UMUR, JK, IMT

Acta Neurol Taiwan. 2011 Jun;20(2):101-6.

The relationship between isolated dizziness/vertigo and the risk

factors of ischemic stroke: a case control study.
Chang CC1, Chang WN, Huang CR, Liou CW, Lin TK, Lu CH.
Author information
Abstract
PURPOSE:
Dizziness/vertigo are important public heath care issues especially in elderly patients. Isolated
dizziness/vertigo without neurological deficits has seldom been considered a symptom/sign due to
vascular origin. Recently, some studies have suggested that vascular origin should be considered in
cases of positional vertigo and isolated vertigo or dizziness when the etiology remains unclear. In this
study, we tried to delineate the correlation of dizziness/vertigo and risk factors of stroke.
METHODS:
We collected adult subjects receiving health screening of the brain at their own expense. All subjects had
undergone brain magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) and
carotid duplex. The chief complaints, body height, body weight, waist circumference and blood pressure
of all subjects were recorded. Most received blood tests including fasting sugar, total cholesterol, low
density lipoprotein, high density lipoprotein (HDL), triglycerides, and uric acid (UA). The relationships
between dizziness/vertigo and blood test data, blood pressure, body mass index (BMI), waist
circumference, metabolic syndrome, carotid duplex, silent brain infarction, leukoaraiosis and MRA were
analyzed.
RESULTS:
After exclusion, a total of 170 out of 210 subjects were collected. The analysis revealed that dizziness/
vertigo had a significant correlation to age, UA , BMI, male HDL and female waist circumference. Among
them, female waist circumference had the highest statistical significance (P = 0.001). Leukoaraiosis on
brain MRI also had a close relationship with dizziness/vertigo.
CONCLUSION:
After careful examination and approach, a vascular origin should be considered in dizzy patients of
unknown etiology.
Aging Dis. 2015 Feb; 6(1): 3847.

Published online 2014 Feb 9. doi: 10.14336/AD.2014.0128

PMCID: PMC4306472

Dizziness and Imbalance in the Elderly: Age-related Decline in the

Vestibular System
Shinichi Iwasaki* and Tatsuya Yamasoba

Author information Article notes Copyright and License information

This article has been cited by other articles in PMC.

Abstract

Dizziness and imbalance are well-recognized problems among older people. A population-based
study in the United States reported that 24% of people older than 72 years have dizziness [1].
Dizziness and imbalance in older people are a growing public health concern, because older
individuals who suffer from dizziness have a significantly higher risk of accidental falls and
consequent injuries [2,3]. Falls are the leading cause of hospital admission and accidental death
in older people. Several studies have shown that older adults with a history of dizziness and
imbalance are at a higher risk of falling [35]. Furthermore, vertigo and unsteadiness lead to a
fear of falling, which is a strong predictor for those who will suffer one or more subsequent falls
[6,7].

The underlying cause of dizziness in the elderly is complex and multi-factorial [8,9]. Postural
stability is maintained by the integration of somatosensory, visual and vestibular inputs to the
central nervous system, followed by outputs to the musculo-skeletal system (Fig. 1). Dizziness
and imbalance can be caused by changes in any of the factors associated the balance system, be
they of sensory, visual, vestibular, neurologic, and muscular origin. Function of all these
components deteriorates with age [10].

Figure 1.
Age-dependent changes in the system maintaining postural
stability. Postural stability is maintained by the integration of somatosensory,
visual and vestibular inputs to the central nervous system, followed by outputs to
the musculoskeltal system. Function ...

This review will focus on the clinical characteristics of dizziness in the elderly and age-related
changes in the peripheral and central vestibular systems, and will report some recent findings on
cellular mechanism of aging and the possible treatment strategies for dealing with dizziness and
imbalance in the elderly.

Go to:

Prevalence of dizziness and imbalance in the elderly

Dizziness and imbalance are one of the most common complaints among older people. The
prevalence ranges from approximately 20% to 30%, depending on the definition of dizziness and
the population studied [1,11,12]. A population-based study in the United States found that 24%
of people older than 72 years reported having an episode of dizziness within the previous 2
months, lasting for at least one month [1]. Another population-based study in the United
Kingdom reported that 30% of people older than 65 years have dizziness [11]. The prevalence of
dizziness has a tendency to increase with age [1,11]. A cross-sectional study in Sweden reported
that the number of adults with dizziness increased up to approximately 50% in people older than
85 [13].

The underlying causes of dizziness in the elderly vary widely [1,8,1417]. Multiple factors
including neurologic, cardiovascular, visual, vestibular, and psychological problems can cause
dizziness in older people. Previous studies have reported conflicting results regarding the
etiologies of dizziness depending on the diagnostic criteria adopted and the population studied.
General population studies have usually assigned the causes of dizziness mainly on the basis of
interview without performing any clinical examinations. A population survey in Germany
reported that a prevalence of vestibular vertigo was 14% in the general population older than 70
years [14]. Their diagnoses were based on telephone interviews by medical staff. Studies in
clinical settings were biased by the types of clinics and physical examinations performed. A
prospective case control study conducted in general practices, in which general physical
examinations were performed, reported 18% of patients with dizziness who were over 60 years
old had a peripheral vestibular disorder [8]. On the other hand, a prospective study in a
neurology clinic, in which detailed neuro-otological examinations were performed, reported that
peripheral vestibular dysfunction was the principal cause of dizziness in 56% of patients older
than 50 years [15]. Similarly, cerebrovascular causes range from 0% to 70% [8,18], and
psychiatric causes in 0% to 40% in older patients with dizziness [8,15,19] depending on the
clinical examination performed. In several studies, no specific diagnosis could be made to
explain the symptoms in approximately 20% to 30% of older people with dizziness [8,9,17].
Belal and Glorig (1986) used the term presbystasis to describe this type of age-related problem
that cannot be attributed to any known diagnosis [17]. On the other hand, other studies assigned
multiple diagnoses in 18% to 85% of older people with dizziness [8,15,18]. Tinetti et al. (2000)
proposed that dizziness in the elderly should be considered as a multifactorial geriatric syndrome
involving many different symptoms and originating from many different causes, including
cardiovascular, neurologic, sensory, psychological and medication-related problems [1].

Go to:

Peripheral vestibular disorders in the elderly

In most studies regarding dizziness in the elderly, peripheral vestibular dysfunction is the first or
the second most frequent cause of dizziness [8,9,15,20]. Benign paroxysmal positional vertigo
(BPPV) is the most frequent form of peripheral vestibular dysfunction, followed by Menieres
disease and vestibular neuritis [9,15].

BPPV is the most common cause of vertigo and dizziness from childhood through to old age,
peaking at about 60 years [21]. Several studies have demonstrated an increase in incidence of
BPPV in older people [20,22,23]. A recent epidemiologic study obtained from a large cross-
sectional neurotologic survey reported that lifetime prevalence of BPPV was estimated to be
2.4% and the one year prevalence of 1.6% but that one-year prevalence of BPPV in adults older
than 60 years was approximately seven times higher than that of adults from 18 to 39 years old
[22]. BPPV is usually diagnosed by the presence of episodic vertigo provoked by changes in
head position and concomitant nystagmus observed during the positioning maneuver [24,25]; it
is effectively treated by physical therapy [2628]. Johkura et al. (2008) reported that about 50%
of elderly patients with chronic dizziness who visited an emergency unit showed extremely
weak, horizontal, direction changing apogeotropic nystagmus, which is characteristic of
horizontal canal BPPV, and that some of symptoms in these patients was improved by daily
positional exercises for BPPV [29]. The results suggest that the reported prevalence of BPPV in
older people might be underestimated.

