eMedicine Specialties > Neurology > Inflammatory and Demyelinating Diseases

Wegener Granulomatosis

Thomas F Scott, MD, Professor, Program Director, Department of Neurology, Drexel University College of Medicine; Director, Allegheny MS Treatment Center

Updated: Nov 25, 2008

Introduction

Background

Wegener's granulomatosis (Wegener granulomatosis) 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). Neurologic 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 Wegener's granulomatosis 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. Wegener's granulomatosis 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.

See eMedicine's other articles Wegener Granulomatosis (Rheumatology), Wegener Granulomatosis (Otolaryngology and Facial Plastic Surgery), Wegener Granulomatosis (Dermatology), Wegener Granulomatosis (Pediatrics).

Pathophysiology

The renal lesion of Wegener's granulomatosis 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 should be kept in mind, since this disorder has overlapping features with Wegener's granulomatosis and this diagnosis also requires lung biopsy in most cases. Lymphomatoid granulomatosis 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 neurologic involvement is fairly common in Wegener's granulomatosis, 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 neurologic involvement in Wegener's granulomatosis prior to the advent of cyclophosphamide treatment; however, only one fourth exhibited neurologic Wegener's granulomatosis in a more recent study.

Nishino et al presented the definitive work on neurologic involvement of Wegener's granulomatosis.¹ This large series remains authoritative due to its size and scope. Of 324 patients reviewed, most 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 patients with Wegener's granulomatosis:

• 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 neurologic disorders include myopathy, aseptic meningitis, and diabetes insipidus. Wegener's granulomatosis rarely presents as a neurologic illness (9 [3%] of 324 presented as ophthalmoplegia in this series). 

A few patients presenting with signs of meningeal inflammation have been reported in whom diffuse dural enhancement was seen on MRI. Similar findings have been reported in cases of neurosarcoidosis. Presentation as cerebritis with edematous masslike lesions and invasive-appearing mass lesions centered around paranasal sinuses are also reported. 

Frequency

International

Wegener's granulomatosis 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 Wegener's granulomatosis, but the mortality rate is very low in patients treated with the usual immunosuppressant regimens (precise data concerning mortality rates in neurologic Wegener's granulomatosis are not available).

Race

Wegener's granulomatosis 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

Wegener's granulomatosis 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

History

• The diagnosis of Wegener's granulomatosis 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 neurologic Wegener's granulomatosis 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 Wegener's granulomatosis 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 neurologic 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)

Differential Diagnoses

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

Laboratory Studies

• Laboratory diagnosis of Wegener's granulomatosis has been assisted greatly by emergence of testing for c-antineutrophil cytoplasmic antibody (ANCA) levels, which if elevated, are 97% specific for Wegener's granulomatosis. 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 Wegener's granulomatosis (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, Wegener's granulomatosis).

Procedures

In patients with neurologic 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 Wegener's granulomatosis 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 neurologic Wegener's granulomatosis 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

Medical Care

Various medication regimens involving immunosuppressants are administered in patients with Wegener's granulomatosis (ie, combinations of steroids and cyclophosphamide, azathioprine, or methotrexate primarily). The authors suggest that most patients with Wegener's granulomatosis 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

Initially, Wegener's granulomatosis 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 neurologic 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.

Antimetabolites

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

Cyclophosphamide (Neosar, Cytoxan)

Alkylating agent with significant potential toxicity to bone marrow, liver, and bladder. Should be used only by experienced clinicians. Well-recognized toxicity of oral cyclophosphamide has led to institution of pulse therapy as present standard of care.

Dosing

Adult

Pulse IV therapy regimens (eg, 600-800 mg/m²/mo) and PO regimens (eg, 1-2.5 mg/kg/d) require careful monitoring of pertinent laboratory tests

Pediatric

Not established

Interactions

Allopurinol may increase risk of bleeding or infection and enhance 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

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Dosing

Adult

Startup dosage and dosage regimen to steady state are variable; treatment with this drug should be attempted only by clinicians experienced in its use and in monitoring for its adverse effects

Pediatric

Not established

Interactions

Allopurinol increases toxicity; ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Contraindications

Documented hypersensitivity; breastfeeding

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Increases risk of neoplasia; caution in patients with liver disease or renal impairment; hematologic toxic effects may occur; routine monitoring of CBC count necessary to watch for development of leukopenia, thrombocytopenia, or macrocytic anemia; rarely causes hepatotoxicity, but 2- 3-fold elevation of hepatic enzymes common; may increase risk of serious infections and neoplasia; 20-30% of patients will have severe flu-like reaction and cannot tolerate medication

Methotrexate (Folex-PFS)

Antimetabolite that inhibits DNA synthesis and cell reproduction in malignant cells; may suppress immune system. Satisfactory response seen in 3-6 wk following administration.
Adjust dose gradually to attain satisfactory response.

