Publications by authors named "Mariarosaria Valente"

94 Publications

Recanalisation theraphy for acute ischemic stroke in cancer patients.

Sci Rep 2021 Jun 2;11(1):11634. Epub 2021 Jun 2.

Clinical Neurology, Udine University Hospital, Udine, Italy.

To date, very few studies focused their attention on efficacy and safety of recanalisation therapy in acute ischemic stroke (AIS) patients with cancer, reporting conflicting results. We retrospectively analysed data from our database of consecutive patients admitted to the Udine University Hospital with AIS that were treated with recanalisation therapy, i.e. intravenous thrombolysis (IVT), mechanical thrombectomy (MT), and bridging therapy, from January 2015 to December 2019. We compared 3-month dependency, 3-month mortality, and symptomatic intracranial haemorrhage (SICH) occurrence of patients with active cancer (AC) and remote cancer (RC) with that of patients without cancer (WC) undergoing recanalisation therapy for AIS. Patients were followed up for 3 months. Among the 613 AIS patients included in the study, 79 patients (12.9%) had either AC (n = 46; 7.5%) or RC (n = 33; 5.4%). Although AC patients, when treated with IVT, had a significantly increased risk of 3-month mortality [odds ratio (OR) 6.97, 95% confidence interval (CI) 2.42-20.07, p = 0.001] than WC patients, stroke-related deaths did not differ between AC and WC patients (30% vs. 28.8%, p = 0.939). There were no significant differences between AC and WC patients, when treated with MT ± IVT, regarding 3-month dependency, 3-month mortality and SICH. Functional independence, mortality, and SICH were similar between RC and WC patients. In conclusion, recanalisation therapy might be used in AIS patients with nonmetastatic AC and with RC. Further studies are needed to explore the outcome of AIS patients with metastatic cancer undergoing recanalisation therapy.
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http://dx.doi.org/10.1038/s41598-021-91257-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172643PMC
June 2021

Clinical and Neurophysiological Effects of Botulinum Neurotoxin Type A in Chronic Migraine.

Toxins (Basel) 2021 May 29;13(6). Epub 2021 May 29.

Clinical Neurology Unit, Santa Maria della Misericordia University Hospital, 33100 Udine, Italy.

Chronic pain syndromes present a subversion of both functional and structural nociceptive networks. We used transcranial magnetic stimulation (TMS) to evaluate changes in cortical excitability and plasticity in patients with chronic migraine (CM) treated with botulinum neurotoxin type A (BoNT/A). We enrolled 11 patients with episodic migraine (EM) and 11 affected by CM. Baseline characteristics for both groups were recorded using single- and paired-pulse TMS protocols. The same TMS protocol was repeated in CM patients after four cycles of BoNT/A completed in one year. At baseline, compared with EM patients, patients with CM had a lower threshold in both hemispheres (right hemisphere: 46% ± 7.8 vs. 52% ± 4.28, = 0.03; left hemisphere: 52% ± 4.28 vs. 53.54% ± 6.58, = 0.02). In EM, paired-pulse stimulation elicited a physiologically shaped response, whereas in CM, physiological intracortical inhibition (ICI) between 1 and 3 ms intervals was absent at baseline. On the contrary, increasing intracortical facilitation (ICF) was observed for all interstimulus intervals (ISIs). In CM, cortical excitability was partially reduced after BoNT/A treatment, along with a significant decrease observed in MIDAS score (from 20.7 to 9.8; = 0.008). The lower motor threshold in CM reflects a higher cortical hyperexcitability. The lack of physiological ICI in CM could indicate sensitisation of the trigeminovascular system. Although reduced, this type of response is still observable after treatment, despite a marked clinical improvement. Our study suggests a long-term alteration of cortical plasticity due to chronic pain.
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http://dx.doi.org/10.3390/toxins13060392DOI Listing
May 2021

Risk Factors for Intraoperative Seizures in Glioma Surgery: Electrocorticography Matters.

J Clin Neurophysiol 2021 Apr 30. Epub 2021 Apr 30.

Neurology and Clinical Neurophysiology Unit, "S. Maria della Misericordia" University-Hospital, Udine, Italy; Neurosurgery Unit, "S. Maria della Misericordia" University-Hospital, Udine, Italy; Department of Medicine (DAME), University of Udine, Italy; Clinical Neurology Unit, "S. Maria della Misericordia" University-Hospital, Udine, Italy; and Department of Mathematics, Informatics and Physics (DMIF), University of Udine, Italy.

Purpose: Few and contradictory data are available regarding intraoperative seizures during surgery for low-grade gliomas. Aim of this study was to evaluate possible risk factors for the occurrence of IOS.

Methods: The authors performed a retrospective analysis of 155 patients affected by low-grade gliomas and tumor-related epilepsy, who underwent surgery in our Department, between 2007 and 2018. A statistical analysis was performed by means of univariate and multivariate regression to evaluate any possible correlation between seizure occurrence and several demographic, clinical, neurophysiological, and histopathological features.

Results: Intraoperative seizure occurred in 39 patients (25.16%) with a total of 62 seizure events recorded. Focal seizures were the prevalent seizure type: among them, 39 seizures did not show motor signs, being those with only electrographic and/or with cognitive features the most represented subtypes. Twenty-six seizures occurring during surgery were not spontaneous: direct cortical stimulation with Penfield paradigm was the most prevalent evoking factor. The univariate analysis showed that the following prognostic factors were statistically associated with the occurrence of intraoperative seizure: the awake technique (P = 0.01) and the interictal epileptiform discharges detected on the baseline electrocorticography (ECoG) (P < 0.001). After controlling for confounding factors with multivariate analysis, the awake surgery and the epileptic ECoG pattern kept statistical significance.

Conclusions: The awake surgery procedure and the epileptic ECoG pattern are risk factors for intraoperative seizure. ECoG is mandatory to detect electrographic seizures or seizures without motor signs.
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http://dx.doi.org/10.1097/WNP.0000000000000854DOI Listing
April 2021

Epilepsy and episodic ataxia type 2: family study and review of the literature.

J Neurol 2021 May 13. Epub 2021 May 13.

