Clinical manifestations

Presentation and course

The majority of cryoglobulin-positive patients do not have symptoms attributable to cryoglobulinemia. For example, symptoms were present in only 27% of cases in a previous study (64). The clinical manifestations of cryoglobulinemia include purpura, weakness, arthralgia or arthritis, fever and glomerulonephritis, Raynaud phenomenon, and neurologic involvement that can present as peripheral neuropathy, vasculitis of the central nervous system, or both (55). Patients with symptomatic cryoglobulinemic vasculitis have significantly higher rheumatoid factor and lower C4 levels than patients with circulating cryoglobulins who are asymptomatic; on the other hand, the titer of cryoglobulins does not correlate with disease severity (13).

Although peripheral neuropathy can present as an isolated syndrome in cryoglobulinemia, it is generally associated with or preceded by other complications of the disease (38). Exacerbation by cold can be seen in patients suffering from different forms of neuropathy associated with cryoglobulinemia. A sensory polyneuropathy, often of small fiber type is by far the most common form of neuropathy in mixed cryoglobulinemia (76% of cases), as well as the presenting manifestation in half of the patients (36). Sensory motor polyneuropathy accounted for 15% of cases in the latter study. Motor involvement can range in severity from subtle to severe leg or hand weakness, or both. In a retrospective study on a cohort of 120 patients with cryoglobulinemia-associated neuropathy of different causes, 70% had a symmetrical, large fiber polyneuropathy, 19% had a small fiber neuropathy, and 12% had a mononeuritis multiplex (33). In that study, the cryoglobulin levels were lower in patients with small fiber neuropathy than in patients with symmetrical large-fiber polyneuropathy and mononeuritis multiplex. Cryoglobulinemic vasculitis rarely presents with a rapidly progressive mononeuritis multiplex without other systemic manifestations (83; 77; 63). Pediatric onset of cryoglobulinemic vasculitis-related neuropathy is very rare; however, a patient with rapidly progressive mononeuritis multiplex associated with cryoglobulinemic vasculitis associated with autoimmune disease (seropositive for rheumatoid arthritis, SSA, and SSB) has been reported (20). In addition, fulminant vasculitic neuropathy has been reported to develop in patients who initially had a slowly progressive distal polyneuropathy (75). Other less common neuropathy phenotypes that are associated with cryoglobulinemia include cranial neuropathy (58; 63) and dysautonomia (04; 41).

Neuropathy associated with hepatitis C virus presents with either a chronic sensory polyneuropathy or an acute mononeuritis multiplex. Nemni and colleagues studied a series of 51 patients with peripheral neuropathy who had hepatitis C virus infection with cryoglobulinemia in 78% of the patients and the rest without cryoglobulinemia (59). In that study, polyneuropathy was more prevalent in patients who had cryoglobulinemia, whereas cranial neuropathy or mononeuritis multiplex was more frequently found in the absence of cryoglobulinemia, and the presence of cryoglobulinemia was associated with a poorer outcome. In another report on a cohort of patients with hepatitis C-related cryoglobulinemic neuropathy who underwent a nerve biopsy, neuropathies associated with vasculitis had an increased frequency of mononeuritis multiplex and acute early-stage disability compared to those who did not have a vasculitis on the nerve biopsy (77).

Cryoglobulinemia is a rare complication of hepatitis B infection. Neuropathy is reported in 20% to 60% of patients who have cryoglobulinemia associated with hepatitis B infection (12; 53; 47).

Nerve conduction studies may be normal in small fiber sensory neuropathy. The clinical diagnosis of small fiber sensory neuropathy may be corroborated by laboratory tests, particularly, assessment of intraepidermal nerve fiber density in the skin biopsy, laser evoked potentials, microneurography, corneal confocal microscopy, quantitative sensory testing, and quantitative sweat test (11; 78). In sensory motor peripheral neuropathy, nerve conduction study may demonstrate a prominent axonal neuropathy with variable degrees of associated demyelination (38; 05). Multifocal pseudo-conduction blocks have been described in a few cases (76). Persistent motor conduction block has been reported in a patient with cryoglobulinemic vasculitis who also had a concomitant immune-mediated demyelination in the setting of antineuronal antibody (60). A picture similar to chronic inflammatory demyelinating polyneuropathy, supported by electromyography or nerve biopsy, has rarely been reported in hepatitis C virus-related cryoglobulinemic vasculitis (32; 23; 15).

