Charcot-Marie-Tooth type 2CC misdiagnosed as Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

BACKGROUND AND AIMS: Charcot-Marie-Tooth (CMT) is a heterogeneous group of genetic neuropathies and is typically characterized by distal muscle weakness, sensory loss, pes cavus and areflexia. Herein we describe a case of CMT2CC presenting with proximal muscle weakness and equivocal electrophysiological features, that was misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). CASE REPORT: A 30-year-old woman complained of proximal muscle weakness with difficulty climbing stairs. Neurological examination showed weakness in lower limb (LL) muscles, that was marked proximally and mild distally, and absence of deep tendon reflexes in the ankles. Nerve conduction studies (NCS) showed sensory-motor neuropathy with non-uniform NC velocity and a partial conduction block (CBs) in peroneal nerve and tibial nerves. Thus, a diagnosis of CIDP was entertained and the patient underwent ineffective treatment with intravenous immunoglobulins. At electrophysiological revaluation CB in peroneal nerve was undetectable as also distal CMAP had decreased whereas the CBs persisted in tibial nerves. Hypothesizing a hereditary neuropathy, we examined the proband's son, who presented mild weakness of distal and proximal muscles at lower limbs. Neurophysiological investigation showed findings consistent with an intermediate-axonal electrophysiological pattern. A targeted-NGS including 136 CMT genes showed the heterozygous frameshift mutation (c.3057dupG; p.K1020fs*43) in the NEFH gene, coding for the neurofilament heavy chain and causing CMT2CC. INTERPRETATION: Diagnosis of a genetic neuropathy may be challenging when clinical features are atypical and/or electrophysiological features are misleading. The most common misdiagnosis is CIDP. Our report suggests that also CMT2CC patients with proximal muscle weakness and equivocal electrophysiological features might be misdiagnosed as CIDP.

ChatGPT vs. neurologists: a cross-sectional study investigating preference, satisfaction ratings and perceived empathy in responses among people living with multiple sclerosis.

BACKGROUND: ChatGPT is an open-source natural language processing software that replies to users' queries. We conducted a cross-sectional study to assess people living with Multiple Sclerosis' (PwMS) preferences, satisfaction, and empathy toward two alternate responses to four frequently-asked questions, one authored by a group of neurologists, the other by ChatGPT. METHODS: An online form was sent through digital communication platforms. PwMS were blind to the author of each response and were asked to express their preference for each alternate response to the four questions. The overall satisfaction was assessed using a Likert scale (1-5); the Consultation and Relational Empathy scale was employed to assess perceived empathy. RESULTS: We included 1133 PwMS (age, 45.26 ± 11.50 years; females, 68.49%). ChatGPT's responses showed significantly higher empathy scores (Coeff = 1.38; 95% CI = 0.65, 2.11; p > z < 0.01), when compared with neurologists' responses. No association was found between ChatGPT' responses and mean satisfaction (Coeff = 0.03; 95% CI = - 0.01, 0.07; p = 0.157). College graduate, when compared with high school education responder, had significantly lower likelihood to prefer ChatGPT response (IRR = 0.87; 95% CI = 0.79, 0.95; p < 0.01). CONCLUSIONS: ChatGPT-authored responses provided higher empathy than neurologists. Although AI holds potential, physicians should prepare to interact with increasingly digitized patients and guide them on responsible AI use. Future development should consider tailoring AIs' responses to individual characteristics. Within the progressive digitalization of the population, ChatGPT could emerge as a helpful support in healthcare management rather than an alternative.

Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop).

BACKGROUND AND PURPOSE: Cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited. METHODS: This retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2-year course of cladribine treatment. The primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2-year treatment course. RESULTS: A total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. The study found a significant reduction in annualized relapse rate at the 12-month follow-up after cladribine completion compared to the year prior to starting therapy (0.07 ± 0.25 vs. 0.82 ± 0.80, p < 0.001). Furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. The safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event. CONCLUSIONS: This study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. Real-world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. However, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long-term impact are necessary.