Clinical Neurology Unit, Department of Neurosciences, Santa Maria della Misericordia University Hospital, ASUFC, Udine, Italy.

Episodic ataxia type 2 (EA2) is a hereditary disorder characterized by paroxysmal attacks of ataxia, vertigo and nausea, due to mutations in the CACNA1A gene, which encodes for α1 subunit of the P/Q-type voltage-gated Ca channel (CaV2.1). Other manifestations may be associated to CACNA1A mutations, such as migraine and epilepsy. The correlation between episodic ataxia and epilepsy is often underestimated and misdiagnosed. Clinical presentation of EA2 varies among patients and within the same family, and the same genetic mutation can lead to different clinical phenotypes. We herewith describe an Italian family presenting with typical EA2 and, in two of the family members (patients II.3 and III.1), epileptic seizures. The sequencing revealed a heterozygous deletion of 6 nucleotides in exon 28 of CACNA1A gene, present in all affected patients. Evidence suggests that mutations of CACNA1A, conferring a loss/reduction of CaV2.1 function, lead to an increase of thalamocortical excitation that contributes to epileptiform discharges. Our description highlights intra-family variability of EA2 phenotype and suggests that mutations in the CACNA1A gene should be suspected in individuals with focal or generalized epilepsy, associated with a family history of episodic ataxia.
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http://dx.doi.org/10.1007/s00415-021-10555-0DOI Listing
May 2021

Spontaneous spinal cord ischemia during COVID-19 infection.

J Neurol 2021 Apr 28. Epub 2021 Apr 28.

Clinical Neurology, Udine University Hospital, Udine, Italy.

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http://dx.doi.org/10.1007/s00415-021-10574-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080085PMC
April 2021

How treatable is narcolepsy with current pharmacotherapy and what does the future hold?

Expert Opin Pharmacother 2021 Apr 22:1-4. Epub 2021 Apr 22.

Neurology Unit, Department of Neurosciences, University Hospital of Udine, Udine, Italy.

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http://dx.doi.org/10.1080/14656566.2021.1915987DOI Listing
April 2021

Benign EEG variants in the sleep-wake cycle: A prospective observational study using the 10-20 system and additional electrodes.

Neurophysiol Clin 2021 Jun 16;51(3):233-242. Epub 2021 Apr 16.

Gui de Chauliac Hospital, Epilepsy Unit, Montpellier, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Comportements et Mouvements Anormaux, Montpellier, France. Electronic address:

Objectives: To study the prevalence of benign EEG variants (BEVs) in the sleep-wake cycle among 1163 consecutive patients.

Methods: Prospective, observational EEG study using the 10-20 system with systematically two additional anterior-temporal electrodes. Depending on clinical indications, other electrodes were added. REM sleep identification was based on its characteristic EEG grapho-elements and rapid eye movements, clearly detectable with the additional anterior-temporal and fronto-polar electrodes due to eye proximity. The video-EEG monitoring duration was between 24hours and eight days.

Results: We identified 710 patients (61%) with BEVs. Positive occipital sharp transients of sleep (POSTs) were observed in 36.4% of participants, mu rhythm in 22.4%, lambda waves in 16.7%, wicket spikes (WS) in 15%, 14- and 6-Hz positive bursts in 8.3%, benign sporadic sleep spikes (BSSS) in 3.3%, rhythmic mid-temporal theta burst of drowsiness (RMTD) in 2.15%, midline theta rhythm in 2.1% and six-Hz spike and wave (SW) bursts in 0.1%. WS and RMTD were present during wakefulness, NREM (14.1%, 1.3%, respectively) and REM sleep (3.3%, 1.1%, respectively). Mu rhythm was also observed during NREM (1.5%) and REM sleep (7.7%). Fourteen- and 6-Hz positive bursts were present during NREM (4.5%) and REM sleep (6.5%). BSSS and six-Hz SW bursts were only observed during NREM sleep.

Conclusions: The prevalence of BEVs is much higher than current estimates. POSTs and WS can no longer be considered as unusual patterns but physiological patterns of NREM sleep. RMTD and mu rhythm may be observed during NREM and REM sleep.
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http://dx.doi.org/10.1016/j.neucli.2021.03.006DOI Listing
June 2021

Hyposmia and Dysgeusia in COVID-19: Indication to Swab Test and Clue of CNS Involvement.

Neurol Clin Pract 2021 Apr;11(2):e92-e96

Clinical Neurology Unit (FB, MV, AM, AS, GP, GLG), and Clinical Infectious Diseases Unit (CT, CDC, VG), University of Udine, Italy.

Objective: To evaluate the prevalence of hyposmia and dysgeusia in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their temporal relationship with the onset of other symptoms.

Methods: We performed a retrospective analysis of patients admitted during the month of March 2020 to the nonintensive COVID unit of Udine University Hospital on the basis of a positive swab test and/or of clinical-radiologic signs of SARS-CoV-2 infection. Patients were interviewed with a standardized questionnaire. Clinical and laboratory data were collected. Data were analyzed with descriptive statistics, and results expressed as point estimates and 95% confidence intervals (CIs).

Results: Of 141 patients admitted, 93 were interviewed. Hyposmia and dysgeusia were present in 58 cases (62.4%). In 22.4% of them, olfactory and gustatory impairment clearly preceded systemic symptoms. The presence of active smoking was very limited in both groups: 8.6% in hyposmic vs 2.9% in normosmic patients (odds ratio 3.2; 95% CI 0.3-28.6). Moreover, total leukocytes and neutrophils count were respectively 23% (effect estimate 1.23; 95% CI 1.06-1.42) and 29% (effect estimate 1.29; 95% CI 1.07-1.54) lower in the hyposmic cohort. No difference was found for other inflammatory biomarkers.

Conclusions: Hyposmia and dysgeusia are common in SARS-CoV-2 infection and can precede systemic symptoms. They should be actively searched and prompt close monitoring and isolation until infection is confirmed or disproven. The lower number of total leukocytes and neutrophils in hyposmic patients might indicate an early-phase virus-induced cytopenia.
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http://dx.doi.org/10.1212/CPJ.0000000000001029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032441PMC
April 2021

Case report and ten-year follow-up of episodic ataxia type 2 due to a novel variant in CACNA1A.

eNeurologicalSci 2021 Jun 13;23:100334. Epub 2021 Mar 13.

