Paraneoplastic cochleovestibulopathy: clinical presentations, oncological and serological associations.

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.

Approach to the Examination and Classification of Nystagmus.

BACKGROUND AND PURPOSE: Physical therapists caring for patients with neurologic or vestibular disorders must routinely examine and characterize nystagmus and other oscillatory eye movements. Often, the diagnosis hinges on proper interpretation of the nystagmus pattern. This requires understanding the terminology surrounding the numerous attributes and influencing factors of nystagmus, a systematic approach to the examination, and a classification structure that guides practitioners to the specific nystagmus type and subsequent evaluation and management. SUMMARY OF KEY POINTS: Nystagmus is an involuntary, rapid, rhythmic, oscillatory eye movement with at least 1 slow phase. Jerk nystagmus has a slow phase and a fast phase. Pendular nystagmus has only slow phases. Nystagmus is distinguished from other types of oscillatory eye movements, such as saccadic intrusions or oscillations. Characterizing nystagmus requires clearly describing its trajectory. This includes choosing a reference frame to describe the axes or planes and direction of eye movements. Several attributes are used to describe nystagmus: binocularity, conjugacy, velocity, waveform, frequency, amplitude, intensity, temporal profile, and age at first appearance. Several factors may influence nystagmus, including gaze position, visual fixation, vergence, and a variety of provocative maneuvers. Classification of nystagmus may be organized by physiologic or pathologic nystagmus versus other nystagmus-like movements. Pathologic nystagmus may be spontaneous, gaze-evoked, or triggered by provocative maneuvers. The combination of attributes allows differentiation between the many peripheral and central forms. RECOMMENDATIONS FOR CLINICAL PRACTICE: Therapists should carefully examine and characterize the trajectory and other attributes and influencing factors of nystagmus to accurately classify it and arrive at the correct diagnosis.

Vestibular migraine and persistent postural perceptual dizziness.

Dizziness is a common symptom among patients in primary care, general neurology, and headache clinic practices. Vestibular migraine is conceptualized as a condition of recurrent attacks of vestibular symptoms attributed to migraine. It is now considered the most common cause of spontaneous episodic vertigo. Persistent postural-perceptual dizziness (PPPD) has more recently been defined based on four previous clinical entities as a syndrome of chronic daily dizziness, unsteadiness, or nonspinning vertigo that fluctuates and is exacerbated by postural, motion, or visual factors. Although PPPD is more often precipitated by other conditions causing vertigo, unsteadiness, or dizziness, it is discussed at length in this chapter because vestibular migraine is among the most common triggers for development of PPPD. Pathophysiology of each is incompletely understood, and with lack of biomarkers, the diagnosis of each rests on consensus-derived, symptom-based criteria. Areas of uncertainty exist regarding some overlapping symptoms that may create potential diagnostic confusion between the conditions. This chapter provides a comprehensive review of the current state of vestibular migraine and PPPD, including diagnostic and management guidance for when they occur separately, together, or along with other common comorbidities.

Episodic Spontaneous Dizziness.

PURPOSE OF REVIEW: Conditions causing recurrent spontaneous episodes of dizziness or vertigo span several medical specialties, making it challenging for clinicians to gain confidence in evaluating and managing the spectrum of episodic vestibular disorders. Patients are often asymptomatic and have normal examinations at the time of evaluation. Thus, diagnosis depends heavily on eliciting key features from the history. Overreliance on symptom quality descriptions commonly leads to misdiagnosis. The goal of this article is to provide the reader with a straightforward approach to the diagnosis and management of conditions that cause episodic spontaneous dizziness. RECENT FINDINGS: Consensus diagnostic criteria have been established for vestibular migraine, Ménière disease, vestibular paroxysmia, and hemodynamic orthostatic dizziness/vertigo. Vertigo has been recognized as a common symptom in vertebrobasilar ischemia, cardiogenic dizziness, and orthostatic hypotension. Treatment recommendations for vestibular migraine still lack high-quality evidence, but controlled trials are occurring. SUMMARY: The evaluation should start with a detailed description of the episodes from the patient and any observers. Rather than focusing first on whether the symptom quality is most consistent with vertigo, dizziness, lightheadedness, or unsteadiness, the clinician should clarify the timing (episode frequency and duration), possible triggers or circumstances (eg, position changes, upright posture), and accompanying symptoms. History should identify any auditory symptoms, migraine features, posterior circulation ischemic symptoms, vascular risk factors, clues for anxiety, and potentially relevant medications. Carefully selected testing can help secure the diagnosis, but excessive and indiscriminate testing can lead to more confusion. Treatments for these conditions are vastly different, so an accurate diagnosis is critical.

