SPECIAL ARTICLE
Elevated Cerebrospinal Fluid Pressures in Patients with Cryptococcal Meiingitis and Acquired Immunodeficiency - Syndrome DAVIDW. DENNING,M.B.B.s., SanJoseandStanford, California,ROBERTW. ARMSTRONG,M.D., San Jose, Stanford, and Los Gatos, California, BRADLEYH. LEWIS,M.D., Berkeley, California, DAVIDA. STEVENS,M.D., San Jose andstanford, California
Increased intracranial pressure has been a noteworthy problem in some of our patients with cryptococcal meningitis and acquired immunodeficiency syndrome (AIDS), and this appears to be a feature observed in patients with cryptococcal meningitis reported in the literature. Whereas most attention of clinicians is presently focused on 0pGmizing the antifungal regimen, so as to improve on high failrates in cryptococcal meningitis in AIDS, little attention has been paid to the problem of intracranial hypertension. We argue that visual loss and some of the ~8888 of death early after the onset of chemotherapy may be related to high cerebrospinal fluid (CSF) pressure, [email protected]~ of antifungal therapy. The possible pathophysiologic mechanisms are discussed, and we postulate that the mechanism is reduced CSF outflow possibly due to increased outflow resistance, not nm accompanied by prominent cerebral edema Optimal therapy of this complication is not yet established, but some measures that may be helpful are ventricular shunting, frequent high-volume lumbar punctures, and possibly glucocorticoida
From the Divisions of Infectious Diseases and Clinical Microbiology, Departments of Medicine and Pathology, Santa Clara Valley Medical Center, San Jose, California (DWD. RWA, DAS). California Institute for Medical Research, San Jose, California (DWD, DAS), Division of Infectious Diseases, Department of Medicine, Stanford University Medical School, Stanford, California (DWD, RWA, DAS), Good Samaritan Hospital, Los Gatos. California (RWA), and East Bay AIDS Center, Berkeley, California (BHL). Requests for reprints should be addressed to David A. Stevens, M.D.. Division of Infectious Diseases, Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, California 95128. Dr. Denning’s current address: Regional Department of Infectious Diseases and Tropical Medicine, Monsall Hospital, Newton Heath, Manchester, Ml0 8WR, England, United Kingdom. Manuscript submitted January 4, 1991, and accepted in revised form May 3, 1991.
September
ittle hasbeenwritten about the clinical diagnoL sis,natural history, pathogenesis,and management of elevated cerebrospinalfluid (CSF) pressures in patients with cryptococcal meningitis. Prior to the advent of the acquired immunodeficiency syndrome (AIDS) epidemic, cryptococcal meningitis diseasewas rare, with probably fewer than 500 casesannually in the United States [l]. The incidenceof cryptococcalmeningitis has risen sharply with the advent of AIDS, and 3,022casesof extrapuhnonarycryptococcosishad been reported to the Centers for DiseaseControl prior to April 1988[2]. As a result, managementissueshavebeen thrust into the limelight and antifungal therapy has occupiedcenter stage.However,in all the large series of cryptococcalmeningitis in AIDS published to date [3-6], a relatively high proportion of patients die in the 2 weeks after diagnosis despite therapy. In patients with cryptococcalmeningitis in relapse,the mortality is much higher; 11 of 13 patients died with active meningitis despitetreatment [4,7,8].This suggeststhat other factors in addition to antifungal therapy may be important in determining outcome. In our studiesof cryptococcalmeningitis [4,6],we haveobservedpatients who havehad elevatedCSF pressures,three of whom had extremely high pressuresin the context of relapsedmeningitis. All three patients had AIDS and had developedcryptococcal meningitis soon after the diagnosisof AIDS. Primary therapy was amphotericin B in two patients and itraconaxole in the third; all had major improvement.After this, relapsefollowing discontinuation of therapy, failure of a secondcourseof amphotericin B after relapse, and recrudescence during itraconaxoletherapy prompted a changein antifungal therapy to itraconaxolein two patients and to amphotericin B and flucytosine in the other. It was at this time that high CSF pressureswere noted in all three patients, varying from 500 to greater than 570 mm CSF. All three had severe papilledema,enlargedblind spots, and reducedvisual acuity. Impairment of cognitive function, cranial nerve abnormalities, and/or systemic manifestations of elevatedintracranial pressure(ICP) were 1991
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CRYPTOCOCCAL MENINGITIS
1
1
1 “a.sC”liti*?
Inflammation
Vismus CSF Plugs of polysaccharide Yeasts
1 clyptococca polysaccharides and sugars
Brai” enraCell”lar fluid acc”m”lmion (osmotic effect)?
(involves meninges. brain. and CSF)
I”CWSed CSF osmolality
4 bllpaireclCSF uptakeby BraCh”Oid villi. lymphaticdrainageblock?
INCREASED INTRACRANIAL PRESSURE
HEADACHE, VOMITING. IMPAIRED COGNITION, CRANIAL NEUROPATHY, PAPILLEDEMA, BLINDNESS, DEATH
Figure
1. Proposed pathophysiology of adverse course of cryptococcal meningitis. In some patients, a space-occupying lesion may be present, and would contribute to increased intracranial pressure.
also present. In these patients, results of computed tomographic (CT) scanning (two patients) and/or magnetic resonance imaging (MRI) (two patients) were normal. Therapy directed specifically at the high CSF pressure was effective in two of the three patients and temporarily successful in one. Our experience complements the described association of hydrocephalus with cryptococcal meningoencephalitis (9% to 58%) and with progressive deterioration of consciousness, the increased morbidity and mortality when these complications of cryptococcosis occur, and the beneficial effects of neurosurgical decompression in that setting [9]. We believe that some of the early deaths observed in all series of cryptococcal meningitis in AIDS may be related to high ICP leading to impaired cerebral circulation. Loss of visual acuity may also follow sustained elevation of ICP. We discuss the possible pathophysiology (Figure 1) and hope that early recognition of this problem may prompt appropriate therapy. Understanding of the pathogenesis, natural history, and treatment of this problem is, however, poor. Further study is urgently needed to address these issues.
