Journal of Neurology, Neurosurgery, and Psychiatry 1988;51:1126-1133

Granulomatous angiitis of the central nervous system:protean manifestations and response to treatmentEDWARD H KOO,* E WAYNE MASSEY,fFrom the Department ofNeurology, University of California School ofMedicine,* San Francisco, CA and theDivision ofNeurology, Duke University School ofMedicine, Durham, NC, USA

SUMMARY Granulomatous angiitis is an uncommon necrotising vasculitis of unknown cause re-stricted to vessels of the central nervous system. Five tissue-proven cases emphasise the proteanmanifestations of this disease and the difficulties encountered in reaching a diagnosis. One patientpresented with a temporoparietal mass, the second, a progressive dementia, the third suggestedherpes simplex encephalitis, the fourth mimicked multi-infarct state; and the fifth presented with acerebellar mass lesion. In four cases with CSF examination, protein was elevated (81-193 gm/l) andthree patients had mononuclear pleocytosis (12-800 WBC/mm3). Cerebral arteriogram suggestedvasculitis in only one of four cases. Diagnosis was made by brain biopsy in three cases and all threewere treated successfully. The diagnosis in the two other cases was made at postmortem exam-ination.

Granulomatous angiitis of the central nervous systemis an uncommon necrotising vasculitis of unknowncause.` Approximately 30 tissue-proven cases un-associated with Hodgkins's disease,4'5 or herpeszoster infections6' have been reported. Althoughgood responses to steroids or immunosuppressivetherapy have been described, the outcome is generallyfatal." Moreover, in most cases, diagnosis was madeonly at necropsy, thus contributing to the apparenthigh fatality rate. We studied five tissue-proven casesunassociated with systemic illnesses which illustratethe varied manifestations of granulomatous angiitis.

Case reports

Case 1: For two months, a 69 year old man had a personalitychange with irritability and apathy. For 3 weeks, he hadglobal headache, eye pain, and hesitancy in speech. Past his-tory included a myocardial infarction and a coronary arterybypass grafting procedure. On examination, he was disori-ented and apathetic with poor comprehension, jargonspeech, mild right hemiparesis, bilateral grasp reflexes, andright Babinski sign. Laboratory studies showed a ESR 22

Address for reprint requests: Edward H Koo, M.D., Neuro-pathology Laboratory, The Johns Hopkins University Schoolof Medicine, 509 Pathology Building, 600 North Wolfe Street,Baltimore, MD 21205, USA.

Received 21 January 1988.Accepted 15 April 1988

mm/h and negative syphilis serology. CT showed a non-enhancing left temporoparietal mass. Arteriogram demon-strated elevation of the Ml segment consistent with masseffect but without tumour blush or segmental narrowing. Abiopsy of the left temporal cortex showed extensive focalvasculitis involving the small penetrating and cortical arte-rioles and arteries up to 250 pm in diameter. Small veins andvenules were also involved. In this and other cases, the sever-ity of inflammation often obliterated distinguishing land-marks between arteries and veins. The meninges were mildlyinflamed with minor vasculitic changes in small pial vessels.The inflammatory infiltrate consisted of lymphocytes,histiocytes, and epithelioid cells which tended to disruptthe vessel walls (fig 1). Rare giant cells were present. Thelesions were often transmural but segmental sparing of theendothelium, intima, or inner media were observed. Somevessels showed concentric or patchy proliferation of the en-dothelium. Special strains for bacteria, fungi, and acid-fastmicroorganisms were negative in all cases of this report. Hewas treated with prednisone (80 mg/day) and cyclo-phosphamide (2 mg/kg), the latter discontinued due topersistent leukopenia. CT at 3 months showed resolution ofthe previous mass with bilateral leukoencephalomalacia inthe parieto-occipital areas. Four months after diagnosis, ex-amination was normal and prednisone dosage was reduced.One year after the onset, while still taking prednisone (5 mgon alternate days), he complained of new headache. CTdemonstrated a new low density lesion in the tip of the righttemporal lobe. MRI confirmed the CT finding with an areaof high signal intensity in the right temporal tip but in addi-tion, similar lesions were seen in multiple areas ofboth hemi-spheres consistent with recent infarction (fig 2). Aftercholecystectomy, prednisone (80 mg/day) was restarted and

