Association between DPP6 polymorphism and the risk of progressive multiple sclerosis in Northern and Southern Europeans.

BACKGROUND: In this study, we investigated the role of the dipeptidyl-peptidase-6 (DPP6) gene in the etiopathogenesis of progressive forms of multiple sclerosis (PrMS). This gene emerged as a candidate gene in a genome-wide association study (GWAS) performed in an Italian sample of PrMS and controls in which two SNPs located in the gene (rs6956703 and rs11767658) showed evidence of association (nominal p-value<10(-4)) (Martinelli-Boneschi et al.) [18]. Moreover, the gene is highly expressed in the central nervous system, and it has been found to be associated with sporadic cases of amyotrophic lateral sclerosis which shares some feature with PrMS. METHODS: We genotyped 19 SNPs selected using a direct and tagging approach in 244 Italian PrMS and 225 controls, and we measured the expression levels of the gene in 13 PrMS cases and 25 controls. RESULTS: Five out of 19 SNPs were found to be associated with the disease (adjusted p<0.05), and they have been tested in an independent sample of 179 primary progressive MS and 198 controls from Northern Europe. None of the SNPs was replicated, but combined analysis confirmed the presence of association for rs2046748 (p=2.5×10(-3),OR=1.82, 95%CI=1.24-2.69). CONCLUSIONS: These results, inflated by the limited sample size determined by the rarity of this condition, suggest a possible role of this gene in the susceptibility to PrMS, at least in Southern Europeans. Moreover, DPP6 was over-expressed in PrMS patients compared to controls.

The expression pattern of inflammatory mediators in cerebrospinal fluid differentiates Guillain-Barré syndrome from chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) share histopathological features but display different disease courses; we measured the concentration of 50 inflammatory mediators in the cerebrospinal fluid (CSF) of patients with either of these diseases. PATIENTS AND METHODS: CSF samples were collected during a diagnostic lumbar puncture and stored at -30 degrees C. We analyzed the CSF of nine subjects with GBS; eight with CIDP; eight with diabetic polyneuropathy (DP) and seven with headache (controls). Fifty inflammatory mediators were simultaneously measured with a multiplex bead-based ELISA on a Suspension Array System. After Bonferroni's correction for repeated measures, non-parametric variance and post hoc test were calculated. RESULTS: Thirty-two inflammatory mediators were expressed. The median concentration of IL-6, IL-9, IL-15, IL-18, CCL4, CXCL1, LIF, MIF, PDGFbb, IFN-gamma2, IL-2ra, IL-12(p40), IL-16, SCGF-b, TRAIL, FGF, G-CSF, GM-CSF, and M-CSF was not different among groups (variance: n.s.). The median concentration of CCL2, CCL7, CCL27, CXCL9, CXCL10, CXCL12, ICAM-1, VCAM1 and VEGF was higher in CIDP and GBS compared with controls (p<0.002). The median concentration of IL-8 and IL-1ra was higher in GBS than CIDP or DP or controls, whereas stem cell factor (SCF) and hepatocyte growth factor (HGF) were higher in CIDP than GBS or DP or controls (p<0.002). DISCUSSION: Mediators of the recruitment and activation of lymphocytes and monocytes are expressed in the CSF of CIDP and GBS. IL-8 and IL-1ra are characteristic of GBS, whereas growth factors (SCF, HGF) of CIDP are possibly related to chronicity or to the survival/repair processes of neurons.

Interictal dysphoric disorder and periictal dysphoric symptoms in patients with epilepsy.

PURPOSE: The issue of phenomenology of mood disorders in epilepsy still remains controversial. It has been suggested that a subgroup of patients may develop an affective syndrome also known as interictal dysphoric disorder (IDD). However, the number of behavioral changes that may occur around the ictus needs to be taken into account for an accurate distinction between "true" psychiatric phenomenology and periictal phenomena. This study aimed at identifying clinical correlates of the IDD, with special attention to the relationship between symptoms and seizures. METHODS: A sample of 142 consecutive adult outpatients with epilepsy were assessed using the Interictal Dysphoric Disorder Inventory (IDDI), a 38-item, self-report questionnaire specifically developed to evaluate presence and severity of IDD symptoms as well as their habitual association with seizures (coded as before, after, during, or when seizure-free) and their duration. RESULTS: IDD was diagnosed in 31 subjects but symptoms showed a clear-cut relationship with epileptic seizures in 54.8% of cases, leading to an operative distinction between true IDD and periictal dysphoric symptoms (PDS). There was no significant difference among patients with IDD, PDS, or those without psychopathology. In the IDD group, symptoms were chronic and unremitting in one-third of cases, with labile affective symptoms being correlated with age at onset of seizures (rho = -0.612, p = 0.020) and duration of the epilepsy (rho = 0.833, p < 0.001). DISCUSSION: An operative distinction between IDD and PDS bears the opportunity to identify different clinical endophenotypes that may have different prognoses and require different treatment strategies.

