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Ocular and visual disorders in Parkinson's disease: Common but frequently overlooked

      Highlights

      • Patients with Parkinson's disease (PD) are highly dependent on visual feedback to compensate for their motor deficits.
      • Visual and ocular disorders are common in patients with Parkinson's disease.
      • Early recognition and treatment of visual problems are necessary to improve patient safety, independence and quality of life.
      • We conducted a literature search covering 50 years.
      • 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.

      Keywords

      1. Introduction

      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) [
      • Hughes A.J.
      • Daniel S.E.
      • Kilford L.
      • Lees A.J.
      Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases.
      ] and non-motor features (e.g. disorders of mood and affect, cognitive decline, sensory dysfunction, autonomic failure [
      • Chaudhuri K.R.
      • Odin P.
      • Antonini A.
      • Martinez-Martin P.
      Parkinson's disease: the non-motor issues.
      ], and visual hallucinations [
      • Diederich N.J.
      • Fenelon G.
      • Stebbins G.
      • Goetz C.G.
      Hallucinations in Parkinson disease.
      ,
      • Urwyler P.
      • Nef T.
      • Killen A.
      • Collerton D.
      • Thomas A.
      • Burn D.
      • McKeith I.
      • Mosimann U.P.
      Visual complaints and visual hallucinations in Parkinson's disease.
      ]) 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 [
      • Urwyler P.
      • Nef T.
      • Killen A.
      • Collerton D.
      • Thomas A.
      • Burn D.
      • McKeith I.
      • Mosimann U.P.
      Visual complaints and visual hallucinations in Parkinson's disease.
      ,
      • Biousse V.
      • Skibell B.C.
      • Watts R.L.
      • Loupe D.N.
      • Drews-Botsch C.
      • Newman N.J.
      Ophthalmologic features of Parkinson's disease.
      ], 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 [
      • Weil R.S.
      • Schrag A.E.
      • Warren J.D.
      • Crutch S.J.
      • Lees A.J.
      • Morris H.R.
      Visual dysfunction in Parkinson's disease.
      ]. Second, ocular and visual disorders can have a disabling impact on activities of daily living such as walking, reading or driving [
      • Amick M.M.
      • Grace J.
      • Ott B.R.
      Visual and cognitive predictors of driving safety in Parkinson's disease patients.
      ], forcing Parkinson patients to reduce their social and physical activities, resulting in a decreased quality of life [
      • Santos-Garcia D.
      • de la Fuente-Fernandez R.
      Impact of non-motor symptoms on health-related and perceived quality of life in Parkinson's disease.
      ]. 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 [
      • Azulay J.P.
      • Mesure S.
      • Amblard B.
      • Blin O.
      • Sangla I.
      • Pouget J.
      Visual control of locomotion in Parkinson's disease.
      ,
      • Davidsdottir S.
      • Cronin-Golomb A.
      • Lee A.
      Visual and spatial symptoms in Parkinson's disease.
      ]. As an illustration: over 80% of PD patients who fell within a one-year timeframe were visually impaired, compared with 66% of non-fallers [
      • Wood B.H.
      • Bilclough J.A.
      • Bowron A.
      • Walker R.W.
      Incidence and prediction of falls in Parkinson's disease: a prospective multidisciplinary study.
      ]. 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 [
      • Nieuwboer A.
      • Kwakkel G.
      • Rochester L.
      • Jones D.
      • van Wegen E.
      • Willems A.M.
      • Chavret F.
      • Hetherington V.
      • Baker K.
      • Lim I.
      Cueing training in the home improves gait-related mobility in Parkinson's disease: the RESCUE trial.
      ,
      • Nonnekes J.
      • Snijders A.H.
      • Nutt J.G.
      • Deuschl G.
      • Giladi N.
      • Bloem B.R.
      Freezing of gait: a practical approach to management.
      ], 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 [
      • Ekker M.S.
      • Janssen S.
      • Nonnekes J.
      • Bloem B.R.
      • de Vries N.M.
      Neurorehabilitation for Parkinson's disease: future perspectives for behavioural adaptation.
      ,
      • Zhao Y.
      • Nonnekes J.
      • Storcken E.J.
      • Janssen S.
      • van Wegen E.E.
      • Bloem B.R.
      • Dorresteijn L.D.
      • van Vugt J.P.
      • Heida T.
      • van Wezel R.J.
      Feasibility of external rhythmic cueing with the Google Glass for improving gait in people with Parkinson's disease.
      ] 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) [
      • Biousse V.
      • Skibell B.C.
      • Watts R.L.
      • Loupe D.N.
      • Drews-Botsch C.
      • Newman N.J.
      Ophthalmologic features of Parkinson's disease.
      ]. 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. 1
      Fig. 1Overview of the visual pathway. Areas of interest linked to are attenuated.
      Table 1Ocular and visual abnormalities in PD, classified by anatomic localization.
      Ocular and visual finding in PDReference(s)
      1.Oculomotor disturbances
      Anatomic localization where ophthalmologic abnormality can be seen/tested.
      Impaired convergence
      • Biousse V.
      • Skibell B.C.
      • Watts R.L.
      • Loupe D.N.
      • Drews-Botsch C.
      • Newman N.J.
      Ophthalmologic features of Parkinson's disease.
      ,
      • Nowacka B.
      • Lubinski W.
      • Honczarenko K.
      • Potemkowski A.
      • Safranow K.
      Ophthalmological features of Parkinson disease.
      ,
      • Lepore F.E.
      Parkinson's disease and diplopia.
      ,
      • Hanuska J.
      • Bonnet C.
      • Rusz J.
      • Sieger T.
      • Jech R.
      • Rivaud-Pechoux S.
      • Vidailhet M.
      • Gaymard B.
      • Ruzicka E.
      Fast vergence eye movements are disrupted in Parkinson's disease: a video-oculography study.
      ,
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      Visual symptoms in Parkinson's disease and Parkinson's disease dementia.
      ,
      • Almer Z.
      • Klein K.S.
      • Marsh L.
      • Gerstenhaber M.
      • Repka M.X.
      Ocular motor and sensory function in Parkinson's disease.
      Diplopia
      • Davidsdottir S.
      • Cronin-Golomb A.
      • Lee A.
      Visual and spatial symptoms in Parkinson's disease.
      ,
      • Lepore F.E.
      Parkinson's disease and diplopia.
      ,
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      Visual symptoms in Parkinson's disease and Parkinson's disease dementia.
      ,
      • Nebe A.
      • Ebersbach G.
      Selective diplopia in Parkinson's disease: a special subtype of visual hallucination?.
      Bradykinesia and hypokinesia of ocular pursuit
      • Corin M.S.
      • Elizan T.S.
      • Bender M.B.
      Oculomotor function in patients with Parkinson's disease.
      ,
      • Shibasaki H.
      • Tsuji S.
      • Kuroiwa Y.
      Oculomotor abnormalities in Parkinson's disease.
      Impaired vertical gaze
      Impaired vertical gaze, with abnormalities of upward gaze slightly more frequent than abnormalities of downward gaze.
      • Corin M.S.
      • Elizan T.S.
      • Bender M.B.
      Oculomotor function in patients with Parkinson's disease.
      ,
      • Repka M.X.
