Treatment modifiers across different regimens of natalizumab treatment in MS: An Italian real-world experience.

Despite its widespread use in clinical practice, the effectiveness of natalizumab extended interval dosing (EID) adopted from treatment start across different treatment intervals and individual modifiers (body mass index - BMI) is still under-investigated. Here, seven-hundred and forty-five multiple sclerosis (MS) patients, exposed to natalizumab for 3.30 â€‹± â€‹1.34 years, were retrospectively enrolled in an observational multicenter study. After stratifying patients in EID or standard interval dosing (SID), we assessed differences in time to relapse, MRI activity and Expanded Disability Status Scale (EDSS) progression. The primary analysis was conducted on patients exposed to EID interval from 5 weeks and 1 day to 7 weeks, while a secondary analysis included also EID periods up to 8 weeks. An additional analysis explored the impact of BMI. No differences in time to first relapse, time to radiological activity, time to EDSS progression or time to EDA (evidence of disease activity) were detected between SID and EID group (EID interval from 5 weeks to 1 day to 7 weeks). When including EID periods from 7 weeks and 1 day to 8 weeks, the EID group showed a trend towards higher risk of experience clinical relapses than the SID group. A higher EDA risk was also identified in EID patients with BMI above median. In conclusion, a higher risk of relapses seems to occur for EID above 7 weeks. Independently from the EID scheme adopted, higher BMI increases the risk of EDA in these patients.

CSF Findings in Relation to Clinical Characteristics, Subtype, and Disease Course in Patients With Guillain-Barré Syndrome.

BACKGROUND AND OBJECTIVES: To investigate CSF findings in relation to clinical and electrodiagnostic subtypes, severity, and outcome of Guillain-Barré syndrome (GBS) based on 1,500 patients in the International GBS Outcome Study. METHODS: Albuminocytologic dissociation (ACD) was defined as an increased protein level (>0.45 g/L) in the absence of elevated white cell count (<50 cells/µL). We excluded 124 (8%) patients because of other diagnoses, protocol violation, or insufficient data. The CSF was examined in 1,231 patients (89%). RESULTS: In 846 (70%) patients, CSF examination showed ACD, which increased with time from weakness onset: ≤4 days 57%, >4 days 84%. High CSF protein levels were associated with a demyelinating subtype, proximal or global muscle weakness, and a reduced likelihood of being able to run at week 2 (odds ratio [OR] 0.42, 95% CI 0.25-0.70; p = 0.001) and week 4 (OR 0.44, 95% CI 0.27-0.72; p = 0.001). Patients with the Miller Fisher syndrome, distal predominant weakness, and normal or equivocal nerve conduction studies were more likely to have lower CSF protein levels. CSF cell count was <5 cells/µL in 1,005 patients (83%), 5-49 cells/µL in 200 patients (16%), and ≥50 cells/µL in 13 patients (1%). DISCUSSION: ACD is a common finding in GBS, but normal protein levels do not exclude this diagnosis. High CSF protein level is associated with an early severe disease course and a demyelinating subtype. Elevated CSF cell count, rarely ≥50 cells/µL, is compatible with GBS after a thorough exclusion of alternative diagnoses. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that CSF ACD (defined by the Brighton Collaboration) is common in patients with GBS.

Skin Thickening of the Scalp and High Signal Intensity of Dentate Nucleus in Multiple Sclerosis: Association With Linear Versus Macrocyclic Gadolinium-Based Contrast Agents Administration.

