Publications by authors named "Massimiliano Di Filippo"

94 Publications

Neuro-Immune Cross-Talk in the Striatum: From Basal Ganglia Physiology to Circuit Dysfunction.

Front Immunol 2021 19;12:644294. Epub 2021 Apr 19.

Section of Neurology, Department of Medicine and Surgery, Università degli Studi di Perugia, Perugia, Italy.

The basal ganglia network is represented by an interconnected group of subcortical nuclei traditionally thought to play a crucial role in motor learning and movement execution. During the last decades, knowledge about basal ganglia physiology significantly evolved and this network is now considered as a key regulator of important cognitive and emotional processes. Accordingly, the disruption of basal ganglia network dynamics represents a crucial pathogenic factor in many neurological and psychiatric disorders. The striatum is the input station of the circuit. Thanks to the synaptic properties of striatal medium spiny neurons (MSNs) and their ability to express synaptic plasticity, the striatum exerts a fundamental integrative and filtering role in the basal ganglia network, influencing the functional output of the whole circuit. Although it is currently established that the immune system is able to regulate neuronal transmission and plasticity in specific cortical areas, the role played by immune molecules and immune/glial cells in the modulation of intra-striatal connections and basal ganglia activity still needs to be clarified. In this manuscript, we review the available evidence of immune-based regulation of synaptic activity in the striatum, also discussing how an abnormal immune activation in this region could be involved in the pathogenesis of inflammatory and degenerative central nervous system (CNS) diseases.
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http://dx.doi.org/10.3389/fimmu.2021.644294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091963PMC
April 2021

Insights into the Pathophysiology of Psychiatric Symptoms in Central Nervous System Disorders: Implications for Early and Differential Diagnosis.

Int J Mol Sci 2021 Apr 23;22(9). Epub 2021 Apr 23.

Section of Neurology, Department of Medicine and Surgery, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.

Different psychopathological manifestations, such as affective, psychotic, obsessive-compulsive symptoms, and impulse control disturbances, may occur in most central nervous system (CNS) disorders including neurodegenerative and neuroinflammatory diseases. Psychiatric symptoms often represent the clinical onset of such disorders, thus potentially leading to misdiagnosis, delay in treatment, and a worse outcome. In this review, psychiatric symptoms observed along the course of several neurological diseases, namely Alzheimer's disease, fronto-temporal dementia, Parkinson's disease, Huntington's disease, and multiple sclerosis, are discussed, as well as the involved brain circuits and molecular/synaptic alterations. Special attention has been paid to the emerging role of fluid biomarkers in early detection of these neurodegenerative diseases. The frequent occurrence of psychiatric symptoms in neurological diseases, even as the first clinical manifestations, should prompt neurologists and psychiatrists to share a common clinico-biological background and a coordinated diagnostic approach.
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http://dx.doi.org/10.3390/ijms22094440DOI Listing
April 2021

Real world experience with teriflunomide in multiple sclerosis: the TER-Italy study.

J Neurol 2021 Feb 22. Epub 2021 Feb 22.

Clinica Neurologica, Centro Sclerosi Multipla, Azienda Ospedaliera di Padova, Padova, Italy.

Objective: To identify baseline factors associated with disease activity in patients with relapsing-remitting multiple sclerosis (RRMS) under teriflunomide treatment.

Methods: This was an independent, multi-centre, retrospective post-marketing study. We analysed data of 1,507 patients who started teriflunomide since October 2014 and were regularly followed in 28 Centres in Italy. We reported the proportions of patients who discontinued treatment (after excluding 32 lost to follow-up) and who experienced clinical disease activity, i.e., relapse(s) and/or confirmed disability worsening, as assessed by the Expanded Disability Status Scale (EDSS). Decision tree-based analysis was performed to identify baseline factors associated with clinical disease activity during teriflunomide treatment.

Results: At database lock (September 2020), approximately 29% of patients (430 out of 1,475) discontinued teriflunomide because of disease activity (~ 46%), adverse events (~ 37%), poor tolerability (~ 15%), pregnancy planning (~ 2%). Approximately 28% of patients experienced disease activity over a median follow-up of 2.75 years: ~ 9% had relapses but not disability worsening; ~ 13% had isolated disability worsening; ~ 6% had both relapses and disability worsening. The most important baseline factor associated with disease activity (especially disability worsening) was an EDSS > 4.0 (p < 0.001). In patients with moderate disability level (EDSS 2.0-4.0), disease activity occurred more frequently in case of ≥ 1 pre-treatment relapses (p = 0.025). In patients with milder disability level (EDSS < 2.0), disease activity occurred more frequently after previous exposure to ≥ 2 disease-modifying treatments (p = 0.007).

Conclusions: Our study suggests a place-in-therapy for teriflunomide in naïve patients with mild disability level or in those who switched their initial treatment for poor tolerability. Adverse events related with teriflunomide were consistent with literature data, without any new safety concern.
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http://dx.doi.org/10.1007/s00415-021-10455-3DOI Listing
February 2021

Defining the course of tumefactive multiple sclerosis: A large retrospective multicentre study.

Eur J Neurol 2021 Apr 12;28(4):1299-1307. Epub 2021 Jan 12.

Department of Clinical and Experimental Epilepsy, Queen Square, UCL Queen Square Institute of Neurology, London, UK.

Background And Purpose: Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions [TDLs]) is a diagnostic and therapeutic challenge. We performed a multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS.

Methods: One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected.

Results: TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11-68 years, interquartile range [IQR]: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute-phase treatment was administered, and almost one-half of the patients (46.6%) were treated with high-efficacy treatments. After a median follow-up of 2.3 years (range: 0.1-10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0-7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03-1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02-2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18-9.5, p < 0.001) at baseline.

