Accuracy of Repetitive Ocular Vestibular-Evoked Myogenic Potentials to Diagnose Myasthenia Gravis in Patients With Ptosis or Diplopia.

BACKGROUND AND OBJECTIVES: We developed repetitive ocular vestibular-evoked myogenic potentials (roVEMP) as an electrophysiologic test that allows us to elicit the characteristic decrement of extraocular muscles in patients with ocular myasthenia gravis (OMG). Case-control studies demonstrated that roVEMP reliably differentiates patients with OMG from healthy controls. We now aimed to evaluate the diagnostic accuracy of roVEMP for OMG diagnosis in patients with ptosis and/or diplopia. METHODS: In this blinded prospective diagnostic accuracy trial, we compared roVEMP in 89 consecutive patients presenting with ptosis and/or diplopia suspicious of OMG with a multimodal diagnostic approach, including clinical examination, antibodies, edrophonium testing, repetitive nerve stimulation of accessory and facial nerves, and single-fiber EMG (SFEMG). We calculated the roVEMP decrement as the ratio between the mean of the first 2 responses compared with the mean of the sixth-ninth responses in the train and used cutoff of >9% (unilateral decrement) in a 30 Hz stimulation paradigm. RESULTS: Following a complete diagnostic work-up, 39 patients (44%) were diagnosed with ocular MG, while 50 patients (56%) had various other neuro-ophthalmologic conditions, but not MG (non-MG). roVEMP yielded 88.2% sensitivity, 30.2% specificity, 50% positive predictive value (PPV), and 76.5% negative predictive value (NPV). For comparison, SFEMG resulted in 75% sensitivity, 56% specificity, 55.1% PPV, and 75.7% NPV. All other diagnostic tests (except for the ice pack test) also yielded significantly higher positive results in patients with MG compared with non-MG. DISCUSSION: The study revealed a high sensitivity of 88.2% for roVEMP in OMG, but specificity and PPV were too low to allow for the OMG diagnosis as a single test. Thus, differentiating ocular MG from other neuro-ophthalmologic conditions remains challenging, and the highest diagnostic accuracy is still obtained by a multimodal approach. In this study, roVEMP can complement the diagnostic armamentarium for the diagnosis of MG. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with diplopia and ptosis, roVEMP alone does not accurately distinguish MG from non-MG disorders. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT03049956.

The role of vestibular cues in postural sway.

Controlling posture requires continuous sensory feedback about body motion and orientation, including from the vestibular organs. Little is known about the role of tilt vs. translation vs. rotation vestibular cues. We examined whether intersubject differences in vestibular function were correlated with intersubject differences in postural control. Vestibular function was assayed using vestibular direction-recognition perceptual thresholds, which determine the smallest motion that can be reliably perceived by a subject seated on a motorized platform in the dark. In study A, we measured thresholds for lateral translation, vertical translation, yaw rotation, and head-centered roll tilts. In study B, we measured thresholds for roll, pitch, and left anterior-right posterior and right anterior-left posterior tilts. Center-of-pressure (CoP) sway was measured in sensory organization tests (study A) and Romberg tests (study B). We found a strong positive relationship between CoP sway and lateral translation thresholds but not CoP sway and other thresholds. This finding suggests that the vestibular encoding of lateral translation may contribute substantially to balance control. Since thresholds assay sensory noise, our results support the hypothesis that vestibular noise contributes to spontaneous postural sway. Specifically, we found that lateral translation thresholds explained more of the variation in postural sway in postural test conditions with altered proprioceptive cues (vs. a solid surface), consistent with postural sway being more dependent on vestibular noise when the vestibular contribution to balance is higher. These results have potential implications for vestibular implants, balance prostheses, and physical therapy exercises.NEW & NOTEWORTHY Vestibular feedback is important for postural control, but little is known about the role of tilt cues vs. translation cues vs. rotation cues. We studied healthy human subjects with no known vestibular pathology or symptoms. Our findings showed that vestibular encoding of lateral translation correlated with medial-lateral postural sway, consistent with lateral translation cues contributing to balance control. This adds support to the hypothesis that vestibular noise contributes to spontaneous postural sway.

