Explore the vast range of titles available.

Models for immune-mediated tumor regression in mice have defined an essential role for cytotoxic T lymphocytes (CTLs); however, naturally occurring tumor immunity in humans is poorly understood 1 . Patients with paraneoplastic cerebellar degeneration (PCD) provide an opportunity to explore the mechanisms underlying tumor immunity to breast and ovarian cancer. Although tumor immunity and autoimmune neuronal degeneration in PCD correlates with a specific antibody response to the tumor and brain antigen cdr2 2 , 3 , this humoral response has not been shown to be pathogenic 3 , 4 . Here we present evidence for a specific cellular immune response in PCD patients. We have detected expanded populations of MHC class I-restricted cdr2-specific CTLs in the blood of 3/3 HLA-A2.1 + PCD patients, providing the first description, to our knowledge, of tumor-specific CTLs using primary human cells in a simple recall assay. Cross-presentation of apoptotic cells by dendritic cells also led to a potent CTL response. These results indicate a model whereby immature dendritic cells that engulf apoptotic tumor cells can mature and migrate to draining lymph organs where they could induce a CTL response to tissue-restricted antigens. In PCD, peripheral activation of cdr2-specific CTLs is likely to contribute to the subsequent development of the autoimmune neuronal degeneration.

Autoimmune cerebellar ataxia (ACA) associated with anti-Homer-3 antibodies is a rare but increasingly recognized immune-mediated neurological condition. It represents a potentially treatable cause of sporadic cerebellar syndrome and may clinically mimic primarily multiple system atrophy of the cerebellar type (MSA-C), and less frequently, other atypical parkinsonian disorders. Because of the significant clinical overlap with neurodegenerative diseases, particularly MSA-C, Homer-3–associated ACA may be underdiagnosed or misdiagnosed, delaying effective treatment. This narrative review synthesizes the currently available literature on anti-Homer-3 immunoglobulins, with a focus on their pathophysiological role, diagnostic utility, therapeutic response, and clinical differentiation from neurodegenerative conditions. Homer-3 is a postsynaptic scaffold protein expressed in Purkinje cells, where it plays a key role in calcium signaling through metabotropic glutamate receptor pathways. Antibodies against Homer-3 have been identified in patients with a wide range of neurological and neuropsychiatric symptoms, most commonly with subacute cerebellar ataxia. Neuroimaging in such cases frequently shows cerebellar atrophy or inflammation, and cerebrospinal fluid analysis often reveals inflammatory markers. The treatment with immunotherapy, particularly corticosteroids and intravenous immunoglobulins, which has showed encouraging results, however therapeutic outcomes can vary. The aim of this review is to collect and analyze all currently available data on anti-Homer-3–associated ACA, with the goal of raising clinical awareness and emphasizing the importance of early recognition and aggressive intervention.

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene–environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

While immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, neurological immune-related adverse events (n-irAEs) associated with these agents are increasingly recognized. However, kelch-like protein-11(KLHL11)-IgG cerebellitis has not been reported as an n-irAE. We report a case of a 53-year-old man with lung adenocarcinoma treated with tislelizumab who developed KLHL11-IgG cerebellitis. First-line immunotherapy, comprising intravenous methylprednisolone and immunoglobulin, failed to improved his symptoms. Subsequent administration of efgartigimod (10 mg/kg weekly for 4 doses) led to seroconversion of KLHL11-IgG and marked clinical recovery. This is the first report of efgartigimod as a successful rescue therapy for isolated ICI-related KLHL11-IgG cerebellitis. These findings support efgartigimod as a promising treatment option for this condition.

Schmallenberg virus (SBV) is an emerging orthobunyavirus of ruminants associated with outbreaks of congenital malformations in aborted and stillborn animals. Since its discovery in November 2011, SBV has spread very rapidly to many European countries. Here, we developed molecular and serological tools, and an experimental in vivo model as a platform to study SBV pathogenesis, tropism and virus-host cell interactions. Using a synthetic biology approach, we developed a reverse genetics system for the rapid rescue and genetic manipulation of SBV. We showed that SBV has a wide tropism in cell culture and \"synthetic\" SBV replicates in vitro as efficiently as wild type virus. We developed an experimental mouse model to study SBV infection and showed that this virus replicates abundantly in neurons where it causes cerebral malacia and vacuolation of the cerebral cortex. These virus-induced acute lesions are useful in understanding the progression from vacuolation to porencephaly and extensive tissue destruction, often observed in aborted lambs and calves in naturally occurring Schmallenberg cases. Indeed, we detected high levels of SBV antigens in the neurons of the gray matter of brain and spinal cord of naturally affected lambs and calves, suggesting that muscular hypoplasia observed in SBV-infected lambs is mostly secondary to central nervous system damage. Finally, we investigated the molecular determinants of SBV virulence. Interestingly, we found a biological SBV clone that after passage in cell culture displays increased virulence in mice. We also found that a SBV deletion mutant of the non-structural NSs protein (SBVΔNSs) is less virulent in mice than wild type SBV. Attenuation of SBV virulence depends on the inability of SBVΔNSs to block IFN synthesis in virus infected cells. In conclusion, this work provides a useful experimental framework to study the biology and pathogenesis of SBV.