Conclusions: The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS.
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http://dx.doi.org/10.1111/ene.14672DOI Listing
April 2021

CSF and Blood Biomarkers in Neuroinflammatory and Neurodegenerative Diseases: Implications for Treatment.

Trends Pharmacol Sci 2020 12 27;41(12):1023-1037. Epub 2020 Oct 27.

Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy. Electronic address:

Neuroinflammatory and neurodegenerative diseases are characterized by the interplay of a number of molecular pathways that can be assessed through biofluids, especially cerebrospinal fluid and blood. Accordingly, the definition and classification of these disorders will move from clinical and pathological to biological criteria. The consequences of this biomarker-based diagnostic and prognostic approach are highly relevant to the field of drug development. Indeed, in view of the availability of disease-modifying drugs, fluid biomarkers offer a unique opportunity for improving the quality and applicability of results from clinical trials. Herein, we discuss the benefits of using fluid biomarkers for patient stratification, target engagement, and outcome assessment, as well as the most recent developments in neuroinflammatory and neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.tips.2020.09.011DOI Listing
December 2020

From Synaptic Dysfunction to Neuroprotective Strategies in Genetic Parkinson's Disease: Lessons From LRRK2.

Front Cell Neurosci 2020 28;14:158. Epub 2020 Jul 28.

Neurologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.

The pathogenesis of Parkinson's disease (PD) is thought to rely on a complex interaction between the patient's genetic background and a variety of largely unknown environmental factors. In this scenario, the investigation of the genetic bases underlying familial PD could unveil key molecular pathways to be targeted by new disease-modifying therapies, still currently unavailable. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are responsible for the majority of inherited familial PD cases and can also be found in sporadic PD, but the pathophysiological functions of LRRK2 have not yet been fully elucidated. Here, we will review the evidence obtained in transgenic LRRK2 experimental models, characterized by altered striatal synaptic transmission, mitochondrial dysfunction, and α-synuclein aggregation. Interestingly, the processes triggered by mutant LRRK2 might represent early pathological phenomena in the pathogenesis of PD, anticipating the typical neurodegenerative features characterizing the late phases of the disease. A comprehensive view of LRRK2 neuronal pathophysiology will support the possible clinical application of pharmacological compounds targeting this protein, with potential therapeutic implications for patients suffering from both familial and sporadic PD.
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http://dx.doi.org/10.3389/fncel.2020.00158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399363PMC
July 2020

Cognitive impairment in multiple sclerosis: lessons from cerebrospinal fluid biomarkers.

Neural Regen Res 2021 Jan;16(1):36-42

Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy.

Cognitive impairment is a common clinical manifestation of multiple sclerosis, but its pathophysiology is not completely understood. White and grey matter injury together with synaptic dysfunction do play a role. The measurement of biomarkers in the cerebrospinal fluid and the study of their association with cognitive impairment may provide interesting in vivo evidence of the biological mechanisms underlying multiple sclerosis-related cognitive impairment. So far, only a few studies on this topic have been published, giving interesting results that deserve further investigation. Cerebrospinal fluid biomarkers of different pathophysiological mechanisms seem to reflect different neuropsychological patterns of cognitive deficits in multiple sclerosis. The aim of this review is to discuss the studies that have correlated cerebrospinal fluid markers of immune, glial and neuronal pathology with cognitive impairment in multiple sclerosis. Although preliminary, these findings suggest that cerebrospinal fluid biomarkers show some correlation with cognitive performance in multiple sclerosis, thus providing interesting insights into the mechanisms underlying the involvement of specific cognitive domains.
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http://dx.doi.org/10.4103/1673-5374.286949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818856PMC
January 2021

Harmonization of real-world studies in multiple sclerosis: Retrospective analysis from the rirems group.

Mult Scler Relat Disord 2020 Oct 12;45:102394. Epub 2020 Jul 12.

Rehabilitation Department, Mons. L. Novarese, Moncrivello, Vercelli, Italy.

Background: Worldwide multiple sclerosis (MS) centers have coordinated their efforts to use data acquired in clinical practice for real-world observational studies. In this retrospective study, we aim to harmonize outcome measures, and to evaluate their heterogeneity within the Rising Italian Researchers in MS (RIReMS) study group.

Methods: RIReMS members filled in a structured questionnaire evaluating the use of different outcome measures in clinical practice. Thereafter, thirty-four already-published papers from RIReMS centers were used for heterogeneity analyses, using the DerSimonian and Laird random-effects method to compute the between-study variance (τ).

Results: Based on questionnaire results, we defined basic modules for diagnosis and follow-up, consisting of outcome measures recorded by all participating centers at the time of diagnosis, and, then, at least annually; we also defined more detailed/optional modules, with outcome measures recorded less frequently and/or in the presence of specific clinical indications. Looking at heterogeneity, we found 5-year variance in age at onset (ES=27.34; 95%CI=26.18, 28.49; p<0.01; τ=4.76), and 7% in female percent (ES=66.42; 95%CI=63.08, 69.76; p<0.01; τ=7.15). EDSS variance was 0.2 in studies including patients with average age <36.1 years (ES=1.96; 95%CI=1.69, 2.24; p<0.01; τ=0.19), or from 36.8 to 41.1 years (ES=2.70; 95%CI=2.39, 3.01; p<0.01; τ=0.18), but increased to 3 in studies including patients aged >41.4 years (ES=4.37; 95%CI=3.40, 5.35; p<0.01; τ=2.96). The lowest variance of relapse rate was found in studies with follow-up duration ≤2 years (ES=9.07; 95%CI=5.21, 12.93; p = 0.02; τ=5.53), whilst the lowest variance in EDSS progression was found in studies with follow-up duration >2 years (ES=5.41; 95%CI=3.22, 7.60; p = 0.02; τ=1.00).

