Ndt_1134 3(6)_reingold et al.indd

Rivastigmine for the treatment of dementia associated with Parkinson's disease Jennifer L Reingold Abstract: Parkinson's disease (PD) affl icts millions of people worldwide and leads to cognitive
impairment or dementia in the majority of patients over time. Parkinson's disease dementia (PDD) is characterized by defi cits in attention, executive and visuospatial function, and memory. The clinical diagnostic criteria and neuropathology surrounding PDD remain controversial with Movement Disorders Program, Department of Neurology, Medical evidence of overlap among PDD, dementia with Lewy bodies (DLB) and Alzheimer's disease College of Georgia, Augusta, GA, USA (AD). Cortical cholinergic defi cits are greater in PDD than in AD, and are well-correlated with the cognitive and neuropsychiatric dysfunction that occurs in PDD. Inhibition of acetylcholine metabolism is therefore a practical therapeutic strategy in PDD.
This review examines current evidence for rivastigmine (a cholinesterase/butyrylcholin- esterase inhibitor) treatment in PDD. In addition to its effi cacy, we examine the safety profi le, side effects, and cost effectiveness of rivastigmine in PDD. Rivastigmine provides modest benefi t in PDD and further long-term studies are needed to determine the effectiveness and safety of rivastigmine over time. Tolerability is a problem for many PDD patients treated with rivastigmine. Future studies of rivastigmine in PDD should focus on pragmatic outcomes such as time to need for nursing home placement, pharmacoeconomic outcomes and simultaneous patient/caregiver quality of life assessments.
Keywords: Parkinson's disease, dementia, rivastigmine, cholinesterase inhibitor
Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disease
behind Alzheimer's disease (AD). James Parkinson (1817) fi rst described PD in his seminal work "An Essay on the Shaking Palsy." The cardinal motor signs of PD (bra- dykinesia, resting tremor, cogwheel rigidity, postural instability) are emphasized in making the diagnosis and in tracking progression of the disease (Gibb and Lees 1988). Most recently, signifi cant attention has been given to the non-motor symptoms of PD, including constipation, depression, olfactory dysfunction and dementia (Chaudhuri et al 2006). Parkinson (1817) was keenly aware of many non-motor aspects of PD including constipation and disturbed sleep. He did not recognize, however, impaired olfaction and dementia as a part of the disease describing "the senses and intellects" as "being uninjured" (Parkinson 1817). His lack of recognition of PD as a dementing illness is understandable given life expectancy in Great Britain in the early 19th century was under 40-years, and we now know that the risk of Parkinson's disease dementia (PDD) increases with age (Levy et al 2002).
PDD has perhaps been more studied and emphasized of late for several reasons: (1) greater emphasis on the non-motor symptoms of PD (Chaudhuri et al 2006), (2) Correspondence: John C Morgan the emergence of cholinesterase inhibitors as effective treatments in AD and PDD, Department of Neurology, Medical College of Georgia, 1429 Harper Street, and (3) ruling-out dementia is important in PD patients being considered for deep HF-1121, Augusta, GA, USA brain stimulation surgery (given it is exclusionary). We do know that PDD is under Tel +1 706 721 2798Fax +1 706 721 1115 recognized and under treated in routine clinical practice. Recent studies have dem- Email jmorgan@mcg.edu onstrated that cognitive decline and/or PDD affl icts the majority of patients with PD Neuropsychiatric Disease and Treatment 2007:3(6) 775–783 2007 Dove Medical Press Limited. All rights reserved over time (Aarsland et al 2003; Hely et al 2005) and that this For an operational method of distinguishing PDD from signifi cantly contributes to increased morbidity and mortality DLB, PDD has recently been defi ned as the onset of dementia (Levy et al 2002; Hughes et al 2004; de Lau et al 2005).
at least one year after the appearance of Parkinsonian motor symptoms (McKeith et al 2005). This defi nition is artifi cial Defi ning Parkinson's disease
and not typically representative of clinical experience (where patients become demented after many years of PD (Aarsland According to DSM-IV criteria (APA 2000), dementia is et al 2005)) and maybe diffi cult to apply in practice. The characterized by "the development of multiple cognitive largest clinical trial in PDD (Emre et al 2004) included defi cits that include memory impairment and at least one patients meeting established clinical diagnostic criteria for of the following cognitive disturbances: aphasia, apraxia, PD (Gibb and Lees 1988) and fulfi lling DSM-IV criteria for agnosia, or disturbance in executive dysfunction. The cogni- PDD with onset at least two years after the diagnosis of PD tive defi cits must be suffi ciently severe to cause impairment (Emre et al 2004).
