The comorbidity of vestibular disorders and related autonomic signs is well accepted, as nausea and vomiting are frequent symptoms in vestibular disease. There has been a linkage between vertigo and affective symptoms for hundreds of years. Vertigo in the mid 19th century was regarded as being a neurological disease. The term “agoraphobia” was coined in 1871 by Westphal to describe the symptom set described by Benedikt in 1870 as “Platzschwindel” (literally; “vertigo in a public place”). This was characterized as a form of the condition known as “ocular vertigo” (still thought to be of neurologic origin). Benedikt reported on the co-occurrence of vertigo and agoraphobia, but there was debate about whether agoraphobia should be recognized as a type of vertigo, a consequence of vertigo, or a separate clinical entity (Balaban and Jacob, 2001). The relationship between agoraphobia and vertigo was debated for some years, as the sensations of agoraphobia did not conform to the contemporaneous definitions of vertigo. More recent work has correlated symptoms of anxiety and vestibular dysfunction. Jacob et al (1985) reported that abnormalities on vestibular tests occurred in a large proportion of patients with panic disorder. Yardley et al (1994) also identified balance disturbances in patients who had been diagnosed with agoraphobia.
The studies contained in this thesis outline the history of this debate and outline criteria that will aid in diagnosing these patients. Visual stimuli alone can provoke vestibular symptoms. This was clearly outlined in the early literature leading to the initial use of the term “agoraphobia”, but it is still important that as much insight as possible be given to the recent rediscovery of this balance- anxiety interface.
It was originally suggested in 1930 (cited in Oman 1998) that the symptoms of motion sickness do not result from motion per se, but from discrepancies in the information provided by different sensory modalities. Guedry (1970) speculated that because of “the invariant correlation between information from otoliths and canals in natural head movements, unnatural stimuli that yield conflicting inputs… are especially potent in the production of motion sickness”. He utilized the term “directional mismatch” and suggested that motion sickness might be the byproduct of the adjustment to such stimulations. Experiments detailed in this thesis have suggested strongly that the symptoms of visual vestibular mismatch closely parallel the symptoms of motion sickness. Patients regularly volunteer that they have newly developed motion sickness as a part of their symptom set (Mallinson et al, 1996; Mallinson and Longridge 1998 , Mallinson and Longridge 1998 ). One hypothesis of this thesis is that this arises from balance system pathology, regardless of whether it is of traumatic, non- traumatic, idiopathic or iatrogenic origin. Perhaps the development de novo of motion sickness is the byproduct of the newly developed conflicts suggested by Guedry. Although VVM is not yet fully defined, it seems to relate to a situation- specific symptom set (i.e. only occurring when one is exposed to a certain set of sensory stimuli). A similar symptom set described by Furman (1998) as “space motion discomfort” also alludes to the fact that there is a strong interrelationship between visual and vestibular signals.
It has become evident in the last few years as reported by several investigators (e.g. Bronstein 1995; Mallinson and Longridge 1998; Longridge, Mallinson and Denton 2002) and also as reported by many of patients in subsequent studies, that this subset of symptoms can be debilitating. Frequently symptoms are unrecognized or disregarded during history taking, because vestibular dysfunction can result in a range of visual disturbances, but this is not well understood outside the vestibular community (Bisdorff et al, 2009). Sometimes a symptom set which is debilitating (e.g. intractable nausea, constant sense of movement) can be caused by a very subtle deficit, which often cannot be detected by our current battery of available diagnostic tests. The resulting situation can be frustrating for patients and also for assessors, (especially in the presence of a normal set of assessments) as the patient may be labeled as “normal” despite being unable to carry on with everyday life.
