Phenotypic spectrum of myelin protein zero-related neuropathies: a large cohort study from five mutation clusters across Italy.

BACKGROUND: We aimed to investigate the clinical features of a large cohort of patients with myelin protein zero (MPZ)-related neuropathy, focusing on the five main mutation clusters across Italy. METHODS: We retrospectively gathered a minimal data set of clinical information in a series of patients with these frequent mutations recruited among Italian Charcot-Marie-Tooth (CMT) registry centres, including disease onset/severity (CMTES-CMT Examination Score), motor/sensory symptoms and use of orthotics/aids. RESULTS: We collected data from 186 patients: 60 had the p.Ser78Leu variant ('classical' CMT1B; from Eastern Sicily), 42 the p.Pro70Ser (CMT2I; mainly from Lombardy), 38 the p.Thr124Met (CMT2J; from Veneto), 25 the p.Ser44Phe (CMT2I; from Sardinia) and 21 the p.Asp104ThrfsX13 (mild CMT1B; from Apulia) mutation. Disease severity (CMTES) was higher (p<0.001) in late-onset axonal forms (p.Thr124Met=9.2±6.6; p.Ser44Phe=7.8±5.7; p.Pro70Ser=7.6±4.8) compared with p.Ser78Leu (6.1±3.5) patients. Disease progression (ΔCMTES/year) was faster in the p.Pro70Ser cohort (0.8±1.0), followed by p.Ser44Phe (0.7±0.4), p.Thr124Met (0.4±0.5) and p.Ser78Leu (0.2±0.4) patients. Disease severity (CMTES=1.2±1.5), progression (ΔCMTES/year=0.1±0.4) and motor involvement were almost negligible in p.Asp104ThrfsX13 patients, who, however, frequently (78%, p<0.001) complained of neuropathic pain. In the other four clusters, walking difficulties were reported by 69-85% of patients, while orthotic and walking aids use ranged between 40-62% and 16-28%, respectively. CONCLUSIONS: This is the largest MPZ (and late-onset CMT2) cohort ever collected, reporting clinical features and disease progression of 186 patients from five different clusters across Italy. Our findings corroborate the importance of differentiating between 'classical' childhood-onset demyelinating, late-onset axonal and mild MPZ-related neuropathy, characterised by different pathomechanisms, in view of different therapeutic targets.

Upper Limbs Muscle Co-Contraction Changes Correlate With The Physical Motor Impairments in CMT.

Background: Subjects with Charcot-Marie-Tooth (CMT) disease show hands impairment which is a relevant problem affecting the quality of life. This symptom is related to muscle weakness and reduced motor coordination of the upper limb. However, most studies focus on lower limb impairment, therefore the investigation of upper limb disability is necessary to identify biomarkers able to monitor disease-specific features and to tailor rehabilitation. Objective: This study aimed at characterizing upper limb muscle co-contraction using the co-contraction index (CCI) in CMT population. Methods: Upper limb kinematic and electromyography (EMG) data were collected from fourteen CMT subjects (6-CMT1A and 8-CMT1X) during motor tasks typical of daily living activities. Rudolph's CCI was used to quantify muscle co-contraction of four muscle pairs acting on shoulder, elbow and wrist. All CMT subjects underwent clinical examination. Thirteen healthy subjects served as the normative reference (HC). Results: CMT1X and CMT1A showed a significant reduction in CCI for distal and proximal muscle pairs compared to HC. Furthermore, CMT1A showed greater values of CCI compared to CMT1X mainly for the axial and axial-to-proximal muscle pairs. Movement speed and smoothness were not altered compared to HC. In addition, EMG metrics showed moderate-to-strong significant correlations with clinical outcomes. Conclusions: CCI was able to quantify disease-specific deficits with respect to the normative reference, highlighting motor control alterations even before motor output impairment. CCI was also sensitive in detecting CMT subtypes-based differences and adopted compensatory strategies. Our findings suggest that CCI can be an outcome measure for CMT disease monitoring and interventional studies.

