Movement Disorders Vol. 16, No. 6, 2001, pp. 1171–1195 © 2001 Movement Disorder Society Published by Wiley-Liss, Inc.
Clinical/Scientific Notes
Of potential relevance, cholinergic agents seem particularly effective at treating neuropsychiatric aspects of other neurodegenerative dementia syndromes, including dementia with Lewy bodies (DLB) and Alzheimer’s disease.20–25 The potential use of cholinergic agents in PD may appear counterintuitive, given the modest efficacy of anticholinergic agents in relieving some of the physical symptoms (particularly tremor) when used early in the illness. However, a small open study using tacrine demonstrated significant improvement in cognitive status and psychotic symptoms in a group of advanced parkinsonian patients while actually improving their motor function.23 An open exploratory study was therefore undertaken to investigate the tolerability and efficacy of the more recent pseudo-irreversible cholinesterase inhibitor rivastigmine in the treatment of psychotic symptoms and cognitive impairment in patients with established PD.
Rivastigmine in the Treatment of Parkinsonian Psychosis and Cognitive Impairment: Preliminary Findings from an Open Trial Paul J. Reading, PhD, MRCP,1* Anna K Luce, BSc,2 and Ian G. McKeith, MD, FRCPsych2 1
Department of Neurology, Regional Neurosciences Centre, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom 2 Institute for the Health of the Elderly, Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom
Abstract: This open study assessed the ability of rivastigmine to treat the neuropsychiatric complications of advanced Parkinson’s disease. In a group of 12 patients, hallucinations, sleep disturbance, and carer distress were all improved and cognitive performance significantly enhanced by the drug. © 2001 Movement Disorder Society.
Patients and Methods Fifteen consecutive patients from neurology outpatient departments in Newcastle upon Tyne and Sunderland, UK, who met the inclusion criteria for the study were screened for entry. Each patient had been initially diagnosed with idiopathic PD in the absence of overt cognitive or psychotic symptoms at least 2 years previously using the clinical criteria of the Parkinson Disease Society Brain Research Centre.26 The key entry criterion for the study at screening was the presence of troublesome and recurrent hallucinations for at least the previous 3 months. The subjects were all required to be taking a stable medication regime that did not include neuroleptic nor anticholinergic agents. A reliable caregiver familiar with the patient’s daily activities and night-time behaviour was also mandatory. Exclusion criteria were severe dementia, defined as Folstein MiniMental State Examination27 (MMSE) scores of less than 10, the presence of significant urinary symptoms, and a history of cardiovascular disease or cardiac arrhythmia. The study was granted ethical approval and all patients and carers gave informed consent. Throughout the study each patient was assessed thoroughly on five occasions including the screening session. Ten weeks following screening, rivastigmine at a dose of 1.5 mg twice daily was commenced (baseline session) and the dose titrated at 2-week intervals until either 6 mg twice daily or the highest tolerated dose was achieved. The patients were then assessed after 8 weeks of dose titration (high dose session) and once again when they had been taking the highest tolerated dose for 6 weeks (experimental session). At this point the drug was discontinued and a final fifth assessment undertaken 3 weeks later (withdrawal session). At each assessment session the Folstein MMSE and the motor subscale of the Unified Parkinson’s Disease Rating Scale28 (UPDRS) were recorded as measures of overall cognitive ability and physical parkinsonian symptoms, respectively. Neuropsychiatric symptoms including hallucinations were measured using the Neuropsychiatric Inventory (NPI). The NPI is a vali-
