Publications by authors named "Giampietro Zanette"

65 Publications

Peripheral nerve enlargement on nerve ultrasound parallels neuropathological changes in adult-onset Krabbe disease.

Muscle Nerve 2021 Jan 16. Epub 2021 Jan 16.

Department of Neuroscience, Biomedicine and Motor Sciences, University of Verona, Verona, Italy.

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http://dx.doi.org/10.1002/mus.27175DOI Listing
January 2021

Brain 18F-FDG and 18F-Flumetamol PET Imaging of Fragile X-Associated Tremor Ataxia Syndrome.

Clin Nucl Med 2021 Jan 13. Epub 2021 Jan 13.

From the Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona Nuclear Medicine Unit, Sacro Cuore Don Calabria Hospital, Negrar Neurology Unit, Pederzoli Hospital, Peschiera del Garda, Italy.

Abstract: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare movement disorder caused by a 55-to-200 CGG-trinucleotide expansion premutation in the FMR1 gene. Core diagnostic criteria are tremor, ataxia, and T2-weighted hyperintensity of the middle cerebellar peduncles on MRI, but FXTAS encompass a broad spectrum of neurological symptoms. FXTAS pathophysiology is largely unknown, and some animal models and neuropathology findings suggest possible overlap with Alzheimer disease. We report the combined PET imaging of a genetically confirmed FXTAS patient, presenting reduced temporal-frontal 18F-FDG uptake, and pathological cortical deposition of amyloid to 18F-flumetamol PET scan. This report may offer clues to FXTAS pathophysiology.
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http://dx.doi.org/10.1097/RLU.0000000000003484DOI Listing
January 2021

Convergent pathological and ultrasound features in hereditary syndromic and non-syndromic minifascicular neuropathy related to DHH.

J Peripher Nerv Syst 2020 12 4;25(4):423-428. Epub 2020 Nov 4.

Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Minifascicular neuropathy (MN) is a rare, autosomal recessive disease with prominent structural changes of peripheral nerves. So far, it has been observed in females with a 46,XY karyotype and mutations of the Desert Hedgehog (DHH) gene, thus linking MN to gonadal dysgenesis (GD) and disorders of sex development (DSD). However, a 46,XX proband with normal female sex and gender development underwent clinical evaluations, nerve conduction studies and genetic screening for a severe motor-sensory neuropathy with a pathological phenotype that hinted at MN. Indeed, sural nerve biopsy revealed a profound disturbance of perineurium development with a thin and loose structure. High-resolution ultrasound (HRUS) also disclosed diffuse changes of nerve echotexture that visibly correlated with the pathological features. After extensive genetic testing, a novel homozygous DHH null mutation (p.Ser185*) was identified in the proband and in her sister, who was affected by a similar motor-sensory neuropathy, but was eventually found to be a 46,XY patient according to a late diagnosis of DSD with complete GD. DHH should therefore be considered as a possible cause of rare non-syndromic hereditary motor-sensory neuropathies, regardless of DSD. Furthermore, HRUS could effectively smooth the complex diagnostic workup as it demonstrated a high predictive power to detect MN, providing the same detailed correlations to the pathologic features of the nerve biopsy and Dhh-/- mice in both sisters. Hence, HRUS may assume a pivotal role in guiding molecular analysis in individuals with or without DSD.
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http://dx.doi.org/10.1111/jns.12417DOI Listing
December 2020

CIDP, CMT1B, or CMT1B plus CIDP?

Neurol Sci 2021 Mar 18;42(3):1127-1130. Epub 2020 Oct 18.

Section of Neurology, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Charcot-Marie-Tooth disease type 1 (CMT1) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have distinct clinical and neurophysiological features that result from dysmyelination in CMT1 and macrophage-mediated segmental demyelination in CIDP. CMT1 may occur in genetically isolated cases with atypical presentations that converge phenotypically with CIDP; in rare cases, however, CMT1 may be complicated by superimposed CIDP. We report the case of a patient harboring a de novo heterozygous null mutation of the myelin protein zero (MPZ) gene and affected by subclinical CMT1B who became symptomatic due to superimposed CIDP. Peripheral nerve high-resolution ultrasound (HRUS) aided in establishing the coexistence of CMT1B and CIDP; the diagnosis was further supported by favorable clinical, neurophysiological, and ultrasound responses to immunoglobulin therapy.
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http://dx.doi.org/10.1007/s10072-020-04789-5DOI Listing
March 2021

Epileptic seizures of suspected autoimmune origin: a multicentre retrospective study.

J Neurol Neurosurg Psychiatry 2020 Nov 28;91(11):1145-1153. Epub 2020 Aug 28.

Department of Neuroscience, Biomedicine and Movement Sciences, Section of Neurology, University of Verona, Verona, Italy

Objective: To analyse autoantibody status in a well-defined European multicentre cohort of patients with epilepsy of unknown aetiology and to validate the recently proposed Antibody Prevalence in Epilepsy (APE2) and Response to ImmunoTherapy in Epilepsy (RITE2) scores.

Methods: We retrospectively collected clinical and paraclinical data of 92 patients referred to the Neurology Units of Verona and Salzburg between January 2014 and July 2019 with new-onset epilepsy, status epilepticus or chronic epilepsy of unknown aetiology. Fixed and live cell-based assays, tissue-based assays, immunoblot, and live rat hippocampal cell cultures were performed in paired serum/cerebrospinal fluid (CSF) to detect antineuronal and antiglial antibodies. The APE2 and RITE2 scores were then calculated and compared with clinical and laboratory data.

