Meningitis, an inflammation of the protective membranes that surround the brain and spinal cord, is a serious global health problem. It usually presents with fever, severe headache, stiff neck and disoriented mental status, and is especially a life-threatening condition in vulnerable groups such as under 5s and over 60s [1]. In Pakistan and the rest of the South Asian region, meningitis is a significant burden of disease, exacerbated by social and economic factors, poor health services and inconsistent immunization rates.

However, the prevalence of bacterial meningitis in Pakistan is estimated to be 15% and is seen disproportionately in hospitalized children [3]. Tuberculous meningitis is responsible for about 42% of the deaths from meningitis among hospitalised patients [4]. Importantly, the risk of death rises up to 8.4 times if antibiotics are not given within the first 4 to 6 hours of onset of symptoms, highlighting the need for timely and accurate diagnosis [6].

Long-term neurologic sequelae of meningitis can occur if the disease goes untreated or is poorly managed, and can include sensorineural hearing loss, cognitive impairments, and epilepsy [7]. Neuroimaging has become an essential diagnostic tool, in addition to cerebrospinal fluid (CSF) analysis. Although computed tomography (CT) with contrast enhancement will identify meningeal enhancement and complications, MRI has the advantage of better soft-tissue contrast resolution, not to mention the lack of interfering bone artifact effects [8].

The standard imaging modality for intracranial infections has been contrast enhanced T1-weighted (CE-T1WI) MRI sequence [9]. But recent studies indicate that the use of contrast enhanced T2 Fluid-Attenuated Inversion Recovery (CE-T2 FLAIR) sequences might provide better sensitivity and specificity in the detection of meningeal enhancement. Previous reports suggest that CE-T2 FLAIR has high sensitivity (up to 97.6%) and specificity (85.8%) compared to CE-T1WI (92.8% sensitivity; 75% specificity) [10-12]. The FLAIR T2 images are superior regarding contrast as T1-shortening effects are present at lower gadolinium doses, and as a result of the T2 effects at higher gadolinium concentrations, the meninges are better seen while the CSF signal is suppressed [11].

Given the high prevalence and grave consequences of meningitis in Pakistan and other regional settings, the aim of this study is to compare the diagnostic accuracy of CE-T2 FLAIR vs CE-T1WI MRI sequence in the diagnosis of infective meningitis against the CSF analysis. If CE-T2 FLAIR is shown to be superior as a diagnostic tool this may lead to substantial changes in clinical imaging strategies, and ultimately, patient outcomes

LITERATURE REVIEW

Epidemiology and Clinical Presentation

Acute meningitis is a potentially fatal infection with a high mortality rate and many long-term morbidity consequences. Despite improvements in both diagnosis and treatment, there is about a 30% case-fatality rate for pneumococcal disease and 5-10% case-fatality rate for meningococcal disease [15]. Initiation of therapy with dexamethasone and appropriate antibiotics, preferably within 1 hour of clinical suspicion of the disease, is significantly associated with better outcomes [16].

Although specific, the classic triad of fever, stiffened neck and altered mental status alone is not sensitive enough to reliably diagnose meningitis, as one or more of these symptoms may not be present in a large proportion of cases [17]. Meningitis may develop an influenza-like prodrome and/or a petechial/purpuric rash particularly during epidemics [18]. Risk factors for pneumococcal meningitis include otitis media, sinusitis, cochlear implants, asplenia, HIV and immunocompromising diseases [19]. In adults over 50 years of age, and those with an immune deficiency, Listeria monocytogenes should be suspected [20].

Viral meningitis is usually self-limited, and usually associated with enteroviruses, although HSV and VZV etiology should be treated with antivirals [21]. For cases of aseptic meningitis, tuberculous or cryptococcal, or other atypical causes should be considered, especially in immunocompromised patients or in patients from endemic areas [22-24].

