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Metronidazole-Induced Central Nervous System Toxicity:
A Systematic Review
Akira Kuriyama, MD,* Jeffrey L. Jackson, MD, MPH,ÞAsako Doi, MD,þand Toru Kamiya, MD§
Objective: To assess patient and medication factors that contribute
to metronidazole toxicity.
Data Sources: We searched PUBMED from 1965 through April 7,
2011, and performed a hand search of bibliographies.
Study Selection: Case reports or case series reporting metronidazole-
induced central nervous toxicity.
Data Extraction: Two authors independently abstracted demo-
graphics, metronidazole indication, dose and duration, neurological man-
ifestations, and outcomes as well as brain imaging findings.
Data Synthesis: Among 64 patients, 48 (77%) had cerebellar dys-
function, 21 (33%) had altered mental status, and 8 (15%) had seizures.
Patients’ ages averaged 53.3 years (range, 12Y87 years), and 64% were
male. The median duration of metronidazole was 54 days, although
26% had taken it less than a week and 11% had taken it less than
72 hours. Among cases with outcome data, most patients either im-
proved (n = 18 [29%]) or had complete resolution of their symptoms
with discontinuation of metronidazole (n = 41 [65%]). There was no
difference in resolution of symptom by age (P= 0.71) or sex (P= 0.34).
The patients with cerebellar dysfunction were less likely to experience
complete resolution than those with mental status changes or seizures
(relative risk, 0.67; 95% confidence interval (CI), 0.49Y0.92). Nearly all
patients (n = 55 [86%]) underwent imaging of the brain: 44 (69%) un-
derwent magnetic resonance imaging (MRI) and 12 (19%) underwent
computed tomographic studies. All patients with cerebellar dysfunction
had abnormalities on imaging: 93% (n = 39) had a cerebellar lesion,
although numerous areas in the brain were affected. On follow-up MRIs,
25 patients (83%) had complete resolution of abnormalities.
Conclusions: Metronidazole can rarely cause central nervous system
toxicity; it does not seem to be a dose- or duration-related phenomenon.
Most patients will have MRI abnormalities. Prognosis is excellent with
metronidazole cessation.
Key Words: metronidazole, adverse effects, cerebellar toxicity,
systematic review
(Clin Neuropharm 2011;34: 241Y247)
Metronidazole is a 5-nitroimidazole antibiotic with potent
activity against anaerobic bacteria and protozoa. The range
of its use is broad and includes trichomonal infection, amebiasis,
management of Crohn disease, hepatic encephalopathy, treat-
ment of Helicobacter pylori infection and Clostridium difficileY
associated diarrhea. While metronidazole is fairly safe and well
tolerated, it can rarely cause serious neurological adverse events,
including peripheral neuropathy,
1Y6
cerebellar dysfunction, en-
cephalopathy, ototoxicity,
7
seizures, visual impairment,
8Y10
and
altered mental status. It has been suggested that neurological
toxicity may be related to prolonged administration, high doses,
or high cumulative doses of metronidazole.
11Y14
We recently had an illustrative case: an 83-year-old woman
with a surgical history of choledochojejunostomy for com-
mon bile duct stone 35 years ago who was transferred to our
emergency department in shock and found to have a multilob-
ular liver abscess. She was discharged on cefoprazone but pre-
sented a month later with recurrent liver abscess. She was
subsequently discharged on ciprofloxacin (250 mg 2 times a
day) and metronidazole (500 mg 3 times a day). After 2 days,
she began to experience difficulty in speaking and dysarthria.
Over the next couple of weeks, she developed an unsteady gait
and bilateral lower extremity paresthesia and by day 14, she was
unable to stand or walk. A magnetic resonance image (MRI)
demonstrated lesions in the splenium of corpus callosum
(Fig. 1), felt to be metronidazole-induced cerebellar toxicity,
and metronidazole was discontinued. She experienced gradual
but complete resolution of symptoms by day 20 and a follow-
up MRI of the brain 28 days after discharge revealed complete
resolution of the previous abnormalities (Fig. 2).
