Full text of DOI:10.1345/aph.10028

Toxic Metronidazole-Induced MRI Changes
Cheryl K Horlen, Charles F Seifert, and Cathy S Malouf
OBJECTIVE: To report a case of changes documented by magnetic resonance imaging (MRI) of the head probably due to
accumulation of metronidazole in a patient with liver dysfunction.
CASE SUMMARY: A 34-year-old Hispanic man with cirrhosis and hepatitis C being treated with metronidazole for Bacteroides fragilis
meningitis and bacteremia developed ataxia, disorientation, and peripheral neuropathy. An MRI at the time meningitis was
diagnosed was negative. After the patient received >60 g of metronidazole, an MRI revealed increased signal intensity below,
behind, and lateral to the fourth ventricle. Concomitant metronidazole serum concentration was toxic at 35.1 µg/mL.
DISCUSSION: This is the second reported case of metronidazole-induced MRI changes. Metronidazole is known to accumulate in
patients with liver dysfunction and can cause peripheral neuropathy and central nervous system (CNS) dysfunction; these effects
may take up to two years to completely resolve.
CONCLUSIONS: Metronidazole dosages should be reduced in patients with liver dysfunction to prevent the accumulation of metronid-
azole, which can lead to CNS dysfunction and peripheral neuropathy.
KEY WORDS: metronidazole, magnetic resonance imaging.
Ann Pharmacother 2000;34:1273-5.
etronidazole is a 5-nitroimidazole antibiotic used for a
variety of indications, including treating anaerobic in-
hours was begun. An MRI of the head without contrast (Figure
) done on June 25 was essentially normal, with some heteroge-
1
M
neous signal intensity in the basal ganglia. The patient was dis-
charged on July 15, with prescriptions for spironolactone 200
mg/d, furosemide 40 mg/d, lactulose 30 mL four times daily,
amitriptyline 10 mg at bedtime, propranolol 10 mg twice daily,
and metronidazole 500 mg four times daily for at least four more
weeks.
fections. Metronidazole is fairly safe when used at appro-
priate dosages, but it can produce peripheral neuropathies
and cerebellar dysfunction, especially with dosages >2 g/d
1
for prolonged periods of time. We report the second case
of magnetic resonance imaging (MRI) changes probably
due to metronidazole toxicity.
Two weeks after discharge, the patient returned to the clinic
for a follow-up appointment. He had no complaints and stated he
was compliant with therapy. He was also evaluated in the clinic
on August 11; his only symptom at that time was some tingling
in his hands and feet. Five days later, the patient presented to the
emergency department with tingling in his feet, dizziness, inabili-
ty to walk, occasional disorientation to person, slowed speech
and incoherence, and vomiting for the past two days. Physical
examination revealed that the patient was afebrile, but was jaun-
diced and had shifting dullness. Neurologic examination was sig-
nificant for horizontal nystagmus in the extremes of vision. He
exhibited past-pointing on the finger-to-nose test. He was severe-
ly ataxic and was unable to walk unassisted without falling. He
had no pronator drift, no tremor, no Kernig’s sign, no Brudzin-
ski’s sign, and no asterixis. Initial laboratory results included nor-
mal complete blood cell count and differential, sodium 136 mEq/L,
calcium 8.7 mg/dL, albumin 2.5 g/dL, international normalized
ratio 1.74, total bilirubin 3.1 mg/dL, alkaline phosphatase 142
IU/L, AST 148 IU/L, and arterial ammonia 14 µg/dL (normal
CASE REPORT
A 34-year-old Hispanic man with a past medical history signifi-
cant for cirrhosis, alcohol abuse since age 9, intravenous drug
abuse, documented hepatitis C for seven years, and an initial
Child–Pugh classification of C was admitted on June 21, 1999,
with chief complaints of nausea, vomiting, malaise, fever, and di-
arrhea for the previous three days. Laboratory results determined
3
3
on June 22 were white blood cell count 11.7 × 10 /mm (neu-
trophils 74%, bands 13%, lymphocytes 6%, monocytes 5%,
eosinophils 0%, basophils 0%), hemoglobin 13.3 g/dL, hemat-
3
3
ocrit 36.8 g/dL, platelets 38 × 10 × mm , sodium 124 mEq/L,
potassium 3.3 mEq/L, chloride 93 mEq/L, carbon dioxide 19
mEq/L, glucose 148 mg/dL, blood urea nitrogen 17 mg/dL, crea-
tinine 1.0 mg/dL, calcium 7.3 mg/dL, total protein 6.1 g/dL, albu-
min 2.2 g/dL, total bilirubin 4.0 mg/dL, alkaline phosphatase 159
IU/L, aspartate transaminase (AST) 105 IU/L, and alanine
transaminase 45 IU/L; γ-glutamic transaminase 235 IU/L was de-
termined on June 25. A lumbar puncture and blood cultures re-
vealed Bacteroides fragilis meningitis and B. fragilis bacteremia.
