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BackgroundTo 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.MethodsThe 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’).ResultsAt 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.ConclusionsA 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.

Background HCV‐related extra‐hepatic complications include peripheral neuropathies, with important prevalence and impact. A recent metanalysis of previous intervention trials concluded for insufficient data to support evidence‐based treatments for this complication. In this longitudinal study, we assessed for the first time prevalence and outcome of neuropathy in a cohort of patients with chronic HCV, before and after direct‐acting antiviral agent (DAA) treatment. Method Ninety‐four patients (mean age 58.5 ± 9.9, infection duration 22.2 ± 6.3 years) without systemic and metabolic diseases, underwent neurological examination and electroneurography studies before (T0) and 10.4 ± 1.7 months after the end of DAA therapy (T1), and cryoglobulins (CG) assessment. Muscle strength was evaluated by Medical Research Council (MRC) score; neuropathic pain, sensory function, disability, quality of life were assessed by validated questionnaires (DN4, NPSI, SSS, INCAT and Euro‐QoL). Results At T0, sensory‐motor neuropathy was detected in 22 patients (23%), reflexes were depressed in 32 (34%) with no association with infection duration, viral load, age, CG. Neuropathic pain (DN4 ≥4) was present in 37 patients (39%). At T1, out of the 22 patients with altered electroneurography, 3 had died or developed HCC, 4 showed normal electroneurography, and nerve amplitude parameters tended to improve in the whole group. Only 11 patients (12%) had depressed reflexes and 10 (11%) DN4 ≥4 (P

Introduction Electrophysiological diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) may be challenging. Thus, with the aim ofproviding some practical advice in electrophysiological approach to a patient with suspected CIDP, we analyzed electrophysiological data from 499 patients enrolled inthe Italian CIDP Database. Methods We calculated the rate of each demyelinating feature, the rate of demyelinating features per nerve, the diagnostic rate for upper andlower limb nerves, and, using a ROC curve analysis, the diagnostic accuracy of each couple of nerves and each demyelinating feature, for every CIDP subtype.Moreover, we compared the electrophysiological data of definite and probable CIDP patients with those of possible and not-fulfilling CIDP patients, and by a logisticregression analysis, we estimated the odds ratio (OR) to make an electrophysiological diagnosis of definite or probable CIDP. Results The ulnar nerve had the highestrate of demyelinating features and, when tested bilaterally, had the highest diagnostic accuracy except for DADS in which peroneal nerves were the most informative.In possible and not-fulfilling CIDP patients, a lower number of nerves and proximal temporal dispersion (TD) measurements had been performed compared to definiteand probable CIDP patients. Importantly, OR for each tested motor nerve and each TD measurement was 1.59 and 1.33, respectively. Conclusion Our findingsdemonstrated that the diagnosis of CIDP may be missed due to inadequate or incomplete electrophysiological examination or interpretation. At the same time, thesedata taken together could be useful to draw a thoughtful electrophysiological approach to patients suspected of CIDP.

This prospective, multicenter, single‐arm, open‐label phase 3 study aimed to evaluate the efficacy and safety of IqYmune in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Patients received one induction dose of 2 g/kg and then seven maintenance doses of 1 g/kg at 3‐week intervals. The primary endpoint was the responder rate at the end of study (EOS), defined as an improvement of ≥1 point on the adjusted inflammatory neuropathy cause and treatment (INCAT) disability scale. The responder rate was compared with the responder rate of a historical placebo group (33.3%). Secondary endpoints included changes from baseline to EOS of adjusted INCAT disability score, grip strength, Medical Research Council (MRC) sum score, Rasch‐modified MRC sum score, Rasch‐built overall disability scale score and the clinical global impression. Forty‐two patients, including 23 Ig‐naïve and 19 Ig‐pre‐treated, were included in the efficacy set. The overall response rate at EOS was 76.2% (95% confidence interval [60.5%‐87.9%]). The superiority of IqYmune compared to the historical placebo control was demonstrated (P

BACKGROUND: The management of epilepsy in older adults has become part of daily practice because of an aging population. Older patients with epilepsy represent a distinct and more vulnerable clinical group as compared with younger patients, and they are generally under-represented in randomized placebo-controlled trials. Real-world studies can therefore be a useful complement to characterize the drug's profile. Brivaracetam is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A and approved as adjunctive therapy for focal seizures in adults with epilepsy. OBJECTIVE: The aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive brivaracetam in older patients (≥65 years of age) with epilepsy treated in a real-world setting. METHODS: The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a 12-month retrospective multicenter study including adult patients prescribed adjunctive brivaracetam. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events and the incidence of adverse events. Data were compared for patients aged ≥65 years of age ('older') vs those aged

