Publications by authors named "Michele Tinazzi"

220 Publications

Opinion, knowledge, and clinical experience with functional neurological disorders among Italian neurologists: results from an online survey.

J Neurol 2021 Oct 19. Epub 2021 Oct 19.

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

Background: Functional neurological disorders (FND) are disabling medical conditions commonly seen in neurological practice. Neurologists play an essential role in managing FND, from establishing a diagnosis to coordination of multidisciplinary team-based treatment for patients. With this study, we investigated the knowledge and the clinical experience of Italian neurologists in managing patients with FND.

Methods: Members of the Italian Society of Neurology were invited via e-mail to participate in this ad hoc online survey; 492 questionnaires were returned completed.

Results: The term "Functional neurological disorders" in reference to FND was used more frequently than other psychological (e.g., psychogenic or conversion), or descriptive terms (e.g., non-organic or stress-related). When speaking with patients, the respondents stated that they preferred explaining symptoms based on abnormal functioning of the nervous system than discussing mental illness and that they would refer their patient to a psychologist rather than to a psychiatrist. Few considered that physiotherapy and psychiatric interventions are useful approaches to treating FND. Some believed that patients simulate their symptoms.

Conclusions: Overall, the responses suggest that knowledge about scientific advances in FND is somewhat sparse. A psychiatric-centered view of FND opens the way to an approach in which neurobiological and psychological aspects constitute essential factors of the condition. In this context, professional education could improve understanding of FND and optimize patient management.
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http://dx.doi.org/10.1007/s00415-021-10840-yDOI Listing
October 2021

Sudden Onset, Fixed Dystonia and Acute Peripheral Trauma as Diagnostic Clues for Functional Dystonia.

Mov Disord Clin Pract 2021 Oct 10;8(7):1107-1111. Epub 2021 Sep 10.

Neurology Unit, Movement Disorders Division, Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy.

Background: The differentiation of functional dystonia from idiopathic dystonia may be clinically challenging.

Objective: To identify clinical features suggestive of functional dystonia to guide physicians to distinguish functional dystonia from idiopathic dystonia.

Methods: Patient data were extracted from the Italian Registry of Functional Motor Disorders and the Italian Registry of Adult Dystonia. Patients with functional and idiopathic dystonia were followed up at the same clinical sites, and they were similar in age and sex.

Results: We identified 113 patients with functional dystonia and 125 with idiopathic dystonia. Sudden onset of dystonia, evidence of fixed dystonia, and acute peripheral trauma before dystonia onset were more frequent in the functional dystonia group. No study variable alone achieved satisfactory sensitivity and specificity, whereas a combination of variables yielded 85% sensitivity and 98% specificity. A diagnostic algorithm was developed to reduce the risk of misclassifying functional dystonia.

Conclusion: Our findings extend the current diagnostic approach to functional dystonia by showing that clinical information about symptom onset, fixed dystonia, and history of peripheral trauma may provide key clues in the diagnosis of functional dystonia.
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http://dx.doi.org/10.1002/mdc3.13322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485608PMC
October 2021

Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism.

Mov Disord 2021 Oct 8. Epub 2021 Oct 8.

Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.

Background: Complex parkinsonism is the commonest phenotype in late-onset PLA2G6-associated neurodegeneration.

Objectives: The aim of this study was to deeply characterize phenogenotypically PLA2G6-related parkinsonism in the largest cohort ever reported.

Methods: We report 14 new cases of PLA2G6-related parkinsonism and perform a systematic literature review.

Results: PLA2G6-related parkinsonism shows a fairly distinct phenotype based on 86 cases from 68 pedigrees. Young onset (median age, 23.0 years) with parkinsonism/dystonia, gait/balance, and/or psychiatric/cognitive symptoms were common presenting features. Dystonia occurred in 69.4%, pyramidal signs in 77.2%, myoclonus in 65.2%, and cerebellar signs in 44.6% of cases. Early bladder overactivity was present in 71.9% of cases. Cognitive impairment affected 76.1% of cases and psychiatric features 87.1%, the latter being an isolated presenting feature in 20.1%. Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias. Five patients benefited from deep brain stimulation. Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%. Presynaptic dopaminergic terminal imaging was abnormal in all where performed. Fifty-four PLA2G6 mutations have hitherto been associated with parkinsonism, including four new variants reported in this article. These are mainly nontruncating, which may explain the phenotypic heterogeneity of childhood- and late-onset PLA2G6-associated neurodegeneration. In five deceased patients, median disease duration was 13.0 years. Brain pathology in three cases showed mixed Lewy and tau pathology.

Conclusions: Biallelic PLA2G6 mutations cause early-onset parkinsonism associated with dystonia, pyramidal and cerebellar signs, myoclonus, and cognitive impairment. Early psychiatric manifestations and bladder overactivity are common. Cerebro/cerebellar atrophy are frequent magnetic resonance imaging features, whereas brain iron deposition is not. Early, severe dyskinesias are a tell-tale sign. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28807DOI Listing
October 2021

Chromatic Pupillometry in Isolated Rapid Eye Movement Sleep Behavior Disorder.

Mov Disord 2021 Oct 7. Epub 2021 Oct 7.

Dipartimento di Neuroscienze, Biomedicina e Movimento, Università di Verona, Verona, Italy.

Background: Melanopsin retinal ganglion cell (mRGC)-mediated pupillary light reflex (PLR) abnormalities have been documented in several neurodegenerative disorders including Parkinson's disease. Overall, isolated rapid eye movement (REM) sleep behavior disorder (iRBD) represents the strongest prodromal risk factor for impending α-synucleinopathies.

Objectives: To quantitatively compare PLR and mRGC-mediated contribution to PLR in 16 iRBD patients and 16 healthy controls.

Methods: iRBD and controls underwent extensive neuro-ophthalmological evaluation and chromatic pupillometry. In iRBD, PLR metrics were correlated with clinical variables and with additional biomarkers including REM atonia index (RAI), DaTscan, and presence of phosphorylated-α-synuclein (p-α-syn) deposition in skin biopsy.

