Autonomic insufficiency in pupillary and cardiovascular systems in Parkinson’s disease

doi:10.1016/j.parkreldis.2010.11.005

Parkinsonism & Related Disorders

Volume 17, Issue 2, February 2011, Pages 119-122

https://doi.org/10.1016/j.parkreldis.2010.11.005 Get rights and content

Abstract

Background

In Parkinson’s disease (PD), neurodegenerative changes have been observed in autonomic pathways involving multiple organ systems. We explore pupillary and cardiac autonomic measures as physiological manifestations of PD neurodegeneration.

Methods

Pupil measures (pupillary unrest (spontaneous changes of pupil diameter in darkness), constriction velocity and redilation velocity) were assessed in 35 participants (17 PD, 18 controls). Simultaneous cardiac measures (respiratory sinus arrythmia during deep breathing, Valsalva ratio, resting heart rate variability (HRV), orthostatic change in blood pressure and orthostatic change in heart rate) were obtained. Nonparametric statistics were used to compare PD with control participants and to calculate correlation coefficients between pupillary and cardiac measures.

Results

Pupillary unrest and orthostatic decreases in systolic blood pressure were greater in PD than controls. Respiratory sinus arrythmia during deep breathing and resting HRV were lower in PD. Among all participants, there was a negative correlation between HRV and redilation velocity and a positive correlation between orthostatic change in heart rate and pupillary unrest. A modifying effect of PD was found on the association between high frequency HRV and pupillary unrest.

Conclusions

Results demonstrate simultaneous autonomic dysfunction in both pupillary and cardiac systems in PD. The correlations between pupillary and cardiac measures suggest shared central centers of autonomic integration, while the modifying effect of PD may reflect autonomic effects of PD-related pathology not present in controls.

Introduction

Parkinson’s disease (PD) neuropathology suggests neurodegenerative changes involve neurons in autonomic pathways affecting multiple organ systems [1] which may lead to widespread changes in autonomic physiology which if quantified may serve as non-motor markers of PD. Such markers could allow earlier diagnosis and better treatment of PD as non-motor features of PD occur earlier and contribute more to the burden of disease than do motor features [2]. Both the pupillary and cardiovascular systems may provide such physiological markers.

The pupil can provide a unique window into brain function as it integrates inputs from both cortical and subcortical structures which influence its autonomic function – parasympathetic constriction or sympathetic dilation. Pupillary measures include pupillary unrest, constriction velocity and redilation velocity. Pupillary unrest refers to spontaneous fluctuations in autonomic tone which lead to changes in pupil diameter in darkness. It is positively associated with arousal related symptoms such as sleepiness which are common in PD [3]. The cardiovascular system is also of clinical significance, as evidenced by the high prevalence of orthostatic hypotension in PD [2]. Cardiac measures include respiratory sinus arrythmia with deep breathing, resting heart rate variability, the Valsalva ratio and orthostatic blood pressure and heart rate. Cardiac measures in PD have been reported, but mostly in isolation without taking account of how other autonomic end-organs are functioning. Our objective in this exploratory study is to simultaneously acquire measures in the pupillary and cardiovascular systems, allowing correlations of autonomic function between the two systems. Results of such analyses would reveal information on hierarchically higher centers of autonomic integration in elderly controls and how such systems may be affected in PD [4].

Section snippets

Methods

All participants were recruited from the University of Pittsburgh Medical Center. The IRB gave ethical approval and the participants signed informed consent. PD participants fulfilled the UK PD Society Brain Bank Clinical Criteria, scoring Hoehn and Yahr Stage (HY) < 5, taking either no anti-parkinsonian medication, carbidopa/levodopa or dopamine agonists. As a group, controls were age and sex matched to PD participants. Exclusion criteria included: pyramidal and/or cerebellar signs, any other

Results

Characteristics of PD and control groups are summarized in Table 1. Pupillary unrest was higher in PD and four of the six cardiovascular measures were lower in PD compared to controls. Medications in the first five participants were not withheld and included: no medications in the first participant; selegiline 5 mg/day and levodopa 800 mg/day in the second; amantadine 200 mg/day and ropinirole 12 mg/day in the third; levodopa 600 mg/day in the fourth; and levodopa 300 mg/day in the fifth. There

Discussion

Simultaneous recordings of pupillary and cardiovascular autonomic measures in PD have not been previously reported. We observed lower HRV in both low and high frequency bands, greater decreases in supine to standing (orthostatic) systolic blood pressure and higher pupillary unrest in PD relative to controls. This represents lower sympathetic and parasympathetic cardiac function, as well as higher autonomic variability in pupillary function in PD.

