INTRODUCTION

This review comprises two separate sections. The first, mostly by Dr Kattah, discusses the topic of transient ischemic attacks (TIA) in the differential diagnosis of vestibular disorders. The second section, mostly by Dr Bronstein, reviews the relationship between small vessel disease (SVD), balance disorders and dizziness. 

Box 1:

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THE DIAGNOSTIC CHALLENGE OF A TRANSIENT ISCHEMIC ATTACK PRESENTING AS SPONTANEOUS EPISODIC VERTIGO

This literature review section focuses on the most recent publications that pertain to recognition of vertigo as a result of TIA involving either the vestibular peripheral receptors or the central nervous system. The term TIA coined by C Miller Fisher in 1956 was characterized by “episodic transient ischemia that may last from a few seconds to several hours, the most common duration being 5 or 10 minutes”. Twenty years later, the NIH defined TIA as temporary focal neurologic deficit of vascular origin, with a rapid onset (between one to five minutes), lasting as long as 24 h. This time frame definition evolved to transient neurologic deficits caused by focal brain, spinal cord or retinal ischemia without acute infarction, and without imaging evidence of infarction, thus, the key modern TIA definition is a tissue-based versus a time-frame diagnosis. In general, the main difficulty clinicians encounter is delayed presentation after symptom resolution [1].

In 2022, the Bárány Society published the consensus document of the committee for the classification of vestibular disorders and defined diagnostic criteria for vertigo of vascular origin [2▪▪]. The document still utilized the 24-h time-frame, for the diagnosis of acute, prolonged vascular vertigo, provided it is continuous and associated with spontaneous nystagmus or truncal ataxia, in addition to other abnormal neurological findings, central HINTS, ocular motor abnormalities or an ABCD [2▪▪] score >4. This time-frame does not imply that transient vascular vertigo should last 24 h, but it adjusts its temporal profile to causes of isolated vertigo of similar duration observed in episodic Meniere's [3] or vestibular migraine [4] as defined by the Bárány Society, which may be at times difficult to differentiate from transient vascular vertigo (TVV). When patients are evaluated prior to the 24-h window, and have abnormal examination, a follow-up exam determines the final temporal syndrome classification.

A recent meta-analysis of acute vestibular syndrome (AVS), defined as acute, prolonged vertigo/dizziness accompanied by nausea, vomiting, gait imbalance, nystagmus and motion intolerance, lasting longer than 24 h, found the HINTS-plus examination performed by experienced clinicians as a strong diagnostic tool with higher diagnostic accuracy for stroke diagnosis than MRI-DWI in the first 24–48 h[5▪▪]. The Bárány Society Vascular Committee proposed additional temporal profiles: Transient vascular vertigo/dizziness in evolution, which included vertigo lasting <24 h with imaging evidence of ischemia or hemorrhage within an appropriate lesion localization. The third category probable acute vascular vertigo lasting more than three hours and pending on the 24-h syndrome classification assessment; these patient may have focal neurologic signs, truncal ataxia, central HINTS and other ocular motor abnormalities, cranio-cervical pain, and increase ABCD [2▪▪] score. The final category and the main subject of this review is probable TVV/dizziness based on significant truncal ataxia during the attack, cranio-cervical pain, high ABCD [2▪▪] score and > than 50% arterial narrowing within the vertebrobasilar system [2▪▪].

TVV represent a heterogeneous group of patients because the spontaneous resolution of the TIA related reversible ischemic penumbra cannot be easily documented, imaging of an ischemic membranous labyrinth is still not possible and these small structures are nestled in a fortress of bone. Therefore, it is only simultaneous compromise of other structures in the arterial distribution of the anterior/inferior cerebellar arteries (AICA) that can be utilized to infer labyrinthine ischemia/infarction, with few exceptions, most notably labyrinthine hemorrhage [6▪]. In addition, small strokes in AICA and PICA vascular territory may be initially false negative [5▪▪]. The recommendation from the Bárány Society consensus for the evaluation transient vascular vertigo/dizziness, suggests any vascular imaging available to demonstrate narrowing of extra and intracranial vertebrobasilar arterial vessels or cranio-cervical pain, the latter considering that vertebrobasilar arterial dissection associates with pain [7].

