

Regulatory Status

Multiple software packages for performing proton MRS have been cleared for marketing 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.

RATIONALE

The evidence review was created in April 2000 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through August 13, 2024.

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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1 

Brain Tumors

Clinical Context and Test Purpose

The purpose of magnetic resonance spectroscopy (MRS) in individuals with brain tumors is to differentiate malignant from nonmalignant tumors, evaluate tumor grade, and distinguish metastatic from primary brain tumors.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals being evaluated for brain tumors.

Interventions

The intervention of interest is MRS.

Comparators

The following practice is currently being used to make decisions about managing brain tumors: standard evaluation with magnetic resonance imaging (MRI).

Outcomes

The outcomes of interest are sensitivity and specificity and the impact of the diagnosis on health outcomes. The time of interest is at biopsy, surgical resection, or clinical follow-up.

Study Selection Criteria

For the evaluation of the clinical validity of the tests, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores);

• Included a suitable reference standard;

• Patient/sample clinical characteristics were described;

• Patient/sample selection criteria were described;

• Included a validation cohort separate from development cohort.

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).

Review of Evidence

Systematic Reviews

Wang et al (2014) reported on a meta-analysis of 24 studies (615 cases, 408 controls) assessing the diagnostic performance of MRS for detecting or grading of brain tumors.^4, Twenty-two studies assessed gliomas, and 2 studies assessed ependymomas and primitive neuroectodermal tumors. Seven studies evaluated recurrence, 9 evaluated the tumor grade, 5 evaluated the detection of tumors, 1 evaluated residual tumors, and 2 assessed 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 curve was 0.78.

Complementary Magnetic Resonance Spectroscopy

Hellstrom et al (2018) 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 individuals.^5, Data are summarized in Table 1. No statistically significant difference was found between MRI and MRI + MRS (p=.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.

Table 1. Clinical Validity Results for MRI vs MRI+MRS

MRI: magnetic resonance imaging; MRS: magnetic resonance spectroscopy.Data adapted from Hellstrom et al (2018).5, 

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, pilocytic astrocytoma, and ependymomas.

Manias et al (2019) prospectively evaluated children with brain lesions aged 16 years and under (N=51) between December 2015 and 2017 via MRI and single-voxel MRS, blinded to histopathology.^6, MRS spectra were obtained in 47/51 eligible children, 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 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=.035) and a significant increase in interrater agreement (p=.046). Children were managed without conclusive histopathology in 25% of cases.

Manias et al (2018) reported on a multicenter U.K. study that retrospectively evaluated MRS for the noninvasive diagnosis of brain tumors.^7, 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 (2018) 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.^8,

Combined MRI and MRS to diagnose the type of pediatric brain tumors were reported by Shiroishi et al (2015) in a study from multiple children's hospitals in the U.S.^9, MRI and MRS were performed in 120 children as part of the usual presurgical workup, followed by biopsy or resection. For the first 60 children (from 2001 to 2004), MRS was performed but was 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 children 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 did not differ significantly from the first MRI reading. These results were compared with blinded diagnosis using MRI plus MRS (87% correct, p<.05). For the second group of 60 children who were diagnosed using MRI plus MRS, tumor type was correctly identified in 87% of patients (p<.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.

Vicente et al (2013) reported on a multicenter study that evaluated the ability of MRS to differentiate 78 histologically confirmed pediatric brain tumors (29 medulloblastomas, 11 ependymomas, 38 pilocytic astrocytomas).^10, Significant metabolic differences in tumor types were identified by MRS when results from short and long echo times were combined, suggesting that MRS might provide noninvasive diagnostic information. MRS has also been evaluated as a prognostic tool.

In another study, Wilson et al (2013) reported on single-voxel, proton MRS to predict survival in 115 children with pediatric brain tumors who were followed for a median of 35 months.^11, Poor survival was associated with lipids and scyllo-inositol while glutamine and N-acetylaspartate (NAA) were associated with improved survival (p<.05).

Diagnosis of Isocitrate Dehydrogenase Mutant Glioma

A systematic review and meta-analysis of 460 individuals with stage II-IV glioma by Suh et al (2018) 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.^12, 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 to 98%) and 91% (95% CI, 83 to 96%), respectively.

Andronesi et al (2018) 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).^13, Eight individuals were enrolled, and data from 5 patients were available for tumor 2HG level analysis at baseline and following 1 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 clinical outcomes were not reported in the present study. Furthermore, the authors acknowledge that recent preclinical data have failed to show an effect on tumor growth with mutant IDH1 inhibitors. Importantly, individuals with mutant IDH1 have significantly longer survival compared to individuals with wild-type IDH1, therefore the value of mutant IDH1 treatment and response monitoring is currently unclear.

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 (N=455).^14, 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 by Amin et al (2012).^15, 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 9 cases of recurrence and were more accurate with SPECT. The specificity and positive predictive value were 100% in both MRS and SPECT; however, the 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 was 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 (N=228) evaluating the diagnostic performance of MRS in differentiating high- from low-grade gliomas.^16, 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 (2018) only noted a significant difference for the Cho/NAA ratio, with a sensitivity and specificity of 61.54% and 86.36%, respectively.^17,

A systematic review conducted by Bhandari et al (2021) 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).^18, Although the systematic review conducted by Suh et al (2018)^12, described above found 2HG MRS for prediction of gliomas with IDH mutations associated with high sensitivity and specificity, results were not stratified according to glioma grade. IDH mutations are found in about 80% of low-grade gliomas, but only about 5% of glioblastomas.

