Publications by authors named "Giuseppe Cosentino"

72 Publications

A multinational consensus on dysphagia in Parkinson's disease: screening, diagnosis and prognostic value.

J Neurol 2021 Aug 21. Epub 2021 Aug 21.

Department of Clinical and Movement Neurosciences, UCL, Queen Square Institute of Neurology, London, UK.

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by a combination of motor and non-motor dysfunction. Dysphagia is a common symptom in PD, though it is still too frequently underdiagnosed. Consensus is lacking on screening, diagnosis, and prognosis of dysphagia in PD.

Objective: To systematically review the literature and to define consensus statements on the screening and the diagnosis of dysphagia in PD, as well as on the impact of dysphagia on the prognosis and quality of life (QoL) of PD patients.

Methods: A multinational group of experts in the field of neurogenic dysphagia and/or PD conducted a systematic revision of the literature published since January 1990 to February 2021 and reported the results according to PRISMA guidelines. The output of the research was then analyzed and discussed in a consensus conference convened in Pavia, Italy, where the consensus statements were drafted. The final version of statements was subsequently achieved by e-mail consensus.

Results: Eighty-five papers were used to inform the Panel's statements even though most of them were of Class IV quality. The statements tackled four main areas: (1) screening of dysphagia: timing and tools; (2) diagnosis of dysphagia: clinical and instrumental detection, severity assessment; (3) dysphagia and QoL: impact and assessment; (4) prognostic value of dysphagia; impact on the outcome and role of associated conditions.

Conclusions: The statements elaborated by the Consensus Panel provide a framework to guide the neurologist in the timely detection and accurate diagnosis of dysphagia in PD.
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http://dx.doi.org/10.1007/s00415-021-10739-8DOI Listing
August 2021

BoNT-A efficacy in high frequency migraine: an open label, single arm, exploratory study applying the PREEMPT paradigm.

Cephalalgia 2021 Aug 18:3331024211034508. Epub 2021 Aug 18.

Deptartment of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.

Introduction: In this open label, single-arm trial we evaluated the efficacy of onabotulinum toxin-A in the prevention of high-frequency episodic migraine (8-14 migraine days/month).

Methods: We enrolled 32 high-frequency episodic migraine subjects (age 44.8 ± 11.9 years, 11.0 ± 2.2 migraine days, 11.5 ± 2.1 headache days, 7 females). After a 28-day baseline period, subjects underwent 4 subsequent onabotulinum toxin-A treatments according to the phase III research evaluating migraine prophylaxis therapy (PREEMPT) paradigm, 12-weeks apart. The primary outcome was the reduction of monthly migraine days from baseline in the 12-week period following the last onabotulinum toxin-A treatment.

Results: Onabotulinum toxin-A reduced monthly migraine days by 3.68 days (-33.1%, p < 0.01). Thirty-nine percent of the patients experienced a ≥50% reduction in monthly migraine days. Onabotulinum toxin-A also reduced the number of headache days (-33.9%, p < 0.01) and the intake of acute medications (-22.9%, p = 0.03). Disability and quality of life (QoL) scores improved markedly (migraine disability assessment (MIDAS) -41.7%; migraine specific questionnaire (MSQ) -31.7%, p < 0.01).

Conclusions: The findings suggest that, when administered according to the PREEMPT paradigm, onabotulinum toxin-A is effective in the prevention of high-frequency episodic migraine. NCT04578782.
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http://dx.doi.org/10.1177/03331024211034508DOI Listing
August 2021

Neuropathological findings from COVID-19 patients with neurological symptoms argue against a direct brain invasion of SARS-CoV-2: A critical systematic review.

Eur J Neurol 2021 Aug 2. Epub 2021 Aug 2.

IRCCS Mondino Foundation, Pavia, Italy.

Background And Purpose: Neuropathological studies can elucidate the mechanisms of nervous system damage associated with SARS-CoV-2 infection. Despite literature on this topic is rapidly expanding, correlations between neurological symptoms and brain pathology findings in COVID-19 patients remain largely unknown.

Methods: We performed a systematic literature review on neuropathological studies in COVID-19, including 438 patients from 45 articles published by April 22, 2021. We retrieved quantitative data regarding demographic, clinical, and neuropathological findings. We carried out a Wilcoxon rank sum test or χ test to compare patients' subgroups based on different clinical and brain pathology features.

Results: Neuropathological findings in COVID-19 patients were microgliosis (52.5%), astrogliosis (45.6%), inflammatory infiltrates (44.0%), hypoxic-ischemic lesions (40.8%), edema (25.3%), and hemorrhagic lesions (20.5%). SARS-CoV-2 RNA and proteins were identified in brain specimens of 41.9% and 28.3% of subjects, respectively. Detailed clinical information was available from 245 patients (55.9%), and among them, 96 subjects (39.2%) had presented with neurological symptoms in association with typical COVID-19 manifestations. We found that: (i) the detection rate of SARS-CoV-2 RNA and proteins in brain specimens did not differ between patients with versus those without neurological symptoms; (ii) brain edema, hypoxic-ischemic lesions, and inflammatory infiltrates were more frequent in subjects with neurological impairment; (iii) neurological symptoms were more common among older individuals.

