Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Its Variants.

PURPOSE OF REVIEW: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and its variants comprise a group of immune-mediated neuropathies with distinctive clinical presentations and electrodiagnostic features. Prompt recognition of these treatable disorders is mandatory as delays result in significant disability and morbidity. This article highlights the clinical presentation, pathophysiology, diagnostic evaluation, and treatment approach of these polyneuropathies. RECENT FINDINGS: The spectrum of CIDP is expanding with the recent characterization of neuropathies associated with nodal and paranodal antibodies. These neuropathies are distinguished by their unique presentations and are often refractory to IV immunoglobulin (IVIg) therapy. Subcutaneous immunoglobulins have recently been approved as a treatment option for CIDP and join corticosteroids, IVIg, and plasma exchange as first-line treatment. SUMMARY: CIDP is characterized by progressive symmetric proximal and distal weakness, large fiber sensory loss, and areflexia, with clinical nadir reached more than 8 weeks after symptom onset. Autoimmune demyelinating neuropathies fall on a continuum, with differences in the type of nerve fibers affected and pattern of deficits. Distinguishing between typical CIDP and its variants allows for selection of the most appropriate treatment.

Different distribution of demyelination in chronic inflammatory demyelinating polyneuropathy subtypes.

In demyelinating polyneuropathies, distribution patterns of demyelination reflect underlying pathogenesis. Median and ulnar nerve conduction studies were reviewed in 85 typical chronic inflammatory demyelinating polyneuropathy (CIDP) patients and 29 multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). Distal latencies were prolonged in typical CIDP and near normal in MADSAM. Abnormal amplitude reductions in the nerve trunks were more frequent in MADSAM than typical CIDP. Presumably because the blood-nerve barrier is anatomically deficient at the distal nerve terminals, antibody-mediated demyelination is a major pathophysiology in typical CIDP. In contrast, blood-nerve barrier breakdown is likely to be predominant in MADSAM.

Clinicopathological characteristics of subtypes of chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: To evaluate the clinical and pathological correlations characterising each clinical subtype of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: We assessed 106 consecutive patients who had CIDP fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society criteria and had been referred for sural nerve biopsy. Patients with anti-neurofascin 155, anti-contactin 1 and anti-LM1 antibodies were excluded. RESULTS: 55 patients were classified as having typical CIDP. Regarding atypical CIDP, the multifocal acquired demyelinating sensory and motor (MADSAM) (n=15), distal acquired demyelinating symmetric (DADS) (n=16) and pure sensory (n=15) forms were major subtypes, while the pure motor (n=4) and focal (n=1) forms were rare. Nerve conduction studies revealed that distal motor latencies and F-wave latencies were markedly prolonged in the typical CIDP group but relatively preserved in the MADSAM group. Motor conduction velocity was conspicuously slowed in the DADS group, and distal motor latencies were markedly prolonged in the pure sensory group. Sural nerve biopsy specimens from patients with MADSAM, DADS and pure sensory type tended to show extreme variation in myelinated fibre density among fascicles due to focal myelinated fibre loss or onion-bulb formation, whereas patients with typical CIDP tended to show mild fascicular variation. Epineurial lymphocytic infiltration was conspicuous in cases with marked fascicular variation in myelinated fibre density. CONCLUSIONS: Preferential involvement of distal and proximal segments and uniform pathological features in typical CIDP indicate a role of humoral factors at sites where the blood-nerve barrier is deficient. By contrast, focal lesions in MADSAM, DADS and pure sensory forms may share neuropathic mechanisms primarily affecting the nerve trunk.

Differences in peripheral myelin antigen-specific T cell responses and T memory subsets in atypical versus typical CIDP.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is presented by a large heterogeneity of clinical phenotypes. Around 50% of patients suffer from typical CIDP and show better therapy response than atypical variants. The goal of our study was to search for cellular immunological differences in typical versus atypical CIDP in comparison to controls. METHODS: We evaluated 26 (9 typical, 17 atypical) patients with mainly active-unstable CIDP using clinical and immunological examinations (enzyme-linked immunospot assay ELISPOT, fluorescence-activated cell sorting FACS) in comparison to 28 healthy, age-matched controls (HC). Typical or atypical CIDP measurements were compared with HC using Kruskal-Wallis test. RESULTS: Atypical CIDP patients showed increased frequencies of T cell subsets, especially CD4+ effector memory T cells (TEM) and CD4+ central memory T cells (TCM) as well as a tendency of higher T cell responses against the peripheral myelin antigens of PMP-22, P2, P0 and MBP peptides compared to typical CIDP. Searching for novel auto-antigens, we found that T cell responses against P0 180-199 as well as MBP 82-100 were significantly elevated in atypical CIDP patients vs. HC. CONCLUSIONS: Our results indicate differences in underlying T cell responses between atypical and typical CIDP characterized by a higher peripheral myelin antigen-specific T cell responses as well as a specific altered CD4+ memory compartment in atypical CIDP. Larger multi-center studies study are warranted in order to characterize T cell auto-reactivity in atypical CIDP subgroups in order to establish immunological markers as a diagnostic tool.

