Effect of edaravone on acute brainstem–cerebellar infarction with vertigo and sudden hearing loss

Auris Nasus Larynx 41 (2014) 303–306

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Effect of edaravone on acute brainstem–cerebellar infarction with vertigo and sudden hearing loss Yuta Inoue *, Takao Yabe, Kazunari Okada, Yuka Nakamura Department of Otolaryngology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan

A R T I C L E I N F O

A B S T R A C T

Article history: Received 15 June 2013 Accepted 4 October 2013 Available online 28 October 2013

We report 2 cases with acute brainstem and brainstem–cerebellar infarction showed improvement of their signs and symptoms after administration of edaravone. Case 1, a 74-year-old woman who experienced sudden vertigo, also had dysarthria and left hemiplegia. Magnetic resonance imaging (MRI) showed an abnormal region in the right ventrolateral medulla oblongata. The patient’s vertigo and hemiplegia improved completely after treatment. Case 2, a 50-year-old man who experienced sudden vertigo and sensorineural hearing loss (SNHL), developed dysarthria after admission. MRI revealed acute infarction in the right cerebellar hemisphere. Magnetic resonance angiography revealed dissection of the basilar artery and occlusion of the right anterior inferior cerebellar artery. The patient’s vertigo and hearing remarkably improved. We have described 2 patients whose early symptoms were vertigo and sudden SNHL, but who were later shown to have ischemic lesions of the central nervous system. Edaravone is neuroprotective drug with free radical-scavenging actions. Free radicals in the ear are responsible for ischemic damage. Edaravone, a free radical scavenger, may be useful in the treatment of vertigo and SNHL. ß 2013 Elsevier Ireland Ltd. All rights reserved.

Keywords: Edaravone Free radical Hearing loss Vertigo

1. Introduction

2. Case report

Edaravone (3-methyl-1-phenyl-pyrazolin-5-one), a free radical scavenger, is a clinical drug that has been widely used in Japan since 2001 to reduce neuronal damage after acute cerebral infarction [1]. Edaravone has been reported to inhibit lipid peroxidation, vascular endothelial cell injury, brain edema, tissue injury, and delayed neuronal death, and consequently to reduce neurological deficits [1]. Free radicals in the ear are responsible for ischemic damage. Recently, edaravone has been reported to markedly reduce the loss of inner hair cells after cochlear ischemia in gerbils [2]. But, its effectiveness for treating cochlear ischemia has not yet been revealed in humans. In this paper, we report 2 cases in which acute brain infarction was accompanied by vertigo and sudden sensorineural hearing loss (SNHL). Treatment of the infarction with edaravone also improved the inner ear symptoms; therefore, edaravone also appears to be effective for treating inner ear problems associated with brain infarction in humans.

In Case 1, the patient was a 74-year-old woman who experienced sudden vertigo accompanied by nausea, numbness and coldness in the left limb when she got up. She had a past history of hypertension, spinal canal stenosis, and a cataract. Electrocardiography revealed that she had atrial fibrillation. Computed tomography (CT) scans of the brain revealed no abnormalities. On physical examination, she had right and left lateral gaze nystagmus. She showed dysdiadokokinesis, finger to nose and heel to knee tests were dysmetric and diminished pain and temperature sensation on the left side. She did not complain about hearing loss, so a pure-tone audiogram was not performed. During the initial 6 h of hospitalization, she appeared dysarthria and incomplete left hemiplegia. Left Babinski reflex were observed. Axial T2- and diffusion-weighted magnetic resonance imaging (MRI) of the brain revealed no obvious abnormalities. However, we strongly suspected a cerebral embolism and administered heparin and edaravone for 2 weeks. Fluid-attenuated inversion recovery (FLAIR) MRI of the brain revealed an abnormal region in the right ventrolateral medulla oblongata on day 10 (Fig. 1). Subsequently, the patient’s vertigo and hemiplegia improved completely. In Case 2, the patient was a 50-year-old otherwise healthy man who experienced sudden vertigo that occurred when he started office work. On physical examination, we observed left-beating horizontal torsional spontaneous nystagmus, which was enhanced

* Corresponding author at: Department of Otolaryngology, Tokyo Metropolitan Hiroo Hospital, 2-34-10 Ebisu, Shibuya-ku, Tokyo 150-0013, Japan. Tel.: +81 3 3444 1181; fax: +81 3 3444 3196. E-mail address: [email protected] (Y. Inoue). 0385-8146/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.anl.2013.10.001