lesion, our view is that the primary deficit is a failure of CSF absorption. A brief review of the normal process of CSF formation, flow patterns, and absorption may be helpful in understanding this viewpoint. It is generally agreed that CSF is formed at the rate of 450 ml/day, mostly by the choroid plexuses in both lateral ventricles and the roof of both the third and fourth ventricles [lo]. As the total volume of CSF is of the order of 150 mL, the whole CSF volume is replaced three times daily. The rate of CSF formation is generally constant over a wide range of ICP, until cerebral perfusion decreases. CSF flows from the lateral ventricles to the third ventricle, then through the aqueduct of Sylvius to the fourth ventricle [ll]. From here it leaves laterally through the foramina of Luschka and medially through the foramen of Magendie to enter the subarachnoid space [ll]. In some circumstances, CSF may flow directly through the brain, extracellularly, by transependymal flow [lo]. Absorption of the CSF takes place mostly via the arachnoid villi and granulations (the only distinction between the two being that the latter are visible to the naked eye) that cover the whole cerebral surface. The arachnoid villi are capable of bulk transport of fluid and particulate matter, including red cells, through oneway valves into the venous circulation [lo]. It is likely that some CSF is also absorbed via lymphatic pathways, and some observations indicate that increased intraventricular pressure results in increased lymph flow of CSF via lymph pathways [lo]; however, the contribution of this pathway to the total is not clear. Under normal conditions, the rate of CSF absorption is pressure-dependent and relatively linear over a fairly wide physiologic range [lo]. The only parameter shown to affect the rate of CSF absorption is the hydrostatic gradient; the greater the ICP, the higher the absorption rate [lo]. Since the CSF space is a confined space, relatively minor alterations in CSF outflow do cause major changes in pressure. Failure of absorption of CSF could theoretically result in intracranial hypertension without hydrocephalus, if the passage of CSF directly through the brain parenchyma is obstructed and intraventricular pressure and subarachnoid pressure were equal.
CSF OUTFLOWRESISTANCE
We believe that the passage of CSF across the arachnoid villi is impaired in some patients with cryptococcal meningitis. Factors possibly influencNORMAL PROCESSOF CSF FORMATION,FLOW, ing this process include the particular cryptococcal AND ABSORPTION strain causing infection, the severity of infection, The pathophysiology of elevated CSF pressures and/or the particular conformation and capacity of in cryptococcal meningitis is not known. In the ab- a given patient’s CSF absorption pathways. It may sence of hydrocephalus, cerebral edema, or a mass be that the viscosity of the CSF in proximity to or in 266
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the arachnoid vilb is elevated to a degree that impairs the passage of CSF, or a microscopic plug of polysaccharide has formed, directly blocking flow. The molecular weight of cryptococcal polysaccharide is high (range 2 X lo7 to lo8 daltons) and varies from isolate to isolate [12]. Cryptococcal polysaccharide can spread rapidly through the brain as demonstrated by implantation experiments in rats [ 131. As viewed by electron microscopy, the polysaccharide appears as sheets of reticulated material [13]; indeed, the estimates of molecular weight quoted above may reflect conglomerations of several molecules of somewhat smaller size. There is considerable isolate-to-isolate variation in the composition and physicochemical behavior of cryptococcal polysaccharide [12]. These differences may be reflected in functional impairment of CSF outflow through arachnoid villi in some patients. In addition, yeast cells, which are often present in profusion in CSF (as seen on India ink preparations) and meninges in autopsy sections, are considerably larger than red cells and may occlude the channels and valves of the subarachnoid villi. Blockage of lymph pathways, the other route of CSF absorption, may occur for similar reasons. Differences in the relative capacity of the CSF absorption pathways between individuals may predispose some to the development of high ICP, because of low reserve or particular conformations of their CSF outflow tracts. Reduction of CSF absorption may therefore depend on the patient, severity of disease, degree of immune impairment, or cryptococcal strain, or any combination of these factors. Whether particular antifungal agents could influence this process, for example, altering the amount and type of extracellular polysaccharide produced or the rate of CSF sterilization and therefore the number of yeast cells available for blocking the arachnoid villi (if this occurs), is not known. Although unlikely, it is also possible that cryptococcal meningitis itself alters the rate of CSF production, which if increased without absorption being correspondingly increased, could lead to elevated ICP. The concept of a reduced rate of removal of CSF has been termed outflow resistance and has been studied in various pathologic conditions holding, as it does, a potentially pivotal role in influencing ICP. Studies examining outflow resistance in humans are few and most have been done by rapid infusion of fluid into the lumbar space with subsequent observation of the rate of reduction of CSF pressure [14-191. Space limitations prevent extensive discussion of details of these tests, their performance, limitations, and results in various other conditions. Suffice it to say that, to our knowledge, only one patient with cryptococcal meningitis has been studSeptember
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ied in this fashion [17]. This was in 1968 in an elderly patient who had probably long-standing undiagnosed cryptococcal meningitis with milky and thickened arachnoid membranes (quite different from cryptococcal meningitis in AIDS patients in almost all respects). A clear-cut increase in CSF pressure occurred on infusion of artificial CSF at a rate of 0.76 ml/minute, which in 11 control subjects was not the case. This probably indicates a reduced CSF absorptive capacity in this patient with cryptococcal meningitis. We would anticipate a similar response in our patients, had such a test been done. Increased outflow resistance has been described in animal models of bacterial meningitis [20]. In pneumococcal meningitis in rabbits, major differences in CSF outflow resistance were seen: from 0.26 mm Hg/pL/minute in uninfected controls to 6.77 f 3.52 mm Hg/pL/minute in infected animals [21]. Penicillin therapy had no reducing effect on this elevation even 15 days later, but methylprednisolone, given early in infection, reduced the outflow resistance to nearly control values. Methylprednisolone and dexamethasone were directly compared in a later set of experiments done in a similar fashion with the same isolate of Streptococcus pneumoniae, also in rabbits [22]. In this experiment, only cisternal pressure was measured, not outflow resistance, but dexamethasone had a much more profound effect on lowering CSF pressure than methylprednisolone (which had no apparent effect). Brain water content was reduced by both steroids. The rabbit model is far from ideal for studies of intracranial hypertension, as more than 90% of CSF drains via lymphatic pathways [23].