Conclusions: Our systematic revision of clinical correlates in COVID-19 highlights the pathogenic relevance of brain inflammatory reaction and hypoxic-ischemic damage rather than neuronal viral load. This analysis indicates that a more focused study design is needed, especially in the perspective of potential therapeutic trials.
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http://dx.doi.org/10.1111/ene.15045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444743PMC
August 2021

Electrokinesiographic Study of Oropharyngeal Swallowing in Neurogenic Dysphagia.

Dysphagia 2021 Jul 27. Epub 2021 Jul 27.

Clinical Neurophysiology Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100, Pavia, Italy.

Electrokinesiographic study of swallowing (EKSS) can be useful for the assessment of patients with suspected or overt neurogenic dysphagia. EKSS consists of multichannel recording of the electromyographic (EMG) activity of the suprahyoid/submental muscle complex (SHEMG), the EMG activity of the cricopharyngeal muscle (CPEMG), and the laryngopharyngeal mechanogram (LPM). The LPM is an expression of the mechanical changes that the laryngopharyngeal structures undergo during the pharyngeal phase of swallowing. This method allows detailed evaluation of the magnitude, duration and temporal relations of the different events that characterize oropharyngeal swallowing, and thus in-depth exploration both of physiological deglutition mechanisms and of pathophysiological features of swallowing in neurogenic dysphagia. Furthermore, EKSS can guide dysphagia treatment strategies, allowing identification of optimal solutions for single patients. For instance, CPEMG recording can identify incomplete or absent relaxation of the upper esophageal sphincter during the pharyngeal phase of swallowing, thus suggesting a therapeutic approach based on botulinum toxin injection into the cricopharyngeal muscle. More recently, the 'shape' of SHEMG and the reproducibility of both SHEMG and LPM over repeated swallowing acts have been implemented as novel electrokinesiographic parameters. These measures could be valuable for straightforward non-invasive investigation of dysphagia severity and response to dysphagia treatment in clinical practice.
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http://dx.doi.org/10.1007/s00455-021-10336-xDOI Listing
July 2021

Prolonged distal motor latency of median nerve does not improve diagnostic accuracy for CIDP.

J Neurol 2021 Jun 26. Epub 2021 Jun 26.

Dysimmune Neuropathies Unit, Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy.

Compression of the median nerve at the carpal tunnel can give demyelinating features and result in distal motor latency (DML) prolongation fulfilling the EFNS/PNS demyelinating criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). Accordingly, being carpal tunnel syndrome (CTS) common in the general population, the EFNS/PNS guidelines recommend excluding the DML of the median nerve when DML prolongation may be consistent with median neuropathy at the wrist from CTS. The main aims of this study were to verify whether the inclusion of DML of the median nerve (when consistent with CTS) could improve electrophysiological diagnostic accuracy for CIDP and if the median nerve at the carpal tunnel was more prone to demyelination. We analyzed electrophysiological data from 499 patients included consecutively into the Italian CIDP Database. According to the EFNS/PNS criteria, 352 patients had a definite, 10 a probable, and 57 a possible diagnosis of CIDP, while 80 were not fulfilling the diagnostic criteria. The inclusion of DML prolongation of median nerve did not improve significantly the diagnostic accuracy for CIDP; overall diagnostic class changed in 6 out of 499 patients (1.2%) and electrodiagnostic class of CIDP changed from not fulfilling to possible in only 2 patients (2.5% of not-fulfilling patients). In conclusion, we can infer that excluding DML prolongation of median nerve does not increase the risk of missing a diagnosis of CIDP thus corroborating the current EFNS/PNS criteria.
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http://dx.doi.org/10.1007/s00415-021-10672-wDOI Listing
June 2021

COVID-19 in patients with myasthenia gravis: Epidemiology and disease course.

Muscle Nerve 2021 08 12;64(2):206-211. Epub 2021 Jun 12.

Neuroncology Unit, IRCCS Mondino Foundation, Pavia, Italy.

Introduction/aims: Coronavirus disease 2019 (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has become a global pandemic. Patients with myasthenia gravis (MG), often treated with immunosuppressants, might be at higher risk of developing COVID-19 and of demonstrating a severe disease course. We aimed to study prevalence and describe features of COVID-19 in MG patients.

Methods: In May 2020, we conducted telephonic interviews with MG patients followed at our referral center. We collected structured data regarding MG and COVID-19, which was diagnosed as probable or confirmed according to the European Centre for Disease Prevention and Control case definition. We compared confirmed-COVID-19 prevalence calculated from the beginning of the pandemic in MG patients with that of the overall Pavia district.

Results: We interviewed 162 MG patients (median age, 66 y; interquartile range 41-77; males 59.9%), 88 from the Pavia district. Three patients had SARS-CoV-2-confirmed by polymerase chain reaction and eight had probable-COVID-19. In the Pavia district, the prevalence of confirmed-COVID-19 among MG patients (1/88, 1.14%) and overall population (4777/546 515, 0.87%) did not differ (P = .538). Higher Myasthenia Gravis Foundation of America clinicalclass and the need for recent rescue treatment, but not ongoing immunosuppressive treatments, were associated with COVID-19 risk. Of 11 MG patients with probable/confirmed-COVID-19, 3 required ventilator support, and 2 elderly patients died of COVID-19 respiratory insufficiency. Only 1 of11 patients experienced worsening MG symptoms, which improved after increasing their steroid dose.