Disease activity in chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: Evaluation of disease status in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is often done by a combination of clinical evaluation and electrodiagnostic studies. A CIDP disease activity status (CDAS) was developed to standardize outcomes in CIDP patients. We aimed to determine if the CDAS was concordant with classical evaluation and whether CDAS enables benchmarking of CIDP. METHODS: We performed a retrospective chart review of 305 CIDP patients and identified 206 patients with >1 visit and applied the CDAS to this cohort. We examined relationships between the CDAS and classical evaluation as to outcomes and compared our cohort to other CIDP cohorts who had CDAS. RESULTS: We found that the CDAS mirrored disease severity as measured by electrophysiology and vibration perception thresholds in that CDAS class 5 had more severe neuropathy. Our results are similar to other cohorts in the middle CDAS strata with the exception of fewer subjects in CDAS 1 and more in CDAS 5. The only demographic factor predicting CDAS 5 in our cohort was age, and the overall treatment response rate using the CDAS classification was 79.3%. CONCLUSIONS: CDAS appears to have sufficient face-validity as a grading system to assess disease activity in relation to treatment status. The use of CDAS appears to allow benchmarking of patients with CIDP that may be useful in subject selection for clinical trials and also to highlight differences in practice.

Childhood CIDP: Study of 31 patients and comparison between slow and rapid-onset groups.

OBJECTIVES: To describe 31 children presenting a CIDP; to compare patients with rapid-onset disease vs. patients with slow-onset disease, a rapid-onset disease being defined by a time to peak impairment of less than 8 weeks. STUDY DESIGN: A retrospective chart review identified 31 patients completing criteria for childhood CIDP, with 24 "confirmed CIDP" and 7 "possible CIDP". Data collected were time to peak impairment, clinical presentation, cerebrospinal fluid analysis, nerve conduction study, nerve biopsy, treatments. Evaluation at the end of follow-up was reported according to modified Rankin scale. RESULTS: Thirteen patients (42%) exhibited symptoms in less than 2 months with more often cranial nerve abnormalities (38% vs. 6%, p = 0.059), and sensitive symptoms (62% vs. 11%, p = 0.0057). They evolved predominantly in a relapsing way (69% vs. 22%, p = 0.0047). Length of the disease was also longer in the rapid-onset group (5.5 years vs. 3.83 years) but without statistical difference. The slow-onset group exhibited more frequently ataxia at onset (28% vs. 8%, p > 0.05), and evolved predominantly in a progressive manner (61% vs. 15%, p > 0.05). Outcome was similar and good in the two groups. At least 3 out of the 4 major electrophysiological criteria were positive for 27/31 children (87%). Axonal involvement could be present very early. Immunoglobulins were given in 29 cases and corticosteroids in 22. A partial or complete recovery 1 month after first treatment was reported in 30 cases. Among second-line treatments, only azathioprine seemed effective in two out of three intractable children. CONCLUSIONS: The differences noted between the two groups should be tested in wider populations. Electrophysiological criteria are restrictive and axonal involvement should be studied. Prospective trials are required to find out the best first and second line treatments.

Severity and patterns of blood-nerve barrier breakdown in patients with chronic inflammatory demyelinating polyradiculoneuropathy: correlations with clinical subtypes.

