MD is a fascinating pathology. Despite being recognized for many years, its underlying pathophysiology is still unknown [27]. MD often imposes a real diagnostic challenge and substantial morbidity due to great difficulties in early detection.[27]. EH is the only pathological abnormality consistently observed [15].
The initial documentation of MD occurred in 1861 when Prosper Ménière published its first description. He was the first to associate this symptomatology with inner ear pathology and refute the idea of a brain disease as it was considered at the time [27]. Nevertheless, in a groundbreaking paper published in 2013, Foster & Breeze revived the possibility of MD being in fact a “brain-ear” disease [12]. In their work, they present the hypothesis of MD attacks arising as an association of EH and vascular risk factors for intracerebral ischemia. Similarly, in a prior study, Rego et al. comprehensively examined a population with MD from a cardiovascular risk perspective, and subsequently correlated the findings with the disease's phenotype and progression [15]. Building on these previous findings, our study highlights the significance of accurately correlating intracerebral ischemia markers with the occurrence of MD. The concept of “brain-ear” disease is explored and MD is addressed by actually measuring the vascular cerebral involvement of MD´s versus controls.
The primary objective of this work was met. A comparison between MD and controls was performed highlighting intracerebral ischemia. Our results showed a significant association between MD and higher rates of cerebral SVD. To compare groups, a small vessel disease score (SVD) was used: the SVD-3 score. It was constructed based on the previously reported "total SVD score" [24–26] to provide an ample estimate of the impact of SVD on the brain. We considered that the total effect of SVD on the brain was better described by SVD-3 than by simply evaluating one or two distinct aspects independently.
Each SVD-3 characteristic correlates to vascular risk factors [23, 28–30]. As WMH represents the most commonly documented SVD feature in the literature [21], we explored the impact of employing an alternative cutpoint for the WMH score. This involved reducing the WMH cutoff to a Fazekas score of 1, which was designated as SVD-3 Low−Fazekas. Other alternative SVD score was also calculated with lowered EPVS and was called SVD-3 Low−EPVS. Lastly, we combined both lowered cutt-offs to one single scale that we called SVD-3 Low−Fazekas + Low−EPVS. Hence, four different subscales of SVD-3 were computed in order to check for differences in sensitivity and ultimately compare MD and controls. Significant differences between MD and controls were encountered in every SVD-3 score. Finally, binary logistic results proved that this association was insoluble even when accounting for potential confounders such as age and sex.
This results then point to a link between end-organ vascular brain disease, namely SVD, and the incidence of MD. Such a link may reinforce the role of vascular disease in MD pathophysiology. Our findings are supported by existent literature. An established connection exists between MD and cerebral ischemia-related conditions, such as migraine. [12]. The observation that every MD patient had at least one major risk factor for cerebral ischemia made Foster et al. ultimately classify MD as a cerebrovascular illness [13]. Teggi et al further supported this notion by speculating that vascular disorders might function as a potential predisposing element for MD [31]. On the other hand, higher rate of comorbidities has been associated with a more severe or therapy-resistant MD [15, 32–34].
The impact of cardiovascular risk factors is widely acknowledged in causing microvasculature compromise, oxidative stress, and damage to the brain-blood and blood-labyrinth barriers. Hence, it is reasonable to hypothesize that, similar to the brain, the inner ear could be susceptible to the effects of the cardiovascular disease spectrum as a target end-organ. [35, 36]. We here call this interaction the “brain-ear” SVD.
In this regard, as a secondary objective, we investigated whether the presence of comorbidities could associate with the incidence of MD, as vascular risk factors would be the logical common link between MD and cerebral SVD. Intriguingly, in our study, the prevalence of comorbidities did not differ between MD and controls. In one hand, this lack of significant differences may relate with a limited sample size. On the other, it could be explained by other unaccounted predictors, such as genetic or acquired propensity for “brain-ear” SVD. Interestingly, emerging data suggests that MD may be a systemic oxidant illness [37]. Excessive free radical generation and oxidative stress play a role in promoting microvascular damage, which could be implicated in both the development of EH/MD and cerebral SVD [37].
