Central nervous system immune-related disorders after SARS-CoV-2 vaccination: a multicenter study.

Background: COVID-19 vaccines have been approved due to their excellent safety and efficacy data and their use has also permitted to reduce neurological complications of SARS-CoV-2. However, clinical trials were underpowered to detect rare adverse events. Herein, the aim was to characterize the clinical spectrum and immunological features of central nervous system (CNS) immune-related events following SARS-CoV-2 vaccination. Methods: Multicenter, retrospective, cohort study (December 1, 2020-April 30, 2022). Inclusion criteria were (1) de novo CNS disorders developing after SARS-CoV-2 vaccination (probable causal relationship as per 2021 Butler criteria) (2); evidence for an immune-mediated etiology, as per (i) 2016 Graus criteria for autoimmune encephalitis (AE); (ii) 2015 Wingerchuk criteria for neuromyelitis optica spectrum disorders; (iii) criteria for myelitis. Results: Nineteen patients were included from 7 tertiary referral hospitals across Italy and France (one of them being a national referral center for AE), over almost 1 year and half of vaccination campaign. Vaccines administered were mRNA-based (63%) and adenovirus-vectored (37%). The median time between vaccination and symptoms onset was 14 days (range: 2-41 days). CSF was inflammatory in 74%; autoantibodies were detected in 5%. CSF cytokine analysis (n=3) revealed increased CXCL-10 (IP-10), suggesting robust T-cell activation. The patients had AE (58%), myelitis (21%), acute disseminated encephalomyelitis (ADEM) (16%), and brainstem encephalitis (5%). All patients but 2 received immunomodulatory treatment. At last follow-up (median 130 days; range: 32-540), only one patient (5%) had a mRS>2. Conclusion: CNS adverse events of COVID-19 vaccination appear to be very rare even at reference centers and consist mostly of antibody-negative AE, myelitis, and ADEM developing approximately 2 weeks after vaccination. Most patients improve following immunomodulatory treatment.

Systemic Connective Tissue Disease and Neuromyelitis Optica Spectrum Disorder Coexistence: A Systematic Review and Meta-Analysis.

BACKGROUND: Several results support the hypothesis that a group of pathologies falling within the Neuromyelitis Optica Spectrum Disorders (NMOSD) diagnostic criteria may coexist with Connective Tissue Diseases (CTD) in patients with a high susceptibility to autoimmune conditions. However, the relationship between NMOSD and rheumatologic diseases deserves further investigations to clarify all clinical aspects of this coexistence. We designed a systematic review and a proportional meta-analysis to estimate the association between CTD and MNOSD, with the aim of helping to plan the best strategy to achieve the most significant public health benefit for these conditions. METHODS: We conducted a systematic review of the literature published until February 2023, searching in four databases: PubMed, Web of Science, EmBase, and OVID. Then, we conducted a random-effects proportional meta-analysis and assessed the risk of bias of the included studies using the Joanna Briggs Institute checklist. RESULTS: The literature search yielded an overall result of 3176 publications (272 from PubMed, 880 from Web of Science, 634 from EmBase and 1390 from OVID). Of these, 29 were included in this systematic review. Analyzing studies that recruited unselected patients with Systemic Lupus Erythematosus (SLE) and Sjogren Syndrome (SjS), the pooled percentages of NMOSD overlapping were 0.6% (95% Confidence Interval [95% CI]: 0.1%-1.4%,) and 6.5% (95% CI: 4.7-8.6), respectively. Studies enrolling rheumatologic patients with nervous system symptoms involvement reported higher percentage of NMOSD (i.e., among SjS patients, a pooled percentage of 26.5%, 95% CI: 5.5-54.6%, was found). Similarly, recruiting patients with NMOSD, we found pooled percentages of SjS or SLE respectively of 7.0% and 3.5%. CONCLUSIONS: Our research found that the coexistence of these two disorders was more frequent in female rheumatologic patients with a SjS diagnosis with neurological manifestations and in neurologic patients for whom a SjS diagnosis was suspected. Similarly, NMOSD are less frequently found in SLE and very rarely incident in Mixed Connective Tissue Disease (MCTD) patients. These considerations should be taken into account in clinical experience of rheumatologists and neurologists, since early diagnosis of both conditions may influence the timing of immunosuppressive therapy and the prevention of systemic disabilities.

