J Clin Pathol 1990;43:1 14-118 Cerebral aspergillosis in liver transplantation A P Boon, D H Adams, J Buckels, P McMaster Abstract Nine cases of cerebral aspergillosis were identified in a series of 44 brains obtained at necropsy from patients who had under- gone liver transplantation. In two of these there was dual infection with Candida albicans. The primary focus of infection was invariably in the lungs. One case of pulmonary Aspergillus infection was found with no evidence of cerebral disease. Infection tended to occur in the period soon after transplantation, was associated with high dose steroids, retransplantation, and showed a sig- nificant seasonal incidence. Neurological findings were non-specific and only two cases were diagnosed before death. Aspergillus infection soon after trans- plantation indicates that this organism is a considerable nosocomial hazard, particularly in the winter and spring months. Positive cultures before death are rarely obtained and antifungal treatment should be started on clinical suspicion alone. Department of Pathology, University of Birmingham A P Boon Liver Unit, Queen Elizabeth Hospital, Birmingham D H Adams J Buckels P McMaster Correspondence to: Dr A P Boon, Department of Pathology, Medical School, University of Birmingham, Birmingham B15 2TJ. Accepted for publication 6 September 1989 Liver transplantation is increasingly being used for the treatment of end stage liver disease. Recently workers have reported a high incidence of neurological morbidity following liver transplantation. '" In many cases the causes are poorly understood and few detailed neuropathological studies have been under- taken.6 We prospectively studied brains obtained at necropsy according to a standard protocol in an attempt to determine the spectrum of neurological disease that may result.7 Systemic aspergillosis is a recognised complication of immunosuppression,8 and cerebral invasion may result in a variety of neurological signs.9 Several factors may account for the higher incidence of fungal infections in patients who have undergone liver transplantation than in recipients of other solid organs.'" Different centres, however, seem to report widely differing incidences.'0 " Diffi- culties in establishing the diagnosis2 " make it probable that exclusive use of microbiological data obtained during life leads to under recognition of systemic infection by Aspergillus spp. We therefore reviewed the cerebral histo- logy in all cases of cerebral mycosis currently identified in our necropsy series to establish the true incidence and pattern of disease. Methods Between January 1982 and May 1989 218 patients received 250 orthotopic liver trans- plantations at the Queen Elizabeth Hospital, Birmingham. Ninety eight (450°) patients had died at the time of this study and of these, 58 (590o) were necropsied at our centre. In some of the earlier cases brain tissue had not been sampled for histological examination, and in others permission for necropsy of the brain was refused. In four cases only paraffin wax- embedded tissue blocks were available for histological examination. A further 40 entire brains were prospectively collected and sampled for histology using a standard protocol. The total sample, therefore, com- prised 44 patients (28 female, 16 male) and represented 44-90o of all liver transplant deaths. The mean age of the group was 40 9 years; 38 were adults (range 21-63 years) and six were children (range 11 months-1 6 years). These patients had received 55 liver trans- plants, including nine retransplants, and one patient received a transplant three times. Gross external findings were described at necropsy and the brains then fixed whole by suspension in 1000, formalin for three to six weeks. In each case the brain stem and cerebellum were detached and the cerebrum sliced coronally at 1 cm intervals. Any grossly obvious lesions were described and sampled for histological examination. Routine large blocks of frontal, temporal, parietal and occipital lobes, hippocampus, basal ganglia, thalamus, cerebellum, pons and medulla were also pro- cessed through a standard technique to paraffin wax. Sections stained with haematoxylin and eosin were prepared from these and also from the four cases for which only paraffin wax embedded tissue was available in file. Special and immunohistochemical stains were perfor- med where indicated. All clinical records were carefully scruti- nised. Particular note was made of any neuro- logical signs and symptoms, microbiological isolates, and previous antifungal treatment. Immunosuppressive treatment followed a previously described standard protocol. 4 General necropsy findings, including histo- logy, were reviewed. Results Invasive cerebral aspergillosis was present in nine brains (200 ). Identification of the species was possible in four cases, either through culture of specimens taken before death or necropsy tissue. In two brains invasive candidiasis was also evident. There were no other forms of cerebral mycosis in the series. Mean age and sex ratio of affected patients (44 0 years and 125F:1M) did not differ sig- 114
Transcript
J Clin Pathol 1990;43:1 14-118
Cerebral aspergillosis in liver transplantation
A P Boon, D H Adams, J Buckels, P McMaster
AbstractNine cases of cerebral aspergillosis were
identified in a series of44 brains obtainedat necropsy from patients who had under-gone liver transplantation. In two ofthesethere was dual infection with Candidaalbicans. The primary focus of infectionwas invariably in the lungs. One case ofpulmonary Aspergillus infection wasfound with no evidence of cerebraldisease. Infection tended to occur in theperiod soon after transplantation, was
associated with high dose steroids,retransplantation, and showed a sig-nificant seasonal incidence. Neurologicalfindings were non-specific and only twocases were diagnosed before death.Aspergillus infection soon after trans-
plantation indicates that this organismis a considerable nosocomial hazard,particularly in the winter and springmonths. Positive cultures before deathare rarely obtained and antifungaltreatment should be started on clinicalsuspicion alone.