Diagnostic Approach and CSF Analysis

The gold standard for diagnosis of meningitis and the causative organism is CSF analysis by lumbar puncture (LP). LP is generally safe, and should be performed promptly in patients without contraindications, and in most cases, without awaiting CT as pre-LP CT scanning delays treatment and rarely changes management [26-28]. CSF parameters such as opening pressure, white cell count (and differential), protein, glucose, Gram stain, and culture are important for diagnosis. If the neutrophilic pleocytosis is >1000 cells/µL, this is more likely to be of bacterial origin, whereas a lymphocytic predominance and a normal glucose strongly suggests viral meningitis [33,34].

Prior to antibiotic treatment, the culture sensitivity is 60-90%, which drops significantly after treatment. PCR based tests are highly specific and sensitive, and are less affected by prior antibiotic treatment, but availability is variable [35]. Procalcitonin in serum and lactate in CSF (cut-off ≥3.9 mmol/L) can be valuable adjuncts in differentiating bacterial from non-bacterial meningitis [34].

Neuroimaging in Meningitis

Neuroimaging is an integral part of the diagnostic evaluation of suspected meningitis and is useful for visualizing meningeal inflammation, evaluating for complications, and excluding other etiologies of headache [36]. In meningitis, infected material may be present in either or all of the meninges (dura, arachnoid, and pia mater) and in the epidural, subdural, and subarachnoid spaces [37].

MRI is more sensitive than CT for the detection of meningitis, and can demonstrate abnormalities in basal cisterns, in the sylvian fissures and in sulcal spaces [46]. For years, meningeal enhancement on post-contrast T1 weighted imaging has been the key imaging sign of meningeal disease. However, inflow effects, vascular signal contamination and flat contrast are issues associated with CE-T1WI, which can make the detection of subtle meningeal enhancement difficult [48].

However, CE-T2 FLAIR has several advantages over it as it suppresses CSF signals and slow-flowing vascular artifacts, as well as being highly T2-weighted with long echo times, which help to distinguish inflamed meninges from adjacent cortical tissue [48,49]. The sequence is especially useful in identification of subtle or early meningeal enhancement and also helpful in the identification of parenchymal infection, demyelination, or metastatic disease [49]. Post processing including subtraction imaging between pre- and post-contrast FLAIR further enhances the sensitivity, but introduces motion and pulsation artefacts that must be corrected using advanced algorithms [50].

Artifacts that are sensitive to CSF pulsation in the posterior fossa, relative hyperintensities in non-infectious conditions such as subarachnoid hemorrhage, and decreased sensitivity in infants as a result of non-myelinated white matter are limitations of CE-T2 FLAIR. Newer sequences are available (black blood T1, 3D T1-SPACE), these sequences have complementary advantages, but the CE-T2 FLAIR is generally superior for basal cistern and cerebellar folia enhancement [50].