ELEVATEDICP WITHOUT HYDROCEPHALUS Assuming that CSF absorption was reduced in the patients we describe, why was hydrocephalus not seen on MRI or CT scanning? No immediate explanation is forthcoming. The experience in our patients contrasts with that of patients with benign intracranial hypertension (pseudotumor cerebri), which is probably a failure of CSF absorption [24]. Although transependymal flow was not demonstrable on the MRI scans of two of our patients, we believe this provides the most likely explanation contributing to the lack of hydrocephalus we have observed. A model of communicating hydrocephalus in dogs and primates using radiolabeled albumin demonstrated considerable transependymal flow of isotope [25]. Histologic and ultrastructural changes in the ventricular lining allowing the passage of labeled albumin accompanied these changes [25]. In patients with AIDS, the subacute onset of meningitis together with the enormously ‘high quantities of cryptococci and cryptococcal polysac1991
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charide may allow the gradual development of a state of pressure equilibrium between the ventricles and the subarachnoid space with free passage of CSF through the brain parenchyma. In other words, we postulate that there is no pressure gradient between any intracranial sites. If this is the case, no ventricular dilatation would be expected. It is also possible that the major reason for the absence of ventricular dilatation is not related to transependymal flow but to the coexistence of cerebral edema and high outflow resistance. The early studies of Hirano et al [13] using intracerebral injections of purified cryptococcal polysaccharide indicate that the latter causes the accumulation of extracellular fluid in the brain parenchyma. The presence or absence of intracellular edema cannot be adequately appraised from these experiments because microscopy is not a good tool for this assessment. Extracellular fluid accumulation may be a purely osmotic effect in these experiments, as the quantity of polysaccharide injected may bear no relationship to that found in human cryptococcal meningitis. On the other hand, AIDS patients have large numbers of cerebral cryptococci as described histopathologically [26] and as evidenced by the high titers of CSF cryptococcal antigen noted in several series [3,4,7,8,27]. Lysis of these fungal cells by chemotherapy in some patients could release large amounts of polysaccharide and constituent sugars, including mannitol. The consequence would be a reverse osmotic effect to that desired when mannitol is given intravenously to reduce cerebral edema in a variety of clinical conditions associated with intracranial hypertension. If marked extracellular fluid expansion did accompany severe cases of cryptococcal meningitis, then brain swelling might be expected. Swelling might not be visualized on scanning because of a concurrent marked increase in ICP related to increased outflow resistance, one pressure balancing the effect of the other. Alternatively, exudation and expansion of extracellular fluid because of cryptococcal meningitis may facilitate transependymal flow of fluid without causing brain swelling.
VASCULITISRELATEDTO CRYPTOCOCCAL MENINGITIS Another factor that could be relevant in this context is the likelihood that at least some isolates of Cryptococcus neoformans appear to have the propensity to induce either vasculitis, arteritis, and/or cerebral infarction. Cerebral vasculitis has been described in meningitis due to other fungi [28]. In the pre-AIDS era, occasional patients with cryptococcal meningitis would develop sudden stroke syn-
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dromes [29]. Cutaneous cryptococcal infection giving rise to vasculitis is also described [30]. Anterior cerebral arteritis was seen in one patient who had angiography [31], a diagnostic study rarely done in cryptococcal meningitis. Among patients with AIDS and cryptococcal meningitis, two of seven patients had associated cerebral infarction at autopsy in one series [32]. Histopathologically, the brain demonstrates a dense perivascular infiltrate in both AIDS and non-AIDS patients with cryptococcal meningitis. A diffuse vasculitis, particularly a venulitis, could significantly elevate capillary pressure leading to a reduction in the rate of removal of CSF as it traverses the subarachnoid villi. It could also contribute directly to focal or global ischemia by further compromising blood supply already reduced because of elevated ICP.
THERAPYOF ELEVATEDICP IN CRYPTOCOCCAL MENINGITIS Three modalities of therapy were used to control elevated CSF pressures in the three patients we treated. A reduction in CSF pressure was seen with each modality: ventriculoperitoneal shunt in one patient, frequent high-volume lumbar punctures in the second, and a combination of corticosteroid therapy and high-volume lumbar punctures in the third. The condition of Patient 3, which was not deteriorating with itraconazole therapy combined with frequent lumbar punctures, subsequently deteriorated with amphotericin B administration accompanied by frequent lumbar punctures. That shunt placement or high-volume frequent lumbar punctures were effective therapy without corticosteroids in two patients is evidence in favor of our hypothesis of increased outflow resistance being the specific pathophysiologic derangement. Frequent lumbar punctures with larger-bore needles may be as effective as high-volume CSF removal because of continued leakage through the dural hole. It should be recalled that CT and MRI brain scans were all normal in these patients-certainly no evidence of cerebral edema was seen. Although parenchymal involvement has been described in cryptococcal meningitis, and could be an alternative explanation for symptoms such as cortical blindness [33], these radiologic studies also exclude this alternative explanation. Moreover, the beneficial effects of lowering ICP, and the papilledema associated with the visual loss, also speak against central blindness. Another alternative explanation for decreased vision in cryptococcal meningitis is invasion of the visual pathways [34], which has been documented pathologically in the optic nerves and tracts [35]. This may occur bilaterally [35], is associated with papil-
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ledema, and conceivably could be missed radiographically. Again, the effects of lowering ICP in our cases argue against this alternative explanation. The major caveat to our interpretation of the specific pressure-reducing measures described is that antifungal therapy was modified or commenced in all three patients at about the same time as these other pressure-reducing measures were initiated. In two patients this was the start of itraconaxole administration, amphotericin B having failed in one patient, and in one it was the initiation of amphotericin B therapy because of recrudescence (failure after initially successful therapy) with itraconaxole. The influence of antifungal therapy on high CSF pressures has not been studied. On the other hand, successful therapy of relapsing cryptococcal meningitis in AIDS is apparently rare; only one of eight patients survived in two series [7,8]. In contrast, two of our three patients responded to further therapy and lived for 8 and 16 months longer. Another therapeutic measure that has been advocated is the use of acetaxolamide, 250 mg four times daily, with the goal of inhibiting CSF production.
