Annals of the Rheumiiatic Diseases 1995; 54: 934-938

LETTERS TOTHE EDITOR

Brown's syndrome: an

important cause ofdiplopia in systemic lupuserythematosusBrown's syndrome is caused by a mechanicallimitation of the superior oblique tendon.This simulates a palsy of the inferior obliquemuscle with limitation of elevation in

adduction. The syndrome can be congenitalor acquired. Acquired Brown's syndrome hasbeen described in collagen vascular diseasesincluding rheumatoid arthritis and Still'sdisease.' 2

Two case reports have described Brown'ssyndrome in systemic lupus erythematosus(SLE) in adults,' 4 but no cases of Brown'ssyndrome in a juvenile with SLE haxe beenreported to date.A 14 year old girl was referred to the

ophthalmic department w-ith a two dayhistory of diplopia and arthralgia of herhands. She had a three vear historv of SLEthat had been complicated by rashes, arthritis,cerebral vasculitis (two years previously),and was recently under investigation forhaematuria. She had been receiving pred-nisolone in variable doses since the diagnosiswas made.On general examination, the patient had a

butterfly rash, cushingoid features, and mildswelling of the small joints of her hands.Ocular examination revealed visual acuties of6/6 in both eyes. Her eye movements showedrestricted elevation in adduction of the lefteye. Pupillarv responses and other ocularexamination were normal. There was tender-ness over the left trochlear, but no clickingsound or sensation noted on eve movement.A Hess chart revealed limited elevation in

adduction, with no superior oblique over-

action of the left eye, consistent with a

left Brown's syndrome (figure). The patientdeclined a forced duction test.

Laboratory studies were consistent withactive SLE: leucocvte count 2-8 x 10"/1 (neutro-

.

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phils 2-0 X 10'/, lymphocytes 0-7 x 109/l);antinuclear factor was increased to 1600 andDNA antibodies to 1650 IU/ml (normalrange up to 60 IU/ml). Serum complementcomponent C3 was 0-64 (normal range0 8-1-9 gA) and C4 was <0-08 (normal range0 12-0 4 g/l).A diagnosis of Brown's sxndrome second-

arv to SLE was made. The patient's steroidswere increased from 5 mg of prednisoloneon alternate days to 30 mg per day. Hersymptoms improved in one week and com-pletely resolved by two weeks, confirmed bynormal Hess test.

Six weeks later, renal investigations showeda plasma creatinine of 70 p.mol/l, plasmaalbumin 43 g/l and a normal protein/creatinine index. Renal biopsy revealed mildlupus nephritis (World Health Organisationtype 2A). During this hospital stay she hada further episode of vertical diplopia.Computed tomography (CT) and magneticresonance imaging scans of her head, forpresumed intracerebral cause, revealed nolocal or intracranial pathology. With thecombination of diplopia and increasedmarkers for SLE activitv, intracerebralinvolvement was assumed and a course ofcvclophosphamide subsequently given on anoutpatient basis. Although no ophthalmicassessment was made, a recurrence of herBrown's syndrome was a possibilitv, and thisdiagnosis ma- have prevented the need forcvclophosphamide.The causes of Brown's syndrome can be

divided into two main categories--inflam-mation and trauma both involving themuscle, tendon, trochlear, or surroundingtissues of the superior oblique muscle.'Two descriptions of Brown's syndrome

associated with SLE have been of a 27 yearold woman and a 30 vear old man,' theformer successfully treated xx ith a combi-nation of indomethacin and prednisoloneorally, the latter with ibuprofen alone. In ourpatient, inflammatorv markers indicatedactive SLE and her diplopia was resolved byincreasing the dose of her oral steroid.

Diplopia in patients with SLE has usuallx,been attributed to nervous svstem diseasecaused by a microvasculitis. The exact causefor Brown's syndrome in SLE is unknown,but is thought to be a tenos-no-itis of thesuperior oblique tendon.