A Blood Test for the Diagnosis of Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune chronic disease characterized by inflammation and demyelination of the central nervous system (CNS). Despite numerous studies conducted, valid biomarkers enabling a definitive diagnosis of MS are not yet available. The aim of our study was to identify a marker from a blood sample to ease the diagnosis of MS. In this study, since there is evidence connecting the serotonin pathway to MS, we used an ELISA (Enzyme-Linked Immunosorbent Assay) to detect serum MS-specific auto-antibodies (auto-Ab) against the extracellular loop 1 (ECL-1) of the 5-hydroxytryptamine (5-HT) receptor subtype 2A (5-HT2A). We utilized an ELISA format employing poly-D-lysine as a pre-coating agent. The binding of 208 serum samples from controls, both healthy and pathological, and of 104 serum samples from relapsing-remitting MS (RRMS) patients was tested. We observed that the serum-binding activity in control cohort sera, including those with autoimmune and neurological diseases, was ten times lower compared to the RRMS patient cohort (p = 1.2 × 10-47), with a sensitivity and a specificity of 98% and 100%, respectively. These results show that in the serum of patients with MS there are auto-Ab against the serotonin receptor type 2A which can be successfully used in the diagnosis of MS due to their high sensitivity and specificity.

Heterogenous electrophysiological features in early stage of hereditary transthyretin amyloidosis neuropathy.

INTRODUCTION: Hereditary transthyretin-mediated amyloidosis (ATTRv, v for variant) is a progressive disease caused by mutations in the TTR gene, leading to sensory-motor, axonal and length-dependent neuropathy. However, some patients may show variable electrophysiological pattern. The aim of this study was to evaluate the electrophysiological features of TTR amyloid neuropathy at the time of the first nerve conduction study (NCS) to assess whether there were distinguishing features useful for early diagnosis. METHODS: We retrospectively revised the first electrophysiological findings of ATTRv patients, and we categorized the neuropathy based on nerve conduction slowing, type of involved fibres and distribution pattern of PNS involvement. Cluster analysis was performed to evaluate the prevalence of neuropathy features between the early and late stage of disease, based on disease duration and disability burden assessed by NIS. RESULTS: We recruited 33 patients (27 males) with mean age 63.9 ± 10.8 years, mean disease duration 2.8 ± 2.4 years and mean NIS 47.6 ± 41.8. Overall, the frequency analysis showed that the most common features of ATTRv neuropathy included the categories of axonal, sensory-motor and neuronopathic-like pattern. This electrophysiological pattern of PNS involvement was constant in patients in late stage of disease, whereas ATTRv patients in early stage of disease displayed variable electrophysiological pattern of PNS involvement. DISCUSSION: Our findings demonstrated that ATTRv neuropathy may present at first NCS in a variable way, and it changes over the course of disease. Such heterogeneity makes the suspicion of ATTRv even more challenging at the time of first electrophysiological examination.

Skin innervation across amyotrophic lateral sclerosis clinical stages: new prognostic biomarkers.

Over recent decades, peripheral sensory abnormalities, including the evidence of cutaneous denervation, have been reported among the non-motor manifestations in amyotrophic lateral sclerosis (ALS). However, a correlation between cutaneous innervation and clinical features has not been found. The aims of this study were to assess sensory involvement by applying a morpho-functional approach to a large population of ALS patients stratified according to King's stages and correlate these findings with the severity and prognosis of the disease. We recruited 149 ALS patients and 41 healthy controls. Patients undertook clinical questionnaires for small fibre neuropathy symptoms (Small Fiber Neuropathy Symptoms Inventory Questionnaire) and underwent nerve conductions studies (NCS) and 3-mm punch skin biopsies from leg, thigh and fingertip. We assessed intraepidermal nerve fibre (IENF) and Meissner corpuscle (MC) density by applying an indirect immunofluorescence technique. Moreover, a subset of 65 ALS patients underwent a longitudinal study with repeat biopsies from the thigh at 6- and 12-month follow-ups. Serum NfL levels were measured in 40 patients. Sensory symptoms and sensory NCS abnormalities were present in 32.2% and 24% of patients, respectively, and increased across clinical stages. Analogously, we observed a progressive reduction in amplitude of the sensory and motor ulnar nerve potential from stage 1 to stage 4. Skin biopsy showed a significant loss of IENFs and MCs in ALS compared with healthy controls (all P < 0.001). Across the clinical stages, we found a progressive reduction in MCs (P = 0.004) and an increase in IENFs (all P < 0.027). The increase in IENFs was confirmed by the longitudinal study. Interestingly, the MC density inversely correlated with NfL level (r = -0.424, P = 0.012), and survival analysis revealed that low MC density, higher NfL levels and increasing IENF density over time were associated with a poorer prognosis (all P < 0.024). To summarize, in patients with ALS, peripheral sensory involvement worsens in parallel with motor disability. Furthermore, the correlation between skin innervation and disease activity may suggest the use of skin innervation as a putative prognostic biomarker.

