Single center, non-profit, prospective accuracy study, registered on clinicaltrial.org as NCT02782962, conducted on consecutive adult patients presenting with vertigo or unsteadiness as defined by the consensus document of the committee for the classification of vestibular disorders of the Bárány Society (1).

Patients were recruited from October 2015 to March 2016 in the ED of a tertiary teaching hospital in Florence, Italy, with an annual census of 130,000 patients. There was no overlap with prior published study populations. According to the study protocol, written informed consent was obtained from the patients or from their relatives for inclusion in the study. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the local ethics committee.

Consecutive adult patients presenting to the ED of the University Hospital Careggi for acute (started within 1 week) vertigo/unsteadiness were screened for the study, 24 h a day, 7 days/week during the study period. The two terms “vertigo” and “unsteadiness,” according to Bárány Society consensus (1), are described as “the sensation of self-motion when no self-motion is occurring” and as “the feeling of being unstable while seated, standing, or walking without a particular directional preference,” respectively. We decided to not include “dizziness” among the complaints leading to the inclusion of patients firstly because a similar concept does not exist in formal Italian medical terminology and also because the Bárány Society consensus warned against using the term “dizziness” that may indicate also “pure sensation of impending faint (pre-syncope), disordered thinking (mental confusion), or detachment from reality (depersonalization or derealization) when such sensation is unaccompanied by a sense of spatial disorientation.” Consequently, patients with pseudovertigo, i.e., orthostatic hypotension, anemia, hypoglycemia, electrolytic disorders, or other medical causes of dizziness, were not considered for the study (19).

Patients unable to participate (those with severe dementia, bedridden patient), unable to be followed for 3 months, with terminal disease (less than three estimated months of survival), with known cervical spine, and neck diseases to whom positioning may be dangerous or who refused to participate the study were excluded.

The attending emergency physician was blind to the results of the clinical algorithm results, determined the need for any blood tests, diagnostic imaging, therapy, admission, or period of observation or discharge from the hospital. Patients were managed independently from their inclusion in the study and from STANDING results.

The STANDING is a structured diagnostic algorithm based on previously described diagnostic signs or bedside maneuvers that we have combined into a four-step sequence (Figure 1) (19).

(1) The presence of nystagmus is assessed with Frenzel lenses in a supine position after at least 5 min of rest. When no spontaneous nystagmus is detected in primary position and in the five main gaze positions, the presence of a positional nystagmus is assessed by the Pagnini–McClure test (supine roll test) first and then by the Dix–Hallpike test (5). The presence of a positional, paroxysmal (lasting 1–2 min) nystagmus, beating on the plane of the investigated canal (counterclockwise, from the observer’s perspective, and up for posterior right canal, clockwise, from the observer’s perspective, and up for posterior left canal, horizontal for the lateral canals) is considered typical of benign positional paroxysmal vertigo.

(2) When spontaneous nystagmus is present, the direction (from the patient’s perspective) is then examined: multidirectional nystagmus, such as bidirectional gaze-evoked nystagmus (i.e., right beating nystagmus present with rightward gaze and left beating nystagmus present with leftward gaze), or vertical (up or down beating) nystagmus are considered signs of central vertigo.

(3) When there is a spontaneous nystagmus and it is horizontal and unidirectional (i.e., horizontal nystagmus beating on the same side independent of the gaze direction) the HIT is performed (13). When an acute unilateral labyrinthine lesion exists, the input from the opposite side is unopposed resulting in the eyes moving with the head, when the latter is rapidly moved toward the affected side. Immediately thereafter, a corrective eye movement (corrective “saccade”) back to the point of reference is seen. When the corrective “saccade” is present, the HIT is considered positive and it indicates a peripheral disorder, whereas a negative HIT indicates central vertigo (14). These components of the ocular-motor exam have been recently described in detail (20).

(4) At the end of nystagmus examination, all patients, and in particular those showing neither spontaneous nor positional nystagmus, are asked to stand and the gait is evaluated. When objective imbalance is present (inability to stand and walk without assistance) they are suspected to have central vertigo (20).