Results: We documented higher baseline pupil diameter and decreased rod-transient PLR amplitude in iRBD patients compared to controls. PLR rod-contribution correlated with RAI. Moreover, only iRBD patients with evidence of p-α-syn deposition at skin biopsy showed reduced PLR amplitude compared to controls.

Conclusion: The observed PLR abnormalities in iRBD might be considered as potential biomarkers for the risk stratification of phenoconversion of the disease. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28809DOI Listing
October 2021

Evidence That Neuromuscular Fatigue Is Not a Dogma in Patients with Parkinson's Disease.

Med Sci Sports Exerc 2021 Sep 17. Epub 2021 Sep 17.

Department of Neurosciences, Biomedicine, and Movement, University of Verona, Italy Department of Internal Medicine, University of Utah, Salt Lake City, UT.

Purpose: Given the increased level of fatigue frequently reported by patients with Parkinson's disease (PD), this study investigated the interaction between central and peripheral components of neuromuscular fatigue (NF) in this population, compared to healthy peers.

Methods: Changes in maximal voluntary activation (ΔVA, central fatigue) and potentiated twitch force (ΔQtw,pot, peripheral fatigue) pre-post exercise were determined via the interpolated twitch technique in 10 patients with PD and 10 healthy controls (CTRL) matched for age, sex and physical activity. Pulmonary gas exchange, femoral blood flow (FBF), and quadriceps electromyography (EMG) were measured during a fatiguing exercise (85% of peak power output (PPO)). For a specific comparison, on another day, CTRLs repeat the fatiguing test matching the time to failure (TTF) and PPO of PDs.

Results: At 85% of PPO (PD = 21 ± 7 W; CTRL = 37 ± 22 W), both groups have similar TTF (~5.9 min), pulmonary gas exchange, FBF, and EMG. After this exercise, the maximal voluntary contraction force (MVC) and Qtwpot decreased equally in both groups (-16%, p = 0.483; -43%, p = 0.932), while VA decreased in PD compared to CTRL (-3.8% Vs -1.1%, p = 0.040). At the same PPO and TTF of PDs (21 W; 5.4 min), CTRLs showed a constant drop in MVC, and Qtwpot (-14%, p = 0.854; -39%, p = 0.540), instead VA decreased more in PD than in CTRL (-3.8% Vs -0.7%, p = 0.028).

Conclusion: In PDs, central NF seems exacerbated by the fatiguing task which, however, does not alter peripheral fatigue. This, besides the TTF like CTRLs, suggests that physical activity may limit NF and counterbalance PD-induced degeneration through peripheral adaptations.
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http://dx.doi.org/10.1249/MSS.0000000000002791DOI Listing
September 2021

Functional gait disorders: Demographic and clinical correlations.

Parkinsonism Relat Disord 2021 Aug 25;91:32-36. Epub 2021 Aug 25.

Clinical Neurology Unit, Department of Medical, Surgical and Health Services, University of Trieste, Trieste, Italy.

Objective: We aimed to describe the prevalence and clinical-demographical features of patients with functional gait disorders (FGDs) and to compare them to patients with functional motor disorders (FMDs) without FGDs (No-FGDs).

Methods: In this multicenter observational study, we enrolled patients with a clinically definite diagnosis of FMDs in 25 tertiary movement disorders centers in Italy. Each subject with FMDs underwent a comprehensive clinical assessment, including screening for different subtypes of functional gait disorders. Multivariate regression models were implemented in order to estimate the adjusted odds ratio (OR; 95% confidence interval) of having FGDs in relation to sociodemographic and clinical characteristics.

Results: Out of 410 FMDs, 26.6% (n = 109) of patients exhibited FGDs. The most frequent FGDs were slow gait (n = 43, 39.4%), astasia-abasia (n = 26, 23.8%), and knee buckling (n = 24, 22%). They exhibited single FGDs in 51.4% (n = 56) or complex FGDs (more than one type of FGDs) in 48.6% (n = 53) of cases. On multivariate regression analysis, the presence of FGDs was more likely associated with older age (OR 1.03, 95% CI 1.01-1.04), functional visual symptoms (OR 2.19, 95% CI 1.08-4.45), and the diagnosis of somatic symptoms disorder (OR 2.97, 95% CI 1.08-8.17). FGDs were also more likely to undergo physiotherapy (OR 1.81, 95% CI 1.08-3.03).

Conclusions: People with FMDs may present with different and overlapping types of FGDs, which may occur in older age. The association of FGDs with functional visual symptoms and somatic symptoms disorder opens up to new avenues to the understanding of the neural mechanisms of these disorders.
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http://dx.doi.org/10.1016/j.parkreldis.2021.08.012DOI Listing
August 2021

Gaps in Functional Motor Disorders care in two European countries: time to address shared terminology, medico-legal barriers and public investments.

Eur J Neurol 2021 Sep 3. Epub 2021 Sep 3.

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

Background And Purpose: Functional motor disorders (FMDs) are frequent and highly disabling conditions. Despite the substantial advances in FMDs diagnosis, mechanisms and treatments, their tangible application to care of patients with FMDs is yet to be established. We aimed to identify the main real-life gaps and barriers in FMDs care, faced by both patients and physicians, in two different European countries, Italy and Czechia.

Methods: A cross-cultural study was performed.

Results: Both patients and physicians are face practical difficulties and pay a high price for the poor management of FMDs as a result of outdated classifications and insufficient education. This, in turn, has led to inadequate access to care and the existence of common misbeliefs regarding symptom severity or even suspicion of malingering. FMDs need to be integrated into national healthcare systems and in research priorities so that substantial cost savings can be achieved and appropriate care provided to patients.