Pregnancy experience in women with spinal muscular atrophy: a case series.

Many women with spinal muscular atrophy (SMA) types II, III, and IV reach fertile age, and some of them may consider pregnancy. However, limited data are available about the potential effects of pregnancy on the course of SMA and the outcomes of pregnancies in these patients. Furthermore, the use of several disease-modifying therapies for the treatment of all types of SMA is expected to increase the number of female SMA patients considering pregnancy in the coming years. The aim of this report is to provide clinicians with an overview of the patients in our cohort who have experienced pregnancies. We conducted a retrospective analysis on these women, through the administration of a questionnaire, which investigated how they experienced the different stages of the pregnancy. Ten patients (3 SMAII; 7 SMA III) participated in the survey; 40% had pregnancies for a total of nine, six of which were term-pregnancies. The mean age of first pregnancy was 32.5 ± 7.8 years for SMA II patients, and 30.5 ± 2.1 years for SMA III. All pregnancies ended in cesarean sections. Interestingly, the sitters had more frequent complications in pre-term labor and delivery, but the newborns were all healthy. This report shows that a successful pregnancy is possible in female patients with SMA. However, the ideal approach should involve a standardized multidisciplinary team capable of effectively addressing every possible scenario. For this reason, it is critically important that clinicians working with SMA patients gain more in-dept knowledge about this topic.

Intra- and Extra-Hospitalization Monitoring of Vital Signs-Two Sides of the Same Coin: Perspectives from LIMS and Greenline-HT Study Operators.

BACKGROUND: In recent years, due to the epidemiological transition, the burden of very complex patients in hospital wards has increased. Telemedicine usage appears to be a potential high-impact factor in helping with patient management, allowing hospital personnel to assess conditions in out-of-hospital scenarios. METHODS: To investigate the management of chronic patients during both hospitalization for disease and discharge, randomized studies (LIMS and Greenline-HT) are ongoing in the Internal Medicine Unit at ASL Roma 6 Castelli Hospital. The study endpoints are clinical outcomes (from a patient's perspective). In this perspective paper, the main findings of these studies, from the operators' point of view, are reported. Operator opinions were collected from structured and unstructured surveys conducted among the staff involved, and their main themes are reported in a narrative manner. RESULTS: Telemonitoring appears to be linked to a reduction in side-events and side-effects, which represent some of most commons risk factors for re-hospitalization and for delayed discharge during hospitalization. The main perceived advantages are increased patient safety and the quick response in case of emergency. The main disadvantages are believed to be related to low patient compliance and an infrastructural lack of optimization. CONCLUSIONS: The evidence of wireless monitoring studies, combined with the analysis of activity data, suggests the need for a model of patient management that envisages an increase in the territory of structures capable of offering patients subacute care (the possibility of antibiotic treatments, blood transfusions, infusion support, and pain therapy) for the timely management of chronic patients in the terminal phase, for which treatment in acute wards must be guaranteed only for a limited time for the management of the acute phase of their diseases.

Cognitive impairment is associated with gait variability and fall risk in amyotrophic lateral sclerosis.

BACKGROUND: In amyotrophic lateral sclerosis (ALS), gait abnormalities contribute to poor mobility and represent a relevant risk for falls. To date, gait studies in ALS patients have focused on the motor dimension of the disease, underestimating the cognitive aspects. METHODS: Using a wearable gait analysis device, we compared gait patterns in ambulatory ALS patients with mild cognitive impairment (ALS MCI+; n = 18), and without MCI (ALS MCI-; n = 24), and healthy subjects (HS; n = 16) under two conditions: (1) normal gait (single task) and (2) walking while counting backward (dual task). Finally, we examined if the occurrence and number of falls in the 3 months following the baseline test were related to cognition. RESULTS: In the single task condition, ALS patients, regardless of cognition, displayed higher gait variability than HS, especially for stance and swing time (p < 0.001). The dual task condition revealed additional differences in gait variability parameters between ALS MCI+ and ALS MCI- for cadence (p = 0.005), stance time (p = 0.04), swing time (p = 0.04) and stability index (p = 0.02). Moreover, ALS MCI+ showed a higher occurrence (p = 0.001) and number of falls (p < 0.001) at the follow-up. Regression analyses demonstrated that MCI condition predicted the occurrence of future falls (ß = 3.649; p = 0.01) and, together with executive dysfunction, was associated with the number of falls (cognitive impairment: ß = 0.63; p < 0.001; executive dysfunction: ß = 0.39; p = 0.03), regardless of motor impairment at clinical examination. CONCLUSION: In ALS, MCI is associated with exaggerated gait variability and predicts the occurrence and number of short-term falls.

