Tuberculous Forty-three
Meningitis
in Childhood
Cases
Ziad H. Idriss, MD; Anwar A. Sinno, MD; Nabil M. Kronfol, MD
\s=b\ Forty-three patients in the pediatric age group had tuberculous meningitis. Therapy included the use of adrenocorticosteroids. All four patients who were in stage 1 on admission to the hospital, seven of the 33 in stage 2, and one of the six in stage 3 (coma) recovered without gross neurological sequelas. Eight patients died, and the remaining 23 recovered, with late neurological sequelas. Early diagnosis and appropriate treatment determine the prognosis of tuberculous
meningitis. (Am J Dis Child 130:364-367, 1976)
meningitis Tubercul o us complication culosis,
is a rare, but serious of tuber¬ and is more common in young children. The purpose of this commu¬ nication is to review the cases of tuberculous meningitis in children admitted to the American University Medical Center of Beirut, Lebanon, during the 20 years from 1952 through 1971. Patient Distribution
Forty-three children with tuberculous meningitis were admitted to the American University Medical Center of Beirut, from January 1952 through December 1971. Received for publication Oct 29, 1974; accepted Feb 15, 1975. From the Department of Pediatrics, American University of Beirut School of Medicine, Beirut, Lebanon. Reprint requests to Department of Pediatrics, American University of Beirut, Beirut, Lebanon
(Dr Sinno).
(This does not include five patients with tuberculoma of the brain, the conditions of two of whom were suspected clinically and three proved pathologically, and two patients with spinal cord tuberculosis, one of whom had an intramedullary tubercu¬ loma of D, to D3, the other multiple tuberculomas of the dura of the dorsal segments.) The age distribution of our patients is shown in Fig 1. The two youngest patients were 5 months old. Twenty-seven (63%) were boys and 16 (37%) were girls. The largest number of admissions of patients with tuberculous meningitis occurred in the last ten years (Fig 2). This was probably due to the greatly increased number of total admis¬ sions to the hospital during the later years of the study, rather than a true increase in the incidence of tuberculous meningitis. Clinical Features The signs and symptoms of our patients initial examination are summarized in Table 1. The most common findings were neck stiffness, fever, vomiting, drowsiness, and headache. Only six patients (14%) were comatose on admission. Cranial nerve involvement was found in 14 cases (33%), with nerves II, VI, VII being the most commonly affected. In our series, four cases (9%) were in stage 1, which is desig¬ nated as including only general symptoms similar to those of many common childhood ailments. Thirty-three cases (77%) were in stage 2, defined as general signs with evidence of neurological involvement. Six cases (14%) were in stage 3, with profound disturbance of the central nervous system (CNS) and distinct change in sensorium, including
on
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/13/2015
coma.
losis
A
positive family history of tubercu¬ obtained in 17 cases (40%).
was
Laboratory
Data
Forty patients (93%) had a positive reac¬ tion to the tuberculin skin test (purified protein derivative [PPD]), with an area of induration at least 10 mm in diameter. In the first ten years, one tuberculin unit was used for the test, while in the last ten years, five tuberculin units were used. In 31 patients (72%) roentgenograms of the chest showed infiltrates or enlargement of hilar nodes, or both. Initial cerebrospinal fluid (CSF) samples revealed a glucose value of 40 mg/100 ml or less, or a CSF blood glucose ratio under 0.67 in 42 cases (98%), a protein level above 100 mg/ml in 40 cases (93%), and more than ten white blood cells per cubic millimeter in all cases. In the majority of cases the CSF pleocytosis was lymphocytic in character; four patients had initial CSF neutrophilia. No child had normal CSF. Only five chil¬ dren (12%) had a positive CSF culture and stain for acid-fast bacilli. Pellicle forma¬ tion was positive in 6 of 13 determina¬ tions. Results of carotid arteriography, which was performed on eight children in the first four weeks of illness because of the suspicion of a brain abscess, were abnormal in five. One child had changes suggesting hydrocephalus, two had obstruction of the middle cerebral artery, and two had obstruction of the anterior cerebral artery. Ventriculography was done in four cases, 6 to 12 months after the diagnosis was made, and revealed communicating hydrocepha¬ lus in three, and obstructive hydrocephalus in one. Electroencephalography revealed
Table
1.—Signs
and
Signs and Symptoms Neck stiffness
No.
