Parkinsonism and Related Disorders 86 (2021) 84–90

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Parkinsonism and Related Disorders

journal homepage: www.elsevier.com/locate/parkreldis

Short communication

Levodopa/dopa decarboxylase inhibitor associated microscopic colitis: An

under-recognized drug reaction
Tien Lee Ong a, Shoaib Dal a, Andrew J. Martin a, c, Florence CF. Chang a, b, Laura J. Williams a,
Sangamithra Babu a, c, Neil Mahant a, Hugo Morales-Briceno a, Naomi Fletcher d,
Jane Nankervis e, Melissa Robbie f, Victor S.C. Fung a, b, *
a
Movement Disorder Unit, Neurology Department, Westmead Hospital, Corner Darcy and Hawkesbury Road, Westmead, NSW 2145, Australia
b
Sydney Medical School, University of Sydney, Sydney, NSW, Australia
c
Neurology Department, Blacktown Hospital, 18 Blacktown Rd, Blacktown, NSW, 2148, Australia
d
ACT Pathology, Anatomical Pathology Department, Building 10 Canberra Hospital, Gilmore Cres, Garran ACT, 2606, Australia
e
Department of Anatomical Pathologist, Southern ImL Pathology, 35 Denison St Wollongong, Australia
f
Capital Pathology, Canberra, PO Box 20, Woden ACT, 2606, Australia

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Microscopic colitis is a form of inflammatory bowel disease characterized by profuse non-bloody
Microscopic colitis watery diarrhea. Macroscopic abnormality is not present on colonoscopy, and it requires biopsy for diagnosis.
Lymphocytic colitis Few cases have been attributed to levodopa/dopa-decarboxylase inhibitor therapy.
Collagenous colitis
Method: A retrospective cohort study of 21 patients on levodopa/benserazide and one patient on levodopa-
Carbidopa
Benserazide
carbidopa intestinal gel with clinically suspected or biopsy proven microscopic colitis.
Results: All 21 patients on oral levodopa/benserazide had resolution of diarrhea with cessation of the medication.
Four patients discontinued levodopa permanently. Two were rechallenged with levodopa/benserazide without
symptom recurrence. One patient on oral levodopa/carbidopa developed diarrhea only with intermittent
dispersible levodopa/benserazide. 14 were switched to levodopa/carbidopa with resolution of diarrhea in 9 but
symptom recurrence in 5. One patient on oral levodopa/benserazide developed profuse diarrhea when switched
to levodopa-carbidopa intestinal gel. Of 7/22 patients who had colonoscopy and biopsy, 5 had histopathological
proven microscopic colitis.
Conclusion: levodopa/dopa-decarboxylase inhibitor induced microscopic colitis may be more common than
previously suspected, with the potential to affect treatment compliance and therapeutic options.

1. Introduction
Microscopic colitis is a form of inflammatory bowel disease, pre­
senting with watery and non-bloody diarrhea [1,2]. Several scoring
systems have been proposed to allow clinical diagnosis, based on various
risk factors and symptoms, but diagnosis can only be unequivocally
established by biopsy of the colonic mucosa demonstrating character­
istic histological changes [3–6]. The natural course of microscopic co­
litis is variable and is typically characterized by alternating
asymptomatic and diarrheal phases [3,4]. The diarrhea is of sudden
onset, peaking within a few days [7] and is often mistakenly attributed
to infectious causes [8]. The disease course can be chronic, intermittent,
or recurrent, and may be associated with abdominal cramping, weight
loss, incontinence, and nocturnal symptoms [1,3,8]. On average, the
patient may have six bowel motions per day but more than 20 is not
unusual and symptoms may present for many months or years before a
diagnosis is made [8]. Most studies published on microscopic colitis are
retrospective in nature, but they consistently report a relatively benign
course with the majority of patients undergoing clinical and histological
remission, although some may suffer from biopsy proven disease relapse

* Corresponding author. Neurology Westmead Hospital, Westmead, NSW, 2145, Australia.