Our review of the literature revealed several case reports
but no distillation of the literature and uncertainty about the
role of dose or duration and the course and outcome of metro-
nidazole toxicity. The purpose of this study was to perform a
systematic review to synthesize the literature on this unusual
adverse event.
MATERIALS AND METHODS
Data Sources and Searches
We searched PUBMED using several search strategies: (1)
(metronidazole or flagyl) AND (seizures [meSH heading {MH}]
or encephalitis or neurotoxicity syndromes [mh] or ataxia [mh]
or confusion [mh] or cerebellar diseases [mh] or cerebellar
dysfunction or dysmetria or delirium [mh]); (2) metronida-
zole AND (case reports [publication type {ptyp}] AND brain
diseases/*chemically induced [mh]); and (3) case reports [ptyp]
AND metronidazole/*adverse effects, from 1966 to March 2011.
Study Selection
We included all articles that reported cases of metronidazole-
induced central nervous system toxicity. We excluded non-
English or Japanese articles and those focusing on peripheral
neuropathy.
Data Extraction and Quality Assessment
From each article, we abstracted demographics (age, sex,
and ethnicity), exposure history (dose and duration), and specific
toxicity. The accumulative doses were estimated by multiplying
the daily dose by the medication duration. We also abstracted data
regarding symptom outcome, including how much improvement
ORIGINAL ARTICLE
Clinical Neuropharmacology &Volume 34, Number 6, November/December 2011 www.clinicalneuropharm.com 241
*Department of General Internal Medicine, Rakuwakai Otowa Hospital,
Kyoto, Japan; †GIM Section, Medical College of Wisconsin, Milwaukee, WI;
‡Department of Infectious Diseases, Rakuwakai Otowa Hospital, Kyoto,
Japan; and §Department of Infectious Diseases and Department of General
Internal Medicine, Rakuwakai Otowa Hospital, Kyoto, Japan.
Disclaimer: The viewpoints reflected in this manuscript are those of the
authors and should be not be construed to reflect, in any way, those
of the US Government or the Department of Veteran Affairs.
Drs Jackson and Kuriyama had full access to the data and take full
responsibility for the integrity of the data and analysis of the same.
Conflicts of Interest and Source of Funding: There was no funding for this
project. The authors have no conflicts of interest to declare.
Address correspondence and reprint requests to Jeffrey L. Jackson,
MD, MPH, 5100 W National St, Milwaukee, WI 53215;
E-mail: jjackson@mcw.edu
Copyright *2011 by Lippincott Williams & Wilkins
DOI: 10.1097/WNF.0b013e3182334b35
Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
occurred and length of time after cessation of metronidazole for
symptoms to resolve. Finally, we abstracted information reported
regarding MRI findings.
Data Synthesis and Analysis
Our process yielded patient-level data. We provided de-
scriptive statistics (means, medians, and proportions) for all data
abstracted. We compared continuous variables between different
groups using either analysis of variance or the Kruskal-Wallis
test, depending on the underlying distribution. Categorical vari-
ables were compared using the W
2
test.
RESULTS
The literature search yielded 261 unique articles. Hand re-
view of the bibliographies of these yielded 5 additional articles.
Review of these 266 articles yielded 46 English and Japanese
articles that reported 64 cases of metronidazole-induced cen-
tral nervous system toxicity (Table 1).
2,8,9,11Y21,23Y54
Reasons
for exclusion are given in Figure 3. Of the 64 cases, 23 (35%)
were from the United States,
11,13Y15,19Y21,23,24,26,31,32,36,39,40,42,
45,50,52,53
19 (30%) were from Korea,
9,17,35,38,48
3 were from
India
29,34,43
and Japan,
33,49
2 each were from Australia,
37,47
Canada,
44
and the United Kingdom,
27,51
and single cases were
from Belgium,
8
Chile,
25
Germany,
46
Israel,
18
the Netherlands,
28
Nigeria,
41
Taiwan,
2,41
Tunisia,
30,41
and Turkey.