Conclusions: We found multiple serious real-life unmet needs in FMD care, ranging from terminology and classification to poor recognition in national healthcare priorities. Based on these findings, we intend to mark the beginning of a collaborative project among researchers even in other different European settings to promote coordinated development efforts and goals in the evolving field of FMDs in clinical and research practice.
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http://dx.doi.org/10.1111/ene.15092DOI Listing
September 2021

Physiotherapy versus Consecutive Physiotherapy and Cognitive Treatment in People with Parkinson's Disease: A Pilot Randomized Cross-Over Study.

J Pers Med 2021 Jul 21;11(8). Epub 2021 Jul 21.

Neuromotor and Cognitive Rehabilitation Research Center, Section of Physical and Rehabilitation Medicine, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy.

Background: Parkinson's disease (PD) is characterized by motor and cognitive dysfunctions that can usually be treated by physiotherapy or cognitive training, respectively. The effects of consecutive physiotherapy and cognitive rehabilitation programs on PD deficits are less investigated.

Objective: We investigated the effects of 3 months of physiotherapy (physiotherapy treatment group) or consecutive physiotherapy and cognitive (physiotherapy and cognitive treatment group) rehabilitation programs on cognitive, motor, and psychological aspects in 20 PD patients.

Methods: The two groups switched programs and continued rehabilitation for another 3 months. The outcomes were score improvement on cognitive (Montreal Cognitive Assessment, Frontal Assessment Battery, Trail Making Test, Verbal Phonemic Fluency, Digit Span, and Rey Auditory Verbal Learning), motor (Unified Parkinson's Disease Rating Scale-III, Berg Balance Scale, Two-Minute Walking Test, and Time Up and Go), and psychological (Beck Depression Inventory and State-Trait Anxiety Inventory) scales.

Results: Between-group comparison revealed a significant difference in functional mobility between the two rehabilitation programs. Improvements in walking abilities were noted after both interventions, but only the patients treated with consecutive training showed better performance on functional mobility and memory tasks.

Conclusion: Our findings support the hypothesis that consecutive physiotherapy plus cognitive rehabilitation may have a greater benefit than physiotherapy alone in patients with PD.
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http://dx.doi.org/10.3390/jpm11080687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399749PMC
July 2021

Olfaction in patients with Parkinson's disease: a new threshold test analysis through turning points trajectories.

J Neural Transm (Vienna) 2021 Nov 30;128(11):1641-1653. Epub 2021 Jul 30.

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

Olfactory deficit is a widely documented non-motor symptom in Parkinson's disease (PD). Abnormal turning points trajectories through olfactory threshold testing have been recently reported in patients with olfactory dysfunction, who seem to adapt faster to olfactory stimuli, but data on PD patients are lacking. The aim of this study is to perform olfactory threshold test and explore the turning points trajectories in PD patients in comparison to normal controls. We recruited 59 PD patients without dementia, and no conditions that could influence evaluation of olfaction and cognition. Sixty healthy subjects served as controls. Patients and controls underwent a comprehensive olfactory evaluation with the Sniffin' Sticks extended test assessing threshold, discrimination and identification and a full neuropsychological evaluation. Besides, threshold test data were analyzed examining all the turning points trajectories. PD patients showed a different olfactory threshold test pattern, i.e., faster olfactory adaptation, than controls with no effect of age. Normosmic PD patients showed different olfactory threshold test pattern, i.e., better threshold score, than normosmic controls. Visuospatial dysfunction was the only factor that significantly influenced this pattern. Olfactory threshold trajectories suggested a possible adaptation phenomenon in PD patients. Our data offered some new insights on normosmic PD patients, which appear to be a subset with a specific psychophysical profile. The analysis of the turning points trajectories, through an olfactory threshold test, could offer additional information on olfactory function in PD patients. Future larger studies should confirm these preliminary findings.
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http://dx.doi.org/10.1007/s00702-021-02387-zDOI Listing
November 2021

The role of glutamatergic neurotransmission in the motor and non-motor symptoms in Parkinson's disease: Clinical cases and a review of the literature.

J Clin Neurosci 2021 Aug 10;90:178-183. Epub 2021 Jun 10.

Parkinson-Klinik Ortenau, Wolfach, Germany. Electronic address:

Glutamate is the major excitatory neurotransmitter in the central nervous system and, as such, many brain regions, including the basal ganglia, are rich in glutamatergic neurons. The importance of the basal ganglia in the control of voluntary movement has long been recognised, with the effect of dysfunction of the region exemplified by the motor symptoms seen in Parkinson's disease (PD). However, the basal ganglia and the associated glutamatergic system also play a role in the modulation of emotion, nociception and cognition, dysregulation of which result in some of the non-motor symptoms of PD (depression/anxiety, pain and cognitive deficits). Thus, while the treatment of PD has traditionally been approached from the perspective of dopaminergic replacement, using agents such as levodopa and dopamine receptor agonists, the glutamatergic system offers a novel treatment target for the disease. Safinamide has been approved in over 20 countries globally for fluctuating PD as add-on therapy to levodopa regimens for the management of 'off' episodes. The drug has both dopaminergic and non-dopaminergic pharmacological effects, the latter including inhibition of abnormal glutamate release. The effect of safinamide on the glutamatergic system might present some advantages over dopamine-based therapies for PD by providing efficacy for motor (levodopa-induced dyskinesia) as well as non-motor (anxiety, mood disorders, pain) symptoms. In this article, we discuss the potential role of glutamatergic inhibition on these symptoms, using illustrative real-world examples of patients we have treated with safinamide.
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http://dx.doi.org/10.1016/j.jocn.2021.05.056DOI Listing
August 2021

Changes in Corticospinal Circuits During Premovement Facilitation in Physiological Conditions.

Front Hum Neurosci 2021 21;15:684013. Epub 2021 Jun 21.