Multiple cranial neuropathy due to varicella zoster virus reactivation without vesicular rash: a challenging diagnosis.

Ramsay Hunt syndrome is due to reactivation of varicella zoster virus (VZV) dormant in the geniculate ganglion of the facial nerve. The diagnosis is typically based on clinical triad of ipsilateral facial paralysis, otalgia, and vesicles in the auditory canal or the auricle. However, Ramsay Hunt syndrome may occur without skin eruption in up to one third of patients. Moreover, the involvement of other cranial nerves in addition to the facial nerve has been also reported. Herein, we reported a case report of a man who developed a multiple cranial neuropathy caused by VZV reactivation without skin vesicular eruption. The present case underlines a possible diagnostic challenge that clinicians may hit when facing a common disorder such as peripheral facial palsy. Indeed, clinicians must be aware that Ramsay Hunt syndrome may develop without skin vesicular eruption as well it may be complicated by multiple cranial nerve involvement. Antiviral therapy is effective in VZV reactivation for recovery of nerve function.

Efficacy of recanalization therapy for ischemic stroke: multicenter hospital network experience.

PURPOSE: Stroke is a leading cause of long-term disability with high mortality rate in the first year after the event. In Campania, mechanical thrombectomy treatment significantly increases in the last 3 years, as well as hospitals delivering acute stroke treatments. The aim of this study is to demonstrate how a full opening of our stroke network improves stroke management and stroked patients' survival in Campania. MATERIAL AND METHODS: In Federico II University Hospital of Naples acting as a HUB center of 7 peripheral SPOKE hospitals in regional territory, 68 patients with acute ischemic stroke were evaluated with NIHSS and m-RS clinical scores and neuroradiological ASPECT scores, from January 1 to December 31, 2021. At hospital discharge, NIHSS score and three months after m-RS score were re-assessed to evaluate the therapeutic effects. RESULTS: Forty-two of 68 patients (63%) admitted to our hub center had ischemic acute stroke at CT evaluation; 29 patients had ASPECT score > 7 (69%), and 6 a score < 7 (14%). At admission, NIHSS score mean value was 10.75, and m-RS score mean value was 0.74. At discharge, NIHSS score mean value was 7.09. After three months, m-RS score mean value was 0.74. DISCUSSION: The inter-company agreement between Federico II University and several peripheral hospitals allows an absolute and relative increase in endovascular mechanical thrombectomy and intravenous thrombolysis procedures, with a relative prevalence of mechanical thrombectomy. A regional implementation of the stroke multi-disciplinary care system is hardly needed to ensure the optimum treatment for the largest number of patients, improving patient's outcome.

25-Hydroxy-Vitamin D and Risk of Recurrent Stroke: A Dose Response Meta-Analysis.

Stroke recurrence significantly improves the prognosis quoad vitam et valetudinem of patients with a first ischemic or haemorrhagic stroke. Other than in bone and skeletal metabolism, vitamin D is involved in the pathogenesis of cardiovascular disorders. This meta-analysis was performed to evaluate the relationship between 25OH-vitamin D [25(OH)D] levels at the first stroke and the stroke recurrence. To 31 July 2022, four prospective studies were identified. The potential non-linear relationship was evaluated by modelling 25(OH)D, using restricted cubic splines of 25(OH)D distribution. The pooled estimated risk (and 95% CI) of the recurrence of stroke, comparing the highest and the lowest levels, was assessed using a random-effect model. A non-linear association was found by dose-response analysis. This study found that 25(OH)D levels at the first stroke ≥9.3 ng/mL were associated with a lower risk of stroke recurrence, compared with 25(OH)D levels ≤8.5 ng/mL. In the pooled analysis, higher 25(OH)D levels at the first stroke significantly reduce the risk of stroke recurrence, with a significant heterogeneity among studies. In conclusion, 25(OH)D levels ≤8.5 ng/mL at the first stroke are significantly associated with a higher risk of recurrent stroke.

A review of current rehabilitation practices and their benefits in patients with multiple sclerosis.

