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Review Article
Recent advances in diagnostic and therapeutic strategies for management of dizzy patients in Japan
Noriaki Takedaorcid
Research in Vestibular Science 2025;24(1):1-9.
DOI: https://doi.org/10.21790/rvs.2025.001
Published online: March 14, 2025

Department of Otolaryngology-Head and Neck Surgery, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

Corresponding author: Noriaki Takeda Department of Otolaryngology, University of Tokushima School of Medicine, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. E-mail: takeda@tokushima-u.ac.jp
• Received: January 13, 2025   • Revised: February 3, 2025   • Accepted: February 19, 2025

© 2025 The Korean Balance Society

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • The present review summarized the recent advances in diagnostic and therapeutic strategies for management of dizzy patients in Japan. Standardization of diagnosis, examination, and treatment of vestibular disorders and nationwide epidemiological surveys of vestibular disorders are high-priority projects of Japan Society for Equilibrium Research (JSER). JSER published clinical practice guidelines for Ménière’s disease, delayed endolymphatic hydrops, benign paroxysmal positional vertigo, vestibular neuritis, vestibular test battery, and vestibular rehabilitation. JSER published a video library of vestibular testing and nystagmus and abnormal eye movements. JSER performed nationwide surveys of Ménière’s disease, delayed endolymphatic hydrops, and bilateral vestibulopathy. Visualization of endolymphatic hydrops in gadolinium-enhanced magnetic resonance imaging (MRI) was developed in Japan. MRI of endolymphatic hydrops becomes an indispensable tool to diagnose Ménière’s disease. The new surgical procedure of endolymphatic sac surgery with steroid instillation and middle ear pressure therapy with a Japanese device become new therapeutic strategies for intractable Ménière’s disease in Japan. Neural and pharmacological mechanisms of static vestibular compensation were revealed in Japan. Diazepam accelerates the initial process of static vestibular compensation and short-term administration with diazepam is recommended for the treatment of acute vertigo in patients with unilateral vestibulopathy. Betahistine accelerates the late process of static vestibular compensation and long-term administration with betahistine is recommended for the treatment of subacute vertigo in patients with unilateral vestibulopathy. Vestibular rehabilitation is effective in developing dynamic vestibular compensation and beneficial for improving chronic dizziness in patients with unilateral vestibulopathy. Vestibular rehabilitation with a Japanese vestibular substitution device is a promising strategy for chronic dizziness in patients with unilateral vestibulopathy.
  • Keywords: Standardization; Epidemiology; Endolymphatic hydrops imaging; Middle ear pressure therapy; Vestibular compensation; Vestibular substitution device
Recently, diagnosis and therapy of dizziness were markedly advanced in Japan. This review summarized the recent advances in diagnostic and therapeutic strategies for management of dizzy patients in Japan. It included (1) standardization of management for dizzy patients by Japan Society for Equilibrium Research (JSER), (2) epidemiological surveys by JSER, (3) visualization of endolymphatic hydrops with magnetic resonance imaging (MRI), (4) new surgical and noninvasive treatments of Ménière’s disease, (5) new insights of mechanisms of Ménière’s attack, (6) mechanisms of static vestibular compensation and its clinical implications, (7) dynamic vestibular compensation and vestibular rehabilitation, and (8) vestibular rehabilitation with new vestibular substitution devices.
Standardization of Management for Dizzy Patients by Japan Society for Equilibrium Research
JSER published Clinical Practice Guideline of Ménière’s Disease and Delayed Endolymphatic Hydrops 2020, Clinical Practice Guideline of Vestibular Neuritis 2021, and Clinical Practice Guideline of Benign Paroxysmal Positional Vertigo 2023. JSER also published Clinical Guideline of Vestibular Test Battery 2018 and Clinical Guideline of Vestibular Rehabilitation 2024. JSER further published Video Library of Vestibular Testing 2023 and Video Library of Nystagmus and Abnormal Eye Movements 2024. Such standardization of diagnosis, examination and treatment of vestibular disorders is a high-priority project of JSER (Fig. 1).
Epidemiological Surveys by Japan Society for Equilibrium Research
JSER continues to conduct nationwide epidemiological surveys of vestibular disorders funded by the Ministry of Health, Labor and Welfare of Japan. The nationwide surveys of Ménière’s disease were conducted five times in 1975–1976, 1982–1984, 1990, 2001–2006, and 2014–2017 in Japan. The findings of the latest survey were as follows. The estimated prevalence of Ménière’s disease was 35 to 48 out of 100,000 population in Japan. High prevalence of females was gaining after the 1980s. Bilateral ear involvement was gradually increased. The number of elderly-onset female Ménière’s patients was increasing, probably because of stress due to care for their more elderly parents [1].