OBJECTIVE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is currently classified into clinical subtypes, including typical and atypical forms (multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) and distal acquired demyelinating symmetric neuropathy (DADS)). The aim of this study was to elucidate the patterns and severity of breakdown of the blood-nerve barrier (BNB) in each CIDP subtype. METHODS: We evaluated the effects of sera obtained from patients with typical CIDP, MADSAM and DADS and control subjects on the expression levels of tight junction proteins and transendothelial electrical resistance (TEER) value in human peripheral nerve microvascular endothelial cells (PnMECs). RESULTS: The sera obtained from the patients with the three clinical phenotypes of CIDP decreased the amount of claudin-5 protein levels and TEER values in the PnMECs. In addition, the sera obtained from typical CIDP patients more prominently reduced claudin-5 protein levels and TEER values in the PnMECs than did that obtained from the MADSAM and DADS patients. Furthermore, the severity of BNB disruption after exposure to the sera was associated with higher Hughes grade, lower MRC score, more pronounced slowing of motor nerve conduction in the median nerve and higher frequency of abnormal temporal dispersion. CONCLUSIONS: Sera derived from typical CIDP patients destroy the BNB more severely than those from MADSAM or DADS patients. The extent of BNB disruption in the setting of CIDP is associated with clinical disability and demyelination in the nerve trunk. These observations may explain the phenotypical differences between CIDP subtypes.

Early identification of 'acute-onset' chronic inflammatory demyelinating polyneuropathy.

Distinguishing patients with acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy prior to relapse is often challenging at the onset of their clinical presentation. In the present study, nerve excitability tests were used in conjunction with the clinical phenotype and disease staging, to differentiate between patients with acute-onset chronic inflammatory demyelinating polyneuropathy and patients with acute inflammatory demyelinating polyneuropathy at an early stage, with the aim to better guide treatment. Clinical assessment, staging and nerve excitability tests were undertaken on patients initially fulfilling the diagnostic criteria of acute inflammatory demyelinating polyneuropathy soon after symptom onset and their initial presentation. Patients were subsequently followed up for minimum of 12 months to determine if their clinical presentations were more consistent with acute-onset chronic inflammatory demyelinating polyneuropathy. Clinical severity as evaluated by Medical Research Council sum score and Hughes functional grading scale were not significantly different between the two cohorts. There was no difference between the time of onset of initial symptoms and nerve excitability test assessment between the two cohorts nor were there significant differences in conventional nerve conduction study parameters. However, nerve excitability test profiles obtained from patients with acute inflammatory demyelinating polyneuropathy demonstrated abnormalities in the recovery cycle of excitability, including significantly reduced superexcitability (P < 0.001) and prolonged relative refractory period (P < 0.01), without changes in threshold electrotonus. In contrast, in patients with acute-onset chronic inflammatory demyelinating polyneuropathy, a different pattern occurred with the recovery cycle shifted downward (increased superexcitability, P < 0.05; decreased subexcitability, P < 0.05) and increased threshold change in threshold electrotonus in both hyperpolarizing and depolarizing directions [depolarizing threshold electrotonus (90-100 ms) P < 0.005, hyperpolarizing threshold electrotonus (10-20 ms), P < 0.01, hyperpolarizing threshold electrotonus (90-100 ms), P < 0.05], perhaps suggesting early hyperpolarization. In addition, using excitability parameters superexcitability, subexcitability and hyperpolarizing threshold electrotonus (10-20 ms), the patients with acute inflammatory demyelinating polyneuropathy and acute-onset chronic inflammatory demyelinating polyneuropathy could be clearly separated into two non-overlapping groups. Studies of nerve excitability may be able to differentiate acute from acute-onset chronic inflammatory demyelinating polyneuropathy at an early stage. Characteristic nerve excitability parameter changes occur in early acute-onset chronic inflammatory demyelinating polyneuropathy, to match the clinical phenotype. Importantly, this pattern of change was strikingly different to that shown by patients with acute inflammatory demyelinating polyneuropathy, suggesting that nerve excitability techniques may be useful in distinguishing acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy at the initial stage.

Chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune disorder of the peripheral nervous system. This article highlights our current understanding of the condition along with its phenotypic variants that are encountered in clinical practice. The diagnostic evaluation of CIDP includes laboratory studies to detect associated medical conditions and electrodiagnostic studies to assess for demyelination. Current treatment options include corticosteroids, plasma exchange, and intravenous immune globulin, along with alternative therapies that may be used as corticosteroid-sparing agents or for treatment-refractory cases. Approximately 85% to 90% of patients eventually improve or stabilize with treatment, and the long-term prognosis of CIDP is favorable.

Atypical idiopathic inflammatory demyelinating lesions: prognostic implications and relation to multiple sclerosis.