Discussion: We suggest common sets of biomarkers to be acquired in clinical practice, that can be used for research purposes. Also, we provide researchers with specific indications for improving inclusion criteria and data analysis, ultimately allowing data harmonization and high-quality collaborative studies.
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http://dx.doi.org/10.1016/j.msard.2020.102394DOI Listing
October 2020

Low doses of Perampanel protect striatal and hippocampal neurons against in vitro ischemia by reversing the ischemia-induced alteration of AMPA receptor subunit composition.

Neurobiol Dis 2020 07 25;140:104848. Epub 2020 Mar 25.

Neurological Clinic, Department of Medicine, Hospital Santa Maria Della Misericordia, University of Perugia, Perugia, Italy. Electronic address:

Energy depletion caused by ischemic brain insults may result in persistent neuronal depolarization accompanied by hyper-stimulation of ionotropic glutamate receptors and excitotoxic phenomena, possibly leading to cell death. The use of glutamate receptor antagonists, such as the AMPARs antagonist Perampanel (PER), might be a pharmacological approach to counteract the excessive over-activation of glutamate receptors providing neuroprotective effects. Using electrophysiological and molecular analyses, we investigated the effect of PER against in vitro ischemia obtained by oxygen and glucose deprivation (OGD) in rat slices of two brain structures particularly sensitive to ischemic insults, the nucleus striatum and the hippocampus. We found that in these regions PER was able to avoid the OGD-induced neuronal suffering, at low doses not reducing basal excitatory synaptic transmission and not altering long-term potentiation (LTP) induction. Furthermore, in both the analysed regions, PER blocked a pathological form of LTP, namely ischemic LTP (iLTP). Finally, we hypothesized that the protective effect of PER against OGD was due to its capability to normalize the altered synaptic localization and function of AMPAR subunits, occuring after an ischemic insult. Taken together these findings support the idea that PER is a drug potentially effective to counteract ischemic damage.
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http://dx.doi.org/10.1016/j.nbd.2020.104848DOI Listing
July 2020

Host and Microbial Tryptophan Metabolic Profiling in Multiple Sclerosis.

Front Immunol 2020 18;11:157. Epub 2020 Feb 18.

Department of Experimental Medicine, University of Perugia, Perugia, Italy.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is associated with demyelination and neuronal loss. Over recent years, the immunological and neuronal effects of tryptophan (Trp) metabolites have been largely investigated, leading to the hypothesis that these compounds and the related enzymes are possibly involved in the pathophysiology of MS. Specifically, the kynurenine pathway of Trp metabolism is responsible for the synthesis of intermediate products with potential immunological and neuronal effects. More recently, Trp metabolites, originating also from the host microbiome, have been identified in MS, and it has been shown that they are differently regulated in MS patients. Here, we sought to discuss whether, in MS patients, a specific urinary signature of host/microbiome Trp metabolism can be potentially identified so as to select novel biomarkers and guide toward the identification of specific metabolic pathways as drug targets in MS.
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http://dx.doi.org/10.3389/fimmu.2020.00157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041364PMC
March 2021

Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation.

Proc Natl Acad Sci U S A 2020 02 5;117(7):3848-3857. Epub 2020 Feb 5.

Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy;

l-tryptophan (Trp), an essential amino acid for mammals, is the precursor of a wide array of immunomodulatory metabolites produced by the kynurenine and serotonin pathways. The kynurenine pathway is a paramount source of several immunoregulatory metabolites, including l-kynurenine (Kyn), the main product of indoleamine 2,3-dioxygenase 1 (IDO1) that catalyzes the rate-limiting step of the pathway. In the serotonin pathway, the metabolite -acetylserotonin (NAS) has been shown to possess antioxidant, antiinflammatory, and neuroprotective properties in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, little is known about the exact mode of action of the serotonin metabolite and the possible interplay between the 2 Trp metabolic pathways. Prompted by the discovery that NAS neuroprotective effects in EAE are abrogated in mice lacking IDO1 expression, we investigated the NAS mode of action in neuroinflammation. We found that NAS directly binds IDO1 and acts as a positive allosteric modulator (PAM) of the IDO1 enzyme in vitro and in vivo. As a result, increased Kyn will activate the ligand-activated transcription factor aryl hydrocarbon receptor and, consequently, antiinflammatory and immunoregulatory effects. Because NAS also increased IDO1 activity in peripheral blood mononuclear cells of a significant proportion of MS patients, our data may set the basis for the development of IDO1 PAMs as first-in-class drugs in autoimmune/neuroinflammatory diseases.
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http://dx.doi.org/10.1073/pnas.1918215117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035626PMC
February 2020

An "all-wheel drive" proposal to accelerate clinical research in common and rare neurological diseases.

Neurol Sci 2020 Apr 19;41(4):789-793. Epub 2019 Dec 19.

Italian Multiple Sclerosis Foundation, Genoa, Italy.

The complex biology of neurological diseases calls for collaborative efforts that may increase the success rate of clinical research. Models have been proposed, but concrete actions remain insufficient. Based on recent considerations from basic science, from science of patient input and from an analysis of scientific resources in Italy, we here explain why our country may represent an appropriate environment for such actions. Furthermore, we sketch operational framework and business model to be applied in order to accelerate, in parallel, the development of therapies in common and rare diseases.
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http://dx.doi.org/10.1007/s10072-019-04189-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160195PMC
April 2020

Cerebrospinal fluid free light chains compared to oligoclonal bands as biomarkers in multiple sclerosis.

J Neuroimmunol 2020 02 7;339:577108. Epub 2019 Nov 7.