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.

Gauging Treatment Response

The possibility of using MRS to track treatment response and failure has been explored. A small (n=16), preliminary study by Sankar et al (2008) assessed tamoxifen treatment for recurrent gliomas and found MRS patterns differed between responders and nonresponders.^19, 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 dynamic contrast-enhanced (DCE) MRI (DCE-MRI), diffusion-weighted MRI, and fluorine 18 fluorodeoxyglucose positron emission tomography. Other studies are needed, including those comparing modalities or evaluating multimodalities.^20,21,

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, more effective therapy, or avoid unnecessary therapy or 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.^7, The prospective study by Manias et al (2019; discussed above) reported that 25% of patients were managed without a conclusive histopathological diagnosis.^6,

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 the 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 offered limited information on the specific MRS spectra associated with the different tumor types. Prospective studies are needed to better define the spectra associated with tumor characteristics, to evaluate the diagnostic accuracy, and to determine the effect on health outcomes.

Population Reference No. 2 

Breast Cancer

Clinical Context and Test Purpose

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

The following PICO was used to select literature to inform this review.

Populations

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

Interventions

The intervention of interest is MRS.

Comparators

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

Outcomes

The outcomes of interest are sensitivity and specificity and the effect on health outcomes. The time of interest is at biopsy, surgical resection, or clinical follow-up.

Study Selection Criteria

For the evaluation of the clinical validity of the tests, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described

• Included a validation cohort separate from development cohort.

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).

Review of Evidence

Diagnosis of Breast Cancer

Billy et al (2023) conducted a systematic review and meta-analysis on the diagnostic accuracy of diffusion weighted imaging (DWI) compared to MRS in differentiating between benign and malignant breast lesions.^22, Eight studies with 632 individuals and 687 breast lesions were included. The sensitivity and specificity of DWI (8 studies, 627 breast lesions) were 92% (95% CI: 85% to 96 %) and 88% (95% CI: 75% to 94%), respectively. The sensitivity and specificity of MRS (8 studies, 685 breast lesions) were 85% (95% CI: 66% to 94 %) and 85% (95% CI: 77% to 91%), respectively. No significant difference was noted in the sensitivity or specificity between DWI and MRS. The authors noted there was a risk of bias due to insufficient methodological reporting and substantial heterogeneity.

Baltzer et al (2013) conducted a systematic review and meta-analysis of 19 studies on MRS for detecting benign versus malignant breast lesions.^22,The studies included 1,183 individuals with 452 benign and 773 malignant lesions. In the pooled estimates, the sensitivity of MRS was 73% (556/761; 95% CI, 64% to 82%) and the specificity was 88% (386/439; 95% CI, 85% to 91%). The area under the receiver operating characteristic curve for MRS detecting breast cancers versus benign lesions was 0.88. There was significant heterogeneity between studies and evidence of publication bias.

Treatment Response

Bayoumi et al (2019) 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.^23, Individuals 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 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.

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.

Population Reference No. 3 

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 following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients 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.

Study Selection Criteria

For the evaluation of the clinical validity of the tests, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described

• Included a validation cohort separate from development cohort.

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).

Review of Evidence

Systematic Reviews

A meta-analysis by Cai et al (2019) reviewed 19 studies utilizing MRS imaging for the diagnosis of prostate cancer.^24, 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.^25, In these studies, the patients had a suspicion of prostate cancer due to elevated prostate-specific antigen levels, despite a previous negative biopsy. Characteristics and results of these reviews are summarized in Tables 2 and 3.

Table 2. SR & M-A Characteristics for Prostate Cancer

M-A: meta-analysis; MRI: magnetic resonance imaging; MRS: magnetic resonance spectroscopy; NR: not reported; PC: prostate cancer; PSA: prostate-specific antigen; SR: systematic review.1 Key eligibility criteria.

Table 3. SR & M-A Results for Prostate Cancer

CI: confidence interval; M-A: meta-analysis; MRI: magnetic resonance imaging; MRS: magnetic resonance spectroscopy; NPV: negative predictive value; NR: not reported; PPV: positive predictive value; SR: systematic review.

Randomized Controlled Trials

A single-institution RCT published by Sciarra et al (2010) compared a second randomly selected biopsy (group A) with a biopsy selected partly based on MRS and DCE-MRI results (group B).^26,Study inclusion criteria required an elevated prostate-specific antigen level (between 4 ng/mL 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 and 45.5% of group B. Fifty individuals from group A with 2 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 also aligned with the suspicious areas detected on imaging. Given the concerns about potential overtreatment among individuals with early-stage prostate cancer, the benefits of detecting these additional cancers must be evaluated by examining clinical outcomes. In a similar report from the same institution and author group, 150 individuals with a negative prostate biopsy, despite prostate-specific antigen elevations, were randomized to MRS or MRS plus DCE-MRI to locate prostate cancer foci for a second targeted biopsy^27, (see also Panebianco et al [2012]^28,). Characteristics, results, and limitations of these studies are summarized in Tables 4 to 7.

Table 4. Summary of Key Prostate Cancer Trial Characteristics

DCE-MRI: dynamic contrast-enhanced magnetic resonance imaging; MRS: magnetic resonance spectroscopy; NR: not reported; PSA; prostate-specific antigen; RCT: randomized controlled trial.1 Number randomized; intervention; mode of delivery; dose (frequency/duration).2 Key eligibility criteria

Table 5. Summary of Key Prostate Cancer Trial Results

CI: confidence interval; DCE-MRI: dynamic contrast-enhanced magnetic resonance imaging; MRS: magnetic resonance spectroscopy; NR: not reported.