Early Onset Inherited Peripheral Neuropathies: The Experience of a Specialized Referral Center for Genetic Diagnosis Achievement.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of inherited peripheral neuropathies. Although the typical disease onset is reported in the second decade, earlier onsets are not uncommon. To date, few studies on pediatric populations have been conducted and the achievement of molecular diagnosis remains challenging. METHODS: During the last 24 years we recruited 223 patients with early-onset hereditary peripheral neuropathies (EOHPN), negative for PMP22 duplication, 72 of them referred by a specialized pediatric hospital. Genetic testing for CMT-associated genes has been carried out with a range of different techniques. RESULTS: Of the 223 EOHPN cases, 43% were classified as CMT1 (demyelinating), 49% as CMT2 (axonal), and 8% as CMTi (intermediate). Genetic diagnosis was reached in 51% of patients, but the diagnostic yield increased to 67% when focusing only on cases from the specialized pediatric neuromuscular centers. Excluding PMP22 rearrangements, no significant difference in diagnostic rate between demyelinating and axonal forms was identified. De novo mutations account for 38% of cases. CONCLUSIONS: This study describes an exhaustive picture of EOHPN in an Italian referral genetic center and analyzes the molecular diagnostic rate of a heterogeneous cohort compared with one referred by a specialized pediatric center. Our data identify MPZ, MFN2, GDAP1, and SH3TC2 genes as the most frequent players in EOHPN. Our study underlines the relevance of a specific neurological pediatric expertise to address the genetic testing and highlights its importance to clarify possible unexpected results when neuropathy is only a secondary clinical sign of a more complex phenotype.

Impact of 2021 European Academy of Neurology/Peripheral Nerve Society diagnostic criteria on diagnosis and therapy of chronic inflammatory demyelinating polyradiculoneuropathy variants.

BACKGROUND AND PURPOSE: There are different criteria for the diagnosis of different variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guidelines provide specific clinical criteria for each CIDP variant even if their therapeutical impact has not been investigated. METHODS: We applied the clinical criteria for CIDP variants of the 2021 EAN/PNS guidelines to 369 patients included in the Italian CIDP database who fulfilled the 2021 EAN/PNS electrodiagnostic criteria for CIDP. RESULTS: According to the 2021 EAN/PNS clinical criteria, 245 patients achieved a clinical diagnosis of typical CIDP or CIDP variant (66%). We identified 106 patients with typical CIDP (29%), 62 distal CIDP (17%), 28 multifocal or focal CIDP (7%), four sensory CIDP (1%), 27 sensory-predominant CIDP (7%), 10 motor CIDP (3%), and eight motor-predominant CIDP (2%). Patients with multifocal, distal, and sensory CIDP had milder impairment and symptoms. Patients with multifocal CIDP had less frequently reduced conduction velocity and prolonged F-wave latency and had lower levels of cerebrospinal fluid protein. Patients with distal CIDP more frequently had reduced distal compound muscle action potentials. Patients with motor CIDP did not improve after steroid therapy, whereas those with motor-predominant CIDP did. None of the patients with sensory CIDP responded to steroids, whereas most of those with sensory-predominant CIDP did. CONCLUSIONS: The 2021 EAN/PNS criteria for CIDP allow a better characterization of CIDP variants, permitting their distinction from typical CIDP and more appropriate treatment for patients.

COVID-19-associated serum and cerebrospinal fluid cytokines in post- versus para-infectious SARS-CoV-2-related Guillain-Barré syndrome.

