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1 These authors have contributed equally to the manuscript.
Affiliations
Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Nijmegen, The NetherlandsUniversity of Twente, MIRA Institute for Biomedical Technology and Technical Medicine, Biomedical Signal and Systems Group, Enschede, The Netherlands
Patients with Parkinson's disease (PD) are highly dependent on visual feedback to compensate for their motor deficits.
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Visual and ocular disorders are common in patients with Parkinson's disease.
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Early recognition and treatment of visual problems are necessary to improve patient safety, independence and quality of life.
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We conducted a literature search covering 50 years.
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We present an overview of the epidemiology, pathophysiology, diagnostics and treatment of ocular and visual disorders in PD.
Abstract
Patients with Parkinson's disease (PD) often compensate for their motor deficits by guiding their movements visually. A wide range of ocular and visual disorders threatens the patients' ability to benefit optimally from visual feedback. These disorders are common in patients with PD, yet they have received little attention in both research and clinical practice, leading to unnecessary – but possibly treatable – disability. Based on a literature search covering 50 years, we review the range of ocular and visual disorders in patients with PD, and classify these according to anatomical structures of the visual pathway. We discuss six common disorders in more detail: dry eyes; diplopia; glaucoma and glaucoma-like visual problems; impaired contrast and colour vision; visuospatial and visuoperceptual impairments; and visual hallucinations. In addition, we review the effects of PD-related pharmacological and surgical treatments on visual function, and we offer practical recommendations for clinical management. Greater awareness and early recognition of ocular and visual problems in PD might enable timely instalment of tailored treatments, leading to improved patient safety, greater independence, and better quality of life.
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by a wide range of motor and non-motor symptoms. The cardinal motor features (tremor, rigidity, bradykinesia, postural instability) [
]) have received considerable attention. However, a broad spectrum of ocular disorders (affecting the eyes or eyelids) and visual disorders (including central visual perception) has, despite being supposedly common in PD [
], remained largely out of focus both in research and clinical practice.
2. Why recognition of visual disorders is important
A better awareness and timely recognition of visual symptoms in PD is important for several reasons. First, recognition of visual symptoms allows for closer determination of disease prognosis. For instance, visuospatial impairment is an important predictor of dementia in PD, and visual hallucinations for admission to a nursing home [
]. The impact of ocular and visual disorders is particularly vexing for patients with PD, because they typically have problems with internally guided movements and postural control, which they can compensate for by guiding their movements visually [
]. Another example is freezing of gait, a debilitating symptom that is prevalent in advanced stages of PD. Visual cueing, e.g. in the form of stationary stripes pasted onto the floor, is an evidence-based neurorehabilitation technique to alleviate freezing of gait [
], but is difficult to employ in the presence of ocular and visual disorders. Also new neurorehabilitation strategies such as exergaming, cueing via smart glasses or personalized neurorehabilitation in the home-situation through telemedicine [
] cannot be benefited from when visual function is insufficient. Timely recognition of ocular and visual disorders is therefore essential, so that tailored treatment can be installed to prevent complications such as falls or injuries, to restore mobility, to enhance the efficacy of visual cueing and various other non-pharmacological interventions, to ascertain a greater independence, and to improve the patient's quality of life.
The assessment of specific ocular and visual disorders also has value for the differential diagnosis of a hypokinetic-rigid syndrome, helping to separate patients with PD from those with a form of atypical parkinsonism such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) [
]. However, this diagnostic aspect is not discussed in this review. Instead, we here provide a detailed, interdisciplinary overview of various ocular and visual disorders in PD.
3. Search strategy and selection criteria
We performed a systematic literature search in the databases PubMed, Medline and the Cochrane library and searched for relevant articles published between 1966 and January 2017. Search terms included: ‘’visual’’, ‘’ocular’’, ‘’vision’’, ‘’ophthalmologic’’, ‘’eyes'’, ‘’eyelid’’, ‘’cornea’’, ‘’retina’’, AND ‘’Parkinson's disease’’. The results of the systematic literature review were supplemented by references acquired from the reference lists of included papers.