In addition to vascular stenosis, studies of Computed tomography Perfusion (CTP) provides detailed evaluation of cerebral blood flow (CBF). CTP of the posterior circulation may offer additional diagnostic information in TVV. In fact, a 2018 study of small cohort of TVV patients with normal MRI concluded it was a complementary tool to predict final stroke [8]. A more recent 2021 retrospective study from a single center in Lǔbeck, included patients with either an AVS or an acute imbalance syndrome (AIS) and found n = 25/610 patients meeting their inclusion criteria, namely: Time widow of 4.5 h from symptom onset, normal noncontrast CT scan and no anticoagulation. All were admitted to the stroke unit, 11 received intravenous rt-PA, and 14 did not. They performed CT angiography (CTA) and CTP in 80% of those patients undergoing thrombolysis; focal hypoperfusion was discovered in n = 7/12 (58%) [9▪▪]. This small group of patients does not allow firm conclusions, except for the fact that it is possible to investigate hypoperfusion in brainstem and cerebellum and utilize a mismatch between the ischemic penumbra and infarct core to identify tissue at risk. The final outcome of the 25 patients who underwent thrombolysis was similar to those who did not; the sample size may account for this finding. For the purpose of this review, AVS and AIS patients presenting within 4.5 h may be still in the TVV category, and if they have CTA vascular abnormalities or an abnormal CTP are eligible for thrombolysis. An additional CTP review of posterior circulation stroke found ischemic lesions of the cerebellum and occipital cortex accessible, particularly if the lesion is greater than 5 ml. This study outlines critical technical hardware and software factors necessary to perform these measures accurately. In addition, the standard measures of CBF less than 30% to define infarct core, and delayed time of regional CBF (DT < than 3 sec), and time to peak (Tmax > than 6 s) to define the ischemic penumbra used in anterior circulation stroke, have not been validated thus far in the posterior circulation [10▪▪].

In 2022, a vertebral artery ultrasound, retrospective study investigated vertebral and basilar artery anatomy, this was a single Institution, 6-year project, seeking to define the anatomical artery variant impact on the clinical findings. Additionally, the study sought to determine the prevalence of vertebral artery hypoplasia (VAH). The authors utilized the standard definition of VAH: 1. Diameter of the VA <2 mm or VA asymmetry defined as 1 mm diameter inter-arterial difference (SVAA). 2500 patients belonged in three groups: VAH, SVAA and symmetric VA. All patients underwent clinical examination, hospitalization, outcome, and brain MRI or CT scan. 80 patients had VAH, this group had the highest frequency of vertigo and greatest incidence of cerebellar stroke (10%) or SVAA (16%). These findings suggest that VAH or SVAA represent a vertigo- predisposing factor to add to the 50% arterial lumen stenosis proposed by the Bárány Society Vascular Committee. The vascular risk factors of the entire cohort were similar except only for arterial hypertension which was most common in the control group. Curiously, there was no difference in the clinical control and VAH/SVAA group outcome [11].

A 2021 comprehensive study of diagnostic pitfalls in the posterior circulation listed factors responsible for lower diagnosis of posterior circulation stroke. Potential solutions include earlier recognition by the emergency response using the BE FAST acronym: Balance, Eye, Face, Arm, Speech Test, increased awareness of the HINTS plus, ataxia, and the STANDING protocols by frontline providers, and appropriate imaging selection to address difference between anterior and posterior circulation outlined in the 1988 New England posterior circulation stroke registry. In particular, CTA, CTP and posterior circulation digital subtraction angiography (DSA) [12▪].

The recent Guideline for Reasonable and Appropriate Care in the Emergency Room (GRACE 3) addresses evidence-based approach for AVS, episodic spontaneous vertigo without trigger and triggered episodic vertigo, it recommends utilizing large vessel imaging based on moderate level of evidence for the evaluation of presumed TIA [13▪▪]. This point is concordant with the Bárány Society recommendation. Here, the future goal is to define and implement the vascular work up, which awaits future evidence-based evaluation [2▪▪].

In summary, this review explored contributions from the Bárány Society, Emergency Medicine Guidelines and Vascular/Neuro-imaging journals, in the evaluation of patients with acute TVV /AIS. A multidisciplinary group to design a clinical study with optimal vascular imaging tools that incorporates the advances outlined in this report may be successful in identifying and prevent those patients with large cerebellar stokes at risk of cerebellar ischemic edema and patients with critical stenosis of the basilar artery who require thrombolysis, thrombectomy or stenting to prevent large brainstem infarcts. Smaller brainstem infarcts may remain elusive, and identified mostly by means of serial neurological and vestibular examination, and repeat imaging when necessary.

