Diffuse brain connectivity changes in Charcot-Marie-Tooth type 1a patients: a resting-state functional magnetic resonance imaging study.

BACKGROUND AND PURPOSE: Changes of brain structure and function have been described in peripheral neuropathies. The aim of our study was to systematically investigate possible modifications of major large-scale brain networks using resting-state functional magnetic resonance imaging (RS-fMRI) in Charcot-Marie-Tooth disease type 1A (CMT1A) patients. METHODS: In this cross-sectional study, 3-T MRI brain scans were acquired of right-handed genetically confirmed CMT1A patients and age- and sex-comparable healthy controls. Patients also underwent clinical and electrophysiological examinations assessing neurological impairment. RS-fMRI data were analysed using a seed-based approach, with 32 different seeds sampling the main hubs of default mode, sensorimotor, visual, salience (SN), dorsal attention, frontoparietal, language and cerebellar networks. Between-group differences in terms of functional connectivity (FC) with the explored seeds were tested voxelwise, correcting for local grey matter density to account for possible structural abnormalities, whilst the relationship between FC modifications and neurological impairment was investigated using robust correlation analyses. RESULTS: Eighteen CMT1A patients (34.0 ± 11.4 years; M/F 11/7) were enrolled, along with 20 healthy controls (30.1 ± 10.2 years; M/F 11/9). In the CMT group compared to controls, clusters of increased FC with the visual cortex (P = 0.001), SN (P < 6 × 10-4 ), dorsal attention network (P < 8 × 10-5 ) and language network (P < 7 × 10-4 ) were found, along with a single cluster of reduced FC with the visual cortex in the left lentiform nucleus (P = 10-6 ). A significant correlation emerged between neurophysiological impairment and increased FC with right temporal language areas (r = 0.655, P = 0.006), along with an association between walking ability and increased FC with the left supramarginal gyrus (SN) (r = 0.620, P = 0.006). CONCLUSIONS: Our data show evidence of diffuse functional reorganization involving multiple large-scale networks in the CMT1A brain, independent of structural modifications and partially correlating with peripheral nerve damage and functional impairment.

Chronic inflammatory demyelinating polyradiculoneuropathy: can a diagnosis be made in patients not fulfilling electrodiagnostic criteria?

BACKGROUND AND PURPOSE: The aim was to identify the clinical and diagnostic investigations that may help to support a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients not fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria. METHODS: The data from patients with a clinical diagnosis of CIDP included in a national database were retrospectively reviewed. RESULTS: In all, 535 patients with a diagnosis of CIDP were included. This diagnosis fulfilled the EFNS/PNS criteria in 468 patients (87.2%) (definite in 430, probable in 33, possible in three, while two had chronic immune sensory polyradiculopathy). Sixty-seven patients had a medical history and clinical signs compatible with CIDP but electrodiagnostic studies did not fulfill the EFNS/PNS criteria for CIDP. These patients had similar clinical features and frequency of abnormal supportive criteria for the diagnosis of CIDP compared to patients fulfilling EFNS/PNS criteria. Two or more abnormal supportive criteria were present in 40 (61.2%) patients rising to 54 (80.6%) if a history of a relapsing course as a possible supportive criterion was also included. Increased cerebrospinal fluid proteins and response to immune therapy most frequently helped in supporting the diagnosis of CIDP. Response to therapy was similarly frequent in patients fulfilling or not EFNS/PNS criteria (87.3% vs. 85.9%). CONCLUSIONS: Patients with a clinical diagnosis of CIDP had similar clinical findings, frequency of abnormal supportive criteria and response to therapy compared to patients fulfilling EFNS/PNS criteria. The presence of abnormal supportive criteria may help in supporting the diagnosis of CIDP in patients with a medical history and clinical signs compatible with this diagnosis but non-diagnostic nerve conduction studies.

The analysis of epidermal nerve fibre spatial distribution improves the diagnostic yield of skin biopsy.

