BACKGROUND:Although new preventive treatments for migraine have emerged, it remains essential to validate the efficacy of established drugs to ensure broader therapeutic options for migraine and, in particular, for vestibular migraine where clinical evidence is more limited. This study aimed to assess the therapeutic effectiveness of nimodipine, an L-type calcium channel blocker, in patients with migraine and vestibular migraine, with reference to outcomes observed with topiramate. METHODS:Using a prospective open-label study involving nine referral-based university hospitals in South Korea, we recruited 850 patients (81% women, mean age ± SD = 41 ± 12) with migraine, including 255 with vestibular migraine. The primary outcome was the change in headache days over three months. The secondary outcomes included changes in pain rating scale, Migraine Disability Assessment Scale (MIDAS) and Headache Impact Test-6 (HIT-6). The outcomes of vestibular migraine included dizziness days and intensity, Dizziness Handicap Inventory, and UCLA-Dizziness Questionnaire. RESULTS:Of the 850 patients, 465 (55%) completed three months of evaluation (205 in the nimodipine group, 160 in the topiramate group, and 100 in the combination group). All groups showed a significant reduction in the headache days (1.2-2 days/week, p < 0.001) without inter-group differences (p = 0.865). The topiramate group showed greater improvements in MIDAS and HIT-6 scores than the nimodipine (p = 0.004) and combination groups (p = 0.040). For vestibular migraine (n = 131), all groups improved in headache and dizziness outcomes (p < 0.001) without inter-group differences. Adverse events leading to study discontinuation were observed only in 14 (2%) patients without a difference among the groups. CONCLUSION:Nimodipine was associated with improvements in headache-related outcomes in migraine and in both headache- and dizziness-related outcomes in vestibular migraine. Given the observed improvements and favorable tolerability, nimodipine may be a valuable treatment option for migraine and vestibular migrain. Trial registration cris.nih.go.kr (KCT0010555).

Positional vertigo and nystagmus may occur when inputs from the semicircular canals and otolithic organs are mismatched, and when this mismatch originates from central dysfunction it is called central positional vertigo and nystagmus (CPVN). Therefore, the velocity-storage (VS) circuit, which computes composite estimates of rotational velocity, gravity orientation, and inertial acceleration from peripheral vestibular signals, underlies the generation of CPVN. In this review, we begin by detailing the VS circuit via a deterministic model that demonstrates how it estimates rotational velocity, gravity orientation, and inertial acceleration. Given the hierarchical and reciprocal information processing within the VS circuit, an error at any stage can propagate and cause subsequent errors. For example, a false rotational estimate can cascade into other estimates, such as gravity orientation and inertial acceleration. Hence, the VS model provides a unified framework for explaining CPVN resulting from central lesions. We then synthesize clinical observations of CPVN to date, classifying them into two temporal forms—paroxysmal and persistent—and provide mechanistic explanations: paroxysmal CPVN is driven by exaggerated post-rotatory rebound, whereas persistent CPVN results from a head-fixed gravity bias. These mechanisms are corroborated by deterministic VS model simulations, in which mechanism-based lesions within the VS circuit faithfully reproduce the paroxysmal and persistent CPVN features observed in patients. Furthermore, by extending the VS model, we show how an adaptive loop in the VS integrator accounts for the positional modulation of periodic alternating nystagmus, and how a conditional (orientation-dependent) error in gravity estimation explains the recently described periodic downbeat nystagmus in the supine position. By capturing the broad clinical spectrum of CPVN and reproducing it with the VS circuit model, we provide key insights for accurately diagnosing central dysfunction in positional vertigo and nystagmus and present a comprehensive pathophysiological framework for CPVN.