Department ofPathology, UniversityofBirminghamA P Boon
Liver Unit, QueenElizabeth Hospital,BirminghamD H AdamsJ BuckelsP McMasterCorrespondence to:Dr A P Boon,Department of Pathology,Medical School,University of Birmingham,Birmingham B15 2TJ.Accepted for publication6 September 1989
Liver transplantation is increasingly beingused for the treatment of end stage liverdisease. Recently workers have reported a highincidence of neurological morbidity followingliver transplantation. '" In many cases thecauses are poorly understood and few detailedneuropathological studies have been under-taken.6 We prospectively studied brainsobtained at necropsy according to a standardprotocol in an attempt to determine thespectrum of neurological disease that may
result.7Systemic aspergillosis is a recognised
complication of immunosuppression,8 andcerebral invasion may result in a variety ofneurological signs.9 Several factors may
account for the higher incidence of fungalinfections in patients who have undergone livertransplantation than in recipients of other solidorgans.'" Different centres, however, seem toreport widely differing incidences.'0 " Diffi-culties in establishing the diagnosis2" make itprobable that exclusive use of microbiologicaldata obtained during life leads to underrecognition of systemic infection by Aspergillusspp. We therefore reviewed the cerebral histo-logy in all cases of cerebral mycosis currentlyidentified in our necropsy series to establish thetrue incidence and pattern of disease.
MethodsBetween January 1982 and May 1989 218
patients received 250 orthotopic liver trans-plantations at the Queen Elizabeth Hospital,Birmingham. Ninety eight (450°) patients haddied at the time of this study and of these, 58(590o) were necropsied at our centre. In someof the earlier cases brain tissue had not beensampled for histological examination, and inothers permission for necropsy of the brain wasrefused. In four cases only paraffin wax-embedded tissue blocks were available forhistological examination. A further 40 entirebrains were prospectively collected andsampled for histology using a standardprotocol. The total sample, therefore, com-prised 44 patients (28 female, 16 male) andrepresented 44-90o of all liver transplantdeaths. The mean age of the group was 40 9years; 38 were adults (range 21-63 years) andsix were children (range 11 months-16 years).These patients had received 55 liver trans-plants, including nine retransplants, and onepatient received a transplant three times.
Gross external findings were described atnecropsy and the brains then fixed whole bysuspension in 1000, formalin for three to sixweeks. In each case the brain stem andcerebellum were detached and the cerebrumsliced coronally at 1 cm intervals. Any grosslyobvious lesions were described and sampled forhistological examination. Routine large blocksof frontal, temporal, parietal and occipitallobes, hippocampus, basal ganglia, thalamus,cerebellum, pons and medulla were also pro-cessed through a standard technique to paraffinwax. Sections stained with haematoxylin andeosin were prepared from these and also fromthe four cases for which only paraffin waxembedded tissue was available in file. Specialand immunohistochemical stains were perfor-med where indicated.
All clinical records were carefully scruti-nised. Particular note was made of any neuro-logical signs and symptoms, microbiologicalisolates, and previous antifungal treatment.Immunosuppressive treatment followed apreviously described standard protocol. 4General necropsy findings, including histo-logy, were reviewed.