Prognosis and complications

The prognosis of cryoglobulinemia primarily depends on the associated or causative disease. The prognosis of hepatitis C virus infection-related mixed cryoglobulinemia was worse than those secondary to type 1 or non-hepatitis C virus-related mixed cryoglobulinemia in the previous studies (17). The overall prognosis, including the long-term outcome of the neuropathy, has improved following the emergence of direct-acting antivirals (52; 89; 39).

Clinical vignette

Clinical findings. A 51-year-old man presented with a 3-year history of sensorimotor mononeuritis multiplex. Clinical examination was otherwise normal.

Diagnostic tests. Laboratory tests demonstrated an IgG kappa monoclonal paraprotein at 18 g/l. EMG revealed a severe axonal neuropathy. A bone marrow specimen contained 22% plasma cells. Serum immunologic studies failed to find any evidence of antibodies to gangliosides or myelin-associated glycoprotein.

A sural nerve biopsy was taken and processed for paraffin sections, epon sections, teased fiber, and electron microscopic examination. The biopsy showed numerous axonal lesions of both myelinated and unmyelinated fibers. In the endoneurial space, abundant granular deposits were visible.

The abnormal deposits were demonstrated to be immunoglobulin G and kappa light chain by specific immunogold labeling.

The cryoprotein was isolated from the blood by sedimentation and examined by electron microscopic examination.

The cryoprotein had the same ultrastructural granular appearance as the deposits located in the endoneurial space. By immuno-electron microscopic examination, the cryoprotein was specifically labeled by anti-IgG and anti-kappa light chain antibodies.

Course and management. Plasma exchange and intravenous immunoglobulin treatment were ineffective. Chemotherapy followed by hematopoietic stem cell transplantation led to incomplete improvement of the sensorimotor neuropathic symptoms and a significant reduction in the paraprotein. The axonal neuropathy of this patient seemed to be directly linked to the IgG type I cryoprotein induced by a plasma call dyscrasia.

Biological basis

Etiology and pathogenesis

The pathophysiology of end-organ injury by cryoglobulins depends on the type of cryoglobulin, the immunoglobulin concentration, and whether the tissue temperature can go low on exposure, such as with the skin and distal peripheral nerves (42). An occlusive vasculopathy of venules and arterioles by large cryoglobulin aggregates is the main mechanism in type I cryoglobulinemia, especially when the paraprotein is of IgM type. On the other hand, cryoglobulinemic vasculitis is the main mechanism in type II cryoglobulinemia. Cryoglobulinemic vasculitis is caused by deposition of immune complexes containing rheumatoid factor and complement components on the endothelial cells in the setting of exposure to cold temperature that triggers a local inflammatory reaction, including inflammatory cells and cytokines. Cryoglobulinemic vasculitis can also be implicated with type I when the monoclonal antibody binds complement fractions, resulting in the formation of immune complexes that deposit on the endothelial cells. Type III cryoglobulins are less pathogenic as the immune complexes are smaller due to the lower concentration of immunoglobulins and usually the lack of rheumatoid factor (42).

It is not known why some patients with cryoglobulinemia develop neuropathy and some do not. A peripheral neuropathy can be found in all three types of cryoglobulinemia; however, most cases have a mixed cryoglobulinemia. Although factors such as age and the amount of the immunoglobulin seem to influence the development of neuropathy in cryoglobulinemia, other genetic or environmental factors are probably involved. The titer of the cryoglobulins in an individual patient is one of the markers of disease activity. In a study, cryoglobulin titers were higher in polyneuropathy and mononeuritis multiplex than in small fiber neuropathy (33).

In some cases, electron microscopic examination and immuno-electron microscopy can demonstrate cryoprotein deposits (82).

The immunoglobulin can frequently be discerned by direct immunofluorescence or ultrastructural examination of a nerve biopsy.

In other cases, however, deposits are not found on ultrastructural studies (21).

In most cases, the neuropathy is of the axonal type, and the lesions are attributed to deposits of immunoglobulin (type I) in the endoneurium (micrograph; clinical vignette), or to vasculitis in the nerve (types II and III).

The particular lesions should be identified on a nerve biopsy specimen. The presence of axonal lesions in a nerve biopsy should prompt a study of several serial sections of the nerve fragment because deposits or vasculitis can be multifocal and segmental.

