Cerebrospinal fluid cell count variability is a major confounding factor in external ventricular drain-associated infection surveillance diagnostics: a prospective observational study.

BACKGROUND: External ventricular drain (EVD)-related infections (EVDIs) are feared complications that are difficult to rapidly and correctly diagnose, which can lead to unnecessary treatment with broad-spectrum antibiotics. No readily available diagnostic parameters have been identified to reliably predict or identify EVDIs. Moreover, intraventricular hemorrhage is common and affect cerebrospinal fluid (CSF) cellularity. The relationship between leukocytes and erythrocytes is often used to identify suspected infection and triggers the use of antibiotics pending results of cultures, which may take days. Cell count based surveillance diagnostics assumes a homogeneous distribution of cells in the CSF. Given the intraventricular sedimentation of erythrocytes on computed tomography scans this assumption may be erroneous and could affect diagnostics. AIMS: To evaluate the consistency of cell counts in serially sampled CSF from EVDs, with and without patient repositioning, to assess the effect on infection diagnostics. METHODS: We performed a prospective single-center study where routine CSF sampling was followed by a second sample after 10 min, allocated around a standard patient repositioning, or not. Changes in absolute and pairwise cell counts and ratios were analyzed, including mixed regression models. RESULTS: Data from 51 patients and 162 paired samples were analyzed. We observed substantial changes in CSF cellularity as the result of both resampling and repositioning, with repositioning found to be an independent predictor of bidirectional cellular change. Glucose and lactate levels were affected, however clinically non-significant. No positive CSF cultures were seen during the study. Thirty percent (30%) of patients changed suspected EVDI status, as defined by the cell component of local and national guidelines, when resampling after repositioning. CONCLUSIONS: CSF cell counts are not consistent and are affected by patient movement suggesting a heterogeneity in the intraventricular space. The relationship between leukocytes and erythrocytes was less affected than absolute changes. Importantly, cell changes are found to increase with increased cellularity, often leading to changes in suspected EVDI status. Faster and more precise diagnostics are needed, and methods such as emerging next generation sequencing techniques my provide tools to more timely and accurately guide antibiotic treatment. Trial Registration NCT04736407, Clinicaltrials.gov, retrospectively registered 2nd February 2021.

Initial Results of Precision Treatment of Postoperative Cerebrospinal Fluid Leak with Ultrasound-Guided Epidural Blood Patch.

BACKGROUND: Incidental durotomy, a known complication of spinal surgery, can lead to persistent cerebrospinal fluid leak and pseudomeningocele if unrecognized or incompletely repaired. We describe the use of ultrasound to visualize the site of durotomy, observe the aspiration of the pseudomeningocele, and guide the precise application of an ultrasound-guided epidural blood patch (US-EBP), under direct visualization in real time. METHODS: A retrospective review was performed to determine demographic, procedural, and outcome characteristics for patients who underwent US-EBP for symptomatic postoperative pseudomeningocele. RESULTS: Overall, 48 patients who underwent 49 unique episodes of care were included. The average age and body mass index were 60.5 (±12.6) years and 27.8 (±4.50) kg/m2, respectively. The most frequent index operation was laminectomy (24.5%), and 36.7% of surgeries were revision operations. Durotomy was intended or recognized in 73.4% of cases, and the median time from surgery to symptom development was 7 (interquartile range 4-16) days. A total of 61 US-EBPs were performed, with 51.0% of patients experiencing resolution of their symptoms after the first US-EBP. An additional 20.4% were successful with multiple US-EBP attempts. Complications occurred in 14.3% of cases, and the median clinical follow-up was 4.3 (interquartile range 2.4-14.5) months. CONCLUSIONS: This manuscript represents the largest series in the literature describing US-EBP for the treatment of postoperative pseudomeningocele. The success rate suggests that routine utilization of US-guided EBP may allow for targeted treatment of pseudomeningoceles, without the prolonged hospitalization associated with lumbar drains or the risks of general anesthesia and impaired wound healing associated with surgical revision.

Cerebrospinal Fluid-Venous Fistulas: A Systematic Review and Examination of Individual Patient Data.