Vomiting Drowsiness Headache Coma Convulsions
Papilledema Sweating
palsy_4 (9)_
Optic atrophy
Eighth nerve palsy Hemiparesis Diabetes insipidus
_1 (2)_
Table 2.—Initial
Stage of Meningitis Admission
No. of Patients
Stage of Meningitis
and Outcome
No. Recovered With
No. Recovered Without
Neurological Sequelas
Neurological Sequelas
No. Died
1
0
33 6
Total (%)
(9) (9) (9) (2) (5)
4 4 4 1 2
Abducens nerve palsy Occulomotor nerve palsy
on
of Cases
(77) (72) 20(47) 13(30) 10(23) 9(21) 6(14) 4 (9) 4(9) 4(9)
Fever
Facial
(%) 33 31
Apathy
43(100)
21
an abnormal tracing in all nine who had this test.
patients
Treatment
Thirty-five patients
were
given
isonia-
zid, streptomycin sulfate, and aminosalicylic acid. Aminosalicylic acid was given in a daily oral dose of at least 200 mg/kg/day, but not to exceed 12 gm/day. The initial dose of isoniazid was 20 mg/kg/day (max¬ imum dose, 300 mg/day) in all but the last six patients who were given 40 mg/kg/day (maximum dose, 500 mg/day). This dose
maintained until the patient showed definite signs of improvement, including return of the CSF glucose concentration to normal, after which it was reduced to 10 to 20 mg/kg/day. Streptomycin sulfate, in a dose of 20 to 40 mg/kg/day was given intramuscularly in one to two doses (not exceeding 1 gm daily). Once signs of clin¬ ical improvement appeared, the same dose of streptomycin was given every other day for two to three months. Aminosalicylic acid and isoniazid therapy was continued for Vk to 2 years. Thirty-six patients received adrenocorticosteroids in an attempt to prevent adhe¬ sions and to reduce cerebral edema. These patients had neurological signs when ther¬ apy was initiated, or they were infants
23
No. (%) Recovered
4(100) (85) 3(50) 35 (81) 28
1
8(19)
(53)
12
(28)
Prednisone, 2 mg/kg/ day orally, was given daily in three to four doses for at least one month or until signs of clinical improvement appeared, after which the dose was gradually reduced over two to three weeks. During the last three years, dexamethasone, 0.5 to 1 mg/kg/day, has been given intravenously in four divided doses for the first few days of therapy in patients with severely increased intracranial pressure and impending herunder 1 year of age.
niation of the brain.
Clinical Course
was
In this series, eight patients (19%) died during hospitalization (Table 2). Three of the six who were in coma died; and the remaining five children who died had been
ill for
more
diagnosis
died, two recovered with sequelas, and one recovered without neuro¬ logical deficits (Table 2).
coma, three
Symptoms on Initial Examination
than two weeks before the made and therapy ini¬
was
tiated. The 35 survivors were followed up for a period ranging from two months to four years. Twelve children, including all four who were in stage 1 of the disease, recov¬ ered without gross neurological deficits. The remaining 23 patients had sequelas including mental deficiency, convulsions, cranial nerve palsies, hemiparesis, spasticity, hydrocephalus, and diabetes insipidus. Of the six patients who were admitted in
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/13/2015
COMMENT
Tuberculous meningitis commonly has an insidious onset, with gradual or intermittent increase in symptoms. The onset of meningitis in a tubercu¬ lous child may be precipitated by measles, head injury, a recent surgical procedure with the patient under
general anesthesia,
or even a severe
sunburn. Fever is almost always pres¬ ent, often low-grade at first and later associated with vomiting. The most striking symptom is apathy, varying from a general lack of interest to drowsiness. Periods of unusual irrita¬ bility may alternate with periods of apathy. The first stage of meningitis usually lasts for one to two weeks. The second stage may start abruptly with signs and symptoms pointing to the involvement of the CNS, which leads, over a period of two to three weeks, to stage 3. The diagnosis of tuberculous menin¬ gitis is based mainly on the results of the intradermal tuberculin test, chest roentgenogram, history of tubercu¬ lous contact, and examination of the CSF. Positive tests are most valuable in combination. In critically ill pa¬ tients, depression of delayed hyper¬ sensitivity to tuberculin varies from total anergy to reactivity only to an increased dose of tuberculin. Most children who develop tuberculous meningitis show roentgenographic evidence of primary pulmonary tuber¬ culosis. In our series, 93% and 72% of the patients had a positive reaction to the tuberculin skin test (PPD) and
positive pulmonary roentgenographic changes, respectively. None of our patients had normal cerebrospinal fluid (CSF) on admission to the hospi¬ tal. The majority had CSF changes consisting of decreased glucose, in¬ creased protein, and pleocytosis. Four children had CSF pleocytosis that was predominantly polymorphonuclear. In some previously reported cases, CSF pleocytosis was absent initially or throughout the course, and in others a marked polymorphonuclear response was observed. Hinman,1 in 1967, found that the CSF glucose concentration
9
8
12 10
C
S
3 2
ß
1
10
Age Fig
in
1.—Age distribution of 43
14
1952
55
57
patients.