Clinically, patients with Brown's syndromepresent with x-ertical diplopia that is wx orse on

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P.s. IlII

II.I, A

DIAGNOSIS

Hess chart showinlg limiiitled clevationi inl adductioni, with 100 superior obliqule overactioni, of the left exv.

adducting and elex-ating the affected eve,often w'ith associated pain and tendernessin the trochlear region. Examination, Hesschart, and forced traction test confirmrestricted elex-ation in adduction. An orbitalCT scan mav reveal local pathologx, but thisis not alwavs the case.Treatment of inflammatory Brovn's

syndrome is dependent on the cause. Inaddition to oral steroids and non-steroidalanti-inflammatory drugs, " local steroidinjections hax-e been used successfully. Inthose patients who fail to respond, superioroblique tenotom- combined with inferioroblique recession has been advocated."

This case report illustrates the importanceof inx'olving the ophthalmologist in cases ofSLE with diplopia. The true incidence ofBrown's syndrome in SLE is probably muchgreater than the few- reported cases wouldsuggest. Ophthalmic assessment xould helpin distinguishing betxween nervous systemdisease and this local mechanical problemfound in these patients.

G WALTERSJ A BRADBURY

D)epartoicwit ofOplilaBraad/Ord Rov-al Iqfira?i-,,Briadfoird, UM'itcdiKiloigLloii

Correspondence to: Dr G WValters, Department ofOphthalmologx, St James Unixersitx Hospital,Beckett Street. Leeds 1,S9 7T1F, United Kingdom.

1 C(ooper C, Kirxwan J R, McGill N W,Dieppe P A. Brown's syndrome: an unusualocular complication of rheumatoid arthritis.Amin Rhciom Dis 1990; 49: 188-9.

2 Kaufman I. D. Siborx P A. Anand A K.Gruber B L. Supenror oblique tenosxnovitis(Brown's sxndrome) as a manifestation ofStill's disease. YRhimiato/()l 1987; 14: 62 l7.

3 Alonso-Valdielv-so J L, Alvarez Lario B,Alegre Lopez J, Sedano '1'ous N1 J, BuitragoGomez A. Acquired Brown's syndrome in apatient xv-ith sxstemic lupus cr-thematosus.Almi RhLioii Di's 1993; 52: 63 4.

4 M\cGalliard J, Bell A L. Acquired Brown'ssxndrome in svstemic lupus erxthematosus:another ocular manifestation. C/lin Rheimioai01990; 9: 399 400.

''rimble R B, KellxN V, .NIitchel .N1. AcquiredBrosn's sxndrome. In: Ravault D, Lenk M,eds. Trai.lactiuins of the. Fifth IwtemnatiMialOrtlhoptioc (iOogtess. Lvon: IIPS, 1983;267-72

6 P'arks Ml XN, Eustis H S. Simultaneoussuperior oblique tenotomx and inferioroblique recession in Brown Is xndromc.()phlthahioolo) - 1987; 94: 1043.

Mechanism ofhaematuriain lupus nephritisW'hile the renal manifestations of s-stemiclupus ervthematosus (SLE) vary with thesxevrity of the renal lesion, proteinuria ispresent in the vast majority of cases.Haematuria, which is less common, is usuallxmicroscopic, but may be macroscopic in anoccasional patient.' Haematuria seems toresult from the passage of red blood cellsthrough anatomical gaps in the glomerularbasement membrane (GBM). While suchgaps have been described in patients w-ithxarious forms of glomerulonephritis, inclu-ding those w-ith lupus nephritis associatedx-ith haematuria,' the passage of red bloodcells (RBCs) through these gaps has beendemonstrated only in patients with focalproliferative glomerulonephritis, mild prolif-eratix e glomerulonephritis,' and membra-nous nephropathy.5 Passage of RBCs has alsobeen demonstrated in our model of experi-mental glomerulonephritis." We now reporta patient with SLE and lupus nephritis in

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whom a renal biopsy specimen showed theescape ofRBC through a gap in the GBM.