BACKGROUND: Spontaneous intracranial hypotension (SIH) is usually caused by a spinal cerebrospinal fluid (CSF) leak. CSF-venous fistula is an underdiagnosed cause of spinal CSF leak, as it is challenging to identify on myelography. OBJECTIVE: To review existing literature to summarize common presentations, diagnostic imaging modalities, and current treatment strategies for CSF-venous fistulas. METHODS: We conducted a systematic review using PubMed, Embase, Scopus, and Web of Science databases to identify studies discussing CSF-venous fistulas. Titles and abstracts were screened. Studies meeting prespecified inclusion criteria were reviewed in full. RESULTS: Of 180 articles identified, 16 articles met inclusion criteria. Individual patient data was acquired from 7 studies reporting on 18 patients. CSF-venous fistula most frequently presented as positional headache. Digital subtraction myelography provided greatest detection of CSF-venous fistula in the lateral decubitus position and detected CSF-venous fistula in all individual patient cases. Dynamic computed tomography (CT) myelogram enabled detection and differentiation of CSF-venous fistulas from low-flow epidural leaks. The majority of fistulas were in the thoracic spine and slightly more common on the right. Epidural blood patch (EBP) provided temporary or no relief in all individual patients. Resolution or improvement of clinical symptoms and radiologic normalization were observed in all surgically treated patients. CONCLUSION: Although rare, CSF-venous fistula is an important cause of spinal CSF leak contributing to SIH. Dynamic CT myelogram and digital subtraction myelography, particularly in the lateral decubitus position, are the most accurate and effective diagnostic imaging modalities. EBPs often provide only transient relief, while surgical management is preferred.

Insights into the natural history of spontaneous intracranial hypotension from infusion testing.

OBJECTIVE: To assess the pathophysiologic changes in patients with spontaneous intracranial hypotension (SIH) based on measures of CSF dynamics, and on the duration of symptoms, in a retrospective case-controlled study. METHODS: We included consecutive patients investigated for SIH at our department from January 2012 to February 2018. CSF leak was considered confirmed if extrathecal contrast spillage was seen on imaging (CT or MRI) after intrathecal contrast application, or dural breach was detected by direct intraoperative visualization. We divided patients with a confirmed CSF leak into 3 groups depending on the symptom duration, as follows: ≤10, 11-52, and >52 weeks. Clinical characteristics and measures of CSF fluid dynamics obtained by computerized lumbar infusion testing were analyzed over time and compared with a reference population. RESULTS: Among the 137 patients included, 69 had a confirmed CSF leak. Whereas 93.1% with <10 weeks of symptoms displayed typical orthostatic headache, only 62.5% with >10 weeks of symptoms did (p = 0.004). Analysis of infusion tests revealed differences between groups with different symptom duration for CSF outflow resistance (p < 0.001), lumbar baseline pressure (p = 0.013), lumbar plateau pressure (p < 0.001), baseline pressure amplitude (p = 0.021), plateau pressure amplitude (p = 0.001), pressure-volume index (p = 0.001), elastance (p < 0.001), and CSF production rate (p = 0.001). Compared to the reference population, only patients with acute symptoms showed a significantly altered CSF dynamics profile. CONCLUSION: A CSF leak dramatically alters CSF dynamics acutely, but the pattern changes over time. There is an association between the clinical presentation and changes in CSF dynamics.

Development and validation of a preclinical model for training and assessment of cerebrospinal fluid leak repair in endoscopic skull base surgery.

BACKGROUND: Achieving an effective endoscopic skull base reconstruction in case of large dural defects requires specific training and can be extremely challenging. The aim of this study was to describe the development and validation of a preclinical model for cerebrospinal fluid (CSF) leak repair, which can be used for training and to test the mechanical efficacy of endoscopic skull base reconstruction. METHODS: Eleven fresh-frozen cadaver heads were dissected. A catheter was inserted in the subdural space via a cervical access, which was sealed with mastic; a vertical graduated tube connected to the catheter measured intracranial pressure (ICP), while stained water was injected intracranially. After endoscopic skull base reconstruction was performed, an expert surgeon assessed its efficacy. ICP was then gradually increased until a leak was evident and CSF leak pressure value was recorded. The correlation between subjective and quantitative evaluations was investigated through Pearson and Spearman correlation tests. RESULTS: The model was successfully tested in 11 specimens. A single, large dural defect was created in each model (transplanum-transtuberculum = 4; transplanum-transtuberculum-transsellar = 3; transclival = 3; transcribriform-transplanum = 1). Skull base reconstruction always comprised a rigid buttress with temporal fascia and/or fat. The CSF leak pressure ranged from 4 to 110 cmH2 O. The correlation between expert subjective and quantitative assessment of skull base reconstruction mechanical efficacy was high (r = 0.7; rs = 0.7; p = 0.010 and p = 0.006, respectively). CONCLUSION: This preclinical model is simple, easily reproducible, and effective in simulating an intraoperative leak and objectively measures the CSF leak pressure point of a skull base reconstruction.

