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Neurology > Inflammatory and Demyelinating Diseases
Polyarteritis Nodosa
Article Last Updated: Sep 28, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Steve Chung, MD, Residency Director; Director, Clinical Epilepsy Research, Department of Neurology, Assistant Professor of Clinical Neurology, Barrow Neurological Institute
Steve Chung is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, American Medical Association, California Medical Association, and Phi Beta Kappa
Editors: Christopher Luzzio, MD, Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center; Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Author and Editor Disclosure
Synonyms and related keywords:
PAN, microscopic polyangiitis, systemic necrotizing vasculitis, arteritis nodosa, Kussmaul disease, Kussmaul's disease, periarteritis nodosa, microscopic polyarteritis, polyarteritis nodosa
Background
Polyarteritis nodosa (PAN) is a rare systemic vasculitis necrotizing vasculitis characterized by necrotizing inflammation of small- and medium-sized arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. PAN was first described by Kussmaul and Maier in 1866. In 1948, the term microscopic polyarteritis was introduced into the literature by Davson. Subsequently, the Chapel Hill Consensus Conference on the nomenclature of systemic vasculitis held in 1992 officially adopted the term polyarteritis nodosa.
Clinically, PAN affects multiple systems, including renal, musculoskeletal, nervous, gastrointestinal, integumentary, cardiac, and genitourinary. However, the lungs are usually spared with PAN. Signs and symptoms of this disease are primarily attributable to diffuse vascular inflammation and ischemia of affected organs.
Pathophysiology
Characteristic of PAN is a necrotizing inflammation of small and medium-sized muscular arteries. Lesions are segmental and tend to involve bifurcations and branches of arteries. Involvement of venules is not seen with classic PAN.
Acute stage: Polymorphonuclear neutrophils infiltrate all layers of the vessel wall.
Subacute stage: Infiltration of mononuclear cells becomes more prominent.
Chronic stage: Fibrinoid necrosis of the vessels causes thrombosis and tissue infarction. Aneurysmal dilatations of the involved arteries, as large as 1 cm in size, are characteristic findings of PAN.
Kidney lesions show predominant arteritis without glomerulonephritis; however, in patients with severe hypertension, glomerulosclerosis may be superimposed with glomerulonephritis. Pulmonary arteries are not involved and bronchial artery involvement is uncommon.
Frequency
United States
Incidence is about 3-4.5 cases per 100,000 population per year.
International
Incidence is in the range of 1.8-6.3 cases per 100,000 per year in most populations; however, it is as high as 7.7 cases per 100,000 population in certain groups in which hepatitis B is endemic.
Mortality/Morbidity
When left untreated, the 5-year survival rate of PAN is 13%. Nearly half of patients die within the first 3 months of onset. Corticosteroid treatment improves the 5-year survival rate to 50-60%. When the steroid is combined with other immunosuppressants, the 5-year survival rate may increase to greater than 80%.
- Cause of death: Renal failure is the most common cause, followed by CNS disease. Other causes include GI complications (bowel infarcts and perforations) and cardiovascular pathology.
- Intractable hypertension contributes to morbidity and mortality rates.
- Fever, weight loss, and malaise are present in 50% of patients; renal failure and hypertension in 60%; arthritis, arthralgia, and myalgia in 64%; peripheral neuropathy and mononeuritis multiplex in 51%.
Race
No racial predisposition is known.
Sex
Men are affected more frequently than women (male-to-female ratio 1.6:1).
Age
Onset is usually in adults aged 40-60 years.
History
Patients typically present with nonspecific signs and symptoms such as fever, weakness, headache, abdominal pain, weight loss, and malaise. PAN may involve any organ system.
- Renal system: About 60% of patients with PAN have renal involvement. Ischemic changes in the glomeruli can cause renal failure or hypertension.
- Musculoskeletal system: Symptoms manifest as arthritis, arthralgia, or myalgia.
- Central nervous system: Transient symptoms of cerebral ischemia, including typical spells of transient monocular blindness, are the most commonly presenting neurologic deficit of polyarteritis nodosa. Cerebral arteritis usually presents late in the course of the disease, usually in the second to third year of the vasculitis. Cerebral arteritis may cause arterial thrombosis with cerebral ischemia or intraparenchymal or subarachnoid hemorrhage. Global CNS dysfunction with encephalopathy and seizures results from metabolic derangements secondary to multiple organ failure. Acute or subacute myelopathy with paraparesis can occur at any cord level. Myelopathy may result, although rarely, from cord compression by an extramedullary hematoma secondary to a ruptured spinal aneurysm.
