Quantitative Electroencephalography as a Diagnostic Aid for Attention-Deficit/Hyperactivity Disorder
This testing would likely be reported with existing electroencephalography CPT codes. The clinician would report the appropriate code for electroencephalography (e.g., 95812-95813) and the code for digital analysis of electroencephalogram (95957) would be reported for the analysis.
Patients with attention-deficit/hyperactivity disorder (ADHD) may have alterations in their brain wave patterns that can be measured by quantitative electroencephalography (QEEG). A commercially available system, the Neuropsychiatric EEG-based ADHD Assessment Aid (NEBA®), measures the resting theta/beta ratio of the EEG. This technology is being evaluated to aid in the diagnosis of ADHD in adolescents and children for whom there is a clinical suspicion of ADHD.
ADHD is a common disorder in children, adolescents, and adults defined by pervasive symptoms of inattention and/or hyperactivity-impulsivity, which lead to impairment in at least 2 domains of the work, school, or home environments. Stimulant medications reduce symptoms associated with ADHD, although there are concerns about the potential for overdiagnosis and overprescribing of medication. Presently, ADHD is diagnosed clinically by assessing behavioral symptoms and impairment via interviews and standard questionnaires. Diagnosis can be challenging, as the core symptoms are nonspecific. They may be present in other psychiatric disorders (e.g., learning disabilities, conduct disorders, affective disorders) or result from environmental influences such as a lack of discipline. In addition, ADHD is a heterogeneous disorder with multiple subtypes, and frequently coexists with other psychiatric disorders.
There has been a substantial amount of research over the last several decades on whether EEG-derived brain wave patterns in patients with ADHD differ from those without ADHD. EEG patterns are typically categorized into 4 frequency ranges, delta (<4 Hz), theta (4-7 Hz), alpha (8-12 Hz), and beta (13-25 Hz). The largest focus of research on brain wave patterns in ADHD has been on whether there is increased theta wave activity and an increased theta/beta ratio in ADHD patients. The NEBA® system is a specific QEEG system that measures the resting theta/beta ratio of the EEG with an electrode located at the central midline position (referred to as position CZ in the international 10-20 EEG system). QEEG uses computer analysis with mathematical transformation from the time domain into the frequency domain (fast -Fourier transform) to determine the total power at each frequency. Relative power of the waveform can then be calculated in relation to the total power of the 4 frequency ranges. The NEBA system uses proprietary cutoffs to generate an estimate of the likelihood of ADHD based on the resting theta/beta ratio.
It is proposed that the NEBA system can be used to confirm a clinical diagnosis or support further testing in children and adolescents with ADHD. The system is not intended to evaluate patients in whom the clinician’s diagnosis of ADHD is negative, and the system does not generate an interpretive report in this situation. It is also proposed that the clinician’s diagnostic impression plus the results generated by the NEBA system may reduce the potential for overdiagnosis of ADHD, and thereby reduce the risks of administering unnecessary pharmacologic therapy in the intended use population. In addition, as a result of research on EEG brain waves in ADHD, neurofeedback has been developed as a potential treatment for ADHD (see policy No. 2.01.28). This treatment employs principles of biofeedback using EEG brain wave activity and attempts to alter the brain wave patterns in beneficial ways.
In 2011, FDA approved a de novo 510k classification (class II, special controls, product code: NCG) for the generic device: Neuropsychiatric Interpretive Electroencephalograph Assessment Aid. According to the FDA documentation, a Neuropsychiatric Interpretive Electroencephalograph Assessment Aid is a device prescribed by a physician that uses a patient’s EEG to provide an interpretation of the patient’s neuropsychiatric condition. In addition to the general controls, approval of these devices is subject to a number of special controls, including the following:
The Neuropsychiatric EEG-based Assessment Aid (NEBA®; Lexicor Medical Technology LLC, Augusta, GA) for ADHD was cleared for marketing in 2013 as a de novo device indicated to measure the theta/beta ratio of the EEG at electrode CZ on patients 6 to 17 years of age, combined with a clinician’s evaluation, to aid in the diagnosis of ADHD (K112711). NEBA should only be used by a clinician as confirmatory support for a completed clinical evaluation or as support for the clinician’s decision to pursue further testing following a clinical evaluation. The device is not intended to be used as a stand-alone in the evaluation or diagnosis of ADHD.
