Description of studies
Our literature search yielded 728 reports of studies, 668 of which were unique. Two further reports were identified by review of reference lists of included studies and were considered for inclusion.53,54 yielding a total of 670 unique records for screening (figure 1). No further studies were identified by expert opinion. 573 records were excluded by title and abstract screening. 31 records were selected for full text review.8,20,44-46,53-78 Eight studies met criteria for inclusion44-46,53,72-75 and 23 were excluded.8,20,54-71 All included studies were observational studies. Two studies included a total of 90 patients with TBM44,46 and six included a total of 48 patients with CM.45,53,72-75
Excluded studies
Of the excluded studies, 15 concerned CM,54-57,59-63,66-69,76,78 four TBM,20,58,64,77 two bacterial meningitis,70,71 one coccoidal meningitis,8 and one included only cases of diagnostic uncertainty.65
Two studies were published only in abstract form and did not present sufficient outcome data for inclusion.67,68 The corresponding authors of these records were therefore contacted to request further details to assess eligibility.8,67,68 The authors one of these responded but were unable to provide further information.8,68 This study was therefore excluded.
The reasons for exclusion from this review are as follows: Two studies included patients with multiple, undocumented modalities of CSF diversion;54,55 one study provided a just single case report;56 three studies reported just one or two cases of surgical intervention and no survival/outcome data;57,60,61 two studies were review articles;58,66 eight reported no HIV-infected patients who underwent VPS;20,59,62-65,71,76-78 in one study reporting <50% HIV-infected patients it was not possible to associate outcome with HIV status8 and; no relevant measures of survival/outcome were studied in four.67-70
Studies of cryptococcal meningitis: characteristics and risk of bias
As no comparative studies were included in this group it was impossible to calculate size of effect. Characteristics of included studies are summarised in table 1 and risk of bias in table 2.
Bach, et al. 199745
This was a retrospective consecutive interrupted time series of all patients admitted with severe intracranial hypertension (lumbar puncture opening pressure >35cmCSF) secondary to CM who received CSF diversion. Four patients received a VP shunt. Three patients were initially managed with serial lumbar puncture. One received primary VPS. All patients presented with visual disturbance, one had seizures and one had bilateral abducens nerve palsies. Initial Glasgow Coma Score (GCS) was not reported. Neither makes nor models of the VPS systems used were described.
One patient was lost to follow-up at an unclear time point. At one month, all three remaining patients were alive. One death at 6 months was attributed to “wasting syndrome”. At 10 months a further death was attributed to Pneumocystis jiroveci pneumonia. Functional outcomes, rates of shunt failure and complication were not presented.
Although this study included consecutive patients and therefore minimised selection bias, it was classified as being globally weak. An interrupted time series is a weak study design. Coupled with small sample size, this rendered meaningful multivariable analysis impossible and it was not attempted. The time until loss to follow up of one patient was unclear, and the reasons for this are not documented. Mortality is a robust outcome measure.
Calvo, et al. 200375
This is an interrupted time series that presents five HIV-infected patients who were treated with VPS whilst admitted to a single Intensive Care Unit (ICU) in Montevideo, Uruguay. It is unclear if the data was collected in a prospective or retrospective fashion or whether patients were recruited consecutively. Median initial GCS was 12 (range 9-15). CD4+ cell count was not reported for any patient, nor was the make or model of VPS system. The VPS was inserted as a primary procedure for four patients with CSF pressures >23cmH2O. One patient initially received an EVD with intraventricular pressure monitoring before having a VPS inserted. All patients were managed with antifungal agents and hyperventilation to a target pCO2 of 30mmHg. Mannitol boluses were used in an unclear number of patients. At discharge from ICU all five patients were alive. Time to discharge from ICU was not reported. At 6 months two patients had been lost to follow-up and three survived. Outcome in this study is described as “good recovery”, “moderately disabled” or “dead” but the criteria for assignment to these descriptors are not described. At ICU discharge, 4 patients had made a “good recovery” and one was “moderately disabled”. At three months, two had a “good recovery” and one was “moderately disabled”. No complications or shunt failure are reported.