In the case of type I cryoglobulinemia, deposits of cryoglobulins may be detected by immunofluorescence. If the immunofluorescence is negative, electron microscopic examination and immuno-electron microscopic examination may visualize small deposits, sometimes well-structured (82; 85) or of a relatively nonspecific ultrastructural morphology.

If the cryoglobulin is of type II or III, axonal lesions may be associated with widespread vasculitis affecting medium and small epineurial vessels, and more rarely endoneurial vessels (59; 86). In the study of Apartis and colleagues, lesions of necrotizing vasculitis were observed in 22% of patients infected with hepatitis C virus infection suffering from peripheral neuropathy associated with a mixed cryoglobulinemia (05).

The association of type II cryoglobulinemia with hepatitis C virus infection in neuropathic patients, as well as the occurrence of peripheral neuropathy in hepatitis C virus-infected patients without cryoglobulinemia, raised the issue as to whether the hepatitis C virus alone could play a direct role in the pathogenesis of neuropathy associated with cryoglobulinemia (48). Nemni and colleagues found pathologic evidence of a vasculitic process in both hepatitis C virus cryoglobulin positive and hepatitis C virus cryoglobulin negative patients (59). The authors claimed that in hepatitis C virus cases without cryoglobulin, the activation of complement pathway is the main cause of vasculitis. Three different mechanisms may be implicated in this process: the ability of hepatitis C virus itself to activate the complement pathway, a reactivity of natural killer cells against the viral proteins, and an interaction between hepatitis C virus and anti-hepatitis C virus antibodies. Nemni and colleagues found more severe disease in hepatitis C virus cryoglobulin-positive patients as compared with cryoglobulin-negative patients, when evaluated by clinical, electrophysiological, or histometric analysis (59). The mechanism of peripheral nerve damage seems to be vasculitic in both cryoglobulin-positive and cryoglobulin-negative patients, as supported by the clinical and morphological findings. Some researchers detected hepatitis C virus RNA around epineurial vessels or in the sural nerve in patients with peripheral neuropathy and cryoglobulinemia (30). Other previous studies did not find viral replication in sural nerve biopsies taken from patients with hepatitis C virus-related cryoglobulinemic neuropathy (08; 67). On the other hand, genomic (and not replicative) RNA was isolated from the nerve extracts of hepatitis C virus-related cryoglobulinemic vasculitis (67), and hepatitis C E2 glycoprotein was detected in the vessel walls of four out of five sural nerve biopsy samples in the aforementioned study. These have led to the conclusion that neuropathy is the result of virus-triggered autoimmunity rather than viral replication per se.

Epidemiology

Serum cryoglobulins are detected in about 25% to 30% of hepatitis C virus-infected patients, often without clinical significance, with cryoglobulinemic vasculitis occurring in only 10% to 15% of these patients (24). On the other hand, the prevalence of hepatitis C virus-positive serodiagnosis in patients with cryoglobulinemia ranges from 40% to more than 90% (09; 81). This variation could be due to differences in diagnostic procedures, geographic location, and ascertainment bias. The prevalence of neuropathy in hepatitis C virus-related cryoglobulinemia increases with increasing age and duration of hepatitis C virus infection (44; 11); about one third of patients had neuropathy symptoms 15 years after the diagnosis of hepatitis C infection in the study by Lauletta and colleagues (44). On the other hand, there was no correlation between the presence of neuropathy and hepatitis C genotype, viral load, cryocrit level, and severity of liver disease in another prospective, single-center study (11).

In an earlier study, neuropathy had a prevalence of 56.8% in patients with essential mixed cryoglobulinemia, and it was the presenting symptom in about 19% of the patients (38). In that study, polyneuropathy was the most common form of neuropathy (51.4%), and mononeuropathy or mononeuritis multiplex occurred in 21.6% of the patients. In another retrospective study on 492 patients with cryoglobulinemia due to different causes, 120 had a probable to definite cryoglobulinemic polyneuropathy (33). Cryoglobulinemia was also detected in 13% of patients who were assessed for peripheral neuropathy of undetermined cause, so a search for cryoglobulinemia was recommended as first-line investigation in patients with unexplained neuropathy in middle to older age (37). Neuropathy occurred in 28% of 102 patients with cryoglobulinemia type 1 in a retrospective study, with sensory neuropathy being the most common type (73).

