| OCR Text |
Show /. Clill. Nellro-0l'hthalmo/. 5: 17-25, 1985. Chronic Ophthalmic Wegener's Granulomatosis JAMES R. COPPETO, M.D. HAROLD YAMASE, M.D. MARIO L. R. t-.lONTEIRO, M.D. Abstract A case of Wegener's granulomatosis is reported which manifested episcleritis followed by scleritis, and followed in turn by separate episodes of right and left orbital pseudotumor spanning 15 years prior to respiratory tract disease, The unusually protracted progression of symptoms in this case may be explained on the basis of the histopathological findings. Areas of fibrinoid necrosis of connective tissue occurred alone or alternated with areas of nongranulomatous fibrinoid necrosis of blood vessel walls. Granulomatours vasculitis was not observed. This histopathological picture is pathognomic of early cases of Wegener's granulomatosis which run especially protracted courses. Introduction Wegener's granulomatosis is an acute necrotizing granulomatous disease usually associated with vasculitis and predominantly involving the face, upper and lower respiratory tracts, and kidneys. 2 A limited, less fulminating form of the disease, which spares kidneys and even the lungs, may evolve over months, or rarely, years.1.3 Inflammatorv disease of the eye and ocular adnexa is commo~ in Wegener's granulomatosis, but rarely is the sole presenting manifestation. We report a case of chronic ophthalmic Wegener's granulomatosis which manifested episcleritis followed by scleritis, and followed in turn by separate episodes of right and left orbital pseudotumor spanning 15 years prior to upper respiratory tract disease. Although there are occasional case reports of ophthalmic dysfunction preceding systemic manifestations of Wegener's granulo- Associate Chmcal Prufessur uf Ophthalmulu~y(JRC) and Fellow in Neura-uphthalmulugy (MLRM). Dt'partment of Ophthalmulogy, and Assistant Professor uf Pathulu~y (IIY), Department of Pathulugy, University uf CunnectlCut Health Center, Farmingtun, Cunnecticut; and Department uf Ophthalmolugy (JRC) and Felluw in Neuro-uphthalmulugy (MLRM), St. Mary's Medical Center, Waterbury, Cunnectlcut. March 1985 matosis, ours documents a unique bilateral orbital inflammation slowly evolving over many years without other evidence of disease. Case Report In January 1968, a 57-year-old woman complained for 3 weeks of redness and photophobia in the left eye. General health had been good. Visual acuity was 20/20, both eyes. Conjunctivitis of the left eye was diagnosed, improved with topical corticosteroid therapy, but relapsed when therapy was tapered on several occasions. In January 1969, she developed keratoconjunctivitis with a marginal corneal ulcer superiorly in the right eye, which enlarged and became associated with an extensive upper corneal infiltrate. Otherwise, the ophthalmic examination was unremarkable. In July 1970, she developed episcleritis nasally in the right eye which responded to prednisilone acetate 1% eyedrops. However. continuous topical therapy was required until March 1972. In April 1974, several marginal infiltrates were noted in the superior cornea of the left eye. They improved with topical chloramphemicol and dexamethasone therapy. Recurrent episcleritis of both eyes in May 1976 also responded quickly to treatment. In July 1979, she complained of pain in the left eye. Visual acuity was 20/25, right eye and 20/ 100, left eye. Bilateral superior marginal ulceration of the corneas was noted, and the superior sclera in the left eye was noted to exhibit dilated vessels (Fig. 1). A corneal disease consultant diagnosed "rheumatoid scleritis' despite her negative past history of rheumatoid arthritis, and subsequently the patient was treated with chronic topical corticosteroids occasionally supplemented by systemic corticosteroids for exacerbations of her scleritis. Despite treatment, there was progressive thinning of the superior sclerae in both eyes over the next year. Posterior synechiae of the left eye and a posterior subcapsular cataract of the left eye developed. 