18ournalofNeurology, Neurosurgery, and Psychiatry 1993;56:188-193

CNS aspergillosis in organ transplantation:a clinicopathological study

Julian Torre-Cisneros, Oscar L Lopez, Shimon Kusne, A Julio Martinez,Thomas E Starzl, Richard L Simmons, Maureen Martin

AbstractThe clinical characteristics and neuropa-thological findings of 22 organ transplantrecipients with CNS aspergillosis werereviewed. Thirteen patients had liver, sixkidney, two heart and one had clustertransplants. The most frequent neuro-logical symptoms were alteration of men-tal status (86%), seizures (41%) and focalneurological deficits (32%). Meningealsigns were less common (19%). Aspergil-lus spp invasion of the blood vessels withsubsequent ischaemic or haemorrhagicinfarcts, and solitary or multiple abs-cesses were the predominant neuropatho-logical findings. The lungs were theprobable portal ofentry; however, isolatedCNS aspergillosis was seen in twopatients. Antemortem diagnosis of theinfection was made in half of the patients.Concomitant diabetes mellitus was notedin 590/o of the patients and bacterial orother severe infections in 86%. No specificclinical or pathological pattern could beidentified among patients with differenttypes of organ transplants. In additionCNS aspergillosis was preceded by organrejection and the need for intense immu-nosuppression and retransplantation inthe majority of the patients.

(i Neurol Neurosurg Psychiatry 1993;56:188-193)

PresbyterianUniversity Hospital,University ofPittsburgh, School ofMedicine, Pittsburgh,Pennsylvania, USADepartment ofSurgeryJ Torre-CisnerosT E StarzlR L SimmonsM MartinDepartment ofNeurology0 L LopezDepartment ofMedicineS KusneDepartment ofPathology(Neuropathology)A J MartinezCorrespondence to:Dr Lopez, 3600 ForbesAvenue, Iroquois Building,Suite 502, Pittsburgh, PA15213, USAReceived 16 November 1991and in revised form6 November 1991.Accepted 30 April 1992

Infection with Aspergillus spp remains an

important cause of morbidity and mortality inimmunosuppressed organ transplant recipi-ents. 1 This opportunistic fungal infection com-monly involves the CNS and producesdevastating neurological sequelae.26 Its asso-

ciation with other severe infections in trans-plant patients makes precise antemortemdiagnosis difficult, and often results in delayedtherapy.2-6 Although successful treatment ofCNS aspergillosis7 8 has been reported,response to antifungal therapy is generally poorin organ transplant patients.9 1o This studyreviews the clinical and neuropathologicalfindings of 22 organ transplant recipients withCNS aspergillosis. Recognition of these fea-tures may encourage clinicians to pursue

empiric therapy based on clinical suspicionalone.

Material and methodsSUBJECTSThe medical records and necropsy reports of

22 adult subjects with CNS aspergillosis (20diagnosed by necropsy and two by brainbiopsy) who had undergone solid organ trans-plantation at the University of PittsburghMedical Center (UPMC) from January 1981to December 1990 were reviewed. The subjectswere eight men and 14 women ranging in agefrom 18 to 58 years, [mean (SD) 38-1 (14-3)years]. Those diagnosed by necropsy included:12 patients who had an orthotopic liver trans-plantation, five patients with kidney trans-plantations, two with heart transplantations,and one patient with an abdominal clustertransplantation, which involved en-blockreplacement with liver, pancreas and smallbowel. The two diagnosed by biopsy included:one patient with a liver transplantation andanother with kidney transplantation. Althoughboth patients died subsequently, necropsy wasnot performed.Our patients were selected from among the

218 transplant patients who had completenecropsy carried out at the UPMC fromJanuary 1981 to December 1990; this included112 liver, 19 kidney, 84 heart and 3 clustertransplant patients. Of 4448 patients who hadorgan transplantation at the UPMC duringthat time, 2180 had liver, 1714 kidney, 538heart and 16 had cluster transplants.

MethodsThe clinical records were reviewed by aninternist (JTC) and a neurologist (OL) in eachcase to identify and characterise the neuro-logical events. Clinical parameters recordedincluded any alteration of the mental status,seizures, focal neurological symptoms andmeningism. Mental status alteration was con-sidered to be rapidly progressive when itevolved within 24 hours and progressive whenit evolved over 24 hours. CT scans of the head,EEGs, laboratory and other specific neuro-radiological reports were reviewed when per-tinent.