Connective tissue diseases and, in particular, Sjögren syndrome, hematologic disorders, and essential mixed cryoglobulinemias remain the main causes of noninfectious mixed cryoglobulinemias (79). In a large retrospective study of 1695 patients with Sjögren syndrome, the prevalence of peripheral nervous system involvement was 3.7%; cryoglobulinemia was one of the predictors of polyneuropathy (odds ratio of 3.5) (19). These reinforce the idea of systemically screening any patient with mixed cryoglobulinemia for the presence of these disorders. About 66% of 213 patients with systemic lupus erythematosus had at least one positive cryoglobulin test, 80% of which were of type III (66). In that study, only about 15% of patients with positive cryoglobulins developed cryoglobulinemia vasculitis, and neuropathy was not reported in any patient.

Prevention

The prevention of neuropathy in cryoglobulinemia involves prevention of the causative diseases, eg, avoidance of hepatitis C and B virus infections, including the detection of these transmissible agents in blood donors.

Differential diagnosis

Confusing conditions

Cryoglobulinemic neuropathy is usually part of a multisystem disease that typically includes a purpuric skin rash. Less commonly, neuropathy is the presenting feature, and systemic features are not present (29; 77; 63). The differential diagnosis includes other systemic inflammatory diseases that cause mononeuritic multiplex or length-dependent polyneuropathy, eg, polyarteritis nodosa, Churg-Strauss syndrome, Sjogren syndrome, rheumatoid arthritis, Wegener granulomatosis, scleroderma, systemic lupus erythematosus, and nonsystemic vasculitis of the peripheral nervous system as well as granulomatous diseases such as sarcoidosis, infections (Lyme, leprosy, and cytomegalovirus in the setting of immunodeficiencies), neoplastic infiltration (eg, lymphoma and leukemia), and microangiopathy secondary to diabetes and amyloidosis.

Associated or underlying disorders

There are multiple causes of cryoglobulinemia, depending on the type:

When no specific disease is associated with cryoglobulinemia, it is labeled “essential.” Cryoglobulinemia has only rarely been categorized as “essential” after the association of cryoglobulinemia and hepatitis C infection was discovered.

Neuropathy may arise in patients with cryoglobulinemia either because of the cryoglobulinemia, the associated disease, or because of treatment with neurotoxic medication, such as antineoplastic chemotherapy.

Diagnostic workup

The diagnosis of cryoglobulinemia-related neuropathy is based on the detection of cryoglobulinemia in a patient with a peripheral neuropathy. Cryoglobulinemia is defined when cryoglobulin concentration of greater than 0.05 g/L is found on at least two different occasions (16). The following guidelines have been proposed for handling the blood sample in order to minimize false negative results (26):

Indirect laboratory markers of cryoglobulinemia include low C4 serum complement fraction, decreased total hemolytic complement levels, presence of a monoclonal immunoglobulin, and rheumatoid factor activity (17). Once the diagnosis of cryoglobulinemia-related neuropathy is established, a workup to unravel underlying systemic disease (hepatitis C virus, lymphoproliferative, and autoimmune disease) has to be conducted.

Management

The treatment strategy for cryoglobulinemic neuropathy consists of treatment of the primary disorder and symptomatic treatment. In patients with hepatitis C-related cryoglobulinemic vasculitis neuropathy, treatment is directed to hepatitis C virus infection, as well as to aberrant immune response, elicited by viral proteins/RNA. Before the emergence of direct antiviral agents for hepatitis C, the use of interferon alpha and ribavirin resulted in sustained virological remission in less than one third of the patients (57), and there was limited effectiveness for cryoglobulinemic neuropathy; for example, there was gradual deterioration of neuropathy in the majority of patients on interferon alpha monotherapy or when it was combined with steroids (03; 10). Furthermore, treatment with interferon alpha may result in autoimmune neuropathy such as chronic inflammatory demyelinating polyneuropathy-like picture (49).

In a prospective study of 30 patients with hepatitis C virus-related cryoglobulinemia, pegylated interferon alpha and ribavirin were used in association with telaprevir or boceprevir, which are orally bioavailable inhibitors of the nonstructural hepatitis C virus NS3/NS4A protease, for a period of 44 weeks (69). About two thirds of the patients had a complete clinical and sustained virological remission, as well as disappearance of the cryoglobulins, at week 72. Significant adverse effects, including anemia, other cytopenias, and various infections were encountered in 47% of the patients. PEGylated interferon and ribavirin have largely been abandoned for the treatment of hepatitis C infection since 2015, after the introduction of direct antiviral agents, which have 90% to 100% rates of sustained virological remission, regardless of the viral genotype (01; 45; 52).

