Levofloxacin-associated transient mixed sensorimotor lacunar syndrome
- 1 Neurology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
- 2 Neurology, NewYork-Presbyterian/Columbia University Medical Center, New York, New York, USA
- 3 Ronald O. Perelman Department of Emergency Medicine, NYU Grossman School of Medicine, New York, New York, USA
- 4 Toxicology, New York City Regional Poison Control Center, New York, New York, USA
- 5 Division of Stroke and Cerebrovascular Diseases, The Neurological Institute of New York, New York, New York, USA
- Correspondence to Dr Imama A Naqvi; ian2108@cumc.columbia.edu
Abstract
Fluoroquinolones are commonly used antimicrobials with multiple known adverse effects, yet overdose events are rarely reported. Here, we report a case of a previously healthy middle-aged woman who unintentionally ingested 7 g of levofloxacin in one dose. Thereafter, she presented to the emergency department with hemiparesis concerning for ischaemic stroke and was administered tissue plasminogen activator. Her brain imaging showed no ischaemic injury and her symptoms resolved within 24 hours; this is consistent with a transient ischaemic attack. Our case highlights potential adverse effects of an acute overdose of levofloxacin that has not previously been well described.
Background
Fluoroquinolones, such as ciprofloxacin and levofloxacin, are an effective class of antimicrobials commonly used for treatment of a wide variety of bacterial infections. Though their usage has decreased over time from growing concern over bacterial resistance and adverse effects, they continue to be commonly prescribed, with 15.7 million outpatient prescriptions of fluoroquinolones dispensed in the USA in the year 2020 alone.1 The US Food and Drug Administration has released black box warnings for several severe adverse effects, including peripheral neuropathy, tendon rupture, aortic aneurysm and broad central nervous system effects.2
The adverse effects of fluoroquinolones are mostly reported in the context of use as prescribed, and reports of fluoroquinolone overdose are relatively rare. The anticipated effects of overdose include nephrotoxicity, hepatotoxicity, prolongation of the QT interval, severe dermatologic reactions, tendon rupture and aortic dissection.2 Interestingly, although focal neurologic deficits are not an anticipated effect of fluoroquinolone overdose, Rosolen et al reported a case of transient hemiparesis and cranial neuropathy in an adolescent, thought to be due to ciprofloxacin exposure.3
We report a case of unintentional overdose of levofloxacin that presented as transient hemiparesthesia and hemiparesis, concerning for transient ischaemic attack (TIA). We discuss the patient’s course of therapies and diagnostics, weigh the evidence for an effect of levofloxacin overdose and propose a potential causal mechanism.
Case
A woman in her 50s with essential hypertension presented to our emergency department with acute left leg weakness. At baseline, the patient had no focal neurologic deficits, managed her own small business and cared for an elderly parent. She reported that she takes 14 supplements daily, including multivitamins, vitamins C, D and calcium, and denied taking any other over the counter or prescription medications. Two days prior to presentation, she filled a 2-week prescription of levofloxacin 500 mg daily for chronic pyelonephritis without renal impairment, and on the morning of presentation, she unintentionally took the entire bottle of 14 tablets of levofloxacin instead of her usual daily 14 supplement pills. One hour later, she became nauseated, flushed and dizzy, and noted that she had weakness of her left leg and presented to the emergency department.
On arrival, her initial vital signs were as follows: blood pressure, 136/89 mm Hg; heart rate, 86 bpm; respiratory rate, 26 breaths/minute; temperature, 36.7°C; O2 Sat, 100%; point of care glucose, 100 mg/dL. A neurologic rapid response was initiated given the acute symptoms of left leg weakness with left-sided sensory changes. The patient received a National Institute of Health Stroke Scale (NIHSS) of 6 for left arm and leg numbness, no movement of her left leg and mild drift of the left arm that did not hit the bed. Computed tomography (CT) of the head did not find a hypodensity, consistent with an acute stroke or TIA and a CT angiogram of the head and neck did not reveal stenosis or obstruction in the large vessels, including the vertebral arteries, the common carotid arteries and the internal and external carotid arteries. Given the time course and presenting symptoms, the most likely diagnosis was thought to be a small-vessel acute ischaemic stroke. Risks and benefits of tissue plasminogen activator (tPA) administration were discussed with the patient and, after she consented, tPA was administered 2 hours and 35 min after symptom onset.