59
61
63
65
67
69
71
Years
years
the first factor to return to normal after the institution of ther¬ apy. This was followed by disappear¬ ance of fever, pleocytosis, and last a fall in CSF protein level. The clinical features of tuberculous meningitis may constitute such a diagnostic puzzle that the physician seeks help from cerebral angiography. An angiographie triad based on patho¬ logical findings was described by Lehler.- This consisted of ventricular dilation shown by the course of the anterior cerebral artery or thalamostriate vein, narrowing of major vessels at the base, and occlusive disease of medium size to smaller vessels due to tuberculous endarteritis. Of the eight children in the present series who had cerebral angi¬ ography, ventricular dilation was demonstrated in one patient, and obstruction of major vessels in four. Lincoln and Sewell,' in 1963, described the concomitant cerebral involvement constituting tuberculous meningoencephalitis. Dastur,4 in 1968, empha¬ sized the high incidence of frank infarction of the brain consequent to compression, and inflammation of the
was
12
Fig
2.—Distribution of
large basal arteries by adhesive proliferative meningitis. Despite triple chemotherapy (ison¬ iazid, aminosalicylic acid, and strepto¬ mycin), the mortality in the present report, and as reported by Hinman,1 remains approximately 50% for pa¬
tients admitted in coma, and 15% to 30% for patients admitted with drows¬ iness or focal signs in the CNS. The present recommended therapy for tuberculous meningitis in children consists of the administration of three first-line antituberculous drugs: ison¬ iazid, streptomycin, and aminosali¬ cylic acid.' "' Although alternate reg¬ imens with other antimicrobial agents have gained acceptance in the litera¬ ture for treatment of pulmonary tuberculosis in adults, such is not the case for tuberculous meningitis in either childhood or adulthood. Paucity of published experience with other
antimycobacterial agents (rifampin, ethambutol hydrochloride, ethionamide) in tuberculous meningitis of childhood renders these drugs inap¬ propriate for use for infections with sensitive strains of Mycobacterium tuberculosis, which comprise approxi-
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/13/2015
patients during 20 years. 90% of the isolates.6 The of contact with a person known to be infected with a resistant strain should be vigorously sought, since in these instances failure is common if conventional antimycobacterial agents (isoniazid, aminosali¬ cylic acid, and streptomycin) are used. In this situation, appropriate substitu¬ tion of alternative forms of therapy would be indicated.""" All three drugs, rifampin, ethambutol, and ethionamide, are well absorbed from the alimentary tract, and adequate blood levels are attained. However, the penetration of these drugs into the CSF is variable. Ethionamide passes into the CSF readily even in the absence of meningitis,1" while etham¬ butol and rifampin achieve modest concentrations in the CSF when the meninges are inflamed." '- The com¬ bination of rifampin with either ison¬ iazid or ethambutol is very effective against resistant tubercle bacilli. Moreover, ethionamide is fully active against isoniazid-resistant tubercle bacilli. However, resistant strains emerge rapidly if rifampin or ethion¬ amide are used alone.