Discussion: The risk of COVID-19 in MG patients seems to be no higher than that of the general population, regardless of immunosuppressive therapies. In our cohort, COVID-19 barely affected MG course.
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http://dx.doi.org/10.1002/mus.27324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242475PMC
August 2021

The neurophysiological lesson from the Italian CIDP database.

Neurol Sci 2021 May 21. Epub 2021 May 21.

Dysimmune Neuropathies Unit, Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy.

Introduction: Electrophysiological diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) may be challenging. Thus, with the aim ofproviding some practical advice in electrophysiological approach to a patient with suspected CIDP, we analyzed electrophysiological data from 499 patients enrolled inthe Italian CIDP Database.

Methods: We calculated the rate of each demyelinating feature, the rate of demyelinating features per nerve, the diagnostic rate for upper andlower limb nerves, and, using a ROC curve analysis, the diagnostic accuracy of each couple of nerves and each demyelinating feature, for every CIDP subtype.Moreover, we compared the electrophysiological data of definite and probable CIDP patients with those of possible and not-fulfilling CIDP patients, and by a logisticregression analysis, we estimated the odds ratio (OR) to make an electrophysiological diagnosis of definite or probable CIDP.

Results: The ulnar nerve had the highestrate of demyelinating features and, when tested bilaterally, had the highest diagnostic accuracy except for DADS in which peroneal nerves were the most informative.In possible and not-fulfilling CIDP patients, a lower number of nerves and proximal temporal dispersion (TD) measurements had been performed compared to definiteand probable CIDP patients. Importantly, OR for each tested motor nerve and each TD measurement was 1.59 and 1.33, respectively.

Conclusion: Our findingsdemonstrated that the diagnosis of CIDP may be missed due to inadequate or incomplete electrophysiological examination or interpretation. At the same time, thesedata taken together could be useful to draw a thoughtful electrophysiological approach to patients suspected of CIDP.
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http://dx.doi.org/10.1007/s10072-021-05321-zDOI Listing
May 2021

Expression pattern of matrix metalloproteinases-2 and -9 and their tissue inhibitors in patients with chronic inflammatory demyelinating polyneuropathy.

Neurol Sci 2021 Oct 14;42(10):4297-4300. Epub 2021 May 14.

Department of Biomedicine, Neuroscience and advanced Diagnostic, University of Palermo (BIND), Palermo, Italy.

Background: Matrix metalloproteinases (MMPs) are a heterogeneous family of endopeptidases that play a role in many physiological functions, including the immune response. An imbalance between the activity of MMPs and their physiological tissue inhibitors (TIMPs) has been proposed in the pathophysiology of different autoimmune disorders. We aimed to assess the plasmatic levels of MMP-2, MMP-9, and their inhibitors TIMP-1 and -2 in patients with chronic inflammatory demyelinating polyneuropathy (CIDP).

Subjects And Methods: Twenty patients with CIDP and 20 age- and sex-matched healthy controls were enrolled. Plasma concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2 were determined by the enzyme-linked immunosorbent assay.

Results: CIDP subjects had higher MMP-9 concentrations along with TIMP-1 downregulation when compared to controls, with the consequent increase in the MMP-9/TIMP-1 ratio (p<0.000002 for all measures). Conversely, the concentration of MMP-2 was lower in the CIDP group (p<0.01) without changes in the TIMP-2 concentration. The MMP-2/TIMP-2 ratio was decreased in the patients' group (p<0.02).

Discussion: We provide first preliminary evidence that the plasmatic pattern of MMPs and TIMPs is markedly altered in patients with CIDP. Future studies are needed to assess the potential usefulness of these new biomarkers in the clinical setting.
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http://dx.doi.org/10.1007/s10072-021-05314-yDOI Listing
October 2021

RFC1 expansions are a common cause of idiopathic sensory neuropathy.

Brain 2021 06;144(5):1542-1550

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.

After extensive evaluation, one-third of patients affected by polyneuropathy remain undiagnosed and are labelled as having chronic idiopathic axonal polyneuropathy, which refers to a sensory or sensory-motor, axonal, slowly progressive neuropathy of unknown origin. Since a sensory neuropathy/neuronopathy is identified in all patients with genetically confirmed RFC1 cerebellar ataxia, neuropathy, vestibular areflexia syndrome, we speculated that RFC1 expansions could underlie a fraction of idiopathic sensory neuropathies also diagnosed as chronic idiopathic axonal polyneuropathy. We retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy) from our general neuropathy clinics in Italy and the UK. All patients underwent full neurological evaluation and a blood sample was collected for RFC1 testing. Biallelic RFC1 expansions were identified in 43 patients (34%) with sensory neuropathy and in none with sensory-motor neuropathy. Forty-two per cent of RFC1-positive patients had isolated sensory neuropathy or sensory neuropathy with chronic cough, while vestibular and/or cerebellar involvement, often subclinical, were identified at examination in 58%. Although the sensory ganglia are the primary pathological target of the disease, the sensory impairment was typically worse distally and symmetric, while gait and limb ataxia were absent in two-thirds of the cases. Sensory amplitudes were either globally absent (26%) or reduced in a length-dependent (30%) or non-length dependent pattern (44%). A quarter of RFC1-positive patients had previously received an alternative diagnosis, including Sjögren's syndrome, sensory chronic inflammatory demyelinating polyneuropathy and paraneoplastic neuropathy, while three cases had been treated with immune therapies.
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http://dx.doi.org/10.1093/brain/awab072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262986PMC
June 2021

Camptocormia in idiopathic normal pressure hydrocephalus: a case report.