17 Wegener's Cranu!lllll.ltusis In January 1980, she developed headache, diplopia and pain, proptosis, and ptosis in the right eye and was referred for neuro-ophthalmic cnnsultation. Otherwise, she felt well and had no respiratory or auditory symptoms. General physical examination was normal, and there was no evidence of rheumatoid arthritis. Visual acuity was 20/25, right eye and 2U/40, left eye. There was virtually complete ophthalmoplegia, cnmplete ptosis and 3-mm proptosis in the right eye. There was slight hypesthesia to Figure 1. Active scleritis with marginal corneal ulcer. left eve. light touch over the right forehead. Orbital resiliency was decreased, and the globe was tender. There was slight flare and cell in the anterior chamber both eyes. There was injection and thinning of the superior sclerae in both eyes and bilateral marginal corneal infiltrates. A CT scan showed a contrast enhancing small mass adjacent to the right lateral rectus muscle (Fig. 2). Westergren erythrocyte sedimentation rate was 111 mm/ hour, but temporal artery biopsy was negative. A serum antinuclear antibody was positive at a titer of 1 to 64 (3+ large speckled), but negative at a titer of 1:128. Alpha-2-globulin fraction was 1.0 g/dl (II 0.4-0.7 g/dl). Ophthalmic Wegener's granulomatosis was diagnosed and rheumatologic, renal, and otorhinologic evaluations were obtained. A gallium scan demonstrated increased uptake in the mediastinum and the right orbit, but tomography of the mediastinum was negative for adenopathy. Rheumatologic consultants concluded that the patient did not have active rheumatologic disease or disseminated vasculitis. Urinalysis revealed a specific gravity of 1.018, 1+ protein, trace hemoglobin, 1+ urobilinogen, 4-6 white blood count/high-power field, 3-5 red blood count/high-power field, 1+ bacteria, 8-14 haline casts/high-power field, 0-2 fine granular casts/high-power field, and 0-4 coarse granular casts/high-power field. Blood urea nitrogen varIed from 35 to 65 mgCC and creatinine from 1.5 to 2 mgCC, and intravenous pyelography showed slightly small kidneys. It was concluded that she 18 Figure 2. CT ,,-,m Ll""111 ,ld"Kl'nt hI nght 1.1t,'r.l1 rectus muscle insertion. Journal of Clinical Neuro-ophthalmology had mild nephrosclerosis and not significant active glomerullmephritis. Otorhinologic examination disclosl'd no abnormality. Biopsy of the leit inferillr turbinate and right maxillary sinus mucosa shlH'\'ed nonspl'cific inflammation. The patient was treated with prednisOl1l' 60 mg a day, and her ophthalmic symptoms cleared rapidly o\'er 2 mlmths. Further sderal thinning slowed (Fi~. 3 <lnd "). Prednisone \Vas tapered to 10 mg a day, but l'lluld nllt be discontinued withllut recurrence of llrbital pain. Ht'r erythro- Figure 3. Scleral thinning. left eW Coppeto, Yamase, Monteiro eyte sedimentation rate varied between 20 and 5'" mm/hour; repeated urinalyses were normal. In February 19~3, she discontinued Prednisone completely. Two weeks later, she noted anorexia, wl'ight loss, somnolence, malaise, fever, nasal stuffiness, intermittent hearing loss, diplopia, and painful proptosis and ptosis in her left eye. On examination, visual acuity was 20/40, right eye and 20/200, left eye. She had bilateral sclerouveitis. There was neovascularization of the left iris and many cells in the anterior vitreous in the left eye. Intraocular pressures were 13 mm Hg, both eyes. Fluorescein angiography demonstrated optic disc edema and cystoid macular edema left eye. Bilateral otitis media was present. Temporal artery pulsations could not be felt. General physical examination was normal, except that it was noted that she had developed a "saddle nose" compared to previous photographs. A Westergren erythrocyte sedimentation rate was 121 mm/hour, and a temporal artery biopsy was negative. Antinuclear antibody was positive at 1:20. C-reactive protein was positive. Angiotensin converting enzyme level, antidoublestranded deoxyribonucleic acid, antisinglestranded deoxyribonucleic acid, ENA, anti-SM, antiribonucleoprotein, and rheumatoid arthritis latex determinations were negative. Hematocrit was 35.8% and hemoglobin was 12.3 mg%. A C3 complement was 100 mg/dl (/1 