Keywords
Encephalopathy - metronidazole - seizure
Introduction
Metronidazole is a nitroimidazole antimicrobial drug that is effective against anaerobic
bacteria and protozoa. Due to its safety and low cost; it is one of the most commonly
used over-the-counter drugs. Generally, well-tolerated, the most common adverse drug
reactions observed in patients with metronidazole include nausea, dysgeusia, and abdominal
cramping. Neurotoxicity is very rare in the form of peripheral neuropathy, headache,
ataxia, seizures, and encephalopathy. While the exact incidence of metronidazole induced
encephalopathy (MIE) is not known, most cases in the literature have occurred after
prolonged treatment. We report a case of MIE that occurred in a patient after a treatment
course for ruptured liver abscess.
Case Report
A 45-year-old male who was a chronic alcohol user presented with high-grade fever,
right upper quadrant abdominal pain, and abdominal distension for past 12 days. On
abdominal examination, he had tender hepatomegaly and ascites. Ultrasound abdomen
revealed ruptured liver abscess and ascites. He was started with intravenous metronidazole
800 mg TDS and piperacillin-tazobactam 2.25 gm QID on the day of admission and the
abscess drained subsequently. With the given treatment and supportive care, he was
improving clinically.
On the 12th day of admission, he developed one episode of generalized tonic-clonic seizures (GTCS)
for 30 s and then he gained consciousness within 10 min. He was loaded with levetiracetam.
Metabolic parameters like blood glucose and electrolytes were within the normal range.
NCCT head was done to rule out new-onset infarct/intracranial hemorrhage or other
gross organic pathology. The next day, he again developed two episodes of seizures
following which he had poor responsiveness; hence he was intubated and mechanically
ventilated as a result of airway protection.
In view of persistently altered sensorium (GCS–8/15) with multiple liver abscesses
and chronic alcohol use, the possibility of hepatic encephalopathy was considered.
However, his ultrasound imaging and metabolic parameters were not suggestive for chronic
liver disease and hepatic encephalopathy. For further evaluation, we were able to
perform MRI on day 29 of admission which showed symmetric areas of FLAIR hyperintensities
and restricted diffusion seen in the dentate nuclei, dorsal Pons, and posterior limb
of internal capsule and splenium of corpus callosum suggestive of metronidazole toxicity
[[Figure 1]]. Subsequently, metronidazole was stopped on the same day. The total dose of metronidazole
received by patient till first episode of seizure was 28.8 g. The total cumulative
dose was 69.6 g. His further hospital stay was complicated by cardiac arrest due to
hypoxia on next day of stopping metronidazole. He attained return of spontaneous circulation
after 20 min of CPR. Following CPR, his sensorium further deteriorated (GCS–3/15)
and did not improve further. Since he had cardiac arrest, clinical improvement with
reversal of metronidazole toxicity was not seen. Repeat MRI was done after 1 month
of previous MRI which showed marked reduction in FLAIR hyperintensities in the dentate
nuclei, dorsal pons, and splenium of corpus callosum suggestive of partial resolution
in changes due to metronidazole toxicity. However, there were new areas of symmetric
FLAIR hyperintensities in basal ganglia and thalamus suggestive of new hypoxic-ischemic
changes due to cardiac arrest [[Figure 2]]. The post-cardiac arrest was managed conservatively, in spite of good supportive
care, he succumbed to ventilator-associated pneumonia.
Figure 1 (A-D): Initial MRI brain scan on day 29 of admission. (A and B) - Axial FLAIR images (C
and D) - Axial Diffusion-Weighted Images. Symmetric areas of FLAIR hyperintensity
and restricted diffusion are seen involving the dentate nuclei (arrow in A and C),
dorsal pons (arrowhead in A and C), posterior limbs of the internal capsule (arrow
in B and D) and splenium of corpus callosum (arrowhead in B and D)
Figure 2 (A-D): Repeat MRI brain on day 59 of admission. (A and B) Axial FLAIR images. There is marked
reduction in the areas of FLAIR hyperintensity in the dentate nuclei (arrow in A),
dorsal pons and splenium of corpus callosum (arrow in B). Symmetric FLAIR hyperintensity
involving bilateral basal ganglia (arrowhead in B). (C) Axial Diffusion-weighted image.
Restriction of diffusion in bilateral basal ganglia (arrow) and thalami (arrowhead).
(D) Axial Susceptibility weighted images. Micro-hemorrhages in bilateral basal ganglia
(arrow)
Discussion
Metronidazole is a nitroimidazole drug, which has broad-spectrum cidal activity against
anaerobic bacterial and protozoal infections, including amoebiasis. The nitro radical
of metronidazole acts as an electron sink that competes with biological electron acceptors
of the anaerobic organism in the PFOR pathway. Although the drug is relatively safe
and well-tolerated in common setting, patient may experience side effects in both
long-term and short-term use. It is occasionally associated with an unpleasant metallic
taste, nausea, and abdominal pain. These side effects are dose-dependent and often
persistent for 24to48 h after consumption. Peripheral neuropathy is the most common
nervous system adverse effect.
Among patients with metronidazole toxicity to the central nervous system, maximum
cases were presented with cerebellar dysfunction (75%) followed by altered mental
status (33%) and seizures (13%). Among cerebellar dysfunction, dysarthria, ataxia,
dysmetria, and nystagmus were the most common findings on examination in descending
order of frequency.[[1]] Altered mental status is generally a part of the encephalopathy; however, it can
be due to nonconvulsive status as well. Metronidazole toxicity can also present as
extrapyramidal manifestations. There are several reported cases of chorea and myoclonus
as presenting symptoms. Sensorineural hearing loss could be a presenting symptom.