The nationwide surveys of delayed endolymphatic hydrops were conducted twice in Japan. The first survey of 198 patients with delayed endolymphatic hydrops conducted in 1998, 2001, and 2006–2008 showed that the incidence of the ipsilateral type was almost the same as the contralateral type, and that the most common diagnosis of precedent deafness was (1) deafness of unknown cause with onset in early childhood, (2) sudden deafness, and (3) mumps deafness [2]. The second survey of 589 patients with delayed endolymphatic hydrops conducted in 1998, 2001, and 2006–2017 showed that the estimated prevalence of delayed endolymphatic hydrops was 0.8 out of 100,000 population in Japan [3]. A nationwide survey of 401 patients with bilateral vestibulopathy conducted in 2019 showed the estimated prevalence of bilateral vestibulopathy was 0.84 out of 100,000 population in Japan [4]. The nationwide epidemiological surveys of vestibular disorders are a high-priority project of JSER.
Visualization of Endolymphatic Hydrops with Magnetic Resonance Imaging
The most important histopathological finding in patients with Ménière’s disease is endolymphatic hydrops. In 1938, Professor Hallpike [5] in London and Professor Yamakawa [6] in Osaka first reported endolymphatic hydrops in the temporal bones of patients with Ménière’s disease. Imaging methods of the endolymphatic space of human temporal bone with MRI were developed in the 1990s in Japan. Professor Koizuka et al. [7] in Kanagawa showed the first MRI of human temporal bone with comparative histological section in 1991. However, MRI of endolymphatic hydrops had not been established for living humans until 2007.
In 2007, Professor Nakashima et al. [8] in Nagoya first visualized endolymphatic hydrops in patients with Ménière’s disease using Siemens 3T MRI with 32ch head coil after intratympanic administration of 1/8 diluted gadolinium (Gd) [8]. Intratympanically administrated Gd is distributed into the perilymphatic space through the round window membrane to enhance perilymph. Consequently, endolymphatic hydrops of the inner ear were visualized. In 2010, Professor Naganawa et al. [9] developed HYDROPS imaging of MRI and accomplished successful visualization of endolymphatic hydrops in patients with Ménière’s disease after intravenous administration of a standard dose of Gd. Furthermore, updated HYDROPS-Mi2 imaging showed an increased contrast-to-noise ratio between endolymph and perilymph of the inner ear in Gd-enhanced MRI [10]. MRI of endolymphatic hydrops has become an indispensable tool to diagnose Ménière’s disease when combined with audio-vestibular functional tests including electrocochleography, vestibular evoked myogenic potential, and caloric tests.
New Surgical and Noninvasive Treatments of Ménière’s Disease
Endolymphatic sac surgery is still a non-destructive surgical option for patients with intractable Ménière’s disease, although various procedures of endolymphatic sac surgery with mastoid shunt were devised. Professor Kitahara et al. [11] in Nara developed a new procedure of endolymphatic sac surgery with steroid instillation; the opened endolymphatic sac is exposed to a high dose of steroid during the operation. Professor Kitahara et al. [12] further reported that endolymphatic sac surgery with steroid instillation was much more effective at improving hearing, although endolymphatic sac surgery with or without steroid instillation was effective at controlling vertigo in patients with intractable Ménière’s disease in the long term of 7 years. Now, endolymphatic sac surgery with steroid instillation has become a new therapeutic strategy for intractable Ménière’s disease in Japan.
Effects of endolymphatic sac surgery on MRI of endolymphatic hydrops were reported in patients with Ménière’s disease [13]. The frequency of vertigo attacks and the presence of vestibular, but not cochlear hydrops decreased 2 years after the surgery. These findings suggest that endolymphatic sac surgery reduces vestibular hydrops, resulting in suppressing vertigo attacks. Taken together with the findings that endolymphatic hydrops progressively increased in accordance with deterioration of hearing function [14], these findings also suggest that endolymphatic sac surgery prevents aggravation of cochlear hydrops, resulting in preservation of hearing function in patients with Ménière’s disease.
Professor Shojaku et al. [15] in Toyama developed a new middle ear pressure device without a transtympanic ventilation tube, unlike Meniett device [15] (Fig. 2). Meniett device produces continuous positive pressure with micropulses, whereas Japanese middle ear pressure device produces biphasic positive and negative pressure. It was reported that vertigo scores during middle ear pressure therapy with a Japanese device were gradually decreased for 4 months in patients with intractable Ménière’s disease [16]. After JSER established guidelines for the proper use of Japanese devices, middle ear pressure therapy was approved by Japanese Pharmaceuticals and Medical Devices Agency and was covered by national health insurance in Japan. Thereafter, long-term therapeutic effects of Japanese middle ear pressure device for up to 12 months were reported [17]. Middle ear pressure therapy with Japanese device has become a new therapeutic strategy for intractable Ménière’s disease in Japan.