mately history
Adrenocorticosteroids should be added to the therapeutic regimen in patients with neurological signs, and in all infants under 1 year of age. Treatment with corticosteroids is in¬ dicated for at least one month in patients with advanced disease. The use of adrenocorticosteroids in pa¬ tients with less-advanced tuberculous meningitis is optional. This form of therapy has not been clearly shown to benefit the patient with early disease, but nevertheless, is an integral part of treatment in many centers. O'Toole et al" concluded that the attenuation of cerebral edema associated with tuber¬ culous meningitis has improved sur¬ vival, and that administration of corti¬ costeroids in high doses is clearly indi¬ cated in the management of cerebral edema. The late sequelas encountered by 23 patients (53%) in our series included mental deficiency, convulsions, cranial
palsies, hemiparesis, spasticity, hydrocephalus, optic atrophy, and dia¬ betes insipidus. Deafness, pituitary disturbances, hydromyelia due to bas¬ al arachnoiditis, and paraplegia from spinal adhesive arachnoiditis have also been reported. Symptoms and signs of cerebral involvement, which
predominate and persist, indicate poor prognosis. Conclusion
Tuberculous meningitis is a disease with high morbidity and mortality. Early diagnosis and treatment are essential in order to prevent late sequelas and death. Follow-up care is of prime importance, and plans for continued education of the child should be instituted as soon as possi¬ ble. Laura Gutman, MD, provided assistance and advice in the preparation of this article.
Nonproprietary
Names and Trademarks of Drugs
Rifampin—Rifadin, Rimactane. Ethambutol hydrochhride-Myambutol. Ethionamide- Trecator-Sc.
References
nerve
"•',
a
1. Hinman AR: Tuberculous meningitis at Cleveland General Hospital (1959-1963). Am Rev Respir Dis 95:670-673, 1967. 2. Lehler H: The angiographic triad of tuberculous meningitis. Radiology 87:829-835, 1966. 3. Lincoln EM, Sewell EM: Tuberculosis in Children. New York, McGraw-Hill Book Co Inc,
1963,
p 173. 4. Dastur DK, Lalitha VS, Prabhakar V: Path-
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/13/2015
ological analysis of intracranial space-occupying lesions in 1,000 cases including children: I. Age, sex, and pattern; and the tuberculomas. J Neurol Sci 6:575-592, 1968. 5. The treatment of tuberculosis in children, American Thoracic Society Ad Hoc Committee on the Treatment of Tuberculosis in Children. Am Rev Respir Dis 99:304-307, 1969. 6. Steiner M, Steiner P, Schmidt H: Primary drug-resistant tuberculosis in children: A continuing study of the incidence of disease caused by primarily drug resistant organisms in children observed between the years 1965 and 1968 at the Kings County Medical Center of Brooklyn. Am Rev Respir Dis 102:75-82, 1970. 7. Bonforte RJ, Karpas CM, Gribetz I, et al: Tuberculous meningitis due to primary drug\x=req-\ resistant Mycobacterium tuberculosis hominis. Pediatrics 42:969-975, 1968. 8. Steiner P, Portugaleza C: Tuberculous meningitis in children. Am Rev Respir Dis 107:22-29, 1973. 9. Zitrin CM, Lincoln EM: Initial tuberculous infection due to drug-resistant organisms. With review of the world literature on initial infection due to isoniazid-resistant tubercle bacilli. J Pediatr 58:219-225, 1961. 10. Hughes IE, Smith H, Kane PO: Ethionamide: Its passage into the cerebrospinal fluid in man. Lancet 1:616-617, 1962. 11. Place VA, Pyle MM, De la Huerga J: Ethambutol in tuberculous meningitis. Am Rev Respir Dis 99:783-785, 1969. 12. D'Oliviera JJG: Cerebrospinal fluid concentrations of rifampin in meningeal tuberculosis. Am Rev Respir Dis 106:432-437, 1972. 13. O'Toole RD, Thorton GF, Mukherjee MK, et al: Dexamethasone in tuberculous meningitis. Ann Intern Med 70:39-48, 1969. 14. Neurological complications of tuberculosis. Lancet 1:1094-1095, 1970. 15. Kocen RS, Parsous M: Neurological complications of tuberculosis: Some unusual manifestations. Q J Med 39:17-30, 1970.
