AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Wegener granulomatosis (WG) is distinguished from other vasculitides by the pattern of organ involvement and by the histologic features of granulomatosis and necrotizing inflammation. Primary involvement occurs in upper and lower respiratory tracts and kidneys (ie, glomerulonephritis). Neurological involvement, seen primarily as cranial neuropathies and peripheral neuropathies, occurs in about 34% of cases. Other commonly affected organs include skin and salivary glands.

The pathogenesis of WG is unknown; some have proposed that an inhaled allergen and/or infectious agent may provoke the disease in susceptible individuals, because limited evidence indicates a possible association with a history of pulmonary infections. Human leukocyte antigen associations have been sought, but no consistent or convincing evidence of such associations has emerged. WG is referred to as a likely autoimmune disease, given the multiple mechanisms by which the characteristic neutrophil cytoplasmic antibodies found in serum in this disease are capable of mediating immune injury in tissues.

Pathophysiology

The lungs may be affected acutely with alveolitis. Necrotizing granulomatosis develops and initially may appear histologically as microabscesses or geographic (irregularly shaped areas) necrosis, surrounded by palisading histiocytes. Granulomas may be either intravascular or extravascular. Arteritis may involve medium and small vessels, both venous and arterial; pathologic specimens generally show both acute and chronic inflammation. Vascularized scarring may be permanent.

The renal lesion of WG is usually a necrotizing glomerulonephritis; however, many types of nephritis may be seen. Granulomatous inflammation may be seen occasionally around glomeruli or may involve small renal arteries. When pathologic specimens are reviewed, lymphomatoid granulomatosis (LG) should be kept in mind, since this disorder has overlapping features with WG and this diagnosis also requires lung biopsy in most cases. LG specimens mostly are distinguished by monoclonal atypical lymphocytes, smaller less-destructive granulomas, and less vessel-wall invasion. Subspecialty pathologists often are consulted in these cases.

Although neurological involvement is fairly common in WG, reports of pathologic specimens are sparse and findings are nonspecific. The few large patient series that are available indicate that about one half of patients manifested neurological involvement in WG prior to the advent of cyclophosphamide treatment; however, only one fourth exhibited neurological WG in a more recent study.

Nishino et al presented the definitive work on neurological involvement of WG. Of 324 patients reviewed, the majority were affected by peripheral neuropathy or cranial neuropathies. A pattern of symmetrical polyneuropathy was seen in some patients, but peripheral neuropathy most often manifests as acute mononeuritis multiplex. Cranial nerves II, VI, and VII are affected most commonly, either by direct vasculitic injury, compression, extension of granulomatous disease from adjacent sinuses, or cavernous sinus thrombosis (see Physical for ocular involvement). As with cerebral parenchymal lesions, injury can occur due to direct effects of inflammation, tissue ischemia due to thrombosis of inflamed blood vessels, or compression due granulomatous tissue formation and edema.

The following is a tally of nervous system involvement in a subsample (n = 324) of WG patients:

• Peripheral neuropathy - 53 patients
• Mononeuritis multiplex - 42 patients
• Cranial neuropathies - 21 patients
• External ophthalmoplegia - 16 patients
• Seizures - 10 patients
• Cerebritis - 5 patients
• Stroke syndrome - 13 patients

Thirty-three percent of patients experienced central or peripheral nervous system involvement in this large series. Cerebral parenchyma may be affected by either cerebritis or stroke syndromes. The most common peripheral nerve injury encountered was peroneal neuropathy, followed by tibial, sural, median, and ulnar neuropathies. Rarely reported neurological disorders include myopathy, aseptic meningitis, and diabetes insipidus. Although WG rarely presents as a neurological illness (9 [3%] of 324) presented as ophthalmoplegia in this series), a few patients presenting with signs of meningeal inflammation have been reported recently in whom diffuse dural enhancement was seen on MRI.

Frequency

International

WG appears to be a rare disease with an incidence of approximately 0.4 case per 100,000 population.

Mortality/Morbidity

Permanent residua occur in many patients with WG, but the mortality rate is very low in patients treated with the usual immunosuppressant regimens (precise data concerning mortality rates in neurological WG are not available).

Race

WG has been observed in persons from all racial groups but is rare in blacks compared with whites.

Sex

A slight male predominance has been reported.

Age

WG can occur in persons of any age; reports indicate onset ranging from individuals as young as 3 months to very elderly persons. The peak incidence is in the fourth and fifth decades of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The diagnosis of WG is suspected when patients present with chronic sinusitis, nasal ulceration, other upper respiratory tract symptoms, or lower respiratory symptoms of hemoptysis, dyspnea, or cough.
• Symptoms of renal involvement are much less common, although renal involvement is often clinically evident at presentation. Manifestations include proteinuria, hematuria, and renal insufficiency.
• Constitutional symptoms such as fever, weight loss, and anorexia may suggest systemic disease.
• Ocular symptoms are common (referable to involved cranial nerves or orbital structures).
• As indicated in the discussion in Pathophysiology, presentations of neurological WG are extremely varied, with manifestations in the CNS such as seizures, altered cognition (ie, cerebritis), focal motor and sensory complaints, and stroke syndromes. Presentations may involve chronic, acute, or stepwise deterioration referable to parenchymal or meningeal inflammation and scarring, and this variable tempo of onset also may be seen in the associated peripheral nerve syndromes and cranial neuropathies. A history of headaches and other symptoms related to inflammation of meningeal or parenchymal structures should be sought initially and on follow-up visits.