Study Design and Setting The cross sectional study was carried out in the Department of Radiology, Mayo Hospital, Lahore, Pakistan for a period of six months from the approval of synopsis in the institution. Ethical clearance has been provided by the relevant institutional review board before the data collection process has started. Sample Size and Sampling A sample size of 60 patients was determined, with a 95% confidence interval, 10% margin of error and an estimated incidence of 15% for patients with meningitis. The sample size calculation was based on the estimates of sensitivity and specificity for MRI (95% and 85.71%, respectively) as compared with CSF analysis as the gold standard [51]. Non-probability sampling method was used which was convenient sampling. Inclusion and exclusion criteria Eligible for participation were patients of either sex (ages newborn to 70 years) who had clinical suspicion of meningitis (defined as two or more of the following: neck stiffness, fever > 102°F, tonic-clonic seizures, visual disturbance). Confirmatory meningitis on FLAIR MRI required enhancement in at least two of the following structures: sulci, cisterns, ventricles or meninges. CSF positivity was determined based on the presence of cells >15/3.2 nL (or >2/3.2 nL eosin-hematoxylin-stained CSF) or total protein >0.45 g/L or CSF glucose <0.5 mmol/L. Patients were excluded if they were sensitive to gadolinium, had received antibiotics at least once in the previous week, papilledema on ophthalmoscopy, spinal surgery or LP in the previous month, or had implants or devices which were incompatible with MRI. All patients and/or blood relatives provided written informed consent. Imaging Protocol Initial clinical evaluation and non-contrast MRI of brain was performed in all patients. Then, CE-T2 FLAIR and CE-T1WI were obtained with the use of gadolinium-based contrast agents. MRI was assessed to look for and the type of meningeal enhancement. All imaging was carried out and reported by trained and experienced radiologists who were not aware of the CSF results. CSF Analysis In eligible patients, lumbar puncture was performed after the acquisition of MRI. The CSF was tested for cell count and differential, protein, glucose, Gram stain and microbiological cultures, in addition to its opening pressure. CSF results were used as the reference standard for the diagnosis of meningitis. Data Analysis The IBM SPSS Statistics 26 was used for data analysis. The demographics, clinical parameters and imaging data of the patients were summarized using descriptive statistics. Analysis of continuous variables was presented as mean ± SD, while analysis of categorical variables were presented as frequencies and percentages. The sensitivity, specificity, PPV, NPV and overall accuracy were determined for both CE-T2 FLAIR and CE-T1WI, and compared to CSF analysis. P value less than 0.05 was considered as statistically significant.

Patient Demographics

The study enrolled 60 patients with a mean age of 44.98 ± 15.11 years (range: 20-70 years). Male patients constituted 60% (n=36) and female patients 40% (n=24) of the cohort.

Table 1. Age Distribution of Patients

Table 2. Gender Distribution of Patients

CSF Findings

CSF analysis confirmed meningitis in 26 patients (43.33%), while 34 patients (56.67%) had negative CSF findings.

Table 3. CSF Findings of Patients

Imaging Findings

CE-T2 FLAIR identified meningeal enhancement in 31 patients (51.67%), while CE-T1WI detected enhancement in 23 patients (38.33%).

          Table 4. CE-T2 FLAIR and CE-T1WI Imaging Findings

Diagnostic Accuracy of CE-T2 FLAIR

CE-T2 FLAIR demonstrated excellent diagnostic performance against CSF analysis. The 2x2 contingency table shows 25 true positives, 28 true negatives, 6 false positives, and 1 false negative. Sensitivity was 96.15% (95% CI: 81.11-99.32), specificity 82.35% (95% CI: 66.49-91.65), PPV 80.65% (95% CI: 63.72-90.81), NPV 96.55% (95% CI: 82.82-99.39), and overall diagnostic accuracy 88.33% (95% CI: 77.82-94.23).

Table 5. Diagnostic Accuracy of CE-T2 FLAIR vs. CSF Analysis (Gold Standard)

Table 6. CE-T2 FLAIR Diagnostic Parameters

Diagnostic Accuracy of CE-T1WI

CE-T1WI demonstrated moderate diagnostic performance. The 2x2 contingency table shows 18 true positives, 29 true negatives, 5 false positives, and 8 false negatives. Sensitivity was 69.23% (95% CI: 50.01-83.50), specificity 85.29% (95% CI: 69.87-93.55), PPV 78.26% (95% CI: 58.10-90.34), NPV 78.38% (95% CI: 62.80-88.61), and overall diagnostic accuracy 78.33% (95% CI: 66.38-86.88).

Table 7. Diagnostic Accuracy of CE-T1WI vs. CSF Analysis (Gold Standard)

Table 8. CE-T1WI Diagnostic Parameters

We assessed the comparative diagnostic value of CE-T2 FLAIR and CE-T1WI MRI sequences in the diagnosis of infective meningitis in this study, using CSF analysis as a reference standard. The mean age of 44.98 years of our patients is lower than the mean age of 57 years in Finland and 58 years in Lithuania, which is related to geographical and demographic differences in disease epidemiology [52,53]. We have similar results to a local study conducted in Lahore that found the mean age of patients to be around 40 years and a study in Qatar that found a similar profile of patient [55].