in occupational or social functioning and must represent Neuropathologically PDD overlaps with DLB and AD a decline from a previously higher level of functioning." in numerous studies (Mahler and Cummings 1990; Perl et al Major cognitive domains that can be affected in dementia 1998; Aarsland et al 2004; Galvin et al 2006). Dementia with include: (1) executive function, (2) recent memory, (3) Lewy Bodies (DLB) and PDD are typically categorized as language, and (4) visuospatial function. PDD is more of a two separate disease states with distinct pathologies, but subcortical dementia with prominent defi cits in executive debate continues as to whether DLB and PDD are, in fact, and visuospatial function typically more so than language along the same disease spectrum (Levy et al 2006; Galvin et al and recent memory (Cummings 1988; Rippon and Marder 2006; Padovani et al 2006). AD pathology has been noted 2005). PDD is also characterized by generalized cognitive in many demented and non-demented patients with PD and slowing (bradyphrenia) and impaired attention (Cummings estimates of AD pathology among PD patients at autopsy 1988; Rippon and Marder 2005).
are as high as 42%–91% (Galvin et al 2006; Padovani et al Mild cognitive impairment (MCI) is differentiated from 2006). Although these changes are present in a large propor- dementia in that it represents a borderland between normal tion of patients with PD, it is diffi cult to defi ne the role these cognition and dementia. MCI remains controversial with changes play in the cognitive decline in PD.
some clinicians viewing this entity as a disease along a It is also suggested that the cognitive dysfunction devel- pathway leading to fulminant AD, while others view MCI oping later in Parkinson's is due to the loss of cholinergic as a heterogeneous syndrome representing an early stage of neurons in the nucleus basalis of Meynert (Whitehouse et al different forms of dementia (Fernandez et al 2005). Cogni- 1987). Supporting this hypothesis, there is evidence that tive decline is perhaps the rule as PD progresses (Hely et al cortical cholinergic defi cits are more pronounced in PD 2005); however, the defi nition of MCI in PD is even less than in AD and well-correlated with cognitive decline and well-defi ned than the defi nition of PDD (Fernandez et al neuropsychiatric disturbances in PD (Bohnen et al 2003; Hilker et al 2005).
Given clinical and neuropathological overlap, the most Most recently, Aarsland et al (2005) reported the neu- important distinction in the diagnosis of PDD is attempting ropathology of 22 PD patients identifi ed in the community to distinguish it from dementia with Lewy bodies (DLB) and followed prospectively until death. Eighteen of the (Aarsland et al 2005; McKeith et al 2005). Clinically, patients 22 patients (82%!!) were diagnosed with dementia with none with DLB are typically characterized as having early demen- of the 18 meeting established neuropathological criteria for tia and parkinsonism with less robust response to levodopa, AD (Aarsland et al 2005). All 18 demented patients had fl uctuations in level of alertness, visual hallucinations in the limbic and neocortical Lewy bodies (Aarsland et al 2005) absence of dopaminergic treatment, rapid progression of however. In accord with clinical practice, the average disease dementia, and severe sensitivity to typical and some atypi- duration for these patients was approximately 16 years with cal antipsychotics (Fuchs et al 2004; McKeith et al 2005). a diagnosis of dementia occurring a mean of three years Unfortunately, neuropsychological testing may not be able before death (Aarsland et al 2005). It thus appears that lim- to distinguish between patients with these two entities (Noe bic and neocortical Lewy bodies associated with signifi cant et al 2004), and the timecourse of the development of the cholinergic defi cits are perhaps the main substrate for the dementia is perhaps most important.
development of PDD.
