Abstract
Background
A good response to levodopa is a key feature of Parkinson's disease (PD), and a poor response suggests an alternative diagnosis, but the extent of variation in the levodopa response in definite PD is not well defined.
Literature Review
A systematic review of articles reporting pathologically confirmed PD and levodopa responsiveness from 1971 to 2018 was performed using the medical subheadings “postmortem,” “Parkinson's disease,” "levodopa," and “l‐dopa” in PubMed, Embase, and Latin American and Caribbean Health Sciences Literature (LILACS) databases.
Cases
A total of 12 articles described 445 PD cases: 61.7% male, age at disease onset 64.0 years (SD 9.6), age at death 77.1 years (SD 7.2). Levodopa responsiveness was reported in 399 cases (89.7%) either as a graded or a binary response. In the 280 cases (70.2%) describing a graded response, it was excellent in 37.5%, good in 45.7%, moderate in 12.1%, and poor in 4.6%. In the 119 cases describing a binary response (29.8%), 73.1% were levodopa responsive, and 26.9% were nonresponsive. Comorbid brain pathology was present in 137 of 235 cases assessed, being cerebrovascular in 46.0% and Alzheimer's disease in 37.2% of these, but its contribution to levodopa responsiveness was unclear.
Conclusions
The levodopa motor response varies in definite PD. Explanations other than diagnostic inaccuracy should be explored.
Keywords: L‐dopa response, Parkinson's disease, pathological
Clinical diagnostic criteria for idiopathic Parkinson's disease (PD) require the presence of core motor features supported by an excellent or clear and dramatic levodopa (l‐dopa) response.1, 2 These criteria help to reduce clinical diagnostic error rates of between 5% and 25%, where idiopathic PD is not confirmed at autopsy.3, 4 These observations might suggest that a less than excellent response to l‐dopa is incompatible with a diagnosis of PD and that variation in the l‐dopa response in clinical trials is the result of diagnostic error.5 Clinically, benign disorders can be excluded by functional neuroimaging,5 but this does not exclude other neurodegenerative parkinsonian conditions. Assessing pathologically confirmed PD cases should give a clearer indication of the degree of variation in l‐dopa response and was the objective of the present study.
Case Series
Features of the l‐dopa Response
A total of 445 pathologically confirmed PD patients (61.7% male) were identified, age at onset was 64.0 (standard deviation [SD] 9.6) years, l‐dopa treatment was started 3.1 (SD 3.6) years after diagnosis, and disease duration at death was 13.0 (SD 6.5) years. Age at death was 77.1 (SD 7.2) years (Tables 1 and 2).
Table 1.
Clinical and pathological features in 445 pathologically confirmed PD patients
| Variables | PD Cases, n = 445 | Publications, n = 12 |
|---|---|---|
| Age at onset, y | 64.0 (9.6) | 12 |
| Disease duration at death, y | 13.0 (6.5) | 12 |
| Age at death, y | 77.1 (7.2) | 12 |
| Symptom onset to starting levodopa treatment, y | 3.1 (3.6) | 2 |
| Levodopa motor response reported | 399/445 (89.7%) | 12 |
| Graded | 280/399 (70.2%) | 5 |
| Excellent (>70%) | 105 (37.5%) | |
| Good (50–70%) | 128 (45.7%) | |
| Moderate (30–50%) | 34 (12.1%) | |
| None‐to‐poor (<30%) | 13 (4.6%) | |
| Binary | 119/399 (29.8%) | 7 |
| Responsive | 87 (73.1%) | |
| Unresponsive | 32 (26.9%) | |
| Treatment duration, y | 10.9 (0.7) | 4 |
| Dementia | 51/445 (11.5%) | 5 |
| Assessed for comorbid pathology | 235/399 (58.9%) | 6 |
| Comorbid pathology present | 137/235 (58.3%) | |
| Cerebrovascular | 63 (46.0%) | |
| Alzheimer type | 51 (37.2%) | |
| Amyloid angiopathy | 17 (12.4%) | |
| Diffuse Lewy body disease | 5 (3.7%) | |
| Progressive supranuclear palsy | 1 (0.7%) |
Data are mean (standard deviation) or n (%).
PD, Parkinson's disease.
Table 2.
