Cryptococcal
Meningitis
in Systemic
Lupus Erythematosus
By Bernard Zimmermann III, Michael Spiegel, and Edward V. Lally Two cases of cryptococcal meningitis occurring in patients with systemic lupus erythematosus (SLE) are presented, and 24 additional cases from the literature are reviewed. The insidious onset of this infrequent complication is emphasized. The nonspecific neurological findings associated with this infection are often mistakenly diagnosed as a central nervous system manifestation of SLE. Earlier diagnosis and effective
P
ATIENTS WITH lupus erythema(SLE), particularly treated with agents, are to the of opportunistic This complication associated with significant of mortality.’ to recognize infections in setting frequently in delayed and treatment contributes to poor Opportunistic infections SLE often insidiously and mimic clinically of the features of disease. Cryptococcal of the nervous system is a but often complication SLE. Meningitis by this organism was in only of 138 of SLE by Harvey a1.2In extensive review 520 SLE by Dubois Tuffanelli, this complication was reported.3 In present report describe two tients with who developed meningitis and the clinical in these and in others reported the English-language We emphasize
From the Division of Rheumatology, Department of Medicine, Roger Williams Medical Center and Brown University School of Medicine, Providence, RI. Bernard Zimmermann III, MD: Assistant Professor of Medicine, Brown University School of Medicine; Michael Spiegel, MD: Rheumatology Fellow; Edward V. Lally, MD: Associate Professor of Medicine and Director, Division of Rheumatology, Brown University School of Medicine. Address reprint requests to Bernard Zimmennann III, MD, Division of Rheumatology, Department of Medicine, Roger Williams Medical Center, 825 Chalkstone Ave, Providence, RI 02908. Copyright o 1992 by WB. Saunders Company 0049-017219212201-0002$5.OOlO 18
antifungal therapy have improved the prognosis of cryptococcal meningitis in SLE patients in recent years. Strategies for the treatment of patients with this complication are discussed. Copyright o 1992 by W. B. Saunders Company INDEX WORDS: Cryptococcal meningitis; systemic lupus erythematosus; central nervous system lupus; cryptococcosis.
cryptococcal infection in SLE frequently develops insidiously, may be confused with exacerbations of SLE, and is associated with significant mortality unless the diagnosis is established at an early stage and appropriate therapy instituted. CASE REPORTS
Case 1
A 21-year-old white woman had SLE diagnosed in 1982. She presented with arthritis, fever, malar rash, and serositis and a positive serological assay for antibodies to doublestranded DNA. Her subsequent course was complicated by pericardial tamponade, pancytopenia during pregnancy, and catatonic psychosis. She was treated with high doses of prednisone which stabilized the major manifestations of SLE. In early 1986, she was receiving prednisone, 40 mg every other day by mouth, and haloperidol for episodes of mania. In July 1986, she developed a persistent headache followed by diplopia and transient numbness of the right half of her tongue. She was evaluated in an emergency department, where left eyelid ptosis and inability to adduct the left eye past the midline were noted. She was sent home with an eyepatch and evaluated by the rheumatology service 3 days later. At that time, her temperature was 38.7”C. She was alert and oriented but depressed. A left third-nerve palsy and a sluggish left pupillary reflex were present. No signs of meningeal irritation were noted. She was admitted to the hospital, where the initial laboratory evaluation was unremarkable. Computerized tomography of the head was normal. A lumbar puncture yielded cerebrospinal fluid (CSF) with 211 white
Seminars in Arthritis and Rheumatism, Vol 22, No 1 (August), 1992: pp 18-24
19
CRYPTOCOCCAL MENINGITIS IN SLE
blood cells (WBC)/mm3, 75% of which were neutrophils. Her glucose level was 23 mg/dL and the protein was 172 mg/dL. CSF Gram’s stain and india ink stain for cryptococcal organisms were also negative. She was treated for presumed CNS lupus with an increased dose of prednisone, and her diplopia improved. After 48 hours, fungal culture of the CSF was reported positive and antibodies to cryptococcal antigen were detected in a dilution titer of 1:128. Treatment with intravenous amphotericin B (1,390 mg) and 5-fluorocytosine (5FC) (4 g/d) was initiated. Prednisone was rapidly tapered and discontinued. After 6 weeks of intravenous antifungal therapy, the CSF was normal except for a cryptococcal antigen titer of 1:8. Six months later, the patient had a mild residual third cranial nerve palsy but no other discrete neurological deficits. CSF analysis at that time was normal.
