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Objective: To establish whether chronic alcoholism and alcohol consumption are risk factors for developing a first symptomatic epileptic seizure. Methods: Multicentre case-control study of 293 patients (160 men, 133 women) [...]

Sneddon's syndrome is a rare vascular disease affecting mainly skin and brain arterioles leading to their occlusion due to excessive endothelial proliferation. The two main features of this syndrome are livedo reticularis and lacunar subcortical infarcts. Here, we describe the case of a 64-year-old woman presenting with a 4-year history of a throbbing, bilateral, parieto-occipital headache associated with facial pain, but without any other accompanying symptom. The pain, initially misdiagnosed as atypical trigeminal neuralgia, worsened up to chronic daily and such severely disabling headache that she was constrained to bed. She presented with reduced cognitive functions, diffuse and severe livedo reticularis, severe myalgias and mild stiffness. All diagnostic test for different diseases were performed and other diseases excluded except for Sneddon's syndrome. Her symptoms were reduced firstly using acetylsalicylic acid, then ticlopidine 250 mg bid was begun and then Pentoxyphillin, resulting in a significant improvement of symptoms with the disappearance of headache. Her worsening in the first year was characterized by obsessive-compulsive behaviours, body-image misperceptions and panic attacks, improved for a period using olanzapine. Considering this case, we remark the importance of using headache classification to avoid diagnostic errors, secondly, we describe an atypical manifestation of Sneddon's syndrome and therapeutic efficacy of using ticlopidine and pentoxyphillin. [ABSTRACT FROM AUTHOR]

Coenzyme A (CoA), which is widely distributed and vital for cellular metabolism, is a critical molecule essential in both synthesizing and breaking down key energy sources in the body. Inborn errors of metabolism in the cellular de novo biosynthetic pathway of CoA have been linked to human genetic disorders, emphasizing the importance of this pathway. The COASY gene encodes the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of the CoA biosynthetic pathway and serves as one of the rate-limiting components of the pathway. Recessive variants of this gene cause an exceptionally rare and devastating disease called COASY protein-associated neurodegeneration (CoPAN) while complete loss-of-function variants in COASY have been identified in fetuses/neonates with Pontocerebellar Hypoplasia type 12 (PCH 12). Understanding why the different symptoms emerge in these disorders and what determines the development of one syndrome over the other is still not achieved. To shed light on the pathogenesis, we generated a new conditional animal model in which Coasy was deleted under the control of the human GFAP promoter. We used this mouse model to investigate how defects in the CoA biosynthetic pathway affect brain development. This model showed a broad spectrum of severity of the in vivo phenotype, ranging from very short survival (less than 2 weeks) to normal life expectancy in some animals. Surviving mice displayed a behavioral phenotype with sensorimotor defects. Ex vivo histological analysis revealed variable but consistent cerebral and cerebellar cortical hypoplasia, in parallel with a broad astrocytic hyper-proliferation in the cerebral cortex. In addition, primary astrocytes derived from this model exhibited lipid peroxidation, iron dyshomeostasis, and impaired mitochondrial respiration. Notably, Coasy ablation in radial glia and astrocytic lineage triggers abnormal neuronal development and chronic neuroinflammation, offering new insights into disease mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Cavestro, D’Amato, Colombo, Cascone, Moro, Levi, Tiranti and Di Meo.)

Objective: COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein-associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY-related disorders., Methods: Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts., Results: We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY-related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4'-phosphopantetheinylated proteins were significantly reduced in COASY patients., Interpretation: These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY-associated diseases., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Coenzyme A (CoA) is a vital and ubiquitous cofactor required in a vast number of enzymatic reactions and cellular processes. To date, four rare human inborn errors of CoA biosynthesis have been described. These disorders have distinct symptoms, although all stem from variants in genes that encode enzymes involved in the same metabolic process. The first and last enzymes catalyzing the CoA biosynthetic pathway are associated with two neurological conditions, namely pantothenate kinase-associated neurodegeneration (PKAN) and COASY protein-associated neurodegeneration (CoPAN), which belong to the heterogeneous group of neurodegenerations with brain iron accumulation (NBIA), while the second and third enzymes are linked to a rapidly fatal dilated cardiomyopathy. There is still limited information about the pathogenesis of these diseases, and the knowledge gaps need to be resolved in order to develop potential therapeutic approaches. This review aims to provide a summary of CoA metabolism and functions, and a comprehensive overview of what is currently known about disorders associated with its biosynthesis, including available preclinical models, proposed pathomechanisms, and potential therapeutic approaches.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a relentlessly progressive neurodegenerative disorder caused by mutations in the C19orf12 gene. C19orf12 has been implicated in playing a role in lipid metabolism, mitochondrial function, and autophagy, however, the precise functions remain unknown. To identify new robust cellular targets for small compound treatments, we evaluated reported mitochondrial function alterations, cellular signaling, and autophagy in a large cohort of MPAN patients and control fibroblasts. We found no consistent alteration of mitochondrial functions or cellular signaling messengers in MPAN fibroblasts. In contrast, we found that autophagy initiation is consistently impaired in MPAN fibroblasts and show that C19orf12 expression correlates with the amount of LC3 puncta, an autophagy marker. Finally, we screened 14 different autophagy modulators to test which can restore this autophagy defect. Amongst these compounds, carbamazepine, ABT-737, LY294002, oridonin, and paroxetine could restore LC3 puncta in the MPAN fibroblasts, identifying them as novel potential therapeutic compounds to treat MPAN. In summary, our study confirms a role for C19orf12 in autophagy, proposes LC3 puncta as a functionally robust and consistent readout for testing compounds, and pinpoints potential therapeutic compounds for MPAN.

