Diagnosis and Management of Seronegative Myasthenia Gravis: Lights and Shadows.

Myasthenia gravis (MG) is an antibody-mediated neuromuscular disease affecting the neuromuscular junction. In most cases, autoantibodies can be detected in the sera of MG patients, thus aiding in diagnosis and allowing for early screening. However, there is a small proportion of patients who have no detectable auto-antibodies, a condition termed "seronegative MG" (SnMG). Several factors contribute to this, including laboratory test inaccuracies, decreased antibody production, immunosuppressive therapy, immunodeficiencies, antigen depletion, and immune-senescence. The diagnosis of SnMG is more challenging and is based on clinical features and neurophysiological tests. The early identification of these patients is needed in order to ensure early treatment and prevent complications. This narrative review aims to examine the latest updates on SnMG, defining the clinical characteristics of affected patients, diagnostic methods, management, and therapeutic scenarios.

Chronic inflammatory demyelinating polyneuropathy after SARS-CoV2 vaccination: update of the literature and patient characterization.

Since the beginning of worldwide vaccination against COVID-19 disease, some reports have revealed a possible relationship between SARS CoV2 vaccination and chronic inflammatory demyelinating polyneuropathy (CIDP). We reviewed the available evidences regarding this topic, adding three new cases to those reported so far, with the purpose to outline the characteristics of these post-vaccinal CIDP. Seventeen subjects were studied. A total of 70.6% of CIDP cases were related to viral vector vaccines, most occurring after the administration of the first dose. CIDPs that occurred after the second dose (17%) were temporally associated with mRNA vaccines. The clinical course and electrophysiology of all patients met the criteria for acute-subacute CIDP (A-CIDP). Administration of the viral vector vaccine was significantly correlated with a higher probability of having cranial nerve impairment (p = 0.004). The electrophysiological phenotype, laboratory and imaging data, and first-line therapies were substantially similar to those of the classical CIDP. The take-home message of the present paper is that the SARS CoV2 vaccine, especially the AstraZeneca vaccine, may be associated with inflammatory neuropathies with acute onset, often indistinguishable from Guillain-Barré syndrome (GBS). Hence, the importance of tracked prospectively patients with GBS occurred post-SARS-CoV2 vaccine. Distinguishing GBS from A-CIDP is crucial because treatment strategies and long-term prognosis are different.

Anti-Cytosolic 5'-Nucleotidase 1A in the Diagnosis of Patients with Suspected Idiopathic Inflammatory Myopathies: An Italian Real-Life, Single-Centre Retrospective Study.

BACKGROUND: Anti-cytosolic 5'-nucleotidase 1A (anti-cN1A) antibodies were proposed as a biomarker for the diagnosis of inclusion body myositis (IBM), but conflicting specificity and sensitivity evidence limits its use. Our study aimed to assess the diagnostic accuracy of anti-cN1A in a cohort of patients who underwent a myositis line immunoassay for suspected idiopathic inflammatory myopathies (IIM). We also assessed the agreement between two testing procedures: line immunoassay (LIA) and enzyme-linked immunoassay (ELISA). MATERIALS AND METHODS: We collected retrospective clinical and serological data for 340 patients who underwent a myositis antibody assay using LIA (EUROLINE Autoimmune Inflammatory Myopathies 16 Ag et cN-1A (IgG) line immunoassay) and verification with an anti-cN1A antibody assay using ELISA (IgG) (Euroimmun Lubeck, Germany). RESULTS: The serum samples of 20 (5.88%) patients (15 females, 5 males, mean age 58.76 ± 18.31) tested positive for anti-cN1A using LIA, but only two out of twenty were diagnosed with IBM. Seventeen out of twenty tested positive for anti-cN1A using ELISA (median IQR, 2.9 (1.9-4.18)). CONCLUSIONS: Our study suggests excellent concordance between LIA and ELISA for detecting anti-cN1A antibodies. LIA may be a rapid and useful adjunct, and it could even replace ELISA for cN1A assay. However, the high prevalence of diseases other than IBM in our cohort of anti-cN1A-positive patients did not allow us to consider anti-cN1A antibodies as a specific biomarker for IBM.

