Incidence,risk factors,and comorbidities of persistent postural-perceptual dizziness after stroke: A prospective study of 284 cases

Abstract

Objective

To explore the incidence, risk factors, and comorbidities of persistent postural-perceptual dizziness (PPPD) after stroke.

Methods

Patients with acute stroke and vestibular symptoms were enrolled prospectively and continuously. Baseline information, risk factors, imaging materials, and diagnosis were collected. PPPD, anxiety, depression, and quality of life were followed up in 6 months after stroke. Binary logistic regression was used to identify the risk factors of PPPD.

Results

In this study, 284 patients (82.0% of males) were enrolled, with a mean age of 56.33 ± 11.87 years. Thirty-five patients (12.3%) had PPPD in 6-month follow-up. Patients with PPPD had a higher proportion of clinically significant anxiety and clinically significant depression and a lower three-level five-dimension EuroQol (EQ-5D-3L) index. Binary logistic regression analysis identified medulla oblongata stroke (OR, 5.549; p < .001), cerebellar stroke in posterior inferior cerebellar artery (PICA) territory (OR, 2.449; p = .026), and clinically significant anxiety at discharge (OR, 5.030; p < .001) were significant predictors for PPPD.

Conclusions

About 12.3% of stroke patients with vestibular symptoms developed PPPD at 6 months after stroke, with a higher prevalence of psychological comorbidities and decreased quality of life. Medulla oblongata lesion, cerebellar (PICA territory) lesion, and clinically significant anxiety at discharge were independent risk factors for PPPD.

Keywords

stroke persistent postural-perceptual dizziness vestibular symptoms chronic dizziness quality of life

Introduction

Dizziness and other vestibular symptoms are prevalent symptoms of stroke, especially posterior circulation stroke, with reported prevalence rates ranging from 4% to 12.5%.^1,2 Some patients recover from dizziness quickly after stroke, while some patients may suffer from persistent dizziness for a long time.^3,4 Chronic dizziness can lead to restriction of social activity and have significantly impact on quality of life through mobility limitations, falls, and psychological comorbidities such as anxiety and depression.^5–7 There has been a lack of unified diagnostic criteria for the state of chronic dizziness for a long time. In 2017, the Barany Society proposed the term “Persistent postural-perceptual dizziness (PPPD)” to elucidate the diagnostic criteria for chronic functional dizziness disorders.⁸ PPPD mainly manifested as dizziness, imbalance, or non-rotating vertigo lasting for at least 3 months. It can originate secondary to a preceding vestibular disorder, including peripheral (e.g., benign paroxysmal positional vertigo) or central triggers (e.g., vestibular migraine or stroke).⁹ Since then, more and more studies have paid attention to this disease entity and reported its related risk factors, complications, and treatment options.

However, PPPD after stroke has not received adequate attention. Small sample size studies only described the clinical characteristics of vestibular symptoms in the acute phase of stroke.¹⁰ The factors associated with PPPD and its impact on patients have not been clearly verified. Therefore, the aim of this study is to explore the incidence, risk factors, and comorbidities of PPPD after stroke in stroke patients with vestibular symptoms.

Methods

Participants

The inpatients with acute stroke and vestibular symptoms in the Neurology Center of Beijing Tiantan Hospital Affiliated to Capital Medical University from September 2020 to September 2022 were prospectively and continuously enrolled.

Inclusion criteria were as follows: age ≥18 years old; acute cerebral infarction or cerebral hemorrhage diagnosed by magnetic resonance imaging (MRI) or computed tomography (CT); presented with vestibular symptoms after stroke; admission within 7 days after stroke onset; National Institutes of Health Stroke Scale (NIHSS) <6; pre-stroke modified Rankin Scale (mRS) <2. We enrolled patients with NIHSS <6, namely mild stroke, as we considered that that moderate to severe neurological deficits may affect the patient’s perception and evaluation of vestibular symptoms.

Exclusion criteria were as follows: subarachnoid hemorrhage, transient ischemic attack, disturbance of consciousness, severe aphasia; NIHSS ≥6 or pre-stroke mRS ≥2; clear diagnosis of severe anxiety, major depression, or mental illness; inability to complete head MRI or CT; refuse to participate in the study.

