Positron Emission Tomography (FDG) and Other Neuroimaging Devices for Suspected Dementia

CMS NCA document | source_status=Closed | review_type=1st Recon | public_comment_open=False | document_id=CAG-00088R

The Centers for Medicare and Medicaid Services (CMS) has made the following determinations regarding the use of FDG-PET in the diagnosis and treatment of mild cognitive impairment (MCI) and early dementia in elderly patients: 1) The evidence is adequate to conclude that a 2-deoxy-2- [F-18] fluoro-D-glucose Positron Emission Tomography (FDG-PET) scan is reasonable and necessary in patients with documented cognitive decline of at least six months and a recently established diagnosis of dementia who meet diagnostic criteria for both Alzheimer's disease (AD) and fronto-temporal dementia (FTD), who have been evaluated for specific alternate neurodegenerative diseases or causative factors, and for whom the cause of the clinical symptoms remains uncertain. The following additional conditions must be met: The onset, clinical presentation, or course of cognitive impairment is atypical for AD, and FTD is suspected as an alternative neurodegenerative cause of the cognitive decline. Specifically, symptoms such as social disinhibition, awkwardness, difficulties with language, or loss of executive function are more prominent early in the course of FTD than the memory loss typical of AD The patient has had a comprehensive clinical evaluation (as defined by the American Academy of Neurology (AAN)) encompassing a medical history from the patient and a well-acquainted informant (including assessment of activities of daily living), physical and mental status examination (including formal documentation of cognitive decline at two time points at least six months apart) aided by cognitive scales or neuropsychological testing, laboratory tests, and structural imaging such as magnetic resonance imaging (MRI) or computed tomography (CT); The patient has been evaluated by a physician experienced in the diagnosis and assessment of dementia; The evaluation did not identify a likely, specific neurodegenerative disease or cause for the clinical symptoms, and information available through FDG-PET is reasonably expected to help clarify the differential diagnosis between FTD and AD; The FDG-PET scan is performed in facilities that have all the accreditation necessary to operate such equipment. The reading of the scan should be done by an expert in nuclear medicine, radiology, neurology, or psychiatry with substantial experience interpreting such scans in the presence of dementia; A brain single photon emission computed tomography (SPECT) or FDG-PET scan has not been obtained for the same indication; The referring and billing providers have documented the appropriate evaluation of the Medicare beneficiary. The referring and billing providers will collect, maintain and furnish upon request to CMS, its agents or other authorized personnel the following documentation to verify that the conditions for coverage described above have been met: date of onset of symptoms; mini mental status exam (MMSE) or similar test score; report from any neuropsychological testing performed; diagnosis of clinical syndrome (e.g., mild cognitive impairment; dementia);M presumptive cause (possible, probable, uncertain AD); results of structural imaging (MRI or CT); relevant laboratory tests (B12, thyroid hormone); number and name of prescribed medications; In addition, the billing provider must furnish upon request a copy of the FDG-PET scan result for use by CMS and its contractors in Medicare quality assessment and improvement activities. 2) The evidence is not adequate to conclude that FDG-PET is reasonable and necessary for the diagnosis of patients with mild cognitive impairment (MCI) or early dementia in clinical circumstances other than that specified above absent safeguards that would be present in formal, protocol-driven clinical investigations. Their trials must compare patients who do and do not receive an FDG-PET scan and have as its goal to monitor, evaluate, and improve clinical outcomes, and must meet the following basic criteria: Written protocol on file; Institutional Review Board review and approval; Scientific review and approval by two or more qualified individuals who are not part of the research team; Certification that investigators have not been disqualified. For purposes of this coverage decision, CMS will determine whether specific clinical trials meet these criteria. CMS will continue to work with the National Institute on Aging (NIA), Agency for Healthcare Research and Quality (AHRQ), Alzheimer's Association (AA), device manufacturers, and experts in AD and imaging to develop a large practical clinical trial to address these questions.

Decision Memo: To: Administrative File: CAG #00088R 2-deoxy-2- [F-18] fluoro-D-glucose Positron Emission Tomography (FDG-PET) for Alzheimer's disease (AD)/Dementia From: Steve Phurrough, MD Director, Coverage and Analysis Group Marcel Salive, MD Director, Division of Medical and Surgical Services Samantha Richardson Lead Analyst, CAG Carlos Cano, MD Lead Medical Officer, CAG Subject: Decision Memorandum for FDG-PET for diagnosis of early dementia in elderly patients for whom the differential diagnosis includes neurodegenerative diseases. Date: September 15, 2004 I. Decision The Centers for Medicare and Medicaid Services (CMS) has made the following determinations regarding the use of FDG-PET in the diagnosis and treatment of mild cognitive impairment (MCI) and early dementia in elderly patients: 1) The evidence is adequate to conclude that a 2-deoxy-2- [F-18] fluoro-D-glucose Positron Emission Tomography (FDG-PET) scan is reasonable and necessary in patients with documented cognitive decline of at least six months and a recently established diagnosis of dementia who meet diagnostic criteria for both Alzheimer's disease (AD) and fronto-temporal dementia (FTD), who have been evaluated for specific alternate neurodegenerative diseases or causative factors, and for whom the cause of the clinical symptoms remains uncertain. The following additional conditions must be met: The onset, clinical presentation, or course of cognitive impairment is atypical for AD, and FTD is suspected as an alternative neurodegenerative cause of the cognitive decline. Specifically, symptoms such as social disinhibition, awkwardness, difficulties with language, or loss of executive function are more prominent early in the course of FTD than the memory loss typical of AD The patient has had a comprehensive clinical evaluation (as defined by the American Academy of Neurology (AAN)) encompassing a medical history from the patient and a well-acquainted informant (including assessment of