OBJECTIVE: The aim of this study was to assess the presence of detectable changes of skin thickness on clinical brain magnetic resonance imaging (MRI) scans in patients with MS, history of multiple gadolinium-based contrast agents (GBCAs) administrations, and evidence of gadolinium deposition in the brain. MATERIALS AND METHODS: In this observational cross-sectional study, 71 patients with MS who underwent conventional brain MRI with an imaging protocol including enhanced 3D volumetric interpolated breath-hold examination (VIBE) T1-weighted with fat saturation were assessed. Patients with bilateral isointense dentate nucleus on unenhanced T1-weighted images were assigned to group A (controls without MRI evidence of gadolinium deposition), and patients with visually hyperintense dentate nuclei were assigned to group B. Qualitative and quantitative assessment of the skin thickness were performed. RESULTS: Group A included 27 patients (median age, 33 years [IQR, 27-46]; 20 women), and group B included 44 patients (median age, 42 years [IQR, 35-53]; 29 women). Qualitative and quantitative assessment of the skin revealed significant differences between group A and group B. The average skin-to-scalp thickness ratios was significantly higher in group B than in group A (mean ± standard deviation = 0.52 ± 0.02 in group B vs 0.41 ± 0.02 in group A, P < 0.0001) and showed a positive correlation with the total number of enhanced MRI scans ( r = 0.39; 95% confidence interval, 0.17-0.57, P < 0.01). CONCLUSIONS: Brain MRI detects increased skin thickness of the scalp in patients with MS and dentate nucleus high signal intensity on unenhanced T1-weighted images and shows positive association with previous exposures to linear GBCAs rather than macrocyclic GBCAs.

Electrodiagnosis of Guillain-Barre syndrome in the International GBS Outcome Study: Differences in methods and reference values.

OBJECTIVE: To describe the heterogeneity of electrodiagnostic (EDx) studies in Guillain-Barré syndrome (GBS) patients collected as part of the International GBS Outcome Study (IGOS). METHODS: Prospectively collected clinical and EDx data were available in 957 IGOS patients from 115 centers. Only the first EDx study was included in the current analysis. RESULTS: Median timing of the EDx study was 7 days (interquartile range 4-11) from symptom onset. Methodology varied between centers, countries and regions. Reference values from the responding 103 centers were derived locally in 49%, from publications in 37% and from a combination of these in the remaining 15%. Amplitude measurement in the EDx studies (baseline-to-peak or peak-to-peak) differed from the way this was done in the reference values, in 22% of motor and 39% of sensory conduction. There was marked variability in both motor and sensory reference values, although only a few outliers accounted for this. CONCLUSIONS: Our study showed extensive variation in the clinical practice of EDx in GBS patients among IGOS centers across the regions. SIGNIFICANCE: Besides EDx variation in GBS patients participating in IGOS, this diversity is likely to be present in other neuromuscular disorders and centers. This underlines the need for standardization of EDx in future multinational GBS studies.

Predicting Outcome in Guillain-Barré Syndrome: International Validation of the Modified Erasmus GBS Outcome Score.

BACKGROUND AND OBJECTIVES: The clinical course and outcome of the Guillain-Barré syndrome (GBS) are diverse and vary among regions. The modified Erasmus GBS Outcome Score (mEGOS), developed with data from Dutch patients, is a clinical model that predicts the risk of walking inability in patients with GBS. The study objective was to validate the mEGOS in the International GBS Outcome Study (IGOS) cohort and to improve its performance and region specificity. METHODS: We used prospective data from the first 1,500 patients included in IGOS, aged ≥6 years and unable to walk independently. We evaluated whether the mEGOS at entry and week 1 could predict the inability to walk unaided at 4 and 26 weeks in the full cohort and in regional subgroups, using 2 measures for model performance: (1) discrimination: area under the receiver operating characteristic curve (AUC) and (2) calibration: observed vs predicted probability of being unable to walk independently. To improve the model predictions, we recalibrated the model containing the overall mEGOS score, without changing the individual predictive factors. Finally, we assessed the predictive ability of the individual factors. RESULTS: For validation of mEGOS at entry, 809 patients were eligible (Europe/North America [n = 677], Asia [n = 76], other [n = 56]), and 671 for validation of mEGOS at week 1 (Europe/North America [n = 563], Asia [n = 65], other [n = 43]). AUC values were >0.7 in all regional subgroups. In the Europe/North America subgroup, observed outcomes were worse than predicted; in Asia, observed outcomes were better than predicted. Recalibration improved model accuracy and enabled the development of a region-specific version for Europe/North America (mEGOS-Eu/NA). Similar to the original mEGOS, severe limb weakness and higher age were the predominant predictors of poor outcome in the IGOS cohort. DISCUSSION: mEGOS is a validated tool to predict the inability to walk unaided at 4 and 26 weeks in patients with GBS, also in countries outside the Netherlands. We developed a region-specific version of mEGOS for patients from Europe/North America. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the mEGOS accurately predicts the inability to walk unaided at 4 and 26 weeks in patients with GBS. TRIAL REGISTRATION INFORMATION: NCT01582763.