Although peripheral vestibular disorders account for the most cases of dizziness or vertigo, approximately 11-15% of patients have central vestibulopathy. This remains a diagnostic challenge for neurotologists, as it can present with acute vestibular syndrome (AVS) in isolation without other obvious neurologic deficits. Despite advances in modern neuroimaging, false-negative results still occur in up to 20% of cases, further complicating the differential diagnosis. Therefore, recognition of the characteristic neurotologic signs associated with each central neural structure is important for the early detection and proper management of central AVS. In this review, we discuss the typical neurotologic findings related to the underlying neural substrates of the brainstem and cerebellum.

BACKGROUND AND PURPOSE:Episodic ataxia type 2 (EA2) is characterized by episodes of vertigo and ataxia due to mutations in CACNA1A that encodes the α1A subunit of the P/Q-type voltage-gated calcium channel. This study aimed to identify neural correlates of cognitive dysfunction in EA2 by investigating brain atrophy in these patients and determining the relationships between regional brain volumes and intellectual dysfunction. METHODS:We recruited 12 patients with EA2 (including 6 males; age=30.5±14.3 years, mean±standard deviation) in 3 university hospitals of South Korea from 2019 to 2023. Regional brain volumes were quantified using voxel-based morphometry and the brainstem-structures feature of FreeSurfer. The results were compared with those for healthy controls. The relationships between regional gray-matter volumes (GMVs) and cognitive function were assessed using voxel-wise multiple regression analyses within the general linear model framework. RESULTS:Brain volumetry revealed a significant decrease in cerebellar volumes, particularly in the vermis (lobules IV, V, and VIII), bilateral flocculi (lobule X), and brainstem. The Full-Scale Intelligence Quotient was positively correlated with the GMVs in the left parahippocampal gyrus, right caudate nucleus, and right cerebellar crus II; the Verbal Comprehension Index was correlated with the GMVs in the bilateral cerebellar crura I and II; and the Processing Speed Index was correlated with the GMV in the right parahippocampal gyrus. CONCLUSIONS:Volumetric analyses revealed brain atrophy in patients with EA2 that was correlated with the clinical features observed in this disorder. These findings may further expand the imaging spectrum of disorders associated with CACNA1A mutations, although the identified correlations need to be interpreted with caution.

Antibodies against glutamic acid decarboxylase (GAD) are associated with various neurological syndromes including cerebellar ataxia and ocular motor abnormalities. We report a 67-year-old man with progressive dizziness and imbalance, who exhibited spontaneous downbeat and torsional nystagmus, normal vertical saccades, and a unilateral loss of torsional saccades during head tilting. Serum anti-GAD antibody was elevated. Tests for other autoantibodies and genes responsible for spinocerebellar ataxia were negative. Brain MRI showed cerebellar vermis atrophy The selective deficit of ipsiversive torsional saccades, with preserved vertical saccades, implicates involvement of the unilateral rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) that generates torsional and vertical saccades. This case highlights a novel ocular motor finding in anti-GAD antibody-associated ataxia and expands the spectrum of eye movement abnormalities related to midbrain and cerebellar dysfunction.

OBJECTIVE:Downbeat nystagmus varies with head position, a phenomenon termed gravity-dependent modulation. We aimed to clarify its mechanism using a velocity-storage model. METHODS:In 10 patients with downbeat nystagmus due to cerebellar disorders, we recorded eye movements at different pitch- and roll-axis head positions. Sine-wave fitting of the nystagmus intensity as a function of head position decomposed the slow-phase velocity of nystagmus into a gravity-dependent component-the amplitude and phase shift of the sine-wave term-and a gravity-independent constant offset. To probe mechanisms, we applied a velocity-storage model simulating the estimation of rotational velocity, gravity orientation, and inertial acceleration, and incorporated a gravity-estimator lesion that produced a gravity-estimation bias. RESULTS:The gravity-dependent component during pitch-axis modulation had a median amplitude of 3.8°/s (interquartile range [IQR] = 2.6) and a phase shift of 158.5° (57.9). During roll-axis modulation, it had an amplitude of 2.1°/s (1.5) and a phase shift of -0.9° (147.6), with two subgroups showing phase shifts near ±90°. The amplitude was significantly larger during pitch- than roll-axis modulation (p < 0.05). The lesion model generated persistent rotational cues that modulated downbeat nystagmus intensity as observed in the patients and additionally explained the interindividual variation in phase shifts and the weaker modulation of downbeat nystagmus during head roll. INTERPRETATION:These findings refine our understanding of cerebellar vestibular processing and provide a computational framework for positional modulation of downbeat nystagmus. The concept of a biased gravity estimate may further account for several clinical phenomena, including atypical patterns of positional nystagmus.