activities of daily living), physical and mental status examination (including formal documentation of cognitive decline at two time points at least six months apart) aided by cognitive scales or neuropsychological testing, laboratory tests, and structural imaging such as magnetic resonance imaging (MRI) or computed tomography (CT); The patient has been evaluated by a physician experienced in the diagnosis and assessment of dementia; The evaluation did not identify a likely, specific neurodegenerative disease or cause for the clinical symptoms, and information available through FDG-PET is reasonably expected to help clarify the differential diagnosis between FTD and AD; The FDG-PET scan is performed in facilities that have all the accreditation necessary to operate such equipment. The reading of the scan should be done by an expert in nuclear medicine, radiology, neurology, or psychiatry with substantial experience interpreting such scans in the presence of dementia; A brain single photon emission computed tomography (SPECT) or FDG-PET scan has not been obtained for the same indication; The referring and billing providers have documented the appropriate evaluation of the Medicare beneficiary. The referring and billing providers will collect, maintain and furnish upon request to CMS, its agents or other authorized personnel the following documentation to verify that the conditions for coverage described above have been met: date of onset of symptoms; mini mental status exam (MMSE) or similar test score; report from any neuropsychological testing performed; diagnosis of clinical syndrome (e.g., mild cognitive impairment; dementia); presumptive cause (possible, probable, uncertain AD); results of structural imaging (MRI or CT); relevant laboratory tests (B12, thyroid hormone); number and name of prescribed medications; In addition, the billing provider must furnish upon request a copy of the FDG-PET scan result for use by CMS and its contractors in Medicare quality assessment and improvement activities. 2) The evidence is not adequate to conclude that FDG-PET is reasonable and necessary for the diagnosis of patients with mild cognitive impairment (MCI) or early dementia in clinical circumstances other than that specified above absent safeguards that would be present in formal, protocol-driven clinical investigations. Their trials must compare patients who do and do not receive an FDG-PET scan and have as its goal to monitor, evaluate, and improve clinical outcomes, and must meet the following basic criteria: Written protocol on file; Institutional Review Board review and approval; Scientific review and approval by two or more qualified individuals who are not part of the research team; Certification that investigators have not been disqualified. For purposes of this coverage decision, CMS will determine whether specific clinical trials meet these criteria. CMS will continue to work with the National Institute on Aging (NIA), Agency for Healthcare Research and Quality (AHRQ), Alzheimer's Association (AA), device manufacturers, and experts in AD and imaging to develop a large practical clinical trial to address these questions. II. Background Alzheimer's disease AD is an age-related and irreversible brain disorder that occurs gradually and results in memory loss, behavior and personality changes, and a decline in thinking abilities. AD is the most common dementia of old age, representing approximately two-thirds of cases. 1 Less common neurodegenerative conditions include FTD, dementia with Lewy bodies (DLB) and (more rarely) Creutzfeldt-Jakob disease (CJD). Cerebrovascular disease is another frequent cause of cognitive decline, which may result in vascular dementia (VAD). Pathological changes characteristic of individual disorders often coexist in one individual and are likely to contribute to the clinical picture of dementia. The term dementia does not imply a specific cause or pathologic process and is usually defined as a syndrome presenting with memory impairment in an alert patient plus one or more of a variety of cognitive signs and symptoms. These include aphasia (problem understanding or expressing language), apraxia (problem performing complex purposeful movements), agnosia (problem identifying objects), and difficulties with executive functioning (making everyday decisions). Dementia of the Alzheimer's type most commonly occurs in late life but a small percentage of patients have onset before age 60 (presenile). The course of AD dementia varies among individuals, as does the rate of decline. On average, patients with this disorder live 8-10 years after they are diagnosed, although the disease can last for up to 20 years. It is estimated that about 4,500,000 people in the United States have AD. 2 AD is typically not reported on death certificates; therefore, estimates of prevalence (how many people have a disease at any one time) are based upon community surveys. The prevalence of AD climbs steadily after age 65 so that 30% to 50% of persons in the 8 th or 9 th decade are estimated to have clinical AD. Most people with AD present with symptoms of cognitive decline after age 60. The earliest symptoms characteristically include loss of recent memory, later compounded by impaired judgment and changes in personality. As AD progresses, people first think less clearly and tend to be easily confused. Later in the disease, they may forget how to do simple tasks, such as how to dress themselves or eat with proper utensils. Eventually, people with AD lose the capacity to function on their own and become dependent upon other persons for their everyday care. Finally, the disease becomes so debilitating that patients are bedridden and are likely to develop other associated medical complications. Most commonly, people with AD die from pneumonia. Although the risk of developing AD increases with age, AD and dementia symptoms are not a part of normal aging. In the absence of disease, the human brain often can function well into the tenth decade of life and beyond. Use of research criteria in clinical studies of aging and cognitive impairment has yielded three groups of subjects: normal elderly, those who are demented, and a third group of individuals who cannot be classified as normal or demented but who are cognitively (usually memory) impaired. Mild cognitive impairment (MCI) refers to the clinical state of cognition and functional ability that is intermediate between normal aging and mild dementia. 