AIM: Small fibre neuropathy (SFN) diagnosis represents a challenge for neurologists. The diagnostic gold standard is intraepidermal nerve fibre (IENF) density, but in about 10-20% of patients with symptoms/signs and abnormalities on functional tests, it remains within normal range. We propose an adjunctive parameter to improve the efficiency of skin biopsy diagnosis. METHODS: We recruited 31 patients with SFN symptoms/signs, normal nerve conduction study, abnormal quantitative sensory testing and normal IENF density. We also included 31 healthy controls and 31 SFN patients with reduced IENF density as control groups. RESULTS: We measured the distance between consecutive IENFs in the three groups. Mean inter-fibre distances did not differ between patients with normal counts and healthy controls (66.7 ± 14.5 µm vs. 76.7 ± 13.4 µm; P = 0.052), while the relative standard deviation was significantly (P < 0.001) higher in patients (79.3 ± 29.9) compared to controls (51.6 ± 12.2). Using ROC analysis, we identified an inter-fibre distance of 350 µm as the measure that better differentiated patients from controls (AUC = 0.85, sensitivity: 74%, specificity: 94%). At least one such segment was also observed in all patients with reduced IENF count. CONCLUSION: Irregular spatial distribution is an SFN intrinsic feature preceding actual nerve loss. The presence of a stretch of denervated epidermis longer than 350 µm is a parameter able to increase the diagnostic efficiency of skin biopsy.

Recommendations for pre-symptomatic genetic testing for hereditary transthyretin amyloidosis in the era of effective therapy: a multicenter Italian consensus.

Hereditary transthyretin amyloidosis (ATTRv, v for variant) is a late-onset, autosomal dominant disease caused by progressive extracellular deposition of transthyretin amyloid fibrils, leading to organ damage and death. For other late-onset fatal diseases, as Huntington's disease, protocols for pre-symptomatic genetic testing (PST) are available since decades. For ATTRv, limited experience has been reported to date, mostly gathered before the availability of approved therapies. We aimed at developing recommendations for a safe and feasible PST protocol in ATTRv in the era of emerging treatments, taking also into account Italian patients' characteristics and healthcare system rules. After an initial survey on ongoing approaches to PST for ATTRv in Italy, two roundtable meetings were attended by 24 experts from 16 Italian centers involved in the diagnosis and care of this disease. Minimal requirements for PST offer and potential critical issues were highlighted. By November 2019, 457 families affected by ATTRv with 209 molecularly confirmed pre-symptomatic carriers were counted. The median age at PST was 41.3 years of age, regardless of the specific mutation. Half of the Italian centers had a multidisciplinary team, including a neurologist, an internist, a cardiologist, a medical geneticist and a psychologist, although in most cases not all the specialists were available in the same center. A variable number of visits was performed at each site. Experts agreed that PST should be offered only in the context of genetic counselling to at risk individuals aged 18 or older. Advertised commercial options for DNA testing should be avoided. The protocol should consist of several steps, including a preliminary clinical examination, a pre-test information session, an interval time, the genetic test and a post-test session with the disclosure of the test results, in the context of an experienced multidisciplinary team. Recommendations for best timing were also defined. Protocols for PST in the context of ATTRv can be refined to offer at risk individuals the best chance for early diagnosis and timely treatment start, while respecting autonomous decisions and promoting safe psychological adjustment to the genetic result.

Risk factors for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): antecedent events, lifestyle and dietary habits. Data from the Italian CIDP Database.

BACKGROUND AND PURPOSE: The role of lifestyle and dietary habits and antecedent events has not been clearly identified in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: Information was collected about modifiable environmental factors and antecedent infections and vaccinations in patients with CIDP included in an Italian CIDP Database. Only patients who reported not having changed their diet or the lifestyle habits investigated in the study after the appearance of CIDP were included. The partners of patients with CIDP were chosen as controls. Gender-matched analysis was performed with randomly selected controls with a 1:1 ratio of patients and controls. RESULTS: Dietary and lifestyle data of 323 patients and 266 controls were available. A total of 195 cases and 195 sex-matched controls were used in the analysis. Patients eating rice at least three times per week or eating fish at least once per week appeared to be at decreased risk of acquiring CIDP. Data on antecedent events were collected in 411 patients. Antecedent events within 1-42 days before CIDP onset were reported by 15.5% of the patients, including infections in 12% and vaccinations in 1.5%. Patients with CIDP and antecedent infections more often had an acute onset of CIDP and cranial nerve involvement than those without these antecedent events. CONCLUSIONS: The results of this preliminary study seem to indicate that some dietary habits may influence the risk of CIDP and that antecedent infections may have an impact on the onset and clinical presentation of the disease.