A number of recent studies have documented the relatively high prevalence of psychotic symptoms in idiopathic Parkinson’s disease (PD).1–4 Hallucinations in particular affect approximately 30% of patients,5–7 and are consistently associated with advanced age and the presence of significant cognitive impairment.1–5 Severe sleep fragmentation, intrusive vivid nightmares, and disruption of rapid eye movement (REM) sleep patterns are also likely to be important factors.8–11 Attempts to treat psychosis and cognitive impairment in PD often present a considerable clinical problem. Atypical neuroleptic agents such as clozapine,12 olanzapine,13 and quetiapine14 may be useful in alleviating hallucinosis but have no reported positive effects on cognitive function.15 Agents such as olanzapine are also capable of worsening extrapyramidal symptoms at clinically effective doses.16 It is also difficult to deduce the precise pharmacological mechanism of atypical neuroleptics, as this class of agents influences dopaminergic, serotinergic, and cholinergic systems.17 Regarding the pathogenesis of psychotic symptomology in PD, although dopaminergic agents may worsen or trigger hallucinations, several lines of evidence suggest that other factors may play a more primary role. In particular, the wellestablished cholinergic deficits in advanced PD may predispose to psychosis as well as producing many of the cognitive or attentional deficits seen in a significant proportion of cases.18,19
*Correspondence to: Paul J. Reading PhD, MRCP, Department of Neurology, Regional Neurosciences Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, UK. Received 14 October 2000; revised 10 January 2001; accepted 16 February 2001 Published online 24 November 2001. DOI 10.1002/mds.1204
1171
1172
CLINICAL/SCIENTIFIC NOTES
dated caregiver informant-rated measure of neuropsychiatric disturbance29 that has been used in the assessment of a number of neurodegenerative conditions, including Alzheimer’s disease29 (AD), progressive supranuclear palsy,30 corticobasal degeneration,31 and Huntington’s disease.30 The NPI evaluates behaviours that have occurred in the 4 weeks preceding the evaluation by assessing in detail 12 separate symptom domains: delusions, hallucinations, agitation/aggression, depression/ dysphoria, anxiety, elation/euphoria, apathy, disinhibition, irritability, aberrant motor behaviours, sleep disturbance, and appetite changes. The presence of symptoms in each domain is initially assessed at interview by a summary screening question which, if answered by a positive response, invokes a more in-depth evaluation of specific behaviours within the domain. Items that have been identified are then collectively rated in terms of their frequency (1, less than once a week; 2, once a week; 3, several times a week; 4, every day) and severity (1, mild; 2, moderate; 3, severe). Severity ratings for each symptom domain are individualised with specific anchoring criteria. For each of the 12 domains rated on the NPI, the product of the frequency score (1–4) and the severity score (1–3) yields a symptom score (0 if absent; 1–12 if present). The total NPI score represents the sum of individual symptom scores (0 to a theoretical maximum of 144). In practice, total scores of around 20 or more correspond to highly significant neuropsychiatric disturbance. The important aspect of carer distress was also recorded and scored for each neuropsychiatric symptom complex. The caregiver was asked to rate their own emotional or psychological distress caused by each symptom, if present (0, no distress; 1, minimal; 2, mild; 3, moderate; 4, moderately severe; 5, very severe). As with the total NPI score, a total carer distress score was obtained by summing the individual scores on the 12 items. In view of the relatively small number of subjects and the non-normal distribution of the NPI data, nonparametric analysis was used throughout. For each measure, the key comparison between baseline and experimental sessions was assessed using the Wilcoxon signed ranks test (two-tailed).
Results Full data were obtained on 12 patients, because three were forced to withdraw. Of these three, one died from septicaemia, thought not related to the trial medication; another experienced side effects of severe nausea; and the third patient’s caregiver became unable to participate further in the study due to ill health. Details of the 12 patients who completed the study are shown in Table 1. All patients had a clear sensorium and were able to cooperate fully with the assessments. Throughout the duration of the study (17 weeks from baseline to withdrawal phase), no changes were made in the patients’ anti-parkinsonian therapy. All patients were established on a levodopa (L-dopa) preparation and three were also taking the dopamine agonist, pergolide. Following titration of the dose of rivastigmine, 3 of the 12 patients were able to tolerate the maximum daily dose of 12 mg (6 mg twice daily). Of the remaining patients, three reached 9 mg daily and five were maintained on 6 mg. One patient could not tolerate doses higher than 3 mg daily. The only significant side effect was nausea which limited the dose escalation in nine patients, as outlined above.
