Cryoglobulinemic Neuropathy Research Articles

Hepatitis C-related cryoglobulinemic neuropathy: potential role of oxcarbazepine for pain control

BackgroundPeripheral neuropathy is one most common, limiting and invalidating neurological symptom in subjects with hepatitis C virus and mixed cryoglobulinemia. Notably, the medical therapy proposed to eradicate HCV, can frequently exacerbate the painful neuropathy. Therefore, neuropathy therapies are insufficient and inadequate, and comprise immunosuppressive drugs, such as steroid or cyclosporine, intravenous immunoglobulin or plasma exchange. These have shown variable success in case reports, with a presumably temporary effect, but with major side effects.MethodsWe assessed the effects of oxcarbazepine treatment in 67 cases of cryoglobulinemia related neuropathy, who did not respond to either steroid or Gabapentin, or Pregabalin. Oxcarbazepine was chosen based on the promising preliminary results.ResultsPatients treated with Oxcarbazepine showed a rapid, discrete and persistent relief of polyneuropathic signs, without consistent side effects, and with a limited interaction with concomitant drugs.ConclusionsThese data favor the use of oxcarbazepine as a useful tool in the management of neuropathic pain associated with Hepatitis–C cryoglobulin neuropathy.

Treatment for cryoglobulinemic and non-cryoglobulinemic peripheral neuropathy associated with hepatitis C virus infection.

Peripheral neuropathy is the most common neurologic complication of hepatitis C virus (HCV) infection.The pathophysiology of the neuropathy associated with HCV is not definitively known; however, proposed mechanisms include cryoglobulin deposition in the vasa nervorum and HCV-mediated vasculitis. The optimal treatment for HCV-related peripheral neuropathy has not been established. To assess the effects of interventions (including interferon alfa, interferon alfa plus ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab) for cryoglobulinemic or non-cryoglobulinemic peripheral neuropathy associated with HCV infection. On 26 August 2014, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, and EMBASE. We also searched two trials registers, the Networked Digital Library of Theses and Dissertations (NDLTD) (October 2014), and three other databases. We checked references in identified trials and requested information from trial authors to identify any additional published or unpublished data. We included all randomized controlled trials (RCTs) and quasi-RCTs involving participants with cryoglobulinemic or non-cryoglobulinemic peripheral neuropathy associated with HCV infection.We considered any intervention (including interferon alfa, interferon alfa plus ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab) alone or in combination versus placebo or another intervention ('head-to-head' comparison study design) evaluated after a minimum interval to follow-up of at least six months. We used standard methodological procedures expected by The Cochrane Collaboration. The planned primary outcome was change in sensory impairment (using any validated sensory neuropathy scale or quantitative sensory testing) at the end of the follow-up period. Other planned outcomes were: change in impairment (any validated combined sensory and motor neuropathy scale), change in disability (any validated disability scale), electrodiagnostic measures, number of participants with improved symptoms of neuropathy (global impression of change), and severe adverse events. Four trials of HCV-related cryoglobulinemia fulfiled selection criteria and the review authors included three in quantitative synthesis. All studies were at high risk of bias. No trial addressed the primary outcome of change in sensory impairment. No trial addressed secondary outcomes of change in combined sensory and motor impairment, disability, or electrodiagnostic measures. A single trial of HCV-related mixed cryoglobulinemia treated with pegylated interferon alfa (peginterferon alfa), ribavirin, and rituximab versus peginterferon alfa and ribavirin did not show a significant difference in the number of participants with improvement in neuropathy at 36 months post treatment (risk ratio (RR) 4.00, 95% confidence interval (CI) 0.27 to 59.31, n = 9). One study of interferon alfa (n = 22) and two studies of rituximab (n = 61) provided adverse event data. Severe adverse events were no more common with interferon alfa (RR 7.00, 95% CI 0.38 to 128.02) or rituximab (RR 3.00, 95% CI 0.13 to 67.06) compared to the control group. There is a lack of RCTs and quasi-RCTs addressing the effects of interventions for peripheral neuropathy associated with HCV infection. At present, there is insufficient evidence from RCTs and quasi-RCTs to make evidence-based decisions about treatment.

