Chronic inflammatory demyelinating polyradiculoneuropathy: can a diagnosis be made in patients not fulfilling electrodiagnostic criteria?

BACKGROUND AND PURPOSE: The aim was to identify the clinical and diagnostic investigations that may help to support a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients not fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria. METHODS: The data from patients with a clinical diagnosis of CIDP included in a national database were retrospectively reviewed. RESULTS: In all, 535 patients with a diagnosis of CIDP were included. This diagnosis fulfilled the EFNS/PNS criteria in 468 patients (87.2%) (definite in 430, probable in 33, possible in three, while two had chronic immune sensory polyradiculopathy). Sixty-seven patients had a medical history and clinical signs compatible with CIDP but electrodiagnostic studies did not fulfill the EFNS/PNS criteria for CIDP. These patients had similar clinical features and frequency of abnormal supportive criteria for the diagnosis of CIDP compared to patients fulfilling EFNS/PNS criteria. Two or more abnormal supportive criteria were present in 40 (61.2%) patients rising to 54 (80.6%) if a history of a relapsing course as a possible supportive criterion was also included. Increased cerebrospinal fluid proteins and response to immune therapy most frequently helped in supporting the diagnosis of CIDP. Response to therapy was similarly frequent in patients fulfilling or not EFNS/PNS criteria (87.3% vs. 85.9%). CONCLUSIONS: Patients with a clinical diagnosis of CIDP had similar clinical findings, frequency of abnormal supportive criteria and response to therapy compared to patients fulfilling EFNS/PNS criteria. The presence of abnormal supportive criteria may help in supporting the diagnosis of CIDP in patients with a medical history and clinical signs compatible with this diagnosis but non-diagnostic nerve conduction studies.

Risk factors for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): antecedent events, lifestyle and dietary habits. Data from the Italian CIDP Database.

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 1-42 days 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.

NADPH oxidase 2 (NOX2) enzyme activation in patients with chronic inflammatory demyelinating polyneuropathy.

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.

Peripheral neuropathy associated with levodopa-carbidopa intestinal infusion: a long-term prospective assessment.

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.

Electrodiagnostic testing in diabetic neuropathy: Which limb?

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.

Variations of the perforin gene in patients with chronic inflammatory demyelinating polyradiculoneuropathy.

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.

Prospective assessment of peripheral neuropathy in Duodopa-treated parkinsonian patients.

BACKGROUND: Although peripheral neuropathies (PN) have been described in patients with Parkinson's disease (PD) treated with oral dopaminergic therapies, anecdotal reports of subacute severe PN have been reported during treatment with enteral levodopa/carbidopa infusion (Duodopa). AIM OF THE STUDY: We prospectively assessed clinical and electrophysiological data of 15 consecutive patients with PD treated with Duodopa for a mean follow-up of 9 months. METHODS: Nerve conduction studies and a clinical evaluation with a standardized battery of peripheral neuropathy scales were performed at baseline and after a mean follow-up of 9 months. RESULTS: At baseline, mild signs of PN were observed in three subjects, and vitamin B12 serum levels were found to correlate with the amplitude of sural sensory action potentials. Follow-up data were available for 10/15 subjects: one patient developed a subacute sensory-motor PN and three subjects with pre-existing PN showed a moderate worsening of electrophysiological and clinical features. Subclinical electrophysiological alterations of peripheral nerves were observed in two subjects. No significant changes were observed in vitamin B12, folate, homocysteine and methylmalonic acid levels. CONCLUSIONS: In this consecutive series of patients treated with Duodopa, we observed one subacute sensory-motor PN and few length-dependent alterations of peripheral nerves, similar to those described during oral levodopa treatment.

Consistence and discrepancy of neuropathic pain screening tools DN4 and ID-Pain.

Pain is a subjective condition that cannot be objectively measured; for this reason, self patient-perspective is crucial. Recently, several screening tools to discriminate between nociceptive and neuropathic pain have been developed. We aimed at assessing the consistence and discrepancy of two widely used screening tools, The Douleur Neuropathique 4 (DN4) and the 6-item questionnaire (ID-Pain), by comparing their ability in discriminating neuropathic from nociceptive pain. DN4 and ID-Pain were administered to 392 Italian patients attending 16 outpatient services for peripheral nerve diseases. Based on medical history, clinical findings and diagnostic tools, patients were divided into two groups (neuropathic and nociceptive). Globally, ID-Pain identified neuropathic pain in 60 % of patients (38 % probable, 22 % likely). Interestingly also DN4 diagnosed neuropathic pain in 60 % of cases. A discrepancy was observed in 16 % of cases. DN4 and ID-Pain resulted to be highly interrelated in the identification of neuropathic pain. Sensitivity of DN4 was 82 % and specificity was 81 %, while ID-Pain (considering both probable and likely groups) showed sensitivity 78 % and specificity 74 %. Reliable screening tools for neuropathic pain are well related between them; hence, they are available for researchers and clinicians who may choose the most appropriate for their activity. Since the gold standard for the diagnosis and treatment of neuropathic pain cannot do without a neurological evaluation, perhaps DN4, that includes physician objective measures, may help reducing the percentage of dubious cases. Conversely, when needing a more agile tool (not needing a physician) ID-Pain may be adopted.