Results: Autoantibodies were detected in 29/92 patients (31.5%), with multiple positivity observed in 6/29 cases. The APE2 score (median 5, range 1-15) significantly correlated with antibody positivity (p=0.014), especially for the presence of neuropsychiatric symptoms (p<0.01), movement disorders (p<0.01), dysautonomia (p=0.03), faciobrachial dyskinesias (p=0.03) and cancer history (p<0.01). Status epilepticus was significantly more frequent in antibody-negative patients (p<0.01). Among the items of the RITE2 score, early initiation of immunotherapy correlated with a good treatment response (p=0.001), whereas a cancer history was significantly more common among non-responders (p<0.01). Persistence of neuropsychiatric symptoms and seizures correlated with antiepileptic maintenance after at least 1 year.

Conclusions: This is the first study that independently validates the APE2 and RITE2 scores and includes the largest cohort of patients whose paired serum and CSF samples have been tested for autoantibodies possibly associated with autoimmune epilepsy.
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http://dx.doi.org/10.1136/jnnp-2020-323841DOI Listing
November 2020

Selective atrophy of the brachialis muscle in neuralgic amyotrophy: ultrasound imaging of fascicular nerve damage.

J Neurol Neurosurg Psychiatry 2020 Oct 30;91(10):1118-1119. Epub 2020 Jul 30.

Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

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http://dx.doi.org/10.1136/jnnp-2020-323989DOI Listing
October 2020

Acute revascularization treatments for ischemic stroke in the Stroke Units of Triveneto, northeast Italy: time to treatment and functional outcomes.

J Thromb Thrombolysis 2021 Jan;51(1):159-167

Stroke Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

It is not known whether the current territorial organization for acute revascularization treatments in ischemic stroke patients guarantees similar time to treatment and functional outcomes among different levels of institutional stroke care. We aimed to assess the impact of time to treatment on functional outcomes in ischemic stroke patients who received intravenous thrombolysis (IVT) alone, bridging (IVT plus thrombectomy), or primary thrombectomy in level 1 and level 2 Stroke Units (SUs) in Triveneto, a geographical macroarea in Northeast of Italy. We conducted an analysis of data prospectively collected from 512 consecutive ischemic stroke patients who received IVT and/or mechanical thrombectomy in 25 SUs from September 17th to December 9th 2018. The favorable outcome measures were mRS score 0-1 and 0-2 at 3 months. The unfavorable outcome measures were mRS score 3-5 and death at 3 months. We estimated separately the possible association of each variable for time to treatment (onset-to-door, door-to-needle, onset-to-needle, door-to-groin puncture, needle-to-groin puncture, and onset-to-groin puncture) with 3-month outcome measures by calculating the odds ratios (ORs) with two-sided 95% confidence intervals (CI) after adjustment for pre-defined variables and variables with a probability value ≤ 0.10 in the univariate analysis for each outcome measure. Distribution of acute revascularization treatments was different between level 1 and level 2 SUs (p < 0.001). Among 182 patients admitted to level 1 SUs (n = 16), treatments were IVT alone in 164 (90.1%), bridging in 12 (6.6%), and primary thrombectomy in 6 (3.3%) patients. Among 330 patients admitted to level 2 SUs (n = 9), treatments were IVT alone in 219 (66.4%), bridging in 74 (22.4%), and primary thrombectomy in 37 (11.2%) patients. Rates of excellent outcome (51.4% vs 45.9%), favorable outcome (60.1% vs 58.7%), unfavorable outcome (33.3% vs 33.8%), and death (9.8% vs 11.3%) at 3 months were similar between level 1 and 2 SUs. No significant association was found between time to IVT alone (onset-to-door, door-to-needle, and onset-to-needle) and functional outcomes. After adjustment, door-to-needle time ≤ 60 min (OR 4.005, 95% CI 1.232-13.016), shorter door-to-groin time (OR 0.991, 95% CI 0.983-0.999), shorter needle-to-groin time (OR 0.986, 95% CI 0.975-0.997), and shorter onset-to-groin time (OR 0.994, 95% CI 0.988-1.000) were associated with mRS 0-1. Shorter door-to-groin time (OR 0.991, 95% CI 0.984-0.998), door-to-groin time ≤ 90 min (OR 12.146, 95% CI 2.193-67.280), shorter needle-to-groin time (OR 0.983, 95% CI 0.972-0.995), and shorter onset-to-groin time (OR 0.993, 95% CI 0.987-0.999) were associated with mRS 0-2. Longer door-to-groin time (OR 1.007, 95% CI 1.001-1.014) and longer needle-to-groin time (OR 1.019, 95% CI 1.005-1.034) were associated with mRS 3-5, while door-to-groin time ≤ 90 min (OR 0.229, 95% CI 0.065-0.808) was inversely associated with mRS 3-5. Longer onset-to-needle time (OR 1.025, 95% CI 1.002-1.048) was associated with death. Times to treatment influenced the 3-month outcomes in patients treated with thrombectomy (bridging or primary). A revision of the current territorial organization for acute stroke treatments in Triveneto is needed to reduce transfer time and to increase the proportion of patients transferred from a level 1 SU to a level 2 SU to perform thrombectomy.
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http://dx.doi.org/10.1007/s11239-020-02142-3DOI Listing
January 2021

Pharmacological treatment for familial amyloid polyneuropathy.

Cochrane Database Syst Rev 2020 Apr 20;4:CD012395. Epub 2020 Apr 20.

University of Verona, Department of Neurosciences, Biomedicine and Movement Sciences, Piazzale L.A. Scuro n. 10, Verona, VR, Italy, 37134.

