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Paraneoplastic neurological syndromes are immune-mediated erroneous attacks on the central or peripheral nervous systems, or both, directed originally against the tumour itself. They have been known for more than 40 years, but recently the discovery of new subgroups of paraneoplastic encephalitis syndromes with a remarkably good response to immune therapy has ignited new clinical and scientific interest. Knowledge of these subgroups and their associated autoantibodies is important in therapeutic decision-making. However, the abundance of new autoantibodies and syndromes can be confusing. This review paper summarizes current knowledge and new developments in the field of paraneoplastic neurological syndromes, their classification, pathophysiology and treatment. [ABSTRACT FROM AUTHOR]

The human teratocarcinoma cell line NTERA-2 cl.D1 (NT2 cells) can be induced with retinoic acid and cell aggregation to yield postmitotic neurones. This seems to model the in vivo situation, as high concentrations of retinoic acid, retinoic acid binding proteins, and receptors have been detected in the embryonic CNS and the developing spinal cord suggesting a role for retinoic acid in neurogenesis. Suppression subtractive hybridization was used to detect genes up-regulated by this paradigm of neuronal differentiation. Microfibril-associated glycoprotein 2 was found to be drastically up-regulated and has not been implicated in neuronal differentiation before. Suppression subtractive hybridization also identified DYRK4, a homologue of the Drosophila gene minibrain. Minibrain mutations result in specific defects in the development of the fly central nervous system. In adult rats, DYRK4 is only expressed in testis, but our results suggest an additional role for DYRK4 in neuronal differentiation. We have shown that suppression subtractive hybridization in conjunction with an efficient screening procedure is a valuable tool to produce a repertoire of differentially expressed genes and propose a new physiological role for several identified genes and expressed sequence tags. [ABSTRACT FROM AUTHOR]

The article focuses on the case of a 65-year-old woman with a 10-month history of progressive gait difficulties and ascending sensory loss in the legs. She had previously received hormone replacement therapy for 11 years. Findings showed that her deep tendon reflexes were absent. She had spastic paraparesis with bilateral extensor plantar responses. Symmetrical T2-hyperintense multi-segmental cervicothoracal lesions of the spinal cord was detected through magnetic resonance imaging.

Presents a letter to the editor about cell cycle.

John Cunningham virus (JCV) infection of the central nervous system causes progressive multifocal leukoencephalopathy (PML) in patients with systemic immunosuppression. With the increased application of modern immunotherapy and biologics in various immune‐mediated disorders, the PML risk spectrum has changed. Thus, new tools and strategies for risk assessment and stratification in drug‐associated PML such as the JCV antibody indices have been introduced. Imaging studies have highlighted atypical presentations of cerebral JCV disease such as granule cell neuronopathy. Imaging markers have been developed to differentiate PML from new multiple sclerosis lesions and to facilitate the early identification of pre‐clinical manifestations of PML and its immune reconstitution inflammatory syndrome. PML can be diagnosed either by brain biopsy or by clinical, radiographic and virological criteria. Experimental treatment options including immunization and modulation of interleukin‐mediated immune response are emerging. PML should be considered in any patient with compromised systemic or central nervous system immune surveillance presenting with progressive neurological symptoms. [ABSTRACT FROM AUTHOR]

There is no other field of neurology where clinically relevant serological biomarkers have witnessed a surge in importance over the past decade resembling that in autoimmune encephalitis and cerebellitis. A multitude of newly discovered neuronal autoantibodies facilitate early diagnosis, estimation of prognosis, and therapeutic decision-making. However, this has led to growing uncertainty with regard to meaningful patient selection, the appropriate extent of testing, and management of seronegative cases. This review summarizes the essential aspects of the clinical presentation, diagnostic work-up, pathophysiology, and treatment of autoimmune encephalitis and cerebellitis. [ABSTRACT FROM AUTHOR]