Movement Disorders, Vol. 16, No. 6, 2001
TABLE 1. Baseline characteristics of 12 patients who completed the study Mean age, yr (range) Sex (M/F) Mean duration of illness, yr (range) Mean daily dose of L-dopa, mg (range) Additional Pergolide Nature of caregiver
71 (64–77) 10/2 12 (3–24) 800 (400–1,600) 3 patients, mean daily dose 1.5 mg 10 spouses; 2 siblings
Comparisons of measures obtained at the experimental session with those at baseline revealed significantly lower scores on the total NPI scores (Fig. 1) (Z ⳱ 2.85; P < 0.004) and individual subscales relating to hallucinations (Fig. 2) (Z ⳱ 2.24; P < 0.025) and sleep disturbance (Fig. 2) (Z ⳱ 2.43; P < 0.015). Scores of carer distress at the experimental session were also significantly improved compared with baseline (Fig. 3) (Z ⳱ 2.71; P < 0.007). Cognitive assessment using the Folstein MMSE revealed significant differences between experimental and baseline sessions, with a mean improvement of 5 points (Z ⳱ 2.81; P < 0.005; see Table 2). Motor symptoms of parkinsonism measured by the UPDRS showed a nonsignificant tendency to improve (Z ⳱ 1.18; P > 0.2; see Table 2). Within the UPDRS scores there were no changes in tremor ratings between the various assessment sessions. At the assessment 3 weeks following withdrawal of rivastigmine, comparisons of total NPI and MMSE scores with corresponding values at the experimental session revealed significant deterioration (Z ⳱ 2.81, P < 0.005; Z ⳱ 2.12, P < 0.034, respectively).
Discussion Rivastigmine significantly reduced neuropsychiatric disturbances in advanced parkinsonian patients suffering from troublesome hallucinations without worsening their extrapyramidal signs and symptoms. Improvements recorded by the NPI were particularly noticeable on the subsections measuring hallucinations and sleep disturbance. Carer distress consequent to the patients’ neuropsychiatric or behavioural problems was also markedly ameliorated by the drug. In addition, overall cognitive performance was significantly enhanced, with a mean gain
FIG. 1. Mean total NPI scores at each assessment session. Comparison of the experimental scores with those at baseline showed significant improvement; * P < 0.004.
CLINICAL/SCIENTIFIC NOTES
FIG. 2. NPI subscale scores for hallucinations and sleep disturbance at each assessment session. Black bars, hallucinations; grey bars, sleep. Significant improvements were seen when scores at the experimental session were compared with those at baseline for both hallucinations and sleep; 夝 P < 0.025; † P < 0.015
of 5 points on the Folstein MMSE. All these indices of improvement were substantially reversed when recorded 3 weeks following withdrawal of rivastigmine. The open nature of this exploratory study cannot exclude the possibility of placebo effects influencing patients and their carers. However, the degree of response seen in many of the patients and the nature of the improvements, such as those of severe sleep disturbance, would make this an unlikely full explanation. Furthermore, most of the patients were maintained on rivastigmine following the study and have not shown signs of significant deterioration after 70 weeks of subsequent detailed follow-up (data not shown). The association of hallucinosis with vivid dreams and sleep fragmentation in PD suggests that REM sleep disturbances may be central.8–11 Hallucinations during wakefulness are known to occur in subjects with prolonged REM sleep deprivation and most likely represent the phenomenon of REM sleep intrusion or rebound.32 In PD, brainstem areas involved in REM sleep processes such as the predominantly cholinergic pedunculopontine nucleus are known to degenerate33 and might be expected to produce a primary sleep disturbance.9 The added presence of dopaminergic drugs could further worsen the quality of REM sleep.34 Of note, hallucinating parkinsonian patients have been found to have severely impaired REM sleep indices when compared with matched nonhallucinating parkinsonian controls.35 The success of rivastigmine in relieving hallucinosis may reflect its ability to enhance REM sleep, which is known to have a cholinergic basis.36
1173
FIG. 3. Scores of overall carer distress at each assessment session. Comparison of score at experimental session with that at baseline revealed significant improvement; 夝 P < 0.007.
