The effect of corticosteroids on visual loss in Cryptococcus neoformans var. gattii meningitis

TRANSACTIONS OFTHE ROYAL SOCIETY OFTROPICAL MEDICINE AND HYGIENE

The effect of corticosteroids meningitis R. Andrew

Seato&*

Medicine, Department New Guinea; 2Centre

, Nitin of Clinical for Tropical

(1997)

on visual loss in Cryptococcus

91,50-52

neoformans

var. gaffii

Vermal,

Sirus Naraqi’, Jacob l? Wexnbri’ and David A. Warrell* ‘Division Science, Medical Faculty, University of Papua New Guinea, l?O. Box 5623, Boroko, Medicine, NufJield Department of Medicine, University qf Oxford, Oxford, UK

of Papua

Abstract In Papua New Guinea visual loss is a frequent sequal to Cryptococcus neoformans var. gattii meningitis in immunocompetent patients. We have previously postulated that visual loss may occur as a result of the immunological response to infection around the optic nerve. This retrospective study set out to explore the effect of corticosteroids on visual outcome. Sixteen patients received varying doses of corticosteroid (mainly loo-250 mg of hydrocortisone daily for the prevention of febrile reactions to amphotericin) and 10 received anticryptococcal therapy alone. Visual deterioration occurred less frequently in those treated with corticosteroids (2116 [12.5%] vs. 7/10 [70%], P=O.O07), blindness was less frequent (1116 [5.3%] vs. 5/10 [50%], P=O.O18), and in 3 patients vision improved. Corticosteroids may have a role in preventing or halting visual loss in C. neoformans var. gattii meningitis in immunocompetent patients. Keywords: meningitis, cryptococcal meningitis, Cryprococcusneoformans

var. g&i,

chemotherapy, corticosteroids

Introduction In Papua New Guinea (PNG), Cryptococcus neojormam var. gattii meningitis is complicated by visual loss in up to 53% of survivors (SEATON et al., 1997). The high incidence of visual loss in this imunocompetent population contrasts with the low incidence elsewhere, particularly in C. neoformans var. neojormans meningitis related to the acquired immunodeficiency syndrome (REX et al., 1993). We have postulated that visual loss occurs more frequently in the immunocompetent population because of a more aggressive immune response, either by way of arachnoid adhesions causing constriction of the cranial nerves, including the optic nerves, or by the inflammatory response to cryptococci in the visual pathway (SEATON et al., 1997). Intracranial pressure is frequently raised in C. neoformans var. gattii meningitis and may be an important cause of death(SEATON et-al., 1996b) but. in contrast to others (TAN, 1988; REX et al., 1993); we have failed to show a‘correlation- between it and visual loss (SEATON et al., 1997). Corticosteroids might prevent visual deterioration through their anti-inflammatory and immunomodulatory effects, although to our knowledge there has been no such report. In PNG, patients who experience immediate side effects associated with non-liposomal amphotericin B infusions (such as rigors, fever, nausea and vomiting) are prescribed either hydrocortisone (usually loo-250 mg daily) or a parenteral antihistamine before the start of the amphotericin infusion. Other patients are prescribed higher doses of corticosteroid. We have performed a retrospective analysis of corticosteroid use and visual outcome in immunocompetent patients with C. neofomans var. gattii meningitis. These data have been presented in part elsewhere (SEATON et al., 1996a), but here we present our findings in full.

ing using 7 common antigens (SEATON et al., 1995). In order to assess the response to corticosteroids, patients with no perception of light in either eye on admission and those who died during treatment were excluded from the study. Only patients who had postdischarge fundoscopy and visual acuity testing were included. Clinical and laboratory data were recorded on standard proformas, as were the dosing regimen of corticosteroids and the reasons for their administration. Because of the high incidence of febrile reactions to amphotericin B it became standard practice from 1994 onwards to treat empirically with hydrocortisone before infusion with amphotericin B. Newer lipid-based amphotericin formulations were not available. Before 1994, patients with febrile reactions were treated with either a narenteral antihistamine (chlorpheniramine) or hydrocortisone. Ophthalmic and cerebrospinal fluid (CSF) findings were recorded as previously described (SEATON et al., 1997). All patients received standard treatment with parenteral amphotericin B (0.3-l mg/kg/d) and oral flucytosine (150 mg/kg/d in divided doses) for more than 6 weeks. The cumulative dose of amphotericin was calculated per kilogram of the patient’s weight on admission. Data were stored and analysed with the aid of the EpiInfo 5 software package. Admission findings were compared for each treatment group and the proportion of patients with visual deterioration in each group was compared using the x2 test and Fisher’s exact 2-tailed test where appropriate. Relative risks and 95% confidence intervals were calculated for ophthalmic findings including visual deterioration. Continuous data were compared using Student’s t test or the Wilcoxon twosample test. Values of -0.05 were regarded as significant.

