Motor function optimization in advanced Parkinson*s disease patients, combined with galantamine to prevent visual hallucinations.

Parkinson*s disease (PD) is frequently accompanied by cognitive disturbances,
mainly consisting of a dysexecutive syndrome, visuospatial and attentional
impairments and memory deficits (Cummings JL 1988). If this cognitive decline
reaches a certain severity, the diagnosis Parkinson*s disease dementia (PDD)
can be made. Recent studies show prevalence data of PDD varying from 20-40% of
the total population with PD (Chaudhuri 2006, Mayeux R 1992). Visual
hallucinations (VH) are often experienced by PD patients and are associated
with a decline in cognitive function (Fenelon G 2000).
Although the exact pathophysiology of VH in PD is unknown, both dopaminergic
and cholinergic neurotransmitter systems seem to play an important role. Until
recently VH in PD were considered to be provoked only by overstimulation of the
dopaminergic receptor system by dopaminomimetic therapy. However, recent
publications suggest that an additional cholinergic defect is needed for VH in
PD to occur (Francis 2007). In line with this, cholinergic enhancement, by
administration of cholinesterase inhibitors (ChEI), in PDD patients has a
positive effect on cognition and reduces the frequency of VH (Emre M 2004).
The ChEi rivastigmine and galantamine both have a moderate effect in the
treatment of cognitive disturbances in Alzheimer*s disease (Kaduszkiewicz 05).
Both substances have comparable side effects. In a double-blind
placebo-controlled trial, rivastigmine has been proven to be effective to treat
cognitive deficits in PD as well (Emre 04). The effectiveness of rivastigmine
in PD was similar to the effectiveness reported in trials of rivastigmine for
Alzheimer's disease (Emre 04). In addition, the occurrence of VH predicted a
larger effect of rivastigmine on cognition and improved VH (Burn 06). A smaller
study has shown that galantamine improved cognitive dysfunction in PD and
improved VH as well (Aarsland 03). ChEI generally do not worsen motor
performance in PD, as is known from the typical antipsychotics.
When PD advances, motor symptoms worsen, resulting in decreased mobility. If
the decreased mobility is accompanied by cognitive deterioration, dopaminergic
suppletion may result in an increase of VH. The addition of a CHEI, for
instance galantamine, seems to result in fewer psychotic symptoms, compared to
patients not receiving ChEI*s (own observations). We hypothesize that
galantamine has both a therapeutic and a preventive effect on psychotic
symptoms, especially the occurrence of VH. Therefore galantamine might even be
able to prevent an increase of VH after the increase of dopaminergic treatment.

To investigate the effects of galantamine on cognitive impairment and visual
hallucinations in Parkinson`s disease, both therapeutic (direct effect) and
preventive (protection against an acute increase of dopaminergic medication
used by the patient).

This study is an open label trial investigating the effect of galantamine on
visual hallucinations (VH) and cognitive decline in patients with PDD. The
therapeutic effect of galantamine will be determined by investigating patients`
score on several tests before medication and when on a stable dose of
galantamine. Also, the possible preventive effect of galantamine will be
investigated, by testing if it protects patients against a dose increase of
L-dopa medication.

The intervention is the administration of the drug galantamine

For the subjects participating in this study, 2 extra visits (regarding a
normal control frequency of 1x per 3 months) to the outpatient clinic
neurology. During these 2 extra and the 2 regular visits, the UM-PDHQ and
SCOPA-cog will be assesed in addition to regular tests (UPDRS-III). The first 3
visits last approximately 45 minutes.
The risc of the optimization of L-dopa therapy is the appearance of adverse
events like VH. After L-dopa is reduced to the original level, galantamine will
be titrated. The risc in this phase is the occurence of adverse events related
to galantamine use, like gastro-intestinal complaints and sleepiness. When
these occur, the dose will be reduced.
After 2,5 months, when patients receive an optimal dose of galantamine, L-dopa
therapy will be increased. It is known that this often leads to VH in patients
with advanced PD. It is expected that galantamine will prevent the emergence or
increase of VH after increase of L-dopa. If galantamine does not have this
expected effect, patients might experience VH.