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Competing Interests: The authors report no conflicts of interest.

Aims of the present article are: 1 ) assessing vestibular contribution to spatial navigation, 2 ) exploring how age, global positioning systems (GPS) use, and vestibular navigation contribute to subjective sense of direction (SOD), 3 ) evaluating vestibular navigation in patients with lesions of the vestibular-cerebellum (patients with downbeat nystagmus, DBN) that could inform on the signals carried by vestibulo-cerebellar-cortical pathways. We applied two navigation tasks on a rotating chair in the dark: return-to-start (RTS), where subjects drive the chair back to the origin after discrete angular displacement stimuli (path reversal), and complete-the-circle (CTC) where subjects drive the chair on, all the way round to origin (path completion). We examined 24 normal controls (20-83 yr), five patients with DBN (62-77 yr) and, as proof of principle, two patients with early dementia (84 and 76 yr). We found a relationship between SOD, assessed by Santa Barbara Sense of Direction Scale, and subject's age (positive), GPS use (negative), and CTC-vestibular-navigation-task (positive). Age-related decline in vestibular navigation was observed with the RTS task but not with the complex CTC task. Vestibular navigation was normal in patients with vestibulo-cerebellar dysfunction but abnormal, particularly CTC, in the demented patients. We conclude that vestibular navigation skills contribute to the build-up of our SOD. Unexpectedly, perceived SOD in the elderly is not inferior, possibly explained by increased GPS use by the young. Preserved vestibular navigation in cerebellar patients suggests that ascending vestibular-cerebellar projections carry velocity (not position) signals. The abnormalities in the cognitively impaired patients suggest that their vestibulo-spatial navigation is disrupted. NEW & NOTEWORTHY Our subjective sense-of-direction is influenced by how good we are at spatial navigation using vestibular cues. Global positioning systems (GPS) may inhibit sense of direction. Increased use of GPS by the young may explain why the elderly's sense of direction is not worse than the young's. Patients with vestibulo-cerebellar dysfunction (downbeat nystagmus syndrome) display normal vestibular navigation, suggesting that ascending vestibulo-cerebellar-cortical pathways carry velocity rather than position signals. Pilot data indicate that dementia disrupts vestibular navigation.

Objective: Horizontal semicircular canal site pathology of benign paroxysmal positional vertigo demonstrating three types of nystagmi on positional test were studied. We have attempted to design a protocol for its diagnosis and treatment., Methods: 320 patients of HSC-BPPV were subjected to two types of positional tests. Of these, patients with bilateral steady apogeotropic nysatgmus were treated with VAV modification of Semont's maneuver. Patients with unsteady or changing apo/geotropic signs were converted into steady geotropic ones by repetitive positional tests; followed by barbecue maneuver with forced prolong positioning., Results: Overall 88% of patients had a total recovery. 92% of patients with geotropic nystagmus showed no symptoms after second maneuveral sitting. 85% of patients with apogeotropic nystagmus recovered fully after third maneuveral sitting., Conclusions: Correct identification of subtypes of HSC-BPPV is based on provoked nystagmus by positional tests. After locating the site and side on the basis of nystagmic pattern, physician can apply the appropriate PRM., Level of Evidence: II a., (Copyright © 2022 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

Abstract: We report a case of pendular seesaw nystagmus caused by bitemporal hemianopia; the nystagmus disappeared while in darkness as previously described, but it also disappeared with monocular occlusion, which indicates the pivotal role of binocular vision in the pathogenesis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by North American Neuro-Ophthalmology Society.)

