Parkinson's Disease

Number: 0307



  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 because their effectiveness for this indication has not been established:

    1. Electrooculography
    2. Growth hormone stimulation with clonidine
    3. Iodine-123 meta-iodobenzylguanidine cardiac imaging
    4. Magnetic resonance imaging (MRI)
    5. Single photon emission computed tomography (SPECT) scanning (e.g., DaTSCAN (Ioflupane I-123 injection) -- a radio-pharmaceutical indicated for striatal dopamine transporter visualization)
    6. Tilt table testing
    7. Transcranial duplex scanning
  5. Aetna considers genetic testing of PD (e.g., testing for alpha-synuclein, apolipoprotein E (APOE), DJ1, glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) polymorphisms, interleukin-10 polymorphisms (-1082A/G and -592C/A), LRRK2/PARK8, parkin/PARK2, PINK1, and sphingomyelin phosphodiesterase 1 gene (SMPD1)) experimental and investigational because its effectiveness for this indication has not been established.

  6. Aetna considers cerebrospinal fluid (CSF) α-synuclein and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) as diagnostic biomarkers for PD experimental and investigational because the effectiveness of this approach for this indication has not been established .

  7. Aetna considers CSF amyloid beta 1-42 as a biomarker for PD progression experimental and investigational because its effectiveness for this indication has not been established.

  8. Aetna considers quantitative EEG (qEEG) measures as predictive biomarkers for the development of dementia in PD experimental and investigational because its effectiveness for this indication has not been established.

  9. Aetna considers SPECT scanning (e.g., DaTSCAN (Ioflupane I-123 injection)) medically necessary to distinguish PD from essential tremor.

  10. Aetna considers the use of serum α-synuclein autoantibody as a biomarker for PD experimental and investigational because its effectiveness for this indication has not been established.

  11. Aetna considers submandibular gland needle biopsy for the diagnosis of PD experimental and investigational because its effectiveness for this indication has not been established.

See also CPB 0071 - Positron Emission Tomography (PET), CPB 0158 - Neuropsychological and Psychological TestingCPB 0168 - Tumor Scintigraphy, CPB 0221 - Quantitative EEG (Brain Mapping), and CPB 0390 - Smell and Taste Disorders: Diagnosis.

Surgical Treatment

  1. Pallidotomy for the Treatment of PD

    Aetna considers pallidotomy medically necessary for the treatment of PD when all of the following selection criteria are met:

    1. Individuals with idiopathic PD 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 2 of 4 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 PD 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, striato-nigral degeneration, progressive supranuclear palsy, or combined Alzheimer's disease and PD); 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. Can not stand or walk (need wheelchair assistance, or are unable to get out of bed)
    3. Invalidism
    4. Requires constant nursing care
  2. Fetal Tissue/Fetal xenografts Transplantation for PD

    Aetna considers transplantation of fetal mesencephalic tissue or fetal xenografts (e.g., from pigs or other animals) experimental and investigational for the treatment of PD because the long-term safety and effectiveness of these procedures have not been established.

  3. Stem Cell Transplantation for PD

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

  4. Adrenal Medullary Transplantation for PD

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

  5. Subthalamotomy

    Aetna considers subthalamotomy experimental and investigational for the treatment of PD 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 experimental and investigational for the treatment of PD because its effectiveness has not been established.

  7. Extra-dural Motor Cortex Stimulation

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

  8. Gene Therapy

    Aetna considers gene therapy for the treatment of PD experimental and investigational because its effectiveness has not been established.

See also CPB 0208 - Deep Brain Stimulation for deep brain stimulation of PD, and CPB 0153 - Thalamotomy for thalamotomy for PD.

Non-Surgical Treatments

Levodopa-Carbidopa Intestinal Gel

Aetna considers levodopa-carbidopa intestinal gel (Duopa) medically necessary for the treatment of motor complications as a consequence of Parkinson's disease when all of the following criteria are met:

  • Member is levodopa responsive with clearly defined “on” periods; and
  • The member has off periods greater than 3 hours per day despite optimization efforts; and
  • Member does not have dementia, severe depression, cerebral atrophy, or Hoehn and Yahr stage V Parkinson's disease (see Note below).

A pump for administering levodopa-carbidopa intestinal gel is considered medically necessary DME for persons who meet criteria for levodopa-carbidopa intestinal gel.

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

  • Cachectic state
  • Cannot stand or walk (need wheelchair assistance, or are unable to get out of bed
  • Invalidism
  • Requires constant nursing care.

Hyperbaric Oxygen Therapy 

Aetna considers hyperbaric oxygen therapy for the treatment of PD experimental and investigational because its effectiveness has not been established (see CPB 0172 - Hyperbaric Oxygen Therapy (HBOT)).

Intravenous Glutathione

Aetna considers intravenous glutathione for the treatment of PD experimental and investigational because its effectiveness has not been established.

Transcranial Direct Current Stimulation/Transcranial Magnetic Stimulation

Aetna considers transcranial direct current stimulation/transcranial magnetic stimulation for the treatment of PD experimental and investigational because their effectiveness have not been established.


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), cortico-basal 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 idiopathic PD (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 3 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 4 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.

de la Fuente-Fernández (2012) evalauted the role of DaTSCAN in the diagnosis of PD.  Using the sensitivity and specificity values obtained in the 2 studies that recently led the Food and Drug Administration to approve the use of DaTSCAN for the diagnosis of PD, calculations were carried out to estimate the accuracy of the clinical diagnosis taking DaTSCAN findings as the standard of truth.  In early PD, a clinical diagnosis of “possible” or “probable” PD has a sensitivity of 98 % and a specificity of 67 %.  The specificity increases to 94 % once the clinical diagnosis becomes established.  The overall accuracy of the clinical diagnosis is 84 % in early PD and 98 % at later stages.  The clinical diagnostic accuracy is mathematically identical to the diagnostic accuracy of DaTSCAN imaging.  The authors concluded that in the absence of neuropathologic validation, the overall accuracy of a clinical diagnosis of PD is very high and mathematically identical to the accuracy of DaTSCAN imaging, which calls into question the use of radiotracer neuroimaging as a diagnostic tool in clinical practice.  They stated that neuropathological studies are definitely needed to evaluate the diagnostic accuracy of radiotracer neuro-imaging compared to the clinical diagnosis.  Until these assessments are available, it may be premature to embark on a large-scale use of DaTSCAN imaging for the diagnosis of PD.

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 2 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 2 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".

Williams-Gray et al (2009) noted that in addition to the well-established association between apolipoprotein E (APOE) and AD, this gene has also been implicated in both susceptibility to, and dementia in, PD.  However studies to date have produced contradictory findings.  These investigators conducted a case-control study in a population of 528 PD patients and 512 healthy controls and found no significant difference in allele or genotype distribution of APOE between the 2 groups.  An updated meta-analysis showed a modest increase of APOE-epsilon2 carriers among PD patients compared to controls (p = 0.017, odds ratios [OR] = 1.16 [95 % confidence interval (CI): 1.03 to 1.31]).  A total of 107 patients were incident cases participating in a population-based epidemiological study.  Longitudinal follow-up of this cohort over a mean of 5.0 +/- 0.7 years from diagnosis revealed no significant impact of APOE-epsilon4 carrier status on risk of dementia or rate of cognitive decline.  An updated meta-analysis indicated an over-representation of APOE-epsilon4 carriers among PD dementia compared to non-dementia cases [OR 1.74 (1.36 to 2.23), p = 1 x 10(-4)], although small sample sizes, heterogeneity of OR and publication bias may have confounded this finding.  The authors concluded that these findings did not support previously reported associations between APOE genotype and susceptibility to, or cognitive decline in, PD.  An updated meta-analysis indicates any association with PD susceptibility is at most modest, an observation with important implications for further study of this issue.  They stated that large scale longitudinal studies would be best placed to further evaluate any impact of APOE genotype on cognitive decline in PD.

The findings by Williams-Gray et al (2009) are in agreement with those of Kurz et al (2009) who investigated the role of APOE alleles in PD and PD dementia.  These researchers determined APOE genotypes in a group of patients with PD (n = 95) and compared them with those of healthy control participants (n = 73).  Additionally, in 64 longitudinally followed patients with PD, the allele types were correlated to development and progression of dementia and to time from onset of PD to dementia using multi-variate and survival analyses.  The APOE e4e4 genotype was more common in patients with PD (7.4 %) than in healthy controls (1.4 %; p = 0.03).  No significant associations between the APOE genotype and development and progression of dementia or time to dementia were found.  The authors stated that more studies with larger PD samples are needed.

Riley and Chelimsky (2003) stated that formal laboratory testing of autonomic function is reported to distinguish between patients with PD and those with MSA, but such studies segregated patients according to clinical criteria that select those with autonomic dysfunction for the MSA category.  These researchers attempted to characterize the profiles of autonomic disturbances in patients in whom the diagnosis of PD or MSA used criteria other than autonomic dysfunction.  A total of 47 patients with parkinsonism and autonomic symptoms who had undergone autonomic laboratory testing were identified and their case records reviewed for non-autonomic features.  They were classified clinically into 3 diagnostic groups: (i) PD (n = 19), MSA (n = 14), and uncertain (n = 14).  The performance of the patients with PD was compared with that of the MSA patients on 5 autonomic tests: (i) R-R interval variations during deep breathing, (ii) heart rate changes with the Valsalva maneuvre, (iii) tilt table testing, (iv) the sudomotor axon reflex test, and (v) thermoregulatory sweat testing.  None of the tests distinguished one group from the other with any statistical significance, alone or in combination.  Parkinson's disease and MSA patients showed similar patterns of autonomic dysfunction on formal testing of cardiac sympathetic and parasympathetic, vasomotor, and central and peripheral sudomotor functions.  The authors concluded that these findings supported the clinical observation that PD is often indistinguishable from MSA when it involves the autonomic nervous system.  The clinical combination of parkinsonism and dysautonomia is as likely to be caused by PD as by MSA.  Current clinical criteria for PD and MSA that direct patients with dysautonomia into the MSA group may be inappropriate.