E-mail addresses: ongtienlee@gmail.com (T.L. Ong), Shoaib.Dal1@health.nsw.gov.au (S. Dal), amar6353@uni.sydney.edu.au (A.J. Martin), Florence.Chang@
health.nsw.gov.au (F.CF. Chang), laurajane.williams@health.gov.nsw.com.au (L.J. Williams), mithrababu@hotmail.com (S. Babu), nmahant@gmail.com
(N. Mahant), moralhu@gmail.com (H. Morales-Briceno), Naomi.Fletcher@act.gov.au (N. Fletcher), Jane.Nankervis@southernpath.com.au (J. Nankervis), Melissa.
Robbie@capitalpath.com.au (M. Robbie), vscfung@ozemail.com.au (V.S.C. Fung).

https://doi.org/10.1016/j.parkreldis.2021.03.031
Received 8 September 2020; Received in revised form 20 March 2021; Accepted 28 March 2021
Available online 20 April 2021
1353-8020/© 2021 Elsevier Ltd. All rights reserved.
T.L. Ong et al.
[8]. Rapid symptom improvement within 1–2 days has been reported in
a subgroup of patients with drug-induced disease [8,9].
The histological hallmark of microscopic colitis is increased intra­
epithelial lymphocytes [1,3], with normal endoscopic colonic lining
appearance. It is divided into two forms: lymphocytic colitis and
collagenous colitis [1,3]. In both subtypes, there is inflammation of
lamina propria but the key distinguishing histological marker is that
collagenous colitis has a broad subepithelial collagen band, >10μm in
thickness beneath the surface epithelium [3,10], whereas in lympho­
cytic colitis, there are more than 20 intraepithelial lymphocytes per 100
epithelial cells [2].
The increased number of T cells in the epithelium suggests an
immunological response triggered by a luminal toxin(s), including
medications, infectious agents, and bile salts [1]. Multiple drugs have
also been implicated, such as nonsteroidal anti-inflammatory drugs and
statins, although the exact mechanism underlying these associations is
unknown and systematic clinical data on the effects of withdrawal and
rechallenge with suspected drugs are lacking [1,3]. Thus, absolute
causality cannot always be inferred from some reported drug associa­
tions [3].
There are limited reports of microscopic colitis in the setting of
levodopa-containing therapies in Parkinson’s disease (PD). The first
report was published in 2000, in a patient taking levodopa/benserazide
[11]. Subsequently three patients were reported to develop biopsy
proven lymphocytic colitis following the addition of entacapone to their
existing levodopa/carbidopa therapy [12]. A clinical study found that
diarrhea occurred in 10% of patients treated with entacapone, generally
presenting within 4–12 weeks of treatment initiation, but sometimes
appearing as early as in the first week or conversely, after many months
on treatment [13]. There are few post-marketing reports of proven
lymphocytic colitis associated with entacapone where diarrhea resolu­
tion or improvement upon entacapone withdrawal has been docu­
mented [12–14]. To our knowledge, there is no paper published on the
association of microscopic colitis with dopaminergic medications other
than from levodopa-containing preparations.
The aim of this study was to (i) identify the demographic and clinical
characteristics of our patient cohort with probable or proven micro­
scopic colitis associated with levodopa/dopa decarboxylase therapy; (ii)
determine other possible associated risk factors; and (iii) document the
response to intervention (i.e., cessation of ongoing therapy, using
alternative levodopa/dopa-decarboxylase inhibitor).
2. Methods
Patients were identified by searching our movement disorder patient
record system for keywords “colitis,” “lymphocytic colitis,” “micro­
scopic colitis,” and “levodopa induced colitis.” Resulting records were
reviewed and 22 patients were identified who developed severe diarrhea
whilst treated with levodopa/dopa-decarboxylase inhibitor from 2008
to 2019 and were suspected of having microscopic colitis (patients pre-
dating 2008 were not available). Among the 22 patients, 17 had clini­
cally probable microscopic colitis and 5 had pathologically proven dis­
ease. 21 patients first developed symptoms with oral levodopa/
benserazide, and one patient had symptoms with levodopa-carbidopa
intestinal gel. The Naranjo algorithm was used to estimate the causal­
ity of the suspected adverse drug reaction in each patient (Table 1) [15].
3. Results
Nineteen patients were identified by searching the clinical database
of one of the authors (VF). The diagnosis of microscopic colitis was
suspected in these patients due to persistent loose or watery, non-bloody