The patient’s routine laboratory tests were notable only for creatinine clearance of 69 mL/min (88–128), venous blood pH of 7.52 (7.31–7.41), venous blood PCO2 of 31 mm Hg (41–51), venous blood PO2 43 mm Hg (30–40) and lactate of 3.47 mmol/L (0.5–2.2) (table 1). Her electrocardiogram (ECG) revealed a normal sinus rhythm with QT interval duration corrected for heart rate (QTc) of 499 ms, which decreased to 472 ms over the next 24 hours (figure 1).
The results of the patient’s routine laboratory tests
| Complete blood count | ||
| White blood cell count | 5.56 | (3.48–9.42×109/L) |
| Haemoglobin | 12.4 | (11.2–14.7 g/L) |
| Haematocrit | 36.0 | (33.8%–43.3%) |
| Platelets | 305 | (167–374x109/L) |
| Basic metabolic panel | ||
| Sodium | 143 | (136–145 mmol/L) |
| Potassium | 3.4* | (3.5–5.1 mmol/L) |
| Chloride | 102 | (98–107 mmol/L) |
| Bicarbonate | 22 | (22–29 mmol/L) |
| Blood urea nitrogen | 19 | (6.0–20.0 mg/dL) |
| Creatinine | 0.81 | (0.70–1.20 mg/dL) |
| Glucose | 110* | (74–99 mg/dL) |
| Calcium | 10.2 | (7.4–10.4 mg/dL) |
| Magnesium | 1.6 | (1.5–2.2 mg/dL) |
| Phosphorus | 2.2* | (2.5–4.5 mg/dL) |
| Anion Gap | 19* | (5–17) |
| Liver function tests | ||
| Total protein | 7.2 | (6.5–8.1 g/dL) |
| Albumin | 4.9 | (3.9–5.2 g/dL) |
| Globulin | 2.3 | (2.0–3.5 g/dL) |
| Total bilirubin | 0.6 | (0.2–1.3 mg/dL) |
| Direct bilirubin | 0.1 | (0.0–0.3 mg/dL) |
| Indirect bilirubin | 0.5 | (0.2–0.9 mg/dL) |
| Aspartate transaminase | 18 | (10–37 U/L) |
| Alanine transaminase | 19 | (9–50 U/L) |
| Alkaline phosphatase | 62 | (40–129 U/L) |
| Coagulation panel | ||
| Prothrombin time | 11.6 | (10.0–13.0 s) |
| International normalised ratio | 1.0 | (0.87–1.13) |
| Activated partial thromboplastin time | 37.0 | (25.0–35.0 s) |
| Venous blood gas | ||
| pH | 7.52* | (7.31–7.41) |
| pC02 | 31* | (41–51 mm Hg) |
| pO2 | 43 | (30–40 mm Hg) |
| Lactate | 3.47* | (0.5–2.2 mmol/L) |
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The laboratory’s reference range for each test is reported in brackets.
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*Abnormal results.
The patient’s initial ECG.
On re-examination 2 hours after tPA administration, the patient’s NIHSS had improved to 3 (1 for sensory loss in the arm and leg and 2 for drift in the left leg that hit the bed). At that time, she reported symptoms of anxiety, palpitations, generalised muscle tightness and bilateral, painful muscle cramps, and physical examination revealed generalised tremulousness, hand stiffness and flushed skin. On non-contrast brain magnetic resonance imaging (MRI), there was no hyperintensity on diffusion weighted imaging, inconsistent with acute stroke, but consistent with TIA. Twenty-four hours after symptom onset, all symptoms had resolved. A levofloxacin blood concentration measured 29 hours after the initial ingestion was 8.51 µg/mL.