Agreement between the Skull Vibration-Induced Nystagmus Test and Semicircular Canal and Otolith Asymmetry.

BACKGROUND: How significant asymmetries in otolith organ function in the presence of symmetrical and asymmetrical semicircular canal function influence skull vibration-induced nystagmus testing (SVINT) has not been well described. PURPOSE: The aim of the study is to examine the agreement between SVINT and caloric testing, ocular vestibular-evoked myogenic potentials (oVEMP), and cervical vestibular-evoked myogenic potentials (cVEMP) for detecting asymmetric vestibular function. RESEARCH DESIGN: This is a retrospective study of patients presenting with the chief complaint of vertigo, dizziness, or imbalance. STUDY SAMPLE: A total of 812 patients were studied with a median age at testing of 59 years (interquartile range 46-70; range 18-93) and included 475 (59%) women. INTERVENTION: Either the monothermal warm caloric test or alternate binaural bithermal caloric test, oVEMP, and cVEMP tests were administered to all patients. All patients underwent the SVINT prior to vestibular laboratory testing. DATA COLLECTION AND ANALYSIS: Agreement between tests categorized as normal versus abnormal was summarized using percent concordance (PC). Sensitivity and specificity values were calculated for SVINT compared with other tests of vestibular function. RESULTS: There was higher agreement between ipsilateral and contralateral SVINT with the caloric test (PC = 80% and 81%, respectively) compared with oVEMP (PC = 63% and 64%, respectively) and cVEMP (PC = 76% and 78%, respectively). Ipsilateral and contralateral SVINT showed higher sensitivity for the caloric test (sensitivity = 47% and 36%, respectively) compared with oVEMP (sensitivity = 26% and 21%, respectively), or cVEMP (sensitivity = 33% vs. 27%, respectively). Specificity of SVINT was high (>80%) for all assessments of vestibular function. CONCLUSION: The presence of SVIN is a useful indicator of the asymmetry of vestibular function between the two ears when making judgments about semicircular canal asymmetry but is less sensitive to asymmetries in otolith organ function.

Approaching Acute Vertigo With Diplopia: A Rare Skew Deviation in Vestibular Neuritis.

Evaluating the patient with acute constant vertigo or diplopia can be a daunting task for clinicians, who recognize that such symptoms can be the manifestation of potentially devastating disorders like stroke but may be uncomfortable eliciting and interpreting the key symptoms and subtle signs that distinguish dangerous from benign causes. We present a novel and highly instructive case of a patient with acute vertigo and binocular diplopia from a large skew deviation due to vestibular neuritis. As the case unfolds, text and video commentary guide the clinician through the important elements of the history, bedside examination, and laboratory evaluation necessary for accurate diagnosis in the acute vestibular syndrome. We demonstrate how to interpret nystagmus and properly perform the head impulse test and test of skew deviation and discuss the pitfalls of overreliance on imaging when evaluating patients with acute vertigo.

Classification of vestibular signs and examination techniques: Nystagmus and nystagmus-like movements.

This paper presents a classification and definitions for types of nystagmus and other oscillatory eye movements relevant to evaluation of patients with vestibular and neurological disorders, formulated by the Classification Committee of the Bárány Society, to facilitate identification and communication for research and clinical care. Terminology surrounding the numerous attributes and influencing factors necessary to characterize nystagmus are outlined and defined. The classification first organizes the complex nomenclature of nystagmus around phenomenology, while also considering knowledge of anatomy, pathophysiology, and etiology. Nystagmus is distinguished from various other nystagmus-like movements including saccadic intrusions and oscillations.View accompanying videos at http://www.jvr-web.org/ICVD.html.

Timing of milestone competency acquisition in neurology residency: What by when?

OBJECTIVE: To determine the stage of training at which neurology residents should achieve individual elements of the Accreditation Council for Graduate Medical Education neurology Milestones and to examine the relationship between perceived importance of Milestones and the stage by which they should be achieved. METHODS: A modified Delphi technique was used to establish consensus postgraduate year (PGY) expectations for neurology Milestone competencies across 3 geographically and administratively distinct Mayo Clinic neurology residency programs. Timing expectations were examined for relationships to perceived importance of the individual Milestones and effects of participant characteristics. RESULTS: PGY expectations for neurology Milestone elements ranged from PGY 1.3 to PGY 4.1. Extent of rater educational seniority had no effect on PGY competency expectations. There was a moderate inverse relationship between perceived importance of the Milestone element and the PGY by which it should be achieved (r s = -0.74, p < 0.0001). CONCLUSIONS AND RELEVANCE: Expectations for neurology Milestone competency acquisition can be measured and may help inform individual program design, educational expectations, and future Milestone design.