Introduction: Multiple sclerosis (MS) is an inflammatory disease of CNS with neuro-axonal injury as the key morphological correlate for long-term disability. Novel ultra-sensitive single molecule array (SiMoA) based detection of neurofilament light (NfL) and other neuroglial proteins is being considered as a promising tool for evaluation of disease activity1. However, clinical applicability is hampered by 1) considerable per-sample-costs, 2) scarcity of inter-laboratory comparisons and 3) absence of accepted cut-off values with good sensitivity and specificity. In this small single-center study, we aimed to a) show feasibility and clinical validity of an adapted reduced-cost protocol and to b) test sensitivity and specificity of an available 4-plex assay for NfL, Tau, UCHL-1 and GFAP in patients vs. controls and active vs. stable disease from a real-world data set of patients with MS and age matched healthy controls. Patients & Methods: We prospectively recruited serum samples from 114 adult patients with relapsing remitting MS (RRMS) including 42 with radiological/clinical active and 72 patients with stable disease as well as 70 healthy controls. Serum samples were measured with Neurology 4-Plex assay on fully automated HD-X-Analyzer (Quanterix) using standard and reduced cost protocols (measuring the serum samples in duplicates and singlicates). We determined precision, inter- and intra-assay variation, inter-laboratory comparisons, ROC-analysis, specificity and sensitivity using standard and modified protocols. Results: Using our reduced-cost approach, we confirmed inter- and intra-assay as well as inter-laboratory comparison coefficients of variations across relevant concentration levels of <10% for NfL. We reproduced higher mean serum NfL concentrations in patients with active RRMS (12.1pg/ml [95%CI 10.1-21.6]) compared to stable RRMS (7.1 pg/ml [95%CI 6.3-8.6], p<0,0001) and healthy controls (9.2 pg/ml [95%CI 8.2-10.3] p<0,0001) and significantly reduced per-sample-costs while applying our adapted approach. Serum tau (p<0.0001) but not GFAP and UCH-L1 concentrations were higher in RRMS versus controls. ROC-analysis (AUC=76.9±0,05) using a cut-off with maximal sensitivity showed a sensitivity of 70% and a specificity of 76% for active RRMS versus stable disease. The combinations of biomarkers showed no additional benefit over serum NfL concentration alone for prediction of disease activity. Conclusion: Using fully-automated analysis pipelines, reduced cost protocols are feasible and precise and could facilitate clinical application of serum neuronal biomarkers. While NfL discriminates fairly well between RRMS and healthy controls, sensitivity and specificity for active disease is lacking. Further prospective studies should evaluate the use of serial NfL measurements to determine clinical validity in detecting active RRMS. References: 1. Bittner et al. The potential of serum neurofilament as biomarker for multiple sclerosis. Brain 2021. [ABSTRACT FROM AUTHOR]

Background: Primary angiitis of the central nervous system (PACNS) is a rare but serious condition. A fraction of patients suffering from PACNS concurrently exhibit pronounced cerebral amyloid angiopathy (CAA) which is characterized by deposits of amyloid-β (Aβ) in and around the walls of small and medium-sized arteries of the brain. PACNS with CAA has been identified as a distinct disease entity, termed Aβ-related angiitis (ABRA). Evidence points to an immune reaction to vessel wall Aβ as the trigger of vasculitis. Objective: To investigate whether the inflammatory response to Aβ has (1) any effect on the status of immune activation in the brain parenchyma and (2) leads to clearance of Aβ from brain parenchyma. Methods: We studied immune activation and Aβ load by quantitative immunohistochemical analysis in brain parenchyma adjacent to affected vessels in 11 ABRA patients and 10 matched CAA controls. Results: ABRA patients showed significantly increased immune activation and decreased Aβ loads in the brain parenchyma adjacent to affected vessels. Conclusion: Our results are in line with the hypothesis of ABRA being the result of an excessive immune response to Aβ and show that this can lead to enhanced clearance of Aβ from the brain parenchyma by immune-mediated mechanisms. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: Paraneoplastic neurological syndromes (PNS) constitute a challenging diagnostic problem, as the underlying tumour often remains unidentified for a long time, even with frequent conventional diagnostic procedures. For appropriate patient management timely identification of the tumour is critical. We evaluated the value of (18)F-FDG-PET/CT in the investigation of PNS.Methods: The case notes of 46 consecutive patients with clinically suspected PNS who underwent (18)F-FDG-PET/CT were reviewed retrospectively and the performance of PET/CT for detecting underlying tumours was assessed.Results: PET/CT detected foci of increased (18)F-FDG uptake in 10 out of 46 patients. In six of these 10 patients combined PET/CT identified the underlying disease: four patients suffered from PNS; vasculitic and local metastatic disease was detected in two other patients.Conclusions: Based on our results, we believe that the role of positron emission tomography in the detection of occult neoplasms in patients with PNS has been overestimated in the past. In clinical practice, PNS is far more often suspected than proven. In our study combined PET/CT identified malignancy as the underlying cause of suspected PNS in only 8.7% (4/46). We believe that combined PET/CT should be reserved for stringently selected patients with a high clinical index of suspicion for PNS and after conventional imaging techniques fail to detect a tumour. [ABSTRACT FROM AUTHOR]

