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.

Author Correction to: L-Acetyl-carnitine in Patients with Carpal Tunnel Syndrome: Effects on Nerve Protection, Hand Function and Pain.

In the original publication the name of third author was incorrectly published.

L-Acetyl-carnitine in Patients with Carpal Tunnel Syndrome: Effects on Nerve Protection, Hand Function and Pain.

BACKGROUND AND AIM: L-Acetyl-carnitine (LAC) exerts an energetic effect on nerves and muscles. Recently, preclinical experiments have demonstrated a central anti-nociceptive action. OBJECTIVE: Our objective was to assess the effects of LAC on neuroprotection, pain, and function in carpal tunnel syndrome (CTS), a very frequent chronic compressive neuropathy. METHODS: In a multicentre, examiner-blinded, clinical and neurophysiological 4-month study, we enrolled 82 patients and examined 120 hands with CTS of mild to moderate severity. Patients were assessed at baseline and 10, 60 and 120 days after treatment with LAC 500 mg twice daily (BID). All patients underwent a conduction study of the median nerve, the Boston Carpal Tunnel Questionnaire (BCTQ) and the Neuropathic Pain Symptom Inventory (NPSI). The primary endpoint was the sensory conduction velocity (SCV) of the median nerve. RESULTS: The primary endpoint was met, with significant improvement of the SCV (P < 0.0001). All sensory neurophysiological measures also significantly improved. BCTQ score changed significantly (P < 0.0001), with a greater improvement in the symptom component. Nine of the NPSI types of pain, particularly squeezing and pressure pain and pain evoked by pressure, showed a significant reduction (P < 0.0001). CONCLUSIONS: Our clinical and neurophysiological study indicated that 4 months of treatment with LAC exerted a neuroprotective effect. LAC reduced pain in patients with mild and moderate CTS, a result that is possibly due to both its neuroprotective action and its central anti-nociceptive properties. Clinical Trials Registration code: EudraCT 2014-002289-62.

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.

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.

Intravenous immunoglobulin is effective in patients with diabetes and with chronic inflammatory demyelinating polyneuropathy: long term follow-up.

BACKGROUND AND AIMS: Chronic inflammatory demyelinating polyneuropathy (CIDP) seems to be more common in patients with diabetes than in the general population. The long term outcome of these patients after receiving intravenous immunoglobulin is unclear and the precise optimal regimen needed has yet to be ascertained. Moreover, the influence of chronic hyperglycaemia on this neuropathy is not clear. METHODS: This prospective follow-up study included all consecutive patients with diabetes with a CIDP referred to our department during the 18 months of the study. RESULTS: 198 consecutive patients were referred to our neuromuscular unit and exhaustively screened. 16 patients with diabetes (8%) had a demyelinating polyneuropathy fulfilling the most restrictive diagnostic criteria for CIDP. They were treated with at least one course of intravenous immunoglobulin and, if responders, retreated in case of relapse. All patients were followed for at least 40 months. Patients with diabetes with CIDP significantly improved after immunotherapy and during follow-up. The Neuropathy Impairment Score changed from 38 at presentation to 16 at the end of the follow-up. Eight patients developed distal sensory disturbances during follow-up and four of these patients complained of distal paresthesias but no neuropathic pain. Sensory disturbances were detected after 30 months (mean time) from baseline. CONCLUSION: CIDP is not an unusual neuropathy in patients with diabetes. Our study underlines the importance of extensively investigating patients with diabetes with polyneuropathy to identify those with a treatment responsive demyelinating polyneuropathy.

Tracer test with As(V) under variable redox conditions controlling arsenic transport in the presence of elevated ferrous iron concentrations.

