Use, tolerability, benefits and side effects of orthotic devices in Charcot-Marie-Tooth disease.

BACKGROUND: Shoe inserts, orthopaedic shoes, ankle-foot orthoses (AFOs) are important devices in Charcot-Marie-Tooth disease (CMT) management, but data about use, benefits and tolerance are scanty. METHODS: We administered to Italian CMT Registry patients an online ad hoc questionnaire investigating use, complications and perceived benefit/tolerability/emotional distress of shoe inserts, orthopaedic shoes, AFOs and other orthoses/aids. Patients were also asked to fill in the Quebec User Evaluation of Satisfaction with assistive Technology questionnaire, rating satisfaction with currently used AFO and related services. RESULTS: We analysed answers from 266 CMT patients. Seventy per cent of subjects were prescribed lower limb orthoses, but 19% did not used them. Overall, 39% of subjects wore shoe inserts, 18% orthopaedic shoes and 23% AFOs. Frequency of abandonment was high: 24% for shoe inserts, 28% for orthopaedic shoes and 31% for AFOs. Complications were reported by 59% of patients and were more frequently related to AFOs (69%). AFO users experienced greater emotional distress and reduced tolerability as compared with shoe inserts (p<0.001) and orthopaedic shoes (p=0.003 and p=0.045, respectively). Disease severity, degree of foot weakness, customisation and timing for customisation were determinant factors in AFOs' tolerability. Quality of professional and follow-up services were perceived issues. CONCLUSIONS: The majority of CMT patients is prescribed shoe inserts, orthopaedic shoes and/or AFOs. Although perceived benefits and tolerability are rather good, there is a high rate of complications, potentially inappropriate prescriptions and considerable emotional distress, which reduce the use of AFOs. A rational, patient-oriented and multidisciplinary approach to orthoses prescription must be encouraged.

Long-term treatment of hereditary transthyretin amyloidosis with patisiran: multicentre, real-world experience in Italy.

BACKGROUND: Hereditary transthyretin (ATTRv, v for variant) amyloidosis with polyneuropathy is a rare disease caused by mutations in the transthyretin gene. In ATTRv amyloidosis, multisystem extracellular deposits of amyloid cause tissue and organ dysfunction. Patisiran is a small interfering RNA molecule drug that reduces circulating levels of mutant and wild-type TTR proteins. Prior to its regulatory approval, patisiran was available in Italy through a compassionate use programme (CUP). The aim of this study was to analyse the long-term outcomes of patients who entered into the CUP. METHODS: This was a multicentre, observational, retrospective study of patients with ATTRv amyloidosis treated with patisiran. The analysis included change from baseline to 12, 24, 36 and 48 months in familial amyloid polyneuropathy (FAP) stage, polyneuropathy disability (PND) class, neuropathy impairment score (NIS), modified body mass index (mBMI), Compound Autonomic Dysfunction Test (CADT), Karnofsky Performance Status (KPS) scale and Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) questionnaire. Safety data were also analysed. RESULTS: Forty patients from 11 Italian centres were enrolled: 23 in FAP 1 (6 in PND 1 and 17 in PND 2) and 17 in FAP 2 (8 in PND 3a and 9 in PND 3b) stage. In this population, the mean NIS at baseline was 71.4 (± 27.8); mBMI, 917.1 (± 207) kg/m2; KPS, 67.1 (± 14.0); Norfolk QoL-DN, 62.2 (± 25.2); and CADT, 13.2 (± 3.3). Statistical analysis showed few significant differences from baseline denoting disease stability. No new safety signals emerged. CONCLUSIONS: Patisiran largely stabilised disease in patients with ATTRv amyloidosis.

Clinical and pathology characterization of small nerve fiber neuro(no)pathy in cerebellar ataxia with neuropathy and vestibular areflexia syndrome.