We report a case of a 19-year-old woman with a subacute onset of visual disturbance and gait instability in the last three months. The neurological examination revealed horizontal nystagmus in the lateral gaze with a change of phase. The patient also described double vision in various gaze positions, with no clear opthalmoparesis. In her next visits to our clinic, the symptoms had progressed. In this presentation, we discuss the approach of subacute cerebellar ataxia in a young adult patient.

Chronic cannabis exposure can lead to cerebellar dysfunction in humans, but the neurobiological mechanisms involved remain incompletely understood. Here, we found that in mice, subchronic administration of the psychoactive component of cannabis, delta9-tetrahydrocannabinol (THC), activated cerebellar microglia and increased the expression of neuroinflammatory markers, including IL-1β. This neuroinflammatory phenotype correlated with deficits in cerebellar conditioned learning and fine motor coordination. The neuroinflammatory phenotype was readily detectable in the cerebellum of mice with global loss of the CB1 cannabinoid receptor (CB1R, Cb1(-/-) mice) and in mice lacking CB1R in the cerebellar parallel fibers, suggesting that CB1R downregulation in the cerebellar molecular layer plays a key role in THC-induced cerebellar deficits. Expression of CB2 cannabinoid receptor (CB2R) and Il1b mRNA was increased under neuroinflammatory conditions in activated CD11b-positive microglial cells. Furthermore, administration of the immunosuppressant minocycline or an inhibitor of IL-1β receptor signaling prevented the deficits in cerebellar function in Cb1(-/-) and THC-withdrawn mice. Our results suggest that cerebellar microglial activation plays a crucial role in the cerebellar deficits induced by repeated cannabis exposure.

Several neurological syndromes have been recognized associated to GAD antibodies. Among those disorders, cerebellar ataxia (CA) is one of the most common, along with stiff-person syndrome. Patients with GAD associated CA present with a progressive pancerebellar syndrome, with a subacute or chronic evolution, along with other neurological manifestations such as stiffness, oculomotor dysfunction, epilepsy, and cognitive dysfunction. These symptoms may be preceded by the so-called “brainstem attacks”, where manifestations consistent with transient dysfunction of the brainstem may be observed. These patients frequently have extra-neurologic autoimmune manifestations such as diabetes mellitus type 1, polyendocrine autoimmune syndrome, pernicious anemia, vitiligo, etc. A proportion of patients may present with an underlying neoplasia, but the course is less aggressive than in those patients with classical paraneoplastic CA with onconeural antibodies. The diagnosis is based on the present of high serum and CSF titers of GAD antibodies, with intrathecal production of such antibodies. Treatment is aimed to decrease the immunological response with intravenous immunoglobulin, steroids, rituximab and oral immunosuppressive drugs. A subacute presentation and rapid initiation of immunotherapy seem to be the predictors of a favorable clinical response.

RGS8-associated paraneoplastic neurologic syndrome (PNS) is a recently-described disorder associated with lymphomas and typically presenting with severe, rapidly-progressing cerebellar dysfunction. We describe a patient who presented with mild signs of cerebellar dysfunction, including ocular motor abnormalities and impaired tandem gait. CSF showed elevated protein and a neural-restricted antibody pattern. Mesenteric lymphadenopathy on abdominal CT was biopsied and diagnosed as follicular B-cell lymphoma. After four years, the previously-detected antibody pattern was identified as RGS8 antibodies. This case describes the first RGS8-PNS patient presenting with a subtle and ocular motor predominant cerebellar syndrome with low-grade lymphoma.

Introduction Varicella may complicate with cerebellitis in previously healthy children, requiring hospitalization. Aim of our study was to define whether children who experienced varicella cerebellitis have a normal immune system. Methods Patients over 3 years of age admitted at Bambino Gesù Children from January 2006 till June 2016 for cerebellitis in varicella were asked to participate to the follow-up study. The immune status was evaluated clinically and by laboratory investigations. Results Twenty-five patients were included in the study. At follow up, at least one immunological alteration was detected in 80% of patients. To avoid bias due to possible effects of the recent disease, we separately analyzed patients who had the follow-up control at least 1 year (Group 1) or between 1 month and 1 year (Group 2) after the hospitalization for acute varicella cerebellitis. The results were similar in both groups with immunological alterations detected in 84,6 and 75% of the patients, respectively. Conclusions Our preliminary results indicate that sub-clinical immunological defects may correlate to cerebellitis in varicella.