Greater Occipital Nerve Block as a Tool to Diagnose Spontaneous Intracranial Hypotension Before Epidural Blood Patch: A Case Report.

Spontaneous intracranial hypotension (SIH) has been increasingly characterized in recent years. A definitive diagnostic algorithm remains controversial because several symptoms are often found to be nonspecific. When neuroimaging fails to identify a cerebrospinal fluid leak and symptoms are atypical, an epidural blood patch (EBP) may be performed but not without risks. Our case shows how greater occipital nerve block (GONB) can expedite SIH diagnosis in a man with atypical presentation by reducing the sensory input from the posterior cranial fossa. The relief provided by GONB allowed to diagnose SIH promptly and the patient underwent a curative EBP.

Spontaneous cerebrospinal fluid leak and idiopathic intracranial hypertension.

PURPOSE OF REVIEW: To review the most recent literature on the relationship of spontaneous cerebrospinal fluid (CSF) leak with idiopathic intracranial hypertension (IIH) and considerations in management of these conditions. RECENT FINDINGS: A link has been proposed between spontaneous CSF leak and IIH based on similar demographics, radiologic, and clinical findings in these patients, and on a plausible mechanism of skull base erosion in the setting of high CSF pressure over time. IIH patients with CSF leak may not present with classic IIH signs and symptoms as the leak can alleviate excess pressure; however, they may develop these after a leak is repaired. There may also be a higher risk of leak recurrence if intracranial hypertension is not treated postoperatively. SUMMARY: A growing body of evidence supports an association between IIH and spontaneous CSF leak. However, this relationship is still not fully elucidated, and there is no current agreement on how to incorporate screening, management, or counseling guidelines for CSF leak into the care of IIH patients. There are also no specific guidelines for evaluation/management of IIH in patients with spontaneous CSF leak. Further interdisciplinary research is needed to explore this connection and to establish screening, evaluation, and management guidelines.

Do Most Patients With a Spontaneous Cerebrospinal Fluid Leak Have Idiopathic Intracranial Hypertension?

BACKGROUND: The association between cerebrospinal fluid (CSF) leaks at the skull base and raised intracranial pressure (ICP) has been reported since the 1960s. It has been suggested that spontaneous CSF leaks might represent a variant of idiopathic intracranial hypertension (IIH). We review the evidence regarding the association between spontaneous CSF leaks and IIH, and the role of ICP in the pathophysiology of nontraumatic skull base defects. We also discuss the management of ICP in the setting of CSF leaks and IIH. EVIDENCE ACQUISITION: References were identified by searches of PubMed from 1955 to September 2018 with the terms "idiopathic intracranial hypertension" and "cerebrospinal fluid leak." Additional references were identified using the terms "pseudotumor cerebri," "intracranial hypertension," "benign intracranial hypertension," and by hand search of relevant articles. RESULTS: A CSF leak entails the egress of CSF from the subarachnoid spaces of the skull base into the surrounding cavitary structures. Striking overlaps exist regarding demographic, clinical, and radiological characteristics between IIH patients and those with spontaneous CSF leaks, suggesting that some (if not most) of these patients have IIH. However, determining whether a patient with spontaneous CSF leak may have IIH may be difficult, as signs and symptoms of raised ICP may be obviated by the leak. The pathophysiology is unknown but might stem from progressive erosion of the thin bone of the skull base by persistent pulsatile high CSF pressure. Currently, there is no consensus regarding the management of ICP after spontaneous CSF leak repair when IIH is suspected. CONCLUSIONS: IIH is becoming more widely recognized as a cause of spontaneous CSF leaks, but the causal relationship remains poorly characterized. Systematic evaluation and follow-up of patients with spontaneous CSF leaks by neuro-ophthalmologists will help clarify the relation between IIH and spontaneous CSF leaks.

