Increased production of inflammatory cytokines by circulating monocytes in mesial temporal lobe epilepsy: A possible role in drug resistance.

We analyzed peripheral blood mononuclear cells (PBMCs) and serum inflammatory biomarkers in patients with mesial temporal lobe epilepsy (drug-resistant - DR, vs. drug-sensitive - DS). Patients with epilepsy showed higher levels of serum CCL2, CCL3, IL-8 and AOPP, and lower levels of FRAP and thiols compared to healthy controls (HC). Although none of the serum biomarkers distinguished DR from DS patients, when analysing intracellular cytokines after in vitro stimulation, DR patients presented higher percentages of IL-1ß and IL-6 positive monocytes compared to DS patients and HC. Circulating innate immune cells might be implicated in DR epilepsy and constitute potential new targets for treatments.

Qualitative evaluation of the Rey-Osterrieth Complex Figure Test in patients with progressive supranuclear palsy.

Objective: In early stages of disease, the differential diagnosis between Parkinson's Disease (PD) and atypical parkinsonism, such as Progressive Supranuclear Palsy (PSP), could be challenging. Growing attention has recently been dedicated to investigating neuropsychological markers of degenerative parkinsonism. The Rey-Osterrieth Complex Figure Test (ROCFT) copy score was hypothesized able to differentiate PSP from PD. However, ROCFT is a drawing test requiring multiple cognitive abilities and it is still unknown which of them assumes an important role in PSP performance. Using a qualitative scoring system, we investigated which cognitive abilities underpin the PSP performance at the ROCFT copy trial. Moreover, we evaluated usefulness of the BQSS scores in discriminating PSP from PD. Methods: Thirty PSP-Richardson's Syndrome (PSP-RS) patients, 30 PD patients, and 30 healthy control (HC) comparable for age, education, and gender were enrolled. All subjects underwent a neuropsychological evaluation; ROCFT copy were evaluated with the 36-Point Score and with the Boston Qualitative Scoring System (BQSS). Results: PSP-RS patients performed worse in ROCFT 36-Point Score and in several BQSS scores compared to other groups. Most suitable scores discriminating PSP-RS from PD were "Perseveration" and "Vertical Expansion" of BQSS. A logistic regression model considering "Perseveration" and "Vertical Expansion" showed a diagnostic accuracy of 83,3% for PSP-RS condition. Conclusion: our findings showed that "Perseveration" and "Vertical Expansion" BQSS scores were useful in discriminating PSP-RS from PD. "Perseveration" and "Vertical Expansion" BQSS scores might be included in the cognitive evaluation along with quantitative scores when PSP diagnosis is considered.

Primary mitochondrial myopathy: 12-month follow-up results of an Italian cohort.

OBJECTIVES: To assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM). METHODS: Twelve months follow-up data of 117 patients with PMM were collected. We analysed the 6-min walk test (6MWT), timed up-and-go test (× 3) (3TUG), five-times sit-to-stand test (5XSST), timed water swallow test (TWST), and test of masticating and swallowing solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional pain inventory as patient-reported outcome measures. PMM patients were divided into three phenotypic categories: mitochondrial myopathy (MiMy) without extraocular muscles involvement, pure chronic progressive external ophthalmoplegia (PEO) and PEO&MiMy. As 6MWT is recognized to have significant test-retest variability, we calculated MCID (minimal clinically important difference) as one third of baseline 6 min walking distance (6MWD) standard deviation. RESULTS: At 12-month follow-up, 3TUG, 5XSST and FSS were stable, while TWST and the perceived pain severity (WHYMPI) worsened. 6MWD significantly increased in the entire cohort, especially in the higher percentiles and in PEO patients, while was substantially stable in the lower percentile (< 408 m) and MiMy patients. This increase in 6MWD was considered not significant, as inferior to MCID (33.3 m). NMDAS total score showed a slight but significant decline at 12 months (0.9 point). The perceived pain severity significantly worsened. Patients with PEO performed better in functional measures than patients with PEO&MiMy or MiMy, and had lower values of NMDAS. CONCLUSIONS: PMM patients showed a slow global decline valued by NMDAS at 12 months; 6MWT was a more reliable measurement below 408 m, substantially stable at 12 months. PEO patients had better motor performance and lower NMDAS than PEO&MiMy and MiMy also at 12 months of follow-up.