Background: Disease-modifying pharmacological agents for transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) have become available in the last decade, but evidence on their efficacy and safety is limited. This review focuses on disease-modifying pharmacological treatment for TTR-related and other FAPs, encompassing amyloid kinetic stabilisers, amyloid matrix solvents, and amyloid precursor inhibitors.

Objectives: To assess and compare the efficacy, acceptability, and tolerability of disease-modifying pharmacological agents for familial amyloid polyneuropathies (FAPs).

Search Methods: On 18 November 2019, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We reviewed reference lists of articles and textbooks on peripheral neuropathies. We also contacted experts in the field. We searched clinical trials registries and manufacturers' websites.

Selection Criteria: We included randomised clinical trials (RCTs) or quasi-RCTs investigating any disease-modifying pharmacological agent in adults with FAPs. Disability due to FAP progression was the primary outcome. Secondary outcomes were severity of peripheral neuropathy, change in modified body mass index (mBMI), quality of life, severity of depression, mortality, and adverse events during the trial.

Data Collection And Analysis: We followed standard Cochrane methodology.

Main Results: The review included four RCTs involving 655 people with TTR-FAP. The manufacturers of the drugs under investigation funded three of the studies. The trials investigated different drugs versus placebo and we did not conduct a meta-analysis. One RCT compared tafamidis with placebo in early-stage TTR-FAP (128 randomised participants). The trial did not explore our predetermined disability outcome measures. After 18 months, tafamidis might reduce progression of peripheral neuropathy slightly more than placebo (Neuropathy Impairment Score (NIS) in the lower limbs; mean difference (MD) -3.21 points, 95% confidential interval (CI) -5.63 to -0.79; P = 0.009; low-certainty evidence). However, tafamidis might lead to little or no difference in the change of quality of life between groups (Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score; MD -4.50 points, 95% CI -11.27 to 2.27; P = 0.19; very low-certainty evidence). No clear between-group difference was found in the numbers of participants who died (risk ratio (RR) 0.65, 95% CI 0.11 to 3.74; P = 0.63; very low-certainty evidence), who dropped out due to adverse events (RR 1.29, 95% CI 0.30 to 5.54; P = 0.73; very low-certainty evidence), or who experienced at least one severe adverse event during the trial (RR 1.16, 95% CI 0.37 to 3.62; P = 0.79; very low-certainty evidence). One RCT compared diflunisal with placebo (130 randomised participants). At month 24, diflunisal might reduce progression of disability (Kumamoto Score; MD -4.90 points, 95% CI -7.89 to -1.91; P = 0.002; low-certainty evidence) and peripheral neuropathy (NIS plus 7 nerve tests; MD -18.10 points, 95% CI -26.03 to -10.17; P < 0.001; low-certainty evidence) more than placebo. After 24 months, changes from baseline in the quality of life measured by the 36-Item Short-Form Health Survey score showed no clear difference between groups for the physical component (MD 6.10 points, 95% CI 2.56 to 9.64; P = 0.001; very low-certainty evidence) and the mental component (MD 4.40 points, 95% CI -0.19 to 8.99; P = 0.063; very low-certainty evidence). There was no clear between-group difference in the number of people who died (RR 0.46, 95% CI 0.15 to 1.41; P = 0.17; very low-certainty evidence), in the number of dropouts due to adverse events (RR 2.06, 95% CI 0.39 to 10.87; P = 0.39; very low-certainty evidence), and in the number of people who experienced at least one severe adverse event (RR 0.77, 95% CI 0.18 to 3.32; P = 0.73; very low-certainty evidence) during the trial. One RCT compared patisiran with placebo (225 randomised participants). After 18 months, patisiran reduced both progression of disability (Rasch-built Overall Disability Scale; least-squares MD 8.90 points, 95% CI 7.00 to 10.80; P < 0.001; moderate-certainty evidence) and peripheral neuropathy (modified NIS plus 7 nerve tests - Alnylam version; least-squares MD -33.99 points, 95% CI -39.86 to -28.13; P < 0.001; moderate-certainty evidence) more than placebo. At month 18, the change in quality of life between groups favoured patisiran (Norfolk QOL-DN total score; least-squares MD -21.10 points, 95% CI -27.20 to -15.00; P < 0.001; low-certainty evidence). There was little or no between-group difference in the number of participants who died (RR 0.61, 95% CI 0.21 to 1.74; P = 0.35; low-certainty evidence), dropped out due to adverse events (RR 0.33, 95% CI 0.13 to 0.82; P = 0.017; low-certainty evidence), or experienced at least one severe adverse event (RR 0.91, 95% CI 0.64 to 1.28; P = 0.58; low-certainty evidence) during the trial. One RCT compared inotersen with placebo (172 randomised participants). The trial did not explore our predetermined disability outcome measures. From baseline to week 66, inotersen reduced progression of peripheral neuropathy more than placebo (modified NIS plus 7 nerve tests - Ionis version; MD -19.73 points, 95% CI -26.50 to -12.96; P < 0.001; moderate-certainty evidence). At week 65, the change in quality of life between groups favoured inotersen (Norfolk QOL-DN total score; MD -10.85 points, 95% CI -17.25 to -4.45; P < 0.001; low-certainty evidence). Inotersen may slightly increase mortality (RR 5.94, 95% CI 0.33 to 105.60; P = 0.22; low-certainty evidence) and occurrence of severe adverse events (RR 1.48, 95% CI 0.85 to 2.57; P = 0.16; low-certainty evidence) compared to placebo. More dropouts due to adverse events were observed in the inotersen than in the placebo group (RR 8.57, 95% CI 1.16 to 63.07; P = 0.035; low-certainty evidence). There were no studies addressing apolipoprotein AI-FAP, gelsolin-FAP, and beta-2-microglobulin-FAP.