Neuropsychiatric Disease and Treatment 2007:3(6) Rivastigmine in Parkinson's disease dementia Risk factors and epidemiology
Acetylcholinesterase (AChE) inhibitors have been the main- The Apo ε2 allele, older age at onset, the presence of depres- stay of treatment in AD for many years. In AD, these drugs sion, development of visual hallucinations, severity of dis- have been shown to slow symptomatic decline in cogni- ease, and an akinetic-rigid phenotype are established risk tion over time, delay nursing home placement, and result factors for the development of PDD (Marder et al 1995; Levy in lower long-term healthcare costs for patients/families et al 2002; de Lau et al 2005; Burn et al 2006). The incidence (Geldmacher 2005). AChE inhibitors theoretically improve and prevalence of PDD depends upon the neuropsychological cognitive function by increasing acetylcholine in the brain tests and the criteria used to defi ne PDD and neuropsycho- through preventing its breakdown. There are numerous logical testing batteries can vary considerably from center AChE inhibitors commercially available including donepezil, to center (Defer et al 1999; Saint-Cyr and Trepanier 2000; galantamine, rivastigmine, and tacrine. All of these drugs Pillon 2002; Burn et al 2006; Voon et al 2006).
are effective in AD, however there is relatively little data The incidence of PDD varies widely across studies with on their use in PDD.
the greatest incidence in elderly PD patients. The risk of Rivastigmine is a second generation, carbamate-type, developing dementia in PD is estimated to be 6 times that of reversible, brain selective cholinesterase inhibitor (Enz et al age-matched controls (Padovani et al 2006). Early estimates 1991). It appears to be more selective for the monomeric form of the prevalence of dementia in PD were in the range of 20% of AChE that is predominantly in the cortex and hippocampus (Brown and Marsden 1984). Cummings (1988) estimated that relative to peripheral forms of AChE (Enz et al 1993). It is as many as 40 percent of PD patients cross-sectionally have dosed twice daily titrating from 1.5 mg twice per day up to PDD. More recently, Aarsland et al (2003) found that 78% 6 mg twice per day as tolerated. The majority of patients of PD patients followed for 8 years develop PDD (Aarsland tolerate total doses of 6 mg/day or higher. Rivastigmine is et al 2003).
slightly different than donepezil and galantamine given it The prevalence of MCI in PD is largely unknown has both AChE inhibitory activity and butyrylcholinesterase (Fernandez et al 2005). Cognitive decline, perhaps consistent inhibitory activity. Inhibition of both forms of cholinesterase with MCI, was present in 84% of survivors from a cohort has theoretical advantages in allowing greater endogenous of PD patients followed 15-years after diagnosis (Hely et al levels of acetylcholine, but it is unknown if this drug provides 2005). Forty-eight percent of these survivors fulfi lled criteria benefi ts above and beyond other AChE inhibitors given head- for dementia (Hely et al 2005). Consistent with these fi ndings, to-head studies have not been done.
most PD patients undergoing neuropsychological testing to Clinical trials of rivastigmine in DLB
exclude dementia before deep brain stimulation surgery display some level of cognitive dysfunction (typically executive dys- function) (Saint-Cyr et al 2000; Pillon 2002). Cognitive decline Donepezil and galantamine have only been studied is therefore perhaps a ubiquitous feature as PD progresses.
in open-label studies or small scale clinical trials in Table 1 Placebo-controlled cholinesterase inhibitor trials in PDD and DLB
Authors
Medication
Study design
Number of patients
Study duration
Diagnostic criteria for
McKeith et al (2000) Probable DLB, mild to Aarsland et al (2002) DSM-IV/probable PDD Leroi et al (2004) DSM-IV or symptoms consistent with PDD Emre et al (2004) DSM-IV, mild to mod- erate dementia with Ravina et al (2005) DSM-IV, mild to mod- erate dementia with Abbreviations: DB, double-blind; PC, placebo-controlled; CO, cross-over.
Neuropsychiatric Disease and Treatment 2007:3(6) PDD (Table 1). Rivastigmine has been studied in large from baseline on treatment (Z = 2.85, p  0.004). Patients randomized, placebo-controlled clinical trials in DLB worsened signifi cantly three weeks after withdrawal of the (McKeith et al 2000) and PDD (Emre et al 2004) (Table 1). rivastigmine (Reading et al 2001).
The data available for rivastigmine has led to the approval Giladi et al (2003) also studied the effi cacy of rivastig- of this medication in the treatment of PDD in Europe, the mine in the treatment of PDD. In this open label study, 20 of United States and elsewhere.