The cause of BPPV is thought to be small particles trapped in the semicircular canals [25,30].
These particles most likely consist of otoconia dislodged from the utricula maculae. Several
studies have demonstrated that a high proportion of otoconia of the utricular macula degenerates
in the elderly, and many have fractures [31,32]. Morphological changes in the otolith organs may
be related to the increased prevalence of BPPV in the older people.
Menieres disease accounts for 3% to 11% of diagnosed dizziness in neuro-otological clinics. Its
annual incidence rate and point prevalence are estimated to be 15/100,000 and 218/100,000,
respectively, in the general population [33]. Menieres disease has generally been regarded as a
disease of middle-aged people [34,35]. However, in a large case series study, Ballester et al.
(2002) reported that 15% of patients with Menieres disease are more than 65 years of age [34].
In that study, 40% of cases were a reactivation of longstanding Menieres disease while 60%
were de novo case of Menieres disease. They also reported that drop attacks, which are caused
by sudden otolithic dysfunction, were more frequent in older people compared to the general
population. A multi-center survey in Japan reported the proportion of de novo cases of Menieres
disease in patients older than 60 years had increased during the previous 30 years [36].

Vestibular neuritis accounts for 3% to 10% of diagnoses in oto-neurological clinics [20,37]. The
epidemiological data on vestibular neuritis is scarce. An epidemiological survey in Japan
reported that the prevalence of vestibular neuritis is 3.5/100,000 and the peak age distribution
was between 40 to 50 years [38]. Although vestibular compensation relieves most of the
symptoms of vestibular neuritis within a few weeks of onset, 30% to 40% of patients have
chronic persistent dizziness [3941]. Furthermore, deterioration in function of the intact side of
the peripheral vestibular organs, vision, and the proprioceptive systems in the elderly may lead to
a breakdown of vestibular compensation.

Go to:

Functional deterioration of vestibular systems in the elderly

The stability of posture and gaze during standing and walking is maintained by the rapid
processing of vestibular, visual and somatosensory inputs in the central nervous systems,
followed by outputs to the musculoskeletal and visual systems. Every factor in this system
deteriorates during aging.

Age-related deterioration of peripheral vestibular function has been documented by measuring

the vestibulo-ocular reflex (VOR) using rotational tests and/or caloric tests, both of which reflect
function of the lateral semicircular canals [4244]. Sinusoidal rotation tests in normal adults over
the age of 75 years showed a decrease in VOR gain as well as the VOR time constant, especially
with high velocity stimulation, as compared with young subjects [42]. In a longitudinal study of
normal subjects older than 75 years old, a progressive decrease in VOR gain and an increase in
phase lead were observed during five annual examinations [45]. Another study assessing
performance in sinusoidal rotational tests and caloric tests in normal subjects from 7 to 81 years
old reported a decline in the response amplitude and less of a compensatory response phase with
increasing age in the rotational test, while the caloric test showed no consistent trends with age
[44]. These results suggest that age-related changes in vestibular system preferentially affect the
high-frequency component of the VOR since the caloric testing reflects the low frequency
component of the VOR.

Age-related deterioration of peripheral vestibular function has been demonstrated in other

vestibular tests. Vestibular evoked myogenic potentials (VEMPs) are short-latency muscle
responses typically recorded from the neck muscles (cVEMPs) or from the eye muscles
(oVEMPs) [4648]. Clinical and physiological studies have shown that cVEMPs reflect the
function of the saccule and the inferior vestibular nerve whereas oVEMPs reflects the function of
the utricle and the superior vestibular nerve [4952]. A cross sectional study of consecutive
patients ranging from 7 to 91 years old showed an age-dependent decrease in cVEMP amplitude
and an increase in cVEMP latency [53]. Similarly, oVEMPs show an age-dependent decrease in
amplitude and an increase in latency (Fig. 2) [54]. These results suggest that the function of the
otolith organs as well as their central pathway also deteriorate with increasing age. Recently,
Agrawal et al. (2012) measured the function of the semicircular canals, utricle, and saccule using
the head thrust test, oVEMP, and cVEMP, respectively, in healthy subjects more than 70 years
old [55]. They showed that the function of the semicircular canals as well as the otolith organs
decline with age, although the magnitude of impairment was greater for the semicircular canals
than the otolith organs. However, deterioration of the results of the head thrust test might reflect
an element of deterioration of oculomotor function as well as the semicircular canal function.

Figure 2.

Age-dependent changes in amplitude and latency of oVEMPs to bone-

conducted vibration. (Left panel) Amplitude of the n10 responses of oVEMP
significantly decreases with age. (Right panel) Latency of the n10 responses of
oVEMP significantly increases with ...

Age-related changes in postural stability have been examined using posturography, in which
changes of the center of pressure was measured during quiet standing [5659]. For estimating the
role of different sensory inputs on postural control, dynamic posturography using a moving
platform or a foam rubber surface have also been developed. In most studies, all measures of
balance performance get worse in older subjects compared with younger subjects (Fig. 3) [57
59]. This age-related decline in balance control is correlated with deterioration of visual,
vestibular, and sensorimotor function as well as reduction in strength of the lower muscles.
Teasdale et al. (1991) have demonstrated that alteration in any two of the three sensory inputs
(visual, vestibular and somatosensory) had a significantly greater effect on older subjects than in
younger subjects whereas alteration in one input did not have a significant effect due to age [59].
These results suggest that decreased inputs from the vestibular, visual and somatosensory
systems in older subjects lead to a decreased capacity for compensation by the other inputs in
order to maintain postural stability.

Figure 3.

Age-dependent changes in the postural stability on the foam rubber. (Left

panel) Age-dependent changes in the velocity of the center of pressure (COP)
during standing with eyes closed on the foam rubber. (Right panel) Age-dependent
changes in the envelopment ...

Go to:

Cellular changes in aging of the vestibular system

Hair cells and neurons in the vestibular system do not regenerate or increase basically in the
mammals. A significant decrease in the number of hair cells and neurons in the vestibular system
in older people has been described in the literature [60,61]. Richter (1980) examined the density
of vestibular hair cells and nerve cells in Scarpas ganglia in human temporal bones from
subjects aged 9 to 91 years old [60]. He reported a decrease in the number of vestibular hair cells
after the age of 20 years old and a decrease in the number of vestibular ganglion neurons after
the age of 50 years. On the other hand, Merchant et al. (2000) reported a gradual loss in the
number of vestibular hair cells in all endrogans, with relative sparing of the utricle, with
increasing age [62]. These early reports, which estimated the number of vestibular hair cells and
neurons from serial sections of the temporal bones, may have been biased as they were based on
several assumptions such as the spherical shape and uniform size of the hair cells as well as the
constant shrinkage and thickness of the specimen. Recently, using unbiased stereology which
overcomes the shortcomings of previous methods, the number of hair cells and neurons in human
temporal bones was re-evaluated [63,64]. Lopez et al. (2005) examined the number of hair cells
in the semicircular canals using unbiased stereology and showed that the number of hair cells
was decreased by 12% in adults in their 80s and by 25% in their 90s as compared with the
younger group (42 to 67 years old) [63]. Gopen et al. (2003) used the same method to estimate
the number of hair cells in the utricle but they failed to show an age-dependent decrease in the
number of hair cells [64]. It remains unclear whether this result reflects the relative sparing of the
utricle in age-related loss of hair cells [62], or is due to bias caused by the paucity of the number
of temporal bones examined.