Sex differences in neuromuscular disorders.

The prevalence, onset, pathophysiology, and clinical course of many neuromuscular disorders (NMDs) may significantly differ between males and females. Some NMDs are more frequently observed in females, and characterized to show a higher grade of severity during or after the pregnancy. Meanwhile, others tend to have an earlier onset in males and exhibit a more variable progression. Prevalently, sex differences in NMDs have a familiar character given from genetic inheritance. However, they may also influence clinical presentation and disease severity of acquired NMD forms, and are represented by both hormonal and genetic factors. Consequently, to shed light on the distinctive role of biological factors in the different clinical phenotypes, we summarize in this review the sex related differences and their distinctive biological roles emerging from the current literature in both acquired and inherited NMDs.

Purtscher-like retinopathy in a patient with systemic tacrolimus vasculopathy.

INTRODUCTION: Purtscher-like retinopathy is a rare occlusive retinal microangiopathy, whose pathogenesis has not been totally defined yet. Most frequent cause of Purtscher-like retinopathy is acute pancreatitis, but it may be triggered by other systemic or toxic conditions. We report herein a case of Purtscher-like retinopathy in the context of systemic tacrolimus vasculopathy. CASE REPORT: A 56-years old male with history of kidney transplant was referred to local emergency room because of a global worsening of health conditions, with fatigue, muscular pain and diuresis contraction. During hospitalization the patient came to our attention for sudden and severe visual acuity impairment in both eyes. Extensive ophthalmological assessment, optical coherence tomography (OCT) and fluorescein angiography (FA) were performed disclosing a marked drop in best corrected visual acuity (BCVA) (20/200 in the right eye and 10/400 in the left eye) caused by a bilateral severe occlusive retinal microangiopathy complicated by diffuse retinal ischaemia and neovascular glaucoma. Muscular biopsy showed a necrotizing myopathy with autoimmune features, as indicated by conspicuous upregulation of MHC-I complex and microangiopathic changes, consistent with tacrolimus toxicity. Tacrolimus administration was interrupted, and intravenous glucocorticoids were administered. The large areas of retinal ischemia and neovascular glaucoma were treated with pan-retinal photocoagulation and intravitreal injections of bevacizumab with complete regression of iris neovascolarization. BCVA measured 20/200 in both eyes at last follow-up visit, 20 months after symptoms onset. CONCLUSIONS: Purtscher-like retinopathy should be suspected in patients under treatment with calcineurin inhibitors especially in case of sudden and severe bilateral visual impairment.

Study of total duration of distal compound muscle action potential in demyelinating and axonal Guillain-Barre' syndrome.

OBJECTIVES: Electrophysiology plays a crucial role in Guillain-Barré syndrome (GBS) diagnosis and subtype classification. The aim of our study was to assess the potential role of distal compound muscle action potential (dCMAP) for early differentiation between acute inflammatory demyelinating polyneuropathy (AIDP) and axonal GBS. METHODS: We retrospectively reviewed the medical records of 24 subjects with AIDP and 18 subjects with axonal GBS. We built up receiver operating characteristic curves for total dCMAP duration and negative phase of dCMAP duration, in order to derive cut-off values able to differentiate between AIDP and axonal GBS. RESULTS: The total duration of dCMAP was significantly prolonged in AIDP compared to axonal GBS. AUCs, odds ratio and positive predictive values were higher for total duration than for negative peak duration. Nerve conduction parameters in the lower limbs were more sensitive than those in the upper limbs in distinguishing AIDP from axonal GBS. DISCUSSION: Total duration of dCMAP dispersion may capture an adjunctive component of distal demyelination, not measured by the more traditional parameters and may thus represent a useful tool for early differentiation between AIDP and axonal GBS.

A Novel Ultrasonographic Anthropometric-Independent Measurement of Median Nerve Swelling in Carpal Tunnel Syndrome: The "Nerve/Tendon Ratio" (NTR).

