Mononeuropathy Multiplex due to Mixed Cryoglobulinemia
This 44-year-old man with chronic hepatitis C infection presented with rapidly progressive, asymmetric weakness of his extremities after a short stay in the hospital for gastrointestinal dysfunction. Based upon the history and physical findings of hypo- or arreflexia, muscle wasting, weakness, and sensory deficits in all extremities, the site of the neuroanatomical lesion in this patient is likely to be the peripheral nerve. Lesions affecting roots, motor neuron, or muscle are unlikely to be the sole explanation for this patient's illness. The asymmetry and tempo of dysfunction in this patient would raise the possibility of multifocal nerve involvement, i.e., mononeuropathy multiplex.
Mononeuropathy multiplex refers to dysfunction of two or more discrete nerves. Usually the onset of symptoms is abrupt in the distribution of one nerve, with subsequent involvement of other nerves at irregular intervals. The differential diagnosis includes endocrine (diabetic), traumatic, infectious, inflammatory, neoplastic or paraneoplastic, vasculitic and inherited causes.
Infectious or para-infectious causes of neuropathy must always be considered in a patient with neuropathy and a preexisting chronic infection (e.g., hepatitis C). Infections which commonly involve the nerves are often viral and include HIV and CMV, usually in immunocompromised patients. Mycobacterial infections (e.g., leprosy) can also produce multifocal involvement of nerves.
HIV infection can be associated with peripheral nerve disease either as a direct pathogen, or in relation to drugs given to combat progression of HIV disease. HIV-induced neuropathy can occur rapidly, presenting as an AIDP (acute inflammatory demyelinating polyradiculoneuropathy) syndrome, usually near the time of seroconversion. It can also result in a chronic progressive neuropathy with a more symmetric presentation, usually with an axonal > demyelinating predominance, which can be very difficult to distinguish from a drug-induced neuropathy. CMV neuropathy is typically the result of opportunistic infection in an immunocompromised host, commonly presenting in an acute or subacute fashion. CMV-associated neuropathy may present as a mononeuropathy multiplex, but more commonly presents as a rapidly progressive symmetric polyneuropathy or polyradiculoneuropathy. The patient presented was seronegative for HIV by history, and there was no evidence of a significantly immunocompromised state from the examinations performed.
The Guillain-Barre syndrome of acute inflammatory (idiopathic) demyelinating polyradiculoneuropathy is an acquired neuropathy usually presenting with paresthesias and weakness. The motor weakness is symmetric, most commonly affecting distal muscles and ascending rapidly to the trunk and upper extremities. The cranial nerves are involved in 40-70% of patients. Autonomic involvement may also occur, with labile blood pressure, and cardiac dysrhythmias. Up to 2/3 of patients will commonly report a preceding event such as a upper respiratory infection or less commonly a gastrointestinal syndrome, surgery, or immunizations occurring 1-4 weeks prior to the onset of the neurologic symptoms. Several infections have been linked to GBS, including the herpes viruses (CMV & EBV), viral hepatitis, and bacterial agents such as Mycoplasma and Campylobacter jejuni. Some cases can occur in immunocompromised hosts with lymphoma or systemic lupus erythematosus, or in association with early stages of HIV infection (see above). Diagnosis is based upon electrodiagnostic and CSF analysis. Electrodiagnostic studies typically reveal demyelinating neuropathy, with frequent conduction abnormalities attributable to nerve root compromise. CSF examination reveals elevated protein levels with normal white blood cell counts. This patient did present with acute and rapid onset of weakness in his extremities, together with erectile dysfunction suggestive of autonomic involvement. He also experienced gastrointestinal symptoms prior to the onset of his weakness. However, the pattern of involvement was consistently asymmetric, and his laboratory evaluations showed normal CSF protein, with no evidence of concomitant infections (see above), and no evidence of demyelination on electrodiagnostic or pathological studies.
Drug-induced neuropathies are typically axonal in presentation. Drugs which induce neuropathy include dapsone, isoniazid, vincristine/vinblastine, thallium, arsenic, and alcohol. Most drug-induced polyneuropathies are symmetric in pattern, although some can present in an acute or subacute fashion. The patient denied exposure or use of any of these drugs/toxins.
Paraneoplastic neuropathies are rare, most commonly distal symmetric sensory or sensorimotor neuropathies, and may be either axonal or demyelinating or both. Mononeuropathy multiplex is an uncommon presentation of paraneoplastic neuropathy, compared to the distal symmetric form. The neuropathy can occur prior to diagnosis of the cancer by months to years or concomitantly with the cancer. Diagnosis is based upon identification of tumor (or in some occasions, assays for specific antibodies), and exclusion of other possible causes. Though this patient may be at increased risk for hepatocellular carcinoma as a result of his chronic hepatitis C infection, there was no other evidence to lead to the diagnosis of a paraneoplastic syndrome, and eventually an alternative diagnosis was made.