To study transport and reactions of arsenic under field conditions, a small-scale tracer test was performed in an anoxic, iron-reducing zone of a sandy aquifer at the USGS research site on Cape Cod, Massachusetts, USA. For four weeks, a stream of groundwater with added As(V) (6.7 muM) and bromide (1.6 mM), was injected in order to observe the reduction of As(V) to As(III). Breakthrough of bromide (Br(-)), As(V), and As(III) as well as additional parameters characterizing the geochemical conditions was observed at various locations downstream of the injection well over a period of 104 days. After a short lag period, nitrate and dissolved oxygen from the injectate oxidized ferrous iron and As(V) became bound to the freshly formed hydrous iron oxides. Approximately one week after terminating the injection, anoxic conditions had been reestablished and increases in As(III) concentrations were observed within 1 m of the injection. During the observation period, As(III) and As(V) were transported to a distance of 4.5 m downgradient indicating significant retardation by sorption processes for both species. Sediment assays as well as elevated concentrations of hydrogen reflected the presence of As(V) reducing microorganisms. Thus, microbial As(V) reduction was thought to be one major process driving the release of As(III) during the tracer test in the Cape Cod aquifer.

Oxcarbazepine is effective and safe in the treatment of neuropathic pain: pooled analysis of seven clinical studies.

The results of 7 open-label clinical studies on oxcarbazepine (OXC) in different neuropathic pain conditions, sharing the same protocols, were pooled together in order to evaluate whether the results obtained in the individual trials were confirmed in the pooled analysis of this larger sample, providing more evidence for efficacy and tolerability of OXC in these conditions. Eligible patients (>18 years old) with a diagnosis of neuropathic pain were enrolled in seven open-label trials, consisting of a one-week prospective Screening Phase followed by an eight-week Treatment Phase. Treatment with OXC was initiated at 150 mg/day, and the daily dose was increased by 150 mg/day on a 2-3 day basis to the maximum tolerated dose over four weeks, up to 1800 mg/day. The primary outcome measure was the change in the actual pain rating assessed on the visual analogue scale (VAS) between the end of the Screening Phase and the end of the Treatment Phase. One hundred and thirty-six patients were enrolled in the trials. The mean VAS score dropped from 77.13 at the end of the Screening Phase to 38.41 at the end of the trial for a mean reduction of 50.2%. The percentage of responders (mean VAS score reduction > or = 50%) was 49.2%. OXC was well tolerated, with the most common adverse events consisting of vertigo, tremor, somnolence, hypotension and nausea. The results of this analysis suggest that OXC administered as monotherapy is an efficacious and safe option for the symptomatic treatment of pain associated with neuropathies.

Diagnostic value of sural nerve matrix metalloproteinase-9 in diabetic patients with CIDP.

Patients with diabetes mellitus (DM) may develop chronic inflammatory demyelinating polyneuropathy (CIDP), which may be difficult to distinguish from diabetic neuropathy (DNP). Here the authors show that immunoreactivity for matrix metalloproteinase-9 on sural nerve biopsies may help to identify CIDP-DM. In a pilot study on 10 CIDP-DM patients with IV immunoglobulins and tight glycemic control, the CIDP-DM patients had a better outcome than DNP patients treated with tight glycemic control only.

[Central nervous system involvement in patients with HCV-related cryoglobulinemia: literature review and a case report]. / Manifestazioni neurologiche centrali in corso di crioglobulinemia HCV correlata: revisione della letteratura e caso clinico.