Movement Disorders Division, Neurology Unit, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Changes in corticospinal excitability have been well documented in the preparatory period before movement, however, their mechanisms and physiological role have not been entirely elucidated. We aimed to investigate the functional changes of excitatory corticospinal circuits during a reaction time (RT) motor task (thumb abduction) in healthy subjects (HS). 26 HS received single pulse transcranial magnetic stimulation (TMS) over the primary motor cortex (M1). After a visual go signal, we calculated RT and delivered TMS at three intervals (50, 100, and 150 ms) within RT and before movement onset, recording motor evoked potentials (MEP) from the abductor pollicis brevis (APB) and the task-irrelevant abductor digiti minimi (ADM). We found that TMS increased MEP amplitude when delivered at 150, 100, and 50 ms before movement onset, demonstrating the occurrence of premovement facilitation (PMF). MEP increase was greater at the shorter interval (MEP) and restricted to APB (no significant effects were detected recording from ADM). We also reported time-dependent changes of the RT and a TMS side-dependent effect on MEP amplitude (greater on the dominant side). In conclusion, we here report changes of RT and side-dependent, selective and facilitatory effects on the MEP amplitude when TMS is delivered before movement onset (PMF), supporting the role of excitatory corticospinal mechanisms at the basis of the selective PMF of the target muscle during the RT protocol.
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http://dx.doi.org/10.3389/fnhum.2021.684013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255790PMC
June 2021

REM sleep behavior disorder: Mimics and variants.

Sleep Med Rev 2021 Jun 10;60:101515. Epub 2021 Jun 10.

IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio-Emilia, Modena, Italy.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia with dream-enactment behaviors occurring during REM sleep and associated with the lack of the physiological REM sleep muscle atonia. It can be isolated and secondary to other neurological or medical conditions. Isolated RBD heralds in most cases a neurodegenerative condition due to an underlying synucleinopathy and consequently its recognition is crucial for prognostic implications. REM sleep without atonia on polysomnography is a mandatory diagnostic criterion. Different conditions may mimic RBD, the most frequent being obstructive sleep apnea during sleep, non-REM parasomnia, and sleep-related hypermotor epilepsy. These diseases might also be comorbid with RBD, challenging the evaluation of disease severity, the treatment choices and the response to treatment evaluation. Video-PSG is the gold standard for a correct diagnosis and will distinguish between different or comorbid sleep disorders. Careful history taking together with actigraphy may give important clues for the differential diagnosis. The extreme boundaries of RBD might also be seen in more severe and complex conditions like status dissociatus or in the sleep disorders' scenario of anti IgLON5 disease, but in the latter both clinical and neurophysiological features will differ. A step-by-step approach is suggested to guide the differential diagnosis.
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http://dx.doi.org/10.1016/j.smrv.2021.101515DOI Listing
June 2021

Motor dual task with eyes closed improves postural control in patients with functional motor disorders: A posturographic study.

Gait Posture 2021 07 11;88:286-291. Epub 2021 Jun 11.

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

Background: Functional motor disorders (FMD) are highly disabling neurological conditions in which postural control deficits increase the risk of falls and disability in performing daily living activities. Scattered evidence suggests that such disturbances may depend on abnormal attentional focus and might improve with distraction.

Research Question: How do motor and cognitive dual tasks performed under two different sensory conditions shape postural control in patients with FMD.

Methods: This posturographic study involved 30 patients with FMD (age, 45.20 ± 14.57 years) and 30 healthy controls (age, 41.20 ± 16.50 years). Postural parameters were measured with eyes open, and eyes closed in quiet stance (single task) and on a motor dual task (m-DT) and a calculation (cognitive) dual task (c-DT). The dual task effect (DTE, expressed in percentage) on motor and cognitive performance was calculated for sway area, length of Center of Pressure (CoP), and velocity of CoP displacement.

Results: There was a statistically significant three-way interaction between task, condition, and group for the DTE on sway area (p = 0.03). The mean sway area DTE on the motor task in the eyes-closed condition was increased by 70.4 % in the healthy controls, while it was decreased by 1% in the patient group (p = 0.003). No significant three-way interaction was observed for the DTE on length of CoP and velocity of CoP displacement.

Significance: This study provides novel preliminary evidence for the benefit of a simple motor dual task in the eyes closed condition as a way to improve postural control in patients with FMD. These findings are relevant for the management of postural control disorders in patients with FMD.
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http://dx.doi.org/10.1016/j.gaitpost.2021.06.011DOI Listing
July 2021

Dystonia Management: What to Expect From the Future? The Perspectives of Patients and Clinicians Within DystoniaNet Europe.

Front Neurol 2021 3;12:646841. Epub 2021 Jun 3.

Expertise Centre Movement Disorders Groningen, Department of Neurology, University Medical Centre Groningen, Groningen, Netherlands.

Improved care for people with dystonia presents a number of challenges. Major gaps in knowledge exist with regard to how to optimize the diagnostic process, how to leverage discoveries in pathophysiology into biomarkers, and how to develop an evidence base for current and novel treatments. These challenges are made greater by the realization of the wide spectrum of symptoms and difficulties faced by people with dystonia, which go well-beyond motor symptoms. A network of clinicians, scientists, and patients could provide resources to facilitate information exchange at different levels, share mutual experiences, and support each other's innovative projects. In the past, collaborative initiatives have been launched, including the , the which however only existed for a limited time), and the Dutch project. The European Reference Network on Rare Neurological Diseases includes dystonia among other rare conditions affecting the central nervous system in a dedicated stream. Currently, we aim to broaden the scope of these initiatives to a comprehensive European level by further expanding the DystoniaNet network, in close collaboration with the ERN-RND. In line with the ERN-RND, the mission of DystoniaNet Europe is to improve care and quality of life for people with dystonia by, among other endeavors, facilitating access to specialized care, overcoming the disparity in education of medical professionals, and serving as a solid platform to foster international clinical and research collaborations. In this review, both professionals within the dystonia field and patients and caregivers representing Dystonia Europe highlight important unsolved issues and promising new strategies and the role that a European network can play in activating them.
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http://dx.doi.org/10.3389/fneur.2021.646841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211212PMC
June 2021

Functional motor phenotypes: to lump or to split?