diarrhea experienced during treatment with levodopa/dopa-
decarboxylase inhibitor, especially if onset was within days or weeks
of initiating the therapy, or if there was no alternative explanation such
as infection. Three patients seen more recently (2018–2020) were
85
Parkinsonism and Related Disorders 86 (2021) 84–90
identified because of increased awareness of this diagnosis in our
Movement Disorder Unit during execution of the present study.
The patients were taking levodopa/dopa-decarboxylase inhibitor for
PD (n = 13), progressive supranuclear palsy (n = 2), multiple system
atrophy (n = 2), dystonia (n = 2), frontotemporal dementia with
Parkinsonism (n = 1), Holmes tremor (n = 1) and Fahr’s disease (n = 1).
Twenty-one patients were taking levodopa/benserazide and one was on
levodopa-carbidopa intestinal gel when they symptoms emerged. No
patient was receiving entacapone.
The mean Naranjo score was 6, which equates to a probable adverse
reaction. Overall, the Naranjo score was in the definite range (>9) for 2
patients, probable range (5–8) for 19 patients and possible range (1–4)
for 1 patient.
3.1. Patients who developed microscopic colitis during oral levodopa/
benserazide therapy
Twenty-one patients in our cohort developed microscopic colitis
whilst on levodopa/benserazide (6 males, 15 females)(Table 1). Median
age at symptom onset was 72 years (41–94 years) with median levo­
dopa/benserazide dose of 300 mg daily (50–800 mg). Two patients had
a previous diagnosis of thyroiditis and one had esophageal carcinoma.
None of our patients reported altered bowel habit unexpected for un­
derlying disease course, prior to development of, or after resolution of,
microscopic colitis. Two had a history of Blastocystis hominis infection
and one patient had a history of Clostridium difficile toxin detected in
stool; all three patients were treated and cleared of infection in repeated
stool samples, but diarrhea persisted. The duration of levodopa therapy
before diarrhea onset varied, ranging from 2 days to 5 years. Seventy six
percent of patients (16/21) complained of watery diarrhea whilst the
remainder had loose stools. Two patients suffered significant weight
loss. Bowel incontinence was reported in two patients and one patient
had mucous discharge. Two patients experienced cramping abdominal
pain.
All 21 patients were asked to suspend levodopa/benserazide until
diarrhea had resolved for at least 1 week. The subsequent management
of these patients’ levodopa therapy and response to switching to levo­
dopa/carbidopa treatment and/or re-challenge with levodopa/benser­
azide is summarized in Fig. 1. Resolution of diarrhea typically occurred
within days of treatment cessation. Four patients discontinued levodopa
permanently. Two patients were rechallenged with levodopa/benser­
azide and had no diarrhea recurrence. One patient who developed
diarrhea following the addition of intermittent dispersible levodopa/
benserazide to his regular oral levodopa/carbidopa was re-challenged 1
month later with immediate symptom recurrence within 24 h. The
remaining 14 patients were switched to levodopa/carbidopa and 5
(35%) suffered recurrence of diarrhea. Amongst these, 2 ceased levo­
dopa therapy completely whereas the other three reattempted levo­
dopa/benserazide with relapse of diarrhea in two. 9/14 (64%) patients
were successfully switched to a higher or equivalent dose of levodopa/
carbidopa without diarrhea. However, four patients were eventually
rechallenged with levodopa/benserazide due to suboptimal control of
their parkinsonian symptoms with levodopa/carbidopa, and three
experienced diarrhea recurrence. Patient-11 experienced an increase in
“off” Parkinsonian symptoms with an increase in left arm stiffness dur­
ing microscopic colitis illness. In all other patients however, the acute
colitis illness did not impact their motor symptoms.
Overall, 5/21 (26%) patients who developed diarrhea with levo­
dopa/benserazide had similar symptoms with levodopa/carbidopa. All
patients ultimately reported symptom resolution following either
cessation of levodopa/dopa-decarboxylase inhibitor or switching to a
different levodopa preparation.
7/21 patients underwent colonoscopy with mucosal biopsy, five of
whom (71%) had features of microscopic colitis (Fig. 2). The biopsies
revealed increased numbers of intraepithelial lymphocytes with asso­
ciated loss of surface mucin and thickening of the subepithelial
T.L. Ong et al. Parkinsonism and Related Disorders 86 (2021) 84–90