Physical

• Ocular manifestations of WG include the following:
• • Proptosis
  • Episcleritis
  • Cavernous sinus thrombosis
  • Corneoscleral ulcers
  • Dacryocystitis
  • Uveitis
  • Conjunctivitis
  • Retinal occlusion/cherry-red spot
  • Scleritis
  • Afferent pupillary defect, decreased acuity (optic neuritis)
  • Ophthalmoplegias (nuclear or supranuclear)
• Other neurological signs/syndromes
• • Delirium (cerebritis)
  • Hemiparesis (stroke, cerebritis)
  • Other cranial neuropathy (potentially any cranial nerve)
  • Seizure (mass lesion)
  • Spasticity, hyperreflexia, Babinski sign (ie, upper motor neuron signs)
  • Weakness, numbness (neuropathy)

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Lymphoma and other multifocal (metastatic) neoplasms
Lymphomatoid granulomatosis (lung and cerebral involvement)
Other disorders causing inflammation or infection of various organs, including sarcoidosis
Carotid disease and stroke

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Laboratory diagnosis of WG has been assisted greatly by emergence of testing for c-antineutrophil cytoplasmic antibody (ANCA) levels, which if elevated, are 97% specific for WG. Testing for c-ANCA is 90% sensitive for the diagnosis when the presentation is classic, involving both upper and lower respiratory system and kidneys; sensitivity drops to 40% in limited WG (ie, limited to only kidneys or respiratory system).
• Along with other markers of inflammation such as C-reactive protein and erythrocyte sedimentation rate, c-ANCA can be used to monitor disease and response to therapy, but cannot reliably predict potential for disease relapse.
• Other laboratory abnormalities often seen include anemias, thrombocytosis, hypergammaglobulinemia, and rarely cryoglobulins or circulating immune complexes; rheumatoid factor is found frequently.
• In cases with myopathy, creatine kinase may be elevated.

Imaging Studies

• Neuroimaging findings are nonspecific.
• Areas of cerebritis may appear as supratentorial, irregularly enhancing, edematous lesions of any size, seen on both MRI and CT scan.
• Meningeal involvement, seen as enhancement, is less common but is reported. Ischemic or hemorrhagic infarcts also may be suggested by neuroimaging.

Other Tests

• Cerebrospinal fluid (CSF) analysis: Nonspecific CSF abnormalities are found commonly (eg, mild to moderate pleocytosis, mostly lymphocytes; elevated protein; elevated immunoglobulin G production) and may provide clues toward ruling in an inflammatory process (ie, WG).

Procedures

• In patients with neurological involvement, electromyography (EMG), nerve conduction studies, CSF analysis, and MRI are the primary investigations used to localize the lesions. EMG and nerve conduction studies may reveal acute and/or chronic denervation in involved muscles, slowed nerve conductions, decreased amplitude of action potentials, and myopathy. A typical picture would involve few to several nerves in an asymmetrical pattern (ie, mononeuritis multiplex).

Histologic Findings

Definitive diagnosis is based on biopsy.

• A characteristic chest radiograph showing pulmonary infiltrates and nodules may suggest a high yield for positive confirmation by transbronchial biopsy or open lung biopsy (yield is highest with open biopsy).
• Renal biopsy is rarely definitive, since the histopathology is generally less specific than that of the lungs.
• Biopsy of the nasal mucosa shows more distinctive features of WG and has a low rate of associated morbidity.
• Biopsy of sural nerve may demonstrate vasculitis with noncaseating granulomas, affecting small arteries. Lesions may contain acute and chronic inflammatory features of vasculitis with focal areas of demyelination.
• Autopsy studies in neurological WG are sparse and, although cerebral vasculitis sometimes has been assumed clinically in patients with infarctions (and seizures), tissues usually appear bland. Similarly, angiography may miss small-vessel vasculitis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Various medication regimens involving immunosuppressants are administered (ie, combinations of steroids and cyclophosphamide, azathioprine, or methotrexate primarily). The authors suggest that most patients with WG have their condition stabilized initially by administering pulse steroids along with cyclophosphamide, 600-800 mg/m²/mo for 6-12 months, followed by methotrexate at 7.5-15 mg/wk for 12-24 months as tolerated. In patients unable to tolerate cyclophosphamide, azathioprine 1.5-2.5 mg/kg/d may be substituted (see Medication).