Motor performance deterioration accelerates after 50 years of age in Charcot-Marie-Tooth type 1A patients.

BACKGROUND AND PURPOSE: The aim of our study was to describe, by a case-control and cross-sectional design, the correlation between clinical impairment and age in Charcot-Marie-Tooth type 1A (CMT1A) patients. METHODS: Seventy CMT1A patients and 70 sex- and age-matched healthy controls were enrolled. Motor performance was assessed through the 10-m walk test, the 6-min walk test and the 9-hole peg test of the dominant and non-dominant side, and muscle strength was measured by using the Medical Research Council score. In the CMT1A group, disability and quality of life were evaluated using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Short Form 36 (SF-36) questionnaire. Cross-sectional relationships between age and all clinical measures were analyzed and differences in the slopes between cases and controls were calculated. The occurrence of a structural change in the age-related progression of clinical measures was explored. RESULTS: The deterioration of motor performance correlated with age in both groups with a greater slope in CMT1A patients than controls. The deterioration of CMTNS and SF-36 correlated with age in the CMT1A group. The deterioration of all clinical measures with the exception of the SF-36 questionnaire showed a structural change at the 50th year of age. The rate of deterioration was no different between patients and controls until 50 years of age, whereupon it became significantly greater in CMT1A patients. CONCLUSION: Our study supports that the disease progression in CMT1A patients is an age-related process and the 50th year of age represents a critical moment after which the clinical decline becomes faster.

Non-motor involvement in amyotrophic lateral sclerosis: new insight from nerve and vessel analysis in skin biopsy.

AIMS: To assess cutaneous sensory and autonomic nerves and the vascular bed in amyotrophic lateral sclerosis (ALS). METHODS: We enrolled 41 patients (M = 20, aged 63.5 ± 11.8 years), and 41 age- and gender-matched healthy volunteers (M = 20, aged 63.5 ± 11.8 years). Disease severity and sensory and autonomic symptoms were scored using dedicated rating scales. Skin biopsies obtained from thigh, leg and fingertip were processed using indirect immunofluorescence. Intraepidermal nerve fibres, Meissner corpuscles (MCs), intrapapillary myelinated endings, cholinergic and noradrenergic pilomotor nerves and dermal vessels were quantified on confocal images. Intraepidermal nerve fibres, pilomotor nerves and vessels were also assessed on distal leg skin samples of 10 spinal cord injury patients to compare our findings with those of a chronic hypomobility condition. RESULTS: Compared to healthy controls skin biopsies showed: (i) non-length-dependent loss of intraepidermal nerve fibres (P < 0.01) and loss of MCs (P < 0.01); (ii) reduced (P < 0.01) density of pilomotor nerves involving cholinergic and noradrenergic fibres and (iii) a reduced (P < 0.01) vascular bed. Autonomic nerve and dermal vessel densities were higher in patients with higher disease progression rate (P < 0.01). Moreover, we observed signs of nerve regeneration coexisting with nerve degeneration and increased complexity of the dermal vessels. In patients with posttraumatic spinal cord injury, the density of intraepidermal nerve fibres, pilomotor nerves and of the vascular bed did not differ from controls (P > 0.05). CONCLUSIONS: We demonstrated a cutaneous sensory and autonomic denervation in ALS and a previously undescribed relationship between autonomic and vascular involvement that appeared to be linked to the disease progression rate.

Upper motor neuron evaluation in multiple sclerosis patients treated with Sativex®.