The Lexicor QEEG system is marketed as a diagnostic aid for ADHD. Lexicor Medical Technology provides an internet analysis service of the QEEG, producing a DataLex report. Lexicor Medical Technology also developed the NEBA system.
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Assessment of a diagnostic technology typically focuses on 3 domains: 1) technical performance (test-retest reliability or inter-rater reliability); 2) diagnostic accuracy (sensitivity, specificity, and positive and negative predictive value) in relevant populations of patients; and 3) demonstration that the diagnostic information can be used to improve patient outcomes. Subsequent use of a technology outside of the investigational setting may also be evaluated. These domains, although not always evaluated in sequence, can be considered similar to the 4 phases of therapeutic studies:
There are no published peer-reviewed studies that evaluate the accuracy of the commercially available device (NEBA) in the diagnosis of ADHD. The currently available evidence consists of studies that report quantitative electroencephalography (QEEG) results using standard EEG equipment and results of the pivotal FDA studies that led to approval of the NEBA system, which is available through the U.S. Food and Drug Administration (FDA) website and is included in this evidence review.
BCBSA TEC Assessment Overview
A Blue Cross and Blue Shield Association (BCBSA) TEC Assessment published in February 2014 evaluated the evidence related to the use of quantitative EEG in the diagnosis of ADHD, which made the following conclusions. (1) The authors identified no published peer-reviewed studies that evaluated the accuracy of the NEBA System in the diagnosis of ADHD. The evidence related to the technical performance of NEBA for the diagnosis of ADHD included data submitted to FDA including test-retest reliability of the NEBA theta/beta ratio for EEG data from 198 patients who had recordings on 2 different days. The intraclass correlation coefficient of repeated NEBA theta/beta ratio was 0.83. No reports were identified that measure the reliability of QEEG.
The evidence related to the diagnostic accuracy of NEBA for the diagnosis of ADHD consisted of data submitted to FDA from a multicenter study of 275 children and adolescents (6-18 years) who presented with attention and/or behavioral concerns to one of 13 clinics in the United States. Diagnostic evaluation for ADHD and other disorders was conducted with clinical interview and rating scales that included behavior rating scales, IQ and achievement testing, and scales of severity and dysfunction. The consensus diagnosis, which served as the reference standard, was determined by a multidisciplinary clinical team composed of a clinical psychologist, a neurodevelopmental pediatrician, and a child/adolescent psychiatrist, which had access to deidentified patient files but did not conduct interviews or have access to parent rating scales. When compared with the consensus diagnosis, the NEBA interpretation (NEBA plus initial clinical diagnosis) was found to have a sensitivity of 89% (95% confidence interval [CI], 73% to 96%), specificity of 87% (95% CI, 74% to 94%), positive predictive value (PPV) of 81% (95% CI, 64% to 91%), and negative predictive value (NPV) of 93% (95% CI, 81% to 98%) for adolescents (12-17 years). The TEC Assessment noted that the reference standard used in the evaluation was problematic.
The authors reported no studies that assessed whether the reclassification of patients with a clinical diagnosis of ADHD, as reported to FDA, improves diagnostic accuracy and health outcomes. The TEC Assessment determined that the use of quantitative EEG as a diagnostic aid for ADHD does not meet BCBSA TEC criteria.
What is the reliability of the NEBA system?
Data submitted to FDA included test-retest reliability of the NEBA theta/beta ratio for EEG data from 198 patients who had recordings on 2 different days (about 2.5 weeks apart on average). (2) The intraclass correlation coefficient of repeated NEBA theta/beta ratio was 0.83, which is considered to be high. In the published studies, there were no reports identified that measured the reliability of QEEG.
Do patients with ADHD have an increased theta/beta brainwave ratio when measured by quantitative EEG?
A number of studies have been published that measured theta activity or the theta/beta ratio in children and adolescents with ADHD compared to non-affected controls. The most commonly reported alteration in EEG is an increase in the theta/beta ratio. However, some studies have reported that other patterns such as increased beta wave activity are found in some patients, and several recent studies have found no significant difference in theta activity in a clinical vs. non-clinical population.