3 The histological diagnosis of AD (and the reference standard for all other diagnostic tests) is based upon specific findings in brain tissue at autopsy. Typical microscopic findings are plaques between neurons, neurofibrillary tangles inside neurons, and neuronal loss. Amyloid plaques are extraneuronal aggregates of amyloid beta (A) protein. Neurofibrillary tangles are aggregates of tau protein and neurofilaments found in neuronal cell bodies. The neuritic plaques and tangles lead to neuronal loss. 4 Glucose metabolism in affected areas decreases as the disease progresses providing the basis for the use of FDG-PET. Loss of cortical acetylcholine is the primary neurotransmitter deficit in AD, providing pathophysiological support for the use of cholinesterase inhibitors, the drugs that have proven most effective for the primary treatment of mild to moderate disease. 5 The degree of clinical cognitive impairment, however, does not directly correlate with that of Alzheimer-type pathology. For instance, a recent study by researchers at Washington University showed that 40% of individuals without dementia presented neuropathological lesions characteristic of AD but no difference in cognitive ability when compared to the other non-demented subjects. 6 In addition, the pathological changes of AD frequently coexist with other lesions affecting cognition such as vascular infarcts resulting in a mixed dementia. There is increasing evidence of the additive effects of vascular pathology and AD-type changes in the development of cognitive decline. 7 There are no established biological or neuroimaging markers for the diagnosis of AD. The clinical diagnosis of possible or probable AD during the life of a person is made when the patient has dementia typical of AD in its clinical course and does not have specific evidence of another diagnosis that could fully account for the patient's symptoms (such as cerebrovascular disease, depression, medication toxicity, or a metabolic disorder like hypothyroidism). The standard clinical evaluation currently recommended by the AAN includes a complete medical history taken from the patient and from an informant who is well acquainted with the affected person, a physical examination comprising a mental status evaluation aided by quantitative scales and/or neuropsychological assessment, laboratory testing and structural neuroimaging such as MRI or CT to rule out other diseases such as brain neoplasms or subdural hematomas. The clinical evaluation involves routine use of the National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria or the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for dementia of the Alzheimer's type. This assessment should include screening for major depression. Thus, the mental status examination remains a cornerstone of the diagnosis of AD. 8 The field of aging and dementia is increasingly focusing on the characterization of early stages of cognitive impairment. Recent research has identified a state between the cognitive changes of normal aging and AD. As indicated above, MCI is a condition in which persons experience memory loss to a greater extent than that expected for age but do not yet meet clinical criteria for probable AD. For most patients with MCI and for some patients in the early stages of dementia, diagnosis often depends on the observation of clinical progression over repeated patient visits. FTD Frontotemporal dementia is often misdiagnosed as AD. FTD is a dementia syndrome characterized histopathologically by the formation of microvacuoles, gliosis (i.e., excess of neuroglial cells) with or without inclusion bodies (Pick's bodies) and swollen neurons. FTD leads to frontotemporally predominant atrophy while in AD the pathology is typically more severe in posterior temporo-parietal regions. 9 It is estimated that 12%-16% (and up to 25% in presenile cases) of patients with degenerative dementia may suffer from this non-AD pathology. 10 The natural history of FTD differs substantially from that of AD. Distinguishing one from the other early in the course of the disease and providing education on the likely progression of FTD as well as appropriate counseling may assist patients and caregivers to cope with this condition more effectively. Specifically, deficits in judgment and conduct appear early in FTD and tend to disrupt family life more acutely. Symptoms such as neglect of hygiene and grooming, sexually provocative or demanding behavior, and impulsivity are out of proportion to memory deficits which in turn often seem to result from lack of concern or effort. 11 In addition, drug therapies available to delay the progression of cognitive decline or contain disruptive behavior in clinical AD appear to be less effective in FTD. The clinical differences between FTD and AD are influenced by the anatomical pattern of the diseases. The neuropathological changes in FTD primarily occur in the frontal regions while those of AD begin in the hippocampus and enthorhinal cortex and then spread to the posterior temporo-parietal cortex. Presenting symptoms have been shown to correlate early in the disease with these anatomic patterns. Thus, behavioral abnormalities, difficulties with language and with executive function are common early in the development of FTD whereas memory loss is a key feature of AD. These clinical distinctions between well established FTD and AD may be blurred in the middle to late stages as the neuropathology of FTD begins to affect the posterior brain while that of AD moves anteriorly. 12 In FTD there is a distinctive focal atrophy of the frontal lobes, the temporal lobes or both. The pathology can show a unilateral predominance or be symmetrical and typically affects the more anterior regions of the temporal lobes. Posterior parietal and temporal regions are relatively preserved. The clinical presentation of FTD varies depending on the focal onset of pathology and thus has led to the definition of three main cognitive sub-types: frontal variant, non-fluent aphasia, and semantic dementia. Dysfunction in the right frontotemporal region has been associated with behavioral disinhibition, bilateral disease with loss of executive function whereas in patients with predominantly left hemisphere involvement, progressive language deficits (expressive or interpretive) predominate. Thus clinical criteria alone can be useful in distinguishing FTD from AD. In addition, cognitive changes in FTD are marked by profound failure on neuropsychological tests sensitive to frontal lobe lesions but absence of severe amnesia and preservation of visuospatial ability. Clinical criteria thus remain the mainstay of diagnosis of FTD. However, neuroimaging studies may assist in distinguishing the disorder from AD in some instances. For example, focal variants of AD may mimic FTD in early stages. Patients with FTD generally tend to show bifrontal and bitemporal hypoperfusion in single photon emission computerized tomography (SPECT) or glucose hypometabolism in FDG PET scans. In contrast, temporoparietal