Revisiting benign paroxysmal positional vertigo pathophysiology.

Abstract

Benign paroxysmal positional vertigo is the most common peripheral cause of vertigo. Although its pathophysiologic mechanisms remain unclear, different locations have been attributed throughout the last century, from the days of Bárány. Disease was initially located by Dix and Hallpike in the utricle, but later, Schuknecht's works elicited the cupulolithiasis and canalolithiasis theories, localizing the pathology to the semicircular canal system and mainly to the posterior one. However, conflicting evidences from temporal bone studies accumulated against this theory, which suggest other explanations. Although this clinical entity is well defined, and can usually be effectively treated with certain physical maneuvers, its pathophysiology is still obscure and is being critically discussed in this article, which reviews the milestones of benign paroxysmal positional vertigo understanding.

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Current reviews
Revisiting benign paroxysmal positional vertigo pathophysiology
Tal Marom, MDa,⁎, Yahav Oron, MDa, Waseem Watad, MDa,
Dalia Levy, MDa, Yehudah Roth, MDa,b
aDepartment of Otolaryngology-Head and Neck Surgery, Edith Wolfson Medical Center, Tel-Aviv University Sackler School of Medicine, Holon, Israel
bDepartment of Public Health Services, University of Toronto, Toronto, Canada
Received 27 April 2008
AbstractBenign paroxysmal positional vertigo is the most common peripheral cause of vertigo. Although its
pathophysiologic mechanisms remain unclear, different locations have been attributed throughout the
last century, from the days of Bárány. Disease was initially located by Dix and Hallpike in the utricle,
but later, Schuknecht's works elicited the cupulolithiasis and canalolithiasis theories, localizing the
pathology to the semicircular canal system and mainly to the posterior one. However, conflicting
evidences from temporal bone studies accumulated against this theory, which suggest other
explanations. Although this clinical entity is well defined, and can usually be effectively treated with
certain physical maneuvers, its pathophysiology is still obscure and is being critically discussed in
this article, which reviews the milestones of benign paroxysmal positional vertigo understanding.
© 2009 Elsevier Inc. All rights reserved.
1. Introduction
Benign paroxysmal positional vertigo (BPPV) is probably
the most common type of vertigo. Lifetime prevalence
is estimated to be 3.2% in females, 1.6% in males, and
2.4% overall.
Although termed benign, it can be a severe and disabling
problem for some of the patients. Of patients admitted to the
emergency medicine department for moderate to severe
vertigo or dizziness, 8% to 9% are diagnosed with BPPV [1].
Throughout the years, and especially after Dix and
Hallpike's [2] reports, this vertigo is characterized with
several clinical manifestations: mixed torsional and vertical
nystagmus (occasionally almost true vertical), provoked by a
positioning test, latency (typically 5–10 seconds) between
the completion of the provocative maneuver and the onset of
vertigo and nystagmus, paroxysmal nature (an increase and
then a decline over a period of 10–20 seconds), fatigability
(reduction in vertigo and nystagmus if the Dix-Hallpike test
is repeated), and reversal of nystagmus upon rising from
supine to an upright position.
Inthelastcentury,differentinnerearsiteswereattributedto
betheillnesscenter,astheywereaccordinglytargetedforboth
medical and surgical therapies, with various rates of success.
The shifting between the sites relied mostly on temporal bone
dissections, which dramatically changed BPPV perception.
2. First descriptions
It is common to quote Bárány's [3] classical report as the
first BPPV description. However, others argue that Adler [4]
was in fact the real pioneer in his description of the same
illness many years before. In his “Unilateral Vertigo” report,
Adler wrote about his 9 patients and another 2 cases
published separately later by Guye [5] who had substantial
injuries to the labyrinth or the eighth nerve, with accompany-
ing severe hearing loss and evidence of nonpositional
vestibular dysfunction. Vertigo and nystagmus were incited
byspecificheadpositioning,butcouldnotbeeitherattributed
to any of the inner ear components or localized. They also
lacked all the principal signs of BPPVas known today.
