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clinmed/2000060004v1 (December 29, 2000)
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Original Article

INTRATHECAL IMMUNOGLOBULIN PRODUCTION IN CASES OF CHILDHOOD BACTERIAL MENINGITIS

Abbreviated Title:

INTRATHECAL Ig PRODUCTION OF BACTERIAL MENINGITIS*

* This study was presented at European Society of Chemotherapy Infectious Diseases 6th Scientific Meeting (May 20-22, 1999 - Istanbul).

1 Ismail H. KARA, MD.
2 Bünyamin DIKICI, MD.
2 Mehmet BOSNAK, MD.
3 Fuat GüRKAN, MD.
4 Kenan HASPOLAT, M.D.

1 Assist. Prof. in Department of Family Medicine, 2 Resident in Department of Pediatrics, 3 Assist. Prof. in Department of Pediatrics, 4 Prof., Head of Department of Pediatrics, Dicle University, School of Medicine, Diyarbakir, TURKEY

Corresponding Address: Ismail H. KARA, M.D.,
Dicle Üniversitesi Tip Fakültesi, Aile Hekimligi ABD.
21280 Diyarbakir / TURKEY
Call: +90 412 2488074 (hospital)
Fax: +90 412 2488074
E-mail: ihkara13{at}hotmail.com

 

Abstract

Objectives: The aim of this study was to evaluate the IgG, IgM and IgE indices of different types of childhood’s bacterial meningitis.

Methods: This prospective cohort study was performed in Dicle University, Paediatric Clinic of Medical Faculty between August 1996 and February 1997. There were 18 patients with bacterial meningitis including eight patients with meningococcal meningitis (MM), five patients with purulent (PM) and five patients with tuberculous (TBM) in the studied group. The diagnosis was confirmed by bacteriologic examination (cultures and gram’s stain), clinical, physical, and laboratory examination and was supported by computed tomography (CT). IgG index was calculated by formula of Link and Tibbling (IgG ratio/albumin ratio of CSF to serum).

Results: Age of patients ranged between 11 and 156 months with a mean of 65±49 months. One of patients with TBM was exitus; shunting operation was performed to three of the rest. Neurological sequelae developed in all patients with TBM, and in 2 patients with PM. Temporary visual impairment was determined in only one patient with MM. The mean IgG, IgM and IgE indices in our cases with TBM were 1.2, 0.8 and 6.9, respectively. The mean CSF IgG and CSF IgE indices were slightly higher in patients with TBM than in other subjects (p<0.01 and p=0.01, respectively). CSF of patients with PM showed significantly high titres of circulating IgE antibodies than in other subjects (p=0.001).

Conclusions: The patients with CNS inflammation, especially TBM, had elevated IgG and IgE indices compared to other groups. BBB (brain-blood barrier) damage was most severe in cases of TBM in our series. Moreover, CSF of patients with PM showed significantly high titres of circulating IgE antibodies than in other subjects.

Key words: Blood-brain barrier, IgG, IgM and IgE indices, meningitis.

 

INTRODUCTION

Meningitis is an infection of the subarachnoid space and leptomeninges caused by a variety of pathogenic organisms. Granulomatous meningitis and bacterial meningitis are the most important forms in the world-wide in terms of incidence, sequelae, and ultimate loss of productive life (1-3). Frequency of granulomatous meningitis caused by M. tuberculosis has been reported as 0.74 % in Southeast Anatolian region and 0.38 % in general of Turkey (4).

Most viral and bacterial infections of the central nervous system (CNS) are associated with intrathecal synthesis of antibody (5). Cerebrospinal fluid (CSF) protein concentration is usually elevated, in the range of 100 to 500 mg/dl, but as elevated protein reflects alteration in the blood-brain barrier (BBB). Elevations in CSF Ig may occur as a result of breakdown in the blood-brain barrier (6,7).

As a general rule, once the diagnosis of meningitis is suspected, immediate examination of the CSF is indicated. A number of tests measuring levels of various CSF proteins, enzymes, and mediators have been proposed as potential discriminators between viral and bacterial meningitis. One of them is CSF/serum antibody index, which can be calculated using the following formula of Tibbling and Link (5). Normal CSF IgG index is lower than 0.7 units, but it was elevated in some conditions (meningitis, parainfectious encephalomyelitis, neoplasm and demyelinating disease). The CSF/serum antibody index is useful when there is CNS inflammation (8-11).

The aim of this study was to evaluate the IgG, IgM and IgE indices of different types of childhood’s bacterial meningitis.

Patients and Methods

This prospective cohort study was performed in Dicle University, Paediatric Clinic of Medical Faculty, between August 1996 and February 1997.

