Cryptococcal disease (cryptococcosis) is caused by Cryptococcus neoformans – Cryptococcus gattii complex, a ubiquitous environmental yeast that is endemic in many countries including Australia. While cryptococcosis can affect many organs, cryptococcal meningoencephalitis is the most frequently recognised, and most severe form with mortality rates, ranging from 24%-47% at 10 weeks.(5-8).
Clinical presentation
Patients typically present with an acute, subacute or chronic meningitis or meningoencephalitis Signs and symptoms include headache, nausea, fever, altered consciousness, cranial neuropathy, memory loss, confusion, meningeal irritation signs, nausea and vomiting, seizures, visual and hearing deficits, and coma. Occasionally, CNS symptoms may be subtle so the absence of CNS symptoms in a patient with positive serum cryptococcal antigen does not exclude CNS involvement.
Diagnosis
The diagnosis of cryptococcal meningoencephalitis is confirmed with a lumbar puncture. Typically, the opening pressure is high (more than 20 cmH20) and the cerebrospinal fluid (CSF) analysis reveals a lymphocytosis, with a positive CSF cryptococcal antigen (CrAg), and a positive India ink. Brain imaging such as CT and MRI may show meningeal enhancement, ventricular compression, or cryptococcomas. Pulmonary lesions (typically lung nodules) are often found incidentally. All patients with a positive serum CrAg, those who have cultured Cryptococcus spp. in their sputum, or has a pulmonary lesion suspicious for cryptococcosis, should be thoroughly investigated to consider CNS involvement, including brain and chest imaging, lumbar puncture, and blood culture (1).
Management
Appropriate antifungal therapy and optimal management of raised intracranial pressure are the two key pillars of cryptococcal meningoencephalitis management. Antifungal therapy in cryptococcosis is traditionally divided into three phases – induction, consolidation and maintenance. Induction with liposomal amphotericin (3-4 mg/kg/day) and 5-flucytosine (100 mg/kg/day in 3-4 divided doses) remains the most optimal regimen for induction treatment of cryptococcal meningoencephalitis in resource-rich settings such as Australia. This is usually given for 2 weeks, with consideration for a more extended course in select clinical settings. Liposomal amphotericin while less toxic than conventional amphotericin, is still associated with renal impairment, hypokalaemia and hypomagenesaemia, thus pre-emptive aggressive fluid, potassium and magnesium replacement is recommended. 5-Flucytosine is associated with cytopenias.
Of note, the single dose of liposomal amphotericin 10 mg/kg given with the backbone of 14 days of Fluconazole 1200 mg daily and 5-Flucytosine 100 mg/kd/day in 3-4 divided doses (sometimes referred to as the Ambition-cm regimen) as induction therapy was compared against sub-optimal induction regimens (9), and is recommended in resource-limited settings (10), but not so, in resource-rich settings.
The general practitioner is likely to be involved predominantly in the maintenance and consolidation phases of cryptococcal meningoencephalitis therapy. Here, the mainstay is fluconazole 400-800 mg daily in consolidation and 200 mg daily in the maintenance phase. Maintenance therapy may be ceased after 12 months of antifungal therapy in people who are on ART with CD4 count > 100 cells/mm3 and a suppressed viral load. Fluconazole should be restarted if the CD4 count drops below this threshold (1).
The main risk of fluconazole is worsening liver function tests, gastrointestinal intolerance such as nausea, vomiting, abdominal pain, and diarrhoea, and also QTc prolongation. The potential of drug-drug interaction should always be considered. Of note, alternative antifungal agents for these phases is rarely required. Any consideration of switching to an alternative therapy should be discussed with an expert.
Most patients with cryptococcal meningoencephalitis have raised intracranial pressure (ICP). This increased pressure is associated with cognitive impairment, neurological defects and increased short-term mortality (11). Aggressive management of raised ICP with therapeutic lumbar punctures is recommended in international cryptococcal meningoencephalitis guidelines. Current recommendations for the management of raised ICP suggests repeated daily CSF drainage until opening pressure is stable, and drainage until CSF closing pressure is ≤ 20 cmH20 or < 50% of the initial opening pressure (1).
There are no prospective treatment studies on isolated pulmonary cryptococcosis. In principle, asymptomatic or mild-to-moderate pulmonary cryptococcosis may be treated with 400-800 mg fluconazole daily for 6-12 months while those with severe symptoms, diffuse infiltrates on imaging, and those with concomitant CNS disease should be treated as for CNS disease (1).
Timing of antiretroviral therapy commencement
The timing of ART commencement in the setting of any newly diagnosed opportunistic infection has been long debated where the risk of immune reconstitution inflammatory syndrome (IRIS) in early ART commencement is measured against the ongoing risk of co-infections in late ART commencement. In cryptococcal meningoencephalitis, two small and one large randomised controlled trial cautioned against very early ART initiation, with most guidelines recommending deferring till 4-6 weeks after cryptococcal meningoencephalitis presentation but noting the importance of individualisation of care. In principle, patients treated with optimal induction antifungal therapy (such as liposomal amphotericin and 5-FC in our settings) clear their CSF of cryptococcosis earlier, and studies have shown that patients who have been able to sterilise their CSF (i.e. attain CSF culture negativity) prior to ART commencement have improved clinical outcomes, including a lower rate of microbiological relapse and C-IRIS (12).
Taken together, current evidence suggests that very early commencement of ART (in the first 11 days after cryptococcal meningoencephalitis diagnosis) is likely harmful. Equally, deliberate delay of antiretroviral therapy commencement to > 5 or 6 weeks after cryptococcal meningoencephalitis diagnosis risks losses in follow-up. It is likely that patients could be risk-stratified – patients who demonstrate good clinical improvement, have normalised their CSF opening pressure and have sterilised their CSF are not likely to require a delay of > 5-6 weeks.
Neurological deterioration post-ART commencement
Patients with cryptococcal meningoencephalitis are known to have symptomatic relapse despite being on adequate antifungal therapy and ART and may re-present with worsening headaches, new seizures or sudden loss of conscious state. Differentiating cryptococcal microbiological relapse from cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) and other infective and non-infective cases is important to guide ongoing management.
A thorough history and examination, and a repeat lumbar puncture is recommended to measure opening pressure, and CSF should be sent for biochemistry, cell counts, cryptococcal culture and other molecular tests as necessary. In addition, brain imaging including CT and MRI scans may be necessary to look for focal brain lesions or meningeal enhancement. A positive CSF cryptococcocal culture suggests microbiological relapse – re-induction of antifungal therapy, therapeutic LPs, and paired antifungal susceptibility testing with the initial isolate are recommended.
Note that while CSF and serum cryptococcal antigen is often performed, the antigen tests will remain positive for months to years, thus a high (even a higher) titre does not necessarily indicate microbiological relapse. Similarly, a CSF with a positive gram stain or India ink for Cryptococcus spp., is not necessarily indicative of microbiological relapse as dead Cryptococci are often seen for a prolonged period.
In patients with C-IRIS, symptomatic management with analgesia including non-steroidal medication, and regular therapeutic LPs, often suffice. In some cases, steroids (Prednisolone 0.5-1.0 mg/kg/day, weaned over 4-6 weeks, may be considered). Steroid-refractory C-IRIS requires expert discussion including for the role of alternative agents such as tumour necrosis factor (TNF) blockers and others.