Benign paroxysmal positional vertigo (BPPV) is the most common cause of peripheral vestibular vertigo (1). It is characterized by short, repeated episodes of intense vertigo and/or positional nystagmus triggered by specific head position changes relative to the gravity vector, and often accompanied by nausea and vomiting (2). BPPV is more common in women and has an overall prevalence of 2.4% in the general adult population that increases with age (2).

While approximately 50–70% of BPPV cases are primary (idiopathic), the remaining cases are often associated with an underlying pathology, such as head trauma, acute unilateral vestibular pathology (3), labyrinthitis, or Menière’s disease (4). BPPV accounts for 24.1% of all hospital visits due to dizziness/vertigo (5). Recurrences of BPPV are frequent with an annual recurrence rate of 15–20% (6).

The five major vestibular sensory organs in the inner ear, the utricle, the saccule, and the lateral, superior and posterior semicircular canals, contain mechanoreceptors (hair cells/stereocilia) that are deflected by accelerations and thereby signal head motion and head tilt via the vestibular nerve to the vestibular nuclei and cerebellum (7). This coordinates the vestibulo-ocular reflex (VOR) and the vestibulospinal reflex (VSR) to maintain orientation and stabilization of the eyes and body that are required for optimal visual acuity during head motion, balance, spatial orientation, navigation and several autonomic functions, as well as cognition. The otolith organs, the utricle, and the saccule, contain hair cells positioned underneath the extrastriolar regions that are covered with heavy otoconia that specifically detect head tilt (gravity) and translational accelerations. The semi-circular canals contain hair cells located in the cupula and by deflection of the cupula specifically detect rotational accelerations of the head.

Canalithiasis has been gradually accepted as the cause of most cases of BPPV (8), a process in which otoconia become detached from the otoconial membrane and fall into the semicircular canals before they can dissolve in the endolymph, hence transforming the affected canals into gravity-sensitive organs (9). Cupulolithiasis, in which free-floating endolymph debris adheres to the cupular membrane and renders the canal responsive to gravity (10) has been proposed to account for the remainder of BPPV cases, especially in older patients (10). Clinical signs of cupulolithiasis have been defined as apogeotropic nystagmus, with new maneuvers developed to manage either utricular- or canal-side cupulolithiasis; however, evidence that otoconia adhere strongly or persistently to the cupula is lacking (8).

In canalithiasis, the motion of otoconial debris within the semicircular canals due to positional changes of the head alters the tonic discharge of the affected labyrinth during BPPV, thereby inducing asymmetrical resting discharges of the vestibular nuclei on both sides and vertigo symptoms. Reduction of the vertigo symptoms likely requires a central adaptation to rebalance the vestibular nuclei activity (11, 12), see Figure 1.

Many types vestibular pathologies result in symptoms that can occur when the head is kept still (static deficits) or when the head is moving (dynamic deficits). Following acute unilateral peripheral vestibular hypofunction, the static symptoms, usually aggravated by nausea and vomiting, are due to the spontaneous resting activity imbalance between the bilateral vestibular nuclei complexes (13, 14) as well as the strong connection between the vestibular nuclei and neurovegetative centers in the brainstem. Static symptoms are generally fully compensated within a few weeks (15). However, dynamic deficits (the impaired responses when the head is moved) are poorly compensated and are exhibited over a longer time period; in many cases, the VOR does not recover at all (14, 16).

The precise cause of otoconial detachment and moving into the semicircular canals (or attaching to the cupula) is still a subject of study and discussion. The most likely causes include head trauma, aging (through pitting, fissuring, and subsequent fragmentation of otoconia), and increased calcium concentration in the canal endolymph.

It has been hypothesized that otolith detachment in idiopathic BPPV could be secondary to microvascular problems and these can be specifically significant for organs supplied by a terminal-type circulation (17). Ischemia of the neuroepithelium of the utricular macula or semicircular canals may facilitate their degeneration with consequent detachment of otoliths (17). Indeed, vascular risk factors have been reported to be closely related to the occurrence and prognosis of BPPV (18). Considering that the labyrinthine artery of the inner ear is a tiny terminal artery, small vessel lesions that directly damage the tiny arteries of the inner ear may lead to microcirculation disorders, which could cause damage to the blood vessels of the inner ear and lead to shedding of otoliths (18). Patients with hypertension, obesity, and diabetes may also have reduced capillary density that negatively affects microvascular tissue perfusion (19).

