Raised intracranial pressure complicating cryptococcal meningitis: immune reconstitution inflammatory syndrome or recurrent cryptococcal disease?

doi:10.1016/j.jinf.2005.04.022

Journal of Infection

Volume 51, Issue 2, August 2005, Pages 165-171

https://doi.org/10.1016/j.jinf.2005.04.022 Get rights and content

Abstract

We report the case of a patient with advanced HIV disease and cryptococcal meningitis, who after an initially good clinical and mycological response to systemic anti-fungal treatment developed symptomatic raised intracranial pressure 10 days after initiation of highly active anti-retroviral therapy. We describe the subsequent clinical management and the features that suggest that this persistently raised ICP was more likely due to an immune reconstitution syndrome (IRIS) following HAART rather than relapse of cryptococcal disease or failure of anti-fungal therapy.

Introduction

A raised intracranial pressure (ICP) (defined as an opening pressure of >20 cm H₂O) is a recognised complication of cryptococcal meningitis in both HIV-positive and HIV-negative patients, and is associated with a poorer clinical response and increased mortality.1, 2 A raised ICP has also been reported as an uncommon manifestation of immune reconstitution inflammatory syndrome (IRIS) in patients with advanced HIV disease and underlying cryptococcal infection who received highly active anti-retroviral therapy (HAART).3, 4, 5, 6, 7, 8 The clinical spectrum of this syndrome is diverse and IRIS associated mycobacterial, cytomegaloviral, herpes zoster, and pnemocystis carinii infections have also all been described with a characteristic paradoxical deterioration in clinical status following HAART.³ The pathogenesis of IRIS remains poorly understood, but is thought to be due to increased inflammatory activity to antigens in tissues from pre-existing infections following recovery of the host's immune system.

We report a case of a patient with cryptococcal meningitis who after an initially good clinical and mycological response to systemic anti-fungal treatment developed symptomatic raised intracranial pressure 10 days after initiation of highly active anti-retroviral therapy (HAART). The case highlights the difficulties in differentiating between a raised ICP due to persistent or recrudescent cryptococcal infection and that due to IRIS, which has important implications for appropriate clinical management.

Section snippets

Case history

A 34-year-old Jamaican woman, who had been resident in the U.K. for 4 years, presented with a 3-day history of severe headache, photophobia, nausea and vomiting. Two weeks prior to admission, she had been diagnosed with advanced HIV infection (CD4 cell count: 9×10⁶/l; viral load (VL) >500 000 copies/ml). She was apyrexial with mild neck stiffness but no focal neurological deficit or evidence of papilloedema. CSF examination showed a normal opening pressure (OP) of 9.5 cm H₂O, protein 290 mg/l,

Discussion

This patient with advanced HIV disease and cryptococcal meningitis developed symptomatic raised intracranial pressure characterised by severe headache, vomiting, loss of visual acuity and papillodema 10 days after starting HAART and 17 days after a good clinical and mycological response to anti-fungal therapy. This was initially interpreted and managed as persistent cryptococcal infection on the basis of evidence of new cryptococcal choroidal lesions. However, the raised ICP persisted despite a