Background and purpose: A diagnostic score was developed to discriminate anti-myelin-associated-glycoprotein (MAG) neuropathy from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and applied it to patients with atypical anti-MAG neuropathy. Methods: The clinical and electrophysiological features of patients with a diagnosis of typical anti-MAG neuropathy were compared to those of patients with a diagnosis of CIDP. The association of each feature with the diagnosis was assessed in the two groups. Features showing a significant association with the diagnosis were included in a multivariable logistic regression model and adjusted odds ratios were estimated for each feature. A score ranging from 1 to 3 was applied to each feature based on the magnitude of the estimated odds ratios. The score was then applied to patients with a clinical diagnosis of CIDP who also had high anti-MAG antibody titers (CIDP-MAG). Results: Thirty-one anti-MAG neuropathy patients, 45 typical CIDP patients and 16 CIDP-MAG patients were included. Scores in anti-MAG antibody patients ranged from 1 to 5 and in CIDP patients from -7 to -1. Using the score, 4/16 CIDP-MAG patients were diagnosed to have anti-MAG neuropathy and 12/16 patients to have CIDP. Response to intravenous immunoglobulin in the CIDP-MAG patients classified as CIDP was similar to that of definite CIDP patients and higher than that of anti-MAG neuropathy patients. Conclusions: Our score allowed an accurate discrimination to be made, amongst patients with anti-MAG antibodies, of those affected by CIDP and the patients with anti-MAG neuropathy. This score may help proper treatment to be chosen for patients with anti-MAG antibodies with a CIDP-like presentation.

ObjectivesTo compare the sensitivity and specificity of the 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with those of the 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS).MethodsSensitivity and specificity of the two sets of criteria were evaluated in 330 patients with CIDP and 166 axonal peripheral neuropathy controls. Comparison of the utility of nerve conduction studies with different number of nerves examined and of the sensitivity and specificity of the two criteria in typical CIDP and its variants were assessed.ResultsEFNS/PNS criteria had a sensitivity of 92% for possible CIDP and 85% for probable/definite CIDP, while the EAN/PNS criteria had a sensitivity of 83% for possible CIDP and 74% for CIDP. Using supportive criteria, the sensitivity of the EAN/PNS criteria for possible CIDP increased to 85% and that of CIDP to 77%, remaining lower than that of the EFNS/PNS criteria. Specificity of the EFNS/PNS criteria was 68% for possible CIDP and 84% for probable/definite CIDP, while the EAN/PNS criteria had a specificity of 88% for possible CIDP and 98% for CIDP. More extended studies increased the sensitivity of both sets of criteria by 4%–7% but reduced their specificity by 2%–3%. The EFNS/PNS criteria were more sensitive for the diagnosis of typical CIDP while the EAN/PNS criteria were more specific for the diagnosis of distal and sensory CIDP.ConclusionsIn our population, the EAN/PNS criteria were more specific but less sensitive than the EFNS/PNS criteria. With the EAN/PNS criteria, more extended nerve conduction studies are recommended to obtain an acceptable sensitivity while maintaining a high specificity.

Objective: Post-stroke epilepsy (PSE) is one of the most common causes of acquired epilepsy and accounts for about 10-15% of all newly diagnosed epilepsy cases. However, evidence about the clinical profile of antiseizure medications in the PSE setting is currently limited. Brivaracetam (BRV) is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A. The aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive BRV in patients with PSE treated in a real-world setting. Methods: This was a subgroup analysis of patients with PSE included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). The BRIVAFIRST was a 12-month retrospective, multicentre study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure‐freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Results: Patients with PSE included in the BRIVAFIRST were 75 and had a median age of 57 (interquartile range, 42-66) years. The median daily doses of BRV at 3, 6, and 12 months from starting treatment were 100 (100-150) mg, 125 (100-200) mg and 100 (100-200) mg, respectively. At 12 months, 32 (42.7%) patients had a reduction in their baseline seizure frequency by at least 50%, and the seizure freedom rates was 26/75 (34.7%). During the 1-year study period, 10 (13.3%) patients discontinued BRV. The reasons of treatment withdrawal were insufficient efficacy in 6 (8.0%) patients and poor tolerability in 4 (5.3%) patients. Adverse events were reported by 13 (20.3%) patients and were rated as mild in 84.6% and moderate in 15.4% of cases. Significance: Adjunctive BRV was efficacious and generally well-tolerated when used in patients with PSE in clinical practice. Adjunctive BRV can be a suitable therapeutic option for patients with PSE.

The maintenance of seizure control over time is a clinical priority in patients with epilepsy. The aim of this study was to assess the sustained seizure frequency reduction with adjunctive brivaracetam (BRV) in real-world practice. Patients with focal epilepsy prescribed add-on BRV were identified. Study outcomes included sustained seizure freedom and sustained seizure response, defined as a 100% and a ≥50% reduction in baseline seizure frequency that continued without interruption and without BRV withdrawal through the 12-month follow-up. Nine hundred ninety-four patients with a median age of 45 (interquartile range = 32-56) years were included. During the 1-year study period, sustained seizure freedom was achieved by 142 (14.3%) patients, of whom 72 (50.7%) were seizure-free from Day 1 of BRV treatment. Sustained seizure freedom was maintained for ≥6, ≥9, and 12months by 14.3%, 11.9%, and 7.2% of patients from the study cohort. Sustained seizure response was reached by 383 (38.5%) patients; 236 of 383 (61.6%) achieved sustained ≥50% reduction in seizure frequency by Day 1, 94 of 383 (24.5%) by Month 4, and 53 of 383 (13.8%) by Month 7 up to Month 12. Adjunctive BRV was associated with sustained seizure frequency reduction from the first day of treatment in a subset of patients with uncontrolled focal epilepsy.

