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Tuberculous meningitis in infancy
Original Articles
Tuberculous Meningitis in Infancy Yu-Ren Tung, MD*, Ming-Chi Lai, MD†, Chun-Chung Lui, MD‡, Kun-Lin Tsai*, Li-Tung Huang, MD*, Ying-Chao Chang, MD*, Song-Chei Huang, MD*, San Nan Yang, MD, PhD*, and Pi-Lien Hung, MD* The lack of specific symptoms and signs in patients with tuberculous meningitis makes early diagnosis difficult. To our knowledge, there has been no report in the literature focusing on tuberculous meningitis patients younger than 1 year of age. In this report, we reviewed the clinical features and laboratory findings of seven infants with tuberculous meningitis encountered during a 15-year period. All patients had fever, cough, and alternation of consciousness at presentation. Five patients had bulging anterior fontanel, and five had generalized tonic-clonic seizures. The purified protein derivative skin test was positive in six patients. Six patients had hyponatremia. All seven patients had abnormal cerebrospinal fluid findings, and six of them demonstrated cell counts less than 500 cells/mm3 with lymphocytic predominance. Brain sonography examination revealed hydrocephalus in all seven patients. Therefore we conclude that antituberculosis therapy should be promptly initiated in any young infant with a clinical impression of meningitis in the context of cerebrospinal fluid white cell count of less than 500 cells/mm3 and lymphocytic predominance, hyponatremia, and hydrocephalus. © 2002 by Elsevier Science Inc. All rights reserved. Tung Y-R, Lai M-C, Lui C-C, Tsai K-L, Huang L-T, Chang Y-C, Huang S-C, Yang SN, Hung P-L. Tuberculous meningitis in infancy. Pediatr Neurol 2002;27: 262-266.
Introduction Tuberculous meningitis is the most life-threatening form of extrapulmonary tuberculosis. Early diagnosis followed by effective treatment may prevent neurologic damage or a fatal outcome [1-6].
From the *Department of Pediatrics, Chang Gung Memorial Hospital; Kaohsiung, Taiwan; the †Department of Pediatrics; Chi Mei Foundation Hospital; Tainan, Taiwan; and the ‡Department of Diagnostic Radiology; Chang Gung Memorial Hospital; Kaohsiung, Taiwan
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Since 1985, there has been a 15% increase in the number of reported cases of tuberculosis, and the increase is more dramatic in children than in adults [1]. Because tuberculous meningitis is rare in developed countries and its presentation is often nonspecific, early recognition of this potentially treatable disease remains a challenge to clinicians. Previous studies usually mixed infants with children and adults; therefore the possible unique presentation could be overlooked in any specific age group [2,3,7-10]. Surprisingly, there has been no report primarily focused on infants with tuberculous meningitis. Furthermore, studies of infants with tuberculosis have been rarely reported in the last 20 years [3,11-15]. This study reviews the clinical features and courses of seven infants with tuberculous meningitis observed in Chang Gung Memorial Hospital at Kaohsiung, Taiwan, during a 15-year period.
Patients and Methods From May 1986 to December 2000, seven patients younger than 1 year of age with tuberculous meningitis were admitted to the Chang Gung Children’s Hospital at Kaohsiung, Taiwan. Because the yield of culture for tuberculous bacilli was relatively low in cerebrospinal fluid, the diagnosis of tuberculous meningitis was based on abnormal neurologic symptoms and signs [3], cerebrospinal fluid abnormalities compatible with tuberculous meningitis, and negative bacteria culture [3] plus at least two or more of the following criteria: (1) discovery of an adult index case with contagious tuberculosis who had significant contact with the infants, (2) presence of the Mantoux tuberculin 1TU unit skin test 10 mm of induration or more, (3) chest radiographic findings compatible with tuberculosis [16], and (4) abnormalities on brain-imaging studies compatible with tuberculous meningitis either by cranial computed tomography or magnetic resonance imaging [12,17,18]. Additionally, the patients who survived demonstrated satisfactory response to antituberculosis medications after a follow-up period that ranged from 2 to 10 years.
Communications should be addressed to: Dr. Huang; Department of Pediatrics; Chang Gung Memorial Hospital at Kaohsiung; No. 123, Ta Pei Road; Niao Sung; Kaohsiung County, 833, Taiwan. Received February 26, 2002; accepted April 16, 2002.
© 2002 by Elsevier Science Inc. All rights reserved. PII S0887-8994(02)00431-9 ● 0887-8994/02/$—see front matter
Table 1.
Clinical, neurologic manifestations, and laboratory results
Case
Age (m/o)
Stage
AF Bulging
Seizure
Na(s) (meq/L)
CXR
PPD
VP Shunt
Outcome
1 2 3 4 5 6 7
5 10 8 5 9 11 5
1 2 2 2 3 3 3
(⫺) (⫹) (⫹) (⫺) (⫹) (⫹) (⫹)
(⫺) (⫹) (⫹) (⫹) (⫺) (⫹) (⫹)
124 127 134 126 127 122 127
(⫺) Consolidation Miliary TB (⫺) Miliary TB (⫺) Hilar LAP
(⫹) (⫹) (⫹) (⫹) (⫺) (⫹) (⫹)
(⫹) (⫹) (⫹) (⫺) (⫺) (⫹) (⫹)
DD Normal Death Normal Death Normal Death
Abbreviations: ⫹ ⫽ Present or done ⫺ ⫽ Absent or no significant finding AF ⫽ Anterior fontanel bulging CXR ⫽ Chest radiography DD ⫽ Developmental delay
LAP Na(s) PPD VP shunt
⫽ ⫽ ⫽ ⫽
Lymphadenopathy Sodium (serum) Purified protein derivative test Ventriculoperitoneal shunt
Results
Radiographic Findings
In the last 15 years, seven patients younger than 1 year of age who were suspected of having tuberculous meningitis were located in our hospital records. There were six males (86%) and one female (14%). The mean age of onset was 7.6 months of age with a range from 5 to 11 months of age.