This study was classified as being globally weak with a high risk of selection bias and weak study design which, coupled with small sample size, did not permit adjustment for modulators of risk of mortality or poor outcome. Outcome assessment did not use a validated outcome measure. 40% of patients were lost to follow-up at 6 months.
Cherian, et al. 201674
This two-cohort analysis reported all patients with CM and CM IRIS presenting to a single hospital in Texas, USA. 49 of 50 patients had associated HIV infection. 49 patients had communicating hydrocephalus, and it is unclear if the patient with non-communicating hydrocephalus was HIV-infected or not. CD4+ cell count was not documented for any patient, nor was initial neurological status. All further demographic and outcome data are specific for the HIV-infected group. Patients who went on to receive CSF diversion had initial lumbar puncture opening pressure >25cm H2O. They were initially managed with antifungals, antiretroviral therapy and a variable number of therapeutic lumbar punctures (median 7; range 2-40) for a variable period (median 27 days; range 4-281 days) before proceeding to VPS. Eight patients underwent VPS.
At one month, five of the eight VPS patients survived. Three deaths had occurred, one due to post-extubation aspiration pneumonia, one due to septic shock of undocumented aetiology and the other due to a gram-negative bacterial pneumonia. At six months, five patients were still alive, and no new deaths were recorded. At 12 months, three patients were alive, four were dead and one was lost to follow-up. The additional death was secondary to an unspecified respiratory complication. Of the three patients initially treated for CM IRIS, at both one and six months, two were alive and one dead. At 12 months, two were confirmed dead and the other lost to follow-up.
One instance of shunt infection was recorded at 12 months. Two other patients, who were followed up for 1512 and 1485 days, suffered a shunt occlusion and a shunt infection, respectively, at some point during their follow-up period. However, the time to these complications was not reported. One other patient who was followed up for 383 days suffered a subdural haematoma, which was attributed to VPS over-drainage. Again, the time point at which this occurred was not reported. Functional outcomes were not reported.
This study was classified as being globally weak with no attempt to undertake multivariable survival analysis, undocumented reasons for loss to follow-up and lack of reporting of times of complications. Survival is a validated outcome measure but was unreliably reported in patients discharged to hospice care. Rates of complication were not measured using a validated method. Patients were consecutively recruited, and the selection process was clearly documented. A two-cohort analysis study has moderate risk of bias.
Corti, et al. 201473
This retrospective interrupted time series included 15 patients with CM who presented to medical services in Buenos Aires, Argentina. 14 of these patients were HIV-infected, however it was not possible to identify which demographic or outcome data pertained to the HIV-non-infected patient. CSF diversion was undertaken in patients who had lumbar puncture opening pressure persistently >25cm H20 after 2 weeks of therapeutic lumbar puncture and antifungal treatment. 14 of the 15 patients were managed with VP shunt, and one with lumboperitoneal shunting. Again, it was not possible to isolate demographic and outcome data from this patient. Medtronic® systems were used for all patients but component models are not described.
Three patients suffered complications including sepsis, multiorgan failure, two cases of meningitis and abdominal pseudocyst formation related to the distal catheter tip and requiring catheter revision. These occurred at unclear time points and the patients were excluded from survival analysis by the study authors. However, the authors did report that at least one of the patients with meningitis and multiorgan failure died. Of the remaining patients, all survived to 12 months. No other complications or outcomes were reported in this group.
This study was classified as being globally weak with high risk of selection bias, a weak study design and small sample size which did not permit adjustment for factors potentially confounding outcome, and poorly documented exclusion from follow up causing high risk of attrition bias. Survival is a validated outcome measure but was unreliably reported in the group with complications.
