Clinical Profile Of Lymphocytic Meningitis And Its Correlation With Prognostication Of Mortality

Clinical Profile Of Lymphocytic Meningitis And Its Correlation With Prognostication Of Mortality

 

Pooja Verma(1), Moti Lal(2), Atul Goel(3), Shilpi Agarwal(4)

 

(1)Senior resident, Department of Medicine, Lady Hardinge Medical College

(2)Professor, Department of Medicine, Lady Hardinge Medical College

(3)Director Professor, Department of Medicine, Lady Hardinge Medical College

(4)Director Professor, Department of Pathology, Lady Hardinge Medical College

 

Abstract

Background-Meningitis is defined as an inflammation of the meninges associated with an abnormal increase in the number of cells in the cerebrospinal fluid, lymphocytic meningitis is a laboratory finding in which cerebrospinal fluid should have more than 5 cells/HPF. This syndrome is associated with transient neurological symptoms in one-half of afflicted patients. Meningitis is one of the most common infectious diseases of the central nervous system (CNS), caused by various bacteria, viruses, fungi, and parasites. The present study evaluated the association of clinical profile of lymphocytic meningitis with mortality.

Methods- It is a prospective study conducted in departm­ent of Internal Medicine, Lady Hardinge Medical College and its associated Hospitals in New Delhi, India. We assessed clinical presentation of 50 patients and linked with mortality to evaluate significant associations. An informed written consent was obtained from all patients or relatives. Qualitative variables were correlated using Chi-Square test/Fisher’s exact test and analysis was done using Statistical Package for Social Sciences (SPSS) version 21.0.

Results- Mortality in patients of lymphocytic meningitis is associated significantly with the following clinical presentations, historically altered sensorium (p-0.020) and various co-morbidity like diabetes, hypertension, stroke (p-0.021), and on examination neck rigidity (p value<0.0001) and poor GCS at admission (p value<0.0001). 

Conclusion- The present study shows significant association of certain clinical presentation in patients of lymphocytic meningitis with mortality, which if known can be used to prognosticate the patients or relatives. To conclude, many factors do affect the outcomes in the patients of lymphocytic meningitis though larger studies need to be done in this field.

 

Keywords

Lymphocytic meningitis, neck rigidity, altered sensorium, comorbidity, prognosis

 

Introduction

Meningitis is defined as an inflammation of the meninges associated with an abnormal increase

in the number of cells in the cerebrospinal fluid [1]. Lymphocytic meningitis is a laboratory finding in which cerebrospinal fluid should have more than 5 cells/HPF and 60 per cent or more of these cells should be lymphocytes [2]. Meningitis has been classified based on time course, associated CSF profile, and underlying cause:

Acute meningitis is typically an isolated event that does not recur and occurs within days [3].

Chronic meningitis is arbitrarily defined as meningitis that persists for 4 or more weeks [4]. The classical triad of “fever, headache and neck rigidity” that occurs in 85% of patients in acute meningitis syndromes, is uncommon in those with chronic meningitis [5].

Meningitis is one of the most common infectious diseases of the central nervous system (CNS). Most cases of lymphocytic meningitis are caused by bacteria or viruses ; however fungi and parasites can also cause lymphocytic meningitis, especially in the immuno-compromised patients [6].

Rare causes of meningitis include autoimmune diseases, certain drugs and few malignancies like lymphoma. No racial differences are reported. Aseptic meningitis tends to occur more frequently in males than in females [2].

Tuberculous meningitis (TBM) is still one of the most common infections of central nervous system (CNS) and diagnosis of TBM can be made on basis of clinical presentation and CSF cytological, biochemical, culture, CSF-ADA, CSF AFB and CBNAAT [7]. In fungal causes, Cryptococcal meningitis (CM), caused by Cryptococcus neoformans, is a serious infectious disease of the CNS occurring in both immuno-compromised and immuno-competent patients [8, 9]. Other fungal causes like Candida can be detected on Gram stain [10]. Coccidioides infection can be detected using complement fixing antibody test in CSF which has 71-94% sensitivity [11]. Amongst viral meningitis most important viruses are enteroviruses, VZV, HSV-2>1, and others are EBV, HIV, mumps. Single most important method for diagnosing CNS viral infection is viral specific DNA/RNA from CSF using PCR amplification test. Early diagnosis and institution of appropriate therapy is important in improving the survival and to prevent adverse clinical outcomes. However, the early diagnosis is a problem because of the non-availability of specific investigations or poor yield of specific diagnostic techniques. This is problematic especially with CNS tuberculosis where specific diagnostic techniques may take up to 12 weeks. As clinical findings are also unreliable, the diagnosis relies on the examination of cerebrospinal fluid obtained from lumbar puncture. Delayed initiation of antibiotics can increase mortality. Treatment should be started promptly in cases where transfer, imaging, or lumbar puncture may slow a definitive diagnosis. Empiric antibiotics should be directed toward the most likely pathogens and should be adjusted by patient’s age and risk factors [12].