Objective: Cochleovestibulopathy is a distinguishable paraneoplastic phenotype. In this study, we evaluate clinical presentation, serological/cancer associations and outcomes of paraneoplastic cochleovestibulopathy., Methods: Retrospective chart review of patients with hearing impairment and/or vestibulopathy who underwent serological evaluations for paraneoplastic antibodies between January 2007 and February 2021 was performed., Results: Twenty-six patients were identified (men, n=23; median age, 45 years, range: 28-70). Biomarkers detected included: KLHL11-IgG‌ ‌(n=20,‌ ‌77% (coexisting LUZP4-IgG, n=8)),‌ ‌‌ANNA1-IgG‌ ‌ ‌(n=3,‌ ‌12%),‌ ‌amphiphysin-IgG‌‌ ‌(n=2,‌ ‌8%)‌ ‌and‌ ‌LUZP4-IgG‌‌ ‌(n=1,‌ ‌4%). Most common neoplastic association was ‌testicular‌/‌extra-testicular‌ ‌seminoma‌ ‌ (n=13,‌ ‌50%).‌‌ Hearing‌ impairment (bilateral, 62%) was ‌present‌ ‌in‌ ‌all‌ ‌patients.‌ ‌Fifteen patients (58%) had cochleovestibular dysfunction as their initial presentation before rhombencephalitis/encephalomyelitis manifestations (hearing loss, four; acute vertigo, eight; both, three). ‌Brain‌ ‌MRI‌ ‌demonstrated‌ ‌internal‌ ‌auditory‌ ‌canal‌ ‌enhancement‌ ‌in‌ ‌four ‌patients.‌ Audiometry commonly revealed severe-profound bilateral sensorineural hearing loss. Most patients ‌had‌ a refractory course ‌despite‌ ‌immunotherapy‌ ‌and/or‌ ‌cancer‌ ‌treatment‌., Conclusion: Cochleovestibulopathy commonly presents with rapidly progressive bilateral hearing loss and/or acute vertigo. However, in some patients, these symptoms present along with or following brainstem/cerebellar manifestations. KLHL11-IgG and seminoma are the most common serological and cancer associations, respectively. Recognition of this phenotype may aid in earlier diagnosis of paraneoplastic autoimmunity and associated cancer., Competing Interests: Competing interests: MBH, SDZE, AM and MJM have no competing interests to disclose. DD and SJP have a patent pending for leucine zipper 4 (LUZP4) and kelch-like protein 11 (KLHL11) as a marker for neurological autoimmunity and testicular germ cell tumours., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Oculopalatal tremor (OPT) is an acquired pathology characterized by continuous and rhythmical soft palatal movements combined with pendular nystagmus. Aside from vascular lesions, oncological masses affecting the dentatorubro-olivary pathway can impair brainstem and/or cerebellar pathways, manifesting as dyssynchronous movement. In this review, we delve into the neurophysiology of OPT along with oncological causes and treatment options based on the most recent clinical trial data. This literature review includes medication treatment data from clinical trials enrolling individuals with features of OPT, including acquired pendular nystagmus (APN). Trials were deemed eligible for inclusion in this review if one or more participants had symptoms determined by the trial authors to be caused by OPT. Trials investigating the treatment of APN secondary to a separate cause, such as multiple sclerosis, were excluded from this review. Several early treatments failed to demonstrate a benefit for patients with APN due to OPT. Trials of anticholinergic agents were largely ineffective and poorly tolerated. Botulinum toxin A demonstrated improvement in APN symptoms. Most recently, trials including memantine and gabapentin have demonstrated success with attenuation of APN. Surgical modalities such as DBS have yet to show improvement, though with only a single case report as evidence. Oculopalatal tremor is a unique manifestation of posterior fossa tumors disrupting the Guillain-Mollaret triangle. Symptom control through medication management has had limited success attributed to poor response and medication intolerance. Surgical modalities like DBS may have an emerging role in OPT treatment by targeting dyssynchronous activity in the dentatorubro-olivary pathway., (© 2021. Belgian Neurological Society.)

Background: We describe for the first time the clinical features and mechanisms of a bilateral dorsomedial pons and left thalamus infarction with seesaw nystagmus and internuclear ophthalmoplegia., Case Presentation: A 62-year-old Chinese man was hospitalized for sudden-onset dizziness, diplopia, and gait disturbance. A neurological examination revealed seesaw nystagmus and internuclear ophthalmoplegia. Magnetic resonance imaging disclosed an acute infarction confined to the bilateral dorsomedial pons and left thalamus. Subsequently, 2 weeks of antithrombotic therapy led to an improvement in his symptoms., Conclusions: This case illustrates that the acute onset of seesaw nystagmus and internuclear ophthalmoplegia accompanied by risk factors for cerebrovascular diseases are highly suggestive of brainstem infarction.

Gaze-evoked nystagmus is not rare among those who have acute balance problem and may indicate a cerebellar dysfunction that is associated with a broad spectrum of disorders. The aim of this study is to analyze optokinetic response in those patients. Eleven males and 7 females (age range: 25-60, 42.5 [9.75]) with gaze-evoked nystagmus were analyzed with optokinetic test (Micromed Inc). Nystagmus was elicited by a stimulator light spot moving across the patient's visual field at a target speed of 30 degree/second. Ten age-matched healthy participants served as controls. The gain and slow-phase velocity difference in oculomotor response from left and right stimulus was compared in patients and the control participants. One-way analysis of variance test was used for multiple variance analysis of the groups. Statistical significance was set at P < .05. Slow-phase velocity of gaze-evoked nystagmus was ranging between 6 and 19 degree/second. The mean slow-phase velocity of gaze-evoked nystagmus to the right and left was 8.1 (3.81) and 6.8 (4.67) degree/second, respectively. Optokinetic gain was out of normal limits in 10 (55.5%) patients. Comparison of mean gain difference between the patients and the normal participants was statistically significant ( P = .025). No statistical difference was found in mean slow-phase velocity difference in optokinetic nystagmus between control participants and patients ( P > .05 [.099]). An acute-onset balance problem may be associated with dysfunction of separate populations of neurons in the brainstem and cerebellum even if there is no radiological neuropathy since gaze-evoked nystagmus is a sign of neural integrator dysfunction. Patients with gaze-evoked nystagmus and optokinetic abnormalities may have disruption of cerebellar pathways and should be followed closely.

A 17-year-old girl with relapsing-remitting multiple sclerosis (MS) was referred for a 2-year history of visual blurriness. Her bedside examination was remarkable for gait unsteadiness only. Optical coherence tomography was performed as part of her workup. Unexpectedly, Spectralis© video imaging revealed left torsional nystagmus that was not apparent on bedside examination. Review of previous brain magnetic resonance images (MRI) revealed left ocular deviation, as well as a left dorsolateral medullary MS plaque, which was the cause of her torsional nystagmus. We highlight how Spectralis© scanning confocal laser ophthalmoscopy allows video imaging that can capture torsional ocular movements., (Copyright © 2019. Published by Elsevier B.V.)