      • Claro M.C.
      • Loupe D.N.
      • Reich S.G.
      Ocular motility in Parkinson's disease.
      Saccadic abnormalities
      Longer reaction times, multiple step, hypometric saccades, frequent square wave jerks.
      • Terao Y.
      • Fukuda H.
      • Ugawa Y.
      • Hikosaka O.
      New perspectives on the pathophysiology of Parkinson's disease as assessed by saccade performance: a clinical review.
      Disturbed smooth ocular pursuit movements
      • Shibasaki H.
      • Tsuji S.
      • Kuroiwa Y.
      Oculomotor abnormalities in Parkinson's disease.
      ,
      • Bares M.
      • Brazdil M.
      • Kanovsky P.
      • Jurak P.
      • Daniel P.
      • Kukleta M.
      • Rektor I.
      The effect of apomorphine administration on smooth pursuit ocular movements in early Parkinsonian patients.
      Ocular tremor
      • Gitchel G.T.
      • Wetzel P.A.
      • Baron M.S.
      Pervasive ocular tremor in patients with Parkinson disease.
      ,
      • Gitchel G.T.
      • Wetzel P.A.
      • Qutubuddin A.
      • Baron M.S.
      Experimental support that ocular tremor in Parkinson's disease does not originate from head movement.
      Dyskinetic eye movements
      • Shimizu N.
      • Cohen B.
      • Bala S.P.
      • Mendoza M.
      • Yahr M.D.
      Ocular dyskinesias in patients with Parkinson's disease treated with levodopa.
      2.EyelidDecreased blink rates
      • Biousse V.
      • Skibell B.C.
      • Watts R.L.
      • Loupe D.N.
      • Drews-Botsch C.
      • Newman N.J.
      Ophthalmologic features of Parkinson's disease.
      ,
      • Reddy V.C.
      • Patel S.V.
      • Hodge D.O.
      • Leavitt J.A.
      Corneal sensitivity, blink rate, and corneal nerve density in progressive supranuclear palsy and Parkinson disease.
      ,
      • Agostino R.
      • Bologna M.
      • Dinapoli L.
      • Gregori B.
      • Fabbrini G.
      • Accornero N.
      • Berardelli A.
      Voluntary, spontaneous, and reflex blinking in Parkinson's disease.
      Apraxia of eyelid opening
      • Biousse V.
      • Skibell B.C.
      • Watts R.L.
      • Loupe D.N.
      • Drews-Botsch C.
      • Newman N.J.
      Ophthalmologic features of Parkinson's disease.
      ,
      • Lamberti P.
      • De Mari M.
      • Zenzola A.
      • Aniello M.S.
      • Defazio G.
      Frequency of apraxia of eyelid opening in the general population and in patients with extrapyramidal disorders.
      Blepharospasm
      • Biousse V.
      • Skibell B.C.
      • Watts R.L.
      • Loupe D.N.
      • Drews-Botsch C.
      • Newman N.J.
      Ophthalmologic features of Parkinson's disease.
      ,
      • Elston J.S.
      A new variant of blepharospasm.
      Eyelid retraction
      • Corin M.S.
      • Elizan T.S.
      • Bender M.B.
      Oculomotor function in patients with Parkinson's disease.
      Ptosis of superior eyelid
      • Corin M.S.
      • Elizan T.S.
      • Bender M.B.
      Oculomotor function in patients with Parkinson's disease.
      Meibomian gland disease
      • Reddy V.C.
      • Patel S.V.
      • Hodge D.O.
      • Leavitt J.A.
      Corneal sensitivity, blink rate, and corneal nerve density in progressive supranuclear palsy and Parkinson disease.
      3.Tear ducts/apparatusDecrease in tear secretion, resulting in dry eyes
      • Biousse V.
      • Skibell B.C.
      • Watts R.L.
      • Loupe D.N.
      • Drews-Botsch C.
      • Newman N.J.
      Ophthalmologic features of Parkinson's disease.
      ,
      • Nowacka B.
      • Lubinski W.
      • Honczarenko K.
      • Potemkowski A.
      • Safranow K.
      Ophthalmological features of Parkinson disease.
      ,
      • Tamer C.
      • Melek I.M.
      • Duman T.
      • Oksuz H.
      Tear film tests in Parkinson's disease patients.
      ,
      • Reddy V.C.
      • Patel S.V.
      • Hodge D.O.
      • Leavitt J.A.
      Corneal sensitivity, blink rate, and corneal nerve density in progressive supranuclear palsy and Parkinson disease.
      ,
      • Kwon O.Y.
      • Kim S.H.
      • Kim J.H.
      • Kim M.H.
      • Ko M.K.
      Schrimer test in Parkinson's disease.
      4.CorneaDecreased corneal sensitivity
      • Reddy V.C.
      • Patel S.V.
      • Hodge D.O.
      • Leavitt J.A.
      Corneal sensitivity, blink rate, and corneal nerve density in progressive supranuclear palsy and Parkinson disease.
      5.LensIncreased frequency of moderate/marked nuclear cataract in Parkinson's disease with dementia
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      Visual symptoms in Parkinson's disease and Parkinson's disease dementia.
      More prominent intensity of posterior subcapsular cataract
      • Nowacka B.
      • Lubinski W.
      • Honczarenko K.
      • Potemkowski A.
      • Safranow K.
      Ophthalmological features of Parkinson disease.
      6.PupilPupillary adaptation disturbances
      • Corin M.S.
      • Elizan T.S.
      • Bender M.B.
      Oculomotor function in patients with Parkinson's disease.
      ,
      • Micieli G.
      • Tassorelli C.
      • Martignoni E.
      • Pacchetti C.
      • Bruggi P.
      • Magri M.
      • Nappi G.
      Disordered pupil reactivity in Parkinson's disease.
      7.RetinaRetinal nerve fibre layer thinning
      • Yu J.G.
      • Feng Y.F.
      • Xiang Y.
      • Huang J.H.
      • Savini G.
      • Parisi V.
      • Yang W.J.
      • Fu X.A.
      Retinal nerve fiber layer thickness changes in Parkinson disease: a meta-analysis.
      ,
      • Satue M.
      • Seral M.
      • Otin S.
      • Alarcia R.
      • Herrero R.
      • Bambo M.P.
      • Fuertes M.I.
      • Pablo L.E.
      • Garcia-Martin E.
      Retinal thinning and correlation with functional disability in patients with Parkinson's disease.
      ,
      • Garcia-Martin E.
      • Larrosa J.M.
      • Polo V.
      • Satue M.
      • Marques M.L.
      • Alarcia R.
      • Seral M.
      • Fuertes I.
      • Otin S.
      • Pablo L.E.
      Distribution of retinal layer atrophy in patients with Parkinson disease and association with disease severity and duration.
      ,
      • Rohani M.
      • Langroodi A.S.
      • Ghourchian S.
      • Falavarjani K.G.
      • Soudi R.
      • Shahidi G.
      Retinal nerve changes in patients with tremor dominant and akinetic rigid Parkinson's disease.
      ,
      • La Morgia C.
      • Barboni P.
      • Rizzo G.
      • Carbonelli M.
      • Savini G.
      • Scaglione C.
      • Capellari S.
      • Bonazza S.
      • Giannoccaro M.P.
      • Calandra-Buonaura G.
      • Liguori R.
      • Cortelli P.
      • Martinelli P.
      • Baruzzi A.
      • Carelli V.
      Loss of temporal retinal nerve fibers in Parkinson disease: a mitochondrial pattern?.
      ,
      • Kirbas S.
      • Turkyilmaz K.
      • Tufekci A.
      • Durmus M.
      Retinal nerve fiber layer thickness in parkinson disease.
      ,
      • Inzelberg R.
      • Ramirez J.A.
      • Nisipeanu P.
      • Ophir A.
      Retinal nerve fiber layer thinning in Parkinson disease.
      ,
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      Retinal thickness in Parkinson's disease.
      Decreased contrast sensitivity
      • Davidsdottir S.
      • Cronin-Golomb A.
      • Lee A.
      Visual and spatial symptoms in Parkinson's disease.
      ,
      • Nowacka B.
      • Lubinski W.
      • Honczarenko K.