In 1921, Bárány [3] described the case of a 27-year-old
woman who had been experiencing repeated short attacks of
vertigo lasting for about 30 seconds, accompanied with
nausea, only when lying on the right side, during 2 weeks
before her visit. Hearing, caloric reactions on both sides, and
neurologic examination results were reported as normal.
Available online at www.sciencedirect.com
American Journal of Otolaryngology–Head and Neck Medicine and Surgery 30 (2009) 250–255
www.elsevier.com/locate/amjoto
⁎Corresponding author. Department of Otolaryngology-Head and Neck
Surgery, Edith Wolfson Medical Center, Tel-Aviv University Sackler School
of Medicine, P.O. Box 5, Holon 58100, Israel.
E-mail address: maromtal@013.net.il (T. Marom).
0196-0709/$ – see front matter © 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjoto.2008.06.009

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Nystagmus was rotatory to the right with a slight vertical
component upwards. However, Brandt [6] misinterpreted his
observations and concluded inaccurately that nystagmus in
BPPV was due to position and not positioning.
Nylen [7], in 1950, emphasized the importance of moving
the head and body together as a unit when performing the
posture test. In a later report, he made a distinction between
nystagmus produced solely by a specific head position
(positional nystagmus) and nystagmus produced by move-
ment of the head to achieve a specific position (positioning
nystagmus) [6]. This clarification was important; however, it
did not promote mechanism understanding further on.
Other researchers in the following years, such as Bruns
[8], Borries [9], and Williams [10], made some progress in
analyzing the nystagmus' properties, yet the understanding
of the pathophysiology was still poor [11].
3. Utricle
In 1952, otologists Dix and Hallpike [2] described a
provocative maneuver to induce positional nystagmus in
patients with BPPV (several decades later, a modified
maneuver was described by Cohen [12], for patients with
disabilities, which precluded them the use of the classical
Dix-Hallpike maneuver). Relying on a postmortem analysis
of a single patient with BPPV, they attributed the pathology
of this disease to the utricle, which had “absence of the
otolith membrane, disorganization of the sensory epithelium
and certain specific tissue changes in the connective tissue
meshwork underlying the epithelium” and normal appear-
ance of semicircular canals.
In the same year, Dix [13] reported a single successful
labyrinthectomy procedure that stopped intractable BPPV
bouts and their related nystagmus. Their conclusion, again,
preferred an underlying utricular pathology.
Five years later, in 1957, Cawthorne and Hallpike [14]
published an autopsy report of a woman who died from
disseminated breast cancer, who also had recurrent episodes
of BPPV. Again, abnormal findings were found in the utricle,
but they also noted similar changes in the ipsilateral
horizontal semicircular canal (HSCC), but they ignored
them. Instead, they reconcluded that the source of the
pathology was again the utricle. However, Jongkees argued
against this localization in his editorial of their report, owing
to changes in the cristae of the semicircular canals as well.
In 1962, Citron and Hallpike [15] reported another case of
BPPV, in which the condition was effectively treated by
vestibular neurectomy. Their conclusion was consistent with
a utricular pathology.
4. Superior vestibular artery
In 1956, Lindsay and Hemenway [16] demonstrated a
completely degenerated superior vestibular ganglion, with a
well-preserved otolith apparatus and inferior vestibular
ganglion, in a temporal bone from a deceased patient who
had BPPV shortly after vestibular neuronitis. They con-
cluded that the cause was occlusion of the superior vestibular
artery supplying this structure, as seen in their work. As their
case was associated with thromboembolic disease, the
assumption that local arterial occlusion leads to BPPV
presentation was neglected, as this finding was not supported
by any of the following reports.
5. Semicircular canals
5.1. Posterior semicircular canal
Stenger [17], in 1955, first suspected that BPPV arises
from the semicircular canal system and not from the otolith
apparatus. However, he had no proofs at that time to
contradict Dix and Hallpike's [2] findings.
In 1962, Schuknecht [18] first suggested an alternative
localization for the pathology accounting for BPPV. After
reviewing previous temporal bone studies, he rejected
previous theories of both neural- and otolith-related
pathology, and proposed the crista of the PSCC as the
cause of BPPV. Loose otoconia from the utricle were
implied, which, in certain positions of the head, are free to
respond to gravitational forces, thereby displacing the cupula
of the PSCC. An ampullofugal reaction was defined as a
reaction that excited the canal and enhanced neural
discharge, whereas ampullopetal reaction resulted in an
inhibitory reaction, in which the neural flow was diminished.
