Role of Retina in Mechanisms of Illusions and Visual Hallucinations Observed in Idiopathic Parkinson's Disease

Parkinson's disease is a neurodegenerative disorder characterized by tremor, rigidity and akinesia, but patients can also present various non-motor symptoms in the course of their illness, including visual hallucinations, delusions or illusions. Visual Hallucinations are false perceptions (no external stimulus is present; generally caused by internal stimulations), whereas illusions are defined by a wrong perception (an external stimulus is always present). Delusions are false believes .The occurrence of hallucinations in PD is of major importance as it has been shown to be associated with an increased risk of cognitive impairment and could lead to nursing home placement and to increased mortality. It is generally believed that delusions/illusions also imply a bad prognosis with time . However recent data suggest that delusions/illusion are not associated with such a poor outcome regarding cognitive functions and mortality compared to hallucinations suggesting different pathological mechanisms and anatomical substrates . Also, a recent study analyzing the neuropsychological correlates of minor hallucinations in PD did not find executive dysfunction to contribute to the onset of minor psychotic phenomena, but was specifically implicated in the progression to well-structured VH.

Thus illusions and minorVH may have a different pathogenesis and a different prognosis compared to complex VH, however studies exploring the structural and functional changes associated with hallucinations in PD have mainly included patients with well-structured VH and moderate to severe cognitive impairment , making it difficult to define early abnormalities associated with minor hallucinations or illusions.

Several hypotheses are proposed regarding the emergence of hallucinations in PD.

• It has been first suggested that hallucinations in PD could be mainly the result of a chronic exposition to dopaminergic therapy . However, the description of hallucination in untreated PD patients goes against that solely explication . Besides, no strong link has been identified between the occurrence of VH and the dosage and duration of dopaminergic treatment . This suggests that Dopaminergic treatment would not directly cause VH but could be a precipiting factor.
• Sleep-wake cycle disturbances have also been reported as risk factors for the occurrence of VH in PD , and particularly the presence of REM Sleep behavior disorders (RBD) . The emergence of VH in PD patients coinciding with daytime episodes of REM sleep may be dream imagery occurring during wake , however this hypothesis is still debated.
• Other risk factors have been associated with VH in PD such as the disease duration, motor symptom severity and mostly cognitive impairment. Indeed, VH occur mainly in PD patients with cognitive decline , but also VH are predictive of dementia . In fact, cognitive impairment in PD patients, and particularly visuoperceptive impairment, would lead to an impaired processing of visual information. Indeed, impaired frontal and parietal cortical activation have been reported in PD patients with VH while being presented visual stimulations, suggesting a diminished answer to external perceptions in posterior cortical areas associated with an increased frontal abnormal activity leading to the emergence of sensorial visual experiences . This shifting visual circuitry from posterior to anterior regions associated with attention process impairment may play a role in the pathophysiology of VH in PD. Thus, the occurrence of Visual Hallucinations in PD Patients appears to be due to a desinhibition of the "top-down" visual stream leading to the emergence of internal mental imagery stocked in memory, and interpreted like visual perceptions coming from the external environment .
• Yet, some evidences also points out to an impaired "bottom-up" processing that could lead to the emergence of VH in PD. Indeed, a dopaminergic denervation and alpha synuclein aggregation have been demonstrated in the retina of PD Patients , even at early stages of the disease . However the functional consequences of such a denervation are still poorly understood , even if impaired contrast discrimination and color vision impairment are widely described in PD . One study has reported an association between retinal impairment, measured with OCT, and VH in PD .

Thus, the emergence of VH and illusions in PD could be due to an inbalance between a hypoactivated "bottom-up" (due to retino-striato-occipital hypoactivation) and a deshinibited "top-down" (mainly frontal) visual stream. However in all these studies, Hallucinations and illusions were not specifically discriminated and investigated in spite of the fact that they could be subtended by different pathophysiological mechanisms and might imply different prognosis for the evolution of the disease.