Heterogeneous spectrum of neuropathies in Waldenström's macroglobulinemia: a diagnostic strategy to optimize their management

Neuropathy in Waldenström's macroglobulinemia (WM) is very heterogeneous. We retrospectively studied 40 patients with WM and neuropathy to analyze the different presentations and mechanisms encountered and to propose a diagnostic strategy. Twenty-five patients (62.5%) had axonal neuropathy, related to the following mechanisms: amyloid neuropathy (n = 5), cryoglobulinemic neuropathy (n = 5), neuropathy associated with tumoral infiltration (n = 2), vasculitic neuropathy (n = 2), a clinical motor neuropathy possibly of dysimmune origin (n = 6), or an unclassified mechanism (n = 5). A demyelinating pattern was observed in 15 patients, 10 having anti-myelin-associated glycoprotein (anti-MAG) antibodies and 5 having neuropathy related to chronic inflammatory demyelinating polyradiculoneuropathy. On the basis of these results, we propose a diagnostic strategy combining: (1) an EMG to distinguish between a demyelinating and an axonal pattern; (2) measurement of anti-MAG and anti-ganglioside antibodies; (3) screening for "red flag" features to orientate further investigations. This strategy may help clinicians to identify the mechanism of neuropathy in order to adapt the therapeutic strategy.

Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 73

Cryoglobulinemic neuropathy is probably the commonest form of vasculitic neuropathy in Mediterranean countries, as usually related to the widespread hepatitis C virus (HCV) infection. We describe the spectrum of manifestations in a large series of patients with cryoglobulinemic neuropathy, also analyzing the impact of comorbid factors, which are quite frequent in HCV‐related mixed cryoglobulinemia. The cohort included 60 patients (10 men, 50 women) with peripheral neuropathy associated with mixed cryoglobulinemia as main or sole cause (type 2 in 36 cases, type 3 in 4, not typized in 20), HCV‐related in all patients but 8 (3 men and 5 women). Median age of patients was 65 years (range 41–85), and median age at onset of neuropathy was 59 (range 40–84). Peripheral neuropathy represented an onset manifestation of mixed cryoglobulinemia in about half patients. The most frequent clinical pattern was pure sensory neuropathy in 40 patients, including 4 patients with prominent ataxia; sensory neuropathy was asymmetrical in distribution in 9 patients, and in 14 patients sensory action potentials (SAPs) of the sural nerve were normal, suggesting selective involvement of the small sensory fibers. The remaining patients had sensorimotor neuropathy (15 cases) and mononeuropathy multiplex (5 cases). Positive sensory symptoms and restless legs syndrome were the most common manifestations. Neurophysiological study showed axonal degeneration of varying severity in all patients. In 20 patients, additional causes of neuropathy were present, including type 2 diabetes (5 patients), glucose intolerance (6 patients), non‐Hodgkin lymphoma (3 patients), and alcohol (2 patients). With respect with this subset of patients, in “pure” cryoglobulinemic neuropathy there was more often a pattern of sensory neuropathy (31/40 vs. 6/20; p = 0.001), with more frequent asymmetrical distribution (9 vs 0; p = 0.05) and small fiber involvement (11 vs 3). Severity of neuropathy, as judged on the basis of the Rankin scale and of neurophysiological changes, was similar in the two subgroups. Our study confirms that sensory neuropathy, often asymmetrical, is the most common clinical pattern in cryoglobulinemic neuropathy, and is consistently present in pure cryoglobulinemic neuropathy rather than in patients with other associated causes of neuropathy; in these latter, paradoxically, clinical and neurophysiological impairment seems not greater than in pure cryoglobulinemic neuropathy.