Reimann et al (2010) stated that differential diagnosis of parkinsonian syndromes is a major challenge in movement disorders.  Dysautonomia is a common feature but may vary in clinical severity and onset.  These investigators attempted to find a pattern of autonomic abnormalities discriminative for patients with different parkinsonian syndromes.  The cross-sectional study included 38 patients with MSA, 32 patients with PSP, 26 patients with IPD, and 27 age-matched healthy controls.  Autonomic symptoms were evaluated by a standardized questionnaire.  The performance of patients and controls was compared on 5 autonomic function tests: (i) deep breathing, (ii) Valsalva maneuvre, (iii) tilt-table testing, (iv) sympathetic skin response, (v) pupillography, as well as 24-hr ambulatory BP monitoring (ABPM).  Disease severity was significantly lower in IPD than PSP and MSA.  Except for pupillography, none of the laboratory autonomic tests distinguished one patient group from the other alone or in combination.  The same was observed on the questionnaire.  Receiver operating characteristic curve revealed discriminating performance of pupil diameter in darkness and nocturnal BP change.  The composite score of urogenital and vasomotor domains significantly distinguished MSA from IPD patients but not from PSP.  These findings supported the observation that even mild IPD is frequently indistinguishable from more severe MSA and PSP.  Thus, clinical combination of motor and non-motor symptoms does not exclusively point at MSA.  Pupillography, ABPM and the questionnaire may assist in delineating the 3 syndromes when applied in combination.

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.

Tokuda et al (2010) stated that to-date, there is no accepted clinical diagnostic test for PD that is based on biochemical analysis of blood or cerebrospinal fluid (CSF).  The discovery of mutations in the SNCA gene encoding α-synuclein in familial parkinsonism and the accumulation of α-synuclein in the PD brain suggested a critical role for this protein in PD etiology.  These researchers investigated total and α-synuclein oligomers levels in CSF from patients clinically diagnosed with PD, PSP, or AD, and age-matched controls, using ELISA.  The levels of α-synuclein oligomers and oligomers/total-α-synuclein ratio in CSF were higher in the PD group (n = 32; p < 0.0001, Mann-Whitney U test) compared to the control group (n = 28).  The area under the receiver operating characteristic curve (AUC) indicated a sensitivity of 75.0 % and a specificity of 87.5 %, with an AUC of 0.859 for increased CSF α-synuclein oligomers in clinically diagnosed PD cases.  However, when the CSF oligomers/total-α-synuclein ratio was analyzed, it provided an even greater sensitivity of 89.3 % and specificity of 90.6 %, with an AUC of 0.948.  In another cross-sectional pilot study, these researchers confirmed that the levels of CSF α-synuclein oligomers were higher in patients with PD (n = 25) compared to patients with PSP (n = 18; p < 0.05) or AD (n = 35; p < 0.001) or control subjects (n = 43; p < 0.05).  The authors concluded that these findings showed that levels of α-synuclein oligomers in CSF and the oligomers/total-α-synuclein ratio can be useful biomarkers for diagnosis and early detection of PD.  Moreover, the authors stated that large-scale, prospective, and well-controlled studies, especially those that include subjects with neuroimaging-supported definite PD and other synucleinopathies, as well as unrelated neurologic disorders, are necessary to validate the quantification of CSF α-synuclein oligomers as an urgently needed surrogate biomarker.  It will be critical to carry out prospective studies to examine if individuals who do not have PD, but have an elevated oligomer-to-total α-synuclein ratio in their CSF will be more prone to develop the disease in the future.

In an editorial that accompanied the afore-mentioned study, Ballard and Jones (2010) noted that there is emerging evidence that measurement of specific forms of α-synuclein in CSF may contribute to diagnosis and treatment development in PD and related disorders.  Moreover, they stated that further validation is still needed; it is too preliminary to put this forward as a diagnostic test for PD.

Siderowf et al (2010) investigated if CSF amyloid beta 1-42 (Aβ[1-42]) would predict cognitive decline in PD.  A total of 45 patients with PD were enrolled in this prospective cohort study and had at least 1 yearly longitudinal follow-up evaluation.  Cerebrospinal fluid was collected at baseline and cognition was assessed at baseline and follow-up visits using the Mattis Dementia Rating Scale (DRS-2); CSF was tested for Aβ[1-42], p-tau(181p), and total tau levels using the Luminex xMAP platform.  Mixed linear models were used to test for associations between baseline CSF biomarker levels and change in cognition over time.  Lower baseline CSF Aβ[1-42] was associated with more rapid cognitive decline.  Subjects with CSF Aβ[1-42] levels less than or equal to192 pg/ml declined an average of 5.85 (95 % CI: 2.11 to 9.58, p = 0.002) points per year more rapidly on the DRS-2 than subjects above that cut-off, after adjustment for age, disease duration, and baseline cognitive status.  Cerebrospinal fluid total tau and p-tau(181p) levels were not significantly associated with cognitive decline.  The authros concluded that reduced CSF Aβ[1-42] was an independent predictor of cognitive decline in patients with PD.  This observation is consistent with previous research showing that AD pathology contributes to cognitive impairment in PD.  This biomarker may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD.  Furthermore, they noted that there are 2 main drawbacks of this study: (i) small number of patients studied for a relatively short period of time, and (ii) the results do not address if the association between reduced Aβ[1-42] and cognitive decline is specific to PD.  These findings need to be validated with well-designed studies with larger number of subjects in longer stduy duration.

In an editorial that accompanied the afore-mentioned study, Aarsland and Ravina (2010) stated that there are several limitations of this study: (i) small cohort recruited at a single center, (ii) lack of a healthy control group, and (iii) large variations in PD duration, severity of disease, length of follow-up, and baseline cognitive impairment.  They stated that the potential clinical utility of these findings is not yet known.

The policy on surgical treatment of PD is based primarily on evidence assessments by the AAN (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.

Martin and Teismann (2009) stated that PD is the second most common neuro-degenerative disease, affecting over a million people in the United States alone.  Its main neuro-pathological feature is the loss of dopaminergic neurons of the substantia nigra pars compacta.  However, the pathogenesis of this loss is not understood fully.  One of the earliest biochemical changes seen in PD is a reduction in the levels of total glutathione (GSH), a key cellular antioxidant.  Traditionally, it has been thought that this decrease in GSH levels is the consequence of increased oxidative stress, a process heavily implicated in PD pathogenesis.  However, emerging evidence suggests that GSH depletion may itself play an active role in PD pathogenesis.

Hauser and colleagues (2009) evaluated the safety, tolerability, and preliminary efficacy of intravenous GSH in PD patients.  This was a randomized, placebo-controlled, double-blind, pilot trial in subjects with PD whose motor symptoms were not adequately controlled with their current medication regimen.  Subjects were randomly assigned to receive intravenous GSH 1,400 mg or placebo administered 3 times a week for 4 weeks.  A total of 21 subjects were randomly assigned, 11 to GSH and 10 to placebo.  One subject who was assigned to GSH withdrew from the study for personal reasons prior to undergoing any post-randomization efficacy assessments.  Glutathione was well-tolerated and there were no withdrawals because of adverse events in either group.  Reported adverse events were similar in the 2 groups.  There were no significant differences in changes in Unified Parkinson's Disease Rating Scale (UPDRS) scores.  Over the 4 weeks of study medication administration, UPDRS ADL + motor scores improved by a mean of 2.8 units more in the GSH group (p = 0.32), and over the subsequent 8 weeks worsened by a mean of 3.5 units more in the GSH group (p = 0.54).  Glutathione was well-tolerated and no safety concerns were identified.  The authors stated that these preliminary efficacy data suggest the possibility of a mild symptomatic effect, but this remains to be evaluated in a larger study.

Sedlacková and associates (2009) examined the effects of one session of high-frequency repetitive transcranial magnetic stimulation (rTMS) applied over the left dorsal premotor cortex (PMd) and left dorsolateral prefrontal cortex (DLPFC) on choice reaction time in a noise-compatibility task, and cognitive functions in patients with PD.  Clinical motor symptoms of PD were assessed as well.  A total of 10 patients with PD entered a randomized, placebo-controlled study with a cross-over design.  Each patient received 10 Hz stimulation over the left PMd and DLPFC (active stimulation sites) and the occipital cortex (OCC; a control stimulation site) in the OFF motor state, i.e., at least after 12 hrs of dopaminergic drugs withdrawal.  Frameless stereotaxy was used to target the optimal position of the coil.  For the evaluation of reaction time, a noise-compatibility paradigm was used.  A short battery of neuropsychological tests was performed to evaluate executive functions, working memory, and psychomotor speed.  Clinical assessment included a clinical motor evaluation using part III of the UPDRS.  Statistical analysis revealed no significant effect of rTMS applied over the left PMd and/or DLPFC in patients with PD in any of the measured parameters.  In this study, these researchers did not observe any effect of 1 session of high frequency rTMS applied over the left PMd and/or DLPFC on choice reaction time in a noise-compatibility task, cognitive functions, or motor features in patients with PD; rTMS applied over all 3 stimulated areas was safe and well-tolerated in terms of the cognitive and motor effects.