β-Mannosidase is a lysosomal enzyme from the glycosyl hydrolase family 2 that cleaves the single β(1-4)-linked mannose at the nonreducing end of N-glycosylated proteins, and plays an important role in the polysaccharide degradation pathway. Mutations in the MANBA gene, which encodes the β-mannosidase, can lead to the lysosomal storage disease β-mannosidosis, as well as nystagmus, an eye condition characterized by involuntary eye movements. Here, we present the first structures of a mammalian β-mannosidase in both the apo- and mannose-bound forms. The structure is similar to previously determined β-mannosidase structures with regard to domain organization and fold, however, there are important differences that underlie substrate specificity between species. Additionally, in contrast to most other ligand-bound β-mannosidases from bacterial and fungal sources where bound sugars were in a boat-like conformation, we find the mannose in the chair conformation. Evaluation of known disease mutations in the MANBA gene provides insight into their impact on disease phenotypes. Together, these results will be important for the design of therapeutics for treating diseases caused by β-mannosidase deficiency. DATABASE: Structural data are available in the Protein Data Bank under the accession numbers 6DDT and 6DDU., (© 2018 Federation of European Biochemical Societies.)

Objective: To demonstrate characteristic nystagmus findings in acute otitis media (AOM) complicated by serous labyrinthitis and discuss the mechanism of direction-changing positional nystagmus (DCPN) in this condition., Patients: A patient with AOM complicated by serous labyrinthitis on the left side., Intervention: Video nystagmography and 3D fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI)., Main Outcome Measures: Characterize positional nystagmus in a head-roll test observing the change of nystagmus direction in process of time and compare findings of temporal bone 3D FLAIR MRI., Results: A previously healthy 50-year-old man who complained of acute otalgia, hearing loss, and vertigo was diagnosed with AOM complicated by serous labyrinthitis on the left side. A head-roll test performed on the day when vertigo developed showed persistent geotropic DCPN. While pre- and postcontrast T1-weighted MRI showed no signal abnormality in both inner ears, 10-minute delay postcontrast 3D FLAIR image showed enhancement in the inner ear on the left side. Four-hour-delay postcontrast 3D FLAIR images showed more conspicuous enhancement of the whole cochlea, vestibule, and semicircular canals on the left side., Conclusions: In AOM complicated by serous labyrinthitis, density of perilymph may increase due to direct penetration of cytokines and other inflammatory mediators from the middle ear into perilymph and breakdown of blood-labyrinth barrier that causes vascular leakage of serum albumin into perilymph. The density difference between perilymph and endolymph makes the semicircular canal gravity sensitive. A buoyant force is also generated by gravity, causing indentation of endolymphatic membrane in the ampulla and cupula displacement. Thus, at the early stage of serous labyrinthitis, a head-roll test may elicit persistent geotropic DCPN, of which the direction can be changed over time.

The diagnosis of central positional vertigo (CPV) is challenging, mainly because symptoms overlap with the common variants of benign paroxysmal positional vertigo (BPPV). Recent correlations of imaging with neurotologic exams have improved our understanding of CPV and ability differentiate it from BPPV. Yet, there is still a need to develop better diagnostic algorithms to improve timely diagnosis and early intervention. Here we present a retrospective review of the clinical characteristics, neurotologic evaluation and imaging of CPV in a cohort of 27 patients and propose a diagnostic algorithm to be tested in future prospective fashion. Most patients had positional nystagmus (downbeat and apogeotropic horizontal), cerebellar ocular motor abnormalities and truncal ataxia indicative of a central lesion. 61.5% of our cohort had paroxysmal CPV, 30.5% had a non-paroxysmal CPV and 8% paroxysmal-evolving-to-non-paroxysmal CPV. The most common pattern of positional nystagmus evoked with maneuvers was positional downbeat nystagmus (pDBN, 69.2%), apogeotropic horizontal nystagmus (42.3%), geotropic (7.69%) and multiplanar (23.0%). Notably, 13 (50%) of patients had cerebral imaging prior to CPV being on the differential diagnosis, whereas another 50% of patients had CPV diagnosis preceding their work-up. Unilateral lesions on imaging were 4× less likely to exhibit nausea and vomiting, nearly 2× less likely to exhibit paroxysmal nystagmus, and 2× less likely to exhibit nystagmus with habituality. Findings of pDBN or apogeotropic nystagmus alone were enough to diagnose CPV in 50% of our patient cohort, underscoring the importance of clinical evaluation in a time when an "imaging-first" philosophy is gaining popularity in Neurology., (© 2019 Elsevier B.V. All rights reserved.)

Individuals suffering from Tullio phenomena experience dizziness, vertigo, and reflexive eye movements (nystagmus) when exposed to seemingly benign acoustic stimuli. The most common cause is a defect in the bone enclosing the vestibular semicircular canals of the inner ear. Surgical repair often corrects the problem, but the precise mechanisms underlying Tullio phenomenon are not known. In the present work we quantified the phenomenon in an animal model of the condition by recording fluid motion in the semicircular canals and neural activity evoked by auditory-frequency stimulation. Results demonstrate short-latency phase-locked afferent neural responses, slowly developing sustained changes in neural discharge rate, and nonlinear fluid pumping in the affected semicircular canal. Experimental data compare favorably to predictions of a nonlinear computational model. Results identify the biophysical origin of Tullio phenomenon in pathological sound-evoked fluid-mechanical waves in the inner ear. Sound energy entering the inner ear at the oval window excites fluid motion at the location of the defect, giving rise to traveling waves that subsequently excite mechano-electrical transduction in the vestibular sensory organs by vibration and nonlinear fluid pumping.