Effects of middle ear pressure therapy with Japanese device on MRI of endolymphatic hydrops were reported in a patient with Ménière’s disease. It was reported that a 68-year-old Ménière’s patient with endolymphatic hydrops in the right ear demonstrated by Gd-enhanced MRI was treated with middle ear pressure therapy with Japanese device for 4 months twice, because his vertigo attacks were resistant to both medicine and endolymphatic sac surgery. MRI showed that his vertigo attacks disappeared in accordance with a reduction of the size of endolymphatic hydrops after middle ear pressure therapy [18].
JSER has proposed a treatment algorithm for Ménière’s disease in Clinical Practice Guideline of Ménière’s Disease and Delayed Endolymphatic Hydrops 2020. Middle ear pressure therapy is indicated for patients with Ménière’s disease, who failed to respond to medical therapy and lifestyle changes. Endolymphatic sac surgery is then indicated for patients with Ménière’s disease, who failed to respond to middle ear pressure therapy.
New Insights of Mechanisms of Ménière’s Attack
In the 1960s, Professor Schuknecht [19] in Boston proposed the membrane rupture hypothesis of Ménière’s disease. The increased endolymphatic pressure causes the rupture of the Reissner’s membrane in the cochlear, and the leakage of endolymph with high concentration of potassium ion into the perilymphatic space of the inner ear induces Ménière’s vertigo attacks. The membrane rupture hypothesis is still valid today, mainly because it can explain initial irritative nystagmus beating to the affected ear, followed by paralytic nystagmus beating to the healthy ear in vertigo attack of Ménière’s disease.
However, an impressive case report of Ménière’s disease by Dr. Fukushima et al. [20] in Osaka raised doubts over the membrane rupture hypothesis. Gd-enhanced MRI of the inner ear showed bilateral endolymphatic hydrops in a 50-year-old patient with Ménière’s disease. He complained of frequent vertigo attacks with fluctuating aural symptoms, and a Gd-enhanced MRI of the inner ear was taken seven times from 2014 to 2018. No shrinkage or disappearance of endolymphatic hydrops was observed in seven times of MRI scanning, even during vertigo attacks. These findings disagree with Schuknecht’s membrane rupture hypothesis of Ménière’s disease.
When Professor Yamakawa [6] reported endolymphatic hydrops in the temporal bone specimen from his colleague Professor Ogata at Osaka University, he speculated that the increased endolymphatic pressure caused the excitation of vestibular hair cells, resulting in vertigo attack of Ménière’s disease. The speculation is based on the tonus hypothesis proposed by Professor Wittmaack [21] in Hamburg in the 1920s; the sensory epithelium of the vestibule responds to the endolymphatic pressure. Although the tonus hypothesis had fallen into neglect for a long time, it was recently re-evaluated after Professor Scherer et al. [22] in Berlin found that caloric nystagmus was evoked in microgravity on the Spacelab 1 mission in 1983. He proposed that changes in endolymphatic pressure at volume expansion or contraction of endolymph induced caloric nystagmus in microgravity.
Now, Professor Yamakawa’s endolymphatic hypertension hypothesis of Ménière’s disease [6] is also going to regain the spotlight with a series of recent animal experiments. In 1954, Professor Naito [23] in Osaka reported that endolymphatic hydrops were developed after endolymphatic sac obliteration in guinea pigs, and in 1967, Professor Kimura [24] in Boston established the animal model of endolymphatic hydrops after surgical blockage of the endolymphatic duct and sac [24]. However, the guinea pigs with experimental endolymphatic hydrops never showed spontaneous nystagmus. Recently, Dr. Egami and Kakigi [25] in Tokyo developed a new animal model of Ménière’s disease in guinea pigs that received desmopressin, a vasopressin V2 agonist, after surgical blockage of the endolymphatic sac. The animal model showed episodes of balance disorder along with spontaneous nystagmus like Ménière’s vertigo attacks. Furthermore, using optical coherence tomography, Professor Kakigi et al. [26] in Kobe reported the abrupt development of endolymphatic hydrops, but not the rupture of Reissner’s membrane was observed after administration of desmopressin in the animal model of Ménière’s disease. These experimental findings suggest that endolymphatic hypertension induces Ménière’s vertigo attack.
Mechanisms of Static Vestibular Compensation and Its Clinical Implications
Unilateral peripheral vestibular lesion causes asymmetries of vestibulo-ocular and vestibulospinal reflexes, resulting in static vestibular symptoms, such as spontaneous nystagmus and postural deviation. The behavioral asymmetries gradually recover after the lesion. The progressive balance restoration is termed vestibular compensation. Vestibular compensation is divided into two phases: static and dynamic. Static vestibular compensation is further divided into the initial and late processes. Professor Takeda in Tokushima and Professor Kitahara in Nara revealed neural mechanisms of static vestibular compensation. They also revealed pharmacology-based clinical implications of static vestibular compensation [27].

