219 Vertigo and Dizziness from Environmental Motion: Visual Vertigo, Motion Sickness, and Drivers’ Disorientation Adolfo M. Bronstein, MD, PhD, FRCP1 John F. Golding, DPhil2 1 Division of Brain Sciences, Department of Neurology, Imperial College London, Charing Cross Hospital, London, United Kingdom 2 Department of Psychology, University of Westminster, London, United Kingdom Michael A. Gresty, PhD1 Address for correspondence Adolfo M. Bronstein, MD, PhD, FRCP, Division of Brain Sciences, Neuro-otology Unit, Centre for Neuroscience, Imperial College London, Charing Cross Hospital, London W6 8RF (e-mail: a.bronstein@imperial.ac.uk). Semin Neurol 2013;33:219–230. Abstract Keywords ► ► ► ► motion sickness vestibular visual motion driving The normal vestibular system may be adversely affected by environmental challenges which have characteristics that are unfamiliar or ambiguous in the patterns of sensory stimulation they provide. A disordered vestibular system lends susceptibility even to quotidian environmental experiences as the sufferer becomes dependent on potentially misleading, nonvestibular sensory stimuli. In both cases, the sequelae may be vertigo, incoordination, imbalance, and unpleasant autonomic responses. Common environmental motion conditions include visual vertigo, motion sickness, and motorists’ disorientation. The core therapy for visual vertigo, motion sickness, and drivers’ disorientation is progressive desensitization within a cognitive framework of reassurance and explanation, plus anxiolytic tactics and autogenic control of autonomic symptoms. The vestibular apparatus is the prime, indeed only organ evolved specifically to signal orientation in space. Therefore, it is unsurprising, that unusual, nonphysiological stimulation and disorders of vestibular function give rise to a variety of symptoms ranging from vertigo, imbalance and incoordination, to autonomic distress. The interpretation, corroboration, and calibration of vestibular signals are dependent on environmental context—important visual and somatosensory cues to orientation. Consequently, challenging visual and mechanical motion in the environment may have adverse effects on vestibular function, producing a similar range of symptoms, whose sufferers may eventually find their way to the neuro-otologist’s office. In the clinic, the foremost symptom is visual vertigo: an inappropriate response to motion of the visual environment due to overreliance or misinterpretation of visual cues due to a sensory (vestibular) disturbance or functional disorder. Panoramic visual motion normally accompanies head movement giving rise to visual motion signals which calibrate and help interpret vestibular signals of head movement and Issue Theme Neuro-Otology 2013; Guest Editor, Terry D. Fife, MD orientation. In normal ndividuals, visual motion alone may occasionally induce sensations of self-motion—“vection,” as in the “railway train” illusion. However, as a means of compensation, many patients with vestibular disease develop an overreliance on environmental visual cues leading to visual dependency, a characteristic also found in people with a certain psychological susceptibility. As a consequence, many forms of visual environmental motion, particularly busy places such as supermarkets, readily induce inappropriate sensations of sway or motion and imbalance. Such visual vertigo may become a major, disabling symptom. Ubiquitous and possessed by all individuals with intact vestibular function is motion sickness that becomes problematic for more-susceptible individuals in modern vehicular and visual environments. All normal individuals with intact vestibular function become motion sick, although individual susceptibility varies widely and is partially determined by inheritance. The major symptom of motion sickness is nausea, leading to vomiting, but headache can also be a significant component and susceptibility and intensity of symptoms are Copyright © 2013 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI http://dx.doi.org/ 10.1055/s-0033-1354602. ISSN 0271-8235. 220 Vertigo and Dizziness from Environmental Motion Bronstein et al. often enhanced in migraineurs. The characteristic stimulus to motion sickness in boats and vehicles is oscillation at a mechanical frequency around 0.2 Hz with provocation diminishing at higher and lower frequencies, but a visual motion counterpart of self-motion alone can provoke symptoms. A frequency of 0.2 Hz is the “break frequency” above which vestibular signals of inertial forces tend to be interpreted as translation, whereas lower frequencies of motion are interpreted as tilt. Ambiguity in interpretation around this frequency is thought to provoke central nervous system (CNS) states similar to toxicity provoking the vomiting response. The zone of ambiguity may also be a region where locomotion and balance change biomechanical characteristics from tilting to translating maneuvers. Susceptibility increases through childhood to peak at puberty, thereafter diminishing gradually. In addition to desensitization, motion sickness may be ameliorated by drug prophylaxis with scopolamine (hyoscine) and cinnarizine being the treatments of choice. Finally, although vehicle control becomes an overlearned skill, dysadaptation in certain individuals renders them susceptible to the instability of the driving environment causing a “motorists’ disorientation” with components of both motion sickness and visual vertigo. Motorists learn to interpret sensory stimuli in the context of the car stabilized by its suspension and guided by steering. However, the sensory stimulation during driving is potentially ambiguous: The forces of cornering may be interpreted as tilt rather than as