Table 6. Study Relevance Limitations

DRE: digital rectal examination.The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 7. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. No intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

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, more effective therapy, or avoid unnecessary therapy or 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 monitoring of individuals with prostate cancer, the cumulative evidence remains uncertain. Data comparing the diagnostic accuracy of MRS with alternative imaging strategies are limited. Additionally, the impact of MRS imaging compared with other imaging strategies on clinical management and health outcomes is unknown.

Population Reference No. 4 

Dementia

Clinical Context and Test Purpose

The purpose of MRS in individuals with dementia is to improve the diagnosis and management of dementia.

The following PICO was used to select literature to inform this review.

Populations

The relevant populations of interest is individuals being evaluated for dementia.

Interventions

The intervention of interest is MRS. Use of positron emission tomography (PET) in Alzheimer disease is addressed separately in evidence review 6.01.55.

Comparators

The following practice is currently being used to make decisions about managing dementia: observation.

Outcomes

The outcomes of interest are sensitivity and specificity and the effect on health outcomes. The time of interest is at the initial evaluation or at clinical follow-up.

Study Selection Criteria

For the evaluation of the clinical validity of the tests, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores);

• Included a suitable reference standard;

• Patient/sample clinical characteristics were described;

• Patient/sample selection criteria were described;

• Included a validation cohort separate from development cohort.

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).

Review of Evidence

Systematic Reviews

Piersson et al (2020) 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.^29, 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 NAA/mI and decreased NAA/Cr was associated with increased tau levels. NAA and glutathione levels are reduced in apolipoprotein E (APOE) ε4 carriers. The authors concluded that large, longitudinal studies are necessary to elucidate the effect of APOE ε4 on brain metabolites.

In a review, Zhang et al (2014) identified 30 studies since 2007 on low-field (<1.5 tesla) MRS and 27 studies on high-field (>3.0 tesla) MRS that compared results from individuals with AD, mild cognitive impairment (MCI), and healthy controls.^30, While metabolite changes are heterogeneous across brain regions, most studies focused on detecting changes in individual metabolites or their ratios. Reviewers concluded that to characterize AD-associated with neurochemical changes effectively, future approaches should interactively analyze multiple quantifiable metabolites from different brain regions.

Tumati et al (2013) conducted a systematic review and meta-analysis of 29 studies on MRS for MCI.^31, Included in the analysis were 607 MCI patients and 862 healthy controls. Patterns in metabolite concentration, including NAA, Cr, Cho, and myo-inositolin, were identified in various regions of the brain; they were associated with MCI. For example, levels of Cr 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, more effective therapy, or avoid unnecessary therapy or 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 does not support 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 on clinical management and health outcomes is unknown.

Population Reference No. 5 

Liver Disease

Clinical Context and Test Purpose

The purpose of MRS in individuals with liver disease is to improve the diagnosis and management of liver disease.

The following PICO was used to select literature to inform this review.

Populations

The relevant populations of interest is individuals being evaluated for liver disease.

Interventions

The intervention of interest is MRS.

Comparators

The following practice is currently being used to make decisions about managing liver disease: liver biopsy.

Outcomes

The outcomes of interest are sensitivity and specificity and the effect on health outcomes. The time of interest is at the initial evaluation or at clinical follow-up.

Study Selection Criteria

For the evaluation of the clinical validity of the tests, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores);

• Included a suitable reference standard;

• Patient/sample clinical characteristics were described;

• Patient/sample selection criteria were described;

• Included a validation cohort separate from development cohort.

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).

Review of Evidence

Diagnostic Accuracy Studies

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, dual-gradient echo MRI (DGE-MRI), and ultrasonography with liver biopsy as the reference standard. 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, with a sensitivity and specificity of 90.9% and 94%, respectively^32, (see also Taouli et al [2009]^33,).

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, more effective therapy, or avoid unnecessary therapy or 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 MRS for assessment of hepatic steatosis.

Population Reference No. 6 

Multiple Sclerosis

Clinical Context and Test Purpose

The purpose of MRS in individuals with multiple sclerosis (MS) is to improve the diagnosis and management of MS.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals being evaluated for MS.

Interventions

The intervention of interest is MRS.

Comparators

The following practice is currently being used to make decisions about managing MS: observation.

Outcomes

The outcomes of interest are sensitivity and specificity and the effect on health outcomes. The time of interest is at the initial evaluation or at clinical follow-up.

Study Selection Criteria

For the evaluation of the clinical validity of the tests, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores);

• Included a suitable reference standard;

• Patient/sample clinical characteristics were described;

• Patient/sample selection criteria were described;

• Included a validation cohort separate from development cohort.

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).

Review of Evidence

Non-Randomized Studies

MS is a chronic disease with variable prognosis and clinical course. Predictors of future disease course might help select individuals who would benefit most from disease-modifying treatments.^35,

Solanky et al (2020) published a cross-sectional analysis of 119 individuals with secondary-progressive MS recruited from the MS-Secondary Progressive Multi-Arm Randomization Trial (MS-SMART).^36, 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 N-acetyl-aspartate (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.

