Lesion network of oculogyric crises maps to brain dopaminergic transcriptomic signature.

Oculogyric crises are acute episodes of sustained, typically upward, conjugate deviation of the eyes. Oculogyric crises usually occur as the result of acute D2-dopamine receptor blockade, but the brain areas causally involved in generating this symptom remain elusive. Here, we used data from 14 previously reported cases of lesion-induced oculogyric crises and employed lesion network mapping to identify their shared connections throughout the brain. This analysis yielded a common network that included basal ganglia, thalamic and brainstem nuclei, as well as the cerebellum. Comparison of this network with gene expression profiles associated with the dopamine system revealed spatial overlap specifically with the gene coding for dopamine receptor type 2 (DRD2), as defined by a large-scale transcriptomic database of the human brain. Furthermore, spatial overlap with DRD2 and DRD3 gene expression was specific to brain lesions associated with oculogyric crises when contrasted to lesions that led to other movement disorders. Our findings identify a common neural network causally involved in the occurrence of oculogyric crises and provide a pathophysiological link between lesion locations causing this syndrome and its most common pharmacological cause, namely DRD2 blockade.

A diagnostic framework to identify vestibular involvement in multi-sensory neurological disease.

BACKGROUND AND PURPOSE: Identifying vestibular causes of dizziness and unsteadiness in multi-sensory neurological disease can be challenging, with problems typically attributed to central or peripheral nerve involvement. Acknowledging vestibular dysfunction as part of the presentation provides an opportunity to access targeted vestibular rehabilitation, for which extensive evidence exists. A diagnostic framework was developed and validated to detect vestibular dysfunction, benign paroxysmal positional vertigo or vestibular migraine. The specificity and sensitivity of the diagnostic framework was tested in patients with primary mitochondrial disease. METHODS: Adults with a confirmed diagnosis of primary mitochondrial disease were consented, between September 2020 and February 2022. Participants with and without dizziness or unsteadiness underwent remote physiotherapy assessment and had in-person detailed neuro-otological assessment. The six framework question responses were compared against objective neuro-otological assessment or medical notes. The output was binary, with sensitivity and specificity calculated. RESULTS: Seventy-four adults completed the study: age range 20-81 years (mean 48 years, ±SD 15.05 years); ratio 2:1 female to male. The framework identified a vestibular diagnosis in 35 participants, with seven having two diagnoses. The framework was able to identify vestibular diagnoses in adults with primary mitochondrial disease, with a moderate (40-59) to very high (90-100) sensitivity and positive predictive value, and moderate to high (60-74) to very high (90-100) specificity and negative predictive value. CONCLUSIONS: Overall, the clinical framework identified common vestibular diagnoses with a moderate to very high specificity and sensitivity. This presents an opportunity for patients to access effective treatment in a timely manner, to reduce falls and improve quality of life.

Towards an explanation for 'unexplained' dizziness in older people.

BACKGROUND: Subjective unsteadiness or dizziness, usually without increase in body sway, is common in older people. The absence of mechanistic understanding of such symptoms renders clinical management difficult. Here, we explore the mechanisms behind such idiopathic dizziness (ID), focusing on postural control abnormalities. METHODS: Thirty patients with ID and 30 age-matched controls stood on a moving platform. Platform oscillations were randomly delivered at different velocities (from 0 to 0.2 m/s). Markers of postural control, including objective sway (trunk sway path, recorded via a sensor attached to vertebrae C7), stepping responses, subjective instability and anxiety ratings were obtained. MRI scans were available for correlations with levels of cerebral small vessel disease in 28 patients and 24 controls. RESULTS: We observed a significant relationship between objective and subjective instability in all groups. The slope of this fit was significantly steeper for patients than controls, indicating greater perceived instability for the same body sway. Stepwise linear regression showed that the slopes of this objective-subjective instability relationship were best explained by concerns about falling (Falls Efficacy Scale-International), clinical physical functioning (Short Physical Performance Battery) and, to some degree, by neuroimaging markers of cerebral small vessel disease. In addition, patients had a reduced stepping threshold, suggesting an overly cautious postural response. CONCLUSION: The distorted perception of instability and subtle impairments in balance control, including abnormal and overly cautious stepping responses, underlies the emergence of ID. It appears to relate to changes in postural performance, psychological functioning and disruption of postural brain networks associated with cerebral small vessel disease.