Saccadic Palsy following Cardiac Surgery: Possible Role of Perineuronal Nets.

OBJECTIVE: Perineuronal nets (PN) form a specialized extracellular matrix around certain highly active neurons within the central nervous system and may help to stabilize synaptic contacts, promote local ion homeostasis, or play a protective role. Within the ocular motor system, excitatory burst neurons and omnipause neurons are highly active cells that generate rapid eye movements - saccades; both groups of neurons contain the calcium-binding protein parvalbumin and are ensheathed by PN. Experimental lesions of excitatory burst neurons and omnipause neurons cause slowing or complete loss of saccades. Selective palsy of saccades in humans is reported following cardiac surgery, but such cases have shown normal brainstem neuroimaging, with only one clinicopathological study that demonstrated paramedian pontine infarction. Our objective was to test the hypothesis that lesions of PN surrounding these brainstem saccade-related neurons may cause saccadic palsy. METHODS: Together with four controls we studied the brain of a patient who had developed a permanent selective saccadic palsy following cardiac surgery and died several years later. Sections of formalin-fixed paraffin-embedded brainstem blocks were applied to double-immunoperoxidase staining of parvalbumin and three different components of PN. Triple immunofluorescence labeling for all PN components served as internal controls. Combined immunostaining of parvalbumin and synaptophysin revealed the presence of synapses. RESULTS: Excitatory burst neurons and omnipause neurons were preserved and still received synaptic input, but their surrounding PN showed severe loss or fragmentation. INTERPRETATION: Our findings support current models and experimental studies of the brainstem saccade-generating neurons and indicate that damage to PN may permanently impair the function of these neurons that the PN ensheathe. How a postulated hypoxic mechanism could selectively damage the PN remains unclear. We propose that the well-studied saccadic eye movement system provides an accessible model to evaluate the role of PN in health and disease.

Saccadic palsy following cardiac surgery: a review and new hypothesis.

The ocular motor system provides several advantages for studying the brain, including well-defined populations of neurons that contribute to specific eye movements. Generation of rapid eye movements (saccades) depends on excitatory burst neurons (EBN) and omnipause neurons (OPN) within the brainstem, both types of cells are highly active. Experimental lesions of EBN and OPN cause slowing or complete loss of saccades. We report a patient who developed a permanent, selective saccadic palsy following cardiac surgery. When she died several years later, surprisingly, autopsy showed preservation of EBN and OPN. We therefore considered other mechanisms that could explain her saccadic palsy. Recent work has shown that both EBN and OPN are ensheathed by perineuronal nets (PN), which are specialized extracellular matrix structures that may help stabilize synaptic contacts, promote local ion homeostasis, or play a protective role in certain highly active neurons. Here, we review the possibility that damage to PN, rather than to the neurons they support, could lead to neuronal dysfunction-such as saccadic palsy. We also suggest how future studies could test this hypothesis, which may provide insights into the vulnerability of other active neurons in the nervous system that depend on PN.

Milestone-compatible neurology resident assessments: A role for observable practice activities.

OBJECTIVE: Beginning in 2014, US neurology residency programs were required to report each trainee's educational progression within 29 neurology Milestone competency domains. Trainee assessment systems will need to be adapted to inform these requirements. The primary aims of this study were to validate neurology resident assessment content using observable practice activities (OPAs) and to develop assessment formats easily translated to the Neurology Milestones. METHODS: A modified Delphi technique was used to establish consensus perceptions of importance of 73 neurology OPAs among neurology educators and trainees at 3 neurology residency programs. A content validity score (CVS) was derived for each neurology OPA, with scores ≥4.0 determined in advance to indicate sufficient content validity. RESULTS: The mean CVS for all OPAs was 4.4 (range 3.5-5.0). Fifty-seven (78%) OPAs had a CVS ≥4.0, leaving 16 (22%) below the pre-established threshold for content validity. Trainees assigned a higher importance to individual OPAs (mean CVS 4.6) compared to faculty (mean 4.4, p = 0.016), but the effect size was small (η(2) = 0.10). There was no demonstrated effect of length of education experience on perceived importance of neurology OPAs (p = 0.23). Two sample resident assessment formats were developed, one using neurology OPAs alone and another using a combination of neurology OPAs and the Neurology Milestones. CONCLUSIONS: This study provides neurology training programs with content validity evidence for items to include in resident assessments, and sample assessment formats that directly translate to the Neurology Milestones. Length of education experience has little effect on perceptions of neurology OPA importance.

