96 POSTGRADUATE MEDICAL JOURNAL February, 1965

That cortisone may be of value in the treatmentof Schuller-Christian's disease was suggested byBlahd, Levy and Bassett (1951). Jn the presentcase prednisone may have been of temporarybenefit. The maximal effect was on the lymphglands. Although the mandibular lesion continuedto improve this was probably due to the radio-therapy as no decrease in size was noted in theother bony lesion.A purulent discharge from the ear is frequently

mentioned in previous case reports and this isoften associated with the presence of granulationtissue in the external auditory canal. It has notbeen considered of much importance but it is socommon a finding that it must form part of theclinical picture. Histological examination of thegranulations in this case identified the tissue asbeing similar to the lesions elsewhere in thepatient.Anamia is a common finding in this disease

and its occurrence has not been completelyexplained. At post-mortem examination in thiscase, granulomatous deposits were found in thebone marrow but they were not so extensive asto completely replace the blood forming elements.That the bone marrow is capable of respondingeven when involved in the disease process wasdemonstrated by Wallgren (1940) who found areticulocyte count of 12.6% in a patient with ahaemoglobin of 32%. The failure to respond toblood transfusion was surprising but this type ofprogressive anaemia in spite of blood replacementhas been reported (Abt and Denenholz, 1936).In this case obvious haemolysis of the red cells was

taking place. It may be that a haemolytic type ofanaemia is usually present in this disease. How-ever, no reference to this can be found in theliterature.

I am indebted to Mr. M. H. Harmer for permissionto publish this case report.

REFERENCESABT, A. F., and DENENHOLZ, E. J. (1936): Letterer-

Siwe's Disease. Splenohepatomegaly Associatedwith Widespread Hyperplasia of Non-lipoid Stor-ing Macrophages; Discussion of the so-calledReticulo-endotheliosis. Amer. J. Dis. Child., 51,499.

BLAHD, W. H., LEVY, M. S., and BASSETr, S. H.(1951): A Case of Hand-Schuller-ChristianSyndrome treated with Cortisone. Ann. intern.Med., 35, 927.

FARBER, S. (1941): The Nature of "Solitary orEosinophilic Granuloma" of Bone. Amer. J. Path.,17, 625.

GREEN, W. T., and FARBER, S. (1942): "Eosinophilicor Solitary Granuloma" of Bone. J. Bone Jt. Surg.,24, 499.

JAFFE, H. L., and LICHTENSTEIN, L. (1944): Eosino-philic Granuloma of Bone. Arch. Path., 37, 99.

LICHTENSTEIN, L. (1953): Histiocytosis X. Integrationof Eosinophilic Granuloma of Bone, "Letterer-Siwe disease", and "Schuller-Christian disease" asrelated Manifestations of a Single NosologicEntity. A.M.A. Arch. Path., 56, 84.

MCGAVRAN, M. H., and SPADY, H. A. (1960):Eosinophilic Granuloma of Bone, J. Bone Jt Surg.,42A, 979.

WALLGREN, A. (1940): Systemic ReticuloendothelialGranuloma. Non-lipoid Reticuloendotheliosis andSchuller-Christian Disease. Amer. J. Dis. Child.,60, 471.

ARTERIAL OCCLUSION TREATED WITH STREPTOKINASEA Report of Two Cases

M. L. CLARK, M.B., M.R.C.P. MARGARET HOWELL, M.B., B.S.

CHRISTINE HAWKEY, M.Sc. R. S. 0. REES, M.B., M.R.C.P., D.M.R.D.

J. STUBBS, PH.D., F.R.C.S.St. George's Hospital and Medical School, London, S.W.1.

THE PLASMINOGEN activator streptokinase wasfirst given intravenously to human volunteers byTillett, Johnson and McCarty (1955) and sub-sequently has been used as a thrombolytic agent,case reports having recently been published inBritish journals (Cotton, Flute and Tsapogas,1962; McNicol, Reid, Bain, and Douglas, 1963;Verstraete, Amery and Vermylen, 1963). Strepto-kinase may be administered by one of twomethods; either intravenous infusion starting with

a calculated loading dose, thus providing a highlevel of streptokinase throughout the circulation,or by local infusion into the affected arteryproximal to the actual occlusion. The secondmethod has the advantage that, whilst usingrelatively small doses, a high concentration ofthe drug can be brought into close contact withthe thrombus, although the level of streptokinasein the general circulation remains too low to causea coagulation defect.

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February, 1965 CLARK, HAWKEY, HOWELL, REES and STUBBS: Arterial Occlusion

FIG. 1.-Femoral arteriogram immediately beforeStreptokinase infusion.

