Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop).

BACKGROUND AND PURPOSE: Cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited. METHODS: This retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2-year course of cladribine treatment. The primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2-year treatment course. RESULTS: A total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. The study found a significant reduction in annualized relapse rate at the 12-month follow-up after cladribine completion compared to the year prior to starting therapy (0.07 ± 0.25 vs. 0.82 ± 0.80, p < 0.001). Furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. The safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event. CONCLUSIONS: This study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. Real-world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. However, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long-term impact are necessary.

Metacognitive impairment in patients with episodic and chronic migraine.

Migraine is one of the most common medical disorder in the world. Metacognition is the ability to monitor one's own cognitive functioning and consequently direct one's behavior. In adult migraine patients, the neuropsychological profile has been poorly investigated, and metacognitive functions have never been assessed. The aim of the present study was therefore to evaluate executive metacognitive abilities in patients with episodic and chronic migraine. Sixty-four migraine patients (male/female = 18/46; mean age = 45.65 ± 11.61 years): 27 patients with episodic migraine without aura (male/female = 9/18; mean age ± SD = 45.11 ± 12.18 years) and 37 patients with chronic migraine and medication-overuse headache (male/female = 9/28; mean age ± SD = 46.05 ± 11.32 years) were selected for the study. Twenty-nine controls (male/female = 12/17; mean age ± SD = 42.86 ± 14.78 years) were also enrolled in the research. Metacognitive and executive skills were assessed using the metacognitive version of Wisconsin Card Sorting Test. Migraine patients exhibited a lower performance in metacognitive tasks in respect to controls in term of worse outcomes in accuracy score (p = 0.012), global monitoring (p = 0.015), monetary gains (p = 0.022), and control sensitivity (p = 0.027). A reduction in accuracy score (p = 0.001), free-choice improvement (p = 0.002), global monitoring (p = 0.003), monetary gains (p = 0.009), and control sensitivity (p < 0.001) was also found in patients with chronic migraine and medication-overuse headache in respect to patients with episodic migraine. Our study supports the hypothesis that migraine patients show metacognitive dysfunctions that become worse with the chronicization of the disease and the increase of medication use.

Subclinical hypothyroidism is associated with migraine: A case-control study.

BACKGROUND: Recent studies suggested a potential association between both overt and subclinical hypothyroidism and migraine. Aims of this study were to estimate the comorbidity of migraine in patients with subclinical hypothyroidism and to evaluate associated clinical characteristics. METHODS: Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine. RESULTS: The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs. 13%, p < 0.001; OR 5.80; 95% CI = 3.35-10.34). Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls ( p < 0.001 and p = 0.010, respectively). Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine. Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine ( p = 0.005). CONCLUSIONS: Our data suggest that migraine is more frequent in patients with subclinical hypothyroidism in respect to controls. Further studies are needed in order to confirm this association.

Migraine: Genetic Variants and Clinical Phenotypes.

Migraine is a common, chronic neurovascular disorder caused by a complex interaction between genetic and environmental risk factors. In the last two decades, molecular genetics of migraine have been intensively investigated. In a few cases, migraine is transmitted as a monogenic disorder, and the disease phenotype cosegregates with mutations in different genes like CACNA1A, ATP1A2, SCN1A, KCNK18, and NOTCH3. In the common forms of migraine, candidate genes as well as genome-wide association studies have shown that a large number of genetic variants may increase the risk of developing migraine. At present, few studies investigated the genotype-phenotype correlation in patients with migraine. The purpose of this review was to discuss recent studies investigating the relationship between different genetic variants and the clinical characteristics of migraine. Analysis of genotype-phenotype correlations in migraineurs is complicated by several confounding factors and, to date, only polymorphisms of the MTHFR gene have been shown to have an effect on migraine phenotype. Additional genomic studies and network analyses are needed to clarify the complex pathways underlying migraine and its clinical phenotypes.

Targeting MTHFR for the treatment of migraines.