Background: Antibodies to human full-length myelin oligodendrocyte glycoprotein (MOG-IgG) as detected by new-generation cell-based assays have recently been described in patients presenting with acute demyelinating disease of the central nervous system, including patients previously diagnosed with multiple sclerosis (MS). However, only limited data are available on the relevance of MOG-IgG testing in patients with chronic progressive demyelinating disease. It is unclear if patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS) should routinely be tested for MOG-IgG.Objective: To evaluate the frequency of MOG-IgG among patients classified as having PPMS or SPMS based on current diagnostic criteria.Methods: For this purpose, we retrospectively tested serum samples of 200 patients with PPMS or SPMS for MOG-IgG using cell-based assays. In addition, we performed a review of the entire English language literature on MOG-IgG published between 2011 and 2017.Results: None of 139 PPMS and 61 SPMS patients tested was positive for MOG-IgG. Based on a review of the literature, we identified 35 further MOG-IgG tests in patients with PPMS and 55 in patients with SPMS; the only reportedly positive sample was positive just at threshold level and was tested in a non-IgG-specific assay. In total, a single borderline positive result was observed among 290 tests.Conclusion: Our data suggest that MOG-IgG is absent or extremely rare among patients with PPMS or SPMS. Routine screening of patients with typical PPMS/SPMS for MOG-IgG seems not to be justified. [ABSTRACT FROM AUTHOR]

Background In 2014 a complex neurological syndrome with parasomnia, sleep breathing dysfunction and variable bulbar symptoms associated with antibodies to IgLON5, a neuronal cell-adhesion protein, was described (Sabater et al., 2016). Postmortal studies revealed tauopathy predominately involving the hypothalamus and tegmentum of the brainstem (Gelpi et al., 2016). To the best of our knowledge, there are 16 published cases so far. Methods (clinical presentation) We report a 72-year-old highly educated male Caucasian patient with a 6 year history of parasomnia with RBD in the beginning, following of multiple falls, parkinsonism, hypomania, frontal lobe disorder and impulse control disorder (ICD; leading to sentence of detention) with aggressive tendencies. By transcranial ultrasound hyperechogenicity of substantia nigra was demonstrated, FDG-PET imaging showed lower 18F-FDG activity in temporal lobes. Thus idiopathic Parkinson’s disease was assumed. Due to neuropsychiatric complications the antiparkinson medication was gradually reduced and eventually discontinued in 2014. Interestingly, there were no relevant changes in symptoms of parkinsonism thereafter. In 2016, after acute coronary syndrome the patient developed a sudden bilateral vocal cord paresis with stridor leading to intubation and following tracheotomy. Subsequently, he showed dysphagia, increasing rigidity, fluctuating level of consciousness with intermittent hypoventilation and hypercapnia, and autonomic dysregulation. Critical decompensation with need of short CPR occurred twice, continuous monitoring with mechanical ventilation was required. Results (workup and treatment, Table 1 ) Brain MRI showed iron accumulation in globus pallidus and dentate nucleus, and a small pineal cyst ( Fig. 1 a). The initial multiple EEGs were normal. Diverse EEGs from 2016 registered generalized slowing with intermittent hyperexcitability; nonconvulsive status epilepticus was captured once ( Fig. 1 b). Laboratory tests displayed neutrophil leukocytosis with MGUS IgG-kappa and -lambda. In serum (1:100) and in CSF (1:10) IgLON5 antibodies (IgG subclass) were detected. HLA-typing revealed HLA-DRB1∗10:01 and HLA-DQB1∗05:01 alleles. Tumor screening (thoracic and abdominal CT, bone marrow examination) did not detect malignancy. Because of suspected IgLON5-syndrome with autoimmune origin an immunosuppressive therapy with initial IV methylprednisolone pulse therapy following oral prednisolone (75 mg/d) and rituximab was initiated. Subsequently, after achieving better vigilance, it was possible to start weaning again. Conclusion Parasomnia, ICD, beginning frontal lobe syndrome with parkinsonism, multiple falls and bulbar symptoms is a new combination in IgLON5 antibody-linked syndrome. A connection to neurodegeneration with brain iron accumulation (NBIA) is possible and requires further investigation. [ABSTRACT FROM AUTHOR]