Clinical and laboratory factors related to acute isolated vertigo or dizziness and cerebral infarction

Abstract Objective To clarify the relationship of clinical factors with isolated vertigo or dizziness of cerebrovascular origin. Methods Clinical data of patients admitted in East Hospital from Jan. 2015 to Apr. 2016, whose complaint were acute vertigo or dizziness were retrospectively collected. All patients arrived at the emergency department within 24 hr of symptom onset, had no acute ischemic lesion first CT and NIHSS score of 0. Patients were divided into cerebral infarction group and noncerebral infarction group according to subsequent cerebral imaging results and clinical and laboratory factors related to cerebral infarction were analyzed. Result 51.6% of patients were female (n = 141). 46 patients (16.8%) were diagnosed with acute cerebral infarction. Baseline demographic data of the two groups was not significantly different. Univariate analysis found that history of smoking (p = 0.009), headache (p = 0.028), unsteadiness (p = 0.009), neuron specific enolase (p = 0.001), and vertebral artery abnormalities found on imaging (p = 0.009) were the significant difference between two groups. Increased neuron specific enolase (p = 0.005) and an abnormal vertebral artery (p = 0.044) were significant on multivariate analysis. Conclusions 16.8% of acute isolated vertigo or dizziness presentations were diagnosed with acute cerebral infarction. Increased serum neuron specific enolase and vertebral artery abnormalities were the strongest indicators of acute cerebral infarction.


| INTRODUC TI ON
Acute onset vertigo or dizziness is a common symptom of posterior circulation ischemia. When vertigo or dizziness occurs in isolation or is accompanied by nausea and vomiting with a lack of other symptoms or signs of neurological impairment, the presentation is often presumed to be due to a benign peripheral cause, such as vestibular neuronitis (Hotson & Baloh, 1998). In recent years, cerebrovascular disease as a cause of isolated vertigo or dizziness has gained increased attention. Norrving, Magnusson, and Hlotás (1995) described 24 patients with acute isolated vertigo, age 50-75 years, in whom cerebellar infarction was found to be the cause in 25%.
A retrospective analysis reviewed 907 case of dizziness visited in emergency department (ED) and found 37 cases (4%) were vascular origin. The vascular dizziness were associated with age >60 years old, accompanying imbalance and focal neurological deficits (Navi et al., 2012). Researches also suggested that vertebral artery hypoplasia, posterior circulation stenosis, and diabetes were correlated with stroke (Mosarrezai, Toghae, Majed, & Aloosh, 2012;Zhang et al., 2017). If a misdiagnosis occurs, patients may deteriorate resulting in permanent disability or a life-threatening course. If such patients can be accurately diagnosed at an early stage and receive proper treatment, their outcomes may significantly improve. Therefore, we conducted a single-center retrospective analysis of patients with isolated vertigo or dizziness to determine the factors related to a cerebrovascular etiology.

| Subjects
We retrospectively collected data of patients with isolated vertigo or dizziness who were hospitalized in the neurology department of East Hospital from January, 2015 to April, 2016.Vertigo and dizziness were defined in accordance with the International Classification of Vestibular Disorders (Bisdorff, Von Brevern, Lempert, & Newman-Toker, 2009). "Vertigo" is the sensation of self-motion when no selfmotion is occurring or the sensation of distorted self-motion during an otherwise normal head movement. "Dizziness" is the sensation of disturbed or impaired spatial orientation without a false or distorted sense of motion. Patients' first neurological deficits were measured by a senior neurologist using the National Institutes of health Stroke Scale (NIHSS) in the ED. The study was approved by the Ethics Committee of East Hospital and the informed consent was obtained from the patients.

| Inclusion criteria
(a) Age ≥18 years; (b) Acute onset vertigo or dizziness accompanied by nausea, headache, and unsteadiness; (c) The interval between symptoms onset and first visit of ED was ≤24 hr;(d) The first NIHSS score was 0 as assessed by a neurologist; (e) The first cerebral CT showed no acute ischemic lesion and subsequent cerebral MRI or repeat CT confirming a diagnosis of acute cerebral infarction.

