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.

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.

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.

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.

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.

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.

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.

θ-burst stimulation of the cerebellum interferes with internal representations of sensory-motor information related to eye movements in humans.

Continuous theta-burst stimulation (cTBS) applied over the cerebellum exerts long-lasting effects by modulating long-term synaptic plasticity, which is thought to be the basis of learning and behavioral adaptation. To investigate the impact of cTBS over the cerebellum on short-term sensory-motor memory, we recorded in two groups of eight healthy subject each the visually guided saccades (VGSs), the memory-guided saccades (MGSs), and the multiple memory-guided saccades (MMGSs), before and after cTBS (cTBS group) or simulated cTBS (control group). In the cTBS group, cTBS determined hypometria of contralateral centrifugal VGSs and worsened the accuracy of MMGS bilaterally. In the control group, no significant differences were found between the two recording sessions. These results indicate that cTBS over the cerebellum causes eye movement effects that last longer than the stimulus duration. The VGS contralateral hypometria suggested that we eventually inhibited the fastigial nucleus on the stimulated side. MMGSs in normal subjects have a better final accuracy with respect to MGSs. Such improvement is due to the availability in MMGSs of the efference copy of the initial reflexive saccade directed toward the same peripheral target, which provides a sensory-motor information that is memorized and then used to improve the accuracy of the subsequent volitional memory-guided saccade. Thus, we hypothesize that cTBS disrupted the capability of the cerebellum to make an internal representation of the memorized sensory-motor information to be used after a short interval for forward control of saccades.

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.

Transcranial magnetic stimulation over the cerebellum and eye movements: state of the art.

Transcranial magnetic stimulation (TMS) transiently induces an electrical field in the tissues beneath the area of application, thereby perturbing local cortical activity if applied over the scalp. It can therefore be used to modulate cerebellar function in healthy humans. Even though the role of the cerebellum in eye movement control and adaptation is well known, few experiments have used eye movements to evaluate the effect of TMS over the cerebellum. Single-pulse TMS over the posterior vermis resulted in impaired accuracy of reflexive saccades, acceleration of smooth pursuit, and coordination of saccades and head movements. TMS over the cerebellar hemisphere decreased pursuit gain. Repetitive TMS (rTMS) over the posterior vermis impaired saccade adaptation in a double-step paradigm. Comparing the effects of TMS on different behavioural paradigms could be useful to test cerebellar control of reflexive and voluntary eye movements, and as a probe of cerebellar plasticity. rTMS appears to be especially interesting since its effects outlast the stimulation period and its behavioural consequences can therefore be measured without interfering with the execution of eye movements or with the experimental procedures.

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.

Seizure frequency and sex steroids in women with partial epilepsy on antiepileptic therapy.

PURPOSE: Neuroactive sex steroids influence neuron excitability, which is enhanced by estradiol (E2) and decreased by progesterone (Pg). In epilepsy, the production, metabolism, biologic availability, and activity of sex hormones may be affected by seizures themselves or by antiepileptic drugs (AEDs). This cross-sectional observational study was aimed at evaluating the relationships between sex steroids, seizure frequency, and other clinical parameters in women with partial epilepsy (PE) on AED treatments. METHODS: Serum E2, Pg, sex hormone binding globulin (SHBG) levels, free E2 (fE2), and E2/Pg ratios were determined during the follicular and luteal phases in 72 adult women with PE, and in 30 healthy controls. Hormonal data were correlated with seizure frequency, age, body weight, body mass index (BMI), disease onset and duration, and AED therapies. RESULTS: In patients, E2, fE2, and Pg levels were lower in both ovarian phases, whereas those of SHBG were higher than in controls. No significant changes in hormone levels and in prevalence of anovulatory cycles were observed between patients grouped according to their seizure frequency. However, when compared with those in healthy controls, luteal fE2 and Pg levels were chiefly impaired in women with more frequent seizures, mostly undergoing AED polytherapies, but not in those with absent or rarer seizures. CONCLUSIONS: The actual changes in sex steroid levels and E2/Pg ratios did not explain an increased seizure frequency in adult women with AED-treated PE, but patients with more severe disease showed more relevant changes in their sex hormone profile and impaired Pg levels during the luteal phase.

Focal epileptic seizures mimicking sleep paralysis.

Sleep paralysis (SP) is a common parasomnia. The diagnostic criteria for SP, as reported in the International Classification of Sleep Disorders, are essentially clinical, as electroencephalography (EEG)-polysomnography (PSG) is not mandatory. We describe a subject whose sleep-related events fulfilled the diagnostic criteria for SP, even though her visual hallucinations were elementary, repetitive and stereotyped, thus differing from those usually reported by patients with SP. Video/EEG-PSG documented the focal epileptic nature of the SP-like episodes.

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.

The N3 potential compared to sound and galvanic vestibular evoked myogenic potential in healthy subjects and in multiple sclerosis patients.

Both sound (s-) and galvanic (g-) vestibular-evoked myogenic potential (VEMP) enable us to study the saccular pathways. However, the VEMP can be abnormal for non-vestibular factors, such as insufficient activation of the sterno-cleido-mastoid (SCM) muscle or a lesion that involves the accessory nucleus and/or nerve or the SCM muscle. These drawbacks do not affect another technique that evaluates the saccular function: the N3 potential. We recorded both the s- and the g-VEMP and the N3 potential in a group of 31 healthy subjects to establish a reference range. The N3 potential and the s-VEMP were recordable bilaterally from all the subjects, whereas the g-VEMP was undetectable uni- or bilaterally in 7 subjects. The latency and amplitude values of the s-VEMP did not differ from those of the g-VEMP. For all three techniques, the latency and amplitude values from the right and from the left recording and/or stimulation side were the same. We suggest using normative latency and amplitude values based on the mean and ratio of the right- and left-side values. The s-VEMP, the N3 potential and the auditory evoked response (ABR) were compared in 15 subjects suffering from multiple sclerosis. The three techniques detected a similar number of abnormalities, but these abnormalities were not correlated. This suggests that these different techniques should be regarded as complementary in evaluating saccular function.

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.