Clinical Neurology Unit, Department of Neurosciences, Santa Maria della Misericordia University Hospital, Udine, Italy.

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http://dx.doi.org/10.1016/j.ensci.2021.100334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994720PMC
June 2021

Clinical and neurophysiological characterization of muscular weakness in severe COVID-19.

Neurol Sci 2021 Jun 23;42(6):2173-2178. Epub 2021 Mar 23.

Department of Neurosciences, Udine University Hospital, Udine, Italy.

Objective: To report clinical and electroneuromyographic (ENMG) characteristics of patients affected by severe COVID-19 infection, evaluated for muscular weakness.

Materials And Methods: ENMGs performed for evaluation of diffuse weakness in patients who could not be discharged from semi-intensive care COVID unit because of difficulties in ventilation weaning were reviewed. Patients with severe COVID-19 infection who had undergone endotracheal intubation and able to co-operate were considered. ENMG protocol was focused on neurophysiological items that excluded or confirmed critical illness polyneuropathy (CIP), myopathy (CIM), or polyneuromyopathy (CIPM). Standardized clinical evaluation was performed using Medical Research Council (MRC) sum score.

Results: Eight patients were included in the study. All presented known risk factors for intensive care unit-acquired weakness (ICU-AW), and none of them had history of underlying neuromuscular disorders. ENMG findings were normal in two patients, while only two patients had an altered MRC sum score (< 48). Neuromuscular involvement was diagnosed in 6/8 patients (75%): 2 had CIP, 1 had possible CIM, 1 had CIPM, while 1 patient, with clinically evident weakness but equivocal ENMG findings, was classified as ICU-AW. Finally, 1 patient was diagnosed with acute demyelinating neuropathy. Patients with neuromuscular involvement were those with longer intubation duration and higher levels of IL-6 at admission.

Conclusion: Neuromuscular complications are frequent in severe COVID-19 and cannot be excluded by MRC sum scores above 48. Standardized ENMG is helpful in guiding diagnosis when clinical evaluation is not reliable or possible. Elevated IL-6 at admission may be a predictor biomarker of ICU-AW in COVID-19.
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http://dx.doi.org/10.1007/s10072-021-05110-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985745PMC
June 2021

May lamotrigine be an alternative to topiramate in the prevention of migraine with aura? Results of a retrospective study.

BMJ Neurol Open 2020 24;2(2):e000059. Epub 2020 Aug 24.

Clinical Neurology, Udine University Hospital, Udine, Italy.

Background: Evidence suggests that lamotrigine could be effective in reducing aura frequency and duration. However, studies comparing lamotrigine to other, first-line prophylactic agents solely involving patients suffering from migraine with aura are still lacking. The aim of this study was to compare the efficacy of lamotrigine and topiramate for the preventive treatment of migraine with aura.

Methods: Fifty-three patients suffering from migraine with aura treated with lamotrigine or topiramate for at least 6 months were included. Pre- and post-treatment clinical data regarding monthly aura frequency and duration, monthly migraine frequency, days of headache and rescue medication used per month were collected.

Results: Responder rates were similar between the two treatment groups at 6-month follow-up. Interestingly, responder rates for aura frequency and duration were higher in the lamotrigine group compared with the topiramate group (88% vs 79% and 73% vs 54%). Moreover, 50% of the lamotrigine-treated patients reported a complete disappearance of migraine aura compared with 37% of topiramate-treated patients. Side effects were more frequent in topiramate group compared with lamotrigine group (p=0.004).

Conclusions: Lamotrigine should be considered in clinical practice for the preventive treatment of migraine with aura especially for patients reporting prolonged aura and who do not respond, have contraindications or discontinue topiramate treatment due to side effects.
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http://dx.doi.org/10.1136/bmjno-2020-000059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871707PMC
August 2020

Neurologic Adverse Events of Immune Checkpoint Inhibitors: A Systematic Review.

Neurology 2021 04 2;96(16):754-766. Epub 2021 Mar 2.

From the Clinical Neurology Unit (A.M., A.B., G.L.G., M.V., A.V.), Santa Maria Della Misericordia University Hospital; Department of Medicine (DAME) (A.M., G.L.G., M.V.), University of Udine Medical School, Italy; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., J.H., A.V.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., J.H., A.V.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310; and University Claude Bernard Lyon 1 (S.M.-C., J.H., A.V.), Université de Lyon, France.

Objective: To define the clinical characteristics, management, and outcome of neurologic immune-related adverse events (n-irAEs) of immune checkpoint inhibitors (ICIs).

Methods: Systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Results: A total of 694 articles were identified. Two hundred fifty-six articles, with 428 individual patients, met the inclusion criteria. Reports regarding neuromuscular disorders (319/428, 75%) were more frequent than those on CNS disorders (109/428, 25%). The most common n-irAEs reports were myositis (136/428, 32%), Guillain-Barré syndrome and other peripheral neuropathies (94/428, 22%), myasthenic syndromes (58/428, 14%), encephalitis (56/428, 13%), cranial neuropathies (31/428, 7%), meningitis (13/428, 3%), CNS demyelinating diseases (8/428, 2%), and myelitis (7/428, 2%). Other CNS disorders were detected in 25/428 (6%) patients. Compared with the whole sample, myasthenic syndromes were significantly more Ab positive (33/56, 59%; < 0.001). Anti-programmed cell death protein 1/programmed cell death ligand 1 was more frequent in myasthenic syndromes (50/58, 86%; = 0.005) and less common in meningitis (2/13, 15%; < 0.001) and cranial neuropathies (13/31, 42%; = 0.005). Anti-cytotoxic T-lymphocyte antigen-4 ICIs were more frequent in meningitis (8/13, 62%; < 0.001) and less common in encephalitis (2/56, 4%; = 0.009) and myositis (12/136, 9%; = 0.01). Combination of different ICIs was more frequent in cranial neuropathies (12/31, 39%; = 0.005). Melanoma was more frequent in patients with peripheral neuropathies (64/94, 68%; = 0.003) and less common in encephalitis (19/56, 34%; = 0.001). The highest mortality rate was reached in myasthenic syndromes (28%).