- Peripheral nervous system: Peripheral neuropathy develops in as many as 60% of patients. Vasculitic neuropathy is often asymmetric and presents as (1) mononeuritis multiplex, (2) distal polyneuropathy, or (3) cutaneous neuropathy. It often takes the form of mononeuritis multiplex or of a pure motor, sensory, or mixed sensorimotor polyneuropathy.
- GI tract: GI involvement presents as specific and nonspecific symptoms and signs such as abdominal pain, nausea and vomiting, bleeding, bowel infarction and perforation, cholecystitis, hepatic infarction, or pancreatic infarction.
- Skin: About 40% of patients manifest dermatologic symptoms and signs including rash, purpura, nodules, cutaneous infarcts, livido reticularis, and Raynaud phenomenon.
- Cardiovascular system: Cardiac disease affects 35% of patients with PAN. The symptoms and signs include congestive heart failure, myocardial infarction, and pericarditis.
- Genitourinary system: Patients may develop pain over the testicular or ovarian area.
Physical
Since PAN is a systemic disease, a complete systemic and neurologic examination is essential for diagnosis.
- Systemic examination
- Skin rash or nodules
- Raynaud phenomenon
- Congestive heart failure
- Pericarditis
- Bowel infarction
- Cholecystitis
- Arthritis
- Hypertension
- Renal failure
- Neurologic examination
- Peripheral neuropathy (sensorimotor)
- Encephalopathy
- Sensory deficit with cord level
- Focal weakness or hemiparesis
- Occasionally, a "locked-in syndrome" develops in a patient with PAN, caused by infarction of the basis pontis following occlusion of the proximal and middle segments of the basilar artery. The patient is quadriplegic and unable to move the lower face or speak, but the sparing of the pontine tegmentum leaves the patient conscious, with preserved vertical eye movements and blinking.
Causes
- Approximately 30% patients with PAN are positive for hepatitis B surface antigen.
- In these patients, hepatitis B antigen and circulating hepatitis B antigen-antibody aggregate in the serum and in vascular lesions.
- This finding suggests that PAN results from complexes of antibodies and exogenous antigen, such as hepatitis B antigen.
Amyloid Angiopathy
Cerebral Aneurysms
Dermatomyositis/Polymyositis
Systemic Lupus Erythematosus
Vasculitic Neuropathy
Other Problems to be Considered
Wegener granulomatosis (WG) involves both pulmonary and renal systems. WG is associated almost exclusively with the cytoplasmic type of antineutrophil cytoplasmic antibody (c-ANCA) but not with the perinuclear type of antineutrophil cytoplasmic antibody (p-ANCA). In PAN, both c- and p-ANCA can be found, although p-ANCA more commonly is associated with the condition.
A clear distinction should be made between limited disease versus systemic disease and idiopathic PAN versus hepatitis B–related PAN because differences exist in the implicated pathogenetic mechanisms, their treatment, and prognosis.
Lab Studies
- Antineutrophil cytoplasmic antibody (ANCA) test: No diagnostic serologic tests are available for PAN. Positive p-ANCA titers often are found; however, they are not diagnostic.
- Other tests
- Serum leukocytes usually are elevated, with neutrophil predominance.
- Erythrocyte sedimentation rate is almost always elevated.
- Hypergammaglobulinemia is found in 30% of patients with PAN.
Imaging Studies
- Arteriogram reveals microaneurysms in the small and medium-sized arteries of the kidneys and abdominal viscera.
- New MRI techniques, including susceptibility for blood, diffusion, and perfusion-weighted images, make it a very powerful tool to differentiate hemorrhage from potentially reversible ischemia.
Other Tests
- EEG shows generalized slow wave activity during periods of encephalopathy or toxic delirium.
- Cerebrospinal fluid findings often are normal.
Procedures
- Biopsy of small arteries from the abdominal viscera in conjunction with arteriography facilitates identification of the vasculitis.
Histologic Findings
Microscopic polyangiitis is seen with PAN but not exclusively, for it also is observed in WG.
Medical Care
Currently, corticosteroids plus cyclophosphamide is the standard of care for idiopathic PAN and for patients with more severe disease. This combination can provide prolonged survival for these patients. In contrast, for hepatitis B–related PAN, treatment consists of schemes that include plasmapheresis and antiviral agents. Treatment may include a regimen of prednisone (1 mg/kg/d) and cyclophosphamide (2 mg/kg/d). In general, patients respond better to combined therapy with immunosuppressants and corticosteroids than to steroids alone (see Mortality/Morbidity).
Surgical Care
Microcoil embolization of cerebral aneurysm may be indicated.
Consultations
- Cardiologist
- Gastroenterologist
- Dermatologist
- Rheumatologist
- Neurologist
- Physiatrist: Physical and occupational therapies are initiated promptly. Once the patient's condition is stable, ambulation and maximizing activities of daily living are the chief goals.
