Acta neurol. scandinav. 59, 127-134, 1979 Department of Neurology, University of Helsinki, Finland
Tuberculous meningitis Jussr KOVANENAND PAULIKARLI Ten patients with confirmed tuberculous meningitis were seen at Meilahti Hospital, University of Helsinki, in 1966-1977. Six of the patients had a positive CSF culture for M. tuberculosis, and a positive CSF smear for acid-fast bacilli was found in one case. On admission, seven patients had an altered state of consciousness, five complained of headache, and nuchal rigidity was noted in two. Five patients recovered completely, three had persistent late sequelae, and two of the patients died. The most important fact influencing the prognosis was an early institution of adequate antituberculous chemotherapy. Key words: Clinical features - meningitis - prognosis - tuberculous
The incidence of tuberculous meningitis has greatly decreased during the last 20 years, and this form of tuberculous infection has become a rarity in most developed countries (Kocen & Parsons 1970). At the same time it almost has disappeared as a disease of children (Barrett-Connor 1967). The possibility of tuberculous meningitis might thus be overlooked by clinicians, with serious consequences for the patient involved. The aim of the present study is to elucidate the clinical features and prognosis of adult patients with tuberculous meningitis. MATERIALS AND METHODS The clinical records were reviewed of all patients seen at Meilahti Hospital, University of Helsinki, from 1966 through 1977 with a confirmed diagnosis of tuberculous meningitis. The patients were included in this series if they had a bacteriologically or histologically confirmed tuberculous meningitis or if the clinical picture and the cerebrospinal fluid (CSF) finding were consistent with a nonpurulent meningitis with a low glucose level and a concomitant active tuberculous infection outside the central nervous system (CNS). Ten patients met the above criteria. There were six patients with a positive CSF culture for M. tuberculosis, one with a positive CSF smear for acid-fast bacilli, two with a histological confirmation of CNS tuberculosis, and one patient with a CSF finding consistent with tuberculous meningitis and a positive culture of sputum for M. tuberculosis. RESULTS
Epidemiology The patients, six males and four females, varied in age between 18 and 61 years, mean 47.1 years. A past history of tuberculosis was present in three cases. 0001-6314/79/020127-08 $0.2.50/0@ 1979 Munksgaard, Copenhagen
128 Six patients had no history of other concomitant disease. A 60-year-old man (case 2) was an alcoholic presenting with acute hematemesis due to hemorrhagic gastritis, and one patient had mitral valvular disease (case 6). A 42-year-old woman had previously been pensioned because of a psychiatric illness (case l), and a 49-year-old man with cervical spondylosis had had a transient attack of vertebrobasilar arterial insufficiency 3 years before admission (case 3). None of the patients had received corticosteroid therapy before admission. History and physical findings on admission The duration of the disease prior to admission ranged from 1 day to 1 year. Five of the 10 patients had had symptoms for less than 2 weeks, and two had a history of fever and weight loss for more than 1 month before admission. The temperature was over 38" C in seven patients on admission, from 37" to 38" C in two, and below 37" C in one case. Five patients complained of headache, and seizures were noted in three. Stiffness of neck was noted in three patients, mild hemiparesis in two and sixth cranial nerve paresis in one. None presented with papilloedema. Seven of the patients had an altered state of consciousness (Table 1). Laboratory studies The hemoglobin level ranged from 113 to 176 g/1 and the blood leucocyte count from 5.0 to 10.4 X 109/l. The differentiation count of leucocytes was studied in four patients, with normal results in three. One patient with simultaneous pneumonia (case 6) had 18 %, rod-shaped polymorphonuclear cells. The sedimentation rate was more than 20 mm/h in four patients. The first lumbar puncture revealed 42 to 941 X 106A leucocytes in CSF and the amount of mononuclear cells varied from 15 to 100 % (Table 2). Most of the patients had mononuclear pleocytosis of less than 350 X 106A The initial erythrocyte count of the CSF was increased in four patients. The protein concentration ranged from 690 to 15,400 mgA and the concentration of CSF sugar was within normal limits in four patients. In one of these patients a second lumbar puncture revealed a lowered CSF glucose level. The chest X-ray was normal in five cases on admission. Two patients had an X-ray finding of active pulmonary tuberculosis and three of pneumonia. An active tuberculosis not involving the CNS was demonstrated in five patients. Clinical course and prognosis Antituberculous chemotherapy was begun within 1 week of admission in three patients and all of them recovered completely (Table 3). Two further patients with complete remission did not receive therapy before the second
129 Table 1 . Symptoms and physical signs on admission, at onset of therapy and during the course of the illness
On admission 10patients
Symptoms and signs
At Onset Of therapy 8 patients
During course 10patients
Headache Nuchal rigidity Convulsions Cranial nerve palsy Limb paresis Ataxia Papilloedema Altered consciousness Mild Serious
seqale 3 patients -
6 5 6 4 6 3 2
I 1 2 3
-
6 3
Tabfe 2. CSF findings before onset of therapy and confirmation of diagnosis
Days after
Case
No. Sex Age 1
F
42
2
M
60
3 4
M M
49 22
Year
sion
Red
x 106/1
Leuc.