16
The first case
report appeared in 1977
26
; 37 (59%) of the reports have occurred
since 2004. The mean age of affected patients was 53.4 years
(95% confidence interval [CI]: 48.8Y57.9). The patients ranged
in age from 12 to 87 years, with the peak occurring in the fifth
and sixth decades. Forty-one (64%) of the patients were male.
The most common indication for metronidazole treatment was
abscess (n = 29 [48%]), followed by inflammatory bowel disease
(n = 7 [12%]), C. difficile (n = 5 [8%]), and cellulitis (n = 4
[7%]). The mean duration of metronidazole treatment was
54 days (95% CI, 21.2Y87.9), although 26% of the patients
had taken the drug for less than a week and 11% had taken it
for less than 3 days. The average daily dose was 719 mg (range,
250Y2000 mg), and the average cumulative dose of metronida-
zole was 93.4 g (range, 0.25Y1095 g).
Types of Metronidazole-Induced Central
Nervous System Toxicity
Of the 64 patients, 48 (75%) had cerebellar dysfunction,
21 (33%) had altered mental status, and 8 (13%) had seizures;
11 (17%) patients had both cerebellar dysfunction and altered
mental status. One case each had cerebellar dysfunction and
seizures; one had all 3 manifestations. Among the 48 patients
with cerebellar dysfunction, dysarthria (n = 32 [66%]) and ataxia
(n = 27 [56%]) were common; 16 (33%) had dysmetria and
4 (8%) nystagmus.
Among the patients with cerebellar dysfunction, 34 (71%)
were male. The average age was 53 years, and the patients
had been on metronidazole for a median of 30 days (range,
2Y730 days). The patients with acute mental status changes
were younger, 43 years of age, and 13 (65%) were male. The
median duration of treatment was 15 days (range, 1Y90 days).
FIGURE 1. Admission MRI.
FIGURE 2. Follow-up MRI.
Kuriyama et al Clinical Neuropharmacology &Volume 34, Number 6, November/December 2011
242 www.clinicalneuropharm.com *2011 Lippincott Williams & Wilkins
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TABLE 1. Case Reports of Metronidazole Toxicity
Author, Year, Country Age Sex
Indication for
Metronidazole
Duration of
Metronidazole
(Days)
Cumulative
Dose (Grams)
Neurological
Manifestation
MRI
Done
Neurological
Outcome
Ahmed,1995, USA
15
45 F Blastocystis hominis diarrhea 30 35 Cerebellar dysfunction Yes Resolved
Acute mental status change
Alvarez,1983, USA
11
20 F Bacteroides fragilis
pelvic abscess 18 25.5 Cerebellar dysfunction No Resolved
Acute mental status change
Arik, 2001, Turkey
16
58 F Cellulitis 2 NS Cerebellar dysfunction Yes Resolved
Bahn, 2010, Korea
17
52 M Brain abscess 20 40 Cerebellar dysfunction Yes Resolved
Bailes,1983, USA
14
12 M Peritonitis 4 4 Cerebellar dysfunction No Resolved
Acute mental status change
Beloosesky, 2000, Israel
18
87 F C. difficile colitis 12 18 Seizure No Resolved
Bonkowsky, 2007, USA
19
27 M C. difficile colitis 14 NS Cerebellar dysfunction Yes Resolved
Acute mental status change
Bottenberg, 2011, USA
12
55 M Collagenous colitis 730 1095 Cerebellar dysfunction Yes Resolved
Cecil, 2002, USA
20
17 M Crohn disease NS NS Cerebellar dysfunction Yes Resolved
Chatzkel, 2010, USA
21
15 F Crohn disease 7 NS Cerebellar dysfunction Yes NS
Dainer, 1979, USA
22
27 F Trichomonas 1 0.25 Acute mental status change No Resolved