18 patients with bacterial meningitis including eight patients with meningococcal meningitis (MM), five patients with purulent meningitis (PM) and five patients with tuberculous meningitis (TBM) were enrolled in study. CSF and serum Ig levels of patients were obtained at the first day of hospitalisation. The diagnosis was confirmed by bacteriologic examination (cultures and gram’s stain), clinical, physical, and laboratory examination and was supported by computed tomography (CT). Criteria for exclusion from the study: one of the following, parainfectious encephalomyelitis, neoplasm and demyelinating disease, juvenile rheumatoid arthritis, and other collagen diseases, and immunodeficiency syndromes.

Case definition of CNC Tuberculosis by either microbiologic or clinical criteria (8):

A. Microbiologic case definition. One of the following:

1. Isolation of M. tuberculosis from CSF.
2. Abnormal neurologic signs and symptoms, CSF, or cranial CT consistent with CNS tuberculosis, and isolation of M. tuberculosis from any site.

B. Clinical case definition. Abnormal neurologic signs and/or symptoms, and 2 or more of the following:

1. Discovery of adult source case with contagious tuberculosis who had significant contact with child.
2. *Presence of Mantoux (5 YU) skin test reaction >= 10 mm of induration, or >= 5 mm of induration if child had close contact with infected adult. *(>= 15 mm of induration was considered positive for children with BCG. BCG is in routine immunisation programme in Turkey).
3. CSF abnormalities without evidence of other infectious cause.
4. Abnormalities on cranial CT consistent with CNS tuberculosis.

Enzymun-Test (Boehringer Mannheim Immunodiagnostics ES 700 etc.) by Nephelometer (Behring 100 Analyser-Germany) was used to measure the Ig levels. Immunoglobulin indices were calculated by formula of Link and Tibbling (5). IgG index was calculated as (IgG ratio/albumin ratio of CSF to serum). CSF IgM index was calculated as (IgM ratio/albumin ratio of CSF to serum), and CSF IgE index was calculated as (IgE ratio/albumin ratio of CSF to serum).

Informed consent was obtained from parents of the study patients, and the ethical committee approved the research protocol.

SPSS/PC 7.5 program was used for statistical analysis. Kruskal-Wallis 1-Way Anova, (Mann-Whitney U test was used to compare of two independent samples) Spearman R, and chi-square tests were used for data analysis. Statistical significance was defined as p<0.05. The results are expressed as mean ±SD.

Results

The demographic and clinico-laboratory characteristics of patients by meningitis types were summarised in table 1. The ages of patients ranged between 11 and 156 months with a mean of 65±49 months. The mean duration of hospitalisation of patients was 15±17 (8-80) days. This duration was significantly higher in patients with TBM than in other patients (p=0.01).

Meningitis groups in figure 1 showed the mean IgG, IgM and IgE indices. CSF of patients with TBM showed high titres of circulating IgG and IgM antibodies, and the mean CSF IgG and CSF IgE indices are higher in patients with TBM than in other subjects (respectively, p<0.01 and p=0.01). CSF of patients with PM showed high titres of circulating IgE antibodies than in other subjects, and it was statistically significant (p=0.001).

There were statistically significant differences in only the mean CSF white cell count Per mm3 and lenfocytes Percent among meningitis groups (p=0.008 and p=0.04, respectively). There were no statistically significant differences in the clinical findings reflecting meningitis as fever, headache, vomiting, convulsion, stiff neck, meningeal irritation and Babinski sign except petechiae / ecchymoses among meningitis groups. Allergic reaction was developed against to isoniasid in only a case with TBM (table 2).

CT revealed 3rd and 4th ventricle dilatation, cortical atrophy, and periventricular hypodens areas in 3 of 5 cases with TBM. However, CT revealed 3rd and 4th ventricle dilatation in one case, and periventricular hypodens areas in another case with PM. Tomographic findings were normal in all patients with MM, in one patient with TBM and in three patients with PM.

After discharge, our patients were monthly controlled in pediatric outpatients clinic. One of patients with TBM died, and shunting operation was performed to three of the rest. Neurological sequelae developed in all patients with TBM and in two of patients with PM. Temporary visual impairment was determined in only one case with MM.

 

DISCUSSION

Meningitis due to N. meningitides is most often encountered in children and young adults and may occur in epidemics. At least 30 countries worldwide, including United States, have reported serious outbreaks of MM in resent years (9). Individuals with MM without overwhelming meningococcemia have a case fatality rate of only 3% (1). We did not observed to the morbid sequelae in any patients with MM.

Hong R (2) reported that levels of CSF IgG and IgM in patients with PM were 9 mg/dl, and 4 mg/dl. But, in our study, the levels of CSFs IgG, and IgM in patients with PM were 19 mg/dl, and 2.6 mg/dl, respectively (table 1).