CONSEOUENCESOF ELEVATEDICP The consequences, particularly the visual consequences, of continuing high ICP are considerable. One of our patients became blind and deaf, another had reduced acuity, and the third developed a strabismus and diplopia in association with reduced acuity; all three had marked papilledema. We are aware of several AIDS patients, not reported in the literature, who became blind, often suddenly, during the course of cryptococcal meningitis; we believe that elevated ICP was probably responsible for blindness in some or all of these patients. A series of patients with cryptococcal meningitis without AIDS in whom visual failure developed are reported by Tan [36] in Malaysia. Of the 34 patients, 23 had papilledema. Eleven of the 23 survived, enabling a limited evaluation of the effects of reducing CSF pressure on visual acuity. Nine of the 11 had bilateral papilledema and all 11 had some impairment of vision; one was blind bilaterally and four were only able to count fingers with one or both eyes. No CSF opening pressure data were given. All cases were treated with intravenous amphotericin B and flucytosine. Either no corticosteroids or small amounts were given. In the four patients who did not have ventriculoperitoneal shunts placed, two were left with major visual deficits, one had normal vision, and one had 6/9 vision bilaterally. In the seven patients who did have a shunt placed (one had hydrocephalus on CT scan), two were left with
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normal vision, four had major improvements in vision, and one remained blind. The average duration of disease prior to treatment was 6.4 weeks. Tan [36] argues cogently that in patients with cryptococcal meningitis and high CSF pressure, antifungal therapy alone is insufficient; pressure-reducing measures are needed to prevent visual loss. He notes that the mechanism of elevated ICP is not clear. In a series of non-AIDS patients from Hong Kong with cryptococcal meningitis requiring neurosurgical management, Chan et al [9] noted a patient with papilledema, blindness, and diffuse cerebral edema in whom hydrocephalus only developed later. After surgical decompression and CSF drainage, vision rapidly recovered. Cerebral blood flow is reduced by high ICP; in children with central nervous system infections, a cerebral perfusion pressure below 30 mm Hg was uniformly associated with death [37]. Elevated ICP in adults with encephalitis was also associated with a worse prognosis [38]. Diamond and Bennett [39], reporting on 111 cases of cryptococcal meningitis in the pre-AIDS era, noted that the higher the initial opening pressure (mean of group), the higher the likelihood of early death. Certainly, in any patient with cryptococcal meningitis whose condition deteriorates during therapy, head CT or MB1 scanning should be performed to exclude the possibility of hydrocephalus. However, intervention against elevated ICP may be needed before the development of hydrocephalus, and possibly even before the development of radiographically evident cerebral edema, as our cases suggest. The data cited associating increased ICP with increased morbidity and mortality and our own experience indicate a need for clinicians to consider pressure-reducing therapy in addition to appropriate antifungal therapy in patients with high CSF pressures and cryptococcal meningitis. Fewer early deaths, less visual loss, and possibly earlier recovery may accrue from such practice. However, considerable work remains to be done to define the pathophysiology, natural history, and most appropriate treatment of high CSF pressures in patients with cryptococcal meningitis and AIDS.
ACKNOWLEDGMENT We are indebted to Drs. John Hotson and Stanley Shatsky. Chairmen of the Neurology and Neurosurgery Departments, respectively, at the Santa Clara Valley Medical Center, for their constructive criticism of the manuscript.
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risk factors and association with decreased survival [abstract 564].28th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. October 25. 19% Los Angeles, California. 3. Chuck SL, Sande MA. Infections with Crypfococcus neoformafts in the acquired immunodeficiency syndrome. N Engl J Med 1989; 321: 7948%. 4. Denning DW. Tucker RM. Hostetler JS. Gill S. Stevens DA. Oral itraconazole therapy of cryptococcal meningitis and cryptococcosis in patients with AIDS. In: Vanden Bossche H, Mackenzie DWR, Cauwenbergh G, Drouhet E, DuPont B, Van Cutsem J, editors. Mycoses in AIDS patients. New York: Plenum Press, 19%: 305-24. 5. Dismukes W. Cloud G. Thompson S, eta/. Fluconazoie versus amphotericin B therapy of acute cryptococcal meningitis [abstract 10651. 29th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 17-20. 1989; Houston, Texas. 6. Denning DW. Tucker RM. Hanson LH. Hamilton JR, Stevens DA. ltraconazole therapy for cryptococcal meningitis and cryptococcosis. Arch Intern Med 1989; 149: 2301-8. 7. Kovacs JA. Kovacs AA. Polis M, et al. Cryptococcosis in the acquired immunodeficiency syndrome. Ann Intern Med 1985; 103: 533-8. 8. Zuger A, Louie E, Holzman RS. Simberkoff MS, Rahal JJ. Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1986; 1041234-40. 9. Chan K-H, Mann KS, Yue CP. Neurosurgical aspects of cerebral cryptococco-
in the pathophysiology of bacterial meningitis. Eur J Clin Microbial Infect Dis 1989; 8: 109-17. 21. Scheld WM, Dacey RG. Winn HR. Welsh JE, Jane JA. Sande MA. Cerebrospinal fluid oufflow resistance in rabbits with experimental meningitis. J Clin Invest 1980; 66: 243-53. 22. Tauber MG. Khayam-Bashi H. Sande MA. Effects of ampicillin and corticosteroids on brain water content, cerebrospinal fluid pressure, and cerebrospinal fluid lactate levels in experimental pneumococcal meningitis. J Infect Dis 1985; 151: 528-34. 23. Erlich SS. McComb JG. Hyman S. Weiss MH. Ultrastructure of the orbital pathways for cerebrospinal fluid drainage in rabbits. J Neurosurg 1989; 70: 926-31. 24. Johnston I. Reduced CSF absorption syndrome. Reappraisal of benign intracranial hypertension and related conditions. Lancet 1973; 2: 418-21. 25. James AE, Strecker EP, Sperber E. Flor WJ. Merz T, Burns B. An alternative pathway of cerebrospinal fluid absorption in communicating hydrocephalus. Transependymal movement. Radiology 1974; 111: 143-6. 26. Chandler FW. Pathology of the mycoses in patients with the acquired immunodeficiency syndrome. In: McGinnis MR. editor. Current topics in medical mycology, vol 1. New York: Springer-Verlag. 1985: 1-23. 27. Hamilton JR, Noble A, Denning DW. Stevens DA. Performance of cryptococ-
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333-9. 28. Huntington RW. Pathology of coccidioidomycosis. In: Stevens DA, editor. Coccidioidomycosis: a text. New York: Plenum Press, 1980: 113-32. 29. Aberfeld DC, Gladstone JL. Cryptococcal meningoencephalitis presenting with hemiplegia of sudden onset. JAMA 1%7; 202: 1150-l. 30. Shrader SK, Watts JC, Dancik JA. Band JA. Disseminated cryptococcosis presenting as cellulitis with necrotizing vasculitis. J Clin Microbial 1986; 24: 860-2. 31. Tjia TL, Yeow YK. Tan CB. Cryptococcal meningitis. J Neurol Neurosurg Psychiatry 1985; 48: 853-8.