Intracranial hypotension and hypertension: reversible Chiari malformation due to dynamic cerebrospinal fluid abnormalities in Gorham-Stout disease. Case report.

Gorham-Stout disease (GSD) is an intractable disease characterized by massive osteolysis caused by abnormal lymphangiogenesis in bone. In rare cases of GSD, CSF abnormalities develop. The authors present the case of a 19-year-old woman with GSD presenting with orthostatic headache due to intracranial hypotension (5 cm H2O). The clinical course of this case was very unusual. Orthostatic headache was associated with a CSF leak from the thigh after pathological fractures of the femur and pelvis. The chronic CSF leak led to acquired Chiari malformation (CM) with syringomyelia. After an epidural blood patch, her neurological status improved; however, after the complete arrest of the CSF leak from the thigh, she presented with severe nonpostural headache and progressive visual acuity loss with optic papilledema. A ventriculoperitoneal shunt was placed to treat intracranial hypertension (50 cm H2O). Headache improved and optic papilledema decreased after shunt surgery. This case shows that dynamic CSF abnormalities may lead to reversible CM in patients with GSD. Sealing a CSF leak rather than performing suboccipital decompression is recommended for acquired CM resulting from a CSF leak.

Cerebrospinal fluid outflow resistance as a diagnostic marker of spontaneous cerebrospinal fluid leakage.

OBJECTIVE Spinal CSF leakage causes spontaneous intracranial hypotension (SIH). The aim of this study was to characterize CSF dynamics via lumbar infusion testing in patients with and without proven spinal CSF leakage in order to explore possible discriminators for the presence of an open CSF leak. METHODS This analysis included all patients with suspected SIH who were treated at the authors' institution between January 2012 and February 2015. The gold standard for "proven" CSF leakage is considered to be extrathecal contrast accumulation after intrathecal contrast injection. To characterize CSF dynamics, the authors performed computerized lumbar infusion testing to measure lumbar pressure at baseline (opening pressure) and at plateau, as well as pulse amplitude, CSF outflow resistance (RCSF), craniospinal elastance, and pressure-volume index. RESULTS Thirty-one patients underwent clinical imaging and lumbar infusion testing and were included in the final analysis. A comparison of the 14 patients with proven CSF leakage with the 17 patients without leakage showed a statistically significantly lower lumbar opening pressure (p < 0.001), plateau pressure (p < 0.001), and RCSF (p < 0.001) in the group with leakage. Sensitivity, specificity, and positive and negative predictive values for an RCSF cutoff of ≤ 5 mm Hg/(ml/min) were 0.86, 1.0, 1.0, and 0.89 (area under the curve of 0.96), respectively. The median pressure-volume index was higher (p = 0.003), and baseline (p = 0.017) and plateau (p < 0.001) pulse amplitudes were lower in patients with a proven leak. CONCLUSIONS Lumbar infusion testing captures a distinct pattern of CSF dynamics associated with spinal CSF leakage. RCSF assessed by computerized lumbar infusion testing has an excellent diagnostic accuracy and is more accurate than evaluating the lumbar opening pressure. The authors suggest inclusion of RCSF in the diagnostic criteria for SIH.

Factors predicting response to the first epidural blood patch in spontaneous intracranial hypotension.

Spontaneous intracranial hypotension results from cerebrospinal fluid leakage. Currently, the treatment of choice for spontaneous intracranial hypotension is the epidural blood patch, which has a variable response rate and no clear outcome predictors. This study aimed to identify predictors for response rate of a first targeted epidural blood patch in patients with spontaneous intracranial hypotension. We reviewed cases of patients with spontaneous intracranial hypotension who received targeted epidural blood patch at our hospital between 1 January 2007 and 1 July 2014. The outcome measure was first epidural blood patch response. We analysed demographics, clinical manifestations, neuroimaging findings (non-contrast heavily T2-weighted magnetic resonance myelography and brain magnetic resonance imaging), and blood volume as potential outcome predictors. Significant predictors were tested and a decision tree was used to construct a predictive model. In total, 150 patients with spontaneous intracranial hypotension were included for final analyses. Their overall first targeted epidural blood patch response rate was 58.7%. Among patients with a greater injected blood volume (≥22.5 versus <22.5 ml), the response rate was higher (67.9% versus 47.0%, P = 0.01). In brain and spinal magnetic resonance imaging studies, significant predictors included anterior epidural cerebrospinal fluid collection length (<8 versus ≥8 segments; 72.5% versus 37.3%, odds ratio = 4.4, 95% confidence interval: 2.2-8.9, P < 0.001) and midbrain-pons angle (≥40° versus <40°; 71.3% versus 37.5%, odds ratio = 4.1, 95% confidence interval 2.1-8.3, P < 0.001). Decision tree analyses showed that patients with anterior epidural CSF collection involving <8 segments and an injected blood volume ≥22.5 ml had an 80.0% response rate. Patients with anterior epidural cerebrospinal fluid collection involving ≥8 segments and a midbrain-pons angle <40° had a 21.2% response rate. These three variables predicted first epidural blood patch response in 71.3% of patients. Brain and spinal neuroimaging findings and epidural blood patch blood volume can be used to predict targeted first epidural blood patch response in patients with spontaneous intracranial hypotension.

