Charles M. Lepkowsky 1*
1Independent Practice, 1143 Deer Trail Lane, Solvang, California 93463, United States
*Corresponding Author: Charles M. Lepkowsky, PhD, Independent Practice, 1143 Deer Trail Lane, Solvang, California 93463, United States, E-mail: email@example.com
Received Date: July 10, 2018 Accepted Date: July 20, 2018 Published Date: July 30, 2018
Citation: Charles M. Lepkowsky (2018). Donepezil for α‐synuclein Constipation: An 18 Month Follow-Up. POJ Clin Case Rep. 1(1):1-4.
Copyright: © 2018 Charles M. Lepkowsky. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
In a series of case studies, four patients diagnosed with the α‐synuclein or “Lewy body” disorders Parkinson’s disease (PD) and Neurocognitive Disorder with Lewy Bodies (NCDLB) at different stages of disease progression were treated for the symptoms of constipation, obstipation, and impaction with the acetylcholinesterase inhibitor (AChEI) Donepezil. Initial findings indicated that the use of Donepezil was associated with significant symptom reduction. The symptom status of each of the four patients was reviewed at six and twelve month intervals, with no apparent reduction in bowel motility, nor the emergence of any new symptoms. After eighteen months, the symptom status of each of the four patients was again assessed. Evaluation of the results suggests that the AChEI Donepezil may have long-term benefit for relieving the symptoms of constipation, obstipation and impaction in patients with α‐synuclein disorders.
Keywords: Neurocognitive Disorder with Lewy Bodies, Parkinson’s disease, constipation, Donepezil, acetylcholinesterase inhibitor
In a series of case studies, four patients at different stages of disease progression diagnosed with α‐synuclein protein pathology, or “Lewy body” disorders including Parkinson’s disease (PD) and Neurocognitive Disorder with Lewy Bodies (NCDLB) were treated for the symptoms of constipation, obstipation, and impaction with the acetylcholinesterase inhibitor (AChEI) Donepezil . The impetus for the studies was a body of research documenting α‐synuclein protein impairment of the predominantly cholinergic neurotransmitter pathways in the myenteric plexus (MP) and the colonic submucosal plexus (CSMP) . α‐synuclein pathology in the MP and the CSMP impairs cholinergic function and thus bowel motility, leading to the observable symptoms of constipation, obstipation, and impaction [3-10].
Complicating the symptom picture, PD and NCDLB patients with significant Parkinsonian features are often prescribed L-dopa agents like Carbidopa-Levodopa (brand names include Sinemet and Stalevo) to preserve basic motor functions including gait and balance [11, 12]. Bowel immotility is included in the list of Carbidopa-Levodopa’s potential side effects . Often overlooked in the literature on PD and NCDLB, constipation, obstipation, and impaction have a significant negative impact on the quality of life for the patient, and complicate care provision [14, 15]. Perplexing to primary care providers and frustrating for patients, over-the-counter medications and other conventional forms of treatment have proven largely ineffective for treating the symptoms of constipation, obstipation and impaction in patients with α‐synuclein pathology .
Cholinergic Agonist Use in NCDLB and PD: Donepezil and Constipation
Historically, patients diagnosed with α‐synuclein disorders including PD and NCDLB have been prescribed acetylcholinesterase inhibitors (AChEIs) with the intention of mitigating α‐synuclein pathology cholinergic impairment [17-22]. An AChEI with demonstrated effectiveness in reducing cholinergic impairment without increasing Parkinsonian symptoms or producing new symptoms is Donepezil [23-28]. Donepezil has also been used with nongeriatric affective patients specifically to address constipation, increasing bowel contractions 477% in a population diagnosed with severe bowel immotility [29, 30].
Donepezil plays a dual role in reducing bowel immotility. As a specific, reversible acetylcholinesterase inhibitor, Donepezil limits the action of the acetylcholine-hydrolyzing enzyme acetylcholinesterase, effectively increasing acetylcholine levels and mitigating the symptoms of cholinergic impairment [31-33]. Donepezil also independently facilitates neuronal nicotinic acetylcholine receptors . Donepezil’s “dual action” has made it an historical drug of choice for mitigating symptoms of cholinergic impairment [22, 23, 25, 31, 34].