Background: There is little consensus on ultrasound (US) normative values of cross-sectional area of median nerve (MN-CSA) in carpal tunnel syndrome (CTS) because of its dependency on anthropometric parameters. We aim to propose a novel anthropometric-independent US parameter: MN-CSA/flexor radialis carpi CSA (FCR-CSA) ratio ("Nerve Tendon Ratio", NTR), in the diagnosis of clinically and electrodiagnostic (EDS)-defined CTS. Methods: 74 wrists of 49 patients with clinically defined CTS underwent EDS (scored by the 1−5 Padua Scale of electrophysiological severity, PS) and US of carpal tunnel with measurement of MN-CSA (at the carpal tunnel inlet), FCR-CSA (over scaphoid tubercle) and its ratio (NTR, expressed as a percentage). US normality values and intra-operator agreement were assessed in 33 healthy volunteers. Results: In controls, the mean MN-CSA was 5.81 mm2, NTR 64.2%. In 74 clinical CTS, the mean MN-CSA was 12.1 mm2, NTR 117%. In severe CTS (PS > 3), the mean MN-CSA was 15.9 mm2, NTR 148%. In CTS, both MN-CSA and NTR correlated with sensitive conduction velocity (SCV) (p < 0.001), distal motor latency (DML) (p < 0.001) and PS (p < 0.001), with a slight superiority of NTR vs. MN-CSA when controlled for height, wrist circumference and weight. In CTS filtered for anthropometric extremes, only NTR maintained a correlation with SCV (p = 0.023), DML (p = 0.016) and PS (p = 0.009). Diagnostic cut-offs were obtained with a binomial regression analysis. In those patients with a clinical diagnosis of CTS, the cut-off of MN-CSA (AUROC: 0.983) was 8 mm2 (9 mm2 with highest positive predictive value, PPV), while for NTR (AUROC: 0.987), the cut-off was 83% (100% with highest PPV). In patients with EDS findings of severe CTS (PS > 3), the MN-CSA (AUROC: 0.876) cut-off was 12.3 mm2 (15.3 mm2 with highest PPV), while for NTR (AUROC: 0.858) it was 116.2% (146.0% with highest PPV). Conclusions: NTR can be simply and quickly calculated, and it can be used in anthropometric extremes.

Clinical Features and Outcome of the Guillain-Barre Syndrome: A Single-Center 11-Year Experience.

Background: Clinical presentation, electrophysiological subtype, and outcome of the Guillain-Barre' Syndrome (GBS) may differ between patients from different geographical regions. This study aims to assess clinical-neurophysiological features of an adult, Italian GBS cohort over 11 years. Methods: Retrospective (from 1 January 2011 to 31 December 2021) analysis was carried out on patients admitted to the Siena University Hospital who fulfilled the GBS diagnostic criteria. Demographic data, clinical characteristics, treatment, need of mechanical ventilation (MV), laboratory and electrophysiological tests, preceding infections/vaccination/other conditions, and comorbidities were collected for each patient. Results: A total of 84 patients (51 men, median age of 61 years), were identified. GBS subtype was classified as acute inflammatory demyelinating polyneuropathy (AIDP) in the 66.6% of patients, acute motor/sensory axonal neuropathy (AMAN/AMSAN) in 20.2%, and the Miller Fisher syndrome in 5 (5.9%). Flu syndrome and gastrointestinal infection were the most common preceding conditions. In total, five (5.9%) subjects had concomitant cytomegalovirus (CMV) infection. Cranial nerve involvement occurred in 34.5% of subjects. Differences between the axonal and AIDP forms of GBS concerned the presence of anti-ganglioside antibodies. In total, seven (8.33%) patients required MV. Discussion: The epidemiological and clinical characteristics of GBS in different countries are constantly evolving, especially in relation to environmental changes. This study provides updated clinical-epidemiological information in an Italian cohort.

Case report: A quantitative and qualitative diffusion tensor imaging (DTI) study in varicella zoster-related brachial plexopathy.