Standard immunosuppressive protocolsconsisting of Cyclosporin A (CyA) and pred-nisone have been published previously. 1-14

Serum levels of CyA were determined rou-tinely, with therapeutic level ranging from 600to 1000 ng/ml. Azathioprine was frequentlyused in combination with CyA and pred-nisone. Rejection episodes were managed withmethylprednisolone as 1 gram intravenousbolus or 1 gram daily for 5 days. A monoclonalanti-lymphocyte globulin (OKT3) was occa-sionally used to treat steroid resistant rejectionepisodes. Rabbit antithymocyte globulin

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(RATG) was administered to one heart trans-plant patient.The underlying diagnoses of liver transplant

recipients were: a) fulminant hepatitis (threecases); b) Hepatitis B Virus cirrhosis (twocases); c) autoimmune cirrhosis (two cases); d)cirrhosis ofunknown aetiology (three cases); e)primary biliary cirrhosis (two cases) and f)Budd-Chiari syndrome (one case). In kidneytransplant patients the diagnoses were: a)hypertensive nephropathy (three cases); b)polycystic kidney disease (one case); c) sys-temic lupus erythematosus nephropathy (onecase) and d) chronic renal failure of unknownaetiology (one case). In heart transplantpatients the diagnoses were: a) atheroscleroticheart disease (one case) and b) dilated cardio-myopathy (one case).

Neuropathological methods used in trans-plant recipients and brain biopsy procedureshave been described in detail previ-USly.2 3 15-17

ResultsNEUROPATHOLOGY

Table 1 summarises the neuropathologicalfindings in each organ recipient. Macroscopicexamination of the CNS showed gross abnor-malities in all but one patient (95%). The mostfrequent pattern observed was solitary or

multiple areas of haemorrhagic or ischaemicencephalomalacia (figure A). One case ofhaemorrhagic softening had obvious cavita-tion. In other cases the macroscopic lesions

were single or multiple abscesses. Both p,at-terns were found most frequently in the cere-brum without preference for areas supplied bythe anterior or posterior circulation. Cere-bellum and brainstem were affected with lessfrequency, but when it occurred the pre-dominant pattern was a haemorrhagic infarct.Two patients (10%) had cerebellar abscesses.Two subjects had subarachnoid haemorrhages,and two others had subdural haematomas. Inone patient subarachnoid haemorrhage wasassociated with a ruptured mycotic aneurysmof the left middle cerebral artery. Uncal hernia-tion from a large cerebral haematoma wasnoted in one patient. The sole patient withoutan apparent macroscopic lesion showed multi-ple microabscesses.

Microscopically, the most frequent findingswere ischaemic and haemorrhagic infarcts,probably due to arteritis and arteriolitis withfungal thrombosis and obliteration of the vessellumen (figure B), in 15 patients (75%). Insome areas the thrombosed hyphae penetratedthe blood vessel walls into the adjacent oede-matous cerebral parenchyma, producing adiffuse pattern of multifocal haemorrhagicinfarcts. Aspergillus invasion of the wall oflarge blood vessels causing a mycotic aneurysmwas observed in one patient.

Cerebral and cerebellar abscesses composedof necrotic CNS parenchyma with minimalacute and chronic inflammatory reaction andthe presence of hyphae were observed in threepatients (15%) at necropsy (figure C), and in

Table Clinicopathological correlations with 22 cases ofCNS Aspergillosis after organ transplantation

Case AgelSex Focal deficits Seizures Alteration of Mental Status Neuropathological Findings

I Liver Transplant1 39/F - Grand mal Progressive Abscesses; R and L Frontal and R parietal2 37/M - - Progressive L Occipital abscess (biopsy)3 40/M - Myoclonus Rapidly Progressive R Frontal and parietal IPH; L Parietal and

occipital SAH4 18/M R hemiparesis - Rapidly Progressive Abscesses; cerebral and midbrain5 31/F - Grand mal Rapidly Progressive Ischaemic infarcts; Leptomeningeal aspergillosis6 58/F R hemiparesis - Rapidly Progressive Microabcesses; cerebral; cerebellar and

midbrain7 18/F - - Rapidly Progressive R occipital, haemorrhagic infarct8 21/F - - - L Frontal ischaemic infarct: Leptomeningeal

aspergillosis9 36/F - - Rapidly Progressive Haemorrhagic and ischaemic infarcts; cerebral,

cerebellar and brainstem10 48/F R Hemiparesis Grand mal Progressive Ischaemic infarcts; L Frontal and Parietal;