glucose, 178 mg/dL). Seventy-five red blood cells (RBC)/mm3 and 3 WBC/mm3 were noted in tube 1, and 6 RBC/mm3 and 3 WBC/mm3 in tube 4. A CSF Gram’s stain and an india ink preparation for cryptococcal organisms were negative. On the second hospital day, a test for antibodies against cryptococcal antigen in the CSF was reported positive in a dilution titer of 1:1,024. Treatment was initiated with intravenous 5-FC and amphotericin B. 5-FC was given at a dose of 3 g/d for 3 weeks but was discontinued because of abnormal liver function tests and pancytopenia. Because of clinical evidence of exacerbation of SLE, prednisone was reinitiated 4 weeks after antibiotics were started. During 6 weeks of hospitalization, she received 525 mg of ampho-
Table 1: Cases of Cryptococcal Meningitis in Patients With Systemic Lupus Erythematosus
Case 2
A 22-year-old Hispanic was had SLE diagnosed in 1986 based on the presence of alopecia, a malar rash, inflammatory polyarthritis, serositis, and a positive serum test for antibodies to double-stranded DNA. She was treated initially with high-dose prednisone, which was subsequently tapered to 10 mg/d. Ten months later, she was brought to the emergency department because of progressive mental status deterioration. The patient complained only of headache but was reported by her family to be confused and disoriented. Physical examination showed a temperature of 37.7”C, a pulse rate of 120, normal blood pressure, and a respiratory rate of 18/min. Malar rash, frontal alopecia, purpuric rash on the right hand, and signs of chronic arthritis were noted. No meningismus was observed, and the rest of the general examination was unremarkable. Neurological findings included fluctuating levels of alertness and a fine resting tremor but no focal deficits. Laboratory evaluation showed WBC count, 5,30O/mm’; hematocrit, 30%; normal platelets; and erythrocyte sedimentation rate, 80 mm/h. Results of computerized tomography of the head were normal. CSF analysis showed protein, 120 mg/dL; and glucose, 68 mg/dL (serum
‘atient
Reference
Age/ Duration TreatGender of SLE ment (mo) of SLE (vr)
1
Harvey et al*
41/M
144
None
2
Rapaport et al5
II/F
24
P
3
Pariser et al6
50/F
1
P
4
MGH’
40/F
1
None
5
Collins et al8
26/F
5
6
Collins et al9
46/F
36
P,A P
7
Cooke et allo
26/F
a
P
a
Khan et all1
41/M
5
P
9
Sieving et all*
30/M
12
10
Sieving et all*
12/F
144
11
Roberts et all3
40/F
120
P,A
12
Speller et all4
48/F
24
P,A
13
Speller et alI4
52/F
a4
P
14
Malas et all5
36/F
48
P,A
15
Lesser et all6
17/F
20
P,A
16
Eiser et all7
30/F
15
17
Perfect et all*
32/F
NS
P,A,C P,C
ia
Perfect et all*
21/F
NS
19
Smith et all9
16/F
3
20
Li et al*O
26/F
36
P,A P,A
21
Kong et aI*’
25/F
27
P
22
Kong et aI*’
21/F
22
P
23
Kong et alzl
28/F
111
P,A
24
Al-Rasheed
8/F
ia
P
25
Present report
21/F
48
P
26
Present report
22/F
12
P
29.5
40
Mean Abbreviations:
et al**
P P,A
P
NS, not stated; P, prednisone; A, azathioprine;
C, cyclophosphamide.