LONG TERM FOLLOW‐UP IN CRYOGLOBULINEMIC NEUROPATHY

We evaluated the course of cryoglobulinemic neuropathy in a small series of patients in whom a long term follow‐up was available. Ten patients with polyneuropathy (8 cases) or multiple mononeuropathy (2 cases) associated with cryoglobulinemia type 2 (7 cases) or type 3 (3 cases) were reexamined after at least 5 years from the first observation (range of follow‐up, 5–14 years, median 9 years). All patients were positive for hepatitis C virus (HCV), but none had severe liver involvement, whereas renal involvement was severe in two cases. Two patients were treated with high‐dose prednisone for prolonged periods and one patient with alfa‐interferon for one year; the remaining patients were treated with low‐dose steroid and/or colchicine and cinnarizine.In the two patients with renal failure, neurological deterioration paralleled the worsening of general condition, and both eventually died after a disease course of less than ten years. In another patient, neurological condition was complicated by steroid‐induced diabetes, and stroke with left‐sided hemiparesis. In the remaining patients (including the patient treated with alfa‐interferon) neurological condition was unchanged, or mildly deteriorated without variation in the Rankin score, although neurophysiological indexes, and in particular amplitude of sensory action potentials, tended to worsen.We conclude that in a number of cases cryoglobulinemic neuropathy may run an indolent course with mild or absent deterioration, and can be controlled without aggressive medication. However, in a minority of cases there may be a malignant course, especially when systemic manifestations of the disease are prominent.

Quality Of Life In Patients With Cryoglobulinemic Polyneuropathy

The assessment of severity of polyneuropathy is usually based on the findings of neurological and electrophysiological examination, which however do not reflect overall function. Health‐related quality of life (HRQOL) measurements aim to measure the impact of a disease on the daily life of a patient, and are expecially useful in chronic diseases, however are seldom used in neuromuscular diseases. It was previously reported that HRQOL assessment may be useful in diabetic neuropathy, chronic idiopathic axonal polyneuropathy, and Charcot‐Marie‐Tooth disease. The aim of this study was to determine whether HRQOL is reduced in cryoglobulinemic polyneuropathy, and whether its measurements add useful information to the assessment of severity of polyneuropathy. We studied 12 patients (10 females, 2 males) with symptomatic cryoglobulinemic neuropathy (HCV‐related in all patients but 1), confirmed by neurophysiological study, and 10 non‐neuropathic patients (4 females, 6 males) with HCV‐related mixed cryoglobulinemia. HRQOL was assessed using the self‐administered 36‐item Short Form Health Survey Questionnaire (SF‐36). The neuropathy patients had lower scores (impaired HRQOL) than the other cryoglobulinemic patients on “physical functioning”, “pain”, and “vitality.” Both neuropathic and non‐neuropathic patients with cryoglobulinemia rated worse than the reference population on “role limitation due to physical problems” and “general health perception.” We conclude that the severity of neuropathy may be measured with a general HRQOL instrument, which provides additional information about the impact of the disease on the general functioning of the patient, and it may be useful in rehabilitation and counseling of neuropathic patients.

CRYOGLOBULINEMIC NEUROPATHY: A CLINICAL STUDY OF 25 CASES

Cryoglobulinemic neuropathy is probably the commonest form of vasculitic neuropathy, at least in Southern Europe. We studied 25 patients (19 females, 6 males) with symptomatic cryoglobulinemic neuropathy (HCV‐related in all patients but 4) clinically evident, and confirmed by neurophysiological study. Cryoglobulin was type 2 in 17 cases, type 3 in 4 cases, and not characterized in 4 cases. Neuropathy was more often in form of asymmetrical (mainly) sensory polyneuropathy (11 cases); other forms included symmetrical sensory polyneuropathy (8 cases), sensorimotor polyneuropathy (2 cases), and mononeuropathy multplex (4 cases). Neuropathy was often the presenting manifestation of the disease (16 cases), usually in association with purpura (9 cases). Purpura was the commonest non‐neurological manifestation (21 cases), and was especially severe in frequency and intensity in 11 cases. Purpura of relevant entity tended to be associated with more severe features of neuropathy, on clinical and neurophysiological grounds, and worsening course. Severe purpura was more often associated with asymmetrical neuropathy or mononeuropathy multiplex. Hepatic involvement, relevant in 7 cases and mild in 11 cases, did not correlate with the severity of neuropathic manifestations.Peripheral nerve involvement in mixed cryoglobulinemia has heterogeneous features, but factors conditioning its expression are poorly known. Our study suggests that the severity of neuropathy is correlated with purpura thus the pathogenic mechanisms of cutaneous and neurological manifestations may be interconnected.