Acta Neurol Belg 2021 Apr 3. Epub 2021 Apr 3.

Clinical Neurophysiology Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100, Pavia, Italy.

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http://dx.doi.org/10.1007/s13760-021-01666-6DOI Listing
April 2021

Clinical and Electrophysiological Outcome Measures of Patients With Post-Infectious Neurological Syndromes Related to COVID-19 Treated With Intensive Neurorehabilitation.

Front Neurol 2021 12;12:643713. Epub 2021 Mar 12.

Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

The clinical spectrum of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, may be quite wide, including neurological symptoms. Among them, para-infectious or post-infectious neurological syndromes (PINS), caused by an inflammatory response against the central and/or peripheral nervous system, have been reported. The aim of this paper is to illustrate the functional and neurophysiological recovery in a series of subjects with COVID-19-related PINS who underwent intensive neurorehabilitation. Five patients with PINS associated with COVID-19 were evaluated at baseline and followed up for 6 months. Three of them had polyradiculoneuropathy and two patients had myelitis. The onset of the neurological syndromes was temporally associated with the SARS-CoV-2 infection. After completing the acute neurological treatments in the intensive care unit, patients underwent a personalized multidisciplinary rehabilitation program. An in-depth clinical, functional, and electrophysiological assessment was carried out at baseline and at 3- and 6-month follow-ups. Among patients with polyradiculoneuropathy, the electrophysiological evaluation at baseline disclosed an acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in two patients and an acute motor and sensory axonal neuropathy (AMSAN) in the third patient. At follow-up, the electrophysiological features improved in one subject with AIDP and were stable in the remaining two cases. The functional assessment after neurorehabilitation showed global recovery and full independence in walking and in activities of daily life in one patient and mild improvement in the other two cases. Of the two subjects with myelitis, the baseline electrophysiological examination showed a prolonged central motor conduction time, which returned to normal in one patient, whereas it improved but remained pathological in the other patient at follow-up. The neurorehabilitation led to a substantial functional improvement in both subjects. This is the first study to describe clinical and electrophysiological aspects along with medium-term outcome in patients with COVID-19-related neurological manifestations who underwent an intensive rehabilitation program. The functional outcome following neurorehabilitation in patients with PINS related to SARS-CoV-2 infection is variable. In our small case series, subjects with polyradiculoneuropathy had a poorer recovery compared to patients with myelitis. The clinical course largely paralleled the follow-up electrophysiological findings.
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http://dx.doi.org/10.3389/fneur.2021.643713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994589PMC
March 2021

Electrophysiological features of acute inflammatory demyelinating polyneuropathy associated with SARS-CoV-2 infection.

Neurophysiol Clin 2021 Mar 18;51(2):183-191. Epub 2021 Feb 18.

Statistics Unit, Department of Economics, University "G. d'Annunzio", Pescara, Italy.

Objective: To assess whether patients with acute inflammatory demyelinating polyneuropathy (AIDP) associated with SARS-CoV-2 show characteristic electrophysiological features.

Methods: Clinical and electrophysiological findings of 24 patients with SARS-CoV-2 infection and AIDP (S-AIDP) and of 48 control AIDP (C-AIDP) without SARS-CoV-2 infection were compared.

Results: S-AIDP patients more frequently developed respiratory failure (83.3% vs. 25%, P=0.000) and required intensive care unit (ICU) hospitalization (58.3% vs. 31.3%, P=0.000). In C-AIDP, distal motor latencies (DMLs) were more frequently prolonged (70.9% vs. 26.2%, P=0.000) whereas in S-AIDP distal compound muscle action potential (dCMAP) durations were more frequently increased (49.5% vs. 32.4%, P=0.002) and F waves were more often absent (45.6% vs. 31.8%, P=0.011). Presence of nerves with increased dCMAP duration and normal or slightly prolonged DML was elevenfold higher in S-AIDP (31.1% vs. 2.8%, P=0.000);11 S-AIDP patients showed this pattern in 2 nerves.

Conclusion: Increased dCMAP duration, thought to be a marker of acquired demyelination, can also be oserved in critical illness myopathy. In S-AIDP patients, an increased dCMAP duration dissociated from prolonged DML, suggests additional muscle fiber conduction slowing, possibly due to a COVID-19-related hyperinflammatory state. Absent F waves, at least in some S-AIDP patients, may reflect α-motor neuron hypoexcitability because of immobilization during the ICU stay. These features should be considered in the electrodiagnosis of SARS-CoV-2 patients with weakness, to avoid misdiagnosis.
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http://dx.doi.org/10.1016/j.neucli.2021.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891083PMC
March 2021

Isolated bulbar palsy after SARS-CoV-2 infection.

Lancet Neurol 2021 03;20(3):169-170

Clinical Neurophysiology Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1016/S1474-4422(21)00025-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906749PMC
March 2021

Guillain-Barré syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions.

J Neurol Neurosurg Psychiatry 2021 07 6;92(7):751-756. Epub 2020 Nov 6.

Unit of Neurology, ASST Valcamonica, Esine (Bs), Italy.

Objective: Single cases and small series of Guillain-Barré syndrome (GBS) have been reported during the SARS-CoV-2 outbreak worldwide. We evaluated incidence and clinical features of GBS in a cohort of patients from two regions of northern Italy with the highest number of patients with COVID-19.