Conclusion: Considering the increasing use of ICI therapy in the forthcoming future, this information can be valuable in assisting neurologists and oncologists in early n-irAEs diagnosis and treatment.
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http://dx.doi.org/10.1212/WNL.0000000000011795DOI Listing
April 2021

Lower lymphocyte counts and older age are associated with reduced multiple sclerosis disease activity during dimethyl fumarate treatment.

Mult Scler Relat Disord 2021 Apr 20;49:102781. Epub 2021 Jan 20.

Clinical Neurology Unit, Udine University Hospital, Piazzale Santa Maria della Misericordia 15, 33100, Udine, Italy; Department of Medicine (DAME), University of Udine, Via Colugna 50, 33100, Udine, Italy.

Background: delayed-release dimethyl fumarate (DMF) is a disease modifying therapy for relapsing-remitting multiple sclerosis (MS) with antioxidant and anti-inflammatory properties. The drug causes lymphocyte count reduction, which can lead to lymphopenia development during treatment. This is an important safety issue, due to infectious risk, mainly progressive multifocal leukoencephalopathy (PML). If the lymphocyte count influences the response to treatment is still a matter of debate, as there are contrasting contrasting data in the literature. Considering this, we aimed to identify DMF induced lymphopenia risk factors and to evaluate lymphopenia impact on MS disease activity in a real world setting.

Methods: a retrospective study on 135 MS patients receiving DMF with a mean treatment duration of 32.3±15.9 months was performed. Baseline and follow-up demographic, clinical, magnetic resonance imaging (MRI) and laboratory data were collected.

Results: 44 patients (32.6%) developed lymphopenia, with 11 (8.1%) grade 1, 23 (17.0%) grade 2 and 10 (7.4 %) grade 3. Older age and lower basal absolute lymphocyte count were found to be associated with lymphopenia development on a binary regression model (p<0.001 and p=0.009). When compared with non lymphopenic+lymphopenia grade 1 patients, those experiencing lymphopenia grade 2+3 had longer disease activity free survival (p<0.001), fewer clinical relapses (p=0.005) and lower MRI disease activity (p≤0.001). On Cox regression model, older age and lymphopenia grade 2+3 were found to be protective factors against disease activity (HR=0.966; 95% C.I.=0.942-0.992; p=0.009 for age; HR=0.137; 95% C.I.=0.043-0.439; p=0.001 for lymphopenia grade 2+3) and MRI disease activity (HR=0.968; 95% C.I.=0.941-0.997; p=0.030 for age; HR=0.142; 95% C.I.=0.034-0.591; p=0.007 for lymphopenia grade 2+3). Only lymphopenia grade 2+3 was found to be a predictor of clinical relapses (HR=0.970; 95% C.I.=0.936-1.005; p=0.095 for age; HR=0.115; 95% C.I.=0.016-0.854; p=0.034 for lymphopenia grade 2+3), with a protective effect.

Conclusion: older age and lower basal lymphocyte count were found to be associated with lymphopenia development. Lymphopenia grade 2+3 and older age could be protective against clinical and radiologic disease activity during DMF treatment.
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http://dx.doi.org/10.1016/j.msard.2021.102781DOI Listing
April 2021

Perampanel as add-on therapy in epilepsies with known etiology: A single center experience with long-term follow-up.

Epilepsy Behav Rep 2021 26;15:100393. Epub 2020 Oct 26.

Department of Medicine (DAME), University of Udine Medical School, Udine, Italy.

We report a retrospective monocentric study performed on 63 patients affected by epilepsy with known etiology, receiving perampanel as add-on therapy with at least 12-month follow-up. The purpose of our study was to evaluate efficacy and tolerability of perampanel in this group of epilepsies. Patients were classified into 2 groups based on the presence/absence of a single focal brain lesion on MRI, as epilepsy etiology: 48 subjects were affected by focal lesional epilepsy and 15 by non-focal lesional epilepsy. The retention rate was 76.2% and 53.9% at 12 and 24 months respectively. At 12 months, at least 40% of patients resulted responders, with a significant reduction in seizure frequency ( = 0.01), confirmed at 24 months. Considering epilepsy etiology, we found a better PER response in patients with focal lesional epilepsy. A significant correlation was observed between responder rates and EEG pattern. Only 30% of patients reported mild-moderate adverse events. Efficacy and tolerability of PER, in our study, are in line with the results reported in other real-world studies. Our data suggest the possibility of better PER response in patients with focal brain lesions, which indicates that this drug could be a therapeutic option in this population.
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http://dx.doi.org/10.1016/j.ebr.2020.100393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797501PMC
October 2020

Perampanel as add-on therapy in epilepsies with known etiology: A single center experience with long-term follow-up.

Epilepsy Behav Rep 2021 26;15:100393. Epub 2020 Oct 26.

Department of Medicine (DAME), University of Udine Medical School, Udine, Italy.

We report a retrospective monocentric study performed on 63 patients affected by epilepsy with known etiology, receiving perampanel as add-on therapy with at least 12-month follow-up. The purpose of our study was to evaluate efficacy and tolerability of perampanel in this group of epilepsies. Patients were classified into 2 groups based on the presence/absence of a single focal brain lesion on MRI, as epilepsy etiology: 48 subjects were affected by focal lesional epilepsy and 15 by non-focal lesional epilepsy. The retention rate was 76.2% and 53.9% at 12 and 24 months respectively. At 12 months, at least 40% of patients resulted responders, with a significant reduction in seizure frequency ( = 0.01), confirmed at 24 months. Considering epilepsy etiology, we found a better PER response in patients with focal lesional epilepsy. A significant correlation was observed between responder rates and EEG pattern. Only 30% of patients reported mild-moderate adverse events. Efficacy and tolerability of PER, in our study, are in line with the results reported in other real-world studies. Our data suggest the possibility of better PER response in patients with focal brain lesions, which indicates that this drug could be a therapeutic option in this population.
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http://dx.doi.org/10.1016/j.ebr.2020.100393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797501PMC
October 2020

Novel Associations of and With REM Sleep Behavior Disorder.