(status) Abscesses; L Frontal and Occipital, and RFrontal and cerebellar

11 24/F - Grand mal Progressive Haemorrhagic and ischaemic infarcts; cerebral,cerebellar and brainstem; CPM; acuteleptomeningitis

12 20/M - - Rapidly Progressive Haemorrhagic infarcts; cerebral and cerebellar;CPM

13 51/F - Grand mal Progressive Haemorrhagic and ischaemic infarcts; cerebraland cerebellar

II Kidney Transplant14 55/F L third nerve - Progressive Ischaemic infarcts; cerebral, cerebellar and

palsy midbrain; L SDH15 58/F - - Progressive Haemorrhagic infarcts; cerebral, cerebellar and

midbrain16 56/F Hemianopia - - Ischaemic infarcts; cerebral and cerebellar; L

SDH17 54/F R Hemiparesis - Rapidly Progressive Ischaemic infarcts; cerebral, cerebellar and

midbrain; ruptured mycotic aneurysm, LMCA18 38/M - Grand mal Rapidly Progressive Haemorrhagic infarcts; cerebral, cerebellar and

midbrain; Acute leptomeningitis19 38/M - _ Progressive Alteration L Temporal abscess, (Biopsy)III Heart Transplant20 51/M R Hemiparesis Grand mal Progressive Abscesses; L Frontal and Temporal21 16/M - Grand mal Progressive Ischaemic and haemorrhagic infarcts; L

occipital and parietalIV Cluster Transplant22 32/F - - - Haemorrhagic and ischaemic infarcts; cerebral,

cerebellar and midbrain; bilateral; SAH

R: right; L: Left; IPH: Intraparenchymatous haemorrhage; CPM: Central pontine myelinolysis; SDH: Subdural haematoma; SAH:Subarachnoid haematoma; LMCA: Left middle cerebral artery.

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Figure A) Coronalsection of the cerebralhemispheres at the level ofthe frontal lobes, showingtwo large areas ofhaemorrhagicencephalomalacia on theright side and two smallfoci on each cingulategyrus; B) Thrombosedmiddle-sized blood-vesselshowing branched hyphaewithin the thrombus,penetrating the arterialwall (Grocott'sMethenamine-Silver,250 x ); C) Abundantpurulent exudatecontaining clusters ofbranched septated hyphae(Haematoxilin & Eosin,250 x); D) Patient 2 intable 1; axial CT-scan withcontrast shows a solitarybrain abscess in the leftoccipital lobe.

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two patients with solitary abscesses diagnosedantemortem by brain biopsy (figure D). Asper-gillus infection of the leptomeninges, accom-

panied by subacute and chronic inflammationwas noted in two patients (10%). Both cases

were associated with necrotising lesions in thecerebral cortex involving both grey and whitematter.

In 18 of 20 patients at necropsy, the mostcommon portal of entry was the lung. Onepatient had concomitant aspergillus infectionof both lungs and middle ear. Aspergillus spppneumonia was characterised by hyphal infil-tration, angioinvasion and necrotising poly-morphonuclear infiltrates. The portal of entryin one liver transplant patient and one clustertransplant patient was not identified.

Disseminated aspergillosis involving theCNS, lungs and at least one other organ wasobserved in 11 patients (55%). Infectionrestricted to CNS and lungs developed inseven patients (35%) and isolated CNS asper-gillosis was present in two patients (10%). Thehistological pattern of inflammation was sim-ilar in all organs examined. The cause of deathin the 20 necropsy cases was multi-organfailure secondary to sepsis.Of 17 patients (77%) with positive cultures,

Aspergillus fumigatus was noted in 13 (76%)and Aspergillus flavus in four (24%).

Clinical neurological featuresThe table summarises the clinical profile ofeach patient and correlates them with theneuropathological findings. Neurological com-

plications were observed in 21 patients (95%).The most common clinical finding was altera-tion of mental status in 19 patients (82%),which was rapidly progressive in nine patients(41%) and progressive in nine (41%).

