Parkinson's Disease Clinical Trial
Official title:
Role of Retina in Mechanisms of Illusions and Visual Hallucinations Observed in Idiopathic Parkinson's Disease
Parkinson's disease is characterized not only by motor symptoms but also by psycho-behavioral
symptoms including Visual Hallucinations (VH) and illusions (I), that are generally
associated with a severe functional impairment and a bad prognosis for patients. Visual
Hallucinations are defined by a visual perception without any real objet to perceive, whereas
illusions are defined by a wrong perceptions of an object that is really present. In most of
studies investigating the pathophysiology of VH in PD, no difference is made between VH and
I, however different mechanisms could lead to the emergence of these two phenomenon, with
different prognosis.
Investigator hypothesize that illusions could be related to a visual impairment, maybe at the
retinal level, known to be impaired in PD, whereas Visual hallucinations would be due to a
more widespread impairment affecting higher levels visuo-perceptive and cognitive functions.
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.
Investigator hypothesize that illusions, which represent the failure to successfully
integrate stimuli that have been physically presented, could be more related to "bottom up"
impairment, unlike Hallucinations, which occur where there is perception in the absence of
any stimulus and could be more related to a "top down" impairment. Thus, PD patients with
illusions (PD-I) might present greater retinal degeneration measured by OCT compared to PD
patients with Visual hallucinations (PD-VH) and PD patients without Hallucinations or
illusion (PD-nVHI), suggesting a sensorial deprivation underlying these disturbed visual
perceptions of reality. Visual Hallucinations that are more elaborated would require a more
widespread cognitive disorder, with increased cognitive and visuoperceptive dysfunction.
OBJECTIVE In this study investigator aim to compare PD patients with visual hallucinations
(PD-VH), with illusions (PD-I), without Visual hallucinations or illusions (PD-nVHI)
regarding retinal degeneration in OCT and cognitive functions (visuoperceptive and
attentional functions) in order to determine whether PD-I might show greater retinal
degeneration compared to PD-VH, and lesser cognitive impairment.
DESIGN OF STUDY:
Investigator will include 30 PD-VH+, 30 PD-I+, 30 PD-VH-I- among the patients consulting at
our center.
During the first visit (Baseline, inclusion visit, 2 hours), each subject will perform a
clinical and neurological examination with : • Diagnosis of PD according to UKPDBB criteria.
• The presence of Visual Hallucinations or Illusions will be characterized according to the
Psychosensory Hallucination Scale. Illusions will be defined by answering "Yes" to at least
one of the "elementary items".
During the second visit (Day 15, one day), each patient will have a neurological,
neuropsychological and ophthalmological examination with an evaluation of
- the severity of the disease (Hoehn and Yahr score, Movement Disorder Society-Sponsored
Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS))
- the cognitive impairment (Montreal Cognitive Assessment, Evaluation of visuo-perceptive
functions and attention)
- the excessive diurnal Somnolence and sleep attacks
- the visual acuity, intraocular pressure, Optical Coherence Tomography (OCT), contrast
and colour evaluations.
Circumstances of emergence and distress caused by Hallucinations/illusions was also evaluated
by measurement of heart rate variability, electrodermal recording, spy glasses and
self-evaluation of Stress.
Finally, each subject will have a Magnetic Resonance Imaging (MRI) acquisition.
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