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Background and aimsTo investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19).MethodsWe conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU)admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL.ResultsWe identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2 ± 15.0years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13-3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with ahigher likelihood of ICU admission, need ofMV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need ofMV and ICU admission, respectively.ConclusionsBlood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19.

BACKGROUND: Epigenetic marks (e.g., DNA methylation) may capture the effect of gene-environment interactions. DNA methylation is involved in blood pressure (BP) regulation and hypertension development; however, no studies have evaluated its relationship with 24-hour BP phenotypes (daytime, nighttime, and 24-hour average BPs). METHODS: We examined the association of whole blood DNA methylation with 24-hour BP phenotypes and clinic BPs in a discovery cohort of 281 African Americans using reduced representation bisulfite sequencing (RRBS). We developed a deep and region-specific methylation sequencing method, Bisulfite ULtrapLEx Targeted Sequencing (BULLET-Seq), and utilized it to validate our findings in a separate validation cohort (n = 117). RESULTS: Analysis of 38,215 DNA methylation regions (MRs), derived from 1,549,368 CpG sites across the genome, identified up to seventy-two regions that were significantly associated with 24-hour BP phenotypes. No MR was significantly associated with clinic BP. Two to three MRs were significantly associated with various 24-hour BP phenotypes after adjustment for age, sex, and BMI. Together, these MRs explained up to 16.5% of the variance of 24-hour average BP, while age, sex, and BMI explained up to 11.0% of the variance. Analysis of one of the MRs in an independent cohort using BULLET-Seq confirmed its association with 24-hour average BP phenotype. CONCLUSIONS: We identified several MRs that explain a substantial portion of variances in 24-hour BP phenotypes, which might be excellent markers of cumulative effect of factors influencing 24-hour BP levels. The BULLET-Seq workflow has potential to be suitable for clinical testing and population screenings on a large scale.

Background: Randomized controlled trials (RCTs) proved that short-term (21–90 days) dual antiplatelet therapy (DAPT) reduces the risk of early ischemic recurrences after a noncardioembolic minor stroke or high-risk transient ischemic attack (TIA) without substantially increasing the hemorrhagic risk. We aimed at understanding whether and how real-world use of DAPT differs from RCTs. Methods: READAPT (Real-Life Study on Short-Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or TIA) is a prospective cohort study including >18-year-old patients treated with DAPT after a noncardioembolic minor ischemic stroke or high-risk TIA from 51 Italian centers. The study comprises a 90-day follow-up from symptom onset. In the present work, we reported descriptive statistics of baseline data of patients recruited up to July 31, 2022, and proportions of patients who would have been excluded from RCTs. We compared categorical data through the χ² test. Results: We evaluated 1070 patients, who had 72 (interquartile range, 62–79) years median age, were mostly Caucasian (1045; 97.7%), and were men (711; 66.4%). Among the 726 (67.9%) patients with ischemic stroke, 226 (31.1%) did not meet the RCT inclusion criteria because of National Institutes of Health Stroke Scale score >3 and 50 (6.9%) because of National Institutes of Health Stroke Scale score >5. Among the 344 (32.1%) patients with TIA, 69 (19.7%) did not meet the RCT criteria because of age, blood pressure, clinical features, duration of TIA, presence of diabetes score 24 hours) DAPT initiation; 776 (72.5%) and 676 (63.2%) patients did not take loading doses of aspirin and clopidogrel, respectively. Overall, 84 (7.8%) patients met the RCT inclusion/exclusion criteria. Conclusions: The real-world use of DAPT is broader than RCTs. Most patients did not meet the RCT criteria because of the severity of ischemic stroke, lower risk of TIA, late DAPT start, or lack of antiplatelet loading dose. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05476081.