Neurological gait assessment.

Gait disorders are a common feature of neurological disease. The gait examination is an essential part of the neurological clinical assessment, providing valuable clues to a myriad of causes. Understanding how to examine gait is not only essential for neurological diagnosis but also for treatment and prognosis. Here, we review aspects of the clinical history and examination of neurological gait to help guide gait disorder assessment. We focus particularly on how to differentiate between common gait abnormalities and highlight the characteristic features of the more prevalent neurological gait patterns such as ataxia, waddling, steppage, spastic gait, Parkinson's disease and functional gait disorders. We also offer diagnostic clues for some unusual gait presentations, such as dystonic, stiff-person and choreiform gait, along with red flags that help differentiate atypical parkinsonism from Parkinson's disease.

Introduction to the assessment and management of persistent postural-perceptual dizziness.

OBJECTIVE: Persistent postural-perceptual dizziness classifies patients with chronic dizziness, often triggered by an acute episode of vestibular dysfunction or threat to balance. Unsteadiness and spatial disorientation vary in intensity but persist for over three months, exacerbated by complex visual environments. METHOD: Literature suggests diagnosis relies on a clinical history of persistent subjective dizziness and normal vestibular and neurological examination findings. Behavioural diagnostic biomarkers have been proposed, to facilitate diagnosis. RESULTS: Research has focused on understanding the neural mechanisms that underpin this perceptual disorder, with imaging data supporting altered connectivity between neural brain networks that process vision, motion and emotion. Behavioural research identified the perceptual and motor responses to a heightened perception of imbalance. CONCLUSION: Management utilises head and body motion detection, and downregulation of visual motion excitability, reducing postural hypervigilance and anxiety. Combinations of physical and cognitive therapies, with antidepressant medications, help if the condition is associated with mood disorder.

Detecting Abnormal Eye Movements in Patients with Neurodegenerative Diseases - Current Insights.

This review delineates the ocular motor disturbances across a spectrum of neurodegenerative disorders, including Alzheimer's Disease (AD) and related disorders (ADRD), Parkinson's Disease (PD), atypical parkinsonism, and others, leveraging advancements in eye-tracking technology for enhanced diagnostic precision. We delve into the different classes of eye movements, their clinical assessment, and specific abnormalities manifesting in these diseases, highlighting the nuanced differences and shared patterns. For instance, AD and ADRD are characterized by increased saccadic latencies and instability in fixation, while PD features saccadic hypometria and mild smooth pursuit impairments. Atypical parkinsonism, notably Progressive Supranuclear Palsy (PSP) and Corticobasal Syndrome (CBS), presents with distinct ocular motor signatures such as vertical supranuclear gaze palsy and saccadic apraxia, respectively. Our review underscores the diagnostic value of eye movement analysis in differentiating between these disorders and also posits the existence of underlying common pathological mechanisms. We discuss how eye movements have potential as biomarkers for neurodegenerative diseases but also some of the existing limitations.

Digital biomarkers from gaze tests for classification of central and peripheral lesions in acute vestibular syndrome.

Acute vestibular syndrome (AVS) is characterised by a sudden vertigo, gait instability, nausea and nystagmus. Accurate and rapid triage of patients with AVS to differentiate central (potentially sinister) from peripheral (usually benign) root causes is a challenge faced across emergency medicine settings. While there exist bedside exams which can reliably differentiate serious cases, they are underused due to clinicians' general unfamiliarity and low confidence interpreting results. Nystagmus is a fundamental part of AVS and can facilitate triaging, but identification of relevant characteristics requires expertise. This work presents two quantitative digital biomarkers from nystagmus analysis, which capture diagnostically-relevant information. The directionality biomarker evaluates changes in direction to differentiate spontaneous and gaze-evoked (direction-changing) nystagmus, while the intensity differential biomarker describes changes in intensity across eccentric gaze tests. In order to evaluate biomarkers, 24 sets of three gaze tests (left, right, and primary) are analysed. Both novel biomarkers were found to perform well, particularly directionality which was a perfect classifier. Generally, the biomarkers matched or eclipsed the performance of quantitative nystagmus features found in the literature. They also surpassed the performance of a support vector machine classifier trained on the same dataset, which achieved an accuracy of 75%. In conclusion, these biomarkers simplify the diagnostic process for non-specialist clinicians, bridging the gap between emergency care and specialist evaluation, ultimately benefiting patients with AVS.