Focal neurological symptoms were noted inseven patients (32%). Hemiparesis was seen infive patients, and was invariably caused byCNS structural lesions manifested by abs-cesses or haemorrhagic or ischaemic infarcts inthe contralateral neocortex and subcorticalwhite matter. One patient with small leftparietal and occipital infarcts had hemianopia.Ipsilateral left third cranial nerve palsy, prob-ably due to increased intracranial pressure withnerve compression, was observed in a patientwith a left lateral frontal subarachnoid haemor-rhage. No lesion was found in third nerve or

Edinger-Westphal nuclei. Seizures were

observed in nine patients (41 %); eight patientshad grand mal, one myoclonus and one patientwith grand mal was in status epilepticus.Meningism was noted in four patients

(18%). It was related to aspergillus leptome-ningitis in one case and to subarachnoidhaemorrhage secondary to the rupture of a

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mycotic aneurysm in another case. Theremaining two subjects with meningism hadacute purulent leptomeningitis due to Pseudo-mona aeruginosa. The infections were concomi-tant with CNS aspergillosis.Headaches were observed in six patients

(27%), four with meningism as describedabove and the other two with cerebral infarcts,one ofwhom developed subarachnoid haemor-rhage. The only patient without clinical symp-toms had a focal aspergillosis ofadenohypophysis, bilateral subarachnoidhaemorrhage and multiple haemorrhagesthroughout the cerebral hemispheres.Although 20 subjects proved to have lung

involvement at necropsy, antemortem diag-nosis was made in only 11 patients (50%).These patients were treated with AmphotericinB without clinical response. In the other ninecases, pulmonary infiltrates consistent withbronchopneumonia were unknowingly man-aged as a bacterial pneumonia.The survival time after transplantation

ranged from 13 to 2705 days [mean (SD):238-2 (568 8) days; median 65 days]. The timeof occurrence ofCNS aspergillosis varied fromseven to 2555 days after the transplant [mean(SD): 221 (540 7) days; median 41 days]. Themost critical period for development CNSaspergillosis was the initial two months aftertransplantation, as noted in 14 patients (64%).Liver transplant patients represented nine ofthese 14 cases, and six of the nine casesoccurred in the first month. There were fourcases occurring after the first year, and threewere liver transplants. Only one liver transplantpatient developed CNS aspergillosis betweenthe second month and one year after trans-plant. Of the six cases after kidney transplant,four cases occurred in the second and thirdmonth. Aspergillosis occurred in a constantrate throughout the year. Twelve episodesoccurred between November and April and 10between May and October. The duration ofsurgery ranged from 10-38 hours [mean (SD):22 (9 6) hours] and in 12 cases (92%) wasmore than 12 hours.CNS aspergillosis was observed following

intense anti-rejection therapy in 18 patients(82%). Nine patients (41%) were treated withantilymphocyte globulin, nine (41%) withboluses of steroids and 14 (64%) with recyclesof steroids. Rabbit anti-thymocyte globulin wasadministered to one patient (4%). Combinedantirejection therapy with two or more of theseagents was used in 12 patients (54%). Elevenpatients had more than one transplant (50%).They were 10 of 13 liver transplant patients(77%) and one of six kidney transplantpatients (17%).CNS aspergillosis was associated with at

least one systemic infection in 19 patients(86%) and with multiple infections in 11(50%) of those patients. Systemic infectionsincluded: cytomegalovirus (CMV) disease(seven cases), peritonitis (eight cases), sepsis ofunknown origin (five cases), pneumonia (threecases), hepatitis B virus (two cases), systemiccandidiasis (one case), herpes simplex virus(HSV) disease (one case), human immunode-

ficiency virus (HIV) infection (one case) andotitis media (one case). The last patient devei-oped an acute purulent meningitis secondaryto the ear infection which was concurrent withthe CNS aspergillosis.

All but one patient received additional intra-venous antibiotics two months before theinfection. The duration of the treatment withantibiotics ranged from five to 70 days [mean(SD): 19-6 (19-7) days].

Cerebral haemorrhagic events in the pres-ence of coagulopathy were observed in 11patients, while six patients had coagulopathywithout haemorrhages. Uncontrolled diabeteswas found in 13 patients (59%) and nine hadreceived liver grafts.

