Peripheral neuropathy is common in many vasculitic syndromes and may be the only manifestation of the underlying vasculitic disease.
Vasculitic neuropathy can be a part of systemic vasculitis. It also can present as a nonsystemic vasculitic neuropathy, without any constitutional symptoms or serologic abnormalities. The clinical and pathologic features are those of an ischemic neuropathy caused by a necrotizing vasculitis of small arterioles.
Patients with vasculitic neuropathy may present with either mononeuritis multiplex or asymmetric sensorimotor neuropathy. Symmetric neuropathy is rare. It can present as acute/subacute relapsing, progressive, or relapsing progressive neuropathy.
Asymmetric or multifocal painful sensorimotor neuropathy is the most common presentation.
Asymmetry and length-independent involvement are the hallmarks of mononeuritis multiplex, which is the most common presenting feature of vasculitic neuropathy.
Peripheral neuropathy due to vasculitis without manifestations of disorders in other systems was first reported by Kernohan and Woltman in 1938.[1] In 1987, Dyck et al described characteristic features of 20 cases of vasculitic neuropathy with no or few clinical symptoms of systemic disease or serological abnormalities. They proposed the term of nonsystemic vasculitic neuropathy (NSVN).[2] In 1996, Davies et al reported 25 patients with vasculitis confined to peripheral nerves using the term isolated peripheral nervous system vasculitis (IPNSV).[3] A few reports describe patients with vasculitis selectively affecting the peripheral nervous system.[4, 5, 6, 7, 8, 9, 10] The largest study (48 patients) was reported by Collins et al in 2003.[11]
Wallerian degeneration of nerves results from ischemic infarction caused by inflammatory occlusion of the blood vessels. Segmental fibrinoid necrosis of a vessel wall and transmural inflammatory cell infiltration are the main pathologic features of vasculitis. Leukocytoclastic reaction traditionally has been considered the primary mechanism of vessel injury in these diseases, although more recent evidence suggests that cellular-mediated mechanisms may be more important in the peripheral nerve.
Immune complexes are formed as a result of antibodies reacting with antigen found within the blood vessel walls. These immune complexes within the circulation activate the complement cascade, generating chemotactic factors responsible for recruitment of polymorphonuclear leukocytes at the local site of deposition of the complex. Degranulation of the polymorphonuclear leukocytes releases proteolytic enzymes, which, along with free radicals, disrupt cell membranes and damage blood vessels. T cell–mediated processes against epineurial and endoneurial vessels likely are also important in the pathogenesis of vasculitic neuropathies.
Necrotizing vasculitis causes neuropathy through ischemic injury to the vessels supplying the nerve. Poor collateral circulation in the nerves makes them susceptible to ischemic injuries. Commonly involved nerves with these features tend to be in the mid upper arm and mid thigh in the "watershed zone."
Vasculitic neuropathy most often presents as mononeuropathy multiplex (ie, in more than 60% of patients), with the peroneal nerve most commonly affected (89% of patients), followed by the sural nerve (84%), tibial nerve (68%), ulnar nerve (42%), and median nerve (26%).
Distal symmetric polyneuropathy is the second most common presentation, seen in less than one third of patients. The nerves most often affected clinically are a diffuse mix of distal more than proximal lower limb nerves, arising either from the lumbosacral plexus or from widespread multifocal nerve involvement (ie, summation of existing patchy lesions).
Cranial nerve involvement also has been reported in systemic vasculitis. Facial nerve neuropathy is observed most commonly, occasionally accompanied by abnormalities in cranial nerve III, VI, or X.
Diagnostic classification of peripheral vasculitic neuropathy (see image below)
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Diagnostic classification of peripheral vasculitic neuropathy (PVN).
Peripheral neuropathy occurs in 60-70% of patients with some systemic vasculitic syndromes. Several reports have noted that approximately 34% of patients with vasculitis have disease restricted to the peripheral nervous system, termed nonsystemic vasculitic neuropathy.[1, 13, 2, 3, 11, 14]
Relapse rates observed in systemic vasculitides range from 11-60%[15] when all manifestations are included (neurologic and systemic). Relapse occurred almost exclusively in patients treated with prednisolone alone. Aggressive early treatment with cyclophosphamide may prevent relapse.