SMALL VESSEL DISEASE

In this section we will review recent papers showing how, in early stages, cerebral small vessel disease (SVD) is involved in the emergence of chronic dizziness. Before that, we will review the more established concept that, in later stages, SVD leads to overt gait and balance disorder.

Most neurologists are familiar with SVD but a recent review by Markus and de Leeuw is an appropriate starting point [14▪▪]. The authors provide a timely appraisal of new developments, including treatments and, despite its largely negative results, it was promising to see that there are currently eight ongoing therapeutic trials for SVD. Whilst the main drive behind research in SVD is its prominent role in dementia and stroke it is encouraging to see papers dealing specifically with dizziness and imbalance.

MRI is the single most relevant tool in diagnosis and follow up of SVD and in addition to white matter hyperintensities (WMH), lacunar infarcts, cerebral microbleeds, enlarged perivascular spaces and brain atrophy are meaningful components of SVD. We are reminded of the basic histopathological components of SVD, namely arteriolosclerosis (related to ageing, hypertension and other vascular risk factors), and cerebral amyloid angiopathy, a main cause of lobar intracerebral hemorrhage, due to vascular deposits of β-amyloid. An exciting advance brought about by 7T MRI scanners is the visualization of individual perforating arteries (responsible for lacunar infarcts) and measurements of their flow characteristics which, potentially, could allow in vivo assessment of drug treatments [15▪].

Markus and de Leeuw also discuss the connection between the “glymphatic system” and the enlarged perivascular spaces seen in SVD. Perivascular spaces are important components in this brain clearing system [16▪] and fluid stagnation may be of pathogenic relevance to SVD in general and to enlarged perivascular spaces in particular. On treatment, they include the 2019 result from the SPRINT research group showing that aggressive control of BP, down to systolic values of 120mmHg, reduces the progression of both WMH and cognitive decline [17]. This important finding however poses a dilemma for neuro-otologists seeing elderly patients where orthostatic dizziness may be the only treatable condition (i.e. stopping/adjusting drugs such as alpha-blockers for prostate hyperplasia and antihypertensive medication). Although the review discusses a paper from the PRESERVE working group showing that MRI measurements of cerebral blood flow are unchanged during aggressive BP treatment [18], these measurements were only taken in the supine position. Furthermore, orthostatic BP does not seem to have been measured and dizziness was only assessed by direct questioning rather than with standardized questionnaires. The conclusion this reviewer reaches is that BP should be lowered as much as possible, because we would be slowing down SVD progression, but without inducing postural hypotension or disabling orthostatic dizziness. Easier said than done.

A similar dilemma is whether to prescribe aspirin. Although most neurologists would not prescribe it, particularly in patients with extensive SVD and microbleeds due to the risk of intracranial hemorrhage, further data are needed. The review by Markus and de Leeuw includes an older paper by Benavente et al.[19] that at least settles one related issue – that dual antiplatelet therapy (aspirin and clopidogrel) is not superior to aspirin alone for lacunar strokes which, as mentioned above, is a component of SVD.

SMALL VESSEL DISEASE AND BALANCE

Although initially it was thought that hemispheric white matter changes and SVD were an innocuous age-related occurrence, several large scale prospective studies, e.g. the LADIS, showed a clear association between MRI lesion load and clinical features such as dementia, mobility and independence [20]. Falls in particular were found to be associated with periventricular and frontal deep white matter changes [21]. Later refinements both in the field of gait analysis and quantitative imaging have allowed the field to explode. An important paper was that of de Laat et al.[22] showing that MRI DTI (fractional anisotropy) demonstrated that areas of apparently normal-looking white matter were critically involved in gait abnormalities. The genu of the corpus callosum was particularly meaningful because its fibers connect frontal areas involved in cognitive control of movement. Much of the research published in 2021–2023 adopts a similar approach, comparing MRI in patients’ groups and establishing correlations between gait features and imaging. A focused article summarized this work [23▪] and, via the paper by Cai et al.[24], continued the theme connecting cognition with gait control. As a clinician this narrative sounds right given the apraxic looks of the gait disorder in SVD. A plus from this review is the brief summary at the end of each sub-section, linking the various subcomponent of SVD with specific gait/balance abnormalities. Personally, this reviewer believes that some of these conclusions are somewhat rigid but interested readers can find the original papers thereby included. Additionally, new research shows that enlarged perivascular spaces per se are also associated with gait and balance dysfunction [25,26].