Liu, et al. 201472
This retrospective single cohort study included nine patients with HIV-associated CM managed with VPS over a five-year period at a Shanghai hospital, China. Although exclusion criteria are documented, the number of exclusions is not. Included patients had a mean CD4+ cell count of 11 cells/mL. Neurosurgical intervention was considered in patients with raised lumbar puncture opening pressure and deteriorating neurological status despite antifungal therapy, repeated therapeutic lumbar puncture and mannitol administration. VPS was undertaken in all patients using a Medtronic® system, but the valve and catheter model are not documented. The authors define raised opening pressure as “>400cm H20” which, presumably, is a typographic error (raised CSF opening pressure defined as >20-35cm H2O in other included studies45,53,73-75). Two patients were described as having loss of consciousness at baseline, but no objective measures were provided.
Eight of the nine patients studied were alive at 1 month. Three patients were lost to follow up at six months and no new deaths were reported. At 12 months, one more patient had died, yielding a survival of four out of six patients for whom follow-up was available. Given the low initial CD4 counts, it is likely that deaths would have occurred in those lost to follow-up by this time point and therefore there is a risk of attrition bias at this time point. The causes of death were VPS obstruction at one month and an unspecified reaction to antiretroviral drugs at 12 months. No other outcome measures, shunt failures or complications were reported.
This study was classified as being globally weak due to a weak study design and unknown risk of selection bias. No confounders were identified, and the primary outcome was survival – which is a robust outcome measure.
Vidal, et al. 201253
This retrospective cohort study investigated associations between various parameters derived from quantitative CSF microscopy with mortality in a cohort of patients who presented to hospital in São Paulo, Brazil, with HIV-associated CM. Included patients were admitted between January 2006 and June 2008, but it is unclear what rate of case acquisition this represents. A median CD4+ cell count of 36 cells/mL, with interquartile range of 17-87 cells/mL was reported across all patients. Neurosurgical intervention was considered in patients with lumbar puncture opening pressure persistently >20cmH2O after 14 days therapeutic lumbar puncture and antifungal treatment.
Although survival was presented in the series of 9 patients undergoing VPS, no other dependent or independent variables were reported in this subgroup to allow comparisons and therefore, for our purposes, this study provided case-series data. Initial neurological status and type of shunt valve or catheter were not described. Of the 9 patients who underwent VPS, 6 survived until hospital discharge. However, time to discharge and length of stay were not reported. No other outcomes were reported.
This study was classified as being globally weak with an unknown risk of selection bias and weak study design and size which did not permit adjustment for confounding variables regards our research question. Survival is a strong primary outcome measure.
Included studies of tuberculous meningitis: risk of bias
Nadvi, et al. 200046
This prospective cohort analysis compared outcome and mortality at one month following VPS between HIV-infected and HIV non-infected patients. Patients who underwent VPS for TBM, over an undefined recruitment period prior to commencement of the national South African antiretroviral treatment (ART) programme in 2004, were recruited from a single hospital in KwaZulu-Natal, South Africa. Of the 30 patients recruited, 15 were HIV-infected and 15 HIV non-infected. The two cohorts differed widely in age range with the HIV-infected group being mostly adult and the HIV non-infected group being mostly paediatric. Patients were diagnosed with hydrocephalus on the basis of CT, transcranial doppler or clinical observation in keeping with hydrocephalus and intraoperative ventricular pressure >20cmCSF. Median initial GCS was 14 (range 9-15) in the HIV-infected group and 12 (range 9-15) in the HIV non-infected group. Use of EVD or therapeutic lumbar puncture was not documented for any patient. VPS was undertaken using a 102cm catheter and low-profile, medium pressure Codman / Unishunt valve (Codman / Johnson & Johnson®, Raynham, MA).
At one month, 5/15 and 11/15 HIV-infected, and HIV non-infected patients were alive, respectively. 11/15 and 6/15 patients in the HIV-infected and HIV non-infected cohorts had an unfavourable Glasgow Outcome Score43 (GOS 1-3) dichotomised GOS at one month. Multivariable analysis was not attempted. Univariate analysis revealed a significant association of CD4+ cell count and outcome (p=0.031), but the magnitude of this association was not reported.