Rivastigmine was generally well tolerated in our patient group, although significant nausea was a dose-limiting side effect in most patients. The observation that tremor did not worsen and that overall motor function even showed a nonsignificant improvement on the UPDRS was not predictable a priori, although this mirrors the findings of Hutchinson and Fazzini.23 Current established therapies for parkinsonian hallucinosis include the atypical neuroleptic agents clozapine12 and olanzapine.13 Although reasonably effective at reducing psychotic symptoms, these drugs are generally poorly tolerated in PD and even less so in the related condition DLB,37 with significant side effects seen even at low doses.16,37 Few studies have addressed their ability to improve cognitive performance but no change in MMSE scores (23.8 both pre- and posttreatment) was observed in a recent randomised trial of clozapine in PD.12 The cholinesterase inhibitor rivastigmine is now an established licensed treatment primarily for the amnestic aspects of mild or moderate AD, but accumulating evidence suggests that dementia syndromes with prominent neuropsychiatric symptomology may be even more responsive to the agent.21,22,24,25,38,39 Our results are very similar to those found in studies using comparable assessments of patients diagnosed with DLB.24,25 This is perhaps not surprising, given the degree of phenotypic similarity between DLB patients and our patient group, even though our subjects presented with motor symptoms of idiopathic PD many years before the onset of neuropsychiatric problems. The use of cholinesterase inhibitors provides a new approach to a difficult clinical problem and emphasises the potential importance of cholinergic mechanisms in the pathogenesis of the neuropsychiatric complications of neu-
TABLE 2. MMSE and UPDRS (motor subscale) scores across five assessment sessions (n = 12)
MMSE (mean ± S.D.) UPDRS (mean ± S.D.)
Screening
Baseline
High dose
Experimental
Withdrawal
20.8 ± 5.4 29.8 ± 9.5
20.4 ± 5.7 32.3 ± 10.4
24.2 ± 3.5 31.4 ± 14.5
25.4* ± 3.5 29.8a ± 11.5
21.2 ± 5.1 34.8 ± 12.2
Higher MMSE values imply improved cognitive ability, whereas higher UPDRS scores indicate worse motor function. *Experimental compared with baseline, P < 0.005. a Experimental compared with baseline, P > 0.2.
Movement Disorders, Vol. 16, No. 6, 2001
1174
CLINICAL/SCIENTIFIC NOTES
rodegenerative diseases. Further randomised trials in parkinsonian patients are warranted. 20.
Acknowledgment: We thank Novartis PLC for financial assistance with this study.
21.
References 1. Sanchez-Ramos JR, Ortoll R, Paulson GW. Visual hallucinations associated with Parkinson’s disease. Arch Neurol 1996;53:1265– 1268. 2. Haeske-Dewick HC. Hallucinations in Parkinson’s disease: characteristics and associated clinical features. Int J Geriatr Psychiatry 1995;10:487–495. 3. Aarsland D, Larsen JP, Cummings JL, Laake K. Prevalence and clinical correlates of psychotic symptoms in Parkinson’s disease. Arch Neurol 1999;56:595–601. 4. Naimark D, Jackson E, Rockwell, Jeste DV. Psychotic symptoms in Parkinson’s disease patients with dementia. J Am Geriatr Soc 1996;44:296–299. 5. Fenelon G, Mahieux F, Huon R, Ziegler M. Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain 2000;123:733–745. 6. Goetz CG, Tanner CM, Klawans HL. Pharmacology of hallucinations induced by long-term drug therapy. Am J Psychiatry 1982; 139:494–497. 7. Moscovitz C, Moses H III, Klawans HL. Levodopa-induced psychosis: a kindling phenomenon. Am J Psychiatry 1978;135:669– 675. 8. Pappert EJ, Goetz CG, Niederman FG, Rema Raman MS, Leurgans S. Hallucinations, sleep fragmentation, and altered dream phenomena in Parkinson’s disease. Mov Disord 1999;14:117–121. 9. Pieri V, Diederich NJ, Comella CL. REM sleep disorder in PD patients with and without coexistent hallucinations [Abstract]. Mov Disord 1998;(Suppl 2):13:274. 10. Nausieda PA, Weiner WJ, Kaplan LR, Weber S, Klawans KL. Sleep disruption in the course of chronic levodopa therapy: an early feature of the levodopa psychosis. Clin Neuropharmacol 1982;5:183–194. 11. Arnulf I, Bonnet AM, Damier P, Bejjani BP, Seilhean D, Derenne JP, Agid Y. Hallucinations, REM sleep, and Parkinson’s disease: a medical hypothesis. Neurology 2000:55;281–288. 12. Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. N Engl J Med 1999;340:757–763. 13. Wolters EC, Jansen ENH, Tuynman-Qua HG, Bergmans PLM. Olanzapine in the treatment of dopaminomimetic psychosis in patients with Parkinson’s disease. Neurology 1996;47:1085–1087. 14. Juncos JL, Arvanitis L, Sweitzer D, Yeung P, Jewart RD, Nemeroff C. Quetiapine improves psychotic symptoms associated with Parkinson’s disease [Abstract]. Neurology 1999;52(Suppl 2):A262 15. Friedman FH, Factor SA. Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson’s disease. Mov Disord 2000;15:201–211. 16. Graham JM, Sussman JD, Ford KS, Sagar HJ. Olanzapine in the treatment of hallucinosis in idiopathic Parkinson’s disease: a cautionary note. J Neurol Neurosurg Psychiatry 1998;65:774–777. 17. Janicak PG, Davis JM, Preskorn SH, Ayd FJ Jr. Principles and practice of psychopharmacology. Baltimore: Williams & Wilkins; 1997. 18. Cummings JL. Managing psychosis in patients with Parkinson’s disease. N Engl J Med 1999;340:801–803. 19. Dubois B, Danze´ F, Pillon B, Cusimano G, Lhermitte F, Agid Y.