On hospital day 4, intravenous metronidazole 250 mg every six
3
1
6–121). A serum metronidazole concentration drawn on August
5 was 35.1 µg/mL (therapeutic range 18–25; personal commu-
nication, Barbara J Struthers PhD DABT, Searle Healthcare In-
formation Services, Skokie, IL, August 17, 1999). A cerebro-
spinal fluid (CSF) metronidazole concentration was not obtained,
1
but it has been reported that CSF and serum concentrations of
metronidazole are approximately equivalent.
Eight weeks after the initial diagnosis of B. fragilis meningitis
(August 17), metronidazole was discontinued to see whether this
Author information provided at the end of the text.
www.theannals.com
The Annals of Pharmacotherapy
■
2000 November, Volume 34
■
1273

was the cause of his symptoms. An MRI of the head with con-
trast was performed that day and revealed a venous angioma in
the medial right frontal lobe just anterior to the frontal horn; pe-
culiar areas of increased signal intensity in the inferior basal gan-
glia lateral to the hypothalamus and also below, behind, and later-
al to the fourth ventricle; and acute mastoiditis (Figure 2). It was
believed that the areas of increased signal intensity were most
likely due to drug toxicity. A lumbar puncture was done the fol-
lowing day and the CSF results were unremarkable.
The patient was diagnosed with metronidazole-induced central
nervous system (CNS) dysfunction and peripheral neuropathy
thought to be secondary to his cirrhosis and accumulation to toxic
metronidazole serum concentrations with normal therapeutic
dosing. The MRI findings shown in Figure 2 are consistent with
this neuropathy. By the day of discharge (August 18), the pa-
tient’s speech was coherent, cerebellar signs were much im-
proved, and he could walk, although he remained unsteady.
At a follow-up appointment on September 1, the patient no
longer displayed any cerebellar signs of toxicity. He only report-
ed continued numbness, tingling, and pain in his hands and feet,
which worsened with cold temperatures and at bedtime; an MRI
was not performed at this visit.
ly complete resolution of the MRI changes was document-
ed with a follow-up MRI six weeks later.
Our patient exhibited the classic symptoms of metroni-
dazole-induced CNS dysfunction and peripheral neuropa-
thy. He received approximately 66 g of metronidazole over
55 days. An MRI performed shortly after metronidazole
was started was essentially negative, whereas the MRI
done on the second admission showed bilateral areas of in-
creased signal intensity. Although a follow-up MRI was
not performed, the temporal relationship of the patient’s
signs and symptoms highly suggests that the MRI changes
may be the result of a toxic accumulation of metronida-
zole. The symptoms began to improve once metronidazole
was discontinued. According to the Naranjo probability
3
scale, this reaction would be considered probable.
There are several case reports describing peripheral neu-
2
,4-8
9
ropathy with metronidazole. Seizures and encephalop-
athy
2,7,10,11
have also been reported. Most cases of peripher-
al neuropathy develop with large daily doses (>2 g/d) and
prolonged courses of therapy. Complete or partial resolu-
Discussion
6
There is only one other report of metronidazole-induced
toxicity documented by MRI changes. Ahmed et al. re-
tion may occur after discontinuation of therapy; however,
symptoms may take up to two years to completely resolve.