In contrast to numerous reports regarding animal models of age-related hearing loss, animal
models of age-related vestibular dysfunction have rarely been reported. Shiga et al. (2005)
examined age-related changes of vestibular endorgans in C57BL/6 mice, which are considered to
be an animal model of age-related hearing loss, and reported an age-related decline in hair cell
density in the horizontal semicircular canals of 30%, with an associated mild decrease in the
VOR gain at 0.8Hz [65]. Since the age-related decrease of VOR gain was not observed at the
other frequencies tested, it was speculated that a differential loss of hair cell types might occur in
the model mice.

The mechanism of age-related cellular loss in the vestibular endorgans is still unclear. However,
the possible etiology of age-related hearing loss has been extensively studied [6668], and it is
now considered to be a multifactorial condition, representing outocome of multiple intrinsic (e.g.
genetic predisposition) and extrinsic (e.g. noise exposure) factors acting on the inner ear over a
life time [66]. A number of studies using animal models have suggested that the cumulative
effect of oxidative stress could induce damage to macromolecules such as mitochondrial DNA
and that the accumulation of mitochondrial DNA and the decline of mitochondrial function play
an important role in inducing apoptosis of the cochlear cells [6971]. Genetic investigations have
shown that several genes, including those related to antioxidant defense and atherosclerosis, have
an association with age-related hearing loss [72]. Exposure to noise is known to induce excess
generation of reactive oxygen species in the cochlea [73]. A similar accumulation of oxidative
stress and damage to mitochondrial DNA may be taking place in age-related changes in the
vestibular endorgans.

Go to:

Management of dizziness in the elderly

Since the causes of dizziness in older people are multi-factorial, management of this disease
should be customized according to the etiology of dizziness in each individual. Management of
dizziness includes various approaches, including medical and rehabilitative ones as well as the
use of prosthetic devices.

Vestibular rehabilitation was first introduced by Cawthorne and Cooksey (1946) to rehabilitate
patients with vestibular disorders [74]. The rehabilitation includes 1) VOR adaptation exercises
to assist the central nervous system to adapt to a change or loss in inputs to the vestibular system,
2) habituation exercises to reduce pathologic responses to a provoking stimulus, and 3)
substitution exercises to promote the use of the remaining sensory system [75]. Currently, these
exercises are found to be effective in treating people with dizziness caused by vestibular
dysfunction, anxiety, head injury, cerebellar dysfunction, or Parkinsons disease [76]. The effect
of vestibular rehabilitation does not differ with respect to patients age and gender [77]. Several
randomized control studies have provided evidence that vestibular rehabilitation exercises are
effective in improving postural control, reports of dizziness symptoms, and emotional status in
dizzy patients with nonspecific causes [75,78,79].

Various prosthetic devices have been developed to improve postural balance in the elderly.
Vibrotactile feedback devices, which fit around the waist and provide augmented feedback about
body tilt thorough vibration, have been shown to improve postural balance during quiet standing
and walking [80,81]. A tongue-placed biofeedback system which provides information about
head position by electrotactile stimulation was also reported to improve head stability in space
[82]. Vibrating insoles which enhance somatosensory input from the lower extremities have been
reported to improve postural performance in the elderly [83].

So far, there are no medical treatments to improve age-related deterioration of vestibular

function. However, several medications have been reported to be effective in preventing age-
related changes in the inner ear. Oral supplementation with mitochondrial antioxidants such as
alpha-lipoic acid and coenzyme Q10 has been shown to reduce age-dependent hair cell loss in
the mouse inner ear [71]. Caloric restriction extends the lifespan of most mammalian species by
down-regulation of the expression of apoptotic genes. It has been reported to be effective for
preventing age-related hearing loss in animal studies [84]. These new treatments which have
been effective in animal studies should be applied in older patients with vestibular dysfunction in
the future.

Go to:

Acknowledgments

We thank Dr. Chisato Fujimoto for critically reading the manuscript. This study was supported
by a grant from the Ministry of Education, Culture, Sports, Science and Technology (25293347).

Acta Otorhinolaryngol Ital. 2016 Jun; 36(3): 215219.

doi: 10.14639/0392-100X-847

PMCID: PMC4977009

Language: English | Italian

R. Teggi, 1 M. Manfrin,2 C. Balzanelli,3 O. Gatti,1 F. Mura,2 S. Quaglieri,2 F. Pilolli,1 L.O. Redaelli de Zinis,3 M.
Benazzo,2 and M. Bussi1

Introduction

Vertigo and dizziness are among the most common reasons for medical consultation 1 and they
account for 2-3% of total consultations in emergency departments 2. It has been reported that
nearly 26 million people needed a visit in an emergency department for dizziness/vertigo over a
period of 10 years (1995-2004) in the US, with a median of 3.6 diagnostic tests per patient 3.

Previous studies focusing on epidemiology of vertigo and dizziness have reported a lifetime
prevalence between 20% and 30% 4 5. In a recent questionnaire-based investigation, the authors
calculated in a large cohort of 2987 French subjects that the 1-year prevalence for vertigo was
48.3%, for unsteadiness it was 39.1%, and for dizziness it was 35.6%. The three symptoms were
correlated with each other and occurred mostly (69.4%) in various combinations rather than in
isolation 6. In a meta-analysis, a lifetime prevalence of vertigo toward a vestibular disorder was
seen in 3% to 10% of the total population 7. Moreover, dizziness, which is a more undefined
condition, is frequently associated with other common diseases and conditions, such as
migraine 8, motion sickness 9, orthostatic hypotension, sensation of fainting 10 and anxiety
disorders11.

A recent study confirmed previous findings on the marked female preponderance among
individuals with vertigo (one-year male to female prevalence ratio of 1:2.7), and showed that
vertigo is almost three times more frequent in the elderly compared to younger individuals 12.

Finally, vertigo and migraine are often comorbid conditions; with the exclusion of vestibular
migraine, with prevalence of 0.98% 12, patients with Menire's disease present a higher rate of
migraines (around 56%) than the total population 13, and migraineurs more often present benign
paroxysmal positional vertigo (BPPV) 14.

The main purpose of our work was to assess the prevalence of vertigo/dizziness in a Caucasian
population and establish the relationship of these symptoms with headache and its migrainous
features.