De Bleecker, 2005, Belgium
8
20 M Ulcerative colitis 730 1110 Cerebellar dysfunction Yes Impaired visual acuity
Deenadayalu, 2005, USA
23
50 M Peritonitis + hepatic
encephalopathy 5 7.5 Cerebellar dysfunction Yes Improved
Frytak, 1978, USA
24
77 F Inoperable pancreatic
carcinoma 5 NS Seizure No Resolved
75 F Hepatic and pulmonary
metastasis of rectal carcinoma 7 42 Seizure No Resolved
52 F Sensitizer for metastatic
carcinoma of the stomach 5 52 Seizure No Resolved
Galvez, 2009, Chile
25
60 M Hepatic encephalopathy NS NS Cerebellar dysfunction Yes Improved
Giannini, 1977, USA
26
19 F Trichomonas 7 5.25 Acute mental status change No Resolved
Graves, 2009, UK
27
61 M Kleb wound infection 77 92.4 Cerebellar dysfunction Yes Resolved
Groothoff, 2010,
Netherlands
28
38 F B. fragilis wound of
osteomyelitis 70 132.0 Cerebellar dysfunction Yes Died
Acute mental status change
Seizure
Gupta, 2003, India
29
50 M Amebic liver abscess 84 200.0 Cerebellar dysfunction No Resolved
Acute mental status change
Halloran, 1982, USA
13
56 M Amebic liver abscess 16 33.6 Seizure No Resolved
Hammami, 2007, Tunisia
30
51 M Anal fistula 21 31.5 Cerebellar dysfunction Yes Resolved
Acute mental status change
Heaney, 2003, USA
31
74 M Abdominal purulent abscess 56 84.0 Cerebellar dysfunction Yes Resolved
(Continued on next page)
Clinical Neuropharmacology &Volume 34, Number 6, November/December 2011 Metronidazole-Induced CNS Toxicity
*2011 Lippincott Williams & Wilkins www.clinicalneuropharm.com 243
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TABLE 1. (Continued)
Author, Year, Country Age Sex
Indication for
Metronidazole
Duration of
Metronidazole
(Days)
Cumulative
Dose (Grams)
Neurological
Manifestation
MRI
Done
Neurological
Outcome
Horlen, 2000, USA
32
34 M B. fragilis meningitis +
bacteremia 50 75.0 Cerebellar dysfunction Yes Resolved
Acute mental status change
Ito, 2004, Japan
33
54 F H. pylori 66 66.0 Cerebellar dysfunction Yes Resolved
Kalia, 2010, India
34
43 M Amebic liver abscess 60 72.0 Cerebellar dysfunction Yes Resolved
Kim, 2004, Korea
35
31 M Crohn disease 6 + chronic use 3 times usual dose +
chronic use Acute mental status change Yes Impaired cognition
46 M Acute cholangitis 6 NS Acute mental status change Yes Vegetative state
Kim, 2007, Korea
9
54 M Spontaneous bacterial
peritonitis 15 22.5 Cerebellar dysfunction Yes Improved
Acute mental status change
64 M Intra-abdominal abscess 17 25.5 Cerebellar dysfunction Yes Improved
55 M Ischemic colitis 11 16.5 Cerebellar dysfunction Yes Improved
71 M DM foot 17 25.5 Cerebellar dysfunction Yes Improved
61 F Pseudomembranous colitis 24 36.0 Cerebellar dysfunction Yes Improved
49 M Crohn disease 52 78.0 Cerebellar dysfunction Yes Improved
70 M Brain abscess 22 33.0 Cerebellar dysfunction Yes Improved
This study
(Kuriyama, 2011, Japan) 83 F K. pneumoniae liver abscess 2 3.0 Cerebellar dysfunction Yes Resolved
Kusumi, 1980, USA
36
45 F B. fragilis anterior
mediastinal abscess 28 84.0 Cerebellar dysfunction No Resolved
Acute mental status change
Lawford, 1994, Australia
37
30 M Amebic liver abscess 14 21.0 Cerebellar dysfunction No Resolved
Lee, 2009, Korea
38
47 M Decubitus ulcer 50 100 Cerebellar dysfunction Yes Improved
61 M Liver abscess 60 120 Cerebellar dysfunction Yes Improved
