Postgraduate Medical Journal (July 1974) 50, 473-478.

Eosinophilic leukaemia terminating with an encephalopathy

G. M. YUILLM.B., M.R.C.P., B.Sc.

R. G. LASCELLESM.D., M.R.C.P., D.P.M.

C. SCHOLTZM.B., B.S., F.R.C.P.A.

Departnmetts of Clinical Neurology and Neuropathology, Manchester University

SummaryA 52-year-old man developed an illness which lastedfor 2 years until its fatal termination. It comprised inchronological order: mild asthma, skin irritation,mature eosinophilia in the peripheral blood, and finallyan encephalopathy. The diagnostic problem of dis-tinguishing between eosinophilic leukaemia and aneosinophilic leukaemoid reaction is discussed. Thecause of the encephalopathy was discovered at autopsyto be a widespread intravascular thrombotic process.Thejuestion of future possible therapy is discussed.

Case historyA 52-year-old male presented with an illness of 12

months' duration, comprising inchronological order:irritation of the skin, rhinorrhoea, mild wheezing,and finally painless enlargement of the glands in theneck. On examination the only abnormality was afirm painless enlargement of the supraclavicular, andsubmandibular glands. The clinical diagnoses con-sidered were Hodgkin's disease, or collagen disease.The following investigations were performed.The urine was normal. The blood haemoglobin

was 16 g/100 ml, blood white cell count 18,000/mm3.Differential white cell count, neutrophils 50 %, lymph-ocytes 8%, monocytes 3 %, eosinophils 38%, baso-phils 1 %, ESR (Wintrobe) 9 mm in the first hour. Agland biopsy was taken from the right side of theneck. It showed a non-specific inflammatory reactionwith significant eosinophilic infiltration. A sternalmarrow was normal except that there was an increasein eosinophils which comprised 23-5% of the totalcell population. There was no parasite infection inthe stools.He was treated with oral prednisolone 10 mg three

times daily, and the lymphadenopathy resolved over2 months. The dosage of prednisolone was slowlyreduced. The sequential changes in the blood countare shown in Fig. 1. After 8 months he complainedof nasal obstruction. There was no local nasal

Correspondence: Dr G. M. Yuill, The department of Neur-ology, Manchester Royal Infirmary, Oxford Road, Man-chester.

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FIG. 1. Graph showing the patient's bloodcount duringthe course of his illness. 0, eosinophils as % of totalwhite cell count; ', total white cell count.

abnormality. X-rays showed mild opacification ofthe frontal sinuses. The spleen was now enlarged 2finger breadths below the costal margin. Furtherinvestigations were as follows.Blood haemoglobin 13-6 g/100 ml, blood white

cell count 86,000/mm3; differential white cell count-neutrophils 9%, lymphocytes 3%, monocytes 1%,eosinophils 87 %. The ESR (Wintrobe) was 13 mm inthe first hour. Serum albumen 2-9 g/100 ml, serumglobulin 4-2 g/100 ml; serum protein electrophoresisshowed a slight increase in alpha 1 and alpha 2globulin, and a moderate diffuse increase in gammaglobulin. Serum alkaline phosphatase 22-5 KingArmstrong units, serum uric acid 6-5 g/100 ml. Theserum Vitamin B12 was 200 pg/ml, serum folic acid0-6 ng/ml. The alkaline phosphatase score was 114(raised) in the neutrophil polymorphs, and was nil inthe eosinophilic polymorphs. The blood urea was 36mg/100 ml; the serum electrolytes were sodium 134mEq/l, potassium 4-8 mEq/l, and chloride 101 mEq/l.The liver function tests were: thymol turbidity 2-0,SGOT 14, SGPT 11, and serum bilirubin 1-0 mg/100