Hereditary motor and sensory neuropathies are usually distal and symmetric. However, HNPP or hereditary neuropathy with liability to pressure palsies, associated with a partial deletion of one copy of the PMP22 gene on chromosome 17, may present with recurrent episodes of isolated peripheral nerve palsies. There is an autosomal dominant inheritance pattern. Most patients experience the initial attacks in the second or third decade of life, usually provoked by compression, slight traction, or other slight trauma to the affected area. Most are of sudden onset, painless, and usually followed by significant recovery. Electrophysiological studies show a diffuse sensory and motor, demyelinating polyneuropathy in both clinically affected and unaffected limbs, accompanied by persistent conduction block at one or more entrapment sites. Sural nerve biopsy demonstrates distinctive, focal sausage-like thickening of myelin sheaths (termed tomaculae) due to concomitant demyelination and remyelination. The patient did not have a family history of neuropathy or prior compressive neuropathy in the past. In addition, the electrodiagnostic studies and biopsy indicated an axonal process.
Neuropathy in connective tissue disease and vasculitides is common. It may occur as a part of the disease process or may be secondary to other organ involvement. The pathogenesis of peripheral neuropathy in connective tissue disorders is presumed to involve circulating immune complexes, and/or cell-mediated immune processes. Immune complexes may be detected in a variety of connective tissue disorders including systemic lupus erythematosus, rheumatoid arthritis, and systemic vasculitides in association with such diseases as polyarteritis nodosa, malignancies, and essential mixed cryoglobulinemia. Vascular lesions are usually characterized by inflammation and necrosis of blood vessel walls, with subsequent nerve ischemia. Neuropathies associated with systemic vasculitides and connective tissue diseases may present in several forms: multiple mononeuropathies, distal symmetrical sensorimotor polyneuropathy, and cutaneous sensory neuropathy. Multiple mononeuropathies (mononeuritis multiplex) is the most common presentation. Nerve biopsy may directly reveal vasculitis of small arterioles, or evidence of vasculitic involvement may be indirect, with axonal degeneration involving discrete nerve fascicles. Distal symmetrical sensorimotor polyneuropathy is the next most common presentation of vasculitic nerve injury. This patient's laboratory evaluation was negative for a distinct connective tissue disease. Although the rheumatoid factor was elevated, this was in the absence of any joint abnormalities. A serum assay for cryoglobulins was positive.
The patient was diagnosed with mononeuropathy multiplex associated with cryoglobulinemia, felt to be secondary to his chronic hepatitis C infection. A more detailed report of the serum protein analysis (not available at time of posting) specified mixed cryoglobulins (type II pattern). He was admitted to the hospital and treated with plasmapheresis, and subsequently with cyclophosphamide. Unfortunately, his condition continued to progress despite treatment, leaving him wheelchair bound without the use of his arms or legs. He deteriorated with subsequent pneumonia, congestive heart failure and death four months after the initial neurologic presentation.
Based upon the clinical presentation, laboratory, and pathologic data, the patient was diagnosed with mononeuropathy multiplex secondary to mixed cryoglobulinemia associated with chronic hepatitis C infection.
Cryoglobulinemia is characterized by the presence of serum proteins which reversibly precipitate in the cold and re-dissolve with warmer temperatures. They are associated with a variety of systemic illnesses, which include infections, malignancies, and immune disorders. There are three main types of cryoglobulinemia (Brouet et al., 1974), composed of isolated monoclonal immunoglobulins (IgG or IgM) without rheumatoid factor activity and commonly associated with malignancies (Type I), combinations of polyclonal IgG and monoclonal IgM rheumatoid factors (Type II), or polyclonal IgG and rheumatoid factors (Type III). Types II and III are referred to as "mixed." Hepatitis C viral infection, a major cause of liver disease, whether contracted sporadically, sexually, or post-transfusion, also appears to be the most common cause of mixed cryoglobulinemias, specifically, type II (Apartis et al., 1996) and has been found in up to 70% of patients with mixed cryoglobulinemia (David et al., 1996).
Cryoglobulinemias are termed "essential" when they are not associated with a lymphoproliferative disorder, yet may often be associated with a systemic vasculitis of small and medium size vessels with involvement of multiple organs, including the kidneys, liver, and peripheral nerves. The reported incidence of peripheral neuropathy in mixed cryoglobulinemias varies greatly among reported studies, from 7-90%. The neuropathy may present as a distal symmetric mixed sensorimotor polyneuropathy (67%), or as a mononeuropathy multiplex (33%).
Vasculitic neuropathies typically develop in an acute (<1 week) or subacute (1 week - 4 months) fashion. There is typically evidence of asymmetric multifocal sensorimotor nerve dysfunction on exam, which appears in a discrete and stepwise pattern. The vast majority of patients complain of sensory dysesthesias and pain. Aspartis et al. (1996) found sensory signs and symptoms in all patients at the time of presentation. Fifty percent experienced a burning, pricking type pain in the distribution of the affected nerve, and decreased sensation to pin prick in a stocking distribution consistent with a concomitant distal symmetric polyneuropathy. The degree of weakness and autonomic dysfunction varies among patients, but has been reported to be less frequent than sensory deficits. In addition, patients often present with other signs of systemic involvement including purpura, skin ulceration, glomerulonephritis and liver damage. However, peripheral neuropathy can be the sole presenting sign of cryoglobulinemia in ~15% of patients (Gemignani et al., 1991).