John et al (2023) published a longitudinal analysis of individuals with secondary-progressive MS (N=108) recruited from the MS-SMART trial.^37, They found that in the placebo group, total choline (tCho) increased in gray matter (mean difference = -0.32 institutional units [IU]) but decreased in normal appearing white matter (NAWM) (mean difference = 0.13 IU) over 96 weeks. Fluoxetine was associated with lower myo-inositol/total creatine (mIns/tCr) (β = -0.21; 95% CI: -0.40 to -0.02) in NAWM, while riluzole reduced glutamate + glutamine (Glx) (β = -0.25; 95% CI: -0.47 to -0.04) and Glx/tCr (β = -0.29; 95% CI: -0.50 to -0.08) in gray matter. Baseline total tNAA (β = 0.22; 95% CI: 0.02 to 0.41) and tNAA/tCr (β = 0.23; 95% CI: 0.5 to 0.42) in NAWM were associated with better 9HPT scores at 96 weeks. The authors noted several methodological limitations of the study, and stated therefore the results are reported as estimates, not absolute concentrations.

Llufriu et al (2014) published a study assessing the use of MRS in a preliminary data set of 59 individuals with MS and 43 healthy controls, and in a confirmatory independent data set of 220 individuals.^38, Change in brain volume and measures of disability were obtained annually. The myo-inositol to NAA ratio in the normal-appearing white matter was found to be a predictor of brain volume change over 4 years (p=.02) and of clinical disability (eg, a decrease in the Multiple Sclerosis Functional Composite evolution scale of -0.23 points annually, p=.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, more effective therapy, or avoid unnecessary therapy or 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 research is needed that includes larger cohorts with progressive MS, serial measurements of outcomes, and complementary measures of disease activity.^34,

Population Reference No. 7 

Psychiatric Disorders

Clinical Context and Test Purpose

The purpose of MRS in individuals with psychiatric disorders is to improve the diagnosis and management of psychiatric disorders.

The following PICO was used to select literature to inform this review.

Populations

The relevant populations of interest are individuals being evaluated for psychiatric disorders.

Interventions

The intervention of interest is MRS.

Comparators

The following practices are currently being used to make decisions about diagnosing and managing psychiatric disorders: standard care (eg, unstructured clinical interview and observation) or structured clinical interviews (ie, application of Diagnostic and Statistical Manual of Mental Disorders, 5th Edition [DSM-5] criteria).

Outcomes

The outcomes of interest are sensitivity and specificity and the effect on health outcomes. The time of interest is at the initial evaluation or at clinical follow-up.

Study Selection Criteria

For the evaluation of the clinical validity of the tests, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores);

• Included a suitable reference standard;

• Patient/sample clinical characteristics were described;

• Patient/sample selection criteria were described;

• Included a validation cohort separate from development cohort.

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).

Review of Evidence

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.^{37,38,39,40,41,42,43,44,45,46,47,}

Prospective Studies

Henigsberg et al (2019) evaluated 48 individuals with unipolar depression from recovery onset until recurrence of depression or until discontinuation of antidepressant maintenance therapy.^48, Depressive symptom remission was confirmed with a Montgomery-Asberg rating Scale (MADRS) score ≤10. 1H MRS scans were performed at the onset of recovery and after 6 months. N-acetylaspartate, Cho, and glutamine/glutamate and GABA metabolic spectra were obtained from the left amygdala region. Individuals were evaluated with psychiatric interviews and MADRS assessments during the study period at regular intervals of 6 months or less, for up to 7 years. Twenty patients experienced recurrence, 23 individuals achieved antidepressant discontinuation, and follow-up data was missing for 5 individuals. Cho levels at the beginning of recovery and subsequent changes conveyed the highest risk for earlier recurrence. Individuals with higher amygdala Cho after recovery were found to be at significantly lower risk for depression recurrence (hazard ratio [HR] 0.32; 95% CI, 0.13 to 0.77). Study participants were managed on various antidepressant medications, and criteria for antidepressant discontinuation were unclear.

Godlewska et al (2019) published a study assessing the use of MRS to track and predict treatment response to lamotrigine in 21 individuals with bipolar depression.^49, Before starting lamotrigine and after 10 to 12 weeks of treatment, patients underwent MRS scanning to determine levels of glutamate (Glx) in the anterior cingulate cortex. Baseline levels of Glx did not predict response to lamotrigine (p=.49). Responders to lamotrigine showed a significant increase in Glx levels from baseline (p=.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.

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, more effective therapy, or avoid unnecessary therapy or 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: Psychiatric Disorders

Although a number of studies have examined the use of MRS for identifying and understanding psychiatric disorders, the present evidence does not support any role for MRS outside of the research setting. Numerous methodologies for the use of MRS in this setting have been described, with inconsistent diagnostic validity results. Additionally, preliminary studies have thus far failed to demonstrate the successful application of MRS for the prediction of treatment response. Furthermore, the impact of MRS on health outcomes for this indication is unknown.

Other Indications

MRS has also been evaluated for other uses, such as tracking disease changes among patients with systemic lupus erythematosus,^50, assessing carotid plaque morphology,^51, identifying biomarkers of traumatic brain injury,^52,53, and predicting long-term neurodevelopmental outcome after neonatal encephalopathy.^54,55,56,57, MRS has also been used to evaluate pediatric patients with seizures,^58, and other applications in children.^59, Additional evidence on these applications is needed.