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Initially, WG was uniformly fatal within a few months of diagnosis; the prognosis was improved minimally after institution of steroid therapy. Cyclophosphamide has since been used very effectively and now is the usual drug of choice for induction of remission. The well-recognized toxicity of oral cyclophosphamide has led to institution of pulse therapy as the present standard of care. Azathioprine may be used as maintenance therapy or as initial therapy in patients unable to tolerate cyclophosphamide. Less frequently used therapies include methotrexate.

Excellent remission is achieved in about 70% of patients, but unfortunately relapses are common. Aggressive treatment of pulmonary and renal involvement at the time of disease onset seems to lessen the probability of later neurological involvement.

Various dosing regimens for steroids have been suggested, ranging from high-dose pulse IV to continuous oral therapy, generally in addition to immunosuppressants. The adverse effects of steroids are well known and are beyond the scope of this review. Cyclophosphamide is an alkylating agent with significant potential toxicity to bone marrow, liver, and bladder, and it should be used only by experienced clinicians. Pulse IV therapy regimens (eg, 600-800 mg/m²/mo) and oral regimens (eg, 1-2.5 mg/kg/d) require careful monitoring of pertinent laboratory tests. Azathioprine and methotrexate (both antimetabolites) have similar toxic effects and also require careful monitoring. None of the immunosuppressant therapies are considered safe during pregnancy.

Drug Category: Antimetabolites

These agents inhibit cell growth and proliferation. They also have immunosuppressant properties.

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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Patients require close follow-up for response to therapy, potential relapse, and medication toxicity (serial chest radiographs, renal function tests, liver function tests, CBC count, urinalysis, and specific neurological tests such as neuroimaging). For example, in patients with active CNS inflammation clinically or by MRI, repeat MRI with contrast every 1-3 months would be reasonable.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Because WG is a treatable condition, failure to diagnose early could be seen as substandard care if presenting symptoms are classic. However, given the rarity of WG and its protean manifestations, standard of care is difficult to establish. Early diagnosis might be made possible by maintaining a low threshold for ordering c-ANCA antibody testing.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bachmeyer C, Cadranel JF, Demontis R. Rituximab is an alternative in a case of contra-indication of cyclophosphamide in Wegener's granulomatosis. Nephrol Dial Transplant. Apr 19 2005;[Medline].
• Bellisai F, Morozzi G, Marcolongo R, Galeazzi M. Pregnancy in Wegener''s granulomatosis: successful treatment with intravenous immunoglobulin. Clin Rheumatol. Dec 2004;23(6):533-5. [Medline].
• Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 9-1999. A 74-year-old woman with hydrocephalus and pleocytosis. N Engl J Med. Mar 25 1999;340(12):945-53. [Medline].
• Cohen Tervaert JW, Huitema MG, Hene RJ. Prevention of relapses in Wegener''s granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre. Lancet. Sep 22 1990;336(8717):709-11. [Medline].
• Drachman DD. Neurological complications of Wegener's granulomatosis. Arch Neurol. 1963;8:144-55.
• Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener''s granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med. Jan 1983;98(1):76-85. [Medline].
• Howell SB, Epstein WV. Circulating immunoglobulin complexes in Wegener''s granulomatosis. Am J Med. Feb 1976;60(2):259-68. [Medline].
• Kelley WN, Harris ED, Ruddy S, Sledge CB. Textbook of Rheumotology. Vol 2. 5th ed. Philadelphia, Pa: WB Saunders; 1997.
• Kerr GS, Fleisher TA, Hallahan CW, et al. Limited prognostic value of changes in antineutrophil cytoplasmic antibody titer in patients with Wegener''s granulomatosis. Arthritis Rheum. Mar 1993;36(3):365-71. [Medline].
• Moore PM. Immune-mediated vasculopathies of the central nervous system. In: Gilchrist J, ed. Prognosis in Neurology. Boston, Mass: Butterworth-Heinemann; 1998.
• Nishino H, Rubino FA, DeRemee RA, et al. Neurological involvement in Wegener''s granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann Neurol. Jan 1993;33(1):4-9. [Medline].
• Scott DG, Watts RA. Classification and epidemiology of systemic vasculitis. Br J Rheumatol. Oct 1994;33(10):897-9. [Medline].
• Spranger M, Schwab S, Meinck HM, et al. Meningeal involvement in Wegener''s granulomatosis confirmed and monitored by positive circulating antineutrophil cytoplasm in cerebrospinal fluid. Neurology. Jan 1997;48(1):263-5. [Medline].
• Travis WD, Hoffman GS, Leavitt RY, et al. Surgical pathology of the lung in Wegener''s granulomatosis. Review of 87 open lung biopsies from 67 patients. Am J Surg Pathol. Apr 1991;15(4):315-33. [Medline].
• Wegener F. [Uber eine eigenartige rhinogene Granulomatose mit besonderer Beteilgung des Arteriensytems und der Nieren]. Beitrage der Pathologischen Anatomie. 1939;102:30-68.

Article Last Updated: Sep 5, 2006