Authors' Conclusions: Evidence on the pharmacological treatment of FAPs from RCTs is limited to TTR-FAP. No studies directly compare disease-modifying pharmacological treatments for TTR-FAP. Results from placebo-controlled trials indicate that tafamidis, diflunisal, patisiran, and inotersen may be beneficial in TTR-FAP, but further investigations are needed. Since direct comparative studies for TTR-FAP will be hampered by sample size and costs required to demonstrate superiority of one drug over another, long-term non-randomised open-label studies monitoring their efficacy and safety are needed.
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http://dx.doi.org/10.1002/14651858.CD012395.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170468PMC
April 2020

Inherited motor-sensory neuropathy with upper limb predominance associated with the tropomyosin-receptor kinase fused gene.

Neuromuscul Disord 2020 03 17;30(3):227-231. Epub 2020 Jan 17.

Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, Skien, Norway.

The Tropomyosin-receptor kinase fused gene (TFG) encodes TFG which is expressed in spinal motor neurons, dorsal root ganglia and cranial nerve nuclei, and plays a role in the dynamics of the endoplasmic reticulum. Two dominant missense TFG mutations have previously been reported in limited geographical areas (Far East, Iran, China) in association with hereditary motor sensory neuropathy with proximal involvement (HMSN-P) of the four limbs, or with Charcot-Marie-Tooth disease type 2 (CMT2). The 60-year-old female proband belonging to a three-generation Italian family presented with an atypical neuropathy characterized by diffuse painful cramps and prominent motor-sensory impairment of the distal upper limbs. Her sural nerve biopsy showed chronic axonal neuropathy without active degeneration or regeneration. Targeted next-generation sequencing of a panel with 98 genes associated with inherited peripheral neuropathies/neuromuscular disorders identified three candidate genes: TFG, DHTKD1 and DCTN2. In the family, the disease co-segregated with the TFG p.(Gly269Val) variant. TFG should be considered in genetic testing of patients with heterogeneous inherited neuropathy, independently of their ethnic origin.
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http://dx.doi.org/10.1016/j.nmd.2019.12.007DOI Listing
March 2020

Nerve size correlates with clinical severity in Charcot-Marie-Tooth disease 1A.

Muscle Nerve 2019 12 10;60(6):744-748. Epub 2019 Sep 10.

Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Introduction: Nerve cross-sectional area (CSA) is larger than normal in Charcot-Marie-Tooth disease 1A (CMT1A), although to a variable extent. We explored whether CSA is correlated with CMT clinical severity measured with neuropathy score version 2 (CMTNS2) and its examination subscore (CMTES2) in CMT1A.

Methods: We assessed 56 patients with CMT1A (42 families). They underwent nerve conduction study (NCS) and nerve high-resolution ultrasound (HRUS) of the left median, ulnar, and fibular nerves.

Results: Univariate analysis showed NCS and HRUS variables to be significantly correlated with CMTNS2 and CMTES2 and with each other. Multivariate analysis showed that ulnar motor nerve conduction velocity (β: -0.19) and fibular compound muscle action potential amplitude (-1.50) significantly influenced CMTNS2 and that median forearm CSA significantly influenced CMTNS2 (β: 5.29) and CMTES2 (4.28).

Discussion: Nerve size is significantly associated with clinical scores in CMT1A, which suggests that it might represent a potential biomarker of CMT damage and progression.
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http://dx.doi.org/10.1002/mus.26688DOI Listing
December 2019

Intravenous thrombolysis for ischemic stroke in the Veneto region: the gap between eligibility and reality.

J Thromb Thrombolysis 2019 Jan;47(1):113-120

Stroke Unit, Azienda Ospedaliera Universitaria Integrata Verona, Piazzale Aristide Stefani, 1, 37126, Verona, Italy.

Intravenous thrombolysis (IVT) is the treatment of choice for most patients with acute ischemic stroke. According to the recently updated guidelines, IVT should be administered in absence of absolute exclusion criteria. We aimed to assess the proportion of ischemic strokes potentially eligible and actually treated with IVT, and to explore the reasons for not administering IVT. We prospectively collected and analyzed data from 1184 consecutive ischemic stroke patients admitted to the 22 Stroke Units (SUs) of the Veneto region from September 18th to December 10th 2017. Patients were treated with IVT according to the current Italian guidelines. For untreated patients, the reasons for not administering IVT were reported by each center in a predefined model including absolute and/or relative exclusion criteria and other possible reasons. Out of 841 (71%) patients who presented within 4.5 h of stroke onset, 704 (59%) had no other absolute exclusion criteria and were therefore potentially eligible for IVT according to the current guidelines. However, only 323 (27%) patients were eventually treated with IVT. Among 861 (73%) untreated patients, 480 had at least one absolute exclusion criterion, 283 only relative exclusion criteria, 56 only other reasons, and 42 a combination of relative exclusion criteria and other reasons. Our study showed that only 46% (323/704) of the potentially eligible patients were actually treated with IVT in the SUs of the Veneto region. All healthcare professionals involved in the acute stroke pathway should make an effort to bridge this gap between eligibility and reality.
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http://dx.doi.org/10.1007/s11239-018-1753-8DOI Listing
January 2019

Nerve ultrasound findings differentiate Charcot-Marie-Tooth disease (CMT) 1A from other demyelinating CMTs.

Clin Neurophysiol 2018 11 1;129(11):2259-2267. Epub 2018 Sep 1.

Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Neurology Division, Department of Neuroscience AOUI Verona, Verona, Italy. Electronic address:

Objective: Ulnar/median motor nerve conduction velocity (MNCV) is ≤38 m/s in demyelinating Charcot-Marie-Tooth disease (CMT). Previous nerve high resolution ultrasound (HRUS) studies explored demyelinating CMT assuming it as a homogeneous genetic/pathological entity or focused on CMT1A.

Methods: To explore the spectrum of nerve HRUS findings in demyelinating CMTs, we recruited patients with CMT1A (N = 44), CMT1B (N = 9), CMTX (N = 8) and CMT4C (N = 4). They underwent nerve conduction study (NCS) and HRUS of the median, ulnar, peroneal nerve, and the brachial plexus.

Results: Median, ulnar and peroneal MNCV significantly differed across CMT subtypes. Cross sectional area (CSA) was markedly and diffusely enlarged at all sites, except entrapment ones, in CMT1A, while it was slightly enlarged or within normal range in the other CMTs. No significant right-to-left difference was found. Age had limited effect on CSA. CSAs of some CMT1A patients largely overlapped with those of other demyelinating CMTs. A combination of three median CSA measures could separate CMT1A from other demyelinating CMTs.

Conclusions: Nerve HRUS findings are heterogeneous in demyelinating CMTs.

Significance: Nerve HRUS may separate CMT1A from other demyelinating CMTs. The large demyelinating CMTs HRUS spectrum may be related to its pathophysiological variability.
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http://dx.doi.org/10.1016/j.clinph.2018.08.016DOI Listing
November 2018

A cross-sectional study investigating frequency and features of definitely diagnosed diabetic painful polyneuropathy.

Pain 2018 Dec;159(12):2658-2666

Department of Human Neuroscience, University Sapienza, Rome, Italy.

This cross-sectional multicentre study aimed at investigating frequency and features of painful diabetic polyneuropathy. We consecutively enrolled 816 patients attending hospital diabetic outpatient clinics. We first definitely diagnosed diabetic polyneuropathy and pure small-fibre polyneuropathy using clinical examination, nerve conduction study, and skin biopsy or quantitative sensory testing. Adhering to widely agreed criteria, we then identified neuropathic pain and diagnosed painful polyneuropathy using a combined approach of clinical examination and diagnostic tests. Of the 816 patients, 36% had a diabetic polyneuropathy associated with male sex, age, and diabetes severity; 2.5% of patients had a pure small-fibre polyneuropathy, unrelated to demographic variables and diabetes severity. Of the 816 patients, 115 (13%) suffered from a painful polyneuropathy, with female sex as the only risk factor for suffering from painful polyneuropathy. In this large study, providing a definite diagnosis of diabetic polyneuropathy and pure small-fibre polyneuropathy, we show the frequency of painful polyneuropathy and demonstrate that this difficult-to-treat complication is more common in women than in men.
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http://dx.doi.org/10.1097/j.pain.0000000000001378DOI Listing
December 2018

Pain Modulation after Oromucosal Cannabinoid Spray (SATIVEX) in Patients with Multiple Sclerosis: A Study with Quantitative Sensory Testing and Laser-Evoked Potentials.

Medicines (Basel) 2018 Jun 21;5(3). Epub 2018 Jun 21.

Neurology Unit, Department of Neuroscience, AOUI Verona, 37126 Verona, Italy.

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) (nabiximols or Sativex) is an oromucosal spray formulation containing THC and CBD at an approximately 1:1 fixed ratio. Its administration for the treatment of pain in patients with multiple sclerosis (MS) has been established. MS patients generally complain of different kinds of pain, including spasticity-related and neuropathic pain. In this study, we compared and evaluated pain modulation and thermal/pain threshold of MS patients before and after THC/CBD administration. 19 MS patients underwent clinical examination, numerical rating scale (NRS), quantitative sensory testing (QST), and laser-evoked potentials (LEPs) before and after 1 month of therapy. Psychophysiological and neurophysiological data were compared to sex- and age-matched controls. Patients reported a significant reduction in pain. We found statistically significant differences in LEP parameters between patients and controls but no significant change in LEP measures after THC/CBD therapy. Cold and heat detection thresholds were altered in patients but did not change after THC/CBD therapy. There was a significant increase in cold pain threshold by hand stimulation and a significant reduction in abnormal cold perception thresholds. Our results indicate that Sativex therapy provides pain relief in MS patients and suggest that it might modulate peripheral cold-sensitive TRP channels.
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http://dx.doi.org/10.3390/medicines5030059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163235PMC
June 2018

Reply to "Relationship between age and nerve dimensions in Charcot-Marie-Tooth disease. Do we know the reality?"

Clin Neurophysiol 2018 06 22;129(6):1335-1336. Epub 2018 Mar 22.

Neurology Division, Pederzoli Hospital, Peschiera del Garda, Verona, Italy.

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http://dx.doi.org/10.1016/j.clinph.2018.03.003DOI Listing
June 2018

Novel Familial Variant of the Desert Hedgehog Gene: Clinical Findings in Two Sisters with 46,XY Gonadal Dysgenesis or 46,XX Karyotype and Literature Review.

Horm Res Paediatr 2018 22;89(3):141-149. Epub 2018 Feb 22.

Background: In humans, Desert Hedgehog (DHH) gene mutations are a very rare cause of 46,XY gonadal dysgenesis (GD), eventually associated with peripheral neuropathy.

Patients And Methods: Clinical records of 12 patients with 46,XY GD and unknown genetic background were reviewed and a 46,XY woman with peripheral neuropathy was individuated. Her 46,XX sister affected by similar neuropathy was also investigated. Genomic DNA was extracted and DHH exons sequenced and analyzed. A comparative genomic hybridization array was also performed.