      • Potemkowski A.
      • Safranow K.
      Ophthalmological features of Parkinson disease.
      ,
      • Pieri V.
      • Diederich N.J.
      • Raman R.
      • Goetz C.G.
      Decreased color discrimination and contrast sensitivity in Parkinson's disease.
      ,
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      Retinal thickness in Parkinson's disease.
      ,
      • Diederich N.J.
      • Raman R.
      • Leurgans S.
      • Goetz C.G.
      Progressive worsening of spatial and chromatic processing deficits in Parkinson disease.
      Impaired colour discrimination
      • Davidsdottir S.
      • Cronin-Golomb A.
      • Lee A.
      Visual and spatial symptoms in Parkinson's disease.
      ,
      • Nowacka B.
      • Lubinski W.
      • Honczarenko K.
      • Potemkowski A.
      • Safranow K.
      Ophthalmological features of Parkinson disease.
      ,
      • Pieri V.
      • Diederich N.J.
      • Raman R.
      • Goetz C.G.
      Decreased color discrimination and contrast sensitivity in Parkinson's disease.
      ,
      • Haug B.A.
      • Kolle R.U.
      • Trenkwalder C.
      • Oertel W.H.
      • Paulus W.
      Predominant affection of the blue cone pathway in Parkinson's disease.
      ,
      • Diederich N.J.
      • Goetz C.G.
      • Raman R.
      • Pappert E.J.
      • Leurgans S.
      • Piery V.
      Poor visual discrimination and visual hallucinations in Parkinson's disease.
      ,
      • Kertelge L.
      • Bruggemann N.
      • Schmidt A.
      • Tadic V.
      • Wisse C.
      • Dankert S.
      • Drude L.
      • van der Vegt J.
      • Siebner H.
      • Pawlack H.
      • Pramstaller P.P.
      • Behrens M.I.
      • Ramirez A.
      • Reichel D.
      • Buhmann C.
      • Hagenah J.
      • Klein C.
      • Lohmann K.
      • Kasten M.
      Impaired sense of smell and color discrimination in monogenic and idiopathic Parkinson's disease.
      ,
      • Muller T.
      • Woitalla D.
      • Peters S.
      • Kohla K.
      • Przuntek H.
      Progress of visual dysfunction in Parkinson's disease.
      8.Macula luteaReduced macular volume
      • Altintas O.
      • Iseri P.
      • Ozkan B.
      • Caglar Y.
      Correlation between retinal morphological and functional findings and clinical severity in Parkinson's disease.
      Thinner and broader mean foveal pit
      • Spund B.
      • Ding Y.
      • Liu T.
      • Selesnick I.
      • Glazman S.
      • Shrier E.M.
      • Bodis-Wollner I.
      Remodeling of the fovea in Parkinson disease.
      9.Optic nerveHigher incidence of glaucoma (optic nerve neuropathy) and glaucomatous-like visual field defects
      • Nowacka B.
      • Lubinski W.
      • Honczarenko K.
      • Potemkowski A.
      • Safranow K.
      Ophthalmological features of Parkinson disease.
      ,
      • Bayer A.U.
      • Keller O.N.
      • Ferrari F.
      • Maag K.P.
      Association of glaucoma with neurodegenerative diseases with apoptotic cell death: Alzheimer's disease and Parkinson's disease.
      ,
      • Tsironi E.E.
      • Dastiridou A.
      • Katsanos A.
      • Dardiotis E.
      • Veliki S.
      • Patramani G.
      • Zacharaki F.
      • Ralli S.
      • Hadjigeorgiou G.M.
      Perimetric and retinal nerve fiber layer findings in patients with Parkinson's disease.
      10.CortexVisual hallucinations
      • Biousse V.
      • Skibell B.C.
      • Watts R.L.
      • Loupe D.N.
      • Drews-Botsch C.
      • Newman N.J.
      Ophthalmologic features of Parkinson's disease.
      ,
      • Davidsdottir S.
      • Cronin-Golomb A.
      • Lee A.
      Visual and spatial symptoms in Parkinson's disease.
      ,
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      Visual symptoms in Parkinson's disease and Parkinson's disease dementia.
      ,
      • Williams D.R.
      • Lees A.J.
      Visual hallucinations in the diagnosis of idiopathic Parkinson's disease: a retrospective autopsy study.
      ,
      • Gibson G.
      • Mottram P.G.
      • Burn D.J.
      • Hindle J.V.
      • Landau S.
      • Samuel M.
      • Hurt C.S.
      • Brown R.G.
      • Wilson K.C.
      Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson's disease: a longitudinal 4-year study.
      ,
      • Goetz C.G.
      • Stebbins G.T.
      • Ouyang B.
      Visual plus nonvisual hallucinations in Parkinson's disease: development and evolution over 10 years.
      ,
      • Diederich N.J.
      • Goetz C.G.
      • Stebbins G.T.
      Repeated visual hallucinations in Parkinson's disease as disturbed external/internal perceptions: focused review and a new integrative model.
      Visuospatial deficits
      • Davidsdottir S.
      • Cronin-Golomb A.
      • Lee A.
      Visual and spatial symptoms in Parkinson's disease.
      ,
      • Levin B.E.
      • Llabre M.M.
      • Reisman S.
      • Weiner W.J.
      • Sanchez-Ramos J.
      • Singer C.
      • Brown M.C.
      Visuospatial impairment in Parkinson's disease.
      Impaired facial expression recognition
      • Gray H.M.
      • Tickle-Degnen L.
      A meta-analysis of performance on emotion recognition tasks in Parkinson's disease.
      a Anatomic localization where ophthalmologic abnormality can be seen/tested.
      b Impaired vertical gaze, with abnormalities of upward gaze slightly more frequent than abnormalities of downward gaze.
      c Longer reaction times, multiple step, hypometric saccades, frequent square wave jerks.
      Table 2Effect of Parkinson treatment on visual functioning in Parkinson's disease.
      Negative side effects
      DrugOcular and visual side effectBest level of evidenceReference(s)
      LevodopaOcular dyskinesiasB
      • Linazasoro G.
      • Van Blercom N.
      • Lasa A.
      • Indakoetxea B.
      • Ruiz J.
      Levodopa-induced ocular dyskinesias in Parkinson's disease.
      ,
      • Grotzsch H.
      • Sztajzel R.
      • Burkhard P.R.
      Levodopa-induced ocular dyskinesia in Parkinson's disease.
      Eyelid melanomaC
      • Haider S.A.
      • Thaller V.T.
      Lid melanoma and parkinsonism.
      Mydriasis, followed later by miosisD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      Lid ptosisD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      BlepharospasmD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      CabergolineReduced contrast sensitivityB
      • Hutton J.T.
      • Morris J.L.
      • Elias J.W.
      Visual contrast sensitivity in Parkinson's disease is worsened with cabergoline treatment.
      Bromocriptine/dopamine agonistsExacerbation of visual hallucinationsB-D
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      ,
      • Stowe R.L.
      • Ives N.J.
      • Clarke C.
      • van Hilten J.
      • Ferreira J.
      • Hawker R.J.
      • Shah L.
      • Wheatley K.
      • Gray R.
      Dopamine agonist therapy in early Parkinson's disease.
      AmantadineBilateral corneal endothelial dysfunction (oedema)B-D
      • Chang K.C.
      • Kim M.K.
      • Wee W.R.
      • Lee J.H.
      Corneal endothelial dysfunction associated with amantadine toxicity.
      ,
      • Kubo S.
      • Iwatake A.
      • Ebihara N.
      • Murakami A.
      • Hattori N.
      Visual impairment in Parkinson's disease treated with amantadine: case report and review of the literature.
      ,
      • Park C.Y.