2
6
ported the case of a 45-year-old woman treated with ap-
proximately 35 g of metronidazole for nearly 30 days. She
developed nausea, vomiting, vertigo, confusion, ataxia,
and peripheral neuropathy with this dosage. An MRI
showed “symmetric abnormal signal within supratentorial
white matter, including the corpus callosum, and within the
cerebellum, including the cerebellar deep gray matter nu-
clei.” No metronidazole concentration was obtained. Near-
The exact mechanism for these adverse effects is not known.
Large doses of metronidazole have been shown to bind the
RNA of rat nerve cells.
Metronidazole has antibacterial activity against anaero-
bic organisms, including B. fragilis. Since it also effective-
8
Figure 2. Magnetic resonance imaging after eight weeks of metronidazole
therapy, with toxic metronidazole serum concentrations and metronidazole-
induced central nervous system dysfunction and peripheral neuropathy. The
arrows mark the increased signal intensity below, behind, and lateral to the
fourth ventricle.
Figure 1. Magnetic resonance imaging in patient with Bacteroides fragilis
meningitis prior to initiation of metronidazole therapy.
1274
■
The Annals of Pharmacotherapy
■
2000 November, Volume 34
www.theannals.com

Case Reports
9
. Frytak S, Moertel CG, Childs DS, Albers JW. Neurologic toxicity associ-
ated with high-dose metronidazole therapy. Ann Intern Med 1978;88:
ly crosses the blood–brain barrier and is almost 100% bio-
available, metronidazole is a good choice to treat B. frag-
ilis meningitis. However, metronidazole undergoes bio-
transformation in the liver to both active and inactive me-
tabolites. It has been shown that in patients with hepatic
disease, there is a tendency toward a longer elimination
half-life and reduced total body clearance for metronida-
zole compared with normal controls. There are no specific
dosage recommendations for patients with hepatic failure,
but it is reasonable to use a reduced dosage or increased
dosing interval in these patients, especially when pro-
longed courses of therapy are expected.
361-2.
1
0. Alvarez RS, Richardson DA, Bent AE, Ostergard DR. Central nervous
system toxicity related to prolonged metronidazole therapy. Am J Obstet
Gynecol 1983;145:640-1.
12-14
11. Lawford R, Sorrell TC. Amebic abscess of the spleen complicated by
metronidazole-induced neurotoxicity: case report. Clin Infect Dis 1994;
19:346-8.
1
2. Farrell G, Zaluzny L, Baird-Lambert J, Cvejic M, Buchanan N. Impaired
elimination of metronidazole in decompensated chronic liver disease. Br
Med J 1983;287:1845.
13. Farrell G, Baird-Lambert J, Cvejic M, Buchanan N. Disposition and me-
tabolism of metronidazole in patients with liver failure. Hepatology
1984;4:722-6.
1
4. Lau AH, Evans R, Chang C, Seligsohn R. Pharmacokinetics of metro-
nidazole in patients with alcoholic liver disease. Antimicrob Agents
Chemother 1987;31:1662-4.
Summary
This is the second case reported in the literature in
which MRI changes were noted in a patient receiving
metronidazole who developed peripheral neuropathy and
CNS dysfunction. Due to the temporal relationship with
metronidazole exposure, the clinical signs and symptoms,
and a toxic metronidazole concentration, the MRI findings
are probably related to toxic metronidazole exposure. Pa-
tients with a history of cirrhosis should have metronidazole
doses reduced and if peripheral neuropathy and CNS dys-
function occur, metronidazole toxicity should be suspect-
ed. Serum and CSF metronidazole concentrations should
be drawn and an MRI may be useful in delineating the
cause.
EXTRACTO
OBJETIVO: Informar un caso de cambios en la imagen de resonancia
magnética (IRM) debido, probablemente, a la acumulación del
metronidazol en un paciente con disfunción hepática.
RESUMEN DE CASO: Una hombre hispano de 34 años de edad con cirrosis
y hepatitis C que recibía tratamiento con metronidazol para meningitis y
bacteremia causadas por Bacteroides fragilis desarrolló ataxia,
desorientación, y neuropatía periférica. Un IRM realizado para
diagnosticar la meningitis resultó negativo. Después de recibir >60 g del
metronidazol, un IRM reveló una intensidad aumentada en la señal
debajo, detrás y lateral al cuarto ventrículo. Concomitantemente, la
concentración sérica del metronidazol era tóxica, con un nivel de 35.1
µg/mL.
