Diagnosis

1. Aetna considers levodopa or apomorphine challenge medically necessary when the diagnosis of Parkinson disease (PD) is in doubt.

2. Aetna considers olfactory testing by means of the University of Pennsylvania Smell Identification Test (UPSIT) or “Sniffin' Sticks” medically necessary to differentiate PD from progressive supranuclear palsy and corticobasal degeneration.

3. Aetna considers neuropsychological testing for the diagnosis of PD medically necessary.

4. Aetna considers any of the following tests experimental and investigational for differentiating PD from other parkinsonian syndromes:

   1. Electrooculography
   2. Growth hormone stimulation with clonidine
   3. Iodine-123 meta-iodobenzylguanidine cardiac imaging
   4. Single photon emission computed tomography (SPECT) scanning
   5. Magnetic resonance imaging (MRI)

   6. Transcranial duplex scanning

5. Aetna considers genetic testing of PD (e.g., testing for alpha-synuclein, DJ1, LRRK2/PARK8, parkin/PARK2, and PINK1) experimental and investigational.
   

See also CPB 071 - Positron Emission Tomography (PET), CPB 158 - Neuropsychological and Psychological Testing, CPB 168 - Tumor Scintigraphy, and CPB 390 - Smell and Taste Disorders: Diagnosis.

Surgical Treatment

1. Pallidotomy for the Treatment of Parkinson's Disease

   Aetna considers pallidotomy for the treatment of Parkinson's disease medically necessary when all of the following selection criteria are met:

   1. Individuals with idiopathic Parkinson's disease who have tried and failed medical therapy as indicated by worsening of Parkinsonian symptoms and/or disabling medication side effects (motor fluctuations with “wearing off”, and unpredictable “on/off”, as well as Sinemet-induced dyskinesia); and
   2. Members exhibit two of four major symptoms (bradykinesia, tremor, rigidity, and gait disturbance); and
   3. Members have a history of positive response to dopaminergic replacement therapy (e.g., Sinemet or bromocriptine); and

   4. Members have been screened by a neurologist who has expertise in movement disorders to ensure all reasonable forms of pharmacotherapies have been tried and failed.

   Pallidotomy for the treatment of Parkinson's disease is of no proven value in persons with the following conditions:

   1. Members with Parkinson's plus or atypical Parkinson's disorders (e.g., multi-system atrophy, striatonigral degeneration, progressive supranuclear palsy, or combined Alzheimer's and Parkinson's disease); or
   2. Members with severe dementia or cerebral atrophy; or

   3. Members with Hoehn and Yahr Stage V Parkinson's disease (see Note below).

   Note: Hoehn and Yahr Stage V individuals exhibit the following characteristics:

   1. Cachectic state
   2. Invalidism
   3. Cannot stand or walk (need wheelchair assistance, or are unable to get out of bed)

   4. Requires constant nursing care.

2. Fetal Tissue Transplantation for Parkinson's Disease

   Aetna considers transplantation of fetal mesencephalic tissue for the treatment of Parkinson's disease experimental and investigational because the long-term safety and effectiveness of this procedure have not been established.
   

3. Stem Cell Transplantation for Parkinson's Disease

   Aetna considers stem cell transplantation for the treatment of Parkinson's disease experimental and investigational because its effectiveness for this indication has not been established.

4. Adrenal Medullary Transplantation for Parkinson's Disease

   Aetna considers adrenal medullary transplantation for the treatment of Parkinson's disease experimental and investigational because of a lack of evidence of effectiveness for this indication.

5. Subthalamotomy

   Aetna considers subthalamotomy for the treatment of Parkinson's disease experimental and investigational because it has not been shown to be effective for that indication.

6. Intra-striatal Implantation of Human Retinal Pigment Epithelial Cells

   Aetna considers intra-striatal implantation of human retinal pigment epithelial cells for the treatment of Parkinson's disease experimental and investigational because its effectiveness has not been established.

7. Extra-dural Motor Cortex Stimulation

   Aetna considers extra-dural motor cortex stimulation for the treatment of Parkinson's disease experimental and investigational because its effectiveness has not been established.

See also CPB 208 - Deep Brain Stimulation for DBS of Parkinson's disease, and CPB 153 - Thalamotomy for thalamotomy for Parkinson's disease.

Parkinson disease (PD) is the most common cause of parkinsonism, which is characterized by bradykinesia, rigidity, resting tremor, and postural reflex impairment. The diagnosis of PD is based on a careful taking of medical history and a thorough physical examination. Currently, there are no laboratory tests or imaging studies that confirm the diagnosis (Nutt and Wooten, 2005). It is important for clinicians to understand the clinical signs that aid to differentiate PD from various parkinsonism syndromes (also known as Parkinson-plus syndromes) that include progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), dementia with Lewy bodies (DLB), vascular parkinsonism, parkinsonism with no clear etiology, and Parkinson-dementia-amyotrophic lateral sclerosis complex.