Multiple sclerosis (MS) is a chronic, debilitating disease characterised by demyelination of the nerves of the central nervous system that results in patients progressively losing the ability to perform daily tasks. As there is no cure for this disease, rehabilitation therapy is an important aspect of care; assisting patients to regain or retain function and improve their physical, mental and social wellbeing. At present there is no current consistent model of care for MS, likely due to the variable symptom presentation. Various forms of rehabilitation therapy are available, and these include physical rehabilitation methods, such as balance and gait therapy, speech and respiration rehabilitation, and occupational therapy. Contrary to previous understanding, exercise-based therapies have shown various benefits for patients with MS, and in addition to improving MS-related physical symptoms, have been shown to reduce the risk of developing cardiovascular disease and can improve cognitive function. Cognition rehabilitation therapy specifically focuses on behavioural tasks and is divided into two main forms: compensatory rehabilitation, which offers cognitive functioning benefits, and restorative rehabilitation, which offers memory benefits. Excitation therapies include cranial stimulation and other stimulation rehabilitation methods such as focal muscle vibration therapy and these non-invasive techniques may improve patient's physical ability. Additionally, more novel rehabilitation methods include robot-assisted gait therapy and telerehabilitation, both of which are expected to play progressively more prominent roles in the future of rehabilitation therapy. The structure of the care team has been found to impact patient outcomes, and both in- and out-patient care settings have been found to be beneficial, dependant on the patient's circumstances, with certain patients better suited to a particular setting. While a single point of care is recommended for patients, a multidisciplinary care team and regular reassessment is recommended to manage changing symptoms and ensure continuity of care. The importance of the critical components of rehabilitation have been identified, and these are of vital importance in achieving beneficial outcomes. These components include the patients' participation in the treatment, goal setting with a multidisciplinary care team, a guiding-light purpose for the patient, which focusses on recognizing their personal potential and obtaining improvements through a tailored plan. The final critical component of rehabilitation is the results measurement, which highlights the need for a quantifiable reduction in impairment and improvement in activity and participation. Overall, a lack of standardisation in outcome measurements makes comparison challenging. This is particularly important when comparing standard methods of care with more novel rehabilitation techniques. However, within the broad area of rehabilitation therapies, it is clear that patients with MS can benefit from rehabilitation practices; physically, mentally and socially.

AQP4-MOG Double-Positive Neuromyelitis Optica Spectrum Disorder: Case Report with Central and Peripheral Nervous System Involvement and Review of Literature.

(1) The co-occurrence of AQP4 and myelin oligodendrocyte glycoprotein (MOG) antibodies in patients with demyelinating disorders is extremely rare. In addition, a concomitant involvement of the peripheral nervous system (PNS) has been described either in association with AQP4 antibodies-positive neuromyelitis optica spectrum disorder (NMOSD), or MOG-associated disease. We report on a case of NMOSD with co-occurrence of AQP4 and MOG antibodies and concomitant central and peripheral nervous system involvement. We also reviewed available cases of AQP4-MOG double-positive patients. (2) Brain and spine MRI, cerebrospinal fluid studies, and electrophysiological test were performed. Serum AQP4 and MOG positivity was assessed with live cell-based assay. (3) A 62-year-old woman presented with recurrent optic neuritis, myelitis, and radiculitis, tested positive for AQP4 and MOG antibodies, and was treated successfully with rituximab. (4) Although few cases of AQP4-MOG double-positive patients were already described mostly affecting females with a concomitant spinal cord and optical nerve involvement, we describe the first case of double-positive NMOSD with the peculiar involvement of both central and peripheral nervous system.

Persistence with Botulinum Toxin Treatment for Spasticity Symptoms in Multiple Sclerosis.