lateral acceleration and visual flow of the road and traffic can be interpreted to indicate veering, a form of visual vertigo. In motorists’ disorientation, certain individuals appear to develop a heightened awareness of these false perceptions of car orientation, readily experiencing stereotypical symptoms of threatened rolling over on corners and veering on open highways or in streaming traffic. There is no consistent pattern of comorbidity, but individuals with vestibular or other sensory disturbances, anxiety, or phobia may be more susceptible. Once developed, it is difficult to suppress the tendency to disorientation when driving. Visual Vertigo Interaction of Vestibular and Visual Mechanisms The vestibular and visual systems complement each other in eliciting slow-phase eye movements to stabilize visual images on the retina. Pursuit-optokinetic eye movements are elicited by visual motion, whereas vestibular eye movements (vestibulo-ocular reflex [VOR]) are elicited by head motion. These two systems work synergistically when a person rotates with eyes open while gazing at the surrounding environment, for instance, a passenger looking out of a bus which is turning (►Fig. 1). However, they are said to be in conflict (visuovestibular conflict) when a person looks at a visual object that rotates with him or her, as when a passenger reads a book on a bus. In this case, instead of collaborating with the VOR, the visual input actually suppresses the VOR (VOR suppression). The interaction between vestibular and visual inputs is not only present in physiological circumstances. In fact, Seminars in Neurology Vol. 33 No. 3/2013 Fig. 1 When a passenger looks out of a bus fixating upon a road sign, vestibular (vestibulo-ocular reflex [VOR]) and visual (pursuit) mechanisms cooperate to stabilize the eyes on the visual target as the bus turns around. In contrast, when a passenger tries to read a newspaper, the VOR takes the eyes off the visual target, but pursuit eye movements suppress the VOR so that reading can proceed. In the latter situation, visual and vestibular inputs are said to be in conflict. (From Bronstein AM, Lempert T. Dizziness: A Practical Approach to Diagnosis and Management. Cambridge Clinical Guides. Cambridge, England: Cambridge University Press; 200219; with permission). the first line of defense against a pathological nystagmus due to a labyrinthine lesion is to resort to VOR suppression mechanisms so that visual stability can be partly restored (►Fig. 2). Similarly, absent1 or altered visual input as in congenital nystagmus2 or external ophthalmoplegia 3 modifies vestibular function and perception. It is thus not surprising that vestibular lesions can cause visual symptoms and that visual input influences vestibular symptoms. Here we review a clinically relevant syndrome in which visuovestibular interaction is prominent—the syndrome of visual vertigo in which vestibular patients report worsening of their symptoms during visual motion stimuli. Vertigo and Dizziness from Environmental Motion Fig. 2 Horizontal electro-oculography in a patient 7 days (top) and one month after a labyrinthectomy (bottom). The nystagmus in the acute phase is almost exclusively seen in the dark. Such suppression of the nystagmus by visual fixation is thought to be akin to normal vestibuloocular reflex suppression, as in Fig. 1 (bottom). Clinical Picture of Visual Vertigo Some vestibular patients report the triggering or worsening of dizziness and imbalance in certain visual environments. These patients dislike moving visual surroundings, as encountered in traffic, crowds, under disco lights, and while watching car-chase scenes in films. Typically, such symptoms develop when walking in busy visual surroundings such as supermarket aisles. The development of these symptoms in some patients with vestibular disorders has long been recognized4,5 (see Bronstein, 20026 for review) and given various names such as visuovestibular mismatch7,8 or visual vertigo.9,10 This syndrome should not be confused with oscillopsia. In oscillopsia, there is oscillation of the visual world—the symptom is visual. In visual vertigo, the trigger is visual, but the symptom is of a vestibular kind such as dizziness, vertigo, disorientation, and unsteadiness. The symptoms of visual vertigo frequently develop after a vestibular insult. A typical patient is a previously asymptomatic person who suffers an acute peripheral disorder (e.g., vestibular neuritis) and after an initial period of recovery of a few weeks, he or she discovers that the dizzy symptoms do not fully disappear. Furthermore, symptoms are aggravated by looking at moving or repetitive images, as described above. Patients may also develop anxiety or frustration because symptoms do not go away or because medical practitioners tend to disregard this syndrome. The origin and significance of the symptoms of visual vertigo in vestibular patients has been the subject of research. We know that tilted or moving visual surroundings have a pronounced influence on these patients’ perception of verticality and balance, over and above what can be expected from an underlying vestibular deficit.9,10 This increased responsiveness to visual stimuli is called visual dependency. Patients with central vestibular disorders and patients combining vestibular disorders and congenital squints or squint surgery can also report visual vertigo and show enhanced visuopostural reactivity.9 Overall, these findings suggest that the combination of a vestibular disorder and visual dependence in a given patient is what leads to the visual vertigo syndrome. Ultimately, what makes some patients with vestibular disorders develop such Bronstein et al. visual dependence is