T-cell-mediated epineurial vasculitis and humoral-mediated microangiopathy in cryoglobulinemic neuropathy

We used immunohistochemistry to assess the role of humoral and cellular factors in endoneurial microangiopathy and epineurial vasculitis in 15 nerve biopsies of patients with axonal neuropathy and monoclonal or mixed cryoglobulinemia (CG). Deposition of immunoglobulins and cytolytic complement was detected in endoneurial capillaries of patients with mixed CG. Epineurial inflammatory infiltrates containing β2-integrin-positive lymphocytes and monocytes surrounded arterioles expressing cell adhesion molecules, thus suggesting a cell-mediated pathogenesis of the epineurial vasculitis. On the other hand, the absence of immune complex deposition and polymorphonuclear elements suggests a minor role for the humoral mechanisms in the formation of the vasculitic lesions. This study indicates that both cell-mediated mechanisms and immune complexes/cryoglobulins are involved, although at different levels, in the pathogenesis of CG neuropathy.

Hepatitis C virus infection and autoimmunity

Hepatitis C virus (HCV) infection has been associated with a plethora ofimmune and autoimmune perturbations. We review serological and clinical autoimmune manifestations associated with HCV infection, discuss treatment regimens for HCV-related autoimmune diseases, and present a framework for understanding HCV-associated autoimmune disease by performing a computerized literature search from which representative articles were used and referenced. The immune response to HCV may include the development of cryoglobulins, rheumatoid factor, antinuclear antibodies (ANA), anticardiolipin, antithyroid, anti-liver/kidney/microsomal antibodies (anti-LKM), as well as HCV/anti-HCV immune complex formation and deposition. HCV infection is a significant cause of mixed essential cryoglobulinemia, which may then be complicated by cryoglobulinemic glomerulonephritis, vasculitis, or neuropathy. It has also been associated with membranous and membranoproliferative glomerulonephritis. Subsets of autoimmune hepatitis patients are infected with HCV and evidence suggests that HCV is a causative agent of antithyroid antibodies and autoimmune thyroid disease. Although cause-and-effect remain to be proved, there are reports of HCV infection preceding or coincident with polyarthritis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and polymyositis/dermatomyositis (PM/DM). HCV-infected patients also have a high incidence of sialoadenitis, and reports of low-grade lymphoproliferative malignancies have emerged. However, HCV is not a major causative factor for most autoimmune diseases. Optimal treatment for HCV-related autoimmune disease remains to be determined. Interferon alpha (IFNα) has successfully reduced viremia/transaminitis, cryoglobulins, proteinuria, and nephritis, but recurrent disease manifestations are frequent after discontinuation of therapy, Moreover, IFNα may precipitate or exacerbate autoimmune disease symptoms. HCV-related autoimmune disease also has been treated successfully with corticosteroids, azathioprine, and cyclophosphamide, although HCV viremia persists and may worsen.

