Benign paroxysmal positional vertigo (BPPV) represents the most common cause of peripheral vertigo and one of the most frequent vestibular disorders encountered in otolaryngological and neurological practice [1]. The lifetime prevalence has been estimated at approximately 2.4%, with a marked increase after the fifth decade of life and a higher incidence among women. Canalith repositioning maneuvers, including those described by Epley and Semont, achieve complete symptom resolution in most patients and currently constitute the gold standard treatment recommended by international guidelines [2][3].

Nevertheless, recurrence remains a major unresolved clinical problem, with reported rates ranging from 15% - 30% during the first year to nearly 50% after prolonged follow-up [2][4]. The currently accepted pathogenetic model is based on the detachment of calcium carbonate crystals (otoconia) from the utricular macula, followed by migration into one or more semicircular canals. Depending on whether these particles remain free within the endolymph (canalolithiasis) or become adherent to the cupula (cupulolithiasis), abnormal stimulation of vestibular hair cells generates the characteristic positional vertigo and nystagmus [5].

Although this mechanical theory adequately explains the immediate clinical manifestations of BPPV, it does not clarify why some individuals experience repeated recurrences despite technically successful repositioning maneuvers. The persistence or recurrence of otoconial detachment strongly suggests that the underlying pathological process involves chronic alterations of the utricular macula rather than merely mechanical displacement of otolithic debris. Electron microscopy studies performed on specimens obtained during posterior semicircular canal occlusion have demonstrated both intact and degenerating otoconia surrounded by amorphous gelatinous material, providing direct evidence of progressive degeneration of the otoconial membrane [5]. These findings indicate that recurrent BPPV should be regarded not simply as a disorder of displaced particles but as a disease affecting the biological integrity of the otolithic extracellular matrix.

Recurrent benign paroxysmal positional vertigo is a clinical condition characterized by recurring episodes of intense rotational vertigo of very short duration (less than one minute), triggered by specific head movements or changes in head position. Medical assessment involves the Dix-Hallpike maneuver, diagnostic imaging (contrast-enhanced MRI), and an evaluation of the symptoms and the circumstances under which they occur.

Over the past decade, numerous epidemiological studies have identified several independent predictors of recurrent BPPV, including advanced age, female sex, osteoporosis, vitamin D deficiency, hypertension, diabetes mellitus, hyperlipidemia, migraine, Ménière’s disease, chronic insomnia, and cerebrovascular disease [3][5][6]. At first glance, these conditions appear unrelated; however, they share a common feature: each may impair systemic or local microvascular function.

This observation raises an important question: rather than representing independent risk factors, could these apparently diverse conditions contribute to a common pathophysiological pathway characterized by chronic labyrinthine hypoperfusion and progressive degeneration of the otoconial membrane?

The present article develops this hypothesis by integrating current knowledge regarding inner ear microcirculation, cellular adaptation to hypoxia, extracellular matrix biology, and metabolic regulation. We propose that recurrent BPPV represents the final clinical expression of chronic microcirculatory dysfunction leading to tissue hypoxia, activation of hypoxia-inducible pathways, extracellular acidification, and structural weakening of the otoconial membrane. Within this theoretical framework, the preliminary clinical observations obtained following oral alkalinizing mineral supplementation are presented not as evidence of therapeutic efficacy but as hypothesis-generating findings deserving further investigation.

Despite the high success rate of canalith repositioning maneuvers, recurrence remains a common clinical event. Recent systematic reviews and meta-analyses have confirmed that recurrence is influenced by multiple systemic conditions rather than by vestibular factors alone [6].

Advanced age is among the strongest predictors of recurrence. Degenerative changes affecting both the utricular neuroepithelium and the extracellular matrix progressively reduce the mechanical stability of the otoconial membrane, facilitating spontaneous detachment of otoconia. Age-related vascular alterations may further aggravate this process through chronic reduction of labyrinthine perfusion.

