Decreased Palpebral Fissure in Patients with Parkinson's Disease

Abstract

Background

The diagnosis of Parkinson's disease (PD) is based exclusively on clinical criteria established by the Queen Square Brain Bank. On occasion, these clinical symptoms may be subtle and inconclusive; therefore, it becomes necessary to appeal to contributory criteria to establish a correct diagnosis. The authors propose the observation of palpebral fissure (PF) asymmetry as an additional criterion for the diagnosis of PD.

Objectives

The objectives of this study were to determine whether decreased PF (DPF) is more prevalent in patients with PD than in the general population and whether DPF in PD coincides with the side of onset of parkinsonian symptomatology.

Methods

In total, 112 consecutive patients with a diagnosis of PD and 112 control participants without PD were selected between April and June 2014. At the office visit, it was established through clinical observation whether DPF was present. In patients with PD, it was determined whether the DPF was consistent with the side of onset of parkinsonian symptomatology.

Results

Of 112 patients with PD, 39 (35%) had DPF clinically evident DPF, and, in 34 (87%), the DPF was consistent with the laterality of parkinsonian signs. In the control group, only 12% (14 of 112 controls) had PF asymmetry. The difference in prevalence of DPF between these groups was statistically significant (P < 0.0001), with an odds ratio of 3.7 (95% confidence interval, 1.8–7.3). Twenty‐eight of the 39 patients with PD who had PF asymmetry were treated with levodopa.

Conclusions

Although the data are purely observational, it may be concluded that DPF coincidental with the side of initial parkinsonian symptomatology in patients with probable PD is an additional sign worth considering.

The diagnosis of Parkinson's disease (PD) is based on clinical criteria established by the Queen Square Brain Bank. In some patients, these clinical symptoms are subtle and inconclusive, so it is necessary to appeal to supportive criteria that may contribute to a correct diagnosis. We propose the observation of palpebral fissure (PF) asymmetry as an additional criterion toward a diagnosis of PD.

Many reviews have been published addressing a variety of ophthalmological alterations observed in PD. However, there are scarcely any data reporting the presence of unilateral decreased PF (DPF) in patients with PD. Here, we attempt to describe this clinical phenomenon, which we have frequently observed in our PD outpatient clinic. The objectives of this study were to determine whether DPF is more prevalent in patients with PD than in the general population, to establish whether the DPF in PD coincides with the initial side of parkinsonian symptomatology, and to describe the general characteristics of patients with PD who have DPF.

Patients and Methods

This was an observational, analytical, case‐control, unblinded, study. Cases were patients aged 21 years or older with an established diagnosis of PD according to Queen Square Brain Bank criteria who were recruited consecutively between April and June 2014 at the Movement Disorders Unit, Institute of Neuroscience, Favaloro Foundation University Hospital in Buenos Aires, Argentina. Controls were defined as patients aged 21 years or older who presented to neurological consultation for other causes unrelated to movement disorders. Sociodemographic variables were collected for cases and controls, including age and sex; for cases only, data also were collected on exposure to levodopa (l‐dopa) therapy, disease duration, side of motor onset, and disease severity based on clinical examination using the Hoehn and Yahr (H&Y) scale and the Unified Parkinson's Disease Rating Scale, motor part (UPDRS III) in the on state (while receiving medication).

A DPF was defined as a reduction of the distance between the upper and lower margin of the eyelid (palpebral) relative to the contralateral eye. The space between the upper and lower palpebral margin is defined as the fissure (Figure 1). The presence of a DPF was established through direct observation by a movement disorders specialist and was assessed at the office visit. In patients with PD, we determined whether the side of the reduced palpebral fissure coincided with the side of initial parkinsonian symptomatology.

Figure 1.

Palpebral fissure. Green, upper eyelid; blue, lower eyelid, orange; palpebral fissure.

Examination room lighting was kept standard for all evaluations. The participating observers were 5 movement disorders specialists from our Institute's Movement Disorders Unit, and all of them were trained for 2 weeks to properly look for a DPF.

To increase the internal validity of the study, photographs were randomly obtained from 50 patients with PD and from 50 controls with and without DPF. The photographs were evaluated by the trained movement disorders specialists who were blinded to the diagnosis so that agreement among them could be assessed.

Patients who had PF asymmetry attributed to other clinical conditions were excluded. Exclusion criteria were: blepharospasm, hemifacial spasm, ocular apraxia, facial trauma with intrinsic ocular involvement, eye surgery, ophthalmoplegic migraine, ocular myasthenia gravis, third cranial nerve palsy, blepharitis, chalazion, and congenital idiopathic lid lag.

A subanalysis was conducted in 10 patients recently diagnosed with PD who had no current or past exposure to dopaminergic agents (including l‐dopa) and who met inclusion/exclusion criteria, and the presence of eyelid asymmetry was documented.