Go to:

Materials and methods

Study design
This was an observational prospective study, based on a self administered questionnaire, carried
on in 3 university centres in the period between January and April 2015; subjects were
anonymously asked to participate, either connecting to a protected site or on a paper support
randomly distributed among outpatients in the withdrawal centres. The first part included only
demographic data (sex and age) and the question "Have you ever experienced vertigo and/or
dizziness during your lifetime?". Patients were instructed to consider either the feeling that you
are dizzily turning around or that your surroundings are dizzily turning about you. Only patients
with a positive history for vertigo and/or dizziness were asked to complete the entire
questionnaire. Questions to be answered are reported in Table I. Only subjects over 18 years old
were included. To characterise the type of headache, four specific questions were included in the
questionnaire regarding the feature of symptoms (hemicranial, pulsatile, associated with phono
and photophobia and worse during physical efforts); a composite migraine risk score (MRS) was
calculated for the patients suffering from headache, giving 2 points for every positive answer, so
that MRS could range between 0 and 8.

Table I.

Questionnaire to be completed by subjects with a positive history for

vertigo/dizziness.

Population sample

A total of 2672 subjects were included in the study; 1249 (46.7%) were males. Mean age was 48
15.2 years (range 18 to 96). No difference was detected between the group of subjects with and
without vertigo for the age at inclusion (48.8 15.3 and 47.6 15.1, respectively). In Table
II sex and age distribution (over or below 50 years) are reported. Figure 1 shows the histogram of
age distribution of subjects with a positive history for vertigo.
Table II.

Age and sex distribution of the sample.

Fig. 1.

Age distribution of patients with a positive history for vertigo at inclusion.

Statistical analysis

Normally distributed continuous variables are reported as mean value standard deviation;
differences were assessed by a two tailed t test. Categorical variables are reported as rates on
total and a chi square test was performed to establish differences between groups. A linear
regression model has been performed to quantify the vertigo risk in the 4 classes of subjects
(males and females, below and over 50 years); data are reported as odds ratio (OR) (95%
confidence interval [CI]). A linear regression test was also performed to correlate MRS with a
clinical history of rotational, positional vertigo and with the age of the first vertigo episode.
Analyses were carried out using STATA software v. 13 (Stata Corporation, College Station, 2013,
Texas, USA).

Go to:

Results

No difference were seen between the group of subjects with and without vertigo for age at
inclusion (48.8 15.3 and 47.6 15.1, respectively). In Table II sex and age distribution (over or
below 50 years) are reported. In Figure 1, the histogram of age distribution of subjects with a
positive history for vertigo at inclusion is shown.

In the sample, 1077 of 2672 (40.3%) subjects reported at least one episode of vertigo/dizziness
during their lifetime; 768 (71.3%) were females, while 309 (28.7%) were males. Independently
from age, females presented a higher rate of vertigo than males (OR = 3.56, 95% CI 3.017225-
4.199935; p 0.001). Independently of sex, vertigo was more represented in people over 50
years; 479 of 1077(44.5%) with a positive history of vertigo, while 367 of 1595 (23%) without
vertigo were over 50 years (OR = 1.37, CI 1.171587- 1.60125; p 0.005). Considering 1 as the
vertigo risk in the sample of males below 50 years, it was 1.8 times higher in males over 50 yo,
4.4 in females below 50 years and 5.2 times higher in females over 50 years (p 0.001). In our
sample, lifetime risk of vertigo risk was estimated to increase by 1% every 10 years.

In the total sample, 367 of 2672 subjects (13.7%) referred a sensation of spinning or movement
of surroundings, 702 relapsing episodes (26.3%), 130 (4.8%) the sensation of fluctuating hearing
level during vertigo and 347 (12.9%) reported the onset or increase of vertigo while lying down.
In the sample of 1077 dizzy subjects, 375 also reported headache episodes (34.8%), 254 with a
MRS of at least 4 points, 110 with a score of 2 and only 11 with a score of 0. The prevalence of
various features of vertiginous episodes was calculated in the total group and in the subgroup of
subjects also referring headache:

the age of the first vertigo (see Fig. 2) was 39.2 15.4 years, while in the
subgroup of 375 subjects with headache it was 33.415.4 (p 0.001). Thirty-
four subjects (1.2%) referred vertigo in a paediatric age, 33 reported
headaches (all with a MRS of at least 4) and 25 were females. The MRS was 5
2.2 in the sample of headache subjects, while it was 6.1 1.7 in the 34
subjects with paediatric vertigo (p 0.01);

Fig. 2.

Age distribution for the first episode of vertigo/dizziness.

a positional component was reported in 351 of 1079 subjects with vertigo

(32.5%), in 146 of 375 (38.9%) subjects with headaches (p = 0.02) and 130
(51.2%) with a MRS of at least 4 (p 0.01);

a relapsing vertigo was reported in 702 of 1077 subjects (65%), in 280 of 375
(74.6%) headache sufferers (p 0.01) and in 242 of 254 (95%) subjects with
a MRS of at least 4 (p 0.001);

a sensation of fluctuating hearing level was reported in 130 of 1077 (12%)

dizzy subjects, in 63 of 375 (16.8%, p = 0.02) headache sufferers and in 52
(20.4%) subjects with at least 4 points on the MRS (p 0.001).
Finally, a linear regression test demonstrated an association between the MRS and a positional
component of vertigo (p = 0.001), rotational vertigo (p 0.01), age of first vertigo attack (p
0.0001) and relapsing episodes of vertigo (p 0.0001).

Go to:

Discussion

Our data are consistent with those published in previous reports. In our sample, the point
prevalence for vertigo and or dizziness of any kind (i.e. without a definition of severity) was
40.3%. Previously published papers have reported different results, with a lifetime prevalence
ranging between 23.2% and 59.2% 4 6, but when patients were asked if they experienced
dizziness bad enough to interfere with daily activities, the positive responders decreased to 16.9-
29.5% 4 12. It should be underlined that dizziness is a common and non-specific symptom and
may be provoked by various disorders, including neurological, cardiovascular, vestibular and
multisensory dysfunctions; moreover, a strict relationship has also been reported with anxiety
and panic disorders 5 15. When asked about vertigo as a symptom (i.e. a sense of rotation or
spinning), 13.7% of our sample referred to have experienced it; our data confirm those of
previous papers reporting a rate in the range between 7.8% and 21% 4 12. Other studies, based on
general practitioner records, estimated a 12 month incidence of vertigo between 1.78% and
3.4% 16 17. Commonly accepted clinical practice makes a distinction between vertigo and
dizziness, with the first more often associated with a dysfunction of the vestibular system.
Nonetheless, it has been underlined in epidemiologic studies that cultural and linguistic factors
may play a role in the description of subjective symptoms 18 19.

In our sample, we found an increased prevalence of vertigo in females and in the elderly; in
particular, females presented a 4.4-fold increased risk for vertigo, while the agerelated risk factor
was estimated to be 1.8; these results are consistent with previously published reports 4 6 12 19-23.