Hypertension has consistently emerged as another important risk factor [6]. Long-standing arterial hypertension induces endothelial dysfunction, arteriolar remodeling, and impairment of capillary blood flow. Because the inner ear is supplied by terminal arteries lacking significant collateral circulation, even modest reductions in microvascular perfusion may compromise metabolic homeostasis of the utricular macula [7].

Similarly, diabetes mellitus contributes to chronic microangiopathy through endothelial injury, oxidative stress, and thickening of capillary basement membranes. Histopathological studies have demonstrated diabetic alterations involving both cochlear and vestibular structures, supporting the concept that vestibular dysfunction may represent one manifestation of systemic microvascular disease.

Hyperlipidemia further contributes to vascular impairment by promoting endothelial dysfunction and progressive atherosclerosis [5]. Reduced blood flow may impair oxygen delivery and nutrient exchange within the metabolically active vestibular neuroepithelium.

Migraine has also been repeatedly associated with recurrent BPPV [5]. Although its precise mechanism remains uncertain, transient vasospasm, neurovascular inflammation, and endothelial dysfunction have all been proposed as possible contributors to repeated otolithic injury.

Vitamin D deficiency has attracted considerable attention because of its role in calcium metabolism and otoconial mineralization. Several randomized studies suggest that correction of vitamin D deficiency reduces BPPV recurrence in selected patients, although the exact biological mechanism remains incompletely understood [5].

More recently, chronic insomnia has emerged as an additional predictor of recurrence [8]. Sleep deprivation is associated with increased sympathetic activity, endothelial dysfunction, oxidative stress, and systemic inflammation, all of which may adversely affect inner ear microcirculation. Improvement of sleep quality through behavioral interventions has been associated with lower recurrence rates in preliminary studies.

Although these risk factors have traditionally been considered separately, their coexistence in many patients suggests the existence of a common pathogenic mechanism. The hypothesis proposed in this article is that chronic microvascular insufficiency represents the biological substrate through which these apparently diverse clinical conditions converge to promote progressive degeneration of the otoconial membrane.

The inner ear possesses one of the most metabolically active microvascular systems in the human body. Its arterial supply derives almost exclusively from the labyrinthine artery, a terminal vessel that lacks functionally significant collateral circulation [9]. Consequently, vestibular tissues are particularly vulnerable to even transient reductions in blood flow.

Experimental studies have demonstrated that relatively mild ischemia rapidly alters ionic homeostasis, mitochondrial metabolism, and extracellular matrix turnover within the vestibular sensory organs. Chronic reductions in tissue perfusion may therefore produce cumulative structural damage long before irreversible cellular degeneration becomes clinically evident.

Interestingly, nearly all clinical conditions associated with recurrent BPPV—including hypertension, diabetes mellitus, hyperlipidemia, aging, migraine, chronic insomnia, smoking, and cerebrovascular disease—share the capacity to impair endothelial function and microvascular perfusion [5][7][8]. Rather than acting as isolated risk factors, these disorders may therefore converge on a common final pathway characterized by chronic labyrinthine hypoxia. This concept provides a coherent biological framework capable of integrating the diverse epidemiological observations reported over the past two decades.

The otoconial membrane is a highly specialized extracellular matrix covering the sensory epithelium of the utricular and saccular maculae. Rather than representing a passive mechanical structure, it is a biologically active extracellular scaffold responsible for maintaining the spatial organization and mechanical stability of otoconia.

Otoconia are microscopic biomineralized particles composed predominantly of calcium carbonate (CaCO₃) deposited on an organic protein matrix [6]. Approximately 90% - 95% of their mineral content consists of calcite crystals, while the remaining fraction is composed of glycoproteins, proteoglycans, collagen, glycosaminoglycans, and other extracellular matrix components that regulate crystal nucleation, growth, and attachment.

Among the structural proteins, Otoconin-90 (OC90) is the major organic constituent of mammalian otoconia and plays a critical role in calcium carbonate biomineralization. Experimental studies have demonstrated that alterations in OC90 expression produce abnormal crystal morphology and reduced mechanical stability of otoconia. Another essential component is Otolin-1, a collagen-like glycoprotein that forms the scaffold connecting otoconia to the gelatinous membrane. Additional extracellular proteins—including keratan sulfate proteoglycans, collagen type IV, laminin, and fibrillar glycoproteins—contribute to maintaining the viscoelastic properties of the otoconial membrane.