The study was approved by the Medical Ethics Committee of Beijing Tiantan Hospital, Capital Medical University.

Definitions of vestibular symtpoms and PPPD

Vestibular symptoms were defined according to the first international classification of vestibular disorders (ICVD-I) proposed by the Barany Society in 2009, including dizziness, vertigo, postural symptoms and vestibulo-visual symptoms.¹ The clinical diagnosis of PPPD refers to the diagnostic standards proposed by the Barany Society in 2017⁸:

(A) One or more symptoms of dizziness, unsteadiness, or non-spinning vertigo are present on most days for 3 months or more.

(B) Persistent symptoms occur without specific provocation, but are exacerbated by three factors:

1. Upright posture,

2. Active or passive motion without regard to direction or position, and

3. Exposure to moving visual stimuli or complex visual patterns.

(C) The disorder is precipitated by conditions that cause vertigo, unsteadiness, dizziness, or problems with balance including acute, episodic, or chronic vestibular syndromes, other neurologic or medical illnesses, or psychological distress.

(D) Symptoms cause significant distress or functional impairment.

(E) Symptoms are not better accounted for by another disease or disorder.

Data collection

Baseline data and clinical information

Collected baseline data included demographic information (gender, age), stroke risk factors (alcohol consumption, smoking, coronary heart disease, hyperlipidemia, diabetes, hypertension), history of vestibular symptoms, and pre-stroke mRS score. The type of vestibular symptoms was documented. Neurological examination was performed to evaluated NIHSS score and nystagmus. Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) were completed to measure the severity of symptoms of anxiety and/or depression at discharge. Clinically significant anxiety was considered when HAMA≥7. Clinically significant depression was considered when HAMD≥8.

Imaging data

The patients underwent head MRI and/or CT after admission. The images were analyzed independently by two professional neuroradiologists to record the type and location of the stroke. Differences between the two observers were resolved by consensus. Stroke regions were divided into posterior circulation and anterior circulation. The lesions of the posterior circulation stroke were precisely described including medulla oblongata, pons, midbrain, cerebellum, thalamus, and occipital lobe. In patients with anterior circulation stroke, we focused on parieto-insular vestibular cortex (PIVC) area, including the posterior insula and retroinsular, which play a central role in the cortical vestibular system.¹¹

Follow-up

Patients were followed up in 6 months after stroke. If the patient still had vestibular symptoms, the type and duration of vestibular symptoms were recorded to assess the diagnosis of PPPD. The mRS score was completed to assess the recovery of neurological function and a good functional outcome was defined as the score of 0–2.¹² The Dizziness Handicap Inventory (DHI) was completed to evaluate the living disability caused by vestibular symptoms. According to the standard, the total DHI index was 0–30 for mild disability, 31–60 for moderate disability, and 61–100 for severe disability.¹³ The Activities-specific Balance Confidence (ABC) scale was completed to evaluate the balance capacity. If the ABC score is lower than 67%, the risk of fall is higher.¹⁴ The severity of symptoms of anxiety and/or depression was assessed through HAMA and HAMD. The three-level five-dimension EuroQol (EQ-5D-3L) was completed to assess the quality of life. The health status was converted into the EQ-5D index based on the time trade-off (TTO) Chinese value set of EQ-5D-3L.¹⁵ The EQ-5D-3L index ranged from 0 to 1, and the higher the score, the better the quality of life.

Statistical analysis

Statistical analysis was performed using SPSS 23.0 software (IBM). Continuous variables were represented as the median (interquartile range, IQR) or the mean ± standard deviation. Comparison between groups was summarized as T-test or Mann-Whitney non-parametric test. The comparison of categorical variables was summarized as χ2 test. The risk factors of PPPD in 6 months after stroke were determined using binary logistic regression analysis. Baseline variables with p < .10 were considered independent variables. The occurrence of PPPD in 6 months after the stroke was considered the dependent variable. The OR value and 95% CI were calculated. p < .05 was considered statistically significant.