defects are predominant in AD. FDG-PET Positron emission tomography (PET) is a minimally invasive diagnostic imaging procedure used to evaluate glucose metabolism in normal tissue as well as in diseases such as cancer, ischemic heart disease, and certain neurological disorders. This procedure begins with injection into the patient of 2- [F-18] fluoro-D-glucose (FDG), which is a radioactive tracer substance (radionuclide) that emits sub-atomic particles, known as positrons, as it decays. The operator then utilizes a positron camera (tomograph) that measures the decay of the FDG radioisotopes in the patient. The rate of FDG decay provides biochemical information on glucose metabolism of the tissue being studied. For instance, as malignancies can cause abnormalities of metabolism and blood flow, FDG-PET evaluation can indicate the probable presence or absence of malignancy based upon observed differences of biologic activity. Diagnostic imaging technologies such as x-ray films, CT, and MRI supply information about the anatomic structure of suspected malignancies, primarily their size and location. The utility of FDG-PET in imaging relates to the ability to differentiate abnormalities based on metabolic function. The test involves the qualitative visual interpretation of the scan images where metabolically active areas of the body "light up" on an FDG-PET scan more so than less active areas. Functional neuroimaging, such as FDG-PET, has been proposed for the evaluation of elderly patients who may have early dementia and for whom the differential diagnosis includes one or more kinds of neurodegenerative diseases. FDG-PET may be able to diagnose AD by identifying anatomical patterns of brain hypometabolism, which typically occur bilaterally in the temporal and parietal lobes. FDG-PET scans typical of AD may be differentiated by visual inspection from scans suggestive of vascular dementia (asymmetric and focal abnormalities) and scans indicative of FTD (marked hypometabolism of frontal or temporal lobes with sparing of parietal lobes). An accurate distinction, for instance between AD and FTD may prove helpful in patient management given the variation in the course of these two diseases. Therapy There is not a known treatment to prevent or cure AD. Current drug therapies are aimed at symptomatic relief and at slowing disease progression. Use of acetylcholinesterase inhibitors (AChE-I) is thought to correct the central cholinergic deficit in persons with AD and has shown beneficial effects relative to placebo in randomized clinical trials, modestly delaying progression of disease in some individuals with mild to moderate dementia. 13 Subjects in these clinical trials have generally been patients with a history of gradual cognitive decline and a diagnosis of probable AD based upon criteria recommended by the AAN. 14 No therapeutic trials have been done using FDG-PET-based diagnosis of AD as an entry criterion. AChE-I therapy may also reduce the rate of institutionalization in patients with more severe dementia. 15 However, whether the reported improvement in cognition translates into clinically important effects on a patient's functional ability remains an issue of debate. 16 Significant adverse events are uncommon with these FDA-approved agents, which include donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl). The most frequently experienced side effects are associated with the digestive system (nausea, vomiting, diarrhea) and most are mild and transient in nature, usually resolving during continued drug use. 17 The FDA recently approved a new agent, memantine, for the treatment of moderate to severe dementia, which presumably limits neuronal damage that may result from excessive release of glutamate. 18 Reconsideration Request This national coverage analysis (NCA) was prompted by a request for reconsideration of a previous national coverage determination (NCD) issued by CMS on the use of FDG-PET. Sponsors of the technology submitted a letter for reconsideration delineating a "more restricted and defined coverage request" as follows. "Medicare coverage is requested to include reimbursement for brain positron emission tomography (PET) performed with the radiopharmaceutical [F-18] fluoro-deoxyglucose (FDG) to distinguish patients with Alzheimer's disease (AD) from those with other causes of symptoms confounding the diagnosis of dementia, or to assist with the diagnosis of early dementia in beneficiaries for whom the differential diagnosis includes one or more kinds of neurodegenerative disease (e.g., AD and frontotemporal dementia), in cases for which the referring physician's medical record documents that all of the following criteria have been met: 1) Patient has a) gradually progressive decline in one or more cognitive domains, and/or b) cognitive impairment representing a change from patient's normal level of functioning which includes: (i) memory loss, (ii) other cognitive impairment, and (iii) functional impairment; 2) Patient has undergone comprehensive history and physical including neurological examination (per American Academy of Neurology guidelines), common screening laboratory tests, and if indicated, structural imaging with CT or MRI, which does not provide explanation for cognitive impairment or symptoms, or which has not resulted in treatment of potentially reversible cause(s) of dementia that has restored patient to normal state of cognition; 3) As determined by a structured assessment of mental status, patient is documented to not suffer from severe dementia at the time of PET scan (such as a MMSE) score of not less than or equal to 10), but is impaired sufficiently to warrant a neuroimaging evaluation (meeting criteria set forth in sub-clause 1); 4) Brain SPECT scan has not been obtained for same indication, after the date of the CMS coverage decision for PET and AD; 5) Diagnosis of dementia will have a specific impact on the care of patient and on major life planning decisions for patient, as made by patient, family or caregiver; and 6) Physician has evidence from a collateral source or a serial examination that cognitive impairment has been present for six months prior to ordering a PET scan." 19 III. History of Medicare Coverage for FDG-PET CMS has previously reviewed scientific literature and established coverage for many uses of FDG-PET. A summary of each prior PET NCD follows. For each indication, there are specific coverage limitations listed in the CMS NCD Manual, Section 220.6. 