Manic/hypomanic symptoms and quality of life measures in patients with epilepsy.

PURPOSE: Although several studies pointed out an association between depression and quality of life (QoL) of patients with epilepsy, data about manic/hypomanic symptoms (MHS) remain scanty. In this study, we sought to investigate their relationship with social and health-related QoL measures in patients with epilepsy. METHODS: Consecutive adult outpatients with epilepsy were assessed using the M.I.N.I. Plus version 5.0.0 and the QOLIE-31. RESULTS: Among 117 evaluated patients, 17 fulfilled DSM-IV criteria for manic/hypomanic episodes. Patients with MHS, as compared to those without, showed lower scores in emotional well-being, energy and fatigue, medication effects, social function and total QOLIE score. However, there was no between-groups difference in educational achievements, employment status, living situation, comorbid psychiatric disorders, history of suicide or abuse of illicit drugs. CONCLUSIONS: MHS are associated with poor QoL measures in patients with epilepsy, though without differences in educational achievements, employment status and independent living.

Participation in medical decision-making: attitudes of Italians with multiple sclerosis.

BACKGROUND: Patient involvement in decisions regarding their care has been advocated, but preferences have not been adequately canvassed, particularly in people with multiple sclerosis (MS). OBJECTIVES: To cross-culturally adapt and validate the Italian version of the Control Preference Scale (CPS) subsequently used to assess preferences of people with MS. METHODS: Translation-adaptation into Italian of CPS from the original Canadian English followed by administration in 140 people with MS from five Italian centers (with re-administration in 35) and semi-structured interview. RESULTS: Cross-cultural adaptation of CPS was successful. The 140 people with MS, who varied in clinical and general characteristics, considered the CPS clear and acceptable. Test-retest reliability was moderate (weighted Kappa 0.65; p<0.001). A collaborative role was preferred (61%), followed by passive (33%) and active (6%) roles. Education (odds ratio [OR] 2.43, 95% confidence limits [CI] 1.05-5.66) and length of follow-up at referral center (OR 0.36, 95% CI 0.14-0.92) were associated with choice of an active/collaborative role in the logistic model. CONCLUSIONS: The Italian CPS was well accepted by our MS population. Our data indicate that a high proportion of Italians with MS prefer a more passive role and this should be considered during the clinical encounter.

Clinical correlates of pathological gambling symptoms in patients with epilepsy.

Pathological gambling symptoms (PGS), that is, the subjective urge to gamble and the actual gambling behaviors, are currently acknowledged as relatively common symptoms among Western countries, with an estimated point prevalence of 0.6-1.1% in the general population. Converging evidence suggests that PGS are overrepresented in patients with neurological conditions affecting dopaminergic reward pathways, and can be expressed in both impulse control disorders and obsessive-compulsive spectrum disorders. This study explored the clinical correlates of PGS in patients with epilepsy. Eighty-eight consecutive adult outpatients recruited at three epilepsy clinics in northern Italy were assessed using the Gambling-Symptom Assessment Scale (G-SAS), along with a battery of psychometric instruments to index depression (Beck Depression Inventory [BDI]), anxiety (Spielberger State-Trait Anxiety Inventory [STAI]), and obsessionality (Yale-Brown Obsessive Compulsive Scale [YBOCS]) symptoms. On the G-SAS, patients with a diagnosis of temporal lobe epilepsy (TLE) reported a mean [sd] G-SAS score of 2.0 [5.7], significantly higher than patients with frontal lobe epilepsy (FLE) (0.6 [1.7]) and idiopathic generalized epilepsy (IGE) (0.4 [1.4]). Moreover, multiple regression analysis showed that G-SAS scores were selectively predicted by YBOCS scores, thus suggesting an association between the expression of obsessional spectrum symptoms and PGS in patients with TLE. Alterations in the mesolimbic reward system could represent the putative neuropathological substrate for this multifaceted clinical picture.

Elevation of Gas6 protein concentration in cerebrospinal fluid of patients with chronic inflammatory demyelinating polyneuropathy (CIDP).

INTRODUCTION: Gas6 enhances survival of Schwann cells and neurons in vitro and participates in autoimmunity in animal models. Since its concentration in human cerebrospinal fluid (CSF) is unknown, we measured it in samples from patients with non-inflammatory/non-autoimmune neurological diseases (NINAD) and autoimmune polyneuropathies. MATERIALS AND METHODS: Samples collected after informed consent during diagnostic lumbar puncture in the period 1999-2006 were stored at -30 degrees C. We considered subjects with NINAD (stroke, ALS, headache, psychiatric conditions simulating neurological diseases, otologic dizziness) or with Guillain-Barré syndrome (GBS) or CIDP. CSF and plasma total protein and age were obtained from clinical records. Gas6 was measured with an ELISA developed and validated in our laboratory (inter-, intra-assay CVs <10%, recovery 96%). Variance, Tukey's post-hoc test, regression were calculated with a statistical software (Statsoft). RESULTS: Mean Gas6 concentration in patients with NINAD was 6.5+/-2.4 ng/ml, 7.2+/-2.6 ng/ml in GBS and significantly higher (11.5+/-1.7 ng/ml) in CIDP than in the other conditions (post-hoc, p<0.005). It was not related to age, CSF total proteins or to CSF/plasma ratio of total proteins (regression, p>0.1). CONCLUSIONS: Gas6 is detectable in CSF and may be involved in chronic autoimmune demyelination or myelin repair.