Hung KL et al (5,6) reported that they evaluated the BBB function in childhood CNS infections, using CSF in 74 patients including 34 cases with aseptic meningitis, 24 with encephalitis and 16 with PM. They suggested that the quantitation of IgG and other derivatives in CSF might have given a sensitive supplementary reference for the detection of CNS infection and the patients with encephalitis, especially chronic encephalitis, had a selectively elevated IgG index compared to other groups. But, BBB damage was most severe in cases of PM in that series.

Tipold A et al (12) performed an experimental study and reported that a surprisingly high number of animals with encephalitis, including dogs with protracted diseases such as chronic distemper encephalitis and granulomatous meningoencephalomyelitis, showed an elevated IgG production with an additional evidence of intrathecal IgM and IgA production.

Forsberg et al (13) stated that 11 patients with bacterial meningitis, all had an increased CSF IgM index, (CSF/serum IgM):(CSF/serum albumin), indicating intrathecal IgM production. Seven patients had a slightly increased CSF IgG index, and 7 a slightly increased IgA index.

Mathai A et al (14) reported that CSF of patients with TBM showed high titres of circulating antimycobacterial antibodies than in nontuberculous subjects. The CSF IgG index was found to be significantly higher in patients with TBM. In cases with multiple sclerosis and various infections of the CNS (TBM, etc.), the mean IgG and IgE indices were reported as 0.45 and 0.29, respectively (15).

The mean IgG, IgM and IgE indices in all our cases with meningitis were 0.7, 0.6 and 4.9 units, respectively. The mean IgG index of our cases with TBM, PM and MM was 1.2, 0.6 and 0.4 units (p<0.01), respectively (Figure 1). However, it has been suggested that most patients with TBM had clearly an increased IgE index suggesting a local biosynthesis (15), but we failed to detect high levels of IgE in the CSF and increased IgE indices in patients with TBM. In contrast, we detected significantly higher levels of IgE in the CSF in patients with PM (p=0.001), but IgE index was not significantly higher (p>0.05). We found statistically significant difference in the mean IgG and IgE indices between TBM and other bacterial meningitis (respectively, p<0.01 and p=0.01), (Figure 1).

The CT scans is useful to demonstrate the presence or absence of focal intracranial suppurative collections, subdural effusions, or progressive ventricular enlargement that may require shunt surgery. Certain findings of CT scan, such as evidence of diffuse microcytic degeneration with associated cortical atrophy or infarctional patterns can be prognostic (1). CT revealed 3rd and 4th ventricle dilatation, cortical atrophy, and periventricular hypodens areas in 3 of 5 cases with TBM. However, CT revealed 3rd and 4th ventricle dilatation in only one case, and periventricular hypodens areas in another case with PM.

Focal motor and sensory deficits, visual impairment, hearing loss, seizures, hydrocephalus, and a variety of cranial nerve deficits can result from meningitis. The immune and inflammatory response in the brain to certain pathogens such as M. tuberculosis may be responsible for much of the morbidity of this disease in that organ system (3,9). In our study, fever, vomiting, Babinski sign and stiff neck were found in almost all patients (p>0.05), nevertheless, Petechiae/ecchymoses were found only in patients with MM (p<0.0001). There were not statistically significant differences in neurological examination findings of patients between groups. After discharge, patients were monthly controlled in pediatric outpatients clinic. After six months follow up, one patient with TBM died, in three of five patients were performed shunting operation because of hydrocephalus. Neurological sequelae developed in all survived patients with TBM and in two patients with PM. There was statistically significant difference in sequelae rate between TBM group and other groups (X2=9.59, df=2, p=0.008).

As a conclusion, the patients with CNS inflammation, especially TBM, had elevated IgG and IgE indices compared to other groups. These results showed that BBB damage was most severe in cases of TBM in our series. In other hand, CSF of patients with PM showed significantly high titres of circulating IgE antibodies than in other subjects.

 

REFERENCES

1. Tureen J. Meningitis. In: Rudolph AM, ed. Rudolph's pediatrics. 19th ed. Connecticut: Appleton & Lange, 1991: 559-93.

2. Hong R. Immunity, allergy, and diseases of inflammation. In: Behrman RE, Kliegman RM, Nelson WE, eds. Nelson Textbook of Pediatrics. Pennsylvania: WB Saunders, 1992: 545-57.

3. Moe PG, Seay AR. Neurologic and muscular disorders. In: Hathaway WE, Hay WW, Groothuis JR, Paisley JW, eds. Current Paediatric Diagnosis And Treatment. 11th ed. Lebanon: Appleton and Lange, 1993: 675-732.