The symptoms described by Bronstein (1995) that he defined as “visual vertigo” (VV) are markedly similar to those seen in VVM patients. Bronstein suggested that the process of compensation from vestibular lesions is associated with visual reliance, and in cases where this reliance is unusually high, a patient can be intolerant of situations involving visual conflict. Pavlou et al (2004) suggested that all vestibular patients rely on visual cues for stability, but that some of them are more susceptible to motion than others. They opined that the terms “visual vertigo”, “space motion discomfort” and “visual vestibular mismatch” were three terms that described the same set of symptoms. If it could be determined exactly where the symptoms of space motion sickness were being generated, then perhaps it would give some answers about what was ailing Bronstein’s patients with visual vertigo, and the patients discussed in this thesis with visual vestibular mismatch. Work by Mallinson and Longridge (2002) (Chapter 7 of this thesis) suggested that caloric-induced nystagmus velocity was not correlated with motion sickness susceptibility. This could infer that graviceptor signal function, not semicircular canal impairment, is instrumental in the development of motion sickness, but it must also be remembered that caloric analysis is an unsatisfactory measure of inner ear function. (While normal low velocity lateral semicircular canal responses are interpreted as suggesting normal inner ear function, this inference must be viewed with caution, as higher physiological velocities needed in normal rapid eye and head movements are not measured by caloric testing.)
As discussed previously in this thesis, the term “visual vestibular mismatch” is preferable to the term “visual vertigo” to describe these patients. It is clear that in some patients (and in many different situational circumstances), symptoms can be distressing.
As this set of symptoms parallels motion sickness so closely, the suggestion is made that there is a common origin. There are clear parallels between this symptom set and motion sickness (Redfern, Yardley and Bronstein, 2001) in healthy humans, as both are provoked by exposure to potentially disorienting motion environments in which the perceptual systems involved in orientation provide ambiguous information about self motion (Yardley, 1992). Similar to motion sickness, it does not require vestibular stimulation as such, but results from the creation of a discongruency of visual and vestibular signals (Mallinson and Longridge, 1998).
It should be emphasized that motion sickness is not a malady of itself. Preber in 1958 suggested that the otoliths play a major role in motion sickness. This was also supported by Quarck et al (1998) who showed that motion sickness susceptibility does not correlate with canal-ocular reflexes but does correlate with otolith-ocular reflexes (1998). Quarck et al also showed that it does not correlate with eye movements or nystagmus characteristics (2000). Space motion sickness has been linked to “altered otolithic function in microgravity” (Yates et al, 1998) and is hypothesized to arise “partly due to otolith asymmetry” (Parker, 1998). The otoliths are also implicated in the development de novo of motion sickness (Longridge and Mallinson, 2005). Although there have been these recent advances in understanding motion sickness and its relationship to vestibular symptomatology, the description of the symptoms of visual vestibular mismatch that are detailed in this thesis were first documented (very accurately) by Soranus, whose description of the offending stimuli over 2000 years ago included “watching the flow of a river from a high point”.
It has been suggested by Basta et al (2005) that patients suffering otolith damage have impaired postural control and rely primarily on visual information for maintenance of balance. In brief, inner ear dysfunction, from whatever cause, results in an inability of the otoliths to detect movement accurately, and this can lead to nausea and/or sensations of instability. This instability is often reflected on Computerized Dynamic Posturography (Equitest®) as a nonspecific “across the board” deficit (i.e. performance scores on all sensory conditions are slightly less than the lower limits of the normal data base). This was initially thought to be suggestive of aphysiologic behaviour (“malingering”) but it has been shown by Longridge and Mallinson (2005) (Chapter 10 in this thesis) that this deficit is legitimate, and parallels the balance deficits measured in all returning astronauts. These deficits are probably arising from the graviceptor otolith system, and it has been “strongly implicated that disrupted processing of otolithic inputs is the source of postural instability upon return from orbital flight” (Black et al, 1999).
Chapter 3 of this thesis (1996) details our study of 18 patients suggesting that their symptoms suggested pathology originating from the inner ear. Three of those patients volunteered that they “felt drunk”. This was also echoed in Chapter 4 (1998), as two of the patients in that paper had principal complaints of “feeling drunk”. The work by Basta et al, (2005) strongly supported this. They were able to document otolithic disorders with unilateral centrifugation in patients who had suffered minor head trauma, and stated that “Patients with otolith disorders typically present with sensations of feeling drunk”. Chapter 11 confirms our suspicions that ethanol affects subjects in a similar manner to the complaints voiced by many of our patients, and this indicates pathology possibly originating in the otolith system.