Sezione di Neurologia, Dipartimento di Medicina, Università degli Studi di Perugia, Perugia, Italy. Electronic address:

Cerebrospinal fluid (CSF) free light chains (FLC) may be an alternative biomarker to oligoclonal bands (OCB) in multiple sclerosis (MS). Herein, we compared the diagnostic accuracy of CSF OCB and FLC and we tested the prognostic value of FLC in a cohort of 64 MS patients and 106 controls. A κ-index >7.83 was more sensitive but less specific than OCB in discriminating MS patients from controls. Additionally, a κ-index >10.61 performed better than OCB in the discrimination between MS and controls with inflammatory neurological diseases (p < .001). In clinically isolated syndrome (CIS) patients, a κ-index >10.61 significantly predicted time to conversion to MS (p = .020). κ-index might be a valid alternative to OCB as a diagnostic biomarker for MS and might also be a prognostic marker in CIS.
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http://dx.doi.org/10.1016/j.jneuroim.2019.577108DOI Listing
February 2020

Serum neurofilament light chain as a preclinical marker of neurodegeneration.

Lancet Neurol 2019 12;18(12):1070-1071

Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy.

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http://dx.doi.org/10.1016/S1474-4422(19)30405-3DOI Listing
December 2019

Characteristics and treatment of Multiple Sclerosis-related trigeminal neuralgia: An Italian multi-centre study.

Mult Scler Relat Disord 2020 Jan 19;37:101461. Epub 2019 Oct 19.

Rehabilitation Department, Mons. L. Novarese, Moncrivello, Vercelli, Italy.

Background: The prevalence of trigeminal neuralgia (TN) in Multiple Sclerosis (MS) patients is higher than in the general population and its management can be particularly challenging. Our aim is to describe the characteristics, treatment and prognostic factors of MS-related TN in a retrospective multicentre study.

Methods: Neurologists members of the RIREMS group (Rising Researchers in MS) enrolled MS patients with a TN diagnosis and filled out a spreadsheet comprising their clinical data.

Results: Population consisted of 298 patients. First-choice preventive treatments were carbamazepine and oxcarbazepine. A surgical procedure was performed in 81 (30%) patients, most commonly gamma knife stereotactic radiosurgery (37%), followed by microvascular decompression (22%) and radiofrequency thermocoagulation (21%); one third of patients underwent at least two procedures. Surgery was associated with higher disability, male sex and longer interval between MS and TN onset. Patients (77%) who stayed on at least one preventive medication at most recent follow-up, after a mean period of 8 years, had a higher disability compared to the untreated group. Furthermore, patients with higher disability at TN onset were less likely to discontinue their first preventive medication due to pain remission, had bilateral TN more frequently and underwent surgical interventions earlier.

Conclusion: MS patients with a higher disability at TN onset and with a longer interval between MS and TN onset had differing clinical features and outcomes: pain was more frequently bilateral, surgery was more frequent and anticipated, and preventive medication discontinuation due to pain remission was less common.
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http://dx.doi.org/10.1016/j.msard.2019.101461DOI Listing
January 2020

Hippocampal epileptogenesis in autoimmune encephalitis.

Ann Clin Transl Neurol 2019 11 15;6(11):2261-2269. Epub 2019 Oct 15.

Neurology Clinic, Department of Medicine, University of Perugia, Perugia, Italy.

Objective: Autoantibody-mediated forms of encephalitis (AE) include neurological disorders characterized by subacute memory loss, movement disorders, and, often, frequent, focal epileptic seizures. Yet, the electrophysiological effects of these autoantibodies on neuronal function have received little attention. In this study, we assessed the effects of CSF containing autoantibodies on intrinsic and extrinsic properties of hippocampal neurons, to define their epileptogenic potential.

Methods: We compared the effects of CSF containing leucine-rich glioma inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and γ-aminobutyric acid receptor B (GABA R) antibodies on ex vivo electrophysiological parameters after stereotactic hippocampal inoculation into mice. Whole-cell patch-clamp and extracellular recordings from CA1 pyramidal neurons and CA3-CA1 field recordings in ex vivo murine brain slices were used to study neuronal function.

Results: By comparison to control CSF, AE CSFs increased the probability of glutamate release from CA3 neurons. In addition, LGI1- and CASPR2 antibodies containing CSFs induced epileptiform activity at a population level following Schaffer collateral stimulation. CASPR2 antibody containing CSF was also associated with higher spontaneous firing of CA1 pyramidal neurons. On the contrary, GABA R antibody containing CSF did not elicit changes in intrinsic neuronal activity and field potentials.

Interpretation: Using patient CSF, we have demonstrated that the AE-associated antibodies against LGI1 and CASPR2 are able to increase hippocampal CA1 neuron excitability, facilitating epileptiform activity. These findings provide in vivo pathogenic insights into neuronal dysfunction in these conditions.
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http://dx.doi.org/10.1002/acn3.50919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856617PMC
November 2019

Beyond clinical changes: Rehabilitation-induced neuroplasticity in MS.

Mult Scler 2019 09;25(10):1348-1362

Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy.

Background: Neural plasticity represents the substrate by which the damaged central nervous system (CNS) re-learns lost behaviors in response to rehabilitation. In persons with multiple sclerosis (MS), rehabilitation can therefore exploit the potential of neural plasticity to restore CNS functions beyond the spontaneous mechanisms of recovery from MS-related damage.

Methods: Here, we reviewed the currently available evidence on the occurrence of mechanisms of structural and functional plasticity following rehabilitation, motor, and/or cognitive training. We presented both data gained from basic laboratory research on animal models and data on persons with MS obtained by advanced magnetic resonance imaging (MRI) techniques.

Results: Studies on physical and environmental enrichment in experimental MS models showed beneficial effects mediated by both immune modulation and activity-dependent plasticity, lowering tissue destruction and restoring of CNS network function. Translational researches in MS people demonstrated structural and/or functional MRI changes after various interventions, but their heterogeneity and small sample sizes (5-42 patients) raise concerns about the interpretation and generalization of the obtained results.