Outcome and follow-up
At discharge, the patient was at her baseline level of function and was able to resume her usual activities of daily living without any rehabilitation needs. She returned to work the following day.
On follow-up at 5 months, the patient reported feeling well overall and continued to perform her activities of daily living without problem. She reported that 2–4 weeks after the event, she began experiencing severe pain in her bilateral wrists and ankles, left greater than right. She was diagnosed with tendinopathy, and at 5 months continued to have intermittent tendon pain. She also reported intermittent episodes of numbness on her left arm and leg that lasted minutes. In addition, she felt as though the strength in her left arm was not at baseline but could not state when she noticed the change. On examination, she demonstrated subtle left arm drift and demonstrated 4+/5 strength in left elbow extension, wrist flexion and finger strength. The rest of her examination was normal. Repeat MRI of the brain was unchanged compared with the prior MRI of the brain.
Discussion
In the case reported here, hemiparesis developed 1 hour after taking a large dose of levofloxacin and was resolved completely 24 hours later. Healthy individuals reach a peak drug plasma concentration (Cmax) of approximately 2.8 and 5.2 µg/mL within 1–2 hours after oral administration of levofloxacin 250 and 500 mg tablets, respectively.4 By comparison, the patient described in this report had a lower creatinine clearance than normal and a blood levofloxacin concentration of 8.51 µg/mL 29 hours after ingestion. As the elimination half-life of levofloxacin is thought to be 6–8 hours for those with normal renal function,4 the patient’s Cmax was most likely many times higher than the Cmax seen in patients taking therapeutic dosages.
In addition to hemiparesis, the patient also presented with nausea, flushing and dizziness, known side effects of levofloxacin use. The patient’s symptoms of muscle rigidity and cramping (spasms) and tremor are reported adverse effects of levofloxacin and could be due to an inhibitory effect of levofloxacin on γ-Aminobutyric acid type-A (GABA-A) receptors and an excitatory effect on N-methyl-D-aspartate (NMDA)receptors.5–7 The patient’s anxiety is also a known side effect of levofloxacin, possibly due to levofloxacin’s potential to stimulate generation of reactive oxygen species, causing diffuse oxidative stress in the brain. Given the presentation and time course of events, an interdisciplinary team of pharmacologists, physicians and the regional poison control centre posited that the hemiparesis was also associated with levofloxacin toxicity. The Naranjo adverse reaction probability score was calculated to assess the probability that this adverse neurologic reaction was associated with levofloxacin.8 The score for this patient was 5, which suggested a ‘probable adverse drug reaction’. There was no rechallenge with levofloxacin after discontinuation.
A literature search with MeSH terms ‘fluoroquinolones’ and ‘hemiparesis’ yielded one case previously reported. In 1994, Rosolen et al reported hemiparesis of a 15-year-old girl after ciprofloxacin exposure.3 The patient was being treated for acute lymphoblastic leukaemia with no central nervous system involvement. She was started on ciprofloxacin 250 mg two times per day for a week of headache and fever. A few hours after the fourth dose, she developed acute left hemiparesis, including ipsilateral face, with partial loss of taste and dysarthria. The following two doses of ciprofloxacin were inadvertently held, and all symptoms resolved. When ciprofloxacin was readministered, the patient redeveloped left hemiparesis and dysarthria as well as dysphagia, right facial paresthesia, left cranial nerve XII neuropathy and bilateral cranial nerve X neuropathy (table 2). Lumbar puncture and CT of the head were negative, and symptoms resolved with ciprofloxacin cessation. The authors considered an underlying vascular mechanism affecting the brain stem as the likely cause, as these symptoms would be associated anatomically with ischaemic injury to the nervous system in this region.
