Kognitivní účinky dlouhodobé léčby subkutánními apomorfinovými infuzemi u pacientů s pokročilou Parkinsonovou nemocí
Cíl: Zjistit, zda je dlouhodobá léčba pomocí kontinuálních denních subkutánních apomorfinových infuzí (CSAI) bezpečná pro pacienty s Parkinsonovou nemocí (PD) se současně přítomnou anamnézou halucinací a/nebo s výrazným kognitivním deficitem. Metoda: Dvanáct pacientů s PD (9 mužů, 3 ženy; věk 71,8 ± 6 let) podstoupilo neuropsychologické vyšetření před a 14 měsíců po nasazení dlouhodobé léčby pomocí CSAI. Výsledky: Léčba pomocí CSAI vedla u všech pacientů k jejich alespoň minimálnímu klinickému zlepšení. Zjistili jsme statisticky významný pokles ve výkonu v testech slovní plynulosti, v celkovém skóre ve škále Mattis Dementia Rating Scale (MDRS) a v jejích částech hodnotících pozornost a iniciaci. Nezaznamenali jsme žádné změny ve škále hodnotící náladu. Závěry: U našich pacientů s PD a s kognitivním deficitem při vstupu do studie jsme po chronické léčbě pomocí CSAI pozorovali signifikantní zhoršení ve výkonu v testech hodnotících „frontální“ funkce. Pro odlišení samotného efektu CSAI a progrese onemocnění bude zapotřebí provést další kontrolované longitudinální studie. Zatím doporučujeme pečlivý výběr pacientů vhodných pro léčbu pomocí CSAI s posouzením jejich kognitivního výkonu a neuropsychiatrických symptomů.
R. Kubíkova 1,2; M. Tyrlík 3; I. Rektorová 1,2
Masaryk University, Brno
Movement Disorders Centre, First Department of Neurology, St. Anne’s Hospital, Brno
1; Masaryk University, Brno
Research Group of Applied Neurosciences, CEITEC (Central European Institute of Technology)
2; Masaryk University, Brno
Faculty of Social Study
Cesk Slov Neurol N 2011; 74/107(4): 463-466
Aims: To determine whether long-term treatment with continuous subcutaneous apomorphine infusions (CSAI) is safe for patients with Parkinson’s disease (PD) with a history of hallucinations and/or marked cognitive deficit. Methods: 12 PD patients (9 men, 3 women; age 71.8 ± 6 years) were given neuropsychological assessment prior to continuous administration of CSAI and fourteen months after it. Results: CSAI led to clinical improvement, at least minimal, in all subjects. However, the treatment led to statistically significant impairment in verbal fluency tasks, the Mattis dementia rating scale (MDRS) score and the attention and initiation subtests. No mood changes were detected. Conclusions: We observed significant impairment in “frontal-like” tasks after continuous treatment with CSAI in our PD patients with baseline cognitive impairment. Further longitudinal controlled studies are needed to assess the impact of both CSAI and PD progression. We suggest cautious selection of patients eligible for CSAI therapy with respect to their cognitive profiles and/or neuropsychiatric complications.
is a dopamine agonist with a high affinity for D1 and D2
dopaminergic receptors, activating both the direct and indirect
pathways. Long-term treatment with CSAI has been shown to reduce
levodopa dosage, reduce time spent ‘off’, and improve dyskinesias
in fluctuating parkinsonian patients . Apomorphine may be
considered a less invasive alternative to pallidotomy or
bilateral subthalamic deep brain stimulation (DBS) in controlling
levodopa-induced dyskynesias [2,3]. Only a few studies have
focused on neuropsychological and neuropsychiatric changes arising
out of CSAI treatment. Ruzicka et al  reported impairment of
visuospatial perception and cognitive slowing after a single
dose of apomorphine. With respect to long-term treatment with CSAI,
Alegret et al  compared the cognitive effects of bilateral
subthalamic DBS and CSAI treatment at six-month and one-year
follow-ups. The CSAI group did not show any significant change
against baseline in neuropsychological evaluation. De Gaspari et al
 evaluated 13 PD patients on CSAI and 12 PD patients after DBS of
the subthalamic nucleus at baseline and after 12 months.