Based on Donepezil’s documented mitigation of cholinergic impairment and demonstrated effectiveness for reducing symptoms of constipation in nongeriatric affective patients, as well as increasing bowel contractions in a patients with severe bowel immotility, it was hypothesized that the use of Donepezil for patients with α‐synuclein pathology would mitigate symptoms of Lewy body cholinergic impairment in the MP and CSMP including constipation, obstipation, and impaction [23-30]. It was also hypothesized that Donepezil might mitigate bowel immotility associated with the use of Carbidopa-Levodopa, which is often prescribed to Lewy body patients exhibiting Parkinsonian features.
To assess Donepezil’s effectiveness in reducing α‐synuclein pathology-mediated bowel immotility, a case study was conducted. Four patients at varying levels of disease progression diagnosed with PD and NCDLB exhibiting symptoms of constipation, obstipation and/or impaction were orally administered Donepezil in daily doses varying from 5 to 10 mg. Two of the patients had been diagnosed with PD based on a series of MRI’s, neurological assessments, and CT scans. The other two patients had been diagnosed with NCDLB, based on scores on a series of MRI’s, CT scans, neurological evaluations, and scores on the Mini-Mental State Examination (MMSE), the Quick Dementia Rating System (QDRS), and the Lewy Body Composite Risk Score [35-37]. The patients were assessed before treatment, and then at intervals of two, four, and six weeks after treatment had begun. The same four patients were later assessed at intervals of six, twelve, and eighteen months.
For all four patients, assessment at two weeks, four weeks, and six weeks after the introduction of orally administered Donepezil (at 5 or 10 mg HS doses) indicated significant reductions in the symptoms of constipation, obstipation and impaction. At each interval there was no increase in existing symptoms, nor the emergence of new symptoms .
Using the methods described above to establish initial diagnosis, six months later, the same four patients were again assessed in a follow-up study. Although there had been progression of some α‐synuclein cognitive and movement pathology in two of the patients diagnosed with NCDLB, there was no increase in the symptoms of constipation, obstipation, or impaction, nor was there emergence of any new symptoms . One patient with NCDLB whose cognitive interference (short-term memory loss and difficulty with word-finding) had increased at the six month assessment had their daily dosage of Donepezil increased from 5 to 10 mg.
Another follow-up study using the same assessment procedures was conducted with the same four patients twelve months after the introduction of Donepezil. The NCDLB patient whose dosage of Donepezil had been doubled at six months demonstrated recovery of cognitive function (reductions in short-term memory loss and difficulty with word-finding). More pertinent to the original case study, assessment of the four patients showed no increase in the symptoms of constipation, obstipation, or impaction, no apparent progression of any other α‐synuclein symptoms, and no emergence of new symptoms .
The same four patients were again assessed eighteen months after the initial introduction of Donepezil, using the same system of evaluation as in the previous assessments. In each of the four patients, assessment indicated no increase in constipation, obstipation, or impaction; no progression of cognitive interference, movement disorders, or other α‐synuclein pathology; and no emergence of new symptoms.
Discussion and Conclusions
In four patients at varying levels of disease progression with PD and NCDLB, oral administration of Donepezil in daily doses varying from 5 to 10 mg was associated with significant reduction in the symptoms of constipation, obstipation and/or impaction. In none of the four patients was there progression of cognitive interference, movement disorders, or other α‐synuclein pathology, nor the emergence of new symptoms. Symptom reduction for constipation, obstipation and/or impaction was consistent over time, assessed at intervals of two, four and six weeks, and later, at intervals of six, twelve, and eighteen months [1, 38, 39].
The findings support the hypothesis that Donepezil might reduce cholinergic impairment in the ENS, specifically the MP and CSMP, with consequent reductions in the symptoms of constipation, obstipation and/or impaction. The findings also support the hypothesis that Donepezil might mitigate or counteract bowel immotility in patients using Carbidopa-Levodopa.
It appears that Donepezil achieves such symptom reduction through it “dual action:” in part, specifically and reversibly limiting the action of the acetylcholine-hydrolyzing enzyme acetylcholinesterase; and in part, by independently facilitating neuronal nicotinic acetylcholine receptors [31, 32, 34]. The combined effect of these two mechanisms is to effectively increase acetylcholine levels and mitigate the symptoms of cholinergic impairment .