INTRODUCTION: Guillain-Barré syndrome associated with Coronavirus-2-related severe acute respiratory syndrome (COV-GBS) occurs as para- or post-infectious forms, depending on the timing of disease onset. In these two forms, we aimed to compare the cerebrospinal fluid (CSF) and serum proinflammatory cytokine profiles to evaluate differences that could possibly have co-pathogenic relevance. MATERIALS AND METHODS: We studied a retrospective cohort of 26 patients with either post-COV-GBS (n = 15), with disease onset occurring > 7 days after SARS-CoV-2 infection, or para-COV-GBS (n = 11), with disease onset 7 days or less. TNF-α, IL-6, and IL-8 were measured in the serum with SimplePlex™ Ella™ immunoassay. In addition to the para-/post-COV-GBS patients, serum levels of these cytokines were determined in those with non-COVID-associated-GBS (NC-GBS; n = 43), paucisymptomatic SARS-CoV-2 infection without GBS (COVID, n = 20), and in healthy volunteers (HV; n = 12). CSF cytokine levels were measured in patients with para-/post-COV-GBS, in those with NC-GBS (n = 29), or with Alzheimer's disease (AD; n = 24). RESULTS: Serum/CSF cytokine levels did not differ in para- vs post-COV-GBS. We found that SARS-CoV-2 infection raises the serum levels of TNF-α, IL-6, and IL-8, as well as an increase of IL-6 (in serum and CSF) and IL-8 (in CSF) in either NC-GBS or COV-GBS than controls. CSF and serum cytokine levels resulted independent one with another. CONCLUSIONS: The change of cytokines linked to SARS-CoV-2 in COV-GBS appears to be driven by viral infection, although it has unique characteristics in GBS as such and does not account for cases with para- or post-infectious onset.

Incident anti-LGI1 autoimmune encephalitis during dementia with Lewy bodies: when Occam razor is a double-edged sword.

In Dementia with Lewy bodies (DLB), rapid cognitive decline and seizures seldom complicate the typical clinical course. Nevertheless, concurrent, treatable conditions may be responsible. We report a case of DLB with superimposed anti-LGI1 encephalitis, emphasizing the importance of thorough diagnostic reasoning beyond the simplest explanation amid distinct clinical cues.

What is the best treatment strategy before autologous peripheral blood stem cell transplantation in POEMS syndrome?

Autologous peripheral blood stem cell transplantation (aPBSCT) provides optimal outcomes in POEMS syndrome but the definition of the best treatment before aPBSCT remains to be defined because of the rarity of the disease and the heterogeneity of published case series. We collected clinical and laboratory data of patients with POEMS syndrome undergoing aPBSCT from 1998 to 2020 in ten Italian centers. The primary endpoint of the study was to evaluate the impact of prior therapies and mobilization regimen on outcome. We divided the patients into three groups: patients who did not receive any treatment before transplant (15 patients, group A: front-line), patients pre-treated with other agents (14 patients, group B) and patients treated with cyclophosphamide as their mobilizing regimen (16 patients, group C). The three groups did not show differences in terms of demographic and clinical characteristics. All 45 patients underwent aPBSCT after a high-dose melphalan conditioning regimen, with a median follow-up of 77 months (range, 37-169 months). The responses were not statistically different between the three groups (P=0.38). Progression-free and overall survival rates at 6 years were: 70% (95% confidence interval: 55-85%) and 91% (95% confidence interval: 82-99) 65%, respectively, and did not differ between the three groups. The cumulative incidence of transplant-related mortality and relapse was 4% and 36%, respectively. In conclusion, in a relatively large number of patients with POEMS syndrome, undergoing an autologous transplant, pre-treatment and disease status at transplant did not appear to have an impact on major transplant outcomes.

Clinical epidemiology of amyotrophic lateral sclerosis in Liguria, Italy: a ten year follow up study.

OBJECTIVE: This article presents an updated analysis of the LIGALS register, a prospective study conducted over a ten-year period (2009-2018) in Liguria, Italy, aimed at evaluating the incidence, prevalence, clinical presentation, and management of amyotrophic lateral sclerosis (ALS). METHODS: We calculated the mean annual crude incidence rate of ALS, assessed the point prevalence of ALS on January 1, 2018, and analyzed demographic factors, clinical characteristics, and clinical management strategies. Data analysis included Cox regression analysis to identify predictors of survival. RESULTS: The mean annual crude incidence rate of ALS was 3.16/100,000 per year (CI 95%) while the point prevalence of ALS on January 1, 2018, was 9.31/100,000 population (CI 95%). Among the patients, 6.5% were familial ALS, while 93.5% were sporadic cases. Clinical management strategies, including percutaneous endoscopic gastrostomy (PEG) and noninvasive ventilation (NIV), were employed. The study observed a stable frequency of NIV initiation and PEG placement over time, with a growing trend toward earlier PEG positioning. The mean survival from symptom onset was 39 months, whereas from diagnosis, it was 26 months. Cox regression analysis identified several predictors of survival, including gender, age at onset and diagnosis, site of onset, diagnostic category, phenotype, and diagnostic delay. CONCLUSIONS: This comprehensive analysis provides valuable insights into the long-term trends in ALS epidemiology and clinical management in Liguria, Italy. It underscores the importance of continued research efforts in understanding and addressing the challenges posed by ALS, particularly in terms of early diagnosis and optimizing clinical interventions to improve patient outcomes.