Cranial sonography and cranial computed tomography were performed in all of the patients on admission, and some patients received further examination by brain magnetic resonance imaging. All seven patients had abnormal findings, including hydrocephalus (100%), basilar cistern enhancement (14%) (Fig 1), and infarction in the bilateral basal ganglion (29%) (Fig 2). Chest radiography revealed abnormalities in four patients (57%), including pulmonary consolidation in one patient, miliary tuberculosis in two patients (Fig 3), and hilar lymphadenopathy in one patient.
Clinical Characteristics Based on clinical severity at admission the patients were categorized according to previous reports [2,3] as follows: stage 1 (n ⫽ 1), without definite neurologic symptoms; stage 2 (n ⫽ 3), with signs of meningeal irritation and focal neurologic signs, although without change of consciousness; stage 3 (n ⫽ 3), severe clouding of consciousness or delirium, seizures, and serious neurologic signs. The neurologic signs and clinical characteristics are summarized in Table 1. All children had fever, lethargy, and cough. Only two patients (29%) had definite history of tuberculosis contact, one with his uncle and the other with his mother. Neurologic presentations on admission included increased intracranial pressure, vomiting (71%), tense or bulging anterior fontanel (71%), seizures (71%), paresis (14%), opisthotonos (14%), and disturbance of consciousness (43%). The seizure pattern in five patients was generalized tonic-clonic in nature.
Laboratory Data and Microbiology On admission, six patients (89%) were noted to have hyponatremia (defined as less than 132 mmol/L) ranging from 120 to 127 mmol/L (Table 1). Hyponatremia was corrected after infusion of 3% sodium chloride solution in all patients.
Skin Test Because bacillus Calmette-Guerin vaccination is a routine procedure in Taiwan, the so-called positive response to the purified protein derivative skin test is defined to be greater than 10 mm of induration to 1 tuberculin unit. All patients had a record of bacillus Calmette-Guerin vaccination, and a positive response to purified protein derivative was evident in six patients (86%).
Figure 1. T1-weighted magnetic resonance imaging (TR ⫽ 600, TE ⫽ 20) after gadolinium-diethylenetriamine penta-acetic acid administration for Patient 3 reveals prominent basal cistern enhancement (arrowheads).
Tung et al: Tuberculous Meningitis in Infancy 263
Table 2.
Figure 2. Precontrast brain computed tomography demonstrates marked hydrocephalus and low-density areas are evident in the bilateral basal ganglion regions (arrowheads).
The cerebrospinal fluid data for all seven patients are summarized in Table 2. All seven patients (100%) had pleocytosis in cerebrospinal fluid, and the mean white blood cell (leukocyte) count was 222/mm3. Only one patient had cell counts greater than 500 cells/mm3. Elevated cerebrospinal fluid protein, ranging from 47.5 mg/dL to 990 mg/dL, and low glucose level, ranging from 17 to 49 mg/dL, were revealed in all patients. Acid-fast stain of cerebrospinal fluid for tuberculous bacilli was negative for all samples. All bacterial cultures of cerebrospinal fluid yielded no growth, with the exception of one that grew Mycobacterium tuberculosis. Treatment With a high index of suspicion, antituberculosis treatment was begun 1 or 2 days after admission. The antituberculosis therapy consisted of isoniazine (15 mg/kg) and rifampin (15 mg/kg) for a duration of 18 months plus dexamethasone (0.5-1.5 mg/kg), streptomycin (20-25 mg/ kg), and pyrazinamide (30 mg/kg) in the acute stage for
Figure 3. Chest x-ray of Patient 5 demonstrates bilateral miliary lesions.