Patients and Methods This retrospective study was based in the Port Moresby General Hospital (PMGH), a 600 beds university teaching hospital in PNG. The case notes and drug charts of all patients with a diagnosis of cryptococcal meningitis between September 1991 and September 1995 were reviewed. The diagnostic criteria for C. neojormans var. gattii meningitis were as previously described (SEATON et al., 1997). All patients were previously healthy and had normal cell-mediated immunity after treatment as detetermined by intradermal test-

Results A total of 26 patients met the stated inclusion criteria; 16 received corticosteroids in conjunction with anticryptococcal therapy and 10 received anticryptococcal therapy with intermittent chlorpheniramine for febrile reactions to amphotericin B. CSF was not cultured from 7 patients who were diagnosed on the basis of detection of cryptococcal antigen in CSF or serum. With the remaining 19 patients, culture of CSF confirmed C. neofornzans infection. Of these 19, C. neoformans var. aattii was confirmed in 15 (13 of whom received corticoiteroids and 2 who did not): With the remaining 4 patients, CSF isolates were not biotyped. The 2 treatment groups were comparable with respect to visual symptoms and ophthalmic findings be-

Address for correspondence: Dr R. Andrew Seaton, Infection and Immunodeficiency Unit, Kings Cross Hospital, Clepington Road, Dundee, DD3 8EA, UK, phone +44 1382 660 111, fax +44 1382 816 178.

STEROIDS

Table

IN CRYPTOCOCCAL

1. Comparison

51

MENINGITIS

of the two treatment Steroids

groups

No steroid

over 4 weeks); and one because of bilateral visual loss associated with optic disc swelling (dexamethasone 4 mg 4 times daily for 7 weeks). The remaining 13 received loo-250 mg of hydrocortisone before amphotericin B infusion daily for the entirety of their in-patient stay.

P

No. Age (years)a Sex (male:female) Length of history (weeks)b Visual loss on admission Optic disc swelling on admission Cranial nerve palsy Abducens nerve palsy Raised intracranial pressure CSF cryptococcal antigen >1:1024 Cumulative dose of amphotericin B (g/kg)b Length of treatment (weeks)b Optic atrophy after treatment Visual deterioration during treatment Blind following treatment

25 $39) 11:5 y;; 00 11(69%) 7 (44%) 2(125%) 11/12(92%)

15 (?30) 6:4 8.6(4.6) 2 (20%) 8 (80%) 4(40%) 3(30%) 3/3(100%)

0.049

9/14(640/u)

2/3(67%)

1.00

41.2(18) 156(10.5) 1115 (6.7%)’

35.8(17) 11.3(6.8) 6/10 (60%)

0.58 0.292 0.007

2/16(125%) l/16(6.3%)

7/10(70%) 5/10(50%)

0.009 0.018

0.079 1.00 0.67 1.00 0.34 1.00

Visual outcome (Table 1) The risk of visual deterioration was significantly greater in the group treated with antifungal agents alone (P=O.O09) and the risk of development of blindness was significantly reduced in the steroid treated group (P=O.O 18). Three patients treated with corticosteroids demonstrated improvement in vision. Optic atrophy developed in significantly more patients who did not receive corticosteroids (-0.007). Of these, 4 developed optic atrophy following optic disc swelling and 2 had optic atrophy without prior disc swelling. One patient treated with corticosteroids developed blindness associated with optic

atrophy

following

optic

disc

swelling.