Discussion: We highlighted the limitations of published studies, focusing on the knowledge gaps to be filled in terms of neuropathological correlations between changes detected in animal models and changes detected in vivo by neuroimaging.
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http://dx.doi.org/10.1177/1352458519846096DOI Listing
September 2019

Cerebrospinal fluid neurofilament light chain predicts disease activity after the first demyelinating event suggestive of multiple sclerosis.

Mult Scler Relat Disord 2019 Oct 27;35:228-232. Epub 2019 Jul 27.

Section of Neurology, Department of Medicine, University of Perugia, piazzale Gambuli 1, 06156 Perugia (PG) Italy.

Background: The prediction of disease activity in patients with a first demyelinating event suggestive of multiple sclerosis (MS) is of high clinical relevance. Cerebrospinal fluid (CSF) neurofilament light chain (NfL) has shown to have prognostic value in MS patients. In this work, we measured CSF NfL in patients at the first demyelinating event in order to find a cut-off value able to discriminate patients who will have disease activity from those who will remain stable during the follow-up.

Methods: We included CSF samples collected within 30 days after the onset of the first demyelinating event from 32 patients followed-up for 3.8 ± 2.5 years. CSF NfL was measured with a newly developed in-house enzyme linked immunosorbent assay (ELISA).

Results: At the first demyelinating event, patients with subsequent disease activity had significantly higher baseline CSF NfL values compared to clinically and radiologically stable patients (median 812.5 pg/mL, range 205-2359 pg/mL vs 329.5 pg/mL, range 156-3492 pg/mL, p = 0.002). A CSF NfL cut-off value of 500 pg/mL significantly discriminated these two groups of patients with a 90% sensitivity and an 83.3% specificity.

Conclusion: Our results confirm that CSF NfL is a prognostic marker in the very early phases of MS. The validation of a cut-off value of 500 pg/mL could provide clinicians with a dichotomous variable that can simplify the prognostic assessment of patients at the first demyelinating event.
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http://dx.doi.org/10.1016/j.msard.2019.07.025DOI Listing
October 2019

Cerebrospinal fluid neurofilament light chain tracks cognitive impairment in multiple sclerosis.

J Neurol 2019 Sep 25;266(9):2157-2163. Epub 2019 May 25.

Section of Neurology, Department of Medicine, Santa Maria Della Misericordia Hospital, University of Perugia, 06132, Perugia, Italy.

Background: Cognitive impairment (CI) is a disabling symptom of multiple sclerosis (MS). Axonal damage disrupts neural circuits and may play a role in determining CI, but its detection and monitoring are not routinely performed. Cerebrospinal fluid (CSF) neurofilament light chain (NfL) is a promising marker of axonal damage in MS.

Objective: To retrospectively examine the relationship between CSF NfL and CI in MS patients.

Methods: CSF NfL concentration was measured in 28 consecutive newly diagnosed MS patients who underwent a neuropsychological evaluation with the Brief Repeatable Battery of Neuropsychological tests (BRBN).

Results: CSF NfL was higher in patients with overall CI (947.8 ± 400.7 vs 518.4 ± 424.7 pg/mL, p < 0.01), and with impairment in information processing speed (IPS) (820.8 ± 413.6 vs 513.6 ± 461.4 pg/mL, p < 0.05) and verbal fluency (1292 ± 511 vs 582.8 ± 395.4 pg/mL, p < 0.05), and it positively correlated with the number of impaired BRBN tests (r = 0.48, p = 0.01) and cognitive domains (r = 0.47, p = 0.01). Multivariate analyses taking into account potential confounders confirmed these findings.

Conclusion: CSF NfL is higher in MS patients with CI and impaired IPS and verbal fluency. Large myelinated axons injury, causing neural disconnection, may be an important determinant of CI in MS and can be reliably measured through CSF NfL.
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http://dx.doi.org/10.1007/s00415-019-09398-7DOI Listing
September 2019

"Better explanations" in multiple sclerosis diagnostic workup: A 3-year longitudinal study.

Neurology 2019 05 1;92(22):e2527-e2537. Epub 2019 May 1.

From the Departments of Neuroscience, Biomedicine and Movement (M.C., A. Gajofatto) and Neurological and Movement Sciences (G.S.), University of Verona; Department of Neurosciences (C.G., C.T.), Azienda Ospedaliera San Camillo Forlanini, Roma; Department of Basic Medical Sciences, Neurosciences and Sense Organs (C.T., D.P.), University of Bari; Policlinico Gemelli (G.F.), Rome; Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche (BIONEC) (P.R.), Università di Palermo; Istituto Neurologico Mediterraneo (R.F.), Pozzilli; Department of Neurology and Psychiatry (L.P.), Sapienza University of Rome; Multiple Sclerosis Center (P.A.), ASST Valle Olona, PO di Gallarate; Multiple Sclerosis Center (C.C.), Ospedale di Montichiari, Spedali Civili di Brescia; Clinica Neurologica (M.D.), Dipartimento di Medicina, Università di Perugia; Department of Biomedical, Metabolic and Neurosciences (D.F.), University of Modena and Reggio Emilia, Modena; Neurologia 2-CRESM (S.M.), AOU San Luigi Gonzaga, Orbassano; Multiple Sclerosis Centre (S.L.), A.O.U. Policlinico-Vittorio Emanuele, Catania; Neurology Clinic (G.D.), Multiple Sclerosis Center, SS. Annunziata Hospital, Chieti; Department of Medicine, Surgery and Neuroscience (M.L.S.), University of Siena; Department of Medical Science and Public Health (E.C.), University of Cagliari; Department of Medical, Surgical, Neurological, Metabolic and Aging Science (A. Gallo), University of Campania; Department of Neuroscience, Reproductive Sciences (R.L.), University Federico II, Naples, Italy; Institute of Psychological Medicine and Clinical Neurosciences (V.T.), Cardiff University School of Medicine, UK; Ospedale di Vaio (I.P.), Centro SM, Fidenza, Parma; Ospedale San Raffaele (M.E.R.), Milan; and Department of Rehabilitation (C.S.), Mons L Novarese Hospital, Moncrivello, Italy.