Comorbidities in vestibular migraine.

A growing body of clinical and epidemiological evidence supports a specific relationship between vestibular symptoms and migraine. Without a biomarker or complete understanding of pathophysiology, diagnosis of vestibular migraine (VM) currently depends upon symptoms in two dimensions: episodic vestibular symptoms temporally related to migraine symptoms. The Bárány Society and the International Headache Society have recently developed consensus diagnostic criteria. However, many issues remain unsettled, including the type, duration, and timing of vestibular symptoms related to headache that should be required for diagnosing VM. This paper focuses on the challenging third dimension of comorbidity, a frequent cause of diagnostic uncertainty that may confound clinical application and research validation of VM criteria. Several other neurotologic conditions occur more frequently in migraineurs than controls, including benign paroxysmal positional vertigo, Ménière's disease, and motion sickness. Patients with VM also have high rates of chronic subjective dizziness, which may be associated with anxious, introverted temperaments that can affect clinical presentation and treatment response. Broadly inclusive studies of well-characterized patients with other neurotologic and psychiatric comorbidities are needed to fully understand how vestibular symptoms and migraine interact in order to truly validate vestibular migraine, distill its essential features, define its boundaries, and characterize overlapping comorbidities.

Anxious, introverted personality traits in patients with chronic subjective dizziness.

OBJECTIVES: Chronic subjective dizziness (CSD) is a neurotologic disorder of persistent non-vertiginous dizziness, unsteadiness, and hypersensitivity to one's own motion or exposure to complex visual stimuli. CSD usually follows acute attacks of vertigo or dizziness and is thought to arise from patients' failure to re-establish normal locomotor control strategies after resolution of acute vestibular symptoms. Pre-existing anxiety or anxiety diathesis may be risk factors for CSD. This study tested the hypothesis that patients with CSD are more likely than individuals with other chronic neurotologic illnesses to possess anxious, introverted personality traits. METHODS: Data were abstracted retrospectively from medical records of 40 patients who underwent multidisciplinary neurotology evaluations for chronic dizziness. Twenty-four subjects had CSD. Sixteen had chronic medical conditions other than CSD plus co-existing anxiety disorders. Group differences in demographics, Dizziness Handicap Inventory (DHI) scores, Hospital Anxiety and Depression Scale (HADS) scores, DSM-IV diagnoses, personality traits measured with the NEO Personality Inventory - Revised (NEO-PI-R), and temperaments composed of NEO-PI-R facets were examined. RESULTS: There were no differences between groups in demographics, mean DHI or HADS-anxiety scores, or DSM-IV diagnoses. The CSD group had higher mean HADS-depression and NEO-PI-R trait anxiety, but lower NEO-PI-R extraversion, warmth, positive emotions, openness to feelings, and trust (all p<0.05). CSD subjects were significantly more likely than comparison subjects to have a composite temperament of high trait anxiety plus low warmth or excitement seeking. CONCLUSION: An anxious, introverted temperament is strongly associated with CSD and may be a risk factor for developing this syndrome.

Progressive multifocal leukoencephalopathy in a patient treated with etanercept.

INTRODUCTION: Recently, increased attention has been paid to the association of progressive multifocal leukoencephalopathy (PML) with the use of immunomodulatory medications for autoimmune diseases. CASE REPORT: A 23-year-old Native American woman with a history of systemic lupus erythematosus and erosive polyarthritis treated with prednisone and etanercept presented with focal weakness, hemiataxia, diplopia, and dysarthria. Brain magnetic resonance imaging demonstrated progressive, T2 signal hyperintensities within the brainstem and cerebellar white matter without mass effect or gadolinium enhancement. Cerebrospinal fluid showed elevated protein and JC virus polymerase chain reaction positive with 28,600 copies/ml diagnostic of PML. CONCLUSIONS: The development of PML in this patient treated with etanercept and prednisone highlights the increased risk for opportunistic infection with JC virus in patients with autoimmune diseases on immunosuppressive therapies.

Acquired progressive ataxia and palatal tremor: importance of MRI evidence of hemosiderin deposition and vascular malformations.