In a double-blind, placebo-controlled study, Arias and co-workers (2010a) evaluated the effect of 10-day rTMS on sleep parameters in PD patients.  A total of 18 IPD patients completed the study.  Sleep parameters were evaluated through actigraphy and the Parkinson's Disease Sleep Scale (PDSS), along with depression (Hamilton Depression Rating Scale, HDS), and the UPDRS.  Evaluations were carried out before treatment with rTMS (pre-evaluation, PRE), after the rTMS treatment programme (post-evaluation, POST), and 1 week after POST (POST-2).  Nine PD patients received real rTMS and the other 9 received sham rTMS daily for 10 days, (100 pulses at 1Hz) applied with a large circular coil over the vertex.  Stimulation had no effect over actigraphic variables.  Conversely PDSS, HDS, and UPDRS were significantly improved by the stimulation.  Notably, however, these changes were found equally in groups receiving real or sham stimulation.  The authors concluded that rTMS, using these researchers' protocol, has no therapeutic value on the sleep of PD patients, when compared to appropriate sham controls.  They stated that future works assessing the possible therapeutic role of rTMS on sleep in PD should control the effect of placebo.

In a double-blind placebo-controlled trial, Arias et al (2010b) evaluated the effect of low-frequency rTMS on motor signs in PD.  Patients with PD were randomly assigned to received either real (n = 9) or sham (n = 9) rTMS for 10 days.  Each session comprises 2 trains of 50-stimuli each delivered at 1 Hz and at 90 % of daily rest motor threshold using a large circular coil over the vertex.  The effect of the stimulation, delivered during the ON-period, was evaluated during both ON and OFF periods.  Tests were carried out before and after the stimulation period, and again 1 week after.  The effect of the stimulation was evaluated through several gait variables (cadence, step amplitude, velocity, the CV(stride-time), and the turn time), hand dexterity, and also the total and motor sections of the UPDRS.  Only the total and motor section of the UPDRS and the turn time during gait were affected by the stimulation, the effect appearing during either ON or OFF evaluation, and most importantly, equally displayed in both real and sham group.  The rest of the variables were not influenced.  The authors concluded that the protocol of stimulation used, different from most protocols that apply larger amount of stimuli, but very similar to some previously reported to have excellent results, has no therapeutic value and should be abandoned.  This contrasts with the positive reported effects using higher frequency and focal coils.  These findings also reinforced the need for sham stimulation when evaluating the therapeutic effect of rTMS.

Filipović et al (2010) examined the effects of low-frequency rTMS on OFF-phase motor symptoms in patients with PD.  A total of 10 patients with PD had rTMS (1,800 stimuli at just below active motor threshold intensity) at 1Hz rate delivered over the motor cortex for 4 consecutive days on 2 separate occasions.  On 1 of these occasions, real rTMS was used and on the other sham rTMS (placebo) was used.  Evaluations with UPDRS Part 3 (Motor Scale) were done in practically defined OFF-phase at the baseline and 1 day after the end of each of the treatment series.  Neither total Motor Scale scores nor subscores for axial symptoms, rigidity, bradykinesia, and tremor showed any significant difference.  The results did not confirm presence of residual beneficial clinical after-effects of consecutive daily applications of low-frequency rTMS on motor symptoms in PD, at least when 1800 stimuli at sub-threshold intensity are applied for 4 days.

In a randomized, double-blind, sham-controlled study, Benninger et al (2011) examined the safety and effectiveness of intermittent theta-burst transcranial magnetic stimulation (iTBS), a novel type of rTMS, in the treatment of motor symptoms in PD. These researchers investigated safety and efficacy of iTBS of the motor and dorso-lateral prefrontal cortices in 8 sessions over 2 weeks (evidence Class I).  Assessment of safety and clinical efficacy over a 1-month period included timed tests of gait and bradykinesia, UPDRS, and additional clinical, neuropsychological, and neurophysiologic measures.  A total of 26 patients with mild-to-moderate PD were included in this study: 13 received iTBS and 13 sham stimulation.  These investigators found beneficial effects of iTBS on mood, but no improvement of gait, bradykinesia, UPDRS, and other measures.  EEG/EMG monitoring recorded no pathologic increase of cortical excitability or epileptic activity.  Few reported discomfort or pain and 1 experienced tinnitus during real stimulation.   The authors concluded that iTBS of the motor and prefrontal cortices appears safe and improves mood, but failed to improve motor performance and functional status in PD.  This study provided Class I evidence that iTBS was not effective for gait, upper extremity bradykinesia, or other motor symptoms in PD.

In a randomized, double-blind, sham-controlled study, Benninger and colleagues (2010) examined the effectiveness of transcranial direct current stimulation (tDCS) in the treatment of PD.  The effectiveness of anodal tDCS applied to the motor and pre-frontal cortices was investigated in 8 sessions over 2.5 weeks.  Assessment over a 3-month period included timed tests of gait (primary outcome measure) and bradykinesia in the upper extremities, UPDRS, Serial Reaction Time Task, Beck Depression Inventory, Health Survey and self-assessment of mobility.  A total of 25 PD patients were studied, 13 receiving tDCS and 12 sham stimulation.  Transcranial direct current stimulation improved gait by some measures for a short time and improved bradykinesia in both the ON and OFF states for longer than 3 months.  Changes in UPDRS, reaction time, physical and mental well being, and self-assessed mobility did not differ between the tDCS and sham interventions.  The authors concluded that tDCS of the motor and prefrontal cortices may have therapeutic potential in PD; but better stimulation parameters need to be established to make the technique clinically viable.  The findings of this preliminary study need to be validated by well-designed studies.

Klassen and colleagues  (2011) evaluated quantitative EEG (qEEG) measures as predictive biomarkers for the development of dementia in PD.  A cohort of subjects with PD in the authors' brain donation program utilizes annual pre-mortem longitudinal movement and cognitive evaluation.  These subjects also undergo biennial EEG recording.  EEG from subjects with PD without dementia with follow-up cognitive evaluation was analyzed for qEEG measures of background rhythm frequency and relative power in δ, α, and β bands.  The relationship between the time to onset of dementia and qEEG and other possible predictors was assessed by using Cox regression.  The hazard of developing dementia was 13 times higher for those with low background rhythm frequency (lower than the grand median of 8.5 Hz) than for those with high background rhythm frequency (p < 0.001).  Hazard ratios (HRs) were also significant for greater than median bandpower (HR = 3.0; p = 0.004) compared to below, and for certain neuropsychological measures.  The HRs for δ, α, and β bandpower as well as baseline demographic and clinical characteristics were not significant.  The authors concluded that qEEG measures of background rhythm frequency and relative power in the band are potential predictive biomarkers for dementia incidence in PD.  These qEEG biomarkers may be useful in complementing neuropsychological testing for studying PD-D incidence.

In a randomized clinical trial, Espay and colleagues (2011) evaluated the effectiveness of methylphenidate (MPD) for the treatment of gait impairment in PD.  A total of 27 subjects with PD and moderate gait impairment were screened for this 6-month placebo-controlled, double-blind study.  Subjects were randomly assigned to MPD (maximum, up to 80 mg/day) or placebo for 12 weeks and crossed-over after a 3-week washout.  The primary outcome measure was change in a gait composite score (stride length + velocity) between groups at 4 and 12 weeks.  Secondary outcome measures included changes in motor function, as measured by the UPDRS, Freezing of Gait Questionnaire (FOGQ), number of gait-diary freezing episodes, and measures of depression, sleepiness, and quality of life.  Three-factor repeated-measures analysis of variance was used to measure changes between groups.  Twenty-three eligible subjects with PD were randomized and 17 completed the trial.  There was no change in the gait composite score or treatment or time effect for any of the variables.  Treatment effect was not modified by state or study visit.  Although there was a trend for reduced frequency of freezing and shuffling per diary, the FOGQ and UPDRS scores worsened in the MPD group compared to placebo.  There was a marginal improvement in some measures of depression.  The authors concluded that MPD did not improve gait and tended to worsen measures of motor function, sleepiness, and quality of life.

The National Institute for Health and Clinical Excellence's clinical practice guideline on "Parkinson's disease: Diagnosis and management in primary and secondary care" (NICE, 2006) stated that "123I-FP-CIT SPECT should be considered for people with tremor where essential tremor can not be clinically differentiated from parkinsonism".  Furthermore, the Scottish Intercollegiate Guidelines Network's clinical practice guideline on "Diagnosis and pharmacological management of Parkinson's disease" (SIGN, 2010) stated that "Single photon emission computed tomography (SPECT) with (123I-labeled N-omega-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)tropane (123I-FP-CIT SPECT scanning) should be considered as an aid to clinical diagnosis in patients where there is uncertainty between Parkinson's disease and non-degenerative parkinsonism/tremor disorders.  Routine use of functional imaging is not recommended for the differential diagnosis of Parkinson's disease and Parkinson's plus disorders such as progressive supranuclear palsy and multiple system atrophy".