BACKGROUND AND PURPOSE: Biallelic mutation/expansion of the gene RFC1 has been described in association with a spectrum of manifestations ranging from isolated sensory neuro(no)pathy to a complex presentation as cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Our aim was to define the frequency and characteristics of small fiber neuropathy (SFN) in RFC1 disease at different stages. METHODS: RFC1 cases were screened for SFN using the Neuropathic Pain Symptom Inventory and Composite Autonomic Symptom Score 31 questionnaires. Clinical data were retrospectively collected. If available, lower limb skin biopsy samples were evaluated for somatic epidermal and autonomic subepidermal structure innervation and compared to healthy controls (HCs). RESULTS: Forty patients, median age at onset 54 years (interquartile range [IQR] 49-61) and disease duration 10 years (IQR 6-16), were enrolled. Mild-to-moderate positive symptoms (median Neuropathic Pain Symptom Inventory score 12.1/50, IQR 5.5-22.3) and relevant autonomic disturbances (median Composite Autonomic Symptom Score 31 37.0/100, IQR 17.7-44.3) were frequently reported and showed scarce correlation with disease duration. A non-length-dependent impairment in nociception was evident in both clinical and paraclinical investigations. An extreme somatic denervation was observed in all patients at both proximal (fibers/mm, RFC1 cases 0.0 vs. HCs 20.5, p < 0.0001) and distal sites (fibers/mm, RFC1 cases 0.0 vs. HCs 13.1, p < 0.0001); instead only a slight decrease was observed in cholinergic and adrenergic innervation of autonomic structures. CONCLUSIONS: RFC1 disease is characterized by a severe and widespread somatic SFN. Skin denervation may potentially represent the earliest feature and drive towards the suspicion of this disorder.

Risk of disease relapse, safety and tolerability of SARS-CoV-2 vaccination in patients with chronic inflammatory neuropathies.

BACKGROUND AND PURPOSE: The aim was to evaluate the risk of relapse after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, and its safety and tolerability, in patients with chronic inflammatory neuropathies. METHODS: In this multicenter, cohort and case-crossover study, the risk of relapse associated with SARS-CoV-2 vaccination was assessed by comparing the frequency of relapse in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) patients who underwent or did not undergo vaccination. Frequency of relapse in the 3 months prior to and after vaccination, and safety and tolerability of SARS-CoV-2 vaccination, were also assessed. RESULTS: In all, 336 patients were included (278 CIDP, 58 MMN). Three hundred and seven (91%) patients underwent SARS-CoV-2 vaccination. Twenty-nine patients (9%) did not undergo vaccination. Mild and transient relapses were observed in 16 (5%) patients (13 CIDP, 3 MMN) after SARS-CoV-2 vaccination and in none of the patients who did not undergo vaccination (relative risk [RR] 3.21, 95% confidence interval [CI] 0.19-52.25). There was no increase in the specific risk of relapse associated with type of vaccine or diagnosis. Comparison with the 3-month control period preceding vaccination revealed an increased risk of relapse after vaccination (RR 4.00, 95% CI 1.35-11.82), which was restricted to CIDP patients (RR 3.25, 95% CI 1.07-9.84). The safety profile of SARS-CoV-2 vaccination was characterized by short-term, mild-to-moderate local and systemic adverse events. CONCLUSIONS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in CIDP and MMN patients does not seem to be associated with an increased risk of relapse at the primary end-point, although a slightly increased risk in CIDP patients was found compared to the 3 months before vaccination.

Real-life experience with inotersen in hereditary transthyretin amyloidosis with late-onset phenotype: Data from an early-access program in Italy.

BACKGROUND AND PURPOSE: Hereditary transthyretin (TTR) amyloidosis (ATTRv) is a dominantly inherited, adult-onset, progressive, and fatal disease caused by mutations in the transthyretin gene. Therapeutic agents approved for this disease include the TTR stabilizer tafamidis and the gene-silencing drugs patisiran and inotersen. Inotersen is an antisense oligonucleotide that suppresses the hepatic production of transthyretin. After European Medical Agency approval in 2018, an early-access program was opened in Italy, and in this article, we present the long-term outcome of a cohort of Italian ATTRv patients who received inotersen within this program. METHODS: This is a multicenter, observational, retrospective study of patients affected by ATTRv that started inotersen during the early-access program. The primary end point was safety. Secondary end points included change from baseline in familial amyloid polyneuropathy (FAP) stage, Polyneuropathy Disability, Neuropathy Impairment Scale, Compound Autonomic Dysfunction Test, Norfolk Quality of Life-Diabetic Neuropathy, troponin, N-terminal pro-brain natriuretic peptide, interventricular septum thickness, and body mass index. RESULTS: In total, 23 patients were enrolled. No patient permanently discontinued the treatment because of thrombocytopenia, and no cases of severe thrombocytopenia were observed. Five patients discontinued the treatment permanently because of voluntary withdrawal (two patients), renal failure after infective pyelonephritis, not related to inotersen, drug-related hypotension, and amyloid-negative crescentic glomerulonephritis. In seven patients, dosing frequency was reduced to every 2 weeks due to recurrent thrombocytopenia. Considering the FAP stage, only two patients worsened, whereas the other 21 patients remained stable until the last follow-up available. CONCLUSIONS: The long-term safety profile of inotersen is favorable. Neurologic disease severity at baseline is the main factor associated with progression.