This is one of the reasons that it is important to investigate the effects of alcohol on the human body, and on the balance system. The effects of ethanol occur at different sites, and are biphasic. Besides its well known sedative effects at high dose, it may be a stimulant at lower doses (Nieschalk et al, 1999).
Acute alcohol intoxication affects balance control in numerous ways (Hafstrom et al, 2007). Positional alcohol induced nystagmus (“PAN”) was first reported by Flourens in 1826 (Nito et al, 1964) and several experimenters have shown (eg. Nito et al 1964; Money et al 1965) that the reason that PAN develops is because the semicircular canals are sensitive to gravity. (It was concluded at that time that PAN had to be related to semicircular canal response, as it disappears after canal plugging (Nito et al 1964; Money et al 1965)). The understanding of the balance system at that time was that “otoliths are sensitive to gravity, but do not cause nystagmus” (Money et al, 1965)). Subsequent research since the work by Money has developed our understanding of otolithic-canal interaction, and has suggested that his initial statement 45 years ago is erroneous. For example, Gresty and Bronstein (1985) presented evidence for a linear- compensatory eye movement reflex which was probably otolithic. Angelaki et al (1992) showed in a series of lesion and canal plugging experiments that the steady-state ocular nystagmus during OVAR was the result of inputs from the otolith.
Aside from the nystagmus generated in an intoxicated person, there is also an alcohol-related contribution to imbalance of the body (Uimonen et al, 1994). They reported an increase in body sway velocity under the effects of alcohol, and work by Mallinson et al (2008) (Chapter 11 of this thesis) showed increased sway as a result of even low levels of alcohol intoxication. Alcohol has a depressant action on spinal motor neurons, but this cannot account for the motor incoordination of alcohol intoxication, as intoxication continues in humans long after the H-response returns to normal (Chandran et al, 1981). This strongly suggests that at least some of the effects of alcohol are exhibited at the peripheral vestibular level.
Although intoxicated subjects are obviously affected because of PAN (i.e. semicircular canal stimulation), intoxicated subjects (and also many of the patients discussed in this thesis) report symptoms that the world is tilting, and they also report a false sensation of motion (Hafstrom et al, 2007). This supports otolithic involvement, as the otoliths detect linear acceleration, and orientation of the head with respect to gravity.
Many of the patients with vestibular abnormalities discussed in this thesis report that they have developed an increased sensitivity to alcohol, and another corollary of the thesis is that this results from damage to the balance system. Of concern is that perhaps a patient with a damaged balance system who has consumed an amount of alcohol which would still allow him to drive legally might be impaired to the point where he would be unsafe behind the wheel of a motor vehicle due to this increased susceptibility. This raises ethical concerns with respect to the general community.
The VVM symptom set can be severe. These symptoms are physiologic and not psychogenic. Many patients have concomitant vegetative symptoms, probably related to the influence of the vestibular system on autonomic function. The vestibulo-autonomic regulation is probably responsible for the fact that vestibular dysfunction contributes to anxiety disorders such as panic disorders, and in particular, agoraphobia. This inexplicably occurs in some individuals but not in others. It also remains unclear why there is such a wide range of individual susceptibility to the symptoms of visual vestibular mismatch and to anxiety disorders (Furman, Jacob and Redfern, 1998). It is important to remember that “symptoms that seem psychiatric in nature might be a consequence of an undiagnosed neuro-otologic disorder” (Furman and Jacob, 1997).