Meningitis
in Childhood
Cases
Ziad H. Idriss, MD; Anwar A. Sinno, MD; Nabil M. Kronfol, MD
\s=b\ Forty-three patients in the pediatric age group had tuberculous meningitis. Therapy included the use of adrenocorticosteroids. All four patients who were in stage 1 on admission to the hospital, seven of the 33 in stage 2, and one of the six in stage 3 (coma) recovered without gross neurological sequelas. Eight patients died, and the remaining 23 recovered, with late neurological sequelas. Early diagnosis and appropriate treatment determine the prognosis of tuberculous
meningitis. (Am J Dis Child 130:364-367, 1976)
meningitis Tubercul o us complication culosis,
is a rare, but serious of tuber¬ and is more common in young children. The purpose of this commu¬ nication is to review the cases of tuberculous meningitis in children admitted to the American University Medical Center of Beirut, Lebanon, during the 20 years from 1952 through 1971. Patient Distribution
Forty-three children with tuberculous meningitis were admitted to the American University Medical Center of Beirut, from January 1952 through December 1971. Received for publication Oct 29, 1974; accepted Feb 15, 1975. From the Department of Pediatrics, American University of Beirut School of Medicine, Beirut, Lebanon. Reprint requests to Department of Pediatrics, American University of Beirut, Beirut, Lebanon
(Dr Sinno).
(This does not include five patients with tuberculoma of the brain, the conditions of two of whom were suspected clinically and three proved pathologically, and two patients with spinal cord tuberculosis, one of whom had an intramedullary tubercu¬ loma of D, to D3, the other multiple tuberculomas of the dura of the dorsal segments.) The age distribution of our patients is shown in Fig 1. The two youngest patients were 5 months old. Twenty-seven (63%) were boys and 16 (37%) were girls. The largest number of admissions of patients with tuberculous meningitis occurred in the last ten years (Fig 2). This was probably due to the greatly increased number of total admis¬ sions to the hospital during the later years of the study, rather than a true increase in the incidence of tuberculous meningitis. Clinical Features The signs and symptoms of our patients initial examination are summarized in Table 1. The most common findings were neck stiffness, fever, vomiting, drowsiness, and headache. Only six patients (14%) were comatose on admission. Cranial nerve involvement was found in 14 cases (33%), with nerves II, VI, VII being the most commonly affected. In our series, four cases (9%) were in stage 1, which is desig¬ nated as including only general symptoms similar to those of many common childhood ailments. Thirty-three cases (77%) were in stage 2, defined as general signs with evidence of neurological involvement. Six cases (14%) were in stage 3, with profound disturbance of the central nervous system (CNS) and distinct change in sensorium, including
on
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/13/2015
coma.
losis
A
positive family history of tubercu¬ obtained in 17 cases (40%).
was
Laboratory
Data
Forty patients (93%) had a positive reac¬ tion to the tuberculin skin test (purified protein derivative [PPD]), with an area of induration at least 10 mm in diameter. In the first ten years, one tuberculin unit was used for the test, while in the last ten years, five tuberculin units were used. In 31 patients (72%) roentgenograms of the chest showed infiltrates or enlargement of hilar nodes, or both. Initial cerebrospinal fluid (CSF) samples revealed a glucose value of 40 mg/100 ml or less, or a CSF blood glucose ratio under 0.67 in 42 cases (98%), a protein level above 100 mg/ml in 40 cases (93%), and more than ten white blood cells per cubic millimeter in all cases. In the majority of cases the CSF pleocytosis was lymphocytic in character; four patients had initial CSF neutrophilia. No child had normal CSF. Only five chil¬ dren (12%) had a positive CSF culture and stain for acid-fast bacilli. Pellicle forma¬ tion was positive in 6 of 13 determina¬ tions. Results of carotid arteriography, which was performed on eight children in the first four weeks of illness because of the suspicion of a brain abscess, were abnormal in five. One child had changes suggesting hydrocephalus, two had obstruction of the middle cerebral artery, and two had obstruction of the anterior cerebral artery. Ventriculography was done in four cases, 6 to 12 months after the diagnosis was made, and revealed communicating hydrocepha¬ lus in three, and obstructive hydrocephalus in one. Electroencephalography revealed
Table
1.—Signs
and
Signs and Symptoms Neck stiffness
No.