Diffusion tensor imaging (DTI) is considered feasible for the nerve plexuses' imaging and quantitative evaluation but its value in the clinical practice is still virtually unexplored. We present the DTI profile of a case of acute varicella-zoster virus (VZV)-related brachial plexopathy. A 72-year-old woman presented with left upper-limb segmental paresis involving the spinal metamers C6-C7, preceded by a painful dermatomal vesicular eruption in C5-T1 dermatomes. Clinical and electrophysiological findings and magnetic resonance imaging indicated a plexus involvement. DTI analysis showed decreased fractional anisotropy (FA) and an increase of all the other diffusivity indexes, i.e., mean, axial, and radial diffusivity. The mechanisms underlying DTI parameter differences between healthy and pathologic brachial plexus sides could be related to microstructural fiber damage. Water diffusion is affected within the nerve roots by increasing the diffusion distance, leading to increased diffusion perpendicular to the largest eigenvalue and therefore to decreased FA values The role of DTI in clinical practice has not been defined yet. Additional quantitative and qualitative DTI information could improve the assessment and follow-up of brachial plexopathy.

Electrophysiological Study of the Tibial Nerve Across the Tarsal Tunnel in Distal Symmetric Diabetic Polyneuropathy.

OBJECTIVE: The aim of the study was to demonstrate abnormalities of motor conduction of the tibial nerve across the tarsal tunnel in type 2 diabetes. DESIGN: One hundred twenty-four consecutive patients (mean age = 66.6 yrs, 62.1% male) with distal symmetric diabetic polyneuropathy clinically diagnosed were prospectively enrolled. Nerve conduction studies of deep peroneal, tibial, superficial peroneal, medial plantar, and sural nerves and standard needle electromyography in the lower limbs were performed. Demographic, anthropometric, and clinical findings were collected. RESULTS: Motor conduction velocity of the tibial nerve across tarsal tunnel was slowed in 60.5% of patients; another 4% showed conduction block across tarsal tunnel without reduction of motor conduction velocity. Overall percentage of abnormalities across tarsal tunnel (64.5%) exceeds that of the sensory conduction velocities of proximal sural and superficial peroneal nerves. Abnormal tibial motor conduction velocity across tarsal tunnel represents the most common abnormality among all motor nerve conduction study parameters and significantly correlates with hemoglobin level, diabetic neuropathic index score, and diabetic complications frequency. CONCLUSIONS: Tibial conduction abnormalities across tarsal tunnel are the most sensitive motor parameter in distal symmetric diabetic polyneuropathy, second only to conduction abnormalities of sensory/mixed distal nerves of the feet. The use of nerve conduction studies across tarsal tunnel of the tibial nerve may be useful in the electrophysiological protocol to confirm the diagnosis of distal symmetric diabetic polyneuropathy.

Somatosensory evoked potentials and transcranial color Doppler monitoring in subarachnoid hemorrhage.

OBJECTIVES: The outcome of patients with subarachnoid hemorrhage (SAH) is broadly influenced by the complications that may result from the hemorrhage. We describe a series of subjects, in which neurophysiological monitoring executed by simultaneous recording of somatosensory evoked potentials (SEPs) and transcranial color Doppler (TCD) was performed to reveal possible, early complications following acute SAH. MATERIALS AND METHODS: We described the absolute and interhemispheric values of SEPs from the upper limb and TCD examinations of the cerebral arteries in 13 subjects with acute SAH. RESULTS: In cases with middle cerebral artery (MCA) vasospasm, N20 SEP amplitude absolute values for the hemisphere involved in the vasospasm were much lower than the contralateral ones. The N20 amplitude ratio reduction correlated with reciprocal of MCA mean flow velocity values detected within each patient. In the subjects with early ischemic damage following SAH, the affected hemisphere showed N20 amplitude drop; in addition, the relationship between SEPs and TCD findings was missing. CONCLUSION: Our findings emphasize the utility of simultaneous evaluation of SEPs and TCD in SAH follow-up, since the two methods reflect different pathomechanisms of possible secondary brain damage in aneurysmal SAH.

A new mutation in DNM2 gene in a large Italian family.

The Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with great clinical and genetic heterogeneity. Mutations in DNM2 have been associated with CMT dominant intermediate B (CMTDIB). However, mutations in the same gene are known to induce also axonal CMT (CMT2M) or centronuclear myopathy. Moreover, the ability of effectively and simultaneously sequencing different CMT-related genes by next-generation sequencing approach makes it possible to detect even the presence of modifier genes that sometimes give reason of clinical variability in the context of complex phenotypes. Here, we describe an Italian family with very variable severity of phenotype among members harboring a novel DNM2 gene mutation which caused a prevalent CMT2M phenotype. The contemporary presence of a de novo variant in PRX gene in the most severely affected family member suggests a possible modulator effect of the PRX variant thus highlighting the possible impact of modifier genes in CMT.

Changes in corticomotor pathway excitability after exercise training in Parkinson's disease.

BACKGROUND: Altered corticospinal excitability in Parkinson's disease (PD) is related to many of the motor signs. OBJECTIVE: We examined whether the recruitment properties of the corticospinal pathway to hand muscles are changed after 8 weeks of specialized upper limbs exercise in PD. METHODS: Seven PD subjects were enrolled. Upper limb exercise was achieved by using a specially designed device. The input-output (I-O) curves were obtained by transcranial magnetic stimulation (TMS). The conduction of peripheral axons and H reflex was also recorded. UPDRS scale, part-III motor examination was used to assess the motor symptom. Clinical and neurophysiological data were obtained before and after 2-month exercise training. RESULTS: After 2-month exercise training, the UPDRS score was significantly improved. Threshold, slope, and V50 (i.e., the stimulus intensity required to obtain a response 50% of the maximum) of the I-O curve were unchanged, whereas the plateau value was significantly higher. CONCLUSIONS: Exercise training affects the larger motoneurons, that is those activated at higher TMS stimulation intensity. These motoneurones are related to the large, type II motor units. Clinical improvement after exercise may depend upon restoration of the recruitment of the large motor unit, i.e., those necessary to perform rapid and strong movements, known to be deficient in PD.

Impact of ß-range-induced oscillatory activity on human input-output relationship of the corticospinal pathway.

Objective: The aim of the study was to show that short-lasting (90 s) transcranial alternating current stimulation (tACS) at 20 Hz delivered over the left primary motor cortex (M1) is able to change the shape of recruitment curve of the corticospinal pathway.Methods: The corticospinal pathway was studied during tACS by means of the relationship between the intensity of transcranial magnetic stimulation (TMS) delivered over the left M1 and corresponding motor evoked potentials (MEPs) recorded from the right first dorsal interosseus muscle (FDI), in nine healthy subjects. In order to extract characteristics of the input-output relationship that have particular physiological relevance, data were fitted to the Boltzmann sigmoidal function by the Levenberg-Marquardt nonlinear, least mean squares algorithm.Results: The ß-rhythm tACS influenced the shape and parameters of the input-output relation, so that the initial segment of the conditioned curve (from threshold to 30% of maximum muscle size) diverged, while the subsequent segment converged to overlap the unconditioned control curve.Discussion: ß-rhythm tACS conditions only a definite subset of corticospinal elements influencing less than 30% of the entire motoneuronal pool. The fact that ß-rhythm tACS mainly affects the most excitable motoneurons could explain the observed antikinetic effect of the tACS at ß-rhythm applied in the motor regions.

The effects of anthropometric and demographic factors on conduction parameters of the ulnar nerve: Multivariate analysis.

The objective of the study is to investigate the effects of age, height, gender, body mass index (BMI), waist-to-hip ratio (WHR), arm and elbow measures on ulnar nerve conduction. We enrolled 261 "disease-free" subjects. We analyzed motor conduction velocity (MCV) in across elbow (AE) and forearm tracts, and sensory conduction velocity in 4th, 5th digit-wrist tracts (U4, U5) and in dorsal ulnar cutaneous nerve (DUC). We calculated the amplitudes of sensory and motor potentials (CMAPa and SNAPa), % of CMAPa drop AE, MCV drop and distal motor latency (DML). Univariate and multivariate analyses were performed. We estimated the predictive equations. The median nerve was examined for comparison. Age was negatively correlated with all conduction parameters. Forearm and AE MCV, % of CMAPa drop, DML, U4 and U5 SCV also depended upon height. Females had higher U4 and U5 SNAPa than males. BMI showed inverse relationship with U4 and U5 SNAPa. DUC parameters depended upon BMI and arm length. Similar trends were observed for the median nerve. "Normative" ulnar conduction parameters should be adjusted for demographic and anthropometric measures to improve diagnostic sensitivity.