Objective: To investigate the frequency and clinical correlates of anti-nerve autoantibodies in an unselected series of Italian patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Methods: Sera from 276 CIDP patients fulfilling the EFNS/PNS criteria and included in the Italian CIDP database were examined for the presence of anti-nerve autoantibodies. Results were correlated with the clinical data collected in the database. Results: Anti-neurofascin155 (NF155) antibodies were found in 9/258 (3.5%) patients, anti-contactin1 (CNTN1) antibodies in 4/258 (1.6%) patients, and anti-contactin-associated protein1 (Caspr1) in 1/197 (0.5%) patients, while none had reactivity to gliomedin or neurofascin 186. Predominance of IgG4 isotype was present in 7of the 9 examined patients. Anti-NF155 patients more frequently had ataxia, tremor, and higher CSF protein levels than antibody-negative patients. Anti-CNTN1 patients more frequently had a GBS-like onset, pain, and ataxia and had more severe motor impairment at enrollment than antibody-negative patients. They more frequently received plasmapheresis, possibly reflecting a less satisfactory response to IVIg or steroids. IgM antibodies against one or more gangliosides were found in 6.5% of the patients (17/260) and were more frequently directed against GM1 (3.9%). They were frequently associated with a progressive course, with a multifocal sensorimotor phenotype and less frequent cranial nerve involvement and ataxia. Conclusions: Anti-paranodal and anti-ganglioside antibodies are infrequent in patients with CIDP but are associated with some typical clinical association supporting the hypothesis that CIDP might be a pathogenically heterogeneous syndrome possibly explaining the different clinical presentations.

Syringomyelia and Chiari malformation are classified as rare diseases on Orphanet, but international guidelines on diagnostic criteria and case definition are missing. Aim of the study: to reach a consensus among international experts on controversial issues in diagnosis and treatment of Chiari 1 malformation and syringomyelia in adults. A multidisciplinary panel of the Chiari and Syringomyelia Consortium (4 neurosurgeons, 2 neurologists, 1 neuroradiologist, 1 pediatric neurologist) appointed an international Jury of experts to elaborate a consensus document. After an evidence-based review and further discussions, 63 draft statements grouped in 4 domains (definition and classification/planning/surgery/isolated syringomyelia) were formulated. A Jury of 32 experts in the field of diagnosis and treatment of Chiari and syringomyelia and patient representatives were invited to take part in a three-round Delphi process. The Jury received a structured questionnaire containing the 63 statements, each to be voted on a 4-point Likert-type scale and commented. Statements with agreement

Fabry disease (FD) is a systemic X-linked lysosomal disorder. A ‘peripheral nerve variant’ of FD has been hypothesized in subjects with neuropathy, without the early manifestations of the classic phenotype. A cohort of undiagnosed neuropathy patients with chronic polyneuropathy of undetermined aetiology and demyelinating neuropathy, unresponsive to immunomodulating treatment, were screened for FD. A total of 103 patients (64% males), were enrolled. No typical pathogenetic mutations for FD were identified. We are aware that the study sample was very small, but only a large, unfeasible theoretical sample size could demonstrate a statistically significant increased prevalence of FD in neuropathy patients, as peripheral neuropathy of undetermined cause is uncommon and there is a low prevalence of FD in the general population. Therefore, we are of the opinion that including tailored FD screening in the neuropathy diagnostic work-up, particularly when there are additional clinical characteristics, should be considered.

Purpose. Brainstem syndromes have frequently been reported in Chiari syndrome and in syringobulbia; previous studies have shown that determining the central motor conduction time (CMCT) along the circuit of the phrenic nerve makes the assessment of the voluntary control of the respiratory pathway possible. In our study, we evaluated the transcranial magnetic stimulation (TMS) of the phrenic nerve in patients affected by Chiari syndrome and/or syringomyelia (Syr) with the aim of identifying subclinical neurophysiological alterations. Methods. One hundred patients (75 females; average age: 51 ± 13.08 SD; range: 18–76) affected by Chiari syndrome and/or Syr without dyspnea were selected. The magnetic stimulation of the second motor neuron correlating with the phrenic nerve was performed using cervical magnetic stimulation (C5-MEP); the cortical MEP after magnetic stimulation (Cz-MEP) was recorded by magnetic stimulation of the motor cortex (areas corresponding to the diaphragm). The CMCT was calculated. The differences between the patients and controls were calculated (Student’s t test). Results. In 13% of the patients, the Cz-MEP were absent bilaterally, and the CMCT was not evaluable. In all these cases, bulbar/cervical Syr was present at MRI; in 10 of them, this was associated with CM1. A bilateral response was obtained in all the other patients (87%), and the CMCTs were normal. All the patients with alterations/absence of Cz-MEP presented bulbar/cervical Syr at MRI. The C5-MEP latency was prolonged or absent in 48%; of these, 84% presented bulbar/cervical Syr associated with CM1 at MRI. The C5-MEP latency values were significantly higher in the group of patients. Conclusions. Neurophysiological alterations of the diaphragmatic pathway were recorded in a group of Chiari syndrome and, particularly, in bulbar/cervical Syr. Future studies with larger cohorts of patients are needed to further assess the specific role of the TMS of the phrenic nerve in CM/Syr patients.