J Neurol 2021 May 7. Epub 2021 May 7.

IRCCS Mondino Foundation, Pavia, Italy.

Introduction: Functional motor disorders (FMDs) are usually categorized according to the predominant phenomenology; however, it is unclear whether this phenotypic classification mirrors the underlying pathophysiologic mechanisms.

Objective: To compare the characteristics of patients with different FMDs phenotypes and without co-morbid neurological disorders, aiming to answer the question of whether they represent different expressions of the same disorder or reflect distinct entities.

Methods: Consecutive outpatients with a clinically definite diagnosis of FMDs were included in the Italian registry of functional motor disorders (IRFMD), a multicenter data collection platform gathering several clinical and demographic variables. To the aim of the current work, data of patients with isolated FMDs were extracted.

Results: A total of 176 patients were included: 58 with weakness, 40 with tremor, 38 with dystonia, 23 with jerks/facial FMDs, and 17 with gait disorders. Patients with tremor and gait disorders were older than the others. Patients with functional weakness had more commonly an acute onset (87.9%) than patients with tremor and gait disorders, a shorter time lag from symptoms onset and FMDs diagnosis (2.9 ± 3.5 years) than patients with dystonia, and had more frequently associated functional sensory symptoms (51.7%) than patients with tremor, dystonia and gait disorders. Patients with dystonia complained more often of associated pain (47.4%) than patients with tremor. No other differences were noted between groups in terms of other variables including associated functional neurological symptoms, psychiatric comorbidities, and predisposing or precipitating factors.

Conclusions: Our data support the evidence of a large overlap between FMD phenotypes.
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http://dx.doi.org/10.1007/s00415-021-10583-wDOI Listing
May 2021

Movement perception of the tonic vibration reflex is abnormal in functional limb weakness.

Parkinsonism Relat Disord 2021 06 20;87:1-6. Epub 2021 Apr 20.

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

Introduction: We tested the hypothesis that functional limb weakness is associated with possible dysfunction of the central processing of proprioceptive information, by evaluating the amount of tonic vibration reflex (TVR) and the perception of the TVR movement.

Methods: The study sample was 20 patients with functional weakness of the lower and/or the upper limbs and 25 healthy controls; delivery of 92-Hz transcutaneous vibration of the biceps brachii tendon of the unrestrained arm stimulated predominantly the muscle spindle afferent and elicited elbow flexion (tonic vibration reflex, TVR). Blindfolded participants had to match the final position of the vibrated arm with their contralateral tracking arm. The TVR and perception of the TVR movement were measured as angle movements of the vibrated arm and the tracking arm, respectively.

Results: The magnitude of the TVR of the vibrated arm and movement perception of the TVR of the tracking arm were significantly reduced in the patients compared to the controls. No correlation was found between magnitude of the TVR and perception of the TVR movement, suggesting that the abnormalities were independent of each other. Moreover, the abnormalities did not differ between the patients with/without bilateral upper limb involvement or between the affected and the unaffected side in patients with unilateral impairment, suggesting that the observed deficits are independent of motor impairment.

Conclusions: Proprioceptive dysfunction may underlie alterations in body movement and in sense of agency in such patients and may play a role in the pathophysiology of functional limb weakness.
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http://dx.doi.org/10.1016/j.parkreldis.2021.04.011DOI Listing
June 2021

Fatigue in hypokinetic, hyperkinetic, and functional movement disorders.

Parkinsonism Relat Disord 2021 05 29;86:114-123. Epub 2021 Mar 29.

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

The emerging science of fatigue has soundly endorsed the need for its unified definition, shared terminology and increased recognition in neurological illnesses. Nevertheless, the real impact of fatigue remains under-recognized. Fatigue describes a sense of tiredness, lack of energy or need for increased effort often perceived as overwhelming, pervasive, and disabling. It is a common feature of chronic medical conditions and neurological diseases, including Parkinson's disease (PD) and other hypokinetic, hyperkinetic, and functional movement disorders (FMD). While there is solid evidence for the burden of fatigue in PD, knowledge of fatigue in other movement disorders (MDS) is still limited. Lack of consensus definition, rigorous measures and the high prevalence of potential confounders such as apathy, depression and sleepiness are the main obstacles in studying fatigue in MDS. This review of the prevalence, impact, and clinical correlates of fatigue in common MDS summarizes current hypotheses for the pathophysiological mechanisms underlying fatigue and gives a brief overview of treatment options. Fatigue is a prevalent, disabling, primary non-motor symptom (NMS) in MDS, including atypical and secondary parkinsonisms, dystonia, essential tremor (ET) and a hallmark feature of FMD. We report the hypothesis that fatigue is a perceptual disorder of the sensorimotor system. Given the relevance of this burdensome symptom, fatigue deserves greater clinical and research attention to better understand its manifestation and pathophysiology and to improve diagnosis and treatment.
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http://dx.doi.org/10.1016/j.parkreldis.2021.03.018DOI Listing
May 2021

Medico-legal aspects of functional neurological disorders: time for an interdisciplinary dialogue.

Neurol Sci 2021 Jul 3;42(7):3053-3055. Epub 2021 Apr 3.

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

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http://dx.doi.org/10.1007/s10072-021-05162-wDOI Listing
July 2021

Motor and non-motor outcomes after a rehabilitation program for patients with Functional Motor Disorders: A prospective, observational cohort study.

NeuroRehabilitation 2021 ;48(3):305-314

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

Background: Rehabilitation has proven effective in improving motor symptoms (i.e., weakness, tremor, gait and balance disorders) in patients with Functional Motor Disorders (FMDs). Its effects on non-motor symptoms (NMSs) such as fatigue, pain, depression, anxiety and alexithymia, have not been explored yet.