The integrity of this extracellular matrix is fundamental for vestibular function. Under physiological conditions, continuous remodeling of extracellular matrix proteins is balanced by controlled synthesis, enzymatic degradation, calcium homeostasis, and local ionic regulation. Aging progressively disrupts this equilibrium, resulting in fragmentation of the gelatinous matrix, partial detachment of otoconia, and increased susceptibility to positional vertigo [6].

Electron microscopy studies have confirmed that patients undergoing surgery for intractable BPPV exhibit both intact and degenerating otoconia surrounded by amorphous matrix material [6]. These observations strongly suggest that recurrent BPPV represents not only a mechanical disorder of displaced particles but also a degenerative disease affecting the extracellular matrix responsible for anchoring otoconia to the utricular macula.

Consequently, degeneration of the otoconial membrane should be viewed as a dynamic biological process rather than a purely age-related phenomenon. Identifying the mechanisms responsible for extracellular matrix instability may therefore provide new therapeutic targets beyond simple canalith repositioning.

Adequate oxygen delivery is essential for the metabolic homeostasis of the inner ear. Vestibular sensory organs possess one of the highest metabolic demands in the human body and rely almost exclusively on oxidative phosphorylation for ATP production. The labyrinthine artery is an end artery with virtually no collateral circulation [7]. Consequently, even modest reductions in blood flow may induce chronic tissue hypoxia, particularly in patients with systemic microvascular disease.

Under normoxic conditions, pyruvate generated through glycolysis enters mitochondria, where pyruvate dehydrogenase converts it into acetyl-CoA, allowing oxidative phosphorylation to generate approximately 30 - 32 ATP molecules per glucose molecule. When oxygen availability decreases, this metabolic pathway undergoes profound reprogramming. Reduced oxygen tension inhibits pyruvate dehydrogenase activity and stabilizes hypoxia-inducible factor-1 alpha, a transcription factor that orchestrates cellular adaptation to hypoxia [9][10].

Factor-1 alpha induces the expression of multiple genes involved in anaerobic metabolism, including glucose transporters (GLUT-1), glycolytic enzymes, pyruvate dehydrogenase kinase (PDK), and lactate dehydrogenase A (LDH-A) [9][11]. Pyruvate is consequently diverted away from mitochondrial oxidation toward conversion into lactate, allowing glycolysis to continue despite reduced oxygen availability.

Although this metabolic adaptation preserves short-term cellular survival, chronic activation of the HIF pathway has important biological consequences [9]. Progressive lactate accumulation contributes to local extracellular acidification, modifies the ionic composition of the extracellular environment, and influences multiple signaling pathways regulating inflammation, extracellular matrix remodeling, angiogenesis, and tissue repair [12].

Recent experimental evidence indicates that chronic hypoxia also alters extracellular matrix turnover through modulation of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), collagen synthesis, and proteoglycan metabolism. Similar mechanisms have been implicated in degenerative diseases affecting cartilage, intervertebral discs, tendons, vascular walls, and other connective tissues.

Although direct evidence involving the otoconial membrane is currently unavailable, it is biologically plausible that chronic labyrinthine hypoxia may induce comparable extracellular matrix remodeling within the utricular macula. Progressive weakening of the gelatinous scaffold could reduce the mechanical anchorage of otoconia, thereby increasing their susceptibility to spontaneous detachment and migration into the semicircular canals. This hypothesis provides a coherent mechanistic link between systemic microvascular disorders and recurrent BPPV.

Figure 1.Proposed pathogenetic cascade linking systemic vascular risk factors to recurrent BPPV (figure created with AI).

The hypothesis proposed in the present study does not replace the canalolithiasis theory [1]; rather, it extends it by addressing the biological events that may precede otoconial detachment.

