Andreas Liampas

Background and ObjectivesChronic active lesions (CALs) reflect chronic inflammation in multiple sclerosis (MS). Slowly expanding lesions (SELs) are CALs identified on conventional MRI by linear, co...

Repulsive guidance molecule-a (RGMa) has emerged as a significant therapeutic target in a variety of neurological disorders, including neurodegenerative diseases and acute conditions. This review comprehensively examines the multifaceted role of RGMa in central nervous system (CNS) pathologies such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, neuromyelitis optica spectrum disorder, spinal cord injury, stroke, vascular dementia, auditory neuropathy, and epilepsy. The mechanisms through which RGMa contributes to neuroinflammation, neuronal degeneration, and impaired axonal regeneration are herein discussed. Evidence from preclinical studies associate RGMa overexpression with negative outcomes, such as increased neuroinflammation and synaptic loss, while RGMa inhibition, particularly the use of agents like elezanumab, has shown promise in enhancing neuronal survival and functional recovery. RGMa’s responses concerning immunomodulation and neurogenesis highlight its potential as a therapeutic avenue. We emphasize RGMa’s critical role in CNS pathology and its potential to pave the way for innovative treatment strategies in neurological disorders. While preclinical findings are encouraging so far, further clinical trials are needed to validate the safety and efficacy of RGMa-targeted therapies.

Introduction Oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) are utilized for diagnosing multiple sclerosis (MS), as they are found in 95% of patients. Additionally, OCBs are linked to disease prognosis. The primary contributors to OCB production are long-lived plasma cells. This study aims to quantify the impact of natalizumab (NTZ) on OCB levels in the CSF of MS patients. Methods A systematic search on MEDLINE, SCOPUS and Web of Science for English-written and peer-reviewed longitudinal studies on adults was performed. Methodological quality was assessed with the Newcastle–Ottawa Scale. Proportional meta-analysis was performed in R using a generalized linear mixed-effects model. We investigated heterogeneity with influence diagnostics, sensitivity analysis and meta-regression. Results Eight eligible studies of adequate quality with a total sample of 326 relapsing–remitting MS patients were included. A summary rate of 14.07% [95% CI, 4.48%—36.36%] for complete loss of OCBs and 42.02% [95% CI, 15.23%—74.51%] for reduction in OCB number or intensity was observed, both with considerable heterogeneity. Pooled estimates dropped (11% [95% CI, 0.04%—0.29%] and 34% [95% CI, 0.11%—0.68%] respectively) after the identification of an influential study. Multivariable meta-regression identified IgG index as a factor contributing to heterogeneity (adj. p = 0.0279), regarding reduction of OCB number or intensity. Discussion In conclusion, our systematic review and meta-analysis showed that NTZ can lead to reduction of intrathecal OCBs in MS patients, indicating a possible effect of NTZ on memory plasma cells, which are the main source of OCBs in MS.

The subventricular zone promotes remyelination through activation differentiation of oligodendroglial precursor cells (OPCs) and neural stem cells (NSCs) into mature oligodendrocytes and thus in the adult brain. In Multiple Sclerosis (MS) this regenerative capability in halted resulting in neurodegeneration. We aimed to systematically search and synthesize evidence on mechanisms and phenomena associated with SVZ dysfunction in MS. Our systematic review was reported according to the PRISMA-ScR statement. MEDLINE, SCOPUS, ProQuest and Google Scholar were searched using the terms "subventricular zone" and "multiple sclerosis", including English-written in vivo and post-mortem studies. 20 studies were included. Thirteen studies on models of experimental autoimmune encephalomyelitis (EAE) reported among others strong stathmin immunoreactivity in the SVZ of EAE models, the role of MOG immunization in neurogenesis impairment, the effect of parenchymal OPCs and NSCs in myelin repair and the importance of ependymal cells (E1/E2) and ciliated B1 cells in SVZ stem cell signalling. CXCR4 signaling and, transcriptional profiles of SVZ microglia, Gli1 pathway, galactin-3 were also explored. Studies in humans demonstrated microstructural SVZ damage in progressive MS and the persistence of black holes near the SVZ, whereas post-mortem confirmed generation of PSA-NCAM and NG2-positive progenitors through SVZ activation, SVZ stathmin immunoreactivity, Shh pathway and Gal-3 upregulation. Oligodendrogenesis defects translate to reduced remyelination, a hallmark of MS, that determines its end-phenotype and disease course. The role of inflammation and subsequent SVZ microenvironment disruption is evident in MS pathology.