474 Case reports

ml. Again no parasites or ova could be found in thestools. The sheep cell agglutination test was negative.The bleeding time was 1 min (normal 2-5), the pro-thrombin time 13 sec (control 12 sec). The plasmaclotting time and the thrombin clotting time wereboth normal. The chest X-ray was normal. The liverbiopsy showed a normal liver architecture, with aminor degree of infiltration by mature eosinophils.The philadelphia chromosome was absent.The diagnosis was felt to be an atypical form of

polyarteritis nodosa, or possibly Wegener's granulo-matosis. He was treated with oral cyclophosphamide100 mg daily, prednisolone 120 mg orally, and septrin1 tablet daily (sulphamethoxazole 400 mg, trimetho-prim 80 mg). The blood white cell count fell and thedosage of prednisolone was reduced over 2 weeks to30 mg orally daily, and he was discharged. Twoweeks later he developed general malaise, cough, anda temperature of 100.4°F. He was readmitted. Theblood pressure was 110/70 mmHg, the pulse 120/minand regular. There was a mild bilateral tonsillarlymphadenopathy. The liver was palpable 2 fingerbreadths and the spleen 1 finger breadth below thecostal margin. There was no abnormality in the heart,lungs, nervous system, or remaining gland fields. Fourdays after this admission he developed herpetic coldsores on the lips. Ten days after admission he becameconfused, restless, and incontinent of urine. A pre-sumptive diagnosis of herpes simplex encephalitiswas made and he was transferred to the neurologicalunit at Manchester Royal Infirmary. He developedright basal pneumonic consolidation, and lapsed intocoma associated with decerebrate rigidity. Therewas no neck stiffness. The fundi were normal. Hewas treated with intravenous hydrocortisone, ampi-cillin, cloxacillin, and 250 mg of cytosine arabinoside.Over the next 24 hr both pupils became fixed and di-lated, respiration became fast and shallow, and hedied. The cerebrospinal fluid was clear, colourless,and under normal pressure. It contained 370 whitecells, polymorphs 30% and lymphocytes 70%. Theprotein was 30 mg/100 ml and the glucose 94 mg/100ml. Gram and Ziehl Neelson stains were negativeand no bacteria were cultured. Attempts to cultureviruses from the cerebrospinal fluid were made inthe following media: Monkey kidney cells, Helacells, HEp 2 cells, human amnion and humanembryo fibroblast (diploid) cells. No virus wasisolated.

Autopsy findings (C.S.)There was no external evidence of a haemorrhagic

diathesis. The main findings were in the abdomen.The spleen was enlarged and on sectioning had a pinkhomogenous appearance and weighed 1500 g. Theliver was enlarged and had a pale grey cut surface.It weighed 2470 g. There was enlargement of the

para-aortic lymph nodes. The upper pole of the leftkidney contained a haemorrhagic yellow tumour, theappearance ofwhich was typical ofa Grawitz tumour.There was bilateral pulmonary oedema. Smallthrombi were noted in the pulmonary arterioles.There was no pathology in the upper respiratorytract. The heart was not enlarged and weighed 345 gand within it were ante-mortem thrombi attached tothe trabeculae carnae under the mitral valve over anarea 2 x 2 cm. Examination of the brain showed avenous thrombosis in the right parieto-occipitalregion with no obvious underlying infarction.Examination of the brain and spinal cord failed toreveal any macroscopic pathology.

Microscopic histological examination revealedwidespread infiltration of tissues, by large numbersof mature eosinophils which were seen in the haemo-poietic and non-haemopoietic organs. The femoralbone marrow contained normal erythropoietic ele-ments and normal megakaryocytes, along with

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Case reports 475

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FIG. 3. A low power section of cerebral cortex showingan infarct of the grey and white matter. Haematoxylinand eosin (x 10).

large numbers of mature eosinophils and their pre-cursors, mainly metamyelocytes and only a few blastcells. The lymph nodes had lost their germinal centreswhich had been replaced by mature eosinophils. Thespleen similarly consisted of sheets of mature eosino-phils almost obliterating the normal architecture.The sections of the heart confirmed the presence ofan ante-mortem thrombus. Large numbers of eosino-phils were present on the left ventricular myocardiumparticularly. There were focal areas of myocardialfibre necrosis with evidence of macrophage activity(Fig. 2). Some of these areas also contained eosino-phils. Adjacent to the areas of myocardial necrosiswere arteries whose lumen contained thrombi, andwhose walls were thickened owing to fibrosis. Theelastic laminae were intact and there was no evidenceof an arteritis.The lungs showed pulmonary oedema and abun-

dant eosinophils in the fluid and interstitial tissues.Some arterioles contained ante-mortem thrombi andthe walls were thickened by an increase in the amountof fibrous tissue. Similarly arterioles in the kidneys