There is evidence that BPPV patients have higher levels of oxidative stress than healthy groups. Oxidative stress is a critical factor in microcirculation disturbances through the induction of erythrocyte adhesion to the vascular endothelium and the reduction of erythrocyte deformability (20). It has also been suggested that oxidative stress might play a role in the development of BPPV through its relationship with calcium metabolism and the direct toxic effects of free oxygen radicals, including the triggering of apoptosis (21).

Risk factors for BPPV include head trauma, a prolonged recumbent position, and disorders involving the inner ear; they may also include female gender, age > 65 years, osteoporosis [e.g., 81% of people with BPPV have a decreased bone mass density (10), hypertension, hyperlipidemia, and vitamin D deficiency (5)]. Moreover, type 2 diabetes, mediated by hypertension, hyperglycemia, and hypercholesterolaemia have been noted as risk factors for BPPV (10, 22).

Around one-third of adults >40 years show evidence of vestibular dysfunction (23), with the number, volume and shape of otoconia changing with age and otoconia in the saccule degenerating at a greater rate than those in the utricle (24). Although aging is normally associated with otoconia degeneration, hair cell degeneration, loss of vestibular afferents, and a reduction in the number of cells in the vestibular nuclei, dizziness is not part of normal aging and should be managed (25). Older patients may experience a longer duration of symptoms prior to receiving a diagnosis due to the belief that it is a normal part of aging (26).

Even though often considered benign in nature, patients with BPPV are markedly limited in their daily activities (5, 14). Almost 86% of patients with BPPV suffer some interruption to their daily activities and lost days at work due to BPPV: 68% reduce their workload; 4% change jobs; and 6% leave their jobs because of the condition (27). Work-related activities tend to be affected more in younger patients (28), while older patients with BPPV experience a greater incidence of falls, depression, and impairments to their daily activities (27, 28).

In the United States, healthcare costs associated with the diagnosis of BPPV alone approach $2 billion per year (27). Much of this can be attributed to the high cost of diagnosis (27), which is estimated to be US$2,000 in the United States, €364 (~US$450) in Spain, RMB 4165.2 Yuan (~US$600) in China, and US$180 in South Korea (5). This healthcare burden is likely to increase as the population ages; in South Korea, the number of hospital visits per 100,000 of general population due to dizziness and vertigo is estimated to increase by around 50% in the next 3 decades (5).

Diagnosis of BPPV is based on clinical history and the presence and type of nystagmus and rotatory vertigo during positional test. The affected semicircular canal may be identified by the characteristics of the positional nystagmus documented by videonystagmography during the supine roll test, Semont, or Dix-Hallpike test (2).

Up to 20% of cases of positional vertigo may be due to central pathology (29), caused by disease affecting the central nervous system, such as multiple sclerosis, cerebellar disease, and cerebellar stroke, with vestibular migraine being the most common central cause (30). Suspicion of central positional vertigo may be raised with an absence of latency or fatigability of nystagmus, a lack of marked vertigo, pure upbeat or downbeat nystagmus, or as a lack of responsiveness to CRM (29). Therefore, it is recommended that a diagnosis of BPPV can only be made if the supine roll maneuver Semont or Dix-Hallpike tests elicit nystagmus that is consistent with BPPV; any features of the nystagmus not consistent with BPPV should raise suspicion of central pathology and warrant further investigation (29).

There is increasing evidence about the association between vestibular migraine (VM) and BPPV (31). Despite their similarities, BPPV can be differentiated from VM by the direction of the nystagmus and the duration of the symptoms (32). Although there is generally no positional nystagmus in VM, pseudo-BPPV is a complex mix of positional, atypical positional and nonpositional vertigo accompanied by migraine features; the ability to distinguish pseudo-BPPV from other vertigo disease has great clinical significance for treatment (33).

Appropriate canalith repositioning maneuvers (CRMs) to remove the otolith from the semicircular canal, typically by the Epley or Semont maneuvers for posterior canal BPPV (the most frequent type of BPPV) (34), provide relief from symptoms and positional nystagmus in 80% of BPPV patients with a single application (35), and in up to 92% with additional CRMs (36). Other specific maneuvers are designed for the treatment of the less common lateral and anterior canal BPPV (37). CRMs are considered the gold standard first-line treatment (27) and are suitable for most patients, although contraindicated in patients with severe cervical disease, suspected vertebrobasilar disease, unstable cardiovascular disease, or high-grade carotid stenosis (4). As BPPV is not easily resolved in some patients, many different CRMs have been developed to address the numerous variants according to the affected canals (such as Apiani, Gufoni, Zuma, Semont plus, Vanuchi-Asprella, and Yacovino). Even then, not all patients can be cured and it is not unusual that several manoevers are needed to achieve resolution of BPPV.

