Clinical relevance of distinguishing autoimmune nodopathies from CIDP: longitudinal assessment in a large cohort.

BACKGROUND: The aim of this study was to determine treatment response and whether it is associated with antibody titre change in patients with autoimmune nodopathy (AN) previously diagnosed as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and to compare clinical features and treatment response between AN and CIDP. METHODS: Serum IgG antibodies to neurofascin-155 (NF155), contactin-1 (CNTN1) and contactin-associated protein 1 (CASPR1) were detected with cell-based assays in patients diagnosed with CIDP. Clinical improvement was determined using the modified Rankin scale, need for alternative and/or additional treatments and assessment of the treating neurologist. RESULTS: We studied 401 patients diagnosed with CIDP and identified 21 patients with AN (10 anti-NF155, 6 anti-CNTN1, 4 anti-CASPR1 and 1 anti-NF155/anti-CASPR1 double positive). In patients with AN ataxia (68% vs 28%, p=0.001), cranial nerve involvement (34% vs 11%, p=0.012) and autonomic symptoms (47% vs 22%, p=0.025) were more frequently reported; patients with AN improved less often after intravenous immunoglobulin treatment (39% vs 80%, p=0.002) and required additional/alternative treatments more frequently (84% vs 34%, p<0.001), compared with patients with CIDP. Antibody titres decreased or became negative in patients improving on treatment. Treatment withdrawal was associated with a titre increase and clinical deterioration in four patients. CONCLUSIONS: Distinguishing CIDP from AN is important, as patients with AN need a different treatment approach. Improvement and relapses were associated with changes in antibody titres, supporting the pathogenicity of these antibodies.

Misdiagnosis and diagnostic pitfalls of chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND PURPOSE: The aim of this study was to determine the frequency of over- and underdiagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and to identify related diagnostic pitfalls. METHODS: We conducted a retrospective study in Dutch patients referred to the Erasmus University Medical Centre Rotterdam between 2011 and 2017 with either a diagnosis of CIDP or another diagnosis that was revised to CIDP. We used the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) 2010 diagnostic criteria for CIDP to classify patients into three groups: overdiagnosis, underdiagnosis, or confirmed diagnosis of CIDP. Clinical and laboratory features and treatment history were compared between groups. RESULTS: A referral diagnosis of CIDP was revised in 32% of patients (31/96; overdiagnosis). Of 81 patients diagnosed with CIDP, 16 (20%) were referred with another diagnosis (underdiagnosis). In the overdiagnosed patients, 20% of muscle weakness was asymmetric, 48% lacked proximal muscle weakness, 29% only had distal muscle weakness, 65% did not fulfil the electrodiagnostic criteria for CIDP, 74% had an elevated cerebrospinal fluid (CSF) protein level, and 97% had another type of neuropathy. In the underdiagnosed patients, all had proximal muscle weakness, 50% had a clinically atypical CIDP, all fulfilled the electrodiagnostic criteria for CIDP, and 25% had an increased CSF protein level. CONCLUSION: Over- and underdiagnosis of CIDP is common. Diagnostic pitfalls include lack of attention to proximal muscle weakness as a diagnostic hallmark of CIDP, insufficient recognition of clinical atypical phenotypes, overreliance on CSF protein levels, misinterpretation of nerve conduction studies and poor adherence to electrodiagnostic criteria, and failure to exclude other causes of polyneuropathy.