If symptoms of VVM were generated from direct trauma to the autonomic nervous system or to the brain, they would have a higher frequency of occurrence in patients who had head injury and/or whiplash type injury. However experiments did not support this conjecture, as it was shown that the rate of newly developed visual vestibular mismatch was 29% in vestibular patients who had a head blow (Chapter 9), 30% in patients who had not suffered head trauma (Chapter 9), and 36% in patients who had undergone intratympanic gentamicin therapy (Chapter 6).
Earlier work compared patients who had suffered whiplash type injuries and head injury, with patients who had suffered whiplash injuries only (Chapter 4). Although this work was done prior to the development of the scoring system to quantify visual vestibular mismatch, symptom frequency was compared between the two groups, and there was no significant difference seen. It was also shown that in patients referred for dizziness from a wide variety of sources and with a wide array of complaints, those who had suffered head injury, whiplash type injury, or both showed no more tendency for the development of VVM than patients we saw with labyrinthine disease not related to trauma (Chapter 9).
The vertiginous spinning nature of complaints in many patients with inner ear disease locates the dizziness to the inner ear, and in the absence of CNS complaints in these patients, the diagnosis of inner ear disease is made based on their typical voiced complaints (e.g. vertigo, etc). In “straightforward” cases such as these, questions about VVM are not needed to diagnose inner ear disease, and frequently are not asked.
The conclusions drawn from the studies that comprise this thesis are also supported by other investigators who have suggested that visual vestibular mismatch is an indirect (not direct) result of trauma (i.e. the trauma causes vestibular damage). Davies and Luxon (1995) looked at dizziness after head injury, and suggested that the variety of audiovestibular injuries found after head injury suggested damage to the sensory organs of the inner ear. They also suggested that given the high incidence of positional vertigo after head injury, the macula of the utricle from which the otoliths arise is the most frequently affected structure.
The theory has been advanced for 2000 years that there is a close vestibular- autonomic interface. But if this is the interface responsible for generating VVM, why is this the case, and what physiological or evolutionary role might such an interface play?
A key role of the central nervous system is to provide for homeostasis (Yates and Miller, 1998). One of the greatest challenges to homeostasis occurs when a human being moves or changes posture. Compensation for such movement requires adjustments by arterial baroreceptors, cardiac baroreceptors, stretch receptors in respiratory muscles, and central and peripheral chemoreceptors, to name but a few. However, effective manipulation of these responses and of their magnitude would arguably require “pre-adaptation”, or initiation of the responses even before the internal environment has been affected. Yates, Sklare and Frey (1998) also outlined that effective maintenance of homeostasis would require action prior to a movement taking place, and it has been suggested that the ability of the vestibular system to detect head position and movement might act as a feed forward system for this purpose. One mechanism for accomplishing this effectively and at maximum speed would be through the actions of the vestibular system, which detects head position and sends this information into the cerebellum without synapsing. Data also exists suggesting that vestibular stimuli can elicit changes in circulation and respiration that provide for stable blood pressure and blood oxygenation during movement and changes in posture (vestibulosympathetic response) (Yates and Miller, 1998). The response characteristics are similar to those of otolithic afferents (Fernandez and Goldberg, 1976) and suggest that the otolith organs are predominantly responsible for producing the vestibulosympathetic response. Thus, the effects of the vestibular system on sympathetic outflow and blood pressure may be acting to offset movement-related challenges to the circulatory system.
“Referred pain” is a concept which is seen in many parts of the body. It is characterized by the fact that it is not felt at the site of origin, but remote from it (Mense, Simons and Russell 2001). Typically the area of referred pain is discontinuous with the site of the lesion. Balaban and Jacob (2001) have suggested that the signs and symptoms that accompany vestibular dysfunction can readily be attributed to specific organs (i.e. they are the organs that are producing the symptoms) but these signs and symptoms can be labeled as referred somatic and visceral manifestations of vestibular dysfunction (Balaban 1999). The “remoteness” of traditional vestibular symptoms is to be expected, as there is no single sense organ that we can identify consciously and intuitively as the source of normal sensations of movement and maintenance of balance. However the importance of the role of the production of these symptoms (followed by the invoked anxiety and situational avoidance strategies) may be a compensatory strategy that has the normal function of preventing exposure to potentially dangerous situations or circumstances.