Comparing the symptoms in the previously described case report to the symptoms in this case report
| Facial weakness | Limb weakness | Loss of sensation | Cranial neuropathies | Anxiety and tremors | Rigidity and spasms | Flushing | |
| Rosolen | x | x | x | x | |||
| Michelassi | x | x | x | x | x | x |
Likewise, the hemiparesthesia and hemiparesis described in our case reported here fits a vascular distribution localising to the small vessels supplying the contralateral thalamus and posterior limb of the internal capsule, suggestive of a mixed sensorimotor lacunar TIA in the context of levofloxacin overdose. An association between fluoroquinolones and first-time ischaemic stroke has previously been reported, with a 17% increase in ischaemic stroke among those who took short courses of fluoroquinolones.9 One previously proposed mechanism for fluoroquinolone-associated increased risk of ischaemic stroke is that fluoroquinolones cause increased collagenolysis and could temporarily weaken the fibrous cap of atherosclerotic plaques, making them more prone to rupture, causing either small-vessel ischaemic infarcts or vessel-to-vessel strokes.10 The limitation in this mechanism is that it does not account for strokes in patients who are unlikely to have atherosclerotic disease, such as the 15-year-old patient described by Rosolen et al and the patient described in this case report, who did not have supporting radiographic evidence of intracranial atherosclerotic disease.
Recent discoveries of the role of collagen in stroke may shed a light on how fluoroquinolones may be associated with stroke and TIA. Mutations in the collagen genes COL4A1/2 prevent collagen cross-linking and are monogenic causes of small vessel strokes.11 12 The mechanism is thought to be due to destabilisation of the basement membrane of the blood–brain barrier, of which collagen IV is an essential component. Fluoroquinolones lead to the inhibition of proline hydroxylation in collagen,13 preventing collagen cross-linking, thought to be responsible for tendon and aortic aneurysm rupture seen within days of initiation of fluoroquinolone use.14 Thus, it may potentially disrupt the integrity of the basement membrane similar to COL4A1/2 mutations. Further evidence of the association of small vessel stroke and collagen dysfunction can be seen with vitamin C deficiency, which also impairs collagen cross-linking.15 Vitamin C deficiency is associated with an increased risk of stroke,15 and a case has been reported of small vessel stroke associated with severe, symptomatic vitamin C deficiency.16 Therefore, the association between fluoroquinolone and small vessel ischaemia may be due to induced collagen dysfunction causing basement membrane weakness in cerebral small vessels similar to the mechanism by which fluoroquinolones may increase the risk of tendon rupture and aortic aneurysm formation (figure 2).
A proposed mechanism for the association between fluoroquinolones and stroke/transient ischaemic attack. (A) At baseline, collagen crosslinks and provides an essential support for tendons, the aorta and the blood–brain barrier. (B) In the presence of fluoroquinolones, collagen crosslinking is impaired, weakening the collagen structures and leading to increased risk of tendon rupture, aortic aneurysm development and brain ischaemia. Figure created with BioRender.com.
Fluoroquinolones, and in particular levofloxacin, are still a commonly prescribed antibiotic class. There are now two cases of hemiparesis associated with acute fluoroquinolone exposure. While seemingly rare, our case may help prescribers consider levofloxacin toxicity as a potential cause for clinical effects that resemble acute stroke, and that withdrawal of this drug may be indicated for patients experiencing this adverse effect.
Learning points
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In this case report, levofloxacin overdose was associated with a transient focal stroke syndrome.
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Fluoroquinolones are associated with an increased risk of stroke.
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Defects in collagen cross-linking are associated with an increased risk of stroke.
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Fluoroquinolones disrupt collagen cross-linking.
Ethics statements
Patient consent for publication
Footnotes
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Twitter @joshb107, @markksu1md, @ImamaNaqviMD
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Contributors FM, JB, MS and IAN equally contributed to the planning and the design of the case report. FM wrote the majority of the drafts, and JB, MS and IAN equally contributed critical edits of the manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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