Hereditary neuropathies: A pathological perspective.

Hereditary neuropathies may result from mutations in genes expressed by Schwann cells or neurons that affect selectively the peripheral nervous system (PNS) or may represent a minor or major component of complex inherited diseases that involve also the central nervous system and/or other organs and tissues. The chapter is constantly expanding and reworking, thanks to advances of molecular genetics; next-generation sequencing is identifying a plethora of new genes and is revolutionizing the diagnostic approach. In the past, diagnostic sural nerve biopsies paved the way to the discovery and elucidation of major genes and molecular pathways associated to most frequent hereditary motor-sensory neuropathies. Nowadays, a sural nerve biopsy may prove useful in selected cases for the differential diagnosis of an acquired neuropathy when clinical examination, nerve conduction studies, and molecular tests are not sufficiently informative. Skin biopsy has emerged as a minimally invasive window on the PNS, which may provide biomarkers of progression and clues to the physiopathology and molecular pathology of inherited neuropathies. The aim of our review is to illustrate the pathological features of more frequent and paradigmatic hereditary neuropathies and to highlight their correlations with the roles of the involved genes and functional consequences of related molecular defects.

Myelin uncompaction and axo-glial detachment in chronic ataxic neuropathy with monospecific IgM antibody to ganglioside GD1b.

To describe clinical features, disease course, treatment response, and sural nerve biopsy findings in a patient with chronic sensory ataxic neuropathy, Binet stage A chronic lymphocytic leukemia, and monoclonal IgMλ paraprotein against ganglioside GD1b. During 9 months of hospitalization at two neurologic centers, the patient underwent serial neurologic examinations, neurophysiologic studies, imaging investigations, extensive laboratory work-up, bone marrow, and sural nerve biopsies. The patient had a severe progressive sensory neuropathy accompanied by motor involvement, dysautonomia, and marked bulbar weakness with preserved ocular movements. Conduction studies were characterized by prolonged F-wave minimal latencies, prolonged distal latencies, reduction of compound motor action potentials, and absence of sensory nerve action potentials. Sural nerve biopsy showed endoneurial edema, axonal degeneration, and regeneration, in the absence of cellular inflammation, macrophagic activation, and B-lymphocyte infiltration; no IgM or complement deposition was detected. Myelinated fibers showed redundant/abnormally thickened myelin, myelin vacuolation, and frank intramyelinic edema with condensed axoplasm. Ultrastructural features included axo-glial detachment, disruption of membrane integrity, and myelin uncompaction. This study shows that monospecific anti-GD1b IgM paraprotein is associated with non-inflammatory nerve damage. We suggest that the loss of myelin and axonal integrity reflects antibody-induced disruption of membrane lipid rafts.

Neuroimaging Findings in Chronic Hepatitis C Virus Infection: Correlation with Neurocognitive and Neuropsychiatric Manifestations.