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FIG. 4. Thrombus in a cerebral capillary, consisting pre-dominantly of mature eosinophils. There is oedema ofthe surrounding brain. Haematoxylin and eosin (x 100).

contained thrombi, focal collections of eosinophilinfiltrates and the walls of the vessels were thickenedby intimal fibrosis. The tumour in the kidney was aclear cell adenocarcinoma. The liver containedeosinophils in both the sinusoids and the portaltracts, but was otherwise normal.The brain sections revealed infarcts of the grey

and white matter in both cerebral hemispheres, seeFig. 3. These were triangular in shape and were upto 1 cm along each edge. There were thrombi in thevessels related to them (Fig. 4). The vessels were notthickened; most contained large numbers of eosino-phils in the lumen. Only one haemorrhagic infarctwas noted.

Electromicroscopy of a mature eosinophil fromthe brain revealed a helical virus-like structure intha nucleus similar to murine leukaemia virus(Fig. 5).

DiscussionThere have been numerous descriptions of so-

called eosinophilic leukaemia in the literature. Some

476 Case reports

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FIG. 5. Electron microscopy. The nucleus of an eosinophilic polymorphcontaining a helical viral structure, Gluteraldehyde-osmic acid fixed,stained with Reynolds lead citrate stain.

do not fulfil the necessary diagnostic criteria re-quired for classification as leukaemias, i.e. a pro-nounced blood eosinophilia with an excess of im-mature forms in the peripheral blood and the bonemarrow; more than 5% blast cell types in the bonemarrow, tissue infiltration by immature cells of pre-dominantly eosinophilic types, anaemia, thrombo-cytopenia and a haemorrhagic tendency (Bentley etal., 1961; Rickles and Miller, 1972). De Gruchy(1970) comments that the eosinophils are commonlyof the mature type, that the philadelphia chromo-some has occasionally been demonstrated and thatendomyocardial fibrosis with mural thrombosis is afairly common complication, which often causescardiac failure and death. He also comments on theoccasional difficulty which may arise in distinguish-ing between eosinophilic leukaemia in which thecells are relatively mature and some cases of secon-dary eosinophilia. Some authors doubt the existenceof eosinophilic leukaemia as a distinct disease entity(Odeberg, 1965).The points in favour of a leukaemic process in our

case were the high white cell count, the lymphadeno-pathy, the terminal hepato-splenomegaly, the loweosinophilic polymorph alkaline phosphatase scoreand the infiltration of tissues by eosinophilic poly-morphs. However, investigation revealed a strikingabsence of immature eosinophils, or other immaturewhite cells, no depression of the platelet count, noanaemia, and no bleeding tendency.

The clinical points in favour of collagen diseasewere as follows. There was a history of asthma;eosinophilia is seen in 25 % of cases of polyarteritisnodosa. The haematological disturbances observedwere those of a leukaemoid reaction as described byDe Gruchy (1970). There was reversal of the serumprotein ratio with hyperglobulinaemia, and electro-phoresis showed this was mainly due to a diffuse risein alpha globulin. On the other hand his ESR wasnever significantly raised, he was persistently normo-tensive, had no proteinuria, and did not becomeuraemic.

Eosinophilia does occur in numerous other con-ditions, of which the ones following are germane toour case. There were no symptoms of gastro-intestinal parasite infestation, and no organisms wereseen in the stools. In Loeffler's syndrome transitoryopacities are seen on chest X-rays, there is frequentlyan Ascaris lumbricoides infection, and the conditionusually settles in 4-6 weeks. This is clearly in markedcontrast to our own case, who also was mildly asth-matic, a feature not seen in Loeffler's syndrome.During life we thought that his encephalopathy

was due to a viral encephalitis, as he had herpeticcold sores on the lips and was on treatment with acytotoxic agent and steroids which would predisposehim to a virus infection. An alternative clinical ex-planation considered was that this represented avasculitis involving the cerebral arterioles. This wasconjectural, as there was no clinical evidence of