28 patients completed 26-weeks of treatment with rivastig- McKeith et al (2000) studied the effi cacy of rivastig- mine therapy (as tolerated up to 12 mg/day). The MMSE and mine in DLB. In this randomized, double-blind, placebo- Alzheimer's Disease Assessment Scale (ADAS-cog) were controlled study, participants were given placebo or titrated used as cognitive measures and the UPDRS for documenting up to 12 mg/day of rivastigmine for 20-weeks followed by Parkinsonian features. Patients were assessed prior to start- a 3-week washout period. Assessments were made at base- ing therapy, at 12 and 26-weeks while on rivastigmine, and line, and at 12-, 20-, and 23-weeks. Neuropsychiatric testing 8-weeks after withdrawal of therapy. Eight of the 28 patients and computerized cognitive assessments were performed at dropped out secondary to side effects. An increase in UDPRS each session. Signifi cant clinical and cognitive performance score was observed from baseline to week 26 (p  0.06) and improvements were noted in those receiving rivastigmine as a non-signifi cant improvement was noted from week 26 to compared with placebo. Thirty-seven subjects (63%) in the 8-weeks after treatment washout. Signifi cant improvement rivastigmine group showed at least a 30 percent improve- was noted in the area of the attentional components of the ment from baseline as compared to only 18 subjects (30%) MMSE at week 26 (p  0.002). In terms of the ADAS-cog, of the placebo group. Patients improved most in the areas of a signifi cant increase in total score (worsening) was noted apathy and indifference and had fewer hallucinations than throughout the study period (p = 0.002).
those receiving placebo.
The authors indicated that the objective cognitive mea- As previously discussed, it is becoming more evident that sures (MMSE and ADAS-cog) did not at all refl ect the clini- DLB and PDD are on a continuum of disease, with signifi cant cal impressions of the caregivers for the patients in the study. overlap in terms of clinical and cognitive signs and symptoms In particular, caregivers seemed surprise by the deterioration (Aarsland et al 2005; Galvin et al 2006; Padovani et al 2006). experienced after washout. This, again, suggests the need for Given the obvious clinical benefi ts of rivastigmine in DLB a cognition assessment tool that is validated and best utilized (McKeith et al 2000), this led to further study in patients in PD. Giladi et al (2003) also noted increased tremor in defi ned as having PDD.
eleven of the original 28 participants in the study and dose In an open label trial by Reading et al (2001), twelve reduction was required.
patients with PD-related cognitive impairment and psychosis In this study, it would be expected for patients to worsen were given rivastigmine at an initial dose of 1.5 mg twice on the UPDRS over 6-months whether they were on an AChE daily and then titrated to 6 mg twice daily or the highest inhibitor or not. A non-signifi cant trend for improvement in tolerated dose. Patients were assessed at 8-weeks after the UPDRS scores following washout, however would make the maximum titration level was reached and once again one consider that rivastigmine negatively infl uenced motor 6-weeks after that period. The drug was discontinued at that performance. An increase in tremor and parkinsonism was point and participants were assessed once again 3-weeks a legitimate concern in this study given we still use anticho- after withdrawal of rivastigmine. At each session, the Fol- linergics for some patients with PD (certainly not demented stein Mini-Mental Status Exam (MMSE) was utilized as a ones, though!) (Morgan and Sethi 2005). There were prior measure of cognition and the Unifi ed Parkinson's Disease case reports of worsening of tremor and parkinsonism in PD Rating Scale (UPDRS) was administered to evaluate the patients treated with AChE (Richard et al 2002). The results motor symptoms of PD. Neuropsychiatric symptoms were of the Reading et al (2001) and Giladi et al (2003) studies evaluated using the Neuropsychiatric Inventory (NPI), which indicated further need to study the effects of this drug on evaluates behaviors over the preceding four weeks. Cognitive cognition and parkinsonism in PDD in a prospective, double- assessment utilizing the MMSE revealed signifi cant improve- blind, placebo-controlled fashion.