not known. The role of the associated anxiety-depression, often observed in these patients, and whether this is a primary or secondary phenomenon is not known. The limited evidence so far does not indicate that anxiety or depression levels are higher in visual vertigo patients than in other patients seen in dizzy clinics.10,11 The more important differential diagnosis in these patients is, however, one of a purely psychological disorder such as panic attacks.12 An accepted set of criteria to distinguish between psychological and vestibular symptoms is not agreed presently.12–14 However, a patient who has never had a clear history of vestibular disease, with no findings on vestibular examination, and with visual triggers restricted to a single particular environment (e.g., only supermarkets) would be more likely to have a primary psychological disorder. Reciprocally, a patient with no premorbid psychological dysfunction who after a vestibular insult may develop cartilting illusions when driving15 or dizziness when looking at moving visual scenes (traffic, crowds, movies) is more likely to have the visual vertigo syndrome. Treatment of Visual Vertigo There are three aspects in the treatment of patients with the visual vertigo syndrome. The first is specific measures for the underlying vestibular disorder, for example, Ménière’s disease, benign paroxysmal positional vertigo (BPPV), or migraine. However, a specific etiological diagnosis cannot be confirmed in many patients with chronic dizziness. Second, patients benefit from general vestibular rehabilitation with a suitably trained audiologist or physiotherapist. These exercise-based programs can be either generic, like the original Cawthorne-Cooksey approach,16 or preferably, customized to the patient’s needs. All regimes involve progressive eye, head, and whole body movements (bending, turning), as well as walking exercises.17–19 Finally, specific measures should be introduced in the rehabilitation program to reduce their hyperreactivity to visual motion. The aim is to promote desensitization and increase tolerance to visual stimuli and to visuovestibular conflict. Patients are therefore exposed, under the instruction of the vestibular physiotherapist, to optokinetic stimuli that can be delivered via projection screens, head-mounted virtual reality systems, video monitors, ballroom planetariums, or optokinetic rotating systems.20 Initially, patients watch these stimuli while seated, then standing, walking, initially without and then with head movements, in a progressive fashion (►Fig. 3). Recent research has shown that these patients benefit from repeated and gradual exposure to such visualmotion-training programs; both the dizziness and associated psychological symptoms improve over and above conventional vestibular rehabilitation.21 Motion Sickness Introduction The primary signs and symptoms of motion sickness are nausea and vomiting. Other commonly related symptoms include stomach awareness, sweating, and facial pallor (soSeminars in Neurology Vol. 33 No. 3/2013 221 222 Vertigo and Dizziness from Environmental Motion Bronstein et al. Fig. 3 Optokinetic or visual motion desensitization treatment for patients with vestibular disorders reporting visual vertigo symptoms. Left: Roll (coronal) plane rotating optokinetic disk; Middle: planetarium-generated moving dots while the subject walks; Right: ‘Eye-Trek’ or head-mounted TV systems projecting visual motion stimuli. In this case, in advanced stages of the therapy, the patient moves the head and trunk while standing on rubber foam. (Based on Pavlou M, Lingeswaran A, Davies RA, Gresty MA, Bronstein AM. Simulator based rehabilitation in refractory dizziness. J Neurol 2004;251(8):983–995, 21 with permission). called cold sweating), increased salivation, sensations of bodily warmth, dizziness, drowsiness, headache, loss of appetite, and increased sensitivity to odors. Motion sickness can be provoked by a wide range of situations—in cars, tilting trains, fair rides, aircraft, weightlessness in outer space, virtual reality, and simulators. The term “motion sickness” embraces car sickness, air sickness, space sickness, sea sickness, etc. Physiological responses associated with motion sickness may vary between individuals. For the stomach, gastric stasis occurs and increased frequency and reduced amplitude of the normal electrogastric rythmn.22 Other autonomic changes include sweating and vasoconstriction of the skin causing pallor (less commonly skin vasodilation and flushing in some individuals) with the simultaneous opposite effect of vasodilation and increased blood flow of deeper blood vessels, changes in heart rate that are often an initial increase followed by a rebound decrease, and inconsistent changes in blood pressure.23 A whole host of hormones are released mimicking a generalized stress response, among which vasopressin is thought to be most closely associated with the time course of motion sickness.24 The observation of cold sweating suggests that motion sickness may disrupt Seminars in Neurology Vol. 33 No. 3/2013 aspects of temperature regulation,25 a notion also consistent with the observation that motion sickness reduces deep corebody temperature during cold-water immersion, accelerating the onset of hypothermia.26 Motion sickness is unpleasant; under some circumstances, it may have adverse consequences for performance and even survival. Motion sickness preferentially causes decrements on the performance of tasks that are complex, require sustained performance, and offer the opportunity for a person to control the pace of his or her effort.27 For pilots and aircrew, it can slow training in the air and in simulators, and even cause a minority to