4. Ocular and visual disorders and PD
We have classified the various ocular and visual disorders in PD according to the anatomical structures that are involved in normal vision (Fig. 1 and Table 1). Some of these disorders are due to the neurodegenerative process underlying PD, and these often respond positively to dopaminergic medication (Table 2). On the other hand, ocular and visual disorders can be side effects of dopaminergic, cholinergic or noradrenergic medication, and of surgical interventions like deep brain stimulation (DBS) and pallidotomy (Table 2).
Fig. 1Overview of the visual pathway. Areas of interest linked to Table 1 are attenuated.
Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson's disease: a longitudinal 4-year study.
Bilateral contemporaneous posteroventral pallidotomy for the treatment of Parkinson's disease: neuropsychological and neurological side effects. Report of four cases and review of the literature.
Levels of evidence: A1 - Systematic review or meta-analysis containing at least some trials of level A2 and of which the results of the trials are consistent. A2 - Randomized comparative clinical trials of good quality (randomized double-blind controlled trials) of sufficient size and consistency. B - Randomized clinical trials of moderate (weak) quality of insufficient size or other comparative trials (non-randomized, cohort studies, patient-control studies. C – Non comparative trials. D – Expert opinion.
Given the widespread dysfunction along the visual pathway in PD, it is not feasible to fully elaborate on every ocular and visual disorder. Instead, we will discuss six common and disabling ocular and visual problems in more detail. These conditions include: dry eye disease; oculomotor disturbances and diplopia; glaucoma and glaucoma-like visual field loss; colour and contrast impairment; visuospatial and visuoperceptual impairments; and visual hallucinations. Recommendations for the management of these and other ocular and visual disorders are summarized in Table 3.
Table 3Recommendations for management of ocular and visual disorders.
Ocular and visual symptom
Possible management options
Impaired convergence
Based-in prismAdapted glasses
Diplopia
Adapted prisms, convergence exercises (in convergence insufficiency)
Regularly testing with Donder's test and timely referral to ophthalmologist
Visual hallucinations
Check for triggers in other drugs and comorbidity. Consider Charles Bonnet syndrome. Atypical neuroleptics when needed. Include addition cholinesterase inhibitors in dementing PD patients with visual hallucinations
In general
In house adjustments to prevent falling Explanation about decreased contrast while driving at night
]. Dry eyes in PD are thought to result from a decreased blink rate, which is a classical feature of PD. A decreased blink rate leads to a diminished distribution of the lipid components of the tear film over the cornea [
], causing the aqueous component to evaporate faster. In addition, dry eyes in PD may result from decreased tear production caused by autonomic dysfunction, based on the partial parasympathetic autonomic innervation of the lacrimal gland [
During history taking, one should not only ask for dry eyes, but also for associated typical symptoms such as burning sensations of the eyes, intermittent lacrimation (e.g. tearing), blurred vision, a gritty or sandy sensation, red eyes, or the feeling of pressure or even pain behind the eye balls or around the orbit. Dry eyes can also be objectively verified by the Schirmer's test, reflecting the amount of aqueous tear production; and the ‘tear breakup time’, measuring the stability of the tear film layer [
Symptomatic treatment of dry eyes is challenging (Table 3) and has not been studied specifically in PD patients. Patients can be advised to consciously increase their blink frequency, but this is difficult to achieve, because they are usually not aware of this. Artificial tears (eye drops) are the current mainstay of treatment, often resulting [
] in a significant reduction of discomfort and better visual acuity, although PD-related motor impairments might impede their self-administration. In addition, oral supplementation with polyunsaturated fatty acids (omega-3 and omega-6) might relieve symptoms [