Mechanisms of the initial process of static vestibular compensation

Normally, the cerebellar flocculus inhibits the vestibular nuclei on both sides ipsilateral predominantly. Just after unilateral labyrinthectomy, the resting activities of neurons in the ipsilesional vestibular nucleus are markedly decreased, resulting in the asymmetry of intervestibular nuclear activities to induce spontaneous nystagmus and postural deviation. Soon after unilateral labyrinthectomy, some Fos-positive activated cholinergic neurons appear in the ipsilesional vestibular nucleus, and the cholinergic mossy fiver inputs from the Fos-positive neurons trigger the initial process of static vestibular compensation. Consequently, N-methyl-ᴅ-aspartate (NMDA) receptor-mediated floccular inhibition on the contra-lesional vestibular nucleus is enhanced, resulting in a rebalance of intervestibular nuclear activities. After the restoration of balanced resting activities of neurons in the vestibular nuclei on both sides, unilateral labyrinthectomy-induced spontaneous nystagmus and postural deviation disappear. The plastic changes in the cerebellovestibular inhibition after unilateral labyrinthectomy are essential in the initial process of static vestibular compensation [28].
Using unilaterally labyrinthectomized rats as an animal model of vestibular compensation, the frequency of unilateral labyrinthectomy-induced spontaneous nystagmus decreases in proportion to the floccular inhibition on the contra-lesional vestibular nucleus and disappears after the restoration of balanced intervestibular nuclear activity in the development of the initial process of static vestibular compensation. Therefore, the declining frequency of unilateral labyrinthectomy-induced spontaneous nystagmus can be used as an index of the initial process of static vestibular compensation in rats.

