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\begin{document}

\title{Metronidazole associated-aseptic neuritis induced irreversible optic
neuritis : A Case Report Of Unfavorable Outcomes And Literature Review}



\author[1]{Haidar Barjas}%
\author[1]{Mohamed Elshafei}%
\author[2]{Shamin Mahmud}%
\author[1]{Abdel-Naser Elzouki}%
\affil[1]{Hamad Medical Corporation}%
\affil[2]{Weill Cornell Medical College in Qatar}%


\vspace{-1em}



  
  \date{May 21, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup








\sloppy


\textbf{Introduction:}

Metronidazole is a bactericidal, amoebicidal, and trichomonacidal agent
targeting anaerobic bacteria, certain amoebic and protozoal species. It
is a nitroimidazole that inhibits nucleic acid synthesis by disrupting
DNA resulting in strand breakage. Its bioavailability is more than 80\%
when taken orally. It is a usually well-tolerated antimicrobial but can
cause gastrointestinal side effects like a gastric upset in the form of
nausea, vomiting, abdominal cramps, diarrhea, or constipation {[}1{]}.
It has also been associated with other adverse effects like dizziness,
darkening of the urine, and joint pain. Disulfiram reaction has been
reported, especially in those drinking ethanol. Neuro-ophthalmologic
side effects such as peripheral neuropathy, ataxia, encephalopathy, and
even seizures have been reported with metronidazole use{[}2{]}. Optic
neuritis, an inflammation of the optic nerve, is an unrecognized side
effect of Metronidazole and has been reported in association with
metronidazole administration in a few case reports. The nerve damage
induced by Metronidazole can be either temporary or permanent.

Here, we are reporting a 30-year-old lady who had a bout of
gastroenteritis and was given a dose of IV Metronidazole and one day
after which she started noticing decreased right eye vision, which
progressed to complete vision loss in her right eye. She was managed
with IV Pulse steroids. She showed a slight improvement in her right
eyesight.

\textbf{Case Presentation:}

A 30-year-old Kenyan lady who is medically free presented to our
hospital with right eye blurry vision that started one week before
admission and gradually progressed over one day to complete right eye
vision loss. Her condition was associated with mild right eye pain,
which was exacerbated by eye movement. Her left eye was normal. She
denied any previous similar episodes; she gave no history of any focal
weakness or sensory abnormalities. She had no headache, no dizziness,
and no abnormal body movements. She reported no fever. She did not have
any history of head trauma, and she denied any urinary or defecation
difficulties. On further questioning, the patient elaborated that she
had an episode of gastroenteritis a week before admission. She has been
given IV Metronidazole 500 mg (one dose) and discharged on Pantoprazole
PO 40 mg daily and Metoclopramide tablets 10 mg as needed for nausea and
vomiting. The day after her discharge, she started complaining of
decreased eye vision which progressively worsened to complete vision
loss in one day; she did not seek medical advice due to financial
issues. Upon admission, her vital signs were normal(Body Temperature:
36.7 Celsius degrees, Heart Rate: 78 beats per minute, Blood Pressure:
117/70 mmHg, SPO2: 98\% on room air). She had unremarkable chest and
abdominal examinations. A central nervous system examination showed
normal higher mental status. Normal power, tone, reflexes, coordination,
and normal sensory function. Her gait was normal. Her cranial nerves
examination showed complete loss of vision in her right eye, otherwise
unremarkable. Her right eye ophthalmologic examination was significant
for right afferent pupillary defect and optic disc edema with the normal
macula with normal left eye examination. Her Complete blood count, serum
electrolytes, renal function, liver function tests, thyroid function
test, and B12 level were all normal. Her Head Computed Tomography was
unremarkable\textbf{.}