BACKGROUND AND PURPOSE:Otoliths degenerate with aging, but the underlying factors are not well understood. We aimed to identify risk factors associated with otolith function in patients with dizziness and vertigo. METHODS:This cross-sectional study analyzed 624 patients with benign paroxysmal positional vertigo, benign recurrent vertigo, or persistent postural-perceptual dizziness who presented at a tertiary referral center between March 2017 and July 2021. Otolith function was assessed using summated amplitudes of cervical and ocular vestibular evoked myogenic potentials (SA-cVEMPs and SA-oVEMPs). The relationships between otolith function and potential risk factors were analyzed using two types of generalized linear model: a zero-adjusted gamma model for SA-cVEMPs and a standard gamma model for SA-oVEMPs. RESULTS:In the multivariable model, SA-cVEMP was negatively associated with age (β=-0.012, effect=-1.23%), female sex (β=-0.110, effect=-10.42%), and free thyroxine (β=-0.298, effect=-25.74%), and positively associated with high-density lipoprotein cholesterol (β=0.005, effect=0.46%). SA-oVEMP was negatively associated with age (β=-0.008, effect=-0.84%) and positively associated with female sex (β=0.141, effect=15.19%). CONCLUSIONS:The findings of this study suggest that various systemic factors beyond age and sex are related to otolith function via effects on the microvasculature and structural constituents. These findings provide new insights into potential mechanisms of otolith degeneration and highlight the impact of systemic factors on otolith function.

IntroductionApart from conventional head-impulse tests (i.e., passive HITs), patency of the vestibulo-ocular reflex (VOR) can also be evaluated through self-generated HITs (i.e., active HITs). We aimed to evaluate the usefulness of active (self-generated) HITs in patients with acute unilateral vestibulopathy/vestibular neuritis (AUVP/VN) during the acute stages.MethodsWe prospectively recruited 24 patients with AUVP/VN and 30 healthy participants from January 2019 to June 2026. All subjects underwent passive as well as active HITs. We compared the latency and amplitude of corrective saccades during active and passive HITs.ResultsDuring active HITs, patients with AUVP/VN exhibited shorter latency (p < 0.001) and larger amplitude (p < 0.001) of their 1st corrective saccade compared with healthy participants. The latency of 1st corrective saccades during active HITs showed a positive correlation (p < 0.001), whereas the amplitude showed a negative correlation (p < 0.001) with the VOR gain during passive HITs. To differentiate patients with AUVP/VN from healthy participants, the sensitivity and specificity were 83.3 and 86.4%, respectively, at a cut-off latency of 242 ms for the 1st corrective saccade during active HITs with an area-under-the-curve (AUC) of 0.907. The sensitivity was 91.7% and the specificity was 93.3% at a cut-off value of 8.15° for amplitude of 1st corrective saccades, with an AUC of 0.971.DiscussionDetection of short-latency (≤ 242 ms) and large (≥ 8.15°) corrective saccades may help identify AUVP/VN during active HITs. Active HITs may provide complementary information for detecting acute unilateral vestibular hypofunction, although further validation is warranted.

