Acute and episodic vestibular syndromes caused by ischemic stroke: predilection sites on diffusion-weighted images

Background Although acute vestibular syndrome (AVS) and episodic vestibular syndrome (EVS) are an increasingly recognized cause of acute ischemic stroke, the predilection sites of AVS/EVS caused by acute ischemic stroke still is less known. Methods From Mar 2014 to Mar 2016 period, we used a new approach of 11thedition of the International Classification of Diseases (ICD-11) to retrospectively enrolled patients with identified AVS/EVS events caused by acute ischemic stroke in the stroke center of tertiary teaching hospital. The patients who had positive diffusion-weighted images (DWI) lesion and MRA were analyzed. Multivariable logistic regression was used to identify the risk of stroke causing AVS/EVS. Results Among 181 AVS/EVS patients with ischemic stroke, 68 (37.6%) patients with acute ischemic stroke were proved by DWI. Of them, the most frequent type was EVS (60.3%); the predilection sites of stroke was in the insular (51.7%, 15/29) in the anterior circulation artery (ACA), followed by the posterior of thalamus (28.6%, 8/28) in the posterior circulation artery (PCA). The lesion on DWI showed a median diameter of 4.0mm (range,0.6-89.4). The risk of AVS/EVS in acute ischemic stroke was found in association with large vessel stenosis/ occlusion (odds ratioOR,, 0.12; 95% confidence interval CI, 0.040-0.357), focal neurological symptom /sign (OR, 0.27; 95% CI, 0.104-0.751), and higher initial ABCD2 score (OR, 0.37; 95% CI, 0.239-0.573). Conclusions The predilection site of the AVS/EVS caused by acute ischemic stroke is in the insular. The risk of AVS/EVS was associated with a large vessel stenosis, focal neurological symptoms, and higher initial ABCD2 score.

The predilection site of the AVS/EVS caused by acute ischemic stroke is in the insular. The risk of AVS/EVS was associated with a large vessel stenosis, focal neurological symptoms, and higher initial ABCD2 score.

Background
Although acute vestibular syndrome has been described by previous studies [1,2], a new approach of the 11thedition of the International Classification of Diseases (ICD-11) is 3 divided patients with vertigo or dizziness into two key categories: a clinical syndrome of acute-onset, continuous vertigo, dizziness, or unsteadiness lasting days to weeks, and generally including features suggestive of new, ongoing vestibular system dysfunction (e.g., vomiting, nystagmus, severe postural instability) is defined as acute vestibular syndrome (AVS); while a clinical syndrome of transient vertigo, dizziness, or unsteadiness lasting seconds to hours, occasionally days, and generally including features suggestive of temporary, short-lived vestibular system dysfunction (e.g., nausea, nystagmus, sudden falls) is defined as episodic vestibular syndrome (EVS). Anatomically, at any point along the vestibular pathway from the peripheral labyrinth to the central vestibular cortex, AVS/EVS may occur. Therefore, the causes of vestibular syndrome is divided into categories which include peripheral (e.g., vestibular neuronitis, acute labyrinthitis, benign paroxysmal positional vertigo [BPPV], Menière's disease) and central causes (e.g., traumatic vestibulopathy, demyelinating disease with vestibular involvement, and strokes affecting central vestibular structures). In fact, the AVS/EVS caused by impaired central vestibular structures is known as central vestibular syndrome [1,3]. Previous studies have suggested that isolated vertigo or dizziness is a symptom of posterior circulation [4,5].
But, some studies were also found a risk of signal in anterior circulating vessel involved [6,7], and the richest vestibular pathways in human beings has been demonstrated in distinct cortical and subcartical areas of both hemispheres [8]. However, few reports have too much information about the predilection sites of central AVS/EVS. We hypothesize that AVS/EVS with positive ischemia events on diffusion-weighted images (DWI) would be more accurately represented the predisposing site of acute vestibular damage. The aims of our study were to determine whether the role of magnetic resonance imaging (MRI)-DWI combined with magnetic resonance angiography (MRA) may clarify the predilection sites of acute ischemic stroke causing AVS/EVS. 4

Study participants
We performed a retrospective observational study (from March 2014 to March 2016) that had consecutively recruited the adult patients with acute vertigo or dizziness and adapting an AVS/EVS definition, and they were underwent a MRI and has been in the neurologic ward and stroke center of Shuyang county hospital-the national three levels of hospital in Northern China. Here sits on a high prevalence zones of cerebrovascular disease [9], thus, the data we have collected may enough to be convincing. included in present study. According to a confirmation of increased signal on DWI for acute infarcts diagnosis, the study population was divided into two groups: AVS/EVS with positive DWI and negative DWI groups.