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Fig. 1. Axial magnetic resonance imaging (MRI) of the brain performed 10 days after the onset of vertigo in patient 1. Fluid-attenuated inversion recovery MRI of the brain revealed an abnormal region in the right ventrolateral medulla oblongata (filled arrow).

when the patient gazed to the left. He had no ophthalmoplegia, facial paralysis or numbness, Horner’s syndrome, or cerebellar dysmetria. CT scans of the brain revealed no abnormalities. In the course of waiting to be examined, he presented with sudden deafness on the right side. The eardrums appeared normal. A puretone audiogram showed profound right-sided SNHL (Fig. 2A). Despite we considered right sudden SNHL with vertigo, he developed dysarthria, numbness in the left hand, and slight dysdiadokokinesis, finger to nose and heel to knee tests were dysmetric after 5 h of hospitalization. Diffusion-weighted MRI of the brain showed acute infarction in the right cerebellar hemisphere (Fig. 3A). Magnetic resonance angiography (MRA) revealed dissection of the basilar artery and occlusion of the right anterior inferior cerebellar artery (AICA) (Fig. 3B). From the same day, the patient was begun administering heparin, glycerol and edaravone. High-dose steroid therapy was started from the same day, it was discontinued on the same day. Two weeks later, a second brain MRA showed reperfusion of the AICA (Fig. 3C). After 22 days later, the patient’s hearing remarkably improved (Fig. 2B). Subsequently, the patient’s vertigo and numbness improved completely. An eye-tracking test and an optokinetic pattern test revealed no abnormalities. The caloric test to cold water revealed normal responses of 308/s on the right side and 208/s on the left side. 3. Discussion We have described 2 patients whose early symptoms were vertigo and sudden SNHL, but who were later shown to have ischemic lesions of the central nervous system. In both cases, edaravone given for the ischemia also resolved the vertigo and associated SNHL. Sudden SNHL and vertigo are potentially caused by cerebrovascular disorders [3]. Distinguishing between peripheral and central lesions is important for ruling out potentially lifethreatening conditions. Diffusion-weighted MRI of the brain is usually an invaluable procedure for early detection of acute

ischemic stroke. However, in Case 1, diffusion-weighted MRI of the brain initially revealed no obvious abnormality. Only in later follow-up scans, after neuro-otological examination indicated aggravation of symptoms, was an infarction of the ventrolateral medulla oblongata revealed. FLAIR MRI of the brain can be used to estimate the onset time of an acute ischemic stroke within 24 h of the onset [4]. A patient suspected of acute ischemic stroke should be examined using both diffusion-weighted and FLAIR MRI of the brain. If MRI shows no definite abnormalities, we suggest neurootological examinations – in particular nystagmus assessment – as highly valuable tools for clinical diagnosis. Case 2 is an instance of AICA infarction because of the basilar artery dissection. In 1943, Adams first described the clinical symptoms of an AICA infarction [5]. Occlusion of the AICA is rare. Roquer et al. reported that AICA infarcts were diagnosed in 0.9% of all acute strokes in their department and accounted for 5.2% of those affecting the vertebrobasilar system [6]. Edaravone is regarded as a readily available neuroprotective drug with free radical-scavenging actions. A randomized controlled study, in which 30 mg of edaravone was infused twice a day for 14 days to patients within 72 h after the onset of ischemic stroke, showed significant improvement of functional outcome in the edaravone group [1]. For patients treated within 24 h, the difference between the edaravone and placebo groups was even clearer. Thus, patients suspected of having an ischemic stroke should be administered edaravone as soon as possible. We suggest that in the cases reported here, the early judgment and treatment prevented the occurrence of serious conditions in both cases. Maetani et al. reported that edaravone had a protective effect against the deterioration of auditory brain response (ABR) thresholds and inner hair cell death by intravenous administration (1 mg/kg) 1 h after cochlear ischemia in Mongolian gerbils [2]. These findings suggest that preventing free radical generation may attenuate ischemia-induced hearing dysfunction. Moreover, they suggest that edaravone might protect against aminoglycoside ototoxicity. A similar result was also observed regarding damage due to noise exposure [7]. Cochlear ischemia and reperfusion dysfunction, inflammation could be possible pathogenesis of sudden SNHL. One previous case in which edaravone was used the treatment of AICA syndrome with acute SNHL has been reported [8]. This is thus the second report of edaravone treatment for severe HL with AICA infarction, and the first case in which edaravone was effective against AICA syndrome with severe SNHL without steroid therapy. The current standard treatment for idiopathic sudden SNHL is systemic steroid therapy. Table 1 shows a summary of comparison between edaravone and steroid treatment. Unlike edaravone, Steroid has been reported to support a beneficial role of anti-inflammatory and immunosuppressive agents in reducing hearing loss and cochlear damage [10]. Intratympanic steroid therapy was not inferior to systemic steroid therapy [11]. One previous report has compared the efficacy of intratympanic steroid therapy, systemic steroid therapy, and combined therapy. No difference in the level of hearing gain or ratio of hearing improvement was observed among the three groups [12]. If steroid therapy proves inadequate, edaravone administration might be one treatment option for acute SNHL. In the cases reported here, heparin was administered with edaravone. Heparin is also used as common medical treatment for acute ischemic stroke. In a prospective study by Mattox and Simmons, 60% of patients with sudden idiopathic SNHL were found to recover with heparin treatment, which is no significant advantage independent of the type of medical therapy [13]. Therefore, we guess edaravone has more effect than heparin for acute SNHL. In a randomized controlled study to investigate whether adding edaravone could improve treatment outcomes in patients