The novel brain-penetrant peroxisome proliferator-activated receptor gamma agonist leriglitazone, previously validated for other rare neurodegenerative diseases, is a small molecule that acts as a regulator of mitochondrial function and exerts neuroprotective, anti-oxidative and anti-inflammatory effects. Herein, we tested whether leriglitazone can be effective in ameliorating the mitochondrial defects that characterize an hiPS-derived model of Pantothenate kinase-2 associated Neurodegeneration (PKAN). PKAN is caused by a genetic alteration in the mitochondrial enzyme pantothenate kinase-2, whose function is to catalyze the first reaction of the CoA biosynthetic pathway, and for which no effective cure is available. The PKAN hiPS-derived astrocytes are characterized by mitochondrial dysfunction, cytosolic iron deposition, oxidative stress and neurotoxicity. We monitored the effect of leriglitazone in comparison with CoA on hiPS-derived astrocytes from three healthy subjects and three PKAN patients. The treatment with leriglitazone did not affect the differentiation of the neuronal precursor cells into astrocytes, and it improved the viability of PKAN cells and their respiratory activity, while diminishing the iron accumulation similarly or even better than CoA. The data suggest that leriglitazone is well tolerated in this cellular model and could be considered a beneficial therapeutic approach in the treatment of PKAN.

Background: The relationship between chronic Helicobacter pylori (HP) infection and headache has been discussed for long; nevertheless, the results of the studies are still contrasting., Objective: This cross-sectional study is aimed to investigate a possible association between HP and headache, mainly migraine., Methods: We screened, by a self-administered questionnaire, the subjects undergoing a breath test or an esophagogastroduodenoscopy. Migraine was diagnosed according to the international criteria., Results: A total of 3914 patients underwent a breath test and 2200 an esophagogastroduodenoscopy at two hospitals, in Piedmont (Italy), in a 5-year period; a total of 1362 questionnaires were included in the study. The mean age of the subjects was 53 years; there were 777 women (57%). HP was detected in 364 (27%) subjects. A total of 702 (51%) subjects suffered from headache: migraine with aura was diagnosed in 176 subjects (176/702, i.e., 25% of the headache group; 176/1362, i.e., 13% of the total population); migraine without aura in 98 subjects (98/702, i.e., 14% of the headache group; 98/1362, i.e., 7% of the total). The logistic regression model did not detect any significant association between HP infection and headache, while a significant association between HP and headache frequency (p =0.009) was found, independently of age, gender, comorbidity, and diagnostic category., Conclusion: Our study does not reveal an association between chronic HP infection and migraine. However, since HP is significantly associated with higher headache frequency, a role for HP as a risk factor for headache chronification, possibly underlain by inflammatory mechanisms, may be supposed., (© 2022. Fondazione Società Italiana di Neurologia.)