The correct diagnosis of PD is important for prognostic as well as therapeutic reasons. Research of the diagnostic accuracy for the disease and other forms of parkinsonism in community-based samples of patients taking anti-parkinsonian medication confirmed a diagnosis of parkinsonism in only 74 % of patients and clinically probable PD in 53 % of patients. Clinicopathological studies based on brain bank material from the United Kingdom and Canada have revealed that clinicians diagnose the disease incorrectly in about 25 % of patients. In these studies, the most common reasons for diagnostic errors were presence of essential tremor, vascular parkinsonism, and atypical parkinsonian syndromes. Infrequent misdiagnosis included Alzheimer's disease (AD), DLB, and drug-induced parkinsonism. Moreover, ancillary tests such as olfactory testing and dopamine-transporter (DAT) single photon emission computed tomography (SPECT) imaging may help with clinical diagnostic decisions (Tolosa, et al., 2006). Winogrodzka, et al. (2005) noted that DAT scintigraphy with SPECT has been used to evaluate the dopaminergic function in patients with PD. Initial studies with several radioligands show significant loss of DAT binding in PD patients as compared to controls.

It should be noted that the role of neuroimaging in the differential diagnosis of PD has not been clearly established. Piccini and Whone (2004) noted that recent improvements in the characterization of the parkinsonian syndromes have led to improvements in clinical diagnostic accuracy; however, clinical criteria alone are not always sufficient to distinguish between idiopathic PD and other parkinsonian syndromes, especially in the early stages of disease and in atypical presentations. Thus, in addition to the development and implementation of diagnostic clinical assessments, there is a need for available objective markers to aid clinicians in the differential diagnosis of IPD. Functional neuroimaging such as positron emission tomography (PET) and SPECT holds the promise of improved diagnosis and allows assessment in early disease.

Seibyl, et al. (2005) stated that the development of imaging biomarkers, which target specific sites in the brain, represents a major advance in neurodegenerative diseases and PD with the promise of new and improved approaches for the early and accurate diagnosis of disease as well as novel ways to monitor patients and assess treatment. The three major applications that imaging may play a role in PD are: (i) the use of neuroimaging as a biomarker of disease in order to improve the accuracy, timeliness, and reliability of diagnosis; (ii) objective monitoring of the progression of disease to provide a molecular phenotype of PD that may illuminate some of the sources of clinical variability; and (iii) the evaluation of disease-modifying treatments designed to retard the progression of disease by interfering with pathways thought to be implicated in the ongoing neuronal loss or replace dopamine-producing cells. Each of these areas has shown a numbers of critical clinical investigations that have better defined the utility of neuroimaging to these tasks. However, current unresolved issues around the clinical role of neuroimaging in monitoring PD patients over time and validation of quantitative imaging measures of dopaminergic function are immediate issues for the field and the subject of current research efforts and the extension of the lessons learned in PD to other neurodegenerative diseases including AD.

In a review on conventional and advanced magnetic resonance imaging (MRI) techniques in the differential diagnosis of neurodegenerative parkinsonism, Seppi and Schocke (2005) noted that research findings suggest that novel MRI techniques such as magnetization transfer imaging, diffusion-weighted imaging, and magnetic resonance volumetry have superior sensitivity compared to conventional MRI in detecting abnormal features in neurodegenerative parkinsonian disorders. They stated that whether these techniques will emerge as standard tools in the work-up of patients presenting with parkinsonism requires further prospective studies during early disease stages.

Ravina and colleagues (2005) reported that radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in PD. These investigators reviewed the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: (i) [18F]fluorodopa PET, (ii) (+)-[11C]dihydrotetrabenazine PET, (iii) [123I]beta-CIT SPECT, and (iv) [18F]fluorodeoxyglucose PET. According to the authors, biomarkers used to study disease biology and facilitate drug discovery and early human clinical trials rely on evidence that they are measuring relevant biological processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biological relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.

In the recent practice parameter on the diagnosis and prognosis of new onset PD (an evidence-based review) by the American Academy of Neurology (AAN), Suchowersky, et al. (2006) provided the following conclusions/recommendations:

• Levodopa or apomorphine challenge should be considered for confirmation when the diagnosis of PD is in doubt.
• Olfactory testing by means of the University of Pennsylvania Smell Identification Test (UPSIT) or “Sniffin' Sticks” should be considered to differentiate PD from PSP and CBD; but not PD from MSA.