Oral D-Aspartate enhances synaptic plasticity reserve in progressive multiple sclerosis.

BACKGROUND: Synaptic plasticity reserve correlates with clinical recovery after a relapse in relapsing-remitting forms of multiple sclerosis (MS) and is significantly compromised in patients with progressive forms of MS. These findings suggest that progression of disability in MS is linked to reduced synaptic plasticity reserve. D-Aspartate, an endogenous aminoacid approved for the use in humans as a dietary supplement, enhances synaptic plasticity in mice. OBJECTIVE: To test whether D-Aspartate oral intake increases synaptic plasticity reserve in progressive MS patients. METHODS: A total of 31 patients affected by a progressive form of MS received either single oral daily doses of D-Aspartate 2660 mg or placebo for 4 weeks. Synaptic plasticity reserve and trans-synaptic cortical excitability were measured through transcranial magnetic stimulation (TMS) protocols before and after D-Aspartate. RESULTS: Both TMS-induced long-term potentiation (LTP), intracortical facilitation (ICF) and short-interval ICF increased after 2 and 4 weeks of D-Aspartate but not after placebo, suggesting an enhancement of synaptic plasticity reserve and increased trans-synaptic glutamatergic transmission. CONCLUSION: Daily oral D-Aspartate 2660 mg for 4 weeks enhances synaptic plasticity reserve in patients with progressive MS, opening the path to further studies assessing its clinical effects on disability progression.

Retrospectively acquired cohort study to evaluate the long-term impact of two different treatment strategies on disability outcomes in patients with relapsing multiple sclerosis (RE.LO.DI.MS): data from the Italian MS Register.

BACKGROUND: The increase in disease-modifying drugs (DMDs) allows individualization of treatment in relapsing multiple sclerosis (RMS); however, the long-term impact of different treatment sequences is not well established. This is particularly relevant for MS patients who may need to postpone more aggressive DMD strategies. OBJECTIVE: To evaluate different therapeutic strategies and their long-term outcomes, measured as relapses and confirmed disability progression (CDP), in MS 'real-world' settings. METHODS: Multicentre, observational, retrospectively acquired cohort study evaluating the long-term impact of different treatment strategies on disability outcomes in patients with RMS in the Italian MS Register. RESULTS: We evaluated 1152 RMS-naïve patients after propensity-score adjustment. Patients included were receiving: interferon beta-1a (IFN-ß1a) 44 µg switching to fingolimod (FTY; IFN-switchers; n = 97); FTY only (FTY-stayers; n = 157); IFN-ß1a only (IFN-stayers; n = 849). CDP and relapses did not differ between FTY-stayers and IFN-switchers [HR (95% CI) 0.99 (0.48-2.04), p = 0.98 and 0.81 (0.42-1.58), p = 0.55, respectively]. However, IFN-stayers showed increased risk of relapses compared with FTY-stayers [HR (95% CI) 1.46 (1.00-2.12), p = 0.05]. CONCLUSION: The ideal treatment option for MS is becoming increasingly complex, with the need to balance benefit and risks. Our results suggest that starting with FTY affects the long-term disease outcome similarly to escalating from IFN-ß1a to FTY.

Interleukin-6 Disrupts Synaptic Plasticity and Impairs Tissue Damage Compensation in Multiple Sclerosis.