fail training.23 Approximately 70% of novice astronauts will suffer space sickness in the first 24 hours of flight. The possibility of vomiting while in a spacesuit in microgravity is potentially life threatening, consequently precluding extravehicular activity for the first 24 hours of spaceflight.28 For survival-at-sea, such as in in life rafts, seasickness can reduce survival chances by a variety of mechanisms, including reduced morale and the will to live, failure to consistently perform routine survival tasks, dehydration due to loss of fluids through vomiting,23 and possibly due to the increased risk of hypothermia.26 Vertigo and Dizziness from Environmental Motion Causes and Reasons for Motion Sickness Any proposed mechanism for motion sickness must account for the observation that the physical intensity of the stimulus is not necessarily related to the degree of nauseogenicity. Indeed, with optokinetic stimuli there is no real motion. A person sitting at the front in a widescreen cinema experiences self-vection and “cinerama sickness,” but there is no physical motion of the body. In this example, the vestibular and somatosensory systems are signaling that the person is sitting still, but the visual system is signaling illusory movement or self-vection. Consequently, the generally accepted explanation is based on some form of sensory conflict or sensory mismatch. The sensory conflict or sensory mismatch is between actual versus expected invariant patterns of vestibular, visual, and kinesthetic inputs.29 Benson23 categorized neural mismatch into two main types: (1) conflict between visual and vestibular inputs, or (2) mismatch between the canals and the otoliths. A simplified model was proposed by Bos and Bles30 that there is only one conflict: between the subjective expected vertical and the sensed vertical. However, despite this apparent simplification, the underlying model is necessarily complex and finds difficulty in accounting for the observation that motion sickness can be induced by types of optokinetic stimuli that pose no conflict concerning the earth’s vertical.31 A useful set of rules was proposed by Stott,32 which if broken, will lead to motion sickness: Rule 1. Visual–vestibular: Motion of the head in one direction must result in motion of the external visual scene in the opposite direction. Rule 2. Canal–otolith: Rotation of the head, other than in the horizontal plane, must be accompanied by appropriate angular change in the direction of the gravity vector. Rule 3. Utricle–saccule: Any sustained linear acceleration is due to gravity, has an intensity of 1 g, and defines “downwards.” In other words, the visual world should remain space stable, and gravity should always point down and average over a few seconds to 1 g. The above describes what might be defined as the “how” of motion sickness in terms of mechanisms. By contrast, it is necessary to look elsewhere for an understanding of the “why” of motion sickness. Motion sickness itself could have evolved from a system designed to protect from potential ingestion of neurotoxins by inducing vomiting when unexpected CNS inputs are detected, the “toxin detector” theory.33 This system would then be activated by modern methods of transport that cause mismatch. This theory is consistent with the observation that people who are more susceptible to motion sickness are also more susceptible to emetic toxins, chemotherapy sickness, and postoperative nausea and vomiting (PONV).34 In addition this theory has been experimentally tested with evidence of reduced emetic response to challenge from toxins after bilateral vestibular ablation.35 Less-popular alternatives to the toxin-detector hypothesis propose that motion sickness could be the result of aberrant activation of vestibular-cardiovascular reflexes,36 that it Bronstein et al. might originate from a warning system that evolved to discourage development of perceptual motor programs that are inefficient or cause spatial disorientation,37 or that motion sickness is a unfortunate consequence of the physical proximity of the motion detector (vestibular) and vomiting circuitry in the brainstem.38 Individual Differences in Motion-Sickness Susceptibility Individuals vary widely in their susceptibility; there is evidence from twin studies that a large proportion of this variation can be accounted for by genetic factors with heritability estimates around 55 to 70%.39 Some groups of people have particular risk factors. Infants and very young children are immune to motion sickness with motion sickness susceptibility beginning from perhaps around 6 to 7 years of age29 and peaking around 9 to 10 years.40 Following the peak susceptibility, there is a subsequent decline of susceptibility during the teenage years toward adulthood around 20 years. This doubtless reflects habituation. Women appear somewhat more susceptible to motion sickness than men; women show higher incidences of vomiting and reporting a higher incidence of symptoms such as nausea.41 This increased susceptibility is likely to be objective and not subjective because women vomit more than men; surveys of passengers at sea indicate a 5:3 female to male risk ratio for vomiting.42 Although susceptibility varies over the menstrual cycle, peaking around menstruation, it is unlikely that this can fully account for the greater susceptibility in females because the magnitude of fluctuation in susceptibility across the cycle is only around one third of the overall difference between male and female susceptibility.43 The elevated susceptibility of females to motion sickness, to postoperative nausea and vomiting, or chemotherapy-induced nausea and vomiting34,44 may serve an evolutionary function. Thus, more