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Elevated Cerebrospinal Fluid Pressures in Patients with Cryptococcal Meiingitis and Acquired Immunodeficiency - Syndrome DAVIDW. DENNING,M.B.B.s., SanJoseandStanford, California,ROBERTW. ARMSTRONG,M.D., San Jose, Stanford, and Los Gatos, California, BRADLEYH. LEWIS,M.D., Berkeley, California, DAVIDA. STEVENS,M.D., San Jose andstanford, California
Increased intracranial pressure has been a noteworthy problem in some of our patients with cryptococcal meningitis and acquired immunodeficiency syndrome (AIDS), and this appears to be a feature observed in patients with cryptococcal meningitis reported in the literature. Whereas most attention of clinicians is presently focused on 0pGmizing the antifungal regimen, so as to improve on high failrates in cryptococcal meningitis in AIDS, little attention has been paid to the problem of intracranial hypertension. We argue that visual loss and some of the ~8888 of death early after the onset of chemotherapy may be related to high cerebrospinal fluid (CSF) pressure, [email protected]~ of antifungal therapy. The possible pathophysiologic mechanisms are discussed, and we postulate that the mechanism is reduced CSF outflow possibly due to increased outflow resistance, not nm accompanied by prominent cerebral edema Optimal therapy of this complication is not yet established, but some measures that may be helpful are ventricular shunting, frequent high-volume lumbar punctures, and possibly glucocorticoida
From the Divisions of Infectious Diseases and Clinical Microbiology, Departments of Medicine and Pathology, Santa Clara Valley Medical Center, San Jose, California (DWD. RWA, DAS). California Institute for Medical Research, San Jose, California (DWD, DAS), Division of Infectious Diseases, Department of Medicine, Stanford University Medical School, Stanford, California (DWD, RWA, DAS), Good Samaritan Hospital, Los Gatos. California (RWA), and East Bay AIDS Center, Berkeley, California (BHL). Requests for reprints should be addressed to David A. Stevens, M.D.. Division of Infectious Diseases, Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, California 95128. Dr. Denning’s current address: Regional Department of Infectious Diseases and Tropical Medicine, Monsall Hospital, Newton Heath, Manchester, Ml0 8WR, England, United Kingdom. Manuscript submitted January 4, 1991, and accepted in revised form May 3, 1991.
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ittle hasbeenwritten about the clinical diagnoL sis,natural history, pathogenesis,and management of elevated cerebrospinalfluid (CSF) pressures in patients with cryptococcal meningitis. Prior to the advent of the acquired immunodeficiency syndrome (AIDS) epidemic, cryptococcal meningitis diseasewas rare, with probably fewer than 500 casesannually in the United States [l]. The incidenceof cryptococcalmeningitis has risen sharply with the advent of AIDS, and 3,022casesof extrapuhnonarycryptococcosishad been reported to the Centers for DiseaseControl prior to April 1988[2]. As a result, managementissueshavebeen thrust into the limelight and antifungal therapy has occupiedcenter stage.However,in all the large series of cryptococcalmeningitis in AIDS published to date [3-6], a relatively high proportion of patients die in the 2 weeks after diagnosis despite therapy. In patients with cryptococcalmeningitis in relapse,the mortality is much higher; 11 of 13 patients died with active meningitis despitetreatment [4,7,8].This suggeststhat other factors in addition to antifungal therapy may be important in determining outcome. In our studiesof cryptococcalmeningitis [4,6],we haveobservedpatients who havehad elevatedCSF pressures,three of whom had extremely high pressuresin the context of relapsedmeningitis. All three patients had AIDS and had developedcryptococcal meningitis soon after the diagnosisof AIDS. Primary therapy was amphotericin B in two patients and itraconaxole in the third; all had major improvement.After this, relapsefollowing discontinuation of therapy, failure of a secondcourseof amphotericin B after relapse, and recrudescence during itraconaxoletherapy prompted a changein antifungal therapy to itraconaxolein two patients and to amphotericin B and flucytosine in the other. It was at this time that high CSF pressureswere noted in all three patients, varying from 500 to greater than 570 mm CSF. All three had severe papilledema,enlargedblind spots, and reducedvisual acuity. Impairment of cognitive function, cranial nerve abnormalities, and/or systemic manifestations of elevatedintracranial pressure(ICP) were 1991
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CRYPTOCOCCAL MENINGITIS
1
1
1 “a.sC”liti*?
Inflammation
Vismus CSF Plugs of polysaccharide Yeasts
1 clyptococca polysaccharides and sugars
Brai” enraCell”lar fluid acc”m”lmion (osmotic effect)?
(involves meninges. brain. and CSF)
I”CWSed CSF osmolality
4 bllpaireclCSF uptakeby BraCh”Oid villi. lymphaticdrainageblock?