The outcome of a CRM is dependent on the type of manoever and on the precision of the execution of the manoever. This encompasses a variety of factors including the angle and velocity of the head and timing during each step (38, 39), fluid dynamics, as well as the amount, size, and location of otoconia in the canal. Reports of BPPV recurrence or residual dizziness (RD) after resolution of the initial nystagmus have become more frequent than when CRMs were first introduced (40–42), possibly due to the CRM variant used, the application of the CRM (43), and/or the pathophysiology underlying BPPV itself. For example, it has been demonstrated that CRMs may be less effective in patients with secondary BPPV (27, 44, 45) or lateral canal cupulolithiasis, the latter of which is more common in older patients compared with other types of BPPV (46).

In BPPV, although the positional vertigo may be effectively reduced or eliminated by one or more CRMs, the underlying pathology might be permanent or unresolved, thus increasing the risk for recurrence. There is debate about the potential for and impact of labyrinthine damage in BPPV, but if it exists, it would not be treatable with CRM and could be a cause of ongoing symptoms such as RD, which will be described in more detail below, along with the methods that may be used to evaluate labyrinthine function. So, although CRMs are highly effective in most patients, there is a clear need to develop a comprehensive BPPV treatment plan in which additional BPPV management strategies could be considered for patients in whom a CRM is contraindicated (4); for patients after successful CRM to improve functional recovery, especially in those at risk of RD symptoms; and to manage risk factors associated with BPPV recurrence.

Where labyrinthine function has been permanently changed or reduced, the process of central vestibular compensation recalibrates the part of the brain that controls balance (47). During this process, the intrinsic plasticity of the nervous system is able to reorganize and overcome damage to the peripheral vestibular system through peripheral and central neuronal repair, sensory and behavioral substitution processes, as well as brain remodeling (15). While this vestibular compensation process occurs naturally in most people, the time course varies (15). External factors that may affect the central compensation process include mobilization (rehab) and medication. There is moderate to strong evidence that facilitating vestibular compensation and behavioral adaptation through vestibular rehabilitation therapy (VRT) is a safe, effective management strategy for unilateral peripheral vestibular dysfunction (47, 48). Although vestibular habituation training, a special type of VRT taking several weeks, was applied successfully in BPPV patients, before CRMs were invented, designed, and applied (49), the current management of BPPV patients relies on the different CRMs described in the literature. The popularity of CRMs is partly due to the potential to resolve the vertigo and nystagmus almost immediately. However, VRT may still help in cases of RD after a successful CRM.

Animal studies have shown that histamine receptors (H1, H2, and H3) are upregulated in the central vestibular system during the first few days of vestibular compensation following labyrinthectomy or vestibular nerve section, and the molecular mechanisms by which histamine modulates vestibular function have been clarified and partly elucidated (50). Betahistine, an H3 receptor antagonist and a weak H1 receptor agonist, has been clinically and experimentally shown to facilitate the functional recovery of vestibular functions (50) through reducing spontaneous resting activity imbalance between the bilateral vestibular nuclei complexes (51) and exerting excitatory effects on the vestibular nuclei neurons (52, 53). This is in contrast to vestibular suppressants, such as antihistamines (dimenhydrinate, cinnarizine, meclizine, and promethazine) and benzodiazepines that may provide symptomatic relief but often interfere with the restoration of vestibular functions (47, 54).

The known and proposed mechanisms of action of betahistine and vitamin D supplementation address many of the underlying pathophysiological mechanisms of BPPV and are summarized in Table 1, along with other potential approaches. In some studies, betahistine as an additional therapy to CRM/VRT has been reported to reduce positional vertigo (68–81), although further research is needed to better define patients in whom betahistine offers clinical benefits and to target the underlying cause(s) of their BPPV as well as any associated comorbidities. Although vitamin D insufficiency has been suggested as a possible factor in the pathophysiology of BPPV (5), there is not yet consistent evidence that correction of vitamin D insufficiency cures or prevents recurrence of BPPV.