20 A synopsis of the CMS NCD Manual Section 220.6 appears in Appendix A. For services performed on or after March 14, 1995, CMS covered PET using Rubidium 82 (not FDG) as the tracer for noninvasive imaging of myocardial perfusion in patients with known or suspected coronary artery disease. Beginning January 1, 1998, FDG-PET was covered when used for the initial staging of suspected metastatic non-small cell lung cancer and for the characterization of suspected solitary pulmonary nodule. On July 1, 1999, FDG-PET coverage was expanded to include 3 additional oncology indications. These were: 1) location of recurrent colorectal tumors when rising CEA suggests recurrence; 2) staging and restaging of lymphoma only when used as an alternative to gallium scan; and 3) evaluating recurrence of melanoma prior to surgery only when used as an alternative to gallium scan. On July 10, 2000, CMS received a request for broad coverage of FDG-PET for 22 oncologic, cardiac, and neurologic conditions. 21 CMS commissioned a technology assessment (TA) from the AHRQ and referred the issue to the Medicare Coverage Advisory Committee (MCAC) for consideration. In a decision memorandum of December 15, 2000, based on available evidence, CMS announced its intent to expand coverage of FDG-PET to include the indications listed below in Table 1. At that time, CMS did not find sufficient evidence to support coverage of FDG-PET for the other indications included in the request. Table 1. Expanded coverage announced in decision memorandum of December 15, 2000 Effective Date Clinical Condition Coverage July 1, 2001 Non small cell lung cancer Diagnosis, staging, and restaging July 1, 2001 Esophageal cancer Diagnosis, staging, and restaging July 1, 2001 Colorectal cancer Diagnosis, staging, and restaging July 1, 2001 Lymphoma Diagnosis, staging, and restaging July 1, 2001 Melanoma Diagnosis, staging, and restaging. Non-covered for evaluating regional nodes. July 1, 2001 Head and neck (excluding CNS and thyroid) Diagnosis, staging, and restaging July 1, 2001 Refractory seizures Pre-surgical evaluation July 1, 2001 to September 1, 2002 Myocardial viability Following inconclusive SPECT On December 15, 2000, CMS accepted a request for FDG-PET for diagnosis of early dementia in certain geriatric patients for whom the differential diagnosis includes one or more kinds of neurodegenerative disease. CMS commissioned a TA from AHRQ and presented the issue to the MCAC Diagnostic Imaging Panel for consideration. The MCAC Executive Committee then met and ratified the Panel's recommendations. In a decision memorandum of April 16, 2003, based on available evidence, CMS announced it would maintain noncoverage of FDG-PET for the requested indications. Effective July 1, 2001 CMS allowed only specific types of PET systems to be covered according to their design characteristics. These characteristics included so-called full-ring, partial-ring, and coincidence systems. 22 On October 18, 2001, CMS accepted a request for FDG-PET for diagnosing, staging, restaging, or monitoring therapy for soft tissue sarcoma. CMS commissioned a TA from AHRQ to evaluate the available literature. CMS determined that the evidence was not adequate to conclude that FDG-PET was reasonable and necessary for the requested indications. As a result, a decision memorandum of April 16, 2003 announced CMS would maintain noncoverage of FDG-PET for soft tissue sarcoma. On October 1, 2002, FDG-PET coverage was expanded to include 2 additional applications. For breast cancer, FDG-PET was covered for certain women as an adjunct to standard imaging for staging or restaging and as an adjunct to standard imaging for monitoring response to therapy when a change in therapy is anticipated. For myocardial viability, FDG-PET was covered for initial diagnosis or following inconclusive SPECT prior to a revascularization procedure. For services performed on or after October 1, 2003, PET coverage was expanded to include 2 additional applications involving two different radiopharmaceuticals. FDG-PET was covered for restaging of recurrent or residual follicular cell thyroid cancer under certain conditions. PET using ammonia N-13 as the tracer was covered for noninvasive imaging of myocardial perfusion. IV. Timeline of Recent Activities Date Action October 7, 2003 CMS formally accepted the reconsideration request for FDG-PET for AD. November 10, 2003 CMS broadened the scope of review of FDG-PET for AD to include neuroimaging for suspected dementias. December 4, 2003 CMS announced that it would collaborate with the NIA to have an expert panel discussion on PET and other neuroimaging devices for the diagnosis of dementia. March 15, 2004 CMS requested input from the public regarding additional questions [PDF, 33KB]we developed after reviewing the NCD request [PDF, 59KB] and an AA statement [PDF, 100KB] regarding this reconsideration. April 5, 2004 CMS and NIA joint expert panel meeting convened. May 5, 2004 CMS received the AHRQ TA on neuroimaging devices for the diagnosis and management of AD. June 15, 2004 Draft Decision Memorandum released. September 10, 2004 CMS met with representatives from NIA, FDA, AHRQ, academia and industry to discuss potential trial designs. V. Food and Drug Administration (FDA) Status The FDA approval letter for new drug application NDA 20-306, dated June 2, 2000 included the following language: "This new drug application provides for the use of fluoro-deoxyglucose F-18 injection for the following indications: Assessment of abnormal glucose metabolism to assist in the evaluation of malignancy in patients with known or suspected abnormalities found by other testing modalities, or in patients with an existing diagnosis of cancer.... We have completed the review of this application and have concluded that adequate information has been presented to demonstrate that the drug product is safe and effective for use as recommended in the agreed upon enclosed labeling text. Accordingly, the application is approved effective on the date of this letter...." 