sensitive sickness thresholds in females may serve to prevent exposure of the fetus to harmful toxins during pregnancy. Individuals who have complete bilateral loss of labyrinthine (vestibular apparatus) function are largely immune to motion sickness. However, this may not be true under all circumstances because there is evidence that some bilateral labyrinthine defective individuals are still susceptible to motion sickness provoked by visual stimuli designed to induce self-vection during pseudo-Coriolis stimulation, which consists of pitching head movements in a rotating visual field.45 Certain groups with medical conditions may be at elevated risk. Many patients with vestibular pathology and disease and vertigo can be especially sensitive to any type of motion. The well-known association among migraine, motion-sickness sensitivity, and Ménière’s disease dates back to the initial description of the syndrome by Prosper Ménière in 1861. The reason for the elevated motion sickness susceptibility in migraineurs is not known, but may be due to altered serotonergic system functioning.46 Patients with vestibular migraine are especially susceptible to motion sickness.47 A rapid estimate of an individual’s susceptibility can be made using Motion Sickness Susceptibility Questionnaires (MSSQ; sometimes called Motion History Questionnaires). A Seminars in Neurology Vol. 33 No. 3/2013 223 224 Vertigo and Dizziness from Environmental Motion Bronstein et al. typical questionnaire is shown in ►Table 1, which has been validated for exposure to motion stimuli in the laboratory and in transport environments.48 An overall indicator of susceptibility may be calculated as the MSSQ score ¼ (total sickness score)  (18) / (18–number of types not experienced), this formula corrects for differing extent of exposure to different motion stimuli in individuals. For the normal population, the median MSSQ score is 11.3, where higher scores indicate greater susceptibility and vice versa. Mal de Debarquement Whittle49 provided an early description of mal de debarquement, after the landing and during the advance of the troops of William of Orange in Torbay in 1688: “As we marched here upon good Ground, the Souldiers would stumble and sometimes fall because of a dissiness in their Heads after they had been so long toss’d at Sea, the very Ground seem’d to rowl up and down for some days, according to the manner of the Waves.” Mal-de-debarquement is the sensation of unsteadiness and tilting of the ground when a sailor returns to land. A similar effect is observed in astronauts returning to 1 g on Earth after extended time in weightlessness in space. This can lead to motion sickness, but symptoms usually resolve within a few hours as individuals readapt to the normal land environment. Individuals susceptible to mal de debarquement may have reduced reliance on vestibular and visual inputs and increased dependence on the somatosensory system for the maintenance of balance.50 In a minority of individuals, symptoms persist and can be troublesome. Customized vestibular exercises have been proposed as a treatment.51 Some temporary relief can be obtained by reexposure to motion, but this is not a viable treatment. Standard antimotion sickness drugs appear ineffective, but benzodiazepines appear to offer some relief.52 Table 1 Motion Sickness Susceptibility Questionnaire Short-Form (MSSQ-Short) Not applicable never travelled Never felt sick Rarely felt sick Sometimes felt sick Frequently felt sick Your CHILDHOOD Experience Only (before 12 years of age), for each of the following types of transport or entertainment please indicate: 1. As a CHILD (before age 12), how often you Felt Sick or Nauseated (tick boxes): Cars Buses or Coaches Trains Aircraft Small Boats Ships, e.g., Channel Ferries Swings in playgrounds Roundabouts in playgrounds Big Dippers, Funfair Rides t 0 1 2 3 Your Experience over the LAST 10 YEARS (approximately), for each of the following types of transport or entertainment please indicate: 2. Over the LAST 10 YEARS, how often you Felt Sick or Nauseated (tick boxes): Cars Buses or Coaches Trains Aircraft Small Boats Ships, e.g., Channel Ferries Swings in playgrounds Roundabouts in playgrounds Big Dippers, Funfair Rides t 0 1 2 3 Source: Adapted from Golding JF. Predicting individual differences in motion sickness susceptibility by questionnaire. Pers Individ Dif 2006;41:237– 248.48 Note: This questionnaire is designed to find out how susceptible to motion sickness you are, and what sorts of motion are most effective in causing that sickness. Sickness here means feeling queasy or nauseated or actually vomiting. Seminars in Neurology Vol. 33 No. 3/2013 Vertigo and Dizziness from Environmental Motion Behavioral Countermeasures Habituation offers the surest countermeasure to motion sickness, but by definition is a long-term approach. Habituation is superior to antimotion sickness drugs, and it is free of side effects.53 The most extensive habituation programs, often denoted “motion sickness desensitization,” are run by the military with success rates exceeding 85%,54 but can be extremely time consuming, lasting many weeks. Critical features include (1) the massing of stimuli (exposures at intervals greater than a week almost prevents habituation); (2) use of graded stimuli to enable faster recoveries and more sessions to be scheduled, which may help avoid the opposite process of sensitization; and (c) maintenance of a positive psychological attitude to therapy.55 Habituation may be specific to a particular stimulus, for example, tolerance car travel may confer no protection to seasickness. Antimotion sickness drugs are of little use in this context because both laboratory56 and sea