GRAPHICAL ABSTRACT

INTRODUCTION

Progressive supranuclear palsy (PSP) is a neurodegenerative disease that is clinically characterized by ocular motor dysfunction, postural instability, parkinsonism, and cognitive impairment [1]. The most striking and diagnostic clinical feature of PSP is oculomotor dysfunction (vertical gaze palsy or slowing of vertical saccades more than horizontal saccades). Vertical saccades are more affected by severe neuronal loss in the midbrain reticular formation (RF), whereas the paramedian pontine reticular formation (PPRF), the generator of horizontal saccades, remains relatively well preserved [2-4]. The Movement Disorders Society (MDS) task force developed new diagnostic criteria for the clinical diagnosis of PSP and PSP subtypes, and vertical gaze palsy or slowness is a major diagnostic feature [5]. Clinical determination of vertical supranuclear gaze palsy (O1) is easy, whereas mild slowness of vertical saccades (O2) may be uncertain, discordant between clinicians, or even missed. A bedside diagnosis of PSP in the absence of vertical gaze palsy is challenging, and many patients with PSP, particularly PSP with predominant parkinsonism (PSP-P) (which may also show a good response to levodopa [6,7]), are misdiagnosed with Parkinson’s disease (PD) (which may show a mild decrease in the amplitude of vertical saccades [8-11]). A standardized video-oculography (VOG) examination can provide an objective and quantitative measure of oculomotor dysfunction in suspected cases of PSP.

VOG is a technique used to obtain quantitative eye movement data, including saccadic velocities and latencies. Objective confirmation of slow vertical gaze by VOG in PSP subtypes and comparison with PD is needed to validate the use of this technique in differentiating PSP subtypes from PD subtypes. Although VOG is a well-recognized and accepted technique for evaluating eye movements, very few studies have investigated its use for confirming clinically suspected slow eye movements and for differentiating PSP or its subtypes from PD and other Parkinsonian syndromes [9]. To date, there are no guidelines for the use of VOG in the diagnosis of PSP or its subtypes, probably due to a lack of sufficient data.

In this study, we investigated the peak velocity of vertical and horizontal saccades and the latencies of both horizontal saccades and vertical saccades in a large set of PSP cases which included the two common PSP subtypes (PSP-P and PSP-Richardson’s syndrome [PSP-RS]), PD cases and healthy controls (HCs) to determine the cutoff values and assess the sensitivity and specificity of the two quantitative parameters to distinguish between these two diseases. The secondary objective was to measure the correlations of both VOG saccadic velocity and latency with the scores of the Montreal Cognitive Assessment (MoCA) [12], the frontal assessment battery (FAB) [13], and the PSP Rating Scale [14]. A minor objective was to assess the frequency of apraxia of eyelid opening (ALO) and blepharospasm in PSP and PD patients to determine whether these two eyelid signs, which can also be confirmed during VOG, differed between the two conditions.

MATERIALS & METHODS

In this single-center, cross-sectional study, all consecutive patients with PSP who were diagnosed by us at the Movement Disorder Clinic of a quaternary care center (a large referral center for movement disorders in South India) from January 2021 to December 2023 were screened. PSP patients with gaze palsy on clinical examination were excluded (n=17), and those with clinical slowness of saccades (n=112) were included. The first 50 PD patients seen in the clinic from the start of the study and willing to participate were recruited. The clinical diagnoses of probable PSP and its subclassification and PD were made according to the appropriate criteria [5,15] by an experienced movement disorder specialist (Asha K). HCs who had no visual or neurological diseases were recruited. HCs who volunteered to participate in the study were examined and recruited after the exclusion of individuals with any visual or neurological disorders. We recruited HCs who were in the same age decade as PD/PSP patients as much as possible. All the subjects underwent VOG using a uniform protocol. ALO and the presence/absence of reflex blepharospasm in all PSP and PD patients were recorded during clinical examination and VOG. For the clinical saccadic examination, the subject’s head was unconstrained and the subject was asked to sit in front of the examiner at a distance of 60 cm, which allowed an arc movement of 20 degrees from the primary visual axis in each direction [16]. The subject was instructed to look quickly back and forth between two targets separated by 45 cm from each other in both the horizontal and vertical directions (blue and red pens or sticks). We also used the MoCA and FAB scales for cognitive assessment and the PSP Rating Scale (PSPRS) for assessing the severity of PSP disease. The Unified Parkinson’s Disease Rating Scale subset III was used for motor assessment in PD patients [17]. FAB and MoCA were not performed in PD patients or HCs.