23 The FDA has cleared PET devices, along with various software packages used to perform PET for general diagnostic use, through the 510(k) clearance process. The FDA approval language cited above indicates that FDG [F-18] is not currently approved by the FDA to assist in the diagnosis of early dementia in patients with possible neurodegenerative disease. Therefore, this use of FDG-PET imaging would represent an off-label use. VI. General Methodological Principles of Study Design When making NCD, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service is reasonable and necessary. The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve net health outcomes for patients. Outcomes of interest to CMS for a diagnostic test are not limited to determining its accuracy but include beneficial or adverse clinical effects such as change in management due to test findings or, preferably, improved health outcomes for Medicare beneficiaries. Accuracy refers to the ability of the test to distinguish patients who have or do not have the target disorder when compared to a reference standard. Measures used to determine accuracy include sensitivity (probability of a positive test result in a patient with the disease) and specificity (probability of a negative test in a patient who does not have the disease). In the absence of direct evidence to show that the diagnostic test under review improves health outcomes, evidence of improved sensitivity or specificity could still prove useful as an intermediary outcome and data point estimate in the construction of a decision or evidence model (indirect evidence). A detailed account of the methodological principles of study design the agency staff utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix B. In general, features of diagnostic studies that improve quality and decrease bias include the selection of a clinically relevant inception cohort, the consistent use of a single good reference standard, the inclusion of patients with and without the disorder in question, and the blinding of readers of the index test, and of reference test results. 24 VII. Evidence Consistent findings across studies of net health outcomes associated with an intervention or diagnostic test as well as the magnitude of its risks and benefits are key to the coverage determination process. In the previous coverage decision on the use of FDG-PET in the diagnosis of early dementia in elderly patients for whom the differential diagnosis included one or more kinds of neurovegetative disease, CMS commissioned an external TA. The Duke Evidence-based Practice Center (EPC) thus completed a review of the existing scientific evidence for that indication. For this reconsideration request, CMS commissioned an update of that TA. CMS staff reviewed the commissioned TA update and evaluated the individual clinical studies in that document to determine if use of FDG-PET improves the health outcomes of patients with dementia or MCI of at least six-month duration who have completed a standard clinical evaluation and whose diagnosis of AD remains uncertain. In addition to our review of the clinical scientific literature, we requested information from experts and professional societies, and participated in discussions with an expert panel convened by the NIA. 25 We also sought and reviewed available evidence-based practice guidelines, consensus statements, and position papers, including a recent expert consensus report published by the AA. 26 1. Assessment questions The development of an assessment in support of Medicare coverage decisions is based on the same general question for almost all requests: "Is the evidence sufficient to conclude that the application of the technology under study will improve net health outcomes for Medicare beneficiaries?" The formulation of specific questions for the assessment recognizes that the effect of an intervention can depend substantially on how it is delivered, to whom it is applied, the alternatives with which it is being compared, and the delivery setting. As mentioned above, in order to appraise the health outcomes of using FDG-PET for the population under consideration, CMS sought to obtain any new clinical data on the use of FDG-PET in the diagnosis of cognitive decline and early dementia in elderly patients published since 2001, the end date of the previous external TA. Specifically, we addressed the following questions: Is the evidence adequate to conclude that FDG-PET can assist with the diagnosis of early dementia and improve health outcomes in individuals for whom the differential diagnosis is uncertain and includes one or more kinds of neurodegenerative disease after completion of a standard clinical work-up? Is the evidence adequate to conclude that FDG-PET can help to distinguish patients with AD from those with other causes of MCI and improve health outcomes for this population when performed after a standard clinical work-up? 2. External systematic reviews/technology assessments Systematic reviews are based on a comprehensive and unbiased search of published studies to answer a clearly defined and specific set of clinical questions regarding use of a diagnostic test or therapeutic intervention in a defined population for a specific indication. A well-defined strategy or protocol (established before the results of the individual studies are known) guides this literature search. Thus, the process of identifying studies for potential inclusion and the sources for finding such articles is explicitly documented at the start of the review. Systematic reviews provide a detailed assessment of the studies included. 27 CMS commissioned a TA from AHRQ to assess the value of FDG-PET by addressing the clinical questions related to the effectiveness of FDG-PET for the specific population and indications stated in the assessment questions. AHRQ selected the Duke University EPC to produce an update of the external TA on FDG-PET for AD developed by this EPC in support of the national coverage decision previously issued by CMS on April 16, 2003. In this section, we summarize the findings of the most recent TA on the use of FDG-PET for the indications included in the reconsideration request. 28 The following question was addressed in the conduct of the TA: What is the new clinical data on the use of PET in the diagnosis of early dementia in elderly patients published since 2001, the end date for the previous technology assessment? The new TA included any articles on use of PET to distinguish patients with AD from those with other causes of MCI, or to assist with the diagnosis of early dementia in individuals for whom the differential diagnosis includes one or more kinds of neurodegenerative disease. The TA included a summary of the data, a critical appraisal of the quality of the studies, and an analysis of how these new data might change the 2001 analysis. Study review was organized by the following considerations: Studies on the use of the technology to discriminate between AD and other causes of cognitive impairment; Studies that predict future clinical course of individual patients; and Studies that predict response to treatment, in terms of both positive and adverse effects. The authors also sought studies on potential harms and benefits of testing and the "value of knowing" (i.e. impact of being told test results - positive or negative - on non-medical decision making and general quality of life). 