Check Your Diagnosis — Patient 77
Justin Kwan, M.D.
Joseph Kass, M.D., J.D.
Crescentic glomerulonephritis, associated with anti-glomerular basement membrane antibodies and anti-neutrophil cytoplasmic antibodies
This 62 year old man experienced the acute onset of severe burning pain in his feet as the presenting sign of illness. His physicians quickly recognized that the patient's pain was neuropathic in character (burning pain with hyperesthesia and allodynia), and instituted trials of medications aimed at alleviating the pain. However, the cause of his neuropathic pain, and in particular the cause of the abrupt onset of symptoms, remained unclear. He subsequently developed additional symptoms indicating the presence of a systemic illness, including unexplained weight loss followed by nausea and vomiting.
The patient's neurologic examination revealed deficits in multiple primary sensory modalities, including crude touch, pin prick, temperature, and proprioception, in a glove and stocking distribution. The lower extremities were more impaired than the upper extremities. The deep tendon reflexes were depressed. Muscle bulk and power were relatively preserved. Cranial nerve functions were essentially normal. These findings, taken together, suggested a distal, relatively symmetric neuropathic process. Laboratory studies suggested acute renal insufficiency with findings suggesting a concomitant nephritis. However, the appearance of neuropathy before the onset of renal dysfunction argued against a diagnosis of neuropathy resulting from uremia.
Nerve conduction studies revealed absent sensory nerve action potentials, and decreased compound motor action potential (CMAP) amplitudes with normal conduction velocities in the motor nerves. These electrical studies suggested an axonal neuropathy. Based on high clinical suspicion for an inflammatory process in this patient, we obtained a muscle and nerve biopsy, and a biopsy of the kidney was also performed. The nerve biopsy revealed evidence of a vasculitic neuropathy, with inflammatory cells invading the walls of multiple small blood vessels. The renal biopsy documented a crescentic glomerulonephritis, with ultrastructural findings suggesting inflammation associated with anti-glomerular basement membrane antibodies. Further laboratory studies revealed elevated quantitative rheumatoid factor as well as the presence of anti-glomerular basement membrane antibodies and cytoplasmic anti-neutrophil cytoplasmic antibodies (c-ANCA) in the patient's serum.
Although anti-glomerular basement membrane (GBM) disease is an uncommon cause of nephritis, the pathophysiology has been well described. In this disease, auto-antibodies are directed against the non-collagenous domain of the alpha-3 chain of type IV collagen. Anti-GBM disease is commonly associated with the combination of pulmonary and renal pathology (the "Goodpasture syndrome"), but it is not as commonly described in association with a peripheral neuropathy. Likewise, anti-neutrophil cytoplasmic antibodies (ANCA), particularly cytoplasmic antibodies (c-ANCA) directed largely against proteinase-3, are well-known for their association with Wegener's granulomatosis, characterized by vasculitis of the upper and lower respiratory tracts as well as glomerulonephritis, with variable degrees of vasculitic involvement of other organ systems. Again, presentations of peripheral neuropathy at the onset of disease associated with ANCA are uncommon, but occasionally reported.
Once the diagnosis of vasculitis with involvement of the peripheral nervous system was established, this patient was treated with intravenous methylprednisolone followed by oral prednisone, in combination with pulse doses of intravenous cyclophosphamide. In addition, he underwent six cycles of plasmapheresis. After two cycles of plasmapheresis, his renal function began to improve markedly, with his blood urea nitrogen levels decreasing from 70 to 20 mg/dL. His nausea and vomiting concomitantly resolved. Upon discharge from the hospital, he was afebrile, ambulatory, and had good oral intake. However, he has continued to experience considerable neuropathic foot pain.
Azathioprine was subsequently added to the patient's chronic immunosuppressive regimen, but was discontinued following development of pancreatitis. He remains on chronic oral prednisone therapy.
Vasculitis and the Peripheral Nervous System
Each peripheral nerve receives its blood supply from branches of several large blood vessels. These arteries penetrate the epineurium, and their branches extend into the perineurium as small muscular arteries and arterioles. By the time they reach the endoneurium, these vessels have divided into pericapillaries and capillaries. A blood- nerve barrier analogous to that of the central nervous system exists, composed of tight junctions between adjacent endothelial cells. Most nerves are relatively resistant to ischemia because of the massive collateral blood supply serving them. In some instances, the peripheral nerve itself may be relatively resistant to ischemia, compared to CNS tissue. However, the lack of local vascular autoregulation, and the presence of watershed zones between major vascular supplies, constitute relative disadvantages for peripheral nerves subjected to ischemia (Griffin 2001, Moore 2000).