ResultsInvasive cerebral aspergillosis was present innine brains (200 ). Identification of the specieswas possible in four cases, either throughculture of specimens taken before death ornecropsy tissue. In two brains invasivecandidiasis was also evident. There were noother forms of cerebral mycosis in the series.Mean age and sex ratio of affected patients(44 0 years and 125F:1M) did not differ sig-
114
Cerebral aspergillosis in liver transplantation
Table 1 Cerebral aspergillosis in liver transplant recipients: summary of clinical details
Survival (days)Indication for after Diagnosis Anti-fungal High dose steroids within
Case No Age Sex transplantation transplantation* Organism identified before death treatmentt two weeks of deathtt
20 36 M ,-antitrypsin 15 Aspergillus sp, No No Yesdeficiency Candida albicans
64/76 21 M Chronic active 130,55 Aspergillus sp No No Nohepatitis
90/91/92 53 F PBC+ 26,11,6 Aspergillus sp No No Yes93/94 44 F PBC$ 20,14 Aspergillusflavus No No Yes114 61 F PBC 96 Aspergillusfumigatus No No No124 56 F Non-A, non-B 12 Aspergillus sp No Amphotericin Yes
hepatitis: (IV: 6 days)220/223 38 M s,-antitrypsin 18.9 Aspergillusfumigatus No Amphotericin Yes
deficiency+ (IV: 15 days)
*Time from first transplant, second transplant etc, until death.tExcluding oral prophylaxis: 100 mg amphotericin daily; 100 000 Units nystatin four times dailytt200 mg prednisolone or 1 g methylprednisolone per day.+Patients in preoperative acute hepatic failure and coma.
nificantly from the group as a whole (40 9 yearsand 1 75F:1M). Survival after first transplan-tation ranged from 12 to 130 days. Signifi-cantly, seven out of 18 deaths occurring one tofour weeks after transplantation were related tosystemic aspergillosis (p < 0.05, x2 test withYates' correction). Five patients underwentretransplantation at least once, compared withfive out of 35 who did not develop cerebralaspergillosis (p < 0.05, x2 test with Yates'correction).
All patients received standard immuno-suppressive treatment based on prednisolone,azathioprine, and cyclosporin A."4 Seven out ofnine were also given high dose corticosteroids(1 g intravenous methylprednisolone or 200 mgoral prednisolone) within two weeks of death.The total number of bolus treatments weresignificantly higher in the group withaspergillosis at necropsy (median 5-5; range0-11-5) than in the other 35 patients (MannWhitney U test: p < 0-01). Only one patient(case 36) became severely neutropenic in theperiod before death. Basic clinical data aresummarised in table 1.
Slicing showed that in seven brains therewere obvious gross abnormalities-multiple,widely distributed haemorrhagic softenings,
Figure I Cavitating haemorrhagic infarction in frontal lobe secondary to cerebralaspergillosis.
some ofwhich showed central cavitation (fig 1).In case 124, however, only a single area oftemporal lobe infarction was grossly evidentand in case 64/76 an invasive focus was onlydetected by microscopic examination. Lesionswere found in most areas of the cerebrum,generally at the grey white matter junction, andwith no tendency, despite previous assertions,'5to favour areas supplied by the posterior cir-culation. Brain stem and cerebellum were, infact, less commonly affected (table 2).
Several histological patterns of disease wereevident. Most brains showed a predominantpattern of haemorrhagic infarction associatedwith thrombosis of medium sized vessels.Grocott silver staining showed invasion ofvessel walls and surrounding parenchyma byseptate fungal hyphae with acute angle branch-ing typical of an Aspergillus species (fig 2). Inthree cases (cases 36, 93/94, and 114), there wasalso a widespread small vessel vasculitis (fig 3),and Grocott staining of such lesions showedonly occasional invasive hyphae. In thesebrains gross examination underestimated thetrue extent of infection. Occasional foci ofmeningeal invasion were noted, but there wereno examples of generalised fungal meningitis.Where there was extensive haemorrhage (case90/91/92), it was difficult to identify organismsand the diagnosis was made from lesionselsewere in the brain. Bleeding was probablydue to vessel rupture, resulting from fungalinvasion. Inflammatory reactions varied inintensity but were polymorphonuclear incharacter with no granulomatous reactions.