      • Chuck R.S.
      Sudden bilateral corneal oedema in a patient with Parkinson's disease.
      ,
      • Pond A.
      • Lee M.S.
      • Hardten D.R.
      • Harrison A.R.
      • Krachmer J.H.
      Toxic corneal oedema associated with amantadine use.
      ,
      • Esquenazi S.
      Bilateral reversible corneal edema associated with amantadine use.
      ,
      • Kim Y.E.
      • Yun J.Y.
      • Yang H.J.
      • Kim H.J.
      • Kim M.K.
      • Wee W.R.
      • Jeon B.S.
      Amantadine induced corneal edema in a patient with primary progressive freezing of gait.
      Superficial keratitisD
      • Chang K.C.
      • Kim M.K.
      • Wee W.R.
      • Lee J.H.
      Corneal endothelial dysfunction associated with amantadine toxicity.
      ,
      • Kubo S.
      • Iwatake A.
      • Ebihara N.
      • Murakami A.
      • Hattori N.
      Visual impairment in Parkinson's disease treated with amantadine: case report and review of the literature.
      MydriasisD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      Reduced accommodationD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      Visual hallucinationsD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      Blurred visionC
      • Pearlman J.T.
      • Kadish A.H.
      • Ramseyer J.C.
      Vision loss associated with amantadine hydrochloride use.
      BenzhexolMydriasis and increased risk for angle-closure glaucomaC
      • Friedman Z.
      • Neumann E.
      Benzhexol-induced blindness in Parkinson's disease.
      ,
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      PhotophobiaD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      Decreased accommodationD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      Dry eyesD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      AnisocoriaD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      Blurred visionD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      MAO-B inhibitorsBlurred visionD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      Dopamine-blocking agentsOculogyric crisesC
      • Schneider S.A.
      • Udani V.
      • Sankhla C.S.
      • Bhatia K.P.
      Recurrent acute dystonic reaction and oculogyric crisis despite withdrawal of dopamine receptor blocking drugs.
      ImipramineMydriasisD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      CycloplegiaD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      Dry eyesD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      Ocular muscle paresisD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      NystagmusD
      • Armstrong R.A.
      Visual symptoms in Parkinson's disease.
      Deep Brain Stimulation (DBS) Stimulated areaOcular and visual side effectBest level of evidenceReference
      Nucleus subthalamicus (STN)Visual hallucinationsC
      • Diederich N.J.
      • Alesch F.
      • Goetz C.G.
      Visual hallucinations induced by deep brain stimulation in Parkinson's disease.
      Vertical diplopia from skew deviation and ipsiversive binocular torsionC
      • Ortiz-Perez S.
      • Sanchez-Dalmau B.
      • Molina J.
      • Adan A.
      • Candela S.
      • Rumia J.
      Ocular tilt reaction as a delayed complication of deep brain stimulation for Parkinson disease.
      Contraversive eye deviationC
      • Sauleau P.
      • Pollak P.
      • Krack P.
      • Pelisson D.
      • Vighetto A.
      • Benabid A.L.
      • Tilikete C.
      Contraversive eye deviation during stimulation of the subthalamic region.
      Reduced voluntary ipsilateral gazeC
      • Tommasi G.
      • Krack P.
      • Fraix V.
      • Le Bas J.F.
      • Chabardes S.
      • Benabid A.L.
      • Pollak P.
      Pyramidal tract side effects induced by deep brain stimulation of the subthalamic nucleus.
      Apraxia of eyelid openingC
      • Umemura A.
      • Oka Y.
      • Yamamoto K.
      • Okita K.
      • Matsukawa N.
      • Yamada K.
      Complications of subthalamic nucleus stimulation in Parkinson's disease.
      ,
      • Gervais-Bernard H.
      • Xie-Brustolin J.
      • Mertens P.
      • Polo G.
      • Klinger H.
      • Adamec D.
      • Broussolle E.
      • Thobois S.
      Bilateral subthalamic nucleus stimulation in advanced Parkinson's disease: five year follow-up.
      ,
      • Strecker K.
      • Meixensberger J.
      • Schwarz J.
      • Winkler D.
      Increase of frequency in deep brain stimulation relieves apraxia of eyelid opening in patients with Parkinson's disease: case report.
      Involuntary closure of eyelidC
      • Weiss D.
      • Wachter T.
      • Breit S.
      • Jacob S.N.
      • Pomper J.K.
      • Asmus F.
      • Valls-Sole J.
      • Plewnia C.
      • Gasser T.
      • Gharabaghi A.
      • Kruger R.
      Involuntary eyelid closure after STN-DBS: evidence for different pathophysiological entities.
      Fixation instabilityC
      • Wark H.A.
      • Garell P.C.
      • Walker A.L.
      • Basso M.A.
      A case report on fixation instability in Parkinson's disease with bilateral deep brain stimulation implants.
      Torsional nystagmusC
      • Gervais-Bernard H.
      • Xie-Brustolin J.
      • Mertens P.
      • Polo G.
      • Klinger H.
      • Adamec D.
      • Broussolle E.
      • Thobois S.
      Bilateral subthalamic nucleus stimulation in advanced Parkinson's disease: five year follow-up.
      ,
      • Poisson A.
      • Tilikete C.
      • Mertens P.
      • Yelnik J.
      • Bardinet E.
      • Broussolle E.
      • Thobois S.
      Torsional nystagmus induced by subthalamic nucleus stimulation.
      Unilateral mydriasisC
      • Gervais-Bernard H.
      • Xie-Brustolin J.
      • Mertens P.
      • Polo G.
      • Klinger H.
      • Adamec D.
      • Broussolle E.
      • Thobois S.
      Bilateral subthalamic nucleus stimulation in advanced Parkinson's disease: five year follow-up.
      Nucleus Pedunculopontine (PPN)OscillopsiaC
      • Jenkinson N.
      • Brittain J.S.
      • Hicks S.L.
      • Kennard C.
      • Aziz T.Z.
      On the origin of oscillopsia during pedunculopontine stimulation.
      Area pallidotomyOcular and visual side effectBest level of evidenceReferences
      Globus pallidus interna (GPi)Visual field defectsC
      • Biousse V.
      • Newman N.J.
      • Carroll C.
      • Mewes K.
      • Vitek J.L.
      • Bakay R.A.
      • Baron M.S.
      • DeLong M.R.
      Visual fields in patients with posterior GPi pallidotomy.
      Disturbed ocular fixationC
      • O'Sullivan J.D.
      • Maruff P.
      • Tyler P.
      • Peppard R.F.
      • McNeill P.
      • Currie J.
      Unilateral pallidotomy for Parkinson's disease disrupts ocular fixation.
      Bilateral contemporaneous Posteroventral pallidotomy (PVP)Apraxia of eyelid openingC
      • Ghika J.
      • Ghika-Schmid F.
      • Fankhauser H.
      • Assal G.
      • Vingerhoets F.
      • Albanese A.
      • Bogousslavsky J.
      • Favre J.
      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.
      Posteroventral pallidotomy (PVP)Homonymous hemianopiaC
      • Bonnen J.G.
      • Iacono R.P.
      • Lulu B.
      • Mohamed A.S.
      • Gonzalez A.
      • Schoonenberg T.
      Gamma knife pallidotomy: case report.
      Therapeutic effects
      DrugsOcular and visual findingBest level of evidenceReference
      LevodopaNormalization of dopamine in retina