studies57 show that although such medication may speed habituation compared with placebo in the short term, in the longer term it is disadvantageous. This is because when the antimotion sickness medication is discontinued, the medicated group relapses and is worse off than those who were habituated under placebo. Immediate short-term behavioral counter measures include reducing head movements, aligning the head and body with gravity and imposed horizontal acceleration to initiate gravito-inertial force, 58,59 or laying supine.60 However, such protective postures may be incompatible with task performance. It is usually better to be in control, that is to be the driver or pilot rather than a passenger.61 Obtaining a stable external horizon reference is helpful.62 Controlled regular breathing has been shown to provide increased motion tolerance, and may involve activation of the known inhibitory reflex between respiration and vomiting.63,64 Supplemental oxygen may be effective for reducing motion sickness in Bronstein et al. patients during ambulance transport, but it is ineffective in healthy individuals. This apparent paradox is explained by the suggestion that supplemental oxygen may work by ameliorating a variety of internal states that sensitize for motion sickness rather than against motion sickness per se.65 Some report acupuncture and acupressure to be effective against motion sickness66 however, other well-controlled trials find no evidence for their value.67 For habitual smokers, acute withdrawal from nicotine provides significant protection against motion sickness.68 Indeed, this finding may explain why smokers are at reduced risk for PONV, whereas nonsmokers have elevated risk because temporary nicotine withdrawal perioperatively and consequent increased tolerance to sickness may explain why smokers have reduced risk for PONV.68 It has been suggested that ginger (main active agent gingerol) acts to calm gastrointestinal feedback,69 but studies of its effects on motion sickness have been equivocal, making it an unlikely potent antimotion sickness agent. The findings for any effects of diet are contradictory; for example, a study suggesting that protein-rich meals may inhibit motion sickness70 may be contrasted with a study which drew the opposite conclusion that any meal of high protein or dairy foods 3 to 6 hours prior to flight should be avoided to reduce air-sickness susceptibility.71 Pharmacological Countermeasures Drugs currently used against motion sickness may be divided into the following categories: antimuscarinics (e.g., scopolamine), H1 antihistamines (e.g., dimenhydrinate), and sympathomimetics (e.g., amphetamine). These drugs have not improved much over 40 years.72 Commonly used antimotion sickness drugs are shown in ►Table 2. Other more recently developed antiemetics are not effective against motion sickness, including D2 dopamine receptor antagonists and 5HT3 antagonists used for side effects of chemotherapy.73 The new Table 2 Common antimotion sickness drugs Drug Route Adult dose Time of onset Duration of action (h) Scopolamine Oral 0.3–0.6 mg 30 min 4 Scopolamine Injection 0.1–0.2 mg 15 min 4 Scopolamine Transdermal patch one 6–8 h 72 Promethazine Oral 25–50 mg 2h 15 Promethazine Injection 25 mg 15 min 15 Promethazine Suppository 25 mg 1h 15 Dimenhydrinate Oral 50–100 mg 2h 8 Dimenhydrinate Injection 50 mg 15 min 8 Cyclizine Oral 50 mg 2h 6 Cyclizine Injection 50 mg 15 min 6 Meclizine Oral 25–50 mg 2h 8 Buclizine Oral 50 mg 1h 6 Cinnarizine Oral 15–30 mg 4h 8 Source: Adapted from Benson AJ. Motion sickness. In: Pandolf K, Burr R, eds. Medical Aspects of Harsh Environments. Vol. 2. Washington, DC: Walter Reed Army Medical Center; 2002:1048-1083.23 Seminars in Neurology Vol. 33 No. 3/2013 225 226 Vertigo and Dizziness from Environmental Motion Bronstein et al. Neurokinin 1 antagonists antiemetics also do not appear effective against motion sickness.74 This is probably because their sites of action may be at vagal afferent receptors or the brainstem chemoreceptor trigger zone (CTZ), whereas antimotion sickness drugs act elsewhere, perhaps at the vestibular brainstem nuclei. All antimotion sickness drugs can produce unwanted side effects, drowsiness being the most common. Promethazine is a classic example.53 Scopolamine may cause blurred vision in a minority of individuals, especially with repeated dosing. The antimotion sickness combination drug amphetamine þ scopolamine (so-called scopdex) is probably the most effective with the fewest side effects, at least for short-term use. This is because both scopolamine and amphetamine are proven antimotion sickness drugs, doubtless acting through different pathways so they have additive efficacy; their side effects of sedation and stimulation cancel each other out. Unfortunately, for legal reasons the scopdex combination is no longer available, apart from specialized military use. Alternative stimulants such as Modafinil seem ineffective.75 Oral administration must anticipate motion because motion sickness induces gastric stasis, consequently preventing drug absorption by this route.76 Injection overcomes the various problems of slow absorption kinetics and gastric stasis or vomiting. Other routes, such as the transdermal route, also offer advantages providing protection for up to 72 hours with low constant concentration levels in blood, thus reducing side effects. However, transdermal scopolamine has a very-slow-onset time (6–8 h), which be offset by simultaneous administration of oral scopolamine enabling protection from 30 minutes onwards.77 There may be variability in absorption via the transdermal route, which alters effectiveness between individuals.78 Buccal absorption is effective