DiscussionThis retrospective study of 22 organ transplantpatients with CNS aspergillosis indicates thatthe most common neurological symptomswere alteration of mental status, seizures andfocal motor deficits. The main neuropatho-logical finding was fungal invasion of the wallof the cerebral blood vessel with thrombosisand subsequent ischaemic or haemorrhagicinfarcts and subdural or subarachnoid haemor-rhages. No specific clinical or pathologicalpattern of the infection could be observedamong patients with different types of organtransplantation.Organ transplant recipients are at risk of

systemic and CNS aspergillosis. Estimates offrequency of aspergillosis after organ trans-plant have varied from 1-10%,'° '8 19 withCNS involvement in 10-50% of thosepatients.20.22 In this study, approximately 9%of the 218 patients where necropsy was carriedout had aspergillosis. The infection wasobserved in 11% of liver transplant, 26% ofkidney transplant and 2% of heart transplantpatients. Although aspergillosis seemed to bemore frequent in kidney transplant patients,these figures represent only patients in whomnecropsy was performed, consequently theymay overestimate the actual rate of CNSaspergillosis.The most important clinical symptom

observed in these patients was alteration ofmental status. Whether these findings were adirect consequence of CNS aspergillosis or dueto the frequent metabolic abnormalities seen inthese patients was difficult to evaluate. Inaddition, these patients had other risk factorsdirectly related to the transplant process. Pri-mary organ dysfunction exerts an importanteffect on mental status, and encephalopathyand coma are not uncommon findings inpatients under immunosuppressive ther-apy.23 24 It is likely that a combination of thesefactors had important deleterious effects onthe mental status of these patients.

Likewise, seizures are a common neuro-logical complication in organ transplantation.Consistent with previous reports, multiplemetabolic abnormalities and CNS structurallesions were major factors contributing to theonset of seizures in most patients.'5 25 Highblood levels or normal levels ofCyA could haveenhanced the risk of seizures in these

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patients.26 27 However, CNS structural lesionssuch as abscesses, haemorrhages and infarctsplayed an important role in the onset ofseizures in this series.

Focal motor deficits were also common andwere often associated with vascular lesions orabscesses. The predilection of Aspergillus sppfor invasion of blood vessel walls with sub-sequent thrombosis, infarcts and haemor-rhages explain, in part, the focal motor deficits.This tendency to invade blood vessels has beendescribed previously,4 including the uncom-mon finding of ruptured Aspergillus mycoticaneurysms. In addition, coagulopathy isanother common occurrence in transplantpatients (for example, liver transplant),28 andwas seen in 77% of patients in this series. Thusthe combination of fungal invasion of cerebralblood vessels and coagulopathy were the prob-able mechanism of cerebral bleeding and theunderlying cause of focal motor deficits inthese patients.Meningeal signs such as headaches, Brud-

zinski's sign and Kernig's sign were uncom-mon, occurring in four patients. They wererelated to Aspergillus spp leptomeningitis inone case, bacterial leptomeningitis in twocases, and to subarachnoid haemorrhage sec-ondary to a rupture mycotic aneurysm inanother case. The paucity ofmeningeal signs inthis study could be explained by the tendencyof the fungus to invade subcortical vessels.4

Aspergillus spp are primary respiratorypathogens, and the lungs are the main portal ofentry of disseminated infection.' In contrast toprevious reports of CNS aspergillosis originat-ing in the lungs,5 we were unable to identify thesource of infection in two patients. In immuno-compromised patients other sources such asskin and paranasal sinuses should be con-sidered.' No patient demonstrated skin abnor-malities in this series, however, sinusexamination was not specifically addressed atnecropsy in most of these patients.The majority of CNS aspergillosis occurred

within the first three months after organtransplantation which is the most criticalperiod for severe infection in general.29 30 Livertransplant patients had earlier onset of symp-toms compared with other transplant reci-pients. A second peak of incidence wasobserved after the first year and was associatedwith chronic rejection and/or retransplantationduring a period of intense immunosuppres-sion. In addition, we did not find the seasonalincidence reported in previous studies.5The concomitant presence of other fungal,

viral or bacterial infections often precludes aclear diagnosis of CNS aspergillosis in immu-nosuppressed organ recipients.' 45 Thus theidentification of a characteristic clinical profilein which this infection occurs is critical. CNSaspergillosis was frequently preceded by organrejection, retransplantation and aggressiveanti-rejection therapy.' Although steroids havebeen noted to be a major predisposing factor,3'these data indicate that CyA, monoclonalanti-lymphocyte globulin (OKT-3) and rabbitanti-thymocyte globulin, individually or incombination, exert an important influence in