ment of 5 points in patients on rivastigmine relative to their In 2003, Fogelson et al (2003) performed another open baseline (Z = 2.81, p  0.005). Motor symptoms and signs label study examining the effects of rivastigmine on quan- were unchanged as measured by UDPRS (Z = 1.18, p  0.2). titative EEG (qEEG) in PDD patients (n = 19), given they NPI scores were also significantly lowered (improved) frequently have a slowing of alpha activity on EEG. Patients Neuropsychiatric Disease and Treatment 2007:3(6) Rivastigmine in Parkinson's disease dementia were treated with rivastigmine at an initial dose of 3 mg/day diagnosis 9-years earlier on average. Essentially all of the and titrated to a dose of 12 mg/day or highest tolerated dos- patients were Caucasian and approximately 2/3 were men. age. Quantitative EEG recordings were performed prior to The mean time since the diagnosis of PDD for patients introduction of rivastigmine and repeated when the patients entering the study was approximately 13–15 months. There had been on treatment for 12-weeks. A signifi cant increase were no signifi cant demographic differences between the in the relative alpha activity was noted after treatment with two treatment groups.
rivastigmine (p = 0.019), however, no correlation between As compared to patients in the placebo group, patients qEEG changes and cognitive improvement was identifi ed who received rivastigmine demonstrated signifi cant improve- (Fogelson et al 2003). It is diffi cult, therefore, to determine ments in ADAS-cog and ADCS-CGIC scores (primary whether these qEEG changes were due to improvement in effi cacy variables) (Emre et al 2004). Patients that were cognitive state rather than just an increase in arousal.
treated with rivastigmine had a mean improvement of A sound neuropathological and pharmacological basis 2.1 points in the ADAS-cog, while patients in the placebo and promising open label studies were followed by the pub- group had a 0.7 point worsening (p, 0.001). Clinically mean- lication of a multi-center, placebo-controlled, double-blind ingful improvement was observed in the investigator rated study in 541 patients with PDD (Emre et al 2004). PD was ADS-CGIC in 19.8% or rivastigmine patients and 14.5% in diagnosed using the UK PD Brain Bank Criteria and dementia placebo-treated patients, while clinically meaningful wors- was diagnosed using DSM-IV criteria. Participants were ening was evident in 13.0% and 23.1 percent, respectively randomly assigned to receive placebo or 3–12 mg (titrated to (p = 0.007). At week 24, rivastigmine provided improvement the maximum tolerated dose over a 16-week dose escalation in all six secondary effi cacy variables relative to the baseline period) of rivastigmine divided twice daily for 24-weeks. evaluation, while placebo-treated patients remained the same Patients were randomized 2:1 to rivastigmine and placebo, (NPI) or worsened (ADCS-ADL, MMSE, CDR, D-KEFS, respectively. The primary outcome measures were the Ten Point Clock-Drawing Test) (Emre et al 2004). These ADAS-cog scores as in previous open label studies (Fogelson benefi ts should be considered moderate and in-line with other et al 2003; Giladi et al 2003) and the Alzheimer's Disease clinical trials of AChE inhibitors in AD.
Cooperative Study-Clinician's Global Impression of Change A total of 410 out of 541 patients enrolled completed (ADCS-CGIC). There were six secondary outcome measures: the study. Ninety-nine patients dropped out of the study in Alzheimer's Disease Cooperative Study – Activities of the rivastigmine arm with 32 dropping-out in the placebo Daily Living (ADCS-ADL), NPI, MMSE, Cognitive Drug arm. Approximately two-thirds of the drop-outs in the riv- Research Power of Attention tests (CDR), Delis-Kaplan astigmine arm were due to adverse events and less than half Executive Function System (D-KEFS) verbal fl uency test, of the drop-outs in the placebo arm were due to the same. and the Ten Point Clock-Drawing Test. Safety monitoring Cholinergic symptoms typical of AChE inhibitors were included recording of adverse events, monitoring ECGs and the most common adverse events, with nausea reported by laboratory data, vital signs and body weight. Patients were 29% of rivastigmine – vs 11.2% of placebo-treated patients also assessed for changes in parkinsonism from baseline (p  0.001) and vomiting by 16.6% vs 1.7% respectively. scores at weeks 16 and 24 using the UPDRS part III (motor In general, Parkinsonian symptoms as a whole were more section) score.