Adult-onset mitochondrial movement disorders: a national picture from the Italian Network.

INTRODUCTION: Both prevalence and clinical features of the various movement disorders in adults with primary mitochondrial diseases are unknown. METHODS: Based on the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases", we reviewed the clinical, genetic, neuroimaging and neurophysiological data of adult patients with primary mitochondrial diseases (n = 764) where ataxia, myoclonus or other movement disorders were part of the clinical phenotype. RESULTS: Ataxia, myoclonus and movement disorders were present in 105/764 adults (13.7%), with the onset coinciding or preceding the diagnosis of the mitochondrial disease in 49/105 (46.7%). Ataxia and parkinsonism were the most represented, with an overall prevalence at last follow-up of 59.1% and 30.5%, respectively. Hyperkinetic movement disorders were reported in 15.3% at last follow-up, being the less common reported movement disorders. The pathogenic m.8344A > G and POLG variants were always associated with a movement disorder, while LHON variants and mtDNA single deletions were more commonly found in the subjects who did not present a movement disorder. The most common neuroimaging features were cortical and/or cerebellar atrophy, white matter hyperintensities, basal ganglia abnormalities and nigro-striatal degeneration. Almost 70% of patients with parkinsonism responded to dopaminergic therapy, mainly levodopa, and 50% with myoclonus were successfully treated with levetiracetam. CONCLUSION: Movement disorders, mainly ataxia and parkinsonism, are important findings in adult primary mitochondrial diseases. This study underlies the importance of looking for a mitochondrial etiology in the diagnostic flowchart of a movement disorder and may help direct genetic screening in daily practice.

Chronic inflammatory demyelinating polyradiculoneuropathy: can a diagnosis be made in patients not fulfilling electrodiagnostic criteria?

BACKGROUND AND PURPOSE: The aim was to identify the clinical and diagnostic investigations that may help to support a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients not fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria. METHODS: The data from patients with a clinical diagnosis of CIDP included in a national database were retrospectively reviewed. RESULTS: In all, 535 patients with a diagnosis of CIDP were included. This diagnosis fulfilled the EFNS/PNS criteria in 468 patients (87.2%) (definite in 430, probable in 33, possible in three, while two had chronic immune sensory polyradiculopathy). Sixty-seven patients had a medical history and clinical signs compatible with CIDP but electrodiagnostic studies did not fulfill the EFNS/PNS criteria for CIDP. These patients had similar clinical features and frequency of abnormal supportive criteria for the diagnosis of CIDP compared to patients fulfilling EFNS/PNS criteria. Two or more abnormal supportive criteria were present in 40 (61.2%) patients rising to 54 (80.6%) if a history of a relapsing course as a possible supportive criterion was also included. Increased cerebrospinal fluid proteins and response to immune therapy most frequently helped in supporting the diagnosis of CIDP. Response to therapy was similarly frequent in patients fulfilling or not EFNS/PNS criteria (87.3% vs. 85.9%). CONCLUSIONS: Patients with a clinical diagnosis of CIDP had similar clinical findings, frequency of abnormal supportive criteria and response to therapy compared to patients fulfilling EFNS/PNS criteria. The presence of abnormal supportive criteria may help in supporting the diagnosis of CIDP in patients with a medical history and clinical signs compatible with this diagnosis but non-diagnostic nerve conduction studies.

Clinical features of mtDNA-related syndromes in adulthood.

Mitochondrial diseases are the most common inheritable metabolic diseases, due to defects in oxidative phosphorylation. They are caused by mutations of nuclear or mitochondrial DNA in genes involved in mitochondrial function. The peculiarity of "mitochondrial DNA genetics rules" in part explains the marked phenotypic variability, the complexity of genotype-phenotype correlations and the challenge of genetic counseling. The new massive genetic sequencing technologies have changed the diagnostic approach, enhancing mitochondrial DNA-related syndromes diagnosis and often avoiding the need of a tissue biopsy. Here we present the most common phenotypes associated with a mitochondrial DNA mutation with the recent advances in diagnosis and in therapeutic perspectives.

Oxidative stress biomarkers in Fabry disease: is there a room for them?