INTRODUCTION: Few well-documented cases of central nervous system involvement in patients with mixed cryoglobulinemia and/or HCV infection have been reported. We can distinguish between acute or subacute diffuse and focal lesions (transient ischemic attack-like syndromes and cerebrovascular accidents). METHODS: A search of two electronic databases (Medline and EMBASE) was conducted from the year of their inception (1966 for Medline and 1988 for EMBASE) to September 2000. The search strategy employed entailed combining these terms: Cryoglobulinemia, Central Nervous System, Hepatitis C, Chronic Hepatitis. Cryoglobulinemia and Central Nervous System were also used as free test words. We analysed articles with case reports and the most frequent articles on the references list. PATHOGENESIS: The main pathophysiologic mechanism of cerebral involvement is ischemia (or rarely hemorrhage) due to diffuse or segmental vasculitis of the small cerebral vessels. In these cases a brain MRI usually shows single or multiple increased T2 signals. Furthermore an occasional occlusive vasculopathy without vasculitis was documented histologically. In these patients ischemia could be started or enhanced by the engorgement of the microvasculature by clumps of red cells and by aggregates of cryoglobulins. In the same patients vasculitis and hemorheological abnormalities can affect the clinical picture of the cerebral involvement in mixed cryoglobulinemia. Finally, the detection of HCV in the lesions induces a hypothesis that, in some cases, CNS involvement could be directly related to chronic HCV infection, even in the absence of cryoglobulin production. CASE REPORT: We describe a 63 year-old woman with acute severe encephalopathy. Laboratory evaluation revealed a high positive test result for rheumatoid factor (3390 U/ml) and hypocomplementemia (C4 less than 1.67 mg/dl). Protein immunofixation electrophoresis demonstrated 5% monoclonal proteins (IgM/k and IgG/k), 3% cryoglobulins were present, HCV antibody and HCV-RNA (type 2a-2c) were positive. Cryoglobulins were never typed, because they disappeared after plasma exchanges. Liver enzymes, renal function and findings on cerebrospinal fluid were normal. Cerebral CT and MRI were also normal. Antinuclear antibodies, anti nDNA antibodies, antiphospholipid antibodies, lupus anticoagulant, ANCA, Lyme disease serology, complete tests for thrombophilia were negative. Bone aspiration was normal. The patient, in coma, was treated with two plasma exchanges. During the first treatment she recovered consciousness. Prednisone (1 mg/Kg/day) and cyclophosphamide (400 mg iv for three days) were added. After a week two plasma exchanges were performed again. Liver enzymes and rheumatoid factor were analysed monthly for six months and than every two months for another six month period up to the present. Liver enzymes were always normal, rheumatoid factor was always at a lower level than the first evaluation (now it's 311 U/ml). At present she is taking Prednisone 5 mg once a day, neurologic symptoms are absent and neurologic examination is normal. DISCUSSION: We can conclude that: central neurologic involvement may be the clinical presentation of HCV infection and mixed cryoglobulinemia. HCV serologic tests and cryoglobulins should be considered in patient with encephalopathy of non-obvious cause; plasma exchange is the treatment of choice in acute severe forms; in some patients HCV could involve directly CNS, even in the absence of cryoglobulin production.

Beta-enolase deficiency, a new metabolic myopathy of distal glycolysis.

A severe muscle enolase deficiency, with 5% of residual activity, was detected in a 47-year-old man affected with exercise intolerance and myalgias. No rise of serum lactate was observed with the ischemic forearm exercise. Ultrastructural analysis showed focal sarcoplasmic accumulation of glycogen beta particles. The enzyme enolase catalyzes the interconversion of 2-phosphoglycerate and phosphoenolpyruvate. In adult human muscle, over 90% of enolase activity is accounted for by the beta-enolase subunit, the protein product of the ENO3 gene. The beta-enolase protein was dramatically reduced in the muscle of our patient, by both immunohistochemistry and immunoblotting, while alpha-enolase was normally represented. The ENO3 gene of our patient carries two heterozygous missense mutations affecting highly conserved amino acid residues; a G467A transition changing a glycine residue at position 156 to aspartate, in close proximity to the catalytic site, and a G1121A transition changing a glycine to glutamate at position 374. These mutations were probably inherited as autosomal recessive traits since the mother was heterozygous for the G467A and a sister was heterozygous for the G1121A transition. Our data suggest that ENO3 mutations result in decreased stability of mutant beta-enolase. Muscle beta-enolase deficiency should be considered in the differential diagnosis of metabolic myopathies due to inherited defects of distal glycolysis.

Prospective follow-up study of chronic polyneuropathy of undetermined cause.

