A Case of Anti-Ma2 Encephalitis Presenting with Pendular Torsional Nystagmus.

Antibodies against the neuronal protein Ma2 have been reported in a peculiar form of paraneoplastic encephalitis with prominent involvement of the limbic, brainstem, and diencephalic structures and usually associated with germ cell testicular, lung, or breast cancer. The diagnosis is frequently challenged by atypical clinical manifestations including parkinsonism, sleep disturbances, hypothalamic-pituitary dysfunctions, and motor neuron-like syndrome. In recent years, the advent of monoclonal antibodies targeting immune checkpoints has deeply changed the treatment of different tumors, especially melanoma and lung cancer. However, given their nature, an increasing number of neurological immune-related adverse events, including ocular motor abnormalities, have been described. Here, we report a woman with advanced non-small cell lung cancer treated with anti-PD-L1 durvalumab, presenting with an isolated pendular torsional nystagmus, in association with anti-Ma2 antibodies. This peculiar case widens our knowledge on the clinical presentation of anti-Ma2 encephalitis associated with checkpoint inhibitors.

New-onset myasthenia gravis after mRNA SARS-CoV-2 vaccination: a case series.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease that targets acetylcholine receptor (AChR) of the neuromuscular junction. New-onset MG after SARS-CoV-2 vaccination has rarely been reported. CASE PRESENTATION: We report about three patients who presented new-onset myasthenia gravis after receiving mRNA SARS-CoV-2 vaccination. The patients were all males and older than 55 years. All the patients presented with ocular and bulbar symptoms. The interval between vaccine administration and MG onset ranged from 3 days after the first dose to 10 days after the second dose. All the patients had elevated serum AChR antibodies and responded to pyridostigmine. Two out of three patients were successfully treated with IVIG or plasma exchange and with long-term immunosuppression. CONCLUSIONS: MG is a rare disease; clinicians should be aware of possible new-onset MG after SARS-CoV-2 vaccination, especially with the current recommendation of booster doses. The hyperstimulation of the innate immune system or the exacerbation of a subclinical pre-existing MG could be possible explanations.

Neurophysiological evaluation of visual function in iRBD: potential role in stratifying RBD conversion risk.

STUDY OBJECTIVES: To evaluate neurophysiological alterations of visual function in idiopathic REM sleep Behavior Disorder (iRBD) both as markers and predictors of neurodegenerative disorders. METHODS: In a longitudinal follow-up study of 46 consecutive iRBD patients (follow-up duration 8.4 ± 3.4 years), the baseline parameters in luminance-contrast pattern (VEPp), red-green color (VEPc) and motion-onset (VEPm) Visual Evoked Potentials in iRBD were compared to early (ePD) and advanced (aPD) Parkinson's Disease subjects. Parameters of latency and amplitude of iRBD converters to neurodegenerative disease were compared with those of the non-converters. RESULTS: The VEP P100 mean latency values for both eyes and for both stimulation checks (30' and 15') were significantly longer in all the three groups of patients as compared to controls; moreover latencies were longer in aPD than in the iRBD group who did not differ from the ePD group. The same held true when we analyzed the number of abnormal subjects belonging to each diagnostic group with a higher number of abnormal subjects in the aPD group compared to both the ePD and in iRBD groups. Chromatic and motion potentials were not different from controls and did not differ in the 3 diagnostic groups. The iRBD subjects who converted to a neurodegenerative disorder showed longer P100 latencies and a higher occurrence of VEPp abnormalities than those who did not convert. Again chromatic and motion VEPs were not different depending on conversion. CONCLUSIONS: In iRBD patients the detection of an abnormal VEPp should be considered as a red flag for possible synnucleinopathy, eventually contributing in stratifying the risk of phenoconversion.

RFC1 expansions are a common cause of idiopathic sensory neuropathy.