1968
2 520 941 4 320 5 1969 21 30 115 Streptomycin begun on day 20 1 2150 80 1971 1 5 353 1973
5
M
46
1974
6
M
52
1974
7
M
35
1975
8
F
9
F
61 47
1975 1975
10
F
61
1977
Mono-
x 10V1 nucl.
Prot. mgA
1.00
1720 3500
0.88 1.00
15400 690
0.60 -
Glucose mmolA
Confirmation of diagnosis
28mg % CSF culture 3 0 m g % CSFsmear
3.7 3.5
autopsy cerebellar tuberculoma months later
1 10 3 5 1
2 307200 4 7 3
325 201 42 115 288
0.42 0.80 0.15
1400 732 772 972
2.4 1.1 1.9 2.0 1.1
1 1 3 7 8 9
802 9 29 150 7 3
113 216 193 300 49 48
0.95 0.97 0.86 0.64 0.84 0.84
1200 1300 2000 2134 1530
20 mg % 2.3 1.5 0.8 CSF culture 3.4 3.4 CSF culture
Pathologically low CSF glucose: 9 Acta neurol. scandinav. 59:2./3
< 2.2 mmoVl or < 40 mg %
+ +
+ 3
+ CSF culture + CSF culture sputum culture + CSF culture +
CSF culture
+ +
130 Table 3. Chemotherapy during the first months of treatment and prognosis of 10 patients with tuberculous meningitis
Patient
Onset of therapy (days after admission)
8
20* (during 8 days)
3
4
3 months
5
9 (during 9 days)
6 7
8
*
9
7
10
9*
Chemotheraphy
Prognosis
streptomycin isoniazide PAS streptomycin streptomycin isoniazide ethambutol no therapy
serious sequelae
streptomycin isoniazide rifampicin streptomycin isoniazide rifampicin isoniazide rifampicin streptomycin isoniazide rifampicin capreomycin isoniazide ethambutol streptomycin isoniazide rifampicin streptomycin isoniazide rifampicin
recovered
died 4 days after admission serious sequelae
died 50 days after admission recovered recovered
recovered
mild sequelae
recovered
Therapy begun 1-2 days after onset of CNS symptoms in hospital.
and third week of admission, respectively (cases 2 and lo), but signs of CNS involvement were noted only 2 days before the onset of therapy. Two patients with later institution of therapy had serious late sequelae and one patient had a mild persistent neurological deficit. Of the two fatal cases, one patient died after an acute illness of 10 days’ duration without any antituberculous therapy. At autopsy a disseminated spread of acid-fast bacilli was noted in the CNS and in various other organs (case 3). In the other fatal case the therapy was instituted 9 days after admission, but withdrawn 5 days later. The patient died 50 days after admission to hospital (case 5).