with scopolamine, but an even faster route is via nasal scopolamine spray. Peak blood levels via the nasal route may be achieved in 10 minutes and this has been shown to be effective against motion sickness.79 Investigations of new antimotion sickness drugs include re-examination of old drugs such as phenytoin, as well as the development of new agents. The range of drugs is wide and the list is long. Such drugs include phenytoin, betahistine, chlorpheniramine, cetirizine, fexofenadine, benzodiazepines and barbiturates, the antipsychotic droperidol, corticosteroids such as dexamethasone, tamoxifen, opioids such as the u-opiate receptor agonist loperamide, neurokinin NK1 receptor antagonists, vasopressin V1a receptor antagonists, NMDA antagonists, 3-hydroxypyridine derivatives, 5HT1a receptor agonists such as the antimigraine triptan rizatriptan, and selective muscarinic M3/m5 receptor antagonists such as zamifenacin and darifenacin. So far, none of these drugs have proven to be of any major advantage over those currently available for motion sickness.80 The reasons are various and include relative lack of efficacy, complex and variable pharmacokinetics, or in those that are effective, unacceptable side effects. Future development of drugs with highly selective affinities to receptor subtypes relevant to motion sickness may produce Seminars in Neurology Vol. 33 No. 3/2013 an antimotion sickness drug of high efficacy with few side effects. A good candidate would be a selective antagonist for the m5 muscarinic receptor.81 Motorists’ Vestibular Disorientation Characteristics of Motorists’ Disorientation Of the many ills associated with an automobile, one in particular falls within the realm of vestibular dysfunction and disorientation. Originally named motorists’ vestibular disorientation82, but better termed motorists’ disorientation syndrome83, the symptoms are remarkably similar between patients. The sufferer is usually the driver who may experience one or more of the following perceptions: that the car is about to roll over when rounding bends in the road and particularly during a hill descent; the car is veering, usually toward the roadside, which develops particularly on open roads (especially motorways, interstate highways) and may be exacerbated by the sight of passing vehicles; instability and veering when exiting roundabouts; or instability and veering when negotiating high bridges. The perception of veering may compel the driver to make inappropriate adjustments in the vehicle’s direction; an occasional patient has reported turning the steering wheel inappropriately in the absence of a definite perception of inappropriate orientation. Many readers will have experienced similar perceptions in the context of driving very fast, taxing the limits of vehicle suspension and control: for example, fast cornering readily provokes the apprehension that a vehicle may roll over. The difference from such normal perceptions is that the symptoms described above emerge under quotidian, relatively benign driving conditions and become disabling. Inappropriate perceptions of rolling and veering are best classified as a form of spatial disorientation,84 in which the sensory stimuli experienced during driving are misinterpreted to give an inappropriate perception of vehicle orientation and motion with respect to the frame of reference of a car, under control, proceeding on a highway. Of relevance to mechanism, vide infra, the sensory stimuli per se, out of this specific context, are open to alternative interpretations. By way of illustration, an experienced female driver repeatedly returned her car to the garage with a query of faulty steering, eventually changing vehicles—so real was her perception that the car veered at speed. In the absence of medical cause, her physician suspected a functional disturbance and referred her to a nearby center for aviation medicine as a case of disorientation. Illustrative Case Histories In each of the following histories, one can see why problems with driving might develop, often within a milieu of anxiety that may be an exacerbating factor. Phobic personality as predisposing to the development of motorist’s disorientation has been proposed on the basis of clinical experience with such patients.85,86 This may well be the case in some individuals, but marked phobia is not typical of the majority of cases we have encountered, and in any case, does not Vertigo and Dizziness from Environmental Motion explain the stereotypical symptoms. Sufferers rarely have any significant organic disorder. 1. After a near-crash in mountain fog, a Special Forces helicopter pilot felt his aircraft to be extremely unstable and could not fly. Feelings of instability extended to driving—the car threatened to veer off the road. Although medically fit, he had some marital anxieties and had recently witnessed a member of his wing beheaded by a rotor blade during a dangerous maneuver, but denied that this was stressful. 