Chronic hepatitis C virus (HCV) infection is commonly associated with neurocognitive dysfunction, altered neuropsychological performance and neuropsychiatric symptoms. Quantifiable neuropsychological changes in sustained attention, working memory, executive function, verbal learning and recall are the hallmark of HCV-associated neurocognitive disorder (HCV-AND). This constellation is at variance with the neuropsychological complex that is seen in minimal hepatic encephalopathy, which is typified by an array of alterations in psychomotor speed, selective attention and visuo-constructive function. Noncognitive symptoms, including sleep disturbances, depression, anxiety and fatigue, which are less easily quantifiable, are frequently encountered and can dominate the clinical picture and the clinical course of patients with chronic HCV infection. More recently, an increased vulnerability to Parkinson's disease among HCV-infected patients has also been reported. The degree to which neurocognitive and neuropsychiatric changes are due to HCV replication within brain tissues or HCV-triggered peripheral immune activation remain to be determined. Without absolute evidence that clearly exonerates or indicts HCV, our understanding of the so-called "HCV brain syndrome", relies primarily on clinical and neuropsychological assessments, although other comorbidities and substance abuse may impact on neurocognitive function, thus confounding an appropriate recognition. In recent years, a number of functional and structural brain imaging studies have been of help in recognizing possible biological markers of HCV-AND, thus providing a rationale for guiding and justifying antiviral therapy in selected cases. Here, we review clinical, neuroradiological, and therapeutic responses to interferon-based and interferon-free regimens in HCV-related cognitive and neuropsychiatric disorder.

Percutaneous alcohol injection under sonographic guidance in Morton's neuroma: follow-up in 220 treated lesions.

PURPOSE: To evaluate the efficacy and safety of percutaneous treatment of Civinini-Morton's syndrome due to solitary Morton's neuroma and analyze the effect of clinico-demographic factors on outcome. MATERIALS AND METHODS: Alcohol injection was performed under sonographic guidance in 220 consecutive patients. Pain intensity using a numerical rating scale (NRS), pain features, limitation of everyday activities and comorbidity with other forefoot conditions were evaluated at presentation. Patients were reassessed for symptoms and the need of rescue therapy with neurectomy after a mean follow-up of 19.0 months (range 15-24). RESULTS: We treated 220 patients (33 males, mean age 55.8 years). Neuromas were located in the III intermetatarsal space in 85.5 %, with a mean size of 5.4 mm. When considering a reduction of pain intensity of ≥50 % of NRS or a complete disappearance of the neuropathic features as a satisfactory clinical response, a 72.3 % (p < 0.001) responder rate was obtained, and only three patients relapsed (1.2 %). An improvement in limitation of everyday activities was observed in 88.6 % (p < 0.001). No influence of clinico-demographic variables on outcome was found. No major complications occurred. Patients with unsatisfactory response had an overload-related comorbid condition in 20/61 (32.8 %). Surgery was later performed in 14 non-responder patients. CONCLUSIONS: Ultrasound-guided alcoholization demonstrated a safe profile, relieved neuropathic symptoms in a majority of patients and improved their quality of life. Rescue therapy with surgery is feasible in patients with unsatisfactory response. However, a thorough evaluation for forefoot comorbidities should be obtained, as they may act as confounding factors.

Leprosy Neuropathy in a Non-Endemic Area: A Clinical and Pathological Study.

The extent of nerve involvement in leprosy is highly variable in distribution and clinical presentation. Mononeuropathies, multiple mononeuropathies, and polyneuropathies can present both in the context of a cutaneous and/or systemic picture and in the form of pure neuritic leprosy (PNL). The differential diagnosis of leprosy neuropathy remains challenging because it is a very rare condition and, especially in Western countries, is often overlooked. We report one case of the polyneuropathic form of PNL (P-PNL) and one case of multiple mononeuropathy in paucibacillary leprosy. In both cases, the diagnosis was achieved by performing a sural nerve biopsy, which showed subverted structure, severe infiltration of inflammatory cells in nerve fascicles, granulomatous abnormalities, and the presence of alcohol-acid-resistant, Ziehl-Neelsen-positive bacilli inside the nerve bundles. Leprosy remains an endemic disease in many areas of the world, and globalization has led to the spread of cases in previously disease-free countries. In this perspective, our report emphasizes that the diagnostic possibility of leprosy neuropathy should always be taken into account, even in Western countries, in the differential diagnostic process of an acquired sensory polyneuropathy or multineuropathy and confirms that nerve biopsy remains a useful procedure in working up neuropathies with unknown etiology.