Movement Disorders, Vol. 16, No. 6, 2001
22.
23. 24.
25.
26. 27. 28.
29.
30. 31.
32.
33.
34. 35.
36. 37.
38. 39.
Cholinergic-dependent cognitive deficits in Parkinson’s disease. Ann Neurol 1986;22:26–30. Cummings JL, Kaufer D. Neuropsychiatric aspects of Alzheimer’s disease: the cholinergic hypothesis revisited. Neurology 1996;47: 876–883. Shea C, MacKnight C, Rockwood K. Donepezil for treatment of dementia with Lewy bodies: a case series of nine patients. Int Psychogeriatr 1999;10:229–238. Kaufer D. Beyond the cholinergic hypothesis: the effect of metrifonate and other cholinesterase inhibitors on neuropsychiatric symptoms in Alzheimer’s disease. Dement Geriatr Cogn Disord 1998;9(Suppl 2):8–14. Hutchinson M, Fazzini E. Cholinesterase inhibition in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1996;61:324–326. McKeith IG, Grace JB, Walker Z, Byrne EJ, Wilkinson D, Stevens T, Perry EK. Rivastigmine in the treatment of dementia with Lewy bodies: preliminary findings from an open trial. Int J Geriatr Psychiatry 2000;15:387–392. McKeith I, Del Ser T, Spano P, Emre M, Wesnes K, Anand R, Cicin-Sain A, Ferrara R, Spiegel R. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebocontrolled international study. Lancet 2000;356:2031–2036. Daniel SE, Lees AJ. Parkinson’s disease brain bank, London: overview and research. J Neural Transm 1993;39(Suppl):165–172. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state‘: a practical method for grading the mental state of patients for the clinician. J Psychiatr Res 1975;12:189–198. Fahn S, Elton RL, members of the UPDRS Development Committee. The unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Goldstein M, Calne DB, editors. Recent developments in Parkinson’s disease, vol. 2. Florham Park, NJ: Macmillan Healthcare Information; 1987. p 153–163, 293–304. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44: 2308–2314. Litvan I, Paulsen JS, Mega MS, Cummings JL. Neuropsychiatric assessment of patients with hyperkinetic and hypokinetic movement disorders. Arch Neurol 1998;55:1313–1319. Litvan I, Cummings JL, Mega M. Neuropsychiatric features of corticobasal degeneration. J Neurol Neurosurg Psychiatry 1998; 65:717–721. Kollar EJ, Pasnau RO, Rubin RT, Naitoh P, Slater GG, Kales A. Psychological, psychophysiological, and biochemical correlates of prolonged sleep deprivation. Am J Psychiatry 1969;126:488–497. Jellinger K. The pedunculopontine nucleus in Parkinson’s disease, progressive supranuclear palsy and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1988;51:540–543. Wyatt RJ, Chase TN, Scott J, Snyder F, Engelman K. Effect of L-DOPA on the sleep of man. Nature 1970;228:999–1001. Comella CL, Tanner CM, Ristanovic RK. Polysomnographic sleep measures in Parkinson’s disease patients with treatment-induced hallucinations. Ann Neurol 1993;34:710–714. Steriade M. Basic mechanisms of sleep generation. Neurology 1992;42(Suppl 6):9–18. Walker Z, Grace J, Overshot R, Satarasinghe S, Swan A, Katona CL, McKeith IG. Olanzapine in dementia with Lewy bodies: a clinical study. Int J Geriatr Psychiatry 1999;14:459–466. Wilcock GK, Scott MI. Tacrine for senile dementia of Alzheimer’s or Lewy body type. Lancet 1994;344:544. Levy R, Eagger S, Griffiths M, Perry E, Honavar M, Dean A, Lantos P. Lewy bodies and response to tacrine in Alzheimer’s disease. Lancet 1994;343:176.