29 The structure of the report section pertaining to FDG-PET summarized below included a brief overview of the goals and results of the previous TA, a discussion of methods used to identify and review new literature, followed by a detailed description of articles meeting all inclusion criteria. These were followed by a summary statement on the effect of the update on the original report. Overview of original TA The main conclusion of the original report was that although FDG-PET is likely to improve the overall accuracy of diagnosis compared to that of a clinical assessment based on AAN parameters, treatment based on a standard AAN-recommended evaluation leads to better health outcomes than treatment based on FDG-PET results, and that this result is robust across a broad range of assumptions. 30 The apparent discordance between overall accuracy and clinical outcomes relates in part to the fact that efficacy of currently available drug therapies, such as acetylcholinesterase inhibitors, has been established from trials using an examination based on AAN guidelines as the reference standard and not on diagnoses made through FDG-PET. In addition, although FDG-PET testing would reduce the number of false positive results, it may concomitantly prevent the provision of beneficial treatment by generating a number of false negative results. Three additional insights emerged from the original TA indicating circumstances in which FDG-PET testing would potentially improved clinical outcomes: Testing would be an attractive option if a new treatment becomes available that is more effective than AChE inhibitors and is associated with a risk of severe adverse effects. However, to our knowledge, no such treatment is currently available. Testing would be useful if it could be demonstrated to be a better reference standard than an examination based on AAN guidelines, i.e., FDG-PET testing would need to better distinguish patients who respond to therapy than is possible with a standard examination. No evidence was uncovered in the original TA to indicate this was the case. Testing could be useful if the results could be shown to have benefits beyond informing anticholinesterase use. This "value of knowing" health status could have both positive and negative components. The authors noted that no FDG-PET research had examined these issues empirically and that estimating the operating characteristics of tests for the diagnosis of AD may not be sufficient to understand the value of testing in disease prognosis, and for predicting response to treatment (in terms of both positive and adverse effects). Search strategy The original literature search, conducted using MEDLINE was updated to include articles that were published during and after 2001. In addition, the authors searched the International Network of Agencies for Health Technology Assessment ( www.inahta.org ) database, the National Institute for Clinical Excellence database ( www.nice.org.uk ), the Health Technology Assessment database (www.hta.nhsweb.nhs.uk), and the Guidelines International Net database ( www.g-i-n.net ) to identify pertinent evidence reports or technology assessments that may have been published in the last 3 years. References from recently published literature reviews were also searched to identify any additional TAs or evidence reports. The published report includes a detailed account of search strategy and results. The MEDLINE search resulted in 22 potential articles for review. For this TA, the authors excluded articles describing the performance of FDG-PET in patients with AD compared to normal controls in part since this comparison leads to biased estimates of sensitivity and specificity for discriminating between AD and other etiologies of cognitive impairment. On this basis four articles were identified for full text review. Results Patients with dementia. One of the four studies identified examined the use of PET in distinguishing Parkinsonian dementia from AD. 31 Bohnen et al. used PET to examine cortical cholinergic function in patients with Parkinsonian Dementia (n = 14), AD dementia (n = 12), Parkinson's disease (PD) without dementia and normal controls (n = 10). Radiopharmaceuticals other than FDG (e.g., [11C] metilpiperidine-propionate) were used in conjunction with PET to determine AChE activity in the four groups. Regions of interest were determined using co-registration with MRI. AD patients were diagnosed using the NINCDS-ADRDA criteria. Patients with Parkinson disease were diagnosed using the Consortium on Dementia with Lewy Bodies criteria. Compared with controls, mean cortical AChE activity was lowest in patients with Parkinsonian dementia, followed by patients with PD without dementia. Mean cortical AChE activity was relatively preserved in patients with AD, except for the lateral temporal cortex, suggesting that reduced cortical AChE activity may be more characteristic of patients with Parkinson dementia than those with AD. Patients with MCI. The three other studies identified for full review described the ability of FDG-PET to predict progression to AD in patients with MCI. Chetelat et al. examined 17 patients with MCI at 6-month intervals for 18 months to determine a metabolic profile that could be used to predict progression to AD. 32 Patients were classified as MCI if they did not meet the criteria for probable AD using the NINCDS-ADRDA criteria and had MMSE with scores of ≥24. The authors theorized that, based on prior studies, the earliest metabolically affected areas in patients with probable AD were the posterior cingulate gyrus (PCG) followed by the temporoparietal posterior association cortex and hippocampal region. For comparison, 15 healthy controls without memory impairment were included. FDG-PET scans were obtained at entry and at each follow-up visit (12 months and 18 months). Statistical parametric testing was used in determining regional activity values. These values were in turn used to determine the percent of patients correctly classified as converters and non-converters. The authors examined the results using a specified cut-off. However, they did not make clear if the cut-point value was determined a priori or was based on multiple comparisons. Neuropsychological testing was also conducted at baseline and at follow up, using scales to assess global functioning, attention, verbal initiation, motor initiation, visuospatial construction, conceptualization, memory, total recall, and delayed recall, blinded to PET results. Of the original 17 patients, 7 eventually met the inclusion criteria for probable AD. These 7 patients were termed rapid converters. Compared to non-converters, these patients were shown to have significantly lower FDG uptake, at inclusion, in the temporoparietal posterior association cortex and based on the described cut-point, FDG-PET differentiated all converters from all non-converters. During the 18-month follow-up, this area continued to be significantly associated with conversion suggesting its potential usefulness in distinguishing MCI rapid