More interesting data may be drawn about the correlation between vertigo from one side and
headache and migraine to the other. Since not all patients referring moderate to severe headaches
in our sample were migraineurs, we decided to assess the migraine probability with a score, the
MRS, by evaluating 4 characteristics related to migraine (hemicranial, pulsatile, associated with
phono and/or photophobia, worse with physical effort). Patients with higher MRS more
frequently presented relapsing episodes of vertigo, referred a sensation of hearing level
fluctuation during vertigo/dizziness and presented a lower age of occurrence of the first vertigo
attack; moreover, all subjects referring vertigo in a paediatric age presented with a MRS greater
than 4.
Far from being exhaustive, it should be noted that the relationship between vertigo and migraine
is complex and it has been stated that it goes beyond the diagnostic concept of vestibular
migraine 24 25, whose prevalence in total population has been estimated at 0.98% 26. For example,
among patients diagnosed with Meniere's disease, 56% also presented migraine compared to
16% in the normal population 13; migraine has been found to be three times more common in
patients with idiopathic BPPV 27 and two times more common in patients with idiopathic BPPV
than in age and sex-matched controls 28. Vertigo may be a migraine precursor in a paediatric
age 29, and motion sickness occurs more frequently in patients with migraine both in paediatric
and adult ages, with a reported prevalence between 30% and 50% 30. Finally, an interrelation
between migraine, anxiety and other psychiatric disorders and dizziness has been postulated and
a clinical entity including the 3 disorders, the MARD, has been proposed 31. It should be
underlined that vertigo/dizziness with a positional component may be related to BPPV, which is
more represented among migraineurs, but it may also be one of the commonest findings in
vestibular migraine 32. Moreover, our data underline that a sensation of decrease of hearing level
during vertigo was reported in 12% of total dizzy patients, and above all in 20.4% of dizzy
patients with a MRS of at least 4. This percentage includes patients with Meniere's disease, even
if not confirmed; nonetheless, a recent paper reported that cochlear symptoms are far from being
rare even in subjects with definite vestibular migraine, since 10.7% of patients referred a
sensation of a hearing loss often during vertigo and 15.5% sometimes during vertigo 33 34.

As a final consideration, we want to underline the possible risks of bias in our work, above all
linked to the representativeness of our sample; even if patients presenting for any ambulatory
visit were excluded, and questionnaires were completed for a large part by subjects referring to
hospital for a blood exam, it cannot be excluded that responders were above all subjects with
previous episodes of vertigo. Nonetheless, our results are in the range of previously published
data and confirm the high prevalence of vertigo/dizziness as a symptom in the general
population.

Go to:

Conclusions

Our data, in accordance with previously published reports, confirm the high prevalence of
symptoms of vertigo/ dizziness in general population. Symptoms present a higher prevalence in
females and in the elderly. Finally, an association with migraine was found.
In a retrospective review of 907 adults
presenting to an academic ED from 2007
through 2009 with a primary complaint of
dizziness, vertigo, or imbalance, 49 patients
had a serious neurologic diagnosis (eg,
cerebrovascular disease).[5] Benign causes of
dizziness included peripheral vertigo (294
cases) and orthostatic hypotension (121 cases).
Factors associated with serious diagnoses
included abnormalities on focal examination,
age greater than 60 years, and imbalance as
the chief complaint.
(1)Kerber KA, Meurer WJ, West BT, Fendrick AM. Dizziness presentations in U.S. emergency departments,
1995-2004. Acad Emerg Med. 2008

The overall incidence of dizziness, vertigo, and imbalance is 5-10%, and it reaches 40% in patients older than
40 years. The incidence of falling is 25% in subjects older than 65 years. A report reviewing presentation to US
emergency departments (EDs) from 1995 through 2004 indicated that vertigo and dizziness accounted for
2.5% of presentations.[1] The estimated number of 2011 US ED visits for dizziness or vertigo was 3.9 million. [2]

(3) Olsson Mller U, Midlv P, Kristensson J, Ekdahl C, Berglund J, Jakobsson U. Prevalence and predictors of
falls and dizziness in people younger and older than 80 years of age-A longitudinal cohort study. Arch Gerontol
Geriatr. 2012 Sep 18.

A report using data from the Swedish National study on Aging and Care (SNAC) found that in patients younger
than 80 years, the prevalence of falls was 16.5% and that of dizziness 17.8%, whereas in patients older than
80 years, the prevalence of falls was 31.7% and that of dizziness 31%. [3] The younger patients tended to have
more specific predictive factors, whereas the older patients tended to have more general ones.

TEKANAN DARAH
What is the Connection Between Blood Pressure and
Dizziness?
 Written By: Marlene Garcia
Edited By: Daniel Lindley
Last Modified Date: 24 August 2016
2003-2016 Conjecture Corporation

Dizziness (Dizzy)
Medical Author: Benjamin Wedro, MD, FACEP, FAAEM

Medical Editor: Melissa Conrad Stppler, MD

Medically Reviewed by a Doctor on 8/4/2016

In individuals who are dehydrated or anemic, blood pressure readings may be normal
when they are lying flat; however, the lack of fluid is unmasked when they stand up
quickly. The lack of blood to the brain may cause dizziness and lightheadedness. This
feeling may pass in a few seconds as the body adapts. However, if dehydration or
medications (for example, beta blockers) prevent the body from reacting by constricting
blood vessels and increasing the heart rate, the dizziness may persist to the point at
which the patient passes out (faints, or experiences syncope).

Some diseases are associated with an inability to compensate for changes in body
position (autonomic dysfunction). Normally when a person stands, blood vessels
contract to increase blood pressure slightly, and the heart rate increases to pump blood
uphill to the brain against gravity. In autonomic dysfunction, a person may become dizzy
when they move from a lying position to sitting or standing up. Examples of these
diseases

Orthostatic hypotension is a common symptom with Shy-Drager syndrome. Shy-Drager

syndrome is a rare disease in which the autonomic nervous system degenerates and
cannot provide the routine control mechanisms for the body including heart rate, blood
pressure, and bowel and bladder function.

High blood pressure

High blood pressure, or hypertension, is known as the "silent killer" since it often has no
symptoms, even if blood pressure readings are markedly elevated. On occasion, a
person may complain of headache, nausea, or dizziness, although the complaints don't
necessarily correlate with the degree of blood pressure elevation.

However, if the blood pressure is elevated and the person has symptoms, there is a
need to bring the blood pressure under control relatively quickly. The more severe the
symptoms, the quicker blood pressure control needs to be achieved. For example, if a
person is having chest pain or stroke symptoms associated with high blood pressure,
the blood pressure needs to be controlled immediately (hypertensive emergency).

JK
Eur Arch Otorhinolaryngol. 2015 Sep;272(9):2221-5. doi: 10.1007/s00405-014-3151-y. Epub 2014 Jun 25.

Sex-specific association of RANTES gene -403 variant in Meniere's

disease.
Yazdani N1, Mojbafan M, Taleba M, Amiri P, Nejadian F, Ashtiani MK, Amoli MM.