often reported by patients in the rivastigmine group relative Patients were included in the effi cacy analysis if they to placebo (27.3% vs 15.6%, p = 0.002). Tremor (10.2% underwent a baseline evaluation and if they took one dose vs 3.9%) and dizziness (5.8% vs 1.1%) were also reported of study medication followed by an assessment of the one more often as an adverse event in rivastigmine-treated of the effi cacy variables after baseline (regardless if they patients. Tremor only caused withdrawal of 1.7% of patients were taking study medication at the time). If no follow- in the rivastigmine group and no one in the placebo group up information was available Emre et al (2004) used the (p = 0.19). There was no signifi cant difference in UPDRS last-observation-carried-forward method to impute missing motor scores and tremor related items between the groups, values for missing follow-up information.
however. Interestingly, hallucinations (4.7% vs 9.5%) and Approximately 30%–35% of patients enrolled in the orthostatic hypotension (1.7% vs 5.0%) were reported more study suffered with co-morbid psychiatric disorders (includ- often in patients treated with placebo.
ing depression, anxiety, and psychosis) (Emre et al 2004). In a letter to the editor, Harada et al (2005) argued that The average age of patients was approximately 72 with PD the number needed to treat in order to reach what Emre et al Neuropsychiatric Disease and Treatment 2007:3(6) (2004) defi ned as "clinically meaningful improvement" does on attention were noted among the rivastigmine group. Dif- not outweigh the side effects experienced by the participants fi culty maintaining attention is a common fi nding in PDD and in the study. Harada et al (2005) only considered those who further asserts that rivastigmine is helpful for this impairment had "clinically meaningful benefi t" in their analysis, how- in these patients (Wesnes et al 2005).
ever, and an important factor in any progressive neurodegen- Economic evaluation of rivastigmine was examined soon erative dementia is how many patients were prevented from after positive studies on PDD were published. Willan et al "clinically meaningful worsening" as well.
(2006) prospectively examined the cost effectiveness of riv- The results of the Emre et al (2004) study are encourag- astigmine in the Emre et al (2004) treated patients. Quality ing for the use of rivastigmine in PDD, however the effi cacy adjusted survival time (QAST) score was transformed from is modest. Adverse events are common with rivastigmine the MMSE score and utilized as a measure of cost effective- and typically cholinergic in nature, however they usually ness. Although an increase in QAST in the rivastigmine do not result in discontinuation of the drug. This study was arm of 2.81 quality-adjusted life-days was noted (two-sided hampered by lack of a validated assessment tool for PDD. p-value 0.13 [90% CI –0.243, 5.86]), no between-treatment The ADAS-cog and the ADCS-CGIC as primary effi cacy differences in cost were seen. The high variability in cost of variables are appropriate, however there needs to be further medications (the study looked at Canadian and UK prices) validation of this scale in PDD. Fortunately, six additional as well as the short duration of the study (six months) could tests of cognitive domains that would be impaired in PDD have interfered with the examination of cost effectiveness were also used (CDR, etc.). The fi nding of fewer reported and further studies need to be performed.
hallucinations in the rivastigmine-treated arm is interesting Patients with PDD and DLB can often have autonomic given this drug may not only provide stabilization and slower nervous system dysfunction, and AChE can potentially decline of cognitive function in PDD, it may also help reduce increase acetylcholine and contribute to cardiac dysfunction. hallucinations, which can be quite troubling for patients and Ballard et al (2006) reviewed cardiac safety of rivastigmine caregivers alike.
in DLB and PDD. Reviewing the Emre et al (2004) PDD trial Another concern is the cost of this drug relative to the (n = 541) and the McKeith et al (2000) DLB trial (n = 120), benefi t. Is the modest benefi t obtained enough to delay nurs- no clinically meaningful treatment differences in bradycardia ing home placement and is it cost-effective over time? Should or abnormalities on ECG were noted. Patients treated with NMDA-receptor antagonists such as memantine be added to rivastigmine did have a mean reduction of 1.5–2 beats per PDD as it advances? Are the other AChE inhibitors equally minute in heart rate, however. In fact, compared with placebo, effi cacious in PDD? it appears that rivastigmine was associated with fewer adverse There was an open-label extension to the Emre et al events (p = 0.002) and fewer syncopal episodes (p = 0.018) (2004) study published recently by Poewe et al (2006). Of 433 among PDD patients (Ballard et al 2006).
