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Background: Lombardy was severely hit by the COVID-19 pandemic since February 2020 and the Health System underwent rapid reorganization. Outpatient clinics were stopped for non-urgent patients: it became a priority to manage hundreds of fragile neurological patients who suddenly had less reference points. In Italy, before the pandemic, Televisits were neither recognized nor priced. Methods: At the Fondazione IRCCS Istituto Neurologico C. Besta, we reorganized outpatient clinics to deliver Neuro-telemedicine services, including Televisits and Teleneurorehabilitation, since March 2020. A dedicated Working Group prepared the procedure, tested the system, and designed satisfaction questionnaires for adults and children. Results: After a pilot phase, we prepared a procedure for Telemedicine outpatient clinics which was approved by hospital directions. It included prescription, booking, consenting, privacy and data protection, secure connection with patients (Teams Microsoft 365), electronic report preparation and delivery, reporting, and accountability of the services. During the March–September 2020 period, we delivered 3167 Telemedicine services, including 1618 Televisits, to 1694 patients (972 adults, 722 children) with a wide range of chronic neurological disorders. We successfully administered different clinical assessment and scales. Satisfaction among patients and caregivers was very high. Conclusions: During the dramatic emergency, we were able to take care of more than 1600 patients by organizing Neuro-telehealth in a few weeks, lessening the impact of the pandemic on fragile patients with chronic neurological disorders; this strategy is now stably embedded in our care pathways. In Italy, Telehealth is at present recognized and priced and is becoming a stable pillar of the health system.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Objective Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot-Marie-Tooth disease type 1A (CMT1A). To address this question, the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of 8 years. CMT1A is caused in most patients by a uniformly sized 1.5 Mb duplication event involving the gene PMP22. Methods We genotyped DNA samples from 971 CMT1A patients on Illumina BeadChips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal-induced proliferation-associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve, and our functional studies identified and confirmed interacting proteins using coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation. Results We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (p < 1 x 10(-7)). Coimmunoprecipitation and mass spectroscopy studies identified beta-actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2 is part of a myelination-associated coexpressed network regulated by the master transcription factor SOX10. Importantly, in vitro knockdown of SIPA1L2 in Schwannoma cells led to a significant reduction of PMP22 expression, hinting at a potential strategy for drug development. Interpretation SIPA1L2 is a potential genetic modifier of CMT1A phenotypic expressions and offers a new pathway to therapeutic interventions. ANN NEUROL 2019;85:316-330.

Background and purpose Charcot−Marie−Tooth (CMT) disease is the most common inherited neuropathy, but therapeutic options have been limited to symptom management. Past pharmacological trials have failed, possibly due to insensitive outcome measures (OMs). The aim of the current study was to evaluate the validity and reliability of the 6-min walk test (6MWT) and StepWatch™ Activity Monitoring (SAM) with other previously validated OMs in CMT disease. Methods A prospective multicenter study was performed, consecutively enrolling 168 CMT patients (104 with CMT1A, 27 with CMT1B, 37 with X-linked CMT) from Italian centers specializing in CMT care. Results Statistical analysis showed that the 6MWT was highly related with all previously used OMs. Some, but not all, SAM parameters were related to commonly used OMs but may provide more information about quality of life. Conclusions The current study demonstrated the validity and reliability of the 6MWT and SAM as OMs for CMT. Moreover, SAM provides data that correlate better with quality of life measures, making it useful in future rehabilitation trials.

Stuttering is a speech disorder that occurs, without known origin, in around 10% of population. The onset is around 33 month (mean age) and the 90% of affected people recovers spontaneously, most of the time within 4 years from the onset. When it persists after puberty it becomes a chronic adult speech disorder throughout the lifespan (Yairi & Ambrose, 2005). Due to difficulties in eradicating stuttering in adulthood, it would be very useful to identify, among pre-school stuttering children, the future persistent stutterers, in order to begin the treatment as early as possible. This would enhance the treatment effectiveness and prolong its benefits (Starkweather, 1993), reserving the therapeutic efforts only to children at-risk of persistence. The purpose of this study is to follow the development of the disorder in 4 pre-school Italian children, audio-recorded from the onset of stuttering to the following 18 months, in order to identify early prognostic indexes of persistence as close as possible to the onset. One of the indexes, proposed by Yairi & Ambrose (2005), aims at tracing the developmental disfluencies profile. According to it, stuttering children who will spontaneously recover reduce the proportion of the "stuttering-like disfluencies" (repetitions of sounds and syllablese, repetitions of monosyllabic words, silent and audible prolongations) over the total number of disfluencies in the first year after the onset. The data show that the predictive power of this index is low in the first year after the onset, but increases in the next six months. Since no reliable clinical tool exists yet for predicting persistent stuttering, it is suggested that this probabilistic index should be studied on a larger sample of stuttering children in order to test its predictive value.

