Single OnabotulinumtoxinA Session Add-On to Carbamazepine or Oxcarbazepine in Treatment-Refractory Trigeminal Neuralgia: A Case Series with 24-Week Follow Up.

We sought to assess the efficacy of combining onabotulinumtoxinA (BoNTA) as add-on therapy to carbamazepine or oxcarbazepine in treatment-refractory patients with trigeminal neuralgia (TGN) who failed to respond (less than 30% response rate) to adequate monotherapy. We conducted a retrospective study on 15 patients with a definite diagnosis of TGN, according to the established criteria, and underwent BoNTA as part of their treatment plan. A single BoNTA session was administered subcutaneously, according to patients' perceived zone of pain, at different dosages ranging from 30 to 200 units (mean ± standard deviation: 87.3 ± 39.2). All patients (15/15; 100%) reported large reductions in the severity of their TGN-related neuropathic pain. The mean pain score on the VAS scale significantly decreased from 9.3 ± 1.1 to 3.7 ± 1.2 at 2 weeks after injecting BoNTA (p < 0.001) and remained stable at 4 and 24 weeks post-injection. Regarding the impact of BoNTA on patients' health-related quality of life, there were significant improvements in both the physical and mental health domains (p < 0.05) of SF-36 tool. BoNTA may be a safe and effective treatment option for patients with refractory TGN when added on to carbamazepine or oxcarbazepine. The use of a single BoNTA session for TGN treatment may be an alternative to surgical interventions and as add-on treatment to oral medications, providing patients with a minimally invasive, effective, safe and well-tolerated option.

Parkinson's Disease, It Takes Guts: The Correlation between Intestinal Microbiome and Cytokine Network with Neurodegeneration.

Parkinson's disease is a progressive neurodegenerative disorder with motor, physical and behavioral symptoms that can have a profound impact on the patient's quality of life. Most cases are idiopathic, and the exact mechanism of the disease's cause is unknown. The current hypothesis focuses on the gut-brain axis and states that gut microbiota dysbiosis can trigger inflammation and advances the development of Parkinson's disease. This systematic review presents the current knowledge of gut microbiota analysis and inflammation based on selected studies on Parkinson's patients and experimental animal models. Changes in gut microbiota correlate with Parkinson's disease, but only a few studies have considered inflammatory modulators as important triggers of the disease. Nevertheless, it is evident that proinflammatory cytokines and chemokines are induced in the gut, the circulation, and the brain before the development of the disease's neurological symptoms and exacerbate the disease. Increased levels of tumor necrosis factor, interleukin-1ß, interleukin-6, interleukin-17A and interferon-γ can correlate with altered gut microbiota. Instead, treatment of gut dysbiosis is accompanied by reduced levels of inflammatory mediators in specific tissues, such as the colon, brain and serum and/or cerebrospinal fluid. Deciphering the role of the immune responses and the mechanisms of the PD-associated gut microbiota will assist the interpretation of the pathogenesis of Parkinson's and will elucidate appropriate therapeutic strategies.

Association between white matter lesions and Parkinson's disease: an impact on Postural/Gait difficulty phenotype and cognitive performance.

BACKGROUND: White matter hyperintensities (WMHs) may be observed on Magnetic Resonance Imaging (MRI) in patients with Parkinson disease with or without vascular risk factors. Whether WMHs may influence motor and non-motor aspects of Parkinson disease is a subject of debate. The aim of this study is to evaluate the impact of WMH severity on various aspects of Parkinson disease in combination to the estimation of the impact of cerebrovascular risk factors. MATERIALS AND METHODS: We included a cohort of patients with Parkinson's disease who underwent MRI examination. The Fazekas visual rating scale was used to assess the severity and location of WMHs, and patient clinical characteristics were correlated with MRI data. RESULTS: All vascular risk factors were associated with higher Fazekas score in both periventricular and deep white matter. Periventricular white matter hyperintensities (PWMHs) and deep white matter hyperintensities (DWMHs) were associated with lower scores in the ACE-R cognitive assessment scale (p < 0.001). Furthermore, PWMHs and DWMHs severity was associated with higher UPDRS motor score (p < 0.001), while the Postural Instability Gait Difficulty (PIGD) phenotype was correlated with higher burden of WMHs. CONCLUSIONS: Comorbid WMHs may contribute to multi-dimension dysfunction in patients with Parkinson disease and consequently the management of vascular risk factors may be crucial to maintain motor and non-motor functions in PD.