Intravenous immunoglobulin (IVIg) is the gold-standard for maintenance treatment of multifocal motor neuropathy (MMN). This phase III, randomised, double-blind, multi-centre, active-control, crossover study, aimed to evaluate the non-inferiority of IqYmune® relative to Kiovig®, primarily based on efficacy criteria. Twenty-two adult MMN patients, treated with any brand of IVIg (except Kiovig® or IqYmune®) at a stable maintenance dose within the range of 1 to 2 g/kg every 4 to 8 weeks, were randomised to receive either Kiovig® followed by IqYmune®, or IqYmune® followed by Kiovig®. Each product was administered for 24 weeks. The primary endpoint was the difference between IqYmune® and Kiovig® in mean assessments of modified Medical Research Council (MMRC) 10 sum score (strength of 5 upper-limb and 5 lower-limb muscle groups, on both sides, giving a score from 0 to 100) during the evaluation period (non-inferiority margin of Δ = 2). A linear mixed model analysis demonstrated the non-inferiority of IqYmune® relative to Kiovig®, independently of the covariates (value at baseline, treatment period, and treatment sequence). The estimated "IqYmune® - Kiovig®" difference was -0.01, with a 95% confidence interval (CI) -0.51 to 0.48. The number of adverse reactions (ARs) and the percentage of patients affected were similar for the two products: 39 ARs in 10 patients with IqYmune® vs 32 ARs in 11 patients with Kiovig®. No thromboembolic events nor haemolysis nor renal impairment were observed. In this first clinical trial comparing two IVIg brands for maintenance treatment of MMN, efficacy and tolerability of both brands were similar.

In Chiari 1 Malformation (CM1) the most frequent symptom is exertional headache, but other headache types have been reported, such as migraine. This cross-sectional study is aimed to examine the prevalence of migraine in a group of CM1 headache patients and to compare clinical-demographic characteristics between migraine and non-migraine patients. 427 adults were enrolled at the multidisciplinary Chiari Center in Torino. 230 headache patients were classified, based on radiological criteria. Frequencies (absolute/percentage values) were calculated in the whole sample for: migraine presence (with and without aura), gender, age, radiologic phenotypes and headache clinical characteristics. The association between CM1 diagnosis and headache characteristics (independent variables) and migraine diagnosis (dependent variable) was estimated by logistic regression models. Seventy-eight patients (67 females) out of 230 presenting headache had a migraine (34%), 44/78 (56%) with aura; in 58/78 (74%) migraine was comorbid with secondary headache attributable to CM1. Migraine prevalence in patients with isolated CM1 (52/120, 43.3%) was higher (p = 0.0016) than in all the other patients (26/110, 23.6%). Although migraine was prevalent in females (86%; 6:1 female:male ratio), age classes and gender were not risk factors for migraine at multivariate analysis, while migraine was associated with isolated CM1 phenotype (OR = 2.6). This study shows a high prevalence of migraine in CM1 patients and a significant association between migraine and isolated CM1. In patients with radiological evidence of CM1, particularly in the absence of neurological signs, a careful headache clinical characterization, according to the International Headache Society criteria, may be advised.

Chronic immune-mediated neuropathies, including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), neuropathies associated with monoclonal gammopathy, and multifocal motor neuropathy (MMN), are a group of disorders deemed to be caused by an immune response against peripheral nerve antigens. Several immune therapies have been reported to be variably effective in these neuropathies including steroids, plasma exchange, and high-dose intravenous (IVIg) or subcutaneous (SCIg) immunoglobulins. These therapies are however far from being invariably effective and may be associated with a number of side effects leading to the use of immunosuppressive agents whose efficacy has not been so far confirmed in randomized trials. More recently, new biological agents, such as rituximab, have proved to be effective in patients with neuropathy associated with IgM monoclonal gammopathy and are currently tested in CIDP.

The Polyneuropathy And Treatment with Hizentra (PATH) study required subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) to show dependency on immunoglobulin G (IgG) and then be restabilized on IgG before being randomized to placebo or one of two doses of subcutaneous immunoglobulin (SCIG). Nineteen of the 51 subjects (37%) randomized to placebo did not relapse over the next 24 weeks. This article explores the reasons for this effect. A post‐hoc analysis of the PATH placebo group was undertaken. A literature search identified other placebo‐controlled CIDP trials for review and comparison. In PATH, subjects randomized to placebo who did not relapse were significantly older, had more severe disease, and took longer to deteriorate in the IgG dependency period compared with those who relapsed. Published trials in CIDP, whose primary endpoint was stability or deterioration, had a mean non‐deterioration (placebo effect) of 43%, while trials with a primary endpoint of improvement had a placebo response of only 11%. Placebo is an important variable in the design of CIDP trials. Trials designed to show clinical improvement will have a significantly lower effect of this phenomenon than those designed to show stability or deterioration.