]. Semi-permanent occlusion of the tear ducts by silicone or collagen plugs, or permanent occlusion by thermal cautery or argon laser can provide symptomatic relief of severe dry eyes, at the price of potential side effects as epiphora (overflow of tears), foreign body sensation, eye irritation, and spontaneous plug loss [
The prevalence of diplopia in PD has only been studied in small cohorts, which reported a prevalence varying between 10 and 30% in PD patients, compared to 1–19% in controls [
]. Diplopia is more common in patients with pre-existent ocular misalignment and with daytime somnolence, suggesting that non-drowsy patients can to some extent compensate for ocular misalignment [
], suggesting that dopamine deficiency in the basal ganglia takes part in its pathophysiology. However, it has also been suggested that convergence insufficiency is due to extranigral pathology [
]. Selective diplopia, a phenomenon where isolated (instead of all) objects or persons are perceived duplicated, has been associated with the presence of dementia, visual hallucinations, changes in antiparkinsonian treatment, and subtle oculomotor disturbances, although a pathophysiological mechanism closer to that of visual hallucinations than to oculomotor disturbances is expected [
]. Diplopia can be constant, but more often it is only present in specific situations, e.g. while reading or when looking nearby. It is therefore important to ask for activities that provoke diplopia. The first diagnostic step is to differentiate between monocular and binocular diplopia (appendix), because monocular diplopia is not caused by PD pathology, but rather suggests ocular media opacities like cataract or a major refractive error of that particular eye. Several tests can detect ocular misalignment, like the ‘Hirschberg corneal reflex test’, the ‘cover test’ and the ‘cover/uncover test’, or more advanced techniques used by (neuro-)ophthalmologists, or eye care practitioners (appendix). Gaze restriction is best detected by clinical examination [
]. Saccades can be examined using video-oculography, to determine amplitudes and latencies (as a measure of ocular bradykinesia).
The treatment strategy of diplopia depends on the underlying mechanism. For example, convergence insufficiency can be treated with base-in prism and convergence exercises [
], OFF-periods should be minimized. In patients with hallucinations, selective diplopia might improve when treating the hallucinations.
4.3 Glaucoma and glaucoma simulating optic neuropathy
Glaucoma is a progressive optic neuropathy in which increased retinal nerve fibre apoptosis leads to thinning of the neuro-retinal rim of the optic disc, increasing the central excavation (Fig. 2) [
]. This causes a characteristic arcuate-shaped visual field defect, which starts in the mid-periphery, and slowly progresses to the periphery and centre. Patients are generally not aware of the visual field defect (negative scotoma) until central defects appear. An increased intraocular pressure (IOP; >21 mmHg) is the main risk factor for developing glaucoma, but in about one third of patients the IOP is not increased and they are diagnosed with normal-pressure glaucoma. In open angle glaucoma, the irido-corneal angle is open, but aqueous outflow is diminished, slowly leading to visual field defects [
]. In angle-closure glaucoma, an immediate occlusion of the anterior chamber leads to blockage of aqueous outflow, resulting in a red, painful eye with symptoms like nausea and vomiting [
Fig. 2Funduscopic appearance of the optic nerve.A. Normal optic disc with sharp borders and no pallor. B. Optic disc atrophy. C. Glaucoma with typical cupping and peripapillary atrophy. D. Papiledema with hyperemia, unsharp borders and prominence of the optic disc.
Epidemiologic data on the association between glaucoma and PD are scarce. Two studies found a prevalence of glaucoma of 16–24% in PD compared with about 7% in controls [
]. Interestingly, in PD all cases concerned primary open angle glaucoma, while the prevalence of increased IOP was lower in PD patients than in controls [
]. Different hypotheses linking PD to open angle glaucoma have been proposed, involving retinal degeneration due to progressive retinal dopamine depletion [
]. In addition, angle-closure glaucoma can occur due to blocked aqueous outflow, associated with dopaminergic and anticholinergic medication, especially in patients with a pre-existent narrow chamber, e.g. in high hypermetropia (Table 2) [
]. The underlying pathology is still unclear and requires further research.