Also, an UpToDate review on "Diagnosis of Parkinson disease" (Chou, 2012) states that "Positron emission tomography (PET) and single photon emission computed tomography (SPECT) may be helpful for the early diagnosis of PD.  With PET, decreased tracer uptake is seen in the mid- and posterior putamen of patients with early PD when compared with controls.  Striatal dopamine transporter imaging using SPECT (e.g., 123I-FP-CIT SPECT scan or DaTscan) can reliably distinguish patients with PD and other parkinsonian syndromes from controls or patients with essential tremor, but it can not differentiate PD and the parkinsonian syndromes from one another".

Fink et al (2000) stated that the observation that fetal neurons are able to survive and function when transplanted into the adult brain fostered the development of cellular therapy as a promising approach to achieve neuronal replacement for treatment of diseases of the adult central nervous system.  This approach has been demonstrated to be effective in patients with PD after transplantation of human fetal neurons.  The use of human fetal tissue is limited by ethical, infectious, regulatory, and practical concerns.  Other mammalian fetal neural tissue could serve as an alternative cell source.  Pigs are a reasonable source of fetal neuronal tissue because of their brain size, large litters, and the extensive experience in rearing them in captivity under controlled conditions.  In phase I studies, porcine fetal neural cells grafted unilaterally into PD and Huntington's disease patients were being evaluated for safety and effectiveness.  Clinical improvement of 19 % has been observed in the Unified Parkinson's Disease Rating Scale "off" state scores in 10 PD patients assessed 12 months after unilateral striatal transplantation of 12 million fetal porcine ventral mesencephalic (VM) cells.  Several patients have improved more than 30 %.  In a single autopsied PD patient some porcine fetal VM cells were observed to survive 7 months after transplantation.  Twelve Huntington's disease patients have shown a favorable safety profile and no change in total functional capacity score 1 year after unilateral striatal placement of up to 24 million fetal porcine striatal cells.  Xenotransplantation of fetal porcine neurons is a promising approach to delivery of healthy neurons to the central nervous system.  The major challenges to the successful use of xenogeneic fetal neuronal cells in neurodegenerative diseases appear to be minimizing immune-mediated rejection, management of the risk of xenotic (cross-species) infections, and the accurate assessment of clinical outcome of diseases that are slowly progressive.

Cederfjall et al (2012) noted that it has been suggested that the beneficial effect of L-DOPA could be re-established by changing the mode of administration.  Indeed, continuous delivery of L-dopa has been shown to be an effective way to circumvent many of the side effects seen with traditional oral administration, which results in an intermittent supply of the dopamine precursor to the brain.  However, all currently tested continuous dopaminergic stimulation approaches rely on peripheral administration.  This is not ideal since it gives rise to off-target effects and is difficult to maintain long-term.  Thus, there is an unmet need for an effective continuous administration method with an acceptable side effect profile.  Viral-mediated gene therapy is a promising alternative paradigm that can meet this demand.  Encouraging pre-clinical studies in animal models of PD showed therapeutic effectiveness after expression of the genes encoding the enzymes required for biosynthesis of dopamine.  Although phase I clinical trials using these approaches have been conducted, clear positive data in placebo-controlled efficacy studies are still lacking.  The authors stated that “We are now at a critical junction and need to carefully review the preclinical data from the clinical translation perspective and identify the key factors that will determine the potential for success in gene therapy for Parkinson's disease”.

Besong-Agbo et al (2013) stated that biomarkers are needed for the diagnosis and monitoring of disease progression in PD.  To date, most studies have concentrated on α-synuclein (α-Syn), a protein involved in PD pathogenesis, as a potential biomarker, with inconsistent outcomes.  Recently, naturally occurring autoantibodies against α-Syn (α-Syn-nAbs) have been detected in the serum of patients with PD.  They represent a putative diagnostic marker for PD.  These researchers established and validated an ELISA to quantify α-Syn-nAbs in serum samples.  They analyzed serum samples from 62 patients with PD, 46 healthy controls (HC), and 42 patients with Alzheimer disease (AD) using this newly established ELISA.  Additionally, serum levels of endogenous α-Syn were measured.  There was a significant difference in α-Syn-nAbs levels between the investigated groups (p = 0.005; Kruskal-Wallis test).  Levels of α-Syn-nAbs were significantly lower in patients with PD compared to HC (p < 0.05; Dunn multiple comparison post-hoc test) or patients with AD (p < 0.05).  Furthermore, these investigators detected no difference between patients with AD and HC.  The sensitivity and specificity of the assay for patients with PD versus HC were 85 % and 25 %, respectively.  The α-Syn-nAbs levels did not correlate with age, Hoehn and Yahr status, or duration of disease.  Endogenous α-Syn had no influence on α-Syn-nAbs levels in sera.  The authors concluded that using a well-validated assay, they detected reduced α-Syn-nAbs levels in patients with PD compared to patients with AD and HC.  The assay did not achieve criteria for use as a diagnostic tool to reliably distinguish PD from HC.  They stated that appropriately powered and independent investigations with validated assays are needed to further evaluate the utility of α-Syn-nAbs as a biomarker in PD.

Gan-Or et al (2013) studied the possible association of founder mutations in the lysosomal storage disorder genes hexosaminidase A (or HEXA), sphingomyelin phosphodiesterase 1 gene (SMPD1), and mucolipin 1 (MCOLN1) (causing Tay-Sachs, Niemann-Pick A, and mucolipidosis type IV diseases, respectively) with PD.  Two PD patient cohorts of Ashkenazi Jewish (AJ) ancestry, that included a total of 938 patients, were studied: (i) a cohort of 654 patients from Tel Aviv, and (ii) a replication cohort of 284 patients from New York.  Eight AJ founder mutations in the HEXA, SMPD1, and MCOLN1 genes were analyzed.  The frequencies of these mutations were compared to AJ control groups that included large published groups undergoing prenatal screening and 282 individuals matched for age and sex.  Mutation frequencies were similar in the 2 groups of patients with PD.  The SMPD1 p.L302P was strongly associated with a highly increased risk for PD (odds ratio 9.4, 95 % CI: 3.9 to 22.8, p < 0.0001), as 9/938 patients with PD were carriers of this mutation compared to only 11/10,709 controls.  The authors concluded that the SMPD1 p.L302P mutation is a novel risk factor for PD.  Although it is rare on a population level, the identification of this mutation as a strong risk factor for PD may further elucidate PD pathogenesis and the role of lysosomal pathways in disease development.  Moreover, these researchers noted that studies of SMPD1 mutations in other populations are needed to further ascertain the role of this gene in PD. 

In an editorial that accompanied the afore-mentioned study, Sharma (2013) stated that “While these data do not change the way in which patients with PD are diagnosed or treated, they do illustrate the utility of performing genetic studies in relatively ethnically homogeneous cohorts that have undergone careful clinical characterization …. The finding that a specific mutation in the SMPD1 enzyme is associated with an increased risk of PD gives further support to the hypothesis that defects in the ALP [autophagy-lysosomal pathway] play a role in the pathogenesis of PD and identifies another cellular pathway as a target for drug development”.

Wang and Wang (2013) stated that the glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) genes have been studied extensively as potential candidate genes for the risk of PD; however, direct evidence from genetic association studies remains inconclusive.  These researchers performed an updated and refined meta-analysis to determine the effect of GSTM1 and GSTT1 polymorphisms on PD.  A fixed-effect model was utilized to calculate the combined OR, OR of different ethnicities, and 95 % CIs.  Potential publication bias was estimated.  Homogeneity of the included studies was also evaluated.  The pooled OR was 1.13 [95 % CI: 1.03 to 1.24)] and 0.96 [95 % CI: 0.82 to 1.12)] for GSTM1 and GSTT1 polymorphisms, respectively.  Analysis according to different races found no association between GSTM1/GSTT1 polymorphisms and PD risks except for GSTM1 variant in Caucasians, which showed a weak correlation (OR 1.16 [95 % CI: 1.04 to 1.29), I squared = 6.2 %, p = 0.384]).  Neither publication bias nor heterogeneity was found among the included studies.  The authors concluded that the results of this meta-analysis suggested that GSTM1 polymorphism is weakly associated with the risk of PD in Caucasians whereas GSTT1 polymorphism is not a PD risk factor.

Jin and colleagues (2014) noted that several studies have been conducted in recent years to evaluate the risk of PD and polymorphisms of interleukin -10 (IL-10); however, the results were conflicting.  These researchers performed a meta-analysis of published case-control studies to assess this association.  Systematic searches of electronic databases PubMed Web of Science, BIOSIS Previews, Science Direct, Chinese Biomedical Database, WANFANG Database, and Chinese National Knowledge Infrastructure with hand-searching of the references of identified articles were conducted.  Data were extracted using a standardized form and pooled ORs with 95 % CIs were calculated to evaluate the strength of the association.  A total of 7 case-control studies involving 1,912 PD cases and 1,740 controls were included, concerning 2 polymorphisms (-1082A/G and -592C/A) of IL-10 gene.  No significant associations were found in the overall analysis for both -1082A/G and -592C/A polymorphisms with PD risk.  Similar lacking associations were observed in subgroup analysis based on ethnicity and age of onset.  The authors concluded that there is inadequate evidence for association between IL-10 polymorphisms (-1082A/G and -592C/A) and risk of PD at present.  Moreover, they stated that well-designed studies with larger sample-size and multi-ethnicity studies are needed in the future.