INTRODUCTION: Migraine is a common neurovascular disorder classified by the World Health Organization as one of the most debilitating diseases. Migraine is a complex disease and is a consequence of an interaction between genetic, epigenetic and environmental factors. The MTHFR gene is one of the few replicated genetic risk factors for migraine and encodes an enzyme that is crucial for the folate and the methionine cycles. Individuals carrying the T allele of the MTHFR C677T polymorphism have increased plasma concentrations of homocysteine which leads to endothelial cell injury and alterations in coagulant properties of blood. Areas covered: This review focuses on the recent advances in genetics and the role of the MTHFR gene and homocysteine metabolism in migraine etiopathogenesis. The article summarizes the potential of targeting MTHFR and homocysteine for disease prevention. Expert opinion: Determination of MTHFR C677T polymorphisms as well as measurement of homocysteine concentrations may be useful to migraine patients, particularly those suffering from migraine with aura. Preliminary studies support the use of folate, vitamin B6 and vitamin B12 for the prevention of migraine. However, the results of these studies await replication in larger randomized controlled clinical trials.

ATXN2 intermediate repeat expansions influence the clinical phenotype in frontotemporal dementia.

Common genetic risk factors are associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Intermediate repeat expansions at the Ataxin-2 locus (ATXN2) are a risk factor for ALS and influence the phenotype. We assessed whether ATXN2 is a risk factor for FTD or modify clinical features in a data set of Italian patients. Three hundred sixty-eight unrelated FTD cases and 342 controls were enrolled. The frequency of intermediate CAG repeats in ATXN2 gene was not different comparing patients and controls. CAG repeats were interrupted by CAA in all patients carrying intermediate repeats. Interestingly, patients with an increased number of CAG repeats had an earlier onset of the disease than those without expansions (p = 0.011), and presented more frequently with parkinsonism (p = 0.010), and psychotic symptoms (p = 0.013) at disease onset. Our study does not support a major role of ATXN2 intermediate CAG expansions in predisposing to FTD but suggests that ATXN2 may act as a phenotype modifier.

High Risk of Suicide in Behavioral Variant Frontotemporal Dementia.

AIM: The purpose of the study was to determine the prevalence of suicidal ideation and attempts in patients with behavioral variant frontotemporal dementia (bvFTD), evaluating possible risk factors for suicidality. METHODS: Risk of suicide was assessed using the Scale for Suicide Ideation (SSI) in 35 patients with bvFTD and 25 controls. RESULTS: According to SSI, 40% of patients with bvFTD had suicidal ideation in comparison to 8% of controls ( P = .009). Four patients with bvFTD have attempted suicide versus none control ( P = .006). Patients with bvFTD with suicide risk showed higher levels of anxiety, depression, stress, and hopelessness than patients without suicide risk ( P < .001). Patients who attempted suicide were younger and had a longer disease duration than those with only suicide ideation. Intriguingly, 40% of patients with parkinsonism presented high level of suicide ideation. CONCLUSIONS: Our findings show that patients with bvFTD have a high risk of suicide. Additional studies in larger populations are needed to confirm our results.

Is Migraine Primarily a Metaboloendocrine Disorder?

PURPOSE OF THE REVIEW: The goals of this review are to evaluate recent studies regarding comorbidity between migraine and different metabolic and endocrine disorders and to discuss the role of insulin resistance as a common pathogenetic mechanism of these diseases. RECENT FINDINGS: Recently, several studies showed that migraine is associated with insulin resistance, a condition in which a normal amount of insulin induces a suboptimal physiological response. All the clinical studies that used the oral glucose tolerance test to examine insulin sensitivity found that, after glucose load, there is in migraine patients a significant increase of both plasmatic insulin and glucose concentrations in comparison with controls. On the contrary, no association was found between migraine and type 2 diabetes, while type 1 diabetes seems to have a protective effect in the disease. Obesity and hypertension were shown to be risk factors for both episodic and chronic migraine. Metabolic syndrome has been recently associated mainly with migraine with aura and is now considered a risk factor also for medication overuse headache. Finally, a bidirectional association between migraine and hypothyroidism has been recently demonstrated, suggesting that common genetic or autoimmune mechanisms underlie both diseases. Recent studies showed that insulin receptor signaling and the related physiological responses are altered in migraine and may have a relevant pathogenic role in the disease. Further studies are warranted in order to better elucidate mechanisms underlying insulin resistance in migraine in order to develop new therapeutic strategies for this debilitating disease.