76 F Liver abscess 50 100 Cerebellar dysfunction Yes Improved
78 F Lung abscess 40 80 Cerebellar dysfunction Yes Improved
64 F Peritoneal abscess 50 100 Cerebellar dysfunction Yes Improved
68 M Lung abscess 44 88 Cerebellar dysfunction Yes Improved
60 M Brain abscess 60 120.0 Cerebellar dysfunction Yes Improved
43 M Peritoneal abscess 30 45 Cerebellar dysfunction Yes Improved
Mahl, 2003, USA
39
75 M C. difficile 2 3.0 Acute mental status change No Resolved
Moosa, 2010, USA
40
52 M Osteomyelitis 35 37.5 Cerebellar dysfunction Yes Resolved
Omotoso, 1997, Nigeria
41
48 M Amebic liver abscess 3 3.6 Acute mental status change No Resolved
Patel, 2008, USA
42
63 M Submental abscess +
mandibular osteomyelitis 42 80.0 Cerebellar dysfunction Yes Resolved
Rothagi, 2000, India
43
55 M Amebic liver abscess 1 0.75 Acute mental status change No Resolved
Kuriyama et al Clinical Neuropharmacology &Volume 34, Number 6, November/December 2011
244 www.clinicalneuropharm.com *2011 Lippincott Williams & Wilkins
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Among the patients with seizures, the average age was 65, most
(n = 6 [75%]) were women, and the median duration of treatment
was 12 days (range, 5Y70 days).
Among the 64 cases, 59 provided outcome data. Most of
the patients either improved (n = 18 [29%]) or had complete
resolution of their symptoms with discontinuation of metronida-
zole (n = 41 [65%]). One patient died from an unrelated cause
and 2 (3%) experienced permanent cognition impairment. There
was no difference in the resolution of symptom by age (P=0.71)
or sex (P= 0.34). The patients with cerebellar dysfunction were
less likely to experience complete resolution than those with
mental status changes or seizures (RR, 0.67; 95% CI, 0.49Y0.92).
Brain Imaging Findings
Nearly all patients (n = 55 [86%]) underwent brain imaging:
44 (69%) underwent MRI examinations, and 12 (19%) under-
went computed tomographic studies (one underwent both).
Subjects with cerebellar dysfunction commonly had an MRI
(n = 42 [88%]) while patients presenting with seizures under-
went computed tomographic examinations (n = 6 [67%]).
All but one patient with cerebellar dysfunction who un-
derwent imaging had an abnormality. Nearly all had cerebellar
lesions (n = 39 [93%]), with the cerebellar dentate nuclei in-
volved in most patients (n = 34 [81%]; Table 2). The corpus
callosum, midbrain, pons, or medulla were involved in 26%
to 40% of the patients with cerebellar dysfunction (Table 2).
Among the 9 patients with altered mental status, most had cer-
ebellar dentate lesions (89%). Of these 9 patients, only 2 had
altered mental status as their only neurological manifestation,
and both had lesions in the cerebellar dentate nuclei and sub-
cortical white matter.
Among the 44 patients who underwent brain MRI,
30 patients had a second brain MRI, performed 3 days to
3 months after cessation of metronidazole. Twenty-five (83%)
had resolution of MRI abnormalities. Five patients had incom-
plete resolution of lesions or new changes.
28,29,31,41,43
There was
poor correlation between symptom outcome and MRIs. The
MRI abnormalities resolved even when the symptoms persisted,
and improvement of symptoms preceded or followed changes in
MRI findings.