The advancing validation and exploitation of CSF and blood neurofilament light chain protein as a biomarker of neuroaxonal damage has deeply changed the current diagnostic and prognostic approach to neurological diseases. Further, recent studies have provided evidence of potential new applications of this biomarker also in non-primary neurological diseases. In the present review we summarize the state of the art, future perspectives, but also limitations, of neurofilament light chain protein as a CSF and blood biomarker in several medical fields, including intensive care medicine, surgery, internal medicine and psychiatry. In particular, neurofilament light chain protein is associated with the degree of neurological impairment and outcome in patients admitted to intensive care units or in the perioperative phase and it seems to be highly interconnected with cardiovascular risk factors. Beyond that, interesting diagnostic and prognostic insights have been provided by the investigation of neurofilament light chain protein in psychiatric disorders as well as in the current coronavirus disease-19 pandemic and in normal ageing. Altogether, current data outline a multifaceted applicability of CSF and blood neurofilament light chain protein ranging from the critical clinical setting to the development of precision medicine models suggesting a strict interplay between the nervous system pathophysiology and the health-illness continuum.

Introduction Nonketotic hyperglycemic hyperosmolar state (NKHHS) is associated with a wide spectrum of neurological syndromes including acute stroke-like deficits. Clinical features and etiology have not been established yet. Methods Here we provide a case illustration and systematic review on non-epileptic acute neurological deficits in NKHSS. The systematic literature search followed PRISMA guidelines and a predefined protocol, including cases of NKHSS with acute stroke-like presentation. Results The database search yielded 18 cases. Hemianopia was the most common clinical presentation (73%), followed by partial or total anterior circulation syndrome (26%). Patients with symptoms of acute anterior circulation infarct were significantly older (69.5 ± 5.1 vs. 52.2 ± 13.9 years; p = 0.03) and showed higher mean glucose levels at the admission vs. those with hemianopia (674.8 ± 197.2 vs. 529.4 ± 190.8 mg/dL; p = 0.16). Brain MRI was performed in 89% of patients, resulting abnormal in 71% of them, especially hemianopic (91%). Subcortical hypointensities in T2-FLAIR MR sequences were present in all the analyzed cases. Cortical DWI hyperintensities were also common (64%). EEG showed diffuse or focal slow wave activity in 68% of patients, especially with visual hallucinations (85%). Neurological symptoms completely resolved in 78% of patients within 6 (IQR 3–10) days, following aggressive treatment and glucose normalization. Conclusions Our results suggest neuronal dysfunction on a metabolic basis as the leading cause of acute neurological deficits in NKHHS. Despite the generally favorable prognosis, prompt identification and aggressive treatment are crucial to avoid irreversible damage. Larger cohort studies are needed to confirm our findings.

Blood-derived biomarkers for brain and spinal cord diseases are urgently needed. The introduction of highly sensitive immunoassays led to a rapid increase in the number of potential blood-derived biomarkers for diagnosis and monitoring of neurological disorders. In 2018, the FDA authorized a blood test for clinical use in the evaluation of mild traumatic brain injury (TBI). The test measures levels of the astrocytic intermediate filament glial fibrillary acidic protein (GFAP) and neuroaxonal marker ubiquitin carboxy-terminal hydrolase L1. In TBI, blood GFAP levels are correlated with clinical severity and extent of intracranial pathology. Evidence also indicates that blood GFAP levels hold the potential to reflect, and might enable prediction of, worsening of disability in individuals with progressive multiple sclerosis. A growing body of evidence suggests that blood GFAP levels can be used to detect even subtle injury to the CNS. Most importantly, the successful completion of the ongoing validation of point-of-care platforms for blood GFAP might ameliorate the decision algorithms for acute neurological diseases, such as TBI and stroke, with important economic implications. In this Review, we provide a systematic overview of the evidence regarding the utility of blood GFAP as a biomarker in neurological diseases. We propose a model for GFAP concentration dynamics in different conditions and discuss the limitations that hamper the widespread use of GFAP in the clinical setting. In our opinion, the clinical use of blood GFAP measurements has the potential to contribute to accelerated diagnosis and improved prognostication, and represents an important step forward in the era of precision medicine.