We formed the impression that VVM can arise from the inner ear. In the patients we see referred for vestibular disease, this symptom set is commonly seen, as shown by the papers discussed in this thesis. In particular, our impression is supported by our study (Chapter 6) which showed that VVM can develop de novo after intratympanic gentamicin injections.
In our clinic we see a preselected group of patients suspected of having vestibular disease. These patients are often “prescreened”, in that central disease is unlikely, because neurologists who refer to our clinic have excluded neurological disease. Our experience with VVM is therefore based on otoneurological disease. Referring physicians would probably have detected significant central disease. This means that central disease has to be subtle because a referring physician would have failed to recognize a neurological component and referred the patients instead for otoneurological assessment. For this reason we rarely see VVM in conjunction with overt neurological disease.
Basta et al (2005) stated that “disorders of the otolithic apparatus are clinical entities which have proven difficult to diagnose in the past” and outlined a typical otolithic disorder patient as presenting with sensations such as “walking on pillows” or “feeling drunk”. They also outlined that Computerized Dynamic Posturography Sensory Organization Testing can “clearly indicate an otolith disorder”, and that these disorders are often seen after minor head injury. It is important to remember that normal assessments do not rule out peripheral vestibular disease, and also in some patients a lesion may exist in central vestibular pathways or in cortex. Because our present tests are limited, we are unable to evaluate this aspect of the vestibular system. In summary, Basta et al (2005) suggest that in patients with documented otolithic pathology, characteristic postural control complaints and characteristic posturography SOT abnormalities, strong suspicions are raised about otolithic pathology. Their work supports the conclusions of this thesis.
In a groundwork paper, the Barany Society Vestibular Disorders Classification Committee has recently generated a first iteration of a classification of vestibular disorders (Bisdorff et al, 2009). The committee is to be commended on their excellent work in attempting to “promote development of an implementable, international and interlinguistic classification of vestibular disorders”. It has also been appropriately hesitant in “labeling” the symptom set or defining it, beyond stating that all definitions developed should be “broad yet specific”; easy to translate into different languages, and also “non- overlapping and non-hierarchical”. It is also emphasized that definitions be developed that reflect the fact that the pathogenesis of almost all symptoms is likely to be incompletely understood (Bisdorff et al, 2009).
The committee has recognized the fact that even “core vestibular symptoms” such as “vertigo” and “dizziness” are not served well by the terminology that is presently used. There is no consensus about the use of the term “vertigo”, as it has been shown to have diverse meanings for patients, generalist physicians and specialist physicians. The committee has wrestled with a definition of the word, as previous attempts to define it have raised controversy. While some vestibular specialists have utilized the term to refer to a sense of spinning only (a commonly accepted usage of the term in North America), the custom in Europe is to utilize the term to refer to any false sense of motion of self or surroundings. The compromise of the terminology committee was to recommend that “vertigo” always be categorized as “spinning”, “non-spinning” or both. Wisely, the committee has recognized that the terms presently in use to describe vestibular disease can be misleading, even to subspecialist practitioners, and that these patients and their presenting symptom sets are not always well understood by those outside the vestibular community.
As has been outlined in this thesis and in many other excellent studies, it is clear that vestibular dysfunction can result in a range of visual disturbances. This visual vestibular interaction (which also involved other sensory modalities) is reasonably well accepted and understood within the vestibular community. The committee has recommended the terms “visually induced vertigo”, as well as “visually induced dizziness”. “Visual-vestibular mismatch” fits into this grouping, as does visual vertigo.
Recognizing the newly developed understanding of the subject, the committee unanimously felt that the concepts of visually induced vertigo and visually induced dizziness should be dealt with as separate entities, partly as an “explicit attempt to promote awareness around this issue”.