Reference values for distal motor conduction of the tibial nerve: Effects of demographic and anthropometric measures.

INTRODUCTION: In this study we collected reference values for the across-tarsal-tunnel conduction of the motor tibial nerve (mTN). METHODS: The mTN compound muscle action potentials (CMAPs) from the abductor hallucis muscle were obtained by stimulating below/above the malleolus and the popliteal fossa. The effect of weight, height, body mass index (BMI), foot and leg length, sex, and age were evaluated using univariate and multivariate correlation analyses, and predictive equations for each mTN conduction parameter were developed. RESULTS: On the basis of data from 185 subjects, there were differences between women and men in all anthropometric parameters and for some nerve conduction values. Through multivariate analysis, age, but not sex, was found to have a significant impact. Height affected both distal and proximal conduction velocity. BMI affected CMAP amplitude. DISCUSSION: mTN conduction is influenced by various demographic and anthropometric factors. For all intrinsic factors, height demonstrated the greatest effect on mTN conduction across the tarsal tunnel.

Effects of elastic stockings on peripheral and central nervous system.

BACKGROUND: Prospective study to investigate the effects of elastic stockings (GCS) 23-32 mmHg at ankle on Hoffmann reflex (H-reflex) from soleus muscle under rest and after a walking program. METHODS: Fourteen subjects wore two types of GCS, at different times. Electrophysiological examinations were carried out at rest without and with GCS, immediately after walking with GCS and 20 minutes later after removing GCS. RESULTS: Peripheral nerve conduction remained unchanged after using the GCS. Conversely, walking with GCS led to changes in a spinal cord pathway expressed as a decrease of H-threshold and an increase of H-size as a function of stimulus intensity, which lasted for at least 20 minutes. CONCLUSIONS: GCS has no effect on the peripheral nervous system. The GCS intolerance and the discomfort sometimes reported by patients do not derive from a dysfunction of the lower limb peripheral nervous system. A positive action on spinal reflex excitability is detected after walking while wearing GCS. We suggest that nervous descending activity due to voluntary contractions, and afferent cutaneous discharge, enhanced by movement under compression, converge on inhibitory interneurons, thus impinging on presynaptic pathways. All this can lead to an enhancement of the monosynaptic responses. Higher limb oxygenation detected during walking with GCS, found by other Authors, could increase the sensitivity of the muscle spindle afferents and/or motor neuron excitability resulting in an increase in H-reflex excitability, with potential positive effects on neuromuscular activities improving proprioception and postural control of the lower limbs.

SPG8 mutations in Italian families: clinical data and literature review.

BACKGROUND: Spastic paraplegia type 8 (SPG8) is an autosomal-dominant form of hereditary spastic paraplegia (AD-HSP) caused by a mutation in the KIAA0196 gene. SPG8 accounts for 1% of less of all AD-HSP and the genotype-phenotype correlation remains poorly understood. METHODS: We report the first clinical and genetic description of SPG8 disease in Italian patients. We identified four new mutations in KIAA0196 gene. These variants were identified using a multigene targeted resequencing HSP panel. We took this opportunity to review the pertinent literature. RESULTS: Age at disease onset was in the third or fourth decade of life. Stiffness of the lower limb with spastic gait, walking impairment, and decreased vibration sense were common early symptoms. Subjects of two families had bladder control abnormalities. Unlike previous reported cases, Italian SPG8 subjects have pure form of spastic paraparesis without cranial nerve involvement, and onset is in adult life. DISCUSSION: By a clinical point of view, it is hard to differentiate SPG8 from the SPG4, in which bladder and vibration sense dysfunctions are frequent signs. The differential diagnosis with other forms of AD-HSPs seems relatively easier if one considers the early-onset manifestations in SPG3A and the peripheral nervous system and cerebellar involvement seen in SPG31.