Background Dysautonomic symptoms (DS) are frequent but often underrecognized in multiple sclerosis (MS) patients, despite the relevant impact on quality of life and physical performance. Objectives To assess frequency and characteristics of DS in our MS population compared with healthy controls (HC). To investigate the relationship between DS and disease characteristics (MS subtype, disease duration, Expanded Disability Status Scale (EDSS), clinical and/or radiological activity, disability progression). Patients and methods Cross-sectional study includes 324 MS patients (mean age 44.9 ± 10.7 years; 66% female) and 190 HC (mean age 40.60 ± 12.83 years; 63% female). DS were assessed using the Italian validated version of the Composite Autonomic Symptom Score-31 (COMPASS-31). Possible confounding factors were considered. Results More than 94% of enrolled MS patients reported alterations in ≥ 2 domains of the COMPASS-31 scale (score > 0) and significantly higher COMPASS-31 total and single domain median scores compared with HC, independently from possible confounding factors (orthostatic intolerance: p = 0.001; vasomotor: p = 0.017; secretomotor: p = 0.040; gastrointestinal: p = 0.047; bladder: p p p p p = 0.01; Rho = 0.25, p = 0.030; Rho = 0.28, p p p p = 0.025), gastrointestinal (p = 0.07), and bladder (p Conclusions Our findings confirm that MS-related DS are frequent and tend to increase paralleling disease duration and clinical worsening, reaching the highest clinical impact in progressive subtypes.

ObjectivesTo evaluate the frequency, clinical and etiologic features, and short- and long-term outcomes of early recurrent TIA.MethodsThis prospective observational cohort study enrolled all consecutive patients with TIA referred to our emergency department and diagnosed by a vascular neurologist. Expedited assessment and best secondary prevention were performed within 24 hours. Primary endpoints were stroke and a composite outcome including stroke, acute coronary syndrome, and vascular death at 3, 12, and, for a subset of patients, 60 months; secondary outcomes were TIA relapse, cerebral hemorrhage, new-onset atrial fibrillation, and death resulting from other causes. Concordance between index TIA and subsequent stroke etiologies was also evaluated.ResultsA total of 1,035 patients (822 with a single TIA, 213 with recurrent TIA = 21%) were enrolled from August 2010 to December 2017. Capsular warning syndrome and large artery atherosclerosis showed the strongest relationship with early recurrent TIA. The risk of stroke was significantly higher in the early recurrent TIA subgroup at each follow-up, and most stroke episodes occurred within 48 hours of index TIA. TIAs with lesion, dysarthria, and leukoaraiosis were the 3- and 12-month independent predictors of stroke incidence after early recurrent TIA subgroup. Index TIA and subsequent stroke etiologies showed substantial concordance. An ABCD3 score >6 predicted a higher risk of stroke recurrence over the entire follow-up.ConclusionsOur study evaluated long-term outcome after early recurrent TIA. Our observations support the importance of promptly detecting and treating patients with early recurrent TIAs to reduce the high early and long-term risk of poor clinical outcomes.

Friedreich ataxia is the most common form of hereditary ataxia. Heart involvement in Friedreich ataxia is common and can include increased left ventricular wall thickness, atrial fibrillation, and in the later stages, a reduction of left ventricular ejection fraction. We present the case of a 45-year-old man with a history of paroxysmal atrial fibrillation and a congestive heart failure, hypertension, age ⩾ 75 years, diabetes mellitus, stroke, vascular disease, age 65–74 years, and female sex (CHA2DS2-VASc) score of only 1 (because of reduced left ventricular ejection fraction) who presented with pneumonia and was also found to have atrial fibrillation with a rapid ventricular response. Despite already being on long-term therapy with a non-vitamin K-antagonist oral anticoagulant, a transesophageal echocardiogram showed a mobile floating thrombus in the left atrial appendage. In accordance with previous necropsy evidence of thrombosis and thromboembolism in Friedreich ataxia subjects who likely have had only non-sex-related CHA2DS2-VASc score ⩽1, this case suggests that the risk of thromboembolism in Friedreich ataxia subjects with atrial fibrillation may not be adequately predicted by the sole CHA2DS2-VASc score.