131 Table 4. CSF findings after the onset of therapy during follow up o f five patients with tuberculous meningitis
Case
1
2
Onset Lumbar of punctherapy* ture** 8
2O***
6
5
8
2
9
8
*
** ***
4 13 18 1 8 14 22 30 40 57 13 24 15 26 10 19
Red cells
Mononucl,
X 10V1
Leucocytes X 10V1
Protein mgA
25 16 7 30 1 0 390 28 47 1 3 5 1120 1350 10 5
240 277 346 115 470 350 55 30 5 5 45 24 73 68 190 57
0.93 0.97 0.97 1.00 0.39 0.39 -
1220 1711 1711 3500 5800 1600 960 660 750 550 1501 978 912 766 1659 1321
-
1.00 1.OO 0.98 0.95 0.98 1.00
Glucose mmoVl 19 mg % 16 mg % 20 mg % 30 mg % 14mg % 26 mg % 50 mg % 51 mg % 59 mg % 59 mg % 1.6 2.1 1.8 1.8 1.8 2.5
Onset of therapy: days after admission Lumbar puncture: days after onset of therapy Therapy was started 2 days after onset of CNS symptoms in hospital
The state of consciousness deteriorated in most cases even after therapy was started. Convulsions and central paresis were noted in six patients and cranial nerve involvement in four cases during the course of the disease. The duration of fever after the institution of chemotherapy ranged from 1 to 5 weeks and the altered state of consciousness from 1 to 6 weeks in the patients who recovered without serious late sequelae. The CSF findings of five patients were followed up during at least 18 days on chemotherapy (Table 4). The CSF glucose concentration returned to normal (= 40 mg/lOO ml or 2.2 mmol/l) in two patients on the 19th and 22nd day, respectively. None of the patients showed completely normal values for CSF leucocyte count or protein concentration at the end of the follow up. The values in case 2, however, were almost normal after 7-8 weeks of therapy. Therapy The therapy consisted in most cases of a combination of isoniazide, rifampin and streptomycin (Table 3). Ethambutol was initially used in two patients '9
132 and during the later course in two more patients. Five patients received corticosteroid therapy. The medication of five patients was changed because of side effects. Two of them had vestibular symptoms after use of 1.0 dday of streptomycin during 2.5 and 4 months, respectively. One of the patients had a serum transaminase rise after 3 weeks of rifampin therapy, one patient receiving ethambutol complained of seeing colored rings, and one patient was interpreted to have psychosis due to isoniazide afte 6 weeks’ therapy. DISCUSSION
The incidence of tuberculous meningitis in Finland has declined considerably during the past 12 years according to the statistics of the National Board of Health. The statistics include 16 patients with this diagnosis in 1966 and five in 1976, respectively. Only one child with CNS tuberculosis has been recorded during these years. The present series indicates, however, that tuberculosis can by no means be omitted as a possible cause of serous meningitis in adults. The classical patient with tuberculous meningitis presents usually with a history of 1-3 weeks of fever and weight loss, followed by headache, an altered state of consciousness and nuchal rigidity (Smith 1965). The CSF finding consists of mononuclear pleocytosis, increased protein concentration and low sugar (Smith 1965). Five of our patients can be classified as the classical type by their history and clinical presentation. The initial lumbar puncture revealed in three of them (cases 5, 8, and 10) CSF pleocytosis with a normal concentration of sugar, but the subsequent CSF samples showed a lowered glucose level in two cases. Four of the patients with classical presentation received adequate therapy and recovered completely. Besides the classical type, two other forms of clinical presentation have been described in the literature, i.e. the tuberculous