CLINICAL/SCIENTIFIC NOTES
Poetic Talent Unmasked by Treatment of Parkinson’s Disease Anette Schrag, MD, PhD, and Michael Trimble, MD* Raymond Way Neuropsychiatry Research Group, Institute of Neurology, University College London, London, United Kingdom
Abstract: Parkinson’s disease is typically characterised by loss of function and previous abilities, often accompanied by complications of treatment in later stages of the disease. We report on a patient who newly developed an artistic skill after starting treatment for Parkinson’s disease. This case offers insight into the neurology of the artistic process as well as into the pathophysiology of psychiatric adverse reactions to the treatment of PD. © 2001 Movement Disorder Society.
Case Report A 55-year-old patient had developed Parkinson’s disease (PD) at age 40 years with tremor of the left hand, dragging of the left leg, and dystonia of the left foot. This gradually progressed, and treatment was started with a combination of the dopamine agonist lisuride and levodopa at age 44 years. His symptoms markedly improved and he had no initial side effects except an increase in libido. Within the first month of starting treatment, he began writing poetry for the first time in his life and went on to write 10 poems in the first year of treatment. He continued writing with success; winning a prize in the annual contest of the International Association of Poets and publishing several poems in newspapers and magazines. He had never written poetry in his life before or felt the desire to do so, rather, on the contrary, described himself as the black sheep in the family due to lower intellectual achievements than his siblings. However, his maternal grandfather had written poetry and he was related to a well-known Irish poet. As his PD progressed, he developed fluctuations in motor response to treatment and dyskinesias. Approximately 12 years after onset, taking 2,000 mg Levodopa (plus decarboxylase inhibitor) and 2,000 g lisuride daily, he developed problems with depression, aggression, and volatile behaviour, which put considerable strain on his family. A year later, he also developed grandiose ideas, paranoid delusions, irritability, extreme circumstantiality, overtalkativeness, and pressure of speech. Discontinuation of lisuride and treatment with olanzapine improved these symptoms but led to deterioration of his parkinsonian symptoms. In the following year, taking 1,900 mg levodopa per day, he developed another episode of impulsivity, grandiose ideas, agitation, hostility, overactivity, pressure of
*Correspondence to: Prof. M Trimble, Raymond Way Neuropsychiatry Research Group, Institute of Neurology, Queen Square, London WC 1N 3BG. E-mail:
[email protected] Received 16 October 2000; Revised 16 March 2001; Accepted 15 May 2001 Published online 24 November 2001. DOI 10.1002/mds.1239
1175
speech, and flight of ideas. This was most likely to be due to self-overmedication and he was hospitalised to readjust his drug regime. Neuropsychological testing revealed an I.Q. of 97 on the verbal subscores of the Wechsler Adult Intelligence test with high-average to low-average performances, and average and low-average scores in the two tests of the Performance scale, which he could complete (Picture Completion and Picture Arrangement, respectively). Abstract reasoning, reading performance, and memory were within the average range, and visual perceptual function was satisfactory. This represented no cognitive decline over 9 years, but a mild underfunctioning compared with his estimated premorbid ability. However, there was some impairment on frontal lobe tests, with impairment on the Wisconsin card sorting test, where he was only able to obtain three categories and made many errors. However, word fluency was satisfactory, producing 25 words starting with the letter S in 60 seconds and normal performance on Cognitive Estimates and the Stroop test. There was no clear relationship between changes in treatment and his poetic activity, and his claims of poetic success were confirmed by his family and friends, and were seen in print.