patients that completed the double-blind trial, 334 entered and 273 completed the active treatment extension study (3–12 mg rivastigmine/day). At 48-weeks the ADAS-cog score had A recent practice parameter from the American Academy improved by 2 points above baseline for the entire group of of Neurology indicated that there was Level B evidence patients. Patients in the placebo treatment arm in the original (moderately strong) for the treatment of PDD with either Emre et al (2004) trial also had a 2-point improvement in donepezil or rivastigmine (Miyasaki et al 2006). Given the their ADAS-cog score. The safety profi le of rivastigmine lack of published large, randomized, placebo-controlled trials in the open label extension was similar to the double-blind of donepezil in PDD, we feel that rivastigmine currently has phase (Poewe et al 2006).
the best data for use in PDD. The benefi ts are modest and Wesnes et al (2005) looked specifi cally at the effects of further studies are needed, but the Emre et al (2004) data rivastigmine on attention in PDD in patient enrolled in the are the best that we have in the use of AChE inhibitors in Emre et al (2004) trial. In this sub-study, 487 patients with PDD and the clinically and pathologically similar condition PDD were given rivastigmine or placebo and assessed at DLB (McKeith et al 2002). The dropout rate in the placebo- baseline, 16 and 24-weeks. Assessment of attention on the controlled phase was higher in the rivastigmine-treated Cognitive Drug Research (CDR) computerized assessment PDD patients vs placebo-treated patients (27.3% vs 17.9%) was performed at each visit in order to assess attention during (Emre et al 2004) and using LOCF analytical techniques various tasks. As compared with placebo, signifi cant benefi ts in a progressive condition like PDD would artifactually Neuropsychiatric Disease and Treatment 2007:3(6) Rivastigmine in Parkinson's disease dementia show less worsening in the rivastigmine treated group. The hopefully be published in its entirety soon. While a decline number needed to treat to provide a clinically meaningful in premorbid function will be necessary for the diagnosis of signifi cant outcome in the Emre et al (2004) trial is perhaps PDD with impairment in at least two cognitive domains, it six if you consider both meaningful improvement in the appears that memory impairment on the MMSE (score  25) rivastigmine arm combined with the group with clinically will not be a required feature to make the diagnosis of PDD meaningful worsening in the placebo-treated arm (Aarsland by these criteria. The current defi nition of PDD is largely et al 2006).
based on the defi nition of dementia as cited in the DSM-IV Given the relatively high drop-out rate in rivastigmine- with a decline in functional level, memory decline and at treated patients, the safety profi le of rivastigmine should be least one additional form of cognitive impairment (executive further examined. Future studies need to specifi cally explore dysfunction, apraxia, agnosia, aphasia) (Fuchs et al 2004) the gastrointestinal side effects and patient perceived wors- and by exclusion of PDD from those with DLB (McKeith ening of motor symptoms (ie, especially tremor). To this et al 2005).
end, a recent study of 26 patients with PDD on rivastigmine Screening and assessment tools for MCI in PD patients revealed only mild worsening of tremor by accelerometry and in PDD must be identifi ed, developed and validated. If and a global tremor rating scale based upon the UPDRS you examine various neuropsychological testing batteries (Gurevich et al 2006). Further study of the possible positive recommended for evaluation of cognitive function in PD, infl uence of rivastigmine on the neuropsychiatric symptoms you will fi nd a hodge-podge of cognitive scales and tests of PDD (hallucinations and delusions) is warranted given with many lacking widespread use and validation in PD these problems were reported signifi cantly less as adverse (Defer et al 1999; Saint-Cyr et al 2000; Pillon et al 2002; events in the rivastigmine arm of the Emre et al (2004) Burn et al 2006; Voon et al 2006). Emre et al (2004), Giladi placebo-controlled study. It will be interesting to see if the et al (2003), Fogelson et al (2003), and Reading et al (2002) other AChE inhibitors like donepezil (a drug with fewer used cognitive scales that were assessed and validated in reported adverse events in AD trials (Birks 2006)) provide AD (ADCS-GCIS, ADCS-ADL, NPI) without signifi cant similar effi cacy in PDD with fewer side effects (Aarsland validation in PDD. Miyasaki et al (2006) identifi ed the most et al 2002; Leroi et al 2004; Ravina et al 2005).