Demographics in pathologically confirmed PD patients reporting the motor response to levodopa
| Study | PD Patients Total, n | Male, n | PD Patients with Reported Levodopa Response, n | Type of Levodopa Response Grading | Clinical Rating Scales Used | Mean Age at PD Onset, Years (SD) | Mean Age at Death, Years (SD) | Disease Duration, Years (SD) | Onset to Starting Levodopa, Years (SD) |
|---|---|---|---|---|---|---|---|---|---|
| Total | 445 (100%) | 221 (61.7%) | 399 (89.7%) | 64.0 (9.6) | 77.1 (7.2) | 13.0 (6.5) | 3.1 (3.6) | ||
| Hughes et al, 19921 | 76 | Not stated | 69 | Graded | H&Y | 63.6 (13.3) | 76.4 (10.25) | 12.8 (7.0) | Not stated |
| Hughes et al, 199310 | 100 | 65 | 95 | Graded | H&Y, MMSE, DSM 3 | 62.5 (9.2) | 75.6 (6.7) | 13.1 (6.3) | 3.2 (3.7) |
| Rajput et al, 199315 | 26 | 18 | 20 | Binary | H&Y, Webster | 58.8 (8.8) | 70.8 (8.5) | 11.7 (9.3) | Not stated |
| De Vos et al, 19957 | 18 | 9 | 18 | Binary | H&Y, MMSE, DSM 3, HAM‐D | 66.2 (NS) | 76.3 (NS) | 10.1 (NS) | Not stated |
| Halliday et al, 19969 | 11 | 8 | 6 | Binary | CDR | 67.4 (8.7) | 77.6 (5.4) | 10.3 (5.7) | Not stated |
| Louis et al, 199712 | 34 | 22 | 14 | Binary | None | 62.0 (NS) | 76.0 (NS) | 14.5 (NS) | Not stated |
| Litvan et al, 19984 | 11 | Not stated | 11 | Graded | None | 54.4 (4.0) | Not stated | 15.6 (1.6) | Not stated |
| Joyce et al, 200211 | 23 | 15 | 23 | Binary | None | 65.0 (10.9) | 78.1 (6.1) | 13.2 (7.9) | Not stated |
| Halliday et al, 20088 | 7 | 2 | 7 | Graded | H&Y, CDR | 59.4 (8.6) | 73.4 (9.3) | 14.0 (3.4) | 1.7 (0.6) |
| Matsumoto et al, 201413 | 16 | 12 | 16 | Binary | None | 63.6 (10.9) | 72.8 (8.4) | 10.2 (6.1) | Not stated |
| De Pablo‐Fernandez et al, 20176 | 100 | 60 | 98 | Graded | None | 63.9 (10.3) | 78.5 (6.9) | 14.6 (7.7) | Not stated |
| Rajput and Rajput, 201714 | 22 | 9 | 22 | Binary | H&Y, Webster/UPDRS, MMSE | 82.7 (2.3) | 91.2 (3.1) | 8.5 (2.7) | Not stated |
PD, Parkinson's disease; SD, standard deviation; H&Y, Hoehn and Yahr; MMSE, Mini Mental State Examination; DSM 3, Diagnostic and Statistical Manual of Mental Disorders, Third Edition; HAM‐D, Hamilton Depression Rating Scales; CDR, Clinical Dementia Rating; UPDRS, Unified Parkinson's Disease Rating Scale; NS, not stated.
The l‐dopa response was reported in 399 of 445 PD cases (89.7%).1, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 It was graded in 280 cases: excellent in 105 (37.5%), good in 128 (45.7%), moderate in 34 (12.1%), and none to poor in 13 (4.6%). In the remaining 119 cases, a binary response to l‐dopa was reported: 87 (73.1%) of these were l‐dopa responsive, and 32 (26.9%) were unresponsive. l‐dopa doses were reported in 5 of 12 articles but were largely declared as “adequate” (often defined as 1000 mg per day) rather than quantified. Where quantified, the mean daily l‐dopa dose was 917 mg (SD 446) in 23 cases.6
Motor Complications (Motor Fluctuations and Dyskinesia)
Motor complications were reported in 148 patients in 4 articles,4, 10, 14, 15 with motor fluctuations in 63 cases (42.6%) and dyskinesia in 79 cases (53.4%).