Background: The exclusion of other diseases that can mimic multiple sclerosis (MS) is the cornerstone of current diagnostic criteria. However, data on the frequency of MS mimics in real life are incomplete.

Methods: A total of 695 patients presenting with symptoms suggestive of MS in any of the 22 RIREMS centers underwent a detailed diagnostic workup, including a brain and spinal cord MRI scan, CSF and blood examinations, and a 3-year clinical and radiologic follow-up.

Findings: A total of 667 patients completed the study. Alternative diagnoses were formulated in 163 (24.4%) cases, the most frequent being nonspecific neurologic symptoms in association with atypical MRI lesions of suspected vascular origin (40 patients), migraine with atypical lesions (24 patients), and neuromyelitis optica (14 patients). MS was diagnosed in 401 (60.1%) patients according to the 2017 diagnostic criteria. The multivariate analysis revealed that the absence of CSF oligoclonal immunoglobulin G bands (IgG-OB) (odds ratio [OR] 18.113), the presence of atypical MRI lesions (OR 10.977), the absence of dissemination in space (DIS) of the lesions (OR 5.164), and normal visual evoked potentials (OR 3.550) were all independent predictors of an alternative diagnosis.

Interpretation: This observational, unsponsored, real-life study, based on clinical practice, showed that diseases that mimicked MS were many, but more than 45% were represented by nonspecific neurologic symptoms with atypical MRI lesions of suspected vascular origin, migraine, and neuromyelitis optica. The absence of IgG-OB and DIS, the presence of atypical MRI lesions, and normal visual evoked potentials should be considered suggestive of an alternative disease and red flags for the misdiagnosis of MS.
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http://dx.doi.org/10.1212/WNL.0000000000007573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659006PMC
May 2019

Neurofilament light chain as a biomarker in neurological disorders.

J Neurol Neurosurg Psychiatry 2019 08 9;90(8):870-881. Epub 2019 Apr 9.

Institute of Neuroscience and Physiology Department of Psychiatry and Neurochemistry, The Sahlgrenska AcademyUniversity of Gothenburg, Mölndal, Sweden.

In the management of neurological diseases, the identification and quantification of axonal damage could allow for the improvement of diagnostic accuracy and prognostic assessment. Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including inflammatory, neurodegenerative, traumatic and cerebrovascular diseases. New immunoassays able to detect biomarkers at ultralow levels have allowed for the measurement of NfL in blood, thus making it possible to easily and repeatedly measure NfL for monitoring diseases' courses. Evidence that both CSF and blood NfL may serve as diagnostic, prognostic and monitoring biomarkers in neurological diseases is progressively increasing, and NfL is one of the most promising biomarkers to be used in clinical and research setting in the next future. Here we review the most important results on CSF and blood NfL and we discuss its potential applications and future directions.
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http://dx.doi.org/10.1136/jnnp-2018-320106DOI Listing
August 2019

Alpha-synuclein targets GluN2A NMDA receptor subunit causing striatal synaptic dysfunction and visuospatial memory alteration.

Brain 2019 05;142(5):1365-1385

Neurological Clinic, Department of Medicine, Hospital Santa Maria della Misericordia, University of Perugia, Perugia, Italy.

Parkinson's disease is a progressive neurodegenerative disorder characterized by altered striatal dopaminergic signalling that leads to motor and cognitive deficits. Parkinson's disease is also characterized by abnormal presence of soluble toxic forms of α-synuclein that, when clustered into Lewy bodies, represents one of the pathological hallmarks of the disease. However, α-synuclein oligomers might also directly affect synaptic transmission and plasticity in Parkinson's disease models. Accordingly, by combining electrophysiological, optogenetic, immunofluorescence, molecular and behavioural analyses, here we report that α-synuclein reduces N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents and impairs corticostriatal long-term potentiation of striatal spiny projection neurons, of both direct (D1-positive) and indirect (putative D2-positive) pathways. Intrastriatal injections of α-synuclein produce deficits in visuospatial learning associated with reduced function of GluN2A NMDA receptor subunit indicating that this protein selectively targets this subunit both in vitro and ex vivo. Interestingly, this effect is observed in spiny projection neurons activated by optical stimulation of either cortical or thalamic glutamatergic afferents. We also found that treatment of striatal slices with antibodies targeting α-synuclein prevents the α-synuclein-induced loss of long-term potentiation and the reduced synaptic localization of GluN2A NMDA receptor subunit suggesting that this strategy might counteract synaptic dysfunction occurring in Parkinson's disease.
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http://dx.doi.org/10.1093/brain/awz065DOI Listing
May 2019

Finding a way to preserve mitochondria: new pathogenic pathways in experimental multiple sclerosis.

Neural Regen Res 2019 Jan;14(1):77-78

Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Perugia, Italy.

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http://dx.doi.org/10.4103/1673-5374.243707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262986PMC
January 2019

2017 revisions of McDonald criteria shorten the time to diagnosis of multiple sclerosis in clinically isolated syndromes.

J Neurol 2018 Nov 8;265(11):2684-2687. Epub 2018 Sep 8.

Clinica Neurologica, Dipartimento di Medicina, Ospedale S. Maria della Misericordia, Università degli Studi di Perugia, 06156, Perugia, Italy.

Objectives: To investigate the impact of the 2017 revisions of McDonald criteria on the diagnosis of multiple sclerosis (MS) in a cohort of patients with clinically isolated syndrome (CIS) and dissemination in space (DIS) of demyelinating lesions.

Methods: We retrospectively analyzed 137 patients with CIS + DIS from two Italian MS centers.

