Vasculitic Neuropathy
Definition
Vasculitic neuropathy is peripheral neuropathy caused by inflammation of the blood vessels (vasculitis) that supply nerves. This inflammation reduces blood flow and ischemic damage to the affected nerves, resulting in pain, weakness, sensory disturbances, and muscle atrophy.
The condition can arise from systemic vasculitic disorders, such as polyarteritis nodosa, microscopic polyangiitis, or Churg-Strauss syndrome. Vasculitic neuropathy typically presents as mononeuritis multiplex, characterized by asymmetric involvement of multiple nerves. Early recognition and treatment of the underlying vasculitis are essential to prevent irreversible nerve damage and improve outcomes.
Epidemiology
Vasculitic neuropathy is a relatively rare condition, often associated with systemic vasculitis or isolated peripheral nerve vasculitis. The exact prevalence varies depending on the underlying vasculitis type, with polyarteritis nodosa, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) among the most common systemic causes. It is estimated that up to 60% of patients with systemic vasculitis may develop peripheral neuropathy. The condition is more frequently observed in middle-aged to older adults, with a slight male predominance in specific vasculitis subtypes like polyarteritis nodosa.
Geographical and ethnic differences exist, as some vasculitic disorders, such as Takayasu arteritis, are more common in specific populations. Isolated vasculitic neuropathy, without systemic involvement, is extremely rare and accounts for a small fraction of peripheral neuropathy cases.
Early diagnosis is challenging, as symptoms often overlap with other neuropathic disorders, leading to potential underreporting. Advances in diagnostic techniques, such as nerve biopsy and serological testing, have improved recognition, though epidemiological data remain limited.
Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome)
Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome, is a systemic vasculitis characterized by asthma, eosinophilia, and granulomatous inflammation. Neuropathy is a common and significant complication, affecting 60–75% of patients, often due to inflammation and ischemia in the small blood vessels (vasa nervorum) supplying the peripheral nerves.
Pathophysiology
The underlying mechanism of neuropathy in EGPA involves necrotizing vasculitis and perivascular eosinophilic inflammation, which leads to ischemic nerve injury and axonal degeneration. Inflammatory mediators and eosinophil degranulation products, such as major essential proteins, contribute to nerve damage.
Clinical manifestations
The most frequent neuropathic presentation in EGPA is mononeuritis multiplex, where multiple individual nerves are affected asymmetrically, leading to sudden-onset weakness, sensory loss, and pain. For example, patients may experience foot drop or wrist drop due to the involvement of the peroneal or radial nerves. In some cases, the neuropathy evolves into a distal symmetric polyneuropathy, causing numbness, tingling, and burning pain in the hands and feet.
Neuropathy is often accompanied by other systemic manifestations of EGPA, such as asthma exacerbations, rhinosinusitis, skin rash, and gastrointestinal symptoms. Cardiac involvement, which occurs in a subset of patients, is a significant cause of morbidity and mortality.
Diagnosis
Diagnosis is based on clinical criteria, eosinophil counts (>10% or >1500/µL), and evidence of systemic vasculitis. ANCA, particularly anti-MPO (p-ANCA), is positive in approximately 40% of cases, but its absence does not exclude the disease. Nerve conduction studies (NCS/EMG) reveal axonal neuropathy, and nerve biopsy may show necrotizing vasculitis with eosinophilic infiltration.
Treatment
The treatment of EGPA-associated neuropathy involves immunosuppressive therapy. Corticosteroids are the cornerstone of treatment, often in combination with cyclophosphamide or rituximab for severe or refractory cases. Maintenance therapy may include azathioprine or methotrexate to prevent relapses. Recent advances include the use of mepolizumab, an IL-5 inhibitor that targets eosinophilic inflammation.
Neuropathic pain is managed with medications such as gabapentin, pregabalin, or duloxetine. Physical therapy is essential for maintaining function and addressing motor deficits. Recovery from neuropathy depends on the severity and duration of nerve damage before treatment, with ischemic injury often leading to incomplete recovery.
Prognosis
The prognosis of EGPA varies, with timely diagnosis and treatment improving outcomes. Relapses are common, requiring regular monitoring and long-term management. Neuropathy is a major contributor to morbidity, emphasizing the importance of addressing it as part of the comprehensive care of patients with EGPA.
Microscopic Polyangiitis
Microscopic polyangiitis (MPA) is a rare systemic vasculitis affecting small blood vessels, often associated with myeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCA). Neuropathy is a common manifestation of MPA, occurring in up to 60% of cases, primarily due to vasculitic inflammation of the vasa nervorum, the small vessels supplying peripheral nerves.