Comorbid Brain Pathology
A total of 235 patients were assessed for the l‐dopa motor response and comorbid brain pathology. Of these, 137 (58.3%) had additional brain pathology, most commonly cerebrovascular disease (46.0%) and Alzheimer's disease (37.2%; Table 1). Data about the l‐dopa response, motor complications, and comorbid pathology were only available in 25 cases, but did not readily explain the degree of l‐dopa responsiveness.
Literature Review
Search Strategy
Following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines, PubMed, Embase, and LILACS (and references in identified papers) were searched from 1971 to March 2018 using the combined medical subheadings “levodopa,” "L‐dopa," “Parkinson's disease,” and “postmortem.” The search was limited to humans, research articles, and the English language. Studies had to include more than 5 pathologically confirmed PD cases, demographic details, and details about the motor response to chronic l‐dopa treatment. One researcher (V.P.) screened potentially eligible studies; a second researcher (D.G.) reviewed these; disagreements were resolved by consensus.
Results
A total of 893 studies were found, 757 full‐text articles were assessed, and 12 studies reporting 445 pathologically confirmed PD cases met the inclusion criteria. The pathological diagnosis was made (in all 12 articles) by microscopic confirmation of severe depletion of pigmented neurons and Lewy body formation in the substantia nigra pars compacta. In addition, immunohistochemistry was reported in 7 of 12 articles, including α‐synuclein staining in 5 of 12. Pathological rating scales were reported in 3 articles. Two articles1, 10 recorded prospective clinical data; the remainder extracted data retrospectively from patient files. A total of 3 studies also used standardized forms.4, 10, 12 All studies reported the chronic outpatient l‐dopa response.
Clinical Assessments
Disease severity was graded by the Hoehn and Yahr scale in 6 of 12 articles and/or scored by the Unified Parkinson's Disease Rating Scale in 1 of 12 papers. A total of 12 articles assessed the motor improvement on l‐dopa,1, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 4 assessed the occurrence of motor complications, and 6 investigated comorbid pathologies. The degree of motor improvement with l‐dopa was defined in 5 of 12 articles following the UK Brain Bank descriptors.1, 10 In the remaining 7 articles, the l‐dopa motor response was categorized as either responsive or nonresponsive.7, 9, 11, 12, 13, 14, 15
Discussion
There is significant variation in the motor response to l‐dopa treatment in pathologically confirmed cases; therefore, errors in the clinical diagnosis of PD do not fully explain this variability. A substantial proportion of pathologically confirmed PD cases have a response to l‐dopa that is less than excellent. The definitions of what is “excellent” regarding the motor response to l‐dopa clearly influence this categorization of patients, and such definitions have evolved. Prior to the Movement Disorder Society criteria for PD,2 the UK Queen Square Brain Bank criteria described an excellent response as 70% to 100%, but this was subjective according to the interpretation of case records.1 This definition, and the similarly defined lesser degrees of response, was predominant in the articles in the current review and applied in 70.2% of the 399 cases. In clinical trials, approximately half of PD cases have an excellent l‐dopa response.5 Approximately three quarters of PD cases fulfilling the Movement Disorder Society clinical diagnostic criteria (73.4% of 434) have an excellent l‐dopa response.16 Future pathological reports would benefit from the inclusion of the more objective definition of an excellent response being >30% improvement in Unified Parkinson's Disease Rating Scale part 32 or ≥ 24.5% improvement in the Movement Disorder Society Unified Parkinson's Disease Rating Scale part 3.17
There are several potential explanations for these findings. A worse motor score in men than women despite higher l‐dopa doses18 may indicate a gender difference. Also, the postural instability gait difficulty phenotype is less therapy responsive than tremor‐dominant PD.5 However, an exception to this is benign tremulous PD: in pathologically confirmed cases, the l‐dopa response during the first 8 years of treatment was definite in only 6 of 16 cases (37.5%), and 3 of 16 (18.8%) had no l‐dopa response.19 Slower progression in younger patients20 may be partly the result of better l‐dopa responsiveness. Some of the variation in drug responsiveness may be the result of genetic variations, such as in the dopamine‐metabolizing enzymes.21 However, the pathological studies did not include demographic or genetic data to allow these factors to be examined in more detail.