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Fig. 2. (A) An initial pure-tone audiogram (PTA) showed severe sensorineural hearing loss on the right side. (B) A PTA following treatment showed recovery from the hearing loss after 22 days.

Fig. 3. MRI and magnetic resonance angiography (MRA) scans of the brain in Patient 2. (A) Diffusion-weighted axial images revealed acute infarction in the right cerebellar hemisphere (filled arrow). (B) MRA before treatment revealed basilar artery dissection (open arrow) and occlusion of the right anterior inferior cerebellar artery (AICA) (arrowhead). (C) MRA following treatment showed recanalization of basilar artery (open arrow) and reperfusion of the AICA (arrowhead).

with severe sudden SNHL, the final hearing levels between the edaravone and control groups were not significantly different [14]. This may have been because of one or more of the following factors: treatment was started within three days from the onset, 3 of 14 patients were administered only 30 mg edaravone once a day, and all patients in the control group received hyperbaric oxygenation therapy. Starting treatment within 24 h of sudden SNHL onset might be of prognostic

significance for hearing levels as with cochlear ischemia. Tanaka et al. suggested that edaravone might be clinically effective in the treatment of acoustic trauma, especially if given within 21 h of noise exposure [7]. If a patient’s hearing level showed no change after an intravenous injection of edaravone, Sano et al. suggested that different dosages or methods such as intratympanic infusion should be used [14]. Consistent with this suggestion, Takumida and Anniko reported that intratympanic

Table 1 Summary of comparison between edaravone and steroid treatment.

Edaravone

Report

Effect

Mechanism

Start of administration

Maetani et al. [2]

Prevent ischemia-induced hearing dysfunction Protect against damage due to noise exposure Direct effects of glucocorticoid action on select inner ear cells

Protection against inner hair cell loss Protection against inner hair cell loss Glucocorticoid receptors were detected in the human inner ear Reducing loss of viable neurons in the spiral ganglion, increase in cochlear blood flow

1 h after ischemia

Tanaka et al. [7] Steroid

Rarey and Curtis [9]

Worsøe et al. [10]

Anti-inflammatory and immunosuppressive effects

9 h before to 33 h after noise exposure –

21 h after bacterial inoculation

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injection of edaravone significantly reduced the shift in the ABR threshold when the drug was injected simultaneously with or 1 h after albino rats were exposed to Pseudomonas aeruginosa exotoxin A [15]. If intravenous edaravone therapy showed no change hearing level, intratympanic edaravone injection might be alternative treatment. The major adverse reactions of edaravone are skin rashes and abnormal liver function. Other side effects that require careful attention are acute renal failure and thrombocytopenia. In the present study, however, none of these adverse reactions were observed in either patient. 4. Conclusion We report 2 cases with acute brainstem and brainstem– cerebellar infarction showed improvement of their signs and symptoms after administration of edaravone. Edaravone is neuroprotective drug with free radical-scavenging actions. Free radicals in the ear are responsible for ischemic damage. Edaravone, a free radical scavenger, may be useful in the treatment of vertigo and SNHL. Conflicts of interest None. Acknowledgment We express our thanks to H. Yamada, MD, Department of neurology, Tokyo metropolitan hiroo hospital, for clinical support.

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