SOX-1 antibodies in a patient with Crohn's disease: a case report.

BACKGROUND: The anti-SOX-1 antibodies have been mainly associated with Lambert-Eaton Myasthenic Syndrome (LETMS) and Small-Cell Lung Cancer (SCLC). In this report, we describe the interesting case of a patient with serum anti-SOX-1 antibodies and Crohn's Disease (CD) with ensuing neurological symptoms. CASE PRESENTATION: A Caucasian 67-year-old female was admitted to the Emergency Department with seizures, vertigo, emesis, nausea, postural instability and recurrent falls, over a period of 10 days. She had been affected by Crohn's Disease since 1991. A CT scan failed to detect any ischemic or haemorrhagic lesion. A brain MRI revealed signs of leukoencephalopathy. Western blot analysis of her serum revealed a high titre of the onconeural antibody anti-SOX1, consistent with a neurological, cerebellar type, paraneoplastic syndrome. In spite of multiple efforts to unmask a possible underlying malignancy, no neoplastic lesion cropped up during hospitalization. Her clinical conditions progressively deteriorated, up to respiratory failure; a few days later she died, due to ensuing septic shock and Multiple Organ Failure. CONCLUSIONS: Our experience may usher and reveal a new role of anti-neural antibodies, so far reckoned an early indicator of associated malignancy, suggesting that neurological syndromes associated with such antibodies may complicate also chronic Gastrointestinal (GI) diseases. As of now, testing for anti-neuronal antibodies appeared unnecessary within the diagnostic assessment of gastroenterological disorders, which may lead to overlooking incident neurologic autoimmune diseases. Further exploration of such research hypothesis in clinical grounds appears intriguing.

Brainstem Reflexes in Idiopathic Cervical Dystonia: Does Medullary Dysfunction Play a Role?

BACKGROUND: Neurophysiological markers in dystonia have so far not been sistematically applied in clinical practice due to limited reproducibility of results and low correlations with clinical findings. Exceptions might be represented by the blink reflex (BR), including its recovery cycle (BRRC) and the trigemino-cervical reflex (TCR) which, compared to other neurophysiological methods, have shown more consistent alterations in cervical dystonia (CD). However, a comparison between the two techniques, and their possible correlation with disease symptoms, have not been thoroughly investigated. OBJECTIVES: To assess the role of BR, BRCC and TCR in the pathophysiology of idiopathic cervical dystonia. METHODS: Fourteen patients and 14 age-matched healthy controls (HC) were recruited. Neurophysiological outcome measures included latency of R1 and R2 components of the BR, R2 amplitude, BRRC, latency and amplitude of P19/N31 complex of TCR. Clinical and demographic features of patients were also collected, including age at disease onset, disease duration, presence of tremor, sensory trick and pain. The Toronto Western Spasmodic Torticollis Rating Scale was used to characterize dystonia. RESULTS: Compared to HC, CD patients showed increased latency of the BR R2 and decreased suppression of the BRRC. They also showed increased latency of the P19 and decreased amplitude of P19/N31 complex of TCR. The latency of P19 component of TCR was positively correlated with disease duration. CONCLUSIONS: We propose that the increased latency of R2 and P19 observed here might be reflective of brainstem dysfunction, mediated either by local interneuronal excitability changes or by subtle structural damage.

Magnetic Resonance Parkinsonism Index: diagnostic accuracy of a fully automated algorithm in comparison with the manual measurement in a large Italian multicentre study in patients with progressive supranuclear palsy.