Vasculitis involves the inflammation, necrosis, and partial destruction of blood vessel walls. The inflammatory response and resulting ischemia may lead to infarction of surrounding tissues, including peripheral nerves. Vasculitis may in some instances remain relatively confined to a particular tissue, whereas in other instances, it represents a life-threatening systemic process.
Systemic vasculitides may involve a primary immune attack on blood vessels of a specific caliber, as seen in polyarteritis nodosa, Churg-Strauss syndrome, and Wegener granulomatosis. They may also occur as a secondary process associated with a systemic auto-immune disorder, an infection, or toxin or drug exposure. Secondary systemic vasculitides includes rheumatoid vasculitis, Sjogren syndrome, and systemic lupus erythematosus-associated vasculitis, as well as hepatitis C with vasculitis associated with cryoglobulins.
Symptomatic Presentation of Vasculitic Neuropathy
Neuropathic findings dominate the clinical picture in patients with either an isolated nonsystemic vasculitic neuropathy or an early systemic vasculitis. The neuropathic features of a vasculitic neuropathy are similar, irrespective of the underlying cause. They appear to reflect the distribution and temporal progression of peripheral nerve ischemia. Manifestations of ischemic nerve injury are usually acute in onset, suggesting possible ischemia, as was seen in this patient's case. Patients often complain of burning, dysesthetic pain in the distribution of the involved nerve, in addition to sensory loss and motor weakness. While mononeuritis multiplex is the classically recognized pattern of presentation of vasculitic neuropathy (10-15% of cases), overlapping asymmetric polyneuropathies are more common (50-60% of cases). Symmetric, apparently length-dependent polyneuropathy may also occur as a presentation of vasculitic neuropathy, and failing to recognize this as a possible presentation of vasculitic nerve involvement may lead to delay in diagnosis. In systemic vasculitic neuropathies, patients often present with constitutional symptoms such as fevers, night sweats, malaise, weight loss and nonspecific arthralgias, prior to evidence of specific involvement of other organs (Kissel 1992, Griffin 2001).
Evaluation of patients with suspected systemic necrotizing vasculitis includes electrodiagnostic studies, serologic markers, histological evaluation and imaging. Electrodiagnostic studies reveal the extent and distribution of nerve involvement. Demonstrable electrophysiologic involvement of a nerve will provide a higher diagnostic yield if nerve biopsy is to be performed. Laboratory markers that may be obtained to support the diagnosis of vasculitic neuropathy include the erythrocyte sedimentation rate, anti-nuclear antibody, rheumatoid factor, perinuclear and cytoplasmic antineutrophil cytoplasmic antibody, cryoglobulins, hepatitis serology, human immunodeficiency virus serology, serum protein electrophoresis, serum complement levels, complete blood counts and metabolic panels. However, no laboratory marker, considered in isolation, can definitively confirm or exclude vasculitis. Cerebrospinal fluid analysis may be necessary to exclude other causes of illness. Elevated cytokine levels may be associated with neuropathic pain, but at present have not been shown to be diagnostically useful.
The diagnosis of vasculitis ultimately depends on tissue confirmation. Nerve biopsy should be performed on a superficial sensory nerve that is clinically and/or electrophysiologically involved, i.e. sural, superficial peroneal, or superficial radial nerve. Sural and superficial peroneal nerves are the most common choices. The superficial peroneal nerve offers the advantage of possible simultaneous muscle biopsy of the ipsilateral peroneus brevis muscle, which may also be involved by the vasculitic inflammatory process. The presence of a perivascular and a transmural inflammatory cell infiltrate on nerve biopsy is diagnostic of vasculitis. Fibrin deposition, thrombosis and recanalization of vessels, and neovascularization, and immune complex deposits in vessel walls are all commonly observed. Patchy, asymmetric, and focal regions of nerve fiber loss are characteristic but less specific features of vasculitic neuropathy. The sensitivity of nerve or nerve and muscle biopsy depends on patient selection, timing, choice of nerve for biopsy, and histological criteria for diagnosis. The overall sensitivity of biopsy is generally taken to be approximately 60%.
The precise immunologic alterations leading to vasculitic neuropathy are unknown. Genetic susceptibility could potentially play roles by modifying inflammatory effector pathways that enhance vascular inflammation, or by promoting tissue resistance to injury. The identification of exogenous substances associated with some forms of vasculitis (e.g., drugs, toxins, infections) also supports a role for environmental influences in the initiation or development of disease. Most investigations, however, have focused on the inflammatory pathways believed to be involved in infiltration of the vasculature by immune cells, as well as pathologic effector mechanisms of activated immune cells.