Case reports 477

vasculitis elsewhere. The transient but definite im-provement in response to steroids and cyclophosph-amides cannot be adduced as evidence in favour ofeither collagen disease or eosinophilic leukaemia. Insummary, the clinical aspects of the case are notthose of a leukaemic process. However, when oneattempts to classify the process, it can be seen thatwe have a non-specific syndrome which could beeither a collagen disease, or an eosinophilic leukae-moid reaction.The findings on histological examination do not

fulfil the necessary diagnostic criteria for a leukaemicprocess. On the other hand there were very fewfeatures to substantiate the presence of a collagendisease. There was slight thickening of the walls ofthe pulmonary and renal arteries, but no arteritis andthere were the small necrotic foci in the myocardium.There were no features to support the possibilitiesof polyarteritis nodosa, lupus erythematosis, orWegener's granulomatosis. The clinical diagnosticdifficulty is to some extent paralleled in the patho-logical findings.The autopsy produced several quite unexpected

findings. Firstly, there was ante-mortem endocardialthrombosis in the left ventricle. Secondly, in the lungsand kidneys thrombi were found in many smallarteries. Thirdly, in the brain there were numerousthrombosed vessels with areas of focal necrosisadjoining them, but there was no evidence of a viralencephalitis. Finally there was an asymptomaticGrawitz tumour in the kidney.The autopsy answers several questions. The final

encephalopathic illness was due to a cerebrovascularthrombotic disorder, not to a virus infection, nor toa vasculitis. The presence of thrombus in the pul-monary arteries, left ventricle, renal and cerebralarteries suggests that a generalized thrombotic ten-dency was present.The relevance of the Grawitz tumour is conjec-

tural. Such tumours are commonly found at autopsywhen there had been no clinical suspicion of theirpresence. We have not found a Grawitz tumour re-ported in the literature in association with eosino-philic leukaemia. We feel that this tumour may be anincidental finding here as Grawitz tumours arecommon, and the eosinophilic leukaemia syndromeis rare.

Clinical involvement of the central nervous systemhas been documented in a few cases. Faddel et al.(1957) described a 27-year-old male who amongstother symptoms complained of attacks of delusionsand dizziness. This could have been related to throm-bo-embolic disease as he had mural thrombi in bothventricles. Bentley et al. (1961) described a 5-year-oldboy who had a week's history of fever, petechialrash, hepatosplenomegaly and lymphadenopathyand went into coma. In this case extensive left

ventricular mural thrombus was present. Bentleyalso described necrotic foci in the myocardium simi-lar to the lesions we have seen.Gardner-Thorpe et al. (1971) described four male

patients who developed headache, parietal lobe syn-dromes, dysphasia, pyramidal signs and disturbanceof eye movement, associated with a mature eosino-philic leukocytosis of the peripheral blood. Autopsyexamination in two showed left ventricular muralthrombi and widespread arteriolar occlusion.

These cases are clearly similar to our case. Theydiffer, however, in several respects, for which we haveno explanation. Their neurological symptoms wererelatively chronic, all four had cardiac galloprhythms, and two died in congestive cardiac failure.This contrasts with our case, presenting with lympha-denopathy, and terminating with a short lived fatalencephalopathy.

Nordlander (1951) described a 44-year-old manwho had definite eosinophilic leukaemia. Terminallyhe developed anaesthesiae of the left side of the faceand infiltration of the skin and retina. Autopsy re-vealed widespread eosinophilic infiltration of manyorgans, including the body of the left gasserianganglion. It can be seen that the pathology in ourcase is similar to other previous reports where throm-botic disease has been present. During life there wereno clinical features to suggest that intravascular co-agulation was present, or that a micro-angiopathichaemolytic anaemia existed. Detailed clotting factorstudies were unfortunately not undertaken, but hisbleeding and clotting times, plasma and thrombinclotting times were normal, and there was no bleed-ing tendency. The only point of note was that hisplatelet count (taken within 24 hr of death) was47,000/mm3. This would have been consistent withthe presence of intravascular coagulation. Somedegree of intra-vascular fibrin deposition is seen inthe haemolytic uraemic syndrome; but our patientwas normotensive and his blood urea was normal.There are now several reports of the efficacy ofheparinization in treating the haemolytic uraemicsyndrome, as well as in the successful treatment ofthe consumption coagulopathies. Had we been ableto make the diagnosis in life it might have beenworthwhile heparinizing him, in the hope of pre-venting widespread thrombosis. We would proposethat further cases of this syndrome should be investi-gated with a view to detecting intravascular coagula-tion at the earliest possible moment and that oncediscovered it should be treated with heparin. Theincidence of this terminal complication is unknownas there are few detailed neuropathological reportsin the literature.