Like the Alegret group, , they found that CSAI did not affect
cognitive or neuropsychiatric functions. In one study, long-term CSAI
treatment was shown to improve mood . All these studies included
non--demented patients, with no history of hallucinations, who
were also eligible for DBS surgery for PD.
The prevalence of dementia in PD
is 30% and the approximate 10-year cumulative prevalence is 75%, with
an incidence increasing to 4 to 6 times higher than the general
age-matched population. In terms of cognitive deficits, those of
memory, executive and constructional functions, attention, and
visuospatial function are common in PD dementia (PD-D) .
The objective of our study was to
assess whether long-term use of CSAI might constitute a safe
treatment alternative with respect to cognitive function in patients
with a history of hallucinations, pronounced cognitive deficit,
and/or dementia, i.e. in patients who are not eligible for PD
surgery. The possible effects of CSAI on symptoms of depression were
studied at the same time.
studied 12 patients with advanced PD and motor complications
refractory to oral medication. Nine of them had a history of
hallucinations, and all exhibited marked cognitive deficit (MDRS
<136) . For demographic data, see Table 1. All patients
had completed at least eight years of education. All of them were
taking oral dopaminergic medication (L-dopa ± entacapone and/or
dopamine receptor agonist).
Patients were given
a comprehensive neuropsychological assessment in the ‘on’
motor state prior to (V1) and 14 months after (V2) long-term
administration of CSAI. Apomorphine was administered during the
waking hours (12–16
hours per day) using a small portable pump. Neuropsychological
assessment included MDRS, which consists of 5 subscales:
attention, initiation, construction, conceptualisation, and
memory . In addition, working memory, executive functions and
verbal production were also assessed by lexical and semantic verbal
fluency tasks; inhibition of habitual responses was measured by
Stroop test; and memory was also tested by the word list test (WLT)
from the Wechsler memory scale (WMS III – revised) .
Symptoms of depression were
evaluated by the Montgomery and Asberg depression rating scale
(MADRS) . Clinical global impression of change (CGIC) was rated on
a scale of 7 points: 1 = very much improved, 2 = much improved,
3 = minimally improved, 4 = no change, 5 = minimally
worse, 6 = much worse, 7 = very much worse . Informed
consent to participate in the study was obtained from all patients.
The study was approved by the local ethics committee.
Statistical analyses were carried
out using SPSS-PC v.13.0. The Wilcoxon matched pairs test was used to
evaluate differences between V1 and V2. Bonferroni correction was
employed to study executive functions (6 multiple comparisons) and
posterior cognitive impairment (memory and construction; 5 multiple
comparisons). The 12-month approximate percentage change in the
respective cognitive tests was calculated from the median test scores
at visits 1 and 2.
daily apomorphine dose was 39.6 ±11.8 mg
(range 20–60 mg/day).
The L-dopa equivalent daily dose was reduced by 28% (see also Table
1). All of the patients completed the study. No major local reactions
at the injection sites were observed. In self-evaluation CGIC
ratings, all of the patients claimed slight or clear improvement; no
patient reported worsening. Evaluation by the examiner produced
similar results. Nine of twelve patients had mild to moderate visual
hallucinations, already reported in the medical history prior to
study commencement. Reduction of L-dopa
and/or the apomorphine dose led to improvement or disappearance of
this symptom in all subjects.
We found statistically
significant changes (decline) in the following tests between V1 and
V2: verbal fluency (semantic and lexical); recognition of verbal
material; MDRS total score and its initiation and attention subtests.
