Movement Disorders in Oncology: From Clinical Features to Biomarkers

Background: the study of movement disorders associated with oncological diseases and anticancer treatments highlights the wide range of differential diagnoses that need to be considered. In this context, the role of immune-mediated conditions is increasingly recognized and relevant, as they represent treatable disorders. Methods: we reappraise the phenomenology, pathophysiology, diagnostic testing, and treatment of movement disorders observed in the context of brain tumors, paraneoplastic conditions, and cancer immunotherapy, such as immune-checkpoint inhibitors (ICIs). Results: movement disorders secondary to brain tumors are rare and may manifest with both hyper-/hypokinetic conditions. Paraneoplastic movement disorders are caused by antineuronal antibodies targeting intracellular or neuronal surface antigens, with variable prognosis and response to treatment. ICIs promote antitumor response by the inhibition of the immune checkpoints. They are effective treatments for several malignancies, but they may cause movement disorders through an unchecked immune response. Conclusions: movement disorders due to focal neoplastic brain lesions are rare but should not be missed. Paraneoplastic movement disorders are even rarer, and their clinical-laboratory findings require focused expertise. In addition to their desired effects in cancer treatment, ICIs can induce specific neurological adverse events, sometimes manifesting with movement disorders, which often require a case-by-case, multidisciplinary, approach.

Autoantigen characterization in the lower esophageal sphincter muscle of patients with achalasia.

OBJECTIVE: To characterize in sera anti-myenteric autoantibody profiles and in tissues MMP-9 proteoforms towards the identification of possible autoantigenic proteins in the muscle of the lower esophageal sphincter (LES) of achalasia patients. METHODS: Biopsies of the LES muscle from 36 achalasia patients, 6 esophagogastric junction outflow obstruction (EGJOO) patients, and 16 transplant donors (TD) were compared in a blind cross-sectional study. Histological characteristics such as inflammation, fibrosis, presence of ganglion cells, cells of Cajal, GAD65, PNMA2, S100, P substance, and MMP-9 proteforms in tissue were assessed by H&E and Picro-Sirius Red stainings, and immunohistochemistry analysis. Antineuronal antibodies (amphiphysin, CV2, and PNMA2 (Ma2/Ta)), onconeural antigens (Ri, Yo, and Hu), recoverin, SOX-1, titin, zic4, GAD65, and Tr (DNER) were evaluated by immunoblot/line assay. RESULTS: Tissue of achalasia patients had heterogeneous inflammatory infiltrates with fibrosis and contrasting higher levels of activated MMP-9 compared with EGJOO and TD. Moreover, lower ganglion cell percentages and cell of Cajal percentages were determined in esophageal tissues of achalasia patients vs. TD. In addition, tissue of achalasia patients had higher GAD65 and PNMA2 protein expression vs. EGJOO. Unexpectedly, these proteins were absent in TD tissue. S100 and P substance had similar expression levels in tissues of achalasia patients vs.TD and EGJOO. Most of the achalasia sera had anti-GAD65 (83%) and anti-PNMA2 (90%) autoantibodies vs. EGJOO (17% and 33%, respectively) and healthy volunteers (10% and 0%, respectively). CONCLUSION: Tissue-specific ectopic expression of GAD65 and PNMA/Ta2 and active MMP-9, associated with the presence of specific autoantibodies directed against these proteins, might participate in the pathophysiology of achalasia triggering and/or perpetuating autoimmune disease.

Role of Immunity in Pathogenesis of Psychosis

The involvement of immunity in the pathogenesis of schizophrenia and related psychoses was suspected a century ago but was shadowed by the dopaminergic hypothesis after the discovery of antipsychotics. We currently know that this latter theory has many limits and cannot account for the wide variety of psychotic conditions. The immune-inflammatory theory is now one of the most promising axes of research in terms of pathogenesis of several mental health conditions. Immunity and inflammation play a role at least in a subgroup of patients with psychosis. The immune system is complex with a variety of components and mediators that can all have effects on the brain and thus mediate psychiatric symptoms. In this chapter we will explore the scientific evidence of the role of immune system in pathophysiology of psychosis. The sections of this chapter will discuss the role of innate system components (cytokines, microglia, inflammation.), the role of adaptive system (lymphocytes and antibodies) with a section focusing on auto-immunity and particularly antineuronal antibodies. Finally we will discuss how this research can impact patients management and elaborate recommendations for future research.

Microbial Induced Autoimmune Inflammation as a Cause of Mental Illness in Adolescents: A Case Series

The incidence of mental health disorders in adolescents continues to rise. The cause of the increase in mental illness is multifactorial, including both environmental and biological causes. To investigate the latter, ten adolescents at a psychiatric residential treatment center in Colorado with the DSM-5 diagnosis of major depressive disorder (MDD), of whom seven were additionally diagnosed with generalized anxiety disorder (GAD), were chosen at random for further serologic study. Testing revealed exposureto group A Streptococcus(GAS) in 2 of 10 (20%); Borrelia Burgdorferi sensulato (Bbsl)in 2 of 10 (20%); and Bartonella speciesin 3 of 10 (30%). In addition, 9 of 10 (90%) subjects had abnormal Cunningham Panels, which measures levels of antineuronal antibodies that have been associated with psychiatric disturbances. Given the degree of psychological dysfunction in these adolescents requiring intensive residential treatment, this case series lends support to the hypothesis that exposure to infectious agents may play a role, perhaps by autoimmune mechanisms, in the significant and ongoing rise in the rate of neuropsychiatric illness in adolescents. This preliminary report adds to this premise and requires further investigation.