ConclusionsIn conclusion we feel that this case-and others

478 Case reports

like it-fall somewhat across the diagnostic boun-daries lying between genuine eosinophilic leukaemia,and eosinophilic collagen disease. These two con-ditions may be extremes of a single spectrum causedby a basic single underlying cause as yet unknown.We would propose that a descriptive title should beused to avoid unintentional categorization, such asidiopathic eosinophilic leukaemoid reaction. Therelation of the terminal diffuse intravascular throm-botic process to the initial disease process is obscure.The role, if any, of the intracellular virus-like

particle, seen only in the nucleus of one eosinophilis quite unknown. There were no pathological fea-tures of encephalitis. As there was no lymphaticvasculitis, one cannot postulate that a sensitivity re-action occurring between the agent and antibodiesagainst it was causing local fibrin deposition andintra-vascular coagulation. It may be present in thesimilar uncertain role played by the polyoma virusin the progressive multifocal leukoencephalopathyseen associated with Hodgkin's disease. We feel un-justified in drawing any conclusions on the strengthof one isolated observation.

AcknowledgmentWe should like to thank Dr C. D. R. Pengelly, Consultant

Physician at Altrincham General Hospital, for referring thispatient.

ReferencesBENTLEY, H.P., REARDON, A.E., KNOEDLER, J.P. & KRIVIT,W. (1961) Eosinophilic leukaemia; report of a case withreview and classification. The American Journal of Medi-cine, 30, 310.

DE GRUCHY, G.C. (1970) Clinical Haematology in MedicalPractice, p. 456. Third Edition. Blackwell Scientific Pub-lications, Oxford.

ENGFELDT, B. & ZETTERSTROM, R. (1956) Disseminated eosi-nophilic collagen disease. A clinical and pathological studyof a clinical entity related to Loeffler's syndrome. ActaMedica Scandinavica, 153 (5), 337.

FADDELL, E.J., CRONE, R.I., LEONARD, M.E. & ALTAMIRANO,M.D. (1957) Eosinophilic leukaemia. Archives of InternalMedicine, 99, 819.

GARDNER-THORPE, C., HARRIMAN, D.G.F., PARSONS, M. &RUDGE, P. (1971) Loeffler's eosinophilic endocarditis withBalint's syndrome (optic ataxia and paralysis of visualfixation). Quarterly Journal of Medicine, 158, 249.

NORDLANDER, N.B. (1951) Eosinophilic leukaemia infiltrat-ing the gasserian ganglion. Acta Medica Scandinavica, 139(2), 146.

ODEBERG, B. (1965) Eosinophilic leukaemia and disseminatedeosinophilic collagen disease-a disease entity. Acta MedicaScandinavica, 177, 129.

RICKLES, F.R. & MILLER, D.R. (1972) Eosinophilic leukae-moid reactions. Report of a case and its relationship toeosinophilic leukaemia and review of the paediatricliterature. Journal of Paediatrics, 80, 418.

Postgraduate Medical Journal (July 1974) 50, 478-481.

Treatment of pulmonary tuberculosis in a patient onmaintenance haemodialysis

F. W. SMITHM.B., Ch.B.

Medical Renal Unit, Aberdeen Royal Infirmary

G. R. D. CATTOM.B., M.R.C.P.(U.K.)University of Aberdeen

M. MACLEODM.D., F.R.C.P.E.

University of Aberdeen

SummaryA case of pulmonary tuberculosis in a patient onmaintenance haemodialysis is reported. A 37-year-oldman who had received intermittent haemodialysis for5 years, developed pulmonary tuberculosis which wastreated initially with isoniazid, sodium aminosalicylate(PAS) and rifampicin. Isoniazid and PAS were dis-continued and treatment continued with rifampicinalone. One year later, the patient is well, has no evi-dence of active tuberculosis and undertakes his owndialysis at home.

IntroductionPulmonary tuberculosis is a serious and not un-

common complication of chronic renal failure treatedby maintenance haemodialysis (Brunner et al., 1972).Adequate therapy for the condition is difficult toassess clinically as the major therapeutic agents, in-cluding streptomycin, sodium aminosalicylate (PAS),isoniazid and ethambutol, are normally excreted inthe urine (Welch, 1954) and produce importanttoxic effects if blood levels become elevated. Thus,in oliguric or anuric patients, safe and effective