BACKGROUND: Spasticity in multiple sclerosis (MS) results from an imbalance of inputs from descending pathways to the spinal motor circuits, as well as from a damage of the corticospinal tract (CST). OBJECTIVES: To assess CST impairment in MS patients with and without spasticity and to evaluate its evolution under Sativex® treatment. METHODS: Ten MS patients with spasticity ("cases") underwent clinical (EDSS, 9-hole Peg, Ashworth scale, Timed 25-Foot Walk, and NRS for spasticity), MRI (CST fractional anisotropy [FA]), and electrophysiological (central motor conduction time [CMCT] and H/M ratio) evaluations at baseline and after 12 months. We selected 20 MS patients without spasticity as control group at baseline. RESULTS: At baseline, cases showed a lower CST FA (0.492±0.045 vs 0.543±0.047; P=.01) and a higher CMCT (P=.001) compared to the control group. No correlations were found between clinical, electrophysiological, and MRI features. After 12 months, cases showed a decrease in non-prevalent degree of impairment (PDI) side FA (0.502±0.023 vs 0.516±0.033; P=.01) without differences for electrophysiological features compared to baseline. Treatment with Sativex® resulted in a reduction of NRS for spasticity (P=.01). CONCLUSIONS: We confirm the presence of CST impairment in MS patients with spasticity. We did not identify structural/electrophysiological correlates that could explain Sativex® clinical effect.

Nerve conduction velocity in CMT1A: what else can we tell?

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease (CMT) type 1A is characterized by uniformly reduced nerve conduction velocity (NCV) that is fully penetrant since the first years of life, remains fairly stable through the life and does not correlate with disability whereas compound muscular action potential (CMAP) amplitude does. The aim of the present study was to analyze the large amount of electrophysiological data collected in the ascorbic acid trial in Italy and the UK (CMT-TRIAAL/CMT-TRAUK) and to use these data to gain insights into the pathophysiology of NCV in CMT1A. METHODS: Baseline electrophysiological data from 271 patients were analysed. Electrophysiological recordings were taken from the motor ulnar, median and peroneal nerves and the sensory ulnar nerve. Distal motor latency (DML), motor (MNCV) and sensory (SNCV) nerve conduction velocity, and amplitudes of CMAPs and sensory action potentials were assessed. Electrophysiological findings were correlated with age of patients at examination and the Charcot-Marie-Tooth Examination Score (CMTES). RESULTS: NCV was markedly and uniformly reduced. CMAP amplitudes were overall reduced but more severely in lower limbs. DML decreased and MNCV and SNCV increased with age of the patients, whereas CMAP amplitudes worsened with age and also correlated with CMTES. CONCLUSIONS: This is the largest sample of electrophysiological data obtained so far from CMT1A patients. Axonal degeneration as assessed by means of CMAP amplitude reflected clinical impairment and was consistent with a slowly progressive length-dependent neuropathy. All patients typically had markedly slowed NCV that did, however, slightly increase with age of the patients. The improvement of NCV might depend on myelin thickness remodelling that occurs during the adult life of CMT1A patients.

Multimodal evoked potentials follow up in multiple sclerosis patients under fingolimod therapy.

BACKGROUND: Clinical trials have shown the therapeutic effect of fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RR-MS), but its influence on nervous conduction assessed by evoked potentials (EPs) has not been previously investigated. METHODS: EP data of 20 patients examined 12months prior to initiation of fingolimod (t=-1), at treatment initiation (t=0) and 1year later (t=+1) were compared. Each EP (VEP, MEP, SEP) and EP sum score, a global evoked potential score as the sum score of the each EP score was evaluated and correlated with Expanded Disability Status Scale (EDSS). RESULTS: During pre-treatment period (1year) EDSS worsened while one year after fingolimod treatment EDSS remained stable. From t-1 to t0 VEP, SEP, MEP and EP sum score worsened while from t0 to t+1 VEP, SEP and EP sum score improved, and MEP score remain stable. VEP and SEP were related to EDSS at baseline (t=-1), while MEP and total EP sum score were related to EDSS at all time points. CONCLUSION: Fingolimod is able to improve visual and somatosensory evoked potential in RR-MS patients even if clinical disability scale remains stable. VEP and SEP could give eloquent information on pathway underweighted in EDSS. EPs are useful to evaluate fingolimod effects in clinical practice.

Novel outcome measures for Charcot-Marie-Tooth disease: validation and reliability of the 6-min walk test and StepWatch(™) Activity Monitor and identification of the walking features related to higher quality of life.