We wish to report the treatment with strepto-kinase of two cases of arterial occlusion, one bylocal infusion and the other by general intra-venous therapy. The second case is of particularinterest because firstly there was evidence thatthrombolysis was still occurring 96 hours afterthe initial occlusion, and secondly continuoustreatment was maintained for seven days.Materials and MethodsThe streptokinase used was a highly purified pre-

paration 'Kabikinase' supplied by Kabi Pharma-ceuticals, London. The SK units referred to are

FIG. 2.-Femoral arteriogram after 17- hours infusionof Streptokinase.

"Manufacturer's' units. In each case samples ofvenous blood were collected before and at intervalsduring the infusion. The following tests were carriedout immediately on all samples: euglobulin lysistime, strong thrombin time (50 N.I.H. unitsthrombin/ml.), weak thrombin time (5 N.M.H. unitsthrombin/ml.) and prothrombin time, and, in addition,an antistreptokinase antibody titration was performedon the initial sample from Case 2. Plasma wasstored at -35'C. for fibrinogen and plasminogenassays to be carried out at a later date. The methodsfor collecting the blood samples and carrying outthe above tests are described elsewhere (Hawkey andHowell, 1964).

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Case No. 1The patient was a 67-year-old man who nine days

after admission to hospital with a left hemiparesiscomplained of coldness in the left leg and foot, nopulse being palpable below the left femoral. By thenext day there was no improvement and the limbhad become cyanosed and mottled over its anterioraspect. A catheter was inserted into the left femoralartery percutaneously by the Seldinger technique andadvanced into the thigh under fluoroscopic control.Slight resistance was encountered at about 10 cm.so 5 ml. of Isopaque was injected and a film exposed(Fig. 1). The medium was seen to enter blood clot,the artery being completely blocked just distal to thecatheter tip. With the catheter in ithis position acontinuous infusion of streptokinase was administeredusing a mechanically driven syringe-driver.The infusion which was started approximately

29 hours after the onset of symptoms was continuedfor 253 hours, a total of 731,000 units of strepto-kinase being given. There was no loading dose andthe initial rate of infusion was 700 units in 0.5 ml.physiological saline per minute. After 15 hours thiswas reduced to 350 units/minute because of evidenceof high systemic fibrinolytic activityy (Table 1) andfour hours later it was reduced further to 250 unitsper minute. Conventional anticoagulant therapy withpheninidione was started 12 hours after the infusionbegan. No reaction attributable to the streptokinaseoccurred during the infusion, the patient's tempera-ture remaining at the pre-infusion level throughout.Soon after starting treatment the upper thigh

became warm; the popliteal pulse returned within14 hours and an arteriogram at that time showedfilling to the upper part of the popliteal arteryalthough the arterial walls appeared to be veryirregular. The catheter was advanced down the thigh,closer to the point of occlusion, and the infusioncontinued. A further arteriogram 31 hours latersh9wed a relatively normal popliteal with good fillingof the proximal parts of the tibial arteries (Fig. 2).The leg continued to improve clinically and when theinfusion was discontinued after a total of 25* hours,the entire limb, apart from the lower part of thedorsum of the foot, was warm. Desquamation ofthe skin of the lower leg occurred during the next14 days but when seen in the outpatient departmentthree months later the leg appeared normal and allpulses, except the dorsalis pedis, were present. Therewere residual signs of hemiparesis, motor functionbeing slightly impaired, but there was no sensoryloss.

Case No. 2A 67-year-old woman with atrial fibrillation

developed a complete right hemiplegia. Ten dayslater she complained of pain in the left leg whichwas found to be cold with no pulse palpable.Sensation was normal but she was only able to moveher toes. A diagnosis of embolic occlusion of the limbwas made and anticoagulation with heparin andphenindione was started. The following day there wasno improvement, the leg being very painful with novoluntary movement possible and diminished cuta-neous sensation. Streptokinase therapy was started 34hours after the onset of symptoms, Sp. herapin beingdiscontinued and 100 mg. hydrocortisone hemisuc-cinate given: phenindione was continued throughoutthe infusion. A loading dose of 200,000 units ofstreptokinase, calculated from the antistreptokinaseantibody titration and the patient's body weight, wasgiven in 40 ml. 5% dextrose over a period of

TABLE 1

INVESTIGATIONS ON PLASMA SAMPLES FROM CASE 1

Hours of infusionEuglobulin lysis

time (minutes)Prothrombin time

(seconds)Thrombin time

(seconds)50 units/ml.5 units/ml.