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) predominantly infects the respiratory system, several investigations have shown the involvement of the central nervous system (CNS) along the course of the illness, with encephalitis being one of the symptoms. The objective of this systematic review was to evaluate the characteristics (clinical, neuro-radiological aspects, and laboratory features) and outcomes of encephalitis in COVID-19 patients. PubMed, Scopus, and Google Scholar databases were searched from 1 December 2019 until 21 July 2022 to identify case reports and case series published on COVID-19 associated with encephalitis. The quality of the included studies was assessed by the Joanna Briggs Institute critical appraisal checklists. This systematic review included 79 studies, including 91 COVID-19 patients (52.7% male) experiencing encephalitis, where 85.6% were adults (49.3 ± 20.2 years), and 14.4% were children (11.2 ± 7.6 years). RT-PCR was used to confirm 92.2% of the COVID-19 patients. Encephalitis-related symptoms were present in 78.0% of COVID-19 patients at the time of diagnosis. In these encephalitis patients, seizure (29.5%), confusion (23.2%), headache (20.5%), disorientation (15.2%), and altered mental status (11.6%) were the most frequently reported neurologic manifestations. Looking at the MRI, EEG, and CSF findings, 77.6%, 75.5%, and 64.1% of the patients represented abnormal results. SARS-CoV-2-associated or -mediated encephalitis were the most common type observed (59.3%), followed by autoimmune encephalitis (18.7%). Among the included patients, 66.7% were discharged (37.8% improved and 28.9% fully recovered), whereas 20.0% of the reported COVID-19-positive encephalitis patients died. Based on the quality assessment, 87.4% of the studies were of high quality. Although in COVID-19, encephalitis is not a typical phenomenon, SARS-CoV-2 seems like a neuropathogen affecting the brain even when there are no signs of respiratory illness, causing a high rate of disability and fatality.

Neurodegeneration associated with defective pantothenate kinase-2 (PKAN) is an early-onset monogenic autosomal-recessive disorder. The hallmark of the disease is the massive accumulation of iron in the globus pallidus brain region of patients. PKAN is caused by mutations in the PANK2 gene encoding the mitochondrial enzyme pantothenate kinase-2, whose function is to catalyze the first reaction of the CoA biosynthetic pathway. To date, the way in which this alteration leads to brain iron accumulation has not been elucidated. Starting from previously obtained hiPS clones, we set up a differentiation protocol able to generate inhibitory neurons. We obtained striatal-like medium spiny neurons composed of approximately 70-80% GABAergic neurons and 10-20% glial cells. Within this mixed population, we detected iron deposition in both PKAN cell types, however, the viability of PKAN GABAergic neurons was strongly affected. CoA treatment was able to reduce cell death and, notably, iron overload. Further differentiation of hiPS clones in a pure population of astrocytes showed particularly evident iron accumulation, with approximately 50% of cells positive for Perls staining. The analysis of these PKAN astrocytes indicated alterations in iron metabolism, mitochondrial morphology, respiratory activity, and oxidative status. Moreover, PKAN astrocytes showed signs of ferroptosis and were prone to developing a stellate phenotype, thus gaining neurotoxic features. This characteristic was confirmed in iPS-derived astrocyte and glutamatergic neuron cocultures, in which PKAN glutamatergic neurons were less viable in the presence of PKAN astrocytes. This newly generated astrocyte model is the first in vitro disease model recapitulating the human phenotype and can be exploited to deeply clarify the pathogenetic mechanisms underlying the disease., (© 2022. The Author(s).)

PLA2G6 is the causative gene for a group of autosomal recessive neurodegenerative disorders known as PLA2G6-associated neurodegeneration (PLAN). We present a case with early-onset parkinsonism, ataxia, cognitive decline, cerebellar atrophy, and brain iron accumulation. Sequencing of PLA2G6 coding regions identified only a heterozygous nonsense variant, but mRNA analysis revealed the presence of an aberrant transcript isoform due to a novel deep intronic variant (c.2035-274G > A) leading to activation of an intronic pseudo-exon. These results expand the genotypic spectrum of PLAN, showing the paramount importance of detecting possible pathogenic variants in deep intronic regions in undiagnosed patients., (© 2021. The Author(s).)