DISCUSIÓN: Este es el segundo caso reportado de cambios en la IRM
inducido por metronidazol. El metronidazol se puede acumular en
pacientes con disfunción hepática y puede causar neuropatía periférica y
disfunción del sistema nervioso central (SNC). Esto puede tardar hasta
dos años en resolverse.
Cheryl K Horlen PharmD, Assistant Clinical Instructor, Pharmacy
Practice Resident, School of Pharmacy, Texas Tech University Health
Sciences Center, Lubbock, TX
Charles F Seifert PharmD FCCP BCPS, Professor of Pharmacy
Practice, Regional Dean for Lubbock Programs, School of Pharma-
cy, Texas Tech University Health Sciences Center
CONCLUSIONES: La dosis del metronidazol se debe reducir en pacientes
con disfunción hepática, para de esta manera, prevenir la acumulación
del metronidazol que puede ser causante de disfunción del SNC, y de
neuropatía periférica.
Cathy S Malouf MD, Assistant Professor of Clinical Internal Med-
icine, School of Medicine, Texas Tech University Health Sciences
Center
Rafaela Mena de Giraldi
Reprints: Charles F Seifert PharmD FCCP BCPS, School of Phar-
macy, Texas Tech University Health Sciences Center, 3601 4th St.,
Ste. 1C162, Lubbock, TX 79430, FAX 806/743-4209, E-mail sopcfs@
ttuhsc.edu
RÉSUMÉ
OBJECTIF: Décrire un cas des changements à l’imagerie par résonance
magnétique électronique (IRM) probablement associés à une
accumulation de métronidazole chez un patient avec problème
hépatique.
References
1
. Ralph ED. Clinical pharmacokinetics of metronidazole. Clin Pharma-
cokinet 1983;8:43-62.
RÉSUMÉ DU CAS: Un homme de 34 ans avec cirrhose et hépatite C traité
avec métronidazole pour une méningite et une bactériémie au
Bacteroides fragilis a présenté de l’ataxie, de la désorientation et une
neuropathie périphérique. Le IRM au moment du diagnostic de la
méningite était négatif. Après avoir reçu plus de 60 g de métronidazole,
le IRM a révélé une augmentation de la densité sous, à l’arrière et du
côté latéral de quatrième ventricule. Les concentrations plasmatiques du
métronidazole étaient toxiques soit à 35.1 µg/mL.
2. Ahmed A, Loes DJ, Bressler EL. Reversible magnetic resonance imag-
ing findings in metronidazole-induced encephalopathy. Neurology 1995;
45:588-9.
3. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A
method for estimating the probability of adverse drug reactions. Clin
Pharmacol Ther 1981;30:239-45.
4. Dreger LM, Gleason PP, Chowdhry TK, Gazzuolo DJ. Intermittent-dose
DISCUSSION: Les auteurs rapportent le deuxième cas dans la littérature
des changements au IRM associés au métronidazole. Il est bien connu
que le métronidazole s’accumule chez les patients en insuffisance
hépatique et peut causer une neuropathie périphérique et des problèmes
au niveau du système nerveux central qui peut prendre deux ans avant
de disparaître.
metronidazole-induced peripheral neuropathy (letter). Ann Pharmacother
1
998;32:267-8.
. Learned-Coughlin S. Peripheral neuropathy induced by metronidazole
letter). Ann Pharmacother 1994;28:536.
5
6
(
. Boyce EG, Cookson ET, Bond WS. Persistent metronidazole-induced
peripheral neuropathy. DICP 1990;24:19-21.
7
. Kusumi RK, Plouffe JF, Wyatt RH, Fass RJ. Central nervous system tox-
icity associated with metronidazole therapy. Ann Intern Med 1980;93:
9-60.
. Bradley WG, Karlsson IJ, Rassol CG. Metronidazole neuropathy. Br
Med J 1977;2:610-1.
CONCLUSIONS: La posologie du métronidazole doit être réduite chez les
patients avec insuffisance hépatique pour prévenir une accumulation et
les effets toxiques.
5
8
Louise Mallet
www.theannals.com
The Annals of Pharmacotherapy
■
2000 November, Volume 34
■
1275