Peripheral nervous system involvement is an American College of Rheumatology (ACR) diagnostic criterion for polyarteritis nodosa and Churg-Strauss syndrome; it occurs in 50-78% of patients.[16, 17, 18, 19] The reported incidence of vasculitic peripheral neuropathy in primary vasculitides has varied from 20-80%[20] , reflecting the clinicopathological overlap between individual syndromes and associated nosological uncertainty.
Mortality/Morbidity
No controlled studies document mortality rate, but death generally is secondary to systemic complications of the vasculitis. Chance of recovery is better in nonsystemic vasculitic neuropathy, with good recovery for most patients.
Mathew et al found that 1-year survival was 90.3%, with death occurring predominantly in older patients with severe multisystem disease.[12]
Studies have shown that morbidity and mortality rates tend to be very high if the condition is untreated and systemic or if the condition is misdiagnosed.
In one study, final disability in those who survived more than 24 month was no sign or symptoms in 17%, mild-to-moderate disability in 65%, moderately severe disability in 13%, and severe disability in 4%. Chronic pain was persistent in more than 60% of patient in this study.
One cohort study showed a 5-year survival rate of 87%.
Race
The racial distribution of vasculitic neuropathy is unknown.
Vasculitic neuropathy can present as acute/subacute relapsing, progressive, or relapsing progressive neuropathy.
Asymmetric or multifocal painful sensorimotor neuropathy is the most common presentation.
Duration of neuropathy symptoms before biopsy or diagnosis ranges from 3 weeks to 5 years (mean 8 ± 11 mo).
Constitutional symptoms, including weight loss, anorexia, fatigue, arthralgias, myalgias, and fevers, occur in about two thirds of patients.
Neuropathies are painful in more than 80% of patients.
About 75% of patients experience at least one acute attack, but about 25% have an indolent slowly progressive course from onset. In about half of all patients, the neuropathy follows an acute relapsing course.
Typically, the initial symptom of vasculitic neuropathy is acute pain poorly localized in the affected area or limb. Deep aching and burning pain or tingling in the affected nerve distribution appears a few days later. This is followed by weakness in the distribution of the involved nerve.
A thorough neurologic examination can assist in localizing the involved nerve(s). In general, the patient presents with asymmetric neurological symptoms involving the peripheral nerve(s), with pain and dysesthesias as initial symptoms followed by weakness.
Weakness in vasculitic neuropathy is mostly focal and presents acutely. On examination, about three quarters of patients have an asymmetric polyneuropathy, either as a multiple mononeuropathy or, less commonly, as an asymmetric polyneuropathy (ie, overlapping multiple mononeuropathies).
Legs are more commonly involved than arms. Distal involvement is more frequent than proximal involvement.
Cranial nerve involvement occurs in 8% of patients, typically involving cranial nerve VII. Asymmetrical lumbosacral plexopathy occurs in 8%. In a small percentage of patients, pure dermatomal sensory loss can also be involved.
A proximal symmetric polyneuropathy is the least frequent presentation.
Pure motor neuropathy is almost unheard of.
Vasculitic neuropathy is unlikely in patients with no asymmetries, pure motor involvement, no pain, and entirely proximal findings.
Peroneal nerve: Patient has weakness of foot dorsiflexion and usually presents with foot drop or slapping gait.[21]
Tibial nerve: Patient has weakness of foot plantar flexion and inversion. Patient may present with unstable gait.
Ulnar nerve: Patient is unable to spread fingers and flex the distal phalanx of the fourth and fifth digits. Weakness of other ulnar-innervated intrinsic hand muscles also is noted.
Median nerve: Patient displays weakness of finger and wrist as well as weakness of other median-innervated intrinsic hand muscles.
Radial nerve: Wrist drop is the most striking clinical presentation of radial nerve palsy. Elbow extension weakness also may be present.
Sensory findings are frequent and usually are the initial presentation of vasculitic neuropathy. Whereas most patients exhibit mixed sensorimotor findings on examination, about 10% have a pure or predominant sensory neuropathy. Both large-fiber and small-fiber sensory modalities are affected in about 90%, with predominant large-fiber loss in the rest.
Burning dysesthetic pain over the distribution of involved nerve is associated with altered or decreased sensation. Large sensory fiber involvement is seen frequently, presenting as decreased vibration sensation and proprioception in affected limbs.
Patients with a previous misdiagnosis or those presenting after the acute inflammatory phase has subsided can present with neuropathic pain. This can be mild tingling or numbness to severe dull or burning pain with or without sensory loss.
Hyporeflexia or areflexia, which can be asymmetric, is observed.