Cases 20 and 36 showed separate foci of amorphologically different organism includingboth yeast. and pseudohyphal forms. Thesewere obvious only on special staining andwere not associated with any noticeableparenchymal damage. In both of these casesblood cultures taken before death had grownCandida albicans. Features were interpreted asdual infection with a Candida species.All cases were associated with Aspergillus
pneumonia confirmed at necropsy. In eightpatients, histology of necropsy showed widelydisseminated aspergillosis (table 3). In case 124the brain was the only extra-pulmonary focus.Review of all liver transplant patients atnecropsy showed only one further case of
115
Boon, Adams, Buckels, McMaster
Table 2 Cerebral aspergillosis in liver transplant recipients: distribution of lesions
BasalCase No Frontal Occipital Temporal Parietal ganglia/thalamus Brain stem Cerebellum
Aspergillus infection (case 12). This wasconfined to the lungs. The series indicates,therefore, a pulmonary source of infection in allcases, with systemic spread in 900/o: the brainwas the most commonly affected organ.Assuming that infection occurred a short
time before death, there was a striking seasonalincidence of Aspergillus infection (fig 4). Allnine patients with cerebral disease and the onecase with exclusively pulmonary disease (case12) died in the six months between Novemberand April. Aspergillus infection was notdiscovered in the 22 patients who were necrop-sied in the summer and autumn months, Mayto October. These differences were significant(p < 0 02, x2 test with Yates' correction).
Neurological signs and symptoms were oflittle value in the diagnosis of cerebral mycosis:eight patients showed progressive neurologicaldeterioration with encephalopathy, terminalcoma, and (in cases 220/223 and 90/91/92)seizures. Case 40/42 showed a more rapid onsetofcoma accompanied by grand mal fits. Similarfeatures have been noted in other liver trans-plant recipients who developed neurologicalcomplications.' Electroencephalogram (EEG)findings in eight cases showed encephalopathy,with evidence of focal lesions in four. Com-puted tomography scanning was performed incase 90/91/92 and showed a posterior fossahaemorrhage. Neither of these investigationswas able to distinguish between infective andnon-infective lesions.
In only two patients (cases 36 and 40/42) was
Figure 2 Aspergillus within lumen and invading the wall of a thrombosed vessel(Grocott stain).
the diagnosis of aspergillosis made beforedeath; in both cases sputum culture resultswere only available within 48 hours of death,allowing little time for treatment. In a furtherthree patients results only became availableafter death: culture of skin vesicle fluid fromcase 93/94 grew A flavus, sputum culture fromcase 114 grew A fumigatus, and cytologicalexamination of bronchial aspirates from case124 showed an Aspergillus sp. In this latter caseand also in case 220/223 amphotericin treat-ment had already been started on clinical andmicrobiological suspicions of systemic can-didiasis. Chest x-ray picts s were generallyunhelpful for specific diag.Losis of Aspergilluspneumonia. Pleural effusions were noted inthree patients and five showed areas ofconsolidation. Only one case (case 124) showedevidence of cavitation. In contrast to thedifficulties in diagnosing aspergillosis, bloodcultures had grown Candida albicans in boththe cases (cases 20 and 36) of mixed cerebralmycosis.
DiscussionCerebral aspergillosis is a recognised compli-cation of immunosuppression, including thatassociated with organ transplantation. Primaryinfection in the lungs is almost invariable andthe brain is the organ most commonly affectedby haematogenous dissemination.'5 The inci-dence of spread to the brain has been pre-viously reported as between 10 and 500.'15-17Our own series shows at least a 90% incidenceof cerebral infection with only one case ofinfection apparently confined to the lungs. Itseems unlikely that rigorous sampling alonecould account for our observed incidence asmost cases showed obvious gross disease. Otherfactors, such as prolonged survival throughintensive supportive treatment and high dosecorticosteroids, may have given the organisman opportunity to disseminate more widely.A higher incidence of fungal infection in liver
transplantation compared with heart andkidney transplantation, has been notedpreviously,'8 but in that series Candida wasdetected much more frequently than Asper-gillus. Cryptococcus neoformans is stated to bethe commonest cause of central nervous systemfungal infection in renal transplant recipients,generally occurring more than six months aftertransplantation. '7 In our series Aspergillus,either alone or combined with Candida, was theonly observed form of cerebral mycosis. Theincidence of aspergillosis in liver transplanta-
116
Cerebral aspergillosis in liver transplantation
*
.,g -..°U.. V0
4o
Figure 3 Necrotising small vessel vasculitis in the brain: Grocott staining showoccasional invasive fungal hyphae.
tion seems to vary among centres. TheCambridge group reported very few cases, butdid not state their criteria for diagnosis.'0Although our series was clearly weighted infavour of deaths occurring soon after trans-plantation, the 230o incidence of pulmonary or
systemic aspergillosis in necropsy cases (100eoof all deaths in transplant recipients) is similarto the Denver" and Pittsburgh4'8 series.