Background: Synaptic plasticity helps in reducing the clinical expression of brain damage and represents a useful mechanism to compensate the negative impact of new brain lesions in multiple sclerosis (MS). Inflammation, altering synaptic plasticity, could negatively influence the disease course in relapsing-remitting MS (RR-MS). Objective: In the present study, we explored whether interleukin (IL)-6, a major proinflammatory cytokine involved in MS pathogenesis, alters synaptic plasticity and affects the ability to compensate for ongoing brain damage. Methods: The effect of IL-6 incubation on long-term potentiation (LTP) induction was explored in vitro, in mice hippocampal slices. We also explored the correlation between the cerebrospinal fluid (CSF) levels of this cytokine and the LTP-like effect induced by the paired associative stimulation (PAS) in a group of RR-MS patients. Finally, we examined the correlation between the CSF levels of IL-6 at the time of diagnosis and the prospective disease activity in a cohort of 150 RR-MS patients. Results:In vitro LTP induction was abolished by IL-6. Consistently, in patients with MS, a negative correlation emerged between IL-6 CSF concentrations and the effect of PAS. In MS patients, longer disease duration before diagnosis was associated with higher IL-6 CSF concentrations. In addition, elevated CSF levels of IL-6 were associated with greater clinical expression of new inflammatory brain lesions, unlike in patients with low or absent IL-6 concentrations, who had a better disease course. Conclusions: IL-6 interfering with synaptic plasticity mechanisms may impair the ability to compensate the clinical manifestation of new brain lesions in RR-MS patients.

Transient Receptor Potential Vanilloid 1 Modulates Central Inflammation in Multiple Sclerosis.

Introduction: Disease course of multiple sclerosis (MS) is negatively influenced by proinflammatory molecules released by activated T and B lymphocytes and local immune cells. The endovanilloid system plays different physiological functions, and preclinical data suggest that transient receptor potential vanilloid type 1 (TRPV1) could modulate neuroinflammation in this disorder. Methods: The effect of TRPV1 activation on the release of two main proinflammatory cytokines, tumor necrosis factor (TNF) and interleukin (IL)-6, was explored in activated microglial cells. Furthermore, in a group of 132 MS patients, the association between the cerebrospinal fluid (CSF) levels of TNF and IL-6 and a single nucleotide polymorphisms (SNP) influencing TRPV1 protein expression and function (rs222747) was assessed. Results: In in vitro experiments, TRPV1 stimulation by capsaicin significantly reduced TNF and IL-6 release by activated microglial cells. Moreover, the anti-inflammatory effect of TRPV1 activation was confirmed by another TRPV1 agonist, the resiniferatoxin (RTX), whose effects were significantly inhibited by the TRPV1 antagonist, 5-iodoresiniferatoxin (5-IRTX). Vice versa, BV2 pre-treatment with 5-IRTX increased the inflammatory response induced by LPS. Moreover, in MS patients, a significant association emerged between TRPV1 SNP rs222747 and CSF TNF levels. In particular, the presence of a G allele, known to result in increased TRPV1 protein expression and function, was associated to lower CSF levels of TNF. Conclusions: Our results indicate that TRPV1 influences central inflammation in MS by regulating cytokine release by activated microglial cells. The modulation of the endovanilloid system may represent a useful approach to contrast neuroinflammation in MS.

Thymomatous myasthenia gravis: novel association with HLA DQB1*05:01 and strengthened evidence of high clinical and serological severity.

BACKGROUND: The relative prevalence of myasthenia gravis (MG) subtypes is changing, and their differential features and association with HLA class II alleles are not completely understood. METHODS: Age at onset, presence/absence of autoantibodies (Ab) and thymoma were retrospectively considered in 230 adult Italian patients. Clinical severity, assessed by MGFA scale, and the highest Ab titer were recorded. Furthermore, we performed low/high resolution typing of HLA-DRB1 and HLA-DQB1 alleles to detect associations of these loci with MG subtypes. RESULTS: There were two peaks of incidence: under 41 years of age, with female preponderance, and over 60 years, with higher male prevalence. The former group decreased and the latter increased significantly when comparing onset period 2008-2015 to 2000-2007. Thymomatous (TMG) patients showed a higher prevalence of severe phenotype and significantly higher anti-AChR Ab titer than non-thymomatous (NTMG) patients. Among the latter, those with onset after 60 years of age (LO-NTMG) displayed significantly higher Ab titers but lower MGFA grade compared to early-onset patients (< 41 years; EO-NTMG). Significant associations were found between HLA DQB1*05:01 and TMG patients and between DQB1*05:02 and DRB1*16 alleles and LO-NTMG with anti-AChR Ab. CONCLUSIONS: Two distinct cutoffs (< 41 and > 60 years) conveniently define EO-NTMG and LO-NTMG, with different characteristics. LO-NTMG is the most frequent disease subtype, with an increasing incidence. TMG patients reach higher clinical severity and higher antibody titers than NTMG patients. Moreover, TMG and LO-NTMG with anti-AChR Ab differ in their HLA-DQ association, providing further evidence that these two forms may have different etiologic mechanisms.