La balbuzie è un disordine della fluenza verbale che si manifesta nella prima infanzia e che persiste in età adulta solo nel 10% dei casi. La diagnosi precoce di balbuzie persistente e l'intervento terapeutico immediato aumentano la possibilità di remissione dal disturbo. Alcuni indici di tipo fonetico sono stati proposti per essere dei buoni marcatori di balbuzie cronica, in bambini vicini all'età di insorgenza del disturbo e la coarticolazione anticipatoria, nel parlato percettivamente fluente, rappresenta uno di questi indici. Nello studio viene testato il valore prognostico di questo indice nel parlato di 5 bambini italiani con balbuzie evolutiva.

Stuttering onset occurs for 95% of people who begin to stutter before the age of 4 years, tipically in the third year of life. Spontaneous remission during childhood is common, with recovery rates estimated at 68-96%, usually no later than the fourth year post-onset. If symptoms persist beyond this time, the efficacy of treatment might result more problematic. As a result it is important to refer the subjects that tend to persist to early treatment. The CNR project "Phonetic indexes predictive of chronic stuttering in preschool children" started in 2008, and aimed to identify among different behavioural indexes the ones which are able to predict stuttering persistence at early ages, in order to assure to more at-risk subjects the best therapeutic interventions. The aim of the current study is to evaluate the clinical efficacy of the Disfluency Profile (i.e. the percentage of Stuttering-Like Disfluencies over 100 syllables spoken) in identifying children at greater risk of persistence. Results of the study suggest that the predictive power of the Disfluency Profile at the session of 9-15 months post-onset is low, according to clinical standards of sensitivity and specificity, but it increases over the next six months, albeit not to the standard minimum of 80%. However, the use of Disfluency Profile is preferable than the Stuttering Severity Instrument (third edition), which has been proposed as a predictive tool by some researchers.

Background and purpose Charcot−Marie−Tooth disease (CMT) is a very slowly progressive neuropathy which makes it difficult to detect disease progression over time and to assess intervention efficacy. Experience from completed clinical trials with ascorbic acid and natural history studies confirm difficulties in detecting such changes. Consequently, sensitive-to-change outcome measures (OMs) are urgently needed. Methods The relative responsiveness of clinical scales of the Italian−UK ascorbic acid trial (placebo arm) were assessed by using the standardized response mean (SRM), which is the ratio of the paired scores mean change over time to the standard deviation of the score change (0 is worst responsiveness). Results Little worsening of OM scores was found over 2 years. In detail, the primary OM of the trial, the CMT Neuropathy Score version 1 (CMTNSv1), showed low responsiveness (SRM 0.13). Some CMTNS items showed slightly greater responsiveness (CMT Examination Score 0.17; CMTNS Signs 0.19). Myometric assessments of handgrip and foot dorsiflexion strength were the most responsive (SRM −0.31 and −0.38, respectively). Amongst the other measures, the nine-hole peg test, which assesses upper limb functioning, showed the best sensitivity to change (SRM 0.28). Conclusions Overall these OMs showed low or negligible responsiveness, confirming the need to improve current OMs and to develop novel ones for prognostic and interventional studies. However, handgrip and foot dorsiflexion myometry are worth retaining for future trials as they were the most responsive and are likely to be clinically relevant for patients.