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Cerebrospinal fluid finding
Case
Total Protein (mg/dL)
Glucose (mg/dL)
WBC (Cells/mm3)
Differential Count
CSF Culture
1 2 3 4 5 6 7
990 72 264 260 282 47.5 477
25 49 44 17 15 25 35
486 100 175 528 45 35 185
L39M50N11 L20M17N63 L7N83M10 L40M32N28 L91N2M7 L47M6N47 L45M26N28
(⫺) (⫺) (⫺) (⫺) (⫹) (⫺) (⫺)
Abbreviations: ⫹ ⫽ Positive culture for Mycobacterium tuberculosis ⫺ ⫽ Negative culture for Mycobacterium tuberculosis L ⫽ Lymphocyte M ⫽ Monocyte N ⫽ Neutrophil WBC ⫽ White blood cell
1-2 months. Five patients required ventriculoperitoneal shunting surgery 3-4 days after admission for the progressive hydrocephalus and increased intracranial pressure. Outcome Three patients (43%) died despite intensive treatment. Two of them who were in stage 3 died 3 and 9 days, respectively, after admission, and one patient was in stage 2 and died 2 months later as a result of obstruction of the ventriculoperitoneal shunting attributed to negligence of caretakers. One patient (14%) in stage 1 had severe sequelae, including mental retardation and developmental delay, after recurrent obstruction of the ventriculoperitoneal shunt. Three patients (43%) appeared normal after 2to 10-year follow-up. Discussion Tuberculous meningitis is rarely encountered in developed countries. Since 1985 there has been a 15% increase in the number of reported cases of tuberculosis [1]. This dramatic rise may be a result of the rise of high-risk patients, including those infected with human immunodeficiency virus, foreign-born persons from underdeveloped or developing countries, and medically underserved populations [1-3]. Surprisingly, there are only few reports describing young infants with tuberculous meningitis [1-5]. Infection with Mycobacterium tuberculosis begins with inhalation of Mycobacacterium tuberculosis bacilli, which then spreads through the lymphohematogenous system to the brain and meninges. The tuberculous bacilli are then discharged from these foci directly into the subarachnoid space to cause meningitis. The meningitis process takes 2-3 months to evolve [1]. Tuberculous meningitis is the most severe life-threatening form of tuberculosis in infants. In our series, all patients were older than 5 months
of age. This finding is consistent with the evolution and development of tuberculous meningitis. Clinicians are often not keen on diagnosing tuberculous meningitis because of its rarity, especially in Western countries [1,6-10]. Therefore a high index of suspicion is especially required in the young age group. Cough and fever are common symptoms in infants. All patients in this study had fever and cough. Moreover, chest radiography revealed abnormal findings in only four patients (57%), including miliary tuberculosis, hilar lymphadenopathy, and right-sided pulmonary consolidation. Chest radiographs could be helpful in evaluating for pulmonary tuberculosis, and positive findings were reported in 25%-84% [2,3,6]. It has been reported by Janner et al. [1] that family history of tuberculosis could be retrospectively found in 47% of patients with tuberculous meningitis. Two of our patients (29%) had a history of exposure to family members with tuberculosis. Although fever was uniformly present in this study, other researchers have reported that only 13% and 19% of their patients had fever [3,5]. Therefore, absence of fever should not exclude the possibility of tuberculous meningitis. The neurologic symptoms and signs in our patients included drowsiness, meningeal irritation, cranial nerve paresis, seizures, hemiparesis, consciousness alternation, and coma, which are similar to previous studies [2-4]. In this report the most prominent sign was bulging anterior fontanel (71%) because of increased intracranial pressure. Vomiting was also evident in all patients. However, Doerr et al. [2] reported that only 38% of children in their study had signs of meningeal irritation. Seizures are less often observed in adults than children and elderly people [5]. Five patients (71%) in this series had generalized tonicclonic seizures developed early in the course of their illness. The purified protein derivative test is routinely used as one of the criteria for the diagnosis of tuberculosis. The positive rate is variable among other series. Thwaites et al. [5] demonstrated that 22% of tuberculous meningitis patients had a positive response to 100 tuberculin units. Six of our patients (86%) had positive purified protein derivative tests to 1 tuberculin unit, which was the standard dosage recommend in Taiwan. Therefore the purified protein derivative test still plays a role in the early diagnosis of tuberculous meningitis, even in infant patients. The coexistence of tuberculous meningitis and hyponatremia because of inappropriate secretion of antidiuretic hormone is well known. Hyponatremia had been reported in 42%-63% of patients [2,6]. Similarly, inappropriate secretion of antidiuretic hormone was present in 89% of our patients. We suggest that tuberculous meningitis should be highly suspected in any infant with meningeal signs associated with inappropriate secretion of antidiuretic hormone. Although there has been a warning of herniation precipitated by lumbar puncture, lumbar puncture carries no
risk of herniation in the absence of hemiparesis or papilledema [19] whether cerebrospinal fluid pressure is raised or not [20]. Therefore we suggest that if brain imaging reveals no evidence of abscess, subdural empyema, or brain infarct, lumbar puncture can be performed safely in clinically suspected tuberculous meningitis patients [19]. The cerebrospinal fluid findings in tuberculous meningitis often demonstrate reduced glucose concentration, increased protein level, and elevated leukocyte counts [11,12]. However, cerebrospinal fluid seldom contains more than 500 cells/mm3, and most cells are lymphocytes [13]. In the study of Alarco´ n et al. [4], leukocyte counts less than 500 cells/mm3 were observed in 26 patients (93.3%), and 20 of 28 patients (71.4%) were with lymphocytic predominance. In this study, six patients had cell counts of less than 500/mm3 with lymphocytic predominance, and Patient 5 had leukocyte counts slightly above 500/mm3. Therefore cerebrospinal fluid leukocyte counts of 500/mm3 may serve as a cut-point to include tuberculous meningitis into the differential diagnosis. However, it should be borne in mind that initial negative results or atypical cerebrospinal