Dosing

Adult

Startup dosage and dosage regimen to steady state are variable; treatment with this drug should be attempted only by clinicians experienced in its use and in monitoring for its adverse effects

Pediatric

Not established

Interactions

Coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase plasma levels
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; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity; may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; inadequate renal function (patients must have CrCl of 100 mL/min); inability to achieve hydration (as might occur with markedly raised intracranial pressure); concurrent immunosuppressive therapy; prior cranial irradiation; pregnancy or lactation; significant ascites or pleural effusions (third space accumulation may delay clearance); diabetes insipidus (complicates fluid management)

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Major adverse effects include myelosuppression, mucositis, and renal toxicity; acute myelotoxicity occurs with nadir for anemia at 6-13 d, for leukopenia at 4-7 d, and for thrombocytopenia at 5-12 d; rapidly reversible liver dysfunction also occurs; leucovorin "rescue" allows minimization of systemic toxicity, markedly reducing bone marrow and mucosal toxicity, but cannot reverse renal toxicity; levels must be monitored daily after administration, and leucovorin continued until levels fall below 1 X 10⁷ M

Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Meticorten, Orasone)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dosing

Adult

Startup dosage and dosage regimen to steady state are variable; treatment with this drug should be attempted only by clinicians experienced in its use and in monitoring for its adverse effects

Pediatric

Not established

Interactions

Estrogens may decrease clearance; may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur

Follow-up

Further Outpatient Care

Patients with Wegener's granulomatosis 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 neurologic 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

Medicolegal Pitfalls

Because Wegener's granulomatosis is a treatable condition, failure to diagnose early could be seen as substandard care if presenting symptoms are classic. However, given the rarity of Wegener's granulomatosis 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

1. Nishino H, Rubino FA, DeRemee RA, Swanson JW, Parisi JE. 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].

2. 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. Jun 2005;20(6):1274. [Medline].

3. 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].

4. 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].

5. Drachman DD. Neurological complications of Wegener's granulomatosis. Arch Neurol. 1963;8:144-55.

6. 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].

7. Howell SB, Epstein WV. Circulating immunoglobulin complexes in Wegener's granulomatosis. Am J Med. Feb 1976;60(2):259-68. [Medline].

8. Kelley WN, Harris ED, Ruddy S, Sledge CB. Textbook of Rheumotology. Vol 2. 5^th ed. Philadelphia, Pa: WB Saunders; 1997.

9. Kerr GS, Fleisher TA, Hallahan CW, Leavitt RY, Fauci AS, Hoffman GS. 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].

10. Moore PM. Immune-mediated vasculopathies of the central nervous system. In: Gilchrist J, ed. Prognosis in Neurology. Boston, Mass: Butterworth-Heinemann; 1998.

11. Scott DG, Watts RA. Classification and epidemiology of systemic vasculitis. Br J Rheumatol. Oct 1994;33(10):897-9. [Medline].

12. Spranger M, Schwab S, Meinck HM, Tischendorf M, Sis J, Breitbart A, 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].

13. Tervaert JW, Huitema MG, Hené RJ, Sluiter WJ, The TH, van der Hem GK, et al. Prevention of relapses in Wegener's granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre. Lancet. Sep 22 1990;336(8717):709-11. [Medline].

14. Travis WD, Hoffman GS, Leavitt RY, Pass HI, Fauci AS. 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].

15. Wegener F. [Uber eine eigenartige rhinogene Granulomatose mit besonderer Beteilgung des Arteriensytems und der Nieren]. Beitrage der Pathologischen Anatomie. 1939;102:30-68.

Keywords

Wegener's granulomatosis, granuloma, lymphomatoid granulomatosis, necrotizing inflammation, autoimmune disease, autoantibodies, neutrophil cytoplasmic antibodies, ANCA, c-ANCA, vasculitis, vasculitides, arteritis

Contributor Information and Disclosures

Author

Thomas F Scott, MD, Professor, Program Director, Department of Neurology, Drexel University College of Medicine; Director, Allegheny MS Treatment Center
Thomas F Scott, MD is a member of the following medical societies: American Neurological Association, Consortium of Multiple Sclerosis Centers, and National Multiple Sclerosis Society Advisory Board, Allegheny Chapter
Disclosure: Nothing to disclose.

Medical Editor

Carmel Armon, MD, MSc, MHS, Professor of Neurology, Tufts University School of Medicine; Chief, Division of Neurology, Baystate Medical Center
Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, American Stroke Association, Massachusetts Medical Society, Movement Disorders Society, and Sigma Xi
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Florian P Thomas, MD, MA, PhD, Drmed, Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University
Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Paraplegia Society, and National Multiple Sclerosis Society
Disclosure: Nothing to disclose.

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Michael K Racke, MD, Professor, Neurology and Molecular Virology, Immunology, and Medical Genetics; Chairman of Neurology, Chief, Neurology Service, Ohio State University Medical Center
Michael K Racke, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association for the Advancement of Science, American Association of Immunologists, and American Neurological Association
Disclosure: Teva Neuroscience Consulting fee Consulting; Peptimmune Inc. Consulting fee Consulting; Bristol Myers Squibb Consulting fee Consulting; EMD Serono Honoraria Speaking and teaching

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