Mutation analysis of CHCHD2 and CHCHD10 in Italian patients with mitochondrial myopathy.

Mutations in CHCHD2 and CHCHD10 were recently reported in a broad spectrum of neurodegenerative diseases, for example, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, or mitochondrial myopathy (MM). The aim of the study was to evaluate the prevalence of CHCHD2 and CHCHD10 mutations in Italian MM patients without mitochondrial DNA mutations. The coding regions of CHCHD2 and CHCHD10 were sequenced in 62 MM patients. None of the patients showed CHCHD2 mutations, whereas 1 sporadic MM patient carried a homozygous Pro96Thr substitution in CHCHD10. Muscle biopsy of this patient showed intracellular glycogen accumulation with cytochrome c oxidase negative and ragged red fibers. Our study suggests that the homozygous Pro96Thr mutation in CHCHD10 might be pathogenic but does not support a major role for CHCHD2 in MM pathogenesis.

Late onset bipolar disorder and frontotemporal dementia with mutation in progranulin gene: a case report.

Bipolar disorder is a chronic psychiatric illness characterised by fluctuation in mood state, with a relapsing and remitting course. Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous syndrome, with the most frequent phenotype being behavioural variant frontotemporal dementia (bvFTD). Here, we report the case of an Italian male presenting with late-onset bipolar disorder that developed into bvFTD over time, carrying a mutation in the GRN gene. Interestingly, the patient carried the c.1639 C > T variant in the GRN gene, resulting in a R547C substitution. Our case report further corroborates the notion that, in addition to FTD, progranulin may be involved in the neurobiology of bipolar disorder type 1, and suggests to screen patients with late-onset bipolar disorder for GRN mutations.

Genetic analysis of CHCHD2 and CHCHD10 in Italian patients with Parkinson's disease.

In recent years, CHCHD2 and CHCHD10 mutations were reported to be associated with a broad spectrum of neurodegenerative diseases, including Parkinson's disease (PD), although with conflicting results in different populations. The present study aimed to evaluate CHCHD2 and CHCHD10 coding variants in Italian patients with PD. All the coding regions and flanking intronic splice sites of CHCHD2 and CHCHD10 were sequenced. None of our 119 PD cases carried CHCHD2 mutations, whereas 1 sporadic PD patient showed the Pro34Ser substitution in CHCHD10. Our data suggest that CHCHD2 and CHCDH10 mutations are not a relevant cause of PD in Italian population.

Investigating the role of adipokines in chronic migraine.

Background and aims Adiponectin, leptin, and resistin are adipocyte-derived secretory factors involved in endothelial function, weight, inflammation, and insulin resistance. Recent studies suggested a role for adipokines in episodic migraine as mediators of inflammatory processes. The aim of this study was to investigate plasma concentrations of adiponectin, leptin, and resistin in patients with chronic migraine. Materials and methods Twenty-seven chronic migraineurs (20 females, 7 males; mean age 49.0 ± 9.0 yrs) and 37 healthy controls (23 females, 14 males; mean age 49.8 ± 15.0 yrs) were selected for the study. Fasting plasmatic levels of total adiponectin, leptin, and resistin were measured using ELISA kits during a pain-free period. Fasting glucose, insulin, total and HDL-cholesterol, triglycerides, and ESR were also determined. Results Serum levels of adiponectin and resistin were significantly increased in chronic migraineurs in comparison with controls ( p = 0.001 and p = 0.032, respectively). After correction for BMI, sex and age, leptin levels were significantly increased in chronic migraineurs ( p = 0.007). A positive correlation between leptin concentrations and both indices of insulin resistance and markers of inflammation was found. Discussion Our data suggest that adiponectin and resistin are altered in non-obese chronic migraineurs. Further studies are needed to elucidate the neurobiological mechanisms underlying adipokine dysfunction in migraine.