After extensive evaluation, one-third of patients affected by polyneuropathy remain undiagnosed and are labelled as having chronic idiopathic axonal polyneuropathy, which refers to a sensory or sensory-motor, axonal, slowly progressive neuropathy of unknown origin. Since a sensory neuropathy/neuronopathy is identified in all patients with genetically confirmed RFC1 cerebellar ataxia, neuropathy, vestibular areflexia syndrome, we speculated that RFC1 expansions could underlie a fraction of idiopathic sensory neuropathies also diagnosed as chronic idiopathic axonal polyneuropathy. We retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy) from our general neuropathy clinics in Italy and the UK. All patients underwent full neurological evaluation and a blood sample was collected for RFC1 testing. Biallelic RFC1 expansions were identified in 43 patients (34%) with sensory neuropathy and in none with sensory-motor neuropathy. Forty-two per cent of RFC1-positive patients had isolated sensory neuropathy or sensory neuropathy with chronic cough, while vestibular and/or cerebellar involvement, often subclinical, were identified at examination in 58%. Although the sensory ganglia are the primary pathological target of the disease, the sensory impairment was typically worse distally and symmetric, while gait and limb ataxia were absent in two-thirds of the cases. Sensory amplitudes were either globally absent (26%) or reduced in a length-dependent (30%) or non-length dependent pattern (44%). A quarter of RFC1-positive patients had previously received an alternative diagnosis, including Sjögren's syndrome, sensory chronic inflammatory demyelinating polyneuropathy and paraneoplastic neuropathy, while three cases had been treated with immune therapies.

The integration of multisensory motion stimuli is impaired in vestibular migraine patients.

BACKGROUND: Vestibular migraine (VM) is a relatively recently acknowledged vestibular syndrome with a very relevant prevalence of about 10% among patients complaining of vertigo. The diagnostic criteria for VM have been recently published by the Bárány Society, and they are now included in the latest version of the International Classification of Headache Disorders, yet there is no instrumental test that supports the diagnosis of VM. OBJECTIVE: In the hypothesis that the integration of different vestibular stimuli is functionally impaired in VM, we tested whether the combination of abrupt vestibular stimuli and full-field, moving visual stimuli would challenge vestibular migraine patients more than controls and other non-vestibular migraineurs. METHODS: In three clinical centers, we compared the performance in the functional head impulse test (fHIT) without and with an optokinetic stimulus rotating in the frontal plane in a group of 44 controls (Ctrl), a group of 42 patients with migraine (not vestibular migraine, MnoV), a group of 39 patients with vestibular migraine (VM) and a group of 15 patients with vestibular neuritis (VN). RESULTS: The optokinetic stimulation reduced the percentage of correct answers (%CA) in all groups, and in about 33% of the patients with migraine, in as many as 87% of VM patients and 60% of VN patients, this reduction was larger than expected from controls' data. CONCLUSIONS: The comparison of the fHIT results without and with optokinetic stimulation unveils a functional vestibular impairment in VM that is not as large as the one detectable in VN, and that, in contrast with all the other patient groups, mainly impairs the capability to integrate different vestibular stimuli.

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion.

Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist.

The functional head impulse test: Comparing gain and percentage of correct answers.

OBJECTIVES: The video head impulse test (vHIT) provides as output a gain value that summarizes the behavior of the vestibulo-ocular reflex as the ratio of a measure of eye movement to the corresponding measure of head movement and is not directly informative of the functional effectiveness of the motor response. The functional HIT (fHIT) is based on the ability to recognize the orientation of a Landolt C optotype that briefly appears on a computer screen during passive head impulses imposed by the examiner over a range of head accelerations; accordingly fHIT is a functional measurement of the vestibular-ocular reflex since it measures the capability to keep clear vision and to read during head movement. METHODS: We compared the results of the fHIT with those of the vHIT and the results of the Dizziness Handicap Inventory (DHI) questionnaire in a group of 27 vestibular neuritis patients recorded acutely and at 3-months follow-up. RESULTS: Both the vHIT and fHIT exams correctly classified all patients as abnormal on the affected side when tested in the acute phase. After a 3-month follow-up, both were able to show that compensation phenomena had occurred. Otherwise the data from the two techniques were not correlated. More specifically, the fHIT detected more abnormalities than the vHIT, for head rotation toward the healthy side, both in the acute phase and after 3 months, and for head rotation toward the affected side after 3 months. The asymmetry indices, that compare the performance of the healthy to the affected side, also were larger for the fHIT than for the vHIT both at onset and after 3 months. There was no significant correlation between the different vHIT and fHIT parameters and indices, or with the DHI values after 3 months. CONCLUSIONS: The fHIT data are able to detect a difference between the healthy and the affected side in the acute phase, and they show an improvement after 3 months. fHIT detects more abnormalities than vHIT, but both these techniques lack a correlation with the DHI score.

Anticipatory Postural Adjustments During Gait Initiation in Stroke Patients.

