BACKGROUND:Diagnosing ocular myasthenia gravis (OMG) remains challenging despite recent diagnostic advances. We addressed this challenge by developing and validating a multivariable prediction model that estimates the OMG probability given the results of any partial selection of available diagnostic tests. METHODS:The source data for our model were retrieved from our blinded prospective diagnostic accuracy study at the University Hospital Zurich (USZ). Patients with ptosis and/or diplopia whose presentation was suspicious for OMG underwent comprehensive diagnostic testing. An independent neuromuscular specialist made the final diagnosis. These data were used to fit and validate a Bayesian network model against additional retrospective USZ and the University of Toronto (UoT) patient data. The primary outcome was to predict the likelihood of a positive OMG diagnosis given the available diagnostic tests. For any set of tests, the model returns an OMG probability together with 95% credible intervals, indicating the prediction uncertainty. RESULTS:Of 89 patients included in the development of the model, 39 were diagnosed with OMG. Based on our Bayesian network model, the following variables were the most useful predictors in descending order: edrophonium test, acetylcholine receptor (AChR) antibodies), single-fiber electromyogram (sfEMG), repetitive nerve stimulations (RNS) facial nerve, RNS accessory nerve, Besinger score, ice test, sustained upgaze test, dysarthria, dyspnea, dysphagia, diplopia, ptosis, age, and sex. The model was validated by determining the mean error rate and the area under the curve (AUC) by both 10-fold cross-validation and prediction on the retrospective USZ and UoT validation data consisting of 69 and 24 patients, respectively. Of all variables, edrophonium (sensitivity 94%, specificity 90%) and AChR antibody testing (sensitivity 85%, specificity 96%) showed the highest predictive value during validation with an AUC of 0.912 and 0.872, respectively. Incorporating more predictors reduced the predictive error in both validation data sets. CONCLUSIONS:Our prediction model serves as a basis to predict the OMG likelihood. It underwent successful internal and external validation and can be used to assist in clinical decision making.

BACKGROUND:Little is known about the characteristics and occurrence frequencies of rapid eye movements (REMs) during REM sleep in movement disorders. OBJECTIVES:The aim of this study was to detect and characterize REMs during polysomnographically defined REM sleep as recorded by electro-oculography (EOG) in 12 patients with progressive supranuclear palsy (PSP), 13 patients with Parkinson's disease (PD) and 12 healthy controls. METHODS:Using a modified EOG montage, we developed an algorithm that automatically detects and characterizes REMs during REM sleep based on their presumptive saccadic kinematics. RESULTS:Compared to PD and healthy controls, REM densities and REM peak velocities were significantly reduced in PSP. These effects were most pronounced in vertical REMs. CONCLUSION:Ocular motor dysfunction, one of the cardinal features of PSP, seems to be equally at play during REM sleep and wakefulness. For future studies, we provide a novel tool for the unbiased analysis of REMs during REM sleep in movement disorders.

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.

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.

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.

Mood disorders are the most common comorbidity in patients with myasthenia gravis (MG). In particular, anxiety and depression are not often diagnosed and treated. The aim is a comprehensive assessment of anxiety and depression in MG patients, using newly validated Russian versions of international questionnaires.

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. 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. 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. 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.

During weekdays, many of us fail meeting their physiologic sleep need. During weekends, however, when given additional sleep opportunity, homeostatic sleep pressure will typically lead to longer bedtimes, manifesting the cumulative sleep debt. This study aims at examining the prevalence and determinants of sleep debt, as indicated by the presence of ≥ 2 h weekend bedtime prolongation, in a general population. We studied 257 healthy subjects living in St. Petersburg, Russia. All participants indicated their habitual bedtimes during weekdays and weekends, and completed the Epworth Sleepiness Scale (ESS), Fatigue Severity Scale, Fatigue Impact Scale, Pittsburgh Sleep Quality Index, and Hospital Anxiety and Depression Scale. One-hundred-three participants (40%) exhibited a relevant sleep debt (≥ 2 h weekend–weekday difference in habitual bedtime). Compared to participants without sleep debt, the frequency of excessive daytime sleepiness (ESS score ≥ 11)—but not of fatigue, impaired sleep quality and mood disturbances—was higher in participants with sleep debt (21% vs. 10%, p = 0.01). Multiple regression analysis revealed younger age, higher ESS and lower body mass index as independent associates of sleep debt. Sleep debt appeared to be very common among healthy subjects, and independently associated with younger age, higher ESS scores and lower BMI. However, the presence of sleep debt did not have an impact on fatigue or mood, as measured by validated questionnaires.

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.

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.

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.

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.

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.

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.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.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.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.

The subjective feeling of fatigue in myasthenia gravis (MG) is poorly elucidated, in part because it is often confounded with the objective sign of muscle fatigability. Another reason is the paucity of validated fatigue questionnaires in MG.

A 31-year-old woman with a 4-day history of diplopia showed slow adducting saccades in the left eye (pseudo–internuclear ophthalmoplegia [P-INO]1,2; see video 1 at [Neurology.org][1]), left inferior rectus muscle weakness, and upper limb fatigability. Edrophonium testing with transient resolution of P-INO led to a diagnosis of myasthenia gravis (MG) (see video 2), which was later confirmed by positive acetylcholine receptor antibodies. [1]: http://neurology.org/lookup/doi/10.1212/WNL.0000000000003985

To determine if the cerebellum contributes to extraction of self-motion information from the vestibular signals provided by the labyrinth

Zusammenfassung. Die Kombination von fluktuierender und belastungsabhängiger Diplopie, Ptose und paretischem Lidschluss – unter Aussparung der Pupillomotorik – ist pathognomonisch für die okuläre Myasthenie. In den ersten zwei Jahren kommt es bei 80 % der Patienten zu einer Generalisierung, mit Entwicklung bulbärer Beschwerden und Schwäche in der Extremitätenmuskulatur. Die Diagnose der okulären Myasthenie gelingt wegen des oft schleichenden Auftretens, der schwierigen Abgrenzung zu anderen neuroophthalmologischen und neurologischen Krankheitsbildern und der niedrigen Sensitivität der apparativen Untersuchungen oft nur mit Verspätung. Eine rasche Diagnose ist wichtig, da effiziente Therapieoptionen eine gute Symptomkontrolle erlauben und weil eine frühe Immunsuppression die Häufigkeit der Konversion zu einer generalisierten Form reduzieren kann.