INCREASED INTRACRANIAL PRESSURE
HEADACHE, VOMITING. IMPAIRED COGNITION, CRANIAL NEUROPATHY, PAPILLEDEMA, BLINDNESS, DEATH
Figure
1. Proposed pathophysiology of adverse course of cryptococcal meningitis. In some patients, a space-occupying lesion may be present, and would contribute to increased intracranial pressure.
also present. In these patients, results of computed tomographic (CT) scanning (two patients) and/or magnetic resonance imaging (MRI) (two patients) were normal. Therapy directed specifically at the high CSF pressure was effective in two of the three patients and temporarily successful in one. Our experience complements the described association of hydrocephalus with cryptococcal meningoencephalitis (9% to 58%) and with progressive deterioration of consciousness, the increased morbidity and mortality when these complications of cryptococcosis occur, and the beneficial effects of neurosurgical decompression in that setting [9]. We believe that some of the early deaths observed in all series of cryptococcal meningitis in AIDS may be related to high ICP leading to impaired cerebral circulation. Loss of visual acuity may also follow sustained elevation of ICP. We discuss the possible pathophysiology (Figure 1) and hope that early recognition of this problem may prompt appropriate therapy. Understanding of the pathogenesis, natural history, and treatment of this problem is, however, poor. Further study is urgently needed to address these issues.
lesion, our view is that the primary deficit is a failure of CSF absorption. A brief review of the normal process of CSF formation, flow patterns, and absorption may be helpful in understanding this viewpoint. It is generally agreed that CSF is formed at the rate of 450 ml/day, mostly by the choroid plexuses in both lateral ventricles and the roof of both the third and fourth ventricles [lo]. As the total volume of CSF is of the order of 150 mL, the whole CSF volume is replaced three times daily. The rate of CSF formation is generally constant over a wide range of ICP, until cerebral perfusion decreases. CSF flows from the lateral ventricles to the third ventricle, then through the aqueduct of Sylvius to the fourth ventricle [ll]. From here it leaves laterally through the foramina of Luschka and medially through the foramen of Magendie to enter the subarachnoid space [ll]. In some circumstances, CSF may flow directly through the brain, extracellularly, by transependymal flow [lo]. Absorption of the CSF takes place mostly via the arachnoid villi and granulations (the only distinction between the two being that the latter are visible to the naked eye) that cover the whole cerebral surface. The arachnoid villi are capable of bulk transport of fluid and particulate matter, including red cells, through oneway valves into the venous circulation [lo]. It is likely that some CSF is also absorbed via lymphatic pathways, and some observations indicate that increased intraventricular pressure results in increased lymph flow of CSF via lymph pathways [lo]; however, the contribution of this pathway to the total is not clear. Under normal conditions, the rate of CSF absorption is pressure-dependent and relatively linear over a fairly wide physiologic range [lo]. The only parameter shown to affect the rate of CSF absorption is the hydrostatic gradient; the greater the ICP, the higher the absorption rate [lo]. Since the CSF space is a confined space, relatively minor alterations in CSF outflow do cause major changes in pressure. Failure of absorption of CSF could theoretically result in intracranial hypertension without hydrocephalus, if the passage of CSF directly through the brain parenchyma is obstructed and intraventricular pressure and subarachnoid pressure were equal.
CSF OUTFLOWRESISTANCE
We believe that the passage of CSF across the arachnoid villi is impaired in some patients with cryptococcal meningitis. Factors possibly influencNORMAL PROCESSOF CSF FORMATION,FLOW, ing this process include the particular cryptococcal AND ABSORPTION strain causing infection, the severity of infection, The pathophysiology of elevated CSF pressures and/or the particular conformation and capacity of in cryptococcal meningitis is not known. In the ab- a given patient’s CSF absorption pathways. It may sence of hydrocephalus, cerebral edema, or a mass be that the viscosity of the CSF in proximity to or in 266
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the arachnoid vilb is elevated to a degree that impairs the passage of CSF, or a microscopic plug of polysaccharide has formed, directly blocking flow. The molecular weight of cryptococcal polysaccharide is high (range 2 X lo7 to lo8 daltons) and varies from isolate to isolate [12]. Cryptococcal polysaccharide can spread rapidly through the brain as demonstrated by implantation experiments in rats [ 131. As viewed by electron microscopy, the polysaccharide appears as sheets of reticulated material [13]; indeed, the estimates of molecular weight quoted above may reflect conglomerations of several molecules of somewhat smaller size. There is considerable isolate-to-isolate variation in the composition and physicochemical behavior of cryptococcal polysaccharide [12]. These differences may be reflected in functional impairment of CSF outflow through arachnoid villi in some patients. In addition, yeast cells, which are often present in profusion in CSF (as seen on India ink preparations) and meninges in autopsy sections, are considerably larger than red cells and may occlude the channels and valves of the subarachnoid villi. Blockage of lymph pathways, the other route of CSF absorption, may occur for similar reasons. Differences in the relative capacity of the CSF absorption pathways between individuals may predispose some to the development of high ICP, because of low reserve or particular conformations of their CSF outflow tracts. Reduction of CSF absorption may therefore depend on the patient, severity of disease, degree of immune impairment, or cryptococcal strain, or any combination of these factors. Whether particular antifungal agents could influence this process, for example, altering the amount and type of extracellular polysaccharide produced or the rate of CSF sterilization and therefore the number of yeast cells available for blocking the arachnoid villi (if this occurs), is not known. Although unlikely, it is also possible that cryptococcal meningitis itself alters the rate of CSF production, which if increased without absorption being correspondingly increased, could lead to elevated ICP. The concept of a reduced rate of removal of CSF has been termed outflow resistance and has been studied in various pathologic conditions holding, as it does, a potentially pivotal role in influencing ICP. Studies examining outflow resistance in humans are few and most have been done by rapid infusion of fluid into the lumbar space with subsequent observation of the rate of reduction of CSF pressure [14-191. Space limitations prevent extensive discussion of details of these tests, their performance, limitations, and results in various other conditions. Suffice it to say that, to our knowledge, only one patient with cryptococcal meningitis has been studSeptember
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ied in this fashion [17]. This was in 1968 in an elderly patient who had probably long-standing undiagnosed cryptococcal meningitis with milky and thickened arachnoid membranes (quite different from cryptococcal meningitis in AIDS patients in almost all respects). A clear-cut increase in CSF pressure occurred on infusion of artificial CSF at a rate of 0.76 ml/minute, which in 11 control subjects was not the case. This probably indicates a reduced CSF absorptive capacity in this patient with cryptococcal meningitis. We would anticipate a similar response in our patients, had such a test been done. Increased outflow resistance has been described in animal models of bacterial meningitis [20]. In pneumococcal meningitis in rabbits, major differences in CSF outflow resistance were seen: from 0.26 mm Hg/pL/minute in uninfected controls to 6.77 f 3.52 mm Hg/pL/minute in infected animals [21]. Penicillin therapy had no reducing effect on this elevation even 15 days later, but methylprednisolone, given early in infection, reduced the outflow resistance to nearly control values. Methylprednisolone and dexamethasone were directly compared in a later set of experiments done in a similar fashion with the same isolate of Streptococcus pneumoniae, also in rabbits [22]. In this experiment, only cisternal pressure was measured, not outflow resistance, but dexamethasone had a much more profound effect on lowering CSF pressure than methylprednisolone (which had no apparent effect). Brain water content was reduced by both steroids. The rabbit model is far from ideal for studies of intracranial hypertension, as more than 90% of CSF drains via lymphatic pathways [23].