Mondello et al (2014) stated that α-synuclein, linked to the pathogenesis of PD, is a promising biomarker candidate in need of further investigation.  The ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a pivotal component of the ubiquitin proteasome system that seems to be disturbed in PD, may also be involved in the pathogenesis of this disorder.  These researchers investigated CSF α-synuclein and UCH-L1 levels from 22 healthy controls, 52 patients with PD, 34 with MSA, 32 with PSP, and 12 with CBD.  Cerebrospinal fluid α-Synuclein levels were significantly decreased in PD and in MSA compared with controls, and in synucleinopathies compared with tauopathies; UCH-L1 levels were significantly decreased in PD, MSA as well as PSP compared with controls, and in PD compared with APD (p < 0.001).  Both markers discriminated PD well from controls (p < 0.0001; AUC = 0.82 and 0.89, respectively).  Additionally, CSF α-synuclein separated patients with synucleinopathies from those with tauopathies (p = 0.015; AUC = 0.63), whereas CSF UCH-L1 discriminated between PD and APD (p = 0.0003; AUC = 0.69).  Interestingly, α-synuclein and UCH-L1 levels were strongly correlated in PD and synucleinopathies, and weakly in tauopathies.  No correlation was found in controls.  The authors concluded that CSF levels of α-synuclein and UCH-L1 showed distinct patterns in parkinsonian syndromes.  Their combined determination may be useful in the differential diagnosis of parkinsonian disorders and provided key to understanding their pathoetiology and clinical course.  Moreover, they stated that further large studies are needed to validate these findings.

Beach and colleagues (2013) stated that the clinical diagnosis of PD is incorrect in 30 % or more of subjects particularly at the time of symptom onset.  Because Lewy-type α-synucleinopathy (LTS) is present in the submandibular glands of PD patients, these researchers assessed the feasibility of submandibular gland biopsy for diagnosing PD.  They performed immunohistochemical staining for LTS in sections of large segments (simulating open biopsy) and needle cores of submandibular glands from 128 autopsied and neuropathologically classified subjects, including 28 PD, 5 incidental Lewy body disease, 5 PSP (3 with concurrent PD), 3 CBD, 2 MSA, 22 AD with Lewy bodies, 16 AD without Lewy bodies, and 50 normal elderly.  Immunoreactive nerve fibers were present in large submandibular gland sections of all 28 PD subjects (including 3 that also had PSP); 3 AD with Lewy bodies subjects were also positive, but none of the other subjects was positive.  Cores from frozen submandibular glands taken with 18-gauge needles (total length, 15 to 38 mm; between 10 and 118 sections per subject examined) were positive for LTS in 17 of 19 PD patients.  The authors concluded that these results suggested that biopsy of the submandibular gland may be a feasible means of improving PD clinical diagnostic accuracy.

Folgoas et al (2013) evaluated the diagnostic performance of minor salivary gland biopsy for PD.  Minor salivary glands were examined for Lewy pathology using phosphorylated alpha-synuclein antibody in 16 patients with clinically diagnosed PD and 11 control subjects with other neurological disorders.  Abnormal accumulation of alpha-synuclein was found in 3 out of 16 PD patients.  Two control subjects exhibited weak phosphorylated alpha-synuclein immunoreactivity.  The authors concluded that these  results did not support the use of minor salivary glands biopsy for the detection of Lewy pathology in living subjects.

Adler et al (2014) examined salivary gland biopsies in living patients with PD.  Patients with PD for greater than or equal to 5 years underwent outpatient transcutaneous needle core biopsies (18-gauge or 16-gauge) of 1 submandibular gland.  Minor salivary glands were removed via a small incision in the lower lip.  Tissue was fixed in formalin and serial 6-µm paraffin sections were immunohistochemically stained for phosphorylated α-synuclein and reviewed for evidence of LTS.  A total of 15 patients with PD were biopsied: 9 females/6 males, mean age of 68.7 years, mean PD duration of 11.8 years.  Twelve of the needle core biopsies had microscopically evident submandibular gland tissue to assess and 9/12 (75 %) had LTS.  Only 1/15 (6.7 %) minor salivary gland biopsies were positive for LTS; 5 patients had an adverse event; all were minor and transient.  The authors concluded that this study demonstrated the feasibility of performing needle core biopsies of the submandibular gland in living patients with PD to assess LTS.  Moreover, they stated that although this was a small study, this tissue biopsy method may be important for tissue confirmation of PD in patients being considered for invasive procedures and in research studies of other PD biomarkers.  One major drawback of this study was the lack of control subjects.  Also, this study did not include patients with other parkinsonian disorders, so determination of the specificity for LTS in submandibular gland biopsies for PD will require further study.  The authors stated that future studies should include patients with early-stage PD, control subjects, subjects with other parkinsonian disorders, and when possible, longitudinal studies extended to autopsy with neuropathologic confirmation of PD.

Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. l-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous  endoscopic gastrojejunostomy tube (PEG-J), which reduces l-dopa-plasma-level fluctuations and can translate to reduced motor complications. 

Olanow, et al. (2014) assessed the efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube. In a 12-week, randomized, double-blind, double-dummy, double-titration trial, investigators enrolled adults (aged ≥ 30 years) with advanced Parkinson's disease and motor complications at 26 centers in Germany, New Zealand, and the United States. Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube, and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. Randomization was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. Investigators assessed change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome. They assessed efficacy in a full-analysis set of participants with data for baseline and at least one post-baseline assessment, and imputed missing data with the last observation carried forward approach. They assessed safety in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4.04 h (SE 0.65) for 35 patients allocated to the levodopa-carbidopa intestinal gel group compared with a decrease of 2.14 h (0.66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference -1.91 h [95% CI -3.05 to -0.76]; p=0.0015). Mean on-time without troublesome dyskinesia increased by 4.11 h (SE 0.75) in the intestinal gel group and 2.24 h (0.76) in the immediate-release oral group (difference 1.86 [95% CI 0.56 to 3.17]; p=0.0059). In the safety analyses 35 (95%) of 37 patients allocated to the levodopa-carbidopa intestinal gel group had adverse events (five [14%] serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven [21%] serious), mainly associated with the percutaneous gastrojejunostomy tube. The investigators concluded that continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson's disease with motor complications.

An accompanying editorial (Rascol, 2014) noted some of the limitations of the RCT by Olanow, et al. The editorialist noted that the trial by Olanow, et al. was small (71 patients) and short (3 months). This design prevented long-term conclusions and provided insufficient power to assess rare adverse events such as polyneuropathy and Guillain-Barré syndrome, or even more common ones such as impulse-control disorders. The editorialist noted that unmasking factors because of efficacy (as with any strongly efficacious intervention) or black coloration of the tube caused by levodopa oxidation might have enhanced placebo response on the active infusion. The editorialist noted that, unfortunately no formal assessment of masking was done. The editorialist noted that patients on sustained-release levodopa-carbidopa formulations had to be converted to immediate-release levodopa-carbidopa to allow double-blind adjustments during the trial. This design deprived the trial participants of the benefit of the long-term oral formulation, thus favoring the active infusion. Moreover, forbidding changes in oral dosing frequency during the titration phase might have induced similar consequences. Finally, head-to-head comparisons have not been done to assess the respective advantages and disadvantages of levodopa jejunal infusion versus the two main alternatives for management of severe problems with refractory off -time complications: continuous subcutaneous apomorphine infusion and functional surgery.

Fernandez, et al. (2014) reported on the results of a prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day "off" time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, "on" time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. The investigators reported that most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. The investigators stated that LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function daily activities, and HRQoL sustained over 54 weeks.

Cáceres-Redondo, et al. (2014) reported on the motor and cognitive outcome of LCIG treatment in advanced PD after a follow-up period of at least 24 months. The investigators assessed 29 patients with advanced PD who started LCIG infusion at one center between 2007 and 2013. Motor fluctuations, parkinsonian symptoms, activities of daily living and impact on quality of life were evaluated. They also evaluated the cognitive outcome using a battery of neuropsychological tests. All adverse events were recorded. Of the 29 PD patients who initiated LCIG, 16 patients reached the follow-up evaluation (24 months), after a mean time period of 32.2 ± 12.4 months. Six patients did not fulfil the 24-month follow-up visit and were evaluated after a mean time period of 8.6 ± 5.4 months. Seven patients discontinued the treatment before the scheduled visit. The authors reported that "Off" time and "On" dyskinesia duration were significantly reduced. LCIG improved quality of life and non-motor symptoms, despite overall unchanged total levodopa doses prior to LCIG beginning. Motor and cognitive decline were detected. The authors noted that a relatively high number of adverse events occurred during the follow-up, above all, technical problems with the infusion device and mild problems related with gastrostomy. There were four cases of peripheral neuropathy (PN), 2 of which were considered serious. The authors stated that their data confirm that LCIG is beneficial in the long-term treatment of advanced PD patients despite a decline in cognitive functions in a subgroup of patients, probably due to disease progression. PN in patients with LCIG may be more frequent than the published data suggest.

Zibetti, et al. (2014) analyzed all PD patients treated with LCIG at their center over a 7-year period to determine the duration of treatment, retention rate, reasons for discontinuation, LCIG efficacy in motor complications, modifications of concomitant therapy and adverse events. Of the 59 patients, seven subjects (12%) died of causes unrelated to LCIG infusion and 11 patients (19%) discontinued therapy prior to the cut-off date. The authors reported that Duodopa improved motor complications and over 90% of patients reported an improvement in their quality of life, autonomy and clinical global status. The most common adverse events were dislocation and kinking of the intestinal tube.