meningitis of acute onset (Taylor et al. 1955) and a mild form of the disease (Norris et al. 1964). Kocen d Parsons (1970) have stressed an atypical presentation of tuberculous meningitis in Great Britain, especially among the immigrant population. The clinical presentation in case 4 in this series can be considered quite unusual, with a transient sixth nerve paresis and a mild mononuclear meningeal reaction without clinical signs of meningitis. The later clinical course with an operated cerebellar tuberculoma and tuberculous encephalitis 3 months after the onset of chemotherapy differs remarkably from that of the other patients in the series. Tuberculous meningitis presents with an acute onset in about 5 % of cases (Taylor et al. 1955). The patients with this syndrome have been ill for less than 1 week when admitted to hospital and the initial CSF often contains
133 more than 500 leucocytes per mm3, a considerable part of which are polymorphonuclears. Three of our patients had a history of less than 1 week‘s duration before admission and one patient (case 2) showed a rather acute onset of CNS symptoms during hospitalization because of hemorrhagic gastritis. Only one of the patients, however, fulfilled the criteria of Taylor et al. (1955) for the total leucocyte count (case 1). Tuberculous infection was demonstrated outside the CNS in five patients, two of whom also had a past history of tuberculosis. One further patient (case 8) with a positive history of tuberculosis showed enlarged cervical lymph nodes during the course of meningitis. The tuberculous meningitis of these patients obviously presented as a complication of secondary tuberculosis. Disseminated or miliary tuberculosis was demonstrated in two patients (cases 3 and 7) and a nonpulmonary tuberculous infection was confirmed in two other patients. This agrees with the results of Auerbach (1951) who demonstrated a disseminated spread of bacilli in 79 % of fatal adult cases with tuberculous meningitis. Thus, a thorough physical examination and a search for acid-fast bacilli from sputum, gastric lavage fluid and urine is indicated in every suspected case of tuberculous meningitis. The most important fact determining the prognosis of tuberculous meningitis seems to be an early suspicion and the institution of adequate chemotherapy. The modem therapy consist of isoniazide, rifampin and ethambutol that readily penetrate through the impaired blood-brain barrier (Place et at. 1969, D’Oliveira 1972, Sippel et al. 1974). The current status of streptomycin has not yet been settled although its use has recently been recommended (Seaton 1978). The advantage of corticosteroids is clearly established in cases with cerebral edema (O’Toole et al. 1969), although their claimed efficacy in preventing late squelae still remains to be proved (Barrett-Connor 1967).
REFERENCES Auerbach, 0. (1951): Tuberculous meningitis: correlation of therapeutic results with the pathogenesis and pathologic changes. I. General considerations and pathogenesis. Am. Rev. Tuberc. 64, 408-418. Barrett-Connor, E. (1967): Tuberculous meningitis in adults. South. Med. J. 60, 10611067. D’Oliveira,J. (1972): Cerebrospinal fluid concentration of Rifampin in meningeal tuberculosis. Am. Rev. Resp. Dis. 106,432-437. Kocen, R. & M. Parsons (1970): Neurological complications of tuberculosis: some unusual manifestations. Quart. J. Med. 39, 17-30. Norris, F. H., P. H. Garvey & G. W. Swalbach (1964): A mild form of tuberculous meningitis. Arch. Neurol. 10, 398-401. OToole, R., G. Thronton, M. Mukherjee & R. Nath (1969): Dexamethasone in tuberculous meningitis. Relation of cerebrospinal fluid effects to therapeutic efficacy.