20
ZIMMERMANN,
tericin B. Despite a complicated course, the patient improved significantly. Fever, arthralgias, pleural effusion, and hypocomplementemia resolved. Mental status normalized and there were no residual neurological abnormalities. She was seen 4 years later with no evidence of recurrent cryptococcal infection.
infections may occur because the clinical manifestations are mild or nonspecific, evolve slowly, or suggest an exacerbation of SLE. The two patients described in the present report each developed fulminent cryptococcal meningitis that was initially believed to represent an exacerbation of CNS lupus. The appropriate diagnosis was established because of a high index of clinical suspicion and persistent diagnostic surveillance. Although the institution of antifungal therapy was delayed, both patients eventually recovered from this infectious complication. Including the two patients described in the present report, we are aware of 26 cases in the English-language literature of cryptococcal meningitis developing in patients with SLE.2,5-22The
DISCUSSION
The most common cause of death in patients with SLE is infection.4 Opportunistic infections, which occur commonly in SLE patients, particularly those receiving corticosteroids, are frequently difficult to diagnose accurately. In one series,’ only 3 of 15 SLE patients (20%) who died with opportunistic infections were diagnosed before death. Delay in diagnosis of such
Table
2:
Signs
SPIEGEL, AND LALLY
and Symptoms
of Cryptococcal
Meningitis Duration
Patient
Signs
Symptoms
1
Restlessness,
2
HA, irritability
disorientation
Meningismus None
weakness
Ataxia, Bells palsy
of Symptoms
Steroid
(wk)
Improvement*
3
No
NS
Yes
24
Yes
4
Yes NG
3
Depression,
4
HA, confusion
Nystagmus,
5
HA, diplopia
Fever, coma, seizures
2
6
HA, malaise
Confusion,
3
NS
7
HA, confusion
1
NG
stiff neck loss, cough
meningismus lethargy
Meningismus None
8
Malaise, weight
9
Disorientation
Seizures
10
HA
Weakness,
11
Psychosis
NS
12
HA, lethargy
Fever
13
HA, vomiting,
14
Ataxia, tremor, weakness
Hemiparesis,
15
Nightmares,
Tremor, ataxia, VI N palsy, fever
16
Hallucinations,
lethargy hallucinations,
incontinence
Stupor, papilledema
+ Babinsky
4
NG
NS
NG
1
NG
3
NG
NS
NG
4
NG
20
NG
4
Yes
Fever
20
Yes
ataxia + Babinsky
diplopia paranoia,
weakness 17
HA, photophobia
Lethargy
NS
NG
18
Confusion
Fever
NS
NG
19
None
None
20
HA
Fever
4
NG
21
NS
NS
2
NS
22
NS
NS
6
NS
23
NS
NS
48
NS
24
Weakness
Fever, disorientation
12
Yes
25
HA, diplopia
Fever, Ill N palsy
8
Yes
26
HA, confusion
Fever, confusion,
2
No
Abbreviations:
NG
tremor
HA, headache; NS, not stated; N, nerve; NG, steroids not given or maintenance dose unchanged.
*Neurological symptoms improved wittkorticosteroid
administration.
21
CRYPTOCOCCALMENINGITIS IN SLE
demographic and clinical features of these patients are shown in Table 1. Eighty-eight percent of the patients were female, and the mean age at the time of diagnosis was 30 years. The mean duration of SLE before the onset of meningitis was 3.3 years. Twenty-four of 26 patients (92%) were receiving corticosteroids, and 10 patients were also being treated with azathioprine. The neurological features of these 15 patients at the time of presentation with meningitis are listed in Table 2. Headache was common (46%) but most symptoms were nonspecific and had been present for many weeks before the diagnosis of meningitis (mean, 9 weeks; range, 1 to 48 weeks). One asymptomatic patient had cryptococcal infection discovered by routine culture of peritoneal dialysate (patient 19). Several patients had cryptococcemia, and 1 (patient 17) had cryptococcal septic arthritis. Alteration of
mental status was noted in 12 patients, and visual symptoms occurred in 5 patients (diplopia in 3, hallucinations in 2). Signs of meningeal irritation often were not present until late in the course of illness. Fever, cranial nerve abnormalities, and psychiatric illness were frequently mistaken for evidence of CNS involvement with SLE. In 7 patients, neurological symptoms improved transiently with increased doses of prednisone, perhaps because of its effect on cerebral inflammation caused by infection or on concomitant or subsequent exacerbation of SLE. Data from CSF analyses are shown in Table 3. In 2 patients (patients 2 and 5) no lumbar puncture was performed and cryptococcal meningitis was diagnosed at postmortem examination. Of the 18 cases in which the CSF WBC count was reported, 11 had mild pleocytosis and 6 had no cells (mean CSF WBC, 92/mm3; range, 0 to 1,000/mm3). CSF protein levels were mod-
Table 3: Cerebrospinal
Patient