fluid findings have also been reported [14]. Hypoglycorrhachia has been reported ranging from 58% to 83% [3,4-6]; however, it was present in all our patients. The search for acid-fast bacilli is the most crucial part of the diagnosis. The reported probability of acid-fast bacilli observed in cerebrospinal fluid smears ranged between 10% and 87% [6]. Unfortunately, none of our patients had positive finding. The culture of Mycobacterium tuberculosis from the cerebrospinal fluid is the gold standard of diagnosis. Previous studies that included patients based on other diagnostic criterion have reported culture-positive rates between 47% and 87% [6]. Thwaites et al. [5] have demonstrated that the success of these two tests depends on the volume of sample collected. Nevertheless, longterm follow-up in our patients does not argue against the diagnosis of tuberculous meningitis. The advent of DNA amplification techniques, such as polymerase chain reaction, to demonstrate the presence of the causal organism in the cerebrospinal fluid has been used in the diagnosis of tuberculous meningitis [10]. The reported sensitivity of polymerase chain reaction varies from 33% to 90%, and specificity varies from 88% to 100% [5]. Because the performance of polymerase chain reaction varies among reference laboratories and is not universally available, the practice for early diagnosis of tuberculous meningitis in children is limited. Clinical diagnosis and early treatment is highly required, as demonstrated in this study The findings of brain imaging in tuberculous meningitis include hydrocephalus, basilar enhancement, and infarcts [15-17], among which the most common abnormality is hydrocephalus on cranial computed tomography [6]. Waecker et al. [11] reported that all of the 30 tuberculous meningitis patients in their study had hydrocephalus detected by cranial computed tomography. Hydrocephalus
Tung et al: Tuberculous Meningitis in Infancy 265
has been detected in 80%-100% of children and 12% of adults with tuberculous meningitis [1,5]. Although computed tomography is more informative, cranial sonography has been demonstrated to be useful [10]. In all seven of our patients (100%), hydrocephalus was detected by brain sonography. The basal meningeal enhancement is the second most common finding in computed tomography, which is usually associated with a poor prognosis. Patient 3 in this series had basal meningeal enhancements and died. Since initial cranial computed tomography can be normal in 13% [2] and 32% [4] of tuberculous meningitis patients, respectively, Curless et al. [18] suggested that a cranial computed tomography should be a routine procedure when atypical cerebrospinal fluid findings for bacterial meningitis are demonstrated and a repeat computed tomography should be performed within a few days if a patient is not progressing well. Early diagnosis is important because children with tuberculous meningitis are associated with a grave outcome. Doerr et al. [2] reviewed a 10-year experience of 31 children with tuberculous meningitis. The mean age of patients in their study was 23.4 months, and the mean length of symptoms before admission was 17.1 days. In this study the average days between admission and initiation of antituberculosis therapy was 2-3 days. Obvious neurologic symptoms and signs and a high index of suspicion contributed to rapid antituberculosis therapy in our patients. We concluded that if hyponatremia and hydrocephalus are detected, any ill infant presenting with a cerebrospinal fluid leukocyte count of less than 500 cells/mm3 and lymphocyte predominance should be immediately treated with antituberculosis medication. References [1] Janner D, Rutherford M, Azimi P. Tuberculous meningitis in children. Pediatr Emerg Care 1993;9:281-4. [2] Doerr CA, Starke JR, Ong LT. Clinical and public health aspects of tuberculosis meningitis in children. J Pediatr 1995;127:27-33. [3] Kennedy DH, Fallon RJ. Tuberculous meningitis. JAMA 1979; 241:264-8.
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[4] Alarco´ n F, Escalante L, Perez Y, Banda H, Chacon G, Duenas G. Tuberculous meningitis: Short course of chemotherapy. Arch Neurol 1990;47:1313-7. [5] Thwaites G, Chau TT, Mai NT, Drobniewski F, McAdam K, Farrar J. Tuberculous meningitis. J Neurol Neurosurg Psychiatry 2000; 68:289-99. [6] Clark WC, Metcalf JC, Muhlbauer MS, Dohan FC, Robertson JH. Mycobacterium tuberculosis meningitis: A report of twelve cases and a literature review. Neurosurgery 1986;18:604-10. [7] DeLage G, Dusseault M. Tuberculous meningitis in children: A retrospective study of 79 patients, with an analysis of prognostic factors. Can Med Assoc J 1979;120:305-9. [8] Medical Research Council Tuberculosis and Chest Disease Unit. Tuberculosis in children: A national survey of notification in England and Wales in 1983. Arch Dis Child J 1986;63:266-76. [9] Visudhiphan P, Chiemchanya S. Tuberculosis meningitis in children: Treatment with isoniazid and rifampin. J Pediatr 1989;114: 875-9. [10] Lee LV. Neurotuberculosis among Filipino children: An 11 years experience at the Philippine Children’s Medical Center. Brain Dev 2000;22:469-74. [11] Waecker NJ, Connor JD. Central nervous system tuberculosis in children: A review of 30 cases. Pediatr Infect Dis J 1990;9:539-43. [12] Berger JR. Tuberculous meningitis. Curr Opin Neurol 1994;7: 191-200. [13] Stockstill MT, Kauffman CA. Comparison of cryptococcal and tuberculous meningitis. Arch Neurol 1983;40:81-5. [14] Klein NC, Damsker B, Hirschman SZ. Mycobacterial meningitis: Retrospective analysis from 1970-1983. Am J Med 1985;79:29-34. [15] Leung AN, Muller NL, Pineda PR, FitzGerald JM. Primary tuberculosis in childhood: Radiographic manifestations. Radiology 1992; 182:87-91. [16] Wallace RC, Burton EM, Barrett FF, Leggiadro RJ, Gerald BE, Lasater OE. Intracranial tuberculosis in children: CT appearance and clinical outcome. Pediatr Radiol 1991;21:241-6. [17] Gupta RK, Gupta S, Singh D, Sharma B, Kohil A, Gujral RB. MR imaging and angiography in tuberculous meningitis. Neuroradiology 1994;6:87-92. [18] Curless RG, Mitchell CD. Central nervous system tuberculosis in children. Pediatr Neurol 1991;7:270-4. [19] Archer AD. Computed tomography before lumbar puncture in acute meningitis: A review of the risks and benefits. Can Med Assoc J 1993;148:961-5. [20] van Crevel H, Hijdra A, de Gans J. Lumbar puncture and the risk of herniation: When should we first perform CT? J Neurol 2002; 249:129-37.