OBJECTIVES: To investigate the reliability of a new in-house automatic algorithm for calculating the Magnetic Resonance Parkinsonism Index (MRPI), in a large multicentre study population of patients affected by progressive supranuclear palsy (PSP) or Parkinson's disease (PD), and healthy controls (HC), and to compare the diagnostic accuracy of the automatic and manual MRPI values. METHODS: The study included 88 PSP patients, 234 PD patients and 117 controls. MRI was performed using both 3T and 1.5T scanners. Automatic and manual MRPI values were evaluated, and accuracy of both methods in distinguishing PSP from PD and controls was calculated. RESULTS: No statistical differences were found between automated and manual MRPI values in all groups. The automatic MRPI values differentiated PSP from PD with an accuracy of 95 % (manual MRPI accuracy 96 %) and 97 % (manual MRPI accuracy 100 %) for 1.5T and 3T scanners, respectively. CONCLUSION: Our study showed that the new in-house automated method for MRPI calculation was highly accurate in distinguishing PSP from PD. Our automatic approach allows a widespread use of MRPI in clinical practice and in longitudinal research studies. KEY POINTS: • A new automatic method for calculating the MRPI is presented. • Automatic MRPI values are in good agreement with manual values. • Automatic MRPI can distinguish patients with PSP from patients with PD. • The automatic method overcomes MRPI application limitations in routine practice. • The automatic method may allow a more widespread use of MRPI.

Pathophysiology of Motor Dysfunction in Parkinson's Disease as the Rationale for Drug Treatment and Rehabilitation.

Cardinal motor features of Parkinson's disease (PD) include bradykinesia, rest tremor, and rigidity, which appear in the early stages of the disease and largely depend on dopaminergic nigrostriatal denervation. Intermediate and advanced PD stages are characterized by motor fluctuations and dyskinesia, which depend on complex mechanisms secondary to severe nigrostriatal loss and to the problems related to oral levodopa absorption, and motor and nonmotor symptoms and signs that are secondary to marked dopaminergic loss and multisystem neurodegeneration with damage to nondopaminergic pathways. Nondopaminergic dysfunction results in motor problems, including posture, balance and gait disturbances, and fatigue, and nonmotor problems, encompassing depression, apathy, cognitive impairment, sleep disturbances, pain, and autonomic dysfunction. There are a number of symptomatic drugs for PD motor signs, but the pharmacological resources for nonmotor signs and symptoms are limited, and rehabilitation may contribute to their treatment. The present review will focus on classical notions and recent insights into the neuropathology, neuropharmacology, and neurophysiology of motor dysfunction of PD. These pieces of information represent the basis for the pharmacological, neurosurgical, and rehabilitative approaches to PD.

Continuous Theta Burst Stimulation Over the Dorsolateral Prefrontal Cortex and the Pre-SMA Alter Drift Rate and Response Thresholds Respectively During Perceptual Decision-Making.

BACKGROUND: The speed-accuracy trade-off (SAT) refers to the balancing of speed versus accuracy during decision-making. SAT is very commonly investigated with perceptual decision-making tasks such as the moving dots task (MDT). The dorsolateral prefrontal cortex (DLPFC) and the pre-supplementary motor area (pre-SMA) are two brain regions considered to be involved in the control of SAT. OBJECTIVES/HYPOTHESES: The study tested whether the DLPFC and the pre-SMA play an essential role in the control of SAT. We hypothesized that continuous theta burst stimulation (cTBS) over the right DLPFC would primarily alter the rate of accumulation of evidence, whereas stimulation of the pre-SMA would influence the threshold for reaching a decision. METHODS: Fifteen (5 females; mean age = 30, SD =5.40) healthy volunteers participated in the study. We used two versions of the MDT and cTBS over the right DLPFC, pre-SMA and sham stimulation. The drift diffusion model was fit to the behavioural data (reaction time and error rate) in order to calculate the drift rate, boundary separation (threshold) and non-decision time. RESULTS: cTBS over the right DLPFC decreased the rate of accumulation of evidence (i.e. the drift rate from the diffusion model) in high (0.35 and 0.5) but not in low coherence trials. cTBS over the pre-SMA changed the boundary separation/threshold required to reach a decision on accuracy, but not on speed trials. CONCLUSIONS: The results suggest for the first time that both the DLPFC and the pre-SMA make essential but distinct contributions to the modulation of SAT.

Somatosensory Temporal Discrimination Threshold Involves Inhibitory Mechanisms in the Primary Somatosensory Area.