Prior to gait initiation (GI), anticipatory postural adjustments (GI-APA) are activated in order to reorganize posture, favorably for gait. In healthy subjects, the center of pressure (CoP) is displaced backward during GI-APA, bilaterally by reducing soleus activities and activating the tibialis anterior (TA) muscles, and laterally in the direction of the leading leg, by activating hip abductors. In post-stroke hemiparetic patients, TA, soleus and hip abductor activities are impaired on the paretic side. Reduction in non-affected triceps surae activity can also be observed. These may result in a decreased ability to execute GI-APA and to generate propulsion forces during step execution. A systematic review was conducted to provide an overview of the reorganization which occurs in GI-APA following stroke as well as of the most effective strategies for tailoring gait-rehabilitation to these patients. Sixteen articles were included, providing gait data from a total of 220 patients. Stroke patients show a decrease in the TA activity associated with difficulties in silencing soleus muscle activity of the paretic leg, a decreased CoP shift, lower propulsive anterior forces and a longer preparatory phase. Regarding possible gait-rehabilitation strategies, the selected studies show that initiating gait with the paretic leg provides poor balance. The use of the non-paretic as the leading leg can be a useful exercise to stimulate the paretic postural muscles.

The functional head impulse test: preliminary data.

The functional head impulse test is a new test of vestibular function based on the ability to recognize the orientation of a Landolt C optotype that briefly appears on a computer screen during passive head impulses imposed by the examiner over a range of head accelerations. Here, we compare its results with those of the video head impulse test on a population of vestibular neuritis patients recorded acutely and after 3 months from symptoms onset. The preliminary results presented here show that while both tests are able to identify the affected labyrinth and to show a recovery of vestibular functionality at 3 months, the two tests are not redundant, but complementary.

Parahippocampal Involvement in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis: A Proof of Concept from Memory-Guided Saccades.

OBJECTIVE: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) may involve extrahippocampal areas of structural damage and dysfunction. The accuracy of medium-term spatial memory can be tested by memory-guided saccades (MGS) to evaluate a functional impairment of the parahippocampal cortex (PHC), while voxel-based morphometry (VBM) analysis can be used to detect a structural damage of the latter region. METHODS: MGS with 3- and 30-s memorization delays were compared between 7 patients affected by right MTLE-HS (r-MTLE-HS), 6 patients affected by left MTLE-HS, and 13 healthy controls. The same subjects underwent brain MRI for a VBM analysis. Correlation analysis was performed between the results of VBM and MGS and with patients' clinical data. RESULTS: Right MTLE-HS patients showed impaired accuracy of leftward MGS with a 30-s memorization delay; their gray-matter volume was reduced in the right hippocampus and inferior temporal gyrus, and bilaterally in the cerebellum. Left MTLE-HS patients had normal MGS accuracy; their gray-matter volume was reduced in the left hippocampus, in the right-inferior temporal gyrus and corpus callosus, and bilaterally in the insular cortex and in the cerebellum. The difference between right and left parahippocampal volumes correlated with MGS accuracy, while right and left hippocampal volumes did not. Hippocampal and parahippocampal volume did not correlate with clinical variables such as febrile seizures, age at disease onset, disease duration, and seizure frequency. CONCLUSION: MGS abnormalities suggested the functional involvement of the right PHC in patients with r-MTLE-HS, supporting a right lateralization of spatial memory control and showing a relation between functional impairment and degree of atrophy.

Validation of the Italian Version of the Dizziness Handicap Inventory, the Situational Vertigo Questionnaire, and the Activity-Specific Balance Confidence Scale for Peripheral and Central Vestibular Symptoms.

Neurophysiological measurements of the vestibular function for diagnosis and follow-up evaluations provide an objective assessment, which, unfortunately, does not necessarily correlate with the patients' self-feeling. The literature provides many questionnaires to assess the outcome of rehabilitation programs for disequilibrium, but only for the Dizziness Handicap Inventory (DHI) is an Italian translation available, validated on a small group of patients suffering from a peripheral acute vertigo. We translated and validated the reliability and validity of the DHI, the Situational Vertigo Questionnaire (SVQ), and the Activities-Specific Balance Confidence Scale (ABC) in 316 Italian patients complaining of dizziness due either to a peripheral or to a central vestibular deficit, or in whom vestibular signs were undetectable by means of instrumental testing or clinical evaluation. Cronbach's coefficient alpha, the homogeneity index, and test-retest reproducibility, confirmed reliability of the Italian version of the three questionnaires. Validity was confirmed by correlation test between questionnaire scores. Correlations with clinical variables suggested that they can be used as a complementary tool for the assessment of vestibular symptoms. In conclusion, the Italian versions of DHI, SVQ, and ABC are reliable and valid questionnaires for assessing the impact of dizziness on the quality of life of Italian patients with peripheral or central vestibular deficit.