Tuberculous Meningitis in Infancy Yu-Ren Tung, MD*, Ming-Chi Lai, MD†, Chun-Chung Lui, MD‡, Kun-Lin Tsai*, Li-Tung Huang, MD*, Ying-Chao Chang, MD*, Song-Chei Huang, MD*, San Nan Yang, MD, PhD*, and Pi-Lien Hung, MD* The lack of specific symptoms and signs in patients with tuberculous meningitis makes early diagnosis difficult. To our knowledge, there has been no report in the literature focusing on tuberculous meningitis patients younger than 1 year of age. In this report, we reviewed the clinical features and laboratory findings of seven infants with tuberculous meningitis encountered during a 15-year period. All patients had fever, cough, and alternation of consciousness at presentation. Five patients had bulging anterior fontanel, and five had generalized tonic-clonic seizures. The purified protein derivative skin test was positive in six patients. Six patients had hyponatremia. All seven patients had abnormal cerebrospinal fluid findings, and six of them demonstrated cell counts less than 500 cells/mm3 with lymphocytic predominance. Brain sonography examination revealed hydrocephalus in all seven patients. Therefore we conclude that antituberculosis therapy should be promptly initiated in any young infant with a clinical impression of meningitis in the context of cerebrospinal fluid white cell count of less than 500 cells/mm3 and lymphocytic predominance, hyponatremia, and hydrocephalus. © 2002 by Elsevier Science Inc. All rights reserved. Tung Y-R, Lai M-C, Lui C-C, Tsai K-L, Huang L-T, Chang Y-C, Huang S-C, Yang SN, Hung P-L. Tuberculous meningitis in infancy. Pediatr Neurol 2002;27: 262-266.
Introduction Tuberculous meningitis is the most life-threatening form of extrapulmonary tuberculosis. Early diagnosis followed by effective treatment may prevent neurologic damage or a fatal outcome [1-6].
From the *Department of Pediatrics, Chang Gung Memorial Hospital; Kaohsiung, Taiwan; the †Department of Pediatrics; Chi Mei Foundation Hospital; Tainan, Taiwan; and the ‡Department of Diagnostic Radiology; Chang Gung Memorial Hospital; Kaohsiung, Taiwan
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Since 1985, there has been a 15% increase in the number of reported cases of tuberculosis, and the increase is more dramatic in children than in adults [1]. Because tuberculous meningitis is rare in developed countries and its presentation is often nonspecific, early recognition of this potentially treatable disease remains a challenge to clinicians. Previous studies usually mixed infants with children and adults; therefore the possible unique presentation could be overlooked in any specific age group [2,3,7-10]. Surprisingly, there has been no report primarily focused on infants with tuberculous meningitis. Furthermore, studies of infants with tuberculosis have been rarely reported in the last 20 years [3,11-15]. This study reviews the clinical features and courses of seven infants with tuberculous meningitis observed in Chang Gung Memorial Hospital at Kaohsiung, Taiwan, during a 15-year period.
Patients and Methods From May 1986 to December 2000, seven patients younger than 1 year of age with tuberculous meningitis were admitted to the Chang Gung Children’s Hospital at Kaohsiung, Taiwan. Because the yield of culture for tuberculous bacilli was relatively low in cerebrospinal fluid, the diagnosis of tuberculous meningitis was based on abnormal neurologic symptoms and signs [3], cerebrospinal fluid abnormalities compatible with tuberculous meningitis, and negative bacteria culture [3] plus at least two or more of the following criteria: (1) discovery of an adult index case with contagious tuberculosis who had significant contact with the infants, (2) presence of the Mantoux tuberculin 1TU unit skin test 10 mm of induration or more, (3) chest radiographic findings compatible with tuberculosis [16], and (4) abnormalities on brain-imaging studies compatible with tuberculous meningitis either by cranial computed tomography or magnetic resonance imaging [12,17,18]. Additionally, the patients who survived demonstrated satisfactory response to antituberculosis medications after a follow-up period that ranged from 2 to 10 years.
Communications should be addressed to: Dr. Huang; Department of Pediatrics; Chang Gung Memorial Hospital at Kaohsiung; No. 123, Ta Pei Road; Niao Sung; Kaohsiung County, 833, Taiwan. Received February 26, 2002; accepted April 16, 2002.
© 2002 by Elsevier Science Inc. All rights reserved. PII S0887-8994(02)00431-9 ● 0887-8994/02/$—see front matter
Table 1.
Clinical, neurologic manifestations, and laboratory results
Case
Age (m/o)
Stage
AF Bulging
Seizure
Na(s) (meq/L)
CXR
PPD
VP Shunt
Outcome
1 2 3 4 5 6 7
5 10 8 5 9 11 5
1 2 2 2 3 3 3
(⫺) (⫹) (⫹) (⫺) (⫹) (⫹) (⫹)
(⫺) (⫹) (⫹) (⫹) (⫺) (⫹) (⫹)
124 127 134 126 127 122 127
(⫺) Consolidation Miliary TB (⫺) Miliary TB (⫺) Hilar LAP
(⫹) (⫹) (⫹) (⫹) (⫺) (⫹) (⫹)
(⫹) (⫹) (⫹) (⫺) (⫺) (⫹) (⫹)
DD Normal Death Normal Death Normal Death
Abbreviations: ⫹ ⫽ Present or done ⫺ ⫽ Absent or no significant finding AF ⫽ Anterior fontanel bulging CXR ⫽ Chest radiography DD ⫽ Developmental delay
LAP Na(s) PPD VP shunt
⫽ ⫽ ⫽ ⫽
Lymphadenopathy Sodium (serum) Purified protein derivative test Ventriculoperitoneal shunt
Results
Radiographic Findings
In the last 15 years, seven patients younger than 1 year of age who were suspected of having tuberculous meningitis were located in our hospital records. There were six males (86%) and one female (14%). The mean age of onset was 7.6 months of age with a range from 5 to 11 months of age.
