Final Diagnosis

Severe active vasculitic neuropathy in a setting of newly diagnosed SLE

Patient Follow-up

The patient’s clinical presentation was initially concerning for Guillain-Barre syndrome and vasculitic neuropathy. She was treated with 5 days of plasmapheresis (PLEX) without a significant improvement. She subsequently received 5 days of IV methylprednisolone 1-gram (g) daily with minor improvement. After obtaining the biopsy diagnosis of a severe active vasculitic neuropathy, which was associated with newly diagnosed SLE with no other apparent organ involvement , she was treated with oral prednisone 60 mg daily and IV cyclophosphamide 1 g monthly for 4 total infusions. She had an improvement in proximal limb muscle strength and overall functioning, but no improvement in distal limb muscle strength. She had several hospitalizations for urosepsis and cryptococcal meningitis. She was transitioned to Mycophenolate Mofetil, and Prednisone was tapered down to 10 mg daily. Several weeks later, the patient died from infectious complications related to immunosuppressive therapy.

Discussion

Vasculitic neuropathy is a debilitating neuropathy that can occur in patients with SLE as a result of immune-mediated damage to the vasa nervorum, leading to ischemic nerve damage and axonal loss [1]. Diagnosing vasculitic neuropathy can be challenging, particularly when neuropathy is isolated to the peripheral nervous system or presents as the first manifestation of systemic vasculitis with no other apparent organ involvement. Typical clinical presentation includes a distal and lower limb predominance, painful sensory disturbances, and an asymmetric or multifocal pattern of sensory or sensorimotor abnormalities [2]. While classically this type of neuropathy presents as an asymmetric painful multifocal sensorimotor process (mononeuropathy multiplex), vasculitic neuropathies can also present as a symmetric length-dependent polyneuropathy [3] in as many as 30–40% of patients [4], similar to our patient’s presentation. In patients with SLE, peripheral nervous system involvement occurs more commonly as a non-vasculitic distal symmetric polyneuropathy, and is more prevalent in patients diagnosed at an older age [5, 6]. But it can also be associated with vasculitic neuropathy as seen in our case, and SLE constitutes 3% of all cases of vasculitic neuropathy [6]. The most frequently affected motor nerves in vasculitic neuropathy include peroneal nerve followed by tibial, ulnar, median, and radial nerves [6], and our patient had widespread involvement of these nerve.

Particular systemic abnormalities , laboratory findings , and electrodiagnostic testing can provide meaningful clues to expand the diagnostic workup. However, it is also noteworthy that the vasculitis can be restricted to the peripheral nerves in up to 60% of cases; these non-systemic vasculitides tend to have a better prognosis than systemic cases [4]. A positive anti-Smith antibody and low complement 3 are frequently seen in SLE polyneuropathy [7]. Laboratory findings and characteristic pathological abnormalities on biopsy proved to be very helpful in the diagnosis and management of this case.

It is considered best practice to select a nerve that is clinically and electrodiagnostically affected for biopsy [8]. Classically, the sural and superficial peroneal sensory nerves are the most commonly selected nerves in the lower extremity, given their location and low rate of post-surgical complications. The superficial radial sensory nerve is another common biopsy target [4] if it is affected. A combination of nerve and muscle biopsy has been advocated to increase the diagnostic yield for vasculitis [9]. A muscle biopsy specimen is much larger than a nerve biopsy specimen, and it contains more blood vessels for detecting vascular abnormalities. The two common combinations are sural nerve with gastrocnemius muscle, and superficial peroneal nerve with peroneal brevis muscle. With one surgical incision, both nerve and muscle biopsies can be obtained.

On biopsy, primary pathological features seen in vasculitis include transmural inflammation of the small-and medium-sized arterial vessel walls, perivascular inflammation, and significant axonal degeneration [10]. Fibrinoid necrosis and transmural inflammation are more specific for the diagnosis of vasculitis, but usually seen when large- to intermeidate-sized arteries are involved, and rarely seen in small-sized vessels that are predominantly affected in vasculitic neuropathy. In our case, the sural nerve biopsy revealed perivascular inflammation and widespread terminal complement complex (C5b-9) deposition in capillaries, which are both non-specific findings and could also be seen in acute and chronic demyelinating neuropathies [10]. C5b-9 deposition in the endoneurial vessels is also seen in a substantial number of patients with diabetes [11]. The muscle biopsy exhibited the more specific and definitive findings of transmural vessel wall inflammation. Our case represents one of the examples that illustrates the usefulness of adding a muscle biopsy to a nerve biopsy for the evaluation of vasculitic neuropathy.

High dose corticosteroid with concomitant cyclophosphamide remains the mainstay of treatment for patients with peripheral neuropathy associated with systemic and non-systemic vasculitis [12]. Treatment with this regimen demonstrated better outcomes with significantly reduced relapse rates compared with prednisone monotherapy [1]. There are not many studies comparing different immunosuppressant treatment regimens in patients with severe ployneuropathy associated with SLE; one controlled clinical trial in this population demonstrated cyclophosphamide treatment to be more effective than pulse steroids [13]. Other maintenance immunosuppressive agents such as azathioprine, mycophenolate mofetil, IVIG, and rituximab have also been used with varying success [13]. Oral cyclophosphamide is associated with much higher toxicity and adverse side effects than intravenous (IV) dosing, thus monthly treatment with IV cyclophosphamide is preferred [4]. While several other steroids-sparing immunosuppressive agents can be used, strong evidence is lacking regarding the efficacy of these agents [12]. Many patients with significant peripheral nervous system involvement will need lifelong therapy [4], however for non-systemic cases, the treatment can be reduced if there is early response to treatment [6]. The benefits of immunosuppression must be balanced with limiting side effects; this challenge was evident in our case, where intense immunosuppressive therapy resulted in recurring and persistent infections and ultimately death. Significant systemic side effects and infectious complications should be closely monitored.

Pearls