      Improves ocular pursuit movements

      Increased blink rate

      Improves contrast sensitivity
      B

      B

      D

      D
      • Harnois C.
      • Di Paolo T.
      Decreased dopamine in the retinas of patients with Parkinson's disease.


      • Marino S.
      • Lanzafame P.
      • Sessa E.
      • Bramanti A.
      • Bramanti P.
      The effect of L-Dopa administration on pursuit ocular movements in suspected Parkinson's disease.


      • Clark D.
      • Eggenberger E.
      Neuro-ophthalmology of movement disorders.


      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      The retina in Parkinson's disease.
      ,
      • Buttner T.
      • Kuhn W.
      • Patzold T.
      • Przuntek H.
      L-Dopa improves colour vision in Parkinson's disease.
      ApomorphineImproves contrast sensitivity

      Improves ocular pursuit movements
      C

      B
      • Geerligs L.
      • Meppelink A.M.
      • Brouwer W.H.
      • van Laar T.
      The effects of apomorphine on visual perception in patients with Parkinson disease and visual hallucinations: a pilot study.


      • Bares M.
      • Brazdil M.
      • Kanovsky P.
      • Jurak P.
      • Daniel P.
      • Kukleta M.
      • Rektor I.
      The effect of apomorphine administration on smooth pursuit ocular movements in early Parkinsonian patients.
      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 symptomPossible management options
      Impaired convergenceBased-in prismAdapted glasses
      DiplopiaAdapted prisms, convergence exercises (in convergence insufficiency)
      Saccadic and ocular pursuit abnormalitiesOptimal dopaminergic treatment
      Decreased blink ratesPatient-awareness
      Apraxia of eyelid openingBrow lifting; deep brain stimulation
      BlepharospasmBotulin injections
      Dry eye diseaseArtificial tears and blinking advice
      RNFL thinningControl for visual field loss and glaucoma
      Decreased contrast and/or colour sensitivityEnough ambient light, filter glasses

      Optimal dopaminergic treatment
      Glaucoma and glaucomatous-like field deficitsRegularly testing with Donder's test and timely referral to ophthalmologist
      Visual hallucinationsCheck 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 generalIn house adjustments to prevent falling

      Explanation about decreased contrast while driving at night

      4.1 Dry eye disease

      Dry eyes disease (‘keratoconjunctivitis sicca’) is common in PD, with an estimated prevalence of 53–60% [
      • Biousse V.
      • Skibell B.C.
      • Watts R.L.
      • Loupe D.N.
      • Drews-Botsch C.
      • Newman N.J.
      Ophthalmologic features of Parkinson's disease.
      ,
      • Nowacka B.
      • Lubinski W.
      • Honczarenko K.
      • Potemkowski A.
      • Safranow K.
      Ophthalmological features of Parkinson disease.
      ], which is higher than the estimated prevalence of 5–35% in the general population aged 50 years and above [
      • E.S.o.t.I.D.E. WorkShop
      The epidemiology of dry eye disease: report of the epidemiology subcommittee of the international dry eye WorkShop (2007).
      ]. 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 [
      • Tamer C.
      • Melek I.M.
      • Duman T.
      • Oksuz H.
      Tear film tests in Parkinson's disease patients.
      ,
      • Reddy V.C.
      • Patel S.V.
      • Hodge D.O.
      • Leavitt J.A.
      Corneal sensitivity, blink rate, and corneal nerve density in progressive supranuclear palsy and Parkinson disease.
      ], 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 [
      • Tamer C.
      • Melek I.M.
      • Duman T.
      • Oksuz H.
      Tear film tests in Parkinson's disease patients.
      ].
      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 [
      • Biousse V.
      • Skibell B.C.
      • Watts R.L.
      • Loupe D.N.
      • Drews-Botsch C.
      • Newman N.J.
      Ophthalmologic features of Parkinson's disease.
      ,
      • Tamer C.
      • Melek I.M.
      • Duman T.
      • Oksuz H.
      Tear film tests in Parkinson's disease patients.
      ] (see the Appendix).
      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 [
      • Drug B.
      Therapeutics. The management of dry eye.
      ] 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 [
      • Drug B.
      Therapeutics. The management of dry eye.
      ,
      • Zhu W.
      • Wu Y.
      • Li G.
      • Wang J.
      • Li X.
      Efficacy of polyunsaturated fatty acids for dry eye syndrome: a meta-analysis of randomized controlled trials.
      ]. 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 [
      • Ervin A.M.
      • Wojciechowski R.
      • Schein O.
      Punctal occlusion for dry eye syndrome.
      ].