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder, caused by deficient activity of the alpha-galactosidase A enzyme leading to progressive and multisystemic accumulation of globotriaosylceramide. Recent data point toward oxidative stress signalling which could play an important role in both pathophysiology and disease progression. METHODS: We have examined oxidative stress biomarkers [Advanced Oxidation Protein Products (AOPP), Ferric Reducing Antioxidant Power (FRAP), thiolic groups] in blood samples from 60 patients and 77 healthy controls. RESULTS: AOPP levels were higher in patients than in controls (p < 0.00001) and patients presented decreased levels of antioxidant defences (FRAP and thiols) with respect to controls (p < 0.00001). In a small group of eight treatment-naïve subjects with FD-related mutations, we found altered levels of oxidative stress parameters and incipient signs of organ damage despite normal lyso-Gb3 levels. CONCLUSIONS: Oxidative stress occurs in FD in both treated and naïve patients, highlighting the need of further research in oxidative stress-targeted therapies. Furthermore, we found that oxidative stress biomarkers may represent early markers of disease in treatment-naïve patients with a potential role in helping interpretation of FD-related mutations and time to treatment decision.

Risk factors for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): antecedent events, lifestyle and dietary habits. Data from the Italian CIDP Database.

BACKGROUND AND PURPOSE: The role of lifestyle and dietary habits and antecedent events has not been clearly identified in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: Information was collected about modifiable environmental factors and antecedent infections and vaccinations in patients with CIDP included in an Italian CIDP Database. Only patients who reported not having changed their diet or the lifestyle habits investigated in the study after the appearance of CIDP were included. The partners of patients with CIDP were chosen as controls. Gender-matched analysis was performed with randomly selected controls with a 1:1 ratio of patients and controls. RESULTS: Dietary and lifestyle data of 323 patients and 266 controls were available. A total of 195 cases and 195 sex-matched controls were used in the analysis. Patients eating rice at least three times per week or eating fish at least once per week appeared to be at decreased risk of acquiring CIDP. Data on antecedent events were collected in 411 patients. Antecedent events within 1-42 days before CIDP onset were reported by 15.5% of the patients, including infections in 12% and vaccinations in 1.5%. Patients with CIDP and antecedent infections more often had an acute onset of CIDP and cranial nerve involvement than those without these antecedent events. CONCLUSIONS: The results of this preliminary study seem to indicate that some dietary habits may influence the risk of CIDP and that antecedent infections may have an impact on the onset and clinical presentation of the disease.

CPEO and Mitochondrial Myopathy in a Patient with DGUOK Compound Heterozygous Pathogenetic Variant and mtDNA Multiple Deletions.

The classic features of deoxyguanosine kinase (DGUOK) deficiency are infantile onset hepatic failure with nystagmus and hypotonia; mitochondrial DNA studies on affected tissue reveal mitochondrial DNA depletion. Later, it has been shown that the mutations in the same gene may present with adult-onset mitochondrial myopathy and mitochondrial DNA multiple deletions in skeletal muscle. Here we report the case of a 42-year-old Italian woman presenting with a chronic progressive external ophthalmoplegia and myopathy with mtDNA multiple deletions and the compound heterozygous c.462T>A (p.Asn154Lys) and c.707+2T>G pathogenic variants in DGUOK.

Oxidative Stress in Cerebral Small Vessel Disease Dizziness Patients, Basally and After Polyphenol Compound Supplementation.

BACKGROUND: Leukoaraiosis (LA) is a common radiological finding in elderly, frequently associated with several clinical disorders, including unexplained dizziness. The pathogenesis of LA is multifactorial, with a dysfunction of cerebral microcirculation resulting in chronic hypoperfusion and tissue loss, with oxidative stress involved in this cascade. OBJECTIVE: The aim of this study was to analyse some oxidative stress biomarkers in a cohort of LA patients. METHOD: Fifty-five consecutive patients (33 males, median age 75 years) with LA were recruited. In a subgroup of 33 patients with LA and unexplained dizziness, we have then performed an open study to evaluate if 60-day supplementation with a polyphenol compound may modify these biomarkers and influence quality of life, analysed with the Dizziness Handicap Inventory (DHI) scale. RESULTS: At baseline, blood oxidative stress parameters values were outside normal ranges and compared to matched healthy controls. After the two months supplementation, we observed a significant decrement of advanced oxidation protein products values and a significant improvement of DHI. CONCLUSION: Oxidative stress biomarkers may be useful to detect redox imbalance in LA and to provide non-invasive tools to monitor disease status and response to therapy.

Recurrent esophageal stricture from previous caustic ingestion treated with 40-year self-dilation: case report and review of literature.