Given the known association of pupillary unrest

Acknowledgments

NIH grants KL2 RR024154, KMH082998, MH55762, P30 AG-024826, UL1 RR024153, Dept. of Veterans Affairs, and the American Parkinson’s Disease Association Center for Advanced Research at the University of Pittsburgh.

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Cited by (31)

Pupillary light reflex as a diagnostic aid from computational viewpoint: A systematic literature review
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They were also sub grouped by region of pupillary signal, short-term characteristics (transient) of the contraction phase and longer duration characteristics (sustained) measured in the dilation phase. In addition to the characteristics presented, there were others that were sometimes considered in the studies: (1) Spontaneous fluctuations in pupil size, also called Hippus [108] or pupillary unrest [109] or Spontaneous Pupillary Fluctuation [110] or Pupil Oscillation Frequency (POF) [67] - which are spontaneous variations in pupillary size when it is not being stimulated. ( 2) Anisocoria of contraction - which occurs when the stimulated pupil (direct reflex) contracts more than the pupil that is not being illuminated (consensual reflex).
This work presents a detailed and complete review of publications on pupillary light reflex (PLR) used to aid diagnoses. These are computational techniques used in the evaluation of pupillometry, as well as their application in computer-aided diagnoses (CAD) of pathologies or physiological conditions that can be studied by observing the movements of miosis and mydriasis of the human pupil. A careful survey was carried out of all studies published over the last 10 years which investigated, electronic devices, recording protocols, image treatment, computational algorithms and the pathologies related to PLR. We present the frontier of existing knowledge regarding methods and techniques used in this field of knowledge, which has been expanding due to the possibility of performing diagnoses with high precision, at a low cost and with a non-invasive method.
The pupillary light reflex for predicting the risk of hypotension after spinal anaesthesia for elective caesarean section
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The surface diameter of the pupil therefore reflects these interactions between the sympathetic and parasympathetic systems. Pupillometry has been adopted in a growing number of medical fields (obstructive sleep apnoea syndrome [23], congenital central hypoventilation syndrome [24], Parkinson's disease [25], schizophrenia [26], diabetic polyneuropathy [27], heart failure [28], bronchial hyperactivity [29] and migraine headaches [30]) and various studies have used this device to highlight autonomic nervous system dysfunction. Its low cost, safety profile, measurement reproducibility, speed and ease of use make it an ideal tool for use during CS.
The balance between the sympathetic and parasympathetic systems could be used to predict the onset of hypotension following spinal anaesthesia. The autonomic innervation of the pupil may reflect this balance. The aim of this study was to evaluate the ability of pupillometry to predict the risk of hypotension after spinal anaesthesia for caesarean section.
Two hundred patients receiving spinal anaesthesia for caesarean section were recruited. Changes in pupillary diameter, pupillary reaction latency, pupil constriction velocity and maximum and minimum pupillary diameters were measured with a pupillometer (Neurolight^®, IDMed) prior to induction of spinal anaesthesia with 10 mg bupivacaine and fentanyl 30 μg. Hypotension was defined as a systolic blood pressure drop of > 20% compared with the baseline value.
A total of 141 patients (70%) presented at least one episode of hypotension. Pupillary reaction latency can poorly predict hypotension and severe hypotension after spinal anaesthesia. The areas under the receiver-operating characteristic curves were 0.654 (95% confidence interval: 0.584–0.720, P = 0.0001) and 0.633 (95% confidence interval: 0.562–0.700, P = 0.004) for optimal threshold values of 223 and 231 ms, respectively. In multivariate analysis, a baseline systolic blood pressure > 130 mmHg (odds ratio: 1.98, P = 0.04) and a PRL > 223 ms (odds ratio: 3.42, P = 0.0002) were independently associated with the risk of spinal anaesthesia-related hypotension.
Following spinal anaesthesia in patients undergoing caesarean section, though the predictive capacity pupillary reaction latency for the onset of hypotension and severe hypotension is poor, it is nevertheless the strongest predictor of hypotension identified in our study.
Differences of sympathetic and parasympathetic modulation in major depression
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The pupillary unrest index (PUI) is mainly used to quantify temporal changes of pupil size (Lüdtke et al., 1998). Alterations of pupillary fluctuations were described in patients suffering from Parkinson's disease, multiple sclerosis or epilepsy (Centeno et al., 2011; Egg et al., 2002; Jain et al., 2011a,b). The objective of this study was the assessment of autonomic function in a more comprehensive way, using HRV, baroreflex sensitivity, pupillary function, electrodermal activity and respiration.
Inconsistent results have been reported with respect to cardiac autonomic function in major depression. The aim of our study was to investigate autonomic function in various branches of the autonomic nervous system in order to better understand parasympathetic and sympathetic modulation in the disease.