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 versus necrosis. Most studies included in the meta-analyses were small, retrospective, and used various ratios of MRS spectra. The largest prospective studies found that combining MRS with MRI resulted in a greater percentage of correct diagnoses of pediatric brain tumor type. These reports had limited information on the specific MRS spectra associated with 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have breast cancer, prostate cancer, dementia, liver disease, MS, or psychiatric disorders who receive MRS, the evidence includes prospective studies on diagnostic accuracy and systematic reviews. Relevant outcomes are test accuracy, change in disease status, morbid events, and functional outcomes. A number of studies have examined the use of MRS for localized prostate cancer for biopsy, for diagnosis, and for the monitoring of patients with prostate cancer. However, the cumulative evidence remains uncertain. Data comparing the diagnostic accuracy of MRS with alternative imaging strategies are limited. A systematic review of MRS to identify dementia concluded that to characterize AD-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 indicated that dual-gradient echo MRI outperforms MRS. Data on the use of MRS in MS has indicated that the measure is not sufficiently reliable to predict the future disease course. Research assessing MRS for the management of bipolar disorder has thus far failed to demonstrate its ability to predict treatment response. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Association of Neurological Surgeons and Congress of Neurological Surgeons

The American Association of Neurological Surgeons and Congress of Neurological Surgeons (2015) gave a level III recommendation (reflecting unclear clinical certainty) 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.^65,

American College of Radiology et al

The American College of Radiology, American Society of Neuroradiology, and Society for Pediatric Radiology (2019) updated their joint practice parameters on MRS of the central nervous system.^66, Most of the update addressed the actual performance of MRS, but it also listed 25 possible indications for MRS when magnetic resonance imaging or computed tomography is inadequate for answering specific clinical questions.

MRS of the head without IV contrast is considered "usually not appropriate" in dementia (including cognitive decline and suspected Alzheimer disease), head trauma in adults and children, movement disorders, and neurodegenerative diseases.^67,

Congress of Neurological Surgeons

The Congress of Neurological Surgeons (2016) published an evidence-based guideline on preoperative imaging assessment of patients with suspected nonfunctioning pituitary adenomas.^68, The Congress found that although the results were promising, there was insufficient evidence to recommend the use of MRS formally.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) clinical guidelines on central nervous system cancers ( v.2.2024) identifies magnetic resonance spectroscopy (MRS) as 1 of several modalities that can be considered to rule out radiation necrosis, as compared with recurrence of brain tumors.^69, 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.

The NCCN clinical guidelines on prostate cancer ( v.4.2024) list MRS as an advanced imaging technique but make no recommendations for its use.^70,

The NCCN clinical guidelines on breast cancer ( v.4.2024) do not mention MRS.^71,

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence (NICE) guidance on primary brain tumors and brain metastases in adults, updated in 2021, includes the following recommendations regarding the use of MRS:^72,

• In patients undergoing imaging for suspected glioma, advanced magnetic resonance imaging (MRI) techniques, such as MR perfusion and MRS may be considered to assess the potential of a high-grade transformation in a tumor appearing to be low grade on standard structural MRI.

• In patients undergoing follow-up for glioma or brain metastases, advanced MRI techniques such as MR perfusion, diffusion tensor imaging and MRS may be considered if findings from standard imaging are unclear regarding whether there is recurrence and early identification is potentially clinically useful.

The NICE guidance on Parkinson's disease in adults, published in 2017, states that MRS should not be used in the differential diagnosis of parkinsonian syndromes.^73,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 8.

Table 8. Summary of Key Trials

NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial. 