      4.2 Oculomotor disturbances and diplopia

      Various oculomotor disturbances are associated with PD, including convergence insufficiency [
      • Nowacka B.
      • Lubinski W.
      • Honczarenko K.
      • Potemkowski A.
      • Safranow K.
      Ophthalmological features of Parkinson disease.
      ,
      • Lepore F.E.
      Parkinson's disease and diplopia.
      ,
      • Hanuska J.
      • Bonnet C.
      • Rusz J.
      • Sieger T.
      • Jech R.
      • Rivaud-Pechoux S.
      • Vidailhet M.
      • Gaymard B.
      • Ruzicka E.
      Fast vergence eye movements are disrupted in Parkinson's disease: a video-oculography study.
      ,
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      Visual symptoms in Parkinson's disease and Parkinson's disease dementia.
      ,
      • Almer Z.
      • Klein K.S.
      • Marsh L.
      • Gerstenhaber M.
      • Repka M.X.
      Ocular motor and sensory function in Parkinson's disease.
      ], abnormal saccades and smooth pursuit [
      • Corin M.S.
      • Elizan T.S.
      • Bender M.B.
      Oculomotor function in patients with Parkinson's disease.
      ,
      • Pinkhardt E.H.
      • Jurgens R.
      • Lule D.
      • Heimrath J.
      • Ludolph A.C.
      • Becker W.
      • Kassubek J.
      Eye movement impairments in Parkinson's disease: possible role of extradopaminergic mechanisms.
      ,
      • Gorges M.
      • Pinkhardt E.H.
      • Kassubek J.
      Alterations of eye movement control in neurodegenerative movement disorders.
      ,
      • MacAskill M.R.
      • Anderson T.J.
      Eye movements in neurodegenerative diseases.
      ], and up-gaze limitation [
      • Corin M.S.
      • Elizan T.S.
      • Bender M.B.
      Oculomotor function in patients with Parkinson's disease.
      ]. Convergence insufficiency is supposedly highly prevalent in PD, and may cause blurred near vision (and thus disturb reading) and diplopia [
      • Lepore F.E.
      Parkinson's disease and diplopia.
      ].
      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 [
      • Urwyler P.
      • Nef T.
      • Killen A.
      • Collerton D.
      • Thomas A.
      • Burn D.
      • McKeith I.
      • Mosimann U.P.
      Visual complaints and visual hallucinations in Parkinson's disease.
      ,
      • Biousse V.
      • Skibell B.C.
      • Watts R.L.
      • Loupe D.N.
      • Drews-Botsch C.
      • Newman N.J.
      Ophthalmologic features of Parkinson's disease.
      ,
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      Visual symptoms in Parkinson's disease and Parkinson's disease dementia.
      ]. The incidence of diplopia in PD increases with disease progression [
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      Visual symptoms in Parkinson's disease and Parkinson's disease dementia.
      ]. 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 [
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      Visual symptoms in Parkinson's disease and Parkinson's disease dementia.
      ].
      The pathophysiology underlying diplopia in PD remains unclear. Diplopia due to convergence insufficiency may improve with dopaminergic therapy [
      • Almer Z.
      • Klein K.S.
      • Marsh L.
      • Gerstenhaber M.
      • Repka M.X.
      Ocular motor and sensory function in Parkinson's disease.
      ], 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 [
      • Lepore F.E.
      Parkinson's disease and diplopia.
      ]. 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 [
      • Nebe A.
      • Ebersbach G.
      Selective diplopia in Parkinson's disease: a special subtype of visual hallucination?.
      ,
      • Sauerbier A.
      • Ray Chaudhuri K.
      Parkinson's disease and vision.
      ].
      A comprehensive neuro-ophthalmologic work-up of patients with PD is useful to evaluate oculomotor disturbances [
      • Liu G.T.
      • Volpe N.J.
      • Galetta S.L.
      Neuro-ophthalmology.
      ]. 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 [
      • Hanuska J.
      • Bonnet C.
      • Rusz J.
      • Sieger T.
      • Jech R.
      • Rivaud-Pechoux S.
      • Vidailhet M.
      • Gaymard B.
      • Ruzicka E.
      Fast vergence eye movements are disrupted in Parkinson's disease: a video-oculography study.
      ]. 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 [
      • Biousse V.
      • Skibell B.C.
      • Watts R.L.
      • Loupe D.N.
      • Drews-Botsch C.
      • Newman N.J.
      Ophthalmologic features of Parkinson's disease.
      ,
      • Lepore F.E.
      Parkinson's disease and diplopia.
      ]. Because ocular motor function may improve with dopaminergic treatment [
      • Pinkhardt E.H.
      • Jurgens R.
      • Lule D.
      • Heimrath J.
      • Ludolph A.C.
      • Becker W.
      • Kassubek J.
      Eye movement impairments in Parkinson's disease: possible role of extradopaminergic mechanisms.
      ,
      • Marino S.
      • Lanzafame P.
      • Sessa E.
      • Bramanti A.
      • Bramanti P.
      The effect of L-Dopa administration on pursuit ocular movements in suspected Parkinson's disease.
      ], 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) [
      • Weinreb R.N.
      • Aung T.
      • Medeiros F.A.
      The pathophysiology and treatment of glaucoma: a review.
      ]. 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 [
      • Weinreb R.N.
      • Aung T.
      • Medeiros F.A.
      The pathophysiology and treatment of glaucoma: a review.
      ]. 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 [
      • Weinreb R.N.
      • Aung T.
      • Medeiros F.A.
      The pathophysiology and treatment of glaucoma: a review.
      ].
      Fig. 2
      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 [
      • Nowacka B.
      • Lubinski W.
      • Honczarenko K.
      • Potemkowski A.
      • Safranow K.
      Ophthalmological features of Parkinson disease.
      ,
      • Bayer A.U.
      • Keller O.N.
      • Ferrari F.
      • Maag K.P.
      Association of glaucoma with neurodegenerative diseases with apoptotic cell death: Alzheimer's disease and Parkinson's disease.
      ]. Interestingly, in PD all cases concerned primary open angle glaucoma, while the prevalence of increased IOP was lower in PD patients than in controls [
      • Nowacka B.
      • Lubinski W.
      • Honczarenko K.
      • Potemkowski A.
      • Safranow K.
      Ophthalmological features of Parkinson disease.
      ,
      • Bayer A.U.
      • Keller O.N.
      • Ferrari F.
      • Maag K.P.
      Association of glaucoma with neurodegenerative diseases with apoptotic cell death: Alzheimer's disease and Parkinson's disease.
      ]. Different hypotheses linking PD to open angle glaucoma have been proposed, involving retinal degeneration due to progressive retinal dopamine depletion [
      • Nucci C.
      • Martucci A.
      • Cesareo M.
      • Garaci F.
      • Morrone L.A.
      • Russo R.
      • Corasaniti M.T.
      • Bagetta G.
      • Mancino R.
      Links among glaucoma, neurodegenerative, and vascular diseases of the central nervous system.
      ] and alpha-synuclein mediated axonal degeneration in both PD and glaucoma [
      • Nucci C.
      • Martucci A.
      • Cesareo M.
      • Garaci F.
      • Morrone L.A.
      • Russo R.
      • Corasaniti M.T.
      • Bagetta G.
      • Mancino R.
      Links among glaucoma, neurodegenerative, and vascular diseases of the central nervous system.
      ,
      • Bodis-Wollner I.
      • Kozlowski P.B.
      • Glazman S.
      • Miri S.
      alpha-synuclein in the inner retina in parkinson disease.
      ]. 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) [
      • Friedman Z.
      • Neumann E.
      Benzhexol-induced blindness in Parkinson's disease.
      ]. However, future studies are needed to map the risk of developing glaucoma in PD patients and to unravel its pathophysiology.
      Apart from glaucoma, patients with PD are at risk for visual field defects and retinal nerve fibre layer (RNFL) thinning not caused by glaucoma [
      • Yu J.G.
      • Feng Y.F.
      • Xiang Y.
      • Huang J.H.
      • Savini G.
      • Parisi V.
      • Yang W.J.
      • Fu X.A.
      Retinal nerve fiber layer thickness changes in Parkinson disease: a meta-analysis.
      ,
      • Tsironi E.E.
      • Dastiridou A.
      • Katsanos A.
      • Dardiotis E.
      • Veliki S.
      • Patramani G.
      • Zacharaki F.
      • Ralli S.
      • Hadjigeorgiou G.M.
      Perimetric and retinal nerve fiber layer findings in patients with Parkinson's disease.
      ]. 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 [
      • Weinreb R.N.
      • Aung T.
      • Medeiros F.A.
      The pathophysiology and treatment of glaucoma: a review.
      ].
      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 [
      • Song W.
      • Huang P.
      • Zhang C.
      Neuroprotective therapies for glaucoma.
      ]. In patients with closed-angle glaucoma, laser peripheral iridotomy is the first-line treatment to eliminate pupillary block [
      • Weinreb R.N.
      • Aung T.
      • Medeiros F.A.
      The pathophysiology and treatment of glaucoma: a review.
      ].