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Cryptococcal meningitis is the most common and severe form of cryptococcal infection. In addition to infiltrative and inflammatory mechanisms, intracranial hypertension commonly complicates cryptococcal meningitis and may cause significant visual and neurological morbidity and mortality. The mainstays of treatment for cryptococcal meningitis include standard antifungal therapy, management of intracranial hypertension, and treatment of underlying immunosuppressive conditions. Early and aggressive management of intracranial hypertension in accordance with established guidelines reduces the risk of long-term visual and neurological complications and death. Traditional recommendations for treating elevated intracranial pressure in idiopathic intracranial hypertension including acetazolamide, weight loss, and avoiding serial lumbar punctures—are not helpful in cryptococcal meningitis and may be harmful.
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Meningitis is one of the most fatal manifestations of cryptococcosis, even with specific treatment. Combination of a prompt diagnosis and appropriate therapy are critical to reduce the fungal load and the inflammatory response effects of the proliferation of yeast into the central nervous system (CNS). Mice with experimental acute meningitis caused by Cryptococcus neoformans were treated with liposomal amphotericin B (L-AmB) administered intrathecally (i.t.c.) at 0.006 mg/kg weekly or intravenously (i.v.) at 10 mg/kg daily or with voriconazole (VCZ) administered orally at 30 mg/kg per dose twice daily or with combinations of both drugs, i.e. L-AmB i.t.c. + VCZ or L-AmB i.v. + VCZ at the same doses as used in the monotherapies. All treatments significantly increased the survival of animals in comparison with the control group, with VCZ being less effective in comparison with all other treatments (P ≤ 0.012). All treatments, with the exception of VCZ (P = 0.533), reduced fungal burdens in the brain in comparison with controls. The combination of L-AmB i.t.c. + VCZ showed a synergistic effect in the reduction of fungal load that was significantly superior to any tested therapy (P ≤ 0.039). Histologically, untreated animals showed a marked inflammatory response with massive fungal cells in the meninges, whilst treated animals showed a variable number of fungal cells in the CNS, with the exception of animals receiving L-AmB i.t.c. + VCZ in which neither yeasts nor inflammation were observed.
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In 12 studies involving a total of 598 patients with known cryptococcal disease before ART, cryptococcal IRIS developed in 8–49% of patients (table 1).8–12,18,21–23,24,25,54 Of 171 cases in which the sites and modes of presentation were both reported, 126 (74%) involved mainly meningeal disease (tables 1 and 2).8–16,19–27,29,31,32,34,38–40,42,46 Other common presentations were complications of CNS disease (19 cases, 11%),12,19,21,22,35–37,41,45 lymphadenopathy (19 cases, 11%),8–11,19,21,24,28,36,30,33,34,43,44 pneumonitis (nine cases, 5%),8–11,24–26,34 multifocal disease (seven cases, 4%),19,25,28,40 and soft-tissue disease (two cases, 2%).29,34
Cryptococcal immune reconstitution inflammatory syndrome (IRIS) may present as a clinical worsening or new presentation of cryptococcal disease after initiation of antiretroviral therapy (ART), and is thought to be caused by recovery of cryptococcus-specific immune responses. We have reviewed reports of cryptococcal IRIS and have developed a consensus case definition specifically for paradoxical crytopcoccal IRIS in patients with HIV-1 and known cryptococcal disease before ART, and a separate definition for incident cryptococcosis developed during ART (termed ART-associated cryptococcosis), for which a proportion of cases are likely to be unmasking cryptococcal IRIS. These structured case definitions are intended to aid design of future clinical, epidemiological, and immunopathological studies of cryptococcal IRIS, to standardise diagnostic criteria, and to facilitate comparisons between studies. As for definitions of tuberculosis-associated IRIS, definitions for cryptococcal IRIS should be regarded as preliminary until further insights into the immunopathology of IRIS permit their refinement.
Neurologic Presentations of AIDS
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Neuroimaging features include development of, or increase in, contrast enhancement, and unusual patterns of contrast enhancement.184 Intracranial pressure may increase,185 requiring the use of corticosteroids. Among the most common CNS infections reported to be involved in IRIS are HIV encephalitis,186–188 TE,187,189 CM,185 and PML.155,184

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Raised intracranial pressure complicating cryptococcal meningitis: immune reconstitution inflammatory syndrome or recurrent cryptococcal disease?

Abstract

Introduction

Section snippets

Case history

Discussion

Hum Pathol

Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis

Clin Infect Dis

Practice guidelines for the management of cryptococcal disease

Clin Infect Dis

Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy

Medicine (Baltimore)

HIV combination therapy: partial immune restitution unmasking latent cryptococcal infection

AIDS

Immune reconstitution cryptococcosis after initation of successful highly active antiretroviral therapy

Clin Infect Dis

Case report. Recurrence of increased intracranial pressure with antiretroviral therapy in an AIDS patient with cryptococcal meningitis

Mycoses