Purpose: To report on a clinical and genetic investigation of a large, multigenerational South African family of mixed ancestry with autosomal dominant congenital cataracts, coloboma, and nystagmus., Methods: Ophthalmic examination was performed in 27 individuals from the same admixed South African family. DNA was sampled from either peripheral blood or buccal swabs in all 27 individuals, and whole genome sequencing was performed in six individuals. Sanger sequencing was used to validate the probable mutation in the remaining family members., Results: Twenty-seven family members with 19 affected individuals were included in the study. The predominant phenotype, with highly variable expression, was congenital cataract (14 individuals), posterior segment coloboma (17 individuals), and nystagmus (18 individuals). Other features present included high myopia, microcornea, and strabismus. An R208W mutation in PAX6 (dbSNP rs757259413; HGMD CM930572; NM&#95;000280.3:c.622G>A; NP&#95;000271.1:p.Arg208Trp) was identified as being the most probable pathogenic mutation. Cosegregation of the mutation with the phenotype was confirmed in all 27 family members., Conclusions: PAX6 is a highly conserved gene crucial for normal oculogenesis, and although mutations within the gene may cause an array of ocular developmental abnormalities, most are associated with aniridia and aniridia-related ocular defects. The observation that PAX6 aniridia phenotypes are largely associated with nonsense mutations and milder non-aniridia phenotypes with missense mutations suggested that there may be specific genotype-phenotype correlations for the gene. The R208W mutation in PAX6 identified in this family challenges this theory as it has previously been reported in three unrelated families and is associated with aniridia and non-aniridia phenotypes across the four families. PAX6 with its wide phenotypic associations and highly variable expression should be considered a candidate gene in the diagnostic screen for any ocular developmental abnormality.

Background: Benign paroxysmal positional vertigo (BPPV) is the most common vestibular disorder affecting about 20% of dizzy patients. Early diagnosis and treatment can improve the quality of life for patients., Objective: We reviewed the classifications of different subtypes of benign paroxysmal positional vertigo and the problems we encountered using the diagnostic criteria of the Bárány Society., Methods: Both the Dix-Hallpike maneuver and supine roll test were performed on 568 patients, and diagnoses were made based on patient history and the type of provoked nystagmus (if any). Next, the numbers of patients with each subtype and other parameters, including age and sex, were analyzed., Results: Posterior semicircular canal BPPV (pc-BPPV) accounted for the largest proportion, followed by horizontal semicircular canal BPPV (hc-BPPV). Both anterior canal BPPV and multiple canal lithiasis BPPV were rare, and no patient was diagnosed with cupulolithiasis of the posterior canal., Conclusions: pc-BPPV, hc-BPPV, and cupulolithiasis of the horizontal canal (hc-BPPV-cu) were the three major subtypes that could be definitively diagnosed, whereas the diagnoses of possible benign paroxysmal positional vertigo (pBPPV) and probable benign paroxysmal positional vertigo [spontaneously resolved] (pBPPVsr) require further investigation, with special attention being paid to appropriate differentiation and repositioning maneuvers.

Episodic Ataxia type 2 (EA2) is an autosomal dominant neuronal disorder linked to mutations in the Ca v 2.1 subunit of P/Q-type calcium channels. In vitro studies have established that EA2 mutations induce loss of channel activity and that EA2 mutants can exert a dominant negative effect, suppressing normal Ca v 2.1 activity through protein misfolding and trafficking defects. To date, the role of this mechanism in the disease pathogenesis is unknown because no animal model exists. To address this issue, we have generated a mouse bearing the R1497X nonsense mutation in Ca v 2.1 (Ca v 2.1 R1497X ). Phenotypic analysis of heterozygous Ca v 2.1 R1497X mice revealed ataxia associated with muscle weakness and generalized absence epilepsy. Electrophysiological studies of the cerebellar circuits in heterozygous Ca v 2.1 R1497X mice highlighted severe dysregulations in synaptic transmission of the two major excitatory inputs as well as alteration of the spontaneous activity of Purkinje cells. Moreover, these neuronal dysfunctions were associated with a strong suppression of Ca v 2.1 channel expression in the cerebellum of heterozygous Ca v 2.1 R1497X mice. Finally, the presence of Ca v 2.1 in cerebellar lipid raft microdomains was strongly impaired in heterozygous Ca v 2.1 R1497X mice. Altogether, these results reveal a pathogenic mechanism for EA2 based on a dominant negative activity of mutant channels., (Copyright © 2017. Published by Elsevier Inc.)