Bilateral Vocal Cord Palsy as the Only Symptom of Thymoma Associated-Myasthenia Gravis.

Bilateral vocal cord paresis is a rare phenomenon caused by different underlying etiologies. Myasthenia gravis is included in this long differential diagnosis. Usually, it happens as part of a serious clinical state of a patient, that also suffers from generalized muscle weakness, diplopia, dysphagia, eyelid ptosis. In our case, a 58-year-old woman presented in the emergency room with solely dyspnea, caused by bilateral cord palsy, and that appeared to be the only symptom of thymoma associated-myasthenia gravis. Another interesting fact about this case is the quick recovery and no need for tracheostomy and intubation in the first hours of her admission to hospital.

Peripheral Inflammatory Markers TNF-α and CCL2 Revisited: Association with Parkinson's Disease Severity.

One of the major mediators of neuroinflammation in PD is tumour necrosis factor alpha (TNF-α), which, similar to other cytokines, is produced by activated microglia and astrocytes. Although TNF-α can be neuroprotective in the brain, long-term neuroinflammation and TNF release can be harmful, having a neurotoxic role that leads to death of oligodendrocytes, astrocytes, and neurons and, therefore, is associated with neurodegeneration. Apart from cytokines, a wide family of molecules with homologous structures, namely chemokines, play a key role in neuro-inflammation by drawing cytotoxic T-lymphocytes and activating microglia. The objective of the current study was to examine the levels of the serum TNF-α and CCL2 (Chemokine (C-C motif) ligand 2), also known as MCP-1 (Monocyte Chemoattractant Protein-1), in PD patients compared with healthy controls. We also investigated the associations between the serum levels of these two inflammatory mediators and a number of clinical symptoms, in particular, disease severity and cognition. Such an assessment may point to their prognostic value and provide some treatment hints. PD patients with advanced stage on the Hoehn-Yahr scale showed an increase in TNF-α levels compared with PD patients with stages 1 and 2 (p = 0.01). Additionally, the UPDRS score was significantly associated with TNF-α levels. CCL2 levels, however, showed no significant associations.

Identification of a novel de novo KMT2B variant in a Greek dystonia patient via exome sequencing genotype-phenotype correlations of all published cases.

Mutations in Lysine-Specific Histone Methyltransferase 2B gene (KMT2B) have been reported to be associated with isolated and complex early-onset generalized dystonia. We describe clinico-genetic features on a Greek patient with a novel de novo variant and demonstrate the phenotypic spectrum of KMT2B variants. We performed whole exome sequencing (WES), in a Greek patient with sporadic generalized dystonia. Additionally, we performed a systematic review of all published cases with KMT2B variants. The patient presented with isolated and mild generalized dystonia. We identified a novel splice site variant that was confirmed by Sanger sequencing and was not found in parents. This is the first reported KMT2B variant, in the Greek population. This case report further highlights the growing trend of identifying genetic diseases previously restricted to few cases in many different ethnic groups worldwide via exome sequencing. In the systematic review, we evaluated the mutation pathogenicity in all previously reported cases to investigate possible phenotype-genotype correlations. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various KMT2B variants.