Hearing rehabilitation of adults with auditory processing disorder: a systematic review and meta-analysis of current evidence-based interventions.

Background: For adults with auditory processing disorder (APD), listening and communicating can be difficult, potentially leading to social isolation, depression, employment difficulties and certainly reducing the quality of life. Despite existing practice guidelines suggesting treatments, the efficacy of these interventions remains uncertain due to a lack of comprehensive reviews. This systematic review and meta-analysis aim to establish current evidence on the effectiveness of interventions for APD in adults, addressing the urgent need for clarity in the field. Methods: Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic search across MEDLINE (Ovid), Embase (Ovid), Web of Science and Scopus, focusing on intervention studies involving adults with APD. Studies that met the inclusion criteria were grouped according to intervention with a meta-analysis only conducted where intervention, study design and outcome measure were comparable. Results: Out of 1,618 screened records, 13 studies were included, covering auditory training (AT), low-gain hearing aids (LGHA), and personal remote microphone systems (PRMS). Our analysis revealed: AT, Mixed results with some improvements in speech intelligibility and listening ability, indicating potential benefits but highlighting the need for standardized protocols; LGHA, The included studies demonstrated significant improvements in monaural low redundancy speech testing (p < 0.05), suggesting LGHA could enhance speech perception in noisy environments. However, limitations include small sample sizes and potential biases in study design. PRMS, Demonstrated the most consistent evidence of benefit, significantly improving speech testing results, with no additional benefit from combining PRMS with other interventions. Discussion: PRMS presents the most evidence-supported intervention for adults with APD, although further high-quality research is crucial for all intervention types. The establishment and implementation of standardized intervention protocols alongside rigorously validated outcome measures will enable a more evidence-based approach to managing APD in adults.

Acceptability of Audiovestibular Assessment in the Home-A Patient Survey.

The COVID-19 pandemic dramatically changed health service delivery with vulnerable patients advised to isolate and appointments provided virtually. This change affected recruitment into an observational cohort study, undertaken at a single site, where participants with mitochondrial disorders were due to have specialist hospital-based audiovestibular tests. To ensure study viability, the study protocol was amended to allow home-based assessment for vulnerable participants. Here, we report outcomes of an online survey of participants who underwent home-based assessment, related to the experience, perceived benefits, and drawbacks of home audiovestibular assessments. Seventeen participants underwent home-based neuro-otological assessment, due to the need to isolate during COVID-19. Following the assessment, 16 out of 17 participants completed an anonymised online survey to share their experiences of the specialist home-based assessment. One hundred percent of participants rated the home-based assessment 'very positively' and would recommend it to others. Sixty-three percent rated it better than attending hospital outpatient testing settings. The benefits included no travel burden (27%) and reduced stress (13%). A majority reported no drawbacks in having the home visit. The patient-reported feedback suggests a person-centred approach where audiovestibular assessments are conducted in their homes is feasible for patients, acceptable and seen as beneficial to a vulnerable group of patients.

Exploring Inner Ear and Brain Connectivity through Perilymph Sampling for Early Detection of Neurological Diseases: A Provocative Proposal.