The consistency of findings over an eighteen month period in patients diagnosed with degenerative α‐synuclein neurocognitive and movement disorders is also consistent with previous research demonstrating that Donepezil is effective for slowing or reversing cognitive symptom progression in α‐synuclein disorders, including short-term memory loss, difficulty with word-finding, hallucinations, and cognitive interference [17, 18, 19, 20, 21].
Further research is recommended following patients over an extended time frame to establish longitudinal outcomes, and using larger numbers of subjects matched for diagnosis, age, gender, and other variables.
Written consent was provided by each of the four patients described in the case studies to release the clinical information contained therein. Patient identifiers have been kept to a minimum.
The authors declare no conflict of interest.
- Lepkowsky CM. Donepezil for constipation in Lewy Body Diseases: Four case studies. Activitas Nervosa Superior. 2017;59(1):19-27. Doi:10.1007/s41470-017-0004-1.
- Lebouvier T, Neunlist M, Bruley desVarannes S, Coron E, Drouard A, N’Guyen J, et al. Colonic Biopsies to Assess the Neuropathology of Parkinson’s Disease and Its Relationship with Symptoms. PLoS One. 2010;5(9):e12728. Doi:10.1371/journal.pone.0012728.
- Wakabayashi K, Takahashi H, Takeda S, Ohama E, Ikuta F. Lewy Bodies in the enteric nervous system in Parkinson’s disease. Arch Histol Cytol. 1989;52(Supplement P):191-194.
- Braak H, de Vos RA, Bohl J, Del Tredici K. Gastric α-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett. 2006;396(1):67-72.
- Hawkes CH, Del Tredici K, Braak H. Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol. 2007;33(6):599-614.
- Minguez-Castellanos A, Chamorro CE, Escamilla-Sevilla F, Ortega-Moreno A, Rebollo AC, Gomez-Rio M, et al. Do α-synuclein aggregates in autonomic plexuses predate Lewy body disorders? a cohort study.Neurology. 2007;68(23):2012-2018. Doi:10.1212/01.wnl.0000264429.59379.d9.
- Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Björklund T, et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014;128(6):805-820.
- Iranzo A, Fernández-Arcos A, Tolosa E, Serradell M, Molinuevo JL, Valldeoriola F, et al. Neurodegenerative disorder risk in idiopathic REM sleep behavior disorder: study in 147 patients. PLoS One. 2014;9(2):e89741.
- Gjerløff T, Fedorova T, Knudsen K, Munk OL, Nahimi A, Jacobsen S, et al. Imaging acetylcholinesterase density in peripheral organs in Parkinson’s disease with 11C-donepezil PET. Brain. 2015;138(3):653-663. Doi:10.1093/brain/awu369.
- A J Porter, D A Wattchow, S J H Brookes, and M Costa. Cholinergic and nitrergic interneurones in the myenteric plexus of the human colon. Gut. 2002;51(1):70-75.
- Molloy S, McKeith IG, O’Brien JT, Burn DJ. The role of levodopa in the management of dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 76(9):1200-1203.
- Lepkowsky CM. Medications Linked to Cognitive Impairment in Older Adults. Practice Innovations. 2016;1(4):253-264. Doi:10.1037/pri0000033.
- Dupont Pharmaceuticals: Product Information: Sinemet CR (carbidopa-levodopa), Wilmington, DE, 2016.
- Jost WH, Schimrigk K. Constipation in Parkinson’s disease. Klinische Wochenschrift. 1991;69(20):906-909.
- Kaye J, Gage H, Kimber A, Storey L, Trend P. Excess burden of constipation in Parkinson’s disease: a pilot study. Mov Disord. 2006;21(8):1270-1273. Doi:10.1002/mds.20942.
- Phillips C, Polakoff D, Maue SK, Mauch R. Assessment of Constipation Management in Long-Term Care Patients. J Am Med Dir Assoc. 2001;2(4):149-154.
- Kosaka K, Oyanagi S, Matsushita M, Akira Hori, Shoji Iwase. Presenile dementia with Alzheimer-, Pick and Lewy-body changes. Acta Neuropathologica. 1976;36(3):221-233.
- Perry EK, Smith CJ, Court JA, Perry RH. Cholinergic nicotinic and muscarinic receptors in dementia of Alzheimer, Parkinson and Lewy body types. J Neural Transm Park Dis Dement Sect. 1990;2(3):149-158.
- McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996;47(5):1113-1124.