none 7 no Sleep-related disorders have been reported to have a higher prevalence in multiple sclerosis (MS) than in the general population. They are often undervalued for the presence of more severe physical problems and the occurrence at night, without a direct observation in common clinical practice, but if not recognized and treated they can negatively affect the quality of life causing daytime drowsiness and worsening fatigue. Sleep related disorders most commonly reported in MS are as follows: insomnia, sleep-related breathing disorders (SRBD), restless legs syndrome (RLS) and periodic limb movement disorders (PLMD). Secondary narcolepsy, REM sleep behavior disorder (RBD) and propriospinal myoclonus have been also described in some case reports or series. The purpose of this review is to correlate the more common sleep disturbances in MS patients to the involvement of specific brain regions, analyzing their relationship with MRI findings. While insomnia is usually secondary to other disabling symptoms such as nocturia or pain, SRBD, RLS, narcolepsy, RBD and propriospinal myoclonus in MS patients can be the consequence of an injury of specific central nervous system (CNS) areas. Lesions in the pontine tegmentum and the dorsal medulla have been associated with SRBD, spinal cord lesions or atrophy with RLS, bilateral lesions in the lateral hypothalamus with narcolepsy-like symptoms, lesions in the dorsal pontine tegmentum with RBD and intramedullary demyelinating plaques in spinal cord with propriospinal myoclonus. MS specialists and general neurologists should be aware of these comorbidities since neuroimaging, which is routinely performed in MS, could provide helpful clinical indications on patients with secondary sleep-related disorders and to categorize symptomatic patients who need to underdo more in-depth sleep studies. mixed Foschi, M.; Rizzo, G.; Liguori, R.; Avoni, P.; Mancinelli, L.; Lugaresi, A.; Ferini-Strambi, L. Foschi, M.; Rizzo, G.; Liguori, R.; Avoni, P.; Mancinelli, L.; Lugaresi, A.; Ferini-Strambi, L.

Background and purpose: Dimethyl fumarate (DMF) causes a mean lymphocyte count drop of approximately 30% in relapsing–remitting multiple sclerosis (RRMS) patients. The relationship between this reduction and DMF effectiveness is controversial. The objective was to investigate if the decrease in absolute lymphocyte count (ALC) from baseline during DMF treatment is associated with clinical and magnetic resonance imaging (MRI) disease activity. A secondary aim was to evaluate ALC variations over time in a real-life cohort of DMF-treated patients. Methods: Demographic, laboratory, clinical and MRI data were collected in this observational multicentre study, conducted on RRMS patients treated with DMF for at least 6months. Multivariate Cox models were performed to evaluate the impact of 6-month ALC drop on time to no evidence of disease activity (NEDA-3) status loss. NEDA-3 is defined as absence of clinical relapses, MRI disease activity and confirmed disability progression. Results: In all, 476 patients (312 females, age at DMF start 38.4±9.97years) were analysed up to 5-year follow-up. A greater lymphocyte decrease was associated with a lower risk of NEDA-3 status loss (hazard ratio 0.87, P=0.01). A worse outcome in patients with lower ALC drop (40.5%), was observed (P=0.008). The nadir of ALC drop (−33.6%) and 35% of grade III lymphopaenia cases occurred after 12months of treatment. Conclusion: A higher lymphocyte count drop at 6months is related to better outcomes in DMF-treated patients. A careful ALC monitoring should be pursued up to 24months of treatment.