Neurology 2021 03 4;96(10):e1402-e1412. Epub 2021 Jan 4.

From the Department of Human Genetics (K.M., E.Y., U.R., L.K., G.A.R., Z.G.-O.), Montreal Neurological Institute (K.M., E.Y., U.R., L.K., J.A.R., F.A., S.B.L., D.S., G.A.R., R.B.P., Z.G.-O.), Department of Neurology and Neurosurgery (J.A.R., F.A., S.B.L., D.S., G.A.R., R.B.P., Z.G.-O.), Centre de Recherche en Biologie Structurale (J.-F.T.), and Department of Pharmacology and Therapeutics (J.-F.T.), McGill University, Montréal, Quebec, Canada; Sleep Disorders Unit (I.A.), Pitié Salpêtrière Hospital, Paris Brain Institute and Sorbonne University, France; Oxford Parkinson's Disease Centre (OPDC) (M.T.M.H.) and Nuffield Department of Clinical Neurosciences (M.T.M.H.), University of Oxford, UK; Center for Advanced Research in Sleep Medicine (J.Y.M., J.-F.G., A.D., R.B.P.), Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l'Île-de-Montréal-Hôpital du Sacré-Coeur de Montréal; Departments of Psychiatry (J.Y.M.) and Neurosciences (A.D.), Université de Montréal; Department of Psychology (J.-F.G.), Université du Québec à Montréal, Canada; National Reference Center for Narcolepsy (Y.D.), Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, France; Clinical Neurology Unit (G.L.G., M.V., F.J., A.B.), Department of Neurosciences, University Hospital of Udine; DMIF (G.L.G.) and Department of Medicine (DAME) (M.V.), University of Udine, Italy; Sleep Disorders Clinic (B.H., A.S., E.H.), Department of Neurology, Medical University of Innsbruck, Austria; Department of Neurology (K.S., D.K.) and Centre of Clinical Neuroscience (K.S., D.K.), Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic; Department of Neurology (W.O., A.J., F.S.-D.), Philipps University, Marburg, Germany; Department of Biomedical, Metabolic and Neural Sciences (G.P.), University of Modena and Reggio-Emilia; IRCCS (G.P.), Institute of Neurological Sciences of Bologna; Neurology Unit (E.A.), Movement Disorders Division, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona; Department of Medical Sciences and Public Health (M.F., M.P.), Sleep Disorder Research Center, University of Cagliari, Italy; Paracelsus-Elena-Klinik (B.M., C.T., F.S.-D.), Kassel; Department of Neurosurgery (B.M., C.T.), University Medical Centre Göttingen, Germany; Sleep and Neurology Unit (V.C.D.C.), Beau Soleil Clinic; EuroMov Digital Health in Motion (V.C.D.C.), University of Montpellier IMT Mines Ales; University Lille North of France (C.C.M.), Department of Clinical Neurophysiology and Sleep Center, CHU Lille; Department of Sleep Medicine and Neuromuscular Disorders (A.H.), University of Müenster, Germany; Department of Neurological Sciences (L.F.-S.), Università Vita-Salute San Raffaele, Milan, Italy; Laboratory for Sleep Disorders (F.D., M.V.) and Department of Neurology (F.D., M.V.), St. Dimpna Regional Hospital, Geel; Department of Neurology (F.D.), University Hospital Antwerp, Edegem, Belgium; Sleep Disorder Unit (B.A.), Carémeau Hospital, University Hospital of Nîmes, France; and Department of Neurology (B.F.B.), Mayo Clinic, Rochester, MN.

Objective: To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated REM sleep behavior disorder (iRBD).

Methods: We fully sequenced 25 genes previously identified in GWASs of PD in a total of 1,039 patients with iRBD and 1,852 controls. The role of rare heterozygous variants in these genes was examined with burden tests. The contribution of biallelic variants was further tested. To examine the potential effect of rare nonsynonymous variants on the protein structure, we performed in silico structural analysis. Finally, we examined the association of common variants using logistic regression adjusted for age and sex.

Results: We found an association between rare heterozygous nonsynonymous variants in and iRBD ( = 0.0003 at coverage >50× and 0.0004 at >30×), driven mainly by 3 nonsynonymous variants (p.V85M, p.I101V, and p.V272M) found in 22 (1.2%) controls vs 2 (0.2%) patients. All 3 variants seem to be loss-of-function variants with a potential effect on the protein structure and stability. Rare noncoding heterozygous variants in were also associated with iRBD ( = 0.0006 at >30×). We found no association between rare heterozygous variants in the rest of genes and iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD.

Conclusion: Our results suggest that rare coding variants in and rare noncoding variants in are associated with iRBD. Additional studies are required to replicate these results and to examine whether loss of function of could be a therapeutic target.
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http://dx.doi.org/10.1212/WNL.0000000000011464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055320PMC
March 2021

HLA and immunological features of SARS-CoV-2-induced Guillain-Barré syndrome.

Neurol Sci 2020 Dec;41(12):3391-3394

Clinical Neurology Unit, Santa Maria della Misericordia University Hospital, Piazzale Santa Maria della Misericordia, 15, 33010, Udine, Italy.

We report the clinical and immunological features in a case of SARS-CoV-2-induced Guillain-Barré syndrome (Si-GBS), suggesting that (1) Si-GBS can develop even after paucisymptomatic COVID-19 infection; (2) a distinctive cytokine repertoire is associated with this autoimmune complication, with increased CSF concentration of IL-8, and moderately increased serum levels of IL-6, IL-8, and TNF-α; (3) a particular genetic predisposition can be relevant, since the patient carried several HLA alleles known to be associated with GBS, including distinctive class I (HLA-A33) and class II alleles (DRB1*03:01 and DQB1*05:01). To the best of our knowledge, this is the first case of GBS in which SARS-CoV-2 antibodies were detected in the CSF, further strengthening the role of the virus as a trigger. In conclusion, our study suggests that SARS-CoV-2 antibodies need to be searched in the serum and CSF in patients with GBS living in endemic areas, even in the absence of a clinically severe COVID-19 infection, and that IL-8 pathway can be relevant in Si-GBS pathogenesis. Further studies are needed to conclude on the relevance of the genetic findings, but it is likely that HLA plays a role in this setting as in other autoimmune neurological syndromes, including those triggered by infections.
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http://dx.doi.org/10.1007/s10072-020-04787-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530349PMC
December 2020

Comprehensive Analysis of Familial Parkinsonism Genes in Rapid-Eye-Movement Sleep Behavior Disorder.