Neurodegeneration and Inflammation-An Interesting Interplay in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder, caused by, so far, unknown pathogenetic mechanisms. There is no doubt that pro-inflammatory immune-mediated mechanisms are pivotal to the pathogenicity and progression of the disease. In this review, we highlight the binary role of microglia activation in the pathophysiology of the disorder, both neuroprotective and neuromodulatory. We present how the expression of several cytokines implicated in dopaminergic neurons (DA) degeneration could be used as biomarkers for PD. Viral infections have been studied and correlated to the disease progression, usually operating as trigger factors for the inflammatory process. The gut-brain axis and the possible contribution of the peripheral bowel inflammation to neuronal death, mainly dopaminergic neurons, seems to be a main contributor of brain neuroinflammation. The role of the immune system has also been analyzed implicating a-synuclein in the activation of innate and adaptive immunity. We also discuss therapeutic approaches concerning PD and neuroinflammation, which have been studied in experimental and in vitro models and data stemming from epidemiological studies.

Screening for the C9ORF72 expansion in Greek Huntington Disease phenocopies and controls and meta-analysis of current data.

Background: Several European studies examined the role of C9orf72 repeat expansion in patients with Huntington-disease like phenotypes (HD-L). The scope of our study is to investigate the expansion frequency in a Greek HD-L cohort and the meta-analysis of all published cases. This will be of use in genetic counseling of these cases. Methods: A cohort of 74 patients with HD-L and 67 healthy controls were screened for the C9orf72 expansion status. Case-controls comparison was assessed with the Pearson's chi-square statistic for a 2 × 2 table.A systematic database search was conducted and seven studies, including the current study, were considered eligible for inclusion in a meta-analysis considering a total of 812 patients with HD phenocopies. Pooled mutation frequency was calculated using a Random Effects model or the Mantel-Haezsel fixed effects model, depending on the observed heterogeneity. Results: In our cohort, one patient was found to have a pathologic expansion of C9orf72, and none from the control group (chi-square: 0.91, p-value: 0.34). Pooled mutation frequency was found at 2% (CI: 1-3%) with low heterogeneity (I2:15%). Discussion: Based on this meta-analysis the recommendation for genetic testing for C9orf72 expansions is further solidified.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy revisited: Genotype-phenotype correlations of all published cases.

OBJECTIVE: The aim of this study was to evaluate the correlation between the various NOTCH3 mutations and their clinical and genetic profile, along with the presentation of a novel mutation in a patient. METHODS: Here, we describe the phenotype of a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) harboring a novel mutation. We also performed an extensive literature research for NOTCH3 mutations published since the identification of the gene and performed a systematic review of all published cases with NOTCH3 mutations. We evaluated the mutation pathogenicity in a great number of patients with detailed clinical and genetic evaluation and investigated the possible phenotype-genotype correlations. RESULTS: Our patient harbored a novel mutation in the NOTCH3 gene, the c.3084 G > C, corresponding to the aminoacidic substitution p.Trp1028Cys, presenting with seizures as the first neurologic manifestation. We managed to find a correlation between the pathogenicity of mutations, severity of the phenotype, and age at onset of CADASIL. Significant differences were also identified between men and women regarding the phenotype severity. CONCLUSIONS: The collection and analysis of these scarce data published since the identification of NOTCH3 qualitatively by means of a systematic review and quantitatively regarding genetic profile and pathogenicity scores, highlight the significance of the ongoing trend of investigating phenotypic genotypic correlations.

Prevalence of C9orf72 hexanucleotide repeat expansion in Greek patients with sporadic ALS.

A total of 178 consecutive patients with definite sALS without frontotemporal dementia (FTD) were enrolled in this study, after complete clinical evaluation. A Repeat-Primed Polymerase Chain Reaction (RP-PCR) protocol was applied to detect the G4C2 repeats expansions. In the studied sALS patients, 5.06% (n = 9) carried the C9orf72 mutation. Among carriers, 2/3 of them were females and spinal onset accounted for 78% and bulbar for 22%, while the mean age of onset was about 60 years. Our study showed that the prevalence of C9orf72 repeat expansion in Greek sALS patients is similar to the overall frequency of the mutation in European populations. The pathogenic mutation remains a promising biomarker for genetic testing and targeted treatment.