Findings inconsistent with a diagnosis of vasculitic neuropathy include the following:
Causes of vasculitic neuropathy can be classified on the basis of size of the vessels or primary versus secondary vasculitis. A simple classification is based on systemic vasculitis, causing vasculitic neuropathy with other constitutional symptoms or serologic abnormalities, versus nonsystemic vasculitis, which presents as neuropathy only.
Systemic vasculitis
Systemic necrotizing vasculitis
These vasculitides classically involve small and medium-sized arteries affecting multiple organ systems, including the peripheral and central nervous systems. Polyarteritis nodosa is the most common necrotizing vasculitis, with greater than 50% involvement of peripheral nerves. The necrotizing vasculitides include the following:
Polyarteritis nodosa
Churg-Strauss syndrome
Wegener granulomatosis
Overlap syndrome
Cryoglobulinemia
Hypersensitivity vasculitis
These vasculitides classically involve small vessels, including capillaries, arterioles, and venules. They rarely cause irreversible dysfunction of vital organs and have better prognosis than systemic necrotizing vasculitides. Trigger is usually endogenous or exogenous antigen exposure. Cutaneous manifestations dominate the clinical picture but involvement of other organs and the peripheral nervous system also is noted. The hypersensitivity vasculitides include the following:
Henoch-Schönlein purpura
Serum sickness
Infectious vasculitis (eg, HIV, hepatitis B)
Drug-induced vasculitis (eg, cocaine, heroin)
Neoplasm (eg, chronic lymphocytic leukemia)
Cryoglobulinemia
Behçet syndrome
Giant cell arteritides
These vasculitides classically involve large and medium-sized vessels. Giant cell formation with mononuclear cell infiltrates is seen frequently. Peripheral neuropathy is rare and is seen in less than 15% of patients with temporal arteritis. The giant cell arteritides include the following:
Temporal arteritis
Takayasu arteritis
Connective tissue disease
Patients with connective tissue disease can present with systemic necrotizing vasculitis or hypersensitivity vasculitis. Rheumatoid arteritis (RA) is the connective tissue disease that most often causes vasculitis. Vasculitis develops in 8-25% of patients with RA, usually 10-15 years after onset of RA. Overall, vasculitic neuropathy occurs in 40-50% of patients with systemic vasculitis. Systemic lupus erythematous presents as polyneuropathy in 6-21% of patients. Connective tissue diseases most often associated with vasculitis include the following:
Rheumatoid arteritis
Systemic lupus erythematous
Sjögren syndrome
Systemic sclerosis
Nonsystemic vasculitic neuropathy
Localized vasculitis affects either the central nervous system (primary central nervous system angiitis) or the peripheral nervous system. Nonsystemic vasculitic neuropathy involves small and medium-sized arteries.
Clinical and histologic presentation is similar to that of neuropathy observed in systemic vasculitis but without any other organ involvement.
Nonsystemic vasculitic neuropathy represents one third of all vasculitic neuropathies. Prognosis is better than that of systemic vasculitic neuropathy.
Paraneoplastic vasculitic neuropathy
Paraneoplastic vasculitic neuropathy is a rare paraneoplastic syndrome characterized by nonsystemic subacute vasculitic neuropathy. The cancers most commonly associated with paraneoplastic vasculitic neuropathy are small cell lung cancer and lymphomas.
Laboratory studies are more helpful in systemic than nonsystemic vasculitis; however, obtain the following studies in any patient in whom vasculitic neuropathy is suspected. In general, place the results in the context of the clinical presentation for a diagnosis. For those individuals with multiple high levels of the inflammatory markers listed here, consultation with a rheumatologist is strongly recommended.
Nonsystemic vasculitic neuropathy has a better prognosis than systemic vasculitic neuropathy. The former may have normal laboratory results, while systemic vasculitis often features elevated antinuclear antibody (ANA) titers, erythrocyte sedimentation rate (ESR), and other more specific markers of disease.
ESR (high, after age adjusted) - More than 70% of patients show ESR >20 mm/h
Antinuclear antibody titer (high in systemic diseases associated with vasculitic neuropathy)
Extractable nuclear antigens, p-ANCA and c-ANCA
Rheumatoid factor
Antineutrophil cytoplasmic antibodies
Hepatic enzymes
Renal function tests
Serum complement
Serum immunoelectrophoresis (or immunofixation) and quantitative immunoglobulins
Cryoglobulins
Hepatitis B antigen and antibody
Hepatitis C antigen
Routine cell count and serum electrolytes are indicated. Anemia is present in up to 30% of patients.