Methods: GBS cases diagnosed in 12 referral hospitals from Lombardy and Veneto in March and April 2020 were retrospectively collected. As a control population, GBS diagnosed in March and April 2019 in the same hospitals were considered.

Results: Incidence of GBS in March and April 2020 was 0.202/100 000/month (estimated rate 2.43/100 000/year) vs 0.077/100 000/month (estimated rate 0.93/100 000/year) in the same months of 2019 with a 2.6-fold increase. Estimated incidence of GBS in COVID-19-positive patients was 47.9/100 000 and in the COVID-19-positive hospitalised patients was 236/100 000. COVID-19-positive patients with GBS, when compared with COVID-19-negative subjects, showed lower MRC sum score (26.3±18.3 vs 41.4±14.8, p=0.006), higher frequency of demyelinating subtype (76.6% vs 35.3%, p=0.011), more frequent low blood pressure (50% vs 11.8%, p=0.017) and higher rate of admission to intensive care unit (66.6% vs 17.6%, p=0.002).

Conclusions: This study shows an increased incidence of GBS during the COVID-19 outbreak in northern Italy, supporting a pathogenic link. COVID-19-associated GBS is predominantly demyelinating and seems to be more severe than non-COVID-19 GBS, although it is likely that in some patients the systemic impairment due to COVID-19 might have contributed to the severity of the whole clinical picture.
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http://dx.doi.org/10.1136/jnnp-2020-324837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650204PMC
July 2021

A Rare Syndrome Causing Neurogenic Dysphagia.

Dysphagia 2020 Nov 4. Epub 2020 Nov 4.

Clinical Neurophysiology Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100, Pavia, Italy.

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http://dx.doi.org/10.1007/s00455-020-10208-wDOI Listing
November 2020

Severe breathlessness in Stiff person syndrome (SPS). Looking under the bonnet.

J Neurol Sci 2020 11 18;418:117144. Epub 2020 Sep 18.

Institute for Biomedical Research and Innovation, National Research Council, Palermo, Italy.

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http://dx.doi.org/10.1016/j.jns.2020.117144DOI Listing
November 2020

Frequency of diabetes and other comorbidities in chronic inflammatory demyelinating polyradiculoneuropathy and their impact on clinical presentation and response to therapy.

J Neurol Neurosurg Psychiatry 2020 10 31;91(10):1092-1099. Epub 2020 Aug 31.

Unit of Neurology, ASST 'Spedali Civili', University of Brescia, Brescia, Italy.

Objectives: To determine the prevalence of different comorbidities in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and their impact on outcome, treatment choice and response.

Methods: Using a structured questionnaire, we collected information on comorbidities from 393 patients with CIDP fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society criteria included in the Italian CIDP database.

Results: One or more comorbidities were reported by 294 patients (75%) and potentially influenced treatment choice in 192 (49%) leading to a less frequent use of corticosteroids. Response to treatment did not differ, however, from that in patients without comorbidities. Diabetes (14%), monoclonal gammopathy of undetermined significance (MGUS) (12%) and other immune disorders (16%) were significantly more frequent in patients with CIDP than expected in the general European population. Patients with diabetes had higher disability scores, worse quality of life and a less frequent treatment response compared with patients without diabetes. Patients with IgG-IgA or IgM MGUS had an older age at CIDP onset while patients with other immune disorders had a younger age at onset and were more frequently females. IgM MGUS was more frequent in patients with motor CIDP than in patients with typical CIDP.

Conclusions: Comorbidities are frequent in patients with CIDP and in almost 50% of them have an impact on treatment choice. Diabetes, MGUS and other immune diseases are more frequent in patients with CIDP than in the general population. Only diabetes seems, however, to have an impact on disease severity and treatment response possibly reflecting in some patients a coexisting diabetic neuropathy.
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http://dx.doi.org/10.1136/jnnp-2020-323615DOI Listing
October 2020

KCTD17-related myoclonus-dystonia syndrome: clinical and electrophysiological findings of a patient with atypical late onset.

Parkinsonism Relat Disord 2020 09 6;78:129-133. Epub 2020 Aug 6.

Clinical Neurophysiology Unit, IRCCS Mondino Foundation, Pavia, Italy.

Introduction: Myoclonus-dystonia is a rare syndrome typically occurring during childhood or adolescence, mainly due to SGCE pathogenic variants. Early-onset, atypical presentations of myoclonus-dystonia have recently been associated with KCTD17 variants. In these cases, laryngeal involvement was reported in the advanced stages.

Methods: We evaluated a 52-year-old man with myoclonus-dystonia and positive family history. He underwent an electromyographic investigation of vocal cord and forearm muscles. Whole-exome sequencing was also performed.

Results: Onset of symptoms was at 51 years with dysphonia and vocal tremor. Electromyography disclosed abductor spasmodic dysphonia and laryngeal myoclonus. The patient later developed writer's cramp, upper limb myoclonus, and blepharospasm. Botulinum toxin injection led to improvement of the writer's cramp and to a lesser extent of the spasmodic dysphonia. Genetic analysis identified a heterozygous missense variant in exon 2 of KCTD17: c.229 C > A (p.Leu77Ile), consistently predicted as damaging.