Lack of association between APOE gene polymorphisms and amyotrophic lateral sclerosis: a comprehensive meta-analysis.

Several studies have evaluated the association between APOE gene polymorphisms and the risk for amyotrophic lateral sclerosis (ALS), with inconclusive results. The aim of our study was to further define the risk associated with carriage of the APOE alleles and development and clinical characteristics of ALS. We performed a comprehensive meta-analysis of all existing studies investigating the association between the APOE gene and ALS published up to September 2013, comprising a total of 4249 ALS patients and 10,397 controls. Pooled odds ratios (OR) were estimated using the random effect (RE) model. Results showed that the carriage of different APOE alleles had no effect on disease risk. In particular, the ϵ4 allele was not associated with a significantly increased disease risk (ϵ4 carriers vs. non-ϵ4 carriers: RE OR 1.18; 95% CI 0.91-1.53). In conclusion, our study suggests that the APOE gene does not have a significant effect in ALS aetiopathogenesis.

Apolipoprotein E polymorphisms in frontotemporal lobar degeneration: a meta-analysis.

OBJECTIVE: Case-control studies have not been consistent in showing association between apolipoprotein E (APOE) polymorphisms and frontotemporal lobar degeneration (FTLD), producing contradictory findings. The study objective was to define and quantify further the disease risk associated with the carriage of different APOE alleles to determine whether APOE gene polymorphism is a risk factor for FTLD. METHODS: A systematic review of all case-control studies investigating the association between the APOE gene and FTLD up to December 2011 was conducted. Case-control studies using clinical or pathological criteria for FTLD and reporting APOE allelic or genotypic data were included. Pooled odds ratios (ORs) were estimated using a random effects model, and 95% confidence intervals (CIs) were calculated. RESULTS: Twenty-eight case-control studies met the inclusion criteria. Carriage of the ε2 allele had no effect on disease risk. On the contrary, carriage of the ε4 allele was associated with a significantly increased disease risk (ε4 carriers vs non-ε4 carriers: OR, 1.94; 95% CI, 1.43-2.64; ε4 vs ε3 allele: OR, 1.83; 95% CI, 1.34-2.52). Furthermore, a gene-dosage effect for the ε4 allele was found. There was no evidence of publication bias, but heterogeneity between the studies was high. CONCLUSIONS: Our study provides evidence for an association between the APOE ε4 allele and frontotemporal lobar degeneration.

Genetic variants in the NOTCH4 gene influence the clinical features of migraine.

BACKGROUND: Recent studies suggested an important role for vascular factors in migraine etiopathogenesis. Notch4 belongs to a family of transmembrane receptors that play an important role in vascular development and maintenance. The aim of this study was to test the hypothesis that polymorphisms of the NOTCH4 gene would modify the occurrence and the clinical features of migraine. FINDINGS: Using a case-control strategy, we genotyped 239 migraine patients and 264 controls for three different non-synonymous polymorphisms (T320A, G835V, R1346P) of the NOTCH4 gene and for the (CTG) n-encoding polyleucine polymorphism in exon 1. Although the analyzed polymorphisms resulted not associated with migraine, the clinical characteristics of our patients were significantly influenced by the different NOTCH4 genotypes. Longer duration of disease and severity of neurovegetative symptoms during headache attacks were associated with the R1346P and G835V polymorphisms, respectively. In female patients, worsening of migraine symptoms at menarche was significantly correlated with T320A polymorphism. CONCLUSIONS: Our study shows that genetic variations within the NOTCH4 gene significantly modify the clinical characteristics of migraine and may have a role in disease pathogenesis.