Limbic encephalitis due to antineuronal antibodies

Limbic encephalitis (LE) is an encephalopathic syndrome caused by antineuronal antibodies against extracellular or intracellular neuronal structures. LE may present clinically with a variety of symptoms, including epileptic seizures, cognitive and memory deficits, and personality changes. Whereas LE mediated by antibodies against intracellular antigens is frequently of paraneoplastic origin and associated with a poorer prognosis, LE mediated by antibodies against extracellular or transmembrane antigens causes potentially reversible neuronal dysfunction and, given early diagnosis and treatment, is associated with a comparatively benign prognosis. We present and discuss four different cases of autoantibody-mediated LE, with different clinical outcomes and both with and without paraneoplastic origin. Red flags pointing to the diagnosis of antibody-mediated LE include rapidly progressing personality changes or memory deficits and disorientation, novel epileptic seizures, and a history of neoplasia.

Frequency of arboviruses antibodies in patients with autoimmune encephalitis: data from the BrAIN network (Brazilian Autoimmune Encephalitis Network) Bruna de Freitas Dias, Fábio Fieni Toso, Rene de Araújo Gleizer, Maria Eduarda

Background: Autoimmune encephalitis (AIE) is the main cause of non-infectious encephalitis and results from the peripheral immune response against cell surface antigens in the central nervous system. The clinical presentations are varied and known triggers are tumors and herpetic infections. Arboviruses Zika (ZIKV), Dengue (DENGV) and Chikungunya (CHIKV) are neurotropic infections that present neurological manifestations whose mechanism is unknown. Objective: Verify the frequency of arboviruses antibodies in patients with autoimmune encephalitis in a Brazilian cohort Design and setting: It is a transversal study performed by Hospital Israelita Albert Einstein in Brazil Methods: Patients who met the criteria for probable AIE (Graus 2016) evaluated at the 18 centers of the BrAIN network were included. Clinical, epidemiological and laboratory data were compiled. Antineuronal antibodies were detected using TBA, CBA and immunoblot in serum and CSF; antibodies against ZIKV, DENGV and CHIKV were detected by ELISA. The cohort was divided into two groups: seropositive encephalitic (SPE) and non-encephalitic (NE) and the frequencies of viral serologies were compared. Results: Among 619 patients included in the BrAIN cohort, serology for arboviruses was performed in 482 patients, being 79 SPE and 99 NE. The SPEgroup showed the following frequency of antibodies: 58.2% anti-NMDA, 7.6% antiLGI1, 6.3% anti-Caspr2, 2.5% anti-GABA B, 1.3% anti-GABA A, 3.8% anti-AMPAr, 1.3% anti-AQ4, 8.9% anti-MOG, 1.3% anti-IgLON5, 7.6% anti-GlyR and 5.1% others. The frequency of serology was IgG DENG (SPE 42.3% X NP 43.4%, p = 0.82); IgG CHIK (SPE 16.5% X 3.1% NP, p = 0.001); IgG ZIKV (SPE31.6% X NP 28.3%, p = 0.62). The frequency of triple positive serology (IgG DENG, ZIKV, CHIK) was 11.39% (SPE X 2.02% NP, p = 0.009). Conclusions: Patients with SPE have IgG CHIKV antibodies most commonly. In addition, they present a higher frequency of positivity for IgG CHIKV, ZIKV, DENGV simultaneously. Future studies should assess the association between arboviruses as a trigger for AIE or as a marker of susceptibility to immunological alteration.

Muddying the waters? A false positive case of autoimmune psychosis

Objective: To discuss challenges with the diagnosis of autoimmune psychosis (AP) in people with chronic psychotic disorders. Method: We present a case of a 23-year-old man with an exacerbation of treatment-refractory psychosis after receiving intravenous immunoglobulin (IVIG) for suspected AP, diagnosed 4 years after the onset of psychosis. We highlight the diagnostic and management challenges in such cases. Results: The diagnosis of AP in people with long-standing illness relies on the interpretation of non-specific clinical and laboratory findings in individuals with psychosocial problems and challenges of acceptance and adherence to complex medical investigations and treatments. Equivocal results from investigations undertaken without logical clinical reasoning can lead to inappropriate interventions that are costly and can cause iatrogenic harm. Conclusion: Psychiatrists should restrict screening for antineuronal antibodies in people with chronic psychosis to those with higher risk features such as persistent treatment refractory symptoms with concurrent neurological signs and symptoms. Further research informing the clinical circumstances for antineuronal antibody testing is needed.