Conclusions: We suggest that the KCTD17-associated phenotypic spectrum may include late onset (even in late adulthood) as well as early and prominent laryngeal involvement.
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http://dx.doi.org/10.1016/j.parkreldis.2020.07.026DOI Listing
September 2020

Reproducibility and reaction time of swallowing as markers of dysphagia in parkinsonian syndromes.

Clin Neurophysiol 2020 09 9;131(9):2200-2208. Epub 2020 Jul 9.

Clinical Neurophysiology Unit, IRCCS Mondino Foundation, Pavia, Italy.

Objective: To investigate reproducibility and reaction time of oropharyngeal swallowing in patients with Parkinson's disease (PD) and atypical parkinsonisms (APs).

Methods: We enrolled 19 patients with PD, 30 with APs, and 20 healthy subjects. Presence and severity of dysphagia were assessed with clinical and fiberoptic endoscopic evaluations of swallowing. Reproducibility of the oral and pharyngeal phases of swallowing were respectively assessed by calculating the 'similarity index' of the electromyography activity of the submental/suprahyoid muscles and of the laryngeal-pharyngeal mechanogram during consecutive swallows. These were performed both 'on command' and spontaneously. The swallowing reaction time was also recorded.

Results: Reproducibility of the oral phase of swallowing was reduced in patients with dysphagia, mainly when swallowing 'on command'. Swallowing reaction time was prolonged in dysphagic patients. These electrophysiological parameters did not vary among different parkinsonian syndromes and correlated with dysphagia severity.

Conclusions: Increased variability of oral swallowing automatisms and abnormal sensorimotor integration may be of relevance for the pathophysiology of dysphagia in parkinsonian syndromes.

Significance: The electrophysiological assessment represents a valuable tool to investigate swallowing alterations in parkinsonian syndromes. It may also provide useful insights into clinical severity and pathophysiology of dysphagia, giving clues for the choice of the best therapeutic approach.
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http://dx.doi.org/10.1016/j.clinph.2020.06.018DOI Listing
September 2020

Sensitivity and specificity of a commercial ELISA test for anti-MAG antibodies in patients with neuropathy.

J Neuroimmunol 2020 08 8;345:577288. Epub 2020 Jun 8.

Neuromuscular and Neuroimmunology Service, Humanitas Clinical and Research Institute, Rozzano, Milan, Italy; Department of Medical Biotechnology and Translational Medicine, Milan University, Milan, Italy.

For the diagnosis of anti-MAG polyneuropathy the commercial ELISA manufacturer currently recommends a cut-off of 1000 Bühlmann Titer Units (BTU). We analyzed sera from 80 anti-MAG neuropathy patients and 383 controls (with other neuropathies or healthy controls) to assess the ELISA sensitivity and specificity at different thresholds. A better combination of sensitivity/specificity was found at a threshold >1500 BTU than at >1000 BTU. The best value of specificity was obtained at threshold >7000 BTU. There was a diagnostic grey area between 1500 and 7000 BTU in which the clinical phenotypes as well as electrophysiological studies need to be carefully assessed particularly to differentiate CIDP and anti-MAG neuropathy.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577288DOI Listing
August 2020

Impact of environmental factors and physical activity on disability and quality of life in CIDP.

J Neurol 2020 Sep 19;267(9):2683-2691. Epub 2020 May 19.

University of Pavia, Pavia, Italy.

A few observational studies and randomized trials suggest that exercise and rehabilitation may improve activity limitation and quality of life (QoL) in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but the impact of other modifiable factors on the severity of the disease is not well understood. Using a structured questionnaire, we collected data on lifestyle and dietary habits of the patients included in the Italian CIDP database to investigate the possible influence of modifiable lifestyle factors on disability and QoL. Questionnaire data were available for 323 patients. The effect of lifestyle and dietary exposures on impairment, disability and QoL was evaluated using logistic regression models, adjusting for age, sex, disease duration, physical activity and smoking. Physical activity was associated with lower sensory impairment by the ISS scale, less disability by the INCAT and RODS scale and a better QoL in all the domains of EURO-QoL scale with the exception of anxiety/depression. None of the other parameters had an impact on these scales. This study adds evidence to the possible role of physical activity in improving symptom severity, disability and QoL in patients with CIDP. None of the other environmental factors investigated appeared to have an impact on the severity and health perception of CIDP.
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http://dx.doi.org/10.1007/s00415-020-09916-yDOI Listing
September 2020

RELEVANCE OF DIAGNOSTIC INVESTIGATIONS IN CHRONIC INFLAMMATORY DEMYELINATING POLIRADICULONEUROPATHY: DATA FROM THE ITALIAN CIDP DATABASE.

J Peripher Nerv Syst 2020 04 28. Epub 2020 Apr 28.

Neuromuscular and Neuroimmunology Service, Humanitas Clinical and Research Institute, Rozzano, Milan, Italy.