During clinical examination, the Donder's confrontation method and Amsler grid (appendix) can be used as a screening tool for moderate to severe central and peripheral field defects. If visual field loss is suspected, the patient can be referred to an ophthalmologist for more specialized testing, including fundoscopy, the Humphrey visual field exam and measurement of the intraocular pressure using applanation tonometry (appendix). Quantitative information about optic nerve fiber cell loss can be obtained using recently developed methods like confocal scanning laser ophthalmoscopy, scanning laser polarimetry, and optical coherence tomography [
In patients diagnosed with open-angle glaucoma, eye drops can be used to lower the production of chamber fluid or to increase the drainage of chamber water. If insufficient, drainage of chamber fluid can be enhanced by laser trabeculoplasty or trabeculectomy. Therapies other than those aimed at decreasing intra-ocular pressure, like neuroprotective therapy, have not yet been studied in sufficiently large clinical trials [
]. Colour discrimination is the ability to distinguish subtle differences in colour. Decreased contrast sensitivity and reduced colour discrimination, which can both be experienced early in the disease, are thought to be common in PD, but exact prevalence numbers are missing [
The pathophysiology of diminished contrast sensitivity and colour discrimination is not fully clear. Deficiency of retinal dopamine is thought to result in impaired processing of visual stimuli, leading to decreased contrast sensitivity and colour discrimination [
]. In addition, the primary visual cortex has been suggested as a source of contrast sensitivity deficits. Impaired colour discrimination has also been described to originate from a cortical origin, although these studies were prone to confounding by cognitive and motor deficits [
In clinical practice, contrast sensitivity can be tested with the Pelli Robson chart or with sine wave gratings at different spatial frequencies (appendix). To test colour discrimination, the Farnsworth-Munsell 100 Hue test (FM) and the D-15 Lanthony test (D-15) are most widely used [
]. Blue haze (short-wavelength light) can veil the patient's view, so yellow filtering glasses may improve contrast sensitivity when patients experience glare [
]. Selective absorption glasses, that may be applied as filter clips onto the patient's own spectacles, can be supportive. In addition, patients should be adviced to read and work with sufficient ambient light to create optimal visual circumstances. Finally, it is presumably wise to advise patients to avoid driving after dusk and before dawn.
4.5 Visuospatial and visuoperceptual impairments
Performance on several visuospatial tasks appears to be impaired in patients with PD [
], but may be common in non-demented PD patients as well. In answer to a self-report questionnaire, 40% of 55 non-demented PD patients reported difficulties in estimating spatial relations, and 50% reported bumping into doorways [
]. Otherwise, few epidemiologic data on visuospatial and visuoperceptual impairments in PD are available.
The pathophysiology of these problems likely resides within the cortex. Indeed, the primary visual cortex is probably involved in processes such as distinguishing between lines with different orientations [
]. Moreover, impairments in higher order visuospatial and visuoperceptual processing in PD have been associated with grey matter atrophy in temporo-parietal cortical regions [
In clinical practice, visuospatial impairments may lead patients into bumping into doorways or objects, and to experience problems driving a car and navigating [
]. Validated bedside tests for visuoperceptual impairments are not yet available.
It is important to raise awareness amongst patients, carers and healthcare workers about the possible presence of visuospatial and visuoperceptual impairments in PD. When visuospatial impairments are suspected, it is advised to refer patients for a driving assessment. Tactical driving skills, such as visual scanning, can be trained with driving rehabilitation strategies [
Visual hallucinations are defined as the perception of an object or event, in the absence of an external stimulus. The visual hallucinations considered in this manuscript comprise simple and complex visual hallucinations, visual illusions and passage of shadows [
]. Visual hallucinations early in the disease course are a typical feature of Lewy body parkinsonism (i.e. PD with dementia (PDD) or dementia with Lewy bodies), differentiating these two conditions from other types of parkinsonism [
Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson's disease: a longitudinal 4-year study.