Table 1
Demographic and management of patients with diarrhea on Levodopa/DDCI.
Pt, Diagnosis Other medications Clinical feature Total dose of Diarrhea Re- Diarrhea Complete Naranjo
Sex, LD/B at recur with challenge recur with cessation scale
Age diarrhea onset LD/C LD/B LD/B re- levodopa/ #
(mg) challenge Outcome

1, F, Dystonia None Watery stool 600 No – Yes/Gabapentin 7

74
2, F, PD Rasagiline, pramipexole Watery stool 300 No – Yes/ 7
60 Pramipexole,
rasagiline
3, F, PD None Watery stool 300 Yes Yes Yes Yes/Safinamide, 9
74 macuna
pruriens
4, F, PD None Watery stool 300 No Yes Yes No/Continue 9
74 LD/C
5, M, PD Sotalol, spironolactone, Loose stool 600 – – – Yes/ 7
74 budesonide/fomoterol - Abdominal cramps Amantadine
inhaler, melatonin - Nocturnal
symptoms
6, F, Holmes Oxybutynin, vitamin D Watery stool 300 Yes No – Yes/Botulinum 6
54 tremor toxin
7, F, FTD with Quetiapine, venlaflaxine Watery stool, 200 Yes Yes No No/Continue 5
67 parkinsonism weight loss 19 kg LD/B
8, F, PD Rasagiline Water stool, mucous 300 No Yes No No/Continue 5
73 LD/B
9, F, Dystonia Warfarin, metoprolol, Watery stool 20 800 Yes No No/Continue 5
41 atorvastatin, times a day LD/B
desvenlafaxine,
alprazolam, agomelatine,
levonorgestrel
10, F, PD Rasagiline, pramipexole Loose stool, weight 300 Yes No No/Continue 5
65 loss 9 kg LD/B
11, PD Tadalafil, rasagiline Watery stool 200 No Yes Yes No/Continue 8
M, LD/C
68
12, F, PD Insulin aspart, celecoxib, Loose stool, bowel 300 No Yes Yes No/Continue 8
71 magnesium, pregabalin, incontinence LD/C
vitamin C, venlafaxine,
metformin, L-thyroxine,
pantoprazole
13, F, PSP Telmisartan, pantoprazole Watery stool 300 Yes No – Yes/Botulinum 6
80 toxin
14, PD Rasagiline, memantine, Watery stool 300 No No – No/Continue 6
M, acetylsalicylic acid, LD/C
83 colchicine, atorvastatin
15, Fahr None Watery stool 3 to 4 600 Yes Yes Yes No/Continue 8
M, syndrome times a day, bowel LD/C
60 incontinence
16, PD None Loose stool 300 No No – Yes/Deceased 3
M,
77
17, F, PD Candesartan, citalopram, Watery stool 6 times 300 No No – No/Continue 6
85 coloxyl, felodipine, a day LD/C
brinzolamide, latanoprost,
rivastigmine
18, F, MSA Rasagiline Watery stool, 300 No No – No/Continue 6
71 abdominal cramps LD/C
19, F, MSA None Watery stool 300 No No – No/Continue 6
60 LD/C
20, F, PD Telmisartan/amlodipine Watery stool, 300 No No No/Continue 7
94 nocturnal LD/C
symptoms
21, PD LD/C, sc apomorphine Watery stool 50 mg No Yes Yes No/Continue 8
M, dispersible LD/C, sc
72 tablet apomorphine
22, F, PSP Acetylsalicylic acid, Watery stool, bowel 1804 LCIG No Yes Yes No/Continue 6
75 rosuvastatin, clonidine, incontinence, LD/B
amlodipine, rabeprazole, nocturnal
amitriptyline, amantadine symptoms, mucous