 

Methodology

The goal of this study is to describe evidence-based association between clinical presentation and short term outcomes of patients with lymphocytic meningitis. It is a prospective, descriptive hospital based study. 50 patients aged more than 15 years diagnosed with lymphocytic meningitis admitted in the department of internal medicine, LHMC and its associated hospitals, New Delhi, India from November, 1st 2017 to March, 31st 2019 were included in the study. An informed written consent was obtained from all patients or relatives. A detailed history was taken including past or current co-morbidities. A structured clinical examination and the laboratory investigation profile of the subjects was recorded on a predesigned Performa. All patients with clinical features of meningitis/ meningoencephalitis were enrolled. They all underwent a lumbar puncture for CSF analysis under aseptic precautions. Patients with lymphocytic pleocytosis were finally selected for the study.

Out of 86 patients with clinical features of meningoencephalitis, 50 with lymphocytic pleocytosis were selected for the study after voluntary and informed consent.

Categorical variables were presented in number and percentage (%) and continuous variables were presented as mean ± SD and median. Qualitative variables were correlated using Chi-Square test/Fisher’s exact test. A p value of <0.05 was considered statistically significant. The data was entered in MS EXCEL spreadsheet and analysis was done using Statistical Package for Social Sciences (SPSS) version 21.0.

 

Results

Out of 86 patients a total of 50 patients with lymphocytic meningitis were taken in the study. Age distribution of the study population varied from 15 years to 75 years.  The mean age was 39.34 ± 19.18 years. Maximum patients were seen in the age group of below 30 years (42%) followed by patients in the age group between 30 to 60 years (38%) and lowest number of patients were there in the age group more than 60 years (20%). Out of 50 cases 31 were males and 19 were females. Gender was not associated with any poor outcome in the present study.

Among 50 patients, fever was present in 33 patients (66%) and was absent in 17 patients (34%). In the present study population, vomiting was present in 19 patients (38%) and was not there in 31 patients (62%), neck rigidity was present in 14 patients (28%) and was absent in 36 patients (72%), 33 patients presented with altered sensorium at presentation and 17 were having normal sensorium, 26 had headache while 24 didn’t had any complaint of headache at the time of presentation, 12 (24%) patients had seizures at the time of presentation while rest 38 were not having seizures at the time of presentation, at the time of admission 9 patients had an evidence of focal neurological deficit (18%), in the study population. In the present study 41 (82%) patients had at least one of the features from the classic triad (fever, headache, and neck rigidity) and only 7 patients (14%) had the complete triad.

In the present study 60% (n=30) of the patients had their CSF lymphocyte count in the range 5-10 while 40% (n=20) had CSF lymphocyte count more than 10. It was observed that patients with CSF lymphocytes more than 10 were associated with poor outcome i.e. death, significantly (p-value=0.021). CSF lymphocytic counts, however were not observed to be associated with various other outcomes significantly.

In the present study 23 (46%) patients had an abnormal CT head finding at presentation while 27 (54%) had a normal CT scan. Out of 23 patients with abnormal CT head finding 8 had hydrocephalus, 5 had infarct, 5 had age related cerebral atrophy, 3 had granuloma, and 2 had cerebral edema.

In the present study, 22 patients were diagnosed with tubercular meningitis, 15 had viral meningitis, 7 had cryptococcal meningitis, 2 had cryptococcal and tubercular meningitis co-existing, 2 had neurocysticercosis, 1 had neuro-sarcoidosis, and 1 had progressive multifocal leukoencephalopathy in the setting of HIV. 