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins. ispartof: NEUROBIOLOGY OF AGING vol:92 ispartof: location:United States status: published

Objectives The efficacy and safety of high-dose intravenous immunoglobulin (IVIG) in treatment-resistant diabetic painful polyneuropathy (DPN) were assessed. Design This was a randomized, double-blind, placebo-controlled, multicenter trial (EudraCT 2010–023883–42). Setting This trial was conducted at eight sites in Italy with a neurology specialist level of care. Subjects Twenty-six diabetic patients with DPN who reported baseline severity of pain >60 units (mm) on a VAS scale at enrollment and were resistant to antidepressants and antiepileptic drugs were enrolled; 23 were randomized (11 in the IVIG arm and 12 in the placebo arm). All patients completed the study and were evaluated. All patients were Caucasian, 15 were male, and 21 had a diagnosis of type II diabetes. Methods IVIG (0.4 g/kg/d) or placebo was given for five consecutive days. Pain intensity (visual analog scale, Neuropathic Pain Symptom Inventory) and quality of life (36-Item Short-Form Health Survey, Clinical/Patient Global Impression of Change questionnaires) assessments were performed at visits: baseline, start of therapy (one week later), end of therapy (five days later), and follow-up (four and eight weeks later). Results The study achieved its prespecified primary end point of ≥50% pain reduction at four weeks after IVIG, achieved in seven of 11 patients (63.6%) in the IVIG group vs zero of 12 in the placebo group (P = 0.0013). Only two adverse events were reported during the study: one patient in the treatment arm reported a mild “dermatitis psoriasiform,” whereas one patient from the placebo group reported a mild “influenza.” Conclusions Treatment with IVIG at the dose given was efficacious and safe for patients with DPN resistant to standard therapies.

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

ObjectivesTo determine the prevalence of different comorbidities in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and their impact on outcome, treatment choice and response.MethodsUsing a structured questionnaire, we collected information on comorbidities from 393 patients with CIDP fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society criteria included in the Italian CIDP database.ResultsOne or more comorbidities were reported by 294 patients (75%) and potentially influenced treatment choice in 192 (49%) leading to a less frequent use of corticosteroids. Response to treatment did not differ, however, from that in patients without comorbidities. Diabetes (14%), monoclonal gammopathy of undetermined significance (MGUS) (12%) and other immune disorders (16%) were significantly more frequent in patients with CIDP than expected in the general European population. Patients with diabetes had higher disability scores, worse quality of life and a less frequent treatment response compared with patients without diabetes. Patients with IgG-IgA or IgM MGUS had an older age at CIDP onset while patients with other immune disorders had a younger age at onset and were more frequently females. IgM MGUS was more frequent in patients with motor CIDP than in patients with typical CIDP.ConclusionsComorbidities are frequent in patients with CIDP and in almost 50% of them have an impact on treatment choice. Diabetes, MGUS and other immune diseases are more frequent in patients with CIDP than in the general population. Only diabetes seems, however, to have an impact on disease severity and treatment response possibly reflecting in some patients a coexisting diabetic neuropathy.

ObjectivesA few variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been described, but their frequency and evolution to typical CIDP remain unclear. To determine the frequency and characteristics of the CIDP variants, their possible evolution to typical CIDP, and treatment response.MethodsWe applied a set of diagnostic criteria to 460 patients included in a database of Italian patients with CIDP. Clinical characteristics and treatment response were reviewed for each patient. The Kaplan-Meier curve was used to estimate the progression rate from atypical to typical CIDP.ResultsAt the time of inclusion, 376 (82%) patients had a diagnosis of typical CIDP while 84 (18%) had atypical CIDP, including 34 (7%) with distal acquired demyelinating symmetric neuropathy (DADS), 17 (4%) with purely motor, 17 (4%) with Lewis-Sumner syndrome (LSS) and 16 (3.5%) with purely sensory CIDP. Based on retrospective review of the symptoms and signs present at onset and for at least 1 year, 180 (39%) patients had an initial diagnosis compatible with atypical CIDP that in 96 (53%) patients evolved to typical CIDP. Mean disease duration was longer in patients evolving to typical CIDP than in those not evolving (p=0.0016). Patients with DADS and LSS had a less frequent response to immunoglobulin than those with typical CIDP, while patients with purely motor and sensory CIDP had a similar treatment response.ConclusionsThe proportion of patients with atypical CIDP varies during the disease course. DADS and LSS have a less frequent response to intravenous immunoglobulin compared with typical CIDP, raising the possibility of a different underlying pathogenetic mechanism.

PATH study group., In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre‐randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did not show CIDP stability (n = 21, analyzed as n = 22 as an additional subject was randomized in error) or withdrew for other reasons (n = 14). Of the 22 subjects who did not achieve clinical stability, follow‐up information in 16 subjects after an additional 4 weeks was obtained. Nine subjects were reported to have improved, leaving a maximum of 27 subjects (13%) who either showed no signs of clinical improvement during the restabilization phase and 4 weeks post‐study or withdrew for other reasons. In conclusion, sudden IVIG withdrawal was effective in detecting ongoing immunoglobulin G dependency with a small risk for subjects not returning to their baseline 17 weeks after withdrawal., Editorial support was provided by Meridian HealthComms Ltd, funded by CSL Behring.