Magnetic resonance neurography and diffusion tensor imaging of the sciatic nerve in hereditary transthyretin amyloidosis polyneuropathy.

The therapeutic advance in hereditary transthyretin amyloidosis (ATTRv amyloidosis) requires quantitative biomarkers of nerve involvement in order to foster early diagnosis and monitor therapy response. We aimed at quantitatively assessing Magnetic Resonance Neurography (MRN) and Diffusion Tensor Imaging (DTI) properties of the sciatic nerve in subjects with ATTRv-amyloidosis-polyneuropathy (ATTRv-PN) and pre-symptomatic carriers (ATTRv-C). Twenty subjects with pathogenic variants of the TTR gene (mean age 62.20 ± 12.04 years), 13 ATTRv-PN, and 7 ATTRv-C were evaluated and compared with 20 healthy subjects (mean age 60.1 ± 8.27 years). MRN and DTI sequences were performed at the right thigh from the gluteal region to the popliteal fossa. Cross-sectional-area (CSA), normalized signal intensity (NSI), and DTI metrics, including fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivity (RD) of the right sciatic nerve were measured. Increased CSA, NSI, RD, and reduced FA of sciatic nerve differentiated ATTRv-PN from ATTRv-C and healthy subjects at all levels (p < 0.01). NSI differentiated ATTRv-C from controls at all levels (p < 0.05), RD at proximal and mid-thigh (1.04 ± 0.1 vs 0.86 ± 0.11 p < 0.01), FA at mid-thigh (0.51 ± 0.02 vs 0.58 ± 0.04 p < 0.01). According to receiver operating characteristic (ROC) curve analysis, cutoff values differentiating ATTRv-C from controls (and therefore identifying subclinical sciatic involvement) were defined for FA, RD, and NSI. Significant correlations between MRI measures, clinical involvement and neurophysiology were found. In conclusion, the combination of quantitative MRN and DTI of the sciatic nerve can reliably differentiate ATTRv-PN, ATTRv-C, and healthy controls. More important, MRN and DTI were able to non-invasively identify early subclinical microstructural changes in pre-symptomatic carriers, thus representing a potential tool for early diagnosis and disease monitoring.

Aducanumab for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most frequent neurodegenerative condition, the most common cause of dementia, and a leading cause of disability and death globally. Mounting evidence supported accumulation of amyloid ß (Aß) as the primary cause of AD pathology and sprouted a number of candidate treatments engaging Aß from its production to its clearance, yet no amyloid-based drug candidate had been proven effective. Alternative pathomechanisms have been proposed, but still current treatments are limited to symptomatic therapy. Aducanumab (BIIB-037) is a fully human monoclonal IgG1 antibody that selectively binds aggregated forms of Aß, inhibits its template activity and promotes clearance of Aß deposits. Three early terminated trials in humans are available. Overall, conflicting results exist over measures of clinical efficacy, despite an objective decrease in Aß burden. Amyloid-related imaging abnormalities emerge as the most significant treatment-related adverse event. Here, we provide a comprehensive review of the available evidence on aducanumab, a drug that recently received a debated accelerated approval for the treatment of mild AD by the U.S. Food and Drug Administration (FDA).

Ischemic stroke due to sporadic and genetic pulmonary arteriovenous malformations: Case report.

Pulmonary arteriovenous malformations (PAVMs) encompass congenital and genetic vascular anomalies characterized by complex interlacing of arteries and veins connected by fistulas, which allow rapid and continuous extracardiac right-to-left shunting (RLS). Presenting neurologic manifestations of PAVM include brain abscess and stroke, as the consequence of paradoxical embolism. Although rare, PAVM represents an overlooked cause of cryptogenic ischemic stroke in young adults, being misdiagnosed as patent foramen ovale and a preventable trigger of silent cerebral ischemic changes. In the emergency clinical setting, the recommended ischemic stroke workup in patients with RLS should include the influence of postural changes and the effect of Valsalva maneuver on the entity of the RLS on contrast-enhanced transcranial color Doppler ultrasound and the delay in the right inferior pulmonary vein and left heart opacification on contrast-enhanced transthoracic echocardiography. This is in addition to the evaluation of chest X-rays or thoracic computed tomography. We here describe two patients with ischemic stroke due to sporadic and genetic PAVM-associated paradoxical embolism.