We investigated 29 unmedicated patients suffering from major depression (MD) in comparison to matched control subjects (gender, age, BMI). The autonomic assessment at rest included values of heart rate variability (HRV), blood pressure variability (BPV), baroreflex sensitivity (BRS), respiration, skin conductance (SC) as well as the calculation of pupillary diameter and the unrest index (PUI). Results were compared by means of a multivariate analysis of variance. In a classification analysis, we identified suitable parameters for patient - control separation. Finally, to analyze interrelations of pupillometric parameters and autonomic indices, we estimated Pearson correlation coefficients and fitted a linear regression model.
Apart from a significantly increased heart rate (75 ± 12 vs. 65 ± 6 min^− 1, p < 0.001) and decreased BRS (14 ± 13 vs. 20 ± 15 ms/mmHg, p < 0.05), we observed a lack of significant differences in HRV and BPV analysis between patients and controls. However, pupillary diameter (left: 4.3 ± 0.9 vs. 3.8 ± 0.6, p < 0.01; right: 4.3 ± 0.9 vs. 3.7 ± 0.6 mm, p < 0.01) and PUI (left: 14.8 ± 6.0 vs. 10.7 ± 4.5 mm/min, p < 0.01; right: 14.1 ± 5.5 vs. 10.7 ± 4.8 mm/min, p < 0.01), as well as the level (left: 7.3 ± 6.2 vs. 4.3 ± 4.4 μS, p < 0.05) and fluctuations of skin conductance (left: 4.2 ± 4.1 vs. 2.5 ± 3.6, p < 0.05; right: 4.2 ± 4.4 vs. 2.6 ± 3.2, p < 0.05) were significantly different. The classification accuracy was 88.5% with high specificity (e = 92.9%) and sensitivity (s = 83.3%) including heart rate, PUI and skin conductance. HRV indices correlated to PUI in controls but not in patients.
Our data add evidence to the current debate on autonomic function in major depression. We suggest that diverse results are mainly caused by methodological shortcomings, in particular by the application of HRV assessment only, which misses changes of sympathetic modulation. The application of broader analyzing tools will clarify the pattern of autonomic function in depression and ultimately its role in cardiac morbidity and mortality.
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When endogenous defenses can no longer resist these stresses, neuropathologic changes may accumulate, notably in dopamine neurons, which are rendered especially susceptible to the combined effects of energy deficit and oxidative stress by the catechol structure and metabolism of dopamine (Cohen, 1994; Kristal et al., 2001; Lamensdorf et al., 2000; Marchitti et al., 2007). Abnormalities in PD also occur outside the central dopaminergic pathways, as there is evidence of widespread dysfunction (shown by biochemical change, gene underexpression, pathology, and functional deficit) in other non-dopamine central neurons, autonomic and sensory pathways, and peripheral structures including nonneural tissue (Beach et al., 2010; Braak et al., 2003; Gibson et al., 2003; Halliday, 2009; Hargreaves et al., 2008; Harris et al., 1992; Hindle, 2010; Jain et al., 2011; Jellinger, 1999; Mytilineou et al.,1994; Zheng et al., 2010), and many patients later develop cortical pathology (Braak et al., 2003) and dementia (Hindle, 2010). Some of the changes in the central nervous system associated with PD are also found, in less severe form, in normal aging tissue.
The aging risk factor for Parkinson's disease is described in terms of specific disease markers including mitochondrial and gene dysfunctions relevant to energy metabolism. This review details evidence for the ability of nutritional agents to manage these aging risk factors. The combination of alpha lipoic acid, acetyl-l-carnitine, coenzyme Q10, and melatonin supports energy metabolism via carbohydrate and fatty acid utilization, assists electron transport and adenosine triphosphate synthesis, counters oxidative and nitrosative stress, and raises defenses against protein misfolding, inflammatory stimuli, iron, and other endogenous or xenobiotic toxins. These effects are supported by gene expression via the antioxidant response element (ARE; Keap/Nrf2 pathway), and by peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1 alpha), a transcription coactivator, which regulates gene expression for energy metabolism and mitochondrial biogenesis, and maintains the structural integrity of mitochondria. The effectiveness and synergies of the combination against disease risks are discussed in relation to gene action, dopamine cell loss, and the accumulation and spread of pathology via misfolded alpha-synuclein. In addition there are potential synergies to support a neurorestorative role via glial derived neurotrophic factor expression.
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^☆: The review of this paper was entirely handled by an Associate Editor, R. L. Rodnitzkyi.

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Short communicationAutonomic insufficiency in pupillary and cardiovascular systems in Parkinson’s disease☆

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgments

Lancet Neurology

Vision Research

Journal of the Neurological Sciences

International Journal of Psychophysiology

Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders

Acta Neuropathologica

The pupil: anatomy, physiology, and clinical applications

Short communication
Autonomic insufficiency in pupillary and cardiovascular systems in Parkinson’s disease☆