Background: The association between thrombophilic alterations, migraine, and vascular events has been broadly investigated but not been completely clarified., Methods: In this cross-sectional, case-control study, we included consecutive outpatients diagnosed with migraine referring to a tertiary headache center. Migraine patients were matched to headache-free control subjects. All participants were evaluated for free protein S anticoagulant, functional protein C anticoagulant, homocysteine, and antiphospholipid antibodies (aPLs). History of ischemic stroke (IS) or transient ischemic attack (TIA), coronary heart disease, and peripheral venous thrombosis was also ascertained., Results: We included 329 migraine patients and 329 control subjects (mean age 41 years, 77% women in both groups). Among migraine patients, 239 (72.6%) had migraine without aura and 90 (27.4%) had migraine with aura. Migraine patients had more frequently arterial hypertension, hypercholesterolemia, history of IS or TIA and, peripheral venous thrombosis compared to control subjects, whereas we found no differences in diabetes mellitus, BMI, and coronary heart disease between the two groups. At least one thrombophilic alteration was detected in 107 (32.5%) migraine patients and in 74 (22.5%) control subjects (OR = 1.66, 95% CI 1.17-2.35, p = 0.004). We identified an association of migraine with aPL positivity (OR = 2.6, 95% CI 1.5-4.7, p = 0.001) and with free protein S deficiency (OR = 4.7, 95% CI 1.6-14.0, p = 0.002), whereas we found no differences in protein C deficiency, APCR, and hyperhomocysteinemia between the two groups. Furthermore, aPL positivity and free protein S deficiency were more common in migraine patients with and without aura than in control subjects. We found that in migraine patients, aPL positivity was associated with both IS or TIA (OR = 5.6, 95% CI 1.5-20.4, p = 0.009) and with coronary heart disease (OR = 27.6, 95% CI 1.4-531.1, p = 0.028), whereas free protein S deficiency was associated with IS or TIA only (OR = 14.3, 95% CI 2.8-74.4, p = 0.002)., Conclusions: Our research documented a significative higher prevalence of aPL positivity and protein S deficiency in migraineurs than in controls. Data also showed an association between these alterations and some vascular thrombotic events in migraine patients. We can argue that thrombophilic disorders associated with migraine may contribute to the occurrence of vascular events., (© 2021. Fondazione Società Italiana di Neurologia.)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by sleep, behavioral, memory, and cognitive deteriorations. Sleep disturbance (SD) is a major disease burden in AD, which has a reciprocal relationship with AD pathophysiology. It aggravates memory, behavioral, and cognitive complications in AD. Different studies have found that melatonin hormone levels reduce even in the pre-clinical stages of AD. Melatonin is the primary sleep-regulating hormone and a potent antioxidant with neuroprotective roles. The decrease in melatonin levels can thus promote SD and AD neuropathology. Exogenous melatonin has the potential to alleviate neuropathology and SD in AD by different mechanisms. Various studies have been conducted to assess the efficacy of exogenous melatonin to treat SD in AD. Though most of the studies suggest that melatonin is useful to ameliorate SD in AD, the remaining studies show opposite results. The timing, dosage, and duration of melatonin administration along with disease condition, genetic, environmental, and some other factors can be responsible for the discrepancies between the studies. More extensive trials with longer durations and higher dosage forms and studies including bright light therapy and melatonin agonists (ramelteon, agomelatine, and tasimelteon) should be performed to determine the efficacy of melatonin to treat SD in AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

COASY protein-associated neurodegeneration (CoPAN) is a rare but devastating genetic autosomal recessive disorder of inborn error of CoA metabolism, which shares with pantothenate kinase-associated neurodegeneration (PKAN) similar features, such as dystonia, parkinsonian traits, cognitive impairment, axonal neuropathy, and brain iron accumulation. These two disorders are part of the big group of neurodegenerations with brain iron accumulation (NBIA) for which no effective treatment is available at the moment. To date, the lack of a mammalian model, fully recapitulating the human disorder, has prevented the elucidation of pathogenesis and the development of therapeutic approaches. To gain new insights into the mechanisms linking CoA metabolism, iron dyshomeostasis, and neurodegeneration, we generated and characterized the first CoPAN disease mammalian model. Since CoA is a crucial metabolite, constitutive ablation of the Coasy gene is incompatible with life. On the contrary, a conditional neuronal-specific Coasy knock-out mouse model consistently developed a severe early onset neurological phenotype characterized by sensorimotor defects and dystonia-like movements, leading to premature death. For the first time, we highlighted defective brain iron homeostasis, elevation of iron, calcium, and magnesium, together with mitochondrial dysfunction. Surprisingly, total brain CoA levels were unchanged, and no signs of neurodegeneration were present.