Reply from the Author

Reply from the Author: We are pleased that Ghini et al confirmed our observation that interferon improves the vasculitic …

Treatment of cryoglobulinemic neuropathy with alpha-interferon

To the Editor: We read with interest the article by Khella et al on the treatment of cryoglobulinemic neuropathy with alpha-interferon (alpha-IFN). [1] Our group has been studying the relationship between HCV and essential mixed cryoglobulinemia (EMC) since 1990. We are a collaborating center of the Italian Group for the Study of Cryoglobulinemias (GISC), and have recently published the results obtained from a large sample (654 patients with EMC). [2] In this context, we have also studied the occurrence …

Hepatitis C Virus Associated Cryoglobulinemic Neuropathy Successfully Treated with Plasma Exchange

A 28-year-old Japanese woman who suffered from mononeuritis multiplex was admitted to our hospital. Serological study revealed cryoglobulinemia (type III), hypocomplementemia, high titers of rheumatoid factor (RF), and positive antihepatitis C virus (HCV) antibody. Nerve conduction velocities were slower in sensory nerves than in motor nerves. Biopsied sural nerve showed a marked decrease of myelinated fibers but no evidence of angitis. She received plasma exchange and cryoglobulinpheresis over a period of 2 months with approximately 2.0 L (40 ml/kg) of plasma replaced in each procedure. Both plasma exchange and cryoglobulinpheresis alleviated clinical symptoms, and nerve conduction velocities were improved in several nerves. The serum cryoglobulin level was markedly reduced after the treatment together with the recovery of the C4 level. Thus, complements appeared to be consumed in large quantities in the presence of cryoglobulinemia in this patient. Efficacy of cryoglobulinpheresis indicates the possibility that cryoglobulins produced in association with HCV infection played a role in damaging the nerve directly through the activation of the complement system.

Increased serum levels of ICAM-1, ELAM-1 and TNF-alpha in inflammatory disorders of the peripheral nervous system.

Endothelial intercellular adhesion molecule-1 (ICAM-1) and glycoprotein E-selectin (ELAM-1) allow the homing of leukocytes to inflammation sites. A circulating form of ICAM-1 markedly increases in inflammatory CNS disorders. In the present study, the serum levels of ICAM-1, ELAM-1 and tumor necrosis factor-alpha (TNF-alpha) were measured in patients with acute (AIDP) and chronic (CIDP) inflammatory demyelinating polyneuropathies and cryoglobulinemic neuropathy (CGN). Immunoenzymometric assays revealed increased sICAM-1 levels in some of these patients; furthermore, high titres of ELAM-1 and TNF-alpha were detected in two patients with AIDP and one patient with CGN. Our data extend previous observations on inflammatory PNS disorders by showing that, in addition to ICAM-1, ELAM-1 also represents a useful marker of endothelial activation and that, taken together, the two molecules may serve as an indicator of specific pathogenetic mechanisms.

Multiples complications d'une IgM monoclonale

A 64 year old woman with monoclonal IgM Kappa cryoglobulinemia had developed neurologic, vascular and bone involvements. If each features were previously reported, their association appears to be rare. The polyneuropathy was consistent with an IgM anti MAG neuropathy rather than a cryoglobulinemic neuropathy. The vascular occlusion is well known in dysglobulinemia. The diffuse osteosclerosis without medullary fibrosis or myeloproliferative disorder was as like as a Schnitzler's syndrome (chronic urticaria, osteosclerosis, monoclonal IgM Kappa gammopathy.

Peripheral neuropathy in cold agglutinin disease

Cold agglutinin disease (CAD) characteristically presents as anemia and cold-induced rash. We report a man with purpura, anemia, cold agglutinins, and a sensory-autonomic polyneuropathy. Treatment with corticosteroids and plasma exchange resulted in resolution of the anemia and polyneuropathy. We propose that CAD may be associated with a reversible sensory-autonomic neuropathy in the absence of cryoglobulinemia. Although unsupported by pathologic findings, pathogenetic hypotheses for the neuropathy in CAD are similar to those proposed for cryoglobulinemic neuropathy.

Peripheral Cryoglobulinemic Neuropathy in a Patient with Gaucher’s Disease

Cryoglobulinemia with peripheral cryoglobulinemic neuropathy is reported in a patient with Gaucher's disease. To the best of our knowledge, a similar relationship has not been previously described. The question whether the cryoglobulinemic neuropathy in this patient is related to Gaucher's disease, or is a mere coincidence, is discussed.