Results: In both the 46,XY and 46,XX sisters, a homozygous c.554C>A mutation in exon 2 of the DHH gene was found, determining a premature termination codon (p.Ser 185*). Heterozygous consanguineous carrier parents showed neither reproductive problems nor peripheral neuropathy. In the proband and her sister, a 499-kb duplication in 9p22.1 was also found.

Conclusion: A 46,XY European woman with 46,XY GD and a novel homozygous DHH pathogenic variant is reported, confirming that this gene plays a key role in male gonadal development. Her 46,XX sister, harboring the same mutation, showed normal internal and external female phenotype. Thus, DHH seems not to be involved in the ovarian development pathway or its postpubertal function. Homozygous DHH mutations cause a specific peripheral neuropathy in humans with both 46,XY and 46,XX karyotypes.
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http://dx.doi.org/10.1159/000485507DOI Listing
September 2018

The spectrum of Charcot-Marie-Tooth disease due to myelin protein zero: An electrodiagnostic, nerve ultrasound and histological study.

Clin Neurophysiol 2018 01 20;129(1):21-32. Epub 2017 Oct 20.

Neurology Division, Pederzoli Hospital, Peschiera del Garda, Verona, Italy.

Objective: Nerve ultrasound (US) data on myelin protein zero (MPZ)-related Charcot-Marie-Tooth disease (CMT) are lacking. To offer a comprehensive perspective on MPZ-related CMTs, we combined nerve US with clinics, electrodiagnosis and histopathology.

Methods: We recruited 36 patients (12 MPZ mutations), and correlated nerve US to clinical, electrodiagnostic measures, and sural nerve biopsy.

Results: According to motor nerve conduction velocity (MNCV) criteria, nine patients were categorized as "demyelinating" CMT1B, 17 as "axonal" CMT2I/J, and 10 as dominant "intermediate" CMTDID. Sural nerve biopsy showed hypertrophic de-remyelinating neuropathy with numerous complex onion bulbs in one patient, de-remyelinating neuropathy with scanty/absent onion bulbs in three, axonal neuropathy in two, mixed demyelinating-axonal neuropathy in five. Electrodiagnosis significantly differed in CMT1B vs. CMT2I/J and CMTDID subgroups. CMT1B had slightly enlarged nerve cross sectional area (CSA) especially at proximal upper-limb (UL) sites. CSA was negatively correlated to UL MNCV and not increased at entrapment sites. Major sural nerve pathological patterns were uncorrelated to UL nerve US and MNCV.

Conclusions: Sural nerve biopsy confirmed the wide pathological spectrum of MPZ-CMT. UL nerve US identified two major patterns corresponding to the CMT1B and CMT2I/J-CMTDID subgroups.

Significance: Nerve US phenotype of MPZ-CMT diverged from those in other demyelinating peripheral neuropathies and may have diagnostic value.
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http://dx.doi.org/10.1016/j.clinph.2017.09.117DOI Listing
January 2018

Diagnosing mild cognitive impairment in Parkinson's disease: which tests perform best in the Italian population?

Neurol Sci 2017 Aug 26;38(8):1461-1468. Epub 2017 May 26.

Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Piazzale Scuro 10, 37134, Verona, Italy.

Mild cognitive impairment (MCI) is common in patients with Parkinson's disease (PD) and should be recognized early because it represents a predictor of PD-related dementia and worse disease course. Diagnostic criteria for PD-related MCI (PD-MCI) have recently been defined by a Movement Disorders Society (MDS) task force. The present study explored which neuropsychological tests perform best for a level II (i.e., comprehensive neuropsychological assessment) diagnosis of PD-MCI according to the MDS task force criteria in Italian-speaking PD patients. To this aim, we assessed a comprehensive 23-item neuropsychological battery, derived the best-performing 10-test battery (i.e., two tests per domain for each of the five cognitive domains), and explored its accuracy for diagnosing PD-MCI in comparison to the full battery in a group of PD patients. A secondary aim was to explore the role of this battery for subtyping PD-MCI according to single-domain vs. multiple-domain involvement. The 10-test battery showed 73% sensitivity and 100% specificity for diagnosing PD-MCI, and 69% sensitivity and 100% specificity for PD-MCI subtyping. In patients older than 70 years, we derived a slightly different 10-test battery with 84% sensitivity and 100% specificity for PD-MCI diagnosis, and 86% sensitivity and 100% specificity for PD-MCI subtyping. These 10-item neuropsychological batteries might represent a good trade-off between diagnostic accuracy and time of application, and their role in PD-MCI diagnosis and subtyping should be further explored in future prospective studies.
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http://dx.doi.org/10.1007/s10072-017-3000-zDOI Listing
August 2017

Electrodiagnosis of Lesions of Median and Ulnar Nerve Hand Sensory Branches: A Case Series.

J Clin Neurophysiol 2016 Oct;33(5):454-457

*Neurology Unit, Pederzoli Hospital, Peschiera del Garda, Italy; and†Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.

Introduction: The authors have recently tested a new electrodiagnostic technique for palmar proper digital nerves sensory nerve action potentials in normal controls. Here the authors explored whether it may offer additional information in comparison to mixed nerve wrist stimulation in a series of patients.

Methods: The authors recorded palmar proper digital nerves sensory nerve action potential to selective antidromic webspace stimulation in a group of 19 patients with suspected lesions of median and ulnar nerve hand sensory branches. Coexistent carpal tunnel syndrome was present in 11 patients.