Objective: To explore the effects of a validated inpatient 5-day rehabilitation program, followed by a home-based self-management plan on functional motor symptoms, NMSs, self-rated perception of change, and quality of life (QoL).

Methods: 33 FMD patients were enrolled. Measures for motor symptoms and NMSs were primary outcomes. Secondary outcomes included measures of self-perception of change and QoL. Patients were evaluated pre-treatment (T0), post-treatment (T1), and 3-month follow-up (T2).

Results: There was an overall significant decrease in functional motor symptoms, general, physical, and reduced-activity fatigue (for all, p < 0.001). Post hoc comparison showed significant improvements at T1, whereas effects remained significant at T2 for motor symptoms and physical fatigue. Gait and balance, alexithymia, and physical functioning (QoL) significantly improved at T2. More than 50% of patients reported marked improvement at T1 and T2.

Conclusions: Our study suggests the benefits of rehabilitation and self-management plan on functional motor symptoms and physical fatigue in the medium-term. More actions are needed for the management of pain and other distressing NMSs in FMDs.
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http://dx.doi.org/10.3233/NRE-201617DOI Listing
June 2021

Pain, Smell, and Taste in Adults: A Narrative Review of Multisensory Perception and Interaction.

Pain Ther 2021 Jun 26;10(1):245-268. Epub 2021 Feb 26.

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

Every day our sensory systems perceive and integrate a variety of stimuli containing information vital for our survival. Pain acts as a protective warning system, eliciting a response to remove harmful stimuli; it may also be a symptom of an illness or present as a disease itself. There is a growing need for additional pain-relieving therapies involving the multisensory integration of smell and taste in pain modulation, an approach that may provide new strategies for the treatment and management of pain. While pain, smell, and taste share common features and are strongly linked to emotion and cognition, their interaction has been poorly explored. In this review, we provide an overview of the literature on pain modulation by olfactory and gustatory substances. It includes adult human studies investigating measures of pain threshold, tolerance, intensity, and/or unpleasantness. Due to the limited number of studies currently available, we have structured this review as a narrative in which we comment on experimentally induced and clinical pain separately on pain-smell and pain-taste interaction. Inconsistent study findings notwithstanding, pain, smell, and taste seem to interact at both the behavioral and the neural levels. Pain intensity and unpleasantness seem to be affected more by olfactory substances, whereas pain threshold and tolerance are influenced by gustatory substances. Few pilot studies to date have investigated these effects in clinical populations. While the current results are promising for the future, more evidence is needed to elucidate the link between the chemical senses and pain. Doing so has the potential to improve and develop novel options for pain treatment.
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http://dx.doi.org/10.1007/s40122-021-00247-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119564PMC
June 2021

The key role of physical activity against the neuromuscular deterioration in patients with Parkinson's disease.

Acta Physiol (Oxf) 2021 04 1;231(4):e13630. Epub 2021 Mar 1.

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

Aim: Decreased muscle strength has been frequently observed in individuals with Parkinson's disease (PD). However, this condition is still poorly examined in physically active patients. This study compared quadriceps (Q) maximal force and the contribution of central and peripheral components of force production during a maximal isometric task between physically active PD and healthy individuals. In addition, the correlation between force determinants and energy expenditure indices were investigated.

Methods: Maximal voluntary contraction (MVC), resting twitch (RT) force, pennation angle (θp), physiological cross-sectional area (PCSA) and Q volume were assessed in 10 physically active PD and 10 healthy control (CTRL) individuals matched for age, sex and daily energy expenditure (DEE) profile.

Results: No significant differences were observed between PD and CTRL in MVC (142 ± 85; 142 ± 47 N m), Q volume (1469 ± 379; 1466 ± 522 cm ), PCSA (206 ± 54; 205 ± 71 cm ), θp (14 ± 7; 13 ± 3 rad) and voluntary muscle-specific torque (MVC/PCSA [67 ± 35; 66 ± 19 N m cm ]). Daily calories and MVC correlated (r = 0.56, P = .0099). However, PD displayed lower maximal voluntary activation (MVA) (85 ± 7; 95 ± 5%), rate of torque development (RTD) in the 0-0.05 (110 ± 70; 447 ± 461 N m s ) and the 0.05-0.1 s (156 ± 135; 437 ± 371 N m s ) epochs of MVCs, whereas RT normalized for PCSA was higher (35 ± 14; 20 ± 6 N m cm ).

Conclusion: Physically active PDs show a preserved strength of the lower limb. This resulted by increasing skeletal muscle contractility, which counterbalances neuromuscular deterioration, likely due to their moderate level of physical activity.
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http://dx.doi.org/10.1111/apha.13630DOI Listing
April 2021

Functional Neurological Disorders as Seen by a Cohort of General Practitioners in Northern Italy: Evidence From an Online Survey.

Front Neurol 2021 25;12:583672. Epub 2021 Jan 25.

Department of Neurosciences, Biomedicine and Movement Sciences, Università di Verona, Verona, Italy.

General practitioners (GPs) provide primary care and advise their patients on which diagnostic and therapeutic pathways they judge most appropriate. For patients with functional neurological disorders (FND), receiving a proper explanation of diagnosis by their GP from the very beginning may drastically improve prognosis. Novel approaches to the diagnosis and treatment of FND have important implications for effective management. The aim of this study was to investigate Italian GP opinion and knowledge about FND in light of new approaches to the illness. To do this, we evaluated the responses to a 13-item web-based survey completed by 133 GPs practicing in northern Italy. Psychological terms to describe FND were more frequently used than functional neurological disorder and mental illness was considered an important predictor of diagnosis. Referral to a neurologist rather than to a psychiatrist was largely preferred, while physiotherapy consultation was seldom recognized as a valuable approach to treating FND. Overall, the survey findings suggest that knowledge about novel approaches to FND is somewhat lacking. Currently, GPs appear to be transitioning from a classical psychological view of the disorder toward a more modern conceptualization, in which neurobiological, psychological, and social factors all play an important role. Professional education during this transition would be an advantageous way to optimize physician management of FND and to enhance diagnosis, explanation, and management across primary and secondary care pathways.
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http://dx.doi.org/10.3389/fneur.2021.583672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868405PMC
January 2021

Reply to the Letter "What does characterize exercise guidelines for Parkinson's disease?"