MRI protocol
MRI was performed with 1.5-T equipment (Siemens AG, Munich, Germany) in all patients.
MRI sequences included conventional T2, T1, FLAIR, and DWI on an axial view, from medulla to cortex, at 5-mm section thickness. The MRA was used for 3D-TOF imaging on axial scan, the interval was -0.6 mm, each slice thickness of 1.1 mm. the range of the brain MRA imaging included the main branches and the trunk in the anterior circulations and posterior circulations, as well as the entire Willis artery cycle.

Assessment of study patients
We referred to the Oxford community stroke project standard, the diagnosis of ischemic infarction in a vascular region of the brain is divided into two regions: anterior circulation artery (ACA) and the posterior circulation artery (PCA). Symptomatic carotid artery or vertebral basilar artery stenosis was defined as ≥50% diameter reduction of in a location of the carotid artery or vertebral basilar artery that was considered likely to be responsible for the any acute infarct or the localization of the clinical symptoms. Based on the trial of ORG 10172 in acute stroke treatment for classification of subtypes in acute ischemic stroke [10], the lesion on brain MRI-DWI is greater than 15mm in diameter as the large infarcts, whereas ≤ 15 mm in diameter as the small infarcts(lacunar infarcts).
Clinically, Isolated AVS/EVS is referred to its caused by pure vestibular structure lesion; while non isolated AVS/EVS is referred to its caused by a vestibular structure lesion and with focal neurological symptom/sign. The ABCD 2 score (age, blood pressure, clinical features, duration, and diabetes mellitus) was also calculated for each patients, which is a risk score for patients with TIA. We definited a TIA as an episode < 24 hours of neurologic dysfunction ( ABCD2>3 scores) caused by focal brain, spinal cord, or retinal ischemia, 6 without recent and new infarction.

Data Collection
The initial diagnosis of MR is determined by a highly qualified radiologist. MRI-DWI infarct diameter (mm) in each MRI slice was measured by a highly qualified neurologist, and detailed the records of each patient's number and position of lesions. The images of MRA were measured, and the location and the abnormal condition of blood vessels were registered by same highly qualified neurologist. At the same time, we also enrolled the patient's other information, including gender, age, history of hypertension, history of diabetes mellitus, atrial fibrillation or history of heart disease, drinking, smoking, clinical symptoms, ABCD 2 score, and laboratory examination. For outcome analyses, the modified Rankin Scale (mRS) score (scores range from 0 to 6, no symptoms=0, slight symptoms=1, restriction=2, slight disability=3, moderate disability=4, severe disability=4-5, death=6) follow-up information at 30-days was gathered and assessed retrospectively by a neurological specialist.

Statistical analysis
The measurement data of all patients in this study were expressed as mean plus or minus standard deviation (mean + SD), median, or percentage, and the count data were measured by t test. Multivariable logistic regression was used to determine the risk factors of stroke causing AVS/EVS. Data analysis using SPSS17.0 Version (SPSS Corporation, Chicago, IL, USA).

Results
During the study period, of 181 patients with an adapting AVS/EVS caused by ischemic events, 68 with positive DWI ischemic events (acute infarcts) and 113 negative DWI ischemic events (e.g., recent ischmic events on FLAIR, TIA, septic shock, cardiac arrhythmia) were observed by MRI and MRA ( in 98.5% and 90.3%, respectively).  (Table SI ).