Statistical Analysis

Descriptive statistics of the population studied are expressed as the mean ± standard deviation or as the median and interquartile range. Frequencies of categorical variables were estimated as percentages with 95% confidence intervals (95% CIs). The χ² test and the Mann‐Whitney test were used to compare frequencies of categorical and continuous variables, respectively. Univariate analysis of each of the independent documented variables was performed to evaluate its association with DPF. A multivariate logistic regression analysis was performed using those variables that demonstrated an association with DPF in the univariate analysis, estimating the odds ratio (OR) with 95% CI for those variables that could be related to age. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. The Stats Direct statistical software program (version 2.7.2; StatsDirect, Ltd., Altrincham, UK) was used for all analyses.

Results

We selected 112 consecutive patients who had a diagnosis of PD (cases) and 112 controls. The mean age was 67 years for PD cases and 56 years for controls. Sixty‐five patients in the PD group (58%) were men, and 81 (72.3%) were receiving l‐dopa. Of 112 patients with PD, 39 (35%) had clinically evident DPF; and, in 34 patients (87%), PF reduction was consistent with the predominant laterality of parkinsonian signs. Of the controls, 12% (14 of 112) had DPF. The difference between these groups was statistically significant (P < 0.0001; OR, 3.7; 95% CI, 1.8–7.3).The clinical features of both cases and controls are presented in Table 1.

Table 1.

Clinical Features of Patients

Feature	No. (%)		OR [95% CI]	P
	Cases (PD)	Controls
Total	11	112	—	—
DPF	39 (35)	13 (12)	3.7 [1.8–7.3]	<0.001a
Age: Mean ± SD/range, y	67 ± 11/42–85	56 ± 15/21–86	—	<0.0001b
Male	65 (58)	74 (66)	—	0.75a
Levodopa treatment	81 (72.3)	—	—	—

^aχ² test.

^bMann‐Whitney U test.

PD, Parkinson's disease; OR, odds ratio; CI, confidence interval; DPF, decreased palpebral fissure; SD, standard deviation.

The mean age of patients who had PD with or without DPF was not significantly different (65 vs 68 years). Twenty‐eight of 39 patients with PD (71%) who had PF asymmetry were treated with l‐dopa. The mean disease duration was 6 years in patients who had PD with DPF versus 5 years in those who had PD without PF asymmetry (P = 0.06). Other features (see Table 2), such as sex, l‐dopa treatment, UPDRS III scores, and H&Y scores, showed no statistically significant differences.

Table 2.

Characteristics of Patients with Parkinson's Disease

Characteristic	PD with DPF	PD without DPF	P
DPF coincident with parkinsonian sign, no. (%)	34 (87)	—	—
Age: Mean ± SD, y	65 ± 10.1	68 ± 11.6	0.88a
Male, no. (%)	23 (59)	45 (62)	0.78b
Levodopa treatment, no. (%)	28 (71)	53 (73)	0.92b
DPF: Right side, no. (%)	17 (43.6)	—	—
Mean disease duration, y	5	6	0.06a
UPDRS III score in on state: Median [IQR]c	14 [9–22]	17 [9–24]	0.46a
Hoehn & Yahr score, mean ± SDd	2 ± 10	2 ± 8	0.89a

^aMann‐Whitney U test.

^bχ² test.

^cPossible scores on the UPDRS III (motor) scale range from 0 to 108.

^dPossible scores on the Hoehn & Yahr scale range from 0 to 5.

PD, Parkinson's disease; DPF, decreased palpebral fissure; SD, standard deviation; UPDRS III, Unified Parkinson's Disease Rating Scale part III (motor); on state, while receiving medication; IQR, interquartile range.

A subanalysis of 10 l‐dopa–naive patients with PD showed that 7 of 10 (70%) had DPF, and the side of PF reduction coincided with the most affected side in all patients. The mean age of this subgroup was 66 years, and the duration of disease since diagnosis was 3 years. Additional clinical features from this subanalysis are provided in Table 3.

Table 3.

Characteristics of Levodopa‐Naive Patients with Parkinson's Disease, n = 10

Characteristic	No. of Patients/Total No.
DPF	7/10
Male sex	6/10
Mean age, y	66
UPDRS motor scale on state, median [range]a	12 [9–21]
Hoehn & Yahr scale, mean ± SDb	1.5 ± 7
Mean duration of disease since diagnosis, y	3
Parkinson medication
Monoamine oxidase B inhibitors	6/10
Amantadine	3/10
COMT inhibitors	0/10
Anticholinergic	2/10
Other: Antidepressants	2/10
No medication	1/10
Nationality, no. of patients
Argentinian	10
Other	0
Other comorbidities
Diabetes	1/10
Hypothyroidism	3/10
Hypertension	3/10
Hypercholesterolemia	2/10

^aPossible scores on the UPDRS motor scale range from 0 to 108.

^bPossible scores on the Hoehn & Yahr scale range from 0 to 5.