Objective.This cross-sectional study analyzes the pattern of ultrasound peripheral nerve alterations in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) at different stages of functional disability.Material and Methods.22 CIDP and 10 MMN patients and a group of 70 healthy controls were evaluated with an ultrasound scan of the median, ulnar, peroneal, tibial, and sural nerves. Results were correlated with clinical disability scales and nerve conduction studies.Results.Patients with intermediate functional impairment showed relatively larger cross-sectional areas than subjects with either a milder (p<0.05) or more severe impairment (p<0.05), both in CIDP and in MMN. In addition, MMN was associated with greater side-to-side intranerve variability (p<0.05), while higher cross-sectional areas were observed in CIDP (p<0.05) and in nerve segments with predominantly demyelinating features (p<0.05). Higher CSA values were observed in nerves with demyelinating features versus axonal damage (p<0.05for CIDP;p<0.05for MMN).Discussion and Conclusions.Greater extent of quantitative and qualitative US alterations was observed in patients at intermediate versus higher functional disability and in nerves with demyelinating versus axonal damage. CIDP and MMN showed differential US aspects, with greater side-to-side intranerve variability in MMN and higher cross-sectional areas in CIDP.

Objective Subcutaneous immunoglobulin (SCIg) administered through infusion pump has been reported as effective in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients. In this study we evaluate an alternative technique of SCIg administration, based on the delivery of lower volumes administered daily using manual push technique (MPT) in 10 CIDP patients. Methods In this randomized, controlled, two-arm, crossover clinical trial, CIDP patients were randomly assigned 1:1 to receive SCIg either by MPT or pumps for 4 consecutive months with crossover to the other. The primary objective was to assess whether MPT had the same effectiveness as pumps. The secondary objectives were to assess whether MPT resulted in greater plasma IgG levels and improved quality of life (QoL). Results Ten patients (mean age = 48.3) were enrolled. No significant changes were observed in the efficacy parameters (INCAT, MRC, R-ODS, and GS scales). A positive mean variation of 5.4 % in plasma IgG levels in the group treated with MPT was observed at the end of MPT periods. Treatment interference, which is one of the dimensions of the Life Quality Index, showed a significant improvement in the MPT periods. Conclusion In CIDP patients, the MPT technique was as effective as pump infusion, allowed comparable, slightly increases plasma IgG levels, and also improved the QoL.

For the diagnosis of anti-MAG polyneuropathy the commercial ELISA manufacturer currently recommends a cut-off of 1000 Bühlmann Titer Units (BTU). We analyzed sera from 80 anti-MAG neuropathy patients and 383 controls (with other neuropathies or healthy controls) to assess the ELISA sensitivity and specificity at different thresholds. A better combination of sensitivity/specificity was found at a threshold >1500 BTU than at >1000 BTU. The best value of specificity was obtained at threshold >7000 BTU. There was a diagnostic grey area between 1500 and 7000 BTU in which the clinical phenotypes as well as electrophysiological studies need to be carefully assessed particularly to differentiate CIDP and anti-MAG neuropathy.

Mika Saarela työryhmän jäsenenä. Background Approximately two-thirds of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) need long-term intravenous immunoglobulin. Subcutaneous immunoglobulin (SCIg) is an alternative option for immunoglobulin delivery, but has not previously been investigated in a large trial of CIDP. The PATH study compared relapse rates in patients given SCIg versus placebo. Methods Between March 12, 2012, and Sept 20, 2016, we studied patients from 69 neuromuscular centres in North America, Europe, Israel, Australia, and Japan. Adults with definite or probable CIDP who responded to intravenous immunoglobulin treatment were eligible. We randomly allocated participants to 0.2 g/kg or 0.4 g/kg of a 20% SCIg solution (IgPro20) weekly versus placebo (2% human albumin solution) for maintenance treatment for 24 weeks. We did randomisation in a 1: 1:1 ratio with an interactive voice and web response system with a block size of six, stratified by region (Japan or non-Japan). The primary outcome was the proportion of patients with a CIDP relapse or who were withdrawn for any other reason during 24 weeks of treatment. Patients, caregivers, and study personnel, including those assessing outcomes, were masked to treatment assignment. Analyses were done in the intention-to-treat and per-protocol sets. This trial is registered with ClinicalTrials. gov, number NCT01545076. Findings In this randomised, double-blind, placebo-controlled trial, we randomly allocated 172 patients: 57 (33%) to the placebo group, 57 (33%) to the low-dose group, and 58 (34%) to the high-dose group. In the intention-to-treat set, 36 (63% [95% CI 50-74]) patients on placebo, 22 (39% [27-52]) on low-dose SCIg, and 19 (33% [22-46]) on high-dose SCIg had a relapse or were withdrawn from the study for other reasons (p=0.0007). Absolute risk reductions were 25% (95% CI 6-41) for low-dose versus placebo (p=0.007), 30% (12-46) for high-dose versus placebo (p=0.001), and 6% (-11 to 23) for high-dose versus low-dose (p=0.32). Causally related adverse events occurred in 47 (27%) patients (ten [18%] in the placebo group, 17 [30%] in the low-dose group, and 20 [34%] in the high-dose group). Six (3%) patients had 11 serious adverse events: one (2%) patient in the placebo group, three (5%) in the low-dose group, and two (3%) in the high-dose group; only one (an acute allergic skin reaction in the low-dose group) was assessed to be causally related. Interpretation This study, which is to our knowledge, the largest trial of CIDP to date and the first to study two administrations of immunoglobulins and two doses, showed that both doses of SCIg IgPro20 were efficacious and well tolerated, suggesting that SCIg can be used as a maintenance treatment for CIDP.