Purpose: Positional nystagmus is usually caused by peripheral vestibular disorder, mostly benign paroxysmal positional vertigo (BPPV). However, positional nystagmus is also encountered in central lesions. We aimed to determine clinical characteristics of the structures responsible for central positional nystagmus (CPN) associated with brain tumors., Methods: All four patients (3 men; range=19-77years) had an evaluation of spontaneous and positional nystagmus using video-oculography. Brain MRIs were performed in all patients., Results: All patients showed apogeotropic positional nystagmus during supine roll tests, and had an initial diagnosis of BPPV. Except for the positional nystagmus, findings of neurological examination were normal. Because all subjects were initially diagnosed with BPPV, canalith repositioning maneuvers were applied repeatedly but without a success. Brain MRI finally disclosed brain tumors involving the midline cerebellar structures around the fourth ventricle and the nodulus. The pathological diagnosis was hemangioblastoma in two and metastatic tumor in the others., Conclusions: An apogeotropic type of CPN may be an isolated finding in patients with a cerebellar tumor. Even in patients with isolated apogeotropic positional nystagmus, a central lesion should be sought especially when refractory to repeated canalith repositioning maneuvers., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Resting in an upright position during daytime decreases downbeat nystagmus (DBN). When measured in brightness only, that is, without intermitting exposure to darkness, it does not make a significant difference whether patients have previously rested in brightness or in darkness. In real-world scenarios, people are often exposed to brightness and darkness intermittently. The aim of this study was to analyze whether resting in brightness or resting in darkness was associated with a lower post-resting DBN after intermitting exposures to brightness and darkness. Eight patients were recorded with three-dimensional video-oculography in brightness and darkness conditions, each following two 2-h resting intervals under either brightness or darkness resting conditions. The dependent variable was DBN intensity, measured in mean slow phase velocity. A repeated measures ANOVA with the factors measurement condition (brightness vs. darkness), resting condition (brightness vs. darkness), and time (after first vs. second resting interval) showed a significant effect for the factor resting condition, where previous resting in darkness was associated with a significantly lower DBN relative to previous resting in brightness (P < 0.01). The clinical relevance is to advise patients with DBN to rest in darkness., (© 2016 New York Academy of Sciences.)

To investigate the frequency and pattern of failure of the fixation suppression (FFS) of spontaneous nystagmus (SN) in unilateral cerebellar infarction, and to identify the structure responsible for FFS, 29 patients with acute, mainly unilateral, isolated cerebellar infarction who had SN with a predominantly horizontal component were enrolled in this study. The ocular fixation index (OFI) was defined as the mean slow phase velocity (SPV) of the horizontal component of SN with fixation divided by the mean SPV of the horizontal component of SN without fixation. The OFI from age- and sex-matched patients with vestibular neuritis was calculated and used as the control data. The FFS of SN was only found in less than half (41 %, 12/29) of the patients. Approximately 65 % (n = 7) of the patients with isolated anterior inferior cerebellar artery territory cerebellar infarction showed FFS, whereas only a quarter (n = 3) of the patients with isolated posterior inferior cerebellar artery (PICA) territory cerebellar infarction showed FFS. The proportion of gaze-evoked nystagmus (6/12 [50 %] vs. 2/17 [12 %], p = 0.04) and deficient gain of ipsilesional pursuit (10/12 [83 %] vs. 6/17 [35 %], p = 0.05) was more frequent in the FFS group than in the group without FFS. Lesion subtraction analysis in isolated PICA territory cerebellar infarction revealed that the nodulus was commonly damaged in patients with FFS, compared to that of patients without FFS. Our study shows that FFS of SN due to acute cerebellar infarction is less common than previously thought and the nodulus may be an important structure for the suppression of SN in humans.

Purpose: Infantile nystagmus syndrome (INS) is often associated with abnormalities of axonal outgrowth and connectivity. To determine if this manifests in extraocular muscle innervation, specimens from children with idiopathic INS or INS and albinism were examined and compared to normal age-matched control extraocular muscles., Methods: Extraocular muscles removed during normal surgery on children with idiopathic INS or INS and albinism were immunostained for neuromuscular junctions, myofiber type, the immature form of the acetylcholine receptor, and brain-derived neurotrophic factor (BDNF) and compared to age-matched controls., Results: Muscles from both the idiopathic INS and INS and albinism groups had neuromuscular junctions that were 35% to 71% smaller based on myofiber area and myofiber perimeter than found in age-matched controls, and this was seen on both fast and slow myosin heavy chain isoform-expressing myofibers (all P < 0.015). Muscles from subjects with INS and albinism showed a 7-fold increase in neuromuscular junction numbers on fast myofibers expressing the immature gamma subunit of the acetylcholine receptor. The extraocular muscles from both INS subgroups showed a significant increase in the number and size of slow myofibers compared to age-matched controls. Brain-derived neurotrophic factor was expressed in control muscle but was virtually absent in the INS muscles., Conclusions: These studies suggest that, relative to the final common pathway, INS is not the same between different patient etiologies. It should be possible to modulate these final common pathway abnormalities, via exogenous application of appropriate drugs, with the hope that this type of treatment may reduce the involuntary oscillatory movements in these children.

Purpose: Subjects with Down syndrome (DS) have an anatomical defect within the cerebellum that may impact downstream oculomotor areas. This study characterized gaze holding and gains for smooth pursuit, saccades, and optokinetic nystagmus (OKN) in DS children with infantile nystagmus (IN)., Methods: Clinical data of 18 DS children with IN were reviewed retrospectively. Subjects with constant strabismus were excluded to remove any contribution of latent nystagmus. Gaze-holding, horizontal and vertical saccades to target steps, horizontal smooth pursuit of drifting targets, OKN in response to vertically or horizontally-oriented square wave gratings drifted at 15°/s, 30°/s, and 45°/s were recorded using binocular video-oculography. Seven subjects had additional optical coherence tomography imaging., Results: Infantile nystagmus was associated with one or more gaze-holding instabilities (GHI) in each subject. The majority of subjects had a combination of conjugate horizontal jerk with constant or exponential slow-phase velocity, asymmetric or symmetric, and either monocular or binocular pendular nystagmus. Six of seven subjects had mild (Grade 0-1) persistence of retinal layers overlying the fovea, similar to that reported in DS children without nystagmus. All subjects had abnormal gains across one or more stimulus conditions (horizontal smooth pursuit, saccades, or OKN). Saccade velocities followed the main sequence., Conclusions: Down syndrome subjects with IN show a wide range of GHI and abnormalities of conjugate eye movements. We propose that these ocular motor abnormalities result from functional abnormalities of the cerebellum and/or downstream oculomotor circuits, perhaps due to extensive miswiring.