Pathophysiology
The pathophysiology involves immune-mediated vessel inflammation, which leads to ischemic damage and axonal degeneration in the peripheral nerves.
Clinical manifestations
The most frequent manifestation of neuropathy in MPA is mononeuritis multiplex, characterized by asymmetric involvement of multiple nerves. Patients may experience sudden-onset pain, sensory loss, and weakness in a patchy distribution, such as foot or wrist drop. In some cases, the neuropathy may evolve into a more diffuse distal symmetric polyneuropathy, causing numbness, tingling, and burning pain in a stocking-glove distribution.
Neuropathy in MPA often coexists with systemic symptoms such as fever, weight loss, fatigue, and organ involvement, including kidney dysfunction (rapidly progressive glomerulonephritis) and pulmonary issues (alveolar hemorrhage).
Diagnosis
Diagnosis is based on clinical findings, serological testing (positive MPO-ANCA or p-ANCA), and confirmatory tissue biopsy showing necrotizing vasculitis without granulomatous inflammation. Electrophysiological studies (NCS/EMG) reveal axonal neuropathy, while nerve or muscle biopsy may show necrotizing vasculitis involving the small arteries and arterioles.
Treatment
Neuropathy treatment in MPA focuses on controlling the underlying vasculitis with immunosuppressive therapy, typically high-dose corticosteroids combined with cyclophosphamide or rituximab. Maintenance therapy may include azathioprine or methotrexate. Early and aggressive treatment can prevent further nerve damage and improve outcomes. Symptomatic management of neuropathic pain includes medications like gabapentin, pregabalin, or duloxetine. Physical therapy may aid in recovering strength and function in affected limbs. Despite treatment, recovery from neuropathy may be incomplete, mainly if ischemic damage is severe.
Prognosis
Prognosis The prognosis depends on the extent of systemic involvement and the timeliness of treatment. Neuropathy is a significant cause of morbidity in MPA, underscoring the importance of early diagnosis and comprehensive care. Regular follow-up is essential to monitor disease progression and prevent relapses.
Cryoglobulinemia
Cryoglobulinemia is characterized by immunoglobulins that precipitate at low temperatures and dissolve upon rewarming. These proteins can cause vascular inflammation, leading to small and medium vessel vasculitis. Neuropathy is a frequent and significant complication of cryoglobulinemia, occurring in approximately 50% of cases, particularly in types II and III cryoglobulinemia associated with mixed cryoglobulins.
Pathophysiology
The pathophysiology of neuropathy in cryoglobulinemia involves immune complex deposition in the vasa nervorum, leading to vasculitis and subsequent nerve ischemia. This ischemic damage results in axonal degeneration, predominantly affecting sensory nerves.
Clinical manifestations
The most common presentation is distal symmetric sensory or sensorimotor neuropathy, characterized by burning pain, paresthesia, and numbness in the feet and hands. Sometimes, mononeuritis multiplex may occur, presenting as asymmetric nerve involvement with sudden-onset weakness and sensory loss.
Symptoms of cryoglobulinemic neuropathy are often accompanied by systemic manifestations such as purpura, arthralgia, and fatigue. Chronic hepatitis C infection is a major underlying cause of mixed cryoglobulinemia and is strongly associated with neuropathy. Other conditions linked to cryoglobulinemia include autoimmune diseases (e.g., Sjögren's syndrome, systemic lupus erythematosus) and hematological malignancies (e.g., multiple myeloma or lymphoma).
Diagnosis
Diagnosis involves detecting cryoglobulins in serum, though the process requires careful handling due to cryoglobulins' temperature sensitivity. Electrophysiological studies (NCS/EMG) typically reveal axonal neuropathy. Nerve or muscle biopsy may demonstrate vasculitis with immune complex deposition, confirming the diagnosis.
Treatment
Treatment of cryoglobulinemic neuropathy focuses on managing the underlying condition and controlling vasculitis. For hepatitis C-associated cryoglobulinemia, antiviral therapy with direct-acting antivirals (DAAs) has significantly improved outcomes. In severe cases of vasculitis or neuropathy, immunosuppressive therapy with corticosteroids, rituximab, or cyclophosphamide may be necessary. Plasmapheresis can be considered for rapidly progressive or life-threatening cases.
Pain management is crucial and often requires medications such as gabapentin, pregabalin, or duloxetine. Physical therapy and supportive care help preserve function and mobility in patients with motor deficits.