The duration of treatment with metronidazole before occurrence of cerebellar symptoms
is variable, and toxic cumulative doses range from 13.2 g to 228 g.[[2]] The half-life of metronidazole is 6–8 h; however, the half-life in patients with
liver dysfunction or renal dysfunction is approximately 3-folds higher.[[3]] Accordingly, it is necessary to limit the total cumulative dose to less than 20
g in such patients. Our patient had mild hepatic dysfunction, and the total cumulative
dose was 69.6 g.
Kumsi et al. reported an adult patient, who developed encephalopathy and cerebellar dysfunction
and sensory neuropathy after receiving oral metronidazole. She recovered fully after
the withdrawal of the drug but the features of neuropathy recovered later.[[4]] On cessation of metronidazole, the symptoms and MRI changes usually resolve. Most
cases have a complete resolution of symptoms after the interruption of metronidazole
(65%) or at least a significant improvement (29%). However, some cases may suffer
a permanent deterioration (3%), even resulting in death. There are two case reports,
in which the patients died due to irreversible MIE despite cessation of the drug.[[5]]
Metronidazole being a lipophilic drug can penetrate cerebrospinal fluid (CSF) and
the central nervous system easily. The ratio of serum and CSF concentration is nearly
1.0.[[6]] The exact mechanisms of metronidazole neurotoxicity remain unclear, several hypotheses
have been proposed by various researchers. The signal intensity changes observed on
the diffusion-weighted (DW) images most likely represent interstitial edemas. Ahmed
et al. first described reversible neuroimaging in MIE and postulated the reversibility
by axonal swelling with increased water content rather than a demyelinating process.[[7]] Most brain lesions induced by metronidazole are reversible. It has been suggested
that metabolites of metronidazole inhibit RNA protein synthesis which could lead to
neurotoxicity. Once the medication is discontinued, the syndrome may improve within
days and can be resolved within several weeks.
The clinical disease concept of MIE was reported over 20 years ago. However, MIE-specific
MRI findings have been reported recently. Patients with metronidazole toxicity usually
have bilaterally symmetric T2 hyperintense reversible lesions in the cerebellar dentate
nucleus and the inferior colliculus. The other regions usually affected are subcortical
white matter, anterior commissure of the splenium, basal ganglia, midbrain, cerebellar
white matter, and inferior olivary nuclei.[[8]] The lesions appear as nonenhancing, hyperintense on T2-weighted, and FLAIR images
without evidence of a mass effect. The DW image signal is high with variable apparent
diffusion coefficient values. The brain MRI findings of MIE were graded as shown in
[[Table 1]].[[9]]
Table 1
Grading of CNS findings in MIE[[9]]
|
Grade
|
Severity
|
Extent of involvement of brain
|
|
Grade 1
|
Minimal
|
Symmetric involvement of one lobe (frontal, temporal, parietal, or occipital) without
the involvement of the corpus callosum, basal ganglia, thalami, or internal capsules
|
|
Grade 2
|
Mild
|
Symmetric involvement of two lobes, or of one lobe plus symmetric involvement of one
of the corpus callosum, basal ganglia, thalami, or internal capsules
|
|
Grade 3
|
Moderate
|
Symmetric involvement of two lobes plus symmetric involvement of one of the corpus
callosum, basal ganglia, thalami, or internal capsules
|
|
Grade 4
|
Severe
|
symmetric extensive, and confluent involvement of three or all lobes from the ventricular
margin to the subcortical white matter, or of two lobes plus symmetric involvement
of two of the following: corpus callosum, basal ganglia, thalami, or internal capsules
|
In view of a lack of accurate diagnostic tools or clinical criteria, diagnosis always
depends upon high clinical suspicion, specific imaging abnormalities, ruling out other
clinical and radiological differentials and significant improvement after the prompt
withdrawal of the metronidazole. It is important to rule out another differential
diagnosis such as demyelinating diseases, metabolic and toxic diseases like Wernicke’s
encephalopathy and osmotic myelinolysis with pontine or extrapontine damage.
Withdrawing metronidazole as early as possible along with supportive care is the only
proven measure. Nevertheless, where a 5-nitroimidazole is indispensable, replacement
with other 5-nitroimidazole like tinidazole or ornidazole may be tried; however, similar
side effects have been observed with these drugs also.[[10]] Though there has been a positive report of diazepam as a measure to shorten the
time of recovery in dogs, no such reports are published in the case of human beings.
Learning points:
-
In the hospital setting, new-onset seizures have various causes, of which drugs are
common culprits. Hence, reviewing drug history is important
-
The side effects of metronidazole may vary from nausea, metallic taste to MIE, or
cerebellar dysfunction
-
Metronidazole-specific MRI findings are bilaterally symmetric T2 hyperintense cerebellar
dentate nuclei and the inferior colliculi. The other regions usually affected are
subcortical white matter, anterior commissure of the splenium, basal ganglia, midbrain,
cerebellar white matter, and inferior olivary nuclei
-
Patients with hepatic dysfunction or renal dysfunction are at an increased risk of
MIE.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form the patient(s) has/have given his/her/their consent for his/her/their
images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.