According to the FDA-approved labeling of Duopa, the maximum recommended daily dose of Duopa is 2000 mg of levodopa (i.e., one cassette per day) administered over 16 hours. Prior to initiating Duopa levodopa and carbidopa enteral suspension, patients should be converted from all forms of levodopa to oral immediate-release carbidopa-levodopa tablets (1:4 ratio). The total daily dose is titrated based on the clinical response for the patient. Duopa is administered into the jejunum through a percutaneous endoscopic gastrostomy with jejunal tube (PEG-J) with the CADD-Legacy 1400 portable infusion pump.

CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
ICD-10 codes will become effective as of October 1, 2015 :
Diagnostic Tests:
CPT codes covered if selection criteria are met:
96118 - 96120 Neuropsychological testing
Surgical Procedures:
CPT codes covered if selection criteria are met:
61720 Creation of lesion by stereotactic method, including burr hole(s) and localizing and recording techniques, single or multiple stages; globus pallidus or thalamus
61735     subcortical structure(s) other than global pallidus of thalamus
61863 Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g., thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), without use of intraoperative microelectrode recording; first array
+ 61864     each additional array (List separately in addition to primary procedure)
61867 Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g., thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), with use of intraoperative microelectrode recording, first array
+ 61868     each additional array (List separately in addition to primary procedure)
CPT codes not covered for indications listed in the CPB:
38232 Bone marrow harvesting for transplantation; autologous
38240 Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241     autologous transplantation
42400 Biopsy of salivary gland; needle [submandibular]
61850 Twist drill or burr hole(s) for implantation of neurostimulator electrodes, cortical
61860 Craniectomy or craniotomy for implantation of neurostimulator electrodes, cerebral, cortical
70551 - 70553 Magnetic resonance (eg, proton) imaging, brain (including brain stem) [for differentiating PD from other parkinsonian syndromes]
78607 Brain imaging, tomographic (SPECT)
80428 Growth hormone stimulation panel (e.g., arginine infusion, l-dopa administration)
81330 SMPD1 (sphingomyelin phosphodiesterase 1, acid lysosomal)(eg, Niemann-Pick disease, Type A) gene analysis, common variants (eg, R496L, L302P, fsP330)
82172 Apolipoprotein, each [not covered for apolipoprotein E (APOE)]
83890 - 83913 Molecular diagnostics [not covered for alpha-synuclein, DJ1, LRRK2/PARK8, parkin/PARK2, PINK1, and CSF amyloid beta 1-42]
88341 - 88344 Immunohistochemistry or immunocytochemistry, per specimen [ICSF alpha-synuclein test as a biomarker for PD] [cerebrospinal fluid ubiquitin carboxy-terminal hydrolase L1 (UCH-L1]
90867 Therapeutic repetitive transcranial [direct current] magnetic stimulation treatment; planning [for the treatment of PD]
90868 Delivery and management, per session [for the treatment of PD]
90869   subsequent delivery and management, per session [for the treatment of PD]
92270 Electro-oculography with interpretation and report
93660 Evaluation of cardiovascular function with tilt table evaluation, with continuous ECG monitoring, with or without pharmacological intervention [for differentiating PD from other parkinsonian syndromes]
93890 Transcranial Doppler study of the intracranial arteries; vasoreactivity study
95961 Functional cortical and subcortical mapping by stimulation and/or recording of electrodes on brain surface, or of depth electrodes, to provoke seizures or identify vital brain structures; initial hour of attendance by a physician or other qualified health care professional
95962     each additional hour of attendance by a physician or other qualified health care professional (List separately in addition to code for primary procedure)
99183 Physician attendance and supervision of hyperbaric oxygen therapy, per session
Modifier 7A APOE, commonly called apolipoprotein E (cardiovascular disease or Alzheimer's disease)
HCPCS codes covered if selection criteris are met:
A9584 Iodine 1-123 ioflupane, diagnostic, per study dose, up to 5 millicuries [to distinguish PD from essential tremor]
HCPCS codes not covered for indications listed in the CPB:
A4575 Topical hyperbaric oxygen chamber, disposable
E0446 Topical oxygen delivery system, not otherwise specified, includes all supplies and accessories
G0277 Hyperbaric oxygen under pressure, full body chamber, per 30 minute interval
G0461 Immunohistochemistry or immunocytochemistry, per specimen; first single or multiplex antibody stain
G0462     each additional single or multiplex antibody stain (list separately in addition to code for primary procedure)
S8042 Magnetic resonance imaging (MRI), low-field [for differentiating PD from other parkinsonian syndromes]
Other HCPCS codes related to the CPB:
J0364 Injection, apomorphine hydrochloride, 1 mg
J0735 Injection, clonidine HCl, 1 mg
J1265 Injection, dopamine HCl, 40 mg
ICD-10 codes covered if selection criteria are met:
F06.8 Other specified mental disorders due to known physiological condition [development of dementia in parkinsonism]
G20 Parkinson's disease
G21.0 - G21.9 Secondary parkinsonism
G23.1 Progressive supranuclear ophthalmoplegia [Steele-Richardson-Olszewski] [supranuclear palsy associated with parkinsonism] [covered for levodopa or apomorphine challenge, olfactory testing by UPSIT or Sniffin' Sticks, and neuropsychological testing]
G31.85 Corticobasal degeneration [covered for levodopa or apomorphine challenge, olfactory testing by UPSIT or Sniffin' Sticks, and neuropsychological testing]
ICD-10 codes not covered for indications listed in the CPB:
F06.0 - F06.4 Other mental disorders due to known physiological condition
G30.0 - G30.9 Alzheimer's disease
G31.01 - G31.9 Other degenerative disease of nervous system, not elsewhere classified [atrophy]
R64 Cachexia
Z74.01 Bed confinement status
SPECT Scanning:
CPT codes covered if selection criteria are met:
78607 Brain imaging, tomographic (SPECT) [to distinguish PD from essential tremor]
HCPCS codes covered if selection criteria are met:
A9584 Iodine 1-123 ioflupane, diagnostic, per study dose, up to 5 millicuries [to distinguish PD from essential tremor]
ICD-10 codes covered if selection criteria are met:
G20 Parkinson's Disease
G21.11 - G21.19 Other drug-induced secondary parkinsonism
G25.0 -G25.2 Essential, drug-induced and other specified forms of tremor