Background and aims to report the clinical features and the relevance of diagnostic investigations in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We retrospectively reviewed data from patients with a clinical diagnosis of CIDP included in a national database. Among the 500 included patients with a clinical diagnosis of CIDP, 437 patients (87%) fulfilled the EFNS/PNS criteria for CIDP (definite in 407, probable in 26, possible in four). In 352 patients (86%) motor nerve conduction abnormalities consistent with demyelination were sufficient for the diagnosis of definite CIDP. In 55 patients this diagnosis required the addition of one or two (from probable or from possible CIDP, respectively) supportive tests, while in 20 cases they improved the diagnosis from possible to probable CIDP, seven patients did not change diagnosis. Considering these 85 patients, CSF studies were performed in 79 cases (93%) upgrading the certainty of diagnosis in 59% of examined patients. Sensory nerve conduction studies were performed in 85% of patients with an improvement of diagnosis in 32% of cases. Nerve biopsy and US/MRI exams resulted positive in about 40% of examined patients, but they were performed in few patients (7 patients and 16 patients, respectively). A response to therapy was present in 84% of treated patients (n = 77), contributing to support the diagnosis in 40 patients in whom the other supportive criteria were not sufficient. In most patients with CIDP the diagnosis is possible solely with motor nerve conduction studies while other investigations may help improving the diagnosis in a minority of patients. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/jns.12378DOI Listing
April 2020

Intranasal midazolam for treating acute respiratory crises in a woman with stiff person syndrome.

Neurol Neuroimmunol Neuroinflamm 2020 07 1;7(4). Epub 2020 Apr 1.

From the Department of Brain and Behavioral Sciences (G. Cosentino, C.T.), University of Pavia; Clinical Neurophysiology Unit (G. Cosentino, E.A.), IRCCS Mondino Foundation, Pavia; Neurophysiopathology Department (M.R.), Villa Sofia-Cervello Hospital; Division of Pulmonology (DIBIMIS) (M.A.), Department of Internal Medicine, Villa Sofia-Cervello Hospital, Palermo; Department of Biomedicine Neuroscience and Advanced Diagnostics (F.B.), University of Palermo; Neurorehabilitation Unit (C.T.), IRCCS Mondino Foundation, Pavia; and Institute for Biomedical Research and Innovation (G. Crescimanno), Italian National Research Council, Palermo; Centre for Respiratory Complications of Neuromuscular Rare Disease (G. Crescimanno), Villa Sofia-Cervello Hospital, Palermo, Italy.

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http://dx.doi.org/10.1212/NXI.0000000000000715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176251PMC
July 2020

Anodal transcranial direct current stimulation and intermittent theta-burst stimulation improve deglutition and swallowing reproducibility in elderly patients with dysphagia.

Neurogastroenterol Motil 2020 05 23;32(5):e13791. Epub 2020 Jan 23.

Clinical Neurophysiology Unit, IRCCS Mondino Foundation, Pavia, Italy.

Background: Dysphagia in the elderly, known as presbydysphagia, has become a relevant public health problem in several countries. Swallowing disorders may be a consequence of different neurological disorders (secondary presbydysphagia) or the expression of the aging process itself (primary presbydysphagia). We aimed to test the therapeutic potential of two different non-invasive brain stimulation (NIBS) techniques in subjects with primary or secondary presbydysphagia.

Methods: A blinded randomized controlled trial with crossover design was carried out in 42 patients, randomly assigned to anodal transcranial direct current stimulation (tDCS) or intermittent theta-burst stimulation (TBS) group. Both tDCS and TBS were applied for 5 consecutive days over the right swallowing motor cortex. The swallowing function was assessed before and 1 and 3 months after the stimulation using the Dysphagia Outcome and Severity Scale (DOSS), scored based on clinical assessment and fiberoptic endoscopic evaluation of swallowing. An electrophysiological method was also applied to evaluate changes in the reproducibility of the swallowing behavior.

Key Results: Both real tDCS and TBS had beneficial effects on the swallowing function in patients with primary and secondary presbydysphagia. Anodal tDCS resulted in an improvement of 0.5 points in DOSS at 1-month follow-up (P = .014), whereas intermittent TBS induced an increase of 0.7 and 0.6 points at 1- and 3-month follow-up evaluations, respectively (P = .0001 and P = .005, respectively). Reproducibility of both the oral and pharyngeal phases of swallowing significantly increased at 1-month follow-up.

Conclusions And Inferences: Our results suggest that non-invasive cortical stimulation may be useful for dysphagia recovery in elderly patients.
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http://dx.doi.org/10.1111/nmo.13791DOI Listing
May 2020

Multisensorial Perception in Chronic Migraine and the Role of Medication Overuse.

J Pain 2020 Jul - Aug;21(7-8):919-929. Epub 2020 Jan 3.

Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, Palermo, Italy. Electronic address:

Multisensory processing can be assessed by measuring susceptibility to crossmodal illusions such as the Sound-Induced Flash Illusion (SIFI). When a single flash is accompanied by 2 or more beeps, it is perceived as multiple flashes (fission illusion); conversely, a fusion illusion is experienced when more flashes are matched with a single beep, leading to the perception of a single flash. Such illusory perceptions are associated to crossmodal changes in visual cortical excitability. Indeed, increasing occipital cortical excitability, by means of transcranial electrical currents, disrupts the SIFI (ie, fission illusion). Similarly, a reduced fission illusion was shown in patients with episodic migraine, especially during the attack, in agreement with the pathophysiological model of cortical hyperexcitability of this disease. If episodic migraine patients present with reduced SIFI especially during the attack, we hypothesize that chronic migraine (CM) patients should consistently report less illusory effects than healthy controls; drugs intake could also affect SIFI. On such a basis, we studied the proneness to SIFI in CM patients (n = 63), including 52 patients with Medication Overuse Headache (MOH), compared to 24 healthy controls. All migraine patients showed reduced fission phenomena than controls (P < .0001). Triptan MOH patients (n = 23) presented significantly less fission effects than other CM groups (P = .008). This exploratory study suggests that CM - both with and without medication overuse - is associated to a higher visual cortical responsiveness which causes deficit of multisensorial processing, as assessed by the SIFI. PERSPECTIVE: This observational study shows reduced susceptibility to the SIFI in CM, confirming and extending previous results in episodic migraine. MOH contributes to this phenomenon, especially in case of triptans.
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http://dx.doi.org/10.1016/j.jpain.2019.12.005DOI Listing
January 2020

Vocal cord electromyographic correlates of stridor in multiple system atrophy phenotypes.