Histopathology on sural nerve biopsy typically shows primarily axonal degeneration with vasculitic destruction of epineural vessels, or thickening and obliteration of the endoneurial vessels, possibly from immune complex deposition. Electrophysiologic studies typically confirm the neuropathy as an axonopathy, with EMG evidence of denervation and low amplitude nerve action potentials on nerve conduction studies.
Epineurial vasculitis is well known to induce fascicular ischemia and axon loss, yet the mechanism that triggers the vasculitis in the setting of hepatitis C infection and cryoglobulinemia is not completely understood. Hepatitis C is an enveloped, single stranded RNA virus of the Flaviviridae family. Its RNA has been identified in peripheral blood B lymphocytes undergoing transformation from benign proliferation to lymphoma. It is possible that it may promote B-cell proliferation and production of immunoglobulins, including rheumatoid factor and cryoglobulins. The cryoglobulins associated with this virus (Type II) activate complement in cold temperatures, resulting in hypocomplementemia. Serum complement activity concentrations decrease in association with the formation of cryoprecipitates. Cryoglobulins associated with hepatitis C virus typically form a precipitate with IgG and activate complement along the surface of blood vessels. This interaction may trigger inflammation of blood vessels, leading to nerve ischemia and mononeuritis multiplex (Scully et al., 1999). The mechanism predisposing to preferential nerve involvement is unknown.
It has also been hypothesized that HCV has a more direct role in the production of cryoglobulinemia and the characteristic features of peripheral neuropathy associated with a mixed, essential cryoglobulinemia (David et al., 1996). The peripheral neuropathy in HCV+ patients with cryoglobulinemia is more severe than in patients with cryoglobulinemia not associated with HCV, mainly because of increased motor involvement. In addition, direct and indirect signs of vasculitis were more frequent and severe in HCV+ patients. Patients with both hepatitis C infection and cryoglobulinemia have more frequent cryoglobulin related cutaneous involvement, higher alanine aminotransferase level, lower CH50, more frequent presence of rheumatoid factor, and a greater extent of histologic liver lesions than patients with cryoglobulinemia in the absence of HCV (Gemignani et al., 1991).
Diagnosis is based upon history and physical examination, and upon a high index of suspicion in any patient with an acute or subacute onset of nerve dysfunction in the setting of HCV seropositivity. Conversely, a patient with cryoglobulinemia and nerve dysfunction should be evaluated for viral hepatitis. Diagnostic tests should include routine laboratory tests including CBC and differential counts, platelets and chemistries, in addition to screens for rheumatoid factor, antinuclear antibodies, complement levels, HIV, hepatitis B and C profile, CSF analysis, cryoglobulins, and protein electrophoresis. Electrodiagnostic studies should be performed to characterize the predominant type and distribution of neuropathy and to confirm the findings on physical examination. Nerve biopsy is indicated in the setting of data suggestive of an immunologic or infectious cause, or in the absence of an obvious diagnosis. Biopsy of the skin and muscle can increase the yield for diagnosis when there is evidence of systemic involvement.
The optimal treatment for this syndrome is not known, but has traditionally involved immunosuppression. Several uncontrolled reports suggest a beneficial response of prednisone, plasmapheresis, and other immunosuppressants and these are considered the mainstays of treatment for cryoglobulinemia, though improvement of neuropathic symptoms has not been consistently achieved (David et al., 1996). Recently, interferon-a has emerged as a promising therapy and is the only approved therapy for chronic hepatitis C. Several small studies have reported a significant response rate (up to 77%) with resolution or normalization of disease manifestations in skin, kidney, cryoglobulin levels, liver enzymes and some neuropathic complaints within 1-2 weeks (David et al., 1996). Prospective, randomized trials of interferon-a in patients with type II mixed cryoglobulinemia and hepatitis C infection found improvement in the cutaneous manifestations of the disease and a reduction in the level of circulating cryoglobulins, serum transaminase levels, rheumatoid factor activity, hepatitis C RNA, hepatitis C antibody, and creatinine levels (Ferri et al., 1993, and Misiani et al., 1992). However, from most case report studies and trials, treatment response is poorly defined for the peripheral neuropathy (David et al., 1996; Ferri et al., 1993; Scelsa et al., 1998).
Some studies have reported patients with HCV-associated cryoglobulinemia with suggested improvement of prednisone-resistant mononeuropathy multiplex following treatment with a-interferon or with a combination of a-interferon and other immunosuppressive agents. However, other reports warn that a-interferon treatment may aggravate extrahepatic manifestations of cryoglobulinemia, including polyneuropathy (Scelsa et al., 1998). At present, larger randomized controlled trials are needed to study the indication of interferon-a as a primary or adjunctive agent and to determine its efficacy and safety in this patient population.
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