Mov Disord 2021 01 1;36(1):235-240. Epub 2020 Oct 1.

Paracelsus-Elena-Klinik, Kassel, Germany.

Background: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD).

Objective: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD.

Methods: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests.

Results: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls.

Conclusion: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28318DOI Listing
January 2021

Evaluating pitolisant as a narcolepsy treatment option.

Expert Opin Pharmacother 2021 Feb 17;22(2):155-162. Epub 2020 Sep 17.

Neurology Unit, Department of Neurosciences, University Hospital of Udine , Udine, Italy.

Introduction: Narcolepsy is a chronic sleep disorder characterized by a pentad of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep. Treatment of narcolepsy remains challenging and current therapy is strictly symptomatically based.

Areas Covered: The present manuscript is based on an extensive Internet and PubMed search from 1990 to 2020. It is focused on the clinical and pharmacological properties of pitolisant in the treatment of narcolepsy.

Expert Opinion: Currently there is no cure for narcolepsy. Although efforts have been made, current treatments do not always allow to obtain an optimal control of symptoms. Pitolisant is an antagonist/inverse agonist of the histamine H3 autoreceptor. Its mechanism of action is novel and distinctive compared to the other available therapies for narcolepsy. Clinical trials suggest that pitolisant administered at a dose of ≤36 mg/day is an effective treatment option for narcolepsy, reducing EDS and cataplexy. Pitolisant is available as oral tablets and offers a convenient once-daily regimen. Pitolisant is generally well tolerated and showed minimal abuse potential in animals and humans. Long-term studies comparing the effectiveness and tolerability of pitolisant with active drugs (e.g. modafinil, sodium oxybate) are needed.
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http://dx.doi.org/10.1080/14656566.2020.1817387DOI Listing
February 2021

Brivaracetam for the treatment of focal-onset seizures: pharmacokinetic and pharmacodynamic evaluations.

Expert Opin Drug Metab Toxicol 2020 Oct 20;16(10):853-863. Epub 2020 Sep 20.

Neurology Unit, Department of Neurosciences, University Hospital of Udine , Udine, Italy.

Introduction: The goal of pharmacologic therapy with antiseizure medications (ASMs) is to achieve a seizure-free state with minimal side effects. About one third of patients treated with available ASMs continue to experience uncontrolled seizures. There is still need for new ASMs with enhanced effectiveness and tolerability.

Areas Covered: The present manuscript is based on an extensive Internet and PubMed search from 1999 to 2020. It is focused on the clinical and pharmacological properties of brivaracetam (BRV) in the treatment of epilepsy.

Expert Opinion: BRV is approved as add-on or monotherapy (in US) for the treatment of focal-onset seizures with or without secondary generalization. BRV is a high affinity synaptic vesicle glycoprotein 2A ligand, with 15-30-fold higher affinity than levetiracetam. The selectivity of BRV may be associated with fewer clinical adverse effects. BRV shares many of the pharmacokinetic characteristics of an ideal ASMs. Additionally, BRV has a low potential for clinically relevant drug-drug interactions. Its pharmacokinetic profile makes BRV a promising agent for the treatment of status epilepticus (SE). Although BRV is not approved for the treatment of SE, it has demonstrated promising preliminary results. Further studies are needed to explore the efficacy and tolerability of BRV in SE.
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http://dx.doi.org/10.1080/17425255.2020.1813277DOI Listing
October 2020

Stress hyperglycemia is predictive of worse outcome in patients with acute ischemic stroke undergoing intravenous thrombolysis.

J Thromb Thrombolysis 2021 Apr;51(3):789-797

Clinical Neurology, Udine University Hospital, Udine, Italy.

No study investigated the possible detrimental effect of stress hyperglycemia on patients affected acute ischemic stroke (AIS) undergoing intravenous thrombolysis (IVT). A new index, the glucose-to-glycated hemoglobin ratio (GAR), has been developed for assessing stress hyperglycemia. We retrospectively analyzed data from a prospectively collected database of consecutive patients admitted to the Udine University Hospital with AIS that were treated with IVT from January 2015 to December 2019. Four hundred and fourteen consecutive patients with AIS undergoing IVT entered the study. The patients were then stratified into four groups by quartiles of GAR (Q1-Q4). The higher GAR index was, the more severe stress hyperglycemia was considered. Prevalence of 3 months poor outcome (37.7% for Q1, 34% for Q2, 46.9% for Q3, and 66.7% for Q4, p for trend = 0.001), 3 months mortality (10.5% for Q1, 7.5% for Q2, 11.2% for Q3, and 27.1% for Q4, p for trend = 0.001), and symptomatic intracranial hemorrhage (0.9% for Q1, 0.9% for Q2, 5.1% for Q3, and 17.7% for Q4, p for trend = 0.001) was significant different among the four groups. AIS patients with severe stress hyperglycemia had a significantly increased risk of 3 months poor outcome (OR 2.43, 95% CI 1.14-5.22, p = 0.02), 3 months mortality (OR 2.38, 95% CI 1.01-5.60, p = 0.04), and symptomatic intracranial hemorrhage (OR 16.76, 95% CI 2.09-134.58, p = 0.008) after IVT. In conclusion, we demonstrated that stress hyperglycemia, as measured by the GAR index, is associated to worse outcome in AIS patients undergoing IVT.
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http://dx.doi.org/10.1007/s11239-020-02252-yDOI Listing
April 2021

variants in REM sleep behavior disorder: A multicenter study.