Vyslonzil [19] demonstrated in 1963 that otoconia were
suspended in a protein-rich mass within the endolymphatic
space, mostly near the PSCC.
In 1969, Schuknecht [20] proposed a modified form of his
primary theory, which he then called cupulolithiasis. He
demonstrated in the temporal bones of 2 patients with BPPV
“basophilic staining masses” of “granular” or “homogenous”
materials, attached to the cupula of the PSCC on the
clinically affected side, and proposed that BPPV was not
caused by the movement of loose otoconia, but rather by the
gravitational depositions on the cupula of the PSCC. It was
assumed that the otoconia had a higher specific gravity than
the surrounding endolymph. A typical change in the head
position resulted in their passive downward movement
toward the PSCC cupula, based on gravity forces.
Cupulolithiasis theory could explain the linear rotatory
nystagmus (due to ampullofugal deflection of the cupula),
the latency of onset (due to the inertia of the mass and
cupula), the fatigability with repeated positioning (due to
spread of the debris attached to the cupula), and recurrence of
nystagmus and vertigo after rest (due to sedimentation of
debris on the cupula). However, it could not explain the
clinical findings of some of their cases, such as the lack of
BPPV attacks with slow head tilt or with linear head
accelerations. In addition, it did not clarify the brief duration
of the nystagmus and the reversal of the nystagmus with the
return to a sitting position.
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In 1970, the works of Harbert [21] supported
Schuknecht's [18,20] theories, on the basis of careful
observations of more than 40 BPPV cases in which the
direction of the nystagmus changed with the direction of
gaze. This could only be explained by an ampullofugal
stimulation of the PSCC.
In 1973, Schuknecht and Ruby [22] reported finding
cupular deposits in 149 (38%) of 391 temporal bone
specimens without gross pathologic changes in the labyrinth.
Although most of these changes (86/149, 58%) were located
in the PSCC, only 3 (2%) were actually in a size comparable
with those found in earlier studies from patients with BPPV.
Later that year, Baker et al [23] confirmed that posterior
semicircular canal excitation activates the vestibuloocular
reflex in its direction.
At that time, most of the treatments for intractable BPPV
were invasive and destructive, especially with the use of
streptomycin, and were associated with unacceptable long-
term morbidity. Relying on the proposed disease center for
BPPV, Gacek [24] was the first to describe the successful
selective transection of the posterior ampullary nerve, in 4 of
5 cases of patients with intractable BPPV in 1974. An
alternative physical therapy approach was introduced by
Brandt and Daroff [25] in 1980 to “promote the loosening
and ultimate dispersion of the degenerated otolithic material
from the cupula.”
In 1979, Hall et al [26] published their “Canalolithiasis”
theory, which was complementary to Schuknecht's [18]
theory, which could only explain the nonfatigable form of
BPPV, which was thought to be due to fixed deposits on the
cupula. In their paper, the fatigable form of BPPV was
incited by the action of free-floating material within the
body of the PSCC.
This led to the evolvement of safe canalolith repositioning
maneuvers, described by Epley [27,28] and Semont et al
[29], on the ground basis of inducing movement of loose
material from the PSCC and its reentrance to the utricle in a
coordinated head and body positioning. It was assumed that
the return of the otoconia might cause the dizziness reported
by some patients after physical therapy, as also proven
recently in models [30].
Another surgical approach, based on this theory, was the
occlusion of the posterior semicircular canal. Parnes and
McClure [31] published their first successful results in 1990.
They also confirmed that this intracanalicular debris (which
was also scanned with an electron microscope) could freely
float within the endolymph of the canal, in the form of loose
particles or a congealed clot or plug [32]. However, it was
possible to visualize this debris in only 8 of 22 patients who
underwent surgery for intractable BPPV.
It is notable that a mathematical model, as proposed by
Squires et al [33], supported both cupulolithiasis and canalo-
lithiasis theories, based on hydrodynamic calculations.