Lumbar Puncture was done and Cerebrospinal fluid (CSF) analysis showed
WBC of 44/ul (Normal range 1-5/ul), 97\% lymphocytic, RBC 2/ul (Normal
range 0-2/ul), Glucose 2.90 mmol/l (Normal range 2.22-3.89 mmol/l) and
protein of 0.65 gm/l (Normal range of 0.15-0.45 gm/l). CSF was negative
for culture and viral panel as well as oligoclonal bands. Her MRI brain
and orbit MRI confirmed right optic neuritis. ( \textbf{figure 1} The
patient was started on IV Methylprednisolone 1000 mg daily for five
doses. She showed a slight improvement in her eyesight from nil to hand
movement at a 50 cm distance on discharge. Follow up visits at one week
and two months after discharge for the patient showed that her vision
stabilized at ``close counting fingers'' level with no further
improvement.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure-1 MRI Sections of the brain and orbit with cont}

The right optic nerve appears swollen with evidence of abnormal T2WI
hyperintensity involving the chiasmatic, canalicular, and proximal to
mid-orbital segments with mild blurring of the retro-orbital
fat.(Arrowed)

\textbf{Discussion:}

Metronidazole is an effective antimicrobial that was first used against
trichomonas infections in the late 1950s and then was found to have
effects on anaerobic bacteria and protozoal species. It is frequently
used and usually has gastrointestinal side effects of gastric upset and
metallic taste feeling. Its neurological adverse effects have been
infrequent and only reported in case reports; these include dizziness,
ataxia, encephalopathy, and seizure {[}2{]}. Ophthalmic side effects
have been rarely reported and only seen in case reports and are not
frequently recognized by healthcare providers. Here we described a case
report of 30-year-old lady who was medically free until around 20 days
before her admission when she had a bout of gastroenteritis and was
given a dose of Metronidazole 500 mg IV the next day. She noticed
progressively worsening vision in her right eye, which progressed to
complete vision loss in one-day duration. She did not seek medical
advice due to financial issues and stayed for around one week waiting
for spontaneous recovery of her vision. Upon admission, she was vitally
stable, and her physical examination was unremarkable apart from
complete vision loss in her right eye and right pupillary afferent
defect. Her Basic laboratory blood tests were normal, and her MRI
findings were consistent with left optic neuritis. CSF analysis showed
lymphocytic pleocytosis and elevated protein level but was negative for
culture, viral panel, and oligoclonal bands. Her hospital course has
been uneventful, and she was started on IV Methylprednisolone 1000 mg
daily for five days. She showed a slight improvement in her right eye
vision from complete vision loss to hand movement at 50 cm distance
which then did improve to only counting fingers at 50 cm distance.

An extensive literature review was done, and we found 10 case reports
and 1 case report with a literature review discussing the
neuro-ophthalmic profile of Metronidazole. The age of patients ranged
from 6 to 67 years, 8 were males, and 9 were females. All of the cases
we could extract data for were administered Metronidazole orally. The
dose ranged between 250 mg to 1500 mg per day, and the duration of drug
administration to symptom development was from one dose of 250 mg up to
chronic use of 2 years. 15 patients developed optic neuritis, three
patients developed aseptic meningitis, one patient developed myelitis,
and two patients had cerebellar involvement. All the patients were
managed with the withdrawal of Metronidazole, except one patient with
aseptic meningitis who was treated with a 3rd generation intravenous
cephalosporin for one week, and another patient with optic neuritis who
was initiated on coenzyme Q10 for 3 months in addition to cessation of
metronidazole. Most patients fully recovered their vision, but one whose
damage was irreversible, and seven other patients had 71\% reversibility
of their sight (Please see table 1 for the summary and comparison of
literature review and our case).