| Exclusion criteria
(a) First NIHSS score ≥ 1, including score for limb ataxia; (b) Dizziness caused by systemic diseases such as cardiac insufficiency, fever, and hypoglycemia; (c) The interval between onset of symptoms and first ED attendance>24 hr.

| Data collection
We collected data including the patient's age, gender, interval between onset and first visit to the ED; past medical history, nature of dizziness -persistent or paroxysmal, and associated symptoms, presence of nystagmus, first assessment of blood pressure; and first laboratory examination results including neuron specific enolase (NSE) within 48 hr of symptom onset. Serum NSE level is determined by electrochemiluminescence immunoassay and reported automatically, which can be done within 18 min.

| Statistical method
Statistical analysis was conducted with SPSS 20.0. Chi-square analysis, t-test and Mann-Whitney test were performed for univariate analysis. Cerebral infarction confirmed by MRI/CT was used as the dependent variable, factors with p < 0.05 on univariate analysis and gender, age were used as co-variables to assess in a multivariate logistic regression model. A p < 0.05 was deemed statistically significant.

| RE SULTS
During the study period, there were 353 patients hospitalized with vertigo or dizziness, 80 patients were excluded and 273 patients were included in the final analysis, details showed in study flow chart ( Figure 1). The mean age was 67.1 ± 12.0 years and 141 cases were female (51.6%).46 patients were diagnosed with acute cerebral infarction through cerebral imaging (16.8%, 45 cases with MRI and 1 case with repeat CT).The smoking history was significantly higher in the cerebral infarction group (37% vs. 19.4%, p < 0.05). There was no statistically significant difference between the two groups regarding other baseline characteristics (Table 1).
Among the 46 patients with acute cerebral infarction, seven patients progressed resulting NIHSS ≥1 within 24 hr. The average time from ED presentation to deterioration was 5 hr. 10 patients had 2 or more regions of acute infarction. The lesions involved the posterior circulation in 42 patients including the cerebellum (n = 25), thalamus (n = 9), occipital lobe (n = 8), and brainstem (n = 7). Four patients were anterior circulation territory infarction including the frontal lobe, corpus callosum, and centrum semiovale (Figures 2,3 and 4).
The frequency of headache when comparing cerebral infarction with noninfarction patients was 8.7% vs. 1.8% ( p < 0.05). The proportion of patients with symptoms of unsteadiness was also higher in the cerebral infarction group(37% vs. 19.4%, p < 0.05). Other accompanying symptoms and signs did not significantly differ between the two groups (p > 0.05) ( Table 2).

| D ISCUSS I ON
Isolated vertigo or dizziness is a common clinical symptom. A German study reported that 5% of adults experience symptoms of vertigo each year, of whom 80% consult a doctor (Neuhauser et al., 2005). A singlecenter study found that 11% of ED visits related to complaints of vertigo or dizziness (Lammers et al., 2011 acutely to ED with isolated vertigo or dizziness. The higher percentage found in our study may be due to differences in selection criteria.
Within our cohort, 91% of acute cerebral infarctions were located in the posterior circulation, most commonly the cerebellum.
We also found four patients with infarction of the anterior circulation. It is postulated in these cases, that the lesions affected multisensory vestibular cortical networks involved in perceptive function, such as the thalamus, temporoparietal cortex, and peninsula adjacent to the inferior frontal gyrus (Dieterich & Brandt, 2008  It is not uncommon for patients with acute vestibular symptoms due to stroke to be either initially misdiagnosed with peripheral vestibular disease or have a delay in definitive diagnosis (Calic, Cappelen-Smith, Anderson, Xuan, & Cordato, 2016). Moreover, DWI is associated with false negative results when performed very early, especially for posterior circulation infarction (Zuo et al., 2015). For these reasons, identification of factors that may indicate which patients have isolated vertigo or dizziness caused by cerebral infarction is clinically important.
We found smoking history, headache, unsteadiness were different between cerebral infarction group and noncerebral infarction group. Other vascular risk factors including atrial fibrillation were not associated with acute cerebral infarction. Recent research showed patients with vertigo had a 3.01 times higher risk for stroke than the control group. And patients with more than three risk factors had a 5.51-fold higher risk for stroke (Lee et al., 2011). The results of patients with vascular risk factors in this article were quite different from our study probably because of different concerns and inclusion criteria. Compared with the anterior circulation, posterior circulation infarction is more commonly accompanied with headache (Mitsias, Ramadan, Levine, Schultz, & Welch, 2006), which may be diffuse or localized to the occipital scalp (Kumral, Bogousslavsky, Van Melle, Regli, & Pierre, 1995).
Other studies have found that the majority of patients with vertigo due to cerebellar infarction report accompanying imbalance (Lee et al., 2006). However, the smoking history, symptoms of headache and unsteadiness showed no significant association of cerebral infarction in regression analysis of our study.