accurate screening tools for PDD as the MMSE and the It is also necessary to look at the cost of rivastigmine Cambridge Cognitive Examination (CAMcog). Both tools versus the benefi ts gained by patients and caretakers. While had similar sensitivities for the diagnosis of PDD; however, there is good pharmacoeconomic data in AD for various the CAMcog (94%) was more specifi c than the MMSE (77%) AChE inhibitors (Geldmacher 2005), it is lacking for these (Miyasaki et al 2006).
drugs in PDD. A pharmacoeconomic assessment performed A more precise definition and characterization of by Willan et al (2006) was possibly not signifi cant because mild cognitive impairment (MCI) in PD is also warranted of the variability of drug costs and the short, six-month study (Fernandez et al 2005). We know that PD is a progressive period. Alternatively, the costs may outweigh the benefi ts illness and patients with MCI and without PD typically go of rivastigmine in PDD. Looking ahead, we must examine on to develop AD over time. In patients with PD, how many costs over a longer treatment horizon. A confounding factor patients have MCI and how many of these go on to develop in PDD is that progression and severity of motor symptoms PDD over time? There is much additional work that needs can lead to long-term care in patients with PD, which is to be done in these areas to characterize and understand the somewhat different than in AD where patients are typically course our patients will take as they progress.
put in a nursing home due to severe dementia.
The Montreal Cognitive Assessment (MoCA) has The publication of the effi cacy of rivastigmine in PDD recently entered into the literature as an assessment tool could be regarded as "the carriage coming before the horse" for MCI. Unlike the MMSE, the MoCA incorporates 8 so to speak. In our opinion, a well-defi ned, clinically and additional cognitive domains including more complex neuropathologically relevant defi nition of PDD must be visuospatial evaluation, naming, attention, memory, lan- developed. The Movement Disorders Society has assembled guage and abstraction tasks. It appears sensitive to the kind a task force to develop this defi nition and the outline of of defi cits that are evident in PDD (executive and visuo- this new defi nition was presented at the 10th International spatial dysfunction, etc.). In a validation study performed Conference of Parkinson's Disease and Movement Disor- by Nasreddine et al (2005), the MoCA was found to have ders in Kyoto, Japan in 2006. This defi nition of PDD will high sensitivity and specifi city for detecting MCI in patients Neuropsychiatric Disease and Treatment 2007:3(6) who performed in normal ranges on the MMSE. Using a Enz A, Amstutz R, Bodekke H, et al. 1993. Brain selective inhibition of acetylcholinesterase: a novel approach to therapy for Alzheimer's normal cut-off score of 26/30, the MMSE had a sensitivity disease. Prog Brain Res, 98:431–8.
of 18% to detect MCI whereas an abnormal MoCA score Enz A, Bodekke H, Gray J, et al. 1991. Pharmacologic and clinicopharma- detected 90%. While the MoCA seems to have much cologic properties of SDZ ENA 713, a centrally selective acetylcho-linesterase inhibitor. Ann N Y Acad Sci, 640:272–5.
promise in detection of MCI, further validation in PD and Fernandez HH, Crucian GP, Okun MS, et al. 2005. Mild cognitive impair- PDD is necessary.
ment in Parkinson's disease: the challenge and the promise. Neuropsy-chiatric Disease and Treatment, 1:37–50.
The publication of the fi rst large-scale, randomized, Fogelson N, Kogan E, Korczyn AD, et al. 2003. Effects of rivastigmine on double-blind controlled trial of rivastigmine in PDD has the quantitative EEG in demented Parkinsonian patients. Acta Neurol generated much interest in the defi nition, recognition, and Fuchs GA, Gemende I, Herting B, et al. 2004. Dementia in idiopathic treatment of PDD. While the clinical benefi ts of rivastigmine Parkinson's syndrome. J Neurol, 251 Suppl 6:VI/28–32.
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Leitlinien der DGN 2008 Diagnostik und Therapie komplexer regionaler Schmerzsyndrome (CRPS) Was gibt es Neues? • Während in der Akutphase eines CRPS peripher-entzündliche Vorgänge vorherrschen, entwickeln sich mit der Dauer der Erkrankung zunehmend neuroplastische Veränderungen im ZNS. Diese Änderung der Pathophysiologie muss in der Therapieplanung berücksichtigt werden.