Choroidal fissure acts as an overflow device in cerebrospinal fluid drainage: morphological comparison between idiopathic and secondary normal-pressure hydrocephalus.

To clarify the pathogenesis of two different types of adult-onset normal-pressure hydrocephalus (NPH), we investigated cerebrospinal fluid distribution on the high-field three-dimensional MRI. The subarachnoid spaces in secondary NPH were smaller than those in the controls, whereas those in idiopathic NPH were of similar size to the controls. In idiopathic NPH, however, the basal cistern and Sylvian fissure were enlarged in concurrence with ventricular enlargement towards the z-direction, but the convexity subarachnoid space was severely diminished. In this article, we provide evidence that the key cause of the disproportionate cerebrospinal fluid distribution in idiopathic NPH is the compensatory direct CSF communication between the inferior horn of the lateral ventricles and the ambient cistern at the choroidal fissure. In contrast, all parts of the subarachnoid spaces were equally and severely decreased in secondary NPH. Blockage of CSF drainage from the subarachnoid spaces could cause the omnidirectional ventricular enlargement in secondary NPH.

Use of fat-suppressed T2 -weighted sagittal images after infusion of excess saline into the subarachnoid space as a new diagnostic modality for cerebrospinal fluid hypovolemia: technical note.

The diagnosis of CSF hypovolemia remains controversial. The primary diagnostic factor relies on confirmation of leakage of the CSF based on reduced spinal fluid pressure. Determining the specific leakage site is the most important issue for effective treatment but remains a difficult task. Although CT myelography, radioisotope cisternography, and MRI are commonly performed in the diagnosis of CSF hypovolemia, these techniques can rarely identify the precise leakage site. Therefore, an epidural blood patch is performed in the lumbar spine in many cases. This study reports a new diagnostic modality that can help to confirm the leakage site. Fat-suppressed T2-weighted sagittal images were compared before and after the infusion of 20 ml of saline into the subarachnoid space of the lumbar region to detect the specific leakage site with high probability. Three patients were successfully treated by the epidural blood patch based on data obtained with the new diagnostic modality. Two patients were treated in the cervical region and 1 in the lumbar region. The use of fat-suppressed T2-weighted sagittal images after saline infusion could be a relevant diagnostic modality compared with images obtained by CT myelography, radioisotope cisternography, and ordinary MRI to achieve accurate diagnosis and effective treatment of patients with CSF hypovolemia.

How common is normal cerebrospinal fluid pressure in spontaneous intracranial hypotension?

Objectives To determine the proportion of patients with spontaneous intracranial hypotension (SIH) who had a cerebrospinal fluid (CSF) pressure >6 cm H2O and to investigate the clinical and imaging variables associated with CSF pressure ( PCSF) in this condition. Methods We retrospectively reviewed 106 patients with SIH. PCSF was measured by lumbar puncture prior to treatment. Clinical and imaging variables - including demographic data, brain imaging results, symptom duration, and abdominal circumference - were collected. Univariate and multivariate analyses were performed to determine the correlation of these variables with PCSF. Results Sixty-one percent of patients had a PCSF between 6 and 20 cm H2O; only 34% had a PCSF ≤6 cm H2O. The factors associated with increased PCSF included abdominal circumference ( p < 0.001), symptom duration ( p = 0.015), and the absence of brain magnetic resonance imaging findings of SIH ( p = 0.003). A wide variability in PCSF was observed among all patients, which was not completely accounted for by the variables included in the model. Conclusions Normal CSF pressure is common in patients with SIH; the absence of a low opening pressure should not exclude this condition. Body habitus, symptom duration, and brain imaging are correlated with PCSF measurements, but these factors alone do not entirely explain the wide variability in observed pressures in this condition and this suggests the influence of other factors.