This 23 year old Japanese women was

admitted to our hospital for the further evalu-ation of the nephrotic syndrome associatedwith SLE. When the diagnosis was first madeeight years earlier, she had exhibited a highfever, typical butterfly rash, and pain in bothknees. Laboratory tests at that time revealedleucopenia, positivity for serum antinuclearantibody and DNA antibody, and a low levelof complement. She received treatment withprednisolone under the supervision of a localphysician. One month before the presentadmission, she felt generally fatigued anddeveloped oedema of the face, hands, andlegs. Physical examination on admissionrevealed a pigmented butterfly rash on theface and leg oedema. Her blood pressure was

106/68 mm Hg. Her heart and the lungs werenormal. Urine analysis showed proteinuria of3-7 g/day, microscopic haematuria (10 RBCs/high power field (HPF)) with dysmorphicerythrocytes, leucouria (15 leucoqytes/HPF),and granular casts. Laboratory study revealeda slight deterioration of renal function (crea-tine clearance 64 ml/min, blood urea nitrogen

240 mgll and creatinine 6-1 mg/l). Serumtotal protein was 41-2 g/l, albumin 25 g/l andtotal cholesterol 3430 mg/l. The RBC countwas 380 X 104/mm3, leucocyte count7400/mm3, and platelet count 18 X 104/mm3.Tests for LE cells and for antinuclear factorwere both positive. The serum DNA anti-body titre was 30 U/ml (normal value (NV)less than 7 U/ml), and serum complementwas decreased: haemolytic complement(CH50) 16-6 U/ml (NV 30-40 CH50 U/ml);C3 262 mg/l (NV 450-870 mg/l); C4 119mg/l (NV 120-370 mg/I).

Examination of a percutaneous renalbiopsy specimen by light microscopy revealed10 glomeruli, one of which showed globalsclerosis. One other glomerulus showedcrescent formation and the remainingglomeruli showed evidence of a mild prolifer-ative lesion with focal wire loop and hyalinethrombi. Immunofluorescent microscopyrevealed a fine granular pattern along theglomerular capillary wall with a slightmesangial staining pattern for antihumanIgG, C3, and Clq.

Electron microscopic study revealed an

increased number of mesangial cells and an

C L

urinaryv .....-

Spac (arrows). B: ,A: Low magnification (original X 1200) of electron micrograph showing many red blood cells in theurinary space (arrows). B: Partial enlargement ofA demonstrating the escape ofa red blood cellthrough a gap (arrows) in the GBM. Note the 1 Am long process of the red blood cell that is crossingthe basement membrane. Note smooth surface ofRBCs in the capillary lumen (CL), in contrast tothe irregular surface ofRBCs in the urinary space (US). Subepithelial (arrowheads) and mesangial(*) deposits are visible. Ep = epithelial cell; Ed = endothelial cell;MC = mesangial cell. Originalmagnification X4000.

infiltration of leucocytes to the glomeruli.Electron dense deposits were observedmainly in the subepithelial region, with lesslocalisation in the mesangium and subendo-thelium. Some electron dense depositsoccupied the entire layer of the GBM.Striking changes in the GBM included ageneralised thickening, attenuation, irregu-larity, wrinkling, notching, and rupturing.Numerous red blood cells with an irregularsurface were observed in the urinary space(figure, A). The RBCs in the capillary lumenwere smooth. Escape of RBCs was observedfrom the capillary lumen into the urinaryspace close to the site of mesangial inter-position (figure, B). Epithelial cells showedvacuolation and fusion of the foot processes.Microscopic findings were compatible with adiagnosis of diffuse membranous glomer-ulonephritis associated with lesions of diffuseglomerulonephritis. The World HealthOrganisation morphological classificationwas lupus nephritis IV-d.The escape of red blood cells through a gap

in the GBM was demonstrated in this patientwith lupus nephritis. The cause ofthis ruptureis not completely understood. Several factorsseem to be involved in damaging the GBMand in leading to its perforation. Patients withthe immune complex type of glomerulo-nephritis exhibit rupture of the GBM in areasin which the thickness of the basementmembrane is infiltrated by electron densedeposits.2 4 Such deposits may replace orgreatly interfere with the structure of theGBM and thus create points of weakness toeven simple mechanical factors.2Leucocyte protease is important in the