Introduction Acute cerebral venous thrombosis (CVT) may result in a variety of clinical presentations, with headache being the most common. The relationship between clinical and neuroradiological characteristics in acute CVT patients is still not univocally characterized. Materials and methods We enrolled 32 consecutive acute CVT patients admitted to our emergency department from January 1, 2012, to June 30, 2019. Clinicoradiological associations and their relationship with the functional outcome at the discharge were tested. Results Headache was the presenting symptom in 85% of patients, more frequently subacute (82%), new-onset (67%), with unusual features in respect to prior headache episodes (100%), and associated with concomitant neurological symptoms/signs (74%). Patients with holocranial headache showed more frequent venous ischemia (VI) compared to those with bilateral and unilateral headache (50% vs. 20% vs. 0%, respectively; p=0.027). Patients with concomitant neurological defects had a higher prevalence of VI (50.0% vs. 15.0%; p=0.049) and superior sagittal sinus thrombosis (67% vs. 30%; p=0.043) than those without. Vomit was more frequently observed in patients with straight sinus thrombosis (67% vs. 8%; p=0.005). Increasing age and VI were independently associated with poor (modified Rankin scale (mRS) 2-5) functional outcome (odds ratio (OR) = 1.081, 95% confidence interval (CI) 1.004-1.165; p=0.038 and OR = 12.089, 95% CI 1.141-128.104; p=0.039, respectively). Conclusions Our study confirms and enriches available data on the clinicoradiological profile of patients with acute CVT and suggests that increasing age and venous ischemia are independently associated with poor outcomes.

Introduction: Known risk factors for multiple sclerosis (MS) include smoking, a low vitamin D status, obesity, and EBV, while the inflammatory feature of the disease strongly suggests the presence of additional infectious agents. The association between use of antibiotics and MS risk that could shed light on these factors is still undetermined. We aimed to evaluate the association between antibiotics and MS risk, in the Emilia-Romagna region (RER), Italy. Methods: All adult patients with MS seen at any RER MS center (2015–2017) were eligible. For each of the 877 patients included, clinical information was collected and matched to 5 controls (RER residents) (n = 4,205) based on age, sex, place of residence, and index year. Information on antibiotic prescription was obtained through the linkage with the RER drug prescription database. Results: Exposure to any antibiotic 3 years prior to the index year was associated with an increased MS risk (OR = 1.52; 95% CI = 1.29–1.79). Similar results were found for different classes. No dose-response effect was found. Discussion/Conclusions: Our results suggest an association between the use of antibiotics and MS risk in RER population. However, further epidemiological studies should be done with information on early life and lifestyle factors.

Early diagnosis and correct risk stratification in patients with transient ischemic attack (TIA) and minor ischemic stroke (MIS) is crucial for the high rate of subsequent disabling stroke. Although highly improved, diagnosis and prognostication of TIA/MIS patients remain still based on clinical and neuroimaging findings, with some inter-rater variability even among trained neurologists.To provide an up-to-date overview of diagnostic and prognostic blood biomarkers in TIA and MIS patients.We performed a bibliographic search on PubMed database with last access on July 10In a narrative fashion, we discussed about blood biomarkers investigated in TIA/MIS patients, including inflammatory, thrombosis, neuronal injury and cardiac analytes, antibodies and microRNAs. Other soluble molecules have been demonstrated to predict the risk of recurrent cerebrovascular events or treatment response in these patients. A rapid point of care assay, combining the determination of different biomarkers, has been developed to improve triage recognition of acute cerebrovascular accidents.The implementation of blood biomarkers in the clinical management of TIA/MIS could ameliorate urgent identification, risk stratification and individual treatment choice. Large prospective and longitudinal studies, adopting standardized sampling and analytic procedures, are needed to clarify blood biomarkers kinetic and their relationship with TIA and minor stroke etiology.