In a retrospective study on 148 patients with hepatitis C-related cryoglobulinemic vasculitis who underwent treatment with direct-acting agents (sofosbuvir plus daclatasvir, ribavirin, ledipasvir, or simeprevir) and who were followed for a median period of about 15 months, neuropathy, when assessed by clinical response and EMG, cleared in 77% of the patients (18). In another study, 88 patients with hepatitis C-related cryoglobulinemia who had received direct-acting antiviral treatment were followed for 17 to 41 (median: 24) months (14). Nineteen patients had neuropathy in that study, 12 of whom had complete resolution of neuropathy symptoms 12 months after sustained virological remission.

In a prospective study, 108 of 109 patients with hepatitis C-related cryoglobulinemic vasculitis who underwent treatment with direct-acting agents had sustained virological remission (39). Neuropathy symptoms were present in 72% of patients at baseline and in 49% of patients at 12 weeks after achieving sustained virological remission and thereafter (until the end of 72 weeks of study follow-up). In that study, neuropathy and sicca symptoms were predictors of incomplete clinical response.

In yet another prospective study of 94 patients with hepatitis C with and without cryoglobulinemia, 37% of the patients had significant neuropathic pain (scale > 4), and sensorimotor neuropathy was present in the nerve conduction in 23% before treatment (89). Ninety-one patients were followed 10 months after treatment with different regimens of direct-acting agents. At the end of that follow-up period, of 19 patients who had neuropathy before the treatment, neuropathic pain persisted in 11%; the nerve conduction study normalized in four and markedly improved in two. The lack of complete resolution of neuropathy after achieving sustained virological response is likely due to irreversible axonal damage during the active phase of the vasculitis.

Relapse of cryoglobulinemic neuropathy in hepatitis C-cured patients has been reported in the setting of infection or emergence of lymphoma or a solid tumor (43; 84). This indicates that the production of cryoglobulins and rheumatoid factors by several clones of B cells may become independent of stimulation by hepatitis C virus proteins (06; 52). In a systematic review of 19 previous studies, 63% to 90% of patients with hepatitis C-related cryoglobulinemic vasculitis who were treated with direct-acting antivirals had a complete clinical response after achieving a sustained virological response; 4% to 18% of those patients later developed a relapse, with neuropathy, nephropathy, and skin rash the most common manifestations (28).

Targeting the downstream immunological response (primarily B cell pathway) through the use of immunosuppressants is a complementary treatment approach for neuropathy secondary to hepatitis C virus-related cryoglobulinemic vasculitis (25). Although the use of steroids and other immunosuppressive medications has been associated with adverse prognosis in hepatitis C-related cryoglobulinemia (80), treatment with rituximab, a chimeric monoclonal antibody directed against CD20, has been shown to improve outcomes. The effectiveness of rituximab is explained by the depletion of the expanded population of reactive B cells that develop in hepatitis C virus-related cryoglobulinemia with the subsequent reduction of the production of rheumatoid factors and cryoglobulin immune complexes (07). Zaja and colleagues treated 15 consecutive patients who had unresponsive mixed cryoglobulinemia (12 of them secondary to hepatitis C virus) with rituximab in an open-labeled trial. This number included eight patients with peripheral neuropathy (88). Despite no obvious change in electrophysiology measures, all the treated patients presented a sustained (6-month) clinical improvement, mostly in subjective sensory symptoms, after four infusions of rituximab. Only one patient had motor disturbances at baseline, which improved after treatment. Thirteen patients with neuropathy associated with type II cryoglobulinemia (12 related to hepatitis C virus) who had previously been unresponsive to immunosuppressants (corticosteroids, mycophenolate, and cyclophosphamide) were treated with rituximab monotherapy in another study and were followed for a period of 12 months (22). The sensory symptoms improved in all of the subjects over a 6-month period of observation after four infusions of rituximab. There was also significant improvement of nerve conduction study parameters in that study.