Results

Baseline characteristics

In this study, 284 patients (82.0% of males) with a mean age of 56.33 ± 11.87 years were enrolled and completed 6-months follow-up (Figure 1). The majority of the patients had cerebral infarction, accounting for 82.7% (235/284). A total of 35 patients (12.3%) was diagnosed with PPPD at 6 months after stroke. In univariate analysis, the PPPD group had a higher incidence of medulla oblongata stroke, pons stroke, cerebellar stroke in posterior inferior cerebellar artery (PICA) territory, clinically significant anxiety at discharge, clinically significant depression at discharge, and higher pre-stroke mRS scores. The PPPD group and the non-PPPD group were comparable regarding demographic information, stroke risk factors, NIHSS score, and type of vestibular symptoms (Table 1).

Figure 1.

Study flow chart.

Table 1.

Demographic and clinical characteristics between PPPD group and non-PPPD group.

Baseline characteristics	Total (n = 284)	PPPD group (n = 35)	Non-PPPD group (n = 249)	p-Value
Age, years	56.33 ± 11.87	58.77 ± 9.18	55.98 ± 12.17	.194
Male, n (%)	233 (82.0)	31 (88.6)	202 (81.1)	.282
Risk factors, n (%)
Smoking, n (%)	181 (63.7)	24 (68.6)	157 (63.1)	.525
Drinking, n (%)	164 (57.7)	19 (54.3)	145 (58.2)	.658
Hypertension, n (%)	199 (70.1)	28 (80.0)	171 (68.7)	.171
Diabetes, n (%)	88 (31.0)	15 (42.9)	73 (29.3)	.105
Hyperlipidemia, n (%)	63 (22.2)	8 (22.9)	55 (22.1)	.918
Coronary heart disease, n (%)	40 (14.1)	6 (17.1)	34 (13.7)	.604
History of anxiety and/or depression, n (%)	4 (1.4)	1 (2.9)	3 (1.2)	.411
History of vestibular symptoms, n (%)	47 (16.5)	8 (22.9)	39 (15.7)	.284
Pre-stroke mRS, median (IQR)	0 (0-0)	0 (0–1)	0 (0–0)	.080
NIHSS on admission, median (IQR)	2 (1–3)	2 (1–4)	2 (1–3)	.179
Vestibular symptoms on admission, n (%)
Vertigo, n (%)	128 (45.1)	18 (51.4)	110 (44.2)	.419
Dizziness, n (%)	201 (70.8)	22 (62.9)	179 (71.9)	.271
Vestibulo-visual symptoms, n (%)	30 (10.6)	6 (17.1)	24 (9.6)	.233
Postural symptoms, n (%)	170 (59.9)	23 (65.7)	147 (59.0)	.450
Stroke type, n (%)				.349
Cerebral infarction, n (%)	235 (82.7)	27 (77.1)	208 (83.5)	-
Cerebral hemorrhage, n (%)	49 (17.3)	8 (22.9)	41 (16.5)	-
Stroke lesion, n (%)^a
Posterior circulation, n (%)	219 (77.1)	30 (85.7)	189 (75.9)	.196
Medulla oblongata, n (%)	49 (17.3)	14 (40.0)	35 (14.1)	<.001
Pons, n (%)	76 (27.1)	5 (14.3)	71 (28.5)	.075
Midbrain, n (%)	7 (2.5)	0 (0)	7 (2.8)	.603
Cerebellar (PICA territory), n (%)	87 (30.6)	15 (42.9)	72 (28.9)	.094
Cerebellar (AICA territory), n (%)	9 (3.2)	0 (0)	9 (3.6)	.607
Cerebellar (SCA territory), n (%)	10 (3.5)	0 (0)	10 (4.0)	.617
Thalamus, n (%)	28 (9.9)	3 (8.6)	25 (10.0)	1.000
Occipital lobe, n (%)	19 (6.7)	0 (0)	19 (7.6)	.144
Anterior circulation, n (%)	55 (19.4)	4 (14.3)	50 (20.1)	.417
PIVC, n (%)	6 (2.1)	0 (0)	6 (2.4)	1.000
Posterior + anterior circulation, n (%)	10 (3.5)	0 (0)	10 (4.0)	.617
Nystagmus, n (%)	90 (31.7)	13 (37.1)	77 (30.9)	.459
Clinically significant anxiety at discharge, n (%)	52 (18.3)	14 (40.0)	38 (15.3)	<.001
Clinically significant depression at discharge, n (%)	40 (14.1)	10 (28.6)	30 (12.0)	.016

mRS: Modified Rankin Scale; IQR: interquartile range; NIHSS: National Institutes of Health Stroke Scale; PICA: posterior inferior cerebellar artery; AICA: anterior inferior cerebellar artery; SCA: superior cerebellar artery; PIVC: parieto-insular vestibular cortex.