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.

A novel de novo variant in POLR3B gene associated with a primary axonal involvement of the largest nerve fibers.

BACKGROUND AND AIMS: POLR3B gene encodes a subunit of RNA polymerase III (Pol III). Biallelic mutations in POLR3B are associated with leukodystrophies, but recently de novo heterozygous mutations have been described in early onset peripheral demyelinating neuropathies with or without central involvement. Here, we report the first Italian case carrying a de novo variant in POLR3B with a pure neuropathy phenotype and primary axonal involvement of the largest nerve fibers. METHODS: Nerve conduction studies, sympathetic skin response, dynamic sweat test, tactile and thermal quantitative sensory testing and brain magnetic resonance imaging were performed according to standard procedures. Histopathological examination was performed on skin and sural nerve biopsies. Molecular analysis of the proband and his relatives was performed with Next Generation Sequencing. The impact of the identified variant on the overall protein structure was evaluated through rotamers method. RESULTS: Since his early adolescence, the patient presented with signs of polyneuropathy with severe distal weakness, atrophy, and reduced sensation. Neurophysiological studies showed a sensory-motor axonal polyneuropathy, with confirmed small fiber involvement. In addition, skin biopsy and sural nerve biopsy showed predominant large fibers involvement. A trio's whole exome sequencing revealed a novel de novo variant p.(Arg1046Cys) in POLR3B, which was classified as Probably Pathogenic. Molecular modeling data confirmed a deleterious effect of the variant on protein structure. INTERPRETATION: Neurophysiological and morphological findings suggest a primary axonal involvement of the largest nerve fibers in POLR3B-related neuropathies. A partial loss of function mechanism is proposed for both neuropathy and leukodystrophy phenotypes.

Daytime sleepiness and sleep quality in Charcot-Marie-Tooth disease.

BACKGROUND: Sleep abnormalities have been reported in Charcot-Marie-Tooth disease (CMT), but data are scanty. We investigated their presence and correlation in a large CMT patients' series. METHODS: Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were administered to CMT patients of the Italian registry and controls. ESS score > 10 indicated abnormal daytime somnolence, PSQI score > 5 bad sleep quality. We analyzed correlation with disease severity and characteristics, Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS), Body Mass Index, drug use. RESULTS: ESS and PSQI questionnaires were filled by 257 and 253 CMT patients, respectively, and 58 controls. Median PSQI score was higher in CMT patients than controls (6 vs 4, p = 0.006), with no difference for ESS score. Abnormal somnolence and poor sleep quality occurred in 23% and 56% of patients; such patients had more frequently anxiety/depression, abnormal fatigue, and positive sensory symptoms than those with normal ESS/PSQI. Moreover, patients with PSQI score > 5 had more severe disease (median CMT Examination Score, CMTES, 8 vs 6, p = 0.006) and more frequent use of anxiolytic/antidepressant drugs (29% vs 7%, p < 0.001). CONCLUSIONS: Bad sleep quality and daytime sleepiness are frequent in CMT and correlated with anxiety, depression and fatigue, confirming that different components affect sleep. Sleep disorders, such as sleep apnea and restless leg syndrome, not specifically investigated here, are other factors known to impact on sleep quality and somnolence. CMT patients' management must include sleep behavior assessment and evaluation of its correlated factors, including general distress and fatigue.

Recurrent motor branch neuropathy in carpal tunnel syndrome: An ultrasound study.