Diagnosing Myasthenia Gravis With Repetitive Ocular Vestibular Evoked Myogenic Potentials.

Timely and accurate diagnosis of myasthenia gravis, particularly in patients with fluctuating, isolated ocular involvement, remains challenging. Serological antibody testing and repetitive nerve stimulation of peripheral muscles usually have low sensitivity in these patients. Edrophonium testing may cause adverse events, single-fiber electromyography (SFEMG) is time-consuming and both tests are often unavailable outside specialized institutions. Repetitive ocular vestibular evoked myogenic potential (roVEMP) stimulation has recently been introduced to facilitate the diagnosis of myasthenia gravis. Similar to repetitive nerve stimulation, roVEMPs detect muscle decrements with the benefit of being non-invasive and allowing for direct measurement of the extraocular muscles. This review summarizes the clinical evidence of the diagnostic value of roVEMP for myasthenia. Prospective clinical trials have demonstrated high sensitivity and specificity. RoVEMPs are of particular interest in challenging myasthenia subgroups with isolated ocular involvement, negative serology, and/or negative conventional electrophysiological results. Optimal roVEMP repetition rates of 20-30 Hz have been identified. This promising novel diagnostic tool merits further attention and investigation to establish its value as a clinical test for myasthenia.

Depression in myasthenia gravis: a heterogeneous and intriguing entity.

BACKGROUND: Depressive symptoms in myasthenia gravis (MG) are common, may mimic other disease features, and contribute to misdiagnosis and diagnostic delay. Nevertheless, the clinical determinants of depressive symptoms in MG remain poorly studied, in particular their overlap with fatigue. Moreover, studies in MG have rarely looked at distinct depression phenotypes. METHODS: In 68 consecutive MG patients, we ascertained cognitive-affective and somatic depression with the Beck Depression Inventory (BDI), and also assessed age at disease onset, education, marital state, work ability, sleepiness, fatigue, and treatment modalities. Disease severity was graded according to the Myasthenia Gravis Foundation of America (MGFA) classification. RESULTS: The prevalence of moderate-severe depression was 20.5%. While depression and fatigue showed large overlap (n = 37, 54.4%), only fatigue increased with disease severity, while BDI scores did not. Thymectomy was independently associated with lower BDI scores, but had no impact on fatigue. Total BDI scores were similar in patients with predominantly cognitive-affective and with predominantly somatic depression. However, ESS correlated only with cognitive-affective BDI, and younger age was independently associated with cognitive-affective BDI. Conversely, female sex and thymectomy were independently associated with somatic BDI. CONCLUSIONS: Depression and fatigue are highly prevalent and largely overlapping comorbidities in MG, but only fatigue increased with disease severity, and only depression was milder in thymectomized patients. Comparative use of BDI subscales in MG reveals distinct depression phenotypes with distinct correlations to other disease features.

The eyes wake up: Screening for benign paroxysmal positional vertigo with polysomnography.

OBJECTIVE: While positional nystagmus of benign paroxysmal positional vertigo (BPPV) has been shown to be detectable in electrooculography (EOG) tracings of polysomnography (PSG), the frequency of undiagnosed BPPV in patients referred for sleep-wake examination has never been investigated. METHODS: Prospective evaluation of positional nystagmus in 129 patients, referred to a neurological sleep laboratory for sleep-wake examination with PSG. Both in the evening and morning, patients had diagnostic positioning maneuvers under ongoing EOG-PSG registration, followed by visual inspection of EOG for positional nystagmus. RESULTS: In 19 patients (14.7%), we found patterns of positional nystagmus, typically appearing few seconds after changes in head position. In 9 of these patients (47%), the nystagmus was also provoked by the positioning maneuvers. Nystagmus only occurred during wakefulness, not during sleep. In a patient with severe cupulolithiasis, we observed disappearance of nystagmus while entering N1 sleep stage. Nocturnal positional nystagmus was independently associated with positive positioning maneuvers. CONCLUSIONS: Inspection of EOG-PSG demonstrated that positional nystagmus is common, occurring only when wake, and independently associated with positive positioning maneuvers. SIGNIFICANCE: By routinely searching for positional nystagmus in PSG, sleep physicians may substantially contribute to the identification of patients with so-far undiagnosed BPPV.