A 76-year-old woman complained of vertigo for two years. She manifested left deafness, loss of caloric response, and right-beaten nystagmus. An imaging study revealed a tumorous lesion located from the clivus to the left temporal bone with inner ear destruction. A tumor biopsy was performed endonasally and the patient was diagnosed with adenocarcinoma mimicking breast cancer. She had undergone surgery for breast cancer 33 years previously, and the current biopsy specimen showed identical pathology. Breast cancer may metastasize to the skull base; however, metastasis 33 years after surgery is very rare.

Objectives: To describe the rationale, intraoperative details, and histopathologic findings discovered when treating an unusual case of apogeotropic horizontal canal positional vertigo with a transmastoid labyrinthectomy., Patient: A single case report., Intervention: Therapeutic., Main Outcome Measures: Resolution of apogeotropic nystagmus and improvement of positional vertigo., Results: The apogeotropic variant of horizontal canal positional vertigo can be a difficult entity to treat. This report describes a patient who developed profound sensorineural hearing loss and vertigo after an acute left labyrinthitis. Ten months later, she developed vertigo with apogeotropic positional nystagmus involving the left horizontal semicircular canal. Particle repositioning maneuvers and vestibular physical therapy were unsuccessful. In addition, she developed intermittent positional vertigo affecting the ipsilateral vertical semicircular canals. Given the persistence of her vertigo, multiple canal involvement, and patient preference for definitive treatment, a transmastoid labyrinthectomy was performed. Intraoperatively, the ampulla of the horizontal canal as well as that of the other canals was grossly abnormal as later confirmed on histology. After surgery, her apogeotropic nystagmus and vertigo resolved, and her balance ability gradually improved to a highly functional level., Conclusion: This case illustrates a unique form of positional vertigo that developed and persisted after acute labyrinthitis. Conservative measures were unsuccessful and a transmastoid labyrinthectomy documented dense inflammatory tissue involving all three ampullae. We postulate that the post-labyrinthitic inflammatory changes resulted in mass loading of the membranous ampullae, causing abnormal nystagmus patterns and positional vertigo, which resolved after the labyrinthectomy.

Genetically engineered mice are valuable models for elucidation of auditory and vestibular pathology. Our goal was to establish a comprehensive vestibular function testing system in mice using: (1) horizontal angular vestibulo-ocular reflex (hVOR) to evaluate semicircular canal function and (2) otolith-ocular reflex (OOR) to evaluate otolith organ function and to validate the system by characterizing mice with vestibular dysfunction. We used pseudo off-vertical axis rotation to induce an otolith-only stimulus using a custom-made centrifuge. For the OOR, horizontal slow-phase eye velocity and vertical eye position were evaluated as a function of acceleration. Using this system, we characterized hVOR and OOR in the caspase-3 (Casp3) mutant mice. Casp3 (-/-) mice had severely impaired hVOR gain, while Casp3 (+/-) mice had an intermediate response compared to WT mice. Evaluation of OOR revealed that at low-to-mid frequencies and stimulus intensity, Casp3 mutants and WT mice had similar responses. At higher frequencies and stimulus intensity, the Casp3 mutants displayed mildly reduced otolith organ-related responses. These findings suggest that the Casp3 gene is important for the proper function of the semicircular canals but less important for the otolith organ function.

Background: Medial longitudinal fasciculus (MLF) syndrome refers to a gaze disorder characterized by impaired adduction on the ipsilateral side to the injured MLF, with dissociated nystagmus of the contralateral abducting eye. The most common cause of the MLF syndrome is ischemic stroke. However, acute ischemic change in the MLF may be undetectable even on diffusion-weighted magnetic resonance imaging (DW-MRI) partly because of its small size and specific brainstem location., Case Report: Herein, we present the first reported case of MLF syndrome in which, compared with the standard-b-value DWI, a higher b-value DWI revealed more clearly a small infarction in the dorsal pons in the acute stage., Conclusions: We suggest that high-b-value DWI can be a useful diagnostic method for patients with MLF syndrome caused by possible brainstem ischemia and thus supportive for deciding the optimal treatment for such patients., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Purpose: Aniridia is a rare panocular disorder characterized by iris hypoplasia and other associated eye anomalies. Heterozygous null mutations in paired box gene 6 (PAX6) are the major cause of the classic aniridia phenotype. This study aims to detect the mutational spectrum of PAX6 and associated phenotypes in southern Indian patients with sporadic and familial aniridia., Methods: Genomic DNA was isolated from peripheral blood from all participants. The coding regions and flanking intronic sequences of PAX6 were screened with Sanger sequencing in 30 probands with aniridia. The identified variations were further evaluated in available family members and 150 healthy controls. The pathogenic potential of the mutations were assessed using bioinformatics tools., Results: Thirteen different mutations were detected in eight sporadic and five familial cases. Eleven novel mutations, including five insertions (c.7&#95;10dupAACA, c.567dupC, c.704dupC, c.868dupA and c.753&#95;754insTA), two deletions (c.242delC and c.249delT), and four splicing variants (c.10+1G>A, c.141G>A, c.141+4A>G and c.764A>G) were identified in this study. Clinical findings of the patients revealed phenotypic heterogeneity with the same or different mutations., Conclusions: This study reported 11 novel mutations and thus expanded the spectrum of PAX6 mutations. Interestingly, all mutations reported in this study were truncations, which confirms the hypothesis that haploinsufficiency of PAX6 causes the aniridia phenotype. Our observations revealed inter- and intrafamilial phenotypic variability with PAX6 mutations. The common ocular findings associated with PAX6 mutations were iris hypoplasia, nystagmus, and foveal hypoplasia reported in almost all cases, with cataract, glaucoma, and keratopathy reported in approximately 50% of the patients.