Recent evidence shows that it is possible to identify the elements responsible for sensorineural hearing loss, such as pro-inflammatory cytokines and macrophages, by performing perilymph sampling. However, current studies have only focused on the diagnosis of such as otologic conditions. Hearing loss is a feature of certain neuroinflammatory disorders such as multiple sclerosis, and sensorineural hearing loss (SNHL) is widely detected in Alzheimer's disease. Although the environment of the inner ear is highly regulated, there are several communication pathways between the perilymph of the inner ear and cerebrospinal fluid (CSF). Thus, examination of the perilymph may help understand the mechanism behind the hearing loss observed in certain neuroinflammatory and neurodegenerative diseases. Herein, we review the constituents of CSF and perilymph, the anatomy of the inner ear and its connection with the brain. Then, we discuss the relevance of perilymph sampling in neurology. Currently, perilymph sampling is only performed during surgical procedures, but we hypothesize a simplified and low-invasive technique that could allow sampling in a clinical setting with the same ease as performing an intratympanic injection under direct visual check. The use of this modified technique could allow for perilymph sampling in people with hearing loss and neuroinflammatory/neurodegenerative disorders and clarify the relationship between these conditions; in fact, by measuring the concentration of neuroinflammatory and/or neurodegenerative biomarkers and those typically expressed in the inner ear in aging SNHL, it could be possible to understand if SNHL is caused by aging or neuroinflammation.

What's in a Name? Chronic Vestibular Migraine or Persistent Postural Perceptual Dizziness?

Current consensus diagnostic criteria for vestibular migraine (VM) describes this as an episodic disorder. However, a minority of patients report prolonged (>72 h duration) or even persistent VM symptoms, prompting whether a chronic variant of vestibular migraine (CVM) should be introduced to the current classification and how best to define it. Here we summarize current evidence of such a potential chronic variant of VM and critically review proposed definitions for CVM. Potential approaches to establish a diagnostic framework for CVM include (a) following the distinction between episodic and chronic migraine headaches, namely, frequent and/or prolonged episodes of VM (but not persistent vertigo or dizziness) in the context of chronic migraine headaches or (b) daily dizzy spells over more than 6 months that responded well to prophylactic anti-migraine therapy. A key challenge when defining diagnostic criteria for CVM is how to distinguish it from other chronic vestibular syndromes such as motion sickness, persistent postural-perceptual dizziness (PPPD), and mal de débarquement syndrome. Indeed, more than 50% of patients with PPPD and up to 46% with mal de débarquement syndrome fulfil diagnostic criteria for episodic migraine headaches, suggesting these disorders may all lie along a spectrum. We propose that when VM becomes persistent, it is best classified as PPPD but that VM and PPPD are not mutually exclusive, such that patients with PPPD need not have features of VM, and the triggering event for persistent dizziness may be independent of migraine. However, further research is needed to better characterize the spectrum of clinical phenotypes in patients with chronic dizziness, migraine headaches and anxiety, to define whether a chronic variant of VM sufficiently differs from current persistent dizziness definitions.

Ocular myasthenia gravis saccades as a measure of extraocular muscle function.

Background: It is important to understand the pathophysiology of ocular myasthenia gravis (OMG) to improve treatment. Aim: To use modern video-oculography to characterise saccadic eye movements in patients with OMG, including anti-AChR, anti-MuSK, anti-LRP4, and seronegative OMG. Methods: In total, 21 patients with OMG and five age-matched healthy control subjects underwent video-oculography. Participants performed a sequence of horizontal saccades (3 minutes each) at ±5°, ± 10°, and ±20°, followed by 3 minutes of saccades directed at randomly presented targets at ±5°, ± 10°, and ±15°. We recorded the direction, amplitude, duration, peak, and average velocity of each saccade for each task for each participant. Results: Saccadic amplitude, duration, and average velocity were all lower in OMG patients than in control subjects (p < 0.021). Saccadic amplitude and velocity decreased over time, but this decrease was similar in OMG patients and control subjects. Fixation drift and ocular disparity tended to be greater in OMG patients than in control subjects. Saccadic intrusions occurred more frequently in OMG patients than in control subjects (p < 0.001). No significant effects of time or group by time on fixation drift or ocular disparity were found. Discussion: Saccadic velocities in OMG patients differed from those in normal control subjects, which suggests that OMG affects fast-twitch fibres, although fast-twitch fibres were still able to generate "twitch" or "quiver" movements in the presence of even severe ophthalmoplegia. Slow-twitch muscle fibres involved in gaze holding were also affected, accounting for increased fixation drift following saccades. Our objective finding of increased fixation drift and a larger number of saccadic intrusions mirror our anecdotal experience of patients with OMG who report significant diplopia despite minimal ophthalmoplegia on examination. Such microsaccades may be a surrogate for compensation of a gaze-holding deficit in MG.