References

1. Sibtain NA, Howe FA, Saunders DE. The clinical value of proton magnetic resonance spectroscopy in adult brain tumours. Clin Radiol. Feb 2007; 62(2): 109-19. PMID 17207692
2. Julià-Sapé M, Griffiths JR, Tate AR, et al. Classification of brain tumours from MR spectra: the INTERPRET collaboration and its outcomes. NMR Biomed. Dec 2015; 28(12): 1772-87. PMID 26768492
3. Sood S, Gupta A, Tsiouris AJ. Advanced magnetic resonance techniques in neuroimaging: diffusion, spectroscopy, and perfusion. Semin Roentgenol. Apr 2010; 45(2): 137-46. PMID 20171345
4. Wang W, Hu Y, Lu P, et al. Evaluation of the diagnostic performance of magnetic resonance spectroscopy in brain tumors: a systematic review and meta-analysis. PLoS One. 2014; 9(11): e112577. PMID 25393009
5. Hellström J, Romanos Zapata R, Libard S, et al. The value of magnetic resonance spectroscopy as a supplement to MRI of the brain in a clinical setting. PLoS One. 2018; 13(11): e0207336. PMID 30440005
6. Manias KA, Gill SK, MacPherson L, et al. Diagnostic accuracy and added value of qualitative radiological review of 1 H-magnetic resonance spectroscopy in evaluation of childhood brain tumors. Neurooncol Pract. Dec 2019; 6(6): 428-437. PMID 31832213
7. Manias K, Gill SK, Zarinabad N, et al. Evaluation of the added value of 1 H-magnetic resonance spectroscopy for the diagnosis of pediatric brain lesions in clinical practice. Neurooncol Pract. Mar 2018; 5(1): 18-27. PMID 29692921
8. Manias KA, Harris LM, Davies NP, et al. Prospective multicentre evaluation and refinement of an analysis tool for magnetic resonance spectroscopy of childhood cerebellar tumours. Pediatr Radiol. Oct 2018; 48(11): 1630-1641. PMID 30062569
9. Shiroishi MS, Panigrahy A, Moore KR, et al. Combined MRI and MRS improves pre-therapeutic diagnoses of pediatric brain tumors over MRI alone. Neuroradiology. Sep 2015; 57(9): 951-6. PMID 26141852
10. Vicente J, Fuster-Garcia E, Tortajada S, et al. Accurate classification of childhood brain tumours by in vivo ¹H MRS - a multi-centre study. Eur J Cancer. Feb 2013; 49(3): 658-67. PMID 23036849
11. Wilson M, Cummins CL, Macpherson L, et al. Magnetic resonance spectroscopy metabolite profiles predict survival in paediatric brain tumours. Eur J Cancer. Jan 2013; 49(2): 457-64. PMID 23036848
12. Suh CH, Kim HS, Jung SC, et al. 2-Hydroxyglutarate MR spectroscopy for prediction of isocitrate dehydrogenase mutant glioma: a systemic review and meta-analysis using individual patient data. Neuro Oncol. Nov 12 2018; 20(12): 1573-1583. PMID 30020513
13. Andronesi OC, Arrillaga-Romany IC, Ly KI, et al. Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate. Nat Commun. Apr 16 2018; 9(1): 1474. PMID 29662077
14. Zhang H, Ma L, Wang Q, et al. Role of magnetic resonance spectroscopy for the differentiation of recurrent glioma from radiation necrosis: a systematic review and meta-analysis. Eur J Radiol. Dec 2014; 83(12): 2181-2189. PMID 25452098
15. Amin A, Moustafa H, Ahmed E, et al. Glioma residual or recurrence versus radiation necrosis: accuracy of pentavalent technetium-99m-dimercaptosuccinic acid [Tc-99m (V) DMSA] brain SPECT compared to proton magnetic resonance spectroscopy (1H-MRS): initial results. J Neurooncol. Feb 2012; 106(3): 579-87. PMID 21912937
16. Wang Q, Zhang H, Zhang J, et al. The diagnostic performance of magnetic resonance spectroscopy in differentiating high-from low-grade gliomas: A systematic review and meta-analysis. Eur Radiol. Aug 2016; 26(8): 2670-84. PMID 26471274
17. Lin MC, Li CZ, Hsieh CC, et al. Preoperative grading of intracranial meningioma by magnetic resonance spectroscopy (1H-MRS). PLoS One. 2018; 13(11): e0207612. PMID 30452483
18. Bhandari A, Sharma C, Ibrahim M, et al. The role of 2-hydroxyglutarate magnetic resonance spectroscopy for the determination of isocitrate dehydrogenase status in lower grade gliomas versus glioblastoma: a systematic review and meta-analysis of diagnostic test accuracy. Neuroradiology. Nov 2021; 63(11): 1823-1830. PMID 33811494
19. Sankar T, Caramanos Z, Assina R, et al. Prospective serial proton MR spectroscopic assessment of response to tamoxifen for recurrent malignant glioma. J Neurooncol. Oct 2008; 90(1): 63-76. PMID 18600428
20. Dhermain FG, Hau P, Lanfermann H, et al. Advanced MRI and PET imaging for assessment of treatment response in patients with gliomas. Lancet Neurol. Sep 2010; 9(9): 906-20. PMID 20705518
21. Harry VN, Semple SI, Parkin DE, et al. Use of new imaging techniques to predict tumour response to therapy. Lancet Oncol. Jan 2010; 11(1): 92-102. PMID 20129132
22. Billy CA, Darmiati S, Prihartono J. Diagnostic accuracy of diffusion weighted imaging compared to magnetic resonance spectroscopy in differentiation of benign and malignant breast lesions: A systematic review and meta-analysis. Eur J Radiol. Nov 2023; 168: 111124. PMID 37820523
23. Baltzer PA, Dietzel M. Breast lesions: diagnosis by using proton MR spectroscopy at 1.5 and 3.0 T--systematic review and meta-analysis. Radiology. Jun 2013; 267(3): 735-46. PMID 23468577
24. Bayoumi D, Zaky M, Ibrahim DA, et al. The additive role of 1 H-magnetic resonance spectroscopic imaging to ensure pathological complete response after neoadjuvant chemotherapy in breast cancer patients. Pol J Radiol. 2019; 84: e570-e580. PMID 32082456