A healthy 53-year-old man developed acute flaccid paraplegia, spinal sensory level, and urinary retention. Examination revealed bilateral pronator drift. MRI demonstrated demyelinating non-enhancing lesions involving corticospinal tracts (CSTs), middle cerebellar peduncles, and spinal cord (figure 1). CSF analysis disclosed lymphocytic pleocytosis and mildly elevated protein. Euroimmun fixed cell-based assay for serum anti–myelin oligodendrocyte glycoprotein (MOG) and anti–aquaporin-4 (AQP4) antibodies showed low positivity for MOG immunoglobulin G (IgG) (1:10). Treatment with high-dose glucocorticoids and IV immunoglobulin was effective (figure 2). Long CST lesions were found in anti–AQP4 IgG–seropositive neuromyelitis optica spectrum disorders.1 Bilateral extensive lesions following CST are a novel finding in MOG-related CNS autoimmunity.2

Since coronavirus disease-2019 (COVID-19) outbreak in January 2020, several pieces of evidence suggested an association between the spectrum of Guillain–Barré syndrome (GBS) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Most findings were reported in the form of case reports or case series, whereas a comprehensive overview is still lacking. We conducted a systematic review and searched for all published cases until July 20th 2020. We included 73 patients reported in 52 publications. A broad age range was affected (mean 55, min 11–max 94 years) with male predominance (68.5%). Most patients showed respiratory and/or systemic symptoms, and developed GBS manifestations after COVID-19. However, asymptomatic cases for COVID-19 were also described. The distributions of clinical variants and electrophysiological subtypes resemble those of classic GBS, with a higher prevalence of the classic sensorimotor form and the acute inflammatory demyelinating polyneuropathy, although rare variants like Miller Fisher syndrome were also reported. Cerebrospinal fluid (CSF) albuminocytological dissociation was present in around 71% cases, and CSF SARS-CoV-2 RNA was absent in all tested cases. More than 70% of patients showed a good prognosis, mostly after treatment with intravenous immunoglobulin. Patients with less favorable outcome were associated with a significantly older age in accordance with previous findings regarding both classic GBS and COVID-19. COVID-19-associated GBS seems to share most features of classic post-infectious GBS and possibly the same immune-mediated pathogenetic mechanisms. Nevertheless, more extensive epidemiological studies are needed to clarify these issues.

This study aimed to quantify 24 h body core temperature (BcT°) and sleep-wake cycle rhythm alterations in craniopharyngioma (CP) patients and to identify markers related to the postsurgical outcomes. Ten consecutive CP patients underwent neuroradiological, endocrinological and ophthalmological evaluations, 24 h BcT° and sleep-wake cycle recordings before and after endoscopic endonasal surgery. The sample included four women and six men. Nocturnal sleep efficiency was pathologically reduced in eight patients before surgery. Seven out of ten patients presented one to three daytime naps. 24 h BcT° rhythm was pathological in six out of ten cases. Post-surgery sleep efficiency normalized in four out of eight patients, whereas nine out of ten patients presented with two to six longer daytime naps. Diurnal naps were mainly present in patients showing pre-operative involvement of the third ventricle floor. 24 h BcT° remained pathological in only one out of six cases, returned to normal in two and improved in three. 24 h BcT° rhythm improved more in papillary CPs than in adamantomatous CPs. Our data confirmed that both CP and surgery frequently disrupt the sleep-wake cycle and BcT° rhythms. Tumour location and histotype may be related to a worse postsurgical outcome. Therefore, in-depth investigation including circadian monitoring is crucial for surgical outcome.