We thank Ravi Uniyal and colleagues for their comments on our results from the PATH trial1 on subcutaneous immunoglobulin (SCIg) for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (CIDP). They express concern about the relapse rates in the treatment groups and hypothesise the cause being the pharmacokinetics of SCIg.

Cases of chronic inflammatory demyelinating poliradiculoneuropathy (CIDP) have been reported in hematopoietic stem cells transplantation complicated by graft versus host disease (GVHD). A systematic review of the CIDP-like neuropathies associated with GVHD was conducted until January 2015, analyzing the clinical presentation and the response to different therapeutic regimens. Nineteen patients have been reported in literature including the present one. Fourteen subjects fulfilled the criteria for CIDP, whereas two cases presented with an asymmetric motor onset and one showed motor involvement only associated with anti-ganglioside antibodies. In addition, two subjects already affected by CIDP developed a significant relapse after GVHD. This study reviews the literature data and reports one additional case of CIDP and GVHD, suggesting that the two clinical entities might share a similar immunological background.

Multifocal motor neuropathy (MMN) is a rare, chronic, motor neuropathy that progressively impairs physical functioning and quality of life. Randomised controlled trials have shown that high-dose intravenous immunoglobulin (IVIg) is superior to placebo in improving muscle strength and disability, but many patients require periodic infusions to maintain long-term improvement. This observational, multicentre, retrospective study investigated the efficacy and tolerability of human normal immunoglobulin (Ig VENA) at high intravenous infusion rates in 20 MMN patients (14 male, 6 female). Thirty days after the first infusion, there was an improvement of at least 1 point in two muscles compared to baseline on the Medical Research Council (MRC) scale and of 1 point in the ONLS (Overall Neuropathy Limitation Scale) scale in 15 patients (75%) and 10 patients (50%), respectively; 45% improved on both scales. At 6 months, 100% of 12 patients had improved on the MRC and 79% of 14 patients had improved on the ONLS scale; 83% improved on both scales. All reported adverse drug reactions (ADR) were mild, transient and possibly related to the study drug. Four patients (20%) reported ADRs, three reported headache and one fever. There were no serious or unexpected ADRs. By confirming that high-dose Ig VENA is efficacious and well tolerated, this study adds to the evidence base for IVIg in MMN and potentially increases clinicians’ and patients’ choice of therapy.

Perforin (PRF) has a key role in the function of cytotoxic T and natural killer cells. Rare variations of PRF1 predispose to autoimmunity. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system, involving defective lymphocyte apoptosis. The aim of this study was to investigate the role of PRF1 in CIDP. The entire coding region of PRF1 was sequenced in 94 patients and 158 controls. We found three missense variations leading to amino acid substitutions and one nonsense variation resulting in a premature stop codon. All variations would decrease PRF activity. Their overall frequency was significantly higher in patients than in controls (odds ratio (OR)=4.47). The most frequent variation was p.Ala91Val (OR=3.92) previously associated with other autoimmune diseases. Clinical analysis showed that PRF1 variations were more frequent in relapsing patients and in patients displaying axonal damage. These data suggest that PRF1 variations may influence CIDP development and course.

Prior researches have suggested that home-based subcutaneous immunoglobulin (SCIG) is equally effective and can be less expensive than hospital-based intravenous immunoglobulin (IVIG) in treating chronic inflammatory demyelinating polyneuropathy (CIDP) patients. This economic evaluation aims at comparing costs of SCIG vs IVIG for CIDP patients in Italy. A 1-year model-based cost-minimization analysis basically populated via neurologists' opinion was undertaken from a societal perspective. Health care resources included immunoglobulin; drugs for premedication and complications (rash, headache, and hypertension) management; time of various health care professionals; pump for SCIG self-administration; infusion disposables. Non-health care resources encompassed transport and parking; losses of working and leisure time for patients and caregivers. Unit or yearly costs for resources valuation were mainly obtained from published sources. Costs were expressed in Euro (euro) 2013. An extensive one-way sensitivity analysis (OWSA) and a scenario SA tested the robustness of the base case findings. Overall costs per patient amount toeuro49,534.75 (SCIG) andeuro50,895.73 (IVIG); saving in favour of SCIG reacheseuro1360.98. For both SCIG and IVIG, the cost driver was immunoglobulin (94.06 vs 86.06 % of the overall costs, respectively). Sensitivity analyses confirmed the consistency of the baseline results. SCIG may be a cost-saving therapy for Italian CIDP patients.

Electrodiagnosis of subclinical diabetic neuropathies by nerve conduction studies remains challenging. The question arises about which nerves should be tested and what the best electrodiagnostic protocol to make an early diagnosis of diabetic neuropathies would be. On the basis of our findings and other evidence, which highlighted the remarkable prevalence of electrophysiological abnormalities in nerve conduction studies of the upper limbs, often in the presence of normal lower limb conduction parameters, we suggest that both ulnar and median nerves, in their motor and sensitive component, should be the two target nerves for electrodiagnostic protocols in diabetic neuropathies.