Delayed treatment of MS is associated with high CSF levels of IL-6 and IL-8 and worse future disease course.

BACKGROUND: Clinical deterioration of relapsing-remitting MS (RR-MS) patients reflects not only the number and severity of overt inflammatory and demyelinating episodes, but also subtle central damage caused by persistent exposure to inflammatory molecules. OBJECTIVE: To explore the correlation between levels of CSF inflammatory molecules at the time of diagnosis and both demographic and clinical characteristics of a large sample of RR-MS patients, as well as the predictive value of cytokine levels on their prospective disease course. METHODS: In 205 patients diagnosed with RR-MS, we measured at the time of diagnosis the CSF levels of inflammatory molecules. Clinical and MRI evaluation was collected at the time of CSF withdrawal and during a median follow-up of 3 years. RESULTS: The time interval between the first anamnestic episode of focal neurological dysfunction and RR-MS diagnosis was the main factor associated with high CSF levels of IL-6 and IL-8. Furthermore, elevated CSF levels of these cytokines correlated with enhanced risk of clinical and radiological disease reactivation, switch to second-line treatments, and with disability progression in the follow-up. CONCLUSIONS: Delayed diagnosis and treatment initiation are associated with higher CSF levels of IL-6 and IL-8 in RR-MS, leading to worsening disease course and poor response to treatments.

Platelet-derived growth factor predicts prolonged relapse-free period in multiple sclerosis.

BACKGROUND: In the early phases of relapsing-remitting multiple sclerosis (RR-MS), a clear correlation between brain lesion load and clinical disability is often lacking, originating the so-called clinico-radiological paradox. Different factors may contribute to such discrepancy. In particular, synaptic plasticity may reduce the clinical expression of brain damage producing enduring enhancement of synaptic strength largely dependent on neurotrophin-induced protein synthesis. Cytokines released by the immune cells during acute inflammation can alter synaptic transmission and plasticity possibly influencing the clinical course of MS. In addition, immune cells may promote brain repair during the post-acute phases, by secreting different growth factors involved in neuronal and oligodendroglial cell survival. Platelet-derived growth factor (PDGF) is a neurotrophic factor that could be particularly involved in clinical recovery. Indeed, PDGF promotes long-term potentiation of synaptic activity in vitro and in MS and could therefore represent a key factor improving the clinical compensation of new brain lesions. The aim of the present study is to explore whether cerebrospinal fluid (CSF) PDGF concentrations at the time of diagnosis may influence the clinical course of RR-MS. METHODS: At the time of diagnosis, we measured in 100 consecutive early MS patients the CSF concentrations of PDGF, of the main pro- and anti-inflammatory cytokines, and of reliable markers of neuronal damage. Clinical and radiological parameters of disease activity were prospectively collected during follow-up. RESULTS: CSF PDGF levels were positively correlated with prolonged relapse-free survival. Radiological markers of disease activity, biochemical markers of neuronal damage, and clinical parameters of disease progression were instead not influenced by PDGF concentrations. Higher CSF PDGF levels were associated with an anti-inflammatory milieu within the central nervous system. CONCLUSIONS: Our results suggest that PDGF could promote a more prolonged relapse-free period during the course of RR-MS, without influencing inflammation reactivation and inflammation-driven neuronal damage and likely enhancing adaptive plasticity.