Results: The webspace stimulation technique offered additional information in 89% patients when compared with mixed nerve wrist stimulation. Webspace stimulation was informative even when carpal tunnel syndrome coexisted with damage to hand sensory branches and biased the interpretation of conventional wrist nerve conduction study.

Conclusions: Webspace PaPDN stimulation is feasible in patients with lesion of median and ulnar nerve hand sensory branches and offer additional information in comparison with wrist-mixed nerve conduction study, also in patients with coexisting carpal tunnel syndrome.
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http://dx.doi.org/10.1097/WNP.0000000000000266DOI Listing
October 2016

Pathophysiology of Motor Dysfunction in Parkinson's Disease as the Rationale for Drug Treatment and Rehabilitation.

Parkinsons Dis 2016 6;2016:9832839. Epub 2016 Jun 6.

Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Piazzale Scuro 10, 37134 Verona, Italy.

Cardinal motor features of Parkinson's disease (PD) include bradykinesia, rest tremor, and rigidity, which appear in the early stages of the disease and largely depend on dopaminergic nigrostriatal denervation. Intermediate and advanced PD stages are characterized by motor fluctuations and dyskinesia, which depend on complex mechanisms secondary to severe nigrostriatal loss and to the problems related to oral levodopa absorption, and motor and nonmotor symptoms and signs that are secondary to marked dopaminergic loss and multisystem neurodegeneration with damage to nondopaminergic pathways. Nondopaminergic dysfunction results in motor problems, including posture, balance and gait disturbances, and fatigue, and nonmotor problems, encompassing depression, apathy, cognitive impairment, sleep disturbances, pain, and autonomic dysfunction. There are a number of symptomatic drugs for PD motor signs, but the pharmacological resources for nonmotor signs and symptoms are limited, and rehabilitation may contribute to their treatment. The present review will focus on classical notions and recent insights into the neuropathology, neuropharmacology, and neurophysiology of motor dysfunction of PD. These pieces of information represent the basis for the pharmacological, neurosurgical, and rehabilitative approaches to PD.
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http://dx.doi.org/10.1155/2016/9832839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913065PMC
July 2016

The Diagnostic Value of Nerve Ultrasound in an Atypical Palmar Cutaneous Nerve Lesion.

Am J Phys Med Rehabil 2016 07;95(7):e103-7

From the Neurology Section, Pederzoli Hospital, Peschiera del Garda, Italy (GZ); and Department of Neurological and Movement Sciences, University of Verona, Verona, Italy (ST).

Detailed knowledge of the fascicular anatomy of peripheral nerves is important for microsurgical repair and functional electrostimulation.We report a patient with a lesion on the left palmar cutaneous branch of the median nerve (PCBMN) and sensory signs expanding outside the PCBMN cutaneous innervation territory. Nerve conduction study showed the absence of left PCBMN sensory nerve action potential, but apparently, no median nerve (MN) involvement. Nerve ultrasound documented a neuroma of the left PCBMN and a coexistent lateral neuroma of the left MN in the carpal tunnel after the PCBMN left the main nerve trunk.Nerve ultrasound may offer important information in patients with peripheral nerve lesions and atypical clinical and/or nerve conduction study findings. The present case may shed some light on the somatotopy of MN fascicles at the wrist.
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http://dx.doi.org/10.1097/PHM.0000000000000468DOI Listing
July 2016

Screening for Mild Cognitive Impairment in Parkinson's Disease: Comparison of the Italian Versions of Three Neuropsychological Tests.

Parkinsons Dis 2015 8;2015:681976. Epub 2015 Nov 8.

Department of Neurological and Movement Sciences, University of Verona, Piazzale Scuro 10, 37134 Verona, Italy.

Mild cognitive impairment (MCI) is frequent in Parkinson's disease (PD). Recently proposed criteria for MCI in PD (PD-MCI) indicate level I diagnosis based on abbreviated assessment and level II based on comprehensive neuropsychological evaluation. The study explored the sensitivity and specificity of the Italian versions of three neuropsychological tests for level I diagnosis of PD-MCI. We recruited 100 consecutive PD patients. After screening for inclusion criteria, 43 patients were included. The sensitivity and specificity of the Mini Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and the Addenbrooke's Cognitive Examination Revised (ACE-R) in comparison to level II diagnosis of PD-MCI were examined. PD-MCI was diagnosed (level II) in 51% of patients. Disease duration was significantly longer and PD motor scales were more severely impaired in MCI group. The receiver-operator characteristics curve documented nonsignificant difference in the performance of the three tests, with slight advantage of MMSE (corrected data). The time of administration favored MMSE. In Italian-speaking PD patients, MMSE might represent a good screening tool for PD-MCI, because of the shorter time of administration and the performance comparable to those of MoCA and ACE-R. Further studies are needed to validate the new PD-MCI criteria across different languages and cultures.
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http://dx.doi.org/10.1155/2015/681976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655066PMC
December 2015

Damage to the Median and Ulnar Nerves After a Snake Bite.

Can J Neurol Sci 2015 Nov 17;42(6):448-9. Epub 2015 Aug 17.

2Department of Neurological and Movement Sciences,University of Verona,Verona,Italy.

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http://dx.doi.org/10.1017/cjn.2015.275DOI Listing
November 2015

Isolated musculocutaneous nerve injury in a kickboxer.

Muscle Nerve 2015 Dec 11;52(6):1137-9. Epub 2015 Sep 11.

Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.

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http://dx.doi.org/10.1002/mus.24783DOI Listing
December 2015

Unexpected Inching Explained by an Ulnar Nerve Anatomic Variant Documented by Sonography.