the development of this fungal infection. Thisfinding is consistent with recent observationson transplant patients that found the use ofantirejection therapy, especially monoclonalantilymphocyte globulin (OKT-3) on trans-plant patients associated with aspergillosis andCMV infection.3 -33 Intravenous antibiotics34and diabetes mellitus35 also facilitate the pro-liferation and dissemination of the fungus.Interestingly, despite the presence of diabetesin 59% of our patients, we did not observeother fungal infections, usually associated withthis metabolic condition (for example, mucor-mycosis, candidiasis).The prognosis for organ transplant patients

with CNS aspergillosis is very poor, even withappropriate treatment.9 Among the possiblereasons for this unfavourable prognosis is thefact that this infection is often diagnosed late orincorrectly. In 11 of the 20 patients who hadnecropsies, the clinical diagnosis was madeantemortem. In the remaining nine, the diag-nosis of aspergillosis was not made untilnecropsy. Torres-Cisneros et al33 recentlyexamined the charts of 2180 liver transplantpatients and found that 39 developed aspergil-losis. Twenty nine of these patients had invasiveaspergillus lung infection; however, aspergillusrespiratory cultures were positive early in thecourse of infection in only 23/29 patients. Inaddition, 92% of these patients died, and allpatients with CNS Aspergillus infection died.We cannot overemphasise the critical need

for aggressive evaluation ofimmunosuppressedpatients, and for early diagnosis of systemicaspergillosis before it disseminates to the CNS.Whether clinicians should institute antifungaltherapy based on clinical suspicion alone is amajor problem in the management of thisinfection. This decision has to be taken on anindividual basis, and our findings may helpclinicians involved in such a situation. Finally,we hope that the introduction of newer anti-fungal agents (for example, liposomal ampho-tericin, itraconazol) will improve the efficacy oftreatment for these patients.

Dr Torre-Cisneros is a Visiting Fellow at the University ofPittsburgh, School of Medicine from the Reina Sofia Hospital,University of Cordoba School of Medicine. Dr Torre-Cisnerosis supported by the 90/5285 grant of the Fondo de Inves-tigaciones Sanitarias (FIS) of Spain. Ms Deborah Pulkowskihelped in the preparation of the manuscript.

1 Bodey GP, Vartivarian S. Aspergillosis. EurJ Microbiol InfectDis 1989;8:413-37.

2 Martinez AJ, Estol C, Faris AA. Neurologic complicationsof liver transplantation. Neurol Clin 1988;6:327-48.

3 Martinez AJ, Puglia J. The neuropathology of liver, heartand heart-lung transplantation. Transplant Proc 1988;20(suppl 1):806-9.

4 Walsh TJ, Hier DB, Caplan LR. Aspergillosis of the centralnervous system: clinicopathological analysis of 17patients. Ann Neurol 1985:18:574-82.

5 Boon AP, Adams DH, Buckels J, McMaster P. Cerebralaspergillosis in liver transplantation. J7 Clin Pathol 1990;43:114-8.

6 Beal MF, O'Carroll CP, Kleinman GM, Grossman RI.Aspergillosis of the nervous system. Neurology 1982;32:473-9._

7 Conen PE, Walker GR, Turner JA, Field P. Invasive primaryaspergillosis of the lung with cerebral metastasis andcomplete recovery. Dis Chest 1962;42:88-94.

8 Burton JR, Zachery JB, Bessin R. Aspergillosis in four renaltransplant recipients. Diagnosis and effective treatmentwith amphotericin B. Ann Intern Med 1972;77:383-8.

9 Denning DW, Stevens DA. Antifungal and surgical treat-ment of invasive aspergillosis. Review of 2121 publishedcases. Rev Infect Dis 1990;12:1147-1201.

10 Weiland D, Ferguson RM, Peterson PK, Snover DC,

192 on F

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/J N

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sychiatry: first published as 10.1136/jnnp.56.2.188 on 1 February 1993. D

ownloaded from

CNS aspergillosis in organ transplantation: a clinicopathological study

Simmons RL, Najarian JS. Aspergillosis in 25 renaltransplant patients. Epidemiology, clinical presentation,diagnosis and management. Ann Surg 1983;198:622-9.

11 Starzl TE, Klintmalm GBG, Weil R, Porter K, et al.Cyclosporin A and steroid therapy in sixty-six cadaverkidney recipients. Surg Gynecol Obstet 1981;153:486-94.

12 Starzl TE, Klintmalm GBG, Porter KA, Schroter GP. Livertransplantation with the use of cyclosporin A and pred-nisone. N Engl J7 Med 1981;305:266-9.

