Cryptococcal meningitis (CCM) accounts for up to 60% of meningitis in adult persons living with HIV (PLWH) in many African countries including South Africa (SA).^1,2 Those with CD4 cell counts < 100 cells/µL are particularly at risk.³ Mortality is high – reaching levels of 70% in sub-Saharan Africa (SSA).³ Altered mental state at presentation, older age, high cerebrospinal fluid (CSF) fungal burden and high peripheral white cell count predict mortality in antiretroviral therapy (ART) naïve patients.⁴ Although the availability of ART has led to a decrease in HIV-associated CCM (HIV/CCM) in high-income countries,⁵ the condition remains responsible for 10% – 20% of HIV-related deaths in SSA.⁶ Notwithstanding improved access to ART, many remain outside of care or on failing treatment and at risk of opportunistic disease.⁷

The initial (induction phase) management of HIV/CCM requires the following: (1) combination antifungal therapy including IV amphotericin B and oral flucytosine (first week only) and high-dose oral fluconazole 1200 mg daily (second week), after that an 8-week consolidation phase of oral fluconazole 800 mg daily, (2) control of raised intracranial pressure (rIP) with therapeutic lumbar punctures (LPs) to maintain the ‘opening-pressure’ (CSF-OP) at < 25 cm of water and (3) minimising the risk of immune reconstitution inflammatory syndrome (IRIS) by delaying the initiation of ART until 4 to 6 weeks after the start of antifungal therapy.^8,9,10,11,12

In the absence of a spinal manometer, the SA guidelines for the prevention, diagnosis and management of CCM recommend performing an LP to remove 20 mL – 30 mL of CSF if the symptoms and signs of rIP are present.¹² However, in clinical practise only 23% – 30% of CCM patients with signs and symptoms receive ‘therapeutic’ LPs.^13,14 A symptom guided approach has the potential to miss asymptomatic patients who might benefit from therapeutic LPs.

We hypothesised that four or more LPs in the first 7 days of treatment could facilitate CSF drainage and reduce in-hospital mortality in PLWH and HIV/CCM in a resource constrained setting where there are no spinal manometers. We, therefore, conducted a single centre retrospective cohort study to determine the impact on in-hospital mortality of four or more LPs in the first 7 days of antifungal therapy compared with PLWH/CCM who received fewer than four LPs.

In this retrospective study of patients with HIV/CCM, receipt of four more LPs in the first week of diagnosis and treatment was associated with reduced in-hospital mortality. These findings inform the recorded 98.2% compliance of hospital staff with local guideline-based treatment of CCM with combination antifungal therapy.

Raised intracranial pressure develops in most PLWH with HIV/CCM and portends a poor prognosis if not adequately treated.¹⁶ Lumbar punctures and CSF drainage have been shown to be effective in managing CCM related rIP.¹⁷ Alternatives such as acetazolamide or corticosteroids have no role in the management of HIV/CCM.^18,19 Despite the increased prevalence of rIP, therapeutic LPs are seldom instituted even when symptoms and signs of rIP are present.^13,16 In a clinical audit by Adeyemi and Ross, only 23% of patients with CCM related headaches received therapeutic LPs despite 82% of patients receiving analgesia for their pain.¹³ Similarly, Rolfes et al. report that only 30% of the 248 patients in their cohort received therapeutic LPs.¹⁴ This was despite the fact that therapeutic LPs were associated with a 69% improvement in survival.¹⁴ In our study we report a 17.4% absolute risk reduction of in-hospital mortality following intervention with four or more LPs in the week of diagnosis and treatment.

Spinal manometers are recommended for the measurement of rIP. In resource limited settings spinal manometers are seldom available. Instead, guidelines recommend using tubing from intravenous giving-sets.²⁰ A small single centre study by Meda and colleagues has confirmed a correlation between spinal manometer and intravenous giving set use in determining CSF-OP in the setting of CCM. However, this study consisted of only 35 subjects and reported technical shortcomings in the reliability of the measurements.²¹ In a recent study, Mogambery et al. found that the use of an intravenous giving set considerably underestimated CSF-OP when compared with that of a spinal manometer, mean 16.2 (s.d. ± 10) cm H₂O versus 22.7 (s.d ± 10) cm H₂O, p < 0.001.²² A schedule of at least four LPs with CSF drainage of 20 mL – 30 mL¹² in the first week of diagnosis and treatment could be life-saving in settings with no access to spinal manometers.

The optimal management of CCM consists of a triad of (1) combination antifungal therapy, (2) intracranial pressure (IP) management with CSF drainage and (3) immune reconstitution with ART after completion of 4 to 6 weeks of combination antifungal therapy to avoid CCM-IRIS.¹² This study provides evidence that rIP in HIV/CCM can be managed without recourse to spinal manometers.

The limitations of this study include it’s retrospective and single centres design. Also, we do not have data on the volume of CSF removed and survival beyond the index hospitalisation.

In conclusion, this study shows that PLWH/CCM can be effectively managed in centres with limited access to spinal manometers. We have shown that ≥ four LPs with CSF drainage in the first 7 days of hospitalisation improves early survival.