Forty consecutive patients with chronic sensorimotor polyneuropathy of undetermined cause were followed to determine disease progression and prognosis. They had had neurological symptoms for at least 1 year before presentation. Neurophysiological examination in all patients showed chronic axonal degeneration, which was confirmed by sural nerve biopsy. Patients were reviewed every 3 months. Laboratory tests were performed every 6 months for the first 2 years and then annually. Neurophysiological examination was performed annually in all patients. Patients were followed up for at least 4 years. In no instance was a possible etiological factor detected during follow-up. The clinical and electrophysiological findings had a slowly progressive course. We suggest that patients with a chronic polyneuropathy of undetermined cause despite detailed investigations do not require further extensive and expensive laboratory tests and neurophysiological studies during follow-up.

Peripheral neuropathy in chronic respiratory insufficiency.

Peripheral neuropathy commonly occurs in patients with chronic obstructive lung disease (COPD). We report the presence of peripheral neuropathy in 19 of our 30 COPD patients (63.3%): 7 patients had clinical signs of a symmetric motor and sensory polyneuropathy, 12 patients had only subclinical evidence of peripheral nervous system involvement. Neurophysiological studies showed low amplitude compound muscle action potentials (CMAP) and sensory action potentials (SAP) with only slight reduction of nerve conduction velocity in affected patients: these data confirm an axonal polyneuropathy. The severity of the peripheral nervous system involvement in COPD patients was correlated with hypercapnia, the degree of disability and thus with the severity of COPD. Hypoxia, age and duration of the disease were not related with the presence of polyneuropathy. Improvement of respiratory function produced slight but progressive improvement of neurological symptoms. Within one year, also neurophysiological studies revealed a progressive and statistically significant improvement in CMAP and SAP amplitude and motor and sensory conduction velocity and, in some cases, normal electromyography.

Congenital myopathy with type 2A muscle fiber uniformity and smallness.

We describe a 12-year-old girl with congenital myopathy. ATPase histochemical reactions and immunocytochemical analysis of muscle fiber-type composition with monoclonal antibodies against slow, fast (2A and 2B) and fetal myosin demonstrate that this congenital disease is characterized by type 2A muscle fiber uniformity and smallness. This is an unusual feature for a congenital myopathy in which the fiber type predominance, when present, is confined to type I.

High-dose intravenous human immunoglobulin in polymyositis resistant to treatment.

Two patients were treated with treatment-resistant polymyositis with intravenous immunoglobulin over four days at a dose of 0.4 g/kg/day. Clinical recovery followed within two months. Serum creatine kinase (CK) activity decreased to normal, and a clear improvement in muscle strength was observed. One patient showed neither clinical relapses nor increase in serum CK activity after 20 months. The other showed a mild increase in serum CK activity after 24 months and was successfully retreated with intravenous immunoglobulin. There were no significant adverse side effects.

Quantitative assessment of class II molecules in normal and pathological nerves. Immunocytochemical studies in vivo and in tissue culture.

We have analysed class II molecules (HLA-DR) expression in human fetal nerves at different stages of gestation, in human control nerves and in nerves of patients with peripheral neuropathies of different aetiology. Immunochemical demonstration of HLA-DR antigens was also performed on isolated human Schwann cells at different times in culture, from the same nerves. In normal nerves, HLA-DR positive material is localized only on endothelial and perivascular cells and in rare perineurial and endoneurial cells. In fetal nerves, HLA-DR positive material is already present by the sixteenth week of gestation. Quantitative analysis of HLA-DR molecules density in pathological nerves showed a wide heterogeneity in different neuropathies with no correlation between the type of pathology and the intensity and pattern of staining. Cultured human Schwann cells obtained from fetal, normal adult and pathological (vasculitic neuropathy) nerves were HLA-DR positive and the percentage of positive cells increased with time in culture. DR antigen appearance on human Schwann cells may reflect not only an immunologically-mediated phenomenon but also a dependence on axon-Schwann cell interaction.