BackgroundBenign paroxysmal positional vertigo (BPPV) is the most common peripheral vestibular disorder, and its prevalence is substantial. While primary BPPV has been well studied, the understanding of secondary BPPV is still limited.ObjectiveTo investigate the prevalence and clinical characteristics of secondary BPPV in a national multicenter retrospective analysis.MethodsThe study involved a retrospective analysis of medical records from 17 institutions across South Korea, between January and June 2022. We evaluated clinical features, presumed etiologies, involvement of semicircular canals, response to canalith repositioning procedures (CRPs), presence of residual dizziness, recurrence, and results of auditory and vestibular function tests for both primary and secondary BPPV cases.ResultsOf the total 1363 BPPV cases, 14.5% (198 patients) were categorized as secondary BPPV. The most prevalent etiology for secondary BPPV was head trauma. Secondary BPPV was associated with a higher prevalence of comorbidities including diabetes and inner ear diseases. Patients with secondary BPPV demonstrated more frequent involvement of multiple semicircular canals, necessitated a greater number of CRPs for resolution, and experienced a higher incidence of residual dizziness compared to primary BPPV cases. Furthermore, secondary BPPV patients exhibited more frequent abnormalities in auditory and vestibular function tests.ConclusionsSecondary BPPV accounts for a significant proportion of BPPV cases, with distinct clinical characteristics compared to primary BPPV.

BACKGROUND:Benign paroxysmal positional vertigo (BPPV) is by far the most frequent cause of positional nystagmus (PN). However, PN may also be encountered in central lesions. In this case report we describe a patient with isolated positional vertigo and central PN which mimicked a lateral-canal cupulithiasis, including initial response to liberation maneuvers. CASE DESCRIPTION:A 44-year-old male patient reported new-onset position-dependent vertigo with nausea and gait-imbalance for 10 days. During supine roll testing for the lateral semicircular canals, he showed a persistent apogeotropic PN (being more intense left-ear-down) accompanied by moderate vertigo. Except for the PN, the neurologic examination was normal. He received a diagnosis of a apogeotropic-variant right-lateral canal BPPV and responded well to a Gufoni maneuver (nose-up). However, on follow-up, apogeotropic PN showed-up again, converted into a geotropic variant after a Barbecue-liberation maneuver, and then disappeared. Due to the re-emergence of the initial PN on the second follow-up consult, a brain-MRI was requested, disclosing disseminated infra- and supratentorial cystic brain metastases. The largest mass compressed midline cerebellar structures. Urgent surgical resection revealed a histopathologic diagnosis of an adeno-carcinoma of the lung. DISCUSSION:Short-lasting responses to liberation maneuvers may also be seen in CPN, mimicking the response-pattern expected in BPPV cases. Thus, response to treatment must be validated on a follow-up consultation. Pressure by a cystic cerebellar mass lesion on the nodulus and uvula that varies with changing head-position relative to gravity, resulting in adaptational changes in PN direction and intensity could explain our findings.

Background and PurposePrevious studies on benign paroxysmal positional vertigo (BPPV) have primarily been performed in referral-based clinics. This study aimed to explore the clinical characteristics of BPPV and its variant (light cupula) in a primary care setting.MethodsWe retrospectively analyzed the clinical data of 1126 patients who visited a primary care neurology clinic due to dizziness or vertigo between March 2023 and February 2024. We collected information on age, sex, affected ear, symptom duration at the first evaluation, BPPV subtypes (including the variant), duration of positional nystagmus (transient: <1 min vs persistent: ≥1 min), and the number of canalith repositioning procedures (CRPs) required for treatment.ResultsA total of 308 patients (27.4%) were diagnosed with BPPV or its variant. Subtypes included posterior canal (PC) type in 183 (59.4%), geotropic horizontal canal (HC) type in 73 (23.7%), apogeotropic HC type in 43 (14.0%), anterior canal type in 4 (1.3%), and mixed type in 5 (1.6%). The proportion of PC type increased with a longer duration of symptoms (p = 0.012). In multinomial regression, only the duration of positional nystagmus was significantly associated with the number of CRPs (p < 0.001), as patients with persistent nystagmus required more CRPs than those with transient nystagmus.ConclusionsIn primary care, the proportion of each subtype of BPPV and its variant differs according to symptom duration. Furthermore, patients with positional nystagmus lasting more than 1 minute tend to be more refractory to CRPs.