Neuropathic pain in Charcot-Marie-Tooth disease: A clinical and laser-evoked potential study.

BACKGROUND: Pain, either nociceptive or neuropathic (NP), is a common symptom in Charcot-Marie-Tooth (CMT) disease. METHODS: We investigated small fibers involvement and its correlation with pain in different CMT subtypes through a systematic clinical and neurophysiological study. We enrolled 50 patients: 19 with duplication of PMP22 (CMT1A), 11 with mutation of MPZ (CMT1B, CMT2I/J, or CMTDID), 12 with mutation of GJB1 (CMTX1), and 8 with mutation of MFN2 (CMT2A and CMT2A2B). Pain was rated with the 11-point Numerical Rating Scale and characterized through Neuropathic Pain Symptoms Inventory. Laser-evoked potentials (LEPs) were recorded after right foot and hand stimulation and N2-P2 complex amplitude and latency were compared with those of 41 controls. RESULTS: Overall pain prevalence was 36%. NP was present in 14.6% of patients, with a length-dependent distribution in 85.7% of cases, and it was significantly more frequent in CMT1A (p < 0.001). Aδ fibers involvement greatly varies between CMT subtypes, reflecting differences in molecular pathology and pathophysiologic mechanisms. Prolonged N2 latency from foot stimulation was noted in 11 CMT1A patients, 5 of which report NP. MPZ-CMTs displayed different neurophysiological phenotypes and a very low prevalence of NP. LEPs were normal in all but one CMTX1 patients, although lower limbs N2-P2 amplitude was significantly reduced in males (p = 0.043). MFN2-CMTs were NP free and LEPs recordings were all normal. NP strictly correlated with LEPs alterations (p = 0.017). CONCLUSIONS: NP prevalence varies among CMTs subtypes and is mainly related to Aδ fibers impairment. SIGNIFICANCE: Neuropathic pain is a frequent finding in Charcot-Marie Tooth disease and is related to Aδ fibers impairment. Patients at higher risk are those belonging to certain genetic subtypes (i.e. CMT1A and CMT2J) or with laser-evoked potentials abnormalities. While managing this disease, clinicians should be aware of this symptom in order to offer best treatment options to their patients.

Italian Real-Life Experience of Patients with Hereditary Transthyretin Amyloidosis Treated with Patisiran.

Hereditary transthyretin amyloidosis (ATTRv) is a multisystemic, rare, inherited, progressive and adult-onset disease, affecting the sensorimotor nerves, heart, autonomic function and other organs. The actual scenario of pharmaceutical approaches for ATTRv amyloidosis includes five main groups: TTR stabilizers, TTR mRNA silencers, TTR fibril disruptors, inhibitor of TTR fibril seeding and gene therapy. Patisiran is a small, double-stranded interfering RNA encapsulated in a lipid nanoparticle, able to penetrate into hepatocytes, where it selectively targets TTR mRNA, reducing TTR production. We report and discuss 9 cases of different patients with ATTRv amyloidosis successfully managed with patisiran in the real clinical practice. Literature data, as well as the above presented case reports, show that this drug is effective and safe in improving both neurological and cardiovascular symptoms of ATTRv amyloidosis, and to maintain a good QoL, independently form the stage of the disease and the involved mutation. Recent studies correlated improved functional and biochemical outcomes with a regression of amyloid burden, especially at the cardiac level. Today, patisiran can be considered a valid therapeutic option for the management of patients with ATTRv amyloidosis and polyneuropathy and cardiovascular symptoms.

Olfactory swab sampling optimization for α-synuclein aggregate detection in patients with Parkinson's disease.