Objective: We investigated the neuro-otological findings, including nystagmus, and the clinical course of patients with the horizontal canal variant of benign paroxysmal positional vertigo (HC-BPPV), who showed spontaneous inversion of nystagmus without a positional change. Furthermore, we speculated on the possible mechanism of spontaneous inversion of nystagmus without a positional change., Patients and Methods: The characteristics of spontaneous inversion of positional nystagmus without a positional change were analyzed in 7 patients with HC-BPPV., Results: All patients were diagnosed as having HC-BPPV. During the positional test, the spontaneous inversion of nystagmus was observed in the same head position in all patients. Spontaneous inversion was observed on both sides in 5 patients, and only on 1 side in 2 patients. All patients presented with geotropic nystagmus in the first phase, and ageotropic nystagmus in the second phase., Conclusions: The coexistence of cupulolithiasis and canalolithiasis appears to be a possible mechanism of the spontaneous inversion of positional nystagmus.

We describe a patient with downbeat nystagmus (DBN) evoked only by eye closure. Brain and spinal cord magnetic resonance imaging revealed a T2 paramedian lesion in the left lower basis pontis and other white matter lesions consistent with multiple sclerosis. One potential mechanism for DBN in this case involves transverse ephaptic spread of excitation from areas that subserve coordinated lid closure to the decussating ventral tegmental tract.

Episodic ataxia type 2 (EA2) is an autosomal dominant disorder associated with attacks of ataxia that are typically precipitated by stress, ethanol, caffeine or exercise. EA2 is caused by loss-of-function mutations in the CACNA1A gene, which encodes the α1A subunit of the CaV2.1 voltage-gated Ca(2+) channel. To better understand the pathomechanisms of this disorder in vivo, we created the first genetic animal model of EA2 by engineering a mouse line carrying the EA2-causing c.4486T>G (p.F1406C) missense mutation in the orthologous mouse Cacna1a gene. Mice homozygous for the mutated allele exhibit a ~70% reduction in CaV2.1 current density in Purkinje cells, though surprisingly do not exhibit an overt motor phenotype. Mice hemizygous for the knockin allele (EA2/- mice) did exhibit motor dysfunction measurable by rotarod and pole test. Studies using Cre-flox conditional genetics explored the role of cerebellar Purkinje cells or cerebellar granule cells in the poor motor performance of EA2/- mice and demonstrate that manipulation of either cell type alone did not cause poor motor performance. Thus, it is possible that subtle dysfunction arising from multiple cell types is necessary for the expression of certain ataxia syndromes., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We describe a patient with dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease) who presented with an acute onset of positional disequilibrium. Video-oculography in the right Hallpike position revealed rightward torsional down-beat nystagmus, initially thought to be right anterior canal benign positional vertigo. However, the presence of spontaneous nystagmus, the persistent character of the positional nystagmus and the absence of fatigability indicated central positional nystagmus, attributable to his right-sided Lhermitte-Duclos disease. These findings emphasise the need for clinicians to reconsider a central cause before diagnosing the rare anterior canal benign positioning vertigo variant., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A 52-year-old man with vertigo and imbalance for two weeks showed spontaneous downbeat (DBN), horizontal gaze-evoked, and positional apogeotropic nystagmus along with severe limb and truncal ataxia. Gadolinium-enhanced brain MRI was normal, but whole body and brain 2-deoxy-2-[F18]fluoro-d-glucose-positron emission tomography revealed hypermetabolism in the right lower lobe of the lung and the cerebellum, especially in the nodulus. The lesion in the lung was confirmed as mixed cell carcinoma. Paraneoplastic DBN may be associated with cerebellar hypermetabolism, especially in the nodulus., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Episodic ataxia type-2 (EA2) is a dominantly inherited human neurological disorder caused by loss of function mutations in the CACNA1A gene, which encodes the CaV2.1 subunit of P/Q-type voltage-gated calcium channels. It remains however unknown whether the deficit of cerebellar CaV2.1 in adult is in direct link with the disease. To address this issue, we have used lentiviral based-vector RNA interference (RNAi) to knock-down CaV2.1 expression in the cerebellum of adult mice. We show that suppression of the P/Q-type channels in Purkinje neurons induced motor abnormalities, such as imbalance and ataxic gait. Interestingly, moderate channel suppression caused no basal ataxia, while β-adrenergic activation and exercise mimicked stress induced motor disorders. Moreover, stress-induced ataxia was stable, non-progressive and totally abolished by acetazolamide, a carbonic anhydrase inhibitor used to treat EA2. Altogether, these data reveal that P/Q-type channel suppression in adult mice supports the episodic status of EA2 disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To propose an etiology for a syndrome of bilateral vestibular hypofunction and sound and/or pressure-evoked eye movements with normal hearing thresholds., Design: Retrospective case series., Setting: Tertiary care referral center., Patients: Four patients with bilateral vestibular hypofunction, sound and/or pressure-evoked nystagmus and normal hearing thresholds were identified over a 3-year period. No evidence of other known vestibular disorders was identified. None of these patients presented with a history of exposure to toxins, radiation, aminoglycosides or chemotherapy; head trauma; or a family history of inherited vestibular loss., Main Outcome Measure: All patients underwent high-resolution CT scan of the temporal bones to evaluate for labyrinthine dehiscence. Additionally, all individuals underwent audiometric testing to ANSI standards, vestibular-evoked myogenic potentials (VEMP) testing using either click stimulus cervical VEMPs (cVEMPs), or tone burst ocular VEMPs (oVEMPs). Bithermal caloric stimulation was used to measure horizontal semicircular canal function, with either videonystagmography (VNG) or electronystagmography (ENG) to record eye movements. Individual responses of each of the 6 semicircular canals (SCC) to rapid head rotations were tested with the bedside head impulse test., Results: We identified 4 patients with a combination of bilateral vestibular hypofunction and sound and/or pressure-induced eye movements, normal-hearing thresholds and no evidence for any other vestibular disorder., Conclusion: We suggest that this unique combination of symptoms should be considered as the clinical presentation of vestibular atelectasis, which has been previously described histologically as collapse of the endolymph-containing portions of the labyrinth.