], depending on the method of assessment and the definition of visual hallucinations (e.g. illusions included or excluded) used, the patient selection (e.g. disease stage and cognitive impairments), and the (cross-sectional or longitudinal) set-up of studies. Longitudinal studies [
Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson's disease: a longitudinal 4-year study.
Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson's disease: a longitudinal 4-year study.
Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson's disease: a longitudinal 4-year study.
Visual hallucinations have a multifactorial aetiology, being associated with low visual acuity, longer disease duration, impaired contrast sensitivity, REM sleep behaviour disorder and reduced colour discrimination [
]. In addition, dopaminergic drugs (dopamine agonists more so than levodopa or monoamine oxidase (MAO) B inhibitors) and drugs with a(n) (partial) anticholinergic working mechanism (such as anticholinergics and amantadine) are important triggers (Table 2) [
]. However, recent studies suggest that the causal role of medication in the pathophysiology of visual hallucinations in PD is smaller than previously thought, and that visual hallucinations are mainly due to underlying disease pathologies themselves. Various mechanisms underlying visual hallucinations in PD have recently thoroughly been discussed in an excellent review by Weil and colleagues [
In clinical practice, it is important to ask explicitly for the presence of visual hallucinations, because they are among the most common “non-declared” symptoms (i.e. they are often not reported spontaneously by patients themselves) [
The nondeclaration of nonmotor symptoms of Parkinson's disease to health care professionals: an international study using the nonmotor symptoms questionnaire.
]. Drugs with high risk-benefit ratios (i.e. high risk of cognitive side effects vs relatively low anti-parkinsonian efficacy) should be tapered first; including anticholinergics, anti-N-methyl-d-aspartate (NMDA) antagonists, and MAO-B inhibitors. If this is insufficiently effective, the next step is to reduce dopamine agonists, and finally to reduce levodopa [
]. It is not always feasible to achieve a dose reduction of dopaminergic drugs to a level that leads to resolution of psychotic symptoms because of an unacceptable increase in motor disability. Initiation of anti-psychotic therapy may be necessary. Clozapine is the only drug with evidence from randomized controlled trials showing a clear efficacy in treating hallucinations in PD [
]. The new serotonergic drug pimavanserin has shown promising results in phase III studies and has recently been approved in the US for the treatment of hallucinations and delusions in PD [
The spectrum of ocular and visual disorders occurring during the course of PD includes all levels of visual processing. Many of these ocular and visual disorders occur more frequently in PD than in the general population, either because of a relation with the PD-related pathology, or because Parkinson-related medication negatively affects the visual system. Importantly, the presence of ocular and visual disorders has great implications for clinical management, because due to their defective motor planning and –programming, patients with PD are particularly dependent on visual feedback to improve the quality and safety of their movements. Also, many current neurorehabilitation strategies rely on sufficient visual function. Therefore, these strategies should be adapted to also fit visually impaired patients with PD, so they can also benefit from these interventions.
Another important message is that the association between ocular symptoms and PD is far from obvious to both patients and clinicians in clinical practice: many patients may not adequately report ophthalmic problems themselves, while clinicians frequently miss ocular disorders that – in many cases – can be treated. This results in a delayed diagnosis and further deterioration of the visual disorders. And most importantly, it leads to suboptimal treatment, unnecessary disability and a compromised quality of life. We therefore strongly encourage clinicians involved in PD care to routinely ask their patients about ocular symptoms and to take action if ocular symptoms are suspected, e.g. by referring their patient to an ophthalmologist. We also advise clinicians to remember that dopaminergic medication, as well as DBS and pallidotomy, can contribute to visual problems. As such, when patients experience sudden visual problems after alterations in medication or surgical interventions like DBS or pallidotomy, evaluation of the new treatment strategy is required. Finally, we conclude that specific evidence on ocular and visual problems in PD and their treatment in clinical practice is still lacking. Much more work remains needed to determine the exact incidence and prevalence of PD-related ocular and visual disorders, to further map the burden of these ocular and visual problems for PD patients, and to create more insight into the underlying pathophysiology. Based on this, tailored interventions can be developed, leading to improved patient safety, greater independence and better quality of life and quality of care.