The vascular endothelium appears to be the site of the initial inflammatory process. The initial stimulating signals are unknown, but sequential expression of cell surface molecules (e.g., selectins, integrins, intercellular adhesion molecules), and their respective receptors, appear to be critical in recruiting inflammatory cells. Recruited T cells produce cytokines that attract and activate additional cells and propagate the inflammatory response. Inflammation is hypothesized to persist because of several factors, including the continued presence of the stimulating antigen, exposure to extracellular matrix, and sustained immune dysregulation (Kissel 1989, Kissel 1992, Moore 2000). The latter could be the result of abnormal expression of specific inhibitory factors that allow inflammatory cells to become resistant to apoptosis and perpetuate injury.
Both humoral and cell-mediated cytotoxic mechanisms have been implicated in the development of vasculitic neuropathy. According to the humoral-mediated model, antibodies interact with vessel wall antigens to form immune complexes. These and other immune complexes in circulation are deposited locally, activating the complement cascade as well as chemotactic factors to recruit inflammatory cells, which may then promote further injury.
The cell-mediated cytotoxicity model of damage posits that T cells, in association with macrophages, are important mediators of vasculitic neuropathy. Histological evidence reveals T cells and macrophages to be the predominant cell infiltrates in pathologic samples (Kissel 1989, Kissel 1992, Moore 2000). Subpopulations of CD4+ T cells also appear to play different roles at different areas of the blood vessel. CD4+ T cells in the adventitia appear to have a regulatory role. T cells located in the intima and media may have a more prominent role in vessel damage. Functionally distinct macrophages with unique products that cause vessel and nerve damage can also be identified in vasculitic lesions (reviewed in Moore 2000).
The cornerstone of treatment for vasculitic neuropathy is immunotherapy. Virus-associated vasculitis, such as hepatitis C-related vasculitis, is frequently treated differently from non-virus associated vasculitis due to concerns that glucocorticoids and cytotoxic drugs could impair immune mechanisms that suppress viral proliferation. In these cases, treatments directed at the associated virus itself, or more aggressive use of agents such as intravenous immune globulin, are often employed. Unfortunately, few data are available as to the optimal approaches to be taken in the treatment of vasculitis associated with virus infections.
Treatment of vasculitis occurring without an association to an identified virus is likewise empiric. An initial oral prednisone dose of 1-2 mg/kg/day for 1-2 months followed by a slow taper is one commonly prescribed regimen. The specific dosage and the duration of treatment are tailored to the underlying disease and the observed therapeutic response. High dose intravenous methylprednisolone is an alternative treatment modality that may minimize some of the adverse side effects of chronic steroid therapy. Simultaneous treatment with cyclophosphamide, either orally or intravenously may be required either in fulminant disease, vasculitis with multisystem involvement, or to allow reduction of the steroid dose.
Vasculitis confined to nerve and muscle is felt by some physicians to require less aggressive treatment than multisystem disease. Many patients with vasculitis apparently limited to nerve and muscle, and without rapid progression, are treated with corticosteroids alone. No randomized, controlled studies have examined the efficacy of corticosteroid monotherapy versus combination therapy with cytotoxic agents in treating non-systemic vasculitic neuropathy. A recent cohort study, however, did suggest that the combination of corticosteroids and cytotoxic therapy was superior to corticosteroid monotherapy in inducing remission and improving disability (Collins 2003). In this study, there was also a trend toward reducing the number of relapses with combination therapy. Alternative treatment modalities that may be used include plasmapheresis, intravenous immunoglobulin, azathioprine, and methotrexate.
Sudden onset of neuropathic pain should raise suspicion for an ischemic process, among which vasculitis should be considered, especially in a non-diabetic patient. Although mononeuropathy multiplex, or asymmetric polyneuropathy, are considered more classic presentations of vasculitic neuropathy, a distal symmetric presentation occurs surprisingly often, and should not dissuade one from considering a diagnosis of vasculitis. Due to patchy involvement of tissue by the inflammatory process, often biopsies of multiple sites are pursued to improve the sensitivity of detection, and to document the extent of involvement. Drs. Kwan and Kass are to be commended for their presentation of this unusual and extremely interesting case.
This patient was evaluated and treated at the M.E. Debakey Veterans Affairs Medical Center in Houston. We thank Dr. H. Machkhas, of the Neurology Service, for investigations of the nerves, and Dr. B. Krishnan, of the Department of Pathology, for assistance with the interpretation of the renal biopsy. Drs. V. Ramanathan (Nephrology) and D.R. Mosier (Neurology) also attended the patient. Most of all, we thank the patient, who gave consent for posting this case presentation.
-- Dennis R. Mosier, M.D., Ph.D.
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