This study was approved by the Institutional Ethics Committee of Aster Medcity, Kerala (Ref No: AM/EC/239-2022). All participants provided written informed consent.

Video-oculographic acquisition

The VOG examination was performed via the balance eye vestibular assessment platform (BalanceEye; Cyclops Medtech Private Limited, Bengaluru, India) in a dedicated VOG lab. The subjects were comfortably seated, facing a 32” television (TV) display positioned 89 cm (35”) from the ground to the bottom edge of the display and at a distance of 54 cm. Before the VOG examination was started, calibration was performed to align the pupils in the reference box for accuracy. Vertical and horizontal saccades were generated by having the patient look at a target appearing on the TV screen with 0.3 Hz frequency and random amplitude. Thirteen cycles (20-second duration) for each horizontal and vertical plane were measured, and for each saccade, the peak velocity (degree/s) and latency (ms) were computed. The data of each patient for the saccades (peak velocity and latency) were computed as the average values.

Statistical analysis

We used R version 4.3 software (https://www.r-project.org) with the tidyverse 2.0 package for statistical analysis. Continuous variables are expressed as the means (standard deviations) and were compared using one-way analysis of variance, with Bonferroni-corrected p values for multiple comparisons in post hoc tests. Age at recruitment-adjusted VOG differences were tested using analysis of covariance. Categorical variables are presented as percentages and were compared using chi-square (χ²) tests. A two-tailed p value less than 0.05 was considered statistically significant. A partial correlation controlling for age at presentation and Pearson correlation were used to measure the associations between each oculomotor parameter and the clinical variables. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the classification ability of each variable, with the cutoff value selected on the basis of the highest Youden index.

RESULTS

The PSP group included 112 patients with clinically probable PSP (65 PSP-RS, 39 PSP-P, 7 PSP-progressive gait freezing, and 1 PSP-frontal), 50 PD patients, and 50 HCs. The demographic, clinical, and video-oculographic data of the PSP and PD patients, HCs, PSP-RS, and PSP-P patients are summarized in Tables 1 and 2. The PSP patients were older than the PD patients (p<0.001). The duration of disease was longer in the PD group than in the PSP group (p<0.001). There were more males in the PSP group than in the PD and HC groups (Table 1).

In the VOG, the horizontal saccadic velocities of individual eyes, as well as the average velocity of both eyes, were significantly lower in the PSP group than in the PD and HC groups (Table 1). Similar results were observed for the vertical saccadic velocities (Table 1). The latencies of individual eyes and the average latency of both eyes were significantly greater in the PSP group than in the PD patient and HC groups (Table 1).

In the subgroup comparisons between PSP-RS and PSP-P, the PSP-RS group was older than the PSP-P group, and the duration of disease was longer in the PSP-P group (Table 2). Both the horizontal and vertical mean saccadic velocities were lower in PSP-RS than in PSP-P, but the difference was not statistically significant (p=0.052 and 0.055, respectively). Similarly, the mean latencies of both horizontal saccades and vertical saccades were greater in the PSP-RS group than in the PSP-P group, but the difference was not statistically significant (p=0.103 and 0.299, respectively) (Table 2). When the PSP-P subgroup was compared with the PD subgroup, both horizontal and vertical saccadic mean velocities were lower in the PSP-P subgroup than in the PD subgroup (p<0.001 and p=0.011 for the vertical and horizontal velocities, respectively). The mean vertical latency but not the horizontal latency was significantly greater in the PSP-P group than in the PD group (p=0.012 and p=0.544, respectively) (Table 2). Age-adjusted comparisons are presented in Supplementary Tables 1 and 2 (in the online-only Data Supplement).

The total PSP severity score, FAB score and MoCA score were significantly more affected in PSP-RS than PSP-P group (p=0.001, <0.001, and 0.045, respectively) (Table 2).