In the present study it was found that neck rigidity if present at the time of presentation then it is associated with poor clinical outcome (death, p value<0.0001). Amongst 14 patients presenting with neck rigidity, 8 died (57%) while in the sub group of patients without neck rigidity, 1 died (2.78%). (Table 1, Figure 1)

Similarly, altered sensorium was also significantly associated with poor outcome (p value=0.020) in the present study, out of 33 patients with altered sensorium 9 died, while out of 17 patients with normal sensorium none died. (Table 2, Figure 2) 

In the present study out of 50, 20 patients had one or another co-morbidity (diabetes mellitus, hypertension, stroke) at presentation along with meningitis while 30 had only lymphocytic meningitis. Patients with prior co- morbidity had a higher probability of a poor outcome which is death. Out of 20 patients with co-morbidity 7 (35%) died as compared to 2% of patients died in the sub group without any co-morbidity which had a significant p value (p value=0.021). (Table 3, Figure 3)

GCS at admission when poor, was found to be associated with poor outcomes such as death (p value<0.0001) and poor GCS at discharge (p value=0.0002). In patients with GCS < 9 (n=14) 9 were lost and 5 were discharged with improved GCS (9 to 14). (Table 4, Figure 4)

 

Discussion

The study was designed to investigate the likelihood of predetermining the mortality by analyzing a series of clinical symptoms at presentation, laboratory findings available and the etiology of lymphocytic meningitis if possible.  This is important in view of the prognostication of patients with lymphocytic meningitis.

In the present study, neck rigidity and death were associated positively and was significant, similarly altered sensorium at presentation was significantly associated with death.  It was also seen that the association between co-morbidity and poor outcome (i.e. death) was significant.  It was observed, poor GCS at admission was also significantly associated with death.

A study by Attia J et al [13] pooled results of 11 studies including 845 patients and showed that the classic triad of fever, neck rigidity, and headache was present in 46% of the patients while 99% had at least one feature.  In the present study also, 41 (82%) patients had at least one of the features from the classic triad and only 7 patients (14%) had the complete triad. This indicates that the classical triad of fever, neck pain and rigidity is absent in more than 50% patients of lymphocytic meningitis; and a diagnosis in such cases is to be based on a high index of suspicion, and at times one needs to perform CSF studies even in the absence of the classical triad of meningitis.

The results of present study, showed that the most common causative pathogen associated with lymphocytic meningitis is mycobacterium tuberculosis (48%), while a study by Kaminski M et al [14] in Germany showed that most common cause of aseptic meningitis was enteroviruses (36%). The differences in the two studies can be attributed to the fact that the present study was conducted in India, where the prevalence of tuberculosis is much higher.  Besides, India is a developing nation where other problems like overcrowding, poor hygiene, poor nutrition, and air-pollution favors transmission of infectious diseases like tuberculosis.

The present study found that presence of neck rigidity at the time of presentation was significantly associated with poor outcome i.e. death (p value <0.0001).  Three facts need to be further explored by more studies.  Firstly, neck rigidity as an independent prognostic factor in patients with lymphocytic meningitis.  Secondly, a comparison of neck rigidity as a symptom in patients with pyogenic meningitis vis-à-vis patients with lymphocytic choriomeningitis.  Thirdly, whether the classification of CNS infections (especially lymphocytic meningitis) needs to be re-looked at with reference to presence or absence of neck-rigidity; which may not be present in every case and hence should not be the determining factor in the requirement for a lumbar puncture in patients with suspected CNS infections of chronic variety i.e. >4 weeks.

Durand ML et al [15] reviewed patients with bacterial meningitis and found that three factors were associated with a significantly higher overall mortality rate among patients with single episodes of community-acquired meningitis: an age of 60 years or more (mortality rate, 37 percent vs. 17 percent for patients < 60 years of age; P < 0.001); obtunded mental state on admission (49 percent among patients who were unresponsive or responsive only to pain vs. 16 percent among those normally alert or lethargic, P < 0.001); and onset of seizures within 24 hours of admission (72 percent vs. 18 percent among those without early-onset seizures, P < 0.001).  Although, again not strictly comparable, this was consistent with the results in the present study, in which altered mental status at admission was found to be associated with significantly higher mortality (p-value = 0.0001) in patients with lymphocytic meningitis.  It is suggested that larger studies should be designed to analyze the association of mortality and outcomes with various factors in patients with lymphocytic meningitis.