M: male, F: female, MC: microscopic colitis, Fig: figure, NA: not available, PD: Pakinson’s disease, MSA: multiple system atrophy- Parkinson, PSP: progressive
supranuclear palsy, sc: subcutaneous. LD/B: levodopa/benserazide, LD/C: Levodopa/carbidopa, LCIG: levodopa carbidopa intestinal gel, #Naranjo scale: ≥9 =
definite ADR, 5–8 = probable, 1–4 = possible, 0 = doubtful. pt 1 - 5: biopsy proven microscopic colitis. pt 6 - 7: normal colonic biopsy.

86
T.L. Ong et al.
Fig. 1. Illustration of treatment adjustment in 21 patients with LD/B and 1 patient on LCIG who developed profuse diarrhea while on treatment.
Legend: pt(s): patient(s), LD/B: Levodopa/
Benserazide, LD/C: Levodopa/
Carbidopa, LCIG: levodopa carbidopa intestinal gel, bold numbers: patients with biopsy proven MC.
membrane. The remaining two patients had no definite pathological
findings. Of these, one patient remained off levodopa therapy, and the
other developed recurrent diarrhea when switched to levodopa/carbi­
dopa but was then able to tolerate a re-challenge with levodopa/
benserazide.
Some patients were prescribed additional therapies for symptomatic
treatment. Patient-6 was given prednisolone and salazopyrine for a
week, but diarrhea persisted. Patient-7 was given a course of mesalazine
without benefit. Both these patients were treated for a presumptive
diagnosis of ulcerative colitis or Crohn’s disease rather than being put on
these agents as a treatment for suspected microscopic colitis. Patient-15
had minor diarrhea improvement on loperamide.
Patient-21 was receiving levodopa/carbidopa 100 mg 2 hourly and
subcutaneous apomorphine injections. He was prescribed 50/12.5 mg of
levodopa/benserazide dispersible tablet as needed to his regime for
beginning of dose off periods with apomorphine. He developed profuse
diarrhea 3 weeks after initiating the medication which then resolved
within a day of ceasing levodopa/benserazide. He tried the medication
again a month later but had immediate recurrence of post-dose diarrhea
within 24 h and had therefore ceased it permanently.
3.2. Patient who developed microscopic colitis during levodopa-carbidopa
intestinal gel therapy
Patient-22 was a 75-year-old female with progressive supranuclear
palsy who had a trial of naso-jejunal levodopa-carbidopa intestinal gel
therapy for severe freezing of gait. She did not have diarrhea whilst on
oral levodopa/benserazide for the preceding 4 years but developed se­
vere watery stools with fecal incontinence, nocturnal symptoms, and
mucous discharge 6 days after equivalent dose of levodopa-carbidopa
intestinal gel initiation. Diarrhea resolved three days after the treat­
ment was withheld. A week later, she was rechallenged with the therapy
and again developed profuse diarrhea overnight. The treatment was
abandoned, and her symptoms did not recur when she was reverted to
87
Parkinsonism and Related Disorders 86 (2021) 84–90
oral levodopa/benserazide. Colonoscopy was not performed as there
was no symptom recurrence. Her Naranjo algorithm score was 6.
4. Discussion
The concept that microscopic colitis may be drug-induced has been
proposed since the 1990s1. Drugs or their metabolites might have direct
pharmacological effects in the colon or render indirect effects by altering
the gastrointestinal flora. Although diarrhea is listed in the product in­
formation as a potential side effect of levodopa/benserazide and levo­
dopa/carbidopa, the exact mechanisms remain poorly understood. To
date, there has been only a single case report of microscopic colitis in
association with levodopa/benserazide [11] and in four patients with
levodopa/carbidopa and entacapone [14]. Here, we report over 22
additional patients with biopsy proven or clinically probable micro­
scopic colitis occurring with levodopa/benserazide, levodopa/carbi­
dopa without entacapone, and levodopa-carbidopa intestinal gel
monotherapy.
We performed biopsies in seven patients (all on levodopa/benser­
azide) and of those, five had histologically proven microscopic colitis
(Fig. 2) whilst the remaining two had no definite pathological finding. It
is recognized that microscopic colitis may be missed on a single biopsy