Fibrinogenmg./100 ml.

0

130

Post Infusion15 21 if 12

13 8 35

16 21 18

8 25 1837 no clot 180

formed

156 84 120 150 198

30 minutes into an antecubital vein. This wasfollowed by a sustaining dose of 50,000 units ofstreptokinase in 30 ml. dextrose per hour, and thisinfusion rate was continued for seven days withonly minor adjustments. During this period a totalof 7,000,000 units of streptokinase was given. Resultsof the investigations carried out on the patient'splasma are shown in Figure 3. There was no delete-rious reaction during the infusion which could beattributed to the streptokinase.Within two hours of starting the infusion the upper

third of the thigh had become warm and this improve-ment continued slowly over the following days untilthe limb was warm to the level of the knee, thefemoral pulse becoming palpable for the first time96 hours after the onset of symptoms. There waslittle further improvement, the warm area finallyextending to just below the knee with the leg distalto this showing gangrenous changes. On the sixthday of the streptokinase infusion 1000 ml. of lowmolecular weight dextran was given (Rheomacrodex,Pharmacia Ltd.-10% solution in dextrose). Thepatient's general condition gradually deteriorated andshe died 25 days after the arterial occlusion. Per-mission for post-mortem examination was not given.

DiscussionThe excellent result achieved in Case 1 was

almost certainly due to thrombolytic therapybeing started relatively soon after the occlusion.Not only was the limb still viable but the throm-bus was still susceptible to lysis. The work ofJohnson and McCarty (1959) suggests that thesusceptibility of an intravascular thrombus tolysis lessens as it becomes older. These workersalso noted that artificially induced clots in theforearm veins of volunteers could only be re-moved by SK infusion for up to 72 hours aftertheir formation. In Case 2 the return of thefemoral pulse 96 hours after the onset of symp-toms of occlusion suggests that thrombolysis wasstill proceeding at this time. Two possibleexplanations for this are that artificially inducedclots may differ from spontaneous intravascularthrombi in their susceptibility to SK, and thatafter embolic occlusion of the artery furtherclotting may have occurred slowly below theblock so that younger thrombus was presentdistally.The percutaneous method of arterial cathe-

terisation used in Case 1 simplifies infusion and

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February, 1965 CLARK, HAWKEY, HOWELL, REES and STUBBS: Arterial Occlusion 99

_1209 EUGLOBULIN LYSIS TIMES- I

60j 0

o 0 000*~~~~~~~

2PLASMINOGEN

0 I_ 1 g i; ; _ IE

~ 12

THROMBIN TIMES

60C.,

* * * * * * * *~~~~~~~~soU/mI

600

FIBRINOGEN

-300

C- 120

=60

PROTHROMBIN TIMES

0-0 O 1 2 3 4 5 6 7

DAYS OF TREATMENT [50.000 SK UNITS / HOUR]FIG. 3.-Investigations on plasma samples from Case

2. Arrows indicate tests which were not followedfor longer than times plotted. Euglobulin lysistimes with added plasminogen are shown assolid circles (top graph).

permits serial arteriograms to be taken. Theseindicate the progress of lysis, enable the catheterto be advanced closer to the occlusion and helpthe duration of the infusion to be determined.The fact that there was some restoration ofcirculation in Case 2 shows that continuoussystemic therapy is also effective and can bemaintained for up to seven days without com-plication, so long as there is no coincidentalcause for hemorrhage.

SummaryThrombolysis induced by streptokinase infusion

is reported in two elderly patients with embolicarterial occlusion.

In the first case local intra-arterial infusionwas started 29 hours after a mid-femoral block.Distal pulsation returned after 14 hours infusionand an excellent result was ultimately achieved.In the second case, systemic streptokinase therapywas begun 36 hours after occlusion of an iliacartery: although recovery was only partialsystemic treatment was maintained for seven dayswithout complication and the femoral pulse re-turned 96 hours after the onset of symptoms.The advantages of local percutaneous infusion

controlled by serial angiography are commentedupon.

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100 POSTGRADUATE MEDICAL JOURNAL February, 1965

We are grateful to Dr. J. Dow and Mr. J. Gillespiefor their permission to report these cases.We would like to thank Miss Noel Lansdown and

Mr. V. Elliott for their expert technical assistance.We are particularly grateful to Mr. A. M. Nicholls

of Kabi Pharmaceuticals for generous supplies ofKabikinase.

This work was supported by grants from theSt. George's Hospital Research Fund and the MedicalResearch Council.

REFERENCESCOTTON, L. T., FLUTE, P. T., and TSAPOGAS, M. J. C.