Background Boucher Neuhäuser Syndrome (BNS) is a rare disease with autosomal recessive inheritance defined by the classical triad; early-onset ataxia, hypogonadism and chorioretinal dystrophy. Case presentation We present two siblings diagnosed with BNS at midlife, identified with homozygous state of a novel PNPLA6 missense mutation. One healthy sibling and the mother were heterozygous carriers of the mutation. The proband presented with the classical triad and the other sibling presented with visual problems at first. The proband was referred to our department by a private Neurologist, in early adulthood, because of hypogonadism, cerebellar ataxia, axonal neuropathy, and chorioretinal dystrophy for further evaluation. The sibling was referred to our department for evaluation, at childhood, due to visual problems. Later, the patient displayed the triad of ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. The unusual medical history of the two siblings led to further examinations and eventually the diagnosis of the first BNS cases in Cyprus. WES-based ataxia in silico gene panel analysis revealed 15 genetic variants and further filtering analysis revealed the PNPLA6 c.3323G > A variant. Segregation analysis in the family with Sanger sequencing confirmed the PNPLA6 homozygous variant c.3323G > A, p.Arg1108Gln in exon 29. Conclusions This highlights the importance of considering rare inherited causes of visual loss, spinocerebellar ataxia, or/and HH in a neurology clinic and the significant role of genetic sequencing in the diagnostic process.

BACKGROUND Boucher Neuhäuser Syndrome (BNS) is a rare disease with autosomal recessive inheritance defined by the classical triad; early-onset ataxia, hypogonadism and chorioretinal dystrophy. CASE PRESENTATION We present two siblings diagnosed with BNS at midlife, identified with homozygous state of a novel PNPLA6 missense mutation. One healthy sibling and the mother were heterozygous carriers of the mutation. The proband presented with the classical triad and the other sibling presented with visual problems at first. The proband was referred to our department by a private Neurologist, at early adulthood, because of hypogonadism, cerebellar ataxia, axonal neuropathy and chorioretinal dystrophy for further evaluation. The sibling was referred to our department for evaluation, at childhood, due to visual problems. Later, the patient displayed the triad of ataxia, hypogonadotropic hypogonadism and chorioretinal dystrophy. The unusual medical history of two siblings led to further examinations and eventually the diagnosis of the first BNS cases in Cyprus. WES-based ataxia in silico gene panel analysis revealed 15 genetic variants, and further filtering analysis revealed the PNPLA6 c.3323G>A variant. Segregation analysis in the family with Sanger sequencing confirmed the PNPLA6 homozygous variant c.3323G>A, p.Arg1108Gln in exon 29. COONCLUSIONS This highlights the importance of considering rare inherited causes of visual loss, spinocerebellar ataxia or/ and HH in a neurology clinic and the significant role of genetic sequencing in diagnostic process.

Introduction The universality and complexity of pain, which is highly prevalent, yield its significance to both patients and researchers. Developing a non-invasive tool that can objectively measure pain is of the utmost importance for clinical and research purposes. Traditionally electroencephalography (EEG) has been mostly used in epilepsy; however, over the recent years EEG has become an important non-invasive clinical tool that has helped increase our understanding of brain network complexities and for the identification of areas of dysfunction. This review aimed to investigate the role of EEG recordings as potential biomarkers of pain perception. Methods A systematic search of the PubMed database led to the identification of 938 papers, of which 919 were excluded as a result of not meeting the eligibility criteria, and one article was identified through screening of the reference lists of the 19 eligible studies. Ultimately, 20 papers were included in this systematic review. Results Changes of the cortical activation have potential, though the described changes are not always consistent. The most consistent finding is the increase in the delta and gamma power activity. Only a limited number of studies have looked into brain networks encoding pain perception. Conclusion Although no robust EEG biomarkers of pain perception have been identified yet, EEG has potential and future research should be attempted. Designing strong research protocols, controlling for potential risk of biases, as well as investigating brain networks rather than isolated cortical changes will be crucial in this attempt.