Background: Migraine is a diffuse and disabling disease. Its pathophysiology is complex and involves both central and peripheral dysfunctions., Objective: This review will discuss the pathogenesis of migraine from the origin of the neuro-inflammatory theory, to the modern pathophysiological model and the latest therapies., Methods: PUBMED and EMBASE (up to May 2019) were searched for: migraine, inflammation, immunomodulation. An additional search was carried out from the bibliography of previous review articles., Results: Migraine was thought to be mainly a vascular disorder, according to the so-called "vascular theory". Based on animal models, a new hypothesis called "the neuro-inflammatory" was conceived at the end of the 20th century. The growing knowledge about the trigeminovascular system and its role in the inflammatory-pain pathway, allowed to identify other specific neurotransmitters, such as the Calcitonin Gene-Related Peptide and Pituitary Adenylate Cyclase-Activating Peptide. Evidence was provided that the inflammatory-pain system could become sensitised and, due to this sensitisation, the pain could also perpetuate, even in the absence of any triggers of the migraine attack. At last, brain immune cells modification during cortical spreading depression in migraine was demonstrated, along with the existence and function of the glymphatic system. The better comprehension of the immune system abnormalities allowed the development of new immunomodulating drugs: the monoclonal antibodies against the CGRP or the CGRP receptor. Moreover, new insights into the molecular mechanism of CGRP, and the function of C-fibres and Aδ-fibres, highlighted the mechanism of action of Botulinum Toxin type A in the treatment of chronic migraine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Autoimmunity is believed to play an important causative role in the pathogenesis of epilepsy. There are evidences for the presence of autoantibodies in patients with epilepsy. To date, many studies have assessed the presence of antiphospholipid antibodies (aPLs) in epilepsy patients, though the relationship has been inconclusive., Aims: The aim of this systematic review and meta-analysis was to evaluate the presence of aPLs in epileptic patients as compared to healthy controls., Methods: Five electronic databases (PubMed, Web of Science, Embase, Scopus and Google Scholar) were searched systematically. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects model. Quality assessment was carried out by using the modified 9-star Newcastle-Ottawa Scale (NOS). L'Abbé plots were generated to visually inspect heterogeneity while publication bias was evaluated via visualization of contour- enhanced funnel plots, and Begg's and Egger's tests., Results: Based on the inclusion criteria, 14 studies were selected involving 1248 epilepsy patients and 800 healthy controls. The majority of epilepsy was categorised as generalised or partial and none had comorbidity with autoimmune diseases. Significant presence of both anticardiolipin (aCL) antibodies (OR: 5.16, 95% CI: 3.21-8.28, p < 0.00001) and anti-β2- glycoprotein I (anti-β2-GPI) antibodies (OR: 2.95, 95% CI: 1.07-8.11, p = 0.04) exhibited comorbid association with epilepsy patients as compared to healthy controls. Subgroup analyses revealed that presence of aCL antibodies was more specifically observed in paediatrics (OR: 4.57, 95% CI: 2.57-8.15, p < 0.00001) than adults (OR: 4.24, 95% CI: 1.80-10.01, p = 0.001). The odds of aCL antibody presence was higher in partial epilepsy patients (OR: 7.88, 95% CI: 3.23-19.24, p < 0.00001) than that of generalised (OR: 3.76, 95% CI: 2.15-6.59, p < 0.00001) and in Asian epileptic patients (OR: 9.56, 95% CI: 2.69-33.95, p = 0.0005) than Europeans (OR: 4.35, 95% CI: 2.74-6.92, p < 0.00001). The presence of anti-β2-GPI antibodies was significant in paediatric (OR: 6.44, 95% CI: 1.39-29.89, p = 0.02) and African population with epilepsies (OR: 10.59, 95% CI: 1.22-92.25, p = 0.03). NOS of the majority of the studies (11/14) indicated a high methodological quality. No substantial heterogeneity was observed either from the quantitative analysis or from the L'Abbé plots while no significant publication bias was detected from funnel plots; Begg's and Egger's tests., Conclusion: Since none of the epilepsy subjects exhibited any comorbid autoimmune disorders, significant presence of aCL and anti-β2-GPI antibodies indicate towards their contribution in immune-mediated general pathogenesis of epilepsy., (Copyright © 2018. Published by Elsevier B.V.)

Background The occurrence of antiphospholipid antibodies (aPLs) and headache comorbidity in the presence or absence of underlying autoimmune diseases remains unclear. Aim The aim of this review was to summarize the relationship between headache and aPLs based on evidences from cohort studies and case reports, in addition to examining the treatment strategies that resolved headache in aPLs-positive individuals. Methods A comprehensive literature search was conducted through PubMed, ISI Web of Science and Google Scholar. A total of 559 articles were screened and the appropriate articles were selected based on quality and level of evidence. Results Cohort studies (n = 27) from Europe, North America and Asia demonstrated comorbidity of aPLs and headache in antiphospholipid syndrome, systemic lupus erythematosus (SLE) and neuropsychiatric SLE patients. Significantly higher association between migraine and aPLs was observed (n = 170/779; p < 0.0001) in individuals without any underlying diseases. Our analysis of shortlisted case reports (n = 17) showed that a higher frequency of anticardiolipin antibodies were present in subjects with different autoimmune disorders (70.6%). Corticosteroids were highly effective in resolving headache in aPLs-positive individuals. Conclusion Higher frequency of comorbidity between aPLs and headache was observed in healthy individuals and patient cases. Therefore, experimental studies are warranted to evaluate the aPLs-induced pathogenic mechanism of headache.