Two controlled trials have examined the safety and efficacy of rituximab for the treatment of patients with HCV-associated cryoglobulinemic vasculitis (31; 74). In the study conducted by De Vita and colleagues, patients with cryoglobulinemic vasculitis were randomized to rituximab monotherapy versus steroids, azathioprine, cyclophosphamide, or plasmapheresis (31). In the patients with hepatitis C virus infection who had failed or had not been offered previous antiviral treatments, rituximab monotherapy was found superior to the other treatment arms in a 24-month follow-up in all organ manifestations, including peripheral neuropathy. Eleven of 16 patients with neuropathy responded to the treatment; two had a complete response, three had major improvements, and six had minor improvements. In the latter study, a possible loss of response after month 6 was treated with another dose of rituximab. In another study, 26 patients with hepatitis C virus-related cryoglobulinemia neuropathy were treated with rituximab 375 mg/m², given on days 1, 8, 15, and 22, then 1 and 2 months later, and followed for a mean duration of about 6 years (65). Complete or significant improvement was noted in 75% of patients with burning feet and 89% of those with weakness.

Immunosuppressants other than rituximab have also been previously used in rapidly progressive neuropathy secondary to cryoglobulinemia. Cyclophosphamide was suggested to be effective in three patients with hepatitis C virus-related vasculitic neuropathy that had entered a rapidly progressive course (75). Plasmapheresis has also been successfully used in patients with refractory hepatitis C virus-related cryoglobulinemic vasculitis, with potential presumed mechanism of action being the removal of circulating immune complexes and viral particles (62; 25; 51). Plasmapheresis was also suggested to be effective in seven patients with hepatitis C virus-related cryoglobulinemic neuropathy in a retrospective study (72). A retrospective study on 159 patients with cryoglobulinemic vasculitis assessed the efficacy of plasmapheresis (51). Eighty-seven percent of the patients had a peripheral neuropathy, 58% of whom had a “very good” to “good” response. Treatment with rituximab with or without plasmapheresis is recommended prior to starting antiviral medications in patients with hepatitis C-related cryoglobulinemia with rapidly progressive vasculitis, such as severe skin disease, declining renal function, or progressive mononeuritis multiplex (17).

Treatment of cryoglobulinemia neuropathy associated with hepatitis B includes nucleoside analogs, which suppress viral replication in more than 90% of cases. Plasma exchange, high-dose corticosteroids, and rituximab are reserved for severe and refractory cases (54).

When cryoglobulinemic neuropathy is not associated with hepatitis B or C virus infections, immunosuppressive or immunomodulatory treatments including steroids, plasma exchange, and immunosuppressants such as cyclophosphamide and rituximab have proven effective (38; 07). Several reports have emphasized the possible usefulness of rituximab in non-hepatitis C related–cryoglobulinemia, at times with an improvement in the peripheral neuropathy (07; 88; 70; 22; 61). A large study by Terrier and colleagues evaluated the effects of rituximab on 242 patients with noninfectious mixed cryoglobulinemia (79). The overall findings suggest that rituximab plus steroids have a greater therapeutic efficacy in achieving a complete response than steroids alone and alkylating agents plus steroids. Therefore, rituximab plus corticosteroids may be considered the first therapeutic option in patients with a severe noninfectious mixed cryoglobulinemia vasculitis; however, steroids should be rapidly tapered to decrease the risk of severe infection. A consensus conference organized by the Italian Group for the Study of Cryoglobulinemia (GISC) concluded that rituximab-based treatments should be considered in patients with skin ulcers, peripheral neuropathy, or glomerulonephritis, and in patients with no response to plasmapheresis (34). Rituximab in combination with belimumab, a monoclonal antibody that targets the B-cell activating factor, resulted in improvement of systemic manifestations in four patients who had relapses after treatment with rituximab--one with hepatitis C infection and three with polyneuropathy (68). Ibrutinib, an inhibitor of Bruton tyrosine kinase, was effective in normalizing IgM and cryoglobulin levels as well as stabilizing polyneuropathy in a type I cryoglobulinemic vasculitis secondary to lymphoblastic lymphoma that was refractory to treatment with rituximab, plasmapheresis, and chlorambucil (27).

First-line treatments for neuropathic pain include tricyclic antidepressants (eg, amitriptyline and nortriptyline), dual reuptake inhibitors of both serotonin and norepinephrine (eg, duloxetine), and antiepileptics such as oxcarbazepine and calcium-channel alpha-2-delta blockers (ie, gabapentin and pregabalin) (56; 71). Tramadol and opioid analgesics are generally considered second-line treatments (71).

Special considerations

Pregnancy

To date, only one report has examined the outcome of pregnancy in a patient with cryoglobulinemia and hepatitis C virus infection. The pregnancy was disrupted with a child born at 31 weeks (02).

Anesthesia

No deleterious effect of anesthesia has been reported in neuropathy associated with cryoglobulinemia.