Distinct Vestibular Evoked Myogenic Potentials in Patients With Parkinson Disease and Progressive Supranuclear Palsy.

Background: Early brainstem neurodegeneration is common in Parkinson's disease (PD) and progressive supranuclear palsy (PSP). While previous work showed abnormalities in vestibular evoked myogenic potentials (VEMPs) in patients with either disorder as compared to healthy humans, it remains unclear whether ocular and cervical VEMPs differ between PD and PSP patients. Methods: We prospectively included 12 PD and 11 PSP patients, performed ocular and cervical VEMPs, and calculated specific VEMP scores (0 = normal, 12 = most pathological) based on latencies, amplitude, and absent responses. In addition, we assessed disease duration, presence of imbalance, motor asymmetry, and motor disability using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III). Moreover, we ascertained various sleep parameters by video-polysomnography. Results: PSP and PD patients had similar oVEMP scores (6 [3-6] vs. 3 [1.3-6], p = 0.06), but PSP patients had higher cVEMP scores (3 [0-6] vs. 0 [0-2.8], p = 0.03) and total VEMP scores (9 [5-12] vs. 4 [2-7.5], p = 0.01). Moreover, total VEMP scores >10 were only observed in PSP patients (45%, p = 0.01). MDS-UPDRS III correlated with cVEMP scores (rho = 0.77, p = 0.01) in PSP, but not in PD. In PD, but not in PSP, polysomnographic markers of disturbed sleep, including decreased rapid eye movement sleep, showed significant correlations with VEMP scores. Conclusions: Our findings suggest that central vestibular pathways are more severely damaged in PSP than in PD, as indicated by higher cervical and total VEMP scores in PSP than PD in a between-groups analysis. Meaningful correlations between VEMPs and motor and non-motor symptoms further encourage its use in neurodegenerative Parkinsonian syndromes.

Repetitive ocular vestibular evoked myogenic potential stimulation for the diagnosis of myasthenia gravis: Optimization of stimulation parameters.

OBJECTIVE: To determine the most effective stimulation parameters for the diagnosis of ocular myasthenia gravis (MG) using repetitive ocular vestibular evoked myogenic potentials (oVEMP) for quantification of the extraocular muscle response decrement. METHODS: Repetitive bone-conducted oVEMPs were elicited in 18 MG patients and 20 healthy subjects. We compared four different stimulus repetition rates (20 Hz, 30 Hz, 40 Hz, 50 Hz) and 100 Hz continuous stimulation, as well as recordings from the inferior oblique muscles and the lateral rectus muscles to determine the most sensitive and specific oVEMP parameters for decrement detection. RESULTS: Repetitive stimulation at all tested repetition rates with recordings from inferior oblique muscles allowed for effective differentiation between MG patients and healthy subjects. Among all repetition rates, 30 Hz showed a trend towards superiority, with a sensitivity of 71% and a specificity of 94% (area under the curve (AUC) 0.88) when using the smaller decrement of the two eyes and -10% as cutoff. Considering the larger decrement for analysis (-9% as cutoff), sensitivity increased to 82%, but specificity decreased to 78% (AUC 0.81). CONCLUSIONS: Our study demonstrates, that repetitive oVEMP stimulation elicits a robust decrement in the inferior oblique muscles of MG patients at repetition rates between 20 Hz and 50 Hz, with a probable optimum at 30 Hz. SIGNIFICANCE: Repetitive inferior oblique oVEMP stimulation with optimal stimulus parameters facilitates early and accurate diagnosis of ocular MG.

Impact of autoimmune comorbidity on fatigue, sleepiness and mood in myasthenia gravis.