Aspergillus infections may be sporadic or
clustered, the latter reflecting a heavilycontaminated environmental source.'5 All buttwo of our cases died within four weeks oftransplantation, which is said to indicate thepresence of an excessive nosocomial hazard.'7No obvious environmental source was identi-fied and the most striking epidemiologicalfeature was a pronounced seasonal variation(fig 4). This has been previously noted'0 andmay be due to a higher concentration of air-borne spores outside the summer months.'9Short of restricting transplantation to thesummer-a clearly impractical course-it isuncertain how environmental contaminationcould be reduced. The use of high efficiencyparticulate air filters does not seem to reducethe incidence of infection.'0There are several reasons why liver trans-
plant recipients may have a particularly highrisk of developing aspergillosis. Until recently,criteria for the diagnosis of rejection were notwell established.20 Consequently, in-appropriate anti-rejection treatment mighthave been given, leading to acquisition,
acceleration, or dissemination of pulmonaryAspergillus infections. Systemic corticosteroidsare a major predisposing factor in aspergillosisof the central nervous system.22 Seven out ofnine of our series received high dose steroidswithin two weeks ofdeath and the total numberof bolus doses were significantly higher in thegroup with aspergillosis. Liver transplantrecipients sometimes require prolongedartificial ventilation after surgery. Those infulminant hepatic failure may have spent sometime preoperatively on a ventilator. The risks ofacquiring a pulmonary infection are conse-quently enhanced. Occasionally a noticeabledisparity in size of the transplanted liver maycause respiratory impairment. There isevidence, furthermore, that liver failure initself may predispose to Aspergillus infection,even without immunosuppressive treat-ment.2324 Six of our patients with cerebralaspergillosis were ventilated before surgery forhepatic coma and may have acquired the infec-tion at that time. Many of these factors mayhave contributed to the significantly increasedrisk in retransplanted cases.The clinical diagnosis of cerebral asper-
gillosis may be difficult, and in most series,including ours, a positive diagnosis is onlymade at necropsy.24 The clinical presentation iseither acute with focal neurological deficits andfitting or subacute with progressive obtun-dation." Both patterns were observed in our
cases, but similar features were noted in otherpatients in whom there was no evidence ofaspergillosis at necropsy.' Likewise, EEG orcomputed tomography scan evidence of focallesions may be found, but neither investigationcan firmly establish an infective aetiology.Diagnostic problems are compounded in livertransplant recipients: rapid changes in elec-trolytes, central pontine myelinolysis,25 drugtoxicity,26 haemorrhage due to coagulopathies,air embolism,27 watershed infarction' andhepatic failure are recognised causes ofneurological problems, occurring alone or incombination. Any of these may mimic or maskthe onset of central nervous system infection.The importance of an aggressive therapeutic
approach to these patients has beenemphasised,6 but the toxicity of systemicantifungal chemotherapy prohibits indis-criminate prophylaxis. Central nervous systemaspergillosis, however, should be strongly sus-pected in those patients who develop pulmon-ary infiltrates and focal neurological signs,22especially if they have received high dosesteroids. Treatment with intravenous antifun-gal agents should be started even in the absenceof positive cultures.
Table 3 Disseminated aspergillosis in liver transplant recipients: organ disease at necropsy
Case No Brain Lung Heart Kidney Liver Large bowel Thyroid Oesophagus Pancreas Spleen Other
Figure 4 Dates of allliver transplant deathsnecropsied at QueenElizabeth Hospital.Infected cases (includingpatient without cerebraldisease) (0); other livertransplant cases (0 ).
1989' * 00
19884 0 0
1987-
1986w
a 1985
19844
1983-
1982-
0
0 000 0
* o 0
0 00 0 0
* * 0 0000
0 0 0 000
0 0
0 0
0 000060 0
0 0 0o0 0
00
0 0 0
0
0
Jan Feb Mar April May June July Aug Sept Oct Nov DecMonth
In view of the poor prognosis of cerebralaspergillosis, early diagnosis and treatment,before dissemination in the central nervoussystem has occurred, seems to offer the bestchance of cure.'7 Despite daily sputumcultures, the organism was identified insputum or bronchial secretions in only fourpatients and so late in the course of the diseaseas to be of no clinical value. Until betterserological techniques become available"3 thediagnosis must rely largely on clinicalsuspicion.The dermatological manifestations of sys-
temic aspergillosis should not be overlooked.28One of our series (case 93/94) developed a"herpetic" rash some days before death.Vesicle fluid was later submitted for fungalculture, resulting in growth of Aspergillusflavus: unfortunately, the patient died the daybefore results were available. The skin is moreaccessible to laboratory investigation than anyother organ, and in disseminated fungal infec-tion, a biopsy specimen of an unusual rash maybe the only means of establishing an earlydiagnosis.