Discussion Enhanced artistic ability has been described in patients with frontotemporal dementia,1 and was postulated to be caused by a loss of inhibition of the posterior visual cortex, thus intensifying visual experiences. In patients with PD, however, artistic productivity has been reported as either decreased2 or unchanged,3 and the development of a new artistic talent in PD has not been described previously. There are several possible explanations for the development of this patient’s new literary creativity. (1) Increased writing activity may be seen as hypergraphia in a number of neurological conditions, particularly when they affect the right hemisphere, and it is interesting to note that our patient’s symptoms started on the left side. However, hypergraphia usually has little or no meaningful content, whereas the production of poetry requires creative, organized, complex and unique thoughts and associations; (2) In a psychodynamic model, the new or enhanced artistic activity may be explained by the concept of sublimation. The socially unacceptable increase in libido would thus have been transformed to artistic productivity in order to neutralise this instinctual energy and to render it conflict-free and socially acceptable. However, the increase in libido did not result in a subjective conflict or cause social problems for this patient; (3) The patient’s artistic ability may have been previously impaired by a premorbid parkinsonian personality resulting from reduced dopaminergic input in the basal ganglia or other dopamine systems. Restoration of this balance by treatment with dopaminergic drugs may have revealed the underlying artistic ability. However, the existence and pathophysiological basis of a “parkinsonian personality” is controversial4,5 and, even if present, it is unlikely to have suppressed the development of an artistic ability for the duration of the patient’s entire previous life. There are a number of important artists in this century (e.g., Salvador Dali) who are known to have suffered from PD, making it unlikely that a premorbid parkinsonian personality prevents artistic activity many years before the onset of symptoms; (4) This patient’s newly developed literary productivity, which first appeared on dopaminer-
Movement Disorders, Vol. 16, No. 6, 2001
1176
CLINICAL/SCIENTIFIC NOTES
gic treatment, may have been a manifestation of drug-induced hypomania, which has been suggested to be due to chronic overstimulation of dopamine receptors in specific brain areas, such as the limbic system.6 Although no alterations of his mental state except an increase of libido were present at the time when poetic activity developed, a hypomanic syndrome developed on dopaminergic treatment later on, and a protracted course of mental state changes on dopaminergic treatment in PD is not unusual. Links between poetic creativity and a predisposition to hypomania are recognised7 but hypomania typically results in subjective overestimation of the patient’s own abilities without a realistic correlate (grandiosity) rather than objective ability of the quality seen in our patient. This makes it unlikely that drug-induced hypomania is the sole explanation for his newly developed literary talent; (5) Dopaminergic treatment in patients with PD8 has also been shown to result in improvement of cognitive function, particularly of frontal tasks. It is thus possible that enhancement of cognitive abilities due to dopaminergic treatment resulted in the creative activity seen in this patient. However, improvement of cognitive function in patients with PD treated with dopaminergic agents normally does not exceed premorbid levels of cognitive function, and deficits of cognitive function usually remain. Moreover, newly acquired skills have not been reported; (6) Treatment was initiated and maintained over many years with a combination of levodopa and the dopamine agonist lisuride, which is also a potent serotonin agonist and has been associated with higher rates of behavioural problems and more psychotic behaviour than other dopamine agonists. Serotonergic stimulation has also been linked to artistic performance, and was used by many artists in the 1960s and 1970s in order to enhance their artistic perceptions. Prolonged treatment with this serotonergic drug may therefore have contributed to the unmasking of the patient’s poetic talent; and (7) in analogy to the emergence of creativity in patients with frontotemporal dementia, the deficits in frontal lobe function, which were already present at the first testing 5 years after onset, may have led to a loss of inhibition of cortical function and an increase of creativity. The mild impairment on frontal lobe tasks may not have been sufficient to produce this new creative activity. However, dopaminergic treatment, through chronic overstimulation of specific dopamine receptors, and serotonergic stimulation may have unmasked specific functions such as a previously inhibited poetic talent in a patient with concomitant loss of inhibitory frontocortical function. We therefore speculate that the effect of dopaminergic and serotonergic drugs, either through cognitive enhancement, increased perception or a hypomanic syndrome, in addition to selective frontocortical dysfunction, led to the release of previously inhibited creative power in this patient.