Genetic biomarkers for intravenous immunoglobulin response in chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a clinical and electrophysiological heterogeneous immune-mediated polyneuropathy. Intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange are proven effective treatments for CIDP. The clinical response to IVIg is variable between patients and currently unexplained. Finding biomarkers related to treatment response can help to understand the diversity of CIDP and personalise treatment choice. METHODS: We investigated whether genetic variation between patients may explain some of these differences in treatment response. Based on previous publications, we selected six candidate genes that might affect immune and axonal functions, IVIg metabolism, and treatment response in CIDP. Genetic variants were assessed in 172 CIDP patients treated with at least one course of IVIg (2 g/kg). A response to IVIg was defined by ≥1 grade improvement on the modified Rankin Scale. Blood samples were tested for variations in CNTN2, PRF1, FCGRT, FCGR2B, GJB1, and SH2D2A genes. RESULTS: In univariate analysis, patients with the FCGR2B promoter variant 2B.4/2B.1 responded more often to IVIg than patients with the 2B.1/2B.1 variant (odds ratio [OR] = 6.9, 95% confidence interval [CI] = 1.6-30; p = 0.003). Patients with the p.(Ala91Val) variant of PRF1 were less often IVIg responsive (OR = 0.34, 95% CI = 0.13-0.91; p = 0.038). In multivariate analysis, both PRF1 and FCGR2B showed discriminative ability to predict the chance of IVIg response (area under the curve = 0.67). CONCLUSIONS: Variations in PRF1 and the promoter region of FCGR2B are associated with the response to IVIg in CIDP. These findings, which require validation, are a first step towards the understanding of the heterogeneity in the treatment response in CIDP.

Incidence and Prevalence of Chronic Inflammatory Demyelinating Polyradiculoneuropathy: A Systematic Review and Meta-Analysis.

BACKGROUND: Prevalence and incidence rates of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are required to determine the impact of CIDP on society. We aimed to estimate the prevalence and incidence of CIDP worldwide and to determine the effect of diagnostic criteria on prevalence and incidence. METHOD: A systematic review was conducted for all published incidence and prevalence studies on CIDP until May 18, 2017. Methodological quality was assessed using the Methodological Evaluation of Observational Research checklist. We performed a random effect meta-analysis to estimate pooled prevalence and incidence rates. RESULTS: Of the 907 studies, 11 were included in the systematic review, 5 in the meta-analysis of incidence (818 cases; 220,513,514 person-years) and 9 in the meta-analysis of prevalence (3,160 cases; 160,765,325 population). These studies had a moderate quality. The pooled crude incidence rate was 0.33 per 100,000 person-years (95% CI 0.21-0.53; I2 = 95.7%) and the pooled prevalence rate was 2.81 per 100,000 (95% CI 1.58-4.39; I2 = 99.1%). Substantial heterogeneity in incidence and prevalence across studies seems to be partly explained by using different diagnostic criteria. CONCLUSION: These findings provide a starting point to estimate the social burden of CIDP and demonstrate the need to reach consensus on diagnostic criteria for CIDP.

Clinical factors, diagnostic delay, and residual deficits in chronic inflammatory demyelinating polyradiculoneuropathy.

Management of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is complicated by the challenging diagnosis, monitoring of disease activity, and treatment response. Real world data about the current practice of care in CIDP are rare, but important to improve clinical guidelines. In this study, we determined the current practice of diagnosis and treatment in relation to the clinical outcome of patients with CIDP in a cross-sectional study in The Netherlands. All patients registered at the Dutch neuromuscular patient organization and patients at the Erasmus Medical Center were approached. CIDP diagnosis was confirmed by using patient files and expert consensus. The response rate was 137/197 (70%) and the diagnosis CIDP was confirmed in 112 patients. The time from onset of symptoms until CIDP diagnosis was median 5 months and > 12 months in 26% of the patients. Patients with a late diagnosis (>5 months) compared to patients with an early diagnosis (≤5 months) more frequently had another initial diagnosis (P < .001), multifocal abnormalities (P = .011), final diagnosis made in university hospitals (P = .001), and more (residual) complaints, also illustrated via two patient reported, validated clinical outcome measures. Although 97% of patients received treatment, 88% reported (residual) neurological symptoms and deficits. CIDP diagnosis is often delayed, especially in patients with atypical CIDP variants. Diagnostic delay may result in delayed initiation of treatment. A more rapid and accurate diagnosis of CIDP may prevent or at least reduce residual neurological deficits and accompanying disability in CIDP.