Hodges GR [16] reviewed 349 cases of acute bacterial meningitis, during a 25-year period (1949-1973), to determine the prognostic significance of initial historical, physical and laboratory findings. A poor prognosis was associated with age greater than or equal to 40 years (p < 0.01), presence of predisposing illness (p < 0.01), associated illness (p < 0.01), absence of nuchal rigidity (p < 0.05), and derangement of cerebral function (p < 0.01).  Similarly, in the present study it was found, that the presence of co-morbidity (diabetes mellitus, hypertension, stroke) is a significant poor prognostic factor for poor outcome i.e. death (p-value = 0.021).

Interestingly, to the best of our knowledge there is little published data to date with respect to predetermination of mortality of lymphocytic meningitis through the use of clinical or laboratory findings.  This is perhaps due to the fact that till some years back all patients with predominantly acute lymphocytic meningitis were often considered viral while those with chronic lymphocytic meningitis were treated as tubercular meningitis.  The availability of rapid diagnostic methods in tuberculosis is perhaps altering our interpretation of lymphocytic meningitis.  However, the availability of specific viral studies still continues to hamper complete understanding of such cases especially in developing nations. 

 

Bibliography

  1. Conly JM, Ronald AR. Cerebrospinal fluid as a diagnostic body fluid. Am J Med. 1983 28;75 :102-8.
  2. de Almeida SM, Nogueira MB, Raboni SM, Vidal LR .Laboratorial diagnosis of lymphocytic meningitis. Braz J Infect Dis. 2007 ;11(5):489-95.
  3. Coyle PK. Overview of acute and chronic meningitis. Neurol Clin. 1999 ;17(4):691-710. 
  4. Anderson NE, Willoughby EW. Chronic meningitis without predisposing illness–a review of 83 cases. Q J Med. 1987 ; 63(240):283-95.
  5. Koski R R, Loo D V, Etiology and Management of Chronic Meningitis. US Pharm. 2010;35(1):HS-2-HS-8.
  6. Sulaiman T, Salazar L, Hasbun R Acute versus subacute community acquired meningitis: Analysis of 611 patients. Medicine (Baltimore). 2017;96(36):e7984.
  7. Rock RB, Olin M, Baker CA, Molitor TW, Peterson PK, Central nervous system tuberculosis: pathogenesis and clinical aspects. Clin Microbiol Rev. 2008 ;21(2):243-61, table of contents.
  8. Tsai WC, Lien CY, Lee JJ, Lin WC, Hsu CW, Huang CR, et al. The prognostic factors of HIV-negative adult cryptococcal meningitis with a focus on cranial MRI-based neuroimaging findings. J Clin Neurosci. 2018; 55:57-61.
  9. Lin YY, Shiau S, Fang CT. Risk factors for invasive Cryptococcus neoformans diseases: a case-control study. PLoS One. 2015; 10(3):e0119090.
  10. Rex JH, Walsh TJ, Sobel JD, Filler SG, Pappas PG, Dismukes WE, et al. Practice guidelines for the treatment of candidiasis. Infectious Diseases Society of America. Clin Infect Dis. 2000; 30(4):662-78. Epub 2000 Apr 20.
  11. Zunt JR, Baldwin KJ. Chronic and subacute meningitis. Continuum (Minneap Minn). 2012 ;18(6 Infectious Disease):1290-318.
  12. Mount HR, Boyle SD. Aseptic and Bacterial Meningitis: Evaluation, Treatment, and Prevention. Am Fam Physician. 2017 Sep 1;96(5):314-322.
  13. Attia J, Hatala R, Cook DJ, Wong JG. The rational clinical examination. Does this adult patient have acute meningitis? Jama. 1999 Jul 14; 282(2):175-81.
  14. Kaminski M, Grummel V, Hoffmann D, Berthele A, Hemmer B. The spectrum of aseptic central nervous system infections in southern Germany – demographic, clinical and laboratory findings. Eur J Neurol. 2017 ;24(8):1062-1070.
  15. Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS Jr, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med. 1993 Jan 7;328(1):21-8.
  16. Hodges GR, Perkins RL. Acute bacterial meningitis: an analysis of factors influencing prognosis. Am J Med Sci. 1975 Nov-Dec; 270(3):427-40.