There was a male predominance in our study (60%), similar to that in Lithuania (62.79%) and Nairobi (54.6%) and overall in the world of the slight male predominance in adult bacterial meningitis [52-54]. The CSF positivity rate in our cohort was 43.33% which is lower than 74.42% reported by Abro et al., but higher than Singh et al. who reported CSF positivity rate as 9.01% in a large North Indian series, showing significant variation between different geographic and clinical settings [56,57]. Such differences are probably related to variations in the rate of antibiotic pre-treatment, to variations in patient selection, to different laboratory methods, and to different endemic pathogen distributions.

This study shows that the sensitivity of CE-T2 FLAIR (96.15%) in the detection of meningeal enhancement is significantly greater than that of CE-T1WI (69.23%) in infective meningitis. The overall diagnostic accuracy of CE-T2 FLAIR (88.33%) was statistically significant vs CE-T1WI (78.33%). These findings are quite similar to the results of Kamr et al., and Khalid et al., who found the sensitivity of CE-T2 FLAIR as 91-95% and specificity as 82-100% [3,60]. Likewise, Dechasasawat et al. found a sensitivity of 97.6% and specificity of 85.8% in CE-T2 FLAIR interpretations, which is very similar to our results [10]. This lower sensitivity of CE-T1WI seen in our study is similar to previous studies by Sanjay et al. (57-73%) and Jawwad et al. (68-79%) [61,62].

Mechanistically, the excellent properties of CE-T2 FLAIR are due to its ability to suppress CSF and slow flowing vascular artefacts, thus improving the contrast between inflamed meninges and surrounding cortical structures. This can help identify subtle or early meningeal enhancement that may be missed with CE-T1WI sequences [13]. Using lower gadolinium concentrations causes a T1 shortening effect, which increases contrast in abnormal meninges, and has T2 effects at higher concentrations that effectively null background CSF signal [64]. By contrast, CE-T1WI images are limited by the presence of much more vascular signal, inflow artifacts and relatively poor contrast which may make the diagnosis of meningeal pathology difficult in early or subtle cases [48].

A high NPV of CE-T2 FLAIR (96.55%) is of specific clinical importance, because it means that a negative CE-T2 FLAIR scan can strongly rule out meningitis. This study lends credence to its usefulness as a screening tool in patients with uncertain clinical presentations and may help to limit the need for invasive LP in certain cases. In contrast, the relatively low NPV of CE-T1WI (78.38%) suggests that there is a significant false-negative rate, which is problematic in a condition with a high risk of mortality if not diagnosed promptly.

A few constraints of this research should be recognized. First, CSF analysis is the reference standard, but it is standard practice and the culture sensitivity is reduced after pre-treatment with antibiotics, which may affect the correlation with imaging findings. Second, there was no inter-observer variability analysis of MRI interpretation, which may impact the imaging results. Third, the majority of the patients were adults, and thus the applicability of the findings in the pediatric setting is unclear because of incomplete myelination and different enhancement patterns of the meninges on FLAIR. Subtraction imaging, T1-SPACE and black-blood techniques were also not used, which might have helped in the detection and characterization of meningeal disease further., 

When measured against CSF analysis, CE-T2 FLAIR has a much higher sensitivity and overall diagnostic accuracy than CE-T1WI in diagnosis of infective meningitis. The high sensitivity (96.15%) and negative predictive value (96.55%) of CE-T2 FLAIR shows that it may be the sequence of choice for MRI meningeal evaluation. We suggest using CE-T2 FLAIR routinely as part of regular MRI brain examinations for all patients with suspected meningitis. Though CE-T1WI has utility as a well-known complementary sequence especially considering its similar specificity, relatively lower sensitivity suggests the danger of diagnostic misclassification using only CE-T1WI. Implementation of CE-T2 FLAIR in clinical MRI practice could be useful to ensure early and accurate diagnosis of meningeal inflammation and to help improve patient outcomes in this life-threatening disease

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