Resolution of the nystagmus is the key focus of treating BPPV and is achieved in the majority of cases with one or more CRMs (5). However, even after the disappearance of typical vertigo and nystagmus following a successful CRM, some patients report imbalance without positional vertigo, referred to as RD (2). Despite the lack of established diagnostic criteria (55), RD has been defined as a sensation of non-specific dizziness in the absence of positional vertigo and typical nystagmus in patients upon resolution of BPPV (2); it has been reported in 31–61% of patients, with symptoms lasting from a few days to several weeks (2). Of note, RD does not usually meet all the criteria for persistent postural-perceptual dizziness (82). RD induces a very poor quality of life and is incapacitating to most patients who suffer from it (83). Dizziness in the elderly has adverse psychological and social effects including, but not limited to, decreased performance in daily living activities and increased fear of falling (84).

The pathogenesis of RD after resolution of nystagmus with CRM is not fully understood, but a number of hypotheses have been suggested, based on our current understanding of vestibular function.

Although still disputed, utricular function can be measured, to some extent, by subjective visual vertical (SVV), ocular vestibular evoked myogenic potential (o-VEMP), or the unilateral centrifugation test (106). SVV is a test of static otolith function (91, 107); however, the test has a number of challenges and, although a small retrospective study suggested that immediate improvement in SVV scores following CRM may predict BPPV resolution and help identify patients who need greater follow-up (45, 108), its usefulness in assessing RD after BPPV is not clear (11). Ocular-VEMPs (o-VEMPs) are short-latency myogenic potentials produced through the activation of saccular and utricular afferents by sound and vibration, which are an indicator of dynamic otolith function (107). Despite lower accuracy than SVV, a Dizziness Handicap Inventory (DHI) score > 30 or VEMPs impairment have been suggested as markers for the risk of short-term moderate-to-severe RD (108). It is, however, worth mentioning that the clinical relevance of VEMPs for the diagnosis of RD are becoming more controversial.

In the absence of agreed objective measures to assess RD after successful CRM to treat BPPV, most clinical studies have used subjective measures to assess efficacy. Although the DHI and the visual analog scale (VAS) to quantify RD are the most commonly-used measures, neither of these are validated specifically for BPPV or RD. The DHI is a self-assessment inventory of 25 items covering the functional, emotional, and physical impacts on daily life; whereas the VAS has the advantage of being able to distinguish dizziness from vertigo, with reliable results in evaluating RD (91).

In addition to the aforementioned measurable factors (SVV, o-VEMP, or c-VEMP), several patient or disease characteristics that increase the risk for RD after successful CRM in BPPV patients have been reported. These include:

Factors not associated with the occurrence of RD after successful CRM treatment include the affected side, location, or type of semicircular involvement; hyperlipidemia; diabetes; hypertension; and heart disease. Studies have yielded mixed results concerning whether the number of CRM maneuvers required to cure nystagmus in BPPV influences the risk of developing RD (2, 111). In sum, older age and anxiety may be the most important predictors for the occurrence of RD (68); aging has also been reported to contribute to delayed recovery of symptoms associated with RD (46).

Benign paroxysmal positional vertigo, recurrent BPPV, and RD are entities often encountered in clinical practice, especially in the elderly in whom RD may contribute to an increased risk of falls, restrictions in activity, and social and economic burdens (114). It is beyond doubt that CRMs are often successful for eliminating positional vertigo (and are currently the first choice in managing BPPV), but there are many underlying pathologies that not only cause BPPV but also relate to BPPV recurrences and the risk of RD after a successful CRM. A greater understanding of the pathophysiology may help clinicians to develop a BPPV treatment plan and identify the most appropriate therapeutic option for each patient (115, 116). Table 2 summarizes the potential treatment approaches to the management of RD, based on the underlying pathophysiologies described earlier. There is robust evidence for the use of vestibular rehabilitation exercises (1, 61, 62) in optimizing vestibular function, and some evidence for the effect of betahistine on vestibular function (73, 77, 81, 120), and both betahistine (51, 121) and vitamin D supplementation (55, 93) on factors affecting otolith structure and function and inner ear circulation. Table 2 highlights specific patient populations that are at higher risk of RD and should therefore be monitored closely. However, the ability to identify objective markers/measures of RD is essential to accurately and definitively demonstrate clinical benefits of any potential treatment.

A bibliometric analysis of global research trends in BPPV identified that 40% of publications focused on the treatment of BPPV, 25% on factors influencing the development of BPPV, and 21% on diagnosis; only 7% focused on the hazards associated with BPPV and 5% on its prevention and pathogenesis (122). Interestingly, there is a surge of activity around secondary BPPV caused by inner ear diseases, such as Menière’s disease and sudden deafness (122).