This study was classified as being globally weak. A prospective cohort study provides a moderate study design. The study included representative patients but the control group was poorly age matched and this was not adjusted for. It is not clear that patients were enrolled consecutively, yielding an unknown risk of selection bias. The authors were not blinded to HIV status. Mortality is a robust primary outcome measure. As this study was undertaken prior to ART being made widely available in South Africa, its findings may not be generalisable to settings where ART is available.79
Sharma, et al. 201544
This retrospective case-control study compared outcome and mortality between HIV-infected and HIV non-infected patients following VPS. All 30 eligible HIV-infected patients who underwent VPS at a single hospital in Bangalore, India, between June 2002 and October 2012 were included. These patients were compared against 30 HIV non-infected control patients that were matched for age, sex and clinical grade of TBM. Patients were included who “had symptoms of raised intracranial pressure, with clinical, radiological and CSF findings characteristic of TBM”. However, specific inclusion criteria were not documented. Initial GCS was dichotomized as 3-8 (unfavourable) and this was present in 13.3% and 3.3% in the HIV-infected and non-infected patients, respectively. The rest had GCS 9-15, which was classified as favourable. 23 and 22 patients in the HIV-infected and non-infected cohorts, respectively, had communicating hydrocephalus. Patients underwent VPS as a primary procedure unless extensive basal infarcts were evident on computed tomography (CT) scan of the brain. In these patients, a frontal EVD was placed and converted to VPS if improvement in “sensorium” was noted. The proportion of those who underwent primary VPS is not reported. VPS was with a medium-pressure Chhabra shunt (Surgiwear® Inc.). 9 HIV-infected patients and 4 HIV non-infected patients were lost to follow-up.
At one month, 13/21 HIV-infected and 20/26 HIV non-infected patients were alive. At six months, 9 HIV-infected and 18 HIV non-infected patients were alive. In the HIV-infected cohort, unfavourable initial GCS was associated with higher rates of mortality. GOS at 3 months was also dichotomized as unfavourable (1-3) or favourable (4-5). 16/21 HIV-infected, and 9/26 HIV-non-infected patients had an unfavourable outcome at 3 months. Binomial logistic regression analysis confirmed that HIV infection (p=0.038) and low Palur grade (p=0.024)80 were significantly associated with unfavourable outcome. No measure of effect was presented for these analyses. Anaemia (haemoglobin <10mg/dL) was associated with unfavourable outcome in the HIV-infected group (Exp.[β]=25.6; p=0.011).
This study was classified as being, globally, of moderate quality. A case-control study provides a moderate quality of study design. The study included representative consecutive cases with appropriate matching of controls. Potential confounders were adjusted for in the multivariable analysis. The authors were not blinded to HIV status. Just under a third of initially recruited patients were lost to follow-up at later time points, but this was appropriately documented. GCS and dichotomised GOS are robust outcome measures but not validated in the context of TBM. Mortality is a robust outcome measure.
Risk of bias between studies: tuberculous meningitis
As two comparative cohort studies were included, it was possible to pool reported measures of effect of HIV-infection on survival at one-month post-VPS. Risk of bias is summarised in Table 3.
Synthesis of results
Effect of pathology
Eight studies of survival and/or outcome in TBM and CM were identified.44-46,53,72-75 However, none of these compared survival or outcome between TBM and CM. Study populations, outcome measures and follow-up varied greatly. Further, all but one study of CM was of weak study design, whilst the two studies of TBM were of moderate quality. There was significant methodological heterogeneity between CM and TBM studies and it was therefore not possible to conduct meaningful meta-analytic comparison of outcomes between these groups. We therefore present a narrative analysis. The results of pooling of reported outcomes within each group are presented in SOF tables, with the purpose of summarising reported outcomes to date. These are of very low to low GRADE of evidence (see risk of bias, above), indicating that the true outcomes for each pathology may be, or are likely to be, substantially different from the pooled measure.81.
Cryptococcal Meningitis
Pooled outcome measures are reported in table 4.