INTRODUCTION/AIMS: The reason for the variable rate of progression of patients with carpal tunnel syndrome (CTS) to thenar muscles impairment is not fully understood. The aim of this study was to evaluate the occurrence of ultrasound signs of recurrent motor branch (RMB) neuropathy in patients with CTS and to correlate imaging findings with clinical and electrophysiological data. METHODS: Two cohorts were recruited, one consisting of CTS patients with electrodiagnostic evidence of prolonged median distal motor latency from wrist to thenar eminence and another consisting of sex- and age-matched healthy controls. Ultrasound reliability of RMB measurement was assessed by the calculation of the interclass correlation coefficient (ICC). Patients were evaluated with electrodiagnostic tests and asked to complete the Boston Carpal Tunnel Questionnaire. The difference between the RMB diameter in patients and controls was analyzed using a t test. Correlations between RMB diameter and other parameters were assessed using linear mixed models. RESULTS: 46 hands from 32 patients with CTS and 50 hands from 50 controls were evaluated. The intra- and interobserver agreements in RMB measurement were very good (ICC = 0.84; 95% confidence interval [CI], 0.75 to 0.90) and good (ICC = 0.79; 95% CI, 0.69 to 0.87). The RMB diameter was significantly larger in patients than in controls (P < .0001). No significant correlation was found between the RMB diameter and other variables, except for BMI and median nerve cross-sectional area. DISCUSSION: Ultrasound is reliable in identifying the RMB and characterizing its abnormalities. In this patient cohort, ultrasound allowed for detection of definite signs of RMB compression neuropathy.

Clinical spectrum and frequency of Charcot-Marie-Tooth disease in Italy: Data from the National CMT Registry.

BACKGROUND AND PURPOSE: Data are reported from the Italian CMT Registry. METHODS: The Italian CMT Registry is a dual registry where the patient registers and chooses a reference center where the attending clinician collects a minimal dataset of information and administers the Charcot-Marie-Tooth (CMT) Examination/Neuropathy Score. Entered data are encrypted. RESULTS: Overall, 1012 patients had registered (535 females) and 711 had received a genetic diagnosis. Demyelinating CMT (65.3%) was more common than axonal CMT2 (24.6%) and intermediate CMT (9.0%). The PMP22 duplication was the most frequent mutation (45.2%), followed by variants in GJB1 and MPZ (both ~10%) and MFN2 (3.3%) genes. A relatively high mutation rate in some "rare" genes (HSPB1 1.6%, NEFL 1.5%, SH3TC2 1.5%) and the presence of multiple mutation clusters across Italy was observed. CMT4A was the most disabling type, followed by CMT4C and CMT1E. Disease progression rate differed depending on the CMT subtype. Foot deformities and walking difficulties were the main features. Shoe inserts and orthotic aids were used by almost one-half of all patients. Scoliosis was present in 20% of patients, especially in CMT4C. Recessive forms had more frequently walking delay, walking support need and wheelchair use. Hip dysplasia occurred in early-onset CMT. CONCLUSIONS: The Italian CMT Registry has proven to be a powerful data source to collect information about epidemiology and genetic distribution, clinical features and disease progression of CMT in Italy and is a useful tool for recruiting patients in forthcoming clinical trials.

Comparing the Impact of COVID-19 on Vaccinated and Unvaccinated Patients Affected by Myasthenia Gravis.

We evaluated 13 patients affected by myasthenia gravis (MG) who had coronavirus disease 2019 (COVID-19) before vaccination and 14 myasthenic patients who contracted severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection after vaccination to evaluate factors related to different COVID-19 outcomes. We compared the two groups' previous stability of MG and the severity of SARS-CoV-2 infection. Vaccinated and non-vaccinated patients were comparable in terms of severity of the previous MG course (mean maximum myasthenia gravis Foundation of America-MGFA-Class III) and during SARS-CoV-2 infection (mean MGFA Class II). In non-vaccinated patients, the hospitalization and severe course percentages were 61.5%, while the mortality reached 30.8%. The hospitalization, severe course, and mortality percentages in vaccinated patients were 7.1%. In deceased, non-vaccinated patients, greater myasthenia severity in the past clinical history, but not at the time of infection, was observed. Similarly, older age at MG onset and at the time of infection correlated with a more severe COVID-19 course in non-vaccinated patients (p = 0.03 and p = 0.04), but not in the group of vaccinated patients. In summary, our data support a protective role of vaccination in myasthenic patients, even if anti-CD20 therapy might be associated with a poor immune response to vaccines.