Prognosis
The prognosis depends on the severity of vasculitis and the underlying condition; early diagnosis and targeted therapy can prevent irreversible nerve damage.
Polyarteritis Nodosa
Polyarteritis nodosa (PAN) is a systemic vasculitis affecting medium-sized arteries. It leads to ischemic damage in various organs, including the peripheral nerves. Neuropathy is a common and debilitating manifestation of PAN, occurring in up to 70% of cases.
Pathophysiology
The neuropathy in PAN typically arises due to inflammation and fibrinoid necrosis in the vasa nervorum, the small vessels supplying peripheral nerves. This vascular injury results in nerve ischemia and subsequent axonal damage.
Clinical manifestations
The most frequent pattern of neuropathy in PAN is mononeuritis multiplex, characterized by asymmetric involvement of multiple individual nerves, leading to sudden-onset weakness and sensory loss. In advanced stages, mononeuritis multiplex can evolve into a confluent pattern resembling symmetric polyneuropathy. Symptoms often begin with pain, paresthesia, or numbness in the affected nerve distributions, followed by motor deficits such as foot or wrist drop. Pain is frequently severe, described as burning or stabbing, and may be one of the earliest signs of nerve involvement.
Commonly affected nerves include the peroneal, radial, and ulnar nerves. Neuropathy may also coexist with systemic symptoms of PAN, such as fever, weight loss, myalgias, and hypertension.
Diagnosis
Diagnosing neuropathy in PAN requires clinical evaluation, supported by nerve conduction studies and electromyography (NCS/EMG) to confirm axonal damage. A nerve or muscle biopsy showing vasculitis with fibrinoid necrosis of blood vessels provides definitive evidence. Laboratory tests may reveal elevated inflammatory markers, but no specific serological marker exists for PAN.
Treatment
Treatment involves immunosuppressive therapy, with high-dose corticosteroids as the cornerstone. Severe cases may require additional agents, such as cyclophosphamide or rituximab, to control vasculitis and prevent further nerve damage. Pain management is essential, utilizing neuropathic pain medications like gabapentin or duloxetine. The prognosis depends on the severity of systemic involvement and the timeliness of treatment. Early and aggressive therapy can improve outcomes, but untreated PAN can lead to significant disability and even mortality.
Relapses are possible, necessitating close monitoring and long-term management. PAN-associated neuropathy is a key driver of morbidity in this condition, emphasizing the importance of recognizing and addressing neurological symptoms promptly.
Prognosis
The prognosis depends on the severity of systemic involvement and the timeliness of treatment. Early and aggressive therapy can improve outcomes, but untreated PAN can lead to significant disability and even mortality. Relapses are possible, necessitating close monitoring and long-term management.
Takayasu's Arteritis
Takayasu's arteritis (TA) is a chronic granulomatous vasculitis that affects large vessels, particularly the aorta and its major branches. It occurs primarily in young women, especially from Asia, and is characterized by inflammatory vessel wall damage leading to stenosis, occlusion, or aneurysm formation.
Pathophysiology
Neuropathy in TA is rare but can occur due to nerve ischemia and reduced blood flow to the vascularized areas. Neuropathopathic damage in TA can arise either through direct nerve ischemia or secondarily via muscle ischemia, causing indirect nerve involvement.
Clinical manifestations
Common symptoms include pain, paresthesias, and muscle weakness, often localized to the extremities. The neuropathy is often peripheral and can affect both sensory and motor functions. Neuropathopathic damage in TA can arise either through direct nerve ischemia or secondarily via muscle ischemia, causing indirect nerve involvement. In some cases, mononeuritis multiplex, an asymmetric involvement of multiple peripheral nerves, can also occur.
Diagnosis
The diagnosis of TA-related neuropathy involves a combination of clinical findings, imaging (e.g., MR angiography), and electrophysiological tests. Laboratory markers such as elevated ESR and CRP indicate systemic inflammation but are not specific.
Treatment
Treatment of neuropathy in TA focuses on controlling the underlying vasculitis with immunosuppressive therapy. Corticosteroids are the first-line treatment, often combined with steroid-sparing agents such as methotrexate or azathioprine when needed. Rituximab, or tocilizumab, an IL-6 receptor inhibitor, is sometimes used for refractory cases. Neuropathic pain can be managed with medications such as gabapentin or pregabalin. Early diagnosis and treatment are critical to preventing irreversible nerve damage.
Prognosis
The prognosis of neuropathy in TA depends on the speed of treatment initiation and the extent of vascular involvement affecting the nerves. Regular follow-ups are essential to monitor disease progression and prevent relapses.