as it can have patchy colonic distribution [1]. The endoscopic appear­
ance of the colonic mucosa is typically normal in microscopic colitis,
thus in patients where there is a high index of suspicion, multiple
random colonic biopsies should be collected. The yield is highest from
biopsies of transverse colon (83%), right colon (70%) and lowest from
the rectosigmoid (66%) [1,10]. In our study, the diagnosis of micro­
scopic colitis was made on clinical grounds and histological confirma­
tion was only performed in a subset of patients. The likelihood of the
diagnosis of levodopa/dopa-decarboxylase inhibitor induced micro­
scopic colitis being correct was estimated using the Naranjo algorithm.
The accuracy of this system is supported by patients 3 and 4, whose
clinically based scores fell into the ‘definite’ category, and who both had
T.L. Ong et al.
biopsy proven microscopic colitis. Although 15/22 patients did not
undergo colonoscopy, the mean Naranjo score of our cohort was 6,
indicating a ‘probable’ association [15].
The risk factors for microscopic colitis are older age, female sex,
presence of other autoimmune diseases, medication use and malignancy
[1], many of which were present in our cohort (Table 1). Patient-7 was
treated for Clostridium difficile during the course of chronic diarrhea
lasting 3 years; the organism has been implicated in the development of
microscopic colitis [1,2]. Two patients were treated for Blastocystis
hominis, a unicellular protozoan that can be found in irritable bowel
syndrome, inflammatory bowel disease and even in healthy subjects; its
role in the pathogenesis of microscopic colitis remains unknown [16].
Amongst them, only patient-14 on acetylsalicylic acid and patient-12 on
celecoxib are listed as drugs with high and intermediate likelihood to
cause microscopic colitis [2]. The patients continued with these medi­
cations during and after resolution of diarrhea.
Our cohort of patients shows heterogeneity in duration of medication
exposure and dosage of levodopa/benserazide at symptom onset. The
variable clinical response to therapy adjustments and to reintroduction
of levodopa/benserazide, raise the question whether the levodopa or
benserazide component are implicated in the development of
88
Parkinsonism and Related Disorders 86 (2021) 84–90
Fig. 2. A1 (Pt 1 in Table 1): Medium power
view of colon shows the lamina propria is
expanded by increased number of chronic
inflammatory cells. A2: High power view of
colon shows early collagen thickening with
increased lymphocyte in surface epithelium
and lamina propria. The crypt shows non-
specific reactive changes with some reduc­
tion in mucin content.
B1
(Pt 2 in Table 1): High power view of right
colon biopsy showing a lymphoplasmacytic
infiltrate within the lamina propria and
thickened subepithelial collagen plate.
Lymphocytes are seen within the surface
epithelium and crypt epithelium and there is
patchy loss of surface mucin. (H&E x20). B2:
High power view of left colon biopsy
showing a lymphoplasmacytic infiltrate
within the lamina propria and thickened
subepithelial collagen plate. Lymphocytes
are seen within the surface and crypt
epithelium and there is patchy loss of surface
mucin. (H&E x20).
C1
(Pt 3 in Table 1): High power view of colon
shows diffuse moderate increase in inflam­
matory cells in the surface and crypt
epithelium and lamina propria. The inflam­
mation includes neutrophils, eosinophils,
plasma cells and lymphocytes. Some
sloughing of surface epithelium is seen with
variable thickening of subepithelial collage­
nous plate. C2: The figure shows large colon
Masson stain for collagen table and the
finding is consistent with collagenous colitis.
microscopic colitis. However, such variation in timing of symptom onset
can also be seen with entacapone [12,13]. It is worth mentioning that
one of our patients who developed diarrhea with both levodopa/­
benserazide and levodopa/carbidopa did not have similar symptom with
Mucuna pruriens. A 16-week randomized, cross over pilot study pub­
lished in 2018 on daily intake of Mucuna pruriens also did not find
diarrhea as one of the common side effects but rather, those patients had
