Quantitative Eye Movement Measurements in Patients with Acute Vestibular Syndrome

BACKGROUND: A chief complaint of acute vertigo/dizziness is related to about 2.1-7.1% of all emergency department (ED) visits. About 25% of all patients with acute prolonged vertigo meeting diagnostic criteria of AVS (acute vestibular syndrome) suffer from a vertebrobasilar stroke and about 35% of these patients are initially missed. Differentiating dangerous central from more benign peripheral causes of AVS is essential. Subtle oculomotor paradigms such as HINTS (Head-Impulse, Nystagmus, Test-of-Skew) have been shown to detect central causes with high diagnostic accuracy, however, require sufficient training. Thus, identifying other bedside tests that can be reliably performed by frontline providers is essential to reduce misdiagnosis.

WORKING HYPOTHESIS: By using additional oculomotor (saccades, pursuit) and pupillomotor parameters at the bedside or quantitatively, the diagnostic accuracy for distinguishing peripheral from central AVS causes can be further improved, especially in the setting when expertise for applying more sophisticated algorithms (HINTS(+), STANDING) is lacking.

AIM 1: Detecting changes in oculomotor and pupillomotor responses in acutely dizzy patients and characterizing the spectrum of abnormalities in peripheral and central AVS.

AIM 2: Comparing different composite oculomotor-/pupillomotor scores to identify those scores with the highest diagnostic accuracy at the bedside and quantitatively.

AIM 3: Comparing the diagnostic accuracy of bedside and quantitative oculomotor and pupillomotor testing in AVS- identifying potential limitations of bedside testing.

METHODS: To assess oculomotor and pupillomotor responses in patients with peripheral or central AVS and healthy controls (25 participants each) at the bedside and quantitatively by use of a Pioneer research eye tracker (PRET) system and to compare the diagnostic accuracy of individual and composite responses.

EXPECTED VALUE OF THE PROJECT: The proposed project will shed more light on the value of different examination techniques in AVS for distinguishing peripheral from central causes. This is achieved by investigating oculomotor and pupillomotor parameters obtained at the bedside and quantitatively in the acute stage and at follow-up. The insights gained will likely have a direct impact on diagnostic accuracy and thus on future strategies how to evaluate acutely dizzy patients in the ED. Eventually, this may reduce the rate of misdiagnosis and may improve patients' outcome.

A chief complaint of acute vertigo or dizziness is related to about 2.1 to 7.1% of all emergency department (ED) visits, translating to about 4.3 million ED visits in the USA per year. With the differential diagnosis of patients presenting with acute or episodic vertigo / dizziness being very broad and cutting across all specialties, frontline providers and specialists may be overwhelmed by the approach to this symptom. In patients presenting to the ED with vestibular symptoms, life-threatening conditions have been identified in a single study in 23.8% of visits, with 12.5% of all visits related to cerebrovascular events. This emphasizes the need to distinguish between dangerous central and benign, self-limited peripheral vestibular disorders to avoid misdiagnosis. Patients with an acute vestibular syndrome (AVS) have acute-onset, continuous vertigo, dizziness, or unsteadiness lasting days to weeks, usually associated with vomiting, nystagmus, severe postural instability and head movement intolerance . Both patients with stroke and vestibular neuritis can present with an AVS. Approximately 25%±15% of AVS patients will be diagnosed with a stroke, usually in the posterior circulation. Established diagnostic workup in the ED include neurologic assessment, followed usually by CT-based imaging of the brain. Often neurology consultations will be ordered.

For posterior circulation strokes presenting with dizziness frontline misdiagnosis appears common, occurring in roughly 35% of cases. The desire to avoid missing a stroke often triggers brain imaging (computed tomography \[CT\] and magnetic resonance imaging including diffusion-weighted imaging \[MRI-DWI\]), laboratory workup and/or electrocardiography. Unfortunately, a recent meta-analysis found that the sensitivity of CT for central causes of dizziness was only 28.5%. Even MRI-DWI in AVS has limited sensitivity, missing about 1 out of 5 vertebrobasilar strokes presenting as an AVS when obtained within the first 24-48 hours after symptom onset. If stroke, the most common central cause of the AVS is missed or delayed, the underlying stroke mechanism goes untreated sometimes resulting in extension of the original infarct or development of a new, larger one.

The evidence base for effective bedside differentiation of inner ear diseases from stroke in patients with acute dizziness and vertigo has grown substantially over time, as emphasized recently. Although useful if present, obvious focal neurologic signs only have a sensitivity of 44% for detecting a central cause of AVS, i.e., more than 50% of strokes will be missed if one were to rely on these findings. Thus, different clinical strategies that emphasize the combined use of targeted neuro-otologic bedside examination techniques, such as the HINTS (Head Impulse, Nystagmus, Test of Skew), HINTS+ (which adds a bedside test of hearing), STANDING or gait/truncal instability (GTI) assessment have been proposed.