Parkinsonism Relat Disord 2020 01 27;70:31-35. Epub 2019 Nov 27.

Parkinson's Disease and Movement Disorders Unit, IRCCS Mondino Foundation, Pavia, Italy.

Introduction: Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by dysautonomia in combination with parkinsonian and cerebellar signs. Stridor may also occur and it is associated with life-threatening events and poor prognosis. The pathophysiology of stridor in MSA is still debated.

Objective: To define correlations between diurnal electromyographic (EMG) abnormalities of vocal cord muscles and stridor in MSA phenotypes.

Methods: We recruited 60 patients with "probable" MSA (45 with parkinsonian [MSA-P] and 15 with cerebellar phenotype [MSA-C]). Nocturnal stridor was detected with video-polysomnography, whereas diurnal stridor was clinically noted when present. A diurnal kinesiologic EMG study of the adductor thyroarytenoid and the abductor posterior cricoarytenoid muscles was also performed.

Results: Among subjects with nocturnal stridor, MSA-P patients predominantly showed a paradoxical burst-like activation of the adductor thyroarytenoid muscle during inspiration. This dystonic pattern was associated with nocturnal stridor in MSA-P (odds ratio [OR] = 23.64, 95% confidence interval [CI] 3.42-70.77, p < 0.001). Conversely, MSA-C patients with nocturnal stridor mainly had additional neurogenic findings of vocal cord muscles. This dystonic-plus pattern correlated with nocturnal stridor in MSA-C (OR = 17.21, 95% CI 4.17-74.92, p < 0.01). The findings of diurnal stridor paralleled the observations for nocturnal stridor.

Conclusions: The pathophysiology of stridor may differ between MSA phenotypes, possibly related to dysfunctional supranuclear mechanisms in MSA-P (dystonic pattern) and to additional nuclear damage in MSA-C (dystonic-plus pattern).
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http://dx.doi.org/10.1016/j.parkreldis.2019.11.025DOI Listing
January 2020

Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP: Clinical relevance of IgG isotype.

Neurol Neuroimmunol Neuroinflamm 2020 01 21;7(1). Epub 2019 Nov 21.

From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico "Carlo Besta," Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples "Federico II," Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi "Bonino Pulejo" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences "Luigi Sacco" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.

Objective: To assess the prevalence and isotypes of anti-nodal/paranodal antibodies to nodal/paranodal proteins in a large chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cohort, compare clinical features in seronegative vs seropositive patients, and gather evidence of their isotype-specific pathogenic role.

Methods: Antibodies to neurofascin-155 (Nfasc155), neurofascin-140/186 (Nfasc140/186), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1) were detected with ELISA and/or cell-based assay. Antibody pathogenicity was tested by immunohistochemistry on skin biopsy, intraneural injection, and cell aggregation assay.

Results: Of 342 patients with CIDP, 19 (5.5%) had antibodies against Nfasc155 (n = 9), Nfasc140/186 and Nfasc155 (n = 1), CNTN1 (n = 3), and Caspr1 (n = 6). Antibodies were absent from healthy and disease controls, including neuropathies of different causes, and were mostly detected in patients with European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite CIDP (n = 18). Predominant antibody isotypes were immunoglobulin G (IgG)4 (n = 13), IgG3 (n = 2), IgG1 (n = 2), or undetectable (n = 2). IgG4 antibody-associated phenotypes included onset before 30 years, severe neuropathy, subacute onset, tremor, sensory ataxia, and poor response to intravenous immunoglobulin (IVIG). Immunosuppressive treatments, including rituximab, cyclophosphamide, and methotrexate, proved effective if started early in IVIG-resistant IgG4-seropositive cases. Five patients with an IgG1, IgG3, or undetectable isotype showed clinical features indistinguishable from seronegative patients, including good response to IVIG. IgG4 autoantibodies were associated with morphological changes at paranodes in patients' skin biopsies. We also provided preliminary evidence from a single patient about the pathogenicity of anti-Caspr1 IgG4, showing their ability to penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN1/Caspr1 complex.

Conclusions: Our findings confirm previous data on the tight clinico-serological correlation between antibodies to nodal/paranodal proteins and CIDP. Despite the low prevalence, testing for their presence and isotype could ultimately be part of the diagnostic workup in suspected inflammatory demyelinating neuropathy to improve diagnostic accuracy and guide treatment.

Classification Of Evidence: This study provides Class III evidence that antibodies to nodal/paranodal proteins identify patients with CIDP (sensitivity 6%, specificity 100%).
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http://dx.doi.org/10.1212/NXI.0000000000000639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935837PMC
January 2020
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