mechanical disruption of the GBM. Themigration of polymorphonuclear leuco-cytes' 7 and of monocytes' into Bowman'sspace has been reported. Exudation ofleucocytes in the glomerulus and in the urineare characteristic of lupus nephritis. Theurinary sediment that contains erythrocytes,leucocytes and various casts is termed'telescoped sediment'.9 Thus the leucocytesin the urine may also originate fromglomerular capillary.One characteristic of glomerular bleeding

is the excretion of dysmorphic RBCs in theurine. The RBCs that originate in theglomerulus are dysmorphic, whereas thosethat originate in other parts of the urinarytract are uniformly isomorphic.10 The alteredmorphology of the RBCs that originate in theglomerulus may reflect the mechanism oftheir entry from the capillary lumen into theurinary space, as described by Lin et al.'Those authors showed that, in a case ofmembranous nephropathy with structuralgaps in the GBM, the deformability of theRBCs allowed them to be pushed through thegaps into the urinary space. They suggestedthat the combined forces of the pulsatileglomerular capillary hydraulic pressure andthe elasticity of the GBM, while pushing thered cells through these gaps, also producedshearing stresses to the red cell surface, thuscausing deformation.

This is the first report demonstrating themorphological basis of haematuria in lupusnephritis.

HIROFUMI MAKiNOHIDETAKA KAWASAKI

KAZUHARU MURAKAMIKAZUE HIRONAKATETSUKI AMANO

ZENSUKE OTAThird Department ofInternal Medicine,Okayama University Medical School,

Okayama, Japan

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Correspondence to: Hirofumi Makino MD, ThirdDepartment of Internal Medicine, OkayamaUniversity Medical School, 2-5-1 Shikata-cho,Okayama 700, Japan.

1 Hill G. Systemic lupus erythematosus andmixed connective tissue disease. In:Heptinstall R H, ed. Pathology of the kidney,4th edn. Boston: Little, Brown andCompany, 1992; 871-950.

2 Stejskal J, Pirani C L, Okada M, MandelanakisN, Pollak V E. Discontinuities (gaps) of theglomerular capillary wall and basementmembrane in renal diseases. Lab Invest 1973;28: 149-69.

3 Mouradian J A, Sherman R L. Passage of anerythrocyte through a glomerular capillarybasement membrane gap. NEnglJMed 1975;293: 940-1.

4 Bohle A, Gise H V, Mikeler E, Rasswiler J.Morphologic contribution of gross hematuriain mild mesangioproliferative glomerulone-phritis without crescents. Kin Wochenschr1985; 63: 371-8.

5 Lin J T, Wada H, Maeda H, et al. Mechanismof hematuria in glomerular disease. Anelectron microscopic study in a case of diffusemembranous glomerulonephritis. Nephron1983; 35: 68-72.

6 Makino H, Nishimura S, Soda K, Takaoka M,Kaneshige T, Ota Z. Mechanism ofhematuria. I. Electron microscopic demon-stration of the passage of a red blood cellthrough a glomerular capillary wall in ratMasugi nephritis. Virchows Arch B Cell Pathol1986; 50: 199-208.

7 Makmno H, Nishimura S, Takaoka M, Ota Z.Mechanism of hematuria. II. Scanningelectron microscopic demonstration of thepassage of blood cells through a glomerularcapillary wall in rabbit Masugi nephritis.Nephron 1988; 50: 142-50.

8 Mazzucco G, Monga G. Monocyte escapethrough a glomerular capillary gap. Anultrastructural observation of a case of acuteglomerulonephritis. Nephron 1985; 39:272-4.