Atypical lesions of a presumably idiopathic inflammatory demyelinating origin present quite variably and may pose diagnostic problems. The subsequent clinical course is also uncertain. We, therefore, wanted to clarify if atypical idiopathic inflammatory demyelinating lesions (AIIDLs) can be classified according to previously suggested radiologic characteristics and how this classification relates to prognosis. Searching the databases of eight tertiary referral centres we identified 90 adult patients (61 women, 29 men; mean age 34 years) with ≥ 1 AIIDL. We collected their demographic, clinical and magnetic resonance imaging data and obtained follow-up (FU) information on 77 of these patients over a mean duration of 4 years. The AIIDLs presented as a single lesion in 72 (80 %) patients and exhibited an infiltrative (n = 35), megacystic (n = 16), Baló (n = 10) or ring-like (n = 16) lesion appearance in 77 (86 %) patients. Additional multiple sclerosis (MS)-typical lesions existed in 48 (53 %) patients. During FU, a further clinical attack occurred rarely (23-35 % of patients) except for patients with ring-like AIIDLs (62 %). Further attacks were also significantly more often in patients with coexisting MS-typical lesions (41 vs. 10 %, p < 0.005). New AIIDLs developed in six (7 %), and new MS-typical lesions in 29 (42 %) patients. Our findings confirm the previously reported subtypes of AIIDLs. Most types confer a relatively low risk of further clinical attacks, except for ring-like lesions and the combination with MS-typical lesions.

Chronic inflammatory demyelinating polyneuropathy (CIDP).

BACKGROUND: Chronic immune-mediated demyelinating polyneuropathies can often lead to severe neurologic disability. MATERIALS AND METHODS: Literature review and personal experience with these types of neuropathies. CONCLUSIONS: It is important to recognize these immune-mediated neuropathies as they respond to treatment.

[Demyelinating polyneuropathies in patients with diabetes mellitus and chronic alcoholic intoxication].

Frequency and nosological attribution of demyelinating polyneuropathies in patients with diabetes mellitus and alcoholism were determined. Eighty-six inpatients with alcoholic (n=46) and diabetic (n=40) polyneuropathy were examined clinically and using electroneuromyography (ENMG). A demyelinating pathogenetic variant was identified by clinical and ENMG data in 27 (31%) patients. Nine patients (33%) had dysimmune polyneuropathies (acute and chronic inflammatory demyelinating polyneuropathy). Polyneuropathies were specified as toxic/metabolic with the prevalence of a demyelinating component within the main disease in 18 (67%) patients. Clinical and ENMG-signs of the demyelinating variant of alcoholic and diabetic neuropathy are presented. The efficacy of the antioxidant berlition was shown for toxic/metabolic polyneuropathies while the addition of immune modulators was needed for treatment of dysimmune polyneuropathy.

Does the chronic inflammatory demyelinating polyradiculoneuropathy due to secondary cause differ from primary?

BACKGROUND: The clinical presentation, neurophysiological findings, and outcome may vary between primary and secondary chronic inflammatory demyelinating polyradiculopathy (CIDP). OBJECTIVE: To compare clinical and electrodiagnostic features of primary and secondary CIDP. SETTING: Tertiary care teaching referral hospital. MATERIALS AND METHODS: The CIDP patients who were diagnosed as per European Federation of Neurological Societies/Peripheral Nerve Society criteria were included and subjected to detailed history and examinations. The clinical disability was graded on a 0-10 scale. Neurophysiology included motor and sensory nerve conductions and F wave studies of all four limbs. Based on investigations for underlying diseases, the patients were categorized into primary or secondary CIDP. Prednisolone was prescribed in all and azathioprine added in resistant cases. The secondary CIDP group received specific treatment in addition. The outcome was assessed at 3 months, 6 months, and last follow-up. RESULTS: A total of 65 patients aged 17 to 72 years were included and 20 were females. Twenty-five patients had secondary CIDP and include diabetes mellitus (16), POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) (4), monoclonal gammopathy of undetermined significance (2), myeloma (1), lymphoma (1), and malignancy (1). The secondary CIDP patients were older (48.35 vs 41.0 years), had less relapsing remitting (0 vs 6) and more frequent dysautonomia (7 vs 1). The demyelinating features were more marked in primary CIDP group and had better outcome compared with secondary CIDP. CONCLUSIONS: Of the total patients with CIDP, 38.5% of patients had secondary CIDP which was associated with progressive course, less demyelinating features, and worse prognosis.

Distal acquired demyelinating symmetric neuropathy associated with anti-GM1 antibodies: is this a CIDP variant?

