Impact of levodopa and deep brain stimulation on visual impairments in Parkinson’s disease

Highlights

• •Levodopa and acute DBS had no significant impact on contrast acuity or reading speed.
• •Black low-contrast acuity improved with DBS stimulation.
• •King-Devick tools effectively captured visuoperceptual changes in Parkinson’s disease.

Abstract

Background

Parkinson’s disease (PD) often causes visual changes that impair visuospatial processing, reading speed, and contrast acuity, impacting patients’ quality of life.

Objectives

This study aimed to investigate the effects of levodopa and deep brain stimulation (DBS) on visual symptoms associated with PD.

Methods

Patients were assessed either before DBS surgery (both off and on medication) or at their first DBS programming session (off medication, with and without stimulation). The King-Devick reading speed and color contrast visual tests were administered in each condition, evaluating high and low contrast across black, red, and yellow.

Results

Reading speed and color contrast acuity did not change following levodopa dosing or when deep brain stimulation was off or on. However, those patients that had testing before and after DBS showed a non-significant trend towards improvement in their rapid reading test scores from pre-DBS to post-DBS and black color contrast sensitivity using the 2.5% contrast.

Conclusions

Although levodopa and DBS did not significantly improve reading speed or contrast acuity after single dosing or turning DBS on and off, in this small study, these findings provide valuable insights into the stability of these visual symptoms under current treatments. There was evidence that DBS surgery may improve certain aspects of reading speed and contrast acuity and further study is needed. This work underscores the need for innovative approaches to enhance visual function in PD.

1. Introduction

Parkinson’s Disease (PD) is the second most common neurodegenerative disease with motor symptoms that include bradykinesia, tremor, and rigidity. There are also multiple nonmotor symptoms, such as impaired cognition, sleep, and mood. Among the nonmotor symptoms not discussed as frequently are visual changes affecting visuospatial processing, reading speed, and contrast acuity, all of which can impact quality of life [1]. Prior research has demonstrated abnormal color contrast visual acuity using the King-Devick (KD) variable contrast application as well as slower reading speed using the KD test in PD [[2], [3], [4]]. Nonmotor symptoms of PD can be influenced, beneficially or detrimentally, by antiparkinsonian medication and deep brain stimulation (DBS) [5,6]. To date the impact on reading speed and contrast visual acuity is not well established with oral medications and has not been investigated with DBS. The objective of this study was to determine if quantitative measurements of color contrast visual acuity and reading speed change following a levodopa dose or DBS in patients with PD.

2. Methods

Patients undergoing medication ON/OFF testing in clinic as part of screening for DBS eligibility were recruited for this study. Additionally, DBS on and off testing was done when patients presented for their initial programming after bilateral subthalamic nucleus DBS surgery. All testing was completed in the levodopa OFF and ON states in patients without DBS. In patients with DBS, testing was done in stimulation OFF and ON when they presented for initial programming. DBS OFF and ON testing was completed in levodopa OFF states. This study was approved by the Dignity Health Institutional Review Board and all participants signed written informed consent.

Inclusion criteria: age > 18 years, diagnosis of idiopathic PD made by a movement disorders’ specialist using UK Brain Bank criteria, and the ability to sign consent. Exclusion criteria: macular degeneration or other visual problems (noted in medical records or by self report) that would prevent completion of visual tests, prior radioablative surgery, or a major neurocognitive disorder. Formal visual testing was not completed prior to testing but patients with self-reported visual impairment were excluded. Patients with reported visual hallucinations were also excluded.

Patients underwent visual testing using the KD rapid number naming test and Variable Contrast KD Test and Color Contrast Sensitivity Chart utilizing the KD Test Pro Monitoring applications on an iPad (King-Devick Test LLC, Oakbrook Terrace, IL). They performed two trials of reading out loud single-digit numbers separated by varying spacing on three test screens that were of different formats [3]. They were also asked to read letters from the iPad at high and low degrees of contrast sensitivity (2.5 %-100 %) and using different colored letters (black, red, and yellow), as well as asked to read numbers out loud across a screen to assess reading speed. A scoring system was used to assign a score between 0 and 95 based on the number of correctly identified letters and visual acuity [[2], [3], [4]]. A higher score reflected fewer errors.