134 Ann. Intern. Med. 70, 39-48. Place, U., M. Pyle & J. de la Huerga (1969): Ethambutol in tuberculous meningitis. Am. Rev. Resp. Dis. 99, 783-785. Seaton, A. (1977): Diseases of the respiratory system: Tuberculosis. Br. Med. J. I , 701-703. Sippel, J., J. Mikhail, N. Girgis & H. Youssef (1974): Rifampin concentrations in cerebrospinal fluid of patients with tuberculous meningitis. Am. Rev. Resp. Dis. 109, 579-580. Smith, H. (1964): Tuberculous meningitis. Int. J. Neurol. 4, 134-157. Taylor, K., A. Smith & R. Vollrum (1955): Tuberculous meningitis of acute onset. J. Neurol. Neurosurg. Psychiatr. 18, 165-173. Received September 26, accepted November 24, 1978
J . Kovanen, M.D. Dept. of Neurology Universtity of Helsinki Haartmaninkatu 4, 00 290 Helsinki 29 Finland
Tuberculous meningitis Jussr KOVANENAND PAULIKARLI Ten patients with confirmed tuberculous meningitis were seen at Meilahti Hospital, University of Helsinki, in 1966-1977. Six of the patients had a positive CSF culture for M. tuberculosis, and a positive CSF smear for acid-fast bacilli was found in one case. On admission, seven patients had an altered state of consciousness, five complained of headache, and nuchal rigidity was noted in two. Five patients recovered completely, three had persistent late sequelae, and two of the patients died. The most important fact influencing the prognosis was an early institution of adequate antituberculous chemotherapy. Key words: Clinical features - meningitis - prognosis - tuberculous
The incidence of tuberculous meningitis has greatly decreased during the last 20 years, and this form of tuberculous infection has become a rarity in most developed countries (Kocen & Parsons 1970). At the same time it almost has disappeared as a disease of children (Barrett-Connor 1967). The possibility of tuberculous meningitis might thus be overlooked by clinicians, with serious consequences for the patient involved. The aim of the present study is to elucidate the clinical features and prognosis of adult patients with tuberculous meningitis. MATERIALS AND METHODS The clinical records were reviewed of all patients seen at Meilahti Hospital, University of Helsinki, from 1966 through 1977 with a confirmed diagnosis of tuberculous meningitis. The patients were included in this series if they had a bacteriologically or histologically confirmed tuberculous meningitis or if the clinical picture and the cerebrospinal fluid (CSF) finding were consistent with a nonpurulent meningitis with a low glucose level and a concomitant active tuberculous infection outside the central nervous system (CNS). Ten patients met the above criteria. There were six patients with a positive CSF culture for M. tuberculosis, one with a positive CSF smear for acid-fast bacilli, two with a histological confirmation of CNS tuberculosis, and one patient with a CSF finding consistent with tuberculous meningitis and a positive culture of sputum for M. tuberculosis. RESULTS
Epidemiology The patients, six males and four females, varied in age between 18 and 61 years, mean 47.1 years. A past history of tuberculosis was present in three cases. 0001-6314/79/020127-08 $0.2.50/0@ 1979 Munksgaard, Copenhagen
128 Six patients had no history of other concomitant disease. A 60-year-old man (case 2) was an alcoholic presenting with acute hematemesis due to hemorrhagic gastritis, and one patient had mitral valvular disease (case 6). A 42-year-old woman had previously been pensioned because of a psychiatric illness (case l), and a 49-year-old man with cervical spondylosis had had a transient attack of vertebrobasilar arterial insufficiency 3 years before admission (case 3). None of the patients had received corticosteroid therapy before admission. History and physical findings on admission The duration of the disease prior to admission ranged from 1 day to 1 year. Five of the 10 patients had had symptoms for less than 2 weeks, and two had a history of fever and weight loss for more than 1 month before admission. The temperature was over 38" C in seven patients on admission, from 37" to 38" C in two, and below 37" C in one case. Five patients complained of headache, and seizures were noted in three. Stiffness of neck was noted in three patients, mild hemiparesis in two and sixth cranial nerve paresis in one. None presented with papilloedema. Seven of the patients had an altered state of consciousness (Table 1). Laboratory studies The hemoglobin level ranged from 113 to 176 g/1 and the blood leucocyte count from 5.0 to 10.4 X 109/l. The differentiation count of leucocytes was studied in four patients, with normal results in three. One patient with simultaneous pneumonia (case 6) had 18 %, rod-shaped polymorphonuclear cells. The sedimentation rate was more than 20 mm/h in four patients. The first lumbar puncture revealed 42 to 941 X 106A leucocytes in CSF and the amount of mononuclear cells varied from 15 to 100 % (Table 2). Most of the patients had mononuclear pleocytosis of less than 350 X 106A The initial erythrocyte count of the CSF was increased in four patients. The protein concentration ranged from 690 to 15,400 mgA and the concentration of CSF sugar was within normal limits in four patients. In one of these patients a second lumbar puncture revealed a lowered CSF glucose level. The chest X-ray was normal in five cases on admission. Two patients had an X-ray finding of active pulmonary tuberculosis and three of pneumonia. An active tuberculosis not involving the CNS was demonstrated in five patients. Clinical course and prognosis Antituberculous chemotherapy was begun within 1 week of admission in three patients and all of them recovered completely (Table 3). Two further patients with complete remission did not receive therapy before the second
129 Table 1 . Symptoms and physical signs on admission, at onset of therapy and during the course of the illness
On admission 10patients
Symptoms and signs
At Onset Of therapy 8 patients
During course 10patients
Headache Nuchal rigidity Convulsions Cranial nerve palsy Limb paresis Ataxia Papilloedema Altered consciousness Mild Serious
seqale 3 patients -
6 5 6 4 6 3 2
I 1 2 3
-
6 3
Tabfe 2. CSF findings before onset of therapy and confirmation of diagnosis
Days after
Case
No. Sex Age 1
F
42
2
M
60
3 4
M M
49 22
Year
sion
Red
x 106/1
Leuc.