9 Krupp M A. Urinary sediment in visceralangitis: quantitative studies. Arch Intern Med1943; 71:54-61.

10 Birch D F, Fairley K F. Hematuria: glomerularor non-glomerular? Lancet 1979; ii: 845-6.

Successful application ofhigh dose intravenousimmunoglobulins inSjogren's syndromeassociated arthritisHigh dose intravenous immunoglobulins(IVIg) have become an important treatmnentin a number of autoimmune disorders.' Bothcontrolled2 and uncontrolled3 4 studies havedemonstrated beneficial effects of IVIg inrheumatic diseases such as dermatomyositis,2rheumatoid arthritis,3 and systemic lupuserythematosus.4 We report our experiencewith IVIg in a patient with Sj6gren'ssyndrome.A 39 year old man presented for the first

time in 1992 with a three year history ofpainful swelling of both parotid glandswithout signs of infection. A keratoconjunc-tivitis sicca which had been confirmed bySchirmer's test required the use of tearsubstitutes. In addition, the patient haddeveloped an incapacitating, non-erosivearthritis involving both wrists, the metacarpo-phalangeal and proximal interphalangeal(PIP) joints, the knees, and the ankles. Sero-logical evaluations revealed high titres of anti-nuclear antibodies (ANA), anti-Ro(SS-A)and anti-La(SS-B) antibodies, and increasedtitres of rheumatoid factor. Serum IgG wasincreased to 30 4 g/l without IgG subclassimbalance.5 The patient fulfilled four of thesix 1993 criteria for the diagnosis of Sjogren'ssyndrome.6 Treatmnent with NSAID wasinitiated because of persisting arthritis, butwithout success. Prednisolone was effective

in doses up to 30 mg per day, but had to bewithdrawn because of signs of iatrogenicCushing's syndrome, including hypertensionand impotence. Treatment with metho-trexate was refused by the patient because ofthe risk of impaired fertility.We therefore decided to institute IVIg

treatment. The patient received 30 g of asulphonated IVIg preparation (VenimmunR,Behringwerke AG, Marburg, Germany) oneach of days 1 to 4 and 21 to 24. Except forone period of headaches, the IVIg were welltolerated and led to a remarkable improve-ment in the arthritis as manifested by areduction in the cumulative PIP joint circum-ference from 562 mm before treatment to550 mm at day 30, and a simultaneousincrease in grip strength from 80/180 mm Hg(left/right) to 280/300 mm Hg. In addition,a distinct resolution of the patient's parotidgland swelling was noted. Serologically, IVIgtreatment resulted in an increase in serumIgG to 56-0 g/l at day 5 and to 41-1 g/l at day30. While titres ofANA, anti-Ro(SS-A), andanti-La(SS-B) antibodies were not affected,the erythrocyte sedimentation rate decreasedfrom 32 mm/lst h to 5 mm/lst h within 50days, accompanied by a parallel decrease inC reactive protein from 22 mg/l to 8-5 mg/l.The beneficial effects lasted for a total ofthree months. During month 4, moderatejoint pain recurred, but it was controlledadequately by NSAID for the ensuing twomonths. However, at the end of month 6 asevere relapse of arthritis occurred. IVIgtreatment was reinstituted, followed again bya distinct relief of joint swelling and pain.Our observations suggest a beneficial effect

of IVIg in a patient with Sj6gren's syndromeassociated arthritis, which is one of the mostcommon extraglandular disease manifesta-tions of this symptom complex.7 Althoughspontaneous remission cannot be excludeddefinitively, this seems to be unlikely becausethe clinical improvement closely followedIVIg administration and was reproducible ina flare of the disease. To our knowledge, thisis the first description of the application ofhigh dose IVIg in Sj6gren's syndrome. Asmany patients with this condition presentwith increased IgG levels, they are consideredat risk of developing symptoms of hyper-viscosity;8 however, despite high IgG levelsbefore treatment, no major side effectsoccurred in our patient. Although our ob-servation in a single patient requiresconfirmation in others, it does suggestan additional therapeutic option forselected Sj6gren's syndrome patients withextraglandular manifestations in whom con-ventional treatment fails or is contra-indicated.