In

the

re-

mainder of the patients with optic disc swelling who were treated with corticosteroids, disc swelling resolved. aRange in parentheses. bStandard deviation in parentheses. The beneficial effects of corticosteroids on visual loss ‘One patient presented with primary optic atrophy before treatdid not appear to be related to the effects of reducing inment and so was not included. tracranial pressure as judged by serial measurement of CSF pressure via lumbar puncture (Table 2). Table 2. Changes in cerebrospinal fluid opening pressure in patients treated with corticosteroids Patient no. 1 2 3 4 5 6 7 98 10 11 12 ii 15 16

Admission 310 High High 370 330 390 600 310 NRb >450 5:; NR High NRb 210

aHC=hydrocortisone, bNot recorded.

CSF pressure (mm) Maximum Discharge 3 10 (admission) 390 (week 10) 350 (week 22) 380 (week 6) >600 (week 6) >400 (week 3) 600 (admission) >400 (week 10) NRb 620 (week 12) 410 (week 4) 500 (admission) NRb >400 (week 4) NRb 380 (week 5)

Dexzdexamethasone,

130 130 350 300 240 >350 340 350 NRb 165 240 220 NR; Eib NRb

Pred=prednisolone

fore treatment (Table l), although the steroid treatment group had a shorter history of meningitis before treatment and were older. However, length of history before treatment was not significantly different in patients in whom vision deteriorated (6.8 weeks, s~~2.8) compared to those in whom vision improved or remained unaltered (6.6 weeks, ~~z4.8; EO.899, Student’s t test), and similarly the ages of patients in whom vision deteriorated were not different from those in whom vision was unaltered or improved (median 25 years, range lo-30 and median 23, range 7-39; EO.957, Wilcoxon two-sample test). There was no difference between the 2 groups with respect to the presence of raised intracranial pressure (measured by opening pressure via lumbar puncture on admission), antifungal treatment received, or length of therapy. Corticosteroid

dosing

regimen

Of the 16 patients who received corticosteroids, 3 received a high dose (Table 2): one patient with normal vision because of persistance of headache and optic disc swelling despite chemotherapy (dexamethasone 4 mg 4 times daily for 14 d); one with bilateral visual loss secondary to optic atrophy with no prior disc swelling (prednisilone 60 mgidaily for 2 1 d and subsequently reducing

Corticosteroid regimei? 100 mg HC daily 250 mg HC daily 16 mg Dex 2 weeks 100 mg HC daily 100 mg HC daily Pred 7 weeks 100 mg HC daily 100 mg HC daily 100 mg HC daily 100 mg HC daily 200 mg HC daily 100 mg HC daily 200 mg HC daily 16 mg Dex 7 weeks 100 mg HC 100 mg HC

60 mg daily for 3 weeks and then reducing

Visual change None None None None None Improved None None None Deteriorated Deteriorated None None Improved None Improved over 4 weeks.

Those treated with corticosteroids were followed up for a median of 10 months (range 2-46 months) following completion of therapy and none showed any clinical or serological evidence of relapse or further visual deterioration. Discussion C. neofomzan~ var. guttii meningitis is frequently complicated by visual loss, despite the use of standard combination antifungal therapy. Our observations suggest that adjuvant treatment with corticosteroids may prevent visual loss in those patients who have at least some perception of light on presentation. Since this was not a prospective, randomized controlled trial it is possible that some bias has been introduced. Hydrocortisone was used as standard treatment for febrile reactions to amphotericin B from 1994 onwards and therefore the patients who did not receive corticosteroids were treated before 1994. Also, with 2 patients with deteriorating vision corticosteroids were used in an (apparently successful) attempt to ‘rescue’ vision. However, we present these preliminary findings first of all to demonstrate the safety of corticosteroids in C. neofomzanS var. g&i meningitis and secondly to alert others, particularly in the tropics, to their possible benefits in preventing this

52 most serious and disabling complication for which, as yet, there is no known treatment. Although the numbers studied were small, the 2 treatment groups were well matched in their ophthalmic findings and other disease features associated with risk of visual loss on admission. The group treated with antifungal agents alone were younger and had a longer history before treatment but in neither this study nor our larger series (SEATON et al., 1997) did we find these to be significant factors in determining visual loss or the progression of disc swelling to optic atrophy. Visual loss and the development of optic atrophy were significantly reduced in those patients treated with corticosteroids and we have also demonstrated that there was no obvious clinically significant effect on intracranial pressure in the steroid treated group, although intracranial pressure monitoring and neuroradiological scanning were not available to confirm this. We postulate that corticosteroids may be beneficial in preventing visual deterioration because of their antiinflammatory or imrnunomodulatory effects preventing the development of optic atropy following optic disc swelling. There are 2 possible mechanisms: by reducing arachnoid adhesions around the optic nerves leading to reperfusion of compromised neural tissue, or by reducing oedema, fibrosis and scarring in the optic nerve by damping down the inflammatory reaction to cryptococcal invasion within the optic nerve. There is little information on the use of corticosteroids in cryptococcal meningitis and there has been no controlled trial investigating their efficacy. In the published case reports there appeared to be no improvement in vision attributable to their use (REX et al., 1993). In one patient reported, whose vision improved following massive doses of corticosteroids, treatment also included optic nerve fenestration (KELTNER et al., 1977).