1968
2 520 941 4 320 5 1969 21 30 115 Streptomycin begun on day 20 1 2150 80 1971 1 5 353 1973
5
M
46
1974
6
M
52
1974
7
M
35
1975
8
F
9
F
61 47
1975 1975
10
F
61
1977
Mono-
x 10V1 nucl.
Prot. mgA
1.00
1720 3500
0.88 1.00
15400 690
0.60 -
Glucose mmolA
Confirmation of diagnosis
28mg % CSF culture 3 0 m g % CSFsmear
3.7 3.5
autopsy cerebellar tuberculoma months later
1 10 3 5 1
2 307200 4 7 3
325 201 42 115 288
0.42 0.80 0.15
1400 732 772 972
2.4 1.1 1.9 2.0 1.1
1 1 3 7 8 9
802 9 29 150 7 3
113 216 193 300 49 48
0.95 0.97 0.86 0.64 0.84 0.84
1200 1300 2000 2134 1530
20 mg % 2.3 1.5 0.8 CSF culture 3.4 3.4 CSF culture
Pathologically low CSF glucose: 9 Acta neurol. scandinav. 59:2./3
< 2.2 mmoVl or < 40 mg %
+ +
+ 3
+ CSF culture + CSF culture sputum culture + CSF culture +
CSF culture
+ +
130 Table 3. Chemotherapy during the first months of treatment and prognosis of 10 patients with tuberculous meningitis
Patient
Onset of therapy (days after admission)
8
20* (during 8 days)
3
4
3 months
5
9 (during 9 days)
6 7
8
*
9
7
10
9*
Chemotheraphy
Prognosis
streptomycin isoniazide PAS streptomycin streptomycin isoniazide ethambutol no therapy
serious sequelae
streptomycin isoniazide rifampicin streptomycin isoniazide rifampicin isoniazide rifampicin streptomycin isoniazide rifampicin capreomycin isoniazide ethambutol streptomycin isoniazide rifampicin streptomycin isoniazide rifampicin
recovered
died 4 days after admission serious sequelae
died 50 days after admission recovered recovered
recovered
mild sequelae
recovered
Therapy begun 1-2 days after onset of CNS symptoms in hospital.
and third week of admission, respectively (cases 2 and lo), but signs of CNS involvement were noted only 2 days before the onset of therapy. Two patients with later institution of therapy had serious late sequelae and one patient had a mild persistent neurological deficit. Of the two fatal cases, one patient died after an acute illness of 10 days’ duration without any antituberculous therapy. At autopsy a disseminated spread of acid-fast bacilli was noted in the CNS and in various other organs (case 3). In the other fatal case the therapy was instituted 9 days after admission, but withdrawn 5 days later. The patient died 50 days after admission to hospital (case 5).