1126

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Fig 1 Microscopic sectionfrom case 1 shows a small cortical vessel with its wall infiltrated by a proliferation oflymphocytes,histiocytes, and epithelioid cells. (H&E; x 1100)

his headache subsided. He remained symptom free onfollow-up.Case 2: For 6 weeks, a 65 year old man had progressiveconfusion and memory loss. His past history included cor-onary artery disease and mild glucose intolerance. Exam-ination demonstrated waxing and waning disorientation andprominent frontal release signs. Laboratory studies includedESR 30 mm/h, normal thyroid functions, B12, syphilis serol-ogy, and rheumatological screens. CSF pressure was 180mm H20, with 12 WBC/mm3 (8L, 4P), protein 142 gm/I,glucose 76 gm/l. CSF cultures and cytologies were negative.On serial CSF examinations, there were between 20 to 50WBC/mm3, primarily lymphocytes, and protein of 146 to193 gm/l. A cerebral angiogram was normal. CT showedmild cortical atrophy and a right posterior frontal lobe den-sity consistent with infarct. A right inferior frontal men-ingeal biopsy showed diffuse vasculitis in the smallmeningeal vessels. The inflammation consisted of peri-vascular and intramural infiltration of lymphocytes and his-tiocytic cells. Patchy endothelial proliferation and scatteredgiant cells were present. Fibrinoid necrosis was not seen.Treatment with prednisone (100 mg/day) was begun.Follow-up lumbar puncture one month later revealed 8WBC/mm3 and protein 43 gm/l. The patient continued toimprove and at 3 months, a tapering dose of steroid wasinstituted. At 18 months, his cognition was normal.Case 3: A 44 year old man had a 2 week history of malaiseand fever. One week before admission, he noted headaches,

vomiting, and became disoriented. There was a remote his-tory of alcohol abuse and hypertension. On examination,temperature was 39°C. He was lethargic and oriented to hisname only. Several small lymph nodes were palpable. Hisspeech was mildly dysarthric. Plantar response was flexorbilaterally. Laboratory data included ESR 41 mm/h, WBC11,600/mm3 (75 P, 7 B, 11 L, 7 M). CSF pressure was245 mm H20 with xanthochromia, RBC 3,000/mm3, WBC800/mm3 (8% P, 92% L), glucose 39 mg/dl (serum 101mg/dl), protein 119 mg/dl and gamma globulin 14% of totalprotein. CSF gram stain, cultures, and VDRL were all nega-tive. He was treated for presumed meningitis. Several dayslater, while still febrile and disoriented, examination showedmild expressive aphasia, right hemiparesis, bilateralBabinski signs, and grasp reflexes. CT showed a hyperdenselesion in the left temporal lobe with surrounding low densityareas consistent with haemorrhage. He was given ara-A forpresumed herpes simplex encephalitis. Arteriogram revealeddiffuse saccular and fusiform dilatations of small intra-cranial arteries in both hemispheres. A biopsy of the lefttemporal cortex without meninges showed intramural andperivascular inflammation of a small artery, measuring lessthan one millimetre in diameter. The infiltrate consisted oflymphocytes, histiocytes, and multinucleated giant cells. Thevessel was thrombosed. The internal elastic lamina was in-tact without fibrinoid necrosis. There was no evidence ofencephalitis and intracellular inclusions were not seen. A re-nal and mesenteric arteriogram was negative as were the

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Fig 2 Magnetic resonance imaging ofcase I demonstratesmultifocal areas ofincreased signal intensity on T2-weightedspin-echo image, most marked in both temporal lobes.