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.

Monitoring effectiveness and safety of Tafamidis in transthyretin amyloidosis in Italy: a longitudinal multicenter study in a non-endemic area.

Tafamidis is a transthyretin (TTR) stabilizer able to prevent TTR tetramer dissociation. There have been a few encouraging studies on Tafamidis efficacy in early-onset inherited transthyretin amyloidosis (ATTR) due to Val30Met mutation. However, less is known about its efficacy in later disease stages and in non-Val30Met mutations. We performed a multi-center observational study on symptomatic ATTR patients prescribed to receive Tafamidis. We followed up patients according to a standardized protocol including general medical, cardiological and neurological assessments at baseline and every 6 months up to 3 years. Sixty-one (42 males) patients were recruited. Only 28 % of enrolled subjects had the common Val30Met mutation, mean age of onset was remarkably late (59 years) and 18 % was in advanced disease stage at study entry. Tafamidis proved safe and well-tolerated. One-third of patients did not show significant progression along 36 months, independently from mutation type and disease stage. Neurological function worsened particularly in the first 6 months but progression slowed significantly thereafter. Autonomic function remained stable in 33 %, worsened in 56 % and improved in 10 %. Fifteen percent of patients showed cardiac disease progression and 30 % new onset of cardiomyopathy. Overall, Tafamidis was not able to prevent functional progression of the disease in 23 (43 %) subjects, including 16 patients who worsened in their walking ability and 12 patients who reached a higher NYHA score during the follow-up period. A higher mBMI at baseline was associated with better preservation of neurological function. In conclusion, neuropathy and cardiomyopathy progressed in a significant proportion of patients despite treatment. However, worsening of neurological function slowed after the first 6 months and also subjects with more advanced neuropathy, as well as patients with non-Val30Met mutation, benefited from treatment. Body weight preservation is an important favorable prognostic factor.

GDAP1 mutations in Italian axonal Charcot-Marie-Tooth patients: Phenotypic features and clinical course.

Mutations in the ganglioside-induced differentiation associated-protein 1 (GDAP1) gene have been associated with both autosomal recessive (AR) and dominant (AD) Charcot-Marie-Tooth (CMT) axonal neuropathy. The relative frequency of heterozygous, dominant mutations in Italian CMT is unknown. We investigated the frequency of dominant mutations in GDAP1 in a cohort of 109 axonal Italian patients by sequencing genomic DNA and search for copy number variations. We also explored correlations with clinical features. All cases had already been tested for variants in common axonal AD genes. Eight patients (7.3%) harbored five already reported heterozygous mutations in GDAP1 (p.Arg120Gly, p.Arg120Trp, p.His123Arg, p.Gln218Glu, p.Arg226Ser). Mutations had different penetrances in the families; the onset of symptoms is in the first decade and progression is slower than usually seen in GDAP1-related AR-CMT. We show that the relative frequency of mutations in GDAP was slightly higher than those observed in MFN2 and MPZ (7.3% vs 6.3% and 5.0%). The relatively milder clinical features and the quite indolent course observed are relevant for prognostic assessment. On the basis of our experience and the data reported here, we suggest GDAP1 as the first gene that should be analysed in Italian patients affected by CMT2.

Responsiveness of clinical outcome measures in Charcot-Marie-Tooth disease.

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.

Recurrence of tako-tsubo syndrome, idiopathic dilated cardiomyopathy, and iterative ventricular tachycardia: just a fortuitous coincidence or a pathophysiological link?

We report the case of a 65-year-old woman with late recurrence of tako-tsubo syndrome, idiopathic dilated cardiomyopathy and prior iterative ventricular tachycardia. We hypothesize that the pathophysiological link among these clinical conditions could be the hyperactivity of the sympathetic nervous system.

Small fiber neuropathy in the chronic phase of Chagas disease: a case report.

We describe the occurrence of small fiber neuropathy in a patient affected by Chagas disease in the indeterminate phase. After the exclusion of all the possible etiologies of small fiber neuropathy, the disorder was considered related to Trypanosoma cruzi infection. Although a peripheral involvement has been described in Chagas disease, this is the first report of a selective involvement of small fibers.