131 Table 4. CSF findings after the onset of therapy during follow up o f five patients with tuberculous meningitis
Case
1
2
Onset Lumbar of punctherapy* ture** 8
2O***
6
5
8
2
9
8
*
** ***
4 13 18 1 8 14 22 30 40 57 13 24 15 26 10 19
Red cells
Mononucl,
X 10V1
Leucocytes X 10V1
Protein mgA
25 16 7 30 1 0 390 28 47 1 3 5 1120 1350 10 5
240 277 346 115 470 350 55 30 5 5 45 24 73 68 190 57
0.93 0.97 0.97 1.00 0.39 0.39 -
1220 1711 1711 3500 5800 1600 960 660 750 550 1501 978 912 766 1659 1321
-
1.00 1.OO 0.98 0.95 0.98 1.00
Glucose mmoVl 19 mg % 16 mg % 20 mg % 30 mg % 14mg % 26 mg % 50 mg % 51 mg % 59 mg % 59 mg % 1.6 2.1 1.8 1.8 1.8 2.5
Onset of therapy: days after admission Lumbar puncture: days after onset of therapy Therapy was started 2 days after onset of CNS symptoms in hospital
The state of consciousness deteriorated in most cases even after therapy was started. Convulsions and central paresis were noted in six patients and cranial nerve involvement in four cases during the course of the disease. The duration of fever after the institution of chemotherapy ranged from 1 to 5 weeks and the altered state of consciousness from 1 to 6 weeks in the patients who recovered without serious late sequelae. The CSF findings of five patients were followed up during at least 18 days on chemotherapy (Table 4). The CSF glucose concentration returned to normal (= 40 mg/lOO ml or 2.2 mmol/l) in two patients on the 19th and 22nd day, respectively. None of the patients showed completely normal values for CSF leucocyte count or protein concentration at the end of the follow up. The values in case 2, however, were almost normal after 7-8 weeks of therapy. Therapy The therapy consisted in most cases of a combination of isoniazide, rifampin and streptomycin (Table 3). Ethambutol was initially used in two patients '9
132 and during the later course in two more patients. Five patients received corticosteroid therapy. The medication of five patients was changed because of side effects. Two of them had vestibular symptoms after use of 1.0 dday of streptomycin during 2.5 and 4 months, respectively. One of the patients had a serum transaminase rise after 3 weeks of rifampin therapy, one patient receiving ethambutol complained of seeing colored rings, and one patient was interpreted to have psychosis due to isoniazide afte 6 weeks’ therapy. DISCUSSION
The incidence of tuberculous meningitis in Finland has declined considerably during the past 12 years according to the statistics of the National Board of Health. The statistics include 16 patients with this diagnosis in 1966 and five in 1976, respectively. Only one child with CNS tuberculosis has been recorded during these years. The present series indicates, however, that tuberculosis can by no means be omitted as a possible cause of serous meningitis in adults. The classical patient with tuberculous meningitis presents usually with a history of 1-3 weeks of fever and weight loss, followed by headache, an altered state of consciousness and nuchal rigidity (Smith 1965). The CSF finding consists of mononuclear pleocytosis, increased protein concentration and low sugar (Smith 1965). Five of our patients can be classified as the classical type by their history and clinical presentation. The initial lumbar puncture revealed in three of them (cases 5, 8, and 10) CSF pleocytosis with a normal concentration of sugar, but the subsequent CSF samples showed a lowered glucose level in two cases. Four of the patients with classical presentation received adequate therapy and recovered completely. Besides the classical type, two other forms of clinical presentation have been described in the literature, i.e. the tuberculous meningitis of acute onset (Taylor et al. 1955) and a mild form of the disease (Norris et al. 1964). Kocen d Parsons (1970) have stressed an atypical presentation of tuberculous meningitis in Great Britain, especially among the immigrant population. The clinical presentation in case 4 in this series can be considered quite unusual, with a transient sixth nerve paresis and a mild mononuclear meningeal reaction without clinical signs of meningitis. The later clinical course with an operated cerebellar tuberculoma and tuberculous encephalitis 3 months after the onset of chemotherapy differs remarkably from that of the other patients in the series. Tuberculous meningitis presents with an acute onset in about 5 % of cases (Taylor et al. 1955). The patients with this syndrome have been ill for less than 1 week when admitted to hospital and the initial CSF often contains