References 1. Miller BL, Ponton M, Benson DF, Cummings JL, Mena I. Enhanced artistic creativity with temporal lobe degeneration. Lancet 1996;348:1744–1745. 2. Kierulf H. Johan Sebastian Welhaven’s parkinsonism. An insight into the history of literature. Tidsskr Nor Laegeforen. 1995;115: 3738–3739. 3. Lakke JP. Art and Parkinson’s disease. Adv Neurol 1999;80:471– 479. 4. Poewe W, Gerstenbrand F, Ransmayr G, Plorer S. Premorbid personality of Parkinson patients. J Neural Transm Suppl 1983;19: 215–224.
Movement Disorders, Vol. 16, No. 6, 2001
5. Hubble JP, Koller WC. The parkinsonian personality. Adv Neurol 1995;65:43–48. 6. Klawans HL, Moskovitz C, Nausieda PA, Weiner WJ. Levodopainduced dopaminergic hypersensitivity in the pathogenesis of psychiatric and neurologic disorders. Int J Neurol 1979;13:225–236. 7. Trimble MR, Charles Lloyd. Epilepsy and poetry. History of Psychiatry (in press). 8. Kulisevsky J, Garcia-Sanchez C, Berthier ML, Barbanoj M, Pascual-Sedano B, Gironell A, Estevez-Gonzalez A.. Chronic effects of dopaminergic replacement on cognitive function in Parkinson’s disease: a two-year follow-up study of previously untreated patients Mov Disord 2000;4:613–626.
Macrogol 3350/Electrolyte Improves Constipation in Parkinson’s Disease and Multiple System Atrophy Tobias E. Eichhorn, MD, and Wolfgang H. Oertel, MD* Department of Neurology, Philipps University Marburg, Marburg, Germany Abstract: We describe an open study of macrogol 3350 in 10 cases of constipated patients with Parkinson’s disease or multiple system atrophy. The agent produced a marked improvement in symptoms in all cases. © 2001 Movement Disorder Society. Constipation is a frequent symptom in patients diagnosed with Parkinson’s disease (PD) and multiple system atrophy (MSA). Besides physical measures (e.g., exercise, high fluid and fiber intake), lactulose and stimulant laxatives (sodiumpicosulfate, bisacodyl) and drugs which accelerate the gastrointestinal, especially colonic, transit (e.g., domperidone and cisapride) have been shown to alleviate constipation associated with PD.1 Psyllium was also demonstrated to increase stool frequency and stool weight in patients with PD without altering colonic transit or anorectal function. In many cases, however, these treatments provide only a transient relief3 or fail to work. We present an open label study on a new effective and reliable means to treat constipation in PD and MSA patients. Macrogol 3350 is a polyethylene glycol with a molecular weight of 3350. For use as a laxative, it is combined with electrolytes (NaHCO3, NaCl, and KCl). The galenic formulation is a white powder dispersed in water to a plasma–isotonic solution (Movicol, 13 g/bag; registered in Germany). Macrogol 3350 acts solely via osmotic action. Through its high water binding capacity, it increases the water content of the stool and its volume, thereby loosening its consistency. A solution of polyethylene glycol 3350/electrolyte has been shown to be more effective than lactulose in the treatment of opiate-induced constipation.4 Similar positive effects have been observed in the treatment of puerperal constipation.5 *Correspondence to: Wolfgang H. Oertel, MD, Neurologische Klinik der Philips-Universita¨t Marburg, Rudolf Bultmann strasse 8, D-35033 Marburg, Germany. E-mail:
[email protected] Received 24 October 2000; Revised 13 February 2001; Accepted 28 March 2001 Published online 6 November 2001. DOI 10.1002/mds.1211
CLINICAL/SCIENTIFIC NOTES
1177
TABLE 1. Clinical data of PD and MSA patients before and after macrogol treatment
Patient no.
Age (yr)
Stool freq. before macrogol 3350
Gender
PD 1 2
75 76
F M
1 per 2 wks 1 per wk
3 4 5 6 7 8
66 70 74 57 60 67
M F F M M M
2 per wk