IDIOPATHIC DIZZINESS OF THE ELDERLY AND SMALL VESSEL DISEASE

The question of whether SVD is involved in the emergence of dizziness in the elderly is not new. Dizziness in the elderly is common and predisposes to falls but it is difficult to diagnose. In approximately 50% of patients a vestibular, cerebellar or cardiovascular explanation for the dizziness can be found but in the other 50% the dizziness remains unexplained or idiopathic [27]. Since the early studies with inconclusive results [28,29] recent advances in MRI and EEG processing have firmed the view that SVD does play a central role in the appearance of dizziness in the elderly. Ibitoye et al. prospectively recruited 38 patients with a median age of 77years and a well age-matched control group [30▪▪]. The patients had dizziness that could not be explained by clinical and instrumental vestibular testing, neurological and cardiovascular examination, including orthostatic blood pressure measurements. The latter is particularly important because, as clinicians know and this study confirmed, the dizziness in these patients is nonspecific and exclusively in the upright position. Of note, the patients had increased vascular risk factors but clinical examination was normal for their age. However, the detailed quantitative examination revealed subtle postural abnormalities in the dizziness group. For instance: increased number of steps during the “pull test”, reduced performance in semi-quantitative gait/mobility scales (SPPB, Berg balance scale, and timed up-and-go test), lower limb proprioceptive function with a quantitative tuning fork test and subclinical psychometric impairment. Whilst these minor findings would be overtly manifest in patients with frank leukoaraiosis, this is the first time they are reported in patients selected only for idiopathic dizziness. These features are important for diagnosis in clinical practice and, given that all findings are easily explained by the underlying micro-angiopathy, the acronym MAID (Micro-Angiopathy Induced Dizziness) can be suggested as an umbrella diagnostic term.

For the MRI analysis, Ibitoye et al.[31▪] firstly identified the white matter tracts associated with balance function. Then, a comparison between the dizzy and control groups showed that the patients had reduced FA in sections of these balance-related tracts, such as the genu of the corpus callosum (Fig. 1).

FIGURE 1: Quantitative MRI analysis in patients with idiopathic dizziness (no neuro-vestibular abnormality) and age-matched controls. In red, balance-relevant tracks, as determined by correlational analysis between fractional anisotropy and balance function. In blue, areas where balance-relevant tracts showed lower fractional anisotropy in patients with “idiopathic dizziness” than controls. In green, the standard white matter skeleton. Modified from Ibitoye et al. [29].

In a separate paper, Ibitoye et al.[30▪▪] produced the first evidence that, on adopting the upright posture, EEG postural networks in these dizzy patients are defective. Desynchronization of Alpha/Theta rhythms on standing was increased in the patients over and above the increased desynchronization due to healthy ageing – effectively indicating that when upright the brain of the idiopathic dizzy patients is “older” than that of controls. A new feature in this research was the co-registration of EEG and body sway, which allowed to establish the quantitative EEG changes brought about by periods of postural instability. Interestingly, it was the low frequency EEG rhythms (Theta and Delta) that showed statistical differences between dizzy versus control groups during periods of instability, as well as a propensity to being disrupted by SVD. Finally, both MRI and EEG analyses showed widespread reductions in brain connectivity in the dizzy patient group.

In summary, evidence continues to accrue on the role of SVD in degrading posture, gait and cognition. Recent data suggests that the dizziness frequently reported by elderly people when upright is related to early involvement of their brain postural networks by the underlying micro-angiopathy. The term Micro-Angiopathy Induce Dizziness (MAID) is proposed for this common condition.

CONCLUSION

In the first part of this paper we reviewed the closely related topics of vestibular TIAs, transient vascular vertigo and dizziness in evolution, largely as delineated by the Barany society recently published consensus paper on vascular vertigo. A new diagnostic tool, computed tomography perfusion provides detailed evaluation of cerebral blood flow and may offer additional diagnostic information in transient vascular vertigo.

In the second part of this paper, we updated our knowledge on the deleterious effects that small vessel disease has on balance and gait. In particular, we reviewed recent evidence indicating that small vessel white matter disease is a likely explanation for the hitherto idiopathic (nonvestibular) dizziness in the elderly.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

Dr Kattah and Dr Bronstein report no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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