nausea [17]. Interestingly, patient-22 did not have symptoms whilst on
high dose oral levodopa/benserazide for 4 years but developed severe
diarrhea with equivalent dose of levodopa-carbidopa intestinal gel
therapy. The inconsistencies in temporal course and response of diar­
rhea with levodopa/dopa-decarboxylase inhibitor in some patients e.g.,
onset within days or after many years on therapy and the dose inde­
pendent response in certain patients, suggest the possibility of an idio­
syncratic drug reaction (IDR). Several papers have described similar
responses in other patients with a suspected IDR based mechanism for
development of microscopic colitis with drugs like non-steroidal anti-­
inflammatory drugs and lansoprazole [10]. For these two medications, a
dose dependent effect has similarly not been demonstrated for the
development of microscopic colitis [2]. One characteristic feature of
idiosyncratic drug reactions is a delay between starting the drug and the
T.L. Ong et al.
onset of symptoms [18]. The risk increases with age and the presence of
concomitant infection is a predisposing factor [18]. In a case series
published on lansoprazole associated microscopic colitis, the diarrhea
resolved with discontinuation of medication and recurred when it was
rechallenged [19]. However, when the patients were given rabeprazole
which has similar cysteine 321 binding site, diarrhea did not recur [9].
Such occurrence resembled our observation in which more than 2/3 of
our patients with levodopa/benserazide associated microscopic colitis
showed resolution of symptoms with either permanent cessation of
levodopa therapy (7/21 patients) or switching to a levodopa/carbidopa
preparation (9/21). Out of the 21 patients who developed diarrhea with
levodopa/benserazide, only 4 tolerated the drug reintroduction. It is
also plausible that medications might act as a trigger for the colitis in
predisposed hosts which then evolves independently, and in these pa­
tients, diarrhea may persist even with medication withdrawal without
complete resolution of colitis. As such, treatment with antidiarrheals
may be required. Fortunately, all our patients had diarrhea resolution
with withdrawal and/or substitution of levodopa/dopa-decarboxylase
inhibitor. This treatment approach was from our experience in previ­
ous patients with suspected microscopic colitis, not included as part of
this report as they pre-dated the records from the database.
Our study has several limitations. Firstly, it is a retrospective analysis
and data from medical records were subjected to recording bias. There is
also ascertainment bias in the study as generally our patients are given
levodopa/benserazide as initial levodopa-containing therapy rather
than levodopa/carbidopa. It is therefore difficult to know from our data
whether microscopic colitis is truly more common with levodopa/ben­
serazide versus levodopa/carbidopa, however it is of note that 5/14
patients who switched to a levodopa/carbidopa preparation develop
recurrent diarrhea. It is also of interest that one of our patients taking
only occasional doses of levodopa/benserazide in a dispersible 50/12.5
mg preparation nevertheless developed microscopic colitis. Medication
dose reduction was not attempted in our patients; therefore, we are
unable to determine if dose reduction can improve diarrheal symptoms.
Not all patients had colonoscopy or biopsy performed. We acknowledge
the heterogeneity of our patient population however it indicates that
microscopic colitis is not confined to Parkinson disease and can poten­
tially affect anyone prescribed levodopa/dopa-decarboxylase inhibitor
therapy. Although we cannot exclude the possibility of polypharmacy as
a synergistic effect in triggering the onset of colitis, 27% (6/22) of pa­
tients were not taking any other medications and 3/6 of these had biopsy
proven microscopic colitis. Therefore, in these patients there was no
possible medication that could be implicated other than their levodopa/
dopa-decarboxylase inhibitor.
Our study is unable to provide an explanation of the underlying
mechanism of microscopic colitis in relation to levodopa/dopa-