A 2005 systematic review included 17 studies evaluating theta activity in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). (3) Meta-analysis found a weighted mean effect size of 0.59 for an absolute increase in theta activity and a mean effect size of 0.91 for theta relative to total EEG activity. A 2006 systematic review by Snyder and Hall included 9 studies (n=1,498) that used DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) criteria and screening tests in a clinical setting.4 Meta-analysis identified a mean increase of theta power of 32% and a pooled effect size of 3.08 for the theta/beta ratio in patients with ADHD compared with unaffected children, adolescents, and adults. It was noted that the included studies often had retrospectively set limits and that an increase in the theta/beta ratio has also been identified in other conditions. In 2008, Snyder et al. reported a significant increase in the theta/beta ratio in patients with ADHD compared with other conditions when prospectively assessed with a predefined threshold. (5) A 2001 study by Monastra et al. found a change in QEEG at CZ in a large study (n=469) of children and adolescents who were diagnosed as ADHD versus controls, although this study used an attention index measured across 4 different tasks (eyes fixed, silent reading, listening, drawing). (6)
Other studies find no significant difference in theta activity in a clinical population with ADHD. For example, in 2013, Liechti et al. reported the theta/beta ratio in 32 children and 22 adults with ADHD compared with healthy controls who were matched for age, gender, and IQ. (7) Resting EEG was measured separately for the 3 midline electrodes (frontal [FZ], central [CZ], parietal [PZ]) and for frontal, central, and parietal regions. The study found a decrease in theta with age, but no consistent increase in theta or theta/beta ratio in patients with ADHD compared with controls. There was no evidence for a maturational lag in patients with ADHD. In 2012, Ogrim et al. assessed differences in theta activity measured at CZ in 62 children and adolescents with a tentative diagnosis of ADHD compared with 39 sex- and age-matched controls. (8) The overall accuracy at CZ was 63% for theta and 58% for the theta/beta ratio compared with non-affected controls. Elevations of theta were found in 25.8% of patients compared with 2.6% of controls. None of the EEG measures reached statistical significance in separating patients from controls. In other studies, subgroups of children with ADHD have been shown to have an increase of beta activity instead of a decrease in beta or increase in the theta/beta ratio. (9,10) In a study of QEEG in combination with the Connors’ Continuous Performance Test and the Test of Variables of Attention in the diagnosis of ADHD in 157 children, 85 with and 72 without ADHD based on Diagnostic Interview Schedule for Children (Version IV), Kim et al reported that the ADHD group had significantly higher values for theta waves in 13 positions, while for the theta/beta ratio, the ADHD group had higher values for only 1 position (right frontal lobe).11
What is the sensitivity, specificity and predictive value of the theta/beta ratio in the diagnosis of ADHD?
Data submitted to FDA regarding diagnostic accuracy were from a multicenter study of 275 children and adolescents (6-18 years) who presented with attention and/or behavioral concerns to one of 13 clinics in the United States. (2) Diagnostic evaluation for ADHD and other disorders was conducted with clinical interview and rating scales that included behavior rating scales, IQ and achievement testing, and scales of severity and dysfunction. A consensus best-estimated diagnosis was determined by a multidisciplinary clinical team composed of a clinical psychologist, a neurodevelopmental pediatrician, and a child/adolescent psychiatrist. The clinical team had access to de-identified patient files, but did not conduct an interview or have access to the parent rating scales, features which are considered critical for a criterion standard diagnosis of ADHD. A separate group of investigators who were unaware of the clinical diagnosis collected the EEG data (NEBA system). When compared with the consensus diagnosis, NEBA was found to have a sensitivity of 89%, specificity of 87%, PPV of 81% and NPV of 93% for adolescents (12-17 years). For children (6-11 years), NEBA had sensitivity of 79%, specificity of 97%, PPV of 96% and NPV of 82%.
Snyder et al. reported the accuracy of the theta/beta ratio for diagnosis of ADHD in an industry -sponsored, investigator-blinded, multicenter study from 2008. (5) Patients (n=159) aged 6 to 18 who had presented to 1 of 4 psychiatric and pediatric clinics with suspected attention and behavioral symptoms were evaluated in a standardized semi-structured manner according to DSM-IV criteria by a clinical team that had been trained on the study instruments. Rating scales were distributed to parents and teachers and held in sealed envelopes until the blind was broken. EEG was collected separately by investigators who were blinded to the clinical diagnosis, using a 19-electrode cap according to the 10-20 system with eyes open and eyes shut. A threshold of 1.5 SD of the theta/beta ratio from normative database values (according to age) at electrode CZ was used to determine ADHD versus non-ADHD. With a prevalence of ADHD of 61% based on clinical diagnosis, the theta/beta ratio had a sensitivity of 87%, specificity of 94%, PPV of 95% and NPV of 82%. The rating scales provided sensitivity of 38% to 79% and specificity of 13% to 61%.