Discussion
Our series of patients by brain DWI study found that 68 (37.6%) patients with AVS/EVS were caused by acute ischemic infarcts. The predilection sites of infarcts causing AVS/EVS is in the insular in the ACA, followed by posterior thalamus in the PCA. supporting that these locations have to exist a potential pathway of the central vestibular projections.
This has also been confirmed by the previous study [8].
Insular infarcts have been sporadic cases reported [6,11,12]. In our series, the acute small insular infarcts were the most frequent cause of AVS/EVS. Moreover, the majority of lesions were located in the posterior of the insular. Prior research has demonstrated that the primary central vestibular cortex is located in the insular cortex [8]. Our current DWI study showed that primary vestibular cortex may be at the posterior of the insular. This has also been confirmed by previous electrophysiological study [13].
Our observations indicated that AVS/EVS may also be caused by frontal, temporal, parietal, and occipital lobe infarcts. The cortical representation of the vestibular projections in human beings is commonly assumed to be located in distinct temporal and parietal area of the brain [14][15][16],although vestibular activation has been demonstrated in frontal lobe area [16,17]. Our current study further confirmed the above view. However, we found that the occipital cortex is also an important vestibular projections area.
Few have reported the thalamic infarcts causing AVS/EVS in the previous literature. Our series showed that thalamic infarcts causing AVS/EVS were not rare. Moreover, almost all lesions were present in the posterior thalamus. Previous study has confirmed that the posterolateral thalamus is a unique relay station for vestibular input to the cortex [18], and this has been supported by our study of DWI. Our current study showed that the posterior insular and posterolateral thalamus was two frequent locations for stroke causing AVS/EVS, suggesting that here is more likely to have a distinct vestibular pathway. Furthermore, this speculation is well-supported by evidence from other studies [18,19].
To our best acknowledge, before the MRI has not emerged, AVS/EVS is very rare to consider the problem of ACA. Our current DWI study suggests that AVS/EVS is also a symptom of anterior circulation impaired. This problem has been found by previous study [20].
According to TOAST classification standards, in our series, approximately 85% of our patients with AVS/EVS showed lacunar or small infarcts, in which the ipsilateral large vessel stenosis in the ACA was common. This finding suggests that the pathological changes with large vessel in the ACA are more likely to be associated with the pathogenesis of small vessel diseases. This point has been confirmed by a previous research [21].
Our current case series also found that all patients with AVS/EVS in the PCA were small infarcts, and having 9 patients with ipsilateral vertebral and basllar large vessel stenosis.
Although vertebral and basllar stenosis is supposed to be a high risk factor for posterior circulation TIA or minor stroke [22]. a recent study indicated that the small infarcts in the PCA is one of the mechanisms causing severe vertigo [23]. This has also been confirmed by our case series.
Moreover, multivariate regression analysis showed that there was a significantly higher risk of AVS/EVS caused by acute infarcts when associated with large vessel stenosis/occlusion, focal neurological symptom/sign, and higher initial ABCD2 score, suggesting the these risk factors may be contributed to acute infarcts causing AVS/EVS, which were reported by previous studies [21,22,24,25].
However, the limitation of our study still is conceded. First, our results confirmed that acute infarcts in the ACA or PCA causing a central AVS/EVS, but that, unfortunately, is less common the nystagmus in this series. To explain this issue there are two possible facts: the first should be that the major of superatentorial AVS/EVS patients without a nystagmus may be due to the labyrinthine and oculomotor vestibular nuelei unperceived to the pathological stimuli from superatentorial vestibular lesions; and the second that, even lesion in inferatentorial, rapid onset nystagmus may also be a transient event, therefore it did not be caught due to the rapid normalization of the ocular motor signs.
Second, acute transient vestibular syndrome (i.e. EVS) has been considered to be a common cause of TIA [4,7,24], but negative DWI may also not be fully excluded acute small infarcts [26,27]. Moreover, we have to admit that the location of standard for diagnosis of acute infarcts is only a confirmation of acute ischemic lesion with DWI. In addition, we excluded the patients who were migrainous vertigo in which this information was unavailable because of present in migrainous rather than isolated vertigo. No matter how, above conditions showed that the prevalence of AVS/EVS caused by acute infarcts might been underestimated.
In conclusion: The insular is the predilection sites leading to AVS/EVS caused by small ischemic stroke, followed by the posterior thalamus, suggesting that there is distinct vestibular pathways between the insular and the posterolateral thalamus. The risk of AVS/EVS was associated with a large vessel stenosis, focal neurological symptom/sgin, and higher ABCD 2 score.

Acknowledgment
We would like to thank everyone who contributed to the study, namely the staff of the ICU who facilitated the access to patient records and the nurses and physicians for reviewing medical records. Availability of data and materials: Please contact author for data requests

Competing interests
All authors declare that no conflicts of interest exist.

Consent for publication
Not applicable.    Risk for disabling events in the first 30 days after initial event for patients with positive DWI events had significantly higher disabling rate than patients with negative DWI events (22.1% vs.7.1% P = 0.002).

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