Results: Application of the 2017 revisions of McDonald criteria in our cohort led to a diagnosis of MS in 82.5% of the patients who could have not been diagnosed with MS according to the previous criteria at the time of the first demyelinating event. After a follow-up of 3.8 ± 2.9 years, 85.8% of these patients eventually satisfied also the previous (2010) criteria.

Conclusions: Application of the 2017 revisions of McDonald criteria results in an earlier diagnosis of MS in a large percentage of CIS patients destined to convert to MS.
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http://dx.doi.org/10.1007/s00415-018-9048-8DOI Listing
November 2018

Multiple sclerosis and cognition: synaptic failure and network dysfunction.

Nat Rev Neurosci 2018 10;19(10):599-609

Clinica Neurologica, Dipartimento di Medicina, Università di Perugia, Perugia, Italy.

Cognitive impairment is increasingly recognized to be a core feature of multiple sclerosis (MS), with important implications for the everyday life of individuals with MS and for disease management. Unfortunately, the exact mechanisms that underlie this cognitive impairment are poorly understood and there are no effective therapeutic options for this aspect of the disease. During MS, focal brain inflammatory lesions, together with pathological changes of both CNS grey matter and normal-appearing white matter, can interfere with cognitive functions. Moreover, inflammation may alter the crosstalk between the immune and the nervous systems, modulating the induction of synaptic plasticity and neurotransmission. In this Review, we examine the CNS structures and cognitive domains that are affected by the disease, with a specific focus on hippocampal involvement in MS and experimental autoimmune encephalomyelitis, an experimental model of MS. We also discuss the hypothesis that, during MS, immune-mediated alterations of synapses' ability to express long-term plastic changes may contribute to the pathogenesis of cognitive impairment by interfering with the dynamics of neuronal networks.
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http://dx.doi.org/10.1038/s41583-018-0053-9DOI Listing
October 2018

Dopamine D2 receptor activation potently inhibits striatal glutamatergic transmission in a G2019S LRRK2 genetic model of Parkinson's disease.

Neurobiol Dis 2018 10 13;118:1-8. Epub 2018 Jun 13.

Santa Lucia Foundation IRCCS, via del Fosso di Fiorano, 64, 00143 Rome, Italy; Neurological Clinic, Department of Medicine, University of Perugia, Santa Maria della Misericordia Hospital, via Gambuli, 1, 06132 Perugia, Italy. Electronic address:

Among genetic abnormalities identified in Parkinson's disease (PD), mutations of the leucine-rich repeat kinase2 (LRRK2) gene, such as the G2019S missense mutation linked to enhanced kinase activity, are the most common. While the complex role of LRRK2 has not been fully elucidated, evidence that mutated kinase activity affects synaptic transmission has been reported. Thus, our aim was to explore possible early alterations of neurotransmission produced by the G2019S LRRK2 mutation in PD. We performed electrophysiological patch-clamp recordings of striatal spiny projection neurons (SPNs) in the G2019S-Lrrk2 knock-in (KI) mouse model of PD, in D1994S kinase-dead (KD), Lrrk2 knock-out (KO) and wild-type (WT) mice. In G2019S Lrrk2 KI mice, basal spontaneous glutamatergic transmission, synaptic facilitation, and NMDA/AMPA ratios were unchanged, whereas the stimulation of dopamine (DA) D2 receptor by quinpirole reduced the spontaneous and evoked excitatory postsynaptic currents (EPSC). Quinpirole reduced the EPSC amplitude of SPNs in KI but not in KD, KO and WT mice, suggesting that the enhanced LRRK2 kinase activity induced by the G2019S mutation is associated with the observed functional alteration of SPNs synaptic transmission. The effect of quinpirole was mediated by a phospholipase C (PLC)-dependent release of endocannabinoid, with subsequent activation of presynaptic cannabinoid receptor 1 and reduced release of glutamate. The key role of DA D2 receptor in reducing glutamatergic output in our LRRK2 genetic model of PD further supports the use of DA agonists in the treatment of early PD patients with LRRK2 mutations to counteract the disease progression.
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http://dx.doi.org/10.1016/j.nbd.2018.06.008DOI Listing
October 2018

Lacosamide protects striatal and hippocampal neurons from in vitro ischemia without altering physiological synaptic plasticity.

Neuropharmacology 2018 06 31;135:424-430. Epub 2018 Mar 31.

Neurological Clinic, Department of Medicine, University of Perugia, Santa Maria della Misericordia Hospital, Perugia, Italy. Electronic address:

Lacosamide ([(R)-2-acetamido-N-benzyl-3-methoxypropanamide], LCM), is an antiepileptic that exerts anticonvulsant activity by selectively enhancing slow sodium channel inactivation. By inhibiting seizures and neuronal excitability it might therefore be a good candidate to stabilize neurons and protect them from energetic insults. Using electrophysiological analyses, we have investigated in mice the possible neuroprotective effect of LCM against in vitro ischemia obtained by oxygen and glucose deprivation (ODG), in striatal and hippocampal tissues, two brain structures particularly susceptible to ischemic injury and of pivotal importance for different form of learning and memory. We also explored in these regions the influence of LCM on firing discharge and on long-term synaptic plasticity. We found that in both areas LCM reduced the neuronal firing activity in a use-dependent manner without influencing the physiological synaptic transmission, confirming its anticonvulsant effects. Moreover, we found that this AED is able to protect, in a dose dependent manner, striatal and hippocampal neurons from energy metabolism failure produced by OGD. This neuroprotective effect does not imply impairment of long-term potentiation of striatal and hippocampal synapses and suggests that LCM might exert additional beneficial therapeutic effects beyond its use as antiepileptic.
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http://dx.doi.org/10.1016/j.neuropharm.2018.03.040DOI Listing
June 2018

A multicentRE observational analysiS of PErsistenCe to Treatment in the new multiple sclerosis era: the RESPECT study.

J Neurol 2018 May 16;265(5):1174-1183. Epub 2018 Mar 16.