Unclassified clinical presentations of chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: To assess the ability of the 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) clinical criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) to include within their classification the whole spectrum of clinical heterogeneity of the disease and to define the clinical characteristics of the unclassifiable clinical forms. METHODS: The 2021 EAN/PNS clinical criteria for CIDP were applied to 329 patients fulfilling the electrodiagnostic (and in some cases also the supportive) criteria for the diagnosis of CIDP. Clinical characteristics were reviewed for each patient not strictly fulfilling the clinical criteria ('unclassifiable'). RESULTS: At study inclusion, 124 (37.5%) patients had an unclassifiable clinical presentation, including 110 (89%) with a typical CIDP-like clinical phenotype in whom some segments of the four limbs were unaffected by weakness ('incomplete typical CIDP'), 10 (8%) with a mild distal, symmetric, sensory or sensorimotor polyneuropathy confined to the lower limbs with cranial nerve involvement ('cranial nerve predominant CIDP') and 4 (1%) with a symmetric sensorimotor polyneuropathy limited to the proximal and distal areas of the lower limbs ('paraparetic CIDP'). Eighty-one (65%) patients maintained an unclassifiable presentation during the entire disease follow-up while 13 patients progressed to typical CIDP. Patients with the unclassifiable clinical forms compared with patients with typical CIDP had a milder form of CIDP, while there was no difference in the distribution patterns of demyelination. CONCLUSIONS: A proportion of patients with CIDP do not strictly fulfil the 2021 EAN/PNS clinical criteria for diagnosis. These unclassifiable clinical phenotypes may pose diagnostic challenges and thus deserve more attention in clinical practice and research.

CSF Findings in Relation to Clinical Characteristics, Subtype, and Disease Course in Patients With Guillain-Barré Syndrome.

BACKGROUND AND OBJECTIVES: To investigate CSF findings in relation to clinical and electrodiagnostic subtypes, severity, and outcome of Guillain-Barré syndrome (GBS) based on 1,500 patients in the International GBS Outcome Study. METHODS: Albuminocytologic dissociation (ACD) was defined as an increased protein level (>0.45 g/L) in the absence of elevated white cell count (<50 cells/µL). We excluded 124 (8%) patients because of other diagnoses, protocol violation, or insufficient data. The CSF was examined in 1,231 patients (89%). RESULTS: In 846 (70%) patients, CSF examination showed ACD, which increased with time from weakness onset: ≤4 days 57%, >4 days 84%. High CSF protein levels were associated with a demyelinating subtype, proximal or global muscle weakness, and a reduced likelihood of being able to run at week 2 (odds ratio [OR] 0.42, 95% CI 0.25-0.70; p = 0.001) and week 4 (OR 0.44, 95% CI 0.27-0.72; p = 0.001). Patients with the Miller Fisher syndrome, distal predominant weakness, and normal or equivocal nerve conduction studies were more likely to have lower CSF protein levels. CSF cell count was <5 cells/µL in 1,005 patients (83%), 5-49 cells/µL in 200 patients (16%), and ≥50 cells/µL in 13 patients (1%). DISCUSSION: ACD is a common finding in GBS, but normal protein levels do not exclude this diagnosis. High CSF protein level is associated with an early severe disease course and a demyelinating subtype. Elevated CSF cell count, rarely ≥50 cells/µL, is compatible with GBS after a thorough exclusion of alternative diagnoses. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that CSF ACD (defined by the Brighton Collaboration) is common in patients with GBS.

Using Cluster Analysis to Overcome the Limits of Traditional Phenotype-Genotype Correlations: The Example of RYR1-Related Myopathies.