• The following tests may not be useful in differentiating PD from other parkinsonian syndromes:

  • Electrooculography
  • Growth hormone stimulation with clonidine

  • SPECT scanning

• There is insufficient evidence to determine if iodine-123 meta-iodobenzylguanidine cardiac imaging is useful in differentiating PD from MSA or PSP.

• In the future, there may be an increasing role for genetic testing to diagnose PD. However, the development of any new diagnostic test will require long-term follow-up and autopsy confirmation to determine its accuracy.

Beyer and colleagues (2007) noted that the nosologic relationship between DLB and PD with dementia (PDD) is continuously being debated. These investigators conducted a study using voxel-based morphometry (VBM) to explore the pattern of cortical atrophy in DLB and PDD. A total of 74 patients and healthy elderly were imaged (healthy elderly, n = 20; PDD, n = 15; DLB, n = 18, and AD, n = 21). Three dimensional T1-weighted MRI were acquired, and images analyzed using VBM. Overall dementia severity was similar in the dementia groups. These researchers found more pronounced cortical atrophy in DLB than in PDD in the temporal, parietal, and occipital lobes. Patients with AD had reduced gray matter concentrations in the temporal lobes bilaterally, including the amygdala, compared to PDD. Compared to DLB, the AD group had temporal and frontal lobe atrophy. The authors concluded that despite a similar severity of dementia, patients with DLB had more cortical atrophy than patients with PDD, indicating different brain substrates underlying dementia in the two syndromes. Together with previous studies reporting subtle clinical and neurobiological differences between DLB and PDD, the findings of this study supported the hypothesis that PDD and DLB are not identical entities, but rather represent two subtypes of a spectrum of Lewy body disease.

While the AAN practice parameter on diagnosis and prognosis of new onset PD (Suchowersky et al, 2006) stated that there is insufficient evidence to support or refute the use of MRI as a means of distinguishing PD from other parkinsonian syndromes, Seppi and Rascol (2007), in an editorial that accompanied the article by Beyer et al, stated that further studies involving larger groups of patients with prospective long-term follow-up and ultimate pathologic diagnosis are needed for verifying the findings of Beyer et al. Furthermore, while such confirmatory data might be available in the future at the level of groups of patients, it is unlikely that MRI will be sufficiently sensitive and specific to allow differential diagnosis at the level of a single patient.

Genetic causes of PD have been identified in approximately 3 % of cases with the discovery of mutations in 6 genes. The most common of these are the gene for leucine-rich repeat kinase 2 (LRRK2 or PARK8), which is autosomal dominant, and parkin (PARK2), which is recessive. LRRK2 produces a phenotype identical to classical PD, with age of onset at approximately 50 to 70 years. The most common mutation (G2019S) has been reported to cause 1.5 % of all cases of PD. Penetrance is age-dependent and is estimated to be 25 % to 35 %. Despite LRRK2 being dominantly inherited, many people who are heterozygous for LRRK2 mutations do not develop the disease.  Homozygous or compound heterozygous mutations of parkin are the most common cause of early-onset PD (10 % to 20 % of cases). However, because single heterozygous mutations also are seen in many people with PD, these mutations are thought to confer a risk for PD. This idea is supported by studies of age of onset and by PET imaging of the dopamine system. However, examinations of mutation frequency in control populations have had conflicting results. Reduced penetrance can cause LRRK2 to act in an apparently recessive or sporadic manner, and parkin may appear to be dominant. Hence, the distinction between dominant and recessive genes in PD is blurred, because the disease is likely multi-factorial, involving causative genes, susceptibility genes, environmental exposures that may have protective effects such as smoking and caffeine, and exposures that may induce neurodegeneration such as pesticides (Factor, 2007).

Klein et al (2007) stated that the association of 6 genes with monogenic forms of parkinsonism has unambiguously established that the disease has a genetic component. Of these 6 genes, LRRK2, parkin, and PINK1 (PTEN-induced putative kinase 1, or PARK6) are the most clinically relevant because of their mutation frequency. Insights from initial familial studies suggested that LRRK2-associated parkinsonism is dominantly inherited, whereas parkinsonism linked to parkin or PINK1 is recessive. However, screening of patient cohorts has revealed that up to 70 % of people heterozygous for LRRK2 mutations are unaffected, and that more than 50 % of patients with mutations in parkin or PINK1 have only a single heterozygous mutation. Deciphering the role of heterozygosity in parkinsonism is important for the development of guidelines for genetic testing, for the counselling of mutation carriers, and for the understanding of late-onset PD. However, much more remains to be understood regarding the pathogenesis of PD before genetic testing can be considered definitive.