(1962): Popliteal Artery Thrombosis treated withStreptokinase, Lancet, ii, 1081.

HAWKEY, C. M., and HOWELL, M. B. (1964): TheLaboratory Control of Thrombolytic Therapy, J.clin. Path., 17, 287. ,

JOHNSON, A. J., and MCCARTY, W. R. (1959): TheLysis of Artificially Induced Intravascular Clots inMan by Intravenous Infusions of Streptokinase,J. clin. Invest., 38, 1627.

MCNICOL, G. P., REID, W., BAIN, W. H., andDOUGLAS, A. S. (1963): Treatment of PeripheralArterial Occlusion by Streptokinase Perfusion,Brit. med. J., i, 1508.

TILLETT, W. S., JOHNSON, A. J., and MCCARTY, W. R.(1955): Intravenous Infusion of the StreptococcalFibrinolytic Principle (Streptokinase) into Patients.J. clin. Invest., 34, 169.

VERSTRAETE, M., AMERY, A., and VERMYLEN, J.(1963): Feasibility of Adequate ThrombolylicTherapy with Streptokinase in Peripheral ArterialOcclusions, Brit. med. J., i, 1499.

CROHN'S DISEASE OF THE STOMACH?G. A. KUNE, M.B., F.R.C.S., F.R.A.C.S.*,

Senior Surgical Registrar.JANE FULLERTON, M.B., B.Ch., D.P.H., F.C.Path.,

Consultant Pathologist.St. Olave's HosDital. London. S.E.16.

THE CONDITION now known as regional ileitis wasestablished as a clinical, radiological and patho-logical entity by Crohn, Ginzburg andOppenheimer in 1932. The histological nature ofthis disease was further underlined by Hadfieldin 1939. Regional ileitis was thus established asa disease of unknown aetiology, characterised bya thickened segment of ileum, consisting histo-logically of non-caseating granulomatous foci,together with a granulomatous involvement ofthe regional lymph nodes. Skip areas in the bowelwere described as a typical feature of thecondition.This type of granulomatous condition affecting

the ileum together with the colon (Crohn, 1949),and cases involving the colon alone (Armitageand Wilson, 1950), were later described. Regionalileitis, together with the involvement of the uppergastrointestinal tract was also reported (Rose1949, Martin and Carr 1953, Richman, Seifer,Winkelstein, Kirschner and Steinhardt 1955,Miller, Sandweiss and Schwachmann 1956).Finally, cases have been described where thisgranulomatous condition affects the stomachalone.

Because of its comparative rarity and interest,a further case of isolated granulomatous gastritisis reported.Case ReportMr. W.F., a 57 year old caretaker, first presented

at this hospital in August 1953. He gave a 15-yearhistory of recurrent episodes of pain in the epigas-trium and right hypochondrium. The pain wouldstart one hour after a meal, persist for about 10minutes and was occasionally associated withvomiting. He was tender in the epigastrium and

*Present address: The Lahey Clinic, Dept. of Surgery,605 Commonwealth Avenue, Boston, U.S.A.

right hypochondrium. There were no other abnormalphysical signs. A barium meal and gastroscopy doneat that time showed no abnormality.

Operation. While in hospital, he developed severeacute pain in the epigastrium. A tender gall-bladderwas palpable. At operation the gall-bladder wasdistended and contained stones. The common bile-duct was dilated and there was a large stone at itslower end. A cholecystectomy with choledocholi-thotomy was performed. He made an uneventfulrecovery.Two months post-operatively his original symptoms

of epigastric pain and vomiting recurred and persistedsince.

Investigations. Over the next 7 years he wasre-admitted to hospital on several occasions andfollowed regularly as an out-patient. The followingis a summary of the investigations done over thatinterval:July 1955 andFebruary 1956 Barium meals-No abnormality seen.November 1960 andMarch 1961 Gastroscopies-No abnormality seen.May 1961 Barium meal-There was a persistent

irregularity of the lesser curvatureof the stomach, near the pyloricantrum, probably an ulcer.

Because of his recurrent symptoms and bariummeal findings, he was re-admitted in May 1961, forconsideration of a further laparotomy. He was notedto have clubbing of the fingers for the first time.There were no other abnormal physical signs.

Operation. At operation there were numerousadhesions present around the porta hepatis and inthe upper abdomen generally, but otherwise noabnormality was found.

His symptoms persisted following this operationin spite of intensive medical treatment which includedhospitalization and bed rest, antacids, antispasmodics,sedatives and tranquilizers.

Investigations. He was followed as an out-patientfor the next two years and had a battery of in-

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