Aging Clin Exp Res 2021 Mar 2;33(3):677-678. Epub 2021 Jan 2.

Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Via F. Casorati 43, 37131, Verona, Italy.

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http://dx.doi.org/10.1007/s40520-020-01770-2DOI Listing
March 2021

Functional and Idiopathic Cervical Dystonia in Two Family Members: A Challenging Diagnosis.

Tremor Other Hyperkinet Mov (N Y) 2020 12 11;10:51. Epub 2020 Dec 11.

Neurology Unit, Movement Disorders Division, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, IT.

Background: Cervical dystonia (CD) often occurs in the same family.

Case Report: A 40-year-old woman presented with a longstanding history of CD and signs of inconsistency at history taking and neurological examination; her 65-year-old mother was diagnosed instead with idiopathic CD, which had begun 7 years after the onset of CD in her daughter.

Discussion: Idiopathic and functional CD share common clinical and endophenotypic traits, making the differential diagnosis particularly challenging. A complete examination is warranted.
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http://dx.doi.org/10.5334/tohm.558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731715PMC
December 2020

Functional motor disorders associated with other neurological diseases: Beyond the boundaries of "organic" neurology.

Eur J Neurol 2021 05 2;28(5):1752-1758. Epub 2021 Jan 2.

Movement Disorder Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Background And Purpose: The aims of this study were to describe the clinical manifestations of functional motor disorders (FMDs) coexisting with other neurological diseases ("comorbid FMDs"), and to compare comorbid FMDs with FMDs not overlapping with other neurological diseases ("pure FMDs").

Methods: For this multicenter observational study, we enrolled outpatients with a definite FMD diagnosis attending 25 tertiary movement disorder centers in Italy. Each patient with FMDs underwent a detailed clinical assessment including screening for other associated neurological conditions. Group comparisons (comorbid FMDs vs. pure FMDs) were performed in order to compare demographic and clinical variables. Logistic regression models were created to estimate the adjusted odds ratios (95% confidence intervals) of comorbid FMDs (dependent variable) in relation to sociodemographic and clinical characteristics (independent variables).

Results: Out of 410 FMDs, 21.7% of patients (n = 89) had comorbid FMDs. The most frequent coexisting neurological diseases were migraine, cerebrovascular disease and parkinsonism. In the majority of cases (86.5%), FMDs appeared after the diagnosis of a neurological disease. Patients with comorbid FMDs were older, and more frequently had tremor, non-neurological comorbidities, paroxysmal non-epileptic seizures, major depressive disorders, and benzodiazepine intake. Multivariate regression analysis showed that diagnosis of comorbid FMDs was more likely associated with longer time lag until the final diagnosis of FMD, presence of tremor and non-neurological comorbidities.

Conclusions: Our findings highlight the need for prompt diagnosis of FMDs, given the relatively high frequency of associated neurological and non-neurological diseases.
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http://dx.doi.org/10.1111/ene.14674DOI Listing
May 2021

Cytokine-, Neurotrophin-, and Motor Rehabilitation-Induced Plasticity in Parkinson's Disease.

Neural Plast 2020 26;2020:8814028. Epub 2020 Nov 26.

Department of Diagnostic and Public Health, University of Verona, Verona, Italy.

Neuroinflammation and cytokine-dependent neurotoxicity appear to be major contributors to the neuropathology in Parkinson's disease (PD). While pharmacological advancements have been a mainstay in the treatment of PD for decades, it is becoming increasingly clear that nonpharmacological approaches including traditional and nontraditional forms of exercise and physical rehabilitation can be critical adjunctive or even primary treatment avenues. Here, we provide an overview of preclinical and clinical research detailing the biological role of proinflammatory molecules in PD and how motor rehabilitation can be used to therapeutically modulate neuroinflammation, restore neural plasticity, and improve motor function in PD.
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http://dx.doi.org/10.1155/2020/8814028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714573PMC
October 2021

REM Sleep Behavior Disorder in Children With Type 1 Narcolepsy Treated With Sodium Oxybate.

Neurology 2021 01 11;96(2):e250-e254. Epub 2020 Nov 11.

From the Neurology Unit (E.A., M.T.), Movement Disorders Division, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona; Department of Biomedical and Neuromotor Sciences (E.A., M.F., F.P., M.M., G.P.), University of Bologna; IRCCS (F.P., S.V., G.P.), Istituto delle Scienze Neurologiche di Bologna; Department of Medicine and Surgery (C.F.), University of Parma; and Sleep Research Centre (R.F.), Department of Neurology IC, Oasi Research institute-IRCCS, Troina, Italy.

Objective: To study the effect of stable treatment with sodium oxybate (SO) on nocturnal REM sleep behavior disorder (RBD) and REM sleep without atonia (RSWA) that severely affected children with type 1 narcolepsy (NT1).

Methods: Nineteen children and adolescents with NT1 (9 female, mean age 12.5 ± 2.7 years, mean disease duration 3.4 ± 1.6 years) underwent neurologic investigations and video-polysomnography (v-PSG) at baseline and after 3 months of stable treatment with SO. v-PSG was independently analyzed by 2 sleep experts to rate RBD episodes. RSWA was automatically computed by means of the validated REM sleep atonia index (RAI).

Results: Compared to baseline, RAI significantly improved ( < 0.05) and complex movements during REM sleep were remarkably reduced after stable treatment with SO. Compared to baseline, children also reported improvement in clinical complaints and showed a different nighttime sleep-stage architecture.

Conclusions: RBD and RSWA improved after treatment with SO, pointing to a direct role of the drug in modulating motor control during REM sleep.