^aSome patients had more than one lesions. Since we focused on the role of different lesions in PPPD, the location of the lesion here refers to the site where the stroke lesion involves or affected but was not necessarily limited to it.

Clinical characteristics and comorbidities of PPPD patients

In 6-month follow-up, patients with PPPD mainly manifested as dizziness (88.6%, 31/35) and postural symptoms (74.3%, 26/35). None of the patients had vertigo. PPPD group showed higher mRS scores (p < 0.001), higher DHI scores (p < 0.001) and lower EQ-5D-3L index (p < .001) than the non-PPPD group. About 45.7% (16/35) of PPPD patients had a moderate-to-severe living disability due to vestibular symptoms, and 34.3% (12/35) had a high risk of fall. The prevalence of clinically significant anxiety and clinically significant depression in patients with PPPD was found to be 48.6% (17/35) and 31.4% (11/35), respectively, which demonstrated a higher incidence compared to non-PPPD patients (p < .001) (Table 2).

Table 2.

Psychological comorbidities and quality of life between PPPD group and non-PPPD group.

	PPPD group (n = 35)	Non-PPPD group (n = 249)	p-Value
DHI score, median (IQR)	30 (19-49)	0 (0)	<.001
Mild disability, n (%)	19 (54.3)	246 (98.8)	-
Moderate disability, n (%)	10 (28.6)	1 (0.4)	-
Severe disability, n (%)	6 (17.1)	2 (0.8)	-
mRS score, median (IQR)	1 (1-2)	1 (0-1)	<.001
EQ-5D-3L index, median (IQR)	0.89 (0.82-0.96)	1.00 (1.00-1.00)	<.001
High risk of fall n (%)^a,	12 (34.3)	3 (1.20)	<.001
Clinically significant anxiety, n (%)	17 (48.6)	17 (6.8)	<.001
Clinically significant depression, n (%)	11 (31.4)	17 (6.8)	<.001

DHI: dizziness handicap inventory; mRS: Modified Rankin Scale; EQ-5D-3L: three-level five-dimension EuroQol; IQR: interquartile range.

^aThe risk of fall is high if the ABC score is lower than 67%.

Risk factors for PPPD in 6 months after stroke

Binary logistic regression analysis identified medulla oblongata stroke (OR, 5.549; 95% CI, 2.397–12.848; p < .001), cerebellar stroke in PICA territory (OR, 2.449; 95% CI, 1.110-5.403; p = .026), and clinically significant anxiety at discharge (OR, 5.030; 95% CI, 2.184-11.582; p < .001) as the independent risk factors for PPPD in 6 months after stroke (Table 3). The association remained significant after adjusting for gender and age.

Table 3.

Risk factors for PPPD in 6 months after stroke.

Risk factors	OR	95% CI	p
Medulla oblongata stroke	5.549	2.397 – 12.848	<.001
Cerebellar stroke (PICA territory)	2.449	1.110 – 5.403	.026
Clinically significant anxiety at discharge	5.030	2.184 – 11.582	<.001

PICA: posterior inferior cerebellar artery.

Discussion

The major findings of this prospective study in patients with acute mild stroke and vestibular symptoms were as follows: (1) A total of 12.3% of the patients developed PPPD in 6 months after stroke. (2) The most relevant predictors for PPPD were medulla oblongata lesion, cerebellar lesion in PICA territory, and clinically significant anxiety at discharge. (3) Patients with PPPD were more likely to be accompanied by clinically significant anxiety, clinically significant depression, high risk of fall, and decreased quality of life.