Arguing against the Canalolithiasis theory was the report
of Bachor et al [34] on the occurrence of cupular deposits
in pediatric temporal bones, given the fact that BPPV
attacks in children are extremely rare. In their examination
of 186 temporal bones from 121 individuals (aged
newborns to 10 years), a total of 276 cupulae were
identified, and a basophilic deposit was found in 35 cases
(12.7%). In many cases, the deposits contained recogniz-
able otoconial crystals. Most deposits were small and were
almost equally distributed between the 3 semicircular ducts.
Their work suggested that the deposits may be a
phenomenon of the normal aging vestibular labyrinth.
Similarly, Morirarty et al [35] reported the presence of
basophilic deposits in the temporal bones of patients
without any previous history of BPPV.
Deposits of basophilic material on the cupula of the
semicircular canals were also found in the temporal bones of
patients who received aminoglycosides within 6 months
before death (when compared with normal temporal bones)
[36], regardless of BPPV history. Such changes may be
either related to BPPV in some patients, who were
administered with aminoglycosides, or to the aminoglyco-
side treatment itself.
5.2. Horizontal semicircular canal
In 1985, McClure [37] reported on several patients with a
characteristic nystagmus, provoked by supine bilateral head
turns and beating toward the undermost ear. That clinical
picture was suggestive of HSCC involvement [37]. In this
variant, there are 2 distinctive subtypes, based on the
direction of nystagmus (geotropic, toward the undermost ear,
and apogeotropic, away from the undermost ear). The more
common geotropic variant is caused by the movement of
otoconial debris within the long arm of the HSCC, which
stimulates utriculopetal endolymph flow, whereas the
apogeotropic variant is assumed to be caused by the
adherence of otoconial debris in the cupula of HSCC,
inducing local “cupulolithiasis,” or by otoconia trapped in
the proximal segment of the canal near, the cupula [38].
5.3. Anterior semicircular canal
Shortly after HSCC BPPV was reported, the anterior
semicircular canal (ASCC) variant was described by
Steddin and Brandt [39], which is still considered to be a
rare variant, more likely associated with head trauma,
accounting for between 2% and 22% in all BPPV reports
[40]. The low occurrence of ASCC BPPV can be explained
by the labyrinth anatomy. Usually, debris within the ASCC
is self-cleared, because its posterior arm descends directly
into the common crus and the utricle. However, when the
debris is unsuccessfully pushed into the utricle (owing to
its size, insufficiency of the circulation process, or a
narrowed pathway), it is retained in the ASCC and excites
it. Anterior semicircular canal BPPV manifests with a
predominant down-beating nystagmus, which has to be
differentiated from other cerebellar diseases, and with a
small torsional component.
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6. Saccule
The knowledge about the interaction between the otolith
apparatus and the canal end receptor system mounted
gradually. It was known for years that saccular inhibition on
the canal system, in cats, is mediated through first-order
neurons in the medial vestibular nucleus [41,42], where both
afferent fibers from the saccule and the HSCC terminate. In
these reports, a selective denervation of the utricle caused a
horizontal nystagmus while the HSCC remained intact.
However, if the HSCC was denervated before utricular
denervation, there was no nystagmus. When the saccule was
selectively denervated and the PSCC was intact, a vertical
nystagmus (upbeat) appeared. If the PSCC was denervated
before saccular denervation, there was no nystagmus as
well. Thus, by neutralizing the otolith role on the canal
system, the response of the canal receptor is shown. Gacek
[43] also speculated that saccular nerve dysfunction might
be able to cause BPPV, when studying virally induced
saccular nerve degeneration in 5 temporal bones with BPPV
without canalithiasis.