Objective: To document a patient with periodic alternating nystagmus (PAN) caused by acute disseminated encephalomyelitis (ADEM) and suggest a mechanism to explain her PAN., Patient: A 34-year-old woman with PAN caused by ADEM., Intervention: Diagnostic., Results: The patient complained of severe disequilibrium from the disease onset. Four years after onset, when she visited us, the patient exhibited prominent PAN consisting of alternating rightward and leftward components, which cycled about every 90 seconds and were accompanied by a 5-second translating phase with downbeating nystagmus. Eye movement analysis that separated the horizontal and vertical components revealed the presence of downbeating movements throughout all phases of the PAN. ENG recordings revealed slightly saccadic pursuit, slightly impaired optokinetic eye movement and an absence of visual suppression of the caloric response. MRI recorded at the onset of the disease revealed lesions in the medulla, the spinal cord at the C2 level, and the frontal horn of the left lateral ventricle, but not the cerebellum., Conclusion: We attribute this patient's PAN to impairment of the nucleus prepositus hypoglossi in the medulla, which plays a role in the velocity storage system. In addition, cerebellar dysfunction is indicated by the occurrence of PAN while fixating.

Multiple sclerosis (MS) causes dizziness and vertigo. Reports suggest responsible lesions are often in the intra-pontine 8th nerve fascicle. We sought to determine frequency and clinical features of demyelinating acute vestibular syndrome (AVS). This is a prospective observational study (1999-2011). Consecutive AVS patients (vertigo, nystagmus, nausea/vomiting, head-motion intolerance, unsteady gait) with a risk for central localization underwent structured bedside examination and neuroimaging. When applicable, we identified MS based on clinical, imaging, and laboratory features. Of 170 AVS presentations, 4% (n = 7) were due to demyelinating disease. Five had an acute MS plaque likely responsible for the clinical syndrome. Lesion location varied-1 medulla; 1 inferior cerebellar peduncle; 1 middle cerebellar peduncle; 1 posterior pontine tegmentum; 1 in the intrapontine 8th nerve fascicle; 1 superior cerebellar peduncle; 1 midbrain. Only two had a lesion in or near the intra-pontine 8th nerve fascicle. Three were first presentations (i.e., clinically isolated demyelinating syndrome), while the others were known MS. All had central oculomotor signs. In two patients, the only central sign was a normal horizontal head impulse test (h-HIT) of vestibular function. All patients improved with steroid therapy. Demyelinating disease was an uncommon cause of AVS in our series. Symptomatic lesions were not restricted to the 8th nerve fascicle. Five patients had relatively obvious oculomotor signs, making differentiation from vestibular neuritis straightforward. Two patients had unidirectional, horizontal nystagmus that followed Alexander's law and was suppressed with fixation (true pseudoneuritis). The presence of a normal h-HIT in these suggested central localization.

Purpose: The iris of the eye appears to satisfy the criteria for a good anatomical characteristic for use in a biometric system. The purpose of this study was to evaluate a biometric iris recognition system: Mobile-Eyes™., Methods: The enrollment, verification, and identification applications were evaluated in a field study for accuracy and reliability using both irises of 277 subjects. Independent variables included a wide range of subject demographics, ambient light, and ambient temperature. A sub-set of 35 subjects had alcohol-induced nystagmus. There were 2710 identification and verification attempts, which resulted in 1,501,340 and 5540 iris comparisons respectively., Results: In this study, the system successfully enrolled all subjects on the first attempt. All 277 subjects were successfully verified and identified on the first day of enrollment. None of the current or prior eye conditions prevented enrollment, verification, or identification. All 35 subjects with alcohol-induced nystagmus were successfully verified and identified. There were no false verifications or false identifications. Two conditions were identified that potentially could circumvent the use of iris recognitions systems in general., Conclusions: The Mobile-Eyes™ iris recognition system exhibited accurate and reliable enrollment, verification, and identification applications in this study. It may have special applications in subjects with nystagmus., (Copyright © 2012 Forensic Science Society. Published by Elsevier Ireland Ltd. All rights reserved.)