We propose that recurrent BPPV represents the final clinical manifestation of a chronic degenerative process affecting the otoconial extracellular matrix [5]. According to this model, several apparently unrelated systemic disorders—including aging, hypertension, diabetes mellitus, hyperlipidemia, migraine, chronic insomnia, smoking, osteoporosis, and other conditions associated with endothelial dysfunction—share the ability to impair labyrinthine microcirculation [5][7][8].

Progressive microvascular dysfunction may produce chronic low-grade hypoperfusion of the utricular macula. Because vestibular sensory organs possess limited metabolic reserve and are supplied by terminal arteries without significant collateral circulation, persistent reduction of oxygen delivery may induce repeated episodes of subclinical tissue hypoxia.

Activation of hypoxia-inducible factor-1 alpha (HIF-1α) constitutes the principal adaptive response to reduced oxygen availability [10]. While this mechanism preserves cellular viability through metabolic reprogramming toward anaerobic glycolysis, prolonged activation may also modify extracellular matrix homeostasis [9][11].

Progressive remodeling of the gelatinous matrix could weaken the structural linkage between otoconia and the utricular macula. Mechanical stresses generated by normal head movements would then be sufficient to detach previously destabilized otoconia, allowing migration into the semicircular canals and producing recurrent episodes of positional vertigo [1]. Within this framework, canalolithiasis represents the terminal mechanical event of a much longer biological process characterized by chronic extracellular matrix degeneration (see Figure 1).

The proposed model should be regarded as an extension rather than an alternative to the current pathogenetic theory of BPPV. The classical canalolithiasis hypothesis, originally formulated by Hall, Ruby and McClure and subsequently refined by Parnes and colleagues, accurately explains the biomechanics responsible for positional nystagmus and the remarkable effectiveness of canalith repositioning maneuvers [2]. Nevertheless, it does not specifically address the biological mechanisms responsible for progressive weakening and repeated detachment of otoconia.

The present hypothesis integrates these observations into a single biological framework based on chronic labyrinthine microvascular dysfunction [7]. Rather than assuming independent mechanisms for each risk factor, it proposes that impaired oxygen delivery constitutes the common upstream event leading to progressive degeneration of the otoconial extracellular matrix [6][9].

If confirmed experimentally, this hypothesis could have relevant clinical implications. Current management of recurrent BPPV focuses primarily on repeated repositioning maneuvers after otoconial displacement has already occurred [2]. A better understanding of the biological mechanisms responsible for otoconial instability may eventually allow preventive strategies aimed at preserving extracellular matrix integrity before recurrent detachment develops, see Table 1.

Table 1. Methodological and conceptual comparison: classical vs. proposed model.

Benign paroxysmal positional vertigo (BPPV) is generally considered a mechanical disorder resulting from the detachment of otoconia from the utricular macula and their migration into the semicircular canals [3][6]. Although canalith repositioning maneuvers effectively resolve individual episodes, they do not address the underlying biological mechanisms responsible for recurrent otoconial detachment. Consequently, recurrence rates remain substantial, particularly in older individuals and in patients with cardiovascular and metabolic comorbidities [3][6].

Growing evidence suggests that recurrent BPPV may reflect chronic impairment of the utricular microenvironment rather than an isolated mechanical event. Aging, hypertension, diabetes mellitus, dyslipidemia, migraine, smoking, osteoporosis, and other vascular risk factors have all been associated with endothelial dysfunction and reduced labyrinthine microcirculation [2][9]. Chronic hypoperfusion of the utricle may induce persistent tissue hypoxia characterized by activation of hypoxia-inducible factor-1α (HIF-1α), metabolic reprogramming toward anaerobic glycolysis, increased lactate production, and extracellular acidification [4][5].

This acidic microenvironment may promote extracellular matrix remodeling through activation of matrix metalloproteinases, alteration of calcium homeostasis, and progressive weakening of the otoconial membrane, thereby facilitating repeated otoconial detachment and recurrent canalolithiasis [8][9].

Within this pathophysiological framework, alkalinizing mineral supplementation may represent a biologically plausible adjunctive strategy aimed at restoring extracellular acid-base balance and preserving the structural integrity of the utricular extracellular matrix.