      4.4 Diminished contrast sensitivity and colour discrimination

      Contrast sensitivity reflects the ability to differentiate luminance differences of objects and areas [
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      The retina in Parkinson's disease.
      ]. Reduced contrast sensitivity can result in problems during situations with low light, e.g. when driving at night [
      • Amick M.M.
      • Grace J.
      • Ott B.R.
      Visual and cognitive predictors of driving safety in Parkinson's disease patients.
      ,
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      The retina in Parkinson's disease.
      ]. 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 [
      • Nowacka B.
      • Lubinski W.
      • Honczarenko K.
      • Potemkowski A.
      • Safranow K.
      Ophthalmological features of Parkinson disease.
      ,
      • Pieri V.
      • Diederich N.J.
      • Raman R.
      • Goetz C.G.
      Decreased color discrimination and contrast sensitivity in Parkinson's disease.
      ]. Which colour axis is mostly affected is still unclear though; both the blue-yellow [
      • Pieri V.
      • Diederich N.J.
      • Raman R.
      • Goetz C.G.
      Decreased color discrimination and contrast sensitivity in Parkinson's disease.
      ,
      • Haug B.A.
      • Kolle R.U.
      • Trenkwalder C.
      • Oertel W.H.
      • Paulus W.
      Predominant affection of the blue cone pathway in Parkinson's disease.
      ] and red-green axis [
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      The retina in Parkinson's disease.
      ,
      • Oh Y.S.
      • Kim J.S.
      • Chung S.W.
      • Song I.U.
      • Kim Y.D.
      • Kim Y.I.
      • Lee K.S.
      Color vision in Parkinson's disease and essential tremor.
      ] have been suggested.
      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 [
      • Weil R.S.
      • Schrag A.E.
      • Warren J.D.
      • Crutch S.J.
      • Lees A.J.
      • Morris H.R.
      Visual dysfunction in Parkinson's disease.
      ,
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      The retina in Parkinson's disease.
      ,
      • Pieri V.
      • Diederich N.J.
      • Raman R.
      • Goetz C.G.
      Decreased color discrimination and contrast sensitivity in Parkinson's disease.
      ]. 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 [
      • Weil R.S.
      • Schrag A.E.
      • Warren J.D.
      • Crutch S.J.
      • Lees A.J.
      • Morris H.R.
      Visual dysfunction in Parkinson's disease.
      ].
      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 [
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      The retina in Parkinson's disease.
      ] (appendix).
      Both contrast sensitivity and colour discrimination have shown variable improvements with dopaminergic therapy (Table 3) [
      • Almer Z.
      • Klein K.S.
      • Marsh L.
      • Gerstenhaber M.
      • Repka M.X.
      Ocular motor and sensory function in Parkinson's disease.
      ,
      • Archibald N.K.
      • Clarke M.P.
      • Mosimann U.P.
      • Burn D.J.
      The retina in Parkinson's disease.
      ,
      • Buttner T.
      • Kuhn W.
      • Patzold T.
      • Przuntek H.
      L-Dopa improves colour vision in Parkinson's disease.
      ], aimed at normalizing the amount of retinal dopamine [
      • Harnois C.
      • Di Paolo T.
      Decreased dopamine in the retinas of patients with Parkinson's disease.
      ]. Blue haze (short-wavelength light) can veil the patient's view, so yellow filtering glasses may improve contrast sensitivity when patients experience glare [
      • Rieger G.
      Improvement of contrast sensitivity with yellow filter glasses.
      ]. 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 [
      • Weil R.S.
      • Schrag A.E.
      • Warren J.D.
      • Crutch S.J.
      • Lees A.J.
      • Morris H.R.
      Visual dysfunction in Parkinson's disease.
      ,
      • Davidsdottir S.
      • Cronin-Golomb A.
      • Lee A.
      Visual and spatial symptoms in Parkinson's disease.
      ,
      • Levin B.E.
      • Llabre M.M.
      • Reisman S.
      • Weiner W.J.
      • Sanchez-Ramos J.
      • Singer C.
      • Brown M.C.
      Visuospatial impairment in Parkinson's disease.
      ]. Amongst these are the perception of space [
      • Lee A.C.
      • Harris J.P.
      • Atkinson E.A.
      • Fowler M.S.
      Evidence from a line bisection task for visuospatial neglect in left hemiparkinson's disease.
      ,
      • Laudate T.M.
      • Neargarder S.
      • Cronin-Golomb A.
      Line bisection in Parkinson's disease: investigation of contributions of visual field, retinal vision, and scanning patterns to visuospatial function.
      ], recognition of line orientation [
      • Uc E.Y.
      • Rizzo M.
      • Anderson S.W.
      • Qian S.
      • Rodnitzky R.L.
      • Dawson J.D.
      Visual dysfunction in Parkinson disease without dementia.
      ,
      • Gullett J.M.
      • Price C.C.
      • Nguyen P.
      • Okun M.S.
      • Bauer R.M.
      • Bowers D.
      Reliability of three Benton Judgment of Line Orientation short forms in idiopathic Parkinson's disease.
      ], mental three-dimensional rotation of objects [
      • Lee A.C.
      • Harris J.P.
      • Calvert J.E.
      Impairments of mental rotation in Parkinson's disease.
      ], identification of figures embedded in complex figures [
      • Flowers K.A.
      • Robertson C.
      Perceptual abnormalities in Parkinson's disease: top-down or bottom-up processes?.
      ], visuospatial problem solving [
      • Cronin-Golomb A.
      • Braun A.E.
      Visuospatial dysfunction and problem solving in Parkinson's disease.
      ,
      • Hodgson T.L.
      • Tiesman B.
      • Owen A.M.
      • Kennard C.
      Abnormal gaze strategies during problem solving in Parkinson's disease.
      ], depth perception [
      • Sun L.
      • Zhang H.
      • Gu Z.
      • Cao M.
      • Li D.
      • Chan P.
      Stereopsis impairment is associated with decreased color perception and worse motor performance in Parkinson's disease.
      ] and spatial working memory [
      • Owen A.M.
      • Beksinska M.
      • James M.
      • Leigh P.N.
      • Summers B.A.
      • Marsden C.D.
      • Quinn N.P.
      • Sahakian B.J.
      • Robbins T.W.
      Visuospatial memory deficits at different stages of Parkinson's disease.
      ]. In addition, visuoperceptual impairments in the detection of motion [
      • Trick G.L.
      • Kaskie B.
      • Steinman S.B.
      Visual impairment in Parkinson's disease: deficits in orientation and motion discrimination.
      ] human movement [
      • Kloeters S.
      • Hartmann C.J.
      • Pundmann V.D.
      • Schnitzler A.
      • Sudmeyer M.
      • Lange J.
      Impaired perception of human movements in Parkinson's disease.
      ,
      • Jaywant A.
      • Shiffrar M.
      • Roy S.
      • Cronin-Golomb A.
      Impaired perception of biological motion in Parkinson's disease.
      ] and facial recognition [
      • Weil R.S.
      • Schrag A.E.
      • Warren J.D.
      • Crutch S.J.
      • Lees A.J.
      • Morris H.R.
      Visual dysfunction in Parkinson's disease.
      ,
      • Sprengelmeyer R.
      • Young A.W.
      • Mahn K.
      • Schroeder U.
      • Woitalla D.
      • Buttner T.
      • Kuhn W.
      • Przuntek H.
      Facial expression recognition in people with medicated and unmedicated Parkinson's disease.
      ,
      • Assogna F.
      • Pontieri F.E.
      • Caltagirone C.
      • Spalletta G.
      The recognition of facial emotion expressions in Parkinson's disease.
      ,
      • Marneweck M.
      • Palermo R.
      • Hammond G.
      Discrimination and recognition of facial expressions of emotion and their links with voluntary control of facial musculature in Parkinson's disease.
      ] have been observed in PD.
      Visuospatial impairments in PD have been associated with freezing of gait [
      • Nantel J.
      • McDonald J.C.
      • Tan S.
      • Bronte-Stewart H.
      Deficits in visuospatial processing contribute to quantitative measures of freezing of gait in Parkinson's disease.
      ] and dementia [
      • Levin B.E.
      • Llabre M.M.
      • Reisman S.
      • Weiner W.J.
      • Sanchez-Ramos J.
      • Singer C.
      • Brown M.C.
      Visuospatial impairment in Parkinson's disease.
      ,
      • Armstrong R.A.
      Oculo-visual dysfunction in Parkinson's disease.
      ], 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 [
      • Davidsdottir S.
      • Cronin-Golomb A.
      • Lee A.
      Visual and spatial symptoms in Parkinson's disease.
      ]. 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 [
      • Weil R.S.
      • Schrag A.E.
      • Warren J.D.
      • Crutch S.J.
      • Lees A.J.
      • Morris H.R.
      Visual dysfunction in Parkinson's disease.
      ]. Moreover, impairments in higher order visuospatial and visuoperceptual processing in PD have been associated with grey matter atrophy in temporo-parietal cortical regions [
      • Pereira J.B.
      • Junque C.
      • Marti M.J.
      • Ramirez-Ruiz B.
      • Bargallo N.
      • Tolosa E.
      Neuroanatomical substrate of visuospatial and visuoperceptual impairment in Parkinson's disease.
      ,
      • Garcia-Diaz A.I.
      • Segura B.
      • Baggio H.C.
      • Marti M.J.
      • Valldeoriola F.
      • Compta Y.
      • Vendrell P.
      • Bargallo N.
      • Tolosa E.
      • Junque C.
      Structural MRI correlates of the MMSE and pentagon copying test in Parkinson's disease.
      ].
      In clinical practice, visuospatial impairments may lead patients into bumping into doorways or objects, and to experience problems driving a car and navigating [
      • Davidsdottir S.
      • Cronin-Golomb A.
      • Lee A.
      Visual and spatial symptoms in Parkinson's disease.
      ]. Visuospatial function can easily be assessed by asking the patient to draw two intersecting pentagons [
      • Pereira J.B.
      • Junque C.
      • Marti M.J.
      • Ramirez-Ruiz B.
      • Bargallo N.
      • Tolosa E.
      Neuroanatomical substrate of visuospatial and visuoperceptual impairment in Parkinson's disease.
      ], a clock or a house, but it should be kept in mind that these tests are also influenced by cognitive domains other than visuospatial function [
      • Weil R.S.
      • Schrag A.E.
      • Warren J.D.
      • Crutch S.J.
      • Lees A.J.
      • Morris H.R.
      Visual dysfunction in Parkinson's disease.
      ,
      • Trick G.L.
      • Kaskie B.
      • Steinman S.B.
      Visual impairment in Parkinson's disease: deficits in orientation and motion discrimination.
      ]. 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 [
      • Devos H.
      • Ranchet M.
      • Emmanuel Akinwuntan A.
      • Uc E.Y.
      Establishing an evidence-base framework for driving rehabilitation in Parkinson's disease: a systematic review of on-road driving studies.
      ].