rheumatological screens. The patient was treated with pred-nisone (80 mg/day) and cyclophosphamide (2 mg/kg) withgradual but not total improvement in his mentation. A re-peat arteriogram 2 months later showed resolution of theprevious abnormalities. CSF pressure was normal withWBC 6/mm3, protein 42 gm/l, glucose 62 gm/l, and gammaglobulin 8-3% of total protein. He was discharged takingprednisone (5 mg/day) and cyclophosphamide (75 mg/day).Six months later, he stopped taking medication and was lostto follow-up. Two years later, he was readmitted after 2 daysof left-sided weakness and disorientation. CT showed mildcortical atrophy with a small lucency in the left thalamus.Arteriogram showed narrowing of right internal carotid ar-tery in supraclinoid region. Between 4 to 8 monocytes/mm3were seen in the CSF with protein from 56 to 63 gm/l andnormal glucose. He was again given cyclophosphamide andprednisone. CSF two months later demonstrated no whitecells but a protein of 76 gm/l. Steroid dosage was taperedafter 3 months while cyclophosphamide was continued forapproximately a year. When last seen, he remained some-what abulic but was otherwise fully oriented. A mild lefthemiparesis persisted with diffusely brisk reflexes, bilateralextensor plantar responses and active frontal release signs.Case 4: A 78 year old man was found unresponsive on thefloor. He had been in good health without complaints. Amajor motor seizure was witnessed. Examination showeddisorientation with a left homonymous hemianopsia, lefthemiparesis, minimal left hyperreflexia, bilateral extensor

Koo, Massey

plantar responses, and frontal release signs. Laboratorystudies included ESR 47 mm/h, normal B12, thyroid func-tions, and syphilis serology. CSF showed normal openingpressure, no cells, glucose 115 gm/il, and protein 81 gm/I withnegative cultures, VDRL, and oligoclonal band. CT demon-strated bifrontal white matter hypodensities withoutenhancement, more on the right (fig 3). His mental statuswaxed and waned, but he remained depressed and abulic.The clinical diagnosis was multi-infarct state. Repeat lumbarpuncture was remarkable only for a protein of 64 gm/I. Twoweeks later, he died after aspiration and cardiopulmonaryarrest. At necropsy, the gyri over both hemispheres wereflattened. Large vessels were minimally atherosclerotic.Marked angiitis of arterioles and small arteries up to 300 .min diameter, and to a lesser extent, veins and venules, wereobserved in both frontal and right occipital cortices. Thisprocess favoured smaller vessels to the extent that larger ves-sels adjacent to an involved arteriole or venule would bespared (fig 4). The vasculitis was most prominent in pial andpenetrating vessels. Deeper vessels in the white matter werespared but patchy areas of ischaemic changes with reactiveastrocytosis were observed. Other regions of the brain, largecerebral vessels, and systemic organs were not involved. Theinflammation consisted of histiocytes and lymphocytes withscattered haemosiderin-laden macrophages and occasionalmultinucleated giant cells in the periphery. The inflamma-tory aggregates were often concentrically positioned aboutthe vessels but segmental involvement was not uncommon.In many smaller vessels, PTAH stain showed prominentfibrinoid necrosis. These vessels were notable for a variabledegree of inflammation and by the presence of scattered

Fig 3 Bilateral white matter lucencies in the centrumsemiovale are seen in the CT scanfrom case 4.

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Granulomatous angiitis of the central nervous system: protean manifestations and response to treatment 1129

neutrophils (fig 4). Endothelial proliferation was pro-nounced in some vessels. Perivascular ring haemorrhagesand necrotic cellular debris were present in the superficialcortical regions. The meninges showed mild fibrosis.Case 5: A 60 year old diabetic man had a several monthhistory of falling and difficulty in walking. On examination,there was mild memory impairment, right hemiparesis andtruncal ataxia. CT revealed minimal cortical atrophy. Onemonth later, CT showed a low density area in the right cere-bellum consistent with infarct. Signs included depressedmentation, dysmetric ocular movements, ataxic limbs, andright Babinski sign. ESR was 28 mm/h and ANA was nega-tive. CSF contained between 30 to 169 WBC/mm3 (100%L), protein about 100 gm/l, normal glucose, pressure of 330mm H20 with negative cytology and cultures. CT suggestedbilateral low density areas deep in the cerebellum. An arte-riogram was normal. Prednisone (100 mg/day) and radiationtherapy were given for presumed cerebellar glioma. After 2weeks, he showed mild improvement together with a de-crease in CSF pleocytosis (2 WBC/mm3) and protein (31gm/l) but died 2 weeks later from complications of a per-forated appendix. At postmortem examination, there wasminimal atherosclerosis of the large vessels. The right cere-bellar hemisphere was soft, with loss of cytoarchitecture anda brown discolouration consistent with subacute infarct.Smaller foci of softening were present in the base of thepons. Microscopically, striking granulomatous angiitis was