2. A young mother of three children, recently deserted by her husband, developed feelings that her car threatened to roll over on bends, even at low speeds. The experience prevented her from both doing the school run and driving herself to work. 3. A middle-aged man retraining after a flagging career, developed perceptions of veering and rolling over on bends when driving the interstate, which was a necessary journey to work. He admitted to anxiety about his life circumstances, which he kept from his family, but was otherwise well. 4. A roadside breakdown engineer who spent his working day on motorways developed sensations of veering when driving at speed so that he was limited to driving at 40 to 50 mph. Apparently happily married for many years, he denied significant stress and was medically well except for mild obesity. He spent long hours being sedentary by the roadside. Mechanisms Motorists’ disorientation was originally ascribed to mild asymmetries of vestibular function causing erroneous tilt and turning sensations or misinterpretations.82,87 However, such disorientation is not typical of patients with even marked vestibular asymmetries; hence, this explanation should probably be discounted as the major mechanism, although it may be a factor contributing to the emergence of the condition in individual patients. Motorists’ disorientation is probably multisensory. During highway driving, the driver must learn to interpret his or her pattern of vestibular and somatic sensations according to the context or “frame of reference” of a four-wheeled vehicle constrained to a highway by the suspension system, which under normal driving conditions, resists tilting from upright under the centripetal accelerations imposed by cornering. The driver is also exposed to a complex pattern of visual flow that the driver must interpret as the normal flow of traffic. In motorists’ disorientation, interpretation of sensory input with respect to a vehicular frame of reference appears to have broken down and the driver is vulnerable to alternative interpretations of inherently ambiguous, visual, and somatosensory stimuli.83,88 Causes of Specific Symptoms A feeling of rolling over is a well-known perception provoked by lateral linear acceleration89 and with rolling of the visual scene.90,91 The lateral centripetal, acceleration experienced Bronstein et al. on a bend causes a tilt of the gravitoinertial vertical from Earth upright toward the center of rotation (like the tilt of a bicycle leaning into a bend). However, the suspension of a car keeps it approximately Earth-upright and a driver normally interprets the centripetal acceleration as a sideways force.92 The disoriented motorist feels that he or she is tilted away from the gravitoinertial upright, out of the bend, and is rolling over. This perception is perhaps facilitated by the lack of structure open highways and by banking of the road.93 A perception of threatened veering when the vehicle is at uniform speed on an open road is likely to be provoked by vection due to optokinetic visual flow, particularly because somatosensory cues to orientation may be masked by vibration, downregulated because of monotony, and adapted because of immobility of the seated driver. Visual flow can induce body reorientations and influence heading, as in the railway train illusion,94 flight simulators, and fairground rides. When proceeding at speed on an open straight highway, differential optic flow, including passing vehicles, may induce a perception of veering, a common experience in many drivers in merging traffic at acutely angled highway intersections. The process may be unconscious, the driver responding to subliminal cues to orientation95 so that steering adjustments can occur before perception of veering. Finally, any tendency to veer or perceive the threat of veering would be enhanced by road camber and perception that other vehicles or barriers are perilously close. Epidemiology The number of disoriented motorists reported is too small to draw firm conclusions about epidemiology. Approximately 1% of patients referred to a well-established, London clinic specializing in vestibular and balance disorders (A. M. Bronstein, personal observation) report motorists’ disorientation, amounting to approximately five individuals per annum. The sufferers have been adults of both sexes, and rarely with a history of significant psychiatric or organic disorder. Treatment The model for rehabilitation of motorists’ disorientation is based on rehabilitation of flying disorientation and motion sickness.96–98 • Explanation of the possible physiological causes of disorientation • Progressive desensitization following an explicit schedule of driving commencing with short-duration exposures on local roads at quiet times and progressing to highway driving • The driver verbalizes the planning and execution of the journey giving a continual appraisal of the road conditions to strengthen cognitive context. • The driver should always stop for a rest if driving becomes significantly stressful and perform anxiolytic exercises such as postural control, controlled breathing, and “stretching his legs.” • Desensitization by “immersion”; driving in one long-session challenge is not recommended, as it may cause Seminars in Neurology Vol. 33 No. 3/2013 227 228 Vertigo and Dizziness from Environmental Motion Bronstein et al. extreme levels of anxiety and panic that impede rehabilitation. Patients who have complied with this therapeutic program have recovered the ability to drive at speed on any type of road, but can readily decompensate. It seems that once a sufferer has experienced motorists’ disorientation it becomes difficult to “quarantine”99 the interpretation of normal patterns of sensory stimulation during driving as a perception of extreme instability. 21 Pavlou M, Lingeswaran A, Davies RA, Gresty MA, Bronstein AM. 22 23 24 25 References 26 1 Seemungal BM, Glasauer S, Gresty MA, Bronstein AM. Vestibular 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 perception and navigation in the congenitally blind. J Neurophysiol 2007;97(6):4341–4356 Okada T, Grunfeld E, Shallo-Hoffmann J, Bronstein AM. Vestibular perception of angular velocity in normal subjects and in patients with congenital nystagmus. Brain 1999;122(Pt 7): 1293–1303 Grunfeld EA, Shallo-Hoffmann JA, Cassidy L, et al. Vestibular perception in patients with acquired ophthalmoplegia. 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