Cranial sonography and cranial computed tomography were performed in all of the patients on admission, and some patients received further examination by brain magnetic resonance imaging. All seven patients had abnormal findings, including hydrocephalus (100%), basilar cistern enhancement (14%) (Fig 1), and infarction in the bilateral basal ganglion (29%) (Fig 2). Chest radiography revealed abnormalities in four patients (57%), including pulmonary consolidation in one patient, miliary tuberculosis in two patients (Fig 3), and hilar lymphadenopathy in one patient.
Clinical Characteristics Based on clinical severity at admission the patients were categorized according to previous reports [2,3] as follows: stage 1 (n ⫽ 1), without definite neurologic symptoms; stage 2 (n ⫽ 3), with signs of meningeal irritation and focal neurologic signs, although without change of consciousness; stage 3 (n ⫽ 3), severe clouding of consciousness or delirium, seizures, and serious neurologic signs. The neurologic signs and clinical characteristics are summarized in Table 1. All children had fever, lethargy, and cough. Only two patients (29%) had definite history of tuberculosis contact, one with his uncle and the other with his mother. Neurologic presentations on admission included increased intracranial pressure, vomiting (71%), tense or bulging anterior fontanel (71%), seizures (71%), paresis (14%), opisthotonos (14%), and disturbance of consciousness (43%). The seizure pattern in five patients was generalized tonic-clonic in nature.
Laboratory Data and Microbiology On admission, six patients (89%) were noted to have hyponatremia (defined as less than 132 mmol/L) ranging from 120 to 127 mmol/L (Table 1). Hyponatremia was corrected after infusion of 3% sodium chloride solution in all patients.
Skin Test Because bacillus Calmette-Guerin vaccination is a routine procedure in Taiwan, the so-called positive response to the purified protein derivative skin test is defined to be greater than 10 mm of induration to 1 tuberculin unit. All patients had a record of bacillus Calmette-Guerin vaccination, and a positive response to purified protein derivative was evident in six patients (86%).
Figure 1. T1-weighted magnetic resonance imaging (TR ⫽ 600, TE ⫽ 20) after gadolinium-diethylenetriamine penta-acetic acid administration for Patient 3 reveals prominent basal cistern enhancement (arrowheads).
Tung et al: Tuberculous Meningitis in Infancy 263
Table 2.
Figure 2. Precontrast brain computed tomography demonstrates marked hydrocephalus and low-density areas are evident in the bilateral basal ganglion regions (arrowheads).
The cerebrospinal fluid data for all seven patients are summarized in Table 2. All seven patients (100%) had pleocytosis in cerebrospinal fluid, and the mean white blood cell (leukocyte) count was 222/mm3. Only one patient had cell counts greater than 500 cells/mm3. Elevated cerebrospinal fluid protein, ranging from 47.5 mg/dL to 990 mg/dL, and low glucose level, ranging from 17 to 49 mg/dL, were revealed in all patients. Acid-fast stain of cerebrospinal fluid for tuberculous bacilli was negative for all samples. All bacterial cultures of cerebrospinal fluid yielded no growth, with the exception of one that grew Mycobacterium tuberculosis. Treatment With a high index of suspicion, antituberculosis treatment was begun 1 or 2 days after admission. The antituberculosis therapy consisted of isoniazine (15 mg/kg) and rifampin (15 mg/kg) for a duration of 18 months plus dexamethasone (0.5-1.5 mg/kg), streptomycin (20-25 mg/ kg), and pyrazinamide (30 mg/kg) in the acute stage for
Figure 3. Chest x-ray of Patient 5 demonstrates bilateral miliary lesions.