13 Griffith BP, Hardests RL, Bahson HT Powerful but limitedimmunosuppression for cardiac transplantation withcyclosporin and low-dose steroids. Jf Thor Card Surg1984;87:35-42.

14 Starzl TE, Rowe MI, Todo S, Jaffe R, et al. Transplantationof multiple abdominal viscera. JAAMA 1989;261:1449-57.

15 Estol CJ, Lopez 0, Brenner RP, Martinez AJ. Seizures afterliver transplantation: a clinicopathologic study. Neurology1989;39: 1297-301.

16 Montero CG, Martinez AJ. Neuropathology of hearttransplantation: 23 cases. Neurology 1986;36:1 149-54.

17 Hall WA, Martinez AJ, Dummer S, Griffith BP. Centralnervous system infections in heart and heart-lung trans-plantation. Arch Neurol 1989;46: 173-7.

18 Peterson PK, Balfour HH, Fryd DS, Ferguson RM,Simmons RL. Fever in renal transplant recipients: causes,prognostic significance and changing patterns at theUniversity of Minnesota Hospital. Am J Med 1981;71:345-51.

19 Britt RH, Enzmann DR, Remington JS. Intracranial infec-tions in cardiac transplant recipients. Ann Neurol198 1;9:107-119.

20 Conti DJ, Rubin RH. Infection of the central nervoussystem in organ transplant recipients. Neurol Clin1988;6:241-60.

21 Kaplan K. Brain abscess. Med Clin 1985;69:345-60.22 Gustafson TL, Schaffner W, Lavely GB, Straton CW.

Invasive aspergillosis in renal transplant recipients: corre-lations with corticosteroid therapy. J7 Infect Dis 1968;148: 230-8.

23 Plum F, Hindfelt B. The neurological complications of liverdisease. In: Vinken DJ, Bruyn GW, eds. Handbook of

clinical neurology. Amsterdam, North Holland, 1976;349-77.

24 Lane RJM, Roche SW, Leung AA, Greco A, Lance L.Cyclosporin neurotoxicity in cardiac transplant recip-ients. J Neurol Neurosurg Psychiatry 1988;51:1434-7.

25 Grigg MM, Costanzo-Nordin MR, Celesia GG, Kelly MA,Silver MA, Sobotka PA, Robinson JA. The etiology ofseizures following cardiac transplantation. Transplant Proc1988;20 (suppl 3):937-44.

26 O'Conner JP, Kleiman DS, Kunze HE. Hypomagnesemiaand cyclosporin toxicity. Lancet 1985;1:103-5.

27 Boogaerts MA, Zachee P, Verwilghen RL. Cyclosporin,methyl-prednisolone and convulsions. Lancet 1982,2:1216-7.

28 Estol CJ, Pessin MS, Martinez AJ. Cerebrovascular compli-cations after orthotopic liver transplantation: a clinico-pathological study. Neurology 1991;41 :815-9.

29 Kusne S, Dummer JS, Singh N, Iwazuki S, et al. Infectionsafter liver transplantation: an analysis of 101 consecutivecases. Medicine 1988;67:132-43.

30 Zeluff BJ. Fungal pneumonia in transplant recipients. SemResp Infect 1990;5:80-9.

31 Singh N, Dummer S, Kusne S, Breinig MK, et al. Infectionswith cytomegalovirus and other herpes viruses in 121 livertransplant recipients: transmission by donated organ andthe effect of OKT3 antibodies. Jf Infect Dis 1978;158:124-31.

32 Singh N, DummerJS, Kusne S, Makown L, StarzlT, Ho M.Impact ofOKT3 therapy on cytomegalovirus and HerpesSimplex virus infections after liver transplantation. Trans-plant Proc 1988;20(Suppl 1):661-2.

33 Torres-Cisneros J, Kusne S, Martin M, Manez R, SimmonsRL, Starzl T Aspergillosis: colonisation versus invasivedisease in liver transplant patients. Abstracts from the31st Interscience Conference on Antimicrobial Agents andChemotherapy. Chicago, Illinois, 1991;221.

34 Seeling MS. Mechanisms by which antibiotics increase theincidence and severity of candidiasis and alter theimmunologic defenses. Bacteriol Rev 1966;30:442.

35 MacCuish AC, Urbaniak SJ, Campbell CJ, Duncan LJP,Irvine WJ. Phytohemagglutinin transformation and acirculating lymphocyte subpopulation in insulin-depend-ent diabetics patients. Diabetes 1974;23:708-12.

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