Rigid Ankle Foot Orthosis Deteriorates Mediolateral Balance Control and Vertical Braking during Gait Initiation.

Rigid ankle-foot orthoses (AFO) are commonly used for impeding foot drop during the swing phase of gait. They also reduce pain and improve gait kinematics in patients with weakness or loss of integrity of ankle-foot complex structures due to various pathological conditions. However, this comes at the price of constraining ankle joint mobility, which might affect propulsive force generation and balance control. The present study examined the effects of wearing an AFO on biomechanical variables and electromyographic activity of tibialis anterior (TA) and soleus muscles during gait initiation (GI). Nineteen healthy adults participated in the study. They initiated gait at a self-paced speed with no ankle constraint as well as wearing an AFO on the stance leg, or bilaterally. Constraining the stance leg ankle decreased TA activity ipsilaterally during the anticipatory postural adjustment (APA) of GI, and ipsilateral soleus activity during step execution. In the sagittal plane, the decrease in the stance leg TA activity reduced the backward displacement of the center of pressure (CoP) resulting in a reduction of the forward velocity of the center of mass (CoM) measured at foot contact (FC). In the frontal plane, wearing the AFO reduced the displacement of the CoP in the direction of the swing leg during the APA phase. The mediolateral velocity of the CoM increased during single-stance prompting a larger step width to recover balance. During step execution, the CoM vertical downward velocity is normally reduced in order to lessen the impact of the swing leg with the floor and facilitates the rise of the CoM that occurs during the subsequent double-support phase. The reduction in stance leg soleus activity caused by constraining the ankle weakened the vertical braking of the CoM during step execution. This caused the absolute instantaneous vertical velocity of the CoM at FC to be greater in the constrained conditions with respect to the control condition. From a rehabilitation perspective, passively- or actively-powered assistive AFOs could correct for the reduction in muscle activity and enhance balance control during GI of patients.

New insights into vestibular-saccade interaction based on covert corrective saccades in patients with unilateral vestibular deficits.

In response to passive high-acceleration head impulses, patients with low vestibulo-ocular reflex (VOR) gains often produce covert (executed while the head is still moving) corrective saccades in the direction of deficient slow phases. Here we examined 23 patients using passive, and 9 also active, head impulses with acute (< 10 days from onset) unilateral vestibular neuritis and low VOR gains. We found that when corrective saccades are larger than 10°, the slow-phase component of the VOR is inhibited, even though inhibition increases further the time to reacquire the fixation target. We also found that 1) saccades are faster and more accurate if the residual VOR gain is higher, 2) saccades also compensate for the head displacement that occurs during the saccade, and 3) the amplitude-peak velocity relationship of the larger corrective saccades deviates from that of head-fixed saccades of the same size. We propose a mathematical model to account for these findings hypothesizing that covert saccades are driven by a desired gaze position signal based on a prediction of head displacement using vestibular and extravestibular signals, covert saccades are controlled by a gaze feedback loop, and the VOR command is modulated according to predicted saccade amplitude. A central and novel feature of the model is that the brain develops two separate estimates of head rotation, one for generating saccades while the head is moving and the other for generating slow phases. Furthermore, while the model was developed for gaze-stabilizing behavior during passively induced head impulses, it also simulates both active gaze-stabilizing and active gaze-shifting eye movements.NEW & NOTEWORTHY During active or passive head impulses while fixating stationary targets, low vestibulo-ocular gain subjects produce corrective saccades when the head is still moving. The mechanisms driving these covert saccades are poorly understood. We propose a mathematical model showing that the brain develops two separate estimates of head rotation: a lower level one, presumably in the vestibular nuclei, used to generate the slow-phase component of the response, and a higher level one, within a gaze feedback loop, used to drive corrective saccades.

After Effects of Cerebellar Continuous Theta Burst Stimulation on Reflexive Saccades and Smooth Pursuit in Humans.