Botulinum toxin (BT) is an effective treatment for spasticity symptoms in multiple sclerosis (MS). Despite its wide use in clinical practices, only few studies have explored long-term persistence. We aim to evaluate the rate of discontinuation of BT treatment and the correlation with MS, spasticity, and injection variables. This retrospective study on 3-year prospectively collected data included 122 MS patients receiving BT injections for spasticity. We collected MS clinical variables (disease durations, Expanded Disability Status Scales [EDSSs], disease-modifying treatments [DMT], and Symbol Digit Modalities Tests [SDMTs]), modified Ashworth scales [MASs], concomitant treatments, and injection variables (formulation, dose, number of injections, and intervals between injections). A total of 14 out of the 122 patients discontinued BT after a mean time of 3.0 ± 1.5 years. In the Cox regression model including the MS clinical variables, the probability of BT discontinuations increased in patients with DMT changes during follow-ups (HR = 6.34; 95%Cl = 2.47, 18.08; p < 0.01) and with impaired SDMTs (HR = 1.20; 95%Cl = 1.04, 1.96; p < 0.01). In the model including the spasticity variables, there were no associations between BT discontinuation and MAS or other spasticity treatments. In the model including the injection variables, the probability of discontinuation decreased by 80% for each cumulative injection (HR = 0.16; 95%Cl = 0.05, 0.45; p < 0.01), but increased by 1% for each additional day over the 3-month interval between injections (HR = 1.27; 95%Cl = 1.07, 1.83; p < 0.01). BT discontinuation was associated with concomitant MS-related issues (e.g., treatment failure and DMT change) and the presence of cognitive impairment, which should be accounted for when planning injections. The interval between injections should be kept as short as possible from regulatory and clinical perspectives to maximize the response across all of the spasticity symptoms and to reduce discontinuation in the long term.

Quantitative Sensory Testing in Late-Onset ATTRv Presymptomatic Subjects: A Single Center Experience.

Backgrounds Hereditary transthyretin amyloidosis (ATTRv) presymptomatic subjects undergo multidisciplinary evaluation to detect, as early as possible, a subclinical involvement of multisystem disease. Quantitative sensory testing (QST) that investigates and discriminates the function of C, Aδ and Aß fibers is included as an instrumental test to monitor nerve fiber function. The purpose of this study was to evaluate the role of QST in the context of the multidisciplinary evaluation in late onset carriers. Methods Four-teen presymptomatic (namely carriers) were enrolled. Subjects underwent thermal [cold and warm detection threshold (CDT, WDT), cold and heat pain (CP and HP)] and tactile QST in four body sites: foot dorsum, distal lateral leg, distal thigh, hand dorsum. Results Overall, presymptomatic subject showed a significant difference in all thermal QST findings compared to the control group. All subjects had at least one altered thermal QST finding; the sites more frequently altered were foot and leg, whilst the thermal modalities which were more frequently abnormal were CDT, WDT and CP. Conclusions Our study highlights the importance of performing thermal QST in subjects carrying TTR mutation, given the high frequency of abnormal findings. Notably, performing both innocuous and painful stimulation in foot and/or leg increases the chance of detecting nerve fiber dysfunction. Moreover, the investigation of the hand may provide useful information in monitoring disease progression before the Predicted Age of Disease Onset (PADO).

Phosphorylated α-Synuclein Deposits in Cutaneous Nerves of Early Parkinsonism.

BACKGROUND: The role of peripheral phosphorylated-α-Synuclein (p-α-syn) deposition on nerve degeneration in synucleinopathies is still unknown. OBJECTIVE: To assess the cutaneous neural distribution of p-α-Syn deposits and its correlation with clinical data and with morphology and function of cutaneous sensory and autonomic nerves in early Parkinson's disease (PD) and multiple system atrophy-parkinson type (MSA-p). METHODS: We recruited 57 PD (F/M = 21/36; age 63.5±9.4 years) and 43 MSA-p (F/M = 16/27; age 62.3±9.0 years) patients within 2 years from motor symptoms. We applied questionnaires and clinical scales, sensory thresholds, and sudomotor testing to assess severity of motor and non-motor involvement and sensory and autonomic dysfunction. We quantified, in skin biopsy from thigh, leg, and fingertip, epidermal, pilomotor, and sudomotor nerve fibers, Meissner corpuscles and intrapapillary myelinated endings and the neural distribution of p-α-syn deposits. RESULTS: Compared to controls, we found a cutaneous denervation paralleling functional and clinical impairment. Sensory and autonomic denervation was more severe in MSA-p than in PD. Deposits of p-α-syn were found in the majority of patients, with no significant differences among sites in both groups. Higher occurrence of p-α-syn deposits in autonomic nerves differentiated (p < 0.01) PD from MSA-p. p-α-syn deposits correlated positively with sudomotor function, epidermal, pilomotor and sudomotor nerve densities, and inversely with non-motor symptoms and disease progression. CONCLUSION: Our work demonstrated an early peripheral sensory and autonomic involvement in synucleinopathies, more severe in MSA-p than in PD. Higher p-α-syn deposits in autonomic nerves differentiated PD from MSA-p. p-α-syn deposits were associated with preserved innervation and slower disease progression.