Immunosuppressive treatment in refractory chronic inflammatory demyelinating polyradiculoneuropathy. A nationwide retrospective analysis.

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.

Rituximab in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a report of 13 cases and review of the literature.

BACKGROUND: A few case reports have shown controversial results of rituximab efficacy in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). OBJECTIVE: To analyse the efficacy of rituximab in a large CIDP cohort. METHODS: A retrospective, observational and multicentre study on the use of rituximab in CIDP. 13 Italian CIDP patients were treated with rituximab after the partial or complete lack of efficacy of conventional therapies. Eight patients had co-occurring haematological diseases. Patients who improved by at least two points in standard clinical scales, or who reduced or discontinued the pre-rituximab therapies, were considered as responders. RESULTS: Nine patients (seven with haematological diseases) responded to rituximab: six of them, who were non-responders to conventional therapies, improved clinically, and the other three maintained the improvement that they usually achieved with intravenous immunoglobulin or plasma exchange. Significantly associated with shorter disease duration, rituximab responses started after a median period of 2.0 months (range, 1-6) and lasted for a median period of 1 year (range, 1-5). CONCLUSIONS: Rituximab seems to be a promising therapeutic choice when it targets both CIDP and co-occurring haematological diseases. Timely post-onset administration of rituximab seems to be associated with better responses.

Altered resting state attentional networks in diabetic neuropathic pain.

BACKGROUND: Chronic pain can be considered as a highly salient stimulus that continuously taxes the attentional and salience processing networks, thus interfering with cognitive abilities and, more specifically, consuming attentional resources. The aim of the paper was to explore whether and how diabetic neuropathic pain (NP) affects attentional networks. METHODS: The authors sought to achieve this by investigating resting state functional connectivity (rsFC) in diabetic NP patients and comparing it with that of matched healthy controls. RESULTS: NP patients showed a widespread reduction in connectivity in both the dorsal and ventral attentional networks, as well as in the dorsal anterior cingulated cortex (ACC), typically implicated in salience processing. The authors also found a generalised reduction in the length of functional connections in the NP group: in all the examined networks, the Euclidean distance between connected voxels was significantly shorter in patients than in controls. CONCLUSION: In diabetic NP, a parieto-fronto-cingulate network controlling attention to external stimuli is impaired. In line with previous studies, chronic pain can disrupt the synchrony of a common pool of brain areas, involved in self-monitoring, pain processing and salience detection.

A nationwide retrospective analysis on the effect of immune therapies in patients with chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND PURPOSE: The guidelines for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) therapy suggest to use immunoglobulins (IVIg) and steroid as first-line therapies. Patients who do not respond to one of the two drugs should be switched to the other drug. We collected therapeutic outcome data in patients followed at 11 centres in order to document the clinical practice in Italy. METHODS: Clinical and electrophysiological data of patients with CIDP were entered into a central database. The clinical outcome (Rankin Scale) and drug side effects (SE) for first- and second-line therapies were recorded. RESULTS: A total of 267 patients were included. The percentage of responders (R) to first-line therapy [steroid or IVIg or plasma exchange (PE)] was 69%; this number increased to 81% when patients who switched to different therapies were included. Overall, the percentage of R to IVIg was similar to R to steroids (P = 0.07) and higher than R to PE (P < 0.001). Of the main therapies, PE frequently caused SE (19%), followed by steroids (12.5%) and IVIg (4%). CONCLUSIONS: Switching between traditional therapies increases the number of responder patients. IVIg was confirmed to be a therapy with low SE.

High prevalence of neuropathies in patients with end-stage liver disease.

OBJECTIVES: Peripheral neuropathy has been reported in association with end-stage liver disease, but there is only a limited number of reports on the incidence and features of these neuropathies. MATERIALS AND METHODS: In this study, 83 patients awaiting liver transplantation were evaluated for the presence of peripheral and autonomic neuropathy. RESULTS: Sixty-five percent of the patients had evidence of neuropathy, in agreement with peripheral NCS or cardiovascular autonomic function test. The neuropathy was more frequent in patients with advanced hepatic failure, evaluated with the MELD score. The most frequent abnormalities in nerve conduction studies were sensory-motor neuropathies and sensory neuropathies, with a length-dependent pattern. CONCLUSION: Peripheral neuropathy and autonomic neuropathy are common in patients with end-stage liver disease with different etiology and correlate with the severity of the liver disease.

Comorbidity between CIDP and diabetes mellitus: only a matter of chance?