R A ZEUNERJO SCHROEDER

F SCHRODERH H EULER

lI. Medical Clinic,Christian-Albrechts-Universty ofKiel,

Chemnitzstrasse 33,D-24116 Kiel, Germany

Correspondence to: R A Zeuner.

1 NIH Consensus Conference. IntravenousImmunoglobulin. Prevention and treatmentof disease. JVAMA 1990; 264: 3189-93.

2 Dalakas M C, lla I, Dambrosia J M, et al. Acontrolled trial of high-dose intravenousimmune globulin infusions as treatment fordermatomyositis. N Engl J Med 1993; 329:1993-2000.

3 Tumiati B, Casoli P, Veneziani M, et al. High-dose immunoglobulin therapy as animmunomodulatory treatment of rheumatoidarthritis. Arthritis Rheum 1992; 35: 1126-33.

4 Francioni C, Galeazzi M, Fioravanti A, et al.Long term I.V. Ig treatment in systemic lupuserythematosus. Clin Exp Rheumatol 1995; 12:163-8.

5 Eriksson P, Almroth G, Denneberg T, et al.IgG2 deficiency in primary Sj6grenssyndrome and hypergammaglobulinemicpurpura. Jf Clin Immunol Immunopathol 1994;70: 60-5.

6 Vitali C, Bombardieri S, Moutsopoulos H M,et al. Preliminary criteria for the classificationof Sjfgren's syndrome. Arthritis Rheum 1993;36: 340-7.

7 Pease C T, Shattles W, Barrett N K, et al. Thearthropathy of Sjogren's syndrome. Br JRheumatol 1993; 32: 609-13.

8 Reinhart W H, Berchtold P E. Effect of high-dose intravenous immunoglobulin therapy onblood rheology. Lancet 1992; 339: 662-4.

Asymmetrical nodularosteoarthritis in a patientwith a hemiparesisA 69 year old woman presented to ourdepartment complaining ofpain and swellingaffecting the fingers of the right hand andwhich had developed over the preceding10-15 years. There were no symptomsarising from the left hand, which was affectedby a hemiparesis, a consequence of thesurgical resection of a cerebral tumour at theage of 12. On examination, the patient hada left hemiparesis with a mild pyramidalweakness and loss of sensation to light touch.She had Heberden's and Bouchard's nodesaffecting all the interphalangeal joints of theright hand, but none on the left (fig 1).The patient had worked full time as a clerk

for 41 years, during which time she waspredominantly right handed, but used her lefthand for light manual tasks. She gave avery clear description of a similar arthritisaffecting her mother who, she recalled, hadmarked symmetrical deformity of herproximal (PIP) and distal interphalangeal(DIP) joints.Radiographs confirmed the diagnosis of

nodular generalised osteoarthritis (OA) withosteophytic lipping, sclerosis, and joint spacenarrowing of the affected joints (fig 2).Serological tests were normal and erythrocytesedimentation rate was within normal limitsfor her age.

Osteoarthritis is the commonest jointdisorder in Westem populations, and thehand the most frequent site of involvement.'Nodular generalised OA affects the joints ofthe hand in a symmetrical manner, the mostfrequent joint groups involved being the DIPand thumb base. In a recent populationstudy,2 the tendency for symmetry waspronounced for both the DIP and PIP joints,and was greater than that for row or rayclustering. For OA affecting the DIP joint,the odds ratio for contralateral involvementof the same joint was 38-8 (95% confidenceinterval (CI) 14-5-103); for any other DIPin the same hand it was 11-5 (95% CI7-8-17-0). It is highly likely, therefore, thatjoint involvement of nodular generalised OAof the hand will be found to be symmetrical.Asymmetrical OA of the hands has been

described occasionally in similar circum-stances. In 1947, Stecher and Kamoschdescribed a woman with a median nerveinjury of the hand who later developedHeberden's nodes in all her fingers exceptthose supplied by the injured nerve.3 Stecheralso described it in a hand paralysed bypoliomyelitis,4 and in 1935 Coste andForrestier reported a case that occurred aftera cerebral accident.5

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