Does continuous positive airway pressure treatment affect autonomic nervous system in patients with severe obstructive sleep apnea?

OBJECTIVE: This study is aimed at evaluating whether Continuous Positive Airway Pressure treatment (CPAP) may affect autonomic nervous system (ANS) in male patients with severe obstructive sleep apnea (OSAS). METHODS: We compared autonomic symptoms of de novo severe OSAS patients, OSAS patients on chronic CPAP treatment and healthy controls, using the Scales for Outcome in Parkinson disease-Autonomic (SCOPA-AUT) questionnaire. All groups underwent cardiovascular function tests including head-up tilt test (HUTT), Valsalva maneuver, deep breathing, hand grip and cold face tests. Statistical significance was set at p < 0.05. RESULTS: Twelve de novo severe OSAS patients, 17 male OSAS on CPAP and 14 controls were studied. The mean SCOPA-AUT total score was significantly higher in de novo OSAS patients compared with controls. Regarding the distinct domains, both de novo OSAS and CPAP group had abnormalities in respect of controls in urinary sphere. In supine rest condition the baseline values of systolic blood pressure were significantly increased in untreated OSAS patients compared with controls, whereas the basal values of diastolic blood pressure were significantly higher in CPAP patients with respect to controls. After ten min of HUTT, diastolic blood pressure changes were significantly higher in controls compared to both OSAS groups. Untreated OSAS patients showed significant different responses at deep breathing compared to controls. Both OSAS groups had a significant reduction of reflex bradycardia at cold face test. CONCLUSIONS: Our study shows that both treated and untreated OSAS patients complain of subjective autonomic symptoms like other sleep disorders reinforcing the close relationship between sleep and autonomic activity. Furthermore, cardiovascular reflexes indicate a tendency to hypertension and a reduced sensitivity to stimuli during wakefulness even in OSA patients on CPAP treatment, suggesting potentially permanent autonomic function deficits.

Nerve growth factor is elevated in the CSF of patients with multiple sclerosis and central neuropathic pain.

Central neuropathic pain (CNP) is common and disabling among patients with multiple sclerosis (MS). The pathological mechanisms underlying CNP in MS are not well understood. We explored whether NGF is implicated in the pathogenesis of CNP in MS. We measured NGF concentration in the CSF of 73 patients affected by MS, 15 with and 58 without CNP and 14 controls. We found increased levels of NGF in the CSF of patients with CNP compared to patients without and to controls. This finding supports the hypothesis that NGF plays a role in MS related CNP.

Amyloid-ß Homeostasis Bridges Inflammation, Synaptic Plasticity Deficits and Cognitive Dysfunction in Multiple Sclerosis.

Cognitive deficits are frequently observed in multiple sclerosis (MS), mainly involving processing speed and episodic memory. Both demyelination and gray matter atrophy can contribute to cognitive deficits in MS. In recent years, neuroinflammation is emerging as a new factor influencing clinical course in MS. Inflammatory cytokines induce synaptic dysfunction in MS. Synaptic plasticity occurring within hippocampal structures is considered as one of the basic physiological mechanisms of learning and memory. In experimental models of MS, hippocampal plasticity is profoundly altered by proinflammatory cytokines. Although mechanisms of inflammation-induced hippocampal pathology in MS are not completely understood, alteration of Amyloid-ß (Aß) metabolism is emerging as a key factor linking together inflammation, synaptic plasticity and neurodegeneration in different neurological diseases. We explored the correlation between concentrations of Aß1-42 and the levels of some proinflammatory and anti-inflammatory cytokines (interleukin-1ß (IL-1ß), IL1-ra, IL-8, IL-10, IL-12, tumor necrosis factor α (TNFα), interferon γ (IFNγ)) in the cerebrospinal fluid (CSF) of 103 remitting MS patients. CSF levels of Aß1-42 were negatively correlated with the proinflammatory cytokine IL-8 and positively correlated with the anti-inflammatory molecules IL-10 and interleukin-1 receptor antagonist (IL-1ra). Other correlations, although noticeable, were either borderline or not significant. Our data show that an imbalance between proinflammatory and anti-inflammatory cytokines may lead to altered Aß homeostasis, representing a key factor linking together inflammation, synaptic plasticity and cognitive dysfunction in MS. This could be relevant to identify novel therapeutic approaches to hinder the progression of cognitive dysfunction in MS.