Importantly, in this cohort cortical stroke incidence did not differ between MD and controls. Although the sample size may have hampered the results, it is also possible that pathophysiological association of MD and cerebral ischemia more highly depends on small – rather than larger – cerebral vessels regulating the inner ear.
Although specific mechanisms linking Ménière's disease to both cardiovascular factors and cerebrovascular disease remain unclear, several plausible pathways have been proposed.
EH, a characteristic feature of MD, could be influenced by alterations in vascular homeostasis. Impaired regulation of the endolymphatic sac's blood flow and fluid balance due to vascular dysfunction might contribute to the accumulation of endolymph, triggering vertigo attacks [38]. A decrease in blood supply to the inner ear due to microvascular damage, oxidative stress, atherosclerotic plaque formation, and microthrombosis can disrupt the equilibrium in the production and absorption of endolymphatic fluid - thereby increasing the risk of EH, and ultimately MD [39–41]. Conversely, in the event of EH development, it acts as a variable Starling resistor on the vasculature of the inner ear – when the person has a baseline low ear perfusion pressure (such as in cases of “brain-ear” SVD), EH itself may trigger ischemic episodes. In such cases, after a series of assaults, small regions of irreparable sensory cell damage aggregate and become confluent, resulting in permanent hearing loss and vestibular impairment, typical of MD [12].
Furthermore, the autonomic nervous system, which plays a crucial role in cardiovascular regulation, has been suggested to be involved in MD pathophysiology. Dysregulation of the autonomic nervous system could also potentially affect inner ear blood flow and fluid dynamics, leading to MD symptoms [18]. Additionally, venous stasis may be another vascular pathogenetic pathway for MD progression, since recent works relate cerebrospinal venous insufficiency to EH and MD [42–44].
Finally, the treatment approach for stabilizing MD involves promoting vascularization of the inner ear and reducing the volume of inner ear fluid. [45]. Coincidently (or not), both betahistine and nimodipine have been used as vasodilators with proved efficacy in MD [45]. Along with the use of diuretics, reducing salt content in the diet remain significant parts of symptomatic therapy. Both have a direct impact on cardiovascular risk by lowering arterial blood pressure [15].
It is essential to acknowledge some limitations of our study. Firstly, the cross-sectional design restricts our ability to establish a causal relationship between cerebrovascular disease and MD. Secondly, the relatively small sample size and the data collection from a single medical center might constrain the generalizability of these findings. A larger multicenter study would strengthen the validity and generalizability of the results. In addition, CMBs are a well-known feature of SVD but were not accounted in the SVD-3 score due to lack of T2* sequence in a significant proportion of the sample. There was also an asymmetry on the percentage of T2 3D FLAIR sequence done in the MD and control groups. This is explained by the fact that the control group only had MRIs done within the previous two years, but the MD group had scans dating back to 2016 (mentioned in Section 2.1 and Fig. 1). 3D sequences have been progressively favored over time. Also, since clinical data was taken from pre-existent records, it is possible that some comorbidities were not accounted due to omission. Frequency of attacks and audiological features were not included in this analysis, which could have provided insights about the impact of cerebral SVD burden on MD severity.
This study has its strengths as well, as it is the first to show a potential association between cerebral microvascular lesions and MD. We also bring relevant equations to estimate the MD´s risk based on MRI´s microvascular burden (see Section 3.2). By pointing to a common vascular “brain-ear” disorder our results provide foundation and stimulate the debate towards the potential cardiocerebrovascular pathway for MD. Further research is definitely warranted to elucidate the precise mechanisms involved and to explore potential therapeutic interventions in patients with MD. Latent implications of such research may exist: as interventions similar to the ones used in cerebral microvascular disease could decrease the incidence of MD at an individual and community level.