The studies in the current review largely predate developments in testing for genetic mutation and variation related to PD, so data relating this to the l‐dopa response was very limited. Larger studies of l‐dopa responses in pathologically confirmed genetic cases are warranted.
Other important variables in assessing the l‐dopa response are the dose5 and duration1, 2 of treatment. A few cases in the pathological studies had a low tolerability of l‐dopa, which was dose limiting, and details regarding l‐dopa doses were lacking in some studies, but the average treatment duration of 11 years before death was clearly adequate to assess treatment responses.
The development of motor complications (motor fluctuations or dyskinesia) is a key feature in later stages of PD. Dyskinesia was present in around half of the post‐mortem‐confirmed PD cases in this review, which is somewhat lower than the prevalence in clinical trials and likely indicates underreporting in clinical notes.22
Our study had certain limitations. Although tissue diagnosis is the gold standard pathological definition of PD, slightly more than half of the studies that we included relied on dopaminergic cell loss and Lewy body formation in the substantia nigra, as they predated α‐synuclein staining. Extraction of clinical information retrospectively may affect the interpretation of the l‐dopa response and be subject to bias. All of the studies reported the chronic l‐dopa response rather than the results from acute challenge tests. Two studies with a total of 176 cases had a partial overlap of up to 69 cases, which could not be unbundled accurately, and affected our results.1, 10 One study of 23 patients had an older age at onset of 82.7 (SD 2.2) years and a disease duration of 8.5 (SD 2.7) years at time of death, which was therefore an outlier.14
Conclusions
Variation in the l‐dopa response in pathologically confirmed PD indicates that diagnostic error alone does not explain this observation. Around 10% of pathologically confirmed PD are unresponsive to l‐dopa treatment, and an additional 12% have a modest response. An analysis of other modifying factors is required to further understand the reasons for these observations.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
V.P.: 1B, 1C, 2A, 2B, 3A
N.M.: 2C, 3B
E.S.T.: 3B
K.A.G.: 1A, 1B, 1C, 2A, 2B, 3B
S.G.: 3B
D.G.G.: 1A, 1B, 1C, 2B, 2C, 3B
Disclosures
Ethical Compliance Statement: The authors confirm that ethical approval or patient consent was not required for this work. This systematic review did not require the obtainment of informed consent. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflict of Interest: Vanessa Pitz has received grant funding from the Miss MJM Smith Trust and the Guarantors of Brain. Edward S. Tobias is supported by the MRC and Scottish Executive Health Department funding for the Scottish Genomes Partnership and also by Medical Research Council (MRC)/Engineering and Physical Sciences Research Council (EPSRC) funding for the Molecular Pathology Node. Steve Gentleman received funding from the National Institute of Aging (US), UK Multiple Sclerosis Society, Parkinson's UK, and the Alzheimer's Society/BUPA. Donald G. Grosset received grants from Parkinson's UK. Naveed Malek and Katherine A. Grosset have nothing to report. The PhD project was funded by Parkinson's UK through the Parkinson's Repository of Biosamples and Network Datasets (Tracking Parkinson's) (PRoBaND) study.
Financial Disclosures for the Previous 12 Months: Donald G. Grosset received honoraria from Merz Pharma, Bial Pharma, and Vectura plc. All other authors have nothing further to disclose.