TA B L E 2 Symptoms and signs of the patients with acute vertigo or dizziness
We found an elevated NSE (>11.85 ng/ml)was associated with cerebral infarction in patients with acute vertigo or dizziness. NSE is located in cytoplasm of nerve cells or neuroendocrine cells, and it is released into blood and cerebrospinal fluid (CSF) when brain tissue is damaged (Isgrò, Bottoni, & Scatena, 2015). Animal experiments have verified that plasma NSE begins rising within 2 hr of ischemia, and continues for 2.5 days (Barone et al., 1993). Stevens, Jakobs, de Jager, Cunningham, and Korf (1999) observed that in 19 patients with acute cerebral embolism, serum NSE levels increased within 4 hr of the attack. Gruener, Gross, Gozlan, and Barak (1994) found that NSE levels in blood and CSF of patients with acute stroke reached peak values after 7 days. Increased levels of NSE have also been reported in a variety of other neurological disorders including Guillain-Barré syndrome and cerebral trauma as well as specific neuroendocrine tumors (Isgrò et al., 2015). Our study findings suggest that an elevated NSE may be a useful indicator of a diagnosis of stroke in patients with acute isolated vertigo or dizziness.
Hypoplasia of the vertebral artery refers to an artery diameter of ≤2 mm. Hypoplasia and arteriosclerosis stenosis of the vertebral artery are commonly associated with ischemic stroke, especially accompanied with other risk factors (Katsanos, Kosmidou, & Kyritsis, 2013;Park, Kim, & Roh, 2007;Zhang et al., 2017). In our study, 65.2% of patients with acute vertigo or dizziness due to cerebral infarction had vertebral artery abnormalities, which was significantly higher than that found in the noninfarction group.
There is literature showing that an increase of blood leukocytes is related to severity of cerebral infarction  and if vertigo patients have accompanying systolic blood pressures >160 mmHg, it is more likely to be of central origin (Okada, Nakagawa, & Inokuchi, 2012). In this study, univariate analysis for the patients' white blood cell counts and first systolic blood pressures were not associated with cerebral infarction. The lack of significance in our study may relate to patient inclusion criteria.
Finally, the head impulse-nystagmus-test of skew (HINTS) examination is a bedside method used to differentiate peripheral from central vertigo. The presence of a normal horizontal head impulse test, direction-changing nystagmus or skew deviation were highly indicative of a stroke with 100% sensitivity and 96% specificity (Kattah, Talkad, Wang, Hsieh, & Newman-Toker, 2009).However, Kim, Park, Kim, and Kim (2015) proposed that positive results from a head impulse test may occur in central vestibular lesions. Among patients in the present study, more than half reported persistent vertigo, so it was difficult completing a bed-side HINT assessment in ED for most of these subjects. Future use of video-assisted vestibular Limitations of the present study included its retrospective singlecenter design and analysis only of patients hospitalized for isolated vertigo or dizziness. Future, prospective studies with a large sample size are warranted to confirm our findings.

| CON CLUS ION
In this study, 16.8% of patients hospitalized with acute isolated vertigo or dizziness had underlying acute cerebral infarction. An increased NSE and abnormal CTA/MRA imaging of the vertebral artery may be markers of acute cerebral infarction in patients presenting to the ED with acute isolated vertigo or dizziness. Prospective studies are warranted to evaluate whether NSE is an early biomarker of cerebral infarction in acute vertigo or dizziness.

ACK N OWLED G M ENT
The authors thank all physicians and patients who participated in this study.

CO N FLI C T O F I NTE R E S T S
The authors declare no financial or other conflicts of interest.