Effects of diazepam on the initial process of static vestibular compensation

Because diazepam, a GABAA receptor agonist, decreases the neural activities of the vestibular nucleus, its inhibitory action is assumed to be responsible for its therapeutic effect [29]. Therefore, diazepam is often classified as a vestibular suppressant. Although diazepam has a long clinical history of use as a vestibular suppressant and clinical evidence showed that diazepam was effective for the treatment of acute vertigo [30], some clinicians claimed that vestibular suppressants may retard the development of vestibular compensation [31]. Thus, the effect of diazepam on vestibular compensation was still a controversial issue.
Recently, Dr. Matsuda and Professor Takeda reported that continuous administration of diazepam dose-dependently reduced the frequency of spontaneous nystagmus after unilateral labyrinthectomy in rats, and suggested that diazepam accelerates the initial process of static vestibular compensation [32]. The experimental findings recommend short-term administration with diazepam for the treatment of acute vertigo in patients with unilateral vestibulopathy. The recommendation is supported by the clinical evidence that diazepam was effective in the treatment of patients with acute vertigo in the emergency department [33]. However, the effects of long-term administration with diazepam on the late process of static vestibular compensation remain unclear.

Mechanisms of the late process of static vestibular compensation

In the late process of static vestibular compensation, the resting activity of neurons in the ipsilesional vestibular nucleus is gradually restored to reinforce the symmetry of intervestibular nuclear activities. Finally, neural activities of the ipsilesional vestibular nucleus fully recover in the development of the late process of static vestibular compensation. The plastic changes of neural activities of the ipsi-lesional vestibular nucleus are essential in the late process of static vestibular compensation.
Using unilaterally labyrinthectomized rats as an animal model of vestibular compensation, the ideal index of the late process is the recovery of the resting activity of neurons in the ipsi-lesional vestibular nucleus after unilateral labyrinthectomy. Alternatively, Dr. Matsuda and Professor Takeda developed a new index that evaluates the development of the late process of static vestibular compensation [34]. After the disappearance of unilateral labyrinthectomy-induced spontaneous nystagmus, the administration of MK801, an NMDA receptor antagonist, induces a temporary decompensation including the reappearance of spontaneous nystagmus and appearance of Fos-positive activated neurons in the contra-lesional vestibular nucleus. MK801-induced Fos-positive neurons in the contra-lesional vestibular nucleus were suppressed by NMDA receptor-mediated floccular inhibition, and Fos is induced in the neurons by the disinhibition due to MK801 in unilaterally labyrinthectomized rats. The number of MK801-induced Fos-positive neurons in the contra-lesional vestibular nucleus is gradually decreased in accordance with the restoration of neuronal activities in the ipsi-lesional vestibular nucleus. Therefore, the declining number of MK801-induced Fos-positive neurons in the contra-lesional vestibular nucleus can be used as an index of the late process of static vestibular compensation after unilateral labyrinthectomy in rats.