In the PSP group, 59% (n=66) had ALO, and 17% (n=19) had reflex blepharospasm (Table 1), with no significant difference between PSP-RS and PSP-P. Neither of these eyelid signs were detected in any PD patient.

VOG in PSP patients versus HCs

The ROC curves comparing the horizontal and vertical saccadic velocities and latencies of both right and left eyes separately and the average values of both sides in the PSP patients and HCs are depicted in Figure 1. The mean vertical saccadic velocity (<214.46 degree/s) showed excellent differentiating power (area under the curve [AUC] of 0.941), with a specificity of 84.0% and a sensitivity of 93.8%. Similarly, the mean horizontal saccadic velocity (<253.19 degree/s) showed very good differentiating power (AUC of 0.845), with a specificity of 94.0% but a low sensitivity of 68.8% (Figure 1A).

The average vertical saccadic latency (≥318.93 ms) showed good differentiating power (AUC of 0.747), with a specificity of 90.0% and a sensitivity of 55.4%. Similarly, the average horizontal saccadic latency (≥290.18 ms) showed sufficient differentiating power (AUC of 0.615), with a specificity of 82.0% and a sensitivity of 48.2% (Figure 1B).

VOG in PSP patients versus PD patients

The ROC curve comparing the horizontal and vertical saccadic velocities and latencies of both the right and left eyes separately and together (average values) in the PSP and PD groups is shown in Figure 2. The average vertical saccadic velocity (<194.80 degree/s) showed excellent differentiating power (AUC of 0.924), with a specificity of 86.0% and a sensitivity of 87.5%. The average horizontal saccadic velocity (<212.15 degree/s) showed good differentiating power (AUC of 0.773), with a specificity of 96.0% and a sensitivity of 52.7% (Figure 2A). The average vertical saccadic latency (≥265.05 ms) showed good differentiating power (AUC of 0.760), with a specificity of 68.0% and sensitivity of 80.4%, and the average horizontal saccadic latency (≥267.59 ms) showed sufficient differentiating power (AUC of 0.663), with a specificity of 74.0% and sensitivity of 61.6% (Figure 2B).

VOG in PSP-P patients versus PD patients

The ROC curve comparing the horizontal and vertical saccadic velocities and latencies of the right and left eyes separately and their averages in the PSP-P subgroup and PD group is shown in Figure 3. The average vertical saccadic velocity (<194.80 degree/s) showed very good differentiating power (AUC of 0.888), with a specificity of 86.0% and a sensitivity of 82.1%. The average horizontal saccadic velocity (<229.58 degree/s) showed good differentiating power (AUC of 0.713), with a specificity of 88.0% and a sensitivity of 51.3% (Figure 3A). The average vertical saccadic latency (≥267.61 ms) showed good differentiating power (AUC of 0.701), with a specificity of 70.0% and a sensitivity of 71.8%. However, the horizontal saccadic latency did not significantly differ (AUC of 0.593, p>0.05) (Figure 3B).

VOG in PSP-P patients versus PSP-RS patients

The ROC curve comparing the horizontal and vertical saccadic velocities and latencies of both the right and left eyes separately and their averages in the PSP-P subgroup and PSP-RS subgroup is shown in Figure 4. The average horizontal saccadic velocity (≥193.07 degree/s) showed sufficient differentiating power (AUC of 0.651), with a specificity of 52.3% and a sensitivity of 79.5% (Figure 4A). The average vertical saccadic velocity and vertical saccadic latency showed sufficient differentiating power (AUC of 0.6–0.7) but were not statistically significant (Figure 4A and B).