International chronic inflammatory demyelinating polyneuropathy outcome study (ICOS): Protocol of a prospective observational cohort study on clinical and biological predictors of disease course and outcome.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a heterogeneous immune-mediated disorder with extensive variation in clinical presentation, electrophysiological phenotype, treatment response and long-term outcome. This heterogeneity may reflect the existence of distinct subtypes of CIDP with a different pathogenesis that require personalized treatment. The International CIDP Outcome Study (ICOS) is a prospective, observational, multicenter cohort study that aims to describe this variation and to define clinical and biological determinants and predictors of these subtypes, disease activity, treatment response and outcome. All patients fulfilling the European Federation of Neurological Societies/Peripheral Nerve Society 2010 diagnostic criteria for CIDP can participate, independent of age, duration and severity of the disease or treatment. We collect data on the clinical presentation, diagnostics, validated clinical outcome measures, (response to) treatment, and we collect biomaterials (DNA, cerebrospinal fluid and serial serum samples). We aim to include at least 1000 CIDP patients with a follow-up of at least 2 years. ICOS started in November 2015 in three academic medical centers in The Netherlands and by October 2018 169 patients are included: 69 new and 100 prevalent cases. ICOS is based on the format of the International Guillain-Barré syndrome (GBS) Outcome Study (IGOS). Dutch centers are invited to participate in ICOS that will continue as an independent national registry. International centers will be able to collect data and biomaterials according to the ICOS protocol by using the optional ICOS module within the INCbase infrastructure. ICOS will help to standardize the collection of data and biosamples for future research in CIDP.

Progress in diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare and heterogeneous but treatable immune-mediated neuropathy. Nerve conduction studies are considered essential for a definite diagnosis, but poor performance and misinterpretation of the results frequently leads to misdiagnosis. Nerve ultrasound and MRI could be helpful in diagnosis. Whereas typical CIDP is relatively easy to diagnose, atypical variants with distinct phenotypes can be a diagnostic challenge. Intravenous or subcutaneous immunoglobulin, corticosteroids, and plasma exchange are effective treatments, but maintenance treatments are often required for years, and treatment regimens require careful and regular adjustments to avoid undertreatment or overtreatment. Patients who do not improve, or insufficiently improve after treatment, might have specific characteristics related to a distinct disease mechanism caused by immunoglobulin G4 antibodies to nodal or paranodal proteins, and could require alternative treatments. Future studies should focus on curative and individualised treatment regimens to improve the patient's condition and to prevent further nerve damage.

Mortality in Guillain-Barre syndrome.

OBJECTIVE: To determine the frequency, timing, causes, and risk factors of death in Guillain-Barré syndrome (GBS). METHODS: Prospectively collected data were reviewed from a cohort of 527 patients with GBS previously included in 1 observational and 3 therapeutic studies. Risk factors were identified by comparing deceased and surviving patients with GBS. RESULTS: Fifteen (2.8%) of 527 patients with GBS died within 6 months of follow-up at highly variable time points during the disease course, with a median time from onset of weakness to death of 76 days (interquartile range 23-152 days). In 356 patients with an extended follow-up of 12 months, the mortality rate was 3.9%. Only 3 patients (20%) died during the acute progressive phase and 2 patients (13%) died during the plateau phase. Ten patients (67%) died during the recovery phase after neurologic improvement, most frequently from respiratory or cardiovascular complications. Eleven patients (73%) were admitted to an intensive care unit during the course of disease, but only 7 patients (47%) died in the intensive care unit. Risk factors for death were age (p < 0.001), severity of weakness at entry (p = 0.02), mechanical ventilation (p < 0.001), delay from onset of weakness to entry (p = 0.035), and time to peak disability (p = 0.039). CONCLUSIONS: Death after GBS predominantly occurs in the elderly and severely affected patients, especially during the recovery phase. Future research is required to determine whether mortality of GBS can be reduced by intensified monitoring in patients with an increased risk profile.