Commenting on the article by Beyer et al, Factor (2007) stated that "[b]ecause gene expression in this disease is so complex, most results will be inconclusive. No published guidelines currently exist regarding how to test and counsel patients appropriately; the tests are costly; and the results, even if conclusive, would not change treatment for individual patients, although one hopes they soon might. For these reasons, no good rationale yet exists for the genetic testing of PD patients".

Although PD is primarily considered a movement disorder, the high prevalence of psychiatric complications suggests that it is more accurately conceptualized as a neuropsychiatric disease. Depression, dementia, and psychosis are common manifestations of idiopathic PD; and are associated with excess disability, worse quality of life, poorer prognosis, as well as caregiver burden. Rihmer and colleagues (2004) noted that depression is one of the most disabling symptoms of PD, with a prevalence of approximately 40 %. Unfortunately, such depression is frequently unrecognized and untreated in patients with PD. Papapetropoulos and Mash (2005) stated that psychotic symptoms are common in patients with PD, and occur in at least 20 % of medication-treated patients. Benign visual hallucinations often appear earlier, while agitation, confusion, delirium, delusions, malignant hallucinations, and paranoid beliefs become more frequent with disease progression. Nearly all anti-parkinsonian medications may produce psychotic symptoms. Moreover, cognitive impairment, increased age, disease duration and severity, depression, as well as sleep disorders have been consistently identified as independent risk factors for their development. Although the exact cause for the pathogenesis of psychosis in PD is not fully known, there is some evidence that links over-activity of the ventral dopaminergic pathway with the involvement of other neurotransmitter system imbalances as likely contributors.

Dementia occurs in up to 30 % of patients with PD. Cognitive impairments involve attentional, executive, memory, and visuospatial dysfunctions (Lauterbach, 2005). Furthermore, Levin and Katzen (2005) stated that early cognitive changes in PD patients are often subtle and influenced by factors that interact with the disease process, including medication, motor symptoms, and age of disease onset. These factors notwithstanding, ample evidence exists that specific cognitive changes occur early in the course of PD. The authors noted that this evidence does not imply that cognitive deficits are pervasive during the early stages. On the contrary, they are usually subtle and often difficult to detect without formal neuropsychological testing. Executive-function deficits are the most frequently reported cognitive problems and, given that executive skills are an integral part of many tasks, it follows that subtle difficulties may be seen on a wide range of cognitive measures, especially in working memory as well as visuospatial dysfunction, two areas that rely heavily on executive skills. Whereas apraxia and language processing deficits occur infrequently, subtle changes in olfaction and contrast sensitivity have also been repeatedly observed.

In the recent practice parameter on the evaluation and treatment of depression, psychosis, and dementia in PD (an evidence-based review) by the AAN, Miyasaki, et al. (2006) provided the following conclusions/recommendations:

• Tools such as the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale (HDRS-17), and the Montgomery Asberg Depression Rating Scale (MADRS) should be considered for screening depression associated with PD.
• Tools such as the Cambridge Cognitive Examination (CAMCog) and the Mini-Mental State Examination (MMSE) should be considered for screening dementia in patients with PD.
• There are no widely used, validated tools for psychosis screening in PD.

In a systematic review on transcranial duplex (TCD) scanning in the differential diagnosis of parkinsonian syndromes, Vlaar and colleagues (2009) concluded that before TCD scanning can be implicated, more research is needed to standardize the TCD technique, to investigate the TCD in non-research settings and to determine the additional value of TCD scanning compared with currently used clinical techniques.

The policy on surgical treatment of Parkinson disease is based primarily on evidence assessments by the American Academy of Neurology (Hallett, et al., 1999), the National Institute for Clinical Excellence (NICE, 2004), the BlueCross BlueShield Association Technology Evaluation Center (BCBSA, 2001), and the Agency for Healthcare Research and Quality (AHRQ) (Levine, et al., 2003).

Arle and colleagues (2008) stated that since the initial 1991 report by Tsubokawa et al, stimulation of the M1 region of the motor cortex has been used to treat chronic pain conditions and various movement disorders. The authors reviewed the literature and found 459 cases in which motor cortex stimulation (MCS) was used. Of these, 72 were related to a movement disorder. More recently, up to 16 patients specifically with PD were treated with MCS, and a variety of results were reported. In this report, the authors described 4 patients who were treated with extra-dural MCS. Although there were benefits seen within the first 6 months in Unified Parkinson's Disease Rating Scale Part III scores (decreased by 60 %), tremor was only modestly managed with MCS in this group, and most benefits seen initially were lost by the end of 12 months. The authors concluded that although there have been some positive findings using MCS for PD, a larger study may be needed to better determine if it should be pursued as an alternative surgical treatment to DBS.