Somatosensory temporal discrimination threshold (STDT) is defined as the shortest time interval necessary for a pair of tactile stimuli to be perceived as separate. Although STDT is altered in several neurological disorders, its neural bases are not entirely clear. We used continuous theta burst stimulation (cTBS) to condition the excitability of the primary somatosensory cortex in healthy humans to examine its possible contribution to STDT. Excitability was assessed using the recovery cycle of the N20 component of somatosensory evoked potentials (SEP) and the area of high-frequency oscillations (HFO). cTBS increased STDT and reduced inhibition in the N20 recovery cycle at an interstimulus interval of 5 ms. It also reduced the amplitude of late HFO. All three effects were correlated. There was no effect of cTBS over the secondary somatosensory cortex on STDT, although it reduced the N120 component of the SEP. STDT is assessed conventionally with a simple ascending method. To increase insight into the effect of cTBS, we measured temporal discrimination with a psychophysical method. cTBS reduced the slope of the discrimination curve, consistent with a reduction of the quality of sensory information caused by an increase in noise. We hypothesize that cTBS reduces the effectiveness of inhibitory interactions normally used to sharpen temporal processing of sensory inputs. This reduction in discriminability of sensory input is equivalent to adding neural noise to the signal. SIGNIFICANCE STATEMENT: Precise timing of sensory information is crucial for nearly every aspect of human perception and behavior. One way to assess the ability to analyze temporal information in the somatosensory domain is to measure the somatosensory temporal discrimination threshold (STDT), defined as the shortest time interval necessary for a pair of tactile stimuli to be perceived as separate. In this study, we found that STDT depends on inhibitory mechanisms within the primary somatosensory area (S1). This finding helps interpret the sensory processing deficits in neurological diseases, such as focal dystonia and Parkinson's disease, and possibly prompts future studies using neurostimulation techniques over S1 for therapeutic purposes in dystonic patients.

Pain perception in major depressive disorder: a neurophysiological case-control study.

BACKGROUND: Depression and pain may sometimes be related conditions. Occasionally, depression may be associated with physical symptoms, such as back pain and headache. Moreover, depression may impair the subjective response to pain and is likely to influence the pain feeling. Conversely, chronic pain may represent an emotional condition as well as physical sensation, and can influence both the mood and behaviour. AIM: To better understand the relationship between pain and depression, we therefore assessed the pain threshold and the tolerance pain threshold in patients with depressive disorders. MATERIALS AND METHODS: We conducted a case-control study and selected patients who had recently received a diagnosis of major depression (DSM-IV), before treatment, and without any significant pain complaints. Age- and sex-matched healthy controls were also included. Tactile and pain thresholds were assessed in all subjects through an electrical stimulation test. All results were compared between the groups. RESULTS: 27 patients and 27 age-matched healthy controls were included in the study. Tactile, pain and tolerance thresholds were evaluated in all subjects. The pain threshold and pain tolerance were lower in patients with major depression than controls. All differences were statistically significant (p<0.05). CONCLUSION: These results suggest the abnormal processing of pain stimuli in depressive disorders.

[Thalamo-mesencephalic aspergillus abscess in a heart transplant subject: a case report and literature review]. / Ascesso aspergillare talamo-mesencefalico in un soggetto sottoposto a trapianto cardiaco: caso clinico e revisione della letteratura.

Cerebral aspergillosis is a rare and highly fatal infection that mainly affects immunocompromised patients. We report on a case of a heart transplanted Caucasian man, who arrived at our hospital because of the onset of diplopy. We performed a broad diagnostic work-up: the brain MRI showed a single ring-enhancing thalamo-mesencephalic area suggestive of abscess lesion; cerebrospinal fluid (CSF) analysis disclosed galactomannan and beta-D-glucan antigens. Thus the antifungal therapy was immediately started. We decided to discontinue the therapy 16 months later because of severe hepatic toxicity, given that the patient was persistently asymptomatic, brain imaging showed a progressive resolution of the abscess area and CSF antigen analysis was persistently negative. The follow-up at three months was unchanged.

Risk factors for post-polio syndrome among an Italian population: a case-control study.