Effects of betahistine on the late process of static vestibular compensation

Betahistine is a histamine H3 receptor antagonist and is clinically used for the treatment of vertigo or dizziness. Clinical evidence showed betahistine was effective for the treatment of vestibular symptoms [35]. Previously, Professor Lacour in Marseille reported that betahistine accelerated the disappearance of spontaneous nystagmus after unilateral labyrinthectomy in cats, suggesting that betahistine facilitates vestibular compensation [36]. However, Dr. Fukuda and Professor Takeda reported that continuous administration with betahistine did not reduce the frequency of unilateral labyrinthectomy-induced spontaneous nystagmus in rats, suggesting that betahistine does not affect the initial process of static vestibular compensation.
Histamine H3 receptors are located in the presynaptic histaminergic fibers and act as inhibitory autoreceptors [37]. The histaminergic neurons in the tuberomammillary nuclei of the posterior hypothalamus give rise to the axons of the vestibular nucleus in rats [38]. Histamine H1 and H2 receptors are postsynaptically expressed in the vestibular nucleus [39] and histamine activates neurons in the vestibular nucleus in rats [40]. Therefore, it is assumed that histamine H3 receptor antagonists increase the release of histamine to activate vestibular nucleus neurons. Recently, Dr. Fukuda and Professor Takeda reported that continuous administration with betahistine dose-dependently reduced the number of MK801-induce Fos-positive neurons in the contra-lesional vestibular nucleus after unilateral labyrinthectomy in rats [41]. The experimental findings suggest that betahistine accelerates the late process of static vestibular compensation.
Moreover, the Intractable Vestibular Disorder Research Group (PI: Professor Takeda) funded by Japan Agency of Medical Research and Development reported that long-term administration of a high-dose betahistine improved scores of Dizziness Handicap Inventory of intractable dizziness in patients with uncompensated unilateral vestibulopathy [42]. The clinical findings suggest that betahistine accelerates the late process of static vestibular compensation in humans and recommend long-term administration with betahistine for the treatment of subacute vertigo in patients with unilateral vestibulopathy.
Dynamic Vestibular Compensation and Vestibular Rehabilitation
Unilateral peripheral vestibular lesion also causes dynamic vestibular symptoms with head movement such as oscillopsia and swaying gait. After the lesion, subsequent to static vestibular compensation, dynamic vestibular compensation develops to restore symmetric dynamics of vestibulo-ocular and vestibulospinal reflexes, and lesion-induced dynamic vestibular symptoms gradually improve. Since repeated exposure to exercises with active head movements facilitates dynamic vestibular compensation [43], vestibular rehabilitation is effective in developing dynamic vestibular compensation. Clinical evidence showed that vestibular rehabilitation is beneficial for improving chronic vestibular symptoms in patients with uncompensated vestibular hypofunction [44].
JSER has proposed a standardized series of vestibular exercises in the Clinical Guideline of Vestibular Rehabilitation 2024. Each exercise involves a progress of corresponding mechanisms of vestibular rehabilitation: (1) facilitation of dynamic vestibular compensation, (2) adaptation of vestibulo-ocular and vestibulospinal reflexes, (3) sensory substitution, and (4) habituation.
New Vestibular Rehabilitation with Vestibular Substitution Devices
Sensory substitution of other sensory modalities to replace impaired vestibular inputs is a new therapeutic strategy to improve dynamic vestibular symptoms after unilateral vestibulopathy. Since the visual, vestibular, and somatosensory inputs are involved in postural control, the central nervous system can efficiently integrate the alternative sensory inputs for controlling posture in uncompensated patients after unilateral vestibulopathy. Therefore, sensory substitution devices have been developed to provide tactile or electrical stimuli by substituting somatosensory inputs for impaired vestibular inputs. It was reported that vestibular rehabilitation with the electro-tactile vestibular substitution device improved postural imbalance in patients with uncompensated vestibular hypofunction [45].
Recently, Dr. Sato and Professor Takeda [46] developed a vibratory vestibular substitution device called tilt perception adjustment device (TPAD) to convey information about the head position to the mandible through two vibrators. The vibrators of TPAD are placed on each chin of the mandible and shake in proportion to the degree of head-tilt. When the head tilts to the right, the right vibrator shakes; when the head tilts to the left, the left one shakes. TPAD is used to substitute the artificial head-tilt information for deficiency of natural vestibular information. In patients with uncompensated vestibular hypofunction, vestibular rehabilitation with TPAD can improve swaying gait, suggesting that TPAD is a promising vestibular rehabilitation device.

Funding/Support

None.

Conflicts of Interest

The author of this review was the president of JSER from 2018 to 2021, and the principal investigator of the Intractable Vestibular Disorder Research Group of Japan funded by the Ministry of Health, Labor and Welfare of Japan and the Japan Agency for Medical Research and Development from 2014 to 2017. No other potential conflicts of interest relevant to this article was reported.

Availability of Data and Materials

The datasets are not publicly available but are available from the corresponding author upon reasonable request.

Fig. 1.
Japan Society for Equilibrium Research published guidelines and videos.
rvs-2025-001f1.jpg
Fig. 2.
Japanese middle ear pressure device for the treatment of intractable Ménière’s disease.
rvs-2025-001f2.jpg
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        Recent advances in diagnostic and therapeutic strategies for management of dizzy patients in Japan
        Res Vestib Sci. 2025;24(1):1-9.   Published online March 14, 2025
        DOI: https://doi.org/10.21790/rvs.2025.001
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      Recent advances in diagnostic and therapeutic strategies for management of dizzy patients in Japan
      Image Image
      Fig. 1. Japan Society for Equilibrium Research published guidelines and videos.
      Fig. 2. Japanese middle ear pressure device for the treatment of intractable Ménière’s disease.

      Fig. 1.

      Fig. 2.

      Recent advances in diagnostic and therapeutic strategies for management of dizzy patients in Japan
      Res Vestib Sci : Research in Vestibular Science
      © Korean Balance Society.
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