VOG correlation with clinical scores

A partial correlation after controlling for age at presentation revealed that the PSP severity score was positively and moderately correlated with the horizontal latency of the right and left eyes separately and with the average latency of both eyes (Table 3). A moderate negative correlation was also found between FAB scores and horizontal saccadic latency in the PSP subgroups (PSP-RS and PSP-P). Similarly, the PSP severity score was negatively and moderately correlated with the vertical saccadic velocity of the right and left eyes separately and the average velocity of both eyes. A moderate positive correlation was also found between the MoCA and FAB scores and the vertical saccadic velocity in the PSP subgroup. However, when we analyzed the clinical scores separately for PSP-RS and PSP-P patients, there was a positive correlation between the PSP severity score and the horizontal latency of the right and left eyes and between the average horizontal latency of both eyes. There was a negative correlation of PSP score with vertical saccadic velocity only in PSP-RS but not in the PSP-P group. However, a moderate negative correlation was found between the MoCA and FAB scores and horizontal latency only in the PSP-RS subgroup, but the correlation was not statistically significant. Similarly, moderate and positive correlations of the MoCA and FAB scores with horizontal saccadic velocity and of the MoCA score with vertical saccadic velocity were observed only in the PSP-P subgroup but were not statistically significant (Supplementary Tables 3 and 4 in the online-only Data Supplement). Pearson correlations of the clinical scores of PSP patients (PSP-RS and PSP-P) and PSP-RS and PSP-P patients with the latency and velocity of each eye and the average latency and velocity of both eyes are presented in Supplementary Tables 5, 6, and 7 (in the onlineonly Data Supplement).

DISCUSSION

We aimed to study the utility of VOG parameters in the diagnosis of PSP with slow saccades and to derive cutoff values for differentiating PSP from PD and the two common PSP subtypes, PSP-RS and PSP-P, from each other. We found that the horizontal and vertical saccadic velocities could differentiate all PSPs from PDs and, more importantly, PSP-Ps from PDs, as the two conditions can resemble each other. PSP severity and cognitive dysfunction were greater in the PSP-RS group than in the PSP-P group. Greater PSP severity was associated with more prolonged horizontal saccadic latency. A moderate correlation was also found between the MoCA and FAB scores and the horizontal saccadic latency. ALO and reflex blepharospasm were observed only in PSP patients.

Comparison of VOG parameters between PSP patients and PD patients

The PSP patients were older than the PD patients in our study, which is concordant with the reported older age of onset of tauopathies than of synucleopathies [18]. The duration of disease was shorter in PSP patients than in PD patients, which could be due to the faster progression of PSP patients, although an enrollment bias cannot be excluded [1].

We determined the normative VOG value range for the average horizontal and vertical saccadic velocities, which were 300.2± 67.2 degree/s and 242.9±48.4 degree/s for the PD and 222.5± 92.3 degree/s and 146.5±58.5 degree/s for the PSP, respectively. We obtained cutoff values for reduced vertical saccadic velocity, i.e., <194.80 degree/s, to differentiate PSP patients from PD patients with 87.5% sensitivity and 86.0% specificity (AUC of 0.924). Quattrone et al. [19]obtained a cutoff for a reduced vertical saccadic velocity of ≤229 degree/s with 55% sensitivity and 99% specificity. This difference could be due to the different VOG machines used (the stationary VOG apparatus used in the previous study and the mobile VOG apparatus in this study). A previous study by Terao et al. [20] also showed that slow vertical and horizontal saccades could differentiate PSP patients from PD patients; however, the cutoff values were not calculated.

The average vertical saccadic latency could differentiate PSP patients from PD patients with a sensitivity and specificity of 80.4% and 68.0%, whereas the average horizontal saccadic latency could differentiate PSP patients from PD patients with a sensitivity and specificity of 61.6% and 74.0%, respectively. In a previous study, there was only a mild, insignificant prolongation of saccadic latency in PSP patients compared with PD patients and was not calculated separately for horizontal and vertical saccades [20]. Neuropathological changes in PSP patients, which occur in basal ganglia structures such as the subthalamic nucleus, globus pallidus, and substantia nigra, are responsible for the initiation and inhibition of eye movements; therefore, saccadic latency could be more affected in PSP patients than in PD patients [21].