Funding sources
Merel S. Ekker: no funding sources.
Sabine Janssen is supported by a research grant from the Netherlands Organisation for Scientific Research (058-14-001).
Klaus Seppi: has received grants from Oesterreichische Nationalbank (14174), from FWF Austrian Science Fund (KLI82-B00), from Michael J. Fox Foundation (project: PPMI study), Stichting Parkinson Fonds (01072016), and personal fees from the International Parkinson and Movement Disorder Society, Teva, UCB, Lundbeck, AOP Orphan Pharmaceuticals AG, Roche and Abbvie, outside the submitted work.
Werner Poewe: has received a grant from Stichting Parkinson Fonds (01072016), and personal consultancy and lecture fees in relation to clinical drug development programmes for PD from AbbVie, Allergan, AstraZeneca, BIAL; Boehringer-Ingelheim, Boston Scientific, GlaxoSmithKline, Ipsen, Lundbeck, Medtronic, MSD, Merck-Serono, Merz Pharmaceuticals, Novartis, Orion Pharma, Teva, UCB and Zambon.
Nienke M. de Vries is supported by a research grant of The Netherlands Organization for Health Research and Development (525001008).
Thomas Theelen: no funding sources.
Jorik Nonnekes: no funding sources.
Prof. Bas Bloem receives funding from the Stichting Parkinson Fonds (01072016), National Parkinson Foundation, the Netherlands organization for scientific research (40-00812-98-15076 and 80-84400-98-086), the Hersenstichting (F2015(1)-21) and the Michael J Fox Foundation (10231.01). He received honoraria from Adamas, Abbvie, Danone, GSK, Teva, UCB, Zambon.
None of the funding sources had any influence on the literature search or interpretation, writing of the review or decision to submit the paper for publication.
Author contributions
Merel S. Ekker: thorough literature search and interpretation, figure design, drafting of manuscript.
Sabine Janssen: finalizing writing of the manuscript; thorough revision of manuscript.
Klaus Seppi: revision of manuscript.
Werner Poewe: revision of manuscript.
Nienke M. de Vries: supervision of literature review, especially from Parkinson's disease perspective; critical revision of manuscript.
Thomas Theelen: supervision of literature review, especially from ophthalmologic perspective; critical revision of manuscript.
Jorik Nonnekes: supervision of literature review, especially from Parkinson's disease perspective; critical revision of manuscript.
Prof Bastiaan R. Bloem: conceived the idea for the study; critical revision of multiple versions of the manuscript for intellectual content.
Declaration of interests
Merel S. Ekker: no conflicts of interests to declare.
Sabine Janssen: no conflicts of interests to declare.
Klaus Seppi: no conflicts of interests to declare.
Werner Poewe: no conflicts of interests to declare.
Nienke M. de Vries: no conflicts of interests to declare.
Thomas Theelen: no conflicts of interests to declare.
Jorik Nonnekes: no conflicts of interests to declare.
Prof. Bas Bloem: no conflicts of interests to declare.
Acknowledgements
We are grateful to Louis van Enckevort for assisting in collecting and interpreting the relevant literature in the earliest phase of the conception of this manuscript. We thank the Stichting Parkinson Fonds (SPF) for their financial support of this review.
Appendix A. Supplementary data
The following is the supplementary data related to this article:
Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson's disease: a longitudinal 4-year study.
The nondeclaration of nonmotor symptoms of Parkinson's disease to health care professionals: an international study using the nonmotor symptoms questionnaire.
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