converters from non-converters. Arnaiz et al. followed 20 patients with MCI to determine whether reduced glucose metabolism could be used to predict progression to AD. 33 No controls were included in this study. FDG-PET scans were obtained at entry and at approximately 3-month intervals. Neuropsychological testing was also conducted at baseline and at follow up, using a variety of scales to assess global functioning (MMSE), intelligence, auditory verbal learning, recognition of words, and other cognitive domains. Of the original 20 patients, 9 eventually met the inclusion criteria for probable AD using the NINCDS-ADRDA criteria. Compared to patients who did not convert, converters had significantly lower baseline results in neuropsychological scales for block design, digit symbol, and trail making time. They also had significantly lower uptake values in the left temporoparietal regions above the level of the basal ganglia. Using logistic regression, the authors explored different statistical models including imaging in combination with the various neuropsychological testing results to predict progression. Two variables that were consistently and significantly associated with progression were left temporoparietal glucose metabolism and performance on the block design test. These measures correctly classified 90% of patients as converters and non-converters, whereas use of either by itself gave 75% (glucose metabolism) and 65% (block design) correct classification, suggesting their potential combined use in determining progression in patients with MCI. No model examined the incremental contribution of FDG-PET to clinical findings. Silverman et al. retrospectively assessed 167 patients with cognitive impairment referred to an academic nuclear medicine clinic for brain FDG-PET, to determine whether reduced glucose metabolism could be used to predict dementia progression. 34 FDG-PET scans were obtained at baseline. Physicians who were blinded to clinical follow-up data read the scans and classified them as progressive or non-progressive based on criteria established a priori . Scans considered positive for signs of progression had focal cortical hypometabolism in parietal, temporal and frontal lobes, or diffuse cortical hypometabolism with sparing of sensorimotor and visual cortex, with cortical deficits unaccounted for by matched findings on CT or MRI indicative of cerebrovascular disease. Negative scans had no abnormal findings or had abnormal findings other than those meeting the definition of a positive scan. Clinical data were based on chart review and a study questionnaire. Progression was assessed using neuropsychiatric data obtained at least 2 years following the initial FDG-PET or at least 3 years later for patients taking cholinesterase inhibitors. Two board certified physicians blinded to PET findings independently confirmed progression. Since MMSE score was the most widely utilized measure across patients, scores were compared for progressors and non-progressors. Patients considered to be progressors using criteria for the FDG-PET scans had an average 4.1 points lower MMSE score (compared to baseline) whereas non-progressors had an average difference of 2.1 points over the same interval (these differences were not statistically significant). One hundred and twenty-eight patients also had clinical data available for assessment of progression obtained at the time of FDG-PET. Of these, 58 were classified as having progressive dementia using clinical criteria, 44 were classified as having a non-progressive dementia and 26 had an indeterminable diagnosis. Of the 102 patients with a clinical diagnosis 64 patients were eventually considered to have met the criteria for progression; 38 patients were considered non-progressors. The sensitivity of clinical exam for predicting progression was 77% (95%: CI 66-87%) and specificity was 76% (95%CI: 63-90%). For this same group of patients, sensitivity of PET was 95% (95%: CI 90-100%) and specificity was 79% (95% CI: 66-92%). Information on specific cause for progression was not presented. Appraisal and conclusions Based on a review of these articles, the TA authors arrived at two conclusions. First, publications since the prior TA did not provide evidence supporting revised estimates of the operating characteristics of PET for discriminating AD from other competing diagnoses. (The one study including patients with dementia examined a variant of PET involving a radiopharmaceutical other than FDG and thus was not clearly relevant to current or near-term clinical practice.) Second, three studies suggested that FDG-PET could be valuable for identifying patients with MCI who rapidly convert to frank AD. Two were relatively small studies that require validation and assessment of incremental value above conventional clinical measures. A third, larger study of FDG-PET for prediction of progression for patients with MCI also suggested a potential role for PET in predicting clinical course for patients with dementia. However, this study did not comment on findings for patients with AD only, and results for FDG-PET, while suggestive of higher sensitivity and specificity, did not differ in a statistically significant manner from clinical findings. 3. Internal technology assessment As indicated above, the TA authors conducted a systematic review of the literature and found no new direct evidence to evaluate use of FDG-PET in the subset of patients with cognitive decline under consideration. CMS staff reviewed the new commissioned TA and concurred with the conclusions of the report authors. We found no additional well-designed studies of FDG-PET in patients with MCI or early dementia that assessed change in management or improved health outcomes in these subgroups. 4. Guidelines, consensus panels and expert opinion The Quality Standards Subcommittee of the AAN, charged with developing practice parameters, has published three systematic reviews addressing major issues in the diagnosis and management of dementia in the elderly. 35 36 37 These evidence-based reports seek to reflect scientifically sound, clinically relevant guidelines for physicians and are formally endorsed as policy by the AAN. The most recent Report of the Quality Standards Subcommittee of the AAN on the diagnosis of dementia published in 2001 states: "PET scanning appears to have promise for use as an adjunct to clinical diagnosis, but further prospective studies with PET are needed to establish the value that it brings to diagnosis over and above a competent clinical diagnosis (...) PET imaging is not recommended for routine use in the diagnostic evaluation of dementia at this time." 38 The American Association of Neuroscience Nurses and the American Geriatrics Soci