[Clinical analysis of Mondini dysplasia with cerebrospinal fluid leakage and preliminary genetic research of it].

OBJECTIVE: To summarize and analyze the clinical characteristics of Mondini dysplasia with cerebrospinal fluid leakage, as well as preliminarily investigate the genetic mechanism of the disease. METHOD: The clinical data of 2 patients diagnosed as Mondini dysplasia with cerebrospinal fluid leakage treated in our hospital were analyzed. Blood samples of these two patients were obtained to extract DNA. We screened DNA samples for gene SLC26A4 mutations by using polymerase chain reaction and direct sequencing. The sequencing results were analyzed in DNASTAR software. RESULT: Both patients came to our hospital because of recurrent meningitis, and the fistula were both located in vestibular window. Patients were cured one-time after surgical closure of the leakages with temporalis + temporalis fascia + temporalis through the mastoid approach. No pathogenic mutations of gene SLC26A4 with exome sequencing were found. CONCLUSION: Mondini dysplasia with cerebrospinal fluid leakage should be considered in patients with recurrent meningitis and hearing disorder. Temporal bone HRCT is helpful to the diagnosis. Surgical closure is an effective therapeutic method and may prevent recurrent meningitis. The molecular mechanism of simple Mondini dysplasia needs further study.

Cerebrospinal fluid drainage through the diploic and spinal epidural veins.

The aim of this study was to quantitatively evaluate the function of the cranial diploic and spinal epidural veins as cerebrospinal fluid (CSF) drainage pathways by measuring lipocalin-type prostaglandin D synthase (PGDS) and cystatin C (CysC) dissolved in the blood of these veins. This was a prospective study involving 51 consecutive patients, 31 males and 20 females, who underwent 41 cranial and 10 spinal surgeries. Intraoperatively, peripheral venous blood and diploic venous blood, or peripheral venous blood and spinal epidural venous blood samples were simultaneously collected and immediately centrifuged. For all samples, dissolved albumin (for reference), PGDS and CysC were measured using an enzyme-linked immunosorbent assay. The diploic vein/peripheral vein ratios in five cranial locations and epidural vein/peripheral vein ratios were calculated and statistically evaluated for the three biomarkers. For PGDS, the diploic vein/peripheral vein ratio was significantly increased in the frontal (P = 0.011), temporal (P = 0.028), parietal (P = 0.046) and skull base (P = 0.039), while it did not reach statistical significance for CysC. For patients older than 45 years, the diploic vein/peripheral vein ratio for PGDS was significantly decreased in the frontal region (P = 0.028), and the epidural vein/peripheral vein ratio for CysC was significantly decreased (P = 0.014). These results show that the diploic veins constitute CSF drainage pathways with heterogeneous functional intensity at different cranial locations. Compared with the diploic veins, spinal epidural veins seem to drain less CSF. The cranial diploic and spinal epidural veins may jointly function as an alternative, age-related trans-dural CSF drainage system.

Visual evoked potentials show strong positive association with intracranial pressure in patients with cryptococcal meningitis.

OBJECTIVE: To verify the relationship between intracranial pressure and flash visual evoked potentials (F-VEP) in patients with cryptococcal meningitis. Method The sample included adults diagnosed with cryptococcal meningitis admitted at a reference hospital for infectious diseases. The patients were subjected to F-VEP tests shortly before lumbar puncture. The Pearson’s linear correlation coefficient was calculated and the linear regression analysis was performed. RESULTS: Eighteen individuals were subjected to a total of 69 lumbar punctures preceded by F-VEP tests. At the first lumbar puncture performed in each patient, N2 latency exhibited a strong positive correlation with intracranial pressure (r = 0.83; CI = 0.60 - 0.94; p < 0.0001). The direction of this relationship was maintained in subsequent punctures. CONCLUSION: The intracranial pressure measured by spinal tap manometry showed strong positive association with the N2 latency F-VEP in patients with cryptococcal meningitis.