Distal acquired demyelinating symmetric (DADS) neuropathy is clinically characterised by distal motor and sensory disturbances. Typically DADS does not respond or responds poorly to intravenous immunoglobulins (IVIg). We report the case of a 58-year-old patient who developed distal paraparesis. Serum electrophoresis demonstrated monoclonal IgM paraproteinemia having an anti-GM1 but no anti-MAG activity. Conduction velocities showed demyelinating pattern. Work-up excluded a lymphoproliferative disorder After IVIg treatment we observed a clinical and neurophysiological improvement. Regarding these peculiar findings, we suggest that DADS needs to be splitted in several forms determined among others by clinical, neurophysiological and antiganglioside profile and therapeutic response. We advocate to perform systematic antiganglioside antibodies assay additionnaly to anti-MAG when DADS is suspected in order to improve dysimmune neuropathies classification.

Chronic inflammatory demyelinating polyneuropathy disease activity status: recommendations for clinical research standards and use in clinical practice.

Defining long-term outcomes in chronic inflammatory demyelinating polyneuropathy (CIDP) has been complicated by varying definitions of treatment response and differing scales measuring impairment or disability. An expert panel was convened to devise a CIDP Disease Activity Status (CDAS) and to classify long-term outcome by applying it to 106 patients with a consensus diagnosis of CIDP. Sixty of these cases were graded blindly by three independent reviewers to assess inter-rater reliability. The mean duration of follow-up was 6.4 years (range, 3 months-23 years). Eleven percent of patients were classified as cured (stable examination and off treatment for ≥5 years), 20% were in remission (stable and off treatment for <5 years), 44% had stable active disease but required ongoing therapy for at least 1 year, 7% were improving after recent initiation of therapy, and 18% had unstable active disease (treatment naïve or treatment refractory). Excellent inter-rater reliability was observed (kappa scores: 0.93-0.97; p < 0.0001). The CDAS is considered a simple and reproducible tool to classify patients with CIDP according to disease activity and treatment status that can be applied easily in practice and potentially to select patients for clinical trials.

Demyelinating findings in typical and atypical chronic inflammatory demyelinating polyneuropathy: sensitivity and specificity.

OBJECTIVE: The objective of this study was to evaluate how the number of demyelinating findings (DF) on nerve conductions affects sensitivity and specificity of electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Electrodiagnostic findings of 26 consecutive patients with CIDP were compared with amyotrophic lateral sclerosis (ALS) and diabetic polyneuropathy controls. Patients with CIDP were divided into typical and atypical CIDP, as defined elsewhere. RESULTS: Depending on the minimal required number (MRN) of DF on nerve conductions, sensitivities decreased from an arbitrary 100% to 58% and 54%, for an MRN of 1, 2, and 3, respectively, as specificities increased, from 48% to 81% and 95%, respectively. The number of DF per patient was higher in typical CIDP than in atypical CIDP. CONCLUSIONS: The considerable gap between specificity and sensitivity is the reason for controversy regarding the MRN for the diagnosis of CIDP. Requiring 2 or more DFs to identify CIDP increases specificity from 48% to 81% but lowers sensitivity from 100% to 58%. For patients with other potential causes of neuropathy, the requirement of 2 or more DFs could further increase specificity.

Epidemiologic variability of chronic inflammatory demyelinating polyneuropathy with different diagnostic criteria: study of a UK population.

Epidemiologic data on chronic inflammatory demyelinating polyneuropathy (CIDP) is limited, and previous studies have shown variable results. The frequencies of CIDP subtypes remain unknown. Variations due to use of different diagnostic criteria have not been studied. We examined the prevalence and incidence of CIDP in Leicestershire and Rutland, UK (population 963,600). Prevalence day was 1 May 2008. The prevalence of CIDP fulfilling the 2006 clinical and electrophysiologic European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria was 4.77 per 100,000 (95% confidence interval [CI] 3.49-6.37). Using the 1991 American Academy of Neurology (AAN) criteria, the prevalence was 1.97 per 100,000 in this population (95% CI 1.19-3.08). Lewis-Sumner syndrome was diagnosed in 15.2% of patients, and 23.9% had pure sensory onset. Over 40% required no immunotherapy, and 84.6% of those treated responded. More than 80% of the AAN criteria-negative but EFNS/PNS criteria-positive patients were responsive to treatment. Both sets of criteria were equally likely to identify patients who required therapy. The mean annual incidence rate over the 3 years preceding the prevalence day was 0.70 per 100,000/year using EFNS/PNS criteria (95% CI 0.43-1.08), and 0.35 per 100,000/year using AAN criteria (95% CI 0.17-0.64). We conclude that the AAN criteria may underestimate prevalence and incidence of the disease. The EFNS/PNS criteria provide higher diagnostic sensitivity and are of greater clinical relevance, and they also offer a useful breakdown of the epidemiologic data for CIDP subtypes.