7. Vestibular nerve changes
In 1998, Gacek and Gacek [44] reported temporal bone
findings from 3 patients with BPPV. Degenerative change,
such as focal axonal degeneration and perineural inflamma-
tion, was found in the inferior vestibular ganglion, with
sparing of the superior vestibular ganglion. No basophilic
deposit was found in the posterior semicircular canals or on
thecupulae.Inalaterreport,Gacek[43]reportedin2003on5
temporal bones from patients with BPPV. Only a small
posterior canal cupular material was found in one bone,
whereas none was seen in the others. The major histopatho-
logic changes observed in these specimens were a reduction
of 50% of ganglion cells in the superior vestibular division in
allthebones,areductionof50%oftheneuronsintheinferior
division in 3 bones, and a reduction of 30% of those neurons
in the remaining 2 bones. Also, abnormal saccular ganglion
cells were noted.
Latent neurotrophic viral infection suggested explaining
these observations, which was similar to findings in temporal
bones from patients with Menière's disease, vestibular
neuronitis, and Bell's palsy. These conditions commonly
antecede BPPV, and viral agents may have a role in their
pathogenesis. The histologic findings from the report of
Gacek and Gacek [45] were similar to the findings in the
temporal bones of patients with these diseases.
The high affinity of the α herpes virinae group to sensory
ganglia [46] and the presence of viral herpes simplex virus
(HSV) DNA fragments in patients with other cranial
neuropathies, such as Bell's palsy [47] and trigeminal
neuralgia [48], might also be associated with BPPV.
However, there were no reports on HSV titers, or on HSV
fragments, in these patients.
8. Back to otoliths
The difference between the almost-vertical nystagmus
that is seen in some patients with BPPV and the mixed
nystagmus (vertical and torsional components) cannot be
explained by the direction of gaze alone according to the
canalolithiasis and cupulolithiasis theories. A 3-dimensional
analysis of the nystagmus properties suggested that BPPV
pathophysiology may not be confined to the canal system
and involved the otoliths [49]. By using an off-vertical axis
rotation device, vestibuloocular reflex gain measurements
were reduced in patients with BPPV, compared to normal
controls, which suggests an otolith impairment [50].
This involvement is also supported by the dizziness
episodes some patients describe after successful reposition-
ing and liberatory maneuvers [51].
An otolith dysfunction assessment tool in patients with
BPPV has been described [52]. The subjective visual vertical
is a useful, easily administered tool for the assessment for
this purpose. The patient is asked to orient a line in a
darkened room vertically or horizontally. Utricular lesions
cause the patient to place the line 10° to 15° toward the
lesioned side. The pathologic deviation may last for months
after the insult. This is a sensitive yet, not a specific, tool for
diagnosing otolith dysfunction in this setting.
9. Discussion
Clinical observations such as head movement–induced
nystagmus, positional dependency of nystagmus, and its
fatigability were well recognizable with vestibulopathies a
long time before Bárány's [3] classical breaking report was
published. Early suggested mechanisms could not explain
any of the striking features of the disease.
Benign paroxysmal positional vertigo characterization
from other peripheral vestibular disease was gradually
carried out, as the pathophysiology became clearer. First
reports were exclusively based on subjective complaints and
objective findings in clinical examinations, but only the
introduction of the provocative positioning maneuver of Dix
and Hallpike [2,13] made a major contribution in expanding
the knowledge regarding BPPV pathophysiology and the
clinical interpretation of the induced nystagmus. Their work
determined the cardinal manifestations of BPPVand helped
in the lateralization of the affected ear, and its characteriza-
tion as benign and peripheral. Treatment at that time was
destructive, aiming at the whole labyrinth, by alcohol
injection (labyrintholysis) [53] or labyrinthectomy [15].
Temporal bone findings were conflicting throughout the
years. The utricle was first suspected to be the inciting site on
BPPV, as reported in several occasions [14,15,53]. One
report even suggested the occlusion of the superior vestibular
artery [16] as the offending factor. These sites were later
abandoned after Schuknecht's [20,22] works had focused on
the semicircular canal system, mainly the PSCC. Schuknecht
253 T. Marom et al. / American Journal of Otolaryngology–Head and Neck Medicine and Surgery 30 (2009) 250–255

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theorized that BPPV is triggered by relatively heavy debris,
from degenerating otoconia of the utricular macule, settling
on the cupula of the PSCC (cupulolithiasis). However, this
theory could not explain either the brief duration of the
nystagmus and the reversal of nystagmus with return to a
sitting position. Later observations indicated that the
intracanalicular debris may float freely within the endo-
lymph of the canal in the form of loose particles or a
congealed clot or plug (canalolithiasis). The concepts of
cupulolithiasis and canalolithiasis have been the working
hypotheses of BPPV for the last 30 years; both medical and
surgical therapies target this site, with huge success.