We compared the two populations studied in each group: 1) PD patients in the medication OFF compared to ON state, 2) PD patients in the medication OFF state but with DBS stimulation OFF compared to ON. Mann-Whitney U test was used for comparisons of medians, due to non-normally distributed data. We also conducted paired samples t-tests of reading speed scores within patients.

3. Results

There were 17 male and 4 female patients in the levodopa OFF/ON group and 11 male and 4 female patients in the stimulation off and on group. Median age was 64.0 years (IQR 58–71). Most patients identified as White, with one patient identifying as Native American. The median disease duration was 8.0 years (IQR 6–9). Eight patients participated overlapped in both groups with testing the levodopa OFF/ON state and then later, after DBS surgery, in the DBS OFF and ON states as well. Median MDS-UPDRS scores in the levodopa OFF/ON and stimulation OFF/ON were 43.5 (IQR 29.0–49.5), 21.0 (IQR 10.5–26.0), 15.0 (IQR 9.5–35.0), and 24.0 (IQR 20.3–39.8) respectively. Motor scores in medication and stimulation OFF, and medication ON and stimulation ON were not significantly different.

Median reading speed scores were similar ON and OFF levodopa (61.6, IQR 51–83.7 vs 65.0, IQR 56.6–81.5 s) as well as on and off stimulation (65.4, IQR 46.7–69.5 vs. 62.0, IQR 50.8–71.9 s). Medians are reported due to skewed distribution of the results for all patients (Table 1.).

Table 1.

Median reading Speed Scores reported with interquartile range. p-values from Mann-Whitney U test comparison of medians.

	Reading speed (seconds)	p-value
OFF meds (n = 21)	65.0 (56.6 – 81.5)
ON meds (n = 21)	61.6 (51 – 83.7)	0.88
OFF stim (n = 15)	62.0 (50.8 – 71.9)
ON stim (n = 15)	65.4 (46.7 – 69.5)	0.77

Paired comparisons of the subset of patients with testing both before and after surgery (n = 8) showed median reading scores of 58 (IQR 43.8–83.7) in medication OFF and 54.2(IQR44.2–78.4) in medication ON states, then 61.4 (IQR 46.8–73.9) in stimulation OFF/medication OFF and 61.1 (IQR 44.4–75.8) in stimulation ON/ medication OFF states. The findings did not statistically differ between medication OFF and stimulation OFF (p = 0.35), nor between medication ON and stimulation ON (p = 0.36) likely due to the small sample size. There were no differences between male and female patients.

Visual contrast acuity did not differ in the levodopa ON state compared to OFF for black at 100 % sensitivity (median 84, IQR 79–85 ON v 79, IQR 70 – 85 OFF; p = 0.0995).1

There were no significant differences in scores in the medication or stimulation group at high or low contrasts for all colors (Fig. 1).

Fig. 1.

Contrast sensitivity scores in medication OFF and ON states; and stimulation OFF and ON states for all participants.

4. Discussion

Parkinson’s Disease (PD) is a neurodegenerative disorder marked by a range of nonmotor symptoms including visual impairments such as contrast acuity and reading speed [1,[2], [3], [4],7]. Although dopaminergic therapy and advanced therapeutics like DBS can influence nonmotor symptoms, their specific effect on these visual symptoms is not well established [5]. This study investigated the impact of levodopa and DBS on contrast acuity and reading speed utilizing the King Devick Test (rapid number reading), Variable Contrast KD Test and Color Contrast Acuity Chart on the KD Test Pro Monitoring applications. Our findings indicated that color contrast visual acuity and reading speed did not improve or worsen after taking levodopa or when DBS was turned ON or OFF. However, amongst the subset of patients that had testing before and after DBS, there was an improvement in their rapid reading test scores from pre-DBS to post-DBS surgery and they also had improvement in black color contrast sensitivity using the 2.5 % contrast, although not statistically significant potentially due to small sample size.