La balbuzie è un disordine della fluenza della parola che è presente nell’1% della popo-lazione mondiale e secondo ricerche recenti compare all’età media di 33 mesi (Yairi & Ambrose, 2005). Gli studi epidemiologici registrano un alto tasso di guarigione spontanea: benché colpisca il 5% dei bambini prescolari, l’80% di essi guarisce spontaneamente entro il quinto anno dalla comparsa. Il restante 20% che, probabilmente a causa di una forte pre-disposizione genetica (Yairi & Ambrose, 2005), è destinato a cronicizzare, deve essere in-dividuato e sottoposto a trattamento terapeutico il prima possibile, in modo che la guarigio-ne possa essere rapida, completa e duratura (Starkweather, 1993). Il presente lavoro illustra i primi risultati di un progetto di ricerca (CNR RSTL 995) vol-to all’individuazione degli indici clinici predittivi, di tipo percettivo e acustico, che dovreb-bero permettere, già dalle prime fasi di comparsa del disturbo, di discriminare i soggetti candidati a cronicizzare rispetto a coloro che, invece, guariranno spontaneamente. Dei circa 40 soggetti finora reclutati, tutti con familiarità al disturbo, quelli studiati a tutt’oggi sono tre (Anna, Giuseppe, Alessandro). Di loro sono state selezionate e analizzate le registrazioni relative alle fasi significative di evoluzione del disturbo: il mese precedente la comparsa della balbuzie (per 2 dei 3 soggetti), il periodo dell’insorgenza, il periodo a distanza di 12 mesi e quello intorno ai 15 mesi (fine della fase di osservazione ed inizio dell’eventuale trattamento). Qui presentiamo i risultati relativi agli indici sperimentali Profilo delle di-sfluenze (Yairi & Ambrose, 2005) e all’analisi acustica del grado di coarticolazione intrasil-labica, secondo il metodo delle ‘Equazioni del Locus’ (Sussman et alii, 1999; Zmarich e Marchiori, 2005). I risultati evidenziano che per due dei tre soggetti il valore prognostico del Profilo delle disfluenze (remissione vs. cronicità) nel secondo semestre è simile a quello dei soggetti de-stinati a cronicizzare (Yairi & Ambrose, 2005). Il terzo soggetto (Anna), invece, a distanza di 12 mesi dall’insorgenza sarebbe, secondo il Profilo delle disfluenze, candidato a remis-sione. Con riferimento ai dati relativi all’analisi della coarticolazione intrasillabica, quest’ultimo soggetto e uno degli altri due (Alessandro) sarebbero destinatati a guarire spontaneamente dal disturbo poiché, a distanza di 12 mesi dall’esordio, il grado di coartico-lazione nelle sillabe percettivamente fluenti si riduce rispetto alle tappe precedenti (come per i soggetti balbuzienti di Subramanian et alii 2003, che in seguito avrebbero recuperato spontaneamente), mentre il terzo soggetto sarebbe destinato a cronicizzare poiché il grado di coarticolazione intrasillabica si mantiene su livelli alti per tutte le tappe d’età studiate.

Visual hallucinations (VHs) represent a frequent and disturbing complication of Parkinson's disease. Evidence suggests that VH can be related to central cholinergic dysfunction. Short-latency afferent inhibition (SAI) technique gives the opportunity to test an inhibitory cholinergic circuit in the human cerebral motor cortex. This inhibition of motor-evoked potentials can be observed when transcranial magnetic stimulation is delivered with a delay ranging from 2 to 8 ms, after a peripheral nerve afferent input has reached the somatosensory cortex. We applied SAI technique in 10 non-demented patients with Parkinson's disease with VHs, in 12 non-demented patients with Parkinson's disease without VHs (NVH-pts) and in 11 age-matched normal controls. All patients with Parkinson's disease underwent a battery of neuropsychological tests to assess frontal and visuospatial functions, memory and attention. SAI was significantly reduced in patients with VHs compared with controls and patients without VHs. Neuropsychological examination showed a mild cognitive impairment in 16 out of 22 patients with Parkinson's disease. In addition, we found that in our patients with VHs, performance of some tasks evaluating visuospatial functions and attentional/frontal lobe functions was significantly more impaired than in patients without VHs. SAI abnormalities, presence of VH and neuropsychological results strongly support the hypothesis of cholinergic dysfunction in some patients with Parkinson's disease, who will probably develop a dementia. A follow-up study of our patients is required to verify whether SAI abnormalities can predict a future severe cognitive decline. Moreover, SAI can also be very useful to follow-up the efficacy of anti-cholinesterase therapies.