Immunosuppression has been the standard therapy for PAN. Recent data suggest that a combination of 2 or more different immunosuppressants can improve the outcome.
Drug Category: Corticosteroids
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
| Drug Name | Prednisone (Deltasone, Orasone, Sterapred) |
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| Description | May inhibit cyclooxygenase, which in turn inhibits prostaglandin biosynthesis. These effects may result in analgesic, antipyretic, and anti-inflammatory activities. |
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| Adult Dose | 1 mg/kg/d PO |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease |
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| Interactions | Estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism (consider increasing maintenance dose); monitor for hypokalemia when diuretics are coadministered |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Abrupt discontinuation may cause adrenal crisis; serious adverse reactions with long-term use include hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections |
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Drug Category: Alkylating/antineoplastic agents
These agents inhibit cell growth and proliferation.
| Drug Name | Cyclophosphamide (Cytoxan, Neosar, Procytox [Canada]) |
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| Description | 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. |
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| Adult Dose | 2 mg/kg/d IV |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity; severely depressed bone marrow function |
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| Interactions | Allopurinol may increase risk of bleeding or infection and exacerbate myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity |
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| Pregnancy | D - Unsafe in pregnancy
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| Precautions | Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis |
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| Drug Name | Methotrexate (Rheumatrex, Folex, Abitrexate, Methotrate, Mexate) |
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| Description | Unknown mechanism of action in treatment of inflammatory reactions; may affect immune function. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust dose gradually to attain satisfactory response. |
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| Adult Dose | 5-7.5 mg/wk PO/IM |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia) |
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| Interactions | Coadministration with NSAIDs may be fatal
Oral aminoglycosides may decrease absorption and blood levels; charcoal lowers levels; etretinate may increase hepatotoxicity; folic acid or its derivatives contained in some vitamins may decrease response; indomethacin and phenylbutazone can increase plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity; may increase plasma levels of thiopurines |
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| Pregnancy | D - Unsafe in pregnancy
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| Precautions | Monitor CBC counts monthly, and liver and renal function q1-3mo, during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated levels, eg, dehydration)—discontinue if significant drop in blood counts; has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested) |
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Further Outpatient Care
- PAN is a chronic disease with diverse neurologic features, which are multifocal and fluctuating. Patients should be educated about the future complications and the risks associated with long-term use of immunosuppressants. Patients are monitored carefully for the following symptoms:
- Headache
- Uncontrolled hypertension
- Dementia
- Psychosis
- Encephalopathy
- Stroke
- Peripheral neuropathy
Complications
- Stroke
- Encephalopathy
- Myelopathy
- Heart failure
- Myocardial infarction
- Pericarditis
- Renal failure
- GI bleeding
- Bowel infarction
- Peripheral neuropathy
Prognosis
- PAN carries a high mortality rate when untreated. Nearly one half of patients die within the first 3 months of onset. Corticosteroid treatment improves the 5-year survival rate to 50-60%. When it is combined with other immunosuppressants, the 5-year survival rate may increase to greater than 80%.
Patient Education
- The benefits of medical treatments should be discussed clearly with the patient. Many patients will attempt to discontinue their medications after initial symptomatic improvement due to the potential side effects. Patients should understand that PAN is a progressive systemic disease, and that further complications and involvement of other organ systems are quite common. They should be monitored closely for many years to come with appropriate immunosuppressive therapy.
Medical/Legal Pitfalls
- Many neurologic and systemic disorders can present with headache. Pathological headaches are often difficult to differentiate from benign headaches solely on clinical grounds. Persisting severe headaches, with or without neurologic deficit, warrant complete neurologic evaluation including brain-imaging studies.
- Even though stroke is a late complication in many cases, it certainly can occur early. PAN and other vasculitic diseases should be considered in many patients with stroke with multiple foci or combination of hemorrhage and infarction.
- Evidence of peripheral neuropathy should be sought carefully with history and electromyography (EMG), since it is a common complication of PAN (as many as 60% of patients). Mononeuritis multiplex is the most common form of PAN neuropathy, but other forms can be present.
| Media file 1:
Polyarteritis nodosa (PAN) is characterized by fibrinoid necrosis of the arterial wall with a leukocytic infiltrate. In this slide, a large pale occlusion of a muscular artery can be seen. Within this collagenous tissue is a leukocytic infiltrate, which is the hallmark of PAN. Courtesy of Urbana Atlas of Pathology. |
 |  View Full Size Image | |
Media type: Photo
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Polyarteritis Nodosa excerpt Article Last Updated: Sep 28, 2006
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