It can be seen that the committee has made progress in defining the concept of visual-vestibular symptoms, and it has been careful enough to define “visually induced vertigo” as a visually-induced illusion of a circular (i.e. rotational) or linear (i.e. vectional) self motion. It has also defined “visually-induced dizziness” which is delineated as visually-induced illusion of a movement which is not rotational or vectional. The committee further outlined that one symptom does not necessarily pre-empt the other, as these symptoms can co-exist or occur sequentially. It can be seen that categorization of a patient requires that a prolonged in-depth history be taken.
The committee was also careful to outline its shortcomings to this point. Wisely on a first iteration, it has chosen to avoid issues which are clearly extremely complex. One of the deliberate decisions it made was not to operationally define the neurovegetative or neuropsychiatric symptoms. The committee recognizes that this may be a separate entity and expressly outlines that “visually induced vertigo”, [and visually induced dizziness] should both be distinguished from motion sickness. This is a valid distinction, as motion sickness per se is not a pathological malady, but as outlined previously, we regard the development de novo of motion sickness to be suggestive of newly developed vestibular impairment. In addition, the “visceral feeling of nausea” which the committee feels should not be incorporated into these initial categories is a symptom set developed by many of our patients. Sometimes these symptoms are the only ones reported by patients, and we feel that this might reflect the predominance of one symptom, to the point where more minor symptoms are not reported, even during in-depth history taking. Again the committee is commended for recognizing that this symptom set (i.e. neurovegetative symptoms) is part of the vestibular spectrum, and it has stated the importance of dealing with it, perhaps in the next iteration of the classification algorithm. It did outline the importance of promoting awareness around this issue, and suggested that further iterations will be made after soliciting input from the vestibular community, and making attempts to try and define diagnostic criteria.
One of the general steps taken by the committee that must also be applauded was to recognize the potential for misleading practitioners, and to be aware of the poor understanding we have of the whole concept of sensory integration, the reasons for this complex process, and its purpose in the normally functioning human.
The work in this thesis strongly supports the complex nature of visual vestibular interaction, and furthermore suggests that the symptom set of visually induced vertigo and visually induced dizziness represents balance system disease arising from the inner ear graviceptors, and also shows that it can be very debilitating. If the hypothesis is correct, then we must turn our efforts towards developing methods of measuring otolithic function and detecting otolithic/SCC interaction. To be generally useful, assessment methods must be affordable, able to supply clinical information in a short period of time, and above all must be tolerable for patients, many of whom are unwell and perhaps frail.
Future directions must include the development of cost effective methods of assessing the balance system more fully, and also more specifically. Technological advances used to explore the balance system include the unilateral centrifugation test (Wuyts et al, 2003). In this test, subjects are rotated about an earth vertical axis. During the ongoing rotation, the subject is gradually translated to either side along an interaural axis, so that one utricle becomes aligned with the axis of rotation, and at this point is subject to gravitational forces only, while the contralateral utricle is subjected both to gravity and to centrifugal acceleration. This technique allows for measurement of the sensitivity of each utricle, and also the difference between utricles (this can be construed as a utricular analogy to the caloric test). To date, this assessment is only available at a few select centres, as the cost of equipment is high.
A simpler easy to administer and much cheaper utricular assessment tool is the rod and frame test developed by Hafstrom et al (2004). This is an “enhanced” method of assessing subjective visual vertical (SVV), which measures the degree to which a subject uses available visual cues to locate earth vertical. It uses an obliquely hung picture frame mounted in an otherwise dark room, so that the tendency of a subject to rely on this erroneous visual cue during SVV testing can be measured. Its down side is that it does require patient participation and is therefore less objective than the unilateral centrifugation tests described by Wuyts et al (2003).
Ocular counterrolling is an accepted otolithic measurement, but has been limited by the lack of effective techniques for accurately measuring rotation of the eyeball, and wide variations of normal. Work is presently being carried out to develop software with video camera methods and also iris recognition technology in the hope of quantifying this in an accurate and hopefully clinically relevant manner.