After Bonferroni correction, only the changes in verbal fluency
tasks, MDRS total score and its initiation and attention subtests
remained significant. The approximate 12-month
percentage change in the total MDRS score was 24% from visit 1. MDRS
attention and initiation subtests disclosed changes of 33% and 15.1%
respectively, and the semantic and lexical verbal fluency tasks
disclosed changes of 54.1% and 51.4 %
respectively. We found no mood changes as assessed by MADRS (see
is the first long-term study to evaluate cognitive effects in
advanced PD patients with prominent cognitive deficits treated with
CSAI for an extended time period. In contrast with existing published
studies on the non-demented PD population [1–3,5], we found
a significant decline in verbal fluency, MDRS total score and
its initiation and attention subscores. In PD dementia, both
dysexecutive syndrome and memory functions (including free recall,
cued recall, and recognition) are compromised . The contribution
of dopamine to cognitive impairment is still a matter of debate.
In this respect, the impairment in executive and verbal fluency tasks
found in accidentally 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
parkinsonism in humans may be considered as a pure dopamine
deficiency . The results of studies which specifically examined
the effect of dopamine agonists on cognition  are consistent with
the view that insufficient, as well as excessive, dopamine
transmission in the prefrontal cortex may impair working memory and
executive functions. Conversely, Huber et al  found that memory
performance was not influenced by the absolute level of dopamine,
either high or low, in spite of a significantly slower memory
acquisition rate when dopamine levels were low. In view of these
findings, our results point rather to a possibly negative role
of long-term dopaminergic treatment with CSAI in attention and
executive functions in PD.
However, the cholinergic system
has also been implicated in cognitive dysfunction in PD and results
of recent studies have shown that rivastigmine (an
acetylcholinesterase inhibitor) promoted a significant cognitive
improvement as compared to placebo in a PD-D population .
Furthermore, other neurotransmitter systems, such as the
serotoninergic or noradrenergic pathways, display projections to
the prefrontal cortex and could also be involved . Therefore, both
dopaminergic treatment with CSAI and the effect of progression of PD
are brought into question. Unfortunately, the study design (an open
label study) does not enable us to determine precisely the specific
cause of cognitive impairment observed in our patients.
To the best of our knowledge, no
longitudinal data has been made available for MDRS score change in
PD-D. According to a large longitudinal study in a PD
population , the approximate annual percentage change in MMSE was
13.9% in patients who developed dementia by the first follow-up
visit. In our study, the approximate 12-month percentage change in
the verbal fluency tasks and the MDRS attention subscore was at least
twice as high when compared with the above-reported data. However,
direct comparison of the two studies is not possible and any
differences must be interpreted with great caution. Unlike MMSE, MDRS
is a sensitive tool for the measurement of frontal--like
cognitive deficit . Furthermore, MMSE does not include evaluation
of verbal fluency, and the progression of dementia in PD is not
linear . Despite the drawbacks mentioned, we consider that the
cognitive decline in our patient group was severe and that long-term
treatment with CSAI could have contributed to its magnitude.
treatment with waking-hour CSAI led to at least minimal clinical
motor improvement in all subjects. We observed no mood changes, but
there were significant impairments, particularly in frontal--like
executive functions. Further controlled studies are required to
explore what is behind our results. To the best of our knowledge,
this is the first study to focus on the cognitive effects of
long-term treatment with CSAI in advanced PD patients with marked
baseline cognitive impairment or dementia. The rate of cognitive
decline was alarming and leads us to suggest both cautious selection
of patients eligible for CSAI therapy, and close monitoring of
cognitive profiles in all PD subjects with established cognitive
deficits and/or neuropsychiatric complications who are given CSAI.
study was supported by Research Plan of the Ministry of Education of
the Czech Republic ref. no. MSM 0021622404.
Prof. MUDr. Irena Rektorova,
Department of Neurology Masaryk
University, St. Anne’s Hospital Pekarska
91 Brno e-mail:
for review: 30. 7. 2010 Accepted
for publication: 14. 2. 2011
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