BACKGROUND: In patients with Parkinson's disease (PD), real-time quaking-induced conversion (RT-QuIC) detection of pathological α-synuclein (α-syn) in olfactory mucosa (OM) is not as accurate as in other α-synucleinopathies. It is unknown whether these variable results might be related to a different distribution of pathological α-syn in OM. Thus, we investigated whether nasal swab (NS) performed in areas with a different coverage by olfactory neuroepithelium, such as agger nasi (AN) and middle turbinate (MT), might affect the detection of pathological α-syn. METHODS: NS was performed in 66 patients with PD and 29 non-PD between September 2018 and April 2021. In 43 patients, cerebrospinal fluid (CSF) was also obtained and all samples were analyzed by RT-QuIC for α-syn. RESULTS: In the first round, 72 OM samples were collected by NS, from AN (NSAN) or from MT (NSMT), and 35 resulted positive for α-syn RT-QuIC, including 27/32 (84%) from AN, 5/11 (45%) from MT, and 3/29 (10%) belonging to the non-PD patients. Furthermore, 23 additional PD patients underwent NS at both AN and MT, and RT-QuIC revealed α-syn positive in 18/23 (78%) NSAN samples and in 10/23 (44%) NSMT samples. Immunocytochemistry of NS preparations showed a higher representation of olfactory neural cells in NSAN compared to NSMT. We also observed α-syn and phospho-α-syn deposits in NS from PD patients but not in controls. Finally, RT-QuIC was positive in 22/24 CSF samples from PD patients (92%) and in 1/19 non-PD. CONCLUSION: In PD patients, RT-QuIC sensitivity is significantly increased (from 45% to 84%) when NS is performed at AN, indicating that α-syn aggregates are preferentially detected in olfactory areas with higher concentration of olfactory neurons. Although RT-QuIC analysis of CSF showed a higher diagnostic accuracy compared to NS, due to the non-invasiveness, NS might be considered as an ancillary procedure for PD diagnosis.

RFC1 AAGGG repeat expansion masquerading as Chronic Idiopathic Axonal Polyneuropathy.

BACKGROUND: A biallelic intronic AAGGG repeat expansion in the Replication Factor C subunit 1 (RFC1) gene has been recently associated with Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome, a disorder often presenting as a slowly evolving sensory neuropathy at the onset. "Chronic Idiopathic Axonal Polyneuropathy" (CIAP) is a common indolent axonal neuropathy of adulthood which remains without an identifiable cause despite thorough investigations. METHODS: We screened 234 probands diagnosed with CIAP for a pathogenic biallelic RFC1 AAGGG repeat expansion. Patients were selected from 594 consecutive patients with neuropathy referred to our tertiary-care center for a sural nerve biopsy over 10 years. RESULTS: The RFC1 AAGGG repeat expansion was common in patients with pure sensory neuropathy (21/40, 53%) and less frequent in cases with predominantly sensory (10/56, 18%, P < 0.001) or sensorimotor (3/138, 2%, P < 0.001) neuropathy. The mutation was associated with sensory ataxia (τb = 0.254, P < 0.001), autonomic disturbances (35% vs 8%, Prevalence Odds Ratio-POR 6.73 CI 95% 2.79-16.2, P < 0.001), retained deep tendon reflexes (score 18.0/24 vs 11.5/24, R = 0.275, P < 0.001). On pathology, we observed absent/scant regenerative changes (τb = - 0.362, P < 0.001), concomitant involvement of large (100% and 99%, n.s.), small myelinated (97% vs 81%, POR 7.74 CI 95% 1.03-58.4, P = 0.02) and unmyelinated nerve fibers (85% vs 41%, POR 8.52 CI 95% 3.17-22.9, P < 0.001). Cerebellar or vestibular involvement was similarly rare in the two groups. CONCLUSIONS: This study highlights the frequent occurrence of the RFC1 AAGGG repeat expansion in patients diagnosed with CIAP and characterizes the clinical and pathological features of the related neuro(no)pathy.

Mechanisms of Nerve Damage in Neuropathies Associated with Hematological Diseases: Lesson from Nerve Biopsies.

Despite the introduction of non-invasive techniques in the study of peripheral neuropathies, sural nerve biopsy remains the gold standard for the diagnosis of several neuropathies, including vasculitic neuropathy and neurolymphomatosis. Besides its diagnostic role, sural nerve biopsy has helped to shed light on the pathogenic mechanisms of different neuropathies. In the present review, we discuss how pathological findings helped understand the mechanisms of polyneuropathies complicating hematological diseases.