We thank Miss Mary Trumper and the MLSO staff of theDepartment of Pathology, University of Birmingham for theirexcellent technical assistance.
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2 de Groen PC, Aksamit AJ, Rakela J, Forbes GS, KromRAF. Central nervous system toxicity after liver trans-plantation: the role ofcyclosporine and cholesterol. N EnglJMed 1987;317:861-6.
8 Wiles CM, Mackenzie DWR. Fungal diseases of the centralnervous system. In: Kennedy PGE, Johnson RT, eds.Infections of the nervous system. London: Butterworths,1987:93-117.
9 Hooper DC, Pruitt AA, Rubin RH. Central nervous systeminfection in the chronically immunosuppressed. Medicine1982;61: 166-88.
11 Schroter GPJ, Hoelscher M, Putnam CW, Porter KA, StarzlTE. Fungus infections after liver transplantation. AnnSurg 1977;186:1 15-22.
12 Nalesnik MA, Myerowitz RL, Jenkins R, Lenkey J, HerbertD. Significance of Aspergillus species isolated from res-piratory secretions in the diagnosis of invasive pulmonaryaspergillosis. J Clin Microbiol 1980;11:370-6.
13 Trull AK, Parker J, Warren RE. IgG enzyme linkedimmunosorbent assay for diagnosis of invasive asper-gillosis: retrospective study over 15 years of transplantrecipients. J Clin Pathol 1985;38:1045-51.
14 Adams DH, Burnett D, Stockley RA, Hubscher SG,McMaster P, Elias E. Biliary ,B2-microglobulin in liverallograft rejection. Hepatology 1988;8:1565-70.
15 Myerowitz RL. The pathology of opportunistic infections withpathogenetic, diagnosis and clinical correlations. New York:Raven Press, 1983.
16 Kaplan K. Brain abscess. Med Clin North Am 1985;69:345-60.
17 Conti DJ, Rubin RH. Infection of the central nervoussystem in organ transplant recipients. Neuro Clin NorthAm 1988;6:241-60.
18 Ho M, Wajszczuk CP, Hardy A, et al. Infections in kidney,heart and liver transplant recipients on cyclosporine.Transplant Proc 1983;15(suppl 1):2768-72.
19 Seaton A, Robertson MD. Aspergillus, asthma andamoebae. Lancet 1989;i:893-4.
20 Hubscher SG, Clements D, Elias E, McMaster P. Biopsyfindings in cases ofrejection ofliver allograft. J Clin Pathol1 985;38: 1366-73.
21 Adams DH, Neuberger JM. Clinical patterns of liverallograft rejection. J Hepatol (in press).
22 Walsh TJ, Hier DB, Caplan LR. Fungal infections of thecentral nervous system: comparative analysis of riskfactors and clinical signs in 57 patients. Neurology1985;35:1654-7.
23 Park GR, Drummond GB, Lamb D, et al. Disseminatedaspergillosis occurring in patients with respiratory, renaland hepatic failure. Lancet 1982;ii:179-83.
24 Walsh TJ, Hier DB, Caplan LR. Aspergillosis of the centralnervous system: clinicopathological analysis of 17patients. Ann Neurol 1985;18:574-82.
25 Boon AP, Carey MP, Salmon MV. Central pontinemyelinolysis not associated with rapid correction ofhyponatraemia. Lancet 1988;ii:458.
26 Boon AP, Adams DH, Carey MP, Williams A, McMaster P,Elias E. Cyclosporin-associated cerebral lesions in livertransplantation. Lancet 1988;i:1457.
27 Starzl TE, Schneck SA, Mezzoni G, et al. Acuteneurological complications after liver transplantation withparticular reference to intra-operative cerebral airembolus. Ann Surg 1978;187:236-40.
28 Wolfson JS, Sober AJ, Rubin RH. Dermatologic manifesta-tions of infections in immunocompromised patients.Medicine 1985;64:1 15-33.