BACKGROUND: Corrosive esophageal strictures are common. The severity of the strictures depends on type, quantity, duration of contact and concentration of the caustic substance ingested. Endoscopic balloon dilation and endoscopic bougienage are a cornerstone in the management of the benign esophageal strictures and are the most widely used treatments, but are expensive and invasive procedures. CASE PRESENTATION: We report the case of an 82-year-old patient with a corrosive esophageal stricture treated for over 40 years by means of home self-bougienage. The procedure has been carried out for the longest lapse of time described in literature, with an excellent control of symptoms. In the case reported, after being carried out for more than 40 years, self-dilation allowed good quality of life and symptoms management, ensuring an excellent nutritional status. CONCLUSIONS: Following an adequate patient training, self-dilatation can be a safe and effective option of treatment, avoiding frequent expensive hospital admissions for endoscopic esophageal dilatation.

Semiautomated Evaluation of the Primary Motor Cortex in Patients with Amyotrophic Lateral Sclerosis at 3T.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis is a neurodegenerative disease involving the upper and lower motor neurons. In amyotrophic lateral sclerosis, pathologic changes in the primary motor cortex include Betz cell depletion and the presence of reactive iron-loaded microglia, detectable on 7T MR images as atrophy and T2*-hypointensity. Our purposes were the following: 1) to investigate the signal hypointensity-to-thickness ratio of the primary motor cortex as a radiologic marker of upper motor neuron involvement in amyotrophic lateral sclerosis with a semiautomated method at 3T, 2) to compare 3T and 7T results, and 3) to evaluate whether semiautomated measurement outperforms visual image assessment. MATERIALS AND METHODS: We investigated 27 patients and 13 healthy subjects at 3T, and 19 patients and 18 healthy subjects at 7T, performing a high-resolution 3D multiecho T2*-weighted sequence targeting the primary motor cortex. The signal hypointensity-to-thickness ratio of the primary motor cortex was calculated with a semiautomated method depicting signal intensity profiles of the cortex. Images were also visually classified as "pathologic" or "nonpathologic" based on the primary motor cortex signal intensity and thickness. RESULTS: The signal hypointensity-to-thickness ratio of the primary motor cortex was greater in patients than in controls (P < .001), and it correlated with upper motor neuron impairment in patients (ρ = 0.57, P < .001). The diagnostic accuracy of the signal hypointensity-to-thickness ratio was high at 3T (area under the curve = 0.89) and even higher at 7T (area under the curve = 0.94). The sensitivity of the semiautomated method (0.81) outperformed the sensitivity of the visual assessment (0.56-0.63) at 3T. CONCLUSIONS: The signal hypointensity-to-thickness ratio of the primary motor cortex calculated with a semiautomated method is suggested as a radiologic marker of upper motor neuron burden in patients with amyotrophic lateral sclerosis. This semiautomated method may be useful for improving the subjective radiologic evaluation of upper motor neuron pathology in patients suspected of having amyotrophic lateral sclerosis.

Proximal Myopathy due to m.5835G>A Mutation in Mitochondrial MT-TY Gene.

Mitochondrial (mt) tRNA (MTT) gene mutations are an important cause of mitochondrial diseases and are associated with a wide range of clinical presentations. Most mutations fall into three mitochondrial tRNAs (tRNAIle, tRNALeu (UUR), and tRNALys) and are responsible for half of the mitochondrial diseasees associated with tRNA mutation, with MERRF, MELAS, mitochondrial myopathy, and Leigh syndrome being the most frequent phenotypes. More than 100 tRNA pathogenetic mutations are described, showing little correlation between the observed clinical phenotype and a specific mitochondrial tRNA mutation. Furthermore different mutation can manifest with similar clinical phenotypes, making the genotype-phenotype correlation difficult. Here we report the case of an Italian 53-year-old woman presenting with a proximal myopathy and the m.5835G>A mutation in MT-TY gene coding for the mitochondrial tRNA Tyrosine gene.

Physical exercise and oxidative stress in muscular dystrophies: is there a good balance?