J Ultrasound Med 2015 Jul;34(7):1336-7

Neurology Unit, Pederzoli Hospital, Peschiera del Garda, Italy (G.Z., M.F.L.), Department of Neurological and Movement Sciences, University of Verona, Verona, Italy (S.T.).

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http://dx.doi.org/10.7863/ultra.34.7.1336DOI Listing
July 2015

The Association between Serum Cytokines and Damage to Large and Small Nerve Fibers in Diabetic Peripheral Neuropathy.

J Diabetes Res 2015 16;2015:547834. Epub 2015 Apr 16.

Department of Neurological and Movement Sciences, University of Verona, Piazzale Scuro 10, 37134 Verona, Italy.

Diabetic peripheral neuropathy (DPN) is a frequent complication of type 2 diabetes mellitus (DM) and may involve small and large peripheral nerve fibers. Recent evidence suggests a role of cytokines in DPN. The paper is aimed at exploring whether the serum concentration of cytokines is associated with small and large nerve fiber function and with neuropathic pain (NP). We recruited a group of 32 type 2 DM patients who underwent serum cytokines (TNF-α, IL-2, IL-4, IL-6, and IL-10) dosage as well as electrodiagnostic and quantitative sensory testing (QST) assessment to explore damage to large and small nerve fibers. Raised serum levels of IL-6 and IL-10 correlated with markers of large nerve fiber sensory and motor axonal damage. Raised IL-10 serum level was associated with signs of motor nerve demyelination. No differences were found in pain characteristics and electrodiagnostic and QST markers of small nerve fiber function in relation to cytokines serum levels. IL-6 and IL-10 serum levels were associated with large nerve fiber damage but not to small fibers function or NP. IL-6 and IL-10 cytokines might play a role in the pathogenesis of nerve fiber damage or represent a compensatory or neuroprotective mechanism.
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http://dx.doi.org/10.1155/2015/547834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415740PMC
February 2016

An electrodiagnostic technique for assessing palmar proper digital nerves of the hand: Normative data and clinical application.

Muscle Nerve 2015 Dec 15;52(6):972-80. Epub 2015 Sep 15.

Department of Neurological and Movement Sciences, University of Verona, Piazzale Scuro 10, I-37134, Verona, Italy.

Introduction: There is no standard electrodiagnostic technique for palmar proper digital nerves (PaPDNs). In this study we investigated sensory nerve action potentials (SNAPs) to PaPDN stimulation in normal subjects and patients.

Methods: SNAPs of PaPDNs were recorded in response to selective antidromic stimulation at the web space and mixed nerve stimulation at the wrist in 14 controls. The selectivity of PaPDN stimulation and the effect of recording electrode position on SNAP amplitude were studied. The technique was tested in 2 patients with PaPDN lesions.

Results: The technique yielded selective PaPDN stimulation at the web space. SNAP amplitude to PaPDN stimulation was influenced by age and was larger than SNAP amplitude to wrist stimulation. The recording electrode positions influenced SNAP amplitude. In patients, we documented PaPDN lesions, which were confirmed at surgery, whereas conventional wrist mixed nerve stimulation yielded negative findings.

Conclusions: Selective PaPDN stimulation at the web space is feasible and may be helpful for electrodiagnosis of PaPDN lesions.
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http://dx.doi.org/10.1002/mus.24668DOI Listing
December 2015

Neurological picture: Sunderland's median nerve fascicular anatomy revisited by ultrasound.

J Neurol Neurosurg Psychiatry 2016 Mar 18;87(3):338-9. Epub 2015 Feb 18.

Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.

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http://dx.doi.org/10.1136/jnnp-2014-310043DOI Listing
March 2016

Cognition and emotional decision-making in chronic low back pain: an ERPs study during Iowa gambling task.

Front Psychol 2014 25;5:1350. Epub 2014 Nov 25.

Department of General Psychology, University of Padova Padova, Italy ; Human Inspired Technologies Research Center, University of Padova Padova, Italy.

Previous reports documented abnormalities in cognitive functions and decision-making (DM) in patients with chronic pain, but these changes are not consistent across studies. Reasons for these discordant findings might include the presence of confounders, variability in chronic pain conditions, and the use of different cognitive tests. The present study was aimed to add evidence in this field, by exploring the cognitive profile of a specific type of chronic pain, i.e., chronic low back pain (cLBP). Twenty four cLBP patients and 24 healthy controls underwent a neuropsychological battery and we focused on emotional DM abilities by means of Iowa gambling task (IGT). During IGT, behavioral responses and the electroencephalogram (EEG) were recorded in 12 patients and 12 controls. Event-related potentials (ERPs) were averaged offline from EEG epochs locked to the feedback presentation (4000 ms duration, from 2000 ms before to 2000 ms after the feedback onset) separately for wins and losses and the feedback-related negativity (FRN) and P300 peak-to-peak amplitudes were calculated. Among cognitive measures, cLBP patients scored lower than controls in the modified card sorting test (MCST) and the score in this test was significantly influenced by pain duration and intensity. Behavioral IGT results documented worse performance and the absence of a learning process during the test in cLBP patients compared to controls, with no effect of pain characteristics. ERPs findings documented abnormal feedback processing in patients during IGT. cLBP patients showed poor performance in the MCST and the IGT. Abnormal feedback processing may be secondary to impingement of chronic pain in brain areas involved in DM or suggest the presence of a predisposing factor related to pain chronification. These abnormalities might contribute to the impairment in the work and family settings that often cLBP patients report.
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http://dx.doi.org/10.3389/fpsyg.2014.01350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243494PMC
December 2014