Heart rate variability is differentially altered in multiple sclerosis: implications for acute, worsening and progressive disability.

BACKGROUND: Sympathovagal imbalance has been associated with poor prognosis in chronic diseases, but there is conflicting evidence in multiple sclerosis. OBJECTIVES: The objective of this study was to investigate the autonomic nervous system dysfunction correlation with inflammation and progression in multiple sclerosis. METHODS: Heart rate variability was analysed in 120 multiple sclerosis patients and 60 healthy controls during supine rest and head-up tilt test; the normalised units of low frequency and high frequency power were considered to assess sympathetic and vagal components, respectively. Correlation analyses with clinical and radiological markers of disease activity and progression were performed. RESULTS: Sympathetic dysfunction was closely related to the progression of disability in multiple sclerosis: progressive patients showed altered heart rate variability with respect to healthy controls and relapsing-remitting patients, with higher rest low frequency power and lacking the expected low frequency power increase during the head-up tilt test. In relapsing-remitting patients, disease activity, even subclinical, was associated with lower rest low frequency power, whereas stable relapsing-remitting patients did not differ from healthy controls. Less sympathetic reactivity and higher low frequency power at rest were associated with incomplete recovery from relapse. CONCLUSIONS: Autonomic balance appears to be intimately linked with both the inflammatory activity of multiple sclerosis, which is featured by an overall hypoactivity of the sympathetic nervous system, and its compensatory plastic processes, which appear inefficient in case of worsening and progressive multiple sclerosis.

Neurophysiology of synaptic functioning in multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory immune-mediate disorder of the central nervous system (CNS), primarily affecting the myelin sheath and followed by neurodegeneration. Synaptic alterations are emerging as critical determinants of early neurodegeneration in MS. Inflammation-induced alterations of synaptic transmission and plasticity have been investigated in vitro and also in human MS using transcranial magnetic stimulation (TMS) techniques. Specific inflammatory cytokines alter glutamatergic and GABAergic transmission, resulting in synaptic hyperexcitability. In both experimental autoimmune encephalomyelitis (EAE) and MS, excitotoxic damage and neurodegeneration are found even in the early phases of disease, conversely inflammation persists in the progressive phases. Inflammatory cytokines also affect synaptic plasticity, as both long-term potentiation (LTP) and long-term depression (LTD) are altered in EAE and in MS patients. In particular, inflammation profoundly subverts plasticity and influence both clinical recovery after a relapse and disease course. Regulation of neuronal activity by cytokines plays important roles in the neuro-immune crosstalk involved in inflammation-associated excitotoxic neuronal damage, and in the chance of developing compensatory plasticity. Innate and adaptive immunity interact with the CNS in MS, in line with the concept that cytokines and chemokines, in concert with neurotransmitters and neuropeptides, represent a major communication system in the CNS.

Remodeling Functional Connectivity in Multiple Sclerosis: A Challenging Therapeutic Approach.

Neurons in the central nervous system are organized in functional units interconnected to form complex networks. Acute and chronic brain damage disrupts brain connectivity producing neurological signs and/or symptoms. In several neurological diseases, particularly in Multiple Sclerosis (MS), structural imaging studies cannot always demonstrate a clear association between lesion site and clinical disability, originating the "clinico-radiological paradox." The discrepancy between structural damage and disability can be explained by a complex network perspective. Both brain networks architecture and synaptic plasticity may play important roles in modulating brain networks efficiency after brain damage. In particular, long-term potentiation (LTP) may occur in surviving neurons to compensate network disconnection. In MS, inflammatory cytokines dramatically interfere with synaptic transmission and plasticity. Importantly, in addition to acute and chronic structural damage, inflammation could contribute to reduce brain networks efficiency in MS leading to worse clinical recovery after a relapse and worse disease progression. These evidence suggest that removing inflammation should represent the main therapeutic target in MS; moreover, as synaptic plasticity is particularly altered by inflammation, specific strategies aimed at promoting LTP mechanisms could be effective for enhancing clinical recovery. Modulation of plasticity with different non-invasive brain stimulation (NIBS) techniques has been used to promote recovery of MS symptoms. Better knowledge of features inducing brain disconnection in MS is crucial to design specific strategies to promote recovery and use NIBS with an increasingly tailored approach.