Serum analysis for other common causes of neuropathy, including hemoglobin A1c (HbA1c) and fasting glucose to rule out diabetes, thyroid function tests, B-12 and folate, and rapid plasma reagent (RPR).
CSF analysis can show high protein levels (>50 mg) in a small percentage of patients.
Brain imaging studies are usually not necessary, and a central nervous system etiology can be excluded comfortably by an accurate neurologic examination.
Magnetic resonance imaging (MRI) of the spine can be helpful in excluding a spinal nerve root lesion when suggested.
Electrodiagnostic testing is essential in making the diagnosis of any neuropathy, especially in vasculitic neuropathy. Electrodiagnostic testing can help accurately define the pathophysiology and localize the extent and distribution of the neuropathy. It also can provide information on whether the disease is active in the form of signs of active denervation, which accordingly facilitates choice of treatment protocol.
The predominant electrophysiologic feature of vasculitic mononeuropathy multiplex is axonal loss. "Conduction block" in vasculitic mononeuropathy multiplex is secondary to focal axonal conduction failure, presumably related to infarct of the axon.
Needle electromyography can demonstrate denervation potentials. Presence of positive sharp waves and fibrillation potentials indicates active denervation. Amplitude and duration of motor units assess the duration of axon loss and the presence of reinnervation changes. Recruitment pattern identifies the amount of functional axonal loss.
Tissue diagnosis is the criterion standard in making the diagnosis of vasculitic neuropathy and is recommended in the presence of any doubtful clinical picture or if ultimate diagnosis is required.
Biopsy may not be necessary if the clinical presentation of multifocal neuropathy is confirmed by electrodiagnostic testing and other systemic signs of vasculitis are present. Many academic institutions perform biopsy initially.
Sural nerve, superficial peroneal nerve, and muscle tissues (peroneus brevis) are most suitable for biopsy.
Blood vessels are infiltrated by inflammatory cells with signs of vascular injury including endothelial cell disruption, fragmentation of the internal elastic lamina, and fibrinoid necrosis with hemorrhage or thrombus; these findings are seen in definitive cases of nerve biopsy.
The diagnosis of peripheral nerve involvement may be established by nerve and muscle biopsies; these tissues typically exhibit inflammatory cell infiltrates and fibrinoid necrosis of the walls of blood vessels. However, the biopsy specimen may demonstrate only axonal degeneration if vasculitis has caused a nerve infarct that is proximal to the site of biopsy or if no affected vessels are encountered in the specimen.
Immunohistochemical evaluation of sural nerve biopsy specimens may be helpful in identifying patients with microvasculitis.
Pathologic features associated with necrotizing vasculitis include muscle fiber necrosis and/or regeneration, predominant axonal nerve pathology, wallerian-like degeneration, and asymmetric nerve fiber loss.
Early use of an aggressive immunosuppressive agent is indicated to treat vasculitic neuropathy.
Combination therapy with corticosteroids and cyclophosphamide is reported to be more effective than monotherapy in inducing remission and improving disability and in reducing relapse rate and chronic pain.
One cohort study shows a 61% response rate with a 59% relapse rate with corticosteroid monotherapy compared with a 95% response rate with a 29% relapse rate in combination therapy of corticosteroids and cyclophosphamide.
Treat systemic necrotizing vasculitis and nonsystemic vasculitis with a combination of prednisone and cyclophosphamide or, less commonly, azathioprine (Imuran), methotrexate, and intravenous immunoglobulin.
Administer prednisone for 2-3 months or until clinical beneficial effect is noted; then taper gradually according to the patient's response. The typical starting dose is 40-100 mg/d, which is eventually tapered to every other day dosing to avoid side effects. Cyclophosphamide is started at 100-150 mg/d.
Continue treatment for 6 months to 1 year or longer. Some patients may require long-term immunosuppression for years.
Discuss adverse affects and toxicity of long-term use of corticosteroids and immunosuppressive agents with the patient and family prior to onset of therapy.
Symptomatic treatment of neuropathic pain can be initiated with amitriptyline and/or nortriptyline, carbamazepine, or gabapentin. Other systemic manifestations of systemic vasculitis require management according to organ involvement and specialty consultation.
Systemic vasculitis can involve multiple organ systems. A multispecialty team effort is recommended.