Fluid Findings
OP
WBC
Differential
Glucose
Protein
(mm HzO)
(cells/mm3)
Cell Count
(mg/dL)
(mg/dL)
1
NS
2
ND
NS
NS
NS
NS
3
150
26
Mostly M
53
210
4 5
245 ND
36
26P, 1OL
NS
68 150
6
230
40
92% P
NS
7
585
16
11 P/5L
0
113
8
200
1000
38
286
82% P/13%
L
108
174
IOM
15
105
NS
NS
40
74
NS
310
NS
NS
NS
13 14
> 400 NS
none NS
NS
490
NS
NS
NS
15
330
45
NS
17
115
16 17
NS NS
none NS
54
12
NS
NS
NS
18
NS
none
NS
NS
19
NS
NS
NS
NS
NS
20
300
NS
100% P
40
580
21
12
130
2
400
22
8
none
2
300
23
23
none
3
140
24
NS
60
90% L/IO%
P
150
84
25
NS
211
75% P/25%
M
23
172
26
NS
3
68
120
9
240
none
IO
NS
13
11
NS
12
NS
NS
Abbreviations: OF’, opening pressure; WBC, white blood cell; ND, lumbar puncture not done; NS, not stated or not reported; P, polvmorphonuclearleukocyte; M, mononuclear IeukocYte;L, lymphocyte.
22
erately elevated (mean, 202 mg/dL) in most cases, but glucose levels were variable. In our 2 patients, the india ink preparations were negative and cryptococcal meningitis was not diagnosed until the results of fungal cultures and serological testing for cryptococcal antigen became available. The prognosis in SLE patients with cryptococcal meningitis is poor. Before the introduction of amphotericin B in 1957, the outcome in such cases was uniformly fatal. Effective antifungal therapy has significantly improved survival in patients in whom the diagnosis is established in a timely fashion and appropriate treatment is initiated. Intravenous amphotericin administered alone or in combination with 5-FC is the recommended treatment.23 Of 20 patients treated in this fashion (patients 6, 8-26), 12 (60%) survived with little or no neurological sequelae (Table 4). One patient (patient 13) apparently died from recurrent meningitis despite treatment with intravenous and intrathecal 5-FC and intravenous amphotericin. One patient (patient 20) developed permanent blindness that was believed to be related to amphotericin toxicity. Of 26 patients, 14 died as a result of cryptococcal infection (54% overall mortality); higher mortality was reported in cases from the earlier literature. The treatment of SLE patients with cryptococcal infection is further complicated by the need to treat concomitant exacerbations of SLE under some circumstances. During the course of cryptococcal meningitis, exacerbations of lupus activity may require treatment with higher doses of corticosteroids. The effect of corticosteroid administration on cryptococcal meningitis is unclear. In one study of prognostic factors in cryptococcal meningitis, corticosteroid therapy was associated with increased mortality and daily corticosteroid dosages greater than 20 mg of prednisone were found to be a risk factor for recurrence of meningitis after treatment.24 However, it is frequently necessary to treat these disease exacerbations aggressively, especially if they are life threatening. In the second case described herein, the cryptococcal infection was successfully eradicated despite reinstitution of prednisone therapy for exacerbation of SLE. Infection with Gyptococcus neofomans devel-
ZIMMERMANN,
SPIEGEL, AND LALLY
ops during the course of diseases that compromise immune function, particularly cell-mediated immunity (CMI), and in association with immunosuppressive drug therapy.25 In certain patients without obvious immune dysfunction, abnormalities in CM1 have been shown by skin testing and in vitro methods.26 Effective killing of cryptococcal organisms by the host requires the participation of neutrophils, activated macrophages, and sensitized T lymphocytes.27 The early immunologic response to cryptococcal infection includes an increase in the number of CD8+ suppressor T cells. Natural killer cells, when present in sufficient numbers, may also inhibit the growth of cryptococcal organisms. Fundamental abnormalities of CM1 have been shown in SLE.28 In particular, significantly reduced numbers of CD8+-suppressor T cells29 Table 4: Therapy and Outcome Patient
Treatment
Outcome
1
None
Died
2
None
Died
3
None
Died
4
None
Died
5
None
Died
6
AMB
Survived
7
NS
Died
Morbidity
None
8
AMB
Survived
None
9
AMB/BFC
Survived
None
10
AMB
Died
11
AMB/5-FC
Survived
12
AMB/5-FC
Died
13
AMB/5-FC
Died
14
AMB/5-FC
Died
15
AMB
Survived
None
16
AMB
Survived
None
17
AMB/5-FC
Died
18
AMB/5-FC
Survived
None
19
AMB
Survived
None
20
AMB/S-FC
Survived
Blindness*
None Recurrent meningitis
Miconazole 21
AMB/5-FC
Died
22
AMB/5-FC
Survived
23
AMB/5-FC
Died
24
AMB/5-FC
Died
25
AMB/5-FC
Survived
Diplopia
26
AMB/5-FC
Survived
None
NS
AMB, amphotericin B; 5-FC, 5-fluorocytosine; NS, not stated. ‘Believed to be caused by AMB toxicity.