Neurology 2020 08 26;95(8):e1008-e1016. Epub 2020 Jun 26.

From the Department of Human Genetics (L.K., U.R., G.A.R., Z.G.-O.), Montreal Neurological Institute (L.K., J.A.R., U.R., E.L., F.A., R.B.P., G.A.R., Z.G.-O.), and Department of Neurology and Neurosurgery (J.A.R., F.A., R.B.P., G.A.R., Z.G.-O.), McGill University, Montréal; Oxford Parkinson's Disease Centre (M.T.M.H.) and Nuffield Department of Clinical Neurosciences (M.T.M.H.), University of Oxford, UK; Sleep Disorders Unit (I.A.), Pitié Salpêtrière Hospital, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière and Sorbonne Universities, Paris; National Reference Center for Narcolepsy, Sleep Unit (Y.D.), Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, France; Sleep Disorders Unit, Department of Neurology (B.H., A.S.), Medical University of Innsbruck, Austria; Department of Clinical Neurophysiology and Sleep Center (C.C.M.), University Lille North of France, CHU Lille; Sleep Disorder Unit (B.A.), Carémeau Hospital, University Hospital of Nîmes, France; Department of Biomedical and Neuromotor Sciences (DIBINEM) (G.P., E.A.), Alma Mater Studiorum, University of Bologna; IRCCS (G.P., E.A.), Istituto delle Scienze Neurologiche, Bologna; Department of Neurological Sciences (L.F.-S.), Università Vita-Salute San Raffaele, Milan, Italy; Department of Neurology with Institute of Translational Neurology (A.H.), University of Muenster, Germany; Department of Neurology (B.F.B.), Mayo Clinic, Rochester, MN; UC Gardner Neuroscience Institute and Gardner Family Center for Parkinson's Disease and Movement Disorders (A.J.E.), Cincinnati, OH; Sleep and Neurology Unit (V.C.D.C.), Beau Soleil Clinic, Montpellier; EuroMov (V.C.D.C.), University of Montpellier, France; Paracelsus-Elena-Klinik (B.M., F.S.-D., C.T.), Kassel; Department of Neurology (B.M., C.T.), University Medical Centre Goettingen; Department of Neurology (F.S.-D., W.O.), Philipps University, Marburg, Germany; Department of Neurology and Centre of Clinical Neuroscience (K.S., D.K.), Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic; Department of Medical Sciences and Public Health, Sleep Disorder Research Center (M.F., M.P.), University of Cagliari, Italy; Laboratory for Sleep Disorders (F.D., M.V.) and Department of Neurology (F.D., M.V.), St. Dimpna Regional Hospital, Geel, Belgium; Department of Medicine (DAME) (M.T., M.V.), University of Udine, Italy; Department of Clinical and Movement Neurosciences (M.T.), UCL Queen Square Institute of Neurology, London, UK; Clinical Neurology Unit (G.L.G., M.V.), Department of Neurosciences, University Hospital of Udine; DMIF (G.L.G.), University of Udine, Italy; Centre d'Études Avancées en Médecine du Sommeil (J.-F.G., A.D., J.Y.M., R.B.P.), Hôpital du Sacré-Cœur de Montréal; and Departments of Psychology (J.-F.G.), Neurosciences (A.D.), and Psychiatry (J.Y.M.), Université du Québec à Montréal, Canada.

Objective: To study the role of variants in the risk for isolated REM sleep behavior disorder (iRBD) and conversion to overt neurodegeneration.

Methods: A total of 4,147 individuals were included: 1,061 patients with iRBD and 3,086 controls. was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of variants on the risk of iRBD, age at onset (AAO), and conversion rates.

Results: variants were found in 9.5% of patients with iRBD compared to 4.1% of controls (odds ratio, 2.45; 95% confidence interval [CI], 1.87-3.22; = 1 × 10). The estimated OR for mild p.N370S variant carriers was 3.69 (95% CI, 1.90-7.14; = 3.5 × 10), while for severe variant carriers it was 17.55 (95% CI, 2.11-145.9; = 0.0015). Carriers of severe variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or noncarriers ( = 0.029). Of the variant carriers with available data, 52.5% had converted, compared to 35.6% of noncarriers ( = 0.011), with a trend for faster conversion among severe variant carriers. However, the results on AAO and conversion were based on small numbers and should be interpreted with caution.

Conclusions: variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of variants should be studied as a potential way to identify variant carriers who will develop a synucleinopathy in the future.
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http://dx.doi.org/10.1212/WNL.0000000000010042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668554PMC
August 2020

Dynamic Hyperglycemic Patterns Predict Adverse Outcomes in Patients with Acute Ischemic Stroke Undergoing Mechanical Thrombectomy.

J Clin Med 2020 Jun 20;9(6). Epub 2020 Jun 20.

Clinical Neurology, Udine University Hospital, 33100 Udine, Italy.

Background: Admission hyperglycemia impairs outcome in acute ischemic stroke (AIS) patients undergoing mechanical thrombectomy (MT). Since hyperglycemia in AIS represents a dynamic condition, we tested whether the dynamic patterns of hyperglycemia, defined as blood glucose levels > 140 mg/dl, affect outcomes in these patients.

Methods: We retrospectively analyzed data of 200 consecutive patients with prospective follow-up. Based on blood glucose level, patients were distinguished into 4 groups: (1) persistent normoglycemia; (2) hyperglycemia at baseline only; (3) hyperglycemia at 24-h only; and (4) persistent (at baseline plus at 24-h following MT) hyperglycemia.

Results: AIS patients with persistent hyperglycemia have a significantly increased risk of poor functional outcome (OR 6.89, 95% CI 1.98-23.94, = 0.002, for three-month poor outcome; OR 11.15, 95% CI 2.99-41.52, = 0.001, for no major neurological improvement), mortality (OR 5.37, 95% CI 1.61-17.96, = 0.006, for in-hospital mortality; OR 4.43, 95% CI 1.40-13.97, = 0.01, for three-month mortality), and hemorrhagic transformation (OR 6.89, 95% CI 2.35-20.21, = 0.001, for intracranial hemorrhage; OR 5.42, 95% CI 1.54-19.15, = 0.009, for symptomatic intracranial hemorrhage) after endovascular treatment. These detrimental effects were partially confirmed after also excluding diabetic patients. The AUC-ROC showed a very good performance for predicting three-month poor outcome (0.76) in-hospital mortality (0.79) and three-month mortality (0.79).