Vomiting Drowsiness Headache Coma Convulsions
Papilledema Sweating
palsy_4 (9)_
Optic atrophy
Eighth nerve palsy Hemiparesis Diabetes insipidus
_1 (2)_
Table 2.—Initial
Stage of Meningitis Admission
No. of Patients
Stage of Meningitis
and Outcome
No. Recovered With
No. Recovered Without
Neurological Sequelas
Neurological Sequelas
No. Died
1
0
33 6
Total (%)
(9) (9) (9) (2) (5)
4 4 4 1 2
Abducens nerve palsy Occulomotor nerve palsy
on
of Cases
(77) (72) 20(47) 13(30) 10(23) 9(21) 6(14) 4 (9) 4(9) 4(9)
Fever
Facial
(%) 33 31
Apathy
43(100)
21
an abnormal tracing in all nine who had this test.
patients
Treatment
Thirty-five patients
were
given
isonia-
zid, streptomycin sulfate, and aminosalicylic acid. Aminosalicylic acid was given in a daily oral dose of at least 200 mg/kg/day, but not to exceed 12 gm/day. The initial dose of isoniazid was 20 mg/kg/day (max¬ imum dose, 300 mg/day) in all but the last six patients who were given 40 mg/kg/day (maximum dose, 500 mg/day). This dose
maintained until the patient showed definite signs of improvement, including return of the CSF glucose concentration to normal, after which it was reduced to 10 to 20 mg/kg/day. Streptomycin sulfate, in a dose of 20 to 40 mg/kg/day was given intramuscularly in one to two doses (not exceeding 1 gm daily). Once signs of clin¬ ical improvement appeared, the same dose of streptomycin was given every other day for two to three months. Aminosalicylic acid and isoniazid therapy was continued for Vk to 2 years. Thirty-six patients received adrenocorticosteroids in an attempt to prevent adhe¬ sions and to reduce cerebral edema. These patients had neurological signs when ther¬ apy was initiated, or they were infants
23
No. (%) Recovered
4(100) (85) 3(50) 35 (81) 28
1
8(19)
(53)
12
(28)
Prednisone, 2 mg/kg/ day orally, was given daily in three to four doses for at least one month or until signs of clinical improvement appeared, after which the dose was gradually reduced over two to three weeks. During the last three years, dexamethasone, 0.5 to 1 mg/kg/day, has been given intravenously in four divided doses for the first few days of therapy in patients with severely increased intracranial pressure and impending herunder 1 year of age.
niation of the brain.
Clinical Course
was
In this series, eight patients (19%) died during hospitalization (Table 2). Three of the six who were in coma died; and the remaining five children who died had been
ill for
more
diagnosis
died, two recovered with sequelas, and one recovered without neuro¬ logical deficits (Table 2).
coma, three
Symptoms on Initial Examination
than two weeks before the made and therapy ini¬
was
tiated. The 35 survivors were followed up for a period ranging from two months to four years. Twelve children, including all four who were in stage 1 of the disease, recov¬ ered without gross neurological deficits. The remaining 23 patients had sequelas including mental deficiency, convulsions, cranial nerve palsies, hemiparesis, spasticity, hydrocephalus, and diabetes insipidus. Of the six patients who were admitted in
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/13/2015
COMMENT
Tuberculous meningitis commonly has an insidious onset, with gradual or intermittent increase in symptoms. The onset of meningitis in a tubercu¬ lous child may be precipitated by measles, head injury, a recent surgical procedure with the patient under
general anesthesia,
or even a severe
sunburn. Fever is almost always pres¬ ent, often low-grade at first and later associated with vomiting. The most striking symptom is apathy, varying from a general lack of interest to drowsiness. Periods of unusual irrita¬ bility may alternate with periods of apathy. The first stage of meningitis usually lasts for one to two weeks. The second stage may start abruptly with signs and symptoms pointing to the involvement of the CNS, which leads, over a period of two to three weeks, to stage 3. The diagnosis of tuberculous menin¬ gitis is based mainly on the results of the intradermal tuberculin test, chest roentgenogram, history of tubercu¬ lous contact, and examination of the CSF. Positive tests are most valuable in combination. In critically ill pa¬ tients, depression of delayed hyper¬ sensitivity to tuberculin varies from total anergy to reactivity only to an increased dose of tuberculin. Most children who develop tuberculous meningitis show roentgenographic evidence of primary pulmonary tuber¬ culosis. In our series, 93% and 72% of the patients had a positive reaction to the tuberculin skin test (PPD) and
positive pulmonary roentgenographic changes, respectively. None of our patients had normal cerebrospinal fluid (CSF) on admission to the hospi¬ tal. The majority had CSF changes consisting of decreased glucose, in¬ creased protein, and pleocytosis. Four children had CSF pleocytosis that was predominantly polymorphonuclear. In some previously reported cases, CSF pleocytosis was absent initially or throughout the course, and in others a marked polymorphonuclear response was observed. Hinman,1 in 1967, found that the CSF glucose concentration
9
8
12 10
C
S
3 2
ß
1
10
Age Fig
in
1.—Age distribution of 43
14
1952
55
57
patients.