Classification Of Evidence: This study offers Class IV evidence of the positive effect of SO on modulation of muscle atonia during REM sleep in children with NT1 because of the absence of a control group.
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http://dx.doi.org/10.1212/WNL.0000000000011157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905776PMC
January 2021

Conditioned pain modulation affects the N2/P2 complex but not the N1 wave: A pilot study with laser-evoked potentials.

Eur J Pain 2021 03 28;25(3):550-557. Epub 2020 Nov 28.

Department of Neurological, Neuropsychological, Morphological and Motor Sciences, University of Verona, Verona, Italy.

Background: The 'pain-inhibits-pain' effect stems from neurophysiological mechanisms involving endogenous modulatory systems termed diffuse noxious inhibitory controls (DNIC) or conditioned pain modulation (CPM). Laser-evoked potentials (LEPs) components, the N2/P2 complex, and the N1 wave, reflect the medial and lateral pain pathway, respectively: anatomically, the lateral thalamic nuclei (LT) project mainly to the somatosensory cortex (N1 generator), while the medial thalamic nuclei (MT) are bound to the limbic cortices (N2/P2 generators).

Methods: We applied a CPM protocol in which the test stimulus was laser stimulation and the conditioning stimulus was a cold pressor test. LEPs recordings were obtained from 15 healthy subjects in three different conditions: baseline, during heterotopic noxious conditioning stimulation (HNCS) and post-HNCS.

Results: We observed a significant reduction in N2/P2 amplitude during HNCS and a return to pre-test amplitude post-HNCS, whereas the N1 wave remained unchanged during and post-HNCS.

Conclusions: Our results indicate that CPM affects only the medial pain system. The spinothalamic tract (STT) transmits to both the LT and the MT, while the spinoreticulothalamic (SRT) projects only to the MT. The reduction in the amplitude of the N2/P2 complex and the absence of change in the N1 wave suggest that DNIC inhibition on the dorsal horn neurons affects only pain transmission via the SRT, while the neurons that give rise to the STT are not involved. The N1 wave can be a reliable neurophysiological parameter for assessment of STT function in clinical practice, as it does not seem to be influenced by CPM.

Significance: No reports have described the effect of DNIC on lateral and medial pain pathways. We studied the N1 wave and the N2/P2 complex to detect changes during a CPM protocol. We found a reduction in the amplitude of the N2/P2 complex and no change in the N1 wave. This suggests that the DNIC inhibitory effect on dorsal horns neurons affects only pain transmission via the SRT, whereas the neurons that give rise to the STT are not involved.
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http://dx.doi.org/10.1002/ejp.1693DOI Listing
March 2021

Clinical Correlates of Functional Motor Disorders: An Italian Multicenter Study.

Mov Disord Clin Pract 2020 Nov 22;7(8):920-929. Epub 2020 Sep 22.

Department of Systems Medicine University of Rome Tor Vergata Rome Italy.

Background: Functional motor disorders (FMDs) are abnormal movements that are significantly altered by distractive maneuvers and are incongruent with movement disorders seen in typical neurological diseases.

Objective: The objectives of this article are to (1) describe the clinical manifestations of FMDs, including nonmotor symptoms and occurrence of other functional neurological disorders (FND); and (2) to report the frequency of isolated and combined FMDs and their relationship with demographic and clinical variables.

Methods: For this multicenter, observational study, we enrolled consecutive outpatients with a definite diagnosis of FMDs attending 25 tertiary movement disorders centers in Italy. Each patient underwent a detailed clinical evaluation with a definition of the phenotype and number of FMDs (isolated, combined) and an assessment of associated neurological and psychiatric symptoms.

Results: Of 410 FMDs (71% females; mean age, 47 ± 16.1 years) the most common phenotypes were weakness and tremor. People with FMDs had higher educational levels than the general population and frequent nonmotor symptoms, especially anxiety, fatigue, and pain. Almost half of the patients with FMDs had other FNDs, such as sensory symptoms, nonepileptic seizures, and visual symptoms. Patients with combined FMDs showed a higher burden of nonmotor symptoms and more frequent FNDs. Multivariate regression analysis showed that a diagnosis of combined FMDs was more likely to be delivered by a movement disorders neurologist. Also, FMD duration, pain, insomnia, diagnosis of somatoform disease, and treatment with antipsychotics were all significantly associated with combined FMDs.

Conclusions: Our findings highlight the need for multidimensional assessments in patients with FMDs given the high frequency of nonmotor symptoms and other FNDs, especially in patients with combined FMDs.
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http://dx.doi.org/10.1002/mdc3.13077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604660PMC
November 2020

Reversal of Temporal Discrimination in Cervical Dystonia after Low-Frequency Sensory Stimulation.

Mov Disord 2021 03 7;36(3):761-766. Epub 2020 Nov 7.

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

Background: Somatosensory temporal discrimination is abnormal in dystonia and reflects reduced somatosensory inhibition. In healthy individuals, both the latter are enhanced by high-frequency repetitive somatosensory stimulation, whereas opposite effects are observed in patients with cervical dystonia.

Objectives: We tested whether low-frequency repetitive sensory stimulation, which in healthy individuals worsens discrimination, might have the opposite effect in patients with cervical dystonia at the physiological level and, in turn, improve their perceptual performance.

Methods: Somatosensory temporal discrimination and several electrophysiological measures of sensorimotor inhibition were collected before and after 45 minutes of low-frequency repetitive sensory stimulation.

Results: As predicted, and opposite to what happened in controls, low-frequency repetitive sensory stimulation in patients enhanced sensorimotor inhibition and normalized somatosensory temporal discrimination.

Conclusions: Patients with cervical dystonia have an abnormal response to repetitive sensory stimulation, which we hypothesize is attributed to abnormally sensitive homeostatic mechanisms of inhibitory circuitry in both sensory and motor systems. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28369DOI Listing
March 2021
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