BACKGROUND: In overwork weakness (OW), muscles are increasingly weakened by exercise, work or daily activities. Although it is a well-established phenomenon in several neuromuscular disorders, it is debated whether it occurs in Charcot-Marie-Tooth disease (CMT). Dominant limb muscles undergo a heavier overload than non-dominant and therefore if OW occurs we would expect them to become weaker. Four previous studies, comparing dominant and non-dominant hand strength in CMT series employing manual testing or myometry, gave contradictory results. Moreover, none of them examined the behaviour of lower limb muscles. METHODS: We tested the OW hypothesis in 271 CMT1A adult patients by comparing bilateral intrinsic hand and leg muscle strength with manual testing as well as manual dexterity. RESULTS: We found no significant difference between sides for the strength of first dorsal interosseous, abductor pollicis brevis, anterior tibialis and triceps surae. Dominant side muscles did not become weaker than non-dominant with increasing age and disease severity (assessed with the CMT Neuropathy Score); in fact, the dominant triceps surae was slightly stronger than the non-dominant with increasing age and disease severity. DISCUSSION: Our data does not support the OW hypothesis and the consequent harmful effect of exercise in patients with CMT1A. Physical activity should be encouraged, and rehabilitation remains the most effective treatment for CMT patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

This study evaluates primary and secondary clinical outcome measures in Charcot-Marie-Tooth disease type 1A (CMT1A) with regard to their contribution towards discrimination of disease severity. The nine components of the composite Charcot-Marie-Tooth disease Neuropathy Score and six additional secondary clinical outcome measures were assessed in 479 adult patients with genetically proven CMT1A and 126 healthy controls. Using hierarchical clustering, we identified four significant clusters of patients according to clinical severity. We then tested the impact of each of the CMTNS components and of the secondary clinical parameters with regard to their power to differentiate these four clusters. The CMTNS components ulnar sensory nerve action potential (SNAP), pin sensibility, vibration and strength of arms did not increase the discriminant value of the remaining five CMTNS components (Ulnar compound motor action potential [CMAP], leg motor symptoms, arm motor symptoms, leg strength and sensory symptoms). However, three of the six additional clinical outcome measures the 10 m-timed walking test (T10MW), 9 hole-peg test (9HPT), and foot dorsal flexion dynamometry further improved discrimination between severely and mildly affected patients. From these findings, we identified three different composite measures as score hypotheses and compared their discriminant power with that of the CMTNS. A composite of eight components CMAP, Motor symptoms legs, Motor symptoms arms, Strength of Legs, Sensory symptoms), displayed the strongest power to discriminate between the clusters. As a conclusion, five items from the CMTNS and three secondary clinical outcome measures improve the clinical assessment of patients with CMT1A significantly and are beneficial for upcoming clinical and therapeutic trials. (C) 2014 Elsevier B.V. All rights reserved.

We assessed inter- and intra-rater reliability of outcome measures in Charcot-Marie-Tooth disease (CMT) patients. In 40 CMT patients, we assessed reliability of Overall Neuropathy Limitations Scale (ONLS), 10-m timed walk (T10MW), 9-hole-peg test (9-HPT), maximal voluntary isometric contraction (MVIC) of arm (elbow flexion, hand-grip, and three-point pinch) and leg (knee extension, foot dorsiflexion/plantar flexion). Reliability was substantial for ONLS, excellent for T10MW and 9-HPT. For MVIC, inter and intra-rater reliability was excellent for hand contractions; for leg contractions, intra-rater agreement was moderate to substantial, whereas inter-rater agreement was poor. An ad hoc device was produced to immobilize the foot and MVIC reliability was re-assessed in 26 CMT patients, resulting in excellent inter-rater and intra-rater reliability for foot dorsiflexion, and clear inter-rater improvement for foot plantar flexion. All outcome measures appear adequate for CMT assessment. Use of an immobilization device improves foot MVIC reliability, preventing biased findings in patients with greater strength.

Highlights ► Charcot-Marie-Tooth 1A cannot rely on effective pharmacological treatment. ► Several human trials failed to provide evidence of a therapeutic role of vitamin C. ► Human vitamin C's pharmacokinetics are tightly regulated. ► Ascorbic acid should not be given in excess of its transport system capacity., Charcot–Marie–Tooth 1A disease (CMT1A) is a disease for which no drug treatments are available. In 2004, it was reported that ascorbic acid reduced the severity of neuropathy in transgenic mice overexpressing PMP22, an animal model of human CMT1A, compared with untreated mice. Based on those results, clinical trials were undertaken at different centers worldwide and four of them have been completed, but none of them resulted in significant improvements. Based on the pharmacokinetics of ascorbic acid, we propose that the randomized clinical trial carried out thus far confirmed the tight control of ascorbic acid's absorption and proved its tolerability at one and two years. The pharmacokinetic considerations discussed in this article might largely explain the disappointing results of the recent CMT1A trials.