DISCUSSION
Metronidazole-induced central nervous system toxicity is a
serious but uncommon event. In this case series, metronidazole
toxicity occurred in both men and women and in adults of any
age. Although previous literature has suggested that toxicity is
Sarna, 2009, Canada
44
72 F Intra-abdominal abscess 25 25.0 Cerebellar dysfunction Yes Resolved
54 M Bronchiectasis 60 60.0 Cerebellar dysfunction Yes Resolved
Seizure
Schentag, 1982, USA
45
65 M Postoperative abscess 2 4.0 Acute mental status change No Resolved
Schreiber, 1997, Germany
46
26 F Adnexitis 5 5.0 Acute mental status change No Resolved
Scott, 1994, Australia
47
81 M B. fragilis hepatic abscess 29 37.2 Cerebellar dysfunction No Resolved
Seok, 2003, Korea
48
74 F Rectovaginal fistula associated
with Crohn disease 90 90.0 Cerebellar dysfunction Yes Nearly resolved
Takase, 2005, Japan
49
69 M Amebic abscess 50 75.0 Cerebellar dysfunction Yes Resolved
Tan, 2010, Taiwan
2
53 M Peptostreptococcus brain
abscess 88 146.0 Cerebellar dysfunction Yes Resolved
Acute mental status change
Uhl, 1996, USA
50
65 F Portosystemic encephalopathy 90 NS Acute mental status change No Resolved
Wienbren, 1985, UK
51
43 F C. difficile 12 18.5 Seizure No Resolved
Woodruff, 2002, USA
52
74 M Intra-abdominal abscesses 28 42.0 Cerebellar dysfunction Yes Resolved
62 M Epidural abscess 30 60.0 Cerebellar dysfunction Yes Resolved
NS indicates Not stated.
FIGURE 3. Flow of article selection.
Clinical Neuropharmacology &Volume 34, Number 6, November/December 2011 Metronidazole-Induced CNS Toxicity
*2011 Lippincott Williams & Wilkins www.clinicalneuropharm.com 245
Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
more common with higher doses or longer duration of therapy,
we found that it occurs even with low doses or short exposure
durations. There are 3 common patterns of toxicity: cerebellar
dysfunction, mental status changes, and seizures. A smaller pro-
portion of patients had more than one manifestation. Abnormali-
ties in MRI are common, with cerebellar dentate lesions present
in most images. The prognosis with cessation of metronidazole is
good, with most of the patients improving or experiencing com-
plete resolution of symptoms. Whereas most MRI findings will
improve or resolve over time, there is only poor correlation be-
tween MRI resolution and symptom outcomes. A second MRI
imaging is not required for patients who experience improve-
ment in their symptoms.
The mechanism of metronidazole-induced central nervous
system toxicity is uncertain. Proposed causes include binding of
metronidazole to neural RNA to inhibit protein synthesis, modu-
lation of inhibitory neurotransmitters F-aminobutyric acid recep-
tor within the cerebellar and vestibular, reversible mitochondrial
dysfunction, and vasogenic and cytotoxic edema. Previous case
reports have demonstrated evidence of vasogenic or cytotoxic
edema on MRI, suggesting either as a potential mechanism of
neurotoxicity. At least one case report suggests having found
evidence of both vasogenic and cytotoxic edema occurring in
different parts of the brain.
Primary treatment of metronidazole-induced central nervous
system toxicity is drug cessation and supportive care. Diazepam
was found to reduce the time to recover the debilitating signs of
dogs with metronidazole toxicosis compared with supportive
care alone. However, there are no reports on using diazepam in
treating metronidazole-induced central nervous system toxicity
in human beings.
CONCLUSIONS
Metronidazole-induced central nervous system toxicity is
uncommon but can present as cerebellar dysfunction, altered
mental status, or seizures. There does not seem to be an asso-
ciation between duration or dose of metronidazole and toxicity;
small amounts of metronidazole can induce neurotoxicity. The
underlying pathophysiology is uncertain, although some have
argued for cytotoxic or vasogenic edema. Treatment is cessation
of metronidazole and supportive care. Although prognosis is gen-
erally good, some subjects wind up with permanent disability.
When T2-weighted fluid attenuated inversion recovery MRIs of
the brain are obtained, abnormalities are commonVpresent in
93% of subjects; cerebellar dentate nuclei lesions are the most
frequent abnormality seen. Repeated MRIs generally show im-
provement or complete resolution of abnormalities.
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Mental Status
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Trigone periventricular
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was missing and was not included in the table.
Kuriyama et al Clinical Neuropharmacology &Volume 34, Number 6, November/December 2011
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Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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