Post-polio syndrome (PPS) is a clinical syndrome of new weakness, fatigue and musculoskeletal pain occurring in a variable proportion of polio survivors decades after acute disease. To date, several risk factors for PPS development have been reported, although the etiology of this disorder remains elusive. Using a case-control design, we aimed to assess risk indicators for PPS in a group of Italian polio survivors. Subjects with prior poliomyelitis attending the rehabilitation hospital of Malcesine, Italy, were the target population. Patients with PPS, diagnosed according to the European Federation of Neurological Societies criteria, served as cases, while patients not meeting diagnostic criteria for PPS were used as controls. All subjects were assessed through a structured questionnaire made of 82 questions and neurological examination. The association with investigated risk factors (sex, age at polio onset, age at onset of symptoms, extension and severity of polio, employment) was analyzed by the calculation of the odds ratio. A total of 161 out of 391 eligible patients met the adopted diagnostic criteria for PPS, giving a frequency of 41.2%. Symptoms most frequently complained by PPS patients were loss of muscle strength, loss of resistance, loss of muscle volume and generalized fatigue. Female gender, the presence of respiratory disturbance during the acute phase of polio and the use of orthoses and aids during the recovery and stabilization represented independent risk factors for PPS in the studied population.

Spread of botulinum neurotoxin type a at standard doses is inherent to the successful treatment of spastic equinus foot in cerebral palsy: short-term neurophysiological and clinical study.

To evaluate whether botulinum toxin type A at standard doses spreads to antagonist leg muscles in dynamic equinus foot, we studied 18 ambulatory children with hemiplegic cerebral palsy. The gastrocnemius muscle on the affected side was injected with botulinum toxin type A (Dysport) (mean ± standard deviation, 14.3 ± 0.9 U/kg). Compound muscle action potential areas were assessed in the lateral gastrocnemius and tibialis anterior muscles on the treated and untreated sides before botulinum toxin type A injections and on days 10 and 30 after injections. In all patients, compound muscle action potential areas recorded from both the muscles on the treated side decreased from preinjection values at day 10 (P < .05) and 30 (P < .002). After injection, ankle spasticity had diminished (P < .05), equinus foot excursion increased (P < .05), and functional gait improved (P < .05). This study shows that botulinum toxin type A spreads from foot flexors to antagonist extensors and suggests that spread may be partly responsible for improving gait in children with cerebral palsy.

Adult-onset migraine-related ophthalmoplegia and omolateral fetal-type posterior cerebral artery.

A 33-year-old woman with a long history of typical migraine without aura developed a pupillary-involving right third nerve palsy, after a typical migraine attack. The right pupil was 5 mm and showed delayed direct and consensual photomotor responses; the left pupil was 3 mm and reactive. Pupillary reaction to convergence was slow on the right eye. Ptosis, impaired elevation of the eye and weakened adduction were noted in the right eye. CT scan of the brain showed no abnormalities, whereas a CT digital cerebral angiography revealed a fetal-type right posterior cerebral artery (PCA). MRI disclosed thickening and contrast-enhancement of the cisternal portion of the right oculomotor nerve. A lumbar puncture, performed 5 days after the onset of ocular symptoms, yielded acellular cerebrospinal fluid (CSF) with normal protein and glucose levels. Ptosis and diplopia recovered within a week, whereas blurred vision, anisocoria and accommodation deficit subsided after 10 weeks.

Effects of hypertension on balance assessed by computerized posturography in the elderly.

Unsteadiness, dizziness and vertigo occur more frequently in hypertensive subjects, compared to the normal ones. This study evaluated the influence of hypertension on balance tests, performed on posturographic platform. The study pool consisted of 112 persons aged 65 and older (65 hypertensives), their mean age was 72.9+/-0.5, scored on the Mini Mental State Examination (MMSE) greater than 24, were able to perform self-care activities, to walk independently for at least 400 m and were free from major diseases. Subjective dizziness and vertigo were assessed by means of Sickness-Impact-Profile-Questionnaire (SIPQ). The static posturographic tests were performed on a vertical force platform, from which the center of foot pressure (COP) positions and displacements were recorded. In balance tests three standardized positions were utilized: feet 30 degrees apart, semitandem and tandem. Subjects with hypertension complained more frequently dizziness and vertigo (41.5% vs. 21.3%). The track-length and COP-velocity were associated with age in all the balance tests. In semitandem and tandem positions, the medio-lateral sway distance significantly increased in elderly subjects compared to young controls. No difference, however, was found in balance tests between normotensive and hypertensive subjects. Those with uncomplicated hypertension compared with normo-tensive subjects, although complaining more frequently symptoms of postural instability, did not show worse performances in static posturographic tests.