62-212 mg/dl), C4 complement was 52 mg/dl (/1 15-44 mg/dl), and total complement was 110 U/ml (/1 22-74 U/ ml). She had a slight reduction in IgA on immunoglobulin electrophoresis. Renal function was considered unchanged from 2 years earlier. Spinal March 1985 Figure 4. Scleral thinning, right <'Yl'. N"tl' al,;" the ',;addle nose" owing to atrophy "f the bridge of the nose. 19 Figure 5. Sinus mucosa biopsy showing transmural fibrinoid necrosis and hemorrhage of a small muscular artery. (H&E. original magnification x 100.) t"lgure b. hbnn thrombus parti.llly orcludlllh .lIl arll'n.ll Vl'SSl'l. 1I1'n1llrrhage into the vessel wall is shown in one area. (H&E, onglndl mdgnJficdtlon X2SII) Cuppetu, Yamase, Monteiro r-igure i. \iuitinudeated gIant cell (arrow) assoCiated with intlamed and necrotizing focus. spatially dissociated from actual \'ascular lesions (H&E. ,'riginal magnification x250.) fluid analysis was normal. A gallium scan showed bilateral pulmonary hilar prominence and bilateral orbital uptake. A cranial CT scan showed complete opacification of the left maxillary sinus. The left maxillary sinus was biopsied through a Caldwell-Luc approach. Stains for acid-fast bacteria and fungi were negative. Histopathologic Examination Multiple levels of the sinus mucosa were examined. Multiple foci of transmural fibrinoid necrosis were seen involving small muscular arteries (Fig. 5) These affected segments had a homogenous, eosinophilic, and fibrinoid quality and showed intramural hemorrhages. Some of the affected vessels were thrombosed (Fig. 6). Although no giant cell and no granulomatous response were noted in direct association with the injured vessels, scattered giant cells were present in association with degenerated and mflamed tissues spatially dissociated from the vascular le-sions (Fig. 7). . The dense connective tissue deep to the smus mucosa showed multiple foci of fibrinoid degeneration and granular degeneration which were March 1985 not associated with significant inflammation (Figs. 8 and 9). Subsequent Course She improved with prednisone 40 mg/day and was discharged. One month later, cyclophosphamide 100 mg a day was begun. Initially she showed marked improvement in her condition. In August 1983, she developed bilateral pulmonary infiltrates, fever, and obtundation owing to bacterial endocarditis, which resolved with the addition of antibiotics to her regimen of cyclophosphamide and corticosteroids. Renal evaluation was unchanged. Ophthalmic findings stabilized with treatment. For the subsequent year she has been maintained on cyclophosphamide 50 mg/day which has arrested her condition totally. There has been no recurrence of bacterial endocarditis. Discussion The clinical constellation of marginal keratitis, anterior scleritis, and painful proptosis with ophthalmoplegia that was present in this case 21 Figure 8. Dense fibrous connective tissue deep to the sinus mucosa showing foci or fibrinoid degeneration, (H&E, original ma~nification x 250) ,, 'II. ... c: . • ... • , ~ , .. ... \, ... ...- '+ " ,. ,"" .... ~ .. ". .- Figure 9. Ill'n,,' fibr"l" <,<>nnl'd"',, t"'Ul' dl"'r' to 11ll' sinus mun)sa at a later stage of degeneration showing extensive fragn1l'nt,ltl"n ,lJ1d d"lIllL'gr,lti"n "f ,,"ll,lgl'n bundll" Notl' thl' lack llf inOammatory cells. (H&E, original magnification x250.) may be caused by Wegener's granulomatosis, lethal midline granuloma, lymphoma, relapsing polychondritis, periarteritis nodosa, syphilis, giant cell arteritis, Crohn's disease, ,1I1d collagen vascular diseases such as svstt'mic lupus erytlwmatosis. 1 ~ 4 ~ Paranasal sit;us invplvenwnt· m,ly occur in all of the ablwe disl)rders t'xcept Cmhn'·s disease, giant cell arteritis, and svstt>mic lupus ervthematosis. l ~ ~ III A IS-year l'llurse would be unlikely for lethal midline granulllm,l or lymphoma: moreover. atypicallvmrhllcytes were not l)bserved histopatholl)gically.1 I Relapsing polychondritis is an unlikeh' diagnl)sis bt'cause of the absence of severe migratl)ry arthritis. ~" Althl) ugh periarteritis nl)dl)sa can cause an orbitopath\' vears before other evidence of systemic disease, corrobl)rative evidence was absent such as eosinophilia, depressed serum complement, peripheral neuropathy, gastrointestinal hemorrhage, hemorrhagic rash, and choroidal infarctil) n.