The use of cerebellar repetitive transcranial magnetic stimulation has been attempted for perturbing reflexive and voluntary eye movements, but discrepancies are seen between the results of distinct studies possibly due to the different stimulation sites, intensities, and paradigms. We describe the after effects of 20 and 40 s continuous Theta Burst Stimulation (cTBS) as compared to sham stimulation, applied over the lateral cerebellar vermis and paravermis on Reflexive Saccades (RS) and Smooth Pursuit (SP) eye movements, recorded in the 30 min following stimulation. The experiments were carried out in eight healthy volunteers, and eye movements were recorded monocularly with video-oculography. The 40 s cTBS significantly increased the amplitude of ipsilateral RS and the acceleration of the ipsilateral SP, and this effect was detectable all over the 30-min recording period; 40 s cTBS did not modify the other parameters, namely the peak velocity, the duration and the latency of RS, and the latency and the velocity of SP. The 20 s cTBS was ineffective on all RS and SP parameters. Finally, we detected a significant quite-linear reduction of RS peak velocity over time, but this was independent from cTBS and was probably caused by fatigue. The effects of 40 s cTBS in our experiments mimic the disorder of ocular motility in Wallenberg's syndrome and could result from functional impairment of cerebellopontine pathways. This effect lasts 30 min at least, and can provide a useful framework for adaptive ocular motor studies.

Body Sway Increases After Functional Inactivation of the Cerebellar Vermis by cTBS.

Balance stability correlates with cerebellar vermis volume. Furthermore, the cerebellum is involved in precise timing of motor processes by fine-tuning the sensorimotor integration. We tested the hypothesis that any cerebellar action in stance control and in timing of visuomotor integration for balance is impaired by continuous theta-burst stimulation (cTBS) of the vermis. Ten subjects stood quietly and underwent six sequences of 10-min acquisition of center of foot pressure (CoP) data after cTBS, sham stimulation, and no stimulation. Visual shifts from eyes closed (EC) to eyes open (EO) and vice versa were presented via electronic goggles. Mean anteroposterior and mediolateral CoP position and oscillation, and the time delay at which body sway changed after visual shift were calculated. CoP position under both EC and EO condition was not modified after cTBS. Sway path length was greater with EC than EO and increased in both visual conditions after cTBS. CoP oscillation was also larger with EC and increased under both visual conditions after cTBS. The delay at which body oscillation changed after visual shift was longer after EC to EO than EO to EC, but unaffected by cTBS. The time constant of decrease or increase of oscillation was longer in EC to EO shifts, but unaffected by cTBS. Functional inactivation of the cerebellar vermis is associated with increased sway. Despite this, cTBS does not detectably modify onset and time course of the sensorimotor integration process of adaptation to visual shifts. Cerebellar vermis normally controls oscillation, but not timing of adaptation to abrupt changes in stabilizing information.

Ocular vestibular evoked myogenic potentials in response to air-conducted 500 Hz short tones: Effect of stimulation procedure (monaural or binaural), age and gender.

BACKGROUND: The ocular vestibular myogenic potentials (oVEMP) can be elicited by monaural air-conducted sound stimulation, and are usually recorded from the contralateral eye. In clinical setting a binaural stimulation would save time and require less effort from the subjects. OBJECTIVE: We evaluated the differences between monaural and binaural stimulation, and the possible effect of age and gender on oVEMP parameters. METHODS: Air-conducted oVEMP were recorded by binaural and by monaural stimulation in a group of 54 normal subjects, aged from 12 to 83 years, and in 50 vestibular patients. From each side, we measured the latency of the N1 component, and the peak-to-peak N1-P1 amplitude. For both parameters we also computed the asymmetry ratio. RESULTS: In normal subjects binaural stimulation produced slightly larger responses than monaural stimulation; detectability, latency and amplitude ratio were the same for the two techniques. We found no differences related to gender, and the age-induced amplitude decline was likely to be negligible.oVEMP recorded not in an acute phase of their disorder, proved to be abnormal in about 20% of the patients, and the normal or abnormal findings obtained either with monaural or with binaural stimulation were always concordant. CONCLUSIONS: The oVEMP obtained after binaural and monaural stimulation are very similar, and they are largely independent from age and gender.

Reading while moving: the functional assessment of VOR.

The head impulse test (HIT) is nowadays recognized as the gold standard for clinical testing of the angular vestibulo-ocular reflex (VOR). By imposing unpredictable, abrupt head rotations in canal pairs' planes it aims at unveiling the dysfunction of the semicircular canal towards which the head is rotated based on Ewald's II law. Functional testing of the VOR aims at assessing the ability of the reflex to stabilize gaze in space and thus allow clear vision during head movements. The HIT device (HITD) approach exploits impulsive head rotations spawning a range of angular accelerations while requiring subjects to identify optotypes briefly displayed on a screen. Here we also recorded eye movements, so that the evaluation of the individual subject is based both on the VOR gain and on the percentage of correct answers with respect to a population of controls. Here we used the HITD to study 14 patients suffering from vestibular neuritis and 7 of those were re-tested after three months. We found that the HITD was able to unveil the ipsilesional deficit and the contralesional impairment, together with the improvement in the follow-up test.