BACKGROUND AND PURPOSE: It is well known that chronic inflammatory demyelinating polyneuropathy (CIDP) and diabetes mellitus (DM) are often associated, but it is not clear if these two disorders are patogenetically correlated. METHODS: An epidemiological study on CIDP in two Italian regions (population 4,334,225) was performed, using multiple concurrent sources of cases. The presence of DM was assessed on basis of the data reported in the clinical records of each patient. Standardized morbidity ratio (SMR) was calculated, using as reference the prevalence of DM in northern Italy. RESULTS: At the prevalence day 155 patients with CIDP resident in Piemonte and Valle d'Aosta were found. Of these, 14 were also affected by either type 1 or type 2 DM. The number of expected individuals with associated DM was 13.03, corresponding to a SMR of 1.07 [95% confidence intervals (CI), 0.58-1.80]. Patients with CIDP associated with DM had a higher level of CSF proteins and a longer delay from onset to diagnosis than patients without DM, but did not differ for age of onset, gender distribution, and type of clinical course. CONCLUSIONS: Our epidemiological findings do not support a pathogenetic correlation between DM and CIDP.

Idiopathic chronic inflammatory demyelinating polyneuropathy: an epidemiological study in Italy.

AIM: The clinical and epidemiological characteristics of chronic inflammatory demyelinating polyneuropathy (CIDP) in an Italian population were assessed. SUBJECTS AND METHODS: All subjects with a diagnosis of demyelinating neuropathy after 1990 in Piemonte and Valle d'Aosta (4,334,225 inhabitants) were considered. The diagnosis of CIDP was based on the research criteria of the American Academy of Neurology. 165 of 294 patients met the diagnostic criteria. RESULTS: The crude prevalence rate was 3.58/100,000 population (95% CI 3.02 to 4.20). At the prevalence day, 76 (49.0%) cases had definite, 67 (43.2%) probable and 12 (7.7%) possible CIDP; disability was mild in 105 (67.7%) cases, moderate in 32 (20.6%) and severe in 18 (11.6%). The course was remitting-relapsing in 40 cases (25.8%), chronic progressive in 96 (61.9%) and monophasic in 19 (12.3%). Considering the 95 patients whose disorder presented in the period 1995-2001, the mean annual crude incidence rate was 0.36/100,000 population (95% CI 0.29 to 0.44), with a male to female ratio of 2.3:1. 14 cases were affected by diabetes mellitus. In multivariate analysis, factors related to severe disability at the prevalence day were: age >60 years; failure of immunomodulating therapies at the time of diagnosis; worse disability at nadir; and chronic course. CONCLUSION: Incidence and prevalence rates of CIDP in Italy were higher than those observed in most previous studies. At the prevalence day, more than 80% of cases had a mild or moderate disability, indicating either a good response to immunomodulating therapy or a tendency of CIDP to have a mild course in most cases.

Pain affects the quality of life of neuropathic patients.

The aim of this study was to verify the extent to which the presence of pain affects the quality of life (QoL) of neuropathic patients. The patients were selected in our Department of Peripheral Nervous System Diseases. We enrolled 120 consecutive patients with chronic polyneuropathy who had not received continuous pain therapy during the two months preceding study entry, and administered them the Total Neuropathy Score (TNS), the official Italian version of the SF-36 and the Italian Pain Questionnaire (QUID). Our main finding was that the QoL is affected not only by the presence of neuropathy, but also by the presence and intensity of pain: the physical aspect of the QoL correlated only weakly with the TNS, but pain was closely related to a worsening in this parameter; moreover, the mental domains of the SF-36 were only correlated with pain. Pain per se worsens the QoL of neuropathic patients, regardless of disease severity.

A further critical evaluation of requests for electrodiagnostic examinations.

The aim of this study was to evaluate the impact of electrophysiological (EDX) tests in the clinical management and diagnosis of patients, and the appropriateness of the referral diagnosis. A study was carried out in three electrodiagnostic services in the Torino area, over a 12-month period. In our study 3,900 individuals (2,340 females, 1,560 males) were evaluated. Patients underwent EDX examinations including nerve conduction study, electromyography and repetitive stimulation test. Most patients had been sent for EDX tests by specialists. Specialists suspected mainly polyneuropathy, whilst general practitioners suspected mainly carpal tunnel syndrome. Seventy-two percent of the requests were correctly formulated, 55% by general practitioners and 77% by specialists. There was a concordance between the results of the EDX tests and diagnostic hypothesis 40% of the time. This study confirms the usefulness and diagnostic impact of EDX examinations and evidences the amount of time and resources wasted as a result of incorrect or incomplete requests.

Differential diagnosis of chronic dysimmune demyelinating polyneuropathies with and without anti-MAG antibodies.

The distinction between chronic demyelinating polyneuropathies associated with IgM paraproteinemia and anti-myelin-associated glycoprotein (MAG) antibodies (MAG-PN) and chronic inflammatory demyelinating polyneuropathies (CIDPs) relies on the anti-MAG antibodies assay. The aim of the study was to identify clinical and electrophysiological features suggesting a diagnosis of MAG-PN. Fourteen patients with MAG-PN and 35 with CIDP were included, and a discriminant analysis was performed to identify the clinical and electrophysiological features suggestive of MAG-PN. Pure sensory clinical phenotype, low median and ulnar terminal latency index, and absence of M responses in the lower limbs were significantly associated with the diagnosis of MAG-PN, and indicate a moderate to large increase in probability of this diagnosis in patients with chronic dysimmune demyelinating polyneuropathies.