59
61
63
65
67
69
71
Years
years
the first factor to return to normal after the institution of ther¬ apy. This was followed by disappear¬ ance of fever, pleocytosis, and last a fall in CSF protein level. The clinical features of tuberculous meningitis may constitute such a diagnostic puzzle that the physician seeks help from cerebral angiography. An angiographie triad based on patho¬ logical findings was described by Lehler.- This consisted of ventricular dilation shown by the course of the anterior cerebral artery or thalamostriate vein, narrowing of major vessels at the base, and occlusive disease of medium size to smaller vessels due to tuberculous endarteritis. Of the eight children in the present series who had cerebral angi¬ ography, ventricular dilation was demonstrated in one patient, and obstruction of major vessels in four. Lincoln and Sewell,' in 1963, described the concomitant cerebral involvement constituting tuberculous meningoencephalitis. Dastur,4 in 1968, empha¬ sized the high incidence of frank infarction of the brain consequent to compression, and inflammation of the
was
12
Fig
2.—Distribution of
large basal arteries by adhesive proliferative meningitis. Despite triple chemotherapy (ison¬ iazid, aminosalicylic acid, and strepto¬ mycin), the mortality in the present report, and as reported by Hinman,1 remains approximately 50% for pa¬
tients admitted in coma, and 15% to 30% for patients admitted with drows¬ iness or focal signs in the CNS. The present recommended therapy for tuberculous meningitis in children consists of the administration of three first-line antituberculous drugs: ison¬ iazid, streptomycin, and aminosali¬ cylic acid.' "' Although alternate reg¬ imens with other antimicrobial agents have gained acceptance in the litera¬ ture for treatment of pulmonary tuberculosis in adults, such is not the case for tuberculous meningitis in either childhood or adulthood. Paucity of published experience with other
antimycobacterial agents (rifampin, ethambutol hydrochloride, ethionamide) in tuberculous meningitis of childhood renders these drugs inap¬ propriate for use for infections with sensitive strains of Mycobacterium tuberculosis, which comprise approxi-
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/13/2015
patients during 20 years. 90% of the isolates.6 The of contact with a person known to be infected with a resistant strain should be vigorously sought, since in these instances failure is common if conventional antimycobacterial agents (isoniazid, aminosali¬ cylic acid, and streptomycin) are used. In this situation, appropriate substitu¬ tion of alternative forms of therapy would be indicated.""" All three drugs, rifampin, ethambutol, and ethionamide, are well absorbed from the alimentary tract, and adequate blood levels are attained. However, the penetration of these drugs into the CSF is variable. Ethionamide passes into the CSF readily even in the absence of meningitis,1" while etham¬ butol and rifampin achieve modest concentrations in the CSF when the meninges are inflamed." '- The com¬ bination of rifampin with either ison¬ iazid or ethambutol is very effective against resistant tubercle bacilli. Moreover, ethionamide is fully active against isoniazid-resistant tubercle bacilli. However, resistant strains emerge rapidly if rifampin or ethion¬ amide are used alone.