The above policy is based on the following references:
    1. Dogali M, Fazzini E, Kolodny E, et al. Stereotactic ventral pallidotomy for Parkinson's disease. Neurology. 1995;45(4):753-761.
    2. Iacono RP, Shima F, Lonser RR, et al. The results, indications, and physiology of posteroventral pallidotomy for patients with Parkinson's disease. Neurosurgery. 1995;36(6):1118-1125; discussion 1125-1127.
    3. Laitinen LV. Pallidotomy for Parkinson's disease. Neurosurg Clin North Am. 1995;6(1):105-112.
    4. Lang AE, Lozano AM, Montgomery E, et al. Posterolateral medial pallidotomy in advanced Parkinson's disease. N Engl J Med. 1997;337(15):1036-1042.
    5. Uitti RJ, Wharen RE Jr, Turk MF, et al. Unilateral pallidotomy for Parkinson's disease: Comparison of outcome in younger versus elderly patients. Neurology. 1997;49(4):1072-1077.
    6. Ondo WG, Jankovic J, Lai EC, et al. Assessment of motor function after stereotactic pallidotomy. Neurology. 1998;50(1):266-270.
    7. Shannon KM, Penn RD, Kroin JS, et al. Stereotactic pallidotomy for the treatment of Parkinson's disease. Efficacy and adverse effects at 6 months in 26 patients. Neurology. 1998;50(2):434-438.
    8. Samuel M, Caputo E, Brooks DJ, et al. A study of medial pallidotomy for Parkinson's disease: Clinical outcome, MRI location and complications. Brain. 1998;121 (Pt 1):59-75.
    9. Parkinsonism. In: Cecil Textbook of Medicine. Vol. 2. JB Wyngaarden, LH Smith, JC Bennett, eds. St. Louis, MO: W.B. Saunders, Co.; 1992: Ch. 458, pp. 2130-2133.
    10. American Academy of Neurology. Practice parameters: Initial therapy of Parkinson's disease. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1993;43:1296-1297.
    11. Beal MF, et al. Parkinson's disease and other extrapyramidal disorders. In: Harrison's Principles of Internal Medicine. Vol. 2. 13th ed. K.J. Isselbacher, et al., eds. New York, NY: McGraw Hill, Inc.; 1994; Ch. 371: 2275-2280.
    12. Langston JW, Widner H, Goetz CG, et al. Core assessment program for intracerebral transplantation (CAPIT). Mov Disord. 1992;7(1):2-13.
    13. Martinez-Martin P, Gil-Nagel A, Gracia LM, et al. Unified Parkinson's disease rating scale characteristics and structure. Mov Disord. 1994;9(1):76-83.
    14. British Columbia Office of Health Technology Assessment (BCOHTA). Fetal tissue transplantation for Parkinson's Disease. Technology Assessment No. 6. Vancouver, BC: BCOHTA; Winter 1994:7-8.
    15. Robert G. Pallidotomy for Parkinson's disease. Development and Evaluation Committee DEC Report No. 51. Southampton, UK: Wessex Institute for Health Research and Development (WIHRD); 1996.
    16. Hoffer BJ, Horne CV. Editorial: Survival of dopaminergic neurons in fetal- issue grafts. N Engl J Med. 1995;332(17):1163-1164.
    17. Olanow CW, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease: Treatment guidelines. American Academy of Neurology. Neurology. 1998;50(3 Suppl 3):S1-S57.
    18. Harstall C, Hailey D. Posteroventral pallidotomy in Parkinson's disease. HTA2. Edmonton, AB: Alberta Heritage Foundation for Medical Research (AHFMR); January 1997.
    19. Kottler A, Hayes D. Stereotactic pallidotomy for treatment of Parkinson's disease. Technology Assessment Program Report No. 8. Boston, MA:  U. S. Department of Veterans Affairs, Office of Patient Care Services, Technology Assessment Program (VATAP); 1998.
    20. Tornqvist AL. Neurosurgery for movement disorders. J Neurosci Nurs. 2001;33(2):79-82.
    21. Lindvall O. Neural transplantation in Parkinson's disease. Novartis Found Symp. 2000;231:110-123.
    22. Follett KA. The surgical treatment of Parkinson's disease. Annu Rev Med. 2000;51:135-147.
    23. Hermanowicz N. Management of Parkinson's disease. Strategies, pitfalls, and future directions. Postgrad Med. 2001;110(6):15-18, 21-23, 28.
    24. Kolchinsky A. Neurosurgical intervention for Parkinson's disease: An update. Surg Neurol. 2001;56(4):277-281.
    25. Eskandar EN, Cosgrove GR, Shinobu LA. Surgical treatment of Parkinson disease. JAMA. 2001;286(24):3056-3059.
    26. Clarkson ED. Fetal tissue transplantation for patients with Parkinson's disease: A database of published clinical results. Drugs Aging. 2001;18(10):773-785.
    27. Djaldetti R, Melamed E. New therapies for Parkinson's disease. J Neurol. 2001;248(5):357-362.
    28. Lindvall O, Hagell P. Cell therapy and transplantation in Parkinson's disease. Clin Chem Lab Med. 2001;39(4):356-361.
    29. Zesiewicz TA, Hauser RA. Neurosurgery for Parkinson's disease. Semin Neurol. 2001;21(1):91-101.
    30. Subramanian T. Cell transplantation for the treatment of Parkinson's disease. Semin Neurol. 2001;21(1):103-115.
    31. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease (2001): Treatment guidelines. Neurology. 2001;56(11 Suppl 5):S1-S88.
    32. Nicholson T, Milne R. Pallidotomy, thalamotomy and deep brain stimulation for severe Parkinson's disease. Development and Evaluation Committee Report; 105. Southampton, UK: Wessex Institute for Health Research and Development; 1999.
    33. Hallett M, Litvan I. Evaluation of surgery for Parkinson's disease: A report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. The Task Force on Surgery for Parkinson's Disease. Neurology. 1999;53(9):1910-1921.
    34. Hagell P. Restorative neurology in movement disorders. J Neurosci Nurs. 2000;32(5):256-262.
    35. Siderowf A, Stern M. Update on Parkinson disease. Ann Intern Med. 2003;138(8):651-658.
    36. BlueCross BlueShield Association (BCBSA), Technology Evaluation Center (TEC). Embryonic mesencephalic transplantation for the treatment of Parkinson's disease. TEC Assessment Program. Chicago IL: BCBSA; 2001;16(8).
    37. Swedish Council on Technology Assessment in Health Care (SBU). Cell transplantation in Parkinson's disease - early assessment briefs (Alert). Stockholm, Sweden: SBU; 2002.
    38. Swedish Council on Technology Assessment in Health Care (SBU). Pallidotomy in Parkinson's disease - early assessment briefs (ALERT). Stockholm, Sweden: SBU; 2002.
    39. Trost M, Su PC, Barnes A, et al. Evolving metabolic changes during the first postoperative year after subthalamotomy. J Neurosurg. 2003;99(5):872-878.
    40. Levine CB, Fahrbach KR, Siderowf AD. Diagnosis and treatment of Parkinson's disease: A systematic review of the literature. Evidence Report/Technology Assessment 57. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2003.
    41. National Institute for Clinical Excellence (NICE). Subthalamotomy for Parkinson's disease. Inteventional Procedures Guidance 65. London, UK: NICE; June 2004.
    42. Roitberg B, Urbaniak K, Emborg M. Cell transplantation for Parkinson's disease. Neurol Res. 2004;26(4):355-362.
    43. Drucker-Colin R, Verdugo-Diaz L. Cell transplantation for Parkinson's disease: Present status. Cell Mol Neurobiol. 2004;24(3):301-316.
    44. Doss MX, Koehler CI, Gissel C, et al. Embryonic stem cells: A promising tool for cell replacement therapy. J Cell Mol Med. 2004;8(4):465-473.
    45. Clarke C, Moore AP. Parkinson's disease. In: BMJ Clinical Evidence. London, UK: BMJ Publishing Group; November 2006.
    46. Snyder BJ, Olanow CW. Stem cell treatment for Parkinson's disease: An update for 2005. Curr Opin Neurol. 2005;18(4):376-385.
    47. Fillmore HL, Holloway KL, Gillies GT. Cell replacement efforts to repair neuronal injury: A potential paradigm for the treatment of Parkinson's disease. NeuroRehabilitation. 2005;20(3):233-242.
    48. Stover NP, Bakay RA, Subramanian T, et al. Intrastriatal implantation of human retinal pigment epithelial cells attached to microcarriers in advanced Parkinson disease. Arch Neurol. 2005;62(12):1833-1837.
    49. Lefaucheur JP. Motor cortex stimulation for Parkinson's disease and dystonia: Lessons from transcranial magnetic stimulation? A review of the literature. Rev Neurol (Paris). 2005;161(1):27-41.
    50. Pagni CA, Altibrandi MG, Bentivoglio A, et al. Extradural motor cortex stimulation (EMCS) for Parkinson's disease. History and first results by the study group of the Italian neurosurgical society. Acta Neurochir Suppl. 2005;93:113-119.
    51. Augustovski F, Pichon Riviere A, Alcaraz A, et al.. Functional magnetic resonance imaging for brain pathologies [summary]. Report IRR No. 50. Buenos Aires, Argentina: Institute for Clinical Effectiveness and Health Policy (IECS); 2005.
    52. Piccini P, Whone A. Functional brain imaging in the differential diagnosis of Parkinson's disease. Lancet Neurol. 2004;3(5):284-290.
    53. Rihmer Z, Seregi K, Rihmer A. Parkinson's disease and depression. Neuropsychopharmacol Hung. 2004;6(2):82-85.
    54. Ghosh B, Mishra A, Sengupta P. Is Parkinson's disease a homogeneous disorder--what is the burden of Parkinson's disease in India. J Indian Med Assoc. 2005;103(3):146, 148, 150 passim.
    55. Winogrodzka A, Booij J, Wolters ECh. Disease-related and drug-induced changes in dopamine transporter expression might undermine the reliability of imaging studies of disease progression in Parkinson's disease. Parkinsonism Relat Disord. 2005;11(8):475-484.
    56. Seibyl J, Jennings D, Tabamo R, Marek K. The role of neuroimaging in the early diagnosis and evaluation of Parkinson's disease. Minerva Med. 2005;96(5):353-364.
    57. Seppi K, Schocke MF. An update on conventional and advanced magnetic resonance imaging techniques in the differential diagnosis of neurodegenerative parkinsonism. Curr Opin Neurol. 2005;18(4):370-375.
    58. Ravina B, Eidelberg D, Ahlskog JE, et al. The role of radiotracer imaging in Parkinson disease. Neurology. 2005;64(2):208-215.
    59. Nutt JG, Wooten GF. Clinical practice. Diagnosis and initial management of Parkinson's disease. N Engl J Med. 2005;353(10):1021-1027.
    60. Papapetropoulos S, Mash DC. Psychotic symptoms in Parkinson's disease. From description to etiology. J Neurol. 2005;252(7):753-764.