- McKeith IG. Spectrum of Parkinson’s disease, Parkinson’s dementia, and Lewy body dementia. Neurol Clin. 2000;18(4):865-902.
- Perez-Lloret S, Barrantes FJ. Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson’s disease. NPJ Parkinsons Dis. 2016;2:16001. Doi:10.1038/npjparkd.2016.1.
- Lepkowsky CM. Mechanisms of α‐synuclein pathology and treatment in the enteric nervous system. International Journal of Genetic Science. 2017;4(1):1-6. Doi:10.15226/2377-4274/4/1/00116.
- Bosboom JLW, Stoffers D, Wolters ECh. Cognitive dysfunction and dementia in Parkinson’s disease. J Neural Transm (Vienna). 2004;111(10):1303-1315.
- Birks JS. Cochrane Database Syst Rev 2006 Jan 25; (1): CD005593 – Cholinesterase inhibitors for Alzheimer’s disease. psychoneuro. 2006;32(11):508-508. Doi: 10.1002/14651858.CD005593.
- Minett TS, Thomas A, Wilkinson LM, Daniel SL, Sanders J, Richardson J, et al. What happens when donepezil is suddenly withdrawn? An open label trial in dementia with Lewy bodies and Parkinson’s disease with dementia. Int J Geriatr Psychiatry. 2003;18(11):988-993.
- Mori E, Ikeda M, Kosaka K, Donepezil-DLB Study Investigators. Donepezil for dementia with Lewy bodies: a randomized, placebocontrolled trial. Ann Neurol. 2012;72(1):41-52.
- Etsuro Mori, Manabu Ikeda, Reiko Nagai, Kazutaka Matsuo, Masaki Nakagawa, Kenji Kosaka. Long-term donepezil use for dementia with Lewy bodies: results from an open-label extension of Phase III trial. Alzheimers Res Ther. 2015;7(1):5. Doi: 10.1186/s13195-014-0081-2.
- Rolinski M, Fox C, Maidment I, McShane R. Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson’s disease dementia and cognitive impairment in Parkinson’s disease. Cochrane Database Syst Rev. Dementia and Cognitive Improvement Group. 2012;14(3):CD006504. Doi:10.1002/14651858.CD006504.pub2.
- Jacobsen FM, Comas-Díaz L. Donepezil for psychotropic-induced memory loss. J Clin Psychiatry. 1999;60(10):698-704.
- Broad J, Kung VW, Boundouki G, Aziz Q, De Maeyer JH, Knowles CH, et al. Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility. Br J Pharmacol. 2013;170(6):1253-1261. Doi:10.1111/bph.12397.
- Davidsson P, Blennow K, Andreasen N, Eriksson B, Minthon L, Hesse C. Differential increase in cerebrospinal fluid-acetylcholinesterase after treatment with acetylcholinesterase inhibitors in patients with Alzheimer’s disease. Neurosci Lett. 2001;300(3):157-160.
- Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J. Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging. 2004;21(7):453-478.
- Parsons CG, Danysz W, Dekundy A, Pulte I. Memantine and cholinesterase inhibitors: Complementary mechanisms in the treatment of Alzheimer’s disease. Neurotox Res. 2013;24(3):358-369. Doi:10.1007/s12640-013-9398-z.
- Di Angelantonio S, Bernardi G, Mercuri NB. Donepezil modulates nicotinic receptors of substantia nigra dopaminergic neurons. Br J Pharmacol. 2004;141(4):644-652. Doi:10.1038/sj.bjp.0705660.
- Folstein MF, Folstein SE, McHugh PR. Mini-mental state: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198.
- Galvin J. The Quick Dementia Rating System (QDRS): A rapid dementia staging tool. Alzheimers Dement (Amst). 2015;1(2):249-259. Doi:10.1016/j.dadm.2015.03.003.
- Galvin J. Improving the clinical detection of Lewy body dementia with the Lewy body composite risk score. Alzheimers Dement (Amst). 2015;1(3):316-324. Doi:10.1016/j.dadm.2015.05.004.
- Lepkowsky CM. Donepezil for Lewy Body constipation: A six month follow-up. J Mol Genet Med. 2017;11:287. Doi: 10.4172/1747-0862.1000287.
- Lepkowsky CM. Donepezil for Constipation in Lewy body disease: A twelve month follow-up. J Mol Genet Med. 2018;12(1):337. Doi: 10.4172/1747-0862.1000337.