mately history
Adrenocorticosteroids should be added to the therapeutic regimen in patients with neurological signs, and in all infants under 1 year of age. Treatment with corticosteroids is in¬ dicated for at least one month in patients with advanced disease. The use of adrenocorticosteroids in pa¬ tients with less-advanced tuberculous meningitis is optional. This form of therapy has not been clearly shown to benefit the patient with early disease, but nevertheless, is an integral part of treatment in many centers. O'Toole et al" concluded that the attenuation of cerebral edema associated with tuber¬ culous meningitis has improved sur¬ vival, and that administration of corti¬ costeroids in high doses is clearly indi¬ cated in the management of cerebral edema. The late sequelas encountered by 23 patients (53%) in our series included mental deficiency, convulsions, cranial
palsies, hemiparesis, spasticity, hydrocephalus, optic atrophy, and dia¬ betes insipidus. Deafness, pituitary disturbances, hydromyelia due to bas¬ al arachnoiditis, and paraplegia from spinal adhesive arachnoiditis have also been reported. Symptoms and signs of cerebral involvement, which
predominate and persist, indicate poor prognosis. Conclusion
Tuberculous meningitis is a disease with high morbidity and mortality. Early diagnosis and treatment are essential in order to prevent late sequelas and death. Follow-up care is of prime importance, and plans for continued education of the child should be instituted as soon as possi¬ ble. Laura Gutman, MD, provided assistance and advice in the preparation of this article.
Nonproprietary
Names and Trademarks of Drugs
Rifampin—Rifadin, Rimactane. Ethambutol hydrochhride-Myambutol. Ethionamide- Trecator-Sc.
References
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1. Hinman AR: Tuberculous meningitis at Cleveland General Hospital (1959-1963). Am Rev Respir Dis 95:670-673, 1967. 2. Lehler H: The angiographic triad of tuberculous meningitis. Radiology 87:829-835, 1966. 3. Lincoln EM, Sewell EM: Tuberculosis in Children. New York, McGraw-Hill Book Co Inc,
1963,
p 173. 4. Dastur DK, Lalitha VS, Prabhakar V: Path-
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/13/2015
ological analysis of intracranial space-occupying lesions in 1,000 cases including children: I. Age, sex, and pattern; and the tuberculomas. J Neurol Sci 6:575-592, 1968. 5. The treatment of tuberculosis in children, American Thoracic Society Ad Hoc Committee on the Treatment of Tuberculosis in Children. Am Rev Respir Dis 99:304-307, 1969. 6. Steiner M, Steiner P, Schmidt H: Primary drug-resistant tuberculosis in children: A continuing study of the incidence of disease caused by primarily drug resistant organisms in children observed between the years 1965 and 1968 at the Kings County Medical Center of Brooklyn. Am Rev Respir Dis 102:75-82, 1970. 7. Bonforte RJ, Karpas CM, Gribetz I, et al: Tuberculous meningitis due to primary drug\x=req-\ resistant Mycobacterium tuberculosis hominis. Pediatrics 42:969-975, 1968. 8. Steiner P, Portugaleza C: Tuberculous meningitis in children. Am Rev Respir Dis 107:22-29, 1973. 9. Zitrin CM, Lincoln EM: Initial tuberculous infection due to drug-resistant organisms. With review of the world literature on initial infection due to isoniazid-resistant tubercle bacilli. J Pediatr 58:219-225, 1961. 10. Hughes IE, Smith H, Kane PO: Ethionamide: Its passage into the cerebrospinal fluid in man. Lancet 1:616-617, 1962. 11. Place VA, Pyle MM, De la Huerga J: Ethambutol in tuberculous meningitis. Am Rev Respir Dis 99:783-785, 1969. 12. D'Oliviera JJG: Cerebrospinal fluid concentrations of rifampin in meningeal tuberculosis. Am Rev Respir Dis 106:432-437, 1972. 13. O'Toole RD, Thorton GF, Mukherjee MK, et al: Dexamethasone in tuberculous meningitis. Ann Intern Med 70:39-48, 1969. 14. Neurological complications of tuberculosis. Lancet 1:1094-1095, 1970. 15. Kocen RS, Parsous M: Neurological complications of tuberculosis: Some unusual manifestations. Q J Med 39:17-30, 1970.