Survival
Three studies reported survival in CM at one-month post VPS.45,72,74 Cherian, et al. reported three deaths in eight patients. Three of these patients had a diagnosis of CM IRIS, one of which died (AIDS-specific mortality). Liu, et al. report one death in nine patients at one month. This was due to shunt obstruction. Bach, et al.’s four patients with documented follow up were all alive at one month. In total, 17 of 21 (81%) patients described in these studies survived one month, with one episode of shunt failure documented.
At six months post-VPS, four studies reported survival.45,72,74,75 Three of Liu, et al’s patients had been lost to follow-up. However, no new deaths were confirmed. Bach, et al. reported one death due to HIV-wasting syndrome. Another had died of cytomegalovirus pancreatitis. These both therefore contributed to AIDS-specific mortality82. Calvo, et al. obtained three months follow up for three patients, all of whom survived. Cherian et al. followed up all of their eight patients and reported no new deaths. With loss to follow-up and addition of three surviving patients from Calvo, et al’s cohort, overall survival remained stable: 17 of 21 (81%) patients that were followed up at six months were alive. No new cases of shunt failure were documented.
Four studies reported 12-month survival.45,72-74 Liu, et al. reported a further death. Cherian, et al. reported a death in one of their patients who had been diagnosed with CM IRIS, contributing to AIDS-specific mortality. Another of their patients was lost to follow-up. One of Bach et al.’s patients had died of Pneumocycstis jiroveci pneumonia, also contributing to AIDS-specific mortality. Corti, et al. report that all of their 12 patients followed-up for one year were alive. In total 20 of 29 patients with 12-month follow-up survived. Five of the 17 (29%) patients reported by studies describing cause of death had AIDS-defining illness as a primary or major contributing cause of death by 12 months.
Liu et al, reported one shunt failure at one month. Cherian and colleagues reported one shunt failure at 12 months, but as they also reported two other instances of shunt failure at unclear timepoints, their shunt failure data was not included in the pooled analysis.
Operative complications
Complications of treatment were reported by two studies.72,74 In Liu, et al.’s series, none of these were related to the surgical management of their patients at 12 months. In addition to their three instances of shunt failure, Cherian and colleagues reported one instance of over drainage subdural haematoma at an unspecified time. Follow-up in this series ranged from 28-1512 days.
Functional outcome
No studies reported any measures of functional outcome at any time point. Calvo, et al. reported that two of three patients made a “good recovery” at 6 months but this measure is not validated.75
Tuberculous meningitis
Pooled outcome measures are reported in table 5.
Survival
Two studies reported 1-month survival following VPS for HIV-associated TBM44,46. Sharma et al. reported 13 of 21 patients surviving for one-month post-VPS. Nadvi, et al. reported just 5 of 15 patients surviving for one-month.
Sharma et al. reported 9 of 21 patients surviving 6 months. Sharma et al. also reported “long-term” survival of 7 of 21 with mean follow-up of 130 days, range 91-760 days. No studies reported causes of death or measures of shunt survival.
Operative complications
No studies reported rates of operative complication.
Functional outcome
Nadvi et al. reported GOS in HIV-infected patients 1 month following VPS.46 11 of 15 patients had an unfavourable functional outcome, with 10 of these being dead. Therefore four of the five surviving patients attained GOS 4-5, signifying moderate to low levels of disability at one month.43
Effect of human immunodeficiency virus infection
As two studies comparing HIV-infected and HIV non-infected patients with TBM were identified, it was possible to examine the impact of HIV-infection on survival.44,46
At one month, the odds ratio for mortality in Sharma, et al.’s HIV-infected group was 2.02 (95% confidence interval [CI]: 0.58-7.01). In Nadvi’s group it was 4.73 (95% CI: 0.58-7.01). The pooled odds ratio (Mantel-Haenszel) for one-month mortality in the HIV-infected group was 3.03 (95% CI: 1.13- 8.12; p=0.03; chi2=0.92; df=2; I2=0%; Figure 2), indicating significantly increased risk of mortality at one-month post-VPS in HIV infection.
Sharma et al. reported six-month survival, but Nadvi, et al. did not.