A novel homozygous SACS mutation identified by whole exome sequencing-genotype phenotype correlations of all published cases.

ARSACS is an autosomal recessive disorder characterized by ataxia, spasticity, and polyneuropathy. A plethora of worldwide distributed mutations have been described so far. Here, we report two brothers, born to non-consanguineous parents, presenting with cerebellar ataxia and peripheral neuropathy. Whole-exome sequencing revealed the presence of a novel homozygous variant in the SACS gene. The variant was confirmed by Sanger sequencing and found at heterozygous state in both parents. This is the first reported mutation in this gene, in Greek population. This case report further highlights the growing trend of identifying genetic diseases previously restricted to single, ethnically isolated regions in many different ethnic groups worldwide. Additionally, we performed a systematic review of all published cases with SACs mutations. ARSACS seems to be an important cause of ataxia and many different types of mutations have been identified, mainly located in exon 10. We evaluated the mutation pathogenicity in all previously reported cases to investigate possible phenotype-genotype correlations. We managed to find a correlation between the pathogenicity of mutations, severity of the phenotype, and age of onset of ARSACS. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various ARSACS variants.

The role of C9orf72 in neurodegenerative disorders: a systematic review, an updated meta-analysis, and the creation of an online database.

A pathologic expansion of a noncoding GGGGCC hexanucleotide repeat of the C9orf72 gene has been strongly associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) cases predominantly in Caucasian populations. In the last decade, scientific interest had been drawn to this gene and many studies conducted have shown a possible correlation with other neurodegenerative diseases as well. We performed an extensive literature search for C9orf72 mutation and its frequency in various neurological and psychiatric diseases. In addition, we performed a meta-analysis of the data related to ALS and familial ALS. An online cloud-based database and an interactive map were developed. The overall mutation frequency of C9orf72 is 20% for familial FTD, 16% for familial ALS and around 6%-8% for sporadic ALS and FTD. The updated meta-analysis that we performed showed that the pooled frequency of C9orf72 repeat expansion in patients with familial ALS was 23% (CI: 18%-28%) and in patients with sporadic ALS 3% (CI: 3%-4%). The subgroup analysis regarding the origin of the population revealed significant differences between Caucasian and Asian patients. Our analysis supports the direct causal relation of the C9orf72 expansion in ALS and FTD. On the contrary, the role of C9orf72 in other neurodegenerative disorders remains controversial. The system that we developed-the online database and the interactive map-is hopefully a stepping stone for an ever-growing platform that will aid scientists from all over the world in contributing to the meta-analysis of C9orf72-related publications.

Replication study of GWAS risk loci in Greek multiple sclerosis patients.

OBJECTIVES: To validate in an ethnically homogeneous Greek multiple sclerosis (MS) cohort, genetic risk factors for the disease, identified through a number of previous multi-ethnic genome-wide association studies (GWAS). METHODS: A total of 1228 MS cases and 1014 controls were recruited in the study, from 3 MS centers in Greece. We genotyped 35 susceptibility SNPs that emerged from previous GWAS or meta-analyses of GWAS. Allele and genotype single locus regression analysis, adjusted for gender and site, was performed. Permutation testing was applied to all analyses. RESULTS: Six polymorphisms reached statistical significance (permutation p value < 0.05). In particular, rs2760524 of LOC105371664, near RGS1 (permutation p value 0.001), rs3129889 of HLA-DRA, near HLA-DRB1 (permutation p value < 1.00e-04), rs1738074 of TAGAP (permutation p value 0.007), rs703842 of METTL1/CYP27B1 (permutation p value 0.008), rs9596270 of DLEU1 (permutation p value < 1.00e-04), and rs17445836 of LincRNA, near IRF8 (permutation p value 0.001) were identified as susceptibility risk factors in our group. CONCLUSION: The current study replicated a number of GWAS susceptibility SNPs, which implies that some similarities between the examined Greek population and the MS genetic architecture of the GWAS populations do exist.