Neurologist: Neurologist consultation is indicated for diagnosis and treatment of the disease. Neurologist consultation is necessary for electrodiagnostic studies and muscle and nerve biopsy.
Rheumatologist: Rheumatologist consultation is necessary, especially in systemic vasculitis.
Physical medicine and rehabilitation specialist: Begin physical therapy and occupational therapy as soon as the patient's condition is stable enough for therapy.
No special diet is required; however, diet precautions should be provided when corticosteroids are initiated. Patients with diabetes need careful glucose control. Patients should be on potassium supplements if long-term steroid treatment is necessary.
Most patients in the acute stage of vasculitic neuropathy can be ill if overt signs of other generalized systemic vasculitis are present. Otherwise, activity may be restricted secondary to weakness in the distribution of involved nerves. Encourage ambulation and physical therapy when the patient's condition is stable.
Treatment of vasculitic neuropathy is based on the underlying cause of the vasculitis. Not all vasculitic neuropathies are treated with similar protocols.
Clinical Context:
Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.
Clinical Context:
Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. In high doses, affects B cells by inhibiting clonal expansion and suppression of production of immunoglobulins. With long-term low-dose therapy, affects T cell functions.
These agents are required for nearly all forms of vasculitic neuropathies; however, the choice of different types of immunosuppressants is based on the underlying cause. Similarly, adjust length of treatment and doses accordingly. In severe cases, IV methylprednisolone is recommended as "pulse" therapy.
Clinical Context:
Has demonstrated effectiveness in treatment of chronic pain. By inhibiting reuptake of serotonin and/or norepinephrine by presynaptic neuronal membrane, increases synaptic concentration of these neurotransmitters in CNS. Pharmacodynamic effects such as desensitization of adenyl cyclase and down-regulation of beta-adrenergic receptors and serotonin receptors also appear to be involved in mechanisms of action. Patients developing sleep cycle disruption or insomnia can be switched to amitriptyline.
Neuropathic pain frequently is seen with axonal degeneration and is secondary to inflammation or ischemia associated with vasculitis and nerve regeneration. Peripheral nerve regeneration is a slow process and may require months after the initial exacerbation or inflammation subsides. Patients may require long-term treatment for neuropathic pain. Use NSAIDs for acute or breakthrough pain; narcotics also are used and are a risk for addiction, especially with the chronicity of the symptoms. TCAs are used as first-line drugs in low doses for chronic or neuropathic pain.
Clinical Context:
A sodium-channel blocker can provide significant relief of neuropathic pain. Adverse effect profile for older patients is more onerous than with newer anticonvulsants, thereby limiting usefulness in this group. Long-term use must be closely monitored and adjusted by treating physician.
Clinical Context:
Can be useful in treatment of neuropathic pain. Often tolerated better than carbamazepine by elderly patients. Can be used in patients with hepatic disease because undergoes renal clearance.
These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.
Vasculitic neuropathy requires prompt diagnosis and treatment to promote good outcome. In patients whose neuropathy is part of a systemic vasculitis, the neuropathy can be expected to improve, leaving only mild or moderately severe functional disability. Nevertheless, the long-term outlook for such patients is poor, with a 5-year survival rate of approximately 50%; most excess deaths are due to vascular disease. The prognosis in nonsystemic vasculitic neuropathy is substantially better than in systemic vasculitis.
Abbas Mehdi, MD, Director, MDA Center of Central California; Consulting Staff, Department of Neurology, California Neurological Center, Inc
Disclosure: Nothing to disclose.
Coauthor(s)
Said R Beydoun, MD, Chief, Professor, Department of Neurology, University Hospital, University of Southern California
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University in St Louis School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital
Disclosure: Nothing to disclose.
Chief Editor
Nicholas Lorenzo, MD, MHA, CPE, Co-Founder and Former Chief Publishing Officer, eMedicine and eMedicine Health, Founding Editor-in-Chief, eMedicine Neurology; Founder and Former Chairman and CEO, Pearlsreview; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc; Chief Strategy Officer, Discourse LLC
Disclosure: Nothing to disclose.
Additional Contributors
Norman C Reynolds, Jr, MD, Neurologist, Veterans Affairs Medical Center of Milwaukee; Clinical Professor, Medical College of Wisconsin
Disclosure: Nothing to disclose.
References
Kernohan JW, Woltman HW. Periarteritis nodosa: a clinicopathologic study with special reference to the nervous system. Arch Neurol Psychiatry. 1938. 39:655-86.
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