Relationship between stroke lesion and PPPD

This study showed that patients with medulla oblongata stroke or cerebellar stroke in PICA territory were more likely to have PPPD in 6 months after stroke, which was consistent with the previous case series and studies with small sample sizes.^16–19 This is possibly related to the damage of vestibular-cerebellar structures and changes in brain network connectivity after stroke. The central vestibular pathway mainly involves the vestibular nucleus, cerebellum, PIVC, and cerebral cortex,²⁰ which plays a key role in visual attention, executive control, spatial orientation, postural control, and balance.^20,21 The plasticity and reorganization of the brain after acute stroke may change the connectivity of brain networks to surrounding or related brain regions.²² For example, studies using diffusion tensor imaging (DTI) showed that the core vestibular projection to PIVC would impair after dorsolateral medulla infarction.²³ After a cerebellar stroke, the vestibular projection pathway connectivity decreased, especially between the vestibular nucleus and the ipsilateral thalamus, PIVC and the contralateral parietal lobe.²⁴ This may be the reason for the susceptibility to PPPD in patients with medulla oblongata or cerebellar stroke.

PPPD and anxiety/depression

In this study, patients with clinically significant anxiety at discharge were more likely to have PPPD in 6 months after stroke, and the PPPD group had a significantly higher ratio of clinically significant anxiety and clinically significant depression than the non-PPPD group, suggesting a close relationship between PPPD and anxiety and depression, especially anxiety.^25,26 On the one hand, dizziness is more likely to persist in patients with high anxiety following an acute vestibular event.^27–30 The high anxiety response to initial vestibular stimulation events may be a key initial pathophysiological process for the occurrence and development of persistent dizziness.²⁷ On the other hand, patients with PPPD tend to have comorbid anxiety and/or depression, leading to longer duration of symptoms and heavier subjective disability.^5,31 The relationship between PPPD and anxiety mainly attributed to the interaction between central vestibular pathways and anxiety neural networks.³² The vestibulo-anxiety brain regions include the hippocampus, anterior insular, inferior frontal gyrus, and anterior cingulate cortex.³³ Studies have suggested that patients with PPPD had reduced gray matter volume in these regions.³⁴ Compared with anxiety, the relationship between PPPD and depression has not been sufficiently studied. A study based on resting-state functional MRI found a positive correlation between Beck Depression Inventory (BDI) score and connectivity between thalamus and inferior temporal gyrus.³⁵ The role of depression in PPPD patients remains to be further investigated.

PPPD and quality of life

Patients with PPPD had higher DHI score, higher risk of fall, and lower EQ-5D-3L index at 6-months follow-up, showed significant deficits in mobility and postural balance control which resulted in decreased quality of life. This suggested that after acute mild stroke, traditional focal neurological deficits were not severe and most patients could achieve functional independence, but the existence of PPPD would affect the quality of life and psychological state of patients. Therefore, it may be important for patients with high risk of PPPD to have screening and therapies targeting anxiety, depression, and balance control.³⁶

Limitations

There are several limitations to this study. Firstly, it is a single-center study with a limited number of participants, which may not be completely representative. Secondly, due to the small sample size, the severity of PPPD was not graded to explore the clinical characteristics and risk factors of patients with different severity levels of dizziness. Finally, this article reports the occurrence of PPPD at 6 months after stroke. A longer follow-up may provide a better understanding of the development and evolution of chronic dizziness after stroke.

Conclusion

In summary, it was found that 12.3% of acute mild stroke patients with vestibular symptoms developed PPPD in 6-month follow-up. Patients with medulla oblongata stroke, cerebellar stroke in PICA territory, and clinically significant anxiety at discharge were more likely to develop PPPD. PPPD patients had a higher prevalence of psychological comorbidities (clinically significant anxiety and clinically significant depression), a high risk of fall, and decreased quality of life. The results of this study suggest that clinicians should evaluate these high-risk PPPD patients as early as possible to prevent the impact on long-term functional recovery and quality of life.

Footnotes

Acknowledgments

The authors sincerely thank the study participants, clinicians, statisticians, and coordinators who aided this study.

ORCID iDs

Jiashu Li

Yi Ju

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; 2022-I2M-C&T-B-116. This work was also supported by the Science and Technology Innovation 2030- Major Project (2022ZD0211805).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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