present in small leptomeningeal vessels in the cerebellumand, to a lesser extent, the brainstem. Arterioles and arteries,up to one millimetre in diameter, and veins were affected.The process was widespread, but in less involved areas, theangiitis clearly favoured the meningeal and penetrating ves-sels over the parenchymal ones (fig 5). The transmuralinflammation consisted of infiltration of lymphocytes, his-tiocytes, and multinucleated giant cells, concentrically orsegmentally extending to or beyond the borders of the ad-ventitia (fig 6). In the periphery, fibroblasts and lympho-cytes, admixed with scattered haemosiderin-ladenmacrophages, predominated. Many vessels were partially ortotally occluded by the proliferation of endothelium,fibroblasts, and inflammatory cells. Features of chronic is-chaemia with marked rarefaction, neuronal loss, and gliosiswere evident in much of the cerebellum. From the uppercervical cord to the midbrain, minor vasculitic changes wereobserved. Lymphocytic infiltration was more intense thanthe fibroblastic response in these vessels, while the ischaemicchanges were more recent than in the cerebellum. Additionalsmall foci were present in the hypothalamus, optic chiasm,and gyrus rectus. The eye and systemic organs were spared.

Discussion

Granulomatous angiitis is a rare disorder presentingin adults with necrotising inflammation of small cere-

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Fig5 The segmental nature ofthe angiitis is illustrated in case 5 by the nodular aggregations ofinflammatory cells along thissmall leptomeningeal artery as it penetrates the rarefied and gliotic cerebellar cortex. (H&E; x 300)

bral arteries and veins2 9-20 with diameter about 200pm.' Larger vessels may sometimes be involved. Theinflammation consists of macrophages, lymphocytes,epithelioid cells, and multinucleated giant cells withinthe vessel walls and may be associated acutely withfibrinoid necrosis2 'o and polymorphonuclear leuko-cytes. Eosinophils and necrosis within granulomasare generally absent. In early cases, lymphocytesinfiltrate in the adventitia,l while in chronic cases,

fibroblastic proliferation may become prominent(case 5). There is a predilection for leptomeningealover the parenchymal vessels' 2 and the involvementmay be segmental, patchy, or diffuse." Blood vesselsin any part of the central nervous system may beaffected9 2' and, occasionally, the disease may be pre-

dominantly venous,'6 meningeal, or even ventricu-lar.22 Rarely, clinically silent lesions have been seen invisceral organs at postmortem exam-

ination.21' 1221 22 Occasionally, the granulomatousnature of this disease may only be a minimal com-

ponent of the inflammatory process.26 As a result,some authors prefer the term "isolated angiitis of thenervous system" to emphasise its unique distributionrather than the histological features.26 Ischaemic ne-

crosis, haemorrhagic infarcts in evolving stages, and

reactive astrocytosis are generally observed in the sur-rounding brain tissue.1 2 The aetiology and patho-genesis are unknown, but particles resemblingmycoplasma23 or viral-like structures24 have been de-scribed. Detailed studies of vessel immunoreactivity,as done in other systemic vasculitides, are lacking.Immunoperoxidase studies in one case did not detectthe presence ofimmunoglobulin deposition within thevessel walls.25

It has not been possible to categorise definitivelygranulomatous angiitis among the inflammatory vas-culitides: whether this disease is a separate entity anddistinct from the other systemic vasculitis which affectthe central nervous system is uncertain. The majordifferential diagnoses include the systemic arteritidessuch as periarteritis nodosa, rheumatoid arteritis,lymphomatoid granulomatosis, Takayasu's disease,and temporal arteritis, sarcoidosis, infectious angiitis,especially herpes zoster, and granulomatous angiitisassociated with Hodgkin's disease. At present, it isdistinguished from the other inflammatory vascu-litides in several ways: the involvement is almost ex-clusively in the central nervous system with absence of

26systemic signs, the lesions affect not only small arte-ries but also veins,' 2 the vessels involved are smaller,