Both the HINTS(+) exam and the STANDING algorithm are very good exclusion tests in the hands of trained emergency physicians, non-sub-specialists and neuro-otology / neuro-ophthalmology subspecialists. Ideally, HINTS+ are combined with a graded GTI rating or the STANDING algorithm is used instead. However, absent or inadequate training in performing and interpreting subtle oculomotor findings constitute important limitations, especially in frontline providers. Most ED physicians are not yet familiar with a structured approach to the dizzy patient as e.g. outlined in the TiTrATE approach and HINTS(+) or similar bedside algorithms. While the introduction of quantitative (video oculography - VOG) HINTS to the ED seems promising, increasing the diagnostic accuracy beyond that of neuro-otology experts, this concept is far from being implemented broadly in routine emergency medicine practice.

This emphasizes the need to further improve the approach to the acutely dizzy patient now, focusing on bedside testing that can be reliably applied by untrained frontline providers including emergency physicians or neurology residents also. Brainstem and cerebellar loss of function have been demonstrated to result in dysmetric saccades and saccadic pursuit eye movements. In a previous study, vertical pursuit was saccadic significantly more often in central AVS patients than in peripheral AVS patients (88% vs. 20%, p\<0.01). In patients with (dorso)lateral medullary lesions or carotid artery dissection, pupillary abnormalities (Horner syndrome) may be noticed and in midbrain lesions an unilaterally dilated pupil (as part of a third nerve palsy) may be observed, whereas for other acute brainstem or for cerebellar lesions little is known about pupillomotor changes. Testing for both saccadic eye movements (SEM), pursuit eye movements (PEM) and pupillary responses is straight-forward and readily applicable by frontline providers.

In this proposal the investigators will address the question whether by using additional oculomotor (SEM, PEM) and pupillomotor (pupillary constriction to light) parameters at the bedside or quantitatively, the diagnostic accuracy for distinguishing peripheral from central causes in AVS can be further improved or not. This will be especially important in any setting where expertise for applying more sophisticated algorithms such as HINTS(+) or STANDING is lacking.

The risk for this study protocol is minimal (Risk Category A) due to the non-invasive nature of the measurements obtained (video-oculography, audiometry), side-effects anticipated are expected to be mild and transient only (discomfort by wearing the video-oculography device, vertigo or dizziness being more intense during the measurements, mild nausea).

The investigators do not anticipate an impact of "sex and gender" on the parameters measured, but they will assess the presence/absence of gender impact by statistical analysis.

The overriding hypothesis of this proposal is, that by using additional oculomotor (SEM, PEM) and pupillomotor (pupillary constriction to light) parameters at the bedside or quantitatively, the diagnostic accuracy for distinguishing peripheral from central causes in AVS can be further improved, especially in the setting when expertise for applying more sophisticated algorithms such as HINTS(+) or STANDING is lacking. To address this, the investigators will first collect oculomotor, pupillomotor and vestibular responses in AVS patients within the first 5 days after symptom onset, characterizing the spectrum of changes in peripheral and central causes of AVS (Aim 1). The gold standard will be brain MRI including diffusion-weighted imaging (DWI), obtained between 48 hours and 14 days after symptom onset. The investigators will compare different composite oculomotor-/pupillomotor scores to identify those scores with the highest diagnostic accuracy (Aim 2). Furthermore, comparing results retrieved when testing clinically at the bedside and quantitatively will allow the investigators to better understand if changes in SEM, PEM and pupillary responses as measured quantitatively will also be perceived by the examiner at the bedside (Aim 3). This will be critical to judge the value and thus the priority for testing these parameters at the bedside.

Eligibility Criteria:
Inclusion Criteria:

* Patient groups

  * patients presenting with an AVS (peripheral or central), with symptom duration of 5 days or less
  * being able to receive brain MRI
* All groups:

  * Being able to give informed consent as documented by signature
  * Age 18 years or above

Exclusion Criteria:

* Aged less than 18 years.
* Pregnant or lactating women
* Inability or contraindications to undergo the investigated intervention (including brain MRI in the patient groups),
* Clinically significant concomitant diseases such neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease)
* Pre-existing peripheral-vestibular / central-vestibular deficits
* History of brainstem / cerebellar stroke
* Pre-existing or acute severe visual loss
* Pre-existing severe hearing loss.
* Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, aphasia.