\textbf{Conclusion:}

Metronidazole is an effective and widely used antimicrobial commonly
associated with gastrointestinal side effects. In addition, its
neuro-ophthalmic profile, though rare, can be sight-threatening,
resulting in irreversible vision loss. Therefore, clinicians should be
attentive to the adverse effect of even one dose of intravenous or oral
Metronidazole.\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Reversibility}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Treatment}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Outcome}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Duration}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Dose}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Route of administration}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Gender}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Age}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Case}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Some reversibility\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
IV Pulse steroid 500 mg IV Methylprednisolone for 5 days\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Right optic neuritis and aseptic neuritis\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
One dose\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
500 mg\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
IV\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
30 years old\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Our Case\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Cefotaxime 500 mg BID IV for one week\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Aseptic meningitis\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
One week\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
400 mg BID\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Oral\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
49 years old\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
A.Viharika et al {[}3{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Stopping Metronidazole\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Bilateral optic neuritis\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
8 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
400 mg BID\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Oral\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
67 years old\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Nicole M McGrath et al {[}4{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Stopping Metronidazole\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Bilateral optic neuritis and meylitis\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1 week\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1000 mg OD\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Oral\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
57 years old\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Pai-Huei-Peng et al {[}5{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Stopping Metronidazole\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Optic neuritis\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Two years\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
36 years old\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Natalie Anwyll et al {[}6{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Stopping Metronidazole\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Aseptic meningitis\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
One dose\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
250 mg\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Oral\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
20 years old\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Audrey P et al {[}7{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Stopping Metronidazole\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Optic neuropathy and cerebellar toxicity\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
For two years\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
500 mg TID\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
oral\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
58 years old\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Erin Nuro et al {[}8{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Stopping Metronidazole\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Bilateral optic neuritis\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Two weeks\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Oral\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
6 years and 8 years old\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Bouraoui R et al {[}9{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Stopping Metronidazole\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Aseptic meningitis\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
One dose\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
400 mg\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Oral\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
42 years old\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Sujoy Khan et a {[}10{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Some reversibility\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Stopping Metronidazole\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Optic neuritis\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
7-365 days\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
750-1000 mg daily\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Oral\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4 females and 3 males\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
7 patients from 26-53 years old\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Putnam et al {[}11{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Stopping Metronidazole Starting coenzyme Q10\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Optic neuropathy and cerebellar toxicity\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Over 6 months\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
500 mg TID\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Oral\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
17 years old\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Kim M Cecil et al {[}12{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Stopping Metronidazole\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Optic neuropathy\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2 years\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1500 mg daily\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Oral\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
20 years old\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
De Bleecker et al {[}13{]}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table-1 Comparison of our case and summary of literature review}

\textbf{References:}

1. Flagyl, Flagyl ER (Metronidazole) dosing, indications, interactions,
adverse effects, and more (medscape.com)

2. Metronidazole: An overview - UpToDate

3.Viharika A, Basheer S, Bharathi GV, Reddy TR, Ramana V. Metronidazole
Induced Meningtis: A Case Report DOI: 10.9790/0853-1811073739.

4. McGrath NM, Kent-Smith B, Sharp DM. Reversible optic neuropathy due
to metronidazole. Clin Exp Ophthalmol. 2007 Aug;35(6):585-6. doi:
10.1111/j.1442-9071.2007.01537.x. PMID: 17760644.

5. Peng PH, Wu TE, Lin TY. Metronidazole-Induced Irreversible Optic
Neuropathy. Case Rep Ophthalmol. 2021 May 10;12(2):392-395. doi:
10.1159/000512625. PMID: 34054490; PMCID: PMC8136306..

6. Anwyll N, Gerry P, Gormley J. Reversible optic neuropathy secondary
to metronidazole. BMJ Case Rep. 2020 Dec 17;13(12):e237141. doi:
10.1136/bcr-2020-237141. PMID: 33334752; PMCID: PMC7747533.

7. Corson AP, Chretien JH. Metronidazole-associated aseptic meningitis.
Clin Infect Dis. 1994 Nov;19(5):974. doi: 10.1093/clinids/19.5.974.
PMID: 7893894.

8. Nuro E, Bursztyn LL, Mendon\selectlanguage{ngerman}ça DA, Pelz DM, Budhram A. Neuroimaging
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