To illustrate our preliminary observations, we report four representative cases of patients affected by recurrent BPPV who received oral alkalinizing mineral supplementation Alkimo HP (after repeated canalith repositioning maneuvers).

Alkimo HP is a mineral supplement produced by IMO SpA and supplied in sachets; it consists of potassium bicarbonate, magnesium citrate, and potassium citrate, along with bulking agents such as calcium phosphates and hydroxypropyl cellulose (E463), as well as zinc gluconate, manganese citrate, and sodium selenite. The recommended dosage for adults is two sachets per day, each to be dissolved in a glass of water and consumed by sipping slowly (one sachet two hours after lunch and one sachet two hours after dinner).

The present case series describes four patients with recurrent benign paroxysmal positional vertigo (BPPV) who remained free of further recurrences after the introduction of an oral alkalinizing mineral supplementation containing potassium bicarbonate, potassium citrate, and magnesium citrate. Although the observational nature of this report precludes any causal inference, the consistent clinical course observed in all patients raises the hypothesis that correction of the metabolic microenvironment of the inner ear may contribute to reducing otoconial instability in selected individuals.

BPPV is traditionally considered a purely mechanical disorder resulting from displacement of otoconia from the utricular macula into one of the semicircular canals. Canalith repositioning maneuvers effectively resolve the acute episode by relocating displaced otoconia back to the utricle; however, they do not address the biological mechanisms responsible for repeated otoconial detachment. Consequently, recurrence remains common, with reported rates ranging from approximately 15% within the first year to more than 50% after long-term follow-up.

Recent evidence indicates that recurrent BPPV should no longer be regarded solely as a mechanical disorder but rather as the clinical manifestation of chronic alterations affecting otoconial homeostasis. Large systematic reviews and meta-analyses consistently identify advanced age, hypertension, diabetes mellitus, hyperlipidemia, migraine, osteoporosis, thyroid disorders, and vitamin D deficiency among the principal risk factors for recurrence. Interestingly, most of these conditions share a common denominator: endothelial dysfunction and chronic microvascular impairment.

The vascular hypothesis of recurrent BPPV has gained increasing attention during the last decade. The inner ear is supplied by terminal arteries without significant collateral circulation, rendering the vestibular neuroepithelium particularly vulnerable to even subtle reductions in blood flow. Using extracranial Doppler ultrasonography, Neri and colleagues demonstrated that patients with recurrent BPPV frequently exhibit reduced vertebral artery flow and proposed that chronic labyrinthine hypoperfusion may induce degeneration of the utricular macula, thereby facilitating repeated otoconial detachment.

Our patients also presented several cardiovascular and metabolic comorbidities—including hypertension, diabetes mellitus, dyslipidemia, migraine, smoking, osteoporosis risk, and advanced age—that have all been independently associated with BPPV recurrence. Rather than acting as isolated risk factors, these conditions may represent different clinical manifestations of a common microvascular disorder affecting the inner ear.

Building upon this vascular hypothesis, we propose a complementary pathophysiological model centered on metabolic adaptation to chronic hypoperfusion. Persistent reduction of labyrinthine perfusion may expose the utricular neuroepithelium to low-grade chronic hypoxia. In numerous tissues, hypoxia activates hypoxia-inducible factor-1α (HIF-1α), promoting a metabolic shift from oxidative phosphorylation toward anaerobic glycolysis with increased lactate production and extracellular acidification. Although this mechanism has not yet been directly demonstrated in the human utricle, it represents a well-established adaptive response in hypoxic tissues and may reasonably be extrapolated to the metabolically active vestibular sensory epithelium.

Progressive extracellular acidification may have several biological consequences relevant to otoconial stability. Acidic conditions favor extracellular matrix remodeling through activation of proteolytic enzymes, alteration of calcium homeostasis, and modifications of matrix protein interactions. Because otoconia consist of calcium carbonate crystals anchored to an organic extracellular matrix rich in otoconin-90, otolin-1, and other glycoproteins, disruption of this delicate microenvironment could progressively weaken the attachment of otoconia to the utricular macula. Experimental studies have shown that aging is associated with structural degeneration of otoconia and weakening of the interconnecting fibrillar network, supporting the concept that deterioration of the extracellular matrix plays a central role in recurrent BPPV.