4. Kibaroglu E. Tüberküloz epidemiyolojisi. Katki Dergisi 1992; 13: 9-12.

5. Hung KL, Chen WC, Huang CS. Diagnostic value of cerebrospinal fluid immunoglobulin G (IgG) in pediatric neurological diseases. J Formos Med Assoc 1991; 90: 1055-9.

6. Hung KL, Tsai ML, Chen WC. Blood-brain barrier damage in children with central nervous system infections. J Formos Med Assoc 1995; 94: 458-62.

7. Kinnman J, Kam-Hansen S, Link H, Norrby E. Studies on the humoral and cell-mediated immune response in a patient with Mollaret's meningitis. J Neurol Sci 1979; 43: 265-75.

8. Doerr CA, Starke JR, Ong LT. Clinical and public health aspects of tuberculous meningitis in children. J Pediatr 1995; 127: 27-33.

9. Scheld WM. Bacterial meningitis, brain abscess, and other suppurative intracranial infections. In: Fauci AS, Braunwald E, Isselbacher KJ, et al., eds. Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Co., 1998: 2419-2451.

10. El-Mallakh RS. CSF evaluation in neurologic disease. Am Fam Physician, 1987; 35: 112-8.

11. Roberg M, Forsberg P, Tegnell A, Ekerfeldt K. Intrathecal production of specific IgA antibodies in CNS infections. J Neurol 1995; 242: 390-7.

12. Tipold A, Pfister H, Zurbriggen A, Vandevelde M. Intrathecal synthesis of major immunoglobulin classes in inflammatory diseases of the canine CNS. Vet Immunol Immunopathol 1994; 42: 149-59.

13. Forsberg P, Frydén A, Link H. Immunoglobulin abnormalities in the cerebrospinal fluid during bacterial meningitis. J Neuroimmunol 1986; 12: 299-310.

14. Mathai A, Radha Krishnan VV. Humoral immune reactions in tuberculous meningitis. Indian J Med Sci 1991; 45: 233-56.

15. Sindic CJ, Magnusson CG, Laterre EC, Masson PL. IgE in the cerebrospinal fluid. J Neuroimmunol 1984; 6: 319-24.

 

 

Table 1. The demographic and clinico-laboratory features of patients by meningitis types.

 

Variable (Mean± SD)

TBM (n=5)

PM (n=5)

MM (n=8)

p

AGE (mo)

60±54

58±50

72±44

NS

Hospitalisation Time (Day)

28±30*

11±3

9±1

=0.01

Blood Leukocytes /mm3

6.900±8.700

16.100±10.100

19.500±7.000

NS

Blood PNL/mm3

8.800±6.000

12.000±9.800

13.400±4.600

NS

ESR mm/hours

48±26

54±34

42±24

NS

CSF cells/mm3

34±35*

940±134

680±450

=0.008

Lenfocytes in Frotti %

75±30*

30±30

15±10

=0.04

CSF PNL %/mm3

35±35

70±30

85±10

NS

CSF Albumin (mg/dl)

80±87

122±76

90±65

NS

CSF Protein (mg/dl)

183±105

218±125

164±96

NS

CSF Glucose (mg/dl)

58±29

39±38

73±25

NS

CSF Chloride (mg/dl)

95±10

109±18

108±13

NS

CSF IgG mg/dl

34±47

19±15

16±30

NS

CSF IgM mg/dl

5.8±4.4

2.6±2.2

3.8±2.9

NS

CSF IgE IU/mL

4.9±3.2

124±157*

3.8±1.1

=0.001

Serum IgG mg/dl

832±370

855±246

847±260

NS

Serum IgM mg/dl

152±51

103±26

92±92

NS

Serum IgE IU/mL

195±231

308±257

46±45

NS

 

 

Table 2. Physical and neurological examination findings of patients.

 

 

Tuberculous Meningitis (n=5)

Purulent

Meningitis (n=5)

Meningococcal

Meningitis (n=8)

X2

p

Fever

5

5

7

1.32

NS*

Headache

2

2

4

0.18

NS

Vomiting

4

4

8

1.8

NS

Convulsion

2

4

4

1.8

NS

Stiff neck

3

5

7

3.06

NS

Meningeal irritation

3

5

8

5.85

NS

Babinski sign

4

5

7

1.04

NS

Petechiae / ecchymoses

1**

0

8

14.8

<0.001

 

*NS=Not Significant,

**Allergic reaction was developed against to Isoniazid in a case with Tuberculous meningitis.

 

 

Figure 1. The mean IgG, IgE and IgM indices of cases with tuberculous, purulent and meningococcal meningitis.





This Article
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Right arrow Similar articles in this netprints
Right arrow Download to citation manager
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Right arrow Articles by KARA, I. H.
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Right arrow Articles by KARA, I. H.
Right arrow Articles by HASPOLAT, K.


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