The real novelties of the STANDING are (a) the sequence (of the tests, i.e., the algorithm), (b) the environment (the ED), and in particular (c) who performed the algorithm: non-sub-specialists in neuro-otology.

One of six specially trained emergency physicians performed the test. The initial training consisted of a 6-h workshop, 4 h of lectures, and 2-h demonstration of STANDING on normal volunteers (five STANDING examinations). Moreover, STANDING trained physicians then performed 10 proctored examinations on ED patients and 1-month use in daily practice under the supervision of a neuro-otologist (Paolo Vannucchi or Rudi Pecci). During the study period, among all physicians working in our ED, only these six physicians have been instructed about the STANDING, and each of these physicians covered 8 h of the 24 h-duty in ED.

Immediately after the exam was done, the STANDING test results were reported on a dedicated data sheet (see Data Sheet 1 in Supplementary Material) and were not shared with the attending emergency physician. At the same time, patient data were collected anonymously in a prospectively designed database (see Data Sheet 2 in Supplementary Material). The STANDING was performed before any neuroimaging testing. The physician who performed the STANDING was blinded to the patient’s clinical data, except those detectable at the time of the STANDING evaluation.

Due to costs and internal policy, not all patients presenting to the ED for vertigo/unsteadiness were routinely studied with magnetic resonance imaging (MRI). Thus, the authors, together with the local ethics committee, established as a reference standard the performance of neuroimaging tests [computed tomography (CT) or MRI of the head] only in case of clinically suspected central disease. In addition, all patients were followed for 3 months. A complete MRI study including diffusion-weighted imaging (DWI) was performed in all cases when a central cause could not be otherwise excluded. This DWI study was performed at least 24 h after symptoms onset. Discharged patients were instructed to return the ED or to contact the neuro-otology unit in case of worsening, recurrent, or unexpected persistence of symptoms or in case of new neurological symptoms. These conditions triggered more diagnostic testing including more neuroimaging tests, as needed to ascertain the diagnosis. All included patients were followed for 3 months and were re-evaluated by the neuro-otologists (Paolo Vannucchi and Rudi Pecci) within 1 week from the index visit and again after 3 months. The following events were recorded during follow-up: death (due to any cause or due to neurological disease), an objective diagnosis of stroke, demyelinating disease, neoplasm, or other new brain disease.

The final diagnosis was established by a panel of experts consisting of an emergency physician (Stefano Grifoni), a neurologist with expertise in neuroimaging (Marco Moretti), and an experienced neuro-otologist (Rudi Pecci), based on all clinical and instrumental data collected during the 3-month follow-up, except for the STANDING results. All neuroimaging digital imaging data performed during the index visit and follow-up were reassessed. Central vertigo was diagnosed when an acute brain process (ischemic, hemorrhagic, neoplastic, and inflammatory) congruent with symptoms was detected by neuroimaging or by autopsy.

Included patients had a mean age of 58 ± 18 years (range 18–99); 59.7% were female (Table 1). Forty (11.4%) patients had a final diagnosis of central vertigo. We diagnosed central vertigo by initial head CT in 12 (30%) patients (7 tumors, 3 ischemic stroke, 1 hemorrhagic stroke, and 1 hydrocephalus), by repeat head CT within 48 h with or without contrast in 8 (20%), and by MRI in 20 (50%) patients. Patients with a final diagnosis of central vertigo were older than those without (P < 0.001) (Table 1). The prevalence of arterial hypertension together with systolic and diastolic blood pressure values measured at presentation was higher in patients with a final diagnosis of central vertigo (P < 0.01 for all). Continuous vertigo (i.e., constant vertigo lasting hours or days) was more often present among patients with central vertigo (60%) compared with those with other diagnoses (13.8%) (P < 0.01). Also the presence of an acute vestibular syndrome (25%), characterized by continuous vertigo, nausea/vomiting, and spontaneous nystagmus, was associated with central vertigo (P < 0.01) (Table 2). Conversely, the presence of positional nystagmus (53.4%) was inversely related to the presence of central vertigo (P < 0.01) (Table 2). The presence of neurological signs was highly predictive of central vertigo, but only about half of the patients with a final diagnosis of central vertigo had associated neurological signs (Table 1).