~ 1.1 Syphilis was excluded l)J1 the basis of the histl)pathl)ll)gical findings and the negative VDRL and FTA ABS. The diagnosis of Wegener's granull) matl)sis is supported by the histologic findings (giant cells and focal fibrinoid necrosis of connective tissue matrix and of arterial walls) and by the clinical and laboratory findings. The latter include, in addition to the ophthalmic findings, progressive atrophy of the nasal bridge, recurrent serous otitis media, and elevated serum complement levels. \-\'egener·s granulomatosis may produce sclerou\·eitis and marginal keratitis, frequently as the initial ophthalmic manifestation. However, in virtually all cases, there is clinical or radiographic evidence of upper respirator~ tract involvement at the time of presentation. 5 415 Orbital involvement may be secondary to invasion of granulomatous tissue from adjacent nasal sinuses or the orbit may be a primary site of inflammation.~ J. Ifl.lh However, even in cases without apparent nasal disease, orbital involvement is unlikely to precede the respiratory tract involvement by more than several months2 . '. 1Il.lh.17 This case presumably represents a limited form of Wegener's granulomatosis, but is unique in its protracted progression of multiple purely ophthalmic symptoms ~rior to the development of sinonasal disease. I. 1. 1. 14. I" One or more of the following concepts are usually invoked to account for particularly chronic cases of the limited form of Wegener's granulomatosis. First, a limited number of target tissues and renal sparing in certain cases eliminates major morbidity and mortality and permits a milder more insidious form of the disease to evolvf>. Second, although Wegener's granulomatosis probably originates multicentrically, initially the process is a low-grade inflammatory process March 1985 Coppeto, Yamase, Monteiro with only mild edemJ and necrosis. Involvement of certain highly symptomatic sites such as the Eustachian tubes, conjunctiva, and face at this st,lge may pmduce symptoms (e.g., chronic otitis media, conJunctivitis, and facial ulcers) out of pmportion to, and long before, symptoms from more serious involvement of vital organs. A third concept is that of "protracted phenomena" in Wegener's granulomatosis. I I This refers to certain caSt'S of Wegener's granulomatosis where localized involvement of an isolated area of skin, mucous membrane, or lung proceeds indolently without spread to adjacent tissues and with little or no involvement elsewhere in the body. Such a localized area of indolent inflammatilln may be the potential source for further spread llf the process and unknown factors may determine whether the local process regresses or spreads systemically. Protracted superficial phenomena have been invoked to explain cases of serous otitis media, conjunctivitis, epistaxis, nonhealing facial ulcers, and focal bronchiectasis long preceding systemic involvement by Wegener's granulomatosisJ.llI. II. IS 14 The histopathoillgy of cases of protracted superficial phenomena in Wegener's granulomatosis is unlike that of fulminant Wegener's granulomatosis, and in its mildest form is more similar to that observed in the sinus mucosa of our case. That is, rather than demonstrating confluent areas of granulomatosis and fibrinoid necrosis of connective tissue and arterial walls producing the picture of a granulomatous vasculitis, areas of fibrinoid necrosis of connective tissue occur alone and alternate with areas of nongranulomatous fibrinoid necrosis of blood vessel walls. Such a histological pattern has not been described in other vasculitides, even at an early stage. Forms of intermediate severity also occur. Whatever accounts for the progression from the mildest histopathological appearance to the more severe appearance of mecrotizing granulomatous vasculitis, probably partly determines the chronicity pisa- uis acuteness of the clinical presentation