The vestibulo-autonomic interaction refers to the neural interplay between the vestibular and autonomic systems. In particular, the vestibular system plays an active role in adjusting blood distribution during movement and changes in posture, thereby complementing the baroreflex. This review summarizes recent clinical evidence highlighting the interaction between the vestibular and autonomic systems, including altered vestibular-evoked myogenic potentials in patients with postural orthostatic tachycardia syndrome, orthostatic hypotension, and neurodegenerative disorders. Additionally, the review introduces a model-based explanation of vestibular modulation of the autonomic system via the velocity storage mechanism. Specifically, the model demonstrates how vertigo attacks influence cardiovascular autonomic outflow by altering the estimation of gravity and inertia under pathological conditions.

Subacute progressive cerebellar ataxia poses a diagnostic challenge due to its wide-ranging etiologies and symptom overlap with acute and chronic cerebellar disorders. Prompt identification and treatment are essential to improve clinical outcomes. A 62-year-old woman presented with worsening vertigo, gait instability, and evolving neurological signs over five months, consistent with a syndrome of subacute progressive cerebellar ataxia. Despite normal findings on serial MRI and PET imaging, as well as negative serological and genetic testing, her recent history of influenza vaccination and clinical progression suggested immune-mediated cerebellitis. High-dose corticosteroid therapy resulted in marked improvement, allowing her to achieve near-complete recovery, with a final diagnosis of autoimmune cerebellar ataxia reached by exclusion. Even when imaging findings are unremarkable, it is crucial to recognize immune-mediated cerebellar ataxia in patients with progressive symptoms, particularly following potential triggers such as vaccination. Empirical corticosteroid therapy demonstrated both diagnostic and therapeutic value, facilitating recovery. Subacute cerebellar ataxia with normal imaging requires careful consideration of immune-mediated etiologies. This case demonstrates the potential benefits of corticosteroid therapy in achieving favorable outcomes, even in diagnostically challenging scenarios.

Alexander’s law states that spontaneous nystagmus increases when looking in the direction of fast-phase and decreases during gaze in slow-phase direction. Disobedience to Alexander’s law is occasionally observed in central nystagmus, but the underlying neural circuit mechanisms are poorly understood. In a retrospective analysis of 2,652 patients with posterior circulations stroke, we found a violation of Alexander’s law in one or both directions of lateral gaze in 17 patients with lesions of unilateral lateral medulla affecting the vestibular nucleus. Patients with vestibular neuritis served as a control. When Alexander’s law is violated, the time constant (Tc) was larger than that in the controls (median [interquartile range, IQR]: 14.4s [6.4–38.9] vs 9.0s [IQR 5.5–12.6], p = 0.036) while the Tc did not differ between the groups when Alexander’ law is obeyed (9.6s [3.6–16.1] vs 9.0s [5.5–12.6], p = 0.924). To test the study hypothesis that an unstable neural integrator may generate nystagmus violating Alexander’s law, we utilized the gaze-holding neural integrator model incorporating brainstem leaky neural integrator and negative velocity feedback loop via the cerebellum. The lesion-induced changes included false rotational cue, primarily attributed to central vestibular imbalance, and unstable neural integrator, examined in two ways: hyperexcitable brainstem neural integrator and paradoxical excitatory effect of Purkinje cells. With normal integrator function, the false rotational cue generated nystagmus consistent with Alexander’s law. However, both types of unstable neural integrators tested produced nystagmus that violated Alexander’s law. We propose that when the neural integrator is unstable with lesions in the brainstem neural integrator itself or the neural synapse between Purkinje cells and the brainstem vestibular nucleus, nystagmus violates Alexander’s law. The spontaneous nystagmus violating Alexander’s law may be the useful clue for identifying central vestibular syndrome.