Clinical and psychopathological definition of the interictal dysphoric disorder of epilepsy.

PURPOSE: Different authors suggested the occurrence of a pleomorphic affective syndrome in patients with epilepsy named interictal dysphoric disorder (IDD). We sought to investigate whether IDD occurs only in patients with epilepsy and to validate IDD features against DSM-IV criteria. METHODS: Consecutive patients with a diagnosis of epilepsy (E) or migraine (M) have been assessed using the BDI, MDQ, and the Interictal Dysphoric Disorder Inventory (IDDI), a questionnaire specifically created to evaluate IDD symptoms. Diagnosis of current and lifetime DSM-IV Axis I disorders was established using the MINI Plus version 5.0.0. RESULTS: A total of 229 patients (E = 117; M = 112) were evaluated. Females were significantly more represented in the migraine group (E = 46.5% vs. M = 73.3% p = 0.009), but there was no difference in age, duration of the disease, or education level. Patients with epilepsy were more likely to screen positively at MDQ (E = 17% vs. M = 5.3% p = 0.006) and to have a diagnosis of bipolar disorder (E = 14.5% vs. M = 4.5% p = 0.013) as compared to migraine patients. There was no between-groups difference in IDD prevalence (E = 17%; M = 18.7%) and IDDI total scores (E = 4.1 +/- 2.0 vs. M = 3.8 +/- 2.0). Validation of IDD against DSM-IV categories showed current major depression being the foremost diagnostic category correlated with IDD in both epilepsy (OR = 0.32-0.12-0.88, p = 0.028) and migraine (OR = 0.10, 95% CI = 0.02-0.49, p = 0.004) samples. Current anxiety disorder correlated with IDD only in migraine patients (OR = 0.19, 95% CI = 0.05-0.77, p = 0.02). CONCLUSION: IDD represents a homogenous construct that can be diagnosed in a relevant proportion of patients but it is not typical only of epilepsy, occurring in other central nervous system disorders such as migraine.

Clinical correlates of schizotypy in patients with epilepsy.

Clinical correlates of schizotypy were evaluated in 89 adult consecutive outpatients with epilepsy, using the Beck Depression Inventory, the State and Trait Anxiety Inventory, and the Schizotypal Personality Questionnaire (SPQ). Age at onset of the epilepsy significantly correlated with the constricted affect subscale of the SPQ, while a diagnosis of temporal lobe epilepsy correlated with the total SPQ score, the cognitive-perceptual factor of the SPQ, and the suspiciousness subscale of the SPQ. Schizotypal symptoms correlated with early onset of the seizures and a diagnosis of temporal lobe epilepsy, further confirming an association between psychoses and epilepsy.

The role of aura in psychopathology and dissociative experiences in epilepsy.

Cognitive auras seem to be associated with depression and anxiety, especially in patients with temporal lobe epilepsy (TLE). Dissociative symptoms may occur as an aura or in the context of psychiatric disorders such as depression, anxiety or schizophrenia. This is a cross-sectional study of 62 patients with TLE, using personality and dissociation measures to investigate their relationship with the presence of aura and its different subtypes. Our findings show no difference in psychopathology in patients with different types of aura and reveal that dissociative symptoms correlate with specific measures of anxiety, suggesting a possible link between these experiences and anxiety disorders.

Obsessionality, obsessive-compulsive disorder, and temporal lobe epilepsy.

We evaluated the prevalence of obsessive-compulsive disorder (OCD) in patients with temporal lobe epilepsy (TLE) and we investigated the hypothesis that obsessionality may represent a trait in TLE. Eighty-two consecutive patients with epilepsy, 62 with TLE and 20 with idiopathic generalized epilepsy (IGE), and 82 matched healthy controls were evaluated using the SCID-IP, Y-BOCS, MMPI-2 (specifically the Psychasthenia and Obsessiveness scales), BDI, and STAI Y1 and Y2. Nine of the TLE patients, none of the IGE patients, and one of the controls had a diagnosis of OCD. Psychasthenia and Obsessiveness scores were significantly higher in the TLE than in the IGE and control groups. Patients with TLE and OCD differed significantly with respect to history of depression when compared with patients with TLE without OCD, whereas there were no differences in age at onset and duration of epilepsy, seizure pattern and frequency, MRI features, laterality of the EEG focus, antiepileptic drug therapy and combinations, and BDI scores.