as well as its tendency to remain localized in certain cases. The histopathological picture lli prlltracted superiicial phenpmena has been dl)cumented in the conjunctiva pf a C,lSt' pi Wegt'nl'r's granulomatosis which presented with chrlmic external eye disease, but h,lS IWVl'r been prl'vil)usly reported to explain a chfllnic. purely llphthalmic syndwme. In pur case, the slow, almost continuous progression of symptomatology from superficial to deep orbital tissues suggests that, in this instance, the disease originated in the conjunctiva and then spread into the deeper orbital tissues. In this regard, our case may be analogous to certain cases of Wegener's granulomatosis pre- 23 Wq~l'nl'r's Cr.lnulll ll1.1tl l sis cl'ckd bv chnlnic recurrent otitis media. Such C,1Sl'S lli 'chrunic lltitiS n1l'dia must harbor microscopic illci of low-grade inflammation in the Eust, Khi,1I1 tubl's illr years before some stimulus presum, lblv ex.Kerb.1!l's the process to produce severe destructive upper rl'spira tory tract disl'ase. The expl.ln,1tilll1 ior the unusually prolonged nlurse lli llur C,1Sl"S llphthalmic symptomatology is prob'lblY rl'I,1!l'd to a persistence of the inflammatllry pruCl'SS at a low-grade level for many years beion' either dissemination of thl' process tll adjacent upper respiratory tract, or the independent multicentric appearance of lesions elsewhere in the upper respiratory tract. The reason \Vhv this evolution happens in some cases like ours is unknown. It is important to recognize this variant of Wegener's granulomatosis because it affords an opportunity to treat the disorder at an early and more curable stage, Although at first we suspected the diagnosis of Wegener's granulomatosis on the basis of the ophthalmic findings, we repeatedly withheld definitive treatment with Cytoxan on the mistaken assumption that corroborative systemic findings would be shortly forthcoming. We believe cases like this should receive Cytoxan therapy early, Whatever the explanation for this patient's protracted localized presentation, this case emphasizes that a comprehension of the ophthalmic manifestations of Wegener's granulomatosis may be important in establishing the diagnosis early. This is all the more crucial since it has been proved that cytotoxic therapy may be curative if initiated before severe pUlmonary and especially renal damage has occurred. I 1 Moreover, optimal ophthalmic management probably requires systemic corticosteroids and cytotoxic agents in order to avoid serious ophthalmic morbidity, 1.1 4 17 Treatment of Wegener's Granulomatosis Bullen and co-authors have presented an excellent review of the treatment of Wegener's granulomatosis. I" Untreated, the generalized form is usually fatal, owing to renal complications. The limited form, in addition to being severely deforming, may prove fatal from upper aIrway obstructIOn. Corticosteroids, once the llnly medications of any consistent benefit, are still utilized selectivelv in certain cases to produce temporary symptomatic relief of inflammatory complications from the underlying vasculitis. However, cytotoxic immunosuppressive drugs, particularly' cyclophosphamIde, have revolutionized the therapy of Wegener's granulllmatllsis by effectively r'eversing the underlying vasculitIS in most cases, with improvement often cllmmencing within days, Thereby the many well-known cumplications' of 24 long-term corticosteroid therapy can be avoided in most cases by reserving topical or systemic corticosteroids for transient local or systemic flare-ups of inflammation which may not demand increasing the dose of cyclophosphamide, However, as our case demonstrates, surveillance must be maintained for opportunistic infections that may complicate immunotherapy, Our case's bacterial endocarditis was probably caused by long-term corticosteroid therapy aggravated by the introduction of cytoxan. Once the infection was controlled with appropriate antibiotics, corticosteroids could be slowly withdrawn while maintaining and reducing cyclophosphamide therapy to the patient's current dose of 50 mg a day. There were no complications