BACKGROUND: Disease burden in myasthenia gravis (MG) and in other autoimmune disorders is often determined by common accompanying symptoms such as fatigue, sleepiness and mood disturbances. Many MG patients have a second autoimmune disease, but it is unclear whether autoimmune comorbidities add to the severity of fatigue, sleepiness and mood disturbances. METHODS: We ascertained the presence of autoimmune comorbidities in 69 well-characterized MG patients. To assess fatigue, sleepiness and mood disturbances, we applied the Fatigue Severity Scale (FSS), the Fatigue Impact Scale (FIS), the Epworth Sleepiness Scale (ESS), as well as the Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI) to all patients. RESULTS: Thirteen MG patients had concomitant autoimmune thyroid disease (AITD), including 1 patient with rheumatoid arthritis as third autoimmune disease. Fatigue (68.1%), excessive daytime sleepiness (14.5%), moderate-severe depression (20.3%) and anxiety (26.1%) were common, but MG patients with and without autoimmune comorbidities had similar FSS, FIS, ESS, BDI and STAI scores. The presence of autoimmune comorbidities was not associated with altered clinical and immunological MG characteristics, but MG patients with autoimmune comorbidities have more often been treated with corticosteroids than patients without autoimmune comorbidities (92.3% vs. 60.7%; p = 0.03). CONCLUSIONS: While many MG patients were affected by fatigue, sleepiness, depression and anxiety, the present study does not suggest that coexisting autoimmune diseases substantially contribute to the magnitude of these cumbersome comorbid symptoms. However, the higher frequency of steroid treatment may have counterbalanced the effects of the autoimmune comorbidity.

Validation of the Russian version of the Fatigue Impact Scale and Fatigue Severity Scale in multiple sclerosis patients.

BACKGROUND: Fatigue is a common complaint in patients with multiple sclerosis (MS), and its detection and monitoring are based on self-reported questionnaires. The objective of this study was to validate the Russian translation of the Fatigue Impact Scale (FIS) and the Fatigue Severity Scale (FSS) in MS patients and controls. METHODS: We included 85 MS patients and 250 age-, sex-, and body mass index (BMI)-matched controls. We ascertained in all subjects levels of education, marital status, and comorbidities, such as sleepiness (using the Epworth Sleepiness Scale, ESS), anxiety and depression (using the Hospital Anxiety and Depression Scale, HADS). The expanded disability status scale (EDSS) reflected physical disability in MS. RESULTS: The Russian versions of the three FIS subscales (cognitive, physical, and psychosocial) and FSS had excellent internal consistencies (Cronbach's α coefficients 0.88-0.96), and good test-retest stability with intraclass coefficients between 0.78 and 0.89. Both convergent and discriminant validity of the Russian FIS and FSS appeared to be good, as expressed by strong inter-correlations between FIS subscales and FSS, and by absent associations between fatigue scales and BMI. Principal components analysis and scree plots indicated unidimensional structures of the physical and cognitive FIS subscales and FSS, but a multidimensional structure of the psychosocial subscale. We identified EDSS and anxiety scores as independent predictors of more severe fatigue in MS. SIGNIFICANCE: The Russian FIS and FSS represent reliable and valid tools for efficient quantification and monitoring of fatigue severity and its clinical impact in MS. EDSS and anxiety are important contributors to fatigue severity in MS.

Cerebellar contributions to self-motion perception: evidence from patients with congenital cerebellar agenesis.

The cerebellum was historically considered a brain region dedicated to motor control, but it has become clear that it also contributes to sensory processing, particularly when sensory discrimination is required. Prior work, for example, has demonstrated a cerebellar contribution to sensory discrimination in the visual and auditory systems. The cerebellum also receives extensive inputs from the motion and gravity sensors in the vestibular labyrinth, but its role in the perception of head motion and orientation has received little attention. Drawing on the lesion-deficit approach to understanding brain function, we evaluated the contributions of the cerebellum to head motion perception by measuring perceptual thresholds in two subjects with congenital agenesis of the cerebellum. We used a set of passive motion paradigms that activated the semicircular canals or otolith organs in isolation or combination, and compared results of the agenesis patients with healthy control subjects. Perceptual thresholds for head motion were elevated in the agenesis subjects for all motion protocols, most prominently for paradigms that only activated otolith inputs. These results demonstrate that the cerebellum increases the sensitivity of the brain to the motion and orientation signals provided by the labyrinth during passive head movements.