ELEVATEDICP WITHOUT HYDROCEPHALUS Assuming that CSF absorption was reduced in the patients we describe, why was hydrocephalus not seen on MRI or CT scanning? No immediate explanation is forthcoming. The experience in our patients contrasts with that of patients with benign intracranial hypertension (pseudotumor cerebri), which is probably a failure of CSF absorption [24]. Although transependymal flow was not demonstrable on the MRI scans of two of our patients, we believe this provides the most likely explanation contributing to the lack of hydrocephalus we have observed. A model of communicating hydrocephalus in dogs and primates using radiolabeled albumin demonstrated considerable transependymal flow of isotope [25]. Histologic and ultrastructural changes in the ventricular lining allowing the passage of labeled albumin accompanied these changes [25]. In patients with AIDS, the subacute onset of meningitis together with the enormously ‘high quantities of cryptococci and cryptococcal polysac1991
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charide may allow the gradual development of a state of pressure equilibrium between the ventricles and the subarachnoid space with free passage of CSF through the brain parenchyma. In other words, we postulate that there is no pressure gradient between any intracranial sites. If this is the case, no ventricular dilatation would be expected. It is also possible that the major reason for the absence of ventricular dilatation is not related to transependymal flow but to the coexistence of cerebral edema and high outflow resistance. The early studies of Hirano et al [13] using intracerebral injections of purified cryptococcal polysaccharide indicate that the latter causes the accumulation of extracellular fluid in the brain parenchyma. The presence or absence of intracellular edema cannot be adequately appraised from these experiments because microscopy is not a good tool for this assessment. Extracellular fluid accumulation may be a purely osmotic effect in these experiments, as the quantity of polysaccharide injected may bear no relationship to that found in human cryptococcal meningitis. On the other hand, AIDS patients have large numbers of cerebral cryptococci as described histopathologically [26] and as evidenced by the high titers of CSF cryptococcal antigen noted in several series [3,4,7,8,27]. Lysis of these fungal cells by chemotherapy in some patients could release large amounts of polysaccharide and constituent sugars, including mannitol. The consequence would be a reverse osmotic effect to that desired when mannitol is given intravenously to reduce cerebral edema in a variety of clinical conditions associated with intracranial hypertension. If marked extracellular fluid expansion did accompany severe cases of cryptococcal meningitis, then brain swelling might be expected. Swelling might not be visualized on scanning because of a concurrent marked increase in ICP related to increased outflow resistance, one pressure balancing the effect of the other. Alternatively, exudation and expansion of extracellular fluid because of cryptococcal meningitis may facilitate transependymal flow of fluid without causing brain swelling.
VASCULITISRELATEDTO CRYPTOCOCCAL MENINGITIS Another factor that could be relevant in this context is the likelihood that at least some isolates of Cryptococcus neoformans appear to have the propensity to induce either vasculitis, arteritis, and/or cerebral infarction. Cerebral vasculitis has been described in meningitis due to other fungi [28]. In the pre-AIDS era, occasional patients with cryptococcal meningitis would develop sudden stroke syn-
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dromes [29]. Cutaneous cryptococcal infection giving rise to vasculitis is also described [30]. Anterior cerebral arteritis was seen in one patient who had angiography [31], a diagnostic study rarely done in cryptococcal meningitis. Among patients with AIDS and cryptococcal meningitis, two of seven patients had associated cerebral infarction at autopsy in one series [32]. Histopathologically, the brain demonstrates a dense perivascular infiltrate in both AIDS and non-AIDS patients with cryptococcal meningitis. A diffuse vasculitis, particularly a venulitis, could significantly elevate capillary pressure leading to a reduction in the rate of removal of CSF as it traverses the subarachnoid villi. It could also contribute directly to focal or global ischemia by further compromising blood supply already reduced because of elevated ICP.
THERAPYOF ELEVATEDICP IN CRYPTOCOCCAL MENINGITIS Three modalities of therapy were used to control elevated CSF pressures in the three patients we treated. A reduction in CSF pressure was seen with each modality: ventriculoperitoneal shunt in one patient, frequent high-volume lumbar punctures in the second, and a combination of corticosteroid therapy and high-volume lumbar punctures in the third. The condition of Patient 3, which was not deteriorating with itraconazole therapy combined with frequent lumbar punctures, subsequently deteriorated with amphotericin B administration accompanied by frequent lumbar punctures. That shunt placement or high-volume frequent lumbar punctures were effective therapy without corticosteroids in two patients is evidence in favor of our hypothesis of increased outflow resistance being the specific pathophysiologic derangement. Frequent lumbar punctures with larger-bore needles may be as effective as high-volume CSF removal because of continued leakage through the dural hole. It should be recalled that CT and MRI brain scans were all normal in these patients-certainly no evidence of cerebral edema was seen. Although parenchymal involvement has been described in cryptococcal meningitis, and could be an alternative explanation for symptoms such as cortical blindness [33], these radiologic studies also exclude this alternative explanation. Moreover, the beneficial effects of lowering ICP, and the papilledema associated with the visual loss, also speak against central blindness. Another alternative explanation for decreased vision in cryptococcal meningitis is invasion of the visual pathways [34], which has been documented pathologically in the optic nerves and tracts [35]. This may occur bilaterally [35], is associated with papil-
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ledema, and conceivably could be missed radiographically. Again, the effects of lowering ICP in our cases argue against this alternative explanation. The major caveat to our interpretation of the specific pressure-reducing measures described is that antifungal therapy was modified or commenced in all three patients at about the same time as these other pressure-reducing measures were initiated. In two patients this was the start of itraconaxole administration, amphotericin B having failed in one patient, and in one it was the initiation of amphotericin B therapy because of recrudescence (failure after initially successful therapy) with itraconaxole. The influence of antifungal therapy on high CSF pressures has not been studied. On the other hand, successful therapy of relapsing cryptococcal meningitis in AIDS is apparently rare; only one of eight patients survived in two series [7,8]. In contrast, two of our three patients responded to further therapy and lived for 8 and 16 months longer. Another therapeutic measure that has been advocated is the use of acetaxolamide, 250 mg four times daily, with the goal of inhibiting CSF production.