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Cerebrospinal fluid finding
Case
Total Protein (mg/dL)
Glucose (mg/dL)
WBC (Cells/mm3)
Differential Count
CSF Culture
1 2 3 4 5 6 7
990 72 264 260 282 47.5 477
25 49 44 17 15 25 35
486 100 175 528 45 35 185
L39M50N11 L20M17N63 L7N83M10 L40M32N28 L91N2M7 L47M6N47 L45M26N28
(⫺) (⫺) (⫺) (⫺) (⫹) (⫺) (⫺)
Abbreviations: ⫹ ⫽ Positive culture for Mycobacterium tuberculosis ⫺ ⫽ Negative culture for Mycobacterium tuberculosis L ⫽ Lymphocyte M ⫽ Monocyte N ⫽ Neutrophil WBC ⫽ White blood cell
1-2 months. Five patients required ventriculoperitoneal shunting surgery 3-4 days after admission for the progressive hydrocephalus and increased intracranial pressure. Outcome Three patients (43%) died despite intensive treatment. Two of them who were in stage 3 died 3 and 9 days, respectively, after admission, and one patient was in stage 2 and died 2 months later as a result of obstruction of the ventriculoperitoneal shunting attributed to negligence of caretakers. One patient (14%) in stage 1 had severe sequelae, including mental retardation and developmental delay, after recurrent obstruction of the ventriculoperitoneal shunt. Three patients (43%) appeared normal after 2to 10-year follow-up. Discussion Tuberculous meningitis is rarely encountered in developed countries. Since 1985 there has been a 15% increase in the number of reported cases of tuberculosis [1]. This dramatic rise may be a result of the rise of high-risk patients, including those infected with human immunodeficiency virus, foreign-born persons from underdeveloped or developing countries, and medically underserved populations [1-3]. Surprisingly, there are only few reports describing young infants with tuberculous meningitis [1-5]. Infection with Mycobacterium tuberculosis begins with inhalation of Mycobacacterium tuberculosis bacilli, which then spreads through the lymphohematogenous system to the brain and meninges. The tuberculous bacilli are then discharged from these foci directly into the subarachnoid space to cause meningitis. The meningitis process takes 2-3 months to evolve [1]. Tuberculous meningitis is the most severe life-threatening form of tuberculosis in infants. In our series, all patients were older than 5 months
of age. This finding is consistent with the evolution and development of tuberculous meningitis. Clinicians are often not keen on diagnosing tuberculous meningitis because of its rarity, especially in Western countries [1,6-10]. Therefore a high index of suspicion is especially required in the young age group. Cough and fever are common symptoms in infants. All patients in this study had fever and cough. Moreover, chest radiography revealed abnormal findings in only four patients (57%), including miliary tuberculosis, hilar lymphadenopathy, and right-sided pulmonary consolidation. Chest radiographs could be helpful in evaluating for pulmonary tuberculosis, and positive findings were reported in 25%-84% [2,3,6]. It has been reported by Janner et al. [1] that family history of tuberculosis could be retrospectively found in 47% of patients with tuberculous meningitis. Two of our patients (29%) had a history of exposure to family members with tuberculosis. Although fever was uniformly present in this study, other researchers have reported that only 13% and 19% of their patients had fever [3,5]. Therefore, absence of fever should not exclude the possibility of tuberculous meningitis. The neurologic symptoms and signs in our patients included drowsiness, meningeal irritation, cranial nerve paresis, seizures, hemiparesis, consciousness alternation, and coma, which are similar to previous studies [2-4]. In this report the most prominent sign was bulging anterior fontanel (71%) because of increased intracranial pressure. Vomiting was also evident in all patients. However, Doerr et al. [2] reported that only 38% of children in their study had signs of meningeal irritation. Seizures are less often observed in adults than children and elderly people [5]. Five patients (71%) in this series had generalized tonicclonic seizures developed early in the course of their illness. The purified protein derivative test is routinely used as one of the criteria for the diagnosis of tuberculosis. The positive rate is variable among other series. Thwaites et al. [5] demonstrated that 22% of tuberculous meningitis patients had a positive response to 100 tuberculin units. Six of our patients (86%) had positive purified protein derivative tests to 1 tuberculin unit, which was the standard dosage recommend in Taiwan. Therefore the purified protein derivative test still plays a role in the early diagnosis of tuberculous meningitis, even in infant patients. The coexistence of tuberculous meningitis and hyponatremia because of inappropriate secretion of antidiuretic hormone is well known. Hyponatremia had been reported in 42%-63% of patients [2,6]. Similarly, inappropriate secretion of antidiuretic hormone was present in 89% of our patients. We suggest that tuberculous meningitis should be highly suspected in any infant with meningeal signs associated with inappropriate secretion of antidiuretic hormone. Although there has been a warning of herniation precipitated by lumbar puncture, lumbar puncture carries no
risk of herniation in the absence of hemiparesis or papilledema [19] whether cerebrospinal fluid pressure is raised or not [20]. Therefore we suggest that if brain imaging reveals no evidence of abscess, subdural empyema, or brain infarct, lumbar puncture can be performed safely in clinically suspected tuberculous meningitis patients [19]. The cerebrospinal fluid findings in tuberculous meningitis often demonstrate reduced glucose concentration, increased protein level, and elevated leukocyte counts [11,12]. However, cerebrospinal fluid seldom contains more than 500 cells/mm3, and most cells are lymphocytes [13]. In the study of Alarco´ n et al. [4], leukocyte counts less than 500 cells/mm3 were observed in 26 patients (93.3%), and 20 of 28 patients (71.4%) were with lymphocytic predominance. In this study, six patients had cell counts of less than 500/mm3 with lymphocytic predominance, and Patient 5 had leukocyte counts slightly above 500/mm3. Therefore cerebrospinal fluid leukocyte counts of 500/mm3 may serve as a cut-point to include tuberculous meningitis into the differential diagnosis. However, it should be borne in mind that initial negative results or atypical cerebrospinal