Comparison of VOG parameters between PSP-P patients and PD patients

Horizontal and vertical saccadic velocities could differentiate PSP-P patients from PD patients with high sensitivity and specificity using cutoff values of <229.58 degrees/s and <194.80 degrees/s, respectively. Pinkhardt et al. [10] reported that slow vertical saccadic velocity could differentiate PSP-P patients from PD patients; however, cutoff values have not been reported. Horizontal saccades are also affected more in PSP patients than in PD patients because of the involvement of brainstem structures such as the superior colliculus and burst neurons in the PPRF [22,23]. We found that the vertical saccadic latency could also differentiate PSP-P patients from PD patients, with a sensitivity of 71.8% and specificity of 70.0%, an observation that has not been reported in earlier studies.

Comparison of VOG parameters between PSP-RS patients and PSP-patients

We found a significant difference in the horizontal and vertical saccadic velocities between PSP-RS patients and PSP-P patients, with cutoff values of ≥193.07 degree/s and ≥163.48 degree/s, respectively. Compared with PSP-P patients, PSP-RS patients have more pronounced pathological changes in the nucleus raphe interpositus, which correlates with supranuclear gaze palsy and this is reflected in our results [24]. Pinkhardt et al. [8] did not find a statistically significant difference in the saccadic velocity between PSP-P patients and PSP-RS patients; however, their study had a small sample size, and the clinical criteria for diagnosing PSP were different.

Correlation with clinical scores

The PSP severity score was moderately correlated with the horizontal latency of the right and left eyes separately and their average latency, implying that patients with prolonged horizontal saccadic latency had greater disease severity. The vertical velocity of both eyes individually, as well as the average vertical velocity of both eyes, was negatively correlated with the PSP severity score. In the initial stages of PSP, the rostral midbrain is affected, but as the disease progresses, the pons becomes involved, and horizontal gaze is also affected. Pinkhardt et al. [8] used the Hoehn and Yahr scale to assess disease severity and did not find an association between severity and VOG parameters. The PSP rating scale used in this study may be a more reliable measure of disease severity than the Hoehn and Yahr staging used with PD. A moderate correlation was also found between the MoCA and FAB scores and the horizontal saccadic latency. The MoCA score was not associated with horizontal velocity. However, the average vertical velocity was moderately and positively correlated with the FAB score, but its correlation with the MoCA score was not significant. The frontal lobe is more affected in PSP patients and hence may be reflected in FAB than in a global score such as the MoCA score. Among the PSP subtypes, PSP severity scores and FAB scores were more affected in PSP-RS patients than in PSP-P patients, possibly because of the more widespread pathology in PSP-RS patients. The involvement of horizontal saccadic parameters appears to be a marker of a more advanced stage of PSP. Physiologically, horizontal saccades are controlled by the paramedian PPRF, whereas vertical saccades are controlled by the rostral interstitial nucleus of the medial longitudinal fasciculus in the rostral midbrain reticular formation (RF). In the early stages, vertical saccades are affected by severe neuronal loss in the midbrain RF. However, the PPRF is also affected in the later stages, leading to impairments in horizontal saccades as well, as the disease progresses [2-4].

ALO and blepharospasm

In this study, 58.9% (66/112) of PSP patients had ALO, and 17.0% had blepharospasm. However, there was no significant difference between PSP-RS patients and PSP-P patients. None of the PD patients had ALO or blepharospasm. ALO is characterized by a transitory inability to initiate lid opening with no evidence of ongoing orbicularis oculi contraction. Lesions of the dorsal midbrain areas involving the superior colliculus, periaqueductal gray matter, and pretectal areas are considered relevant to the pathogenesis of ALO in PSP [25]. This is concordant with the findings that neurofibrillary tangles in the pars compacta of the substantia nigra, the pallidosubthalamic complex, the superior colliculus, the periaqueductal gray matter, and pretectal areas are also specifically damaged in PSP.26 Blepharospasm is a focal cranial dystonia characterized by spasms of contraction of the orbicularis oculi muscles and was initially described as being secondary to rostral brainstem or basal ganglia lesions [27]. A similar pathophysiological mechanism may account for reflex blepharospasm in PSP [26].