Posterior circulation ischemic stroke was the main diagnosis (67.5%) among patients with central vertigo, followed by neoplastic disease (25%) (Table 3). Benign paroxysmal positional vertigo (56.4%) represented the main diagnosis of the other group, followed by acute peripheral vestibulopathy (17.9%). This latter term includes patients with vestibular neuritis and labyrinthitis.

Nineteen patients with central vertigo did not show any additional neurological sign/symptom at the time of physical examination, including headache. Twelve (63%) patients had a final diagnosis of stroke, 10 in the vascular territory of the posterior inferior cerebellar artery (8 in the right or left cerebellar hemispheres and 2 including also the nodulus), 1 in the territory of the anterior inferior cerebellar artery, and 1 showed the dissection of the right vertebral artery without clear ischemia on the MRI. Of the other seven non-ischemic patients, one had hydrocephalus, two had demyelinating disease, two had a primary cerebral neoplasm (one of the right cerebellar hemisphere and one of the acoustic nerve, both presenting with positional nystagmus), and two patients had metastatic cerebral neoplasms (one with multiple secondary lesions, the main cerebellar, from colon cancer and one with a final diagnoses of meningeal lymphoma in a patients with an already known non-Hodgkin lymphoma).

During the 3-month follow-up two patients died, one due to cerebral metastasis and the other from basilar artery obstruction.

Test characteristics of STANDING algorithm are reported in Table 4.

Inter-rater reliability of the STANDING was tested on the first 129 consecutive patients. Each step showed excellent agreement, the third step, the HIT, showing the lowest (0.74) and the second step, the evaluation of the direction of the nystagmus, showing the highest (0.95) agreement. The agreement of the final result of the sequential algorithm was very good (0.83).

When we looked at the diagnostic accuracy of each single step, we found that the presence of and the direction of spontaneous nystagmus showed a low sensitivity for the final diagnosis of central vertigo (45 and 38%, respectively). Conversely, negative HIT and an altered equilibrium were the most sensitive findings for central vertigo. In terms of specificity, the best predictors were the presence of a bidirectional or vertical nystagmus and the inability to stand and walk autonomously.

From the diagnostic point of view, a worrisome STANDING result (i.e., the presence of at least one central finding) showed a very good overall accuracy (88%), specificity (87%), and sensitivity (95%). The derived negative (99%) and positive (48%) predictive values of the algorithm were at the top of the range of each single step thus indicating that the final result of the multistep algorithm allowed a better balance between sensitivity and specificity in respect to each single step. In particular, the very high-negative predictive value allowed us to exclude the presence of central vertigo with a high level of certainty.

As a sensitivity analysis, we calculated the diagnostic characteristics of STANDING considering the 19 patients with posterior circulation transient ischemic attack in the central vertigo group. In this case, the overall sensitivity, specificity, and NPV of STANDING were 83% (95% CI 72–91%), 87% (95% CI 85–89%), and 96% (95% CI 94–98%), respectively.

In order to assess the diagnostic power of the STANDING algorithm in clinical context, that is, the capability of STANDING to increase the diagnostic probability of a central “origin” of vertigo/unsteadiness in patients with an otherwise normal clinical examination, we compared the diagnostic accuracy obtained by ordinary physical examination with and without STANDING algorithm. The logistic regression analysis showed that beyond the typical clinical variables used to estimate the risk of central vertigo (i.e., the presence of cardiovascular risk factors, continuous vertigo, headache, and of at least one associated neurological sign), a worrisome STANDING result maintained a significant, independent association with the final diagnosis of central vertigo (OR 122, 95% CI 15–943).