Acknowledgment
We thank Andrew Gillespie for his assistance on this project.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
- 1. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico‐pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181–184. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord 2015;30:1591–1601. [DOI] [PubMed] [Google Scholar]
- 3. Hughes AJ, Daniel SE, Ben‐Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 2002;125:861–870. [DOI] [PubMed] [Google Scholar]
- 4. Litvan I, MacIntyre A, Goetz CG, et al. Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease, and dementia with Lewy bodies: a clinicopathologic study. Arch Neurol 1998;55:969–978. [DOI] [PubMed] [Google Scholar]
- 5. Hauser RA, Auinger P, Oakes G, Parkinson Study Group. Levodopa response in early Parkinson's disease. Mov Disord 2009;24:2328–2336. [DOI] [PubMed] [Google Scholar]
- 6. De Pablo‐Fernandez E, Tur C, Revesz T, Lees AJ, Holton JL, Warner TT. Association of autonomic dysfunction with disease progression and survival in Parkinson disease. JAMA Neurol 2017;74:970–976. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. de Vos RA, Jansen EN, Stam FC, Ravid R, Swaab DF. “Lewy body disease”: clinico‐pathological correlations in 18 consecutive cases of Parkinson's disease with and without dementia. Clin Neurol Neurosurg 1995;97:13–22. [DOI] [PubMed] [Google Scholar]
- 8. Halliday G, Hely M, Reid W, Morris J. The progression of pathology in longitudinally followed patients with Parkinson's disease. Acta Neuropathol 2008;115:409–415. [DOI] [PubMed] [Google Scholar]
- 9. Halliday GM, McRitchie DA, Cartwright H, Pamphlett R, Hely MA, Morris JG. Midbrain neuropathology in idiopathic Parkinson's disease and diffuse Lewy body disease. J Clin Neurosci 1996;3:52–60. [DOI] [PubMed] [Google Scholar]
- 10. Hughes AJ, Daniel SE, Blankson S, Lees AJ. A clinicopathologic study of 100 cases of Parkinson's disease. Arch Neurol 1993;50:140–148. [DOI] [PubMed] [Google Scholar]
- 11. Joyce JN, Ryoo HL, Beach TB, et al. Loss of response to levodopa in Parkinson's disease and co‐occurrence with dementia: role of D3 and not D2 receptors. Brain Res 2002;955:138–152. [DOI] [PubMed] [Google Scholar]
- 12. Louis ED, Klatka LA, Liu Y, Fahn S. Comparison of extrapyramidal features in 31 pathologically confirmed cases of diffuse Lewy body disease and 34 pathologically confirmed cases of Parkinson's disease. Neurology 1997;48:376–380. [DOI] [PubMed] [Google Scholar]
- 13. Matsumoto H, Sengoku R, Saito Y, Kakuta Y, Murayama S, Imafuku I. Sudden death in Parkinson's disease: a retrospective autopsy study. J Neurol Sci 2014;343:149–152. [DOI] [PubMed] [Google Scholar]
- 14. Rajput AH, Rajput EF. Octogenarian parkinsonism—clinicopathological observations. Parkinsonism Relat Disord 2017;37:50–57. [DOI] [PubMed] [Google Scholar]
- 15. Rajput AH, Rozdilsky B, Rajput A. Alzheimer's disease and idiopathic Parkinson's disease coexistence. J Geriatr Psychiatry Neurol 1993;6:170–176. [DOI] [PubMed] [Google Scholar]
- 16. Postuma RB, Poewe W, Litvan I, et al. Validation of the MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord 2018;33:1601–1608. [DOI] [PubMed] [Google Scholar]
- 17. Merello M, Gerschcovich ER, Ballesteros D, Cerquetti D. Correlation between the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) and the Unified Parkinson's Disease Rating Scale (UPDRS) during L‐dopa acute challenge. Parkinsonism Relat Disord 2011;17:705–707. [DOI] [PubMed] [Google Scholar]
- 18. Lyons KE, Hubble JP, Troster AI, Pahwa R, Koller WC. Gender differences in Parkinson's disease. Clin Neuropharmacol 1998;21:118–121. [PubMed] [Google Scholar]
- 19. Selikhova M, Kempster PA, Revesz T, Holton JL, Lees AJ. Neuropathological findings in benign tremulous parkinsonism. Mov Disord 2013;28:145–152. [DOI] [PubMed] [Google Scholar]
- 20. Wickremaratchi MM, Ben‐Shlomo Y, Morris HR. The effect of onset age on the clinical features of Parkinson's disease. Eur J Neurol 2009;16:450–456. [DOI] [PubMed] [Google Scholar]
- 21. Guin D, Mishra MK, Talwar P, et al. A systematic review and integrative approach to decode the common molecular link between levodopa response and Parkinson's disease. BMC Med Genomics 2017;10:56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Hauser RA, Rascol O, Korczyn AD, et al.Ten‐year follow‐up of Parkinson's disease patients randomized to initial therapy with ropinirole or levodopa. Mov Disord 2007;22:2409–2417. [DOI] [PubMed] [Google Scholar]