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Granulomatous angiitis of the central nervous system: protean manifestations and response to treatment 1131*_ _t _0iFig 6 Microscopic sectionfrom case 5 shows extensive involvement ofa leptomeningeal vessel with proliferation ofmononuclear and epithelioid cells surrounded by a rim oflymphocytes andfibroblasts in the periphery. (H&E; x 1000)

the inflammation tends to be less necrotising incharacter,11 and eosinophils are absent.1 10 Granu-lomatous angiitis is separated from sarcoidosis by thegeneral absence of necrosis in the latter, the promi-nent perithelial granulomas, a greater tendency toinvolve the base of the brain, and the involvement ofsystemic organs."1 The pathology may be inseparablefrom herpetic angiitis.67 27 The distinction then lies inthe invariable antecedent herpetic eruption, often inthe ophthalmic division of the trigeminal nerve withresultant contralateral hemiparesis. Some authorsconsider this disease to be a variant of temporal arte-ritis.10 28 However, even though there have been rare

cases where the vasculitis involved both the temporaland intracranial arteries,29 30 granulomatous angiitisis generally considered to be distinct from temporalarteritis.3 1 The latter tends to involve older patients,is frequently coincidental with polymyalgia rheu-matica, and the sedimentation rate is strikingly el-evated.3 Anatomically, the lesions of temporalarteritis involve larger arteries while sparing the intra-cranial arteries and veins, and are not characterisedby the prominent granulomatous response.'1 31While not absolute, these clinicopathologic features,taken together, define a characteristic entity. Our five

cases all share features of a chronic necrotising vascu-litis involving small cerebral vessels and lack evidenceof an underlying systemic vasculitis. Although the in-tensity of the lesions varied, the changes generallycorrelated with the duration of neurological symp-toms.The clinical manifestations are chiefly neurological

and no consistent clinical pattern suggests the diagno-sis. Non-specific manifestations include weight loss,malaise, headache, vomiting, visual loss, confusion,

Table Comparison of laboratory values between presentseries and tissue-proven cases in the literature

Present series Literature*

ESR (> 30 mm/hr) 2/4 6/19CSF opening pressure(>220mmH 0) 2/3 6/18

CSF WBC (> /mm) 3/4 19/24CSF protein (>45gm/1) 4/4 19/26CSF glucose (<45gm/1) 1/4 5/19Any CSF abnormality

(OP, WBC, protein, glucose) 4/4 26/28

*Tabulated from ref. 1, 2, 9-26, 34-36; but does not include thefollowing cases: ref. 1, case 4 (herpes zoster ophthalmicus), ref. 10,cases 1, 2 (temporal arteritis), ref. 17, case 2 (Churg-Strauss), ref. 26,cases 1, 2, 3 (no tissue diagnosis).

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1132and lethargy. Systemic symptoms, such as arthalgia,myalgia, or skin rash, are absent. Focal signs of hemi-paresis, aphasia, myelopathy, or seizures, are presentat some point in the clinical course. In addition, signsof increased intracranial pressure and encepha-lopathy are common. A stepwise progression or mul-tifocal signs point towards a vasculitis. But thesecharacteristic findings are frequently absent in theearly phases of the illness. Our cases emphasise theprotean manifestations of this disease. Features of aprogressive multifocal disorder were lacking and theymimicked stroke, tumour, or infection. The threecases (1, 2 and 3) reported here with long term sur-vival suggests clinical remission may be achieved withearly diagnosis and treatment.

In diagnosing this disease, routine laboratory stud-ies including rheumatological screens are uniformlyunrevealing.26 The erythrocyte sedimentation rateis often normal (table). The CSF is almost alwaysabnormal with mononuclear pleocytosis and highprotein, as in our cases. In addition, CSF pressureis often increased while hypoglycorrhachia2426 orxanthochromia,29 1224 as in Case 3, is infrequent.Increased CSF gamma globulin'025 has been notedwhile oligoclonal bands have not been described.The CSF abnormalities can resolve with clinicalimprovement.The diagnosis cannot definitively be made by cere-