An intriguing observation emerging from previous studies is that alterations in endolymphatic calcium concentration and pH have long been hypothesized to influence otoconial integrity. Otoconia exist in dynamic equilibrium with the surrounding endolymph, and their mineralization depends upon tightly regulated calcium and carbonate concentrations. Changes in local pH may modify calcium carbonate solubility and interfere with normal biomineralization processes. Although experimental confirmation in humans is currently lacking, this concept provides an attractive biological explanation linking systemic metabolic disturbances with recurrent otoconial instability.

Within this framework, the rationale for alkalinizing mineral supplementation becomes biologically plausible. Potassium bicarbonate directly increases systemic bicarbonate availability, improving extracellular buffering capacity and reducing chronic low-grade metabolic acidosis. Potassium citrate contributes to the same effect after hepatic metabolism of citrate into bicarbonate while simultaneously improving calcium balance and reducing urinary calcium loss. Magnesium citrate provides highly bioavailable magnesium, an essential cofactor involved in mitochondrial ATP production, endothelial nitric oxide synthesis, calcium transport, and antioxidant defense. Together, these compounds may improve endothelial function, optimize mineral homeostasis, reduce extracellular acid load, and preserve extracellular matrix integrity.

It is important to emphasize that our hypothesis does not imply that systemic alkalinization directly changes endolymph pH. The blood-labyrinth barrier and the tightly regulated ionic composition of endolymph make such a direct effect unlikely. Rather, we hypothesize that correction of chronic low-grade metabolic acidosis may improve the metabolic and vascular environment of the inner ear, indirectly promoting preservation of the utricular extracellular matrix and otoconial attachment. This interpretation is consistent with current knowledge of endothelial biology and acid-base physiology while remaining appropriately cautious in the absence of direct experimental evidence.

Interestingly, all four patients in our series shared the common feature of repeated recurrences despite technically successful canalith repositioning maneuvers. After introduction of alkalinizing mineral supplementation, no additional episodes occurred during the available follow-up, and all patients reported subjective improvement in balance or quality of life. Although spontaneous remission cannot be excluded and placebo effects cannot be ruled out, the consistency of these observations suggests that modification of the metabolic milieu deserves further investigation.

The principal limitation of this study is the small sample size and the uncontrolled observational design, which preclude conclusions regarding efficacy. Follow-up duration differed among patients, and biochemical markers of systemic acid-base status, endothelial dysfunction, inflammatory activation, or oxidative stress were not serially assessed. Furthermore, no direct measurements of labyrinthine perfusion or utricular metabolism are currently feasible in routine clinical practice. Therefore, our findings should be regarded as hypothesis-generating rather than confirmatory.

Despite these limitations, this case series introduces a novel conceptual framework integrating several independent observations reported in the literature. Current evidence already supports the association between recurrent BPPV and vascular-metabolic disorders, age-related degeneration of otoconia, calcium metabolism abnormalities, and endothelial dysfunction. Our proposed model extends these observations by suggesting that chronic labyrinthine hypoperfusion may induce metabolic remodeling characterized by HIF-1α activation, increased anaerobic glycolysis, lactate accumulation, and extracellular acidification, ultimately promoting weakening of the otoconial membrane and recurrent otoconia detachment. Within this integrated model, alkalinizing mineral supplementation could represent a simple, inexpensive, and biologically plausible adjunctive strategy aimed at stabilizing the utricular microenvironment and reducing recurrence risk.

Future prospective randomized controlled studies incorporating serum biomarkers of acid-base homeostasis, endothelial function, vestibular function tests, and long-term recurrence rates will be necessary to validate this hypothesis and determine whether modulation of systemic metabolic homeostasis can influence the natural history of recurrent BPPV.

All authors have read and approved the document.

All authors contributed equally to this work.