      4.6 Visual hallucinations

      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 [
      • Urwyler P.
      • Nef T.
      • Killen A.
      • Collerton D.
      • Thomas A.
      • Burn D.
      • McKeith I.
      • Mosimann U.P.
      Visual complaints and visual hallucinations in Parkinson's disease.
      ]. 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 [
      • Williams D.R.
      • Lees A.J.
      Visual hallucinations in the diagnosis of idiopathic Parkinson's disease: a retrospective autopsy study.
      ].
      The estimated prevalence of visual hallucinations in PD ranges between 4 and 82.7% [
      • Urwyler P.
      • Nef T.
      • Killen A.
      • Collerton D.
      • Thomas A.
      • Burn D.
      • McKeith I.
      • Mosimann U.P.
      Visual complaints and visual hallucinations in Parkinson's disease.
      ,
      • Nowacka B.
      • Lubinski W.
      • Honczarenko K.
      • Potemkowski A.
      • Safranow K.
      Ophthalmological features of Parkinson disease.
      ,
      • Gibson G.
      • Mottram P.G.
      • Burn D.J.
      • Hindle J.V.
      • Landau S.
      • Samuel M.
      • Hurt C.S.
      • Brown R.G.
      • Wilson K.C.
      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 [
      • Gibson G.
      • Mottram P.G.
      • Burn D.J.
      • Hindle J.V.
      • Landau S.
      • Samuel M.
      • Hurt C.S.
      • Brown R.G.
      • Wilson K.C.
      Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson's disease: a longitudinal 4-year study.
      ,
      • Goetz C.G.
      • Stebbins G.T.
      • Ouyang B.
      Visual plus nonvisual hallucinations in Parkinson's disease: development and evolution over 10 years.
      ] report a prevalence of around 60%, which makes visual hallucinations a core non-motor symptom [
      • Urwyler P.
      • Nef T.
      • Killen A.
      • Collerton D.
      • Thomas A.
      • Burn D.
      • McKeith I.
      • Mosimann U.P.
      Visual complaints and visual hallucinations in Parkinson's disease.
      ,
      • Gibson G.
      • Mottram P.G.
      • Burn D.J.
      • Hindle J.V.
      • Landau S.
      • Samuel M.
      • Hurt C.S.
      • Brown R.G.
      • Wilson K.C.
      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 are important predictors for future development of dementia and nursing home admission [
      • Diederich N.J.
      • Fenelon G.
      • Stebbins G.
      • Goetz C.G.
      Hallucinations in Parkinson disease.
      ,
      • Gibson G.
      • Mottram P.G.
      • Burn D.J.
      • Hindle J.V.
      • Landau S.
      • Samuel M.
      • Hurt C.S.
      • Brown R.G.
      • Wilson K.C.
      Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson's disease: a longitudinal 4-year study.
      ]. Once visual hallucinations exist, they will persist and progress, unless adequately treated [
      • Goetz C.G.
      • Stebbins G.T.
      • Ouyang B.
      Visual plus nonvisual hallucinations in Parkinson's disease: development and evolution over 10 years.
      ].
      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 [
      • Biousse V.
      • Skibell B.C.
      • Watts R.L.
      • Loupe D.N.
      • Drews-Botsch C.
      • Newman N.J.
      Ophthalmologic features of Parkinson's disease.
      ,
      • Sauerbier A.
      • Ray Chaudhuri K.
      Parkinson's disease and vision.
      ]. They are often seen in patients with a higher age and cognitive decline or dementia [
      • Biousse V.
      • Skibell B.C.
      • Watts R.L.
      • Loupe D.N.
      • Drews-Botsch C.
      • Newman N.J.
      Ophthalmologic features of Parkinson's disease.
      ,
      • Poewe W.
      When a Parkinson's disease patient starts to hallucinate.
      ]. 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) [
      • Poewe W.
      When a Parkinson's disease patient starts to hallucinate.
      ,
      • Diederich N.J.
      • Goetz C.G.
      • Stebbins G.T.
      Repeated visual hallucinations in Parkinson's disease as disturbed external/internal perceptions: focused review and a new integrative model.
      ]. 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 [
      • Weil R.S.
      • Schrag A.E.
      • Warren J.D.
      • Crutch S.J.
      • Lees A.J.
      • Morris H.R.
      Visual dysfunction in Parkinson's disease.
      ] and are not discussed here.
      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) [
      • Chaudhuri K.R.
      • Prieto-Jurcynska C.
      • Naidu Y.
      • Mitra T.
      • Frades-Payo B.
      • Tluk S.
      • Ruessmann A.
      • Odin P.
      • Macphee G.
      • Stocchi F.
      • Ondo W.
      • Sethi K.
      • Schapira A.H.
      • Martinez Castrillo J.C.
      • Martinez-Martin P.
      The nondeclaration of nonmotor symptoms of Parkinson's disease to health care professionals: an international study using the nonmotor symptoms questionnaire.
      ]. In some cases, visual hallucinations can improve by simplifying or reducing antiparkinsonian medication [
      • Diederich N.J.
      • Goetz C.G.
      • Stebbins G.T.
      Repeated visual hallucinations in Parkinson's disease as disturbed external/internal perceptions: focused review and a new integrative model.
      ]. 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 [
      • Poewe W.
      When a Parkinson's disease patient starts to hallucinate.
      ]. 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 [
      • Seppi K.
      • Weintraub D.
      • Coelho M.
      • Perez-Lloret S.
      • Fox S.H.
      • Katzenschlager R.
      • Hametner E.M.
      • Poewe W.
      • Rascol O.
      • Goetz C.G.
      • Sampaio C.
      The movement disorder society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson's disease.
      ]. In clinical practice, many physicians prefer to try quetiapine first, hoping to avoid the small but definite risk of agranulocytosis [
      • Poewe W.
      When a Parkinson's disease patient starts to hallucinate.
      ]. However, randomized trials have failed to clearly support quetiapine's efficacy [
      • Seppi K.
      • Weintraub D.
      • Coelho M.
      • Perez-Lloret S.
      • Fox S.H.
      • Katzenschlager R.
      • Hametner E.M.
      • Poewe W.
      • Rascol O.
      • Goetz C.G.
      • Sampaio C.
      The movement disorder society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson's disease.
      ]. 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 [
      • Markham A.
      Pimavanserin: first global approval.
      ].

      5. Conclusion and future perspectives

      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:

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