fluid findings have also been reported [14]. Hypoglycorrhachia has been reported ranging from 58% to 83% [3,4-6]; however, it was present in all our patients. The search for acid-fast bacilli is the most crucial part of the diagnosis. The reported probability of acid-fast bacilli observed in cerebrospinal fluid smears ranged between 10% and 87% [6]. Unfortunately, none of our patients had positive finding. The culture of Mycobacterium tuberculosis from the cerebrospinal fluid is the gold standard of diagnosis. Previous studies that included patients based on other diagnostic criterion have reported culture-positive rates between 47% and 87% [6]. Thwaites et al. [5] have demonstrated that the success of these two tests depends on the volume of sample collected. Nevertheless, longterm follow-up in our patients does not argue against the diagnosis of tuberculous meningitis. The advent of DNA amplification techniques, such as polymerase chain reaction, to demonstrate the presence of the causal organism in the cerebrospinal fluid has been used in the diagnosis of tuberculous meningitis [10]. The reported sensitivity of polymerase chain reaction varies from 33% to 90%, and specificity varies from 88% to 100% [5]. Because the performance of polymerase chain reaction varies among reference laboratories and is not universally available, the practice for early diagnosis of tuberculous meningitis in children is limited. Clinical diagnosis and early treatment is highly required, as demonstrated in this study The findings of brain imaging in tuberculous meningitis include hydrocephalus, basilar enhancement, and infarcts [15-17], among which the most common abnormality is hydrocephalus on cranial computed tomography [6]. Waecker et al. [11] reported that all of the 30 tuberculous meningitis patients in their study had hydrocephalus detected by cranial computed tomography. Hydrocephalus
Tung et al: Tuberculous Meningitis in Infancy 265
has been detected in 80%-100% of children and 12% of adults with tuberculous meningitis [1,5]. Although computed tomography is more informative, cranial sonography has been demonstrated to be useful [10]. In all seven of our patients (100%), hydrocephalus was detected by brain sonography. The basal meningeal enhancement is the second most common finding in computed tomography, which is usually associated with a poor prognosis. Patient 3 in this series had basal meningeal enhancements and died. Since initial cranial computed tomography can be normal in 13% [2] and 32% [4] of tuberculous meningitis patients, respectively, Curless et al. [18] suggested that a cranial computed tomography should be a routine procedure when atypical cerebrospinal fluid findings for bacterial meningitis are demonstrated and a repeat computed tomography should be performed within a few days if a patient is not progressing well. Early diagnosis is important because children with tuberculous meningitis are associated with a grave outcome. Doerr et al. [2] reviewed a 10-year experience of 31 children with tuberculous meningitis. The mean age of patients in their study was 23.4 months, and the mean length of symptoms before admission was 17.1 days. In this study the average days between admission and initiation of antituberculosis therapy was 2-3 days. Obvious neurologic symptoms and signs and a high index of suspicion contributed to rapid antituberculosis therapy in our patients. We concluded that if hyponatremia and hydrocephalus are detected, any ill infant presenting with a cerebrospinal fluid leukocyte count of less than 500 cells/mm3 and lymphocyte predominance should be immediately treated with antituberculosis medication. References [1] Janner D, Rutherford M, Azimi P. Tuberculous meningitis in children. Pediatr Emerg Care 1993;9:281-4. [2] Doerr CA, Starke JR, Ong LT. Clinical and public health aspects of tuberculosis meningitis in children. J Pediatr 1995;127:27-33. [3] Kennedy DH, Fallon RJ. Tuberculous meningitis. JAMA 1979; 241:264-8.
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[4] Alarco´ n F, Escalante L, Perez Y, Banda H, Chacon G, Duenas G. Tuberculous meningitis: Short course of chemotherapy. Arch Neurol 1990;47:1313-7. [5] Thwaites G, Chau TT, Mai NT, Drobniewski F, McAdam K, Farrar J. Tuberculous meningitis. J Neurol Neurosurg Psychiatry 2000; 68:289-99. [6] Clark WC, Metcalf JC, Muhlbauer MS, Dohan FC, Robertson JH. Mycobacterium tuberculosis meningitis: A report of twelve cases and a literature review. Neurosurgery 1986;18:604-10. [7] DeLage G, Dusseault M. Tuberculous meningitis in children: A retrospective study of 79 patients, with an analysis of prognostic factors. Can Med Assoc J 1979;120:305-9. [8] Medical Research Council Tuberculosis and Chest Disease Unit. Tuberculosis in children: A national survey of notification in England and Wales in 1983. Arch Dis Child J 1986;63:266-76. [9] Visudhiphan P, Chiemchanya S. Tuberculosis meningitis in children: Treatment with isoniazid and rifampin. J Pediatr 1989;114: 875-9. [10] Lee LV. Neurotuberculosis among Filipino children: An 11 years experience at the Philippine Children’s Medical Center. Brain Dev 2000;22:469-74. [11] Waecker NJ, Connor JD. Central nervous system tuberculosis in children: A review of 30 cases. Pediatr Infect Dis J 1990;9:539-43. [12] Berger JR. Tuberculous meningitis. Curr Opin Neurol 1994;7: 191-200. [13] Stockstill MT, Kauffman CA. Comparison of cryptococcal and tuberculous meningitis. Arch Neurol 1983;40:81-5. [14] Klein NC, Damsker B, Hirschman SZ. Mycobacterial meningitis: Retrospective analysis from 1970-1983. Am J Med 1985;79:29-34. [15] Leung AN, Muller NL, Pineda PR, FitzGerald JM. Primary tuberculosis in childhood: Radiographic manifestations. Radiology 1992; 182:87-91. [16] Wallace RC, Burton EM, Barrett FF, Leggiadro RJ, Gerald BE, Lasater OE. Intracranial tuberculosis in children: CT appearance and clinical outcome. Pediatr Radiol 1991;21:241-6. [17] Gupta RK, Gupta S, Singh D, Sharma B, Kohil A, Gujral RB. MR imaging and angiography in tuberculous meningitis. Neuroradiology 1994;6:87-92. [18] Curless RG, Mitchell CD. Central nervous system tuberculosis in children. Pediatr Neurol 1991;7:270-4. [19] Archer AD. Computed tomography before lumbar puncture in acute meningitis: A review of the risks and benefits. Can Med Assoc J 1993;148:961-5. [20] van Crevel H, Hijdra A, de Gans J. Lumbar puncture and the risk of herniation: When should we first perform CT? J Neurol 2002; 249:129-37.