CONSEOUENCESOF ELEVATEDICP The consequences, particularly the visual consequences, of continuing high ICP are considerable. One of our patients became blind and deaf, another had reduced acuity, and the third developed a strabismus and diplopia in association with reduced acuity; all three had marked papilledema. We are aware of several AIDS patients, not reported in the literature, who became blind, often suddenly, during the course of cryptococcal meningitis; we believe that elevated ICP was probably responsible for blindness in some or all of these patients. A series of patients with cryptococcal meningitis without AIDS in whom visual failure developed are reported by Tan [36] in Malaysia. Of the 34 patients, 23 had papilledema. Eleven of the 23 survived, enabling a limited evaluation of the effects of reducing CSF pressure on visual acuity. Nine of the 11 had bilateral papilledema and all 11 had some impairment of vision; one was blind bilaterally and four were only able to count fingers with one or both eyes. No CSF opening pressure data were given. All cases were treated with intravenous amphotericin B and flucytosine. Either no corticosteroids or small amounts were given. In the four patients who did not have ventriculoperitoneal shunts placed, two were left with major visual deficits, one had normal vision, and one had 6/9 vision bilaterally. In the seven patients who did have a shunt placed (one had hydrocephalus on CT scan), two were left with
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normal vision, four had major improvements in vision, and one remained blind. The average duration of disease prior to treatment was 6.4 weeks. Tan [36] argues cogently that in patients with cryptococcal meningitis and high CSF pressure, antifungal therapy alone is insufficient; pressure-reducing measures are needed to prevent visual loss. He notes that the mechanism of elevated ICP is not clear. In a series of non-AIDS patients from Hong Kong with cryptococcal meningitis requiring neurosurgical management, Chan et al [9] noted a patient with papilledema, blindness, and diffuse cerebral edema in whom hydrocephalus only developed later. After surgical decompression and CSF drainage, vision rapidly recovered. Cerebral blood flow is reduced by high ICP; in children with central nervous system infections, a cerebral perfusion pressure below 30 mm Hg was uniformly associated with death [37]. Elevated ICP in adults with encephalitis was also associated with a worse prognosis [38]. Diamond and Bennett [39], reporting on 111 cases of cryptococcal meningitis in the pre-AIDS era, noted that the higher the initial opening pressure (mean of group), the higher the likelihood of early death. Certainly, in any patient with cryptococcal meningitis whose condition deteriorates during therapy, head CT or MB1 scanning should be performed to exclude the possibility of hydrocephalus. However, intervention against elevated ICP may be needed before the development of hydrocephalus, and possibly even before the development of radiographically evident cerebral edema, as our cases suggest. The data cited associating increased ICP with increased morbidity and mortality and our own experience indicate a need for clinicians to consider pressure-reducing therapy in addition to appropriate antifungal therapy in patients with high CSF pressures and cryptococcal meningitis. Fewer early deaths, less visual loss, and possibly earlier recovery may accrue from such practice. However, considerable work remains to be done to define the pathophysiology, natural history, and most appropriate treatment of high CSF pressures in patients with cryptococcal meningitis and AIDS.
ACKNOWLEDGMENT We are indebted to Drs. John Hotson and Stanley Shatsky. Chairmen of the Neurology and Neurosurgery Departments, respectively, at the Santa Clara Valley Medical Center, for their constructive criticism of the manuscript.
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risk factors and association with decreased survival [abstract 564].28th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. October 25. 19% Los Angeles, California. 3. Chuck SL, Sande MA. Infections with Crypfococcus neoformafts in the acquired immunodeficiency syndrome. N Engl J Med 1989; 321: 7948%. 4. Denning DW. Tucker RM. Hostetler JS. Gill S. Stevens DA. Oral itraconazole therapy of cryptococcal meningitis and cryptococcosis in patients with AIDS. In: Vanden Bossche H, Mackenzie DWR, Cauwenbergh G, Drouhet E, DuPont B, Van Cutsem J, editors. Mycoses in AIDS patients. New York: Plenum Press, 19%: 305-24. 5. Dismukes W. Cloud G. Thompson S, eta/. Fluconazoie versus amphotericin B therapy of acute cryptococcal meningitis [abstract 10651. 29th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 17-20. 1989; Houston, Texas. 6. Denning DW. Tucker RM. Hanson LH. Hamilton JR, Stevens DA. ltraconazole therapy for cryptococcal meningitis and cryptococcosis. Arch Intern Med 1989; 149: 2301-8. 7. Kovacs JA. Kovacs AA. Polis M, et al. Cryptococcosis in the acquired immunodeficiency syndrome. Ann Intern Med 1985; 103: 533-8. 8. Zuger A, Louie E, Holzman RS. Simberkoff MS, Rahal JJ. Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1986; 1041234-40. 9. Chan K-H, Mann KS, Yue CP. Neurosurgical aspects of cerebral cryptococco-
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333-9. 28. Huntington RW. Pathology of coccidioidomycosis. In: Stevens DA, editor. Coccidioidomycosis: a text. New York: Plenum Press, 1980: 113-32. 29. Aberfeld DC, Gladstone JL. Cryptococcal meningoencephalitis presenting with hemiplegia of sudden onset. JAMA 1%7; 202: 1150-l. 30. Shrader SK, Watts JC, Dancik JA. Band JA. Disseminated cryptococcosis presenting as cellulitis with necrotizing vasculitis. J Clin Microbial 1986; 24: 860-2. 31. Tjia TL, Yeow YK. Tan CB. Cryptococcal meningitis. J Neurol Neurosurg Psychiatry 1985; 48: 853-8.
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meningitis.
A