Ocular vestibular evoked myogenic potentials as a test for myasthenia gravis.

OBJECTIVE: To explore whether ocular vestibular evoked myogenic potentials (oVEMP) can be used to detect a decrement in the extraocular muscle activity of patients with myasthenia gravis (MG). METHODS: Twenty-seven patients with MG, including 13 with isolated ocular and 14 with generalized MG, and 28 healthy controls participated. We applied repetitive vibration stimuli to the forehead and recorded the activity of the inferior oblique muscle with 2 surface electrodes placed beneath the eyes. To identify the oVEMP parameters with the highest sensitivity and specificity, we evaluated the decrement over 10 stimulus repetitions at 3 different repetition rates (3 Hz, 10 Hz, and 20 Hz). RESULTS: Repetitive stimulation at 20 Hz yielded the best differentiation between patients with MG and controls with a sensitivity of 89% and a specificity of 64% when using a unilateral decrement of ≥15.2% as cutoff. When using a bilateral decrement of ≥20.4% instead, oVEMP allowed differentiation of MG from healthy controls with 100% specificity, but slightly reduced sensitivity of 63%. For both cutoffs, sensitivity was similar in isolated ocular and generalized MG. CONCLUSION: Our study demonstrates that the presence of an oVEMP decrement is a sensitive and specific marker for MG. This test allows direct and noninvasive examination of extraocular muscle activity, with similarly good diagnostic accuracy in ocular and generalized MG. Thus, oVEMP represents a promising diagnostic tool for MG. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that oVEMP testing accurately identifies patients with MG with ocular symptoms (sensitivity 89%, specificity 64%).

Automated Romberg testing in patients with benign paroxysmal positional vertigo and healthy subjects.

OBJECTIVE: Benign paroxysmal positional vertigo (BPPV) is the most common cause of dizziness. The underlying pathomechanism responsible for the recurrent vertigo attacks has been elucidated in detail and highly effective treatment strategies (liberation maneuvers) have been developed. However, many BPPV patients complain about problems of balance especially following liberation maneuvers. AIM: To objectively demonstrate differences in balance performance in BPPV patients compared to healthy subjects both prior and after BPPV liberation maneuvers. METHODS: Seven patients with BPPV of the posterior semicircular canal and nine healthy subjects participated. To assess balance while standing, we analyzed the location and temporal stability of the center of pressure recorded by pressure-sensitive electronic soles during Romberg testing (on stable ground and on foam) and tandem stand. To assess regularity of gait, we analyzed the step frequency during walking of 50 m. All tests were performed prior and after liberation maneuvers in both groups. RESULTS: Healthy subjects and patients differ significantly in their balance performance and use different stabilization strategies both prior and after liberation maneuvers. Both Romberg tests indicated poorer balance in BPPV patients (mean COP shifted towards toes), especially in posttreatment tests, while tandem stand appeared unaltered. We did not observe differences in escorted (by an experimenter) walking regularities between patients and healthy subjects and between pre- and post-maneuver testing. CONCLUSION AND SIGNIFICANCE: Our findings confirm the typical clinical observation of a further posttreatment deterioration of already impaired postural performance in BPPV patients. While the etiology and the time course of this peculiar problem warrants further studies, the treating physician should be familiar with this transient side effect of therapeutic maneuvers to provide adequate counseling of patients. Finally, we successully demonstrated the pressure-sensitive electronic soles as a new and potentially useful tool for both clinical and research purposes.

Motion Perception in Patients with Idiopathic Bilateral Vestibular Hypofunction.