Background Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) with a consistent safety profile in clinical trials. We report three cases of multiple teeth loss during teriflunomide treatment. Case reports Case 1: a 39 year-old woman started teriflunomide for RRMS, switching from interferon beta. Four months later she complained about mandibular pain followed by the sudden loss of 4 teeth, in the absence of bleeding or trauma. Suspecting a causal role, we discontinued teriflunomide and started the accelerated elimination procedure with cholestyramine. Orthopantomography and a subsequent dental CT scan showed diffuse alveolar atrophy and periapical bone loss in several residual roots. Investigating retrospectively the patient's dental history, and revising previous orthopantomographies dating from 2009, we highlighted a chronic and progressive dental pathology with several cavities and teeth loss. Case 2: A 52-year-old woman affected by multiple sclerosis (MS) since 1988, switched from interferon beta to teriflunomide treatment due to poor tolerability. One year later she experienced the sudden loss of five teeth in the absence of traumatic events. Dental assessment and orthopantomography confirmed moderate chronic periodontitis. Teriflunomide was discontinued and the accelerated elimination procedure with cholestyramine was performed. Case 3: A 56-year-old woman affected by MS for thirty years. She switched from interferon beta to teriflunomide due to injection site reactions. After eighteen months she experienced hypermobility of several teeth without gum inflammation or pain, followed by sudden loss of twelve teeth. No dental examination is available. Teriflunomide was discontinued without accelerated elimination procedure. Discussion Odontogenic infections (periodontal disease and dental caries) are common and can cause teeth loss if left untreated as in case 1. It is conceivable that local infections favoured by teriflunomide accelerated pulpitis, endodontic infections and periapical reactions followed by teeth loss in predisposed subjects. Poor oral hygiene is common in MS patients and might favour dental infections. Conclusions We underline the importance to assess concomitant teeth morbidity and to recommend accurate oral hygiene before and during teriflunomide treatment.

Introduction: Multiple sclerosis (MS) is a demyelinating disease, causing axonal damage and disability. Dalfampridine (DAL) is an extended-release formulation of 4-aminopyridine (4AP) and broad-spectrum voltage-dependent potassium channel blocker that is reported to improve motor, visual and cognitive functions. Furthermore, it is presently the only approved drug for walking impairment in MS. Areas covered: Herein, the authors evaluate DAL as a relapsing-remitting MS treatment, reporting and commenting on all aspects of the drug including its chemistry, safety, pharmacokinetics, and cost-effectiveness. A bibliographic search was performed on PubMed using the terms ‘dalfampridine OR fampridine OR 4-aminopyridine’. Expert opinion: Evidence from post-marketing studies suggests that DAL, consistent with the effects of 4AP, may not only improve walking speed, but also arm function, fatigue, mood and cognition through restored nerve conduction in central nervous system demyelinated areas. Long-term safety data confirm that the approved dose of 10 mg twice daily is generally well tolerated. However, despite the reported efficacy, the extent of the benefits is limited in real life activities, although significant improvements have been demonstrated in the clinical setting. Patients often complain of side effects (such as cramps and painful paraesthesia) or lack of efficacy. Also, its considerably higher pricing in comparison to 4AP represents an important limitation.

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none 6 no Psoriasis and multiple sclerosis (MS) are both considered T cell-mediated diseases, with similarities in the pathophysiology.To our knowledge, only a case of severe disseminated psoriasis eruption has been described during natalizumab treatment [3]. We describe a patient affected by relapsing remitting (RR)MS with new-onset psoriatic arthritis during natalizumab treatment. In conclusion, taking into account the possible genetic susceptibility for cutaneous autoimmune diseases, we believe that it is important to investigate not only personal, but also family history for autoimmune comorbidities, to select the most suitable disease-modifying treatment for each MS patient. mixed Vacchiano, V.; Foschi, M.; Sabattini, L.; Scandellari, C.; Lugaresi, A. Vacchiano, V.; Foschi, M.; Sabattini, L.; Scandellari, C.; Lugaresi, A.