133 more than 500 leucocytes per mm3, a considerable part of which are polymorphonuclears. Three of our patients had a history of less than 1 week‘s duration before admission and one patient (case 2) showed a rather acute onset of CNS symptoms during hospitalization because of hemorrhagic gastritis. Only one of the patients, however, fulfilled the criteria of Taylor et al. (1955) for the total leucocyte count (case 1). Tuberculous infection was demonstrated outside the CNS in five patients, two of whom also had a past history of tuberculosis. One further patient (case 8) with a positive history of tuberculosis showed enlarged cervical lymph nodes during the course of meningitis. The tuberculous meningitis of these patients obviously presented as a complication of secondary tuberculosis. Disseminated or miliary tuberculosis was demonstrated in two patients (cases 3 and 7) and a nonpulmonary tuberculous infection was confirmed in two other patients. This agrees with the results of Auerbach (1951) who demonstrated a disseminated spread of bacilli in 79 % of fatal adult cases with tuberculous meningitis. Thus, a thorough physical examination and a search for acid-fast bacilli from sputum, gastric lavage fluid and urine is indicated in every suspected case of tuberculous meningitis. The most important fact determining the prognosis of tuberculous meningitis seems to be an early suspicion and the institution of adequate chemotherapy. The modem therapy consist of isoniazide, rifampin and ethambutol that readily penetrate through the impaired blood-brain barrier (Place et at. 1969, D’Oliveira 1972, Sippel et al. 1974). The current status of streptomycin has not yet been settled although its use has recently been recommended (Seaton 1978). The advantage of corticosteroids is clearly established in cases with cerebral edema (O’Toole et al. 1969), although their claimed efficacy in preventing late squelae still remains to be proved (Barrett-Connor 1967).
REFERENCES Auerbach, 0. (1951): Tuberculous meningitis: correlation of therapeutic results with the pathogenesis and pathologic changes. I. General considerations and pathogenesis. Am. Rev. Tuberc. 64, 408-418. Barrett-Connor, E. (1967): Tuberculous meningitis in adults. South. Med. J. 60, 10611067. D’Oliveira,J. (1972): Cerebrospinal fluid concentration of Rifampin in meningeal tuberculosis. Am. Rev. Resp. Dis. 106,432-437. Kocen, R. & M. Parsons (1970): Neurological complications of tuberculosis: some unusual manifestations. Quart. J. Med. 39, 17-30. Norris, F. H., P. H. Garvey & G. W. Swalbach (1964): A mild form of tuberculous meningitis. Arch. Neurol. 10, 398-401. OToole, R., G. Thronton, M. Mukherjee & R. Nath (1969): Dexamethasone in tuberculous meningitis. Relation of cerebrospinal fluid effects to therapeutic efficacy.
134 Ann. Intern. Med. 70, 39-48. Place, U., M. Pyle & J. de la Huerga (1969): Ethambutol in tuberculous meningitis. Am. Rev. Resp. Dis. 99, 783-785. Seaton, A. (1977): Diseases of the respiratory system: Tuberculosis. Br. Med. J. I , 701-703. Sippel, J., J. Mikhail, N. Girgis & H. Youssef (1974): Rifampin concentrations in cerebrospinal fluid of patients with tuberculous meningitis. Am. Rev. Resp. Dis. 109, 579-580. Smith, H. (1964): Tuberculous meningitis. Int. J. Neurol. 4, 134-157. Taylor, K., A. Smith & R. Vollrum (1955): Tuberculous meningitis of acute onset. J. Neurol. Neurosurg. Psychiatr. 18, 165-173. Received September 26, accepted November 24, 1978
J . Kovanen, M.D. Dept. of Neurology Universtity of Helsinki Haartmaninkatu 4, 00 290 Helsinki 29 Finland