bral angiography despite claims to the contrary.32One quarter of the tissue-proven cases had normalstudies,9 10 13 23 while 50% showed non-specific arte-rial narrowing, 1 19 21-23 2 33 34 and only 25% dem-onstrated segmental narrowing or beading."1 142035In the latter group, angiograms of two patients werenon-diagnostic at first and were abnormal on a sec-ond study."1 35 Angiographic changes in cases notsupported by tissue diagnosis are of uncertainvalue.2632 In a case of "benign cerebral vasculitis"biopsy of an angiographically abnormal vessel wasunremarkable.36 In our cases, angiography was nor-mal in cases 2 and 5; and showed only mass effect incase 1. In case 3, irregular dilatations resolved withtreatment.CT abnormalities were seen in all of our five

patients. However, these changes were nonspecific,with areas oflow density, mass effect, or cortical atro-phy. Lesions consistent with haemorrhagic infarctioncan also be seen (case 3). Similar abnormalities weredescribed in five of seven reported cases withCT.14 21 22 25 34 In case 4, CT showed bilateral whitematter hypodensities suggesting early infarction (fig3). Similar white matter lucency was described in twoother cases,'4 22 and one case associated with Hodg-kin's disease.5 This feature offers a clue to the diagno-sis because of the multifocal lesions that do notconform to major vascular territories. CT findings

Koo, Masseymay similarly subside (cases 1 and 3).

Brain biopsy has been advocated when the angio-gram is negative." 26 The present series probablyskews the emphasis towards the need for biopsy sincepathological confirmation was required for inclusioninto this study. However, of the three premortem di-agnoses, the diagnosis was suggested by the angio-gram in only case 3. The remaining two cases (1 and2) still required a biopsy. Thus, this study reaffirms aposition held by some authors for the need to proceedto brain biopsy for definitive diagnosis, especiallywhen the arteriogram is unrevealing.26Among reported cases, diagnosis was established

by biopsy in seven'920252633-35 but not in 10others. 1 913 lS- 18 22 23 The patchy nature of thisdisease may account for the low yield of open biopsy.However, many of the negative cases were from theearly reports when the disease was less well known.Temporal artery biopsy is uniformly negative23 35and thus should not be routinely pursued. One biopsywas abnormal'0 (case 1 of ref.) but the case moreaccurately fits a diagnosis of temporal arteritis. Tomaximise the yield on biopsy, it is imperative toobtain both leptomeningeal and cortical tissue forpathological examination.8Although a generally fatal outcome was described

in earlier cases, 1 12 13 15- 17 several patients have re-covered or survived. Specifically, of the tissue-provencases, apparent spontaneous improvement was re-ported in two patients,25 33 their only treatment beingfive days of tapering doses ofdexamethasone given aspart of the biopsy procedure. Four cases improved orstabilised on corticosteroids,' 9 19 20 while two addi-tional cases responded to steroid and cytotoxic drugs,either azothioprine35 or cyclophosphamide.26 How-ever, the remission was not sustained in four of the sixcases.' 9 19 35 The time course in those cases was un-predictable. Brief trials of corticosteroids in the ante-mortem period did not alter the outcome in five othercases.10 14 21 23 In two patients with Hodgkin's dis-ease, the neurological signs remitted following treat-ment of the malignancy.45 In our three treatedpatients, the responses have been satisfactory. Case 1had asymptomatic involvement of the contralateralhemisphere detected by CT and MRI and case 3 re-lapsed while off medication but stabilised withreinstitution of treatment. These cases suggest thateven with early response, prolonged treatment is indi-cated. Furthermore, the fluctuating courses in cases 1and 3 suggest that follow-up might include CT orlumbar puncture to diagnose early relapse. In anec-dotal reports, high dose steroid was the drug ofchoicewhile additional benefits from immunosuppressiveagents such as cyclophosphamide may be seen. Whileadequate clinical trials are lacking, the outcome inthose patients given steroids appears to be better than

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Granulomatous angiitis of the central nervous system: protean manifestations and response to treatment 1133no treatment. Whether immunosuppressive drugsshould be added routinely is uncertain. In view of thelikelihood of an extended period of treatment withpotentially hazardous drugs, the need to establish anunequivocal diagnosis is of utmost importance.

We are grateful to Dr R Young for referring case one

and to Dr M V Solbrig for her assistance with cases 1

and 4.

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