Author information

Abstract

Several studies have shown the correlation between RANTES gene and inflammatory disorders; the aim
of the present study was to investigate the association between RANTES promoter gene polymorphism
and Meniere's disease (MD) in an Iranian population. In this study patients with MD comprising definite
MD (N = 56) and probable MD (N = 15) were selected according to diagnostic criteria of AAO-HNS. The
control group (N = 101) were healthy normal subjects who did not have a history of ear disease
and vertigo. PCR-RFLP for RANTES -403G>A has been performed. We found a protective role for
RANTES -403A allele in male group in our population. None of the male patients with MD were carrier of
allele A which was significantly different from the presence of allele A in the male control group (AA+GA
vs. GG: p = 0.0004, OR 0.05, 95 % CI 0.001-0.39). This difference was not significant in female group.
There was no significant association between RANTES gene polymorphism and the level of hearing loss.
our results showed a sex-specific association between RANTES gene polymorphism and MD but more
studies are necessary to further assess this association.
Curr Opin Neurol. 2008 Feb;21(1):3-7. doi: 10.1097/WCO.0b013e3282f41ca0.

GENETIK
Recent advances in the genetics of recurrent vertigo and
vestibulopathy.
Jen JC1.

Author information

Abstract

PURPOSE OF REVIEW:

To focus on recent advances in the genetics of recurrent vertigo, with an overview on episodic ataxia,
benign recurrentvertigo (mainly migraine-associated vertigo), bilateral vestibulopathy, and Mnire's
disease.

RECENT FINDINGS:

Since the identification more than a decade ago of the genetic causes of episodic ataxia type 1 with
myokymia caused by KCNA1 mutations and episodic ataxia type 2 with nystagmus caused by CACNA1A
mutations, the list of episodic ataxia syndromes with distinct clinical features and genetic loci is slowly
expanding, now up to episodic ataxia type 7. There is growing recognition for a correlation between
benign recurrent vertigo and migraine, and acceptance for vertigo as a manifestation of migraine; efforts
to identify susceptibility loci for migraine and migraine-associated vertigo are underway. A handful of
families with vestibulopathy spanning several generations have been identified. Although no gene has yet
been found, vestibulopathy with normal hearing variably associated with migraine is likely monogenic and
heterogeneous, similar to nonsydromic deafness. There is also continuing effort to identify genetic causes
of familial Mnire's disease.

SUMMARY:

Overlapping clinical features among different familial syndromes of recurrent vertigo and strong
association with migraine suggest shared mechanisms. Collaborative efforts in patient identification and
recruitment will facilitate progress in understanding disease mechanisms to improve diagnosis and
treatment of recurrent vertigo.
Curr Genomics. 2011 Sep; 12(6): 443450.

doi: 10.2174/138920211797248600

PMCID: PMC3178912

Genetics of Recurrent Vertigo and Vestibular Disorders

Irene Gazquez1 and Jose A Lopez-Escamez*,1,2

Author information Article notes Copyright and License information

This article has been cited by other articles in PMC.

Abstract
Go to:

INTRODUCTION

Genomic medicine in complex middle or inner ear diseases such as chronic otitis media,
otosclerosis or age-related hearing loss is an emerging topic [1]. Patients with imbalance or
recurrent vertigo are a heterogeneous group of complex disorders affecting the peripheral and
central vestibular system and they represent a diagnostic challenge for the clinicians since their
genetic basis is largely not known. Familiar episodic ataxias are rare cause of recurrent vertigo,
but molecular genetics has identified several mutations on KCNA1 and CACNA1A genes that
suggest a key role for voltage-gated channels and solute carriers in the plasma membrane of
neurons in recurrent vertigo. Moreover, recent advances in familiar vestibular disorders and
particularly in familial Menires disease have facilitated the pathways for clinical
characterization and recruitment of patients for large collaborative studies.

Recurrent vertigo with vestibular hypofunction is a common symptom in clinical practice and
there is a hereditary component in neurotologic disorders that is not well defined. Migraine has a
strong genetic background and it is frequently observed in these patients and although the
genomics for migraine has started to become known [2, 3], the shared allelic variants between
vertigo and migraine remain to be discovered. This review will include syndromes with recurrent
or episodic vertigo: familial episodic ataxia, migrainous vertigo, bilateral vestibular hypofunction
and Mnires disease.
 Go to:

FAMILIAL EPISODIC ATAXIAS

Familial episodic ataxias are monogenic recurrent vertigo syndromes. Most of them are
autosomal dominant disorders of early onset characterized by recurrent attacks of incoordination,
dysarthria and truncal ataxia. There are several subtypes defined by associated interictal findings
and genetic characterizations (Table 11). The key clinical feature that raises the diagnosis of
episodic ataxia is discrete attacks of incoordination with a clear onset and resolution of
symptoms, which also distinguishes episodic ataxia with progressive features from progressive
ataxia with intermittent exacerbation. The presence of interictal findings in most patients
provides a helpful distinction with vestibular migraine.

Table 1

Genetic and Clinical Summary of Episodic Ataxia Syndromes

Episodic Ataxia Type 1 (EA1)

EA1 is a potassium channelopathy characterized by constant myokymia and episodes of spastic

contractions of muscles of the head, arms and legs. The attacks consist of episodes of vertigo
lasting minutes associated with diplopia, headache, stiffness of the body and dysarthric speech.

EA1 is caused by mutations in KCNA1 gene located on chromosome 12p13 (MIM 160120),
which encodes Kv1.1, a voltage-gated potassium channel [4]. Functional Kv1.1 channels are
tetrameric structures composed of four identical monomers, but K+ channel diversity is greatly
enhanced by the ability to form heteromeric channels composed of Kv1.1 and
Kv1.2/Kv1.4/KvB1.1. In several brain areas, Kv1.1 co-assembles with Kv1.4 which confers N-
type inactivating properties to heteromeric channels. It is likely that the rate of inactivation will
be determined by the number of Kv1.4 subunits which is increased in EA1 [4], resulting in an
increase in neuronal excitability [5, 6]. Individuals with EA1 are heterozygous for a KCNA1
disease-causing mutation, and they have a wild-type and a mutated allele, which may be equally
expressed; so, channels composed of wild-type and mutated subunits may be formed, but this
heterozygous allele is enough to alter the function of heteromeric channels containing Kv1.1
subunits [7, 8].

The KCNA1 gene has a transcript of 7983 nucleotides with a coding region of 1488 [7]. To date,
more than 20 KCNA1 mutations have been described and most are missense mutations
distributed throughout the gene [9]. Interestingly, four different mutations of the highly
conserved threonine 226 in the second transmembrane segment (T226M/A/R/K) that lead to
diverse phenotype have been identified [10].

Episodic Ataxia Type 2 (EA2)

EA2 is a Ca2+ channelopathy characterized by recurrent vertigo lasting from hours to days, with
imbalance, vomiting, ataxia with interictal nystagmus (MIM 108500). It is distinguished from
EA1 by the absence of myokymia (fine rippling of muscles). Episodes are triggered by exercise,
an intercurrent infection, stress, alcohol and caffeine and they are often relieved by treatment
with the carbonic anhydrase inhibitor, acetazolamide [11]. Migraine occurs in about 50% of
patients with EA2.

EA2 is caused by mutations in the CACNA1A gene, mapped to chromosome 19p13 [12], which
encodes the -subunit of the P/Q-type voltage-gated calcium channel, Cav2.1 [13, 14]. This gene
is widely expressed throughout the CNS, showing highest levels at Purkinje and granule cells of
the cerebellum.