Thanks to advances in gene sequencing, RYR1-related myopathy (RYR1-RM) is now known to manifest itself in vastly heterogeneous forms, whose clinical interpretation is, therefore, highly challenging. We set out to develop a novel unsupervised cluster analysis method in a large patient population. The objective was to analyze the main RYR1-related characteristics to identify distinctive features of RYR1-RM and, thus, offer more precise genotype-phenotype correlations in a group of potentially life-threatening disorders. We studied 600 patients presenting with a suspicion of inherited myopathy, who were investigated using next-generation sequencing. Among them, 73 index cases harbored variants in RYR1. In an attempt to group genetic variants and fully exploit information derived from genetic, morphological, and clinical datasets, we performed unsupervised cluster analysis in 64 probands carrying monoallelic variants. Most of the 73 patients with positive molecular diagnoses were clinically asymptomatic or pauci-symptomatic. Multimodal integration of clinical and histological data, performed using a non-metric multi-dimensional scaling analysis with k-means clustering, grouped the 64 patients into 4 clusters with distinctive patterns of clinical and morphological findings. In addressing the need for more specific genotype-phenotype correlations, we found clustering to overcome the limits of the "single-dimension" paradigm traditionally used to describe genotype-phenotype relationships.

Mild behavioral impairment as a potential marker of predementia risk states in motor neuron diseases.

BACKGROUND AND PURPOSE: Mild behavioral impairment (MBI) has been increasingly regarded as the neurobehavioral axis of predementia risk states, but a specific investigation of its detection as a potential marker of prodromal dementia in motor neuron diseases (MNDs) is still lacking. The aims of our study were therefore to explore MBI in MNDs both at onset and over the disease course, and to evaluate its relationship with baseline and longitudinal cognitive features. METHODS: Sixty MND patients with cognitive/behavioral, mood, and motor examinations were recruited and followed longitudinally for up to 15 months. Associations between baseline MBI symptoms and clinical features were tested using the Spearman correlation coefficient. Based on longitudinal data, relative deltas of variation for each cognitive measure were generated, and linear regression models were then used to evaluate the role of baseline MBI symptoms in predicting longitudinal rates of cognitive decline. RESULTS: At disease onset, the most impaired MBI domain was affective/emotional dysregulation, followed by impulse dyscontrol, apathy, and social inappropriateness. Greater MBI symptoms correlated with more severe baseline motor, cognitive/behavioral, and mood disturbances (p values from <0.001 to 0.05). Longitudinally, the greatest decline was observed in the affective/emotional dysregulation domain, followed by impulse dyscontrol, apathy, and social inappropriateness. Greater MBI symptoms at onset were significant predictors of more severe longitudinal cognitive decline in both amyotrophic lateral sclerosis (ALS)-specific and ALS-nonspecific functions (p values from <0.001 to 0.03). CONCLUSIONS: MBI represents a valuable clinical marker of incident cognitive decline in MNDs, and its evaluation has good potential for detecting dementia in its preclinical/prodromal phase.

Anxiety and depression in Charcot-Marie-Tooth disease: data from the Italian CMT national registry.

BACKGROUND: There is little information about neuropsychiatric comorbidities in Charcot-Marie-Tooth disease (CMT). We assessed frequency of anxiety, depression, and general distress in CMT. METHODS: We administered online the Hospital Anxiety-Depression Scale (HADS) to CMT patients of the Italian registry and controls. HADS-A and HADS-D scores ≥ 11 defined the presence of anxiety/depression and HADS total score (HADS-T) ≥ 22 of general distress. We analysed correlation with disease severity and clinical characteristics, use of anxiolytics/antidepressants and analgesic/anti-inflammatory drugs. RESULTS: We collected data from 252 CMT patients (137 females) and 56 controls. CMT patient scores for anxiety (mean ± standard deviation, 6.7 ± 4.8), depression (4.5 ± 4.0), and general distress (11.5 ± 8.1) did not differ from controls and the Italian population. However, compared to controls, the percentages of subjects with depression (10% vs 2%) and general distress (14% vs 4%) were significantly higher in CMT patients. We found no association between HADS scores and disease duration or CMT type. Patients with general distress showed more severe disease and higher rate of positive sensory symptoms. Depressed patients also had more severe disease. Nineteen percent of CMT patients took antidepressants/anxiolytics (12% daily) and 70% analgesic/anti-inflammatory drugs. Patients with anxiety, depression, and distress reported higher consumption of anxiolytics/antidepressants. About 50% of patients with depression and/or general distress did not receive any specific pharmacological treatment. CONCLUSIONS: An appreciable proportion of CMT patients shows general distress and depression. Both correlated with disease severity and consumption of antidepressants/anxiolytics, suggesting that the disease itself is contributing to general distress and depression.