Neurology Unit, Centro di Recupero e Rieducazione Funzionale, Moncrivello, VC, Italy.

In this independent, multicenter, retrospective study, we investigated the short-term persistence to treatment with first-line self-injectable or oral disease-modifying treatments (DMTs) in patients with relapsing-remitting multiple sclerosis. Data of patients regularly attending 21 Italian MS Centres who started a self-injectable or an oral DMT in 2015 were collected to: (1) estimate the proportion of patients discontinuing the treatment; (3) explore reasons for discontinuation; (3) identify baseline predictors of treatment discontinuation over a follow-up period of 12 months. We analyzed data of 1832 consecutive patients (1289 women, 543 men); 374 (20.4%) of them discontinued the prescribed DMT after a median time of 6 months (range 3 days to 11.5 months) due to poor tolerability (n = 163; 43.6%), disease activity (n = 95; 25.4%), adverse events (n = 64; 17.1%), convenience (i.e. availability of new drug formulations) and pregnancy planning (n = 21; 1.1%). Although the proportion of discontinuers was higher with self-injectable (n = 107; 22.9%) than with oral DMT (n = 215; 16.4%), the Cox regression model revealed no significant between-group difference (p = 0.12). Female sex [hazard ratio (HR) = 1.39, p = 0.01] and previous exposure to ≥ 3 DMTs (HR = 1.71, p = 0.009) were two independent risk factors for treatment discontinuation, regardless of prescribed DMTs. Our study confirms that persistence to treatment represents a clinical challenge, irrespective of the route of administration.
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http://dx.doi.org/10.1007/s00415-018-8831-xDOI Listing
May 2018

A new enzyme-linked immunosorbent assay for neurofilament light in cerebrospinal fluid: analytical validation and clinical evaluation.

Alzheimers Res Ther 2018 01 23;10(1). Epub 2018 Jan 23.

Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Background: Cerebrospinal fluid (CSF) neurofilament light (NfL) is a reliable marker of neuro-axonal damage in different neurological disorders that is related to disease severity. To date, all recent studies performed in human CSF have used the same enzyme-linked immunosorbent assay (ELISA). To confirm the large body of evidence for NfL, we developed a new ELISA method and here we present the performance characteristics of this new ELISA for CSF NfL in different neurological disorders.

Methods: We produced two monoclonal antibodies (NfL21 and NfL23) directed against the NfL core domain, and developed a novel sandwich ELISA method that we evaluated in patients with: 1) inflammatory demyelinating diseases (IDD; n = 97), including multiple sclerosis (MS; n = 59), clinically isolated syndrome (CIS; n = 32), and radiologically isolated syndrome (RIS; n = 6); 2) Alzheimer's disease (AD; n = 72), including mild cognitive impairment due to AD (MCI-AD, n = 36) and probable AD dementia (AD-dem; n = 36); 3) Parkinson's disease (PD; n = 30); and 4) other neurological noninflammatory and non-neurodegenerative diseases (OND; n = 30).

Results: Our new NfL ELISA showed a good analytical performance (inter-plate coefficient of variation (CV) < 13%), with no cross-reactivity with neurofilament medium and heavy (NfM and NfH). With respect to the other available ELISAs, CSF NfL showed the same range of values with a strong correlation (r = 0.9984, p < 0.001) between the two methods. CSF NfL levels were significantly higher in MCI-AD/AD-dem and IDD patients as compared with both PD and OND patients. The highest discriminative power was obtained between IDD and OND patients (area under the curve (AUC) 0.87, 95% confidence interval (CI) 0.80-0.95). Within the IDD group, CSF NfL positively correlated with several clinical and radiological disease severity parameters.

Conclusions: These results show a good analytical performance of the new ELISA for quantification of NfL concentrations in the CSF. CSF NfL is confirmed to be a reliable marker in AD and MS, and a disease-severity marker in MS patients.
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http://dx.doi.org/10.1186/s13195-018-0339-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389166PMC
January 2018

Treatment of multiple sclerosis relapses with high-dose methylprednisolone reduces the evolution of contrast-enhancing lesions into persistent black holes.

J Neurol 2018 Mar 11;265(3):522-529. Epub 2018 Jan 11.

Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, 06156, Perugia, Italy.

Introduction: The MRI evidence of persistent black holes (pBHs) on T1-weighted images reflects brain tissue loss in multiple sclerosis (MS). The evolution of contrast-enhancing lesions (CELs) into pBHs probably depends on the degree and persistence of focal brain inflammation. The aim of our retrospective study was to evaluate the effect of a single cycle of intravenous methylprednisolone (IVMP), as for MS relapse treatment, on the risk of CELs' evolution into pBHs.

Patients And Methods: We selected 57 patients with CELs on the baseline MRI scan. We evaluated the evolution of CELs into pBHs on a follow-up MRI scan performed after ≥ 6 months in patients exposed and not exposed to IVMP for the treatment of relapse after the baseline MRI.

Results: In our cohort, 182 CELs were identified in the baseline MRI and 57 of them (31.3%) evolved into pBHs. In the multivariate analysis, the exposure of CELs to IVMP resulted to be a significant independent protective factor against pBHs' formation (OR 0.28, 95% CI 0.11-0.766, p = 0.005), while ring enhancement pattern and the fact of being symptomatic were significant risk factors for CELs' conversion into pBHs (OR 6.42, 95% CI 2.55-17.27, p < 0.001 and OR 13.19, 95% CI 1.56-288.87, p = 0.037).

Conclusions: The exposure of CELs to a cycle of IVMP as for relapse treatment is associated with a lower risk of CELs' evolution into pBHs. Future studies are required to confirm the potential independent protective effect of IVMP on CELs' evolution into pBHs.
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http://dx.doi.org/10.1007/s00415-017-8726-2DOI Listing
March 2018