Dominant mutations in CACNA1A underlie at least three allelic diseases: EA2, familial
hemiplegic migraine type 1 and spinocerebellar ataxia type 6. A large number of different single
nucleotide mutations have been shown to cause EA2 which results in premature stop codons and
a non functional protein with loss of Cav2.1 channel function [15, 16], including recent mutations
in the promoter and a new final exon 48 [16]. Moreover, these mutant subunits may disrupt the
membrane trafficking of wild-type subunits [17]. CACNA1A alternative splicing in the
cerebellum of selected exons harboring nonsense mutations (such as exon 37A) can also cause
EA2 [18]. Direct sequencing of CACNA1A in some patients with EA2 does not identify any
point mutation, but the use of methods such as MLPA (multiplex ligation-dependent probe
amplification) and QMPSF (quantitative multiplex PCR of short fluorescent fragments) has
demonstrated large-scale CACNA1A gene rearrangements (deletions and duplications) in
patients with EA2 [19,20].

Familial hemiplegic migraine type 1 is a form of migraine with aura and reversible hemiparesis
also caused by missense nucleotide mutations in the CACNA1A gene that alter channel gating
and enhance the channel activity at negative potentials [21].
Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant disorder characterized by a late
onset slowly progressive ataxia, dysarthria and nystagmus associated with an abnormal CAG
expansion in exon 47 of CACNA1A gene [22]. The normal number of CAG repeats ranges up to
18 and individuals with SCA6 have 20 to 33 repeats in the carboxy-terminal domain, resulting in
a polyglutamine expansion of the carboxyl- terminal domain [22].

Episodic Ataxia Type 3 (EA3)

EA3 (MIM 606554) was described in 26 members of a single large Canadian family with
episodic vertigo, tinnitus, ataxia, migraine and interictal myokimia [23]. Patients respond to
acetazolamide and no residual ataxia was observed after the episodes. The disease locus for EA3
has been mapped to chromosome 1q42 [24].

Episodic Ataxia Type 4 (EA4)

EA4, also called familial periodic vestibulocerebellar ataxia (MIM 606552), is an autosomal
dominant disorder characterized by episodes of vertigo and ataxia beginning in the third to sixth
decade of life described in two families of North Caroline, USA [25, 26]. Patients may have
interictal nystagmus and mild ataxia similar to EA2 or they may be completely normal in
between attacks. The episodes usually last for hours and are not relieved by acetazolamide. The
most consistent symptom is the inability to suppress the vestibulo-ocular reflex. Linkage analysis
ruled out the EA1 and EA2 loci as well as loci for SCA15 [27], but the locus has not been
identified.

Episodic Ataxia Type 5 (EA5)

EA5 (MIM601949) was identified when a series of families with episodic ataxia and epilepsy
harboured mutations in the calcium channel b4 subunit CACNB4, on chromosome 2q22-23 [28].
The premature-termination mutation R482X was identied in a patient with juvenile myoclonic
epilepsy. The R482X protein lacks the 38 C-terminal amino acids containing part of an
interaction domain for the subunit. The missense mutation C104F was discovered both in a
German family with generalized epilepsy and praxis-induced seizures and in a Canadian family
with episodic ataxia. These coding mutations were not detected in unaffected controls [29].

Episodic Ataxia Type 6 (EA6)

EA6 (MIM612656) was first identified in a 10-year-old child with an episodic and progressive
ataxia, seizures, alternating hemiparesis and episodes of migraine [30]. A de-novo P290R
heterozygous mutation was identified by candidate gene approach in SLC1A3 (MIM 600111).
This is a solute carrier gene which encodes the glial excitatory amino acid transporter type 1
(EAAT1), which is involved in glutamate removal from the synapses [30]. A second mutation
C186S was identified in 3 symptomatic members of a family with EA, without motor symptoms
or seizures, suggesting a relationship between the phenotype and the extent of glutamate
transporter dysfunction [31].

Episodic Ataxia Type 7 (EA7)

EA7 (MIM611907) was described in a family of 7 members with vertigo, weakness, dysarthria
and ataxia lasting from hours to days typically triggered by exercise or excitement, with onset
before age 20 [32]. There is no interictal finding (which distinguishes it from EA3). Genome
scan mapped the locus of EA7 between rs1366444 and rs952108 on chromosome 19q13.

Go to:

VESTIBULAR MIGRAINE (VM)

Migraine is an episodic headache disorder affecting 8% of males and 17% of females [33].
Clinically, the International Classification of Headache Disorders (ICHD-II) [34] recognizes two
main common forms of migraine: migraine with aura and migraine without aura. The two forms
are distinguished from each other based on the presence of aura, a period of variable and diverse
neurological symptoms that precedes the headache phase. There is a dilemma among the
scientific community whether migraine with aura and migraine without aura attacks represent
two different disorders or if they are variations of a single disease having a common complex
genetic background.

The clinical criteria required for diagnosing VM are current or previous history of migraine
according to ICHD-II criteria [34] and at least 2 attacks of vertigo presenting with 1 of the
following symptoms: migrainous headache, photophobia, phonophobia, or visual or other auras.
Vertigo is not considered to be an aura of migraine [35]. VM is found in 1-3% of the population,
being the most common cause of recurrent vertigo. Migraine is a complex polygenic disease and
this may explain clinical heterogeneity (migraine, aura or vertigo).

A recent genome-wide association study of 2731 European migraine patients has identified
rs1835740 on chromosome 8q22.1 (P = 5.38 1 109, odds ratio = 1 1.23, 95% CI 1 1.150
1.324). The association was replicated in 3,202 cases and 40,062 controls [2]. The rs1835740 is
located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding
plasma glutamate carboxypeptidase). In an expression study in lymphoblastoid cell lines,
transcript levels of the MTDH were found to have a significant correlation with rs1835740 minor
allele. MTDH downregulates SLC1A2, the gene encoding the major glutamate transporter
(EAAT2) in the brain [36, 37], suggesting that the identified variant regulates glutamate in the
synapsis. In another population-based genome-wide analysis including 5122 migraineurs and
18108 non-migraineurs individuals, rs2651899 (1p36.32, PRDM16) rs10166942 (2q37.1,
TRPM8) and rs11172113 (12q13.3, LRP1) were among the top markers associated with
migraine. The meta-analysis of three replication cohorts including 774 from Netherlands, 306
from Germany and 2748 from the International Headache Genetics Consortium confirmed the
association when discovery and replication cohorts were pooled [3]. TRPM8 encodes a sensor
for cold and cold-induced pain and is a target for neuropathic pain [38]. The potential role of
PRDM16 in migraine is unclear. LRP1 is a member of the lipoprotein family which modulates
synaptic transmission and co-localizes with NMDA receptor in neurons [39], supporting that
glutamate homeostasis is relevant in the pathophysiology of migraine. Future challenges should
be a GWAS in VM patients, since this is a subtype of migraine patients to define endophenotypes
and a fine mapping analysis of MTDH, TRPM8 and LRP1 genes in VM.