over the last year while on cyclophosphamide alone, Th~re exist other potential complications of cyctotoxic immunosuppressive treatment which also must be avoided. These include bone marrow depression, hemorrhagic cystitis, alopecia, gastrointestinal dysfunction, sterility, and increased incidence of malignancy" I" The lowest tolerable dose of cyclophosphamide that maintains clinical remission is utilized indefinitely or until spontaneous remission occurs. In cases of ophthalmic involvement, topical corticosteroids provide symptomatic relief although cataract. as in our case, or glaucoma may be complications. Therefore, such treatment should be reserved as a temporary adjunct to cyclophosphamide therapy when it is believed that the ocular flare-up can be alleviated without increasing the overall dose of cyclophosphamide, A prominent exception to this rule is that marginal corneal ulceration does not respond consistently to corticosteroids alone whether topically or systemically, and requires the reintroduction or augmentation of cyclophosphamide therapy, References ] Scull\', R.E. Mark. EI., and McNeel\', B.U.: Case Recl)rds oi the Massachust'tts Gt'neral Hospital. Cast' ·D-1981 ,\1 E/lSI. , Mt'd. 305: 999-1008,1981. ., Jal..llbiec, FA, and Jont's, 1.5.: Orbital in flammatillOS. In Dist'ast' l'l tht' Orht, 1.5. Jones and F.A. Jal..obiec, Eds Harper & Row Pub!. Inc., New York, 1Q 79, pp. :!lb-:!:!1. J. Ht'ndt'rson, J\\': Or/lital Tl/mMs. (2nd ed.). Brain C Decl..er, New )\lrl... 1980, pp. 533-539, -l.I.1mpol. L.M, West. C, and Goldberg, M,F.: Ther,1pV of scleritis with cytotoxic agents. Alii, f. Ol'htlllllmtli. 86: :!b6-271, 1978. 5. Austin, P., Grt'en, W.K, 5allyer, D.C, Walsh, F.B., and Kleinielter, H.T.: Peripheral corneal degeneration and llCclusive vasculitis in Wegener's granulomatosis. Am. , Ophthalmol. 85: 311-317,1978. 6. Watson, P.G., and Hayreh, 5.5.: Scleritis and episclt'ritis. Br. f. Ophthalmol, 60: 163-191, 1976, 7. Scully, R.E" Galdabini, J.J., and McNeely, B,U.: Journal of Clinical Neuro-ophthalmology Case Records of lht' Massachusetts Ct'Ill'r,ll I Ills ' pita\. Cast' I 0-1 q~ I. N EIISI, I Med. 304: l)5~-l)Oh, I qt\!. 8. Scull\', R.E., Caldabini, 1.1., ,lnd McNeely, H.U.: CISt" Rt'cl)rds llf lht' t-.t.I~S;lchuSl'lIS G,'neral Ilus pila\. Cast' 3ll-Il)7~. N. EIISII Med. 299: 7h570l), IQ7~ ll. BWnSlln, LI., and Fishl'L Y.I.-: S.Hn)idl)sis uf till' pM,ln.lsal sinUSl'S \\'ilh l)rl'it,11 e"\lensilln. Ardl. Ol'/l/llll/llh>l. 94: 243-4, Ill70. 10. Bll)di, F.e., ,md C,ISS, .I.n.: Intllmm,lh)r\' pSl'lIdll' lunll'r l)f lht' l)rbit. Tr./lls Alii. AC'ld. 01"ltllll/lll(,I. lltl'/lln/ll~l>1 71: 303-323, Illh/. II Fit'nb~r~·. R: Tl1t' pwtr.lckd su~,<,rfici.ll pl1l'l1lln1l'nl) n in p.ltherpc (\\'e~l'lll'r's) ~r,mullHn.ltllsis. HI/m Pillll,'I. 12: 4'i~-4h7, Il)~ 1 12. Scull\'. RL t-.1.Hk, EI., ,md McNl,t'I\', B.U: Case rt'cl)rJs l)f thl' t-.t.lss.lchusetts Celll:ral IhlSpita\. CISt' 'i1-lllS2 ,\'. EIISI 1 "'1<'d. 307: 1031-1639, IllS2 U CHrin~tl)n, e.B, .md LIebl)\\', A.: Limitt'd forms l)f .ln~lltls .lnd ~r.mul,)m.ltl)sis of Wt'~t'nt'r's typt'. March 1985 COppl'lo, Yamast', Monteiro Alii. I Med. 41: 4t17-527, 1%6. 14. I3rub.l"l'r, R, Font, R.t.. and Shepherd, E,M.: Granulomatous scleruuveitis. Regression of ocular Il'siuns with cyclophosphamide and prednisone. Ardl. (ll"ltlltl/lll,,1 86: 517-524, 1971 15. Str.lahTlla, I3.R.: Ocular manifestatiuns uf WegeIll'r'. s p,\I1ulomatusis. Alii. /. 01'"tlallll"l. 44: 78944, IlJ57. Ih. l3ullen, c.L., Liesegang, TJ, McDonald. T.)., and DeReml'l', R.k: Ocular cllmplicatiuns uf Wegener's granuillmalllsis. 0l'"t"allllology 90: 279-290, Jl)H3. 17. AlIl'n, J.c., and France, T.D Pseudulumur as pre,,' nting sign uf Wegl'ner's granulomatusis in a child. /. Pediatr. 0l'"t"almol 14: 15H-159, 1977. IH. Cl1utu, R.E, Klein. M., Lessell, S., Friedman. E., and Snider, C.L.: Limited form of Wegener granuillmatosis. Eye involvement as a major sign. /.AMA 233: 868-871, 1975 IlJ. Fauci, AS, and Wulff. S.M.: Wegener's granulumatosis. Studit's in eighteen patients and a review uf the literature. McdicilldBal1.) 52: 535-56 L 1973 25 |