25. Cai W, Zhu D, Byanju S, et al. Magnetic resonance spectroscopy imaging in diagnosis of suspicious prostate cancer: A meta-analysis. Medicine (Baltimore). Apr 2019; 98(14): e14891. PMID 30946315
26. Mowatt G, Scotland G, Boachie C, et al. The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation. Health Technol Assess. May 2013; 17(20): vii-xix, 1-281. PMID 23697373
27. Sciarra A, Panebianco V, Ciccariello M, et al. Value of magnetic resonance spectroscopy imaging and dynamic contrast-enhanced imaging for detecting prostate cancer foci in men with prior negative biopsy. Clin Cancer Res. Mar 15 2010; 16(6): 1875-83. PMID 20197480
28. Panebianco V, Sciarra A, Ciccariello M, et al. Role of magnetic resonance spectroscopic imaging ([¹H]MRSI) and dynamic contrast-enhanced MRI (DCE-MRI) in identifying prostate cancer foci in patients with negative biopsy and high levels of prostate-specific antigen (PSA). Radiol Med. Dec 2010; 115(8): 1314-29. PMID 20852963
29. Panebianco V, Sciarra A, Lisi D, et al. Prostate cancer: 1HMRS-DCEMR at 3T versus [(18)F]choline PET/CT in the detection of local prostate cancer recurrence in men with biochemical progression after radical retropubic prostatectomy (RRP). Eur J Radiol. Apr 2012; 81(4): 700-8. PMID 21330082
30. Piersson AD, Mohamad M, Rajab F, et al. Cerebrospinal Fluid Amyloid Beta, Tau Levels, Apolipoprotein, and 1 H-MRS Brain Metabolites in Alzheimer's Disease: A Systematic Review. Acad Radiol. Oct 2021; 28(10): 1447-1463. PMID 32651050
31. Zhang N, Song X, Bartha R, et al. Advances in high-field magnetic resonance spectroscopy in Alzheimer's disease. Curr Alzheimer Res. May 2014; 11(4): 367-88. PMID 24597505
32. Tumati S, Martens S, Aleman A. Magnetic resonance spectroscopy in mild cognitive impairment: systematic review and meta-analysis. Neurosci Biobehav Rev. Dec 2013; 37(10 Pt 2): 2571-86. PMID 23969177
33. Lee SS, Park SH, Kim HJ, et al. Non-invasive assessment of hepatic steatosis: prospective comparison of the accuracy of imaging examinations. J Hepatol. Apr 2010; 52(4): 579-85. PMID 20185194
34. Taouli B, Ehman RL, Reeder SB. Advanced MRI methods for assessment of chronic liver disease. AJR Am J Roentgenol. Jul 2009; 193(1): 14-27. PMID 19542391
35. Miller DH. Magnetic resonance spectroscopy: a possible in vivo marker of disease progression for multiple sclerosis?. JAMA Neurol. Jul 01 2014; 71(7): 828-30. PMID 24842800
36. Solanky BS, John NA, DeAngelis F, et al. NAA is a Marker of Disability in Secondary-Progressive MS: A Proton MR Spectroscopic Imaging Study. AJNR Am J Neuroradiol. Dec 2020; 41(12): 2209-2218. PMID 33154071
37. John NA, Solanky BS, De Angelis F, et al. Longitudinal Metabolite Changes in Progressive Multiple Sclerosis: A Study of 3 Potential Neuroprotective Treatments. J Magn Reson Imaging. Jun 2024; 59(6): 2192-2201. PMID 37787109
38. Llufriu S, Kornak J, Ratiney H, et al. Magnetic resonance spectroscopy markers of disease progression in multiple sclerosis. JAMA Neurol. Jul 01 2014; 71(7): 840-7. PMID 24839987
39. Fervaha G, Remington G. Neuroimaging findings in schizotypal personality disorder: a systematic review. Prog Neuropsychopharmacol Biol Psychiatry. Jun 03 2013; 43: 96-107. PMID 23220094
40. Chitty KM, Lagopoulos J, Lee RS, et al. A systematic review and meta-analysis of proton magnetic resonance spectroscopy and mismatch negativity in bipolar disorder. Eur Neuropsychopharmacol. Nov 2013; 23(11): 1348-63. PMID 23968965
41. Fisher E, Gillam J, Upthegrove R, et al. Role of magnetic resonance spectroscopy in cerebral glutathione quantification for youth mental health: A systematic review. Early Interv Psychiatry. Apr 2020; 14(2): 147-162. PMID 31148383
42. Moriguchi S, Takamiya A, Noda Y, et al. Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Mol Psychiatry. Jul 2019; 24(7): 952-964. PMID 30315224
43. Quadrelli S, Mountford C, Ramadan S. Systematic review of in-vivo neuro magnetic resonance spectroscopy for the assessment of posttraumatic stress disorder. Psychiatry Res Neuroimaging. Dec 30 2018; 282: 110-125. PMID 30097168
44. Pruett BS, Meador-Woodruff JH. Evidence for altered energy metabolism, increased lactate, and decreased pH in schizophrenia brain: A focused review and meta-analysis of human postmortem and magnetic resonance spectroscopy studies. Schizophr Res. Sep 2020; 223: 29-42. PMID 32958361
45. Truong V, Cheng PZ, Lee HC, et al. Occipital gamma-aminobutyric acid and glutamate-glutamine alterations in major depressive disorder: An mrs study and meta-analysis. Psychiatry Res Neuroimaging. Feb 28 2021; 308: 111238. PMID 33385764
46. Sydnor VJ, Roalf DR. A meta-analysis of ultra-high field glutamate, glutamine, GABA and glutathione 1HMRS in psychosis: Implications for studies of psychosis risk. Schizophr Res. Dec 2020; 226: 61-69. PMID 32723493
47. Wang YM, Xiao YH, Xie WL. Metabolite abnormalities in psychosis risk: A meta-analysis of proton magnetic resonance spectroscopy studies. Asian J Psychiatr. Dec 2020; 54: 102220. PMID 32653847