Strengths and limitations of the study

The strength of this study lies in the classification of the PSP subtypes on the basis of the latest MDS task force criteria. The role of the VOG in the objective confirmation of the slowness of saccades in any PSP subtype diagnosed using the new MDS task force criterion has not been previously tested. The technique of the VOG procedure was well defined and consistent, which ensures the reproducibility of the results. We also studied the correlation of the saccadic velocities and latencies with the relevant clinical scales, further expanding its clinical utility as a biomarker, not only for classification but also for severity of the disease. To the best of our knowledge, none of the published studies have methodically evaluated the latency of vertical saccades obtained by VOG in PSP. In this study, we showed that prolonged latency of vertical saccades can differentiate PSP patients from PD patients and PSP-P patients from PD patients with good sensitivity and specificity (cutoffs of ≥265.05 ms and ≥267.59 ms, respectively).

The limitations of this study are that the PSP subtypes were diagnosed clinically and that we could not include the rarer PSP subtypes in the analysis because of the small sample size. Many PSP patients were unable to complete the assessment of the PSP severity score, frontal score or MoCA score because of their disability. Hence, the associations between clinical findings (saccades and latencies) and scores (determined by clinical features) also need to be addressed with a greater degree of statistical confidence in larger and more focused studies.

In conclusion, VOG is a useful tool for the detection and confirmation of slow saccades in PSP patients and assists in increasing the diagnostic accuracy of PSP subtypes and in the differentiation of PSP-P patients from PD patients. It is possible that mild slowness of saccades may be missed by naked-eye examination, thus delaying the early diagnosis of PSP, which may have implications for treatment as well as research. In this study, we could study only the more common PSP subtypes in our clinic during the study period, which were PSP-RS and PSP-P. The detection of oculomotor dysfunction from the VOG in other less common subtypes and the reproduction of our results in larger samples will further establish the value of VOG in the detection of oculomotor dysfunction in PSP patients even before gaze palsy sets in. This study also provides normative data in HCs and in both PD patients and PSP patients and cutoff values to differentiate PSP patients from PD patients.

Supplementary Materials

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

The study was conducted with intramural funds from Aster Medcity, Kerala, India (project number IMRS030).

Author Contributions

Conception: Asha Kishore. Data curation: all authors. Formal analysis: Asha Kishore, Manas Chacko. Funding acquisition: Asha Kishore. investigation: Asha Kishore. Methodology: Asha Kishore. Project administration: Asha Kishore, Harshad Chovatiya. Resources: Asha Kishore. Software: Manas Chacko. Supervison: Asha Kishore. Validation: Asha Kishore. Visualization: Manas Chacko. Writing—orignal draft : Harshad Chovatiya. Writing—review & edting: Asha Kishore, Kanchana Pillai, Chakradhar Reddy, Manas Chacko.

Acknowledgments

We thank all the participants of the study and their care givers.

Figure 1.

ROC curves comparing VOG values to differentiate PSP from healthy control. A: Saccades velocity. B: Latency. Saccadic velocity unit degree/s. Saccadic latency unit ms. *p<0.05. AUC, area under the curve; ROC, receiver operating characteristic; VOG, video-oculography; PSP, progressive supranuclear palsy.

Figure 2.

ROC curves comparing VOG values to differentiate PSP from PD. A: Saccades velocity. B: Latency. Saccadic velocity unit degree/ s. Saccadic latency unit ms. *p<0.05. AUC, area under the curve; ROC, receiver operating characteristic; VOG, video-oculography; PSP, progressive supranuclear palsy; PD, Parkinson’s disease.

Figure 3.

ROC curves comparing VOG values to differentiate PSP-P from PD. A: Saccades velocity. B: Latency. Saccadic velocity unit degree/ s. Saccadic latency unit ms. *p<0.05. AUC, area under the curve; ROC, receiver operating characteristic; VOG, video-oculography; PSP-P, PSP with predominant parkinsonism; PD, Parkinson’s disease; PSP, progressive supranuclear palsy.

Figure 4.

ROC curves comparing VOG values to differentiate PSP-P from PSP-RS. A: Saccades velocity. B: Latency. Saccadic velocity unit degree/s. Saccadic latency unit ms. *p<0.05. AUC, area under the curve; ROC, receiver operating characteristic; VOG, video-oculography; PSP-P, PSP with predominant parkinsonism; PSP-RS, PSP-Richardson’s syndrome; PSP, progressive supranuclear palsy.

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