The effect of oxidative stress on muscle damage inducted by physical exercise is widely debated. It is generally agreed that endurance and intense exercise can increase oxidative stress and generate changes in antioxidant power inducing muscle damage; however, regular and moderate exercise can be beneficial for the health improving the antioxidant defense mechanisms in the majority of cases. Growing evidences suggest that an increased oxidative/nitrosative stress is involved in the pathogenesis of several muscular dystrophies (MDs). Notably, physical training has been considered useful for patients with these disorders. This review will focus on the involvement of oxidative stress in MDs and on the possible effects of physical activities to decrease oxidative damage and improve motor functions in MDs patients.

The proposal of a clinical protocol to assess central and peripheral fatigue in myotonic dystrophy type 1.

DM1 is an autosomal-dominant disorder characterized by muscle weakness, myotonia, and multisystemic involvement. According to current literature fatigue and daytime sleepiness are among the main symptoms of DM1. Oxidative stress has been proposed to be one of the pathogenic factors of fatigue consequent to DM1. In this study, we investigated the dimensions of experienced fatigue and  physiological fatigue in a sample of 26 DM1 patients (17 males, 9 females, mean age 41.6 years, SD±12.7); experienced fatigue has been studied through Fatigue Severity Scale (FSS), and physiological fatigue was measured through an intermittent incremental exercise of the forearm muscles using a myometer; oxidative stress balance markers trend during aerobic exercise test have been collected. The occurrence of central fatigue in the sample means that central activation worsens during the motor contraction; interestingly FSS score was significantly correlated to MVC (before and after the effort, r-before=-0.583, p<0.01, r-after= -0.534, p<0.05), and to motor disability measured by MRC (r=-0.496, p<0.05); moreover we found a strong tendency towards significance in the association to lactate baseline (r=0.378, p=0.057).Results are discussed to define whether or not, based on clinical and laboratory grounds, such exercise training protocol may be suitable for proper management of DM1 patients; proper assessment of fatigue should be included in algorithms for data collection in DM1 patient registries.

Revisiting mitochondrial ocular myopathies: a study from the Italian Network.

Ocular myopathy, typically manifesting as progressive external ophthalmoplegia (PEO), is among the most common mitochondrial phenotypes. The purpose of this study is to better define the clinical phenotypes associated with ocular myopathy. This is a retrospective study on a large cohort from the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases". We distinguished patients with ocular myopathy as part of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy), and then PEO with isolated ocular myopathy from PEO-plus when PEO was associated with additional features of multisystemic involvement. Ocular myopathy was the most common feature in our cohort of mitochondrial patients. Among the 722 patients with a definite genetic diagnosis, ocular myopathy was observed in 399 subjects (55.3%) and was positively associated with mtDNA single deletions and POLG mutations. Ocular myopathy as manifestation of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy, n = 131) was linked to the m.3243A>G mutation, whereas the other "PEO" patients (n = 268) were associated with mtDNA single deletion and Twinkle mutations. Increased lactate was associated with central neurological involvement. We then defined, among the PEO group, as "pure PEO" the patients with isolated ocular myopathy and "PEO-plus" those with ocular myopathy and other features of neuromuscular and multisystem involvement, excluding central nervous system. The male proportion was significantly lower in pure PEO than PEO-plus. This study reinforces the need for research on the role of gender in mitochondrial diseases. The phenotype definitions here revisited may contribute to a more homogeneous patient categorization, useful in future studies and clinical trials.

Magnetic susceptibility in the deep layers of the primary motor cortex in Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurological disorder that entails degeneration of both upper and lower motor neurons. The primary motor cortex (M1) in patients with upper motor neuron (UMN) impairment is pronouncedly hypointense in Magnetic Resonance (MR) T2* contrast. In the present study, 3D gradient-recalled multi-echo sequences were used on a 7 Tesla MR system to acquire T2*-weighted images targeting M1 at high spatial resolution. MR raw data were used for Quantitative Susceptibility Mapping (QSM). Measures of magnetic susceptibility correlated with the expected concentration of non-heme iron in different regions of the cerebral cortex in healthy subjects. In ALS patients, significant increases in magnetic susceptibility co-localized with the T2* hypointensity observed in the middle and deep layers of M1. The magnetic susceptibility, hence iron concentration, of the deep cortical layers of patients' M1 subregions corresponding to Penfield's areas of the hand and foot in both hemispheres significantly correlated with the clinical scores of UMN impairment of the corresponding limbs. QSM therefore reflects the presence of iron deposits related to neuroinflammatory reaction and cortical microgliosis, and might prove useful in estimating M1 iron concentration, as a possible radiological sign of severe UMN burden in ALS patients.