Diabetic peripheral neuropathic pain is a stronger predictor of depression than other diabetic complications and comorbidities.

AIMS: To investigate the independent effect on depression of painless diabetic polyneuropathy, painful diabetic polyneuropathy, and general and diabetes-related comorbidities. METHODS: In 181 patients, the presence of painless diabetic polyneuropathy, painful diabetic polyneuropathy, comorbidities and depression was assessed using the Michigan Neuropathy Screening Instrument Questionnaire, the Michigan Diabetic Neuropathy Score, nerve conduction studies, the Douleur Neuropathique en 4 Questions, the Charlson Comorbidity Index and the Beck Depression Inventory-II. RESULTS: In all, 46 patients met the criteria of confirmed painless diabetic polyneuropathy and 25 of painful diabetic polyneuropathy. Beck Depression Inventory-II scores indicative of mild-moderate-severe depression were reached in 36 patients (19.7%). In a multiple logistic regression analysis (including age, sex, body mass index, being unemployed, duration, haemoglobin A1c, insulin treatment, systolic blood pressure, nephropathy, retinopathy, Charlson Comorbidity Index and painful diabetic polyneuropathy), female sex (odds ratio: 5.9, p = 0.005) and painful diabetic polyneuropathy (odds ratio: 4.6, p = 0.038) were the only independent predictors of depression. Multiple regression analysis, including Douleur Neuropathique en 4 Questions and Michigan Diabetic Neuropathy Score instead of painful diabetic polyneuropathy, showed that Douleur Neuropathique en 4 Questions, in addition to female sex, was a significant predictor of depressive symptoms severity (p =0.005). CONCLUSION: Painful diabetic polyneuropathy is a greater determinant of depression than other diabetes-related complications and comorbidities. Painful symptoms enhance depression severity more than objective insensitivity.

Cerebrospinal fluid lactate is associated with multiple sclerosis disease progression.

BACKGROUND: Altered cerebrospinal fluid (CSF) levels of lactate have been described in neurodegenerative diseases and related to mitochondrial dysfunction and neuronal degeneration. We investigated the relationship between CSF lactate levels, disease severity, and biomarkers associated with neuroaxonal damage in patients with multiple sclerosis (MS). METHODS: One-hundred eighteen subjects with relapsing-remitting multiple sclerosis (RRMS) were included, along with one-hundred fifty seven matched controls. CSF levels of lactate, tau protein, and neurofilament light were detected at the time of diagnosis. Patients were followed-up for a mean of 5 years. Progression index (PI), multiple sclerosis severity scale (MSSS), and Bayesian risk estimate for multiple sclerosis (BREMS) were assessed as clinical measures of disease severity and progression. Differences between groups and correlation between CSF lactate, disease severity and CSF biomarkers of neuronal damage were explored. RESULTS: CSF lactate was higher in RRMS patients compared to controls. A negative correlation was found between lactate levels and disease duration. Patients with higher CSF lactate concentration had significantly higher PI, MSSS, and BREMS scores at long-term follow-up. Furthermore, CSF lactate correlated positively and significantly with CSF levels of both tau protein and neurofilament light protein. CONCLUSIONS: Measurement of CSF lactate may be helpful, in conjunction with other biomarkers of tissue damage, as an early predictor of disease severity in RRMS patients. A better understanding of the alterations of mitochondrial metabolic pathways associated to RRMS severity may pave the way to new therapeutic targets to contrast axonal damage and disease severity.