Familial Migranous Vertigo/Familial VM

In 1994, a set of three families with multiple members who experienced migraine and episodes
of vertigo lasting minutes followed years later by progressive loss of peripheral vestibular
function was reported [40]. A 4-generation family with 23 members with vestibular migraine
inherited as a dominant trait has been described [41]. Members of this family have episodic
vertigo and migraine with aura. A genome-wide screen for loci linked to MV segregating in this
large family and subsequent fine structure mapping demonstrated that the disease gene is located
between loci rs244895 and D5S2073 in chromosome 5q35. Candidate genes in this region,
including KCNMB1 (Kv channel interacting protein 1 isoform 1), KCNIP1 (potassium large
conductance calcium activated), ATP6V0E (ATPase, H+ transporting, lysosomal, V0 subunit E),
SLC34A1 (solute carrier family 34 sodium phosphate), GABRP (gamma-amino butyric acid-
GABA A receptor); DRD1 (dopamine receptor D1); and HRH2 (histamine receptor H2) were
sequenced, but no mutation was identified [41].

Go to:

BILATERAL VESTIBULAR HYPOFUNCTION (BVH)

A small family with recurrent vertigo without migraine neither hearing loss was described in
2003 [42]. The episodes of vertigo were triggered by exercise and stress, and patients showed
improvement with acetazolamide. In the later stages, when the frequency of vertigo attacks
diminished, the patients developed imbalance and oscillopsia. In contrast to the large number of
deafness genes, no mutations have been identified in BVH with normal hearing. Improving of
phenotyping of patients with recurrent vertigo and BVH, excluding ototoxicity is essential to
investigate their genome. BVH is usually progressive and it is observed after longer periods of
follow up, usually in subjects over 60 years-old, making difficult the recruitment of patients
within a family from more than two generations. Moreover, selection of sporadic cases with
BVH also requires long follow-up periods to confirm BVH.

There has been a single report of linkage analysis in families with a dominantly inherited
bilateral vestibulopathy syndrome associated with migraine and normal hearing [43]. The
preliminary analysis showed genetic heterogeneity. Since the human inner ear transcriptome has
been obtained, collaborative efforts in identifying and recruiting patients with familial
vestibulopathy will help identify genes by high throughput sequencing methods.

Go to:

MENIERE DISEASE

Menieres disease (MD [MIM 156000]) is defined as an inner ear disorder characterized initially
by fluctuating low-frequency sensorineural hearing loss, recurrent vertigo attacks, aural fullness,
and tinnitus. Patients experience a high frequency of vertigo attacks during the first years which
decrease over time and develop progressive imbalance and severe profound hearing loss [44].
The second ear could be affected in around 15-40% of cases. A disturbance of the cochlear fluid
homeostasis and the endocochlear potential has been involved in the development of MD [45],
and endolymphatic hydrops has been consistently identified as a histological feature in temporal
bone specimens from patients with MD.

MD is a complex genetic disorder and several features of MD suggest a genetic or epigenetic

component. The prevalence of the disease is more common in European Caucasians than in
Asian or African populations. Familial cases represent 4-20% of all patients and several MD
pedigrees have been reported, mostly in Caucasians [46, 47].

Familial Menieres Disease (FMD)

A familial history of MD has been described in 10-19% of cases (Table 22). The inheritance of
MD has been reported to be autosomal dominant with incomplete penetrance estimated around
60% [48-50]. Anticipation for FMD, dependent upon the number of MD patients per generation
has been described in several families, including both earlier onset and tendency to more severe
symptoms in successive generations [51-54]. In addition, several Brazilian families with
concurrent MD and migraine have also been described [55].
Table 2

Linkage Association Studies in Familial Mnires Disease

A candidate region for FMD was identified on chromosome 12p12.3 from linkage analysis in
three large Swedish families [56]. This region was analyzed in 15 families with several cases
segregating FMD in at least two patients. The confirmed allelic association defines an haplotype
in 12p12.3 between the markers D12S373 and GT27 [57]. Two genes are located in the region:
RERG/RAS-like gene (RERGL) and PIK3C2G gene; however, none of these genes show any
alterations in the coding sequences in patients with FMD. In contrast, two non-coding SNPs
close to exon 29 of PIK3C2G, rs12827507 and rs11044211 were strongly associated with FMD
in Swedish families [57].

Another study in 19 German families with 52 members affected by FMD (27% bilateral FMD)
found linkage with a region on chromosome 5 (LOD score =1.9) and 13/19 families showed
consistent linkage to the region identified by D5S644, which contains 105 known genes [47].
The association observed in these families replicates an earlier linkage analysis using data from
different families. Moreover, these families had a prevalence of migraine around 39% and
presented an earlier onset in the third and fourth generation.

FMD has also been investigated in Finland in 8 families with 17 individuals with definite FMD
[58]. The inheritance was autosomal dominant and the majority of patients were women, a
finding also observed in British and German patients with FMD [47, 49]. A recent study in 16
Finnish families did not confirm anticipation, co segregation with migraine or linkage to the
12p12.3 region found in Swedish FMD, suggesting genetic heterogeneity within FMD [58].

Massive parallel sequencing of the whole exoma in selected cases of FMD is an emerging high-
throughput method that will facilitate the discovery of new genes by eliminating the need for
linkage analysis and candidate gene screening [59].

Sporadic Menieres Disease

A candidate gene approach, either by case-control studies or by the sequencing of selected genes,
has been used to search genetic markers associated with MD (Table 33). These genes include
antiquitin [60], aquaporin 2 [61], COCH (coagulation factor C homology) [62], potassium
channels genes (KCNE1 and KCNE3) [63], MHC class II genes [64, 65], alpha-adducin [66],
heat-shock protein 70 [67], PARP-1 [68], PTPN22 [69], Fc gamma receptors CD32 and CD16a
[70] and nitric oxide synthases type 1 and 2 [71]. However, none of these genes could be
replicated in an independent set of MD patients [72-74].

Table 3

History of Candidate Gene Association Studies in Mnires disease. None of them

were Replicated in an Independent Population

The HapMap3 Project has defined 10 million single nucleotide polymorphisms (SNPs)
throughout the human genome providing markers for a detailed analysis in any chromosomal
region, predicting that an SNP will be in linkage disequilibrium to the gene or mutation of
interest. The combination of efficient techniques for high throughput genotyping with dense SNP
maps offers a high level of definition for genome-wide association studies.

SNP-based scans using biallelic polymorphisms are most likely to detect common sequence
variants associated with disease development than candidate gene or familial linkage approaches.
The effect size of these common variants has been small (odds ratio, <2), and a common genetic
variant will not account for the entire heritability of MD. This observation leads to investigations
of rare variants, copy number variation, and epigenetic modifications to explain the entire
heritability of a given disease [75, 76]. Rare structural variants are suspected to account for the
molecular differences underlying varied clinical phenotypes and they will be associated with
FMD.

Ultimately, definition of allelic variants for MD will need confirmation through experimental
modeling demonstrating physiologic dysfunction. Discovery of a mechanism of disease
development will advance accuracy of the diagnosis and refinement of clinical phenotypes, and
provide new targets for pharmacologic intervention. Currently, an international consortium,
named GENOMEN, has been organized to define the clinical phenotype and to investigate
common and rare variants in 2000 European Caucasian adults with MD, to identify genetic
markers for the disease and define its biochemical pathways.