We measured vestibular perceptual thresholds in patients with idiopathic bilateral vestibulopathy to assess the distribution of peripheral vestibular damage in this disorder. Thresholds were measured with standard psychometric techniques in 4 patients and compared with thresholds in normal subjects and patients with completely absent peripheral vestibular function. Motion paradigms included yaw rotation (testing the lateral canals), interaural translation (testing the utricles), superior-inferior translation (testing the saccules), and roll tilt (testing the vertical semicircular canals and the otolith organs). We found that perceptual thresholds were abnormally elevated in the patients with idiopathic bilateral vestibulopathy for yaw rotation at all frequencies and for interaural translation at only the lower frequencies. Thresholds were normal for the other 2 motion paradigms. The results demonstrate that the distribution of vestibular dysfunction in this disorder is not uniform but, rather, can affect lateral canal and utricular thresholds while relatively sparing vertical canal and saccular function.

Vestibular labyrinth contributions to human whole-body motion discrimination.

To assess the contributions of the vestibular system to whole-body motion discrimination in the dark, we measured direction recognition thresholds as a function of frequency for yaw rotation, superior-inferior translation ("z-translation"), interaural translation ("y-translation"), and roll tilt for 14 normal subjects and for 3 patients following total bilateral vestibular ablation. The patients had significantly higher average threshold measurements than normal (p < 0.01) for yaw rotation (depending upon frequency, 5.4× to 15.7× greater), z-translation (8.3× to 56.8× greater), y-translation (1.7× to 4.5× greater), and roll tilt (1.3× to 3.0× greater)--establishing the predominant contributions of the vestibular system for these motions in the dark.

Experimental parameter estimation of a visuo-vestibular interaction model in humans.

Visuo-vestibular interactions in monkeys can be accurately modelled using the classical Raphan and Cohen's model. This model is composed of direct vestibular and visual contributions to the vestibulo-ocular reflex (VOR) and of a velocity storage. We applied this model to humans and estimated its parameters in a series of experiments: yaw rotations at moderate (60°/s) and high velocities (240°/s), suppression of the VOR by a head-fixed wide-field visual stimulus, and optokinetic stimulation with measurements of optokinetic nystagmus (OKN) and optokinetic afternystagmus (OKAN). We found the velocity storage time constant to be 13 s, which decreased to 8 s during visual suppression. OKAN initial velocity was 12% of the OKN stimulus velocity. The gain of the direct visual pathway was 0.75 during both visual suppression and OKN; however, the visual input to the velocity storage was higher during visual suppression than during OKN. We could not estimate the time constant of the semicircular canals accurately. Finally, we inferred from high-velocity rotations that the velocity storage saturates around 20-30°/s. Our results indicate that the dynamics of visuo-vestibular interactions in humans is similar as in monkeys. The central integration of visual cues, however, is weaker in humans.

Relative diagnostic value of ocular vestibular evoked potentials and the subjective visual vertical during tilt and eccentric rotation.

OBJECTIVE: We compared vibration-induced ocular vestibular evoked myogenic potentials (OVEMPs) with the visual vertical during whole-body roll tilt and eccentric rotation in healthy subjects and patients with unilateral vestibular loss, to determine which test was most sensitive in discriminating impaired utricle function. METHODS: OVEMPs and the visual vertical were measured in 11 patients and 11 healthy subjects. Visual vertical was measured during roll tilts between -9.6° and 9.6°, and during rotation at 400°/s with the head upright and the vertical rotation axis located between ±3.5 cm from the head center. RESULTS: OVEMPs in patients were strikingly asymmetric, whereas they were approximately symmetric in healthy subjects. Patients showed impaired visual vertical gain during eccentric rotation and increased errors for both roll tilt and eccentric rotation tests. OVEMPs were superior at discriminating between patients and healthy subjects, although eccentric rotation performed nearly as well. CONCLUSIONS: OVEMPs provide a powerful test for discriminating between healthy subjects and patients with chronic unilateral vestibular loss, and testing the visual vertical testing during eccentric rotation was superior to testing during whole-body roll tilt. SIGNIFICANCE: OVEMPs are easier to administer, less demanding on patients, and in general are more effective at identifying chronic unilateral vestibular loss than visual vertical measurements.