OBJECTIVES: We aimed to assess the potential relationship between intrasubject 9-tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray plasma profiles and clinical effects elicited by subacute dosing in chronically treated patients with multiple sclerosis (MS). METHODS: The study design was pilot, single center, open, and prospective. The patients were challenged with a morning test dose of 2 THC/CBD sprays at a 15-minute interval. Venous blood samples were collected before the first spray administration and every 30 minutes after the second spray, until 240 minutes postdosing. Patients rated their spasticity by the Numerical Rating Scale (NRS) simultaneously with blood drawings. Postural and motor tests were performed before the first spray and 90 and 180 minutes thereafter. RESULTS: Twelve patients were recruited. Peak plasma concentrations of THC/CBD largely varied among patients, from 0.60 to 13.29 ng/mL for THC and 0.55 to 11.93 ng/mL for CBD. Time to peak plasma concentrations ranged from 150 to 240 minutes for THC and 90 to 240 minutes for CBD. Patients' NRS serial scores decreased after dosing, from a median value of 6 to 3.5 (P < 0.001). A significant inverse correlation was observed between median intrasubject repeated NRS scores and corresponding median values of both THC (P < 0.01) and CBD (P < 0.002) plasma concentrations. No significant effect of cannabinoids dosing could be appreciated according to posturographic and motor tests. CONCLUSIONS: Our kinetic dynamic findings from THC/CBD oromucosal spray are the first obtained in real MS patients. Although preliminary, they suggest that subacute dosing might elicit a subjective clinically significant effect on MS-related spasticity, paralleling cannabinoids measurable plasma concentrations.

none 22 no OBJECTIVE: The introduction of oral disease-modifying drugs (DMDs) in addition to the available, injectable, ones for Relapsing-Remitting Multiple Sclerosis (RRMS) could be expected to improve medication persistence due to a greater acceptability of the route of administration. Aim of the study was to compare the proportion of patients discontinuing injectable DMDs (interferon beta 1a/1b, pegylated interferon, glatiramer acetate) with those discontinuing oral DMDs (dimethylfumarate and teriflunomide) during an observation period of at least 12 months. Secondary aims were to compare the time to discontinuation and the reasons for discontinuation between the two groups and to explore the demographic and clinical factors associated with DMD discontinuation. METHODS: In this prospective, multi-center, real-life observational study, patients commencing any first-line DMD between January 1st 2015 and July 31st 2016 were enrolled and followed-up for at least twelve months or until the drug was discontinued. RESULTS: Of the 520 included patients, 262 (49.6%) started an injectable, and 258 (50.4%) an oral DMD. There was no difference in the proportion of patients on oral (nr = 62, 24%) or on injectable (nr = 60, 23%) DMDs discontinuing treatment, the most frequent reason being adverse events/side-effects. Higher baseline EDSS scores and younger age increased the odds of treatment withdrawal. Time to treatment discontinuation was not different between the two groups and was not influenced by the initiated DMD (oral versus injectable), even after adjustment for baseline differences. CONCLUSION: The sole route of administration (i.e. oral versus injectable) was not a significant predictor of persistence with first-line DMDs in RRMS. none Ferraro, Diana; Camera, Valentina; Baldi, Eleonora; Vacchiano, Veria; Curti, Erica; Guareschi, Angelica; Malagù, Susanna; Montepietra, Sara; Strumia, Silvia; Santangelo, Mario; Caniatti, Luisa; Foschi, Matteo; Lugaresi, Alessandra; Granella, Franco; Pesci, Ilaria; Motti, Luisa; Neri, Walter; Immovilli, Paolo; Montanari, Enrico; Vitetta, Francesca; Simone, Anna Maria; Sola, Patrizia Ferraro, Diana; Camera, Valentina; Baldi, Eleonora; Vacchiano, Veria; Curti, Erica; Guareschi, Angelica; Malagù, Susanna; Montepietra, Sara; Strumia, Silvia; Santangelo, Mario; Caniatti, Luisa; Foschi, Matteo; Lugaresi, Alessandra; Granella, Franco; Pesci, Ilaria; Motti, Luisa; Neri, Walter; Immovilli, Paolo; Montanari, Enrico; Vitetta, Francesca; Simone, Anna Maria; Sola, Patrizia