Other studies have reported lower accuracy of QEEG in the diagnosis of ADHD. In the Kim et al study previously reported, on receiver operator curve analysis, QEEG theta wave amplitude showed low accuracy for the diagnosis of ADHD (56.4%), and theta/beta wave amplitude did not significantly predict ADHD diagnosis. (11) Sangal et al. evaluated the discriminatory power of QEEG measurements during auditory and visual tasks requiring selective attention in 28 control children and 58 children with ADHD.12 Subjects with ADHD had significantly higher average theta/beta ratios (2.6 vs 2.25; p=0.007) and lower average beta-I amplitudes (3.66 vs 4.22; p=0.01). The average theta/beta ratio had sensitivity and specificity in diagnosing ADHD of 69% and 50%, respectively, while the theta/beta ratio at the CZ position had sensitivity and specificity of 69% and 43%, respectively.
Patients with ADHD may have altered brain wave patterns on QEEG compared with patients without ADHD. While an increased theta/beta ratio is the most common alteration reported, not all studies have found this association, and some report other brain wave patterns in ADHD patients. A few studies report on sensitivity and specificity of quantitative EEG compared with clinical diagnosis. In these studies, sensitivity ranges from 69% to 89% and specificity ranges from 43% to 97%.
Effect on Clinical Outcomes
A proposed benefit of the NEBA system is a reduction in the overdiagnosis of ADHD, thereby reducing the risks of administering unnecessary pharmacologic therapy in children and adolescents. There were no published studies that directly reported on clinical outcomes, such as measures of disease activity and/or medication use. The pivotal FDA study reported reclassification of diagnosis following NEBA; this may be considered an indirect measure that may impact outcomes.
Can quantitative EEG accurately reclassify patients with an initial clinical diagnosis of ADHD into the correct diagnostic categories?
The evidence related to the question of whether QEEG improves the clinical diagnosis of patients with suspected ADHD consists of the material submitted to FDA as part of the NEBA’s approval process, as previously described. (2) The study included reclassification tables to demonstrate whether NEBA provides additional information beyond the clinician’s initial diagnosis, which are summarized in Table 1 based on the BCBSA TEC Assessment. (1) Use of NEBA resulted in little change in categorization for patients diagnosed with ADHD by both the initial clinical diagnosis and the consensus diagnosis. For example, 95 of 130 children and adolescents (73%) who were considered to have ADHD by the consensus diagnosis were classified as ADHD by both the clinician alone and NEBA. Greater reclassification was observed when using NEBA for patients diagnosed by retrospective consensus as non-ADHD. For example, there were 145 children and adolescents who had a non-ADHD diagnosis by the consensus. Of the 145, 93 had received an initial clinical diagnosis of ADHD, but 85 (91%) of these were negative by NEBA.
Table 1: NEBA Reclassification of Patients With Consensus ADHD Diagnosis
NEBA: Neuropsychiatric EEG-Based Assessment Aid for Attention Deficit Hyperactivity Disorder (ADHD); NEBA interpretation: NEBA results plus initial clinical diagnosis.
a The consensus diagnosis is assumed to be the reference standard (i.e., correct). Two categories are included in the ADHD consensus diagnosis: diagnosed with ADHD or referred for more testing for the condition. Similarly, the “not ADHD” diagnosis included those diagnosed as not having ADHD or as needing more testing for other conditions.
b The NEBA interpretation is a composite of both the initial clinical diagnosis and the NEBA results, like a dichotomized posttest probability. The performance measures are presumably calculated assuming that a negative NEBA result can override a positive initial clinical diagnosis, but in the FDA summary, it is stated that a negative diagnosis can only result from a negative initial clinical diagnosis (ie, the NEBA interpretation cannot override it).