Several nutraceuticals are available with suggested benefits in patients with RD, although the clinical evidence is limited. Using a metabolomics approach, a proprietary polyphenol compound supplementation was reported to affect six metabolites related to RD: 1-methylnicotinamide, anserine, hippurate, lysine, methyl-succinate, and urea (123). However, this was a small study (n = 30) and further research is required.

Historically, clinical studies investigating treatments alongside CRM or for the management of RD have not provided conclusive evidence for efficacy due to the lack of a robust measure. Two biomarkers—otolin-1 and elevated red blood cell distribution width (RDW)—have recently been proposed and may prove useful in future clinical studies. Otolin-1 has been identified as a potential biomarker both for the diagnosis of BPPV and in monitoring the effectiveness of betahistine in BPPV patients (124). Otolin-1 is considered an inner ear-specific glycoprotein that can pass the blood-labyrinth barrier and be detected in peripheral blood (124). Elevated RDW is a potential rapid, inexpensive, and readily available laboratory biomarker of RD (20). Elevated RDW promotes platelet activation and aggregation and is a marker of the procoagulant status of red blood cells. It may impair the microcirculation of the labyrinthine artery and increase oxidative stress (20), thus making it a possible indicator of RD. Of note, another assessment—the modified Clinical Test of Sensory Integration and Balance—has been proposed as an objective evaluation of both RD and postural imbalance after a successful CRM for BPPV (125), but it is not specific for RD in BPPV patients.

In terms of our understanding of BPPV pathophysiology, reduced serum levels of superoxide dismutases (SOD) have been associated with a higher risk of BPPV and BPPV recurrence events; possibly due to the role of SOD on inflammatory process. However, further studies are needed to clarify the exact mechanism and whether there is a suitable intervention to ameliorate this process (21). Lastly, a novel mechanism has been proposed for betahistine; animal studies have suggested that the alleviation of BPPV with betahistine may occur through induction of multiple complement 1q/tumor necrosis factor-related proteins and activation of the ERK1/2-AKT/PPARy pathway (126).

Research into BPPV and RD should aim to generate a deeper and more accurate theoretical basis on which clinicians can treat the condition through matching treatment modalities to the underlying pathophysiology. Figure 2 provides a general picture highlighting the current potential management approaches that may be considered based on known and proposed mechanisms of BPPV.

Benign paroxysmal positional vertigo is a common condition, particularly in older people, associated with decreases in quality of life and interference with daily activities. For the majority of patients, one or more applications of CRM can be successful in relocating the errant otolith debris and restoring normal vestibular function quickly. However, an increasing number of reports indicate that residual symptoms of dizziness are more frequent than previously reported which, although not true vertigo, also reduce quality of life and affect the individual ability to return to normal life. These RD symptoms are more likely to be reported in older patients and those with greater baseline anxiety or stress. As discussed, there are several proposed mechanisms for RD that potential treatments could target. We have suggested a range of additional investigations and treatment options to help clinicians base their management decisions on the underlying pathophysiology for each patient. In particular, these include the use of vestibular habituation therapies and vestibular rehabilitation programs to facilitate vestibular compensation (121); and the potential for betahistine to improve labyrinthine microcirculation and promote vestibular compensation (51, 56); vitamin D supplementation to improve labyrinthine microcirculation in those with a confirmed deficiency (55); and appropriate counseling before and after CRM for patients with a high level of anxiety. On the contrary, vestibular suppressants, such as antihistamines (dimenhydrinate, cinnarizine, meclizine, and promethazine) and/or benzodiazepines, are not recommended for routine use in patients with BPPV (27, 54). For elderly patients, comorbid conditions that may affect labyrinthine microcirculation, including hypertension, dyslipidemia, and diabetes, should be monitored and treated effectively, particularly since BPPV and RD can increase the risk of falls and subsequent morbidity/mortality. A holistic approach to the management of BPPV is key to successful outcomes and reducing the risk of residual dizziness symptoms or BPPV recurrence (Figure 3).

OÖ: Conceptualization, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing. HK: Conceptualization, Methodology, Resources, Visualization, Writing – original draft, Writing – review & editing. LM: Conceptualization, Investigation, Methodology, Resources, Visualization, Writing – original draft, Writing – review & editing. ML: Conceptualization, Investigation, Methodology, Resources, Visualization, Writing – original draft, Writing – review & editing.