    61. Lauterbach EC. The neuropsychiatry of Parkinson's disease. Minerva Med. 2005;96(3):1551-73.
    62. Levin BE, Katzen HL. Early cognitive changes and nondementing behavioral abnormalities in Parkinson's disease. Adv Neurol. 2005;96:84-94.
    63. McInerney-Leo A, Hadley DW, Gwinn-Hardy K, Hardy J. Genetic testing in Parkinson's disease. Mov Disord. 2005;20(1):1-10.
    64. Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson's disease. Lancet Neurol. 2006;5(1):75-86.
    65. Klein C. Implications of genetics on the diagnosis and care of patients with Parkinson disease. Arch Neurol. 2006;63(3):328-334.
    66. Suchowersky O, Reich S, Perlmutter J, et al. Practice Parameter: Diagnosis and prognosis of new onset Parkinson disease (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66(7):968-975.
    67. Miyasaki JM, Shannon K, Voon V, et al. Practice Parameter: Evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66(7):996-1002.
    68. Suchowersky O, Gronseth G, Perlmutter J, et al. Practice parameter: Neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66(7):976-982.
    69. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: Treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66(7):983-995.
    70. Elbaz A, Nelson LM, Payami H, et al. Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: A large-scale international study. Lancet Neurol. 2006;5(11):917-923.
    71. Benvenuti E, Cecchi F, Colombini A, Gori G. Extradural motor cortex stimulation as a method to treat advanced Parkinson's disease: New perspectives in geriatric medicine. Aging Clin Exp Res. 2006;18(4):347-348
    72. National Institute for Health and Clinical Excellence (NICE). Parkinson's disease: Diagnosis and management in primary and secondary care. Clinical Guideline 35. London, UK: NICE; 2006.
    73. Nichols WC, Marek DK, Pauciulo MW, et al; Parkinson Study Group - PROGENI Investigators. R1514Q substitution in Lrrk2 is not a pathogenic Parkinson's disease mutation. Mov Disord. 2007;22(2):254-257.
    74. Beyer MK, Larsen JP, Aarsland D. Gray matter atrophy in Parkinson disease with dementia and dementia with Lewy bodies. Neurology. 2007;69(8):747-754.
    75. Seppi K, Rascol O. Dementia with Lewy bodies and Parkinson disease with dementia: Can MRI make the difference? Neurology. 2007;69(8):717-718.
    76. Klein C, Lohmann-Hedrich K, Rogaeva E, et al. Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol. 2007;6(7):652-662.
    77. Factor SA. Genetics of Parkinson disease is complex. Journal Watch Neurology, September 11, 2007.
    78. Cioni B. Motor cortex stimulation for Parkinson's disease. Acta Neurochir Suppl. 2007;97(Pt 2):233-238.
    79. Arle JE, Apetauerova D, Zani J, et al. Motor cortex stimulation in patients with Parkinson disease: 12-month follow-up in 4 patients. J Neurosurg. 2008;109(1):133-139.
    80. Vlaar AM, Bouwmans A, Mess WH, et al. Transcranial duplex in the differential diagnosis of parkinsonian syndromes: A systematic review. J Neurol. 2009 Feb 17. [Epub ahead of print].
    81. Williams-Gray CH, Goris A, Saiki M, Foltynie T, et al. Apolipoprotein E genotype as a risk factor for susceptibility to and dementia in Parkinson's disease. J Neurol. 2009;256(3):493-498.
    82. Kurz MW, Dekomien G, Nilsen OB, et al. APOE alleles in Parkinson disease and their relationship to cognitive decline: A population-based, longitudinal study. J Geriatr Psychiatry Neurol. 2009;22(3):166-170.
    83. Riley DE, Chelimsky TC. Autonomic nervous system testing may not distinguish multiple system atrophy from Parkinson's disease. J Neurol Neurosurg Psychiatry. 2003;74(1):56-60.
    84. Martin HL, Teismann P. Glutathione -- a review on its role and significance in Parkinson's disease. FASEB J. 2009;23(10):3263-3272.
    85. Hauser RA, Lyons KE, McClain T, et al. Randomized, double-blind, pilot evaluation of intravenous glutathione in Parkinson's disease. Mov Disord. 2009;24(7):979-983.
    86. Sedlácková S, Rektorová I, Srovnalová H, Rektor I. Effect of high frequency repetitive transcranial magnetic stimulation on reaction time, clinical features and cognitive functions in patients with Parkinson's disease. J Neural Transm. 2009;116(9):1093-1101.
    87. Arias P, Vivas J, Grieve KL, Cudeiro J. Double-blind, randomized, placebo controlled trial on the effect of 10 days low-frequency rTMS over the vertex on sleep in Parkinson's disease. Sleep Med. 2010a;11(8):759-765.
    88. Arias P, Vivas J, Grieve KL, Cudeiro J. Controlled trial on the effect of 10 days low-frequency repetitive transcranial magnetic stimulation (rTMS) on motor signs in Parkinson's disease. Mov Disord. 2010b;25(12):1830-1838.
    89. Filipović SR, Rothwell JC, Bhatia K. Low-frequency repetitive transcranial magnetic stimulation and off-phase motor symptoms in Parkinson's disease. J Neurol Sci. 2010;291(1-2):1-4.
    90. Benninger DH, Lomarev M, Lopez G, et al. Transcranial direct current stimulation for the treatment of Parkinson's disease. J Neurol Neurosurg Psychiatry. 2010;81(10):1105-1111.
    91. Reimann M, Schmidt C, Herting B, et al. Comprehensive autonomic assessment does not differentiate between Parkinson's disease, multiple system atrophy and progressive supranuclear palsy. J Neural Transm. 2010;117(1):69-76.
    92. Tokuda T, Qureshi MM, Ardah MT, et al. Detection of elevated levels of α-synuclein oligomers in CSF from patients with Parkinson disease. Neurology. 2010;75(20):1766-1772.
    93. Ballard CG, Jones EL. CSF α-synuclein as a diagnostic biomarker for Parkinson disease and related dementias. Neurology. 2010;75(20):1760-1761.
    94. Siderowf A, Xie SX, Hurtig H, et al. CSF amyloid {beta} 1-42 predicts cognitive decline in Parkinson disease. Neurology. 2010;75(12):1055-1061.
    95. Aarsland D, Ravina B. Biomarkers of PD progression: Is CSF the answer? Neurology. 2010;75(12):1036-1037.
    96. Benninger DH, Berman BD, Houdayer E, et al. Intermittent theta-burst transcranial magnetic stimulation for treatment of Parkinson disease. Neurology. 2011;76(7):601-609.
    97. Klassen BT, Hentz JG, Shill HA, et al. Quantitative EEG as a predictive biomarker for Parkinson disease dementia. Neurology. 2011;77(2):118-124.
    98. Espay AJ, Dwivedi AK, Payne M, et al. Methylphenidate for gait impairment in Parkinson disease: A randomized clinical trial. Neurology. 2011;76(14):1256-1262.
    99. de la Fuente-Fernández R. Role of DaTSCAN and clinical diagnosis in Parkinson’s disease. Neurology. 2012;78(10):696-701.
    100. Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and pharmacological management of Parkinson's disease. A national clinical guideline. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network (SIGN); January 2010.
    101. Chou KL. Diagnosis of Parkinson disease. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed May 2012.
    102. Fink JS, Schumacher JM, Ellias SL, et al. Porcine xenografts in Parkinson's disease and Huntington's disease patients: Preliminary results. Cell Transplantation. 2000; 9(2):272-278.
    103. Cederfjall E, Sahin G, Kirik D. Key factors determining the efficacy of gene therapy for continuous DOPA delivery in the Parkinsonian brain. Neurobiol Dis. 2012;48(2):222-227.
    104. Besong-Agbo D, Wolf E, Jessen F, et al. Naturally occurring α-synuclein autoantibody levels are lower in patients with Parkinson disease. Neurology. 2013;80(2):169-175.
    105. Beach TG, Adler CH, Dugger BN, et al. Submandibular gland biopsy for the diagnosis of Parkinson disease. J Neuropathol Exp Neurol. 2013;72(2):130-136.
    106. Folgoas E, Lebouvier T, Leclair-Visonneau L, et al. Diagnostic value of minor salivary glands biopsy for the detection of Lewy pathology. Neurosci Lett. 2013;551:62-64.
    107. Adler CH, Dugger BN, Hinni ML, et al. Submandibular gland needle biopsy for the diagnosis of Parkinson disease. Neurology. 2014;82(10):858-864.
    108. Gan-Or Z, Ozelius LJ, Bar-Shira A, et al. The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease. Neurology. 2013;80(17):1606-1610.
    109. Sharma N. Lysosomal enzyme defects and Parkinson disease. Neurology. 2013;80(17):1544-1545.
    110. Wang T, Wang B. Association between glutathione S-transferase M1/glutathione S-transferase T1 polymorphisms and Parkinson's disease: A meta-analysis. J Neurol Sci. 2013 Dec 17. [Epub ahead of print]
    111. Jin J, Wu P, Li W, et al. Interleukin-10 -1082A/G and -592C/A polymorphisms with risk of Parkinson's disease: A meta-analysis. Int J Neurosci. 2014 Jan 7. [Epub ahead of print]
    112. Mondello S, Constantinescu R, Zetterberg H, et al. CSF α-synuclein and UCH-L1 levels in Parkinson's disease and atypical parkinsonian disorders. Parkinsonism Relat Disord. 2014 Jan 22. [Epub ahead of print]
    113. Fernandez HH, Standaert DG, Hauser RA, et al. Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: Final 12-month, open-label results. Mov Disord. 2014 Dec 24 [Epub ahead of print].
    114. Cáceres-Redondo MT, Carrillo F, Lama MJ, et al. Long-term levodopa/carbidopa intestinal gel in advanced Parkinson's disease. J Neurol. 2014;261(3):561-569.
    115. Olanow CW, Kieburtz K, Odin P, et al.; LCIG Horizon Study Group. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: A randomised, controlled, double-blind, double-dummy study. Lancet Neurol. 2014;13(2):141-149.
    116. AbbVie, Inc. Duopa (carbidopa and levodopa) intestinal suspension. Prescribing Information. North Chicago, IL: AbbVie; revised May 2015.
    117. Zibetti M, Merola A, Artusi CA, et al. Levodopa/carbidopa intestinal gel infusion in advanced Parkinson's disease: A 7-year experience. Eur J Neurol. 2014;21(2):312-318.
    118. Rascol O. Jejunal levodopa infusion in Parkinson's disease. Lancet Neurol. 2014;13(2):128-129.

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