The evidence related to the question of whether NEBA, or QEEG more generally, leads to improved accuracy of ADHD diagnosis consists of a single study, with results presented to FDA. The results of this FDA study suggest that QEEG might be used to decrease the over diagnosis of ADHD by identifying patients with an initial clinical diagnosis who may not have the disorder. Strengths of this study include that it is multicenter and the reclassification analysis of data was obtained from a blinded analysis. However, a weakness of this study is the lack of a true criterion standard for diagnosis of ADHD. It cannot be determined from the study description whether the initial diagnosis by the single clinician according to DSM-IV criteria or the consensus diagnosis (conducted without interview or parent rating scales) was more accurate. No studies were identified that address whether QEEG improves clinical outcomes for patients with suspected ADHD by improving diagnosis.
Ongoing and Unpublished Clinical Trials
An online search of ClinicalTrials.gov on September 8, 2014, identified no studies that evaluate outcomes after the use of EEG for the diagnosis of ADHD.
Summary of Evidence
The evidence related to the use of quantitative EEG (QEEG) in the diagnosis of attention-deficit/hyperactivity disorder (ADHD) includes numerous studies that have evaluated quantitative EEG at the CZ position and other positions with standard EEG equipment, and one pivotal trial submitted to the U.S. Food and Drug Administration (FDA) that used the NEBA system to assess test-retest reliability, sensitivity, specificity, and reclassification analysis in an appropriate population of patients. In the FDA pivotal trial, the specificity and positive predictive value of QEEG was high, although the reclassification analysis showed little benefit of a positive NEBA over clinical assessment alone. The reclassification analysis suggests that a negative NEBA might make ADHD less likely, although it is not clear from this study whether the consensus diagnosis was more accurate than the initial clinical diagnosis that included patient interview and parent rating scales. Further research is needed to evaluate the potential impact of NEBA on management of ADHD. In addition, the effect of the test on patient outcomes, such as rates of medication use, would allow greater certainty regarding the usefulness of NEBA.
The larger body of evidence also raises questions about the utility of measuring the theta/beta ratio in patients suspected of ADHD, as this has not been a consistent finding across studies. Recent studies show low accuracy (58%) and no significant increase in the theta/beta ratio in children and adolescents with ADHD compared with age- and sex-matched controls. Other studies show an increase in beta (rather than a decrease) in a subgroup of affected children and adolescents. Given the uncertainty of an increase in the theta/beta ratio in children and adolescents with ADHD, additional study is needed to determine how strongly the theta/beta ratio is associated with ADHD. Therefore, quantitative EEG as a diagnostic aid for ADHD is considered investigational.
Practice Guidelines and Position Statements
2011 Practice guidelines for the diagnosis, evaluation, and treatment of ADHD by the American Association of Pediatrics state that to make a diagnosis of ADHD, the primary care clinician should determine that Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, criteria have been met (including documentation of impairment in more than 1 major setting), and information should be obtained primarily from reports from parents or guardians, teachers, and other school and mental health clinicians involved in the child’s care. The primary care clinician should also rule out any alternative cause (quality of evidence B/strong recommendation). (13) Assessment by QEEG is not mentioned in these guidelines.
The American Academy of Neurology has requested public comments on a draft of a proposed new guideline, “Evidence-based Practice Advisory: The Utility of EEG Theta/Beta Power Ratio in the Diagnosis of ADHD.” The draft guidelines state:
“The combination of theta/beta ratio and frontal beta power should not be used in place of a standard clinical evaluation, because of the risks of misdiagnosis of 6-15% of patients when using the theta/beta ratio (Level B). There is neither evidence for, nor against the use of theta/beta EEG power ratio either to confirm a diagnosis of ADHD, nor to support further testing after a clinical evaluation.” (14)
U.S. Preventive Services Task Force Recommendations
Quantitative electroencephalography is not a preventive service.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
Electroencephalogram (EEG) extended monitoring; 41-60 minutes
Electroencephalogram (EEG) extended monitoring; greater than 1 hour
Electroencephalogram (EEG); including recording awake and drowsy
Electroencephalogram (EEG); including recording awake and asleep
Digital analysis of electroencephalogram (EEG) (e.g., for epileptic spike analysis)
New policy. New policy created with literature review through August 26, 2013; considered investigational.
Annual Review. Policy updated with literature review through September 8, 2014. References 1, 11-12, and 14 added. Wording of policy statement changed to clarify the type of quantitative EEG and the diseases addressed in the policy; intent of the policy statement unchanged.
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