Oculopalatal tremor is frequently accompanied by progressive ataxia. In symptomatic oculopalatal tremor the ataxia frequently is delayed in onset. Progressive ataxia is a defining clinical feature of superficial siderosis. We report 5 cases with palatal tremor and ataxia. Four cases had evidence of intraparenchymal hemosiderin deposition on T2-gradient-echo imaging. Three cases had a brainstem vascular malformation. In two cases the hemosiderin deposition was likely due to prior trauma. The significance of these associations and possible similarities between ataxia related to superficial siderosis and ataxia and intraparenchymal hemosiderin is discussed.

Investigation of the coherence of definite and probable vestibular migraine as distinct clinical entities.

OBJECTIVES: To investigate the following: 1) associations between vestibular symptoms and migraine in a well-characterized cohort of tertiary neurotology patients, 2) effects of comorbidity on clinical presentations, and 3) validity of proposed definitions of definite (dVM) and probable vestibular migraine (pVM). STUDY DESIGN: Retrospective chart review. SETTING: Tertiary neurotology center. PATIENTS: All 228 subjects with headache were selected from a larger investigation of 410 patients with vestibular symptoms who underwent comprehensive medical, surgical, and behavioral neurotologic consultations. Subjects had at least one of 4 diagnoses: dVM/pVM, Ménière's disease, benign paroxysmal positional vertigo, or chronic subjective dizziness. INTERVENTIONS: Subjects were divided into migraine (n = 164) and nonmigraine headache (n = 64) groups by International Headache Society criteria, then subdivided by those with vestibular symptoms related or unrelated to headache. Subjects meeting proposed criteria for dVM (n = 46) and pVM (n = 42) were identified. Statistical analyses investigated discriminating features and cohesiveness in each group, with or without comorbidity. MAIN OUTCOME MEASURES: Characteristics of dVM and pVM. RESULTS: Migraine, particularly migraine with aura, was more often related to vestibular symptoms than nonmigrainous headache. dVM and pVM groups did not differ in demographics, clinical histories, examinations, or vestibular testing. Numerous differences existed between dVM/pVM subjects with and without comorbid Ménière's disease, benign paroxysmal positional vertigo, or chronic subjective dizziness. The pVM group contained 4 subtypes. CONCLUSION: These results support an association between vestibular symptoms and migraine but not proposed distinctions between dVM and pVM. pVM does not appear to be a coherent diagnostic entity. Comorbid conditions are important causes of vestibular symptoms in patients with migraine.

Migraine-related vertigo: diagnosis and treatment.

A comprehensive review of the neurotologic manifestations of migraine is presented, focusing on the most recent publications regarding the epidemiology, clinical presentation, pathophysiology, diagnosis, and management of migraine-related vertigo (MV). A strong association exists between vertigo and migraine, with MV being the most common cause of spontaneous (nonpositional) episodic vertigo. Symptoms can be quite variable among patients and within individual patients over time, creating a diagnostic challenge. MV generally presents with attacks of spontaneous or positional vertigo lasting seconds to days with associated migrainous symptoms. Operational diagnostic criteria have been proposed but are not included in the most recent International Headache Society classification of migraine. Better elucidation of the neurologic linkages between the central vestibular pathways and migraine-related pathways and the discovery of ion channel defects underlying some causes of familial migraine, ataxia, and vertigo have furthered the understanding of MV pathophysiology. Treatment of MV currently parallels that of migraine headache, as proper studies of optimal MV management are just beginning.

Migraine-related vertigo: diagnosis and treatment.

A comprehensive review of the neurotologic manifestations of migraine is presented, focusing on the most recent publications regarding the epidemiology, clinical presentation, pathophysiology, diagnosis, and management of migraine-related vertigo (MV). A strong association exists between vertigo and migraine, with MV being the most common cause of spontaneous (nonpositional) episodic vertigo. Symptoms can be quite variable among patients and within individual patients over time, creating a diagnostic challenge. MV generally presents with attacks of spontaneous or positional vertigo lasting seconds to days with associated migrainous symptoms. Operational diagnostic criteria have been proposed but are not included in the most recent International Headache Society classification of migraine. Better elucidation of the neurologic linkages between the central vestibular pathways and migraine-related pathways and the discovery of ion channel defects underlying some causes of familial migraine, ataxia, and vertigo have furthered the understanding of MV pathophysiology. Treatment of MV currently parallels that of migraine headache, as proper studies of optimal MV management are just beginning.