DPF, decreased palpebral fissure; UPDRS, Unified Parkinson's Disease Rating Scale; on state, while receiving medication; SD, standard deviation; COMT, catechol‐O‐methyltransferase.

To avoid bias because of differences in age between PD patients and controls, a multivariate logistic regression analysis was performed to estimate the OR with 95% CI for DPF. The variables that were included were: age, sex, PD, and the use of l‐dopa treatment. Age stratification was performed, because this variable could act as a modifier of effect, and the results showed no significant difference (Table 4). Based on the results from that multivariate analysis, we can conclude that age does not change the variable DPF or any other variable.

Table 4.

Multivariate Logistic Regression in Patients with Decreased Palpebral Fissure

Variable	OR	P	95% CI
PD	3.66	0.007	1.42–9.42
Male sex	0.80	0.52	0.41–1.57
Age, y
<45	1.00	0.85	0.97–1.02
45–59	3.00	0.128	0.72–12.4
60–74	2.62	0.15	0.70–9.82
≥75	0.83	0.82	0.17–3.91
Levodopa treatment	1.23	0.65	0.48–3.11

OR, odds ratio; CI, confidence interval; PD, Parkinson's disease.

To increase the internal validity of the study, 50 photographs from each group were evaluated by movement disorders specialists, who were blind to the patient's diagnosis, and the resulting certainty was 100%. Sensitivity of DPF in patients with PD was 34.8%, and specificity was 87%, with a PPV of 73.5% and an NPV of 57.3%.

Discussion

In the present report, we tried to describe an infrequently reported sign (DPF), which we have observed to be quite common in patients with PD. More important is the finding that DPF coincides with the side of initial parkinsonian involvement. The clinical value of this finding is that it adds another supportive diagnostic feature in patients who have subtle symptoms of the disease.

It is difficult to establish a reasonable pathophysiological hypothesis to explain this phenomenon. Several published reports1, 2, 3 have mainly described ocular changes secondary to the use of l‐dopa, such as an initial mydriasis followed by miosis. There is also a single report that described 3 patients who developed ptosis secondary to the use of l‐dopa.2 Furthermore, a communication published in 1970 mentioned the finding of pupillary dilation 3 hours after starting oral l‐dopa.2 All of these publications mentioned the finding of pupillary changes, rather than changes in the PF, in patients with PD who were receiving l‐dopa.

The most likely explanation for this observation in the few published reports is believed to be related to interference with sympathetic activity by l‐dopa. However, this is not an entirely valid hypothesis, because patients without prior exposure to l‐dopa present this sign in a high proportion. For this reason, we conducted a subanalysis in patients who had not been exposed to dopaminergic medication. In that subanalysis, we observed that 70% of patients who had never been exposed to l‐dopa or dopamine agonists had an asymmetric DPF coincident with the affected side. The inclusion of an l‐dopa–naive population was also important to avoid possible confounds due to l‐dopa–induced, involuntary movements in the region of the eyes, because dyskinesia can change facial expression.

We also assessed the degree of disease severity by means of the UPDRS part III (motor) and H&Y scales in patients who had PD with DPF versus those who had PD without DPF. We found no differences between the two groups, which allowed us to assume that the degree of severity of disease would not be directly related to the presence of DPF.

We believe that the strengths of this study are that it is a novel idea and that it is a simple and easily reproducible, exploratory maneuver in our patient population. The main weakness is our subjective definition of DPF; it would be better to have a quantitative DPF assessment tool for future confirmatory studies. However, our primary objective was first to establish the validity of this novel idea and then to determine whether this sign was unilateral (asymmetric) and coincided with the side of initial parkinsonian symptoms. In addition, our population was ethnically homogeneous; therefore, we believe additional studies will be necessary to confirm its applicability in other countries that have ethnically diverse patient populations. The study could not be carried out blindly, because the majority of patients were known to the treating neurologist; and, in those patients who presented for the first time to the clinic, the gait and mimic of the patients was highly suggestive of the disease. We tried to avoid this bias, at least in part, by using an internal validity method.

This phenomenon can be hypothesized to be an incomplete form of a Horner syndrome caused by interference with sympathetic innervation both by the disease process and/or secondary to dopaminergic drug effects.

The method of assessment described here is easy and fast, and it is performed by direct observation of the patient. It is worth taking it into account for patients who have subtle and inconclusive symptoms. We are aware that the simple observation of DPF in our patient population was performed subjectively; however, the consistency of the results warrants further studies to establish a direct relationship of DPF with the disease and its value as an additional clinical sign in patients with PD.

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 the First Draft, B. Review and Critique.

M.S.A.: 1B, 1C, 2A, 2B, 3A

G.G.A.: 2B

S.S.G.: 2B

G.M.: 2B

A.C.: 2B

O.G.: 1A, 2C, 3B

Disclosures

Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the previous 12 months: The authors declare that there are no additional disclosures to report.