 Advertisement | ||||||||
 | ||||||||
|
||||||||
 |
 |
 |
 |
 |
 |
 |
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
| Cases |
From the Department of Clinical Neurosciences, University of Calgary, Calgary, Alta.
Correspondence to: Dr. Sarah Furtado, Movement Disorders Clinic, University of Calgary, 3350 Hospital Dr. NW, Calgary AB T2N 4Z5; fax 403 944-4063; furtado{at}ucalgary.ca
 |
Patient 1 |
|---|
 Top Patient 1 Patient 2DiscussionREFERENCES |
|---|
Neurological examination showed cerebellar dysarthria, bilateral dysmetria and an ataxic wide-based gait. The rest of the examination was unremarkable. The results of magnetic resonance imaging (MRI) of the patient’s brain were reported to be normal, although, in retrospect, faint hyperintensities within the dentate nuclei could be seen on the T2-weighted fluid-attenuated inversion recovery (FLAIR) scans. The patient’s symptoms and signs improved over the next 4 days.
One week later, the patient’s dysarthria and ataxia (gait and appendicular) worsened, and he was admitted to hospital. Repeat T2-weighted FLAIR MRI showed obvious bilateral symmetric hyperintensities within the dentate nuclei of the cerebellum (Figure 1A). The results of a thorough work-up for cerebellar disorders were negative: nutritional causes (vitamin B12 and vitamin E deficiencies) and genetic disorders (Friedreich ataxia, spinocerebellar ataxias 1, 2, 3, 6, 7 and 8, cerebrotendinous xanthomatosis) were ruled out. About 1 month after admission, phenytoin was initiated after a second seizure.
|
At the initial presentation, the cause of the patient’s difficulties was not recognized, and he continued to take metronidazole for bronchiectasis until this therapy was discontinued about 2 months later. At a follow-up examination 3 months after discontinuation of metronidazole, the patient’s cerebellar syndrome had resolved. A repeat MRI scan of the patient’s brain showed complete resolution of signal changes within the dentate nuclei (Figure 1B).
|
Patient 2 |
|---|
|
TopPatient 1Patient 2DiscussionREFERENCES |
|---|
About 3 weeks after initiation of metronidazole (500 mg twice a day, cumulative dose of about 25 g), she developed a cerebellar syndrome with cerebellar dysarthria, dysmetria and gait ataxia. An MRI scan of her brain taken about 2 months after the onset of this syndrome showed abnormal signal within the cerebellar dentate nuclei bilaterally on T2-weighted FLAIR imaging (Figure 1C), which was virtually identical to the findings for patient 1. Based on these findings, metronidazole toxicity was suspected, and the drug was discontinued. The patient’s symptoms gradually resolved over the next few weeks. An MRI scan of her brain taken 1 month after metronidazole was stopped showed complete resolution of the cerebellar dentate lesions (Figure 1D). The patient died 2 months later of unrelated causes.
|
Discussion |
|---|
|
TopPatient 1Patient 2DiscussionREFERENCES |
|---|
|
A reversible cerebellar syndrome with characteristic cerebellar dentate nuclei lesions on T2-weighted FLAIR MRI scans has been attributed to metronidazole use, as described for our 2 patients and by others. 4–7 Patients usually present with cerebellar dysarthria and ataxia that may occasionally fluctuate, as in our first patient. The duration of treatment with metronidazole before cerebellar symptoms manifest is variable, ranging from 28 days 6 to 3 months, 7 and cumulative doses range from 25 g (as in our second patient) to 90 g. 7 Patients usually experience complete resolution of the symptoms after discontinuation of metronidazole, sometimes within a few days. To our knowledge, there have been no published reports of cerebellar syndrome associated with metronidazole that have not improved after discontinuation of metronidazole therapy. Our patients’ symptoms and signs resolved within weeks of stopping metronidazole. The MRI changes also resolved in both patients, thereby implicating the drug as the causative agent.
The reversible cerebellar syndrome described by us and by others is correlated with striking and symmetric MRI T2–FLAIR hyperintensities within the dentate nuclei of the cerebellum. Other areas of the brain may also be affected by metronidazole use, including the midbrain, pons, medulla, corpus callosum and other brainstem regions. 8 The cerebellar dentate nuclei is the most commonly affected area.
The mechanism of action of metronidazole-induced neurotoxicity on the central and peripheral nervous systems is not well understood. Proposed mechanisms include binding of metronidazole to RNA, DNA and inhibitory neurotransmitters, as well as inducing both vasogenic and cytotoxic edema. 6 Metronidazole is structurally similar to the thiazole precursor of thiamine and could thereby lead to a reduction in thiamine absorption by acting as a thiamine analog. 9
The propensity to develop these adverse effects is poorly understood. There may be some relation to dose, but in both of our patients, the administered dose was within the recommended range. Patient 2 developed the syndrome after a relatively low cumulative dose of only 25 g, which is at the low end of the range of doses associated with cerebellar syndrome. Synergistic toxicity with other medications is also possible. 10
The neurotoxic adverse effects of metronidazole continue to be underrecognized despite its widespread use. Our recognition of the cause for the dentate lesions in our first patient was delayed until one of us (S.F.) came across a case description in a specialty journal. Recognition of the syndrome prompted discontinuation of metronidazole for patient 2.
Adverse side effects from medications, particularly when unexpected and serious, should be reported to the Canada Vigilance Program (www.healthcanada.gc.ca/medeffect).
|
Footnotes |
|---|
This article has been peer reviewed.
Competing interests: None declared.
|
REFERENCES |
|---|
|
TopPatient 1Patient 2DiscussionREFERENCES |
|---|
Related Article
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | HELP | SEARCH |
|
|||||
|
Copyright 1995-2009, Canadian Medical Association. All rights reserved. ISSN 1488-2329
(e) 0820-3946 (p)
All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association. |
|||||