Conclusions: Our study suggests that it is useful to perform the prolonged monitoring of glucose levels lasting 24-h after MT.
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http://dx.doi.org/10.3390/jcm9061932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355777PMC
June 2020

Guillain-Barré syndrome in the COVID-19 era: just an occasional cluster?

J Neurol 2021 Apr 19;268(4):1195-1197. Epub 2020 May 19.

Clinical Neurology Unit, Santa Maria della Misericordia University Hospital, Udine, Italy.

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http://dx.doi.org/10.1007/s00415-020-09911-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236438PMC
April 2021

SMPD1 variants do not have a major role in rapid eye movement sleep behavior disorder.

Neurobiol Aging 2020 09 18;93:142.e5-142.e7. Epub 2020 Apr 18.

Paracelsus-Elena-Klinik, Kassel, Germany; Department of Neurology, University Medical Centre Goettingen, Goettingen, Germany.

Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson's disease and dementia with Lewy bodies. In the current study, we aimed to evaluate the role of SMPD1 variants in isolated rapid eye movement sleep behavior disorder (iRBD). SMPD1 and its untranslated regions were sequenced using targeted next-generation sequencing in 959 iRBD patients and 1287 controls from European descent. Our study reports no statistically significant association of SMPD1 variants and iRBD. It is hence unlikely that SMPD1 plays a major role in iRBD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.005DOI Listing
September 2020

To Treat or Not to Treat: Importance of Functional Dependence in Deciding Intravenous Thrombolysis of "Mild Stroke" Patients.

J Clin Med 2020 Mar 12;9(3). Epub 2020 Mar 12.

Clinical Neurology, Udine University Hospital, 33100 Udine, Italy.

Intravenous thrombolysis (IVT) in patients with a low National Institutes of Health Stroke Scale (NIHSS) score of 0-5 remains controversial. IVT should be used in patients with mild but nevertheless disabling symptoms. We hypothesize that response to IVT of patients with "mild stroke" may depend on their level of functional dependence (FD) at hospital admission. The aims of our study were to investigate the effect of IVT and to explore the role of FD in influencing the response to IVT. This study was a retrospective analysis of a prospectively collected database, including 389 patients stratified into patients receiving IVT (IVT) and not receiving IVT (IVT ) just because of mild symptoms. Barthel index (BI) at admission was used to assess FD, dividing subjects with BI score < 80 (FD) and with BI score > 80 (FD). The efficacy endpoints were the rate of positive disability outcome (DO) (3-month mRS score of 0 or 1), and the rate of positive functional outcome (FO) (mRS score of zero or one, plus BI score of 95 or 100 at 3 months). At the multivariate analysis, IVT treatment was an independent predictor of DO (OR 3.12, 95% CI 1.34-7.27, = 0.008) and FO (OR: 4.70, 95% CI 2.38-9.26, = 0.001). However, FD IVT patients had a significantly higher prevalence of DO and FO than those FD IVT. Differently, IVT treatment did not influence DO and FO in FD patients. In FD patients, IVT treatment represented the strongest independent predictor of DO (OR 6.01, 95% CI 2.59-13.92, = 0.001) and FO (OR 4.73, 95% CI 2.29-9.76, = 0.001). In conclusion, alteplase seems to improve functional outcome in patients with "mild stroke". However, in our experience, this beneficial effect is strongly influenced by FD at admission.
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http://dx.doi.org/10.3390/jcm9030768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141285PMC
March 2020

Primary Orthostatic Tremor in 2 Siblings.

Mov Disord Clin Pract 2020 Feb 30;7(2):234-236. Epub 2019 Dec 30.

Neurology Unit, Department of Neurosciences Santa Maria della Misericordia University Hospital Udine Italy.

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http://dx.doi.org/10.1002/mdc3.12869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011815PMC
February 2020

Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.

Ann Neurol 2020 04 12;87(4):584-598. Epub 2020 Feb 12.

Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy.

Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants.

Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis.

Results: A 5'-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD.

Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584-598.
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http://dx.doi.org/10.1002/ana.25687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025046PMC
April 2020

Epilepsia partialis continua revealing idelalisib-associated PML-IRIS: clinical and pathological features.

J Neurovirol 2020 06 5;26(3):437-441. Epub 2019 Dec 5.

Clinical Neurology Unit, Santa Maria della Misericordia University Hospital, Piazzale Santa Maria della Misericordia, 15, 33010, Udine, Italy.

Idelalisib, a selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, is a newly approved second-line drug for patients with chronic lymphocytic leukemia. Recent clinical trials have suggested a possible association between idelalisib treatment and development of progressive multifocal leukoencephalopathy (PML) due to John Cunningham virus (JCV) reactivation. Nevertheless, clinical course and radiological and pathological features of idelalisib-induced PML still need to be clarified. We provide here the first clinicopathological description of idelalisib-associated PML in a patient who developed epilepsia partialis continua (EPC) as the first manifestation of the disease. Since EPC could present without electroencephalogram alterations, it is crucial to recognize the clinical features of this epileptic condition. EPC is characterized by the presence of repetitive, irregular, clonic jerking, often associated with hemiparesis and involvement of distal rather than proximal muscle groups. Moreover, we highlight the importance of brain biopsy in selected cases when there is a high clinical suspicion of PML, despite negative JCV testing in the cerebrospinal fluid. The pathological finding of prominent inflammatory infiltrate observed here was consistent with a diagnosis of immune reconstitution inflammatory syndrome (IRIS). IRIS is often associated with PML as a paradoxical worsening of clinical symptoms due to an overreacting immune response, in the context of previous immunosuppression. The unprecedented pathologic observation of IRIS in idelalisib-associated PML provides further insights into the pathogenesis of this rare neurological side effect.
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http://dx.doi.org/10.1007/s13365-019-00821-3DOI Listing
June 2020