Abbreviations:
CRYPTOCOCCAL
MENINGITIS
23
IN SLE
and impaired natural killer cells30 have been found in SLE patients. The latter abnormalities provide a possible explanation for the development of cryptococcal infections in certain lupus patients. Cryptococcal infection frequently localizes to the CNS and may progress insidiously in this location for several reasons.31 Soluble anticryptococcal factors, present in normal serum, are lacking in the CSF. Furthermore, no significant complement activation occurs in the CSF, and thus inflammatory reactions are minimal. Finally, high CNS levels of dopamine may favor local proliferation of more virulent yeasts. In SLE, clinically significant neurological dis-
ease is frequently assumed to be a feature of the underlying illness. The nonspecific presentation and paucity of clinical findings in SLE patients with cryptococcal meningitis enhances the likelihood that the appropriate diagnosis will be overlooked or delayed. A heightened index of suspicion, close attention to CSF analysis, and early aggressive therapy may reduce the high mortality rate associated with this complication of SLE.
ACKNOWLEDGMENT The authors acknowledge the fine secretarial assistance of Paula Hennebury and Geraldine Bouchard.
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two cases of cryptococcosis within 3 months on the same general medical ward. Can Med Assoc J 115:537-538,1976 14. Speller DCE, Fakunle F, Cairns SA, et al: Cryptococcal meningitis complicating systemic lupus erythematosus: Two patients treated with flucytosine and amphotericin B. J Clin Path01 30:254-261, 1977 15. Malas D, Weiss S: Progressive multifocal leukoencephalopathy and cryptococcal meningitis with systemic lupus erythematosus and thymoma. Ann Neurol 1:188-191, 1977 16. Lesser RL, Simon RM, Leon H, et al: Cryptococcal meningitis and internal ophthalmoplegia. Am J Ophthalmol 87:682-687, 1979 17. Eiser AR, Neff MS, Slifkin RF: Cure of cryptococcemia in an immunocompromised patient with lupus nephritis. Am J Nephrol2:95-97,1982 18. Perfect JR, Durack DT, Gallis HA: Cryptococcemia. Medicine 62:98-109, 1983 19. Smith JW, Arnold WC: Cryptococcal peritonitis in patients on peritoneal dialysis. Am J Kidney Dis 11:430-433, 1988 20. Li PK, Lai KN: Amphotericin B induced ocular toxicity in cryptococcal meningitis. Br J Ophthalmol73:397398,1989 21. Kong NC, Shaariah W, Morad Z, et al: Cryptococcosis in a renal unit. Aust NZ J Med 20:645-649, 1990 22. Al-Rasheed SA, Al-Fawaz IM: Cryptococcal meningitis in a child with systemic lupus erythematosus. Ann Trop Paediatr 10:323-326, 1990 23. Bennet JE, Dismukes WE, Duma RJ, et al: A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 301:126-131,1979 24. Diamond RD, Bennet JE: Prognostic factors in cryptococcal meningitis. A study in 111 cases. Ann Intern Med 80:176-181, 1974 25. Sabetta JR, Andriole VT: Cryptococcal infection of the central nervous system. Med Clin North Am 69:333-343, 1985 26. Schimpff SC, Bennett JE: Abnormalities in cell-
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