Background and purpose Subacute and chronic peripheral neuropathies (PNP) have been reported in Parkinson's disease (PD) patients treated with levodopa/carbidopa intestinal gel infusion (LCIG), although several aspects of their incidence and pathogenesis still remain to be clarified. This study main objective is to prospectively report the 2-year incidence of PNP in patients treated with LCIG. Methods and results The clinical, hematological, nutritional and electrophysiological assessments of 33 consecutive patients have been prospectively collected and evaluated. At baseline (before the start of LCIG therapy), 3/33 (9%) patients showed symptomatic PNP and 7/33 (21%) subclinical PNP. During a follow-up of 24.36 ± 12.18 months, 2/23 patients with normal baseline clinical-electrophysiological assessment developed a subacute PNP, 2/23 developed a chronic PNP and 7/23 developed a subclinical PNP. LCIG was immediately halted in the subacute cases, while the infusion therapy was not interrupted in chronic and subclinical forms. All PNP were supplemented with vitamin B1 and B12, showing a clinical improvement and/or substantial stability at the following evaluations. Higher levodopa-equivalent daily dose (P: 0.024) and homocysteine levels (P: 0.041) were found in chronic PNP, while no correlations were observed with vitamin B12, folate and UPDRS values. A trend towards BMI reduction was observed in both PNP and unaffected subjects and one patient developed a symptomatic PNP associated with a relevant weight loss. Conclusions Serial clinical-electrophysiological evaluations are mandatory in patients treated with LCIG, given the possible risk of subacute and chronic PNP. No clear causative factors has been recognized in the subacute forms, whilst homocysteine-mediated neurotoxicity seems to underlie the pathogenesis of chronic forms.

Background and purpose Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immunomediated condition affecting the peripheral nervous system where probably macrophages are the primary effector cells for demyelination. Reactive oxygen species (ROS), catalyzed by the NOX family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzymes, can induce peroxidation and are potentially injurious to myelin. Our aim was to assess the activity of NOX2, an isoform of NOX, in a series of CIDP patients and to analyze the effect of intravenous immunoglobulin (IVIg) on NOX2. Methods Thirty CIDP patients treated with IVIg and 30 control subjects were enrolled. To evaluate NOX2 activity, neutrophil and monocyte oxidative burst was measured directly in fresh whole blood using the Phagoburst™ assay, a fluorescence-activated cell sorting method. The mean fluorescence intensity, emitted in response to different stimuli, leads to the production of ROS and corresponds to the percentage of oxidizing cells and their enzymatic activity. Results Mean fluorescence intensity values for granulocyte and monocyte burst in patients (mean 633.3, SD 191; mean 111.8, SD 28.5) were different from those measured in healthy controls (granulocytes, mean 436.6, SD 137.0, P = 0.0003; monocytes, mean 78.2, SD 17.3, P = 0.000001). Moreover, IVIg administration increased both granulocyte (P = 0.005) and monocyte (P = 0.0009) burst. Conclusion Our findings demonstrate that oxidative burst is significantly increased in CIDP patients and that treatment with IVIg enhances oxidative values, thus representing a possible IVIg therapeutic effect linked to a regulatory effect of ROS. Based on this, the development of treatments targeting the specific activation of NOX may be beneficial in autoimmune disorders.

Introduction: Pain complicates hypertrophic post-burn pathologic scars (PPS) Methods: To investigate the possible neuropathic origin of pain, 13 patients with painful PPS involving at least 1 hand underwent clinical examination, including the Douleur Neuropathique en 4 questions (DN4) questionnaire; median, ulnar, and radial nerve conduction studies (NCS); cold- (CDT) and heat-induced pain threshold evaluation by quantitative sensory testing; and cutaneous silent period (CSP) testing of the abductor pollicis brevis. Controls included 9 patients with non-painful PPS, 52 healthy subjects, and 28 patients with carpal tunnel syndrome (CTS). Results: All patients with painful PPS had possible neuropathic pain (DN4 score ≥4). NCS signs of CTS were similarly present in PPS subjects with or without pain. Hands with painful PPS had lower CDT and CSP duration, more frequent cold- and heat-pain hypesthesia, and more thermal allodynia than controls. Conclusions: In PPS, possible neuropathic pain is associated with psychophysical and neurophysiological abnormalities suggestive of small-fiber damage. Muscle Nerve 45: 883–890, 2012

Background and purpose: There are other options open to patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who are non-responders to conventional treatment, including immunosuppressive and immunomodulatory agents (IA). The aim of this study was to assess whether the use of IA is able to increase the number of responders. Methods: Clinical and electrophysiological data of patients with refractory CIDP, followed at 10 Italian centres, were collected, and the clinical outcome (Rankin Scale) and drug side effects (SE) for the different therapies were analysed. Results: A total of 110 patients were included. These patients underwent 158 different therapeutic procedures with IA. Seventy-seven patients were treated with azathioprine, 18 rituximab, 13 cyclophosphamide, 12 mycophenolate mofetil, 12 cyclosporine, 12 methotrexate, 11 interferon-alpha and three interferon beta-1a. The percentage of patients who responded to azathioprine (27%) was comparable to the percentage of responders to other therapies, after the exclusion of interferon beta-1a that was not effective in any of the three patients treated. The percentage of SE ranges from 8% (methotrexate) to 50% (cyclosporine). Conclusions: One-fourth of patients, refractory to conventional treatment, showed an improvement in their disability with IA. Methotrexate had the lowest SE; cyclosporine was associated with severe SE and often led to drug discontinuation.