decarboxylase inhibitor therapy, as little is known on the exact patho­
physiology of the disease. The aim of our study is instead to highlight its
occurrence and variable nature of the associated colitis; both in the time
of symptom onset and response to the change of dopa-decarboxylase
inhibitor which has not received adequate attention.
Regarding management, we recommend a stepwise approach to
patients who develop diarrhea whilst on levodopa/dopa-decarboxylase
inhibitor therapy. Initial management should ensure adequate hydra­
tion and avoidance of electrolyte disturbances. A thorough assessment
for other precipitants and reversible insults should be performed and,
ideally, the expert opinion of a gastroenterologist sought. If other causes
are excluded, microscopic colitis should be considered as a diagnostic
possibility. If clinically significant, a trial of substitution with an alter­
nate levodopa/dopa-decarboxylase inhibitor agent at an equivalent dose
should be considered as the first line of management. Close follow up by
the treating neurologist is recommended and clinical response should be
evaluated after 10–14 days. If no clinical improvement is seen, endo­
scopic examination should be arranged [2]. For patients with severe
diarrhea who fail a trial of substitution, rarely a trial of withdrawal of all
levodopa/dopa-decarboxylase inhibitor may need to be considered
89
Parkinsonism and Related Disorders 86 (2021) 84–90
before endoscopy, but close observation is recommended and rescue
with other dopaminergic agents may be required. For endoscopically
proven microscopic colitis that does not improve with withdrawal of the
suspected drug, or in cases whereby withdrawing or replacing the drug
is not feasible for medical reasons, short term budesonide may be
beneficial as recommended by evidence-based medicine published by
both European and Spanish Microscopic Colitis group and American
Gastroenterology Association [3,10]. Prednisolone, mesalazine, chole­
styramine and bismuth have been anecdotally trialed with some success,
but the recommendation is not evidenced based [2,3,10].
The cases here illustrate that early recognition and prompt medica­
tion withdrawal, or preparation substitution, may have a significant
beneficial and early impact on patients’ diarrheal symptoms.
5. Conclusions
We propose that microscopic colitis should be suspected in any PD
patient with unexplained and persistent non-bloody or watery diarrhea
of acute, subacute, or chronic onset while taking levodopa/dopa-
decarboxylase inhibitor therapy. Withdrawal and substitution with an
alternative levodopa preparation should be considered as the initial
treatment strategy accompanied by close clinical observation. If diar­
rhea persists, colonoscopy with biopsy at multiple sites should be per­
formed, even if the endoscopic appearance of the mucosa is normal.
Some patients will tolerate an alternative levodopa preparation or, oc­
casionally, even re-challenge with the original causative medication.
Our observations suggest that microscopic colitis may be an under-
recognized complication of levodopa/dopa-decarboxylase inhibitor
treatment.
Author contributions
1. Research project: A. Conception, B. Organization, C. Execution;
2. Statistical Analysis: A. Design, B. Execution, C. Review and
Critique;
3. Manuscript Preparation: A. Writing of the first draft, B. Review
and Critique.
T.L.O.: 1B, 1C, 2A, 2B, 2C, 3A, 3B.
S.R.D.: 1B, 1C, 2A, 2B, 2C, 3B.
A.M.: 1B, 1C, 2A, 2B, 2C, 3B.
F.C.F.C.: 1B, 2C, 3B.
L.J.W: 1B, 2C, 3B.
S.B.: 1B, 2C, 3B.
N.M.: 1B, 2C, 3B.
H.M.B.: 2C, 3B.
N.F.: 1B, 1C.
J.N.: 1B, 1C.
M.R.: 1B, 1C.
V.S.C.F.: 1A, 1B, 2A, 2C, 3B.
Funding sources and conflict of interest
The work was performed during research time of the authors using
the database which is available without fee in the department of the
authors.
Ethical compliance statement
We confirm that we have read the Journal’s position on issues
involved in ethical publication and affirm that this work is consistent
with those guidelines.
Acknowledgments
None.
T.L. Ong et al.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.parkreldis.2021.03.031.
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