Benign paroxysmal positional vertigo mechanical theory,
as proposed, could not explain several features such as long
remissions between symptomatic episodes and absence of
nystagmus in the presence of subjective symptoms when
triggered with the Dix-Hallpike maneuver. Moreover, it was
evident that this debris was not seen in all patients with
BPPV [35]; debris was also found in asymptomatic young
children [34], healthy subjects [35], and patients treated with
aminoglycosides [36]. Therefore, cupular basophilic debris
might have represented a morphological change as merely
associated with the aging labyrinth.
Some research work in recent years focused on under-
standing the post repositioning maneuver dizziness in some
patients and the different types of nystagmus in patients with
BPPV. Because the planes of the superior part of the saccule
and the posterior canal crista oppose each other, a Dix-
Hallpike positioning results in depolarizing these neurons,
which activate antagonist extraocular muscles. If the saccule,
or its neural afferents (the inferior vestibular ganglion and
nerve), is damaged, then its inhibitory outflow is reduced.
Electrophysiological and mathematical analysis of nystag-
mus suggested a contribution of the otolith apparatus to the
canal system in nystagmus appearance. This has led to the
acknowledgment of the potential role of the otolith apparatus
once again, after being abandoned for years.
Benign paroxysmal positional vertigo is a recurring
disease with a recurrence rate of approximately 15% per
year [54]. However, a recurrence rate of BPPV in 56% of
affected individuals was reported in a 1-year cross-sectional
study [1]. It is still not known what causes this variation
among patients.
Benign paroxysmal positional vertigo can occur after
another vestibular disease. In most patients, the trigger
bringing the attack is unknown. However, some patients had
suffered a previous ipsilateral inner ear disease, such as
Menière's disease or acute unilateral peripheral vestibulo-
pathy. It was proposed that endolymphatic hydrops damages
the utricle resulting in loose otoconia. Vestibular neurolabyr-
inthitis often affects the superior vestibular nerve. Simulta-
neous damage to the utricle could detach the otoconia and
bring upon PSCC BPPV [55].
BPPV was also associated with migraine. Lempert et al
[56] found that the prevalence of migraine in patients with
BPPV was twice as high as that in age- and sex-matched
controls. The relationship between migraine and BPPV is
poorly understood. It has been suggested that migraine
causes vasospasm of the labyrinthine arteries, hence
inducing local ischemia which facilitates otoconia detach-
ment from the utricular macula [57].
Benign paroxysmal positional vertigo also occurs in
patients after cochlear implantation. Several mechanisms
have been suggested: the fall of bone dust particles into the
cochlea during the cochleostomy, the vibration caused when
boring the cochlea is probably sufficient to dislodge the
otoconia into the labyrinth, and the displacement of an
otolith because of the electric stimulation [58].
Future research will further contribute to the under-
standing of BPPV pathophysiology. Human research is
confined to clinical observation of symptomatic patients
andtemporalbonedissections;henceitlimitstheaccesstothe
innerearinrealtime.However,animalmodelexperimentsare
still scarce and difficult to replicate to the human vestibule.
Inagaki et al [59] reconfirmed the otoconia role in BPPV in
bullfrogs, whose posterior semicircular canal or their utricle
was removed. However, better models are desirable.
A space traveler's brain no longer relies on the gravity
sensation of inner ear structures for information about
position and motion, as they are more dependent on the
visual system. No data are available regarding the possible
occurrence of BPPV in a zero-gravity environment. It would
be interesting to try to induce BPPV under these terms.
Higher vestibular central centers are continuously being
studied for their role in the outflow of the peripheral
vestibular centers. Their role is still undetermined in BPPV
pathophysiology. The role of the flocculus in mediating
vestibular nucleus neuron plasticity during vestibular
compensation in the rat, described by Johnston et al [60],
might be an important one.
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