48. Smucny J, Carter CS, Maddock RJ. Medial Prefrontal Cortex Glutamate Is Reduced in Schizophrenia and Moderated by Measurement Quality: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies. Biol Psychiatry. Nov 01 2021; 90(9): 643-651. PMID 34344534
49. Nakahara T, Tsugawa S, Noda Y, et al. Glutamatergic and GABAergic metabolite levels in schizophrenia-spectrum disorders: a meta-analysis of 1 H-magnetic resonance spectroscopy studies. Mol Psychiatry. Jan 2022; 27(1): 744-757. PMID 34584230
50. Maximo JO, Briend F, Armstrong WP, et al. Higher-order functional brain networks and anterior cingulate glutamate + glutamine (Glx) in antipsychotic-naïve first episode psychosis patients. Transl Psychiatry. Apr 10 2024; 14(1): 183. PMID 38600117
51. Saccaro LF, Tassone M, Tozzi F, et al. Proton magnetic resonance spectroscopy of N-acetyl aspartate in first depressive episode and chronic major depressive disorder: A systematic review and meta-analysis. J Affect Disord. Jun 15 2024; 355: 265-282. PMID 38554884
52. Henigsberg N, Savić A, Radoš M, et al. Choline elevation in amygdala region at recovery indicates longer survival without depressive episode: a magnetic resonance spectroscopy study. Psychopharmacology (Berl). May 2021; 238(5): 1303-1314. PMID 31482202
53. Godlewska BR, Emir UE, Masaki C, et al. Changes in brain Glx in depressed bipolar patients treated with lamotrigine: A proton MRS study. J Affect Disord. Mar 01 2019; 246: 418-421. PMID 30599363
54. Zimny A, Szmyrka-Kaczmarek M, Szewczyk P, et al. In vivo evaluation of brain damage in the course of systemic lupus erythematosus using magnetic resonance spectroscopy, perfusion-weighted and diffusion-tensor imaging. Lupus. 2014; 23(1): 10-9. PMID 24192079
55. Hermus L, Tielliu IF, Wallis de Vries BM, et al. Imaging the vulnerable carotid artery plaque. Acta Chir Belg. 2010; 110(2): 159-64. PMID 20514826
56. Kou Z, Wu Z, Tong KA, et al. The role of advanced MR imaging findings as biomarkers of traumatic brain injury. J Head Trauma Rehabil. 2010; 25(4): 267-82. PMID 20611045
57. Gardner A, Iverson GL, Stanwell P. A systematic review of proton magnetic resonance spectroscopy findings in sport-related concussion. J Neurotrauma. Jan 01 2014; 31(1): 1-18. PMID 24047225
58. Thayyil S, Chandrasekaran M, Taylor A, et al. Cerebral magnetic resonance biomarkers in neonatal encephalopathy: a meta-analysis. Pediatrics. Feb 2010; 125(2): e382-95. PMID 20083516
59. Wilkinson D. MRI and withdrawal of life support from newborn infants with hypoxic-ischemic encephalopathy. Pediatrics. Aug 2010; 126(2): e451-8. PMID 20603255
60. van Laerhoven H, de Haan TR, Offringa M, et al. Prognostic tests in term neonates with hypoxic-ischemic encephalopathy: a systematic review. Pediatrics. Jan 2013; 131(1): 88-98. PMID 23248219
61. Zou R, Xiong T, Zhang L, et al. Proton Magnetic Resonance Spectroscopy Biomarkers in Neonates With Hypoxic-Ischemic Encephalopathy: A Systematic Review and Meta-Analysis. Front Neurol. 2018; 9: 732. PMID 30233483
62. Wu YW, Monsell SE, Glass HC, et al. How well does neonatal neuroimaging correlate with neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy?. Pediatr Res. Sep 2023; 94(3): 1018-1025. PMID 36859442
63. Rincon SP, Blitstein MB, Caruso PA, et al. The Use of Magnetic Resonance Spectroscopy in the Evaluation of Pediatric Patients With Seizures. Pediatr Neurol. May 2016; 58: 57-66. PMID 26948493
64. Yuh EL, Barkovich AJ, Gupta N. Imaging of ependymomas: MRI and CT. Childs Nerv Syst. Oct 2009; 25(10): 1203-13. PMID 19360419
65. Fouke SJ, Benzinger T, Gibson D, et al. The role of imaging in the management of adults with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline. J Neurooncol. Dec 2015; 125(3): 457-79. PMID 26530262
66. American College of Radiology (ACR), American Society of Neuroradiology (ASNR). ACR-ASNR-SPR practice parameter for the performance and interpretation of magnetic resonance spectroscopy of the central nervous system. 2019; https://www.acr.org/-/media/ACR/Files/Practice-Parameters/MR-Spectroscopy.pdf. Accessed August 22, 2024.
67. American College of Radiology (ACR). ACR Appropriateness Criteria: AC Portal. 2021; https://www.acr.org/Clinical-Resources/ACR-Appropriateness-Criteria. Accessed August 21, 2024.
68. Chen CC, Carter BS, Wang R, et al. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on Preoperative Imaging Assessment of Patients With Suspected Nonfunctioning Pituitary Adenomas. Neurosurgery. Oct 2016; 79(4): E524-6. PMID 27635958
69. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Accessed August 21, 2024.
70. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 4.2024. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed August 20, 2024.
71. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Breast Cancer. Version 4.2024. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed August 22, 2024.
72. National Institute for Health and Care Excellence (NICE). NICE Guidance: Brain tumours (primary) and brain metastases in adults [NG99]. 2021; https://www.nice.org.uk/guidance/ng99. Accessed August 22, 2024.
73. National Institute for Health and Care Excellence (NICE). NICE Guidance: Parkinson's disease in adults [NG71]. 2017; https://www.nice.org.uk/guidance/ng71. Accessed August 21, 2024.

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