The minimum dose of corticosteroid used in this study was 100 mg of hydrocortisone daily (in 10 patients), and this may be sufficient to prevent visual deterioration in immunocompetent patients with C. ~zeofomzans var. gut& meningitis. The most appropriate dose and regimen of corticosteroid need to be assessed in properly designed randomized controlled trials. Daily divided doses may be more efficacious, giving a more reliable serum and CSF steady state. With the doses of hydrocortisone used in this study, we did not observe any side effect or infectious sequela attributable to their use. However, in one patient treated with a prolonged course of high dose dexamethasone, pulmonary tuberculosis was reactivated and herpes zoster occurred. Clearly

R.ANDREWSEATON

when these higher culosis is endemic ministered. We hope future pua New Guinea var. guttii infection these preliminary rent high incidence

ETAL

doses are used in areas where tuberprophylactic isoniazid should be adrandomized controlled studies in Paand elsewhere where C. neoformuns is endemic will help to substantiate observations and so reduce the curof visual loss in this infection.

Acknowledgements

We extend our gratitude to the medical. nursine and laboratory staff of Port horesby General Hospital and-Department of Medical Sciences, University of Papua New Guinea for their help in the diagnosis and management of our patients, to Drs I. Amban (Madann Hosaital). T.Amini (Angau Memorial Hoshital. Laei and I. F. La&en& for allowin; us to reuort their patients and to B. Waian and l? Kila for pezorming &ptococcal antigen assays.Dr David Ellis of the Australian mycology reference laboratory, Adelaide, confirmed the C. neoformans var. gattii biotypes. We are also grateful to Professors A. Seaton and R. J. Hay and Dr Anne Soutar for critical reading of the manuscript. Provisional data from this study were presented at the ‘Research in progress’ meeting of the Royal Society of Tropical Medicine and Hygiene, Manson House, London, on 16 November 1995 (SEATON et al., 1996a). 1~~

I

,

References

Keltner, J. L., Albert, D. M., Lubow, M., Fritsch, E. & Davey, L. M. (1977). Optic nerve decompression: a clinical patbologic study. Archives of Ophthalmology, 95,97-104. Rex, J. H., Larsen, R. A., Dismukes, W. E., Cloud, G. A. & Bennett, J. E. (1993). Catastrophic visual loss due to Cryptococcusneoformans meningitis. Medicine, ?2,209-224. Seaton, R. A., Naraqi, S. & Wembri, J. I? (1995). Immunological aspects of cryptococcal meningitis in Papua New Guinea. Australian and New ZealandJournal of Medicine, 25,562. Seaton, R. A., Verma, N. & Naraqi, S. (1996a). Ophthalmic findings in Cryptococcus neoformans var. gattii meningitis. Transactions of the Royal Society giene, 90,7.

of Tropical Medicine

and Hy-

Seaton, R. A., Naraqi, S., Wembri, J. I? & Warrell, D. A. (1996b). Predictors of outcome in Cryptococcus neoformans var. gattii meningitis. Quarterly Journal of Medicine, 89, 423428.

Seaton, R. A.,Verma, N., Naraqi, S., Wembri, J. l? & Warrell, D. A. (1997). Visual loss in immunocompetent patients with Cryptococcus neoformans var. gattii meningitis. Transactions of the Roval Societv of Troaical

Medicine

and Hveiene,

91,44-49.

Tan, C. ?. (1988): I&acianial hypertension &sing vi&al failure in cryptococcal meningitis. Journal of Neurology, Neurosurgery and Psychiatry, 51,944-946. Received 31 July 1996; revised 19 September for publication 19 September 1996

1996;

accepted