Contrast visual acuity is known to be impaired in PD relative to controls and some studies have associated it with a higher risk of cognitive decline as well as greater impairment in those experiencing visual hallucinations [1]. This change is thought to arise from dysfunction of dopaminergic cells in the retina, likely in association with impairments in visual pathways [8]. A combination of changes in oculomotor function and visual cognitive processing in PD likely contribute to slower reading speed [3]. Levodopa may have a positive impact on eye movements and tracking but does not appear to play a role in the cognitive component of reading speed [9]. We did not find an effect of levodopa on these symptoms in keeping with prior studies utilizing different techniques to measure contrast visual acuity and reading speed [9]. The reading speed at baseline was similar to that reported previously by Lin et al.³ Subthalamic DBS in PD may improve oculomotor control through improvements in saccade velocity and amplitude, and smooth pursuit eye movements [[10], [11], [12], [13]] potentially through the restoration of physiologic oscillatory activity within the basal ganglia-thalamo-cortical circuits which in turn influence oculomotor pathways [11,14]. Though previous studies have shown that long-term subthalamic nucleus DBS may not significantly affect contrast visual acuity, this study uniquely explores the immediate post-op effects and the immediate effects of DBS on contrast visual acuity across different colors, sensitivities, and reading [15]. Although we did not find an effect of stimulation,., in patients with both pre- and post-surgical testing, the mean reading speed was slower in the medication OFF states suggesting a possible effect of surgery itself. It is also possible that a practice effect contributed to the observed changes in this group, as patients completed the task both pre- and post-operatively, despite the use of different letter sets across administrations.

There were several limitations to this study. There was a small sample size in the levodopa group and even smaller in the DBS group. Whether combining DBS and levodopa could improve visual symptoms should be studied. Patients in this study were assessed on their optimal settings and there may be variability in response based on stimulation settings as well as the area stimulated within the subthalamic nucleus. Chronic stimulation may also have a differential effect on visual pathways. Novel technology allowing for the assessment of electrophysiological biomarkers while conducting these tests can provide further insight into stimulation as well as medication related changes. An advantage of this study was using rapid and readily available bedside tests for the measurement of contrast visual acuity and reading speed. Future studies should aim for larger sample sizes, exploring additional nuances such as disease phenotype, extent of levodopa responsiveness, and varying stimulation parameters and duration.

CRediT authorship contribution statement

Sana Aslam: Writing – original draft, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Data curation, Conceptualization. Markey Olson: Project administration, Data curation. Melissa Kovacs: Writing – review & editing, Methodology, Formal analysis. Pireh Ansari: Project administration, Investigation. Amputch Karukote: Project administration, Investigation. Justine Chan: Project administration, Investigation. Shadi Barbu: Project administration, Investigation. Sydney Felsen: Project administration, Investigation, Data curation. Holly A. Shill: Conceptualization, Methodology, Writing – review & editing. Charles H. Adler: Writing – review & editing, Supervision, Methodology, Formal analysis, Conceptualization.

Funding

This work was funded by the Barrow Neurological Foundation.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sana Aslam reports financial support was provided by Barrow Neurological Foundation. Sana Aslam reports a relationship with University of Colorado Anschutz Medical Campus School of Medicine that includes: funding grants. Holly Shill reports a relationship with Intra-Cellular Therapies Inc that includes: funding grants. Holly Shill reports a relationship with Jazz Pharmaceuticals Inc that includes: funding grants. Holly Shill reports a relationship with Michael J Fox Foundation for Parkinson’s Research that includes: funding grants. Holly Shill reports a relationship with Parkinson Study Group that includes: funding grants. Holly Shill reports a relationship with National Institute of Neurological Disorders and Stroke that includes: funding grants. Holly Shill reports a relationship with Fasikl that includes: funding grants. Holly Shill reports a relationship with Barrow Neurological Foundation that includes: funding grants. Charles H. Adler reports a relationship with Centessa that includes: consulting. Charles H. Adler reports a relationship with Cionic that includes: consulting. Charles H. Adler reports a relationship with CND Life Science that includes: consulting. Charles H. Adler reports a relationship with Photopharmics that includes: consulting. Charles H. Adler reports a relationship with Precon Health that includes: consulting. Charles H. Adler reports a relationship with RegenXbio that includes: consulting. Charles H. Adler reports a relationship with SunPharma that includes: consulting. Charles H. Adler reports a relationship with XW Pharma that includes: consulting. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.